Means for inhibiting glucose-6-phosphatase system of mammalian liver

 

(57) Abstract:

The proposed tool for the inhibition of glucose-6-phosphatase system of mammalian liver. The tool represents the esters of cyclohexane derivatives of General formula I

< / BR>
where A-B, R3, R4, R5, Y and Z have the specified values. The invention expands the Arsenal of tools specified destination. 2 C.p. f-crystals, 5 PL.

The clinical picture of diabetes is characterized by increased amounts of sugar in the blood. In the case of insulin-dependent or type I diabetes is caused by the death of producing insulin - cells of the pancreas; therefore, treatment is carried out by receiving insulin (hormone replacement therapy). On the contrary, is not dependent on insulin or type II diabetes is characterized by reduced insulin action in muscle and adipose tissue (insulin resistance) and increased production of glucose by the liver. The cause of these metabolic disorders is far from clear. Known therapy with sulfonylureas tries to compensate for insulin resistance by increasing the body's own insulin secretion, but this is not in all cases leads to normalization of blood sugar levels and may not stop the spread of the independent and later suffer from such illnesses, as cataract, nephropathy and angiopathy.

What is desired, therefore new therapeutic principles of treatment of type II diabetes.

Fasting glucose concentration in the blood is determined by the secretion of glucose by the liver. Different groups of researchers showed that the increase of blood sugar in diabetes type II correlates proportionally with increased secretion of glucose from the liver. Glucose is secreted by the liver into the blood, can be formed as a result of decomposition of liver glycogen (glycogenolysis), and also by gluconeogenesis.

Glucose-6-phosphate is a common end product of both gluconeogenesis and glycogenolysis. The final stage of selection the liver glucose-6-phosphate is catalyzed by glucose-6-phosphatase (EC 3.1.3.9). Glucose-6-phosphatase is mnogovershinny complex, found in the endoplasmic grid (ER). This enzyme complex consists of being in the ER-membrane glucose-6-phosphotransferase localized on luminale side of the endoplasmic grid glucose-6-phosphatase and posttranslate [see J. Ashmore and G. Weber, "the Role hepatitis glucose-6-phosphatase in the regulation of carbohydrate metabolism" in the book "Vitamins and hormones", T. XVII, (ed Harris R. S., Marrian G who we are", Biochim. Biophys. Acta, 1092, 129-137 (1990)]. The existing extensive literature shows that under all investigated conditions, resulting in experiments on animals to high concentrations of glucose in the blood, such as when using streptozocin, alloxan, cortisol, thyroid hormones and in the case of starvation, the activity of this mnogovershinnoe complex also increases. Moreover, numerous studies indicate that observed in diabetics of type II increased allocation glucose is associated with increased activity of glucose-6-phosphatase. The importance of glucose-6-phosphatase system for normal glucose homeostasis is emphasized further hypoglycemic symptoms in patients with disease type IB, associated with the accumulation of glycogen in which there is no translocase component of glucose-6-phosphate system.

The decreased activity of glucose-6-phosphatase through suitable active substances (inhibitors) should lead to reduced hepatitis selection glucose. These biologically active substances must be able to adapt the allocation of glucose by the liver to the effective peripheral flow. Declining due to it in accordance NAT is in respect of damage later diabetes harm.

The literature describes a number of nonspecific inhibitors of glucose-6-phosphatase, as, for example, phlorhizin [Soodsma J. F., B. Legler, and Nordlie, R. C., J. Biol. Chem, 242, 1955-1960 (1967)], 5,5'-dithio-bis-nitrobenzoic acid [Wallin B. K. and Arion, W. J. , Biochem. Biophys. Res. Commun. 48, 694-699 (1972)], 2,2'-diisothiocyanate and 2-isothiocyanato-2'-acetoxy-stilbene M. A. Zoccoli, Karnowski J. Biol Chem. 255, 1113-1119 (1980)]. However, still no therapeutically applicable inhibitors of glucose-6-phosphatase system.

Substituted derivatives of cyclohexane, which are described in more detail below, are partly known from the chemical and biological literature compounds that can be isolated from many plants [R. Krasemann, Arch. Pharm. 293, 721 (1960)]. However, pharmacological and biochemical actions of these esters is known to only a few. Chlorogenic acid, a typical representative of the compounds considered here, incidentally described as an inhibitor of lipoxygenase [M. Nishizawa, etc., Chem. Pharm. Bull., 34 (3), 1419 (1986)].

Currently, the applicant has found that certain esters of substituted cyclohexanecarboxylic acids, such as chlorogenic acid (N 17 of the investigated compounds are inhibitors of glucose-6-phosphatase system is R> where A-B means a group

< / BR>
or group

< / BR>
R1means CN, COOH, COO-(C1-C4-alkyl), C1-C4-alkanoyl, SO3-(C1-C4-alkyl), SO3H, PO(OH)2, PO(OH)(O-C1-C4-alkyl) or PO(O-C1-C4-alkyl)2;

R2denotes H, OH or F;

R3means H, phenyl, naphthyl, pyridyl, thienyl, furyl, and aromatic or heteroaromatic residue may be single - or multi-substituted by fluorine, chlorine, bromine, iodine, OH, NO2C1-C4-alkanoyl, (C1-C4-alkoxy), C1-C4-alkyl, phenyl, phenoxy, teinila, fullam, pyridium, imidazolium or benzyloxy, and the substituents are the same or different;

R4, R5, R6denote H, OH, fluorine, chlorine, bromine, C1-C4-alkanoyl, C1-C4-alkyl, phenyl, phenoxy, thienyl, furyl, pyridyl, imidazolyl or benzyloxy, and R4, R5, R6are the same or different;

X is -(CH2)n-; -CH=CH - or-CH2OCH2-;

Y represents -(CH2)n-; O, S or NH;

Z means -(CH2)n-; or-CH=CH - and n stands for zero, 1, 2, 3, or 4

are inhibitors of glucose-6-phosphatase system p and have the following meaning:

R1means COOH, COO-(C1-C4-alkyl), PO(OH)2, PO(OH)(O-C1C4-alkyl) or PO(O-C1-C4)-alkyl)2;

R2means H or OH;

R3means H, phenyl, naphthyl, pyridyl, thienyl, furyl, and aromatic or heteroaromatic residue may be one-, two - or three-fold substituted by fluorine, chlorine, bromine, iodine, NO2, OH, C1-C4-alkanoyl, C1-C4-alkoxyl, C1-C4-alkyl, phenyl, phenoxy, teinila, fullam, pyridium, imidazolium or benzyloxy, and the substituents are the same or different;

R4, R5and R6means H, OH, fluorine, chlorine, bromine, C1-C4-alkanoyl, C1-C4-alkyl, phenyl, thienyl, furyl, pyridyl, imidazolyl or benzyloxy, and R4, R5, R6are the same or different;

X is -(CH2)n-; -CH=CH - or-CH2OCH2-;

Y represents -(CH2)n-; O, S or NH;

Z means -(CH2)n- or-CH=CH - and

n = 0, 1, 2, 3, or 4.

Preferably the use of such compounds of formula (I) in which residues have the following meaning:

R1means COOH or COO-(C1-C4-alkyl);

R2means H or OH;< a residue may be one, two or three times substituted by fluorine, chlorine, OH, NO2C1-C4-alkanoyl, C1-C4-alkyl, phenyl, phenyloxy or benzyloxy, and the substituents are the same or different;

R4, R5, R6denote H or OH, and R4, R5, R6are the same or different;

X is -(CH2)nand

n = 0, 1, or 2;

Y represents oxygen or NH;

Z means -(CH2)n- with

n = 0 or 2

or-CH=CH-.

Available in compounds of formula (I) alkyl, CNS and alcoholnye residues are linear or branched.

Further, the invention relates to the use of compounds of formula (I) for the treatment of diseases associated with increased activity of glucose-6-phosphatase system.

The invention also relates to the use of compounds of formula (I) for the treatment of diseases associated with increased secretion of glucose by the liver.

In addition, the invention relates to the use of compounds of formula (I) for the treatment of type II diabetes (non-insulin-dependent or senile diabetes).

Further, the invention encompasses the use of compounds of formula (I) for the preparation of drugs for the treatment of dia the capacity of glucose-6-phosphatase system.

The action of the compounds according to the invention on glucose-6-fosfatazu system was studied in enzyme test liver microsomes.

For the preparation of microsome fraction containing glucose-6-phosphatase, using fresh liver of male Wistar rats and treated as described in the literature [Canfield W. K. and Arion, W. J., J. Biol.Chem. 263, 7458-7460 (1988)] . This microsome fraction can be stored at -70oC at least 2 months without significant loss of activity.

Detection of glucose-6-phosphatase activity, as indicated in the literature (Arion, W. J. Methods Enzymol 174, Acdemic Press, 1989, S. 58 - 67), is carried out by determination of phosphate released from glucose-6-phosphate. 0.1 ml of the test mixture contains glucose-6-phosphate [1 mmol/l], the test substance 0.1 g of microsome fraction and 100 mmol/l HEPES-buffer [4-(2-hydroxyethyl)piperazine-1-econsultancy], pH=7.0. The reaction is initiated by adding enzyme. After 20 min at room temperature the reaction is stopped by adding 0.2 ml of phosphate reagent. The sample is incubated for 30 min at 37oC and then measure the absorption (A) blue color at 570 nm. Inhibitory activity of the test substance is obtained by comparison with a control reaction that does not soda the ve example of the magnitude of inhibition, obtained for a number of compounds of the formula (I). The investigated compounds are partially known from the literature. Obtaining described in the embodiments.

The medicine according to the present invention, obtained in the usual way, except for compounds of formula (I) may also contain pharmaceutically acceptable additives such as diluents and/or carriers. Under this you need to understand physiologically acceptable substances, which after mixing with a biologically active material make it suitable for the reception of the form. Preferably oral administration.

Suitable solid and liquid galenovye forms of the compositions are, for example, tablets, pills, powders, capsules, syrups, emulsions, suspensions, drops, and preparations with prolonged release of biologically active substances. As commonly used media, respectively diluent should be called, for example, various sugars and types of starch, cellulose derivatives, magnesium carbonate, gelatin, animal and vegetable oils, polyethylene glycols, water or other suitable solvents, and a water-containing buffers that by adding salts can be done isotonic. In addition, in localizator, and preservatives as other additives in the pharmaceutical compositions according to the invention.

Drugs predominantly possible to obtain in the form of dosage units, especially in the form of tablets and capsules. Each dosing unit, especially for oral administration may contain up to 500 mg, preferably, however, from 10 to 200 mg, of active components. However, you can also use lying above or below these values, dosing units, which, if necessary, before taking you to share. If necessary, dosage units for oral administration can be microcapsulating, in order, for example, to slow down the selection. Controlled allocation of reach, for example, by coating or embedding justicialismo material in a suitable polymers, waxes or similar

The investigated compound is synthesized as described below.

Obtaining compound (b) from the compound (a) (compound a-f, see the end of the description. Reaction scheme 1).

163.3 g (0.85 mol) of the compound (a) [Fischer, Dangschat, Chem. Ber. 65, 1009 (1932)] are suspended in 186 ml (1.8 mol) of cyclohexanone and add 0.5 ml of concentrated sulfuric acid. Then slowly heated up to the temperature of the heating bath 200oC. Then the reaction solution is cooled to 70oC and add 10 g of sodium bicarbonate. After this is mixed with 700 ml of ethyl acetate, the organic phase is washed with water, saturated solution of sodium chloride. Then the organic phase was concentrated in vacuo. Light yellow residue is crystallized from a mixture of isopropanol with water (1:1) and get 142.1 (75%) of the lactone (b) in the form of colorless crystals; so pl. 140-141oC.

Obtaining compound (c) from the compound (b):

at 38.14 g (0.15 mol) of hydroxyacetone (b) are dissolved in 180 ml of dichloromethane. Add 53.0 ml (0.3 mol) of diisopropylethylamine. To this solution at room temperature was added dropwise 45.0 ml (0,254 mol) of trimethylsilyldiazomethane and stirred for 6 h at boiling temperature under reflux. Then the reaction solution make a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic phases are extracted with chilled until about 6oC 1 n solution of potassium hydrosulfate and dried over sodium sulfate. After concentration in vacuo receive light yellow residue which is crystallized from a mixture of heptane with ethyl acetate (6 : 1). Get 57.0 g (98%) of compound (c); so pl. 100-102oC.

Obtaining the deposits of 0.4 ml of water was added dropwise at room temperature, 3.8 ml of 1 n sodium hydroxide solution. The reaction mixture was stirred for 2 h and then concentrated in vacuo. Obtain 1.3 g (85%) of compound (d) as amorphous solids.

1H-NMR (270 MHz, d6-DMSO) , M. D. = 0.01 (C., 9H); 0.72-0.89 (m, 2H), 1.21-1.62 (m , 10H); 1.65-1.78 (m, 1H); 1.82-1.92 (m, 1H); 1.94-2.08 (m, 2H); 3.38-3.63 (m, 3H); 3.82-3.88 (m, 1H); 4.18-4.47 (m, 2H); 7.80-7.90 (m, 1H).

Stage (d), (e) and (f) describe the example of a connection 8.

Obtaining compounds 8C (from compound 8A through connection 8B) (compounds 8A-8E cm. at the end of the description. Reaction scheme 2).

10.0 g (0.052 mol) of ester p-hydroxycortisol acid (8A) is dissolved in 60 ml of anhydrous dichloromethane. Add 27 ml (0,156 mol) of diisopropylethylamine and at room temperature and in an atmosphere of argon was added dropwise 19.5 ml (0.11 mol) of trimethylsilylamodimethicone. Stirred for 4 h at room temperature and then the reaction solution was poured into ice solution of ammonium chloride. Extracted with ethyl acetate, the combined organic phases are washed successively ice 1 n solution of potassium hydrosulfate and a saturated solution of sodium chloride. After drying the organic phase over sodium sulfate concentrated in vacuo. Obtain 16.8 g of a simple ester 8B, Col) 5 n sodium hydroxide solution. After 24 hours the methanol is distilled off in vacuum and the aqueous suspension of the sodium salt of compound 8C acidified with 2 n hydrochloric acid to pH 4. Acid 8C precipitates almost quantitatively, and it is possible to suck and rinse with water. Get 16.02 g of compound 8C; so pl. 93-96oC.

The connection is obtained from compounds 8E 8C and (d) (corresponds to stage (e) in scheme 1).

a) 7.95 g (27 mmol) of compound 8C was dissolved in 35 ml of anhydrous dimethylformamide. At room temperature was added dropwise a solution of 4.54 (27 mmol) of carbonyldiimidazole in 35 ml of anhydrous dimethylformamide. Then this solution is heated for 1 h at 60-70oC, and you can observe the production of CO2.

b) To a solution of 8.92 g (0.021 mol) of sodium salt of compound (d) in 50 ml of anhydrous dimethylformamide added at room temperature and in an atmosphere of argon 0.75 g (0.025 mol) of 80% sodium hydride. This suspension is stirred for 1 h at room temperature and then add to it at 0-5oC obtained according to p.(a) solution imidazoline 8D. The solution is stirred for 2.5 h at 0-5oC and then the reaction mixture was poured into a saturated solution of ammonium chloride. By adding 1 n solution of potassium hydrosulfate the mixture is acidified to pH 4 and extracted with Oia, water and a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate, concentrated in vacuo and the oily residue chromatographic on silica gel (solvent: ethyl acetate/n-heptane/glacial acetic acid = 20 : 60 : 1). Obtain 10.3 g (78%) of compound 8 as a colorless oil.

1H-NMR (270 MHz, CDCl3): , M. D. = 0.02 (C., 9H). 0.05 (C., 9H); 0.91-1.03 (m , 4H); 1.5-1.78 (m, 10H); 1.91-2.05 (m, 1H); 2.28-2.42 (m, 2H); 2.57-2.63 (m , 1H); 3.68-3.90 (m, 4H); 4.14-4.20 (m, 1H); 4.42-4.52 (m, 1H); 4.91-4.96 (m, 1H); 5.11-5.18 (m, 1H); 5.24 (SD, 2H); 5.21-5.34 (m, 1H); 6.32 (D., J = 10 Hz, 1H); 7.02-7.08 (m, 2H); 7.42-7.5 (m, 2H); 7.65 (D., J = 10 Hz, 1H); 13 (C., S., COOH, 1H).

Obtaining of compound 8 from compound 8E (corresponding to stage (f) in scheme 1).

5.02 g (7.4 mmol) of compound 8E was dissolved in 130 ml of dioxane and at room temperature and stirring is mixed with 95 ml (0.19 mol) of 2 n hydrochloric acid. Stirred for 20 h at room temperature. Upon completion of the reaction in a transparent solution set pH 3-4 with 2 n sodium hydroxide solution and concentrated in vacuo. The solid residue is stirred in a mixture of ethyl acetate with methanol (3 : 1) and filtered, the insoluble sodium chloride. The filtrate is again concentrated and the residue chromatographic on silica gel (ethyl acetate/methanol/water the table. 4 as examples of compounds receive the above way. While the synthesis of compounds containing a hydroxyl group in the residue R3General formula (I), at the expense of related transactions with a protective group different from other syntheses in which these operations are not needed.

In table. 4 and 5 (see below) presents the physical characteristics of synthesized as examples of the compounds.

The connection 20, 20 respectively (compound 20A-20 provided at the end of the description. Reaction scheme 3).

Getting connection 20B of the connection 20A.

4.0 g (17.5 mmol) of known compounds 20A [S. A. Bowles and others, Tetrahedron 46, 3981 (1990)] was dissolved in 30 ml of anhydrous dimethylformamide. Added 1.61 g (23.7 mmol) of imidazole, and 2.64 g (12.5 mmol) of tert.-butyldimethylsilyloxy. After 12 h at 25oC the reaction solution is mixed with 200 ml of saturated solution of ammonium chloride and extracted with portions using 300 ml of methyl tert. -butyl ether. The combined organic phases are washed with water and saturated sodium chloride solution and dried over magnesium sulfate. Obtain 5.4 g (90%) of compound 20B in the form of a colorless oil.

1H-NMR (270 MHz, CDCl3): , M. D. = 0.06 (SD, 3/P> Getting connection 20C, 20D respectively of compound 20B:

5.4 g (15.8 mmol) of compound 20B was dissolved in 100 ml of tert.-butanol. Added 1.9 g (25.3 mmol) of trimethylamine-N-oxide and 20 ml of water. Then add 100 mg (0.4 mmol) of osmium tetroxide in the form of a complex with 2.0 g of pyridine and stirred for 14 h at boiling temperature. After filtered off the catalyst and concentrating the filtrate and the residue chromatographic on silica gel (solvent: ethyl acetate/n-heptane = 1:1). Obtain 2.5 g (42%) of a mixture of compounds 20C/20D in the ratio of 3 : 1 as a colorless oil.

The mixture of both isomers 20C/20D:

1H-NMR (270 MHz, CDCl3): , M. D. = 0.08 - 0.14 (m, 6H); 0.88 - 0.92 (m , 9H); 1.38 - 1.40 (m, 3H); 1.51 - 1.55 (m, 3H); 1.80 - 2.0 (m, 1H); 2.28 - 2.48 (m, 1H); 3.61 - 4.52 (m, 7H).

Obtaining compounds 20E and 20F of the compounds 20C, and 20D respectively.

2.5 g (6.6 mol) of a mixture of compounds 20C/20D in the ratio 3 : 1 are dissolved in 60 ml of anhydrous dichloromethane. Add 5 ml of 2,2-dimethoxypropane, and 200 mg pyridine-p-toluensulfonate. The reaction solution is boiled for 6 h and then the solution was concentrated in vacuo. The residue, a mixture of compounds 20E and 20F, share on silica gel (solvent: ethyl acetate/n-heptane = 3:1) and generally get 2.4 g (87%) 28 (C., 3H); 0.09 (C., 3H); 0.90 (C. , 9H); 1.34 (c. 3H); 1.39 (C., 3H); 1.45 (C., 3H); 1.50 (C., 3H); 1.72 (DD. J = 13.5 Hz, J = 12 Hz, 1H); 2.19 (DD., J = 4.0 Hz, J = 14.5 Hz, 1H); 3.81 (C., 3H); 3.81 - 3.92 (m, 1H); 4.05 - 4.11 (m, 1H); 4.42 - 4.48 (m, 1H); 4.68 - 4.70 (m, 1H).

The connection is 20G of connection 20E.

1.4 g (3.4 mmol) of the compound 20E dissolved in 30 ml of dioxane. Was added dropwise 2 ml of 6 n sodium hydroxide solution. After 2 h the reaction solution is concentrated and mixed with 20 ml of ethyl acetate and poured into 200 ml of saturated solution of ammonium chloride. This mixture is acidified with 1 n solution of potassium hydrosulfate to pH 5 and the organic phase is washed with a saturated solution of sodium chloride and dried over sodium sulfate. After concentrating oily residue is dissolved in 15 ml anhydrous THF and added 3.0 g (9.5 mmol) tetrabutylammonium fluoride (trihydrate), and 0.5 ml of triethylamine. After that, the solution is heated for 12 h at 60oC. Then the solution is concentrated and the residue purified on silica gel (solvent: ethyl acetate/n-heptane/glacial acetic acid = 30:10:1. Allocate 600 mg (54%) of compound 20G in the form of a colorless oil.

The connection is obtained from 20H connection 20F.

Connection 20H from compound 20F get the same connection 20G of connection 20E.

On the value 20, accordingly, the connection 20, carried out analogously to methods of synthesis of d - f (as described for compound 8).

The connection 20; so pl. 275oC (decomposition).

The connection 20; so pl. 165-175oC (decomposition).

The connection 21

< / BR>
Known from the literature lactone 21A [S. Hanessian, Tetrahedron, 45, 6623 (1989)] is transformed into the connection 21 is similar to methods of synthesis of d - f (as described for compound 8); so pl. 227-229oC.

The connection 22

< / BR>
Well-known compound 22A [S. Mills and others, Tetrahedron. Let. 29, 281 (1988)] in turn, the connection 22 is similar to methods of synthesis of d - f (as described for compound 8); so pl. 204 - 206oC.

The connection 23 (see the end of the description. Reaction scheme 4).

Getting connection 23B of compounds 23A.

20.0 g (88.4 mmol) known from literature connections 23A [J. C. Barriere, etc., Helv.Chim.Acta 66, 296 (1983)] was dissolved in 200 ml of anhydrous dichloromethane and 25oC is mixed with 14.9 g (176.8 mmol) dihydropyran and 200 mg pyridine-p-toluensulfonate. This solution was stirred for 12 h at room temperature. Then add 500 ml of ethyl acetate and the organic phase is washed with sodium hydrogen carbonate solution and saturated sodium chloride solution. The PR is izvetnogo solids; so pl. 55 - 58oC.

Getting connection 23C of compound 23B.

3.66 g (36 mmol) of Diisopropylamine dissolved in 100 ml of anhydrous tetrahydrofuran. In an argon atmosphere and at -20oC was added dropwise 25 ml of 1.5 M solution of n-utility in hexane. The reaction solution allowed to warm to 0oC and then cooled to -60oC. At this temperature slowly added dropwise 4.1 g (35,3 mmol) tert.-butyl ester of acetic acid, dissolved in 20 ml of anhydrous tetrahydrofuran. The solution is stirred for 30 min at -60oC and then at -60oC was added dropwise 10.0 g (32.2 mmol) of compound 23B, dissolved in 30 ml of anhydrous tetrahydrofuran. After stirring for 1 h at the same temperature, the reaction mixture was hydrolized with a saturated solution of sodium bicarbonate. Extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. After concentrating obtain 11.9 g (87%) of compound 23C in the form of a light brown oil.

Getting connection 23D of compound 23C.

11.9 g (27.9 mmol) of compound 23C are dissolved in 200 ml of methanol. Add 1.8 g pyridine-p-toluensulfonate, boil reverse holo is smetana and added 8.6 g (93.5 mmol) of dimethoxypropane. After 72 h at room temperature the solution was concentrated in vacuo and the residue purified by chromatography on silica gel (solvent: ethyl acetate/n-heptane = 1:1). Obtain 6.6 g (82%) of compound 23D.

1H-NMR (270 MHz, CDCl3) , M. D. = 1.35 (C., 3H); 1.47 (C., 9H); 1.53 (C. , 3H); 1.9 - 2.12 (m, 1H); 2.22 - 2.32 (m, 1H); 2.43 (SD, 1H); 3.87 - 3.94 (m, 1H); 4.12 - 4.25 (m, 1H); 4.35 - 4.45 (m, 1H).

The connection 23 from compound 23D.

Similar methods d - f (as described for compound 8) get the connection 23 in the form of colorless solids; so pl. 85 - 92oC.

Obtain compound 24 (see the end of the description. Reaction scheme 5).

Getting connection 24B of the connection 24A.

15.0 g (39 mmol) of compound 24A [J. R. Falck,. J. Org. Chem. 54, 5851 (1989)] was dissolved in 200 ml of anhydrous toluene. At -70oC was added dropwise 38 ml (43 mmol) of a 1.2 M solution of diisobutylaluminium in hexane. Within 2 h, allowed to warm to 0oC and hydrolyzing the reaction mixture with 10 ml of saturated solution of sodium bicarbonate. Then add 10 ml of 1 n sodium hydroxide solution and 10 ml of water. The reaction mixture with vigorous stirring and mixed with 50 g of magnesium sulfate and 50 g of sodium sulfate. Stirred for 30 min p in the form of a colorless oil, which crystallizes at 0oC; so pl. 20-25oC.

Getting connection 24C of compound 24B:

To a suspension of 0.9 g (29.9 mmol) of 80% sodium hydride in 200 ml of anhydrous tetrahydrofuran in an argon atmosphere and at 0oC, was added dropwise 7.5 (33.5 mmol) teeterboro ether phosphonooxy acid. The reaction mixture was left to slowly warm to room temperature and then a transparent brown solution is cooled to -30oC. was added dropwise 7.7 g (19.9 mmol) of compound 24B, dissolved in 20 ml of anhydrous tetrahydrofuran. This solution is stirred for 2 hours at a temperature of -20 to -30oC and then mixed with 100 ml of saturated solution of sodium chloride. Extracted with ethyl acetate, washed with a saturated solution of sodium chloride and the combined organic phases are dried over magnesium sulfate. After concentration in vacuo the residue is purified on silica gel (solvent : ethyl acetate/n/heptane = 1:1) and obtain 7.5 g (82%) of compound 24C in the form of a colorless oil.

1H-NMR (200 MHz, CDCl3): , M. D. = 0.01 (C., 9H); 0.85 - 1.0 (m, 2H); 1.1 - 1.85 (m, 15H); 2.1 - 2.25 (m, 2H); 2.35 - 2.5 (m, 1H); 3.42 - 3.9 (m, 3H); 4.1 - 4.4 (m, 4H); 4.65 - 4.8 (m, 2H); 5.92 (D., J = 15 Hz, 1H).

Mass spectrum (FAB): 463.3 (M + Li+).

Receiving the 100 mg Rh/Al2O3[5% Rh]. Shaken for 3 h in an atmosphere of hydrogen at 25oC and normal pressure. The catalyst is filtered off and the filtrate was concentrated in vacuo. Obtain 0.95 g (94%) of compound 24D in the form of a colorless solid.

The connection 24 of the connection 24D.

Similarly, methods of syntheses of d - f (as described for compound 8) from compound 24D get a connection 24; so pl. 172oC (H2O).

Obtaining compounds 25

< / BR>
Similarly, methods of syntheses of d - f (as described for compound 8) known from the literature predstavi 25A [J. L. Pawlak, etc., J. Org. Chem. 52, 1765 (1987)] get connection 25; so pl. 75-80oC (foaming).

The connection 26 of the connection 26A

< / BR>
Similarly, methods of syntheses of d - f (as described for compound 8) known from the literature predstavi 26A receives the connection 26 in the form of colorless amorphous solid.

1H-NMR (270 MHz, d6-DMSO): , M. D. = 1.95 - 2.14 (m, 1H); 2.55 - 2.70 (m , 1H); 3.62 - 3.76 (m, 1H); 4.08 - 4.26 (m, 2H); 4.55 - 4.75 (m, 1H); 4.9 - 5.1 (m, 1H); 6.48 (D., J = 10.0 Hz, 1H); 6.63 - 6.72 (m, 1H); 6.75 - 6.88 (m , 2H); 7.29 - 7.46 (m, 3H); 7.89 (D., J = 5 Hz, 1H); 9.70 - 10.0 (1H); 12.2 - 12.6 (1H).

Mass spectrum (Cl): 225.2 (M + H+).

The connection 27 from soedinen> 6.0 g (17.5 mmol) of compound 20B was dissolved in 100 ml of anhydrous toluene. At -20oC was added dropwise 29.2 ml of a 1.2 M solution of diisobutylaluminium in hexane. Within 1 h, allowed to warm to 25oC, again cooled to 0oC and carefully added dropwise 20 ml of a mixture of methanol with water in the ratio of 9 : 1. Then added dropwise 30 ml of a saturated solution of ammonium chloride and the reaction mixture was stirred 30 min at 25oC. then extracted with ethyl acetate and the combined phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (ethyl acetate/n-heptane = 1:3). Get 3.5 g (63%) of compound 27B in the form of a colorless oil.

1H-NMR (270 MHz, CDCl3) , M. D. = 0.08 (C., 3H); 0.11 (C., 3H); 0.89 (C. , 9H); 1.39 (C., 3H); 1.46 (C., 3H); 1.97 - 2.09 (m, 1H); 2.19 - 2.30 (SD, 2H); 3.88 - 3.92 (m, 1H); 3.98 - 4.09 (m, 4H); 4.62 - 4.68 (m, 1H); 5.76 - 5.82 (m, 1H);.

Getting connection 27B of compounds 27A.

To a solution of 2.9 g (16.2 mmol) of N-bromosuccinimide in 100 ml of anhydrous dichloromethane at 0oC was added dropwise 1.43 ml (19.6 mmol) of dimethyl sulfide. After 5 min, cooled to -20oC and added dropwise 3.4 g (10.8 mmol) of compound 27A, dissolved in 20 ml of anhydrous dichloromethane. Then the seal solution of ammonium chloride and extracted with 500 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. After concentration the residue is purified by chromatography on silica gel (solvent: ethyl acetate/heptane = 1:3) and obtain 3.7 g (98%) of compound 27B in the form of a colorless oil.

1H-NMR (270 MHz, CDCl3): , M. D. = 0.09 (C., 3H); 0.10 (C., 3H); 0.89 (C. , 9H); 1.38 (C., 3H); 1.41 (C., 3H); 2.09 - 2.21 (m, 1H); 2.35 - 2.45 (m , 1H); 3.92 (SD, 2H); 3.97 - 4.05 (m, 2H); 4.38 - 4.65 (m, 1H); 5.83 - (m, 1H).

Mass spectrum (Cl): 377.1 (M + H+).

The connection is 27C of compound 27B.

3.0 g (7.6 mmol) of compound 27B in 42 ml of trimethylphosphite heated 6 h at 90oC. Then distilled off in vacuum excess postit and the residue purified by chromatography on silica gel (solvent: ethyl acetate/methanol = 5:1). Obtain 3.0 g (93%) of compound 27C in the form of a colorless oil.

Getting connection 27D of compound 27C.

3.0 g (7.4 mmol) of compound 27C dissolved in 50 ml of methanol. Add 1 ml of 1 n hydrochloric acid. After 24 h the reaction solution is neutralized 1 n sodium hydroxide solution and concentrated in vacuo to dryness. The residue is treated with 50 ml of anhydrous dichloromethane, add 5 ml of dimethoxypropane, and 0.5 g pyridine-p-colorsort Giroud 500 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (solvent: ethyl acetate/methanol = 10:1) and obtain 1.5 g (70%) of compound 27D in the form of a colorless oil.

The connection 27 of the connection 27D.

Similarly, methods of syntheses e - f (as described for compound 8) from compound 27D get a connection 27.

1H-NMR (200 MHz, d6-DMSO): , M. D. = 2.05 - 2.22 (m, 1H); 2.55 - 2.8 (m, 1H); 3.4 - 3.55 (m, 1H); 3.6 (C., 3H); 3.65 (C., 3H); 4.05 - 4.15 (m, 1H); 4.3 - 4.4 (m, 1H); 4.6 - 4.8 (m, 3H); 5.05 - 5.15 (m, 1H); 5.55 - 5.68 (m , 1H); 6.3 - 6.45 (m, 1H); 6.37 - 6.45 (m, 2H); 7.5 - 7.7 (m, 3H); 10.0 (S., 1H).

Mass spectrum (Cl): 399 (M+); 381 (M+- H2O).

The connection 28 of the connection 27.

135 mg (0.34 mmol) of the compound 27 was dissolved in 10 ml of anhydrous acetonitrile. At 0oC was added dropwise 155 mg (1 mmol) trimethylsilylpropyne. Stirred for 30 min and then add 5 ml of water. Mix with 1 n solution of sodium hydroxide to about pH 5 and concentrated in vacuo. The residue is purified by chromatography on silica gel RP-8 (solvent: water/methanol = 4:1) and obtain 23 mg (18%) of compound 28 as a colourless solid prophetic Messiah.

Example 1. Tablets.

Tablets suitable for oral administration and containing the following component parts, get in a known manner by granulation of biologically active substances and excipients and subsequent compaction into tablets.

The composite part (pill) Weight (mg)

the compound of formula (I) (e.g. compound 17) - 50

milk sugar - 100

corn starch - 30

talc - 3

colloidal silicon dioxide - 3

magnesium stearate - 2

Example 2. The capsule.

Capsules suitable for oral administration, contain the following component parts and are obtained in a known manner by mixing of the biologically active substances and excipients, and depositing the mixture in gelatin capsules.

The composite part (pill) Weight (mg)

the compound of formula (I) (e.g. compound 21) - 50

milk sugar - 100

corn starch - 30

talc - 3

colloidal silicon dioxide - 3

magnesium stearate - 22

1. Means for inhibiting glucose-6-phosphatase system of mammalian liver, representing a compound of General formula I

< / BR>
where a - denotes a group or group

R1the convoy is 3H,PO(OH)2, PO(OH)(O-C1- C4-alkyl) or RO(O-C1- C4-alkyl)2;

R2denotes H, HE, or F;

R3denotes H, phenyl, naphthyl, pyridyl, thienyl, furyl, while aromatic or heteroaromatic residue may be single - or multi-substituted by fluorine, chlorine, bromine, iodine, HE, NO2C1- C1-alkanoyl,1- C4-alkoxy, C1- C4-alkyl, phenyl, phenoxy, teinila, fullam, pyridium, imidazolium or benzyloxy, with the substituents are the same or different;

R4, R5and R6denote H, HE, F, Cl, Br, C1- C4-alkanoyl,1- C4-alkyl, phenyl, phenoxy, thienyl, furyl, pyridyl, imidazolyl or benzyloxy, R4, R5, R6are the same or different;

X represents -(CH2)n-, -CH=CH - or-CH2-O-CH2;

Y represents -(CH2)n-, 0, or NH;

Z represents -(CH2)n-, -CH-CH-;

n represents zero, 1,2,3 or 4.

2. Means under item 1, wherein in formula I R1denotes COOH, COO-(C1- C4-alkyl), RHO(OH)2, RHO(OH) (O-C1- C4-alkyl) or RO(O-C1- C4-alkyl)22C1- C4-alkanoyl,1- C4-alkoxy, C1- C4-alkyl, phenyl, phenoxy, teinila, fullam, pyridium, imidazolium or benzyloxy, with the substituents are the same or different; R4, R5, R6denotes H, HE, F, Cl, Br, C1- C4-alkanoyl,1- C4-alkyl, phenyl, phenoxy, thienyl, furyl, pyridyl, imidazolyl or benzyloxy, R4, R5, R6are the same or different; X represents -(CH2)n-, -CH=CH - or CH2-O-CH2-;

Y represents -(CH2)n-, O, S or NH;

Z represents -(CH2)n-, -CH=CH-;

n represents zero, 1, 2, 3, or 4.

3. Means under item 1, wherein in formula I R1denotes COOH or COO-(C1- C4-alkyl); R2denotes H or HE; R3denotes H, phenyl, naphthyl, pyridyl, thienyl, furyl, while aromatic or heteroaromatic residue may be one -, two - or three-fold substituted by fluorine, chlorine, HE, NO2WITH1- C4-alkanoyl,1- C4-alkoxy, C1- C4-alkyl, phenyl, phenoxy, or benzyloxy, the>R5, R6are the same or different; X represents -(CH2)n-, n = 0, 1, or 2, Y represents 0 or NH; Z represents -(CH2)n-, n = 0, or 2, or-CH=CH-.

 

Same patents:

The invention relates to new cycloalkenyl exhibiting the properties of inhibitors of the biosynthesis of cholesterol, in particular, inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity and can find application in the treatment and prevention of, for example, hyperlipidemia, hypercholesterinemia, atherosclerosis, and pharmaceuticals based on them

The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to pharmaceutical compositions for topical application for the treatment of allergic diseases of the eye and nose

The invention relates to Amida sulfamido and sulphonilecarbomide-2-carboxylic acids and their use in pharmaceutical compositions for the treatment of fibrosis

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to medicine, specifically to pharmacology

The invention relates to substituted derivative asalaam, which is an effective anti-Helicobacter tools that can be used as monotherapy for eradication of Helicobacter pylori and related species

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to medicine and veterinary

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to pharmacy - suppositories with vasodilator and antispasmodic effect

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to the field of pharmacy and for the preparation of soft medicinal forms, including ointments buttonboy

The invention relates to a series of new derivatives of 1-biphenylether imidazole having hypotensive activity and are therefore intended for the treatment and prevention of hypertension, including heart disease and circulatory system

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts
Up!