Quinolone derivatives and pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

 

The present invention relates to quinolone derivative and pharmaceutical compositions.

The level of technology

Parkinson's disease is a chronic, progressive neurodegenerative disease that usually develops after middle age. Primary symptoms include unilateral tremor at rest, akineziyu and rigidity. Tremor, akineziyu and rigidity referred to as the three main symptoms of Parkinson's disease, and the cause of each is the selective death of dopaminergic neurons projecting itself from the black substance in the striatum. The etiology of this disease is still unknown, however, the collected data suggest that neurodegenerative disorder runs weakened power generating system coupled with abnormal mitochondrial function nigrostriatum dopaminergic neurons. It is assumed that mitochondrial dysfunction subsequently causes oxidative stress and deficiency of calcium homeostasis, leading, thus, to neurodegeneration (Ann. N. Y. Acad. Sci. 991:111-119(2003)).

Methods of treating Parkinson's disease approximately divided into therapeutic tactics (drug therapy) and surgical approach (stereotactic surgery). Among them drug therapy is an established therapy is considered to be the main type of treatment. In drug therapy to compensate nigrostriatal dopaminergic neuronal function, as amended by Parkinson's disease, symptomatic used therapeutic agent. The most excellent therapeutic properties shows levodopa. They say that no agent is superior to l-DOPA efficacy. Currently, levodopa is used in conjunction with inhibitor dofadekarboksilazy to prevent its metabolism in the periphery, and received the desired clinical effects.

However, one disadvantage of treatment with levodopa is that after several years of treatment reducing the duration and stability of the effectiveness of this drug leads to recurrent musculoskeletal disorders, such as dyskinesia and daily fluctuations. In addition, a cause of concern were side effects from the digestive system, such as nausea and vomiting caused by excessive release of dopamine, problems with blood supply of organs, such as orthostatic hypotension, tachycardia and arrhythmia, and neurological symptoms, such as hallucinations, delusions and otvlekaemost.

Thus, to reduce the dosage of the drug levodopa and, due to this, reduce side effects, use combination drug therapy, in which COI the box is used the combination of agonists of dopamine receptors, inhibitors of the enzyme dopamine metabolism, relizer dopamine, anticholinergic agents Central action and so on. Such therapeutic achievements remarkably improve the forecasts, however, even at the present time there are no fundamental methods of treating Parkinson's disease and other neurodegenerative diseases. Medications must be taken throughout the remaining life of the patient, and the above-mentioned disadvantages of low efficiency during long-term administration, side-effects and uncontrolled progression of the disease can occur because of monotherapy with levodopa. In addition, even when using combination drug therapy is difficult to expect impressive results.

Description of the invention

The purpose of the present invention is to provide a new compound which has a functional improving effect and suppresses neurological dysfunction due to chronic inhibition of progression of Parkinson's disease or protect dopamine neurons from this disease etiology, increasing, thus, the amount of time that elapses before the first introduction of levodopa.

The authors of the present invention conducted a thorough investigation to achieve the above goals and is the result they managed to get the connection represented by the following General formula (1), which includes the protection and enhancement of mitochondrial functional activity, and the protection and restoration of the activity of neurons. The present invention was completed based on the aforementioned videolooking data.

In the present invention provided quinolone derivative, pharmaceutical composition containing the specified connection, use the specified connection, the method of treating or preventing disorders, and the method of obtaining the compounds described in the following paragraphs 1 through 11.

Paragraph 1. Derived quinolone represented by the General formula (1)

or its salt,

in which R1represents a hydrogen atom, a lower alkyl group, cyclo3-8alkyl lower alkyl group or lower alkoxy lower alkyl group;

R2represents a hydrogen atom, a lower alkyl group or halogen-substituted lower alkyl group;

R3represents a phenyl group, follow group, thienyl group or pyridyloxy group, with each of these groups optionally substituted by one or more groups selected from the group consisting of the following (1) through (16) in the aromatic or heterocyclic ring represented by the above is th R 3;

(1) lower alkyl groups,

(2) a lower alkoxy group,

(3) halogen-substituted lower alkoxy group;

(4) phenoxy-group

(5) lower alkylthio-group

(6) a hydroxy group,

(7) hydroxy lower alkyl group,

(8) the atoms of halogen,

(9) lower alcoholnye group,

(10) lower alkoxycarbonyl group,

(11) amino group, optionally substituted by one or more lower alkyl groups,

(12) carbamoyl group, optionally substituted by one or more lower alkyl groups,

(13) cyclo3-8alkyl lower alkoxy group,

(14) pyrrolidinylcarbonyl group,

(15) morpholinylcarbonyl group and

(16) carboxyl group;

R4represents a halogen atom;

R5represents a hydrogen atom or a halogen atom;

R6represents a hydrogen atom; and

R7is any of the following groups (1) through (15):

(1) hydroxy group,

(2) a halogen atom,

(3) a lower alkoxy group,

(4) halogen-substituted lower alkoxy group,

(5) hydroxy lower alkoxy group,

(6) a lower alkoxy lower alkoxy group,

(7) an amino group optionally substituted by one or more members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl group, cyclo3-8alkyl GRU is p,

(8) amino lower alkoxy group, optionally substituted on the amino group by one or more members selected from the group consisting of lower alkyl groups, lower alkanoyl groups, lower alkylsulfonyl groups and carbamoyl groups, optionally substituted by one or more lower alkyl groups,

(9) cyclo3-8alkoxy group,

(10) cyclo3-8alkyl lower alkoxy group,

(11) tetrahydrofuryl lower alkoxy group,

(12) lower alkylthio-group

(13) a heterocyclic group selected from the group consisting of morpholinyl groups, pyrrolidinyl groups, fueling groups, thienyl groups, and benzothiazoline groups,

(14) a phenyl lower alkoxy lower alkoxy group, and

(15) pyrrolidinylcarbonyl group.

Paragraph 2. Derived quinolone General formula (1) or its salt according to claim 1,

in which R1represents a hydrogen atom or a lower alkyl group;

R2represents a hydrogen atom or a lower alkyl group;

R3represents a phenyl group or pyridyloxy group, with each of these groups optionally substituted with one or two groups selected from the group consisting of the following from(1), (2), (6) and (8) in the aromatic or heterocyclic ring represented by the above R3:

(1) lower alkyl groups,

(2) Nissi the alkoxy group,

(6) hydroxy group, and

(8) the atoms of halogen,

R4represents a halogen atom;

R5represents a hydrogen atom;

R6represents a hydrogen atom; and

R7is any of the following groups (3), (4) and (7):

(3) a lower alkoxy group,

(4) halogen-substituted lower alkoxy group, and

(7) an amino group optionally substituted by one or two lower alkyl groups.

Item 3. Derived quinolone General formula (1) or its salt according to claim 2, selected from the group consisting of:

5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinoline-4-one,

5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinoline-4-one,

3-(2,4-acid)-5-fluoro-8-propoxy-1H-quinoline-4-one,

5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinoline-4-one,

3-(2,4-dichlorophenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one,

8 ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one,

5-fluoro-3-(4-methoxy-2-were)-8-propoxy-1H-quinoline-4-one,

5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one,

5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one,

5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinoline-4-one,

8 cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one,

5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinoline-4-one,

5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinoline-4-one

5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-triptoreline)-1H-quinoline-4-the N.

Item 4. Pharmaceutical composition comprising a quinolone derivative of General formula (1) or its salt according to claim 1, as active ingredient, and a pharmaceutically acceptable carrier.

Paragraph 5. Preventive and/or therapeutic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by deterioration of the function of mitochondria, comprising as an active ingredient derived quinolone General formula (1) or its salt according to claim 1.

Item 6. Preventive and/or therapeutic agent according to claim 5, where the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's disease, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear paralysis, true akinesia, Alzheimer's disease, diseases of the Peak, prion disease, corticobasal degeneration, disease, diffuse Taurus Levi, Huntington's disease, Horai-acanthocytosis, benign hereditary horei, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Tourette's syndrome, rett syndrome, degenerative shake, the lordotic Dabashi, acetosa, spastic Krivoshei syndrome Maia, cerebral palsy, Wilson's disease, syndrome Segawa, syndrome Hallervorden-Spitze, not reasonale dystrophy, pridumannoj atrophy, spinocerebellar degeneration of the retina, atrophy of the cerebral cortex, cerebellar atrophy Holmes, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, disease Joseph, dentatorubral-pallidoluysian atrophy, disease Gerstmann-Straussler-Sheinker, frda, syndrome, Roussy-levy syndrome may-white, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia-telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscle atrophy, disease, werdnig-Hoffman disease Kugelberg-Welander, hereditary spastic paraparesis, those of syringomyelia, syringobulbia syndrome Arnold-Chiari syndrome muscle stiffness, syndrome Klippel-Fala syndrome Fazio-Londe, lower myelopathy syndrome dandy-Walker, spina bifida, syndrome Sjogren-Larsson, radiation myelopathy, age-related macular degeneration and apoplexy of the brain selected from the group consisting of ischemic stroke and hemorrhage in the brain.

Item 7. Preventive and/or therapeutic agent according to claim 5, where the disease is caused by neurological dysfunction, which are selected from the group consisting of spinal cord injury, is caused chemotherapy neuropathy, diabetic neuropathy, radiation injury, and demyelinating disease selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive mnogofotonnoi leukoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinative polyneuropathy syndrome of Gillen-Barre.

Item 8. Preventive and/or therapeutic agent according to claim 5, where the disease caused by the deterioration of the function of mitochondria, which are selected from the group consisting of Pearson syndrome, diabetes, deafness, migraine malignant course, Leber's disease, MELAS, MERRF syndrome overlap MERRF/MELAS, NARP, true myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia caused by aminoglycosides hearing loss, complex III deficiency due to a hereditary variants of cytochrome b, multiple symmetric lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, disease ANT1, disease Twinkle, the POLG disease, recurrent myoglobinuria, SANDO, ARCO, deficiency of complex I deficiency of complex II, optic nerve atrophy, fatal child's deficiency of complex IV deficiency, mitochondrial DNA deficiency syndrome mitochondri the social DNA encephalomyelopathy Lee, syndrome, chronic progressive external ophthalmoplegia (CPEO), syndrome of Core-Saury, encephalopathy, lactacidemia, mioglobinurii caused by drugs mitochondrial diseases, schizophrenia, major depressive disorder, bipolar I disorder, bipolar II disorder, mixed episode, estimatesa disorders, atypical depression, seasonal affective disorder, postpartum depression, minor depression, recurrent brief depressive disorder, persistent depression/chronic depression, double depression and acute renal failure.

Item 9. The use of quinolone derivative of General formula (1) or its salt according to claim 1 as a drug.

Paragraph 10. Method for the treatment or prevention of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by deterioration of the function of mitochondria, including the introduction of a human or animal quinolone derivative of General formula (1) or its salt according to claim 1.

Paragraph 11. A method of obtaining a quinolone derivative of General formula (1)

or its salt, in which each of R1, R2, R3, R4, R5, R6and R7defined above in claim 1, including the interaction of the compounds represented by the General formula (4)

in which each of R1, R4, R5, R6and R7defined above in claim 1, with a compound represented by the General formula (5)

in which each of R2and R3defined above in claim 1, and R8represents a lower alkoxy group, receiving the intermediate compounds represented by the General formula (6)

in which each of R1, R2, R3, R4, R5, R6, R7and R8defined above; and subjecting the compound obtained in the cyclization reaction.

Specific examples of the groups in General formula (1) are as follows.

Examples of lower alkyl groups include linear or branched C1-6(preferably1-4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, terbutyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl and so on.

Examples3-8cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and so on.

Examples of cyclo3-8alkyl lower alkyl groups include the lower alkyl groups substituted by one to three (preferably one) described the above cyclo 3-8alkyl group(the group).

Examples of lower alkoxy groups include linear or branched C1-6(preferably1-4) alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, verboeket, n-pentox, isopentane, neopentane, n-hexyloxy, isohexane, 3 methylpentane and so on.

Examples of the lower alkoxy lower alkyl groups include the lower alkyl groups substituted by one to three (preferably one) of the above-described lower alkoxy group(the group).

Examples of halogen atoms include fluorine, chlorine, bromine and iodine.

Examples of halogen-substituted lower alkyl groups include the lower alkyl groups substituted by one or seven atoms(atoms) halogen, preferably one to three atoms(atoms) halogen. Their examples include vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, dichloromethyl, 2,2-dottorati, 2,2,2-triptorelin, pentafluoroethyl, 2-foretel, 2-chloroethyl, 3,3,3-cryptochromes, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 3-chloropropyl, 2-chloropropyl, 3-dibromopropyl, 4,4,4-tripcomputer, 4,4,4,3,3-PENTACARBONYL, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-tryptophanyl, 5-chloropentyl, 6,6,6-triptorelin, 6-chlorhex, perferences and so on.

Examples halogentated is the R lower alkoxy groups include lower alkoxy groups, substituted one-seven-atom(atoms) halogen, preferably one to three atoms(atoms) halogen. Their examples include formatosi, deformedarse, triptoreline, chloromethoxy, dichloromethoxy, trichlormethane, bromoethoxy, dibromethane, dichloromethoxy, 2,2,2-triptoreline, pentaborate, 2-chloroethoxy, 3,3,3-cryptocracy, heptafluoropropoxy, heptafluoroisopropoxy, 3 chloropropoxy, 2-chloropropoxy, 3 bromopropane, 4,4,4-triptoreline, 4,4,4,3,3-pentafluorobutane, 4-chloroethoxy, 4-bromoethoxy, 2-chloroethoxy, 5,5,5-triterpenes, 5-chlorphenoxy, 6,6,6-triptoreline, 6-chlorhexidine and so on.

Examples of lower alkylthio groups include alkylthio-groups in which the alkyl fragment is the above-mentioned lower alkyl group.

Examples of hydroxy lower alkyl groups include the above-mentioned lower alkyl group substituted by one to three (preferably one) hydroxyl group(or groups).

Examples of the lower alkanoyl groups include linear or branched C1-6(preferably1-4) alcoholnye groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbamoyl, hexanoyl and so on.

Examples of the lower alkoxycarbonyl groups include alkoxycarbonyl group, in which CNS fragment is referred to enter the lower alkoxy group.

Examples of amino groups, optionally substituted by one or more lower alkyl groups include amino group, optionally substituted by one or two lower alkyl group(the group)as described above.

Examples carbamoyl groups, optionally substituted by one or more lower alkyl groups include carbamoyl group, optionally substituted by one or two lower alkyl group(the group)as described above.

Examples of cyclo3-8alkyl lower alkyl groups include the above-mentioned lower alkyl group substituted by one to three (preferably one) cyclo3-8alkyl group(the group)as described above.

Examples of hydroxy lower alkoxy groups include the above-mentioned lower alkoxy group substituted by one to three (preferably one) hydroxyl group(or groups).

Examples of the lower alkoxy lower alkoxy groups include the above-mentioned lower alkoxy group substituted by one to three (preferably one) of the lower alkoxy group(the group)as described above.

Examples of amino groups, optionally substituted by one or more members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl groups, cyclo3-8alkyl groups include amino group, optionally substituted by one or two member of the us selected from the group consisting of the above-mentioned lower alkyl groups, the above-mentioned lower alkoxy lower alkyl group and the above-mentioned cyclo3-8alkyl groups.

Examples of the lower alkylsulfonyl groups include alkylsulfonyl groups in which the alkyl fragment is the above-mentioned lower alkyl group.

Examples of amino lower alkoxy groups optionally substituted on the amino group by one or more members selected from the group consisting of lower alkyl groups, lower alkanoyl groups, lower alkylsulfonyl groups and carbamoyl groups, optionally substituted by one or more lower alkyl groups include lower alkoxy groups substituted by one to three (preferably one) amino group(or groups). In the present description amino lower alkoxy group optionally substituted on the amino group by one or two members selected from the group consisting of the above-mentioned lower alkyl groups, the above-mentioned lower alkanoyl groups, the above-mentioned lower alkylsulfonyl groups, carbamoyl groups, optionally substituted by one or more lower alkyl groups referred to above.

Examples of cyclo3-8alkoxy groups include groups in which cyclo3-8an alkyl group and an oxygen atom linked.

Examples tetrahydrofuryl lower alkoxy groups include the above-mentioned lower alkoxy group substituted by one to three (preferably one) tetrahydrofuryl group(or groups).

Examples of lower alkylthio groups include alkylthio-groups in which the alkyl fragment is the above-mentioned lower alkyl group.

Examples of phenyl lower alkoxy groups include the above-mentioned lower alkoxy group substituted by one to three (preferably one) of the phenyl group(or groups).

Examples of phenyl lower alkoxy lower alkoxy groups include the above-mentioned lower alkoxy group substituted by one to three (preferably one) phenyl lower alkoxy group(the group).

The method of obtaining the compounds of this invention are described in detail below.

Derived quinolone represented by the General formula (1) (hereinafter also referred to as compound (1)can be obtained in various ways; for example, the method according to the following reaction scheme 1 or 2.

The reaction scheme 1

in which R1, R2, R3, R4, R5, R6and R7same as defined above, and X1represents a halogen atom.

Examples of halogen atoms represented by X1include fluorine, chlorine, bromine and iodine.

Preferably, the leaving group in the data is th reaction include a halogen. Among them, particularly preferred iodine.

The compound (1) can be obtained by entering into cooperation compound of General formula (2) and the compound of General formula (3) in an inert solvent or without using any solvents, in the presence or in the absence of a basic compound, in the presence of palladium catalyst.

Examples of inert solvents include water, solvents based on ethers, such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of ethylene glycol; solvents on the basis of aromatic hydrocarbons, such as benzene, toluene and xylene; solvents on the basis of lower alcohols, such as methanol, ethanol and isopropanol; solvent-based ketones, such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Data inert solvents can be used individually or in combination of two or more of them.

Used in this reaction the compound of palladium is not particularly limited, but include, for example, catalysts based on tetravalent palladium, such as the tetrahydrate of hexachloropalladate(IV) sodium and hexachloropalladate(IV) potassium catalysts on the basis of divalent palladium, that is their as palladium(II)chloride, bromide, palladium(II)acetate, palladium(II)acetylacetonate, palladium(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorethylene palladium(II), dichlorobis(cycloocta-1,5-diene)palladium(II), triptorelin palladium(II) complex of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane, catalysts based on nonvalence palladium, such as Tris(dibenzylideneacetone)palladi(0), complex Tris(dibenzylideneacetone)Palladia(0) with chloroform and tetrakis(triphenylphosphine)palladium(0) and so on. Data palladium catalysts can be used individually or in combination of two or more of them.

In this reaction, the amount of palladium catalyst is not particularly limited, but usually it is in the range from 0.000001 to 20 mol based on palladium relative to 1 mol of compound (2). The amount of palladium catalyst is preferably in the range from 0.0001 to 5 mol based on palladium relative to 1 mol of compound (2).

This reaction proceeds predominantly in the presence of a suitable ligand. Examples of ligands of the palladium catalyst include, for example, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), tri-o-tolylphosphino, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-tert-butylphosphine and 9,9-dimethyl-4,5-bis(diphenylprop the but)xanthene (XANTPHOS). These ligands are used individually or in combination of two or more of them.

The ratio of palladium catalyst and ligand is not particularly limited. The amount of ligand is from about 0.1 to about 100 moles per mole of palladium catalyst, and preferably from about 0.5 to about 15 mol per mol of palladium catalyst.

As the basic compounds can be used various known inorganic and organic bases.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium; phosphates such as sodium phosphate and potassium phosphate; amides such as sodium amide, and hydrides of alkali metals, such as sodium hydride and potassium hydride.

Organic bases include, for example, low alkali metal alcoholate such as sodium methylate, sodium ethylate, tert-butyl sodium, potassium methylate, potassium ethylate and tert-butyl potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-utilties the Propylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and so on.

Such basic compounds can be used individually or in combination of two or more of them. Preferred basic compounds used in this reaction include carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate.

The basic compound is usually used in an amount of from 0.5 to 10 mol per mol of compound (2) and preferably from 0.5 to 6 mol per mol of compound (2).

The compound (3) is usually used in amounts of at least about 1 mol per mol of compound (2), and preferably from about 1 to about 5 mol per mol of compound (2).

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 200°C, and preferably at a temperature from room temperature up to 150°C, and is usually completed within from about 1 to about 30 hours. The reaction is brought to the end by heating at a temperature of from 100 to 200°C for from 5 minutes to 1 hour using a reactor with microwave radiation.

The compound represented by General what armoloy (3), used as starting compound in the reaction scheme 1 is described readily available connection. The connection represented by the General formula (2), includes a new connection, and this connection will receive the following reaction scheme 6.

The reaction scheme 2

in which R1, R2, R3, R4, R5, R6and R7same as defined above, and R8represents a lower alkoxy group.

The lower alkoxy group represented by R8in the General formula (5)has a definition similar to that described above.

Compounds represented by the General formulas (4) and (5)enter into interaction in an inert solvent or without using any solvents, in the presence or in the absence of acid catalyst, resulting in the intermediate compound represented by the General formula (6). The resulting connection cyclist, receiving the connection represented by the General formula (1).

Examples of inert solvents include water; solvent-based ethers, such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of ethylene glycol; solvents on the basis of aromatic hydrocarbons, such as benzene, olwal and xylene; solvents based on lower alcohols, such as methanol, ethanol and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Data inert solvents can be used individually or in combination of two or more of them.

You can use any type of known acidic catalysts, including toluensulfonate, methanesulfonate, killswitches, sulfuric acid, glacial acetic acid, boron TRIFLUORIDE, acidic ion-exchange resin, and so forth. Data acidic catalysts can be used individually or in combination of two or more of them.

Among these acids are preferably used acidic ion-exchange resin. Examples of acidic ion-exchange resins include commercially available polymeric cation exchange resin, such as Lewatit S100, Zeo-karb 225, Dowex 50, Amberlit IR120 or Amberlyst 15 and similar polymers styrelseledamot; Lewatit PN, Zeo-karb 215 or 315 and such condensates of polysulfones; Lewatit CNO, Duolit CS100 and such resin-based m-phenol carbonic acids; or Permutit C, Zeo-karb 226 or Amberlite IRC 50 and such polyacrylates. Among them, particularly preferred Amberlyst 15.

Oxide catalyst is usually used in amounts of from 0.0001 to 100 mol per mol of compound (4), and preferably from 0.5 to 6 mol per mol with the organisations (4).

In the reaction scheme 2, the compound (5) are usually used in amounts of at least about 1 mol of compound (4), and preferably from about 1 to about 5 mol per mol of compound (4).

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 200°C, and preferably at a temperature from room temperature to 150°C. during the reaction carried out the azeotropic distillation of water up until the release of water during the reaction will not stop. The reaction is usually completed within from about 1 to about 30 hours.

The method of obtaining compounds of General formula (1) by the reaction of cyclization of the intermediate compounds represented by the General formula (6)can be applied by heating this compound in a solvent such as diphenyl ether, or by heating this compound in the absence of solvent. The reaction is carried out at a temperature of from 150 to 300°C for from 5 minutes to 2 hours.

The connection represented by the General formula (4)used as the starting material in the above reaction scheme 2, is a known compound or can be easily obtained from known compounds. The connection represented by the General formula (5), includes a new connection, and this connection receive, e.g. the, in accordance with the methods presented in the above reaction scheme 4 and scheme of reaction 5.

The reaction scheme 3

in which R2, R3, R4, R5, R6and R7same as defined above, and R1' represents a group represented by R1different from hydrogen, and X2represents a group which undergoes the same substitution reaction as the reaction of substitution of a halogen or halogen atom.

The halogen represented by X2in the General formula (1A)include the above-described halogen atom. Groups that are the same substitution reaction as the reaction of substitution of the halogen atoms represented by X2include lower alkylsulfonate group, arylsulfonate group, Arakishvili groups and so on.

Examples of lower alkylsulfonate groups include linear or branched C1-6alkylsulfonate groups, such as methanesulfonate, econsultancy, n-propanesulfonate, isopropanolamine, n-butanesulfonate, tert-butanesulfonate, n-pentanesulfonate and n-hexanesulfonate.

Examples of arylsulfonyl groups include naftiliaki, phenylsulfonyl, optionally containing phenyl ring as a substituent with one to three group(s), select the R group, consisting of linear or branched C1-6alkyl groups, linear or branched C1-6alkoxy groups, nitro groups, and halogen atoms. Examples of phenylsulfonyl group optionally substituted by the above-mentioned substituent(s), include phenylsulfonyl, 4-methylphenylsulfonyl, 2-methylphenylsulfonyl, 4-nitrophenylacetylene, 4-methoxyphenylalanine, 2-nitrophenylacetylene, 3 chlorophenylsulfonyl and so on. Examples of naftiliaki groups include α-naftiliaki, β-naftiliaki and so on.

Examples of Arakishvili groups include phenylsilane linear or branched C1-6alkylsulfonate group that may contain a phenyl ring as a substituent of one to three substituent(substituents), selected from the group including linear or branched C1-6alkyl groups, linear or branched C1-6alkoxy group, nitro group and halogen atoms, or naphthylamine linear or branched C1-6alkylsulfonate group. Examples of alkylsulfonate group substituted by the above-mentioned phenyl group(or groups)include benzylmalonate, 2-phenylethylperoxo, 4-phenylmethylsulfonyl, 4-methylbenzenesulfonate, 2-methylbenzenesulfonate, 4-nitrobenzyl is sulfonyloxy, 4 methoxybenzenesulfonamide, 3 chlorobenzenesulfonate and so on. Examples of alkylsulfonate groups, substituted mentioned above naftilos group(or groups)include α-naphthylenediisocyanate, β-naphthalenyloxy and so on.

The connection represented by the General formula (1b)can be obtained by the interaction of the compounds represented by the General formula (1A), with the compound represented by General formula (7), in an inert solvent or without using any solvents, in the presence or in the absence of the primary connection.

Examples of inert solvents include water; solvent-based ethers, such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of ethylene glycol; solvents on the basis of aromatic hydrocarbons, such as benzene, toluene and xylene; solvents on the basis of lower alcohols, such as methanol, ethanol and isopropanol; solvent-based ketones, such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Data inert solvents can be used individually or in combination of two or more of them.

As the basic compounds can be used various is known inorganic bases and organic bases.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium; amides such as sodium amide, and hydrides of alkali metals, such as sodium hydride and potassium hydride.

Organic bases include, for example, low alkali metal alcoholate such as sodium methylate, sodium ethylate, tert-butyl sodium, potassium methylate, potassium ethylate and tert-butyl potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and so on.

Such basic compounds can be used individually or in combination of two or more of them. Preferred basic compounds used in this reaction include inorganic bases such as sodium hydride and potassium hydride.

The basic compound is usually used in quantities is from 0.5 to 10 mol per mol of compound (1A), and preferably from 0.5 to 6 mol per mol of compound (1A).

In the reaction scheme 1, the compound (7) is usually used in amounts of at least about 1 mol of compound (1A), and preferably from about 1 to about 5 mol per mol of compound (1A).

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from 0°C to 200°C, and preferably at a temperature from room temperature up to 150°C, and is usually completed within from about 1 to about 30 hours.

The connection represented by the General formula (7), which is used as the starting material in the above reaction scheme 3, is readily available well-known compound.

The compound (5) and the compound (2), which is the starting material for compounds of the invention include new compounds and can be obtained in various ways, for example, methods in accordance with the following schemes reactions 4 through 6.

The reaction scheme 4

in which R2, R3and R8same as defined above, and R9represents a lower alkoxy group.

The lower alkoxy group represented by R9in the General formula (9)has a definition similar to that described above.

The connection represented by the General the formula (5), can be obtained by the interaction of the compounds represented by the General formula (8), with the compound represented by the General formula (9), in an inert solvent or without using any solvents, in the presence or in the absence of the primary connection.

Examples of inert solvents include water; solvent-based ethers, such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of ethylene glycol; solvents on the basis of aromatic hydrocarbons, such as benzene, toluene and xylene; solvents on the basis of lower alcohols, such as methanol, ethanol and isopropanol; solvent-based ketones, such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Data inert solvents can be used individually or in combination of two or more of them.

As the primary connection, you can use various known inorganic bases and organic bases.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, the carbonate to the lia, the cesium carbonate and lithium carbonate, hydrogen carbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium, amides such as sodium amide, and inorganic bases based hydrides of alkali metals such as sodium hydride and potassium hydride.

Organic bases include, for example, low alkali metal alcoholate such as sodium methylate, sodium ethylate, tert-butyl sodium, potassium methylate, potassium ethylate and tert-butyl potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and so on.

Such basic compounds can be used individually or in combination of two or more of them. Preferred basic compounds used in this reaction include inorganic bases such as sodium hydride and potassium hydride.

The basic compound is usually used in an amount of from about 1 to about 10 mol per mol of compound (8), and preferably from about 1 to about 6 mol per mol of compound (8).

In the reaction scheme 4, the compound (9) is usually used in a quantity at IU is e, about 1 mol of compound (8), and preferably from about 1 to about 5 mol per mol of compound (8).

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 200°C, and preferably at a temperature from room temperature up to 150°C and is usually completed within from about 1 to about 30 hours.

Compounds represented by General formulas (8) and (9), which are used as starting substances in the reaction scheme 4, are readily available well-known connection.

The reaction scheme 5

in which R2, R3and R8same as defined above, and X3represents a halogen atom.

The halogen atom represented by X3in the General formula (9')has a definition similar to that described above.

The connection represented by the General formula (5), can be obtained by the interaction of the compounds represented by the General formula (8'), with the compound represented by the General formula (9'), in an inert solvent or without using any solvents, in the presence of a basic compound such as cesium carbonate and a copper catalyst such as copper iodide.

Examples of inert solvents include polar solvents, such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Data inert solvents can be used individually or in combination of two or more of them.

This reaction can be carried out in the presence of amino acids such as L-Proline.

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 200°C, and preferably at a temperature from room temperature up to 150°C, and is usually completed within from about 1 to about 30 hours.

The above reaction is specifically described in the following standard example 58.

Compounds represented by General formulas (8) and (9'), which are used as starting materials in the above reaction scheme 5, are known compounds or can be easily obtained from known compounds.

A reaction scheme 6

in which R4, R5, R6and R7same as defined above, and X1Arepresents a halogen atom. R10represents a lower alkyl group.

The lower alkyl group represented by R10and the halogen atom represented by X1Ahave definitions similar to those described above.

Connection, predstavleniya formula (12), can be obtained by condensation reaction of the compounds represented by the General formula (4), (10) and (11), in an inert solvent or without using any solvents.

Examples of inert solvents include water; solvent-based ethers, such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of ethylene glycol; solvents on the basis of halogen-substituted hydrocarbons, such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; solvents on the basis of aromatic hydrocarbons, such as benzene, toluene and xylene; solvents on the basis of lower alcohols, such as methanol, ethanol and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Instead of the above-mentioned solvents as a solvent, you can use the connection represented by the General formula (11). Data inert solvents can be used individually or in combination of two or more of them.

In reaction scheme 6, the compound (10) is usually used in amounts of at least about 1 mol of compound (4), and preferably from about 1 to about 5 mol per mol of compound (4).

With respect to the compound (10) use an excess of the compound (11).

annoy reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 200°C, and preferably at a temperature from room temperature up to 150°C, and is usually completed within from about 1 to about 30 hours.

The connection represented by the General formula (13), can be obtained by annelation reaction of the compounds represented by the General formula (12), in an inert solvent or without using any solvents.

Examples of inert solvents include solvents on the basis of simple ethers such as diphenyl ether.

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 300°C., and preferably at a temperature from 150°C to 300°C, and is usually completed within from about 1 to about 30 hours.

The connection represented by the General formula (2A), can be obtained by reaction of the compound represented by the General formula (13), with the compound represented by the General formula (14), in an inert solvent or without using any solvents, in the presence or in the absence of the primary connection.

Examples of inert solvents include water; solvent-based ethers, such as dioxane, tetrahydrofur the Academy of Sciences, diethyl ether, 1,2-dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of ethylene glycol; solvents on the basis of aromatic hydrocarbons, such as benzene, toluene and xylene; solvents on the basis of lower alcohols, such as methanol, ethanol and isopropanol; solvent-based ketones, such as acetone and methyl ethyl ketone; polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphorotriamide and acetonitrile. Data inert solvents can be used individually or in combination of two or more of them.

As the primary connection, you can use various known inorganic bases and organic bases.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide, carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, hydrogen carbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium; amides such as sodium amide, and inorganic bases based hydrides of alkali metals such as sodium hydride and potassium hydride.

Organic bases include, for example, dissolve the fir on the basis of the lower alcoholate of alkali metals, such as sodium methylate, sodium ethylate, tert-butyl sodium, potassium methylate, potassium ethylate and tert-butyl potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and so forth.

Such basic compounds can be used individually or in combination of two or more of them. Preferred basic compounds used in this reaction include carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, and so forth.

The basic compound is usually used in an amount of from about 0.5 to about 10 mol per mol of compound (13), and preferably from about 0.5 to about 6 mol per mol of compound (13).

In reaction scheme 6, the compound (14) is usually used in amounts of at least 0.5 mol of compound (13), and preferably from about 0.5 to about 5 mol per mol of compound (13).

This reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, and so forth, or at elevated pressures.

The reaction generally proceeds at a temperature from room temperature up to 200°C, and preferably at a temperature from room what things to 150°C, and usually completed within from about 1 to about 30 hours.

Compounds represented by the General formulas (10), (11) and (14), which are used as starting substances in the reaction scheme 6, are readily available well-known connection.

Raw source compounds used in each of the above schemes reactions may include suitable salts, and the target compounds obtained from each of these reactions can form suitable salts. Such preferred salts include the following preferred salts of the compounds (1).

Suitable salts of the compounds (1) are pharmacologically acceptable salts, including metal salts, such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), salts of alkaline earth metals (e.g. calcium salt, magnesium salt, etc.), ammonium salts, salts of inorganic bases, such as carbonates of alkali metals (e.g. lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, and so forth), carbonates of alkali metals (such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), hydroxides alkali metals (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), salts of organic bases, such as tri(lower)alkylamine (for example, trimethyl is in, the triethylamine, N-ethyldiethanolamine and so on), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkalifying (for example, N-methylmorpholine and so on), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, aconsultant, p-toluensulfonate and glutamate.

In addition, in each of the General formulas included compound in the form, which was added to the MES (for example, hydrate, ethanolate and so on) in the parent compound and the target compound represented by each of the schemes of reactions. Preferred solvate includes hydrates.

Each of the target compounds obtained according to the above schemes of reactions, you can select and clear from the reaction mixture, for example, after cooling the reaction mixture, the procedure of separation, such as filtration, concentration, extraction and so on, for separation of the crude reaction product, and then subjecting this crude reaction product to conventional purification method such as column, chromatography is, recrystallization and so on.

The compound of formula (1) according to the present invention naturally includes geometric isomers, stereoisomers, optical isomers and the like isomers.

In respect of the above compounds of General formula (1) note the following points. In the case when R1in the General formula (1) represents a hydrogen atom, the compound includes tautomer quinolone cycle. That is, when R1b is a hydrogen atom (1') in connection quinolone General formula (1)

in which R2, R3, R4, R5, R6and R7same as defined above,

the connection of this tautomer can be represented by the formula (1")

in which R2, R3, R4, R5, R6and R7similar defined above.

That is, both compounds represented by the formulas (1') and (1"), are in a state of tautomeric equilibrium, represented by the following formula balance.

in which R2, R3, R4, R5, R6and R7similar defined above.

Such tautomerism between the compound 4-quinolone and connection 4-hydroxyquinoline solution is technically known, and for professionals in this field is evident that both opican the x above tautomer are in equilibrium and mutual transformation.

Thus, the compound (1), of course, includes the above-mentioned tautomers.

In the description of the structural formula of the compound 4-quinolone suitably used as a structural formula source or target substances, including compounds such tautomers.

The compound of General formula (1) and its salt are used in the form of a General pharmaceutical drugs. These drugs get using commonly used diluents or excipients such as fillers, dry diluents, binders, wetting agents, disintegrating agents, surfactants, lubricants, and so forth. The form of such pharmaceutical preparations can be selected in accordance with the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, and so forth), and the like.

To obtain tablets you can use any of a variety of media, well-known in this field. Their examples include lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, sugar syrup, glucose solutions, solutions of starch solutions, gelatin, carboxymethylcellulose, W is Llac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate powder, agar-agar, laminarinase powder, sodium bicarbonate, calcium carbonate, polyoxyethylene ether of sorbitol and fatty acids, sodium lauryl sulfate, monoglycerides of stearic acid, starch, lactose and other leavening agents; white sugar, stearin, cacao butter, hydrogenated oils and other inhibitors of fragmentation; Quaternary ammonium bases, sodium lauryl sulfate, and other promoters of absorption; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, powdered boric acid, polyethylene glycol and other lubricating substances, and so forth. In addition, if necessary, such tablets can be coated from an ordinary covering substances, for example, to obtain tablets, sugar coated tablets, gelatin coated tablets, enteric-soluble coating, film-coated tablets, tablets with dual-or multi-layer coating and so on.

To get of pills you can use any of a variety of media, well-known in this field. Their examples include glucose, lactose, starch, cacao butter, hydrogenated vegetable m is s'la, kaolin, talc and other excipients; powdered gum Arabic, powdered tragacanth gum, gelatin, ethanol and other binders; laminarin, agar-agar and other leavening agents and so on.

To obtain suppositories can be used any of various media, well-known in this field. Their examples include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and so on.

Capsules can be obtained by mixing the active primary connection with the above-mentioned media for the conclusion of the first hard gelatin capsule, soft gelatin capsule, or the like.

To obtain the drug for injection solution, emulsion or suspension is sterilized and preferably make it isotonic to the blood. To obtain a preparation for injection can be used any solvent commonly used for such forms in this area. Examples of such diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, polyoxyethylene esters of sorbitol and fatty acids, and so forth.

In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient for making isoto the practical solution, and may contain conventional soljubilizatory, buffer agents, analgesic remedies, and so forth. In addition, if necessary, the pharmaceutical preparation may contain dyes, preservatives, flavorings, sweeteners and so on, and/or other medicines.

The amount of compounds represented by the General formula (1) and salts thereof, included in the pharmaceutical composition of the present invention is not limited and can be appropriately selected from a wide interval. This proportion is usually from about 0.1 to about 70 wt.%, preferably from about 0.1 to about 30 wt.% pharmaceutical drug.

Route of administration of the pharmaceutical preparation of the present invention is not particularly limited, and the drug is administered in a way that is suitable for the form of the drug, the patient's age, sex and other conditions, and the status of the disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Preparations for injection is injected separately or in a mixture with conventional intravenous infusion, such as glucose, amino acid solutions, or the like, or separately administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, if necessary. Suppositories administered vnutriuretrale.

The dosage of the pharmaceutical preparation of this invented what I choose appropriately in accordance with the method of application, the patient's age, sex and other conditions, and severity of disease. The number of active basic compound is usually from about 0.1 to about 10 mg/kg body weight/day. In addition, it is desirable that the pharmaceutical drug in each dose forms introduction contained in an amount of from about 1 to about 200 mg.

When using compounds of the present invention in combination with drugs levodopa, dopamine agonists receptors, inhibitors of the enzyme dopamine metabolism, drugs that increase the rate of release of dopamine, anticholinergic agents Central action and the like it is possible to achieve effects such as dose reduction, improvement of side effects, improving therapeutic efficacy, and so forth, which are not achieved in the conventional therapies.

The result of inventions

The compound of the present invention has a protective and improve activity against mitochondrial function and protective and restorative neural activity, and so forth, and, thus, is effective for the treatment and prevention of neurodegenerative diseases, diseases related to neurodegenerative disorders, and diseases related to mitochondrial dysfunction.

Neurodegenerative diseases include Parkinson's disease, with ngram Parkinson, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear paralysis, true akineziyu, Alzheimer's disease, the disease Peak, prion disease, corticobasal degeneration, diffuse disease Taurus Levi, Huntington's disease, chorey-acanthocytes, benign hereditary horey, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Tourette syndrome, rett syndrome, degenerative shake, the lordotic dibasio, Atmos, spastic Krivoshey syndrome Maia, cerebral palsy, Wilson's disease, syndrome Segawa, syndrome Hallervorden-Spitze, neuroaxonal dystrophy, pridumannuyu atrophy, spinocerebellar degeneration of the retina, atrophy of the cerebral cortex, cerebellar atrophy Holmes, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, a disease Joseph, dentatorubral-pallidoluysian atrophy, a disease of Gerstmann-Straussler-Sheinker, ataxia, syndrome, Roussy-levy syndrome may-white, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia-telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, a disease of werdnig-Hoffman disease Kugelberg-Veland is R, hereditary spastic prepares, syringomyelia, syringobulbia, syndrome, Arnold-Chiari syndrome muscle stiffness, syndrome Klippel-Fala syndrome Fazio-Londe, lower myelopathy syndrome dandy-Walker, spina bifida, syndrome Sjogren-Larsson, radiation myelopathy, age-related macular degeneration and stroke (for example, ischemic stroke, brain hemorrhage, and so on).

Diseases caused by neurological dysfunction, include spinal cord injury, caused chemotherapy neuropathy, diabetic neuropathy, radiation injury, and demyelinating diseases such as multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive mnogopikselnoy the leucoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinizing the polyneuropathy syndromes Gillen-Barre, and so on).

Diseases caused by deterioration of the function of the mitochondria include Pearson syndrome, diabetes, deafness, migraine malignant course, Leber's disease, MELAS, MERRF syndrome overlap MERRF/MELAS, NARP, true myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia caused by aminoglycosides hearing loss, failure included the sa III due to inherited variants of cytochrome b, multiple symmetric lipomas, ataxia, myoclonus, retinopathy, MNGIE disease ANT1 disease Twinkle, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, deficiency of complex II, optic nerve atrophy, fatal infant failure of complex IV deficiency, mitochondrial DNA deficiency syndrome, mitochondrial DNA, encephalomyelopathy Lee, syndrome, chronic progressive external ophthalmoplegia (CPEO), a syndrome of Core-Saury, encephalopathy, lactacidemia, myoglobinuria caused by drugs mitochondrial disease, schizophrenia, major depressive disorder, bipolar I disorder, bipolar II disorder, mixed episode, estimatesa disorder, atypical depression, seasonal affective disorder, postpartum depression, minor depression, recurrent brief depressive disorder, persistent depression/chronic depression, double depression and acute renal failure.

The best way of carrying out the invention

Further the present invention is described in more detail with reference to reference examples, examples and pharmacological test examples.

Reference example 1

N-Cyclohexyl-4-fluoro-2-nitro-N-methylaniline

To a solution of 2,5-deformirovannoe (5.0 g, of 31.4 mmol who) in N-organic (NMP) (20 ml) was added potassium carbonate (6.0 g, to 43.5 mmol) and N-methylcyclohexylamine (4.6 g, to 40.6 mmol), and stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The obtained dry product was concentrated under reduced pressure, to thereby obtain 7.0 g of oily N-cyclohexyl-4-fluoro-2-nitro-N-methylaniline yellow (yield: 89%).

1H NMR (CDCl3) dppm: 1,12-of 1.80 (10H, m)to 2.67 (3H, c), 3,00-to 3.09 (1H, m), 7,07-7,20 (2H, m), 7,42-7,47 (1H, m).

Compounds of the following reference examples 2-5 were obtained in a manner analogous to the above reference example 1, using appropriate starting materials.

Reference example 2

4-Fluoro-N-(2-methoxyethyl)-N-methyl-2-nitroaniline

1H NMR (CDCl3) dppm: 2,85 (3H, c), 3,25-3,31 (5H, m), 3,52 (2H, t, J=5.6 Hz), 7,16-7,20 (2H, m), 7,43-7,47 (1H, m).

Reference example 3

4-Fluoro-N-isobutyl-N-methyl-2-nitroaniline

1H NMR (CDCl3) dppm: 0,89 (3H, c), of 0.91 (3H, c), 1,89-to 1.98 (1H, m), of 2.81(3H,c), of 2.92 (2H, d, J=7.5 Hz), 7,15-7,20 (2H, m), 7,42-7,46 (1H, m).

Reference example 4

4-Fluoro-N-isopropyl-N-methyl-2-nitroaniline

1H NMR (CDCl3) dppm: to 1.16 (3H, c)to 1.19 (3H, c)to 2.67 (3H, c), 3,50-3,61 (1H, m), 7,15-7,20 (2H, m), 7,43-7,46 (1H, m).

Reference example 5

4-Fluoro-N-methyl-2-nitro-N-propylaniline

1H NMR (CDCl3) dppm: from 0.84 (3H, t, J=7.5 G is), 1,51-of 1.66 (2H, m), 2,77 (3H, c)of 3.00 (2H, t, J=7.5 Hz), 7,05-7,20 (2H, m), 7,44 (1H, DD, J=2,75 Hz, J=8.0 Hz).

Reference example 6

4-fluoro-2-nitro-1-propylsulfonyl

To a solution of 2,5-deformirovannoe (5.0 g, of 31.4 mmol) in N-organic (NMP) (15 ml) was added potassium carbonate (5.0 g, and 36.2 mmol) and 1-propanethiol (2.7 g, 35.5 mmol) and stirred the mixture at 90°C for 2 hours. After cooling the reaction mixture to room temperature, added water (50 ml) and was extracted with the reaction product with ethyl acetate (100 ml). The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The obtained dry product was concentrated under reduced pressure, thus obtaining 6.7 g of powdered 4-fluoro-2-nitro-1-propylsulfonyl yellow (yield: 99%).

1H NMR (CDCl3) dppm: of 1.06 (3H, t, J=7.5 Hz), 1,68 of-1.83 (2H, m), 2,89 (2H, t, 7.5 Hz), 7,27-7,42 (2H, m), 7,89 (2H, DD, J=2,75 Hz, J=8,5 Hz).

Reference example 7

1-tert-Butoxy-4-fluoro-2-nitrobenzene

A solution of potassium tert-butylate (3.55 g, of 31.6 mmol) in tetrahydrofuran (THF) (20 ml) was cooled in a methanol-ice bath and then added to 4.2 g of 2,5-deformirovannoe (26,4 mmol). The mixture was heated to room temperature, was stirred for 96 hours and was stirred during 60°C for 1 hour. To the reaction mixture were added water (2 ml) and 2n. hydrochloric acid (2 ml) under cooling in a bath of ice water, and then to allali water. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was then purified column chromatography on silica gel (n-hexane:ethyl acetate=19:1). The purified product was concentrated under reduced pressure, thus obtaining 4.5 g of oily 1-tert-butoxy-4-fluoro-2-nitrobenzene orange (yield: 80%).

1H NMR (CDCl3) dppm: to 1.38 (9H, c), 7,18-7,20 (2H, m), 7,47 (1H, d,J=1.1 Hz).

Reference example 8

4-fluoro-2-nitro-1-propoxybenzene

A solution of potassium carbonate (3,48 g of 25.2 mmol) and 1-jumprope (3,95 g, 23.2 mmol) in N,N-dimethylformamide (DMF) (3 ml) was added to a solution of 4-fluoro-2-NITROPHENOL 3,3 g, 21,0 mmol) in DMF (7 ml). The mixture was stirred at room temperature for 48 hours. To the reaction mixture were added water and the resulting mixture was extracted with ethyl acetate. The organic layer was twice washed with a saturated solution of sodium chloride and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure, thus obtaining a 4.03 g of oily 4-fluoro-2-nitro-1-propoxybenzene yellow (yield: 96%).

1H NMR (CDCl3) dppm: of 1.06 (3H, t, J=7.4 Hz), 1,78-of 1.92 (2H, m), Android 4.04 (2H, t, J=6.4 Hz),? 7.04 baby mortality (1H, DD, J=4.3 Hz, J=9,2 Hz), 7,21-7,29 (1H, m), 7,58 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Connection trace is the corresponding reference examples 9 to 16 were obtained by way similar to the above reference examples 7 and 8, using the appropriate starting materials.

Reference example 9

4-Fluoro-1-isopropoxy-2-nitrobenzene

1H NMR (CDCl3) dppm: 1,36 (3H, c), 4,54-4,63 (1H, m), 7,02-7,05 (1H, m), 7.18 in-7,26 (1H, m), 7,49 (1H, DD, J=3.0 Hz, J=7.5 Hz).

Reference example 10

1 Ethoxy-4-fluoro-2-nitrobenzene

1H NMR (CDCl3) dppm: the 1.44 (3H, t, J=7.0 Hz), 4,08 (2H, q, J=7.0 Hz), 7,02 (1H, DD, J=4,25 Hz, J=9,25 Hz), 7,22-7,30 (1H, m), 7,56 (1H, DD, J=3,25 Hz, J=7,75 Hz).

Reference example 11

1 Cyclopropylmethoxy-4-fluoro-2-nitrobenzene

1H NMR (CDCl3) dppm: 0,36-0,41 (2H, m), and 0.61 to 0.69 (2H, m), 1,22 of 1.28 (1H, m), 3,95 (2H, d, J=6.8 Hz),? 7.04 baby mortality (1H, DD, J=4.4 Hz, J=9,2 Hz), 7,20-7,27 (1H, m), EUR 7.57 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 12

4-fluoro-2-nitro-1-(4,4,4-triptoreline)benzene

1H NMR (CDCl3) dppm: 2,04-of 2.16 (2H, m), 2,31 is 2.44 (2H, m), 4,14 (2H, t, J=5,9 Hz),? 7.04 baby mortality (1H, DD, J=4.3 Hz, J=9,2 Hz), 7.24 to to 7.32 (1H, m), to 7.61 (1H, DD, J=3.2 Hz, J=7,8 Hz).

Reference example 13

4-Fluoro-1-(2-methoxyethoxy)-2-nitrobenzene

1H NMR (CDCl3) dppm: to 3.45 (3H, c), of 3.78 (2H, t, J=4,8 Hz), 4,24 (2H, t, J=4,8 Hz), 7,12 (1H, DD, J=4.4 Hz, J=9,2 Hz), 7.23 percent-7,30 (1H, m), to 7.59 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 14

1 Cyclopentyloxy-4-fluoro-2-nitrobenzene

1H NMR (CDCl3) dppm: 1,62-of 1.66 (2H, m), 1,83-of 1.94 (6H, m), 4,82-a 4.86 (1H, m),? 7.04 baby mortality (1H, DD, J=4.4 Hz, J=9.3 Hz), 7,19-7,27 (1H, m), 7,54 (1H, DD, J=3.2 Hz, J=7,8 Hz).

Reference example 15

1 Cyclobutylmethyl-4-fluoro-2-nitrobenzene

1H NMR (CDCl 3) dppm: 1,90-2,02 (4H, m), 2,08-of 2.15 (2H, m), 2.77-to of 2.81 (1H, m), a 4.03 (2H, d, J=6.2 Hz),? 7.04 baby mortality (1H, DD, J=4.3 Hz, J=9,2 Hz), 7,21-7,28 (1H, m), 7,58 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 16

2-(4-fluoro-2-nitrophenoxy)tetrahydrofuran

1H NMR (CDCl3) dppm: 1,88-2,12 (4H, m), 3,80-of 3.94 (2H, m), 4,11 (2H, d, J=4.0 Hz), 4,27-4,32 (1H, m), 7,10 (1H, DD, J=4.4 Hz, J=9.3 Hz), 7,22-7,30 (1H, m), to 7.59 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 17

2-[3-(4-Fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione

Potassium carbonate (10.8 g, 78,1 mmol) and N-(3-bromopropyl)phthalimide (12.1 g, 45,1 mmol) was added to a solution of 4-fluoro-2-NITROPHENOL (6.0 g, is 38.2 mmol) in N,N-dimethylformamide (DMF) (80 ml) and the mixture was stirred at 60°C for 4 hours. After cooling the reaction mixture to room temperature, added water (200 ml) and then cooled reaction mixture with ice. Precipitated insoluble substance was isolated by filtration. After washing with water (50 ml × 3) remaining on the filter substance was dried in the air, getting to 13.2 g of powdered 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione pale yellow (yield: 100%).

1H NMR (CDCl3) dppm: 2,18-of 2.28 (2H, m), 3,93 (2H, t, J=6.5 Hz), is 4.15 (2H, t, J=6.0 Hz),? 7.04 baby mortality (1H, DD, J=4.3 Hz, J=9,2 Hz), 7.23 percent-7,28 (1H, m), 7,58 (1H, DD, J=3.1 Hz, J=7.8 Hz), 7,69-7,74 (2H, m), 7,81-a 7.85 (2H, m).

Reference example 18

3-(4-Fluoro-2-nitrophenoxy)Propylamine

6.5 g of 2-[3-(4-fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione suspended in ethanol (140 ml) and was added to the obtained is Uspenie hydrazinehydrate (3.0 ml). The mixture was stirred for 3.5 hours while boiling under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added 13 ml of 5 N. aqueous sodium hydroxide solution and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The obtained dry product was concentrated under reduced pressure, thus obtaining a 4.03 g of oily 3-(4-fluoro-2-nitrophenoxy)Propylamine red-orange color (yield: 100%).

1H NMR (CDCl3) dppm: 1,92-2,02 (2H, m)to 2.94 (2H, t, J=6.5 Hz), 4,19 (2H, t, J=5,9 Hz), 7,07 (1H, DD, J=4.3 Hz, J=9,2 Hz), 7,22-7,30 (1H, m), to 7.59 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 19

N-[3-(4-fluoro-2-nitrophenoxy)propyl]ndimethylacetamide

To a solution of 3-(4-fluoro-2-nitrophenoxy)Propylamine (2.0 g, was 9.33 mmol) in dichloromethane was added pyridine (1.5 ml, of 18.6 mmol) and acetic anhydride (0.97 g, or 10.3 mmol) under cooling with ice and then added dichloromethane (4 ml). The resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture were added 2 N. hydrochloric acid (9.5 ml) and stirred the mixture. To the mixture was added water and the resulting mixture was extracted with dichloromethane. After washing with a saturated aqueous solution of sodium chloride organic SL the St was concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane:methanol=30:1→20:1). The purified product was concentrated under reduced pressure, thus obtaining a 2.13 g of oily N-[3-(4-fluoro-2-nitrophenoxy)propyl]ndimethylacetamide yellow (yield: 89%).

1H NMR (CDCl3) dppm: 2,04 (3H, c), 2,03-2,12 (2H, m), 3,48-3,55 (2H, m), 4,20 (2H, t, J=5.5 Hz), 6,56 (1H, users), was 7.08 (1H, DD, J=4.3 Hz, J=9.3 Hz), 7,26 and 7.36 (1H, m), of 7.70 (1H, DD, J=3.2 Hz, J=7,8 Hz).

Reference example 20

N-[3-(4-Fluoro-2-nitrophenoxy)propyl]methanesulfonamide

To a solution of 3-(4-fluoro-2-nitrophenoxy)Propylamine (2.0 g, was 9.33 mmol) in dichloromethane was added under ice cooling, pyridine (1.5 ml, of 18.6 mmol) and methanesulfonamide (0.8 ml, or 10.3 mmol) was added methyl chloride (4 ml). The resulting mixture was stirred at room temperature for 24 hours and was additionally added to it methanesulfonanilide (of 0.12 ml, 1.5 mmol) and the mixture is then stirred at room temperature for 15 hours. To the reaction mixture were added 2 N. hydrochloric acid (9.5 ml) and the mixture was extracted with dichloromethane. After washing with a saturated aqueous solution of sodium chloride the organic layer was concentrated under reduced pressure and the residue was then purified column chromatography on silica gel (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated under reduced pressure, while it is 1.2 g of oily N-[3-(4-fluoro-2-nitrophenoxy)propyl]methanesulfonamide yellow-orange color (yield: 44%).

1H NMR (CDCl3) dppm: 2,09-to 2.18 (2H, m)of 3.00 (3H, c), 3,39-of 3.46 (2H, m)to 4.23 (2H, t, J=5.6 Hz), 5,00 (1H, users), to 7.09 (1H, DD, J=4.3 Hz, J=9,2 Hz), 7,26-to 7.35 (1H, m), 7,66 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 21

Phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate

To a solution of 3-(4-fluoro-2-nitrophenoxy)Propylamine (a 4.03 g of 18.8 mmol) in dioxane (43 ml) was added triethylamine (2,90 ml, with 21.4 mmol) and phenylcarbamate (2,52 ml to 20.0 ml) under ice cooling and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was then purified column chromatography on silica gel (dichloromethane:ethyl acetate=30:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining of 5.92 g of powdered phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate yellow (yield: 94%).

1H NMR (CDCl3) dppm: 2,09-to 2.18 (2H, m), 3,48 of 3.56 (2H, m), is 4.21 (2H, t, J=5.7 Hz), 5,69 (1H, users), 7,05-7,20 (4H, m), 7,26-7,37 (3H, m), the 7.65 (1H, DD, J=3.1 Hz, J=7,8 Hz).

Reference example 22

3-[3-(4-Fluoro-2-nitrophenoxy)propyl]-1,1-dimethyloxetane

To a solution of phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (of 5.89 g, 17.6 mmol) in DMF (25 ml) was added 50%aqueous solution of dimethylamine (2.5 ml) and the mixture was stirred at room temperature for 24 hours. To the reaction mixture were added water and the resulting mixture was extracted with ethyl acetate. The organic layer twice item is washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane:ethyl acetate=19:1→4:1→2:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 4,10 g of oily 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyloxetane pale yellow (yield: 82%).

1H NMR (CDCl3) dppm: 2,03-2,12 (2H, m), 2,89 (6H, c), 3,42-to 3.49 (2H, m), 4,17 (2H, t, J=5.8 Hz), is 4.85 (1H, users), to 7.09 (1H, DD, J=4.3 Hz, J=9.3 Hz), 7.24 to to 7.32 (1H, m), to 7.61 (1H, DD, J=3.2 Hz, J=7,8 Hz).

Reference example 23

1-[3-(4-Fluoro-2-nitrophenoxy)propyl]-1,3,3-trimethyloctane

To a solution of 2.0 g of 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyloxetane (7.0 mmol) in DMF (9 ml) was added sodium hydride (55% in oil) (396 mg, 9.1 mmol)under ice cooling and the mixture was stirred at room temperature for 5 minutes. To the mixture was added methyl iodide (0,735 ml of 11.8 mmol) and stirred the mixture at room temperature for 48 hours. To the reaction mixture were added water and extraction was performed with ethyl acetate. After washing with a saturated aqueous solution of sodium chloride the organic layer was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (dichloromethane:ethyl acetate=9:1→6:1). The purified product was concentrated under reduced pressure, thus obtaining 0,83 g of oily 1-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,3,3-trimethyloctane Bleue is but yellow (yield: 40%).

1H NMR (CDCl3) dppm: 2,04-and 2.14 (2H, m), was 2.76 (6H, c), and 2.83 (3H, c), to 3.38 (2H, t, J=6.9 Hz), 4.09 to (2H, t, J=5,9 Hz),? 7.04 baby mortality (1H, DD, J=4.3 Hz, J=9.3 Hz), 7,22-7,30 (1H, m), 7,60 (1H, DD, J=3.1 Hz, J=7,7 Hz).

Reference example 24

5-fluoro-2-propociacion

4-fluoro-2-nitro-1-propoxybenzene (2.0 g, 10.0 mmol) and 5% palladium on coal (750 mg) was added to ethanol (30 ml). The catalytic reaction was conducted at room temperature and atmospheric pressure (normal pressure). The catalyst was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate. The obtained dry product was concentrated under reduced pressure, thus obtaining 1.45 g of oily 5-fluoro-2-propoxyimino red-orange color (yield: 86%).

1H NMR (CDCl3) dppm: the 1.04 (3H, t, J=7.4 Hz), 1,74-of 1.88 (2H, m)to 3.89 (2H, users), 3,90 (2H, t, J=6.5 Hz), of 6.31-6,46 (2H, m), of 6.66 (1H, DD, J=5,1 Hz, J=8.7 Hz).

Compounds of the following reference examples 25 through 42 was obtained in a manner analogous to the above-described method of reference example 24, using appropriate starting compounds.

Reference example 25

5-fluoro-2-isopropoxyaniline

1H NMR (CDCl3) dppm: to 1.32 (3H, c), of 1.35 (3H, c), 3,88 (2H, users), to 4.38-4,48 (1H, m), of 6.31-6,46 (2H, m), 6,68-of 6.73 (1H, m).

Reference example 26

2 Ethoxy-5-ftoranila

1H NMR (CDCl3) dppm: of 1.39 (3H, t, J=7.0 Hz), 3,90 (2H, users), ,97 (2H, kV, J=7,0 Hz), of 6.31-6,46 (2H, m), 6,63 of 6.68 (1H, m).

Reference example 27

5-fluoro-2-morpholine-4-ranelin

1H NMR (CDCl3) dppm: and 2.83 (4H, t, J=4.6 Hz), 3,81 (4H, t, J=4,6Hz), 4,13 (2H, users), 6,38-of 6.45 (2H, m), 6,93-6,97 (1H, m).

Reference example 28

5-fluoro-2-pyrrolidin-1-ranelin

1H NMR (CDCl3) dppm: 1,88-of 1.94 (4H, m), 2,94-of 3.00 (4H, m), a 4.03 (2H, users), 6,35-6,46 (2H, m), 6.90 to-6,95 (1H, m).

Reference example 29

2 Cyclopropylmethoxy-5-ftoranila

1H NMR (CDCl3) dppm: of 0.29 to 0.35 (2H, m), is 0.58-0.65 (2H, m), 1,22-of 1.29 (1H, m), of 3.77 (2H, d, J=6.9 Hz), of 3.94 (2H, users), 6,29-6,46 (2H, m), only 6.64 (1H, DD, J=5,1 Hz, J=8,8 Hz).

Reference example 30

N1-Cyclohexyl-4-fluoro-N1-methylbenzol-1,2-diamine

1H NMR (CDCl3) dppm: a 1.11 to 1.31 (4H, m), 1,55-to 1.82 (6H, m), 2.57 m) of 2.68 (4H, m), 4,18 (2H, users), 6,33-6,44 (2H, m), 6,92-6,98 (1H, m).

Reference example 31

4-Fluoro-N1-(2-methoxyethyl)-N1-methylbenzol-1,2-diamine

1H NMR (CDCl3) dppm: 2,70 (3H, c), 2,96 (2H, t, J=5.4 Hz), 3,39 (3H, c), of 3.45 (2H, t, J=5.4 Hz), to 4.38 (2H, users), 6,33-to 6.43 (2H, m), 6,93-6,99 (1H, m).

Reference example 32

4-Fluoro-N1-isobutyl-N1-methylbenzol-1,2-diamine

1H NMR (CDCl3) dppm: to 0.92 (3H, c), of 0.94 (3H, c), 1,62 of-1.83 (1H, m), 2,54-2,60 (5H, m), 6.30-in-of 6.49 (2H, m), 6,82-6,93 (1H, m).

Reference example 33

4-Fluoro-N1-isopropyl-N1-methylbenzol-1,2-diamine

1H NMR (CDCl3) dppm: of 1.05 (3H, c), with 1.07 (3H, c), to 2.55 (3H, c), 3,06-3,17 (1H, m)to 4.16 (2H, users), 6,34-of 6.45 (2H, m), 6,91-6,97 (1H, m).

Reference example 34

4-Fluoro-N N-methyl-N1-propylbenzoyl-1,2-diamine

1H NMR (CDCl3) dppm: 0,86 (3H, t, J=7.4 Hz), 1.41 to and 1.56 (2H, m), to 2.57 (3H, c), of 2.72 (2H, t, J=7,25 Hz), 4,18 (2H, users), 6,35-6,44 (2H, m), 6,91-6,97 (1H, m).

Reference example 35

N-[3-(2-Amino-4-pertenece)propyl]ndimethylacetamide

1H NMR (CDCl3) dppm: 1,95-of 2.05 (2H, m)of 1.97 (3H, c), 3,42-3,50 (2H, m)to 3.92 (2H, users), was 4.02 (2H, t, J=5,9 Hz), of 5.83 (1H, users), 6,32-6,47 (2H, m), of 6.68 (1H, DD, J=5.0 Hz, J=8,8 Hz).

Reference example 36

N-[3-(2-Amino-4-pertenece)propyl]methanesulfonamide

1H NMR (CDCl3) dppm: 2,02-2,11 (2H, m)to 2.94 (3H, c), 3.33 and is 3.40 (2H, m), 3,91 (2H, users), 4,07 (2H, t, J=5.7 Hz), was 4.76 (1H, users), 6,32-6,46 (2H, m), of 6.68 (1H, DD, J=5.0 Hz, J=8,8 Hz).

Reference example 37

5-fluoro-2-(4,4,4-triptoreline)aniline

1H NMR (CDCl3) dppm: 2,01-2,12 (2H, m), 2,22-to 2.41 (2H, m), a 3.87 (2H, users), to 4.01 (2H, t,J=6.0 Hz), 6,32-6,47 (2H, m), of 6.65 (1H, DD, J=5.0 Hz, J=8,8 Hz).

Reference example 38

1-[3-(2-Amino-4-pertenece)propyl]-1,3,3-trimethyloctane

1H NMR (CDCl3) dppm: 1,99-2,10 (2H, m), 2,78 (6H, c)2,84 (3H, c), 3,37 (2H, t, J=6.9 Hz), of 3.94 (2H, users), of 3.97 (2H, t, J=6,1 Hz), 6.30-in-6,45 (2H, m), of 6.65 (1H, DD, J=5,1 Hz, J=8,8 Hz).

Reference example 39

5-fluoro-2-(2-methoxyethoxy)aniline

1H NMR (CDCl3) dppm: 3,43 (3H, c), 3,70-to 3.73 (2H, m)to 3.99 (2H, users), 4,07-4,10 (2H, m), 6.30-in-6,45 (2H, m), 6,72 (1H, DD, J=5,1 Hz, J=8.7 Hz).

Reference example 40

2 Cyclopentyloxy-5-ftoranila

1H NMR (CDCl3) dppm: 1,56-of 1.66 (2H, m), a 1.75-to 1.87 (6H, m), 3,85 (2H, users), 4,69-4,72 (1H, m), 6.30-in-6,45 (2H, m), of 6.66 (1H, DD, J=5,1 Hz, J=8,8 Hz).

p> Reference example 41

2 Cyclobutylmethyl-5-ftoranila

1H NMR (CDCl3) dppm: 1,86 is 1.96 (4H, m), 2,08-of 2.16 (2H, m), 2,74 is 2.80 (1H, m), 3,90 (2H, users), 3,91 (2H, d, J=6,7 Hz), of 6.31-of 6.45 (2H, m), of 6.66 (1H, DD, J=5,1 Hz, J=8,8 Hz).

Reference example 42

2 Tributoxy-5-ftoranila

1H NMR (CDCl3) dppm: to 1.37 (9H, c), a 3.87 (2H, users), 6,27-of 6.45 (2H, m), 6,85 (1H, DD, J=5.6 Hz, J=8,8 Hz).

Reference example 43

5-fluoro-2-propylsulfonyl

4-fluoro-2-nitro-1-propylsulfonyl (6.7 g, and 31.1 mmol) was dissolved in a mixture solvent of ethanol (40 ml) and water (4 ml). To the mixture was added ammonium chloride (17 g, 0.32 mol) and gradually added powdered zinc (20 g, 0.31 mol). The resulting mixture was stirred at room temperature for 1 hour. The insoluble substance was removed by filtration and the filtrate was concentrated under reduced pressure, thus obtaining 5.8 g of oily 5-fluoro-2-propylsulfonyl brown (yield: 93%).

1H NMR (CDCl3) dppm as 0.96 (3H, t, J=7,3 Hz), 1,49-of 1.64 (2H, m), 2,62 (2H, t, J=7.4 Hz), 4,51 (2H, users), 6,35-6,47 (2H, m), 7,32-7,38 (1H, m).

Reference example 44

4,5-Debtor-2-propociacion

To a solution of 1-bromo-4,5-debtor-2-propoxybenzene (3.0 g, to 11.9 mmol) in toluene (60 ml) solution was added benzophenone (2.38 g, 13,1 mmol), Tris(dibenzylideneacetone)diplegia (275 mg, 0.3 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (347 mg, 0.6 mmol) and the carb is Nata cesium (of 5.83 g, of 17.9 mmol) in toluene (20 ml). The mixture was stirred in nitrogen atmosphere at 100°C. for 23 hours. After cooling the reaction mixture to room temperature, added water and a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether (60 ml) was added concentrated hydrochloric acid (10 ml) to the resulting solution, which was then stirred for 2 hours. To the reaction mixture were added 5 N. aqueous sodium hydroxide solution (24 ml) to obtain a pH of 11 and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure, thus obtaining 850 mg oily 4,5-debtor-2-propoxyimino dark brown (yield: 38%).

1H NMR (CDCl3) dppm: the 1.04 (3H, t, J=7,4Hz), a 1.75-to 1.86 (2H, m), 3,71 (2H, users), 3,88 (2H, t, J=6.5 Hz), 6,51 (1H, DD, J=8.0 Hz, 11.5 Hz), 6,60 (1H, DD, J=7,3 Hz, J=11.8 Hz).

Reference example 45

1-(2-Amino-4-perbenzoic)pyrrolidin

To a solution-florentinamoy acid (2.0 g, 12.8 mmol) in DMF (4 ml) solution was added pyrrolidine (1,93 g, 27,1 mmol) in DMF (4 ml), a solution of triethylamine (3,79 g, 37.5 mmol) in DMF (4 ml), 1-hydroxybenzotriazole (HOBt) (3.11 g, 23,0 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) (3,91 g of 20.4 mmol) in this order. The mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure, thus obtaining of 1.65 g of oily 1-(2-amino-4-perbenzoic)pyrrolidine orange (yield: 62%).

1H NMR (CDCl3) dppm: 1,75-2,00 (4H, m), 3,40 of 3.75 (4H, m), is 4.85 (2H, users), 6,33-6,40 (2H, m), 7,14-7,21 (1H, m).

Reference example 46

Ethyl α-(hydroxymethylene)-4-methoxyphenylacetate

To a solution of ethyl 4-methoxyphenylacetate (2.0 g, of 10.3 mmol) in benzene (10 ml) was added sodium hydride (60% in oil) (467 mg, 11.7 mmol) under cooling with ice. The mixture was stirred at room temperature for 5 minutes. Stir the mixture was again cooled with ice was added thereto ethyl formate (of 1.02 ml, 12.6 mmol) and stirred at room temperature for 3 hours. the ri ice cooling was added to the reaction mixture, water and ethyl acetate and then added 2 N. hydrochloric acid (6 ml) to separate the reaction mixture into two layers. The organic layer was concentrated under reduced pressure, and the residue was then purified column chromatography on silica gel (n-hexane:ethyl acetate=4:1). The purified product was concentrated under reduced pressure, thus obtaining of 1.97 g of oily ethyl α-(hydroxymethylene)-4-methoxyphenylacetate slightly reddish-brown color (yield: 86%). The compound obtained is subjected to nitrogen replacement, and stored in the freezer.

1H NMR (CDCl3) dppm: of 1.28 (3H, t, J=7,1 Hz), 3,81 (3H, c), 4,28 (2H, q, J=7,1 Hz), 6.87 in (2H, d,J=8,8 Hz), 7,16-7,26 (3H, m), 12,02 (1H, d, J=12,5 Hz).

Compounds of the following reference examples from 47 to 57 was obtained in a manner analogous to the above-described method of reference example 46, using appropriate starting compounds.

Reference example 47

Ethyl 2,4-dimethoxy-α-(hydroxymethylene)phenylacetate

1H NMR (CDCl3) dppm: to 1.21 (3H, t, J=7,1 Hz), 3,76 (3H, c), 3,81 (3H, c), 4,22 (2H, q, J=7,1 Hz), to 6.43-of 6.49 (2H, m), 7,00 (1H, d, J=8,9Hz), 7,12 (1H, d, J=12,6 Hz), 11,89 (1H, d, J=12,6 Hz).

Reference example 48

Ethyl 2,4-dichloro-α-(hydroxymethylene)phenylacetate

1H NMR (CDCl3) dppm: to 1.15 (3H, t, J=7.2 Hz), 4,22 (2H, q, J=7.2 Hz), 7,11-7,26 (3H, m), 7,40-the 7.43 (1H, m), 12,00 (1H, d, J=12,2 Hz).

Reference example 49

Ethyl α-(hydroxymethylene)-2-methoxyphenylacetate

1H NMR (CDCl3) dppm: 1,19 (3H,t, J=7,1 Hz), with 3.79 (3H, c), is 4.21 (2H, q, J=7,1 Hz), 6,86-to 7.68 (5H, m), 11,91 (1H, d, J=12.3 Hz).

Reference example 50

Ethyl α-(hydroxymethylene)-2-isopropoxy-4-methoxyphenylacetate

1H NMR (CDCl3) dppm: of 1.20 to 1.31 (9H, m), 3,80 (3H, c)to 4.17 (2H, q, J=7,1 Hz), 4,43-4,47 (1H, m), 6.42 per-6,46 (2H, m), 6.90 to for 7.12 (2H, m), 11,85 (1H, d, J=12,6 Hz).

Reference example 51

Ethyl α-(hydroxymethylene)-4-methoxy-2-methylphenylacetic

1H NMR (CDCl3) dppm: of 1.20 (3H, t, J=7.2 Hz), 2,19 (3H, c), of 3.80 (3H, c), 4,22 (2H, q, J=1,2Hz), 6,54 to 6.75 (2H, m), 7,02-7,26 (2H, m)11,94 (1H, d, J=12,7 Hz).

Reference example 52

Ethyl 2-fluoro-α-(hydroxymethylene)-4-methoxyphenylacetate

1H NMR (CDCl3) dppm: 1,22 (3H, t, J=7,1 Hz), 3,80 (3H, c), is 4.21 (2H, q, J=7,1 Hz), 6,61-6,69 (2H, m), 7.03 is-7,26 (2H, m), a 12.05 (1H, d, J=12.3 Hz).

Reference example 53

Ethyl 4-ethoxy-α-(hydroxymethylene)-2-methoxyphenylacetate

1H NMR (CDCl3) dppm: 1,19-of 1.45 (6H, m in), 3.75 (3H, c), 4,00-4.26 deaths (4H, m), 6.42 per-6,48 (2H, m), 6,97-7,26 (2H, m), up 11,86 (1H, d, J=12.3 Hz).

Reference example 54

Ethyl α-(hydroxymethylene)-4-isopropoxy-2-methoxyphenylacetate

1H NMR (CDCl3) dppm: of 1.20 to 1.31 (9H, m in), 3.75 (3H, c)to 4.16 (2H, q, J=7.2 Hz), 4,43-4,47 (1H, m), to 6.43-6.48 in (2H, m), 6,99-7,22 (2H, m), 11.87 per (1H, d, J=12.3 Hz).

Reference example 55

Ethyl 4-cyclopropylmethoxy-α-(hydroxymethylene)phenylacetate

1H NMR (CDCl3) dppm: 0,35-0,37 (4H, m)of 1.24 (3H, t, J=7,1 Hz), 3,81-a 3.83 (2H, m), 4,25 (2H, q, J=1.1 Hz), 6,85-6,91 (2H, m), 7,16-7,27 (3H, m), 12,02 (1H, d, J=12,5 Hz).

Reference example 56

Ethyl α-(hydroxymethylene)-4-matilal phenylphenolate

1H NMR (CDCl3) dppm: 1,22 (3H, t, J=7,1 Hz), 2,47 (3H, c), 4.09 to (2H, q, J=7,1 Hz), 6,85-6,94 (2H, m), 7,16-7,26 (3H, m), 11,99 (1H, d, J=12.3 Hz).

Reference example 57

Ethyl 4-ethoxy-α-(hydroxymethylene)phenylacetate

1H NMR (CDCl3) dppm: of 1.23 to 1.47 (6H, m), 4,00-4,32 (4H, m), 6,85-to 6.88 (2H, m), 7,15-7,27 (3H, m), 12,00 (1H, d, J=12,5 Hz).

Reference example 58

Ethyl 4-methoxy-α-propionylacetate

To a solution of ethylbromoacetate (3.8 g, to 26.3 mmol) and 4-yoganidra (5.0 g, is 21.3 mmol) in dimethyl sulfoxide (DMSO) (40 ml) was added L-Proline (980 mg, charged 8.52 mmol), copper iodide(I) (810 mg, 4.26 deaths mmol) and cesium carbonate (27.7 g, to 85.2 mmol) in this order. The mixture was stirred in nitrogen atmosphere at a temperature of from 40 to 45°C for 27 hours. The reaction mixture was cooled to room temperature and then added water and an aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate. The organic layer was twice washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=19:1→8:1). The purified product was concentrated under reduced pressure, thus obtaining 2,97 g of oily ethyl 4-methoxy-α-propionylacetate yellow (yield: 56%).

1H NMR (CDCl3) dppm: 1,01-1,11 (3H, m), of 1.18 to 1.31 (3H, m), 2,52-2,61 (2H, m), 3,80 3,82 and (3H, c), 4,15-4,24 (2H, m)and 4.65 (0,6H, c), 6,84-7,28 (4H, m), 13,13 (0,4H, c).

Obedinenie the following reference example 59 was obtained by way similar to the above described method of reference example 58, using appropriate starting compounds.

Reference example 59

Ethyl α-acetyl-4-methoxyphenylacetate

1H NMR (CDCl3) dppm: 1,16-of 1.29 (3H, m), 1.85 to (1,4H, c), 2,17 (1,6H, c), 3,80 3,82 and (1.4 and 1,6H, c), 4,13-of 4.25 (2H, m), 4,62 (0,6H, c), 6,85-7,28 (4H, m), to 13.09 (0,4H, c).

Reference example 60

5-[(5-fluoro-2-propoxyphenyl)methylene]-2,2-dimethyl[1,3]dioxane-4,6-dione

To meteorophobia (31 ml) was added the acid Meldrum (5.29 g, to 36.7 mmol) and the mixture was stirred for 2 hours while boiling under reflux. The resulting mixture was cooled to 50°C and added to it 5-fluoro-2-propociacion (4,28 g, to 25.3 mmol) and meteorophobia (3 ml). The resulting mixture was stirred for 6 hours while boiling under reflux. After that, the obtained reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from methanol, thus obtaining to 7.61 g of powdered 5-[(5-fluoro-2-propoxyphenyl)methylene]-2,2-dimethyl[1,3]dioxane-4,6-dione pale brown (yield: 93%).

1H NMR (CDCl3) dppm: of 1.12 (3H, t, J=7.4 Hz), a 1.75 (6H, c), 1.85 to to 1.98 (2H, m), was 4.02 (2H, t, J=6.3 Hz), 6,86-6,91 (2H, m), 7,06-7,10 (1H, m), at 8.60 (1H, d, J=14.6 Hz), 11,68 (1H, d, J=14,8 Hz).

The connection of the next reference example 61 was obtained in a manner analogous to the above-described method reference PR is a measure 60, when using the appropriate starting compounds.

Reference example 61

5-[(2-Cyclopropylmethoxy-5-forgenerating)methylene]-2,2-dimethyl[1,3]dioxane-4,6-dione

1H NMR (CDCl3) dppm: 0,39-of 0.43 (2H, m), 0,65-to 0.73 (2H, m), is 1.31 to 1.37 (1H, m)of 1.75 (6H, c)to 3.92 (2H, d, J=6.9 Hz), 6,86-6,91 (2H, m), 7,07-7,11 (1H, m), at 8.60 (1H, d, J=14,5 Hz), of 11.69 (1H, d, J=14,3 Hz).

Reference example 62

5-fluoro-8-propoxy-1H-quinoline-4-one

5-[(5-fluoro-2-propoxyphenyl)methylene]-2,2-dimethyl-[1,3]-dioxane-4,6-dione (7.6 g, 23.5 mmol) was added to diphenyl ether (15 ml) and the mixture was heated by means of the mantle, and then left at boiling under reflux for 2 hours. After cooling the reaction mixture to room temperature, was added ethyl acetate (5 ml) and n-hexane (10 ml). The resulting mixture was stirred and was allocated the obtained insoluble substance by filtration. The filtrate was recrystallized from a solvent mixture of ethyl acetate-n-hexane, thus obtaining a 3.15 g of powdered 5-fluoro-8-propoxy-1H-quinoline-4-it is dark brown (yield: 61%).

1H NMR (DMSO-d6) dppm: of 1.03 (3H, t, J=7,3 Hz), 1,74-of 1.88 (2H, m), 4,07 (2H, t, J=6.4 Hz), 5,97 (1H, d, J=7,4 Hz), 6.87 in (1H, DD, J=8,8 Hz, to 11.9 Hz), 7,13 (1H, DD, J=4.0 Hz, J=8,8 Hz), of 7.70 (1H, t, J=1,2Hz), 11,07 (1H, users).

The connection of the next reference example 63 was obtained in a manner analogous to the above-described method of reference example 62, using relevant is similar compounds.

Reference example 63

8 Cyclopropylmethoxy-5-fluoro-1H-quinoline-4-one

1H NMR (DMSO-d6) dppm: 0,34-0,40 (2H, m), 0.55 to 0,61 (2H, m), of 1.27 and 1.33 (1H, m), 3,98 (2H, d, J=7,0 Hz), 5,97 (1H, d, J=7,4 Hz)6,86 (1H, DD, J=8,8 Hz, J=11,9 Hz), 7,13 (1H, DD, J=4.0 Hz, J=8,8 Hz), 7,71 (1H, t, J=7.4 Hz), 11,10 (1H, users).

Reference example 64

5-fluoro-2-methyl-8-propoxy-1H-quinoline-4-one

To a solution of 5-fluoro-2-propoxyimino (10 g, 59 mmol) and ethylacetoacetate (7.7 g, 59 mmol) in benzene (200 ml) was added Amberlyst 15 (1.0 g, product of Sigma Aldrich Corp.). The mixture was stirred while boiling under reflux for 6 hours and the use of nozzles Dean-stark. The reaction mixture was cooled to room temperature, the resin was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added diphenyl ether (20 ml). The mixture was heated with mantle and stirred at the boil under reflux for 2 hours. After cooling the reaction mixture to room temperature, the insoluble matter obtained by adding a mixture of n-hexane-ethyl acetate (2:1), was isolated by filtration. Remaining on the filter substance was washed with a mixture of n-hexane-ethyl acetate (2:1) and dried, thus obtaining 6.0 g of powdered 5-fluoro-2-methyl-8-propoxy-1H-quinoline-4-it is pale yellow (yield: 43%).

1H NMR (DMSO-d6) dppm: to 0.97 (3H, t, J=7,3 Hz), 1,77-to 1.87 (2H, m), of 2.34 (3H, c), 4,08 (2H, t, J=6,4 Hz) of 5.84 (1H, c), 6,79-to 6.88 (1H, m), 7,10-7,14 (1H, m), of 10.58 (1H, users).

Reference example 65

5-fluoro-3-iodine-8-propoxy-1H-quinoline-4-one

5-fluoro-8-propoxy-1H-quinoline-4-one (1.0 g, to 4.52 mmol) suspended in DMF (11 ml) was added to a suspension of potassium carbonate (0.7 g, of 5.06 mmol) and iodine (1.27 g, 5.00 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into aqueous sodium thiosulfate solution (3.94 g, 25 mmol) (45 ml). The mixture was stirred for 5 minutes. To the obtained reaction mixture was added ethyl acetate and stirred, while highlighting the insoluble substance by filtration. The filtrate was separated and washed organic layer with a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure. The residue and dedicated insoluble substance was combined, and then was purified column chromatography on silica gel (dichloromethane:methanol=50:1→40:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining a 1.25 g of powdered 5-fluoro-3-iodine-8-propoxy-1H-quinoline-4-she is pale dark brown (yield: 80%).

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.4 Hz), 1,78 is 1.86 (2H, m), 4.09 to (2H, t, J=6.5 Hz), 6,97 (1H, DD, J=8,8 Hz, J=11,9 Hz), 7,19 (1H, DD, J=4.0 Hz, J=8,8 Hz), 8,19 (1H, c), 11,44 (1H, users).

Compounds of the following reference examples 66 and 67 received in a manner analogous to the above-described method reference is about example 65, when using the appropriate starting compounds.

Reference example 66

5-fluoro-3-iodine-2-methyl-8-propoxy-1H-quinoline-4-one

1H NMR (CDCl3) dppm: to 0.97 (3H, t, J=7.4 Hz), 1,78-of 1.88 (2H, m), 2,70 (3H, c), 6,92-7,00 (1H, m), 7,17-7,22 (1H, m).

Reference example 67

8 Cyclopropylmethoxy-5-fluoro-3-iodine-1H-quinoline-4-one

1H NMR (DMSO-d6) dppm: 0,36-0,40 (2H, m), of 0.56 to 0.63 (2H, m), of 1.28 to 1.31 (1H, m), 3,99 (2H, d, J=7,0 Hz), 6,97 (1H, DD, J=8,8 Hz, J=11,9 Hz), 7,19 (1H, DD, J=4.0 Hz, J=8,8 Hz), 8,19 (1H, c), of $ 11.48 (1H, users).

Reference example 68

8 Cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodine-1H-quinoline-4-one

To a solution of 8-cyclopropylmethoxy-5-fluoro-3-iodine-1H-quinoline-4-she (910 mg, 2,53 mmol) in DMF (5 ml) was added potassium carbonate (450 mg, 3,26 mmol). The mixture was stirred for 15 minutes at room temperature. Was added thereto ethyl iodide (0.31 in ml, a 3.87 mmol) and stirred the mixture at 60°C for 2 hours. After cooling the reaction mixture to room temperature was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue is then purified column chromatography on silica gel (dichloromethane:ethyl acetate=40:1→15:1). The purified product was concentrated to dryness under reduced pressure, while receiving 750 mg powder 8 cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodine-1H-quinoline-4-it is pale-dark-brown color (yield: 77%).

1H NMR (DMSO-d6) dppm: 0,34-0,38 (2H, m), 0,57-of 0.64 (2H, m), 1,26-of 1.36 (4H, m), 3,93 (2H, d, J=7,3 Hz), 4,56 (2H, q, J=7.0 Hz), 7,05 (1H, DD, J=8,9 Hz, J=11.4 in Hz)of 7.24 (1H, DD, J=4,6 Hz, J=9.0 Hz), to 8.45 (1H, c).

Reference example 69

2,2,2-Cryptor-N-(5-fluoro-2-propoxyphenyl)ndimethylacetamide

A solution of 5-fluoro-2-propoxyimino (10.0 g, 59,1 mmol) in dichloromethane (60 ml) cooled in ice was added thereto triethylamine (16.5 ml). Then add the anhydride triperoxonane acid (14.8 g, 70.5 mmol) and stirred the mixture at room temperature for 1 hour. To the reaction mixture were added water and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous sodium sulfate. The obtained dry product was concentrated under reduced pressure and the residue was then purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 15,83 g powdered 2,2,2-Cryptor-N-(5-fluoro-2-propoxyphenyl)ndimethylacetamide white (yield: 99%).

1H NMR (CDCl3) dppm: of 1.03 (3H, t, J=7.5 Hz), 1,79-of 1.93 (2H, m), 3,98 (2H, t, J=6.5 Hz), 6,80-6,86 (2H, m), 8,10-to 8.12 (1H, m)8,64 (1H, users).

Reference example 70

Ethyl ester 4,4,4-Cryptor-3-(5-fluoro-2-propoxyphenyl)buta-2-ene acid

To a solution of 2,2,2-Cryptor-N-(5-fluoro-2-propoxyphenyl)ndimethylacetamide (15,83 g, 59,1 mmol) in toluene (100 ml) was added carboethoxy is methyltriphenylphosphonium (41,52 g, 119,2 mmol). The mixture was stirred in nitrogen atmosphere while boiling under reflux for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was then purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1). The purified product was concentrated under reduced pressure, thus obtaining of 19.7 g of oily ethyl ester 4,4,4-Cryptor-3-(5-fluoro-2-propoxyphenyl)buta-2-ene acid yellow (yield: 99%).

1H NMR (CDCl3) dppm: of 1.02 (3H, t, J=7.5 Hz), of 1.28 (3H, t, 7.0 Hz), 1,74-of 1.88 (2H, m), 3,85 (2H, t, J=6.5 Hz), 4,17 (2H, q, J=7.0 Hz), 5,41 (1H, c), 6,77-6,97 (3H, m), 9,77 (1H, users).

Reference example 71

5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

To ethyl ether 4,4,4-Cryptor-3-(5-fluoro-2-propoxyphenyl)buta-2-ene acid (19.7 g, or 59.0 mmol) was added to diphenyl ether (15 ml) and the mixture was stirred for 1.5 hours while boiling under reflux. The reaction mixture was cooled to room temperature, was added n-hexane, and provided the precipitation by filtration. Remaining on the filter substance was washed with n-hexane and dried, to thereby obtain 16.2 g of powdered 5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinoline-4-it is white in color (yield: 94%).

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7.5 Hz), 1,76-1,90 (2H, m), 4,07 (2H, t, J=6.5 Hz), 7.18 in-to 7.32 (3H, m), of 12.26 (1H, users).

The fair is full example 72

5-fluoro-3-iodine-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

To a solution of 5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinoline-4-it (6.0 g, of 20.7 mmol) in DMF (20 ml) was added potassium carbonate (of 3.73 g, 27 mmol) and iodine (6.85 g, 27 mmol) in this order and stirred the mixture at room temperature for 1.5 hours. To the reaction mixture were added saturated aqueous solution of sodium sulfite (20 ml) and ethyl acetate, and provided the precipitation by filtration. The filtrate was washed with water and then dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced pressure. The balance and substance, selected pre-filtration were combined and dissolved in ethanol, and then concentrated. The residue was recrystallized from a solvent mixture of ethyl acetate-n-hexane, thus obtaining 4.7 grams of powdered 5-fluoro-3-iodine-8-propoxy-2-trifluoromethyl-1H-quinoline-4-it is white in color (yield: 55%).

1H NMR (DMSO-d6) dppm as 0.96 (3H, t, J=7.5 Hz), 1,70-1,80 (2H, m), of 3.95 (2H, t, J=6.5 Hz), 6,64-6,85 (2H, m), 12,02 (1H, users).

Reference example 73

1-(5-Bromo-2-cyclopentylacetyl)alanon

To a solution of 5'-bromo-2'-hydroxyacetophenone (8.5 g, to 39.5 mmol) in DMF (10 ml) was added potassium carbonate (6,55 g, with 47.4 mmol), cyclopentylamine (8,25 g, 55.3 mmol) and DMF (5 ml), and stirred the mixture at 60°C for 4.5 hours. To the mixture was added potassium carbonate (3.0 g, and 21.7 mmol) ecyclopedia (2.0 g, the 13.4 mmol) and stirred at 60°C for 9 hours. After cooling the reaction mixture to room temperature was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure, thus obtaining 11.3 g of oily 1-(5-bromo-2-cyclopentylacetyl)ethanone pale yellow (yield: 100%).

1H NMR (CDCl3) dppm: 1,68-of 1.95 (8H, m), 2,58 (3H, c), a 4.83-to 4.87 (1H, m), 6,83 (1H, d, J=8,9 Hz), 7,49 (1H, DD, J=2,6 Hz and 8.9 Hz), 7,82 (1H, d, J=2,6 Hz).

Reference example 74

The oxime 1-(5-bromo-2-cyclopentylacetyl)ethanone

1-(5-Bromo-2-cyclopentylacetyl)alanon (5.0 g, 17,65 mmol) was dissolved in a mixture solvent of chloroform (18 ml) and methanol (70 ml). To the resulting solution was added hydroxylamine hydrochloride (1.88 g, of 27.0 mmol) and pyridine (4,36 ml, 54.1 mmol) and the mixture was stirred for 6 hours at the boil under reflux. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added 2 N. hydrochloric acid (to 13.9 ml) and the resulting mixture was extracted with dichloromethane. The organic layer was washed with saturated waters is the first solution of sodium chloride, was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with n-hexane and dried, thus obtaining 4.6 g of powdery oxime 1-(5-bromo-2-cyclopentylacetyl)ethanone white (yield: 87%).

1H NMR (CDCl3) dppm: 1,65-1,90 (8H, m), 2,17 (3H, c), 4,72 was 4.76 (1H, m), 6,76 (1H, d, J=8,4 Hz), 7,35-7,41 (2H, m), to 7.99 (1H, users).

Reference example 75

N-(5-Bromo-2-cyclopentylacetyl)ndimethylacetamide

The oxime 1-(5-bromo-2-cyclopentylacetyl)ethanone (4,56 g of 15.3 mmol) suspended in acetonitrile (100 ml). Add to it the chloride indium(III) (507 mg, to 2.29 mmol) and heated the mixture at boiling under reflux for 2 hours in nitrogen atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was extracted with dichloromethane. The organic layer was washed saturated aqueous sodium chloride and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=8:1→4:1). The purified product was concentrated under reduced pressure, thus obtaining 3,41 g of oily N-(5-bromo-2-cyclopentylacetyl)ndimethylacetamide pale yellow (yield: 75%).

1H NMR (CDCl3) dppm: 1,67-of 1.94 (8H, m)to 2.18 (3H, c), 4,75-to 4.81 (1H, m), 6,72 (1H, d, J=8.7 Hz), 7,10 (1H, DD, J=2.3 Hz, 8.7 Hz), to 7.67 (1H, users), 8,55 (1H, d, J=2.3 Hz).

Reference example 76

5-Bromo-2-cyclopentylacetyl

To a solution of N-(5-bromo-2-cyclopentylacetyl)ndimethylacetamide (3.4 g, to 11.4 mmol) in ethanol (100 ml) was added concentrated hydrochloric acid (5.8 ml) and stirred the mixture for 3 hours at the boil under reflux. After cooling the reaction mixture to room temperature was added 5 n sodium hydroxide solution (14,2 ml) to obtain a pH of 11. After that obtained was extracted with a mixture of dichloromethane. The organic layer was washed saturated aqueous sodium chloride and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=4:1). The purified product was concentrated under reduced pressure, thus obtaining 2,97 g of oily 5-bromo-2-cyclopentylacetyl pale yellow (yield: 100%).

1H NMR (CDCl3) dppm: 1,62-1,89 (8H, m), 3,80 (2H, users), 4,71-of 4.75 (1H, m), is 6.61 (1H, d, J=8,4 Hz), 6.75 in-for 6.81 (2H, m).

Example 1

5-fluoro-3-furan-3-yl-8-propoxy-1H-quinoline-4-one

5-fluoro-3-iodine-8-propoxy-1H-quinoline-4-one (780 mg, 2,24 mmol) suspended in a solvent mixture of toluene (10 ml) and methanol (1.6 ml) was added furan-3-Bronevoy acid (752 mg), tetrakis(triphenylphosphine)palladium (130 mg, 0.11 mmol) and 2 N. aqueous sodium carbonate solution (2.25 ml) in this order. The mixture paramesh the Wali in nitrogen atmosphere at 110°C for 20 hours. After cooling the reaction mixture to room temperature was added water and the resulting mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, then the residue was purified column chromatography on silica gel (dichloromethane:methanol=60:1→50:1). The purified product was concentrated under reduced pressure and recrystallized from ethanol, to thereby obtain 180 mg of powdered 5-fluoro-3-furan-3-yl-8-propoxy-1H-quinoline-4-it is pale yellow (yield: 58%).

The melting point of 214-215°C.

1H NMR (DMSO-d6) dppm: 1,02 (3H, J=7,3 Hz), 1,78-to 1.87 (2H, m), 4.09 to (2H, t, J=6.4 Hz), 6.87 in-6,95 (2H, m), 7,13 (1H, DD, J=3.8 Hz, J=8,8 Hz), to 7.67 (1H, c), 8,11 (1H, c), 8,51 (1H, c), 11,50 (1H, users).

Compounds of the following examples 2 through 5 were obtained in a manner analogous to the method described above in example 1, using appropriate starting compounds.

Example 2

5-fluoro-3-(3-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

Grey powder (ethanol).

Melting point 194-195°C.

1H NMR (DMSO-d6) dppm: of 1.03 (3H, t, J=7,3 Hz), 1,79-to 1.87 (2H, m), of 3.84 (3H, c), 4.09 to (2H, t, J=6.4 Hz), make 6.90 (1H, DD, J=8.7 Hz, J=12.1 Hz), 7,12-7,19 (2H, m), 7,35-7,39 (1H, m), 7,56 (1H, DD, J=2.0 Hz, J=13.5 Hz), 7,87 (1H, c), 11,40 (1H, users).

Example 3

5-fluoro-8-propoxy-3-thiophene-3-yl-1H-quinoline-4-one

Pale brown powder (ethanol).

Melting point 208-210°C.

1H NMR (DMSO-d6)dppm: 1,02 (3H, t, J=7.4 Hz), 1,75-1,89 (2H, m), 4,08 (2H, t, J=6.4 Hz), make 6.90 (1H, DD, J=8.7 Hz, J=12.1 Hz), 7,13 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,50-EUR 7.57 (2H, m), 8,14 (1H, c), 8,19-8,21 (1H, m), 11,42 (1H, users).

Example 4

3-(3-Chloro-4-methoxyphenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale yellow powder (ethanol).

Melting point 217-218°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz), 1,78 is 1.86 (2H, m), 3,85 (3H, s)4,08 (2H, t, J=6.4 Hz), make 6.90 (1H, DD, J=8,8 Hz, J=12.0 Hz), 7,10-to 7.15 (2H, m), 7,51 (1H, DD, J=2.1 Hz, J=8.5 Hz), 7,74 (1H, d, J=2.1 Hz), 7,87 (1H, s), of 11.45 (1H, users).

Example 5

5-fluoro-8-propoxy-3-(4-trifloromethyl)-1H-quinoline-4-one

Pale grey powder (ethanol).

Melting point 212-214°C.

1H NMR (DMSO-d6) dppm: of 1.03 (3H, t, J=7,3 Hz), 1,79-to 1.87 (2H, m), 4.09 to (2H, t, J=6.4 Hz), 6,92 (1H, DD, J=8,8 Hz, J=12.0 Hz), 7,16 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,35 (2H, d, J=8.5 Hz), 7,73 (2H, d, J=8.7 Hz), to $ 7.91 (1H, c), of 11.45 (1H, users).

Example 6

5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

To a solution of 5-fluoro-2-propoxyimino (16,25 g, 96,0 mmol) and ethyl α-(hydroxymethylene)-4-methoxyphenylacetate (21,34 g, 96,0 mmol) in benzene (150 ml) was added Amberlyst 15 (1.0 g, product of Sigma Aldrich Corp.). The mixture was heated at the boil under reflux for 14 hours when using nozzles Dean-stark and stirring. The reaction mixture was cooled to room temperature, the resin was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added diphenyl ether (40 ml) and load the Wali mixture using mantle, and stirred at the boil under reflux for 2 hours. The reaction mixture was cooled to room temperature and directly purified column chromatography on silica gel (dichloromethane:methanol=100:0→30:1→20:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from ethanol, thus obtaining 5,28 g of powdered 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-it is pale yellow (yield: 17%).

Melting point 196-197°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz), 1,78 is 1.86 (2H, m in), 3.75 (3H, c)4,07 (2H, t, J=6.4 Hz), 6,83-of 6.96 (3H, m), 7,11 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,53 (2H, d, J=8,8 Hz), 7,81 (1H, c), 11,50 (1H, users).

Compounds of the following examples 7 to 46 was obtained in a manner analogous to the method described above in example 6, using appropriate starting compounds.

Example 7

5-fluoro-3-(2-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

The melting point of 193-195°C.

1H NMR (CDCl3) dppm: of 1.05 (3H, t, J=7.5 Hz), 1,82-of 1.97 (2H, m), of 3.77 (3H, c), of 4.05 (2H, t, J=6.3 Hz), 6,77-7,02 (4H, m), 7,26-7,29 (1H, m), 7,42 was 7.45 (1H, m), 7,72-7,74 (1H, m), 8,83 (1H, users).

Example 8

3-(2,4-Acid)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 116-118°C.

1H NMR (CDCl3) dppm with 1.07 (3H, t, J=7.5 Hz), 1,84-to 1.98 (2H, m), 3,76 (3H, c), of 3.84 (3H, c)4,06 (2H, t, J=7.5 Hz), 6,54 return of 6.58 (2H, m),6,77-6,92 (2H, m), 7,38-7,42 (1H, m), 7,72 to 7.75 (1H, m), 8,79 (1H, users).

Example 9

5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 193-194°C.

1H NMR (CDCl3) dppm: of 1.39 (6H, d, J=5.0 Hz), with 3.79 (3H, c), 4,58 (1H, q, J=5.0 Hz), 6,79-6,92 (4H, m), 7,54-EUR 7.57 (2H, m), 7.68 per-7,71 (1H, m), 8,80 (1H, users).

Example 10

3-(2,4-Dichlorophenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 256-259°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7.5 Hz), 1,79-to 1.87 (2H, m), 4,08 (2H, t, J=6.3 Hz), 6,88-6,98 (1H, m), of 6.96-7,72 (1H, m), 7,37-7,47 (2H, m), 7,65-to 7.67 (1H, m), 7,75-to 7.77 (1H, m), 11,42 (1H, users).

Example 11

8 Ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 155-156°C.

1H NMR (CDCl3) dppm: of 1.46 (3H, t, J=7.5 Hz), 3,81 (3H, c), 4,14 (2H, q, J=7.5 Hz), 6,77-6,94 (4H, m), 7,54-of 7.60 (2H, m), 7,71-7,73 (1H, m), of 9.02 (1H, users).

Example 12

3-(2,4-Acid)-8-ethoxy-5-fluoro-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 154-155°C.

1H NMR (CDCl3) dppm: the 1.44 (3H, t, J=7.5 Hz), to 3.73 (3H, c), 3,81 (3H, c), of 4.12 (2H, q, J=7.5 Hz), 6,50-6,53 (2H, m), 6,54-6,89 (2H, m), 7,35-7,39 (1H, m), 7,69-7,72 (1H, m), 8,97 (1H, users).

Example 13

3-(2,4-Dichlorophenyl)-8-ethoxy-5-fluoro-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 236-237°C.

1H NMR (DMSO-d6) dppm: of 1.40 (3H, t, J=1,5Hz), 4,17 (2H, q, J=7.5 Hz), 6,88-7,00 (1H, m), 722-7,32 (1H, m), 7,38 was 7.45 (2H, m), of 7.64-the 7.65 (1H, m), 7,74 to 7.75 (1H, m), 11,40 (1H, users).

Example 14

5-fluoro-3-(4-methoxyphenyl)-8-morpholine-4-yl-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 249-251°C.

1H NMR (CDCl3) dppm: 2,75-up 3.22 (4H, m), 3,65-to 4.15 (4H, m), 6,85-6,93 (3H, m), 7,34-7,40 (1H, m), 7,54-7,58 (2H, m), 7,74-to 7.77 (1H, m), 10,02 (1H, users).

Example 15

5-fluoro-3-(2-isopropoxy-4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 204-206°C.

1H NMR (CDCl3) dppm: 1,09 (3H, t, J=6.3 Hz), of 1.23 (3H, c), of 1.26 (3H, c), 1,87 is 2.01 (2H, m), 3,83 (3H, c), 4,08 (2H, t, J=6.3 Hz), 4,34-4,50 (1H, m), 6,55-6,60 (2H, m), 6,78-6,93 (2H, m)to 7.50 (1H, d, J=7.5 Hz), 7,80 (1H, d, J=7.5 Hz), 8,73 (1H, users).

Example 16

5-fluoro-3-(4-methoxy-2-were)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 197-199°C.

1H NMR (CDCl3) dppm: of 1.06 (3H, t, J=6.3 Hz), 1,80-2,00 (2H, m), 2,24 (3H, c), of 3.80 (3H, c)4,07 (2H, t, J=6.3 Hz), 6,70-6,94 (4H, m), 7,07 (1H, d, J=7.5 Hz), 7,54 (1H, d, J=7.5 Hz), 8,80 (1H, users).

Example 17

5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate-ethanol).

Melting point 230-232°C.

1H NMR (CDCl3) dppm: of 1.05 (3H, t, J=7.5 Hz), 1,80-2,00 (2H, m), 3,80 (3H, c)4,06 (2H, t, J=7.5 Hz), 6,64-6,93 (4H, m), 7,53-of 7.60 (1H, m), 7,74 for 7.78 (1H, m), 8,86 (1H, users).

Example 18

5-fluoro-3-(4-methoxyphenyl)-8-pyrrolidin-1-yl-1H-quinoline-4-one

Pale brown powder (ethyl acetate-n-hexane).

Temperature is Lavinia 100-105°C.

1H NMR (CDCl3) dppm: 1,90-of 2.08 (4H, m), 3,01-3,20 (4H, m), 3,81 (3H, c), for 6.81-6,94 (3H, m), 7,29-7,34 (1H, m), 7,55-of 7.60 (2H, m), 7,74-7,76 (1H, m), 9,41 (1H, users).

Example 19

3-(4-Ethoxy-2-methoxyphenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate).

The melting point of 118-120°C.

1H NMR (CDCl3) dppm: of 1.06 (3H, t, J=7.5 Hz), of 1.39 (3H, t, J=7.5 Hz), 1,83-to 1.98 (2H, m in), 3.75 (3H, c), 4,00-to 4.14 (4H, m), 6,51-6,55 (2H, m), 6,76-6,91 (2H, m), 7,38 (1H, d, J=6.2 Hz), 7,72 (1H, d, J=6.2 Hz), 8,65 (1H, users).

Example 20

5-fluoro-3-(4-isopropoxy-2-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate-n-hexane).

Melting point 113-115°C.

1H NMR (CDCl3) dppm: the 1.04 (3H, t, J=7.5 Hz), of 1.33 (3H, c), of 1.36 (3H, c), 1,80-of 1.95 (2H, m), and 3.72 (3H, c), a 4.03 (2H, t, J=7.5 Hz), 4,50-4,71 (1H, m), of 6.49-6,53 (2H, m), 6,78-6,86 (2H, m), 7,34-7,38 (1H, m), 7,42-7,74 (1H, m,), 8,82 (1H, users).

Example 21

5,6-Debtor-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate-n-hexane).

Melting point 198-200°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz), 1,78 is 1.86 (2H, m in), 3.75 (3H, c), 4,11 (2H, t, J=6.4 Hz), 6,93 (2H, d, J=8,8 Hz), 7,38 (1H, DD, J=6,5 Hz, J=12.3 Hz), 7,54 (2H, d, J=8,8 Hz), 7,81 (1H, c), 11,50 (1H, users).

Example 22

8-Bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 134-135°C.

1H NMR (DMSO-d6) dppm: of 3.78 (3H, c), 6,94-7,02 (3H, m), 7,52 (2H, d, J=6.3 Hz), to 7.84 (1H, c), 7,89-8,00 (1H, m), 11,20 (1H, users).

Example 23

5-Ft is R-3-(4-methoxyphenyl)-8-(pyrrolidin-1-carbonyl)-1H-quinoline-4-one

Orange powder (ethyl acetate).

Melting point 236-237°C.

1H NMR (DMSO-d6) dppm: 1,77 is 1.91 (4H, m), 3,29-to 3.34 (2H, m), 3,54-3,59 (2H, m), 3,76 (3H, c)6,94 (2H, d, J=8,7Hz), 7,02 (1H, DD, J=8,3 Hz, J=11.8 Hz), 7,53 (2H, d, J=8.7 Hz), 7,71 (1H, DD, J=5,1 Hz, J=8,3 Hz), 7,88 (1H, c), of 11.26 (1H, c).

Example 24

8 Cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate-ethanol).

The melting point of 190-191°C.

1H NMR (DMSO-d6) dppm: of 0.33 to 0.39 (2H, m), 0.55 to to 0.62 (2H, m), of 1.26 to 1.34 (1H, m in), 3.75 (3H, c)to 3.99 (2H, d, J=7,0 Hz), 6,83-to 6.95 (3H, m), 7,12 (1H, DD, J=3.8 Hz, J=8,8 Hz), 7,53 (2H, d, J=8.6 Hz), 7,82 (1H, c), 11,34 (1H, users).

Example 25

8-(N-cyclohexyl-N-methylamino)-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 224-225°C.

1H NMR (DMSO-d6) dppm: 1,00-1,24 (5H, m), 1,53 of 1.99 (5H, m), 2,65 (3H, c), of 3.78 (3H, c), 6,92-of 6.99 (3H, m), 7,50-EUR 7.57 (3H, c), 7,87 (1H, c), of 10.93 (1H, users).

Example 26

N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]propyl}ndimethylacetamide

Pale brown powder (ethanol).

Melting point 229-231°C.

1H NMR (DMSO-d6) dppm: 1,80 (3H, c), 1,91 is 1.96 (2H, m), 3,24-and 3.31 (2H, m), 3,74 (3H, c), of 4.12 (2H, t, J=5.6 Hz), 6,84-7,13 (4H, m), 7,53 (2H, d, J=8.6 Hz), 7,83 (1H, c), 8,01 (1H, users), 11,40 (1H, users).

Example 27

N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]propyl}methanesulfonamide

Pale brown powder (ethanol).

Temperature plavini is 120-121°C.

1H NMR (DMSO-d6) dppm: 1,96-to 2.06 (2H, m), is 2.88 (3H, c), 3,10-3,30 (2H, m in), 3.75 (3H, c), 4,18 (2H, t, J=5,9 Hz), 6,85-to 6.95 (3H, m), 7,00-7,16 (2H, m), 7,54 (2H, d, J=8.7 Hz), 7,82 (1H, c), 11,34 (1H, users).

Example 28

5-fluoro-8-(N-isobutyl-N-methylamino)-3-(4-methoxyphenyl)-1H-quinoline-4-one

White powder (ethyl acetate).

The melting point of 144-145°C.

1H NMR (DMSO-d6) dppm: 0,86 (3H, c), of 0.91 (3H, c), 1,61-to 1.67 (1H, m), 2,61 (3H, c), 2,80 (2H, d, J=6.75 Hz), with 3.79 (3H, c), 6,91-of 6.99 (3H, m), 7,46-EUR 7.57 (3H, m), 7,88 (1H, c), 11,02 (1H, users).

Example 29

5-fluoro-8-(N-isopropyl-N-methylamino)-3-(4-methoxyphenyl)-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 267-269°C.

1H NMR (DMSO-d6) dppm: 1,04 (3H, c), of 1.06 (3H, c), 2,62 (3H, c), 3,10-3,18 (1H, m), 3,76 (3H, c), 6,90-6,98 (3H, m), 7,47-of 7.55 (3H, m), a 7.85 (1H, c), 10,94 (1H, users).

Example 30

5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 145-146°C.

1H NMR (DMSO-d6) dppm: of 0.79 (3H, t, J=7.5 Hz), 1,31-to 1.45 (2H, m), 2.63 in (3H, c), 2,85 (2H, t, J=7.5 Hz), 3,76 (3H, c), 6,89-6,97 (3H, m), 7,43-rate of 7.54 (3H, m), 7,82 (1H, c), 11,07 (1H, users).

Example 31

5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-triptoreline)-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 171-172°C.

1H NMR (DMSO-d6) dppm: 1,99-of 2.08 (2H, m), 2,48-2,61 (2H, m), 3,74 (3H, c)to 4.17 (2H, t, J=5,9 Hz), 6,84-6,94 (3H, m), 7,11 (1H, DD, J=3.8 Hz, J=8,8 Hz), 7,53 (2H, d, J=8.7 Hz), 7,82 (1H, c), 11,40 (1H, users).

Example 32

1-{3-[5-fluoro-3-(4-methoxyphenyl is)-4-oxo-1,4-dihydroquinoline-8 yloxy]propyl}-1,3,3-trimethyloctane

Brown amorphous solid (diethyl ether).

1H NMR (DMSO-d6) dppm: 2,00-of 2.05 (2H, m), 2.63 in (6H, c)to 2.74 (3H, c), 3,20-3,40 (2H, m), 3,76 (3H, c), of 4.12 (2H, t, J=6.0 Hz), 6,85-of 6.96 (3H, m), 7,14 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,55 (2H, d, J=8.7 Hz), 7,81 (1H, c), 11,40 (1H, users).

Example 33

3-(4-Ethoxyphenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 203-205°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz)of 1.13 (3H, t, J=7.0 Hz), 1,76 is 1.91 (2H, m), 3,99 is 4.13 (4H, m), 6,84-6,94 (3H, m), 7,12-7,17 (1H, m)to 7.50 (2H, d, J=7.5 Hz), 7,79 (1H, c), 11,25 (1H, users).

Example 34

Hydrochloride 5-fluoro-8-[N-(2-methoxyethyl)-N-methylamino]-3-(4-methoxyphenyl)-1H-quinoline-4-it

Pale yellow powder (ethyl acetate).

The melting point of 100-101°C.

1H NMR (DMSO-d6) dppm: 2,78 (3H, c), is 3.08 (2H, t, J=5.3 Hz), to 3.33 (3H, c)to 3.49 (2H, t, J=5.3 Hz), 3,81 (3H, c), 6,94-7,02 (3H, m), 7,50 to 7.62 (3H, m), 8,00 (1H, c), 11,16 (1H, users).

Example 35

3-(4-Cyclopropylmethoxy)-5-fluoro-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 162-163°C.

1H NMR (DMSO-d6) dppm: 0,30-0,35 (2H, m), 0,54 is 0.58 (2H, m), a 1.01 (3H, t, J=7.5 Hz), 1,10-1,30 (1H, m), 1,72 is 1.91 (2H, m), 3,80 (2H, d, J=7,0 Hz), 4,07 (2H, t, J=6.4 Hz), 6,84-6,93 (3H, m), 7,11-7,16 (1H, m)to 7.50 (2H, d, J=8,8 Hz), 7,79 (1H, c), 11,25 (1H, users).

Example 36

5-fluoro-8-(2-methoxyethoxy)-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 142-144°C.

1H NMR (DMSO-d6 ) dppm: 3,31 (3H, c), 3,70-of 3.80 (2H, m in), 3.75 (3H, c), 4,20-4,30 (2H, m), 6,84-6,94 (3H, m), 7,16 (1H, DD, J=3,6 Hz, J=8.7 Hz), 7,53 (2H, d, J=8,4 Hz), 7,82 (1H, c), 11,10 (1H, users).

Example 37

8 Cyclopentyloxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 213-215°C.

1H NMR (DMSO-d6) dppm: 1,50-1,70 (2H, m), 1,71 is 2.00 (6H, m in), 3.75 (3H, c), 4,92-of 4.95 (1H, m), 6,83-to 6.95 (3H, m), to 7.09 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,53 (2H, d, J=8.6 Hz), 7,80 (1H, c), 11,20 (1H, users).

Example 38

5-fluoro-3-(4-methylsulfinylphenyl)-8-propoxy-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 198-199°C.

1H NMR (CDCl3) dppm with 1.07 (3H, t, J=7.4 Hz), 1.85 to 2,04 (2H, m)of 2.50 (3H, c)4,07 (2H, t, J=6.6 Hz), 6,80-6,94 (2H, m), 7,27-7,31 (2H, m), 7,56 (2H, d, J=8,4 Hz), 7,74 (1H, d, J=8,2 Hz), 8,81 (1H, users).

Example 39

5-fluoro-3-(4-methoxyphenyl)-8-(tetrahydrofuran-2-ylethoxy)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 108-110°C.

1H NMR (DMSO-d6) dppm: 1,67-of 1.75 (1H, m), 1,81-1,90 (2H, m), 2,02-of 2.09 (1H, m), 3,65-a 3.83 (2H, m in), 3.75 (3H, c), 4,10 (2H, d, J=4.6 Hz), 4,25-the 4.29 (1H, m), 6,84-to 6.95 (3H, m), 7,17 (1H, DD, J=3.8 Hz, J=8,8 Hz), 7,53 (2H, d, J=8,7 Hz), 7,82 (1H, c), 11,20 (1H, users).

Example 40

5-fluoro-3-(4-methoxyphenyl)-8-propylsulfonyl-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 173-174°C.

1H NMR (DMSO-d6) dppm: from 0.90 (3H, t, J=7,3 Hz), 1,40-of 1.52 (2H, m), and 2.79 (2H, t, J=7.2 Hz), of 3.77 (3H, c), 6,93? 7.04 baby mortality (3H, m), 7,51-of 7.55 (2H, m), 7,79-7,87 (2H, m), 11,24 (1H, users).

When is EP 41

8 Cyclobutylmethyl-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 193-194°C.

1H NMR (DMSO-d6) dppm: 1,79-of 1.93 (4H, m), 2,04-of 2.09 (2H, m), was 2.76-of 2.81 (1H, m), 3,74 (3H, c), 4,08 (2H, d, J=6.8 Hz), 6,83-6,93 (3H, m), 7,11 (1H, DD, J=3.8 Hz, J=8,8 Hz), 7,52 (2H, d, J=8.6 Hz), 7,82 (1H, c), 11,20 (1H, users).

Example 42

8-tert-Butoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale brown powder (ethyl acetate-diethyl ether).

Melting point 206-208°C.

1H NMR (DMSO-d6) dppm: of 1.40 (9H, c)3,76 (3H, c), 6,84-of 6.96 (3H, m), 7,31 (1H, DD, J=4.3 Hz, J=8,8 Hz), 7,54 (2H, d, J=8,8 Hz), 7,82 (1H, c), 10,95 (1H, users).

Example 43

5-fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale-dark-brown powder (ethyl acetate).

1H NMR (DMSO-d6) dppm: 3,76 (3H, c), of 3.95 (3H, c), 6,87-to 6.95 (3H, m), to 7.15 (1H, DD, J=3.8 Hz, J=8,8 Hz), 7,54 (2H, d, J=8.7 Hz), 7,76 (1H, c), 11,50 (1H, users).

Example 44

5-fluoro-8-methoxyethoxy-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale-dark-brown powder (dichloromethane-methanol).

1H NMR (CDCl3) dppm: 3,44 (3H, c), 3,76 (3H, c), 5,20 (2H, c), 6,76-6,87 (3H, m), 7.18 in-of 7.23 (1H, m), 7,52 (2H, d, J=7.8 Hz), 7,69 (1H, c)9,68 (1H, users).

Example 45

8-(3-Benzyloxypropionic)-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Dark brown amorphous solid.

1H NMR (DMSO-d6) dppm: of 2.08 and 2.13 (2H, m), 3,68 (2H, t, J=6.2 Hz), of 3.77 (3H, c), 4,22 (2H, t, J=6.0 Hz), 4,48 (2H, c), 6,84-6,97 (3H, m), 7,13-to 7.18 (1H, m), 7,21-7,29 (5H, m), 7,55 (H, d, J=8.7 Hz), 7,76 (1H, c), 11,25 (1H, users).

Example 46

8-(2-Benzyloxypropionic)-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Dark brown amorphous solid.

1H NMR (DMSO-d6) dppm: to 1.32 (3H, d, J=6.2 Hz), 3,76 (3H, c), 3,98-4,24 (3H, m), 4,54-4,69 (2H, m), 6,84-of 6.96 (3H, m), 7,16-7,30 (6H, m), 7,54 (2H, d, J=8.7 Hz), 7,78 (1H, c), 11,19 (1H, users).

Example 47

8 Cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-2-methyl-1H-quinoline-4-one

To a solution of 2-cyclopropylmethoxy-5-foronline (760 mg, 4.2 mmol) and ethyl α-acetyl-4-methoxyphenylacetate (1.0 g, 4.2 mmol) in benzene (40 ml) was added Amberlyst 15 (350 mg, product of Sigma Aldrich Corp.) and the mixture was heated at the boil under reflux for 19 hours by using the nozzles Dean-stark and under stirring. The reaction mixture was cooled to room temperature, the resin was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added diphenyl ether (2.2 ml) and the mixture was heated by means of the mantle, and then stirred for 1 hour at the boil under reflux. The reaction mixture was cooled to room temperature and directly purified column chromatography on silica gel (dichloromethane:methanol=80:1→60:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, thus obtaining 120 mg powder 8 cyclopropylmethoxy-5-fluoro-3-(4-IU is oxyphenyl)-2-methyl-1H-quinoline-4-it is pale yellow (yield: 8%).

Melting point 167-169°C.

1H NMR (DMSO-d6) dppm: 0,35-0,39 (2H, m), 0,54-0,61 (2H, m), is 1.31 to 1.37 (1H, m), of 2.23 (3H, c), 3,76 (3H, c), was 4.02 (2H, d, J=7,0 Hz), 6,80-6,94 (3H, m), 7,08-to 7.18 (3H, m), to 10.62 (1H, users).

Connection the following example 48 was obtained in a manner analogous to the method described above in example 47, using appropriate starting compounds.

Example 48

2-Ethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate-n-hexane).

Melting point 169-171°C.

1H NMR (DMSO-d6) dppm: 0,98-1,05 (6H, m), 1,80-1,89 (2H, m), of 2.56 (2H, t, J=7.5 Hz), of 3.77 (3H, c), of 4.13 (2H, t, J=6.6 Hz), for 6.81-to 6.95 (3H, m), 7,05-7,17 (3H, m), the 10.40 (1H, users).

Example 49

5-fluoro-8-propoxy-3-pyridin-3-yl-1H-quinoline-4-one

5-fluoro-3-iodine-8-propoxy-1H-quinoline-4-one (600 mg, at 1.73 mmol) suspended in 1,2-dimethoxyethane (12 ml). To the resulting suspension was added 3-pyridineboronic acid (752 mg), a complex of 1,1'-bis(diphenylphosphino)periodically(II)-dichloromethane (PdCl2(DPPF)) (76 mg, 0,093 mmol) and 2 N. aqueous solution of sodium carbonate (2,54 ml) in this order. The mixture was stirred at 90°C for 2 hours in nitrogen atmosphere. After cooling the reaction mixture to room temperature was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was then purified column chromatography on Sealy is agile (dichloromethane:methanol=15:1). The purified product was concentrated under reduced pressure and then recrystallized from ethanol, to thereby obtain 185 mg of powdered 5-fluoro-8-propoxy-3-pyridin-3-yl-1H-quinoline-4-it is pale brown (yield: 36%).

Melting point 234-236°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7,3 Hz), 1,77 is 1.86 (2H, m), 4,08 (2H, t, J=6.4 Hz), 6,93 (1H, DD, J=8,8 Hz, J=12.0 Hz), 7,13-to 7.18 (1H, m), 7,37-7,42 (1H, m), of 7.97 (1H, c), 8,01-with 8.05 (1H, m), 8,44-8,46 (1H, m), 8,77 (1H, d, J=2.1 Hz), for 11.55 (1H, users).

Compounds of the following examples 50 to 66 received in a manner analogous to the method described above in example 49, using appropriate starting compounds.

Example 50

3-(4-Ethoxy-3-forfinal)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale yellow powder (ethanol).

Melting point 176-177°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz)of 1.33 (3H, t, J=6.9 Hz), 1,75-1,89 (2H, m), 4,05-to 4.14 (4H, m), 6.90 to (1H, DD, J=8.7 Hz, J=12.1 Hz), 7,09-7,16 (2H, m), to 7.32 and 7.36 (1H, m), 7,52-7,58 (1H, m), 7,87 (1H, c), of 11.45 (1H, c).

Example 51

5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinoline-4-one

Pale brown powder (ethanol).

Melting point 259-261°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz), 1,78 is 1.86 (2H, m), 4.09 to (2H, t, J=6.4 Hz), of 6.96 (1H, DD, J=8,8 Hz, J=12.0 Hz), 7,19 (1H, DD, J=3.8 Hz, J=8,8 Hz), 7,71 (2H, d, J=6,1 Hz), of 8.06 (1H, c), charged 8.52 (2H, d, J=6,1 Hz), 11,50 (1H, users).

Example 52

5-fluoro-3-(4-phenoxyphenyl)-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethanol.

Melting point 228-230°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7,3 Hz), 1,77-of 1.85 (2H, m), 4,07 (2H, t, J=6.2 Hz), make 6.90 (1H, DD, J=8,8 Hz, J=12.1 Hz), 6,97-7,02 (4H, m), 7,10-to 7.15 (2H, m), 7,34-7,63 (4H, m), 7,88 (1H, c), 11,40 (1H, users).

Example 53

3-(4-Ethylphenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 153-154°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz)of 1.17 (3H, t, J=7.5 Hz), 1,78 is 1.86 (2H, m), 2,59 (2H, q, J=7.5 Hz), 4,08 (2H, t, J=6.4 Hz), 6.89 in (1H, DD, J=8,8 Hz, J=12.1 Hz), 7,10-7,21 (3H, m)to 7.50 (2H, d, J=8.0 Hz), 7,83 (1H, c), 11,40 (1H, users).

Example 54

3-(4-Acetylphenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 180-181°C.

1H NMR (DMSO-d6) dppm: of 0.95 (3H, t, J=7.5 Hz), 1,71 of-1.83 (2H, m), of 2.51 (3H, m), was 4.02 (2H, t, J=6.6 Hz), 6,84-6,91 (1H, m), 7,10-7,14 (1H, m), 7,72 (2H, d, J=8,4 Hz), 7,87-of 7.90 (3H, m), 11,40 (1H, users).

Example 55

Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)benzoate

White powder (ethyl acetate).

The melting point of 201-202°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7,3 Hz), 1,77 is 1.91 (2H, m), 3,86 (3H, c), 4.09 to (2H, t, J=6.5 Hz), 6.90 to-6,99 (1H, m), 7,17-7,22 (1H, m), 7,80 (2H, d, J=8.5 Hz), 7,94-7,98 (3H, m), of $ 11.48 (1H, users).

Example 56

5-fluoro-8-propoxy-3-[4-(pyrrolidin-1-carbonyl)phenyl]-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 236-237°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.4 Hz), 1,79-1,89 (6H, m), 3.43 points-to 3.49 (4H, m), 4,08 (2H, t, J=6.5 Hz), 6.89 in-6,97 (H, m), 7,15-7,20 (1H, m), 7,51 (2H, d, J=8.6 Hz), to 7.67 (2H, d, J=8.6 Hz), of 7.90 (1H, c), 11,40 (1H, users).

Example 57

4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)-N,N-dimethylbenzamide

Pale brown powder (ethyl acetate).

Melting point 235-237°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.4 Hz), 1,80-1,89 (2H, m), of 2.97 (6H, c)4,08 (2H, t, J=6.4 Hz), 6.89 in-6,93 (1H, m), 7,15-7,20 (1H, m), 7,39 (2H, d, J=8.0 Hz), to 7.67 (2H, d, J=8.0 Hz), of 7.90 (1H, c), 11,41 (1H, users).

Example 58

5-fluoro-3-furan-2-yl-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate).

Melting point 210-212°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=1.4 Hz), of 1.78-1.90 (2H, m), 4,10 (2H, t, J=6.6 Hz), 6,54-6,56 (1H, m), 6.90 to-6,99 (1H, m), 7,15-7,21 (2H, m), of 7.64-the 7.65 (1H, m), to 8.20 (1H, c), 11,47 (1H, users).

Example 59

5-fluoro-8-propoxy-3-thiophene-2-yl-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 211-213°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.5 Hz), of 1.78-1.90 (2H, m), 4,10 (2H, t, J=6.5 Hz), 6,92-7,20 (3H, m), 7,41-to 7.59 (2H, m), a 8.34 (1H, c), 11,63 (1H, users).

Example 60

3-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)thiophene-2-carbaldehyde

White powder (ethyl acetate).

The melting point of 190-191°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7.4 Hz), 1,79-of 1.88 (2H, m), 4,08 (3H, t, J=6.5 Hz), 6,92-7,00 (1H, m), 7.18 in-of 7.23 (1H, m), 7,32 (1H, d, J=5.0 Hz), 7,98 (1H, c), 8,04-of 8.06 (1H, m), 9,73 (1H, c), 11,40 (1H, users).

Example 61

3-(4-Dimethylaminophenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one

White powder (this is acetat).

Melting point 206-207°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7.4 Hz), 1,79-of 1.88 (2H, m), 2,90 (6H, c)4,07 (2H, t, J=6.4 Hz), of 6.71 (2H, d, J=9.0 Hz), 6,82-of 6.90 (1H, m), 7,09-7,14 (1H, m), 7,45 (2H, d, J=9.0 Hz), 7,76 (1H, c), 11,18 (1H, users).

Example 62

3-(3,4-Acid)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 217-218°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.5 Hz), 1,78-of 1.88 (2H, m), 3,76 (6H, c)4,07 (2H, t, J=6.4 Hz), 6,85-6,97 (2H, m), 7,08-7,16 (2H, m), 7,30 (1H, c), of 7.82 (1H, c), to 11.28 (1H, users).

Example 63

5-fluoro-3-(6-methoxypyridine-3-yl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

The melting point of 215-216°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.5 Hz), 1,77 is 1.91 (2H, m), 3,86 (3H, c), 4,08 (2H, t, J=6.3 Hz), for 6.81-of 6.96 (2H, m), 7,14-7,19 (1H, m), to 7.77-to 7.99 (2H, m), 8,35 (1H, c), is 11.39 (1H, users).

Example 64

3-(2,6-Dimethoxypyridine-3-yl)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 198-199°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7,3 Hz), 1,76-1,90 (2H, c), 3,83 (3H, c), with 3.89 (3H, c)4,07 (2H, t, J=6.3 Hz), to 6.39 (1H, d, J=7,1 Hz), 6,86-6,94 (1H, m), 7,13-7,17 (1H, m), 7,68 (1H, d, J=7,1 Hz), 7,81 (1H, c), 11,23 (1H, users).

Example 65

3-(2,5-Acid)-5-fluoro-8-propoxy-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 156-157°C.

1H NMR (DMSO-d6) dppm: of 1.03 (3H, t, J=7,3 Hz), 1,80-1,90 (2H, m), the 3.65 (3H, c), 3,71 (3H, c), 4.09 to (2H, t, J=6.3 Hz), 6.87 in-6,91 (4H, m), 6,94-to 6.95 (1H, m),7,73 (1H, c), 11,18 (1H, users).

Example 66

8 Cyclopropylmethoxy-1-ethyl-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Brown powder (ethyl acetate-n-hexane).

The melting point of 150-152°C.

1H NMR (DMSO-d6) dppm: 0,34-0,38 (2H, m), 0,57-of 0.64 (2H, m), 1,27-of 1.39 (4H, m in), 3.75 (3H, c)to 3.92 (2H, d, J=7.2 C)4,60 (2H, q, J=6.8 Hz), 6,91-of 6.99 (3H, m), 7,17 (1H, DD, J=4.5 Hz, J=8,9 Hz), 7,60 (2H, d, J=8.7 Hz), 7,98 (1H, c).

Example 67

5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinoline-4-one

5-fluoro-3-iodine-2-methyl-8-propoxy-1H-quinoline-4-one (400 mg, 1.11 mmol), 4-methoxyphenylalanine acid (504 mg, 3.3 mmol), the complex of 1,1'-bis(diphenylphosphino)periodically(II)-dichloromethane (PdCl2(DPPF)) (100 mg, 0.12 mmol) and 2 N. aqueous solution of sodium carbonate (1 ml) was added to 1,2-dimethoxyethane (3 ml) and the mixture was heated at 170°C for 10 minutes (the reactor with microwave irradiation). The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane:methanol=100:0→40:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate, thus obtaining 230 mg of powdered 5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-ol is poxi-1H-quinoline-4-it is white in color (yield: 61%).

Melting point 211-212°C.

1H NMR (DMSO-d6) dppm: and 0.98 (3H, t, J=7,3 Hz), 1,79-1,90 (2H, m), of 2.23 (3H, c), 3,76 (3H, c), 4,10 (2H, t, J=6.5 Hz), 6,93-to 6.95 (2H, m), 7,07-to 7.09 (2H, m), 7,72-7,73 (1H, m), 7,83 (1H, c), 10,50 (1H, users).

Compounds of the following examples, with 68 of 85 was obtained in a manner analogous to the method described above in example 67, using appropriate starting compounds.

Example 68

5-fluoro-2-methyl-8-propoxy-3-pyridin-3-yl-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 190-192°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7.5 Hz), 1.77 in-1,89 (2H, m), and 2.27 (3H, c), of 4.12 (2H, t, J=6,1Hz), 6,85-6,93 (1H, m), 7,16-7,21 (1H, m), 7,38-the 7.43 (1H, m), 7,63-to 7.67 (1H, m), 8,40-of 8.50 (2H, m), 10,70 (1H, users).

Example 69

5-fluoro-2-methyl-8-propoxy-3-pyridin-4-yl-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 265-266°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7.5 Hz), 1,78-of 1.92 (2H, m), 2,28 (3H, c), of 4.12 (2H, t, J=6.8 Hz), 6,86-6,94 (1H, m), 7,17-7,21 (1H, m), 7,25 (2H, d, J=6.0 Hz), 8,55 (2H, d, J=6.0 Hz), of 10.72 (1H, users).

Example 70

5-fluoro-2-methyl-8-propoxy-3-(4-trifloromethyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 167-168°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7,3 Hz), 1,78-of 1.92 (2H, m), of 2.25 (3H, c), 4,10 (2H, t, J=6.6 Hz), 6,83-6,92 (1H, m), 7,15-7,20 (1H, m), 7,31-7,38 (4H, m), at 10.64 (1H, users).

Example 71

3-(4-Ethylphenyl)-5-fluoro-2-methyl-8-propoxy-1H-quinoline-4-one

Pale red powder (ethyl acetate).

Melting point 221-222°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7,3 Hz)of 1.18 (3H, t, J=7.5 Hz), 1,80-1,89 (2H, m), of 2.23 (3H, c), 2,58 (2H, q, J=7.5 Hz), 4,10 (2H, t, J=6.6 Hz), 6,82-6,89 (1H, m), 7,08-7,22 (5H, m), 10,53 (1H, users).

Example 72

5-fluoro-2-methyl-8-propoxy-3-thiophene-2-yl-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 233-234°C.

1H NMR (DMSO-d6) dppm: and 0.98 (3H, t, J=7,3 Hz), 1.77 in-1,89 (2H, m), 2,46 (3H, c), 4,11 (2H, t, J=6.8 Hz), 6,86-7,20 (4H, m), 7,52-of 7.55 (1H, m), 10,70 (1H, users).

Example 73

3-(4-Dimethylaminophenyl)-5-fluoro-2-methyl-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 255-257°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7.5 Hz), 1,80-1,90 (2H, m), and 2.26 (3H, c), only 2.91 (6H, c), 4,11 (2H, t, J=6.6 Hz), 6,72 (2H, d, J=8.7 Hz), 6,80-6,89 (1H, m), 7,00 (2H, d, J=8.7 Hz), 7,11-7,17 (1H, m), 10,45 (1H, users).

Example 74

5-fluoro-3-(4-forfinal)-2-methyl-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate).

Melting point 196-197°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7,3 Hz), 1,80 is 1.91 (2H, m), of 2.25 (3H, c), of 4.12 (2H, t, 6.8 Hz), 6,84-6,92 (1H, m), 7,15-7,29 (5H, m), 10,06 (1H, users).

Example 75

3-(2,4-Acid)-5-fluoro-2-methyl-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate).

The melting point of 100-101°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7.5 Hz), 1,80-to 1.86 (2H, m), 2,11 (3H, c), the 3.65 (3H, c), of 3.78 (3H, c), 4,10 (2H, t, J=6.8 Hz), 6,51-6,59 (2H, m), 6,80-6,94 (2H, m), 7,11-7,17 (1H, m), of 10.47 (1H, users).

Example 7

5-fluoro-3-furan-2-yl-2-methyl-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate).

Melting point 203-204°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7.5 Hz), 1,78-1,89 (2H, m), 2,47 (3H, c), 4,10 (2H, t, J=6.8 Hz), 6,52-is 6.54 (1H, m), 6,67-6,69 (1H, m), 6,86-to 6.95 (1H, m), 7,15-7,20 (1H, m), to 7.67-to 7.68 (1H, m), 10,66 (1H, m).

Example 77

5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

White powder (n-hexane-ethyl acetate).

Melting point 170-171°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7,3 Hz), 1,76-1,90 (2H, m), 3,80 (3H, c), 4,11 (2H, t, J=6.5 Hz), 6,98 (2H, d, J=8.7 Hz), 7,15-of 7.25 (4H, m), 10,11 (1H, users).

Example 78

5-fluoro-3-furan-2-yl-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

Pale yellow powder (n-hexane-ethyl acetate).

Melting point 134-136°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7.5 Hz), 1,76-1,90 (2H, m), 4,11 (2H, t, J=6.6 Hz), 6,59-of 6.65 (2H, m), 7,21-7,33 (2H, m), 7,81 (1H, m), 10,08 (1H, users).

Example 79

3-(4-Dimethylaminophenyl)-5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

Pale yellow powder (n-hexane-ethyl acetate).

Melting point 176-177°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7.4 Hz), 1,76 is 1.91 (2H, m)to 2.94 (6H, c), 4,11 (2H, t, J=6.6 Hz), to 6.75 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,21-7,24 (2H, m), 10,00 (1H, users).

Example 80

3-(4-Ethylphenyl)-5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

White powder (n-hexane-ethyl acetate).

The melting point of 187-188°C.

1H NMR (DMSO- 6) dppm: a 1.00 (3H, t, J=7,3 Hz)of 1.20 (3H, t, J=7.5 Hz), 1,77 is 1.91 (2H, m), 2,62-a 2.71 (2H, q, J=7.5 Hz), of 4.12 (2H, t, J=6.6 Hz), 7,13-7,29 (6H, m), 10,23 (1H, users).

Example 81

5-fluoro-3-(4-forfinal)-8-propoxy-2-trifluoromethyl-1H-quinoline-4-one

Brown powder (n-hexane-ethyl acetate).

Melting point 154-155°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7,3 Hz), 1,81-1,89 (2H, m), of 4.13 (2H, t, J=6.5 Hz), 7,10-7,31 (4H, m), 7,80-7,86 (1H, m), 8,08 (1H, c), 10,24 (1H, users).

Example 82

5-fluoro-8-propoxy-3-(4-trifloromethyl)-2-trifluoromethyl-1H-quinoline-4-one

Pale red powder (n-hexane-ethyl acetate).

The melting point of 143-144°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7,3 Hz), 1,77 is 1.91 (2H, m), of 4.12 (2H, t, J=6.6 Hz), 7,19-rate of 7.54 (6H, m), 10,44 (1H, users).

Example 83

5-fluoro-2-isopropyl-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate-n-hexane).

Melting point 195-197°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7,3 Hz)of 1.16 (6H, d, J=7,0 Hz), 1,78-of 1.92 (2H, m), 2,86-of 2.97 (1H, m), of 3.77 (3H, c), of 4.13 (2H, t, J=6.4 Hz), 6,84-7,22 (6H, m), 8,98 (1H, users).

Example 84

5-fluoro-3-furan-2-yl-2-isopropyl-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate-n-hexane).

Melting point 113-114°C.

1H NMR (DMSO-d6) dppm: 0,99 (3H, t, J=7.5 Hz), to 1.21 (6H, d, J=7,0 Hz), 1,80-1,89 (2H, m), 3,11 -, and 3.16 (1H, m), of 4.12 (2H, t, J=6.4 Hz), 6.48 in-6,54 (2H, m), 6.90 to-6,98 (1H, m), 7,20-of 7.25 (1H, m), 7,69-of 7.70 (1H, m), 9,29 (1H, users).

Example 85

5-fluoro-8-propoxy-3-thiophene-2-yl-2-trifluoromethyl-1H-Hino is in-4-one

Pale yellow powder (ethyl acetate-n-hexane).

Melting point 149-150°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7.4 Hz), 1,76-1,90 (2H, m), 4,11 (2H, t, 6.4 Hz), 7,10-7,30 (4H, m), 7,72 to 7.75 (1H, m), 10,52 (1H, users).

Example 86

5-fluoro-8-furan-2-yl-3-(4-methoxyphenyl)-1H-quinoline-4-one

8-Bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one (150 mg, 0.43 mmol), 2-Farnborough acid (145 mg, 1.3 mmol), the complex of 1,1'-bis(diphenylphosphino)periodically(II)-dichloromethane (PdCl2(DPPF)) (35 mg, 0.04 mmol) and 2 N. aqueous solution of sodium carbonate (1 ml) was added to 1,2-dimethoxyethane (3 ml) and the mixture was heated at 180°C for 10 minutes (the reactor with microwave irradiation). After cooling the reaction mixture to room temperature, was added dichloromethane and then filtered through celite. The filtrate was extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane). The purified product was concentrated under reduced pressure and the residue was recrystallized from a mixture of n-hexane-ethyl acetate, while receiving 100 mg of powdered 5-fluoro-8-furan-2-yl-3-(4-methoxyphenyl)-1H-quinoline-4-it is slightly orange color (yield: 70%).

Melting point 209-211°C.

1H NMR (DMSO-d6) dppm: with 3.79 (3H, c) 6,74-6,77 (1H, m)of 6.96-to 7.00 (3H, m), 7,07-to 7.15 (1H, m), 7,55-to 7.59 (2H, m), 7,81-to 7.93 (3H, m), 11,00 (1H, users).

Compounds of the following examples 87 and 88 received in a manner analogous to the method described above in example 86, using appropriate starting compounds.

Example 87

5-fluoro-3-(4-methoxyphenyl)-8-thiophene-3-yl-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 183-184°C.

1H NMR (DMSO-d6) dppm: 3,76 (3H, c), 6,93-to 7.09 (3H, m), 7,30-to 7.32 (1H, m), 7,49-rate of 7.54 (3H, m), 7,76-7,80 (3H, m), at 10.64 (1H, users).

Example 88

8-Benzo[b]thiophene-2-yl-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale yellow powder (ethyl acetate).

Melting point 276-277°C.

1H NMR (DMSO-d6) dppm: 3,76 (3H, c), 6,84-6,92 (3H, m), 7,30-7,40 (2H, m), 7,62-7,66 (2H, m), 7,84-7,99 (5H, m), 11,03 (1H, users).

Example 89

4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)benzoic acid

Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)benzoate (330 mg, of 0.93 mmol) suspended in a mixture solvent of ethanol (3 ml) and THF (3 ml). Added 1,24 N. aqueous solution of lithium hydroxide (2 ml) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, and then the resulting mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure, thus obtaining 300 mg poroshkoobraznoj-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)benzoic acid white (yield: 95%).

1H NMR (DMSO-d6) dppm: 1,01-of 1.07 (3H, t, J=7,3 Hz), 1,80 is 1.91 (2H, m), 4.09 to to 4.14 (2H, t, J=6.4 Hz), 6,85-7,24 (3H, m), 7,75 for 7.78 (2H, m), 7,92-of 7.95 (2H, m), 11,51 (1H, users), 12,84 (1H, users).

Example 90

5-fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinoline-4-one

4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)benzoic acid (260 mg, from 0.76 mmol), morpholine (99,5 mg, to 1.14 mmol), WSC (189 mg, 0,99 mmol) and HOBT (151 mg, 0,99 mmol) was added to DMF (10 ml) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was then purified column chromatography on silica gel (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate, while receiving 80 mg of powdered 5-fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinoline-4-it is white in color (yield: 26%).

Melting point 234-236°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.4 Hz), 1,80-1,89 (2H, m), 3,40-of 3.60 (8H, m), 4.09 to (2H, t, J=6.5 Hz), 6.89 in-6,98 (1H, m), 7,16-7,21 (1H, m), 7,41 (2H, d, J=8,3 Hz), 7,69 (2H, d, J=8,3 Hz), to $ 7.91 (1H, c), 11,41 (1H, users).

Example 91

5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinoline-4-one

To a solution of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-it (400 mg, 1,22 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 76 mg, 1.9 mmol). The mixture was stirred at room temperature for 15 minutes. To allali to her, methyl iodide (225 mg, 1.6 mmol) and then stirred the mixture at room temperature for 19 hours. To the reaction mixture were added water and ethyl acetate to separate the mixture into two layers. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, thus obtaining 365 mg of powdered 5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinoline-4-it is pale yellow (yield: 72%).

Melting point 147-148°C.

1H NMR (DMSO-d6) dppm: and 0.98 (3H, t, J=7.5 Hz), or 1.77 (2H, m), 3,76 (3H, c), 3,98 (2H, t, J=6.4 Hz), 4,08 (3H, c), 6,91-7,01 (3H, m), 7,19-7,24 (1H, m), EUR 7.57-to 7.61 (2H, m), of 7.96 (1H, c).

Compounds of the following examples, with 92 94 was obtained in a manner analogous to the method described above in example 91, using appropriate starting compounds.

Example 92

1-Ethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

The melting point of 123-125°C.

1H NMR (DMSO-d6) dppm: a 1.00 (3H, t, J=7,3Hz)of 1.29 (3H, t, J=6.8 Hz), 1,79-of 1.88 (2H, m), 3,76 (3H, c), a 4.03 (2H, t, J=6.5 Hz), to 4.52 (2H, q, J=6.8 Hz), 6,91-7,02 (3H, m), 7,22-7,27 (1H, m), 7,60 (2H, d, J=8.7 Hz), 8,00 (1H, c).

Example 93

1-(2-Ethoxyethyl)-5-fluoro-3-(4-methoxyphenyl the)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

The melting point of 108-109°C.

1H NMR (DMSO-d6) dppm: 0,96-of 1.09 (6H, m), 1.77 in-1,89 (2H, m), the 3.65 (2H, t, J=5.0 Hz), of 3.78 (3H, s), was 4.02 (2H, t, J=6.8 Hz), 4.72 in (2H, t, J=5.0 Hz), 6,94? 7.04 baby mortality (3H, m), 7.23 percent-7,29 (1H, m), EUR 7.57 (2H, d, J=8.7 Hz), to 7.93 (1H, c).

Example 94

1-Cyclopropylmethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

Pale yellow powder (n-hexane).

The melting temperature of 60-62°C.

1H NMR (DMSO-d6) dppm: 0,36-0,51 (4H, m)of 1.07 (3H, t, J=7.4 Hz), 1,26-of 1.30 (1H, m), 1,86-of 1.94 (2H, m), 4.09 to (2H, t, J=6.5 Hz), of 6.96-was 7.08 (3H, m), 7,28-7,33 (1H, m), to 7.61-7,66 (2H, m), with 8.05 (1H, c).

Example 95

5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinoline-4-one

A solution of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-it (249 mg, from 0.76 mmol) in dichloromethane (5 ml) was cooled to -10°C in a bath of methanol with ice. Was added 1 N. trichromacy boron (4,08 ml) and the mixture was stirred at room temperature for 6 hours. To the reaction mixture were added ice water and dichloromethane, and provided the obtained insoluble substance by filtration. The filtrate was separated and concentrated the organic layer under reduced pressure. The residue remaining on the filter substance was mixed, and cleansed the mix column chromatography on silica gel (dichloromethane:methanol=60:1→25:1). The purified product was concentrated under reduced pressure. For crystallization of the residue was added ethyl acetate. The crystals were isolated filter the cation, washed with ethyl acetate and then dried, to thereby obtain 220 mg of powdered 5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinoline-4-it is pale yellow (yield: 92%).

Melting point 271-272°C.

1H NMR (DMSO-d6) dppm: of 1.03 (3H, t, J=7,3 Hz), 1,78-to 1.87 (2H, m), 4,08 (2H, t, J=6.4 Hz), 6,77 (2H, d, J=8.6 Hz), 6.87 in (1H, d, J=8,8 Hz, J=12.1 Hz), 7,12 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,41 (2H, d, J=8.6 Hz), to 7.77 (1H, c), 9,43 (1H, users), 11,20 (1H, users).

Example 96

5-fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinoline-4-one

5-fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinoline-4-one (1.0 g, to 3.34 mmol) suspended in dichloromethane (40 ml), and cooled suspension of up to -10°C in a bath of methanol with ice. Was added 1 N. trichromacy Bor (17 ml) and stirred the mixture at room temperature for 15 hours. To the reaction mixture were added ice water and dichloromethane, and provided the obtained insoluble substance by filtration. Remaining on the filter substance was washed with water, dried and purified column chromatography on silica gel (dichloromethane:methanol=20:1→8:1→ethyl acetate:methanol=4:1). The purified product was concentrated under reduced pressure and then added ethyl acetate for crystallization of the residue. The crystals were isolated by filtration, washed with ethyl acetate and dried, to thereby obtain 360 mg of powdered 5-fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinoline-4-it is pale gray (yield: 40%).

1H NMR (DMSO-d6) dppm: 6,74-PC 6.82 (3H, m)6,94 (1H, DD, J=4,1 Hz, J=8.5 Hz), 7,41 (2H, d, J=8,3 Hz), 7,74 (1H, c), 9,46 (1H, users), 10,70 (1H, users), made 11.32 (1H, users).

Example 97

5-fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

To a solution of 5-fluoro-3-(4-isopropoxy-2-methoxyphenyl)-8-propoxy-1H-quinoline-4-it (120 mg, 0.31 mmol) in dichloromethane (5 ml) was added aluminium chloride (108 mg, 0.81 mmol). The mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and dichloromethane and separated. After that, the organic layer was washed with water. The washed organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified column chromatography on silica gel (dichloromethane:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, while receiving 100 mg of powdered 5-fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinoline-4-it is white in color (yield: 90%).

Melting point 251-253°C.

1H NMR (DMSO-d6) dppm: 1,01-of 1.07 (3H, t, J=7,4Hz), 1.77 in-a 1.88 (2H, m), 3,63 (3H, c), 4,07-of 4.12 (2H, t, J=6.6 Hz), 6,33-to 6.43 (2H, m), 6,84-of 6.90 (1H, m), 7,02-7,11 (2H, m), to 7.61-to 7.64 (1H, m), 9,39 (1H, c), 11,07 (1H, users).

Connection the following example 98 was obtained in a manner analogous to the method described above in example 97 using corresponding source is x connections.

Example 98

5-fluoro-3-(2-hydroxy-4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 208-209°C.

1H NMR (DMSO-d6) dppm: of 1.02 (3H, t, J=7.5 Hz), 1,81-1,90 (2H, m), of 3.73 (3H, c), 4,11 (2H, t, J=6.5 Hz), to 6.43-6,51 (2H, m), 6,98-7,06 (1H, m), 7,16-of 7.25 (2H, m), 7,95 (1H, c), 10,23 (1H, c), 11,93 (1H, users).

Example 99

5-fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinoline-4-one

To a solution of 5-fluoro-8-methoxyethoxy-3-(4-methoxyphenyl)-1H-quinoline-4-it (350 mg, 1.06 mmol) in ethanol (18 ml) was added 2 N. hydrochloric acid (6.0 ml). The mixture was stirred at 55°C for 1 hour. Stir the mixture was cooled to room temperature and was added a 1 n sodium hydroxide (to 11.6 ml) to obtain a pH of from 3 to 4. Mix with increased pH was concentrated under reduced pressure and the residue is then purified column chromatography on silica gel (dichloromethane:methanol=50:1→20:1). The purified product was concentrated under reduced pressure and the residue was led from ethanol, was isolated by filtration, washed with ethanol and dried, to thereby obtain 165 mg of powdered 5-fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinoline-4-it is pale-dark-brown color (yield: 54%).

Melting point 270-272°C.

1H NMR (DMSO-d6) dppm: 3,75 (3H, c), 6,79 (1H, DD, J=8.5 Hz, J=2.1 Hz), 6.90 to-6,97 (3H, m), 7,53 (2H, d, J=8.6 Hz), to 7.77 (1H, c), or 10.60 (1H, users), 11,40 (1H, users).

Example 100

5-fluoro-3-(2-hydroxym titipan-3-yl)-8-propoxy-1H-quinoline-4-one

3-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)thiophene-2-carbaldehyde (120 mg, 0,39 mmol) suspended in ethanol (5 ml) and added to a suspension of sodium borohydride (19,24 ml). The resulting mixture was stirred at room temperature for 1 hour. Added dichloromethane to the reaction mixture, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from ethyl acetate, thus obtaining 110 mg of powdered 5-fluoro-3-(2-hydroxyethylthio-3-yl)-8-propoxy-1H-quinoline-4-it is white in color (yield: 82%).

Melting point 181-184°C.

1H NMR (DMSO-d6) dppm: a 1.01 (3H, t, J=7,3 Hz), 1,79-of 1.88 (2H, m), 4,07 (2H, t, J=6.4 Hz), 4,47 (2H, d, J=5.4 Hz), of 5.48 (1H, t, J=5.4 Hz), 6.87 in-of 6.96 (1H, m), 7,11-7,19 (2H, m), 7,39-7,40 (1H, m), 7,88 (1H, c), 11,36 (1H, users).

Example 101

5-fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinoline-4-one

8-(3-Benzyloxypropionic)-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one (1,95 g of 4.49 mmol) and 10%palladium on coal (720 mg) was added to ethanol (50 ml). The mixture was stirred at 55°C for 7.5 hours in an atmosphere of hydrogen (1 atmosphere) and subjected to catalytic recovery. The reaction mixture was cooled to room is temperature and filtered through celite, to remove the solvent. The filtrate was concentrated under reduced pressure. Then the residue was purified column chromatography on silica gel (dichloromethane:methanol=80:1→20:1). The purified product was concentrated under reduced pressure and the residue was concentrated to dryness, thus obtaining 820 mg of an amorphous solid 5-fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinoline-4-it is pale-dark-brown color (yield: 53%).

1H NMR (DMSO-d6) dppm: 1,92-2,02 (2H, m), the 3.65 (2H, t, J=5,9 Hz), 4,20 (2H, t, J=6.2 Hz), 4,59 (1H, users), 6,84-to 6.95 (3H, m), 7,14 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,55 (2H, d, J=8.7 Hz), 7,80 (1H, c), 11,27 (1H, users).

Connection the following example 102 was obtained in a manner analogous to the method described above in example 101, using appropriate starting compounds.

Example 102

5-fluoro-8-(2-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinoline-4-one

White powder (ethyl acetate).

Melting point 216-218°C.

1H NMR (DMSO-d6) dppm: 1,19 (3H, d, J=6.2 Hz), 3,76 (3H, c), 3,82-4,12 (3H, m), 5.25-inch (1H, users), 6,84-of 6.96 (3H, m), 7,12 (1H, DD, J=3,9 Hz, J=8,8 Hz), 7,56 (2H, d, J=8,8 Hz), 7,86 (1H, c), 11,20 (1H, users).

Compounds of the following examples 103 and 104 was obtained in a manner analogous to the method described above in example 1, using appropriate starting compounds.

Example 103

5-Chloro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one

Pale brown powder (ethyl acetate).

Temp is the temperature of the melting point 194-196°C.

1H NMR (DMSO-d6) dppm: of 1.03 (3H, t, J=7,3 Hz), 1,80-to 1.87 (2H, m), 3,76 (3H, c), 4,11 (2H, t, J=6.4 Hz), 6,93 (2H, d, J=8.6 Hz), 7,12 (1H, d, J=8.5 Hz), 7,17 (1H, d, J=8.5 Hz), 7,54 (2H, d, J=8.6 Hz), 7,80 (1H, c), 11,23 (1H, users).

Example 104

5-Bromo-8-cyclopentane-3-(4-methoxyphenyl)-1H-quinoline-4-one

Pale brown powder (ethanol).

Melting point 213-215°C.

1H NMR (DMSO-d6) dppm: 1,59 is 1.70 (2H, m), 1,71 is 2.00 (6H, m in), 3.75 (3H, c), equal to 4.97-5,00 (1H, m)6,94 (2H, d, J=8.7 Hz),? 7.04 baby mortality (1H, d, J=8.5 Hz), 7,40 (1H, d, J=8,4 Hz), 7,53 (2H, d, J=8.7 Hz), 7,81 (1H, c), 11,20 (1H, users).

Pharmacological test 1

Assessment improve mitochondrial dysfunction when using cell lines of human neuroblastoma SH-SY5Y treated with 1-methyl-4-phenylpyridinium (MRD+).

Cell lines human neuroblastoma SH-SY5Y, in which the mitochondrial activity was impaired processing of RAM+(Bollimuntha S. et al., J Biol. Chem, 280, 2132-2140 (2005) and T. Shang et al., J Biol. Chem, 280, 34644-34653 (2005)), improving mitochondrial dysfunction has been evaluated on the basis of the measurement of mitochondrial redox activity using the fluorescent dye Alamar Blue after adding the connection (M. Nakai et al., Exp. Neurol, 179, pp. 103 -- 110 (2003)).

Cell lines human neuroblastoma SH-SY5Y were grown in modified according to the method of Dulbecco environment Needle containing 10% fetal calf serum (DMEM containing 50 units/ml penicillin and 50 µg/the l streptomycin as antibiotics) at 37°C in the presence of 5% carbon dioxide. The cells were placed on coated with poly-D-lysine 96-well black plate at a concentration of 3-6×104cells/cm2(the number of protection: 100 µl/well) and were grown in the above medium for two days. After that, the medium was replaced with DMEM containing 1% supliment N2 (N2-DMEM), or medium (100 µl/well), which was dissolved 1.5 mm MRD+. Cells were grown for 39-48 hours and then subjected to measurements of mitochondrial redox activity. Test the connection, which was previously dissolved in dimethylformamide (DMSO), diluted in N2-DMEM was added in a volume of 10 µl per well 24 hours prior to activity measurement (final concentration: 0.01 to 1 ál/well).

After removal of the medium by suction was added balanced salt solution containing 10% Alamar Blue (154 mm NaCl, 5.6 mm KCl, 2.3 mm calcium chloride, 1.0 mm magnesium chloride, 3.6 mm sodium bicarbonate, 5 mm glucose, 5 mm HEPES, pH 7,2) in the amount of 100 μl/well, and were injected into the interaction in the incubator at 37°C for 1 hour. The intensity of fluorescence was determined using a fluorescence detector (Hamamatsu Photonics K.K., wavelength excitation 530 nm, the wavelength measuring 580 nm)to measure, thus, mitochondrial redox activity.

A comparative assessment is intensively fluorescence wells of cells, grown in a medium containing MRD+and each of the tested compounds was carried out on the basis of 100% of the fluorescence intensity of the wells of cells grown in a medium containing only DMSO (the final concentration is 0.1%). When groups MRD+induced cells showed higher fluorescence intensity than groups of cells grown only in DMSO, the test compound was assessed as having improved activity against mitochondrial dysfunction.

Table 1
Assessment improve mitochondrial dysfunction when using cell lines of human neuroblastoma SH-SY5Y treated with 1-methyl-4-phenylpyridinium (MRD+)
The concentration of the test compound (μg/ml)The intensity of fluorescence (%)
00,010,030,10,31
Compound of example No. 1505162706664
Compound of example No. 3515463707874
Compound of example No. 4475661707259
Compound of example No. 6535971858883
Compound of example No. 21465259637457
Compound of example No. 24546070827884
Compound of example No. 254146566650 24
Compound of example No. 30465054696456
Compound of example No. 31384545575948
Compound of example No. 34606974777887
Compound of example No. 35637588999565
Compound of example No. 36596365747191
Compound of example No. 3757647378 7061
Compound of example No. 38546667868178
Compound of example No. 40536064767072
Compound of example No. 47495158717382
Compound of example No. 53485356676067
Compound of example No. 59505356676654
Compound of example No. 61617065 858086
Compound of example No. 62556662798480
Compound of example No. 63565865747585
Compound of example No. 64565565747277
Compound of example No. 66576672837760
Compound of example No. 70535657677163
Compound of example No. 715056 61737872
Compound of example No. 86465259686139
Compound of example No. 87586366796351
Compound of example No. 91556569818283
Compound of example No. 92556375776955
Compound of example No. 93586679868069
Compound of example No. 9451 5667695941
Compound of example No. 100535656717384

Pharmacological test 2

Assessment of dopaminergic neuronal protective activity using C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR)

When using a mouse with MRTR-damaged dopaminergic neurons (Chan, R. et al., J Neurochem, 57, 348-351 (1991)), the assessment of dopaminergic neuroprotective activity was carried out on the basis of the content of dopamine and protein levels of tyrosine hydroxylase (TH) and dopamine carrier (DAT) (i.e. dopaminergic neuronal marker proteins) in striatum of the brain after administration of the compound (A. Mori et al., Neurosci Res, 51, 265-274 (2005)).

As a test animal used male mice C57BL/6 (provided by Japan Charles River Inc., from 10 to 12 weeks). MRTR was dissolved in a physiological salt solution to obtain a concentration of 4 mg/ml and then were injected mice subcutaneously in a volume of 10 ml/kg of the Test compound suspended in 5%solution of gum Arabic/physiological saline rest the RA (mass./about.) thus, in order to obtain a concentration of 1 mg/ml Each of test compounds or solvents were injected mouse oral 30 minutes, 24 hours and 48 hours after administration MRTR. The mouse was deceptional 72 hours after injection MRTR, removed the brain and analyzed each side of the striatum.

The left striatum was used as a sample for determining the protein level using Western blotting. Each tissue is homogenized in HEPES buffer solution of sucrose (of 0.32 M sucrose, 4 mg/ml of pepstatin, 5 μg/ml Aprotinin, 20 μg/ml trypsin inhibitor, 4 μg/ml leupeptin, 0.2 mm of phenylmethylsulfonyl, 2 mm ethylenediaminetetraacetic acid (EDTA), 2 mm ethylene glycol bis(β-aminoacylase ether)tetraoxane acid, 20 mm HEPES, pH of 7.2) and were analyzed for protein content using a set of reagents with bicinchoninic acid for protein analysis (provided by Pierce Corporation). Each homogenized sample containing equal amounts of protein dissolved in buffer solution Lemley, was subjected to electrophoresis through polyacrylamide gels in the presence of sodium dodecyl sulfate. Separated by electrophoresis protein electrically transferred to PVDF membrane. These membranes were introduced in the interaction with specific primary antibody on T, DAT and proteins "household", that is here α1 subgroup of Na +/K+-ATPase and actin (Na+/K+-ATPase, product UpState Biotechnology Inc.: other products are Chemi-Con Corporation). Then recorded a secondary antibody labeled with horseradish peroxidase (Amersham product K.K.) for each of the primary antibodies was determined by a chemiluminescence associated with the enzyme peroxidase activity, using x-ray film. The density of the protein layer on the film was analyzed using a densitometer (Bio-rad Laboratories Inc.), to obtain a value of T relative to the Na+/K+-ATPase and the value of the DAT relative to actin.

Right striatum, a mass of tissue which was determined directly after preparation, was used as a sample for analysis to determine the levels of dopamine. Each tissue is homogenized in 0.1 N. the solution of chloric acid containing isoproterenol as compounds internal standard of measurement using ultrasonic homogenizer under ice cooling. The supernatant obtained at 20000×g homogenate, which was centrifuged at 4°C for 15 minutes, subjected to high performance liquid chromatography on a column of reversed phase (product Eicom Corporation). The mobile phase 15% methanol 0.1 M citric acid/0.1 M buffer solution of sodium acetate (containing 190 mg/l 1-octanesulfonate sodium, 5 mg/l EDTA, pH 3.5) was filed with the MSE of the awn 0.5 ml/min, and were detected peak dopamine for each sample using an electrochemical detector (applied voltage of +750 mV vs. Ag/AgCl, product Eicom Corporation). With regard to the identified peak dopamine, the dopamine content in the mass of tissue in each sample was calculated by using analytical software (product Gilson Inc.).

In both analyses, the value of the sample taken from MRTR-induced mice, which were administered only the test compound or solvent, expressed relative to the value of the sample taken from mice without treatment MRTR (100%). Statistical analysis values were performed using the non-clinical statistical analysis. Values with significance level <of 0.05 was defined as statistically significant. If MRTR-induced mice, when in the group treated with the test drug, manifested in enhancement of protein level compared with the group treated with the solvent, and t-test showed a significant difference between these groups, the test drug was evaluated as having dopamine neuroprotective activity.

1. Derived quinolone represented by the General formula (1)

or its pharmaceutically acceptable salt,
in which R1represents a hydrogen atom, a lower alkalinuria, cyclo3-8alkyl lower alkyl group or lower alkoxy lower alkyl group;
R2represents a hydrogen atom, a lower alkyl group or halogen-substituted lower alkyl group;
R3represents a phenyl group, follow group, thienyl group or pyridyloxy group, with each of these groups optionally substituted with one or two groups selected from the group consisting of the following (1) through (16) in the aromatic or heterocyclic ring represented by the above R3;
(1) lower alkyl groups,
(2) a lower alkoxy group,
(3) halogen-substituted lower alkoxy group;
(4) phenoxy group,
(5) lower alkylthio group,
(6) a hydroxy group,
(7) hydroxy lower alkyl group,
(8) the atoms of halogen,
(9) lower alcoholnye group,
(10) lower alkoxycarbonyl group,
(11) amino group, optionally substituted by one or two lower alkyl groups,
(12) carbamoyl group, optionally substituted by one or two lower alkyl groups,
(13) cyclo3-8alkyl lower alkoxy group,
(14) pyrrolidinylcarbonyl group,
(15) morpholinylcarbonyl group and
(16) carboxyl group;
R4represents a halogen atom;
R5represents a hydrogen atom or a halogen atom;
R6is and what Ohm hydrogen; and
R7is any of the following groups (1) through (15):
(1) hydroxy group,
(2) a halogen atom,
(3) a lower alkoxy group,
(4) halogen-substituted lower alkoxy group,
(5) hydroxy lower alkoxy group,
(6) a lower alkoxy lower alkoxy group,
(7) an amino group optionally substituted by one or two members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl group, cyclo3-8alkyl groups,
(8) amino lower alkoxy group, optionally substituted on the amino group by one or two members selected from the group consisting of lower alkyl groups, lower alkanoyl groups, lower alkylsulfonyl groups and carbamoyl groups, optionally substituted by one or two lower alkyl groups,
(9) cyclo3-8alkoxy group,
(10) cyclo3-8alkyl lower alkoxy group,
(11) tetrahydrofuryl lower alkoxy group,
(12) lower alkylthio group,
(13) a heterocyclic group selected from the group consisting of morpholinyl groups, pyrrolidinyl groups, fueling groups, thienyl groups, and benzothiazoline groups,
(14) a phenyl lower alkoxy lower alkoxy group and
(15) pyrrolidinylcarbonyl group.

2. Derived quinolone General formula (1) or its pharmaceutically acceptable salt according to claim 1,
W is R 1represents a hydrogen atom or a lower alkyl group;
R2represents a hydrogen atom or a lower alkyl group;
R3represents a phenyl group or pyridyloxy group, with each of these groups optionally substituted with one or two groups selected from the group consisting of the following from(1), (2), (6) and (8) in the aromatic or heterocyclic ring represented by the above R3:
(1) lower alkyl groups,
(2) a lower alkoxy group,
(6) hydroxy group, and
(8) the atoms of halogen,
R4represents a halogen atom;
R5represents a hydrogen atom;
R6represents a hydrogen atom; and
R7is any of the following groups (3), (4) and (7):
(3) a lower alkoxy group,
(4) halogen-substituted lower alkoxy group, and
(7) an amino group optionally substituted by one or two lower alkyl groups.

3. Derived quinolone General formula (1) or its pharmaceutically acceptable salt according to claim 1, selected from the group consisting of:
5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinoline-4-one,
5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinoline-4-one,
3-(2,4-acid)-5-fluoro-8-propoxy-1H-quinoline-4-one,
5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinoline-4-one,
3-(2,4-dichlorophenyl)-5-fluoro-8-propoxy-1H-quinoline-4-one,
8 ethoxy-5-fluoro-3-(4-methoxyphenyl is)-1H-quinoline-4-one,
5-fluoro-3-(4-methoxy-2-were)-8-propoxy-1H-quinoline-4-one,
5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one,
5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinoline-4-one,
5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinoline-4-one,
8 cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinoline-4-one,
5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinoline-4-one,
5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H-quinoline-4-one and
5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-triptoreline)-1H-quinoline-4-one.

4. Pharmaceutical composition for treatment and/or prevention of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by deterioration of the function of mitochondria, including quinolone derivative of General formula (1) or its pharmaceutically acceptable salt according to claim 1 as an active ingredient, and a pharmaceutically acceptable carrier.

5. Preventive and/or therapeutic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by deterioration of the function of mitochondria, comprising as an active ingredient derived quinolone General formula (1) or its pharmaceutically acceptable salt according to claim 1.

6. Preventive and/or therapeutic agent according to claim 5, where the neurodegenerative disease is selected from the group consisting of bol is FDI Parkinson, of Parkinson's disease, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, Alzheimer's disease, diseases of the Peak, prion disease, corticobasal degeneration, disease, diffuse Taurus Levi, Huntington's disease, essential tremor, Tourette's syndrome, rett syndrome, acetosa, cerebral palsy, Wilson's disease, syndrome Hallervorden-Spitze, neuroaxonal dystrophy, spinocerebellar degeneration of the retina, olivopontocerebellar atrophy, disease Joseph, dentatorubral-pallidoluysian atrophy, disease Gerstmann-Straussler-Sheinker, Friedreich's ataxia syndrome may-white, ataxia-telangiectasia, amyotrophic lateral sclerosis, spinobulbar muscle atrophy, diseases of werdnig-Hoffman disease Kugelberg-Welander, hereditary spastic paraparesis, syringobulbia, syndrome, Arnold-Chiari, splitting spine syndrome Sjogren-Larsson, age-related macular degeneration and apoplexy of the brain selected from the group consisting of ischemic stroke and hemorrhage in the brain.

7. Preventive and/or therapeutic agent according to claim 5, where the disease is caused by neurological dysfunction, which are selected from the group consisting of spinal cord injuries caused chemotherapy neuropathy, diabetic Neuve is Opatija, radiation injury, and demyelinating disease selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive mnogofotonnoi leukoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinative polyneuropathy syndrome of Gillen-Barre.

8. Preventive and/or therapeutic agent according to claim 5, where the disease caused by the deterioration of the function of mitochondria, which are selected from the group consisting of Pearson syndrome, diabetes, deafness, migraine malignant course, Leber's disease, MELAS, MERRF syndrome overlap MERRF/MELAS, NARP, true myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal kishechnoi ataxia, acquired sideroblastic anemia caused by aminoglycosides hearing loss, complex III deficiency due to a hereditary variants of cytochrome b, multiple symmetric lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, disease ANT1, disease Twinkle, the POLG disease, recurrent myoglobinuria, SANDO, ARCO, deficiency of complex I deficiency of complex II, optic nerve atrophy, fatal child's deficiency of complex IV deficiency, mitochondrial DNA deficiency syndrome, mitochondrial DNA, encephalomyelopathy and, syndrome, chronic progressive external ophthalmoplegia (CREO), syndrome of Core-Saury, encephalopathy, lactacidemia, mioglobinurii caused by drugs mitochondrial diseases, schizophrenia, major depressive disorder, bipolar I disorder, bipolar II disorder, atypical depression, seasonal affective disorder, postpartum depression, minor depression, recurrent brief depressive disorder, persistent depression/chronic depression, double depression and acute renal failure.

9. The use of quinolone derivative of General formula (1) or its pharmaceutically acceptable salt according to claim 1 as a drug for the treatment and/or prevention of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by deterioration of the function of the mitochondrion.

10. Method for the treatment or prevention of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by deterioration of the function of mitochondria, including the introduction of a human or animal quinolone derivative of General formula (1) or its pharmaceutically acceptable salt according to claim 1.

11. A method of obtaining a quinolone derivative of General formula (1)

or headlamp is asepticheski acceptable salt, in which each of R1, R2, R3, R4, R5, R6and R7defined above in claim 1, including the interaction of the compounds represented by the General formula (4)

in which each of R1, R4, R5, R6and R7defined above in claim 1, with a compound represented by the General formula (5)

in which each of R2and R3defined above in claim 1, and R8represents a lower alkoxy group, receiving the intermediate compounds represented by the General formula (6)

in which each of R1, R2, R3, R4, R5, R6, R7and R8defined above; and subjecting the compound obtained in the cyclization reaction.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 5-hydroxy-6-methyl-1-(thietanyl-3)pyrimidine-2,4(1H,3H)-dione of formula , which inhibits generation of active forms of oxygen and has antioxidant activity.

EFFECT: improved properties of compounds.

2 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an improved method for preparing 2-arylamino-4-hetarylpyrimidines of formula (I) which possess inhibitory action on serine-threonine kinase Haspin on the enzymatic level, and may be used as drug substances for oncological diseases. In formula (I), wherein Het = , , , , , , , , , , ,

R=H; 2-Me; 3-Me; 4-Me; 2,3-di-Me; 2-MeO; 3-MeO; 4-MeO; 4-EtO; 4-PhO; 2-Cl; 3-Cl; 4-Cl; 4-F; 2-Me, 3-Cl. The method consists in a reaction of related hetarylmethylketone and N,N-dimethylformamide dimethylacetale on boiling of reagents in isopropyl alchohol for 6 hours to produce 3-dimethylamino-1-hetaryl-2-propen-1-ones with adding in situ related aryl guanidine and further boiling for 2 hours. The process is conducted at molar ratio (mole) of hetarylmethylketone: N,N-dimethylformamide dimethylacetale : aryl guanidine = 1:1.5:1.

EFFECT: method simplifies the process due to cutting a process time and reducing consumption of the initial ingredients.

6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a novel compound - 6-methyl-1-(thietanyl-3)uracil of formula 1 , which stimulates the protective activity of phagocytes.

EFFECT: obtaining compounds which stimulate the protective activity of phagocytes.

2 cl, 1 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and medicine and specifically to a novel compound - 6-(thietanyl-3)aminopyrimidine-2,4(1H,3H)-dione of formula (1), which inhibits lipid peroxidation.

EFFECT: obtaining a compound which inhibits lipid peroxidation.

2 cl, 1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cyclic indole-3-carboxamide of formula (I) or physiologically acceptable salts thereof of formula (I): wherein the values A, R, R10, R20, R30, R40, n, p and q are specified in clause 1 of the patent claim. A method for preparing them is described.

EFFECT: compounds have renin-inhibitory activity that allows using them for preparing a pharmaceutical composition and a drug preparation for treating the diseases associated with renin activity.

11 cl, 4 tbl, 127 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

,

where X is O, NH or N-Rx, and Rx, Ra, Rb, R10a, R11a, R2, R3, R4 are selected from hydrogen, different aliphatic, alicyclic, aromatic, heteroaromatic and functional groups which can be optionally substituted, wherein R4 together with R2 can form a C1-C5alkylene or C3-C5alkenylene fragment. Said compounds are positive modulators of metabotropic glutamate receptor 2 and can be used in medicine.

EFFECT: novel biologically active compounds are efficient when treating a range of diseases of the nervous system which are mediated by the dysfunction of the glutamate receptor.

23 cl, 590 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic synthesis and specifically to a method of producing 2-(2-thienyl)-3-alkyl pyrroles and N-vinyl derivatives thereof of general formula and , where Alk denotes any linear alkyl substitute. The method is a single-reactor three-component reaction of 2-acylthiophene, hydroxylamine chloride and excess acetylene in the presence of an alkali metal hydroxide with adding sodium bicarbonate to DMSO in an autoclave under acetylene pressure for 1-3 hours at temperature of 80-120°C in a wide range of molar concentration of reactants; molar ratio of reactants acylthiophene: hydroxylamine chloride: acetylene: MOH: DMSO varies in the range of 1:1.0-1.5:2-25:1.5-2.5:30-50.

EFFECT: method of obtaining novel compounds which can be used as monomers for producing electroconductive polymers, particularly as active components of electrodes of polymer rechargeable batteries and electrochromic devices.

2 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to a piperidine derivative of general formula (I)

,

where R1 denotes hydrogen or a substitute selected from the following (b)-(i): b) acrylic acid (including alkyl ester and hydroxyalkyl amide), (c) ureide, (d) alkenyl, (e) aminoalkyl which can be substituted with alkyl carbonyl or aminocarbonyl, (f) carbonyl alkyl, substituted with hydroxy, alkoxy or hydroxyalkylamino, (g) carbonyl, substituted with hydroxy, morpholino, alkoxy, hydroxyalkyl aminoalkoxy or cyclohexyloxy carbonyloxyalkoxy, (h) carbonylamino, substituted with alkyl or alkoxy, (i) aminocarbonyl which can be substituted with one or two substitutes selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which can be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy); R2 denotes hydrogen or a substitute selected from the following (j)-(r): (j) cyano, (k) acrylic acid, (l) alkyl, substituted with hydroxy or piperidino, (m) carbonyl alkyl, substituted with hydroxy, alkoxy (which can be substituted with cyclohexyloxy carbonyloxy) or hydroxyalkylamino, (n) carbonyl, substituted with hydroxy or alkoxy, (o) carbonyl alkoxy, substituted with alkoxy, (p) carbonyl alkyl sulphanyl, substituted with hydroxy or alkoxy, (q) alkoxy, (r) halogen; and R3 denotes hydrogen or a substitute selected from the following (s)-(w): (s) alkyl which can be substituted with carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkyl sulphanyl or one or two hydroxy, (t) carbonyl, substituted with alkyl or alkoxy, (u) carbonyl alkoxyalkyl, substituted with hydroxy or alkoxy, (v) carbonyl alkyl, substituted with alkyl, alkoxy or alkylphenyl, (w) aminoalkyl, substituted with aminocarbonyl or alkane sulphonyl, where one of said R1 and R2 denotes a substitute other than hydrogen, A is unsubstituted or is an oxo, B denotes carbon or oxygen, one of X and Y denotes carbon and the other denotes sulphur, the dotted line denotes a single bond or a double bond, under the condition that when R2 denotes halogen or alkoxy, A is unsubstituted, R1 denotes a substitute other than hydrogen and B denotes oxygen. The invention also relates to an antihistamine which contains a compound of formula I and use of the described compound for treatment and production of a medicinal agent.

EFFECT: novel compounds having antagonistic action on histamine receptors are obtained and described and can be suitable as active ingredients of a pharmaceutical composition, especially an antihistamine composition.

17 cl, 40 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an improved method for preparing 2-arylamino-4-hetarylpyrimidines of formula (I) which possess inhibitory action on serine-threonine kinase Haspin on the enzymatic level, and may be used as drug substances for oncological diseases. In formula (I), wherein Het = , , , , , , , , , , ,

R=H; 2-Me; 3-Me; 4-Me; 2,3-di-Me; 2-MeO; 3-MeO; 4-MeO; 4-EtO; 4-PhO; 2-Cl; 3-Cl; 4-Cl; 4-F; 2-Me, 3-Cl. The method consists in a reaction of related hetarylmethylketone and N,N-dimethylformamide dimethylacetale on boiling of reagents in isopropyl alchohol for 6 hours to produce 3-dimethylamino-1-hetaryl-2-propen-1-ones with adding in situ related aryl guanidine and further boiling for 2 hours. The process is conducted at molar ratio (mole) of hetarylmethylketone: N,N-dimethylformamide dimethylacetale : aryl guanidine = 1:1.5:1.

EFFECT: method simplifies the process due to cutting a process time and reducing consumption of the initial ingredients.

6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cyclic indole-3-carboxamide of formula (I) or physiologically acceptable salts thereof of formula (I): wherein the values A, R, R10, R20, R30, R40, n, p and q are specified in clause 1 of the patent claim. A method for preparing them is described.

EFFECT: compounds have renin-inhibitory activity that allows using them for preparing a pharmaceutical composition and a drug preparation for treating the diseases associated with renin activity.

11 cl, 4 tbl, 127 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1,3-disubstituted 4-methyl-1H-pyrrol-2-carboxamides of formula I: wherein the values R1, R2, R3, R4 are presented in cl.1 of the patent claim.

EFFECT: preparing the compounds found to be serotonin-5-HT reuptake inhibitors that enables using them in medicine.

14 cl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted quinoxaline-type piperidine compounds of formula or to a pharmaceutically acceptable derivative thereof, wherein: Y1 represents O; Q is specified in condensed benzo or pyridino; each R2 is independently specified in: (a) -halogen or -CN; (b) -(C1-C6)alkyl; a is an integer specified in 0, 1 or 2; a dash line in a 6-member ring containing a nitrogen atom which is condensed with Q group means the presence or absence of a bond, and when the dash line means the absence of the bond, then R3, and one R4 are absent; R3 is specified in: (a) -H; each R4 is independently specified in: (a) -H; or (b) - halogen or CN; or (c) -X, -(C1-C6)alkyl-X, -(5- or 6-member)heterocyclyl-X or -(5- or 6-member)heterocyclyl-(C1-C6)alkyl-X; or (d) -C(=Y)X, -C(=Y)T3, -C(=Y)YX, - C(=Y)YT3, -C(-Y)N(T1)(T2), -C(=Y)N(R9)CN, -C(=Y)N(R9)X, -C(=Y)N(R9)YH, -C(=Y)N(R9)YX, -C(=Y)N(R9)YCH2X, -C(-Y)N(R9)YCH2CH2X or -C(=Y)N(R9)S(K))2T3; or (e) -N(R9)X, -N(R9)-CH2X, -N(R9)-CH2CH2X, -N(R9)CH2N(R9)C(=N(R12))N(R12)2, -N(R9)-CH2CH2N(R9)C(=N(RI2))N(R12)2, -N(T1)(T2), -N(T3)C(=Y)T3, -N(T3)C(=Y)YT3, -N(T3)C(=Y)N(T1)(T2), -N(T3)S(=O)2T3 or -N(T3)S(=O)2N(T1)(T2); X represents: (a) -H, -( C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkoxy, -(C3-C7)cycloalkyl, -(5- or 6-member)heterocycle or -(7-10-member)bicycloheterocycle each of which is unsubstituted or substituted with 1, 2 or 3 of optionally substituted R8 groups; or (b) -phenyl, -naphthalenyl, or -(5- or 6-member)heteroaryl each of which is unsubstituted or substituted with 1 or 2 of independently specified in R7 groups; each Y is independently specified in O; A and B are independently specified in: (a) -H; or (c) A-B together can form a (C2-C6)bridge each can optionally contain -HC=CH- or -O- in a (C2-C6)bridge; wherein the 6-member ring containing a nitrogen atom which is condensed with Q group can be found in the endo- or exo- configuration in relation to the A-B bridge; or (d) A-B together can form the -CH2-N(Ra)-CH2- bridge wherein the 6-member ring containing a nitrogen atom is condensed with Q group, and can be found in the endo- or exo- configuration in relation to the A-B bridge; Ra is specified in -H or -(C1-C6)alkyl; Z represents -[(C1-C10)alkyl optionally substituted with R1]h-, wherein h is equal to 0 or 1; each R1 is independently specified in: (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl3 -(C3-C7)cycloalkoxy, -(C6-C14)bicycloalkyl, -(C8-C10)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C7-C14)bicycloalkenyl, -(3-7-member)heterocyclyl each of which is unsubtituted or substituted with 1, 2 or 3 of independently specified in R8 groups;

or or (d) -phenyl, -naphthalenyl each of which is unsubstituted or substituted with R7 group; each R6 is optionally specified in -H; each R7 is independently specified in -(C1-C4)alkyl, -OR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, -halogen, -N(R9)2, -C(=O)OR9; each R8 is independently specified in -(C1-C4alkyl, tetrzolyl, imidazolyl, furanyl, -(C1-C6)alkylCOOR9, -OR9, -SR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, =O, -halogen, -N(R9)(C1-C6)alkylCOOR9, -N(R9)2, -N(R9)S(=O)2R12, -N(R9)C(=O)R12, -N(R9)C(=O)OR12, -C(=O)R9, -C(=O)N(T1)(T2), -C(=O)OR9, -OC(=O)R9, or -S(=O)2R9; each R9 is independently specified in -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -phenyl, -benzyl, -(5- to 6-member)heterocycle, -C(halogen)3; -CH(halogen)2 or -CH2(halogen); if h is equal to O, then R11 can be specified in -H, -C(=O)OR9 or -C(=O)N(R6)2 or R11 can be -(C1-C4)alkyl; if h is equal to 1, then R11 can be specified in -H; each R12 is independently specified in -H or -(C1-C4)alkyl; m is equal to an integer specified in 3, 4, 5, 6, 7, 8 or 9; each e and f is equal to an integer independently specified in 0 or 1, provided 2≤(e+f)≤5; each j and k is equal to an integer independently specified in 0 or 1, provided 1≤(j+k)≤4; each p is equal to an integer independently specified in 0 or 1; each T1, T2, and T3 is independently specified in -H or -(C1-C10)alkyl which is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups, or T1 and T2 together can form 5- to 8-member ring wherein the number of ring atoms contains a nitrogen atom wherein T1 and T2 are bound; the above 5- to 8-member ring is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups and optionally any carbon atom in the above 5- to 8-member ring is independently substituted with O or N(R6); each halogen is independently specified in -F, -CI, -Br or -I.

EFFECT: invention refers to the intermediate compounds of formula

, , for preparing the above compounds of formula (II), compositions containing the above compounds and to a method of treating or preventing a diseased state, such as a pain.

36 cl, 58 ex, 2 tbl

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