BRPI0615631A2 - compound, pharmaceutical composition, and use of a pharmaceutical composition - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A PHARMACEUTICAL COMPOSITION The present invention relates to the pyrimidine derivatives of the general formula 1 or their salts and their use as openers of the KNCQ family potassium ion channels, particularly in the treatment of epilepsy.

Description

"COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A PHARMACEUTICALPOSAL"

FIELD OF INVENTION

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

BACKGROUND OF THE INVENTION

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

Humans have over 70 potassium channel subtype coding genes (Jentsch, Nature Reviews Neuroscience 2000, 1, 21-30) with a wide diversity with respect to both structure and function. Neuronal potassium channels, which are found in the brain, are primarily responsible for maintaining a membrane potential in negative home as well as controlling membrane repolarization after an action potential.

A subset of potassium channel genes is the KCNQ family. Mutations in four of five of the KCNQ genes have been shown to be responsible for diseases including cardiac arrhythmias, deafness and epilepsy (Jentsch, Nature Reviews Neuroscience 2000, 1, 21-30).

It is considered that the KCNQ4 gene encodes the molecular correlate of a potassium channel found in decochlear external hair cells and vestibular Type I hair cells, in which mutations may lead to a form of hereditary deafness.

KCNQ1 (KvLQTl) is co-assembled with the gene product KCNEl (minimal K (+) potassium channel protein) in the heart to form a K (+) current similar to a delayed cardiac rectifier. Mutations in this channel can cause a form of type 1 long QT syndrome (LQT1) as well as being associated with a form of deafness (Robbins, Pharmacol. Ther. 2001, 90, H9).

The KCNQ2 and KCNQ3 genes were discovered in 1988 and appear to be mutated in a hereditary form of known epilepsy as benign familial neonatal seizures (Rogawski, Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are located in the hippocampal pyramidal neurons of the human cortex, brain regions associated with seizure generation and propagation. (Cooper et al. Proeeedings National Aeademy of Science USA 2000, 97, 4914-4919).

KCNQ2 and KCNQ3 are two potassium channel subunits that form "M-currents" when expressed in vitro. M-current is a non-inactivating potassium current found in many types of celluluronal cells. In each cell type, it is dominant in controlling membrane excitation because it is the only current maintained at the initiation of action potential (Marrion, Annual Review Physiology 1997,59, 483-5-04). M-current modulation has dramatic effects on neuronal excitation, for example current activation will reduce excitation. Openers of these KCNQ channels, or M-current activators, will reduce excessive neuronal activity and thus may be used to treat seizures and other diseases and disorders characterized by excessive neuronal activity, such as neuronal hypersensitivity including seizure disorders, epilepsy and neuropathic pain.

Retigabine (D-23129; N- (2-Amino-4- (4-fluoro-benzyl-amino) -phenyl) -carbamic acid ethyl ester) and analogues thereof are described in EP554543. Retigabine is an anticonvulsant compound with a broad spectrum and potent anticonvulsant properties, both in vitro and in vitro. It is active following oral and intraperitoneal administration in mice and rats in a variety of anticonvulsant tests including: electrically induced seizures; chemically induced seizures by pententylene tetrazole, picrotoxin and N-methyl-D-aspartate (NMDA) and in a genetic animal model, the DBA / 2 mouse (Rostock et al. Epilepsy Research 1996, 23, 211-223). In addition, retigabine is active in the amygdeal deignition model of complex partial seizures, further indicating that this compound has potential for anticonvulsive therapy. In clinical trials, retigabine has recently been shown to be effective in reducing the incidence of seizures in epileptic patients (Bialer et al. Epilepsy Research 2002, 51, 31-71).

Retigabine has been shown to activate a K (+) current in neuronal cells and the pharmacology of this induced current exhibits agreement with the published M-channel pharmacology, which has recently been correlated with KCNQ2 / 3 K (+) channel heteromultimer. This suggests that KCNQ2 / 3 channel activation may be responsible for some anticonvulsant activity of this agent (Wickenden et al. Molecular Pharmacology2000, 58, 591-600) and that other agents functioning by the same mechanism may have similar uses.

KCNQ channels 2 and 3 have also been reported to be up-regulated in neuropathic pain models (Wickenden et al. Society forNeuroscience Abstracts 2002,454.7), and have been hypothesized to be active in both neuropathic pain and epilepsy (Schroder et al. al. Neuropharmacology 2001, 40, 888-898).

Retigabine has also been shown to be beneficial in animal models of neuropathic pain (Blackburn-Munro and Jensen, European Journal of Pharmacology 2003, 460, 109-116), and thus it is suggested that KCNQ channel openers will be used in the treatment of dorneuropathic disorders.

Localization of KCNQ channel mRNA is reported in the brain and in other areas of the central nervous system associated with pain (Goldstein et al. Society for Neuroscienee Abstracts 2003, 53.8).

In addition to a role in neuropathic pain, the demRNA expression for KCNQ 2-5 in the dorsal and trigeminal root ganglia and trigeminal nucleus implies that the openers of these channels can also affect sensory processing of migraine pain (Goldstein et al. Soeietyfor Neuroscience Abstraets 2003, 53.8).

Recent reports demonstrate that mRNA for KCNQ 3 and 5, in addition to that for KCNQ2, are expressed in astrocytes and glial cells. Thus KCNQ channels 2, 3 and 5 can help modulate CNS synaptic activity and contribute to the neuroprotective effects of openers. of channel KCNQ (Voda et al., Soeiety for Neuroscience and Abstracts 2003, 53.9).

Retigabine and other KCNQ modulators may thus exhibit protection against neurodegenerative aspects of epilepsy, because retigabine has been shown to prevent limbic neurodegeneration and apoptosis marker expression following rat-induced kapic acid-induced epileptic status (Ebert et al. Epilepsy 2002,43 Suppl 5 86-95). This may have relevance in preventing the progression of epilepsy in patients, i.e. being antiepileptogenic. Retigabine has also been shown to retard the progression of hippocampal ignition in the rat, another developmental model of epilepsy (Tober et al. European Journal of Pharmaeology 1996, 303, 163-169).

Thus it is suggested that these properties of retigabine and other KCNQ modulators may prevent neuronal damage induced by excessive neuronal activation, and such compounds may be used to treat neurodegenerative diseases, and be disease modifying (or antiepileptogenic) in patients with epilepsy. Anticonvulsants such as benzodiazepines and chlormetiazole are clinically used in the treatment of ethanol withdrawal syndrome and that other anticonvulsivose compounds.g. gabapentin are very effective in animal models of this syndrome (Watson et al. Neuropharmacology 1997, 36, 1369-1375), other anticonvulsant compounds such as KCNQ openers and are thus expected to be effective in this condition.

mRNA for KCNQ 2 and 3 subunits are found in brain regions associated with anxiety and emotional behaviors such as bipolar disorder and hippocampus and amygdala (Saganich et al. Journalof Neuroscience 2001, 21, 4609-4624), and retigabine is reportedly active in some animal models. anxiety-like behavior (Hartz et al. Journal of Psychopharmacology 2003, 17 suppl. 3, A28, B16), and other anticonvulsant compounds clinically used to treat bipolar disorder. Thus, KCNQ openers may be useful for the treatment of anxiety and bipolar disorder.

WO 200196540 describes the use of M-stream modulators by expressing KCNQ2 and KCNQ3 genes for insomnia, whereas WO 2001092526 describes that KCNQ5 modulators may be used for the treatment of sleep disorders.

WO01 / 022953 describes the use of retigabine for prophylaxis and treatment of neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, diabetic neuropathy-related neuropathic pain and migraine-related dorneuropathic pain.

WO02 / 049628 describes the use of retigabine for the treatment of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, phobiasocial, performance anxiety, posttraumatic stress disorder, acute stress reaction, adjustment disorders , hypochondriac disorders, separation anxiety disorder, agoraphobia and specific phobias.

WO97 / 15300 describes the use of retigabine for the treatment of neurodegenerative disorders such as Alzheimer's disease; Huntington's Korea; sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis; Creutzfeld-Jakob disease; Parkinson's disease; encephalopathies induced by AIDS or rubella virus infection, herpes virus, borrelia and known pathogens; trauma-induced neurodegeneration; neuronal hyperexcitation states such as abstinence or drug intoxication; and neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polyneuritides.

KCNQ channel openers are also found to be effective in treating stroke, so it can be expected that selective KCNQ openers are effective in treating stroke (Schroder et al., Pflugers Arch., 2003; 446 (5): 607- 16; Cooper and Jan 5 ArchNeurol., 2003, 60 (4): 496-5-00; Jensen5 CNSDrugRev., 2002, 8 (4): 353-60).

KCNQ channels have been shown to be expressed in dopaminergic and cholinergic circuits in the brain that are associated with the brain reward system, particularly the ventral tegmental area (Cooper et al., J. Neurosei., 2001, 21, 9529-9540). Therefore, KCNQ channel openers are expected to be effective in hyperexcitability disorders involving the brain reward system such as cocaine abuse, nicotine withdrawal and ethanol withdrawal.

Potassium channels comprised of the KCNQ4 subunits are expressed in the inner ear (Kubisch et al., Cell, 1999 Feb5; 96 (3): 437-46) and therefore opening of these channels is expected to treat tinnitus.

As a consequence, there is a great desire for new compounds that are potent KCNQ family potassium channel openers.

Novel compounds with improved properties over known compounds, which are KCNQ family potassium decanters such as retigabine, are also desired. Improvement of one or more of the following parameters is desired:

half-life, clearance, selectivity, interactions with other medications, bioavailability, potency, formulability, chemical stability, metabolic stability, membrane permeability, solubility and therapeutic index. Improvement of such parameters may lead to improvements such as:

an improved dosing regimen by reducing the number of doses required per day,

· Ease of administration to patients on multiple medications,

• reduced side effects,

• increased therapeutic index,

• improved tolerability or

· Improved consent.

SUMMARY OF THE INVENTION

An object of the invention is the provision of compounds that are potent openers of the KCNQ family potassium channels.

The compounds of the invention are derivatives of the substituted pyrimidines of formula I below or salts thereof.

<formula> formula see original document page 8 </formula>

wherein R1, R2, R3, R4, R5 and q are as defined below.

The invention provides a compound of formula I for use as a medicament.

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

The invention provides the use of a compound of formula I for the preparation of a medicament for the treatment of convulsive disorders, anxiety disorders, neuropathic pain and migraine pain disorders, other pain disorders such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, denicotin withdrawal, ethanol withdrawal or hearing disorders such as tinnitus.

The invention further relates to the use of a compound of formula I in a method of treating seizure disorders, anxiety disorders, neuropathic pain and migraine pain disorders, other pain disorders such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, denicotin withdrawal, ethanol withdrawal or hearing disorders such as tinnitus.

DEFINITION OF SUBSTITUENTS

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

"Halogen" means fluoro, chloro, bromo or iodo. "Halo" means halogen.

"Cyano" means O = N which is attached to the remainder of the molecule via the carbon atom.

"Amino" means NH2, which is attached in the remainder of the molecule to the nitrogen atom.

The term "C 1-6 alkyl (en / in) yl" means C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl.

The term "C 1-6 alkyl" refers to an unbranched or branched alkyl group having from one to six 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, 2,2-dimethyl-prop-1-yl, but-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" refers to an alkenylamified or unbranched group having two to six carbon atoms and a double bond, including but not limited to ethenyl, propenyl and butenyl.

The term "C 2-6 alkynyl" refers to an alkynylamified or unbranched group having two to six carbon atoms and a triple bond, including but not limited to ethinyl, propynyl and butynyl.

The term "CM0-alkyl (en / yn) yl" means C1-10-alkyl, C2-10-alkenyl or C2-10-alkynyl.

The term "C1-10 alkyl" refers to an unbranched or branched alkyl group having from one to ten 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, 2,2-dimethyl-prop-1-yl, but-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 "C20-10 alkenyl" refers to an alkenylamified or unbranched group having from two to ten carbon atoms and a double bond, including but not limited to ethenyl, propenyl and butenyl.

The term "C 2-10 alkynyl" refers to an alkynylamified or unbranched group having from two to ten carbon atoms and a triple bond, including but not limited to ethinyl, propynyl and butynyl.

The term "C3.8-cycloalkyl (en) yl" means C3.8-cycloalkyl or C3.8-cycloalkenyl.

The term "C 3-8 cycloalkyl" means a carbocyclomonomonocyclic or bicyclic having three to eight carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, bicycloheptyl such as 2-bicyclo [2.2 .1] heptyl.

The term "C 3-8 cycloalkenyl" means a carbocyclomonomonocyclic or bicyclic having three to eight carbon atoms and a double bond, including but not limited to cyclopentenyl and cyclohexenyl.

The term "C 1-6 alkyl (en / in) yl)" means C 1-6 alkyl (en / in) yl being halogen substituted, including but not limited to atrifluoromethyl.

The term "halo-C1-6-alkyl (en / in) yloxy" means C1-6-alkyl (en / in) yloxy being substituted with halogen, including but not limited to trifluoromethyloxyl

Similarly, "C 3-8 halo-cycloalkyl" means C 3-8 cycloalkyl being substituted with halogen, including but not limited to chloro-cyclopropane and chlorocyclohexane.

Similarly, "C 3-8 -cycloalkyl (en) yloxy" means C 3-8 -cycloalkyl (en) yloxy being substituted with halogen, including but not limited to chloro-cyclopropyloxy and chloro-cyclohexyloxy.

Similarly, "halo-C 3-8 -cyclo-alkyl (en) yl-C 1-6-alkyl (en / in) yloxy" means halo-C 3-8 -cycloalkyl (en) yl being linked to the north-east of the molecule via C1 Alkyl (en / in) yloxy.

The term "C 1-6 alkyl (en / in) yloxy" means C 1-6 alkyl (en / in) yl being attached to the remainder of the molecule via an oxygen atom.

Similarly, "C3-8-cycloalkyl (en) yloxy" means C3-8-cycloalkyl (en) yl being attached to the remainder of the molecule via an oxygen atom.

The term "aryl" refers to monocyclic or bicyclic aromatic systems being selected from the group consisting of phenyl, naphthyl, thiophene, furan, benzothiophene and benzofuran.

The term "optionally substituted aryl-C1-6 alkyl (en / in) yl" means aryl-C1-6 alkyl (en / in) yl in which the aryl group is optionally substituted, such as with 1, 2 or 3 substituents. independently selected from the group consisting of halogen, cyano, C1-6-alkyl (en / in) yl, C3-8-cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6-alkyl (en / in) yl, halo-C 1-6 -alkyl (en / in) yl, halo-C 3-8 -cycloalkyl (en) yl, halo-C 3-8-cycloalkyl (en) yl -6-alkyl (en / in) yl, C 1-6-alkyl (en / in) yloxy, C 3-8-cycloalkyl and C 3-8 -cyclo-C 1-6 alkyl alkyl (en / in) yloxyl.

Similarly, "optionally substituted aryl" means arylane which aryl is optionally substituted on, such as with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6-alkyl (en / in) yl, C3-8-cyclo -C 1-8 alkyl, C 3-8 -cyclo (C 1-6) alkyl-C 1-6 alkyl (en / in) yl, halo C 1-6 alkyl (en / in) yl, C 3-8 halo -cyclo-alkyl (en) yl, halo C 3-8 -cyclo-alkyl (en) yl C 1-6 alkyl (en / in) yl, C 1-6 alkyl (en / in) yloxy, C 3-8 -cyclo-alkyl (en) yloxy and C 3-8-cycloalkyl (en) yl-C 1-6 alkyl (en / in) yloxy.

In the terms "C3-8-cycloalkyl (en) yl-C1-6-alkyl (en / in) yla", "aryl-C1-6-alkyl (en / in) yla" and "C3-8-cycle" -C1-6-alkyl (en / in) yloxy "," C1-6-alkyl (en / in) yl "," C3-8-cycloalkyl "," aryl "and" C1-6-alkyl (en / in) yloxy "are as defined above.

DESCRIPTION OF THE INVENTION

The present invention relates to substituted pyrimidine derivatives which are potent KCNQ potassium channel openers.

The present invention relates to a compound represented by general formula I or salts thereof:

<formula> formula see original document page 12 </formula>

in which:

q is 0 or 1;

R 1 and R 2 are independently selected from the group consisting of hydrogen and optionally substituted aryl-C 1-6 alkyl (en / in) yl, provided that R 1 and R 2 are not both hydrogen, or R 1 and R 2 together with onitrogen to which they are attached form a ring. 5 to 7 members optionally containing another heteroatom;

R3 and R4 are independently selected from hydrogen, halogen, cyano, amino, C1-6 alkyl (en / in) yl, C3.8-cycloalkyl (en) yl, halo-C1-6 alkyl (en / in) yl , halo-C 3-8 -cycloalkyl (en) yl, C 1-6 -alkyl (en / in) yloxy, C 3-8-cycloalkyl (en) yloxy, C 3-8-cycloalkyl (en) yl -C 1-6 alkyl (en / in) yloxy, halo-C 1-6 alkyl (en / in) yloxy, halo C 3-8 -cycloalkyl (en) yloxy and halo C 3-8-cycloalkyl (en) yl Alkyl (en / in) yloxy, provided that R 3 and R 4 are not both hydrogen;

R5 is selected from the group consisting of C1-10-alkyl (en / in) yl, C3-8-cyclo-alkyl (en) yl-C1-6-alkyl (en / in) yl, aryl-C1-6-alkyl (en) (in) optionally substituted yl and optionally substituted aryl;

In one embodiment of the compound of formula I, q is 0.

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

In another embodiment of the compound of formula I R 1 and R 2 are independently selected from hydrogen and optionally substituted aryl-C 1-6 alkyl (en / in), provided that R 1 and R 2 are not both hydrogen.

In another embodiment of the compound of formula I R 1 and R 2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing another heteroatom; in another mode the aforementioned other heteroatom is oxygen; in another embodiment said ring is a 6 membered ring; in another embodiment said ring is a morpholine ring.

In another embodiment of the compound of formula I R 3 and R 4 are independently selected from amino and C 1-6 alkyl (en / in) yl, preferably methyl.

In another embodiment of the compound of formula I R5 is selected from the group consisting of CM0-alkyl (en / in) yl, C3-8-cycloalkyl (en) yl-C1-6-alkyl (en / in) yl, aryl Optionally substituted and optionally substituted aryl (en / in) alkyl.

Another embodiment relates to a compound of formula I as the free base or a salt thereof, said compound is selected from the compounds of the following scheme:

Example no. Name

1a N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2-cyclopentyl-acetamide N- [4-Amino-6-methyl-2 - (4-trifluoromethyl-benzyl-amino) -pyrimidiri-5-yl] -3,3-dimethyl-butyramide N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-2-one N-[4-Amino-6-methyl-2- (44-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -amide-5-yl] -2- (4-fluoro-phenyl) -acetamide N- [4 -Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2- (3-chloro-phenyl) -acetamide2a 2-Cyclopentyl-N- (4,6- dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -acetamide2b N- (4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -3,3-dimethyl-butyramide2c N- ( 4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -2- (4-fluorophenyl) acetamide2d 2- (3,4-Difluoro-phenyl) -N- (4,6 -dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) acetamide2- N- (4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -2- (3-fluoro-phenyl ) - hexanoic acid acetamide2f (4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -amide

Each of these compounds is considered a specific embodiment and may be subject to individual claims.

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

The salts of the invention are preferably acid addition salts. The acid addition salts of the invention are preferably pharmaceutically acceptable salts of the compounds of the invention formed as 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, nitric and the like. Examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malonic, mandelic, oxalic, picric, pyruvic, salicylic acids, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanesulfonic, glyconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-amino-benzoic, glutamic, benzene- sulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, as well as 8-halo theophyllines, for example 8-bromo-theophylline and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Know. 1977, 66, 2, which is incorporated herein by reference.

Also intended as acid addition salts are the hydrates, which the present compounds are capable of forming.

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

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

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

The compounds of the present invention may have one or more asymmetric centers and it is intended that any optical isomers (ie enantiomers or diastereomers) as separate, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, ie a mixture of stereoisomers, are included within. scope of the invention.

Racemic forms may be resolved into antipodasoptics by known methods, for example by separating their diastereomeric salts with an optically active acid, and optically active amino compound release by treatment with a base. Another method for resolving racemates in optical antipodes is based on chromatography on an optically active matrix. Racemic compounds of the present invention may also be resolved into their antipodasoptics, for example by fractional crystallization. The compounds of the present invention may also be resolved by formation of diastereomeric derivatives. Additional methods for resolving optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J.Jaques, A. Collet and S. Wilen in the textbook Enantiomers, Racemates, andResolutions, John Wiley and Sons, New York (1981). Optically active compounds may also be prepared from optically active starting materials or by stereoselective synthesis.

Further, when a double bond or a fully or partially saturated deanel system is present in the isometric isomers molecule may be formed. Any geometric isomers, such as separate, pure or partially purified geometric isomers or mixtures thereof, are intended to be included within the scope of the invention. Also, molecules having a restricted rotation bond may form geometric isomers. These are also intended to be included within the scope of the present invention.

In addition, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are capable of forming are within the scope of the present invention.

The invention also includes prodrugs of the present compounds, which upon administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of compounds of formula I, which are readily convertible in vivo to the required compound of formula I. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

The invention also includes active metabolites of the present compounds.

The compounds according to the invention have affinity for the KCNQ2 receptor subtype with an EC50 of less than 15,000 nMtal as less than 10,000 nM as measured by the "KCNQ2 channel efflective" test which is described below. such compounds of formula I having affinity for the KCNQ2 receptor subtype having an EC50 of less than 2,000 nM as less than 1,500 nM as measured by the "KCNQ2 decanal relative efflux" test which is described below. To further illustrate without limiting the invention one embodiment relates to such compounds having affinity for the KCNQ2 receptor subtype with an EC50 of less than 200 nM as less than 150 nM as measured by the "Relative Flow Through KCNQ2 Channel" test which is described. below, down, beneath, underneath, downwards, downhill.

One embodiment relates to such compounds of formula having an ED50 of less than 15 mg / kg in the "Electroshock" test which is described below. To further illustrate without limiting the invention one embodiment relates to such compounds having an ED50 of less than 5 mg / kg in the "Maximum Electroshock" test which is described below.

One embodiment relates to such compounds of formula having an ED50 of less than 5 mg / kg in the "Electrical Seizure Threshold Test" and "Chemical Seizure Threshold Test" which is described below.

One embodiment relates to such compounds of formula having few or clinically insignificant side effects. Some of the compounds according to the invention are therefore tested on unwanted sedative, hypothermic and ataxic action models.

One embodiment relates to such compounds of formula having a large therapeutic index between anticonvulsant efficacy and side effects such as impairment of locomotor activity or ataxic effects as measured by performance on a rotating stick. Such compounds will be expected to be well tolerated in patients allowing high dosages to be used making treatment more effective in patients who would otherwise have side effects with other medications.

As already mentioned, the compounds according to the invention have an effect on KCNQ family potassium channels, in particular the KCNQ2 subunit, and are therefore considered useful for increasing ionic flux in a voltage-dependent potassium channel in a mammal such as a human. The compounds of the invention are applicable in the treatment of a disorder or disease being responsive to an increased ionic flux in a potassium channel such as the KCNQ family potassium ion channels. Such disorder or disorder is preferably a disorder or disorder of the central nervous system.

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

In another aspect the compounds of the invention may be administered as a part of a combination therapy, i.e. the compounds of the invention may be administered in combination with other therapeutically effective compounds having e.g. anticonvulsive properties. The effects of such other compounds having anticonvulsant properties may include but are not limited to activities on:

• ion channels such as sodium, potassium or calcium channels;

Excitatory amino acid systems e.g. blocking or modulating NMDA receptors;

• inhibitory neurotransmitter systems e.g. GABA release, or GABA uptake block or

• membrane stabilization effects.

Current anticonvulsant medications include, but are not limited to, tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, etosuximide, levetiracetam, phenytoin, topiramate, zonisamide as well as members of the benzodiazepine and barbiturate class.

One aspect of the 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 treatment method.

One embodiment of the invention provides a pharmaceutical composition comprising a compound of formula I or a salt thereof and one or more pharmaceutically acceptable diluents or carriers. The composition may comprise any of the embodiments 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 to increase the ionic flux in a potassium channel 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 disorder or disease being responsive to an increased ion flux in a depotassium channel, such disorder or disease is preferably a disorder 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 disorder in which a KCNQ potassium channel opener such as a potassium channel opener is used. potassiumKCNQ2 is beneficial. Typically, such disorder or disease is selected from the group consisting of seizure disorders, anxiety disorders, dorneuropathic and migraine pain disorders, other pain disorders, such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal, withdrawal ethanol 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 seizure disorders.

Typically, seizure disorders to be treated are selected from the group consisting of acute seizures, seizures, epileptic status and epilepsy such as epileptic syndromes 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.

Typically, anxiety disorders to be treated are selected from the group consisting of anxiety and panic attack-related disorders and diseases, agoraphobia, panic disorder, agoraphobia, panic disorder without agoraphobia, history of panic disorder, specific phobia, and social phobia. other specific phobias, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to general medical condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorder, anxiety performance, hypochondriac disorders, anxiety disorder due to general medical condition, and substance-induced anxiety disorder, and anxiety disorder not differently specified.

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 neuropathic pain and migraine pain disorders.

Typically, neuropathic pain and migraine pain disorders to be treated are selected from the group consisting of dealodynia, hyperalgesic pain, phantom pain, diabetic neuropathic-related neuropathic pain, trigeminal neuralgia-related neuropathic pain and migraine-related dorneuropathic pain.

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 neurodegenerative disorders.

Typically the neurodegenerative disorders to be treated are selected from the group consisting of Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Parkinson's disease, AIDS-induced encephalopathy, rubella virus infection, herpes virus and known pathogens, trauma-induced neurodegeneration, states of neuronal hyperexcitation such as in abstinence or drug intoxication, and peripheral nervous system neurodegenerative diseases such as polyneuropathies and polyneuritides.

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 bipolar disorder or attention deficit hyperactivity disorder.

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 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 fibromyalgia, a motor disorder or movement disorder, spasms, myopia or urinary incontinence.

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 stroke, cocaine abuse, nicotine withdrawal, ethanol withdrawal or hearing impairment such as tinnitus. .

The term "treatment" as used herein in connection with a disease or disorder also includes prevention, inhibition and amelioration according to the circumstances.

The invention provides compounds showing effect in one or more of the following tests:

• "Relative flow through channel KCNQ2" Which is a measure of compound power as a target channel.

• "Maximum Electroshock"

Which is a measurement of non-specific CNS stimulation induced seizures

• "Pilocarpine-induced seizures"

Pilocarpine-induced seizures are often difficult to treat with many of the existing anticonvulsant medications and thus reflect a "drug-resistant seizures" model.

"Electrical Seizure Threshold Tests" and "Chemical Seizure Boundary Tests" These models measure the threshold at which seizures are initiated, and thus models that detect whether the compounds could delay seizure initiation.

"Amygdala Ignition"

Which is used as a measure of disease progression, because in normal animals the convulsions in this model are more severe as the animal receives other stimulations.

PHARMACEUTICAL COMPOSITIONS

The present invention also relates to a pharmaceutical composition. The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable diluents or carriers in either single or multiple doses. Pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable diluents or carriers as well as any other known adjuvant excipients according to conventional techniques such as those described in Remington: The Science and Practice of Pharmaey, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

Pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral routes (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), the oral route is 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 to be treated and the active ingredient chosen.

The pharmaceutical compositions formed by the compound of the invention and the pharmaceutically acceptable carriers are then administered in a variety of dosage forms suitable for the administration routes described. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

The compounds of this invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. An example is an acid addition salt of a compound having the utility of a free base. Where a compound of the invention contains a base booklets salts are prepared in a conventional manner by treating a solution or suspension of a free base of the invention with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above.

Pharmaceutical compositions for oral administration may be solid or liquid. Solid dosage forms for oral administration include e.g. capsules, tablets, pills, pills, lozenge pellets, etablete powders e.g. added in a hard gelatin capsule in powder or depot form or e.g. in the form of a lozenge tablet or tablet. Accordingly, pharmaceutical compositions for oral administration may be prepared with coatings such as enteric coatings or may be formulated to provide controlled release of the activotal ingredient as prolonged or delayed release according to methods well known in the art. Liquid dosage forms for oral administration include e.g. solutions, emulsions, suspensions, syrups and elixirs.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of active ingredient, and which may include one or more appropriate excipients. Further, orally available formulations may be in the form of a powder. or granules, a solution or suspension in an aqueous or non-aqueous liquid, or in an oil-in-water or water-in-oil emulsion.

Suitable pharmaceutical carriers include inert fillers or diluents, sterile aqueous solution 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 esters of cellulose, corn starch, potato starch, similar gums. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.

The carrier or diluent may include any prolonged deliberation material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

Any adjuvants or additives commonly used for purposes such as colorings, flavorings, preservatives etc. may be used provided they are compatible with the active ingredients.

The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft degelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid solution or suspension.

Tablets may be prepared by mixing the active ingredient with ordinary adjuvants or diluents and subsequent mixing compression in a conventional tabletting machine.

Pharmaceutical compositions for parenteral administration include injectable or non-aqueous injectable aqueous sterile emulsions, suspensions, dispersions as well as sterile powders to be reconstituted into sterile injectable dispersions or solutions prior to use. Injectable deposition formulations are also contemplated as being within the scope of the present invention.

For parenteral administration, solutions of the inventive compound in sterile aqueous solutions, aqueous propylene glycol, aqueous vitamin E, peanut or sesame oil may be employed. Aqueous solutions should be adequately buffered if necessary and the odorous liquid first made isotonic with sufficient saline or glucose agent. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Sterile aqueous media employed are all readily available standard techniques known to those skilled in the art.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling ampoules or vials with it. Any suitable additive conventionally used in the art can be added such as tonicity agents, preservatives, antioxidants, etc.

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

A typical oral dosage is within the range of about 0.001 mg / kg bodyweight per day to about 100 mg / kg bodyweight per day, preferably about 0.01 mg / kg bodyweight per day. 50 mg / kg body weight per day, and most preferably about 0.05 mg / kg body weight per day to about 10 mg / kg body weight per day administered at one or more strengths such as 1 to 3 strengths . Exact dosing will depend on the frequency and mode of administration, gender, age, weight and general condition of the individual being treated, the nature and severity of the condition being treated and any concomitant diseases to be treated, and other factors evident to those experienced. in art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration once or more times a day such as 1 to 3 times a day may contain from 0.01 mg to about 1,000 mg, preferably from about 0.05 mg to about 500 mg, and more frequently. preferably from about 0.5 mg to about 200 mg.

For parenteral routes such as intravenous, intrathecal, intramuscular administration and the like, doses typically are in the order of about half the dose employed for oral administration.

Typical examples of recipes for formulating the invention are as follows:

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

base:

<table> table see original document page 27 </column> </row> <table>

2) Tablets containing 0.5 mg of a compound of the invention.

<table> table see original document page 27 </column> </row> <table> 4) Solution for injection containing per milliliter:

Compound of the invention 0.5 mg

Sorbitol 5.1 mg

Acetic Acid 0.05 mg

Sodium saccharin 0.5 mg

Water ad ImL

The term a compound of the invention means any of the embodiments of formula I as described herein.

In another aspect the present invention relates to a method of preparing a compound of the invention as described below.

METHODS FOR PREPARING COMPOUNDS OF THE INVENTION

The compounds of the invention formula I, wherein R 1, R 2, R 3, R 4, R 5, and q are as defined above may be prepared by the methods as set forth in the schemes and as described below.

In the compounds of formulas I-XX, R1, R2, R3, R4, R5 and q are as defined under formula I.

For compounds which may exist as equilibrium between or more tautomers, only one tautomer is represented in the schemes, although it may not be the most stable tautomer. Such compounds include, but are not limited to, hydroxy pyrimidines of formula IX, Χ, XVII, XVIII well known to those skilled in the art.

Compounds of general formulas II, III, VII, VIII, IX, Χ, XI, XIV, XVI, XVII, XIX and XX are either obtained from commercial suppliers or prepared by standard methods known to those skilled in the art.

Compounds of formula IV (Scheme 1) may be obtained by reacting compounds of formula II with amines of formula III with or without the addition of bases such as trialkyl amines, potassium carbonate or sodium in a suitable solvent such as such as acetonitrile, Ν, Ν-dimethylformamide or ethanol, at a suitable temperature, such as room temperature, reflux temperature or higher temperature under microwave irradiation in a sealed vessel.

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

Compounds of the invention of formula I may be prepared by reacting compounds of formula V with suitable electrophilic reagents such as, but not limited to, carboxylic acid fluorides, carboxylic acid chlorides, carboxylic acid bromides, carboxylic acid iodides, carboxylic acid, activated esters, chloro-formates, and with or without the addition of bases such as pyridine, trialkyl amines, potassium carbonate, magnesium oxide or lithium, sodium or potassium alcoholates in a suitable solvent, such as ethyl acetate, dioxane, tetrahydrofuran, acetonitrile or diethyl ether, at suitable temperatures, such as room temperature, reflux temperature or higher temperature in a sealed vessel under microwave irradiation.

Activated esters and carboxylic anhydrides may be prepared from suitably substituted carboxylic acids under conditions known to chemists skilled in the art, for example as described by F.Albericio and LA Carpino, "Coupling reagents and activation" in Methods inenzymology: Solid-phase peptide synthesis, pp. 104-126, Academic Press, New York, 1997. Carboxylic acid halides may be prepared from carboxylic acids suitably substituted by activation with reagents such as, but not limited to, thionyl chloride, oxalyl chloride, phosphorus tribromide or phosphorus triiodide. under conditions well known by chemists skilled in the art.

Scheme I

<formula> formula see original document page 30 </formula>

Compounds of formula II may be prepared as shown in Scheme 2. Compounds of formula IX are prepared by the urea condensation with 1,3-dicarbonyl compounds VII or their equivalent as carbonyl unsaturated compounds VIII in a suitable solvent such as Ν, Ν- dimethylformamide, N-methylpyrrolidinone or ethanol, with or without the addition of catalyst such as hydrochloric, sulfuric, methanesulfonic acids, or polyphosphoric or Lewis acids at a suitable temperature, such as room temperature, reflux temperature or temperature highest under microwave irradiation in a sealed vessel. Compounds of formula X may be prepared from compounds of formula IX by nitration reactions known to chemists skilled in the art such as concentrated nitric acid, sodium nitrite or sodium nitrate in a suitable solvent such as glacial acetic acid , acetic anhydride, trifluoroacetic acid, concentrated sulfuric acid or mixtures thereof, at appropriate temperatures, for example as described by PBD by Ia Mare eJ.H. Ridd, "Preparative methods of nitration" in Aromatic substitutions, pp.48-5-6, Butterworths Scientific Publications, London, 1959. Compounds of formula X may be converted to compounds of formula II by methods known to chemists skilled in the art such as dechlorination or bromination reaction with phosphorus oxide chloride or phosphorus oxide bromide. Compounds of formula II, in which X is fluorine or iodide, may be prepared from compounds of formula II, in which X is chloride or bromide, by halogen substitution reaction with suitable reagents such as hydroiodic acid, hydrofluoric acid, sodium iodide, potassium fluoride under conditions known to chemists skilled in the art.

<formula> formula see original document page 31 </formula>

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

<formula> formula see original document page 32 </formula>

In particular, condensation of substituted guanidines of formula XI with ketoesters or keto acids of formula XVI (Scheme 4) under conditions described above under Scheme 3 may lead to the formation of compounds of formula XVII, which may be nitrated under conditions described above to provide compounds. of formula XVIII. The hydroxyl group in XVIII can be converted to compounds of general formula XX (XIII where R4 is halogen) by halogenation reaction under the conditions described above for the preparation of compounds of formula II. Alternatively, compounds of formula XX (XIII where R4 is halogen) may be prepared from compounds of formula XIX (XIII where R4 is amino) by diazotation reaction followed by nucleophilic substitution in the presence of halogen ion under conditions well known by chemists experienced in the art. art. Compounds of formula XIII, wherein R4 is C1-6-alkyl (en / in) yl, C3.8-cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6 alkyl (en / in) ) yl, halo-C1-6 alkyl (en / in) yl, halo-C3.8-cycloalkyl (en) yl or Iialo-C3.8-cycloalkyl (en) yl-C1-6 alkyl (en) (in) ila, can be prepared from decompositions of general formula XX (XIII where R4 is halogen) by cross-coupling reactions known to chemists skilled in the art, such as Negishi copulation (Ε. I. Negishi, AO King and N. Okukado, J. Org Chem., 1977, 42, 1821), Sonogashira copulation (K. Sonogashira, Y.Tohda and N. Hagihara, Tet.Lett., 1975, 16, 4467), or other cross-coupling reactions. transition metal catalyzed (W. Dohle, MD Lindsaye P. Knochel, Org.Lett., 2001, 3, 2871).

Additionally, compounds of formula XIII, wherein R 4 is cyano, may be prepared from compounds of formula XX (XIII where R 4 is halogen) by means of pornographic catalyzed cyanation reactions known to chemists skilled in the art for example as described by L. Cassar, J. Organomet.Chem., 1973, 54, C57-058.

In addition, compounds of formula XIII, wherein R4 is Cw-alkyl (en / in) yloxy, C3.8-cycloalkyl (en) yloxy or C3.8-cycloalkyl (en) yl-C1-6. alkyl (en / in) yloxyl may be prepared from compounds of formula XX (XIII where R4 is halogen) by reaction with appropriate lithium, disodium, or potassium alcoholates or alcohols in the presence of base such as lithium hydroxide, sodium, or potassium, lithium hydride, sodium, or depotassium, and with or without the addition of a catalyst such as copper sulphate, in a suitable solvent such as dioxane, at appropriate temperatures, such as room temperature or reflux.

Scheme 4

<formula> formula see original document page 33 </formula>

Alkines prepared by the Sonogashira reactions may be reduced to alkenes or alkanes by reduction with hydrogen gas or ammonium formiat in the presence of a suitable hydrogenation catalyst such as activated carbon palladium or activated carbon platinum in suitable solvents such as methanol, ethanol or tetrahydro- furan, at suitable temperatures for example as described by S. Siegel, "Heterogeneous catalytichydrogenation of C = C and alkynes" in Comprehensive Organic Synthesis, v.8, pp. 25-30. 417-442, Pergamon Press, 1991.

Preparation of compounds of the invention

Examples

Analytical LC-MS data were obtained on a Sciex API 150EX PE instrument equipped with atmospheric pressure photoionization and a Shimadzu LC-8A / SLC-10A LC system. Column: WatersSymmetry Cl8 30 mm X 4.6 mm column with 3.5 μηι particle size; Solvent system: A = water / trifluoroacetic acid (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid ( 5: 95: 0.03); Method: Gradient elution with 90% A to 100% B in 4 minutes and with a flow rate of 2 mL / minute. Retention times (tR) are expressed in minutes.

1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument.

Deuterated dimethyl sulfoxide (99.8% D) was used as a solvent. Tetramethyl silane was used as the internal reference standard. Chemical displacement values are expressed in ppm values relative to tetramethyl silane. The following abbreviations are used for NMR signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, chi = quintet, h = heptet, dd = double doublet, ddd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet and br = broad singlet.

Microwave experiments were performed on sealed reactors or process flasks using an Emrys Synthesizer or EmrysOptimizer EXP from Personal Chemistry or Milestone Microsynthesis Instrument of Milestone. When the reaction was heated in a microwave oven, it was cooled to 25 ° C prior to the next process step.

<formula> formula see original document page 35 </formula>

6-Methyl-5-nitro-N * 2 * - (4-trifluoromethyl-benzyl) -pyrimidine-2,4-diamine

A mixture of 2-chloro-6-methyl-5-nitro-pyrimidin-4-yl-amine (300 mg, 1.591 mmol), 4-trifluoromethyl-benzyl-amine (369 mg, 2.107 mmol) in acetonitrile (3 mL) and triethylamine (0.5 ml) was blasted with argon, sealed in the Emrys process flask and heated at 120 ° C for 2 min under demi-microwave irradiation. The suspension obtained was quenched with 10% aqueous sodium bicarbonate (2 mL) and organic volatiles were evaporated under reduced pressure. Methanol (5 mL) and water (100 mL) were added to the residue. The product was filtered off, washed with water and dried in vacuo to give 490 mg yellow solid. Yield 94%. LC-MS (m / z) 328.1 (MH +); t R = 2.58.1H NMR (500 MHz, DMSO-Cl6): ca. 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, NH 2), 8.0 (s, 1.5H, NH 2), 8.17 (t, 0.25H, NH), 8.48 ( t, 0.75H, NH).

<formula> formula see original document page 35 </formula>

6-Methyl-N * 2 * - (4-trifluoromethyl-benzyl) -pyrimidine-2,4,5-triamine.

In a vigorously stirred solution of 6-methyl-5-nitro-N * 2 * - (4-trifluoromethyl-benzyl) -pyrimidine-2,4-diamine (450 mg, 1.376 mmol) in tetrahydrofuran (20 mL ) and acetic acid (5 ml) in cold water bath, zinc dust (particle size <10 micrometers, 5 g) was added portionwise within 2 min. Water bath was removed and more zinc dust (2 g) was added. The suspension was stirred at room temperature for 60 min and quenched with 10% aqueous sodium bicarbonate to pH> 8. The suspension obtained was extracted with ethyl acetate (10 times). The combined organic solution was filtered via silica gel layer (10 g) and eluted with 20% in ethyl acetate to give 430 mg of pale yellow oil after evaporation. The product solidified after vacuum drying. Yield 100%. It was used in the next step without further purification. LC-MS (m / z) 298.1 (MH +); t R = 1.68. 1H NMR (500 MHz, DMSO-d6): 2.02 (s, 3H), 3.1-3.8 (br, NH 2 + H 2 O), 4.43 (d, 2H), 5.88 (br, 2H) 6.26 (t, 1H, NH), 7.48 (d, 2H), 7.62 (d, 2H).

3,4-Difluoro-phenyl acetyl chloride.

3-Chloro-phenyl acetic acid (19.7 g) in thionyl chloride (100ml) was heated under reflux for 3 h. Volatiles were removed in vacuo and the obtained oily residue was used in the next step without further purification.

1H NMR (500 MHz, 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-Chloro-phenyl acetyl chloride.

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

3-Fluoro-phenyl acetyl chloride.

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

<formula> formula see original document page 36 </formula> 4- (4,6-Dimethyl-pyrimidin-2-ü) -morpholine.

In a suspension of morpholine-formamidine hydrobromide (2.0 g, 9.52 mmol) in ethanol (6 mL) potassium tert-butoxide (1.068 g, 9.52 mmol) then acetyl acetone (2 mL, 20 mmol) have been added. The reaction mixture was rapidly sprayed with argon, sealed in an Emrys pressure-vial and heated under microwave irradiation at 140 ° C for 5 min. After cooling it was quenched with ethyl acetate (50 ml), filtered via SiO2 (5 g) and filtered. eluted with ethyl acetate. Volatiles were removed under vacuum at 70 ° C to give 1.65 g of pale brown oil which solidified overnight. Yield 90%. LC-MS (m / z) 193.9 (MH +); t R = 0.71.1H NMR (500 MHz, DMSOd6): 2.23 (s, 6H), 3.62 (m, 4H), 3.67 (m, 4H), 6.44 (s, 1H).

Method A. In a stirred solution of 4- (4,6-Dimethyl-pyrimidin-2-yl) -morpholine (8.94 g, 46.3 mmol) in glacial acetic acid (50ml) fiery nitric acid (5.75 ml, 3 eq.) was added dropwise. Reaction mixture was heated at 70 ° C for 15 min then more nitric acid (3.8 ml, 2 eq.) Was added. After an additional 15 min at 70 ° C it was cooled and poured into small portions into a mixture of ice and sodium hydroxide solution (44g) in water (200ml). The product was filtered off to give 0.637 g of yellow solid. Yield 6%. LC-MS (m / z) 239.0 (MH +); t R = 2.76.

Method B. In a hot (65 ° C) stirred solution of 4- (4,6-dimethyl-pyrimidin-2-yl) -morpholine (4 g, 20.7 mmol) in trifluoroacetic acid (100 mL) sodium nitrate (3.52 g, 41.4 mmol) was added. After 3 h more sodium 4- (4,6-Dimethyl-5-nitro-pyrimidin-2-yl) -morpholininitrate was added (1.8 g, 20.7 mmol) and the reaction mixture was kept at 65 ° C overnight. . It was carefully poured into portions of 10% aqueous sodium bicarbonate (600 ml) and the product was filtered off. Yield 1.637 g, 33%. LC-MS (m / z) 238.9

(MH +); t R = 2.70. 1H NMR (500 MHz, DMSOd6): 2.44 (s, 6H), 3.65 (m, 4H), 3.83 (m, 4H).

<formula> formula see original document page 38 </formula>

4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl-amine.

The suspension of 4- (4,6-dimethyl-5-nitro-pyrimidin-2-yl) -morpholine (2.2 g, 9.23 mmol), 5% palladium on carbon (50% wet, 1.09g) , ammonium formate (8.76 g) was sealed in an Emrys process flask and heated to 150 ° C under microwave irradiation for 2 min. The reaction mixture was filtered and evaporated. The residue was treated with filtered ethyl acetate to give 1.62 g of orange crystalline product after vacuum evaporation. Yield 84%. LC-MS (m / z) 208.9 (MH +); t R = 0.44. 1H NMR (500 MHz, DMSOd6): 2.2 (s, 6H), 3.44 (m, 4H), 3.62 (m, 4H), 4.19 (br, 211) readily formed by methods known in the art. experienced person in the art.NH2).

Compounds of the invention

Acid addition salts of the compounds of the invention may be

Example 1

1a N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2-cyclopentyl-acetamide. <formula> formula see original document page 39 </ formula >

In a cold stirred (ice / water bath) solution of 6-methyl

N * 2 * - (4-trifluoromethyl-benzyl) -pyrimidine-2,4,5-triamine (119 mg, 0.401 mmol) in acetonitrile (3 mL), cyclopentyl acetyl chloride (59 mg, 0.402 mmol) was added dropwise in 2 min. Cold bath was removed and stirring continued for 20 min. The suspension obtained was quenched with water (85 ml) and 10% aqueous sodium bicarbonate (0.5 ml). Organic volatiles were removed under reduced pressure, ethyl acetate (0.5 mL) was added and the mixture was quenched with heptane (20 mL). The obtained biphasic suspension was filtered. The product was washed with water and heptane, dried in vacuo to give 40mg of pale yellow solid. Yield 25%. LC-MS (m / z) 408.3 (MH +); t R = 2.11. 1H NMR (500 MHz, DMSOd6): 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, 211, NH 2), 6.96 (br, IH5 NH ), 7.5 (d, 2H), 7.64 (d, 2H), 8.57 (s, 1H, NHCO).

Ib N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzylamino) -pyrimidin-5-yl] -3,3-dimethyl-butyramide.

<formula> formula see original document page 39 </formula>

N * 2 * - (4-trifluoromethyl-benzyl) -pyrimidine-2,4,5-triamine (341 mg, 1.15 mmol) in acetonitrile (7.5 mL), tert-butyl acetyl chloride (0.16 ml, 1.15mmol) was added dropwise within 2 min. Cold bath was removed and shaking

In a cold stirred (ice / water bath) solution of 6-methyl continued for 45 min. The obtained reaction mixture was poured onto SCX column (10 g, H + form), washed with acetonitrile (20 mL), methanol (100 mL), and the product was eluted with 4 M NH3 in methanol (60 mL). The volatiles were removed in vacuo and the crude product was purified by flash chromatography on silica gel (20 g) with heptane-ethyl acetate gradient to give 153 mg of solid. Yield 33.7%. LC-MS (m / z) 395.9 (MH +); tR = 2.00. 1H NMR (500 MHz, DMSO-Cl6): 1.02 (s, 9H), 1.96 (s, 3H), 2.15 (s, 2H), 4.5 (d, 2H), 5.9 (br, 2H, NH 2), 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-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2- (4-fluoro-phenyl) -acetamide.

<formula> formula see original document page 40 </formula>

Yield 12%. LC-MS (m / z) 434.3 (MH +); t R = 2.07. 1 H NMR (500 MHz, DMSO-d 6): 1.81 (s, 3H), 3.57 (d, 2H), 4.49 (d, 2H), 6.08 (br, 2H, NH 2), 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).

Hexanoic acid 1d [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyridin-5-yl] -amide. Yield 39.7 mg, 50%. LC-MS (m / z) 396.1 (MH +); t R = 2.08. 1H NMR (500 MHz, DMSO-d6): 0.87 (t, 3H), 1.28 (m, 4H), 1.56 (thi, 2H), 1.91 (s, 3H), 2.24 (t, 2H), 4.49 (d, 2H), 5.98 (br, 2H, NH 2), 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-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2- (3-chloro-phenyl) -acetamide.

<formula> formula see original document page 41 </formula>

Yield 45.4 mg, 50%. LC-MS (m / z) 450.1 (AlHf); t R = 2.17. 1H NMR (500 MHz, DMSO-Cl6): 1.82 (s, 3H), 3.61 (s, 2H), 4.49 (d, 2H), 6.12 (br, 2H, NH 2), 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

<formula> formula see original document page 41 </formula>

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

In a cold stirred (ice / water bath) solution of 4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl-amine (2.04 g, 9.79 mmol) emacetonitrile (40 ml) cyclopentyl acetyl chloride (1.65 ml, 11.75 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 min. It was poured into aq. Sodium hydrogen carbonate. sat. (100 ml) and water and filtered. The obtained solid was recrystallized from acetonitrile to give 1.877 g of colorless solid. Yield 60%. LC-MS (m / z) 318.9 (MHt); t R = 1.80. 1H NMR (500 MHz, DMSOd6): 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'-pyrimidin-5-U-S-3-dimethylbutyramide.

<formula> formula see original document page 42 </formula>

In a solution of 4,6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl-amine (2.1 g, 10.4 mmol) in acetonitrile (30 mL) and triethylamine (2.9 mL, 20.8mmol) tert-Butyl ketyl chloride (2.9 ml, 20.8 mmol) was added in stock. After 90 min the reaction mixture was quenched with water and extracted with ethyl comacetate twice. The organic phase was washed with aq. Sodium hydrogen carbonate. sat. NaHCO 3 (100 ml), dried over magnesium sulfate and purified by flash chromatography on SiO 2 (20 g, heptane-ethyl acetate gradient). The obtained crude product was recrystallized from hot toluene to give 946 mg of colorless solid.

Yield 30%. LC-MS (m / z) 307.9 (MH +); t R = 1.69. 1H NMR (500MHz, DMSOd6): 1.04 (s, 9H), 2.16 (s, 6H), 2.19 (s, 2H), 3.64 (m, 8H), 9.13 (s, 1H).

The following compound was prepared analogously from the corresponding acid chloride.

2c N- (4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl-2- (4-fluoro-phenyl) -acetamide

<formula> formula see original document page 42 </formula> The title compound was recrystallized from hot ethyl acetate after purification by flash chromatography. Yield 1.193 g, 37%. LC-MS (m / z) 345.1 (MH +); t R = 1.81. 1H NMR (500 MHz, DMSOd6): 2.09 (s, 6H), 3.6-3.66 (m, 10H), 7.16 (t, 2H), 7.38 (dd, 2H) 9.42 (s, 1H).

2d 2- (3,4-Difluoro-phenyl) -N- (4,6-dimethyl-2-morpholin-4-U-pyrimidin-5-yl) -acetamide.

<formula> formula see original document page 43 </formula>

In a cold stirred (ice / water bath) solution of 4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl-amine (52.4 mg, 0.25 mmol) emacetonitrile (1 ml) 3,4-Difluoro-phenyl ketyl chloride (0.065 ml, 0.3 mmol) was added. The reaction mixture was kept at 60 ° C for 1 min and allowed to cool. It was poured onto SCX column (10g, H + form), washed with comacetonitrile and methanol and eluted with 4 M NH3 in methanol. After evaporation the crude product was precipitated from concentrated solution in ethyl acetate with heptane and filtered to give 34 mg of colorless solid. Yield 37%. LC-MS (m / z) 363.3 (MH +); t R = 1.96. 1H NMR (500 MHz, DMSOd6): 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 appropriate acid chlorides:

2e N- (4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-yl-2- (3-fluoro-phenyl) -acetamide.

<formula> formula see original document page 43 </formula> The title compound was purified by flash chromatography on SiO 2 (20 g, heptane-ethyl acetate gradient). Yield 27 mg, 31%. LC-MS (m / z) 345.0 (MIT); t R = 1.83. 1H NMR (500 MHz, DMSOd6): 2.09 (s, 6H), 3.62 (m, 4H), 3.64 (m, 4H), 3.66 (s, 2H), 7.08 (dt, 1H), 7.18 (dc, 1H), 7.19 (dc, 1H), 7.38 (dt, 1H), 9.45 (s, 1H).

Hexanoic Acid 2f (4,6-Dimethyl-2-morpholin-4Al-pyrimidin-5-yl-amide)

<formula> formula see original document page 44 </formula>

The title compound was purified by flash chromatography on SiO 2 (20 g, heptane-ethyl acetate gradient). Yield 49 mg, 64%. LC-MS (m / z) 307.2 (MH +); t R = 1.84. 1H NMR (500 MHz, DMSO-d6): 0.88 (t, 3H), 1.31 (m, 4H), 1.60 (Thi, 2H), 2.14 (s, 6H), 2.28 ( t, 2H), 3.63 (m, 4H), 3.65 (m, 4H), 9.16 (s, 1H).

Table 1. Reagents used for compound preparation.

<formula> formula see original document page 44 </formula>

In vitro and in vivo tests The compounds of the invention have been tested and shown to be effective in one or more of the following models:

Relative flow through channel KCNQ2

This exemplifies a KCNQ2 screening protocol for evaluating the compounds of the present invention. The assay measures relative efflux through the KCNQ2 channel, and was performed according to a method described by Tang et al. (Tang, W. et al., J. Biomol. Screen. 2001, 6, 325-331) hERG potassium parachannels with the modifications described below.

An adequate number of CHO cells stably expressing voltage-unlocked KCNQ2 channels were plated at a density sufficient to give a mono-confluent layer in the day of the experiment. Cells were seeded the day before the experiment and loaded with 1 μα / ml [°° Rb] overnight. On the day of the experiment, cells were washed with a buffer containing HBSS. Cells were preincubated with drug for 30 minutes and 86 Rb + efflux was stimulated by a submaximal concentration of 15 mM KCl in the continued presence of drug for an additional 30 minutes. After a suitable incubation period, the supernatant was removed and counted in a liquid scintillation counter (Tricarb). The cells were lysed with 2 mM NaOH and the amount of 86 Rb + was counted. Relative efflux was calculated ((CPMSUper / (CPMSUper + CPMceii)) cmpd / (CPMsuper / (CPMsuper + CPMcell)) 15mMKCI) * 100-100.

The compounds of the invention have an EC 50 of less than 20,000 nM, in most cases less than 2,000 nM and in many cases less than 200 nM. Accordingly, the compounds of the invention are considered useful in the treatment of diseases associated with the KCNQ family depotassium channels.

Patch Clamp Electrophysiological Records

Voltage-activated KCNQ2 streams have been recorded from mammalian CHO cells by use of conventional patch-clamp recording techniques in the whole-cell patch-clamp configuration (Hamill O. P. et al. Pflügers Arch 1981; 391: 85-100). CHO cells with stable expression of voltage-activated KCNQ2 channels were grown under normal cell culture conditions in CO2 incubators and used for electrophysiological records 1-7 days after plating. The KCNQ2 potassium channels were activated by voltage steps up to + 80 mV in 5-20 mV increments (or with a ramp protocol) of a potential membrane maintenance between -100 mV and -40 mV (Tatulian L et al J

Neuroscience 2001; 21 (15): 5535-5-545). The electrophysiological effects induced by the compounds were evaluated on several voltage-activated KCNQ2 current parameters. In particular, effects on the activation threshold for current and maximum induced current have been studied.

Some of the compounds of the invention have been tested in this test. It is expected that a left shift of the activation threshold or an increase in maximum induced potassium current will decrease activity in neuronal networks and thus make the compounds useful in diseases with increased neuronal activity - such as epilepsy.

Maximum electroshock

The test was conducted on groups of male mice using corneal electrodes and administering a 26 mA square wave current for 0.4 seconds to induce a seizure characterized by a posterior limb tonic extension (Wlaz et al. Epilepsy Research 1998, 30, 219-229).

Pilocarpine-induced seizures

Pilocarpine-induced seizures are induced by intraperitoneal injection pilocarpine injection 250mg / kg in male mouse groups observing seizure activity resulting in posture loss within a 30-minute period (Starr et al. Pharmacology Biochemistry and Behavior 1993, 45, 321-325) .

Electrical seizure threshold test

A modification of the up-and-down method (Kimball et al.Radiation Research 1957, H2) was used to determine the mean threshold to induce posterior limb tonic extension in response to electroshock in groups of male mice. The first cadagroup mouse received a 14 mA electroshock (0.4 s, 50 Hz) and was observed for seizure activity. If a seizure was observed the current was reduced by 1 mA for the next mouse, however, if no convulsion was observed then the current was increased by 1 mA. This procedure was repeated for all 15 mice in the treatment group.

Chemical Seizure Threshold Test

The threshold dose of pentylene tetrazole required to induce clonic convulsion was measured by timed infusion of pentylene tetrazole (5 mg / mL at 0.5 mL / min) into the lateral tail vein of male mouse groups (Nutt et al. J Pharmacy and Pharmaeology 1986, 38,697-698).

Tonsil ignition

Rats underwent surgery for implantation of electrodostripolar electrodes in the dorsolateral tonsil. After surgery the animals were allowed to recover before the rat groups received either varying doses of test compound or the drug vehicle. Animals were stimulated with their initial post-discharge limit of + 25 μΑ daily for 3-5 weeks and on each occasion seizure severity, seizure duration, and electrical post-discharge duration were noted. (Racine, Electroencephalography and Clinical Neurophysiology 1972, 32, 281-294).

Side effects Central nervous system side effects were measured by measuring the time the mice would remain on rotarod mating (Capacio et al. Drug and Chemical Toxicology 1992,15, 177-201); or by measuring its locomotor capacity by counting the number of infrared beams crossed in a test cage (Watsonet al. Neuropharmacology 1997, 36, 1369-1375). Hypothermic actions on the body core temperature of the animals were measured either by rectal probe or by implanted radiotelemetry transmitters capable of measuring temperature (Keeney et al. Physiology and Behavior 2001,74, 177-184).

Pharmacokinetics

Pharmacokinetic properties of the compounds were determined via i.v. and p.o. Sprague Dawley rats, and then collecting blood samples for 20 hours. Plasma concentrations were determined with LC / MS / MS.

Claims (22)

Compound, characterized in that it is of formula I: <formula> formula see original document page 49 </formula> wherein: q is 0 or 1, R1 and R2 are independently selected from the group consisting of hydrogen and aryl-C1 Optionally substituted alkyl (en / in) yl, provided that R 1 and R 2 are not both hydrogen, or R 1 and R 2 together with onitrogen to which they are attached form a 5 to 7 membered ring optionally containing another heteroatom; independently selected from hydrogen, halogen, cyano, amino, C1-6-alkyl (en / in) yl, C3-8-cycloalkyl (en) yl, halo-C1-6-alkyl (en / in) yl, halo -C3-8-cycloalkyl (en) yl, C1-6-alkyl (en / in) yloxy, C3-8-cycloalkyl (en) yloxy, C3-8-cyclo (C1-6) alkyl -6-alkyl (en / in) yloxy, halo-C1-6-alkyl (en / in) yloxy, halo-3-8-cycloalkyl (en) yloxy and halo-3-8-cycloalkyl ) yl-C1-6-alkyl (en / in) yloxy, provided that R3 and R4 are not both hydrogen, R5 is selected from the group consisting of C1-10-alkyl (en / in) yl, C3-8-cyclohexyl C1-6 alkyl (en / in) ) optionally substituted aryl-C 1-6 alkyl (en / yn) yl and optionally substituted aryl as the free base or salts thereof. A compound according to claim 1, characterized in that q is 0. A compound according to claim 1, characterized in that q is 1. A compound according to any one of claims 1-3, wherein R1 and R2 are independently selected from hydrogen and optionally substituted aryl-C1-6-alkyl (en / in) yl, provided that R1 and R2 are not. both hydrogen. A compound according to any one of claims 1-3, characterized in that R 1e R 2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing another heteroatom. A compound according to claim 5, characterized in that said other heteroatom is oxygen. A compound according to any one of claims 5 and 6, characterized in that said ring is a 6 membered ring. A compound according to any one of claims 5-7, characterized in that said ring is a morpholine ring. A compound according to any one of claims 1-8, characterized in that R 3 and R 4 are independently selected from amino and C 1-6 alkyl (en / in) yl, preferably methyl. A compound according to any one of claims 1-9, characterized in that R5 is selected from the group consisting of C1-10-alkyl (en / in) yl, C3.8-cycloalkyl (en) yl- C6-6 alkyl (en / in) yl, aryl-C6-6 alkyl (en / in) optionally substituted aryl and optionally substituted aryl. A compound according to any one of claims 1-10, characterized in that it is selected from the group consisting of: N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin -5-yl] -2-cyclopentyl-acetamide, N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -3,3-dimethyl- butyramide, N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2- (4-fluoro-phenyl) -acetamide, [4-Amino-6 hexanoic acid-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -amide, N- [4-Amino-6-methyl-2- (4-trifluoromethyl-benzyl-amino) -pyrimidin-5-yl] -2- (3-chloro-phenyl) -acetamide, -2-cyclo-pentyl-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-dimethyl-butyramide, N- (4,6-Dimethyl-2-morpholin-4 -ylpyrimidin-5-yl) -2- (4-fluoro-phenyl) -acetamide, -2- (3,4-Difluoro-phenyl) -N- (4,6-dimethyl-2-morpholin-4-yl-pyrimidin-2-yl) -5-yl) -acetamide, N- (4,6-Dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (3-fluoro-phenyl) -acetamide and (4,6-Dimethyl) Hexanoic acid -2-morpholin-4-ylpyrimidin-5-yl) -amide as the free base or a salt thereof. Pharmaceutical composition, characterized in that it comprises the compound as defined in any one of claims 1-11 in a therapeutically effective amount together with one or more pharmaceutically acceptable diluents or carriers. Use of a pharmaceutical composition as defined in claim 12, characterized in that it is for increasing the ionic flux in a potassium channel of a mammal such as a human. Use according to claim 13, characterized in that it is for the treatment of a disorder or disease responsive to an increased ion flux in a potassium channel, a thaldisturbance or disease is preferably a central nervous system disorder or disease. Use according to claim 14, characterized in that the disorder or disease to be treated is selected from the group consisting of seizure disorders, anxiety disorders, dorneuropathic disorders and migraine pain disorders, other disorders. pain, such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal, ethanol withdrawal, and hearing disorders such as tinnitus. Use according to claim 15, characterized in that the seizure disorders are selected from the group consisting of acute seizures, seizures, epileptic status, epilepsy such as epileptic syndromes and epileptic seizures. Use according to claim 15, characterized by the fact that anxiety disorders are selected from the group consisting of anxiety and panic attack disorders, agoraphobia, agoraphobia panic disorder, semagoraphobia panic disorder, agoraphobia without history. panic disorder, specific phobia, social phobia and other specific phobias, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, general medical anxiety disorder, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorders, performance anxiety, hypochondriacs disorder, anxiety disorder due to general medical condition and substance-induced anxiety disorder and unspecified anxiety disorder. Use according to claim 15, characterized in that the neuropathic pain and migraine pain disorders are selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, diabetic neuropathic-related neuropathic pain, trigeminal neuralgia-related dorneuropathic pain and neuropathic pain. related to migraine. Use according to claim 15, characterized in that the neurodegenerative disorders are selected from the group consisting of Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Parkinson's disease, AIDS-induced encephalopathies. or infection with darubola virus, herpes virus, borrelia or unknown pathogens, trauma-induced neurodegeneration, neuronal hyperexcitation states such as withdrawal or drug intoxication, and peripheral nervous system neurodegenerative diseases such as epolineuritide polyneuropathies. Use according to claim 14, characterized in that the disorder or disease to be treated is selected from the group consisting of bipolar disorders and attention deficit hyperactivity disorder. Use according to claim 14, characterized in that the disorder or disease to be treated (a) is selected from the group consisting of sleep disorders; such as insomnia. Use according to claim 13, characterized in that it is for the treatment of a disorder or disease responsive to an increased ion flux in a potassium channel in which the disorder or disease to be treated (a) is selected ( a) of the group consisting of fibromyalgia, a motor disorder or movement disorder, spasms, myopia and urinary incontinence.