MXPA00012207A - Benzothiepine-1,1-dioxide derivatives, method for producing them, medicaments containing these compounds and their use - Google Patents

Abstract

The invention relates to benzothiepine-1,1-dioxide derivatives and their acid addition salts, i.e. compounds of formula (I) wherein R1, R2, R3, R4, R5 and Z have the meanings given in the description and their physiologically compatible salts and physiologically functional derivatives. The invention also relates to a method for producing said compounds, which are suitable for use as e.g. hypolipidaemics.

Description

DERIVATIVES OF BENZOTIEPIN-1, 1-DIOXIDQ, METHOD FOR YOUR PRODUCTION, DRUGS CONTAINING THESE COMPOUNDS AND THEIR USE The invention relates to benzothiepine 1,1-dioxide derivatives, their physiologically tolerable salts and physiologically functional derivatives. The derivatives of benzothiepine 1,1-dioxide and its use for the treatment of hyperlipidemia as well as of arteriesclerosis and hypercholesterolemia have already been described [see PCT Application No. PCT / US97 / 04076, publication No. WO 97 / 33882]. The object of the invention is to make available additional compounds which have a therapeutically usable hypolipidemic action. Particularly, the object of the present invention is the discovery of novel compounds which, in comparison with the compounds described in the prior art, provide a higher fecal excretion of bile acid, even at a lower dose. A dose reduction of the ED value; cc by at least factor 5 compared to the compounds described in the prior art is particularly desirable. The invention to compounds of the formula I wherein R1 is methyl, ethyl, propyl, butyl; f R2 is H, OH, NH2, NH-alkyl (C? -C5); R 3 is a sugar radical, a diazugar radical, a sugar radical, a sugar tetra radical, a sugar radical, a sugar radical, a sugar radical or a sugar radical is optionally monosubstituted or polysubstituted by a sugar protecting group; R4 is methyl, ethyl, propyl, butyl; R5 is methyl, ethyl, propyl, butyl; Z is - (C = 0) n-alkyl (Co-Cie), - (C = 0) n-alkyl (C0-C? 6) -NH-, (C = 0) n-alkyl (Co-CißJ- O-, - (C = 0) n-alkyl (C? -C? 6) - (C = 0) m, a covalent bond, n is 0 or 1; 15 m is 0 or 1; and its salts pharmaceutically tolerable and physiologically functional derivatives Preferred compounds of formula I are those compounds in which one or more radical (s) have the following meaning: R 1 is ethyl, propyl, butyl, R 2 is H, OH, NH 2 , NH-alkyl (C? -C5), R3 is a sugar radical, a diazugar radical, the sugar radical or the diazugar radical can be monosubstituted or polysubstituted by a sugar protecting group; R 4 is methyl, ethyl, propyl, butyl; R5 is methyl, ethyl, propyl, butyl; Z is - (C = 0) n-alkyl (Co-Cie) -, - (C = 0) n-alkyl (C0-C? 6) -NH-, - (C = 0) n-alkyl (Co- C? 6) -0-, - (C = 0) n-alkyl (C? -C16) - (C = 0) r "a covalent bond; n is 0 or 1; m is 0 or 1; and their pharmaceutically tolerable salts and physiologically functional derivatives. Particularly preferred compounds of formula I are those compounds in which one or more radical (s) have the following meaning: R 1 is ethyl, butyl; R2 is OH; R3 is a diazucar radical, the diazucar radical is optionally monosubstituted or polysubstituted by an amino protecting group; R4 is methyl; R5 is methyl; Z is - (C = 0) -alkyl (Co-C4), a covalent bond; and its pharmaceutically tolerable salts. Taking into account their high solubility in water compared to the initial or base compounds, the pharmaceutically tolerable salts are particularly suitable for medical applications. These salts must have an anion or pharmaceutically tolerable cation. Suitable pharmaceutically tolerable acid addition salts of the compounds according to the present invention are salts of inorganic acids such as for example hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and organic acids such as for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, heptanesulfonic acid, fumaric acid, acid ^ m Gluconic, glycolic acid, isotonic acid, lactic acid, 9 10 lactobionic acid, aleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid. For medical purposes, the chlorine salt is used in a particularly preferred manner. Pharmaceutically tolerable basic salts Suitable are ammonium salts, alkali metal salts (such as sodium and potassium salts) as well as ferrous alkali metal salts (such as magnesium and calcium salts). You leave with an anion 'that is not pharmaceutically tolerable are also included within the scope of the present invention as intermediates useful for the preparation or purification of pharmaceutically tolerable salts and / or for use in non-therapeutic applications, for example in vitro. 25 The term "physiologically functional derivative" as used used herein refers to any physiologically tolerable derivative of a compound according to the present invention, for example, an ester which, when administered to a mammal, such as a human being, can (directly or indirectly) form a compound of this type or an active metabolite thereof. A further aspect of this invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to provide a compound according to the invention. These prodrugs can themselves be active or inactive. The compounds according to the present invention can also be found in various polymorphic forms, for example amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the present invention are included within the scope of the present invention and represent a further aspect of the invention. In the following, all references to "compound (s) according to formula (I)" refer to compound (s) of formula (I) in accordance with that described above, and to their salts, solvates and physiologically functional derivatives in accordance with what is described here. The amount of a compound according to formula (I) that is required in order to achieve the biological effect desired depends on several factors, for example the specific compound selected, the intended use, the manner of administration and the clinical condition of the patient. In general, the daily dose is within the range of 0.1 mg to 100 mg (typically 0.1 mg to 50 mg) per day per kilogram of body weight, eg, 0.1-10 mg / kg / day.

Tablets or capsules may contain, for example, 0.01 to 100 mg, typically 0.02 to 50 mg. In the case of pharmaceutically tolerable salts, the aforementioned weight data refer to the weight of the benzothiepine ion derived from the salt. For the prophylaxis or therapy of the conditions mentioned above, the compounds according to formula (I) can be used per se as the compound, but are preferably present in the form of a pharmaceutical composition with a tolerable excipient. The excipient must obviously be tolerable in the sense that it must be compatible with the other constituents of the composition and not be harmful to the patient's health. The excipient may be a solid or a liquid, or both, and is preferably formulated with the compound in the form of a single dose such as, for example, in the form of a tablet, which may contain from 0.05% to 95% by weight of the active compound Additional pharmaceutically active substances may also be present, including additional compounds according to formula (I). The pharmaceutical compositions of according to the invention can be prepared by any of the known pharmaceutical methods, which 99 consists essentially of mixing the constituents with - pharmacologically tolerable excipients and / or auxiliaries. The pharmaceutical compositions according to the present invention are those compositions which are suitable for oral and oral administration (for example, sublingual), although the most suitable form of administration depends on each individual case, on the nature and severity of the administration.

The condition to be treated and the type of compound according to the formula (I) used in each case. Coated formulations or coated prolonged release formulations are also included within the scope of the invention. Formulations resistant to acids and enterics are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, ^ hydroxypropylmethylcellulose phthalate as well as anionic polymers of methacrylic acid and methyl ethacrylate. Pharmaceutical compounds suitable for oral administration may be present in separate units such as for example capsules, dragees, pills or tablets, which, in each case, contain a specific amount of the compound according to formula (I); in the form of a powder or granules; in the form of a solution or suspension in a liquid aqueous or non-aqueous; or in the form of an oil emulsion in water or water in oil. As already mentioned, these compositions can be prepared in accordance with any suitable pharmaceutical method which includes a step in which the active compound and the excipient (which may consist of one or more additional constituents) come into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and / or finely divided solid carrier, after which the product is shaped, if necessary. For example, a tablet can be prepared - in this way by pressing or supplying a form to a powder or granules of the compound, if appropriate, with one or more additional constituents. Pressed tablets can be produced by tabletting the compound in free flowing form such as a powder or granules, if appropriate mixed with a binder, luant, inert diluent and / or a surfactant / dispersing agent (various agents). surfactants / dispersants) in a suitable machine. The tablets formed can be produced by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions which are suitable for peroral (sublingual) administration include dragees containing a compound according to formula (I), with a flavoring, usually sucrose and gum arabic or tragacanth, and pills that include the compound in an inert base such as for example gelatin and glycerol or sucrose and gum arabic. The invention also relates both to mixtures of isomers of the formula I and to the pure stereoisomers of the formula I, as well as mixtures of diastereomers of the formula I and the pure diastereomers. The separation of the mixtures is carried out in particular chromatographically. The preferred racemic compounds as well as the compounds • Preferred enantiomerically pure of the formula I are the compounds having the following structure: 0 Sugar radicals are understood as compounds derived from aldoses and quetoses having from 3 to 7 carbon atoms and which may belong to the D or L series; they also include amino sugars, sugar alcohols or sugar acids.

Examples that we can mention are glucose, crafty, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, • galacturonic acid, gluconic acid, galactonic acid, manonic acid, glucamine, 3-amino-l, 2-propanediol, glucaric acid and galactárico acid. Preferred sugar radicals are: Particularly preferred sugar radicals are: Diazúcares refer to saccharides that consist of two sugar units. Di-, tri-, or tetrasa aggregates are formed by acetal type bonding of two or more sugars. The links can in this case occur in the alpha form or in the beta form. Examples that may be mentioned are lactose, maltose, and cellobiose. If the sugar is replaced, the substitution is made Preference in the hydrogen atom of an OH group of the sugar. Possible protecting groups for the hydroxyl groups of the sugars are essentially the following: benzyl, acetyl, benzoyl, pivaloyl, trifly, tert-butyldimethylsilyl, benzylidene, cyclohexylidene or isopropylidene. The invention also relates to a process for the preparation of benzothiepine 1,1-dioxide derivatives of the formula I: A process for the preparation of compounds of the formula I, comprising the. reaction of an amine of formula II, wherein R, R, R; and R: have a meaning indicated for formula I with a compound of formula III, wherein R and Z have the meanings indicated for formula I, with removal of water to provide a compound of formula I and optionally converting the compound of the formula I obtained in a physiologically tolerable salt or a physiologically functional derivative. If the radical P.J is a mono-sugar, this radical can also optionally be stepwise prolonged in such a way as to provide the diazúcar radical, triazúcar radical or tetra-sugar radical after the union with the amine of the formula II. The compounds of the formula I and their pharmaceutically tolerable salts and physiologically functional derivatives are ideal pharmaceutical agents for the treatment of disorders of lipid metabolism, particularly of hyperlipidemia. The compounds of the formula I are in the same way suitable for influencing the serum cholesterol level and for the prevention and treatment of arteriosclerotic symptoms. The compounds can optionally also be administered in combination with statins, such as for example simvastatin, fluvastatin, pravastatin, cerivastatin, lovastatin, or atorvastin. The following findings confirm the pharmacological efficacy of the compounds according to the present invention. The biological test of the compounds according to the invention was carried out by determining the expression ED2oo. This test investigates the action of the compounds according to the invention on the transport of bile acid in the ileum and the fecal excretion of bile acids in the rat after oral administration twice a day. Diastereomer mixtures were tested of the compounds. The test was carried out in the following manner: 1) preparation of test and reference substances The following recipe was used for the formulation of an aqueous solution: the substances were dissolved in adequate volumes of an aqueous solution containing Solutol (= hydroxystearate). polyethylene glycol 600; BASF, Ludwigshafen, Germany; lot No. 1763), such that a final concentration of 5% Solutol was present in the aqueous solution. The solutions / suspensions were administered orally in a dose of 5 ml / kg. 2) Experimental conditions Male Wistar rats (Kastengrund, Hoechst AG, weight range: 250-350 g) were kept in groups of 6 animals each and received a standard food mixture (Altromin, Lage, Germany) for 10 days before of the beginning of the treatment (day 1) with inverted day / night rhythm (4.00 -16.00 darkness, 16.00 - 4.00 light). Three days before the start of the experiment (day 0), the animals were divided into groups of 4 animals each. Division of animals into treatment groups: No. of no. of animal / substance of group dose no. Analysis test 1 (mg / kg / d) 1 1-4 negative control vehicle 2 5-8 test substance 2 x 0.008 dose 1 3 9- 12 test substance 2 x 0. 02 dose 2 4 13-16 test substance 2 x 0.1 dose 3 5 17-20 test substance 2 x 0.5 dose 4 1 dissolved / suspended in 5% Solutol HS 15 / 0.4% starch mucilage 3) performance of the experiment After intravenous or subcutaneous administration of 5 μCi of 1C-taurocholate per rat (day 0), vehicles or test substances were administered at 0700-8.00 and 15.00-16.00 the following day (day 1) (one day treatment). Stool samples for 14C-taurocholate analysis were taken every 24 hours directly after the administration of the morning dose. The faeces were weighed, stored at a temperature of -18 ° C and then suspended in 100 ml of demineralized water and homogenized (Ultra Turrax, Janke &Kunkel, IKA-Werk). Aliquots (0.5 g) were weighed and burned in combustion lids (Combusto Cones, Canberra Packard) in a combustion apparatus (Tri Carb® combuster 307 Canberra Packard GmbH, Frankfurt am Main, Germany). The resulting 14C? 2 was absorbed with Carbo-Sorb® (Canberra Packard). The following measurements of radioactivity 14C were determined after the addition of the scintillator (complete scintillation mixture Perma-Fluor No. 6013187, Packard) to the samples with the help of liquid scintillation counting (LSC). Fecal excretion of 14C-labeled taurocholic acid was calculated as accumulated and / or residual radioactivity in percent (see below). 4) Observations and measurements The fecal excretion of 14C-TCA was determined by the aliquots burned from stool samples taken at 24-hour intervals, calculated as the "cumulative percentage" of the activity administered and expressed as a percentage of residual activity (= remaining activity, that is, activity administered less activity already excreted). For the calculation of the dose-response curves, the excretion of 14C-labeled taurocholic acid was expressed as a percentage of the corresponding values of the control group (treated with the vehicle). The ED2oo, that is, the dose that increases the fecal excretion of taurocholic acid marked with 14C in 200% in relation to the control group, is calculated from a linear or sigmoid dose-response curve by interpolation. The calculated ED2oo corresponds to a dose that doubles the fecal excretion of bile acids.

) Results Table 1 shows measurements of ED20o excretion.

Table 1 Compounds of eg excretion ED20o 0 (mixture of diastereomers) (mg / kg / d) p. or, 1 0.009 5- - 2 0.008 3 0.04 5 0.03 6 0.04? 7 0.04 10 8 0.007 9 0.007 10 0.04 3 (pure structure lia) 0.008 Comparison examples 15 1 0.8 1.0 0.9 • 6) Comments 20 It can be inferred from the measured data that the compounds of formula I according to the invention have an action that is better by a factor of 20 to 100 compared to the compounds described in the prior art. The following examples serve to illustrate the invention with more details without restricting said invention to products and modalities described in the examples.

Example 1 C3CH N2O9S (608.76). MS (M + H) '= 609.3 Example 2 C4: H54N2014S (818.40). MS (M + H) = 819.3 Example 3 C35H55N3O9S (693.91). MS (M + H) + = 694.4 Example 4 C 37 H 59 N 3 O 9 S (721.96). MS (M + H) + = 722.3 Example 5 15a 15b C4iH65N30: -S (792.05). MS (M + H) * = 792.5 Example 6 C42H5eN; 0i S (846.97). MS (M + H) '= 847.4 Example 7 C:.; H43N2? 9S (636.80). MS (M + H) + = 637.4 Example 8 C4? H63N30I5S (918.06). MS (M + H) + = 918.6 Example 9 C3 = H53N3O? OS (707.88). MS (M + H) t = 708.4 Example 10 C47H6-N3015S (946.12). MS (M + H) + = 946.5 Comparison examples from PCT / US97 / 04076: Comparison example 1 Example of comparison 3 The examples and comparison examples were prepared in the following manner (in the preparations only the synthesis of diastereomers a) is shown: Reaction scheme 1 Reaction scheme 2 11a Reaction scheme 3 19a Synthesis of compound 3 as a mixture of diastereomers: 300 mg (0.69 mmol) of the / b (preparation analogous to PCT / US 97/04076) and 700 mg (1.7 mmol) of penta-O-acetyl-D- acid are dissolved. gluconic acid (Org Synth, Volume 5, 887) in 10 ml of DMF (dimethylformamide). 700 mg (2.1 mmol) of TOTU (Fluka), 250 mg (1.7 mmol) of oxime (ethyl hydroxyiminocyanoacetate, Fluka) and 0.7 ml (5.5 mmol) of NEM (4-ethylmorpholine) are successively added. After one hour at room temperature, the mixture is diluted with 100 ml of ethyl acetate and washed three times with water. The organic phase is dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (ethyl acetate / n-heptane 2: 1) and 502 mg (88%) of 3a / b are obtained in the form of an amorphous solid. TLC (ethyl acetate / n-heptane 2: 1) RF = 0.3. The product 3a / b has the same retention as the initial material a / b, but has different stains with 2 M sulfuric acid. C4oH54 2O? 4S (818.40), MS (M + H) + = 819.3 Synthesis of compound 4 in the form of a mixture of diastereomers: 455 mg (0.55 mmol) of 3a / b are dissolved in 20 ml of methanol. After the addition of 0.3 ml of a 1 M methanolic sodium methoxide solution, the mixture is allowed to stand at room temperature for 1 hour. It is then neutralized with a methanolic HCl solution and concentrated. The residue it is purified by flash chromatography (methylene chloride / methanol / concentrated ammonia 30/5/1) and obtained 280 mg (83%) of 4a / b as an amorphous solid. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). RF = 0.2 C 30 H 44 N 2 O 9 S (608.76), MS (M + H) + = 609.3 Synthesis of compound 11 in the form of a mixture of diastereomers: 77 mg (0.013 mmol) of 9a / b (preparation analogous to PCT / US 97/04076) are dissolved in 4 ml of DMF. After the addition of 150 mg (0.082 mmol) of 10 (glucamine, Fluka), the mixture is heated to a temperature of 80 ° C for two hours. It is then diluted with 50 ml of ethyl acetate and washed three times with water. The organic phase is dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (methylene chloride / methanol / concentrated ammonia 30/5/1) and 55 mg (61%) of lla / b are obtained in the form of an amorphous solid. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). RF = 0.3 C 35 H 55 N 3 O 9 S (693.91), MS (M + H) "= 694.4 Synthesis of compound 14: 8.0 g (18.8 mmol) of 12 (penta-O-acetyl-D-gluconic acid chloride, Synth Org. , 887) to a suspension of 8.0 g (40 mmol) of 13 (Fluka) in 150 ml of DMF anhydrous This suspension is stirred vigorously at room temperature for 20 hours. 500 ml of ethyl acetate and 200 ml of water are then added. The aqueous phase is extracted again with 250 ml of ethyl acetate. The combined organic phase is washed three times with a sodium chloride solution, dried over MgSO4, filtered and concentrated. Yield: 9.5 g (86%) of 14 as a colorless oil. TLC (methylene chloride / methanol / ammonia concentrate 30/10/3). Rf = 0.8. C27H43NO13 (589.64), MS (M + H) + = 590.4. Synthesis of compound 15 in the form of a mixture of diastereomers: 200 mg (0.34 mmol) of 14, 78 mg (0.18 mmol) of the / b, 240 mg of TOTU, 80 mg of oxime and 0.3 ml of NEM react in 4 ml of DMF in a manner analogous to the procedure of compound 4. After flash chromatography (methylene chloride / methanol / concentrated ammonia 30/5/1), 47 mg (33% in two steps) of 15a / b are obtained in the form of an amorphous solid. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). Rf = 0 .2. C4? H65N3O? OS (792.05), MS (M + H) + = 792. 5 .

Claims (11)

1. CLAIMS Wherein R1 is methyl, ethyl, propyl, butyl; R2 is H, OH, NH2, NH-alkyl (C6C6); R3 is a sugar radical, a diazugar radical, a triazugar radical, a tetra-sugar radical, the sugar radical, a diazugar radical, a triazugar radical or a tetra-sugar radical is optionally monosubstituted or polysubstituted by a sugar protecting group; R 4 is methyl, ethyl, propyl, butyl; R: is methyl, ethyl, propyl, butyl; 20 Z is - (C = 0) n-alkyl (Co-Cis), - (C = 0) - (C0-C; 5) alkyl -NH-, - (C = 0) ^ -alkyl (Cc- C16) -0-, - (C = 0) r.-alsuyl (C: -C? 6) - (C = 0) m, a covalent bond; n is 0 or 1; m is 0 or 1; 25 or its pharmaceutically tolerable salts and physiologically functional derivatives. • The compound of the formula I according to claim 1, wherein one or more of the radicals 5 have the following meanings: R 1 is ethyl, propyl, butyl; R2 is H, OH, NH
2. 2, NH-alkyl? (C? -C6); R3 is a sugar radical, a diazúcar radical, the radical ^^ sugar or the diazúcar radical are optionally 10 monosubstituted or polysubstituted by a sugar protecting group; R 4 is methyl, ethyl, propyl, butyl; R5 is methyl, ethyl, propyl, butyl; Z is - (C = 0) n (C0-C16) alkyl -, - (C = 0) n-C0-C6 alkyl) -NH-, 15 - (C = 0) n-alkyl (Co -Cie) -O-, - (C = 0) n-alkyl (d-C16) - (C = 0) m, a covalent bond; n is 0 or 1; m is 0 or 1; or its pharmaceutically tolerable salts.
3. 3. A compound according to formula I according to claim 1 or 2, wherein one or more of the radicals have (n) the following meanings: R1 is ethyl, butyl; R2 is OH; 25 R3 is a sugar radical, the sugar radical is optionally monosubstituted or polysubstituted by a sugar protecting group; R4 is methyl; R5 is methyl; Z is - (C = 0) -alkyl (C; -C4) a covalent bond; or its pharmaceutically tolerable salts.
4. A compound of the formula I in accordance with that claimed in one or more of claims 1 to 3, where the compound has the following structure or its pharmaceutically tolerable salts.
5. A compound according to formula I according to one or more of claims 1 to 3, wherein the compound has the following structure 10 or its pharmaceutically tolerable salts.
6. 6. A process for the preparation of compounds of formula I according to one or more of claims 1 to 5, which comprises the reaction, according to the following equation, of an amine of formula II, wherein R1, R2, R4 and R: 25 have the meanings indicated for formula I, with a compound of the formula III, wherein R3 and Z have the meanings indicated for the formula I, with removal of water to provide a compound of the formula I and optionally to convert the compound of the formula I obtained into a physiologically tolerable salt or a physiologically functional derivative.
7. 7. A pharmaceutical agent comprising one or more of the compounds according to one or more of claims 1 to 5.
8. 8. A pharmaceutical agent comprising one or more of the compounds according to one or more of claims 1 to 5 and one or several statins.
9. 9. A compound according to one or more of claims 1 to 5 for use as a drug for the treatment of disorders of lipid metabolism.
10. 10. A compound according to one or more of claims 1 to 5 for use as a drug for the treatment or prophylaxis of gallstones. A process for the production of a pharmaceutical agent comprising one or more of the claimed compounds in one or more of claims 1 to 5, which comprises mixing the active compound with a pharmaceutically suitable excipient and providing this mixture with a suitable form for its administration. Use of compounds in accordance with any of claims 1 to 5 for the production of a drug for the treatment of hyperlipidemia. The use of the compounds according to one or more of claims 1 to 5 for the production of a drug for influencing the serum cholesterol level. The use of the compounds according to one or more of claims 1 to 5 for the production of a drug for the prevention of arteriosclerotic symptoms. The use of the compounds according to one or more of claims 1 to 5 for the production of a drug for the treatment or prophylaxis of gallstones.