Pyrazolquinolines with immunomodulating activity

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the formula (I) or their pharmaceutically or veterinary-acceptable salts: where: R1 and R3 independently represent H; F; Cl; Br; C1-C6alkyl; R2 represents H or C3-C7cycloalkyl; Y represents -S- or -N(R5)-, where R5 represents H; X represents the bind; R4 represents -C(=O)NR6R7, where R6 represents H or radical of formula -(Alk)b-Q, where b is equal to 0 or 1, and Alk is not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, F, Cl, Br, oxo, COOH, bivalent C1-C12alkylen, C2-C12alkenylen with direct or ramified chain, which can be disconnected with one ore several non-adjacent -O-, -S- or -N(R8)-, where R8 represents H or C1-C4alkyl, C3-C4alkenyl or C3-C6cycloalkyl, and Q represents H; -SH; -NR8R8, where each R8 can be similar or different; the complex ether group; or not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, phenyl, benzyl, phenoxy, C3-C8cycloalkyl, amino, fluor, bromine, oxo, -COOH, -CORA, -COORA, NHRA, -NRARB, where RA and RB are independent (C1-C6)alkyl group, phenyl, C3-C7cycloalkyl, C5-C7cycloalkenyl or heterocyclilc ring containing 5 to 8 ring atoms; and R7 represents H or C1-C6alkyl; or, taken together with atom or atoms, they are bound with, R6 and R7 form not necessarily substituted with (C1-C6)alkyl, COORA, where RA is the (C1-C6)alkyl group, phenyl, not necessarily substituted with F, Cl, Br, heterocyclilc ring containing 5 to 8 ring atoms. The invention also relates to N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropirazol[4,3-c]quinoline-2-il]benzamide; to application of the compounds; to the immunomodulation method and to the pharmaceutical and veterinary composition.

EFFECT: production of novel immunobiologic compounds.

14 cl, 173 ex, 1 tbl

 

The present invention relates to new heterocyclic compounds, to processes for their preparation, to compositions containing them and to methods and application to clinical treatment of medical conditions that immunomodulation may have a beneficial effect, including rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosus and psoriasis. More specifically, the present invention relates to new heterocyclic compounds, which are the CD80 antagonists capable of inhibiting the interaction between CD80 and CD28.

The immune system has the ability to regulate the homeostasis between activation and inactivation of lymphocytes through different regulatory mechanisms during and after the immune response. Among them there are mechanisms that specifically inhibit and/or switch off the immune response. So, when the antigen presented by MHC molecules (the main complex tissue compatibility) receptors of T cells, T-cells become properly activated only in the presence of additional jointly stimulating signals. In the absence of additional signals no activation of lymphocytes and induced or state of functional inactivation which is called anergy or tolerance, or T-cell specific d is supplied by apoptosis. One such co-stimulatory signal includes the interaction of CD80 on specialized, representing the antigen cells with CD28 on T-cells, which, as demonstrated, is essential for full activation of T cells (Lenschow et al. (1996) Annu. Rev. Immunol., 14, 233-258).

In article Erbe et al., in J. Biol. Chem. Vol.277, No. 9, pp.7363-7368 (2002) describes 3 small molecular ligand that bind to CD80 and inhibit the binding of CD80 to CD28 and CTLA4. Two of these ligands are condensed pyrazolones structures a and b:

In accordance with the present invention provides a compound of formula (I) or its pharmaceutically or veterinary acceptable salt:

where:

R1and R3independently represent H; F; Cl; Br; -NO2; -CN; C1-C6alkyl, optionally substituted by F or Cl; or (C1-C6alkoxy, optionally substituted by F;

R2represents H or optionally substituted C1-C6alkyl, C3-C7cycloalkyl or optionally substituted phenyl;

Y represents-O-, -S-, N-oxide or-N(R5)-, where R5represents N or C1-C6alkyl;

X represents a bond or a divalent radical With1-C6alkylen;

R4represents-C(=O)NR6R7, -NR7C(=O)R6 , -NR7C(=O)OR6, -NHC(=O)other6or-NHC(=S)other6where

R6represents H or a radical of the formula -(Alk)b-Q, where b is 0 or 1, and

Alk represents an optionally substituted divalent C1-C12alkilinity,2-C12alkenylamine or2-With12alkynylaryl radical with a straight or branched chain which may be interrupted by one or more non-adjacent-O-, -S - or-N(R8)-, where R8represents N or C1-C4alkyl, C3-With4alkenyl,3-C4quinil or3-C6cycloalkyl, and

Q represents H; -CF3; -OH; -SH; -NR8R8where each R8may be the same or different; ester group; or optionally substituted phenyl,3-C7cycloalkyl,5-C7cycloalkenyl or heterocyclic ring having from 5 to 8 ring atoms; and

R7represents N or C1-C6alkyl; or taken together with the atom or atoms to which they are attached, R6and R7form an optionally substituted heterocyclic ring having from 5 to 8 ring atoms.

Compounds of General formula (I) are antagonists CD80. They inhibit the interaction between CD80 and CD28 and, thus, the activation of the T cells, modulating through this immune response.

With therefore, its, the invention also includes:

(i) a compound of formula (I) or its pharmaceutically or veterinary acceptable salt for the treatment of conditions in which immunomodulation has a beneficial effect;

(ii) the use of the compounds of formula (I) or its pharmaceutically or veterinary acceptable salts for the manufacture of a medicinal product for the treatment of conditions in which immunomodulation has a beneficial effect;

(iii) a method of immunomodulation in humans and primates besides humans, including the introduction in need of such treatment the subject immunomodulatory effective dose of the compounds of formula (I) or its pharmaceutically or veterinary acceptable salt;

(iv) a pharmaceutical or veterinary composition comprising a compound of formula (I) or its pharmaceutically or veterinary acceptable salt together with a pharmaceutically or veterinary acceptable excipient or the media.

The conditions under which the immunomodulation has a beneficial effect include:

Adrenal insufficiency

Allergic anghit and granulomatous

Amyloidosis

Ankylosing spondylitis

Asthma

Autoimmune Addison disease

Autoimmune alopecia

Autoimmune chronic active hepatitis

Autoimmune hemolytic anemia

Autoimmune neutropenia

AU is ommanney thrombocytopenic purple

Autoimmune vasculitis

Behcet's disease

Cerebellar degeneration

Chronic active hepatitis

Chronic inflammatory demyelinated polyradiculoneuropathy

Herpetiformis dermatitis

Diabetes mellitus

Myasthenic syndrome of Eaton-Lambert

Encephalomyelitis

Bubble a bullosa

Nodular erythema

Sensitive to gluten enteropathy

Cider Goodpasture

The disease is graft versus host"

Syndrome Jullena-Barre

Thyroiditis Hashimoto

Hyperthyroidism

Idiopathic hemochromatosis

Idiopathic membranous glomerulonephritis

Renal disease with minimal changes

Mixed disorder of connective tissue

Multifocal motor neuropathy

Multiple sclerosis

Generalized myasthenia

Syndrome opsoclonus-myoclonus

Pseudopuberty

The bladderwort

Pernicious anemia

Polyarteritis polyarteritis

Polymyositis/dermatomyositis

Post-infectious arthritis

Primary bile duct sclerosis

Psoriasis

Reactive arthritis

Disease Reuter

Retinopathy

Rheumatoid arthritis

Sclerosing cholangitis

Sjogren syndrome

Cider "rigid person"

Subacute thyroiditis

Systemic lupus erythematosus

Systemic sclerosis (scle is termio)

Temporal Takayasu

Obliterating thromboangiitis

Graft rejection

Autoimmune polyglandular syndrome type I and type II

Ulcerative colitis

Uveitis

Granulomatous's granulomatosis

Used in the present description, the term "alkylene" refers to a straight or branched alkyl chain having two free valencies, for example-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(-CH2CH3)CH2CH2CH3and-C(CH3)3.

Used in the present description, the term "heteroaryl" refers to 5 - or 6-membered aromatic ring containing one or more heteroatoms. Such groups are, for example, thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.

Used in the present description the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl", as defined above, and, in particular, means 5-8-membered aromatic or nonaromatic heterocyclic ring containing one or more heteroatoms selected from S, N and O, including, for example, pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, Tyagi who was Salil, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinil, indolyl, morpholinyl, benzofuranyl, pyranyl, isoxazolyl, hinokitiol, azabicyclo[3.2.1]octenyl, benzimidazolyl, methylenedioxyphenyl, maleimido and succinimide.

In the absence of other definitions in the context where it occurs, the term "substituted"relating to any specified in this part, means substituted by one or more of the following substituents, namely, (C1-C6)alkyl, trifluoromethyl, (C1-C6)alkoxy (including the special case when the ring is replaced by the atom With the adjacent ring methylendioxy or Ethylenedioxy), triptoreline, (C1-C6)alkylthio, phenyl, benzyl, phenoxy, (C3-C8)cycloalkyl, hydroxy, mercapto, amino, fluorine, bromine, cyano, nitro, oxo, -COOH, -SO2OH, -CONH2, -SO2NH2, -CORA, -COORA, -SO2ORA, -NHCORA, -NHSO2RA, -CONHRA, -SO2OtherA-The otherA, -NRARB, -CONRARBor-SO2NRARBwhere RAandRBare independently (C1-C6)alkyl group. When "substituted" means substituted (C3-C8)cycloalkyl, phenyl, benzyl or phenoxy, his ring itself may be substituted by any one pointed to by the x above groups, except for (C3-C8)cycloalkyl, phenyl, benzyl or phenoxy.

Used in the present description the unqualified term "carbocycle" or "carbocyclic" refers to a 5-8-membered ring all ring atoms of which are carbon.

Some compounds of the invention contain one or more chiral centers due to the presence of asymmetric carbon atoms. The presence of asymmetric carbon atoms causes stereoisomers or diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such stereoisomers and diastereoisomers and mixtures thereof.

Salts of salt-forming compounds of the invention include physiologically acceptable acid additive salts, such as hydrochloride, hydrobromide, sulphates, methansulfonate, paratoluenesulfonyl, phosphates, acetates, citrates, succinate, lactates, tartratami, fumarate and maleate; and basic additive salts, for example salts of sodium, potassium, magnesium and calcium. When the compound contains an amino group, it is also possible salts of Quaternary amino, and they are included in the invention.

Compounds of the invention are the following examples of structural options:

R1can represent, for example, H, F, Cl, methyl, methoxy or methylenedioxy. In this case, preferably, R1 was a H, Cl, or, especially, F;

R2can represent, for example, H, methyl, methoxy, cyclopropyl, phenyl or fluorine-, chlorine-, methyl-or methoxy-substituted phenyl. In this case, the preferred N or cyclopropyl;

R3can represent, for example, H, F, Cl, methyl, methoxy or methylenedioxy. In this case, preferably, R3was a F or Cl, and most preferably, R3was a N;

Y may represent, for example, -O-, -S - or-N(R5)-, where R5represents H or methyl. In this case the preferred-NH - or-S-;

X may represent, for example, a bond or a radical-CH2- or-CH2CH2-. In this case, the preferred communication;

R4represents-C(=O)NR6R7, -NR7C(=O)R6, -NR7C(=O)OR6, -NHC(=O)other6or-NHC(=S)other6. Of them in this case preferred-NR7C(=O)R6and, especially, -C(=O)NR6R7and-NHC(=O)other6. R7represents preferably N, however, a wide range of substituents R6caused the emergence of a highly active compounds of the invention. Many illustrative substituents R6shown in the connection examples below;

R6can represent, for example, H or a radical of formula-Alkb-Q, where b is 0 Il is 1, and

Alk can represent, for example, the radical -(CH2)n-, -CH((CH2)mCH3)(CH2)n-, -C(CH2)mCH3)((CH2)pCH3)(CH2)n-, -(CH2)n-O-(CH2)m-, -(CH2)n-NH-(CH2)m- or -(CH2)n-NH-(CH2)m-NH-(CH2)pwhere n is 1, 2, 3 or 4, and m and p independently are 0, 1, 2, 3 or 4, and

Q can represent H, -OH, -of SOON3, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl or oxazolyl; and

R7can represent, for example, H, or taken together with the atom or atoms to which they are connected, R6and R7may form a 5, 6 or 7-membered heterocyclic ring.

Specific examples of the groups R4include groups present in the compounds described in the examples of the present description.

Compounds of the invention can be obtained by synthetic methods known in the literature, compounds which are commercially available or can be obtained from commercially available compounds. For example, the compounds of formula (I), where R4is a group-NR7C(=O)R6can be obtained by acylation of amine of the formula (II) with the acid chloride of the acid of formula (III):

Compounds of the invention where R4predstavljaet a group-NHC(=O)other 6you can get by the interaction of the amine of formula (IIA) with an isocyanate of the formula (IIIA)

Compounds of the invention where R4represents a group-C(=O)other6you can get the interaction of the carboxylic acid of the formula (IIB) with an amine other6R7:

Compounds of the invention where R4is a group-NR7C(=O)OR6you can get by the interaction of the amine of formula (II) with CHLOROFORMATES ClC(=O)OR6.

The following examples illustrate the formation of compounds of the invention.

The production of intermediate compounds 1

2-(4-nitrophenyl)-6-fluoro-2,5-dihydropyrazolo[4,3-c]quinoline-3-one

4-nitrophenylhydrazine (2.28 g, 0.14 mol) is added in one portion to a stirred solution of ethyl ether 4-chloro-8-ftorhinolon-3-carboxylic acid (3.58 g, 0.014 mol) in anhydrous n-butyl alcohol (50 ml) at room temperature. The mixture is refluxed for 16 h under nitrogen atmosphere, cooled to room temperature and then filtered to leave an orange solid. The solid is purified by washing successively with ethyl acetate (20 ml) and heptane (20 ml) and then finally dried in vacuum conditions with obtaining pyrazolone (3,93 g, 87%) as a dark orange solid is the first substance, liquid chromatography, mass spectrometry (IHMS) m/z 325,24 [M+H]+when RT1,47 minutes

Obtaining the intermediate 2

2-(4-AMINOPHENYL)-6-fluoro-2,5-dihydropyrazolo[4,3-c]quinoline-3-one

The dihydrochloride of tin (II) (12.5 g, by 0.055 mol) is added in one portion to a stirred solution of 2-(4-nitrophenyl)-6-fluoro-2,5-dihydropyrazolo[4,3-c]quinoline-3-one (intermediate compound 1) (3,59 g to 0.011 mol) in ethanol (110 ml) at room temperature. The mixture was then heated to 80°C for 8 h, cooled to room temperature and filtered to obtain yellow solid. The solid is suspended in a two-phase solution of ethyl acetate (1 l), saturated solution of Rochelle salt (500 ml) and saturated sodium bicarbonate solution (500 ml) and stirred at room temperature for 2 hours the Mixture was filtered and the remaining solid is washed with water and dried in vacuum to obtain specified in the connection header (3,39 g, 99%) as a bright yellow solid, IHMS m/z 295,30 [M+H]+when RT0,84 minutes

Example 1

N-[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]-2-methylbutyrate

(±)-2-Methylbutyrate (to 13.6 μl, 0.11 mmol) is added dropwise during 30 seconds to mix the solution of 2-(4-AMINOPHENYL)-6-fluoro-2,5-Digi reperusal[4,3-c]quinoline-3-one (intermediate compound 2) (30 mg, 0.10 mmol), triethylamine (14 μl, 0.11 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) in dichloromethane (1 ml) at room temperature. The mixture is stirred at room temperature for 16 hours Then the yellow solid is filtered off, purified by washing successively with a saturated solution of sodium bicarbonate (1 ml), ethyl acetate (1 ml) and ethanol (0.5 ml) and finally dried in vacuum conditions with obtaining specified in the title compound (10 mg, 26%) as a bright yellow solid. IHMS m/z 379,36 [M+H]+when RT1,18 minutes δN(400 MHz, (CD3)2SO) of 9.89 (1H, s), charged 8.52 (1H, s), 8,15 (2H, d,J=9.0 Hz), 8,01 (1H, d,J=1,0Hz), 7,69 (2H, dJ=9.0 Hz), EUR 7.57-7,46 (2H, m), 2,46-2,39 (1H, m), 1,69-of 1.36 (2H, m), is 1.11 (3H, d,J=6,8 Hz)of 0.91 (3H, t,J=7,3 Hz).

Specified in the header of the connection and the connection of the following examples were tested in the following analysis in the section "Tests" to determine their activity as inhibitors of the interaction of CD80-CD28. Specified in the header of this compound had an assessment activity ***.

Examples 2-49

The following compounds were synthesized as described in example 1, replacing (±)-2-methylbutyrate the corresponding acid chloride acid.

Example 2

[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]amide 2-methylpentanoic acid

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δH(400 MHz, (CD3)2SO) 9,92 (1H, s), 8,53 (1H, s)to 8.12 (2H, d,J=9,2 Hz), with 8.05 (1H, d,J=a 7.6 Hz), of 7.70 (2H, d,J=9,2Hz), 7,63-7,53 (2H, m), 1,68 is 1.58 (1H, m), 1,38 of 1.28 (3H, m), is 1.11 (3H, d,J=6,6 Hz)of 0.91 (3H, t,J=7,1 Hz).

Activity ***

Example 3

[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]amide 1-methyl-1H-pyrrole-2-carboxylic acid

δH(400 MHz, (CD3)2SO) 9,76 (1H, s), and 8.50 (1H, s), compared to 8.26 (2H, d, 9.0 Hz), 7,97-7,94 (1H, m), 7,73 (2H, dJ=9.0 Hz), 7,39-7,28 (2H, m), 7,07-7,01 (2H, m), 3,91 (3H, s).

Activity *

Example 4

N-[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]-3-methylbutyrate

δH(400 MHz, (CD3)2SO) 9,92 (1H, s), charged 8.52 (1H, s)to 8.14 (2H, d, J=9,2 Hz), 8,01 (1H, d,J=the 7.3 Hz), to 7.67 (2H, d,J=9,2 Hz), EUR 7.57-7,47 (2H, m), of 2.21 (2H, d,J=the 6.8 Hz), 12,14-2,07 (1H, m)to 0.96 (6H, d,J=6,6 Hz).

Activity **

Example 5

[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]amide 2-propylpentanoic acid

δH(400 MHz, (CD3)2SO) to 9.93 (1H, s), 8,53 (1H, s), 8,11 (2H, d,J=9.0 Hz), with 8.05 (1H, d,J=7,8 Hz), of 7.70 (2H, d,J=9.0 Hz), to 7.59-7,46 (2H, m), 2,46 to 2.35 (1H, m), 1,63-of 1.27 (4H, m)of 0.90 (6H, t,J=7,1 Hz).

Activity *

Example 6

Methyl ester 5-[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenylcarbamoyl]pentanol acid

δH(400 MHz, (CD3)2SO) 9,85 (1H, s), of 8.47 (1H, s), of 8.25 (2H, d,J=9.0 Hz), to $ 7.91-of 7.90 (1H, m), to 7.59 (2H, d,J=9.0 Hz), 7,29-7,20 (2H, m), 3,61 (3H, s), 2,38-of 2.28 (4H, m), 1,64 of 1.50 (4H, m).

Activity ***

Example 7

N-[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]-2,2-dimethylpropanamide

δH(400 MHz, (CD3)2SO) 9,26 (1H, s), charged 8.52 (1H, s), 8,15 (2H, d,J=9,2 Hz), 8,03 (1H, d,J=8,8 Hz), 7,71 (2H, d, J=9,2 Hz), 7,56-7,47 (2H, m)of 1.26 (9H, s).

Activity **

Connection examples 8-28 also obtained by the method of example 1 using the appropriate carboxylic acid:

The production of intermediate compound 3

4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoic acid

3-hydrazinophenyl acid (1,91 g of 0.013 mol) is added in one portion to the stirred solution of the ethyl ester of 4-chloro-8-ftorhinolon-3-carboxylic acid (2,93 g to 0.011 mol) in n-butanol (60 ml) at room temperature. The solution is refluxed for 16 h, cooled to room temperature and the resulting yellow solid is filtered off, washed with tert-butylmethylamine ether and then dried. Solids is re-dissolved in a solution of tetrahydrofuran:water (2:1; 21 ml) and add lithium hydroxide (1.27 g, 0,031 mol). After stirring at room temperature for 16 h, concentrated hydrochloric acid (3 ml) is added dropwise to the mixture with the precipitation of a yellow solid, which was filtered and dried in vacuum to obtain specified in the title compound (intermediate compound 3) (2,32 g, 63%) as a bright yellow solid.

Obtain intermediate compound 4

3-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride

Oxalicacid (20 ml, 0.2 mol) is added dropwise over 2 min to a stirred solution of 3-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoic acid (intermediate compound 3) (2.0 g, 6.1 mmol) in dichloromethane (10 ml) at room temperature. Then add N,N-dimethylformamide (50 ml) and the resulting mixture was heated to 50°C for 1 h Then the solution is cooled to room temperature and concentrated in vacuo to obtain specified in the title compound (intermediate compound 4) (2.0 g, 96%) as a beige solid.

Example 50

3-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)-N-(3-methoxypropyl)benzamide

3-methoxypropylamine (0,026 g, 0.29 mmol) is added to a stirred solution of 3-(6-f the PR-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride (intermediate compound 4) (26 mg, 0.29 mmol) in tetrahydrofuran (2 ml) and the mixture is stirred at room temperature for 15 minutes Then add triethylamine (0.2 ml, 1.4 mmol) and the resulting mixture is stirred over night. 1M hydrochloric acid (3-4 ml) is added dropwise with precipitation of a yellow solid, which was filtered and dried in vacuum conditions with obtaining amide (79 mg, 0.20 mmol) as a yellow solid. IHMS m/z 395,25 [M+H]+when RTthe 1.04 min; δH(400 MHz, (CD3)2SO) 8,59 (1H, m), to 8.57 (1H, s), 8,39 (1H, appr d,J=and 9.3 Hz), 8,08 (1H, appr d, J=7,3 Hz), 7,66-7,53 (5H, m), 3,37-to 3.33 (4H, m), with 3.27 (3H, s)and 1.83-1.77 in (2H, m).

Activity **

Example 51

N-ethyl-3-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzamid

Receive by way of example 50, substituting 3-methoxypropylamine ethylamine.

δH(400 MHz, (CD3)2SO main quoted rotamer; 8,56 (1H, users), of 8.47 (1H, m), 8,21 (2H, d,J=8.5 Hz), 7,94 (2H, d, J=8.5 Hz), of 3.96 (3H, s), and 3.31 (2H, q,J=the 7.3 Hz), 2,58 (3H, s)and 1.15 (3H, t,J=7,4 Hz).

Activity **

Example 52

N-benzyl-3-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzamid

Receive by way of example 50, substituting 3-methoxypropylamine benzylamino.

IHMS m/z 427,16 [M+H]+when RT1,28 minutes

Activity *

Connection examples 53-64 by poluchilosb of example 50, using the appropriate amine.

Example 65

N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl]benzamide

Stage 1

Ethyl ester of 2-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

A solution of methyl ester 3-cyclopropyl-3-oxopropionate acid (6.2 g, of 0.038 mol), 2-ethyl ester 2-aminobutanoic acid (4,95 g, 0.03 mol) and paratoluenesulfonyl acid (0.04 g, 0.2 mol) in toluene (25 ml) is heated at 125°C for 2 h; then 15 ml of solvent is distilled off. To the residual orange solution add ethoxide sodium (2M, 15 ml) in ethanol (reaction mixture turns red). The red mixture was stirred at 120°C for 2 h; 15 ml of the solvent is again distilled off. The reaction mixture is left to cool to room temperature, diluted with ethyl acetate (1 l), extracted with HCl 0.1 m and water. The combined organic extract is dried over sodium sulfate and concentrated in vacuo to obtain an orange residue, which once washed with cold ethyl acetate to obtain ethyl ester 2-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (a 3.87 g, 53%) as not quite white solid. IHMS m/z 244,14 [M+H]+when RT0,78 min, 89%, m/z 230,11 [Acid+H]+when RT/sub> 1,27 min, 11%.

δH(400 MHz, (CD3)2SO) 11,04 (1H, s), of 8.06 (1H, DD,J1=1,1,J2=8,1), 7,76-7,66 (2H, m), of 7.36 (1H, TD,J1=1,1,J2=7,5), the 3.89 (3H, s)of 2.16 (1H, m)of 1.18 (4H, d,J=7,0).

Stage 2

Ethyl ester of 4-chloro-2-cyclopropylamino-3-carboxylic acid

The phosphorus oxychloride (of 0.77 ml, 0,082 mol) is added in one portion to a suspension of ethyl ether 2-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.0 g, 0,041 mol) in acetonitrile and the mixture is heated at 75°C for 90 min (solution becomes transparent at a temperature above 65°). The obtained light brown solution was poured into saturated sodium bicarbonate (100 ml); the suspension is extracted with ethyl acetate, the combined organic extract is dried and concentrated in vacuo to obtain ethyl ester 4-chloro-2-cyclopropylamino-3-carboxylic acid (1,15 g, 106%) as not quite white solid. Rf(AcOEt)=0,73.

Stage 3

4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoic acid

Ethyl ester of 4-chloro-2-cyclopropylamino-3-carboxylic acid (1,15 g, 0,0041 mol) and 4-hydrazinobenzene acid (1.0 g, 0,0068 mol) is stirred in ethanol (30 ml) by boiling under reflux for 16 h Light yellow suspension rasb the keys heptane, filtered, washed with cold tert-butylmethylamine ether and left to dry in the conditions of vacuum to obtain the crude solids containing hydrazine. The solid is suspended in 1M HCl, filtered, washed with water and then dried in vacuum to obtain 4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoic acid (1,135 g, 80%) as a yellow solid. IHMS m/z 346,20 [M+H]+when RT1,05 min: purity 96%.

δH(400 MHz, (CD3)2SO) to 11.4 (1H, s), 8,43 (2H, d,J=8,1), 8,21 (1H, DD,J=1,2,J=8,1), 8,07 (2H, d,J=8,1), 7,92 (1H, d,J=8,1), to 7.67 (1H, t,J=6,6), 7,52 (1H, t,J=6,5), of 3.43 (1H, m)to 1.59 (2H, m), USD 1.43 (2H, m).

Stage 4

4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride

To a suspension of finely powdered 4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoic acid (0,19 g, 0.55 mmol) in dichloromethane (4 ml) add oxalicacid (1.6 ml, 0.01 mol) followed by addition of drops of dimethylformamide. The mixture is stirred in nitrogen atmosphere at 45°C for 8 hours, the Solvent is then removed in vacuum to obtain 4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride as a pale yellow solid. IHMS m/z 346,20 [M+MeOH-Cl]+when RT1,46 min: purity 95%. Used without further purification.

<> Stage 5

N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzamid

To incomplete solution of 4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride (0.1 g, 0.28 mmol) in tetrahydrofuran (6 ml) under nitrogen atmosphere add a solution of 3-dimethylaminopropylamine (0.03 g, 0.3 mmol) in tetrahydrofuran (3 ml). The mixture is stirred at room temperature for 3 hours the Solvent is removed under reduced pressure, a yellow solid is washed with a small amount of saturated sodium bicarbonate, water and dried in vacuum to obtain N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzamide (57 mg, 47%) as a yellow solid. IHMS m/z 430,11 [M+H]+when RT0,99 min: purity 100%.

Activity ***

Obtaining an intermediate compound 5

4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride

To a suspension of finely powdered 4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoic acid (1.1 g, 3.4 mmol) in dichloromethane (6 ml) add oxalicacid (2.4 ml, 29 mmol) followed by addition of drops of dimethylformamide. The mixture is stirred in nitrogen atmosphere at 45°C for 3 hours the Solvent is removed in vacuum to obtain 4-(6-fluoro--oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride (1,15 g, quantitative) as a pale yellow solid which is used without further purification.

Example 66

The hydrochloride of N-(3-dimethylaminopropyl)-4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzamide

To incomplete solution of 4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzoyl chloride (0.1 g, 0.3 mmol) in tetrahydrofuran (5 ml) under nitrogen atmosphere add a solution of 3-dimethylaminopropylamine (0.03 g, 0.3 mmol) in tetrahydrofuran. The mixture is stirred at room temperature for 90 minutes the Solvent is removed under reduced pressure and the yellow solid is purified liquid chromatography on silica gel (gradient elution, MeOH:H2O, Fluka inverted phase With18) to obtain the hydrochloride of N-(3-dimethylaminopropyl)-4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)benzamide (70 mg, 53%) as a yellow solid.

IHMS m/z 408,39 [M+H]+when RT0,89 min: purity 90%.

Activity ***

Connection examples 67-141 get a similar manner from the corresponding benzoyl chloride and the appropriate amine

The use of the 142

Ethyl ester {3-[4-(6-fluoro-3-oxo-3,5-dihydropyrazolo[4,3-c]quinoline-2-yl)phenyl]ureido}acetic acid

Ethylcyanoacrylate (31 mg, 0.24 mmol) is added in one portion to a stirred solution of 2-(4-AMINOPHENYL)-6-fluoro-2,5-dihydropyrazolo[4,3-c]quinoline-3-one (intermediate compound 2) (50 mg, 0,17 mmol) in N-dimethylformamide (2 ml) and the mixture is stirred at room temperature for 16 hours Then added to the mixture water (1 ml) to precipitate a solid substance is filtered off, washed with water (1 ml) and then ethyl acetate (1 ml) and finally, dried in vacuum conditions with obtaining urea as a yellow solid. IHMS m/z 424,40 [M+H]+when RT1,06 minutes

Activity ***

Examples 143 and 144

Example 143Example 144
IHMS m/z 438,41 [M+H]+< / br>
when RT1,13 min

Activity **
IHMS m/z 514,46 [M+H]+< / br>
when RT1,35 min

Activity *

The following compounds are synthesized by the method of example 142, replacing ethylcinnamate corresponding isocyanate, isothiocyanato or chloroformiate.

The intermediate compound 6: Getting ethyl-4-axochiapan-3-carboxylate

Dry tetrahydrofuran (60 ml) cooled in a nitrogen atmosphere up to 50-60°C. Add a 1M solution of bis(trimethylsilyl)amide lithium in hexane (56 ml, 56 mmol). The temperature of the support at (-50)-(-60)°and add thiochroman-4-one is added dropwise within 20 minutes Stirring is continued at a low temperature for 60 min Medicinepharmacy (4,84 ml, 60,9 mmol) is added dropwise within 5 min to the reaction mixture. The resulting suspension is stirred at (-50)-(-60)°C for 80 min and then allow to warm to room temperature. Add a saturated solution of ammonium chloride (100 ml). The phases are separated, the aqueous phase is extracted with ethyl acetate (2×100 ml). The combined organic phases are washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Get orange oil and purified column chromatography. Specified in the title compound is isolated in the form of a yellow solid (4,70 g, 21.1 mmol, 42%). JHMS: m/z 221 [M-H]*.

Intermediate compound 7: Obtain 4-(3-oxo-3A,4-dihydro-3H-thiochroman[4,3-c]pyrazole-2-yl)benzoic acid

4-axochiapan-3-carboxylate (0.50 g, 2.25 mmol) and hereinbelow acid (0,377 g, 2.48 mmol) was stirred in acetic acid (6 ml). The mixture is refluxed for 30 m is N. Excess acetic acid is distilled off to obtain a brown oil. Add diethyl ether, a precipitate, which is filtered off and dried in vacuum. The crude product is isolated in the form of a red-brown solid (797 mg). JHMS: m/z 325 [M+H]+.Cleaning is not performed.

Intermediate compound 8: Obtain 4-(3-occational[4,3-c]pyrazole-2(3H)-yl)benzoic acid

The crude 4-(3-oxo-3A,4-dihydro-3H-thiochroman[4,3-c]pyrazole-2-2-yl)benzoic acid (250 mg, 0.77 mmol) dissolved in dimethyl sulfoxide (6 ml). Add On-chloranil (189 mg, 0.77 mmol) and the mixture is stirred at room temperature overnight. Add water (20 ml) and the solids filtered and washed with water. The filter cake triturated in toluene, filtered and dried in vacuum. Specified in the title compound is isolated in the form of a dark brown solid (230 mg, 0.71 mmol, 92%). JHMS: m/z 323 [M+H]+.

Alternatively, the crude 4-(oxo-3A,4-dihydro-3H-thiochroman[4,3-c]pyrazole-2-yl)benzoic acid can be mixed in dimethyl sulfoxide in contact with air. It was found that the air oxidation provides a clean product, however, the reaction proceeds much more slowly.

Example 165

Obtaining N-[3-(dimethylamino)propyl]-4-(3-occational[4,3-c]pyrazole-2(3H)-yl)benzo is the Ministry of foreign Affairs

4-(3-occational[4,3-c]pyrazole-2(3H)-yl)benzoic acid (55 mg, 0,17 mmol) suspended in anhydrous dimethylacetamide (1 ml). Add diisopropylethylamine (46,5 mg, 0.36 mmol, 62 μl) followed by addition of 3-dimethylaminopropylamine (17.5 mg, 0,17 mmol) and hexaphosphate [(benzotriazol-1 yloxy)dimethylaminomethylene]dimethylammonio (65 mg, 0,17 mmol). The mixture is stirred at room temperature for 4 h and purified preparative IHMS. Specified in the title compound is isolated in the form of a brown solid. JHMS: m/z 407 [M+H]+.

Activity **

Example 166

Obtaining N-[(cyclohexylamino)propyl]-4-(3-occational[4,3-c]pyrazole-2(3H)-yl)benzamide

The reaction is performed as described above. JHMS: m/z 461 [M+H]+.

Activity ***

Example 167

Obtaining N-(pyrrolidin-1-libutil)-4-(3-occational[4,3-c]pyrazole-2(3H)-yl)benzamide

The reaction is performed as described above. JHMS: m/z 447 [M+H]+.

Activity *

Example 168

Getting 4-(3-occational[4,3-c]pyrazole-2(3H)-yl)-N-1,2,2,6,6-pentamethylpiperidin-4-ilasamaja

The reaction is performed as described above. JHMS: m/z 475 [M+H]+.

Activity **

Intermediate compound 9: Obtain 3-(2-forfinal)sulfanyl]propanoic acid

2-portifino (5.0 g, 39 mmol) is dissolved in tetrahydrofuran (50 ml) under nitrogen atmosphere. Add triethylamine (3.94 g, 5,33 ml, to 85.8 mmol). Acrylic acid (2,81 g, to 2.67 ml, 39 mmol) is dissolved in tetrahydrofuran and added dropwise to the reaction solution for 2 h at room temperature. The mixture is stirred at room temperature overnight. Added 1M hydrochloric acid (50 ml) and separated phases. The aqueous phase is washed with ethyl acetate (2×50 ml). The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. Receives a yellow oil, which solidifies upon standing at room temperature. The solid is triturated in hexane, filtered and dried in vacuum. Specified in the title compound is isolated in the form of not-quite-white solid (4,19 g of 20.9 mmol, 54%).

The intermediate connection 10: Getting 8-fluoro-2,3-dihydro-4H-trichrome-4-it

3-[(2-forfinal)sulfanyl]propanoic acid (4.0 g, 20 mmol) is mixed with concentrated sulfuric acid (20 ml) at 0-5°C. the Reaction solution was stirred at 0-5°C for 3 h, then allow to warm to room temperature over night. The mixture is cooled rapidly making dropwise into ice to obtain a white suspension. Water the second phase is extracted with ethyl acetate (1× 200 ml, 1×100 ml). The combined organic phases are washed with saturated sodium bicarbonate solution (1×50 ml), water (1×50 ml), 1M hydrochloric acid (50 ml) and water (2×50 ml). The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. Specified in the title compound is isolated in the form of a yellow solid (2.10 g, 11.5 mmol, 58%).

The intermediate connection 11: Obtain methyl 8-fluoro-4-axochiapan-3-carboxylate

1M solution hexamethyldisilazide lithium in hexane (13,2 ml) dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere. The solution is cooled to -78°C. 8-Fluoro-2,3-dihydro-4H-thiochroman-4-one (2.00 g, 11 mmol) dissolved in tetrahydrofuran (40 ml), the solution is transferred into an addition funnel and added dropwise within 30 min to the reaction mixture, keeping the temperature below -60°C. Receive orange transparent solution, which is stirred at a temperature of from -78°C to -65°C for 2 hours Medicinepharmacy (0.935 g, of 0.87 ml) dissolved in tetrahydrofuran (2 ml) and added dropwise to the reaction solution. Stirring is continued at low temperature for 1 h, then the mixture allow to warm to room temperature. Add a saturated solution of ammonium chloride (20 ml) and water (10 ml), the phases are mixed for 5min and share. The aqueous phase is washed with ethyl acetate (2×100 ml) and the combined organic phases are dried over magnesium sulfate. The mixture is filtered and the solvent is removed in vacuum to obtain an orange oil. The crude oil is purified column chromatography; mobile phase: hexane, gradient mixture hexane/ethyl acetate [90:10]. Specified in the title compound is isolated in the form of a yellow solid (1.19 g, of 4.95 mmol, 45%).

The intermediate connection 12: Obtain 4-(6-fluoro-3-Katihar[4,3-c]pyrazole-2(3H)-yl)benzoic acid

Methyl-8-fluoro-4-axochiapan-3-carboxylate (1.19 g, of 4.95 mmol) and 4-hydrazinophenyl acid (755 mg, of 4.95 mmol) is mixed with glacial acetic acid (10 ml). The mixture is refluxed for 4 hours the Excess acetic acid is removed in vacuo to obtain an orange oil. Add ethyl acetate (10 ml) and the mixture is treated with ultrasound. See the precipitation of an orange solid. Solids filtered and washed with ethyl acetate. The filter cake is taken in dimethyl sulfoxide (10 ml) and oxidized with air at room temperature for 1 week. To the reaction mixture are added water (20 ml), the solids filtered off, suspended in ethyl acetate, filtered and dried in vacuum. Specified in the title compound is isolated in the form of Oran is avago powder (175 mg, 0.51 mmol, 10%). JHMS: m/z 341.

Example 169

Obtaining N-[3-(dimethylamino)propyl]-4-(6-fluoro-3-occational[4,3-c]pyrazole-2(3H)-yl)benzamide

4-(6-fluoro-3-occational[4,3-c]pyrazole-2(3H)-yl)benzoic acid (41 mg, 0.12 mmol) dissolved in anhydrous dimethylacetamide (1 ml). Add diisopropylethylamine (46 mg, 0.36 mmol, 62 μl) followed by the addition of hexaphosphate [(benzotriazol-1 yloxy)dimethylaminomethylene]dimethylammonio (65 mg, 0,17 mmol) and 3-dimethylaminopropylamine (12 mg, 0.12 mmol). The mixture is stirred at room temperature overnight and purified preparative HPLC. Specified in the title compound is isolated in the form of a brown solid. JHMS: m/z 425 [M+H]+.

Activity **

Example 170

Obtaining N-[(cyclohexylamino)propyl]-4-(6-fluoro-3-occational[4,3-c]pyrazole-2(3H)-yl)benzamide

The reaction is performed as described above. JHMS: m/z 479 [M+H]+.

Activity **

Example 171

Obtaining N-(pyrrolidin-1-libutil)-4-(6-fluoro-3-occational[4,3-c]pyrazole-2(3H)-yl)benzamide

The reaction is performed as described above. JHMS: m/z 465 [M+H]+.

Activity ***

Example 173

Getting 4-(6-fluoro-3-occational[4,3-c]pyrazole-2(3H)-yl)-N-1,2,2,6,6-pentamethylpiperidin-4-ilasamaja

The reaction is performed as described above. JHMS: m/z 493 [M+H]+.

Activity ***

Analytical section

Compounds of the above examples were tested in a cell-free analysis of homogeneous resolved in time fluorescence (HTRF) to determine their activity as inhibitors of the interaction of CD80-CD28.

In the analysis of europium and allophycocyanin (ARS) indirectly (through linkers antibodies) bind to CD28 and CD80 with the formation of a complex that enters the europium and ARS in close proximity to generate the signal. The complex includes the following 6 protein: fluorescent label 1, the linker antibody 1, protein CD28, protein CD80, linker 2 antibody and fluorescent label 2. In the table below are described in more detail these reagents.

Fluorescent label 1Anti-rabbit IgG labeled with europium (1 µg/ml)
Linker antibody 1Rabbit IgG specific for murine Fc fragment (3 µg/ml)
Protein CD28CD28-protein murine Fc fragment (of 0.48 µg/ml)
Protein CD80CD80-protein mouse Fab fragment (C215) (1.9 µg/ml)
Linker antibody 2GαMκ-Biotin: biotinylated the th goat IgG, specific for mouse Kappa chain (2 µg/ml)
Fluorescent label 2SA-APC: labeled streptavidin allophycocyanin (2 µg/ml)

In the formation of a complex of europium and ARS directly contiguous and generates a signal.

The nonspecific interaction is measured by the replacement of CD80 fused protein of mouse Fab fragment (C215) (1.9 µg/ml) mouse Fab fragment (C125). The analysis is performed in black 384-well tablets in a final volume of 30 µl. Analytical buffer: 50 mm Tris-HCl, 150 mm NaCl, pH 7.8, containing 0.1% BSA (bovine serum albumin) (wt./vol.), add immediately prior to use.

Connections add to the above reagents in a series of concentrations ranging from 100 μm to 1.7 nm. The reaction mixture was incubated for 4 h at room temperature. Spend double the measurements with the meter set labels Wallac Victor 1420. First measurement: excitation 340 nm, emission 665 nm, a delay of 50 μs, the time window 200 µs. Second measurement: excitation 340 nm, emission 615 nm, a delay of 50 μs, the time window 200 µs. Counted pulses automatically corrigida on the crossover fluorescence, quenching the reaction and the background.

To illustrate the results of the EU50for the compounds of examples 15, 21, 29, 35 and 83 respectively 8 μm to 1.9 μm, 950 nm, 148 nm and 90 nm. For convenience, the magnitude of activity is with50 tested compounds registered above in final form:

AS: *=>10 μm, **=1-10 μm, ***=≤1 μm

1. The compound of formula (I) or its pharmaceutically or veterinary acceptable salt

where R1and R3independently represent H; F; Cl; Br;1-C6alkyl;

R2represents N or C3-C7cycloalkyl;

Y represents-S - or-N(R5)-, where R5is N;

X represents a bond;

R4represents-C(=O)NR6R7where

R6represents H or a radical of the formula -(Alk)b-Q, where b is 0 or 1 and Alk represents an optionally substituted C1-C6the alkyl, C1-C6alkoxy, F, Cl, Br, oxo, COOH, bivalent1-C12alkilinity,2-C12alkenylamine straight or branched chain which may be interrupted by one or more non-adjacent-O-, -S - or-N(R8)-, where R8represents N or C1-C4alkyl, C3-C4alkenyl or3-C6cycloalkyl, and

Q represents H; -SH; -NR8R8where each R8may be the same or different; the group of ester; or optionally substituted C1-C6the alkyl, C1-C6alkoxy, phenyl, benzyl, phenoxy,3-C8cycloalkyl, amino, fluorine, bromine, oxo, -COOH, -COR A-COORA, OtherA, -NRARBwhere RAand RBare independently (C1-C6)alkyl group, phenyl, C3-C7cycloalkyl,5-C7cycloalkenyl or heterocyclic ring having from 5 to 8 ring atoms; and

R7represents N or C1-C6alkyl; or taken together with the atom or atoms to which they are attached, R6and R7form an optionally substituted (C1-C6)alkyl, COORAwhere RAis a (C1-C6)alkyl group, phenyl, optionally substituted by F, Cl, Br, heterocyclic ring, having from 5 to 8 ring atoms.

2. The compound according to claim 1, where R1represents H, F, Cl, methyl.

3. The compound according to claim 1 or 2, where R2represents H, cyclopropyl.

4. The compound according to claim 1, where R3represents H, F, Cl, methyl.

5. The compound according to claim 1, where Y represents-S - or-N(R5)-, where R5represents N.

6. The compound according to claim 1, where X represents the connection.

7. The compound according to claim 1, where R4represents-C(=O)other6and where R6represents H or a radical of formula-Alkb-Q, where

b is 0 or 1, and

Alk represents a radical -(CH2)n-, -CH((CH2)mCH3)(CH2)n-, -CH((CH2 )mCH3)((CH2)pCH3)(CH2)n-, -(CH2)n-O-(CH2)m- or -(CH2)n-O-(CH2)n-O-(CH2)mwhere n is 1, 2, 3 or 4, and m and p independently are 0, 1, 2, 3 or 4, and

Q represents H, -SOON3, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl or oxazolyl; and

R7represents N.

8. The compound according to claim 1, where R1represents H, F or Cl; R2represents H; R3represents H, F or Cl; Y represents-NH-; X is a bond; and R4represents-C(=O)other6where

R6represents H or a radical of the formula -(Alk)b-Q, where

b is 0 or 1, and

Alk represents a radical -(CH2)n-, -CH((CH2)mCH3)(CH2)n-, -CH((CH2)mCH3)((CH2)pCH3)(CH2)n-, -(CH2)n-O-(CH2)m- or -(CH2)n-O-(CH2)n-O-(CH2)mwhere n is 1, 2, 3 or 4, and m and p independently are 0, 1, 2, 3 or 4, and

Q represents H, -SOON3, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl or oxazolyl; and

R7represents N.

9. The compound according to claim 1, where R1represents the t a F R2represents H or cyclopropyl, R3represents H, X represents a bond and R4represents-C(=O)other6.

10. N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropyrazolo[4,3-C]quinoline-2-yl]benzamide or its pharmaceutically or veterinary acceptable salt.

11. The compound according to claim 1 for the treatment of conditions in which immunomodulation has a beneficial effect.

12. The use of compounds according to any one of claims 1 to 10 for the manufacture of a medicinal product for the treatment of conditions in which immunomodulation has a beneficial effect.

13. A method of immunomodulation in humans and non-human primates, including the introduction in need of such treatment the subject immunomodulatory effective dose of a compound according to any one of claims 1 to 10.

14. Pharmaceutical or veterinary composition for the treatment of conditions in which immunomodulation has a beneficial effect, comprising as active agent a compound according to any one of claims 1 to 10 in an effective amount together with a pharmaceutically or veterinary acceptable excipient or the media.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds, which contain pyrrolo[1,2-а][1,4]diazepine fragment, annelated to aromatic and heteroaromatic ring. Method for preparation of derivatives of pyrrolo[1,2-а][1,4]diazepine of general formula I, where А =

, is described. The said derivatives may be of use as substances with potential CNS activity, or with analgesic, antimicrobial and antifungal effect. Method implies recyclization of furan ring of 5-methyl-furfurylamides of general formula 2, , where А stands for above shown groups, by exposure to temperature of 60-70°С in the mixture of glacial acetic acid and strong hydrochloric acid in volumetric ratio 1:0.15 for 10-15 minutes.

EFFECT: provides for simultaneous formation of pyrrole and diazepine rings and improves yield of end products due to less number of process steps.

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new method for synthesis of derivative of thieno[3,2-c]pyridine of the formula (1): (ticlopidine and clopidogrel). Method involves interaction of compound of the formula (2e): with compound of the formula (3): or its salt wherein R represents hydrogen atom or methoxycarbonyl; each among X' and Y' represents independently chlorine, bromine atom, methanesulfonyl or p-toluenesulfonyl, and to novel intermediate compounds and methods for their synthesis. Ticlopidine and clopidogrel possess the high inhibitory activity with respect to blood platelets aggregation and antithrombosis activity.

EFFECT: simplified process of synthesis, valuable medicinal properties of compounds.

15 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to heterocycle-substituted tricyclic compounds of the formula (I): or their pharmaceutically acceptable salts wherein R means hydrogen atom; R1 and R2 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R3 means hydrogen atom; n1 and n2 = 0-3 independently under condition that they both do not mean 0; Het means pyridyl wherein pyridyl is added to B through cyclic carbon atom and it comprises from 1 to 4 substitutes (W) chosen independently from group comprising -NR4R5, -NHCOR26, -NHSO2R16; R21 means aryl and R21 means heteroaryl wherein heteroaryl represents furyl, thienyl, pyridyl, thiazolyl, pyrrolidinyl, azethidinyl; R4 and R5 mean hydrogen atom or alkyl comprising 1-6 carbon atoms, or R4 and R5 mean in common -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)2NR7-(CH2)2- wherein R7 means hydrogen atom or alkyl comprising 1-6 carbon atoms; R8, R, R10 and R11 mean hydrogen atom; B means -(CH2)n4CR12=CR12a(CH2)n5 wherein n4 and n5 = 0-2 independently; R12 and R12a are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R21 means from 1 to 3 substitutes chosen independently from group comprising hydrogen atom, trifluoromethyl, trifluoromethoxy, halogen atom, cyano, alkyl comprising 1-6 carbon atoms, alkoxy group comprising 1-6 carbon atoms, or -CR29(=NOR28); R22 means -COR23, -S(O)R31, -S(O)2R31 or -COOR27; R23 means cycloalkyl comprising 3-7 carbon atoms, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, cycloalkyl comprising 3-7 carbon atoms containing from 1 to 3 substitutes chosen from group comprising halogen atom, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy group and alkoxy group comprising 1-6 carbon atoms, aryl, aryl-(C2-C6)-alkyl; R27 means alkyl comprising 1-6 carbon atoms, phenyl or benzyl; R28 and R29 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R31 means alkyl comprising 1-6 carbon atoms, halogenalkyl comprising 1-6 carbon atoms, aryl, aryl-(C1-C6)-alkyl. Also, invention relates to pharmaceutical compositions containing these substances and their using for preparing a drug used in treatment of thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, heart failure and cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 11 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzonaphthoazulene of the formula (I): wherein X represents oxygen (O) or sulfur (S) atom; Y and Z mean hydrogen atom; groups of the formula or the formula mean structures of formulae ; R1 represents compound of the formula (II): wherein R2 and R3 can represent simultaneously and independently of one another hydrogen atom (H), (C1-C4)-alkyl, or in common with nitrogen atom (N) they mean heterocycle chosen from morpholinyl, piperidinyl or pyrrolidinyl; n means a whole number from 0 to 3; m means a whole number 1; Q1 and Q2 represent independently of one another oxygen atom or group of the formula: wherein y1 and y2 represent independently of one another hydrogen atom or (C1-C4)-alkyl. Also, invention describes derivatives of benzonaphthoazulene of the formula (Ia) given in the invention description and differing from compounds of the formula (I) wherein R1 represents (C1-C7)-alkyl substituted with hydroxyl or (C1-C7)-alkyloxycarbonyl. Compounds of the formula (I) inhibit producing TNF-α, and compounds of the formula (Ia) are intermediate substances used in synthesis of compounds of the formula (I). Also, invention describes using compounds of the formula (Ia) wherein R1 means CO2Et, CH2OH for preparing compounds of the formula (I), and using compounds of the formula (I) for preparing pharmaceutical compositions designated for inhibition of production of TNF-α.

EFFECT: valuable properties of compounds and pharmaceutical compositions.

10 cl, 5 tbl, 10 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to diazacycloalkanes of the general formula (I): wherein G1 represents condensed polycyclic group. Compounds are selective and strong acting agonists of oxytocin and can useful in treatment of erectile dysfunction. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and their using in manufacturing the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

31 cl, 136 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula 1 (G1 is group of general formulae 2 G1 is group of general formulae ; meanings of the rest substituents are as described in specification) or pharmaceutically acceptable salts thereof and use thereof in srug production. Said compounds are useful in treatment of male and female sexual disorders.

EFFECT: new oxytocin antagonists.

30 cl, 177 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new amide-type carboxamide derivatives of formula [1] , wherein X represents -N= or -CH= group; R1 represents halogen atom, lower alkyl and a like; R1 represents -CO-R21-R22 (meanings of R21 and R22 are as defined in claim 1); Y1 and Y2 are independently halogen atom, lower alkyl, lower alcoxy group, and a like; ring A represents phenyl and a like; or pharmaceutically acceptable salts thereof. Said derivatives are useful as FXa inhibitors. Also disclosed are pharmaceutical composition based on abovementioned compounds and uses thereof.

EFFECT: new amide-type carboxamide derivatives.

7 cl, 105 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

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

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted indoline phemylsulfamide derivatives with the common formula , where A means C-R11 group or nitrogen, and R11 means hydrogen or alkyl with 1-4 carbon atoms, X means oxygen, R1 means aryl with 6-10 carbon atoms, unsubstituted or once-triple substituted with the similar or different substitutes, selected from the group which includes halogen, zyano, alkyl with 1-6 carbon atoms, alkoxi with 1-6 carbon atoms, phenoxi, benziloxi, trifluoromethyl, trifluorometoxi, alkenil with 2-6 carbon atoms, phenyl, alkylthio with 1-6 carbon atoms, mono- and dialkylamino with 1-6 carbon atoms in each alkyl group, or means the group with formula , R2 and R3 similar or different and independently from each other mean hydrogen or alkyl with 1-6 carbon atoms, or with the carbon atom they are bound to form the 3-7-membered spiro-compound cycloalkylic ring, R4 means hydrogen or alkyl with 1-6 carbon atoms, R5 R4 means hydrogen or alkyl with 1-6 carbon atoms, R6 means hydrogen or alkyl with 1-6 carbon atoms, R7 means hydrogen, alkyl with 1-6 carbon atoms, R8 - R10 mean hydrogen; as well as to their pharmaceutically compatible salts.

EFFECT: compounds are designated for prevention and/or treatment of cardio-vascular diseases, particularly dislipidemia and ischemic heart disease.

4 cl, 1 dwg, 96 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to derivatives of 7-phenylpyrazolopyridine with formula (I) ,where R1, R5, R6, R40, R41 and R42 represent different hydrocarbon substitutes or functional groups, its salts or hydrates, and especially to salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine. The compound with formula (I), especially salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine, act as antagonists of the receptor of corticotrophin release factor and can be used in medicine for treating various diseases of the nervous system and the gastrointestinal tract.

EFFECT: obtaining of new biologically active substances.

162 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of indole with general formula 1: where R is unsubstituted or substituted quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to nitrogen of the amide group; R1 is unsubstituted or substituted alkly-aryl; R2 represents hydrogen; R3-R6 represent hydrogen, R7 represents (C1-C6)-alkylcarbonyl or (C1-C6)- alkoxycarbonyl, and X, Y represent oxygen or sulphur, under the condition that, when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 have the above mentioned values, R7 is not an acetyl radical or tert-butyloxycarbonyl group. The invention also relates to physiologically tolerant salts of the indole derivatives, as well as to pharmaceutical compositions based on them and their use in obtaining medicinal preparations.

EFFECT: obtaining of medicinal preparations, used as medicines for curing tumorous diseases, especially in case of resistance to other drugs and metastasising carcinomas.

14 cl, 7 tbl, 6 dwg, 25 ex

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compounds of and formula: I II those developing antiviral activity allowing application in pharmaceutical formulations and for antiviral medicines production.

EFFECT: new compounds have useful biological properties.

5 cl, 3 dwg, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.

EFFECT: compounds possess inhibiting activity.

13 cl, 1 tbl, 8 ex

FIELD: CHEMISTRY.

SUBSTANCE: invention relates to novel method for preparation of compounds of formula IX or IXа, which implies reaction of compound of formula Va, in solvent, with compound of formula VII or formula VIIa, in the presence of palladium catalyst and phospho ligand, in the presence of amine base, resulting in compound of formula VIII or VIIIa. The method also implies reaction of compound of formula VIII or VIIIa, in solvent, with cyclopropylamine, not necessarily in the presence of catalyst. Also, invention relates to method for purification of compound of formula IX or IXa.

Va - R1 may be either С1-8alkyl, aryl or heteroaryl, not necessarily aryl- and/or С1-8alkyl-substituted; and

.

EFFECT: method for preparation of biologically useful compounds is described.

17 cl, 3 tbl, 77 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically suitable salt or solvate thereof, where dashed line stands for additional bond, а is a number from 0 to 2, b is a number from 0 to 2, n is 2, p is 2, r is 1, М1 stands for nitrogen, М2 stands for С(R3), X stands for either a bond or alkylene group with number of carbon atoms from 1 to 6, Y stands for -С(О)- group, Z stands for a bond, or alkylene group with number of carbon atoms from 1 to 6, or alkenylene group with number of carbon atoms from 1 to 6, or -С(O)-, -CH(CN)-, -SO2- or СН2С(O)NR4- group, R1 stands for groups, R2 stands for six-membered heteroaryl ring with one or two heteroatoms chosen independently of each other from either nitrogen atom or N-O group, other atoms of the cycle being carbon, five-membered heteroaryl ring with one, two, three or four heteroatoms chosen independently of each other from nitrogen, oxygen or sulphur, other atoms of the cycle being carbon, R32 stands for substituded quinoline group, R32 stands for substituted aryl group, heterocycloalkyl group, cycloalkyl group with number of carbon atoms from 3 to 6, alkyl group with number of carbon atoms from 1 to 6, group, where the said six-membered heteroaryl ring or the said five-membered heteroaryl ring may be R6-substituted, R12 independently of others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group or fluorine atom, provided in case R12 stands for hydroxyl or fluorine the rest of R12 cannot be bonded to a nitrogen-bonded carbon atom, or two R12 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjaicent carbon atoms of the ring, R13 independently of the others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group, alcoxy group with number of carbon atoms from 1 to 6, or fluorine atom, provided in case R13 stands for hydroxyl or fluorine the rest of R13 cannot be bonded to a nitrogen-bonded carbon atom, or two R13 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjacent carbon atoms of the ring. See description for meaning of the other structural elements. Invention relates also to pharmaceutical compositions, as well as to application of compounds of formula I.

EFFECT: preparation of novel biologically active substances and pharmaceutical compositions.

20 cl, 659 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method (variants) for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone and its (+)-enantiomer. The first variant of method for synthesis of racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone involves step (e) and another variant involves steps (b)-(e). Method for synthesis of (+)-enantiomer involves the following steps (a)-(f): (a) interaction of 2,6-diaminopyridine with malic and sulfuric acids to form 2-amino-7-hydroxy-1,8-naphthyridine hydrosulfate that (b) is treated with phthalyl reagent in a solvent medium to form phthalimidylnaphthyridine of the formula (2): that (c) is chlorinated to form chloride of the formula (3): that (d) is reduced to hydroxyindolinone of the formula (4): that (e) is treated with 5-methyl-2-oxohexyltriphenylphosphonium halide to yield racemic 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone that (f) is separated and final (+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone is prepared. Invention provides improving method for synthesis of 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone from 2-(7-chloro-1,8-naphthyridine-2-yl)-3-hydroxyisoindolinone-1-one based on using 5-methyl-2-oxohexyltriphenylphosphonium halide.

EFFECT: improved methods of synthesis.

13 cl, 1 ex

FIELD: medicine; immunology.

SUBSTANCE: method implies that animals' thymus, e.g. sea animals' thymus, is defatted and connective tissue cleaned, milled, lyophilised, degreased with liquid CO2, hydrated in isotonic phosphate buffer at pH 7.2-7.4, sediment is removed by centrifugation, supernatant is collected and warmed up at 80°C during 10-15 min, centrifugated, supernatant is collected and pH is reduced to 4.0-4.2, deposited with ammonium sulphate, formed sediment is removed by centrifugation, dissolved in tris-HCl buffer, pH 8.0-8.2, ammonium sulphate is removed on column with Sephadex G-15, material of column outer content is, lyophilised, dissolved in 0.01 M tris-HCl, buffer containing 0.14 M NaCl, pH 8.0-8.2, gel- chromatographed on column with Sephadex G-50, end product is collected by molecular weight 500 to 25000 dalton, lyophilised, dissolved in bidistilled water and desalted on column with Sephadex G-15, end product produced in column free content is lyophilised.

EFFECT: method provides higher product yield and storage stability.

1 tbl, 4 ex

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