HK1088317B

HK1088317B - 1,2,4-triaminobenzene derivatives useful for treating disorders of the central nervous system

Info

Publication number: HK1088317B
Application number: HK06108672.2A
Authority: HK
Inventors: Rottländer Mario; Ritzén Andreas; Bang Nørgaard Morten; Khanzhin Nikolay; Wenzel Tornøe Christian
Original assignee: H. Lundbeck A/S
Priority date: 2002-12-27
Filing date: 2003-12-18
Publication date: 2009-09-25

Description

1, 2, 4-triaminobenzene derivatives for the treatment of central nervous system diseases

Technical Field

The present invention relates to novel 1, 2, 4-triaminobenzene derivatives as openers of the KCNQ family of potassium channels. These compounds are useful for the prevention, treatment and/or inhibition of central nervous system disorders.

Background

Ion channels are cellular proteins that regulate the flow of ions, including potassium, calcium, chloride, and sodium, into and out of cells. This pathway is present in all animal and human cells and affects a variety of processes, including nerve conduction, muscle contraction, and cellular secretion.

There are over 70 structurally and functionally diverse potassium channel subtypes in humans (Jentsch nature reviews Neuroscience 2000, 1, 21-30). The main roles of neuronal potassium channels found in the brain are to maintain negative resting membrane potentials and to control membrane repolarization by action potentials.

One subtype of potassium channel genes is the KCNQ family. Four fifths of mutations in the KCNQ gene have been found to cause diseases including arrhythmia, deafness and epilepsy (Jntsch nature reviews Neuroscience 2000, 1, 21-30).

The KCNQ4 gene is believed to encode a molecule associated with potassium channels in the outer hair cells of the cochlea and type I hair cells of the vestibule, the mutation of which leads to hereditary deafness.

KCNQ1(KvLQT1) forms cardiac delayed rectifier K + currents together with the product of the KCNE1 (minimum K (+) -channel protein) gene in the heart. Mutations in this channel cause an inherited long QT syndrome type I (LQT1) and are associated with deafness (robbins pharmacol Ther 2001, 90, 1-19).

Genes KCNQ2 and KCNQ3 were discovered in 1988 and were thought to be variant in an inherited epilepsy known as benign familial neonatal convulsion (Rogawski Trends in neurosciens 2000, 23, 393 398). The proteins encoded by the KCNQ2 and KCNQ3 genes are concentrated in the cortex of the human brain region and pyramidal neurons of the hippocampus, and are associated with seizures and spread (Cooper et al, Proceedings National Academy of Science U S A2000, 97, 4914-.

When expressed in vitro, KCNQ2 and KCNQ3 are two potassium channel subtypes that form "M-currents". M-current is an inactive potassium current present in a variety of neuronal cell types. Membrane excitability is mainly controlled by persistent current as the only sustained current in the range of action potential initiation in various cell types (Marrion Annual Review Physiology1997, 59, 483-504). Modulation of the M-current has a large effect on the excitability of the neuron, e.g. activation of the current will reduce the excitability of the neuron. Thus, in conditions such as epilepsy and diseases characterized by excessive neuronal activity (e.g., epilepsy and neuropathic pain), these KCNQ channel openers will reduce excessive neuronal activity.

EP 554543 discloses retigabine (D-23129; N- (2-amino-4- (4-fluorobenzylamino) -phenyl) carbamic acid ethyl ester) and analogues thereof. An anticonvulsant compound which is broad-spectrum and has potent anticonvulsant properties, both in vivo and in vitro. After oral and intraperitoneal administration to rats and mice, they were effective in a series of anticonvulsant tests and genetic animal models (DBA/2 mice, Rostock et al, Epilepsy Research 1996, 23, 211-223), including: electrically induced epilepsy; pentaerythrin, tetrandrine, and N-methyl-D-aspartate (NMDA) chemically induced epilepsy. In addition, retigabine is effective in the amygdalae seizure (amygdala-kindling) model of complex incomplete epilepsy, which also suggests that this compound may be useful in anticonvulsant therapy. In clinical trials, retigabine has recently been shown to be effective in reducing the chance of seizures in epileptic patients (Bialer et al, Epilepsy Research2002, 51, 31-71).

Retigabine has been shown to activate K (+) currents in neuronal cells, and the pharmacology of this induced current suggests agreement with the pharmacology of the published M-channel, which was recently found to be associated with KCNQ2/3K (+) channel heteromultimers (hetermulltime). This suggests that activation of the KCNQ2/3 channel may lead to some anticonvulsant activity of the agent (Wickenden et al, Molecular Pharmacology 2000, 58, 591-one 600), and that other agents acting by the same mechanism may have the same utility.

KCNQ2 and 3 have been reported to be useful in modulating (upper) neuropathic pain models (Wickenden et al, Society for Neuroscience extracts 2002, 454.7), and potassium channel modulators are hypothesized to be active against both neuralgia and epilepsy (Schroder et al, Neuropharmacology2001, 40, 888-. In addition, localization of KCNQ channel mRNA in brain and other central nervous system regions associated with pain was reported (Goldstein et al, Society for Neuroscience extracts 2003, 53.8).

In addition to its role in neuropathic pain, the expression of mRNA for KCNQ2-5 in the trigeminal and dorsal root ganglia and in the caudal trigeminal nucleus suggests that openers of these channels may also influence the sensory process of migraine (Goldstein et al, Society for neurosciennerce extracts 2003, 53.8).

Recent reports demonstrated that mRNA of KCNQ3 and 5 and KCNQ2 was expressed in spider cells and glial cells. The KCNQ2, 3 and 5 channels therefore modulate synaptic activity in the central nervous system and contribute to neutral protection of KCNQ channel openers (Noda et al, Society for Neuroscience Abstracts 2003, 53.9). Retigabine and other KCNQ modulators may therefore protect against neurodegeneration in epilepsy as retigabine has been shown to prevent limbic neurodegeneration and marker expression of post-epileptic apoptosis induced by pamoic acid in rats (Ebert et al, Epilepsia 2002, 43 supplement 5, 86-95). This prevents the seizure of patients, i.e. anti-epileptic. In another model Of epilepsy studies, retigabine has been shown to delay the onset Of hippocampal epilepsy in rats (Tober et al, European Journal Of Pharmacology 1996, 303, 163-169).

By administration of anticonvulsant compounds (e.g. benzodiazepines) for clinical treatment of withdrawal from ethanol syndromeAnd chloromethylthiazole (chloromethyl thiazole)) as well as other anticonvulsant compounds (e.g., gabapentin) that are very effective in animal models of this syndrome (Watson et al, Neuropharmacology 1997, 36, 1369-.

mRNA of KCNQ2 and the subtype 3 is found in brain regions associated with anxiety and emotional behavior (e.g. bipolar diseases such as hippocampus and amygdala) (saganic et al, journal of neuroosistic 2001, 21, 4609-one 4624), retigabine has been reported to be active in certain animal models of anxiety-type behavior (Hartz et al, journal of Psychopharmacology2003, 17 supplementation 3, a28, B16), and other anticonvulsant compounds used clinically for the treatment of bipolar diseases.

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

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

WO02/049628 describes the use of retigabine for the prevention, treatment, inhibition and alleviation of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety disorder, obsessive compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute stress response, regulatory disorders, hypochondriasis, separation anxiety disorder, agoraphobia and specific phobias.

WO97/15300 describes the use of retigabine for the treatment of neurodegenerative diseases such as alzheimer's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other encephalopathies caused by infections with rubella viruses, herpes viruses, borrelia and other unknown pathogens, creutzfeldt-jakob disease, parkinson's disease, neurodegeneration caused by trauma and neuronal hyperexcitability states during drug withdrawal and due to intoxication, degenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis (polyneuritides).

Therefore, there is a great need for novel compounds that are effective openers of KCNQ family potassium channels.

There is also a need for novel compounds with improved properties compared to known compounds (e.g. retigabine) which are openers of the KCNQ family of potassium channels. There is a need to improve one or more of the following parameters: half-life, clearance, selectivity, interaction with other drugs, bioavailability, potency, tailorability, chemical stability, metabolic stability, membrane permeability, solubility, and therapeutic index. Improvements in these parameters lead to the following improvements:

● improve the dosage regimen by reducing the number of doses required per day,

● facilitate administration of drugs to patients by a variety of medications,

● the side effects are reduced, and,

● the therapeutic index is increased by increasing the ratio of the total body weight,

● increased tolerance, and/or

● improve compliance.

Summary of The Invention

It is therefore an object of the present invention to provide a novel compound which is an effective opener of potassium channels of the KCNQ family.

The compounds of the present invention are 1, 2, 4-triaminobenzene derivatives of the general formula I:

wherein R is¹、R²、R²’、R³X, Z, Y and q are defined below.

The invention also relates to pharmaceutical compositions comprising compounds of formula I and uses thereof.

Description of the invention

The present invention relates to novel 1, 2, 4-triaminobenzene derivatives of formula I:

wherein:

R¹selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, acyl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group;

R²and R²' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl-C_1-6-alk (en/yn) yl, acyl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group;

R³selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6Alk (en/yn)) Radical, aryl radical-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl, aryl-C_3-8Cycloalkyl (en) yl, NR¹⁰R¹⁰’-C_1-6Alk (en/yn) yl, NR¹⁰R¹⁰’-C_3-8Cycloalkyl (en) yl and hydroxy-C_3-8-a cycloalk (en) yl group; wherein:

R¹⁰and R¹⁰' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3- ₈-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl, hydroxy-C_3-8Cycloalkyl (en) yl, hydroxy-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, halo-C_1-6-alk (en/yn) yl, halo-C_3-8Cycloalkyl (en) yl, halo-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, cyano-C_1-6-alk (en/yn) yl, cyano-C_3-8Cycloalkyl (en) yl and cyano-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, or

R¹⁰And R¹⁰' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring optionally containing 1, 2 or 3 other heteroatoms;

x is CO or SO₂；

Z is O or NR⁴Wherein:

R⁴selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group; or

R³And R⁴Together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring optionally containing 1, 2 or 3 further heteroatoms, said ring being substituted by R³And R⁴And the nitrogen atom is optionally substituted by one or more groups independently selected from C_1-6Alk (en/yn) yl, aryl and aryl radicalsradical-C_1-6-substituent substitution of an alk (en/yn) yl group;

q is 0 or 1;

and is

Y represents a heteroaryl group of formula II or III:

wherein:

w is O or S;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

p is 0 or 1; and is

R⁵Each independently selected from C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl-C_1-6-alk (en/yn) yl, acyl, halogen, halo-C_1-6-alk (en/yn) yl, C_1-6-alk (en/yn) yloxy, -CO-NR⁶R⁶', cyano, nitro, -NR⁷R⁷’、-S-R⁸、-SO₂R⁸And SO₂OR⁸；

Wherein:

R⁶and R⁶' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl and aryl;

R⁷and R⁷' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl and acyl; and is

R⁸Is selected from C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl and-NR⁹R⁹'; wherein:

R⁹and R⁹' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl and C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl.

When q is 0, R³Is linked to X and R is when q is 1³Attached to Z which is attached to X. Thus X- (Z)_q-R³Can represent X-R³、X-O-R³Or X-NR³R⁴。

In a particular embodiment, the present invention relates to a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, wherein:

R¹、R²、R²', X and q are as defined above; and is

R³Selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group; and is

Z is as defined above, provided that R⁴Selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group; and is

Y is as defined above, provided that R⁵Each independently selected from C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl-C_1-6-alk (en/yn) yl, acyl, halogen, halo-C_1-6-alk (en/yn) yl, -CO-NR⁶R⁶', cyano, nitro, -NR⁷R⁷’、-S-R⁸、-SO₂R⁸And SO₂OR⁸。

In one embodiment, R¹Selected from acyl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group.

In another embodiment, the invention relates to compounds wherein R is¹Selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl and C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl compounds.

In a preferred embodiment, the invention relates to compounds wherein R¹Selected from hydrogen and C_1-6-alk (en/yn) yl compounds.

In a particular embodiment, the invention relates to compounds wherein R is¹A compound which is a hydrogen atom.

In another specific embodiment, the present invention relates to compounds wherein R is¹Is C_1-6-alk (en/yn) yl compounds.

In one embodiment, R²And R²' at least one of them is selected from aryl, aryl-C_1-6-alk (en/yn) yl, acyl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group.

In another embodiment, R²And R²' at least one is selected from hydrogen and C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl and C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl.

In yet another embodiment, the present invention relates to wherein the substituent R²And R²' at least one of which is a hydrogen atom.

In yet another embodiment, the invention relates to compounds wherein R is²And R²' are allA compound of a hydrogen atom.

In one embodiment, R³Selected from hydroxy-C_1-6-alk (en/yn) yl, aryl-C_3-8Cycloalkyl (en) yl, NR¹⁰R¹⁰’-C_1-6Alk (en/yn) yl, NR¹⁰R¹⁰’-C_3-8Cycloalkyl (en) yl and hydroxy-C_3-8-a cycloalk (en) yl group; wherein

R¹⁰And R¹⁰' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3- ₈-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl, hydroxy-C_3-8Cycloalkyl (en) yl, hydroxy-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, halo-C_1-6-alk (en/yn) yl, halo-C_3-8Cycloalkyl (en) yl, halo-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, cyano-C_1-6-alk (en/yn) yl, cyano-C_3-8Cycloalkyl (en) yl and cyano-C_3-8-cycloalkyl (en) yl-C_1-6-an alk (en/yn) yl group; or

R¹⁰And R¹⁰' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring optionally containing 1, 2 or 3 additional heteroatoms.

In yet another embodiment, the invention relates to wherein q is 1 and Z is NR⁴And R is³A compound which is a hydrogen atom.

In yet another embodiment, the invention relates to compounds wherein R is³A compound other than a hydrogen atom.

In yet another embodiment, R³Is selected from C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl and aryl-C_1-6-alk (en/yn) yl.

In yet another embodiment, the invention relates to compounds wherein R is³Is selected from C_1-6-alk (en/yn) yl and aryl-C_1-6-alk (en/yn) yl compounds.

In yet another embodiment, the invention relates to compounds wherein R is³Is C_1-6-alk (en/yn) yl compounds.

In yet another embodiment, R³Is C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl.

In yet another embodiment, the invention relates to compounds wherein R is³Is aryl-C_1-6-alk (en/yn) yl compounds.

In one embodiment, the present invention relates to wherein X is SO₂The compound of (1).

In yet another embodiment, the present invention relates to compounds wherein X is CO.

In one embodiment, q is 0.

In yet another embodiment, the invention relates to compounds wherein X is CO and q is 0.

In yet another embodiment, the invention relates to wherein X is CO, q is 0 and R³A compound other than aryl.

In another embodiment, q is 1.

In one embodiment, the invention relates to compounds wherein q is 1 and Z is NR⁴The compound of (1).

In one embodiment, q is 1 and Z is NR⁴And R is³And R⁴Together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring optionally containing 1, 2 or 3 further heteroatoms, said ring being substituted by R³And R⁴And the nitrogen atom is optionally substituted by one or more groups independently selected from C_1-6-alk (en/yn) yl, aryl and aryl-C_1-6-substituent substitution of an alk (en/yn) yl group;

in another embodimentIn one embodiment, q is 1 and Z is NR⁴And R is⁴Selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl and hydroxy-C_3-8-a cycloalk (en) yl group.

In yet another embodiment, q is 1 and Z is NR⁴And R is⁴Is a hydrogen atom.

In one embodiment, q is 1 and Z is NR⁴And R is³And R⁴At least one of which is different from a hydrogen atom.

In yet another embodiment, the invention relates to compounds wherein q is 1 and Z is an oxygen atom.

In yet another embodiment, the invention relates to compounds wherein X is CO, q is 1 and Z is an oxygen atom.

In yet another embodiment, the invention relates to compounds wherein R is²And R²' is a hydrogen atom, X is CO, q is 1 and Z is an oxygen atom.

In yet another embodiment, the present invention relates to compounds wherein W is an oxygen atom.

In yet another embodiment, the present invention relates to compounds wherein W is a sulfur atom.

In yet another embodiment, the invention relates to compounds wherein W is a sulfur atom and X is CO.

In yet another embodiment, the invention relates to compounds wherein W is a sulfur atom and q is 0.

In yet another embodiment, the invention relates to compounds wherein W is a sulfur atom, X is CO and q is 0.

In yet another embodiment, the invention relates to compounds wherein W is a sulfur atom, q is 1 and Z is an oxygen atom.

In yet another embodiment, the invention relates to compounds wherein W is a sulfur atom, X is CO, q is 1 and Z is an oxygen atom.

In yet another embodiment, m is 0.

In yet another embodiment, m is 1.

In yet another embodiment, m is 2.

In one embodiment, m is 3.

In yet another embodiment, n is 0.

In yet another embodiment, n is 1.

In one embodiment, n is 2, 3 or 4;

in one embodiment, p is 0.

In another embodiment, p is 1.

In one embodiment, at least one R is⁵Selected from acyl, -CO-NR⁶R⁶', nitro, -S-R⁸And SO₂OR⁸。

In another embodiment, R⁵Each independently selected from C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, aryl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, aryl-C_1-6-alk (en/yn) yl, halogen, halo-C_1-6-alk (en/yn) yl, C_1-6-alk (en/yn) yloxy, cyano, NR⁷R⁷' and-SO₂R⁸。

In yet another embodiment, R⁵Each independently selected from C_1-6Alk (en/yn) yl, aryl, halogen, C_1-6-alk (en/yn) yloxy, -NR⁷R⁷' and-SO₂R⁸。

In yet another embodiment, the invention relates to compounds wherein R is⁵Each independently selected fromC_1-6-alk (en/yn) yl, halogen and-SO₂R⁸Wherein R is⁸A compound which is an aryl group.

In yet another embodiment, at least one substituent R⁵Is C_1-6-alk (en/yn) yl.

In yet another embodiment, at least one substituent R⁵Is an aryl group.

In yet another embodiment, at least one substituent R⁵Is C_1-6-an alk (en/yn) yloxy group.

In yet another embodiment, at least one substituent R⁵is-SO₂R⁸。

In yet another embodiment, at least one substituent R⁵Is a halogen atom.

In yet another embodiment, at least one substituent R⁵Is a halogen atom selected from chlorine, bromine and iodine.

In yet another embodiment, at least one substituent R⁵Is fluorine.

In yet another embodiment, at least one substituent R⁵Is chlorine.

In yet another embodiment, at least one substituent R⁵Is bromine.

In yet another embodiment, at least one substituent R⁵is-NR⁷R⁷’。

In one embodiment, at least one substituent R⁵is-NR⁷R⁷', and R⁷And R⁷' at least one of which is aryl or acyl.

In one embodiment, at least one substituent R⁵is-NR⁷R⁷', and R⁷And R⁷' at least one is selected from hydrogen and C_1-6-alkanes (alkenes/alkynes)Base, C_3-8Cycloalkyl (en) yl and C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl.

In another embodiment, at least one substituent R⁵is-NR⁷R⁷', and R⁷And R⁷' at least one of which is selected from hydrogen and C_1-6-alk (en/yn) yl.

In yet another embodiment, at least one substituent R⁵is-NR⁷R⁷', and R⁷And R⁷At least one of which is C_1-6-alk (en/yn) yl.

In yet another embodiment, at least one substituent R⁵is-NR⁷R⁷', and R⁷And R⁷' are all C_1-6-alk (en/yn) yl.

In one embodiment, at least one substituent R⁵is-SO₂R⁸And R is⁸is-NR⁹R⁹'; wherein R is⁹And R⁹' independently selected from hydrogen, C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl and C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl.

In one embodiment, at least one substituent R⁵is-SO₂R⁸And R is⁸Is selected from C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl and aryl.

In yet another embodiment, at least one substituent R⁵is-SO₂R⁸(ii) a And R is⁸Is an aryl group.

In yet another embodiment, the invention relates to compounds wherein Y is formula II.

In yet another embodiment, the invention relates to compounds wherein Y is formula III.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIb or IIIb:

wherein W, m, n, p and R⁵As defined above.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIb.

In yet another embodiment, the invention relates to compounds wherein m is 0 and Y is formula lib.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIb.

In yet another embodiment, the invention relates to compounds wherein n is 0 and Y is formula IIIb.

In yet another embodiment, the invention relates to compounds wherein p is 0 and Y is formula IIIb.

In yet another embodiment, the invention relates to compounds wherein n is 0, p is 0 and Y is formula IIIb.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIIb and n + p is 1, in one particular instance n is 1 and p is 0, in another particular instance n is 0 and p is 1.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIIb and n + p is 2, in one particular instance n is 2 and p is 0, in another particular instance n is 1 and p is 1.

In yet another embodiment, the invention relates to compounds wherein Y is of the formula IIb¹、IIb²、IIb³、IIIb¹、IIIb²、IIIb³Or IIIb⁴The compound of (1):

wherein

W is as described above;

r is 0, 1 or 2;

s is 0, 1, 2 or 3; and is

R⁵' and R⁵Independently as R⁵Definition of R⁵Each independently as defined above.

In yet another embodiment, the present invention relates to compounds wherein each group is defined as follows:

● m is 0 and Y is formula IIb; or

● n is 0 and Y is of formula IIIb; or

● p is 0 and Y is formula IIIb; or

● n is 0, p is 0 and Y is of formula IIIb; or

● Y is of formula IIIb and n + p is 1, in one particular case n is 1 and p is 0, in another particular case n is 0 and p is 1; or

● Y is of formula IIIb and n + p is 2, in one particular case n is 2 and p is 0, in another particular case n is 1 and p is 1; or

● Y is of formula IIb¹、IIb²、IIb³、IIIb¹、IIIb²、IIIb³Or IIIb⁴。

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIb¹、IIb²Or IIb³A compound of (1); or wherein m is 0 and Y is a compound of formula IIb.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIb¹The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIb²The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIb³The compound of (1).

● Y is of formula IIIb¹、IIIb²、IIIb³Or IIIb⁴(ii) a Or

● n is 0 and Y is of formula IIIb; or

● p is 0 and Y is formula IIIb; or

● n is 0, p is 0 and Y is of formula IIIb; or

● Y is of formula IIIb and n + p is 2, in one particular case n is 2 and p is 0, in another particular case n is 1 and p is 1.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIb¹The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIb²The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIb³The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIb⁴The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIc or IIIc:

wherein W, m, n, p and R⁵As defined above.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIc.

In yet another embodiment, the invention relates to compounds wherein m is 0 and Y is formula IIc.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIIc.

In yet another embodiment, the invention relates to compounds wherein n is 0 and Y is formula IIIc.

In yet another embodiment, the invention relates to compounds wherein p is 0 and Y is formula IIIc.

In yet another embodiment, the invention relates to compounds wherein n is 0, p is 0 and Y is formula IIIc.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIIc and n + p is 1, in one particular instance n is 1 and p is 0, in another particular instance n is 0 and p is 1.

In yet another embodiment, the invention relates to compounds wherein Y is formula IIIc and n + p is 2, in one particular instance n is 2 and p is 0, in another particular instance n is 1 and p is 1.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIc¹、IIc²、IIc³、IIIc¹、IIIc²、IIIc³Or IIIc⁴The compound of (1):

wherein:

w is as defined above;

r is 0, 1 or 2;

s is 0, 1, 2 or 3; and is

● m is 0 and Y is formula IIc; or

● n is 0 and Y is of formula IIIc; or

● p is 0 and Y is of formula IIIc; or

● n is 0, p is 0 and Y is of formula IIIc; or

● Y is of formula IIIc and n + p is 1, in one particular case n is 1 and p is 0, in another particular case n is 0 and p is 1; or

● Y is of formula IIIc and n + p is 2, in one particular case n is 2 and p is 0, in another particular case n is 1 and p is 1; or

● Y is of formula IIc¹、IIc²、IIc³、IIIc¹、IIIc²、IIIc³Or IIIc⁴。

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIc¹、IIc²Or IIc³A compound of (1); or m is 0 and Y is a compound of formula IIc.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIc¹The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIc²The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIc³The compound of (1).

● Y is of formula IIIc¹、IIIc²、IIIc³Or IIIc⁴(ii) a Or

● n is 0 and Y is of formula IIIc; or

● p is 0 and Y is of formula IIIc; or

● n is 0, p is 0 and Y is of formula IIIc; or

● Y is of formula IIIc and n + p is 2, in one particular case n is 2 and p is 0, in another particular case n is 1 and p is 1.

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIc¹The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIc²The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIc³The compound of (1).

In yet another embodiment, the invention relates to compounds wherein Y is of formula IIIc⁴The compound of (1).

In yet another embodiment, the invention relates to compounds wherein r is 0.

In yet another embodiment, the invention relates to compounds wherein r is 1.

In yet another embodiment, the invention relates to compounds wherein r is 2.

In yet another embodiment, the invention relates to compounds wherein s is 0.

In yet another embodiment, the invention relates to compounds wherein s is 1, 2 or 3.

In a further embodiment, the invention relates to compounds wherein Y of formula II represents the following group:

●IIb¹、IIb²、IIb³、IIc¹、IIc²or IIc³(ii) a Or

● A group of formula IIb, wherein m is 0; or

● A group of formula IIc, wherein m is 0.

●IIb¹、IIb²or IIb³(ii) a Or

● A group of formula IIb, wherein m is 0; or

● A group of formula IIc, wherein m is 0.

In a further embodiment, the invention relates to compounds wherein Y of formula III represents the following group:

●IIIb¹、IIIb²、IIIb³、IIIb⁴、IIIc¹、IIIc²、IIIc³or IIIc⁴；

Or

● A group of formula IIIb, wherein n is 0; or

● A group of formula IIIb, wherein p is 0; or

● A group of formula IIIb, wherein n is 0 and p is 0; or

● A group of formula IIIb, wherein n + p is 1, in one particular case n is 1 and p is 0, in another particular case n is 0 and p is 1; or

● Y is of formula IIIb and n + p is 2, in one particular case n is 2 and p is 0, in another particular case n is 1 and p is 1;

● A group of formula IHc, wherein n is 0; or

● A group of formula IIIc, wherein p is 0; or

● A group of formula IIIc, wherein n is 0 and p is 0; or

● A group of formula IIIc, wherein n + p is 1, in one particular case n is 1 and p is 0, in another particular case n is 0 and p is 1; or

●IIIb²or IIIc²(ii) a Or

● A group of formula IIIb, wherein n is 0 and p is 0; or

● A group of formula IIIc, wherein n is 0 and p is 0.

In yet another embodiment, the invention relates to compounds wherein m is 0 and Y is formula II, in one particular instance, Y is formula IIb or IIc.

In yet another embodiment, m is 1 and Y is formula II, in one particular instance Y is formula IIb, in a more particular instance Y is formula IIb¹、IIb²Or IIb³。

In yet another embodiment, m is 1, R⁵Is selected from C_1-6-alk (en/yn) yl and halogen, and Y is of formula II, in one particular case Y is of formula IIb, in a more particular case Y is of formula IIb¹、IIb²Or IIb³。

In yet another embodiment, the invention relates to wherein m is 1, R⁵Is C_1-6-alk (en/yn) yl and Y is a compound of formula II, in one particular case Y is formula IIb, in a more particular case Y is formula IIb¹Or IIb³。

In yet another embodiment, the invention relates to wherein m is 1, R⁵Is a halogen atom (e.g., bromine, chlorine or fluorine), and Y is a compound of formula II, in one particular instance Y is of formula IIb, in a more particular instance Y is of formula IIb¹、IIb²Or IIb³。

In yet another embodiment, the invention relates to wherein m is 1, R⁵Is bromine or chlorine, and Y is a compound of formula II, in one particular instance Y is of formula IIb, in a more particular instance Y is of formula IIb¹、IIb²Or IIb³。

In yet another embodiment, the invention relates to wherein m is 1, R³Is C_1-6-alk (en/yn) yl, and Y is a compound of formula II, in one particular case Y is formula IIb, in a more particular case Y is formula IIb¹、IIb²Or IIb³In one most specific case, Y is of formula IIb³。

In yet another embodiment, the invention relates to compounds wherein R is¹Is C_1-6-alk (en/yn) yl, m is 1, R⁵Is C_1-6-alk (en/yn) yl or halo and Y is a compound of formula II, in one particular case Y is formula IIb, in one more particular case Y is formula IIb³。

In yet another embodiment, the invention relates to compounds wherein n is 0, p is 0 and Y is formula III, in particular instances, Y is formula IIIb or IHc.

In yet another embodiment, the invention relates to compounds wherein n is 1 and Y is formula III, where the specific case isIn the case where Y is of formula IIIb or IIIc, more specifically Y is of formula IIIb²、IIIb³Or IIIc²。

In yet another embodiment, the invention relates to compounds wherein n + p is 1 and Y is formula III, in one particular instance Y is formula IIIc, in one more particular instance Y is formula IIIc²。

In yet another embodiment, the invention relates to compounds wherein n + p is 2 and Y is formula III, in one particular instance Y is formula IIIb, in one more particular instance Y is formula IIIb²Or IIIb³。

In yet another embodiment, when W is an oxygen atom, Y is not of formula II.

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

The following compounds and their pharmaceutically acceptable salts are preferred:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

{ 2-amino-4- [ (5-fluoro-thiophen-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-chloro-thiophen-2-ylmethyl) amino ] -phenyl } -2- (4-fluoro-phenyl) -acetamide; and

n- { { 2-amino-4- [ (5-chloro-thiophen-2-ylmethyl) amino ] -phenyl } -3, 3-dimethyl-butyramide

In a particular aspect, the following compounds and their pharmaceutically acceptable acid addition salts are preferred:

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

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

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

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

The present invention provides a pharmaceutical composition for oral or parenteral administration comprising a therapeutically effective amount of at least one compound of formula I or a salt thereof, and one or more pharmaceutically acceptable carriers or diluents.

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

In another embodiment, the compounds of the invention may be administered as part of a combination therapy, i.e. the compounds of the invention may be administered together with other therapeutically effective compounds, e.g. having anticonvulsant properties. The effects of these other compounds with anticonvulsant properties may include, but are not limited to, activity with respect to:

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

● excitatory amino acid systems, such as the blockade or modulation of NMDA receptors;

● inhibitory neurotransmitter systems, e.g. enhancement of GABA release or blocking of GABA absorption, and/or

● film stabilization.

Current anticonvulsants include, but are not limited to, tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide, and benzodiazepinesAnd barbiturate salts.

It is believed that the compounds of the present invention can be used to increase ion flow in potassium channels as a function of pressure.

The compounds of the present invention are believed to be useful in the prevention, treatment and/or inhibition of disorders or diseases that respond to increased ion flow in potassium channels, such as KCNQ family potassium ion channels.

In one aspect, the compounds of the invention have been found to be effective against potassium ion channels of the KCNQ family, in particular the KCNQ2 subtype.

According to one aspect, the compounds of the present invention are believed to be useful in the prevention, treatment and/or inhibition of various central nervous disorders, for example, seizure disorders such as convulsions, epilepsy and status epilepticus; anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute stress response, regulatory disorders, hypochondriacal disorders, separation anxiety disorder, agoraphobia, and specific phobias.

Accordingly, the compounds of the present invention are believed to be useful in the prevention, treatment and/or inhibition of various central nervous disorders, such as:

● seizure disorders such as convulsions, epilepsy, and status epilepticus;

● neuropathic pain such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine;

● anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute stress disorder, regulation disorder, hypochondriacal disorder, separation anxiety disorder, agoraphobia, and specific phobias;

● neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other encephalopathies caused by infection with rubella virus, herpes virus, Borrelia and other unknown pathogens, Creutzfeldt-Jakob disease, Parkinson's disease, trauma-induced neurodegeneration; and

● neuronal hyperexcitability states, such as during drug withdrawal and neuronal hyperexcitability due to intoxication; degenerative diseases of the peripheral nervous system, such as polyneuropathy and polyneuritis.

Accordingly, the compounds of the present invention are believed to be useful in the prevention, treatment and/or inhibition of diseases or disorders such as seizure disorders, neuropathic and migraine disorders, anxiety disorders and neurodegenerative disorders.

According to a particular aspect of the invention, it is believed that the compounds of the invention are useful for the prevention, treatment and/or inhibition of seizure disorders, such as convulsions, epilepsy and status epilepticus.

According to a particular aspect of the invention, the compounds of the invention are considered to be useful in the prevention, treatment and/or inhibition of neuropathic pain and migraine, such as allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy and neuropathic pain associated with migraine.

The compounds of the present invention are also believed to be useful in the prevention, treatment and/or inhibition of anxiety disorders such as anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute stress response, adjustment disorders, hypochondriasis, separation anxiety disorder, agoraphobia, anxiety disorder resulting from general health conditions and substance-induced anxiety disorder, and specific phobias.

It is also believed that the compounds of the invention are useful for preventing, treating and/or inhibiting neurodegenerative diseases such as alzheimer's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other encephalopathies caused by infections with rubella viruses, herpes viruses, borrelia and other unknown pathogens, creutzfeldt-jakob disease, parkinson's disease, neurodegeneration caused by trauma, and neuronal hyperexcitability states, for example during drug withdrawal and due to alcohol intoxication.

In another aspect, the invention provides various compounds that exhibit effects in one or more of the following assays:

● "relative flux through KCNQ2 channel", which is used to determine the potency of a compound at the target channel;

● "maximal shock", which test is used to determine epilepsy induced by non-specific CNS stimulation by means of electric shock;

● "pilocarpine-induced epilepsy", which is difficult to treat with existing antiepileptic drugs, so a "drug-resistant epilepsy" model is considered;

● "electric epilepsy threshold test" and "chemical epilepsy threshold test", which determine the threshold for onset of epilepsy and thus can be used as a model to detect whether individual compounds delay the onset of epilepsy;

● "Almond ignition induced", this test is used to determine disease progression and, since these animals receive more stimulation, epilepsy is more severe in this model than in normal animals.

According to a particular aspect of the invention, the compounds have KCNQ2 activity, EC, as determined by the test "relative flux through KCNQ2 channel" described below₅₀Less than 15000 nM.

According to a particular aspect of the invention, the compounds have KCNQ2 activity, EC, as determined by the test "relative flux through KCNQ2 channel" described below₅₀Less than 1500 nM.

According to another particular aspect of the invention, the compounds have KCNQ2 activity, EC, as determined by the test "relative flux through KCNQ2 channel" described below₅₀Less than 150 nM.

According to another specific aspect of the invention, the ED of the compound is measured in the "Max shock" test as described below₅₀Less than 15 mg/kg.

According to yet another particular aspect of the invention, the ED of the compound is in the "Max shock" test as described below₅₀Less than 5 mg/kg.

According to a further particular aspect of the invention, the "electric epileptic threshold test" and the "chemical epilepsia" are described belowEpilepsy threshold test "ED of said Compounds₅₀Less than 5 mg/kg.

Some compounds have little or no clinically insignificant side effects. Thus, some compounds do not require sedation, hypothermia, and dyskinesia model testing of the compound.

Certain compounds have a suitable half-life and a suitable clearance rate, which means that the patient only needs to take the tablet, for example, once or twice daily. Patients remember easily and help comply with medication.

Certain compounds have a large therapeutic index between anticonvulsant effects and side effects (e.g., motor impairment or dyskinesia responses as measured by behavior on rotating rods). This means that the compound can be expected to be well tolerated by patients before side effects are visible, thus allowing high doses. Thus, a very good therapeutic tolerability is expected and high doses can be administered, making it more efficacious for those patients who experience side effects with other drugs.

Definition of

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

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

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

The term "C_1-6By "alkyl" is meant a branched or unbranched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-2-dimethyl-1-propyl and 2-methyl-1-propyl.

Similarly, "C_2-6-alkenyl "and" C_2-6-alkynyl "refers to such groups having 2-6 carbon atoms containing one double and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethenylAlkynyl, propynyl and butynyl.

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

The term "C_3-8-cycloalkyl "is a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term "C_3-8Cycloalkenyl is a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms and comprising 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 optionally containing 1, 2 or 3 further heteroatoms, then the monocyclic ring system is formed from 4-8 atoms selected from nitrogen atoms, 1-7 carbon atoms and 0-3 heteroatoms selected from N, S or O. Examples of such ring systems are azetidine, beta-lactam (lactame), pyrrolidine, piperidine, piperazine, morpholine, pyrrole, oxazolidine, thiazolidine, imidazolidine, tetrazole and pyrazole.

The term "aryl" refers to an aryl system optionally substituted with one or more substituents independently selected from hydroxy, halogen, C, such as pyridine, thiazole, oxazole, phenyl, naphthyl, thiophene and furan_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, halo-C_1-6-alk (en/yn) yl, C_1-6-alkoxy, C_3-8-alkoxy, acyl, nitro, cyano, -CO-NH-C_1-6-alk (en/yn) yl, -CO-N (C)_1-6-alk (en/yn) yl)₂、-NH-C_1-6-alk (en/yn) yl, -N (C)_1-6-alk (en/yn) yl)₂、-S-C_1-6-alk (en/yn) yl, -SO₂-C_1-6-alk (en/yn) yl, -SO₂O-C_1-6-alk (en/yn) yl, -NH₂、SO₂N(C_1-6-alk (en/yn) yl)₂or-SO₂NH-C_1-6-an alk (en/yn) yl group; or

Two adjacent substituents may be taken together with the aryl to which they are attached to form a 4-8 membered ring optionally containing one or two heteroatoms.

When two adjacent substituents together with the aryl to which they are attached form a 4-8 membered ring optionally containing one or two heteroatoms, the ring system is formed from 4-8 atoms selected from 3-8 carbon atoms and 0-2 heteroatoms selected from N, S or O. Two adjacent substituents may together form: - (CH)₂)_n”-CH₂-、-CH＝CH-(CH₂)_m”-、-CH₂-CH＝CH-(CH₂)_p”、-CH＝CH-CH＝CH-、-(CH₂)_n”-O-、-O-(CH₂)_m”-O-、-CH₂-O-(CH₂)_p”-O-、-CH₂-O-CH₂-O-CH₂-、-(CH₂)_n”-S-、-S-(CH₂)_m”-S-、-CH₂-S-(CH₂)_p”-S-、-CH₂-S-CH₂-S-CH₂-、-(CH₂)_n”-NH-、-NH-(CH₂)_m”-NH-、-CH₂-NH-(CH₂)_p”-NH-、-CH＝CH-NH-、-O-(CH₂)_m”-NH-、-CH₂-O-(CH₂)_p”-NH-、-O-(CH₂)_p”-NH-CH₂-、-S-(CH₂)_m”-NH-, -N ═ CH-O-, or-N ═ CH-S-, wherein m "is 1, 2, or 3, N" is 2, 3, or 4, and p "is 1 or 2.

The term "acyl" as used herein refers to formyl, C_1-6-alk (en/yn) ylcarbonyl, C_3-8Cycloalkyl (en) carbonyl, arylcarbonyl, aryl-C_1-6-alk (en/yn) ylcarbonyl or C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) ylcarbonyl, wherein C_1-6-alk (en/yn) yl, C_3-8Cycloalkyl (en) yl and aryl are as defined above.

The term "halo-C_1-6-alk (en/yn) yl "means C substituted by one or more halogen atoms_1-6-alk (en/yn) yl including, but not limited to, trifluoromethyl. Similarly,'halo-C_3-8-cycloalkyl (en) yl "means C substituted by one or more halogen atoms_3-8-cycloalkyl (en) yl, -halo-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl "means C substituted by one or more halogen atoms_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl.

The term "C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl "," C_3-8-cycloalkyl (en) yl "and" C_1-6-alk (en/yn) yl "is as defined above.

Furthermore, terms such as hydroxy-C_1-6-alk (en/yn) yl, hydroxy-C_3-8Cycloalkyl (en) yl, aryl-C_1-6-alk (en/yn) yl, C_1-6-alk (en/yn) yloxy, C_3-8Cycloalk (en) yloxy, C_1-6-alk (en/yn) ylcarbonyl, C_3-8Cycloalkyl (en) carbonyl, arylcarbonyl, aryl-C_1-6-alk (en/yn) ylcarbonyl, C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) ylcarbonyl, aryl-C_3-8Cycloalkyl (en) yl, hydroxy-C_3-8-cycloalkyl (en) yl-C_1-6-alk (en/yn) yl, hydroxy-C_1-6-alk (en/yn) yl-C_3-8Cycloalkyl (en) yl, cyano-C_1-6-alk (en/yn) yl, cyano-C_3-8Cycloalkyl (en) yl, cyano-C_3-8-cycloalkyl (en) yl-C_1-6Alk (en/yn) yl, NR¹⁰R¹⁰’-C_1-6-alk (en/yn) yl and NR¹⁰R¹⁰’-C_3-8-Cycloalk (en) yl and the like mean wherein C_1-6-alk (en/yn) yl, C_3-8-cycloalkyl (en) yl and aryl are as defined above.

The salt of the present invention is preferably a pharmaceutically acceptable salt. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts.

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

Acid addition salts include salts of inorganic and organic acids.

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

Examples of such organic salts are salts with maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylene salicylic acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetate, and 8-halotheophylline (e.g. 8-bromotheophylline).

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

Another pharmaceutically acceptable acid addition salt is a hydride which the compound can form.

Furthermore, geometric isomers may be formed when double bonds or fully or partially saturated ring systems are present in the molecule. Any geometric isomer, such as an isolated, pure or partially purified geometric isomer or mixtures thereof, is included within the scope of the present invention. Likewise, molecules with rotation-constrained bonds may form geometric isomers. These are also included in the scope of the present invention.

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

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

Certain compounds of the present invention contain chiral centers and these compounds exist as isomers (i.e., optical isomers). The present invention includes all such isomers and any mixtures thereof (including racemic mixtures).

The racemic form can be resolved into the optical antipodes by known methods, for example by separation of the diastereomeric salts with an optically active acid, followed by treatment with a base to liberate the optically active amine compound. Another method for resolving racemates into optical antipodes is chromatography on an optically active matrix. The racemic compounds of the present invention can also be resolved into their optical antipodes by fractional crystallization of, for example, the d-or 1-tartrate, mandelate or camphorsulfonate salts. The compounds of the present invention may also be resolved by forming diastereomeric derivatives.

Other methods of resolving optical isomers known to those skilled in the art may be used. These methods include those described in j.jaques, a.colet and s.wilen in "Enantiomers, Racemates and resolution" ("Enantiomers, racemics, and solutions", John Wiley and Sons, New York, 1981).

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

The invention also includes prodrugs of the compounds of the invention which, upon administration, undergo chemical conversion by metabolic action to pharmacologically active substances. Typically, such prodrugs are functional derivatives of the compounds of formula I that are readily converted in vivo to the desired compounds of formula I. The general procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "prodrug Design" ("Design of Prodrugs", h.bundgaard eds., Elsevier, 1985).

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

Terms relating to compounds of formula I: "epilepsy and epilepsy of various kinds" is included in the international anti-epileptic union: recommendations for revising clinical and electroencephalographic classification of seizures, international classification of the antiepileptic alliance and technical committee, Epilepsia, 198122: 489-: recommendations for revising the classification of epilepsy and epileptic syndrome, the international classification of the antiepileptic alliance and technical committee, Epilepsia, 198930 (4): 389-399 for any epilepsy, epileptic syndrome and seizures.

Pharmaceutical composition

The compounds of the invention are generally employed as the free base or in the form of a pharmaceutically acceptable salt thereof. Representative examples are described above.

If desired, the pharmaceutical compositions of the present invention may comprise a compound of formula I in combination with other pharmacologically active agents as described above.

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

The pharmaceutical compositions of the invention or those prepared according to the invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, granules, pills, dragees, pills or lozenges, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water or water-in-oil liquid emulsions, elixirs, syrups, and the like, 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 into sterile injectable solutions or dispersions just prior to use. Long acting injectable formulations are also contemplated within the scope of the present invention. Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.

Methods well known in the art may be used to prepare such compositions, and any pharmaceutically acceptable carrier, diluent, excipient or other additive conventionally used in the art may be used.

The compounds of the present invention are administered in unit doses containing from about 0.01 to 100mg of the compound. In general the total daily dose will be in the range of from about 0.05 to 500mg or even from 0.05 to 1500mg or from 0.05 to 3000mg, most preferably from about 0.1 to 50mg, of the active compound of the invention. For parenteral routes (e.g., intravenous, intrathecal, intramuscular and the like), the dosage is typically about half that of oral administration.

The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in a single or multiple dosage form. The pharmaceutical compositions of the present invention may be formulated with a pharmaceutically acceptable carrier or diluent and any other additives and excipients known according to conventional techniques in the art, such as Remington: those disclosed in The Science and Practice of pharmacy (19 th edition, Gennaro eds., Mack Publishing Co., Easton, Pa., 1995). The formulations may be presented in unit dosage form by methods well known in the art of pharmacy.

Any other adjuvants or additives commonly used for coloring, flavoring, preserving, etc., such as coloring agents, flavoring agents, preservatives, etc., may be used, provided that they are compatible with the active ingredient.

The pharmaceutical formulations of the present invention may be prepared according to conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with various adjuvants and/or diluents, as are conventional, and then compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives conventionally used for coloring, flavoring, preserving and the like may be used, such as coloring agents, flavoring agents, preservatives and the like, provided that they are compatible with the active ingredient.

Where appropriate, coated (e.g., enteric coated) solid dosage forms may be prepared according to methods known in the art, or otherwise formulated so as to provide controlled (e.g., sustained or extended) release of the active ingredient.

If a liquid carrier is used, the formulation can be a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid (e.g., an aqueous or nonaqueous liquid suspension or solution).

For parenteral administration, solutions of the novel compounds of the invention in sterile water, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be used. Solutions for injection can be prepared by the following method: the active ingredient and possible additives are dissolved in a portion of the solvent for injection, preferably in sterile water, the solution is adjusted to the desired volume, the solution is sterilized and filled into suitable ampoules or vials. Any suitable additive conventionally used in the art such as tonicity agents, preservatives, antioxidants, and the like may be added. Thus, if desired, such aqueous solutions may be suitably buffered and the dilution first rendered isotonic with sufficient salt or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed is readily available via standard procedures well known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any release-delaying material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Typical examples of formulations of the invention are as follows:

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

a compound of formula I	5.0mg
a compound of formula I	5.0mg	Lactose	60mg
Corn starch	30mg	Lactose	60mg
Corn starch	30mg	Hydroxypropyl cellulose	2.4mg
Microcrystalline cellulose	19.2mg	Hydroxypropyl cellulose	2.4mg
Microcrystalline cellulose	19.2mg	Croscarmellose sodium A form	2.4mg
Magnesium stearate	0.84mg	Croscarmellose sodium A form	2.4mg

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

a compound of formula I	0.5mg
a compound of formula I	0.5mg	Lactose	46.9mg
Corn starch	23.5mg	Lactose	46.9mg
Corn starch	23.5mg	Povidone	1.8mg
Microcrystalline cellulose	14.4mg	Povidone	1.8mg
Microcrystalline cellulose	14.4mg	Croscarmellose sodium A form	1.8mg
Magnesium stearate	0.63mg	Croscarmellose sodium A form	1.8mg

3) Syrup, containing per ml:

a compound of formula I	25mg
a compound of formula I	25mg	Sorbitol	500mg
Hydroxypropyl cellulose	15mg	Sorbitol	500mg
Hydroxypropyl cellulose	15mg	Glycerol	50mg
P-hydroxybenzoic acid methyl ester	1mg	Glycerol	50mg
P-hydroxybenzoic acid methyl ester	1mg	Propyl p-hydroxybenzoate	0.1mg
Ethanol	0.005ml	Propyl p-hydroxybenzoate	0.1mg
Ethanol	0.005ml	Flavoring agent	0.05mg
Saccharin sodium salt	0.5mg	Flavoring agent	0.05mg
Saccharin sodium salt	0.5mg	Water (W)	1ml

4) Injectable solutions, containing per ml:

a compound of formula I	0.5mg
a compound of formula I	0.5mg	Sorbitol	5.1mg
Acetic acid	0.05mg	Sorbitol	5.1mg
Acetic acid	0.05mg	Saccharin sodium salt	0.5mg
Water (W)	Adding to 1ml	Saccharin sodium salt	0.5mg

Preparation of the Compounds of the invention

The compounds of the invention of the general formula I, wherein R¹、R²、R²’、R³X, Y, Z and q are as defined above, prepared by the methods shown in the schemes and described below:

hereinafter, any R¹、R²、R²’、R³、R⁴、R⁵、R⁶、R⁶’、R⁷、R⁷’、R⁸、R⁹、R⁹’、R¹⁰、R¹⁰', X, Y, Z, W, m, n, p and q are as defined above.

The compounds of formula VII are prepared according to methods well known to those skilled in the art (v. Bebenburg et al, Chemiker Zeitung 1979, Sonderdruck 103, 3-15) and are summarized below:

the compounds of formula IV are prepared by the following method: the nitro group is reduced by reacting the 4-nitroaniline with a suitable electrophile such as, but not limited to, an acid chloride, an acid bromide, an acid iodide, a sulfonyl chloride, an isocyanate, carbon dioxide, an active ester, and an alkyl haloformate, with or without the addition of a base such as trialkylamine, potassium carbonate, or an alkoxide of lithium, sodium, or potassium, at a suitable temperature (such as room temperature or reflux temperature) obtained by conventional heating or microwave irradiation, followed by reduction of the nitro group with a suitable reducing agent such as sodium hydrosulfite, iron or zinc powder in hydrochloric acid, or hydrogen, in a suitable solvent such as methanol or ethanol, in the presence of a suitable hydrogenation catalyst such as palladium on carbon, at a suitable temperature.

The compounds of formula V are prepared by reacting a compound of formula IV with a reagent that forms a protecting group on the anilino group, such as phthalic anhydride, in a suitable solvent, such as glacial acetic acid, at a suitable temperature.

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

The compounds of formula VII are obtained by deprotecting a aniline function from a compound of formula VI with hydrazine hydrate at a suitable temperature in a suitable solvent, such as dioxane.

Alternatively, the compounds of formula VII may be prepared from 2-nitro-1, 4-diaminobenzene in the three steps shown in the scheme, described below. In a first step, the nitrogen of the less sterically hindered and more reactive aniline is protected with a suitable protecting group PG (e.g. tert-butoxycarbonyl, Boc) by reaction with a suitable protecting group-forming reagent (e.g. di-tert-butyl dicarbonate) in a suitable solvent (e.g. acetonitrile) at a suitable temperature (see "protective groups in Organic Synthesis", 3 rd edition, T.W.Greene, P.G.M.Wuts, Wiley Interscience 1999) to give compounds of general formula XI.

Compounds of formula XII are prepared by reacting compounds of formula XI with the formation of R at a suitable temperature (room temperature or reflux temperature) obtained by conventional heating or microwave irradiation, in a suitable solvent (such as acetonitrile, tetrahydrofuran, 1, 2-dichloroethane or dichloromethane), with or without the addition of a base (such as magnesium oxide, potassium carbonate, trialkylamine, pyridine or sodium bicarbonate) for compounds of formula IV above³Suitable electrophiles for the (Z) q-X group (e.g.chloroformylalkyl ester, chloroformylaryl ester, chloroformylheteroaryl ester, carbamoyl chloride, acid bromide, acid iodide, sulfonyl chloride, isocyanate, carbonic anhydride, activated carbonic acid) and activators (e.g.carbodiimide or other activators known to the person skilled in the art).

The protecting group is removed using methods well known to those skilled in the art of chemistry. Specifically, treatment with a suitable acid (e.g., trifluoroacetic acid) at an appropriate temperature, in the absence or presence of a solvent (e.g., dichloromethane or toluene) removes the Boc group to provide the compound of formula VII.

Preparation of a compound of formula VIII:

using a reducing agent (such as sodium borohydride or sodium cyanoborohydride) and an aldehyde of formula IIa or IIIa (wherein R is R) in which R is hydrogen, an aldehyde of formula IIa or IIIa, in which R is hydrogen, in a suitable solvent (such as methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof) with or without the addition of a catalytic amount of an acid (such as acetic acid) at a suitable temperature⁵W, m, n and p are as defined above) subjecting a compound of formula VII to a reductive alkylation reaction well known to those skilled in the art to form a compound of formula VIII wherein R is¹Is hydrogen.

Alternatively, the compound of formula VII is reacted with an aldehyde of formula IIa or IIIa to form an imine, which may be isolated by crystallization or evaporation of the solvent, in a suitable solvent (such as methanol, ethanol, tetrahydrofuran, dioxane, xylene or mixtures thereof) at a suitable temperature, with or without the addition of a catalytic amount of an acid (such as acetic acid or an acidic ion exchange resin). Followed by dissolving in a suitable solvent (e.g. methanol, ethanol, tetrahydrofuran, water, dioxane)Or mixtures thereof) with a reducing agent (e.g., sodium borohydride or sodium cyanoborohydride) to provide a compound of formula VIII, wherein R¹Is hydrogen.

Optionally, in order to change R¹The resulting compound of formula VIII can be reductively alkylated again with a suitable aldehyde and a reducing agent such as sodium borohydride or sodium cyanoborohydride at a suitable temperature as described above, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with or without the addition of a catalytic amount of an acid such as acetic acid. This step can also be carried out in situ after the first reductive alkylation with an aldehyde of the general structure IIa or IIIa.

Or, to change R¹The resulting compound of formula VIII can be acylated with a suitable electrophile (e.g., an acid chloride, acid bromide, acid iodide, sulfonyl chloride, and alkyl haloformate) by adding a base (e.g., trialkylamine, potassium carbonate, or lithium, sodium, or potassium alcoholate) in a suitable solvent (e.g., ethyl acetate, dioxane, tetrahydrofuran, or diethyl ether) at a suitable temperature as described above.

The compound of formula IX is obtained by reducing a compound of formula VIII with a suitable reducing agent, such as sodium dithionite, iron or zinc powder in hydrochloric or acetic acid in the presence or absence of an organic solvent, such as tetrahydrofuran or ethanol, or hydrogen in the presence of a suitable hydrogenation catalyst, such as palladium on carbon, in a suitable solvent, such as methanol or ethanol or a water/tetrahydrofuran mixture, at a suitable temperature. The resulting compounds are the same as the compounds of general formula I of the present invention, wherein R is²And R²' is hydrogen, and wherein R¹、R³X, Y, Z and q are as defined above.

A compound of the general formula I (wherein R¹Is not hydrogen and R²And optionally R²' other than Hydrogen) from compounds of formula IX (wherein R is¹Not hydrogen) to yield:

R²by heating in a suitable solvent (e.g. at a suitable temperature as described above)Methanol, ethanol, tetrahydrofuran, water, dioxane, or mixtures thereof), with or without a catalytic amount of an acid (e.g., acetic acid), using a suitable aldehyde and a reducing agent (e.g., sodium borohydride or sodium cyanoborohydride) for the reductive alkylation step.

Optionally R²' is introduced by again performing an additional reductive alkylation step using a suitable aldehyde and a reducing agent such as sodium borohydride or sodium cyanoborohydride, at a suitable temperature as described above, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water, dioxane or mixtures thereof, with or without the addition of a catalytic amount of an acid such as acetic acid.

Or, R²Or R²' is introduced by acylation reaction using a suitable electrophile (such as an acid chloride, acid bromide, acid iodide, sulfonyl chloride and alkyl haloformate) at a suitable temperature as described above, in a suitable solvent (such as ethyl acetate, dioxane, tetrahydrofuran or diethyl ether), with the addition of a base (such as a trialkylamine, potassium carbonate or an alcoholate of lithium, sodium or potassium).

To obtain wherein R¹Is hydrogen, and R²And optionally R²' Compounds of formula I other than Hydrogen, before reduction of the nitro group, a protecting group (e.g., tert-butoxycarbonyl) is introduced as R by methods well known to those skilled in the art of chemistry¹. By known methods in the introduction of R²And optionally R²After this, the protecting group is removed.

The compounds of formulae IIa and IIIa are prepared by methods well known to those skilled in the art of chemistry and are summarized below:

the resulting benzyl alcohol is reduced with a suitable reducing agent, such as diisobutylaluminum hydride, and then oxidized with a suitable oxidizing agent, such as tetrapropylammonium perruthenate/N-methylmorpholine-N-oxide, pyridinium chlorochromate, dimethyl sulfoxide/oxalyl chloride. Alternatively, compounds of formula Ha and IIIa can be prepared by formylation with dichloromethylmethyl ether and titanium tetrachloride (Gross et al, org. Synth. Coll, 1973, Vol. V365; Fanghaene et al, J.Prakt. chem.1997, 339, 277). Alternatively, the compounds of formula II and IIIa can be prepared by methods well known to those skilled in the art, for example, deprotonation of the heteroaromatic compound with a strong base (e.g., lithium alkyl) followed by reaction with N, N-dimethylformamide. Alternatively, the compounds of formulae IIa and IIIa may be prepared by methods well known to those skilled in the art, for example, by halogen metal exchange reaction of a halo-heteroaromatic compound (e.g., iodide or bromide) with a metallating agent (e.g., an alkyl lithium or alkyl magnesium halide or dialkyl magnesium). Alternatively, compounds of formula IIa and IIIa may be prepared by methods well known to those skilled in the art, for example, thiophene and benzothiophene are reacted with phosphorus oxychloride in the presence of N-methyl-N-phenyl formamide (King et al, J.org.chem.1949, 14, 638) or N, N-dimethylformamide (Vilsmeier formation, Raimudo et al, J.org.chem.2002, 67, 205).

Examples

LC-MS data were obtained from a PE Sciex API 150EX instrument equipped with an ion spray source and Shimadzu LC-8A/SLC-10A LC system. Column: 30 x 4.6mm Waters symmetry C18 column, filler particle size 3.5 μm; solvent system a ═ water/trifluoroacetic acid (100: 0.05), B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); the method comprises the following steps: elution was performed with a linear gradient from 90% A to 100% B over 4 minutes at a flow rate of 2 ml/min. Purity was determined by integration of UV (254nm) and ELSD traces. Retention time (RT or t)_RIn minutes.

Preparative LC-MS-purification was performed on the same instrument. Column: 50 x 20mm YMCODS-A column with filler particle diameter of 5 μm; the method comprises the following steps: elution was performed with a linear gradient from 80% A to 100% B over 7 minutes at a flow rate of 22.7 ml/min. Fractions were collected by split MS detection.

Recording at 500.13MHz on a Bruker Avance DRX500 instrument or at 250.13MHz on a Bruker AC250 instrument¹H NMR spectrum. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.8% D) was used as solvent. TMS was used as internal standard. Chemical shift values are expressed in ppm. The following abbreviations are used to represent various NMR signals:s is singlet, d is doublet, t is triplet, q is quartet, qui is quintet, h is heptat, dd is doublet, ddd is doublet, dt is doublet, dq is doublet, tt is triplet, m is multiplet, and b is broad singlet. In some cases, the coupling constant J is given. Melting points (M.P.) were recorded on a Buchi B-540 apparatus and the data was uncorrected.

Preparation of intermediates

Preparation of (4-amino-phenyl) -carbamic acid ethyl ester

4-nitroaniline (100g, 0.72mol) was dissolved in ethyl acetate (800ml), followed by addition of diisopropylethylamine (89.6ml, 0.936 mol). Ethyl chloroformate (252ml, 1.45mol) dissolved in ethyl acetate (200ml) was added, and the solution was then stirred at ambient temperature for 18 hours. The mixture was washed with 2M HCl (300ml) and brine (300ml), dried over magnesium sulfate and concentrated in vacuo to half the original volume. To the resulting solution was added palladium on carbon (10g, 5% Pd, 50% H)₂O), the mixture is placed in a Parr apparatus (PH) at ambient temperature₂3bar) for 12 hours. The reaction mixture was filtered through Celite (Celite) and the solvent evaporated in vacuo to give 118g (90%) of the title compound as a crystalline product.

LC/MS(m/z)180.9(MH⁺)；t_R＝0.60min.¹H NMR(CDCl₃)；1.27(t，3H)；3.42(b，，2H，NH₂)；4.19(q，2H)；6.52(b，1H NH)；6.64(m，2H)；7.14.(m，2H).

The following compounds were prepared in a similar manner:

(4-amino-phenyl) -carbamic acid propyl ester

Yield: 98 percent.

¹H NMR(CDCl₃)：0.96(t，3H)；1.68(m，2H)；3.51(b，2H)；4.09(t，2H)；6.46(b，1H)；6.63(d，2H)；7.14(m，2H).

(4-phthalimido-phenyl) -carbamic acid ethyl ester

(4-amino-phenyl) -carbamic acid ethyl ester (118g, 0.65mol) was dissolved in glacial acetic acid (2.0L) under a nitrogen atmosphere, and the mixture was subsequently heated to 90 ℃. Phthalic anhydride (102.0g, 0.69mol) was added portionwise over 30 minutes and the reaction was carried out at 90 ℃ for 2 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was filtered off. The solid was washed on the filter with water (2L), diethyl ether (3L) and dried in vacuo. 127g (62%) of the title compound are obtained as white crystals.

LC/MS(m/z)311.3(MH⁺)；t_R＝2.57min.¹HNMR(DMSO-d₆)：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，NH).

The following compounds were prepared in a similar manner:

(4-phthalimido-phenyl) -carbamic acid propyl ester

Yield: 81 percent.

(2-Nitro-4-phthalimido-phenyl) -carbamic acid ethyl ester

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

LC/MS(m/z)355.0(MH⁺)；t_R＝3.34min.¹H NMR(DMSO-d₆)：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，NH).

The following compounds were prepared in a similar manner:

(2-Nitro-4-phthalimido-phenyl) -carbamic acid propyl ester

Yield: 70 percent.

(4-amino-2-nitro-phenyl) -carbamic acid ethyl ester

1, 2-Dimethoxyethane (1.0L) was added to (2-nitro-4-phthalimido-phenyl) -carbamic acid ethyl ester (101g, 0.28mol), and the mixture was heated to reflux. Hydrazine monohydrate (19.6g, 0.39mol) was added dropwise over 10 minutes and the mixture was stirred at reflux for 1.5 hours. Once cooled to ambient temperature, the mixture was filtered and the solid was washed on the filter with dimethoxyethane (250 ml). The filtrate was concentrated by evaporation, the red crystals were recrystallized from toluene (350ml), the precipitated product was filtered off and dried in vacuo. The mother liquor was concentrated to half of the original volume and left for 16 hours. The precipitate was filtered and recrystallized as above. The recrystallized solids were combined to yield 57.6g (90%) of the title compound as a dark red color.

LC/MS(m/z)225.1(MH⁺)；t_R＝2.08min.¹HNMR(CDCl₃)：1.33(t，3H)；3.77(s，2H，NH₂)；4.23(q，2H)；6.98(dd，1H)；7.45(d，1H)；8.28(d，1H)；9.39(s，1H，NH).

The following compounds were prepared in a similar manner:

(4-amino-2-nitro-phenyl) -carbamic acid propyl ester

Yield: 91 percent.

¹H NMR(CDCl₃)：0.98(t，3H)；1.71(m，2H)；3.78(b，2H)；4.13(t，2H)；6.98(dd，1H)；7.44(d，1H)；8.27(d，1H)；9.39(s，1H).

(4-amino-3-nitro-phenyl) -carbamic acid tert-butyl ester

To refluxing 2-nitro-1, 4-diaminobenzene (10.135g, 66.18mmol) in tetrahydrofuran (b) (b100ml) solution was added in portions with Boc₂O (di-tert-butyl dicarbonate, 32.6g, 149 mmol). The resulting solution was poured into heptane (2L), sonicated for 15 minutes, filtered and dried in vacuo to yield 13.40g of the title compound as a red solid. Yield: 80 percent.

LC/MS(m/z)295.4([M+H+MeCN]⁺)；t_R＝2.54(UV，ELSD)96％，100％.¹H NMR(DMSO-d₆)：1.47(s，9H)；6.96(d，1H)；7.24(s，2H，NH₂)，7.41(dd，1H)；8.20(s，1H)；9.28(s，1H，NH).

[4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-yl ] -methanol

A solution of 4- (4-chloro-benzenesulfonyl) -3-methyl-thiophene-2-carboxylic acid methyl ester (992mg, 3.00mmol) in anhydrous tetrahydrofuran (20ml) and anhydrous dichloromethane (10ml) was cooled to 0 ℃ under a nitrogen atmosphere, followed by the addition of DIBAL-H (9.0ml, 9.0mmol, 1M in toluene). After 3 hours, another portion of DIBAL-H (4.5ml, 4.5mmol) was added and stirring was continued for 2 hours. The reaction was quenched by addition of saturated Rochelle (Rochelle) salt solution (30ml) followed by stirring at room temperature for 1 hour. The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 50ml) and the combined organic phases were dried over sodium sulphate and evaporated in vacuo. The product was purified by chromatography on silica gel on a FlashMaster system with heptane/ethyl acetate as eluent (linear gradient elution 1: 0-6: 4). The fractions containing the product were combined and evaporated in vacuo to give the desired compound (788mg, 87%). LC-MS: (M/z) ═ 285.2 (M-H)₂O+H⁺)，C₁₂H₁₀ClO₂S₂Calculated values: 284.9805,

t_R＝2.45min.¹HNMR(CDCl₃)：1.84(t，J＝5.7Hz，1H)，2.20(s，3H)，4.73(d，J.＝5.7Hz，2H)，7.49(d，J＝8.5Hz，2H)，7.84(d，J＝8.5Hz，2H)，8.18(s，1H).

the following compounds were prepared using a similar procedure:

(3-chloro-thiophen-2-yl) -methanol

Yield: 73 percent.

¹HNMR(CDCl₃)：1.92(b，1H)，4.81(s，2H)，6.91(d，J＝5.2Hz，1H)，7.25(d，J＝5.2Hz，1H).

(5-dimethylamino-benzo [ b ] thiophen-3-yl) -methanol

Yield: and 63 percent.

¹HNMR(CDCl₃)：1.62(b，1H)，3.01(s，6H)，4.89(s，2H)，6.96(dd，1H)，7.11(d，1H)，7.34(s，1H)，7.68，(d，J＝9.0Hz，1H).

(5-dimethylamino-3-methyl-benzo [ b ] thiophen-2-yl) -methanol

Yield: 56 percent.

¹HNMR(CDCl₃)：1.69(t，J＝5.9Hz，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-methoxy-thiophen-2-yl) -methanol

4-bromo-3-hydroxy-thiophene-2-carboxylic acid methyl ester (948mg, 4.00mmol), dimethyl sulfate (0.57ml, 6.0mmol) and K₂CO₃A suspension of (1.11g, 8.0mmol) in acetone (10ml) was heated at reflux for 4 h. After cooling to room temperature, water (25ml) was added. The reaction was extracted with ethyl acetate (2X 25ml), the extracts combined, dried over sodium sulphate and evaporated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20ml), the solution was cooled to 0 ℃ under a nitrogen atmosphere, and DIBAL-H (12ml, 12mmol, 1M in toluene) was added. After 2 hours, another portion of DIBAL-H (6ml, 6mmol) was added and stirring continued for 2 hours. The reaction was quenched by addition of saturated rochelle salt solution (30ml) and the mixture was stirred at room temperature for 1 hour. The phases were separated and the organic phase was extracted with ethyl acetate (2X 50ml), the combined organic phases were dried over sodium sulphate and evaporated in vacuo. The product was purified by silica gel chromatography on a FlashMaster system, heptaneThe alkyl/ethyl acetate is used as eluent (linear gradient elution is 1: 0-6: 4). The fractions containing the product were combined and evaporated in vacuo to give the desired compound (482mg, 54%).

¹H NMR(CDCl₃)：1.86(b，1H)，3.90(s，3H)，4.77(s，2H)，7.15(s，1H).

The following compounds were prepared using a similar procedure:

(6-chloro-3-methoxy-benzo [ b ] thiophen-2-yl) -methanol

Yield: 75 percent.

¹HNMR(CDCl₃)：1.92(t，J＝5.9Hz，1H)，3.99(s，3H)，4.90(d，J＝5.7Hz，2H)，7.33(dd，J＝1.9，8.5Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.73(d，J＝1.9Hz，1H).

Preparation of heteroarylaldehydes of the general formulae IIa and IIIa

4- (4-chloro-benzenesulfonyl) -3-methyl-thiophene-2-carbaldehyde

To [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-yl group]Methanol (786mg, 2.60mmol), 4-methylmorpholine N-oxide (0.46g, 3.9mmol) and pulverulentTo a suspension of molecular sieves (1.3g, activated by short heating in vacuo) in dichloromethane (7ml) was added tetrapropylammonium perruthenate (46mg, 0.13 mmol). The resulting mixture was stirred for 1 hour, then filtered through a column of silica gel (about 25g), eluting with ethyl acetate. The eluate was evaporated in vacuo and the product was subsequently purified by chromatography on silica gel on a FlashMaster system with heptane/ethyl acetate as eluent (linear gradient elution 1: 0-1: 1). The product containing fractions were combined and evaporated in vacuo to give the title compound (644mg, 82%).

¹HNMR(CDCl₃)：2.60(s，3H)，7.53(d，J＝9.0Hz，2H)，7.87(d，J＝8.5Hz，2H)，8.53(s，1H)，10.01(s，1H).

The following aldehydes were prepared using a similar procedure:

3-chloro-thiophene-2-carbaldehyde

Yield: 94 percent.

¹HNMR(CDCl₃)：7.07(d，J＝5.2Hz，1H)，7.72(d，J＝0.5，4.7Hz，1H)，10.07(d，J＝0.9Hz，1H).

4-bromo-3-methoxy-thiophene-2-carbaldehyde

Yield: 45 percent.

¹HNMR(CDCl₃)：4.18(s，3H)，7.60(d，J＝1.4Hz，1H)，10.08(d，J＝1.4Hz，1H).

6-chloro-3-methoxy-benzo [ b ] thiophene-2-carbaldehyde

Yield: 86 percent.

¹HNMR(CDCl₃)：4.34(s，3H)，7.36(dd，J＝1.7，8，7Hz，1H)，7.75(d，J＝1.4Hz，1H)，7.82(d，J＝8.5Hz，1H)，10.36(s，1H).

5-dimethylamino-benzo [ b ] thiophene-3-carbaldehyde

Yield: 72 percent.

¹HNMR(CDCl₃)：3.05(s，6H)，7.00(dd，J＝2.4，9.0Hz，1H)，7.68(d，J＝9.0Hz，1H)，7.99(d，J＝2.8Hz，1H)，8.24(s，1H)，10.11(s，1H).

5-dimethylamino-3-methyl-benzo [ b ] thiophene-2-carbaldehyde

Yield: 73 percent.

¹HNMR(CDCl₃)：2.74(s，3H)，3.03(s，6H)，7.00(d，J＝2.4Hz，1H)，7.12(dd，J＝2.4，9.0Hz，1H)，7.69(d，J＝9.0Hz，1H)，10.30(s，1H).

5-fluoro-benzofuran-3-carbaldehyde

Dimethyl sulfoxide (3.27g, 41.8rmmol) in dichloromethane (10ml) was added to a solution of oxalyl chloride (2.65g, 20.9mmol) in dichloromethane (30ml) at-60 ℃ at constant temperature, and the solution was subsequently stirred for 15 min. 1- (5-fluorobenzofuran-3-yl) methanol (3.16g, 19.0mmol) dissolved in dichloromethane (60ml) was added dropwise at-60 ℃. The mixture was stirred for 20 min, followed by addition of triethylamine (9.61g, 0.095 mmol). After stirring for 10 minutes, the reaction mixture was heated to ambient temperature and stirred for an additional 20 minutes. Washed successively with 50ml of water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give the crude title product in quantitative yield as a light brown crystalline solid.

¹H NMR(CDCl₃)：7.13(dt，1H)；7.50(dd，1H)；7.86(dd，1H)；8.30(s，1H)；10.15(s，1H).

5-fluoro-thiophene-2-carbaldehyde

To thiophene (4.8ml, 60mmol) in dry ether (200ml) was added n-tert-butyllithium (70ml, 66mmol, 0.95M in hexane) dropwise at 0 ℃ followed by stirring the solution at-5-0 ℃ for 1 hour. The temperature was subsequently adjusted to-70 ℃ and (PhSO) was added₂)₂NF (28.4g, 90mmol) in dry tetrahydrofuran (200ml) while maintaining the temperature below-50 ℃. The resulting mixture was then allowed to slowly warm to room temperature overnight, 2N NaOH (300ml) was added, the mixture was filtered, and saturated NH was added with 2N NaOH (2X 300ml)₄The organic phase was washed with Cl (300ml) and then dried over sodium sulfate. Most of the ether was distilled off using a 40cm Vickers column and finally co-distilled with heptane (50ml) to give 20.7mmol of 2-fluorothiophene and 4.6mmol of thiophene (by distillation)¹H NMR determined using 200 μ l DME as internal standard) in about 100ml tetrahydrofuran and heptane (boiling point 60-100 ℃). The solution was cooled to 0 ℃ and n-butyllithium (44ml, 41mmol, 0.95M in hexane) was added dropwise. After 1h, a solution of DMF (4.8ml, 62mmol) in diethyl ether (15ml) was added dropwise and stirring was continued at 0 ℃ for 1 h. Followed by saturationNH₄The reaction was quenched with Cl (200ml), extracted with diethyl ether (2X 200ml) and the extracts dried over sodium sulfate. Distillation (40cm Vickers) at atmospheric pressure removed most of the solvent and distillation of the dark residue under reduced pressure gave a mixture ((1.32g, 44%)) of 5-fluoro-thiophene-2-carbaldehyde and thiophene-2-carbaldehyde (boiling point: 78-79 ℃, 25mmHg) as a golden oil in a ratio of about 10: 1.

¹H NMR(CDCl₃)：6.65(d，J＝4.2，1H)，7.50(d，J＝3.8Hz，1H)，9.76(d，J＝4.2Hz，1H).

Preparation of intermediates of the formula VII

Intermediates of formula VII were prepared by the general procedure for the preparation of {4- [ (5-fluoro-benzofuran-3-ylmethyl) -amino ] -2-nitro-phenyl } -carbamic acid ethyl ester described below or by the general procedure for the preparation of N- (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) acetamide described below.

{4- [ (5-fluoro-benzofuran-3-ylmethyl) -amino ] -2-nitro-phenyl } -carbamic acid ethyl ester

5-fluoro-benzofuran-3-carbaldehyde (3.59g, 21.9mmol) and (4-amino-2-nitro-phenyl) -carbamic acid ethyl ester (4.48g, 19.9mmol) were combined in o-xylene (80ml) in a three-necked round bottom flask equipped with a Dean-Stark apparatus followed by the addition of a catalytic amount of acidic ion exchange resin (Amberlite IRC-84, 100 mg). The mixture was heated to reflux for 5 hours, filtered hot and concentrated in vacuo. The crude product was dissolved in a mixture (90ml) of dioxane and methanol (4: 1) followed by the addition of sodium borohydride (1.50g, 39.8mmol) in portions over 30 minutes. The reaction mixture was stirred at ambient temperature overnight, then poured into water (200ml) and extracted with ethyl acetate (3X 75 ml). The combined organic fractions were washed with brine, dried over magnesium sulfate and evaporated to give a crude solid which was purified by silica gel chromatography (eluent: ethyl acetate: heptane 1: 2). 4.50g (61%) of the title compound are obtained in the form of red crystals.

¹H NMR(CDCl3)：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 prepared using a similar procedure:

{4- [ (5-methyl-thiophen-2-ylmethyl) -amino ] -2-nitro-phenyl } -carbamic acid ethyl ester

Yield: 73 percent. LC/MS (m/z)336 (MH)⁺)；t_R＝3.41min。

{4- [ (3-methyl-thiophen-2-ylmethyl) -amino ] -2-nitro-phenyl } -carbamic acid ethyl ester

Yield: 89 percent. LC/MS (m/z)

{4- [ (thiophen-2-ylmethyl) -amino ] -2-nitro-phenyl } -carbamic acid ethyl ester

Yield: 71 percent. LC/MS (m/z)321 (MH)⁺)；t_R＝3.24min。

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

Yield: and 69 percent. LC/MS (m/z)320 (MH)⁺)；t_R＝3.08min。

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

Yield: 87 percent. M.p.151-152 ℃. LC-MS (m/z)371.0 (MH)⁺)，t_R＝3.59min。

N- (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) acetamide.

To a stirred suspension of {4- [2- (4-fluorophenyl) -acetylamino ] -3-nitro-phenyl } -carbamic acid tert-butyl ester (2.40g, 6.16mmol) in dichloromethane (5ml) was added trifluoroacetic acid (5 ml). After 15 minutes the dichloromethane was distilled off and the remaining solution was transferred to saturated aqueous sodium bicarbonate solution (200ml) for sonication. The precipitate was filtered, washed with water and dried in vacuo to give 1.70g of the title compound as a reddish brown solid. Yield: 96.3 percent.

LC/MS；t_R＝2.25(UV，ELSD)89％，100％.¹H NMR(DMSO-d₆)：3.59(s，2H)；5.65(b，2H，NH₂)；6.83dd，1H)；7.08(d，1H)；7.15(t，2H)，7.21(d，1H)；7.32(dd，2H)；9.91(s，1H，NH).

The following compounds were prepared using a similar procedure:

n- (4-amino-2-nitrophenyl) -3, 3-dimethylbutanamide

Yield: 680mg, 93%.

LC/MS(m/z)293.43([M+H+MeCN]⁺)；t_R＝2.29(UV，ELSD)99.5％，99.1％.¹H NMR(DMSO-d₆)：1.00(s，9H)；2.12(s，2H)；3.45(b，H₂O+NH₂)；6.84(dd，1H)；7.06(d，1H)；7.14(d，1H)；9.64(s，1H，NH).

Preparation of intermediates of formula VIII

N- {4- [ (5-chlorothien-2-ylmethyl) amino ] -2-nitrophenyl } -2- (4-fluorophenyl) acetamide

A solution of N- (4-amino-2-nitrophenyl) -2- (4-fluorophenyl) acetamide (306mg, 1.06mmol) and 5-chloro-2-thiophenecarboxaldehyde (186mg, 1.2 eq) in absolute ethanol (40ml) was heated at 70 ℃ for 30 minutes. The resulting solution was concentrated to a small volume (approximately 3ml) and quenched with heptane (15 ml). The brown crystalline product was isolated by filtration to give 350mg of the intermediate imine N- {4- [ (5-chlorothien-2-ylmethylene) amino]-2-nitrophenyl } -2- (4-fluorophenyl) acetamide. The yield was 79.2%.¹H NMR(DMSO-d₆): 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 (5ml) and NaBH was added₃CN (200mg), followed by addition of acetic acid (2 ml). The resulting solution becomes a suspension. After 15 minutes treatment with water (50ml) and filtration to isolate the productAfter drying in vacuo, 330mg of a red solid were obtained. Yield: 93.8 percent.

LC/MS(m/z)420([M+H]⁺)；t_R＝3.34(UV，ELSD)97％，100％.¹H NMR(DMSO-d₆)：3.60(s，2H)；4.45(d，2H)；6.87(t，1H，NM)；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 compounds were prepared from the corresponding anilines using a similar procedure:

n- {4- [ (5-chlorothien-2-ylmethyl) amino ] -2-nitrophenyl } -3, 3-dimethylbutanamide

The crude intermediate imine is isolated by evaporation and reduced as described above. Subsequently, the reaction mixture was evaporated to a small volume, treated with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was evaporated. The residue was dissolved in hot diisopropyl ether, precipitated with heptane and filtered.

Yield: 880mg, 87.6%.

LC/MS(m/z)382.48([M+H]⁺)；t_R＝3.46(UV，ELSD)88％，91％.¹H NMR(DMSO-d₆)：0.99(s，9H)；2.12(s，2H)；4.45(d，2H)；6.84(t，1H，NH)；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 the formula XII

{4- [2- (4-fluorophenyl) acetylamino ] -3-nitrophenyl } carbamic acid tert-butyl ester

Add tert-butyl (4-amino-3-nitrophenyl) -carbamate (1.992g, 7.87mmol) and NaHCO₃(5.4g) to a suspension in acetonitrile (20ml) was added (4-fluorophenyl) acetyl chloride (1.8ml, 1.3 eq). The resulting suspension was sonicated for 5 minutes and stirred at ambient temperature for 16 hours. The reaction was poured into water (200ml), sonicated for 5 minutes, filtered and washed with water and heptane. The obtained residueThe material was dissolved in hot ethyl acetate (30ml), saturated aqueous sodium bicarbonate solution (50ml) was added, and the resulting mixture was quenched with heptane (200 ml). The resulting suspension was sonicated for 5 minutes and then filtered. The residue was washed with water and heptane and dried in vacuo to give 2.48g of a tan solid. Yield: 80.9 percent.

LC/MS(m/z)412.54([M+Na]⁺)，453.58([M+MeCN+Na]⁺)；t_R＝3.33(UV，ELSD)97％，100％.¹H NMR(DMSO-d₆)：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，NH)，10.29(s，1H，NH).

The following compounds were prepared in a similar manner from the corresponding acid chlorides:

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

The reaction mixture was stirred at 45 ℃ for 30 minutes with an excess of tert-butylacetyl chloride (3 equivalents). The crude product was isolated after treatment with ethyl acetate-saturated aqueous sodium bicarbonate solution and then purified by flash chromatography on silica gel (50g) eluting with 10-15% ethyl acetate-heptane. Yield: 2.20g (78.6%) of a yellow solid.

LC/MS(m/z)415.58([M+MeCN+Na]⁺)；t_R＝3.31(UV，ELSD)99.5％，99.9％.¹H NMR(DMSO-d₆)：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，NH)；10.01(s，1H，NH).

Compounds of the invention

Acid addition salts of the compounds of the present invention may be conveniently prepared by methods well known to those skilled in the art.

Example 1

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

Reacting {4- [ (5-fluoro-benzofuran-3-ylmethyl) -amino]-2-Nitro-phenyl } -carbamic acid ethyl ester (4.50g, 12.1mmol) was dissolved in absolute ethanol (140ml), to which was added 6N hydrochloric acid (38ml) and iron powder (5.70g, 0.10 mol). The red mixture was heated at 60 ℃ until the vivid color disappeared (20 min). The solid was filtered off and the ethanol was removed from the filtrate by evaporation in vacuo. To the residue was added aqueous ammonia (saturated), followed by extraction with ethyl acetate (3X 100 ml). The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (eluent: ethyl acetate: heptane 1: 1) to yield 2.70g (66%) of the title compound in solid form. M.p.150-151 ℃. C₁₈H₁₈FN₃O₃Calculated values: c62.96; h5.28; n12.24, found: c63.00; h5.38; and (4) N12.13.

LC/MS(m/z)344(MH⁺)；t_R＝2.00min.¹H NMR(DMSO-d₆)：1.19(t，3H)；4.03(q，2H)；4.26(d，2H)；4.55(s，2H，NH2)；5.79(t，1H)；5.91(dd，1H)；6.02(d，1H，NH)；6.72(d，1H)；7.13(dt，1H)；7.56(m，2H)；7.95(s，1H)；8.16(b，1H，NH).

The following compounds were prepared in a similar manner and isolated in the form of their acid addition salts:

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

Ethereal hydrochloric acid was added and the crude product was precipitated from ethyl acetate to give the title compound.

M.p.190 ℃ (decomposition). C₁₅H₁₉N₃O₂S.2hcl calculated C47.00; h5.67; n10.97, found: c46.84; h5.86; n11.10.

LC/MS(m/z)306(MH⁺)；t_R＝1.77min.¹HNMR(DMSO-d₆)：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(b，1H，NH).

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

LC/MS(m/z)306(MH⁺)；t_R＝1.68min.¹HNMR(CDCl₃) (free base): 1.25(t, 3H); 2.23(s, 3H); 3.78(b, 3H); 4.13(q, 2H); 4.32(s, 2H); 6.05-6.10(m, 2H + NH); 6.82(d, 1H); 6.93(d, 1H); 7.11(d, 1H).

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

Ethereal hydrochloric acid was added and the crude product was precipitated from ethanol to give the title compound.

M.p.195℃。C₁₄H₁₇N₃O₂S.2hcl calculated: c46.16; h5.26; the content of the N11.54 is,

measured value: c46.34; h5.43; n11.28.

LC/MS(m/z)292(MH⁺)；t_R＝1.58min.¹HNMR(DMSO-d₆)：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(b，1H，NH).

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

M.p.196-197℃。C₁₄H₁₇N₃O₂S.2hcl calculated: c46.16; h5.26; n11.54, found: c46.23; h5.47; n11.30.

LC/MS(m/z)292(MH⁺)；t_R＝1.54min.¹H NMR(DMSO-d₆)：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(b，1H，NM).

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

M.p.213-214℃。C₁₈H₂₁N₃C1₂O₂S calculated value: c51.68; h4.95; n10.05, found: c51.88; h5.35; and (9) N9.95.

LC/MS(m/z)342.2(M+H⁺)；t_R＝2.08min.¹HNMR(DMSO-d₆)：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(b，1H，NH).

Example 2

2a (2-amino-4- { [4- (4-chloro-benzenesulfonyl) -3-methyl-thiophen-2-yl-methyl ] -amino } -phenyl) -carbamic acid ethyl ester

A suspension of 4- (4-chloro-benzenesulfonyl) -3-methyl-thiophene-2-carbaldehyde (301mg, 1.00mmol) and (4-amino-2-nitro-phenyl) -carbamic acid ethyl ester (293mg, 1.30mmol) in absolute ethanol (10ml) was heated at reflux for 20 hours under a nitrogen atmosphere. After cooling, the formed orange to red solid imine was collected by filtration and dried in vacuo to give the crude product (312mg, 61%) which was suspended in a methanol-acetic acid mixture (10ml, methanol: acetic acid 10: 1). Adding NaBH₃CN (0.19g, 3.0mmol), and the mixture was then stirred at room temperature for 1 hour. Adding another portion of NaBH₃CN (0.19g, 3.0mmol), stirred for an additional 1h, and added saturated aqueous sodium bicarbonate solution (20 ml). The red solid formed was collected by filtrationAmine, and dried in vacuo to give a crude product (293mg, 94%), which was suspended in anhydrous ethanol (10 ml). 6N HCl (1.1ml, 6.6mmol) and iron powder (193mg, 3.46mmol) were added thereto, and the red mixture was then heated to 60 ℃ until the red color faded yellow, which took approximately 10-20 minutes. The mixture was poured into saturated sodium bicarbonate solution (50ml) and ethyl acetate (50ml), the resulting mixture was filtered, the phases were separated and the aqueous phase was extracted again with ethyl acetate (2X 50 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo. The product was purified by chromatography on silica gel on a FlashMaster system using a heptane/ethyl acetate eluent (linear gradient elution, usually 8: 2 to 1: 1). The product-containing fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (213mg, 78%). LC-MS: (M/z) ═ 480.1(M + H)⁺)，C₂₁H₂₃ClN₃O₄S₂Calculated values: 480.0813, t_R2.35min, 72.4% UV purity and 86.5% ELS purity.

¹HNMR(DMSO-d₆)：1.19(b，3H)，2.16(s，3H)，4.02(q，J＝6.9Hz，2H)，4.23(d，J＝6.1Hz，2H)，4.57(s，2H)，5.81(dd，J＝2.4，8.5Hz，1H)，5.91-5.95(m，2H)，6.72(broad d，J＝6.6Hz，1H)，7.72(d，J＝8.5Hz，2H)，7.90(d，J＝8.5Hz，2H)，8.15(b，1H)，8.31(s，1H).

The following compounds were prepared using a similar procedure:

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

Yield: 76 percent. LC-MS: (M/z) ═ 326.0(M + H)⁺)，C₁₄H₁₇ClN₃O₂S calculated value: 326.0725, t_R1.95min, 85.8% of UV purity and 98.1% of ELS purity.

¹H NMR(DMSO-d₆)：1.19(b，3H)，4.03(q，J＝7.1Hz，2H)，4.30(d，J＝6.1Hz，2H)，4.57(s，2H)，5.83(dd，J＝2.4，8.5Hz，1H)，5.93-5.97(m，2H)，6.73(broad d，J＝7.1Hz，1H)，6.99(d，J＝5.2Hz，1H)，7.48(d，J＝5.2Hz，1H)，8.16(b，1H).

2c { 2-amino-4- [ (4-bromo-3-methoxy-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester

Yield: 66 percent. LC-MS: (M/z) ═ 402.0(M + H)⁺)，C₁₅H₁₉BrN₃O₃S calculated value: 400.0325 (100%), 402.0310 (97.3%), t_R1.97min, 87.9% UV purity and 98.2% ELS purity.

¹HNMR(DMSO-d₆)：1.20(b，3H)，3.83(s，3H)，4.03(q，J＝6.9Hz，2H)，4.32(d，J＝6.1Hz，2H)，4.58(s，2H)，5.84-5.89(m，2H)，5.97(d，J＝2.4Hz，1H)，6.74(b，1H)，7.46(s，1H)，8.17(b，1.H).

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

Yield: 60 percent. LC-MS: (M/z) ═ 405.3(M + H)⁺)，C₁₉H₂₁ClN₃O₃S calculated value: 406.0987, t_R2.39min, 95.0% UV purity and 99.6% ELS purity.

¹H NMR(DMSO-d₆)：1.19(b，3H)，3.95(s，3H)，4.02(q，J＝7.1Hz，2H)，4.43(d，J＝6.1Hz，2H)，4.56(s，2H)，5.90(dd，J＝2.4，8.5Hz，1H)，5.96(t，J＝5.9Hz，1H)，6.00(d，J＝2.8Hz，1H)，6.73(broad d，J＝6.6Hz，1H)，7.39(dd，J＝1.9，8.5Hz，1H)，7.68(d，J＝8.5Hz，1H)，7.98(d，J＝1.9Hz，1H)，8.15(b，1H).

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

Yield: 13 percent. LC-MS: (M/z) ═ 385.0(M + H, C)₂₀H₂₅N₄O₂S calculated value: 385.1693 tR 1.29min, the UV purity was 87.8% and the ELS purity was 93.5%.

¹HNMR(DMSO-d₆)：1.19(b，3H)，2.94(s，6H)，4.02(q，J＝6.9Hz，2H)，4.34(d，J＝5.7Hz，2H)，4.53(s，2H)，5.81(t，J＝5.9Hz，1H)，5.93(dd，J＝2.4，8.5Hz，1H)，6.03(d，J＝2.4Hz，1H)，6.72(b，1H)，6.95(dd，J＝2.4，9.0Hz，1H)，7.08(d，J＝2.4Hz，1H)，7.38(s，1H)，7.71(d，J＝8.5Hz，1H)，8.15(b，1H).

2f { 2-amino-4- [ (5-dimethyl-amino-3-methyl-benzo [ b ] thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester

Yield: 36 percent. LC-MS: (M/z) ═ 399.2(M + H)⁺)，C₂₁H₂₇N₄O₂S calculated value: 399.1849, t_R1.31min, 98.4% UV purity and 99.4% ELS purity.

¹H NMR(DMSO-d₆)：1.19(b，3H)，2.33(s，3H)，2.93(s，6H)，4.02(q，J＝6.9Hz，2H)，4.37(d，J＝5.7Hz，2H)，4.54(s，2H)，5.86(dd，J＝2.4，8.5Hz，1H)，5.89(t.J＝6.6Hz，1H)，5.96(d，J＝2.4Hz，1H)，6.71(b，1H)，6.84-6.89(m，2H)，7.58(d，J＝8.5Hz，1H)，8.16(b，1H).

Example 3

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

A mixture of 5-methyl-2-thiophenecarboxaldehyde (108. mu.L, 1.00mmol), (4-amino-2-nitro-phenyl) -carbamic acid ethyl ester (225mg, 1.00mmol) and Amberlite eIRC-84(10mg) in o-xylene (4ml) was heated at reflux under an argon atmosphere for 5 hours. The volatiles were removed by evaporation in vacuo and the residue was subsequently dissolved in acetonitrile (5 ml). Adding NaBH to the resulting solution₃CN (0.25g, 4.0mmol), followed by the addition of HOAc (5 drops). After stirring for 5 minutes, the solution turned dark red. Formaldehyde (37% aqueous solution, 0.89ml, 12mmol) was added and stirring continued for 30 minHOAc was added when not needed. The mixture was evaporated to dryness in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate (50ml) and ethyl acetate (50 ml). The aqueous phase was extracted with ethyl acetate (50ml), the combined organic layers were dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was then dissolved in ethanol (10 ml). 6N hydrochloric acid (2.0ml, 12mmol) and iron powder (0.34g, 6.0mmol) were added and the red mixture was subsequently heated at 60 ℃ until the red discoloured to yellow, approximately 15 minutes. The mixture was poured into saturated aqueous sodium bicarbonate (50ml) and ethyl acetate (50ml), the resulting mixture was filtered, the phases separated and the aqueous phase extracted with ethyl acetate (2X 50 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo. The product was purified by chromatography on silica gel on a FlashMaster system using a heptane/ethyl acetate eluent (linear gradient elution, usually 8: 2 to 1: 1). The product-containing fractions were combined and evaporated in vacuo to give the title compound as a pale yellow solid (145mg, 45% total). LC-MS: (M/z) ═ 319.9(M + H)⁺)，C₁₆H₂₂N₃O₂S calculated value: 320.1427, t_R1.80min, 98.4% UV purity and 97.2% ELS purity.

¹HNMR(CDCl₃)：1.29(t，J＝7.1，3H)，2.41(s，3H)，2.91(s，3H)，3.76(b，2H)，4.19(q，J＝7.1Hz，2H)，4.52(s，2H)，6.02(b，1H)，6.17(d，J＝2.8Hz，1H)，6.25(dd，J＝2.8，8.5Hz，1H)，6.53-6.58(m，1H)，6.66(d，J＝3.3Hz，1H)，6.98(d，J＝8.5Hz，1H).

The following compounds were prepared analogously:

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

Yield: 34 percent. LC-MS: (M/z) ═ 340.0(M + H)⁺)，C₁₅H₁₉ClN₃O₂S calculated value: 340.0881, t_R2.14min, 82.3% UV purity and 90.2% ELS purity.

¹HNMR(CDCl₃)：1.29(t，J＝6.8，3H)，2.91(s，3H)，3.78(b，2H)，4.20(q，J＝7.2Hz，2H)，4.49(s，2H)，6.05(b，1H)，6.16(d，J＝2.4Hz，1H)，6.24(dd，J＝2.4，8.5Hz，1H)，6.73(d，J＝3.8Hz，1H)，6.99(d，J＝8.5Hz，1H).

The following compounds were prepared analogously, except that acetaldehyde was used instead of formaldehyde:

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

Yield: 12 percent. LC-MS: 353.9 parts (M + H) = (M/z)⁺)，C₁₆H₂₁ClN₃O₂S calculated value: 354.1038, t_R2.02min, 97.5% UV purity and 99.0% ELS purity.

¹H NMR(CDCl₃)：1.16(t，J＝7.1，3H)，1.29(t，J＝6.8，3H)，3.36(q，J＝7.1Hz，2H)，3.76(b，2H)，4.19(q，J＝7.2Hz，2H)，4.47(s，2H)，6.05(b，1H)，6.13(d，J＝2.4Hz，1H)，6.19(dd，J＝2.4，9.0Hz，1H)，6.73(d，J＝3.8Hz，1H)，6.96(d，J＝8.0Hz，1H).

The following compounds were prepared similarly except that no formaldehyde addition was performed.

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

Yield: 65% (25% after preparative LC-MS purification to remove non-fluorinated by-products).

LC-MS：(m/z)＝310.2(M+H⁺)，C₁₄H₁₇FN₃O₂S calculated value: 310.1020, t_R1.76min, 96.6% UV purity and 83.4% ELS purity.

¹H NMR(CDCl₃)：1.29(b，3H)，3.82(b，2H)，4.19(q，J＝7.2Hz，2H)，4.31(d，J＝2.0Hz，2H)，6.05(b，1H)，6.09(d，J＝8.0Hz，1H)，6.29(dd，J＝1.5，3.8Hz，1H)，6.58(t，J＝3.5Hz，1H)，6.94(d，J＝8.0Hz，1H).

Example 4

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

A solution of 5-chlorothiophene-2-carbaldehyde (240. mu.L, 111. mu. mol, 463mM) in 1, 2-dichloroethane was added to a solution of 4-amino-2-nitrophenylurethane (240. mu.L, 111. mu. mol, 463mM) in 1, 2-dichloroethane. Sodium triacetoxyborohydride (118mg, 555. mu. mol) was added, and then the resulting mixture was stirred at 40 ℃ for 3.5 hours. The mixture was allowed to cool to ambient temperature and water (100 μ L) was added. The mixture was filtered through silica gel (500mg), and the column was washed with 1, 2-dichloroethane (3 ml). The combined organic phases were evaporated to dryness under vacuum. The resulting solid was dissolved in ethanol (3 ml). Iron (19mg) was added to one third of the resulting solution (1ml) followed by an aqueous solution of hydrochloric acid (96 μ L, 6M). The mixture was placed in an ultrasonic bath for 10 minutes. Subsequently, saturated aqueous sodium bicarbonate (2ml) was added. The mixture was extracted with ethyl acetate (3 ml). The organic phase was washed with water (3ml) and brine (3ml), dried over magnesium sulphate, filtered and evaporated to dryness in vacuo. The resulting product was dissolved in 190 μ L of dimethyl sulfoxide and subjected to preparative LC-MS purification. The resulting solution was evaporated to dryness in vacuo. Yield (6.8mg, 56%). LC-MS (M/z) (M + H)⁺326.1；RT＝1.90；(UV，ELSD)92％，99％。

The following compounds were prepared using a similar method:

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

LC-MS(m/z)(M+H)⁺371.9；RT＝1.94；(UV，ELSD)89％，98％。

4c { 2-amino-4- [ (4-bromo-thiophen-2-ylmethyl) -amino ] -phenyl } -carbamic acid ethyl ester

LC-MS(m/z)(M+H)⁺372.0；RT＝1.96；(UV，ELSD)76％，100％。

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

LC-MS(m/z)(M+H)⁺320.1；RT＝1.90；(UV，ELSD)72％，96％。

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

LC-MS(m/z)(M+H)⁺342.1；RT＝2.06；(UV，ELSD)75％，100％。

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

LC-MS(m/z)(M+H)⁺368.2；RT＝2.21；(UV，ELSD)90％，99％。

Example 5

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

A benzene ring [ b ]]Thiophene-2-carbaldehyde (1.36g, 8.38mmol) was added to a solution of (4-amino-2-nitro-phenyl) -carbamic acid propyl ester (2.00g, 8.36mmol) in acetonitrile (10 ml). The mixture was heated to 160 ℃ for 2 minutes in a20 ml sealed microwave treated vial. Once cooled, NaBH was added₃CN (1.06g, 16.7mmol) and acetic acid (48. mu.L, 0.84mmol) and the mixture was stirred at 25 ℃ for 30 min. Water/brine (1: 1, 100ml) was added and the mixture was extracted with ethyl acetate (3X 100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude intermediate is purified by flash chromatography on silica gel (eluent: ethyl acetate: heptane 1: 9) and evaporated to dryness. The intermediate was then dissolved in tetrahydrofuran (20ml) and Na was added₂S₂O₄(3.67g, 21mmol) in water (50 ml). The resulting mixture was stirred at 40 ℃ for 5 hours under an argon atmosphere. The resulting mixture was extracted with ethyl acetate (3 × 100ml), and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (eluent: B)Ethyl acetate: heptane 1: 1) to yield 0.3g (10%) of the title compound as a solid.

LC/MS(m/z)356([M+H]⁺)；RT＝2.45min。

¹HNMR(CDCl₃)：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 compounds were prepared in a similar manner:

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

Yield: 16 percent. LC/MS (M/z)356([ M + H)]⁺)；RT＝2.24min。

¹H NMR(CDCl₃)：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 N- { 2-amino-4- [ (5-chlorothien-2-ylmethyl) -amino ] -phenyl } -2- (4-fluorophenyl) -acetamide

N- {4- [ (5-chlorothien-2-ylmethyl) amino group stirred in portions periodically over 30 minutes]-2-Nitrophenyl } -2- (4-fluorophenyl) acetamide (320mg, 0.762mmol) in tetrahydrofuran (25ml) and acetic acid (8ml) was added zinc dust (particle size < 10 μm, 10 g). After 5 minutes, the solution became colorless. The resulting colorless suspension was filtered through a plug of silica gel (10g) and ethyl acetate was used as eluent, after which the resulting solution was evaporated in vacuo. The resulting solid was dissolved in ethyl acetate/acetone/trifluoroacetic acid (3ml/3ml/0.2ml) and treated with saturated aqueous sodium bicarbonate (50ml) and heptane (30ml) and the product isolated by filtration as a light grey solid 280 mg. Yield: 94.2 percent. LC/MS (M/z)390.4([ M + H)]⁺)；RT＝2.26；(UV，ELSD)99％，100％。

¹HNMR(DMSO-d₆)：3.56(s，2H)；4.28(d，2H)；4.57(s，2H，NH₂)；5.87(dd，1H)；5.98(m，2H，NH 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(s，1H).

The following compounds were prepared analogously from the corresponding nitro compounds:

6b N- { 2-amino-4- [ (5-chlorothien-2-ylmethyl) amino ] phenyl } -3, 3-dimethylbutanamide

Through SiO₂After filtration and evaporation, the product was precipitated from a biphasic solution of ethyl acetate-saturated aqueous sodium bicarbonate (5ml/20ml) and heptane (50ml), yield: 580mg, 71.5%. LC/MS (M/z)352.48([ M + H)]⁺)；RT＝2.16；(UV，ELSD)96％，99％。

¹H NMR (DMSO-d₆)：1.01(s，9H)，2.11(s，2H)；4.29(d，2H)；4.54(s，2H，NH₂)；5.88(dd，1H)；5.97(t，1H，NH)；5.99(d，1H)；6.72(d，1H)；6.87(d，1H)；6.93(d，1H)；8.82(s，1H).

In vivo and in vitro assays

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

relative flow through KCNQ2 channel

Cells stably expressing a voltage-gated KCNQ2 channel were inoculated the day before the test, and loaded⁸⁶Rb]. On the day of the assay, the cells were washed with HBSS-containing buffer. The cells are pre-cultured with the drug and stimulated with a submaximal concentration of 15mM KCl in the continued presence of the drug⁸⁶Rb⁺]. After a suitable incubation time, the supernatant was removed and counted in a liquid scintillation counter (Tricarb). The cells were lysed with 2mM NaOH and counted⁸⁶Amount of Rb +. ComputingRelative flow rates:

((CPM_suoer/CPM_super+CPM_cell)C_mpd/(CPM_suoer/CPM_super+CPM_cell)_15mMKCl)*100-100。

EC of the Compounds of the invention₅₀Less than 20000nM, in most cases less than 2000nM, and in most cases less than 200 nM. Accordingly, the compounds of the present invention are believed to be useful in the treatment of diseases associated with the KCNQ family of potassium channels.

Maximum electric shock

The experiment was performed on each male mouse group using a corneal electrode (comeal electrode) and in order to induce Epilepsy characterized by tonic extension of the hind limbs, a square wave current of 26mA was used for 0.4 seconds (Wlaz et al, Epilepsy Research 1998, 30, 219-229).

Pilocarpine-induced epilepsy

Pilocarpine-induced epilepsy was induced by intraperitoneal injection of 250mg/kg of pilocarpine into a group of male mice, and seizure events leading to a loss of state within 30 minutes were observed. (Starr et al, Pharmacology Biochemistry and Behavior 1993, 45, 321-

Electric epilepsy threshold test

The median threshold for inducing hind limb tonic extension in male mouse groups in response to corneal shocks was determined using a modified method of up-and-down (Kimball et al, Radiationresearch 1957, 1-12) approach. The first mouse of each group was given a shock of 14mA (0.4s, 50Hz) and observed for seizures. If the appearance of epilepsy was observed, the current used in the next mouse was reduced by 1mA, but if no appearance of epilepsy was observed, the current was increased by 1 mA.

This procedure was repeated for 15 mice of this treatment group.

Chemical epilepsy threshold test

The threshold dose of pentamtetrazine required to induce clonic convulsions was determined by timed intravenous injection of pentamtetrazine (5mg/mL, 0.5mL/min) into the caudal side of male mice (Nutt et al, J.Pharmacy and Pharmacology 1986, 38, 697-698).

Almond kernel ignition induction

The rat is operated, and a tripolar electrode is implanted in the amygdala on the back and the outside. After surgery, the animals were allowed to recover and various doses of test compound or drug carrier were given to the rat groups. Stimulation was performed daily with an initial post-discharge threshold of +25 μ Α for 3-5 weeks, and seizure severity, duration of epilepsy and duration of post-discharge current were recorded in each case (racine. electronegativity and Clinical neurology 1972, 32, 281- "294").

Side effects

Central nervous system side effects were measured by the time mice stayed on a rotarod (rotarod) device (Capacio et al, Drug and Chemical biology 1992, 15, 177-; or by counting the number of beams of infrared light passing through the test cage (Watson et al, Neuropharmacology 1997, 36, 1369-. The cooling behaviour of the compound on the temperature of the animal subject is measured by a rectal thermometer or an implanted radio remote sensor capable of measuring the temperature. (Keeney et al, Physiology and Behavviour 2001, 74, 177-.

Pharmacokinetics

Pharmacokinetic properties were determined by intravenous and oral administration of the compounds to Spraque Dawley rats, and blood samples were then drawn after 20 hours.

Plasma concentrations were determined by LC/MS/MS.

Claims

1. A 1, 2, 4-triaminobenzene derivative of formula I or a pharmaceutically acceptable salt thereof:

wherein:

R¹selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, hydroxy-C_1-6-alkyl, hydroxy-C_2-6-alkenyl, hydroxy-C_2-6-alkynyl, hydroxy-C_3-8-cycloalkyl and hydroxy-C_3-8-a cycloalkenyl group;

R²and R²' independently selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, hydroxy-C_1-6-alkyl, hydroxy-C_2-6-alkenyl, hydroxy-C_2-6-alkynyl, hydroxy-C_3-8-cycloalkyl and hydroxy-C_3-8-a cycloalkenyl group;

R³selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8Cycloalkenyl, aryl, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, aryl-C_1-6Alkyl, aryl-C_2-6-alkenyl, aryl-C_2-6-alkynyl, hydroxy-C_1-6-alkyl, hydroxy-C_2-6-alkenyl, hydroxy-C_2-6-alkynyl, aryl-C_3-8-cycloalkyl, aryl-C_3-8-cycloalkenyl radical, NR¹⁰R¹⁰’-C_1-6Alkyl, NR¹⁰R¹⁰’-C_2-6-alkenyl, NR¹⁰R¹⁰’-C_2-6-alkynyl, NR¹⁰R¹⁰’-C_3-8-cycloalkyl, NR¹⁰R¹⁰’-C_3-8Cycloalkenyl, hydroxy-C_3-8-cycloalkyl and hydroxy-C_3-8-a cycloalkenyl group; wherein:

R¹⁰and R¹⁰' independently selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6Alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, hydroxy-C_1-6-alkyl, hydroxy-C_2-6-alkenyl, hydroxy-C_2-6-alkynyl, hydroxy-C_3-8-cycloalkyl, hydroxy-C_3-8Cycloalkenyl, hydroxy-C_3-8-cycloalkyl-C_1-6-alkyl, hydroxy-C_3-8-cycloalkyl-C_2-6-alkenyl, hydroxy-C_3-8-cycloalkyl-C_2-6-alkynyl, hydroxy-C_3-8-cycloalkenyl-C_1-6-alkyl, hydroxy-C_3-8-cycloalkenyl-C_2-6-alkenyl, hydroxy-C_3-8-cycloalkenyl-C_2-6-alkynyl, halo-C_1-6-alkyl, halo-C_2-6-alkenyl, halo-C_2-6-alkynyl, halo-C_3-8-cycloalkyl, halo-C_3-8Cycloalkenyl, halo-C_3-8-cycloalkyl-C_1-6-alkyl, halo-C_3-8-cycloalkyl-C_2-6-alkenyl, halo-C_3-8-cycloalkyl-C_2-6-alkynyl, halo-C_3-8-cycloalkenyl-C_1-6-alkyl, halo-C_3-8-cycloalkenyl-C_2-6-alkenyl, halo-C_3-8-cycloalkenyl-C_2-6-alkynyl, cyano-C_1-6-alkyl, cyano-C_2-6-alkenyl, cyano-C_2-6-alkynyl, cyano-C_3-8-cycloalkyl, cyano-C_3-8Cycloalkenyl, cyano-C_3-8-cycloalkyl-C_1-6-alkyl, cyano-C_3-8-cycloalkyl radical-C_2-6-alkenyl, cyano-C_3-8-cycloalkyl-C_2-6-alkynyl, cyano-C_3-8-cycloalkenyl-C_1-6-alkyl, cyano-C_3-8-cycloalkenyl-C_2-6-alkenyl, and cyano-C_3-8-cycloalkenyl-C_2-6-alkynyl, or

x is CO or SO₂；

Z is O or NR⁴Wherein:

R⁴selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, hydroxy-C_1-6-alkyl, hydroxy-C_2-6-alkenyl, hydroxy-C_2-6-alkynyl, hydroxy-C_3-8-cycloalkyl and hydroxy-C_3-8-a cycloalkenyl group; or

R³And R⁴Together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring optionally containing 1, 2 or 3 further heteroatoms, said ring being substituted by R³And R⁴And the nitrogen atom is optionally substituted by one or more groups independently selected from C_1-6Alkyl radical, C_2-6-alkenyl and C_2-6-substituent substitution of alkynyl;

q is 0 or 1;

and is

Y represents a heteroaryl group of formula II or III:

wherein:

w is O or S;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

p is 0 or 1; and is

R⁵Each independently selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8Cycloalkenyl, aryl, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, halogen, halo-C_1-6-alkyl, halo-C_2-6-alkenyl, halo-C_2-6-alkynyl, C_1-6-alkyloxy, C_2-6-alkenyloxy, C_2-6-alkynyloxy, -CO-NR⁶R⁶', cyano, nitro, -NR⁷R⁷’、-S-R⁸、-SO₂R⁸And SO₂OR⁸；

Wherein:

R⁶and R⁶' independently selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl and C_3-8-cycloalkenyl-C_2-6-an alkynyl group;

R⁷and R⁷' independently selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenesRadical and C_3-8-cycloalkenyl-C_2-6-an alkynyl group; and is

R⁸Is selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl, C_3-8-cycloalkenyl-C_2-6-alkynyl, aryl and-NR⁹R⁹'; wherein:

R⁹and R⁹' independently selected from hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl, C_3-8-cycloalkenyl radical, C_3-8-cycloalkyl-C_1-6Alkyl radical, C_3-8-cycloalkyl-C_2-6-alkenyl, C_3-8-cycloalkyl-C_2-6-alkynyl, C_3-8-cycloalkenyl-C_1-6Alkyl radical, C_3-8-cycloalkenyl-C_2-6-alkenyl and C_3-8-cycloalkenyl-C_2-6-an alkynyl group;

wherein said aryl is phenyl optionally substituted with one or more substituents independently selected from hydroxy, halogen, C_1-6Alkyl radical, C_2-6-alkenyl and C_2-6-substituent substitution of alkynyl.

2. The compound of claim 1, wherein R¹Selected from hydrogen and C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl.

3. A compound according to any one of claims 1 and 2, wherein the substituent R²And R²At least one of them is a hydrogen atom.

4. The compound of claim 3, wherein R²And R²' are both hydrogen atoms.

5. The compound of any one of claims 1-2, wherein X is CO.

6. The compound of any one of claims 1-2, wherein q is 0.

7. The compound of any one of claims 1-2, wherein q is 1 and Z is an oxygen atom.

8. The compound of any one of claims 1-2, wherein R³Is selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, aryl-C_1-6Alkyl, aryl-C_2-6-alkenyl, aryl-C_2-6-alkynyl, wherein said aryl is as defined in claim 1.

9. The compound of claim 8, wherein R³Is C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl.

10. The compound of claim 8, wherein R³Is aryl-C_1-6Alkyl, aryl-C_2-6-alkenyl, aryl-C_2-6-alkynyl, wherein said aryl is as defined in claim 1.

11. The compound of any one of claims 1-2, wherein W is an oxygen atom.

12. A compound according to any one of claims 1-2, wherein W is a sulfur atom.

13. The compound of any one of claims 1-2, wherein Y is formula II.

14. The compound of any one of claims 1-2, wherein Y is formula III.

15. The compound of any one of claims 1-2, wherein Y is of formula lib or IIIb:

wherein W, m, n, p and R⁵As defined above.

16. The compound of any one of claims 1-2, wherein Y is of formula IIc or IIIc:

wherein W, m, n, p and R⁵As defined above.

17. The compound of any one of claims 1-2, wherein R⁵Each independently selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, aryl, halogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyloxy, -NR⁷R⁷’、-SO₂R⁸Wherein said aryl group is as defined in claim 1.

18. The compound of any one of claims 1-2, selected from the following compounds, or a pharmaceutically acceptable salt thereof:

n- { 2-amino-4- [ (5-chloro-thiophen-2-ylmethyl) amino ] -phenyl } -3, 3-dimethyl-butyramide.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-18 and one or more pharmaceutically acceptable carriers or diluents.

20. Use of a compound according to any one of claims 1 to 19 for the preparation of a pharmaceutical preparation for the prevention, treatment and/or inhibition of central nervous system disorders.

21. Use according to claim 20, characterized in that the disorders of the central nervous system are selected from seizure disorders.

22. Use according to claim 21, characterized in that the seizure disorder is convulsions, epilepsy or status epilepticus.

23. Use according to claim 20, characterized in that the disorders of the central nervous system are selected from the group consisting of neuralgia and migraine.

24. Use according to claim 23, characterized in that the neuropathic pain and migraine are allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy or neuropathic pain associated with migraine.

25. Use according to claim 20, characterized in that the central nervous system disorder is selected from anxiety disorders.

26. Use according to claim 25, characterized in that the anxiety disorder is anxiety, generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, behavioral anxiety, post-traumatic stress disorder, acute stress response, regulatory disorders, hypochondriasis, separation anxiety disorder, agoraphobia, specific phobias, anxiety disorder resulting from a general health condition or substance-induced anxiety disorder.

27. Use according to claim 20, characterized in that the disorders of the central nervous system are selected from neurodegenerative disorders.

28. Use according to claim 27, characterized in that the neurodegenerative disease is alzheimer's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-induced encephalopathy and other neurodegenerative diseases caused by infections with rubella virus, herpes virus, borrelia and other unknown pathogens, creutzfeldt-jakob disease, parkinson's disease or trauma.

29. Use according to claim 20, characterized in that the disorders of the central nervous system are selected from the group consisting of hyperexcitable states.

30. Use according to claim 29, characterized in that the neuronal hyperexcitability state is a neuronal hyperexcitability state during drug abstinence or due to intoxication.