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Definitions

• PYRAZOLYL-PYRIMIDINES AS POTASSIUM CHANNEL MODULATING AGENTS AND THEIR MEDICAL USE
• This invention relates to novel potassium channel modulating agents, and their use in the preparation of pharmaceutical compositions.
• the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular respiratory diseases, epilepsy, convulsions, seizures, absence seizures, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorders, dementia, memory and attention deficits, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscle dystrophia, spasti
• Ion channels are transmembrane proteins, which catalyse the transport of inorganic ions across cell membranes.
• the ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, secretion of hormones, contraction of muscles, etc.
• K + channels All mammalian cells express potassium (K + ) channels in their cell membranes, and the channels play a dominant role in the regulation of the membrane potential. In nerve and muscle cells they regulate the frequency and form of the action potential, the release of neurotransmitters, and the degree of broncho- and vasodilation.
• the K + channels represent the largest and most diverse group of ion channels. For an overview they can be divided into five large subfamilies: Voltage-activated K + channels (K v ), long QT related K + channels (KvLQT), inward rectifiers (K
• Kca The latter group, the Ca 2+ -activated K + channels, consists of three well- defined subtypes: SK channels, IK channels and BK channels.
• SK, IK and BK refer to the single-channel conductance (Small, Intermediate and Big conductance K channel).
• the SK, IK, and BK channels exhibit differences in e.g. voltage- and calcium- sensitivity, pharmacology, distribution and function.
• SK channels are present in many central neurons and ganglia, where their primary function is to hyperpolarize nerve cells following one or several action potentials, in order to prevent long trains of epileptogenic activity to occur.
• the SK channels are also present in several peripheral cells including skeletal muscle, gland cells, liver cells, and T-lymphocytes.
• the significance of SK channels in normal skeletal muscle is not clear, but their number is significantly increased in denervated muscle, and the large number of SK channels in the muscle of patients with myotonic muscle dystrophia, suggest a role in the pathogenesis of the disease.
• K + channels may be a therapeutic target in the treatment of a number of diseases including asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness,
• WO 97/19065 describes substituted 2-anilinopyrimidines useful as protein kinase inhibitors.
• the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators certainly not suggested.
• WO 2001/29009 describes 4,5-disubstituted anilinopyrimidines useful as protein kinase inhibitors.
• the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators certainly not suggested.
• WO 2003/075828 describes various compounds useful for the treatment of cancer including compounds of formulas Vl, VII and Xl.
• the pyrazolyl-pyrimidine derivatives of the present invention are not disclosed and their activity as potassium channel modulators certainly not suggested.
• the present invention resides in the provision of novel chemical compounds capable of selectively modulating SK channels, or subtypes of SK channels. Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, including diseases or conditions like respiratory diseases, epilepsy, convulsions, seizures, absence seizures, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorders, dementia, memory and attention deficits, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's
• n 0, 1 , 2 or 3;
• X represents O, S or NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, which heterocyclic ring is optionally substituted one or two times with substituents selected from the group consisting of alkyl and phenyl;
• Y represents alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1 ,2,3,4- tetrahydro-naphthyl, indenyl, 1 ,2-dihydro-indenyl, furanyl, thienyl, pyranyl, tetrahydro- pyran-4-yl, pyridinyl, indolinyl or quinolinyl, which phenyl, benzyl, naphthyl, 1 ,2,3,4- tetrahydro-naphthyl, indenyl, 1 ,2-dihydro-indenyl, furanyl, thienyl, pyranyl, 2,3,5,6-
• R 1 , R 2 , R 3 and R 4 independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy, cyano, nitro and/or amino.
• the invention provides pharmaceutical compositions comprising an effective amount of a chemical compound of the invention.
• the invention relates to the use of a chemical compound of the invention for the manufacture of a medicament for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, and to method of treatment or alleviation of disorders or conditions responsive to modulation of potassium channels.
• the invention provides novel pyrazolyl-pyrimidine derivatives of Formula I
• n 0, 1 , 2 or 3;
• X represents O, S or NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, which heterocyclic ring is optionally substituted one or two times with substituents selected from the group consisting of alkyl and phenyl;
• Y represents alkyl, cycloalkyl, alkyl-cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1 ,2,3,4- tetrahydro-naphthyl, indenyl, 1 ,2-dihydro-indenyl, furanyl, thienyl, pyranyl, tetrahydro- pyran-4-yl, pyridinyl, indolinyl or quinolinyl, which phenyl, benzyl, naphthyl, 1 ,2,3,4- tetrahydro-naphthyl, indenyl, 1 ,2-dihydro-indenyl, furanyl, thienyl, pyranyl, 2,3,5,6-
• R 1 , R 2 , R 3 and R 4 independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy, cyano, nitro and/or amino; provided, however, that the pyrazolyl-pyrimidine derivative is not Methyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine;
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is 0, 1 , 2 or 3;
• X represents O, S or NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0, R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring;
• Y represents alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy- alkyl, alkoxy-alkyl, alkenyl, or a monocyclic or polycyclic, carbocyclic or heterocyclic group, which carbocyclic or heterocyclic groups may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino; or, when n is 0, Y together with R' and together with the nitrogen to which they are attached form a heterocyclic ring; and
• R 1 , R 2 and R 3 independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino; and R 4 represents hydrogen.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is 0, 1 , 2 or 3.
• n is 0 or 1.
• n 0.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein X represents O, S or NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, which heterocyclic ring is optionally substituted one or two times with substituents selected from the group consisting of alkyl and phenyl.
• X represents O, S or NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein X represents O, S or NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl.
• X represents NR'; wherein R' represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl. In an even more preferred embodiment X represents NR'; wherein R' represents hydrogen or alkyl, in particular methyl or ethyl.
• X represents NR'; wherein R' represents hydrogen, methyl or ethyl.
• X represents NR'; wherein R' represents hydrogen.
• X represents NR'; wherein R' represents methyl or ethyl.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is 0;
• X is NR'; and R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in particular pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or pyrazolyl, which heterocyclic ring is optionally substituted one or two times with substituents selected from the group consisting of alkyl and phenyl.
• n is 0;
• X represents NR'; and R' together with Y and together with the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl ring.
• n 0;
• X is NR'; and R' together with Y and together with the nitrogen to which they are attached form a piperidinyl, piperazinyl or pyrazolyl ring, which heterocyclic ring is optionally substituted one or two times with substituents selected from the group consisting of alkyl and phenyl.
• n is 0;
• X is NR'; and R' together with Y and together with the nitrogen to which they are attached form a piperidinyl, a 4-methyl-piperidinyl, a piperazinyl, a 4-phenyl- piperazinyl, a pyrazolyl or a 3,5-dimethyl-pyrazolyl ring.
• n is 0;
• X is NR'; and R' together with Y and together with the nitrogen to which they are attached form a 4-methyl-piperidinyl, a 4-phenyl-piperazinyl or a 3,5-dimethyl- pyrazolyl ring.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein Y represents alkyl, cycloalkyl, alkyl- cycloalkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, phenyl, benzyl, naphthyl, 1 ,2,3,4-tetrahydro-naphthyl, indenyl, 1 ,2-dihydro- indenyl, furanyl, thienyl, pyranyl, tetrahydro-pyran-4-yl, pyridinyl, indolinyl or quinolinyl, which phenyl, benzyl, naphthyl, 1 ,2,3,4-tetrahydro-naphthyl, indenyl, 1 ,2-dihydr
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein Y represents alkyl, amino-alkyl, alkyl- amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl, or a monocyclic or polycyclic, carbocyclic or heterocyclic group, which carbocyclic or heterocyclic groups may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino; or, when n is 0 and X is NR', Y together with
• Y represents alkyl, in particular methyl, ethyl, propyl, butyl or pentyl; cycloalkyl, in particular cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; alkyl-cycloalkyl, in particular methyl-cyclohexyl or t-butyl-cyclohexyl; hydroxy-alkyl, in particular hydroxyl-methyl, 2-hydroxy-ethyl or 3- hydroxy-propyl; alkenyl, in particular propenyl; phenyl, benzyl, or naphthyl, which phenyl, benzyl and naphthyl groups may optionally be substituted one or two times with substituents selected from the group consisting of alkyl, in particular methyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular
• Y represents methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl- cyclohexyl, t-butyl-cyclohexyl, hydroxyl-methyl, 2-hydroxy-ethyl, 3-hydroxy-propyl, phenyl, benzyl, or naphthyl, which phenyl, benzyl and naphthyl groups may optionally be substituted one or two times with substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy.
• Y represents alkyl, alkenyl or cycloalkyl.
• Y represents phenyl, benzyl, or naphthyl, which phenyl, benzyl and naphthyl groups may optionally be substituted one or two times with substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy.
• Y represents phenyl or benzyl, which phenyl and benzyl groups may optionally be substituted one or two times with substituents selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl and methoxy.
• Y represents naphthyl
• Y represents a monocyclic or polycyclic carbocyclic group selected from phenyl, naphthyl or 1 ,2,3,4-tetrahydro- naphthyl; or a monocyclic or polycyclic heterocyclic group selected from pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl; which phenyl, naphthyl, 1 ,2,3,4-tetrahydro- naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl groups may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, hal
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein R 1 , R 2 , R 3 and R 4 , independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl- alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy, cyano, nitro and/or amino.
• R 1 , R 2 , R 3 and R 4 independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl- alkyl, halo, haloalkyl, hydroxy, alkoxy, alkoxy-carbonyl, haloalkoxy, cyano, nitro and/or amino.
• R 1 and R 2 independently of each other, represent hydrogen or alkyl, in particular methyl, ethyl or propyl;
• R 3 and R 4 independently of each other, represent hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl; and/or cyano.
• alkyl in particular methyl, ethyl or propyl
• halo in particular fluoro, chloro, bromo or iodo
• haloalkyl in particular trifluoromethyl
• alkoxy-carbonyl in particular methoxy-carbonyl or ethoxy-carbonyl
• cyano in an even more preferred embodiment
• R 1 and R 2 independently of each other, represent alkyl, in particular methyl, ethyl or propyl;
• R 3 and R 4 independently of each other, represent hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trilfuoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl; and/or cyano.
• R 1 and R 2 independently of each other, represent methyl, ethyl or propyl
• R 3 and R 4 independently of each other, represent hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl; and/or cyano.
• alkyl in particular methyl, ethyl or propyl
• halo in particular fluoro, chloro, bromo or iodo
• haloalkyl in particular trifluoromethyl
• alkoxy-carbonyl in particular methoxy-carbonyl or ethoxy-carbonyl
• cyano in a yet more preferred embodiment
• R 1 and R 2 represent methyl
• R 3 and R 4 independently of each other, represent hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl; and/or cyano.
• R 1 and R 2 represent methyl
• R 3 represents hydrogen or alkyl, in particular methyl, ethyl or propyl
• R 4 represents hydrogen; alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro, chloro, bromo or iodo; alkoxy-carbonyl, in particular methoxy-carbonyl or ethoxy-carbonyl; and/or cyano.
• R 1 and R 2 represent methyl
• R 3 represents hydrogen, methyl, ethyl or propyl
• R 4 represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxy- carbonyl and/or cyano.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein R 1 , R 2 and R 3 , independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino, and R 4 represents hydrogen.
• R 1 , R 2 and R 3 independently of each other, represent alkyl, cycloalkyl or cycloalkyl-alkyl, and R 4 represents hydrogen.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is 0;
• X is NH
• Y represents alkyl, in particular methyl, ethyl, propyl, butyl or pentyl; cycloalkyl, in particular cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; alkyl-cycloalkyl, in particular methyl-cyclohexyl or t-butyl-cyclohexyl; hydroxy-alkyl, in particular hydroxyl-methyl, 2-hydroxy-ethyl or 3-hydroxy-propyl; phenyl, benzyl or naphthyl;
• R 1 and R 2 represent methyl;
• R 3 represents hydrogen, methyl, ethyl or propyl;
• R 4 represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxy- carbonyl and/or cyano.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is O;
• X represents NR'; wherein R' represents hydrogen, methyl, ethyl or propyl;
• Y represents alkyl, cycloalkyl, cycloalkyl-alkyl, or alkenyl, piperidinyl or phenyl, which phenyl may optionally be substituted one or two times with halo or trifluoromethyl; and R 1 , R 2 and R 3 , independently of each other, represent methyl, ethyl or propyl, and R 4 represents hydrogen.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is O; X represents NR'; and R' together with Y and together with the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl ring; and
• R 1 , R 2 and R 3 independently of each other, represent methyl, ethyl or propyl, and R 4 represents hydrogen.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is 1 ; and X represents NR'; wherein R' represents hydrogen, methyl, ethyl or propyl;
• Y represents furanyl, thienyl or phenyl, which phenyl may optionally be substituted one or two times with halo or trifluoromethyl; and R 1 , R 2 and R 3 , independently of each other, represent methyl, ethyl or propyl, and R 4 represents hydrogen.
• the pyrazolyl-pyrimidine derivative of the invention is a compound of Formula I, wherein n is 0; X is NH;
• Y represents phenyl or benzyl, which phenyl and benzyl groups may optionally be substituted one or two times with substituents selected from the group consisting of alkyl, in particular methyl; halo, in particular fluoro, chloro, bromo or iodo; haloalkyl, in particular trifluoromethyl; and alkoxy, in particular methoxy; R 1 and R 2 represent methyl;
• R 3 represents hydrogen, methyl, ethyl or propyl
• R 4 represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxy- carbonyl or cyano.
• n is 0;
• X is NH
• Y represents phenyl or benzyl, which phenyl and benzyl groups may optionally be substituted one or two times with substituents selected from the group consisting of methyl, chloro, trifluoromethyl and methoxy;
• R 1 and R 2 represent methyl
• R 3 represents hydrogen, methyl, ethyl or propyl
• R 4 represents hydrogen, methyl, ethyl, propyl, chloro, bromo, ethoxy- carbonyl or cyano.
• the pyrazolyl-pyrimidine derivative of the invention is
• halo represents fluoro, chloro, bromo or iodo.
• a trihalomethyl group represents e.g. a trifluoromethyl group, a trichloromethyl group, and similar tri halo-substituted methyl groups.
• a haloalkyl group designates an alkyl group as defined herein, which alkyl group is substituted one or more times with halo.
• Preferred haloalkyl groups of the invention include trihalomethyl, preferably trifluoromethyl.
• an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
• the hydrocarbon chain preferably contain of from one to eighteen carbon atoms (C- M ⁇ -alkyl), more preferred of from one to six carbon atoms (d- ⁇ -alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
• alkyl represents a d- 4 - alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
• alkyl represents a d- 3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
• a hydroxy-alkyl group designates an alkyl group as defined above, which hydroxy-alkyl group is substituted with one or more hydroxy groups.
• Examples of preferred hydroxy-alkyl groups of the invention include 2- hydroxy-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl and 6-hydroxy- hexyl.
• an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes.
• the alkenyl group of the invention comprises of from two to eight carbon atoms (C 2 - 8 -alkenyl), more preferred of from two to six carbon atoms (C 2 - 6 - alkenyl), including at least one double bond.
• the alkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl, or 1 ,3- butenyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1 ,3-hexenyl, or 1 ,3,5-hexenyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1 ,3-octenyl, or 1 ,3,5-octenyl, or 1 ,3,5,7-octenyl.
• a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to ten carbon atoms (C 3 -io-cycloalkyl), preferably of from three to eight carbon atoms (C 3 - 8 -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• a cycloalkyl-alkyl group designates a cycloalkyl group as defined above, which cycloalkyl group is substituted on an alkyl group as also defined above.
• Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.
• an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above.
• a haloalkoxy group designates an alkoxy group as defined herein, which alkoxy group is substituted one or more times with halo.
• Preferred haloalkoxy groups of the invention include trihalomethoxy, preferably trifluoromethoxy.
• an amino group may be a primary (-NH 2 ), secondary (-NH-alkyl), or tertiary (-N(alkyl)2) amino group, i.e. it may be substituted once or twice with an alkyl group as defined above.
• a mono- or poly-cyclic carbocyclic group designates a mono- or polycyclic hydrocarbon group, which group may in particular be an aromatic hydrocarbon group, i.e. a mono- or polycyclic aryl group, or a saturated hydrocarbon group, or a partially saturated hydrocarbon group.
• Preferred poly- carbocyclic group are the bicyclic carbocyclic groups.
• carbocyclic group designates a monocyclic or polycyclic hydrocarbon group.
• preferred carbocyclic groups of the invention include cycloalkyl, phenyl, naphthyl, indenyl, azulenyl, anthracenyl, and fluorenyl.
• Most preferred carbocyclic groups of the invention include phenyl, naphthyl and 1 ,2,3,4-tetrahydro-naphthyl.
• a monocyclic or polycyclic, heterocyclic group designates a mono- or polycyclic group, which group holds one or more heteroatoms in its ring structure.
• Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur (S).
• One or more of the ring structures may in particular be aromatic (i.e. a heteroaryl), saturated or partially saturated.
• Preferred heterocyclic monocyclic groups of the invention include 5- and 6 membered heterocyclic monocyclic groups.
• Preferred poly-heterocyclic groups of the invention are the bicyclic heterocyclic groups.
• heterocyclic monocyclic groups of the invention include pyrrolidinyl, in particular pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl; piperidinyl, in particular piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl; furanyl, in particular furan-2-yl and furan-3-yl; thienyl, in particular thien-2-yl and thien-
• pyrrolyl in particular pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl.
• the compounds of the present invention may exist in different stereoisomeric forms, including enantiomers, diastereomers, as well as geometric isomers (cis-trans isomers).
• the invention includes all such isomers and any mixtures thereof including racemic mixtures. Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the enantiomeric compounds (including enantiomeric intermediates) is by use of an optically active amine, and liberating the diastereomeric, resolved salt by treatment with an acid. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of D- or L- (tartrates, mandelates, or camphorsulphonate) salts for example.
• D- or L- fractional crystallisation of D- or L- (tartrates, mandelates
• the chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like. Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, & Wilen S in "Enantiomers. Racemates. and Resolutions". John Wiley and Sons, New York (1981 ).
• Optical active compounds can also be prepared from optical active starting materials or intermediates.
• the chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.
• Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from
• acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
• Metal salts of a chemical compound of the invention include alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
• onium salts of N-containing compounds are also contemplated as pharmaceutically acceptable salts.
• Preferred “onium salts” include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
• the chemical compound of the invention may be provided in dissoluble or indissoluble forms together with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
• the chemical compounds of the invention may be prepared by conventional methods of chemical synthesis, e.g. those described in the working examples.
• the starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
• the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
• the chemical compounds of the invention have been subjected to in vitro experiments and found particularly useful as potassium channel modulating agents. More particularly the compounds of the invention are capable of selectively modulating SK1 , SK2 and/or SK3 channels. Therefore, in another aspect, the invention relates to the use of a chemical compound of the invention for the manufacture of medicaments, which medicament may be useful for the treatment or alleviation of a disease or a disorder associated with the activity of potassium channels, in particular SK channels, more particularly SK1 , SK2 and/or SK3 channels.
• the disease or a disorder associated with the activity of potassium channels is a respiratory disease, epilepsy, convulsions, seizures, absence seizures, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorders, dementia, memory and attention deficits, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscle dystrophia, spasticity, xerostomi,
• ALS am
• the disease or a disorder associated with the activity of potassium channels is a respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain.
• the disease or a disorder associated with the activity of potassium channels is a respiratory disease, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.
• COPD chronic obstructive pulmonary disease
• the disease or a disorder associated with the activity of potassium channels is urinary incontinence.
• the disease or a disorder associated with the activity of potassium channels is epilepsy, seizures, absence seizures or convulsions.
• the disease or a disorder associated with the activity of potassium channels is a respiratory disease, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.
• COPD chronic obstructive pulmonary disease
• the compounds tested all showed a biological activity in the micromolar and sub-micromolar range, i.e. of from below 1 to above 100 ⁇ M.
• Preferred compounds of the invention show a biological activity determined as described herein in the in the sub-micromolar and micromolar range, i.e. of from below 0.1 to about 10 ⁇ M.
• compositions comprising a therapeutically effective amount of the chemical compound of the invention, including the following compounds:
• the pharmaceutical composition of the invention comprises a therapeutically-effective amount of a pyrazolyl-pyrimidine derivative as described above, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent.
• a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, or in the form of a prodrug, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers and/or diluents.
• the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
• sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
• compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
• forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
• Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
• the chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
• pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• a solid carrier can be one or more substances that may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
• Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
• the active component is dispersed homogeneously therein, as by stirring.
• the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
• compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
• parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
• the chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
• the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
• the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
• a suitable vehicle e.g. sterile, pyrogen-free water
• Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
• viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
• liquid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
• liquid forms include solutions, suspensions, and emulsions.
• These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like
• the chemical compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
• Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
• compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form.
• Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
• a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
• CFC chlorofluorocarbon
• the aerosol may conveniently also contain a surfactant such as lecithin.
• the dose of drug may be controlled by provision of a metered valve.
• the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
• a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
• PVP polyvinylpyrrolidone
• the powder carrier will form a gel in the nasal cavity.
• the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
• compositions intended for administration to the respiratory tract including intranasal compositions
• the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
• compositions adapted to give sustained release of the active ingredient may be employed.
• the pharmaceutical preparations are preferably in unit dosage forms.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
• a therapeutically effective dose refers to that amount of active ingredient which ameliorates the symptoms or condition.
• Therapeutic efficacy and toxicity e.g. ED 5O and LD 5O , may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD 50 /ED 50 . Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.
• the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
• compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
• the active ingredient may be administered in one or several doses per day.
• a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
• the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
• Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
• the invention provides a method for the prevention, treatment or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of potassium channels, in particular SK channels, and which method comprises comprising administering to such a living animal body, including a human, in need thereof a therapeutically-effective amount of a compound of the invention.
• suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
• a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o.
• the upper limit of the dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o.
• Preferred ranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10 mg/kg p.o.
• Benzyl-(2-chloro-6-methyl-pyrimidin-4-yl)-amine (460 mg; 2.01 mmol) was dissolved in acetonitrile (5 ml_) and 3,5-dimethylpyrazole (290 mg; 3.02 mmol) was added. The mixture was heated in a microwave oven at 17O 0 C for 20 minutes. Evaporation followed by extraction between dichloromethane and sodium hydroxide 1M, drying
• This example demonstrates the biological activity of a compound representative of the invention (Compound A2).
• the ionic current through small- conductance Ca 2+ -activated K + channels (SK channels, subtype 3) is recorded using the whole-cell configuration of the patch-clamp technique.
• the small-conductance Ca 2+ -activated K + channel, subtype 3 (SK3) was cloned from human skeletal muscle and stably expressed in HEK293 cells.
• hSK3 Human SK3 was sub-cloned into the expression vector pNS3n, a customized vector derived from pcDNA3 (InVitrogen) to give the plasmid construct pNS3_hSK3.
• HEK293 tissue culture cells were grown in DMEM (Dulbecco's Modified Eagle Medium) supplemented with 10% FCS (foetal calf serum) at 37°C in 5% CO 2 . Cells cultured to 50% confluency in a T25 cell culture flask were transfected with 2.5 ⁇ g pNS3_hSK3 using lipofectamin (InVitrogen). Transfected cells were selected in media supplemented with 0.25mg/ml Zeocin. Single clones were picked and propagated in selection media until sufficient cells for freezing were available. Hereafter the cells were cultured in regular medium without selection agent. Expression of functional hSK3 channels was verified by patch-clamp measurements.
• the test compound was dissolved 1000 times in DMSO from a concentrated stock solution and then diluted in the extracellular solution.
• the calculated free concentration of Ca 2+ in this solution is 300 nM and that of Mg 2+ is 1 mM.
• voltage-ramps (normally -120 to +30 mV) are applied to the cell every 5 seconds from a holding potential of -80 mV.
• a stable baseline current is obtained within a period of 100-500 seconds, and the compound is then added by changing to an extracellular solution containing the test compound.
• Very little endogenous current ( ⁇ 200 pA at 30 mV compared to 2-10 nA SK3 current) is activated under these circumstances in native HEK293 cells.
• Active compounds are quantified by calculating the change in baseline current at -20 mV.
• the current in the absence of compound is set to 100%.
• Activators will have values greater than 100, and a value of 200% indicates a doubling of the current.
• a value of 50% indicates that the compound has reduced the baseline current to half its value.
• SC100 value For activators a SC100 value may be estimated.
• the SC100 value is defined as the Stimulating Concentration required for increasing the baseline current by 100%.
• the SC1 00 value determined for Compound A2 of the invention was 0.1 ⁇ M, which is an indication of its strong SK3 activating properties.

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