Intermediate products for producing oxazolidinone and quinolone derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

 

The present invention relates to intermediate products for new and efficient synthesis of the final products in which pharmacophore quinolone and oxazolidinone interconnected chemically stable linker. The final products of this type, described in WO 03/032962, are highly effective against bacteria in humans and animals. The present invention further relates to a new and efficient synthesis of these intermediates, and final products.

The present invention relates to compounds of formula (ZP)

,

where U denotes a nitrogen atom or a group CH,

V represents an oxygen atom, a sulfur atom or a group of formula CR6R7,

W represents a bond, an oxygen atom, a sulfur atom, a group of the formula NR8, optionally substituted cycloalkenyl, geteroseksualbnogo, alkylcyclohexanes, heteroalicyclic, Allenova, heteroarenes, Aracinovo or heteroalkyl group,

X denotes an oxygen atom or a sulfur atom,

Y is selected from the group including

,,,

,,,

Z represents optionally substituted alkyl is new, alkenylamine, alkynylamino, heteroalkyl, cycloalkenyl, geteroseksualbnogo, alkylcyclohexanes, heteroalicyclic, Allenova, heteroarenes, Aracinovo or heteroalkyl group, the residues R6and R7independently from each other represent a hydrogen atom, halogen atom, hydroxy-, amino-, nitro -, or thiol group, optionally substituted alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R8represents a hydrogen atom, optionally substituted alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest.

The term "alkyl" refers to saturated pravarasena or branched hydrocarbon group containing 1-20, preferably 1-12, particularly preferably 1-6, carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, n-bucilina, isobutylene, tert-bucilina, n-pencilina, n-exilda or 2,2-dimethylbutyl group.

Under the concepts of "alkenyl" and "quinil" refers to p is at least partially unsaturated remotemachine or branched hydrocarbon group, containing 2-20, preferably 2-12, particularly preferably 2-6, carbon atoms, for example Attila, allyl, acetylenyl, propargyl, isoprenaline or Gex-2-anilina group. Preferably alkeneamine groups contain one or two (especially preferably one) double bond, and alkyline groups contain one or two (especially preferably one triple bond.

Under the terms "alkyl", "alkenyl" and "quinil" refers, in addition, groups in which one or more hydrogen atoms are independently from each other substituted(s) atom(s), halogen (preferably F or Cl), such groups as 2,2,2-trichlorethylene or triptorelin group.

The term "heteroalkyl" refers to alkyl, Alchemilla or Alchemilla group (for example, heteroalkyl, respectively heteroalkyl), in which one or more carbon atoms (preferably 1, 2 or 3) independently from each other substituted(s) atom(s) of oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur, preferably oxygen, sulfur or nitrogen). The term "heteroalkyl" means, in addition, carboxylic acid or group - derived carboxylic acids, such as acyl, arylalkyl, alkoxycarbonyl, alloctype, aryloxyalkyl, carboxyaniline or alkoxycarbonylmethyl.

In the quality of examples heteroalkyl groups include groups of formula R a-O-Ya-, Ra-S-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-where Radenotes a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rbdenotes a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rcdenotes a hydrogen atom, a C1-C6alkyl, C2-C6Ala is nilou or 2-C6alkylamino group, Rddenotes a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, a Y3represents a direct link, C1-C6alkylenes,2-C6alkenylamine or2-C6alkynylamino group, each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may(may) be replaced by(s) atom(s) fluorine or chlorine. Specifically as heteroalkyl groups can be named, among others, methoxy, triptoreline, ethoxy, h-propyloxy, isopropoxy-, tert-butylacrylate, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino-, dimethylamino-, diethylamino, isopropylethylene, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, simple enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, etoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. As other examples heteroalkyl groups can be called nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alternately group. One example heterouncinata group is a group of formula-CH2CH(OH)-.

The term "cycloalkyl" implies is by saturated or partially unsaturated (for example, a cyclic group containing one, two or more double bonds, such as cycloalkenyl group) is a cyclic group with one or several cycles (preferably 1 or 2), containing 3-14 carbon atoms in the cycle, preferably 3 to 10 (especially 3, 4, 5, 6 or 7, carbon atoms in the cycle. The term "cycloalkyl" refers to the corresponding group in which one or more hydrogen atoms are independently from each other substituted(s) atom(s) fluorine, chlorine, bromine or iodine, or a group(s) IT, =O, SH, =S, NH2, =NH or NO2i.e., for example, cyclic ketones such as cyclohexanone, 2-cyclohexanone or Cyclopentanone. As other specific cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, Spiro[4,5]deganello, norbornylene, tsiklogeksilnogo, cyclopentenyl, cyclohexadienyl, decolonising, bicyclo[4.3.0]nonalloy, tetralinyl, Cyclopentasiloxane, forceclosing or cyclohex-2-enelow group.

The term "heteroseksualci" means cycloalkyl group from among the above, in which one or more (preferably 1, 2 or 3) carbon atoms in the cycle independently from each other substituted(s) atom(s) of oxygen, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or as the PTA). Preferably heterocytolysine group contains 1 or 2 cycle 3 to 10 (especially 3, 4, 5, 6 or 7) atoms in the cycle. The term "heteroseksualci" refers, in addition, groups in which one or more hydrogen atoms are independently from each other substituted(s) atom(s) fluorine, chlorine, bromine or iodine, or a group(s) IT, =O, SH, =S, NH2, =NH or NO2. As examples piperidinol, piperazinilnom, morpholinyl, urotropine, pyrrolidinyloxy, tetrahydrothiophene, tetrahydropyranyloxy, tetrahydrofuryl or 2-pyrazolidine group, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

The term "alkylsilanes" refers to the group that in accordance with the disclosures provided above values contain both cycloalkyl, and alkyl, alkeline or alkyline group, for example alkylcyclohexane, cycloalkylation, alkylcyclohexanes, alkenylacyl and alkylcyclohexane group. Preferably alkylcyclohexane group contains cycloalkyl group with one or two cyclic systems contain 3 to 10 (especially 3, 4, 5, 6 or 7) carbon atoms and one or two alkyl, alkeline or alkyline group with 1 or 2-6 carbon atoms.

The term "heteroalicyclic" refers alkylthiol the strong group from among the above-mentioned, in which one or more (preferably 1, 2 or 3) carbon atoms independently from each other substituted(s) atom(s) of oxygen, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or nitrogen). Preferably heteroalicyclic group contains 1 or 2 cyclic system of 3 to 10 (especially 3, 4, 5, 6 or 7) atoms in the cycle and one or two alkyl, alkeline, alkyline or heteroalkyl group with 1 or 2-6 carbon atoms. As examples of such groups may be called alkylchlorosilanes, alkylchlorosilanes, alkenylsilanes, alginolyticus, heteroalicyclic, heterooligomerization and heterooligomerization, this cyclic group is saturated or single, double or triple unsaturated.

The term "aryl" (acronym Ar) refers to an aromatic group that contains one or several cycles with 6-14 carbon atoms, preferably 6-10 (especially 6) carbon atoms in the cycle. The term "aryl" (Ar) refers, in addition, groups in which one or more hydrogen atoms are independently from each other substituted(s) atom(s) fluorine, chlorine, bromine or iodine, or a group(s) HE, SH, NH2or NO2. As examples are phenyl, naftalina, biphenylene, 2-florfenicol, Academy of Sciences of Lanovoy, 3-nitroaniline or 4-hydroxyphenyl group.

The term "heteroaryl" refers to an aromatic group that contains one or several cycles with 5-14, preferably 5-10 (especially 5 or 6), the atoms in the cycle and one or more (preferably 1, 2, 3, or 4 atoms of oxygen, nitrogen, phosphorus or sulfur cycle (preferably O, S or N). The term "heteroaryl" refers, in addition, groups in which one or more hydrogen atoms are independently from each other substituted(s) atom(s) fluorine, chlorine, bromine or iodine, or a group(s) HE, SH, NH2or NO2. As examples can be called 4-pyridyloxy, 2-imidazolidinyl, 3-phenylpyrrolidine, thiazolidine, oxazolidine, triazolyl, tetrazolyl, isoxazolyl, indazolinone, indolenine, benzimidazolyl, pyridazinyl, hyalinella, parinello, carbazolyl, criminology, pyramidalnou, 2,3'-biphenylol, 3-pyrazolidine and athinodorou group.

The term "aralkyl" refers to the group that in accordance with the disclosures provided above values contain both aryl and alkyl, alkeline, alkyline and/or cycloalkyl groups, such as arylalkyl, arylalkyl, arylalkylamine, arylcyclohexylamine, arylcyclohexylamine, alkylalcohol and alkylresorcinols g is uppy. Specifically as Arakelov can be called, for example, toluene, xylene, mesitylene, styrene, benzylchloride, o-vtortola, 1H-inden, tetralin, dihydronaphthalene, indanan, vinylcyclopentane, cumene, cyclohexylphenol, fluoren and indan. Preferably kalkilya group contains one or two aromatic cyclic system (1 or 2 cycles) with 6-10 carbon atoms and one or two alkyl, alkeline and/or alkyline group with 1 or 2-6 carbon atoms and/or cycloalkyl group with 5 or 6 carbon atoms in the loop.

The term "heteroalkyl" means kalkilya group from among the above mentioned, in which one or more (preferably 1, 2, 3, or 4) carbon atoms independently from each other substituted(s) atom(s) of oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur, preferably oxygen, sulfur or nitrogen), that refers to the group that in accordance with the disclosures provided above values contain aryl, respectively, heteroaryl, and alkyl, alkeline, alkyline and/or heteroalkyl, and/or cycloalkyl, and/or heterocytolysine group. Preferably heteroalkyl group contains one or two aromatic systems (1 or 2 cycles) with 5 or 6-10 carbon atoms in the cycle and one or two alkyl, alkeline and/or alkyline group with 1 or 2-6 carbon atoms, and/or the well cycloalkyl group with 5 or 6 carbon atoms in the cycle, 1, 2, 3 or 4 carbon atoms independently from each other substituted(s) atom(s) of oxygen, sulfur or nitrogen.

As examples arylheteroacetic, analgeticalkie, allgemeingultige, arrangementvalentine, arrangedelementcollection, arylaminomethylidene, arrangementvalentine, heteroallyl, heteroarylboronic, heteroallyl, heterooligomerization, heteroalicyclic, heteroarylboronic, heterooligomerization, heterooligomerization, heteroresistance, heterooligomerization, heterooligomerization, heterooligomerization and heterooligomerization groups and cyclic groups are saturated either single, double or triple unsaturated. Specifically, as examples tetrahydroisoquinolinium, benzoyloxy, 2 - or 3-ethylindole, 4-methylpyridine-, 2-, 3 - or 4-metoksifenilny, 4-ethoxyphenyl, 2-, 3-or 4-carboxypenicillins group.

Under the terms "alkyl", "alkenyl", "quinil", "heteroalkyl", "cycloalkyl", "heteroseksualci", "alkylsilanes", "heteroalicyclic", "aryl", "heteroaryl", "aralkyl and heteroalkyl" podrazumeva the tsya groups, in which one or more hydrogen atoms are independently from each other substituted(s) atom(s) fluorine, chlorine, bromine or iodine, or a group(s) IT, =O, SH, =S, NH2, =NH or NO2.

The term "optionally substituted" refers to groups in which one or more hydrogen atoms are independently from each other substituted(s) atom(s) fluorine, chlorine, bromine or iodine, or a group(s) IT, =O, SH, =S, NH2, =NH or NO2. This concept refers to groups that are substituted by unsubstituted C1-C6alkyl, C2-C6alkenylamine,2-C6alkenylamine, C1-C6heteroalkyl,3-C10cycloalkenyl,2-C9heteroseksualnymi,

With6-C10aryl, C1-C9heteroaryl, C7-C12Uralkalij or2-C11heteroalkyl groups.

Described in this application connection, thanks to a scheme of his replacement can contain one or more chiral centers. In the scope of the present invention are included in accordance with this, as all pure enantiomers and all pure diastereoisomers and mixtures thereof in any ratio of these components. In the scope of the present invention also includes all CIS - and TRANS-isomers of compounds of General formula (I), as well as mixtures thereof. In the scope of the present izobreteniya then all tautomeric forms of the described compounds

Preferably U denotes the group SN. Also preferably, R6and R7represent hydrogen atoms. Preferably then V denotes the oxygen atom. Preferably also, Y represents a structural fragment of the following formula:

.

Preferably further, W represents an oxygen atom, a sulfur atom, a group of the formula NR8, optionally substituted geteroseksualbnogo, heteroalicyclic, heteroarenes or heteroalkyl group, while associated with the group W H atom are preferably linked to an oxygen atom, a sulfur atom or a nitrogen atom.

W, furthermore preferably denotes optionally substituted geteroseksualbnogo group containing a cycle with 4, 5, 6 or 7 atoms in the cycle, primarily W replaced IT-group.

Preferably further, Z represents optionally substituted C1-C4alkylenes group. Particularly preferably, Z represents the group CH2or group of CH2CH2.

The preferred value of W in addition to these is piperidinyl or pyrrolidinyl group, and these groups optionally can be substituted by the groups HE, ORO3H2, OSO3H or heteroalkyl group which carries at least one HE, NH2-SO3H-, RHO3H2- or COOH-is the Rupp (above all HE is-a group).

Particularly preferably, Z and W together form a group of the formula:

.

where n denotes 1 or 2, m represents 1 or 2 and denotes 1 or 2, this group optionally may be substituted by a group HE, ORO3H2, OSO3H or heteroalkyl group which carries at least one HE, NH2-SO3H-, RHO3H2- or COOH-group.

Particularly preferably W has the following structural formula:

or

The compounds of formula (ZP) can be used for the synthesis of compounds of formula (I)

where Z represents optionally substituted C1-C4alkylenes group, And denotes a nitrogen atom or a group CH and W represents optionally substituted geteroseksualbnogo group containing at least one nitrogen atom, and quinoline residue associated with the indicated nitrogen atom.

The compounds of formula (I) can be obtained as follows:

when this compound of formula (XI) represents a connection proposed in the present invention, a compound of formula (XII) is preferably used in the form of complex compounds of boron (for example, in the form of bonecutter complex).

If this is eacli preferred conditions, where it is envisaged to use N-organic, trimethylsilylmethyl, the base Hunga or2CO3and the temperature is 80°C.

Proposed in the invention compounds can be synthesized, for example, in the following way:

Stage 1:

Stage 2:

Stage 3:

Stage 4:

Stage 5:

Step 6:

Step 7:

Step 8:

According to another variant, the compounds of formula (ZP), respectively, of formula (XI) can be synthesized in the following way:

Stage 1:

Stage 2:

Stage 3:

Stage 4:

Stage 5:

Step 6:

Step 7:

If in this embodiment the synthesis as a protective group PG to choose the protective group is Cbz, the need for stage 7 disappears, as in this case, the compound of formula (XI) is formed directly on the stage 6.

When PG represents about is Chou protective group for amines, first of all benzyloxycarbonyl (Cbz) group,

R1represents an optionally substituted benzyl (e.g., n-methoxybenzyloxy) or allyl group,

R2represents a C1-C4alkyl, allyl or benzyl group,

R3represents a C1-C4alkyl group,

R4represents mesilate, tosyloxy, triplelux any Textilexpo or chlorine atom, bromine or iodine and

R5represents mesilate, tosyloxy, triplelux any Textilexpo or chlorine atom, bromine or iodine.

The protective group for the specialist in this area known and described, for example, P.J.Kocienski in "Protecting Groups", published by Georg Thieme Verlag, Stuttgart, 1994, and T.W.Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis", published by John Wiley & Sons, New York, 1999. As commonly used aminosidine groups include, for example, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz, Z), benzyl (Bn), benzoyloxy (Bz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trichlorocarbanilide (Troc), acetyl or trifluoracetyl group.

Preferably R1represents a benzyl group.

Preferably R2represents a benzyl group.

Preferably R3is a n-through the group.

Preferably R 4is methyloxirane.

Preferably R5is methyloxirane.

In the implementation of the synthesis according to the first embodiment, it is preferable to work under the following conditions using the specified components.

Stage 1: CH2Cl2, potassium hydroxide, at room temperature.

Stage 2: hydrogen/Pt/C, then Cbz-Cl, NaHCO3, acetone/water, both at room temperature.

Stage 3: (R)-glycidylether (V), n-utility, -60°C, respectively, GAVE (diisopropylamide lithium), -15°C.

Stage 4: methylsulfonylamino, triethylamine, CH2Cl2.

Stage 5: NaN3in DMF, catalytic amounts Bu4NI, 90°C.

Stage 6: the hydrogen/Pd(OH)2, THF, Meon, then Asón, AU2Oh, both at room temperature.

Stage 7: dimethylformamide (DMF), sodium hydride, 70°C.

Stage 8: H2/Pd(OH)2, THF, methanol, room temperature.

In the implementation of the synthesis according to the second variant is preferable to work under the following conditions using the specified components.

Stage 1: reaction of Mitsunobu or base (such as NaH), DMF, toilet PG-W-Z-OH.

Stage 2: hydrogen/Pt/C, then Cbz-Cl, NaHCO3, acetone/water, both at room temperature or Sn, HCl.

Stage 3: (R)-glizid lbuterol (V), n-utility, -60°C, respectively, GAVE (diisopropylamide lithium), -15°C.

Stage 4: methylsulfonylamino, triethylamine, CH2Cl2.

Stage 5: NaN3in DMF, catalytic amounts Bu4NI, 90°C.

Stage 6: the hydrogen/Pd(OH)2, THF, Meon, then Asón, AU2Oh, both at room temperature.

In the examples given below in more detail, describes the synthesis of compounds of formula (ZP), as well as their use for the synthesis of compounds of formula (I).

Examples

Example 1

7-(4-{4-[(5S)-5-(Acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Step 1: benzyl ether (4-benzyloxy-3-forfinal)carbamino acid

A mixture of 34,9 g of 1-benzyloxy-2-fluoro-4-nitrobenzene (WO 03064413) (mol. weight 247,28, 141 mmol) and 340 mg of platinum (5%on charcoal) in 350 ml of ethyl acetate was stirred in hydrogen atmosphere at room temperature (RT) and normal pressure. The course of the reaction was monitored using GHUR (liquid chromatography high resolution), and after 20 h the reaction was completed. The catalyst was filtered and the filtrate under reduced pressure, concentrated to dryness by centrifugation. The oily residue was dissolved in 500 ml of acetone and mixed with 250 ml of saturated solution of hydroca is bonate sodium and 17.5 g of sodium bicarbonate (mol. weight 84,01, 208 mmol). Then the mixture was cooled to 5°C. and to it was added dropwise 26,08 g benzylchloride (mol. weight 170,59, 152 mmole). After this mixture for 2 h and was stirred at RT and the course of the reaction was tracked through TX (thin layer chromatography) (hexane/ethyl acetate in the ratio 3:1). The acetone was removed under reduced pressure, the residue was mixed with 500 ml of water and the solid was filtered.

The resulting crystals were washed with 500 ml of water and dried. Output 48,05 g, 95,8%. MS: AZN 352.5 (M+N)+, 350,8 (M-N)-. Method: ESI+, ESI-.

Stage 2: (5R)-3-(4-benzyloxy-3-forfinal)-5-hydroxymethylimidazole-2-he

The mixed solution of 17.5 g of benzyl ether (4-benzyloxy-3-forfinal)carbamino acid (mol. weight 351,38, 50 mmol) in 30 ml of dry tetrahydrofuran was cooled with a bath of dry ice and acetone to -78°C. Then was added dropwise to 22.8 ml of 2,3-molar solution of n-utility in n-hexane (52,5 mmole) and the mixture at -78°C was stirred for 15 minutes Then added a 7.92 g of R(-)-glycidylether (mol. weight 144,17, 60 mmol) and the reaction mixture was heated up to CT. The reaction was monitored using GHUR, then adding a saturated solution of ammonium chloride was stopped and the mixture was diluted with 100 ml of ethyl acetate. The organic phase was washed with 200 ml of water and 200 ml of saturated common salt solution. The organic phase was dried over Sul is blockhead magnesium, was filtered and the filtrate was concentrated under reduced pressure. The residue was led from 200 ml of ethyl acetate/hexane (1:1 ratio). The obtained solid was recrystallized from 150 ml of ethyl acetate/dichloromethane (in a ratio of 9:1). Colorless crystals were collected and dried. Yield 10.4 g, 65.5 per cent. MS: 318,1 (M+N)+. Method: ESI+.

Stage 3: (5S)-5-azidomethyl-3-(4-benzyloxy-3-forfinal)oxazolidin-2-he

A mixture of 10 g of (5R)-3-(4-benzyloxy-3-forfinal)-5-hydroxymethylimidazole-2-she (mol. weight 317,32, 31,51 mmole) and 4,78 g of triethylamine (mol. weight 101,19, 47,26 mmole) in 300 ml of dichloromethane were mixed at 10°C under stirring with 4,32 g methanesulfonanilide (mol. weight 114,55, 37,82 mmole). The reaction mixture was stirred at RT for 1 h and the course of the reaction was tracked through TX (ethyl acetate/hexane in the ratio 1:1). The reaction was stopped by adding 100 ml of water and the organic phase is washed with 100 ml saturated sodium chloride solution. Then the organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 100 ml of dimethylformamide and to the solution was added 5,12 g of sodium azide (mol. weight 65,01, 78,7 mmole) and a catalytic amount of tetrabutylammonium iodide. The suspension was stirred overnight at 90°C. during the reaction was monitored using GHUR. Demetillo is mamid under reduced pressure was removed by centrifugation, the residue was dissolved in 200 ml of dichloromethane and the organic phase is then washed with 100 ml water and 100 ml saturated sodium chloride solution. The dichloromethane solution was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was led from 150 ml of ethyl acetate/hexane (1:1 ratio). Yield 10.4 g, 97%. MS: 343,1 (M+N)+. Method: ESI+.

Stage 4: N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide

A suspension of 10.4 g of (5S)-5-azidomethyl-3-(4-benzyloxy-3-forfinal)oxazolidin-2-she (mol. weight 342,33, 30,38 mmole) and 1.5 g of palladium (10%on charcoal) in 400 ml of a mixture of methanol and ethyl acetate in the ratio of 1:1 was stirred at room temperature in a hydrogen atmosphere for two days. Then the catalyst was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 100 ml of acetic acid and mixed with and 3.72 g of acetic anhydride (mol. weight 102,09, 36,45 mmole). The solvent under reduced pressure, evaporated and the residue was recrystallized from a mixture of ethyl acetate and hexane (1:1 ratio). Output 6,76 g, 83%. MS: 269,4 (M+N)+, 267,3 (M-N)-. Method: ESI+, ESI-.

Stage 5: benzyl ether of 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid

Suspension 22,72 g b is solovovo ether 1-oxa-6-azaspiro[2,5]Octan-6-carboxylic acid (WO 9803507) (mol. weight 247,29, 92 mmole), 21,45 g of N-[(5S)-{3-(3-fluoro-4-hydroxyphenyl)}-2-oxoacridine-5-ylmethyl]ndimethylacetamide (mol. weight 268,246, 80 mmol) and 16,58 g of potassium carbonate (mol. weight 138,20, 120 mmol) in 150 ml of dimethylformamide was stirred at 100°C for 7 hours during the reaction was tracked through TX (dichloromethane/methanol in the ratio 9:1). The dimethylformamide under reduced pressure, evaporated and the residue was dissolved in 600 ml of a mixture of dichloromethane and methanol in the ratio 9:1.

The organic phase is washed with 400 ml of water and 400 ml of saturated common salt solution, dried with magnesium sulfate, filtered and the filtrate was diluted with 250 ml ethyl acetate. The mixture is then concentrated under reduced pressure to a final volume of 400 ml of the mixture during the night was stirred at RT. The resulting crystals were filtered off and then washed with 150 ml of ethyl acetate and 100 ml of pentane. Output 31,65 g, 76.7 per cent. MS: 516,8 (M+N)+. Method: ESI+.

Stage 6: N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}]ndimethylacetamide

A suspension of 31 g of benzyl ester 4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-carboxylic acid (mol. weight 515,54, 60,13 mmole) and 2.5 g of palladium (10%on charcoal) in 310 ml of methanol and 150 ml of ethyl acetate was stirred for 4 h in an atmosphere of hydrogen. During the reaction dleivery using TX (using ethyl acetate). Then the suspension was diluted with 300 ml of methanol was heated to 40°C. and the catalyst was filtered through glass fiber filter paper. The filtrate was concentrated to a volume of 150 ml, diluted with 300 ml of ethyl acetate and again concentrated to a volume of 200 ml was Then added 200 ml of diethyl ether and the suspension was cooled with stirring to 0°C. the Solid is collected and dried. The output of 21.6 g, 94,3%. MS: 382,6 (M+N)+. Method: ESI+.

Step 7:

7-(4-{4-[(5S)-5-(acetamidomethyl)-2-oxoacridine-3-yl]-2-forfinancial}-4-hydroxypiperidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A solution of 60 g of N-[{(5S)-3-[3-fluoro-4-(4-hydroxypiperidine-4-ylethoxy)phenyl]-2-oxoacridine-5-ylmethyl}]ndimethylacetamide (C18H24FN3O5, mol. weight 381,40, of) 0.157 mol) and 26,87 ml ethyldiethanolamine (mol. weight 129,25, of) 0.157 mol) in 300 ml of N-methylpyrrolidine-2-it was mixed with 67,81 g of a complex of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and boron diacetate (mol. weight 410,57, 0,165 mol) and the mixture for 5 h and stirred at 80°C. N-Methylpyrrolidine-2-he was separated under reduced pressure by centrifugation and the residue was dissolved in 300 ml of methanol. Through this solution for 30 min at 10°C was passed a stream of dry hydrogen chloride. Then, the solution was stirred at RT, the precipitate precipitated solid yellow color. The transformation of the boron complex in the free acid was tracked through GHUR. The mixture was diluted with 300 ml of ethyl acetate. The solid was filtered and washed with 100 ml of ethyl acetate/methanol (8:2 ratio) and 100 ml of ethyl acetate. Solid yellow dried, resulting in to 86.4 g of this yellow substance. Then this solid substance was dissolved in 200 ml of dimethylsulfoxide at 40°C and the yellow solution was poured with stirring into 1000 ml of water. The yellow solid was collected, washed with water and dried. The yield was 73 g of 74.5%. MS: 627,8 (M+H)+, 625,8 (M+N)-. Method: ESI+, ESI-.

Example 2

Reaction conditions and components used

Stage 1: CH2Cl2, KOH (50%), 3 h, CT, 97%.

Stage 2: H2Pt/C, 20 h, CT, then Cbz-Cl, acetone/water, NaHCO3, 12 h, CT, 98%.

Stage 3: n-BuLi, -60°C, 24 h, 80%.

Stage 4: MsCl, tea, CH2Cl2, 100%.

Stage 5: NaN3in DMF, 90°C, cat. Bu4NI, 5 h, 90%.

Stage 6: H2Pd(OH)2, THF, Meon, 24 h, and then the Asón, AU2Oh, CT, 2 h, 70%.

Stage 7: DMF, NaH, 70°C, 12 h, 75%.

Step 8: N2Pd(OH)2, Meon, THF, 24 h, CT, 100%.

Stage 9: N-organic, 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naftalin-3-carboxylic acid (commercially available product), TSH (trimethylsilane), the base Hunga or2CO3, 80°C, 5 h, 80%.

In all these stages of chromatographic separation is not required.

Below are the compounds of formula (ZP), respectively, of formula (X)obtained by methods similar to the above, using appropriate starting materials. When using compounds containing free Oh-group was also compounds in which the Oh-group were protected by a protective group, such as acetate, benzoate, mom-ether (methoxymethyl ether) or isopropylidene).

1. The compounds of formula (ZP)

in which U represents a group CH;
V represents an oxygen atom;
W denotes substituted by hydroxyl geteroseksualbnogo group containing from 5 to 7 atoms in the cycle, including the N atom as the heteroatom;
X denotes an oxygen atom;
Y represents a
,
Z represents C1-C6-alkylenes group.

2. Compounds according to claim 1, where Z denotes a1-C4-alkylenes group.

3. Compounds according to claim 1, where Z represents the group CH2or group of CH2CH3 .

4. Compounds according to claim 1, where Z and W together form a group of the formula
,
where n denotes 1 or 2, m represents 1 or 2 and denotes 1 or 2, with m and at the same time does not mean 1.

5. Compounds according to claim 1, where W has the following structural formula
or.

6. The use of compounds according to claim 1 for obtaining the compounds of formula (I)
,
where And denotes the nitrogen atom or a group CH, and the remaining residues have the above in claim 1 values.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound of the formula (I) , where R1 is a group of the formula and, in which R2, R3, R4, R5, R6, R7 and R8, each one independently represents a hydrogen atom or C1-6alkyl or its salt, to the method of its producing, to the method of antagonist effect on angiotensin II in the mammal, to the application of compounds of formula (I) as well as to methods of diseases prevention or treatment.

EFFECT: there are produced and provided new compounds that can be applied for prevention or treatment of disturbed circulation.

16 cl, 2 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of general formula (I) in the state of base salt or acid-addition salt, to method of their preparation and to the pharmaceutical composition thereof In the said formula R1 is (C1-C6)alkyl; (C3-C7)cycloalkyl unsubstituted or substituted once or more than once; (C3-C7)cycloalkylmethyl unsubstituted or substituted once or more than once; phenyl unsubstituted or substituted ; benzyl unsubstituted or substituted once or twice ; thienyl unsubstituted or substituted ; R2 is atom hydrogen or (C1-C3)alkyl; R3 is (C1-C5)alkyl; R4, R5, R6, R7, each R8 and R9 independently represents the atom of hydrogen, atom of halogen, (C1-C7)alkyl, (C1-C5)alkoxy or trifluoromethyl radical; n is 0, 1 or 2; Alk is (C1-C4)alkyl.

EFFECT: new compounds possess useful biological activity.

5 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the aminopyridin compound of general formula (I) or its salt wherein X1, X2, X3, Z, Y1, Y2 are carbon or nitrogen atom, R, R1, R5, R6 are hydrogen atom, alkyl group, further see formula of the invention, and R7 is hydrogen or halogen atom, nitro or cyano group, -CpH2(p-1)(Ra1)(Ra2)-O-Ra3, -C(=O)-Rd1, 5-or 6-membered saturated heterocycle group, aromatic heterocycle group, -N(Rh1)(Rh2), further see formula of the invention. The invention refers also to the pharmaceutic composition thereof intended for treatment or prevention of allergic diseases, autoimmune diseases caused by malignant tumour, to the Syk inhibitor containing the compound of formula I and to the therapeutic and/or preventive agent.

EFFECT: compounds which not only possess high Syk inhibition activity but are selective Syk inhibitors are obtained and described.

24 cl, 24 ex, 2 tbl

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 2-[2-(3-oxomorpholin-4-yl)ethylthio]benzimidazoles of general formula: , where R1, R2, R3, R4, R5 are identical or different: H, lower alkyls or alkoxy groups.

EFFECT: obtaining new compounds with anxiolytic properties, which allows for their potential use in medicine for treating neuropsychic disorders.

2 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula I, in which R1 represents hydrogen or a group, which forms a biologically labile ester, R2 represents hydrogen, C1-C4-alkyl or C1-C4-hydroxyalkyl, and R3 represents C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkyl; C1-C4-hydroxyalkyl, which is optionally substituted with a second hydroxy group and all hydroxy groups of which are optionally esterified with C2-C4-alkanoyl or amino-acid residue; (C0-C4-alkyl)2amino-C1-C6-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; phenyl-C1-C4-alkyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen; naphthyl-C1-C4-alkyl; C3-C6-oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen, or 2-oxoazepanyl, or R2 and R3 together represent C4-C7-alkylene, methylene groups of which are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and/or sulphur and/or optionally substituted once with a hydroxy group, which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; C1-C4-alkyl; C1-C4-hydroxyalkyl, the hydroxy group of which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; phenyl or benzyl, and R4 represents hydrogen or a group, which forms a biologically labile ester, where R1 and R4 groups are independently chosen from C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkoxy-C1-C4-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; N,N-di-(C0-C4-alkyl)amino-C1-C6-alkyl; phenyl or phenyl-C1-C4-alkyl, optionally substituted 1 or 2 times in the phenyl ring with halogen, C1-C4-alkyl or C1-C4-alkoxy group or C1-C4-alkylene chain, bonded with two neighbouring carbon atoms; dioxolanylmethyl, optionally substituted in the dioxolane ring with C1-C4-alkyl; C1-C6-alkanoyloxy-C1-C4-alkyl, optionally substituted in the oxy-C1-C4-alkyl group with C1-C4-alkyl; 1-[[(C1-C4-alkyl)carbonyl]oxy]C1-C4-alkyl esters; 1-[[(C4-C7 cycloalkyloxy)carbonyl]oxy]C1-C4-alkyl esters, 2-oxo-1,3-dioxolan-4-yl-C1-C4-alkyl esters, which optionally contain a double bond in the dioxolane ring; 2-oxo-1,3-dioxolan-4-ylmethyl; and to physiologically compatible salts of acids with formula I and/or to physiologically compatible acid-additive salts of formula I compounds. The invention also relates to a pharmaceutical composition, to use of formula I compounds in paragraph 1, to a method of obtaining formula I compounds, as well as to compounds with general formula II.

EFFECT: obtaining new biologically active compounds, with inhibitory activity towards neutral endopeptidase, endothelin converting enzyme and soluble human endopeptidase.

20 cl, 80 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: or its pharmacologically acceptable salts, where n equals 1, 2 or 3; and values of R1, R2, R3, R4, R3', R10, R11 are given in i.1 of formula.

EFFECT: compounds I have ability to inhibit release and/or synthesis of β-amyloid peptide, which allows to apply them in pharmaceutical composition.

25 cl, 3 dwg, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new coumarin derivatives and their carboxamides, with general formula (I) , where R3 is chosen from a group consisting of H, carboxyl, alkyloxycarbonyl, 5'-(phenyloxadiazol-2')-yl, 5'-(pyridyl-4"-oxadiazol-2')-yl, , CONHR9, where R9 is chosen from a group consisting of fatty acids C2-C8, benzoxamido, isonicotinamido, unsubstituted, or mono-, or polysubstituted phenyl, in which the substitute can be hydroxy, C1-C8-alkoxy, CF3, carboxyl, alkyloxycarbonyl, OCH2CO2H, NO2, halogen, SO3H, SO2NHR11, where R11 is chosen from a group consisting of hydrogen, amidino, 2"-thizolyl, 3"-(511-methylisooxazolyl), 2"-pyrimidinyl, 2"-(4",6"-dimethylpyrimidinyl), 4"-(5",6"-dimethoxypyrimidinyl); R4 is chosen from a group consisting of hydrogen, CONHR10, where R10 is chosen from a group consisting of C2-C8 fatty acids, unsubstituted phenyl; R5 is chosen from a group consisting of H, C1-C4 alkyl; R6 is chosen from a group consisting of H, C1-C12-alkyl, halogen, NO2, CONHR13, where R13 is substituted phenyl; R7 is chosen from a group consisting of H, hydroxyl, C1-C4alkyl or alkoxyl, carboxyalkyleneoxyl, OCH2CONHR14, where R14 is chosen from a group consisting of unsubstituted, mono-, or polysubstituted phenyl, in which the substitute can be hydroxyl, OCH3, CF3, CO2H, CO2C2H5, NO2; R8 is chosen from a group consisting of H, C1-C4-alkyl or alkoxyl, NO2; under the condition that, when R3, R5 and R6 are H, and R7 is OH, R4 and R7 are not groups, chosen from H, C1-C6-alkyl or C1-C6-alkoxy. The invention also relates to pharmaceutical compositions based on formula I compounds and their use as medicinal preparations for protecting kidneys, for curing hypertonia, cardio-cerebrovascular diseases, non-achrestic diabetes, tumours, precancerous diseases and oedema.

EFFECT: enhanced effectiveness of the composition and treatment method.

17 cl, 6 tbl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

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