HK1039490B - Benzothiepine-1, 1-dioxide derivatives, method for producing them, composition containing these compounds and their use - Google Patents

Description

Benzothiepin-1, 1-dioxide derivatives, process for their preparation, compositions containing them and their use

The present invention relates to substituted benzothiepin-1, 1-dioxide derivatives, to their physiologically acceptable salts and to physiologically functional derivatives.

Benzothiepin-1, 1-dioxide derivatives and their use in the treatment of hyperlipidemia as well as arteriosclerosis and hypercholesterolemia have been disclosed [ see PCT application No. PCT/US97/04076, publication No. WO 97/33882 ].

The object of the present invention is to prepare more effective compounds which show a favourable hypolipidemic effect in therapy. In particular, the object was to find new compounds which, compared to existing compounds, can produce high faecal bile acid secretion even at lower doses. ED (electronic device)₂₀₀It is particularly desirable to reduce the dosage of the value by at least a factor of 5 over the compounds described in the prior art.

The present invention relates to novel compounds of formula I:

wherein

R¹Is methyl, ethyl, propyl, butyl;

R²is H, OH, NH₂、NH-(C₁-C₆) -an alkyl group;

R³is a glycosyl, disaccharide, trisaccharide, tetrasaccharide residue, said glycosyl, disaccharide, trisaccharide or tetrasaccharide residue being optionally mono-or polysubstituted with a sugar protecting group;

R⁴is methyl, ethyl, propyl, butyl;

R⁵is methyl, ethyl, propyl, butyl;

z is- (C ═ O)_n-C₀-C₁₆-alkyl, - (C ═ O)_n-C₀-C₁₆-alkyl-NH-, - (C ═ O)_n-C₀-C₁₆-alkyl-O-, - (C ═ O)_n-C₁-C₁₆-alkyl- (C ═ O)_mOne covalent bond;

n is 0 or 1;

m is 0 or 1;

and pharmaceutically acceptable salts and physiologically functional derivatives thereof.

Preferred compounds of the formula I are those in which one or more of the radicals have the following meanings:

R¹is ethyl, propyl, butyl;

R²is H, OH, NH₂、NH-(C₁-C₆) -an alkyl group;

R³is a glycosyl, disaccharide, said glycosyl or disaccharide optionally mono-or polysubstituted with a glycosyl protecting group;

R⁴is methyl, ethyl, propyl, butyl;

R⁵is methyl, ethyl, propyl, butyl;

z is- (C ═ O)_n-C₀-C₁₆-alkyl, - (C ═ O)_n-C₀-C₁₆-alkyl-NH-, - (C ═ O)_n-C₀-C₁₆-alkyl-O-, - (C ═ O)_n-C₁-C₁₆-alkyl- (C ═ O)_mOne covalent bond;

n is 0 or 1;

m is 0 or 1;

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of the formula I are those in which one or more radicals have the following meanings:

R¹is ethyl, butyl;

R²is OH;

R³is a glycosyl group, optionally mono-or polysubstituted with a glycosyl protecting group;

R⁴is methyl;

R⁵is methyl;

z is- (C ═ O) -C₀-C₄-an alkyl group, one covalent bond;

and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because of their higher water solubility than the starting-or base-compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention are: salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acids, and sulfuric acid; and salts of organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothiocarboxylic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, and trifluoroacetic acid. For pharmaceutical purposes, the hydrochloride salt is particularly preferred. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts).

In addition, salts with pharmaceutically unacceptable anions are included within the scope of the invention, e.g. for use as intermediates in the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic, e.g. in vitro, use.

The term "physiologically functional derivative" as used herein refers to any physiologically acceptable derivative of a compound of the invention, e.g. an ester, which is capable of forming (directly or indirectly) said compound or an active metabolite thereof upon administration to a mammal, such as a human.

Another aspect of the present invention is a prodrug of a compound of the present invention. The prodrugs can be metabolized in vivo to compounds of the invention. These prodrugs may be active or inactive themselves.

The compounds of the present invention may also exist in different polymorphs, such as amorphous and crystalline polymorphs. All polymorphs of the compounds of the present invention are included within the scope of the present invention and are further aspects of the present invention.

The compounds of the invention are also suitable for the prevention or treatment of gallstones.

Hereinafter, all "compounds of formula (I)" refer to the compounds of formula (I) as described above and their salts, solvates and physiologically functional derivatives as described herein.

The amount of a compound of formula (I) required to achieve a desired biological effect depends on a variety of factors, for example, the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. Generally, the daily dose will be in the range of 0.1mg to 100mg (typically from 0.1mg to 50mg) per day per kg of body weight, such as 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, 0.01 to 100mg, typically 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the weight data set forth above relate to the weight of benzothiepine ion derived from the salt. For the prophylaxis or treatment of the abovementioned conditions, the compounds of the formula (I) can be used per se, but preferably they are present in the form of a pharmaceutical composition with acceptable excipients. Obviously, said excipients must be acceptable, that is to say compatible with the other components of the composition and not harmful to the health of the patient. Excipients may be solid or liquid or both and are suitable for formulating the compounds into individual doses, for example tablets, which may contain from 0.05 to 95% by weight of active compound. In addition to the compounds comprising formula (I), other pharmaceutically active substances may also be present. The pharmaceutical compositions of the present invention may be prepared by a known pharmaceutical process which essentially comprises mixing the components with pharmaceutically acceptable excipients and/or adjuvants.

The pharmaceutical compositions of the invention are those suitable for oral and peroral (e.g. sublingual) administration, while the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the kind of compound of formula (I) used in each case. Coated formulations and coated sustained release formulations are also within the scope of the invention. Acid resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyethylene acetate phthalate, hydroxypropyl methylcellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical compounds suitable for oral administration may be presented as separate units, for example: capsules, caplets, lozenges or tablets, which in each case contain the compound of the formula (I) in specific amounts; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water-or water-in-oil emulsion. As noted above, these compositions may be prepared according to any suitable pharmaceutical method, including the step of contacting the active compound therein with an excipient (which may be comprised of one or more components). In general, the compositions are prepared by homogeneous and homogeneous mixing of the active compound with liquid and/or finely divided solid excipients, and the product may be subsequently shaped, if necessary. For example, tablets may be prepared by compressing or forming powders or granules of the compound, and if appropriate, one or more additional ingredients may be employed. Compressed tablets may be prepared by compressing the compound in a free-flowing form such as a powder or granules, and mixing, if appropriate, with a binder, lubricant, inert diluent, and/or surfactant/dispersant(s) in suitable equipment. Compressed tablets may be prepared by forming the powdered compound moistened with an inert liquid diluent in suitable equipment.

Pharmaceutical compositions suitable for oral (sublingual) administration include: lozenges comprising a compound of formula (I) and a flavouring agent, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

The invention further relates to mixtures of isomers of formula I and pure stereoisomers of formula I, as well as mixtures of diastereomers and pure diastereomers of formula I. The separation of these mixtures is carried out by, in particular, chromatography.

Preferred racemic and enantiomerically pure mixtures of formula I are those having the following structures:

"glycosyl" is understood to be a compound derived from aldoses and ketoses having 3 to 7 carbon atoms and may belong to the D or L series; these include amino sugars, sugar alcohols or sugar acids. Examples which may be mentioned are glucose, mannose, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, galactonic acid, mannonic acid, glucosamine, 3-amino-1, 2-propanediol, glucaric acid and galactaric acid.

Preferred sugar groups are:

particularly preferred sugar groups are:

disaccharides are sugars consisting of two sugar units. Di-, tri-, or tetrasaccharides are formed by bonding acetals of 2 or more saccharides. In this case, the construct may be presented in either alpha or beta form. Examples which may be mentioned are lactose, maltose and cellobiose.

If the saccharide is substituted, the substitution reaction preferably occurs on the hydroxyl hydrogen atom of the saccharide.

Useful protecting groups for the hydroxyl groups of sugars are mainly: benzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzylidene, cyclohexylidene or isopropylidene protecting groups.

The invention further relates to a process for the preparation of benzothiepine-1, 1-dioxide derivatives of formula I:

a process for preparing a compound of formula I comprises reacting an amine of formula II wherein R¹、R²、R⁴And R⁵Having the meaning given above for formula I, with compounds of the formula III, in which R is³And Z has the meaning given in formula I, removing the water to produce a compound of formula I, and optionally converting the compound of formula I into a physiologically acceptable salt or a physiologically functional derivative. If the radical R is³Is a monosaccharide radical, which, after bonding to the amine of the formula II, may optionally be further lengthened in steps to give a disaccharide, trisaccharide or tetrasaccharide radical.

The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal drugs for the treatment of lipid metabolism disorders, particularly hyperlipidemia. The compounds of the formula I also suitably influence serum cholesterol levels and are therefore suitable for the prophylaxis and treatment of arteriosclerotic symptoms. The compounds may also optionally be administered in combination with a statin, such as simvastatin, fluvastatin, pravastatin, cerivastatin, lovastatin or atorvastatin (atorvastatin). The following findings confirm the pharmacological efficacy of the compounds of the present invention.

Biological experiments with the compounds of the invention were performed by determining ED₂₀₀Excretion is performed. This experiment investigated the effect of the compounds of the invention on bile acid transport in the ileum and fecal excretion of bile acids after 2 daily administrations in rats. Diastereomeric mixtures of the compounds were tested. The tests were carried out as follows:

1) test formulations and reference

The following protocol was used to prepare the aqueous solutions: the active substance is dissolved in a sufficient amount of an aqueous solution containing Solutol (═ polyethylene glycol 600 hydroxystearate; BASF, Ludwigshafen, germany; batch No. 1763) so that the final concentration of Solutol in the aqueous solution is 5%. The solution/suspension was administered orally at a dose of 5 ml/kg.

2) Test conditions

Male Wistar rats (Kastenrudd, Hoechst AG bodyweight 25-350) were maintained in 6 animals per group and received standard mixed feed (Altromin, Lage, Germany) and day/night cycle rhythm (4:00-16:00 night, 16:00-4:00 light) for 10 days before treatment began (day 1). Three days before the start of the experiment (day 0), the animals were divided into 4 animals per group.

Animals were divided into treatment groups:

numbering of groups	Animal/test numbers	Test substance1	Dosage (mg/kg/day)
1	1-4	Negative control	Excipient
				2	5-8	Test substance dosage 1	2×0.008
3	9-12	Test substance dosage 2	2×0.02
				4	13-16	Test substance dosage 3	2×0.1
5	17-20	Test substance dose 4	2×0.5

¹Dissolved/suspended in 5% Solutol HS 15/0.4% starch mucilage

3) Procedure of the test

5 μ Ci administered intravenously or subcutaneously to each rat¹⁴After C-taurocholate (day 0), the vehicle or test compound was administered at 7.00-8.00 and 15.00-16.00 days (day 1) later (day 1 treatment).

Stool samples were collected every 24 hours since morning dosing for analysis¹⁴C-taurocholate. The faeces were weighed, preserved at-18 ℃ and then suspended in 100ml of demineralized water and homogenized (UltraTurrax, Janke)&Kunkel, IKA-Werk). An aliquot (0.5g) was weighed and burned on a combustion hood (Combusto cons, kanperra Packard) in a combustion apparatus (Tri Carb  307 combustion kanperra Packard GmbH, Frankfurt am Main, germany). The resulting material was absorbed by Carbo-Sorb  (Kanbera Packard)¹⁴CO₂. The samples were measured by Liquid Scintillation Counting (LSC) after addition of a scintillator (Perma-Fluor complete scintillation cocktail, code 6013187, Packard)¹⁴C, radioactivity. For fecal discharge¹⁴C-taurocholic acid was calculated as cumulative and/or percent residual radioactivity (see below).

4) Observing and measuring

Measuring fecal excretion in aliquots of burning fecal samples at 24-hour intervals¹⁴C-TCA, calculated as the "cumulative percentage" of the effect of administration and expressed as the percentage of residual activity (═ residual activity, i.e. activity administered minus activity excreted). For calculation of dose-response curves, excreted¹⁴Taurocholic acid is expressed as a percentage of the corresponding value of the control group (treated with vehicle). ED (electronic device)₂₀₀Is intended to cause excretion¹⁴The dose of C-bonded cholic acid increased to 200% of the control group, and ED was calculated from sigmoidal or linear dose response curves by interpolation₂₀₀. Calculated ED₂₀₀Is equivalent to makingFecal excretion of bile acids doubled the dose.

5) Results

Table 1 shows ED₂₀₀Measurement of excretion

Table 1:

the compounds of the examples (mixture of diastereomers)	ED200Excreted (mg/kg/day) orally
		1	0.009
2	0.008
		3	0.04
5	0.03
		6	0.04
7	0.04
		8	0.007
9	0.007
		10	0.04
3 (pure structure 11a)	0.008
		Comparative example
1	0.8
		2	1.0
3	0.9

6) Discussion of the related Art

From the measured data it can be concluded that the compounds of formula I according to the invention have a factor of 20 to 100 better effect than the compounds of the prior art.

The following examples serve to illustrate the invention in more detail, but without limiting the products and embodiments in example 1.

Example 1

C₃₀H₄₄N₂O₉S(608.76).MS(M+H)⁺＝609.3

Example 2

C₄₀H₅₄N₂O₁₄S(818.40)，MS(M+H)⁺＝819.3

Example 3

C₃₅H₅₅N₃O₉S(693.91).MS(M+H)⁺＝694.4

Example 4

C₃₇H₅₉N₃O₉S(721.96).MS(M+H)⁺＝722.3

Example 5

C₄₁H₆₅N₃O₁₀S(792.05).MS(M+H)⁺＝792.5

Example 6

C₄₂H₅₈N₂O₁₄S(846.97)，MS(M+H)⁺＝847.4

Example 7

C₃₂H₄₈N₂O₉S(636.80).MS(M+H)⁺＝637.4

Example 8

C₄₅H₆₃N₃O₁₅S(918.06).MS(M+H)⁺＝918.6

Example 9

C₃₅H₅₃N₃O₁₀S(707.88).MS(M+H)⁺＝708.4

Example 10

C₄₇H₆₇N₃O₁₅S(946.12).MS(M+H)⁺＝946.5

Comparative example from PCT/US 97/04076.

Comparative example 1

Comparative example 2

Comparative example 3

The inventive and comparative examples were prepared according to the following procedure (preparation giving only the synthesis of the α -diastereomer):

scheme 1:

scheme 2:

scheme 3:

synthesis of Compound 3 as a mixture of diastereomers

300mg (0.69mmol) of 1a/b (in analogy to PCT/US 97/04076) and 700mg (1.7mmol) of penta-O-acetyl-D-gluconic acid (volume 5, 887 from organic Synthesis) are dissolved in 10ml of DMF. 700mg (2.0mmol) of TOTU, 250mg (1.7mmol) of oxime (ethyl hydroxyiminocyanoacetate; Fluka) and 0.7ml (5.5mmol) of NEM are added successively. After 1 hour at room temperature, it was diluted with 100ml of ethyl acetate and washed 3 times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate/n-heptane 2: 1) to yield 502mg (88%) of 3a/b as an amorphous solid. DC (ethyl acetate/n-hexane 2: 1), R_r0.3. The product 3a/b was used as educt 1a/b in the same reaction, but with the difference that it was dyed with 2M sulfuric acid.

C₄₀H₅₄N₂O₁₄S(818.40)。MS(M+H)⁺＝819.3。

As diastereoisomersSynthesis of Compound 4 as a mixture of constructs

455mg (0.55mmol) of 3a/b were dissolved in 20ml of methanol. After addition of 0.3ml of a 1M solution of sodium methoxide in methanol, the mixture was allowed to stand at room temperature for 1 hour. It was then neutralized with HCl in methanol and concentrated. The residue was purified by flash chromatography (dichloromethane/methanol/concentrated aqueous ammonia 30/5/1) to yield 280mg (83%) of 4a/b as an amorphous solid. DC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.2。

C₃₀H₄₄N₂O₉S(608.76)。MS(M+H)⁺＝609.3。

Synthesis of Compound 11 as a mixture of diastereomers

77mg (0.013mmol) of 9a/b (prepared analogously to PCT/US 97/04076) are dissolved in 4ml of DMF. After addition of 150mg (0.082mmol) of 10 (glucosamine, Fluka), the mixture is heated at 80 ℃ for 2 hours. It was then diluted with 50ml of ethyl acetate and washed 3 times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The mixture was left at room temperature for 1 hour. It was then neutralized with HCl in methanol and concentrated. The residue was purified by flash chromatography (dichloromethane/methanol/concentrated aqueous ammonia 30/5/1) to yield 55mg (61%) of 11a/b as an amorphous solid. DC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.3。

C₃₅H₅₅N₃O₉S(693.91)。MS(M+H)⁺＝694.4。

Synthesis of Compound 14

8.0g (18.8mmol) of 12 (penta-O-acetyl-D-gluconoyl chloride; volume 5, 887, Organic Synthesis) are added to a suspension of 8.0g (40mmol) of 13(Fluka) in 150ml of anhydrous DMF. The suspension was stirred vigorously at room temperature for 20 hours. 500ml of ethyl acetate and 200ml of water are added. The aqueous phase is extracted with further 250ml of ethyl acetate. The combined organic phases were washed 3 times with sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Yield 9.5g of (86%) 14 as a colorless oil. DC (dichloromethane/methanol/concentrated ammonia 30/10/3), R_f＝0.8。

C₂₇H₄₃NO₁₃(589.64)。MS(M+H)⁺＝590.4。

Synthesis of Compound 15 as a mixture of diastereomers

200mg (0.34mmol) of 14, 78mg (0.18mmol) of 1a/b, 240mg of TOTU, 80mg of oxime and 0.3ml of NEM in 4ml of DMF are reacted in a similar manner to compound 4. After flash chromatography (dichloromethane/methanol/concentrated aqueous ammonia 30/5/1), 47mg (33% over 2 steps) of 15a/b were obtained as amorphous solid. DC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.2。

C₄₁H₆₅N₃O₁₀S(792.05)。MS(M+H)⁺＝792.5。

Claims (12)

1. A compound of formula I:

wherein the content of the first and second substances,

R¹is methyl, ethyl, propyl, butyl;

R²is OH;

R³is a monosaccharide radical, which is unsubstituted or mono-or polysubstituted with a sugar protecting group;

R⁴is methyl, ethylAlkyl, propyl, butyl;

R⁵is methyl, ethyl, propyl, butyl;

z is- (C ═ O)_n-C₀-C₁₆-alkyl, - (C ═ O)_n-C₀-C₁₆-alkyl-NH-, one covalent bond;

n is 0 or 1;

m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. A compound of formula I according to claim 1, wherein,

R¹is ethyl, propyl, butyl;

R²is OH;

R³is a monosaccharide radical which is unsubstituted or mono-or polysubstituted with a glycosyl protecting group;

R⁴is methyl, ethyl, propyl, butyl;

R⁵is methyl, ethyl, propyl, butyl;

z is- (C ═ O)_n-C₀-C₁₆-alkyl, - (C ═ O)_n-C₀-C₁₆-alkyl-NH-, one covalent bond;

n is 0 or 1;

m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

3. A compound of formula I according to claim 1 or 2, wherein,

R¹is ethyl, butyl;

R²is OH;

R³is a monosaccharide radical, optionally mono-or polysubstituted with a glycosyl protecting group;

R⁴is methyl;

R⁵is methyl;

z is- (C ═ O) -C₀-C₄-an alkyl group, one covalent bond;

or a pharmaceutically acceptable salt thereof.

4. A compound of formula I according to claim 1 or 2, wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

5. A compound of formula I according to claim 1 or 2, wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

6. A process for the preparation of one or more compounds of formula I according to claim 1, which process comprises, according to the following reaction scheme:

in which R is¹、R²、R⁴And R⁵Amines of the formula II having the meaning indicated in claim 1, formula I and where R³And Z has the meaning stated in claim 1, removing water to give the compound of the formula I, and optionally converting the compound of the formula I into a physiologically acceptable salt.

7. A medicament containing one or more compounds as claimed in claim 1.

8. A medicament containing one or more compounds as claimed in claim 1 and one or more statins.

9. A process for the preparation of a medicament containing one or more compounds as claimed in claim 1, which comprises mixing the active compound with pharmaceutically suitable excipients and bringing this mixture into a suitable administration form.

10. Use of one or more compounds according to claim 1 for the preparation of a medicament for the treatment of hyperlipidemia.

11. Use of one or more compounds according to claim 1 for the preparation of a medicament for affecting serum cholesterol levels.

12. Use of one or more compounds of claim 1 for the preparation of a medicament for the prevention of symptoms of arteriosclerosis.