DE102007051338A1 - Use of substituted glycerin derivatives for producing pharmaceutical preparation to prevent or treat isolated and/or combined dyslipidemia, hypertriglyceridemia and/or hypercholesterolemia, and for treating e.g. Parkinson's disease - Google Patents

Abstract

Use of substituted glycerin derivatives (I) or their salts for producing a pharmaceutical preparation to prevent or treat isolated and/or combined dyslipidemia, hypertriglyceridemia and/or hypercholesterolemia, is claimed. Use of substituted glycerin derivatives of formula (R5-C(R4)(-B6-R6)-C(R3)(-B7-R7)-C(R2)(-B8-R8)-R1) (I) or their salts for producing a pharmaceutical preparation to prevent or treat isolated and/or combined dyslipidemia, hypertriglyceridemia and/or hypercholesterolemia, is claimed. B6-B8 : O, S, NH, PO 4, Se, SO 4, preferably B6-R6, B7-R7 and/or B8-R8 is a phosphocholine derivative, which is a phosphatidylethanolamine, a phosphatidylserine and/or a phosphatidylinositol residue; R1 : H or 6-26C-alkyl chain or 20C-alkyl chain, preferably lecithin or cephalin residue; R2-R5 : H or 1-3C alkyl, alkanol, alkyl amine and/or alkyl thiol (where at least two of R2-R5 can jointly forms a polyol residue); R6-R8 : H or optionally substituted 6-26C-alkyl residue, a glycoside residue, a positively or negatively charged amino acid residue or -(CH 2)-N +>(R9, R10, R11); R9-R11 : methyl-, ethyl- and/or propyl residue; and n : 1-5, preferably 1-3. An independent claim is included for the pharmaceutical preparation comprising (I) and a carrier. ACTIVITY : Antilipemic; Hemostatic; Antiinflammatory; Hepatotropic; Antiparkinsonian; Cytostatic; Antiarteriosclerotic; Antidote. MECHANISM OF ACTION : None given.

Description

The The invention relates to the use of substituted glycerol derivatives or pharmaceutically acceptable salts of these compounds, for Preparation of a pharmaceutical preparation for the treatment and for the prevention of dyslipidaemias.

In the not pre-published PCT / DE2007 / 000767 describes the use of substituted glycerol derivatives and their pharmaceutically acceptable salts for the preparation of a pharmaceutical preparation, inter alia for the treatment of alcohol-induced fatty liver hepatitis or alcoholic steato-hepatitis, Parkinson's disease and as an antitumor agent or for reperfusion damage atherosclerosis or as an antidote as environmental toxins ,

Müller-Enoch et al. describe in Z. Naturforsch. (2001) 56c, pages 1082-1090 the inhibition of rat cytochrome P450 2B1 by means of lysophosphatidylcholines, lysophosphatidylinositol and arachidonic and oleic acids or by means of monoacylglycerols, monooleylglycerols, and monopalmitoylglycerols.

Furthermore, from T. Haehner, D. Muller-Enoch et al. in Z. Naturforschung (2004) 59c, page 599-605 describe the influence of single-chain lipid molecules on the activity of the cytochrome P 450 2B1 isoform of the rat.

task the present invention is means for producing a to provide pharmaceutical preparation for prevention or treatment of hyperlipidemias.

These Task is with a connection according to the in meets the requirements defined features.

It namely, it was surprisingly found that to treat the aforementioned diseases with such compounds to let.

there It has been found that by the administration of the invention used Substances the concentration of serum lipids such. The triglycerides, the HDL or LDL cholesterol and the VLDL significantly improved can be. This is especially true in dyslipidemias to, both in isolated or combined dyslipidemias such as hypertriglyceridemias and hypercholesterolemias. It was also found that especially by a prophylactic Administration of these substances will damage the serum levels of the vessel Lipids can be improved. It was also found that by the administration of these substances, for example the triglycerides, compared to a control group to a normal reference value the HDL, the so-called "good" cholesterol, even slightly increased, and the LDL as well as VLDL, so the "bad" cholesterol is reduced. Without thinking of this interpretation Being bound by these results is believed to be the substances according to the invention by the Lecithin-cholesterol-acyl-transferase (LCAT) mediated uptake promote serum cholesterol. The inven tion proper Effect also occurs in liver diseases such as NASH, ASH and others, e.g. As viral liver diseases such as hepatitis, caused dyslipidaemias.

auf. Ebenso kann es sich übrigens um pharmazeutisch akzeptable Salze dieser Verbindungen handeln.The compounds of the invention have the formula

on. Incidentally, they may also be pharmaceutically acceptable salts of these compounds.

The radicals R ₁ / R ₆ / R ₇ / R ₈ can in principle assume the form RX. In this case, R is an aliphatic or aromatic hydrocarbon radical preferably having 6 to 40 carbon atoms, which has a particularly terminal, hydrophilic radical A and X is a, at least one free carbon or heteroelectrene pair and / or Π-electron-containing radical. The radical R is especially lipophilic.

Usually the radical R is an alkyl radical. So it can be straight-chain or branched be, have single, double or triple bonds and substituted be. It usually has an aliphatic backbone 6 to 26, in particular 8 to 22 carbon atoms. expedient are carbon hydrogen chains with a backbone of 10 to 15, in particular 10 to 13 carbon atoms. R is an alicyclic or aromatic hydrocarbon radical which condenses and / or may be substituted by lipophilic, it usually has at least 5 or 6 and at most 40 or at most 25 carbon atoms on. Further functional minimum lengths are 7 or 8 carbon atoms and other functional Maximum lengths are 22 or 20 C atoms.

expedient X radicals are heterocycles, and alkynyl radicals. The heterocycles are in particular nitrogen, oxygen and / or sulfur-containing Heterocycles. The heterocycles may be aromatic and / or not aromatic and usually have 5 or 6 Ring atoms on. In appropriate cases, X can also be a condensed one Be heterocycle. Examples of such heterocycles are imidazole, Pyrrole, pyrazole, pyridine, pyrazine, indole, isoindole, indazole. preferred Heterocycles are 6 and in particular 5 atoms having rings with one, two or three heteroatoms. Other suitable heterocycles are, for example, thiazoles, triazoles, furans.

• – primäre, sekundäre und tertiäre Amine,
• – substituierte oder nicht substituierte Diazofunktionen wie z. B. Hydrazone und Hydrazone,
• – Nitril, Isonitril,
• – S-haltige funktionelle Gruppen, wie z. B. Thio- und Isothiocyanate, Alkylsulfide, Sulfoxide, Thiolgruppen,
• – Methylendioxyfunktion,
• – Alkyläther und Alkylthioäther.

Preferred alkynes have the structure -C≡CR ₁₂ , where R _{12 is} a hydrogen or an optionally substituted C ₁ - to C ₁₅ - or at most C ₁₀ -alkyl radical, which in turn may optionally have double or triple bonds. Usually, however, R ₁₂ has a maximum of 5, in particular a maximum of 3 C atoms. In a further expedient embodiment of the invention, the radical X is for example

• Primary, secondary and tertiary amines,
• - substituted or unsubstituted diazo functions such. Hydrazones and hydrazones,
• - nitrile, isonitrile,
• - S-containing functional groups, such as. B. thio and isothiocyanates, alkyl sulfides, sulfoxides, thiol groups,
• Methylene dioxy function,
• - Alkyl ethers and alkylthioethers.

The Radicals X are expediently radicals which with coordinate the prosthetic heme group.

R ₁ , which is normally a hydrogen or a C ₆ - or C ₇ - to C ₂₆ - or C ₂₀ -alkyl chain, in one preferred embodiment has one or more double and / or triple bonds. Likewise, the hydrocarbon backbone can be formed with alicyclic and / or aromatic hydrocarbon, which may be necessary because of the ring structures up to 40 carbon atoms. In a particularly preferred embodiment, R _{1 has} an α-double bond and an ω-permanent triple bond such. A ω-acetylenic sphingosine. In principle, it is also possible to arrange the triple bond in a long molecule in the middle, and that it coordinates with the heme, such. As in the Eicosatetrainsäuren or ω-acetylenized sphingosine. In another preferred embodiment, the terminal triple bond may be substituted by a heterocycle or other heme coordinating group. In principle, may have ₁ or more substituents R. If R _{1 contains} a terminal heterocycle, then this heterocycle may have one of the definitions given for R ₆ to R ₈ .

The radicals R ₂ to R ₅ may be identical or different and are usually a C ₁ to C ₅ alkyl radical or hydrogen. The alkyl radicals may optionally be substituted and, for example, be an alkanol, alkylamine or alkylthiol radical. Particular preference is given to hydrogen, methyl, ethyl and propyl radicals or derivatives thereof.

R ₆ to R ₈ are connected via the bond B ₆ , B ₇ and B ₈ to the respective glycerol C atom and may be identical or different and hydrogen, a C ₆ or C ₇ to C ₂₆ and C ₂₀ , in particular C ₈ or C ₉ to C ₂₂ or C _{18 be} alkyl radical. These alkyl radicals can be both substituted and unsubstituted, preference being given to those substituents which have one or more triple bonds between the C ₄ or C ₉ to C ₁₅ or C ₁₄ C atoms. Likewise, the hydrocarbon backbone can be formed with alicyclic and / or aromatic hydrocarbons, in which case up to 40 or up to 25 carbon atoms may be necessary because of the ring structures.

It has been found that in compounds of the invention in which at least one of R ₁ , R ₆ , R ₇ and / or R _{8 has} a heme-coordinating hydrocarbon backbone, such as. For example, 17-octadecinyl-1-acid, have been shown to be particularly effective in vitro, the residence time of these substances in the blood can be significantly extended if the carboxy terminus of such a molecule z. B. replaced by a sulfate radical, or a carboxyterminus nearby C-atom of the aliphatic backbone by addition of 2 methyl groups or by insertion of an aliphatic or aromatic ring is substituted. In this way also the in vivo activity corresponding to the in vitro activity is improved.

So has z. B. 2,2-Dimethy1-11-dodecynoic acid in vitro a comparable high inhibition of cytochrome P450 activity such as 10-undecynylic acid whereas in vivo they are far superior to the latter is.

Prefers is provided that the length of the aliphatic Backbone 6 or 9-26 or 13 carbon atoms when R1 is an imidazole radical. One Representative of this preferred group is z. As the 12-imidazolyl dodecanol or the 1-imidazolyl dodecane. Regarding the structural formulas These and other substances are listed in the attached tables directed.

Prefers is further provided that the length of the aliphatic Backbone 6 or 14-26 or 18 carbon atoms when R1 is ethynyl. representative this preferred group is z. For example, 17-octadecinyl-1-acid.

As well Preferably, the length of the aliphatic backbone comprises 9-13 carbon atoms when R1 is ethynyl is. Representatives of this preferred group are z. B. 2,2-dimethyl-11-dodecynoic acid, 10-undecynyl sulfate, 10-undecynoic acid or 10-undecinol.

In a further preferred embodiment, at least one of the radicals R ₆ to R _{8 is} a glycoside, in particular a monosaccharide, which is optionally substituted, for example by means of a sulfate or an amino radical. In individual embodiments, di- or oligosaccharides are quite suitable for the purpose of the invention. Preferred saccharides are pentoses and hexoses and mixed saccharides. In principle, the glycosides can also be thiosugars.

In a particularly preferred embodiment, at least one of R ₆ to R _{8 is} a positively or negatively charged amino acid residue, especially an amino acid having an additional amino group, wherein amino acid groups of the structure - (CH ₂ ) _n -N ⁺ (R ₉ -R ₁₁ ) represent appropriate alternative embodiment. In this case, n is usually an integer between 1 and 5, with 1 to 3, in particular 2 being preferred. The radicals R ₉ to R ₁₁ are usually hydrogen or a methyl, ethyl or propyl group. In this case, R ₉ to R _{11 may be the} same or different. In a very preferred embodiment, one of the X with one of the R ₆ to R ₈ radicals together form a phosphocholine group or other phosphate esters, such as. B. phosphatidylethanolamine, phosphatidylserine or phosphatidylinositol residues.

In an expedient embodiment of the invention, the heme-coordinating group is an imidazole radical attached via a nitrogen atom or an ethynyl radical (-C≡CR ₁₂ ), where R _{12 is} hydrogen or a substituted or unsubstituted aliphatic C ₁ to C ₁₂ hydrocarbon radical.

It has now shown that the biocompatibility of compounds mentioned, in particular those which are physiologically Conditions are poorly soluble and / or due to certain Properties cell membranes can happen badly and therefore insufficient to reach the site of action, by further below described Measures can be improved. This also applies to such compounds by the body's own enzyme activity degraded or excreted easily via the renal excretion become.

So some of the used in the invention Compounds containing a heme coordinating hydrocarbon backbone, after administration rapidly absorbed by muscle or fat cells, so that only a small proportion reaches the site of action, which is why These must be administered in higher doses.

For this reason, it is provided in a further embodiment of the invention to develop the compounds according to the invention in such a way that the functional groups of the hydrocarbon radicals R ₁ , R ₆ , R ₇ , R ₈ , ie the terminal hydrocarbon radicals, the alcoholic OH group, the sulfate or the Co-A group or the organic acid group are modified by addition of a further, hydrophilic residue.

The Compounds used in the invention the heme-coordinating hydrocarbon radical already described include compounds having the basic structure of sphingosines, Mono-, di- and triglycerides, as well as imidazolated or ethinylated Phosphoglycerides, glycolipids, sphingolipids, gangliosides and cerebrosides, in particular their imidazolated or ethinylated forms.

It is important here that the hydrophilic residue binds the molecule to the active site of Cy tochrome's P450 is not affected. This can be precisely controlled by choosing the length of the carbon backbone.

In a further alternative embodiment, one of R ₁ , R ₆ , R ₇ , R _{8 is} a choline or ethanolamine, an α, β, or γ-hydroxy amino acid, such as. As serine, threonine, inositol or galactose.

B _{6 ,} B ₇ and B ₈ may be the same or different and represent O, S, NH, PO ₄ , Se, SO _4. The bond B _6,7,8 , which represents the respective carbon atom of the glycerol or polyol part R _6,7,8 linked, is usually an ether and / or an ester bond between an alcoholic polyol or glycerol and an organic and / or inorganic acid group of R _{6 , 7,8} , such as. A -COC (O) -R _{6 ,} 7,8- group or a -COP (O) -OR _6,7,8- group.

Examples for such compounds are z. B. 12-imidazolyldodecanol-1-phosphatidylcholine, 10-imidazolyl-decanol-1-phosphatidylcholine or 17-octadecynyl-1-phosphatidylcholine, 12-imidazolyldodecanol and 12-imidazolyldodecane.

The Compounds used in the invention include in particular mono-, di- or triglycerides, phospholipids and glycolipids.

The use according to the invention has the advantage that the compounds not directly for enzymes of β-oxidation metabolism are accessible and therefore can not be metabolized immediately.

It has been found that the phosphoglycerides and triglycerides used in one embodiment according to the invention, which are substituted at one or more sites of the glycerol residue with a radical R ₁ , R ₆ , R ₇ , R ₈ , in particular with such radicals which have a heme. coordinating hydrocarbon radical, without significant degradation to the solid organs and tumors are spent. It is believed that these are first hydrolyzed after absorption in the intestine, whereby one or more hydrocarbon radicals are split off. In this way, inter alia, haemo-coordinating monoglycerides are produced, which are also referred to as lysolipids, and which serve with the help of lipoproteins, ie non-covalent aggregates of lipids and proteins that form micelle-like particles and the transport of water-insoluble lipids in the blood.

The same thing Incidentally, it also applies to heme-coordinating Monoglycerides, such as. B. ethinylated or imidazolierte monoglycerides according to the above definition, already as such were administered.

The Heme-coordinating compounds have the property on that they interact with the active site of cytochrome P450 and thus inhibit its activity.

It is also important that the hydrophilic residue R ₂ does not interfere with the binding of the molecule to the active site of the cytochrome P450. This can be precisely controlled by choosing the length of the carbon backbone.

According to the invention further provided a pharmaceutical preparation containing a compound of the invention in a pharmaceutical acceptable carrier.

The Substances according to the invention have in particular as inhibitors of human isoforms of gene family 2 of the cytochrome P450 and in particular the isoforms 2E1 and 2J2 and caused by them Diseases proved.

In A particularly preferred embodiment of the invention is provided, that the pharmaceutical preparation is incorporated in liposomes. Due to the fact that the underlying the preparation Compounds have long hydrocarbon radicals, their involvement in liposomes a very suitable form of administration. Such liposomes are suitable for intravenous, intramuscular, intraperitoneal, percutaneous or oral administration. As well An administration as aerosol is also suitable.

The Compounds according to the invention can however, also be administered as such directly. Also in this Trap, the above administration are suitable.

The syntheses and other preferred formulas of these compounds used in the invention are already in the unpublished PCT / DE2007 / 000767 described and in the 3 - 6 illustrated.

Treatment of dyslipidemias.

Influence of 12-imidazolyl-1-dodecanol and 1-imidazolyldodecane on the serum lipids in the rat ASH and rat NASH model.

Of the Influence of the two substances 12-imidazolyl-1-dodecanol and 1-imidazolyldodecane on alcoholic steato-hepatitis (ASH) and non-alcoholic Steato-hepatitis (NASH) was determined in the animal model in rats. The rat ASH model is rat, which additionally were treated with ethanol. Rats of the NASH model were used with a specific Dear De Carli-high fat diet. After application of 12-imidazolyl-1-dodecanol (I-ol) or 1-imidazolyl-dodecane (I-an) of NASH and ASH rats was almost 100% reduction the alcohol-induced serum triglyceride increase be achieved.

The results are given in the following tables. Table 1 shows the change of serum lipids in rats on NASH model, wherein the respective serum levels of untreated control animals with NASH was set as 100% compared to non-sick control animals. As can be seen from Table 1, serum triglyceride levels decrease by half as compared to untreated control animals when administered with the I-ol substance at a concentration of 0.4 mg / kg, whereas in substance I-triglyceride levels are even lower minus 73% in relation to healthy control animals. Accordingly, the good HDL is increased for both substances and the pathogenic LDL and VDL are also drastically reduced. For better illustration, the results are again in 1 shown as a block diagram. Table 1 triglycerides HDL LDL VLDL NASH 100 -100 100 100 NASH + I-ol (0.4 mg / kg) 52.63 146.67 10 -100 NASH + I-an (0.4 mg / kg) -73.68 -42.22 10 -50

The same experiment was performed on rats that had alcoholic steato-hepatitis (ASH). Here, too, the average value of the respective serum levels of the untreated sick animals was set as a 100% reference point compared to healthy control animals. As can also be seen from the following Table 2, the triglyceride levels decrease to around 17% in the treatment of I-ol and to 2.4% in the case of I-an. Here, too, the good HDL levels are correspondingly increased and the LDL and VDL causing illness are drastically reduced. For better presentation, the results are again in 2 shown. Table 2 triglycerides HDL LDL VLDL ASH 100 100 100 100 ASH + I-ol (4.0 mg / kg) 16.93 200. -20 -175 ASH + I-an (4.0 mg / kg) 2.42 375 40 -175

This applies equally to humiliation LDL and VLDL cholesterol concentrations. On the other hand leads the treatment of the rats with the two substances to an increase the HDL cholesterol values.

QUOTES INCLUDE IN THE DESCRIPTION

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Cited patent literature

• - DE 2007/000767 [0002, 0044]

Cited non-patent literature

• Müller-Enoch et al. describe in Z. Naturforsch. (2001) 56c, pp. 1082-1090 [0003]
• - T. Haehner, D. Muller-Enoch et al. in Z. Naturforschung (2004) 59c, pp. 599-605 [0004]

Claims (10)

Use of a compound of the formula

or pharmaceutically acceptable salts of this compound, for the preparation of a pharmaceutical preparation for the prevention or treatment of isolated and / or combined dyslipidemias, hypertriglyceridemias and / or hypercholesterolemias, wherein B ₆ , B ₇ and B _{8 are the} same or different and O, S, NH, PO ₄ , Se, SO ₄ and R ₁ is H or a C ₆ - or C ₇ - to C ₂₆ - or C ₂₀ alkyl chain, R ₂ , R ₃ , R ₄ and R _{5 are the} same or different and an H or a C ₁ to C _{3 is} alkyl, alkanol, alkylamine and / or alkylthiol, wherein R ₂ to R _{5 may be the} same or different, R ₆ , R ₇ and R _{8 are the} same or different and H, is a substituted or unsubstituted C ₆ or C ₇ to C ₂₆ -alkyl radical, a glycoside radical, a positively or negatively charged amino acid radical, a - (CH ₂ ) -N ⁺ (R ₉ , R ₁₀ , R ₁₁ ), where R ₉ , R ₁₀ , R _{11 is} H, methyl, ethyl and / or propyl, and wherein at least two of R ₂ , R ₃ , R ₄ and R ₅ together form a Po lyolrest and n is an integer from 1 to 5. Use according to claim 1, characterized in that one of the B ₆ -R ₆ , B ₇ -R ₇ and / or B ₈ -R _{8 is} a Phosphorcholinderivat. Use according to one of the preceding claims, characterized in that n = an integer of 1 to 3. Use according to one of the preceding claims, characterized in that R _{1 is} a C ₁₂ to C ₁₆ alkyl radical. Use according to one of the preceding claims, characterized in that R _{1 has} one or more double and / or triple bonds. Use according to one of the preceding claims, characterized in that at least two of the radicals R ₂ to R ₅ together form a polyol radical. Use according to one of the preceding claims, characterized in that the radical R _{1 is} lecithin or cephalin radical. Use according to any one of the preceding claims, characterized in that one of B ₆ -R ₆ to B ₈ -R _{8 is} a phosphatidylethanolamine, a phosphatidylserine and / or a phosphatidylinositol residue. Pharmaceutical preparation containing a compound according to any one of the preceding claims in a pharmaceutically acceptable carrier. Pharmaceutical preparation according to claim 9, characterized characterized in that the preparation is bound in liposomes.