Bicyclic derivatives of guanidine and their therapeutic using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

 

The present invention relates to bicyclic guanidine derivative which are useful for the treatment of pathologies associated with syndrome of insulin resistance.

Bicyclic guanidine derivatives with protivogipertonicheskoe or bactericidal properties have been described in US 3855242, US 4260628 and Yaoxue Xuebao, 1982, 17(3), 229-232.

The present invention is directed to the provision of new bicyclic guanidine compounds with new properties.

The present invention therefore relates to compounds of General formula (I):

in which:

And denotes a benzene or pyridine nucleus, optionally substituted by one or more of the following groups:

- a branched or non-branched (C1-C20)alkyl group,

- OR2, where R2 represents:

- hydrogen

- a branched or non-branched (C1-C5)alkyl,

- (C3-C8)cycloalkyl or

- benzyl,

- NR3R4, where R3 and R4 denote, independently of one another:

- hydrogen

- a branched or non-branched (C1-C20)alkyl,

- benzyl,

- acetyl,

- (C3-C8)cycloalkyl,

or, alternatively, R3 and R4 together form a cycle containing from 3 to 8 atoms, including the nitrogen atom,

- SR5 wherein R5 represents:

- hydrogen

- a branched or non-branched (C1 -C5)alkyl,

- (C3-C8)cycloalkyl or

- benzyl,

- halogen

the cyano group

the nitro group

- CO2R6, where R6 represents:

is hydrogen or

- a branched or non-branched (C1-C5)alkyl, or

- triptorelin group,

X represents a radical-CH=,-CH2-, -N=, or-NH-,

Y denotes a radical CH2, an oxygen atom or sulfur or a group NR7, where R7 represents:

- hydrogen

- a branched or non-branched (C1-C5)alkyl.

- benzyl,

- (C3-C8)cycloalkyl, or

group CH2CO2N

R1 denotes one of the following groups

- hydrogen

- a branched or non-branched (C1-C5)alkyl, or

- benzil

with the exception of the compounds of formula (I)in which:

a) And denotes a benzene nucleus, X represents-CH= or-CH2-, Y denotes an oxygen atom and R1 is a hydrogen atom;

b) - denotes a benzene nucleus substituted in the 5' position of the double ring by halogen atom, X represents-CH=, Y represents a sulfur atom and R1 is a hydrogen atom,

C) - denotes unsubstituted benzene nucleus, X represents-CH2-, R1 denotes a hydrogen atom or a branched or non-branched (C1-C5)alkyl radical, and Y represents NR7, where R7 is a hydrogen atom, a branched or narasu twinny (C 1-C5)alkyl radical or a benzyl radical,

g) denotes unsubstituted benzene nucleus, X represents-CH=, R1 is a hydrogen atom and Y represents NR7, where R7 denotes the ethyl radical, and also the tautomeric, enantiomeric, diastereoisomeric and epimeria form, a solvate and a pharmaceutically acceptable salt.

Among branched or unbranched alkyl radicals containing from 1 to 20 carbon atoms, which may especially be mentioned are the radicals methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, penttila, hexyl, heptyl, Attila, Manila, decyl, dodecyl, pentadecyl and hexadecyl.

In particular, to the group of compounds of formula (I), in which the alkyl radicals are C1-C5alkyl radicals.

Among the radicals cycloalkyl containing from 3 to 8 carbon atoms, which may especially be mentioned are the radicals of cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycles containing from 3 to 8 atoms, including the nitrogen atom, which may especially be mentioned include cycles of aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinil and piperidyl.

Another private group of compounds of formula (I) is that in which And denotes optionally substituted benzene nucleus. One specific subgroup is one in the cat is Roy X denotes the radical-CH= or-CH 2-. Another specific subgroup is one in which X represents a radical-N= or-NH-.

Another specific group of compounds of formula (I) is one in which Y represents a radical-CH2-, a sulfur atom or a group-NR7, where X preferably represents-CH= or-CH2.

One target sub-group of these compounds of formula (I) are compounds in which a denotes a substituted benzene nucleus, more preferably a benzene nucleus, monosubstituted other than 5', the position of the double ring or the benzene nucleus is substituted by at least two groups.

One specific subgroup of compounds of formula (I) is one in which Y represents a sulfur atom and a represents a benzene nucleus, monosubstituted other than 5', the position of the double ring or the benzene nucleus is substituted by at least two groups.

Another specific group of compounds of formula (I) is one in which Y represents the group-NR7 and a denotes a substituted benzene nucleus.

Another specific group of compounds of formula (I) is one in which Y represents a radical-CH2-, a sulfur atom or a group-NR7, where a preferably denotes a substituted benzene nucleus, more preferably a benzene nucleus, monosubstituted other than 5', the position of the double ring or the benzene nucleus is substituted by at least two is a group.

The invention also relates to the tautomeric, enantiomeric, diastereoisomeric and epimeric forms of the compounds of General formula (I).

Compounds of General formula (I) contain basic nitrogen atoms, which may form a mono - or dial with organic or inorganic acids.

Compounds of General formula (I) can be obtained from compounds of General formula (II):

in which A, X, Y and R1 are set above

and according to the methods of obtaining guanidine, which are described in the literature.

As an example of these methods, in particular, is described in the following literature: Tetrahedron Letters. 1993, 34 (48), 7677-7680; Tetrahedron Letters, 1993, 34 (21), 3389-3392; Tetrahedron Letters, 1996, 37 (14), 2483-2486; WO 98/52917; Journal of Medicinal Chemistry, 1990, 33 (1), 434-444; Journal of Organic Chemistry, 1998, 63, 3804-3805; WO 94/29269; Tetrahedron Letters, 1994, 35 (7), 977-980; Journal of Organic Chemistry, 1992, 57, 2497-2502; Synthesis, 1986, 777-779; Synthetic Communications, 1987, 17 (15), 1861-1864.

The compounds of formula (II) are obtained in a simple and standard reactions, easily accessible to professionals skilled in this art. As an example, the following links explain these syntheses: Oppi Briefs, 1996, 28 (6), 702-704; Heterocycles, 1988, 27 (6), 1421-1429; Pharmazie, 1999, 54 (9), 651-654; WO 95/09159; WO 91/09023; WO 97/42183; Synthetic Communications, 1993, 23 (6), 743-748; Journal of the American Chemical Society, 1952, 74, 664-665; DE 2 739 723; Journal of Medicinal Chemistry, 1994, 37 (23), 3956-3968; WO 93/17025; WO 96/00730; Heterocycles, 1995, 41 (3), 477-486; Journal of Medicinal Chemistry, 1968, 11, 1164-1167; Monatsheft fü r Chemie, 1957, 1087-1094; Journal of Medicinal Chemistry, 1989, 32, 1988-1996.

Compounds according to the present invention, and more generally, the compounds of formula (I)

in which:

And denotes a benzene or pyridine nucleus, optionally substituted by one or more of the following groups:

- a branched or non-branched (C1-C20)alkyl group,

- OR2, where R2 represents:

- hydrogen

- a branched or non-branched (C1-C5)alkyl,

- (C3-C8)cycloalkyl or

- benzyl,

- NR3R4, where R3 and R4 denote, independently of one another:

- hydrogen

- a branched or non-branched (C1-C20)alkyl,

- benzyl,

- acetyl,

- (C3-C8)cycloalkyl,

or, alternatively, R3 and R4 together form a cycle containing from 3 to 8 atoms, including the nitrogen atom,

- SR5 wherein R5 represents:

- hydrogen

- a branched or non-branched (C1-C5)alkyl,

- (C3-C8)cycloalkyl or

- benzyl,

- halogen

the cyano group

the nitro group of CO2R6, where R6 represents:

is hydrogen or

- a branched or non-branched (C1-C5)alkyl, or

- triptorelin group,

X represents a radical-CH=, -CH2-, -N=, or-NH-,

Y represents a radical CH2the oxygen atom is, or sulfur, or a group-NR7, where R7 represents:

- hydrogen

- a branched or non-branched (C1-C5)alkyl,

- benzyl,

- (C3-C8)cycloalkyl, or

group CH2CO2N.

R1 denotes one of the following groups:

- hydrogen

- a branched or non-branched (C1-C5)alkyl, or

- benzyl,

and their tautomeric, enantiomeric, diastereoisomeric and epimeria form, solvate, and pharmaceutically acceptable salts, are useful for the treatment of pathologies associated with insulin resistance syndrome (Syndrome X).

Insulin resistance is characterized by the lowering action of insulin (Cf Presse Medicale, 1997, 26 (No.14), 671-677) and includes a large number of pathological conditions, such as diabetes and, in more detail, non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia (dyslipidaemia), obesity and some of microvascular and macrovascular complications, for instance atherosclerosis, retinopathy and neuropathy.

In this respect one can refer, for example, Diabetes, Vol.37, 1988, 1595-1607; Journal of Diabetes and its Complications, 1998, 12, 110-119 or Horm. Res., 1992, 38, 28-32.

Compounds according to the invention in particular have a strong hypoglycemic activity.

Thus, the present invention also relates to pharmaceutical compositions containing as an active component of the is giving according to the invention.

The pharmaceutical compositions according to the invention can be provided in forms that are intended for parenteral, oral, rectal, permucosal or transcutaneous applications.

Therefore, they will be presented in the form of injection solutions or suspensions or multidose vials, in the form of a simple or coated tablets, tablets, sugar coated, plate capsules, gel capsules, pills, wafers, powders, suppositories or rectal capsules, solutions or suspensions, for intradermal use in a polar solvent or permucosal application.

Inert fillers which are suitable for such applications are derivatives of cellulose derivative microcrystalline cellulose, carbonates of alkaline earth metals, magnesium phosphate, starches, modified starches and lactose for solid forms.

For rectal use cocoa butter or polyethylene glycol stearates are the preferred inert fillers.

For parenteral use water, aqueous solutions, physiological, and isotonic solutions are fillers that are most suitable for use.

The dosage may vary within wide limits (from 0.5 mg or less up to 1000 mg) depending on therapeutic indication and the JV is soba application, as well as the age and weight of the person.

The following examples explain the formation of compounds of formula (I).

EXAMPLE 1

Synthesis of 2-(aminoiminomethyl(methylamino)methyl)-benzothiazole hydrochloride

Stage 1: 2-chloromethylthiazole (A)

Chloroacetyl chloride (81,6 ml) was bury to a solution containing 2-aminothiophenol (112 ml, 1.04 mol) in dichloromethane (1.2 l) and three drops of dimethylformamide while maintaining the temperature below 40°C. After stirring for 18 hours the precipitate was filtered using vacuum and dissolved in minimum amount of water. The aqueous phase was extracted with pentane extracts were concentrated in vacuum at room temperature, received 120 g (65%) flocculent precipitate.

1H NMR (DMSO-d6, 200 MHz) δ: 8,32, D. 1H, fragrance. N; 8,21, d, 1H, fragrance. N; to 7.77-7,63, m 2N, fragrance. N, 5,43, s, 2H, CH2Cl

Stage 2: 2-methylaminoethanol (In)

(115 g of 0.62 mol) and 580 ml of aqueous 40% solution of methylamine was heated in an autoclave for 18 hours at 60°C. the Reaction mixture was concentrated, the residue was purified by chromatography on a column of silica gel (7/3 petroleum ether / dichloromethane)received 96 g (87%) of orange oil.

1H NMR (DMSO-d6, 200 MHz) δ: 8,03-7,39, m, 4H, aromatic. N; 4,24, s, 1H, CH2; 2,61, s, 3H, CH3

Stage 3: 2-(aminoiminomethyl(methylamino)methyl)benzo is iatola hydrochloride

55.7 g (0,449 mol) aminobenzenesulfonic acid was added in portions to a cooled to 5°With the solution containing (80 g, 0,449 mol) in dimethylformamide (400 ml)while maintaining the temperature below 5°C. the Reaction mixture was stirred for 48 hours, cooled to 5°and added 75 ml (0.9 mol) of concentrated hydrochloric acid. After stirring for 1 hour the solution was concentrated and the remaining oil was dissolved in acetonitrile. The formed precipitate was filtered using vacuum and then recrystallize from water. Received 40 g (35%) of a white precipitate.

TPL=203-205°

1H NMR (DMSO-d6, 200 MHz) δ: 8,32, D., 1H, fragrance. N; 8,25-7,40 m, 8H, aromatic. N, NH and HCl; 5,20, s, 2H, CH2; 3,10, s, 3H, NCH3

13With NMR (DMSO-d6, 50 MHz) δ: 168,32, 159,08, 154,12, 136,33, Quaternary; 128,20, 127,27, 124,30 and 124,15 aroma. SN; 53,19, CH2; 38,88, NCH3

EXAMPLE 2

Synthesis of 2-(aminoiminomethyl)methylbenzimidazole hydrochloride

Stage 1: 2-aminomethylpyrimidine (C)

A solution of 2-aminoaniline (27 g, 0.25 mol) and aminouksusnoy acid (27.7 g, and 0.37 mol) in 250 ml of 5.5 M hydrochloric acid was boiled under reflux for 30 hours and then placed in the refrigerator for 24 hours. The precipitation was filtered using vacuum, dissolved in 400 ml of methanol and treated with activated charcoal. The mixture was filtered, actuarial was evaporated and obtained 22 g (49%) of a white precipitate.

TPL=81-83°

1H NMR (DMSO-d6, 200 MHz) δ: 7,40-6.90, m, 4H, aromatic. N; 3,70, s, 2H, CH2

Stage 2: 2-(aminoiminomethyl)methylbenzimidazole hydrochloride

The solution (15 g, 0,101 mol) and 1-(aminoiminomethyl)pyrazole hydrochloride (15 g, is 0.102 mol) was heated in 50 ml of dioxane under reflux for 18 hours and then concentrated to dryness. The crude product was dissolved in methanol (300 ml) and treated with activated charcoal. The mixture was filtered and concentrated, the residue was dissolved in minimum amount of water, any insoluble impurities were removed by filtration. The solution was dried on the plant for freeze-drying. Received 14 g (62%) of a white precipitate.

TPL=171-173°

1H NMR (DMSO-d6, 200 MHz) δ: 8,20-7,10, m, 8H, aromatic. N, NH and HCl; 4,60, s, 2H, CH2

13With NMR (DMSO-d6, 50 MHz) δ: 158,56, 151,26, 138,98, Quaternary; 122,88, 115,76 aroma. SN; 40,32, CH2

EXAMPLE 3

Synthesis of 2-(aminoiminomethyl)methylinden sulfate

Stage 1: 2-methylcarboxyethyl (D)

Solution α,α'-dibromo-o-xylene (203,51 g, 0.77 mol) in 1.5 l of ether was added to a mixture of diethyl ester of malonic acid (127 g of 0.79 mol), sodium methylate (314 ml, 1.70 mol), ethanol (100 ml) and ether (500 ml). The mixture was heated under reflux for 5 hours, then filtered and finally, scancenter the Wali. The residue was transferred into 500 ml of water. To the solution was added 173 g of potassium hydroxide, and the mixture was heated under reflux for 18 hours. The reaction mixture was poured into a solution of hydrochloric acid, the precipitate was filtered by suction and then dried. The precipitate was kept at 200°C for 20 minutes, and again obtained solid substance was recrystallize from 400 ml of heptane. The obtained crystals were transferred into 400 ml of methanol was added 5 drops of concentrated sulfuric acid, the mixture was heated under reflux for 4 hours and then concentrated. The residue was dissolved in 600 ml of ether. The ether phase is washed with a saturated solution of sodium bicarbonate and saturated sodium chloride solution, dried over sodium sulfate and concentrated. Got 73,6 g (54%) of pure oil.

1H NMR (DMSO-d6, 200 MHz) δ: of 6.96, m, 4H, aromatic. N; 3,43, s, 3H, CH3; 3,11, m, 1H, CH; 2,91, m, 4H, CH2

Stage 2: 2-carboxamid-indan (E)

D (102,1 g of 0.58 mol) and 500 ml of concentrated ammonia solution were placed in the autoclave, and the mixture was maintained at 80°C for 18 hours. The formed precipitate was filtered by suction and washed with water. Received 63.4 g (68%).

MP=181-183°

1H NMR (DMSO-d6, 200 MHz) δ: 7,39, s, 1H, NH; 7,11, m, 4H, aromatic. N; 6,85, s, 1H, NH; 3,12-2,97 m, 5H, CH2and SN

With the adiya 3: 2-aminomethyl-indan (F)

Solution E (63 g, 0,391 mol) in tetrahydrofuran (1.5 l) was bury cooling to a suspension of LiAlH4(74,15 g, 1,95 mol) (300 ml), tetrahydrofuran, using a dry ice/acetone bath, then the mixture was heated under reflux for 2 hours. The reaction medium was neutralized (75 ml of water, 75 ml of a 5 M solution of sodium hydroxide and 225 ml of water and then filtered. After removal of solvent received oil (56,9 g, 99%), quickly forming carbonate.

1H NMR (DMSO-d6, 200 MHz) δ: 6,95 m, 4H, aromatic. N; 2,90-2,14, m, 7H, SN2and SN; 1,63, s, 2H, NH2

Stage 4: 2-(aminoiminomethyl)methylinden sulfate

The mixture F (20,63 g, 0,140 mol) and S-methylisothiazoline sulfate (19.5 g, 0.07 mol) and 10 ml of water was maintained at 90°C for 30 minutes (until gas evolution stops methylmercaptan). The crude residue was recrystallize from water-alcohol mixture. Received 12.7 g (38%) of a white precipitate.

TPL=231-233°

1H NMR (DMSO-d6, 200 MHz) δ: 7,05 m, 4H, aromatic. N; 2,95 m, 2H, CH2; 2,40 m, 5H, 2CH2and SN

13With NMR (DMSO-d6, 50 MHz) δ: 157,07, 142,57, Quaternary; 126,59, 124,83 aroma. SN; 45,28, CH2N; 38,74, CH; 36,57, 2CH2

EXAMPLE 4

Synthesis of 2-(aminoiminomethyl)methylbenzamide hydrochloride

Stage 1: 2-carboxymethylation (G)

Ethyl 2-mercaptoacetate added is cooled to 0° With the solution of dimethylformamide (800 ml), 2-nitrobenzaldehyde (73 g, 0.48 mol) and potassium carbonate (80 g, of 0.57 mol), maintaining the temperature of the reaction solution at 0°C. After stirring for 24 hours the mixture was poured into 2 l of water and the aqueous phase was extracted with ether. The ether phase is dried over sodium sulfate and concentrated. The crude obtained product was purified by chromatography on a column of aluminum oxide (petroleum ether). Got 34 g (35%) of yellow oil.

1H NMR (DMSO-d6, 200 MHz) δ: 8,04, s, 1H, CH; of 7.90, m, 2H, aromatic. SN; 7,35 m, 2H, aromatic. N; 4,20, kV, 2H, CH2; 1,93, t, 3H, CH3

Stage 2: 2-carboxymethylation (H)

G (34 g, 0,165 mol), concentrated aqueous ammonia (120 ml) and ethanol (50 ml) were loaded into an autoclave and kept at a temperature of 80°C for 24 hours. The resulting solution was concentrated, and the crude residue was ground into powder in a simple isopropyl ether and was washed with pentane (26 g, 89%).

MP=209-211°

1H NMR (DMSO-d6, 200 MHz) δ: 8,59, s, 1H, NH; 8,32, s, 1H, CH; 8,15, m, 2H, aromatic. N; 7,89, s, 1H, NH; to 7.64 m, 2H, aromatic. N

Stage 3: 2-aminomethylbenzoic (I)

A suspension of N (26 g, 0,146 mol) in tetrahydrofuran (500 ml) was added to a suspension of LiAlH4(33,5 g, 0.88 mol) in tetrahydrofuran (100 ml)and the reaction mixture was heated under reflux in those who tell 6 hours. Then the reaction mixture was cooled to 0°and laid out the excess LiAlH4(33 ml of N2Oh, 33 ml of a 5 M solution of sodium hydroxide and 99 ml of N2About). After filtration and subsequent concentration the crude product was purified on a column of silica gel (dichloromethane and then dichloromethane/methanol 4/1). Received 13 g (56%) of oil.

1H NMR (DMSO-d6, 200 MHz) δ: 7,65 m, 2H, aromatic. N; 7.12, m, 2H, aromatic. N; 7,08, s, 1H, CH; 5,46 m, 2H, NH2; 4,60, d, 2H, CH2

Stage 4: 2-(aminoiminomethyl)ethylbenzamide hydrochloride

Solution I (11 g, 0,067 mol), 1-(aminoiminomethyl)pyrazole hydrochloride (9.8 g, 0,067 mol) in isopropyl alcohol (50 ml) was heated under reflux for 24 hours. The reaction mixture was concentrated, and the crude product was recrystallize from water (7 g, 41%).

TPL=163-165°

1H NMR (200 MHz) δ: 8,44-7,26, m, N aroma. N and exchanged N.; 4,70, d, 2H, CH2

13With NMR (DMSO-d6, 50 MHz) δ: 157,56, 141,73, 139,49, 139,36, Quaternary; 124,90, 124,76, 123,88, 122,88, 122,68, the aroma. SN; at 40.28, CH2

Table 1 summary data formulas and characteristics of the compounds of formula (I).

Table 1
ConnectionStructureTPL in °Köfler)13With NMR and 50 MHz δ ppm
1203-205 (hydrochloride)(DMSO-d6) 168,32, 159,08, 154,12, 136,33, Quaternary 128,20, 127,27, 124,30 and 124,15 aroma. SN 53,19, CH2, 38,88, NCH3
2171-173 (hydrochloride)(DMSO-d6) 158,56, 151,26, 138,98, Quaternary 122,88, 115,76 aroma. SN 40,32, CH2
3231-233 (sulfate)(DMSO-d6) 157,07, 142,57, Quaternary 126,59, 124,83 aroma. SN 45,28, CH2N 38,74, CH 36,57, 2CH2
ConnectionStructureTPL in °Köfler)13With NMR and 50 MHz δ ppm
4163-165 (hydrochloride)(DMSO-d6) 157,56, 141,73, 139,49, 139,36, Quaternary 124,90, 124,76, 123,88, 122,88, 122,68, the aroma. SN 40,28, CH2
5196-198 (hydrochloride)(1H, D2O)

8,20-7,50 m, 4H, aromatic. N 5,00, s, 2H, CH2
6253-255 (hydrochloride)(1H, D2O)

7,80-of 7.25, m, 4H, aromatic. N 4,90, s, 2H, CH2, 3,20, s, 3H, NCH3
7Decomposition of >130 (carbonate)(DMSO-d6) 160,90, 157,71, 136,73, 135,58, 128,08, Quaternary 121,37, 120,16, 119,30, 111,59, 100,08, the aroma. SN 38,51, CH2
8189-191 (hemisulfate)(DMSO-d6)

157,68, 151,74,127,89, Quaternary 127,40,124,66, 117,33, 108,75 aroma. SN
ConnectionStructureTPL in °Köfler)13With NMR and 50 MHz δ ppm
57,99, CHN 46,50, CH2N 33,55, CH2
9139-141 (carbonate)(DMSO-d6) 159,10, 126,84, Quaternary 128,27, 125,57, 120,84, 109,49, fragrance. SN 81,04, SNO 44,87, CH2N 32,56, CH2
10187-189 (carbonate)(AMCO-d6) 160,88, 139,93, 138,91, Quaternary 127,83, 125,53, 124,72, 122,31 aroma. SN 48,46, CHS 45,54, CH2N 38,97, CH2
11191-193 (sulfate)(DMSO-d6) 157,54, 148,11, 134,07, Quaternary 108,80 aroma. SN 55,89, CH3About 45,77, CH2N to 39.22, CH of 36.76, CH2
ConnectionStructure13With NMR and 50 MHz δ ppm
12233-235 (sulfate)(DMSO-d6) 157,33, 153,86, 136,64, 133,10, 127,45, Quaternary 111,38, 110,51, 102,24, 100,20, fragrance. SN 55,66, CH3About 30,00, CH2N
13213-215 (sulfate)(DMSO-d6) 162,77, 158,79,141,39, 137,09, 133,67, Quaternary 117,47, 116,40,107,18, 105,15, fragrance. SN 60,81, co343,84, CH2N
14181-183 (hydrochloride)(DMSO-d6) 157,80, 148,00, 134,80, 127,00, Quaternary 11,02, 109,50, 104,80, 100,30, fragrance. SN 37,72, CH230,28, CH3
15244-247 (sulfate)(DMSO-d6) 157,75, 154,49, 128,33, Quaternary 124,46, 123,23, 121,48, 111,35, 104,33, the aroma. SN
ConnectionStructureTPL in °Köfler)13With NMR and 50 MHz δ ppm
39,92, CH2
16209-211 (hydrochloride)(DMSO-d6)

157,31, 144,40, 143,51, Quaternary 128,22, 126,66, 124,80, 124,04, 120,96, the aroma. SN 50,46, 40,33, With the 2of 36.75, CH3
17>250 (sulfate)(TFU) 158,30, 154,00, 149,00, 139,00, Quaternary 114,5 aroma. SN 47,26, 37,12, CH240,30, SN

The results of pharmacological studies below.

The STUDY of ANTIDIABETIC ACTIVITY NOSTZ RATS

Oral anti-diabetic activity of the compounds of formula (I) was determined in an experimental model of non-insulin-dependent diabetes caused in rats by streptozotocin.

The model of non-insulin-dependent diabetes obtained in rats by injection of streptozotocin newborn (birth day) to rats.

Diabetic rats use at the age of eight weeks. Animal place, from the day of birth until the day of the experiment, in the premises for the keeping of animals under controlled temperature 21-22°With and subject to the established cycle lighting (from 7 a.m. to 19 p.m.) and dark (from 19 PM to 7 am). Their diet consists of supported diet, and food and water given ad libitum" (Fluent), except hungry exposure for two hours before testing, during this period, the food is removed (postabsorptive state).

Rats were exposed to the test product when administered orally within one (D1) or four (D4) days. Two hours after the conclusion is sustained fashion the effects of the product and within 30 minutes after as animals have besbelli pentobarbital sodium (Nembutal®from the end of the tail was collected 300 ál blood samples.

As an example, the obtained results are compared in Table 2. These results show the effectiveness of the compounds of formula (I) for lowering blood glucose in diabetic animals. These results are expressed as the percentage change in glycemia on D1 and D4 (the number of days of exposure) relative to DO (prior to the impact of the drug).

Table 2
Connection20 mg/kg/day200 mg/kg/day
D1D4D1D4
1+5-4-9-23
2-17-13-10-25
3+2-10-14-29
5-18-3-30-26
6+30-6-16
7-5-9-19-28
8-7-12-10-9
10-3-5-21-25
11-1-8-8-14
12-22-26
13-16-26
15-23-28-29-31

1. Compounds of General formula (I)

in which:

And denotes a benzene ring, optionally substituted by one or more of the following groups:

OR2, where R2 represents:

branched or non-branched (C1-C5)alkyl,

halogen,

X represents-CH=, -CH2-, -N=, or-NH - radical, Y represents a radical CH2the atom of oxygen or sulfur or a group NR7, where R7 represents:

hydrogen or

branched or non-branched (C1-C5)alkyl, R1 denotes one of the following groups:

hydrogen or

branched or non-branched (C1-C5)alkyl, with the exception of the compounds of formula (I)in which:

(a) (a denotes a benzene ring, X represents-CH= or-CH2-, Y denotes an oxygen atom and R1 is a hydrogen atom;

b) And the hereafter which includes a benzene ring, substituted in the 5' position of the double ring by halogen atom, X represents-CH=, Y represents a sulfur atom and R1 is a hydrogen atom,

in) And denotes unsubstituted benzene ring, X represents-CH2-, R1 denotes a hydrogen atom or a branched or non-branched (C1-C5) alkyl radical, and Y represents NR7, where R7 represents a hydrogen atom, a branched or non-branched (C1-C5)alkyl radical or a benzyl radical,

g) denotes unsubstituted benzene ring, X represents-CH=, R1 denotes a hydrogen atom and Y represents NR7, where R7 denotes the ethyl radical,

d) A denotes a benzene ring, X represents-CH=, Y represents a sulfur atom and R1 is a hydrogen atom;

e) compounds of the formula

where R and R1denote hydrogen, halogen or alkoxygroup containing from 1 to 6 carbon atoms,

and their pharmaceutically acceptable salts.

2. The compounds of formula (I) according to claim 1, in which a denotes an optionally substituted benzene ring.

3. The compounds of formula (I) under item 1 or 2, in which Y represents a radical-CH2-, a sulfur atom or a group-NR7.

4. The compounds of formula (I) according to claim 3, in which Y represents a sulfur atom and a represents monoelement benzene ring, substituted otherwise than 5' on which ogenyi double ring, or a benzene ring substituted by at least two groups.

5. The compounds of formula (I) according to claim 3, in which Y denotes the group-NR7 and means zameshennoe benzene ring.

6. The compounds of formula (I) under item 1 or 2, in which Y denotes an oxygen atom, X represents a radical-CH= or the radical-CH2and a is a substituted benzene ring.

7. The compounds of formula (I) according to claim 1 or 2, in which Y denotes an oxygen atom and X represents a radical-N= or-NH-.

8. Pharmaceutical composition having anti-diabetic activity, containing as an active ingredient the compound according to any one of claims 1 to 7 and an inert filler.



 

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The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of benzodioxole, benzofuran, dihydrobenzofuran and benzodioxane or their pharmaceutically acceptable solvate of General formula I

< / BR>
where Q1and Q2every means independently hydrogen or halogen;

X is CH2CH or oxygen;

Y represents CR3, CR3R4or (CH2)nwith n = 1-4;

Z denotes CH2CH or oxygen;

R means hydrogen, halogen or alkyl WITH1-4in both cases;

m denotes 1 or 2;

R1means1-6-alkyl, C3-6-cycloalkyl,1-3-haloalkyl,1-6-alkylamino,2-6alkenyl,1-4-alkoxy(C1-4)alkyl, C1-C4-alkylthio(C1-4)alkyl or triptorelin-C1-4;

R2means hydrogen, halogen or C1-4-alkyl; and

R3and R4each independently mean hydrogen or C1-4-alkyl,

containing pharmaceutical compositions for the treatment of sleep disorders, and disorders associated with disturbance of circadian rhythms

The invention relates to benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H, Cl, Br, OH or OA;

R3denotes benzyl or itself known protective for the amine function group;

X denotes a CN, COON, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Het;

R4and R5each independently of one another denotes H, A or benzyl;

A denotes alkyl with 1-4 C-atoms;

Ph denotes phenyl;

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Py denotes a pyridyl;

and their salts

The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

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The invention relates to the field exitlinks acids, in particular to the intermediate compounds - derivatives of 1-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(A) where R1-C1-C6-alkyl, and the method of obtaining derivatives complex alilovic esters of 4-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(I) where R1-C1-C6-alkyl, R2and R3may be the same or different and represent a hydrogen atom, chlorine or trifluoromethyl, which are inhibitors oldselected

The invention relates to a new benzimidazole derivative of the formula (I), where a represents a single bond or C1-2-alkylenes group; R6is a hydrogen atom or a C1-4is an alkyl group; b - C2-3-alkylenes group; X represents an oxygen atom, each of R1and R2is a hydrogen atom; E is C1-2-alkylenes group; R3is a phenyl group (this phenyl group may be optionally substituted by halogen atom), each of R4and R5that are independent from each other, represents a hydrogen atom or a C1-4is an alkyl group; D - C1-2-alkylenes group and Ar is a phenyl group (this phenyl group may be optionally substituted by a halogen atom, a C1-4is an alkyl group, a C1-4-alkoxygroup or triptorelin group)
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