EA008589B1 - 1,2,4-triaminobenzene derivatives useful for treating disorders of the central nervous system - Google Patents

Abstract

The present invention concerns 1,2,4-triaminobenzene derivatives of the general formula I or pharmaceutically acceptable salts thereof and the use thereof.

Description

FIELD OF THE INVENTION

The present invention relates to new derivatives of 1,2,4-triaminobenzene, which open potassium channels of the Ι <ί.'ΝΟ family. The compounds are suitable for the prophylaxis, treatment and / or suppression of disorders of the central nervous system.

State of the art

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

People have more than 70 subunits of potassium channels (ZsShksy No. 1Shge Ks \ ss \ yk No.igo5S1Spes 2000, 1, 21-30) with a wide variety of structures and functions. The potassium channels of neurons that are found in the brain are mainly responsible for maintaining the negative resting potential of the membranes, as well as the regulation of membrane repolarization after the action potential.

One subgroup of potassium channel genes is the Ι <ί.'ΝΟ family. Mutations in four of the five genes Ι <ί.'ΝΟ have been shown to lead to the development of diseases, including cardiac arrhythmias, deafness, and epilepsy (.TeShksy No. 1Shgs Ks \ zs \ uk Leigo8S1epse 2000, 1, 21-30).

It is believed that the ί <ί.'ΝΟ4 gene encodes a molecular correlate of potassium channels found in the outer hair cells of the cochlea and in the hair cells of type I of the vestibular apparatus, mutations in which lead to hereditary deafness.

Ι <ί.’ΝΟ1 (KUBOT1) is organized with the product of the Κί.’ΝΕ1 gene (the minimum K (+) is the channel protein) in the heart with the formation of a cardiac slowing-down rectifier-like K (+) current. Mutations in this channel can lead to the development of a congenital long tooth syndrome of type I OT (LOT1), as well as they are associated with the form of deafness (Kölšk Ryattaso. Tyeg. 2001, 90, 1-19).

The genes Ι <ί.'ΝΟ2 and Ι <ί.'ΝΟ3 were discovered in 1988, and it turned out that they are mutant in the hereditary form of epilepsy, known as benign familial cramps of newborns (Koda \ ukk | Tepbk ίη No.igo5C1epee5 2000, 23, 393-398). Proteins encoded by the Ι <ί.’ΝΟ2 and Ι <ί.’ΝΟ3 genes. are located in the pyramidal neurons of the cerebral cortex and the hippocampus of the person, areas of the brain associated with the onset and development of convulsive seizures (Sooreg c1 a1. Prgosebshdk Να1yupa Asabetu £ Bsiups I8A 2000, 97, 4914-4919).

Ι <ί.'ΝΟ2 and Ι <ί.'ΝΟ3 are two subunits of potassium channels that form “Mtoki” upon expression of ίη νίΙΐΌ. M-current is a non-inactivating potassium current found in many types of neurons. In each type of cell, it is dominant in the regulation of membrane excitability, being the only direct current during the initiation of the action potential (Maykop Appia1 Ke \ ze \\ Ryukyuodu 1997, 59, 483-504). Modulation of the M-current has a significant effect on the excitability of neurons, for example, activation of the current will lead to a decrease in the excitability of neurons. Thus, substances that open these channels of CSIS will reduce the excessive activity of neurons in conditions such as seizures and diseases characterized by excessive activity of neurons, for example, with epilepsy and neuropathic pain.

Retigabin (Ό-23129, Y- (2-amino-4- (4-fluorobenzylamino) phenyl) carbamic acid ethyl ester) and its analogues are disclosed in patent EP554543. Retigabin is an anticonvulsant drug with a wide spectrum of action and high anticonvulsant properties under both ίη and ίη у1уо conditions. It is active in oral and intraperitoneal administration to rats and mice in a number of anticonvulsant tests, including: electricity-induced convulsive seizures, seizures induced by the chemical effects of pentylenetetrazole, picrotoxin and Ό-methylΌ-aspartate (ΝΜΌΑ), and a test on the genetic model, mice ΌΒΑ / 2 (Kokyusk c1 a1. Yerjeku Kekeagsy 1996, 23, 211-223). In addition, retigabin is active in a model of complex partial seizures with kindling caused by stimulation of the tonsil, which further indicates that this compound has the potential for use in anticonvulsant therapy. Recent clinical trials have shown that retigabin is effective in reducing the incidence of seizures in patients with epilepsy (B1a1eg c1 a1. Erkerku Kekeagsy 2002, 51, 31-71).

It was shown that retigabin activates the K (+) current in neurons, and the pharmacology of this induced current is consistent with published data on the pharmacology of the M-channel, indicating a correlation with the hetero multimer KSYO2 / 3 K (+) channel. Based on this, it can be assumed that the activation of the KSYO2 / 3 channels may be partially responsible for the anticonvulsant activity of this drug (\ νΚ1 ^ ι ^ η c1 a1. Mo1eci1ag Ryagtasodu 2000, 58, 591-600), and that other means acting on this the same mechanism may have similar applications.

It was reported that the Ι <ί.'ΝΟ2 and 3 channels were stimulated on neuropathic pain models (ХУ ^ кемИ-СМ с1 а1. 8ос1е1у £ from No. igoksse Ак1гас1к 2002, 454, 7), and a hypothesis was put forward that potassium channel modulators They are active in case of neuropathic pain and epilepsy (Zsigobeg c1 a1. No. Igoryagtasodu 2001, 40, 888-898; Briskat-Micho ip6 1spksp Engorsag! Zoit1 o £ Ryagtasododu 2003, 460, 109-116). In addition, it was reported that the presence of mRNA channels Ι <ί.'ΝΟ in the brain and other parts

- 1 008589 of the central nervous system is associated with pain (Co1bChst e! A1. 8os1e1u £ from Yeigokaepse L51gas15 2003, 53, 8).

In addition to its role in neuropathic pain, the expression of CSIC 2-5 mRNA in the ganglion of the trigeminal and dorsal roots and in the trigeminal caudate nucleus suggests that these channels can also affect the sensory processing of migraine (Co1b8! Ex e! A1. 8oc1e1u £ from Ieigo8C1pee AL Chas 2003, 53, 8).

Recently published reports have shown that mRNA of CSIC 3 and 5, in addition to that of CSIC2, is expressed in astrocytes and glial cells. Thus, the channels of CSIC 2, 3, and 5 can modulate synaptic activity in the central nervous system and contribute to the neuroprotective effect of substances that open the channels of the CSIC (Ioba e! A1., 8ae1u £ from #igo8c1epse L51gas15 2003, 53. 9). Thus, retigabin and other CSIC modulators can exert a protective effect on the neurodegenerative effects of epilepsy, since it has been shown that retigabin prevents limb neurodegeneration and expression of apoptosis markers after rat-induced epileptic status in kainic acid (Eb! E! A1. Eperea 2002, 43, 43). 8irr. 1, 5, 86-95). This may be relevant in preventing the progression of epilepsy in patients, i.e. expressed in antiepileptogenic effect. It has also been shown that retigabin slows down the progression of the hippocampus kindling in rats, which is an additional model for the development of epilepsy (Thoeb e! A1. Eigoreap 1oigpa1 o £ Ryattasodu 1996, 303, 163-169).

Given that anticonvulsant compounds, such as benzodiazepines and chloromethiazole, are used in the clinic to treat ethanol withdrawal syndrome, and that other anticonvulsants, such as gabapentin, are very effective on animal models of this syndrome (Huaiop e! A1. No. goryagtasodu 1997 , 36, 1369-1375), the applicants have suggested that other anticonvulsant compounds, such as substances that open CSIC, will also be effective in this condition.

The mRNA of the subunits of CSIC 2 and 3 was found in areas of the brain associated with anxiety and emotional behavior, such as bipolar disorder, for example, in the hippocampus and amygdala (8ad e! a1. 1poje1 Meexoxepse 2001, 21, 4609-4624), and it was reported that retigabin is active in some models of anxiety-like conditions in animals (Nagai e! a1. 1oitp1o £ P8syoryoryagtasodu 2003, 17 §irr1. 3, A28, B16), and other anticonvulsant compounds used in the clinic are used to treat bipolar disorder.

The application \ ¥ O 200196540 discloses the use of M-current modulators formed by the expression of the KSYZ2 and KSYZ3 genes for the treatment of insomnia, while the application \ ¥ O 2001092526 discloses that the KSYZ5 modulators can be used to treat sleep disorders.

Application \ ¥ O 01/022953 discloses the use of retigabin for the prevention and treatment of neuropathic pain such as allodynia, hyperalgic pain, phantom pain, neuropathic pain associated with neuropathy in diabetes, and neuropathic pain associated with migraine.

Application \ ¥ O 02/049628 discloses the use of retigabin for the prevention, treatment, suppression and alleviation of anxiety-related conditions, such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, anxiety state, post-traumatic stress disorder acute stress reaction, regulatory disorder, hypochondria disorder, fear of separation, agoraphobia and specific phobias.

Application \ ¥ O 97/15300 discloses the use of retigabin for the treatment of neurodegenerative diseases such as Alzheimer's disease, Huntington’s chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other infections associated with encephalopathy caused by herpes viruses and herpes viruses pathogens, Creutzfeldt-Jakob disease, Parkinson's disease, neurodegeneration caused by trauma, and neuronal hyper-excitation states, such as those resulting from drug withdrawal and caused by intoxication, neurodegenerative diseases of the peripheral nervous system, such as polyneuropathies and polyneuritis.

Therefore, there is a great need for new compounds that open potassium channels of the CSIC family.

Also desirable are new compounds with improved properties compared to known compounds that open potassium channels of the XICC family, such as retigabin. It is desirable to improve one or more of the following parameters: elimination half-life, clearance, selectivity, interaction with other drugs, bioavailability, effectiveness, formulation ability, chemical stability, metabolic stability, membrane permeability, solubility, and therapeutic index. Improving these parameters can lead to improvements such as an improved administration schedule with a decrease in the number of required doses per day;

ease of administration to patients with repeated use;

reduced side effects;

increased therapeutic index;

- 2 008589 increased tolerance and / or improved perception.

SUMMARY OF THE INVENTION

In accordance with the foregoing, the aim of the invention is the provision of new compounds that effectively open potassium channels of the ΚΟΝρ family.

The compounds of the invention are derivatives of 1,2,4-triaminobenzene of the general formula I or their pharmaceutically acceptable salts

wherein

K ¹ , K ² , K ² ', K ³ , X, Ζ, Υ and ς have the meanings defined below.

The invention further relates to a pharmaceutical composition comprising a compound of formula I, and to its use.

Description of the invention

The present invention relates to new derivatives of 1,2,4-triaminobenzene of the formula I

wherein

K ^{1 is} selected from the group consisting of a hydrogen atom, C _1-6 alk (en / yn) silt, C _3-8 cycloalk (en) silt, C _3-8 cycloalk (en) yl-C _1-6 alk (en (in) silt, acyl, hydroxy-C _1-6 alk (en / in) silt and hydroxy-C _3-8 cycloalk (en) silt;

K ² and K ^{2 are} independently selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, aryl, C _3-8 cycloalk (en) il-C _1-6 alk (en / in) silt, aryl-C _1-6 alk (en / in) silt, acyl, hydroxy-C _1-6 alk (en / in) silt and hydroxy-C3-8 cycloalk (en) silt ;

K ^{3 is} selected from the group consisting of a hydrogen atom, C1-6 alk (en / in) silt, C3-8 cycloalk (en) silt, aryl, C3-8 cycloalk (en) il-C1-6 alk (en / in) silt, aryl C1-6alk (en / in) silt, hydroxy-C1-6 alk (en / in) silt, aryl-C3-8 cycloalk (en) silt, NK ¹⁰ K ¹⁰ C1-6 alk (en / in) silt, NK ¹⁰ K ¹⁰ -C _3-8 cycloalk (en) silt and hydroxy-C _3-8 cycloalk (en) silt; Where

K ¹⁰ and K ^{10 are} independently selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C _3-8 cycloalk (en) yl-C _{1- 6} alk (en / in) silt, hydroxy-C _1-6 alk (en / in) silt, hydroxy-C _3-8 cycloalk (en) silt, hydroxy-C _3-8 cycloalk (en) il-C _{1- 6} alk (en / in) silt, halogen-C _1-6 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, cyano-C _1-6 alk (en / in) silt, cyano-C _3-8 cycloalk (en) silt and cyano-C _3-8 cycloalk (en) il-C _{1- 6} alk (en / in) silt or

K ¹⁰ and K ¹⁰ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 additional heteroatoms;

X represents CO or 8O ₂ ;

Ζ is O or ΝΚ ⁴ , where

K ^{4 is} selected from the group consisting of a hydrogen atom,

C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C _3-8 cycloalk (en) yl-C _1-6 alk (en / in) silt, hydroxy-C _1-6 alk (en / in) silt and hydroxy-C3-8cycloalk (en) silt; or

K ³ and K ⁴ together with the nitrogen atom to which they are bonded form a 4-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 additional heteroatoms, the ring formed by K ³ and K ⁴ and a nitrogen atom, optionally substituted by one or more substituents independently selected from C _1-6 alk (en / in) sludge, aryl and aryl-C _1-6 alk (en / in) sludge;

ς is 0 or 1; and

Υ represents heteroaryl of formulas II and III

- 3 008589 in which

A represents O or 8;

t is 0, 1, 2 or 3;

η is 0, 1, 2, 3 or 4;

p is 0 or 1; and each K ^{5 is} independently selected from the group consisting of C1-6 alk (en / in) silt, C3-8 cycloalk (en) silt, aryl, C3-8 cycloalk (en) il-C1-6 alk (en / in) silt, aryl C1-6alk (en / in) silt, acyl, halogen atom, halogen-C1-6 alk (en / in) silt, C1-6 alk (en / in) yloxy, -ΟΘ-ΝΚ ⁶ Κ ⁶ ', cyano, nitro, -ΝΚ ⁷ Κ ⁷ '; -8-K ⁸ , -8O2K ⁸ and 8O ₂ OK ⁸ ;

Where

K ⁶ and K ^{6 are} independently selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C3-8 cycloalk (en) il-C1-6 alk (en (in) silt and aryl;

K ⁷ and K ^{7 are} independently selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C3-8 cycloalk (en) il-C1-6 alk (en (in) silt, aryl and acyl; and

K ^{8 is} selected from the group consisting of C1-6 alk (en / in) silt, C3-8 cycloalk (en) silt, C3-8 cycloalk (en) silt-C1-6 alk (en / in) silt, aryl and -Ν ^ Ή ⁹ '; Where

K ⁹ and K ^{9 are} independently selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt and C3-8 cycloalk (en) il-C1-6 alk (en (in) sludge;

or their pharmaceutically acceptable salts.

When s. | equal to 0, then K ^{3 is} connected to X, while with. | is 1, then K ^{3 is} connected to Ζ, which is connected to X. Thus, Χ- (Ζ) ₄ -Β. ³ may be X-K ³ , X-O-K ³ or Χ-ΝΒ ³ ^ ' ¹ .

In a specific embodiment, the present invention relates to a compound of formula I, in which

K ¹ , K ² , K ² , X and s. | have the meanings defined above; and

K ^{3 is} selected from the group consisting of a hydrogen atom, C1-6 alk (en / in) silt, C3-8 cycloalk (en) silt, aryl, C _3-8 cycloalk (en) yl-C _1-6 alk (en / in ) sludge, aryl-C _1-6 alk (en / yn) silt, hydroxy-C _1-6 alk (en / yn) silt and hydroxy-C _3-8 cycloalk (en) silt; and

Ζ has the meanings given above, provided that K ^{4 is} selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C _3-8 cycloalk ( en) yl-C _1-6 alk (en / yn) silt, hydroxy-C _1-6 alk (en / yn) silt and hydroxy-C3-8 cycloalk (en) silt; and

Υ has the meanings given above, provided that each K ^{5 is} independently selected from the group consisting of C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, aryl, C _3-8 cycloalk (en) yl-C _1-6 alk (en / yn) silt, aryl- _1-6 alk (en / yn) silt, acyl, halogen atom, halogen-C _1-6 alk (en / yn) silt, -ί .Ό-ΝΒ ⁶ Β ⁶ . cyano, nitro, -Ν ^ Ή ⁷ , -8-К ⁸ , -8О2К ⁸ and 8О2ОК ⁸ ;

or its pharmaceutically acceptable salts.

In one embodiment, K ^{1 is} selected from the group consisting of acyl, hydroxy-C1-6 alk (en / in) silt and hydroxy-C3-8 cycloalk (en) silt.

In another embodiment, the invention relates to those compounds in which K ^{1 is} selected from the group consisting of a hydrogen atom, C _1-6 alk (en / yn) silt, C _3-8 cycloalk (en) silt and C _3-8 cycloalk ( en) yl-C _1-6 alk (en / yn) silt.

In one preferred embodiment, the invention relates to those compounds in which K ^{1 is} selected from the group consisting of a hydrogen atom and C _1-6 alk (en / in) silt.

In a specific embodiment, the invention relates to those compounds in which K ¹ represents a hydrogen atom.

In another specific embodiment, the invention relates to those compounds in which K ¹ represents C _1-6 alk (en / in) yl.

In one embodiment, at least one of K ² and K ^{2 is} selected from the group consisting of aryl, aryl-C _1-6 alk (en / in) silt, acyl, hydroxy-C _1-6 alk (en / in) silt and hydroxy-C _3-8 cycloalk (en) sludge.

In another embodiment, at least one of K ² and K ^{2 ′ is} selected from the group consisting of a hydrogen atom, C _1-6 alk (en / yn) silt, C _3-8 cycloalk (en) silt and C _3-8 cycloalk (en) yl-C _1-6 alk (en / yn) silt.

In yet another embodiment, the invention relates to those compounds in which at least one of the substituents K ² and K ² ′ is a hydrogen atom.

In yet another embodiment, the invention relates to those compounds in which both K ² and K ² ′ are hydrogen atoms.

In one embodiment, K ³ is selected from the group consisting of hydroxy-C 1-6 alkyl (en / yn) yl, aryl-C 3-8 cycloalk (en) yl, IU ¹⁰ TO ¹⁰ '-S1-6alk (en / yn) yl, MV ¹⁰ K C ₃ ¹⁰ - ₈ cycloalk (en) yl and _{hydroxy-C3-8-cycloalk} (en) yl; Where

K ¹⁰ and K ^{10 are} independently selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C _3-8 cycloalk (en) il- _C1-6 alk (en / in) silt, hydroxy- _C1-6 alk (en / in) silt, hydroxy-C _3-8 cycloalk (en) silt, hydroxy-C _3-8 cycloalk (en) il-C _1-6 alk (en / in) silt, halogen-C _1-6 alk (en / in) silt, halogen-C _3-8 cycloalk (en) silt, halogen-C3-8 cycloalk (en) il-C1-6 alk (en / in ) silt, cyano-C1-6alk (en / in) silt, cyano-C3-8cycloalk (en) silt and cyano-C3-8cycloalk (en) il-C1-6alk (en / in) silt; or

K ¹⁰ and K ¹⁰ together in the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 additional heteroatoms.

- 4 008589

In yet another embodiment, the invention relates to those compounds in which c. | equals 1, Ζ represents ΝΚ ⁴ , and K ³ is a hydrogen atom.

In another embodiment, the invention relates to those compounds in which K ³ is other than a hydrogen atom.

In another embodiment, K ^{3 is} selected from the group consisting of C ₁ . ₆ alk (en / in) silt, C _3-8 cycloalk (en) silt, aryl, C ₃ . ₈ cycloalk (en) yl-C ₁ . ₆ alk (en / in) silt and aryl-C ₁ _ ₆ alk (en / in) silt.

In another embodiment, the invention relates to those compounds in which K ^{3 is} selected from the group consisting of C _1-6 alk (en / in) silt and aryl-C _1-6 alk (en / in) silt.

In yet another embodiment, the invention relates to those compounds in which K ³ is C _1-6 alk (en / in) yl.

In yet another embodiment, K ³ is C _3-8 cycloalk (en) yl-C _1-6 alk (en / in) yl.

In yet another embodiment, the invention relates to those compounds in which K ³ is aryl-C _1-6 alk (en / in) yl.

In one embodiment, the invention relates to those compounds in which X is §O ₂ .

In yet another embodiment, the invention relates to those compounds in which X is CO.

In one embodiment with. | equal to 0.

In another embodiment, the invention relates to those compounds in which X is CO and s. | equal to 0.

In yet another embodiment, the invention relates to such compounds in which X represents CO, and C. | is 0, and K ³ is other than aryl.

In another incarnation with. | equal to 1.

In one embodiment, the invention relates to those compounds in which c. | equals 1 and Ζ represents ΝΕ ⁴ .

In one embodiment with. | equal to 1, Ζ represents ΝΒ ⁴ and K ³ and K ⁴ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 additional heteroatoms, the ring formed by K ³ and K ⁴ and a nitrogen atom, optionally substituted with one or more substituents independently selected from C _1-6 alk (en / in) yl, aryl and aryl C1 _-6 alk (en / in) yl.

In another incarnation with. | equal to 1, Ζ represents ΝΒ ^4, and K ^{4 is} selected from the group consisting of a hydrogen atom, _C1-6 alk (en / in) silt, C _3-8 cycloalk (en) silt, C _3-8 cycloalk (en) silt _C1-6 alk (en / yn) silt, hydroxy- _C1-6 alk (en / yn) silt and hydroxy-C3-8 cycloalk (en) silt.

In yet another incarnation with. | equals 1, Ζ represents ΝΒ ⁴ and K ⁴ is a hydrogen atom.

In one embodiment with. | is 1, Ζ represents ΝΒ ^4, and at least one of K ³ and K ⁴ is other than a hydrogen atom.

In another embodiment, the invention relates to those compounds in which c. | equals 1, Ζ is an oxygen atom.

In another embodiment, the invention relates to those compounds in which X is CO, s. | is 1 and Ζ represents an oxygen atom.

In another embodiment, the invention relates to those compounds in which K ² and K ² are hydrogen atoms, X represents CO, s. | equals 1 and Ζ is an oxygen atom.

In another embodiment, the invention relates to those compounds in which it is an oxygen atom.

In another embodiment, the invention relates to those compounds in which it is a sulfur atom.

In yet another embodiment, the invention relates to those compounds in which it is a sulfur atom and X is CO.

In another embodiment, the invention relates to those compounds in which it is a sulfur atom and s. | equal to 0.

In another embodiment, the invention relates to those compounds in which it is a sulfur atom, X is CO and s. | equal to 0.

In yet another embodiment, the invention relates to such compounds in which it is a sulfur atom, pp. | is 1 and Ζ represents an oxygen atom.

In another embodiment, the invention relates to such compounds in which it is a sulfur atom, X represents CO, s. | equals 1 and Ζ is an oxygen atom.

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, m is 3.

In another embodiment, η is 0.

In another embodiment, η is 1.

In one embodiment, η is 2, 3 or 4.

In one embodiment, p is 0.

- 5 008589

In another embodiment, p is 1.

In one embodiment, at least one K ^{5 is} selected from the group consisting of acyl, —CO — YK ⁶ K ⁶ , nitro, —8 — K ^8, and 8O ₂ OK ⁸ .

In another embodiment, each K ^{5 is} independently selected from the group consisting of C1-6 alk (en / yn) silt, C3-8 cycloalk (en) silt, aryl, C3-8 cycloalk (en) yl-C1-6 alk (en / yn) silt , aryl-C1-6 alk (en / in) yl, halogen atom, halogen-C1-6 alk (en / in) yl, C1-6 alk (en / in) yloxy, cyano, -YK ⁷ K ⁷ and -8O2K ⁸ .

In yet another embodiment, each K ^{5 is} independently selected from the group consisting of C1-6 alk (en / in) yl, aryl, halogen atom, C1-6 alk (en / in) yloxy, -YK ⁷ K ⁷ and -8O2K ⁸ .

In yet another embodiment, the invention relates to those compounds in which each K ^{5 is} independently selected from the group consisting of C _1-6 alk (en / yn) silt, a halogen atom and -8O ₂ K ⁸ , where K ⁸ is aryl.

In yet another embodiment, the at least one K ⁵ substituent is C _1-6 alk (en / in) yl.

In yet another embodiment, the at least one K ⁵ substituent is aryl.

In yet another embodiment, the at least one K ⁵ substituent is C _1-6 alk (en / in) yloxy.

In another embodiment, the at least one K ⁵ substituent is -8O ₂ K ⁸ .

In another embodiment, at least one K ⁵ substituent is a halogen atom.

In another embodiment, at least one K ⁵ substituent is a halogen atom that is selected from the group consisting of chlorine, bromine, and iodine atoms.

In another embodiment, at least one K ⁵ substituent is a fluorine atom.

In yet another embodiment, the at least one K ⁵ substituent is a chlorine atom.

In another embodiment, the at least one K ⁵ substituent is a bromine atom.

In yet another embodiment, the at least one K ⁵ substituent is —K ⁷ K ⁷ .

In one embodiment, at least one K ⁵ substituent is —YK ⁷ K ⁷ and at least one of K ⁷ and K ⁷ is aryl or acyl.

In one embodiment, at least one K ⁵ substituent is —YK ⁷ K ⁷ and at least one of K ⁷ and K ^{7 is} selected from the group consisting of a hydrogen atom, C _1-6 alk (en / in) silt, C _{3 -8} cycloalk (en) silt; and C _3-8 cycloalk (en) il-C _1-6 alk (en / in) silt.

In another embodiment, at least one K ⁵ substituent is —YK ⁷ K ⁷ and at least one of K ⁷ and K ^{7 is} selected from the group consisting of a hydrogen atom and C _1-6 alk (en / in) silt.

In yet another embodiment, at least one K ⁵ substituent is —YK ⁷ K ⁷ and at least one of K ⁷ and K ⁷ is C _1-6 alk (en / in) yl.

In yet another embodiment, the at least one K ⁵ substituent is —YK ⁷ K ⁷ and both K ⁷ and K ⁷ are C _1-6 alk (en / in) yl.

In one embodiment, at least one K ⁵ substituent is -8O2K ⁸ and K ⁸ is -K ⁹ K ⁹ , where K ⁹ and K ^{9 are} independently selected from the group consisting of a hydrogen atom, C1-6 alk (en / in) sludge, C _3-8 cycloalk (en) sludge and C ₃ . ₈ cycloalk (en) yl-C _1-6 alk (en / yn) silt.

In one embodiment, at least one K ⁵ substituent is -8O2K ⁸ and K ^{8 is} selected from the group consisting of C1-6 alk (en / in) sludge, C _3-8 cycloalk (en) sludge, C ₃ . ₈ cycloalk (en) yl-C _1-6 alk (en / yn) silt and aryl.

In yet another embodiment, the at least one K ⁵ substituent is -8O ₂ K ⁸ and K ⁸ is aryl.

In another embodiment, the invention relates to those compounds in which Υ has the formula

II.

In another embodiment, the invention relates to those compounds in which Υ has the formula

III.

In yet another embodiment, the invention relates to those compounds in which Υ has the formulas PI or SH.

in which m, n, p and K ⁵ have the meanings defined above.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula Pb.

In yet another embodiment, the invention relates to those compounds in which m is 0 and Υ has the formula PI.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula SH.

In yet another embodiment, the invention relates to those compounds in which n is 0 and Υ has the formula SH.

- 6 008589

In yet another embodiment, the invention relates to those compounds in which p is 0 and Υ has the formula SH.

In yet another embodiment, the invention relates to those compounds in which η is 0, p is 0, and Υ has the formula 111b.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111b and η + p is 1, and in its particular aspect, η is 1 and p is 0, and in its other particular aspect, η is 0 and p equal to 1.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111b and η + p is 2, in its particular aspect, η is 2, and p is 0, and in its other particular aspect, η is 1 and p is one.

In yet another embodiment, the invention relates to those compounds in which Υ has the formulas ^{1 1} , 11 ^{2 2} , 11 ^{3 3} , Ь ^{1 1} , 111 ^{2 2} , Ь или ^3, or 111 ^{4 4} , shown below

in which has the meanings defined above;

g is 0, 1 or 2;

§ is 0, 1, 2 or 3 and

B ⁵ and B ⁵ independently have meanings like B ⁵ , and each B ⁵ independently has the meanings defined above.

In yet another embodiment, the invention relates to those compounds in which m is 0 and Υ has the formula 11b; or η is 0, and Υ has the formula 111b; or p is 0, and Υ has the formula 111b; or η is 0, p is 0, and Υ has the formula 111b; or

Υ has the formula 111b, and η + p is 1, in its particular aspect, η is 1, and p is 0, and in its other specific aspect, η is 0 and p is 1; or

Υ has the formula 111b, and η + p is 2, in its particular aspect, η is 2, and p is 0, and in its other specific aspect, η is 1 and p is 1; or

Υ has the formula ПЬ ¹ , or 11Ь ² , or 11Ь ³ , or ШЬ ¹ , or ШЬ ² , 111Ь ³ , or 111Ь ⁴ .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula PI ¹ , or 11L ² , or 11L ³ , or in which m is 0, and Υ has the formula 11b.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula PI ¹ .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 11b ² .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 11b ³ .

In yet another embodiment, the invention relates to those compounds in which

Υ has the formula ШЬ ¹ , or 111Ь ² , or 111Ь ³ , or 111Ь ⁴ ; or η is 0 and Υ has the formula ШЬ; or p is 0 and Υ has the formula 111b; or η is 0, p is 0, and Υ has the formula SH; or

- 7 008589

Υ has the formula SH, and η + p is 1, in its particular aspect, η is 1, and p is 0, and in its other specific aspect, η is 0 and p is 1; or

Υ has the formula 111b, and η + p is 2, in its particular aspect, η is 2, and p is 0, and in its other specific aspect, η is 1 and p is 1.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula SH ¹ .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111 L ² .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111 L ³ .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111L ⁴ .

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 11c or 111c.

in which m, η, p and K ⁵ have the meanings defined above.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 11c.

In yet another embodiment, the invention relates to those compounds in which t is 0 and Υ has the formula 11c.

In another embodiment, the invention relates to those compounds in which Υ has the formula 111c.

In yet another embodiment, the invention relates to those compounds in which η is 0 and Υ has the formula 111c.

In yet another embodiment, the invention relates to those compounds in which p is 0 and Υ has the formula 111c.

In yet another embodiment, the invention relates to those compounds in which η is 0, p is 0, and Υ has the formula 111c.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111c and η + p is 1, and in its particular aspect, η is 1 and p is 0, and in its other particular aspect, η is 0 and p equal to 1.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 111c and η + p is 2, and in its particular aspect, η is 2 and p is 0, and in its other specific aspect, η is 1 and p equal to 1.

In yet another embodiment, the invention relates to such compounds wherein Υ has formula 11c ^1, 11c ^2, 11c ^3, 111c ^1, 111c ^2, 111c ^{3, 4} or 111c, shown below:

- 8 008589 in which

A has the meanings defined above;

g is 0, 1 or 2;

equal to 0, 1, 2 or 3; and

K ⁵ and K ⁵ independently have meanings, like K ⁵ and each K ⁵ independently has the meanings defined above.

In yet another embodiment, the invention relates to those compounds in which t is 0 and Υ has the formula 11c; or η is 0, and Υ has the formula 111c; or p is 0, and Υ has the formula 111c; or η is 0, p is 0, and Υ has the formula Cc; or

Υ has the formula 111c, and η + p is 1, in its particular aspect, η is 1, and p is 0, and in its other specific aspect, η is 0, and p is 1; or

Υ has the formula 111c, and η + p is 2, in its particular aspect, η is 2, and p is 0 and in its other specific aspect, η is 1, and p is 1; or

Υ has the formula 11s, or 11s, or 11s, or 111s, Shs, or 111s, or 111s.

In yet another embodiment, the invention relates to those compounds in which Υ has the formula 11c ¹ , or 11s ² , or 11s ³ , or t is 0, and Υ has the formula 11c.

In another embodiment, the invention relates to those compounds in which Υ has the formula 11c ¹ .

In another embodiment, the invention relates to those compounds in which Υ has the formula 11c ² .

In another embodiment, the invention relates to those compounds in which Υ has the formula 11c ³ .

In another embodiment, the invention relates to those compounds in which Υ has the formula 111c ¹ , or 111c ² , or 111c ³ , or 111c ⁴ ; or η is 0, and Υ has the formula 111c; or p is 0, and Υ has the formula 111c; or η is 0, p is 0, and Υ has the formula Cc; or

Υ has the formula 111c, and η + p is 1, in its particular aspect, η is 1, and p is 0, and in its other specific aspect, η is 0 and p is 1; or

Υ has the formula 111c, and η + p is 2, in its particular aspect, η is 2, and p is 0, and in its other specific aspect, η is 1 and p is 1.

In another embodiment, the invention relates to those compounds in which Υ has the formula Cc ¹ .

In another embodiment, the invention relates to those compounds in which Υ has the formula 111c ² .

In another embodiment, the invention relates to those compounds in which Υ has the formula 111c ³ .

In another embodiment, the invention relates to those compounds in which Υ has the formula 111c ⁴ .

In yet another embodiment, the invention relates to those compounds in which g is 0.

In another embodiment, the invention relates to those compounds in which g is 1.

In another embodiment, the invention relates to those compounds in which g is 2.

In yet another embodiment, the invention relates to those compounds in which 8 is 0.

In yet another embodiment, the invention relates to those compounds in which 8 is 1, 2 or

3.

In yet another embodiment, the invention relates to those compounds in which Υ of formula II represents

Lib ^{1, 2} or lib, lib or ^3, or ¹ 11c or 11c ^2, 11c or ^3; or a group of formula Pb in which m is 0; or a group of formula 11c in which m is 0.

In yet another embodiment, the invention relates to those compounds in which Υ of formula II represents

PI ¹ , or PI ² , or PI ³ ; or a group of formula Pb in which m is 0; or a group of formula Ps in which m is 0.

In yet another embodiment, the invention relates to those compounds in which Υ of formula III is

IDL ¹ or ² IDL, IDL or ³ or ^4, IDL, or Ric ¹ or ² Ric, Ric or ³ or ⁴ Ric; or a group of formula bb in which η is 0; or a group of formula SH, in which p is 0; or

- 9 008589 a group of formula SH, in which η is 0 and p is 0; or a group of formula Bb in which η + p is 1, in its particular aspect, η is 1, and p is 0, and in its other specific aspect, η is 0 and p is 1;

Υ has the formula SH, and η + ρ is 2, in its particular aspect, η is 2, and p is 0, and in its other specific aspect, η is 1 and p is 1;

a group of formula Cc in which η is 0; or a group of formula Cc in which p is 0; or a group of formula Cc in which η is 0 and p is 0; or a group of formula 111c in which η + p is 1, in its particular aspect, η is 1, and p is 0, and in its other specific aspect, η is 0 and p is 1; or

Υ has the formula 111c, and η + p is 2, in its particular aspect, η is 2, and p is 0, and in its other specific aspect, η is 1 and p is 1.

In yet another embodiment, the invention relates to such compounds in which Υ of formula III is:

SH ² , or SH ³ ; or a group of formula bb in which η is 0 and p is 0; or a group of formula Cc in which η is 0 and p is 0.

In yet another embodiment, the invention relates to those compounds in which m is 0 and Υ has the formula II, in its specific aspects, Υ has the formulas PI or 11c.

In yet another embodiment, m is 1, and Υ has the formula II, in its specific aspects, Υ has the formula Pb, and in its more specific aspects, Υ has the formulas P ¹ , P ² or P ³ .

In another embodiment, m is 1, and B ^{5 is} selected from the group consisting of _C1-6 alk (en / yn) sludge and a halogen atom, and Υ has the formula II, in its particular aspect, Υ has the formula PI, and in its more specific aspects Υ has the formulas PI ¹ , PI ² or PI ³ .

In yet another embodiment, the invention relates to those compounds in which m is 1, and B ⁵ represents _C1-6 alk (en / yn) yl, and Υ has the formula II, in its particular aspect, Υ has the formula PI, and in its more specific aspects Υ has the formulas PI ¹ or PI ³ .

In yet another embodiment, the invention relates to those compounds in which m is 1, and B ⁵ represents a hydrogen atom, such as a bromine, or chlorine, or fluorine atom, and Υ has the formula II, in its particular aspect, Υ has the formula PI, and in its more specific aspects, Υ has the formulas PI ¹ , PI ² or PI ³ .

In yet another embodiment, the invention relates to those compounds in which m is 1, and B ⁵ represents a bromine or chlorine atom, and Υ has the formula II, in its particular aspect, Υ has the formula PI, and in its more specific aspects, Υ has the formula PI ¹ , PI ² or PI ³ .

In yet another embodiment, the invention relates to those compounds in which m is 1, and B ³ represents _C1-6 alk (en / yn) yl, and Υ has the formula II, in its particular aspect, Υ has the formula PI, and in more specific aspects Υ has the formulas PI ¹ , PI ² or PI ³ , and in its most specific aspect, Υ has the formula PI ³ .

In another embodiment, the invention relates to those compounds in which B ¹ is C1-6 alk (en / in) yl, m is 1, B ⁵ is C1-6 alk (en / in) yl or a halogen atom, and Υ has the formula II , in its specific aspect, Υ has the formula PI, and in its more specific aspect, Υ has the formula PI ³ .

In yet another embodiment, the invention relates to those compounds in which η is 0, p is 0, and Υ has the formula III, in its specific aspects, Υ has the formula SH or Sch.

In yet another embodiment, the invention relates to those compounds in which η is 1, and форм has the formula III, in its specific aspects, Ш has the formulas SH or Sch, and in its more specific aspects, Υ has the formulas SH ² , SH ³ or Sch ² .

In yet another embodiment, the invention relates to those compounds in which η + p is 1 and Υ has the formula III, in its particular aspect, Υ has the formula Cc, and in its more specific aspect, Υ has the formula Cc ² .

In yet another embodiment, the invention relates to those compounds in which η + p is 2 and Υ has the formula III, in its particular aspect, Υ has the formula SH, and in its more specific aspects, Υ has the formula SH ² or SH ³ .

In yet another embodiment, Υ does not have the formula II when it represents an oxygen atom.

In yet another embodiment, the compound of formula I contains no more than 3 aryl groups as defined herein.

Compounds from the following list and their pharmaceutically acceptable salts are preferred:

{2-amino-4 - [(5-chlorothiophen-2-ylmethyl) methylamino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-methylthiophen-2-ylmethyl) methylamino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(6-chloro-3-methoxybenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbam ethyl ester

- 10 008589 new acid;

{2-amino-4 - [(benzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(4-bromo-3-methoxythiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-phenylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(3-chlorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

(2-amino-4 - {[4- (4-chlorobenzenesulfonyl) -3-methylthiophen-2-ylmethyl] amino} phenyl) carbamic acid ethyl ester;

{2-amino-4 - [(3-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-fluorobenzofuran-3-ylmethyl) amino] phenyl1} carbamic acid ethyl ester; {2-amino-4 - [(thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(4-bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-ethylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-chlorothiophen-2-ylmethyl) ethylamino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(benzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-dimethylaminobenzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-dimethylamino-3-methylbenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-fluorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(benzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid propyl ester; {2-amino-4 - [(benzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid propyl ester; Y- {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} -2- (4-fluorophenyl) acetamide and N- {2-amino-4 - [(5-chlorothiophen-2 - ylmethyl) amino] phenyl} -3,3-dimethylbutyramide.

In a specific aspect, compounds of the following list and pharmaceutically acceptable acid addition salts thereof are preferred:

{2-amino-4 - [(5-chlorothiophen-2-ylmethyl) methylamino] phenyl} carbamic acid ethyl ester, {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} carbamino ethyl ester acids;

{2-amino-4 - [(5-methylthiophen-2-ylmethyl) methylamino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(6-chloro-3-methoxybenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(benzo) [b] 1 thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(4-bromo-3-methoxythiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-phenylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(3-chlorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

(2-amino-4 - {[4- (4-chlorobenzenesulfonyl) -3-methylthiophen-2-ylmethyl] amino} phenyl) carbamic acid ethyl ester;

{2-amino-4 - [(3-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(5-fluorobenzofuran-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester; (2-amino-4 - [(thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester;

{2-amino-4 - [(4-bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester, {2-amino-4 - [(5-ethylthiophen-2-ylmethyl) amino] phenyl} carbamino ethyl ester acids;

{2-amino-4 - [(thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester and {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) ethylamino] phenyl} carbamic acid ethyl ester.

In one aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, together with one or more pharmaceutically acceptable carriers or diluents.

In one specific aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above, or a pharmaceutically acceptable acid addition salt thereof, in a therapeutically effective amount, together with one or more pharmaceutically acceptable carriers or diluents.

The invention provides a pharmaceutical composition for oral or parenteral administration, wherein said pharmaceutical composition comprises at least one compound of formula I or a salt thereof in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.

In one embodiment, the compounds of the invention can be administered as only one tera

- 11 008589 a songtically effective compound.

In another embodiment, the compounds of the invention can be administered as part of a combination therapy, i.e. the compounds of the invention can be administered in combination with other therapeutically effective compounds having anticonvulsant properties. The effects of such other compounds having anticonvulsant properties may include, but are not limited to, activity on ion channels, such as sodium, potassium or calcium channels;

excitatory amino acid systems, for example, blockade or modulation of ΝΜΌΑ receptors;

inhibitory systems of neurotransmitters, for example, when enhancing the release of GABA or blockade the absorption of GABA and / or stabilizing the membrane.

Currently available anticonvulsants include, but are not limited to tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide, as well as members of the benzodiazepine and barbiturate group.

The compounds of the invention are considered suitable for increasing the ion flux in a voltage-dependent potassium channel.

The compounds of the invention are considered to be suitable for the prophylaxis, treatment and / or suppression of a disorder or condition responsive to an increased ion flux in a potassium channel, such as potassium ion channels of the Κί' семействаρ family.

In one aspect, the compounds of the invention were found to influence potassium channels of the ΚΠΝρ family, in particular the Κί.'ΝΟ2 subunit.

In one aspect, the compounds of the invention are considered useful in the prophylaxis, treatment, and / or suppression of various central nervous system disorders, such as seizures such as convulsions, epilepsy, and status epilepticus; anxiety-related conditions such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, anxiety disorder, post-traumatic stress disorder, acute stress response, regulatory disorder, hypochondria disorder, separation anxiety, agoraphobia and specific phobias.

Therefore, the compounds of the invention are considered to be suitable for the prophylaxis, treatment and / or suppression of various disorders of the central nervous system, such as seizures, such as seizures, epilepsy and status epilepticus;

neuropathic pain such as allodynia, hyperalgic pain, phantom pain, neuropathic pain associated with neuropathy in diabetes, and neuropathic pain associated with migraine;

anxiety-related conditions, such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, anxiety state, post-traumatic stress disorder, acute stress reaction, regulatory disorder, hypochondria disorder, separation anxiety, agoraphobia and specific phobias;

neurodegenerative diseases, such as Alzheimer's disease, Huntington’s chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other encephalopathy infections caused by rubellaviruses, herpes viruses, spirochetes and unknown pathogens, herdroedenocetina disease, Cretein disease ;

states of hyper-excitation of neurons, such as those arising from drug withdrawal or intoxication, neurodegenerative diseases of the peripheral nervous system, such as polyneuropathies and polyneuritis.

Therefore, the compounds of the invention are considered to be suitable for the prophylaxis, treatment and / or suppression of disorders or conditions, such as seizures, neuropathic pain and migraine, anxiety and neurodegenerative diseases.

In one particular aspect, the compounds of the invention are considered suitable for the prophylaxis, treatment and / or suppression of seizures, such as seizures, epilepsy and status epilepticus.

In another specific aspect, the compounds of the invention are considered suitable for the prophylaxis, treatment and / or suppression of neuropathic pains and migraines, such as allodynia, hyperalgic pain, phantom pain, neuropathic pain associated with diabetes neuropathy, and neuropathic pain associated with migraine .

Additionally, the compounds of the invention are considered suitable for the prophylaxis, treatment and / or suppression of anxiety-related conditions, such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, anxiety state, post-traumatic stress disorder, acute stress reaction, regulatory disorder, hypochondria disorder, fear of separation, agoraphobia and anxiety disorder arising from the general condition, and disorder GUT anxiety caused by chemicals, and

- 12 008589 specific phobias.

Additionally, the compounds of the invention are considered suitable for the prophylaxis, treatment and / or suppression of neurodegenerative diseases such as Alzheimer's disease, Huntington’s chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy, and other infections associated with encephalopathy caused by rubellaviruses, herpes viruses spirochetes and unknown pathogens, Creutzfeldt-Jakob disease, Parkinson's disease, trauma-induced neurodegeneration and hyper-excitation states neurons, such as those arising from drug withdrawal or caused by intoxication.

In another aspect, the invention provides compounds showing an effect in one or more of the following tests:

"Relative flow through the channel Κί.'ΝΟ2". which is an indicator of the activity of the compound with respect to the target channel;

“Maximum electric shock”, which is an indicator of seizures induced by nonspecific stimulation of the central nervous system by electricity;

“Pilocarpine-induced seizures”, pilocarpine-induced seizures are often difficult to treat with many available anticonvulsants and are thus a model of “drug-resistant seizures”;

“Tests to establish a threshold for seizures induced by electricity” and “tests to establish a threshold for seizures induced by chemicals” on these models determine the threshold at which seizures occur, so these models determine how much the compounds can slow development convulsive seizures;

“Tonsil kindling,” which is used as an indicator of disease progression, since in healthy animals, seizures in this model become more severe with additional stimulation of the animals.

According to one particular aspect of the invention, the compounds are active with respect to Ι <ί.'ΝΟ2 with an EC ₅₀ value of less than 15000 nM according to the “relative flow through channel ΚΠΝΡ2” test, which is described below.

According to one particular aspect of the invention, the compounds are active against Κί.'ΝΟ2 with an EC ₅₀ value of less than 1500 nM according to the “relative flow through channel ΚΠΝΡ2” test, which is described below.

According to another specific aspect of the invention, the compounds are active against Κί.'ΝΟ2 with an EC ₅₀ value of less than 150 nM according to the “relative flow through channel теста2” test, which is described below.

According to another specific aspect of the invention, the compounds have EC 50 values of less than 15 mg / kg in the Maximum Electroshock test, which is described below.

According to another specific aspect of the invention, the compounds have EC ₅₀ values of less than 5 mg / kg in the Maximum Electroshock test, which is described below.

According to one particular aspect of the invention, the compounds have EC50 values of less than 5 mg / kg in the tests “Establishing a threshold for seizures induced by electricity” and / or “Establishing a threshold for seizures induced by chemicals”, which are described below.

Some compounds have minor or clinically insignificant side effects. Thus, some compounds are tested on models of undesirable sedative, hypothermic and ataxic effects.

Some compounds have such an appropriate half-life or appropriate clearance value that patients are required to take tablets, for example, once or twice a day. Patients easily remember this, and thus it contributes to a better perception of drug treatment.

Some compounds have a high therapeutic index of anticonvulsant action and side effects, for example, impaired motor activity or ataxic action, which is determined by setting a test on a rotating rod. This means that the compounds, as expected, will be well tolerated by patients, which will allow the use of high doses until side effects occur. In this case, the perception of treatment will be good, and the introduction of high doses will make treatment more effective in patients with side effects from other drugs.

Definitions

The term heteroatom refers to nitrogen, oxygen or sulfur atoms.

A halogen atom means fluorine, chlorine, bromine or iodine atoms.

The expression C _1-6 alk (en / in) yl means C _1-6 alkyl, C _1-6 alkenyl or C _2-6 alkynyl.

The term C _1-6 alkyl refers to branched or unbranched alkyl containing 1-6 carbon atoms, including, but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl , 2,2-dimethyl-1-propyl and 2-methyl-1-propyl.

- 13 008589

Similarly, C _2-6 alkenyl, and C2- ₆ alkynyl, respectively, designate such groups which contain 2-6 carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The expression C _3-8 cycloalkyl (en) yl means C _3-8 cycloalkyl or cycloalkenyl.

The term C _3-8 cycloalkyl means a monocyclic or bicyclic carbocycle containing

3-8 C atoms, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.

The term C _3-8 cycloalkenyl means a monocyclic or bicyclic carbocycle containing

3-8 C-atoms and including one double bond.

When two substituents together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 additional heteroatoms, then the monocyclic ring system is formed by 4-8 atoms selected from the nitrogen atom ,

1-7 carbon atoms and 0-3 heteroatoms selected from Ν, 8 or O. Examples of such ring systems are azetidine, beta-lactam, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, oxazolidine, thiazolidine, imidazolidine, tetrazole and pyrazole.

The term aryl refers to aromatic systems, such as pyridine, thiazole, oxazole, phenyl, naphthyl, thiophene and furan, which are optionally substituted with one or more substituents independently representing hydroxy, halogen atom, C _1-6 alk (en / in) yl C _3-8 cycloalk (en) yl, C ₃₈ cycloalk (en) yl-C _1-6 alk (en / in) yl, halogen-C _1-6 alk (en / in) yl, C _1-6 alkoxy , C ₃ - ₈ alkoxy, acyl, nitro or cyano, -CΟ-NΗ-C _1-6 alk (en / in) yl, -CO-H (C _1-6 alk (en / in) yl) ₂ , - NΗ-C _1-6 alk (en / in) yl, -H (C _1-6 alk (en / in) yl) ₂ , 8-C _1-6 alk (en / in) yl, -8O ₂ -C _1-6 alk (en / in) silt, -8О ₂ О-С _1-6 alk (en / in) silt, -ΝΗ ₂ ,

-8O ₂ M (C _1-6 alk (en / in) yl) ₂ or -8O ₂ NH-C _1-6 alk (en / in) yl; or two adjacent substituents, together with the aromatic group to which they are attached, may form a 4-8 membered ring, which optionally contains one or two heteroatoms.

When two adjacent substituents together with the aromatic group to which they are attached form

If a 4- to 8-membered ring, which optionally contains one or two heteroatoms, then the ring system is formed by 4-8-atoms selected from 3-8 carbon atoms and 0-2 heteroatoms selected from Ν, 8 or O. Such two adjacent together, the substituents can form - (CH ₂ ) _p ~ —CH ₂ -, —CH = CH— (CH ₂ ) _t ~ -, —CH ₂ CH = CH— (CH2) p, —CH = CH — CH = CH -, - (CH2) p-O-, -O- (CH2) t-O-, -CH2-O- (CH2) p-O-, -CH2-O-CH2-O-CH2-, - (CH2 ) p-8-, -8- (СН2) t-8-, -CH ₂ -8- (СН ₂ ) p-8-, -CH2-8-СН2-8-СН2-, - (ϋΗ ₂ ) η -ΝΗ-, -ΝΗ- (ϋΗ ₂ ν-ΝΗ-, -CH ₂ ΝΗ- (ϋΗ ₂ ) ρ-ΝΗ-, ^ Η ^ Η-ΝΗ-, -O- (СΗ2) t-NΗ-, - ^ - ^ ΟΙ ^ -ΝΗ or -O- (СН + -ХН-С11-, -8 - (^^ - ΝΗ-, -Ν ^ Η-ΝΗ-, - ^ СШО- or -Ν = ΘΗ-8-, where t is 1, 2 or 3, p p avo 2, 3 or 4, and p is 1 or

2.

In the sense in which it is used herein, the term acyl refers to formyl, C1 _-6 alk (en / yn) carbonyl, C3-8 cycloalkyl (ene) ilkarbonilu, arylcarbonyl, aryl-C1-6 alkyl (en / yn) ilkarbonilu or C3 -8 cycloalk (en) yl- _C1-6 alk (en / yn) ylcarbonyl, where _C1-6 alk (en / yn) yl, C _3-8 cycloalk (en) yl and aryl are as defined above.

The term halo- _C1-6 alk (en / yn) yl means _C1-6 alk (en / yn) yl substituted with one or more halogen atoms, including but not limited to the trifluorometype. Similarly, _{halo-C3-8-cycloalk} (en) yl designates C3-8 cycloalkyl (en) yl substituted with one or more halogen atoms and halo-C3-8 cycloalkyl (en) yl-C1 _-6 alk (en / yn) yl designates C _3-8 cycloalk (en) yl- _C1-6 alk (en / yn) yl substituted with one or more halogen atoms.

In the term C _3-8 cycloalk (en) yl-C _1-6 alk (en / yn) silt, C _3-8 cycloalk (en) yl and C _1-6 alk (en / yn) silt have the meanings defined above .

In addition, terms such as hydroxy-C _1-6 alk (en / in) yl, hydroxy-C _3-8 cycloalk (en) yl, aryl-C _1-6 alk (en / in) yl, C _{1- 6} alk (en / in) yloxy, C _3-8 cycloalk (en) yloxy, C _1-6 alk (en / in) ilcarbonyl, C _3-8 cycloalk (en) ilcarbonyl, aryl carbonyl, aryl-C _1-6 alk (en / in) ylcarbonyl, C _3-8 cycloalk (en) yl-C _1-6 alk (en / yn) ilcarbonyl, aryl-C3-8cycloalk (en) yl, hydroxy-C3-8cycloalk (en) yl-C1 -6alk (en / in) yl, hydroxy-C1-6alk (en / in) ilC _3-8 cycloalk (en) il, cyano-C _1-6 alk (en / in) yl, cyano-C _3-8 cycloalk (en) yl, cyano-C _3-8 cycloalk (en) il-C _1-6 alk (en / in) yl, MK. ¹⁰ MK. ¹⁰ '-S1-6alk (en / yn) yl and MC. ¹⁰ MK. ¹⁰ '-S3-8tsikloalk (en) yl etc. denote groups in which C _1-6 alk (en / yn) yl, C _3-8 cycloalk (en) yl and aryl have the meanings defined above.

The salts of the invention are preferably pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkyl ammonium salts.

The pharmaceutically acceptable salts of the invention are preferably acid addition salts.

Additive acid salts include salts of inorganic acids as well as organic acids.

The acid addition salts of the invention are preferably pharmaceutically acceptable salts of the compounds of the invention formed by non-toxic acids.

Examples of such salts of organic acids are those obtained with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, dairy, apple, cinnamic mines citraconic, aspartic, stearic, palmitic, itaconic,

- 14 008589 glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as 8-halogenophyophyllines, for example 8-bromteophylline.

Examples of such salts of inorganic acids are salts obtained with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Such acid addition salts can be prepared by methods known to those skilled in the art. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in 1. Reagent. δει. 1977, 66, 2, which is incorporated herein by reference.

Hydrates that are capable of forming the present compounds are also intended as pharmaceutically acceptable acid addition salts.

In addition, when the molecule has a double bond, either a fully or partially saturated ring system, geometric isomers can be obtained. It is understood that any geometric isomers, isolated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention. Similarly, molecules containing a bond with limited rotation can form geometric isomers. They are also intended to be included within the scope of the present invention.

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

In addition, the compounds of this invention may be 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 the invention.

Some of the compounds of the present invention contain chiral centers, and such compounds are in the form of isomers (i.e., enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Racemic forms can be resolved into optical antipodes by known methods, for example, by resolving their diastereoisomeric salts with an optically active acid and isolating the optically active amine with a base treatment. 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, by fractional crystallization of B- or 1-tartrates, mandelates or camphorsulfonates. The compounds of the present invention can also be resolved by the preparation of diastereoisomeric derivatives.

You can use additional methods for the separation of optical isomers known to specialists in this field. Such methods include those available at 1. 1ac. | Is5. A. Co11e! apB 8.№11ei ίη "Eiaiyoteg, Cassette! e8, aiB KekoYyoik", Ιοίιη йyeu aiB 8oik, Yeto Wogk (1981).

Optically active compounds can also be obtained from optically active starting materials.

The invention also includes prodrugs of the present compounds which, when administered, undergo chemical conversion as a result of metabolic processes before they are converted to pharmacologically active compounds. Basically, such prodrugs will be functional derivatives of the compounds of general formula I, which can easily be converted to the necessary compound of formula I. The generally accepted methods for the selection and preparation of suitable prodrugs are described, for example, in Oekldi o RgoBgidk, eB. N.ViiBdaagB, Eee ^ zeg 1985.

The invention also includes active metabolites of the present compounds.

When used with respect to compounds of Formula I, the terms epilepsy and epilepsy include any epilepsy, epileptic syndromes, and seizures described in Chapter II of Adadz! Yeryerku: Prigorok1 ог ге ге ке Б с с Б Б 1 1 1 1! Гос гос гос 1 с!!!!!! № № ζ ζ ζ ζ.................. We have the same oi S1a88Shsa1yui and in Tegtto1ode o £ 1ye Iηΐе ^ ηаΐ ^ οηа1 Геадие Адатк! Yeryerku. Yeryershcha 1981, 22: 489-501, and in 1 and 1, 1, 1, 1, 1) Yeryerku: Rgoroka 1 £ ог ге ке Б Б Ц Ц Ц к Н Н Н ои Ц Ц 11 11 к к к к к к к к к ад ад ад ад ад ад ад ад ад ад ад ад ад ад ад ад Е Е ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк р ерк ерк р ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк р ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк р ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ерк ад ерк r

Pharmaceutical Compositions

The compounds of this invention are mainly used in the form of a free base or in the form of its pharmaceutically acceptable salt. Typical examples are mentioned above.

If desired, the pharmaceutical composition of the invention may comprise a compound of formula I in combination with additional pharmacologically active compounds, such as those described below.

The pharmaceutical compositions can be specially formulated for administration by any suitable route, such as oral, rectal, intranasal, inhalation, local (including buccal and sublingual), through the skin, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, an oral route of administration is preferred. Obviously, it’s clear that you prefer

The actual path will depend on the general condition and age of the subject being treated, the nature of the condition being treated, and the selected active ingredient.

The pharmaceutical compositions of this invention or those obtained according to this invention can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, granules, pellets, dragees, pills or lozenges, solutions or suspensions in aqueous or non-aqueous liquids or liquid oil-in-water or water-in-oil emulsions, etc., or parenterally in the form of injectable solutions. Other pharmaceutical compositions for parenteral administration include dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions before use. Also within the scope of the present invention are injectable depot compositions. Other suitable administration forms include suppositories, sprays, ointments, creams, gels, aerosols, dermal patches, implants, etc.

To obtain such compositions, methods well known in the art can be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used.

Typically, the compounds of the invention are administered in a unit dosage form containing the compounds in an amount of about 0.01-100 mg. Typically, the total daily dose is in the range of about 0.05-500 mg, or even 0.05-1500 mg, or 0.05-3000 mg, and most preferably 0.1-50 mg of the active compound of the invention. Typically, for parenteral routes of administration, such as intravenous, intrathecal, intramuscular, and similar administration, the doses are at about half the dose used for oral administration.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients in single or multiple doses. The pharmaceutical compositions of the invention can be formulated using pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients according to the usual methods, for example, disclosed in Ket ^ ηdΐοη: TH Zasnss an Rgasyse o £ Ryagtasu, 19 ηοη, Seiiago, Εά., Mask RNIMind Co., Eaiosh RA, 1995. The compositions can usually be presented in a single dosage form using methods known in the pharmaceutical field.

You can use any other adjuvants or additives commonly used for these purposes, such as colorants, flavors, preservatives, etc., provided that they are compatible with the active ingredients.

The pharmaceutical compositions of the invention can be prepared using methods generally accepted in the art. For example, tablets can be prepared by mixing the active ingredient with conventional adjuvants and / or diluents and then compressing the mixture using a conventional tabletting apparatus. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. You can use any other adjuvants or additives commonly used for these purposes, such as colorants, flavors, preservatives, etc., provided that they are compatible with the active ingredients.

When appropriate, a solid dosage form can be prepared with shells such as intestinal membranes, or they can be formulated to provide controlled release of the active ingredient, for example, continuous or sustained release according to methods well known in the art.

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

For parenteral administration, solutions of the new compounds of the invention in a sterile aqueous solution, an aqueous solution of propylene glycol, an aqueous solution of vitamin E, or sesame or peanut oil can be used. Injectable solutions can be prepared by dissolving the active ingredient and possible additives in part of the injection solvent, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling in suitable ampoules or vials. Any suitable additive commonly used in the art can be added, such as osmotic agents, preservatives, antioxidants, etc. Therefore, such aqueous solutions should be suitably buffered if necessary, and at the beginning the liquid diluent is made isotonic with sufficient amounts of salt and glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used are readily prepared using conventional methods known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or excipients, a sterile aqueous solution, and various organic solvents. Examples of liquid carriers are syrup, peanut butter, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, 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.

- 16 008589

Typical examples of the formulation of the compositions of the invention are as follows:

1) tablets containing 5.0 mg of the compounds of the invention in the form of a free base:

compound of formula I

5.0 mg lactose mg corn starch mg hydr ok sypropilce cellulose

2.4 mg

19.2 mg microcrystalline cellulose structured carmellose sodium salt 2.4 mg (type A) 0.84 mg magnesium stearate

2) tablets containing 0.5 mg of the compound of the invention in the form of a free base:

compound of formula I *

0.5 mg lactose

46.9 mg corn starch

23.5 mg povidone

14.4 mg microcrystalline cellulose structured carmellose sodium 1.8 mg (type A) magnesium stearate

3) Syrup containing per milliliter:

0, 63 mg

glycerol

0.5 mg sorbitol compound of formula I

4) Injection solution containing per milliliter:

a compound of formula I sorbitol

5.1 mg acetic acid

0.05 mg saccharin sodium

0.5 mg water to 1 ml

Preparation of Compounds of the Invention

The compounds of the invention of general formula I, in which K ¹ , K ² , K ² , K ³ , X, Υ, Ζ and ς have the meanings given above, are prepared by the methods shown in the diagram and described below:

- 17 008589

and ί] have the meanings defined above.

Compounds of the general formula VII are prepared by methods known to chemists in the field (ν. Bjepbigde! A1. Skethe keg Ζυίΐιιηΰ 1979, Zopbeggbisk 103, 3-15) and are schematically described below.

Compounds of general formula IV are prepared by reacting 4-nitroaniline with suitable electrophilic reagents, such as, but not limited to, acid chlorides, acid bromides, acid iodides, sulfonyl chlorides, isocyanates, carboxylic acid anhydrides, activated esters and alkyl halides, such as the addition of bases, trialkylamines, potassium carbonate or alcoholates of lithium, sodium or potassium, or without them, in a suitable solvent, for example ethyl acetate, dioxane, tetrahydrofuran, acetonitrile or ethyl ether, at an appropriate temperature, such as room temperature or boiling point, achieved by ordinary heating or microwave irradiation, followed by reduction of the nitro group using a suitable reducing agent, for example sodium dithionite, powdered iron or zinc in an aqueous solution of hydrochloric acid or hydrogen gas in the presence of a suitable catalyst for hydrogenation, such as palladium on activated carbon, in suitable solvents, such as methanol or ethano At a suitable temperature.

Compounds of general formula V are prepared by reacting compounds of general formula IV with a reagent forming a protecting group on an aniline group, for example phthalic acid anhydride, in a suitable solvent, such as glacial acetic acid, at a suitable temperature.

Compounds of general formula VI are prepared from compounds of general formula V by nitration reactions known to those skilled in the art, such as a reaction with fuming nitric acid, in a suitable solvent, such as glacial acetic acid, at a suitable temperature.

Compounds of general formula VII are prepared from compounds of general formula IV by deprotection of aniline functional group with hydrazine hydrate in a suitable solvent, such as 1,2 dioxane, at a suitable temperature.

Alternatively, compounds of general formula VII can be prepared from 2-nitro-1,4-diaminobenzene in 3 steps, as shown in the scheme and described below. In the first stage, less spatially hindered and more reactive aniline nitrogen is protected by the corresponding protective group RO | ΡΐΌΐυυΐίνυ Ogirs ΐη Ogdashs 8up! Ke818, 3 ^ha 1999], such as tert-butyloxycarbonyl (Boc group), by reacting with an appropriate reagent to form a protecting group, for example di-tert-butyldicarbonate, in an appropriate solvent, such as acetonitrile, at an appropriate temperature to give compounds of general formula XI.

Compounds of general formula XII are prepared from compounds of general formula XI by reaction with suitable electrophilic reagents forming [^ - (/.) ^ - 1 ^) 5411 ^, such as alkyl, aryl or heteroaryl chloroformates or carbamoyl chlorides, acid chlorides, acid bromides, iodohydrides acids, sulfonyl chlorides, isocyanates, carboxylic anhydrides, activated carboxylic acids, with activating agents such as carbodiimides or others known to chemists in the art in suitable solvents, for example acetonitrile, tetrahydride rofuran

1,2-dichloroethane or methylene chloride, at an appropriate temperature, such as room temperature or boiling point, achieved by conventional heating or microwave irradiation, with the addition of bases such as magnesium oxide, potassium carbonate, trialkylamines, pyridine or sodium bicarbonate, such as described above for compounds of general formula IV.

The protecting group is removed by methods known to chemists in the art. In particular, Vos

- 18 008589, the group can be cleaved by treatment with an appropriate acid, for example trifluoroacetic acid, in the absence or presence of a solvent, for example methylene chloride or toluene, at an appropriate temperature, to give compounds of general formula VII.

Obtaining compounds of General formula VIII

Compounds of the general formula VII are subjected to reductive alkylation reactions known to those skilled in the art with aldehydes of the general formulas Pa or Sha in which B ⁵ , V. t, η and p have the meanings given above using reducing agents such as sodium borohydride or sodium cyanoborohydride, in a suitable solvent, for example methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with the addition of catalytic amounts of acid, such as acetic acid or without it, at a suitable temperature, to give compound neny general formula VIII, wherein B ¹ is a hydrogen atom.

Alternatively, compounds of general formula VII may be reacted with aldehydes of general formulas Pa or Sha in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, dioxane, xylene, or mixtures thereof, with the addition of catalytic amounts of an acid, such as acetic acid, or an ionic exchange resin or without it, at the appropriate temperature with the formation of imines, which can be distinguished by crystallization or by evaporation of the solvent. Imines can then be reduced using reducing agents, such as sodium borohydride or sodium cyanoborohydride, in a suitable solvent, for example methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, to give compounds of general formula VIII in which B ¹ is a hydrogen atom.

Optionally for modification B ^{1, the} resulting compounds of general formula VIII can be further reductively alkylated using suitable aldehydes and reducing agents, such as sodium borohydride or sodium cyanoborohydride, in a suitable solvent, for example methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with the addition of catalytic amounts of an acid, such as or without acetic acid, at a suitable temperature, as described above. This reaction can also be carried out with ίη 8 Pu after the first reductive alkylation with aldehydes of the general formulas Pa or Sha.

Alternatively, for modification of B ^{1, the} resulting compounds of general formula VIII can be acylated using suitable electrophilic reagents, such as acid chlorides, acid bromides, acid iodides, sulfonyl chlorides and alkyl halides, with the addition of bases such as trialkylamines, potassium carbonate or lithium alkoxides or potassium, in a suitable solvent, for example ethyl acetate, dioxane, tetrahydrofuran or diethyl ether, at an appropriate temperature, as described above.

Compounds of general formula IX are prepared by reduction of compounds of general formula VIII using a suitable reducing agent, for example sodium dithionite, powdered iron or zinc, in an aqueous solution of hydrochloric acid or acetic acid, in the absence or presence of organic solvents such as tetrahydrofuran or ethanol, or hydrogen gas in the presence of a suitable hydrogenation catalyst, such as palladium on activated carbon, in suitable solvents, such as methanol or ethanol, or a mixture of yes / tetrahydrofuran, at a suitable temperature. The compounds obtained are identical to the compounds of the invention of general formula I, in which B ² and B ² are a hydrogen atom, and in which B ¹ , B ³ , X, Υ, Ζ and μ are as defined above.

Compounds of general formula I in which B ^{1 is} not a hydrogen atom and where B ² and optionally ² are not a hydrogen atom are prepared by reacting compounds of general formula IX in which B ^{1 is} not a hydrogen atom using the following methods:

by introducing B ^{2 by} reductive alkylation using suitable aldehydes and reducing agents, such as sodium borohydride or sodium cyanoborohydride, in a suitable solvent, for example methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with the addition of catalytic amounts of an acid such as acetic acid or without it, at a suitable temperature, as described above;

optionally introducing B ^{2 by} additional reductive alkylation using suitable aldehydes and reducing agents, such as sodium borohydride or sodium cyanoborohydride, in a suitable solvent, for example methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with the addition of catalytic amounts of acid such as acetic acid acid or without it, at a suitable temperature, as described above.

Alternatively, B ² or B ² is introduced by acylation with suitable electrophilic reagents such as acid chlorides, acid bromides, iodangidridy acids, sulfonyl chlorides and alkyl haloformate with the addition of bases, such as trialkyl amines, potassium carbonate or alcoholates of lithium, sodium or potassium hydroxide in a suitable solvent, for example ethyl acetate, dioxane, tetrahydrofuran or diethyl ether, at an appropriate temperature, as described above.

In order to obtain compounds of the general formula I in which B ¹ is a hydrogen atom and in which B ² and optionally B ² are not a hydrogen atom, a protective group, such as tert-butyloxycarbonyl, as B ¹ , is introduced before the reduction of the nitro group by methods known to chemists in this

- 19 008589 area. This protecting group is cleaved after the introduction of K ² and optionally K ^{2 by} known methods.

Compounds of the general formulas Pa and Sha are prepared by conventional methods known to chemists in the art, shown schematically below:

reduction of the carboxylic acid ester with an appropriate reducing agent, such as diisobutylaluminum hydride, followed by oxidation of the obtained benzyl alcohol with a suitable oxidizing agent, such as tetrapropylammonium perutenate / U-methylmorpholine-U-oxide, pyridinium chlorochromate, dimethyl sulfoxide / oxalylchloro mixture. Alternatively, the compounds of the general formulas Pa and Sha can be obtained by formylation using dichloromethyl methyl ether and titanium tetrachloride (6go88 s1 a1., Ogd. 8uSh11. Co11, 1973, Uo1. V, 365; Εαηβΐιαοηοΐ s1 a1., I. Proc. , 277). Alternatively, compounds of general formulas Na and Sha can be prepared by methods known to those skilled in the art, such as deprotonation of a heteroaromatic compound with a strong base such as alkyl lithium and subsequent reaction with Ν, Ν-dimethylformamide. Alternatively, compounds of general formulas Pa and Sha can be prepared by methods known to those skilled in the art, such as the halogen metal exchange reaction of halogenated heteroaromatic compounds, such as bromides or iodides, by reaction with a metalizing agent such as alkyl lithium or alkyl magnesium halide or dialkyl magnesium. Alternatively, compounds of the general formulas Pa and Sha can be prepared by methods known to chemists in the art, for example, the reaction of thiophenes and benzothiophenes with phosphoryl chloride in the presence of Ν-methyl-Y-phenylformamide (Κίη§ c1 a1.

I. Ogd. S11st. 1949, 14, 638) or Ν, Ν-dimethylformamide (KhP8te1eg Gogtu1a11on. Papttyo s1 a1. I. Ogd. Stat. 2002, 67, 205).

Examples

Analytical LC / MS data were obtained on PE 8c1ex AI 150EX equipment equipped with a Top8rgau source and 81ιίιηηάζιι С-8А / 8ЬС-10А system. Column: 30x4.6 mm Aa1eg8 8utte1gu C18 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 of 90% A to 100% B for 4 minutes and with a flow rate of 2 ml / min. Purity was determined by integrating UV data (254 nm) and ΕΕ8Ό. Retention time (CT or 1 _K ) was expressed in minutes.

Preparative purification of LC / MS was performed on the same equipment. Column: 50x20 mm UMS ΟΌδ-A with a particle size of 5 microns; method: elution with a linear gradient of 80% A to 100% B for 7 min and with a flow rate of 22.7 ml / min. The fractions were collected during the detection of MS with flow separation.

¹ H NMR spectra were recorded at 500.13 MHz using Vgikeg Luais ΌΠΧ500 equipment or

250.13 MHz on Vgikeg AC 250 equipment. Deuterated chloroform (99.8% ϋ) or dimethyl sulfoxide (99.8% ϋ) were used as solvents. TMS was used as an internal standard. The values of chemical shifts were expressed in ppm. The following abbreviations were used for many NMR signals: 8 = singlet, ά = doublet, 1 = triplet, d = quartet, dsh = quintet, d = heptet, yb = doublet of doublets, άάά = doublet of doublets of doublets, άΐ = doublet of triplets, ys . | = quartet doublet, й = triplet of triplets, t = multiplet and b = wide singlet. In some cases, the values of the cleavage constants are presented I. Melting points (mp.) Were determined on a Visa B-540 device, and they are presented without correction.

Preparation of Intermediates

(4-aminophenyl) carbamic acid ethyl ester.

4-Nitroaniline (100 g, 0.72 mol) was dissolved in ethyl acetate (800 ml) and diisopropylethylamine (89.6 ml, 0.936 mol) was added. Ethyl chloroformate (252 ml, 1.45 mol) dissolved in ethyl acetate (200 ml) was added, and the solution was stirred for 18 hours at room temperature. The mixture was washed with 2M HCl (300 ml) and brine (300 ml), dried (MgO ₄ ) and concentrated in vacuo to half the original volume. Palladium on activated carbon (10 g, 5% Ρά, 50% H ₂ O) was added to the resulting solution, and the mixture was hydrogenated in a Parr apparatus (p (H ₂ ) = 3 bar) at room temperature for 12 hours. The mixture was filtered through celite. and the solvent was evaporated in vacuo to give 118 g (90%) of the title compound as a crystalline product.

LC / MS (t / ζ) 180.9 (MH ⁺ ); retention time = 0.60 min. ¹ H NMR (SES _{1 3} ): 1.27 (t, 3H); 3.42 (br., 2H, ΝΗ ₂ ); 4.19 (q, 2H); 6.52 (broad. 1H ΝΗ); 6.64 (m, 2H); 7.14 (m, 2H).

In a similar manner, the following compound was obtained. (4-Aminophenyl) carbamic acid propyl ester.

Yield: 98%. Ή NMR (COC1 ₃ ): 0.96 (t, 3H); 1.68 (m, 2H); 3.51 (br., 2H); 4.09 (t, 2H); 6.46 (br., 1H); 6.63 (d, 2H); 7.14 (m, 2H).

(4-Phthalimidophenyl) carbamic acid ethyl ester.

(4-Aminophenyl) carbamic acid ethyl ester (118 g, 0.65 mol) was dissolved in glacial acetic acid (2.0 L) under nitrogen and the mixture was heated to 90 ° C. Phthalic anhydride (102.0 g, 0.69 mol) was added in portions over 30 minutes and the reaction mixture was kept at 90 ° C for 2 hours. The mixture was allowed to cool to room temperature and the precipitate was filtered off. The precipitate was washed on the filter with water (2 L), then with diethyl ether (3 L) and then dried in vacuo

- 20 008589 me.

Yield 127 g (62%) of the title compound as a white crystalline solid. LC / MS (t / ζ) 311.3 (MH ⁺ ); retention time = 2.57 min. ¹ H NMR (DMSO-4 ₆ ): 1.26 (t, 3H); 4.15 (q, 2H);

7.34 (dd, 2H); 7.58 (dd, 2H); 7.90 (ddd, 2H); 7.95 (ddd, 2H); 9.80 (s, 1H, OH).

In a similar manner, the following compound was obtained.

(4-Phthalimidophenyl) carbamic acid propyl ester.

Yield: 81%.

(2-Nitro-4-phthalimidophenyl) carbamic acid ethyl ester.

(4-Phthalimidophenyl) carbamic acid ethyl ester (99.0 g, 0.32 mol) was suspended in glacial acetic acid (1.5 L) and heated to 90 ° C. Fuming nitric acid (17.2 ml, 0.41 mol) was added dropwise over 30 minutes at 90-95 ° C. Then the reaction mixture was stirred at 100 ° C for 1 h and cooled to room temperature. The crystalline solids were filtered and washed on the filter with glacial acetic acid (500 ml), water (1 L) and diethyl ether (1 L), then dried in vacuo to give 101 g (90%) of the title compound as a yellow solid .

LC / MS (t / ζ) 355.0 (MH ⁺ ); retention time = 3.34 min. '11 NMR (DMSO- ^ ₆ ): 1.25 (t, 3H); 4.16 (q, 2H); 7.81 (m, 2H); 7.93 (ddd, 2H); 7.99 (ddd, 2H); 6.15 (dd, 1H); 9.99 (s, 1H, ΝΗ).

In a similar manner, the following compound was obtained.

(2-Nitro-4-phthalimidophenyl) carbamic acid propyl ester.

Yield: 70%.

(4-amino-2-nitrophenyl) carbamic acid ethyl ester.

1,2-Dimethoxyethane (1.0 L) was added to (2-nitro-2-phthalimidophenyl) carbamic acid ethyl ester (101 g, 0.28 mol) and the mixture was refluxed. Hydrazine monohydrate (19.6 g, 0.39 mol) was added dropwise over 10 minutes and the mixture was stirred at reflux for 1.5 hours. After cooling to room temperature, the mixture was filtered and the solids were washed on the filter with dimethoxyethane ( 250 ml). The filtrate was concentrated by evaporation and the red crystalline product was recrystallized from toluene (350 ml), the precipitated product was filtered off and dried in vacuo. The mother liquor was concentrated to half the original volume and held for 16 hours. The precipitated material was filtered off and recrystallized as previously described. Recrystallized solids were combined to give a total of 57.6 g (90%) of a dark red compound.

LC / MS (t / ζ) 225.1 (MH ⁺ ); retention time = 2.08 min. '11 NMR (SPS1 ₃ ): 1.33 (t, 3H); 3.77 (s, 2H, ΝΗ ₂ ); 4.23 (q, 2H); 6.98 (dd, 1H); 7.45 (d, 1H); 8.28 (d, 1H); 9.39 (s, 1H, ΝΗ).

In a similar manner, the following compound was obtained.

Yield: 91%. '11 NMR (SPS1 ₃ ): 0.98 (t, 3H); 1.71 (m, 2H); 3.78 (broad, 2H); 4.13 (t, 2H); 6.98 (dd, 1H); 7.44 (d, 1H); 8.27 (d, 1H); 9.39 (s, 1H).

(4-amino-3-nitrophenyl) carbamic acid tert-butyl ester.

To a solution of 2-nitro-1,4-diaminobenzene (10.135 g, 66.18 mmol) in tetrahydrofuran (100 ml) heated under reflux was added Boc ₂ O (di-tert-butyl dicarbonate, 32.6 g, 149 mmol) in portions within 2 hours. The resulting solution was poured into heptane (2 L), sonicated for 15 minutes, filtered and dried in vacuo to give 13.40 g of the title compound as a red solid.

Yield 80%. LC / MS (t / ζ) 295.4 ([M + H + MeC ^ ⁺ ); retention time = 2.54 (UV, E1.51)) 96%, 100%. '11 NMR (DMSO-a ₆ ): 1.47 (s, 9H); 6.96 (d, 1H); 7.24 (s, 2H, ΝΗ ₂ ), 7.41 (dd, 1H); 8.20 (s, 1H); 9.28 (s, 1H, ΝΗ).

[4- (4-Chlorobenzenesulfonyl) -3-methylthiophen-2-yl] methanol.

A solution of 4- (4-chlorobenzenesulfonyl) -3-methylthiophene-2-carboxylic acid methyl ester (992 mg, 3.00 mmol) in anhydrous tetrahydrofuran (20 ml) and anhydrous CH ₂ Cl ₂ (10 ml) was cooled to 0 ° C. in an atmosphere of Ν ₂ and ΌΙΒΆΒ-H (9.0 ml, 9.0 mmol, 1M solution in toluene) was added. After 3 hours, another portion of ΌΙΒΆΒ-H (4.5 ml, 4.5 mmol) was added and stirring was continued for another 2 hours. The reaction was quenched by the addition of a saturated solution of Rochelle salt (30 ml) and the mixture was stirred for 1 h at room temperature. The phases were separated, the aqueous phase was extracted with JULS (2x50 ml), and the combined organic layers were dried over No. ₂ 8O ₄ and evaporated in vacuo. The product was purified by silica gel chromatography on an IckMa ^ eg system using an eluent of a heptane / ethyl acetate mixture (elution with a linear gradient from 1: 0 to 6: 4). The product containing fractions were combined and evaporated in vacuo to give the desired compound (788 mg, 87%). LC / MS (ιη / ζ) = 285.2 (M-H ₂ O + H ⁺ ), calculated for C1 ₂ H1 ₀ C1O ₂ 8 ₂ : 284.9805; retention time = 2.45 min.

Ή NMR (SPS1 ₃ ) 1.84 (t, 1 = 5.7 Hz, 1H), 2.20 (s, 3H), 4.73 (d, 1 = 5.7 Hz, 2H), 7.49 (d, 1 = 8.5 Hz, 2H), 7.84 (d, 4 = 8.5 Hz, 2H), 8.18 (s, 1H).

The following compounds were prepared analogously.

(3-Chlorothiophen-2-yl) methanol.

Yield: 73%. '11 NMR (SPS1 ₃ ): 1.92 (br, 1H), 4.81 (s, 2H), 6.91 (d, 1 = 5.2 Hz, 1H), 7.25 (d, 7 = 5.2 Hz

- 21 008589

1H).

(5-Dimethylaminobenzo [b] thiophen-3-yl) methanol.

Yield: 63%. ¹ H NMR (SBS _{1 3} ): 1.62 (broad, 1H), 3.01 (s, 6H), 4.89 (s, 2H), 6.96 (dd, 1H), 7.11 (d , 1H),

7.34 (s, 1H); 7.68 (d, 1 = 9.0 Hz, 1H).

(5-Dimethylamino-3-methylbenzo [b] thiophen-2-yl) methanol.

Yield: 56%. '11 NMR (SBS1 ₃ ): 1.69 (t, 1 = 5.9 Hz, 1H), 2.35 (s, 3H), 3.00 (s, 6H), 4.88 (d, 2H) 6.90 (d, 1H); 6.93 (dd, 1H); 7.63 (d, 1H).

(4-Bromo-3-methoxythiophen-2-yl) methanol.

A suspension of 4-bromo-3-hydroxythiophene-2-carboxylic acid methyl ester (948 mg, 4.00 mmol), dimethyl sulfate (0.57 ml, 6.0 mmol) and K ₂ CO ₃ (1.11 g, 8, 0 mmol) in acetone (10 ml) was refluxed for 4 hours. After cooling to room temperature, water (25 ml) was added. The mixture was extracted with EuAc (2x25 ml) and the extracts were combined, dried over Na ₂ 8O ₄ and evaporated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20 ml), the solution was cooled to 0 ° C in a nitrogen atmosphere, and BSAE-N (12 ml, 12 mmol, 1M solution in toluene) was added. After 2 hours, another portion of BHWAB-N (6 ml, 6 mmol) was added and stirring was continued for another 2 hours. The reaction was quenched by the addition of a saturated solution of Rochelle salt (30 ml) and the mixture was stirred for 1 hour at room temperature. The phases were separated, the aqueous phase was extracted with EyAc (2x50 ml) and the combined organic layers were dried over Na ₂ 8O ₄ and evaporated in vacuo. The product was purified by silica gel chromatography on a NakyMakZeg system using heptane / ethyl acetate eluent (elution with a linear gradient from 1: 0 to 2: 1). The product containing fractions were combined and evaporated in vacuo to give the desired compound (482 mg, 54%).

Ί1 NMR (SBS _{1 3} ): 1.86 (br., 1H), 3.90 (s, 3H), 4.77 (s, 2H), 7.15 (s, 1H).

The following compound was similarly prepared.

(6-Chloro-3-methoxybenzo [b] thiophen-2-yl) methanol.

Yield: 75%. '11 NMR (SBS1 ₃ ): 1.92 (t, 1 = 5.9 Hz, 1H), 3.99 (s, 3H), 4.90 (d, 1 = 5.7 Hz, 2H), 7 33 (dd, 1 = 1.9, 8.5 Hz, 1H), 7.64 (d, 1 = 8.5 Hz, 1H), 7.73 (d, 1 = 1.9 Hz, 1H) .

Obtaining heteroaryl aldehydes of the general formula Na and Sha

4- (4-Chlorobenzenesulfonyl) -3-methylthiophene-2-carbaldehyde.

To a suspension of [4- (4-chlorobenzenesulfonyl) -3-methylthiophen-2-yl] methanol (786 mg, 2.60 mmol), Ν'-oxide 4-methylmorpholine (0.46 g, 3.9 mmol) and molecular powders 4A sieve (1.3 g, activated by brief heating in vacuo) in CH2C12 (7 ml) tetrapropylammonium perruthenate (46 mg, 0.13 mmol) was added. The resulting mixture was stirred for 1 h, after which it was filtered through a layer of silica gel (about 25 g), eluting with ElAc. The eluate was evaporated in vacuo and the product was purified by silica gel chromatography on a NakyMayeg system using an eluent of a heptane / ethyl acetate mixture (elution with a linear gradient from 1: 0 to 1: 1). The product containing fractions were combined and evaporated in vacuo to give the title compound (644 mg, 82%).

'11 NMR (SBS _{1 3} ): 2.60 (s, 3H), 7.53 (d, 1 = 9.0 Hz, 2H), 7.87 (d, 1 = 8.5 Hz, 2H), 8 53 (s, 1H); 10.01 (s, 1H).

The following aldehydes were similarly prepared.

3- Chlorothiophen-2-carbaldehyde.

Yield: 94%. '11 NMR (SBS1 ₃ ): 7.07 (d, 1 = 5.2 Hz, 1H), 7.72 (d, 1 = 0.5, 4.7 Hz, 1H), 10.07 (d, 1 = 0.9 Hz, 1H).

4- Bromo-3-methoxythiophene-2-carbaldehyde.

Yield: 45%. '11 NMR (SBS _{1 3} ): 4.18 (s, 3H), 7.60 (d, 1 = 1.4 Hz, 1H), 10.08 (d, 1 = 1.4 Hz, 1H). 6-Chloro-3-methoxybenzo [b] thiophene-2-carbaldehyde.

Yield: 86%. '11 NMR (SBS _{1 3} ): 4.34 (s, 3H), 7.36 (dd, 1 = 1.7, 8.7 Hz, 1H), 7.75 (d, 1 = 1.4 Hz, 1H), 7.82 (d, 1 = 8.5 Hz, 1H), 10.36 (s, 1H).

5- Dimethylaminobenzo [b] thiophene-3-carbaldehyde.

Yield: 72%. '11 NMR (SBS _{1 3} ): 3.05 (s, 6H), 7.00 (dd, 1 = 2.4, 9.0 Hz, 1H), 7.68 (d, 1 = 9.0 Hz, 1H), 7.99 (d, 1 = 2.8 Hz, 1H), 8.24 (s, 1H), 10.11 (s, 1H).

5-Dimethylamino-3-methylbenzo [b] thiophene-2-carbaldehyde.

Yield: 73%. '11 NMR (SBS _{1 3} ): 2.74 (s, 3H), 3.03 (s, 6H), 7.00 (d, 1 = 2.4 Hz, 1H), 7.12 (dd, 1 = 2.4, 9.0 Hz, 1H), 7.69 (d, 1 = 9.0 Hz, 1H), 10.30 (s, 1H).

5-fluorobenzofuran-3-carbaldehyde.

At a constant temperature of -60 ° C, dimethyl sulfoxide (3.27 g, 41.8 mmol) in dichloromethane (10 ml) was added to a solution of oxalyl chloride (2.65 g, 20.9 mmol) in dichloromethane (30 ml) and the solution was stirred in for 15 minutes 1- (5-Fluorobenzofuran-3-yl) methanol (3.16 g, 19.0 mmol) dissolved in dichloromethane (60 ml) was added dropwise at -60 ° C. The mixture was stirred for 20 minutes, followed by the addition of triethylamine (9.61 g, 0.095 mmol). After stirring for 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for another 20 minutes. The organic fraction was washed successively with 50 ml portions of water, 1N. aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, then dried (Md ₈ O ₄ ) and concentrated in vacuo to give the crude title compound if

- 22 008589 in a quantitative yield as a beige crystalline solid.

^! H NMR (SIS _1-3 ): 7.13 (dt, 1H); 7.50 (dd, 1H); 7.86 (dd, 1H); 8.30 (s, 1H); 10.15 (s, 1H).

5-fluorothiophen-2-carbaldehyde.

To a solution of thiophene (4.8 ml, 60 mmol) in anhydrous Εΐ ₂ Ο (200 ml) at 0 ° C, LiBu (70 ml, 66 mmol, 0.95 M solution in hexane) was added dropwise and the solution was stirred for 1 h at -5 ° C - 0 ° C. Then the temperature was brought to -70 ° C and a solution of (ΡΕ8ΡΕ ₂ ) ₂ ΝΡ (28.4 g, 90 mmol) in anhydrous tetrahydrofuran (200 ml) was added, keeping the temperature below -50 ° C. Then the resulting mixture was allowed to slowly warm to room temperature overnight, 2n was added. ΝαΟΗ solution (300 ml), the mixture was filtered and the organic layer was washed with 2n. ΝαΝ solution (2x300 ml) and saturated ΝΗ ₄ Ο solution (300 ml), and then dried over Na ₂ 8O ₄ . Distillation using a 40 cm Vigro column removed most of Εΐ ₂ Ο, and the final co-distillation with heptane (50 ml) gave 20.7 mmol

2-fluorothiophene and 4.6 mmol of thiophene (determined by 'H NMR using 200 μl ΌΜΕ as the internal standard) in about 100 ml of tetrahydrofuran and heptane (mp 60-100 ° C). This solution was cooled to 0 ° C. and n-CuB (44 ml, 41 mmol, 0.95 M solution in hexane) was added dropwise. After 1 h, a solution of DMF (4.8 ml, 62 mmol) in Εΐ ₂ Ο (15 ml) was added dropwise and stirring was continued for another 1 h at 0 ° C. The reaction mixture was quenched with a saturated solution of ΝΗ ₄ ί.Ί (200 ml) and extracted with Εΐ ₂ Ο (2x200 ml), and the extract was dried over Ν; · ι ₂ 8Ο. · |. Most of the solvent was removed by evaporation at atmospheric pressure (Vigro column 40 cm long) and then the dark residue was evaporated in vacuo to give a mixture of 5-fluorothiophen-2-carbaldehyde and thiophene-2-carbaldehyde in a ratio of about 10: 1 (b.p. 78 -79 ° C, 25 mm Hg) in the form of a golden oil (1.32 g, 44%). This mixture was used without further purification. ¹ H NMR (SIS _{1 3} ): 6.65 (d, 1 = 4.2, 1H), 7.50 (d, 1 = 3.8 Hz, 1H),

9.76 (d, 1 = 4.2 Hz, 1H).

Obtaining intermediate compounds of General formula VII

Intermediates of general formula VII were prepared by the general method as described below for the preparation of {4 - [(5-fluorobenzofuran-3-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester, or by the general method as described below for the preparation of Y- (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) acetamide.

{4 - [(5-Fluorobenzofuran-3-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester.

In a three-necked round-bottom flask equipped with a Dean-Stark apparatus, 5-fluorobenzofuran-3-carbaldehyde (3.59 g, 21.9 mmol) and ethyl (4-amino-2-nitrophenyl) carbamic acid (4.48 g, 19.9 mmol) in o-xylene (80 ml) and a catalytic amount of an acidic ion-exchange resin (Amber® [KC-84, 100 mg) was added. The mixture was heated to boiling for 5 hours, filtered warm and concentrated in vacuo. This crude product was dissolved in dioxane: methanol (4: 1) (90 ml) and sodium borohydride (1.50 g, 39.8 mmol) was added in portions over 30 minutes. The reaction mixture was stirred at room temperature overnight, then poured into water (200 ml) and extracted with ethyl acetate (3x75 ml). The combined organic fractions were washed with brine, dried (Μ§δΟ ₄ ) and evaporated to give a crude solid, which was purified by silica gel chromatography (eluent: ethyl acetate: heptane 1: 2). This gave 4.50 g (61%) of the title compound as a red crystalline solid. ¹ H NMR (SIS _1-3 ): 1.33 (t, 3H); 4.07 (t, 1H); 4.23 (q, 2H); 4.42 (d, 2H); 6.99 (dd, 1H); 7.05 (dt, 1H); 7.25 (dd, 1H); 7.42 (t, 1H); 7.44 (d, 1H);

7.65 (s, 1H); 8.31 (d, 1H); 9.39 (s, 1H).

The following intermediates were similarly prepared.

{4 - [(5-Methylthiophen-2-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester.

Yield: 73%. LC / MS (t / ζ) 336 (MH ⁺ ); retention time = 3.41 min.

{4 - [(3-Methylthiophen-2-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester. Yield: 89%. LC / MS (t / ζ).

{4 - [(Thiophen-2-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester.

Yield: 71%. LC / MS (t / ζ) 321 (MH ⁺ ); retention time = 3.24 min.

{4 - [(thiophen-3-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester.

Yield: 69%. LC / MS (t / ζ) 320 (MH ⁺ ); retention time = 3.08 min.

{4 - [(Benzo [b] thiophen-3-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester. Yield: 87%. Mp 151-152 ° C. LC / MS (t / ζ) 371.0 (MH ⁺ ); retention time = 3.59 min. Y- (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) acetamide.

To a stirred suspension of {4 - [(2- (4-fluorophenyl) acetylamino] -3-nitrophenyl} carbamic acid tert-butyl ester (2.40 g, 6.16 mmol) in methylene chloride (5 ml) was added trifluoroacetic acid (5 ml) After 15 minutes the methylene chloride was evaporated and the remaining solution was transferred into a saturated aqueous solution of Ν; · ιΗί.Ό ₃ (200 ml) by sonication, the precipitate was filtered off, washed with water and dried in vacuo to obtain 1.70 g of the title compound as a red brown solid Yield: 96.3% LC / MS; retention time = 2.25 (UV, ΕΕ8Ό) 89%, 100 %. ^! H NMR (DMSO-b ₆ ): 3.59 (s, 2H); 5.65 (br., 2H, ΝΗ ₂ ); 6.83 (dd, 1H); 7.08 (d, 1H) ); 7.15 (t, 2H), 7.21 (d, 1H); 7.32 (dd, 2H); 9.91 (s, 1H, ΝΗ).

The following compound was similarly prepared.

- 23 008589

N- (4-amino-2-nitrophenyl) -3.3-dimethylbutyramide.

Yield: 680 mg, 93%. LC / MS (t / ζ) 293.43 (| Μ + Η + Μοί.'Ν | '); retention time = 2.29 (UV, EB8E) 99.5%, 99.1%. '11 NMR (DMSO-a ₆ ): 1.00 (s, 9H); 2.12 (s, 2H); 3.45 (broad, Η ₂ Ο + ΝΗ ₂ ); 6.84 (dd, 1H); 7.06 (d, 1H); 7.14 (d, 1H); 9.64 (s, 1H, ΝΗ).

Preparation of Intermediates of General Formula VIII No. {A - [(5-Chlorothiophen-2-ylmethyl) amino] -2-nitrophenyl} -2- (4-fluorophenyl) acetamide. Solution No. (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) acetamide (306 mg, 1.06 mmol) and 5-chloro-2-thiophenecarboxaldehyde (186 mg, 1.2 equiv.) In anhydrous ethanol (40 ml) was heated at 70 ° C for 30 min. The resulting solution was concentrated to a small volume (about 3 ml) and quenched with heptane (15 ml). The brown crystalline product was separated by filtration to obtain 350 mg of the intermediate imine No. {4 - [(5-chlorothiophen-2-ylmethylene) amino] -2-nitrophenyl} -2- (4-fluorophenyl) acetamide.

Yield: 79.2%. ¹ H NMR (DMSO-a ₆ ): 3.71 (s, 2H); 7.17 (t, 2H); 7.29 (d, 1H); 7.36 (dd, 2H); 7.62 (d, 1H); 7.63 (dd, 1H); 7.71 (d, 1H); 8.83 (s, 1H); 10.44 (s, 1H).

The solid was suspended in methanol (5 ml), NaΒΗzCN (200 mg) was added, followed by acetic acid (2 ml). The resulting solution turned into a suspension. After 15 minutes, it was treated with water (50 ml) and the product was separated by filtration to obtain, after drying in vacuum, 330 mg of a red solid.

Yield: 93.8%. LC / MS (t / ζ) 420 ([M + H] ⁺ ); retention time = 3.34 (UV, E1.811) 97%, 100%. '11 NMR (DMSO-a ₆ ): 3.60 (s, 2H); 4.45 (d, 2H); 6.87 (t, 1H, ΝΗ); 6.93 (dd, 1H); 6.94 (d, 1H); 6.97 (d, 1H); 7.11 (d, 1H); 7.14 (t, 2H); 7.28 (d, 1H); 7.32 (dd, 2H); 9.98 (s, 1H).

The following compound was similarly prepared from the corresponding aniline. No. {4 - [(5-Chlorothiophen-2-ylmethyl) amino] -2-nitrophenyl} -3,3-dimethylbutyramide.

The crude intermediate imine was isolated by evaporation and reduction as described above. Then the reaction mixture was evaporated to a small volume, treated with saturated aqueous Na NCΟ3 and ethyl acetate, and the organic layer was evaporated. The residue was dissolved in hot diisopropyl ether, precipitated with heptane and filtered. Yield: 880 mg, 87.6%. LC / MS (t / ζ) 382.48 ([M + H] ⁺ ); retention time = 3.46 (UV, E1.811) 88%, 91%. '11 NMR (DMSO-a ₆ ): 0.99 (s, 9H); 2.12 (s, 2H); 4.45 (d, 2H); 6.84 (t, 1H, ΝΗ); 6.92 (dd, 1H); 6.94 (d, 1H); 6.97 (d, 1H); 7.07 (d, 1H); 7.19 (d, 1H); 9.69 (s, 1H).

Preparation of Intermediates of General Formula XII [4- [2- (4-fluorophenyl) acetylamino] -3-nitrophenyl} carbamic acid tert-Butyl ester. To a suspension of (4-amino-3-nitrophenyl) carbamic acid tert-butyl ester (1.992 g, 7.87 mmol) and NaΗCΟ3 (5.4 g) in acetonitrile (20 ml) was added (4-fluorophenyl) acetyl chloride (1, 8 ml, 1.3 eq.). The resulting suspension was sonicated for 5 minutes and stirred at room temperature for 16 hours. It was poured into water (200 ml), sonicated for 5 minutes, filtered and washed with water and heptane. The resulting residue was dissolved in hot ethyl acetate (30 ml), a saturated aqueous NaΗCΟz solution (50 ml) was added, and the resulting salt was quenched with heptane (200 ml). The resulting suspension was sonicated for 5 minutes and filtered. The residue was washed with water and heptane and dried in vacuo to give 2.48 g of a brown-yellow solid.

Yield: 80.9%. LC / MS (t / ζ) 412.54 ([M + No.] ⁺ ), 453.58 ([M + MeC ^ No.] ⁺ ); retention time = 3.33 (UV, EB8E) 97%, 100%. Ή NMR (DMSO-a ₆ ): 1.48 (s, 9H); 3.66 (s, 2H) 7.16 (t, 2H); 7.34 (dd, 2H); 7.54 (d, 1H); 7.64 (dd, 1H); 8.16 (d, 1H); 9.79 (s, 1H, ΝΗ); 10.29 (s, 1H, ΝΗ).

Similarly, using the appropriate acid chloride, the following compound was obtained.

[4- [3,3-Dimethylbutyrylamino) -3-nitrophenyl] carbamic acid tert-butyl ester.

The reaction mixture was stirred at 45 ° C. for 30 minutes with an excess of tert-butyl acetyl chloride (3 equiv.). The crude product was isolated after treatment with a mixture of ethyl acetate and a saturated aqueous solution ΝαΗSΟz and purified by flash chromatography on 8ίΟ ₂ (50 g) using a mixture of 10-15% ethyl acetate-heptane as eluent.

Yield: 2.20 mg (78.6%), yellow solid. LC / MS (t / ζ) 415.58 ([M + MeC ^ No.] ⁺ ); retention time = 3.31 (UV, EbO) 99.5%, 99.9%. Ή NMR (DMSO-a ₆ ): 1.01 (s, 9H); 1.49 (s, 9H); 2.17 (s, 2H); 7.43 (d, 2H); 7.63 (dd, 1H); 8.11 (d, 1H); 9.77 (s, 1H, ΝΗ); 10.01 (s, 1H, ΝΗ).

Compounds of the Invention

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

Example 1

1a. {2-amino-4 - [(5-fluorobenzofuran-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

{4 - [(5-Fluorobenzofuran-3-ylmethyl) amino] -2-nitrophenyl} carbamic acid ethyl ester (4.50 g, 12.1 mmol) was dissolved in absolute ethanol (140 ml), to this was added 6N. aqueous HC1 solution (38 ml) and iron powder (5.70 g, 0.10 mol). The red mixture was heated at 60 ° C until it disappeared.

- 24 008589 innovations of intensive coloring (20 min). The solids were filtered off and ethanol was removed from the filtrate by evaporation in vacuo. Aqueous ammonia (saturated solution) was added to the residue, which was then extracted with ethyl acetate (3x100 ml). The combined organic fractions were washed with brine, dried (Md8O ₄₎ and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: ethyl acetate: heptane 1: 1) to obtain 2.70 g (66%) of the title compound as a solid.

Mp 150-151 ° C. Calculated for C ₁₈ H ₁₈ E ^ O ₃ : C 62.96; H 5.28; N, 12.24. Found: C, 63.00; H 5.38; N, 12.13. LC / MS (t / ζ) 344 (MH ⁺ ); retention time = 2.00 min. Ή NMR (DMSO-b ₆ ): 1.19 (t, 3H); 4.03 (q, 2H); 4.26 (d, 2H); 4.55 (s, 2H _; ΝΗ ₂ ); 5.79 (t, 1H); 5.91 (dd, 1H); 6.02 (d, 1H, ΝΗ); 6.72 (d, 1H); 7.13 (dt, 1H); 7.56 (m, 2H); 7.95 (s, 1H); 8.16 (br., 1H, ΝΗ).

The following compounds were prepared analogously and isolated in the form of their acid addition salts, hydrochlorides.

lb. {2-amino-4 - [(5-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester dihydrochloride.

Precipitation of the crude product from ethyl acetate by addition of a solution of hydrochloric acid in diethyl ether gave the title compound.

Mp 190 ° C (with decomposition). Calculated for C1 ₅ H ₁₉ ^ O ₂ 8-2HC1: C 47.00; H 5.67; Ν 10.97. Found: C, 46.84; H 5.86; Ν 11.10. LC / MS (t / ζ) 306 (MH ⁺ ); retention time = 1.77 min. Ή NMR (DMSO-b ₆ ): 1.22 (t, 3H); 2.37 (s, 3H); 4.08 (q, 2H); 4.37 (s, 2H); 6.64 (m, 1H); 6.67 (dd, 1H); 6.72 (d, 1H); 6.86 (d, 1H);

7.13 (d, 1H); 8.93 (br., 1H, ΝΗ).

lc. {2-amino-4 - [(3-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester dihydrochloride.

Precipitation of the crude product from ethyl acetate by addition of a solution of hydrochloric acid in diethyl ether gave the title compound.

LC / MS (t / ζ) 306 (MH ⁺ ); retention time = 1.68 min. ¹ H NMR (SES _{1 3} ) (free base):

I, 25 (t, 3H); 2.23 (s, 3H); 3.78 (br., 3H); 4.13 (q, 2H); 4.32 (s, 2H); 6.05-6.10 (m, 2Η + ΝΗ); 6.82 (d, 1H); 6.93 (d, 1H); 7.11 (d, 1H).

1ά. {2-amino-4 - [(thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester dihydrochloride.

Precipitation of the crude product from ethanol by addition of a solution of hydrochloric acid in diethyl ether gave the title compound.

Mp 195 ° C. Calculated for C ₁₄ H ₁₇ ^ O ₂ 8-2HC1: C 46.16; H 5.26; Ν 11.54. Found: C, 46.34; H 5.43; Ν

II, 28. LC / MS (t / ζ) 292 (MH ⁺ ); retention time = 1.58 min. Ή NMR (DMSO-b ₆ ): 1.22 (t, 3H); 4.08 (q, 2H); 4.48 (s, 2H); 6.71 (dd, 1H); 6.79 (d, 1H); 6.97 (dd, 1H); 7.10 (d, 1H); 7.16 (d, 1H); 7.40 (d, 1H); 8.97 (br. 1H, Ν4).

1st {2-amino-4 - [(thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester dihydrochloride.

Precipitation of the crude product from ethyl acetate by addition of a solution of hydrochloric acid in diethyl ether gave the title compound.

Mp 196-197 ° C. Calculated for C ₁₄ H ₁₇ ^ O ₂ 8-2HC1: C 46.16; H 5.26; Ν 11.54. Found: C, 46.23; H 5.47; Ν 11.30. LC / MS (t / ζ) 292 (MH ⁺ ); retention time = 1.54 min. Ή NMR (DMSO-b ₆ ): 1.21 (t, 3H); 4.08 (q, 2H); 4.29 (s, 2H); 6.66 (dd, 1H); 6.73 (d, 1H); 7.14 (dd, 1H); 7.16 (d, 1H); 7.45 (m, 1H); 7.51 (dd, 1H);

8.86 (br., 1H, OH).

1 £. Ethyl dihydrochloride of {2-amino-4 - [(benzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid.

Precipitation of the crude product from ethyl acetate by addition of a solution of hydrochloric acid in diethyl ether gave the title compound.

Mp 213-214 ° C. Calculated for C1 ₈ H ₂₁ No., C1 ₂ O ₂ 8: C 51.68; H 4.95; Ν 10.05. Found: C, 51.88; H 5.35; Ν 9.95. LC / MS (t / ζ) 342.2 (M + H ⁺ ); retention time = 2.08 min. Ή NMR (DMSO-b ₆ ): 1.22 (t, 3H); 4.08 (q, 2H); 4.53 (s, 2H); 6.81 (dd, 1H); 6.93 (d, 1H); 7.19 (d, 1H); 7.41 (m, 2H); 7.70 (s, 1H); 7.98 (m, 2H); 8.97 (br. 1H, Ν4).

Example 2

2a. (2-amino-4 - {[4- (4-chlorobenzenesulfonyl) -3-methylthiophen-2-ylmethyl] amino} phenyl) carbamic acid ethyl ester.

Suspension of 4- (4-chlorobenzenesulfonyl) -3-methylthiophene-2-carbaldehyde (301 mg, 1.00 mmol) and ethyl ester (4-amino-2-nitrophenyl) carbamic acid (293 mg, 1.30 mmol) in absolute ethanol (10 ml) was refluxed for 20 h in an atmosphere of Ν2. After cooling, the resulting orange-red imine was filtered off and dried in vacuo to give a crude product (312 mg, 61%), which was suspended in a 10: 1 methanol: acetic acid (10 ml) mixture. NaΒΗ ₃ CN (0.19 g, 3.0 mmol) was added and the mixture was stirred for 1 h at room temperature. Then, a further portion of NaΒΗ ₃ CN (0.19 g, 3.0 mmol) was added and after another 1 hour was added to

- 25 008589 saturated aqueous sodium bicarbonate solution (20 ml). The resulting amine, a red solid, was separated by filtration and dried in vacuo to give a crude product (293 mg, 94%), which was suspended in absolute ethanol (10 ml). To this was added 6N. HC1 (1.1 ml, 6.6 mmol) and powdered iron (193 mg, 3.46 mmol) and a red mixture were heated to 60 ° C until the red color turned yellow, for about 10-20 minutes. The mixture was poured into a saturated aqueous solution of sodium bicarbonate (50 ml) and EUAc (50 ml), the resulting mixture was filtered, the phases were separated and then the aqueous phase was extracted with EUAc (2x50 ml). The combined organic phases were dried (Na ₂ 8 O ₄ ) and the solvent was evaporated in vacuo. The product was isolated by silica gel chromatography on a Na ^ HMaChsg system using heptane / ethyl acetate as an eluent (elution with a linear gradient, usually from 8: 2 to 1: 1). The product containing fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow solid (213 mg, 78%).

LC / MS (t / h) = 480.1 (M + H ⁺ ); calculated for C21H23C1Y3O482: 480.0813; retention time = 2.35 min; purity by UV = 72.4%, purity by E8 = 86.5%. ¹ H NMR (DMSO-b6): 1.19 (br., 3H), 2.16 (s, 3H), 4.02 (q, 1 = 6.9 Hz, 2H), 4.23 (d, 1 = 6.1 Hz, 2H), 4.57 (s, 2H), 5.81 (dd, 1 = 2.4, 8.5 Hz, 1H), 5.91-5.95 (m, 2H) ),

6.72 (broad d, 1 = 6.6 Hz, 1H), 7.72 (d, 1 = 8.5 Hz, 2H), 7.90 (d, 1 = 8.5 Hz, 2H), 8, 15 (br., 1H); 8.31 (s, 1H).

The following compounds were prepared analogously.

2b. {2-amino-4 - [(3-chlorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

Yield: 76%. LC / MS (t //) = 326.0 (M + H ⁺ ), calculated for 0 |. · | Η | -01Ν3028: 326.0725; retention time = 1.95 min., UV purity = 85.8%; purity by E8 = 98.1%. ¹ H NMR (DMSO-b6): 1.19 (br., 3H), 4.03 (q, 1 = 7.1 Hz, 2H), 4.30 (d, 1 = 6.1 Hz, 2H) 4.57 (s, 2H), 5.83 (dd, 1 = 2.4, 8.5 Hz, 1H), 5.93-5.97 (m, 2H),

6.73 (broad d, 1 = 7.1 Hz, 1H), 6.99 (d, 1 = 5.2 Hz, 1H), 7.48 (d, 1 = 5.2 Hz, 1H), 8, 16 (br., 1H).

2s {2-amino-4 - [(4-bromo-3-methoxythiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

Yield: 66%. LC / MS (t / ζ) 402.0 (M + H ⁺ ) calculated for C .1 Ι ΙιΝ _; 0 _; 8: 400.0325 (100%), 402.0310 (97.3%); retention time = 1.97 min; UV purity = 87.9%; purity by E8 = 98.2%. ¹ H NMR (DMSObe): 1.20 (br., 3H), 3.83 (s, 3H), 4.03 (q, 1 = 6.9 Hz, 2H), 4.32 (d, 1 = 6.1 Hz, 2H), 4.58 (s, 2H), 5.84-5.89 (m, 2H), 5.97 (d, 1 = 2.4 Hz, 1H), 6.74 ( broad. 1H), 7.46 (s, 1H), 8.17 (br., 1H).

26. Ethyl ester of {2-amino-4 - [(6-chloro-3-methoxybenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid.

Yield: 60%. LC / MS (t //) = 405.3 (M + H ⁺ ), calculated for C19H21SSh3O38: 406.0987; retention time = 2.39 min; UV purity = 95.0%; purity by E8 = 99.6%. ¹ H NMR (DMSO-b6): 1.19 (br., 3H),

3.95 (s, 3H), 4.02 (q, 1 = 7.1 Hz, 2H), 4.43 (d, 1 = 6.1 Hz, 2H), 4.56 (s, 2H), 5.90 (dd, 1 = 2.4, 8.5 Hz, 1H), 5.96 (t, 1 = 5.9 Hz, 1H), 6.00 (d, 1 = 2.8 Hz, 1H ), 6.73 (brd, 1 = 6.6 Hz, 1H), 7.39 (dd, 1 = 1.9, 8.5 Hz, 1H), 7.68 (d, 1 = 8, 5 Hz, 1H), 7.98 (d, 1 = 1.9 Hz, 1H), 8.15 (br., 1H).

2e. {2-amino-4 - [(5-dimethylaminobenzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

Yield: 13%. LC / MS (t //) = 385.0 (M + H ⁺ ), calculated for C20H25X4O28: 385.1693; retention time = 1.29 min; UV purity = 87.8%; purity by E8 = 93.5%. ¹ H NMR (DMSO-b6): 1.19 (br., 3H), 2.94 (s, 6H), 4.02 (q, 1 = 6.9 Hz, 2H), 4.34 (d, 1 = 5.7 Hz, 2H), 4.53 (s, 2H), 5.81 (t, 1 = 5.9 Hz, 1H), 5.93 (dd, 1 = 2.4, 8.5 Hz, 1H), 6.03 (d, 1 = 2.4 Hz, 1H), 6.72 (br, 1H), 6.95 (dd, 1 = 2.4, 9.0 Hz, 1H) , 7.08 (d, 1 = 2.4 Hz, 1H), 7.38 (s, 1H), 7.71 (d, 1 = 8.5 Hz, 1H), 8.15 (br. 1H )

2 £. {2-amino-4 - [(5-dimethylamino-3-methylbenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

Yield: 36%. LC / MS (t //) = 399.2 (M + H ⁺ ), calculated for C21H27Y4O28: 399.1849; retention time = 1.31 min; UV purity = 98.4%; purity by E8 = 99.4%. ¹ H NMR (DMSO-b6): 1.19 (br., 3H), 2.33 (s, 3H), 2.93 (s, 6H), 4.02 (q, 1 = 6.9 Hz, 2H), 4.37 (d, 1 = 5.7 Hz, 2H), 4.54 (s, 2H), 5.86 (dd, 1 = 2.4, 8.5 Hz, 1H), 5, 89 (t, 1 = 6.6 Hz, 1H), 5.96 (d, 1 = 2.4 Hz, 1H), 6.71 (br. 1H), 6.84-6.89 (m, 2H), 7.58 (d, 1 = 8.5 Hz, 1H), 8.16 (br., 1H).

Example 3

3a. {2-amino-4 - [(5-methylthiophen-2-ylmethyl) (methyl) amino] phenyl} carbamic acid ethyl ester.

A mixture of 5-methyl-2-thiophenecarboxaldehyde (108 μl, 1.00 mmol), ethyl ester (4-amino-2 nitrophenyl) carbamic acid (225 mg, 1.00 mmol) and Amberbetone C. C-84 (10 mg) o-xylene (4 ml) was refluxed in an Ar atmosphere for 5 hours. Volatiles were removed by evaporation in vacuo and the residue was dissolved in acetonitrile (5 ml). ΝαΒΜΧ Ν (0.25 g, 4.0 mmol) was added to the resulting solution, followed by HOAc (5 drops). After stirring for 5 minutes, the solution turned dark red. Formaldehyde (37% solution in water, 0.89 ml, 12 mmol) was added and stirring was continued for 30 minutes with periodic addition of HOAc. The reaction mixture was evaporated to dryness in vacuo, and the residue was partitioned between saturated aqueous sodium bicarbonate (50 ml) and EyAc (50 ml). The aqueous phase was extracted with EyAc (50 ml), and the combined organic layers were dried (Na ₂ 8O ₄ ) and the solvents were evaporated in vacuo. Then the residue was dissolved in ethanol (10

- 26 008589 ml). 6N was added. an aqueous HC1 solution (2.0 ml, 12 mmol) and iron powder (0.34 g, 6.0 mmol) and a red mixture were heated at 60 ° C until the red color turned yellow, for about 15 minutes. The mixture was poured into a saturated aqueous solution of sodium bicarbonate (50 ml) and EUAc (50 ml), the resulting mixture was filtered, the phases were separated, and then the aqueous phase was extracted with EUAc (2x50 ml). The combined organic layers were dried (No. ₂ 8O ₄ ) and the solvents were evaporated in vacuo. The product was purified by silica gel chromatography on an Ia8JMa81eg system using heptane / ethyl acetate as an eluent (elution with a linear gradient, usually from 8: 2 to 1: 1). The product containing fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow solid (145 mg, 45% overall). LC / MS (t //) = 319.9 (M + H ⁺ ), calculated for 0ι6Η22Ν3Ο28: 320.1427; retention time = 1.80 min; UV purity = 98.4%; purity by E8 = 97.2%. ¹ H NMR (SES 13): 1.29 (t, 1 = 7.1, 3H), 2.41 (s, 3H), 2.91 (s, 3H), 3.76 (br., 2H), 4.19 (q, 1 = 7.1 Hz, 2H), 4.52 (s, 2H), 6.02 (br. 1H), 6.17 (d, 1 = 2.8 Hz, 1H) 6.25 (dd, 1 = 2.8, 8.5 Hz, 1H), 6.53-6.58 (m, 1H),

6.66 (d, 1 = 3.3 Hz, 1H); 6.98 (d, 1 = 8.5 Hz, 1H).

The following compound was similarly prepared.

3b. {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) (methyl) amino] phenyl} carbamic acid ethyl ester.

Yield: 34%. LC / MS (t / x) = 340.0 (M + H ⁺ ), calculated for Οΐ5Ηι901Ν3Ο28: 340.0881; retention time = 2.14 min; UV purity = 82.3%; purity by E8 = 90.2%. ¹ H NMR (SES 13): 1.29 (t, 1 = 6.8, 3H), 2.91 (s, 3H), 3.78 (br., 2H), 4.20 (q, 1 = 7 , 2 Hz, 2H), 4.49 (s, 2H), 6.05 (br, 1H), 6.16 (d, 1 = 2.4 Hz, 1H), 6.24 (dd, 1 = 2.4, 8.5 Hz, 1H), 6.73 (d, 1 = 3.8 Hz, 1H), 6.99 (d, 1 = 8.5 Hz, 1H).

The following compound was similarly prepared, except acetaldehyde was used instead of formaldehyde:

3s {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) (ethyl) amino] phenyl} carbamic acid ethyl ester.

Yield: 12%. LC / MS (111 //) = 353.9 (M + H ⁺ ), calculated for C16H21SSH3O28: 354.1038; retention time = 2.02 min., UV purity = 97.5%; purity by E8 = 99.0%. ¹ H NMR (SES 13): 1.16 (t, 6 = 7.1, 3H), 1.29 (t, 1 = 6.8, 3H), 3.36 (q, 1 = 7.1 Hz, 2H), 3.76 (br, 2H), 4.19 (q, 1 = 7.2 Hz, 2H), 4.47 (s, 2H), 6.05 (br, 1H),

6.13 (d, 1 = 2.4 Hz, 1H), 6.19 (dd, 1 = 2.4, 9.0 Hz, 1H), 6.73 (d, 1 = 3.8 Hz, 1H ), 6.96 (d, 1 = 8.0 Hz, 1H).

The following compound was similarly prepared, except formaldehyde was not added.

36. Ethyl ester of {2-amino-4 - [(5-fluorothiophen-2-ylmethyl) amino] phenyl} carbamic acid.

Yield: 65% (25% after preparative LC / MS purification to remove non-fluorinated by-products). LC / MS (t //) = 310.2 (M + H ⁺ ), calculated for C14H17E ^ O28: 310.1020; retention time = 1.76 min; UV purity = 96.6%; purity by E8 = 83.4%. ¹ H NMR (SES 13): 1.29 (br., 3H), 3.82 (br., 2H), 4.19 (q, 1 = 7.2 Hz, 2H), 4.31 (d, 1 = 2.0 Hz, 2H), 6.05 (br, 1H), 6.09 (d, 1 = 8.0 Hz, 1H), 6.29 (dd, 1 = 1.5, 3.8 Hz, 1H), 6.58 (t, 1 = 3.5 Hz, 1H), 6.94 (d, 1 = 8.0 Hz, 1H).

Example 4

4a. {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

A solution of 5-chlorothiophene-2-carbaldehyde (240 μl, 111 μmol, 463 mmol in 1,2-dichloroethane) was added to a solution of 4-amino-2-nitrophenylcarbamic acid ethyl ester (240 μl, 111 μmol, 463 mmol in 1.2 dichloroethane). Sodium triacetoxyborohydride (118 mg, 555 μmol) was added and the resulting mixture was stirred for 3.5 hours at 40 ° C. The mixture was allowed to cool to room temperature and water (100 μl) was added. The mixture was filtered through silica gel (500 mg) and the column was washed with 1,2-dichloroethane (3 ml). The combined organic phases were evaporated to dryness in vacuo. The resulting solid was dissolved in ethanol (3 ml). Iron (19 mg) was added to one third of the resulting solution (1 ml), followed by the addition of an aqueous hydrochloric acid solution (96 μl, 6M solution). The resulting mixture was placed in an ultrasonic bath for 10 minutes. Then, saturated aqueous sodium bicarbonate solution (2 ml) was added. The mixture was extracted with ethyl acetate (3 ml). The organic phase was washed with water (3 ml) and brine (3 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The resulting product was dissolved in 190 μl of dimethyl sulfoxide and purified by preparative LC-MS. The resulting solution was evaporated to dryness in vacuo. Yield (6.8 mg, 56%). LC / MS (t / ζ) ([M + H] ⁺ ) 326.1; retention time, 90 (UV, E8E) 92%, 99%.

The following compounds were prepared in a similar manner.

4b. {2-amino-4 - [(5- (Bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

LC / MS (t / ζ) (M + H ⁺ ) 371.9; retention time = 1.94 (UV, EZE) 89%, 98%.

4s {2-amino-4 - [(4- (bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

LC / MS (t / ζ) (M + H ⁺ ) 372.0; retention time = 1.96 (UV, EZE) 76%, 100%.

46. Ethyl ester of {2-amino-4 - [(5-ethylthiophen-2-ylmethyl) amino] phenyl} carbamic acid.

LC / MS (t / ζ) (M + H ⁺ ) 320.1; retention time = 1.90 (UV, EZE) 72%, 96%.

4th. {2-amino-4 - [(benzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

LC / MS (t / ζ) (M + H ⁺ ) 342.1; retention time = 2.06 (UV, EZE) 75%, 100%.

4 £. {2-amino-4 - [(5-phenylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester.

- 27 008589

LC / MS (t / ζ) (M + H ⁺ ) 368.2; retention time = 2.21 (UV, EE81)) 90%, 99%.

Example 5

5a. Propyl ester of {2-amino-4 - [(benzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid.

Benzo [b] thiophene-2-carbaldehyde (1.36 g, 8.38 mmol) was added to a solution of propyl ester (4 amino-2-nitrophenyl) carbamic acid (2.00 g, 8.36 mmol) in acetonitrile (10 ml ) The mixture was heated to 160 ° C. for 2 minutes in a hermetically sealed microwave processing reactor. After cooling, No. 1BH ₃ SI (1.06 g, 16.7 mmol) and AcOH (48 μl, 0.84 mmol) were added and the mixture was stirred for 30 min at 25 ° C. Water / brine (1: 1, 100 ml) was added and the mixture was extracted with ethyl acetate (3x100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude intermediate was purified by flash chromatography on silica gel (eluent: ethyl acetate: heptane 1: 9) and evaporated to dryness. Then the intermediate was dissolved in tetrahydrofuran (20 ml) and IA ₂ 8 ₂ O ₄ (3.67 g, 21 mmol) dissolved in water (50 ml) was added. The resulting mixture was stirred at 40 ° C. for 5 hours under argon. The resulting mixture was extracted with ethyl acetate (3x100 ml), the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (eluent: 1: 1 ethyl acetate: heptane mixture) afforded 0.3 g (10%) of the title compound as a solid. LC / MS (t / ζ) 356 ([M + H] ⁺ ); retention time = 2.45 min. ¹ H NMR (SBS _{1 3} ): 0.95 (t, 3H); 1.67 (m, 2H); 4.08 (t, 2H); 4.55 (s, 2H); 6.08 (d, 1H); 6.13 (dd, 1H); 6.93 (d, 1H); 7.20 (s, 1H); 7.27 (dt, 1H); 7.32 (dt, 1H); 7.68 (d, 1H); 7.77 (d, 1H).

The following compound was similarly prepared:

5b. Propyl ester of {2-amino-4 - [(benzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid.

Yield: 16%. LC / MS (t / ζ) 356 ([M + H] ⁺ ); retention time = 2.24 min. ¹ H NMR (SECE): 0.96 (t, 3H); 1.68 (m, 2H); 4.10 (t, 2H); 4.51 (s, 2H); 6.12 (d, 1H); 6.14 (dd, 1H); 6.95 (d, 1H); 7.36 (s, 1H); 7.39 (dt, 1H); 7.40 (dt, 1H); 7.79 (dd, 1H); 7.87 (dd, 1H).

Example 6

6a. I- {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} -2- (4-fluorophenyl) acetamide.

To a stirred solution of I- {4 - [(5-chlorothiophen-2-ylmethyl) amino] -2-nitrophenyl} -2- (4-fluorophenyl) acetamide (320 mg, 0.762 mmol) in tetrahydrofuran (25 ml) and acetic acid (8 ml) of red color, powdered zinc was periodically added (particle size <10 μm, 10 g) in portions over 30 minutes. After 5 minutes, the solution became colorless. The resulting colorless suspension was filtered through a 81O ₂ layer (10 g) using ethyl acetate as an eluent, and the resulting solution was evaporated in vacuo. The resulting solid was dissolved in ethyl acetate / acetone / trifluoroacetic acid (3 ml / 3 ml / 20 ml), treated with saturated aqueous INSO ₃ (50 ml) and heptane (30 ml), and the product was separated by filtration to obtain 280 mg pale gray solid. Yield: 94.2%. LC / MS (t / ζ) 390.4 ([M + H] ⁺ ); retention time = 2.26 (UV, EB80) 99%, 100%. ¹ H NMR (DMSO-b ₆ ): 3.56 (s, 2H); 4.28 (d, 2H); 4.57 (s, 2H, IN ₂ ); 5.87 (dd, 1H); 5.98 (m, 2H, IN and arom. H);

6.74 (d, 1H); 6.86 (d, 1H); 6.93 (d, 1H); 7.13 (t, 2H); 7.35 (dd, 2H); 9.10 (8, 1H).

The following compound was similarly prepared from the corresponding nitro compound.

6b. I- {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} -3,3-dimethylbutyramide.

After filtration through 81O ₂ and evaporation, the product was precipitated from a biphasic solution in a mixture of ethyl acetate / saturated aqueous Inso ₃ (5 ml / 20 ml) with heptane (50 ml). Yield: 580 mg, 71.5%. LC / MS (t / ζ) 352.48 ([M + H] ⁺ ); retention time = 2.16 (UV, EB80) 96%, 99%. Ή NMR (DMSO-bb): 1.01 (s, 9H), 2.11 (s, 2H); 4.29 (d, 2H); 4.54 (s, 2H, IN ₂ ); 5.88 (dd, 1H); 5.97 (t, 1H, IN); 5.99 (d, 1H); 6.72 (d, 1H);

6.87 (d, 1H); 6.93 (d, 1H); 8.82 (s, 1H).

Testing ΐη νϊίΐΌ and ΐη νίνο

The compounds of the invention were tested and their effects were shown in one or more of the models presented below.

Relative flow through channel ΚΟΝΟ2

Cells stably expressing the voltage-controlled channels of CSIC2 were seeded the day before the experiment and labeled [ ⁸⁶ K ⁺ ]. On the day of the experiment, the cells were washed with HB88-containing buffer. Cells were pre-incubated with the drug and the incorporation of [ ⁸⁶ KL ⁺ ] was stimulated with a submaximal concentration of KCl equal to 15 mM, with the continued presence of the drug. After an appropriate incubation period, the supernatant was removed and the radioactivity of the CCPM was determined on a scintillation counter (Tpsb). Cells were lysed with 2 mM IAOH and the amount of ⁸⁶ K. was determined. The relative flux was calculated ^((CP ^ 4supernatant ^{/ CP} ^ 4cuPernatant ^{+ CP} ^ 4 Cells ⁾ Strb ^{/ (CP} ^ 4suPernatant ^{/ CP} ^ 4supernatant ^{+ CP} ^ 4Cells ⁾ 15tM KC1 ⁾ * ^100-100 .

The EC ₅₀ value of the compounds of the invention is less than 20,000 nM, in most cases less than 2,000 nM and in many cases less than 200 nM. Therefore, the compounds of the invention are considered useful in the treatment of diseases associated with potassium channels of the CSIC family.

- 28 008589

Maximum electric shock

The test was performed on groups of male mice using corneal electrodes and exposure to rectangular electric impulses of 26 mA for 0.4 s to induce seizures, which are manifested in tonic extrusions of the hind limbs (Ш1а / е! А1. Ерерзе Кееэгсй 1998, 30, 219229) .

Pilocarpine-induced seizures

Pilocarpine-induced seizures were induced by intraperitoneal administration of pilocarpine at a dose of 250 mg / kg to groups of male mice, and seizures were observed that showed a loss of ability to take a position for 30 minutes (81 ug e! A1. , 45, 321-325).

Threshold Test for Electric-Induced Seizures

We used the up-and-down method in the modification (K1bLa11 e! A1. KaFa! Kezeages 1957, 1-12) to determine the average threshold for the induction of tonic traction of the hind limbs in response to corneal electroshock in male mice. The first mouse from each group received an electroshock of 14 mA (0.4 sec, 50 Hz), and then a seizure was observed. If convulsions were observed, then for the next mouse the current was reduced by 1 mA, if convulsions were not observed, the current was increased by 1 mA. This procedure was repeated for all 15 mice in the experimental group.

Threshold Test for Chemical-Induced Seizures

The threshold dose of pentylenetetrazole required for the induction of clonic seizures during infusion of pentylenetetrazole at a certain rate (5 mg / ml at a rate of 0.5 ml / min) into the lateral tail vein of male mice was determined (ΝιιΙΙ е! А1. I. Ryagtasu Βηά Ryagtasodu 1986, 38, 697-698).

Kindling caused by electrical stimulation of the tonsils

Rats underwent surgery to implant tripolar electrodes into the dorsolateral tonsil. After the operation, the animals were allowed to recover before administration to the rats of the test compound in various doses or carrier compounds. Animals were stimulated with an initial threshold of +25 μA discharge daily for 3-5 weeks, and in each case, the severity of seizures, the duration of seizures and the duration of the discharge after the action were recorded (Kaste. .

Side effects

Side effects from the central nervous system were evaluated when determining the time spent by mice on a rotating rod (Sarasyu e! A1. Ogiv aηά Sjet1ca1 Tokh1odu 1992, 15, 177201) or when determining their motor activity by the number of crossed infrared beams in the experimental cell (Ша18оп е! A1. No. igoryagtasoogu 1997, 36, 1369-1375). The hypothermic effect of the compound on the internal body temperature in animals was determined by a rectal probe or an implanted radio telemetry sensor capable of measuring temperature (Keepeu e! A1. Ryuyudu aηά Vejuyuig 2001, 74, 177-184).

Pharmacokinetics

The pharmacokinetic parameters of the compound were determined by iv or oral administration to rats of 8rgia Oa \ x1eu and blood sampling for 20 hours. The concentration of the compounds in blood plasma was determined by LC / MS / MS.

Claims (19)

CLAIM 1. A derivative of 1,2,4-diaminobenzene of the formula I in which K ^{1 is} selected from the group consisting of hydrogen and C _1-6 alk (en / yn) sludge; K ² and K ² ′ are independently selected from the group consisting of hydrogen; K ^{3 is} selected from the group consisting of C _1-6 alk (en / yn) sludge and aryl-C _1-6 alk (en / yn) sludge; X represents CO; Ζ is O; ς is 0 or 1; and Υ is heteroaryl of formulas II and III - 29 008589 in which V is O or 8; t is 0, 1 or 2; η is 0, 1, 2, 3, or 4; p is 0 or 1; and each B ^{5 is} independently selected from the group consisting of C1-6alk (en / in) silt, aryl, halogen, C16alk (en / in) iloxy, -BV ⁷ B ⁷ and -8O2B ⁸ ; Where B ⁷ and B ^{7 are} independently selected from the group consisting of C _1-6 alk (en / yn) sludge; and In ^8, selected from the group consisting of aryl; or its pharmaceutically acceptable salts. 2. The compound according to claim 1, in which ς is 0. 3. The compound according to claim 1, in which ς is 1 and Ζ represents oxygen. 4. The compound according to one of claims 1 to ³ , in which B ³ is C _1-6 alk (en / yn) yl. 5. The compound according to one of claims 1 to ³ , in which B ³ is aryl-C _1-6 alk (en / yn) yl. 6. The compound according to one of claims 1 to 5, in which V is oxygen. 7. The compound according to one of claims 1 to 5, in which V is sulfur. 8. The compound according to one of claims 1 to 7, in which Υ has the formula II. 9. The compound according to one of claims 1 to 7, in which Υ has the formula III. 10. The compound according to one of claims 1 to 9, in which Υ has the formulas Pb or Sb (Pn PI in which V, t, η, p and B ⁵ have the meanings defined above. 11. A compound according to one of claims 1 to 9, in which Υ has the formulas Ps or Bc in which V, t, η, p and B ⁵ have the meanings defined above. 12. The compound according to one of claims 1 to 11, wherein said compound is selected from the group consisting of {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) methylamino] phenyl} -carbamic acid ethyl ester; {2-Amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} -carbamic acid ethyl ester; {2-amino-4 - [(5-methylthiophen-2-ylmethyl) methylamino] phenyl} -carbamic acid ethyl ester; {2-amino-4 - [(5-bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-Amino-4 - [(6-chloro-3-methoxybenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(benzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-Amino-4 - [(5-methylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-Amino-4 - [(4-bromo-3-methoxythiophen-2-ylmethyl) amino] phenyl} -carbamic acid ethyl ester; {2-Amino-4 - [(5-phenylthiophen-2-ylmethyl) amino] phenyl} -carbamic acid ethyl ester; {2-Amino-4 - [(3-chlorothiophen-2-ylmethyl) amino] phenyl} -carbamic acid ethyl ester; (2-Amino-4 - {[4- (4-chlorobenzenesulfonyl) -3-methylthiophen-2-ylmethyl] amino} phenyl) carbamic acid ethyl ester; {2-Amino-4 - [(3-methylthiophen-2-ylmethyl) amino] phenyl} -carbamic acid ethyl ester; {2-amino-4 - [(5-fluorobenzofuran-3-ylmethyl) amino] phenyl1} carbamic acid ethyl ester; {2-Amino-4 - [(thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(4-bromothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; - 30 008589 {2-amino-4 - [(5-ethylthiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-Amino-4 - [(thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-Amino-4 - [(5-chlorothiophen-2-ylmethyl) ethylamino] phenyl} -carbamic acid ethyl ester; {2-amino-4 - [(benzo [b] thiophen-3-ylmethyl) amino] phenyl} -carbamic acid ethyl ester; {2-amino-4 - [(5-dimethylaminobenzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(5-dimethylamino-3-methylbenzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-Amino-4 - [(5-fluorothiophen-2-ylmethyl) amino] phenyl} carbamic acid ethyl ester; {2-amino-4 - [(benzo [b] thiophen-2-ylmethyl) amino] phenyl} carbamic acid propyl ester; {2-amino-4 - [(benzo [b] thiophen-3-ylmethyl) amino] phenyl} carbamic acid propyl ester; N - {2-amino-4 - [(5-chlorothiophen-2-ylmethyl) amino] phenyl} -2- (4-fluorophenyl) acetamide and N- {2-amino-4 - [(5-chlorothiophen-2- ylmethyl) amino] phenyl} -3,3-dimethylbutyramide; and their pharmaceutically acceptable salts. 13. A pharmaceutical composition for the prevention, treatment and / or suppression of a central nervous system disorder, comprising a compound according to one of claims 1 to 12 in a therapeutically effective amount together with one or more pharmaceutically acceptable carrier or diluent. 14. The use of compounds according to one of claims 1 to 13 for the manufacture of a pharmaceutical preparation for the prevention, treatment and / or suppression of disorders of the central nervous system. 15. The use according to claim 14, wherein the central nervous system disorder is selected from the group consisting of convulsive seizures, such as convulsions, epilepsy and continuous epileptic seizure. 16. The application of claim 14, wherein the central nervous system disorder is selected from the group consisting of neuropathic pain and migraine, such as allodynia, hyperalgic pain, phantom pain, neuropathic pain associated with neuropathy in diabetes, and neuropathic pain, associated with migraine. 17. The application of claim 14, wherein the central nervous system disorder is selected from the group consisting of anxiety-related conditions, such as anxiety, generalized anxiety disorder, panic anxiety, obsessive-compulsive disorder, social phobia, anxiety, post-traumatic stress disorder, acute stress response, regulatory disorder, hypochondriacal disorders, fear of separation, agoraphobia, specific phobias, anxiety disorder arising due to the general state I, or anxiety disorders caused by chemical substances. 18. The application of claim 14, wherein the central nervous system disorder is selected from the group consisting of neurodegenerative diseases such as Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy, and others associated with infections of encephalopathy caused by rubella viruses, herpes viruses, spirochetes and unknown pathogens, Creutzfeldt-Jakob disease, Parkinson's disease, caused by trauma of neurodegeneration. 19. The use according to claim 14, wherein the central nervous system disorder is selected from the group consisting of hyper-excitation states of neurons, such as those arising from drug withdrawal or caused by intoxication.