1,4-benzothiazepine-1,1-dioxide, pharmaceutical composition, lowering the level of blood lipids, the method of treatment of a clinical condition of a mammal, the method for obtaining compounds

 

(57) Abstract:

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula II, where R1, R2are primocane C1-6alkyl group; R4represents unsubstituted phenyl; R5and R8represent hydrogen; R6represents methoxy or bromo; R7arepresents methoxy, hydroxy or trifluoromethyl; R9and R10represent hydrogen, salts, solvate or physiologically functional derivatives, as well as the way they are received. In addition, the disclosed pharmaceutical composition on the basis of these compounds, which lowers the level of blood lipids, and the method of treatment of a clinical condition of a mammal. The invention can be used in medicine, in particular for the prevention and treatment of such hyperlipidemics conditions as atherosclerosis. 4 c. and 5 C.p. f-crystals, 3 PL.

The invention relates to a new lipid-lowering compounds, to processes for their preparation and intermediate compounds and containing their pharmaceutical compositions and their use in medicine, in particular for the prevention and treatment of such hyperlib the s in the blood plasma urine low cholesterol (LDL) and very low lipoproteins (VLDL) density. These concentrations can be lowered by loosening the absorption of bile acids from the intestine. One of the ways in which this can be achieved, is the suppression of the active absorption of bile acids in the ileum. This suppression stimulates the conversion of cholesterol to bile acids by the liver, and increase as a result of this needs cholesterol leads to a corresponding acceleration of the removal of LDL and lonp cholesterol from plasma or serum.

Discovered a new class of heterocyclic compounds that decrease the concentration of LDL and lonp cholesterol in plasma or serum and, therefore, applicable as lipid. Reducing the concentration of cholesterol and cholesterol complex ester in plasma, the compounds according to the invention inhibit the development of atherosclerotic lesions and reduce the frequency of coronary heart and related diseases. The latter is defined as heart disease, associated with high concentrations of cholesterol and cholesterol complex ester in plasma or serum.

In this description gipolipidemicheskoe condition is defined as any condition in which the total concentration of the hole is"ptx2">

In the application N WO 93/16055 described compounds of the formula (0)

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in which l is an integer from 0 to 4;

m is an integer from 0 to 5;

n is an integer from 0 to 2;

R and R' are atoms or functional groups arbitrarily selected from the group consisting of halogen, a nitro-group, phenylalkyl, C1-4alkoxy, C1-6alkyl, -SO3R"- CO2R-O(CH2)pSO3P", where p is an integer from 1 to 4, and R" is hydrogen or C1-6alkyl group, in which these phenylalkyl, alkoxy and alkyl arbitrarily substituted by one or more halogen atoms;

Ra- premiani C1-6alkyl and

Rb- premiani C2-6alkyl;

and their salts, solvate and physiologically active derivatives suitable as lipid.

We have discovered a group of compounds with a higher lipid-lowering activity in vivo in comparison with concrete examples of applications N WO 93/16055.

According to the proposed invention the compounds of formula (I):

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in which R1- premiani C1-6alkyl,

R2- premiani C1-6alkyl,

R3is hydrogen or a group OR11where R11is hydrogen, optionally substituted C1-6alkyl or C1-6alkitab encovi or different and each selected from the group containing hydrogen, halogen, CYANOGEN, R15-acetylide, OR15optionally substituted C1-6alkyl, COR15CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R13and O(CH2)pN+R12R13R14where p is an integer from 1 to 4, n is an integer from 0 to 3, a R12, R13, R14and R15arbitrarily selected from the group consisting of hydrogen and arbitrarily substituted C1-6alkyl;

or R6and R7linked in group

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in which R12and R13identical to previously defined and m = 1 or 2; and

R9and R10the same or different and each is represented by hydrogen or C1-6by alkyl; and their salts, solvate or physiologically active derivatives, if R3is hydrogen, or R7is not hydrogen or at least two of the radicals R5, R6, R7and R8not yenny phenyl, possible from one to five, preferably one or two identical or different substituents, each selected from the group consisting of halogen, hydroxyl, nitro-group, a phenyl-C1-6alkoxy, C1-6alkoxyl, optionally substituted C1-6alkyl, S(O)nR15, CO2R15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R13and O(CH2)pN+R12R13R14where p, n, R12, R13, R14and R15identical to those specified previously.

In addition, according to the proposed invention the compounds of formula (I) in which:

R1and R2- premiani C1-6alkyl;

R3is hydrogen or hydroxyl;

R4is unsubstituted phenyl;

R5- hydrogen:

R9and R10is hydrogen; and

R7is selected from the group consisting of halogen, hydroxyl, C1-6alkoxyl, optionally substituted C1-6of alkyl, - S(O)nR15, -OC(O)R15and CH2OR15where R15is hydrogen or C1-6alkyl; and R6and R8- randomly selected from the group consisting of hydrogen and groups mentioned in the definition of R7; or

R8is hydrogen, a R6and the derivative.

Preferred compounds of formula (I) in which R8is hydrogen, a R6and R7- C1-6alkoxyl, more specifically methoxyl.

Among the preferred compounds of formula (I) include compounds of formulas (II), (III), (IV) or (IVa):

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in which R1-R10defined previously, a R7aselected from the group consisting of halogen, CYANOGEN, R15-acetylide, OR15optionally substituted C1-6alkyl, COR15CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)pR15, O(CH2)pSO3R15, O(CH2)pNR12R13and O(CH2)pN+R12R13R14where n, p, R12, R13, R14and R15identical to previously defined, provided that in compounds of formula (III) at least two of the radicals R5- R8are not hydrogen, and their salts, solvate and physiologically active derivatives.

If one or more of the PU, the substituents may be the same or different and each is selected from the group consisting of hydroxyl, halogen, C1-6alkyl, C1-6alkoxy, COR16, nitrile, CO2R16, SO3R16, NR17R18N+R17R18R19where R16-R19the same or different and each is represented by hydrogen or C1-6the alkyl.

As R1suitable methyl, ethyl or n-propyl, preferably ethyl, and as R2is methyl, ethyl, n-propyl, n-butyl or n-phenyl, preferably n-butyl.

R5- preferably hydrogen.

Suitable R7and R7aselected from the group consisting of OR15, S(O)nR15, OCOR15, OCF3, OCN, SCN, CHO, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R15and O(CH2)p; N+R12R13R14where p is an integer from 1 to 4, n is an integer from 0 to 3 and R12, R13, R14and R15- randomly selected from the group consisting of hydrogen and arbitrarily substituted C1-6the alkyl. R7and R7a- preferably OR15.

As R9and R10the prigoda the l or phenyl, arbitrarily substituted preferably in the 4th and/or 3rd position Deputy, selected from the group consisting of halogen, methyl, ethyl, methoxyl, ethoxyl, trifluoromethyl, hydroxyl, carboxyl or O(CH2)3SO3H. Preferred R4is unsubstituted phenyl.

In the compounds of formula (II) one or two, preferably one of the radicals R5, R6and R8must not be hydrogen, and each of them selected from the group consisting of arbitrarily substituted with fluorine C1-4alkyl, C1-4alkoxyl, halogen and hydroxyl. Better if each of them is selected from the group consisting of methyl, methoxy, hydroxyl, trifluoromethyl and halogen. Preferably, when R6- methoxyl or bromine, a R5and R8- hydrogen. R7aselected from the group consisting of arbitrarily substituted with fluorine C1-4alkyl, C1-4alkoxyl, halogen and hydroxyl. Better when R7a- methoxyl, hydroxyl or trifluoromethyl, but preferred methoxyl.

In the compounds of the formula (III) at least one, and preferably two of the radicals R5- R8must be hydrogen. Preferably, at least one of the radicals R6and R7was not hydrogen. If none of R5- R8not l, halogen and hydroxyl, preferably from the group consisting of methyl, methoxy, hydroxyl, trifluoromethyl or chlorine, and most preferred methoxyl.

In the compounds of the formula (IV) two, three or four of the radicals R5- R8must be hydrogen, and the remaining selected from the group consisting of arbitrarily substituted with fluorine C1-4alkyl, C1-4alkoxyl, halogen and hydroxyl, preferably from the group consisting of methyl, methoxy, hydroxyl, trifluoromethyl or chloro. The most preferred methoxyl.

In the compounds of the formula (IVa) at least one, and preferably two of the radicals R5- R8must be hydrogen. Preferably, at least one of the radicals R6and R7was not hydrogen. If none of R5- R8not hydrogen, they are selected from the group consisting of arbitrarily substituted with fluorine C1-4alkyl, C1-4alkoxyl, halogen and hydroxyl, preferably from the group consisting of methyl, methoxy, hydroxyl, trifluoromethyl or chloro. Most preferably, when R1-n-butyl, R2is ethyl, R3, R5, R8, R9and R10is hydrogen, R4- pyridyl or arbitrarily substituted phenyl, and R6and R7- methoxyl.

the-7,8-dimethoxy-5 - phenyl-1,4-benzothiazepine-1,1-dioxides;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy - 5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl - 1,4-benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5 - phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;

(3R, 5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl - 1,4-benzothiazepine-1,1-dioxide;

(3R, 5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl - 1,4-benzothiazepin-4-ol-1,1-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin - 7,8-diol-1,1-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4 - benzothiazepin-7-ol-1,1-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4 - benzothiazepin-8-ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4 - benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepin-8-ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepin-4,8-diol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenyl-1,4 - benzothiazepine-1,1-dioxide;

()-TRANS-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5 - phenyl-1,4-benzod sepin-7-carbaldehyde-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepin-8-thiol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepin-8-acid-1,1-dioxide;

(7R, 9R)-7-butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-dioxolo (4,5 H)(1,4)-benzodiazepin-5,5-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,0 - dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide:

(3R, 5R)-3-butyl-3-ethyl-5-(4-forfinal)-2,3,4,5-tetrahydro-7,8 - dimethoxy-1,4-benzodiazepin-4-ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl - 1,4-benzothiazepin-7-methanol-S,S-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl - 1,4-benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7- (methoxymethyl)-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin - 7,8-diyl-diacetate-1,1-dioxide;

(8R, 10R)-8-butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-1,4 - dioxane(2,3-H)(1,4)-benzodiazepin-6,6-dioxide;

(3R, 5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5 - phenyl-1,4-benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 - phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride;
5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4 - benzothiazepine-1,1-dioxide;

3,3-diethyl-5-(4-forfinal)-2,3,4,5-tetrahydro-8-methoxy-1,4 - benzothiazepine-1,1-dioxide:

3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine - 1,1-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,8-diol - 1,1-dioxide;

(RS)-3,3-diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl - 1,4-benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl - 1,4-benzothiazepin-4-ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5 - phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimetoksi-5 - phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin - 4,7,8-triol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimetoksi-5 - phenyl-1,4-benzothiazepine-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8 - dimethoxy-1,4-benzothiazepin-4-yl-acetate-S,S-dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1 - dioxide;

3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin - 8-ol-1,1-dioxide;

3,3-dibutil-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8 - ol-1,1-dioxide;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5 - phenyl-1,4-benzothiazepin-8-yl-hydrosulphate;
2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin - 8-yl-hydrosulphate;

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin - 8-yl-dihydrophosphate;

()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5 - phenyl-1,4-benzothiazepin-8-yl-aspartate; and

3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin - 8-yl-aspartate.

For use in medicine, particularly suitable pharmaceutically acceptable salts due to their better solubility in water in comparison with the original (i.e., in the form of bases) connections. It is obvious that such salts must contain a pharmaceutically acceptable anion or cation. In a number of suitable pharmaceutically acceptable acid salts of the accession of the compounds according to the invention include salts of such inorganic acids as hydrochloric, Hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric, and such organic acids as acetic, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, sotynova, dairy, meat, maleic, malic, methansulfonate, succinic, p-toluensulfonate, wine and triperoxonane. For medical purposes especially preferred chlorides. In a number of suitable pharmaceutically acceptable basic salts accession connection cogley metals, as magnesium and calcium.

Salts according to the invention with a pharmaceutically unacceptable anion can serve as intermediate compounds for obtaining or purification of pharmaceutically acceptable salts and/or for non-therapeutic purposes, for example for use in vitro.

The term "physiologically active derivative" means any physiologically active derivative compounds according to the invention, for example an ester, which after the introduction of the animal (e.g. human) contributes (directly or indirectly) the emergence of such a compound or its active metabolite.

A further object of the invention are "prodrugs" of the compounds according to the invention. Such prodrugs can in metabolism in vivo to form compounds according to the invention. These prodrugs can be or not to be active themselves.

Compounds according to the invention can exist in different, for example, amorphous and crystalline polymorphous forms. All polymorphic variants of the compounds according to the invention is included in its volume and are further objects.

Used herein, the term "alkyl" means, unless stipulated by valentao the radical with a straight or branched chain, which the oxygen atom is connected to its parent by the remainder of the molecule. The term "phenylalkyl" means a monovalent phenyl group, bonded to the divalent C1-6alkenyl, and as such, the oxygen atom is connected to its parent by the remainder of the molecule.

The compounds of formula (I) exist in the form when carbon centers-C(R1)(R2) & CHR4-chiral. The invention includes each possible substantially free, i.e., connected in less than 5% of any other possible isomers, optical isomers and mixtures thereof with one or more optical isomers in any ratio, including racemic mixtures.

For purposes of describing the absolute chirality of the above-mentioned carbon centers are in order: -C(R1)(R2)-, then-CHR4-.

In cases of uncertainty the absolute stereochemistry at C(R1)(R2) & CHR4connection according to the invention described in terms of the relative positions of the substituents R1/R2and H/R4. Thus, compounds in which larger, i.e. more massive of the substituents R1and R2and the substituent R4located on one side diazepinone ring, shown here in "CIS", and a preference for Specialist obviously, each of the CIS - and TRANS-compounds according to the invention can exist in two enantiomeric forms, individually referred to as ( + ) - or ( - ) -, " respectively, to the direction of rotation of the plane of polarization of light as it passes through the sample compounds. CIS - or TRANS-compounds according to the invention, in which the individual enantiomers are not separated, here marked by the prefix "(+-)-".

Further objects of the invention are:

(a) the compounds of formula (I) and their pharmaceutically acceptable salt, solvate and physiologically active derivatives used as therapeutic agents, in particular for the prevention and treatment of clinical conditions, which shows the suppression of the absorption of bile acids, such hyperlipidemics conditions as atherosclerosis;

(b) pharmaceutical compositions containing the compounds of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically active derivatives along with at least one pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents;

(C) the use of the compounds of formula (I) or its pharmaceutically acceptable salt, colonscope state, when showing the suppression of the absorption of bile acids, such hyperlipidemics conditions as atherosclerosis;

(g) a method of suppressing the absorption of bile acids in the gut of the animal (e.g. human), including the introduction of animal compounds of formula (I), its pharmaceutically acceptable salt, MES or physiologically active derivative in an amount necessary for the effective suppression of absorption bile acid;

(d) a method of reducing the concentration of LDL and lonp cholesterol in plasma or serum of the animal (e.g. human), which includes the introduction of animal compounds of formula (1), its pharmaceutically acceptable salt, MES or physiologically active derivative in an amount necessary for the effective reduction of cholesterol;

(e) a method of reducing the concentration of cholesterol and cholesterol complex ester in plasma or serum of the animal (e.g. human), which includes the introduction of animal compounds of formula (I), its pharmaceutically acceptable salt, MES or physiologically active derivative in an amount necessary to effectively reduce the concentration of cholesterol and complex holesterinesterzy includes the introduction of animal compounds of formula (I), its pharmaceutically acceptable salt, solvate or physiologically active derivatives in an amount necessary for enhancing the excretion of bile acids in faeces;

(C) method of prevention or treatment of a clinical condition in animals (e.g., human), which shows the suppression of the absorption of bile acids, such gipolipidemicheskoe conditions such as atherosclerosis, including the introduction of animal compounds of formula (I), its pharmaceutically acceptable salt, MES or physiologically active derivative in therapeutically effective amounts;

(and) the way to reduce the frequency of coronary heart and related diseases in animals (e.g., human), comprising introducing the compound of the formula (I), its pharmaceutically acceptable salt, MES or physiologically active derivative in an amount necessary to effectively reduce the likelihood of coronary heart and related diseases.

(K) a method of reducing the concentration of cholesterol in plasma or serum of the animal (e.g. human), which includes the introduction of the compounds of formula (I) in an amount necessary for effectively reducing concentrationtime derivatives, which is defined here):

(m) new intermediate chemical compounds used in the preparation of compounds of formula (I);

(h) compounds, the synthesis of which is described later in examples 1-13.

All available hereinafter references to "compound(I) of the formula (I) belong to the previously defined connection(s) (I), their salts, solvate or physiologically active derivatives.

Naturally, the amount of the compounds of formula (I) required to achieve the desired biological effect depends on many factors, such as selected to use a specific type of connection, the route of administration and the clinical condition of the recipient. The daily dose usually ranges from 0.3 mg to 100 mg (typical dose from 3 mg to 50 mg) per kg of body weight, for example 3-10 mg/Khadi. For example, the dose for intravenous administration may range from 0.3 mg to 1.0 mg/kg, and it is convenient to introduce, pouring from 10 to 100 ng/kg per minute. Suitable liquids for injection may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg/ml Unit doses may contain, for example, from 1 mg to 10 g of the active compound. So, for example, ampoules for injection may contain from 1.0 to 100 mg, such as unit dose formulations for peroral what I pharmaceutically acceptable salts listed weight should be attributed to the ion's mass benzothiazepine in the salt.

For the prevention or treatment of the above conditions the compounds of formula (I) can be used per se, but preferably their application with an acceptable carrier, i.e., in the form of a pharmaceutical composition. Of course, the carrier must be acceptable in the sense of compatibility with other ingredients of the composition and harmless to the recipient. It can be solid, or liquid, or suspension, and its composition with the compound preferably manufactured in the form of a unit dose, for example tablets, which may contain from 0.05 to 95% by weight of active compound. There could be other pharmacologically active ingredients, including other compounds of formula (I). The pharmaceutical compositions according to the invention can be prepared by any pharmaceuticals method consisting essentially of mixing components.

The pharmaceutical compositions according to the invention include compositions for oral, rectal, local, transbukkalno (i.e. under the tongue) and parenteral (for example, subcutaneously, intramuscularly, intradermally, or intravenous) administration, although the most appropriate method in each case depends on the type and severity of the condition and connection-specific FD is Locke with controlled release of the active ingredient is also included in the scope of the invention. For the manufacture of membranes suitable acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and its methyl ester.

Pharmaceutical compositions for oral administration can be presented in such forms as capsules, starch wafers, pellets or tablets, each containing a certain number of compounds of formula (I) in the form of powder or granules, a solution, or aqueous or non-aqueous suspensions or in the form of melanosomes or oil-water emulsion. As mentioned, such compositions can be prepared by any pharmaceuticals by a method including mixing the active compound with a carrier (which may contain one or more accessory ingredients). Typically, the compositions are prepared to obtain a homogeneous and well-mixed mixture of the active compound with a liquid or finely chopped, or both carriers, followed (if necessary) by molding. For example, a tablet may be made by extrusion or blow in the form of powdery or granular compounds together (optionally) with one or more auxiliary ingredients. Pressed that the R in the form of powder or granules, and if necessary, mixed with a binder or lubricant, inert diluent and/or surface active/dispersing(s) agent(s). Molded tablets are manufactured by forming on the respective setting the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions for transbukkalno include the introduction containing the compounds of formula (I) pellet-based corrigenda taste (usually sucrose and the Arabian gum or tragakant) and mints on the inert base such as gelatin and glycerine or sucrose with Arabian gum).

Pharmaceutical compositions for parenteral administration typically comprise sterile aqueous preparations of the compounds of formula (I), preferably isotonic to the blood of the intended recipient. These preparations are preferably administered intravenously, although they can also be administered by subcutaneous, intramuscular or intradermal injection. Such medications conveniently be prepared by mixing the compound with water followed by sterilization and bringing to isotonicity with blood. Formulations for injection according to the invention usually contain from 0.1 to 5% (by weight) of the beginning.

Pharmaceutical is Jew. They can be obtained by mixing the compounds of formula (I) with one or more conventional solid carriers, for example cocoa butter, and then shaping the mixture.

Pharmaceutical compositions for local injection preferably applied in the form of ointment, cream, lotion, paste, gel, spray solution, aerosol or oil. As carriers suitable petrolatum, lanolin, polyethylene glycol, alcohols and combinations of two or more of the listed substances. Such compositions typically contain from 0.1 to 15%, for example from 0.5 to 2% (by weight) of the beginning.

It is also possible transdermal administration. Pharmaceutical compositions, it can be applied in the form of individual labels adapted for prolonged close contact with the epidermis of the recipient. These stickers contain the necessary active principle in the buffer (if necessary) aqueous solution, or dissolved/dispersed in the adhesive agent, or dispersed in the polymer. A suitable concentration of the active start is about 1 to 35%, preferably from about 3% to 15%. In special cases, the transfer of an active connection with the stickers can be made electro - or iontophoresis, as described, for example, in Pharmaceutical Research, 3(6), 318, (1986).

For example, the compounds of formula (I) in which R3is hydrogen, can be obtained by oxidation of the corresponding compounds of formula (V)

< / BR>
in which R1- R10identical specified earlier, and I is 0 or 1. The oxidation can be carried out by a peroxide such as hydrogen peroxide, in the presence of triperoxonane acid at moderate temperatures, for example -20 to 50oC, preferably from -10 to 10oC. the Compound of formula (V), where I=1, can be prepared from the corresponding compound where I = 0, partial oxidation of peroxide, as described above.

The compounds of formula (V) can be obtained by reduction of kinoway regard, the compounds of formula (VI)

< / BR>
in which R1-R10identical to the previously specified, for example, such compounds of boron as boron, in a suitable solvent, such as ether, as tetrahydrofuran, or by catalytic hydrogenation using a catalyst such palladium, 10% Pd/C, at moderate temperatures, for example from 20 to 100oC, preferably from -10 to 50oC.

The compounds of formula (VI), as defined here, as well as their every possible optical isomer, which is essentially free, so the proportions are treated as novelty items and serve as the object of the invention.

The compounds of formula (VI) can be obtained by closing the loop in the compounds of the formula (VII)

< / BR>
in which R1- R8identical specified earlier, the distillation of the azeotrope or keeping under reflux in the presence of such a suitable desiccant, molecular sieve, in a suitable solvent, such as 2,6-lutidine, in the presence of acid such as HCl.

The compounds of formula (VII) can be obtained by reaction of compounds of formula (VIII)

< / BR>
in which R4-R8identical to the previously specified, with an appropriately substituted aziridines usually in a polar solvent, for example methanol.

The compounds of formula (VII) can also be obtained by reaction of compounds of formula (IX)

< / BR>
in which R4-R8identical to the previously specified, a L - suitable tsepliaeva group, for example halogen, with a compound of the formula HSC(R9)(R10)C(R1)(R2)NH2where R1, R2, R9and R10identical to the above.

The compounds of formula (IX) can be obtained by reaction of the appropriate acid with the compound of the formula R4H, where R4identical to above, i.e. by reaction of the Friedel-using, typically chloride by kotoroy R5- R8identical to the previously specified, with such dinucleophiles base, like sodium hydride, followed by treatment of the salts N, N-dimethylthiocarbamate and pyrolysis obtained O-kildalkey-carbamate (for example, in such a high-boiling solvent, as tetradecane at a temperature of about 255oC) and hydrolysis (for example, such a strong base like KOH) to S-alltelringtoneslyt.

An alternative method of preparing compounds of the formula (VIII) is the reaction of compounds of formula (IX) with sodium hydrosulfide (NaSH).

The above-mentioned starting materials may be purchased or prepared by methods known to experts in this field or described in the chemical literature; for example, aziridine can be obtained from the corresponding 2-substituted 2-aminoethanols.

The compounds of formula (V), in which one or more groups R5-R8-halogen-free, can be converted into compounds of formula (V) in which R5-R8are other groups, by methods known in the art or described in the literature.

The compounds of formula (I) in which R3-OH, can be obtained from corresponding compounds of formula (I) in which R3e from other optical isomers, can be obtained by chiral synthesis using, for example, such a source of chiral substances, as aziridine or achiral separation of the products of synthesis, such as chiral HPLC, or classical separation of chiral acids.

An arbitrary transformation of the compounds of formula (I) or the compounds of formula (I) with the principal Deputy to the corresponding acid salt of the joining may be effected by reaction with the appropriate solution (for example, one of the above acids. An arbitrary transformation of the compounds of formula (I) with acid substituent in the corresponding basic salt may be carried out by reaction with a solution of an appropriate base, for example sodium hydroxide. Arbitrary transformation in such physiologically active derivative, as an ester, can be carried out by methods known in the art or described in the literature.

In addition, the compounds of formula (I) can be converted into other compounds of formula (I) standard described in the literature and known in the art methods, for example by alkylation of the hydroxyl group.

The illustrative purposes of the following examples, passaustralia-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide

(a) hydrochloride of the ethyl-2-aminobutyrate

A suspension of 2-aminobutyric acid (100 g, Aldrich) in 300 g of absolute ethanol stirred at 0oC in nitrogen atmosphere, was added dropwise 120,8 g of thionyl chloride, stirred at 0oC during the night and then gradually warmed up to room temperature. The obtained white suspension is heated under reflux for 3 h, left to cool for 10 min and poured into 600 ml of chilled diethylether while stirring manually. The suspension is filtered and the solid is dried, obtaining 150 g of the desired product as a white powder.1H NMR was consistent with the expected structure.

(b) ethyl-2-benzylidenemalonate

The solution 149,6 g of the product of stage (a) of 74.3 g of magnesium sulfate and 246 ml of triethylamine in 1500 ml of dichloromethane is stirred at room temperature under nitrogen atmosphere was added dropwise and benzaldehyde (94,9 g, Aldrich). The mixture is stirred at room temperature for 3 h, then filtered. The filtrate is concentrated, fray with titilation, filtered and concentrated, receiving 174 g of the desired product as a yellow oily substance.1H NMR was consistent with the expected structure.

() ()- ethyl-2-benzylidenemalonate

Hydride Mosphere nitrogen, was added dropwise a solution of 178,1 g of the product of stage (b) in DMF, was stirred at room temperature for 2 h, was added dropwise a solution of 149.5 g butylated in DMF) and incubated with stirring for another 2 h to complete the reaction. The reaction mixture is poured into ice-cold mixture of 560 ml of water, 300 ml of diethylether and 120 g of ammonium chloride. The obtained organic layer is dried over potassium carbonate, then concentrate getting 220 g of the desired product as a brown oily substance.

(g) (a)-ethyl-2-amino-2-ethylhexanoate

223,0 g of the product of stage (b) is treated with petroleum ether and 421 ml of 10% (by mass) hydrochloric acid, stirring at room temperature for 2 h and defend. The aqueous layer was extracted twice with petroleum ether and then cooled with ethyl acetate colledani tub. The mixture was added grain of sodium hydroxide to reach pH 10 water layer. This layer extracted twice with ethyl acetate, the extracts are mixed and dried over potassium carbonate and then concentrated and distilled under vacuum, obtaining the target product as a colorless oily substance.1H NMR was consistent with the expected structure.

(d) (R)- 2-amino-2-ethylhexanoic acid

Dredge the pork liver esterase bring the pH of the mixture to 9.7 and support this value, adding 1N NaOH solution. After adding a certain amount of 1N aqueous NaOH solution (83 g for 10 hours) the mixture is washed with deethylation to remove unreacted (S)-ethyl-2-amino-2-ethylhexanoate. The remaining aqueous phase is evaporated under vacuum, obtaining white solid containing the desired compound and its sodium salt.

(e) (R)-2-amino-2-ethylhexan-1-ol

20 g of the product of stage (d) is added to the equivalent of 1.5 moles of lithium aluminum hydride his 1M solution in tetrahydrofuran, the mixture was kept under reflux for 3 h and stirred at room temperature for 16 hours the Reaction mixture is cooled to about 0oC, then quenched with water and 1N aqueous solution of NaOH. The obtained solid substance is dispersed in an additional amount of water. The suspension is heated to 50oC for 5 min, cooled to room temperature, add 100 ml of diethylether, stirred and filtered. Diethylamine layer is separated, dried and concentrated in vacuo, obtaining the target product in the form of oily substance (yield 82%).1H NMR was consistent with the expected structure.

(W) (R)-2-amino-2 - ethylhexylphthalate

20 g of the product of stage (e) is dissolved in 170 ml dichloro for 17 PM A large part of the solvent is distilled off and the resulting suspension is diluted with acetone, filtered and dried, obtaining a white solid.1H NMR was consistent with the expected structure.

(C) 2-hydroxy-4,5-dimethoxybenzaldehyde

1.0 M solution of trichloride boron (210 ml, Aldrich) in dichloromethane are added to a solution of benzoyl chloride (30.1 g, Aldrich) in 350 ml of benzene. Then add a solution of 3,4-dimethoxyphenol (30.0 g, Aldrich) in 130 ml of benzene, the reaction mixture was stirred at room temperature for 2.5 hours, add 55 ml of 50% NaOH solution and again stirred for 15 minutes, the Organic layers separated, dried and concentrated in vacuo. The obtained residue within 40 min fray with 1N NaOH solution and filtered. The alkaline aqueous filtrate is neutralized with concentrated HCl, obtaining the target product as a yellow solid (25,9 g) with tpl.104-105oC.1H NMR was consistent with the expected structure.

(and) O-(2-benzoyl-4,5-acid)-N,N-diethylthiocarbamate

The triethylamine (106,3 g, Aldrich), 4-dimethylaminopyridine (6.3 g, Aldrich) and 86.4 g of diethylthiocarbamoyl add to 130,4 g of the product of stage (C) and mixture make 1 l of dioxane. The reaction mixture under stirring withstand reverse goodbasic 600 ml of 1N HCl and 500 ml of diethylether. The mixture is left for 45 min, then filtered. The precipitate is washed thoroughly with titilation and dried in vacuumsealed Cabinet, obtaining the target product as a yellow solid (of 120.5 g) with tpl.94-95oC. 1H NMR was consistent with the expected structure.

(K) S-(2-benzoyl-4,5-acid)-N,N-diethylthiocarbamate

Suspension 106,3 g of the product of stage (I) in 250 ml of tetradecane is heated to a temperature in the mass of 250oC and incubated for 25 minutes, the Reaction mixture was cooled in an ice bath. The solvent strain, and the remainder of the fray with titilation, receiving the target product as a beige solid (43,4 g) with tPL114-116oC.1H NMR was consistent with the expected structure.

(l) 2-mercapto-4,5-dimethoxybenzophenone

and 48.8 g of granulated potassium hydroxide is added slowly to a solution 85,0 g of the product of stage (K) 1 l 1:1-mixture of methanol and tetrahydrofuran. After a three-hour exposure under reflux, the reaction mixture was cooled to room temperature and concentrated in vacuo. The obtained residue fray with 1N HCl, then extracted with EtOAc. The organic layer was separated and sequentially washed with 1N HCl (2x250 ml) and IN NaOH solution (3x400 ml). the th solids (of 54.8 g).1H NMR was consistent with the expected structure.

(m) (H)-2-(2-amino-2-ethylhexyl)-4,5-dimethoxybenzophenone

and 48.8 g of the product of stage (g) are dissolved in 250 ml of water and to this solution was added to 54.2 g of the product of stage (l) in 300 ml of butyl acetate. The reaction mixture is stirred, heated to a temperature in the mass of 93oC and added dropwise a solution of 18.9 g of NaOH in 250 ml of water, then stirred for another 25 minutes at a temperature of 93oC and then cooled to room temperature. The organic layer is separated, dried and concentrated, obtaining the target product in the form of a solid RangeValidator substances with tPL75 - 78oC.1H NMR was consistent with the expected structure.

(n) (3R)-3-butyl-3-ethyl-2,3-dihydro-7,8-dimethoxy-5-phenyl-1,4 - benzothiazepin

78.0 g of the product of stage (m) dissolved in 400 ml of 2,6-lutidine, add 0,70 g p-toluensulfonate acid and the reaction mixture was kept under reflux, using a trap Dean-stark for 22 hours During this time, the solvent leaves the apparatus and replace it with fresh. The reaction mixture was concentrated in vacuo and the residue is treated with 300 ml of a 5% solution of NaHCO3and 300 ml of EtOAc. The EtOAc layer was separated, washed with brine, dried and concentrated in vacuo, gives the 64.1 g of the target product as a pale brown oily substance.1H NMR was consistent with the expected structure.

(o) (3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5 - phenyl 1,4-benzothiazepin.

1 M solution of DIBORANE in 200 ml of tetrahydrofuran are added to a solution 64,0 g of the product of stage (n) in 350 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 17 h, add 150 ml of 6N HCl and the solution concentrated d vacuo to remove tetrahydrofuran. Water balance omelicheva 50% NaOH solution and extracted with EtOAc. The EtOAc layer is separated, dried and concentrated in vacuo, obtaining an oily substance that chromatographic on silica gel, elwira a mixture of 85:15 hexane and EtOAc, and the gain of 25.5 g of the desired product in the form of a beige solid with tPL64-66oC.1H NMR was consistent with the expected structure.

(p) (3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy - 5-phenyl-1,4-benzothiazepine-1,1-dioxide.

A solution of 25.5 g of the product of stage (a) in 125 ml triperoxonane acid is added to 18,8 g 30% H2O2100 ml with the same acid. The reaction mixture was stirred at room temperature for 17 h, then pour in 800 ml of water, then add 50% NaOH solution to reach pH 10. Then the reaction mixture rasclaat EtOAc and n is K, which is recrystallized from EtOH, receiving of 18.5 g of the desired product with tPL148-149oC.1H NMR was consistent with the expected structure.

Analysis. Calculated: C - 66,16: H - of 7.48; N - 3,35; S of 7.68; found: C - 66,01; H - 7,56: N - 3,31: S - 7,74.

1H NMR (DMSO-d6),; 0,74 is 0.86 (6H, m); 1,07-of 1.39 (4H, m); 1,39-of 2.20 (4H, m); of 3.33 (2H, q); 3,44 (3H, s); a 3.83 (3H, s); of 5.92 (1H, d); 6,11 (1H, s); 7,33-of 7.48 (6H, m).

Example of synthesis 2. Obtain (3R,5R)-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide

Oxon (146,7 g, Aldrich) in 550 ml of water are added to a solution of 18.4 g of the product of stage (a) of example 1 in 500 ml MeOH. The reaction mixture was stirred at room temperature for 17 h, then carefully omelicheva 50% NaOH solution. Heterogeneous mixture rasclaat EtOAc and stirred for 1 h the Organic layer is separated, dried and concentrated in vacuo, getting a pink solid. Chromatography on silica gel with elution with a mixture of 65: 35 hexane and EtOAc gives 6.7 g of the final product in the form of a white solid with tPL174-175oC.

Analysis. Calculated: C - 63,72; H - 7,21: N - 3,23; S - 7,39; found: C expenses 63.81; H - 7,22; N - 3,19; S - 7,47.

1H NMR (DMSO-d6) ; 0,77 - of 0.90 (6H, m); 1,10-2,17 (8H, m); 3.27 to is-3.45 (5H, m); a-3.84 (3H, s); 6,14 (1H, s); 6,38 (1H, s); 7,30-7,53 (5H, m); of 7.97 (1H, s).


(a) ()-2-amino-2-ethylhexan-1-ol

of 22.2 g of lithium aluminum hydride is added to 450 ml of anhydrous diethylether in nitrogen atmosphere, was added dropwise 129 g of the product of stage (d) of example 1, diluted with 40 ml of diethylether, the reaction mixture was kept under reflux for 1 h and after cooling to room temperature was added dropwise 23 ml of 1M sodium hydroxide solution and then with deionized water. The resulting suspension is filtered and the filtrate is concentrated and getting to 87.9 g of the desired product as colorless oily substance. 1H NMR was consistent with the expected structure.

(b) ()-2-butyl-2-utilizedin.

150 g of acetonitrile and 20.0 g of the product of stage (a) are mixed in a nitrogen atmosphere, cooled to 2-3oC and maintaining the temperature below 10oC, was added dropwise chlorosulfonic acid (16,0, Aldrich). The cooling is stopped and the suspension is stirred for 80 min at room temperature. The reaction mixture was concentrated in vacuo and distil with 50 ml of water. Add to 55.2 g of 50% aqueous sodium hydroxide solution and 50 ml of water and distil the mixture at atmospheric pressure. The organic layer of the distillate is selected and dried over solid potassium hydroxide, receiving 12.8 g of the target product.1H NMR?>/BR>of 14.7 g of the product of stage (l) of example 1 in 50 ml of 2,6-lutidine are added to a solution of 6.5 g of the product of stage (b) of this example in 200 ml of 2,6-lutidine, stirred for 1 h, add concentrated HCl and then incubated with a reflux condenser with a trap Dean-stark for 17 hours, the Reaction mixture was concentrated in vacuo, and the residue is divided between 5%-s ' solution of NaHCO3and EtOAc. The organic layer is separated, dried and concentrated, obtaining an oily substance that chromatographic on silica gel, elwira a mixture of 7: 3 hexane and EtOAc, and obtain 12.0 g of the desired product as an oily substance.1H NMR was consistent with the expected structure.

(g) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy - 5-phenyl-1,4-benzothiazepine-1,1-dioxide;

The desired product is obtained according to stages (a)-(p) of example 1 using the product of stage (b) of this example, getting a white solid with tPL146-147oC.

Analysis (0,50 H2O). Calculated: C - 64,54; H - 7,35; N - 3,24; S - 7,40; found: C - 64,76; H - 7,56; N - 3,28; S - 7,52.

1H NMR (DMSO-d6), , 0,74 is 0.86 (6H, m); 1,07-of 1.39 (4H, m); 1,40-of 2.20 (4H, m); of 3.33 (2H, q); 3,44 (3H, s); a 3.83 (3H, s); of 5.92 (1H, d): 6,11 (1H, s); 7,30-of 7.48 (6H, m).

Example of synthesis 4. Receive ()-TRANS-3-butyl-3 - ethyl-2,3,4,5-Castoro 1.7 g of the product of stage (d) of example 3 in 100 ml of MeOH. The reaction mixture was stirred at room temperature for 17 h and add water and EtOAc. After stirring for 1 h, the organic layer is separated, dried and concentrated, getting foamy substance. Chromatography on silica gel with elution with a mixture of 4:1 hexane and EtOAc gives 1.2 g of the desired product as a white solid tPL172-174oC.

Analysis. Calculated: C - 63,72; H - 7,21: N - 3,23; S - 7,39; found: C - 63,79; H - 7,26; N-3,18; S - 7,47.

1H NMR (DMSO-d6), ; 0,78-of 0.90 (6H, m); 1,14 - 2,14 (8H, m); 3.27 to 3,41 (5H, m); a-3.84 (3H, s); 6,13 (1H, s); 6,37 (1H, s); 7,34-7,53 (5H, m); of 7.96 (1H, s).

The synthesis example 5. Obtain (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide

(a) O-(2-benzoyl-5-methoxyphenyl)dimethylthiocarbamate

Sodium hydride (8.8 g, Aldrich) is added slowly to a solution of 2 - hydroxy-4-methoxybenzophenone (50.0 g, Aldrich) in 300 ml of dimethylformamide, was added dropwise to 43.0 g hexamethylphosphoramide and stirred at room temperature for 2 h, add dimethylthiocarbamate (37,0 g, Aldrich) and stirred at 50oC during the night. The reaction mixture is poured into 300 ml of deionized water and extracted with a mixture of 1:4 petroleum ether and chloroform. The organic layer is washed with 10% g is 40,0.1H NMR was consistent with the expected structure.

(b) S-(2-benzoyl-5-methoxyphenyl)dimethylthiocarbamate

of 97.4 g of the product of stage (a) are suspended in 500 ml of tetradecane and heated to a temperature of 255oC throughout the mass for 30 minutes After cooling to room temperature the reaction mixture chromatographic on silica gel, elwira a mixture of 7:3 hexane and ethyl acetate, and get 65.0 g of the desired product as light brown solid with tPL95-97oC.1H NMR was consistent with the expected structure.

(a) 2-mercapto-4-methoxybenzophenone

to 20.0 g of granulated potassium hydroxide is added slowly to a solution of 28.0 g of the product of stage (b) in 800 ml of 1:1-mixture of methanol and tetrahydrofuran. After four hours of exposure under reflux, the reaction mixture was cooled to room temperature, add dichloromethane and the solution extracted with 5% hydrochloric acid. The organic layer is dried and concentrated. Chromatography on silica gel with elution with a mixture of 99:1 hexane and ethyl acetate to give 17.1 g of the desired product as an orange oily substance.1H NMR was consistent with the expected structure.

(g) (R)-2-(2-amino-2-ethylhexyl)-4-methoxybenzophenone

It with the and (g) of example 1. Concentration of the organic layer gives 66.5 g of the desired product as a red oily substance.1H NMR was consistent with the expected structure.

(d) (3R)-3-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,4 - benzothiazepin

This connection get on stage (h) of example 1, using 66.5 g of the product of stage (d) of this example. Chromatography on silica gel with elution with a mixture of 9:1 hexane and EtOAc network of 54.5 g of the desired product as a yellow oily substance.1H NMR was consistent with the expected structure.

(e) (3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4 - benzothiazepin

This connection get on the stage (a) of example 1, using 66.5 g of the product of stage (d) of this example. Chromatography on silica gel with elution with a mixture of 9: 1 hexane and EtOAc network of 22.8 g of the desired product as an orange oily substance. 1H NMR was consistent with the expected structure.

(W) (3R, 5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin

18.6 g of bromine are added to a solution of 10.4 g of the product of stage (e) in 150 ml of glacial acetic acid, stirred at room temperature for 2 h, evaporated under vacuum, acetic acid, add 100 ml of acetic acid and com NaOH. The organic layer is separated, dried and concentrated in vacuo, obtaining a brown oily substance, which was transformed later in hydrochloride with a solution of HCl in ether. The precipitation is filtered off, washed with ether and treated with 1N NaOH solution and EtOAc, getting a 8.9 g of the desired product as an orange oily substance. 1H NMR was consistent with the expected structure.

(C) (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8 - methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide

This connection receive phase (p) of example 1, using of 8.2 g of the product of stage (f) of this example. Chromatography on silica gel with elution with a mixture of 4:1 hexane and EtOAc gives the foam, from which after grinding with ether to obtain 5.0 g of the final product in the form of a white solid with tPL132-134oC.

Analysis. Calculated: C - 56,65; H - 6,05; N - 3,00; Br - 17,13; S - 6,87 found: C - 56,71; H - 6,01; N - 2,94; Br - 17,07: S - 6,95.

1H NMR (DMSO-d6), ; 0,64 is 0.81 (6H, m); 0,97-1,19 (4H, m); 1,22 of 1.50 (2H, m); 1,69-of 1.78 (1H, m); 1,98 e 2.06 (1H, m); to 2.67 (1H, d); 3,39 (2H, q); to 3.92 (3H, s); 5,88 (1H, d); 6,63 (1H, s); 7,29-the 7.43 (5H, m); at 7.55(1H, s).

Example of synthesis 6. Obtain (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide

Metallocarborane acid (57-86%, about 0.90 g, Aldrich) in 50 m is at room temperature for 1 h, add 100 ml of a 5% solution of NaHCO3and stirred for 30 minutes the Organic layer is separated, dried and concentrated in vacuo, getting foamy substance. Chromatography on silica gel with elution with a mixture of 9:1 hexane and EtOAc gives a foamy substance from which after grinding with ether to obtain 1.3 g of the final product in the form of a white solid with tPL202-204oC.

Analysis. Calculated: C - 54,77; H - 5,85; N - 2,90; Br - 16,56; S of 6.65; found: C - 54,92; H - 5,90; N - 2,85; Br - 16,65; S - 6.75 in.

1H NMR (DMSO-d6), ; 0,75 is 0.86 (6H, m); of 1.05 to 1.41 (5H, m); 1,43-of 1.64 (1H, m); 1,66-to 1.79 (1H, m); 1,83-2,49 (1H, m); of 3.46 (2H, S); 3,93 (3H, s); 6,33 (1H, s); to 6.67 (1H, s); 7,30 is 7.50 (6H, m); 8,07 (1H, s).

The synthesis example 7. Obtain (3R,5R)-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-5-phenyl-1,4-benzothiazepin-7,8-diol-1,1-dioxide;

5.0 g of the product of stage (n) of example 1 are dissolved in 36 ml of glacial acetic acid and 36 ml of 48% HBr solution and stirred under reflux for 2 hours, the Reaction mixture was poured into a mixture of water and ice and omelicheva 50% NaOH solution to pH 7. The mixture is filtered, the solid, which chromatographic on silica gel, elwira a mixture of 3:2 hexane and EtOAc, and obtain 1.6 g of the final product in the form of a white solid with tPL117 - 118oC.

Analysis SUB>6), ; 0,76 (3H, t); 0,81 (3H, t); 1,08-to 2.41 (8H, m); 3,24 (2H, q); of 5.83 (1H, d); 6,03 (1H, s); 7,31-7,42 (6H, m); 9,60 (3H, bs).

Example 8 synthesis. Obtain (3R,5R)-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol-1,1-dioxide

Chromatography of the reaction products of example 7 gives a mixture that connect and re-chromatographic, elwira toluene and a mixture of 95:5 toluene and EtOAc, and get to 0.29 g of the final product in the form of a white solid with tPL155-156oC.

Analysis. Calculated: C - 65,48; H - 7,24; N - 3,47; S of 7.95; found: C - 65,58; H - 7,28; N - 3,43; S - 8,03.

1H NMR (DMSO-d6), ; 0,76 (3H, t): 0,81 (3H, t); 1,18-2,04 (8H, m); for 3.28 (2H, q); is 3.82 (3H, s); of 5.85 (1H, d); 6,09 (1H, s); 7,31 was 7.45 (6H, m); 9,43 (1H, s).

Example 9 synthesis. Obtain (3R,5R)-3-butyl-3-ethyl - 2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol-1,1 - dioxide

Chromatography of the reaction mixture of example 7 gives the final compounds of examples 7 and 8. Chromatography of the mixture of example 8 to give 0.35 g of one of the end product in the form of a white solid with tPL165-166oC.

Analysis. Calculated: C - 65,48; H - 7,24; N - 3,47: S of 7.95; found: C - 65,32; H - 7,28: N - 3,49; S - 8,00.

1H NMR (DMSO-d6), ; of 0.77 (3H, t); 0,81 (3H, t); 1,11 - of 2.08 (8H, m); 3,29 (2H, q); 3,44 (3H, s); 5,86 (1H, d); the 6.06 (1H, s); 7,32-the 7.43 (6H, m); 9,73 (1H, s).

When is/BR> (a) O-(2-benzoyl-5-methoxyphenyl)dimethylthiocarbamate

Sodium hydride (8.8 g, Aldrich) is added slowly to a solution of 2 - hydroxy-4-methoxybenzophenone (50.0 g, Aldrich) in 300 ml of dimethylformamide, was added dropwise to 43.0 g hexamethylphosphoramide and stirred at room temperature for 2 h, add dimethylthiocarbamate (37,0 g, Aldrich) and stirred at 50oC during the night. The reaction mixture is poured into 300 ml of deionized water and extracted with a mixture of 1:4 petroleum ether and chloroform. The organic layer is washed with 10% sodium hydroxide, then with brine and concentrated, obtaining the target product as a yellow solid (40,0 g).1H NMR was consistent with the expected structure.

(b) S-(2-benzoyl-5-methoxyphenyl)dimethylthiocarbamate

of 97.4 g of the product of stage (a) are suspended in 500 ml of tetradecane and heated to a temperature of 255oC throughout the mass for 30 minutes After cooling to room temperature the reaction mixture chromatographic on silica gel, elwira a mixture of 7:3 hexane and ethyl acetate, and get 65.0 g of the desired product as light brown solid with tPL95-97oC.1H NMR was consistent with the expected structure.

(a) 2-mercapto-4-methoxybenzophenone
the 1:1 methanol and tetrahydrofuran. After four hours of exposure under reflux, the reaction mixture was cooled to room temperature, add dichloromethane and the solution extracted with 5% hydrochloric acid. The organic layer is dried and concentrated. Chromatography on silica gel with elution with a mixture of 99:1 hexane and ethyl acetate to give 17.1 g of the desired product as an orange oily substance.1H NMR was consistent with the expected structure.

(g) of the hydrochloride of the ethyl-2-aminobutyrate

A suspension of 2-aminobutyric acid (100 g, Aldrich) in 300 g of absolute ethanol stirred at 0oC in an atmosphere of nitrogen was added dropwise and 120,8 g of thionyl chloride, the reaction mass at 0oC is stirred overnight and then gradually warmed to room temperature. The obtained white suspension is heated under reflux for 3 h, cooled for 10 min, poured into 600 ml of chilled diethylether when mixing manually, filtered and the solid is dried, obtaining 150 g of the desired product as a white powder.1H NMR was consistent with the expected structure.

(e) ethyl-2-benzylidenemalonate

The solution 149,6 g of the product of stage (a) of 74.3 g of magnesium sulfate and 246 ml of triethylamine in 1500 ml of dichloromethane displacement is at room temperature for 3 h and filtered. The filtrate is concentrated, fray with titilation, filtered and concentrated, receiving 174 g of the desired product as a yellow oily substance.1H NMR was consistent with the expected structure.

(e) (a)-ethyl-2-benzylideneamino-2-ethylhexanoate.

of 32.5 g of 60% dispersion of sodium hydride in oil and 700 ml of N,N-dimethylformamide (DMF) is stirred at room temperature under nitrogen atmosphere was added dropwise and the solution 178,1 g of the product of stage (d) in DMF, was stirred at room temperature for 2 h, was added dropwise a solution of 149.5 g butylated in DMF and conducting the reaction for a further 2 h under stirring. The reaction mixture is poured into ice-cold mixture of 560 ml of water, 300 ml of diethylether and 120 g of ammonium chloride. The obtained organic layer is dried over potassium carbonate and concentrated, getting 220 g of the desired product as a brown oily substance.

(W) (a)-ethyl-2-amino-2-ethylhexanoate

223,0 g of the product of stage (e) is extracted with petroleum ether and 421 ml of 10% (by mass) hydrochloric acid and stirred at room temperature for 2 hours the Aqueous layer was extracted twice with petroleum ether, then cooled with ethyl acetate colledani tub, add granules of sodium hydroxide to reach pH 10, C is t and distil under vacuum, receiving target product as a colorless oily substance.1H NMR was consistent with the expected structure.

(C) ()-2-amino-2-ethylhexan-1-ol

of 22.2 g of lithium aluminum hydride is added to 450 ml of anhydrous diethylether in nitrogen atmosphere, was added dropwise 129 g of the product of stage (g), diluted with 40 ml of diethylether. The reaction mixture was kept under reflux for 1 h, cooled to room temperature and added dropwise 23 ml of 1M sodium hydroxide solution, then with deionized water. The resulting suspension is filtered and the filtrate is concentrated and getting to 87.9 g of the desired product as colorless oily substance. 1H NMR was consistent with the expected structure.

(and) ()-2-butyl-2-utilizedin

150 g of acetonitrile and 20.0 g of the product of stage (C) are mixed in a nitrogen atmosphere, cooled to 2-3oC and maintaining the temperature below 10oC, was added dropwise chlorosulfonic acid (16,0, Aldrich). The cooling is stopped and the suspension is stirred for 80 min at room temperature. The reaction mixture was concentrated in vacuo and distil with 50 ml of water. Add to 55.2 g of 50% aqueous sodium hydroxide solution and 50 ml of water and distil the mixture at atmospheric pressure. The organic layer of the distillate emnd structure.

() ()- 3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3-dihydrobenzofuran

of 55.2 g of the product of stage (I) in 100 ml of 2,6-lutidine are added to a solution 118,5 g of the product of stage (C) in 400 ml of 2,6-lutidine. The reaction mixture was stirred for 1 h, add p-toluensulfonate acid, incubated with a reflux condenser with a trap Dean-stark for 17 h, concentrated in vacuo and the residue extracted with a 5% solution of NaHCO3and EtOAc. The organic layer is separated, dried and concentrated, obtaining an oily substance that chromatographic on silica gel, elwira a mixture of 85:15 hexane and EtOAc, and get 124,3 g of the desired product as an orange oily substance. 1H NMR was consistent with the expected structure.

(l) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8 - methoxy-5-phenyl-1,4-benzothiazepin

1 M solution of DIBORANE in 40 ml of tetrahydrofuran are added to a solution of 12.3 g of the product of stage (a) in 150 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 17 h, injected 50 ml of 6N HCl and the solution was concentrated in vacuo. The remainder omelicheva 50% NaOH solution and extracted with EtOAc. The EtOAc layer is separated, dried and concentrated in vacuo, obtaining an oily substance that chromatographic on silica gel, AluI H NMR was consistent with the expected structure.

(m) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5 - phenyl-1,4-benzothiazepine-1,1-dioxide

A solution of 4.9 g of the product of stage (l) in 50 ml triperoxonane acid is added to 30% H2O2in 50 ml of triperoxonane acid. The reaction mixture was stirred at room temperature for 17 h, poured into 200 ml deionized water and add NaOH pellets to pH 14. Then the reaction mixture was kept at 45oC for 1 h and extracted with dichloromethane. The organic layer is separated, dried and concentrated, obtaining an oily substance that chromatographic on silica gel, elwira a mixture of 9:1 hexane and EtOAc, and obtain 4.9 g of the final product in the form of a white solid with tPL123-125oC.

Analysis. Calculated: C - 68,18; H - rate of 7.54; N - 3,61; S of 8.27; found: C - 68,19; H - 7,49: N - 3,55; S - 8,35.

1H NMR (DMSO-d6), ; 0,73-of 0.85 (6H, m, CH3); of 1.07 to 1.47 (4H, m, CH2); 1,48-of 2.20 (4H, m, CH2); 2,48 of $ 2.53 (1H, d, NH); 3,51 (2H, q, CH2SO2); a-3.84 (3H, s, OMe); 5,90 (1H, d, CHPh); 6,50 (1H, d, ArH); 7,09-7,20 (1H, m, Ar); 7,32-of 7.48 (6H, m, ArH).

Example 11 synthesis. Receive ()-TRANS-3-butyl-3-ethyl-2,3,4,5-Tetra-hydro-5-phenyl-1,4 - benzothiazepin-8-ol-1,1-dioxide

This connection will receive the procedure of example 7, using 4.8 g of the product of stage (m) of example 10. Crematogaster with tPL130-132oC.

Analysis. Calculated: C - 67,53; H - 7,28; N - 3,75; S - 8,58; found: C - 67,26; H - 7,21: N - 3,76; S - 8,65.

1H NMR (DMSO-d6), ; 0,70 is 0.86 (6H, m); 0,96 is 1.23 (4H, m); 1,25-1,49 (1H, m); of 1.66 and 1.75 (1H, m); 1,98-2,07 (1H, m); 2.40 a (1H, d); to 3.33 (2H, q); of 5.82 (1H, d): 6.35mm(1H, d); 6,77-to 6.80 (1H, m); 7.24 to 7,38 (6H, m); and 10.0 (1H, s).

Example 12 synthesis. Receive ()-TRANS-3-butyl-3 - ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,8-diol-1,1 - dioxide

1.0 g of product from example 11 are dissolved in 100 ml of dichloromethane, cooled to 0oC and type m-chloroperbenzoic acid (0.55 g, 57-86%, Aldrich). The reaction mixture is stirred for 5 hours at a temperature of ice baths and neutralize excess acid 5% solution of NaHCO3. The organic layer is separated, dried and concentrated in vacuo. The obtained residue chromatographic on silica gel, elwira with a mixture of hexane and EtOAc and receiving of 0.68 g of the final product as a pale yellow solid with tPL213-214oC.

Analysis. Calculated: C - 64,76; H - 6,99; N - 3,60; S - 8,23; found: C - 64,86; H, 7.03 is: N - 3,63: S - 8,31.

1H NMR (DMSO-d6), ; 0,77-to 0.89 (6H, m); 1,09-of 1.64 (6H, m); 1,68-2,03 (2H, m); to 3.36 (2H, q); 6,30 (1H, s); 6,44 (1H, d); 6,82-6,87 (1H, m); 7,27 - 7,49 (6H, m); 7,89 (1H, s); and 10.0 (1H, s).

Example of synthesis 13. Receive ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenyl - 1,4-bikebeat in a mixed solution of m-cresol (25,0 g, Aldrich) and triethylamine (27,2 g, Aldrich) in 500 ml of ether, then stirred at room temperature for 1 h and filtered. The ethereal filtrate is washed with saturated solution of NaHCO3and water and dried over Na2SO4. The ether layer is separated, dried and concentrated in vacuo, getting 104,0 g of the desired product as a white solid with tPL45-47oC. 1H NMR was consistent with the expected structure.

(b) 2-hydroxy-4-methylbenzophenone

48 g of the product of stage (a) is melted (at 70oC) and portions add to 30.2 g of aluminium chloride. The reaction mixture for 5 min, heated to 200oC, then cooled to room temperature. The obtained solid is ground into a powder and slowly bring to a mixture of 800 ml of concentrated HCl and ice. The mixture is extracted with ether and wash the extract with water. The ether layer is separated, dried and concentrated. The obtained residue chromatographic on silica gel, elwira toluene, and obtain 39 g of the desired product as a yellow oily substance.1H NMR was consistent with the expected structure.

() ()- TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methyl-5 - phenyl-1,4-benzothiazepine-1,1-dioxide

The product of stage (b) is transformed into the final product, after

Analysis. Calculated: C - 71,12; H - 7,87: N - Of 3.77; S - 8,63; found: C -71,23; H - 7,94; N - 3,67; S - a total of 8.74.

1H NMR (DMSO-d6), ; 0,77-of 0.82 (6H, m); 1,16-2,07 (8H, m); a 2.36 (3H, s); 3,37 (2H, q); of 5.92 (1H, d); 6,47 (1H, d); 7,27-7,39 (6H, m); and 10.0 (1H, s).

Example 14 synthesis. Receive ()-TRANS-3-butyl-3 - ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7 - carbaldehyde-1,1-dioxide

a) ()-7-Bromo-3-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl - 1,4-benzothiazepin

2,3-Dichloro-5,6-decianus-1,4-benzoquinone (16,9 g) is added directly to a solution of the product (as the racemate) (30,2 g) stage (g) of example 5 in 300 ml of benzene. The reaction mixture is stirred under reflux for 3 h and cooled to room temperature. Add 1N NaOH solution (200 ml), stirred for 30 minutes Then the organic layer was separated, washed with brine and 1N NaOH solution. Bentley layer is separated, dried and concentrated, obtaining an oily substance that is dissolved in gensan, filtered and concentrated, receiving, and 25.8 g of the desired product as a red oily substance.1H NMR was consistent with the expected structure.

b) ()-3-butyl-7-carbaldehyde-3-ethyl-2,3-dihydro-8-methoxy - 5-phenyl-1,4-benzothiazepin

49,0 solution of 1.6 M n-utility added to ice-cold solution of 25.8 g of the product MES removed from the ice bath and stirred at room temperature for 2.5 h, then quickly cooled in 250 ml of a saturated solution of NH4Cl and stirred for 1 h the Organic layer is separated, dried and concentrated, receiving and 26.9 g of a red oily substance. Chromatography on silica gel with elution with a mixture of 85: 15 hexane and EtOAc gives a 13.9 g of the desired product as an orange oily substance.1H NMR was consistent with the expected structure.

C) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5 - phenyl - 1,4-benzothiazepin-7-carbaldehyde

Ethylene glycol (9.3 g) and pyridine p-toluensulfonate (1.3 g) are added to a solution of the product (19,0) stage (b) in 250 ml of benzene and the mixture was kept under reflux with trap Dean-stark for 17 hours, the Reaction mixture was cooled to room temperature and treated for 15 min in an aqueous solution of NaHCO3(150 ml). The organic layer is separated, dried and concentrated, obtaining of 19.7 g of a thick yellow-orange oily substance.1H NMR consistent with the derived dioxolane. This oily substance is treated with B2H6according to stage (0) of example 1, obtaining 3.5 g of the desired product as an orange oily substance.1H NMR was consistent with the expected structure.

(g) ()-TRANS-3-butyl-3-ethyl-what oraut in 60 ml of a mixture of t-butanol and tetrahydrofuran (ratio 1: 4) and added 3.4 g of N-methylmorpholin-N-oxide and then 5 ml of 2.5% (by weight) solution 0s042-methyl-2-propanol. The reaction mixture is then stirred at room temperature for 17 h, then diluted with 250 ml EtOAc. The organic layer is separated, washed with 1 N NaOH (g ml) and brine, dried and concentrated, resulting in the oily substance that fray in diethyl ether and receive 3,10 g of the desired product as a white solid with the pace. plvl. 127-128oC.

The results of the analysis:

Calculated data: C - 66,48; H - 7,03; N - 3,37; S - 7,72.

Received: C - 66,26; H? 7.04 Baby Mortality; N - 3,30; S - 7,82.

1H NMR (DMSO-d6), ; 0,73 is 0.86 (6H, m); 1,07-of 2.05 (8H, m); to 2.65 (1H, d); 3,50 (2H, q); a 4.03 (3H, s); 5,91 (1H, s); 6,92 (1H, s); 7,33-of 7.48 (5H, m); 7,74 (1H, s); 10,28 (1H, s).

Example 15 synthesis. Receive ()-TRANS-2-((3-butyl-3-ethyl - 2,3,4,5 - tetrahydro-8-methoxy-5-phenyl-1,4-benzodiazepin-7 - yl)methoxy)ethanol-1,1-dioxide

Chromatography of the product of stage (b) of example 14 gives 2.3 g of the corresponding sulfide compound of the desired product as an oily substance. Data H1NMR are in agreement with the expected structure. This oily substance is then treated according to the procedure of example 1 (n) and is obtained 0.65 g of the desired product as a white solid with the pace. plvl. 83-85oC.

The Result Of The

1H NMR (DMSO-d6), ; 0,74 is 0.86 (6H, m); 1,07-2,14 (8H, m); 2,52(1 H, d); at 3.35 (4H, m); to 3.41 (2H, q); a 3.87 (3H, s); 4,39 (2H, s); of 4.54 (1H, t); 5,91 (1H, d); only 6.64 (1H, s); 7.29 trend was 7.45 (5H, m); 7,51 (1H, s).

Example 16 synthesis. Receive ()-TRANS-3-butyl-3-ethyl - 2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,4-benzothiazepin-7 - carbaldehyde-1,1-dioxide

2.0 g of the product of stage (d) of example 14 is added to 20 ml of glacial acetic acid and 20 ml of 48% HBr and heated at 150oC for 24 h, the Reaction mixture was concentrated in vacuo and share between diethyl ether and 5% NaHCO3. The organic layer is separated, dried and concentrated, obtaining of 0.85 g of the desired product as light brown solid with the pace. plvl. 158-159oC.

The results of the analysis:

Calculated data: C - 65,81; H - is 6.78; N - 3,49; S - 7,99.

Received: C - 65,63; H? 7.04 Baby Mortality: N - 3,32: S - 7,74.

1H NMR (DMSO-d6), ; 0,72-of 0.85 (6H, m); 1,07 - of 2.05 (8H, m); of 2.58 (1H, d); of 3.46 (2H, q); to 5.85 (1H, d); 6,83 (1H, s); 7,34-7,47 (5H, m); of 7.70 (1H, s); of 10.25 (1H, s); 11,33 (1H, broad s).

Example 17 synthesis. Receive ()-TRANS-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol-1,1-dioxide

The product of example 11 is treated by following the procedure of stages (K) - (l) of example 1, and get the desired product in the form of a white solid with the pace. plvl. 108-110oC.

1H NMR (DMSO-d6), ; 0,70 is 0.81 (6H, m); 1,05 e 2.06 (8H, m); 2,54 (1H, d); 3,37 (2H, q); to 5.85 (1H, d); the 6.06 (1H, broad s); 6,40 (1H, d); 7,26-7,40 (6H, m); of 7.90 (1H, s).

Example 18 synthesis. Receive ()-TRANS-3-butyl-3-ethyl - 2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,4-benzothiazepin-8 sulfoxylate-1,1-dioxide

to 5.3 g of the product of example 17 is dissolved in 13 ml of DMSO, then add 0.3 ml of water and 0.2 ml of 48% HBr. The reaction mixture is heated at 120oC for 4 h prior to the removal of distillate, then cooled to room temperature, diluted with 1N NaOH and filtered through a sintered glass filter. The filtrate zachisliaut 1N HCl, the obtained solid is filtered and dried, resulting in the 1.6 g of the desired product in the form of a beige solid with the pace. plvl. > 295oC.

The results of the analysis:

Calculated data: C - 57,64; H - 6,22; N - 3,20; S - 14,65.

Received: C - 57,48: H - To 6.19; N - 3,25; S - 14,73.

1H NMR (DMSO-d6), ; 0,82-of 0.95 (6H,m); 1.32 to to 2.06 (8H, m); 2,54 (1H, d); 3,93 (2H, q); 4,70 (1H, broad s); 6,23 (1H, s); 6,93 (1H, d); 7,60 (6H, broad s); to 7.84 (1H, d); 8,30 (1H, s).

Example 19 synthesis. Receipt of (7R,9R)-7-butyl-7-ethyl-6,7,8,9-tetrahydro - 9-phenyl-1,3-dioxolo(4,5-H)(1,4)-benzodiazepin-5,5-dioxide

0.74 g of the product of example 7 is dissolved in 5 ml of N,N-dimethylformamide. To the reaction is filtered through brownmillerite, washed with EtOAc, and the filtrate is dried and concentrated, resulting in the oily substance. Chromatography on silica gel using for the extraction of a mixture of hexane-EtOAc (1:1 ratio) gives the result of 0.68 g of the desired product as a white solid with the pace. plvl. 71-73oC.

The results of the analysis:

Calculated data: C - 65,81: H - 6,78: N - 3,49; S - 7,99.

Received: C - 65,89; H - 6,80; N - 3,50; S - 8,09.

1H NMR (DMSO-d6), ; 0,71-of 0.85 (6H, m); 1,05-2,12 (8H, m); 2.49 USD (1H, d); of 3.25 (2H, q); of 3.42 (2H,s); 5,91 (1H, d); the 6.06 (1H, s); 7,27-7,41 (6H, m).

Example 20 synthesis. Receive ()-TRANS-3-butyl-3-ethyl - 2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide

(a) 2-hydroxy-3,4-methoxybenzaldehyde

21,81 aluminium chloride are added spatula to ice-cold solution of benzoyl chloride (22.1 g) and 1,2,3-trimethoxybenzene (25,0 g) in 250 ml of 1,2-dichloroethane. The reaction mixture is stirred at 0 to 5oC for 3 h, then heated under reflux for 2 h, poured into 100 ml of ice-cold concentrated HCl and stirred for 30 min, then extracted with diethyl ether. The organic layer is separated, dried and concentrated, obtaining 23,0 g solids. Chromatography on silica gel using DL the logo substances with the pace. plvl. 127-128oC. Data H1NMR are in agreement with the expected structure

(b) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9 - dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide

The product of stage (a) turn in required, following the procedures of steps (a) - (m) of example 10. The final product is isolated in the form of a white solid with the pace. plvl. 142-144oC

The results of the analysis:

Calculated data: C - 66,16: H - of 7.48; N - 3,35; S - 7,68.

Received: C - 66,03; H - 7,53; N - 3,28; S - To 7.77.

1H NMR (DMSO-d6), : of 0.64 (3H, t); 0,81 (3H, t); 0,87-of 2.08(8H,m); 2.42(1H, d): to 3.73(2H, q); of 3.75(3H,S) with 3.79 (3H, s); of 5.50 (1H, d); 6,05 (1H, d); 6,97 (1H, d); 7,27-7,41 (5H, m).

Example 21 synthesis. Obtain (3R,5R)-3-butyl-3-ethyl-5-(4-forfinal)- 2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzodiazepin-4-ol-1,1-dioxide

(a) 2-hydroxy-4,5-dimethoxy-4'-(terbinafine

1M solution of trichloride boron (142 ml) in dichloromethane are added to a solution of 4-tormentilla (16,8 g) in benzene. Then add 20 g of 3,4-dimethoxyphenol in 100 ml of benzene and stirred the reaction mixture for 2 h at room temperature, after which the mixture is poured into ice water and left to stir for 15 minutes, then add 500 ml of 1N HCl and stirred at room temperature for 17 h

Reactivity of solids. Data H1NMR are in agreement with the expected structure

(b) (3R, 5R)-3-butyl-3-ethyl-5-(4-forfinal)-2,3,4,5-tetrahydro-7,8-dimethoxy - 1,4-benzodiazepin-4-ol-1,1-dioxide

The product of stage (a) turn in required, following the procedures of steps (a) - (p) of example 1 and the procedure of example 2. The final product is isolated in the form of a white solid with the pace. plvl. 170-171oC

The results of the analysis:

Calculated data: C - 61,18; H - 6,70; N - 3,10; S-7,10.

Received: C - 61,28; H - Is 6.78; N - 2,99; S - 7,27.

1H NMR (DMSO-d6), ; 0,75-0,85 (6H, m); 1,07-2,04 (8H, m); at 3.35 (2H, q); of 3.42 (3H, s); 3,81 (3H, s); 6,07 (1H, s); 6,33 (1H, s); 7,22 (2H, t); 7,39 (1H, s); 7,40 is 7.50 (2H, m); of 7.96(1H, s).

Examples of the synthesis of 22-54

For each of the following examples of the method of preparation similar to that shown in example 1 and other examples, or chemical methods known in the art. In all cases, the data H1NMR and elemental analysis are in soglasen with the expected structure.

(2) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy - 5-phenyl-1,4-benzothiazepin-7-methanol-S,S-dioxide, temp. melting point 122-123oC

(23) (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro - 5-phenyl-1,4-benzothiazepine-1,1-dioxide (0,40 hydrate), temp. melting point 122-123oC

(24) (the Oia 118-119oC

(25) ()-TRANS-7-bromo-3-butyl-3-ethyl-2,3,4,5 - tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol-1,1-dioxide (0,40 hydrate), temp. melting point 137-138oC

(26) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9 - trimetoksi-5-phenyl-1,4-benzothiazepine-1,1-dioxide, temp. melting point 169-170oC

(27) (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl - 1,4-benzothiazepin-7,8-diyl-diacetate-1,1-dioxide (0,40 hydrate), temp. melting 79-81oC

(28) (8R, 10R)-8-butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-1,4 - dioxane(2,3-H)(1,4)-benzodiazepin-6,6-dioxide, temp. melting 82oC

(29) (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5 - phenyl-1,4-benzothiazepine-1,1-dioxide (0.20 hydrate), temp. melting point 110-111oC

(30) ()-TRANS-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro - 5-phenyl-1,4-benzothiazepine-1,1-dioxide, temp. melting 45-54oC

(31) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8- (methylthio)-5-phenyl - 1,4-benzothiazepine-1,1-dioxygenase, temp. melting 194-197oC

(32) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8 - isopropoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxygenase, temp. melting 178-181oC

(33) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl - 1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide, temp. melting point 165 - 170oC

(34) 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4 - benzodi is Alenia 163-164oC

(36) 3,3-diethyl-5-(4-forfinal)-2,3,4,5-tetrahydro-8 - methoxy-1,4-benzothiazepine-1,1-dioxide, temp. melting 101-103oC

(37) 3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4 - benzothiazepine-1,1-dioxide, temp. melting point 132-133oC

(38) 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepin-4,8-diol-1,1-dioxide, temp. melting 225-227oC

(39) (RS)-3,3-diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8 - dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide, temp. melting point of 205-206oC

(40) ()-TRANS-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro - 5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide, temp. melting point 149 - 150oC

(41) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8 - isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide, temp. melting 109-115oC

(42) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9 - trimetoksi-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide, temp. melting 84-96oC

(43) (3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4 - benzothiazepin-4,7,8-triol-1,1-dioxide, temp. melting 215-220oC

(44) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8 - trimetoksi-5-phenyl-1,4-benzothiazepine-1,1-dioxide, temp. melting 169-187oC

(45) ()-TRANS-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro - 7,8-dimethoxy-1,4-benzothiazepin-4-yl-acetate-S,S-dioxide, temp. melting point 154-156o47) 3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4 - benzothiazepin-8-ol-1,1-dioxide

(48) 3,3-dibutil-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin - 8-ol-1,1-dioxide

(49) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1 - dioxo-5-phenyl-1,4-benzothiazepin-8-yl-hydrosulphate, temp. melting 196,5-200oC

(50) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1 - dioxo-5-phenyl-1,4-benzothiazepin-8-yl-dihydrophosphate, temp. melting point 154-156oC

(51) 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4 - benzothiazepin-8-yl-hydrosulphate

(52) 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4 - benzothiazepin-8-yl-dihydrophosphate

(53) ()-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1 - dioxo-5-phenyl-1,4-benzothiazepin-8-yl-aspartate

Biological test. Suppression of absorption of bile acids in vitro.

Suppression of intestinal absorption of bile acids from substances that increase the excretion, or auxiliary ileal bypass surgery is used as an effective means of reducing the concentration of LDL in plasma. Another way of reducing the absorption of bile acids is the suppression of the transport system active absorption of bile acids in the ileum. Experimentally revealed that such a suppression, a certain allocation of bile acids in faeces, causes of hypercholesterolemia1.

(1) Lewi bile acids in faeces

Male rats of Sprac-Share weight of 220 to 260 g were placed in individual cages and fed a normal Casuarina homevideos. Rats were divided into 6 experimental groups of 10-12 individuals within two days, at 9:00 and 15:30 rats were administered orally through a feeding tube, doses of 1 ml/100 g body weight, experienced connection in the form of a suspension in 0.5% methylcellulose. The control group received only 0.5% methylcellulose. On the second day after the morning dose the rats were injected orally with a small amount (1.3 nmol) taurine 23, 25 -75Se-homogeneou acid (75SeHCAT) in 1.0 ml of saline solution.

75SeHCAT is a synthetic gamma-emitting analogue absorbed by the system absorption of bile acids in the ileum and are similar to human beings need it to acid. With some time used in clinics as an indicator of the absorption of bile acids in the ileum.

(1) Galatola, G. ; Jazrawi, R. P. ; Bridges, C.; Joseph, A. E. A. and Northfield, T. C. Direct Measurement of First-Pass lleal Clearance of a Bile Acid in Humans. Gastroenterology. 1991, 100, 1100-1105.

(2) Ferraris, R.; Galatoa, G.; Barlotta, A; Pellerito, R.; Fracchia. M.; Cottino, F. and De La Pierre. M. Measurement of Bile Acid Half-Life Using [75Se] HCAT in Health and Intestinal Diseases. Dig. Dis. Sci. 1992, 37, 225-232. After the introduction of the75SeHCAT faeces were collected during the day. The content of theSUP>75SeHCAT in percentage are presented in table. 1.

For comparison, the most active compound specifically described in International patent application WO 93/16055, in this test suppressed 9%75SeHCAT at the dose of 1.0 mg/kg

Examples of pharmaceutical compounds

In the following examples, the active compound may be any compound of formula (I) and/or its pharmaceutically acceptable salt, MES or physiologically active derivative, and preferably - (3R,5R)-3-bugil-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy - 5-phenyl-1,4-benzothiazepine-1,1-dioxide or one of the compounds according to examples of synthesis 2-53.

(1) Compounds tablets

The following compositions a and B (table. 2 and 3) can be prepared by wet granulation of the ingredients (a) - (C) and (a) - (g) together with a solution of polyvinylpyrrolidone (povidone") followed by the addition of magnesium stearate and compression. In all the examples of solids number of ingredients are given in mg/tablet (or mg/capsule, a pessary or suppository. ). When this sign (*) noted the preparations according to the British Pharmacopoeia, and sign (**- The Pharmacopoeia of the United States.

The composition of

(a) active ingredient - 100

(b) legislatie compositions D and e can be prepared directly compressing the mixture of ingredients. Lactose in the composition D is suitable for direct pressing.

The composition G

(a) active ingredient 250

(b) magnesium stearate - 4

(C) pre-gelatinising starch NF15 - 146- --- - 400

Part D

(a) active ingredient 250

(b) magnesium stearate - 5

(C) lactose - 145

(g) avicel - 100- --- - 500

The composition of E (controlled release)

(a) active ingredient: 500

(b) hypromellose (Methocel K4M Premium) - 112

(C) lactose*- 53

(d) povidone C. R. C. - 28

(d) magnesium stearate - 7- --- - 700

The composition can be prepared by wet granulation of the ingredients (a) - (C) with a solution of povidone followed by the addition of magnesium stearate and pressed.

The composition W (pill intersolubility shell)

Tablet composition In intersolubility shell can be manufactured by application of the coatings of such interpolymers" as acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose or anionic polymers of methacrylic acid and its ester (Eudragit L), in the amount of 25 mg per pill. Except for Eudragit L they should include 10% (by weight of the used polymer) plasticizer to prevent RA is utiltity and triacetin.

Part 3 (pill intersolubility shell with adjustable release).

Tablet composition E in intersolubility shell can be manufactured by application of the coatings of such interpolymers" as acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose or anionic polymers of methacrylic acid and its ester (Eudragit L), in the amount of 50 mg per tablet. Except for Eudragit L they should include 10% plasticizer (from the weight of polymer used) to prevent cracking of the shell with the introduction or storage. Suitable plasticizers can be diethylphthalate, tributyltin and triacetin.

(II) Compounds capsules

The composition AND

Capsules can be manufactured by mixing the above composition G and fill this mixture two-piece gelatin shells. Composition B (infra) can be made this way.

Part B

(a) active ingredient 250

(b) lactose*- 143

(C) starch glycolate, sodium - 25

(d) magnesium stearate - 2- --- - 420

The composition of

(a) active ingredient 250

(b) Macrogol 4000 BP - 350- --- - 600

Capsules can be manufactured by melting Macrogol 4000 BP, S="ptx2">

The composition G

(a) active ingredient 250

(b) lecithin - 100

(C) peanut butter - 100- --- - 450

Capsules can be manufactured by dispersing the active ingredient in the lecithin and peanut oil and filling soft elastic gelatin shells.

Composition D (capsule with controlled release)

(a) active ingredient 250

(b) microcrystalline cellulose - 125

(C) lactose BP - 125

(d) ethylcellulose - 13- --- - 513

Composition for capsules with controlled release may be made by extrusion of a mixture of ingredients (a)-(C), sportitalia and drying the extrudate. The dried beads are covered with a sheath (g) regulating the release, and fill them two-piece hard gelatin capsules.

The composition of the E (intersolubility capsule)

(a) active ingredient 250

(b) microcrystalline cellulose - 125

(C) lactose BP - 125

(d) acetated cellulose - 50

(e) diethylphthalate - 5- --- - 555

Composition for intersolubility capsules can be manufactured by extrusion of a mixture of ingredients (a)-(C), spheroidization and drying the extrudate. The dried beads cover intersolubility shell (g) plasticizer (d) and is filled with what has been created release)

Intersolubility capsules composition of W with adjustable release can be manufactured by coating beads such "interpolymer" as acatitla cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose or anionic polymers of methacrylic acid and its ester (Eudragit L) in an amount of 50 mg/caps. Except for Eudragit L they must contain 10% plasticizer (from the weight of polymer used) to avoid cracking the shell with the introduction or storage. Suitable plasticizers can be diethylphthalate, tributyltin and triacetin.

(III) the Composition for intravenous infusion (1 ampoule)

(a) active ingredient - 0,200 g

(b) Sterile pyrogen-free phosphate buffer 10 ml

The active ingredient is dissolved in most of the phosphate buffer at 35-40oC, then brought to the desired volume and filtered through a sterile micropore filter into a sterile 10 ml vial (type 1), which is sealed with a sterile tube and seal from the outside.

(IV) the Composition for intramuscular injection (1 ampoule)

(a) active ingredient - 0.20 g

(b) benzyl alcohol - 0,10

(C) glycoluril 75 - 1.45 g

(d) water for injection, add up to 3.00 ml

Active in the comfort through a sterile Millipore filter and sealed in sterile 3 ml vial (type 1).

(V) the Composition for syrup

(a) active ingredient 0.25 g

(b) sorbitol solution of 1.50 g

(C) glycerol - 1,00 g

(g) sodium benzoate - 0,005 grams

(e) corrigent taste - of 0.0125 ml

(e) purified water to 5.0 ml

Sodium benzoate is dissolved in parts of purified water and add a solution of sorbitol, enter and dissolve the active ingredient. The resulting solution is mixed with glycerin and bring purified water to the desired volume.

(VI) the Composition for suppositories

(a) active ingredient 250

(b) hard fat (Witepsol H15-Dynamit Nobel) - 1770 - --- - 2020

The fifth part of the Witepsol H15 is melted in a boat on a couple of not more than 45oC. the Active ingredient is sifted through 2001 m a stainless steel sieve and while stirring add to the melt, using the apparatus of Silvertone with a cutting head. Maintaining the temperature of the mixture 45oC, to a suspension add the remaining Witepsol H15 with stirring to obtain a homogeneous mixture. The entire suspension is then forced through 2501 m a stainless steel sieve and with constant stirring, cooled to 40oC. When the temperature of 38-40oC 2,02-gram portions of the mixture are filled suitable plastic casting form, after which the suppositories allowed to cool to room and - 380

(C) potato starch - 363

(d) magnesium stearate - 7- --- - 1000

The above ingredients are mixed and pessaries are made by compressing the mixture.

(VIII) the Transdermal composition

The active ingredient 200 mg

Alcohol**0.1 ml

Hydroxyethylcellulose

The active ingredient and alcohol delirous with hydroxyethyl cellulose and Packed in a device for transdermal administration, with an area of 10 cm2.

1. 1,4-benzothiazepine-1,1-dioxide of the formula II

< / BR>
where R1represents promoteyou1-6alkyl group;

R2represents promoteyou1-6alkyl group;

R4represents unsubstituted phenyl;

R5and R8represent hydrogen;

R6represents methoxy or bromo;

R7arepresents methoxy, hydroxy or trifluoromethyl;

R9and R10represents hydrogen,

or its salt, MES or physiologically functional derivative.

2. Connection on p. 1, where R1represents ethyl, and R2represents n-butyl.

3. The compound according to any one of paragraphs.1 and 2, where R7apredstavlja-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;

(+-)-TRANS-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;

(3R, 5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;

(3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide and

3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide,

or its salt, MES or physiologically functional derivative.

5. Connection on p. 1, representing (3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide or its salt, MES or physiologically functional derivative.

6. Connection on p. 1, representing (3R, 5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide or its salt, MES or physiologically functional derivative.

7. Pharmaceutical composition, lowering the level of blood lipids containing an effective amount of a compound according to PP.1 - 6 or its pharmaceutically acceptable salt, MES or physiologically functional derivative, the media and, if necessary, other physiologically active agent.

8. The method of treatment of a clinical condition is mu PP.1 - 6 in an effective amount.

9. The method of obtaining the compounds of formula II or its salt, MES or physiologically functional derivative, in which (a) oxidizing a compound of formula V

< / BR>
where R7is an R7a;

I is 0 or 1,

and possibly (b) divide the mixture thus obtained isomers and/or convert the formed compound of formula II into its corresponding salt, MES or physiologically functional derivative.

 

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< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

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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 then is called diltiazem
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