The method of obtaining 3-hydroxy-5-[2-(dimethylamino)-ethyl]-2,3 - dihydro-4-(methoxyphenyl)-1,5-benzo thiazepine-4(5h)-it is a method of obtaining derivatives benzodiazepine, the method of obtaining cis-(+)-3-acetoxy-5-[2-(dimethylamino)-ethyl]-2,3 - dihydro-2-(4-methoxyphenyl )-1,5-benzothiazepin-4(5h)-she

 

(57) Abstract:

This invention relates to a method for producing 3-hydroxy-5-[2-(dimethylamino)-ethyl] -2,3-dihydro-4-(methoxyphenyl)-1,5-benzothiazepin-4(5H)-she and its salts, which can be used to produce pharmaceutically active compounds, such as diltiazem, which is used in cardiovascular therapy. The method consists in the N-alkylation of 3-hydroxy-2,3-dihydro-4-(methoxyphenyl)-1,5-benzothiazepin-4 (5H)-she (dimethylamino)acylhalides, and the reaction of the N-alkylation is carried out in a reaction mixture containing 2-butanol and water. The proposed method is simpler, more efficient and safer than a known way, and gives a product of high purity. 3 S. and 8 C.p. f-crystals.

< / BR>

The invention relates to a method for producing 3-hydroxy-5- [2-(dimethylamino)-ethyl] -2,3-dihydro-4-(methoxyphenyl)-1)5 - benzothiazepin-4(5H)-she and its salts, which can be used to produce pharmaceutically active compounds, such as CIS-(+)-3-acetoxy-5-[2-(dimethylamino)-ethyl] -2,3 - dihydro-4-(methoxyphenyl)-1,5-benzothiazepin-4(5H)he who is referred to as diltiazem. Diltiazem General formula (Ia) is used in cardiovascular therapy and special is both CIS-(+)-3-hydroxy-2,3-dihydro-2-(4-methoxyphenyl)- 1,5-benzothiazepin-4(5H)-he General formula (II)

< / BR>
reacts with 2-(dimethylamino)ethylchloride in the presence of a base such as sodium hydride, metallic sodium or sodium amide, in a solvent such as dimethyl sulfoxide, dioxane, toluene or xylene to obtain CIS-(+)-3-hydroxy-5- (2 - dimethylamino)-ethyl-2,3-dihydro-2- (4-methoxyphenyl)-benzothiazepin - 4(5H)-it General formula (I)

< / BR>
which reacts with acetic anhydride to obtain diltiazem.

In the European patent EP-A-0081234 describes another method of N-alkylation. This patent discusses a method of obtaining or derived benzodiazepine (I ) or diltiazem (Ia) or any of compounds of General formula (II) to obtain the derived benzodiazepine (I) or CIS-(+)-3-acetoxy-2,3 - dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-she (IIa)

< / BR>
to get diltiazem (Ia), respectively, with 2- (dimethylamino)-ethylchloride in the presence of potassium hydroxide in acetone or in the presence of potassium carbonate in a solvent selected from acetone, lower alkyl acetate, a mixture of acetone and water and a mixture of lower alkyl acetate and water. This method has several disadvantages. In all methods described in the examples of the patent EP-A - 0081234 required product stands out cristalli in order to obtain a sufficiently pure product.

Moreover, because the acetone is completely miscible with water, regular removal of salts by washing with water is impossible. Thus, it must be removed first solvent and replaced by another solvent, such as toluene, which subsequently, after removal of the salts is replaced by ethanol, from which the product can be crystallized and which can be removed impurities. This is inefficient, time-, energy - and materialsafety way.

All the examples of the patent EP-A-0081234 show that the method requires the amount of the solvent is 8-10 times higher in relation to the amount by weight of starting material and the reaction time ranges from 3 hours to 30 hours, which makes the method expensive and materialsafety.

Moreover, since the ethyl acetate and methyl acetate hydronauts in alkaline conditions, regeneration and re-use of these solvents is becoming very difficult.

In the patent application WO 92/110485 describes the alkylation reaction using toluene as solvent and potassium carbonate as the base, with dimethylformamide or N - methylpyrrolidinone as an additional solvent. This reaction, however, requires a catalyst with f is P> The purpose of this invention is to provide a simple, inexpensive and reliable method for industrial preparation of pharmaceutically active derivative benzothiazepine the General formula (I) and diltiazem the General formula (Ia).

Another purpose of this invention is to provide a method by which the pharmaceutically active derivative benzothiazepine the General formula (I) and pharmaceutically active reaction products using the thus obtained compound (I) as the desired product (intermediate compounds), such as diltiazem (Ia), can be charged quickly and with high productivity.

An additional objective of this invention is the occupational and environmental safety.

These and other objectives of the invention are achieved by the invention, as set forth in the attached formula of the invention.

One aspect of the invention is a method, which includes alkylation derived benzodiazepine the General formula (II), which may be in CIS - or transform and has a (+) or (-) optical rotation, or its salts 2-(dimethylamino)acylhalides or its salt in the presence of potassium carbonate or potassium hydroxide, characterized in that the method of the invention is that, that the required amount of organic solvent is much smaller than that required in the known methods. In one embodiment of this invention, the amount by weight of 2-butanone used for carrying out this reaction, only 1.3-1.9 times the amount by weight of the starting material.

Another advantage of this invention lies in the fact that in the process according to this invention can be used in considerably smaller amounts of very toxic and carcinogenic alkylating agent 2-(dimethylamino)acylhalides, less than 1.2 mol per 1 mol derived thiazepine (II).

Another advantage is the high efficiency of this method. In one embodiment, the time required for at least 90%, preferably at least 95%, conversion of starting material into product ranges from 50 minutes to 2.5 hours, and the reaction is preferably conducted for a time from 50 minutes to 1.5 hours, often even depending on the amount of potassium hydroxide or potassium carbonate.

The preferred quantitative interval 2-(dimethylamino)- acylhalides is 1.05-1.18 to begging, especially 1,12-of 1.16 mol per 1 mol of derived benzoate is inoe amount of potassium carbonate or potassium hydroxide, used in the above method, is in the range from 3 to 3.5 mol, especially of 3.1 to 3.3 mol per 1 mol derived benzodiazepine (II).

The preferred amount of 2-butanone in the reaction mixture is in the range of 1-2, and more preferably 1.3 to 1.9, and even more preferably in the near 1.615% times the amount by weight derived benzodiazepine (II).

The amount of water in the reaction mixture is preferably not less than 0.4 mol (equivalent to approximately 9.8 per cent of water in 2-butanone (m/m), more preferably not less than 0.6 mol (corresponding to about 15% water in 2-butanone (m/m)) and even more preferably not less than 0.7 or 0.8 mol mol (which corresponds to about 17 or 20% water in 2-butanone (m/m) mol 2-butanone. The most preferred amount of added water is about 0.8 mole per mole of 2-butanone (about 20% (m/m)).

The maximum amount of water is not specifically limited, but in the preferred embodiment, the amount of water present in the process of transformation derived benzodiazepine (II) in the derived benzodiazepine (I), 0.9 mol or less per mole of 2 - butanone (which corresponds to about 22% water in 2-butanone (/m/) or less). Especially predpochtitel the share at the temperature of reflux distilled reaction mixture, or preferably at a temperature in the range from 75 to 85oC if the reaction is carried out at atmospheric pressure. Method of course can be done at a higher temperature, when the pressure is above atmospheric, and in the preferred embodiment, the derived benzodiazepine (I) 2- (dimethylamino)-ethylchloride, potassium hydroxide or potassium carbonate and 2-butanone are combined and heated at an elevated temperature such as a temperature in the range from 40 to 85oC, preferably in the range from 50 to 65oC, before adding water to the reaction mixture,

After the reaction of the salt can be washed, for example, by adding the aqueous phase from the organic productdatabase phase. The reaction is very selective, and there is no additional cleaning required product is not required.

This product or its pharmaceutically acceptable salt is used as an active ingredient of a pharmaceutical preparation for the treatment of coronary insufficiency and hypertension, as described in the patent EP-A-0154895, and, in addition, is used as intermediate compounds in the method of instruction pharmaceutically active compounds, such as derivatives of 2-phenyl-1,5-benzothiazepine with antigipnoticescoe and vasodilator aktivnosta treatment of angina pectoris. Method N-alkylation of the present invention, preferably, carried out with the derived benzodiazepine (II) with the necessary CIS - and TRANS-conformation corresponding to the desired CIS - or TRANS-conformation of the desired product (I). It is preferable to use a derived benzodiazepine (II) having a CIS(+)-configuration, i.e., 2S,3S-isomer.

Alkilirovanny product (I), preferably, secreted by simply removing, for example, by distillation or evaporation, 2 - butanone organic productdatabase phase, for example, at atmospheric pressure or at reduced pressure (for example, by vacuum distillation). Remote from the reaction mixture of 2-butanone can be reused in this way that saves costs and avoids the problems of chemical waste. The remaining end product containing the derived benzazepine (I), can then be subjected to crystallization, for example, in the form of pharmaceutically acceptable salts and then included in the formulation of pharmaceutical compositions is known, or can be practically used as such as a chemical intermediate to produce different pharmaceutically active with the water benzothiazepine the General formula (I), obtained after removal of 2-butanone has sufficient yield and purity, as it does not require isolation and/or purification by stage of extraterestrial or some other type of cleaning, if you want to use derivative (I) as starting compound for further reaction. This allows you to add new reagents and solvents in the same vessel, from which was removed 2 - butanone, to turn derived benzodiazepine General formula (I) in other derivatives, such as diltiazem (Ia).

Therefore, another aspect of the present invention is a method, which contains the alkylation derived benzodiazepine (II), as described above, and subsequent acylation alkylated product (I) at the 3-position of the active reagent to obtain pharmaceutically active compounds (Ia').

The active reagent is carboxylated, the anhydride of the carboxylic acid or activated derivative of ester, or a compound of General formula (III):

R2-Y-COOH (III)

or its salt, where R2is cycloalkyl, lower alkoxycarbonyl, COOH, lower alkanoyl, heterocyclyl, halogen atom, lower alkyl, lower alkoxy, aryloxy, mono-, di - or trihalomethyl, hydroxy, alloc honil, arylcarbamoyl, lower alkoxycarbonyl or phenyl, which optionally may have 1-3 substituent, and Y represents a bond, lower alkylene, lower albaniles or lower alkylene. The terms "lower alkyl", "lower alkylene", "lower alkoxy" and so on mean group with 1 to 5, preferably 1 to 3, carbon atoms. The final reaction product (I) with the above active reagent is benzothiazepin the General formula (Ia')

< / BR>
in which the hydroxyl group at the 3-position is replaced by the Vice-OCO-Y-R2and in which the substituents Y and R have the above significance.

The reaction order of pharmaceutically active compounds, derived using benzodiazepine (I) which is obtained as described above as intermediate (source) connection, can be carried out in situ (in place) in the same vessel, which was implemented method of N-alkylation of the present invention, or in the same vessel in which 2-butanone was removed from the organic productdatabase phase separated from the reaction mixture obtained in the reaction

N-alkylation of the present invention.

Pharmaceutically active compounds described in JP-A2-63 - 275572, can be thus obtained at first it is eaten in the implementation of the above acylation of the active reagent.

In the preferred embodiment of this aspect of the invention the compound (I) obtained by the method of N-alkylation of the present invention, serves as an intermediate connection and azetiliruetsa in the 3-position with receiving diltiazem (Ia). Diltiazem (Ia) can be converted to the corresponding pharmaceutically acceptable salt, such as cleaners containing hydrochloride salt in the usual way, such as extraction diltiazem appropriate organic solvent, such as toluene, and processing the extracted diltiazem corresponding acid with formation of the corresponding salt, such as a solution of ethanol-HCl with the formation of cleaners containing hydrochloride salt.

In accordance with one preferred variant of the method of the invention for receiving diltiazem (Ia) alkylation derived benzodiazepine General formula (II) is 2- (dimethylamino)-ethylchloride in the presence of potassium carbonate and a mixture of 2-butanone and water. After an additional amount of water is added to the reaction mixture to remove salts, the aqueous phase is separated from the phase 2-butanone, and 2-butanone is removed, for example, distilled for regeneration. Acetic anhydride is added to the residue and reacts with the derived benzodiazepine Oei, and the desired product, HCl-salt of diltiazem (Ia), crystallized by using a solution of ethanol-HCl.

As stated here, in comparison with previously known methods, the above method of the present invention is clearly more promising and more economical to obtain a derived benzodiazepine (I) and other derivatives benzodiazepine, such as diltiazem (Ia), especially at the industrial level. Using this new method, it is possible to avoid some complicated stages of the working cycle, can be used in much smaller amounts of solvents and toxic reagents, which results in significantly less waste, and also presents the benefits of occupational safety in addition to much less necessary in the bulk of the equipment and the power consumption

A high yield of product high quality is also an important advantage.

The following examples illustrate the present invention.

EXAMPLE 1.

A mixture containing 40 g of CIS - (+)-3-hydro-2,3-dihydro-2-(4 - methoxyphenyl)-1,5-benzothiazepin-4(5H)-she, of 21.9 g of 2-(dimethylamino) -ethylchlorothioformate, of 57.5 g of potassium carbonate and 64 g of 2-butanone, heated to 58oC and to it is added to 12.8 ml of water. C is 1.5 hours, then added 104 ml of water, and the organic and aqueous phases are separated, 2-butanone Argonauts from organic productdatabase phase for regeneration, and distilled residue is added acetic anhydride. After the reaction with acetic anhydride product diltiazem extracted in toluene, from which it is then crystallized using a solution of ethanol-HCl.

After the alkylation reaction of the obtained intermediate compound is not allocated, but its output is determined as follows: after removal of 2-butanone remains of 50.5 g of crude intermediate product. By liquid chromatography medium pressure (GHSL=MPLC) determined that CIS-(+)-3-hydroxy-5-[2- (dimethylamino)-ethyl] -2,3-dihydro-2-(4-methoxyphenyl)- benzothiazepin-4(5H)-it is obtained with a yield of 97.2 per cent. The purity of the product alkylation reaction is confirmed by NMR spectroscopy.

EXAMPLE 2.

A mixture containing 40 g of CIS-(2)-3-hydroxy-2,3-dihydro-2- (4-methoxyphenyl)-1,5-benzothiazepin-4(5H)she, of 21.9 g of 2-(dimethylamino) ethylchloride hydrochloride, 64 g of potassium carbonate and 64 g of 2 - butanone, heated to 58oC, and to the mixture is added to 12.8 ml of water, after which the mixture is boiled under reflux for 50 minutes. Then doba product, used to continue the process as described above in example 1. After removal of the 2-butanone by distillation of the obtained residue 50,23 g, which is in accordance with GHSL is CIS-(+)-3-hydroxy-5-[2-(dimethylamino) ethyl]- 2,3-dihydro-2-(4-methoxyphenyl)-benzothiazepin-4-(5H)-one with a yield of 96.1 per cent.

1. The way to obtain CIS-(+)-3-hydroxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-it General formula I

< / BR>
or its salts by alkylation of water benzodiazepine General formula II

< / BR>
or its salts 2-(dimethylamino)acylhalides or its salt in the presence of potassium carbonate or potassium hydroxide, characterized in that the alkylation is carried out in a reaction mixture containing 2-butanone and water.

2. The method according to p. 1, characterized in that the number of water is not less than 0.4 mole per mole of 2-butanone.

3. The method according to p. 1, characterized in that the amount of water is at least equal to 0.6 mole per mole of 2-butanone.

4. The method according to p. 1, characterized in that the amount of water is in the range of 0.7 to 0.9 mole per mole of 2-butanone.

5. The method according to PP.1-4, characterized in that the amount of potassium carbonate or potassium hydroxide is in the range from 3 to 3.5 mol per mole number of 2-butanone is 1.3-1.9 times greater amount by weight derived benzodiazepine General formula II or its salts.

7. The method according to PP.1-6, characterized in that the number of 2-(dimethylamino)acylhalides or its salt is in the range from 1.05 to 1.18 per mole derived benzodiazepine General formula II or its salts.

8. The method according to PP.1-7, characterized in that 2-(dimethylamino)acylhalides or its salt is 2-(dimethylamino)ethylchloride or its salt.

9. The method according to PP.1-8, characterized in that is carried out over a period of time ranging from 50 min to 2.5 h, then the reaction mixture is added water, the resulting aqueous phase is then separated from the organic productdatabase phase and 2-butanone is removed from the organic productdatabase phase.

10. The method of obtaining derivatives benzodiazepine General formula Ia

< / BR>
or their pharmaceutically acceptable salts, in which the product benzodiazepine General formula I obtained in accordance with subparagraph.1-9 claims, alleroed in the 3 - position of the active reagent, such as carboxylic, the anhydride of the carboxylic acid or activated derivative of ester, or a compound of General formula III

R2-Y-COOH,

or its salts, where R2is cycloalkyl, lower alkoxycarbonyl, -COOH, lower alkanoyl, heterocyclyl, halogen atom, NII alkylthio, lowest alkylsulfonyl, lower alkylsulfonyl, di-(lower alkyl)-aminosulfonyl, arylcarbamoyl, lower alkoxycarbonyl or phenyl, which optionally may have 1-3 substituent, and Y represents a bond, lower alkenyl, lower albaniles or lower alkylene, in a known manner, characterized in that the acylation reaction is carried out in situ (in place) directly after the reaction of alkylation and removal of water and 2-butanone from the reaction mixture without cleaning or stage of crystallization between the removal of water and 2-butanone from the reaction mixture and the stage of the acylation reaction and, optionally, turning acylated product Ia its pharmaceutically acceptable salt.

11. The way to obtain CIS-(+)-3-acetoxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-2(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-it General formula Ia by p. 10 claims

< / BR>
or its pharmaceutically acceptable salt, where the product benzodiazepine General formula I obtained by the PP.1-9 claims, azetiliruetsa 3-position perse known manner, characterized in that the acetylation reaction is carried out in the city (on the spot) directly after the reaction of alkylation and removal of water and 2-butanone of the operating mixture and stage acetylation reaction and, optionally, conversion of acetylated product (Ia) into its pharmaceutically acceptable salt.

 

Same patents:

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component

The invention relates to derivatives of 2, 3, 4, 5-tetrahydro - 1,4-benzothiazepine, containing pharmaceutical compositions, and methods for their preparation and to their use in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means to prevent such painful conditions as paralysis

The invention relates to methods for new nitrogen-containing compounds of General formula I

Rwhere R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

ororor< / BR>
ororwhere n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R

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

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

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new oxoazepanylacetamide and oxoazepanylphenoxyacetamide derivatives, or to their stereoisomers or pharmaceutically acceptable salts described by general formula I where Q means O, S or N(R25); R25 means H; R80 is C6arylC1-4alkyl substituted by one or two substituted independently chosen from R3 groups; each R3 is independently chosen from a group including C1-4alkyl, C1-4alkoxy group, C2-6alkenyloxy group, halogen, C6aryloxy group, N(R20)(R21), R50, heteroaryl chosen from pyridine and thiazol where each alkoxy group and heteroaryl has optionally up to three substitutes independently chosen from R61 groups; and alkyl has optionally three substitutes independently chosen from R60 groups; or two R3 groups when they are present on carbon neighbours, together can form a fragment of formula -(O)a-(CH2)b-(O)c-(CH2)d-(O)e- where a, c and e independently mean 0 or 1, and both b and d independently mean 0, 1, 2 or 3; provided the fragment does not contain two oxygen neighbors and summed a, b, c, d and e are equal to 3 at least; R1 is chosen from a group including H, C1-4alkyl, C6arylC1-4alkyl; each R60 independently is chosen from a group including C1-C6a alkoxy group, NR12R13, halogen, heterocycloalkyl, such as piperidine; each R61 independently is chosen from a group including R60 and C1-C6alkyl; X means a group of formula -(CH2)n- where n means 2 or 3; or a group of formula II where Y means CH2, S; R75 and R76 means H; Z means C6aryl or heteroaryl, such as pyridine; each of which has optionally one substitutes chosen from R2 groups; R2 is chosen from a group including H, C1-4alkyl, halogen, heterocycloalkylC1-4alkyl, C6arylC1-4alkylaminoC1-4alkyl and a group of formula -(CH2)fN(R11)-(R10); where each heterocycloalkyl, arylalkylaminoalkyl has oprtionally one substitute chosen from R61 groups; f means 1; R11 means H; R10 means C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, aryl, C6arylC1-4alkyl, heteroarylC1-4alkyl where aryl has optionally one substitute chosen from R61 groups; each R12 and R13 independently mean C1-4alkyl; each R20 and R21 independently mean C1-4alkyl where alkyl has optionally one substitute chosen from R60 groups; and provided that the compound does not represent N-(4-ethoxybenzyl)-N-(2-oxoazepane-2-yl)-2-phenoxyacetamide or N-[(2-fluorophenyl)methyl]-N-(2- oxoazepane-3-yl)-2,2-diphenylacetamide. Also, the invention refers to a pharmaceutical composition of the compound of formula I, to methods of treating HCV viral infection and methods of relieving the symptoms of HCV viral infection with using the compound of formula I.

EFFECT: there are produced new oxoazepanylacetamide and oxoazepanylphenoxyacetamide derivatives showing HCV replication inhibiting activity.

1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to use of compounds of formula II for treating and/or preventing liver disease mediated IBAT selected from Alajil syndrome (ALGS), progressive family inside liver cholestasis (PFIC), primary billiar cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic liver steatohepatitis (NASH) and itching caused by cholestatic liver disease, as well as to based pharmaceutical composition and method of treating said diseases. In general formula II M denotes CH2 or NH; R1 denotes H or hydroxy; R2 represents H, CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2OH, -CH2OCH3, -CH(OH)CH3, -CH2SCH3 or -CH2CH2SCH3.

EFFECT: treating and preventing hepatic disorders.

11 cl, 1 tbl, 20 ex

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