JP2009507052A - Pyrimidine derivatives and their use as KCNQ potassium channel openers - Google Patents

Abstract

The present invention relates to pyrimidine derivatives of general formula I or salts thereof, and methods of using them as openers of KNCQ family potassium ion channels, particularly in the treatment of epilepsy.

Description

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

  Ion channels are cellular proteins that control the flow of ions, including potassium, calcium, chloride and sodium, into and out of the cell. The channel is present in all animal and human cells and affects various processes including neurotransmission, muscle contraction and cell secretion.

  Humans have genes encoding more than 70 potassium channel subtypes with great diversity in both structure and function (Non-Patent Document 1). Neuronal potassium channels found in the brain are primarily associated with maintaining a negative resting membrane potential, as well as controlling membrane repolarization following action potentials.

  One subset of potassium channel genes is the KCNQ family. Mutations in four of the five KCNQ genes have been shown to be found in diseases including cardiac arrhythmias, hearing loss and epilepsy (Non-Patent Document 1).

  The KCNQ4 gene encodes a potassium channel-related molecule found in the outer hair cells of the cochlea and type I hair cells of the vestibular organ, and it is thought that mutation of this gene forms hereditary hearing loss.

  KCNQ1 (KvLQT1) is the KCNE1 (minimal K (+)-channel protein) gene product in the heart to form a cardiac-delayed rectifier-like K (+) current Meet with. Mutations in this channel can cause a form of hereditary long QT syndrome type 1 (LQT1) as well as associated with the formation of hearing loss (2).

    The KCNQ2 and KCNQ3 genes were discovered in 1988, and mutations are found in the inherited form of epilepsy known as benign familial neonatal convulsions (Non-patent Document 3). Proteins encoded by the KCNQ2 and KCNQ3 genes are localized in the cortical and hippocampal pyramidal nerves of the human brain, which are involved in seizure development and transmission (Non-patent Document 4).

KCNQ2 and KCNQ3 are two potassium channel subunits that form an “M current” when expressed in vitro. M current is the non-inactivating potassium current found in many types of neurons. In any cell type, membrane excitability is controlled mainly by a continuous current in the region of action potential initiation (Non-patent Document 5). Modulation of M current has a dramatic effect on nerve excitability, for example, activation of the current reduces nerve excitability. These KCNQ channel openers or M-current activators reduce excessive neural activity, such as treatment of seizures and other diseases and convulsive disorders, such as neuronal excitability, including epilepsy and neuropathic pain It can be used to treat disorders characterized by excessive neural activity. .
Retigabine (D-23129; N- (2-amino-4- (4-fluorobenzylamino) -phenyl) carbamic acid ethyl ester) and its analogs are disclosed in US Pat. Retigabine is an anticonvulsant compound with a broad spectrum of action and strong anticonvulsant properties both in vitro and in vivo. It is within the scope of anticonvulsant trials, including electrically induced seizures, seizures chemically induced by pentylenetetrazole, picrotoxin and N-methyl-D-aspartate (NMDA). It has activity after oral and intraperitoneal administration in rats and mice and DBA / 2 mice, a genetic animal model (Non-patent Document 6). In addition, retigabine is active in the amygdala kindling model of complex partial seizures, further indicating that this compound has efficacy in anticonvulsant therapy. In clinical trials, retigabine has recently shown the effect of reducing the incidence of seizures in epileptic patients (Non-Patent Document 7).

  Retigabine activates the K (+) current in neurons, and the pharmacology of this induced current has recently been published in association with the KCNQ2 / 3K (+) channel heteromultimer. Indicates a match. This is because activation of KCNQ2 / 3 channel is responsible for some anticonvulsant activity of this agonist (Non-patent Document 8), and other agonists that act by the same mechanism have similar uses. Suggests that

  KCNQ2 and 3 channels have been reported to be up-regulated in a model of neuropathic pain (9) and potassium channel modulators are expected to be active in both neuropathic pain and epilepsy (Non-Patent Document 10).

  Retigabine has also been shown to be effective in animal models of neuropathic pain (11), and KCNQ channel openers should be used to treat painful disorders, including neuropathic pain It is thought that you can.

  Localization of KCNQ channel mRNA has been reported in other central nervous system regions related to brain and pain (Non-patent Document 12).

  In addition to its role in neuropathic pain, expression of KCNQ2-5 mRNA in the trigeminal and dorsal root ganglia and trigeminal nucleus caudalis indicates that these channel openers are migraine pain ) Is implicated in the sensory process (Non-Patent Document 12).

  Recent reports indicate that in addition to KCNQ2, KCNQ3 and 5 mRNAs are expressed in astrocytes and glial cells. Therefore, KCNQ2, 3 and 5 channels help regulate synaptic activity in the CNS and contribute to the neuroprotective effect of KCNQ channel openers (Non-patent Document 13).

  Retigabine and other KCNQ modulators, therefore, have shown that retigabine prevents the expression of apoptotic markers following limbic neurodegeneration and status epilepticus induced by kainic acid in rats Shows protection against the neurodegenerative aspect of epilepsy (Non-Patent Document 14). This impedes the progression of epilepsy in the patient, i.e. has relevance to anti-epileptic induction. Retigabine has been shown to delay the progression of hippocampal kindling in rats, which is a further model of epilepsy (Non-patent Document 15).

  Thus, these properties of retigabine and other KCNQ modulators can prevent nerve damage induced by excessive neural activation, treat neurodegenerative diseases, and preventive maintenance (or anti-epileptic induction in epilepsy patients) ).

  Anticonvulsant compounds such as benzodiazepines and chlormethiazole are clinically used to treat ethanol withdrawal syndrome, and other anticonvulsant compounds such as gabapentin are Other anticonvulsant compounds such as KCNQ openers are expected to be effective in this disease if they are very effective in animal models of the syndrome (Non-Patent Document 16).

  KCNQ2 and 3 subunit mRNAs are found in areas of the brain associated with emotional behavior such as anxiety and bipolar disorder, such as the hippocampus and tonsils (17), and retigabine has been reported Active in several animal models of anxiety-like behavior (18), other clinically used anticonvulsant compounds have been used to treat bipolar disorder. Thus, KCNQ openers are useful for the treatment of anxiety and bipolar disorders.

  Patent Document 2 discloses the use of a modulator of M current formed by the expression of KCNQ2 and KCNQ3 genes for insomnia. Furthermore, Patent Document 3 discloses that a modulator of KCNQ5 is used to treat sleep disorders. It is disclosed that it can be used.

  Patent Document 4 describes neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, and neuropathy associated with migraine. The use of retigabine for the prevention and treatment of sexual pain is described.

  Patent Document 5 includes anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social fear, performance anxiety, post-traumatic stress disorder, acute stress reaction, adaptation disorder, and psychosis. It describes the use of retigabine for the treatment of anxiety disorders such as hypochondriacal disorders, separation anxiety disorder, agoraphobia and specific phobias.

  Patent Literature 6 includes Alzheimer's disease; Huntington's chorea; sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis; Creutzfeldt-Jakob disease; Parkinson's disease; AIDS-induced encephalopathy or rubella virus, herpes Encephalopathy caused by infection with viruses, Borrelia and unknown pathogens; trauma-induced neurodegenerations; drug withdrawal or hyperexcitation states such as in addiction; and The use of retigabine to treat neurodegenerative disorders of the peripheral nervous system such as polyneuropathy and polyneuritides has been described.

  It has also been found that KCNQ channel openers are effective in the treatment of stroke, and therefore selective KCNQ openers are expected to be effective in the treatment of stroke (Non-Patent Document 19; Non-Patent Document 20; Non-patent document 21).

  KCNQ channels have been shown to be expressed in the brain dopaminergic and cholinergic circuits associated with the brain reward system, particularly in the ventral tegmental area (22). Thus, KCNQ channel openers are expected to be effective in hyperexcitability disorders associated with the brain reward system, such as cocaine abuse, nicotine withdrawal symptoms and ethanol withdrawal symptoms.

  Potassium channels containing KCNQ4 subunits are expressed in the inner ear (Non-Patent Document 23), and therefore opening of these channels is expected to treat tinnitus.

  Therefore, new compounds that are potent openers of KCNQ family potassium channels are eagerly awaited.

New compounds with improved properties compared to known compounds that are openers of KCNQ family potassium channels such as retigabine are also eagerly desired. The following parameters: half-life, clearance, selectivity, interaction with other drugs, bioavailability, potency, formulation, chemical stability, metabolic stability, membrane permeability Improvements in one or more of sex, solubility and therapeutic index are desired. Improvements in these parameters include:
・ Improved dose therapy by reducing the required daily dose ・ Reduction of administration of multi-drug therapy to patients ・ Reduced side effects ・ Increased therapeutic index ・ Improved tolerability or ・ Improved compliance ,
Bring improvements like.
European Patent (EP) No. 554543 International Publication No. 200196540 Pamphlet International Publication No. 2001092526 Pamphlet International Publication No. 01/022953 Pamphlet International Publication No. 02/049628 Pamphlet WO 97/15300 pamphlet Jentsch Nature Reviews Neuroscience 2000, 1, 21-30 Robbins Pharmacol Ther 2001, 90, 1-19 Rogawski Trends in Neurosciences 2000, 23, 393-398 Cooper et al. Proceedings National Academy of Science USA 2000, 97, 4914-4919 Marrion Annual Review Physiology 1997, 59, 483-504 Rostock et al. Epilepsy Research 1996, 23, 211-223 Bialer et al. Epilepsy Research 2002, 51, 31-71 Wickenden et al. Molecular Pharmacology 2000, 58, 591-600 Wickenden et al. Society for Neuroscience Abstracts 2002, 454.7 Schroder et al. Neuropharmacology 2001, 40, 888-898; Blackburn-Munro and Jensen European Journal of Pharmacology 2003, 460, 109-116 Goldstein et al. Society for Neuroscience Abstracts 2003, 53.8 Noda et al., Society for Neuroscience Abstracts 2003, 53.9 Ebert et al. Epilepsia 2002, 43 Suppl 5, 86-95 Tober et al. European Journal Of Pharmacology 1996, 303, 163-169 Watson et al. Neuropharmacology 1997, 36, 1369-1375 Saganich et al. Journal of Neuroscience 2001, 21, 4609-4624 Hartz et al. Journal of Psychopharmacology 2003, 17 suppl 3, A28, B16 Schroder et al., Pflugers Arch., 2003; 446 (5): 607-16 Cooper and Jan, Arch Neurol., 2003, 60 (4): 496-500 Jensen, CNS Drug Rev., 2002,8 (4): 353-60 Cooper et al., J Neurosci, 2001, 21, 9529-9540 Kubisch et al., Cell., 1999 Feb 5; 96 (3): 437-46

  One object of the present invention is to provide compounds that are potent openers of KCNQ family potassium channels.

  The compounds of the invention have the following formula I

で表される置換されたピリミジン誘導体またはその塩であり、式中、R¹、R²、R³、R⁴、R⁵およびq は以下に定義されるとおりである。

Embedded image wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and q are as defined below.

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

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

  The present invention includes seizure disorders, anxiety disorders, neuropathic and migraine pain disorders, other pain disorders such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal Methods of using a compound of formula I for the manufacture of a medicament for the treatment of symptoms or hearing disorders such as tinnitus are provided.

  The invention further provides seizure disorders, anxiety disorders, neuropathic and migraine pain disorders, other pain disorders such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol It relates to a method of using a compound of formula I for the treatment of withdrawal symptoms or hearing disorders such as tinnitus.

<Definition of substituents>
The phrase “heteroatom” represents a nitrogen, oxygen or sulfur atom.

  “Halogen” means fluoro, chloro, bromo or iodo. “Halo” means halogen.

  "Cyano" is linked to the rest of the molecule via a carbon atom

を表す。

Represents.

“Amino” refers to NH ₂ linked to the rest of the molecule through a nitrogen atom.

The expression “C _1-6 -alkyl (alkenyl / alkynyl)” means C _1-6 -alkyl, C _2-6 -alkenyl or C _2-6 -alkynyl. The phrase “C _1-6 -alkyl” is 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- Branched or unbranched alkyl having 1 to 6 carbon atoms including but not limited to 2-yl, pent-3-yl, hex-1-yl, hex-2-yl and hex-3-yl Indicates a group. The phrase “C _2-6 -alkenyl” refers to 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.

The expression “C _1-10 -alkyl (alkenyl / alkynyl)” means C _1-10 -alkyl, C _2-10 -alkenyl or C _2-10 -alkynyl.

The term “C _1-10 -alkyl” includes, but is not limited to, methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl 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- Denotes branched or unbranched alkyl groups having 1 to 10 carbon atoms, including 1-yl.

The phrase “C _2-10 -alkenyl” refers to 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 phrase “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.

The expression “C _3-8 -cycloalkyl (cycloalkenyl)” means C _3-8 -cycloalkyl or C _3-8 -cycloalkenyl. The phrase “C _3-8 -cycloalkyl” has 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, bicycloheptyl, for example, 2-bicyclo [2.2.1] heptyl. Represents a monocyclic or bicyclic carbocycle.

The phrase “C _3-8 -cycloalkenyl” is monocyclic or bicyclic carbon having 3 to 8 carbon atoms and 1 double bond, including but not limited to cyclopentenyl and cyclohexenyl. Represents a ring.

The phrase “halo-C _1-6 -alk (en / yn) yl” represents C _1-6 -alk (en / yn) yl substituted with halogen, including but not limited to trifluoromethyl.

The phrase “halo-C _1-6 -alkyl (alkenyl / alkynyl) oxy” refers to C _1-6 -alkyl (alkenyl / alkynyl) oxy substituted with halogen, including but not limited to trifluoromethyloxy. .

Similarly, “halo-C _3-8 -cycloalkyl (cycloalkenyl)” includes C _3-8 -cycloalkyl (cycloalkenyl) substituted with halogen, including but not limited to chlorocyclopropane and chlorocyclohexane. To express.

Likewise, "halo -C _3-8 - cycloalkyl (cycloalkenyl) oxy", but not limited to including chloro cyclopropyloxy and chloro cyclohexyloxy, C _3-8 substituted with halogen - cycloalkyl (cyclo Represents alkenyl) oxy.

Similarly, “halo-C _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl) oxy” is linked to a molecule via C _1-6 -alkyl (alkenyl / alkynyl) oxy. Represents halo-C _3-8 -cycloalkyl (cycloalkenyl) linked to the remainder.

The phrase “C _1-6 -alkyl (alkenyl / alkynyl) oxy” represents C _1-6 -alk (en / yn) yl linked to the rest of the molecule through an oxygen atom.

Similarly, “C _3-8 -cycloalkyl (alkenyl) oxy” refers to C _3-8 -cycloalkyl (alkenyl) linked to the remainder of the molecule through an oxygen atom.

  The phrase “aryl” refers to a monocyclic or bicyclic aromatic system selected from the group consisting of phenyl, naphthyl, thiophene, furan, benzothiophene and benzofuran.

The phrase “optionally substituted aryl-C _1-6 -alkyl (alkenyl / alkynyl)” refers to an aryl moiety, for example, halogen, cyano, C _1-6 -alk (en / yn) yl, C _{3 -8} -cycloalkyl (alkenyl), C _3-8 -cycloalkyl (alkenyl) -C _1-6 -alkyl (alkenyl / alkynyl), halo-C _1-6 -alkenyl (alkenyl / alkynyl), halo-C _{3 -8} -cycloalkyl (alkenyl), halo-C _3-8 -cycloalkyl (alkenyl) -C _1-6 -alkyl (alkenyl / alkynyl), C _1-6 -alkyl (alkenyl / alkynyl) oxy, C _{3- 8} - cycloalkyl (en) oxy and C _3-8 - cycloalkyl (alkenyl) -C _1-6 - alkyl (en / yn) two or three independently selected from the group consisting of oxy Aryl -C substituted with substituent _1-6 - an alkyl (en / yn).

Similarly, the phrase “optionally substituted aryl” refers to aryl optionally, for example, halogen, cyano, C _1-6 -alk (en / yn) yl, C _3-8 -cycloalkyl (alkenyl), C _3-8 -cycloalkyl (alkenyl) -C _1-6 -alkyl (alkenyl / alkynyl), halo-C _1-6 -alkyl (alkenyl / alkynyl), halo-C _3-8 -cycloalkyl (alkenyl), halo -C _3-8 -cycloalkyl (alkenyl) -C _1-6 -alkyl (alkenyl / alkynyl), C _1-6 -alkyl (alkenyl / alkynyl) oxy, C _3-8 -cycloalkyl (alkenyl) oxy and C _{3-8 -Cycloalkyl} (alkenyl) -C _1-6 -aryl substituted with 1, 2 or 3 substituents independently selected from the group consisting of (alkenyl / alkynyl) oxy.

“C _3-8 -cycloalkyl (alkenyl) -C _1-6 -alkyl (alkenyl / alkynyl)”, “aryl-C _1-6 -alkyl (alkenyl / alkynyl)” and “C _3-8 -cycloalkyl ( In the expression “alkenyl) -C _1-6 -alkyl (alkenyl / alkynyl) oxy”, “C _1-6 -alkyl (alkenyl / alkynyl)”, “C _3-8 -cycloalkyl (alkenyl)”, “aryl” And the phrase “C _1-6 -alk (en / yn) yloxy” is as defined above.

<Description of the invention>
The present invention relates to substituted pyrimidine derivatives that are KCNQ potassium channel openers.

  The present invention relates to general formula I:

で表される化合物であって、
式中、qが0または1であり；
R¹およびR²が水素および場合により置換されるアリール-C_1-6-アルキル（アルケニル／アルキニル）からなる群から独立して選択され、ただし、R¹およびR²は両方とも水素ではないことを条件とし、あるいは、R¹およびR²がこれらが連結する窒素と一緒に場合によりさらなるヘテロ原子を含有する5〜7員環を形成し；
R³およびR⁴が水素、ハロゲン、シアノ、アミノ、C_1-6-アルキル（アルケニル／アルキニル）、C_3-8-シクロアルキル（シクロアルケニル）、ハロ-C_1-6-アルキル（アルケニル／アルキニル）、ハロ-C_3-8-シクロアルキル（シクロアルケニル）、C_1-6-アルキル（アルケニル／アルキニル）オキシ、C_3-8-シクロアルキル（シクロアルケニル）オキシ、C_3-8-シクロアルキル（シクロアルケニル）-C_1-6-アルキル（アルケニル／アルキニル）オキシ、ハロ-C_1-6-アルキル（アルケニル／アルキニル）オキシ、ハロ-C_3-8-シクロアルキル（シクロアルケニル）オキシまたはハロ-C_3-8-シクロアルキル（シクロアルケニル）-C_1-6-アルキル（アルケニル／アルキニル）オキシから独立して選択され、ただし、R³およびR⁴は両方とも水素ではないことを条件とし；
R⁵がC_1-10-アルキル（アルケニル／アルキニル）、C_3-8-シクロアルキル（シクロアルケニル）-C_1-6-アルキル（アルケニル／アルキニル）、場合により置換されるアリール-C_1-6-アルキル（アルケニル／アルキニル）および場合により置換されるアリールからなる群から選択される、
前記の化合物またはその塩に関する。

A compound represented by:
Where 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 (alkenyl / alkynyl), provided that both R ¹ and R ² are not hydrogen Or R ¹ and R ² together with the nitrogen to which they are attached optionally form a 5-7 membered ring containing additional heteroatoms;
R ³ and R ⁴ are hydrogen, halogen, cyano, amino, C _1-6 -alkyl (alkenyl / alkynyl), C _3-8 -cycloalkyl (cycloalkenyl), halo-C _1-6 -alkyl (alkenyl / alkynyl) ), Halo-C _3-8 -cycloalkyl (cycloalkenyl), C _1-6 -alkyl (alkenyl / alkynyl) oxy, C _3-8 -cycloalkyl (cycloalkenyl) oxy, C _3-8 -cycloalkyl ( Cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl) oxy, halo-C _1-6 -alkyl (alkenyl / alkynyl) oxy, halo-C _3-8 -cycloalkyl (cycloalkenyl) oxy or halo-C Independently selected from _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl) oxy, provided that R ³ and R ⁴ are not both hydrogen. ;
R ⁵ is C _1-10 -alkyl (alkenyl / alkynyl), C _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alk (en / yn) yl, optionally substituted aryl-C _1-6 Selected from the group consisting of -alkyl (alkenyl / alkynyl) and optionally substituted aryl;
The present invention relates to the aforementioned compound or a salt thereof.

  In one embodiment of the compound 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, R ¹ and R ² are independently selected from hydrogen or optionally substituted aryl-C _1-6 -alk (en / yn) yl, provided that R ¹ and R ² is conditional on both not being hydrogen.

In another embodiment of the compounds of formula I, R ¹ and R ² together with the nitrogen to which they are linked form a 5-7 membered ring optionally containing additional heteroatoms; in another embodiment, The further 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, R ³ and R ⁴ are independently selected from amino or C _1-6 -alk (en / yn) yl, preferably methyl.

In another embodiment of the compounds of formula I, R ⁵ is C _1-10 -alkyl (alkenyl / alkynyl), C _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl), It is selected from the group consisting of optionally substituted aryl-C _1-6 -alkyl (alkenyl / alkynyl) and optionally substituted aryl.

  Another embodiment relates to the compound of formula I as the free base or a salt thereof, wherein said compound is selected from the compounds in the table below.

これらの化合物はそれぞれが特定の実施態様であり、個々の請求項に含めることもできるものである。

Each of these compounds is a specific embodiment and can be included in individual claims.

  The present invention also includes salts of the compounds of the present invention, typically pharmaceutically acceptable salts. The salts of the present invention include acid addition salts, metal salts, ammonium and alkylammonium salts.

  The salt of the present invention is preferably an acid addition salt. 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 and organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid and the like. Examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid, maleic acid, Malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamonic acid, bismethylene salicylic acid, ethanedisulfonic acid, Gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid and 8-halotheophylline such as 8-bromo Theophylline and the like are included. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include those described in “J. Pharm. Sci. 1977, 66, 2” incorporated herein by reference. Acceptable salts are included.

  Hydrates that can be formed by the compounds of the present invention are also contemplated as acid addition salts.

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

  Examples of ammonium and alkylammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts Etc. are included.

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

  The compounds of the present invention have one or more asymmetric centers, which means that they are resolved, mixtures containing pure or partially purified optical isomers and their racemic mixtures, i.e. stereoisomers. Any optical isomers (ie, enantiomers or diastereomers) such as a mixture of isomers are meant to be included within the scope of the present invention.

  Racemates can be resolved into the optical antipodes by known methods, for example, separation of the diastereomeric salts with an optically active acid and release of the optically active amine compound by treatment with a base. Another method for resolution of racemates into optical enantiomers is based on chromatography using an optically active matrix. The racemates of the invention can also be resolved into their optical enantiomers, for example, by fractional crystallization. The compounds of the invention can also be resolved by the formation of diastereomeric derivatives. Furthermore, a method for splitting an optical enantiomer known to those skilled in the art can also be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, New York (1981). Optical active compounds can also be prepared from optical active starting materials or by stereoselective synthesis.

  Furthermore, geometric isomers are formed when double bonds or fully or partially saturated ring systems are present in the molecule. Any geometric isomers such as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the present invention. Similarly, molecules having bonds with restricted rotation can form geometric isomers. These are also included in the scope of the present invention.

  In addition, some of the compounds of the present invention may exist in different tautomeric forms, and any tautomeric form that the compounds may form is within the scope of the invention.

  The invention also encompasses prodrugs of the compounds of the invention that upon administration undergo chemical conversion by metabolic processes before becoming pharmaceutically active substances. In general, the prodrugs are functional derivatives of the compounds of general formula I and are readily converted in vivo to the desired compounds of formula I. Conventional means for the selection and production of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” (ed. H. Bundgaard, Elsevier, 1985).

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

The compounds of the invention have an affinity for the KCNQ2 receptor subtype and exhibit an EC ₅₀ of less than 15000 nM, for example less than 10000 nM, as measured by the “Relative Flow Through KCNQ2 Channel” test described below. One embodiment is a compound of formula I that has an affinity for the KCNQ2 receptor subtype and exhibits an EC ₅₀ of less than 2000 nM, such as less than 1500 nM, as measured by the “Relative Flow Through KCNQ2 Channel” test described below. Relates to compounds. An embodiment to further illustrate the invention without limiting it has an affinity for the KCNQ2 receptor subtype, as measured by the “Relative Flow Through KCNQ2 Channel” test described below, and less than 200 nM, for example 150 relates to the above compounds exhibiting an EC ₅₀ of less than nM

One embodiment relates to compounds of formula I having an ED ₅₀ of less than 15 mg / kg in the “maximum electric shock” test described below. An embodiment to further illustrate the invention without limiting it relates to said compounds having an ED ₅₀ of less than 5 mg / kg in the “maximum electric shock” test described below.

One embodiment relates to compounds of formula I having an ED ₅₀ of less than 5 mg / kg in the “Electrical Seizure Threshold Test” and “Chemical Seizure Threshold Test” below.

  One embodiment relates to compounds of formula I that show little or no clinically significant side effects. Thus, some compounds of the invention are tested in models of unwanted analgesia, hypothermia and ataxia.

  One embodiment provides a large therapeutic index between anticonvulsant effects and side effects, such as locomotor activity impairment or ataxic effects, as measured by behavior on a rotating rod. Relates to compounds of formula I having Such compounds can be used at high doses in patients before side effects appear. Therefore, compliance in the treatment is good, and it is expected that administration of a higher dose, which is a more effective treatment, is possible in patients who have side effects with other drugs.

  As already mentioned, the compounds of the invention have an effect on the KCNQ family of potassium channels, in particular the KCNQ2 subunit, and thus they increase ion flux in voltage-gated potassium channels in mammals, for example humans. It is considered useful for The compounds of the present invention are considered applicable to the treatment of disorders or diseases that respond to increased ion flow in potassium channels, eg, KCNQ family potassium ion channels. Such a disorder or disease is preferably a disorder or disease of the central nervous system.

  In one embodiment, the compounds of the invention can be administered alone with a therapeutically effective compound.

In another embodiment, the compounds of the invention can be administered as part of a combination therapy, i.e., the compounds of the invention can be administered in combination with, for example, other therapeutically effective compounds having anticonvulsant properties. . The effects of other compounds having such anticonvulsant properties include, but are not limited to:
Ion channels such as sodium, potassium or calcium channels excitatory amino acid systems such as NMDA receptor blockade or modulation inhibitory neurotransmitter systems such as GABA release or GABA uptake blockade or membranes Activity in the stabilizing effect is included.

  Anticonvulsants currently in use include but are not limited to tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide ( ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide, and benzodiazepine and barbiturate derivatives are included.

  Embodiments of the present invention provide a compound of formula I or a salt thereof for use as a medicament.

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

  An embodiment of the present invention provides a pharmaceutical formulation comprising a compound of formula I or a salt thereof, and a pharmaceutically acceptable carrier or diluent. The formulation can include any of the embodiments of Formula I as described above.

  Another embodiment of the invention relates to a method of using a compound of formula I or a salt thereof to increase ion flux in a mammalian, eg, human, potassium channel.

  Another embodiment of the present invention is a method of using a compound of formula I or a salt thereof for the treatment of a disorder or disease responsive to increased ion flow in potassium channels, said disorder or disease preferably Relates to the use, as described above, which is a disorder or disease of the central nervous system.

  Another embodiment of the invention relates to a method of using Formula I or a salt thereof for the manufacture of a pharmaceutical formulation for the treatment of a disease or disorder for which a KCNQ potassium channel opener, such as a KCNQ2 potassium channel opener is useful. Usually such diseases or disorders are seizure disorders, anxiety disorders, neuropathic and migraine pain disorders, other pain disorders such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, Selected from the group consisting of nicotine withdrawal symptoms, ethanol withdrawal symptoms, and hearing impairments such as tinnitus.

  Another embodiment of the invention relates to a method of using a compound of formula I or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of seizure disorders.

  Usually, the seizure disorder to be treated is selected from the group consisting of acute seizures, convulsions, status epilepticus, and epilepsy, eg, epilepsy syndrome and epileptic seizures.

  An embodiment of the invention relates to a method of using a compound of formula I or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of anxiety disorders.

  Anxiety disorders usually treated include anxiety, panic anxiety, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific fear , Social phobia and other specific phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder for general physical disease, substance-induced anxiety disorder, isolated anxiety disorder Selected from the group consisting of disorders and diseases related to adaptation disorders, performance anxiety, psychosis disorders, anxiety disorders for general physical disorders and substance-induced anxiety disorders, and other unspecified anxiety disorders.

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

  Neuropathic pain and migraine pain disorders that are usually treated include allodynia, hyperalgesia, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain and fragments associated with trigeminal neuralgia Selected from the group consisting of neuropathic pain associated with headache.

  Another embodiment of the invention relates to a method of using a compound of formula I or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of neurodegenerative disorders.

  Usually, neurodegenerative disorders to be treated are Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Parkinson's disease, AIDS or rubella virus, herpesvirus, Borrelia Or encephalopathy induced by infection with unknown pathogens, trauma-induced neurodegeneration, neuroexcitability such as in drug withdrawal symptoms or addiction, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuropathy Selected from the group consisting of flames.

  Another embodiment of the invention relates to a method of using a compound of formula I or a salt thereof for the manufacture of a pharmaceutical formulation for the treatment of bipolar disorder or attention deficit hyperactivity disorder.

  Another embodiment of the invention relates to a method of using a compound of formula I or a salt thereof for the manufacture of a pharmaceutical formulation for the treatment of sleep disorders such as insomnia.

  Another embodiment of the present invention uses a compound of formula I or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of fibromyalgia, movement disorder or motion disorder, spasticity, myokemia or urinary incontinence Regarding the method.

  Another embodiment of the present invention is a method of using a compound of formula I or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of hearing disorders such as stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal symptoms or tinnitus About.

  As used herein in connection with a disease or disorder, the phrase “treatment” optionally also includes prevention, suppression and amelioration.

The present invention provides compounds that show efficacy in one or more of the following tests:
・ "Relative flow rate through KCNQ 2 channel"
This measures the effectiveness of a compound in the target channel • “Maximum electroshock”
This measures seizures induced by non-specific CNS stimulation by electrical means. “Pilocarpine-induced seizures”
The seizures induced by pilocarpine are often difficult to treat with many existing anti-seizure drugs and reflect a model of “drug-resistant seizures” • “Electrical seizure-threshold tests” "And" Chemical seizure-threshold tests "
These models measure the threshold at which seizures begin and detect whether a compound can delay seizure onset. “Amygdala kindling”
In this model, normal animals are used to measure disease progression since seizures become more severe in the animals when they are further stimulated.

<Pharmaceutical formulation>
The invention also relates to pharmaceutical formulations. The compounds of the invention or salts thereof can be administered in a single or multiple doses, alone or in combination with a pharmaceutically acceptable carrier or diluent. A pharmaceutical formulation according to the present invention, together with pharmaceutically acceptable carriers or diluents and other known adjuvants and excipients, is described in “Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack”. Can be formulated according to conventional techniques such as those disclosed in Publishing Co., Easton, PA, 1995.

  Such pharmaceutical preparations are specifically oral, rectal, nasal, lung, topical (including oral and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral ( It may be formulated for administration by any suitable route, such as subcutaneous, intramuscular, intrathecal, intravenous and intradermal routes, preferably the oral route. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the disorder or disease to be treated and the active ingredient chosen.

  The pharmaceutical formulations formed by combining the compounds of the present invention and a pharmaceutically acceptable carrier can then be easily administered in a variety of dosage forms suitable for the disclosed route of administration. Such formulations may conveniently be present in unit dosage form by methods known in the art.

  The compounds of the present invention are usually utilized as the free base or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound for which the free base is effective. When the compound of the present invention contains a free base, the salt is prepared in a conventional manner by treating a solution or suspension of the free base of the present invention with a chemical equivalent of a pharmaceutically acceptable acid. Manufactured. A typical example is as described above.

  Pharmaceutical formulations for oral administration can be solid or liquid. Solid dosage forms for oral administration include, for example, capsules, tablets, dragees, pills, lozenges, powders, granules, and hard gelatin capsules, for example, in the form of powders or pills, or Tablets in the form of lozenges or lozenges are included. Where appropriate, oral pharmaceutical formulations can be prepared with a coating, such as an enteric coating, or they can provide a controlled release, such as sustained or sustained release of the active ingredient. Thus, it can be formulated by a known method. Liquid dosage forms for oral administration include, for example, solutions, emulsions, suspensions, syrups and elixirs.

  Formulations of the present invention suitable for oral administration can be presented as discrete units, such as capsules or tablets each containing a predetermined amount of the active ingredient, which can contain suitable excipients. . Furthermore, formulations which can be used orally 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 extenders, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, gypsum, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, increased Examples thereof include gums. Examples of liquid carriers include syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.

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

  Any adjuvant or additive commonly used for such purposes, such as colorants, flavorings, preservatives, etc., may be used provided that it is compatible with the active ingredient.

  The amount of solid carrier can 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 gelatin capsule or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.

  Tablets can be made by mixing the active ingredient with the usual adjuvants or diluents and then compressing the mixture in a conventional tablet press.

  Pharmaceutical formulations for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions, as well as sterile powders reconstituted with sterile injection solutions or dispersions prior to use. Or an emulsion is included. Depot injectable formulations are also contemplated as being within the scope of the present invention.

  For parenteral administration, solutions of the compounds of the invention are used in sterile aqueous solutions, aqueous propylene glycol solutions, aqueous vitamin E solutions or sesame oil or peanut oil. The aqueous solution is suitably buffered if necessary and is first made isotonic with a liquid diluent using sufficient saline or glucose. Said aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Any of the sterilized aqueous media used can be readily utilized by standard techniques known to those skilled in the art.

  An injection solution is prepared by dissolving the active ingredient and possible additives in a solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and placing it in a suitable ampoule or vial. It can manufacture by satisfying. Appropriate additives conventionally used in the art can be added, for example, isotonic agents, preservatives, antioxidants and the like.

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

  A typical oral dose is about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 50 mg per kg body weight per day, more preferably about 0.05 to about 0.05 to 1 kg per body weight per day. Within the range of about 10 mg, one or more doses are administered, such as 1-3 doses. The exact dose will depend on the frequency and form of administration, the sex, age, weight and general condition of the subject, the nature and severity of the disorder or disease being treated, and the associated disease being treated, and for those skilled in the art Depends on other obvious factors.

  The formulation may conveniently be present in unit dosage form by methods known to those skilled in the art. Typical unit dosage forms for oral administration one or more times per day, such as 1 to 3 times per day, are about 0.01 to about 1000 mg, about 0.01 to about 100 mg, preferably about 0.05 to about 500 mg, and more preferably from about 0.5 to about 200 mg.

  The dose for parenteral routes such as intravenous, intrathecal, intramuscular and similar administration is typically about half of the dose used for oral administration.

A typical example of a formulation for formulation of the present invention is as follows:
1) Tablets containing 5.0 mg of the compound of the invention calculated as the free base:
Compound of the present invention 5.0 mg
Lactose 60 mg
Maze starch 30 mg
Hydroxypropylcellulose 2.4 mg
Microcrystalline cellulose 19.2 mg
Croscarmellose sodium type A 2.4 mg
Magnesium stearate 0.84 mg
2) Tablets containing 0.5 mg of the compound of the invention calculated as the free base:
Compound of the present invention 0.5 mg
Lactose 46.9 mg
Maze starch 23.5 mg
Povidone 1.8 mg
Microcrystalline cellulose 14.4 mg
Croscarmellose sodium type A 1.8 mg
Magnesium stearate 0.63 mg
3) Syrup containing the following per milliliter:
Compound of the present invention 25 mg
Sorbitol 500 mg
Hydroxypropylcellulose 15 mg
Glycerol 50 mg
Methyl-paraben 1 mg
Propyl-paraben 0.1 mg
Ethanol 0.005 mL
Flavor 0.05 mg
Saccharin sodium 0.5 mg
1 mL with water
4) Injection solution containing the following per milliliter:
Compound of the present invention 0.5 mg
Sorbitol 5.1 mg
Acetic acid 0.05 mg
Saccharin sodium 0.5 mg
To 1 mL with water Such an example of a compound of the invention means any one of the embodiments of formula I described herein.

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

<Production of the compound of the present invention>
The compounds of the invention of general formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and q are defined as above, are prepared as described below by the method depicted in the scheme be able to.

In the compounds of general formula I, XX, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and q are as defined under formula I.

  For compounds that may exist as an equilibrium between two or more tautomers, only one tautomer is shown in the scheme, but it may not be the most stable tautomer . Such compounds include, but are not limited to, hydroxypyrimidines of general formulas IX, X, XVII, XVIII that are also known to those skilled in the art.

  Compounds of general formulas II, III, VII, VIII, IX, X, XI, XIV, XVI, XVII, XIX and XX can be obtained commercially or can be obtained by standard methods known to those skilled in the art. Can be manufactured by.

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

  The compound of general formula V is prepared in the presence of an acid such as acetic acid or aqueous hydrochloric acid, using a suitable reducing agent such as zinc or iron powder, or at a suitable temperature or microwave irradiation, such as a suitable solvent such as From a compound of general formula IV by reducing the nitro group to an amino group with hydrogen gas or ammonium formate in the presence of a suitable hydrogenation catalyst such as palladium on activated carbon in methanol, ethanol, ethyl acetate or tetrahydrofuran. Can be manufactured. Alternatively, tin (II) chloride or sodium dithionite can be used as a reducing agent under conditions known to those skilled in the art.

  The compounds of the general formula I can be obtained in suitable solvents such as ethyl acetate, dioxane, tetrahydrofuran, acetonitrile or diethyl ether at a suitable temperature, such as room temperature, reflux temperature or elevated temperature in a sealed solution under microwave irradiation. A compound of the general formula V with or without the addition of a base, such as pyridine, trialkylamine, potassium carbonate, magnesium oxide, or lithium-, sodium- or potassium alcoholate, with a suitable electrophile, for example Although not limited, it can be produced by reacting with an appropriately substituted carboxylic acid fluoride, carboxylic acid chloride, carboxylic acid bromide, carboxylic acid iodide, carboxylic acid anhydride, active ester, or chloroformate. Active esters and carboxylic acid anhydrides are described in, for example, “F. Albericio and LA Carpino,“ Coupling reagents and activation ”in Methods in enzymology: Solid-phase peptide synthesis, pp. 104-126, Academic Press, New York, 1997”. It can be prepared from the appropriately substituted carboxylic acid under conditions known to those skilled in the art as described. Carboxylic acid halides are appropriately substituted by activation with reagents such as but not limited to thionyl chloride, oxalyl chloride, phosphorus tribromide or phosphorus triiodide under conditions known to those skilled in the art. It can be produced from carboxylic acid.

一般式IIの化合物は、スキーム2に示されるように製造することができる。一般式IXの化合物は、適当な温度、例えば室温、還流温度での、または密封容器中におけるマイクロ波照射下の高温での、触媒、例えば塩酸、硫酸、メタンスルホン酸またはポリリン酸またはルイス酸の添加を伴うまたは伴わない、適当な溶剤、例えばN,N-ジメチルホルムアミド、N-メチルピロリジノンまたはエタノールにおける、尿素の1,3-ジカルボニル化合物VIIとの、またはその等価物、例えば不飽和カルボニル化合物VIIIとの縮合により製造される。一般式Xの化合物は、例えば「P.B.D. de la Mare and J.H. Ridd, “Preparative methods of nitration” in Aromatic substitutions, pp. 48-56, Butterworths Scientific Publications, London, 1959」に記載されるように、適当な温度で、適当な溶剤、例えば氷酢酸、酢酸無水物、トリフルオロ酢酸、濃硫酸またはこれらの混合物において、濃硝酸、亜硝酸ナトリウムまたは硝酸ナトリウムを用いる反応のような当業者に公知のニトロ化反応によって、一般式IXの化合物から製造することができる。一般式Xの化合物は、当業者に公知の方法、例えばオキシ塩化リンまたはオキシ臭化リンでの塩素化または臭素化によって一般式IIの化合物に転化することができる。Xが塩素または臭素である一般式IIの化合物は、当業者に公知の条件下における、適当な試薬、例えばヨウ化水素酸、フッ化水素酸、ヨウ化ナトリウム、フッ化カリウムを用いるハロゲン交換反応によって、Xが塩素または臭素である一般式IIの化合物から製造することができる。

Compounds of general formula II can be prepared as shown in Scheme 2. Compounds of the general formula IX are suitable for use in catalysts such as hydrochloric acid, sulfuric acid, methanesulfonic acid or polyphosphoric acid or Lewis acid at a suitable temperature, for example at room temperature, reflux temperature, or at elevated temperatures under microwave irradiation in a sealed container. Urea with 1,3-dicarbonyl compound VII or equivalent thereof, such as an unsaturated carbonyl compound, in a suitable solvent, such as N, N-dimethylformamide, N-methylpyrrolidinone or ethanol, with or without addition Manufactured by condensation with VIII. Compounds of general formula X are suitable as described in, for example, “PBD de la Mare and JH Ridd,“ Preparative methods of nitration ”in Aromatic substitutions, pp. 48-56, Butterworths Scientific Publications, London, 1959”. Nitration reactions known to those skilled in the art, such as reactions using 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 temperature Can be prepared from compounds of general formula IX. Compounds of general formula X can be converted to compounds of general formula II by methods known to those skilled in the art, for example chlorination or bromination with phosphorus oxychloride or phosphorus oxybromide. Compounds of the general formula II in which X is chlorine or bromine are halogen exchange reactions using suitable reagents such as hydroiodic acid, hydrofluoric acid, sodium iodide, potassium fluoride under conditions known to those skilled in the art Can be prepared from compounds of general formula II in which X is chlorine or bromine.

一般式XIIおよびXVの化合物（スキーム3）は、一般式IXの化合物の製造に関するスキーム2に記載されるような条件下での、1,3-ジカルボニル化合物またはそれと同等の一般式VII、VIII（LGは適当な脱離基、例えばアルコキシまたはジアルキルアミノである）またはXIVの不飽和カルボニル化合物との縮合反応により 適当に置換された一般式XIのグアニジンから製造することができる。一般式XIIの化合物を、当業者に公知のジアゾカップリングによって、一般式XVの化合物に転化することができる。あるいは、一般式XVの化合物を、一般式Xの化合物の製造に関するスキーム2に記載されるようにニトロ化することができる。一般式Vの化合物は、スキーム1で一般式Vの化合物の製造に関して記載されるような条件下で、ニトロ基またはジアゾ基をそれぞれアミノ基に還元することによって、一般式XIIIの化合物から製造することができる。

Compounds of general formula XII and XV (Scheme 3) can be prepared from 1,3-dicarbonyl compounds or equivalent general formulas VII, VIII under the conditions as described in Scheme 2 for the preparation of compounds of general formula IX. (LG is a suitable leaving group such as alkoxy or dialkylamino) or can be prepared from a suitably substituted guanidine of the general formula XI by condensation reaction with an unsaturated carbonyl compound of XIV. Compounds of general formula XII can be converted to compounds of general formula XV by diazo coupling known to those skilled in the art. Alternatively, compounds of general formula XV can be nitrated as described in Scheme 2 for the preparation of compounds of general formula X. A compound of general formula V is prepared from a compound of general formula XIII by reducing the nitro or diazo group to an amino group, respectively, under the conditions as described for the preparation of the compound of general formula V in Scheme 1. be able to.

特に、スキーム3に記載される条件下における、一般式XIの置換されたグアニジンと一般式XVIのケトエステルまたはケト酸（スキーム4）との縮合によって、一般式XVIIの化合物が形成し、これを上述の条件下でニトロ化することにより、一般式XVIIIの化合物を得ることができる。XVIIIのヒドロキシ基は、一般式IIを有する化合物の製造に関する上述の条件下でのハロゲン化反応によって、一般式XX（R⁴がハロゲンであるXIII）の化合物に転化することができる。あるいは、一般式XX（R⁴がハロゲンであるXIII）の化合物は、当業者に公知の条件下での適当なハロゲンアニオンの存在下におけるジアゾ化反応、それに続く求核置換反応によって、一般式XIX（R⁴がハロゲンであるXIII）の化合物から製造することができる。一般式XIIIで表され、R⁴がC_1-6-アルキル（アルケニル／アルキニル）、C_3-8-シクロアルキル（シクロアルケニル）、C_3-8-シクロアルキル（シクロアルケニル）-C_1-6-アルキル（アルケニル／アルキニル）、ハロ-C_1-6-アルキル（アルケニル／アルキニル）、ハロ-C_3-8-シクロアルキル（シクロアルケニル）またはハロ-C_3-8-シクロアルキル（シクロアルケニル）-C_1-6-アルキル（アルケニル／アルキニル）である化合物は、当業者に公知のクロスカップリング反応、例えば根岸カップリング（E.-I. Negishi, A.O. King and N. Okukado, J.Org.Chem., 1977, 42, 1821）、薗頭カップリング（K. Sonogashira, Y. Tohda and N. Hagihara, Tet.Lett., 1975, 16, 4467）、または、他の金属触媒クロスカップリング反応、例えば銅触媒反応（W. Dohle, D.M. Lindsay and P. Knochel, Org.Lett., 2001， 3, 2871）によって、一般式XX（R⁴がハロゲンであるXIII）の化合物から製造することができる。

In particular, condensation of a substituted guanidine of general formula XI with a keto ester or keto acid of general formula XVI (Scheme 4) under the conditions described in Scheme 3 forms a compound of general formula XVII, which is described above. The compound of the general formula XVIII can be obtained by nitration under the following conditions. The hydroxy group of XVIII can be converted to a compound of general formula XX (XIII where R ⁴ is halogen) by a halogenation reaction under the conditions described above for the preparation of compounds having general formula II. Alternatively, a compound of general formula XX (XIII where R ⁴ is halogen) can be prepared by a diazotization reaction in the presence of a suitable halogen anion under conditions known to those skilled in the art followed by a nucleophilic substitution reaction. It can be produced from a compound of (XIII where R ⁴ is halogen). Represented by the general formula XIII, R ⁴ is C _1-6 -alk (en / yn) yl, C _3-8 -cycloalkyl (cycloalkenyl), C _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -Alkyl (alkenyl / alkynyl), halo-C _1-6 -alkyl (alkenyl / alkynyl), halo-C _3-8 -cycloalkyl (cycloalkenyl) or halo-C _3-8 -cycloalkyl (cycloalkenyl)- Compounds that are C _1-6 -alk (en / yn) yl are known to be cross-coupling reactions known to those skilled in the art, such as Negishi coupling (E.-I. Negishi, AO King and N. Okukado, J. Org. Chem. 1977, 42, 1821), Sonogashira coupling (K. Sonogashira, Y. Tohda and N. Hagihara, Tet. Lett., 1975, 16, 4467), or other metal catalyzed cross-coupling reactions such as By copper catalysis (W. Dohle, DM Lindsay and P. Knochel, Org. Lett., 2001, 3, 2871). , General formula XX may be prepared from compounds of (R ⁴ is XIII halogen).

Furthermore, compounds of the general formula XIII in which R ⁴ is cyano are nickel-catalyzed cyanos known to those skilled in the art, for example as described in “L. Cassar, J. Organomet. Chem., 1973, 54, C57-C58”. It can be produced from a compound of the general formula XX (general formula XIII where R ⁴ is a halogen) by a chemical reaction.

And a compound of the general formula XIII, wherein R ⁴ is C _1-6 -alk (en / yn) yl, C _3-8 -cycloalkyl (cycloalkenyl) oxy or C _3-8 -cycloalkyl (cycloalkenyl) ) -C _1-6 -alkyl (alkenyl / alkynyl) oxy compounds with or with the addition of a catalyst, such as copper sulfate, in a suitable solvent, such as dioxane, at a suitable temperature, such as room temperature or reflux temperature. By reaction with a suitable lithium-, sodium- or potassium alcoholate or alcohol in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, lithium hydride, sodium hydride or potassium hydride. , general formula XX may be prepared from compounds of (R ⁴ is formula XIII is halogen)

薗頭反応によって製造されるアルキンは、例えば「S. Siegel, “Heterogeneous catalytic hydrogenation of C=C and alkynes” in Comprehensive Organic Synthesis, v. 8, pp. 417-442, Pergamon Press, 1991」に記載されるように、適当な温度で、適当な溶剤、例えばメタノール、エタノールまたはテトラヒドロフラン中において、適当な水素化触媒、例えば活性炭担持パラジウムまたは活性炭担持白金の存在下で水素ガスまたはギ酸アンモニウムを用いる反応によって、アルケンまたはアルカンに還元することができる。

Alkynes produced by Sonogashira reaction are described in, for example, “S. Siegel,“ Heterogeneous catalytic hydrogenation of C = C and alkynes ”in Comprehensive Organic Synthesis, v. 8, pp. 417-442, Pergamon Press, 1991”. By reaction with hydrogen gas 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, Can be reduced to alkenes or alkanes.

  <Production of the compound of the present invention>

Analytical LC-MS data was obtained with a PE Sciex API 150EX instrument equipped with atmospheric pressure photoionization and a Shimadzu LC-8A / SLC-10A LC system. Column: 30 x 4.6 mm Waters Symmetry C18 column with a particle size of 3.5 μm; solvent system: A = water / trifluoroacetic acid (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid (5: 95: 0.03); method : Elution with a linear gradient from 90% A to 100% B over 4 minutes and a flow rate of 2 mL / min. Purity was determined by integration of UV (254 nm) and ELSD traces. Retention time (t _R ) is expressed in minutes.

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

  Microwave experiments were performed using Emerys Synthesizer or Emrys Optimizer EXP from Personal Chemistry, or Milestone Microsynth equipment from Milestone, in sealed process vials or in the reactor. If the reaction was heated with a microwave device, it was cooled to 25 ° C. before the next process step.

  <Production of intermediate>

6-メチル-5-ニトロ-N*2*-(4-トリフルオロメチルベンジル)-ピリミジン-2,4-ジアミン
アセトニトリル（3 ml）およびトリエチルアミン（0.5 ml）における2-クロロ-6-メチル-5-ニトロピリミジン-4-イルアミン（300 mg, 1.591 mmol）、4-トリフルオロメチルベンジルアミン（369 mg, 2.107 mmol）の混合物をアルゴンでフラッシュし、Emrys製プロセスバイアル中に密閉して、マイクロ波照射下において120℃で2分間加熱した。得られた懸濁液を10%水性炭酸ナトリウム（2 ml）および有機揮発性物質を減圧下で蒸発させた。メタノール（5 ml）および水（100 ml）を残渣に添加した。生成物をろ過により分離し、水で洗浄し、減圧下で乾燥することによって490 mgの黄色固体を得た。収率 94%。LC-MS (m/z) 328.1 (MH⁺); t_R = 2.58。¹H NMR (500 MHz, DMSO-d₆): 2つの回転異性体の約3:1の混合物, 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-5-nitro-N * 2 *-(4-trifluoromethylbenzyl) -pyrimidine-2,4-diamine 2-chloro-6-methyl-5 in acetonitrile (3 ml) and triethylamine (0.5 ml) -Nitropyrimidin-4-ylamine (300 mg, 1.591 mmol), 4-trifluoromethylbenzylamine (369 mg, 2.107 mmol) was flushed with argon, sealed in an Emrys process vial and microwaved Under heating at 120 ° C. for 2 minutes. The resulting suspension was evaporated under reduced pressure with 10% aqueous sodium carbonate (2 ml) and organic volatiles. Methanol (5 ml) and water (100 ml) were added to the residue. The product was isolated by filtration, washed with water and dried under reduced pressure to give 490 mg of a yellow solid. Yield 94%. LC-MS (m / z) 328.1 (MH +); t R = 2.58. ¹ H NMR (500 MHz, DMSO-d ₆ ): about 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, 0.75 H, NH).

6-メチル-N*2*-(4-トリフルオロメチルベンジル)-ピリミジン-2,4,5-トリアミン
冷水浴において激しく撹拌したテトラヒドロフラン（20 ml）および酢酸（5 ml）における6-メチル-5-ニトロ-N*2*-(4-トリフルオロメチルベンジル)-ピリミジン-2,4-ジアミン（450 mg、1.376 mmol）の溶液に、亜鉛粉（粒子径＜10ミクロン、5 g）を少量ずつ2分間で添加した。水浴を取り外し、さらに亜鉛粉（2 g）を添加した。懸濁液を常温で60分間撹拌し、10%の水性炭酸ナトリウムでpH＞8にクエンチした。得られた懸濁液を酢酸エチルで抽出した（10倍）。合わせた有機溶液をシリカゲルプラグ（10 g）によってろ過し、20%酢酸エチルで溶出することにより、蒸発後に430 mgの淡黄色油状物を得た。生成物は減圧下での乾燥後に凝固した。収率 100%。これをさらに精製することなく次の段階に使用した。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, NH₂ + H₂O), 4.43 (d, 2H), 5.88 (br, 2H), 6.26 (t, 1H, NH), 7.48 (d, 2H), 7.62 (d, 2H)。

6-methyl-N * 2 *-(4-trifluoromethylbenzyl) -pyrimidine-2,4,5-triamine 6-methyl-5 in tetrahydrofuran (20 ml) and acetic acid (5 ml) stirred vigorously in a cold water bath -Nitro-N * 2 *-(4-trifluoromethylbenzyl) -pyrimidine-2,4-diamine (450 mg, 1.376 mmol) in a solution of zinc powder (particle size <10 microns, 5 g) in small portions Added in 2 minutes. The water bath was removed and more zinc powder (2 g) was added. The suspension was stirred at ambient temperature for 60 minutes and quenched with 10% aqueous sodium carbonate to pH> 8. The resulting suspension was extracted with ethyl acetate (10 times). The combined organic solution was filtered through a silica gel plug (10 g) and eluted with 20% ethyl acetate to give 430 mg of a pale yellow oil after evaporation. The product solidified after drying under reduced pressure. Yield 100%. This was used in the next step without further purification. LC-MS (m / z) 298.1 (MH +); t R = 1.68. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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-Chlorophenylacetyl chloride 3-Chlorophenylacetic acid (19.7 g) in thionyl chloride (100 ml) was heated under reflux for 3 hours. Volatiles were removed under reduced pressure and the resulting oily residue was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ ): 4.12 (s, 2H), 7.16 (d, 1H), 7.27-7.34 (m, 3H).

The following acid chlorides were similarly prepared from the corresponding acids:
3,4-difluorophenylacetyl chloride
¹ H NMR (500 MHz, CDCl ₃ ): 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-ジメチル-ピリミジン-2-イル)-モルホリン
エタノール（6 ml）におけるモルホリノホルムアミジンヒドロクロリド（2.0 g、9.52 mmol）の懸濁液にカリウムtert-ブトキシド（1.068 g、9.52 mmol）を添加し、その後アセチルアセトン（2 ml、20 mmol）を添加した。反応混合物をアルゴンでフラッシュし、Emrysプロセスバイアル中に密閉し、マイクロ波照射下において140℃で5分間加熱した。これを冷却した後、酢酸エチル（50 ml）でクエンチし、SiO₂プラグ（5 g）によってろ過し、そして酢酸エチルで溶出した。揮発性物質を減圧下において70℃で除去することにより、1.65 gの薄茶色の油状物を得、これを一晩凝固させた。収率 90%。LC-MS (m/z) 193.9 (MH⁺); t_R= 0.71。¹H NMR (500 MHz, DMSO-d₆): 2.23 (s, 6H), 3.62 (m, 4H), 3.67 (m, 4H), 6.44 (s, 1H)。

4- (4,6-Dimethyl-pyrimidin-2-yl) -morpholine To a suspension of morpholinoformamidine hydrochloride (2.0 g, 9.52 mmol) in ethanol (6 ml) potassium tert-butoxide (1.068 g, 9.52 mmol) ) Was added followed by acetylacetone (2 ml, 20 mmol). The reaction mixture was flushed with argon, sealed in an Emrys process vial and heated at 140 ° C. for 5 minutes under microwave irradiation. After cooling, it was quenched with ethyl acetate (50 ml), filtered through a SiO ₂ plug (5 g) and eluted with ethyl acetate. Volatiles were removed under reduced pressure at 70 ° C. to give 1.65 g of a light brown oil that solidified overnight. Yield 90%. LC-MS (m / z) 193.9 (MH +); t R = 0.71. ¹ H NMR (500 MHz, DMSO-d ₆ ): 2.23 (s, 6H), 3.62 (m, 4H), 3.67 (m, 4H), 6.44 (s, 1H).

4-(4,6-ジメチル-5-ニトロ-ピリミジン-2-イル)-モルホリン
方法A：撹拌した氷酢酸（50 ml）における4-(4,6-ジメチルピリミジン-2-イル)-モルホリン（8.94 g、46.3 mmol）の溶液に、発煙硝酸（5.75 ml、3当量）を滴加した。反応混合物を70℃で15分間加熱し、その後さらに硝酸（3.8 ml、2当量）を添加した。70℃でさらに15分間置いた後、これを冷却し、氷と水酸化ナトリウム（44g）の水溶液（200 ml）の混合物に少量ずつ加えた。生成物をろ過により分離することにより、0.637 gの黄色固体を得た。収率 6%。LC-MS (m/z) 239.0 (MH⁺); t_R= 2.76。

4- (4,6-Dimethyl-5-nitro-pyrimidin-2-yl) -morpholine Method A: 4- (4,6-Dimethylpyrimidin-2-yl) -morpholine (50 ml) in stirred glacial acetic acid ( To a solution of 8.94 g, 46.3 mmol) fuming nitric acid (5.75 ml, 3 eq) was added dropwise. The reaction mixture was heated at 70 ° C. for 15 minutes, after which more nitric acid (3.8 ml, 2 eq) was added. After an additional 15 minutes at 70 ° C., it was cooled and added in small portions to a mixture of ice and an aqueous solution of sodium hydroxide (44 g) (200 ml). The product was separated by filtration to give 0.637 g of a yellow solid. Yield 6%. LC-MS (m / z) 239.0 (MH +); t R = 2.76.

Method B: To a solution of 4- (4,6-dimethylpyrimidin-2-yl) -morpholine (4 g, 20.7 mmol) in trifluoroacetic acid (100 ml) stirred with warming (65 ° C.) was added sodium nitrate (3.52 g, 41.4 mmol) was added. After 3 hours more sodium nitrate (1.8 g, 20.7 mmol) was added and the reaction mixture was kept at 65 ° C. overnight. This was carefully added in small portions to 10% aqueous sodium carbonate (600 ml) and the product was isolated by filtration. Yield 1.637 g, 33%. LC-MS (m / z) 238.9 (MH +); t R = 2.70. ¹ H NMR (500 MHz, DMSO-d ₆ ): 2.44 (s, 6H), 3.65 (m, 4H), 3.83 (m, 4H).

4,6-ジメチル-2-モルホリン-4-イル-ピリミジン-5-イルアミン
4-(4,6-ジメチル-5-ニトロピリミジン-2-イル)-モルホリン（2.2 g、9.23 mmol）、活性炭担持5%パラジウム（50% wet, 1.09 g）、ギ酸アンモニウムの懸濁物をEmrys process vial中に密閉し、マイクロ波照射下で150℃において2分間加熱した。反応混合物をろ過し、蒸発させた。残渣を酢酸エチルで処理し、ろ過することにより、減圧下での蒸発の後に1.62 gの橙色の結晶質生成物を得た。収率 84%。LC-MS (m/z) 208.9 (MH⁺); t_R = 0.44。¹H NMR (500 MHz, DMSO-d₆): 2.2 (s, 6H), 3.44 (m, 4H), 3.62 (m, 4H), 4.19 (br, 2H, NH₂)。

4,6-Dimethyl-2-morpholin-4-yl-pyrimidin-5-ylamine
A suspension of 4- (4,6-dimethyl-5-nitropyrimidin-2-yl) -morpholine (2.2 g, 9.23 mmol), 5% palladium on activated carbon (50% wet, 1.09 g), and ammonium formate suspension Sealed in a process vial and heated at 150 ° C. for 2 minutes under microwave irradiation. The reaction mixture was filtered and evaporated. The residue was treated with ethyl acetate and filtered to give 1.62 g of orange crystalline product after evaporation under reduced pressure. Yield 84%. LC-MS (m / z) 208.9 (MH +); t R = 0.44. ¹ H NMR (500 MHz, DMSO-d ₆ ): 2.2 (s, 6H), 3.44 (m, 4H), 3.62 (m, 4H), 4.19 (br, 2H, NH ₂ ).

<Invention Compound>
Acid addition salts of the compounds of the present invention can 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

冷却し、撹拌したアセトニトリル（3 ml）における6-メチル-N*2*-(4-トリフルオロメチル-ベンジル)-ピリミジン-2,4,5-トリアミン（119 mg、0.401 mmol）の溶液（氷／水浴）に、シクロペンチルアセチルクロリド（59 mg、0.402 mmol）を2分間で滴加した。冷却浴を取り外し、撹拌を20分間継続した。得られた懸濁液を水（85 ml）および10%の水性炭酸ナトリウム（0.5 ml）でクエンチした。有機揮発性物質を減圧下で除去し、酢酸エチル（0.5 ml）を添加し、そして混合物をヘプタン（20 ml）でクエンチした。得られた二相性懸濁液をろ過した。生成物を水およびヘプタンで洗浄し、減圧下で乾燥することにより、40 mgの淡黄色固体を得た。収率 25%。LC-MS (m/z) 408.3 (MH⁺); t_R = 2.11。¹H NMR (500 MHz, 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)。

Cooled and stirred solution of 6-methyl-N * 2 *-(4-trifluoromethyl-benzyl) -pyrimidine-2,4,5-triamine (119 mg, 0.401 mmol) in acetonitrile (3 ml) (ice / Water bath) was added dropwise with cyclopentylacetyl chloride (59 mg, 0.402 mmol) over 2 minutes. The cooling bath was removed and stirring was continued for 20 minutes. The resulting suspension was quenched with water (85 ml) and 10% aqueous sodium carbonate (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 resulting biphasic suspension was filtered. The product was washed with water and heptane and dried under reduced pressure to give 40 mg of a pale yellow solid. Yield 25%. LC-MS (m / z) 408.3 (MH +); t R = 2.11. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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, NH ₂ ), 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-dimethylbutyramide

冷却し、撹拌したアセトニトリル（7.5 ml）における6-メチル-N*2*-(4-トリフルオロメチル-ベンジル)-ピリミジン-2,4,5-トリアミン（341 mg、1.15 mmol）の溶液（氷／水浴）に、tert-ブチルアセチルクロリド（0.16 ml, 1.15 mmol）を2分間で滴加した。冷却浴を取り外し、撹拌を45分間継続した。得られた反応混合物をSCXカラム（10 g、H⁺ form）に加え、アセトニトリル（20 ml）、メタノール（100 ml）で洗浄し、生成物をメタノール（60 ml）における4M NH₃で溶出した。揮発性物質を減圧下で除去し、粗製生成物をシリカゲル（20 g）においてヘプタン-酢酸エチル勾配を用いるフラッシュクロマトグラフィーによって精製することにより、153 mgの固体を得た。収率 33.7%。LC-MS (m/z) 395.9 (MH⁺); t_R = 2.00。¹H NMR (500 MHz, 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)。

Cooled and stirred solution of 6-methyl-N * 2 *-(4-trifluoromethyl-benzyl) -pyrimidine-2,4,5-triamine (341 mg, 1.15 mmol) in ice (7.5 ml) (ice / Water bath) was added dropwise over 2 minutes with tert-butylacetyl chloride (0.16 ml, 1.15 mmol). The cooling bath was removed and stirring was continued for 45 minutes. The obtained reaction mixture was added to an SCX column (10 g, H ⁺ form), washed with acetonitrile (20 ml) and methanol (100 ml), and the product was eluted with 4M NH ₃ in methanol (60 ml). Volatiles were removed under reduced pressure and the crude product was purified by flash chromatography on silica gel (20 g) using a heptane-ethyl acetate gradient to give 153 mg of solid. Yield 33.7%. LC-MS (m / z) 395.9 (MH +); t R = 2.00. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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 similarly prepared using the corresponding acid chlorides.

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

収率 12%。LC-MS (m/z) 434.3 (MH⁺); t_R = 2.07。¹H NMR (500 MHz, 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)。

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).

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

収量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 (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)。

Yield 39.7 mg, 50%. LC-MS (m / z) 396.1 (MH +); t R = 2.08. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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, 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-trifluoromethylbenzylamino) -pyrimidin-5-yl] -2- (3-chlorophenyl) -acetamide

収量 45.4 mg、50%。LC-MS (m/z) 450.1 (MH⁺); t_R = 2.17。¹H NMR (500 MHz, 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)。

Yield 45.4 mg, 50%. LC-MS (m / z) 450.1 (MH +); t R = 2.17. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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>

2a 2-シクロペンチル-N-(4,6-ジメチル-2-モルホリン-4-イル-ピリミジン-5-イル)-アセトアミド
冷却し、撹拌したアセトニトリル（40 ml）における4,6-ジメチル-2-モルホリン-4-イル-ピリミジン-5-イルアミン（2.04 g, 9.79 mmol）の溶液（氷／水浴）に、シクロペンチルアセチルクロリド（1.65 ml, 11.75 mmol）を添加した。冷却浴を取り外し、反応混合物を室温で30分間撹拌した。これを炭酸水素ナトリウム飽和水溶液（100 ml）および水に加え、ろ過した。得られた固体をアセトニトリルから再結晶化させることにより、1.877 gの無色固体を得た。収率 60%。LC-MS (m/z) 318.9 (MH⁺); t_R = 1.80。¹H NMR (500 MHz, 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)。

2a 2-cyclopentyl-N- (4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl) -acetamide 4,6-dimethyl-2-morpholine in cooled and stirred acetonitrile (40 ml) To a solution of -4-yl-pyrimidin-5-ylamine (2.04 g, 9.79 mmol) (ice / water bath) was added cyclopentylacetyl chloride (1.65 ml, 11.75 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. This was added to a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and water, and filtered. The obtained solid was recrystallized from acetonitrile to obtain 1.877 g of a colorless solid. Yield 60%. LC-MS (m / z) 318.9 (MH +); t R = 1.80. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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-dimethylbutyramide

アセトニトリル（30 ml）およびトリエチルアミン（2.9 ml、20.8 mmol）における4,6-ジメチル-2-モルホリン-4-イルピリミジン-5-イルアミン（2.1 g, 10.4 mmol）の溶液に、tert-ブチルアセチルクロリド（2.9 ml, 20.8 mmol）を滴加した。90分後に、反応混合物を水でクエンチし、酢酸エチルで2回抽出した。有機相を炭酸水素ナトリウム飽和水溶液（100 ml）で洗浄し、硫酸マグネシウムで乾燥し、SiO₂ におけるフラッシュクロマトグラフィー（20 g、ヘプタン-酢酸エチル勾配）によって精製した。得られた粗製生成物を熱トルエンから再結晶化させることにより、946 mgの無色固体を得た。収率 30%。LC-MS (m/z) 307.9 (MH⁺); t_R = 1.69。¹H NMR (500 MHz, DMSO-d₆): 1.04 (s, 9H), 2.16 (s, 6H), 2.19 (s, 2H), 3.64 (m, 8H), 9.13 (s, 1H)。

To a solution of 4,6-dimethyl-2-morpholin-4-ylpyrimidin-5-ylamine (2.1 g, 10.4 mmol) in acetonitrile (30 ml) and triethylamine (2.9 ml, 20.8 mmol), tert-butylacetyl chloride ( 2.9 ml, 20.8 mmol) was added dropwise. After 90 minutes, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (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 obtain 946 mg of a colorless solid. Yield 30%. LC-MS (m / z) 307.9 (MH +); t R = 1.69. ¹ H NMR (500 MHz, DMSO-d ₆ ): 1.04 (s, 9H), 2.16 (s, 6H), 2.19 (s, 2H), 3.64 (m, 8H), 9.13 (s, 1H).

The following compounds were similarly prepared from the corresponding acid chlorides:
2c N- (4,6-Dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (4-fluorophenyl) -acetamide

フラッシュクロマトグラフィ精製後に表題化合物を熱酢酸エチルから再結晶化させた。収量 1.193 g、37%。LC-MS (m/z) 345.1 (MH⁺); t_R= 1.81。¹H NMR (500 MHz, DMSO-d₆): 2.09 (s, 6H), 3.6-3.66 (overlapping m, 10H), 7.16 (t, 2H), 7.38 (dd, 2H), 9.42 (s, 1H)。

The title compound was recrystallized from hot ethyl acetate after flash chromatography purification. Yield 1.193 g, 37%. LC-MS (m / z) 345.1 (MH +); t R = 1.81. ¹ H NMR (500 MHz, DMSO-d ₆ ): 2.09 (s, 6H), 3.6-3.66 (overlapping 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

冷却し、撹拌したアセトニトリル（1 ml）における4,6-ジメチル-2-モルホリン-4-イルピリミジン-5-イルアミン（52.4 mg、0.25 mmol）の溶液（氷／水浴）に、3,4-ジフルオロフェニルアセチルクロリド（0.065 ml, 0.3 mmol）を滴加した。反応混合物を60℃で1分間置いて冷却した。これをSCXカラム（10 g、H⁺ form）に加え、アセトニトリルおよびメタノールで洗浄し、メタノールにおける4M NH₃で溶出した。蒸発させた後に、粗製組成物を酢酸エチルにおける濃縮溶液からヘプタンで沈殿させ、ろ過することにより、34 mgの無色固体を得た。収率 37%。LC-MS (m/z) 363.3 (MH⁺); t_R = 1.96。¹H NMR (500 MHz, 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)。

To a cooled and stirred solution of 4,6-dimethyl-2-morpholin-4-ylpyrimidin-5-ylamine (52.4 mg, 0.25 mmol) in acetonitrile (1 ml), 3,4-difluoro. Phenylacetyl chloride (0.065 ml, 0.3 mmol) was added dropwise. The reaction mixture was allowed to cool at 60 ° C. for 1 minute. This was added to an SCX column (10 g, H ⁺ form), washed with acetonitrile and methanol, and eluted with 4M NH ₃ in methanol. After evaporation, the crude composition was precipitated with heptane from a concentrated solution in ethyl acetate and filtered to give 34 mg of a colorless solid. Yield 37%. LC-MS (m / z) 363.3 (MH +); t R = 1.96. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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 similarly prepared using the appropriate acid chloride:
2e N- (4,6-Dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2- (3-fluorophenyl) -acetamide

表題化合物をSiO₂におけるフラッシュクロマトグラフィー（20 g、ヘプタン-酢酸エチル勾配）によって精製した。収量 27 mg、31%。LC-MS (m/z) 345.0 (MH⁺); t_R = 1.83。¹H NMR (500 MHz, DMSO-d₆): 2.09 (s, 6H), 3.62 (m, 4H), 3.64 (m, 4H), 3.66 (s, 2H), 7.08 (dt, 1H), 7.18 (overlapping dd, 1H), 7.19 (overlapping d, 1H), 7.38 (dt, 1H), 9.45 (s, 1H)。

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 (MH +); t R = 1.83. ¹ H NMR (500 MHz, DMSO-d ₆ ): 2.09 (s, 6H), 3.62 (m, 4H), 3.64 (m, 4H), 3.66 (s, 2H), 7.08 (dt, 1H), 7.18 ( overlapping dd, 1H), 7.19 (overlapping d, 1H), 7.38 (dt, 1H), 9.45 (s, 1H).

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

表題化合物をSiO₂におけるフラッシュクロマトグラフィー（20 g、ヘプタン-酢酸エチル勾配）によって精製した。収量 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 (qui, 2H), 2.14 (s, 6H), 2.28 (t, 2H), 3.63 (m, 4H), 3.65 (m, 4H), 9.16 (s, 1H)。

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. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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 used for compound production

＜生体外（In vitro）および生体内（in vivo）試験＞
本発明の化合物について試験が行われ、以下の1つまたは２つ以上のモデルにおいて効果が示された。

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

<Relative flow rate through KCNQ2 channel>
Here we illustrate the KCNQ2 screening protocol for evaluating the compounds of the present invention. This assay measures the relative flow rate through the KCNQ2 channel and is described in “Tang et al. (Tang, W. et. Al., J. Biomol. Screen. 2001, 6, 325-331)” for the hERG potassium channel. The method described above was carried out with modifications as described below.

A suitable number of CHO cells stably expressing voltage-gated KCNQ2 channels were seeded on the plate at a density sufficient to obtain one more confluent layer the day before the experiment was performed. Cells were loaded with 1 μCi / ml [ ⁸⁶ Rb] overnight. On the day of the experiment, the cells were washed with HBSS-containing buffer (Hanks balanced salt solution, manufactured by Invitrogen, catalog number: 14025-050). Cells were pre-incubated with the drug for 30 minutes and the ⁸⁶ Rb ⁺ efflux was stimulated by a submaximal concentration of 15 mM potassium chloride in the presence of the drug for the next 30 minutes. After incubation for an appropriate time, the supernatant was removed and counted with a liquid scintillation counter (manufactured by Tricarb). Cells were lysed with 2 mM sodium hydroxide and the amount of ⁸⁶ Rb ⁺ was counted. The relative flow rate was calculated ((CPM _super / (CPM _super + CPM _cell )) _Cmpd / (CPM _super / (CPM _super + CPM _cell )) _{15 mM KCl} ) * 100-100.

The compounds of the present invention had an EC ₅₀ of less than 20000 nM, in most cases an EC _{50 of} less than 2000 nM, and in many cases an EC ₅₀ of less than 200 nM. Accordingly, the compounds of the present invention are considered useful in the treatment of diseases associated with KCNQ family potassium channels.

<Electrophysiological patch clamp recording>
Voltage-activated KCNQ2 currents were recorded from mammalian CHO cells by using the conventional patch clamp recording technique in the whole cell patch clamp method (Hamill OP et.al. Pfluegers Arch 1981; 391: 85-100). CHO cells stably expressing voltage-activated KCNQ2 channels were cultured under normal cell culture conditions in a CO ₂ incubator and used for electrophysiological recording 1-7 days after seeding. KCNQ2 potassium channels were activated by increasing the voltage from the membrane holding potential of -100 mV to -40 mV in increments of 5-20 mV (or using the ramp protocol) to +80 mV (Tatulian L et al. J Neuroscience 2001; 21 (15): 5535-5545). The electrophysiological effects induced by the compounds were evaluated using various parameters of the voltage-activated KCNQ2 current. In particular, the effect on the activation threshold and the maximum induced current on current was examined.

  Several compounds of the present invention were tested in this test. Shifting the activation threshold to the left or increasing the maximum induced potassium current decreases activity in the neural network, and thus the compound is expected to be useful in diseases with increased neuronal activity such as epilepsy.

<Maximum electric shock>
To induce convulsions characterized by tonic hind limb extension, a study was performed in a group of male mice using a corneal electrode and a square wave current treatment at 26 mA for 0.4 seconds (Wlaz et al. Epilepsy Research 1998, 30, 219-229).

<Pilocarpine-induced seizure>
Pilocarpine-induced seizures were induced by intraperitoneal injection of 250 mg / kg pilocarpine into a group of male mice to observe seizure activity resulting in a loss of posture within 30 minutes (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 a., Radiation Research 1957, 1-12) was applied to tonic hind-stretch in male mice in response to corneal electrical shock. Used to measure the median threshold to induce limb extension). Seizure activity was observed in the first mouse of each group that received 14 mA (0.4 s, 50 Hz) electric shock. If a seizure was observed, the current for the next mouse was decreased by 1 mA, but if no seizure was observed, the current was increased by 1 mA. This process was repeated for all 15 mice in the treatment group.

<Chemical seizure-threshold test>
The threshold dose of pentylenetetrazole required for inducing clonic convulsions is continuously infused into the lateral tail vein of male mice in the group of male mice (5 mg / mL at 0.5 mL / min) ) (Nutt et al. J Pharmacy and Pharmacology 1986, 38, 697-698).

<Amygdala kindling>
Surgery was performed to implant the triode electrode in the lateral amygdala of the rat. Following surgery, the animals were allowed to recover before groups of rats received either doses of either test compound or drug vehicle. The animals were stimulated with the same current as the beginning of each day for 3-5 weeks after discharge at the threshold +25 μA, each time seizure severity, seizure duration, and duration of electricity after discharge Time was observed (Racine. Electroencephalography and Clinical Neurophysiology 1972, 32, 281-294).

<Side effects>
Central nervous system side effects are measured by measuring the time the mouse stays in the rotarod device (Capacio et al. Drug and Chemical Toxicology 1992, 15, 177-201); or measuring the number of infrared rays traversing the test cage By measuring locomotor activity (Watson et al. Neuropharmacology 1997, 36, 1369-1375). The hypothermic effect of compounds on animal core body temperature was measured with a rectal probe or a remote transmitter of an implant capable of measuring temperature (Keeney et al. Physiology and Behavior 2001, 74, 177-184).

<Pharmacokinetics>
The pharmacokinetic properties of the compound were determined by intravenous (iv) and oral (po) administration to Spraque Dawley rats and blood samples taken over 20 hours thereafter. Plasma concentration was measured by LC / MS / MS.

Claims (22)

Formula I:

A free base having a salt or a salt thereof,
Where 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 (alkenyl / alkynyl), provided that both R ¹ and R ² are not hydrogen Or R ¹ and R ² together with the nitrogen to which they are attached optionally form a 5-7 membered ring containing additional heteroatoms;
R ³ and R ⁴ are hydrogen, halogen, cyano, amino, C _1-6 -alkyl (alkenyl / alkynyl), C _3-8 -cycloalkyl (cycloalkenyl), halo-C _1-6 -alkyl (alkenyl / alkynyl) ), Halo-C _3-8 -cycloalkyl (cycloalkenyl), C _1-6 -alkyl (alkenyl / alkynyl) oxy, C _3-8 -cycloalkyl (cycloalkenyl) oxy, C _3-8 -cycloalkyl ( Cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl) oxy, halo-C _1-6 -alkyl (alkenyl / alkynyl) oxy, halo-C _3-8 -cycloalkyl (cycloalkenyl) oxy or halo-C Independently selected from _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl) oxy, provided that R ³ and R ⁴ are not both hydrogen. ;
R ⁵ is C _1-10 -alkyl (alkenyl / alkynyl), C _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alk (en / yn) yl, optionally substituted aryl-C _1-6 Selected from the group consisting of -alkyl (alkenyl / alkynyl) and optionally substituted aryl;
Said compound.   2. The compound according to claim 1, wherein q is 0.   2. The compound according to claim 1, wherein q is 1. R ¹ and R ² are independently selected from hydrogen or optionally substituted aryl-C _1-6 -alk (en / yn) yl, provided that R ¹ and R ² are not both hydrogen The compound according to any one of claims 1 to 3. R ¹ and R ² form a 5- to 7-membered ring containing a further heteroatom optionally together with the nitrogen to which they are linked, a compound according to any one of claims 1 to 3.   6. A compound according to claim 5, wherein said further heteroatom is oxygen.   7. A compound according to any one of claims 5 or 6, wherein the ring is a 6-membered ring.   The compound according to any one of claims 5 to 7, wherein the ring is a morpholine ring. R ³ and R ⁴ are amino or C _1-6 - are independently selected from alkyl (en / yn), preferably methyl, A compound according to any one of claims 1 to 8. R ⁵ is C _1-10 -alkyl (alkenyl / alkynyl), C _3-8 -cycloalkyl (cycloalkenyl) -C _1-6 -alkyl (alkenyl / alkynyl), optionally substituted aryl-C _1-6 10. A compound according to any one of claims 1 to 9 selected from the group consisting of -alkyl (alkenyl / alkynyl) and optionally substituted aryl. The compound is:

The compound as a free base or a salt thereof according to any one of claims 1 to 10, which is selected from the group consisting of:   12. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 11 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.   13. A method of using a pharmaceutical formulation according to claim 12 to increase the flow of ions in a mammalian, eg, human potassium channel.   Use according to claim 13, for the treatment of a disorder or disease responsive to increased ion flow in potassium channels, wherein the disorder or disease is preferably a disorder or disease of the central nervous system. How to use.   The disorder or condition being treated is seizure disorder, anxiety disorder, neuropathic and migraine pain disorder, other pain disorders such as cancer pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal symptoms 15. The method according to claim 14, wherein the method is selected from the group consisting of: an ethanol withdrawal symptom, and a hearing disorder 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, epilepsy, e.g. epilepsy syndrome and epileptic seizures.   Anxiety disorder is anxiety, and panic anxiety, agoraphobia, panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, interpersonal phobia and Other specific phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder for general physical disease, substance-induced anxiety disorder, isolation anxiety disorder, adaptation disorder, performance anxiety 16. The use according to claim 15, selected from the group consisting of disorders and diseases related to psychiatric disorders, anxiety disorders for general physical diseases and substance-induced anxiety disorders, and other unspecified anxiety disorders Method.   Neuropathic pain and migraine pain disorder are allodynia, hyperalgesia, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia and nerve associated with migraine 16. Use according to claim 15, wherein the method is selected from the group consisting of pathogenic pain.   Neurodegenerative disorder is caused by Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Parkinson's disease, AIDS or by rubella virus, herpesvirus, Borrelia or unknown pathogen From the group consisting of infection-induced encephalopathy, trauma-induced neurodegeneration, nerve hyperexcitability such as in drug withdrawal symptoms or addiction, and neurodegenerative diseases of the peripheral nervous system, such as polyneuropathy and polyneuritis 16. Use according to claim 15, which is selected.   15. Use according to claim 14, wherein the disorder or disease to be treated is selected from the group consisting of bipolar disorder and attention deficit hyperactivity disorder.   15. Use according to claim 14, wherein the disorder or disease to be treated is selected from the group consisting of sleep disorders, e.g. insomnia.   Claim for the treatment of a disorder or disease responsive to increased ion flow in potassium channels, wherein the disorder or disease to be treated is selected from fibromyalgia, movement disorder or motion sickness, spasticity, myokemia or urinary incontinence Item 14. The method according to Item 13.