Antibacterial heterobicyclic substituted phenyloxazolidinones

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

 

The present invention relates to compounds of phenyloxazolidine possessing antibacterial activity against gram-positive and gram-negative bacteria containing pharmaceutical compositions, and to methods for treating bacterial infections using these compounds.

In the last twenty years oxazolidinone were identified as a new class of antibacterial agents that have activity against various gram-positive organisms resistant to multiple drugs. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA)resistant intermediate glycopeptides Staphylococcus aureus (GISA), vancomycin-resistant enterocci (VRE) and are resistant to penicillin and cephalosporin Streptococcus pneumoniae. As a class, oxazolidinone demonstrate a unique mechanism of action. Studies have shown that these compounds selectively bind to the 50S ribosomal subunit and inhibit bacterial translation in the initial phase of protein synthesis. The members of the class of oxazolidinones are linezolid (see WO 95/07271) and eperezolid.

U.S. patent No. 5792765 issued Riedl with al., discloses a number of substituted oxazolidinones (cyanoguanidine, cyanoaniline and amidine), which can be used as antibacterial drugs the military preparations.

In U.S. patent No. 5910504 issued Hutchinson, revealed a number of phenyloxazolidine with substituted heteroaromatic rings, including indolizidine compounds that can be used as antibacterial agents.

In WO 98/54161 (Hester with al.) disclosed amides, thioamides, urea and thiourea, which are antibacterial agents.

In WO 95/07271 (Barbachyn with al.) disclosed oxazinone and triazinone derivative oxazolidinone, such as linezolid and its analogues, which can be used as antimicrobial agents, and are effective against a number of pathogens of humans and animals, including gram-positive aerobic bacteria such as resistant to many drugs staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroldes spp. and Clostndia spp. species, and acid-fast organisms such as Mycobactenum tuberculosis, Mycobacterium avium and Mycobacterium spp.

In WO 93/09103 (Barbachyn with al.) disclosed substituted aryl - and heterogenisation that can be used as antibacterial agents.

The present invention relates to compounds of phenyloxazolidine formula I:

where:

R is chosen from the group consisting of HE, N3, OR', O-aryl, O-heteroaryl, OSO2R", -NR"'R"", or

where:

(i) R' Ave dstanley unbranched or branched acyl, containing up to 6 carbon atoms, or benzyl;

(ii) R is unbranched or branched alkyl containing up to 5 carbon atoms, phenyl or tolyl; and

(iii) R"' and R"" are independently selected from the group consisting of N, cycloalkyl containing from 3 to 6 carbon atoms, phenyl or tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, unbranched or branched alkyl containing up to 6 carbon atoms, which is optionally substituted by cyano or alkoxycarbonyl containing up to 4 carbon atoms, -CO2-R1, -CO-R1, -CO-SR1, -CS-R1, P(O)(OR2)(OR3and-SO2-R4where

R1selected from the group consisting of N, cycloalkyl containing from 3 to 6 carbon atoms, trifloromethyl or phenyl of the benzyl or acyl containing up to 5 carbon atoms, nerazvedennogo or branched alkyl containing up to 6 carbon atoms, with the specified alkyl optionally substituted unbranched or branched alkoxycarbonyl containing up to 5 carbon atoms, IT, cyano, up to 3 halogen atoms, and-NR5R6where R5and R6the same or different and are selected from H, phenyl or unbranched or branched alkyl containing up to 4 carbon atoms;

R2and R3od is nakova or different and are selected from hydrogen or an unbranched or branched alkyl, containing up to 4 carbon atoms; and

R4selected from unbranched or branched alkyl containing up to 4 carbon atoms or phenyl; and

R4arepresents CN, COR4c, COOR4c, CONHR4c, CO-NR4cR4d, SO2R4S, SO2Other4c, SO2-NR4cR4dor NO2;

R4brepresents H, alkyl, OR4c, SR4c, amino, other4c, NR4cR4d, (C1-8) alkylaryl or mono-, di-, tri -, pergola(C1-8)-alkyl;

R4Sand R4dindependently selected from H, alkyl, aryl, or if any NR4cR4dgroup R4cand R4dtaken together with the nitrogen atom to which they are attached, form an unsubstituted or substituted group pyrrolidinyl, piperidinyl or morpholinyl;

X represents from 0 to 4 members independently selected from the group consisting of halogen, HE, mercapto, nitro, halo,-C1-8-alkyl, C1-8alkoxy, thio-C1-8of alkyl, C1-8alkylamino, di(C1-8-alkyl) amino, formyl, carboxy, alkoxycarbonyl, C1-8alkyl-CO-O-, C1-8alkyl-CO-NH-, carboxamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, CN, Amin, C3-6-cycloalkyl,1-8the alkyl, optionally substituted by one or more members selected from the group consisting of F, Cl, HE, WITH1-8alkoxy and Csub> 1-8acyloxy; and

Y represents a radical of the formula II or III:

where

R5, R6, R7and R8independently represent H, alkyl, CN, nitro, C1-8alkyl, halo,-C1-8alkyl, formyl, carboxy, alkoxycarbonyl, carboxamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R5and R6and/or R7and R8together form oxoprop;

R9and R10independently represent H, halogen, alkyl, HE, CN, mercapto, nitro, C1-8alkyl, halo,-C1-8alkyl, C1-8alkoxy, thio-C1-8alkyl, amino, C1-8alkylamino, di(C1-8alkyl) amino, formyl, carboxy, alkoxycarbonyl, C1-8-alkyl-CO-O-, C1-8-alkyl-CO-NH-, carboxamide, aryl, substituted aryl, heteroaryl, substituted heteroaryl or amine;

A, b, C and D are selected from C, S, O and N with the formation of any 5-10 membered aromatic or heteroaromatic ring, and the specified heteroaromatic ring contains from one to four members selected from the group consisting of S, O and N;

Z is selected from halogen, alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, CN, CHO, Salkil, Amin (dialkylamino)alkyl, where dialkylamino selected from dimethylamine, diethylamine, morpholine, thiomorpholine, pyrrolidine or piperidine, or alkoxy, or NHCO-(C1-8/sub> the alkyl); and

m represents 0 or 1,

and its pharmaceutically acceptable salts and esters.

Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.

The present invention relates also to a method of treatment of subjects, whose States are caused by bacterial infections or conditions that contribute to bacterial infections, which includes an introduction to the specified mammal a therapeutically effective amount of compounds of formula I.

The present invention relates also to a method of prevention in subjects conditions caused by bacterial infections or conditions that contribute to bacterial infections, which includes an introduction to the specified mammal prophylactically effective dose of the pharmaceutical compositions of the compounds of formula I.

Other objectives and advantages will become apparent to experts from the following description.

Detailed description of the invention

In respect to the above description of the compounds of phenyloxazolidine of the present invention used the following definitions.

Unless otherwise indicated, the terms "alkyl", "alkenyl" and "quinil" refers to an unbranched or branched groups containing from 1 to 8 carbon atoms.

The term "ACI is" refers to an organic radical, containing a specified number of carbon atoms derived from the organic acids resulting from the removal of the hydroxyl group of formula RCO, as in the case of acetyl, where R is CH3.

The term "aryl" means unsubstituted carbocyclic aromatic group, including (but not limited to, phenyl, 1-or 2-naphthyl and the like, the Term "heteroaryl" refers to a cyclic aromatic radical containing from five to ten atoms in the ring; where from one to three ring atoms are independently a heteroatom such as S, O and N, and the remaining ring atoms are carbon atoms, for example pyridinoline, personilnya, pyrimidinyl, pyrrolidinyl, personilnya, imidazolidinyl, diazolidinyl, oxazolidinyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, farnily, finalininkiu or izohinolinove radicals, etc.

The term "substituted aryl" or "substituted heteroaryl" refers to aryl or heteroaryl, whose 1 to 3 hydrogen atoms are independently substituted with halogen, HE, CN, mercapto, nitro, C1-8by alkyl, halo,-C1-8the alkyl, C1-8alkoxy, thio-C1-8alkylamino, C1-8alkylamino, di(C1-8alkyl) amino, formyl, carboxy, alkoxycarbonyl,1-8alkyl-CO-O-, C1-8alkyl-CO-NH - or carboxamido. In addition, substituted heteroaryl can the t to be replaced by morooka, forming as a result, for example, 4-oxo-1-N-quinoline. Substituted heteroaryl can also be substituted substituted aryl or replaced by the second heteroaryl, resulting in, for example, 4-phenylimidazol-1-yl or 3-pyridinyl-imidazole-1-yl, etc.

The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine, (mono-, di-, tri-, and per-)haloalkyl means alkyl radical obtained by independent replacement of its hydrogen atoms by halogen. P stands for phosphorus.

Compounds of the present invention are asymmetric in oxazolidinone ring in 5-position and therefore exist as optical antipodes. As such, all possible optical antipodes, enantiomers or diastereoisomers resulting from additional asymmetric centers may exist in the optical antipodes, racemates and racemic mixtures, are also part of the present invention. Antipodes can be divided known in the art methods, such as fractional recrystallization diastereoisomeric salts enantiomerically pure acids. In another embodiment, the antipodes can be divided chromatography on a Pirkle column.

The phrase "pharmaceutically acceptable salt" refers to salts of the free bases, which have the necessary pharmacological activity its the same reason and are not junk either biological, or from any other point of view. These salts can be obtained from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, Hydrobromic acid, sulfuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, paratoluenesulfonyl acid, methylsulfonate acid, salicylic acid, etc. in Addition, suitable salts are salts of organic and inorganic bases, such as KOH, NaOH, CA(Oh)2, Al(OH)3, piperidine, morpholine, ethylamine, triethylamine, etc.

In the scope of the present invention also includes hydrated forms of the compounds, which contain various amounts of water, for example hydrated, palpitate and sesquihydrate form.

The term "subject" includes (without limitation) any animal or artificially modified animal. In the preferred embodiment, this term refers to a person.

The term "resistant to treatment" or "resistance to l is carstvo" refers to such characteristics of microbes, as the ability to survive in the presence of currently available antimicrobial agent in his usual effective concentration.

Compounds of the present invention possess antibacterial activity against gram-positive and some gram-negative bacteria. They are useful as antibacterial agents for the treatment of bacterial infections in humans and animals. In particular, these compounds possess antibacterial activity against S.aureus, S.epidermidls, S.pneumoniae, E.faecalis, E.faecium, Moraxella catarrhalis and H.influenzae. More specifically, these compounds can be used against resistant bacteria such as MRSA and GISA, and they are less susceptible to mechanisms for the acquisition of resistance. The compounds of formula I, preferred for these purposes are those compounds in which R takes any of the following values:

In addition to the compounds of formula I which are preferred for such purposes, the preferred compounds in which Y has the following values:

isoindole-;

(1,3-dihydro-2H-isoindole-2-yl)-;

(1,3-dihydro-2H-pyrrolo[3,4-C]pyridine-6-yl)-;

(5,7-dihydro-6N-pyrrolo[3,4-b]pyrazin-6-yl)-;

(5,7-dihydro-6N-pyrrole,4-d]pyrimidine-6-yl)-;

(5,7-dihydro-6N-pyrrolo[3,4-b]pyridine-6-yl)-;

(4,6-dihydro-3-methyl-5H-pyrrolo[3,4-d]isoxazol-5-yl)-;

(3,5-dihydro-5-methylpyrazolo[3,4-C]pyrrol-2(1H)-yl)-; and

(4,6-dihydro-1-methylpyrrole[3,4-d]-1,2,3-triazole-5(1H)-yl)-

Specific examples of the compounds of the present invention include the following:

N-[[(5S)-3-[4-(1,3-dihydro-2H-isoindole-2-yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

N-[[(5S)-3-[4-(1,3-dihydro-2H-pyrrolo[3,4-C]pyridine-2-yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

N-[(5S)-3-[3-fluoro-4-(5-oxido-2H-pyrrolo[3,4-C]pyridine-2-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

N-[[(5S)-3-[4-(5,7-dihydro-6N-pyrrolo[3,4-b]pyridine-6-yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

N-[[(5S)-3-[4-(1,3-dihydro-1-oxo-2H-isoindole-2-yl)-3-forfinal] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide; and

(5R)-3-[4-(5,7-dihydro-6N-pyrrolo[3,4-b]pyridine-6-yl)-3-forfinal]-5-(hydroxymethyl)-2-oxazolidinone.

The compounds of formula I, which are the subject of the present invention, can be obtained from readily available starting materials, such as indole (Gawley et al., J. Org. Chem., 1988, 53:5381), 6,7-dihydro-5H-pyrrolo[3,4-C]pyridine and 6,7-dihydro-5H-pyrrolo [3,4-b] pyridine (U.S. patent No. 5371090 Petersen with al.) in accordance with the method of the mi synthesis, well known in the art. Examples of the methods presented in schemes I-V:

In accordance with scheme I, bicyclic heterocycles of General formula IV is treated with a substituted nitrobenzene derivative (L represents a corresponding tsepliaeva group, such as halogen or tripterocalyx) in a suitable base and a solvent such as Diisopropylamine and ethyl acetate, obtaining compound substituted nitrophenyl V.

Then nitrobenzene derivative V is reduced to aniline in an appropriate reaction, for example, processing SnCl2or by catalytic hydrogenation in the presence of an appropriate catalyst, such as palladium-on-charcoal grill. Then aniline is treated with benzyl or methylchloroform and sodium bicarbonate, receiving the corresponding derived benzyl - or methylcarbamate VI.

Then Cbz aniline VI deprotonated using a lithium base such as n-utility, and interact with (R)-glycidylether getting oxazolidinone VII. Then hydroxymethylene group is transformed into amide as shown in scheme I, getting mesilate into azide VIII and restoring to the amine IX appropriate method, such as hydrogenation. In the other embodiment, the substitution nelfinavir (scheme II) or the corresponding tsepliaeva group, such as toilet or chlorine, phthalimide potassium and remove falorni protective group hydrazinolysis results in amine IX. Amin IX can be converted into amide X in the acylation reaction using known in the art methods such as treatment with acetic anhydride in the presence of a base, such as pyridine. In another embodiment, the amine IX can be converted into carbamate XI as a result of processing methylchloroform and pyridine or as a result of interaction with sulphonylchloride in an inert solvent in the presence of organic bases such as pyridine, receiving a sulfonamide XII

To obtain oxazolidinone, where R=O-heteroaryl (XIII), oxazolidinediones VII can be converted into the corresponding mesilate or other suitable tsepliaeva group and to interact with HO-Het (suitable heterocycle containing hydroxyl), or in the presence of base, or with HO-Het as received in advance of the alkoxide in an appropriate solvent, such as DMF or acetonitrile (scheme III). Alternatively, you can use conditions Mitsunobu for attachment VII to the BUT-heterocycle in the treatment with triphenylphosphine or diisopropylcarbodiimide (DIAD) in an appropriate solvent, such as THF, at a suitable the temperature, preferably at room temperature. Reaction conditions and appropriate references can be found in WO 99/64416, Gravestock with TCS.

The cream in treating VII with a suitable dinucleophiles base, for example NaH, replacement tsepliaeva group (LG)such as chlorine or bromine, can be done using the appropriate reactive Aza-heterocycle (LG-Het)(scheme III).

Compounds of structure XIV can be obtained by the method presented in scheme IV. Amin IX can be converted into various functionalityand amidine in the reaction with activated Minami, where Q is tsepliaeva group, such as methylthio or methoxy, in a suitable solvent without catalyst or in the presence of a catalyst (such as AgNO3at temperatures in the range of 0-110°C.

In accordance with scheme V pyrrolidine XV (obtained by the method WO96/13502) is first subjected to interaction with methoxy-bis(dimethylamine) or other active reagent dimethylformamide and then heated in a suitable solvent (for example DMF or benzene), or with substituted amidine education pyrrolopyrimidine, such as XVI, or with substituted hydrazines with education pyrrolopyrimidine, such as XVII. Getting enamine, alkoxymethyl anovich or alkoxycarbonyl derivatives of pyrrolidinone XV by way Brighty with TCS. U.S. patent A also gives access to such systems.

As shown in scheme VI, the compound of structure XIX can be obtained by oxidation of various compounds XVIII, using an appropriate oxidizing agent (e.g. manganese dioxide, peroxisomal acid, DDQ or air) in a suitable solvent, such as methylene chloride.

Oxoproline formula XXII in scheme VII (X=0, Y=H2or X=H2Y=0) can be obtained by interaction of 1,2-originallocalities (where in the XXI U=N) with aniline XX (obtained according to the method of WO 96/23788) in the presence of acids, such as acetic acid, in a suitable solvent, such as methylene chloride. Di-oxoproline (formula XXII, where X=Y=0) are obtained by the interaction of aniline XX with the selected reagents 1,2-aryldiazonium with suitable atmasamyama groups (XXI, where U=Cl, Br and so on).

Definition

All temperatures are given in °

The term "brine" refers to aqueous saturated solution of sodium chloride

DMF refers to N,N-dimethylformamide

THF refers to tetrahydrofuran

Cbz refers to carbobenzoxy

n-BuLi represents n-utility

MS denotes the mass spectrum, expressed as m/e or mass/unit charge

[M+H] denotes the positive ion of the connection plus the atom odor is Yes

Ether refers to diethyl ether

CT denotes room temperature

Mr denotes the melting point

CH2Cl2denotes methylene chloride

NaOH denotes sodium hydroxide

Meon denotes methanol

EtOAc means ethyl acetate

ppt denotes sediment

These compounds have antimicrobial activity against bacterial pathogens, which have or assume that they are resistant to the drugs against such pathogens as S.aureus, S.epidermidis, S.pneumoniae, these bacteria to antibiotics, Enterococcus spp., Moraxella catarrhalis and .influenzae. These compounds are especially useful against drug-resistant gram-positive cocci, such as methicillin-resistant S.aureus and vancomycin-resistant enterococci. These compounds are useful for the treatment of acquired company pneumonia, respiratory infections upper and lower respiratory tract infections, skin infections and soft tissue infections acquired in the hospital for lung infections, bone and joint infections, and other bacterial infections.

Minimum inhibitory concentration (MIC), which is a measure of antibacterial activity in vitro, is widely used by professionals. In vitro antimicrobial activity of the compounds of the present invention is determined by way of microrasbora broth with further test the way the nation is on the Committee for laboratory standards (National Committee for Laboratory Standards (NCCLS). This method is disclosed in NCCLS Document M7-A4, Vol.17, No. 2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically-Fourth Edition", which is included here for reference.

In this way a twofold serial dilution of the drug in the broth Mueller-Hinton with the added cation added to the wells tablet microrasbora. The test organisms are prepared by adjusting the turbidity of the cultures in broth with active growth so that the final concentration of the test organism after it is added to the wells was approximately 5×104culture-forming units/well.

After insulinopenia tablets microrasbora tablets incubated at 35°C for 16-20 h, and then read the testimony. MIC is the lowest concentration of test compound that completely inhibits growth of the test organism. A growing number of organisms in the wells containing the test compound, compared with the number of organisms in the wells with controlled growth (without test compound)used for each plate. As can be seen from table 1, some compounds of the present invention were tested against a variety of pathogenic bacteria, which gave the interval of the activities from 1 to ≥128 µg/ml depending on the tested organism. S.aureus OC2878 is MRSA and E. faecium OC3312 are resistant to the namizimu Enterococcus.

tr>
Table 1

The MIC for some of the compounds of formula I
Connection # MIC (mg/ml) for the test strains
S. aureus OC4172S. aureus OC2878E. faecium OC3312
1222
2214
30,50,250,5
410,51
5>32>32>32
6643232
7>32816
8848
9>32>32>32
10>32864
11212
12824
13212
14321616
152 22
16888
17422
18161616
19848
20424
21>64>64>64
22222
23888
24888
25>64>12832
2610,51
27848
280,50,50,5
29>32816
30>128>128>128
31>16>16>16
32422
33323232
34824
350,50,252
3610,51
37110,5
38221
39121
40111
41222
42222
43111
44111
45444
46448
47321632
48888
491648

Further, in the present invention, a method for treatment of bacterial infections or enhancement or potentiation of the activity of other antimicrobial agents in the subject, a condition which is caused by a bacterial infection or a condition which contributes to bacterial infection, which includes wvedenia.grudnam compounds of the present invention alone or in a mixture with another antibacterial agent in the form of medication in accordance with the present invention. The term "treating" and "treatment" includes simultaneous, separate or sequential introduction of pharmaceutically effective amounts of compounds containing one or more of the disclosed here compounds to a subject, which is necessary to inhibit the growth of bacteria. Pharmaceutically effective amount of a compound that is used in the practice of the present invention for the treatment varies depending on the method of administration, age, weight and General condition of the subject treated of the subject and, ultimately, determined by physicians or veterinarians.

Compounds of the present invention it is possible to introduce the subject, such as man, by any means, subject to appropriate treatment of the condition, and suitable methods include oral, rectal, nasal, external (including the introduction of the cheek and under the tongue), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, through the trachea and the epidural). The preferred method may vary, for example, depending on the condition of the recipient, and the type of preparation and ease of administration.

If the connection is used for the above purposes, they can be combined with one or more of pharmaceutically acceptable carriers, that is, solvents, diluents and the like, and can be administered orally in such forms, the AK pills, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol and the like, or parenteral, in the form of sterile solutions or suspensions for injection, containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with a carrier, usually from 5% to 60%.

Compositions for topical application can be in the form of liquids, creams or jellies containing therapeutically effective concentrations of the compounds of the present invention in a mixture with a dermatologically acceptable carrier.

Upon receipt of the songs in dose form for oral administration can be any of the pharmaceutically acceptable environments. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surface-active agents and edible oils such as corn, peanut and sesame oils, consistent with the nature of the active ingredient and the desired specific form of introduction. With success, you can enable adju the antes, usually used in the preparation of pharmaceutical compositions, such as flavouring agents, colouring agents, preservatives and antioxidants, etc. such as vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and introduction are solid compositions, particularly tablets and capsules with solid or liquid contents. Preferably oral administration of the compounds. These active compounds can also enter parenteral or intraperitoneal. Solutions or suspensions of these active compounds as free bases or pharmacologically acceptable salts can be obtained in water suitably mixed with a surface-active agent such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and their mixtures in oils. Under normal conditions of storage and use, these preparations can contain preservatives to prevent the growth of microorganisms.

Pharmaceutical forms for use in injection include sterile aqueous solutions or dispersions and sterile powders for cooked for immediate injection of sterile solutions or dispersions for injection. In all cases the form must be sterile and must be fluid datakey degree, so it can be easily administered with a syringe. It must be stable under conditions of manufacture and storage and must be taken to prevent contamination by microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures and vegetable oil.

Used effective dose of active ingredient may vary depending on the specific compound, the route of administration and the severity of the condition to be treated. However, generally satisfactory results are obtained if compounds of the present invention is administered in a daily dose from about 0.1 mg/kg to about 400 mg/kg body weight of the animal, preferably injected in divided doses two to four times a day. For most large mammals the full daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 1000 mg Dose forms suitable for internal use comprise from about 100 mg to 500 mg of active compound, thoroughly mixed with solid or liquid pharmaceutically acceptable carrier. This dose schedule can be set for optimal therapeutic response. For example, several divided the military doses can be administered daily or the dose can be proportionally reduced in accordance with the indications of therapeutic situation.

Obtaining the above-mentioned pharmaceutical compositions and medicaments can be done by any of the well-known specialists of ways, for example by mixing the active ingredient (the ingredient) with the diluent (solvent) to obtain a pharmaceutical composition (e.g., pellets), and then forming the composition in the form of drugs (for example, in the form of tablets).

The examples below explore in detail the methods of chemical synthesis of representative compounds of the present invention. These methods are illustrations and do not consider the invention as limited by the chemical reactions and conditions that they specify. No effort was made to optimize the outputs achieved in these reactions, and specialists should be obvious that, by varying the time of reaction, temperature, solvents and/or reagents, the outputs can be increased.

Example 1

(5R)-3-[4-(1,3-Dihydro-1-oxo-2H-isoindole-2-yl)-3-forfinal]-5-(hydroxymethyl)-2-oxazolidinone

Isoindoline synthesized using the method R..Gawley, S.R.Chemburkar, A.L.Smith, .V.Anklekar J. Org. Chem. 1983, 53, 5381.

Stage 1:

To 3,4-deformirovannogo (3,02 ml and 27.3 mmol) in ethyl acetate at room temperature add diisopropylethylamine (5,03 ml of 28.9 mmol), then isoindoline (3.50 g, 29.4 mmol) and stirred t is the significance of the night. The resulting yellow precipitate (ppt) collected on a filter, washed with water and ether and dried in a vacuum thermostat (30° (C)receiving the product in a solid yellow color (6,69 g, 95% yield). So melting = 200-202°C. Mass spectrum (M+1)=327 m/z.

Stage 2:

To the above nitrosoaniline (2,62 g, 10.2 mmol) in ethanol (100 ml) add SnCl2(9,84 g of 50.9 mmol) and refluxed for 16 hours. After cooling to room temperature the reaction mixture was added to 10% aqueous solution of NaOH (300 ml) and extracted with CH2Cl2(6×50 ml). The combined organic extracts washed with brine (100 ml), dried over Na2SO4and concentrate, receiving 2,63 g olive-green solid substance (aniline), which is used without further purification. This aniline in acetone (150 ml) and water (20 ml) is added NaHCO3(1.84 g, 21.9 mmol) and then benzylchloride (1,68 ml of 11.8 mmol). After stirring overnight the mixture was poured into ice-cold water (100 ml) and the resulting yellow-brown precipitate is collected on a filter, washed with water and dried in vacuum, obtaining Cbz aniline as a yellow-brown solid (3.50 g, 95% yield). So melting = 146-148°C. Mass spectrum (M+1)=363 m/z.

Stage 3:

To the above Cbz aniline (0.74 g, 2.04 mmol) in THF (10 ml) at -78°With added dropwise n-BLi (2.5 M, of 0.82 ml, 2.05 mmol). After stirring for 40 minutes, added dropwise (R)-glycidylether (0,31 ml, 2.10 mmol) in THF (0.5 ml) and the resulting mixture left to stand at room temperature overnight. The resulting white precipitate is collected on a filter and washed with water and ether. As a result of processing through column chromatography with silica gel, 25% mixture of ethyl acetate/hexane as eluent receive the product as a white solid (0,58 g, 87% yield). Mass spectrum (M+1)=329 m/z.

Example 2

(5R)-3-[4-(1,3-dihydro-1-oxo-2H-isoindole-2-yl)-3-forfinal]-5-[[(methylsulphonyl)oxy]methyl]-2-oxazolidinone

To oxazolidinecarboxylate obtained in example 1 (0,58 g, 1.78 mmol) in DMF (10 ml), and acetonitrile (10 ml) at 0°With add triethylamine (0.74-ml 5,31 mmol) and after 10 minutes add methanesulfonanilide (of 0.28 ml, 3.62 mmol). The reaction mixture is left for 1 hour at room temperature and then still have the source material, so I repeat cooling and adding triethylamine (0.37 sq ml, approximately 2.65 mmol) and methanesulfonamide (0,14 ml of 1.81 mmol). This mixture was poured into water (50 ml) and extracted with CH2Cl2(6×20 ml), washed with brine (4×10 ml), dried over Na2SO4and concentrate give crude product as brown oil (0.95 g). Mass spectrum (M+1)=407 m/z.

p> Example 3

(5R)-5-(azidomethyl)-3-[4-(1,3-dihydro-1-oxo-2H-isoindole-2-yl)-3-forfinal]-2-oxazolidine

To mesilate obtained in example 2 (0.95 g, 1.78 mmol) in DMF (25 ml), add sodium azide (0,47 g of 7.23 mmol) and heated at 70°C for 16 hours. After cooling to room temperature, water is added, and the mixture was extracted with ethyl acetate (6×25 ml), washed with brine (4×10 ml), dried over Na2SO4and concentrate, receiving 0,48 g solid yellow-brown color. Mass spectrum (M+1)=354 m/z.

Example 4

N-[[(5S)-3-[4-(1,3-dihydro-2H-isoindole-2-yl)-3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Connection 1

Azide obtained in example 3, ethyl acetate (25 ml) is placed in a flask of Para and through it bubbled nitrogen for 15 min, then add 10% Pd/C (0.15 g, 0.14 mmol) to the mixture to create a pressure of 50 psi H2(g) and shaken for 16 h, after which add an additional amount of 10% Pd/C (0.15 g, 1.4 mmol) and the resulting mixture is shaken additionally within 6 hours (at this point, mass spectrum (M+1)=328 m/z). After the mixture is placed in a nitrogen atmosphere, add pyridine (0,22 ml of 2.72 mmol) and then AU2(0.51 ml, and 5.30 mmol)and the resulting mixture is stirred for 2 hours. The mixture is filtered through celite, washed with utilize the atom (100 ml), concentrated and purified through column chromatography with silica gel (gradient elution of 1%-5% Meon/CH2Cl2), then triturated with ethyl acetate (3×3 ml), resulting in a gain 0,19 g solid white (Connection 1, 29% yield over 4 steps). So melting = 240-242°C. Mass spectrum (M+1)=370 m/z.

Example 5

Connection 2

Stage 1:

6,7-dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine: To dihydrochloride salt of 6,7-dihydro-5H-pyrrolo-[3,4-b]pyridine (as disclosed in Petersen with TCS. (Bayer) ERA) (42.8 g, 222 mmol) in DMF (1/2 l) is added 2,4-diplomarbeit (25 ml, 224 mmol). The mixture is heated to 60°and added dropwise DIPEA (195 ml, 1.12 mol) via an addition funnel over 2 hours. After heating overnight, the reaction mixture was cooled to room temperature, poured into water (3 l), filtered and dried in a vacuum thermostat (50° (C)receiving solid yellow-green (53,8 g, 94% yield). Mass spectrum (M+1)=260 m/z.

Stage 2:

6,7-dihydro-6-(2-fluoro-4-AMINOPHENYL)-5H-pyrrolo [3,4-b]-pyridine

To the obtained above nitrosoaniline (53,8 g, 208 mmol) in THF (175 ml) and methanol (600 ml) is added ammonium formate (59.0 g, 907 mmol). After the reaction mixture was bubbled nitrogen for about 30 minutes, the Les which add 10% Pd/C (2/20 g, 21 mmol). After stirring overnight at room temperature in a nitrogen atmosphere, the reaction mixture was filtered through a layer of celite, thoroughly washed with methanol (400 ml) and concentrated to a volume of about 200 ml. of water is Added (300 ml) and the mixture extracted with ethyl acetate (5×200 ml). Combined organic layers washed with brine, dried (Na2SO4), filtered and used directly in the next stage without additional purification. Mass spectrum (M+1)=230 m/z.

Stage 3:

6,7-dihydro-6-(2-fluoro-4-(aminocarbonylmethyl)phenyl)-5H-pyrrolo-[3,4-b]pyridine

The result of the above aniline (about 208 mmol) in acetone (1 l) and water (160 ml) cooled to 0°With, then add sodium bicarbonate (or 37.4 g, 445 mmol)and then dropwise add benzylchloride (34,2 ml, 228 mmol). The reaction mixture was left to warm to room temperature and stirred overnight, after which a precipitate. The reaction mixture was poured into ice water (2 l) and the precipitate collected by filtration. The obtained solid is washed with water and dried in a vacuum thermostat (50° (C)receiving Cbz derivative (73,0 g, 97% yield) in the form of powder color itself. Mass spectrum (M+1)=364 m/z.

Stage 4:

(Compound 2)

Obtained above Cbz derivative (40,8 g, 112 mmol) in THF (1 l) cooled to -78°in almost the re nitrogen. To this mixture dropwise via syringe add n-BuLi (2.5 M, with 45.8 ml of 114.5 mmol) for 15 minutes. The reaction mixture is heated to room temperature and left under stirring for 45 minutes, again cooled to -78°C. At this point add (R)-glycidyl butyrate (17,2 ml, 117 mmol) and the reaction mixture left to warm to room temperature overnight, forming a precipitate. The precipitate is collected, washed with several portions of ether (5×100 ml) and dried in a vacuum thermostat (50° (C)receiving 40.6 g of essential MES alkoxide of lithium in the form of a fluffy powder yellow-brown color. This material is washed with several portions of water (4×200 ml) and dried in a vacuum thermostat (50° (C)receiving oxazolidinone alcohol (34,1 g, 92% yield) in the form of granular solids yellow-brown color. So melting = 208-212°With decomposition. Mass spectrum (M+1)=330 m/z.

Example 6

Oxazolidinone mesilate. The above oxazolidinediones (from example 4) cases (33.8 g, 103 mmol) suspended in DMF (1.25 l, previously degassed with nitrogen) at room temperature under nitrogen atmosphere. Add triethylamine (50 ml, 360 mmol)and then dropwise add methanesulfonanilide (13,5 ml, 174 mmol). After stirring for 3 hours the reaction mixture was poured into water (200 ml) is added methylene chloride (1 liter). The precipitate is filtered off, washed with water (3×200 ml) and dried in a vacuum thermostat (50° (C)receiving mesilate in the form of a solid yellow-brown (28,1 g, 67%). The organic layer is dried (Na2SO4), filtered and evaporated, resulting also get mesilate (11,7 g, 28% yield) as a solid yellow-brown color. Both characterize them using mass spectroscopy. Mass spectrum (M+1)=408 m/z.

Example 7

Oxazolidinone azide. Obtained above mesilate (from example 5) (27.8 g, 68.2 mmol) and sodium azide (17,7 g, 271 mmol) in anhydrous DMF (1 l), previously degassed with nitrogen, heated at 95°C for 6 hours in nitrogen atmosphere. After cooling, the mixture was poured into stirred ice water (2 l), resulting in a fluffy white precipitate. The precipitate is collected on filter paper, washed with water (4×200 ml), dried in a vacuum thermostat (50° (C)receiving azide in a solid light beige color (22,7 g, 94% yield). So melting = 175-180°With decomposition. Mass spectrum (M+1)=355 m/z.

Example 8

Connection 3

Oxazolidinones. The result of the above azide (example 6) (21,67 g, 61,16 mmol)dissolved in DMF (400 ml) and THF (500 ml), Tegaserod nitrogen for 30 minutes, then add 10% Pd/C (4,74 g, 4.4 mmol) and reactionuses hydronaut in a Parr apparatus (60 psi of hydrogen for 14 hours. The reaction mixture was removed from the Parr apparatus and placed in a nitrogen atmosphere, and then add pyridine (5,44 ml, to 67.3 mmol) and acetic anhydride (6,35 ml, to 67.3 mmol). After stirring for 1 hour the reaction mixture was filtered through a layer of celite, thoroughly washed with methanol and then large amounts of 50% MeOH/CH2Cl2(approximately 2 liters). The resulting filtrate is evaporated, obtaining the crude ndimethylacetamide in DMF. The mixture is slowly added to water (2 l) and the precipitate collected on a filter, washed with water (5×400 ml) and dried in a vacuum thermostat (50° (C)receiving ndimethylacetamide in the form of an analytically pure solid white (14.2 g, 63% yield). The combined filtrates are extracted with methylene chloride (5×200 ml), dried over Na2SO4and concentrate. To the residue water is added and the precipitate filtered and dried in a vacuum thermostat (50° (C)receiving a second portion of ndimethylacetamide in the form of a fluffy solid light yellow-brown (5,61 g, 25%). For the analytically pure material So melting = 229-230°With decomposition. Mass spectrum (M+1)=371 m/z.

Example 9

Connection 4

The above ndimethylacetamide from example 8 (of 2.51 g of 6.78 mmol) is placed in CH2Cl2and add MnO2(23.9 g, 234 mmol). After stirring over night the reaction mixture was filtered through the elite, concentrate and process through column chromatography with silica gel, elwira 10% MeOH/CH2Cl2and getting the product in the form of a solid light-yellow color (0,48 g, 19% yield). So melting = 220-225°With decomposition. Mass spectrum (M+1)=369 m/z.

Example 10

Connection 5

Connection 5 receive according to the method of example 8 except that in the formation of oxazolidinone use (S)-glycidylether. The product is isolated in the form of solid light yellow-brown color. So melting = 227-230°With decomposition. Mass spectrum (M+1)=371 m/z.

Example 11

The connection 6. Oxidized enantiomer

Connection 6 received by the method of example 9 and isolated in the form of a solid of light yellow color. So melting = 181-185°With decomposition. Mass spectrum (M+1)=369 m/z.

Example 12

Connection 7

To 5-hydroxycarbazole (obtained by the method Chem Pharm Bull 1966, 14(11), 1277) (0,174 g, 2.04 mmol) in DMF added NaH (60% in oil) (0,105 g, 2,62 mmol). After stirring for 30 minutes to one portion add mesilate (from example 6) (0,744 g, 1.82 mmol) and the resulting mixture was stirred at 60°With during the night. After cooling to room temperature, water is added and the precipitate collected on a filter, dried air and the process x is autographically column of silica gel, elwira to 2.5% MeOH/CH2Cl2in the result, receive the product in a solid white color (0,140 g, 19 % yield). So melting = 182-185°C. Mass spectrum (M+1)=397 m/z.

Example 13

Compound 8

To the obtained above oxazolidinone (example 12) (0,264 g of 6.66 mmol)placed in CH2Cl2add MnO2(1.66 g, 16.2 mmol) in two portions over two days. After stirring for two days, the reaction mixture was filtered through celite, concentrated and treated through column chromatography with silica gel, elwira 10% MeOH/CH2Cl2and getting the product in the form of a solid light-yellow color (0,086 g, 32% yield). So melting = 133-135°C. Mass spectrum (M+1)=395 m/z.

Example 14

Connection 9

To NaH (60% by weight in oil) (0.03 g, from 0.76 mmol) in DMF (5 ml) add oxazolidinediones (from example 5) (0,23 g, 0.71 mmol) in four portions. After stirring for 30 minutes using a syringe add 2-chloropyrazine (0,065 ml, 0.71 mmol) and stirred overnight at room temperature. Add water and the precipitate collected on a filter, dried by air and process chromatographic column with silica gel, elwira 5% MeOH/CH2Cl2getting the product in the form of a solid white color (0,067 g, 23 % yield). So melting = 225-230°Mass spectrum (M+1)=408 m/z.

Example 15

Connection 10

To the obtained above oxazolidinone (example 14) (0,024 g 0,058 mmol) in CH2Cl2(5 ml) is added MnO2(0.07 g, 0.7 mmol). After stirring over night the reaction mixture was filtered through celite and concentrated, obtaining the product in the form of solid substances of very light yellow color (0.015 g, 64% yield). So melting = 192-194°C. Mass spectrum (M+1)=406 m/z.

Example 16

Connection 11

To a suspension of oxazolidinecarboxylate (obtained in example 5) (330 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.1 mmol) and 4-hydroxy-1,2,5-thiadiazole (100 mg, 1.0 mmol) (obtained according to the method of example the U.S. patent 3391150 [7.2.68]) in THF (8 ml) add diisopropylethylamine (0,20 ml, 1.1 mmol). After stirring over night at room temperature the reaction mixture is filtered, washed with methanol and dried by air, getting a crystalline solid yellow (60 mg, 15% yield). So melting = 185-187°C. Mass spectrum (M+1)=414 m/z.

Example 17

Connection 12

The oxazolidinone (obtained in example 16) (160 mg, 0,39 mmol), suspended in CH2Cl2(1.0 ml), add MnO2(four portions 150 mg for four days). The reaction mixture was filtered through a layer of celite, washed with CH2Cl2(15 ml), concentrate under reduced pressure, obtaining the product in the form of a solid crystalline substance white (63 mg, 40% yield). So melting = 185-188°C. Mass spectrum (M+1)=412 m/z.

Example 18

Connection 13

To the amine (obtained in example 8) (100 mg, 0.30 mmol) and potassium carbonate (100 mg, to 0.72 mmol), suspended in methanol (1.0 ml), add propionate (50 mg, 0.54 mmol). After stirring overnight at 80°the reaction mixture is cooled and water is added. The precipitate is filtered off, washed with methanol and dried by air, getting the product in the form of a crystalline solid brown (15 mg, 13 % yield). So melting = 110-112°C. Mass spectrum (M+1)=385 m/z.

Example 19

The connection 14

To the amide (obtained in example 18) (15 mg, 0.04 mmol), suspended in CH2Cl2(1.0 ml), add MnO2(200 mg) at room temperature. After stirring over night the reaction mixture was filtered through a layer of celite, washed with CH2Cl2(10 ml) and concentrated under reduced pressure, obtaining the product as a crystalline solid light brown color (1.6 mg, 8 % yield). Mass spectrum (M+1)=383 m/z.

Example 20

The connection 15

To the amine (obtained by the method of example 8) (60 mg, 0.8 mmol) and potassium acetate (60 mg, 0.61 mmol), suspended in methanol (1.0 ml), add cyclopropanecarboxamide (120 mg, 1.15 mmol). After stirring at room temperature overnight, the reaction mixture was filtered, washed with methanol and then concentrated to dryness under reduced pressure. The obtained solid residue triturated with water and filtered, obtaining a product in the form of a crystalline solid brown (36 mg, 50% yield). So melting = 235-240°C. Mass spectrum (M+1)=397 m/z.

Example 21

The connection 16

To the amide (obtained in example 20) (36 mg, 0.09 mmol), suspended in CH2Cl2(1.0 ml), add MnO2(with three portions of 100 mg for three days) at room temperature. The reaction mixture was filtered through a layer of celite, washed with CH2Cl2(10 ml) and concentrated under reduced pressure, obtaining the product as a crystalline solid off-white color (3 mg, 8 % yield). Mass spectrum (M+1)=395 m/z.

Example 22

Connection 17

To the amine (obtained in example 8) (60 mg, 0.18 mmol) and potassium acetate (60 mg, 0.61 mmol), suspended in methanol (1.0 ml), added dropwise methylchloroform (120 mg, of 1.27 mmol). After stirring for four hours at room temperature, the reaction mixture was filtered, diluted with the ode and concentrated under reduced pressure, removing the methanol. The aqueous solution is extracted with ethyl acetate (5×5 ml). The combined organic extracts washed with water, dried over MgSO4filter and concentrate getting the product in the form of oil, which is triturated with ether, obtaining crystalline solid brown (35 mg, 50% yield). Mass spectrum (M+1)=387 m/z.

Example 23

The connection 18

To the carbamate (obtained in example 22) (33 mg, 0.08 mmol), suspended in CH2Cl2(1.0 ml), add MnO2(150 mg). After stirring over night at room temperature the reaction mixture was filtered through a layer of celite, washed with CH2Cl2(10 ml) and concentrated under reduced pressure, obtaining the product as a crystalline solid yellow (6.0 mg, 18% yield). Mass spectrum (M+1)=385 m/z.

Example 24

Connection 19

To the amine (obtained in example 8) (60 mg, 0.18 mmol) and potassium acetate (60 mg, 0.61 mmol), suspended in methanol (1.0 ml), added dropwise ethylchloride (0.1 ml, 1.04 mmol). After stirring over night at room temperature the reaction mixture was filtered, diluted with water and concentrated under reduced pressure to remove methanol. The aqueous solution is extracted with ethyl acetate (5×5 ml). The combined organic extra is you washed with water, dried over MgSO4filter and concentrate. The obtained semi-solid substance is treated with water, filtered and dried air, getting a crystalline solid brown (18 mg, 30% yield). Mass spectrum (M+1)=401 m/z.

Example 25

The connection 20

To the amine (obtained in example 8) (95 mg, 0.29 mmol), suspended in pyridine (0.5 ml), add methanesulfonanilide (of 0.08 ml, 1.0 mmol). After stirring over night at room temperature the pyridine is removed in a nitrogen atmosphere. The residue is treated with water, filtered and dried air, getting a solid brown (45 mg, 38% yield). So melting = 172-176°C. Mass spectrum (M+1)=407 m/z.

Example 26

Connection 21

The sulfonamide (obtained in example 25) (10 mg, 0.02 mmol), suspended in CH2Cl2(1.0 ml), add MnO2(100 mg, 10 mmol). After stirring over night the reaction mixture was filtered through a layer of celite, washed with CH2Cl2(10 ml) and concentrated under reduced pressure, obtaining the product as a crystalline solid brown color (0.5 mg, 5% yield). Mass spectrum (M+1)=405 m/z.

Example 27

The connection 22

To the amine (obtained in example 8) (200 mg, 0.61 mmol)suspended in toluene (8 ml), add auth dimethyl-N-cyanodithioiminocarbonate (89 mg, 0.61 mmol). After stirring over night at boiling under reflux the toluene is decanted and the oily residue is treated with methanol, filtered and dried air, getting a crystalline solid brown (62 mg, 20% yield). So melting = 204-207°C. Mass spectrum (M+1)=427 m/z.

Example 28

The connection 23

Suspension of thioimidate (from example 27) (45 mg, 0.10 mmol) and MnO2(200 mg, 2.0 mmol) in CH2Cl2stirred at room temperature for one day, then the second time add MnO2(150 mg, 1.5 mmol). After another day of mixing, the mixture is filtered through celite, washed with CH2Cl2(10 ml) and concentrated, obtaining crystalline solid yellow (20 mg, 45% yield). Mass spectrum (M+1)=426 m/z.

Example 29

Connection 24

A suspension of amine (obtained in example 8) (165 mg, 0.5 mmol) and 2-methyl-1-nitro-2-thiopseudourea (94 mg, 0.70 mmol) (obtained according to the method of EP 0539204/1993) in methanol (2 ml) is refluxed for four hours. After cooling to room temperature the reaction mixture is filtered and dried air, getting a crystalline solid yellow (50 mg, 24% yield). So melting = 202-206°C. Mass spectrum (M+1)=416 m/z.

Example 30

The connection 25

To nitroguanidine (obtained in example 29) (35 mg, 0.08 mmol), suspended in CH2Cl2(1.0 ml), add MnO2(with three portions of 100 mg for three days). The reaction mixture was filtered through a layer of celite, washed with CH2Cl2(10 ml) and concentrated under reduced pressure, obtaining the product as a crystalline solid yellow (1.6 mg, 4% yield). Mass spectrum (M+1)=414 m/z.

Example 31

The connection 26

Source material, 6,7-dihydro-5H-pyrrolo[3,4-C]pyridine, prepared as in the method of U.S. patent No. 5371090 issued Petersen with TCS. Then get a connection 26 to the method of example 8 except that the ndimethylacetamide recrystallized from acetonitrile, getting solid light yellow-brown color. So melting = 182 to 190°With decomposition. Mass spectrum (M+1)=371 m/z.

Example 32

Connection 27

Connection 27 are separated from the final stage of example 31 using chromatographic processing (5% MeOH/CH2Cl2as eluent) the mother liquor, obtained by recrystallization. Get the solid light yellow color, So melting = 219-225°With decomposition. Mass spectrum (M+1)=385 m/z.

Example 33

The connection 28

The connection 28 get p the method of example 9 except as eluent used 10% CH2Cl2. Get the solid light yellow color. So melting = 219-225°With decomposition. Mass spectrum (M+1)=369 m/z.

Example 34

The connection 29

The connection 30

Isothiazol (0,088 g, 0.87 mmol)(obtained according to the method of J. Heterocyclic Chem 1971, 8, 591) is added by portions at room temperature to a suspension of sodium hydride (0.036 g, of 0.91 mmol, 60 in oil) in DMF (4 ml) under nitrogen atmosphere. The mixture is stirred for 30 minutes, then add all at once mesilate obtained in example 31 (0.31 g, from 0.76 mmol)in DMF (10 ml). After stirring for 6 h at 60°the reaction mixture is cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed several times with water, then once with brine, dried over sodium sulfate, concentrated and treated through column chromatography with silica gel, elwira 5% MeOH/EtOAc. In the chromatographic processing produce two products: 0,050 g of compound 29 and of 0.022 g of compound 30. The total yield of 30%.

The connection 29. Mass spectrum (M+1)=413,0.

The connection 30. Mass spectrum (M+1)=411,1.

Example 35

The connection 31

The connection 32

It is Uspenie of sodium hydride (0.036 g, of 0.91 mmol, 60% in oil) in DMF (4 ml) at room temperature under nitrogen atmosphere add portions of 4-hydroxy-1,2,5-thiadiazole (0,088 g, 0.87 mmol) (obtained according to the method of U.S. patent 3391150 [7/2/68]). After stirring for 30 minutes add all at once mesilate obtained in example 31 (0,310 g, from 0.76 mmol) in DMF (10 ml). After stirring for 6 hours at 60°the reaction mixture is cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed several times with water, then once with brine, dried over sodium sulfate, concentrated and treated through column chromatography with silica gel, elwira 2% MeOH/EtOAc. In the chromatographic processing receive two products: 0.035 g of Compound 31 and 0,0093 g of Compound 32. The total yield of 14%.

The connection 31. Mass spectrum (M+1)=414,0.

The connection 32. Mass spectrum (M+1)=412,1.

Example 36

The connection 33

Stage 1:

To mesilate obtained in example 31 (2,45 g, 6,01 mmol)dissolved in degassed DMF (100 ml) under nitrogen atmosphere, add phthalimide potassium (2,23 g, 12,0 mmol). After heating at 65°C for 3 hours the reaction mixture is cooled, poured into water (300 ml) and extracted with methylene chloride (3×200 ml). United organizes the e extracts washed with water (3× 150 ml), dried over sodium sulfate and concentrated, gaining solid yellow-brown color. This solid is washed with water and dried in a thermostat with high vacuum at 50°receiving 2.20 g ( 80%) phthalimide oxazolidinone. Mass spectrum = 459,1 (M+1).

Stage 2:

To the obtained above phthalimide (0.97 g, 2.1 mmol) in degassed methanol (30 ml) in nitrogen atmosphere are added dropwise hydrazine monohydrate (0.2 ml, 4.3 mmol). After boiling under reflux for 12 hours, the reaction mixture was cooled to room temperature, concentrated, suspended in CH2Cl2and filtered. Crude oxazolidinone concentrated and used without further purification.

Stage 3:

The connection 33

To the crude amine (0.14 g, 0.44 mmol) in CH2Cl2(5 ml) is added pyridine (0,14 ml, 18 mmol), and then propionitrile (0,76 ml, 0.88 mmol). After stirring for 5 hours at room temperature the solution was poured into water (20 ml) and extracted with methylene chloride (3×10 ml). The combined extracts washed with water (10 ml) and 1 M NaOH (aq.) (10 ml), dried over sodium sulfate, concentrated and treated through column chromatography with silica gel, using as eluent pure EtOAc and getting propionamide in the form of a Golden oil (0,020 g, 12% yield). Mass spectrum = 385,2 (M+1).

<> Example 37

The connection 34

To the crude amine (obtained by the method of example 36) (0,144 g, 0,437 mmol) in methylene chloride (5 ml) is added pyridine (of 0.14 ml, 1.7 mmol), and then cyclopropanecarbonitrile (0,08 ml, 0.88 mmol). After stirring for 5 hours at room temperature the solution was poured into water (20 ml) and extracted with methylene chloride (3×10 ml). The combined extracts washed with water (10 ml) and 1 M NaOH (aq.) (10 ml), dried over sodium sulfate, concentrated and treated through column chromatography with silica gel using a gradient elution from 1% to 5% to 10% Meon/ EtOAc. Elute the desired product 5% Meon/-EtOAc and concentrate getting the product in the form of a white powder (0,012 g, 7% yield). Mass spectrum = 397,2 (M+1).

Example 38

The connection 35

Stage 1

To N-[(3-pyrrolidino-3-forfinal) 5-oxazolidinyl]methylacetamide (obtained according to the method of WO 96/13502)(0,150 g, 0/447 mmol) is added methoxy-bis(dimethylamino)methane (1 ml). After heating at 50°C for 15 minutes, the reaction mixture was concentrated, give crude β-ketoenamine, which is used without further purification.

Stage 2

The connection 35

To the ethanol solution of NaOEt (from 0,027 g Na in 3 ml EtOH) add acetamidomalonate (0,113 g, 1,19 mmol) and the floor is built above β -ketenagalistrikan the ndimethylacetamide. After boiling under reflux for 3 hours, the reaction mixture was cooled to room temperature, concentrated and placed in chloroform and washed with water (3×8 ml). After drying over sodium sulfate the crude product is concentrated, dissolved in 5% MeOH/EtOAc and filtered, obtaining the product as off-white solids (0,052 g, 45% yield). So melting = 234°With decomposition. Mass spectrum = 385,9 (M+1).

Example 39

The connection 36

To N-[(3-pyrrolidino-3-forfinal) 5-oxazolidinyl]methylacetamide (obtained according to the method of WO 96/13502) (0,099 g, 0.29 mmol) is added methoxy-bis(dimethylamino)methane (1.0 ml). After heating at 50°C for 2 hours, the reaction mixture was concentrated, give crude β-ketoenamine. To this mixture is added benzene (5 ml), DMF (1 ml) and acetate of formamidine (0.55 g, 5.3 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% MeOH/CH2Cl2in the result, get the product as white powder (0.037 g, 34% yield). So melting = 230-232°C. Mass spectrum (M+1)=372 m/z.

Por what measures 40

The connection 37

The above ndimethylacetamide from example 39 (0,020 mg, 0,054 mmol) is placed in CH2Cl2(5 ml) and add MnO2(0.10 g, 0.98 mmol). After stirring over night at room temperature the reaction mixture was filtered through celite and concentrated, obtaining the product in the form of a solid light-yellow color (0,016 g, 80% yield). So melting = 164-166°C. Mass spectrum (M+1)=370 m/z.

Example 41

Compound 38

It β-ketoenamine (obtained by the method of example 39) is added benzene (5 ml), DMF (1 ml) and pyrazin-2-carboximetilceluloza (0,62 g, 3.9 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% MeOH/CH2Cl2, resulting in a product in the form of a solid light-yellow color (0,0026 g, 2% yield). So melting = 212-214°C.

Mass spectrum (M+1)=450 m/z.

Example 42

Connection 39

The connection 40

The above ndimethylacetamide from example 39 (0,040 g, 0,088 mmol) is placed in CH2Cl2(10 ml) and add MnO 2(0.36 g, 3.5 mmol) in three portions over three days. After stirring for three days, the reaction mixture was filtered through celite, concentrated and treated through column chromatography with silica gel, using as eluent 7% Meon/CH2Cl2. In the chromatographic processing produce two products: 0,001 g of Compound 39 in the form of a solid light-yellow (4% yield) and 0.002 g of Compound 40 in the form of a solid yellow (4% yield).

Compound 39: Mass spectrum (M+1)=448 m/z.

The connection 40: Mass spectrum (M+1)=464 m/z.

Example 43

The connection 41

It β-ketoenamine (obtained by the method of example 39) is added benzene (5 ml), DMF (1 ml) and 4-amidinohydrolase (0,81 g, 5.2 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% Meon/CH2Cl2, resulting in a product in the form of a solid light-yellow color (0,072 g, 55% yield). So melting = 245-250°With decomposition. Mass spectrum (M+1)=449 m/z.

Example 44

The connection 42

It β -ketoenamine (obtained by the method of example 39) is added benzene (5 ml), DMF (1 ml) and 2-amidinohydrolase (0,61 g, 3.9 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% MeOH/CH2Cl2in the result, get the product as yellow powder (0/054 g, 40% yield). So melting = 216-220°C. Mass spectrum (M+1)=449 m/z.

Example 45

The connection 43

It β-ketoenamine (obtained by the method of example 39) is added benzene (5 ml), DMF (2 ml) and 3-amidinohydrolase (0,49 g, 3.1 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% MeOH/CH2Cl2, resulting in a product in the form of a crystalline solid light purple color (0,044 g, 33% yield). T melt = 265-270°C. Mass spectrum (M+1)=449 m/z.

Example 46

With the Association 44

It β-ketoenamine (obtained by the method of example 39) is added benzene (5 ml), DMF (2 ml) and hydrazinehydrate (0,22 g, 3.2 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% MeOH/CH2Cl2, resulting in a product in the form of powder off-white color (0,022 g, 21% yield). So melting = 244-247°C. Mass spectrum (M+1)=360 m/z.

Example 47

The connection 45

It β-ketoenamine (obtained by the method of example 39) is added benzene (5 ml), DMF (2 ml) and n-propylpiperazine (0.87 g, 5.3 mmol). After heating overnight at 95°the reaction mixture is cooled to room temperature and add water (8 ml). The resulting precipitate is collected by filtration, dried in a vacuum thermostat (50° (C) and process through column chromatography with silica gel, using as eluent 5% MeOH/CH2Cl2, resulting in a product in the form of a solid light-yellow color (of 0.081 g, 55% yield). So melting = 204-208°C. Mass spectrum (M+1)=402 m/z.

Example 48

The connection 46

IP is odny material - aniline (N-[[(5S)-3-(4-amino-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide) are obtained according to the method of WO 96/23788. To phthalic dicarboxaldehyde (0,0522 g, 0,378 mmol) in acetonitrile (1 ml) was added glacial acetic acid (0.05 ml, 0.87 mmol) and then the above aniline (0,0955 g, 0,357 mmol) in acetonitrile (5 ml) dropwise. After 4 hours, add water (10 ml) and the precipitate collected on a filter, washed with water and ether, receiving the connection 46 in the form of a solid light green (0,0655 g, 48%). So melting = 211-214°C. Mass spectrum (M+1)=384 m/z.

Example 49

Connection 47

For source material - aniline (N-[[(5S)-3-(4-amino-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide) (0,095 g, 0.36 mmol) (obtained according to the method of patent WO 96/23788) in CH2Cl2(5 ml), add triethylamine (0.15 ml, 1.1 mmol) and tuloldalarol (0,056 ml to 0.39 mmol). After stirring overnight, the solid is collected on filter, washed with water (10 ml) and dried in a vacuum thermostat (50° (C)to give product as a solid off-white color (to 0.060, 42%). So melting = 240-242°C. Mass spectrum (M+1)=398 m/z.

Example 50

The connection 48

The connection 49

For source material - aniline (N-[[(5S)-3-(4-amino-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide) (0.20 g, 0.75 mmol (obtained by the method of patent WO 96/23788) in acetonitrile (5 ml) was added 2,3-pyridinedicarboxylate (0.10 g, 6.6 mmol) and glacial acetic acid (0,050 ml, 0.87 mmol). After stirring for 5 hours the reaction mixture was concentrated and treated through column chromatography with silica gel, using as eluent a 2.5% MeOH/CH2Cl2, resulting in receive two products: 0.035 g of Compound 52 (12%) as a solid yellow; and to 0.011 g of Compound 53 (4%) in a solid yellow color. The connection 48, melting point=230-232°C. Mass spectrum (M+1)=385 m/z. Compound 49: So melting=207-209°C. Mass spectrum (M+1)=385 m/z.

EXAMPLE 51

The connection 56

To compound 44 (0.1098 g, 0.306 mmol) in dimethylformamide (4 ml) at room temperature is added sodium hydride (60% in oil) (0.018 g, 0.45 mmol) and the mixture stirred for 30 min, followed by addition of MeI (23.0 μl, 0.369 mmol). The mixture of regioisomers (as shown N1NMR) is stirred for 2 hours and then poured into ice water. The resulting precipitate is collected on a filter, dried in a vacuum oven (50°C) and chromatographic on silica using as eluent 2.5% MeOH/CH2Cl2receiving target product as a white solid (0.0215 g, 19%). The melting point is 234-238°C. MS (M+1)=374 m/z.

The present invention has been disclosed in more detail with specific reference to presents viseeo specific options. The above options and examples are presented merely to illustrate the scope and essence of the present invention. Based on these options and examples specialists will be apparent and more options and examples. These other options and examples included in the consideration of the present invention. Note that, without leaving the scope of the present invention, it is possible to make various variations and modifications, therefore, the present invention is limited only by the attached claims.

1. The compound of the formula I

where R is selected from the group consisting of HE, O-heteroaryl, N3, OSO2R", NR"'R"", or

where (ii) R is unbranched or branched alkyl containing up to 5 carbon atoms, and

(iii) R"' and R"" are independently selected from the group consisting of H, -CO2-R1, -CO-R1, -CS-R1and-SO2-R4where

R1selected from the group consisting of cycloalkyl containing from 3 to 6 carbon atoms, unbranched or branched alkyl containing up to 6 carbon atoms;

R4selected from unbranched or branched alkyl containing up to 4 carbon atoms;

R4arepresents CN or NO2;

R 4bis SR4c, amino, other4cor NR4cR4d;

R4cand R4dindependently selected from H or alkyl;

X represents from 0 to 4 members independently selected from the group consisting of halogen, and

Y represents a radical of the formula II or III

where

R5, R6, R7and R8independently represent H or R5and R6and/or R7and R8together form oxoprop;

R9and R10independently represent H;

A, b, C and D are selected from C and N with the formation of phenyl ring or a 5-6 membered heteroaromatic ring, and the specified heteroaromatic ring contains from one to four members selected from the group consisting of N;

Z is selected from alkyl, heteroaryl containing N, and

m represents 0 or 1.

2. The compound according to claim 1, where Y is chosen from the group consisting of

isoindole-;

(1,3-dihydro-2H-isoindole-2-yl)-;

(1,3-Dihydro-2H-pyrrolo[3,4-C]pyridine-6-yl)-;

(5,7-dihydro-6N-pyrrolo[3,4-b]pyrazin-6-yl)-;

(5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-yl;

(5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-yl;

(4,6-dihydro-3-methyl-5H-pyrrolo[3,4-d]isoxazol-5-yl)-;

3,5-dihydro-5-methylpyrazolo[3,4-C]pyrrol-2(1H)-yl) -

(4,6-dihydro-1-methylpyrrole[3,4-d]-1,2,3-triazole-5(1H)-yl)-.

3. The compound according to claim 1 where R is-NHCOCH3or it is chosen from the group consisting of

4. The compound according to claim 1 of the formula

5. The compound according to claim 1 of the formula

6. The compound according to claim 1 of the formula

7. The compound according to claim 1 of the formula

8. The compound according to claim 1 of the formula

9. The compound according to claim 1 of the formula

10. The compound according to claim 1 of the formula

11. The compound according to claim 1 of the formula

12. The compound according to claim 1 of the formula

13. The compound according to claim 1 of the formula

14. The compound according to claim 1 is ormula

15. The compound according to claim 1 of the formula

16. The compound according to claim 1 of the formula

17. The compound according to claim 1 of the formula

18. The compound according to claim 1 of the formula

19. The compound according to claim 1 of the formula

20. The compound according to claim 1 of the formula

21. The compound according to claim 1 of the formula

22. The compound according to claim 1 of the formula

23. The compound according to claim 1 of the formula

24. The compound according to claim 1 of the formula

25. The compound according to claim 1 of the formula

26. The compound according to claim 1 of the formula

27. The compound according to claim 1 of the formula

28. The compound according to claim 1 of the formula

29. The compound according to claim 1 of the formula

30. The compound according to claim 1 of the formula

31. The compound according to claim 1 of the formula

32. The compound according to claim 1 of the formula

< num="475">

33. The compound according to claim 1 of the formula

34. The compound according to claim 1 of the formula

35. The compound according to claim 1 of the formula

36. The compound according to claim 1 of the formula

37. The compound according to claim 1 of the formula

38. The compound according to claim 1 of the formula

39. The method of treatment of a subject whose status is caused by a bacterial infection or contribution which makes the bacterial infection is caused by S.aureus and .Faecium, which includes an introduction to the specified mammal a therapeutically effective amount of a compound according to claim 1.

40. The way to prevent the suffering of the subject from a condition caused by a bacterial infection or condition, the contribution which makes the bacterial infection is caused by S.aureus and .Faecium, which includes an introduction to the subject prophylactically effective dose of a compound according to claim 1.

41. The method according to § 39 or 40, where said conditions are selected from the group consisting of acquired as a result of communication pneumonia, respiratory infections upper and lower respiratory tract infections, skin infections, soft tissue infections, bone and joint infections acquired in the hospital environment is the third lung infections.

42. The method according to § 39 or 40, where the specified bacterium selected from the group consisting of S.aureus, S.epidermldls, S.pneumoniae, these bacteria to antibiotics Snterococcus spp., Moraxella catarrhalis and H.influenzae.

43. The method according to § 39 or 40, where specified by the bacterium is a Gram-positive cocc.

44. The method according to item 43, where the specified Gram-positive cock is resistant to the drugs COCOM.

45. The compound of formula I, representing



 

Same patents:

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.

EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

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

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to 5-aminoalkylpyrazolo[4,3-d]pyrimidines of the general formula (I): wherein R1 and R2 are similar or different and represent independently of one another (C1-C8)-alkyl group; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl groups, (C1-C8)-alkoxy-, amino-, mono-(C1-C8)-alkyl-amino-, di-[(C1-C8)-alkyl]-amino-, N-morpholino- or pyridyl groups or in common with nitrogen atom to which they are bound form unsaturated heterocyclic ring that comprises optionally one or more additional atoms of nitrogen and/or oxygen and substituted with one or more hydroxyl, (C1-C8)-alkylol, (C1-C6)-oligohydroxyalkyl, amino-, mono-[(C1-C8)-alkyl]-amino- or di-[(C1-C8)-alkyl]-amino-groups. Proposed compounds inhibit activity of cGMP-phosphodiesterase and can be used in treatment of states of cardiovascular system and for treatment in potency disturbances. Also, invention relates to a medicinal preparation used for inhibition of activity of cGMP-phosphodiesterase based on indicated compounds, a method for preparing compounds of the formula (I) and a method for preparing the medicinal preparation.

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

7 cl, 15 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

EFFECT: improved preparing method, valuable properties of compounds and agents.

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

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

17 cl, 6 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

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