DE4136325A1 - New cyclodextrin derivs. used as bile acid adsorption agents - useful for treating hyperlipidaemia, can be administered at lower does than cholestyramine or colestipol resin - Google Patents

Abstract

Cyclodextrin derivs. of formula (I) are new. Where R1 = OH; a 6-30C fatty acid bonded via a carboxy gp.; 6-30C alcohol bonded via the alcohol function; an amino acid bonded via the carboxy gp.; bile acid bonded via a 2-12C alkyl or alkoxy gp. in position 3; and/or X-A-N(R3)R4; X = O or OC(=O)-; A = 2-15 (pref. 2-8C) alkylene, alkenylene or alkynylene (pref. branched); R3, R4 = H or 1-6C alkyl; pref. 1-3C alkyl; R2 = CH2R1 or C(=O)YAB; Y = O or NH; B = H, NH2, a bile acid bonded via position 3 or a mono-or di(1-3C alkyl) amino; and n = 6-8. Also claimed is a conjugate contg. (I) and a bile acid. (I) has a mol. wt. of 600-2000. The conjugate has a substitution percent DS of 0.01-1 pref. 0.3-0. USE/ADVANTAGE - (I) are bile acid adsorption agents useful for treating hyperlipidaemia. They are administered at lower doses than cholestyramine or cholesterol resin, e.g. 0.5-10 g/kg/day. The conjugate can be used in food and fruit juice. They can be used to treat blood plasma, serum, urine or bile.

Description

The invention relates to water-soluble and insoluble cyclodextrin derivatives, Cyclodextrin derivatives loaded with bile acids; a process for their Production and their use as medicines.

Bile acids have an important physiological function in fat digestion, e.g. B. as cofactors of pancreatic lipases. As the end product of Cholesterol metabolism, they are synthesized in the liver, in the gallbladder stored and released from this by contraction in the small intestine, where they develop their physiological effect.

The majority of the secreted bile acids is via the enterohepatic Circulation regained, via the mesenteric veins of the small intestine and the portal vein system they return to the liver. With reabsorption Both active and passive transport processes play a role in the intestine. in the enterohepatic circulation occurs both as free acids, but the bile acids also in the form of glycine and taurine conjugates.

So far it is known to bile acid to non-absorbable, insoluble, basic to bind cross-linked polymers (ion exchange resins = "Resins"). As All diseases in which an inhibition of the Bile acid reabsorption in the intestine, especially in the small intestine, is desirable appears, viewed. For example, the chologic diarrhea after Ileum resection, or even increased cholesterol blood levels in this way treated. In the event of elevated cholesterol blood levels, the procedure may result  a lowering of this level can be achieved in the enterohepatic circulation. By lowering the bile acid pool in the enterohepatic cycle is the corresponding new synthesis of bile acids from cholesterol in the Liver forced. To cover the cholesterol requirement in the liver, the LDL cholesterol (low density lipoprotein) in the bloodstream resorted to, the hepatic LDL receptors in increased numbers for Come into effect. The resulting acceleration of LDL catabolism has an effect by reducing the amount of atherogenic cholesterol in the blood. So far presented these polymeric, insoluble ion exchange resins is the only way to increase the enterohepatic circulation Bile acid excretion and consequent lowering of cholesterol to influence.

It has now been found that the medicinal products based on crosslinked ion exchange resins based, have various disadvantages.

For the "Resins" used as medicinal products, it is particularly important to maintain a very high daily dose. It is z. B. for colestyramine (contains quaternary ammonium groups) 12-24 g, maximum dose 32 g, for colestipol (contains secondary or tertiary amino groups) 15-30 g.

Another disadvantage is that taste, smell and the said high Dosage complicate patient compliance.

It is also known that conventional "resins" have side effects. These Side effects are due to a lack of selectivity (e.g. avitaminoses) also be taken into account when dosing medications given simultaneously need, but also on bile acid depletion, the various gastrointestinal Cause disorders (constipation, steatorrhea) of various degrees.  

Combination with other hypolipidemic drugs such as fibrates, HMG-CoA reductase Inhibitors, probucol (see, e.g., M.N. Cayen, Pharmac. Ther. 29, 187 (1985) and 8th International Symposium on Atherosclerosis, Rome, Oct. 9-13, 1988, abstracts S. 544, 608, 710), the effects achieved also the therapy of allow severe hyperlipidemia. Therefore, it seems significant Given the active principle, suitable substances without the disadvantages of Find currently used preparations. The following features of the above Preparations and especially Colestipol are in need of improvement to watch:

• 1. The high daily doses that are necessary because only a relatively low one Binding rate at neutral pH in isotonic medium, as well as (partially) Re-release of the adsorbed bile acids.
• 2. The qualitative shift in the bile acid composition of the bile with decreasing tendency for chenodeoxycholic acid and the related increasing risk of cholelithiasis.
• 3. The lack of a depressant effect on the cholesterol metabolism Intestinal bacteria.
• 4. The too high binding rate of vitamins and pharmaceuticals makes you Substitution needs for these substances and blood level checks may be necessary necessary.
• 5. The pharmaceutical form has so far been considered inadequate.

The object of the invention was to create a way in bile acids to bind in a concentration-dependent manner, the bile acid-binding Compounds themselves are not resorbed and therefore not in the enterohepatic circulation. The connections should also be high  Have binding rate for bile acids at neutral pH and at the same time ensure that these do not reappear under physiological conditions are released and therefore cannot be reabsorbed.

In addition, these connections are said to address the existing drawbacks of known "Resins" do not have or no longer to the known extent.

The solution to the problem is to provide cyclodextrin derivatives general formula I.

wherein
R ₁ OH, a saturated or unsaturated natural or synthetic fatty acid with 6-30 C atoms bound via its carboxy group, an alcohol with 6-30 C atoms bound via its alcohol function, a natural amino acid bound via its carboxy group, one via its carboxy group bound synthetic amino acid, a bile acid bound via an alkyl radical or alkoxy radical with 2-12 C atoms at position 3 and / or an aminoalkyl radical of the general formula II

-X-A-N (R₃) R₄ (II)

means what

where the carbonyl functions are not adjacent to the cyclodextrin residue,
A is an alkylene, alkenylene or alkynylene radical having 2 to 15, preferably 2 to 8 C atoms, which is branched or straight-chain, preferably straight-chain,
R ₃ , R _{4 are} identical or different and are H or (C ₁ -C ₆ ) alkyl, preferably (C ₁ -C ₃ ) alkyl,

means what
Y stands for -O- or -NH-,
A has the meaning already mentioned and
BH, NH ₂ , an amino group mono- or dialkylated with (C ₁ -C ₃ ) -alkyl or a bile acid bonded via position 3, and
n means 6,7 or 8.

The radicals R mentioned can be present side by side in the cyclodextrin.

However, it is preferred that only one type of substituent is preferred, e.g. B. only amino acids, including the residues of formula II or the fatty acids and / or the alcohols. It is particularly preferred that the amino acids and the radicals of the formula II are not present side by side cyclodextrin polymers.

The compounds according to the invention generally have a molecular weight from 600 to 2000.  

The degree of substitution of the radicals R to be achieved, based on a glucose unit in cyclodextrin, depends on the radical R used and on the selected one Reaction conditions. Finally, it is set in such a way that one too pharmacological effect of the compounds according to the invention is optimally achieved.

In general, the degree of substitution DS is between 0.2 and 1.0, preferably between 0.3 and 1.0.

The derivatization of cyclodextrin with natural or synthetic Amino acids or the conversion to compounds with the residues of formula II leads to cationization of the cyclodextrin. Of the amino acids are here especially preferred the basic amino acids.

If derivatization is carried out with fatty acids or alcohols, one is achieved Lipophilization.

In both cases, the derivatization leads to increased bile acids and particularly at a physiological pH fixed to the cyclodextrin be bound adsorptively. This is a bond made up of an ionic and a structural interaction between the Bile acid molecule and the cyclodextrin derivative.

Bile acids are ionized or protonated at a physiological pH in front. In this respect there is an ionic interaction. The structural Interaction is based on the fact that bile acids from the lipophilized cyclodextrin be spatially surrounded. It is therefore inclusion compounds.

In principle, it is therefore possible to both ionize the cyclodextrins (Amino acid, aminoalkoxy residues) how to lipophilize (fatty acids, alcohols), where the adsorptive effects can increase. It is also possible  Use bile acids as derivatization reagents for cyclodextrins, and the To use derivatives as adsorbers for bile acids.

In this case, the degree of substitution for the covalently bound bile acids 0.01 to 1, preferably 0.3 to 0.8.

The following are mentioned as natural amino acids; Glycine, L-alanine, L-valine, L-leucine, L-serine, L-threonine, L-lysine, L-arginine, L- Asparagine, L-glutamine, L-phenylalanine, L-tyrosine, L-proline, L-tryptophan.

Mixtures of natural and natural enantiomers are used as synthetic amino acids Amino acids, homoamino acids, isoamino acids, γ-aminobutyric acid, α- Aminobutyric acid etc. preferred.

Suitable fatty acids are saturated and unsaturated, straight-chain or branched carboxylic acids such as Capron, heptane, octane, decane, dodecane, Tetradecanoic, hexadecanoic, octadecanoic acid, oleic acid, linoleic acid, linolenic acid, 2- Methylhexanoic acid, u. Ä.

Also compatible are aromatic carboxylic acid residues, such as. B. cinnamic acid or di- Hydrocinnamic acid can be used.

The following of the alcohols are used for lipophilization: saturated and unsaturated linear or branched alcohols such as hexanol, octanol, Decanol, dodecanol, tetradecanol, hexadecanol, octadecanol, and the like. a. Likewise are also to be understood as meaning those which can carry further OH groups, such as about 1,2-hexanediol, 1,2-dodecanediol or 1,2-hexadecanediol.

The following aminoalkyl radicals of the formula XAN (R ₃ ) R ₄ are used: 2-aminoethanol, 3-aminopropanol, N, N-dimethyl- or -diethyl-2-aminoethanol, N, N-dimethyl- or -diethyl-3-aminopropanol, 4-aminobutanol, 6-aminohexanol, 4-aminobutyric acid, 6-aminocaproic acid, etc. The following bile acids can be bound to the cyclodextrins according to the invention: cholic acid, deoxycholic acid, lithocholic acid, ursodeoxycholic acid, chenodeoxycholic acid, and their corresponding taurine and glycine conjugates.

By using the compounds according to the invention, the described deficiencies of those on the market in the enterohepatic Circulatory "Resins" are completely eliminated. By inhibiting the Bile acid reabsorption with the aid of the compounds according to the invention in The small intestine becomes effectively in the enterohepatic circulation located bile acid concentration reduced, so that a decrease in Cholesterol level in the serum. Avitaminoses are when using the Compounds according to the invention are then no more present than the Influencing the absorption of other drugs or the negative effect on the intestinal flora, since the bile acid binding to the invention Connections is extremely stable.

By using the compounds according to the invention, the otherwise customary Dosage of the resins can be significantly reduced, the recommended dose is 0.5 10 g / kg / day. The known side effects (constipation, steratorrhoe) are therefore not been observed d. H. the natural digestion of fat Origin of the polyaspartamides on the one hand and due to the known positive The influence of so-called fiber on the digestion, on the other hand, will not negatively influenced.

Because of the high affinity of the compounds according to the invention for bile acids compared to the high daily dose of "Resins", the problem of Dosage and therefore no longer compliance. In addition, the Compliance improved in that the cyclodextrins according to the invention are water-soluble and therefore no surcharges such as B. Flavor improvers, emulsifiers, sweeteners etc. are required.  

Compounds of the general formula I can be essentially subtracted establish known methods. The esterification of Polysaccharides with fatty acids or N-protected amino acids after activation the carboxylic acid with carbonyldiimidazole (C.H. BAMFORD, I.P. MIDDLETON, K.G. AL-LAMEE, Polymer 27, 1981 (1986)) in good yields under mild Conditions. The reaction of the polysaccharide in is suitable for the alkylation DMSO solution with alkyl bromides and iodides under the action of strong bases such as Sodium hydride or potassium hydroxide (J. S. BRIMACOMBE Meth. Carbohydr. Chem. Vol. VI, 376 (1972)). The corresponding implementation is carried out analogously Cholic acid tosylates in which the tosyl group is located at position 3 on a spacer bound acts as a leaving group, to covalently linked cholic acid Cyclodextrin conjugates.

Amino groups can be obtained by reacting N-containing alkyl halides such as N-2- Chlorethyl-N, N-diethylamine with dextrans (R.W. HOLLEY, J. Am. Chem. Soc. 83, 4861 (1961)), reaction with aminoepoxides such as 1,2-epoxypropyldiethylamine, Addition of acrylonitrile to polysaccharides and subsequent reduction (J. COMPTON Meth. Carbohydr. Chem. Vol III, 317 (1963) or after splitting off the Release N-protecting group from amino acid esterified cyclodextrins.

Compounds with the following radicals R were according to the above Regulation produced.

• 1) Natural amino acids: L-serine, L-alanine, L-arginine, L-lysine, L-valine.
• 2) synthetic amino acids: D, L mixtures of all (natural) amino acids, Ornithine, homo-serine, homo-alanine, iso-serine, γ-aminobutyric acid, α- Aminobutyric acid.
• 3) fatty acids: caproic acid, capric acid, caprylic acid, lauric acid, Stearic acid, oleic acid, linoleic acid, linolenic acid.  
• 4) Alcohols: butanol, hexanol, octanol, decanol, dodecanol, hexadecanol, 2- Hydroxyhexanol, 2-hydroxydodecanol.
• 5) aminoalkyl radicals of the formula II in which the following applies:

The degree of substitution is 0.1-1.0, preferably 0.3-0.8.

The invention further relates to a conjugate from the invention derivatized cyclodextrin derivative and at least one bile acid resulting as a result a structural interaction adsorptive to the derivatized Cyclodextrin derivative is bound.

The invention further relates to the use of the conjugates according to the invention for the manufacture of a drug. The connections can be solved or suspended in pharmacologically acceptable organic solvents, such as mono- or polyhydric alcohols such as B. ethanol or glycerin, in triacetin, Oils such as B. sunflower oil, cod liver oil, ethers, such as. B.  Diethylene glycol dimethyl ether or polyethers such. B. polyethylene glycol, or also in the presence of other pharmacologically acceptable polymer carriers, such as. B. Polyvinyl pyrrolidone or other pharmaceutically acceptable additives such as starch, cyclodextrin or polysaccharides. Furthermore, the Compounds according to the invention in combination with other drugs are given.

The conjugates according to the invention are in various dosage forms administered, preferably orally in the form of tablets, capsules or liquids, such as B. also food or fruit juices.

The conjugates of derivatized cyclodextrin and Bile acids can be used as medicines, especially for Inhibition of bile acid reabsorption in the intestine and as a hypolipidemic.

The derivatized cyclodextrins according to the invention can also be used in analytical Process for group-selective enrichment of bile acids from biological Liquids such as As plasma, serum, urine, bile, etc. can be used.

Determination of adsorber capacity

For in vitro testing of the absorber capacity of the compounds according to the invention the following bile acids: 15.1 mg cholic acid, 13.8 mg deoxycholic acid, 13.8 mg chenodeoxycholic acid, 13.2 mg lithocholic acid, 17.1 mg glycocholic acid, 15.8 mg glycodeoxycholic acid, 16.6 mg glycochenodeoxycholic acid and 16.0 mg Glycolithocholic acid dissolved in 700 ul methanol, with 0.92 ml phosphate buffered Saline solution (pH 7.2) added and together with 5 mg of the invention Connections incubated for 24 h at 37 ° C in a shaking water bath. After that the Mix in a dialysis tube of the type Visking filled and 72 h at Dialyzed room temperature against phosphate-buffered saline (pH 7.2). The Bile acid binding is determined by analysis of the external medium, e.g. B. by the methods described below.  

1) HPLC with fluorescence detection

Devices: HPLC system from Kontron, consisting of three pumps and mixing chamber, autosampler, UV detector and evaluation unit with software MT2. Fluorescence detector from Merck and Hitachi. Since the samples are sensitive to light and temperature, the autosampler is cooled to approx. 5 ° C.
Mobile phase:
Solvent A: Millipore water (own plant)
Mobile phase B: acetonitrile / methanol 60:30
Column: Li Chrospher 100 RP-18, 25 mm, 5 µm, from Merck
Guard column: LiChrospher 60 RP-select B, 4 mm, 5 µm, from Merck
Flow rate: 1.3 ml / min
Detection:
Excitation: 340 nm
Emission: 410 nm
Gradient:
0.00 min 66% B
7.50 min 66% B
8.00 min 76% B
12.50 min 76% B
13.00 min 83% B
25.00 min 83% B
25.50 min 91% B
40.00 min 91% B

2) Enzymatic determination of total bile acid

- 900 µl of the following mixture are added to Eppendorf tubes: 6 ml tetra sodium diphosphate buffer 0.1 M, pH 8.9 2 ml NAD solution (4 mg / ml water) 20 ml of Millipore water

• - 30 µl of the sample and 30 µl enzyme solution are pipetted into it.
• - Enzyme solution: 3-alpha-hydroxysteroid dehydrogenase 0.5 units / ml  
• - The batches are mixed and incubated for 2 h at room temperature. Then transfer to 1 ml disposable cuvettes and measure in the photometer at 340 nm.
• - Only partially suitable for bile acid samples, because the green color is disturbing.

3) HPLC with UV detection

Devices: HPLC system from Kontron, consisting of three pumps and mixing chamber, autosampler, UV detector and evaluation unit with software MT2.
Mobile phase: mobile phase A: ammonium carbamate buffer 0.019 M, adjusted to pH 4.0 with phosphoric acid.
Solvent B: acetonitrile
Column: LiChrospher 100 RP-8, 25 mm, 5 µm, from Merck
Guard column: LiChrospher 60 RP-select B, 4 mm, 5 µm, from Merck
Flow rate: gradient:
0.00 min 0.8 ml / min
20.00 min 0.8 ml / min
23.00 min 1.3 ml / min
51.00 min 1.3 ml / min
Detection: 200 nm (for preparations additionally at 254 nm)
Gradient:
0.00 min 32% B
8.00 min 35% B
17.00 min 38% B
20.00 min 40% B
24.00 min 40% B
30.00 min 50% B
45.00 min 60% B

The following results could be obtained. They are summarized in Table 1. Table 1 shows the adsorption properties of the cyclodextrin derivatives according to the invention with respect to:
GC glycolic acid
GCDC Glycochenodeoxycholic Acid
GDC glycodeoxycholic acid
GLC glycolithocholic acid.

example 1 Heptakis [6- (3-dimethylaminopropyl) amino-6-deoxy-β-cyclodextrin

8 g (3.6 mmol) of heptakis-6-O-tosyl-β-cyclodextrin are dissolved in 36 ml (29 g, 288 mmol) of 3-dimethylaminopropylamine and boiled under reflux for 24 hours (133 ° C.). The solution is then poured into 200 g of a strongly basic ion exchanger, concentrated, taken up in water and again passed through an ion exchanger loaded with chloride. The solution is concentrated and freeze-dried.
Yield: 4.26 g
According to ¹ H-NMR, the toxyl signals have completely disappeared and have been replaced by the dimethylaminopropyl absorptions.

Example 2 β-cyclodextrin L-lysine ester

According to Example 1, 5.5 g (13.2 mmol) of N _α -N _w -bis-ZL-lysine are activated with 2.14 g (13.2 mmol) of CDI and then with 5 g (4.4 mmol) of β -Cyclodextrin and 100 mg DMAP implemented.

After working up, hydrogenation and ultrafiltration, 6.3 g of the product are obtained as white, amorphous powder.

Degree of acylation: approx. 2.5 lysine residues per β-cyclodextrin ring (according to ¹³ C-NMR)
Analysis: C 49.2%, H 7.85%, N 9.80%

Example 3 β-Cyclodextrin (6-aminocaproic acid) ester

4.1 g (15.4 mmol) of 6-NZ-aminocaproic acid in 100 ml of DMSO abs. stirred with 2.5 g (15.4 mmol) carbonylimidazole (CDI) at 50 ° C for 1 h and then mixed with a solution of 5 g (4.4 mmol) β-cyclodextrin in 150 ml DMSO and 100 mg dimethylamine pyridine. The mixture is stirred at 50 ° C. for 2 h and then concentrated. The crude product is dissolved in ethyl acetate, washed with dil. HCl and water, dried over MgSO ₄ and concentrated.

The residue is dissolved in 100 ml of THF, 0.5 ml of conc. HCl and 0.5 g palladium / 10% on activated carbon and hydrogenated for 24 h at room temperature. After filtration from the catalyst, the solution is concentrated, taken up in water and filtered through a membrane with an exclusion limit of 1000 D. The retentate is freeze-dried.
Yield: 4.9 g
Degree of acylation approx. 3 aminocaproic acid residues (according to NMR) per cyclodextrin ring.

Example 4 β-cyclodextrin arginine ester

In 10 ml of anhydrous DMSO, 2.9 g (5 mmol) of Na-NN-Tri-ZL-arginine are stirred with 0.81 g (5 mmol) of N, N′-carbonyldiimidazole at room temperature for 1 h and then 0.81 g ( 0.7 mmol) β-cyclodextrin added. After 5 h, the solution is concentrated, the residue is taken up in ethyl acetate and the solution is washed twice with dilute hydrochloric acid and NaCl solution. The product is obtained as a syrup after drying with magnesium sulfate and concentration. To split off the Z groups, the compound is dissolved in 50 ml of THF, 3 ml of hydrochloric acid (30%) and 1 g of palladium / activated carbon (10%) are added and the mixture is hydrogenated with vigorous stirring for 48 h. The catalyst is then filtered off, the solution is concentrated in vacuo and the residue is then freeze-dried.
Yield: 1.5 g

Example 5 Hexadecanoyl-β-cyclodextrin (β-cyclodextrin palmitic acid ester)

6.7 g (26 mmol) of palmitic acid are dissolved in 150 ml of DMSO and a total of 4.5 g (30 mmol) of N, N′-carbonyldiimidazole are added in portions at 50 ° C. after the CO ₂ evolution has subsided, the mixture is stirred for a further 1 h at 50 ° C and then adds a solution of 10 g (8.8 mmol) β-cyclodextrin in 150 ml DMSO and 500 mg N, N-dimethylaminopyridine. The mixture is stirred at 50 ° C. for 2 h and then concentrated in vacuo. The residue is taken up in water, ultrafiltered through a membrane with a connection limit of 3000 D and freeze-dried.
Yield: 7.2 g as an amorphous powder.

The last traces of free palmitic acid are obtained by extracting the solid product removed with ether.

According to ¹ H-NMR and ¹³ C-NMR, the product has a degree of substitution of 0.4 palmitic acids per glucose unit.
Analysis:
calc .: C 68.32%, H 9.26%
found: C 67.99%, H 9.41%

Example 6

6- (3-Dimethylamino-propylamido) -6-carboxy-β-cyclodextrin or β-cyclodextrin-6-carboxylic acid- (3-dimethylamino) propylenamide 2 g (1.6 mmol) of oxidized β-cyclodextrin (2.7 carboxyl groups each Cyclodextrin ring) are stirred in 10 ml of water with 11.5 g (110 mmol) of 3-dimethylaminopropylamine and 1.2 g (6 mmol) of EDCI (N-ethyl-N'-dimethylaminopropyl-carbodiimide) for 12 h at room temperature. The solution is then concentrated, the residue is dissolved in water and ultrafiltered through a membrane with an exclusion limit of 1000 D. The retentate is freeze-dried.
Yield: 1.2 g as a beige, amorphous powder
Analysis: C 44.15%, H 6.95%, N 5.9%

In vivo studies

The in vivo investigations were carried out as in FGJ Poelma et al. (J. Pharm. Sci. 78 (4), 285-89, 1989) with some modifications. The compounds according to the invention were instilled into the intestinal segment together with 10 mM taurocholate, with ³ H-taurocholate or ¹⁴ C-taurocholate and the perfusion solution was pumped around for 2 hours using a peristaltic pump. The decrease in the tracer in the intestine or the appearance of the tracer in the bile was determined using scintillation measurements. The results are shown in diagram 1.

Claims (13)

1. Cyclodextrin derivatives of the general formula I wherein
R ₁ OH, a saturated or unsaturated natural or synthetic fatty acid with 6-30 C atoms bound via its carboxy group,
an alcohol with 6-30 C atoms bound via its alcohol function,
a natural amino acid bound via its carboxy group,
a synthetic amino acid bound via its carboxy group,
a bile acid bonded via an alkyl radical or alkoxy radical with 2-12 C atoms at position 3
and or
is an aminoalkyl radical of the general formula II-XAN (N₃) R₄ (II), wherein A is an alkylene, alkenylene or alkynylene radical having 2 to 15, preferably 2 to 8 C atoms, which is branched or straight-chain, preferably straight-chain,
R ₃ , R _{4 are} identical or different and are H or (C ₁ -C ₆ ) alkyl, preferably (C ₁ -C ₃ ) alkyl, means what
Y stands for -O- or -NH-,
A has the meaning already mentioned and
BH, NH ₂ , an amino group mono- or dialkylated with (C ₁ -C ₃ ) -alkyl or a bile acid bonded via position 3, and
n means 6, 7 or 8. 2. Compounds according to claim 1, characterized in that only one type a substituent, in addition the radicals of the formula II and / or an alcohol, is included. 3. Compounds according to claims 1 or 2, characterized in that this type corresponds to the amino acids. 4. Compounds according to claims 1 or 2, characterized in that the amino acids and the residues of formula II do not coexist in the cyclodextrin available. 5. Compounds according to claims 1 to 4, characterized in that they have a molecular weight of 600 to 2000.   6. Compounds according to claims 1 to 5, characterized in that they have a degree of substitution DS between 0.2 and 1.0, preferably between 0.3 and 1.0. 7. conjugates consisting of a compound according to claims 1 to 6 and at least one bile acid. 8. Conjugates according to claim 7, characterized in that the Degree of substitution DS is 0.01 to 1, preferably 0.3 to 0.8. 9. Medicament containing a conjugate according to claims 7 and 8 and a carrier. 10. A method for producing a medicament, characterized in that converting a medicament according to claim 9 into a suitable dosage form. 11. Use of the conjugates according to claim 7 or 8 as a hypolipidemic. 12. Use of the conjugates according to claim 7 or 8 in foods and Fruit juices. 13. Use of the compounds according to claims 1 to 6 for Group-selective enrichment of bile acids from biological liquids.