WO2003057205A2 - KOMBINATION VON MTP INHIBITOREN ODER apoB-SEKRETIONS-INHIBITOREN MIT FIBRATEN ZUR VERWENDUNG ALS ARZNEIMITTEL - Google Patents

KOMBINATION VON MTP INHIBITOREN ODER apoB-SEKRETIONS-INHIBITOREN MIT FIBRATEN ZUR VERWENDUNG ALS ARZNEIMITTEL Download PDF

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WO2003057205A2
WO2003057205A2 PCT/EP2003/000057 EP0300057W WO03057205A2 WO 2003057205 A2 WO2003057205 A2 WO 2003057205A2 EP 0300057 W EP0300057 W EP 0300057W WO 03057205 A2 WO03057205 A2 WO 03057205A2
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group
alkyl
phenyl
carbonyl
amino
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PCT/EP2003/000057
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German (de)
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French (fr)
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WO2003057205A3 (de
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Leo Thomas
Michael Mark
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority claimed from DE2002100633 external-priority patent/DE10200633A1/de
Priority claimed from DE10256184A external-priority patent/DE10256184A1/de
Application filed by Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority to CA002471566A priority Critical patent/CA2471566A1/en
Priority to JP2003557563A priority patent/JP2005525309A/ja
Priority to AU2003205570A priority patent/AU2003205570A1/en
Priority to EP03702391A priority patent/EP1465613A2/de
Publication of WO2003057205A2 publication Critical patent/WO2003057205A2/de
Publication of WO2003057205A3 publication Critical patent/WO2003057205A3/de

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Definitions

  • the invention relates to the use of a combination of microsomal triglyceride transfer protein (MTP) inhibitors with fibrates for the treatment of hyperlipidemia, dyslipidemia, atherosclerosis, diabetes mellitus, obesity and pancreatitis for the purpose of mediating the mechanism-related side effects of an MTP inhibitor in the liver Combination with a fibrate and thereby at least to obtain the effect of the MTP inhibitor, pharmaceuticals containing this combination and their preparation.
  • MTP inhibitors reduce lipid concentration in the blood by inhibiting the secretion of apolipoprotein B (apoB) -containing lipoproteins in the liver and intestine. This leads to a lipid accumulation (steatosis) in the target organs, which can lead to cell damage, especially in the liver. Cell damage is detectable by positive liver function tests (e.g., transaminase elevation).
  • apoB apolipoprotein B
  • the steatosis caused by MTP inhibitors is reduced in combination with fibrates which stimulate a metabolism of the fatty acids in the liver and that the liver function tests are normalized.
  • this preserves the positive therapeutic effect of the MTP inhibitors, while at the same time preventing the mechanism-related toxicity.
  • the combination with fibrate can enhance the positive lipid-modulating effect of the MTP inhibitor (synergistic effect).
  • the invention relates to all MTP inhibitors.
  • all fibrates are included.
  • the administration of the two active substances can be carried out both simultaneously in a single pharmaceutical preparation or successively in two pharmaceutical preparations.
  • the application is preferably in a single preparation.
  • MTP Microsomal triglyceride transfer protein
  • PDI protein disulfide isomerase
  • MTP is necessary for the intracellular production of apolipoprotein B (apoB) -containing plasma lipoproteins.
  • apoB apolipoprotein B
  • Apolipoprotein B is the major protein component of hepatic VLDL (very low density lipoproteins) and intestinal chylomicrons.
  • Substances that inhibit MTP decrease the secretion of apoB-containing lipoproteins [Haghpassand M et al., J. Lipid Res. 37, 1468-1480 (1996); Jamil H et al., Proc Natl Acad. USA 93, 11991-11995 (1996); Wetterau JR et al., Science 282, 751-754 (1998)]. Therefore, inhibition of MTP decreases the plasma concentrations of cholesterol and triglycerides in apoB-containing lipoproteins.
  • ApoB-containing triglyceride-rich lipoproteins and their cholesterol-enriched residues are atherogenic and contribute to the morbidity and mortality of coronary heart disease.
  • the relationship between the concentration of LDL cholesterol (or total cholesterol as a closely related deputy Parameters) and clinical findings is generally recognized.
  • Numerous intervention studies have shown a reduction in coronary events with lipid-lowering treatment.
  • An advantage has been shown in the secondary prevention of patients with both elevated cholesterol levels (4S [Anonymous, Lancet 8934, 1383-1389 (1994)], POSCH [Buchwald H et al., Archives of Internal Medicine 11, 1253-1261 (1998)].
  • CDP [Canner PL et al., J. Am. Coll.Cardiol.
  • Lp (a) apoB-related lipid parameters
  • Lp (a) are risk factors for the development of atherosclerotic cardiovascular disease [Ridker PM et al., JAMA 270, 2195-2199 (1993); Bostom AG et al., JAMA 276, 544-548 (1996)].
  • substances which inhibit MTP in the liver or intestine are useful for lowering the plasma concentration of apoB-containing lipoproteins. This includes the conditions of general and postprandial hypercholesterolemia and hypertriglyceridemia. Also included is the treatment of elevated levels of Lp (a).
  • apoB-containing lipoproteins contribute to the development of atherosclerosis, these substances are also useful for the prevention and treatment of atherosclerotic disorders. Likewise, they are useful for the treatment of dyslipidaemic conditions and complications of related diseases such as diabetes mellitus (type II diabetes), obesity and pancreatitis.
  • the inhibition of intestinal absorption of dietary fats by inhibitors of MTP is useful for the treatment of diseases such as obesity and diabetes mellitus, in which excessive fat intake makes a significant contribution to the development of the disease [Grundy SM, Am J Clin Nutr 57 (suppl ), 563S-572S (1998)].
  • fibrinic acid represents a class of lipid-lowering drugs that primarily lowers plasma triglycerides and increases HDL cholesterol [Miller DB & Spence JD, Clin Pharmacokinet 34, 155-162 (1998)].
  • the VA-HIT study (Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial) has for the first time demonstrated that increasing HDL cholesterol reduces morbidity and mortality [New England Journal of Medicine 431, 410-418 (1999)].
  • the class of fibrates on the market include clofibrate [Kesaniemi YA & Grundy SM, JAMA 251, 2241-2247 (1984)], Bezafibrat [Goa KL et al., Drugs 52, 725-753 (1996)], ciprofibrate [Turpin G & Bruckert E, Atherosclerosis 124 Suppl, S83-S87 (1996)], fenofibrate [Balfour JA et al., Drugs 40, 260-290 (1990); Packard CJ, Eur Heart J19 Suppl A, A62-A65 (1998)] and gemfibrozil [Spencer CM & Barradell LB, Drugs 51, 982-1018 (1996)].
  • PPAR ⁇ peroxisome proliferator-activated receptor alpha
  • fibrates are PPAR ⁇ agonists [Gervois P et al., Clin Chem Lab Med 38, 3-11 (2000)].
  • PPAR ⁇ mediates the lipid-modifying effects of fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia.
  • PPAR ⁇ is considered to be the main regulator of intracellular and extracellular lipid metabolism.
  • PPAR ⁇ downregulates the expression of the apolipoprotein C-III gene and upregulates the expression of the lipoprotein lipase gene, resulting in enhancement of VLDL catabolism.
  • PPAR ⁇ activation results in induction of apolipoprotein Al and A-II genes, resulting in an increase in HDL cholesterol.
  • PPAR ⁇ activation also causes an upregulation of the genes for the cholesterol transporters ABCA-1 and SR-B1 and thus an increase in reverse cholesterol transport.
  • PPAR ⁇ plays in intracellular lipid metabolism [Everett L et al., Liver 20, 191-199 (2000)].
  • Activation of PPAR ⁇ causes an increase in gene expression of enzymes required for ⁇ -oxidation of fatty acids. These include enzymes of fatty acid activation (acyl-CoA synthetase, fatty acid-binding proteins) and enzymes that mediate the entry of fatty acids into mitochondria (camitin-palmitoyl transferase I).
  • enzymes of the mitochondrial ⁇ -oxidation of fatty acids are induced (eg acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase).
  • enzymes of the peroxisomal ⁇ -oxidation of fatty acids eg acyl-CoA oxidase
  • microsomal ⁇ -oxidation of fatty acids eg cytochrome P450 4A1 (lauryl ⁇ -hydroxylase)
  • MTP inhibitors reduce the fasting levels of cholesterol and triglycerides in the blood by inhibiting the secretion of very low density lipoproteins (VLDL) in the liver. This leads to an accumulation of lipids in the hepatocytes (hepatic steatosis). Once a certain degree of steatosis is achieved, this leads to damage to the liver cells. This cell damage can be detected by a release of intracellular enzymes, which then increasingly occur in the blood. These enzymes, which are responsible for hepatocellular damage, include alanine aminotransferase (ALT), aspartate amino transferase (AST), and glutamate dehydrogenase (GLDH). The hepatic steatosis-related cell damage severely restricts the use of effective MTP inhibitors.
  • VLDL very low density lipoproteins
  • the present invention shows a way to reduce the mechanism-related side effects of an MTP inhibitor in the liver.
  • a MTP inhibitor When a MTP inhibitor is combined with a fibrate, ⁇ -oxidation of fatty acids in the liver is stimulated by the PPAR ⁇ agonism of the fibrate.
  • the released from the accumulated triglycerides after hydrolysis fatty acids can thus be increasingly degraded.
  • the liver content of triglycerides and free fatty acids decreases.
  • the hepatic steatosis is thereby reduced to a level that is no longer detrimental to the liver cells. This can be recognized by a normalization of the hepatocellular enzymes in the blood. In this way, the effective lipid lowering that MTP inhibitors cause in the blood can be obtained without toxic side effects in the liver.
  • Another aspect of the invention is that the effects of MTP inhibitors and fibrates complement lipids in the blood.
  • the reduction of cholesterol and triglycerides can be increased by combining the two classes of drugs.
  • fibrates to increase the HDL cholesterol. This allows the effectiveness of MTP inhibitors to reduce triglycerides and atherogenic cholesterol in apolipoprotein B-containing compounds. to combine lipoproteins with a desired increase in HDL cholesterol by fibrates.
  • the invention generally relates to the combination of any MTP inhibitor with any fibrate for preventing the mechanism-induced liver toxicity of MTP inhibitors. At the same time, the desired effect of the MTP inhibitor is enhanced.
  • MTP inhibitors of the general formula I for example, MTP inhibitors of the general formula I.
  • Xi is the group CR 1 ,
  • X 2 is the group CR 2 ,
  • X 4 is the group CR 4 or
  • one or two of the groups X 1 to X 4 are each a nitrogen atom and the remaining of the groups X 1 to X 4, three or two of the groups CR 1 to CR 4, wherein R 1 , R 2 , R 3 and R 4 each represent a hydrogen atom or
  • one or two of the groups R 1 to R 4 are each independently a fluorine, chlorine or bromine atom, a C 1-3 alkyl group, a trifluoromethyl, hydroxy, C 1-3 alkoxy, trifluoromethoxy, amino, C ⁇ 3- alkylamino or di- (C 1-3 -alkyl) -amino group and the remaining groups R 1 to R 4 each represent a hydrogen atom,
  • R 4 may additionally together with R 5 have the meaning of a - (CH 2 ) n bridge, in which n represents the number 1, 2 or 3, and
  • a a is a bond, an oxygen or sulfur atom, an -NH-, -N (C 1-3 -alkyl), sulfinyl, sulfonyl or carbonyl group,
  • a bonded to a carbon atom of hydrogen atom or / and bound to a nitrogen atom hydrogen atom may each be replaced by a C- ⁇ - 3 alkyl group and where a hetero atom of the group A a not with a nitrogen atom a 5-membered heteroaryl group the group R a is linked,
  • R a represents a phenyl, 1-naphthyl or 2-naphthyl group
  • a phenyl ring may be fused and the bicyclic heteroaryl groups thus formed may be bonded via the heteroaromatic or carbocyclic moiety and
  • phenyl and naphthyl groups as well as the above-mentioned mono- and bicyclic heteroaryl groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a d ⁇ alkyl group, by a C 3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy , C- ⁇ - 3 -alkoxy, trifluoromethoxy, amino, C- ⁇ - 3 alkylamino, di- (3 C ⁇ - alkyl) amino, acetylamino, N- (3 C ⁇ - alkyl) - acetylamino, propionylamino, N- (C ⁇ -3 alkyl) -propionyIamino-, acetyl, propionyl, C- ⁇ - 3 -alkoxy-carbonyl, aminocarbonyl, C ⁇ - 3 -alkylamino-carbonyl, di- (C 1-3 -alkyl) monocarbon
  • the cycloalkyl part may be condensed with a phenyl ring or
  • one or two hydrogen atoms may each be replaced by a C 1-3 alkyl group or / and
  • a -CH 2 group linked to the imino nitrogen atom may be replaced by a carbonyl group or a - (CH 2 ) 2 group linked to the imino nitrogen atom by a
  • -CO-NR 8 - group can be replaced or linked to the imino nitrogen atom - (CH 2 ) 3 group by a
  • R 8 represents a hydrogen atom or a C 1-3 -alkyl group
  • R 5 is a hydrogen atom or a C 5 -alkyl group
  • R 9 is a hydrogen atom, a cis-alkyl group, a terminal through. ! amino, C ⁇ -3 -A kylamino-, di- (3 C ⁇ - alkyl) amino or C ⁇ - 5 alkoxy carbonyl-amino group, substituted C 2 - 3 alkyl group, a carboxy-C ⁇ - 3- alkyl, -C. 3 alkoxy-carbonyl-C ⁇ -3 alkyl, phenyl, phenyl C- ⁇ - 3 -alkyl, C ⁇ - 5 alkylcarbonyl or phenylcarbonyl group or R 9 together with R 6 represents a - (CH 2 bridge in which p is the number 2 or 3,
  • R 6 is a hydrogen atom or a C ⁇ - 6 alkyl group
  • R 7 is a Ci.g-alkyl group
  • 3- alkoxy-carbonyl group may be replaced or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyl radical by an oxygen or sulfur atom or by an optionally by a C ⁇ - 6 alkyl, phenyl, C ⁇ -6 alkyl-carbonyl, benzoyl , phenyl- (C ⁇ -3 -AL- alkyl) -carbonyl, C ⁇ _ 6 alkyl-aminocarbonyl, di- aminocarbonyl, phenyl aminocarbonyl, N- (C 1-3 (C ⁇ -C5 alkyl.) - Alkyl) -phenylaminocarbonyl, phenyl -C ⁇ . 3 -alkylaminocarbonyl- or N-isis-alky-phen-C 1 -C 6 -alkylamino-carbonyl group-substituted imino group may be replaced or
  • one or two single bonds separated by at least one bond from one another and from position 1 may each be fused with a phenyl radical, the radical attached to the saturated carbon atom in position 1 in a bi- or tricyclic ring system thus formed bonded hydrogen atom through a cis-alkylamino-carbonyl ,.
  • Di- (C ⁇ -5- alkyl) amino-carbonyl-., Phenyl -C ⁇ . 3 -alkylamino-carbonyl or C- ⁇ -5-alkoxycarbonyl group in which terminal methyl groups may each be completely or partially fluorinated, may be replaced,
  • a phenyl ring can be fused to the above-mentioned 5- or 6-membered heteroaryl groups via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,
  • a phenyl-C2-5 alkenylene-CH2-, phenyl-C2-5 alkynylene-CH 2 -, heteroaryl-C 2 -5-alkenylene-CH 2 - or heteroaryl-C 2 - 5 alkynylene CH 2 group in which a hydrogen atom of the methyl group in position 1 by a C- ⁇ - may be replaced 3 alkyl group and independently thereof the phenyl and the heteroaryl moiety by fluorine, chlorine or bromine atoms, by alkyl C ⁇ - 6 , C 3-7 cycloalkyl, trifluoromethyl, d-3 alkoxy, phenyl, heteroaryl, or cyano groups may be mono- or di-substituted, wherein the substituents may be the same or different and the disubstitution is excluded by two aromatic groups .
  • heteroaryl is a 5-membered heteroaryl group bonded via a carbon or nitrogen atom
  • an imino group optionally substituted by a C 1-3 -alkyl group, an oxygen or sulfur atom,
  • a phenyl ring can be fused to the above-mentioned 5- or 6-membered heteroaryl groups via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,
  • R b is optionally substituted by fluorine, chlorine, bromine or iodine atoms, by C ⁇ _ alkyl, C 2 - 7 cycloalkyl, trifluoromethyl - 4 alkenyl, C 2 - alkynyl, C 3 Hydroxy, C 1-3 -alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,.
  • a b represents a bond
  • a -CH 2 -, - (CH 2 ) 2-, sulfonyl or carbonyl group may also be bonded via a nitrogen atom and the
  • a phenyl ring can be fused to the above-mentioned 5- or 6-membered heteroaryl groups via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,
  • one or two hydrogen atoms may each be replaced by a C ⁇ _ 3 alkyl group and / or
  • the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or by an optionally C 1 -C 3 -alkyl radical, C ⁇ . 3 alkyl-carbonyl, C ⁇ -3 alkoxy-carbonyl, C ⁇ -3 alkyl-aminocarbonyl or di- (C ⁇ - 3 alkyl) aminocarbonyl group substituted imino group may be substituted or
  • the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in the 3- or 4-position of a cyclohexyl or cycloheptyl group by an n-butylene, n-pentylene, n-hexylene, 1,2-ethylenedioxy or 1,3-propylenedioxy group may be replaced and in the rings thus formed one or two hydrogen atoms may be replaced by C 1-3 -alkyl groups,
  • the cycloalkyl part may be condensed with a phenyl ring or
  • one or two hydrogen atoms in each case by a C- ⁇ -3 alkyl group may be replaced and / or
  • Imino nitrogen atom linked -CH 2 - group may be replaced by a carbonyl group or an imino nitrogen-linked - (CH 2 ) 2 - group by a
  • -CO-NR 8 - group can be replaced or one with the imino nitrogen atom linked - (CH 2 ) 3 - group by a
  • R 8 is a hydrogen atom or represents C- ⁇ - 3 alkyl group
  • a b is a bond, an oxygen or sulfur atom, an -NH-, -N (-C 3 -alkyl) -, sulfinyl, sulfonyl or a carbonyl group,
  • a bonded to a carbon atom of hydrogen atom or / and bound to a nitrogen atom hydrogen atom may each be replaced by a C- ⁇ - 3 alkyl group and where a hetero atom of the group A do not b with a nitrogen atom a 5-membered heteroaryl group the group R b is linked,
  • E b is optionally substituted by a fluorine, chlorine or bromine atom, by a C ⁇ - alkyl group, by a trifluoromethyl, hydroxy, C ⁇ . 3 -alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C 3 -alkylamino, Di- (C 3 -alkyl) amino, amino-C ⁇ . 3 -alkyl-, C ⁇ - 3 -alkylamino -C. 3 -alkyl-, di- (C ⁇ .3-alkyl) amino-C ⁇ . 3 -alkyl, acetylamino, propionylamino, acetyl, propionyl, carboxy, C ⁇ .
  • R c assumes the meanings mentioned above for R b , wherein a reference to A b is to be replaced by a reference to A c ,
  • a c assumes the meanings mentioned above for A b , wherein a reference to R b is to be replaced by a reference to R c ,
  • E c is a 5-membered heteroarylene group bonded via two carbon atoms or via a carbon atom and an imino nitrogen atom, where the imino nitrogen atom of the heteroarylene group is not linked to a heteroatom of the group A c and where the heteroarylene group
  • a phenyl ring may be fused to the above-mentioned 5-membered, one or two heteroatom group-containing heteroarylene groups and the above-mentioned 6-membered heteroarylene groups via two adjacent carbon atoms, and the bicyclic heteroarylene groups thus formed may be bonded through the heteroaromatic and / or carbocyclic portion can,
  • R 6 and R 7 together form an n-alkylene bridge having 3 to 6 carbon atoms, in
  • one or two hydrogen atoms may each be replaced by a C 1-3 alkyl group and / or
  • a -CH 2 -CH 2 group may be replaced by a 1, 2-linked phenylene group, by fluorine, chlorine or bromine atoms, by C ⁇ -3 alkyl, trifluoromethyl, hydroxy, C ⁇ - 3 alkoxy , Trifluoromethoxy, amino, C 3 -alkylamino, di (C 3 -3 alkyl) amino, acetylamino, propionylamino, acetyl, propionyl, C ⁇ _ 3 alkoxy-carbonyl, aminocarbonyl, C ⁇ _ 3 -alkylamino-carbonyl, cyano, phenyloxy or phenyl-C ⁇ -3 -alkyl groups may be mono- or disubstituted, with a disubstitution is excluded with the latter group, wherein the above-mentioned phenyloxy and phenyl-d- 3 -alkyl in the phenyl part, by a fluorine, chlorine or bromine
  • a methylene group in position 1 in an n-butylene, n-pentylene or n-hexylene group may be replaced by a carbonyl group
  • the hydrogen atoms may be replaced in the mentioned in the definition of the above groups C ⁇ -3 alkyl and alkoxy partially or totally substituted by fluorine atoms, and
  • alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts having more than two carbon atoms contained in groups of the formula I defined above may be straight-chain or branched, unless stated otherwise.
  • the carboxy groups mentioned in the definition of the abovementioned radicals may be replaced by a group convertible in vivo into a carboxy group or by a group negatively charged under physiological conditions,
  • amino and imino groups mentioned in the definition of the abovementioned radicals can each be substituted by a residue which can be split off in vivo and thus be present in the form of a prodrug residue.
  • Such groups are described, for example, in WO 98/46576 and N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
  • a convertible in vivo into a carboxy group is, for example, a hydroxymethyl group, an esterified carboxy group with an alcohol in which the alcoholic moiety is preferably a C- ⁇ - 6 alkanol, a phenyl-C ⁇ - 3 -alkanol, a C 3- 9 -Cycloalkanol, wherein a C 5-8 cycloalkanol may additionally be substituted by one or two C 1-3 alkyl groups, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an optionally by a C 1-3 alkyl, phenyl-3 C ⁇ _ alkyl, phenyl-C ⁇ -3 alkoxy carbonyl or C 2 - 6 alkanoyl group substituted imino group is replaced and the cycloalkanol moiety may additionally be substituted by one or two d-3 alkyl, a C.
  • R p is a Ci-s-AIkyl-, C 5 _ 7 -cycloalkyl, ds-alkyloxy, C 5-7 -cycloalkyloxy, phenyl or
  • R q represents a hydrogen atom, a C 1-3 -alkyl, C 3-8 -cycloalkyl or phenyl group and
  • R r is a hydrogen atom or a C 3 alkyl group represents,
  • a group negatively charged under physiological conditions for example a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C 1-6 -alkylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C 1-6 -alkylsulfonylaminocarbonyl -, Phenylsulfonylaminocarbonyl-, Benzylsulfonylaminocarbonyl- or perfluoro -C. 6- alkylsulfonylaminocarbonyl group
  • an imino or amino group in vivo radical such as a hydroxy group
  • an acyl group such as a mono- 3 alkoxy optionally substituted by fluorine, chlorine, bromine or iodine atoms, by alkyl or C ⁇ _ or C ⁇ -3 disubstituted phenylcarbonyl group, where the substituents may be the same or different, a pyridinoyl group or a -C.- 6- alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C 16 -alkoxycarbonyl or C ⁇ . ⁇ 6 -Alkylcarbonyloxy distr, in which hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such as methoxy
  • 6 -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxyearbonyl group, a 3-amino-propionyl group in which the amino group mono- or disubstituted by G ⁇ - 6 ⁇ Alky!
  • R s and R t which may be the same or different, represent hydrogen atoms or d-3-alkyl groups
  • Xi to X4 are defined as mentioned above,
  • a a is a bond, an oxygen atom, an -NH-, -N (d- 3- alkyl) -, sulfonyl or carbonyl group, one of the groups -CH 2 -, - (CH 2 ) 2 -, - NH-CH 2 -, -CH 2 -NH-, -NH-CO-, -CO-NH-, -NH-SO 2 - or - SO 2 -NH-,
  • 3- alkyl group can be replaced and wherein a heteroatom of the group A a is not linked to a nitrogen atom of a 5-membered heteroaryl group of the group R a ,
  • R a is a phenyl group
  • a C 3-7 cycloalkyl group wherein the methylene group in the 4-position of a 6-membered cycloalkyl group through an oxygen or sulfur atom, through a sulfonyl group or an optionally by a C ⁇ - 3 alkyl, phenyl, C ⁇ -4 alkyl-carbonyl or C ⁇ - 4 - Alkoxy-carbonyl group substituted imino group may be replaced,
  • one or two hydrogen atoms in each case by a -C. 3- alkyl group may be replaced or / and
  • a -CH 2 - group linked to the imino nitrogen atom may be replaced by a carbonyl group or a - (CH 2 ) 2 - group linked to the imino nitrogen atom by a -CO-NR 8 - May be replaced or a group linked to the imino nitrogen atom - (CH 2 ) 3- group may be replaced by a -CO-NR 8 -CO- group,
  • R 8 represents a hydrogen atom or a C 3 alkyl group
  • R 5 is a hydrogen atom or a C 1-3 -alkyl group
  • R 9 is a hydrogen atom, a C 5 alkyl group, a terminal by an amino, C ⁇ -3-alkylamino, di- (3 C ⁇ - -alkyl) -amino or C 5 alkoxy carbonyl-amino group substituted -C 2 - 3 alkyl group, a carboxy-d- 3- alkyl, C ⁇ _ 3 alkoxy-carbonyl -C. 3 -alkyl-, phenyl-, phenyl- C 3 -alkyl, C 5 -alkylcarbonyl or phenylcarbonyl group or R 9 together with R 6 represents a - (CH 2 bridge in which p is the number 2 or 3 .
  • heteroarylene above in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C 3 alkyl group, by a cyclopropyl, trifluoromethyl, 3 C ⁇ _ alkoxy, trifluoromethoxy, C ⁇ - 3 alkylamino, di - (C ⁇ - 3 -alkyl) amino, acetylamino, N- (-C-3-alkyl) -acetylamino, acetyl, d -3 -Al-kylamino-carbonyl or di- (C ⁇ -3 -alkyl) amino carbonyl group can be substituted,
  • R 6 is a hydrogen atom or a C ⁇ - 4 alkyl group
  • R 7 is a d. 6- alkyl group, a straight-chain C 2 - 6 alkyl group which is terminally substituted by an amino, C ⁇ . 3- Alkylamino- or di- (C ⁇ _ 3 -alkyl) -amino group is substituted,
  • Phenyl-C 3 -alkylamino-carbonyl, carboxy or C 3 -alkoxy-carbonyl may be replaced or
  • the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical by an optionally substituted by a phenyl, Ci- ⁇ -alkyl-carbonyl, benzoyl, phenyl (C 3 -3 alkyl) carbonyl, Phenylaminocarbonyl- , N- (C ⁇ - 3 alkyl) -phenylaminocarbonyl, phenyl-C ⁇ -3 -alkylamino-carbonyl or N- (-C 3 alkyl) -phenyl-C ⁇ -3 -alkyl-amino-carbonyl group substituted imino be replaced can or
  • one or two single bonds separated by at least one bond from one another and from position 1 may each be fused with a phenyl radical, the radical attached to the saturated carbon atom in position 1 in a bi- or tricyclic ring system thus formed bonded hydrogen atom by a C ⁇ _ 3 alkylamino-carbonyl, di- (C ⁇ - 3 -alkyl) amino-carbonyl or C ⁇ - 5 alkoxy-carbonyl group in which terminal methyl groups may each be wholly or partially fluorinated, may be replaced,
  • an imino group optionally substituted by a C 1-3 -alkyl or trifluoromethyl group, an oxygen or sulfur atom or
  • an imino group optionally substituted by a C 1-3 -alkyl group or an oxygen or sulfur atom and additionally containing a nitrogen atom,
  • R b is optionally substituted by fluorine, chlorine or bromine atoms, by d-3-alkyl, cyclopropyl, trifluoromethyl, hydroxy, C 3 -alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C ⁇ - 3- Alkylamino-, di- (C ⁇ - 3 -alkyl) amino, acetylamino, acetyl, carboxy, d -3 alkoxy-carbonyl, aminocarbonyl, -C. 3 alkyl amino-carbonyl, di- (C ⁇ -3 alkyl) amino-carbonyl or cyano groups mono- or disubstituted phenyl wherein the substituents may be identical or different,
  • a b represents a bond
  • a -CH 2 -, - (CH 2 ) 2-, sulfonyl or carbonyl group may also be bonded via a nitrogen atom and the
  • one or two hydrogen atoms may each be replaced by a d -3 -alkyl group and / or
  • the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in the 3- or 4-position of a cyclohexyl or cycloheptyl group by an n-butylene, n-pentylene, n-hexylene, 1, 2-ethylenedioxy or 1,3-propylenedioxy group may be replaced, a 4- to 7-membered cycloalkyleneimino group in which
  • the cycloalkyl part may be condensed with a phenyl ring or
  • one or two hydrogen atoms may each be replaced by a C 1-3 alkyl group or / and
  • a -CH 2 - group linked to the imino nitrogen atom may be replaced by a carbonyl group
  • a b is a bond, an oxygen atom, an -NH-, -N (-C 3 -alkyl) -, sulfonyl or a carbonyl group,
  • E b is a optionally substituted by a fluorine, chlorine or bromine atom, by a C 4 alkyl group, by a trifluoromethyl, hydroxy, d- 3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C ⁇ , 3- Alkylamino-, di- (C ⁇ - 3 -alkyl) amino, acetylamino, acetyl, carboxy, d- 3 -alkoxycarbonyl, C ⁇ - 3 -alkoxy-carbonyl-C ⁇ - 3 -alkyl, aminocarbonyl -, C ⁇ _ 3 -Alkylamino-carbonyl, di- (C ⁇ - 3 -alkyl) amino-carbonyl or cyano group substituted phenylene group, or
  • R c assumes the meanings mentioned above for R, wherein a reference to A b is to be replaced by a reference to A °,
  • a c is a bond, an oxygen atom, a -CH 2 -, -NH-, -N (C 1, 3 -alkyl) - > -NH-CO-, -CO-NH- or carbonyl group,
  • heteroatom of the group A c is not linked to a nitrogen atom of a 5-membered heteroaryl group of the group R c , and
  • E c is a 5-membered heteroarylene group bonded via two carbon atoms or via a carbon atom and an imino nitrogen atom, where the imino nitrogen atom of the heteroarylene group is not linked to a heteroatom of the group A c and where the heteroarylene group
  • R ⁇ and R 7 together represent an n-alkylene bridge having 4 or 5 carbon atoms in which
  • a hydrogen atom may be replaced by a C ⁇ -3 alkyl group and / or a -CH 2 -CH 2 group may be replaced by a 1, 2-linked phenylene group by a fluorine, chlorine or bromine atom, by a d -3-alkyl, trifluoromethyl, hydroxy, d- 3 -alkoxy, trifluoromethoxy, amino, C ⁇ .
  • 3- alkyl group may be substituted,
  • the methylene group in position 3 of an n-pentylene group atom by an oxygen may be replaced by a sulfonyl group or an optionally by a C 3 alkyl or C-3 carbonyl-alkyl substituted imino group,
  • carbon skeleton may additionally by a fluorine, chlorine or bromine atom, by a C 3 alkyl group , by a trifluoromethyl, hydroxy, C ⁇ _ 3 -alkoxy, trifluoromethoxy, amino, C 3 -alkylamino, acetylamino, acetyl, C ⁇ .3-alkoxycarbonyl, aminocarbonyl, C ⁇ .3- Alkylamino-carbonyl or cyano group may be substituted,
  • alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts having more than two carbon atoms contained in the above-defined groups of the formula I may be straight-chain or branched, unless otherwise stated,
  • radicals can each be substituted by a radical cleavable in vivo
  • Xi is the group CR 1 ,
  • X 2 is the group CR 2 ,
  • X 4 is the group CR 4 or
  • one of the groups X 1 to X 4 is a nitrogen atom and the remaining of the groups X 1 to X 4, three of the groups CR 1 to CR 4,
  • R 1 , R 2 , R 3 and R 4 each represent a hydrogen atom or
  • one or two of the groups R 1 to R 4 independently of one another in each case a fluorine, chlorine or bromine atom, a d -3 alkyl group, a trifluoromethyl, amino, d- 3- alkylamino or di (C 1-3 -alkyl) -amino group and the remaining groups R 1 to R 4 each represent a hydrogen atom,
  • R 4 may additionally together with R 5 have the meaning of a - (CH 2 ) n bridge, in which n represents the number 1, 2 or 3, and A a is a bond, an oxygen atom, a -CH 2 -, - (CH 2 ) 2-, -NH-, -N (-C 3 alkyl) -, sulfonyl or carbonyl group or one via the carbon or sulfur atom -NH-CH 2 -, -NH-CO-, -NH-SO 2 - group linked to the group R a in formula (I),
  • R a is a phenyl or pyridinyl group
  • a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group may be substituted by a C 1-3 -alkyl group and the phenyl group and the abovementioned heteroaromatic groups in the carbonyl skeleton by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl group.
  • trifluoromethyl may be substituted d- 3 -alkoxy, trifluoromethoxy, amino, C ⁇ .3 -alkylamino, di- (C ⁇ .3-alkyl) amino or cyano group
  • the methylene group in position 4 of a 6-membered cycloalkyleneimino group may be substituted by a methyl group or replaced by an oxygen or sulfur atom or by an imino group optionally substituted by a d -3 -alkyl group, or
  • a -CH 2 group linked to the imino nitrogen atom may be replaced by a carbonyl group or a - (CH 2 ) 2 group linked to the imino nitrogen atom may be replaced by a -CO-NR 8 - group or a - (CH 2) 3 group linked to the imino nitrogen atom may be replaced by a -CO-NR 8 -CO- group,
  • R 8 represents a hydrogen atom or a C 1-3 -alkyl group
  • R 5 is a hydrogen atom or a C 1-3 -alkyl group
  • R 9 is a hydrogen atom, a 3 C ⁇ - alkyl group, a terminal by an amino, C ⁇ -3-alkylamino, di- (3 C ⁇ - alkyl) amino or C ⁇ - 4 alkoxy carbonyl-amino group substituted -C- 2-3- alkyl group, a carboxy-C ⁇ - 3 -alkyl, Ci-s-alkoxycarbonyl-Ci-s-alkyl or -C.
  • R 9 represents 3- alkylcarbonyl group or R 9 together with R 6 represents a - (CH 2 ) P - bridge, in which p denotes the number 2 or 3,
  • heteroarylene in the carbon skeleton by a fluorine, chlorine or bromine atom, by a d -3 alkyl, trifluoromethyl, C ⁇ alkoxy- -3 -AI-, trifluoromethoxy, amino, C ⁇ -3 alkylamino , Di- (d -3 -alkyl) amino, acetylamino or cyano group may be substituted,
  • R 6 is a hydrogen atom or a C 1-3 -alkyl group
  • R 7 is a C ⁇ -6 alkyl group
  • one or two single bonds separated by at least one bond from one another and from position 1 may each be condensed with a phenyl radical, wherein in a bi-or tricyclic ring system thus formed the hydrogen atom bonded to the saturated carbon atom in position 1 is replaced by a C 1-3 -alkylamino-carbonyl- or di- (C 1-3 -alkyl) -amino-carbonyl group, in which terminal methyl groups may in each case be completely or partially fluorinated, may be replaced,
  • a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group by a C ⁇ -3 alkyl or trifluoromethyl group may be substituted and the phenyl group and the above-mentioned heteroaromatic groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C 4 alkyl, trifluoromethyl, C ⁇ -3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, d ⁇ Alkoxy-carbonylamino-ds-alkyl, amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) amino or cyano group may be substituted,
  • Trifluoromethyl, C ⁇ _ 3 alkoxy, phenyl or cyano group may be substituted,
  • R b is optionally substituted by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl, trifluoromethyl, hydroxy, d -3- alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxy or d - 3- alkoxy-carbonyl group substituted phenyl group,
  • a b is a bond
  • Alkyl group substituted imino group and two nitrogen atoms an optionally by a.
  • heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom by a C ⁇ - 3 alkyl, trifluoromethyl, phenyl, C ⁇ -3 alkoxy, trifluoromethoxy, amino; Mono-substituted C 1-3 alkylamino, di- (3 C ⁇ - alkyl) amino or acetylamino group, or, with the exception of containing more than two heteroatoms 5-membered heteroaryl selected by a C ⁇ -4 alkyl group, and a substituent selected from fluorine, chlorine, bromine, C1-3 alkyl, trifluoromethyl, phenyl, d-, 3 alkoxy, and trifluoromethoxy may also be disubstituted,
  • the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in the 3- or 4-position of a cyclohexyl group may be replaced by an n-butylene, n-pentylene or 1, 2-ethylenedioxy group,
  • the cycloalkyl part may be condensed with a phenyl ring or
  • a hydrogen atom may be replaced by a -C 3 alkyl group and / or in each case the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino membered 7 by a 4- to Cycloalkylenimino-, phenyl or 4- (C ⁇ -3 alkyl) -1, 2,4-triazol-3-yl group may be substituted can or
  • the two hydrogen atoms of the methylene group in position 3 of a 5-membered or in position 3 or 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
  • a b is a bond, an oxygen atom, a -CH 2 -, -NH-, -O-CH 2 , carbonyl, -NH-CO or -CO-NH group,
  • E is an optionally by a fluorine, chlorine or bromine atom, by a C 3 alkyl, trifluoromethyl, C 1-3 -alkoxy, trifluoromethoxy, amino, C ⁇ - 3 alkylamino, di- (C ⁇ - 3- alkyl) amino, acetylamino or d- 3 -alkoxycarbonyl group substituted phenylene group, or
  • R c is an optionally substituted by a fluorine, chlorine or bromine atom, by a -C 3-alkyl, trifluoromethyl, C 3 alkoxy, trifluoromethoxy, carboxy or C 3 -alkoxy-carbonyl substituted phenyl group or
  • the cycloalkyl part may be condensed with a phenyl ring or a hydrogen atom may be replaced by a C ⁇ -3 alkyl group and / or
  • the two hydrogen atoms of the methylene group in position 3 of a 5-membered or in position 3 or 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
  • a c is a bond
  • E c is a five-membered heteroarylene group bound via two carbon atoms
  • a hydrogen atom may be replaced by a C ⁇ -3 alkyl group and / or
  • a -CH 2 -CH 2 group may be replaced by an optionally substituted by a phenyloxy or benzyl 1, 2-linked phenylene group, wherein
  • the phenyloxy or benzyl group in the aromatic moiety and the phenylene group independently of one another by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl, trifluoromethyl, C 1-3 -alkoxy, trifluoromethoxy, amino, C 1-6 -alkyl, 3- alkylamino, di- (C 3 -alkyl) amino, acetylamino, d 3 -alkoxy-carbonyl or cyano group may be substituted,
  • 3- alkyl group may be monosubstituted or disubstituted by a phenyl group and a cyano group,
  • phenyl groups mentioned in the definition of the abovementioned radicals are denoted by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl group. by a trifluoromethyl, d- 3 -alkoxy, trifluoromethoxy, phenyl, amino, C ⁇ . 3- alkylamino, acetylamino, C ⁇ _ 3 alkoxycarbonyl or cyano group may be substituted,
  • the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts having more than two carbon atoms contained in the above-defined groups of the formula I may be straight-chain or branched, unless otherwise stated, the carboxy groups mentioned in the definition of the abovementioned radicals may be replaced by a group convertible in vivo into a carboxy group or by a group negatively charged under physiological conditions and / or
  • Xi is the group CR 1 ,
  • X 2 is the group CR 2 ,
  • X 4 is the group CR 4 or
  • one of the groups Xi to X 4 is a nitrogen atom and the remaining groups Xi to X 4 are three of the groups CR 1 to CR 4 ,
  • R 1, D R2, n R3 and R each represents a hydrogen atom or
  • one or two of the groups R 1 to R 4 independently of one another each represent a fluorine, chlorine or bromine atom, a C 1-3 -alkyl group, a trifluoromethyl-, Amino, C ⁇ . 3- Alkylamino- or di- (C ⁇ - 3 -alkyl) -amino group and the remaining of the groups R 1 to R 4 each represent a hydrogen atom,
  • R 4 may additionally together with R 5 have the meaning of a - (CH 2 ) n bridge, in which n represents the number 1, 2 or 3, and
  • a a is a bond, an oxygen atom, a -CH 2 -, - (CH 2 ) 2 -, -NH-, -N (-C 3 alkyl) -, sulfonyl or carbonyl group or one via the carbon or sulfur atom -NH-CH 2 -, -NH-CO-, -NH-SO 2 - group linked to the group R a in formula (I),
  • R a is a phenyl or pyridinyl group
  • a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C 3 alkyl group and the phenyl group and the above-mentioned heteroaromatic groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C 3 alkyl , trifluoromethyl, C ⁇ _ 3 -alkoxy, trifluoromethoxy, amino, C ⁇ -3 alkylamino, di- (C ⁇ . 3 alkyl) amino or cyano group can be substituted,
  • Group may be replaced by a carbonyl group or one associated with the imino nitrogen atom - (CH 2) 2- group by a
  • -CO-NR 8 - group can be replaced or one with the imino nitrogen atom linked - (CH 2 ) 3 - group by a
  • R 8 is a hydrogen atom or a -C. Represents 3- alkyl group
  • R 5 is a hydrogen atom or a -C. 3- alkyl group
  • R 6 is a hydrogen atom or a C 1-3 -alkyl group
  • R 7 is a terminal by a C 3 - 7 cycloalkyl substituted d- C4 alkyl group, wherein
  • a hydrogen atom in the 4-position of a cyclohexyl radical through a d -5 -alkoxy-, d. 3 -alkoxy-C ⁇ -3 alkyl, phenyl-C 1-3 alkoxy-methyl, phenyl-C ⁇ - 3 alkylamino, phenyl-2 C ⁇ - alkyl-carbonylamino, benzoylamino, phenylaminocarbonyl, phenyl C 3 -alkyl-aminocarbonyl, carboxy or C 3 -alkoxy-carbonyl group may be replaced or
  • one or two single bonds separated by at least one bond from one another and from the position 1 can each be condensed with a phenyl radical, in which case a bi or a radical formed in such a way Tricyclic ring system bound to the saturated carbon atom in position 1 hydrogen atom by a C ⁇ _ 3 alkylamino-carbonyl or di- (C ⁇ - 3 -alkyl) amino-carbonyl group in which terminal methyl groups may each be wholly or partially fluorinated, may be replaced .
  • a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C 3 alkyl or trifluoromethyl group and the phenyl group and the above-mentioned heteroaromatic groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C 4 alkyl, trifluoromethyl, C ⁇ - 3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C ⁇ -4 alkoxy-carbonylamino-C ⁇ -3 alkyl, amino, d -3 alkylamino, di- (C 1-3 alkyl) amino or cyano group may be substituted,
  • R b is a optionally substituted by a fluorine, chlorine or bromine atom, by a C 3 alkyl, trifluoromethyl, hydroxy, C ⁇ -3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxy or C ⁇ . 3- alkoxy-carbonyl group substituted phenyl group,
  • a b is a bond, may also be bonded via a nitrogen atom and the imino group optionally substituted by a C 1-3 -alkyl group, an oxygen or sulfur atom,
  • an imino group optionally substituted by a C 1-3 -alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or
  • the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in the 3- or 4-position of a cyclohexyl group may be replaced by an n-butylene, n-pentylene or 1, 2-ethylenedioxy group,
  • the cycloalkyl part may be condensed with a phenyl ring or
  • a hydrogen atom may be replaced by a C ⁇ -3 alkyl group and / or
  • each of the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group is substituted by a 4- to 7-membered cycloalkyleneimino, phenyl or 4- (d- 3- alkyl) -1, 2,4-triazol-3-yl group can be or
  • the two hydrogen atoms of the methylene group in position 3 of a 5-membered or in position 3 or 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
  • a b is a bond, an oxygen atom, a -CH 2 -, -NH-, -O-CH 2 -, carbonyl-, -NH-CO- or -CO-NH- group,
  • E b is optionally substituted by a fluorine, chlorine or bromine atom, by a C 1-3 -alkyl, trifluoromethyl, C 1-3 -alkoxy, trifluoromethoxy, amino, C 1-3 -alkylamino, di (C 1-4 -alkyl ), 3 alkyl) amino, acetylamino or C ⁇ -3 alkoxy carbonyl group represents substituted phenylene group, or
  • R G is optionally substituted by a fluorine, chlorine or bromine atom, by a. 3- alkyl, trifluoromethyl, d- 3- alkoxy, trifluoromethoxy, carboxy or C ⁇ _ 3 alkoxy-carbonyl substituted phenyl group or
  • the cycloalkyl part may be condensed with a phenyl ring or
  • a hydrogen atom may be replaced by a d- 3 -Alkyilitis and / or
  • the two hydrogen atoms of the methylene group in position 3 of a 5-membered or in position 3 or 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
  • a c is a bond
  • E c is a five-membered heteroarylene group bound via two carbon atoms
  • an imino group optionally substituted by a C 1-3 -alkyl group, an oxygen or sulfur atom, optionally substituted by a C ⁇ -3 alkyl substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or
  • R 6 and R 7 together represent an n-alkylene bridge having 4 or 5 carbon atoms, in
  • a hydrogen atom may be replaced by a C 3 alkyl group and / or
  • a -CH 2 -CH 2 group may be replaced by an optionally substituted by a phenyloxy or benzyl 1, 2-linked phenylene group, wherein
  • the phenyloxy or benzyl group in the aromatic part and the phenylene independently of one another by a fluorine, chlorine or bromine atom, by a C ⁇ _ 3 alkyl, trifluoromethyl, C ⁇ -3 alkoxy, trifluoromethoxy, amino, C ⁇ .
  • 3- alkylamino, di- (C ⁇ - 3 -alkyl) amino, acetylamino, C ⁇ _3-alkoxy-carbonyl or cyano group may be substituted, or the carbon atom in position 3 of an n-pentylene group through a terminal by an amino, d- 3 alkylamino, di (C ⁇ - 3 alkyl) amino, acetylamino or N- (methyl) acetylamino group or a 5- to 7-membered cycloalkyleneimino group substituted C ⁇ monosubstituted -3 alkyl group or may be di-substituted by a phenyl group and a cyano group,
  • phenyl groups mentioned in the definition of the abovementioned radicals are denoted by a fluorine, chlorine or bromine atom, by a d. 3- alkyl group, by a trifluoromethyl, C ⁇ _ 3 alkoxy, trifluoromethoxy, phenyl, amino, d -3 alkylamino, acetylamino, d -3 alkoxy carbonyl or cyano group may be substituted,
  • the carboxy groups mentioned in the definition of the abovementioned radicals may be replaced by a group convertible in vivo into a carboxy group or by a group negatively charged under physiological conditions and / or
  • X 2 is the group CR 2 ,
  • X 4 is the group CR 4 ,
  • R 1 , R 2 , R 3 and R 4 each represent a hydrogen atom or
  • one of the groups R 1 to R represent a fluorine, chlorine or bromine atom, a C ⁇ -3 alkyl group or a trifluoromethyl group and the remaining of the groups R 1 to R 4 each represents a hydrogen atom,
  • a a is a bond, an oxygen atom, a -CH 2 -, - (Cl - ⁇ )? .-; i NH->, or -N (C ⁇ -3 alkyl) group,
  • R a represents a phenyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl group
  • nitrogen atom of the pyrrolyl group may be substituted by a C 1-3 alkyl group and the phenyl group and the above-mentioned heteroaromatic groups in the carbon skeleton may be substituted by a fluorine, chlorine or bromine atom, by a C 1-3 alkyl or trifluoromethyl group can,
  • R 5 is a hydrogen atom
  • R 6 is a hydrogen atom or a C 3 alkyl group
  • R 7 is the group R d -CH 2 - or R d -CH 2 -CH 2 -, in which one hydrogen atom of the methylene group in position 1 may be replaced by a C 1-3 alkyl group or a cyclopropyl group and in which
  • R d is a phenyl, 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl or 5-pyrimidinyl group,
  • phenyl group and the above-mentioned heteroaromatic groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C 4 alkyl, trifluoromethyl d-, 3 alkoxy or fluoromethoxy group may be substituted,
  • the group R b -A b -E b -CH 2 - may be replaced a hydrogen atom of the methyl group in position 1 by a methyl group and in the O 03/05720
  • R b is an optionally substituted by a fluorine, chlorine or bromine atom, by a C ⁇ - alkyl, trifluoromethyl, hydroxy, methoxy, carboxy or methoxycarbonyl-substituted phenyl group,
  • a pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazole or thiadiazolyl group bonded via a carbon atom or, if A b is a bond, also via a nitrogen atom, in which one to a nitrogen atom -bonded hydrogen atom may be replaced by a C 3 alkyl group,
  • the two hydrogen atoms of the methylene group in the 3-position of the cyclopentyl group or in the 4-position of the cyclohexyl group may be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
  • the compounds of general formula I can be prepared by processes known from the literature, for example by the following processes: - 66 -
  • Xi to X 4 , R a , A a , R 5 and Het are defined as mentioned above and Z is a
  • R 6 and R 7 are defined as mentioned above.
  • reaction is conveniently carried out with a corresponding halide or anhydride of general formula II in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C performed.
  • an acid activating agent e.g. B.
  • Xi to X 4 , R a and A a are as defined above and Z represents a carboxy group or a reactive derivative of a carboxy group,
  • R 5 to R 7 and Het are defined as mentioned above.
  • reaction can be carried out according to the conditions mentioned above in process (a).
  • a compound of the general formula I which contains an olefinic double bond or a C-C triple bond it may be converted by means of catalytic hydrogenation into a corresponding alkyl or alkylene compound of the general formula I.
  • the subsequent acylation or sulfonylation is optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative optionally in the presence of a tertiary organic base or in the presence of an inorganic base or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N Hydroxysuccin
  • the post-alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • methyl iodide ethyl bromide, dimethyl sulfate or benzyl chloride
  • a tertiary organic base preferably at temperatures between 0 and 100 ° C.
  • the subsequent reductive alkylation is conveniently carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride at a pH of 6-7 and at room temperature or in the presence a hydrogenation catalyst, eg with hydrogen in the presence of palladium / carbon, carried out at a hydrogen pressure of 1 to 5 bar.
  • methylation is preferably carried out in the presence of formic acid as the reducing agent at elevated temperatures, e.g. at temperatures between 60 and 120 ° C, carried out.
  • the subsequent esterification is optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, or particularly advantageously in an appropriate alcohol optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, eg in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxybenzotriazole and, if appropriate additionally in the presence of 4-di
  • phosphine / carbon tetrachloride expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, carried out.
  • the subsequent amidation is carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding amine optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, wherein the amine used can simultaneously serve as a solvent, optionally in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, eg in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, O- (benzotriazol-1-yl) -N, N, N
  • the subsequent catalytic hydrogenation is carried out with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, if appropriate with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50.degree. but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar performed.
  • a catalyst such as palladium / carbon or platinum
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, if appropriate with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50.degree. but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar performed.
  • optionally present reactive groups such as hydroxyl, carboxy, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction. - 71 -
  • the protective radical for a hydroxy group is trimethylsilyl, tert-butyl-dimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl,
  • protective radicals for an amino, alkylamino or imino group the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally the phthalyl group for the amino group consideration.
  • cleavage of a used protective moiety takes place; for example, hydrolytically in an aqueous solution !, e.g. in water, isopropanol / water, acetic acid, water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • the cleavage of a silyl group can also be effected by means of tetrabutylammonium fluoride as described above.
  • the cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrestes example, hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • the cleavage of a 2,4-dimethoxybenzyl radical is preferably carried out in trifluoroacetic acid in the presence of anisole. - 72 -
  • tert-butyl or tert-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • Trifluoracetylrestes The cleavage of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid
  • sodium hydroxide optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
  • the cleavage of a phthalyl radical is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, oluol / water or. Dioxane at temperatures between 20 and 50 ° C.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be resolved into their enantiomers.
  • the cis- / trans mixtures obtained can be purified by chromatography into their cis and trans isomers, the compounds of general formula I which are obtained in racemates, by methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I having at least 2 asymmetric carbon atoms due to their physico-chemical differences according to known methods, eg by chromatography and / or fractional crystallization , into their diastereomers - 73 -
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts or derivatives such as esters or amides forming optically active substance, in particular acids and their activated derivatives or alcohols, and Separation of the thus obtained diastereomeric salt mixture or derivative, for example due to different solubilities, wherein from the pure diastereomeric salts or derivatives, the free antipodes can be released by the action of suitable agents.
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-toluenoic, malic, mandelic, camphorsulfonic, glutamic, aspartic or. • China ⁇ ä .rSi be for example (+) An optically active alcohol - or. (-) - menthol and an optically active acyl group in amides, for example (+) - or (-) - carbonyl Menthyloxy- into consideration.
  • the resulting compounds of the formula I can be converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts with inorganic or organic acids.
  • suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • novel compounds of the formula I thus obtained if they contain an acidic group such as a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for the pharmaceutical application into their physiologically tolerated salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • a compound of the general formula II is obtained, for example, by reacting a compound of the general formula
  • Z 1 represents a carboxy group or a reactive derivative of a carboxy group, with an amine of the general formula
  • R 5 and Het are defined as mentioned above and Z 2 represents a protective group for a carboxy group, followed by removal of the protective group.
  • the amines of general formula III are known from the literature or accessible by literature methods.
  • aromatic or heteroaromatic carboxylic acids according to the general formula IV are known from the literature or can be prepared by literature methods from corresponding aryl or heteroaryl starting materials. - 75 -
  • amino-heteroarylcarbonklarileamide according to the general formula V are also known from the literature or can be prepared in a simple manner from optionally substituted amino-heteroarylcarbonklaren by reaction with the corresponding amines or nitro-heteroarylcarbonklaren by reaction with the corresponding amines and subsequent reduction of the nitro group.
  • the compounds of general formula I and their physiologically acceptable salts have valuable pharmacological properties. These represent, in particular, valuable inhibitors of microsomal triglycerides. - 76 -
  • the compounds of the invention can be tested for their biological effects as follows:
  • Inhibitors of MTP were identified by a cell-free MTP activity assay. Solubilized liver microsomes from different species (eg rat, pig) can be used as MTP source.
  • Solubilized liver microsomes from different species eg rat, pig
  • MTP source e.g. rat, pig
  • the solution used to make donor vesicles contained 400 ⁇ M phosphatidylcholine, 75 ⁇ M cardiolipin and 10 ⁇ M [ 14 C] triolein (68.8 ⁇ Ci / mg).
  • a solution of 1.2 mM P osphatidylchoiin, 5 ⁇ M triolein and 15 ⁇ M [ 3 H] dipalmitoylphosphatidylcholine (108 mCi / mg) was used.
  • Vesicles are formed by wetting the dried lipids with test buffer and subsequent sonication. Vesicle populations of uniform size were obtained by gel filtration of the sonicated lipids.
  • the MTP activity test contains donor vesicles, acceptor vesicles and the MTP source in assay buffer. Substances were added from concentrated stock solutions containing DMSO, the final concentration of DMSO in the test was 0.1%. The reaction was started by addition of MTP.
  • n is the number 2, 3, 4 or 5
  • X is a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N- (C 1-3 -alkyl) -imino group,
  • Y a is a carbonyl or sulfonyl group
  • Yb represents the group - (CH 2) m -, where m is the number 2 or 3 and in which one hydrogen atom is replaced by a C 3 alkyl group or a nitrogen atom linked to a methylene group may be replaced by a carbonyl group,
  • R a is a d- ⁇ -alkoxy, phenyl-d -3 -alkoxy or amino group, wherein the amino group by C. May be mono- or disubstituted 3- alkyl, phenyl-d- 4- alkyl or phenyl groups and the substituents may be the same or different,
  • a phenyl, naphthyl, tetrahydronaphthyl, phenoxy or heteroaryl group an optionally represented by a hydroxy, d- 3- alkoxy, C ⁇ - 4 alkoxycarbonyl or - 78 -
  • Ci-g-alkyl group substituted in the alkyl moiety by a -C 3 alkyl group, by one or two phenyl groups, by a naphthyl, Fluorenyi-, phenoxy, heteroaryl or C 3-7 cycloalkyl group may be, or substituted by a phenyl group C 3 - 7 cycloalkyl group,
  • a phenylcarbonyl, naphthylcarbonyl, Tetrahydronaphthylcarbonyl-, phenoxy carbonyl or heteroarylcarbonyl group an alkylcarbonyl group C ⁇ - 9, which in the alkyl moiety by one or two phenyl groups, by a naphthyl, Fluorenyi-, phenoxy, heteroaryl or C 3 - 7 -cycloalkyl group may be substituted, or substituted by a phenyl group C 3 _ 7 -cycloalkylcarbonyl group,
  • R a phenyl, naphthyl and heteroaryl parts may be substituted by the radicals Ri and R 2 , wherein
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ -3 alkyl, hydroxy or C ⁇ _4-alkoxy wherein in the above-mentioned alkyl and Alk 2 oxy turnover of the radicals R 1 and R are hydrogen atoms in each case wholly or partly replaced by fluorine atoms, or
  • Ri and R 2 together represent a methylenedioxy group
  • R a may each be substituted by three chlorine or bromine atoms or by three to five fluorine atoms, - 79 -
  • R b is a carboxy, C ⁇ - 6 alkoxycarbonyl, C ⁇ - 6 alkoxycarbonyl -C. 3 -alkylcarbonyl, C 3 - 7 -cycloalkoxycarbonyl or phenyl-d- 3- alkoxycarbonyl group or an R 3 NR -CO-group in which
  • R 3 and R 4 which may be identical or different, are hydrogen atoms, d- 6 alkyl groups, in which the hydrogen atoms may be replaced by fluorine atoms entirely or partially and the alkyl portion of a C ⁇ -3 C ⁇ - 3 alkylamino group by Carboxy- or d- 3 alkoxycarbonyl or in the 2- or 3-position may also be substituted by an amino, C ⁇ -3 -alkylamino or di- (C ⁇ -3 alkyl) - amino group, C 3-7 -cycloalkyl -, pyridyl, pyridinyl- d- 3 -alkyl, phenyl, naphthyl or phenyl -C ⁇ .
  • Alkyl groups 3 wherein the aforementioned phenyl groups in each case by a fluorine, chlorine or bromine atom, by a C 3 alkyl group in which the hydrogen atoms may be replaced by fluorine atoms entirely or partially, by a hydroxy, d- 3 - alkoxy, carboxy, C ⁇ - 3 alkoxycarbonyl, aminocarbonyl, aminocarbonyl C ⁇ - 3 alkyl, N, N-di- (3 C ⁇ - alkyl) -aminocarbonyl or N, N-di- (C ⁇ - 3- alkyl) - amino group may be substituted, or
  • R 3 and R 4 together with the intervening nitrogen atom, a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 in a 6- or 7-membered cycloalkyleneimino group additionally by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (C ⁇ -3 alkyl) may be substituted imino, showing,
  • R c represents a hydrogen atom or a C ⁇ -3 -Alkylgmppe
  • tricyclic group in the above-mentioned general formula I may additionally be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents may be the same or different, - 80 -
  • heteroaryl groups a 6-membered heteroaryl group containing one, two or three nitrogen atoms, or
  • a 5-membered heteroaryl group containing an optionally substituted by a C ⁇ - 3 alkyl imino group, an oxygen or sulfur atom or
  • Residues mentioned carboxy group may also be replaced by a in vivo into a carboxy group convertible group or by a negatively charged group under physiological conditions,
  • a very particularly preferred embodiment relates to combinations of one of the following MTP inhibitors with fibrates, in particular with fenofibrate:
  • MTP inhibitors can also be used according to the invention:
  • fibrates invention for example the following compounds can be used (International Nonproprietary Name): bezafibrate ciprofibrate clofibrate fenofibrate gemfibrozil '
  • the substances generally and specifically mentioned in the invention are administered systemically, e.g. oral or parenteral. Preference is given to oral administration. They may be included in systemic formulations such as tablets, capsules, powders, solutions, suspensions, injection formulations or the like. Suitable pharmaceutically acceptable carriers that can be used with the substances of this invention include, for example, inert solid fillers or diluents, as well as sterile aqueous or organic solutions. If necessary, other substances may be added to the pharmaceutical compositions, such as anti-oxidants, lubricants, buffers, fragrances and sweeteners.
  • MTP inhibitors and fibrates can be administered either in separate systemic formulations or in a single formulation.
  • the dosage in which a substance of this invention is administered to warm-blooded animals, including humans, may be varied according to the physical condition. This includes consideration of, for example - 84 -
  • the dosage is further determined by the mode of administration.
  • the daily dose of MTP inhibitor will be between about 0.5 mg and about 500 mg, preferably between 1 mg and 200 mg. Particularly preferred is the range between 1 mg and 50 mg. This amount can be administered as a single dose or divided into multiple doses.
  • the daily dose of fibrate will be between about 50 mg and about 5000 mg, preferably between 50 mg and 1000 mg. Particularly preferred is the range between 50 and 600 mg. This amount can be administered as a single dose or divided into multiple doses.
  • Hyperlipemic rats eg the rat strain fa / fa
  • the concentrations of cholesterol and triglycerides as well as the activities of the liver enzymes are determined by well-known methods of clinical chemistry.
  • These substrates and enzymes in the plasma can be measured, for example, with a HITACHI 917 Automatic Analyzer using reagents from Roche Diagnostics (Mannheim) in accordance with the following protocols from Roche Diagnostics: ALT: BM / HITACHI 917 / Keysys no. 1876805
  • Triglycerides BM / HITACHI 917, Boehringer Mannheim System No. 1,730,711.
  • the liver can be harvested to detect hepatic steatosis by measuring the lipid content (triglycerides, free fatty acids, cholesterol) in this organ.
  • lipid content triglycerides, free fatty acids, cholesterol
  • 200 mg of liver are homogenized after addition of 2 ml of isopropanol and extracted with shaking for 10 min. The extract is centrifuged for 10 min at 4 ° C and 4000 rpm and an aliquot of the supernatant used to determine the lipid parameters.
  • the measurement of the lipids in the liver is carried out using commercially available test kits according to the manufacturer's instructions (for triglycerides: triglyceride Duo S from BIOMED Laboratory Diagnostics GmbH, Oberschleissheim, for cholesterol: cholesterol Duo S from BIOMED Laboratory Diagnostics GmbH, Oberschl oftenheim for free fatty acids: NEFA C from Wako Chemicals GmbH, Neuss).
  • FIG. 1a shows the plasma content of cholesterol following administration of an MTP inhibitor alone (M), after administration of a fibrate alone (F) or after administration of a MTP inhibitor alone Combination of MTP inhibitor and fibrate (M + F) and the corresponding content of an untreated control group.
  • Figure 1b shows the plasma content of triglycerides after administration of an MTP inhibitor alone (M), after administration of a fibrate alone (F) or after administration of a combination of MTP inhibitor and fibrate (M + F) and the corresponding content one untreated control group.
  • the numbers above the bar of the chart indicate the percentage changes from the control group.
  • Figures 2a and 2b also relate to the first pharmacological example (Example A) and show in the blood plasma of the activity of alanine aminotransferase (ALT, Figure 2a) and glutamate dehydrogenase (GLDH, Figure 2b), which is a characteristic sign of the Damage to liver cells is the side effects of administration of an MTP inhibitor alone (M), a fibrate alone (F) and a combination of MTP inhibitor and fibrate (M + F) in comparison - 86 -
  • MTP inhibitor alone M
  • F fibrate alone
  • M + F combination of MTP inhibitor and fibrate
  • FIGS. 3a and 3b show the content of triglycerides or of free fatty acids in the liver, respectively, after administration of an MTP inhibitor alone (M), a fibrate alone (F) or a combination of MTP inhibitor and fibrate ( M + F) according to pharmacological Example B compared to a control group.
  • the fibrate was bezafibrate at a dosage of 100 mg / kg. Twenty four hours after the last administration of the MTP inhibitor or 15 hours after the last administration of the fibrate, the animals were bled and plasma cholesterol, triglycerides and liver enzymes were measured. Compared with the control group, which was treated with vehicle twice a day, the MTP inhibitor lowered the triglycerides in the plasma by 84%, the fibrate by 56% and the combination of both by 91%. Plasma cholesterol was lowered by 29% by the MTP inhibitor, by 47% by the fibrate and by 76% by the combination. This shows that the effects of MTP inhibitor and fibrate complement the plasma lipid levels ( Figures 1a and 1b). The numbers above the bar of the graph indicate the percentage change from the control group.
  • MTP inhibitor was 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] -piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluoren-9-carboxamide at a dose of 0.3 mg / kg.
  • the fibrate was bezafibrate at a dosage of 100 mg / kg. 24 hours after ;
  • the MTP inhibitor leads to an increase of the triglycerides and the free fatty acids in the liver (FIGS. 3a and 3b).
  • the lipid accumulation caused by the MTP inhibitor is reduced by about 50% (triglycerides in the liver) or by about 80% (free fatty acids in the liver).
  • MTP inhibitor was N- [4- (3-aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl- pyrrole-2-carboxylic acid amide (compound (c)) at a dosage of 10 mg / kg.
  • the fibrate was fenofibrate at a dosage of 100 mg / kg. 24 hours after the last dose of the MTP inhibitor or 15 hours after the last dose of 88
  • Fenofibrate was bled from the animals and plasma cholesterol, triglycerides and liver enzymes were measured.
  • the MTP inhibitor Compared to the control group, which was treated with vehicle twice a day, the MTP inhibitor lowered plasma cholesterol by 58%, fenofibrate by 15% and the combination of both by 68%. Plasma triglycerides were reduced by 94% by the MTP inhibitor, by 20% by fenofibrate and by 87% by combination of both. As in Example A, these data demonstrate that the effects of MTP inhibitor and fibrate can complement plasma lipid levels.
  • liver enzymes in plasma The effects of the treatment on the activity of liver enzymes in plasma can be found in the following table: 89
  • the side effects of the MTP inhibitor on the liver are indicated by a 4.5-fold (AST) and a 3.6-fold increase in the activity of these transaminases in plasma. Combined with fenofibrate, this increase is completely normalized.
  • MTP inhibitor was N- [3- (biphenyl-4-yl) -prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide (Compound (a)) in a dosage of 3 mg / kg.
  • the fibrate was fenofibrate at a dosage of 100 mg / kg. 24 hours after the last administration of the MTP inhibitor or 15 hours after the last administration of fenofibrate, the animals were bled and plasma cholesterol, triglycerides and liver enzymes were measured.
  • the side effects of the MTP inhibitor on the liver are due to a 6.7-fold (AST) or a 5-fold increase in the activity of these transaminases in the plasma 91 -
  • the active ingredient is mixed for 15 minutes together with lactose monohydrate, microcrystalline cellulose and carboxymethylcellulose sodium in a suitable diffusion mixer. Magnesium stearate is added and mixed with the remaining materials for a further 3 minutes.
  • the finished mixture is pressed on a tablet press into round, flat tablets with facet.
  • Diameter of the tablet 7 mm; Weight of one tablet: 120 mg 92 -
  • a starch paste is made by swelling some of the cornstarch with an appropriate amount of hot water. The paste is then allowed to cool to room temperature.
  • the active ingredient is premixed in a suitable mixer with lactose monohydrate and corn starch for 15 minutes.
  • the starch paste is added and the mixture is sufficiently mixed with water to obtain a homogeneous wet mass.
  • the moist mass is passed through a sieve with a mesh size of 1, 6 mm.
  • the sieved granules are dried on trays at about 55 ° C for 12 hours.
  • the dried granules are then passed through sieves of mesh sizes 1, 2 and 0.8 mm. Fumed silica is mixed in a suitable mixer in 3 minutes with the granules. Thereafter, magnesium stearate is added and mixed for a further 3 minutes.
  • the finished mixture is filled with the aid of a capsule filling machine into empty capsule capsules of size 1 gelatin. - 93 -
  • HPMC hydroxypropyl methylcellulose
  • the active ingredients are premixed in a suitable mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose.
  • the HPMC solution is added and mixing continued until a homogeneous wet mass is obtained.
  • the wet mass is passed through a sieve with a mesh size of 1, 6 mm.
  • the sieved granules are dried on trays at about 55 ° C for 12 hours.
  • magnesium stearate is added and mixed for a further 3 minutes.
  • the finished mixture is pressed on a tablet press to oblong-shaped tablets (16.2 x 7.9 mm).
  • HPMC HPMC is dispersed in hot water. The mixture gives a clear solution after cooling.
  • the active ingredients are premixed in a suitable mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose.
  • the HPMC solution is added and mixing continued until a homogeneous wet mass is obtained.
  • the moist mass is passed through a sieve with a mesh size of 1, 6 mm. - 95 -
  • the sieved granules are dried on trays at about 55 ° C for 12 hours.
  • the dried granules are then passed through sieves of mesh size 1, 2 and 0.8 mm.
  • Poly-1-vinyl-2-pyrrolidone is mixed in a suitable mixer for 15 minutes with the granules. Thereafter, magnesium stearate is added and mixed for a further 3 minutes.
  • the finished mixture is pressed on a tablet press to oblong-shaped tablets (16.5 x 8.5 mm). Weight of one tablet: 615 mg
  • Example 1d Prepared analogously to Example 1d from 2- (biphenyl-2-carbonylamino) -thiazole-4-carboxylic acid, 4-phenylbenzylamine, TBTU and N-ethyldiisopropylamine in
  • Example 1d Prepared analogously to Example 1d from 2- (biphenyl-2-carbonylamino) -thiazole-4-carboxylic acid, 4-benzoylaminobenzylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
  • Catalyst is filtered off and the solution is evaporated.
  • Example 1d Prepared analogously to Example 1d from 5- (4'-trifluoromethyl-biphenyl-2-carbonylamino) nicotinic acid, 4- (3-methyl-5-phenyl-pyrazol-1-yl) -benzylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide. - 104 -
  • Example 11 Prepared analogously to Example 11 from 4- (6-methyl-pyridazin-3-yl) -benzylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-imidazole-2-carboxylic acid in dichloromethane with the addition of Propane phosphonic acid cyclohexane and N-methylmorpholine.
  • Example 11 Prepared analogously to Example 11 from 4- (1,4-dioxa-spiro [4.5] dec-8 ⁇ yS) -benzyIamin and 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxylic acid in Dichloromethane with the addition of propanephosphonic anhydride and N-methylmorpholine.
  • Example 1d Prepared analogously to Example 1d from 4'-methylbiphenyl-4-methyl-amine, 4- (biphenyl-2-carbonylamino) -1-methylpyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
  • Example 1d Prepared analogously to Example 1d from 4- (N-methyl-N-cyclohexylaminocarbonyl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methylpyrrole-2-carboxylic acid, TBTU and N- Ethyldiisopropylamine in dimethylformamide.

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PCT/EP2003/000057 2002-01-10 2003-01-07 KOMBINATION VON MTP INHIBITOREN ODER apoB-SEKRETIONS-INHIBITOREN MIT FIBRATEN ZUR VERWENDUNG ALS ARZNEIMITTEL WO2003057205A2 (de)

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CA002471566A CA2471566A1 (en) 2002-01-10 2003-01-07 Combination of mtp inhibitors or apob-secretion inhibitors with fibrates for use as pharmaceuticals
JP2003557563A JP2005525309A (ja) 2002-01-10 2003-01-07 医薬品としての使用のためのＭＴＰインヒビター又はａｐｏＢ分泌インヒビターとフィブレートの組み合わせ
AU2003205570A AU2003205570A1 (en) 2002-01-10 2003-01-07 Combination of mtp inhibitors or apob secretion inhibitors with fibrates for use as drugs
EP03702391A EP1465613A2 (de) 2002-01-10 2003-01-07 KOMBINATION VON MTP INHIBITOREN ODER apoB-SEKRETIONS-INHIBITOREN MIT FIBRATEN ZUR VERWENDUNG ALS ARZNEIMITTEL

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DE10200633.4 2002-01-10
DE2002100633 DE10200633A1 (de) 2002-01-10 2002-01-10 Kombination von MTP Inhibitoren oder apoB-Sekretions-Inhibitoren mit Fibraten zur Verwendung als Arzneimittel
DE10256184A DE10256184A1 (de) 2002-12-02 2002-12-02 Kombination von MTP Inhibitoren oder apoB-Sekretions-Inhibitoren mit Fibraten zur Verwendung als Arzneimittel
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WO2004056777A1 (en) * 2002-12-20 2004-07-08 Pfizer Products Inc. Microsomal triglyceride transfer protein inhibitors
WO2005035503A1 (ja) * 2003-10-15 2005-04-21 Ube Industries, Ltd. 新規イソキノリン誘導体
WO2006112703A2 (en) * 2005-04-20 2006-10-26 Academisch Medisch Centrum Bij De Universiteit Van Amsterdam Induction of omega-oxidation of fatty acids by cytochrome p450 for counteracting fatty acid accumulation
JP2009502816A (ja) * 2005-07-29 2009-01-29 ４エスツェー アクチェンゲゼルシャフト 新規ヘテロ環状ＮＦ−κＢ阻害剤
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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GB0215293D0 (en) 2002-07-03 2002-08-14 Rega Foundation Viral inhibitors
AU2004309390B2 (en) 2003-12-22 2011-06-02 Gilead Sciences, Inc. Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment
JP2008524335A (ja) 2004-12-21 2008-07-10 ギリアド サイエンシズ， インコーポレイテッド イミダゾ［４，５−ｃ］ピリジン化合物および抗ウイルス処置法
ES2339298T3 (es) 2006-07-07 2010-05-18 Gilead Sciences, Inc. Compuesto de piridazina novedoso y uso del mismo.
JP5642922B2 (ja) * 2007-04-24 2014-12-17 サントリーホールディングス株式会社 複数の肝障害マーカーを指標とする肝障害の評価方法
TWI444379B (zh) * 2007-06-29 2014-07-11 Sunesis Pharmaceuticals Inc 有用於作為Ｒａｆ激酶抑制劑之化合物
UA99466C2 (en) 2007-07-06 2012-08-27 Гилиад Сайенсиз, Инк. Crystalline pyridazine compound

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WO2003004020A1 (de) * 2001-07-05 2003-01-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Heteroarylcarbonsäureamide, ihre herstellung und ihre verwendung als inhibitoren des mikrosmalen triglycerid-transferproteins (mtp)

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EP1099701A1 (en) * 1999-11-10 2001-05-16 Pfizer Products Inc. 7-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)amino]-quinoline-3-carboxylic acid amides, and methods of inhibiting the secretion of apolipoprotein B
DE10033337A1 (de) * 2000-07-08 2002-01-17 Boehringer Ingelheim Pharma Biphenylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2003004020A1 (de) * 2001-07-05 2003-01-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Heteroarylcarbonsäureamide, ihre herstellung und ihre verwendung als inhibitoren des mikrosmalen triglycerid-transferproteins (mtp)

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SUDHOP T ET AL: "CHOLESTEROL ABSORPTION INHIBITORS FOR THE TREATMENT OF HYPERCHOLESTEROLAEMIA" DRUGS, ADIS INTERNATIONAL LTD, AT, Bd. 62, Nr. 16, 2002, Seiten 2333-2347, XP008011717 ISSN: 0012-6667 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056777A1 (en) * 2002-12-20 2004-07-08 Pfizer Products Inc. Microsomal triglyceride transfer protein inhibitors
WO2005035503A1 (ja) * 2003-10-15 2005-04-21 Ube Industries, Ltd. 新規イソキノリン誘導体
WO2006112703A2 (en) * 2005-04-20 2006-10-26 Academisch Medisch Centrum Bij De Universiteit Van Amsterdam Induction of omega-oxidation of fatty acids by cytochrome p450 for counteracting fatty acid accumulation
WO2006112703A3 (en) * 2005-04-20 2007-05-18 Amc Amsterdam Induction of omega-oxidation of fatty acids by cytochrome p450 for counteracting fatty acid accumulation
JP2009502816A (ja) * 2005-07-29 2009-01-29 ４エスツェー アクチェンゲゼルシャフト 新規ヘテロ環状ＮＦ−κＢ阻害剤
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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