Thienopyridone carboxamides and their medical use

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I)

, where R is selected from ethyl, n-propyl, iso-propyl, n-butyl and allyl; R' is selected from hydrogen, straight, branched or cyclic C1-C4alkyl; straight, branched or cyclic C1-C3alkoxy; fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x=0, 1, 2, y=1, 2, 3 under the condition that, x+y=3; R" is selected from hydrogen, fluorine and chlorine, with the condition that, R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine; R3 is selected from hydrogen and straight, branched or cyclic C1-C5alkyl; R4 is selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic or organic cations, and COR4', where R' is straight, branched or cyclic C1-C5alkyl, phenyl, benzyl or phenethyl; R7 is selected from methyl and ethyl; one of A and B is sulphur, and the other is C-R2; when A is S, R2 is selected from hydrogen and methyl, with the condition that R2 is methyl only when R3 is not hydrogen; and when B is S, R2 is hydrogen; and to any tautomer thereof, as well as to a pharmaceutical composition which contains formula (I) compound, to a method of producing said compounds and to a method of treating diseases which are a result of autoimmune response or pathologic inflammation.

EFFECT: new compounds are disclosed, which can be used in treating diseases which are a result of autoimmune response or pathologic inflammation.

35 cl, 2 tbl, 18 ex

 

The technical field relates to inventions

The present invention relates to substituted derivatives of thieno[2,3-b]pyridine-5-carboxamide and 2-thia-4-Aza-inden-6-carboxamide, to methods for their preparation, to compositions comprising them and to methods and application to clinical treatment of diseases, the cause of which is the emergence of autoimmune response and pathological inflammation, and malignant tumors. Examples of such autoimmune diseases are multiple sclerosis (MS), insulin-dependent diabetes mellitus (LDDM), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis. Other diseases where inflammation plays a major role, are diseases such as asthma, atherosclerosis, stroke and Alzheimer's disease. In addition, the compounds of the present invention is particularly well inhibit the development of solid tumors, including breast cancer, colon cancer, Kaposi's sarcoma, lung cancer, ovarian cancer, prostate cancer and skin cancer. More specifically, the present invention relates to derivatives of thieno[2,3-b]pyridine-5-carboxamide.

The level of technology

Autoimmune diseases such as MS, LDDM, SLE, RA, IBD and psoriasis represent attacks the body's immune system, which may be in the nature of a system or aimed at the individual who xual organs of the body. They, apparently, are diseases in which the immune system makes mistakes, and instead of providing protective functions, becomes the aggressor (1).

MS is the most common acquired neurological disease among young adults in Western Europe and North America. He is the reason for the larger number of cases resulting in disability and financial loss (as at the expense of foregone revenues and costs in the area of health care)than any other neurological disease in this age group. The total number of cases of MS is approximately 1000000 in the United States and Europe.

Although the cause of MS is unknown, advances in imaging of the brain, immunology and molecular biology have improved our understanding by researchers of the disease. Currently, for the treatment of MS are several types of therapy, but none of them provides a significant treatment effectiveness. Modern methods of treatment of MS fall into three categories: treatment of acute modulation of the progress of the disease and the treatment of specific symptoms.

MS affects the Central nervous system and leads to the process of demyelinization, that is, to the loss of the myelin sheaths of neurons, while axons are preserved. Myelin is the insulating material is ω neuron, which makes possible the rapid conduction of nerve impulses. Obviously, when demyelination this property is lost. Although the pathogenic mechanisms responsible for MS remains unclear, several lines of evidence indicate that demyelination has immunopathological basis. Pathological damage, stains, characterized by infiltration of immunologically active cells, such as macrophages and activated T-cells (2).

In U.S. patent 5219864 some derivatives of thieno[2,3-b]pyridine and Taino[3,2-b]pyridine represented by the formula (A)

where Z is represented by peridian are claimed as immunoregulatory and means for the prevention and treatment of osteoporosis.

In WO 94/29295 disclosed compounds of General formula (In)

where Y other is

that is, derivatives of thieno[3,2-b]pyridine, and N represents a bicyclic heterocyclic group containing at least one nitrogen atom, R5 is a lower alkyl and R6 is hydroxy, and which possess immunomodulatory activity, antiinflammatory activity and anticancer activity.

Disclosure of inventions

The primary objective of the present invention is to provide new derivatives of thieno[2,3-b]pyridine-5-carboxamid the a and 2-thia-4-Aza-inden-6-carboxamide, which by taking advantage of their pharmacological profile, high efficiency actions in experimental models and low level of side effects are considered valuable in the treatment of diseases resulting from an autoimmune response and pathological inflammation, and malignant tumors. The present invention relates to new substituted derivatives of thieno[2,3-b]pyridine-5-carboxamide and 2-thia-4-Aza-inden-6-carboxamide, processes for their preparation, to compositions comprising them and to methods and application to clinical treatment of diseases resulting from an autoimmune response and pathological inflammation, and malignant tumors. Examples of such autoimmune diseases is MS, IDDM, SLE, RA, IBD and psoriasis, and other diseases where inflammation plays a major role: asthma, atherosclerosis, stroke and Alzheimer's disease.

Types of solid tumors, which are particularly well suppressed by compounds of the present invention include, for example, breast cancer, colon cancer, Kaposi's sarcoma, lung cancer, ovarian cancer, prostate cancer and skin cancer. The approach, which was chosen by the authors of the invention is the inhibition induced tumor angiogenesis and stimulation of the immune system of the host to induce/enhance antitumor response.

More specifically, the present invention relates to new derivatives of thieno[2,3-b]pyridine-5-carboxamide and 2-thia-4-Aza-inden-6-carboxamide.

The term "treatment"as used here, includes the prevention, relief of symptoms and healing from disease.

It has been unexpectedly found that compounds of General formula (I)

where

R is selected from methyl, ethyl, n-propyl, ISO-propyl, n-butyl and allyl;

R' is selected from hydrogen, an unbranched, branched or cyclic C1-C4the alkyl, preferably unbranched, branched or cyclic C1-C3of alkyl; an unbranched, branched or cyclic C1-C3alkoxy, fluorine, chlorine, bromine, trifloromethyl and OCHxFy,

where x=0, 1, 2,

y=1, 2, 3 provided that

x+y=3;

R" is selected from hydrogen, fluorine and chlorine, provided that R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine;

R3selected from hydrogen and unbranched, branched or cyclic C1-C5of alkyl, more preferably unbranched, branched or cyclic C1-C4of alkyl;

R4 is selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic cations, such as lithium, sodium, potassium, magnesium, calcium, copper (II), zinc, aluminum

and iron (III); and organic cations such as monoethanolamine and diethanolamine; and COR4'where R4/sub> ' is selected from unbranched or branched C1-C5of alkyl, phenyl, benzyl, Venetia and the like;

R7selected from methyl and ethyl;

one of a and b is sulfur and the other is C-R2;

if a is S, R2selected from hydrogen and methyl, provided that R2represents only the methyl,

if R3is not hydrogen; and

when is an S, R2is not hydrogen;

and any tautomer,

are unexpectedly effective in the treatment of individuals suffering from autoimmune and inflammatory diseases and malignant tumors.

In the above formula (I), if a is a sulfur, the ring

has the following form

that is, the connection is derived from thieno[2,3-b]pyridine; and if In the mean sulphur, the ring

has the following form

(R2is hydrogen, i.e. the compound is a derivative of 2-thia-4-Aza-indene.

Compounds of General formula (I) may exist in different tautomeric forms, and all these forms are included in the invention.

In the preferred embodiment of the invention

And means sulphur,

R is selected from methyl and ethyl,

R' is selected from para-methoxy, para-fluorine, time-chlorine, paradiplomacy and pair-triptoreline, when R ' means hydrogen,

R is ortho-fluoro, provided that R' represents a para - or meta'-fluoro,

R2means hydrogen,

R3selected from methyl, ethyl and ISO-propyl, and

R7means methyl.

In another preferred embodiment of the invention

In the mean sulphur,

R is selected from methyl and ethyl,

R' is selected from para-methoxy, para-fluorine, para-chloro, para-trifloromethyl and pair-triptoreline, when R ' means hydrogen,

R" means ortho-fluorine, provided that R' represents a para - or meta'-fluoro,

R3selected from methyl, ethyl and ISO-propyl, and

R7means methyl.

The preferred embodiments of the invention are compounds represented by the formula (1A) in table 1.

Table 1.
ConnectionR2R3R7RR'R"
No. 1NCH3CH3CH3NN
No. NCH3CH3C2H5NN
No. 3NWith2H5CH3CH3NN
No. 4NISO-C3H7CH3CH3NN
No. 5NCH3CH3CH3pair-CH3N
No. 6NCH3CH3CH3a pair of co3N
No. 7NCH3CH3CH3 para-ClN
No. 8NCH3CH3CH3pair-Fo-F
No. 9NCH3CH3CH3pair-OCF3N

Another preferred embodiment of the invention is the compound (Ib)

where R3and R7is methyl, R is methyl or ethyl, and R' and R" is hydrogen. In the preferred compound (compound No. 10), R is the stands.

For several spontaneous autoimmune diseases there are experimental models that spontaneously arise in certain lines of laboratory animals or can be induced in laboratory animals by immunization specific(and) antigen(s) of the target organ.

Experimental autoimmune encephalomyelitis (EAE) as a model of autoimmune inflammatory diseases of the Central nervous system (CNS) was the most widespread model of the human disease MS.

<> Autoimmune response against collagen type II can be experimentally induced in certain strains of mice or rats, and may lead to the development of arthritis. Induced collagen arthritis has several common features with the human disease RA.

Compounds of General formula (I)and compounds of the prior art/connections comparisons were tested for inhibition of acute EAE in mice. When the comparison of the derivatives of thieno [3,2-b]pyridine-6-carboxamide with the corresponding derivatives of thieno[2,3-b]pyridine-5-carboxamide and 2-thia-4-Aza-inden-6-carboxamide of the present invention were obtained surprising and unexpected results. Derivatives of thieno[2,3-b]pyridine-5-carboxamide and 2-thia-4-Aza-inden-6-carboxamide of the invention are clearly the best. In contrast to the compounds of the invention, for example, 6,7-dihydro-N,7-dimethyl-4-hydroxy-N-phenyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide and 4,5-dihydro-N,4-dimetil-7-hydroxy-N-phenyl-5-oxo-2-thia-4-Aza-inden-6-carboxamide, compound comparison 4,5-dihydro-N,4-dimethyl-7-hydroxy-N-phenyl-5-oxo-thieno[3,2-b]pyridine-6-carboxamide is inactive in a model of acute EAE. Similarly replacement of the N-phenyl group on the N-pyridinol in carboxamides part leads to a better activity. Hence, the connection comparison 6,7-dihydro-4-hydroxy-N-(3-pyridyl)-N,3,7-trimethyl-6-OK what about thieno [2,3-b] pyridine-5-carboxamide shows less activity in comparison with the compound of the invention 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide. The compound 6,7-dihydro-4-hydroxy-N-(3-pyridyl)-6-oxo-thieno[2,3-b]pyridine-5-carboxamide, disclosed in U.S. patent 5219864 is inactive.

All embodiments of the invention as disclosed in the claims included, therefore, in the description.

Compounds of General formula (I) can be obtained by methods described in the literature, and also in the following ways:

Method:

Compounds of General formula (I) can be prepared by known methods, and, for example, as shown above, by reaction of a derivative of an ether carboxylic acid (II; RAis an alkyl group of 1-4 carbon atoms) with aniline in a suitable solvent, for example, aliphatic hydrocarbon, such as heptane, octane and the like, or aromatic hydrocarbon, such as toluene, xylene and the like. The main methods of preparation of derivatives of ether carboxylic acids of the formula (II) described below, starting with 2-aminothiophene-3-carboxylate or 4-aminothiophene-3-carboxylate. Aminothiophene-3-carboxylates commercially available or known from the literature(3, 4, 5, 6, 7). N-alkylated anilines of formula (III) are commercially available or known from the literature (8). New aminothiophene-3-carboxylates and N-alkylated anilines of formula (III) can be prepared by methods which are basically similar to those found in the literature. Pic is b:

The compounds of formula (I) can also be obtained by reaction of compounds of formula (IV) with an aniline of formula (III). Can be applied to various interfacing reagents known in the art, for example, carbodiimide known from U.S. patent 4547511. In one of the appropriate ways of pairing applies thionyl chloride in the presence of triethylamine and acceptable solvent, such as dichloromethane. This method can be applied in some cases when the direct coupling between the ether and aniline yields no results, for example, when aniline includes electron-withdrawing substituents. Derivatives of carboxylic acids of the formula (IV) can be obtained from the corresponding esters of the formula (II) due to acid cleavage, as described below.

The following examples are intended to illustrate the invention without limiting its scope.

Example 1.

Ethyl ester of 6,7-Dihydro-3,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid (Intermediate)

Ethyl-2-amino-4-methylthiophene-3-carboxylate (27,0 mmol, 5.0 g) was heated in diethylmalonate (25 ml) at 180°C for 3 h and the formed ethanol was allowed to perekanatisya. The oil bath temperature was lowered, and diethylmalonate was distilleria under reduced pressure to obtain an intermediate product, malonic amide, complex Adilov the th ether 2-(2-ethoxycarbonylethyl)-4-methylthiophene-3-carboxylic acid in the form of oil, which slowly crystallized upon standing (7.7 g, 95%). Malonic amide was dissolved in N,N-dimethylacetamide (DMA, 40 ml), then was added sodium hydride (NaH 80%, 2.0 EQ., 54 mmol, of 1.62 g). The mixture was heated at 60°C for 1 h, After cooling and adding water (300 ml) the product was precipitated by adding concentrated hydrochloric acid (HCl) to a pH of 1.5. The precipitate was collected by filtration and recrystallize from a mixture, receiving complex ethyl ester of 6,7-dihydro-4-hydroxy-3-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid (3.8 g, 56%). Ethyl ester of carboxylic acid (11,9 mmol, to 3.02 g) was dissolved in DMA (40 ml) was added NaH (2.1 EQ., 25 mmol, 750 mg). The mixture was heated to 40°C for 10 minutes then it was cooled to 10°C was added dimethylsulfate (1.2 EQ., of 14.3 mmol, 1,37 ml). The mixture was stirred at room temperature for 1 h and then cooled in an ice bath. Then added water (200 ml)and the mixture was acidified with 5 M HCl to a pH of 1.5. Collected precipitate and recrystallize it from a mixture of toluene/heptane, receiving the connection specified in the header (2.4 g, 75%).

1H NMR (CDCl3): σ of 1.45 (3H, t), 2,48 (3H, d), 3,55 (3H, s), of 4.45 (2H, q), 6,46 (1H, q, ush.), 14,22 (1H, s).

Essentially the same method were obtained the following compounds from the corresponding starting materials:

methyl ester of 6,7-dihydro-4-hydroxy-2,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

m is tilby ester of 6,7-dihydro-3-ethyl-4-hydroxy-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-4-hydroxy-3-isopropyl-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-4-hydroxy-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-2,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

ethyl ester of 6,7-dihydro-3-(4-forefeel)-4-hyroxy-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid; and

methyl ester of 4,5-dihydro-7-hydroxy-4-methyl-5-oxo-2-thia-4-ashenden-6-carboxylic acid.

Example 2.

Ethyl ester of 4,5-dihydro-1,4-dimethyl-7-hydroxy-5-oxo-2-thia-4-Aza-inden-6-carboxylic acid (Intermediate).

Ethyl-4-amino-2-methylthiophene-3-carboxylate (12.8 mmol, 2.37 g) was dissolved in 1,4-dioxane (20 ml), then added ethylmalonyl chloride (90%) (19.2 mmol, 2,73 ml). The reaction mixture was heated at 50°C for 1 h, then it was allowed to cool to ambient temperature. The reaction mixture was placed in ice (60 g), and the product was obtained by filtration, washed with water and dried (3,32 g, 87%). Malonic amide was dissolved in N,N-dimethylacetamide (DMA, 35 ml) was added sodium hydride (NaH 60%, 2.0 EQ., to 22.1 mmol). The reaction mixture was heated at 60°C for 1 h, After cooling and adding water (50 ml) and the product precipitated with addition of 1 M hydrochloric acid (HCl aq.) (30 ml). The precipitate was collected by filtration and recrystallize from ethanol, getting this is levy ester of 4,5-dihydro-7-hydroxy-1-methyl-5-oxo-2-thia-4-ashenden-6-carboxylic acid (1,46 g, 52%). Ethyl ester of the carboxylic acid was dissolved in dimethylformamide (DMA, 40 ml) and NaH (3.0 EQ., 17.3 mmol, 692 mg). The reaction mixture was heated to 40°C for 15 min, and then cooled to 10°C. was Added iodomethane (1.3 EQ., 7,49 mmol, of 0.47 ml), then the reaction mixture was stirred at room temperature for 2 h and was poured into 0.5 M HCl (aq.) (50 ml). The precipitate was collected by filtration and recrystallize from ethanol, and then again from isobutyl ketone, receiving the connection specified in the header (524 mg, 89%).

1H NMR (NaOD/D2O): σ of 1.28 (3H, t), and 2.79 (3H, s), 3,82 (3H, s), 4,30 (2H, q), for 6.81 (1H, s).

Essentially the same method were obtained the following compounds from the corresponding starting materials:

methyl ester of 6,7-dihydro-3-ethyl-4-hydroxy-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-4-hydroxy-7-methyl-3-tert-butyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-4-hydroxy-3-isobutyl-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-3-(2,2-dimethylpropyl)-4-hydroxy-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 6,7-dihydro-3-(1-ethylpropyl)-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

methyl ester of 3-cyclohexyl-6,7-dihydro-4-hyroxy-7-methyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid; and

methyl ester of 4,5-dihyd the o-3,4-dimethyl-7-hydroxy-5-oxo-2-thia-4-ashenden-6-carboxylic acid.

Example 3.

Ethyl ester of 4,5-dihydro-7-hydroxy-4-methyl-5-oxo-thieno[2,3-b]pyridine-5-carboxylic acid (Not in accordance with the invention)

A mixture of methyl-3-aminothiophene-2-carboxylate (63 mmol, 10.0 g) and ethylchloride (50 ml) was subjected to reflux distilled for 2 h and then evaporated until complete dryness. The residue was dissolved in ethanol (130 ml), then added an aqueous solution of sodium hydroxide (NaOH, 65 mmol, of 3.84 g). After stirring at room temperature for 48 h the mixture was acidified using 1 M HCl and diluted with water. The precipitate was collected, washed with water, dried under vacuum and recrystallize from a mixture of toluene/heptane with 3-ethoxycarbonylmethylene-2-carboxylic acid (10.2 g, 73%). This acid (23.2 mmol, 5.0 g) and tribromide phosphorus (12 mmol, 1,14 ml) was dissolved in 1,4-dioxane (50 ml). The mixture was stirred at 100°C for 2 h and then cooled before was concentrated on a rotary evaporator. The precipitate formed by the addition of toluene was separated by filtration to obtain 1H-thieno-[3,2-b][1,3]oxazin-2,4-dione (3,96 g, 100%). This intermediate (20,6 mmol, 3.5 g) was dissolved in DMA (40 ml) and cooled in an ice bath. Then was added NaH (22.7 mmol, 780 mg) followed by the addition under the conditions (25 mmol, 1.6 ml). The mixture was stirred at room temperature overnight and then added diethylmalonate (25 mmol, of 3.85 ml) and NaH (22.7 mmol, 80 mg). After the addition the mixture was heated at 85°C for 2 h and then cooled. Added water, the mixture sekilala 1 n HCl and was extracted with chloroform. The extract was dried, concentrated and chromatographically (SiO2, chloroform/methanol/acetic acid; 40/1/0,1) to obtain the connection specified in the header of the example (1.4 g, 26%).

1H NMR (CDCl3): σ of 1.45 (3H, t), 3,61 (3H, s), of 4.45 (2H, q)to 7.00 (3H, d), 7,76 (1H, d), 13,92 (1H, s, ush.).

Example 4.

6,7-dihydro-3,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid (Intermediate)

Ethyl ester of 6,7-dihydro-3,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid (5,72 mmol, 1, 45 g) was heated to 55°C in 33% of a mixture of Hydrobromic acid/acetic acid (35 mmol of HBr, 6,0 ml). After 2 h the mixture was cooled and was added 2-propanol (30 ml). The precipitate was collected by filtration and dried in vacuum to obtain the desired compound (1.28 g, 93%).

1H NMR (CDCl3): σ of 2.53 (3H, d)to 3.67 (3H, s), 6,63 (1H, q ush.), 14, 48mm (1H, s), 15,29 (1H, s).

Essentially the same method were obtained the following compounds from the corresponding starting materials:

6,7-dihydro-2,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

6,7-dihydro-4-hydroxy-2,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

6,7-dihydro-2,7-dimethyl-3-ethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid;

4,5-dihydro-7-hydroxy-4-methyl-5-the CSR-2-thia-4-ashenden-6-carboxylic acid; and

4,5-dihydro-7-hydroxy-4-methyl-5-oxathiane[3,2-b]pyridine-6-carboxylic acid.

Example 5.

6,7-dihydro-4-hydroxy-N-(4-methoxyphenyl)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (Method A)

Ethyl ester of 6,7-Dihydro-3,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid (3,74 mmol, 1.0 g), N-methyl-para-anisidine (3 EQ., of 11.2 mmol, of 1.57 g) and n-octane (60 ml) was heated to the boiling point under nitrogen in an oil bath. Volatile substances (about 40 ml) was allowed to distilleries for 6 h, and the remaining n-octane was removed on a rotary evaporator. The residue was dissolved in chloroform and washed with cold 1 M sulfuric acid. The organic phase was extracted with 0.5 M NaOH, and the pH in the aqueous phase was brought about to 6.5. The turbid solution was filtered through morh. Next was added methanol (respectively up to 10% of the volume), and then the clear solution was acidified with 1 M HCl to a pH of 1.5. The precipitate was left overnight, collected by filtration and dried under vacuum to obtain the desired compound (1.06 g, 79%).

1H NMR (CDCl3): σ of 2.51 (3H, d), 3,29 (3H, s, ush.), of 3.43 (3H, s), of 3.78 (3H, s), of 6.45 (1H, q ush.), 6,79 (2H, d ush.), for 7.12 (2H, d ush.), 12,60 (1H, s ush.).

Essentially the same method were obtained the following compounds from the corresponding starting materials.

6,7-dihydro-N,7-dimethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 53%.

H NMR (CDCl3): σ is 3.27 (3H, s ush.), of 3.48 (3H, s), to 6.88 (1H, d), 7,15-7,22 (3H, m), 7,27 (2H, t ush.), to 7.32 (2H, d), 12,50 (1H, s ush.).

6,7-dihydro-N,7-dimethyl-3-ethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 86%.

1H NMR (CDCl3): σ is 1.31 (3H, t), 2,98 (2H, q), 3,26 (3H, s ush.), of 3.48 (3H, s), 6.48 in (1H, s), 7,14-7,30 (5H, m), 12,78 (1H, s).

6,7-dihydro-N,7-dimethyl-4-hydroxy-3-ISO-propyl-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 66%.

1H NMR (CDCl3): σ 1,28 (6N, (d), 3,24 (3H, s ush.), 3,47 (3H, s), 3,57-3,68 (1H, m), of 6.52 (1H, s), 7,12-7,20 (3H, m), 7.23 percent-7,29 (2H, m), 12,94 (1H, s ush.).

6,7-dihydro-N,7-dimethyl-4-hydroxy-3-ISO-butyl-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 76%.

1H NMR (CDCl3): σ of 0.97 (6H, d), 2,04 (1H, m), 2,77 (2H, d), or 3.28 (3H, s ush.), to 3.50 (3H, s), 6,47 (1H, s), 7,17-to 7.32 (5H, m), is 12.85 (1H, s).

6,7-dihydro-N,7-dimethyl-4-hydroxy-N-phenyl-3-tert-butyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 83%.

1H NMR (CDCl3): σ of 1.47 (9H, s), or 3.28 (3H, s), 3,49 (3H, s), is 6.61 (1H, s), 7,15-to 7.32 (5H, m), 13,60 (1H, s).

6,7-dihydro-N,7-dimethyl-3-(1-ethylpropyl)-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield: 23%.

1H NMR (CDCl3): σ to 0.89 (6H, t), was 1.69 (4H, m), with 3.27 (3H, bs), 3,44 (1H, bs), of 3.48 (3H, s), 6.48 in (1H, s), 7,18 (3H, m), 7,28 (2H, m), 12,97 (1H, bs).

6,7-dihydro-N,7-dimethyl-3-(2,2-dimethyl-propyl)-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 63%; not included in the claims.

1H NMR (CDCl3): σ 0.98 (9Hs), 2,96 (2Hs), 3,29 (3Hs ush.), 3,51 (3H, s), 6.48 in (1H, s), 7,17-7,33 (5H, m), is 12.85 (1H, s).

3-Cyclohex the Il-6,7-dihydro-N,7-dimethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 60%; not included in the claims.

1H NMR (CDCl3): σ 1,22-2,18 (10H, m, cyclohexyl-CH2), 3,30 (4H, broad signal, N-Me and cyclohexyl CH), 3,50 (3H, s), of 6.52 (1H, s), 7,17-to 7.32 (5H, m), to 12.95 (1H, s).

6,7-dihydro-3,7-dimethyl-N-ethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 87%.

1H NMR (DMSO-d6): σ is 1.01 (3H, t), 2,31 (3H, s), 3,29 (3H, s), 3,74 (2H, q ush.), 6,72 (1H, s ush.), 7,10-7,31 (5H, m), and 11.0 (1H, s ush.).

N,3-Diethyl-6,7-dihydro-4-hydroxy-7-methyl-N-phenyl-6-oxathiane [2,3-b]pyridine-5-carboxamide, yield 76%.

1H NMR (CDCl3) σ of 1.20 (3H, t), of 1.30 (3H, t), of 2.97 (2H, q), 3,19 (3H, s), of 3.97 (2H, q), 6,47 (1H, s), to 7.15 (3H, t), 7,24 (2H, t), 12,83 (1H, bs).

6,7-dihydro-N-ethyl-4-hydroxy-3-ISO-propyl-7-methyl-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 67%.

1H NMR (CDCl3) σ to 1.21 (3H, t), of 1.30 (6H, d), 3,19 (3H, s), to 3.64 (1H, m), of 3.97 (2H, q), 6,51 (1H, s), to 7.15 (3H, t), from 7.24 (2H, m), 12,98 (1H, bs).

6,7-dihydro-3,7-dimethyl-4-hydroxy-N-phenyl-N-propyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 58%.

1H NMR (CDCl3) σ 0,92 (3H3t), and 1.63 (2H, m), 2,52 (3H, d), 3,17 (3H, s), a 3.87 (2H, t), to 6.43 (1H, d), 7,14 (3H, t), of 7.23 (2H, t), br12.62 (1H, ush.).

Pyrolidine salt of 6,7-dihydro-N,3-dimethyl-7-ethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 75%.

1H NMR (CDCl3): σ a 1.08 (3H, broad signal)to 1.79 (4H, m), of 2.45 (3H, s), 2,98 (4H, m), the 3.35 (3H, s), 3,85 (2H, broad signal), and 6.25 (1H,s ush.), 7,08 and 7.36 (5H, m).

6,7-dihydro-4-hydroxy-N-(4-were)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide you the od 81%.

1H NMR (CDCl3): σ to 2.29 (3H, s), 2,50 (3H, d), 3,26 (3H, s ush.). of 3.43 (3H, s), to 6.43 (1H, q ush.), 7,06 (4H, s)12,70 (1H, s ush.).

6,7-dihydro-4-hydroxy-N-(4-ISO-propyl)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 85%.

1H NMR (CDCl3): σ to 1.22 (6H, d), of 2.53 (3H, s), is 2.88 (1H, m), of 3.25 (3H, s ush.), of 3.46 (3H, s), of 6.45 (1H, s ush.), 7,07-7,17 (4H, m), 12,8 (1H, s).

6,7-dihydro-4-hydroxy-N-(4-trifloromethyl)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 76%.

1H NMR (CDCl3): σ 2,52 (3H, s), 3,23 (3H, s), 3,47 (3H, s), 6,47 (1H, s ush.), for 7.12 (2H, d), 7,22 (2H, d)12,70 (1H, s).

6,7-dihydro-N,7-dimethyl-4-hydroxy-3-ethyl-N-(4-methoxyphenyl)-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 67%.

1H NMR (CDCl3) σ of 1.29 (3H, t), 2,96 (2H, dq), 3,29 (3H, bs), of 3.43 (3H, s), of 3.77 (3H, s), 6.48 in (1H, s), 6,79 (2H, d), 7,11 (2H, d), 12,69 (1H, bs).

N-(4-Chlorophenyl)-6,7-dihydro-3,7-dimethyl-N-ethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 54%.

1H NMR (CDCl3): σ to 1.19 (3H, t), of 2.51 (3H, d), 3,23 (3H, s), 3,93 (2H, q), of 6.45 (1H, d), to 7.09 (2H, d), 7,21 (2H, d)of 12.73 (1H, bs).

N-(4-Chlorophenyl)-6,7-dihydro-N,7-dimethyl-3-ethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 57%.

1H NMR (CDCl3): σ of 1.29 (3H, t), 2,96 (2H, q), or 3.28 (3H, s), of 3.45 (3H, s), 6,50 (1H, s), 7,13 (2H, d), of 7.23 (2H, d), 12,79 (1H, bs).

N-(2,4-Differenl)-6,7-dihydro-N,7-dimethyl-3-ethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 44%.

1H NMR (CDCl3): σ of 1.29 (3H, t), 2,96 (2H, q)of 3.25 (3H, bs), to 3.38 (3H, s), of 6.49 (1H, s), 6,69 (1H, bs), 6,86 (1H, bt), 7,05 (1H, bs), 12,72 (1H, bs).

N-(2,4-Differenl-1,6-dihydroxy-4-hydroxy-3-ISO-propyl-N,7-dimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 37%.

1H NMR (CDCl3): σ of 1.29 (6H, d)of 3.25 (3H, bs), to 3.38 (3H, s), 3,62 (1H, m), is 6.54 (1H, s), of 6.71 (1H, bs), 6,87 (1H, bs), 7,05 (1H, bs), is 12.85 (1H, bs).

6,7-dihydro-N,7-dimethyl-3-(4-forefeel)-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 92%, are not included in the claims.

1H NMR (CDCl3): σ 3,30 (3H, s ush.), 3,44 (3H, s), of 6.68 (1H, s),? 7.04 baby mortality-7,11 (2H, m), 7,14-7,20 (3H, m), 7.23 percent-7,30 (1H, m), 7,42-7,49 (1H, m), 12,67 (1H, s ush.).

4,5-Dihydro-7-hydroxy-N-phenyl-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 87%.

1H NMR (CDCl3): σ of 2.86 (3H, s), 3,21 (3H, s, ush.), of 3.48 (3H, s), 6,17 (1H, s), 7,13-to 7.32 (5H, m), 12,89 (1H, s ush.).

4,5-Dihydro-1,4-dimethyl-N-ethyl-7-hydroxy-N-phenyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 76%.

1H NMR (CDCl3): σ of 1.20 (3H, t), of 2.86 (3H, s), 3.04 from (3H, s), of 3.97 (1H, q), 6,14 (1H, s), to 7.15 (3H, m), 7,24 (2H, m), 12,93 (1H, bs).

4,5-Dihydro-7-hydroxy-N-(4-were)-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 68%.

1H NMR (CDCl3): σ is 2.30 (3H, s), 2,85 (3H, s), of 3.13 (3H, bs), 3,44 (3H, s), 6,18 (1H, s), 7,07 (4H, bs), 12,88 (1H, bs).

4,5-Dihydro-7-hydroxy-N-(4-methoxyphenyl)-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 55%.

1H NMR (CDCl3): σ to 2.85 (3H, s), 3,14 (3H, bs), of 3.78 (3H, s), 6,18 (1H, s), to 6.80 (2H, bd), 7,11 (2H, bd), 12,79 (1H, bs).

N-(4-Chlorophenyl)-4,5-dihydro-7-hydroxy-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, the yield is 50%.

1H NMR (CDCl3): σ of 2.86 (3H, bs), 3,14 (3H, s), 3,44 (3H, s), of 6.20 (1H, s), 7,12 (2H, d), of 7.23 (2H, d), 12,87 (1H, bs).

N-(2,4-Differenl)-4,5-dihydro-7-guide is hydroxy-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, exit 14%.

1H NMR (CDCl3): σ to 2.85 (3H, s), to 3.09 (3H, bs), 3,37 (3H, s), 6,18 (1H, bs), 6,70 (1H, bs), 6,86 (1H, bt), 7,05 (1H, bs), 12,83 (1H, bs).

N-(2,5-Differenl)-4,5-dihydro-7-hydroxy-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 48%.

1H NMR (CDCl3): σ of 2.86 (3H, s)and 3.15 (3H, bs), 3,39 (3H, s), to 6.19 (1H, s), to 6.88 (2H, m), 7,06 (1H, dt), 12,89 (1H, bs).

4,5-Dihydro-7-hydroxy-N-(4-trifloromethyl)-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 36%.

1H NMR (CDCl3): σ 2,87 (3H, s), is 3.08 (3H, s), 3,50 (3H, s), 6,21 (1H, s), 7,30 (2H, d), 7,52 (2H, d), 12,98 (1H, bs).

4,5-Dihydro-7-hydroxy-N-(4-trifloromethyl)-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 52%.

1H NMR (CDCl3): σ of 2.86 (3H, s), to 3.09 (3H, s), of 3.46 (3H, s), to 6.19 (1H, s), 7,11 (2H, d), 7,21 (2H, d), 12,87 (1H, bs).

Example 6.

N-(2,5-Differenl)-6,7-dihydro-4-hydroxy-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (Method B).

To 6,7-dihydro-3,7-dimethyl-4-hydroxy-6-oxathiane[2,3-b]pyridine-5-carboxylic acid (4,18 mmol, 1.0 g) in dichloromethane (10 ml) was added triethylamine (4 EQ., of 16.7 mmol, 2.4 ml) and N-methyl-2,5-diptiranjan (1.2 EQ., 5.0 mmol, 720 mg). To the mixture, stirred under nitrogen and cooled to 0°C for 30 min was added a solution of thionyl chloride (1.3 EQ., 5.4 mmol, 0.4 ml) in dichloromethane (5 ml). Stirring was continued at 0°C for 1 h and then at room temperature for a further 20 minutes, the Reaction mixture was diluted with chloroform, and quickly washed with cold the th 1 M sulfuric acid. The organic phase was immediately extracted with 0.5 M NaOH. The remaining trace amounts of chlorinated organic solvents were removed on a rotary evaporator. the pH was brought just above the point where it starts to precipitate the desired product (approximately pH 6.5), and the solution was filtered through morh. The product was besieged by bringing the pH of 1M HCl to approximately 1-2, and the mixture was left for 2 hours the precipitate was collected by filtration, washed with water and dried under reduced pressure to obtain the desired compound (1.26 g, 83%).

1H NMR (CDCl3): σ of 2.53 (3H, d), and 3.31 (3H, s ush.), of 3.42 (3H, s), of 6.49 (1H, q ush.), 6,84-to 6.95 (2H, m), 7,05 for 7.12 (1H, m)of 12.73 (1H, s ush.).

Essentially the same method were obtained the following compounds from the corresponding starting materials.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 81%.

1H NMR (CDCl3): σ of 2.50 (3H, d), 3,23 (3H, s ush.), of 3.46 (3H, s), 6.42 per (1H, q), 7,12-7,19 (3H, m), 7,21-7,27 (2H, m), 12,65 (1H, s ush.).

6,7-dihydro-4-hydroxy-N-phenyl-N,2,3,7-tetramethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 75%.

1H NMR (CDCl3): σ 2,32 (3H, s), is 2.40 (3H, s), 3,21 (3H, s ush.), 3,47 (3H, s), 7,14-7,29 (3H, m), 7,26 (2H, t ush.), 12,60 (1H, s ush.).

6,7-dihydro-3-ethyl-4-hydroxy-N-phenyl-N,2,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 87%.

1H NMR (CDCl3): σ to 1.19 (3H, t), of 2.34 (3H, s), of 2.86 (2H, q), up 3.22 (3H, s), 3,47 (3H, s), 7,14-7,22 (3H, m), 7,27 (2H, t ush.), was 12.75 (1H, s is.).

N-(4-Chlorophenyl)-6,7-dihydro-4-hydroxy-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 90%.

1H NMR (CDCl3): σ of 2.50 (3H, d), 3,26 (3H, s), 3.43 points (3H, s), of 6.45 (1H, q ush.), 7,11 (2H, d), 7,21 (2H, d), 12,66 (1H, S ush.).

N-(2,4-Differenl)-6,7-dihydro-4-hydroxy-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 92%.

1H NMR (CDCl3): σ of 2.51 (3H, d)of 3.25 (3H, s ush.), to 3.38 (3H, s), of 6.45 (1H, s), 6,70 (1H, s ush.), 6,87 (1H, t ush.), ? 7.04 baby mortality (1H, s ush.), br12.62 (1H, s ush.).

6,7-dihydro-4-hydroxy-N-(4-trifloromethyl)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 76%.

1H NMR (CDCl3): σ 2,52 (3H, d), 3,23 (3H, s), 3,50 (3H, s), 6.48 in (1H, q ush.), 7,31 (2H, d), 7,53 (2H, d) of 12.76 (1H, s ush.).

6,7-dihydro-3,7-dimethyl-N-ethyl-4-hydroxy-N-(4-trifloromethyl)-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 68%.

1H NMR (CDCl3): σ to 1.21 (3H, t), 2,52 (3H, s), 3,18 (3H, s)to 3.99 (2H, q), 6,46 (1H, q ush.), 7,27 (2H, d), to 7.50 (2H, d), 12, 86 (1H, s ush.).

Triethylamine salt of 6,7-dihydro-4-hydroxy-N-(3-pyridyl)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 94%; (control connection, in accordance with the invention).

1H NMR (CDCl3): σ 0,86 (9H, t), 2,24 (3H, d ush.), is 2.37 (6H, q), 3,10 (3H, s), 3,29 (3H, s), 6,18 (1H, q ush.), 7,10 (1H, dd), to 7.67 (1H, dt), of 8.00 (1H, dd), to 8.34 (1H, d).

6,7-dihydro-4-hydroxy-N-phenyl-N,2,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide, yield 80%; not included in the formula.

1H NMR (CDCl3): σ of 2.45 (3H, d), up 3.22 (3H, s ush.), 3,47 (3H, s), to 6.95 (1H, q ush.), 7,14-7,28 (5H, m), 12,10 (1H, s ush.).

4,-Dihydro-N,4-dimethyl-7-hydroxy-N-phenyl-5-oxo-2-thia-4-ashenden-6-carboxamide, exit 33%.

1H NMR (CDCl3): σ a 3.15 (3H, s ush.), to 3.49 (3H, s), of 6.49 (1H, d), 7,15-7,21 (3H, m), 7.24 to 7,30 (2H, m), 7,98 (1H, d), 12,36 (1H, s ush.).

4,5-Dihydro-N-ethyl-7-hydroxy-4-methyl-N-phenyl-5-oxo-2-thia-4-ashenden-6-carboxamide, 30%yield.

1H NMR (CDCl3+TFA): σ to 1.22 (3H, t), of 3.45 (3H, s), of 3.97 (2H, q), 6,85 (1H, d), 7,21-of 7.25 (3H, m), 7,28-to 7.32 (2H, m), 8,10 (1H, d).

N-(2,5-Differenl)-4,5-dihydro-N,4-dimethyl-7-hydroxy-5-oxo-2-thia-4-ashenden-6-carboxamide, yield 46%.

1H NMR (CDCl3): σ up 3.22 (3H, s ush.), to 3.41 (3H, s), 6,55 (1H, d), 6,82-of 6.96 (2H, m), 7,02-7,11 (1Hm), 8,03 (1H, d), 12,41 (1H, s ush.).

N-(2,4-Differenl)-4,5-dihydro-N,4-dimethyl-7-hydroxy-5-oxathiane[3,2-6]pyridine-6-carboxamide; yield 57%; (control connection, in accordance with the invention).

1H NMR (CDCl3): σ of 3.32 (3H, s ush.), to 3.38 (3H, s), 6,69 (1H, s ush.), 6,87 (1H, t ush.), 6,94 (1H, s ush.), ? 7.04 baby mortality (1H, s ush.), of 7.70 (1H, d), 12,46 (1H, s ush.).

Example 7.

4,5-Dihydro-N,4-dimethyl-7-hydroxy-N-phenyl-5-oxathiane[3,2-6]pyridine-6-carboxamide (control connection, in accordance with the invention) (Method).

4,5-Dihydro-7-hydroxy-4-methyl-5-oxathiane[3,2-6]pyridine-6-carboxylic acid (1,27 mmol, 288 mg), N-methylaniline (1.92 mmol, 0,211 ml) and dicyclohexylcarbodiimide (1.92 mmol, 0,41 g) were heated in toluene (3 ml) at 70°C for 4 h the Mixture was cooled, was added 0.5 M sulfuric acid (20 ml) and then the mixture was extracted with chloroform. The organic phase was extracted with 1 M NaOH, the pH was brought to about 6 and the precipitate was filtered di is iloveceline. Then the precipitate formed upon acidification with an aqueous solution of HCl was collected and dried under vacuum to obtain the desired compound (225 mg, 56%).

1H NMR (CDCl3): σ 3,30 (3H, s ush.), 3,47 (3H, s), 6,92 (1H, d), 7,13-7,21 (3H, m).

Example 8.

Calcium salt of 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (0,304 mmol, 100 mg) was dissolved in a mixture of 1 M NaOH (0,304 mmol, 0,304 ml) and ethanol (1 ml). The mixture was heated to 50°C. and dropwise with stirring was added aqueous 1 M solution of acetate monohydrate calcium (of 1.05 EQ., 0.16 mmol, 0.16 ml). After stirring at 50°C for 30 min the precipitate was filtered, washed with a mixture of ethanol/water and dried under vacuum to obtain the title compound (101 mg, 96%).

The calculation for C34H30CaN4O6S2; With 58,77%, N 4,35%, N 8,06%found From 58.8, N 4,73, N 7,86. EDTA - titrimetrically definition of Sa gave 5,64% (theoretical - 5,77%).

Example 9.

Diethanolamine Sol 6.7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (0,304 mmol, 100 mg), methanol (3 ml) and diethanolamine (0.33 mmol, to 0.032 ml) was mixed and allowed to retire volatile substances. The precipitate was led from ethyl acetate (2 ml) and hept is on (5 ml) to give the desired compound (101 mg, 76%).1H-NMR in D2O revealed two isomeric forms in a ratio of 4/1. Reported only on signals from the main form.

1H-NMR (D2O) (main rotamer) σ is 2.37 (3H, s), is 3.21 (4H, t), 3,26 (3H, s), 3,37 (3H, s), 3,85 (4H, t), 6,38 (1H, s), 7,10 (1H, t), 7,19 (2H, t), 7,33 (2H, d).

The calculation for C21H27N3O5S; 58,18%, N 6,28%, N RS 9.69%found 57,58, N 6,40, N 9,51.

Example 10.

Lithium salt of 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (0,304 mmol, 100 mg) and ethanol (0.48 ml) was stirred, after which was added dropwise a solution of hydrate of lithium hydroxide (1.04 equiv., 13.2 mg) in water (0,26 ml). After stirring for 5 min the mixture was concentrated and added ethyl acetate (5 ml). The precipitate was collected and dried to obtain the desired compound (79 mg, 77%).1H-NMR in D2O revealed two isomeric forms in a ratio of 4/1. Reported only on signals from the main form.

1H-NMR (D2O) (main rotamer) σ is 2.37 (3H, s), of 3.25 (3H, s), 3,37 (3H, s), 6,37 (1H, s), to 7.09 (1H, t), 7,19 (2H, t), 7,33 (2H, d).

Example 11.

Sodium salt of 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (0,304 mmol, 100 mg) and 2-propanol (0,40 ml) were mixed, and the solution was added sodium methoxide is I in methanol (0.5 M, 0,305 mmol, 0,609 ml). The mixture was concentrated, was added diethyl ether (2 ml) and treated with ultrasound for 15 min in a bath for ultrasound. The resulting crystalline precipitate was collected by filtration and dried to obtain the desired compound (49 mg, 46%).1H-NMR in D2O revealed two isomeric forms in a ratio of 4/1. Reported only on signal from the main form.

1H-NMR (D2O) (main rotamer) σ is 2.37 (3H, s), of 3.25 (3H, s), 3,37 (3H, s), 6,37 (1H, s), to 7.09 (1H, t), 7,19 (2H, t), 7,33 (2H, d).

Example 12.

Copper (II) salt of 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (0,304 mmol, 100 mg), water (1.0 ml), and 1M NaOH (0,304 mmol, 0,304 ml) was stirred and to the resulting clear solution was added a solution of sulfate pentahydrate copper (II) (0,152 mmol, 38,0 mg) in water (0.2 ml). Got a thick pale green precipitate. Added chloroform (2.0 ml), which resulted in obtaining a colorless transparent aqueous phase and a transparent greenish organic phase. The organic phase was collected, dried and evaporated. When processing of the residue with methanol (2.0 ml) was awarded a green crystalline precipitate, which was separated by filtration and dried to obtain the desired product. NMR in CDCI3gave a very broad signals, which is probably due to the Parama is celebrated features of copper (II).

Example 13.

Salt of iron (III) 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide (0,304 mmol, 100 mg), water (1.0 ml) and 1 M NaOH (0,304 mmol, 0,304 ml) was stirred and to the resulting clear solution was added a solution of ferric sulfate pentahydrate (III) (0,051 mmol, is 0.102 mmol Fe (III), 25.0 mg) in water (0.1 ml). Got a thick red sludge. Added chloroform (2.0 ml), which resulted in obtaining a colorless transparent aqueous phase and painted in dark red color of the organic phase. The organic phase was collected, dried and evaporated. When processing the remaining portion of diethyl ether (2.0 ml) was received red crystalline precipitate, which was separated by filtration to obtain the desired connection (to 25.3 mg, 25%).

Example 14.

The ester of acetic acid and 6,7-dihydro-3,7-dimethyl-5-(methylphenylcarbinol)-6-kotieno[2,3-6]pyridine-4-yl.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-kotieno[2,3-b]pyridine-5-carboxamide (from 0.76 mmol, 250 mg) was dissolved in pyridine (3 ml) was added acetic anhydride (1 ml). The reaction mixture was stirred at room temperature for 2 h, then was added 1 M HCl (aq.) (20 ml). The precipitate was collected by filtration, washed with water and dried to obtain the desired compound (209 mg, 74%).

1H-NMR (CDCl3) (on the main rotamer) σ of 2.27 (3H, d)of 2.38 (3H, s), of 3.45 (3H, s), of 3.46 (3H, s), 6,51 (1H, d), 7,14-7,42 (5H, m); (second rotamer) σ is 2.37 (3H, s), of 2.38 (3H, s)to 3.34 (3H, s), 3,71 (3H, s), 6,63 (1H, d), 7,14-7,42 (5H, m).

Example 15.

Ether of 2,2-dimethyl-propionic acid and 6,7-dihydro-3,7-dimethyl-5-(methylphenylcarbinol)-6-kotieno[2,3-b]pyridine-4-yl.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-kotieno[2,3-b]pyridine-5-carboxamide (from 0.76 mmol, 250 mg) was dissolved in pyridine (3 ml) was added pivaloyl chloride (0,12 ml). The reaction mixture was stirred at room temperature for 2 h, then was added 1 M HCl (aq.) (20 ml). The precipitate was collected by filtration, washed with water and dried to obtain the desired compound (116 mg, 37%).

1H-NMR (CDCl3) (main rotamer) σ of 1.44 (9H, s in), 2.25 (3H, d), of 3.42 (3H, s), of 3.46 (3H, s), of 6.49 (1Hd), 7,17-7,41 (5H, m); (second rotamer) σ of 1.36 (9H, s), is 2.37 (3H, d)to 3.33 (3H, s), and 3.72 (3H, s), 6,62 (1H, d), 7,17-7,41 (5H, m).

Example 16.

Ether of 2,2-dimethyl-propionic acid and 6,7-dihydro-3,7-dimethyl-5-(methylphenylcarbinol)-6-kotieno[2,3-b]pyridine-4-roximately.

6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-kotieno[2,3-b]pyridine-5-carboxamide (from 0.76 mmol, 250 mg) was dissolved in DMF (3 ml). Added chloromethyl pivalate (1,14 mmol, 0,171 ml), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, to 1.14 mmol, 0,175 ml) and potassium iodide (10 mg). The reaction mixture was stirred at room temperature for 72 h, after which was added 1 M HCl (aq.) (20 ml). The precipitate was collected by filtration, washed with water and dry the Ali obtaining the desired compound (172 mg, 51%).

1H-NMR (CDCl3) (main rotamer) σ 1.25 (9H, s)to 2.29 (3H, d), 3,50 (3H, s), 3,51 (3H, s), 5,85 (1Hd), 6,11 (1Hd), to 6.43 (1Hd), 7,15-of 7.48 (5H, m); (second rotamer) σ of 1.25 (9H, s), 2,43 (3H, d), 3,47 (3H, s), 3,68 (3H, s), 5,86 (1Hd), 6,13 (1Hd), 6,56 (1H, d), 7,15-of 7.48 (5H, m).

The pharmaceutical composition

Example 17.

Pharmaceutical compositions in accordance with the present invention in the form of capsules, are prepared as follows: sodium salt of compound No. 1 is dissolved in excess aqueous sodium carbonate solution and granulated wet with mannitol and optionally entered by the sodium carbonate. The capsule is filled with all the required excipients except the lubricant, which is present in the granulation phase. The obtained granulate is dried in a conventional manner and passed through a sieve with holes of suitable size. The dried granules can be mixed with sodium fumarate obtained mixture is filled capsules. The capsules contain an appropriate amount of the active ingredient.

Example 18.

The pharmaceutical composition in accordance with the present invention in the form of capsules prepared as follows: preparing a preliminary mixture of the calcium salt of compound No. 1, mannitol and microcrystalline cellulose. Pre-granulated wet with a solution of water aceta is and calcium. All excipients necessary for filling the capsules are present in the granulation phase. The obtained granulate is dried in a conventional manner and passed through a sieve with apertures of suitable size. The dry granules are placed in capsules. Capsules include an appropriate amount of the active ingredient.

Pharmacological methods

Acute experimental EAE.

In our experiments we used female mice of line SJL/N at the age of 8 weeks. Received spinal cord homogenate (MSCH) female mice SW 1/6 at the age of 8-12 weeks. The tissue is homogenized on ice and diluted with cold PBS. Incomplete adjuvant's adjuvant containing 1 mg/ml .tuberculosis hominis H37Ra was emulsified with equal volumes of MSCH obtaining a final concentration of MSCH 10 mg/ml Inoculation volume of 0.1 ml were injected with intradermally at the base of the tail. Vnutriarterialno were injected with pertussis toxin at 0 and 3 days after immunization. The medicine was given per os daily for 3-7 and 10-12 days. Control animals received saline. Animals, eight per group for each dose was assessed by clinical signs of paralytic disease on a scale from 0 to 5 as follows: 0 - normal; 1 - soft tail; 2 - paresis of hind limbs; 3 - hind limb paralysis and lameness of the front legs; 4 - bilateral paralysis of fore and hind limbs; 5, death. Clinical evaluation of p is bodily on the 7th day and every day, since 9 days before the end of the experiment on day 14. The treatment effect was calculated as the percentage inhibition of clinical assessment compared with the control treated with saline.

Induced collagen arthritis.

For experiments we used mouse male line DBA/I between the ages of 8-10 weeks. On day 0 mice were immunized intradermally at the base of the tail with bovine collagen type II (100 μg/mouse) in complete Freund's adjuvant. Treatment was given per os daily for 3-7, 10-14, 17-21, 24-28 and 31-35 days. Fifteen days after immunization, the mice were examined for signs of arthritis. Animals were inspected three times per week. Every second or third day legs of the individual animals with arthritis was evaluated on a scale of 0-4 (0 - no arthritis, 1 - arthritis in one of the interphalangeal joints, metatarsophalangeal or vnutrisemejnyh joints, 2 - two arthritic joint, 3 - three arthritic joint, 4) as in item 3, but with more serious redness and swelling of the legs). Given the evaluation of each of the legs to obtain the highest possible grades in 16 points for each mouse.

R-3327 at-1 prostate cancer rats

Dunning R-3327 AT-1 prostate cancer represents a rat and serves as an experimental animal model of human disease. The tumor AT-1 serially transferred subcutaneously (sc) in syngeneic rats Copenhagen. Small pieces of the tumor transplantion and rats recipients sc and treatment of rats with tumors started when the tumor was easily determined, by about day 10 after transplantation. The dosage of the compounds were given either orally or parenterally, 5 days a week for four weeks. During the experiment were recorded tumor growth and increased body weight.

Derivatives of thieno[2,3-b]pyridine and 2-thia-4-Aza-indene tested for their ability to inhibit acute EAE in mice after treatment with different dosages. Table 2 summarizes data for screening the treatment of acute EAE. Among the preferred compounds represented 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-kotieno[2,3-b]pyridine-5-carboxamide (compound No. 1), 6,7-dihydro-3,7-dimethyl-N-ethyl-4-hydroxy-N-phenyl-6-kotieno[2,3-b]pyridine-5-carboxamide (compound No. 2), 6,7-dihydro-N,7-dimethyl-3-ethyl-4-hydroxy-N-phenyl-6-kotieno[2,3-b]pyridine-5-carboxamide (compound No. 3), 6,7-dihydro-4-hydroxy-N-(4-methoxyphenyl)-N,3,7-trimethyl-6-kotieno[2,3-b]pyridine-5-carboxamide (compound No. 6) and 4,5-dihydro-7-hydroxy-N-phenyl-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-carboxamide (compound No. 10). Additionally, to illustrate the stage of the invention includes compounds of the invention 6,7-dihydro-N,7-dimethyl-4-hydroxy-N-phenyl-6-kotieno[2,3-b]pyridine-5-carboxamide (compound No. 11) comparison (not relevant to the invention) 4,5-dihydro-N,4-dimethyl-7-hydroxy-N-phenyl-5-kotieno[3,2-6]pyridine-6-carboxamide (connect the tion No. 12) and 6,7-dihydro-4-hydroxy-N-(3-pyridyl)-N,3,7-trimethyl-6-kotieno[2,3-b]pyridine-5-carboxamide (compound No. 13).

Table 2.
Suppression of acute EAE.
ConnectionSuppression of acute EAE (%)
Dosage (mg/kg R/o)
0,21,05,0
No. 1 (invention)8599
No. 2 (invention)6684
No. 3 (invention)84100
No. 6 (invention)92
No. 10 (invention)7895
No. 11 (control)53
No. 12 (control)No. 13 (control)46

Inactive is defined as providing inhibition of <35%.

Effective amounts of compounds of formula (I) preferably are introduced to the patient in need of such treatment in accordance with customary methods of introduction and are provided with conventional pharmaceutical compositions comprising an effective amount of the active ingredient and a suitable pharmaceutically acceptable nontoxic excipients and carriers. Such compositions may be in various forms, for example in the form of solutions, suspensions, emulsions, tablets, capsules and powders, prepared for oral administration, aerosols for inhalation, sterile solutions for parenteral administration, suppositories for rectal injection or suitable compositions for local application. The concentration of the compounds described herein in a therapeutic composition will vary depending on a number of factors, including the dosage of drugs that needs to be entered, the chemical characteristics of the compounds and method of administration. Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described, for example, in Pharmaceuticals - The Science of DosageForm Design", M.B.Aulton, Churchill Livingstone, 1988.

The composition can be traditionally introduced in unit dosage form. The preferred dosage of injected compounds probably depends on such variables as the type and extent of progression of the disease or disorder, the overall health status of a patient, excipient, the relative biological effectiveness of selected compounds and compositions of compounds and excipients, as well as a way of introduction. A suitable daily dose for use in the treatment of the aforementioned diseases is considered as ranging between 0.0005 mg/kg to about 10 mg/kg body weight, in particular between 0.005 mg/kg to 1 mg/kg of body weight depending on the specific disorders that are treated, the age and weight of the specific patient and the specific response of the patient to treatment. The exact individual dosages as well as daily dosage will be determined according to standard medical principles for the physician. Discusses various additives to enhance stability or easy drug administration. The pharmaceutical composition may also include additional pharmaceutically useful substance, other than a compound of formula (I).

Some derivatives of thieno[2,3-b]pyridine-5-carboxamide and 2-thia-4-ashenden-6-carboxamide susceptible to himicheskoi degradation in solid pharmaceutical compositions. In one embodiment of the present invention, as illustrated above in Examples 17 and 18, this problem is solved by providing a method of preparing a stable solid pharmaceutical composition, which includes derivative salt thieno[2,3-b]pyridine-5-carboxamide or 2-thia-4-Aza-inden-6-carboxamide of the formula (I) with monovalent or multivalent cations. The method includes forming a capsule or tablet, including salt derivatives of thieno[2,3-b]pyridine-5-carboxamide or 2-thia-4-Aza-inden-6-carboxamide and evenly distributed alkali-reactive component, such as sodium carbonate, capable to neutralize any dissociation of protons from the excipients, hold, therefore, derivatives of thieno[2,3-b]pyridine-5-carboxamide or 2-thia-4-ashenden-6-carboxamide in the form of a salt.

Sources of information

1. Talal, N.: Autoimmune diseases. In: Roitt, I.M. and Delves, P J. (eds.) Encyclopedia of Immunology, pp.195-198. Academic Press, 1992.

2. Prineas, J.W.: The neuropathology of multiple sclerosis. In: Koetsier, J.C. (ed.) Handbook of Clinical Neurology, pp.213-257. Elsevier Science Publ., Amsterdam, 1985.

3. Gutschow, M. et at, J. Med. Chem. 1999, 42, 5437-5447.

4. Gewald, K. et at, Chem. Ber. 1966, 99, 94-100.

5. Shinkwin, A.E. et al., Bioorg. Med. Chem. 1999, 7, 297-308.

6. Buchstaller, H.-P. et al., Monatsh. Chemie 2001, 132, 279-293.

7. Liu, H.-.T. et al., Can. J. Chem., 1982, 60, 437-439.

8. Johnstone, R.A.W. et al., J. Chem. Soc. 1969, 2223-2224.

1. The compound of formula (I)

where R is selected from ethyl, n-propyl, and is oprofile, n-butyl and allyl;
R' is selected from hydrogen, an unbranched, branched or cyclic With1-C4of alkyl; an unbranched, branched or cyclic C1-C3alkoxy, fluorine, chlorine, bromine, trifloromethyl and OCHxFywhere x=0, 1,2,
y=1, 2, 3, provided that
x+y=3;
R" is selected from hydrogen, fluorine and chlorine, with the proviso that R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine;
R3selected from hydrogen and unbranched, branched or cyclic With1-C5of alkyl;
R4selected from hydrogen, CH2EA(CH3)3, pharmaceutically acceptable inorganic or organic cations, and COR4'where R' is an unbranched, branched or cyclic With1-C5of alkyl, phenyl, benzyl and Venetia;
R7selected from methyl and ethyl;
one of a and b is sulfur and the other is C-R2;
when a represents S, R2selected from hydrogen and methyl, with the proviso that R2means methyl only when R3is not hydrogen; and
when the means S, R2is hydrogen;
and any tautomer.

2. The compound according to claim 1 where R' is selected from hydrogen, an unbranched, branched or cyclic With1-C3of alkyl; an unbranched, branched or cyclic With1-C3alkoxy, fluorine, chlorine, bromine, t is iftramadol and OCH xFy.

3. The compound according to claim 1 or 2, where R' is selected from paramethoxy, paraver, perchlor, precriptionzetia, paradiplomatic, when R ' means hydrogen.

4. The compound according to claim 1, where R - orthofer and R' is a pair - or metaphor.

5. The compound according to claim 1, where R3is unbranched, branched or cyclic With1-C4alkyl.

6. The compound according to claim 5, where R3selected from methyl, ethyl, isopropyl and tert-butyl.

7. The compound according to claim 1, where R is selected from methyl and ethyl.

8. The compound according to claim 1, where R7is methyl.

9. The compound according to claim 1, where the inorganic cation is sodium or calcium.

10. The compound according to claim 1, where a is sulfur.

11. The compound according to claim 1, where In - sulphur.

12. The compound according to claim 1, which is 6,7-dihydro-4-hydroxy-N-phenyl-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

13. The compound according to claim 1, which is 6,7-dihydro-3,7-dimethyl-N-ethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

14. The compound according to claim 1, which is 6,7-dihydro-N-dimethyl-3-ethyl-4-hydroxy-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

15. The compound according to claim 1, which is N,3-diethyl-6,7-dihydro-4-hydroxy-7-methyl-N-phenyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

16. The compound according to claim 1, which is 6,7-dihydro-N,7-dimethyl-4-hydroxy-3-ISO-propyl-N-phenyl-6-oxathiin the[2,3-b]pyridine-5-carboxamide.

17. The compound according to claim 1, which is 6,7-dihydro-4-hydroxy-N-(4-methoxyphenyl)-N,3,7-dimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

18. The compound according to claim 1, which is N-(2,4-defloriani)-6,7-dihydro-4-hydroxy-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

19. The compound according to claim 1, which is 6,7-dihydro-4-hydroxy-N-(4-were)-N,3,7-trimethyl-6-oxetine[2,3-b]pyridine-5-carboxamide.

20. The compound according to claim 1, which is 6,7-dihydro-4-hydroxy-N-(4-trifloromethyl)-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

21. The compound according to claim 1, which is N-(4-course)-6,7-dihydro-4-hydroxy-N,3,7-trimethyl-6-oxathiane[2,3-b]pyridine-5-carboxamide.

22. The compound according to claim 1, which is 4,5-dihydro-7-hydroxy-N-phenyl-N,1,4-trimethyl-5-oxo-2-thia-4-ashenden-6-
carboxamid.

23. The compound according to claim 1, which is 4,5-dihydro-1,4-dimethyl-N-ethyl-7-hydroxy-N-phenyl-5-oxo-2-thia-4-ashenden-6-
carboxamid.

24. The compound according to claim 1 for use as a therapeutic agent.

25. Pharmaceutical composition for treating diseases caused by an autoimmune response or pathological inflammation, comprising as active ingredient a compound according to any one of claim 1 to 23 together with pharmaceutically acceptable nontoxic excipients the media.

26. The pharmaceutical composition according A.25 for use as a therapeutic agent with a daily dosage of active ingredient 0.005 to 1 mg/kg body weight.

27. The method of obtaining compounds of General formula (I) as defined in claim 1 (method A) by reaction of a derivative of an ether carboxylic acids of the formula (II)

where RAis an alkyl group of C1-C4;
with an aniline of formula (III) in a suitable solvent; or
(method B) by reaction of carboxylic acids of General formula (IV) with an aniline of General formula (III)

with the use of proper interfacing of the reagent and a suitable solvent.

28. The method according to item 27, where the solvent in the way And n-octane.

29. A method of treating a mammal suffering from diseases that are the result of an autoimmune response or pathological inflammation, including the introduction of the said mammal therapeutically effective amounts of compounds of formula (I)

where R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and allyl;
R' is selected from hydrogen, an unbranched, branched or cyclic With1-C4of alkyl; an unbranched, branched or cyclic C1-C3alkoxy, fluorine, chlorine, bromine, trifloromethyl and OCHx Fywhere x=0, 1, 2,
y=1, 2, 3, provided that
x+y=3;
R" is selected from hydrogen, fluorine and chlorine, provided that R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine;
R3selected from hydrogen, an unbranched, branched or cyclic With1-C5of alkyl;
R4selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic and organic cations, and COR4'where R4' is selected from unbranched or branched C1-C5of alkyl, phenyl, benzyl and Venetia;
R7selected from methyl and ethyl;
one of a and b means sulfur, and the other is C-R2;
when A-S, R2selected from hydrogen and methyl, provided that R2means methyl only when R3is not hydrogen; and
when B-S, R2is hydrogen;
and any tautomer.

30. The method according to clause 29, in which the mammal suffers from multiple sclerosis (MS).

31. The method according to clause 29, in which the mammal suffers from systemic lupus erythematosus (SLE).

32. The method according to clause 29, in which the mammal suffers from rheumatoid arthritis (RA).

33. The method according to clause 29, in which the mammal suffers from inflammatory bowel disease (IBD).

34. The method according to clause 29, in which the mammal suffers from psoriasis.

35. The method according to clause 29, in which the mammal suffers from inflammatory RES is irating disorders.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

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

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: medicine.

SUBSTANCE: invention relates to the method for production of the compound of the formula (1a), being an inhibitor of thrombocyte aggregation (1a), where X is halogen atom. The method includes interaction of compounds of the formula (II), (II), where X has above mentioned value and Y and Z independently from each other are leaving groups, with optically active alkamine with formation of diastereoisomers admixture.

EFFECT: development of the new advantageous method for production of the bioactive compound.

48 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

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23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the method for preparation of hexachloroantimonates of 2,3-dihydro[1,3]thiazolium of general formula wherein R1 is alkyl or phenyl, R2 is alkyl, phenyl or hydrogen, R1+R2 is cycloalkyl by the interreaction of 4,6-dimethyl-2-pyrimidinsulfenyl chloride with corresponding olefine in presence of antimony pentachloride in equimolar ratio in the media of methylene chloride.

EFFECT: claimed compounds can be used in production of pharmaceutical preparations and biologically active substances.

2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

Thienopyrazoles // 2358978

FIELD: chemistry.

SUBSTANCE: description is given of thienopyrazol of formula I its pharmaceutically acceptable salts or esters, in which X represents N or C-R7; X1 represents N or C-R1; R1, R2, R3, R4, R5 and R6 are independently chosen from a group which contains hydrogen, possibly substituted acyl, alkyl, alkoxy group, acylaminogroup, alkoxyalkyl, (Y1)(Y2)NC(=O)-, alkoxycarbonyl, aryl, halogen, carboxy group; or R5 and R6 together with two carbon atoms with a double bond, with they are bonded, form a benzene ring; R7 is a hydrogen atom, halogen or alkyl; and Y1 and Y2 are independently a hydrogen atom, alkyl, aryl or heteroaryl, or Y1 and Y2 together with a nitrogen atom, with which they are bonded, form a heteroaryl group or heterocycloalkyl group. The invention also relates to pharmaceutical compositions, containing these compounds. Thienopyrazoles can be used for treating diseases, which can be affected by protein kinase inhibition, particularly, interleukin-2-induced tyrosine kinase.

EFFECT: wider field of application of the compounds.

14 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Clopidogrel process by optical separation of its racemic form with using optically active amine of formula V to make optically active form of compound of formula III or its acid-additive salt followed with methylation of compound III or its salts. The intermediate product of formula resulted from reaction of racemic form of Clopidogrel and amine V.

EFFECT: possibility to make a high-yield end product.

22 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention concerns development of method of obtaining furylhetarylmethane derivatives of the general formula I applicable as semiproducts for obtainment of new polycyclic derivatives of thieno[2,3-b]pyridine. Method of obtaining furylhetarylmethanes with thieno[2,3-b]pyridine fragment of the general formula I involves forming furylhetarylmethane structure by alkylation of furane ring catalysed by acids; reaction is performed by boiling alcohols of 3-amino[2,3-b]pyridine and 2-methylfurane range in dioxane in the presence of 0.2-0.4 ml of acid catalyst, which is a mix of 70% perchloric acid, acetic anhydride and glacial acetic acid at the ratio of HClO4:(CH3CO2)O:CH3COOH=0.056:0.033:0.052 mol for 1.5-8 hours. It allows forming new heterocyclic system of furylhetarylmethanes with thieno[2,3-b]pyridine fragment by alkylation of 2-methylfurane by 2-hydroxy(phenyl)methyl-4,6-disubstituted-3-substituted carboxamidothieno[2,3-b]pyridines.

EFFECT: obtaining compounds applicable as semiproducts for obtainment of new polycyclic derivatives.

2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a new derivative of sulfonamide substituted imidazoquinolines, and specifically to N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo-[4,5-c]-qunolin-1-yl]-1,1-dimethylethyl}-methanesulfonamide and its pharmaceutically acceptable salts, as well as to a pharmaceutical composition based on this compound.

EFFECT: invention also relates to a method of inducing biosynthesis of cytokines in an animal organism and methods of treating viral and oncological diseases in animals using said compound and pharmaceutical composition based on said compound.

5 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, particularly to the technology of producing selenoxanthenes and can be used in producing food additives, medicinal agents and cosmetic agents, which exhibit broad biological activity. An agent is described, which is an α-crystalline form of 9-phenyl-sym-octahydroselenoxanthene, which has antixodant, detoxication, immunomodulating, antiatherogenic, antisclerotic, anabolic, hypolipid action, and the corresponding structural formula with powder X-ray pattern obtained on Cu-K radiation sources with characteristic reflection indices expressed in degrees of the diffraction angle 2θ: 6.0 12.0 15.0 17.0 19.0 20.0 21.5, 21.7, 20.9 25.0 27.0 28.0 29.0 37.0 and melting temperature 96.8°C, as well as to a method of producing said agent, involving crystallisation of the corresponding 9-R-sym-hydroselenoxanthene from low-polar or non-polar solvent, preferably hexane, chloroform or isopropyl alcohol.

EFFECT: design of an efficient method of producing selenoxanthenes.

3 cl, 1 dwg, 1 tbl

FIELD: food industry.

SUBSTANCE: preparation for usage as feeding contains Bifidobacterium breve in quantity 1×104 -1×1010 cfu/g and a mixture of indigestible carbonhydrates. Carbohydrates are chosen from indigestible monosaccharides up to hexasaccharides of the same carbohydrate structure and from indigestible heptasaccharides and top polysaccharides of the same structure including inuline. Addition to children feeding and infant food containing mentioned preparation are proposed as its usage for healing or prevention of children immune disturbances as for usage for children obtaining artificial of partly breast-feeding.

EFFECT: usage of the preparation for producing of composition for prevention and healing of insufficient energy consumption, also for preparation of composition for inhibiting of eosinophils infiltration when having allergy.

16 cl, 7 tbl, 29 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology and design of agents with immunomodulating properties. A new fungal strain Penicillium verrucosum VKPM F-984 and a new immunomodulating agent based on the strain are proposed. The strain is extracted from microflora of ginseng roots and is kept in a medium which contains mineral salts, glucose and asparagine. Fungus mycelium is extracted with a water-alcohol solution (70% ethanol solution). The advantage of this agent is its natural occurrence and effecient stimulation of adaptive capabilities of the body.

EFFECT: obtaining an extract which has stimulating action on cell and humoral immunity, improves immune status of the body.

3 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns an ellagic acid composition for immune system enhancement, differing that additionally is contains chitosan beta-1.3/1.6-glucans or oligosaccharides.

EFFECT: offered composition possesses enhanced immunostimulating effect.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmacology and can be used in veterinary science and medicine for chemotherapy. There is disclosed immunostimulating and antioxidant lithium composition containing lithium ascorbate and lithium aspartate in percentage ratio 50:50.

EFFECT: expansion of the list of low-toxicity immunomodulators applicable for manufacture of drugs.

1 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly therapy, and can be applied in chronic disease treatment. Method involves causative agent extraction or determination of antibodies to causative agents or extraction of genetic components from blood, body fluid or smear. Treatment is performed by vaccine drugs specific to one or several identified causative agents, additionally immunomodulators are administered.

EFFECT: activated repair processes, arrested development of disease state of organs and systems due to elimination of identified pathogen from organism and to immune correction.

3 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention concerns veterinary medicine, bioactive stimulation agent and method of secondary immunodeficiency correction applying the agent. Method involves subcutaneous injection of non-specific immunoglobulin and additional oral application of alcohol infiltration of minced herbal mix including grass and inflorescence of Echinacea purpurea, coltsfoot, harmala shrub grass and common licorice roots at equal amount in the form of aqueous solution of 7-8% concentration in the dosage of 1.5-2.0 ml per kg of live weight for 15 days at 24 hour interval. Bioactive stimulation agent renders positive effect on all animal organs and systems, adjusts metabolic processes and enhances organisms resistance (activation of B- and T-systems, phagocytosis), allowing for correction of secondary immunodeficiency to physiological standard level.

EFFECT: natural origin, easy metabolic assimilation and excretion, high compatibility with other medicines, absent sensibilisation and induction of immunopathological reactions.

2 cl, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention concerns obtainment of cells of monocyte origin, inducing transplant acceptance, expressing antigens CD3 and CD14, and can be applied in transplantology. Monocytes are extracted from blood, reproduced in cultural medium with 1-20 mcg/l of cell growth factor M-CSF and cultivated for 24-72 hours in cultural medium with 0.1-20 ng/ml of interferon γ-IFN. Further the cells are extracted from cultural medium. For cell CD3 and CD14 expression antibodies produced by hybridoma DSM ACC2542 are used. If necessary, obtained cells are suspended and freezed.

EFFECT: obtainment of cells of monocyte origin, inducing transplant acceptance and suppressing transplant rejection reaction.

26 cl, 29 dwg, 1 tbl, 13 ex

FIELD: pharmacology.

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

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

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