Glutamine fructose-6-phosphate amidotransferase inhibitors

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula (I): , where R1 is -COOH or -(CH2)n-R14; R2 is or , where X is -CH or -N; each of R3, R4, R5 and R6 is selected out of group including -H, -(lower) alkyl, -N(CH3)2, -O-(lower) alkene, -(lower) alcoxy, or where R5 and R6 are substitutes in adjoining carbon atoms in ring, R5 and R6 optionally form 5- or 6-member saturated carbocyclic ring together with adjoining carbon atoms, R14 is unsaturated 5-member substituted or non-substituted heterocyclic ring including 1 to 4 heteroatoms selected out of N, O and S, n is 0 or 1, or their pharmaceutically acceptable salts or complex ethers. Invention also concerns pharmaceutical composition.

EFFECT: obtaining new bioactive compounds and pharmaceutical composition based on them, with inhibition effect on glutamine fructose-6-phosphate amidotransferase (GFAT).

16 cl, 16 ex

 

Diabetes is characterized by peripheral insulin resistance, which increases the rate of formation of glucose and reduce insulin secretion. In General this increases the level of glucose in the serum. Moreover, the level of glucose in blood serum increases over a long period of time after a meal and returned to normal slowly. The effects of increasing the level of glucose in the blood are well known, although the biochemical and molecular mechanisms underlying this phenomenon have not yet been investigated. Free fatty acids, triglycerides and other factors can also directly lead to higher glucose levels.

The metabolic pathway of hexosamine is one of the biochemical pathways associated with insulin resistance, elevated glucose levels and reduced insulin secretion. Path hexosamine includes synthesis UDF-GlcNAc. The glucose is subsequently converted to fructose-6-phosphate, glucosamine-6-phosphate and, ultimately, D.O.-GlcNAc. Formed UDF-GlcNAc is included in various carbohydrate-containing macromolecules, many of which are the basic components of cells. UDF-GlcNAc is also a substrate for the enzyme OGT, O-linked GlcNAc transferase, which catalyzes the transfer of GlcNAc residues in various letocnazelre, including cytoplasmic proteins, nuclear proteins, membrane proteins and transcription factors. The activity of these proteins can significantly modulate. Limiting the speed of the enzyme in this way is glutenfreeda-6-fosfatdegidrogenaza (GFAT), which catalyzes the transfer of amides and isomerization of fructose-6-phosphate into glucosamine-6-phosphate. GFAT is included in the mechanism of development of the symptoms of diabetes, as GFAT-transgenic mice show insulin resistance. The biochemical pathway leading to the emergence of insulin resistance include activation piruvatkinase complex RKS, changing components of cell membranes, changes in the activity of transcription, as well as other biochemical mechanisms that are not yet understood.

Elevated levels of GFAT observed in diabetes mellitus type 2 (T2DM) and in rodent models T2DM. The GFAT-transgenic mice (primarily in muscle, liver, adipose tissue and pancreas) can be seen as insulin resistance and hyperinsulinemia. Glucosamine and path components of hexosamine cause insulin resistance, increase the rate of removal of glucose from the liver and reduce insulin secretion. GFAT may cause complications of the kidneys in diabetes T2DM. GFAT is limiting the speed of the enzyme in the way of hexosamine, and the reduction of enzyme is aktivnosti GFAT leads to lower glucose levels, that can be used in the treatment of diabetes.

Known classes of GFAT inhibitors include abstractable or not abstractable and inhibited by reversible or irreversible (covalent) mechanisms. The two substrates GFAT are sugar ID fructose-6-phosphate and the amino acid glutamine. Fructose-6-postadoptive inhibitors include N-idaceciliachapman-6-phosphate (S.L.Bearne, J. Biol. Chem., 271, s-3057 (1996)) and 2-amino-2-desoxyglucose-6-phosphate (M-.Badet-Denisot, .Leriche, F.Massiere, and .Badet, Bioorg. Med. Chem. Letters, 5, s-820 (1995)). Glutaminate inhibitors or inhibitors on the basis of glutamine include: glutamate-γ-tolualdehyde (S.L.Bearne and R.Wolfenden, Biochem., 34, SS-11520 (1995)), L-γ-glutamyl-2-[((pair-deformity)phenyl)thio]glycine (F. Massiere, M.-A.Badet-Denisot, L.Rene and .Badet, J. Amer. Chem. Soc., 119, cc.5748-5749 (1997)), antisepsis (.Chmara, J. Gen, Environ, 131, 265-271 (1985)), 6-diazo-5-exoneration (DON), azaserine and N3-halogenoacetyl-L-2,3-diaminopropionic acid (where the halogen means I, Br and Cl, S.Milewski, .Chmara, R.Andruszkiewicz and .Borowski, Biochim. Biophys. Acta, 1115, cc.225-229 (1992)).

Papaverales (name in Chemical Abstracts collection: (6,7-dimethoxy-1-ethenolysis)(3,4-acid)(S)methanon) has properties that can be used for the treatment of cardiovascular diseases (Anselmi Elsa and others, "Selective inhibition of calcium entry induced by benzylisoquinolines in rat smooth muscle", J. Pharm. Pharmacol. 44(4), cc.337-43, (1992); Markwardt Fritz and others, "Influence of 6,7-dimethoxyisoquinoline derivatives on the function of thrombocytes", Ata Biologica et Medica Germanica 23(2), cc.295-306, (1969)).

Brief description of the invention

The present invention relates to compounds of formula (I)

R1means-COOH, -(ness.)alkyl-COOH, -(ness.)alcohol, -CH2OCH3, -CH2NH2,

-CH2NHSO2R7, -C(=O)R8,

-CNHCH2CH2-R8, -C(=NH)-R8,

-(CH2)nNHC(=O)R9, -(CH2)mC(=O)N(R11)(R12),

-C(NH)-R13or -(CH2)n-R14;

R2means

or

where X represents CH or N,

R3, R4, R5and R6each is chosen from the group comprising-H, -(ness.)alkyl, -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)CH2CH3, -halogen, -O-(ness.)alkene, -(ness.)alkoxy, -O-(ness.)alcohol and-O(CH2)n-cycloalkyl or

where R5and R6are substituents at adjacent carbon atoms in the cycle, R5and R6optional together with the carbon atoms to which they are attached, form a 5 - or 6 - membered saturated carbocyclic ring,

R7means-CF3, -(ness.)alkyl, -CH2Cl, -CH2CF3or-R8,

R8means 5 - or 6-membered saturated substituted or unsubstituted heterocyclic ring containing one hetero is, selected from N, O and S, and substituted ring means a heterocyclic ring, substituted by a group-Oh or phenyl,

R9means -(ness.)alkyl, -(ness.)alkoxy or -(CH2)nR10,

R10means 5 - or 6-membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms, which are selected from N and O,

R11means-N or-CH3,

R12means-N -(ness.)alkyl, -C≡N, -OH, -(ness.)alkoxy or-CH2SOON2CH3,

R13means -(ness.)alkoxy, -NH2or-N(ness.)alkyl,

R14means a saturated or unsaturated 5-membered substituted or unsubstituted heterocyclic ring containing from 1 to 4 heteroatoms, whereby the heteroatoms are selected from N, O and S, and the saturated ring is a heterocyclic ring substituted by one or two cyclic carbon atoms by a group =O, or substituted on the N atom in the ring group(ness.)alcohol or nits.)alkyl,

m is 0, 1 or 2,

n is 0 or 1, or pharmaceutically acceptable salts or esters.

Compounds of the present invention are GFAT inhibitors that can be used for the treatment of type II diabetes.

Detailed description of the invention

The present invention relates to compounds of formula (I)

R1means-COOH, -(ness.)alkyl-COOH, -(ness.)alcohol, -CH2Och3,

-CH2NH2, -CH2NHSO2R7, -C(=O)R8, -CNHCH2CH2-R8, -C(=NH)-R8,

-(CH2)nNHC(=O)R9,

-(CH2)mC(=O)N(R11)(R12), -C(=NH)-R13or -(CH2)n-R14,

R2means

or

where X denotes CH or N,

R3, R4, R5and R6each is chosen from the group comprising-H, -(ness.)alkyl,

-N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)CH2CH3,

halogen, -O-(ness.)alkene,

-(ness.)alkoxy, -O-(ness.)alcohol and-O(CH2)n-cycloalkyl or

where R5and R6mean the substituents at adjacent carbon atoms in the cycle, R5and R6optional together with the carbon atoms to which they are attached, form a 5 - or 6-membered saturated carbocyclic ring,

R7means-CF3, -(ness.)alkyl, -CH2Cl, -CH2CF3or-R8,

R8means 5 - or 6-membered saturated substituted or unsubstituted heterocyclic ring containing one heteroatom selected from N, O and S, and substituted ring means a heterocyclic ring, substituted by the groups HE or phenyl,

R9about the means -(ness.)alkyl, -(ness.)alkoxy or -(CH2)nR10,

R10means 5 - or 6-membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms, which are selected from N and O,

R11means-N or-CH3,

R12means-N -(ness.)alkyl, -C≡N, -OH, -(ness.)alkoxy or-CH2SOON2CH3,

R13means -(ness.)alkoxy, -NH2or-N(ness.)alkyl,

R14means a saturated or unsaturated 5-membered substituted or unsubstituted heterocyclic ring containing from 1 to 4 heteroatoms, whereby the heteroatoms are selected from N, O and S, and substituted ring means a heterocyclic ring, substituted by one or two cyclic carbon atoms by a group =O, or substituted on the N atom in the ring group(ness.)alcohol or nits.)alkyl,

M is 0, 1 or 2,

N is 0 or 1,

or their pharmaceutically acceptable salts or esters.

Compounds of the present invention are inhibitors GFAT and used for the treatment of type II diabetes.

In the present description uses the following definitions of terms. The term "ness." means a group containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.

The term "cycloalkyl" means non-aromatic, partially or fully saturated, cyclic hydrocarbon gr the PPU, containing from 3 to 7 carbon atoms. Examples cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "halogen" or "heteroatom", unless specified otherwise, means all four Halogens, i.e. fluorine, chlorine, bromine and iodine.

The term "(ness.)alkyl" means a branched or unbranched alkyl group containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. Typical examples (ness.)alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl and hexyl. If (ness.)alkyl attached to another functional group, it is divalent, for example -(ness.)alkyl-COOH.

The term "(ness.)alkoxy" means a group of the formula-O-(ness.)alkyl, in which the term "(ness.)alkyl" is defined above. Typical group (ness.)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "(ness.)alcohol" means -(ness.)alkyl in which at least one hydrogen atom at any position, including the end, replaced by a hydroxyl group. Typical examples (ness.)alcohol groups include ethanol, isopropanol and n-propanol.

The term "(ness.)alkene" means a group -(ness.)alkyl containing at least 3 carbon atoms, in which at least one bond between carbon atoms starting in rainy least from the second carbon atom is(ness.)the alkyl group is a double and at least one atom of N, each of these carbon atoms is missing. Thus (ness.)alkene is at least partly unsaturated group. Typical examples (ness.)alkenovich groups include 2-propene, 3-methyl-2-butene and 2,3-dimethyl-2-butene.

The term "aryl" means a phenyl group. As indicated in this context, the aryl group may contain the specified substituent in one or more positions. In more detail, the term "aryl" alone or in combination, means a phenyl or a phenyl group which optionally contains one or more substituents, preferably from one to three independently selected from the group comprising halogen, trifluoromethyl, triptoreline, amino, alkyl, alkoxy, alkylsulphonyl, cyano, carbarnoyl, alkoxycarbonyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, hydroxy, nitro, alkyl-SO2-, amino-SO2-cycloalkyl and the like, Preferred is phenyl.

The term "heteroaryl" means 5 - or 6-membered unsaturated, primarily aromatic heterocyclic ring containing at least one heteroatom selected from N, O and s As specified in this context, heteroaryl may contain one or more of the specified position Deputy or deputies.

"IC50" means the concentration of the compounds of the present invention, in which the observed inhibition is aktivnosti GFAT in vitro by 50% when measured as specified in this context.

The term "pharmaceutically acceptable salt" refers to acceptable acid-additive or basic additive salts, which do not affect the biological effectiveness and properties of the compounds of formula I and which are obtained from suitable non-toxic organic or inorganic acids or with organic and inorganic bases. Typical acid additive salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and organic acids such as para-toluensulfonate, salicylic acid, methanesulfonate, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. are Examples of basic additive salts include salts of ammonium, potassium, sodium and hydroxides of Quaternary ammonium, such as a hydroxide of Tetramethylammonium.

Method of chemical modification of pharmaceutical compounds (drug) with the formation of salts is well known and is used to improve the product properties, such as chemical or physical stability, for example, hygroscopicity, flowability or the solubility of the compounds, see for example .Ansel and others, Pharmacetical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) cc.196 and 1456-1457.

The term "pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient etc., means pharmacologically acceptable and practically non-toxic compound that is intended for administration to a subject.

The term "pharmaceutically acceptable ester" refers to esterified standard method the compound of formula I containing a carboxy group, which retains the biological effectiveness and properties of the compounds of formula I and is cleaved in vivo (in the body) with the formation of the corresponding active carboxylic acid. In the present invention esters can be obtained, for example, from the compounds in which R1means-COOH or -(ness.)alkyl-COOH. Examples of ester groups, which are oxidized in vivo (in this case hydrolyzed) to the corresponding carboxylic acids include compounds in which ottsepleny hydrogen is replaced by (ness.)alkyl, optionally substituted heterocycle, cycloalkyl etc. Examples of substituted (ness.)alilovic esters include compounds in which (ness.)alkyl substituted by a group pyrrolidine, piperidine, morpholine, N-methylpiperazine etc.

More detailed information and examples of esters for the delivery of pharmaceutical compounds found in the book "Design of Prodrugs", Bundgaard, H. ed. Elsevier (1985). Cm. also .Ansel and others, PharmaceuticalDosage Forms and Drug Delivery Systems, 6th Ed, cc.108-109, (1995); Krogsgaard-Larsen and others, "in Textbook of Drug Design and Development, 2d Ed, cc.152-191, (1996).

This application incorporates by reference U.S. provisional application No. 60/471690, filed may 19, 2003/ "Glutamine Fructose-y-Phosphate Amedotransferase (GFAT Inhibitors)".

The present invention relates to pharmaceutical compositions containing at least one compound of formula I, or

pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

The pharmaceutical composition is administered by oral way, for example, in the form of tablets, coated tablets, pills, hard or soft gelatin capsules, solutions, emulsions or suspensions. The pharmaceutical compositions can be entered and rectal method, for example, in the form of suppositories, or parentally way, for example, in the form of solutions for injection.

The pharmaceutical compositions of the present invention containing the compound of the formula I and/or their salts or esters, get known in the art methods, for example, mixing, encapsulating, dissolving, granulating, emulsifying, getting pills or lyophilization. Pharmaceutical drug can be mixed with therapeutically inert, inorganic or organic carriers. As such carriers to obtain tablets, coated tablets, dragées and hard gelatin capsules IP is result lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes and fats. In the case of soft gelatin capsules, depending on the nature of the active compounds usually do not require any medium. In this case, a pharmaceutically suitable carrier is a soft gelatin capsule. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection solutions are water, alcohols, polyols, glycerine, vegetable oil, phospholipids and surfactants. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid polyols.

Moreover, the pharmaceutical preparations contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffer substances, masking agents or antioxidants.

The preparations can also contain other therapeutically valuable substances, including additional active ingredients other than the compounds of formula I.

Compounds of the present invention is used as a medicinal means is for the treatment of type II diabetes. A therapeutically effective dose of the drug prescribed by your doctor.

Therapeutically effective amount or dose of a compound of the present invention varies within wide limits and is determined by a specialist. The dose is selected taking into account the individual requirements in each particular case, including the use of specific compounds, the route of administration, the disease to be treated, and the patient in need of treatment. Mainly in the case of oral or parentline the introduction of the daily dose for adult humans weighing approximately 70 kg is from about 10 mg to about 1000 mg, however, if necessary, the upper dose limit can be exceeded. The daily dose can be administered as a single dose or in divided doses, if parentline introduction you can use continuous infusion.

Preferred are the compounds of formula I, where R1means-COOH, -(ness.)alkyl-COOH, (CH2)nNHC(=O)R9, -CH2NHSO2R7or -(CH2)n-R14

More preferred are the compounds of formula I, where R1means-COOH, -(ness.)alkyl-COOH, and -(ness.)alkyl-COOH means-CH2COOH, or -(CH2)n-R14.

Other preferred compounds of the present invention are compounds of the Fort the uly I, where R1means-COOH or -(CH2)n-R14and R14means unsubstituted heterocyclic ring.

Preferred are also the compounds of formula I, where R1means tetrazol.

Even more preferred are the compounds of formula I, where R1means -(CH2)nNHC(=O)R9or-CH2NHSO2R7.

In addition, the preferred embodiment of the present invention are the compounds of formula I, where R9means (ness.)alkyl.

Preferred are also the compounds of formula I, where R7means-CF3.

Another preferred aspect of the present invention are the compounds of formula I, where R2means

or

More preferred are the compounds of formula I where X is CH.

Even more preferred are the compounds of formula I where X is-n

Preferred are also the compounds of formula I, where

R1means -(CH2)nR14and where R14means unsubstituted ring,

-COOH, -CH2COOH, -(ness.)alcohol, -CH2Och3or-CH2NH2,

R2means

or

where X represents CH or N,

R3R 4, R5and R6each independently selected from the group including:

-H, -(ness.)alkoxy,

-N(CH3)CH3,

-(ness.)alkyl and-O-(ness.)alkene or where R5and R6substituted at adjacent carbon atoms of the ring, R5and R6optional together with the carbon atom to which they are attached, form a 5 - or 6-glenanne saturated carbocyclic ring.

Even more preferred are the compounds of formula I, where

-(ness.)alkyl means methyl, -(ness.)the alcohol is methanol, -(ness.)alkoxy means methoxy, and -(ness.)alkyl-COOH means-CH2-COOH.

Another preferred aspect of the present invention are the compounds of formula I, where R3, R4, R5and R6each is chosen from a group including:

-H, -(ness.)alkyl containing from 1 to 4 carbon atoms, -N(CH3)2, -(ness.)alkoxy containing from 1 to 4 carbon atoms, halogen and-O-(ness.)alkene containing from 1 to 4 carbon atoms, or

where R5and R6are substituents at adjacent cyclic carbon atoms,

R5and R6optional together with the carbon atoms to which they are attached, form a six-membered saturated carbocyclic ring.

More preferred are the compounds of formula I, selected from the group including

(naphthalene-2-yl)[6,-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]metano,

and

(naphthalene-1-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]metano, or their pharmaceutically acceptable salts.

Preferred are the compounds of formula I, selected from the group including

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]quinoline-3-ylmethanol and

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]quinoline-8-ylmethanol, or their pharmaceutically acceptable salts.

Preferred are also the compounds of formula I, selected from the group including

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-methoxynaphthalene-1-yl)methanon,

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-dimethylaminonaphthalene-1-yl)methanon,

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-methylnaphthalene-1-yl)methanon,

(2-allyloxymethyl-1-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]metano,

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](7-methylnaphthalene-2-yl)methanon,

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](1,2,3,4-tetrahydrofurane-9-yl)methanon and

[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](2-methoxynaphthalene-1-yl)methanon, or their pharmaceutically acceptable salts.

Most preferred are also the compounds of formula I, selected from the group including:

1-(4-dimethylaminonaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid,

1-(4-methoxynaphthalene-1-CT is of IMT)-6,7-dimethoxyisoquinoline-4-carboxylic acid and

6,7-dimethoxy-1-(1,2,3,4-tetrahydrofurane-9-carbonyl)isoquinoline-4-carboxylic acid,

or their pharmaceutically acceptable salts.

In addition, preferred is the following compound of the formula I:

6,7-dimethoxy-1-(naphthalene-1-carbonyl)isoquinoline-4-carboxylic acid or its pharmaceutically acceptable salt.

In addition, preferred is a method of obtaining a compound according to any one of items 1 to 19, including

a) interaction of the compounds of formula

in the presence of NaN3and NH4Cl, preferably in DMF with the formation of the compounds of formula

where R2'means

,or;

X represents CH or N,

R3'means H or CH3,

R5'means H, och3or

Och2CH=CH2,

or

b) interaction of the compounds of formula

in the presence of a base, preferably NaOH, first of all, in the presence of EtOH and N2Oh, with the formation of the compounds of formula

where R2"means

or

and R4"means H, och3or N(CH3)2.

Preferred are also with the organisations of the formula I, obtained in the above way.

The compounds of formula I preferably use as therapeutically active substances.

To obtain medicines for the prevention and treatment of type II diabetes, it is preferable to use the compounds of formula I.

Another preferred aspect of the present invention are pharmaceutical compositions containing the compounds of formula I and a therapeutically inert carrier.

Preferred is also the use of compounds of formula I to obtain drugs intended for the treatment and prevention of type II diabetes.

Preferred is a method of treating type II diabetes patients in need of such treatment, comprising administration to the patient a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt in an amount of from about 10 mg to about 1000 mg per day.

Compounds of the present invention receives, as indicated, or by known methods.

The General scheme of synthesis

Scheme 1

Scheme 2

X is CH, N

R3'means H, CH3

R5'means N, co 3,

Och2CH=CH2

R6'means H, och3N(CH3)2,

CH3

R4"for example, mean H, och3N(CH3)2

Example 1

Triptorelin (naphthalene-2-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]methanone

In a mixture of homoveratrylamine (17,7 g of 0.1 mol) and sodium methoxide (7,7 g of 0.11 mole) in ether (300 ml) was added ethyl formate sodium (8.2 ml) in ether (100 ml) and the resulting mixture was intensively stirred for 3 days. The solid precipitate was filtered, washed with ether and dissolved in water (100 ml), acidified with 10% acetic acid to pH 3. The precipitate was collected by filtration, washed with water and dried, it was obtained 2-(3,4-acid)-3-oxopropionate (19 g, 93%) as a solid white color. MS-LC: (m/f) Rasch. for C11H11NO3206 (MN+), calc. 206.

In a mixture of 2-(3,4-acid)-3-oxopropanenitrile of 20.5 g of 0.1 mol) and urethane (8,9 g of 0.1 mol) in toluene (400 ml) was added conc. sulfuric acid (0.5 ml, 10 mmol). The mixture was boiled under reflux and then concentrated by evaporation in low boiling to a volume of about 50 ml.

The cooled mixture was filtered, the precipitate washed with benzene and dried. After the cleaning Express chromatography (silica gel 60 Merck, 70-230 mesh, eluent: 20% methylene chloride) was obtained ethyl ester [2-cyano-2-(3,4-acid)vinyl]carbamino acid in the form of solids. MS-LC: (m/f) Rasch. for C14H16N2O4277 (MN+), calc. 277.

1H-NMR (300 MHz): corresponds to the connection structure. Conc. sulfuric acid (0.4 ml) was added to a mixture of ethyl ester of [2-cyano-2-(3,4-acid)vinyl]carbamino acid (33,5 g, 121 mmol) and diphenyl ether (230 ml). The resulting mixture was heated at 230°C for 6 hours After cooling and addition of ether were formed precipitate in the form of a solid, which was collected by filtration, washed with ether and dried, it was obtained 6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (20.7 g, 74.1 per cent) in a solid brown color, which was used without further purification. MS-LC: (m/f) Rasch. for C12H10N2O3231 (MN+), calc. 231.

A mixture of 6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (8 g, 35 mmol) and oxybromide phosphorus (70 g, 244 mmole) in anisole (30 ml) was heated at 80°C for 12 h, the Solvent and excess POBr3was removed on a rotary evaporator. The obtained solid was washed with hexane and dried, then was slowly added to ice and the product was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of CA is bonate sodium, saturated aqueous sodium chloride (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuum, when it received a solid brown color. After cleaning, Express chromatography (silica gel 60 Merck, 70-230 mesh, eluent: methylene chloride) was obtained 1-bromo-6,7-dimethoxyisoquinoline-4-carbonitrile (7.5 g, 75%) as a solid brown color. MS-LC: (m/f) Rasch. for C12H9BrN2O2293 (MN+), calc. 293.

In a mixture of 1-bromo-6,7-dimethoxyisoquinoline-4-carbonitrile (50 mg, 0.17-mmole), 2-naphthaldehyde (40,6 mg of 0.26 mmole) and iodide 1,3-dimethylimidazole (16 mg, 0.26 per mmole) in DMF (2 ml) was added sodium hydride (11 mg, 0.26 per mmole). The mixture acquired a dark color. After 1 h was added water (4 ml) and the solution was extracted with chloroform (6 ml). The extract was washed with water (4 ml), dried over sodium sulfate, filtered and concentrated in vacuum to receive solid, which was used without further purification.

The mixture obtained above solids (0,17 mmole), sodium azide (34 mg, of 0.51 mmole) and ammonium chloride (27 mg, of 0.51 mmole) in DMF (2 ml) was stirred at 100°C for 24 h After removal of the solvent the crude product was purified by reversed-phase GHUR (18, eluent: 10%-90% acetonitrile in water over 10 min), it was obtained the desired product as a solid which substances. MS-LC: (m/f) Rasch. for C22H16N6O3412 (MN+), calc. 412.

Example 2

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]quinoline-3-ylmethanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 3-hyalinobatrachium (0,26 mmole). MS-LC: (m/f) Rasch. for C22H16H6About3413 (MH+), calc. 413.

Example 3

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]-(4-methoxynaphthalene-1-yl)methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 4-methoxy-1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C24H19N5O4442 (MN+), calc. 442.

Example 4

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-dimethylaminonaphthalene-1-yl)methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 4-dimethylamino-1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C25H22N6O3455 (MN+), calc. 455.

Example 5

Triptorelin (naphthalene-1-yl)6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C23H17N5O3412 (MN+), calc. 412.

Example 6

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl] (4-methylnaphthalene-1-yl)methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 4-methyl-1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C24H19N5O3426 (MN+), calc. 426.

Example 7

Triptorelin (2-allyloxymethyl-1-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (0,26 mmole) 2-allyloxy-1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C26H21N5O4468 (MH+), calc. 468.

Example 8

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](7-methylnaphthalene-2-yl)methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but PR is the replacement 2-naphthaldehyde (of 0.26 mmole) of 7-methyl-2-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C24H19N5O3426 (MN+), calc. 426.

Example 9

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]quinoline-8-ylmethanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 8-hyalinobatrachium (0,26 mmole). MS-LC: (m/f) Rasch. for C22H16H6About3413(MH+), NID.

Example 10

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](1,2,3,4-tetrahydrofurane-9-yl)methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 9-(1,2,3,4-tetrahydroprotoberberine) (0,26 mmole). MS-LC: (m/f) Rasch. for C27H23N5O3466 (MN+), calc. 466.

Example 11

Triptorelin [6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](2-methoxynaphthalene-1-yl)methanone

The specified connection was received in the form of solid substances in the same way as described in example 1, but replacing 2-naphthaldehyde (of 0.26 mmole) of 2-methoxy-1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C24H19N5O4442 (MN+), calc. 442.

Example 12

Triforce is at 1-(4-dimethylaminonaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid

In a mixture of 1-bromo-6,7-dimethoxyisoquinoline-4-carbonitrile (see example 1, 50 mg, 0,17 mmole), 4-dimethylamino-1-naphthaldehyde (51,8 mg of 0.26 mmole) and iodide 1,3-dimethylimidazole (16 mg, 0.26 per mmole) in DMF (2 ml) was added sodium hydride (11 mg, 0.26 per mmole). The resulting reaction mixture had become a dark color. After 1 h, to the mixture was added water (4 ml) and the solution was extracted with chloroform (6 ml). The extract was washed with water (4 ml), dried over sodium sulfate, filtered and concentrated in vacuum to receive solid. After cleaning, Express chromatography (silica gel 60 Merck, 70-230 mesh, eluent: 0-40% EtOAc in methylene chloride for 30 min) was obtained 1-(4-dimethylaminonaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carbonitrile (31 mg, 41%) as a solid white color. MS-LC: (m/f) Rasch. for C21H18N2O5379 (MN+), calc. 379.

To a suspension of 1-(4-dimethylaminonaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carbonitrile (31 mg, 0,082 mmole) in methanol (2 ml) was added 25% aqueous sodium hydroxide solution (0,27 ml, 1.68 mmole). The resulting mixture was stirred at 90°C for 12 hours After cooling to room temperature the reaction mixture was acidified to pH 2 by addition of 2 n solution model HC1. The product was extracted with chloroform (2×200 ml). The combined organic layers were washed water is (3×50 ml), was dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (C18, eluent: 10%-90% acetonitrile in water over 10 min), it was obtained the desired product 1-(4-dimethylaminonaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid (9 mg) as a solid. MS-LC: (m/f) Rasch. for C25H22N2O5431 (MN+), calc. 431.

Example 13

Triptorelin 1-(4-methoxynaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid

The specified connection was received in the form of solid substances in the same way as described in example 12, but replacing 4-dimethylamino-1-naphthaldehyde (of 0.26 mmole) of 4-methoxy-1-naphthaldehyde (0,26 mmole). MS-LC: (m/f) Rasch. for C24H19NO6418 (MN+), calc. 418.

Example 14

Triptorelin 6,7-dimethoxy-1-(1,2,3,4-tetrahydrofurane-9-carbonyl)isoquinoline-4-carboxylic acid

The specified connection was received in the form of solid substances in the same way as described in example 12, but replacing 4-dimethylamino-1-naphthaldehyde (of 0.26 mmole) of 9-(1,2,3,4-tetrahydroprotoberberine) (0,26 mmole). MS-LC: (m/f) Rasch. for C27H23NO5442 (MN+), calc. 442.

Example 15

6,7-Dimethoxy-1-(naphthalene-1-carbonyl)isoquinoline-4-carboxylic acids of the Sabbath.

Compounds were obtained according to the method described above in example 12, but replacing 4-dimethylamino-1-naphthaldehyde (of 0.26 mmole) of 1-naphthaldehyde (0,26 mmole), received the product in the form of solids. LC/MS: m/e Rasch. for C23H17NO5388 (MN+), calc. 388.

Example 16

The determination of the activity of GFAT in vitro

Preparation of enzyme

The COS cells, transfection GFAT-α or GFAT-β, cultured until confluently 90%, was transferred to a buffer solution containing 100 mm FSB, 50 mm KCl, 10 mm EDTU and protease inhibitors leupeptin And Aprotinin, PMSF and pepstatin. The final concentration was 4×10-7cells/ml and the Mixture was voiced using microelectrode at intensity 4 in 15 seconds in the volume of 3-4 ml under ice cooling.

Buffer solution for incubation

Prepared buffer containing glutamine (8 mm), 0.01 ml), fructose-6-phosphate (100 mm, 0.01 ml), 10X FSB (0.01 ml), EDTU (50 mm), 0.01 ml), ± inhibitor (0.01 ml), enzyme (0,005 ml) and water (dilution up to 0.10 ml).

The method

The inhibitors were prepared in 100% DMSO and diluted in microtiter tablet. Then the inhibitors were added in the device for analysis, quality control used DMSO. The reaction mixture was obtained in sufficient quantity, which is used to construct a calibration curve and kept under ice cooling. The reaction of the INIC is Aravali added to the wells of the 96-hole tablet 90 ál of the mixture. The tablet tightly closed adhesive film for tablet and kept for 60 min in a water bath at 37°C. When the incubation is required to prevent the formation of air bubbles under the tablet. After incubation the wells were added to 10 μl of the standard, glucosamine-6-phosphate in DMSO to prepare the calibration curve. The range of standard concentrations ranged from 2.5 to 30 nmoles that corresponded to the number of defined glucosamine-6-phosphate and was on the linear range of the calibration curve. Cold incubation mixture containing the enzyme was added in the control hole and the hole to obtain the calibration curve, then the glucosamine-6-phosphate was azetilirovanie by adding 10 μl of 1.5% acetic anhydride in acetone and 50 ál of potassium tetraborate (200 mm). The tablet has closed a new film and was shaken for 2 min on micromachine. The tablet was kept in a water bath at a water temperature of 80°C for 25 min, and then for 5 min in ice. In the wells was added to 130 μl of Ehrlich reagent and the plate was kept for 20 min in a water bath at a water temperature of 80°C, then the tablet was read at 585 nm. The amount of enzyme was determined using optical absorption of the samples, the calibration curve and the software softmax.

Compounds of the present invention possess ing Bermuda activity against GFAT, i.e. the value of the IC50ranged from 1 nm to 100 μm, preferably from 10 nm to 20 μm.

The compound obtained in preparative quantities as described in example 13, characterized by the following values IC50:

GFAT-α IC50=8 μm, GFAT-β IC50=3,25 mm.

1. The compound of formula (I)

R1means-COOH or -(CH2)n-R14;
R2means
or
where X is CH or N;
R3, R4, R5and R6each is chosen from the group comprising-H, -(ness.)alkyl, -N(CH3)2, -O-(ness.)alkene, -(ness.)alkoxy, or
where R5and R6are substituents at adjacent carbon atoms in the ring;
R5and R6optional together with the carbon atoms to which they are attached, form a 5 - or 6-membered saturated carbocyclic ring;
R14means unsaturated 5-membered substituted or unsubstituted heterocyclic ring containing from 1 to 4 heteroatoms, whereby the heteroatoms are selected from N, O and S;
n is 0 or 1,
or their pharmaceutically acceptable salts or esters.

2. The compound according to claim 1, where R1means-COOH or -(CH2)n-R14and R14means unsubstituted heterocyclic ring.

3. The compound according to claim 1, where R2means
or

4. The compound according to claim 1, where X denotes-CH.

5. The compound according to claim 1, where X means.

6. The compound according to claim 1, where
R1means-COOH or -(CH2)nR14where R14means unsubstituted ring,
R2means
or
where X is CH or N;
R3, R4, R5and R6each is chosen from a group including:
-H, -(ness.)alkoxy,
-N(CH3)CH3,
-(ness.)alkyl and-O-(ness.)alkene or
where R5and R6are substituents at adjacent carbon atoms in the ring,
R5and R6optional together with the carbon atoms to which they are attached, form a 5 - or 6-membered saturated carbocyclic ring.

7. Compounds according to claim 1, where (ness.)alkyl means methyl, -(ness.)alkoxy means methoxy.

8. Compounds according to claim 1, where R3, R4, R5and R6each is chosen from a group including:
-H, -(ness.)alkyl containing from 1 to 4 carbon atoms, -N(CH3)2,
-(ness.)alkoxy containing from 1 to 4 carbon atoms and -- O-(ness.)alkene,
containing from 1 to 4 carbon atoms, or
where R5and R6are substituents at adjacent carbon atoms in the ring,
R5and R6optional together with the carbon atoms to which they are attached, education is the comfort 6-membered saturated carbocyclic ring.

9. The compound according to claim 1, selected from the group including:
(naphthalene-2-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]metano and
(naphthalene-1-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]metano
or their pharmaceutically acceptable salts.

10. The compound according to claim 1, selected from the group including:
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]quinoline-3-ylmethanol and
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)-isoquinoline-1-yl]quinoline-8-ylmethanol
or their pharmaceutically acceptable salts.

11. The compound according to claim 1, selected from the group including:
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-methoxynaphthalene-1-yl)methanon,
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-dimethylaminonaphthalene-1-yl)methanon,
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](4-methylnaphthalene-1-yl)methanon,
(2-allyloxymethyl-1-yl)[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl]metano,
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](7-methylnaphthalene-2-yl)-methanon,
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](1,2,3,4-tetrahydrofurane-9-yl)methanon and
[6,7-dimethoxy-4-(1H-tetrazol-5-yl)isoquinoline-1-yl](2-methoxynaphthalene-1-yl)methanon,
or their pharmaceutically acceptable salts.

12. The compound according to claim 1, selected from the group including:
1-(4-dimethylaminonaphthalene-1-carbonyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid,
1-(4-methoxynaphthalene-1-CT is of IMT)-6,7-dimethoxyisoquinoline-4-carboxylic acid and
6,7-dimethoxy-1-(1,2,3,4-tetrahydrofurane-9-carbonyl)isoquinoline-4-carboxylic acid,
or their pharmaceutically acceptable salts.

13. The compound according to claim 1, where the connection means
6,7-dimethoxy-1-(naphthalene-1-carbonyl)isoquinoline-4-carboxylic acid
or its pharmaceutically acceptable salt.

14. The compound according to any one of claims 1 to 13, intended for use as inhibitor activity glutenfreeda-6-phosphatidylserine (GFAT).

15. Compounds according to any one of claims 1 to 13, with the ability to inhibition activity glutenfreeda-6-phosphatidylserine (GFAT), to obtain drugs for the prevention and treatment of type II diabetes.

16. The pharmaceutical composition which is capable of inhibiting the activity glutenfreeda-6-phosphatidylserine (GFAT), containing a compound according to any one of claims 1 to 13 and a therapeutically inert carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydrochinoline derivatives represented by general formula , where t is equal 0, 1 or 2; each R independently represents H, alkyl, alkenyl or cycloalkyl; n is equal 0; R is selected from group, consisting of H, alkyl, halogenalkyl, cycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5 or group - Racycloalkyl, and where R2 is not substituted with amine or alkylamine; each R4 independently represents halogen; m is equal 0, 1 or 2; each R5 independently represents H, alkyl, alkenyl, alkinyl, cycloalkyl; p is equal 0 or 1; y represents -NR10-, -O-, -S-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, -RaHetRaN(R10)2, -HetRaAy or -HetRaHet; each Ra independently represents alkylene, possibly suibstituted with one or more than one alkyl or hydroxyl, cycloalkylene, possibly substituted with one or more than one alkyl or hydroxyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl or -Ra-cycloalkyl; each Ay independently represents possibly substituted phenyl or naphtyl group; each Het independently represents possibly substituted 3-12-member mono- or polycyclic heterocyclyl group, containing as heteroatoms N, or 5-7-member possibly substituted heteroaryl group, containing as heteroatom N; or its pharmaceutically acceptable salts or ethers. Also described are methods of obtaining compounds of formula (I-G).

EFFECT: obtained are novel compounds, which demonstrate protective against HIV-infection effect on target-cells by means of specific binding with chemokine receptor and which influence binding of natural ligand or chemokine with target-cell receptor, such as CXCR4 and/or CCR5.

54 cl, 2 tbl, 90 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed N-hydroxyformamide compound of formula (I) or its pharmaceutically acceptable salt where ring B represents phenyl, pyridinyl or pyrimidinyl; R2 represents the group chosen from C1-6alkyl, phenyl or naphthyl where the specified group is substituted with one or more fluoro group; n is equal to 1, 2 or 3; and R1 represents tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-, 2-pyrimidinyl-CH2CH2CH2-, SF-2-pyrimidinyl-CH2CH2-, C1-6alkyl or phenyl.

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed compounds of formula II , where each R2 independently stands for H, halogen, cyano, NO2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl; B represents O, S, SO or SO2; each W and X independently represents C or N; n is within 0 to 4 if both W and X represent C, 0 to 3, if either X or W represent N, and 0 to 2 if both X and W represent N; R3, R5, R6, R7 are independently chosen from H, alkyl, substituted alkyl, alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo; R4 represents optionally substituted 5-6-merous heteroaryl containing nitrogen atom provided (a) if R4 stands for pyridyl, R4 is not substituted with both hydroxy and methoxy groups; and (b) R4 stands for pyrimidinyl, it is n-substituted =O; A is chosen from following compounds of formula: , where D stands for S or O; m is within 0 to 6; R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently chosen from H, halogen, NR30R31, OR32, CO2R33, SO2R36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; R28 and R29 are independently chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or together they form carbocyclic or heterocyclic ring consisting of 3 to 8 atoms; and R30, R31, R32, R33 and R36 are independently chosen from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, heterocycloalkyl or substituted heterocycloalkyl as pharmaceutical composition for cancer treatment containing compound of formula II.

EFFECT: production of new compounds and based pharmaceutical composition applied for cancer treatment.

18 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula I , R1 is hydrogen; R2 is phenyl substituted by trifluoromethyl and optionally by other substitute selected out of a group including lower hydroxyl alkyl, lower alkylamino, lower hydroxyl alkylamino, dilower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trilfuoro-lower alkoxy, phenyl, pyridyl and halogenyl; R4 is methyl; where 'lower' prefix denotes radical with up to 7 carbon atoms. Also invention concerns pharmaceutical composition and method of treatment, as well as application of the claimed compounds in obtaining pharmaceutical composition.

EFFECT: improved proteinkinase inhibition properties.

9 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: description is given of a derivative of propane-1,3-dione with general formula (I) and its pharmaceutical salt, in which symbols denote the following: ring A: benzol, which can be substituted, pyridine, which can be substituted or a thiophene ring; ring B: benzene or thiophene ring; R1: H or -CO-inferior alkyl; R2: H, -O-R5, -N(R6)R7, -N3, -S(O)m-inferior alkyl, pyridyl or imidazole, which can be substituted; R3: H or inferior alkyl; X: a bond, inferior alkylene, which can be substituted, or cycloalkanediyl. Description is also given of propane-1,3-dione derivatives with formulae (Ia) and (Ib) and a pharmaceutical composition. The proposed compounds are useful as GnRH receptor antagonists, can be used in curing diseases, which depend on sex hormones, such as prostate cancer, breast cancer, endometriosis, uterine leiomyoma and non-malignant hypertrophy of the prostate gland.

EFFECT: obtaining compounds, useful for curing diseases, which depend on sex hormones, such as prostate cancer, breast cancer, endometriosis, uterine leiomyoma and non-malignant hypertrophy of the prostate gland.

10 cl, 26 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention concerns 2,4-bis(trifluorethoxy)pyridine compound represented by the formula (1), where X1 is fluorine or hydrogen atom or its salt as inhibitor of acyl-coenzyme A of cholesterol acyltransferase (ACAT), and medicine and pharmaceutical composition based on them, its application, method of obtainment, and new intermediary compounds.

EFFECT: obtaining compounds which can be applied in prevention or treatment of diseases mediated by ACAT activity, such as hyperglycemia and arterial sclerosis.

10 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining mirtazapine enantiomer, containing less than 10% of other enantiomer, which includes reaction of closing cycle of compound of formula , where X represents leaving group, said stage includes processing with acid, by means of which mirtazapine with enantiomer excess is obtained by closing cycle R- or S-enantiomer of formula (II) compound by processing with polyphosporic acid in absence of solvent or combination of polyphosphoric acid and N-methylpyrrolidinol or DMF.

EFFECT: stereochemical purity of target product.

10 ex

FIELD: chemistry.

SUBSTANCE: method of obtaining water-soluble diethylamine salts of aryl sulphonylureas by formula (1): , where R1-Cl, CF3, COOCH3, COOC2H5, CH2CH2CF3, OCH2CH2Cl, OCH2CH2OCH3, SO2CH2CH3, CON(CH3)2;R2-CH3, OCH3, OCHF2, OC2H5; R3-CH3; OCH3, OCHF2, Cl, NHCH3; R4-H, CH3; X-N, CH; Y-N, CH; M-(C2H5-NH-C2H5), includes interaction of equimolar quantities of proper aryl sulphonylurea and diethylamine in water medium with further separation of target product. As a rule interaction of initial reagents is carried out mainly at temperature 30-45°C, if necessary, in mother liquor medium, obtained after separating target product in previous cycle. Separation of product is usually realized by target product crystallisation or salting-out at temperature not more than 20°C.

EFFECT: possibility to use in agriculture as herbicidal means or in herbicidal compositions.

3 cl, 1 tbl, 7 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: there are disclosed compounds composed as to formula , where n and m stand for integer 1 to 3; z stands for integer 0 to 1; R is chosen from hydrogen, hydroxy or alkoxy; R2 stands for hydrogen; R3 and R4 are independently chosen from the group consisting of hydrogen, halogen; R5 is chosen from the group consisting of halogen, alkyl; R6 represents alkyl; E is chosen from the group specified in item 1 of formula of invention, A is chosen from N and C(R11), X is chosen from C, a stands for double bond and b stands for single bond; and Y is chosen from N(R1) provided when Y stands for N(R1), X stands for C, where R1 is chosen from C3-C6-cyclolkyl, phenyl; provided if A stands for C(R11), X stands for C, and Y stands for N(R1), then R11 and R1 can be bonded thus forming morpholinyl.

EFFECT: compounds possess antibacterial activity and are suitable as antibacterial means for treating bacterial infections in humans and animals.

13 cl, 10 tbl

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed compounds of formula II , where each R2 independently stands for H, halogen, cyano, NO2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl; B represents O, S, SO or SO2; each W and X independently represents C or N; n is within 0 to 4 if both W and X represent C, 0 to 3, if either X or W represent N, and 0 to 2 if both X and W represent N; R3, R5, R6, R7 are independently chosen from H, alkyl, substituted alkyl, alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo; R4 represents optionally substituted 5-6-merous heteroaryl containing nitrogen atom provided (a) if R4 stands for pyridyl, R4 is not substituted with both hydroxy and methoxy groups; and (b) R4 stands for pyrimidinyl, it is n-substituted =O; A is chosen from following compounds of formula: , where D stands for S or O; m is within 0 to 6; R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently chosen from H, halogen, NR30R31, OR32, CO2R33, SO2R36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; R28 and R29 are independently chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or together they form carbocyclic or heterocyclic ring consisting of 3 to 8 atoms; and R30, R31, R32, R33 and R36 are independently chosen from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, heterocycloalkyl or substituted heterocycloalkyl as pharmaceutical composition for cancer treatment containing compound of formula II.

EFFECT: production of new compounds and based pharmaceutical composition applied for cancer treatment.

18 cl, 147 ex

Quinolone analogues // 2349586

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (1): and to their pharmaceutical salts, where B, X, A or V are not present, if Z1, Z2, Z3 or Z4 respectively represent N, and independently H, halogen atom, azido, R2, CH2R2, SR2, OR2 or NR1R2, when Z1, Z2, Z3 or Z4 represent C. In each NR1R2, R1 and R2 together with N there can be formation of an optionally substituted piperidine, pyrrolidine, piperazine or morpholine ring. Z1 represents N and Z2, Z3 and Z4 represent C, or Z1 and Z3 represent N and Z2 and Z4 represent C. W together with N and Z form an optionally substituted thiazole, imidazole or pyrimidine ring, which is condensed with an optionally substituted ring, chosen from a group consisting of: or . U represents NR1R2, NR1-(CR12)n-NR3R4, where in NR3R4, R3 and R4 together with N there can be formation of an optionally substituted piperidine, pyrrolidine, piperazine or morpholine ring. R1 and R3 independently represent H or C1-6alkyl. Each R2 represents H or C1-10alkyl, each optionally substituted with a halogen atom, or C3-6cycloalkyl, aryl, heteroaryl or pyridine, pyrrolidine, piperazine or morpholine ring, where each ring is optionally substituted; or R2 is optionally substituted with piperidine, pyrrolidine, pyridine, piperazine, pyrazine, morpholine or benzimidazole. R2 represents H or C1-10alkyl. Each R5 represents a substitute in any position in ring W, and is H, OR2, amino, alkoxy, amido, halogen atom or cyano; or R5 represents C1-6alkyl, -CONHR1-, each optionally substituted with a halogen atom; or two adjacent R5 are linked with formation of a 5-6-member ring, an optionally substituted heterocyclic ring, chosen piperidine, pyrrolidine, piperazine or morpholine ring. n equals 1-6, and each optionally substituted part can be substituted with one or more halogens, OR2, NR1R2 , carbamate, C1-10alkyl, each optionally substituted with a halogen atom, C=O, cyano, nitro, COR2, NR2COR2, sulphonyl amides, NR2SOOR2; SR2, SOR2, COOR2, CONR22, OCOR2, OCOOR2 or OCONR22. The invention also relates to pharmaceutical compositions, to the method of suppressing proliferation of cells and/or weakening cell proliferative breakdown, to the method of reducing microbe titre and/or weakening microbe infection, to the method of inducing death of cells and/or inducing apoptosis, to compounds, chosen from a group, to pharmaceutical compositions, as well as to the method of producing compounds with formula (1).

EFFECT: obtaining new biologically active compounds, which can suppress proliferation of cells and/or induce apoptosis.

41 cl, 113 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: in compound of formula I , R1 is hydrogen; R2 is phenyl substituted by trifluoromethyl and optionally by other substitute selected out of a group including lower hydroxyl alkyl, lower alkylamino, lower hydroxyl alkylamino, dilower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trilfuoro-lower alkoxy, phenyl, pyridyl and halogenyl; R4 is methyl; where 'lower' prefix denotes radical with up to 7 carbon atoms. Also invention concerns pharmaceutical composition and method of treatment, as well as application of the claimed compounds in obtaining pharmaceutical composition.

EFFECT: improved proteinkinase inhibition properties.

9 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or its pharmaceutically acceptable salts: , where R1 is phenyl group optionally substituted by substitutes selected out of halogen atom, -O-C1-6-alkyl; or R1 is phenyl condensed with aromatic or non-aromatic 5-7-member ring where the ring can optionally include up to three heteroatoms selected independently out of N, O and S; R2 is hydrogen, -O-C1-6-alkyl, -C1-6-alkyl or halogen atom; R3 is C1-6-alkyl, -(CH2)P-NO2, -(CH2)p-NR4R5, -(CH2)P-CONHOH, -(CH2)p-CN, -(CH2)P-CO2H, -(CH2)p-CO2R4, -(CH2)P-CONR4R5, -(CH2)p-OR4, -(CH2)p-NHCOR4 or -(CH2)p-NHSO2R4; R4 and R5 are independently hydrogen or C1-6-alkyl; p is 0, 1, 2, 3 or 4; X is C1-10-alkylene group; one of A1 and A2 is nitrogen atom, while the other is NR7; and R7 is hydrogen atom or OH-group. Also invention concerns pharmaceutical composition, method of TGF-β and/or activine signal transit route inhibition, method of reduction of excessive exocellular matrix accumulation for mammals, method of tumour cell metastasis inhibition for mammals, method of treatment of cancer neoplasm caused by TGF-β superexpression by TGF-β signal transit route inhibition for mammals, method of disease treatment, and method of thrombosis inhibition for mammals.

EFFECT: new compounds with useful biological properties.

16 cl, 19 ex, 2 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula (I): and/or all stereoisomer forms of compound of the formula (I) and/or mix of these forms at any ratio, and/or physiologically acceptable salt of compound of the formula (I), where A is -(C0-C4)-alkylene; B is -(C0-C4)-alkylene or residue -B1-B2-B3-, where B1 is -(CH2)n-, where m is integer 0; B3 is -(CH2)m-, where m is integer 0; so that amount of n and m is 0; and B2 is -O-; cycle 1 or cycle 2 are equal or differ and denote independently 1) covalent link, 2)-(C6-C14)-aryl which is an aromatic hydrocarbon residue with 6-14 carbon atoms in a cycle, where the said aryl is unsubstituted or independently monosubstituted by G, or 3) 4-15-member heterocycle which is a cyclic system with 4-15 carbon atoms located in one, two or three interconnected cyclic systems, and containing one heteroatom selected out of nitrogen or oxygen, where the said heterocycle is unsubstituted or independently monosubstituted by G; G is 1) hydrogen atom, 2) halogen atom, 3)-O-R12, where R12 is a) hydrogen atom, b)-(C1-C6)-alkyl, where alkyl is unsubstituted or trisubstituted by halogen atom, c)-C(O)-O-R13, where R13 is c)1)-(C1-C6)-alkyl, where alkyl is unsubstituted, 4)-NO2, 5)-CN, 6)-N(R15)-R12, where R15 is 6)1)hydrogen atom, X stands for -OH or -NH-OH; n1 is integer 2; n2 is integer 3; together with that, that the sum of n1 and n2 is 5; R1, R2, R3, R4 and R5 are equal or different and independently from each other stand for 1) hydrogen atom, 2)-C(O)-R8, where R8 is 2)1) hydrogen atom, 2)2)-(C1-C6)-alkyl, where alkyl is unsubstituted. The invention also concerns method of obtaining compounds of the formula (I) and medical preparation for matrix metalloproteinase inhibition.

EFFECT: new derivatives of saturated bicyclic iminoacids with useful biological properties.

4 cl, 1 tbl, 29 ex

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