EA016244B1 - Substituted pyridine derivatives - Google Patents

Abstract

The present invention relates to pyridine derivatives of the general formula (I) and their use as openers of the KCNQ family potassium ion channels for the treatment of CNS disorders.

Description

The present invention relates to compounds that are channel openers of potassium ions of the family Ι <ί.'Νρ. The compounds are useful in the treatment of disorders and diseases susceptible to opening channels of potassium ions of the Ι <ί.'Νρ family. moreover, one such disease is epilepsy.

Ion channels are cellular proteins. which regulate the flow of ions. including potassium ions. calcium. chloride and sodium into and out of cells. Such channels are present in all cells of animals and humans and affect various processes. including neuron transfer. muscle contraction and cell secretion.

People have over 70 genes. coding subtypes of potassium channels (Tep18sy No. 1Shgs Ks \ zs \\ ъ No.igo5s1spss 2000. 1. 21-30) with a huge variety in relation to how the structure. so are the functions. Neural potassium channels. which are found in the brain. are primarily responsible for maintaining the negative residual potential of the membrane. and also regulation of membrane repolarization after action of the potential.

One subpopulation of potassium channel genes is the Ι <ί.'Νρ family. Shown. that mutations in four of the five Ι <ί.'Νρ genes underlie diseases. including cardiac arrhythmia. deafness and epilepsy (1sp15s11 Ba! iggs Ks \ zs \\ ı No. 5S1spss 2000. 1. 21-30).

It is considered. that the Ι <ί.'Νρ4 gene encodes a molecular correlation of the potassium channel. found in the outer cells of the cochlear hairs (inner ear) and in the cells of the type I hairs of the vestibular apparatus. in which mutations can lead to the induction of inherited deafness.

Ι <ί’Νρ1 (КЬрТ1) is assembled together with the product of the Κί’ΝΕ1 gene (the minimal K (+) channel protein) in the heart with the formation of the heart. slow motion. like purifier K (+) - current.

Mutations in this channel can cause one form of the inherited long-term type 1 PT syndrome (BRT1). and they are also associated with the form of deafness (Köbšk Rjagshaso Tysg 2001. 90. 1-19).

The genes Ι <ί.'Νρ2 and Ι <ί.'Νρ3 were discovered in 1988 and. as it turned out. they mutate into a hereditary form of epilepsy. known as weak familial neonatal convulsions (Koda \\ bk | Tgspfk ίη No.ig8s1spss8 2000. 23. 393-398). Squirrels. encoded by the genes Ι <ί’Νρ2. and squirrels. encoded by the genes Ι <ί.'Νρ3. localized in pyramidal neurons of the cerebral cortex and hippocampus. areas of the brain. associated with the generation and reproduction of epileptic seizures (Soorsg s! a1. PrgosssFshdk Ya! yupa1 AsaFsshu o! Bsyupss I8A 200. 97. 4914-4919).

KSIR2 and Ι <ί.'Νρ3 are two subunits of potassium channels. which form M currents upon expression of ίη νίίΐΌ. M-current is a non-inactivating potassium current. found in many types of neural cells. In each type of cell, it is dominant in the regulation of membrane excitability due to this. that it is only a continuous current in the range of initiation of the action potential (Matop Appia1 Kc \ ss \\ · Ryu8yuodu 1997. 59. 483-504). Modulation of the M-current has a strong effect on neural excitability. eg. activation of the current will decrease neuronal excitability. Discoverers of these channels of the IRGC. or M-current activators. can reduce excessive neural activity and therefore they can be used in the treatment of epilepsy and other diseases and disorders. characterized by excessive neural activity. such as neural over-excitability. including convulsive disorders. epilepsy and neuropathic pain.

Retigabin (Ό-23129; Y- (2-amino-4- (4-fluorobenzylamino) phenyl) carbamic acid ethyl ester) and its analogues are described in EP 554543. Retigabin is a broad-spectrum anticonvulsant with strong anticonvulsant properties. like w νίΙΐΌ. so w νί \ Ό. It is active after oral and intraperitoneal administration to rats and mice in a number of anticonvulsant trials. including electric shock-induced epileptic seizures. epileptic seizures. chemically induced pentylenetetrazole. picrotoxin and Ν-methyl-E-aspartate (ΝΜΌΑ). and on a genetic animal model. mice ΌΒΑ / 2 (Ko§! Osk s! a1. Eryskru Ksksagsy 1996. 23. 211-223). Besides. retigabin is active in the amygdala excitation model of combined individual epileptic seizures. which thus additionally shows. that this compound is promising in anticonvulsant therapy. In clinical trials, retigabin has recently been shown to be effective in reducing the incidence of epileptic seizures in epileptic patients (B1a1cg! A1. Eryskru Ksksagsy 2002. 51. 3171).

Detected. that retigabin activates the (K (+) - current in neuron cells. and the pharmacology of this induced current demonstrates compliance with the published pharmacology of the M-channel, which has recently been correlated with the hetero multimer of the K (+) - channel Ι <ί.'Νρ2 / 3. This allows suppose that the activation of the Ι <ί.'Νρ2 / 3 channels may be responsible for some of the anticonvulsant activity of this agent (HUuykspfsp s! a1. Mo1ssi1ag Ryagshasoodu 2000. 58. 591-600) and that other agents acting according to the same mechanism. may have similar uses.

It is described. that the channels Ι <ί.'Νρ2 and 3 are positively regulated in models of neuropathic pain (\ U | skspFsp s! a1. 8os1s1u Gog Msigokasss Aigask 2002. 454.7). and a hypothesis was put forward. that potassium channel modulators are active as in neuropathic pain. and in case of epilepsy (8goGFsg! a1. No. igoryagshasoodu 2001. 40. 888-898).

- 1 016244

It has also been found that retigabin is useful in animal models of neuropathic pain (Blaspig-Mipgo aib 1eikei Eigoreap 1oigpa1 οί Ryattasodu 2003, 460, 109-116), and this suggests that the openers of the ΚCN ^ channels can be used in the treatment of pain disorders, including neuropathic pain.

It has been described that the localization of the mRNA of the ΚCN ^ channels in the brain and other parts of the central nervous system is associated with pain (Oo1bk1et e1 a1. 8ae1u Gog nihox1epse LkGgasGk 2003, 53.8).

In addition to its role in neuropathic pain, mRNA expression for ΚCN ^ 2-5 in the trigeminal ganglia and spinal nodes and in the nuclear caudal part of the trigeminal nerve means that the openers of these channels can also affect the sensory process of migraine pain (O1bkGet eG a1. LkGgasGk 2003, 53.8).

Recent publications show that mRNA for ΚCN ^ 3 and 5, in addition to mRNA for ΚCN ^ 2, are expressed in astrocytes and glial cells. Therefore, the ΚCN ^ 2, 3, and 5 channels can help modulate synaptic activity in the central nervous system and contribute to the neuroprotective actions of the открыCN ^ channel openers (Noba eG a1., 8os1eGu Gog No.igokselse LkGgasGk 2003, 53.9).

Retigabin and other ΚCN ^ modulators can, therefore, have a protective effect against neurodegenerative varieties of epilepsy, since it has been found that retigabin prevents neurodegeneration in the extremities and the expression of apoptosis markers after a kainic acid-induced epileptic state in rats (EGG eG a1. 8irr1 5, 8 6-95). It may be useful in preventing the progress of epilepsy in patients, i.e. is antiepileptogenic. It was also found that retigabin slows down the progression of excitation of the hippocampus in rats, the next model for the development of epilepsy (Toeb eG a1. Eigoreap 1oigpa1 oG Ryattasodu 1996, 303, 163-169).

Thus, it is assumed that these properties of retigabin and other ΚCN ^ modulators can prevent neuronal damage induced by excessive neuronal activation, and such compounds can be used in the treatment of neurodegenerative diseases and in the modification (or antiepileptogenic) of diseases in patients with epilepsy.

Knowing that anticonvulsant compounds, such as benzodiazepines and chloromethiazole, are used clinically in the treatment of ethanol withdrawal syndrome, and that other anticonvulsant compounds, such as gabapentin, are very effective in animal models of this syndrome (^ aGcop eG a1. No. igoryagtasodu 1997, 36, 1369 -1375), therefore, suggest that other anticonvulsant compounds, such as openers ΚCN ^. are effective in this condition.

mRNA for subunits ΚCN ^ 2 and 3 were found in areas of the brain associated with anxious and emotional behaviors, such as bipolar disorder, such as the hippocampus and amygdala (8adG e1. 1igpa1 oG noigoxepse 2001, 21, 4609-4624), and it is described that retigabin is active in some animal models of similar anxiety behavior (Nag1x eG a1. 1oigpa1 oG P8syoryoryagtasodu 2003, 17 kirr1 3, A28, B16), and other clinically used anticonvulsants are used in the treatment of bipolar disorder. Thus, ΚCN ^ discoverers may be useful in the treatment of anxiety disorders and bipolar disorder.

XVO 200196540 describes the use of M-current modulators formed by the expression of ΚCN ^ 2 and ΚCN ^ 3 genes. for the treatment of insomnia, while in νθ 2001092526 it is described that ΚCN ^ 5 modulators can be used to treat sleep disorders.

Νθ 01/022953 describes the use of retigabin for the prophylaxis and treatment of neuropathic pain, such as allodynia, hyperalgic pain, phantom pain, neuropathic pain related to diabetic neuropathy, and neuropathic pain related to migraine.

Νθ 02/049628 describes the use of retigabin for the treatment of anxiety disorders such as anxiety, generalized anxiety disorder, panic fear, compulsive compulsive disorder, social phobia, anxiety due to the possibility of work being done, post-traumatic stress disorder, acute stress reaction, disturbances due to adaptability, disorders associated with hypochondriac syndrome, violation associated with fear of separation, agoraphobia and specific phobias.

Νθ 97/15300 describes the use of retigabin for the treatment of neurodegenerative disorders, such as Alzheimer's disease; Huntington's chorea; sclerosis, such as multiple sclerosis and amyotrophic lateral sclerosis; Creutzfeldt-Jakob disease; Parkinson's disease; encephalopathies induced by AIDS or infection by rubella viruses, herpes viruses, borrelia, and unknown pathogens; trauma-induced neurodegeneration; conditions of increased neuronal irritability, such as drug withdrawal syndrome or intoxication, and neurodegenerative diseases of the peripheral nervous system, such as polyneuropathy and polyneuritis.

It was found that каналовCN ^ channel openers are effective in the treatment of stroke, therefore, it is expected that selective ΚCN ^ openers are effective in the treatment of stroke (8sigobeg eG a1., RDidegk LgsK. 2003; 446 (5): 607-16; Soreg apb 1ap. Agsy No. 1, 2003, 60 (4): 496500; / bureau ΟΝ8 Pgid Neu., 2002, 8 (4): 353-60).

It was found that ΚCN ^ channels are expressed in dopaminergic and cholinergic circuits in the brain, which are associated with the supply system of the brain, especially in the ventral

- 2 016244 integument site (Sooreg s1 a1., 1. No. ox1, 2001, 21, 9529-9540). Therefore, открыCN ^ channel openers are believed to be effective in treating irritability-related disorders that include a brain supply system such as cocaine abuse, nicotine withdrawal syndrome, and ethanol withdrawal syndrome.

Potassium channels, consisting of subunits ΚCN ^ 4. are expressed in the inner ear (KiXx1 e1 a1., Ce11., 1999 Eb5; 96 (3): 437-46), and therefore it is assumed that the opening of these channels will treat tinnitus.

Therefore, there is a huge need for new compounds that are potent openers of potassium channels of the ΚCN ^ family.

Also desirable are new compounds with improved properties compared to known compounds which are potassium channel openers of the ΚCN ^ family. such as retigabin. It is desirable to improve one or more of the following parameters: half-life (drug compound in the body), removal of the drug compound (from the body), selectivity, interactions with other drugs, bioavailability, activity, technological properties in the manufacture of the drug, chemical stability, metabolic stability membrane permeability, solubility and therapeutic index. Improving such parameters can lead to improvements such as an improved drug regimen by reducing the number of required doses per day, ease of administration to a patient with multiple drug therapies, reduced side effects, increased therapeutic index, increased tolerance or improved patient compliance with the treatment regimen and regimen.

One object of the invention is the creation of compounds that are potent openers of potassium channels of the ΚCN ^ family.

The compounds of the invention are derivatives of substituted pyridines of the following formula I in the form of a free base or its salt

where K ¹ , K ² , K ³ and S. | have the meanings indicated below.

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

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

The invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of epileptic disorders, anxiety disorders, neuropathic pain and disorders related to migraine pain or neurodegenerative disorders.

In addition, the invention relates to the use of a compound of formula I in a method for the treatment of epileptic disorders, anxiety disorders, neuropathic pain and disorders related to migraine pain or neurodegenerative disorders.

Determination of substituents

The term heteroatom refers to an atom of nitrogen, oxygen or sulfur.

Halogen means an atom of fluorine, chlorine, bromine or iodine.

Cyano means ΤΑΝ, which is attached to the rest of the molecule through a carbon atom.

Expression of C1 _-6 -alk (en / yn) yl means C1 _-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-methylprop -1-yl, 2-methylprop-2-yl, 2,2-dimethylprop-1-yl, but-1-yl, but-2-yl, 3-methylbut-1yl, 3-methylbut-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 a straight or branched alkenyl group having from two to six carbon atoms and one double bond, including, but not limited to, ethenyl, propenyl and butenyl. The term C2-6 alkynyl refers to an unbranched or branched alkynyl group having from two to six carbon atoms and one triple bond, including, but not limited to, ethynyl, propynyl, and butynyl.

The expression C1 _-8 alk (en / in) yl means C _{! -8} alkyl, C _2-8 alkenyl or C _2-8 alkynyl. The term C _1-8 alkyl refers to an unbranched or branched alkyl group having from one to eight carbon atoms, including, but not limited to, methyl, ethyl, prop-1-yl, prop-2-yl, 2-methylprop -1-yl, 2-methylprop-2-yl, 2,2-dimethylprop-1-yl, but-1-yl, but-2-yl, 3-methylbut-1yl, 3-methylbut-2-yl, pent -1-yl, pent-2-yl, pent-3-yl, hex-1-yl, hex-2-yl, hex-3-yl, 2-methyl-4,4-dimethylpent-1-yl and hep-1 -il. The term C2-8 alkenyl refers to straight or branched

- 3 016244 alkenyl group having from two to eight carbon atoms and one double bond, including, but not limited to, ethenyl, propenyl and butenyl. The term C _2-8 alkynyl refers to a straight or branched alkynyl group having from two to eight carbon atoms and one triple bond, including, but not limited to, ethynyl, propynyl, and butynyl.

The expression C _3-8 cycloalkyl (en / in) yl means C _3-8 cycloalkyl or C _3-8 cycloalkenyl. The term C _3-8 cycloalkyl means a monocyclic or bicyclic carbocycle having from 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 monocyclic or bicyclic carbocycle having from three to eight carbon atoms and one double bond, including, but not limited to, cyclopentenyl and cyclohexenyl.

The term C _3-8 heterocycloalkyl (en / in) yl means C _3-8 heterocycloalkyl or C _3-8 heterocycloalkenyl. The term C3-8-heterocycloalkyl means a monocyclic or bicyclic ring system in which the ring is formed by 3-8 atoms selected from 2-7 carbon atoms and 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms. Examples of C _3-8 heterocycloalkyls are pyrrolidine, azepan, morpholine, piperidine, piperazine and tetrahydrofuran. The term C _3-8 heterocycloalkenyl means a monocyclic or bicyclic ring system with one double bond, in which the ring is formed by 3-8 atoms selected from 2-7 carbon atoms and 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms. Examples of C _3-8 heterocycloalkenyls are dihydropyrrole, dihydrofuran and dihydrothiophene. When C _3-8 heterocycloalk (en / in) yl includes a nitrogen atom, then C _3-8 heterocycloalk (en / in) yl is attached to the rest of the molecule via a carbon atom or a nitrogen atom of the heterocyclic ring. When C3-8 heterocycloalkyl (en / in) yl does not include a nitrogen atom, then the C3-8 heterocycloalkyl (en / in) yl is attached to the rest of the molecule via a carbon atom of the heterocyclic ring.

The term halo-C _1-6 alk (en / yn) yl means C _1-6 alk (en / yn) yl substituted with halogen, including, but not limited to, trifluoromethyl. Similarly, halogen-C _3-8 cycloalkyl (en) yl means C3-8-cycloalkyl (en) yl substituted with halogen, including, but not limited to, chlorocyclopropane and chlorocyclohexane. Similarly, halo-C3-8 cycloalkyl (en) yl-C _1-6 -alk (en / yn) yl means a _{halogeno-C3-8-cycloalkyl} (en) yl, attached to the remainder of the molecule via C1-6-alk (en / in) ill.

The term C1-6-alk (en / in) yloxy means C1-6-alk (en / in) yl attached to the rest of the molecule via an oxygen atom. Similarly, C3-8-cycloalk (en) yloxy means C3-8-alk (en) yl, attached to the rest of the molecule via an oxygen atom.

In the expressions, C3-8-cycloalk (en) yl-C1-6-alk (en / in) yl, aryl-C1-6-alk (en / in) yl, aryl-C3-8 cycloalk (en) yl, aryl C3-8-cycloalk (en) yl-C1-6-alk (en / in) yl, C3-8-heterocycloalk (en) yl-C1-6 alk (en / in) yl, C1-6-alk (en / in) yl-C3-8-heterocycloalk (en) yl-C1-6-alk (en / in) yl, heteroaryl-C1-6 alk (en / in) yl, heteroaryl-C3-8-cycloalk (en) yl, heteroaryl-C3-8-cycloalk (en) yl-C1-6-alk (en / in) yl,

CF ^{4 5} -S1-6-alk (en / yn) yl, CF ⁴ -S3-8 ^5-cycloalk (en) yl, CF ^{4 5} _-C3-8 cycloalkyl (en) yl-C _{1 -6-} alk (en / in) yl, C3-8-cycloalk (en) yl-C1-6-alk (en / in) yloxy, C1-6-alk (en / in) yloxy-C1-6-alk (en / in) yl, C3-8cycloalk (en) yloxy-C1-6-alk (en / in) yl and C3-8-cycloalk (en) yl-C2-6-alk (en / in) yloxy-C1 -6-alk (en / in) yl terms C1-6-alk (en / in) yl, C3-8-cycloalk (en) yl, aryl, C3-8-heterocycloalk (en) yl, heteroaryl, C _{1- 6-} alk (en / in) yloxy and C _3-8 -cycloalk (en) yloxy are as defined above.

The term heteroaryl refers to monocyclic or bicyclic heteroaromatic systems selected from the group consisting of pyridine, thiophene, furan, pyrrole, pyrazole, triazole, tetrazole, oxazole, imidazole, thiazole, benzofuran, benzothiophene and indole.

The term aryl means monocyclic or bicyclic aromatic systems selected from the group consisting of phenyl and naphthyl.

The term optionally substituted aryl-C1-6-alk (en / in) yl means aryl-C1-6-alk (en / in) yl, where the aryl part is optionally substituted, such as an aryl part with 1, 2 or 3 substituents, independently selected from the group consisting of halogen, cyano, C1-6-alk (en / in) silt, C3-8-cycloalk (en) silt, C3-8 cycloalk (en) yl-C1-6-alk (en / in) silt, halogen-C1-6-alk (en / in) silt, halogen-C3-8-cycloalk (en) silt, halogen-C3-8 cycloalk (en) il-C _1-6- alk (en / in) silt , C _1-6 alk (en / in) yloxy, C _3-8 cycloalk (en) yloxy and C _3-8 cycloalk (en) yl-C1-6 alk (en / in) yloxy. Similarly, an optionally substituted aryl-C3-8cycloalkyl (en) yl means aryl-C3-8-cycloalkyl (en) yl, wherein the aryl part is optionally substituted, such as an aryl part with 1, 2 or 3 substituents independently selected from the group consisting of from halogen, cyano, C1-6-alk (en / yn) silt, C3-8-cycloalk (en) silt, C3-8-cycloalk (en) silt-C1-6-alk (en / yn) silt, halogen - C1-6alk (en / in) silt, halogen-C3-8-cycloalk (en) silt, halogen-C3-8-cycloalk (en) il-C2-6-alk (en / in) silt, C1-6alk (en / in) yloxy, C _3-8 cycloalkyl (en) yloxy, and C _3-8 cycloalk (en) yl-C _1-6 alk (en / in) yloxy. Similarly, an optionally substituted aryl-C3-8-cycloalk (en) yl-C1-6-alk (en / in) yl means aryl-C3-8

- 4 016244 cycloalk (en) yl-C1_b-alk (en / in) yl, where the aryl part is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C _1-6 alk (en (in) sludge, C _3-8 cycloalk (en) sludge, C _3-8 -cycloalk (en) yl-C _1-6- alk (en / in) sludge, halogen-C _2-6- alk (en / in) silt, halogen-C _3-8 cycloalk (en) silt, halogen-C _3-8- cycloalk (en) il-C _1-6- alk (en / in) silt, C _1-6 -alk (en (in) yloxy, C _3-8 cycloalkyl (en) yloxy and C _3-8 cycloalkyl (en) yl-C _1-6 alk (en / in) yloxy.

Description of the invention

The present invention relates to derivatives of substituted pyridines, which are potassium channel openers Ι <ί.'Νρ.

The present invention relates to a compound represented by general formula I

where s. | equal to 0 or 1;

each of I ¹ and I ^{2 is} independently selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _{3 -8-} cycloalkyl (en) il-C _1-8 -alkyl, C _3-8 -cycloalk (en) il-C _2-8 alkenyl, C _3-8 -cycloalk (en) il-C _2-8 -alkynyl C _1-6 alkyloxy, C _2-6 alkenyloxy, C _2-6 alkyloxy and halogen; and

I ^{3 is} selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 cycloalk (en ) il-C _1-6 -alkyl, C _3-8 -cycloalkyl (en) il-C _2-6- alkenyl, C _3-8 -cycloalk (en) ilC _2-6 -alkynyl, optionally substituted aryl-C _{1 -6-} alkyl, optionally substituted aryl-C _2-6 alkenyl, optionally substituted aryl-C2-6-alkynyl, optionally substituted aryl-C3-8 cycloalkyl (en) yl, optionally substituted aryl-C _3-8 -cycloalk (en) yl-C _1-6 -alkyl, optionally substituted aryl-C3-8-cycloalk (en) yl-C2-6-alkenyl, optionally substituted with o aryl-C3-8cycloalkyl (en) yl-C2-6-alkynyl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl, heteroaryl-C2-6 alkynyl, heteroaryl-C3-8-cycloalkyl (en) yl heteroaryl-C3-8-cycloalkyl (en) yl-C1-6-alkyl, heteroaryl-C3-8cycloalkyl (en) yl-C2-6-alkenyl and heteroaryl-C3-8-cycloalkyl (en) yl-C2-6 alkynyl;

wherein the aryl portion is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl enyl , C3-8-cycloalkyl (en) yl-C2-6-alkyl, C3-8-cycloalkyl (en) yl-C2-6-alkenyl, C3-8-cycloalk (en) yl-C2-6-alkynyl, halogen -C1-6-alkyl, halogen-C2-6-alkenyl, halogen-C2-6-alkynyl, halogen-C3-8-cycloalk (en) silt, halogenC3-8-cycloalk (en) il-C1-6-alkyl halogen-C3-8-cycloalkyl (en) yl-C2-6-alkenyl, halogen-C3-8-cycloalkyl (en) ilC _2-6 -alkynyl, C _1-6 -alkyloxy, C _2-6 -alkenyloxy, C ₂ - ₆ -alkiniloksi, _C3-8 -tsikloal (en) yloxy and _{C3-8-cycloalk} (en) yl-C _1-6 -alkyloxy, C _3-8 cycloalkyl (en) yl-C _2-6 -alkeniloksi _{C3-8-cycloalkyl} (en) yl- C _2-6 alkynyloxy; and where heteroaryl is selected from the group consisting of pyridine, thiophene, furan, pyrrole, pyrazole, triazole, tetrazole, oxazole, imidazole, thiazole, benzofuran, benzothiophene and indole;

and its pharmaceutically acceptable salt.

In one embodiment, the compounds of formula I C. | equal to 0; in another embodiment of a compound of formula I c. | equal to 1.

In one embodiment, the compounds of formula I, I ¹ and I ² are C _1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl.

In a further embodiment of the compound of formula I, I ¹ represents C _1-6 alkyloxy, C2-6 alkenyloxy or C2-6 alkynyloxy and I ² represents halogen or where I ¹ represents halogen and I ² represents C1-6- alkyloxy, C2-6 alkenyloxy or C2-6 alkynyloxy;

in another embodiment, each of I ¹ and I ^{2 is} independently selected from the group consisting of halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyloxy, C _{2 -6-} alkenyloxy, C _2-6 -alkynyloxy;

in another embodiment, each of I ¹ and I ^{2 is} independently selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 -cycloalkenyl, C _3-8 -cycloalkyl (en) yl-C _1-8 alkyl, C3-8-cycloalkyl (en) yl-C2-8-alkenyl, C3-8-cycloalkyl (en) yl-C2-8- alkynyl;

in another embodiment, I ¹ is C _1-6 alkyl, such as methyl;

in another embodiment, I ² is C _1-6 alkyl, such as methyl;

in another embodiment, I ¹ represents C _1-6 alkyloxy, such as methoxy, and I ² represents halogen;

in another embodiment, I ¹ represents halogen and I ² represents C _1-6 alkyloxy, such as methoxy.

Typically, both I ¹ and I ² are C _1-6 alkyl, such as methyl;

in another embodiment, I ^{3 is} selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 cycloalkyl (en) il-C _1-6 -alkyl, C _3-8 cycloalkyl (en) il-C _2-6

- 5 016244 alkenyl, C _3-8 cycloalkyl (en) yl-C _2-6 alkynyl, optionally substituted aryl-C _1-6 alkyl, optionally substituted aryl-C _2-6 alkenyl, optionally substituted aryl-C _2-6 alkynyl, optionally substituted aryl-C _3-8 cycloalkyl (en) sludge, optionally substituted aryl-C _3-8 cycloalkyl (en) yl-C _1-6 alkyl, optionally substituted aryl-C _{3- 8-} cycloalkyl (en) yl-C _2-6 alkenyl optionally substituted with aryl C _3-8 -cycloalk (en) yl-C _2-6 alkynyl, heteroaryl-C _1-6 -alkyl, heteroaryl-C _2-6 -alkenyl, heteroaryl-C _2-6 alkynyl, heteroaryl-C _3-8 -cycloalk (en) silt, hetero aryl-C _3-8 -cycloalkyl (en) yl-C _1-6 -alkyl, heteroaryl-C _3-8 cycloalkyl (en) yl-C _2-6- alkenyl and heteroaryl-C _3-8 -cycloalk (en) il-C _2-6 alkynyl;

in another embodiment, K ^{3 is} selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl (en) yl-C _1-6 alkyl, C _3-8 cycloalkyl (en) yl-C _2-6 alkenyl, C _3-8 cycloalkyl (en) yl-C _2-6 alkynyl, optionally substituted aryl-C _1-6 alkyl, optionally substituted aryl C _2-6 alkenyl, optionally substituted aryl-C2-6-alkynyl, optionally substituted aryl-C3-8-cycloalkyl (en) yl, heteroaryl-C _1-6 -alkyl, heteroaryl-C _2-6- alkenyl, heteroaryl -C _2-6 alkynyl;

in another embodiment, K ^{3 is} selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 -cycloalkyl (en) yl-C _1-6 -alkyl, C _3-8 -cycloalkyl (en) yl-C _2-6 alkenyl, C _3-8 -cycloalkyl (en) yl-C _2-6 -alkynyl, optional substituted aryl-C _1-6 -alkyl, optionally substituted aryl-C2-6-alkenyl, optionally substituted aryl-C2-6-alkynyl, optionally substituted aryl-C _3-8 -cycloalkyl (en) yl, optionally substituted aryl-C _3-8 -cycloalkyl (en) yl-C _1-6 -alkyl optionally substituted with aryl-C3-8-cycloalkyl (en) yl-C2-6-a lkenyl, optionally substituted aryl C _3-8 cycloalkyl (en) yl-C _2-6 alkynyl, heteroaryl C _1-6 alkyl, heteroaryl C _2-6 alkenyl, heteroaryl C _2-6 alkynyl.

Typically, K ^{3 is} selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalk (en) yl-C1-6 alkyl, C3-8- cycloalk (en) yl-C2-6-alkenyl, C3-8-cycloalk (en) yl-C2-6-alkynyl, optionally substituted aryl-C1-6-alkyl, optionally substituted aryl-C2-6-alkenyl, optionally substituted aryl-C2-6-alkynyl, optionally substituted aryl-C3-8-cycloalkyl (en) yl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl, heteroaryl-C2-6-alkynyl.

To further illustrate the invention, but without limiting it, in one embodiment, K ³ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl;

in another embodiment, K ³ is C _3-8 cycloalkyl (en) yl-C _1-6 alkyl, C _3-8 cycloalkyl (en) yl-C2-6 alkenyl, C3-8 cycloalk (en) il-C2-6 alkynyl;

in another embodiment, K ³ is optionally substituted aryl-C _1-6 alkyl, optionally substituted aryl-C2-6-alkenyl, optionally substituted aryl-C2-6-alkynyl;

in another embodiment, K ³ is an optionally substituted aryl-C _3-8 cycloalk (en) yl;

in another embodiment, K ³ is heteroaryl-C _1-6 -alkyl, heteroaryl-C _2-6 alkenyl, heteroaryl-C2-6-alkynyl.

In a further embodiment of the invention, in the compound of formula I, any heteroaryl that is indicated either individually or as part of a larger substituent is selected from the group consisting of pyridine, furan, pyrrole, pyrazole, triazole, tetrazole, oxazole, imidazole, thiazole, benzofuran, benzothiophene and indole; in another embodiment, any heteroaryl that is indicated either singly or as part of a larger substituent is thiophene.

In a further embodiment of the invention, in the compound of formula I, any aryl, which is indicated either individually or as part of a larger substituent, is phenyl; in another embodiment, any aryl that is indicated either singly or as part of a larger substituent is naphthyl.

In a further embodiment of the invention, in the compound of formula I, any optionally substituted aryl, which is indicated either individually or as part of a larger substituent, may be substituted with 1 or 2 substituents.

To further illustrate the invention, but without limiting it, an embodiment relates to those compounds of formula I in which any optionally substituted aryl, which is indicated either individually or as part of a larger substituent, is unsubstituted;

in another embodiment, any optionally substituted aryl, which is indicated either individually or as part of a larger substituent, is substituted with 1 substituent;

in another embodiment, any optionally substituted aryl, which is indicated either individually or as part of a larger substituent, is substituted with 2 substituents.

In a further embodiment of the invention, in the compound of formula I, any optionally substituted aryl, which is indicated either singly or as part of a larger substituent, may be substituted with substituents selected from the group consisting of cyano, C3-8-cycloalkyl (en) yl, C3- 8cycloalkyl (en) yl-C2-6-alkyl, C3-8-cycloalkyl (en) yl-C2-6-alkenyl, C3-8-cycloalkyl (en) yl-C2-6-alkynyl, halogen-C _3-8 cycloalkyl (en) silt, halogen-C _3-8 cycloalkyl (en) il-C _1-6 -alkyl, halogen-C _3-8 cycloalkyl (en) il-C _2-6 alkenyl, halogen-C _{3 -8-} cycloalkyl (en) yl-C _2-6 alkynyl, C _3-8 -cycloalk (en) yloxy and C _{3- 8-} cycloalkyl (en) yl-C _1-6 alkyloxy, C3-8-cycloalk (en) yl-C2-6-alkenyloxy C3-8-cycloalk (en) yl-C2-6-alkynyloxy;

in another embodiment, any optionally substituted aryl that is indicated

- 6 016244 either alone or as part of a larger substituent may be substituted with substituents selected from the group consisting of halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, _halo-6 S1_ -alkyl, haloC _2-6 alkenyl, halo-C _2-6 alkynyl and C _1-6 alkyloxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy.

In the following non-limiting illustration, an embodiment relates to those compounds of formula I in which any optionally substituted aryl, which is indicated either individually or as part of a larger substituent, is substituted with halogen;

in another embodiment, any optionally substituted aryl, which is indicated either singly or as part of a larger substituent, is substituted with C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl;

in another embodiment, any optionally substituted aryl, which is indicated either singly or as part of a larger substituent, is substituted with halo-C1-6 alkyl, halogen-C2-6 alkenyl, halogen-C2-6 alkynyl;

in another embodiment, any optionally substituted aryl that is indicated either singly or as part of a larger substituent is substituted with C _1-6 alkyloxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy.

A further embodiment relates to a compound of formula I in the form of a free base or a salt thereof; wherein said compound is selected from the compounds shown in the following table:

Ν ' an example Connection Name 1aa Benzyl ether (2,4-dimethyl-6-morpholin-4-ylpyridin- 3-yl) carbamic acid 1ab 2-chlorobenzyl ether (2,4-dimethyl-b-morpholin-4- ilpyridin-3-yl) carbamic acid 1ac 2- (4-Chlorophenyl) -Ν- (2,4-dimethyl-6-morpholin-4ylpyridin-3-yl) acetamide

1ac1 (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) amide 2- phenylcyclopropanecarboxylic acid 1st Ν- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2 thiophen-2-yl-acetamide 1a £ 3-Cyclohexyl-Y- (2,4-dimethyl-6-morpholin-4-ylpyridin- 3-yl) propionamide 1ad Isobutyl ether (2,4-dimethyl-6-morpholin-4- ilpyridin-3-yl) carbamic acid 1ab 3- (3-Chlorophenyl) -Ν- (2,4-dimethyl-6-morpholin-4ylpyridin-3-yl) propionamide 1a1 Ν- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3,5 dimethyl phenyl) acetamide

- 7 016244

1a Ν- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-m- t olyl ace t amide 1b Ν- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4 fluorophenyl) acetamide 1bc Ν- (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) -3,3dimethyl tilbutyr amide 1st Ν- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3 fluorophenyl) acetamide 1b 2-Bicyclo [2.2.1] hept-2-yl-Y- (2,4-dimethyl-6-morpholine- 4-ylpyridin-3-yl) acetamide £ b 2- (3,4-Difluorophenyl) -Ν- (2,4-dimethyl-6-morpholin-4ylpyridin-3-yl) acetamide 1d (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) amide 4- methylpentanoic acid 1Ы1 2- (Cyclopent-2-enyl) -Ν- (2,4-dimethyl-6-morpholin-4ylpyridin-3-yl) acetamide 1Y 2- Cyclohexyl-I- (2,4-dimethyl-6-morpholin-4-ylpyridin- 3-yl) acetamide 1b) {2,4-Dimethyl-6 ^ morpholin-4-yl-pyridin-3-yl) amide 5 ^ methylhexanoic acid 1k 2- Cyclopentyl-M- (2,4-dimethyl-6-morpholin-4-ylpyridin- 3-yl) acetamide 1Y 3-Cyclopentyl-Ν- (2,4-dimethyl-6-morpholin-4-ylpyridin- 3-IL) propionamide 1sh (2 _g 4-Dimethyl-b ~ morpholin-4-yl-pyridin-3-yl) hexanoic acid amide Ln Ν- (4-Chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) -2 cyclopentylacetamide L0 Ν- (2-Chloro-4-methoxy-b-morpholin-4-ylpyridin-3-yl) -2 cyclopentylacetamide Lb Ν- (2-Chloro-4-methoxy-6-morpholin-4-ylpyridin-3-yl) - 3,3-dimethylbutyramide 1d Ν- (4-Chloro-2-methoxy ~ 6-morpholin-4-ylpyridin-3-yl) - 3,3-dimethylbutyramide

1b Ν- (4-Chloro-2-methoxy-6 ~ morpholin-4-ylpyridin-3- sludge) propionamide

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

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

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 with non-toxic acids. Acid addition salts include salts of inorganic acids as well as organic acids. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Examples of Suitable Organic

- 8 016244 acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamon, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malaric, oxalic, pyruvic, yellow, pyruvic, pyruvic acid , methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, ΕΌΤΆ, glycolic, p-aminobenzoic, glutamic, benzenesulfono acid, ptoluenesulfonic acid, theophylline acetic acids, as well as 8-halogenophyophyllines, for example 8bromteophylline, and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in publication 1. Ryatt. 8s1. 1977, 66, 2, which is incorporated herein by reference.

Also included in the invention are acid addition salts in the form of 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, methyl, dimethyl, trimethyl, ethyl, hydroxyethyl, diethyl, n-butyl, sec-butyl, tert-butyl, tetramethylammonium salts and the like.

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

The compounds of the present invention may have one or more asymmetric centers, and it is contemplated that any optical isomers (i.e., enantiomers or diastereomers), in the form of separated, pure or partially purified optical isomers and any mixtures thereof, including racemic mixtures, t .e. mixtures of stereoisomers are included in the scope of the invention.

Racemic forms can be resolved into optical antipodes by known methods, for example, by separating diastereomeric salts with an optically active acid and isolating the optically active amine compound by treatment with a base. Another method for separating racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can also be divided into their optical antipodes, for example, fractional crystallization. The compounds of the present invention can also be separated by the formation of diastereomeric derivatives. You can apply additional methods for the separation of optical isomers, known to specialists in this field. Such methods include the methods described by 1. 1ac. | Is5. A. Co11e1 apb 8. \ Ubsp ίη Epapbotet, Vaseta! E8, apb K.e8o1ibop8, Ιοίιη \ Upps apb 8op§, No. \ ν Wogk (1981). Optically active compounds can also be obtained from optically active starting materials or by stereoselective synthesis.

In addition, when a double bond or a system of fully or partially saturated rings is present in the molecule, geometric isomers can form. It is intended that any geometric isomers in the form of separated, pure or partially purified geometric isomers or mixtures thereof be included within the scope of the invention. Similarly, molecules with a limited rotation coupling can form geometric isomers. It is believed that they are also included in the scope of the present invention.

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

The invention also includes prodrugs of the present compounds which, when administered, are chemically converted by metabolic processes before they become pharmacologically active substances. Typically, such prodrugs are functional derivatives of the compounds of general formula I, which are capable of easily converting to the desired compound of formula I. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in Ebdp! Rgobgidk, fuck. N. Vipbdaagb, Ekeuet, 1985.

The invention also includes active metabolites of the present compounds.

The compounds of the invention have an affinity for the Κί.'Κί2 receptor subtype with an EC ₅₀ value of less than 15,000 nM, such as 10,000 nM, as measured by the Relative Flow Through Channel XYR2, which is described below. One embodiment relates to those compounds of formula I that have an affinity for the receptor subtype Ι <ί.'ΝΟ2 with an EC ₅₀ value of less than 2000 nM, such as 1500 nM, as measured by the Relative leakage through the KSYR2 channel, which is described below. To further illustrate the invention, but without limiting it, an embodiment relates to those compounds that have an affinity for a receptor subtype Ι <ί.'ΝΟ2 with an EC ₅₀ value of less than 200 nM, such as 150 nM, measured by the test Relative leakage through channel KSR2 which is described below.

One embodiment relates to those compounds of formula I which have a value

- 9 016244

ΕΟ ₅₀ less than 15 mg / kg, when tested Maximum electric shock, which is described below. To further illustrate the invention, but without limiting it, an embodiment relates to those compounds that have a ΕΌ ₅₀ value of less than 5 mg / kg when tested with the Maximum Electroshock, which is described below.

One embodiment relates to those compounds of formula I which have an EC ₅₀ value of less than 5 mg / kg, when tested for a Threshold value by electric current-induced epileptic seizures and a Test on a Threshold value caused by a chemical compound epileptic seizures, which are described below.

One embodiment relates to those compounds of formula I that have little or no clinically minor side effects. For example, some of the compounds of the invention were tested on models for unwanted sedative, hypothermic and ataxic effects.

One embodiment relates to those compounds of formula I that have a high therapeutic index between anticonvulsant activity and side effects, such as lack of motor activity or ataxic effects, as measured in a rotating rod test. It is expected that such compounds will be completely tolerant for patients, which will allow the use of high doses before side effects are detected. Thus, it is expected that the patient's compliance with the therapy will be good, and the administration of high doses may allow the treatment to be more effective for patients who may otherwise have side effects with other drugs.

As already indicated, the compounds of the invention have an effect on potassium channels of the семейства family. in particular, to subunit ΚΟΝΟ2. and therefore, they are considered suitable for increasing the flow of ions in a voltage-dependent potassium channel in a mammal, such as a human. The compounds of the invention are useful in the treatment of a disorder or disease susceptible to an increased flow of ions in a potassium channel, such as channels of potassium ions of the ΚΟΝΟ family. Such a disorder or disease is preferably a disorder or disease of the central nervous system.

In one aspect, the compounds of the invention can be administered as the only therapeutically effective compound. In another aspect, the compounds of the invention can be administered as part of combination therapy, that is, the compounds of the invention can be administered in combination with other therapeutically effective compounds having, for example, anticonvulsant properties. The actions of such other compounds with anticonvulsant properties may include, but are not limited to, actions on ion channels, such as sodium, potassium or calcium channels, excitatory amino acid systems, for example, blockade or modulation of receptors ΝΜΌΑ, a system of inhibitory neurotransmitters, for example, amplification release ΟΑΒΑ or absorption block ΟΑΒΑ, or stabilization of membranes.

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

The invention relates to the use of a compound of formula I in the form of a base or a salt thereof as a medicine.

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

An embodiment of the invention is a pharmaceutical composition comprising a compound of formula I in the form of a free base or a salt thereof and a pharmaceutically acceptable carrier or diluent. The composition may include any of the embodiments of formula I described above.

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for treating a disease or disorder in which a potassium channel opener ΚΟΝΟ, such as a potassium channel opener ΚΟΝΟ2, is useful. Typically, such a disorder or disease is selected from the group consisting of epileptic disorders, anxiety disorders, disorders related to neuropathic pain and migraine pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal syndrome, ethanol withdrawal syndrome and tinnitus .

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for treating epileptic disorders. Typically, the epileptic disorders being treated are selected from the group consisting of acute epileptic seizures, seizures, an epileptic state, and

- 10 016244 epilepsy, such as epileptic syndromes and epileptic seizures.

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety disorders. Typically, the anxiety disorders being treated are selected from the group consisting of anxiety and disorders and diseases related to a panic attack, agoraphobia, panic disorder with agarophobia, panic disorder without agarophobia, agoraphobia without a medical history of panic disorder, specific phobia, social phobia, and others specific phobias, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety an underlying disorder due to a general medical condition, an anxiety disorder caused by a substance, an anxiety disorder related to fear of separation, disturbances due to adaptability, anxiety regarding the ability to perform work, an disorder associated with hypochondriac syndrome, anxiety disorder due to a general medical condition, anxiety disorder, caused by the substance, and anxiety disorder.

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of neuropathic pain and disorders related to migraine pain. Typically, the treated neuropathic pain and migraine pain related disorders are selected from the group consisting of allodynia, hyperalgic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to trigeminal neuralgia, and neuropathic pain, related to migraine.

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of neurodegenerative disorders. In a typical case, the neurodegenerative disorders being treated are selected from the group consisting of Alzheimer's disease; Huntington’s chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Parkinson’s disease, encephalopathy induced by AIDS or rubella virus infection, herpes viruses, borrelia and unknown pathogens induced by trauma of neurodegeneration syndrome, neuronal conditions, neuron conditions agents or intoxication, and neurodegenerative diseases of the peripheral nervous system, such as polyneuropathy and polyneuritis.

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of bipolar disorders.

A further embodiment of the invention relates to the use of a compound of formula I in the form of a free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of sleep disorders such as insomnia.

The term treatment used in the description in connection with a disease or disorder also includes the prevention, suppression and reduction of the intensity of symptoms, depending on what the case may be.

The invention relates to compounds exhibiting activity in at least one of the following tests:

relative leakage through the channel Κί.'ΝΟ2. which is an indicator of the activity of the compound at the target channel;

maximum electroshock, which is an indicator of epileptic seizures induced by nonspecific CNS stimulation by electrical methods;

pilocarpine-induced epileptic seizures;

pilocarpine-induced epileptic seizures are often difficult to treat with many existing anti-epilepsy drugs and therefore they depict a model of drug-resistant epileptic seizures.

Tests for the electrical threshold of an epileptic seizure and tests for the chemical threshold of an epileptic seizure. These models measure the threshold at which epileptic seizures begin, thus being models that determine whether compounds can delay the onset of an epileptic seizure.

An amygdala excitation test, which is used as an indicator of the development of the disease, since in normal animals, epileptic seizures in this model become more severe when the animal receives additional stimulation.

Electrophysiological patch-clamp recording of data in CHO cells and electrophysiological recording of data from ΚΓΝΟ2, Ι <ί.’ΝΟ3 / Ι <ί.’ΝΟ3 or ΚΓΝΟ4 channels in oocytes.

In these tests, currents of voltage-activated channels ΚΓΝΟ2, ΚΓΝΟΑΚΓΝΟΙ or ΝΟΙΓΝΟ4 are recorded.

- 11 016244

Pharmaceutical Compositions

The present invention also relates to a pharmaceutical composition. The compounds of the invention in the form of the free base or its salts can be administered alone or in combination with pharmaceutically acceptable carriers or diluents in the form of either one or many doses. The pharmaceutical compositions of the invention can be prepared with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, according to generally accepted methods, such as those described in K. et al.: Tha § apse apb Rgasbes οί Ryughtasu, 19 Ybyup, Seppago. , Musk Rybikpd Co., Eaglop, RA, 1995.

Pharmaceutical compositions can, in particular, be prepared for administration by any suitable route, such as oral, rectal, nasal, pulmonary, local (including buccal and sublingual), percutaneous, intracavitary, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular , intrathecal, intravenous and intradermal) route, with the oral route being preferred. It should be understood that the preferred route will depend on the general condition and age of the subject being treated, the nature of the disorder or disease being treated, and the active ingredient selected.

Pharmaceutical compositions prepared by admixing a compound of the invention and pharmaceutically acceptable carriers are then readily administered in various dosage forms suitable for the described routes of administration. The preparations can be suitably converted to a standard dosage form by methods known in the pharmaceutical field.

The compounds of this invention are usually used in the form of a free base or in the form of its pharmaceutically acceptable salt. One example is the acid addition salt of a compound that is useful as the free base. When the compound of the invention is a free base, such salts are prepared in a conventional manner by treating a solution or suspension of the free base of the invention with the chemical equivalent of a pharmaceutically acceptable acid. Representative examples are indicated above.

Pharmaceutical compositions for oral administration may be solid or liquid. Solid dosage forms for oral administration include, for example, capsules, tablets, dragees, pills, lozenges, powders, granules and pills, for example, placed in a hard gelatin capsule, in the form of a powder or granules, or, for example, in the form of a troche or lozenge . If necessary, pharmaceutical compositions for oral administration can be prepared with coatings, such as enteric coatings, or they can be formulated to provide controlled release of the active ingredient, such as sustained or sustained release, by methods well known in the art. Liquid dosage forms for oral administration include, for example, solutions, emulsions, suspensions, syrups and elixirs.

Formulations of the present invention suitable for oral administration may be presented in discrete units such as capsules or tablets, each unit containing a predetermined amount of the active ingredient, which may include a suitable excipient. In addition, orally suitable preparations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or a liquid emulsion such as oil in water or water in oil.

Suitable pharmaceutical carriers include inert solid diluents or excipients, a sterile aqueous solution, and various organic solvents. Examples of solid carriers are lactose, calcium sulfate, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, lower alkyl cellulose ethers, corn starch, potato starch, gums and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amides, polyoxyethylene and water.

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

You can use any adjuvants or additives commonly used for certain purposes, such as coloring agents, flavoring agents, preservatives, etc., provided that they are compatible with the active ingredients.

The amount of solid carrier usually ranges 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 a sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

Tablets can be prepared by mixing the active ingredient with traditional adjuvants or diluents, followed by compressing the mixture in a tablet machine.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Injecting

- 12 016244 depot preparations are also considered to be within the scope of the present invention.

For parenteral administration, solutions of a compound of the invention in a sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil can be used. If necessary, such aqueous solutions should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used are readily available using standard techniques known to those skilled in the art.

Injectable solutions can be prepared by dissolving the active ingredient and possible additives in a portion of the injection solvent, preferably sterile water, adjusting the volume of the solution to the desired size, sterilizing the solution and filling in suitable ampoules and vials. Any suitable additive commonly used in the art can be added, such as tonicity agents, preservatives, antioxidants, etc.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalation dosage forms, skin patches, implants, etc.

A typical oral dose is in the range of from about 0.001 to about 100 mg / kg body weight per day, preferably from about 0.01 to about 50 mg / kg body weight per day, and more preferably from about 0.05 to about 10 mg / kg body weight per day, and the specified dose is administered in the form of one or more doses, for example 1-3 doses. The exact dose will depend on the frequency and route of administration, gender, age, weight and general condition of the subject being treated, the nature and severity of the disorder or disease being treated, and any concomitant diseases being treated and other factors that are obvious to one skilled in the art.

The preparations may suitably 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 several times a day, for example 1-3 times a day, may contain from 0.01 to about 1000 mg, for example from about 0.01-100 mg, preferably from about 0.05 to about 500 mg and more preferably from about 0.5 to about 200 mg.

For parenteral routes of administration, such as intravenous, intrathecal, intramuscular, and similar administration, typical doses are on the order of about half the dose used for oral administration.

Typical examples of recipes for the preparation according to the invention are the following examples.

1) Tablets containing 5.0 mg of a compound of the invention, the amount of compound calculated for the free base:

compound of the invention 5.0 mg lactose 60 mg corn starch 30 mg hydroxypropyl cellulose 2.4 mg microcrystalline cellulose 19.2 mg croscarmellose type A sodium salt 2.4 mg magnesium stearate 0.84 mg.

2) Tablets containing 0.5 mg of the compound of the invention, the amount of compound calculated for the free base:

compound of the invention 0.5 mg lactose 46.9 mg corn starch 23.5 mg povidone 1.8 mg microcrystalline cellulose 14.4 mg croscarmellose type A sodium salt 1.8 mg magnesium stearate 0.63 mg.

3) A syrup containing 25 mg sorbitol 500 mg hydroxypropyl cellulose 15 mg glycerol 50 mg methyl paraben 1 mg propyl paraben 0.1 ml sorbitol 500 mg hydroxypropyl cellulose 15 mg glycerol 50 mg per 1 ml of the compound of the invention

- 13 016244 methylparaben 1 mg propylparaben 0.1 ml ethanol 0.005 mg flavor 0.05 mg sodium saccharin 0.5 mg water to 1 ml.

4) An injection solution containing 1 ml of the compound of the invention 0.5 mg sorbitol 5.1 mg acetic acid 0.05 mg saccharin sodium 0.5 mg water to 1 ml.

The expression compound of the invention means any compound of formula I of the described embodiments.

A further aspect of the present invention relates to a method for producing a compound of the invention as described below.

Obtaining compounds of the invention

The present invention relates to a compound represented by general formula I

where s. | equal to 0 or 1;

each of K ¹ and K ² are independently selected from the group consisting of C1 _-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkenyl, C _{3- 8-cycloalkyl} (en) yl-C 1 _{-8-alkyl, C3-8-cycloalkyl} (en) yl-C _2-8 alkenyl, C 3-8 cycloalk (en) yl-C2-8-alkynyl, C1-6 -alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy and halogen; and

K ^{3 is} selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C _3-8 cycloalkyl (en) yl- _C1-6 -alkyl, C _3-8 -cycloalkyl (en) yl-C _2-6 alkenyl, C _3-8 -cycloalkyl (en) ylC2-6-alkynyl, optionally substituted aryl-C1-6-alkyl, optionally substituted aryl- C2-6 alkenyl, optionally substituted aryl-C2-6 alkynyl, optionally substituted aryl-C3-8 cycloalkyl (en) yl, optionally substituted aryl-C _3-8 cycloalk (en) yl- _C1-6 alkyl, optionally substituted aryl -C3-8-cycloalk (en) yl-C2-6-alkenyl optionally substituted with aryl-C3 -8-cycloalkyl (en) yl-C2-6-alkynyl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl, heteroaryl-C2-6-alkynyl, heteroaryl-C3-8-cycloalk (en) silt heteroaryl-C3-8-cycloalkyl (en) yl-C1-6-alkyl, heteroaryl-C3-8-cycloalkyl (en) yl-C2-6-alkenyl and heteroaryl-C3-8-cycloalkyl (en) yl-C2 -6-alkynyl;

wherein the aryl portion is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl enyl , C3-8-cycloalkyl (en) yl-C1-6 alkyl, C3-8-cycloalkyl (en) yl-C2-6 alkenyl, C3-8-cycloalk (en) yl-C2-6 alkynyl, halogen -C1-6-alkyl, halogen-C2-6-alkenyl, halogen-C2-6-alkynyl, halogen-C3-8-cycloalk (en) silt, halogenC3-8-cycloalk (en) il-C1-6-alkyl , halogen-C3-8-cycloalkyl (en) yl-C2-6-alkenyl, halogen-C3-8-cycloalkyl (en) ilC _2-6- alkynyl, C1 _-6- alkyloxy, C _2-6- alkenyloxy, C _2-6- alkyloxy, C _3-8 -cycloalk ( en) yloxy and _{C3-8-cycloalk} (en) yl-C1 _-6 -alkyloxy, C _3-8 cycloalkyl (en) yl-C _2-6 -alkeniloksi _{C3-8-cycloalkyl} (en) yl-C _{2 -6} alkynyloxy; and where heteroaryl is selected from the group consisting of pyridine, thiophene, furan, pyrrole, pyrazole, triazole, tetrazole, oxazole, imidazole, thiazole, benzofuran, benzothiophene and indole;

and its pharmaceutically acceptable salt.

Compounds of the invention of general formula I, wherein K ¹ , K ² , K ³ and s. | have the values indicated above, can be obtained by the methods presented in the diagrams and described below.

In the compounds of the general formulas Σ-ХУ К ¹ , К ² , К ³ и с. | have the meanings indicated for formula I.

Compounds of the general formulas II, VII, VIII, IX, X, XI, and XII are either obtained from commercial sources or obtained by standard methods known to those skilled in the art.

- 14 016244

Compounds of general formula III (Scheme 1) can be prepared by reacting compounds of general formula II with bis- (2-haloethyl) ethers with or without addition of bases, such as trialkylamines, potassium carbonate or lithium, sodium or potassium alcoholates, with or without addition adding catalysts, such as sodium iodide, in a suitable solvent, such as dimethyl sulfoxide, Ν, Ν-dimethylformamide or ethanol, at a suitable temperature, such as room temperature or reflux temperature. Compounds of general formula IV (Scheme 1) can be prepared from compounds of general formula III by a nitration reaction known to those skilled in the art, such as reaction with concentrated nitric acid, sodium nitrite or sodium nitrate, in a suitable solvent such as glacial acetic acid, acetic acid anhydride, trifluoroacetic acid, concentrated sulfuric acid, or mixtures thereof, at suitable temperatures, for example, as described by Ρ.Β.Ώ. Be 1a Mage apb Ι.Η. ΚΪ66, Rgeragayue teSchobz o1 pigayop ΐη LgotaPeziszShiyopz, pp. 48-56, Vi11eg \ uoy118 8s1ep11ys Rybisyops, Lopbop, 1959.

Scheme 2

P

K2

Compounds of general formula V (Scheme 2) can be prepared from compounds of general formula II by nitration reactions known to those skilled in the art as described in Scheme 1 for the preparation of compounds of formula IV. Compounds of general formula IV (Scheme 2) can be prepared by reacting compounds of general formula V with suitably substituted bis (2-haloethyl) ethers as described in Scheme 1 to prepare compounds of general formula III.

Scheme 3

Compounds of general formula VI (Scheme 3) can be prepared from compounds of general formula IV by reduction of the nitro group to an amino group with suitable reducing agents, such as zinc or iron powder in the presence of an acid, such as acetic acid or aqueous hydrochloric acid, or with gaseous hydrogen, 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, with suitable Temperature or ultrasonic radiation. Alternatively, tin (P) chloride or sodium dithionite can be used as reducing agents under suitable conditions well known to those skilled in the art.

Compounds of general formula I (Scheme 3) can be prepared by reacting compounds of general formula VI with suitable electrophilic reagents, such as, but not limited to, fluorides of suitably substituted carboxylic acids, carboxylic acid chlorides, carboxylic bromides, carboxylic acid iodides, activated esters chloroformates, with or without addition of bases, such as pyridine, trialkylamines, potassium carbonate, magnesium oxide or lithium, sodium or potassium alcoholates, in a suitable astvoritele such as ethyl acetate, dioxane, tetrahydrofuran, acetonitrile or diethyl ether, at a suitable temperature such as room temperature or reflux temperature. Activated carboxylic esters and anhydrides can be prepared from suitably substituted carboxylic acids under conditions known to qualified chemists in the art, for example, as described by P. / Mjepso apb Ι..Α. Sagrto, Soir1t§ geadep1z apb asyuyop ΐη MeShobz ΐη en / utodu: 8oybryase reybe 8up1yyz1z, pp. 104-125, Sábetz s Rörz, \ e \ u Wogk, 1997. Carboxylic acid halides can be prepared from suitably substituted carboxylic acids by activation with reagents such as, but not limited to, thionyl chloride, oxalyl chloride, phosphorus tribromide or phosphorus triiodide, conditions well known to qualified chemists in the field.

- 15 016244

Scheme 4

Compounds of general formula II (Scheme 4) can be prepared by reacting compounds of general formula VII with sodium amide in a suitable solvent, such as xylene, at a suitable temperature, such as reflux temperature, as described by I. Hesson, Vi11. §Os. Sat. Rg., 1950, 188.

Compounds of general formula VII, wherein ^B2 represents P, C1, Br or I (Scheme 5), can be prepared from compounds of general formula VIII by metallation and subsequent reaction with a suitable electrophile known to those skilled in the art using suitable bases, such as butyllithium or di-tert-butyl- (2,2,6,6-tetramethylpiperidino) lithium zincate, followed by the addition of a suitable electrophile, such as fluorine, chlorine, bromine, iodine, iodine, carbon tetrabromide or hexachloroethane, in suitable solvents such as heptane or tetrahydrofuran, at suitable temperatures, such as -78 ° C or room temperature, for example, as described by R. Mopdt apb 6. Onedspeg. Those! Gayebgop, 2001, 57, 4059.

Compounds of general formula VII, wherein B ¹ is P, C1, Br or I (Scheme 5), can be prepared from compounds of general formula IX by metallation and subsequent electrophilic aromatic substitution as described above.

Compounds of formula VII, wherein B ² represents a C1 _-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkenyl, C _3-8 cycloalkyl (ene ) il-C1 _-8- alkyl, C _3-8 -cycloalk (en) il-C _2-8- alkenyl, C _3-8 cycloalk (en) il-C _2-8 -alkynyl (Scheme 6), it is possible to obtain from compounds of the general formula X by means of cross-coupling reactions known to qualified chemists in the field, such as the combination of No. dy1i (E.-to No. D18Y, A.O. Kshd apb N. Okikabo, I. Ogd. Set., 1977, 42 , 1821), a combination of 8 sub-assumptions (K. Zopodazyga, U. Tokba apb N. Nadstepa, Te !. Le !!., 1975, 16, 4467) or others, catalysis e mye transition metal cross-coupling reactions such as copper catalyzed reactions (A. EoYe, Ό.Μ. shbzau APB R. Kposye1, JRT. rd., 2001, 3, 2871).

Compounds of formula VII, wherein B ¹ represents a C1 _-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkenyl, C _3-8 cycloalkyl (ene ) il-C1 _-8- alkyl, C _3-8 -cycloalk (en) il-C _2-8- alkenyl, C _3-8 cycloalk (en) il-C _2-8 -alkynyl (Scheme 6), it is possible to obtain of compounds of general formula XI by cross-coupling reactions as described above.

In addition, compounds of the general formula VII, wherein B ² is cyano (Scheme 6), can be prepared from compounds of the general formula X by nickel-catalyzed cyanidation reactions known to those skilled in the art, for example, as described in b. Sazzag, I. Ogdapote !. Siet., 1973, 54, C57-C58.

Compounds of general formula VII, wherein B ¹ is cyano (Scheme 6), can be prepared from compounds of general formula XI via nickel-catalyzed cyanidation reactions as described above.

Compounds of general formula VII, where B ^{1 =} B ² (Scheme 6), can be prepared from compounds of general formula X, where B ^! = B ² = Br, by cross-coupling reactions or cyanidation reactions as described above.

- 16 016244

In addition, compounds of formula XIII (Scheme 7), where K ¹ and K ² are halogen, can be obtained from 2,4,6-trihalo-pyridines of the general formula XII, where K ¹ and K ² are halogen, by nitration reactions known to those skilled in the art. chemists in this field, as described in scheme 1 to obtain compounds of General formula IV.

Compounds of general formula XIV (Scheme 7) wherein K ¹ and K ² are halogen can be prepared from compounds of general formula XII where K ¹ and K ² are halogen by reaction with morpholine in a suitable solvent such as dimethyl sulfoxide or Ν- methylpyrrolidinone, with or without addition of bases, such as pyridine, trialkylamines, potassium carbonate, magnesium oxide, at suitable temperatures, such as room temperature or reflux temperature.

Compounds of general formula XV may be prepared from compounds of general formula XIII by reaction with morpholine in a suitable solvent, such as dimethyl sulfoxide or Ν-methylpyrrolidinone, with or without addition of bases such as pyridine, trialkylamines, potassium carbonate, magnesium oxide, at suitable temperatures, such like room temperature or reflux temperature. In addition, compounds of general formula XV can be prepared from compounds of general formula XIV by nitration reactions known to those skilled in the art as described in Scheme 1 to prepare compounds of general formula IV.

In addition, compounds of general formula IV, wherein K ¹ or K ^2, or both K ¹ and K ² are cyano (Scheme 7), can be prepared from compounds of general formula XV using cyanation reactions as described above. Compounds of general formula III, wherein K ¹ or K ^2, or both K ¹ and K ² are cyano, can be prepared from compounds of general formula XIV using cyanation reactions as described above.

Compounds of general formula III, wherein K ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 cycloalk (en) il-C _1-8 -alkyl, C _3-8 -cycloalk (en) il-C _2-8 alkenyl, C _3-8 -cycloalk (en) il-C _2-8 -alkynyl (Scheme 6) can be obtained from compounds of general formula XIV by cross-coupling reactions as described above (Scheme 6).

Compounds of general formula III, wherein K ² is C _2-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 - cycloalk (en) il-C _1-8 -alkyl, C _3-8 -cycloalk (en) il-C _2-8- alkenyl, C _3-8 cycloalk (en) il-C _2-8 -alkynyl (Scheme 6 ) can be obtained from compounds of general formula XIV by cross-coupling reactions as described above (Scheme 6).

Compounds of general formula IV, wherein K ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 - cycloalk (en) il-C _1-8 -alkyl, C _3-8 -cycloalk (en) il-C _2-8- alkenyl, C _3-8 cycloalk (en) il-C _2-8 -alkynyl (Scheme 6 ) can be obtained from compounds of general formula XV by cross-coupling reactions as described above (Scheme 6).

Compounds of general formula VI wherein K ² is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _3-8 - cycloalk (en) il-C _1-8 -alkyl, C _3-8 -cycloalk (en) il-C _2-8- alkenyl, C _3-8 cycloalk (en) il-C _2-8 -alkynyl (Scheme 6 ) can be obtained from compounds of general formula XV by cross-coupling reactions as described above (Scheme 6).

Compounds of general formula IV, wherein K ¹ or K ^2, or both K ¹ and K ² are C _1-6 alkyloxy, C _2-6 alkenyloxy, C _2-6 alkyloxy, may be prepared from compounds of general formula XV by reaction with suitable lithium, sodium or potassium alcoholates or with alcohols in the presence of a base such as lithium, sodium or potassium hydroxide, lithium, sodium or potassium hydride, and with or without the addition of a catalyst, such as copper sulfate, in a suitable solvent such as dioxane, at suitable temperatures, such as room temperature or tamper reflux tour.

Compounds of general formula III, wherein K ¹ or K ^2, or both K ¹ and K ² are C _1-6 alkyloxy, C _2-6 alkenyloxy, C _2-6 alkyloxy, may be prepared from compounds of general formula XIV by reaction with suitable lithium, sodium or potassium alcoholates or with alcohols in the presence of a base such as lithium, sodium or potassium hydroxide, lithium, sodium or potassium hydride, and with or without the addition of a catalyst, such as copper sulfate, in a suitable solvent such as dioxane, at suitable temperatures, such as room temperature or tempera Atur reflux.

- 17 016244

In addition, for the next option, I ¹ and I ² compounds containing a methoxy group can be demethylated by methods known to those skilled in the art, such as treatment with boron tribromide in a suitable solvent, such as dichloromethane, at suitable temperatures, such as 0 ° C or room temperature. The phenols formed can then be alkylated by methods known to those skilled in the art. Such methods include (a) reacting with electrophiles, such as alkyl chlorides, alkyl bromides, alkyl iodides, carbonic chlorides, carbonic bromides or carbonic anhydrides, in the presence of suitable bases, such as potassium carbonate, in a suitable solvent such as tetrahydrofuran, Ν, Ν-dimethylformamide or 1,2-dichloroethane, at suitable temperatures, such as room temperature or reflux temperature; (B) a reaction with alkyl alcohols under conditions known as the Mitsunobu reaction (O. Mykipo, Sin11ekhk 1981, 1).

Compounds containing functional groups, such as hydroxy groups, which are not compatible with the intended reaction conditions, can be protected and deprotected by methods known to those skilled in the art, for example, as described by T. ^. Szhepe apb R.S.M. \ Uhh. RgoΙοοΙίνο dgoirh ίη ogdashs hugiNehk, 2 ^pb eShNop, \ ¥ Peu YeshDepse, 1991. In particular, the hydroxy group may be protected by conversion to the ethers, but not limited as methyl, tert-butyl, trialkylsilyl, triarilsililovye, allyl or trityl ethers .

Alkines prepared by the reactions of 8Hydr can be reduced to alkenes or alkanes by reduction 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 suitable solvents such as methanol, ethanol or tetrahydrofuran, at suitable temperatures, for example, as described in 8. 81ede1, Ne1edepeo8a! a1ubs yubgodepopop o! C = C apb a1kupeh sh SosrgeyephAe Ogdashs 8up1Neh1h, ν. 8, pp 417-442, Regdatop Rgeh, 1991.

Obtaining compounds of the invention

Examples

LC-MS analytical data were obtained on a Re 8aex ΑPI 150EX instrument equipped with a photoionization system at atmospheric pressure and LC 81shphabhi EC-8A / 8LC-10A. Column: C18 30x4.6 mm \ ¥ a1egh 8utte1gu with a particle size of 3.5 microns; solvent system: A = water / trifluoroacetic acid mixture (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid mixture (5: 95: 0.03); method: elution with a linear gradient from 90% A to 100% B for 4 min and with a flow rate of 2 ml / min. Purity was determined by a combination of UV spectroscopy (254 nm) and a recording instrument for the ΕΕ8ΕΕ method. Retention times (1 _I ) were expressed in minutes.

Purification by preparative LC-MS was carried out on the same instrument with chemical ionization at atmospheric pressure. Column: UMS ΟΌ8-Α 50x20 mm with a particle size of 5 microns; method: elution with a linear gradient from 80% A to 100% B for 7 min and with a flow rate of 22.7 ml / min. The fractions were collected by detecting the MS separation stream.

LC-MS-TOE analytic data (TOU - time of flight) was obtained on a 1shotshot LST 4 \ uaukh MIK instrument equipped with a detection system \ ¥ а1егх 2488 / 8ехех 754. Column: C18 30x4.6 mm \ ¥ a1egkh 8ustegu with a particle size of 3, 6 microns; solvent system: A = water / trifluoroacetic acid mixture (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid mixture (5: 95: 0.03); method: elution with a linear gradient from 90% A to 100% B for 4 min and with a flow rate of 2 ml / min. The purity was determined by a combination of UV (254 nm) and a recording instrument for the ΕΕ8Ό method. Retention times (1 _I ) were expressed in minutes.

GC-MS data were obtained on a Wapap CP 3800 gas chromatograph equipped with a P1epotepech column (2eLGoP-5, length: 15 m, internal diameter: 0.25 mm) connected to a mass spectrometer with a Wapap 8a1igp 2000 ion trap. Method: duration analysis 15 min, flow rate in the column 1.4 ml / min (the carrier gas was helium), gradient of the column thermostat: 0-1 min, 60 ° C; 1-13 minutes, 60-300 ° C; 13-15 minutes, 300 ° C.

¹ H NMR spectra were recorded at 500.13 MHz on a Vgikeg Ανаηсе ΌΚΧ500 instrument. As a solvent, deuterated dimethyl sulfoxide (99.8% Ό) was used. Tetramethylsilane was used as an internal standard. Chemical shifts were expressed in ppm. relative to tetramethylsilane. The following abbreviations are used for signal multiplicity:

c = singlet; d = doublet, t = treblet, sq. = quartet, qui. = quintet, g = heptet, dd = double doublet, ddd = double double doublet, dt = double triplet, dkv. = double quartet, tt = triplet of triplets, m = multiplet and width c = wide singlet.

Preparation of Intermediates

4- (4,6-Dimethylpyridin-2-yl) morpholine.

2-amino-4,6-dimethylpyridine (50 g), bis- (2-chloroethyl) ether (57.5 ml), sodium iodide (6.13 g) and triethylamine (137 ml) are mixed in dry Ν, Ν -dimethylformamide (1 L) under argon and the mixture was heated to 150 ° C. for 16 hours. Water / saturated brine / saturated aqueous sodium bicarbonate (2: 1: 1, 750 ml) was added to the cooled reaction mixture.

- 18 016244 ethyl acetate (5x200 ml). The combined organic phases are concentrated in vacuo to approximately 500 ml. Water (500 ml) and concentrated aqueous hydrochloric acid (35 ml) were added, the phases were separated, and the aqueous phase was washed with ethyl acetate (200 ml). The aqueous phase is made basic by the addition of concentrated aqueous sodium hydroxide (50 ml) and extracted with isopropyl acetate (5x200 ml). The combined phases were dried over magnesium sulfate and concentrated in vacuo to give 44.0 g (56% yield) of the title compound as a black oil. The crude product is used without further purification. GC-MS (t / ζ) 192 (M ⁺ ); 1, = 5.60.

Ή NMR (500 MHz. DMSO-b ₆ ): 2.08 (s. 3H), 2.26 (s. 3H), 3.39 (m. 4H). 3.68 (m, 4H). 6.05 (s. 1H). 6.44 (s. 1H).

4- (4,6-Dimethyl-5-nitropyridin-2-yl) morpholine.

Sodium nitrite (3.54 g) was added over 15 minutes to 4- (4,6-dimethylpyridin-2-yl) morpholine (9.4 g) dissolved in trifluoroacetic acid (250 ml), cooled to 0 ° C. and the reaction mixture is then stirred for 15 minutes at 0 ° C. The reaction mixture was concentrated in vacuo to approximately 100 ml and the pH was adjusted to 11 with concentrated aqueous sodium hydroxide (150 ml). Saturated brine (200 ml) was added and the mixture was extracted with diethyl ether (4x150 ml), the organic phase was dried over magnesium sulfate and concentrated in vacuo.

The crude product was purified by flash chromatography (δίθ ₂ , heptane / ethyl acetate, 4: 1) to obtain 2.01 g (17% yield) of the title compound as a yellow solid. GC-MS (t / ζ) 237 (M *); I., 7.69.

Ή NMR (500 MHz, DMSO-b ₆ ): 2.28 (s, 3H), 2.39 (s, 3H), 3.60 (m, 4H), 3.67 (m, 4H), 6, 72 (s, 1H).

2,4-Dimethyl-6-morpholin-4-ylpyridin-3-ylamine.

Glacial acetic acid (25 ml) was slowly added to a mixture of zinc dust (2.76 g) and 4- (4,6dimethyl-5-nitropyridin-2-yl) morpholine (2.01 g) in tetrahydrofuran (100 ml), cooled up to 0 ° С. The reaction mixture was then stirred for 16 hours at 25 ° C, filtered through celite, made basic with 25% aqueous ammonia and extracted with tetrahydrofuran (3x75 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give 1.76 g (100%) of the title compound as a dark red solid. GC-MS (t / ζ) 207 (M *); 1, = 7.27.

Ή NMR (500 MHz, DMSO-bb): 2.07 (s, 3H), 2.20 (s, 3H), 3.16 (m, 4H), 3.67 (m, 4H), 4.10 (broad., 2H); 6.38 (s, 1H).

4- (4,6-Dichloropyridin-2-yl) morpholine.

Morpholine (5.0 g) is added to a suspension of 2,4,6-trichloropyridine (10.0 g) and sodium carbonate (5.9 g) in acetonitrile (100 ml). The reaction mixture was then stirred at 70 ° C. for 16 hours, cooled to ambient temperature, filtered through celite and concentrated in vacuo. The crude product was purified by flash chromatography (8ίΘ _2, heptane / ethyl acetate, 4: 1) to obtain 3.90 g (yield 30%) of the title compound as an off-white solid. LC-MS (t / ζ) 323.8 (M *); 1, = 3.10. (UV, ΕΌδΌ) 98.5%, 98.9%.

Ή NMR (500 MHz, ΟΌΟ1 ₃ ): 3.50 (m, 4H), 3.80 (m, 4H), 6.45 (s, 1H), 6.67 (s, 1H).

4- (4,6-Dichloro-5-nitropyridin-2-yl) morpholine.

To a solution of 4- (4,6-dichloropyridin-2-yl) morpholine (3.90 g) in concentrated sulfuric acid (40 ml) was added potassium nitrate (1.80 g) over 10 minutes. The reaction mixture was stirred for 16 hours at ambient temperature and then poured into crushed ice (500 g). The reaction mixture was made basic with concentrated sodium hydroxide and extracted with ethyl acetate (2x100 ml). The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (δίθ ₂ , heptane / ethyl acetate, 3: 1) to obtain 2.26 g (49% yield) of the title compound as a yellow solid. LCMS (t / ζ) 278.0 (M *); 1, = 3.10. (UV, ΕΌδΌ) 96.5%, 98.8%.

Ή NMR (500 MHz, ΟΌΟ1 ₃ ): 3.62 (m, 4H), 3.80 (m, 4H), 6.50 (s, 1H).

4- (4-Chloro-6-methoxy-5-nitropyridin-2-yl) morpholine; and 4- (6-chloro-4-methoxy-5-nitropyridin-2yl) morpholine.

To a solution of 4- (4,6-dichloro-5-nitropyridin-2-yl) morpholine (2.02 g) in methanol (15 ml) was added sodium methoxide (0.98 g) and the mixture was heated for 65 hours at 65 ° C. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The crude product is purified by flash chromatography (δίθ ₂ , heptane / ethyl acetate, 3: 1) to obtain 0.89 g (45% yield) of 4- (4chloro-6-methoxy-5-nitropyridin-2-yl) morpholine (rapidly eluting band) and 0.38 g (19%) of 4- (6-chloro-4-methoxy-5-nitropyridin-2-yl) morpholine (late-eluting band), both compounds being obtained as yellow solids.

4- (4-Chloro-6-methoxy-5-nitropyridin-2-yl) morpholine: LC-MS (t / ζ) 273 (M *); 1, = 2.77, (UV, ΕΕδΌ) 95%, 97%.

Ή NMR (500 MHz, ΟΌΟ1 ₃ ): 3.60 (m, 4H), 3.80 (m, 4H), 3.96 (s, 1H), 6.17 (s, 1H).

4- (6-Chloro-4-methoxy-5-nitropyridin-2-yl) morpholine: LC-MS (t / ζ) 273 (M *); 1, = 2.39, (UV, ΕΌδΌ) 93%, 95%.

- 19 016244

Ή NMR (500 MHz, ΟΌ α ₃ ): 3.57 (m, 4H), 3.80 (m, 4H), 3.95 (s, 3H), 5.95 (s, 1H).

4-Chloro-2-methoxy-6-morpholin-4-ylpyridin-3-ylamine.

To a solution of 4- (4-chloro-6-methoxy-5-nitropyridin-2-yl) morpholine (0.82 g) in concentrated hydrochloric acid (50 ml) is added a solution of tin dichloride (11) (3.38 g ) in concentrated hydrochloric acid (80 ml).

The reaction mixture was heated to 75 ° C for 1 h and then poured onto crushed ice (400 g) and extracted with ethyl acetate (2x100 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give 0.45 g (61% yield) of the title compound as an off-white solid. LC-MS (t / ζ) 244 (M ⁺ ); 1 _K = 1.48. (UV, HF) 89%, 94%.

Ή NMR (500 MHz, C1) C1 _; ): 3.30 (m, 4H), 3.65 (br s, 2H), 3.85 (m, 4H), 3.97 (s, 3H), 6.20 (s, 1H).

2-Chloro-4-methoxy-6-morpholin-4-ylpyridin-3-ylamine.

To a solution of 4- (6-chloro-4-methoxy-5-nitropyridin-2-yl) morpholine (0.38 g) in concentrated hydrochloric acid (20 ml) is added a solution of tin dichloride (11) (1.57 g ) in concentrated hydrochloric acid (60 ml). The reaction mixture was heated to 75 ° C for 5 minutes and then poured onto crushed ice (100 g) and extracted with ethyl acetate (2x20 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give 0.28 g (83% yield) of the title compound as an off-white solid.

Ή NMR (500 MHz, C1) C1 _; ): 3.35 (m, 4H), 3.65 (br s, 2H), 3.80 (m, 4H), 3.90 (s, 3H), 6.10 (s, 1H).

Compounds of the invention

The acid addition salts of the compounds of the invention can be readily prepared by methods known to those skilled in the art.

Example 1

laa. (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) carbamic acid benzyl ester.

Benzyl chloroformate (18 mg) is added to a 0.085 M solution of 2,4-dimethyl-6-morpholin-4-ylpyridin-3ylamine and a 0.17 M solution of Ν, Ν-diisopropylethylamine in 1,2-dichloroethane (1 ml). The reaction mixture in the ampoule is shaken for 16 hours in an argon atmosphere and its contents are concentrated in vacuo. Aqueous sodium hydroxide (1M, 1 ml) was added and the crude mixture was extracted with isopropyl acetate / tetrahydrofuran (4: 1, 2x1 ml).

The organic phase is washed with brine (1 ml), concentrated in vacuo and redissolved in 1-propanol / dimethyl sulfoxide (1: 1, 0.4 ml), 0.2 ml of the solution is purified by preparative LC-MS, thereby obtaining 4.5 mg (31% yield) of the title compound as an oil. LC-MS (t / ζ) 342 (MH) ⁺ ; C = 1.58, (UV, Ε1.8ΙΗ 99%, 99%.

The following compounds are prepared analogously.

lab. (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) carbamic acid 2-chlorobenzyl ester.

Yield: 18%. LC-MS (t / ζ) 376 (MH) ⁺ ; 1 _K = 1.78, (UV, ΕΕ8ΙΗ 99%, 100%.

lac. 2- (4-Chlorophenyl) -I- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 4%. LC-MS (t / ζ) 360 (MH) ⁺ ; C = 1.59, (UV, ΕΕ8ΙΗ 96%, 100%.

1ab. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) 2-phenylcyclopropanecarboxylic acid amide.

Yield: 24%. LC-MS (t / ζ) 352 (MH) ⁺ ; 1 _K = 1.64, (UV, ΕΕ8ΙΗ 96%, 100%.

1 ae. No. (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) -2-thiophen-2-yl-acetamide.

Yield: 16%. LC-MS (t / ζ) 332 (MH) ⁺ ; 1 _K = 1.20, (UV, ΕΕ8ΙΗ 93%, 99%.

1aG. 3-Cyclohexyl-I- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) propionamide.

Yield: 15%. LC-MS (t / ζ) 346 (MH) ⁺ ; 1 _K = 1.81, (UV, ΕΕ8ΙΗ 91%, 100%.

1ad (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) carbamic acid isobutyl ester.

Yield: 29%. LC-MS (t / ζ) 308 (MH) ⁺ ; 1 _K = 1.44, (UV, ΕΕ8ΙΗ 97%, 99%.

1a11. 3- (3-Chlorophenyl) -I- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) propionamide.

3- (3-Chlorophenyl) propionic acid (20 mg) was stirred at 25 ° C for 2 hours under argon in oxalyl chloride (2M solution in dichloromethane, 1 ml). The solvent was removed in vacuo and a 0.085 M solution of 2,4-dimethyl-6-morpholin-4-yl-pyridin-3-ylamine and a 0.17 M solution of Ν, Ν-diisopropylethylamine in 1,2-dichloroethane (1 ml) were added to the reaction mixture. The reaction mixture in the ampoule is shaken for 16 hours under argon and concentrated in vacuo. Aqueous sodium hydroxide (1M, 1 ml) was added and the crude mixture was extracted with isopropyl acetate / tetrahydrofuran (4: 1, 2x1 ml). The organic phase is washed with brine (1 ml), concentrated in vacuo and redissolved in 1-propanol / dimethyl sulfoxide (1: 1, 0.4 ml), 0.2 ml of the resulting solution is purified by preparative LC-MS, yielding this 2.3 mg (yield 14%) of the title compound as an oil. LC-MS (t / ζ) 374 (MH) ⁺ ; ΐ _κ = 1.71, (UV, ΕΕ8ΙΗ 99%, 99%.

The following compounds are prepared analogously.

1a1. No. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3,5-dimethylphenyl) acetamide.

Yield: 19%. LC-MS (t / ζ) 354 (MH) ⁺ ; 1 _K = 1.69, (UV, ΕΕ8ΙΗ 99%, 99%.

1a_). No. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -3-p-tolylpropionamide.

Yield: 20%. LC-MS (t / ζ) 354 (MH) ⁺ ; 1 _K = 1.64, (UV, ΕΕ8ΙΗ 99%, 100%.

- 20 016244 lak. 2- (3-Chlorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 14%. LC-MS (t / ζ) 360 (MH) ⁺ ; 1 _K = 1.58, (UV, Ε1.8Ι1). 97%, 99%.

lal. 2- (3,4-Dichlorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 9%. LC-MS (t / ζ) 395 (MH) ⁺ ; 1 _K = 1.84, (UV, ΕΕ8Ι1). 97%, 99%.

1at. Y- (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) -2-thiophen-3-yl-acetamide.

Yield: 18%. LC-MS (t / ζ) 332 (MH) ⁺ ; 1 _K = 1.18, (UV, ΕΕ8Ι1). 97%, 99%.

1ap. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-p-tolylacetamide.

Yield: 16%. LC-MS (t / ζ) 340 (MH) ⁺ ; 1 _K = 1.50, (UV, ΕΕ8Ι1). 96%, 99%.

lao. 2- (3-Bromophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 12%. LC-MS (t / ζ) 405 (MH) ⁺ ; 1 _K = 1.63, (UV, ΕΕ8Ι1). 96%, 99%.

lap. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3-trifluoromethylphenyl) acetamide.

Yield: 20%. LC-MS (t / ζ) 394 (MH) ⁺ ; 1 _K = 1.77, (UV, ΕΕ8Ι1). 94%, 99%.

1ac. |. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-phenylacetamide.

Yield: 11%. LC-MS (t / ζ) 326 (MH) ⁺ ; 1 _K = 1.29, (UV, ΕΕ8Ι1). 93%, 99%.

1ag. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) 3,5,5-trimethylhexanoic acid amide.

Yield: 20%. LC-MS (t / ζ) 348 (MH) ⁺ ; 1 _K = 1.97, (UV, ΕΕ8Ι1). 93%, 99%.

1a8. (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) octanoic acid amide.

Yield: 44%. LC-MS (t / ζ) 334 (MH) ⁺ ; 1 _K = 1.92, (UV, ΕΕ8Ι1). 92%, 99%.

1a1. Y- (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) -2-naphthalene-2-yl-acetamide.

Yield: 4%. LC-MS (t / ζ) 376 (MH) ⁺ ; 1 _K = 1.73, (UV, ΕΕ8Ι1). 92%, 99%.

1ai. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) heptanoic acid amide.

Yield: 24%. LC-MS (t / ζ) 320 (MH) ⁺ ; 1 _K = 1.56, (UV, ΕΕ8Ι1). 90%, 99%.

1au. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3,4-dimethylphenyl) acetamide.

Yield: 26%. LC-MS (t / ζ) 354 (MH) ⁺ ; 1 _K = 1.65, (UV, ΕΕ8Ι1). 77%, 99%.

1a \\\ 2-Cyclohex-1-enyl-Y- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) acetamide.

Yield: 13%. LC-MS (t / ζ) 330 (MH) ⁺ ; 1 _K = 1.50, (UV, ΕΕ8Ι1). 72%, 99%.

lax. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4-methoxy-3-methylphenyl) acetamide.

Yield: 16%. LC-MS (t / ζ) 370 (MH) ⁺ ; 1 _K = 1.56, (UV, ΕΕ8Ι1). 94%, 99%.

lay. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4-methoxyphenyl) acetamide.

Yield: 19%. LC-MS (t / ζ) 356 (MH) ⁺ ; 1 _K = 1.35, (UV, ΕΕ8Ι1). 96%, 99%.

18ζ. Y- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -3- (4-methoxyphenyl) propionamide.

Yield: 15%. LC-MS (t / ζ) 370 (MH) ⁺ ; 1 _K = 1.48, (UV, ΕΕ8Ι1). 76%, 99%.

lba. N- (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-m-tolylacetamide.

m-Tolylacetic acid (0.33 g), Ν, Ν-diisopropylethylamine (0.90 ml) and Ν-hexafluorophosphate oxide No. [(dimethylamino) -1H-1,2,3-triazolo [4,5-b] pyridine -1-ylmethylene] -№methylmethananamine (1.00 g) was mixed in dry Ν, Ν-dimethylformamide (3 ml) and the mixture was stirred under argon for 2 minutes. 2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-ylamine (0.30 g) dissolved in dry Ν, Ν-dimethylformamide (2 ml) was added to the reaction mixture, and the mixture was stirred at 25 ° C. in atmosphere argon for 16 hours. Ethyl acetate (20 ml) was added and the organic phase was washed with saturated aqueous ammonium chloride / water (1: 1, 20 ml), water (20 ml), saturated brine / water (1: 1, 20). mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (8ίΘ _2, heptane / ethyl acetate 3: 1) to give 0.069 g (yield 14%) of the title compound as a white solid. LC-MS (t / ζ) 340 (MH ⁺ ); 1 _K = 1.42, (UV, ΕΕ8Ό) 96%, 100%.

Ή NMR (500 MHz, DMSO-a ₆ ): 2.00 (s, 3H), 2.11 (s, 3H), 2.29 (s, 3H), 3.37 (m, 4H), 3, 56 (s, 2H), 3.67 (m, 4H), 6.52 (s, 1H), 7.06 (d, 1H), 7.15 (m, 2H), 7.21 (t, 1H) ), 9.30 (s, 1H).

The following compounds are prepared analogously.

lbb. No. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4-fluorophenyl) acetamide.

Yield: 14%. LC-MS (t / ζ) 344 (MH ⁺ ); 1 _K = 1.34, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, DMSO-a ₆ ): 1.99 (s, 3H), 2.10 (s, 3H), 3.37 (m, 4H), 3.60 (s, 2H), 3, 66 (m, 4H), 6.52 (s, 1H), 7.16 (dd, 2H), 7.38 (dd, 2H), 9.33 (s, 1H).

lbc. No. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -3,3-dimethylbutyramide.

Yield: 53%. LC-MS (t / ζ) 306 (MH ⁺ ); 1 _K = 1.26, (UV, ΕΕ8Ό), 99%, 98%.

Ή NMR (500 MHz, DMSO-a ₆ ): 1.05 (s, 9H), 2.07 (s, 3H), 2.18 (s, 2H), 2.19 (s, 3H), 3, 37 (m, 4H), 3.67 (m, 4H), 6.54 (s, 1H), 9.01 (s, 1H).

1a. No. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3-fluorophenyl) acetamide.

Yield: 15%. LC-MS (t / ζ) 344 (MH ⁺ ); 1 _K = 1.54, (UV, ΕΕ8Ό), 100%, 100%.

Ή NMR (500 MHz, DMSO-a ₆ ): 2.00 (s, 3H), 2.11 (s, 3H), 3.37 (m, 4H), 3.64 (s, 2H), 3, 66 (m, 4H), 6.52 (s, 1H), 7.08 (dt, 1H), 7.18 (m, 2H), 7.38 (m, 1H), 9.34 (s, 1H) )

1b. 2-Bicyclo [2.2.1] hept-2-yl-no. (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 62%. LC-MS (t / ζ) 344 (MH ⁺ ); 1 _K = 1.58, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, DMSO-a ₆ ): 1.14 (m, 4H), 142 (m, 4H), 1.90 (m, 1H), 2.01 (m, 1H), 2.04 ( s, 3H), 2.10 (m, 1H), 2.16 (s, 3H), 2.21 (m, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H); 9.04 (s, 1H).

- 21 016244

Lg. 2- (3,4-Difluorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 9%. LC-MS (t / ζ) 362 (MH ⁺ ); ΐ _κ = 1.52, (UV, Ε1.8ΙΗ 95%, 99%.

Ή NMR (500 MHz, DMSO-b ₆ ): 2.00 (s, 3H), 2.11 (s, 3H), 3.37 (m, 4H), 3.63 (s, 2H), 3, 66 (m, 4H), 6.52 (s, 1H), 7.19 (m, 1H), 7.39 (m, 2H), 9.32 (s, 1H).

1 dd (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) 4-methylpentanoic acid amide.

Yield: 34%. LC-MS (t / ζ) 306 (MH ⁺ ); 1, = 1.33, (UV, ΕΕ8ΙΗ 100%, 99%.

Ή NMR (500 MHz, DMSO-b ₆ ): 0.91 (d, 6H), 1.49 (dt, 2H), 1.58 (m, 1H), 2.04 (s, 3H), 2, 16 (s, 3H), 2.28 (t, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.07 (s, 1H) )

1Y1. 2-Cyclopent-2-enyl-X- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 13%. LC-MS (t / ζ) 316 (MH ⁺ ); 1, = 1.25, (UV, ΕΕ8ΙΗ 97%, 94%.

Ή NMR (500 MHz, DMSO-b ₆ ): 1.51 (m, 1H), 2.05 (m, 1H), 2.06 (s, 3H), 2.17 (s, 3H), 2, 26 (m, 2H), 2.35 (m, 2H), 3.07 (m, 1H), 3.38 (m, 4H), 3.68 (m, 4H), 5.73 (m, 1H ), 5.77 (m, 1H), 6.54 (s, 1H), 9.09 (s, 1H).

1b1. 2-Cyclohexyl-X- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

Yield: 12%. LC-MS (t / ζ) 332 (MH ⁺ ); 1, = 1.50, (UV, ΕΕ8ΙΗ 99%, 95%.

Ή NMR (500 MHz, DMSO-f): 0.98 (m, 2H), 1.20 (m, 3H), 1.71 (m, 6H), 2.05 (s, 3H), 2.15 (d, 2H), 2.16 (s, 3H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.05 (s, 1H) .

1b). (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) 5-methylhexanoic acid amide.

Yield: 40%. LC-MS-ΤΘΓ (t / ζ) 320 (MH ⁺ ); ΐ _κ = 1.51, (UV, ΕΕ8ΙΗ 97%, 100%.

Ή NMR (500 MHz, DMSO-b ₆ ): 0.87 (d, 6H), 1.21 (m, 2H), 1.60 (m, 3H), 2.05 (s, 3H), 2, 16 (s, 3H), 2.25 (t, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.05 (s, 1H) )

lbk. 2-Cyclopentyl-X- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide.

2,4-Dimethyl-6-morpholin-4-ylpyridin-3-ylamine (0.22 g) and cyclopentylacetyl chloride (0.19 ml) were dissolved in acetonitrile (5 ml) and the solution was heated to 150 ° C for 10 min in sealed ampoule under microwave irradiation. The reaction mixture was concentrated in vacuo and purified by flash chromatography (8ίΘ _2, heptane / ethyl acetate, 3: 1) to obtain 0.17 g (yield 49%) of the title compound as a white solid. LC-MS (t / ζ) 318 (MH) ⁺ ; 1, = 1.40, (UV, ΕΕ8Ό), 97%, 99%.

Ή NMR (500 MHz, DMSO-b ₆ ): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2, 05 (s, 3H), 2.17 (s, 3H), 2.24 (m, 1H), 2.26 (m, 2H), 3.37 (m, 4H), 3.67 (m, 4H) ), 6.53 (s, 1H), 9.05 (s, 1H).

The following compounds are prepared analogously, with the exception of compounds L1 and Lt, which are recrystallized from ethyl acetate after flash chromatography.

lbl. 3-Cyclopentyl-L- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) propionamide.

Yield: 34%. LC-MS (t / ζ) 332 (MH ⁺ ); 1, = 1.57, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, DMSO-b ₆ ): 1.11 (m, 2H), 1.49 (m, 2H), 1.60 (m, 4H), 1.77 (m, 3H), 2, 04 (s, 3H), 2.16 (s, 3H), 2.28 (t, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H ), 9.06 (s, 1H).

1t. (2,4-Dimethyl-6-morpholin-4-ylpyridin-3-yl) hexanoic acid amide.

Yield: 51%. LC-MS (t / ζ) 306 (MH ⁺ ); 1, = 1.39, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, DMSO-b ₆ ): 0.88 (t, 3H), 1.31 (m, 4H), 1.60 (m, 2H), 2.05 (s, 3H), 2, 16 (s, 3H), 2.27 (t, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.03 (s, 1H) )

1bn. Y- (4-Chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) -2-cyclopentylacetamide.

Yield: 53%. LC-MS (t / ζ) 354 (MH ⁺ ); I., 2.68, (UV, ΕΕ8Ό), 98%, 99%.

Ή NMR (500 MHz, SIS1 ₃ ): 1.25 (m, 2H), 1.50-1.65 (m, 4H), 1.90 (m, 2H), 2.45 (m, 3H), 3.45 (m, 4H), 3.77 (m, 4H), 3.90 (s, 3H), 6.20 (s, 1H), 6.50 (s, 1H).

lbo. Y- (4-Chloro-4-methoxy-6-morpholin-4-ylpyridin-3-yl) -2-cyclopentylacetamide.

Yield: 69%. LC-MS (t / ζ) 354 (MH ⁺ ); 1, 2.39, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, SIS1 ₃ ): 1.25 (m, 2H), 1.50-1.70 (m, 4H), 1.90 (m, 2H), 2.35 (m, 3H), 3.50 (m, 4H), 3.80 (m, 4H), 3.85 (s, 3H), 6.00 (s, 1H), 6.45 (s, 1H).

lbp. Y- (2-Chloro-4-methoxy-6-morpholin-4-ylpyridin-3-yl) -3,3-dimethylbutyramide.

Yield: 56%. LC-MS (t / ζ) 342 (MH ⁺ ); 1, = 2.31, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, SIS1 ₃ ): 1.10 (s, 9H), 2.25 (s, 2H), 3.50 (m, 4H), 3.77 (m, 4H), 3.85 ( s, 3H), 6.00 (s, 1H), 6.45 (s, 1H).

1bc. |. Y- (4-Chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) -3,3-dimethylbutyramide.

Yield: 68%. LC-MS (t / ζ) 342 (MH ⁺ ); 1, = 1.39, (UV, ΕΕ8Ό), 99%, 99%.

Ή NMR (500 MHz, DMSO-b ₆ ): 1.10 (s, 9H), 2.15 (s, 2H), 3.45 (m, 4H), 3.70 (m, 4H), 3, 80 (s, 3H), 6.45 (s, 1H), 8.95 (s, 1H).

1b. Y- (4-Chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) propionamide.

Yield: 71%. LC-MS (t / ζ) 300 (MH ⁺ ); 1, = 0.97, (UV, ΕΕ8Ό), 98%, 98%.

Ή NMR (500 MHz, DMSO-be): 1.05 (t, 3H), 2.25 (q, 2H), 3.45 (m, 4H), 3.70 (m, 4H), 3, 80 (s, 3H), 6.45 (s, 1H), 9.00 (s, 1H).

- 22 016244

Table 1

The reagents used to obtain the compounds in example 1

Name Supplier No. SAZ Catalog No.

1- Cyclohexenylacetic acid A1 £ a 18294-87-6 19462

3.4- Difluorophenylacetic acid ABCK 658-93-5 ΕΌ2874Ε

3-Bromophenylacetic acid A1bg1cb. 1878-67-7 28.866-1

3-Chlorophenylacetic acid AShgtsN 1878-65-5 C6.335-9

2- (Trifluoromethyl) phenylacetic A1c1g1cb 351-35-9 19.335-6 acid

2-amino-4,6-dimethylpyridine A1dg ± b 5407-87-4 Ά5.180-7

2-Chlorobenzylchloroformate A1b1cb 39545-31-8 49.379-1

2-Cyclopentene-1-acetic A10g1cb 13668-61-6 SI, 285-2 acid

2-Naphthylacetic Acid ΑΙάΓίοΗ 581-96-4 31,791-8

2- Phenylacetic acid AChr3cb 103-82-2 P1.662-1

2,4,6-Trichloropyridine A1c3r1cb 16063-69-7 63.353-4

3- (3-Chlorophenyl) propionic ABCK 21640-48-2 TYS2925 acid

3- (4-Methoxyphenyl) propionic A1yg1cb 1929-29-9 M2.352-7 acid

3- (4-Methylphenyl) propionic A1 <1g1cb 1505-50-6 11.826-5 acid

3.4- Dichlorophenylacetic acid A1c! G1c11 5807-30-7 28,000-3

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3,4-Dimethylphenylacetic acid U1Saz-M 17283-16-8 TVV000367 3,5,5-trimethylhexane acid Asgoz 3302-10-1 26944-0250 3,5-dimethylphenylacetic acid ABC 42288-46-0 S-42288-46 Z-Cyclohexylpropionyl chloride Asgoz 39098-75-4 35071-0250 Z-cyclopentylpropionyl chloride A1 <Zl1cb 104-97-2 26,859-3 3-fluorophenylacetic acid A1szg1s11 331-25-9 24,804-5 4-chlorophenyl and ethyl chloride Baptist 25026-34-0 6317 4-fluorophenylacetic acid A13g1s11 405-50-5 ΕΊ, 330-4 4-Me-toxi-3-me-phenyl-acetic acid acid U1AZ-M 4513-73-9 TVV000371 4-methoxyphenylacetic acid A1YG1sN 104-01-8 ΜΙ, 920-1 4-methylpentanoic acid A1YG1s11 646-07-1 27,782-7 5-methylhexanoic acid Marg / x 628-46-6 3527 Benzyl chloroformate ΑΙάτίοΕ 501-53-1 11,993-8 Bicyclo [2.2.1] hept-2-ylacetic acid А10г1сЬ 1007-01-8 12,726-4 Bis (2-chloroethyl) simple ether A1c1g1cb 111-44-4 04,113-4 Cyclohexylacetic acid А13г1сЬ 5292-21-7 SJ, 450-7 Cyclopentylacetyl chloride Lapsaz Deg 1122-99-2 14562 Heptanoic acid A1c1g ± cb 111-14-8 14,687-0 Hexanoyl chloride Αΐάτίσίι 142-61-0 29,465-9 Isobutyl Chloroformate ΑΙάτϊοΐΊ 543-27-1 17,798-9 m-Tolylacetic acid ΑΙάτίοΗ 621-36-3 TK, 809-1 Ν-Hexafluorophosphate Окс- [(dimethylamino) -1H-1,2 _g 3 triazolo [4,5-b] pyridin-1 methylmethylene] -Y-methylmethanamine P1ika 148893-10-1 11373 Octanoic acid Α1άτιсЬ 124-07-2 15,375-3 Ok salyl chloride ΑΙάτίοΗ 79-37-8 32,042-0 p-Tolylacetic acid A1c1g1cb 622-47-9 TK, 810-5 Sodium iodide ΑΙάτίοΗ 7681-82-5 32,245-8 Sodium nitrite A1c1g1cb 7632-00-0 51,091-2 tert-butyl acetic acid A1g1cb 1070-83-3 B8,840-3 Thiophene-2-acetyl chloride ΑΙάτΐσΗ 39098-97-0 19,599-5

Thiophene-3-acetic acid A1 (1g1cb 6964-21-2 22,063-9 trans-2-phenyl-1- A1s1g1s11 939-87-7 13,430-9 cyclopropanecarbonyl chloride Zinc A1g1cb 52374-36-4 20,998-8

The test of sh uygo and sh u1uo.

The compounds of the invention were tested and determined to be active in at least one of the following models.

Relative leakage through channel I <CN ^ 2.

Here is an example of a screening protocol I <CN ^ 2 for evaluating the compounds of the present invention. This analysis measures the relative leakage through channel I <CN ^ 2. it was carried out according to the method described by Tapd eG a1. (Tapd, V. eG a1., 1. B1oto1. 8cep. 2001, 6, 325-331) for the potassium channels of NEX with modifications described below.

Adequate number of CHO cells stably expressing voltage-regulated channels I <CN ^ 2. seeded in the tablet at a density sufficient to form a confluent monolayer, a day before the experiment. Cells were loaded with 1 μCi [ ⁸⁶ KB] overnight. On the day of the experiment, the cells were washed with HB88-containing buffer (Hanks balanced salt solution obtained from

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1pu11godep, sa! # 14025-050). Cells were pre-incubated with the drug for 30 minutes and leakage of E ^{+ was} stimulated with a submaximal concentration of 15 mM potassium chloride with the constant presence of the drug for an additional 30 minutes. After a suitable incubation period, the supernatant was removed and the counts were carried out using scintillation fluid (Tpsum). Cells were lysed with 2 mM sodium hydroxide and the amount of E ′ was counted. Relative leakage was calculated as follows:

((CPM supernatant / (CPM supernatant + CPM cell)) compound / (CPM supernatant / (CPM supernatant + CPM glue)) 15 mm KS1) * 100 ^_ 100.

The compounds of the invention have an EC50 of less than 20,000 nM, in most cases less than 2000 nM, and in many cases less than 200 nM. Accordingly, it is believed that the compounds of the invention are useful in the treatment of diseases associated with potassium channels of the Xyr family.

Electrophysiological patch clamp recording in CHO cells.

Voltage-activated currents Ι '.' ΝΟ2 were detected in CHO cells of mammals using generally accepted patch-clamp registration methods in the patch-clamp configuration of whole cells (NatSh OR.e! A1. RDideg AgsN 1981; 391: 85-100). CHO cells with stable expression of voltage activated channels Ι '''' каналов 2 were grown under normal cell cultivation conditions in CO ₂ incubators and used for electrophysiological recordings 1–7 days after plating. The potassium channels Ι '''ΝΟ2 were activated by voltage surges up to + 80 mV with increments of 5–20 mV (or a protocol with a linear increase) from the potential of maintaining the membrane between –100 and –40 mV (Ta1i11ai b. E! A1. I Heigokaepse 2001 ; 21 (15): 5535-5545). The electrophysiological effects induced by the compounds were evaluated by various parameters of the current activated by voltage Ι 'ΝΟ 2. The effects on the activation threshold for current and on the maximum induced current were especially studied.

According to the test studied some of the compounds of the invention. It is assumed that a shift of the activation threshold to the left or an increase in the maximum induced potassium current reduces the activity of neural networks and therefore makes the compounds useful in diseases with increased neural activity, such as epilepsy.

Electrophysiological registration of channels Ι <Χ'’ΝΟ2. 1 <C ^ O2 / KC ^ O3 or Ι <Χ'’ΝΟ5 in oocytes.

The voltage-activated currents KSYR2, 1 <C ^ O2 / KS ^ O3 or Ι <Χ''ΝΟ5 were detected from Heporik oocytes, which were injected with mRNA encoding the ion channels KSYR2, KS ^ O2 + Ι <Χ''ΝΟ3 or KSHO5 (\\ aiu e! a1., 8c1epse 1998, 282, 1890-1893; Lebie e! a1., I. Bü1 Set 2000, 275, 22395-400). The potassium channels 'ΝΟΣ, Ι' ΝΟ 2 / 'ΝΟ 3, or Ι' ΝΟ ΝΟ 5 were activated by voltage surges from the membrane support potential (between -100 and -40 mV) to + 40 mV with increments of 5-20 mV (or a protocol with linear increase). The electrophysiological actions induced by the compounds were evaluated by various parameters of voltage-activated currents KSYR2, 1 <C ^ O2 / KS ^ O3 or KS ^ O5. The effects on the activation threshold for current and on the maximum induced current were especially studied.

The effects of hyperpolarization of some compounds were also tested directly on the membrane potential during current fixation.

Maximum electric shock.

The test was carried out in groups of male mice using corneal electrodes and introducing a rectangular pulse current of 26 mA for 0.4 s to induce a seizure characterized by tonic straightening of the hind limbs (\ 1ax e! A1. ErPerku Kekeagsy 1998, 30, 219-229).

Pilocarpine-induced epileptic seizures.

Pilocarpine-induced epileptic seizures are induced by intraperitoneal injection of 250 mg / kg of pilocarpine into a group of male mice and epileptic activity is observed leading to a loss of body position within a period of 30 minutes (§! Arg e! A1. .

Test for electrical threshold of an epileptic seizure.

A modification of the up and down method (K1tba11 e! A1. Kab1a! Yup RekeagSN 1957, 1-12) was used to determine the average threshold for the induction of tonic straightening of the hind limbs in response to corneal electroshock in groups of male mice. The first mouse of each group received electroshock at 14 mA (0.4 s, 50 Hz) and then it was examined for epileptic activity. If an epileptic seizure was observed, the current was reduced by 1 mA for the next mouse, however, if an epileptic seizure was not observed, then the current was increased by 1 mm. This procedure was repeated for all 15 mice in the treatment group.

Test for the chemical threshold of an epileptic seizure.

The threshold dose of pentylenetetrazole required for the induction of clonic seizure was measured by time-controlled infusion of pentylenetetrazole (5 mg / ml at a rate of 0.5 ml / min) into the lateral tail vein of a group of male mice (ΙΙιιΙΙ е! А1. I. Ragnas apb Rnagtasoodu 1986, 38, 697-698).

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Activation of the amygdala.

Rats underwent surgery to implant tripolar electrodes into the dorsolateral amygdala. After surgery, animals were allowed to recover before groups of rats received either variable doses of the test compound or a drug carrier. The animals were stimulated with an initial current after a discharge threshold of + 25 μA daily for 3-5 weeks, and in each case, the severity of the seizure, the duration of the seizure, the duration of the presence of electric current after discharge (Caste. -294).

Side effects.

Side effects on the central nervous system were determined by measuring the time during which the mice could remain on the apparatus with a rotating rod (Sarasyu e1 a1. Aegid aib Sjetka1 Tokh1so1odu 1992, 15, 177-201), or by measuring their locomotor activity by counting the number of infrared rays intersecting in the cell for testing (^ a! koi e1 a1. No. horbagtasodu 1997, 36, 13691375). Hypothermal effects of the compound on the temperature of the internal part of the animal’s body were measured either with a rectal probe or with implanted radio telemetry sensors capable of measuring temperature (Keepeu e1 a1.

Pharmacokinetics

The pharmacokinetic properties of the compounds were determined by intravenous and oral dosed administration to rats Zrgas. | Oa \\ '1еу and after that by blood sampling for 20 hours. Their plasma concentrations were determined by LC / MS / MS.

Claims (20)

CLAIM 1. The compound having the General formula I where with. | equal to 0 or 1; each of K ¹ and K ² are independently selected from the group consisting of C1 _-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8-cycloalk (en) yl-C1-8-alkyl, C3-8-cycloalkyl (en) yl-C2-8 alkenyl, C3-8-cycloalkyl (en) yl-C2-8-alkynyl, C1-6-alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy and halogen; and K ^{3 is} selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C _3-8 cycloalkyl (en) yl- _C1-6 -alkyl, C _3-8 -cycloalkyl (en) yl-C _2-6 alkenyl, C _3-8 -cycloalkyl (en) ylC2-6-alkynyl, optionally substituted aryl-C1-6-alkyl, optionally substituted aryl- C2-6 alkenyl, optionally substituted aryl-C2-6 alkynyl, optionally substituted aryl-C3-8 cycloalkyl (en) yl, optionally substituted aryl-C _3-8 cycloalk (en) yl- _C1-6 alkyl, optionally substituted aryl -C3-8-cycloalk (en) yl-C2-6-alkenyl optionally substituted with aryl-C3 -8 cycloalkyl (en) yl-C2-6-alkynyl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl, heteroaryl-C2-6 alkynyl, heteroaryl-C3-8-cycloalkyl (en) yl, heteroaryl-C3 -8-cycloalkyl (en) yl-C1-6-alkyl, heteroaryl-C3-8cycloalkyl (en) yl-C2-6-alkenyl and heteroaryl-C3-8-cycloalkyl (en) yl-C2-6-alkynyl; wherein the aryl portion is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl enyl , C3-8-cycloalkyl (en) yl-C1-6 alkyl, C3-8-cycloalkyl (en) yl-C2-6 alkenyl, C3-8-cycloalk (en) yl-C2-6 alkynyl, halogen -C1-6-alkyl, halogen-C2-6-alkenyl, halogen-C2-6-alkynyl, halogen-C3-8-cycloalk (en) silt, halogenC3-8-cycloalk (en) il-C1-6-alkyl , halogen-C3-8-cycloalkyl (en) yl-C2-6-alkenyl, halogen-C3-8-cycloalkyl (en) ylC2-6-alkynyl, C1-6-alkyloxy, C2-6-alkenyloxy, C2-6 -alkynyloxy, C3-8-cycloalk (en) yl Xi and C3-8 cycloalkyl (en) yl-C1-6-alkyloxy, C3-8 cycloalkyl (en) yl-C2-6 alkenyloxy, C3-8 cycloalkyl (en) yl-S2-6alkiniloksi; and where heteroaryl is selected from the group consisting of pyridine, thiophene, furan, pyrrole, pyrazole, triazole, tetrazole, oxazole, imidazole, thiazole, benzofuran, benzothiophene and indole; and its pharmaceutically acceptable salt. 2. The compound according to claim 1, where S. | equal to 0. 3. The compound according to claim 1, where S. | equal to 1. 4. A compound according to claim 2 or 3, wherein both K ¹ and K ² represent a C 1 _-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl. 5. A compound according to claim 2 or 3, where R ¹ represents a C1 _-6 -alkyloxy, C _2-6 -alkeniloksi or C _2-6 alkynyloxy and R ² is halo or where R ¹ represents halo and R ² represents 26 016244 is C _1-6 alkyloxy, C _2-6 alkenyloxy or C _2-6 alkyloxy. 6. The compound according to claim 4 or 5, where K ^{3 is} selected from the group consisting of C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 alkynyl, C _3-8 -cycloalkyl (en) il- C _1-6 alkyl, C _3-8 cycloalkyl (en) yl-C _2-6 alkenyl, C _3-8 cycloalkyl (en) yl-C _2-6 alkynyl optionally substituted with aryl-C _1-6 -alkyl, optionally substituted aryl-C _2-6- alkenyl, optionally substituted aryl-C2-6-alkynyl, optionally substituted aryl-C3-8-cycloalkyl (en) yl, heteroaryl-C _1-6 -alkyl, heteroaryl-C _2-6 alkenyl, heteroaryl-C _2-6 alkynyl. 7. The compound according to claim 6, where the optionally substituted aryl may be substituted by one or more substituents independently selected from the group consisting of halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, halogen C _1-6 alkyl, halo C _2-6 alkenyl, halo C _2-6 alkynyl, C _1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy. 8. The compound according to claim 1, selected from the group consisting of (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) carbamic acid benzyl ester; (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) carbamic acid 2-chlorobenzyl ester; 2- (4-chlorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) -amide of 2-phenylcyclopropanecarboxylic acid; Y- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) -2-thiophen-2-yl-acetamide; 3- cyclohexyl-Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) propionamide; (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl) carbamic acid isobutyl ester; 3- (3-chlorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) propionamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3,5-dimethylphenyl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -3-p-tolylpropionamide; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, selected from the group consisting of 2- (3-chlorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) acetamide; 2- (3,4-dichlorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) -2-thiophen-3-yl-acetamide; Y- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) -2-p-tolylpropionamide; 2- (3-bromophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3-trifluoromethylphenyl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-phenylacetamide; 3,5,4-trimethylhexanoic acid (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) amide; (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) octanoic acid amide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-naphthalene-2-yl-acetamide; or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, selected from the group consisting of (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) heptanoic acid amide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3,4-dimethylphenyl) acetamide; 2- (cyclohex-1-enyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4-methoxy-3-methylphenyl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4-methoxyphenyl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -3- (4-methoxyphenyl) propionamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2-m-tolylacetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (4-fluorophenyl) acetamide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -3,3-dimethylbutyramide; Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) -2- (3-fluorophenyl) acetamide; 2-bicyclo [2.2.1] hept-2-yl-Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; 2- (3,4-difluorophenyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; 4-methylpentanoic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) amide; 2- (cyclopent-2-enyl) -Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; 2-cyclohexyl-Y- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; 5-methyl-hexanoic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl) amide; 2- cyclopentyl-L- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) acetamide; 3- cyclopentyl-L- (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) propionamide; (2,4-dimethyl-6-morpholin-4-ylpyridin-3-yl) hexanoic acid amide; Y- (4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) -2-cyclopentylacetamide; Y- (2-chloro-4-methoxy-6-morpholin-4-ylpyridin-3-yl) -2-cyclopentylacetamide; Y- (2-chloro-4-methoxy-6-morpholin-4-ylpyridin-3-yl) -3,3-dimethylbutyramide; Y- (4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) -3,3-dimethylbutyramide; Y- (4-chloro-2-methoxy-6-morpholin-4-ylpyridin-3-yl) propionamide; or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition for therapy, comprising one or more pharmaceutically acceptable carriers or diluents and a compound according to claim 1. - 27 016244 12. The use of the pharmaceutical composition according to claim 11 for increasing the flow of ions in the potassium channel of a mammal. 13. The use of the pharmaceutical composition according to claim 11 for the treatment of a disorder or disease susceptible to increased ion flux in the potassium channel, wherein the disorder or disease is a disorder or disease of the central nervous system. 14. The use of claim 13, wherein the disorder or disease being treated is selected from the group consisting of epileptic disorders, anxiety disorders, disorders related to neuropathic pain and migraine pain, neurodegenerative disorders, stroke, cocaine abuse, nicotine withdrawal syndrome, syndrome withdrawal of ethanol and tinnitus. 15. The use of claim 14, wherein the epileptic disorders are selected from the group consisting of acute epileptic seizures, seizures, an epileptic state, epilepsy such as epileptic syndromes and epileptic seizures. 16. The application of clause 14, where anxiety disorders are selected from the group consisting of anxiety and disorders and diseases related to a panic attack, agoraphobia, panic disorder with agarophobia, panic disorder without agarophobia, agoraphobia without a medical history of panic disorder, specific phobia, social phobia and other specific phobias, compulsive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder property due to a general medical condition, anxiety disorder caused by a substance, anxiety disorder associated with fear of separation, disturbances due to adaptability, anxiety regarding the ability to perform work, disorders associated with hypochondriac syndrome, anxiety disorder due to general medical condition and anxiety disorder, caused by a substance. 17. The use of claim 14, wherein the disorders related to neuropathic pain and migraine pain are selected from the group consisting of allodynia, hyperalgic pain, phantom pain, neuropathic pain related to diabetic neuropathy, neuropathic pain related to trigeminal neuralgia. 18. The use of claim 14, wherein the neurodegenerative disorders are selected from the group consisting of Alzheimer's disease; Huntington’s chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Parkinson’s disease, encephalopathy induced by AIDS or infection with rubella viruses, herpes viruses, borrelia or unknown pathogens, induced by trauma of neurodegenerative neurodegenerative diseases and neuronal conditions. 19. The use of claim 13, wherein the disorder or disease being treated is selected from the group consisting of bipolar disorders. 20. The use of claim 13, wherein the disorder or disease being treated is selected from sleep disorders. 4 ^ 8) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2