Polyether derivatives, a method for their preparation and their use as pharmaceuticals.

The present invention relates to new polyether derivatives, several processes for their preparation and their use as medicaments, in particular as lipid absorption inhibitors.

It is already known that surface-active polyethers, which consist of propylene oxide and ethylene oxide units, have lipid absorption-inhibiting properties. Bochenek and Rodgers point out that non-ionic Pluronik polyols with a hydrophobic block of 90% (ie 90% propylene oxide) have lipid absorption-inhibiting effects, while the more hydrophilic polyethers from the same series have only a minor influence on lipid absorption (cf. Biochimica et Biophysica Acta, 489, (1977) 503-506). U.S. Patent 3,202,578 describes polyalkylene which can be used as a laxative.

In addition to the laxative effect, this patent also mentions an effect on lowering cholesterol in the blood. According to the statements in this patent specification, such polyoxyalkylenes are particularly suitable as cholesterol-lowering compounds which have a molecular weight of approximately 7,500 and contain 80% ethylene oxide.

The invention relates to polyether derivatives of the general formula (I)<chemistry id="chem0001" num="0001"><img file="EP0011237A1_D0001.tif" /></chemistry>in which<ul id="ul0001" list-style="none"><li>X in each case represents oxygen, sulfur, an NH or an N-alkyl group,</li><li>R represents alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or aralkyl, these groups ^GE are optionally substituted by nitro, cyano, azido, halogen, trifluoromethyl, trifluoromethoxy, phenyl, hydroxy, amino, alkyl, alkoxy, alkoxycarbonyl, acyloxy, acylamino, hydroxy, carboxy or S0₂-Alkyl and</li><li>a, b and c stand for integers which are chosen so that an average molecular weight of 3,000-5,000 results and that the propylene oxide portion (b) 60 to 80% and the ethylene oxide portion (a and c) 20-40 % is.</li></ul>

In the event that the substituent R contains a carboxy or amino group, the invention also relates to salts of these compounds which are formed either with bases or, in the case of the amino group, with acids in a manner known per se.

Of particular interest are compounds of the general formula (I) with an average molecular weight of approximately 4,000, a propylene oxide content of 70% and an ethylene oxide content of 30%.

Surprisingly, the polyether derivatives of the general formula (I) show a very strong li_Did absorption-inhibiting effect despite the low molecular weight and an ethylene oxide content of 20 to 40%.

The polyether derivatives of the general formula (I) according to the invention are obtained by<ul id="ul0002" list-style="none"><li>a) polyether of the general formula (II)<chemistry id="chem0002" num="0002"><img file="EP0011237A1_D0002.tif" /></chemistry>in which<ul id="ul0003" list-style="none"><li>a, b and c have the meaning given above, converted into the corresponding dialcoholate in an inert organic solvent in a manner known per se using sodium hydride, sodium amide or sodium alcoholate and then using a halide of the general formula (III)<chemistry id="chem0003" num="0003"><img file="EP0011237A1_D0003.tif" /></chemistry>in which</li><li>R¹ has the meaning given above and</li><li>Hal represents halogen, in particular bromine or chlorine,</li></ul>implements, or</li><li>b) the hydroxyl groups of the polyether of the general formula (II) into the halide of the general formula (IV) by known methods<chemistry id="chem0004" num="0004"><img file="EP0011237A1_D0004.tif" /></chemistry>in which<ul id="ul0004" list-style="none"><li>a, b, c and Hal have the meaning given above</li><li>and this halide then in the presence of a inert solvent in a manner known per se with an alcohol, mercaptan or amine of the general formula (V)<chemistry id="chem0005" num="0005"><img file="EP0011237A1_D0005.tif" /></chemistry>in which</li><li>R¹ and X have the meaning given above,</li></ul>implements.</li></ul>

If R is aryl and X is oxygen, process variant b) (reaction of IV with V) is a preferred embodiment.

If the polyether of the general formula (II), sodium hydride and ethyl bromoacetate is used, the reaction sequence according to variant a) can be represented by the following formula:<chemistry id="chem0006" num="0006"><img file="EP0011237A1_D0006.tif" /></chemistry>

Stranding

<chemistry id="chem0007" num="0007"><img file="EP0011237A1_D0007.tif" /></chemistry>

If the polyether of the general formula (II), thionyl bromide and the sodium salt of ethyl p-hydroxybenzoate are used as starting materials, the reaction sequence according to variant b) can be represented by the following formula:<chemistry id="chem0008" num="0008"><img file="EP0011237A1_D0008.tif" /></chemistry>

The polyethers of the general formula (II) to be used as starting materials are known or can be prepared by known methods (cf. US Pat. 3,674,619 and IR Schmolka in J. Am. Oil Chemists Soc. 54, No. 3, 110-16, 1977).

The halides of the general formula (III) to be used as starting materials are known or can be prepared by known methods (cf. Houben Weyl Vol. 5/3, pp. 830-838, 862-870 (1962); Vol. 5/4, Pp. 361-411, 610-628 (1960).

Examples include:<ul id="ul0005" list-style="none"><li>Methyl bromoacetate, ethyl bromoacetate, 2-Brombuttersäureäthylester, 4-bromobutyrate, 4-Bromcrotonsäureäthylester, 2-Bromisobuttersäureäthylester, 2-Brompropionsäureäthylester, 3-bromopropionate, 2-Bromvaleriansäureäthylester, 5-Bromvalerian-: iäureäthylester.</li></ul>

Polyether derivatives of the general formula (I) are of particular importance<ul id="ul0006" list-style="none"><li>in which</li><li>_Xrepresents oxygen, sulfur, -NH or N-alkyl (1-2 C atoms) and</li><li>_R¹represents alkyl having 1 to 10, in particular 1 to 8, carbon atoms, benzyl or a phenyl radical, where the alkyl radicals are optionally substituted by one or two optionally esterified carboxyl groups and the phenyl radical is optionally substituted by alkyl, alkoxy (each 1-4 C -Atoms), halogen, nitro or trifluoromethyl.</li></ul>

Compounds of the general formula (I) are very particularly<ul id="ul0007" list-style="none"><li>in which</li><li>X means oxygen and</li><li>R¹ represents alkyl having 1 to 4 carbon atoms, which is substituted by a carboxylic acid function.</li></ul>

The compounds of the invention have a narrow molecular weight distribution.

The compounds according to the invention are characterized and analyzed analytically by determining the molecular weight from the hydroxyl number. The ethylene oxide content is determined from the H-NMR spectrum.

The polyethers according to the invention surprisingly show very strong effects in the treatment of fat and carbohydrate metabolism disorders. In particular, they lower the elevated cholesterol in serum and tissue and at the same time reduce hypertriglyceridaemia. The compounds according to the invention are suitable for the treatment of hyperlipoproteinaemia, atherosclerosis, obesity and for the treatment of metabolic disorders triggered thereby.

It is extremely surprising that the polyethers according to the invention of the present application have such a pronounced hypolipidemic effect in this molecular weight range from 3 to 5000, in particular 4000, and the special propylene oxide / ethylene oxide ratio. Since the compounds according to the invention are at the same time very well tolerated in addition to this strong action, they represent an enrichment of the pharmaceutical industry.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the above formula or which consist of one or more compounds of the above formula, and processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, for example tablets, dragées, capsules, pills, suppositories and ampoules, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can contain, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Non-toxic, internal pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes may be mentioned as preferred pharmaceutical preparations.

Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, for example carboxymethyl cellulose, Alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol, glycerol monostearate, (h) adsorbents, for example kaolin and bentonite and (i) lubricants, for example talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) - (i).

The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as Embedding compounds such as polymer substances and waxes can be used.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C14 alcohol with C₁₆Fatty acid) or mixtures of these substances.

In addition to the active ingredient (s), solutions and emulsions can include the usual carriers, such as solvents, solubilizers and emulsifiers, for example Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glyceryl formaldehyde, fatty acid, fatty acid, fatty acid, fatty acid, fatty alcohol of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can include the customary carriers, such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methane hydroxide, bentonite, agar agar and tragacanth or mixtures of these contain.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.

The therapeutically active compounds should be present in the pharmaceutical preparations listed above in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95 percent by weight of the total mixture.

In addition to compounds of the above formula, the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.

The pharmaceutical preparations listed above are prepared in a customary manner by known methods, for example by mixing the active ingredient (s) with the carrier (s).

The present invention also includes the use of the compounds of the above formula and the use of pharmaceutical preparations which contain one or more compounds of the above formula in human and veterinary medicine for preventing, ameliorating and / or curing the above-mentioned diseases.

The active substances or the pharmaceutical preparations can be administered orally, parenterally, intraperitoneally and / or rectally, preferably orally.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) in amounts of about 0.05 to about 500, preferably 0.5 to 100 mg / kg body weight per 24 hours. , to be applied over 1 to 6 administrations, specifically before or / and during or / and after the meal. A single dose contains the active ingredient (s) preferably in amounts of about 0.1 to about 100 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval, within which the administration takes place. So it may be sufficient in some cases, with less than the above Amount of active ingredient to get by, while in other cases the amount of active ingredient mentioned above must be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.

Examples:

Example 1 (process variant a)

20 g of polyether with an average molecular weight of 4,000 (compound II) are reacted in 100 ml of tetrahydrofuran with 3 g of sodium hydride under nitrogen. After 1 hour, 2.6 g of ethyl bromoacetate are added and then refluxed for 14 hours. After the excess sodium hydride has decomposed, the reaction mixture is evaporated and chromatographed over neutral aluminum oxide with chloroform as the eluent. The eluate is evaporated. The residue shows no OH band in the IR spectrum but a CO band at 1710 cm^-1. After saponification of the ester groups with sodium hydroxide solution in ethanol, the polyether derivative according to the invention with two free carboxyl groups is obtained. n<maths id="math0001" num=""><img file="EP0011237A1_D0009.tif" /></maths>= 1,457₂; _CO at ₁₇₁₀ cm^-1. Example 2

20 g of the polyether used in Example 1 are reacted with 3 g of sodium hydride analogously to Example 1 and then 2.2 g of methyl iodide are added. The reaction mixture is purified by chromatography on neutral aluminum oxide. The IR spectrum of the dimethyl ether obtained and the polyether used no longer contains any OH band. n_D= 1,4561

Example 3

If the 3-bromopropionic acid ethyl ester is used instead of per ethyl acetate, analogously to Example 1, after saponification of the two ester groups, the propionic acid derivative of the polyether is obtained in an oily consistency with two free carboxyl groups. n<maths id="math0002" num=""><img file="EP0011237A1_D0010.tif" /></maths> = 1,45₇₀.

Example 4

If, instead of ethyl bromoacetate, the 2-bromovaleric acid ethyl ester is obtained, analogously to Example 1, after saponification of the ester groups, the corresponding polyether derivative is obtained in an oily form. n<maths id="math0003" num=""><img file="EP0011237A1_D0011.tif" /></maths> = 1,4570.

Example 5

If, instead of methyl iodide, the alkylating agent ethyl iodide is used, analogously to Example 2, the corresponding diethyl ether derivative of the polyether used, which no longer has an OH band, is obtained in an oily form. n<maths id="math0004" num=""><img file="EP0011237A1_D0012.tif" /></maths> = 1,4563.

Example 6

By using octyl iodide, the corresponding octyl ether is obtained in an oily form analogously to Example 2. n<maths id="math0005" num=""><img file="EP0011237A1_D0013.tif" /></maths> = ₁,45₆5.

Example 7

By using benzyl bromide, analogously to Example 2, the corresponding benzyl ether is obtained in an oily form. n<maths id="math0006" num=""><img file="EP0011237A1_D0014.tif" /></maths> = 1,4569.

Example (variant b)

80 g polyether according to claim 1 are reacted with 5 ml of thionyl bromide. After chromatographic separation over aluminum oxide, 40 g of polyether dibromide are obtained, to which 3 g of sodium hydroxide and 2.4 ml of ethyl thioessiaate are added in 100 ml of ethanol. After a reaction of 4 hours at 80 ° C., the corresponding thioether from Essi is obtained^Gacid ethyl ester.

Sulfur content approx. 1.6%; found 1.7%. n<maths id="math0007" num=""><img file="EP0011237A1_D0015.tif" /></maths> = 1,4702

Examples 9 to 16

If the reaction is carried out analogously to Example 9 and the following thioalcohols are used instead of methyl thioacetate, the corresponding thioethers of the polyether (average MW 4000) are retained after the analogous working conditions of Example 9.<tables id="tabl0001" num="0001"><img file="EP0011237A1_D0016.tif" /></tables>

36 Halide IV (Hal = Br) are mixed with 1 liter of ethanol saturated with ammonia and left to stand for 7 days at room temperature. The alcohol is then stripped off and the reaction mixture is chromatographed on neutral aluminum oxide using petroleum ether / benzene (1: 1). IR: -NH₂ st 3200-3300 n_D²⁰ = 1.4605 nitrogen content calc. 0.7 % found. 1.0%

Examples 18-22

If the following amine compounds are used instead of ammonia in Example 18, the corresponding amine derivatives of the polyether are obtained by the procedure of Example 18.<tables id="tabl0002" num="0002"><img file="EP0011237A1_D0017.tif" /></tables>