HK1122273A - Pyrimidine derivatives and their use as kcnq potassium channels openers - Google Patents

Description

Pyrimidine derivatives and their use as KCNQ potassium channel openers

Technical Field

The present invention relates to compounds which are openers of the KCNQ family of potassium ion channels. The compounds may be used in the treatment of disorders and diseases responsive to the opening of KCNQ family potassium ion channels, one such disease being epilepsy.

Background

Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chloride, and sodium, into and out of cells. The channels are present in all animal and human cells and affect a variety of processes including neuronal transmission, muscle contraction and cellular secretion.

Humans have more than 70 genes encoding potassium channel subtypes with significant diversity with respect to structure and function (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30). Neuronal potassium channels found in the brain are primarily responsible for maintaining negative resting membrane potentials and controlling the repolarization of action potentials by membranes.

One subset of potassium channel genes is the KCNQ family. Mutants of four of the five KCNQ genes have been shown to be the basis for the development of diseases including arrhythmia, deafness and epilepsy (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30).

It is believed that the KCNQ4 gene encodes a molecular association of potassium channels found in snail outer hair cells and vestibular organ type I hair cells, where mutations can lead to a form of hereditary deafness.

KCNQ1(KvLQT1) was co-formulated with KCNE1 (the smallest K (+) -channel protein) gene product in the heart, resulting in a K (+) current similar to that of the cardiac delayed rectifier. Mutations in this channel can lead to an inherited long QT syndrome type 1 (LQT1) and to forms associated with the deafness form (Robbins Pharmacol Ther 2001, 90, 1-19).

Genes KCNQ2 and KCNQ3 were discovered in 1988 and appear to be inherited epilepsy mutated to a form of new tics known as benign familial (Rogawski Trends in neurosciens 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localized in human cerebral cortex and pyramidal cells of the hippocampus, the brain regions associated with disease production and development (Cooper et al Proceedings National Academy of Science U S A2000, 97, 4914-.

When expressed in vitro, KCNQ2 and KCNQ3 are two potassium channel subunits that form an "M-current". M-current is a non-inactivating potassium current found in a variety of neuronal cell types. In various cell types, it controls membrane excitability by dominating current flow for only one sustained period within the onset range of action potential (Marion Annual Review Physiology 1997, 59, 483-504). Modulation of M-current also has a significant effect on neuronal excitability, e.g., activating current will reduce neuronal excitability. Openers of these KCNQ channels or activators of M-current will reduce excessive neuronal activity and thus may be useful in the treatment of seizures and other diseases and disorders characterized by excessive neuronal activity, such as neuronal hyperexcitability including convulsive disorders, epilepsy and neuropathic pain.

Retigabine (D-23129; N- (2-amino-4- (4-fluorobenzylamino) -phenyl) carbamic acid ethyl ester) and its analogues are disclosed in EP 554543. Retigabine is an anticonvulsant compound with broad-spectrum and effective anticonvulsant properties both in vitro and in vivo. It works after oral and intraperitoneal administration to rats and mice in the following antispasmodic test: electrically induced seizures, chemically induced seizures by pentamethylenetetrazole, picotoxin and N-methyl-D-aspartate (NMDA), and in genetic animal models, DBA/2 mice (Rostock et al Epilepsy research 1996, 23, 211-. In addition, retigabine is active in the tonsil fire model in coordination with partial seizures, further suggesting that this compound may be useful in anticonvulsant therapy. In clinical trials, retigabine has recently been shown to be effective in reducing the occurrence of seizures in epileptic patients (Bialer et al Epilepsy Research 2002, 51, 31-71).

Retigabine has been shown to activate K (+) currents in neuronal cells, and the pharmacology of this induced current suggests agreement with the pharmacology of the published M-channel, which has recently been associated with the KCNQ2/3K (+) channel heteropolybody. This suggests that activation of the KCNQ2/3 channel may determine some of the anticonvulsant activity of this agent (Wickenden et al Molecular Pharmacology2000, 58, 591-one 600) and that other agents acting by the same mechanism may have similar utility.

KCNQ2 and 3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden et al Society for Neuroscience extracts 2002, 454.7), and potassium channel modulators have been hypothesized to be active in both neuropathic pain and epilepsy (Schroder et al Neuropharmacology 2001, 40, 888-.

Retigabine has also been shown to be beneficial in models of neuropathic pain (Blackburn-Munro and Jensen European Journal of Pharmacology2003, 460, 109-.

Localization of KCNQ channel mRNA has been reported in the brain and other central nervous systems associated with pain (Goldstein et al, Society for Neuroscience extracts 2003, 53.8).

In addition to its role in neuropathic pain, the expression of KCNQ 2-5 mRNA in the trigeminal and dorsal root ganglia and the tail of the trigeminal nucleus suggests that openers of these channels may also affect migraine headache perception (Goldstein et al, Society for neurosciennenecceabscacts 2003, 53.8).

Recent reports indicate that mRNA of KCNQ3 and 5 is expressed in astrocytes and glial cells in addition to mRNA of KCNQ 2. Thus, the KCNQ2, 3 and 5 channels would contribute to the modulation of synaptic activity in the CNS and to the neuroprotective effect of KCNQ channel openers (Noda et al, Society for Neuroscience Abstracts2003, 53.9).

Thus, retigabine and other KCNQ modulators may exhibit protective effects on the neurodegeneration of epilepsy, for example retigabine has been shown to prevent marginal neurodegeneration and expression of apoptosis markers following kainic-induced status epilepticus in rats (Ebert et al, epileepsia 2002, 43 Suppl 5, 86-95). This may have relevance to preventing the development of epilepsy in a patient, i.e. anti-epileptic. It was also shown that retigabine delays the development Of hippocampal fire in another model Of rats in the study Of epilepsy (Tober et al, European journal Of Pharmacology 1996, 303, 163-169).

These properties of retigabine and other KCNQ modulators are thus indicative of the prevention of neuronal damage induced by excessive neuronal activation, and the compounds may be used in the treatment of neuronal degenerative diseases, and in patients with epilepsy to produce disease modification (or anti-epileptic effects).

Other anticonvulsant compounds, such as KCNQ openers, are expected to be effective in this condition based on the fact that anticonvulsant compounds (such as benzodiazepines and clomephiazoles) and other anticonvulsant compounds (such as gabapentin) used clinically in the treatment of alcohol withdrawal syndrome are very effective in animal models of this syndrome (Watson et al, Neuropharmacology 1997, 36, 1369-.

mRNA of KCNQ2 and 3 subunits is found in brain regions associated with anxiety and emotional behavior (such as bipolar disorders, e.g. hippocampus and amygdala) (saganic et al, Journal of neuroscience 2001, 21, 4609-one 4624), and retigabine has been reported to be active in several animal models of anxiety-like behavior (Hartz et al, Journal of psychopharmacography 2003, 17 suppl 3, a28, B16), and other clinically used anticonvulsant compounds are used in the treatment of bipolar disorders. Thus, KCNQ openers may be used in the treatment of anxiety disorders and bipolar disorder.

WO 200196540 discloses the use of M-current modulators formed by expression of KCNQ2 and KCNQ3 genes for insomnia, while WO 2001092526 discloses that modulators of KCNQ5 can be used to treat sleep disorders.

WO01/022953 describes the use of retigabine for the prevention and treatment of neuropathic pain, such as hyperalgesia, hyperalgesia pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine.

WO02/049628 describes the use of retigabine for the treatment of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, executive anxiety, post traumatic stress disorder, acute stress response, adjustment disorders, melancholia, separation anxiety disorder, agoraphobia and specific phobias.

WO97/15300 describes the use of retigabine for the treatment of neurodegenerative diseases such as alzheimer's disease; huntington's chorea; sclerosis such as multiple brain sclerosis and amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; parkinson's disease; encephalopathy induced by AIDS or infections produced by rubella virus, herpes virus, borrelia, and unknown pathogens; trauma-induced neurodegeneration; neuronal hyperexcitability states, such as those produced in drug withdrawal or intoxication; and neurodegenerative diseases of the peripheral nervous system, such as polyneuropathy and polyneuritis.

KCNQ channel openers have also been found to be effective in the treatment of stroke, and thus selective KCNQ openers can be expected to be effective in the treatment of stroke (Schroder et al, Pfleger sArch., 2003; 446 (5): 607-16; Cooper and Jan, Arch neurol., 2003, 60 (4): 496-500; Jensen, CNS Drug Rev., 2002, 8 (4): 353-60).

KCNQ channels have been shown to be expressed in the dopaminergic and cholinergic circuits of the brain associated with the brain's responsive system, particularly in the lateral cap region (Cooper et al, J Neurosci, 2001, 21, 9529-9540). Thus, KCNQ channel openers are expected to be effective in hyperexcitable diseases involving the brain responsive system, such as cocaine abuse, nicotine withdrawal and alcohol withdrawal.

Potassium channels, consisting of the KCNQ4 subunit, are expressed in the inner ear (Kubisch et al, cell., 1999 Feb 5; 96 (3): 437-46), and thus the opening of these channels is expected to treat tinnitus.

Thus, novel compounds that are effective openers of the potassium channel KCNQ family are highly desirable.

Novel compounds having improved properties over known compounds that are potassium channel openers of the KCNQ family, such as retigabine, are also desired.

Improvements in one or more of the following parameters are desirable:

half-life, clearance, selectivity, interaction with other drugs, bioavailability, potency, formulability, chemical stability, metabolic stability, membrane permeability, solubility, and therapeutic index. The improvement in the parameters may result in improvements such as:

improved dosage regimens by reducing the number of doses required per day,

ease of administration to the patient over multiple administrations,

a reduced side-effect profile and a reduced side-effect profile,

an increased therapeutic index of the therapeutic agent,

improved resistance or

Improved adaptability.

Summary of The Invention

It is an object of the present invention to provide compounds which are effective openers of KCNQ family potassium channels.

The compounds of the present invention are substituted pyrimidine derivatives of the formula or salts thereof

Wherein R is¹、R²、R³、R⁴、R⁵And q is defined as follows.

The present invention provides compounds of formula I for use as medicaments.

The present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent.

The present invention provides the use of a compound of formula I for the preparation of a medicament for the treatment of seizure disorders, anxiety disorders, neuropathic pain and migraine headache disorders, other pain disorders (such as cancer pain), neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal, alcohol withdrawal or hearing disorders (such as tinnitus).

The invention further relates to the use of compounds of formula I in methods of treating seizure disorders, anxiety disorders, neuropathic pain and migraine headache disorders, other pain disorders (such as cancer pain), neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal, alcohol withdrawal or hearing disorders (such as tinnitus).

Definition of substituents

The term "heteroatom" refers to a nitrogen, oxygen or sulfur atom.

"halogen" means fluorine, chlorine, bromine or iodine. "halo" means halogen.

"cyano" means C.ident.N.

Which is attached to the remainder of the molecule via a carbon atom.

"amino" means NH₂Which is attached to the remainder of the molecule via a nitrogen atom.

Expression "C_1-6-alk (en/yn) yl "means C_1-6Alkyl radical, C_2-6-alkenyl or C_2-6-alkynyl.

The term "C_1-6Alkyl "refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, 2-dimethyl-prop-1-yl, but-2-yl, 3-methyl-but-1-yl, 3-methyl-but-2-yl, pent-1-yl, pent-2-yl, pent-3-yl, hex-1-yl, hex-2-yl and hex-3-yl.

The term "C_2-6-alkenyl "means a branched or unbranched alkenyl group having 2 to 6 carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl.

The term "C_2-6-alkynyl "refers to a branched or unbranched alkynyl group having 2 to 6 carbon atoms and one triple bond, including but not limited to ethynyl, propynyl, and butynyl.

Expression "C_1-10-alk (en/yn) yl "means C_1-10Alkyl radical, C_2-10-alkenesRadical or C_2-10-alkynyl.

The term "C_1-10-alkyl "refers to branched or unbranched alkyl groups having 1 to 10 carbon atoms including but not limited to methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, 2-dimethyl-prop-1-yl, but-2-yl, 3-methyl-but-1-yl, 3-methyl-but-2-yl, pent-1-yl, pent-2-yl, pent-3-yl, hex-1-yl, hex-2-yl, hex-3-yl, 2-methyl-4, 4-dimethyl-pent-1-yl and hept-1-yl.

The term "C_2-10The-alkenyl group' means a branched or unbranched alkenyl group having 2 to 10 carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl.

The term "C_2-10-alkynyl "refers to a branched or unbranched alkynyl group having 2 to 10 carbon atoms and one triple bond, including but not limited to ethynyl, propynyl, and butynyl.

Expression "C_3-8-Cycloalk (en) yl "means C_3-8-cycloalkyl or C_3-8-cycloalkenyl groups.

The term "C_3-8Cycloalkyl represents a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, bicycloheptyl, such as 2-bicyclo [2.2.1]A heptyl group.

The term "C_3-8-cycloalkenyl "denotes a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms and one double bond, including but not limited to cyclopentenyl and cyclohexenyl.

The term "halogen-C_1-6-alk (en/yn) yl "represents C substituted by halogen_1-6-alk (en/yn) yl including, but not limited to, trifluoromethyl.

The term "halogen-C_1-6-alk (en/yn) yloxy "represents C substituted by halogen_1-6-alk (en/yn) yloxy including, but not limited to, trifluoromethoxy.

Similarly, "halogen-C_3-8-Cycloalk (en) yl "represents C substituted by halogen_3-8-cycloalk (en) yl groups including but not limited to chlorocyclopropane and chlorocyclohexane.

Similarly, "halogen-C_3-8-Cycloalk (en) yloxy "represents C substituted by halogen_3-8-cycloalk (en) yloxy, including but not limited to chlorocyclopropoxy and chlorocyclohexyloxy.

Similarly, "halogen-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yloxy "denotes C_1-6halogen-C with an alk (en/yn) yloxy group attached to the remainder of the molecule_3-8-a cycloalk (en) yl group.

The term "C_1-6-alk (en/yn) yloxy "denotes C attached to the rest of the molecule via an oxygen atom_1-6-alk (en/yn) yl.

Similarly, "C_3-8-Cycloalk (en) yloxy "denotes C attached to the remainder of the molecule via an oxygen atom_3-8-a cycloalk (en) yl group.

The term "aryl" denotes a monocyclic or bicyclic aromatic system selected from phenyl, naphthyl, thiophene, furan, benzothiophene and benzofuran.

The term "optionally substituted aryl-C_1-6-alk (en/yn) yl "represents aryl-C wherein the aryl moiety is optionally substituted_1-6-an alk (en/yn) yl group, such as substituted with 1, 2 or 3 substituents independently selected from: halogen, cyano, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, halogen-C_1-6-alk (en/yn) yl, halogen-C_3-8Cycloalkyl (en) yl, halogen-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, C_1-6-alk (en/yn) yloxy, C_3-8Cycloalk (en) yloxy and C_3-8-cycloalkyl (en) yl-C_1-6-an alk (en/yn) yloxy group.

In a similar manner to that described above,the term "optionally substituted aryl" denotes aryl in which the aryl moiety is optionally substituted, such as by 1, 2 or 3 substituents independently selected from: halogen, cyano, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, halogen-C_1-6-alk (en/yn) yl, halogen-C_3-8Cycloalkyl (en) yl, halogen-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, C_1-6-alk (en/yn) yloxy, C_3-8Cycloalk (en) yloxy and C_3-8-cycloalkyl (en) yl-C_1-6-an alk (en/yn) yloxy group.

Under the expression "C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl "," aryl-C_1-6-alk (en/yn) yl "and" C_3-8-cycloalkyl (en) yl-C_1-6In the group-alk (en/yn) yloxy, the term "C_1-6-alk (en/yn) yl "," C_3-8-cycloalkyl (en) yl "," aryl "and" C_1-6-alk (en/yn) yloxy "is as defined above.

Description of the invention

The present invention relates to substituted pyrimidine derivatives which are effective openers of KCNQ potassium channels.

The present invention relates to compounds represented by the general formula I:

wherein: q is 0 or 1;

R¹and R²Independently selected from hydrogen and optionally substituted aryl-C_1-6-alk (en/yn) yl, with the proviso that R¹And R²Not all being hydrogen, or R¹And R²Together with the nitrogen to which they are attached form a 5-7 membered ring optionally containing one additional heteroatom;

R³and R⁴Independently selected from hydrogen, halogen, cyano, amino, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, halogen-C_1-6-alk (en/yn) yl, halogen-C_3-8Cycloalkyl (en) yl, C_1-6-alk (en/yn) yloxy, C_3-8Cycloalk (en) yloxy, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yloxy, halogen-C_1-6-alk (en/yn) yloxy, halogen-C_3-8Cycloalk (en) yloxy and halogen-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yloxy, with the proviso that R³And R⁴Not all are hydrogen;

R⁵is selected from C_1-10-alk (en/yn) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, optionally substituted aryl-C_1-6-an alk (en/yn) yl group and an optionally substituted aryl group;

in one embodiment of the compounds of formula I, q is 0.

In another embodiment of the compounds of formula I, q is 1.

In another embodiment of the compounds of formula I, R¹And R²Independently selected from hydrogen and optionally substituted aryl-C_1-6-alk (en/yn) yl, with the proviso that R¹And R²Not all are hydrogen.

In another embodiment of the compounds of formula I, R¹And R²Together with the nitrogen to which they are attached form a 5-7 membered ring optionally containing another heteroatom; in another embodiment, the other heteroatom is oxygen; in another embodiment, the ring is a 6 membered ring; in another embodiment, the ring is a morpholine ring.

In another embodiment of the compounds of formula I, R³And R⁴Independently selected from amino and C_1-6-alk (en/yn) yl, preferably methyl.

In another embodiment of the compounds of formula I, R⁵Is selected from C_1-10Alk (en/yn)) Base, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, optionally substituted aryl-C_1-6-an alk (en/yn) yl group and an optionally substituted aryl group.

Another embodiment relates to compounds of formula I, or a salt thereof, which are free bases, selected from the following schemes:

example number name

1a N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2-cyclopentyl

Acetamide radical

1b N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -3, 3-di

Methylbutanamide

1c N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2- (4-fluoro

Phenyl) -acetamides

1d hexanoyl [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -amide

1e N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2- (3-chloro

Phenyl) -acetamides

2a 2-cyclopentyl-N- (4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -acetamide

2b N- (4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -3, 3-dimethylbutanamide

2c N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (4-fluorophenyl) -acetamide

2d 2- (3, 4-difluorophenyl) -N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -acetyl

Amines as pesticides

2e N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (3-fluorophenyl) -acetamide

2f hexanoic acid (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -amide

Each of these compounds is considered a specific embodiment and may be claimed individually.

The invention also encompasses salts, typically pharmaceutically acceptable salts, of the compounds of the invention. Salts of the present invention include acid addition salts, metal salts, ammonium salts and alkylated ammonium salts.

The salts of the present invention are preferably acid addition salts. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts of the compounds of the present invention formed with non-toxic acids. Acid addition salts include salts of inorganic acids as well as organic acids. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic and nitric acids, and the like. 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, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, dimethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acid, and 8-halotheophylline (e.g., 8-bromotheophylline), and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977, 66, 2, which is incorporated herein by reference.

Acid addition salts are also contemplated as hydrates of the compounds of the present invention.

Examples of metal salts include lithium, sodium, potassium, magnesium salts, and the like.

Examples of ammonium and alkylated ammonium salts include ammonium, methyl-ammonium, dimethyl-ammonium, trimethyl-ammonium, ethyl-ammonium, hydroxyethyl-ammonium, diethyl-ammonium, n-butyl-ammonium, sec-butyl-ammonium, tert-butyl-ammonium, tetramethylammonium salts, and the like.

In addition, the compounds of the present invention may exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and the like. In general, for the purposes of the present invention, solvated forms are considered equivalent to unsolvated forms.

The compounds of the present invention may have one or more asymmetric centers and are intended to include within the scope of the invention optical isomers (i.e., enantiomers or diastereomers) in any form, isolated, pure or partially purified optical isomers and any mixtures thereof, including racemic mixtures, i.e., mixtures of stereoisomers.

The racemic form can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into optical antipodes is based on chromatographic separation of optically active substrates. The racemic compounds of the present invention can also be resolved into their optical antipodes by, for example, fractional crystallization. The compounds of the present invention may also be resolved by forming diastereomeric derivatives. Additional methods of resolving optical isomers known to those skilled in the art may also be used. Such methods include those discussed in j.jaques, a.collet and s.wilen, "enertiomers, racemes, and solutions," John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials or by stereoselective synthesis.

Furthermore, geometric isomers may be formed when double bonds or fully or partially saturated cyclic systems are present in the molecule. Any geometric isomer in the form of an isolated, pure or partially purified geometric isomer or a mixture thereof is intended to be included within the scope of the present invention. Likewise, molecules with rotation-limiting bonds may form geometric isomers. These are also intended to be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms, and it is intended that any tautomeric form which a compound is capable of forming is included within the scope of the present invention.

The invention also encompasses prodrugs of the compounds of the invention which, after administration, undergo chemical conversion by metabolic processes and then become pharmacologically active substances. Typically, the prodrug will be a functional derivative of the compound of formula I that can be readily converted in vivo to the compound of formula I. Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of produgs", eds h.

The invention also includes active metabolites of the compounds of the invention.

The compounds according to the invention have an EC for the KCNQ2 receptor subtype₅₀Affinity, EC, of less than 15000nM, such as less than 10000nM₅₀As determined by the test "relative flow through KCNQ2 channel" described below. One embodiment relates to having an EC for the KCNQ2 receptor subtype₅₀Said compound of formula I having an affinity of less than 2000nM, such as less than 1500nM, EC₅₀As determined by the test "relative flow through KCNQ2 channel" described below. To further illustrate the invention, without limitation, one embodiment relates to having an EC for the KCNQ2 receptor subtype₅₀(ii) an affinity of less than 200nM, such as less than 150nM, EC₅₀As determined by the test "relative flow through KCNQ2 channel" described below.

One embodiment involves testing as described below"maximum shock" middle ED₅₀Less than 15mg/kg of said compound of formula I. For further non-limiting illustration of the invention, one embodiment relates to ED in the test "maximum shock" described below₅₀Less than 5mg/kg of said compound.

One embodiment relates to the ED in the tests "electroepileptic seizure-limiting value assay" and "chemical seizure-limiting value assay" as described below₅₀Less than 5mg/kg of said compound of formula I.

One embodiment relates to said compounds of formula I having substantially no or clinically insignificant side effects. Thus, some compounds according to the invention were tested in a model that did not require sedative, hypothermia, and ataxic effects.

One embodiment relates to the compounds of formula I having a high therapeutic index between anticonvulsant potency and side effects such as a defect in locomotor activity or dyskinesia effects as measured by performance on a rotating rod. It is expected that the compounds will be well tolerated in patients, allowing high doses to be used before side effects are observed. Thus, the suitability for therapy is expected to be good, and high-dose administration can be permitted, which makes the treatment more effective in patients who have side effects using other drugs.

As noted above, the compounds according to the invention have an effect on potassium channels of the KCNQ family (in particular the KCNQ2 subunit) and thus they may be considered useful for elevating ion flow in pressure sensitive potassium channels of mammals, such as humans. The compounds of the invention are believed to be useful in the treatment of conditions or diseases that respond to increased ion flow in potassium channels, such as KCNQ family potassium channels. The disorder or disease is preferably a disorder or disease of the central nervous system.

In one aspect, the compounds of the present invention may be administered as the only therapeutically effective compound.

In another aspect, the compounds of the invention may be administered as part of a combination therapy, i.e., the compounds of the invention may be administered in conjunction with other therapeutically effective compounds having, for example, antispasmodic properties. The effects of the other compounds with antispasmodic properties may include, but are not limited to, activity against:

ion channels, such as sodium, potassium or calcium channels

Excitatory amino acid systems, e.g. blocking or modulation of NMDA receptors

An inhibitory neurotransmitter system, e.g. an enhancement of GABA release or a blockade of GABA-uptake, or

Membrane stabilization.

Existing antispasmodics include, but are not limited to, tiagabine, carbamazepine, valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide, and benzodiazepinesAnd members of the barbiturates class.

One aspect of the present invention provides a compound of formula I or a salt thereof for use as a medicament.

In one embodiment, the invention relates to the use of a compound of formula I or a salt thereof in a method of treatment.

One embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula I or a salt thereof and one or more pharmaceutically acceptable carriers or diluents. The composition may include any embodiment of formula I as described above.

Another embodiment of the invention relates to the use of a compound of formula I or a salt thereof for increasing the ion current in potassium channels of a mammal, such as a human.

Another embodiment of the invention relates to the use of a compound of formula I or a salt thereof for the treatment of a condition or disease which is responsive to increased ion flow in potassium channels, preferably a condition or disease of the central nervous system.

Another embodiment of the invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or condition, wherein a KCNQ potassium channel opener (such as a KCNQ2 potassium channel opener) is advantageous. Typically, the condition or disease is selected from seizure disorders, anxiety disorders, neuropathic pain and migraine disorders, other pain disorders (such as cancer pain), neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal, alcohol withdrawal or hearing disorders (such as tinnitus).

Another embodiment of the invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a seizure disorder.

Generally, the seizure disorders intended to be treated are selected from the group consisting of acute seizures, convulsions, status epilepticus and epilepsy, such as epileptic syndrome and epileptic seizures.

Another embodiment of the invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety disorders.

In general, the anxiety disorder intended for treatment is selected from anxiety and disorders and diseases associated with panic destruction, agoraphobia, panic disorders with agoraphobia, panic disorders without agoraphobia, agoraphobia without history of panic disorders, specific phobias, social phobias and other specific phobias, obsessive-compulsive disorders, post-traumatic stress disorders, acute stress disorders, generalized anxiety disorders, anxiety disorders due to general medical conditions, substance-induced anxiety disorders, separation anxiety disorders, regulatory disorders, executive anxiety disorders, melancholia, anxiety disorders due to general medical conditions and substance-induced anxiety disorders, and anxiety disorders not explicitly described.

Another embodiment of the present invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of neuropathic pain and migraine pain conditions.

In general, the neuropathic pain and migraine pain conditions intended for treatment are selected from hyperalgesia, hyperalgesia pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, and neuropathic pain associated with migraine.

Another embodiment of the present invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a neurodegenerative disorder.

In general, the neurodegenerative disorder intended for treatment is selected from the group consisting of alzheimer's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, parkinson's disease, encephalopathy induced by AIDS or infections produced by rubella virus, herpes virus, borrelia and unknown pathogens, trauma-induced neurodegeneration, neuronal hyperexcitability states such as those produced in drug withdrawal or intoxication, and neurodegenerative diseases of the peripheral nervous system such as multiple neuropathy and polyneuritis.

Another embodiment of the present invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of bipolar disorder or attention deficit hyperactivity disorder.

Another embodiment of the present invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of sleep disorders, such as insomnia.

Another embodiment of the invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of fibrosarcoma, motor myopathy or movement disorder, spasticity, myokyphosis or urinary incontinence.

Another embodiment of the present invention relates to the use of a compound of formula I or a salt thereof for the preparation of a pharmaceutical composition for the treatment of stroke, cocaine abuse, nicotine withdrawal, alcohol withdrawal or hearing disorders such as tinnitus.

The term "treating" as used herein in connection with a disease or condition also includes preventing, inhibiting, and ameliorating, as the case may be.

The present invention provides compounds that exhibit an effect in one or more of the following assays:

relative flow through KCNQ2 channel

It is a measure of the potency of a compound in a target channel

"maximum electric shock"

It is a measure of non-specific CNS-stimulation-induced seizures by electrical means

'pilocarpine-induced seizures'

Epileptic seizures induced by pilocarpine are often difficult to treat with many existing antiepileptic drugs, and thus reflect a model of "drug-resistant seizures

"determination of electroepileptic seizure Limit" and "determination of chemical-induced seizure Limit"

These models measure the limits at which a seizure is triggered, and thus are models that detect whether a compound can delay the onset of a seizure.

'tonsil excessive internal heat'

It is used as a measure of disease progression because in normal animals, the epileptic seizures produced in this model are more severe when the animals receive further stimulation.

Pharmaceutical composition

The invention also relates to pharmaceutical compositions. The compounds of the present invention or salts thereof may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent in a single dose or in multiple doses. The pharmaceutical compositions according to the invention may be formulated according to conventional techniques, such as those disclosed in Remington: those of The Science and Practice of Pharmacy, 19 th edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, with oral routes being preferred. It will be appreciated that the preferred route will depend upon the general condition and age of the subject to be treated, the nature of the condition or disease to be treated and the active ingredient selected.

The pharmaceutical compositions formed by combining the compounds of the present invention and a pharmaceutically acceptable carrier may then be administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may desirably be presented in unit dosage form prepared by methods known in the pharmaceutical arts.

The compounds of the invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of the free base. When a compound of the invention contains a free base, the compound is used in a conventional manner to prepare the salt by treating a solution or suspension of the free base of the invention with a stoichiometric amount of a pharmaceutically acceptable acid. Representative examples are set forth in the above section.

Pharmaceutical compositions for oral administration may be solid or liquid. Solid dosage forms for oral administration include, for example, capsules, tablets, dragees, pills, lozenges, powders, granules and strips, for example in the form of powders or pills placed in hard gelatin capsules or for example in the form of tablets or lozenges. Pharmaceutical compositions for oral administration may be prepared with coatings, such as enteric coatings, where appropriate, or they may be formulated according to methods well known in the art so that they provide controlled, such as sustained or extended, release of the active ingredient. Liquid dosage forms for oral administration include, for example, solutions, emulsions, suspensions, syrups, and elixirs.

Formulations of the invention suitable for oral administration may be presented as discrete units, such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include suitable excipients. Furthermore, orally applicable formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch and gums and the like. Examples of liquid carriers are fruit juices, peanut oil, olive oil, phosphate esters, fatty acids, fatty acid amines, polyoxyethylene and water.

The carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a paraffin wax.

Any adjuvants or additives conventionally used for such purposes may be used, such as colorants, flavorants, preservatives and the like, provided that they are compatible with the active ingredient.

The amount of solid carrier can vary, but will generally be from about 25mg to about 1 g.

If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Tablets may be prepared by mixing the active ingredient with conventional adjuvants or diluents and subsequently compressing the mixture in a conventional tabletting machine.

Pharmaceutical compositions for parenteral administration comprise sterile aqueous or nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Depot injectable formulations are also contemplated within the scope of the invention.

For parenteral administration, solutions of the compounds of the present invention in sterile aqueous solutions, aqueous propylene glycol, aqueous vitamin E, or sesame or peanut oil may be used. The aqueous solution should be suitably buffered if necessary, and the liquid formulation first rendered sufficiently isotonic with saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used can all be readily obtained by standard techniques well known to those skilled in the art.

The injection solution can be prepared by the following method: the active ingredient and possible additives are dissolved in a portion of the injection solvent, preferably sterile water, the solution is adjusted to the desired volume, the solution is sterilized and filled in suitable ampoules or vials. Any suitable additive commonly used in the art may be added, such as tonicity agents, preservatives, antioxidants, and the like.

Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.

Typical oral dosages range from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50mg/kg body weight per day, and more preferably from about 0.05 to about 10mg/kg body weight per day, in one or more doses, such as 1 to 3 doses. The precise dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject being treated, the nature and severity of the condition or disease being treated, any complications of the disease for which treatment is intended and other factors which will be apparent to those skilled in the art.

The formulations may desirably be presented in unit dosage form prepared by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day (e.g., 1 to 3 times per day) may contain from 0.01 to about 1000mg, such as from about 0.01 to 100mg, preferably from about 0.05 to about 500mg, and more preferably from about 0.5mg to about 200 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscular and the like, typical dosages are about half of those used for oral administration.

A general example of a formulation of the present invention is as follows:

1) tablets containing 5.0mg of a compound of the invention calculated as the free base:

compound of the invention 5.0mg

Lactose 60mg

Corn starch 30mg

Hydroxypropyl cellulose 2.4mg

Microcrystalline cellulose 19.2mg

Type A croscarmellose sodium 2.4mg

Magnesium stearate 0.84mg

2) Tablets containing 0.5mg of a compound of the invention calculated as the free base:

free base:

compound of the invention 0.5mg

Lactose 46.9mg

Corn starch 23.5mg

Polyvinylpyrrolidone 1.8mg

Microcrystalline cellulose 14.4mg

1.8mg of A-type croscarmellose sodium

Magnesium stearate 0.63mg

3) Syrup, containing per ml:

compound of the invention 25mg

Sorbitol 500mg

Hydroxypropyl cellulose 15mg

Glycerol 50mg

Nipagin methyl ester 1mg

Propyl p-hydroxybenzoate 0.1mg

0.005mL of ethanol

Edible spice 0.05mg

Saccharin sodium 0.5mg

Water to 1mL

4) The injection solution per ml contains:

compound of the invention 0.5mg

Sorbitol 5.1mg

Acetic acid 0.05mg

Saccharin sodium 0.5mg

Water to 1mL

The expression of a compound of the invention refers to any of the embodiments of formula I described herein.

In another aspect, the invention relates to a process for preparing the compounds of the invention as described below.

Process for the preparation of the compounds of the invention

Wherein R is¹、R²、R³、R⁴、R⁵And q the compounds of formula I as defined above may be prepared by the methods shown in the schemes and described below.

In the compounds of the formulae I-XX, R¹、R²、R³、R⁴、R⁵And q is as defined in formula I.

For compounds that may exist in equilibrium of two or more tautomers, only one tautomer is shown in the scheme, although it may not be the most stable tautomer. Such compounds include, but are not limited to, hydroxypyrimidines of the general formulae IX, X, XVII, XVIII, which are well known to the chemist skilled in the art.

Compounds of formulas II, III, VII, VIII, IX, X, XI, XIV, XVI, XVII, XIX and XX are either obtained from commercial sources or prepared by standard methods well known to the skilled chemist.

The compound of formula IV (scheme 1) can be obtained by reacting a compound of formula II with an amine of formula III in a suitable solvent (such as acetonitrile, N-dimethylformamide or ethanol) in a sealed vessel with or without the addition of a base (such as trialkylamine, potassium carbonate or sodium carbonate) at a suitable temperature (such as room temperature, reflux temperature or higher under microwave irradiation).

The compounds of formula V can be prepared from compounds of formula IV by reducing the nitro group to amino groups with a suitable reducing agent such as zinc or iron powder in the presence of an acid such as acetic acid or aqueous hydrochloric acid, or by reducing the nitro group to amino groups with hydrogen or ammonium formate in the presence of a suitable hydrogenation catalyst such as palladium on activated carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or tetrahydrofuran at a suitable temperature or under ultrasonic irradiation. Alternatively, tin (II) chloride or sodium dithionite may be used as the reducing agent under conditions well known to the skilled chemist.

The compounds of the invention of formula I can be prepared by: the compound of formula V is reacted with a suitable electrophile (such as, but not limited to, an appropriately substituted carboxylic acid fluoride, carboxylic acid chloride, carboxylic acid bromide, carboxylic acid iodide, carboxylic acid anhydride, activated ester, chloroformate) in a suitable solvent (such as ethyl acetate, dioxane, tetrahydrofuran, acetonitrile or diethyl ether) with or without a base (such as pyridine, trialkylamine, potassium carbonate, magnesium oxide or lithium, sodium or potassium alkoxides) under microwave irradiation in a sealed vessel. Activated esters and carboxylic anhydrides can be prepared from appropriately substituted carboxylic acids under conditions known to the skilled chemist in the art, such as, for example, f.albericio and l.a.carpino, "Coupling reagents and activation" in Methods in enzymology: solid-phase peptide synthesis, pp.104-126, Academic Press, New York, 1997. The carboxylic acid halide may be prepared from an appropriately substituted carboxylic acid by activation with a reagent such as, but not limited to, thionyl chloride, oxalyl chloride, phosphorus tribromide or phosphorus triiodide under conditions well known to those skilled in the art.

Scheme I

The compounds of formula II can be prepared as shown in scheme 2. The compounds of formula IX are prepared by the following process: the condensation of urea with a 1, 3-dicarbonyl compound VII or their equivalent (such as an unsaturated carbonyl compound VIII) in a suitable solvent (such as N, N-dimethylformamide, N-methylpyrrolidone or ethanol) is carried out in a sealed vessel under microwave irradiation at a suitable temperature (such as room temperature, reflux temperature or at higher temperatures) with or without the addition of a catalyst (such as hydrochloric acid, sulfuric acid, methanesulfonic acid or polyphosphoric acid or a lewis acid). The compounds of formula X may be prepared from compounds of formula IX by nitration reactions known to the skilled chemist, for example with concentrated nitric acid, sodium nitrite or sodium nitrate in a suitable solvent such as glacial acetic acid, acetic anhydride, trifluoroacetic acid, concentrated sulphuric acid or mixtures thereof, at a suitable temperature, for example as described in P.B.D.de la Mare and J.H.Ridd, "preparation methods of nitration" in Aromatic suspensions, pp.48-56, Butterworks Scientific Publications, London, 1959. The compounds of formula X may be converted to compounds of formula II by methods known to the skilled chemist, such as chlorination or bromination with phosphorus oxychloride or phosphorus tribromooxide. Compounds of formula II wherein X is fluorine or iodine can be prepared from compounds of formula II wherein X is chlorine or bromine by halogen exchange reaction with appropriate reagents (such as hydroiodic acid, hydrofluoric acid, sodium iodide, potassium fluoride) under conditions known to the skilled chemist.

Scheme II

Compounds of formula XII and XV (scheme 3) may be prepared from suitably substituted guanidines of formula XI by condensation with 1, 3-dicarbonyl compounds or their equivalent unsaturated carbonyl compounds of formula VII, VIII (where LG is a suitable leaving group such as alkoxy or dialkylamino) or XIV under the conditions described for the preparation of compounds of formula IX in scheme 2. Compounds of formula XII may be converted to compounds of formula XV by diazo coupling reactions well known to chemists of ordinary skill in the art. Alternatively, the compound of formula XV can be nitrated as described in scheme 2 for the preparation of the compound of formula X. Compounds of formula V can be prepared from compounds of formula XIII or XV, respectively, by reduction of the nitro or diazo group to an amino group under the conditions described above for the preparation of compounds of formula V in scheme 1.

Scheme 3

In particular, the condensation reaction of a substituted guanidine of formula XI with a keto ester or keto acid of formula XVI (scheme 4) under the conditions described in scheme 3 above can result in the formation of a compound of formula XVII, which can be nitrated under the conditions described above to provide a compound of formula XVIII. The hydroxy group in XVIII can be converted to a compound of formula XX (wherein R is R) by performing the halogenation reaction under the conditions described above for the preparation of a compound of formula II⁴XIII as halogen). Alternatively, compounds of formula XX (wherein R is⁴XIII as halogen) may be prepared from compounds of formula XIX (wherein R is⁴XIII, which is an amino group), followed by diazotization and subsequent nucleophilic substitution in the presence of an appropriate halide anion under conditions well known to the skilled chemist. Compounds of the formula XIII, in which R⁴Is C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, halogen-C_1-6-alk (en/yn) yl, halogen-C_3-8Cycloalkyl (en) yl or halogen-C_3-8-cycloalkyl (en) yl-C_1-6An alk (en/yn) yl group, which may be represented by the general formula XX (wherein R is⁴XIII, which is a halogen) is prepared by cross-coupling reactions known to the skilled chemist in the art, such as Negishi couplings (e. -i. Negishi, a.o.king and n.okukado, j.org.chem., 1977, 42, 1821), Sonogashira couplings (k.sonogashira, y.tohda and n.hagihaa, tet.lett., 1975, 16, 4467), or other transition metal catalyzed cross-coupling reactions, such as copper catalyzed reactions (w.dohle, d.m.lindsay and p.knochel, org.lett., 2001, 3, 2871).

In addition, wherein R⁴Compounds of formula XIII which are cyano groups may be prepared from compounds of formula XX (wherein R is⁴XIII, which is halogen) is prepared by nickel-catalyzed cyanation reactions known to the skilled chemist in the art, as described, for example, in l.cassar, j.organometc. chem., 1973, 54, C57-C58.

Further, wherein R⁴Is C_1-6-alk (en/yn) yloxy, C_3-8A cycloalk (en) yloxy group or C_3-8-cycloalkyl (en) yl-C_1-6The compound of formula XIII with an (alk/alkynyl) oxy group may be prepared from a compound of formula XX (wherein R is⁴XIII, which is a halogen) by reaction with an appropriate lithium, sodium or potassium alkoxide or alcohol in the presence of a base such as lithium, sodium or potassium hydroxide, lithium, sodium or potassium hydride, with or without a catalyst such as copper sulfate, in a suitable solvent such as dioxane, at a suitable temperature such as room temperature or reflux temperature.

Scheme 4

Alkynes prepared by Sonogashira reactions can be reduced to alkenes or alkanes by reduction with hydrogen or ammonium formate in the presence of a suitable hydrogenation catalyst (such as palladium on activated carbon or platinum on activated carbon) in a suitable solvent (such as methanol, ethanol or tetrahydrofuran) at a suitable temperature, for example as described in s.siegel, "heterologous catalytic hydrogenation of C ═ C and alkines" comprehensive Organic Synthesis, v.8, pp.417-442, permamon Press, 1991.

Preparation of the Compounds of the invention

Examples

Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with atmospheric pressure photoionization and Shimadzu LC-8A/SLC-10A LC system. Column: 30X4.6mm Waters Symmetry C18 column, 3.5 μm particle size; solvent system: a ═ water/trifluoroacetic acid (100: 0.05) and B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); the method comprises the following steps: elution was with a linear gradient from 90% A to 100% B over 4 minutes and a flow rate of 2 mL/min. Retention time (t)_R) Expressed in minutes.

¹H NMR spectra were recorded at 500.13MHz on a Bruker Avance DRX500 instrument. Deuterated dimethylsulfoxide (99.8% D) was used as solvent. Tetramethylsilane was used as an internal reference standard. Chemical shift values are expressed in ppm relative to tetramethylsilane. The following abbreviations are used for the multiplicity of NMR signals: s is singlet, d is doublet, t is triplet, q is quartet, qui is quintet, h is heptat, dd is doublet, ddd is doublet, dt is doublet, dq is doublet, tt is triplet, m is multiplet and br is broad singlet.

Microwave testing was performed in a sealed process vial or reactor using an Emrys Synthesizer or Emrys Optimizer EXP from Personal chemistry or a Milestone Microsynth instrument from Milestone. When the reaction is heated in the microwave instrument, it is cooled to 25 ℃ before the next process step.

Preparation of intermediates

6-methyl-5-nitro-N x 2- (4-trifluoromethylbenzyl) -pyrimidine-2, 4-diamine

A mixture of 2-chloro-6-methyl-5-nitropyrimidin-4-ylamine (300mg, 1.591mmol), 4-trifluoromethylbenzylamine (369mg, 2.107mmol) in acetonitrile (3ml) and triethylamine (0.5ml) was flushed with argon, sealed in an Emrys process vial and heated under microwave radiation at 120 ℃ for 2 minutes. The resulting suspension was quenched with 10% aqueous sodium carbonate (2ml) and the organic volatiles were evaporated under reduced pressure. Methanol (5ml) and water (100ml) were added to the resulting residue. The product was isolated by filtration, washed with water and dried in vacuo to give 490mg of a yellow solid. The yield was 94%. LC-MS (m/z)328.1 (MH)⁺)；t_R＝2.58.¹H NMR(500MHz，DMSO-d₆): an approximately 3: 1 mixture of two rotamers, 2.54(s, 3H), 4.57(d, 1.5H), 4.63(d, 0.5H), 7.52(t, 2H), 7.68(d, 2H), 7.81(s, 0.5H, NH2), 8.0(s, 1.5H, NH2), 8.17(t, 0.25H, NH), 8.48(t, 0.75H, NH).

6-methyl-N x 2- (4-trifluoromethylbenzyl) -pyrimidine-2, 4, 5-triamine.

To a vigorously stirred solution of 6-methyl-5-nitro-N2- (4-trifluoromethylbenzyl) -pyrimidine-2, 4-diamine (450mg, 1.376mmol) in tetrahydrofuran (20ml) and acetic acid (5ml) on a cold water bath was added zinc powder (particle size < 10 μm, 5g) in portions over a period of 2 minutes. The water bath was removed and more zinc dust (2g) was added. The resulting suspension was stirred at ambient temperature for 60 minutes and quenched with 10% aqueous sodium carbonate to pH > 8. The obtained suspension was extracted with ethyl acetate (1)0 times). The combined organic solutions were filtered through a silica gel plug (10g) and eluted with 20% ethyl acetate to give 430mg of a pale yellow oil after evaporation. After drying in vacuo, the product was cured. The yield was 100%. It was used in the next step without further purification. LC-MS (m/z)298.1 (MH)⁺)；t_R＝1.68.¹H NMR(500MHz，DMSO-d₆)：2.02(s，3H)，3.1-3.8(br，NH₂+H₂O)，4.43(d，2H)，5.88(br，2H)，6.26(t，1H，NH)，7.48(d，2H)，7.62(d，2H).

3-chlorophenyl acetyl chloride.

3-Chlorophenylacetic acid (19.7g) in thionyl chloride (100ml) was heated under reflux for 3 hours. The volatiles were removed in vacuo and the resulting oily residue was used in the next step without further purification.¹H NMR(500MHz，CDCl₃)：4.12(s，2H)，7.16(d，1H)，7.27-7.34(m，3H).

The following acid chlorides were prepared analogously from the corresponding acids:

3, 4-difluorophenylacetyl chloride.

¹H NMR(500MHz，CDCl₃)：4.10(s，2H)，7.0(m，1H)，7.11(ddd，1H)，7.17(dt，1H).

3-fluorophenylacetyl chloride.

The title compound was used in the next step without characterization.

4- (4, 6-dimethyl-pyrimidin-2-yl) -morpholine.

To a suspension of morpholinylformamidine hydrobromide (2.0g, 9.52mmol) in ethanol (6ml) was added potassium tert-butoxide (1.068g, 9.52mmol) followed by acetylacetone (2ml, 20 mmol). The above reaction mixtureThe composition was flushed with argon, sealed in an Emrys process vial and heated under microwave radiation at 140 ℃ for 5 minutes. After cooling, quench with ethyl acetate (50ml) over SiO₂The plug (5g) was filtered and eluted with ethyl acetate. The volatiles were removed in vacuo at 70 ℃ to afford 1.65g of a light brown oil which solidified overnight. The yield was 90%. LC-MS (m/z)193.9 (MH)⁺)；t_R＝0.71.¹H NMR(500MHz，DMSO-d₆)：2.23(s，6H)，3.62(m，4H)，3.67(m，4H)，6.44(s，1H).

4- (4, 6-dimethyl-5-nitro-pyrimidin-2-yl) -morpholine

Method A. To a stirred solution of 4- (4, 6-dimethylpyrimidin-2-yl) -morpholine (8.94g, 46.3mmol) in glacial acetic acid (50ml) was added dropwise fuming nitric acid (5.75ml, 3 equivalents). The reaction mixture was heated at 70 ℃ for 15 minutes and then more nitric acid (3.8ml, 2 equivalents) was added to it. After an additional 15 minutes of heating at 70 ℃, it was cooled and poured in portions into a mixture of ice and sodium hydroxide (44g) in water (200 ml). The product was isolated by filtration to provide 0.637g of a yellow solid. The yield was 6%. LC-MS (m/z)239.0 (MH)⁺)；t_R＝2.76.

Method B. To a warm (65 ℃) stirred solution of 4- (4, 6-dimethylpyrimidin-2-yl) -morpholine (4g, 20.7mmol) in trifluoroacetic acid (100ml) was added sodium nitrate (3.52g, 41.4 mmol). After 3 hours, more sodium nitrate (1.8g, 20.7mmol) was added and the reaction mixture was kept at 65 ℃ overnight. It was carefully poured in portions into 10% aqueous sodium carbonate solution (600ml), and the product was isolated by filtration. Yield 1.637g, 33%. LC-MS (m/z)238.9 (MH)⁺)；t_R＝2.70.¹H NMR(500MHz，DMSO-d₆)：2.44(s，6H)，3.65(m，4H)，3.83(m，4H).

4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-ylamine.

A suspension of 4- (4, 6-dimethyl-5-nitropyrimidin-2-yl) -morpholine (2.2g, 9.23mmol), 5% palladium on activated carbon (50% wet, 1.09g), ammonium formate (8.76g) was sealed in an Emrys process vial and heated at 150 ℃ under microwave radiation for 2 minutes. The resulting reaction mixture was filtered and evaporated. The resulting residue was treated with ethyl acetate and filtered to give 1.62g of orange crystalline product after evaporation in vacuo. The yield was 84%. LC-MS (m/z)208.9 (MH)⁺)；t_R＝0.44.¹H NMR(500MHz，DMSO-d₆)：2.2(s，6H)，3.44(m，4H)，3.62(m，4H)，4.19(br，2H，NH₂).

Compounds of the invention

Acid addition salts of the compounds of the present invention may be readily formed by methods known to those skilled in the art.

Example 1

1a N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2-cyclopentylacetamide.

To a cooled (ice/water bath) stirred solution of 6-methyl-N2- (4-trifluoromethyl-benzyl) -pyrimidine-2, 4, 5-triamine (119mg, 0.401mmol) in acetonitrile (3ml) was added dropwise cyclopentylacetyl chloride (59mg, 0.402mmol) over a period of 2 minutes. The cooling bath was removed and stirring was continued for 20 minutes. The resulting suspension was quenched with water (85ml) and 10% aqueous sodium carbonate (0.5 ml). Under reduced pressureOrganic volatiles were removed, ethyl acetate (0.5ml) was added and the mixture was quenched with heptane (20 ml). The biphasic suspension obtained was filtered. The resulting product was washed with water and heptane and dried in vacuo to give 40mg of a pale yellow solid. The yield was 25%. LC-MS (m/z)408.3 (MH)⁺)；t_R＝2.11.¹H NMR(500MHz，DMSO-d₆)：1.17(m，2H)，1.50(m，2H)，1.59(m，2H)，1.74(m，2H)，1.93(s，3H)，2.2(m，1H)，2.25(d，2H)，4.5(d，2H)，5.96(br，2H，NH₂)，6.96(br，1H，NH)，7.5(d，2H)，7.64(d，2H)，8.57(s，1H，NHCO).

1b N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -3, 3-dimethylbutanamide.

To a cooled (ice/water bath) stirred solution of 6-methyl-N x 2- (4-trifluoromethyl-benzyl) -pyrimidine-2, 4, 5-triamine (341mg, 1.15mmol) in acetonitrile (7.5ml) was added dropwise tert-butylacetyl chloride (0.16ml, 1.15mmol) over a period of 2 minutes. The cooling bath was removed and stirring was continued for 45 minutes. The reaction mixture obtained was poured onto a column (10g, H)⁺Form), washing with acetonitrile (20ml), methanol (100ml), and product with 4M NH₃Was eluted with a methanol (60ml) solution. The volatiles were removed in vacuo and the resulting crude product was purified by flash chromatography on silica gel (20g) with a gradient of heptane-ethyl acetate to give 153mg of solid. The yield was 33.7%. LC-MS (m/z)395.9 (MH)⁺)；t_R＝2.00.¹H NMR(500MHz，DMSO-d₆)：1.02(s，9H)，1.96(s，3H)，2.15(s，2H)，4.5(d，2H)，5.9(br，2H，NH₂)，6.97(br，1H，NH)，7.5(d，2H)，7.65(d，2H)，8.57(s，1H，NHCO).

The following compounds were prepared analogously using the corresponding acid chlorides:

1c N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2- (4-fluorophenyl) -acetamide.

Yield 12%. LC-MS (m/z)434.3 (MH)⁺)；t_R＝2.07.¹H NMR(500MHz，DMSO-d₆)：1.81(s，3H)，3.57(d，2H)，4.49(d，2H)，6.08(br，2H，NH₂)，6.96(br，1H，NH)，7.13(t，2H)，7.36(dd，2H)，7.49(d，2H)，7.64(d，2H)，8.83(s，1H，NHCO).

1d hexanoic acid [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -amide.

Yield 39.7mg, 50%. LC-MS (m/z)396.1 (MH)⁺)；t_R＝2.08.¹H NMR(500MHz，DMSO-d₆)：0.87(t，3H)，1.28(m，4H)，1.56(qui，2H)，1.91(s，3H)，2.24(t，2H)，4.49(d，2H)，5.98(br，2H，NH₂)，6.95(br，1H，NH)，7.5(d，2H)，7.65(d，2H)，8.55(s，1H，NHCO).

1e N- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2- (3-chlorophenyl) -acetamide.

Yield 45.4mg, 50%. LC-MS (m/z)450.1 (MH)⁺)；t_R＝2.17.¹H NMR(500MHz，DMSO-d₆)：1.82(s，3H)，3.61(s，2H)，4.49(d，2H)，6.12(br，2H，NH₂)，6.97(br，1H，NH)，7.3(m，2H)，7.35(t，1H)，7.41(s，1H)，7.49(d，2H)，7.64(d，2H)，8.87(s，1H，NHCO).

Example 2

2a 2-cyclopentyl-N- (4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -acetamide.

To a cooled (ice/water bath) stirred solution of 4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-ylamine (2.04g, 9.79mmol) in acetonitrile (40ml) was added cyclopentylacetyl chloride (1.65ml, 11.75 mmol). The cold bath was removed and the resulting reaction mixture was stirred at room temperature for 30 min. It was poured into a saturated aqueous sodium bicarbonate solution (100ml) and water, and it was filtered. The obtained solid was recrystallized in acetonitrile to give 1.877g of a colorless solid. The yield was 60%. LC-MS (m/z)318.9 (MH)⁺)；t_R＝1.80.¹H NMR (500MHz，DMSO-d₆)：1.21(m，2H)，1.52(m，2H)，1.61(m，2H)，1.76(m，2H)，2.15(s，6H)，2.25(m，1H)，2.28(d，2H)，3.63(m，4H)，3.65(m，4H).

2b N- (4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -3, 3-dimethylbutanamide.

To a solution of 4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-ylamine (2.1g, 10.4mmol) in acetonitrile (30ml) and triethylamine (2.9ml, 20.8mmol) was added tert-butylacetyl chloride (2.9ml, 20.8mmol) dropwise. After 90 minutes, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The resulting organic phase was washed with saturated aqueous sodium bicarbonate (100ml)Dried over magnesium sulfate and in SiO₂(20g, gradient heptane-ethyl acetate) by flash chromatography. The crude product obtained was recrystallized from hot toluene to provide 946mg of a colorless solid. The yield was 30%. LC-MS (m/z)307.9 (MH)⁺)；t_R＝1.69.¹H NMR(500MHz，DMSO-d₆)：1.04(s，9H)，2.16(s，6H)，2.19(s，2H)，3.64(m，8H)，9.13(s，1H).

The following compounds were prepared analogously from the corresponding acid chlorides:

2c N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (4-fluorophenyl) -acetamide

After purification by flash chromatography, the title compound was recrystallized from hot ethyl acetate. Yield 1.193g, 37%. LC-MS (m/z)345.1 (MH)⁺)；t_R＝1.81.¹H NMR(500MHz，DMSO-d₆): 2.09(s, 6H), 3.6-3.66 (overlap m, 10H), 7.16(t, 2H), 7.38(dd, 2H), 9.42(s, 1H).

2d 2- (3, 4-difluorophenyl) -N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -acetamide.

To a cooled (ice/water bath) stirred solution of 4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-ylamine (52.4mg, 0.25mmol) in acetonitrile (1ml) was added 3, 4-difluorophenylacetyl chloride (0.065ml, 0.3 mmol). The reaction mixture was held at 60 ℃ for 1 minute and allowed to cool. It was poured onto an SCX-column (10g, H)⁺-form), washing with acetonitrile and methanol and with 4M NH₃Eluted with methanol solution. After evaporation, coarseThe product was precipitated from a concentrated solution of ethyl acetate with heptane and filtered to give 34mg of a colorless solid. The yield was 37%. LC-MS (m/z)363.3 (MH)⁺)；t_R＝1.96.¹H NMR(500MHz，DMSO-d₆)：2.09(s，6H)，3.63(m，10H)，7.19(m，1H)，7.38(m，1H)，7.41(m，1H)，9.43(s，1H).

The following compounds were prepared analogously using the appropriate acid chlorides:

2e N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (3-fluorophenyl) -acetamide.

The title compound is in SiO₂(20g, gradient heptane-ethyl acetate) by flash chromatography. Yield 27mg, 31%. LC-MS (m/z)345.0 (MH)⁺)；t_R＝1.83.¹HNMR(500MHz，DMSO-d₆): 2.09(s, 6H), 3.62(m, 4H), 3.64(m, 4H), 3.66(s, 2H), 7.08(dt, 1H), 7.18 (overlap dd, 1H), 7.19 (overlap d, 1H), 7.38(dt, 1H), 9.45(s, 1H).

2f hexanoic acid (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -amide

The title compound is in SiO₂(20g, gradient heptane-ethyl acetate) by flash chromatography. Yield 49mg, 64%. LC-MS (m/z)307.2 (MH)⁺)；t_R＝1.84.¹HNMR(500MHz，DMSO-d₆)：0.88(t，3H)，1.31(m，4H)，1.60(qui，2H)，2.14(s，6H)，2.28(t，2H)，3.63(m，4H)，3.65(m，4H)，9.16(s，1H).

Table 1. Reagents for the preparation of compounds.

In vitro and in vivo assays

The compounds of the invention have been tested and show effects in one or more of the following models:

relative flow through KCNQ2 channel

This illustrates a KCNQ2 screening protocol for the evaluation of the compounds of the invention. This assay measures the relative flux through the KCNQ2 channel and was performed as described for the hERG potassium channel by Tang et al (Tang, W. et al, J.Biomol.Screen.2001, 6, 325-331) with the modifications described below.

A sufficient number of CHO cells stably expressing the voltage-gated KCNQ2 channel were placed on the plate at a density sufficient to obtain a single confluent layer on the day of the experiment. One day before the test, the cells were seeded and the concentration of the seed was 1. mu. Ci/ml⁸⁶Rb]Load overnight. On the day of the assay, cells were washed with HBSS-containing buffer. The cells were pre-incubated with the drug for 30 minutes and in the continued presence of the drug, the cells were pre-incubated by a sub-maximal concentration of 15mM KCl⁸⁶Rb + flux was stimulated for an additional 30 minutes. After a suitable incubation period, the supernatant was removed and counted on a liquid scintillation counter (Tricarb). The cells were lysed with 2mM NaOH and washed⁸⁶The amount of Rb + was counted. The relative flow is calculated as ((CPM)_super/(CPM_super+CPM_cell))C_mpd/(CPM_super/(CPM_super+CPM_cell))_{15mM KCl})*100-100。

The compounds of the invention have an EC of less than 20000nM₅₀In most cases less than 2000nM and in most cases less than 200 nM. Accordingly, the compounds of the present invention are considered to be useful for diseases associated with KCNQ family potassium channelsIn the treatment of the disease.

Electrophysiology patch-splint recording

In the whole-cell patch-splint configuration, voltage-activated KCNQ2 currents of mammalian CHO cells were recorded by using conventional patch-splint recording techniques (Hamill OP et al, Pfl ü gers Arch 1981; 391: 85-100). Stably expressing CHO cells of voltage-activated KCNQ2 channel in CO₂Growth was performed under standard cell culture conditions in a bacterial incubator and used for electrophysiological recording for 1-7 days after plating. KCNQ2 potassium channel was activated by stepping up the voltage from a membrane fixed potential of-100 mV to-40 mV to +80mV at 5-20mV (or in a ramp rate protocol) (Tatulian L et al, J Neuroscience 2001; 21 (15): 5535-. Electrophysiological effects induced by the compounds were evaluated based on various parameters of voltage-activated KCNQ2 current. In particular, the activation limit of the current and the influence on the maximum induced current were investigated.

Some of the compounds of the invention, acetonitrile, were tested in this test. A shift to the left of the activation limit or an increase in maximum induced potassium current is expected to decrease the activity of the neuronal network and thereby make the compounds useful in epileptic diseases with an increased trait of neuronal activity.

Maximum electric shock

The test was performed in a group of male mice, using corneal electrodes and applying a square wave current of 26mA for 0.4 sec (Wlaz et al, Epilepsy research 1998, 30, 219-.

Pilocarpine-induced seizures

Pilocarpine-induced seizures were induced by intraperitoneal injection of 250mg/kg of pilocarpine into male mouse groups, and seizure activity leading to a loss of state within a period of 30 minutes was observed (Starr et al, Pharmacology Biochemistry and Behavior 1993, 45, 321-325).

Electroepileptic seizure-threshold determination

The median limit of hindlimb extension in response to corneal shock-induced enhancement in the male mouse group was determined using a variation of the rolling method (Kimball et al, Radiation Research 1957, 1-12). The first mouse in each group received a 14mA shock (0.4s, 50Hz) and observed for seizure activity. If a seizure was observed, the current was reduced by 1mA for the next mouse, however, if no seizure was observed, the current was increased by 1 mA. This method was repeated for all 15 mice in the treatment group.

Chemical seizure-limiting value determination

The limiting value of pentyltetrazole required to induce clonic convulsions was measured by timed infusion (5mg/mL, 0.5 mL/min) of pentyltetrazole into the lateral tail vein of a male rat group (Nutt et al, J Pharmacy and Pharmacology 1986, 38, 697-698).

Excessive internal heat of tonsil

The rats were operated so that the tripolar electrodes were implanted into the dorsolateral tonsils. Following surgery, animals were allowed to recover from surgery before the rat group received either different doses of test compound or drug carrier. Animals were challenged with their initial post-release limit of +25 μ Α/day for 3-5 weeks, indicating the severity of each occurrence of seizures, the duration of the seizures and the duration of power after release (racine. electrotechnical and clinical neurology 1972, 32, 281- "294").

Side effects

Central nervous system side effects were measured by measuring the time the mouse remained on the rotating device (Capacio et al, Drug and Chemical Toxicology 1992, 15, 177-; or by counting the number of infrared beams that pass through the test cage to measure their locomotor activity (Watson et al, Neuropharmacology 1997, 36, 1369-. The hypothermic effect of compounds on the core temperature of animals was measured either by rectal probes or by implanted radiotelemetry transmitters capable of measuring temperature (Keeney et al, Physiologyand Behaviouur 2001, 74, 177-184).

Pharmacokinetics

The pharmacokinetic performance of the compounds was determined by i.v. and p.o. dosing to Spraque Dawley rats and then drawing blood samples over a 20 hour period. Plasma concentrations were determined by LC/MS/MS.

Claims (22)

1. A compound having the general formula I:

wherein: q is 0 or 1;

R¹and R²Independently selected from hydrogen and optionally substituted aryl-C_1-6-alk (en/yn) yl, with the proviso that R¹And R²Not all being hydrogen, or R¹And R²With themThe attached nitrogens join to form a 5-7 membered ring optionally containing an additional heteroatom;

R³and R⁴Independently selected from hydrogen, halogen, cyano, amino, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, halogen-C_1-6-alk (en/yn) yl, halogen-C_3-8Cycloalkyl (en) yl, C_1-6-alk (en/yn) yloxy, C_3-8Cycloalk (en) yloxy, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yloxy, halogen-C_1-6-alk (en/yn) yloxy, halogen-C_3-8Cycloalk (en) yloxy and halogen-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yloxy, with the proviso that R³And R⁴Not all are hydrogen;

R⁵is selected from C_1-10-alk (en/yn) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, optionally substituted aryl-C_1-6-an alk (en/yn) yl group and an optionally substituted aryl group;

as the free base or a salt thereof.

2. A compound according to claim 1 wherein q is 0.

3. A compound according to claim 1 wherein q is 1.

4. A compound according to any one of claims 1-3, wherein R¹And R²Independently selected from hydrogen and optionally substituted aryl C_1-6-alk (en/yn) yl, with the proviso that R¹And R²Not all are hydrogen.

5. A compound according to any one of claims 1-3, wherein R¹And R²Together with the nitrogen to which they are attached form a 5-7 membered ring optionally containing additional heteroatoms.

6. A compound according to claim 5, wherein the further heteroatom is oxygen.

7. A compound according to any one of claims 5 and 6, wherein the ring is a 6-membered ring.

8. A compound according to any one of claims 5 to 7, wherein the ring is a morpholine ring.

9. A compound according to any one of claims 1-8, wherein R³And R⁴Independently selected from amino and C_1-6-alk (en/yn) yl, preferably methyl.

10. A compound according to any one of claims 1-9, wherein R⁵Is selected from C_1-10-alk (en/yn) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, optionally substituted aryl-C_1-6-an alk (en/yn) yl group and an optionally substituted aryl group.

11. A compound according to any one of claims 1 to 10, selected from:

n- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2-cyclopentylacetamide,

n- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -3, 3-dimethylbutanamide,

n- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2- (4-fluorophenyl) -acetamide,

hexanoic acid [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -amide,

n- [ 4-amino-6-methyl-2- (4-trifluoromethylbenzylamino) -pyrimidin-5-yl ] -2- (3-chlorophenyl) -acetamide,

2-cyclopentyl-N- (4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -acetamide,

n- (4, 6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -3, 3-dimethylbutanamide,

n- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (4-fluorophenyl) -acetamide,

2- (3, 4-difluorophenyl) -N- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -acetamide,

n- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (3-fluorophenyl) -acetamide and

hexanoic acid (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -amide;

as a free base or salt thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11 together with one or more pharmaceutically acceptable carriers or diluents.

13. Use of a pharmaceutical composition according to claim 12 for increasing the ion current in potassium channels of a mammal, such as a human.

14. Use according to claim 13 for the treatment of a condition or disease responsive to increased ion flow in potassium channels, preferably a condition or disease of the central nervous system.

15. Use according to claim 14, wherein the condition or disease intended for treatment is selected from seizure disorders, anxiety disorders, neuropathic pain and migraine pain disorders, other pain disorders, such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal, alcohol withdrawal and hearing disorders, such as tinnitus.

16. Use according to claim 15, wherein the seizure disorder is selected from the group consisting of acute seizures, convulsions, status epilepticus and epilepsy, such as epileptic syndrome and epileptic seizure epilepsy.

17. Use according to claim 15, wherein the anxiety disorder is selected from anxiety and disorders and diseases associated with panic destruction, agoraphobia, panic disorders with agoraphobia, panic disorders without agoraphobia, agoraphobia without history of panic disorders, specific phobias, social phobias and other specific phobias, obsessive-compulsive disorders, post-traumatic stress disorders, acute stress disorders, generalized anxiety disorders, anxiety disorders due to general medical conditions, substance-induced anxiety disorders, separation anxiety disorders, adjustment disorders, executive anxiety disorders, melancholia, anxiety disorders due to general medical conditions and substance-induced anxiety disorders, and anxiety disorders not explicitly specified.

18. Use according to claim 15, wherein the neuropathic pain and migraine pain conditions are selected from hyperalgesia, hyperalgesia pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia and neuropathic pain associated with migraine.

19. Use according to claim 15, wherein the neurodegenerative disorder is selected from the group consisting of alzheimer's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, parkinson's disease, encephalopathy induced by AIDS or infections produced by rubella virus, herpes virus, borrelia and unknown pathogens, trauma-induced neurodegeneration, neuronal hyperexcitability states such as those produced in drug withdrawal or intoxication, and neurodegenerative diseases of the peripheral nervous system such as multiple neuropathy and polyneuritis.

20. Use according to claim 14, wherein the condition or disease intended for treatment is selected from bipolar disorder and attention deficit hyperactivity disorder.

21. Use according to claim 14, wherein the condition or disease to be treated is selected from the group consisting of sleep disorders; such as insomnia.

22. Use according to claim 13 for the treatment of a disorder or disease responsive to increased ion flow in potassium channels, said disorder or disease intended for treatment being selected from fibrosarcoma, motor myopathy or movement disorder, spasticity, myokyphosis and urinary incontinence.