DE10256184A1 - Reducing hepatotoxicity of microsomal triglyceride transfer protein inhibitors, used e.g. in treatment of hyperlipemia, atherosclerosis or diabetes, by co-administration with fibrate - Google Patents

Abstract

The invention relates to the use of fibrates to reduce the liver toxicity of MTP inhibitors and pharmaceutical compositions containing an MTP inhibitor and a fibrate.

Description

The invention relates to the use a combination of microsomal triglyceride transfer inhibitors Proteins (MTP) with fibrates for the treatment of hyperlipidemia, dyslipidemia, atherosclerosis, Diabetes mellitus, obesity and pancreatitis with the purpose of Mechanism-related side effects of an MTP inhibitor in the Reduce liver by combining with a fibrate while doing so to get the effect of the MTP inhibitor at least, drug containing this combination and its manufacture. MTP inhibitors lower the lipid concentration in the blood by reducing the secretion of Apolipoprotein B (apoB) -containing lipoproteins inhibit in the liver and intestines. Lipid accumulation occurs (Steatosis) in the target organs, specifically in the liver to one cell damage to lead can. The cell damage can be recognized by positive liver function tests (e.g. increase in transaminases).

Surprisingly it has now been found that the steatosis caused by MTP inhibitors in combination with fibrates, that stimulate fatty acid metabolism in the liver, is reduced and that the Liver function tests can be normalized. On the one hand, the Received positive therapeutic effect of the MTP inhibitors, thereby but at the same time prevents the mechanism-related toxicity. By the combination with fibrate can also be the positive lipid modulating Effect of the MTP inhibitor increased become (synergistic effect). The invention relates to all MTP inhibitors. All fibrates are also included. The administration of the two active substances can take place simultaneously in one single drug preparation or consecutively in two drug preparations respectively. Application in a single preparation is preferred.

BACKGROUND OF THE INVENTION

1. Microsomal inhibitors Triglyceride transfer protein

Microsomal triglyceride transfer protein (MTP) catalyzes the transport of lipids between phospholipid surfaces [Wetterau JR et al., Biochim Biophys Acta 1345, 136-150 (1997)]. The protein is located in the lumen of liver and intestinal microsomes. MTP is a heterodimer, that from an MTP-specific large subunit (97 kD) and consists of protein disulfide isomerase (PDI, 58 kD). PDI is a wide one common protein of the endoplasmic reticulum (ER) and a for the structural and functional integrity of MTP essential component. MTP is necessary for the intracellular Production of apolipoprotein B (apoB) -containing plasma lipoproteins. Even though the exact role of MTP in the assembly of lipoproteins is not is known, it most likely transports lipids out of the Membrane of the ER to the lipoprotein particles that form in the lumen of the ER.

Apolipoprotein B is the main protein component Hepatic VLDL (very low density lipoproteins) and intestinal Chylomicrons. Substances that inhibit MTP reduce secretion apoB-containing lipoproteins [Haghpassand M et al., J Lipid Res 37, 1468-1480 (1996); Jamil H et al., Proc Natl Acad Sci USA 93, 11991-11995 (1996); Wetterau JR et al., Science 282, 751-754 (1998)]. Therefore humiliated inhibition of MTP and cholesterol plasma concentrations Triglycerides in apoB-containing lipoproteins. This could be done in hamsters and rabbits [Wetterau JR et al., Science 282, 751-754 (1998)], in heterozygous MTP-deficient mice [Raabe M et al., Proc Natl Acad Sci USA 95, 8686-8691 (1998)] and in human clinical studies [Roevens P et al., Atherosclerosis 144, 38-39 (1999); Wilder DE, Drugs Affecting Lipid Metabolism - XIVth International Symposium, New York, NY, USA, September 9-12, 2001, abstract; Famier M, Drugs Affecting Lipid Metabolism - XIVth International Symposium, New York, NY, USA, 9-12 September 2001, abstract].

ApoB-containing triglyceride-rich lipoproteins and their cholesterol-enriched remains (e.g. LDL) are atherogenic and contribute to morbidity and mortality coronary artery disease. The relationship between the concentration LDL cholesterol (or total cholesterol as a closely related representative parameter) and clinical findings is general accepted. Numerous intervention studies have a reduction coronary events shown under lipid-lowering treatment. On There was an advantage in 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. 6, 1245-1255 (1986)]) as well normal to borderline cholesterol levels (LIPID [Anonymous, New England Journal of Medicine 19, 1349-1357 (1998)], CARE [Pfeffer MA et al., Journal of the American College of Cardiology 1, 125-130 (1999)], LRC-CPPT [Anonymous, Archives of Internal Medicine 7, 1399-1410 (1992)], Helsinki Heart Study [Frick MH et al., New England Journal of Medicine 20, 1237-1245 (1987)]), and also in primary prevention by people with elevated Cholesterol levels (WOSCOPS [Shepherd J et al., New England Journal of Medicine 20, 1301-1307 (1995)]) and without increased Cholesterol levels (AFCAPS [Downs JR et al., JAMA 20, 1615-1622 (1998)]).

In a recent meta-analysis of 17 prospective studies, triglyceride levels were elevated mirrors an independent risk factor for coronary artery disease [Austin MA et al., American Journal of Cardiology 4A, 7B-12B (1998)]. The ARIC study has shown that elevated postprandial triglyceride levels are an independent risk factor for atherosclerosis, even after taking the fasting lipid levels into account [Sharrett AR et al., Arterioscler Thromb Vasc Biol 15, 2122-2129 (1995)]. In the guidelines of the National Cholesterol Education Program of the National Heart, Lung and Blood Institute of the USA (Adult Treatment Panel III, ATP III), elevated triglyceride levels are regarded as an independent risk factor for atherosclerosis and coronary heart disease [JAMA 285, 2486–2497 (2001 )]. There are also indications that other lipid parameters associated with apoB, such as Lp (a), are risk factors for the development of atherosclerotic cardiovascular diseases [Ridker PM et al., JAMA 270, 2195-2199 (1993); Bostom AG et al., JAMA 276, 544-548 (1996)].

Substances that have MTP in the liver or inhibit in the intestine are therefore useful for lowering the concentration of apoB-containing lipoproteins in plasma. This closes the states more general and postprandial hypercholesterolemia and hypertriglyceridemia on. Treatment of elevated levels is also included from Lp (a). Because apoB-containing lipoproteins for the development of atherosclerosis contribute, these substances are also useful for prevention and treatment atherosclerotic diseases. They are also useful for Treatment of dyslipidemic conditions and complications from related diseases such as diabetes mellitus (Type II diabetes), obesity and pancreatitis. The inhibition of intestinal absorption of fats from food by inhibitors of the MTP is useful for the treatment of diseases such as obesity and diabetes mellitus, where excessive fat intake makes a significant contribution to the development of the disease [Grundy SM, Am J Clin Nutr 57 (suppl), 563S-572S (1998)].

2. Fibrates

Derivatives of fibric acid (fibrates) are a class of substances that lower lipids, above all Reduce plasma triglycerides and increase HDL cholesterol [Miller DB & Spence JD, Clin Pharmacokinet 34, 155-162 (1998)]. The effects on LDL cholesterol, however, are less pronounced and more variable. The VA-HIT study (Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial) first shown that a increase of HDL cholesterol morbidity and mortality decreased [New England Journal of Medicine 431, 410-418 (1999)]. Clofibrate belongs to the class of fibrates on the market [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 J 19 Suppl A, A62-A65 (1998)] and Gemfibrozil [Spencer CM & Barradell LB, Drugs 51, 982-1018 (1996)].

The clinical effects of fibrates are through change in the transcription of genes that have important roles play in lipid metabolism.

Changes in transcription is based on the activation of a transcription factor that activates the peroxisome proliferator Receptor alpha (PPARα). Peroxisome proliferator-activated receptors (PPARs) belong to the Family of nuclear Hormone receptors. PPAR, the first identified member of this family is mainly in Expressed tissues that have a high rate of β-oxidation (liver, Kidney, heart, muscle). PPARα will through fatty acids in food, through eicosanoids and pharmacologically through fibrates activated. Mechanically, fibrates are PPARα agonists [Gervois P et al., Clin Chem Lab Med 38, 3-11 (2000)]. PPARα mediates the lipid-modifying effects of fibrates in treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPARα will regarded as the main regulator of intra- and extracellular lipid metabolism. After activation by fibrates, PPARα regulates the expression of apolipoprotein C-III gene down and expression of the lipoprotein lipase gene high, resulting in reinforcement of VLDL catabolism. additionally leads the Activation of PPARα too an induction of the genes for Apolipoprotein A-I and A-II, resulting in an increase in HDL cholesterol results. PPARα activation also upregulates the genes for the cholesterol transporters ABCA-1 and SR-B1 and thus an increase in reverse cholesterol transport.

In connection with the present The role of PPARα in intracellular lipid metabolism is particularly important to the invention plays [Everett L et al., Liver 20, 191-199 (2000)]. Activation of PPARα conditional an increase the gene expression of enzymes that are required for the β-oxidation of fatty acids. To belong first Enzymes of fatty acid activation (Acyl-CoA synthetase, fatty acid binding Proteins) and enzymes that mediate the entry of fatty acids into mitochondria (Carnitine palmitoyl transferase I). In addition, the enzymes of mitochondrial β-oxidation of fatty acids induced (e.g. acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase). In rodents in particular, enzymes of peroxisomal β-oxidation are also found of fatty acids (e.g. acyl-CoA oxidase) and the microsomal ω-oxidation of fatty acids (e.g. cytochrome P450 4A1 (Lauryl ω-hydroxylase)) upregulated.

DETAILED DESCRIPTION

MTP inhibitors lower the fasting concentration of cholesterol and triglycerides in the blood by reducing secretion of lipoproteins in the liver (Very Low Density Lipoproteins, VLDL) inhibit. The lipids accumulate in the hepatocytes (hepatic steatosis). As soon as a certain degree of steatosis is reached is leads this causes injury of the liver cells. This cell damage is recognizable by the release of intracellular enzymes, which then occur more in the blood. To those enzymes that indicate hepatocellular damage, belong alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). The through hepatic Steatosis-related cell damage restricts very strongly the use of effective MTP inhibitors.

The present invention shows one Way on, the mechanism-related side effects of an MTP inhibitor decrease in the liver. When combining an MTP inhibitor with a fibrate, the β-oxidation of fatty acids in the liver by PPARα agonism of the fibrate stimulated. Those from the accumulated triglycerides fatty acids released after hydrolysis can thus be broken down to an increased extent become. The liver's levels of triglycerides and free fatty acids decrease. The hepatic steatosis is thereby reduced to a level that is no longer harmful for the Is liver cells. This may be due to normalization of the hepatocellular enzymes be recognized in the blood. In this way, effective lipid lowering, which cause MTP inhibitors in the blood without toxic side effects be preserved in the liver.

Another aspect of the invention is that the effects of MTP inhibitors and fibrates on lipids in the blood complete. Lowering cholesterol and triglycerides can be done by combining the strengthened in both drug classes become. About that It is also a special property of fibrates, HDL cholesterol to increase. this makes possible it, the effectiveness of MTP inhibitors on lowering triglycerides and atherogenic cholesterol in apolipoprotein B-containing lipoproteins with a desired increase of HDL cholesterol by combining fibrates.

The invention relates generally on the combination of any MTP inhibitor with any Fibrate to prevent mechanism-related liver toxicity from MTP Inhibitors. At the same time, the desired effect of the MTP inhibitor strengthened.

deren Tautomere, deren Diastereomere, deren Enantiomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträglichen Salze, verwendet werden.According to the invention, for example MTP inhibitors of the general formula 1

their tautomers, their diastereomers, their enantiomers, their mixtures and their salts, in particular their physiologically tolerable salts, are used.

In the general formula I mean
X ₁ the group CR ¹ ,
X ₂ the group CR ² ,
X ₃ the group CR ³ and
X _{4 is} the group CR ⁴ or
one or two of the groups X ₁ to X ₄ each have a nitrogen atom and the rest 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, independently of one another, in each case a fluorine, chlorine or bromine atom, a C _1-3 alkyl group, a trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, Represent C _1-3 alkylamino or di (C _1-3 alkyl) amino group and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom,
where R ⁴ together with R ^{5 can} additionally 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,
one of the groups -CH ₂ -, - (CH ₂ ) ₂ -, -CH = CH-, -C≡C-, -OCH ₂ -, -CH ₂ O-, -NH-CH ₂ -, -CH ₂ - NH-, -NH-CO-, -CO-NH-, -NH-SO ₂ - or -SO ₂ -NH-,
in which a hydrogen atom bonded to a carbon atom and / or a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a C _1-3 alkyl group and wherein a hetero atom from group A ^a does not have a nitrogen atom from a 5-membered heteroaryl group from group R ^a is linked
R ^{a is} a phenyl, 1-naphthyl or 2-naphthyl group,
a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the
an imino group optionally substituted by a C _1-4 alkyl or C _1-4 alkylcarbonyl group, an oxygen or sulfur atom,
an imino group optionally substituted by a C _1-4 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C _1-4 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a 6-membered heteroaryl group containing one or two nitrogen atoms,
wherein 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 and
wherein the above-mentioned phenyl and naphthyl groups and the mono- and bicyclic heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl group, by a C _3-7 cycloalkyl, trifluoromethyl, phenyl -, Hydroxy-, C _1-3 -alkoxy-, trifluoromethoxy-, amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino-, acetylamino-, N- (C _1-3 -Alkyl) -acetylamino-, propionylamino-, N- (C _1-3 -alkyl) -propionylamino-, acetyl-, propionyl-, C _1-3 -alkoxy-carbonyl-, aminocarbonyl-, C _1-3 -alkylamino- carbonyl, di (C _1-3 alkyl) amino carbonyl or cyano group monosubstituted or, with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, can also be disubstituted by the abovementioned substituents, where the substituents are identical or can be different
a C _3-7 cycloalkyl group, wherein
each the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical through an oxygen or sulfur atom, through a sulfinyl or sulfonyl group or through an optionally by a C _1-5 alkyl, phenyl, C _1-4 Alkyl carbonyl, C _1-4 alkoxy carbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted imino group can be replaced,
a 4- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
each the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a hydroxycarbonyl, C _1-3 alkoxycarbonyl, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino , Aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or phenyl C _1-3 alkylamino group or substituted
by an oxygen or sulfur atom, by a sulfinyl or sulfonyl group or by an optionally by a C _1-5 alkyl, phenyl, C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted imino group can be replaced or
in a 5-, 6- or 7-membered cycloalkyleneimino group, a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group or
a - (CH ₂ ) ₂ - group linked to the imino nitrogen atom can be replaced by a --CO-NR ⁸ - group or
a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO- group,
where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group,
R ^{5 represents} a hydrogen atom or a C _1-5 alkyl group,
Het has a 5-membered heteroarylene group which is bonded via two carbon atoms or, if Het denotes a 2-bonded pyrrole group, also via a carbon and the imino nitrogen atom, the latter being linked to the adjacent carbonyl group in formula (I)
an imino group substituted by the group R ⁹ , an oxygen or sulfur atom or
an imino group substituted by the group R ⁹ or an oxygen or sulfur atom and additionally a nitrogen atom,
where R ^{9 is} a hydrogen atom, a C _1-5 alkyl group, a terminal through an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or C _1-5 alkoxy carbonyl-amino group substituted -C _2-3 alkyl group, a carboxy-C _1-3 -alkyl-, C _1-3 -alkoxy-carbonyl-C _1-3 -alkyl-, phenyl-, phenyl-C _1-3 - represents alkyl, C _1-5 alkylcarbonyl or phenylcarbonyl group or R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p - bridge in which p represents the number 2 or 3,
or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
or a 6-membered heteroarylene group which contains one or two nitrogen atoms,
wherein the above-mentioned heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-5 alkyl group, by a C _3-7 cycloalkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, Trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, N- (C _1-3 alkyl) acetylamino, propionylamino, N- (C _1-3- alkyl) -propionylamino-, acetyl-, propionyl-, benzoyl-, C _1-3 -alkoxy-carbonyl-, aminocarbonyl-, C _1-3 -Alkylamino-carbonyl-di- (C _1-3 -alkyl) amino-carbonyl or cyano group monosubstituted or, with the exception of more than one heteroatom-containing 5-membered monocyclic heteroaryl radicals, may also be disubstituted by the abovementioned substituents where the substituents can be the same or different,
R ^{6 represents} a hydrogen atom or a C _1-6 alkyl group,
R ^{7 is} a C _1-9 alkyl group,
a linear or branched, mono-, di- or tri-unsaturated C _{3- 9} alkenyl or C _3-9 alkynyl group, wherein the multiple bonds are isolated from the nitrogen-carbon bond,
a straight-chain C _{2- 6} alkyl group which is terminally substituted by an amino, C _1-3 -alkylamino or di- (C _1-3 alkyl) amino group,
a C _1-6 alkyl group substituted by a C _3-7 cycloalkyl radical, where
a hydrogen atom in the 3-position of the cyclopentyl radical and in the 4-position of a 6- or 7-membered cycloalkyl radical each by a hydroxy, hydroxy-C _1-3 alkyl, C _1-5 alkoxy, C _1-5 alkoxy -C _1-3 -alkyl, phenyl-C _1-3 -alkoxy-C ₁ _ ₃ -alkyl, amino-, C _1-5 -alkylamino-, di- (C _1-5 -alkyl) amino-, phenyl- C _1-3 alkylamino, C _1-5 alkylcarbonylamino, benzoylamino, aminoC _1-3 alkyl, C _1-3 alkylaminoC _1-3 alkyl, di- (C _1-3 - alkyl) amino-C _1-3 -alkyl, phenyl-C _1-3 -alkylamino-C _1-3 -alkyl-, C _1-3 -alkylcarbonylamino-C _1-3 -alkyl-, benzoylamino-C _1-3 - alkyl, phenylamino-carbonyl, phenyl-C _1-3 -alkylamino-carbonyl, carboxy or C _1-3 -alkoxy-carbonyl group can be replaced or
in each case the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical through an oxygen or sulfur atom or through one optionally through a C _1-6 alkyl, phenyl, C _1-6 alkyl carbonyl, benzoyl, Phenyl- (C _1-3 alkyl) carbonyl, C _1-6 alkyl aminocarbonyl, di (C _1-5 alkyl) aminocarbonyl, phenylaminocarbonyl, N- (C _1-3 alkyl) ) -phenylaminocarbonyl-, phenyl-C _1-3 -alkylaminocarbonyl- or N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino-carbonyl group substituted imino group can be replaced or
in a 5- or 6-membered cycloalkyl radical one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bi- or tricyclic ring system formed in this way the one attached to the saturated carbon atom in position 1 bonded hydrogen atom through a C _1-5 alkylamino carbonyl, di (C _1-5 alkyl) amino carbonyl, phenyl C _1-3 alkylamino carbonyl or C _1-5 alkoxy carbonyl group, in which terminal methyl groups can be completely or partially fluorinated, can be replaced,
an optionally by a C _{3- 7} cycloalkyl group substituted C _1-6 alkyl group
by a carboxy or C _1-3 alkoxycarbonyl group,
by a phenyl, 1-naphthyl or 2-naphthyl group,
by a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the
an imino group optionally substituted by a C _1-3 alkyl, trifluoromethyl, phenyl, phenyl C _1-3 alkyl, C _1-3 alkylcarbonyl, phenylcarbonyl or phenyl C _1-3 alkylcarbonyl 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
by a 6-membered heteroaryl group containing one or two nitrogen atoms,
where 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,
wherein the above-mentioned phenyl and naphthyl groups and the mono- and bicyclic heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-5 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy , Fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl, C _1-3 alkylamino -C _1-3 alkyl, di (C _1-3 alkyl) aminoC _1-3 alkyl, C _1-5 alkoxycarbonylaminoC _1-3 alkyl, acetylamino, propionylamino -, N- (C _1-3 alkyl) -benzoylamino-, acetyl, propionyl, carboxyl, C _{1- 3} alkoxy-carbonyl, C _1-3 alkoxy-carbonyl-C _1-3 alkyl , Aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) aminocarbonyl, or cyano group monosubstituted or, with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, by the abovementioned substituents can also be disubstituted, where the substituents can be the same or different,
is substituted,
a C _1-6 - substituted by a phenyl radical and a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group alkyl group,
a phenyl-C _{2- 5} -alkenylene-CH ₂ -, phenyl-C _{2- 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 methylene group in position 1 can be replaced by a C _1-3 alkyl group and independently of this the phenyl part and the heteroaryl part by fluorine, chlorine or bromine atoms, by C _1-6 alkyl, C _3-7 cycloalkyl, trifluoromethyl, C _1-3 alkoxy, phenyl, heteroaryl or cyano groups can be mono- or disubstituted, the substituents being the same or different can be and disubstitution by two aromatic groups is excluded,
where heteroaryl is a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the
an 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
or a 6-membered heteroaryl group which contains one or two nitrogen atoms,
where 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,
in the C _1-3 -alkyl moiety is optionally substituted by a C _1-4 alkyl or C _{3- 5} cycloalkyl substituted group R ^b -A ^b -E ^b -C _1-3 alkyl, in the
R ^{b is} optionally by fluorine, chlorine, bromine or iodine atoms, by C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 cycloalkyl, trifluoromethyl -, Hydroxy-, C _1-3 -alkoxy-, fluoromethoxy-, difluoromethoxy-, trifluoromethoxy-, amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino-, amino-C _{1 - 3-} alkyl-, C _1-3 -alkylamino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) amino-C _1-3 -alkyl-, acetylamino-, propionylamino-, acetyl-, Propionyl, carboxy, C _1-3 alkoxy carbonyl, C _1-3 alkoxy carbonyl C _1-3 alkyl, aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _{1 - 3} alkyl) amino-carbonyl or cyano groups mono- or disubstituted phenyl wherein the substituents may be identical or different,
a 5-membered heteroaryl group, the
via a carbon atom or, if A ^{b represents} a bond, a -CH ₂ -, - (CH ₂ ) ₂ -, sulfonyl or carbonyl group, can also be bound via a nitrogen atom and the
an 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a 6-membered heteroaryl group containing one or two nitrogen atoms,
where 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,
the abovementioned mono- and bicyclic heteroaryl radicals in the carbon skeleton being replaced by a fluorine, chlorine or bromine atom, by a C _1-4 -alkyl, C _2-4 -alkenyl, C _2-4 -alkynyl, C _{3- 7} cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di- (C _{1- 3} alkyl) amino, Acetylamino, propionylamino, acetyl, propionyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) amino carbonyl or Cyano group monosubstituted or, with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, can also be disubstituted by the abovementioned substituents, where the substituents can be the same or different,
a C _{3- 7} cycloalkyl group, in which
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
each the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical through an oxygen or sulfur atom, through a sulfinyl, sulfonyl or optionally through a C _1-3 alkyl, C _1-3 alkyl carbonyl, C _1-3 alkoxycarbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted imino group may be replaced 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 substituted and may be replaced in the rings thus formed one or two hydrogen atoms are replaced by C _{1- 3} alkyl,
a 4- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
each have the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group through a hydroxy-C _1-3 alkyl, C _1-6 alkoxy-C _1-3 alkyl, hydroxycarbonyl, C _1-6 alkoxycarbonyl -, Aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, 4- to 7-membered cycloalkylenimino-, phenyl-, 4- (C _1-3 -alkyl) - 1,2,4-triazol-3-yl, phenyl-C _1-3 alkylamino or N- (C _1-3 alkyl) phenyl-C _1-3 alkylamino group substituted or
by an oxygen or sulfur atom, by a sulphinyl or sulphonyl group or by an optionally by a C _{1- 3} alkyl, phenyl, C _1-3 alkyl-carbonyl, benzoyl, phenyl-C _{1- 3} - alkyl-carbonyl, C _1-3 -alkylaminocarbonyl-, di- (C _{1- 3} alkyl) aminocarbonyl, phenylaminocarbonyl or N- (C _1-3 alkyl) -phenylaminocarbo nyl group-substituted imino group can be replaced 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 by an n-butylene, n-pentylene, n-hexylene, 1,2-ethylenedioxy or 1,3-propylenedioxy group can be replaced and one or two hydrogen atoms in the rings thus formed can be replaced by C _1-3 alkyl groups or
in a 5-, 6- or 7-membered cycloalkyleneimino group, a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group or
a - (CH ₂ ) ₂ - group linked to the imino nitrogen atom can be replaced by a --CO-NR ⁸ - group or
a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO- group,
where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group,
A ^{b is} a bond, an oxygen or sulfur atom, an -NH-, -N (C _1-3 -alkyl) -, sulfinyl, sulfonyl or a carbonyl group,
one of the groups -CH ₂ -, - (CH ₂ ) ₂ -, -O-CH ₂ -, -CH ₂ -O-, NH-CH ₂ -, -CH ₂ -NH-, -NH-CO-, - CO-NH-, -NH-SO ₂ -, -SO ₂ -NH-, -CH = CH- or -C≡C-,
in which a hydrogen atom bonded to a carbon atom and / or a hydrogen atom bonded to a nitrogen atom can each be replaced by a C _1-3 alkyl group and wherein a hetero atom from group A ^b does not have a nitrogen atom from a 5-membered heteroaryl group from group R ^b is linked
E ^b a optionally by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl group, by a trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino , C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, di ( C _1-3 alkyl) amino C _1-3 alkyl, acetylamino, propionylamino, acetyl, propionyl, carboxy, C _1-3 alkoxycarbonyl, C _1-3 alkoxycarbonyl -C _1-3 alkyl, aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) amino carbonyl or cyano substituted phenylene group,
in the C _1-3 -alkyl moiety is optionally substituted by a C _1-4 alkyl or C _{3- 5} cycloalkyl substituted group R ^c -A -E ^{c c} -C _1-3 alkyl, in the
R ^c assumes the meanings mentioned above for R ^b , a reference to A ^{b being} replaced by a reference to A ^c ,
A ^c assumes the meanings mentioned above for A ^b , a reference to R ^{b being} 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, the imino nitrogen atom of the heteroarylene group not being linked to a hetero atom of group A ^c and the heteroarylene group
an 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
an imino group optionally substituted by a C ₁ _ ₃ alkyl group and two nitrogen atoms or
contains an oxygen or sulfur atom and two nitrogen atoms, or a 6-membered heteroarylene group which contains one or two nitrogen atoms,
a phenyl ring may be fused to the above-mentioned 5-membered heteroarylene groups containing one or two heteroatoms and to the above-mentioned 6-membered heteroarylene groups and the bicyclic heteroarylene groups thus formed may be bonded via the heteroaromatic and / or the carbocyclic part can,
and the abovementioned mono- and bicyclic heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl group, by a C _3-7 cycloalkyl, trifluoromethyl, hydroxy, C _{1- 3} -alkoxy-, trifluoromethoxy-, amino-, C _1-3 -alkylamino-, acetylamino-, propionylamino-, acetyl-, propionyl-, C _1-3 -alkoxy-carbonyl-, aminocarbonyl-, C _1-3 -alkylamino carbonyl or cyano group can be substituted,
or R ⁶ and R ⁷ together form an n-alkylene bridge with 3 to 6 carbon atoms, in which
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
a -CH ₂ -CH ₂ group may be replaced by a 1,2-phenylene group linked, by fluorine, chlorine or bromine atoms, by C _{1- 3} alkyl, trifluoromethyl, hydroxy, C _1-3 -Alkoxy-, trifluoromethoxy-, amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino-, acetylamino-, propionylamino-, acetyl-, propionyl-, C _1-3 -alkoxy- carbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl, cyano, phenyloxy or phenyl C _1-3 alkyl groups can be mono- or disubstituted, disubstitution with the latter group being excluded,
the above-mentioned phenyloxy and phenyl-C _1-3 alkyl groups in the phenyl part in turn 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 _1-3 alkyl) amino, acetylamino or cyano group,
or in each case the carbon atom in position 3 of an n-pentylene or n-hexylene by a terminal by a phenyl, cyano, hydroxy, C _{1- 3} alkoxy, amino, C _1-3 alkylamino, di - (C _1-3 alkyl) amino or a 5- to 7-membered cycloalkyleneimino group substituted C _1-3 alkyl group, by a carboxy, C _1-3 alkoxycarbonyl, amino C _1-3 alkyl -, C _1-3 alkyl-C _1-3 alkylamino, NC _{1 3} alkyl-N- (C _1-3 -alkyl-carbonyl) -amino-C _1-3 -alkyl, di- ( C _1-3 alkyl) amino C _1-3 alkyl, aminocarbonyl, C _1-3 alkylamino carbonyl or di (C _1-3 alkyl) aminocarbonyl group monosubstituted or by a phenyl group. and a cyano, hydroxy or C _1-3 alkoxy group may be disubstituted or
the methylene group in position 3 of an n-pentylene or n-hexylene group through an oxygen or sulfur atom, through a sulfinyl or sulfonyl group or through one optionally through a C _1-3 alkyl, phenyl C _1-3 alkyl , C _1-3 alkyl carbonyl, benzoyl, C _1-3 alkyl aminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, phenylaminocarbonyl or N- (C _1-3 alkyl ) -phenylaminocarbonyl substituted imino group can be replaced or
a methylene group in position 1 in an n-butylene, n-pentylene or n-hexylene group can be replaced by a carbonyl group,
mean, where the phenyl groups mentioned in the definition of the abovementioned radicals as unsubstituted or monosubstituted and aromatic or heteroaromatic parts of the molecule, unless stated otherwise, in the carbon skeleton optionally additionally by fluorine, chlorine or bromine atoms, by C _1-3 alkyl groups, by trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 Alkylamino-carbonyl or cyano groups can be substituted, where the substituents can be the same or different and the resulting aromatic groups and molecular parts are maximally disubstituted,
the hydrogen atoms in the C _1-3 alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals can be partially or completely replaced by fluorine atoms and
the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts containing more than two carbon atoms contained in the groups of formula 1 defined above can be straight-chain or branched, unless stated otherwise.

The carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions,
furthermore, the amino and imino groups mentioned in the definition of the above-mentioned radicals can each be substituted by a radical which can be split off in vivo and thus be in the form of a prodrug radical. Such groups are described, for example, in WO 98/46576 and by NM Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).

A group which can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C _1-6 alkanol, a phenyl C _1-3 alkanol, a C _{3- 9} -cycloalkanol, where a C _5-8 -cycloalkanol can additionally be substituted by one or two C _1-3 -alkyl groups, a C _5-8 -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-C _1-3 -alkyl, phenyl-C _1-3 alkoxy carbonyl or C ₆ alkanoyl group substituted _2- imino group and the cycloalkanol moiety replaced by an additional or two _C1-3 alkyl groups may be substituted, a C _4-7 -Cycloalkenol, C _{3- 5} alkenol, a phenyl-C _{3- 5} alkenol, C _{3- 5} -alkynol or phenyl-C _{3 - 5-} Alkinol with the proviso that no bond to the oxygen atom starts from a carbon atom which is a double or triple ifachbindung carries a C _{3- 8} -cycloalkyl-C _1-3 -alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C _{1- 3} alkyl groups, a 1,3- Dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula R _p -CO-O- (R _q CR _r ) -OH, by doing
R _p is a C _1-8 alkyl, C _5-7 cycloalkyl, C _1-8 alkyloxy, C _5-7 cycloalkyloxy, phenyl or phenyl C _{1- 3} alkyl group,
R _q represents a hydrogen atom, a C _{1- 3} alkyl, C _5-7 cycloalkyl or phenyl group and
R _{r represents} a hydrogen atom or a C _1-3 alkyl group,
under a negatively charged under physiological conditions, for example, a tetrazol-5-yl, Phenylcarbonylaminocarbonyl-, Trifluormethylcarbonylaminocarbonyl-, C _1-6 alkylsulfonylamino, phenylsulfonylamino, Benzylsulfonylamino-, Trifluormethylsulfonylamino-, C _1-6 -Alkylsulfonylaminocarbonyl-, Phenylsulfonylaminocarbonyl- , Benzylsulfonylaminocarbonyl or perfluoro-C _1-6 alkylsulfonylaminocarbonyl group
and under a cleavable by an imino or amino group in vivo radical such as a hydroxy group, an acyl group such as optionally substituted by fluorine, chlorine, bromine or iodine atoms, by C _{1- 3} alkyl or C _1-3 alkoxy groups mono- or disubstituted phenylcarbonyl group, where the substituents may be the same or different, a pyridinoyl group or a C _{1-1 6} -alkanoyl group such as the formyl, acetyl, Propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C _1-16 alkoxycarbonyl or C _{1-1 6} alkylcarbonyloxy group in which hydrogen atoms are wholly or partly by fluorine or Chlorine atoms can be replaced, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyladoxycarbonyl -, Methylcarbonyloxy-, Ethylcarbonyloxy-, 2,2,2-Trichlorethylcarbonyloxy-, Propylcarbonyloxy-, Isopropylcarbonyloxy-, Butylcarbonyloxy-, tert.Butylcarbonyloxy-, Pentylcarbonyloxy-, Hexylcarbonyloxy-, Octylcarbonyloxy-, Nonylcarbonyloxy-, Decylcarbonylyloxy-, Undylylcarbonyl - Or hexadecylcarbonyloxy group, a phenyl-C _1-6 alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbony lgruppe, a 3-amino-propionyl group wherein the amino group by C _1-6 alkyl or C _{3- 7} cycloalkyl groups mono- or disubstituted and the substituents may be the same or different, a C _1-3 alkylsulfonyl-C _2-4 -alkoxycarbonyl-, C _1-3 -alkoxy-C _2-4 -alkoxy-C _2-4 -alkoxycarbonyl-, R _p -CO-O- (R _q CR _r ) -O-CO-, C _{1 -6-} alkyl-CO-NH- (R _s CR _t ) -O-CO- or C _1-6 -alkyl-CO-O- (R _s CR _t ) - (R _s CR _t ) -O-CO- Group in which R _p to R _r are defined as mentioned above,
R _s and R _t , which may be the same or different, represent hydrogen atoms or C _1-3 alkyl groups,
to understand.

Preferred compounds of the formula I are those in which
X ₁ to X ₄ are defined as mentioned above,
A ^{a is} a bond, an oxygen atom, an -NH-, -N (C _1-3 -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-,
in which 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 _{1- 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 is} a phenyl group,
a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the
an imino group optionally substituted by a C _1-4 alkyl or C _1-4 alkylcarbonyl group, an oxygen or sulfur atom or
contains an imino group optionally substituted by a C _1-4 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom,
a 6-membered heteroaryl group containing one or two nitrogen atoms,
wherein the above-mentioned phenyl and heteroaryl groups in the carbon structure through a fluorine, chlorine or bromine atom, through a C _1-4 alkyl group, through a C _3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _{1 -3} alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di- (C _{1- 3} alkyl) amino, acetylamino, N- (C _1-3 alkyl) acetylamino, Acetyl or cyano group can be substituted,
a C _{3- 7} cycloalkyl group, wherein
the methylene group in the 4-position of a 6-membered cycloalkyl radical through an oxygen or sulfur atom, through a sulfonyl group or through one optionally through a C _1-3 alkyl, phenyl, C _1-4 alkyl carbonyl or C _{1 -4-} alkoxy-carbonyl-substituted imino group can be replaced,
a 4- to 7-membered cycloalkyleneimino group in which
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group through an oxygen or sulfur atom, through a sulfonyl group or through one optionally through a C _1-5 alkyl, phenyl, C _1-4 alkyl carbonyl , C _1-4 alkoxycarbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted imino group can be replaced or
in a 5-, 6- or 7-membered cycloalkyleneimino group, a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group or
a - (CH ₂ ) ₂ - group linked to the imino nitrogen atom can be replaced by a --CO-NR ⁸ - group or
a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO- group,
where 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,
Het a 5-membered heteroarylene group bonded via two carbon atoms, the
an imino group substituted by the group R ⁹ , an oxygen or sulfur atom or
an imino group substituted by the group R ⁹ or an oxygen or sulfur atom and additionally a nitrogen atom,
where R ^{9 is} a hydrogen atom, a C _1-5 alkyl group, a terminal through an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or C _1-5 alkoxycarbonyl amino group substituted -C _{2- 3} -alkyl group, a carboxy-C _1-3 -alkyl-, C _1-3 -alkoxy-carbonyl-C _1-3 -alkyl-, phenyl-, phenyl-C _1-3 -alkyl- , C _1-5 alkylcarbonyl or phenylcarbonyl group or R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p - bridge, in which p is the number 2 or 3 be indicated
or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
or a 6-membered heteroarylene group which contains one or two nitrogen atoms,
where the above-mentioned heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl group, by a cyclopropyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, C _1-3 - Alkylamino, di (C _1-3 alkyl) amino, acetylamino, N (C _1-3 alkyl) acetylamino, acetyl, C _1-3 alkylamino carbonyl or di (C _{1 -3-} alkyl) amino-carbonyl group can be substituted,
R ^{6 represents} a hydrogen atom or a C _1-4 alkyl group,
R ^{7 is} a C _1-6 alkyl group,
a straight-chain C ₂ - ₆ alkyl group which is terminally substituted by an amino, C _1-3 -alkylamino or di- (C _{1- 3} alkyl) amino group,
a C _1-6 alkyl group substituted by a C _3-7 cycloalkyl radical, where
a hydrogen atom in the 3-position of the Cyclopentylrestes and in the 4 position of a 6- or 7-membered cycloalkyl radical in each case _1-3 alkoxyC _{1- 3} alkyl by a C _{1- 5} alkoxy, phenyl-C, phenyl C _1-3 alkylamino, C _1-5 alkylcarbonylamino, benzoylamino, phenyl-C _1-3 alkylamino-C _1-3 alkyl, benzoylamino-C _{1- 3} alkyl, phenylamino-carbonyl , Phenyl-C _1-3 alkylamino-carbonyl, carboxy or C _1-3 alkoxy-carbonyl group can be replaced or
each the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical, optionally by a phenyl-, C _1-6 -alkylcarbonyl-, benzoyl-, phenyl- (C _1-3 -alkyl) -carbonyl-, phenylaminocarbonyl, N- (C _1-3 alkyl) -phenylaminocarbonyl-, phenyl-C _1-3 alkylamino-carbonyl or N- (C _{1- 3} alkyl) -phenyl-C _1-3 alkylamino-carbonyl group substituted imino group can be replaced or
in a 5- or 6-membered cycloalkyl radical one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bi- or tricyclic ring system formed in this way the one attached to the saturated carbon atom in position 1 -bonded hydrogen atom by a C _{1- 3} -alkylamino-carbonyl, di- (C _{1- 3} alkyl) amino-carbonyl or C _1-5 alkoxy-carbonyl group, in which terminal methyl groups can be fluorinated in each case wholly or partly, can be replaced
a C _1-6 alkyl group optionally substituted by a C _1-4 cycloalkyl group, the
by a carboxy or C _1-3 alkoxycarbonyl group,
by a phenyl, 1-naphthyl or 2-naphthyl group,
by a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the
an imino group optionally substituted by a C _1-3 alkyl or trifluoromethyl group, an oxygen or sulfur atom or
contains an imino group optionally substituted by a C _1-3 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom,
by a 6-membered heteroaryl group containing one or two nitrogen atoms,
where the above-mentioned phenyl groups and the heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl, acetylamino, acetyl, C _1-3 alkoxycarbonylC _1-3 -alkyl-, C _1-5 -alkoxy-carbonylamino-C _1-3 -alkyl-, C _1-3 -alkylamino-carbonyl or di- (C _1-3 -alkyl) amino-carbonyl group monosubstituted or by the aforementioned Substituents can also be disubstituted, where the substituents can be the same or different,
is substituted,
a C _1-6 - substituted by a phenyl radical and a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group alkyl group,
a phenyl-C _{2- 3} -alkenylene-CH ₂ - or phenyl-C _{2- 3} -alkynylene-CH ₂ group, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and the phenyl part thereof by an independently Fluorine, chlorine or bromine atom, through a C _1-4 alkyl, C _3-7 cycloalkyl, trifluoromethyl, C _1-3 alkoxy, phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl -, pyrrolyl, pyrazolyl or thiazolyl group may be substituted,
optionally substituted alkyl in the C _1-3 -alkyl moiety by a methyl group substituted group R ^b -A ^b -E ^b -C _1-3 in which
R ^{b is} optionally by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, cyclopropyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino , C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, acetyl, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl C _1-3 alkylamino carbonyl, di- (C _{1- 3} alkyl) amino-carbonyl or cyano groups mono- or disubstituted phenyl wherein the substituents may be the same or different,
a 5-membered heteroaryl group, the
via a carbon atom or, if A ^{b represents} a bond, a -CH ₂ -, - (CH ₂ ) ₂ -, sulfonyl or carbonyl group, can also be bound via a nitrogen atom and the
an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom tom,
an imino group optionally substituted by a C _1-3 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a 6-membered heteroaryl group containing one or two nitrogen atoms,
wherein the above-mentioned heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, C _3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _1-3 alkoxy -, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino-carbonyl or di- (C _{1- 3} alkyl) amino-carbonyl group or mono-substituted, with the exception of containing more than two heteroatoms 5-membered heteroaryl may also be di-substituted by the aforementioned substituents wherein the substituents can be the same or different,
a C _3-7 cycloalkyl group in which
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
the methylene group in the 4-position of a cyclohexyl radical through an oxygen atom, through a sulfonyl group or through one optionally through a C _1-3 alkyl, C _1-3 alkyl carbonyl, C _1-3 alkoxy carbonyl, C _1-3 alkyl-aminocarbonyl or di- (C _{1- 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 can be replaced,
a 4- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and
each the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group by a 4- to 7-membered cycloalkylenimino, phenyl or 4- (C _1-3 alkyl) -1,2,4-triazol-3-yl group substituted or
by an oxygen atom, by a sulfonyl group or by an optionally by a C _1-3 alkyl, C _1-3 alkyl carbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) ) -aminocarbonyl group substituted imino group can be replaced 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 by an n-butylene, n-pentylene, n-hexylene, 1,2-ethylenedioxy or 1,3-propylenedioxy group can be replaced or
in a 5-, 6- or 7-membered cycloalkyleneimino group, a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group
A ^{b is} a bond, an oxygen atom, an -NH-, -N (C _1-3 -alkyl) -, sulfonyl or a carbonyl group,
one of the groups -CH ₂ -, - (CH ₂ ) ₂ -, -C≡C-, -O-CH ₂ -, -CH ₂ -O-, NH-CH ₂ -, -CH ₂ -NH-, - NH-CO-, -CO-NH-, -NH-SO ₂ -, -SO ₂ -NH-,
in which a hydrogen atom bonded to a carbon atom and / or a hydrogen atom bonded to a nitrogen atom can each be replaced by a C _1-3 alkyl group and wherein a hetero atom from group A ^b does not have a nitrogen atom from a 5-membered heteroaryl group from group R ^b is linked, and
E ^b a optionally by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl group, by a trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino , C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, acetyl, carboxy, C _1-3 alkoxycarbonyl, C _1-3 alkoxycarbonyl C _1-3 alkyl, aminocarbonyl, C _{1- 3} -alkylamino-carbonyl, represents di- (C _{1- 3} alkyl) amino-carbonyl or cyano substituted phenylene group, or
the group R ^c -A ^c -E ^c -C _1-3 alkyl-, in which
R ^c assumes the meanings mentioned above for R ^b , a reference to A ^{b being} replaced by a reference to A ^c ,
A ^{c is} a bond, an oxygen atom, a -CH ₂ -, -NH-, -N (C _1-3 -alkyl) -, -NH-CO-, -CO-NH or carbonyl group,
wherein a hetero atom of group A ^{c is} not linked to a nitrogen atom of a 5-membered heteroaryl group of 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, the imino nitrogen atom of the heteroarylene group not being linked to a hetero atom of group A ^c and the heteroarylene group
an 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
or a 6-membered heteroarylene group which contains one or two nitrogen atoms,
wherein the above-mentioned 5- and 6-membered heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl group, by a C _{3- 7} cycloalkyl, trifluoromethyl, hydroxy, C _{1 -3} alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl or cyano group may be substituted mean
or R ⁶ and R ⁷ together represent an n-alkylene bridge with 4 or 5 carbon atoms, in which
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and a -CH ₂ -CH ₂ group can be replaced by a 1,2-linked phenylene group which is replaced by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino -, Acetyl-, C _1-3 -alkoxy-carbonyl-, aminocarbonyl-, C _1-3 -alkylamino-carbonyl- or cyano group or by one in the phenyl part optionally 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 _1-3 -alkyl) amino-, acetylamino- or cyano-substituted phenyloxy- or phenyl-C _1-3 alkyl group may be substituted,
or the carbon atom in position 3 of an n-pentylene group by a terminally substituted by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or a 5- to 7-membered cycloalkyleneimino group _{1- 3} alkyl group, monosubstituted by a phenyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl or di (C _1-3 alkyl) aminocarbonyl group or by a phenyl group and a cyano group may be disubstituted or
the methylene group in position 3 of an n-pentylene group can be replaced by an oxygen atom, by a sulfonyl group or by an imino group optionally substituted by a C _1-3 alkyl or C _1-3 alkyl carbonyl group,
mean, the phenyl groups mentioned in the definition of the abovementioned radicals as unsubstituted or monosubstituted, and also aromatic or heteroaromatic parts of the molecule, unless stated otherwise, in the carbon structure optionally additionally by a fluorine, chlorine or bromine atom, by a C _1-3 Alkyl group, through a trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl , C _1-3 alkylamino-carbonyl or cyano group may be substituted,
the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts containing more than two carbon atoms contained in the groups of the formula I defined above can be straight-chain or branched, unless stated otherwise,
the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions or / and
the amino and imino groups mentioned in the definition of the radicals mentioned above can each be substituted by a radical which can be split off in vivo, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

Those compounds of the formula I in which
X ₁ the group CR ¹ ,
X ₂ the group CR ² ,
X ₃ the group CR ³ and
X _{4 is} the group CR ⁴ or
one of the groups X ₁ to X _{4 is} a nitrogen atom and the rest of the groups X ₁ to X _{4 are} three 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, independently of one another, are each a fluorine, chlorine or bromine atom, a C _1-3 alkyl group, a trifluoromethyl, amino, C _1-3 alkylamino or di (C _{1 -3-} alkyl) -amino group and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom,
where R ⁴ together with R ^{5 can} additionally 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 _1-3 -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),
where a heteroatom from group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group from group R ^a ,
R ^{a is} a phenyl or pyridinyl group,
a pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or thiazolyl group bonded via a carbon or nitrogen atom,
where a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl group and the phenyl group and the abovementioned heteroaromatic groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 - alkyl, trifluoromethyl, C _{1- 3} alkoxy, trifluoroacetic ormethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or cyano group,
a 5- to 7-membered cycloalkyleneimino group in which
the methylene group in position 4 of a 6-membered cycloalkyleneimino group can be substituted by a methyl group or can be replaced by an oxygen or sulfur atom or by an imino group which is optionally substituted by a C _1-3 alkyl group or
in a piperidino group, a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group or
a - (CH ₂ ) ₂ - group linked to the imino nitrogen atom can be replaced by a --CO-NR ⁸ - group or
a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO- group,
where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group,
R ^{5 represents} a hydrogen atom or a C _1-3 alkyl group,
Het a 5-membered heteroarylene group bonded via two carbon atoms, the
an imino group substituted by the group R ⁹ , an oxygen or sulfur atom or
contains an imino group substituted by the group R ⁹ or an oxygen or sulfur atom and additionally a nitrogen atom,
where R ^{9 is} a hydrogen atom, a C _1-3 alkyl group, a terminal through an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or C _1-4 alkoxy carbonyl-amino group substituted _2- -C ₃ alkyl group, a carboxy-C _{1- 3} alkyl, alkyl C _1-3 alkoxy-carbonyl-C _1-3 or C _1-3 alkylcarbonyl or R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p bridge, in which p denotes the number 2 or 3,
or a pyridinylene or pyrimidinylene group,
wherein the above-mentioned heteroarylene radicals in the carbon skeleton 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- 3} alkyl) amino, acetylamino or cyano group can be substituted,
R ^{6 is} a hydrogen atom or a C _1-3 alkyl group, R ^{7 is} a C _1-6 alkyl group,
a straight-chain C _{2- 6} alkyl group which is terminally substituted by an amino, C _1-3 -alkylamino or di- (C _1-3 alkyl) amino group,
a C _1-4 alkyl group terminally substituted by a C _3-7 cycloalkyl radical, where
a hydrogen atom in the 4-position of a cyclohexyl radical by C _1-5 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, phenyl-C _1-3 alkoxy-methyl, phenyl-C _1-3 -alkylamino-, phenyl-C _1-2 -alkyl-carbonylamino-, benzoylamino-, phenylaminocarbonyl, phenyl-C _1-3 -alkyl-aminocarbonyl, carboxy or C _1-3 -alkoxy-carbonyl group can be replaced or
in a cyclopentyl radical one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bi- or tricyclic ring system formed in this way the hydrogen atom bound to the saturated carbon atom in position 1 by a C _{1 -3-} alkylamino-carbonyl or di- (C _1-3 -alkyl) amino-carbonyl group, in which terminal methyl groups can in each case be wholly or partly fluorinated, can be replaced,
an optionally by a C _{3- 5} cycloalkyl group substituted C _1-6 alkyl group
by a carboxy or C _1-3 alkoxycarbonyl group or
by a phenyl, 1-naphthyl, 2-naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group,
where a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl or trifluoromethyl group and the phenyl group and the heteroaromatic groups mentioned above in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _{1 -4-} alkyl-, trifluoromethyl-, C _1-3 -alkoxy-, fluoromethoxy-, difluoromethoxy-, trifluoromethoxy-, C _1-4 -alkoxy-carbonylamino-C _1-3 -alkyl-, amino-, C _1-3 Alkylamino, di (C _1-3 alkyl) amino or cyano group may be substituted,
is substituted,
a C _1-6 alkyl group substituted by a phenyl radical and a carboxy or C _1-3 alkoxycarbonyl group,
a phenyl-C _{2- 3} -alkynylene-CH ₂ group, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and the phenyl part independently of this by a fluorine, chlorine or bromine atom, by a C _{1- 4} -alkyl, trifluoromethyl, C _1-3 -alkoxy, phenyl or cyano group may be substituted,
optionally substituted alkyl in the C _1-3 -alkyl moiety by a methyl group substituted group R ^b -A ^b -E ^b -C _1-3 in which
R ^b a optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxy or C _1-3 alkoxy carbonyl group substituted phenyl group,
a 5-membered heteroaryl group, the
can be bound via a carbon atom or, if A ^{b represents} a bond, also via a nitrogen atom and the
an 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a 6-membered heteroaryl group containing one or two nitrogen atoms,
wherein the above-mentioned heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _{1- 3} alkylamino, di (C _1-3 alkyl) amino or acetylamino group monosubstituted or, with the exception of 5-membered heteroaryl radicals containing more than two heteroatoms, by a C _1-4 alkyl group and a substituent selected from fluorine , Chlorine, bromine, C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy and trifluoromethoxy can also be disubstituted,
a C _{3- 6} cycloalkyl group, wherein
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 can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
a 5- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
each the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group by a 4- to 7-membered cycloalkylenimino, phenyl or 4- (C _1-3 alkyl) -1,2,4-triazol-3-yl group can be substituted 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 can 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,
in which a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a C _1-3 alkyl group,
E ^b an optionally 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 _1-3 alkyl) amino, acetylamino or C _1-3 alkoxycarbonyl group substituted phenylene group, or
the group R ^c -A ^c -E ^c -C _1-3 alkyl-, in which
R ^{c is} optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, carboxy or C _1-3 alkoxycarbonyl group Phenyl group or
a 5- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
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 can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
A ^c a bond,
E ^{c is} a 5-membered heteroarylene group bonded via two carbon atoms, the
an 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
or a pyridinylene, pyridazinylene or pyrimidinylene group,
the abovementioned 5- and 6-membered heteroarylene residues in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, C _1-3 alkoxycarbonyl or cyano group may be substituted,
or R ⁶ and R ⁷ together represent an n-alkylene bridge with 4 or 5 carbon atoms, in which
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
a -CH ₂ -CH ₂ group can be replaced by a 1,2-linked phenylene group optionally substituted by a phenyloxy or benzyl group, where
the phenyloxy or benzyl group in the aromatic part 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 _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, C _1-3 alkoxycarbonyl or cyano group may be substituted,
or the carbon atom in position 3 of an n-pentylene group through a terminal through an amino, C _1-3 -Al kylamino, di (C _1-3 alkyl) amino, acetylamino or N- (methyl) acetylamino group or a 5- to 7-membered cycloalkyleneimino group substituted by C _1-3 alkyl group monosubstituted or by a phenyl group and one Cyano group can be disubstituted
mean, where the phenyl groups mentioned in the definition of the abovementioned radicals, unless stated otherwise, by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl group, by a trifluoromethyl, C _1-3 alkoxy -, trifluoromethoxy, phenyl, amino, C _{1- 3} alkylamino, acetylamino, C _1-3 alkoxy-carbonyl or cyano group can be substituted,
the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts containing more than two carbon atoms contained in the groups of the formula I defined above can be straight-chain or branched, unless stated otherwise,
the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions or / and
the amino and imino groups mentioned in the definition of the abovementioned radicals can each be substituted by a radical which can be split off in vivo,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

Those compounds of the formula I in which
X ₁ the group CR ¹ ,
X ₂ the group CR ² ,
X ₃ the group CR ³ and
X _{4 is} the group CR ⁴ or
one of the groups X ₁ to X _{4 is} a nitrogen atom and the rest of the groups X ₁ to X _{4 are} three 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, independently of one another, are each a fluorine, chlorine or bromine atom, a C _1-3 alkyl group, a trifluoromethyl, amino, C _1-3 alkylamino or di (C _{1 -3-} alkyl) -amino group and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom,
where R ⁴ together with R ^{5 can} additionally 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 _1-3 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),
where a heteroatom from group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group from group R ^a ,
R ^{a is} a phenyl or pyridinyl group,
a pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or thiazolyl group bonded via a carbon or nitrogen atom,
where a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl group and the phenyl group and the abovementioned heteroaromatic groups in the carbon skeleton 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 _1-3 alkyl) amino or cyano group may be substituted,
a 5- to 7-membered cycloalkyleneimino group in which
the methylene group in position 4 of a 6-membered cycloalkyleneimino group may be substituted by a methyl group or may be replaced by an oxygen or sulfur atom or by an imino group which may be substituted by a C _1-3 alkyl group or
in a piperidino group a -CH ₂ group linked to the imino nitrogen atom can be replaced by a carbonyl group or
a - (CH ₂ ) ₂ - group linked to the imino nitrogen atom can be replaced by a --CO-NR ⁸ - group or
a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO- group,
where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group,
R ^{5 represents} a hydrogen atom or a C _1-3 alkyl group,
Het a 2,4-linked pyrrolylene or imidazolylene group, which are each bonded via position 2 to the adjacent carbonyl group of the formula I and
are substituted on a nitrogen atom by a C _1-3 alkyl group and may be substituted in the carbon skeleton by a C _1-3 alkyl group or a trifluoromethyl group,
R ^{6 is} a hydrogen atom or a C _1-3 alkyl group,
R ^{7 is} a C _1-4 alkyl group which is terminally substituted by a C _3-7 cycloalkyl radical, where
a hydrogen atom in the 4-position of a cyclohexyl radical through a C _1-5 alkoxy, C _1-3 alkoxyC _1-3 alkyl, Phe nyl-C _1-3 -alkoxy-methyl-, phenyl-C _1-3 -alkylamino-, phenyl-C _1-2 -alkyl-carbonylamino-, benzoylamino-, phenylaminocarbonyl-, phenyl-C _1-3 -alkyl-aminocarbonyl -, carboxy or C _1-3 alkoxy-carbonyl group can be replaced or
in a cyclopentyl radical one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bi- or tricyclic ring system formed in this way the hydrogen atom bound to the saturated carbon atom in position 1 by a C _{1 -3-} alkylamino-carbonyl or di- (C _1-3 -alkyl) amino-carbonyl group, in which terminal methyl groups can in each case be wholly or partly fluorinated, can be replaced,
an optionally by a C _{3- 5} cycloalkyl group substituted C _1-6 alkyl group
by a phenyl, 1-naphthyl, 2-naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group,
where a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl or trifluoromethyl group and the phenyl group and the heteroaromatic groups mentioned above in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _{1 -4-} alkyl-, trifluoromethyl-, C _1-3 -alkoxy-, fluoromethoxy-, difluoromethoxy-, trifluoromethoxy-, C _1-4 -alkoxy-carbonylamino-C _1-3 -alkyl-, amino-, C _1-3 Alkylamino, di (C _1-3 alkyl) amino or cyano group may be substituted,
is substituted,
a C _1-6 alkyl group substituted by a phenyl radical and a carboxy or C _1-3 alkoxycarbonyl group,
a phenyl-C _{2- 3} -alkynylene-CH ₂ group, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and the phenyl part independently of this by a fluorine, chlorine or bromine atom, by a C _{1- 4} -alkyl, trifluoromethyl, C _1-3 -alkoxy, phenyl or cyano group may be substituted,
optionally substituted alkyl in the C _1-3 -alkyl moiety by a methyl group substituted group R ^b -A ^b -E ^b -C _1-3 in which
R ^b a optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxy or C _1-3 alkoxy carbonyl group substituted phenyl group,
a 5-membered heteroaryl group, the
can be bound via a carbon atom or, if A ^{b represents} a bond, also via a nitrogen atom and the
an 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
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
a 6-membered heteroaryl group containing one or two nitrogen atoms,
wherein the above-mentioned heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _{1- 3} alkylamino, di (C _1-3 alkyl) amino or acetylamino group monosubstituted or, with the exception of 5-membered heteroaryl radicals containing more than two heteroatoms, by a C _1-4 alkyl group and a substituent selected from fluorine , Chlorine, bromine, C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy and trifluoromethoxy can also be disubstituted,
a C _{3- 6} cycloalkyl group, wherein
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 can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
a 5- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
each the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group by a 4- to 7-membered cycloalkylenimino, phenyl or 4- (C _1-3 alkyl) -1,2,4-triazol-3-yl group can be substituted 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 can 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,
in which a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a C _1-3 alkyl group,
E ^b an optionally 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 _1-3 alkyl) amino, acetylamino or C _1-3 alkoxycarbonyl group substituted phenylene group, or
the group R ^c -A ^c -E ^c -C _1-3 alkyl-, in which
R ^{c is} optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, carboxy or C _1-3 alkoxycarbonyl group Phenyl group or
a 5- to 7-membered cycloalkyleneimino group in which
the cycloalkylene part can be condensed with a phenyl ring or
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
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 can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
A ^c a bond,
E ^{c is} a 5-membered heteroarylene group bonded via two carbon atoms, the
an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom,
an optionally by a C _{1- 3} alkyl substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or
contains one oxygen or sulfur atom and two nitrogen atoms,
or a pyridinylene, pyridazinylene or pyrimidinylene group,
wherein the above-mentioned 5- and 6-membered heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy _; Trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, C _1-3 alkoxycarbonyl or cyano group may be substituted,
or R ⁶ and R ⁷ together form an n-alkylene bridge with 4 or 5 carbon atoms, in which
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
a -CH ₂ -CH ₂ group can be replaced by a 1,2-linked phenylene group optionally substituted by a phenyloxy or benzyl group, where
the phenyloxy or benzyl group in the aromatic part 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 _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, C _1-3 alkoxycarbonyl or cyano group may be substituted,
or the carbon atom in position 3 of an n-pentylene group through a terminal through an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino or N- (methyl) acetylamino group or a 5- to 7-membered cycloalkyleneimino group substituted C _1-3 alkyl group may be monosubstituted or may be disubstituted by a phenyl group and a cyano group,
mean, where the phenyl groups mentioned in the definition of the abovementioned radicals, unless stated otherwise, by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl group, by a trifluoromethyl, C _1-3 alkoxy -, trifluoromethoxy, phenyl, amino, C _1-3 alkylamino, acetylamino, C _1-3 alkoxycarbonyl or cyano group,
the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts containing more than two carbon atoms contained in the groups of the formula I defined above can be straight-chain or branched, unless stated otherwise,
the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions or / and
the amino and imino groups mentioned in the definition of the abovementioned radicals can each be substituted by a radical which can be split off in vivo,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts,
in particular, however, those compounds of the formula I in which
X ₁ the group CR ¹ ,
X ₂ the group CR ² ,
X ₃ the group CR ³ and
X ₄ the group CR ⁴ ,
wherein R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom or
one of the groups R ¹ to R ^{4 represents} a fluorine, chlorine or bromine atom, a C _1-3 alkyl group or a trifluoromethyl group and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom,
A ^{a is} a bond, an oxygen atom, a -CH ₂ -, - (CH ₂ ) ₂ -, -NH-, or -N (C _1-3 alkyl) group,
wherein a nitrogen atom from group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group from group R ^a ,
R ^{a is} a phenyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl group,
a 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl or 3-thienyl group,
where the nitrogen atom of the pyrrolyl group can be substituted by a C _1-3 alkyl group and the phenyl group and the heteroaromatic groups mentioned above in the carbon skeleton by a fluorine, Chlorine or bromine atom, which may be substituted by a C _1-3 alkyl or trifluoromethyl group,
a pyrrolidino, piperidino or morpholino group
R ^{5 is} a hydrogen atom,
Het a 2,4-linked pyrrolylene or imidazolylene group, which are each bonded via position 2 to the adjacent carbonyl group of the formula I and
are substituted on a nitrogen atom by a C _1-3 alkyl group and can be substituted in the carbon skeleton by a C _1-3 alkyl group or a trifluoromethyl group,
R ^{6 is} a hydrogen atom or a C _1-3 alkyl group,
R ^{7 is} the group R ^d -CH ₂ - or R ^d -CH ₂ -CH ₂ -, in which a hydrogen atom of the methylene group in position 1 can 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,
where the phenyl group and the heteroaromatic groups mentioned above in the carbon skeleton can be substituted by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, trifluoromethyl, C _1-3 alkoxy or fluoromethoxy group,
means
a phenyl-C≡C-CH ₂ group in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and, independently thereof, the phenyl part by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl -, trifluoromethyl or phenyl group can be substituted,
the group R ^b -A ^b -E ^b -CH ₂ -, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and in which
R ^{b is} a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, hydroxyl, methoxy, carboxy or methoxycarbonyl group,
a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazole or thiadiazolyl group, bonded via a carbon atom or, if A ^{b represents} a bond, also via a nitrogen atom, in which a to a nitrogen atom bonded hydrogen atom can be replaced by a C _1-3 alkyl group,
a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl or 4-pyridazinyl group,
wherein the above-mentioned 5- and 6-membered heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, phenyl, amino, C _1-3 alkylamino, Di- (C _1-3 alkyl) amino or acetylamino group monosubstituted or, with the exception of 5-membered heteroaryl radicals containing more than two heteroatoms, by a C _1-3 alkyl group and a substituent selected from fluorine, chlorine, bromine, C _1-3 alkyl, trifluoromethyl, phenyl, can also be disubstituted,
a C ₅ _ ₆ cycloalkyl group, wherein
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 can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
or a 5- to 6-membered cycloalkyleneimino group in which the cycloalkylene part is fused with a phenyl ring which is optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl or C _1-3 alkoxy group can or
a hydrogen atom can be replaced by a C _1-3 alkyl group or / and
the two hydrogen atoms of the methylene group in position 3 of the 5-membered or in position 4 of the 6-membered cycloalkyleneimino group can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group,
A ^{b is} a bond, a -CH ₂ -, -NH-, -O-CH ₂ -, -NH-CO- or -CO-NH group,
in which a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a methyl group,
E ^{b is} a 1,4-linked phenylene group, optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 -alkyl, trifluoromethyl, C _1-3 -alkoxy or trifluoromethoxy group, or
the group R ^c -A ^c -E ^c -C _1-3 alkyl-, in which
R ^{c is} a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C _1-3 -alkyl, trifluoromethyl, methoxy, carboxy or methoxycarbonyl group,
A ^c a bond,
E ^{c is} a pyrrolylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, [1,3,4] oxadiazole or [1,3 , 4] -Thiadiazolengruppe, in which a hydrogen atom bound to a nitrogen atom can be replaced by a C _1-3 alkyl group,
or a 1,4-linked pyridinylene, pyridazinylene or pyrimidinylene group,
wherein the above-mentioned 5- and 6-membered heteroarylene radicals in the carbon skeleton can be substituted by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl or methoxy group, be indicated
represent, where the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl parts contained in the groups of formula I defined above with more than two carbon atoms can be straight-chain or branched, unless stated otherwise,
the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions or / and
the amino and imino groups mentioned in the definition of the abovementioned radicals can each be substituted by a radical which can be split off in vivo,
their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.

The following compounds of the general formula I are particularly suitable for the combination according to the invention:
N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [4- (pyridin-4-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- (4'-chlorobiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [3- (4-methylphenyl) -prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [3- (4-isopropylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [4- (6-methylpyridazin-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- (4'-methoxycarbonylbiphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide,
N- [4- (1,4-dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide .
N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [4- (pyridin-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-fluoro-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-methylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide,
N- (4'-Hydroxycarbonylbiphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide,
N- (4'-hydroxybiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide,
N- [4- (1,4-dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide,
N- [3- (4-tert-butylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide,
N- [4- (5-dimethylaminopyridine-2-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [3- (biphenyl-4-yl) -prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- [4- (4-methylpiperidino) phenylmethyl) -4- (4'-trifluoro-methyl-biphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxylic acid amide,
N- [4- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2 carboxamide,
N- [4- (3-Aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
N- (4-benzyloxy-benzyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide and
N- [4- (3,4-dihydro-1H-isoquinolin-2-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
and their salts.

• (a) N-[3-(Biphenyl-4-yl)-prop-2-inyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (b) N-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (c) N-[4-(3-Aza-spiro[5.5]undec-3-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (d) N-[4-(6-Methylpyridazin-3-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (e) N-(4'-Hydroxybiphenyl-4-yl)methyl-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (f) N-[4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (g) N-(4'-Methylbiphenyl-4-yl)methyl-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (h) N-[3-(4-Isopropylphenyl)-prop-2-inyl]-4-(4'-trifluormethyl-biphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid
  
• (i) N-[3-(4-Biphenyl)-prop-2-inyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-imidazol-2-carbonsäureamid
  
• (j) N-[3-(4-Trifluormethylphenyl)-prop-2-inyl]-4-(4'-trifluor-methylbiphenyl-2-carbonylamino)-1-methyl-imidazol-2-carbonsäureamid
  
• (k) N-[4-(4-Propylpiperidino)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäure-amid
  

sowie deren Salze, insbesondere jedoch

• (a) N-[3-(Biphenyl-4-yl)-prop-2-inyl)-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid,
• (c) N-[4-(3-Aza-spiro[5.5]undec-3-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid,
• (f) N-[4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-phenylmethyl]-4-(4'-tri-fluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbon-säureamid,
• (i) N-[3-(4-Biphenyl)-prop-2-inyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-imidazol-2-carbonsäureamid und
• k) N-[4-(4-Propylpiperidino)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäure-amid

sowie deren Salze.The following compounds of the general formula I are very particularly suitable for the combination according to the invention:

• (a) N- [3- (Biphenyl-4-yl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
  
• (b) N- [4- (1,4-Dioxa-8-aza-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl- pyrrole-2-carboxamide
  
• (c) N- [4- (3-Aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
  
• (d) N- [4- (6-Methylpyridazin-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
  
• (e) N- (4'-Hydroxybiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
  
• (f) N- [4- (1,4-Dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrol-2- carboxamide
  
• (g) N- (4'-Methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
  
• (h) N- [3- (4-Isopropylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
  
• (i) N- [3- (4-Biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide
  
• (j) N- [3- (4-Trifluoromethylphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide
  
• (k) N- [4- (4-Propylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide
  

and their salts, in particular, however

• (a) N- [3- (biphenyl-4-yl) prop-2-ynyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
• (c) N- [4- (3-aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
• (f) N- [4- (1,4-Dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-tri-fluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole- 2-carboxylic acid amide-,
• (i) N- [3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide and
• k) N- [4- (4-Propylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

and their salts.

The connections of the general Formula I can be prepared by methods known from the literature, for example according to the following procedures:

• a. Implementation of a compound of the general formula
  
  in which X ₁ to X ₄ , R ^a , A ^a , R ⁵ and Het are defined as mentioned at the outset and Z represents a carboxy group or a reactive derivative of a carboxy group, with an amine of the general formula
  
  in which R ⁶ and R ⁷ are defined as mentioned at the beginning.
• The implementation will be convenient with a corresponding halide or anhydride of the general Formula II in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, Dioxane, benzene, toluene, acetonitrile or sulfolane if necessary in the presence of an inorganic or organic base at temperatures between –20 and 200 ° C, but preferably carried out at temperatures between -10 and 160 ° C. However, this can also with the free acid optionally in the presence of an acid-activating agent, z. B. propanephosphonic cycloanhydride or 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), or a dehydrating agent, e.g. in present of isobutyl chloroformate, Thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclo-hexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, preferably however at temperatures between -10 and 160 ° C.
• b. Implementation of a compound of the general formula
  
  in which X ₁ to X ₄ , R ^a and A ^a are defined as mentioned above and Z represents a carboxy group or a reactive derivative of a carboxy group, with an amine of the general formula
  
  in which R ⁵ to R ⁷ and Het are defined as mentioned at the beginning.

The reaction can take place in accordance with the conditions mentioned above in process (a) gene.

If, according to the invention, a compound of the general formula I is obtained which contains an amino, alkylamino or imino group, this can be converted into a corresponding acyl or sulfonyl compound of the general formula I by means of acylation or sulfonylation or
a compound of the general formula I which contains an amino, alkylamino or imino group, this can be converted into a corresponding alkyl compound of the general formula I by means of alkylation or reductive alkylation or
a compound of the general formula I which contains a carboxy group, this can be converted by esterification into a corresponding ester of the general formula I or
a compound of the general formula I which contains a carboxy or ester group, this can be converted by means of amidation into a corresponding amide of the general formula I or
a compound of the general formula I which contains an olefinic double bond or a CC triple bond, this can be converted into a corresponding alkyl or alkylene compound of the general formula I by means of catalytic hydrogenation.

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, e.g. 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-hydroxy-benzotriazole and optionally additionally in Presence of 4-dimethylaminopyridine, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, carried out.

The subsequent alkylation is optionally in a solvent or solvent mixture like 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. with methyl iodide, Ethyl bromide, dimethyl sulfate or benzyl chloride, optionally in Presence of a tertiary organic base or in the presence of an inorganic base expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, carried out.

The subsequent reductive alkylation with a corresponding carbonyl compound such as formaldehyde, Acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride suitably at a pH of 6-7 and at Room temperature or in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium / carbon, at a Hydrogen pressure of 1 to 5 bar carried out. The methylation will however, preferably in the presence of formic acid as a reducing agent increased Temperatures, e.g. at temperatures between 60 and 120 ° C.

The subsequent esterification is, if necessary in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, Tetrahydrofuran, benzene / tetrahydrofuran or dioxane or especially advantageously in an appropriate alcohol, optionally in the presence an acid like hydrochloric acid or in the presence of a dehydrating agent, e.g. in present 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-hydroxy-benzotriazole and optionally additionally in Presence of 4-dimethylaminopyridine, N, N'-carbonyldiimidazole or triphenylphosphine / 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 Implementation of a corresponding reactive carboxylic acid derivative with an appropriate amine, optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, Tetrahydrofuran, benzene / tetrahydrofuran or dioxane, the one used Amine simultaneously as a solvent can serve, 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, e.g. in present of isobutyl chloroformate, Thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, Phosphorus pentoxide, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, N, N'-dicyclohexylcarbodiimide N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in Presence of 4-dimethylamino-pyridine, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, carried out.

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, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

In the above Implementations can optionally present reactive groups such as hydroxyl, carboxy, Amino, alkylamino or imino groups during the reaction by conventional protective groups protected which are split off after the implementation.

For example, the trimethylsilyl, tert.butyldimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,
as protective residues for a carboxy group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and
as protective residues for an amino, alkylamino or imino group, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group consideration.

The subsequent subsequent splitting, if applicable of a protective residue used is, for example, hydrolytic in an aqueous Solvent, 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 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 secession However, a silyl group can also be formed using tetrabutylammonium fluoride as described above.

The cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical, for example, takes place hydrogenolytically, e.g. 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 however, it is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl radical is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, if necessary Use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The cleavage of a trifluoroacetyl residue is preferably carried out, if appropriate, by treatment with an acid such as hydrochloric acid in the presence of a solvent like acetic acid at temperatures between 50 and 120 ° C or by treatment with Sodium hydroxide solution 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, toluene / water or dioxane Temperatures between 20 and 50 ° C.

Furthermore, the compounds obtained general formula I, as already mentioned at the beginning, be separated into their enantiomers and / or diastereomers. So can for example cis / trans mixtures in their cis and trans isomers, and compounds with at least one optically active carbon atom be separated into their enantiomers.

For example, the obtained cis / trans mixtures by chromatography in their cis and trans isomers, the compounds of the general formula obtained I, which occur in racemates, according to methods known per se (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general Formula I based on at least 2 asymmetric carbon atoms their physico-chemical differences according to known Methods, e.g. by chromatography and / or fractional crystallization, separate into their diastereomers which, if in racemic Form, then as mentioned above can be separated into the enantiomers.

The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol is, for example, (+) - or (-) - Menthol and as an optically active acyl radical in amides, for example (+) - or (-) - menthyloxycarbonyl.

Furthermore, the compounds obtained of the formula I in their salts, in particular for pharmaceutical use in their physiologically tolerable Salts with inorganic or organic acids. Come as acids therefor for example hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the so obtained new compounds of formula I if they are an acidic group contain a carboxy group, if desired subsequently in their salts with inorganic or organic bases, in particular for the pharmaceutical application in their physiologically acceptable Salts, transfer. As Bases come here for example sodium hydroxide, potassium hydroxide, Arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine into consideration.

The used as raw materials Compounds of the general formulas II to V are either known from the literature or you get these according to methods known from the literature or are in the examples described.

in der X₁ bis X₄, A^a und R^a wie eingangs erwähnt definiert sind und Z¹ eine Carboxy-gruppe oder ein reaktives Derivat einer Carboxygruppe darstellt, mit einem Amin der allgemeinen Formel

in der R⁵ und Het wie eingangs erwähnt definiert sind und Z² ein Schutzgruppe für eine Carboxygruppe darstellt, und anschließender Abspaltung der Schutzgruppe.A compound of the general formula II is obtained, for example, by reacting a compound of the general formula

in which X ₁ to X ₄ , A ^a and R ^a are defined as mentioned at the outset and Z ^{1 represents} a carboxy group or a reactive derivative of a carboxy group, with an amine of the general formula

in which R ⁵ and Het are defined as mentioned at the outset and Z ^{2 represents} a protective group for a carboxy group, and then the protective group is split off.

The amines of the general formula III are known from the literature or according to processes known from the literature accessible.

The aromatic or heteroaromatic carboxylic acids according to the general Formula IV are known from the literature or can be known from the literature Prepare the process from appropriate aryl or heteroaryl starting materials.

The amino-heteroarylcarboxamides according to the general Formula V are also known from the literature or can be simplified Way from optionally substituted amino-heteroarylcarboxylic acids Reaction with the corresponding amines or from nitro-heteroarylcarboxylic acids Reaction with the corresponding amines and subsequent reduction the nitro group.

Starting compounds of the formula V 'in which Het denotes a 5-membered heteroarylene group which contains an imino group substituted by the group R ⁹ , where R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p - bridge, are obtained, for example, analogously to that following synthesis scheme:

As already mentioned at the beginning, point the compounds of general formula I and their physiological compatible Salts valuable pharmacological properties. These pose especially valuable inhibitors of the microsomal triglyceride transfer protein (MTP) and are therefore suitable for lowering the plasma levels of atherogenic lipoproteins.

For example, the biological effects of the compounds according to the invention can be examined as follows:
MTP inhibitors were identified by a cell-free MTP activity test. Solubilized liver microsomes from different species (eg rat, pig) can be used as an MTP source. To produce donor and acceptor vesicles, lipids dissolved in organic solvents were mixed in a suitable ratio and applied to a glass vessel wall as a thin layer by blowing the solvent in a stream of nitrogen. The solution used to prepare donor vesicles contained 400 μM phosphatidylcholine, 75 μM cardiolipin and 10 μM [ ¹⁴ C] triolein (68.8 μCi / mg). A solution of 1.2 mM phosphatidylcholine, 5 μM triolein and 15 μM [ ³ H] -dipalmitoylphosphatidylcholine (108 mCi / mg) was used to produce acceptor vesicles. Vesicles are formed by wetting the dried lipids with test buffer and subsequent sonication. Uniform size vesicle populations were obtained by gel filtration of the ultrasound lipids. The MTP activity test contains donor vesicles, acceptor vesicles and the MTP source in test buffer. Substances were added from concentrated DMSO-containing stock solutions, the final concentration of DMSO in the test was 0.1%. The reaction was started by adding MTP. After an appropriate incubation period, the transfer process was stopped by adding 500 μl of a SOURCE 30Q anion exchange suspension (Pharmacia Biotech). The mixture was shaken for 5 minutes and the donor vesicles bound to the anion exchange material were separated by centrifugation. The radioactivity of [3H] and [14C] in the supernatant was determined by liquid scintillation measurement and from this the recovery of the acceptor vesicles and the triglyceride transfer rate were calculated.

die aus der WO 01/47899 bereits bekannt sind, sowie deren Isomere und deren Salze verwendet werden. Auf die WO 01/47899 wird diesbezüglich vollinhaltlich Bezug genommen.A second embodiment of the invention relates to combinations containing MTP inhibitors of the general formula VIII

which are already known from WO 01/47899, and their isomers and their salts are used. In this regard, reference is made in full to WO 01/47899.

In the general formula VIII mean
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,
Y _{b is} the group - (CH ₂ ) _m -, where m is the number 2 or 3 and in which a hydrogen atom can be replaced by a C _1-3 alkyl group or a methylene group linked to a nitrogen atom by a carbonyl group,
R _{a is} a C _1-6 alkoxy, phenyl-C _1-3 alkoxy or amino group, the amino group being mono- or disubstituted by C _1-3 alkyl, phenyl-C _1-4 alkyl or phenyl groups can be and the substituents can be the same or different,
a phenyl, naphthyl, tetrahydronaphthyl, phenoxy or heteroaryl group, a C _1-9 alkyl group optionally substituted by a hydroxy, C _1-3 alkoxy, C _1-4 alkoxycarbonyl or C _1-4 alkylcarbonyloxy group , which can be substituted in the alkyl part by a C _1-3 alkyl group, by one or two phenyl groups, by a naphthyl, fluorenyl, phenoxy, heteroaryl or C _3-7 cycloalkyl group, or a C substituted by a phenyl group _3-7 cycloalkyl group,
a phenylcarbonyl, naphthylcarbonyl, tetrahydronaphthylcarbonyl, phenoxycarbonyl or heteroarylcarbonyl group, a C _1-9 alkylcarbonyl group which is in the alkyl part by one or two phenyl groups, by a naphthyl, fluorenyl, phenoxy, heteroaryl or C _3-7 cycloalkyl group may be substituted, or a substituted by a phenyl C _{3- 7} cycloalkylcarbonyl,
all of the phenyl, naphthyl and heteroaryl parts mentioned above under R _{a can} each be substituted by the radicals R ₁ and R ₂ , where
R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a cyano, C _1-3 alkyl, C _2-4 alkenyl, phenyl, hydroxy, C _1-4 alkoxy, phenyl C _1-3 alkoxy, carboxy; C _1-3 -alkoxycarbonyl-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, N, N-di (C _1-3 -alkyl) -aminocarbonyl-, nitro-, amino-, C _1-3 -alkylamino-, Di- (C _1-3 alkyl) amino, phenyl-C _1-3 alkylamino, N- (C _1-3 alkyl) phenyl-C _1-3 alkylamino, C _1-3 alkylcarbonylamino -, N- (C _1-3 alkyl) -C _1-3 alkylcarbonylamino, C _1-3 alkylsulfonylamino or N- (C _1-3 alkyl) -C _1-3 alkylsulfonylamino group and
R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a C _1-3 alkyl, hydroxy or C _1-4 alkoxy group, wherein in the above-mentioned alkyl and alkoxy parts of the radicals R ₁ and R ₂ the Hydrogen atoms can be replaced in whole or in part by fluorine atoms, or
R ₁ and R ₂ together represent a methylenedioxy group,
or where all phenyl parts mentioned above under R _a can each be substituted by three chlorine or bromine atoms or by three to five fluorine atoms,
R _{b is} a carboxy, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylC _1-3 alkylcarbonyl, C _3-7 cycloalkoxycarbonyl or phenylC _1-3 alkoxycarbonyl group or an R ₃ NR ₄ -CO group in which
R ₃ and R ₄ , which can be the same or different, are hydrogen atoms, C _1-6 alkyl groups in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms and the C _1-3 alkyl part of a C _1-3 alkylamino group by a carboxy or C _1-3 alkoxycarbonyl group or in the 2- or 3-position can also be substituted by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group, C _{3- 7-} cycloalkyl, pyridyl, pyridinyl-C _1-3 alkyl, phenyl, naphthyl or phenyl-C _1-3 alkyl groups, the above-mentioned phenyl groups each having a fluorine, chlorine or bromine atom a C _1-3 alkyl group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, by a hydroxy, C _1-3 alkoxy, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _{1 -3} -alkylaminocarbonyl-, N, N-di- (C _1-3 -alkyl) -aminocarbonyl- or N, N-di- (C _1-3 -alkyl) -amino group may be substituted, or
R ₃ and R ₄ together with the intervening nitrogen atom represent a 3- to 7-membered cycloalkyleneimino group, the methylene group in position 4 in a 6- or 7-membered cycloalkyleneimino group being additionally represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino - or N- (C _1-3 alkyl) imino group can be replaced, represent
and R _{c is} a hydrogen atom or a C _1-3 alkyl group,
where the tricyclic group in the above-mentioned general formula I can additionally be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents can be identical or different,
among the heteroaryl groups mentioned above, a 6-membered heteroaryl group containing one, two or three nitrogen atoms, or
a 5-membered heteroaryl group containing an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom or
an imino group optionally substituted by a C _1-3 alkyl group and one or two nitrogen atoms or an oxygen or sulfur atom and a nitrogen atom is to be understood,
where a phenyl ring can be fused onto the heteroaryl groups mentioned above via a vinylene group,
and the carboxy group mentioned in the definition of the abovementioned radicals can also be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions,
and all of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms can be straight-chain or branched, unless stated otherwise.

The following compounds of the general formula VIII are particularly valuable in combination with fibrates, in particular with fenofibrate, and are therefore preferred according to the invention:
9- {4- [4- (4-trifluoromethyl-phenylacetyl) -piperazino] -butyl} -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- [4- (4-phenylacetyl-piperazino) -butyl] -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- (4- {4- [2-phenyl-butyryl] -piperazino} -butyl) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- (4- {4- (3-phenylpropionyl) -piperazino} -butyl) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- {4- [4- (4-phenyl-butyryl) -piperazino] -butyl} -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- (4- {4- (4- (pyridin-2-yl-acetyl) -piperazino} -butyl) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- (4- {4- [2-oxo-2-phenyl-acetyl] -piperazino} -butyl) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide
9- (4- {4 - [(2,4-dichlorophenyl) -acetyl] -piperazino} -butyl) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide.

• (a) N-[3-(Biphenyl-4-yl)-prop-2-inyl]-4-(4'-trifluormethylbiphenyl-2-carbonylarnino)-1-methyl-pyrrol-2-carbonsäureamid,
• (c) N-[4-(3-Aza-spiro[5.5]undec-3-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbonsäureamid,
• (f) N-[4-(1,4-Dioxa-spiro[4.5]dec-8-yl)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-pyrrol-2-carbon-säureamid,
• (i) N-(3-(4-Biphenyl)-prop-2-inyl]-4-(4'-trifluormethylbiphenyl-2-carbonylamino)-1-methyl-imidazol-2-carbonsäureamid oder
• k) N-[4-(4-Propylpiperidino)-phenylmethyl]-4-(4'-trifluormethylbiphenyl-2-carbonyl-amino)-1-methyl-pyrrol-2-carbonsäure-amidsowie deren Salze.

A very particularly preferred embodiment relates to combinations of one of the following MTP inhibitors with fibrates, in particular with fenofibrate:

• (a) N- [3- (biphenyl-4-yl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylarnino) -1-methyl-pyrrole-2-carboxamide,
• (c) N- [4- (3-aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide,
• (f) N- [4- (1,4-Dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrol-2- carboxylic acid amide-,
• (i) N- (3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide or
• k) N- [4- (4-Propylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide and its salts.

The following MTP inhibitors can also be used according to the invention:
9- [4- [4- [2- (4-Trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluorene-9-carboxamide (BMS -201038; Compound 9 from Wetterau JR et al., Science 282, 751-754 (1998); Compound 1 from Robl JA et al., J Med Chem 44, 851-856 (2001))
9- [4- [2,5-dimethyl-4 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -2-yl] carbonyl] amino] -1H-benzimidazol-1-yl] butyl ] -N- (2,2,2-trifluoro-ethyl) -9H-fluoren-9-carboxamide (BMS-212122; compound 3g from Robl JA et al., J Med Chem 44, 851-856 (2001))
2 (S) -cyclopentyl-2- [4- (2,4-dimethyl-9H-pyrido [2,3-b] indole-9-ylmethyl) phenyl] -N- (2-hydroxy-1 (R) - phenylethyl) acetamide (Implitapide, BAY-13-9952; Sorbera LA et al, Drugs of the Future 25 (11): 1138-1144 (2000))
2-Cyclopentyl-2- {4 - [(2,4-dimethyl-9H-pyrido [2,3-b] indol-9-yl) methyl] phenyl} -2'-phenylacetohydrazide (WO 00/71502)
2- {4 - [(2,4-Dimethylpyrimido [1,2-a] indol-10-yl) methyl] phenyl} -3-methyl-2'-phenylbutane hydrazide (WO 01/4817)
(-) - [2S- [2α, 4α (S *)]] - 4- [4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H- 1,2,4-triazol-3-yl) thio] methyl] -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1 methylpropyl) -3H-1,2,4-triazol-3-one (R-103757; compound 40 from WO 96/13499) and their sulfoxides such as (-) - [2S- [2α, 4α (S *)] ] -4- [4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1,2,4-triazol-3-yl) sulfonyl] methyl] -1,3-diox olan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one etc. (WO 00 / 37463)

Compounds from WO 00/05201:
(S) -6-Methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid- (2-methylsulfonylamino-indan-5-yl) -amide (Example 13b)
(R) -6-methyl-4 ^c -trifluoromethylbiphenyl-2-carboxylic acid- (2-methoxycarbonylarninoindan-5-yl) -amide (Example 13i)
and (S) -6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid- (2-methoxycarbonylamino-indan-5-yl) -amide
(R) -4-fluoro-4'-trifluoromethylbiphenyl-2-carboxylic acid- (2-methylsulfonylamino-indan-5-yl) -amide (Example 13al)
and (S) -4-fluoro-4'-trifluoromethylbiphenyl-2-carboxylic acid (2-methylsulfonylamino-indan-5-yl) amide
6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid- (2-dimethylaminocarbonylamino-indan-5-yl) -amide (Example 2ey)
4'-Trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide ( CP-346,086 ; WO 97/41111 and WO 96/40640)
4'-Trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylamino-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide ( CP-395,919 ; WO 98/23593 and EP 0 887 345 )

According to the invention, the following compounds can be used as fibrates (international free names):
bezafibrate
ciprofibrate
clofibrate
fenofibrate
gemfibrozil

The general in the invention and specifically named substances are administered systemically, e.g. orally or parenterally. Oral administration is preferred. You can in systemic formulations such as tablets, capsules, powders, solutions, Suspensions, injection formulations or the like are included. Suitable pharmaceutically acceptable carriers, together with the substances of this invention can be used for example inert solid fillers or thinning Agents as well as sterile aqueous or organic solutions. If necessary, you can further substances are added to the pharmaceutical compositions, such as anti-oxidants, lubricants, buffers, fragrances and sweeteners.

MTP inhibitors and fibrates can either in separate systemic formulations or in a common one Formulation to be administered.

The dosage in which a substance this invention to warm-blooded Animals including of man can be administered according to the physical Condition to be varied. This includes taking into account, for example, age, Weight, gender, race and general health. The dosage is also determined by the type of administration.

Generally the daily dose the MTP inhibitor is between about 0.5 mg and about 500 mg, preferably between 1 mg and 200 mg. The is particularly preferred Range between 1 mg and 50 mg. This amount can be given as a single dose or divided into several doses.

Generally the daily dose of the fibrate is between about 50 mg and about 5000 mg, preferred between 50 mg and 1000 mg. The range is particularly preferred between 50 and 600 mg. This amount can be given as a single dose or divided administered on multiple doses.

test Description

The effectiveness of the combination of an MTP inhibitor with a fibrate and the influence on hepatic steatosis and liver toxicity can be tested in vivo in the following manner. Hyperlipemic rats (eg the rat strain fa / fa) receive the active substances as a suspension in 0.45% NaCl and 5% polyethylene glycol 400 orally administered with a gavage (5 ml / kg body weight). The applications can be carried out once or several times a day for a period of 4 days, or alternatively over a longer period. The day after the last application, blood samples are taken by puncturing the retroorbital venous plexus and plasma is prepared. In plasma, the concentrations of cholesterol and triglycerides as well as the activities of the liver enzymes (eg ALT, AST, GLDH) are determined according to well-known methods of clinical chemistry. These substrates and enzymes in the plasma can be measured, for example, with a HITACHI 917 Automatic Analyzer, reagents from Roche Diagnostics (Mannheim) according to the following protocols from Roche Diagnostics are used:
ALT: BM / HITACHI 917 / Keysys No. 1876805
AST: BM / HITACHI 917 / Keysys No. 1876848
GLDH: Glutamate Dehydrogenase, No. 1929992
Cholesterol: BM / HITACHI 917, Boehringer Mannheim System No. 1 491 458
Triglycerides: BM / HITACHI 917, Boehringer Mannheim System No. 1 730 711.

In addition, the liver can be removed be used to measure hepatic steatosis by measuring lipid content (Triglycerides, free fatty acids, Cholesterol) in this organ. This is followed by 200 mg of liver Add 2 ml of isopropanol and homogenize for 10 min with shaking. The extract is used for 10 min at 4 ° C centrifuged at 4000 rpm and an aliquot of the supernatant to determine the Lipid parameters used. The lipids are measured in the liver with commercially available Test kits according to the manufacturer (for triglycerides: triglyceride duo S from BIOMED Labordiagnostik GmbH, Oberschleissheim; for cholesterol: Cholesterol Duo S from BIOMED Labordiagnostik GmbH, Oberschleissheim; for free fatty acids: NEFA C from Wako Chemicals GmbH, Neuss).

Description of the drawings

The 1a and 1b put that. Findings of the first pharmacological example (example A) graphically. 1a shows the plasma cholesterol content 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 of a non- treated control group. 1b shows the plasma content of trigycerides 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 of a non- treated control group. The numbers above the bars of the diagram indicate the percentage changes compared to the control group.

The 2a and 2 B also refer to the first pharmacological example (Example A) and show on the basis of the activity of alanine aminotransferase (ALT, 2a ) or glutamate dehydrogenase (GLDH, 2 B ) in blood plasma, which are a characteristic sign of damage to liver cells, 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 to a control group. The numbers above the bars of the diagram indicate the increase compared to the control group.

The 3a and 3b represent the content of triglycerides or free fatty acids in the liver, which is determined after administration of an MTP inhibitor alone (M), a fibrate alone (F) or a combination of MTP inhibitor and fibrate (M + F) the pharmacological example B compared to a control group.

Example A

Female fa / fa rats at 33 weeks of age were either treated four times with an MTP inhibitor (once daily, oral application at 7 a.m.) or eight times with a fibrate (twice daily, oral application at 7 a.m. and 4 p.m.). A third group received both the MTP inhibitor and the fibrate. The MTP inhibitor was 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) - 9H-fluorene-9-carboxamide in a dosage of 1 mg / kg. The fibrate was bezafibrate at a dose of 100 mg / kg. 24 hours after the last administration of the MTP inhibitor or 15 hours after the last administration of the fibrate, blood was drawn from the animals and cholesterol, triglycerides and liver enzymes were measured in the plasma. Compared to the control group, which had been treated with vehicle twice a day, the MTP inhibitor reduced the triglycerides in plasma by 84%, the fibrate by 56% and the combination of both by 91%. Plasma cholesterol was reduced by 29% with the MTP inhibitor, 47% with the fibrate and 76% with the combination. This shows that the effects of MTP inhibitor and fibrate on lipid levels in plasma complement each other ( 1a and 1b ). The numbers above the bars of the diagram indicate the percentage change compared to the control group.

The side effects of the MTP inhibitor on the liver are evident from a 5.2-fold increase in ALT activity and a 7.7-fold increase in GLDH activity in the blood plasma compared to the control group. Combined with the fibrate, these increases are either completely normalized (ALT) or significantly reduced (GLDH) ( 2a and 2 B ). The horizontal line in the diagram shows three times the value of the control group and is interpreted as a limit for a clearly toxic side effect. The numbers above the bars of the diagram indicate the increase compared to the control group.

Example B

Female fa / fa rats at 38 weeks of age were either treated four times with an MTP inhibitor (once daily, oral application at 7 a.m.) or eight times with a fibrate (twice daily, oral application at 7 a.m. and 4 p.m.). A third group received both the MTP inhibitor and the fibrate. The MTP inhibitor was 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H -fluorene-9-carboxamide in a dosage of 0.3 mg / kg. The fibrate was bezafib rat in a dose of 100 mg / kg. 24 hours after the last administration of the MTP inhibitor or 15 hours after the last administration of the fibrate, the liver was removed from the animals and the content of triglycerides and free fatty acids was determined therein. The MTP inhibitor leads to an increase in triglycerides and free fatty acids in the liver ( 3a and 3b ). When combined with the fibrate, the lipid accumulation caused by the MTP inhibitor is reduced by approximately 50% (triglycerides in the liver) or by approximately 80% (free fatty acids in the liver).

Example C

male fa / fa rats at the age of 32 weeks were either included four times treated with an MTP inhibitor (once daily, oral application approx. between 7 a.m. and 8 a.m. or eight times with a fibrate (twice daily, oral Application approx. Between 7 a.m. and 8 a.m. and 4 p.m.). Another Group received both the MTP inhibitor and the fibrate. at the 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 dose of 10 mg / kg. The fibrate was Fenofibrate in a dosage of 100 mg / kg. 24 hours after the last administration of the MTP inhibitor or 15 hours after the last Fenofibrate was taken from the animals' blood and in plasma Cholesterol, triglycerides and liver enzymes measured.

The effects of the treatment on plasma lipid levels are shown in the following table:

Towards the control group, the Having been treated with vehicle twice a day, de MTP inhibitor lowered Plasma cholesterol by 58%, fenofibrate by 15% and the combination of both by 68%. Plasma triglycerides were inhibited by the MTP reduced by 94%, by fenofibrate by 20% and by the combination of both by 87%. As in Example A, these data show that the Effects of MTP inhibitor and fibrate on lipid levels in plasma complete can.

The effects of the treatment on the activity of liver enzymes in plasma can be seen in the following table:

The side effects of the MTP inhibitor on the liver are 4.5 times (AST) and 3.6 times increase in activity of these transaminases in plasma. By combination with fenofibrate this increase completely normalized.

Example D

male fa / fa rats at the age of 33 weeks were either included four times treated with an MTP inhibitor (once daily, oral application approx. between 7 a.m. and 8 a.m. or eight times with a fibrate (twice daily, oral Application approx. Between 7 a.m. and 8 a.m. and 4 p.m.). Another Group received both the MTP inhibitor and the fibrate. at the MTP inhibitor was N- [3- (biphenyl-4-yl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide (Compound (a)) at a dose of 3 mg / kg. The fibrate was Fenofibrate in a dosage of 100 mg / kg. 24 hours after the last one Administration of the MTP inhibitor or 15 hours after the last administration of Fenofibrate was taken from the animals' blood and cholesterol in the plasma, Triglycerides and liver enzymes measured.

The effects of the treatment on plasma lipid levels are shown in the following table:

Towards the control group, the Having been treated with vehicle twice a day, the MTP lowered Inhibitor cholesterol in plasma by 26%, which led to fenofibrate an increase of 10% and the combination of both into one 55% reduction. Plasma triglycerides were inhibited by the MTP reduced by 76%, increased by 33% by fenofibrate and by the Combination of both reduced by 73%. As in example A and C these data show that the effects of MTP inhibitor and fibrate on lipid levels supplement in the plasma can.

The effects of the treatment on the activity of liver enzymes in plasma can be seen in the following table:

The side effects of the MTP inhibitor on the liver are 6.7 times (AST) and 5.1 times increase in activity of these transaminases in plasma. By combination with fenofibrate this increase completely normalized.

The following are four specific ones examples for Tablets and capsules containing one or two active substances of this Contain invention specified.

1. Tablet with 5 mg of active ingredient

The active ingredient is for 15 minutes together with lactose monohydrate, microcrystalline cellulose and carboxymethyl cellulose sodium mixed in a suitable diffusion mixer. magnesium stearate is added and for another 3 minutes with the rest Mixed fabrics.

The finished mixture is on a Tablet press to round, flat tablets pressed with facet.

Tablet diameter: 7 mm; Weight one tablet: 120 mg

2. Capsule with 50 mg of active ingredient

A starch paste is made by part of the cornstarch with an appropriate amount of hot water is swollen. The paste is then left cool to room temperature.

The active ingredient is in a suitable Mixer with lactose monohydrate and corn starch premixed for 15 minutes. The starch paste is added and enough water is added to the mixture to make it homogeneous to get moist mass. The moist mass is passed through a sieve given with a mesh size of 1.6 mm. The sieved granulate becomes on hordes at around 55 ° C for 12 Hours dried.

The dried granules are then given by sieves with mesh sizes 1.2 and 0.8 mm. colloidal anhydrous Silicon dioxide is mixed in a suitable mixer in 3 minutes mixed with the granules. Then magnesium stearate is added and for further Mixed for 3 minutes.

The finished mixture is made with the help a capsule filling machine in empty capsule shells filled with size 1 hard gelatin.

3rd tablet with 200 mg of active ingredients

HPMC (hydroxypropylmethyl cellulose) will be in hot Water dispersed. The mixture gives one after cooling clear solution.

The active ingredients are in a suitable Mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose premixed. The HPMC solution will be added and mixing continued until a homogeneous moist mass was obtained becomes. The wet mass is passed through a sieve with a mesh size Given 1.6 mm. The sieved granules are placed on trays at about 55 ° C for 12 hours dried.

The dried granules are then given by sieves with a mesh size of 1.2 and 0.8 mm. Poly-1-vinyl-2-pyrrolidone in a suitable mixer for 3 minutes with the granules mixed. Then magnesium stearate is added and for more Mixed for 3 minutes.

The finished mixture is on a Tablet press to oblong shaped Tablets pressed (16.2 x 7.9 mm).

Weight of one tablet: 480 mg

4. Tablet with 500 mg of active ingredients

HPMC is dispersed in hot water. The Mixture gives after cooling a clear solution.

The active ingredients are in a suitable Mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose premixed. The HPMC solution will be added and mixing continued until a homogeneous moist mass was obtained becomes. The wet mass is passed through a sieve with a mesh size 1.6 mm. The sieved granules are placed on trays at about 55 ° C for 12 hours dried.

The dried granules are then given by sieves with a mesh size of 1.2 and 0.8 mm. Poly-1-vinyl-2-pyrrolidone in a suitable mixer for 15 minutes with the granules mixed. Then magnesium stearate is added and for more Mixed for 3 minutes.

The finished mixture is on a Tablet press to oblong shaped Tablets pressed (16.5 × 8.5 mm).

Weight of one tablet: 615 mg

Further examples

example 1

N- [4- (3-methyl-5-phenyl-pyrazol-1-yl) phenylmethyl] -2- (biphenyl-2-carbonyl) -thiazol-4-carboxamide

a. 4- (3-methyl-5-phenyl-pyrazol-1-yl) -benzonitrile

A solution of 20.0 g (0.118 mol) of 4-cyanophenylhydrazine and 19.1 g (0.118 mol) of benzoylacetone in 600 ml of methanol is mixed with 16.7 mg of triethylamine and stirred for two days. The solvent is distilled off, the residue is taken up in dichloromethane, washed with water and dried with sodium sulfate. It is then chromatographed on a silica gel column, eluting with dichloromethane.
Yield: 22.2 g (73% of theory),
R _f value: 0.9 (silica gel; dichloromethane / methanol = 19: 1)
C ₁₇ H ₁₃ N ₃ (259.31)
Mass spectrum: (M + H) ⁺ = 260

b. 4- (3-methyl-5-phenyl-pyrazol-1-yl) phenylmethylamine

22.2 g (0.086 mol) of 4- (3-methyl-5-phenyl-pyrazol-1-yl) benzonitrile are dissolved in 660 ml of methanolic ammonia and, after addition of Raney nickel, hydrogenated at room temperature with hydrogen (3 bar). The catalyst is filtered off and the solution is evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol = 4: 1.
Yield: 22 g (97% of theory),
R _f value: 0.2 (silica gel; dichloromethane / methanol = 9: 1)
C ₁₇ H ₁₇ N ₃ (263.35)
Mass spectrum: (M + H) ⁺ = 264
M ⁺ = 263

c. 2-amino-thiazole-4-carboxylic acid ethyl ester

7.2 g (0.094 mol) of thiourea are dissolved in 100 ml of ethanol, 12.0 g (0.086 mol) of ethyl bromopyruvate are added at room temperature and the mixture is then heated under reflux for 1.5 hours. After cooling, diluted with 50 ml of water, with conc. Ammonia made alkaline and the precipitate is suctioned off.
Yield: 12.5 g (84% of theory),
R _f value: 0.5 (silica gel; dichloromethane / ethanol = 19: 1)
C ₆ H ₈ N ₂ O ₂ S (172.21)
Mass spectrum: (M - H) ^- = 171
(M + H) ⁺ = 173
(M + Na) ⁺ = 195

d. 2- (biphenyl-2-carbonyl) -thiazol-4-carboxylic acid ethyl ester

1.0 g (5.0 mmol) of 2-biphenylcarboxylic acid are placed in 15 ml of dimethylformamide and, after adding 0.9 g (5.45 mmol) of 2-amino-thiazole-4-carboxylic acid ethyl ester, 1.8 g (5.60 mmol) of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and 2.9 ml (15.4 mmol) of N-ethyl-diisopropyl-amine stirred for 12 hours. The solution is evaporated and chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (10-30%).
Yield: 0.5 g (28% of theory),
R _f value: 0.3 (silica gel; petroleum ether / ethyl acetate = 7: 3)
C ₁₉ H ₁₆ N ₂ O ₃ S (352.41)
Mass spectrum: (M + H) ^- = 351
(M + Na) ⁺ = 375

e. 2- (biphenyl-2-carbonyl) -thiazol-4-carboxylic acid

0.5 g (1.4 mmol) of ethyl 2- (biphenyl-2-carbonylamino) -thiazole-4-carboxylate are stirred in 30 ml of ethanol and 1.6 ml of 2 molar sodium hydroxide solution at room temperature for 18 hours. The solvent is distilled off, the residue is mixed with water and acidified with 2 molar hydrochloric acid. The precipitated product is suctioned off.
Yield: 0.3 g (72% of theory),
R _f value: 0.4 (silica gel; dichloromethane / ethanol = 4: 1)
C ₁₇ H ₁₂ N ₂ O ₃ S (324.36)
Mass spectrum: (M - H) ^- = 323

f. N- [4- (3-methyl-5-phenyl-pyrazol-1-yl) phenylmethyl] -2- (biphenyl-2-carbonyl) -thiazol-4-carboxamide

Prepared analogously to Example 1 d from 2- (biphenyl-2-carbonylamino) thiazol-4-carboxylic acid, 4- (3-methyl-5-phenyl-pyrazol-1-yl) benzylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 23% of theory,
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₇ N ₅ O ₂ S (569.69)
Mass spectrum: (M - H) ^- = 568
(M + Na) ⁺ = 592

Example 2

N- (biphenyl-4-yl) methyl-2- (biphenyl-2-carbonyl) -thiazol-4-carboxamide

Prepared analogously to Example 1d from 2- (biphenyl-2-carbonylamino) thiazole-4-carboxylic acid, 4-phenylbenzylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 86% of theory,
R _f value: 0.40 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₀ H ₂₃ N ₃ O ₂ S (489.60)
Mass spectrum: (M - H) ^- = 488

Example 3

N- (4-benzoylamino-phenylmethyl) -2- (biphenyl-2-carbonyl) -thiazol-4-carboxamide

Prepared analogously to Example 1d from 2- (biphenyl-2-carbonylamino) thiazole-4-carboxylic acid, 4-benzoylaminobenzylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 25% of theory
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₂₄ N ₄ O ₃ S (532.62)
Mass spectrum: (M - H) ^- = 531
(M + H) ⁺ = 533
(M + Na) ⁺ = 555

Example 4

N- (biphenyl-4-yl) methyl-5- (4'-trifluoromethylbiphenyl-2-carbonylamino) thiophene-2-carboxamide

a. N- (biphenyl-4-yl) methyl-5-nitro-thiophene-2-carboxamide

A mixture of 766 mg (4.0 mmol) of 5-nitrothiophene-2-carbonyl chloride, 733 mg (4.0 mmol) of 4-phenylbenzylamine and 1 ml of triethylamine are stirred in 45 ml of tetrahydrofuran for 18 hours. The solvent is distilled off and chromatographed on silica gel, eluting with dichloromethane.
Yield: 540 mg (40% of theory),
R _f value: 0.30 (silica gel; dichloromethane)
C ₁₈ H ₁₄ N ₂ O ₃ S (338.39)
Mass spectrum: (M - H) ^- = 337

b. N- (biphenyl-4-yl) methyl-5-aminothiophene-2-carboxamide

500 mg (1.47 mmol) of N- (biphenyl-4-yl) methyl-5-nitrothiophene-2-carboxamide are dissolved in 35 ml of methanol and 15 ml of dichloromethane and, after adding 300 mg of Raney nickel, at room temperature with hydrogen (3 bar ) hydrogenated. The catalyst is filtered off and the solution is evaporated.
Yield: 400 mg (88% of theory),
R _f value: 0.30 (silica gel; dichloromethane / ethanol = 50: 1)

c. N- (biphenyl-4-yl) methyl-5- (4'-trifluoromethylbiphenyl-2-carbonylamino) thiophene-2-carboxamide

Prepared analogously to Example 4a from N- (biphenyl-4-yl) methyl-5-aminothiophene-2-carboxamide, 4'-trifluoromethylbiphenyl-2-carboxylic acid chloride and triethylamine in tetrahydrofuran.
Yield: 43% of theory
R _f value: 0.50 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₂ H ₂₃ F ₃ N ₂ O ₂ S (556.61)
Mass spectrum: (M - H) ^- = 555

Example 5

N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6- (4'-trifluoromethylbiphenyl-2-carbonylamino) -pyrimidine-4-carboxylic acid amide

a. 4- (3,4-dihydro-2H-quinolin-1-yl) -benzonitrile

5.3 g (0.04 mol) of 1,2,3,4-tetrahydroquinoline are dissolved in 60 ml of dimethyl sulfoxide, 7.1 g (0.064 mol) of potassium tert-butoxide are added and the mixture is stirred for 20 minutes. Then 7.7 g (0.064 mol) of 4-fluorobenzonitrile in dimethyl sulfoxide are added dropwise and the mixture is stirred at 90 ° C. for three days. The reaction mixture is poured onto saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are chromatographed on aluminum oxide, eluting with petroleum ether / dichloromethane 1: 1.
Yield: 4.5 g (48% of theory),
R _f value: 0.30 (silica gel; dichloromethane / petroleum ether = 1: 1)
C ₁₆ H ₁₄ N ₂ (234.30)
Mass spectrum: (M - H) ^- = 233

b. 4- (3,4-dihydro-2H-quinolin-1-yl) benzylamine

Manufactured analogously to Example 1b 4- (3,4-dihydro-2H-quinolin-1-yl) benzonitrile, Raney nickel and methanolic Ammonia with the addition of hydrogen.
Yield: 88% of theory
R_f-Value: 0.20 (silica gel; Dichloromethane / ethanol = 19: 1)
C₁₆H₁₈N₂ (238.34)
Mass Spectrum: (M + H)⁺ = 239

c. N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6-chloro-pyrimidine-4-carboxamide

Prepared analogously to Example 4a from 4- (3,4-dihydro-2H-quinolin-1-yl) benzylamine, 6-chloropyrimidine-4-carboxylic acid chloride and triethylamine in tetrahydrofuran.
Yield: 69% of theory
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 50: 1)
C ₁₂ H ₁₉ ClN ₄ O (378.86)
Mass spectrum: (M - H) ^- = 377/79 (chlorine isotopes)

d. N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6- (2,3-dimethoxy-phenylmethylamino) pyrimidine-4-carboxamide

300 mg (0.79 mmol) of N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6-chloropyrimidine-4-carboxamide and 500 mg (3.0 mmol) of 2,4- Dimethoxybenzylamine are stirred at 160 ° C for two hours. After cooling, it is chromatographed on silica gel, eluting with dichloromethane.
Yield: 380 mg (94% of theory),
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₀ H ₃₁ N ₅ O ₃ (509.61)
Mass spectrum: (M - H) ^- = 508
(M + Na) ⁺ = 532

e. N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6-amino-pyrimidin-4-carboxamide

350 mg (0.68 mmol) of N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6- (2,3-dimethoxy-benzylamino) pyrimidine-4-carboxamide are dissolved in 30 ml of dichloromethane dissolved and after adding 7 ml of trifluoroacetic acid stirred for two days. The solvent is distilled off, made alkaline with methanolic ammonia and chromatographed on silica gel, eluting with dichloromethane / ethanol = 99: 1.
Yield: 130 mg (53% of theory),
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 19: 1)
C ₂₁ H ₂₁ N ₅ O (359.43)
Mass spectrum: (M - H) ^- = 358

f. N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6- (4'-trifluoromethylbiphenyl-2-carbonylamino) -pyrimidine-4-carboxylic acid amide

Prepared analogously to Example 4a from N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -6-aminopyrimidine-4-carboxamide, 4'-trifluoromethylbiphenyl-2-carboxylic acid chloride and triethylamine in tetrahydrofuran.
Yield: 17% of theory
R _f value: 0.40 (silica gel; petroleum ether / ethyl acetate = 2: 1)
C ₃₅ H ₂₈ F ₃ N ₅ O ₂ (607.63)
Mass spectrum: M ⁺ = 607
(M + Na) ⁺ = 630

Example 6

N- [4- (3,4-dihydro-1H-isoquinolin-2-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (3,4-dihydro-1H-isoquinolin-2-yl) benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 100% of theory
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₆ H ₃₁ F ₃ N ₄ O ₂ (608.67)
Mass spectrum: (M - H) ⁺ = 609
(M-H) ^- = 607
(M - HCOO) ^- = 653

Example 7

N- (4'-methylbiphenyl-4-yl) methyl-5- (4'-trifluoromethylbiphenyl-2-carbonylamino) -nicotinsäureamid

Prepared analogously to Example 1d from 5- (4'-trifluoromethyl-biphenyl-2-carbonylamino) nicotinic acid, 4'-methylbiphenyl-4-methylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 26% of theory
R _f value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₆ F ₃ N ₃ O ₂ (565.60)
Mass spectrum: (M - H) ^- = 564
(M + Na) ⁺ = 588

Example 8

N- (4-phenylaminocarbonyl-phenylmethyl) -5- (4'-trifluoromethylbiphenyl-2-carbonylamino) -nicotinsäureamid

Prepared analogously to Example 1d from 4-phenylaminocarbonylbenzylamine, 5- (4'-trifluoromethylbiphenyl-2-carbonylamino) nicotinic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 21% of theory
R _f value: 0.41 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ N ₂₅ F ₃ N ₄ O ₃ (594.59)
Mass spectrum: M ⁺ = 594

Example 9

N- [4- (3-methyl-5-phenyl-pyrazol-1-yl) phenylmethyl] -5- (4'-trifluoromethylbiphenyl-2-carbonylamino) -nicotinsäureamid

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.
Yield: 32% of theory
R _f value: 0.48 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₇ H ₂₈ F ₃ N ₅ O ₂ (631.66)
Mass spectrum: (M + Na) ⁺ = 654

Example 10

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid, 4'-methylbiphenyl-4-methylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 10% of theory
R _f value: 0.95 (silica gel; dichloromethane / ethanol = 4: 1)
C ₃₃ H ₂₇ F ₃ N ₄ O ₂ (568.60)
Mass spectrum: (M - H) ^- = 567
(M + Na) ⁺ = 591

Example 11

 N- (biphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

A solution of 100 mg (0.25 mmol) 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid, 48 mg (0.25 mmol) 4-phenylbenzylamine and 0.2 ml (1 .5 mmol) of N-methylmorpholine in 6 ml of dichloromethane is added at -10 ° C with 0.3 ml (0.5 mmol) of propanephosphonic acid cycloanhydride (50% by weight in ethyl acetate) and stirred for 2 hours with cooling. The mixture is then washed with 2 molar hydrochloric acid and 2 molar sodium hydroxide solution, the combined organic extracts are dried and evaporated.
Yield: 0.12 g (84% of theory),
R _f value: 0.59 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₅ F ₃ N ₄ O ₂ (554.57)
Mass spectrum: (M - H) ^- = 553
(M + H) ⁺ = 555
(M + Na) ⁺ = 577

Example 12

N- [4- (piperidino) phenylmethyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4- (piperidino) benzylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methylimidazole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 88% of theory
R _f value: 0.53 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₃₀ F ₃ N ₅ O ₃ (561.51)
Mass spectrum: (M - H) ^- = 560

Example 13

N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -4- (4'-tri-fluormethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4- (3,4-dihydro-2H-quinolin-1-yl) benzylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in Dichloromethane with the addition of propanephosphonic cycloanhydride and N-methylmorpholine.
Yield: 85% of theory
R _f value: 0.71 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H _{3 0} F ₃ N ₅ O ₂ (609.65)
Mass spectrum: (M - H) ^- = 608

Example 14

N- (4'-Trifluormethybiphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4'-trifluoromethylbiphenyl-4-methylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methylimidazole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 83% of theory
R _f value: 0.52 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₄ F ₆ N ₄ O ₂ (622.57)
Mass spectrum: (M - H) ^- = 621

Example 15

N- (4'-chlorobiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4'-chlorobiphenyl-4-methylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methylimidazole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 88% of theory
R _f value: 0.54 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₄ ClF ₃ N ₄ O ₂ (589.02)
Mass spectrum: (M - H) ^- = 587/89 (chlorine isotopes)

Example 16

N- [4- (pyridin-4-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4- (pyridin-4-yl) benzylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 94% of theory
R _f value: 0.41 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₂₄ F ₃ N ₅ O ₂ (555.56)
Mass spectrum: (M - H) ^- = 554

Example 17

N- [4 - ([1,2,3] thiadiazole-4-yl) phenylmethyl] -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4 - ([1,2,3] thiadiazol-4-yl) benzylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in Dichloromethane with the addition of propanephosphonic cycloanhydride and N-methylmorpholine.
Yield: 88% of theory
R _f value: 0.52 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₁ F ₃ N ₆ O ₂ S (562.57)
Mass spectrum: (M - H) ^- = 561

Example 18

N- [4- (6-methyl-pyridazin-3-yl) phenylmethyl] -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

a. 4- (6-methyl-pyridazin-3-yl) -benzonitrile

875 mg (6.8 mmol) 3-chloro-6-methylpyridazine and 237 mg (0.2 mmol) tetrakistriphenylphosphine-pal Ladium (0) are placed in 40 ml of toluene, a solution of 1.0 g (6.8 mmol) of 4-cyano-phenylboronic acid in 20 ml of methanol and 1.4 g (13.6 mmol) of sodium carbonate in 20 ml of water are added and the mixture is heated under reflux for 7 hours. The reaction mixture is stirred for two days at room temperature and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / ethanol = 9: 1.
Yield: 340 mg (26% of theory),
R _f value: 0.53 (silica gel; dichloromethane / ethanol = 9: 1)
C ₁₂ H ₉ N ₃ (195.23)
Mass spectrum: (M + H) ⁺ = 196

b. 4- (6-methyl-pyridazin-3-yl) benzylamine

Prepared analogously to Example 1 b from 4- (6-methyl-pyridazin-3-yl) benzonitrile and Raney nickel in methanolic ammonia with the addition of hydrogen (3 bar).
Yield: 73% of theory,
R _f value: 0.13 (silica gel; dichloromethane / ethanol = 75:25)
C ₁₂ H ₁₃ N ₃ (199.26)
Mass spectrum: (M + H) ⁺ = 200

c. N- [4- (6-methyl-pyridazin-3-yl) phenylmethyl] -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4- (6-methyl-pyridazin-3-yl) benzylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in dichloromethane with the addition of Propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 96% of theory
R _f value: 0.51 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₂₅ F ₃ N ₆ O ₂ (570.57)
Mass spectrum: (M - H) ^- = 569
(M + H) ⁺ = 571
(M + Na) ⁺ = 593

Example 19

N- [3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

a. N-tert-butoxycarbonyl-prop-2-ynyl-amine

6.9 g (0.12 mol) of propargylamine are placed in 50 ml of dichloromethane, at 0 ° C. a solution of 27.3 g (0.12 mol) of di-tert-butyldicarbonate in 50 ml of dichloromethane is added dropwise and the mixture is stirred for three hours at room temperature. The mixture is then cooled to −20 ° C. and the precipitated product is suctioned off.
Yield: 18.2 g (94% of theory),

b. N-tert-butoxycarbonyl-3- (4-biphenyl) prop-2-ynyl-amine

A mixture of 1.3 g (5.3 mmol) of 4-bromobiphenyl, 0.1 g (0.53 mmol) of copper (I) iodide, 0.6 g (0.53 mmol) of tetrakis-triphenylphosphine-palladium (0) and 2.2 ml (16.1 mmol) of triethylamine in 30 ml of tetrahydrofuran heated to reflux for 10 minutes, then 1.0 g (6.4 mmol) of N-tert-butoxycarbonyl-prop-2-ynylamine is added and the mixture is heated to reflux for a further 10 hours. The precipitate is filtered off and the filtrate is evaporated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate 96: 4.
Yield: 370 mg (22% of theory),
R _f value: 0.62 (silica gel; petroleum ether / ethyl acetate = 7: 3)
C ₂₀ H ₂₁ NO ₂ (307.4)
Mass spectrum: (M + Na) ⁺ = 330

c. 3- (4-biphenyl) prop-2-ynyl-amine trifluoroacetate

365 mg (1.1 mmol) of N-tert-butoxycarbonyl-3- (4-biphenyl) prop-2-ynylamine are stirred in 20 ml of dichloromethane and 2 ml of trifluoroacetic acid for 2 hours. Then it is evaporated and the residue is immediately implemented further.
Yield: 381 mg (quantitative),
R _f value: 0.22 (silica gel; dichloromethane / ethanol = 9: 1)

d. N- [3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 3-biphenyl-4-yl-prop-2-ynylamine trifluoroacetate and 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in dichloromethane with the addition of Propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 58% of theory
R _f value: 0.59 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₅ F ₃ N ₄ O ₂ (578.59)
Mass spectrum: (M - H) ^- = 577
(M + H) ⁺ = 579
(M + Na) ⁺ = 601

Example 20

N- (4'-hydroxybiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4'-hydroxybiphenyl-4-methylamine and 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 30% of theory
R _f value: 0.45 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₅ F ₃ N ₄ O ₃ (570.57)
Mass spectrum: (M - H) ^- = 569

Example 21

N- [3- (4-Trifluoromethylphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide

Prepared analogously to Example 11 from 3- (4-trifluoromethylphenyl) prop-2-ynylamine and 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methylimidazole-2-carboxylic acid in dichloromethane with the addition of Propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 71% of theory
R _f value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₉ H ₂₀ F ₆ N ₄ O ₂ (570.49)
Mass spectrum: (M - H) ^- = 569
(M + Na) ⁺ = 593

Example 22

N- [4- (1,4-dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 4- (1,4-dioxa-spiro [4.5] dec-8-yl) benzylamine and 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazole-2- carboxylic acid in dichloromethane with the addition of propanephosphonic cycloanhydride and N-methylmorpholine.
Yield: 67% of theory
R _f value: 0.62 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₃₃ F ₃ N ₄ O ₄ (618.66)
Mass spectrum: (M - H) ^- = 617

Example 23

N- [3- (4-tert-butylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 3- (4-tert-butylphenyl) prop-2-ynylamine and 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxylic acid in dichloromethane with the addition of Propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 33% of theory
R _f value: 0.52 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₉ F ₃ N ₄ O ₂ (558.60)
Mass spectrum: (M - H) ^- = 557
(M + Na) ⁺ = 581

Example 24

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1 d from 4'-methylbiphenyl-4-methyl-amine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.40 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₄ N ₂₈ F ₃ N ₃ O ₂ (567: 61)
Mass spectrum: (M - H) ^- = 566
(M + Na) ⁺ = 590

Example 25

N- (4-phenylcarbonylamino-phenylmethyl) -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1 d from 4-phenylcarbonylamino-benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 62% of theory
R _f value: 0.20 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₄ N ₂₇ F ₃ N ₄ O ₃ (596.61)
Mass spectrum: (M - H) ^- = 595
(M + Na) ⁺ = 619

Example 26

N- [4- (3-methyl-5-phenyl-pyrazol-1-yl) phenylmethyl] -4- (4'-tri-fluormethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- (3-methyl-5-phenyl-pyrazol-1-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.25 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₇ H ₃₀ F ₃ N ₅ O ₂ (633.67)
Mass spectrum: (M - H) ^- = 632
(M + Na) ⁺ = 656

Example 27

N- (4'-methylbiphenyl-4-yl) methyl-4- (biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-methylbiphenyl-4-methylamine, 4- (biphenyl-2-carbonylami no) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 99% of theory
R _f value: 0.40 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₃ H ₂₉ N ₃ O ₂ (499.61)
Mass spectrum: M ⁺ = 499

Example 28

N-Benzyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₇ H ₂₂ F ₃ N ₃ O ₂ (477.49)
Mass spectrum: (M - H) ^- = 476
(M + Na) ⁺ = 490

Example 29

N-pyridin-2-ylmethyl-4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 2- (aminomethyl) pyridine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.50 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₆ H ₂₁ F ₃ N ₄ O ₂ (478.47)
Mass spectrum: (M - H) ^- = 477

Example 30

N-pyridin-3-ylmethyl-4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 3- (aminomethyl) pyridine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.40 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₆ H ₂₁ F ₃ N ₄ O ₂ (478.47)
Mass spectrum: (M - H) ^- = 477
(M + Na) ⁺ = 501

Example 31

N-pyridin-4-ylmethyl-4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (aminomethyl) pyridine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.35 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₆ H ₂₁ F ₃ N ₄ O ₂ (478.47)
Mass spectrum: (M - H) ^- = 477
(M + Na) ⁺ = 501

Example 32

N-methoxycarbonylmethyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from glycine methyl ester hydrochloride, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₃ H ₂₀ F ₃ N ₃ O ₄ (459.42)
Mass spectrum: (M - H) ^- = 458
(M + Na) ⁺ = 482

Example 33

N- (2-methoxycarbonylethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1 d from β-alanine methyl ester hydrochloride, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₄ H ₂₂ F ₃ N ₃ O ₄ (473.45)
Mass spectrum: (M - H) ^- = 472
(M + Na) ⁺ = 496

Example 34

N- (4- [1,2,3] thiadiazol-4-yl-phenylmethyl) -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- [1,2,3] thiadiazol-4-yl-benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₉ H ₂₂ F ₃ N ₅ O ₂ S (561.59)
Mass spectrum: (M - H) ^- = 560

Example 35

N- [2- (4-methylphenyl) pyridin-5-ylmethyl] -4- (4'-trifluoro-methyl-biphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from (2- (4-methylphenyl) pyridin-5-yl) methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N -Ethyl-diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.55 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₇ F ₃ N ₄ O ₂ (568.60)
Mass spectrum: (M - H) ^- = 567
(M + Na) ⁺ = 591

Example 36

N- [4- (pyridin-4-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (pyridin-4-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.45 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₅ F ₃ N ₄ O ₂ (554.57)
Mass spectrum: (M - H) ^- = 553

Example 37

N- [4- (N-methyl-N-cyclohexylaminocarbonyl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (N-methyl-N-cyclohexylaminocarbonyl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 98% of theory
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₃₅ F ₃ N ₄ O ₃ (616.68)
Mass spectrum: (M - H) ^- = 615

Example 38

N- (4-bromophenylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4-bromobenzylamine hydrochloride, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₇ H ₂₁ BrF ₃ N ₃ O ₂ (556.38)
Mass spectrum: (M - H) ^- = 554/56 (bromine isotopes)

Example 39

N- (4'-trifluoromethylbiphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-trifluoromethylbiphenyl-4-methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₅ F ₆ N ₃ O ₂ (621.58)
Mass spectrum: (M - H) ^- = 620

Example 40

N- (4'-chlorobiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-chlorobiphenyl-4-methyl-amine, 4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₅ CIF ₃ N ₃ O ₂ (588.03)
Mass spectrum: (M - H) ^- = 586/88 (chlorine isotopes)

Example 41

N- [3- (4-methylphenyl) -prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 3- (4-methylphenyl) prop-2-ynylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methylpyrrole-2-carboxylic acid, TBTU and N- Ethyldiisopropylamine in dimethylformamide.
Yield: 57% of theory
R _f value: 0.6 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₀ H ₂₄ F ₃ N ₃ O ₂ (515.54)
Mass spectrum: (M - H) ^- = 514

Example 42

N- [3- (4-isopropylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 3- (4-isopropylphenyl) prop-2-ynylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 82% of theory
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₈ F ₃ N ₃ O ₂ (543.59)
Mass spectrum: (M - H) ^- = 542

Example 43

N-hydroxycarbonylmethyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1e from N-methoxycarbonylmethyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide and 2 molar sodium hydroxide solution in methanol.
Yield: 77% of theory
R _f value: 0.3 (silica gel; dichloromethane / ethanol = 4: 1)
C ₂₂ H ₁₈ F ₃ N ₃ O ₄ (445.40)
Mass spectrum: (M - H) ^- = 444
(M + Na) ⁺ = 468

Example 44

N- (2-hydroxycarbonylethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1e from N- (2-methoxycarbonylethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide and 2 molar sodium hydroxide solution in methanol.
Yield: 67% of theory
R _f value: 0.3 (silica gel; dichloromethane / ethanol = 4: 1)
C ₂₃ H ₂₀ F ₃ N ₃ O ₄ (459.42)
Mass spectrum: (M - H) ^- = 458

Example 45

N- (biphenyl-3-methyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 3-phenylbenzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.8 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₆ F ₃ N ₃ O ₂ (553.58)
Mass spectrum: (M - H) ^- = 552

Example 46

N- (2'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 2'-methylbiphenyl-4-methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.75 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₈ F ₃ N ₃ O ₂ (567.61)
Mass spectrum: (M - H) ^- = 566

Example 47

N- (4'-methoxycarbonylbiphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-methoxycarbonylbiphenyl-4-methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.75 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₂₈ F ₃ N ₃ O ₄ (611.62)
Mass spectrum: (M - H) ^- = 610

Example 48

N- [4- (piperidino) phenylmethyl) -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (piperidino) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₃₁ F ₃ N ₄ O ₂ (560.62)
Mass spectrum: (M - H) ^- = 559

Example 49

N- [4- (1,4-dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- (1,4-dioxa-spiro [4.5] dec-8-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrol-2- carboxylic acid, TBTU and N-ethyldi-isopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₃₄ F ₃ N ₃ O ₄ (617.67)
Mass spectrum: (M + Na) ⁺ = 640

Example 50

N- (4-tert.Butylphenylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4-tert-butylbenzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₃₀ F ₃ N ₃ O ₂ (533.59)

Example 51

N- (4-chlorophenylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4-chlorobenzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₇ H ₂₁ CIF ₃ N ₃ O ₂ (511.93)
Mass spectrum: (M - H) ^- = 510/12 (chlorine isotopes)

Example 52

N- (2-Phenyl-thiazol-4-ylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from (2-phenylthiazol-4-yl) methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₀ H ₂₃ F ₃ N ₄ O ₂ S (560.60)
Mass spectrum: (M - H) ^- = 559

Example 53

N- (3-chloro-5-trifluoromethyl-pyridin-2-yl-methyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 3-chloro-5-trifluoromethyl-pyridin-2-yl-methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₇ H ₁₉ CIF ₆ N ₄ O ₂ (580.92)
Mass spectrum: (M - H) ^- = 579/81 (chlorine isotopes)

Example 54

N- (5-phenyl- [1,3,4] oxadiazol-2-yl-methyl) -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from (5-phenyl- [1,3,4] oxadiazol-2-yl) methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid , TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 76% of theory
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₉ H ₂₂ F ₃ N ₅ O ₃ (545.52)
Mass spectrum: (M - H) ^- = 544

Example 55

N- [4- (pyrimidin-4-yl-carbonylamino) -phenyl-methyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (pyrimidin-4-yl-carbonylamino) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: 99% of theory
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₅ F ₃ N ₆ O ₃ (598.58)
Mass spectrum: (M - H) ^- = 597

Example 56

N- (biphenyl-4-yl) methyl-N-methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from N-methyl-4-phenylbenzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 77% of theory
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₈ F ₃ N ₃ O ₂ (567.61)
Mass spectrum: (M - H) ^- = 566

Example 57

N- [4- (3,4-dihydro-2H-quinolin-1-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (3,4-dihydro-2H-quinolin-1-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.65 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₆ H ₃₁ F ₃ N ₄ O ₂ (608.66)
Mass spectrum: (M - H) ^- = 607

Example 58

N- [4- (pyridin-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (pyridin-3-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 37% of theory
R _f value: 0.65 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₅ F ₃ N ₄ O ₂ (554.57)
Mass spectrum: (M - H) ^- = 553

Example 59

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-fluoro-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-methylbiphenyl-4-methyl-amine, 4- (4'-fluorobiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 82% of theory
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₈ FN ₃ O ₂ (517.60)

Example 60

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-methylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-methylbiphenyl-4-methyl-amine, 4- (4'-methylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₃₁ N ₃ O ₂ (513.64)
Mass spectrum: (M - H) ^- = 512

Example 61

N- (4'-Hydroxycarbonylbiphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1e from N- (4'-methoxycarbonyl-biphenyl-4-yl) methyl-4- (4'-trifluoromethyl-biphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxamide and 2 molar Sodium hydroxide solution in ethanol.
Yield: quantitative
R _f value: 0.40 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₆ F ₃ N ₃ O ₄ (597.59)
Mass spectrum: (M - H) ^- = 596

Example 62

N- (4'-hydroxybiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4-hydroxyphenyl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 58% of theory
R _f value: 0.50 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₆ F ₃ N ₃ O ₃ (569.58)
Mass spectrum: (M - H) ^- = 568

Example 63

N- (4-Methaxycarbonyl-4-phenyl-hexyl) -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 5-amino-2-ethyl-2-phenyl-pentanoic acid methyl ester, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: 21% of theory
R _f value: 0.40 (silica gel; petroleum ether / ethyl acetate = 2: 3)
C ₃₄ H ₃₄ F ₃ N ₃ O ₄ (605.66)
Mass spectrum: (M - H) ^- = 604

Example 64

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1H-pyrrole-2-carboxamide

Prepared analogously to Example 11 from 4'-methylbiphenyl-4-methylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1H-pyrrole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 17% of theory
R _f value: 0.58 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₂₆ F ₃ N ₃ O ₂ (553.58)
Mass spectrum: (M - H) ^- = 552

Example 65

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-ethyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-methylbiphenyl-4-methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-ethyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 78% of theory
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₃₀ F ₃ N ₃ O ₂ (581.64)
Mass spectrum: (M - H) ^- = 580

Example 66

N- [4- (6-methylpyridazin-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (6-methylpyridazin-3-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 28% of theory
R _f value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₆ F ₃ N ₅ O ₂ (569.59)
Mass spectrum: (M - H) ^- = 568
(M + H) ⁺ = 570
(M + Na) ⁺ = 592

Example 67

N- [4- (pyridin-2-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (pyridin-2-yl) benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.55 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₅ F ₃ N ₄ O ₂ (554.57)
Mass spectrum: (M - H) ^- = 553
(M + Na) ⁺ = 577

Example 68

N- [3- (4-methylphenyl) propyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

50 mg (0.097 mmol) of N- [3- (4-methylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide are dissolved in 10 ml of ethanol and, after addition of 20 mg of palladium on activated carbon (10%), hydrogenated with hydrogen. The catalyst is filtered off and the solution is evaporated.
Yield: 40 mg (79% of theory),
R _f value: 0.35 (silica gel; petroleum ether / ethyl acetate = 1: 1)
C ₃₀ H ₂₈ F ₃ N ₃ O ₂ (519.57)
Mass spectrum: (M - H) ^- = 518

Example 69

N- (4'-methylbiphenyl-4-yl) methyl-4- [2- (morpholin-4-yl) -phenyl-carbonylamino] -1-methyl-pyrrole-2-carboxamide

a. 2- (morpholin-4-yl) -benzoic acid ethyl ester

A mixture of 1.7 ml (10.6 mmol) ethyl 2-bromobenzoate, 1.0 ml (11.0 mmol) morpholine, 5.4 g (16.5 mmol) cesium carbonate, 75 mg (0.33 mmol) palladium-II-acetate and 270 mg (0.43 mmol) 2.2 '-Bis- (diphenylphosphino) -1,1'-binaphthyl are stirred in 30 ml of xylene at 100 ° C for 12 hours. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane / ethanol 9: 1.
Yield: 0.6 g (25% of theory),
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 19: 1)
C ₁₃ H ₁₇ NO ₃ (235.29)
Mass spectrum: (M + H) ⁺ = 236
(M + Na) ⁺ = 258

b. 2- (morpholin-4-yl) benzoic acid

Prepared analogously to Example 1e from ethyl 2- (morpholin-4-yl) benzoate and 2 molar sodium hydroxide solution in methanol.
Yield: 90% of theory,
R _f value: 0.75 (silica gel; dichloromethane / ethanol / ammonia = 8: 4: 0.2)
C ₁₁ H ₁₃ NO ₃ (207.23)
Mass spectrum: (M - H) ^- = 206
(M + H) ⁺ = 208

c. 1-Methyl-4- [2- (morpholin-4-yl) -phenylcarbonylamino] pyrrole-2-carbonsäuremethylester

0.2 g (0.89 mmol) of 2- (morpholin-4-yl) benzoic acid are stirred in 1.0 ml (13.7 mmol) of thionyl chloride with the addition of 2 drops of dimethylformamide for 90 minutes. The solution is evaporated, 0.2 g (0.89 mmol) of 1-methyl-4-amino-pyrrole-2-carboxylic acid methyl ester, 0.4 ml (2.7 mmol) of triethylamine and 20 ml of tetrahydrofuran are added and the mixture is stirred for 17 hours. The solvent is distilled off, the residue is dissolved in dichloromethane and washed with water. The combined organic extracts are dried and evaporated.
Yield: 0.3 g (100% of theory),
R _f value: 0.35 (silica gel; dichloromethane / ethanol = 19: 1)
C ₁₈ H ₂₁ N ₃ O ₄ (343.39)
Mass spectrum: (M - H) ^- = 342
(M + Na) ⁺ = 366

d. 1-Methyl-4- [2- (morpholin-4-yl) -phenylcarbonylamino] pyrrole-2-carboxylic acid

Prepared analogously to Example 1e from 1-methyl-4- [2- (morpholin-4-yl) phenylcarbonylamino] pyrrole-2-carboxylic acid methyl ester and 2 molar sodium hydroxide solution in methanol.
Yield: 75% of theory
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₁₇ H ₁₉ N ₃ O ₄ (329.36)
Mass spectrum: (M - H) ^- = 328
(M + Na) ⁺ = 352

e. N- (4'-methylbiphenyl-4-yl) methyl-4- [2- (morpholin-4-yl) -phenyl-carbonylamino] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1e from 1-methyl-4- [2- (morpholin-4-yl) phenylcarbonylamino] pyrrole-2-carboxylic acid, 4'-methylbi-phenyl-4-methylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 94% of theory
R _f value: 0.55 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₃₂ N ₄ O ₃ (508.62)
Mass spectrum: (M - H) ^- = 507

Example 70

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1- (3-tert.butoxycarbonylaminopropyl) pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4'-trifluoromethylbiphenyl-2-carboxylic acid and N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1- (3-tert.butoxycarbonylaminopropyl) pyrrole-2-carboxamide, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₄₁ H ₄₁ F ₃ N ₄ O ₄ (710.80)
Mass spectrum: (M - H) ^- = 709
(M + Na) ⁺ = 733

Example 71

N- (4-benzyloxy-benzyl) -N-methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, N- (4-benzyloxy-benzyl) methylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 79% of theory
R _f value: 0.54 (silica gel; petroleum ether / ethyl acetate = 1: 2)
C ₃₅ H ₃₀ F ₃ N ₃ O ₃ (597.64
Mass spectrum: (M - H) ^- = 596
(M + H) ⁺ = 598

Example 72

N- [4- (2-methoxycarbonyl-ethyl) phenylmethyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (2-methoxycarbonyl-ethyl) benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 85% of theory
R _f value: 0.78 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₂₈ F ₃ N ₃ O ₄ (563.58)
Mass spectrum: (M - H) ^- = 562
(M + H) ⁺ = 564

Example 73

N-methyl-N-benzyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, N-methyl-benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 79% of theory
R _f value: 0.77 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₄ F ₃ N ₃ O ₂ (491.52)
Mass spectrum: (M - H) ^- = 490
(M + H) ⁺ = 492

Example 74

N- (2-difluoromethoxy-phenylmethyl) -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 2-difluoromethoxy-benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 69% of theory
R _f value: 0.75 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₂ F ₅ N ₃ O ₃ (543.49)
Mass spectrum: (M - H) ^- = 542
(M + H) ⁺ = 544
(M + Na) ⁺ = 566

Example 75

N- (2-methyl-phenylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 2-methyl-benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 66% of theory
R _f value: 0.76 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₄ F ₃ N ₃ O ₂ (491.52)
Mass spectrum: (M - H) ^- = 490
(M + H) ⁺ = 492

Example 76

N- [2- (biphenyl-4-yl) ethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 2- (biphenyl-4-yl) ethylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 88% of theory
R _f value: 0.76 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₈ F ₃ N ₃ O ₂ (567.61)
Mass spectrum: (M - H) ^- = 566
(M + H) ⁺ = 568
(M + Na) ⁺ = 590

Example 77

N- [4- (4-methylpiperidino) phenylmethyl) -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (4-methylpiperidino) benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 48% of theory
R _f value: 0.25 (silica gel; petroleum ether / ethyl acetate = 3: 2)
C ₃₃ H ₃₃ F ₃ N ₄ O ₂ (574.65)
Mass spectrum: (M - H) ^- = 573
(M + H) ⁺ = 575

Example 78

N- [4- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2 -carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (1,4-dioxa-8-aza-spiro [4.5] dec-8 -yl) -benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 90% of theory
R _f value: 0.65 (silica gel; petroleum ether / ethyl acetate = 3: 2)
C ₃₄ H ₃₃ F ₃ N ₄ O ₄ (618.66)
Mass spectrum: (M - H) ^- = 617
(M + H) ⁺ = 619

Example 79

N- [4- (3-Aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (3-aza-spiro [5.5] undec-3-yl) -benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 65% of theory
R _f value: 0.21 (silica gel; petroleum ether / ethyl acetate = 3: 2)
C ₃₇ H ₃₉ F ₃ N ₄ O ₂ (628.74)
Mass spectrum: (M + H) ⁺ = 629

Example 80

N- [1- (4-chlorophenyl) -ethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 1- (4-chlorophenyl) ethylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 100% of theory
R _f value: 0.82 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₃ CIF ₃ N ₃ O ₂ (525.96)
Mass spectrum: (M - H) ^- = 524/26 (chlorine isotopes)
(M + H) ⁺ = 526/28 (chlorine isotopes)

Example 81

N- [4- (3-methyl- [1,2,4] oxadiazol-5-yl) methyl-phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (3-methyl- [1,2,4] oxadiazol-5-yl) methyl-benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 84% of theory
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₂₆ F ₃ N ₅ O ₃ (573.58)
Mass spectrum: (M - H) ^- = 572
(M + H) ⁺ = 574
(M + Na) ⁺ = 596

Example 82

N- (4-methoxycarbonyl-cyclohexylmethyl) -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4-aminomethyl-cyclohexanecarboxylic acid methyl ester, TBTU and triethylamine in tetrahydrofuran.
Yield: 62% of theory
R _f value: 0.72 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₉ H ₃₀ F ₃ N ₃ O ₄ (541.57)
Mass spectrum: (M - H) ^- = 540
(M + H) ⁺ = 542

Example 83

N- (4-benzyloxy-benzyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4-benzyloxy-benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 83% of theory
R _f value: 0.73 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₂₈ F ₃ N ₃ O ₃ (583.61)
Mass spectrum: (M + H) ⁺ = 584
(M + Na) ⁺ = 606
(M-H) ^- = 582
(M + HCOO) ^- = 628

Example 84

N- [4- (3-methylpiperidino) phenylmethyl) -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (3-methylpiperidino) benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 16% of theory
R _f value: 0.81 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₃₃ F ₃ N ₄ O ₂ (574.65)
Mass spectrum: (M + H) ⁺ = 575
(M + HCOO) ^- = 619

Example 85

N- [cyclopropyl (4-methoxy-phenyl) methyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide and N- [1- (4-methoxyphenyl) butyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide in relation to 1: 1

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, a 1: 1 mixture of 1- (4-methoxyphenyl) butylamine and C- Cyclopropyl-C- (4-methoxyphenyl) methylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 100% of theory
R _f value: 0.74 (silica gel; dichloromethane / ethanol = 9: 1)
N- [cyclopropyl (4-methoxy-phenyl) methyl] -4- (4'-trifluoro-methylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide
C ₃₁ H ₂₈ F ₃ N ₃ O3 (547.58)
Mass spectrum: (M) ⁺ = 547
(M + H) ⁺ = 548
(M + Na) ⁺ = 570
(M-H) ^- = 546
N- [1- (4-methoxy-phenyl) -butyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide
C ₃₁ H ₃₀ F ₃ N ₃ O ₃ (549.59)
Mass spectrum: (M) ⁺ = 549
(M + H) ⁺ = 550
(M + Na) ⁺ = 572
(M-H) ^- = 548

Example 86

N- [5- (4-Cyano-4-phenyl-piperidino-carbonyl) -1-methyl-pyrrol-3-yl] -4'-trifluoro-methyl-biphenyl-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4-cyano-4-phenyl-piperidine, TBTU and triethylamine in tetrahydrofuran.
Yield: 67% of theory
R _f value: 0.83 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₇ F ₃ N ₄ O ₂ (556.59)
Mass spectrum: (M - H) ^- = 555
(M + H) ⁺ = 557

Example 87

N- [4- (9-ethylaminocarbonyl-fluoren-9-yl) butyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (9-ethylaminocarbonyl-fluoren-9-yl) butylamine, TBTU and N- Ethyldiisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₄₀ H ₃₇ F ₃ N ₄ O ₃ (678.76)
Mass spectrum: (M - H) ^- = 677
(M + Na) ⁺ = 701

Example 88

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1- (3-aminopropyl) -pyrrole-2-carboxamide

Prepared analogously to Example 19c from N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1- (3-tert.butoxycarbonylamino propyl) pyrrole-2-carboxamide and trifluoroacetic acid in dichloromethane.
Yield: quantitative
R _f value: 0.35 (silica gel; dichloromethane / ethanol / ammonia = 50: 45: 5)
C ₃₆ H ₃₃ F ₃ N ₄ O ₂ (610.68)
Mass spectrum: (M - H) ^- = 609
(M + H) ⁺ = 611

Example 89

N- [4- (5-dimethylaminopyridine-2-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (5-dimethylamino-pyridin-2-yl) benzylamine, TBT and N- Ethyl diisopropylamine in dimethylformamide.
Yield: 57% of theory
R _f value: 0.55 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₄ H ₃₀ F ₃ N ₅ O ₂ (597.64)
Mass spectrum: (M - H) ^- = 596
(M + H) ⁺ = 598
(M + Na) ⁺ = 620

Example 90

N- [3- (biphenyl-4-yl) -prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 3- (biphenyl-4-yl) prop-2-inylamine trifluoroacetate, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: 22% of theory
R _f value: 0.70 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₂₆ F ₃ N ₃ O ₂ (577.60)
Mass spectrum: (M - H) ^- = 576
(M + H) ⁺ = 578

Example 91

N- [3- (4-isopropylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 11 from 3- (4-isopropylphenyl) prop-2-ynylamine and 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methylimidazole-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
Yield: 24% of theory
R _f value: 0.49 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₂₇ F ₃ N ₄ O ₂ (544.58)
Mass spectrum: (M - H) ^- = 543
(M + Na) ⁺ = 567

Example 92

N- (4'-methylbiphenyl-4-yl) methyl-4- [2- (pyrrolidin-1-yl) phenyl-carbonylamino] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- [2- (pyrrolidin-1-yl) phenylcarbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4'-methyl-biphenyl-4-methylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 82% of theory
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₁ H ₃₂ N ₄ O ₂ (492.62)
Mass spectrum: (M - H) ^- = 491
(M + Na) ⁺ = 515

Example 93

N- [5- (1,2,3,4-tetrahydroisoquinoline-2-yl-carbonyl) -1-methyl-pyrrol-3-yl) -4'-trifluoromethylbiphenyl-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 70% of theory
R _f value: 0.72 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₉ H ₂₄ F ₃ N ₃ O ₂ (503.52)
Mass spectrum: (M - H) ^- = 502
(M + H) ⁺ = 504

Example 94

N- [5- (1,3-dihydro-isoindol-2-yl-carbonyl) -1-methyl-pyrrol-3-yl) -4'-trifluoromethylbiphenyl-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 2,3-dihydro-1H-isoindole, TBTU and N-ethyldiisopropylamine in dimethylformamide.
Yield: 79% of theory
R _f value: 0.64 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₂ F ₃ N ₃ O ₂ (489.50)
Mass spectrum: (M - H) ^- = 488
(M + H) ⁺ = 490
(M + Na) ⁺ = 512

Example 95

N- (4'-methylbiphenyl-4-yl) methyl-4- [1-oxo-7- (4-trifluoromethylphenyl) -1,3-dihydro-isoindol-2-yl] -1-methyl-pyrrole-2-carboxamide

a. 3-methyl-4'-trifluoromethylbiphenyl-2-carbonsäuremethylester

A mixture of 1.1 g (4.58 mmol) of 2-bromo-6-methyl-benzoic acid methyl ester, 0.9 g (4.7 mmol) of 4- (trifluoromethyl) benzene boronic acid, 0.3 g (0.26 mmol) of tetrakistriphenylphosphine-palladium (O) and 0.2 g (0.24 mmol) 2,2'-bis- (diphenylphosphino) -1,1'-binaphthyl are placed in 150 ml dimethoxyethane, mixed with 7 ml (7 mmol) 1 molar sodium carbonate solution after 10 minutes and then heated under reflux for 5 hours. The solvent is distilled off, the residue is distributed in water / dichloromethane, the combined organic extracts are dried and chromatographed on silica gel, eluting with ethyl acetate / petroleum ether 95: 5.
Yield: 1.1 g (83% of theory),
R _f value: 0.8 (silica gel; dichloromethane / ethanol = 99: 1)
C ₁₆ H ₁₃ F ₃ O ₂ (294.28)
Mass spectrum: (M + Na) ⁺ = 317

b. 3-bromomethyl-4'-trifluoromethylbiphenyl-2-carboxylic acid methyl ester

0.5 g (1.7 mmol) of 3-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid methyl ester are dissolved in 10 ml of carbon tetrachloride and, after adding 0.45 g (2.57 mmol) of N-bromosuccinimide and 10 mg (0.06 mmol of 2,2-azoisobutyronitrile) The precipitated succinimide is filtered off with suction and the filtrate evaporated, and the residue is chromatographed on silica gel, eluting with petroleum ether / dichloromethane 8: 2.
Yield: 0.4 g (62% of theory),
R _f value: 0.45 (silica gel; petroleum ether / ethyl acetate = 9: 1)
C ₁₆ H ₁₂ BrF ₃ O ₂ (373.17)
Mass spectrum: M ⁺ = 372/74 (bromine isotopes)

c. 4- [1-oxo-7- (4-trifluoromethylphenyl) -1,3-dihydro-isoindol-2-yl] -1-methyl-pyrrole-2-carbonsäuremethylester

0.4 g (1.0 mmol) of 3-bromomethyl-4'-trifluoromethylbiphenyl-2-carboxylic acid methyl ester are dissolved in 15 ml of acetonitrile and after the addition of 0.2 g (1.0 mmol) of 4-amino-1-methyl-pyrrole-2-carboxylic acid methyl ester 3.5 Stirred at 80 ° C for hours. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate 85:15 and 75:25.
Yield: 0.2 g (43% of theory),
R _f value: 0.25 (silica gel; dichloromethane / ethanol = 99: 1)
C ₂₂ H ₁₇ F ₃ N ₂ O ₃ (414.39)
Mass spectrum: (M - H) ^- = 413
(M + H) ⁺ = 415
(M + Na) ⁺ = 437

d. 4- [1-oxo-7- (4-trifluoromethylphenyl) -1,3-dihydro-isoindol-2-yl] -1-methyl-pyrrole-2-carboxylic acid

Prepared analogously to Example 1e from 4- [1-oxo-7- (4-trifluoromethylphenyl) -1,3-dihydroisoindol-2-yl] -1-methyl-pyrrole-2-carboxylic acid methyl ester and sodium hydroxide solution in methanol.
Yield: 85% of theory
R _f value: 0.35 (silica gel; dichloromethane / ethanol = 19: 1)
C ₂₁ H ₁₅ F ₃ N ₂ O ₃ (400.36)
Mass spectrum: (M - H) ^- = 399
(M + H) ⁺ = 401
(M + Na) ⁺ = 423

e. N- (4'-methylbiphenyl-4-yl) methyl-4- [1-oxo-7- (4-trifluoromethylphenyl) -1,3-dihydro-isoindol-2-yl] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- [1-oxo-7- (4-trifluoromethylphenyl) -1,3-dihydroisoindol-2-yl] -1-methyl-pyrrole-2-carboxylic acid, C- (4'-methyl-biphenyl -4-yl) methylamine, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: 96% of theory
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₂₈ F ₃ N ₃ O ₂ (579.62)
Mass spectrum: (M + H) ⁺ = 580
(M + Na) ⁺ = 602

Example 96

N- (4-dimethylaminobutyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 1-amino-4- (dimethylamino) butane, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and triethylamine in dimethylformamide.
Yield: 99% of theory
R _f value: 0.17 (silica gel; ethyl acetate / ethanol / ammonia = 50: 45: 5)
C ₂₆ H ₂₉ F ₃ N ₄ O ₂ (486.54)
Mass spectrum: (M - H) ^- = 485
(M + H) ⁺ = 487

Example 97

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1- (2-methoxycarbonyl-ethyl) -pyrrole-2-carboxamide

Prepared analogously to Example 4a from 4'-trifluoromethylbiphenyl-2-carboxylic acid chloride, N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1- (2-methoxycarbonyl-ethyl) -pyrrole-2-carboxylic acid and triethylamine in tetrahydrofuran.
Yield: 80% of theory
R _f value: 0.60 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₇ H ₃₂ F ₃ N ₃ O ₄ (639.68)
Mass spectrum: (M + H) ⁺ = 640

Example 98

N- (4-Hydroxycarbonylcyclohexylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1a from N- (4-methoxycarbonylcyclohexylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide and sodium hydroxide solution in methanol.
Yield: 88% of theory
R _f value: 0.91 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₈ F ₃ N ₃ O ₄ (527.54)
Mass spectrum: (M - H) - = 526
(M + H) ⁺ = 528

Example 99

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1- (2-hydroxycarbonylethyl) pyrrole-2-carboxamide

Prepared analogously to Example 1e from N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1- (2-methoxycarbonylethyl) pyrrole-2-carboxamide and sodium hydroxide solution in methanol.
Yield: 62% of theory
R _f value: 0.30 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₆ H ₃₀ F ₃ N ₃ O ₄ (625.65)
Mass spectrum: (M - H) - = 624
(M + H) ⁺ = 626
(M + Na) ⁺ = 648

Example 100

1-methyl-2- [4- (piperidin-1-yl) methyl-piperidinocarbonyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) pyrrole

Prepared analogously to Example 1d from 4- (piperidin-1-yl) methyl-piperidine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and triethylamine in dimethylformamide.
Yield: 96% of theory
R _f value: 0.29 (silica gel; dichloromethane / ethanol = 4: 1)
C ₃₁ H ₃₅ F ₃ N ₄ O ₂ (552.64)
Mass spectrum: (M - H) ^- = 551
(M + H) ⁺ = 553

Example 101

2- [4- (N-acetyl-N-methyl-aminomethyl) piperidinocarbonyl] -1-methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) pyrrole

Prepared analogously to Example 1d from N-methyl-N- (piperidin-4-yl) methyl acetamide, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and triethylamine in dimethylformamide ,
Yield: quantitative
C ₂₉ H ₃₁ F ₃ N ₄ O ₃ (540.59)
Mass spectrum: (M - H) ^- = 539
(M + H) ⁺ = 541

Example 102

2- [7- (4-Cyano-phenoxy) -1,2,3,4-tetrahydroisoquinoline-2-ylcarbonyl] -1-methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) pyrrole

Prepared analogously to Example 1d from 7- (4-cyanophenoxy) -1,2,3,4-tetrahydroisoquinoline, 4- (4'-trifluoro methylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and triethylamine in dimethylformamide.
Yield: 96% of theory
R _f value: 0.85 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₆ H ₂₇ F ₃ N ₄ O ₃ (620.63)
Mass spectrum: (M - H) ^- = 619
(M + H) ⁺ = 621

Example 103

N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-isopropyl-pyrrol-2-carboxamide

a. 1-isopropyl-4-nitro-pyrrole-2-carboxylate

0.5 g (2.7 mmol) of 4-nitropyrrole-2-carboxylic acid ethyl ester are dissolved in 8 ml of dimethylformamide and, after addition of 73 mg (3 mmol) of sodium hydride in portions, the mixture is stirred for 45 minutes. Then 0.29 ml (2.9 mmol) of isopropyl iodide are added and the mixture is stirred for 12 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane.
Yield: 0.32 g (49% of theory)
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 99: 1)

b. 4-amino-1-isopropyl-pyrrol-2-carboxylic acid ethyl ester

0.32 g (1.4 mmol) of 1-isopropyl-4-nitro-pyrrole-2-carboxylic acid ethyl ester are dissolved in 30 ml of ethanol and, after addition of 0.15 g of palladium on activated carbon, 10% hydrogenated at room temperature with hydrogen. The catalyst is filtered off and the solution is evaporated.
Yield: 0.26 g (94% of theory)
R _f value: 0.15 (silica gel; dichloromethane / ethanol = 99: 1)

c. 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-isopropyl-pyrrol-2-carboxylic acid ethyl ester

Prepared analogously to Example 4a from 4'-trifluoromethylbiphenyl-2-carboxylic acid chloride, 4-amino-1-isopropyl-pyrrole-2-carboxylic acid ethyl ester and triethylamine in tetrahydrofuran.
Yield: 65% of theory
R _f value: 0.75 (silica gel; dichloromethane / ethanol = 19: 1)

d. 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-isopropyl-pyrrol-2-carboxylic acid

Prepared analogously to Example 1e from 4- (4'-trifluoromethylbiphenyl-2-carbonylarnino) -1-isopropyl-pyrrole-2-carboxylic acid ethyl ester and sodium hydroxide solution in methanol.
Yield: 80% of theory
R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1)

e. N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-isopropyl-pyrrol-2-carboxamide

Prepared analogously to Example 1d from (4'-methylbiphenyl-4-yl) methylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-isopropyl-pyrrole-2-carboxylic acid, TBTU and N-ethyl-diisopropylamine in dimethylformamide ,
Yield: 94% of theory
R _f value: 0.75 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₆ H ₃₂ F ₃ N ₃ O ₂ (595.67)
Mass spectrum: (M - H) ^- = 594
(M + H) ⁺ = 596

Example 104

N- [3- (biphenyl-4-yl) propyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide

Prepared analogously to Example 103b from N- [3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide and palladium on activated carbon 10 % in ethanol.
Yield: 99% of theory
R _f value: 0.5 (silica gel; petroleum ether / ethyl acetate = 1: 1)
C ₃₄ H ₂₉ F ₃ N ₄ O ₂ (582.63)
Mass spectrum: (M - H) ^- = 581
(M + H) ⁺ = 583

Example 105

N- (cyclohexylmethyl) -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from (aminomethyl) cyclohexane, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and triethylamine in dimethylformamide.
Yield: 99% of theory
R _f value: 0.7 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₇ H ₂₈ F ₃ N ₃ O ₂ (483.53)
Mass spectrum: (M - H) ^- = 482
(M + H) + = 484

Example 106

N- (4'-methylbiphenyl-4-yl) methyl-4- (2-phenoxyphenyl-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 2-phenoxybenzoic acid, N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1-methyl-pyrrole-2-carboxamide, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.4 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₃ H ₂₉ N ₃ O ₃ (515.61)
Mass spectrum: (M + H) ⁺ = 516
(M + HCOO) - = 560

Example 107

N- (4'-methylbiphenyl-4-yl) methyl-4- [2- (2-phenylethyl) phenyl-carbonylamino] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 2- (2-phenylethyl) benzoic acid, N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1-methyl-pyrrole-2-carboxamide, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
Yield: quantitative
R _f value: 0.5 (silica gel; dichloromethane / ethanol = 19: 1)
C ₃₅ H ₃₃ N ₃ O ₂ (527.67)
Mass spectrum: (M - H) - = 526
(M + H) + = 528

Example 108

N- [4- (tert.Butoxycarbonylaminomethyl) phenylmethyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4-tert-butoxycarbonylaminomethyl-benzylamine, 4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, TBTU and triethylamine in dimethylformamide.
Yield: 96% of theory
R _f value: 0.67 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₃ H ₃₃ F ₃ N ₄ O ₄ (606.65)
Mass spectrum: (M - H) - = 605
(M + Na) + = 629

Example 109

N- (4-aminomethyl) phenylmethyl-4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 19c from N- [4- (tert-butoxycarbonylaminomethyl) phenylmethyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide and trifluoroacetic acid in dichloromethane.
Yield: quantitative
R _f value: 0. 7 (silica gel; dichloromethane / ethanol = 4: 1)
C ₂₈ H ₂₅ F ₃ N ₄ O ₂ (506.53)
Mass spectrum: (M - H) - = 505
(M + H) + = 507

Example 110

N- (4'-methylbiphenyl-4-yl) methyl-4- [3-methyl-2- (piperidin-1-yl) -phenyl-carbonylamino] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 3-methyl-2- (piperidin-1-yl) benzoic acid, N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1-methyl-pyrrole-2-carboxamide, TBTU and triethylamine in dimethylformamide.
Yield: 66% of theory
R _f value: 0.4 (silica gel; dichloromethane / ethanol = 4: 1)
C ₃₃ H ₃₆ N ₄ O ₂ (520.68)
Mass spectrum: (M + H) + = 521

Example 111

N- (4'-methylbiphenyl-4-yl) methyl-4- [2- (benzylamino) phenyl-carbonylamino] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from N-benzylanthranilic acid, N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1-methyl-pyrrole-2-carboxamide, TBTU and triethylamine in dimethylformamide.
Yield: 74% of theory
R _f value: 0.44 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₃₂ N ₄ O ₂ (528.65)
Mass spectrum: (M - H) - = 527
(M + H) + = 529

Example 112

N- (4'-methylbiphenyl-4-yl) methyl-4- [2- (4-methyl-phenylsulfonylamino) -phenylcarbonylamino] -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 2- (4-methyl-phenylsulfonylamino) benzoic acid, N- (4'-methylbiphenyl-4-yl) methyl-4-amino-1-methyl-pyrrole-2-carboxamide, TBTU and triethylamine in dimethylformamide ,
Yield: 5% of theory
R _f value: 0.65 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₄ H ₃₂ N ₄ O ₄ S (592.72)
Mass spectrum: (M - H) ^- = 591

Example 113

N- [4- (4-propylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyr rol-2-carboxylic acid, 4- (4-propylpiperidino) benzylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 100% of theory
R _f value: 0.80 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₅ H ₃₇ F ₃ N ₄ O ₂ (602.71)
Mass spectrum: (M + H) ⁺ = 603

N-{4-[4-(Pyrrolidin-1-yl)-piperidino]-phenylmethyl}-4-(4'-trifluormethylbiphenyl-2-carbonyl-amino)-1-methyl-pyrrol-2-carbonsäure-amid Example 114

N- {4- [4- (pyrrolidin-1-yl) piperidino] -phenyl-methyl} -4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxylic acid amide

Can be produced from Example 1d 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- [4- (pyrrolidin-1-yl) piperidino] benzylamine, TBTU and triethylamine in tetrahydrofuran.

Example 115

N- [4- (4-phenylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Can be produced from Example 1d 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (4-phenylpiperidino) benzylamine, TBTU and triethylamine in tetrahydrofuran.

N-{4-[4-(4-Methyl-4-H-[1,2,4]triazol-3-yl)-piperidino]-phenylmethyl}-4-(4'-trifluormethylbiphenyl-2-carbonyl-amino)-1-methyl-pyrrol-2-carbonsäure-amid Example 116

N- {4- [4- (4-methyl-4-H- [1,2,4] triazol-3-yl) piperidino] -phenyl-methyl} -4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino ) -1-methyl-pyrrole-2-carboxylic acid amide

Can be produced from Example 1d 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- [4- (4-methyl-4-H- [1,2,4] triazole-3- yl) piperidino] benzylamine, TBTU and triethylamine in tetrahydrofuran.

Example 117

N- [4- (4,4-dimethylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide

Can be produced from Example 1d 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- (4,4-dimethylpiperidino) benzylamine, TBTU and triethylamine in tetrahydrofuran.

Example 118

N- {4- [4- (4-methylphenyl) piperidino] -phenyl-methyl} -4- (4'-trifluoromethylbiphenyl-2-carbonyl-amino) -1-methyl-pyrrole-2-carboxylic acid amide

Can be produced from Example 1d 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, 4- [4- (4-methylphenyl) piperidino] benzylamine, TBTU and triethylamine in tetrahydrofuran.

Example 119

(S) -N- [1- (naphth-2-yl) ethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Can be produced from Example 1d 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, (S) -1- (naphth-2-yl) ethylamine, TBTU and triethylamine in tetrahydrofuran.

Example 120

(R) -N- [1- (naphth-2-yl) ethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, (R) -1- (naphth-2-yl) ethylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 98% of theory
R _f value: 0.79 (silica gel; dichloromethane / ethanol = 9: 1)
C ₃₂ H ₂₆ CIF ₃ N ₃ O ₂ (541.58)
Mass spectrum: (M - H) ^- = 540
(M + H) ⁺ = 542
(M + HCOO) - = 586

Example 121 enantiomerically pure Example 80)

(S) -N- [1- (4-chlorophenyl) -ethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, (R) -1- (4-chlorophenyl) ethylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 77% of theory
R _f value: 0.83 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₃ CIF ₃ N ₃ O ₂ (525.96)
Mass spectrum: (M - H) ^- = 524/26 (chlorine isotopes)
(M + H) ⁺ = 526/28 (chlorine isotopes)

Example 122 enantiomerically pure Example 80)

(R) -N- [1- (4-chlorophenyl) -ethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide

Prepared analogously to Example 1d from 4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid, (S) -1- (4-chlorophenyl) ethylamine, TBTU and triethylamine in tetrahydrofuran.
Yield: 56% of theory
R _f value: 0.82 (silica gel; dichloromethane / ethanol = 9: 1)
C ₂₈ H ₂₃ CIF ₃ N ₃ O ₂ (525.96)
Mass spectrum: (M - H) ^- = 524/26 (chlorine isotopes)
(M + H) ⁺ = 526/28 (chlorine isotopes) Example 123 tablets with 5 mg of active ingredient per tablet Composition: active substance 5.0 mg Lactose monohydrate 70.8 mg Microcrystalline cellulose 40.0 mg Carboxymethyl cellulose sodium, insoluble cross-linked 3.0 mg magnesium stearate 1.2 mg

production:

The active ingredient is for 15 minutes together with lactose monohydrate, microcrystalline cellulose and carboxymethyl cellulose sodium mixed in a suitable diffusion mixer. magnesium stearate is added and for another 3 minutes with the rest Mixed fabrics.

The finished mixture is compressed on a tablet press into round, flat tablets with a facet.
Tablet diameter: 7 mm
Weight of a tablet: 120 mg Example 124 capsules with 50 mg of active ingredient per capsule Composition: active substance 50.0 mg Lactose monohydrate 130.0 mg corn starch 65.0 mg Highly disperse silicon dioxide 2.5 mg magnesium stearate 2.5 mg

production:

A starch paste is made by part of the cornstarch with an appropriate amount of hot water is swollen. The paste is then left cool to room temperature.

The active ingredient is in a suitable Mixer with lactose monohydrate and corn starch premixed for 15 minutes. The starch paste is added and enough water is added to the mixture to make it homogeneous to get moist mass. The moist mass is passed through a sieve given with a mesh size of 1.6 mm. The sieved granulate becomes on hordes at around 55 ° C for 12 Hours dried.

The dried granules are then given by sieves with mesh sizes 1.2 and 0.8 mm. colloidal anhydrous Silicon is mixed with the granulate in a suitable mixer in 3 minutes mixed. Then magnesium stearate is added and for more Mixed for 3 minutes.

The finished mixture is filled into empty capsule shells made of size 1 hard gelatin using a capsule filling machine. Example 125 tablets with 200 mg of active ingredient per tablet Composition: active substance 200.0 mg Lactose mMonohydrat 167.0 mg Microcrystalline cellulose 80.0 mg Hydroxypropyl methyl cellulose, type 2910 10.0 mg Poly-1-vinyl-2-pyrrolidone, insoluble cross-linked 20.0 mg magnesium stearate 3.0 mg

production:

HPMC is dispersed in hot water. The Mixture gives after cooling a clear solution.

The active ingredient is in a suitable Mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose premixed. The HPMC solution will be added and mixing continued until a homogeneous moist mass was obtained becomes. The wet mass is passed through a sieve with a mesh size 1.6 mm given. The sieved granules are placed on trays at about 55 ° C for 12 hours dried.

The dried granules are then given by sieves with mesh sizes 1.2 and 0.8 mm. Poly-1-vinyl-2-pyrrolidone in a suitable mixer for 3 minutes with the granules mixed. Then magnesium stearate is added and for more Mixed for 3 minutes.

The finished mixture is compressed on a tablet press to oblong tablets (16.2 × 7.9 mm).
Weight of one tablet: 480 mg

Claims (38)

Use of a fibrate to lower the liver toxicity of MTP inhibitors. Use according to claim 1, the fibrate from the group consisting of bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil selected is. Use according to claim 1 or 2, wherein the MTP inhibitor is a compound of general formula I.

in X ₁ the group CR ¹ , X ₂ the group CR ² , X ₃ the group CR ³ and X ₄ the group CR ⁴ or one or two of the groups X ₁ to X ₄ each have a nitrogen atom and the rest of the groups X ₁ to X ₄ three or two of the groups CR ¹ to CR ⁴ , where 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 are each fluorine, chlorine or Bromine, a C _1-3 alkyl group, a trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino or Represent di- (C _1-3 -alkyl) -amino group and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom, where R ⁴ together with R ^{5 can} additionally 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, a -NH, -N (C _1-3 alkyl) -, sulfinyl, sulfonyl or carbonyl group, one the groups -CH ₂ -, - (CH ₂ ) ₂ -, -CH = CH-, -C≡C-, -OCH ₂ -, -CH ₂ O-, -NH-CH ₂ -, -CH ₂ -NH -, -NH-CO-, -CO-NH-, -NH-SO ₂ - or -SO ₂ -NH-, in which a hydrogen atom bonded to a carbon atom and / or a hydrogen atom bonded to a nitrogen atom are each represented by a C _{1 -3} alkyl group can be replaced and wherein a hetero atom of group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group of group R ^a , R ^{a is} a phenyl, 1-naphthyl or 2-naphthyl group, one via a carbon or 5-membered heteroaryl group attached to nitrogen atom, the an imino group optionally substituted by a C _1-4 alkyl or C _1-4 alkylcarbonyl group, an oxygen or sulfur atom, an imino group optionally substituted by a C _1-4 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or contains an imino group optionally substituted by a C _1-4 alkyl group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, a 6-membered heteroaryl group containing one or two nitrogen atoms, the 5 or 6-membered groups mentioned above Heteroaryl groups can be fused to two phenyl rings via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bound via the heteroaromatic or carbocyclic part, and the abovementioned phenyl and naphthyl groups and the mono- and bicyclic heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or or broma tom, through a C _1-4 alkyl group, through a C _3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino -, Di- (C _1-3 alkyl) amino, acetylamino, N- (C _1-3 alkyl) acetylamino, propionylamino, N- (C _1-3 alkyl) propionylamino, acetyl -, Propionyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) amino carbonyl or cyano group monosubstituted or, with the exception of 5-membered heteroaryl radicals containing more than two heteroatoms, through which the above-mentioned substituents can also be disubstituted, where the substituents can be the same or different, a C _3-7 cycloalkyl group, the methylene group in the 4-position of a 6- or 7 -linked cycloalkyl radicals through an oxygen or sulfur atom, through a sulfinyl or sulfonyl group or through one optionally through a C _1-5 alkyl, phenyl, C _1-4 alkyl carbonyl, C _1-4 alkoxy carbonyl, C _1-3 -Alkylaminocarbonyl- or di- (C _1-3 alkyl) aminocarbonyl group substituted imino group can be replaced, a 4- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be fused with a phenyl ring or one or two hydrogen atoms each by a C _1-3 alkyl group can be replaced or / and in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group can be replaced by a hydroxycarbonyl, C _1-3 alkoxycarbonyl, amino, C _1-3 alkylamino , Di- (C _1-3 alkyl) amino, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl or phenylC _1-3 alkylamino group substituted or by an oxygen or sulfur atom, by a sulfinyl or sulfonyl group or by an optionally by a C _1-5 alkyl, phenyl, C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, C Imino group substituted by _1-3- alkyl-aminocarbonyl or di- (C _1-3 -alkyl) -aminocarbonyl group can be replaced or in a 5-, 6- ode r 7-membered cycloalkyleneimino group, a -CH ₂ group linked to the imino nitrogen atom can be replaced by a carbonyl group or a - (CH ₂ ) ₂ group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ group or one with - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO- group, where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group, R ^{5 represents} a hydrogen atom or a C _{1- 5} -alkyl group, Het has a 5-membered heteroarylene group which is bonded via two carbon atoms or, if Het denotes a 2-bonded pyrrole group, also via a carbon and the imino nitrogen atom, the latter being linked to the adjacent carbonyl group in formula (I) , an imino group substituted by the group R ⁹ , an oxygen or sulfur atom or an imino group substituted by the group R ⁹ or an oxygen or sulfur atom and additionally a nitrogen atom ; where R ^{9 is} a hydrogen atom, a C _1-5 alkyl group, a terminal through an amino, C _1-3 alkylamino, Di- (C _1-3 alkyl) amino or C _1-5 alkoxy-carbonyl-amino group, substituted C _2-3 alkyl group, a carboxy-C _{1- 3} alkyl, C _1-3 alkoxy -carbonyl-C _1-3 -alkyl-, phenyl-, phenyl-C _1-3 -alkyl-, C _1-5 -alkylcarbonyl or phenylcarbonyl group or R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p - bridge represents in which p represents the number 2 or 3, or contains an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, or a 6-membered heteroarylene group which contains one or two nitrogen atoms contains, the above-mentioned heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-5 alkyl group, by a C _3-7 cycloalkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy -, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, N- ( _1-3 alkyl) acetylamino, propionylamino, N- ( C _1-3 alkyl) propionylamino, Acetyl, propionyl, benzoyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl di (C _1-3 alkyl) amino carbonyl or cyano group monosubstituted or, with the exception of more than one heteroatom-containing 5-membered monocyclic heteroaryl radicals, through which the above-mentioned substituents can also be disubstituted, where the substituents can be the same or different, R ^{6 is} a hydrogen atom or a C _1-6 alkyl group, R ^{7 is} a C _1-9 alkyl group, a linear or branched, mono-, di- or tri-unsaturated C _3- C ₉ alkenyl or alkynyl _{3- 9,} wherein the multiple bonds from the nitrogen-carbon bond are insulated, a straight-chain C _{2- 6} alkyl group which is terminally substituted by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group, a C _1-6 alkyl group substituted by a C _3-7 cycloalkyl radical , wherein a hydrogen atom in the 3-position of the cyclopentyl radical and in the 4-position a 6- or 7-membered cycloalkyl radical in each case by a hydroxy-, hydroxy-C _1-3 -alkyl, C _1-5 -alkoxy-, C _1-5 -alkoxy-C _1-3 -alkyl, phenyl-C _{1- 3} -alkoxy-C _1-3 -alkyl, amino-, C _1-5 -alkylamino-, di- (C _1-5 -alkyl) amino-, phenyl-C _1-3 -alkylamino-, C _1-5 - Alkyl-carbonylamino-, benzoylamino-, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, di- (C _1-3 -alkylamino-C _1-3 -alkyl, phenyl- C _1-3 -alkylamino-C _1-3 -alkyl-, C _1-3 -alkyl-carbonylamino-C _1-3 -alkyl-, benzoylamino-C _1-3 -alkyl-, phenylamino-carbonyl-, phenyl-C _{1- 3} -alkylamino-carbonyl, carboxy or C _1-3 -alkoxy-carbonyl group can be replaced or in each case the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical may be replaced by an oxygen or sulfur atom or by an optionally a C _1-6 alkyl, phenyl, C _1-4 alkyl carbonyl, benzoyl, phenyl (C _1-3 alkyl) carbonyl, C _1-6 alkyl aminocarbonyl, di - (C _1-5 alkyl) aminocarbonyl, phenylaminocarbonyl, N- (C _1-3 alkyl) phenylaminocarbon yl-, phenyl-C _1-3 -alkylaminocarbonyl- or N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino-carbonyl group substituted imino group can be replaced or in a 5- or 6-membered cycloalkyl radical or two single bonds separated from one another and from position 1 by at least one bond can each be fused with a phenyl radical, in which case in a bicyclic or tricyclic ring system thus formed the hydrogen atom bonded to the saturated carbon atom in position 1 by a C _1-5 alkylamino -carbonyl-, di- (C _1-5 -alkyl) amino-carbonyl-, phenyl-C _1-3 -alkylamino-carbonyl or C _1-5 -alkoxy-carbonyl group, in which terminal methyl groups are fluorinated in whole or in part may may be substituted, an optionally substituted C by a C _3-7 cycloalkyl _1-6 alkyl group, the _1-3 alkoxycarbonyl group by a carboxy or C, by a phenyl, 1-naphthyl or 2-naphthyl , through a carbon or nitrogenate om bonded 5-membered heteroaryl group, which is optionally substituted by a C _1-3 alkyl, trifluoromethyl, phenyl, phenyl C _1-3 alkyl, C _1-3 alkylcarbonyl, phenylcarbonyl or phenyl-C _1-3- alkylcarbonyl group substituted imino 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 an imino group optionally substituted by a C _1-3 alkyl group and contains two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, by a 6-membered heteroaryl group which contains one or two nitrogen atoms, it being possible for a phenyl ring to be fused to the above-mentioned 5- or 6-membered heteroaryl groups via two adjacent carbon atoms and that bicyclic heteroaryl groups thus formed can be bound via the heteroaromatic or carbocyclic part, the above phenyl and naphthyl groups mentioned and the mono- and bicyclic heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-5 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy , Difluoromethoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl, C _1-3 alkylamino C _{1 -3-} alkyl-, di- (C _1-3 -alkyl) amino-C _1-3 -alkyl-, C _1-5 -alkoxy-carbonylamino-C _1-3 -alkyl-, acetylamino-, propionylamino-, N - (C _1-3 alkyl) benzoylamino, acetyl, propionyl, carboxy, C _1-3 alkoxy carbonyl, C _1-3 alkoxy carbonyl C _1-3 alkyl, aminocarbonyl , C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) aminocarbonyl, or cyano group monosubstituted or, with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, which may also be disubstituted by the abovementioned substituents, where the substituents may be the same or different, one is substituted by a phenyl radical and a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted C _1-6 alkyl group, a phenyl C _{2- 5} alkenylene CH ₂ -, phenyl C _{2- 5} -alkynylene-CH ₂ -, heteroaryl-C _{2- 5} -alkenylene-CH ₂ - or heteroaryl-C _{2- 5} -alkinylene-CH ₂ group in which a hydrogen atom of the methylene group in position 1 is replaced by a C _1-3 - Alkyl group can be replaced and independently of the phenyl part and the heteroaryl part by fluorine, chlorine or bromine atoms, by C _1-6 alkyl, C _3-7 cycloalkyl, trifluoromethyl, C _1-3 alkoxy, phenyl -, Heteroaryl- or cyano groups can be mono- or disubstituted, where the substituents can be the same or different and the disubstitution dur ch two aromatic groups are excluded, heteroaryl being a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, which has an imino group which is optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom, and which is optionally a C _1-3 -Alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or an oxygen or sulfur atom and two nitrogen atoms, or egg ne 6-membered heteroaryl group, which a or contains two nitrogen atoms, it being possible for a phenyl ring to be fused to the 5- or 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed to be bonded via the heteroaromatic or carbocyclic part which may be bonded in the C _1-3 alkyl part gegebenenf alls by a C _1-4 alkyl or C _{3- 5} cycloalkyl substituted group R ^b -A ^b -E ^b -C _1-3 alkyl, ^b in which R a is optionally substituted by fluorine, chlorine, bromine - or iodine atoms, by C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 cycloalkyl, trifluoromethyl, hydroxy; C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl , C _1-3 -Alkiamino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) amino-C _1-3 -alkyl-, acetylamino-, propionylamino-, acetyl-, propionyl-, carboxy- , C _1-3 -alkoxy-carbonyl-, C _1-3 -alkoxy-carbonyl-C _1-3 -alkyl, aminocarbonyl-, C _1-3 -alkylamino-carbonyl-, di- (C _1-3 -alkyl) amino-carbonyl or cyano groups mono- or disubstituted phenyl group, where the substituents may be the same or different, a 5-membered heteroaryl group which has a carbon atom or, if A ^{b is} a bond, a -CH ₂ -, - (CH ₂ ) ₂ -, sulfonyl or carbonyl group, can also be bonded via a nitrogen atom and which has an 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 e in nitrogen atom or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, a 6-membered heteroaryl group containing one or two nitrogen atoms, the abovementioned 5- or 6-membered heteroaryl groups can be fused to two phenyl rings via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bound via the heteroaromatic or carbocyclic part, the abovementioned mono- and bicyclic heteroaryl radicals in the carbon skeleton being represented by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, C ₂ _ ₄ alkenyl, C _2-4 alkynyl, C _3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _1-3 alkoxy , Trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, propionylamino, acetyl, propionyl, C _1-3 alkoxycarbonyl , Aminocarbonyl-, C _1-3 -A lkylamino-carbonyl, di- (C _1-3 alkyl) amino-carbonyl or cyano group monosubstituted or, with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, may also be disubstituted by the abovementioned substituents, where the substituents may be the same or different, a C _3-7 cycloalkyl group in which one or two hydrogen atoms can each be replaced by a C _1-3 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 by a C _1-3 alkyl, C _1-3 alkyl carbonyl, C _1-3 alkoxy carbonyl, C _{1 -3-} alkyl-aminocarbonyl or di- (C _1-3 -alkyl) -aminocarbonyl group substituted imino group can be replaced 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 can be replaced and one or two was in the rings thus formed can be replaced by C _1-3 alkyl groups, a 4- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be condensed with a phenyl ring or one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and in each case the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group by a hydroxy-C _1-3 -alkyl-, C _1-6 -alkoxy-C _1-3 -alkyl-, hydroxycarbonyl-, C _1-6 - Alkoxycarbonyl, aminocarbonyl, C _1-3 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, 4- to 7-membered cycloalkylenimino, phenyl, 4- (C _1-3 alkyl) -1,2,4-triazol-3-yl, phenyl-C _1-3 alkylamino or N- (C _1-3 alkyl) phenyl-C _1-3 alkylamino group or substituted by an oxygen or Sulfur atom, by a sulfinyl or sulfonyl group or by an optionally by a C _1-3 alkyl, phenyl, C _1-3 alkyl carbonyl, benzoyl, phenyl C _1-3 alkyl carbonyl, C _1-3 alkyl aminocarbonyl, di (C _1-3 al kyl) -aminocarbonyl-, phenylaminocarbonyl- or N- (C _1-3 -alkyl) -phenylaminocarbonyl group substituted imino group can be replaced or the two hydrogen atoms of the methylene group in position 3 a 5-membered or in position 3 or 4 a 6- or 7 -linked cycloalkyleneimino group can be replaced by an n-butylene, n-pentylene, n-hexylene, 1,2-ethylenedioxy or 1,3-propylenedioxy group and one or two hydrogen atoms in the rings thus formed by C _1-3 -Alkyl groups can be replaced or in a 5-, 6- or 7-membered cycloalkyleneimino group, a -CH ₂ group linked to the imino nitrogen atom can be replaced by a carbonyl group or a - (CH ₂ ) ₂ group linked to the imino nitrogen atom by -CO-NR ⁸ - group can be replaced or. a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ -CO group, where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group, A ^b a bond, an oxygen or sulfur atom, an -NH-, -N (C _1-3 -alkyl) -, sulfinyl, sulfonyl or a carbonyl group, one of the groups -CH ₂ -, - (CH ₂ ) ₂ -, -O-CH ₂ -, -CH ₂ -O-, NH-CH ₂ -, -CH ₂ -NH-, -NH-CO-, -CO-NH-, -NH-SO ₂ -, -SO ₂ -NH-, -CH = CH- or -C≡C-, in which a hydrogen atom bonded to a carbon atom and / or a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a C _1-3 alkyl group and wherein a heteroatom from group A ^b cannot be replaced by a Nitrogen atom of a 5-membered heteroaryl group of the group R ^{b is} linked, E ^b optionally through a fluorine, chlorine or bromine atom, through a C _1-4 alkyl group, through a trifluoromethyl, hydroxy, C _1-3 alkoxy -, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C _1-3 - Alkylamino, di (C _1-3 alkyl) amino, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, di (C _1-3 alkyl ) amino-C _1-3 -alkyl-, acetylamino-, propionylamino-, acetyl-, propionyl-, carboxy-, C _1-3 -alkoxy-carbonyl-, C _1-3 -alkoxy-carbonyl-C _1-3 - alkyl, aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) amino carbonyl or cyano group substituted phenylene group, which in the C _1-3 alkyl part is optionally substituted by a C _1-4 - alkyl or C _{3- 5} cycloalkyl substituted group R ^c -A -E ^{c c} -C _1-3 alkyl, where R ^c have the meanings mentioned for R ^b above assumes, wherein a reference to a ^b by a reference is to be replaced by A ^c , A ^c assumes the meanings mentioned above for A ^b , where reference to R ^{b is to be} replaced by reference to R ^c , E ^{c is} one bonded via two carbon atoms or via a carbon atom and an imino nitrogen atom 5-membered heteroarylene group, the imino nitrogen atom of the heteroarylene group nic ht is linked to a heteroatom of group A ^c and the heteroarylene group is an 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 Contains sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or an oxygen or sulfur atom and two nitrogen atoms, or a 6-membered heteroarylene group which contains one or two nitrogen atoms, the above mentioned 5-membered heteroarylene groups containing one or two heteroatoms and a phenyl ring may be fused to the above-mentioned 6-membered heteroarylene groups via two adjacent carbon atoms and the bicyclic heteroarylene groups thus formed are bonded via the heteroaromatic or / and the carbocyclic part n, and the abovementioned mono- and bicyclic heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 -alkyl group, by a C _3-7 -cycloalkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, propionylamino, acetyl, propi onyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl or cyano group, or R ⁶ and R ⁷ together represent an n-alkylene bridge having 3 to 6 carbon atoms , in which one or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and a -CH ₂ -CH ₂ group can be replaced by a 1,2-linked phenylene group which is replaced by fluorine, chlorine or or bromine atoms, by C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, propionylamino, acetyl, propionyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl, cyano, phenyloxy or phenyl C _1-3 alkyl groups can be mono- or disubstituted, disubstitution with the latter group being excluded, the phenyloxy and phenyl-C _1-3 -alkyl groups mentioned above in turn in the phenyl part being caused 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 _1-3 alkyl) amino, acetylamino , or cyano group, or in each case the carbon atom in position 3 of an n-pentylene or n-hexylene group by a terminal by a phenyl, cyano, hydroxy, C _1-3 alkoxy, amino, C _{1 -3-} alkylamino-, di- (C _1-3 -alkyl) -amino- or a 5- to 7-membered cycloalkyleneimino group substituted C _1-3 -alkyl group, by a carboxy, C _1-3 -alkoxycarbonyi, amino -C _1-3 -alkyl-, C _1-3 -alkylamino-C _1-3 -alkyl-, NC _1-3 -alkyl-N- (C _1-3 -alkyl-carbonyl) -amino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-, aminocarbonyl-, C _1-3 -alkylamino-carbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl group may be monosubstituted or disubstituted by a phenyl group and a cyano, hydroxy or C _1-3 alkoxy group or the methylene group in position 3 of an n-pentylene or n-hexylene group by an oxygen or Sulfur atom, by a sulfinyl or sulfonyl group or by an optionally by a C _1-3 alkyl, phenyl C _1-3 alkyl, C _1-3 alkyl carbonyl, benzoyl, C _1-3 - Alkyl-aminocarbonyl, di- (C _1-3 alkyl) amino carbonyl, phenylaminocarbonyl or N- (C _1-3 alkyl) phenylaminocarbonyl group substituted imino group or a methylene group in position 1 in a n -Butylene, n-pentylene or n-hexylene group can be replaced by a carbonyl group, the phenyl groups mentioned in the definition of the above radicals as unsubstituted or monosubstituted, and aromatic or heteroaromatic molecular parts, unless stated otherwise, in the carbon skeleton optionally additionally by fluorine, chlorine or bromine atoms, by C _1-3 alkyl groups, by trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino , Acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylla Minocarbonyl or cyano groups can be substituted, where the substituents can be the same or different and the resulting aromatic groups and molecular parts are maximally disubstituted, the hydrogen atoms in the C _1-3 alkyl and alkoxy groups mentioned in the definition of the above radicals can be partially or completely replaced by fluorine atoms, which may be straight-chain or branched in the definition of the abovementioned radicals alkyl and alkoxy groups or in the alkyl parts contained in the groups of formula I defined above with more than two carbon atoms, unless stated otherwise which may be replaced by a carboxy group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions when defining the above-mentioned radicals or / and which amino groups mentioned when defining the above-mentioned radicals and imino groups can in each case be substituted by a residue which can be split off in vivo, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. Use according to claim 3, wherein the MTP inhibitor is a compound of the general formula I in which X ₁ to X _{4 are defined} as mentioned in claim 3, A ^{a is} a bond, an oxygen atom, a -NH-, -N (C _1-3 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-, in which a hydrogen atom bonded to a carbon atom and / or a hydrogen atom bonded to a nitrogen atom can each be replaced by a C _1-3 alkyl group and where a heteroatom from group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group from group R ^a , R ^{a is} a phenyl group, a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, which is optionally substituted by a C _1-4 - Alkyl or C _1-4 alkylcarbonyl group substituted imino group, an oxygen or sulfur atom or an imino group optionally substituted by a C _1-4 alkyl group or an oxygen or sulfur atom and additionally contains a nitrogen atom, a 6-membered heteroaryl group which a or contains two nitrogen atoms, wherein the above-mentioned phenyl and heteroaryl groups in the carbon structure through a fluorine, chlorine or bromine atom, through a C _1-4 alkyl group, through a C _3-7 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _{1 -3-} alkoxy-, trifluoromethoxy-, amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino-, acetylamino-, N- (C _1-3 -alkyl) -acetylamino-, Acetyl or cyano group can be substituted, a C _3-7 cycloalkyl group, the methylene group in the 4-position of a 6-membered cycloalkyl radical being substituted by an oxygen or sulfur atom, by a sulfonyl group or by an optionally by a C _1-3 alkyl -, Phenyl-, C _1-4 -alkyl-carbonyl or C _1-4 -alkoxy-carbonyl-substituted imino group can be replaced, a 4- to 7-membered cycloalkyleneimino group in which one or two hydrogen atoms are each substituted by a C _{1- 3} -alkyl group can be replaced and / or in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group by a Oxygen or sulfur atom, through a sulfonyl group or through one optionally through a C _1-5 alkyl, phenyl, C _1-4 alkyl carbonyl, C _1-4 alkoxy carbonyl, C _1-3 - Alkyl-aminocarbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted imino group can be replaced or in a 5-, 6- or 7-membered cycloalkyleneimino group a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group can or a - (CH ₂ ) ₂ - group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ - group or a - (CH ₂ ) ₃ - group linked to the imino nitrogen atom by a -CO-NR ⁸ -CO - Group can be replaced, wherein R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group, R ^{5 represents} a hydrogen atom or a C _1-3 alkyl group, Het is a 5-membered heteroarylene group bonded via two carbon atoms, one of which is defined by the group R ⁹ substituted imino group, an oxygen or sulfur atom or a major ch the group R ⁹ substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom, where R ^{9 is} a hydrogen atom, a C _1-5 alkyl group, a terminally substituted by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or C _1-5 alkoxy carbonyl amino group substituted -C _2-3 alkyl group, a carboxy C _1-3 alkyl, C _1-3 alkoxy carbonyl C _{1-3 means} alkyl, phenyl, phenyl-C _1-3 alkyl, C ₁ _ ₅ alkylcarbonyl or phenylcarbonyl group or R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p - bridge in which p denotes the number 2 or 3, or contains an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, or a 6-membered heteroarylene group which contains one or two nitrogen atoms, where the above-mentioned heteroarylene radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl group, by a e Cyclopropyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, N- (C _1-3 - Alkyl) acetylamino, acetyl, C _1-3 alkylamino carbonyl or di (C _1-3 alkylamino carbonyl group) may be substituted, R ^{6 is} a hydrogen atom or a C _1-4 alkyl group, R ^{7 is} a C _1-6 alkyl group, a straight chain C _2-6 alkyl group which is terminally substituted by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group, one by a C _3-7 cycloalkyl radical substituted C _1-6 alkyl group, a hydrogen atom in the 3-position of the cyclopentyl radical and in the 4-position of a 6- or 7-membered cycloalkyl radical in each case by a C _1-5 alkoxy-, phenyl-C _{1 -3-} akoxy-C _1-3 alkyl, phenyl-Ci _1-3 alkylamino, C _{1- 5} alkylcarbonylamino, benzoylamino, phenyl-C _1-3 alkylamino-C _1-3 alkyl -, Benzoylamino-C _1-3 alkyl, phenylamino-carbonyl, phenyl-C _1-3 alkylamino-carbonyl, carboxy or C _1-3 alkoxy-carbonyl group or the methylene group in the 4-position of a 6- or 7-membered cycloalkyl radical may be replaced by a phenyl, C _1-6 alkylcarbonyl, benzoyl, phenyl (C _1-3 alkyl) -carbonyl-, phenylaminocarbonyl-, N- (C _1-3 -alkyl) -phenylaminocarbonyl-, phenyl-C _1-3 -alkylamino-carbonyl- or N- (C _1-3 -alkyl) -phenyl-C _1-3 alkylamino-carbonyl-substituted imino group can be replaced or in a 5- or 6-membered cycloalkyl radical one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bi- or tricyclic ring system the hydrogen atom bonded to the saturated carbon atom in position 1 through a C _1-3 -alkylamino-carbonyl, di- (C _1-3 -alkyl) amino-carbonyl or C _1-5 -alkoxy-carbonyl group, in which terminal methyl groups may each be wholly or partially fluorinated, may be replaced, a given if C _1-6 alkyl group substituted by a C _3-7 cycloalkyl group, by a carboxy or C _1-3 alkoxycarbonyl group, by a phenyl, 1-naphthyl or 2-naphthyl group, by a 5-membered heteroaryl group bonded via a carbon or nitrogen atom, the 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 contains an oxygen or sulfur atom and additionally a nitrogen atom, through a 6-membered heteroaryl group which contains one or two nitrogen atoms, the abovementioned phenyl groups and the heteroaryl radicals in the carbon structure being replaced by a fluorine, chlorine or bromine atom, by a C _{1- 3-} alkyl-, trifluoromethyl-, C _1-3 -alkoxy-, fluoromethoxy-, difluoromethoxy-, trifluoromethoxy-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino-, amino-C _{1 -3-} alkyl-, acetylamino-, acetyl-, C _1-3 -alkoxy-carbonyl-C _1-3 -alkyl-, C _1-5 -alkoxy-carbonylamino-C _1-3 -alkyl-, C _1-3 -Alkylamino-carbonyl- or di- (C _1-3 alkyl) amino-carbonyl group monosubstituted or by the vorst before mentioned substituents can also be disubstituted, where the substituents can be the same or different, one is substituted by a phenyl radical and a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkyl aminocarbonyl - or di- (C _1-3 -alkyl) -aminocarbonyl group substituted C _1-6 -alkyl group, a phenyl-C ₂ _ ₃ -alkenylene-CH ₂ - or phenyl-C ₂ _ ₃ -alkynylene-CH ₂ group, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and, independently thereof, the phenyl part by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, C _3-7 cycloalkyl, trifluoromethyl , C _1-3 alkoxy, phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl or thiazolyl group, which may be substituted in the C _1-3 alkyl part optionally by a methyl group R ^b -A ^b -E ^b -C _1-3 -alkyl-, in which R ^{b is} optionally by fluorine, chlorine or bromine atoms, by C _1-3 -alk yl, cyclopropyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, acetyl, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl, di (C _1-3 alkyl) amino carbonyl or Cyano groups mono- or disubstituted phenyl group, where the substituents may be the same or different, a 5-membered heteroaryl group which has a carbon atom or, if A ^{b is} a bond, a -CH ₂ -, - (CH ₂ ) ₂ -, sulfonyl or carbonyl group, may also be attached via a nitrogen atom and optionally substituted by a C ₁ _ ₃ alkyl imino group, an oxygen or sulfur atom, optionally substituted by a C _1-3 -alkyl substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C _1-3 alkyl group and two sti Contains nitrogen atoms or an oxygen or sulfur atom and two nitrogen atoms, a 6-membered heteroaryl group which contains one or two nitrogen atoms, the above-mentioned heteroaryl radicals in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl -, C _1-4 cycloalkyl, trifluoromethyl, phenyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl ) -amino, acetylamino, acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl or di (C _1-3 alkyl) amino carbonyl group monosubstituted or , with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, may also be disubstituted by the abovementioned substituents, where the substituents may be the same or different, a C _3-7 cycloalkyl group in which one or two hydrogen atoms are each represented by one C _1-3 alkyl group can be replaced or / and the methylene group in the 4-position a cyclohexyl radical through an oxygen atom, through a sulfonyl group or through one optionally through a C _1-3 alkyl, C _1-3 alkyl carbonyl, C _1-3 alkoxy carbonyl, C _1-3 alkyl -aminocarbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl group substituted imino group can be replaced 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 can be replaced, a 4- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be fused with a phenyl ring or a or two hydrogen atoms can each be replaced by a C _1-3 alkyl group or / and in each case the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group can be replaced by a 4- to 7-membered cycloalkyleneimino, phenyl or 4- (C _1-3 alkyl) -1,2,4-triazol-3-yl group substi tuiert or by an oxygen atom, by a sulfonyl group or by an optionally by a C _1-3 alkyl, C _1-3 alkyl carbonyl, C _1-3 alkyl aminocarbonyl or di (C _1-3 -alkyl) -aminocarbonyl group substituted imino group can be replaced 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 by an n-butylene, n-pentylene, n -Hexylene-, 1,2-ethylene dioxy or 1,3-propylenedioxy group can be replaced or in a 5-, 6- or 7-membered cycloalkyleneimino group a -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group A ^b a bond, an oxygen atom, a - NH-, -N (C _1-3 alkyl), sulfonyl or a carbonyl group, one of the groups -CH ₂ -, - (CH ₂ ) ₂ -, -C≡C-, -O-CH ₂ -, -CH ₂ -O-, NH-CH ₂ -, -CH ₂ -NH-, -NH-CO-, -CO-NH-, -NH-SO ₂ -, -SO ₂ -NH-, in which a a carbon atom-bonded hydrogen atom and / or a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a C _1-3 -alkyl group and wherein a hetero atom from group A ^{b is} not linked to a nitrogen atom of a 5-membered heteroaryl group from group R ^b , and E ^b a optionally by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl group, by a trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino , C _{1 -3-} alkylamino-, di- (C _1-3 -alkyl) amino-, acetylamino-, acetyl-, carboxy-, C _1-3 -alkoxy-carbonyl-, C _1-3 -alkoxy-carbonyl-C _{1- 3} -alkyl, aminocarbonyl, C _1-3 -alkylamino-carbonyl, di- (C1- ₃ -alkyl) amino-carbonyl or cyano group, substituted phenylene group, or the group R ^c -A ^c -E ^c -C _{1 -3} -alkyl-, in which R ^c assumes the meanings mentioned above for R ^b , a reference to A ^{b being} replaced by a reference to A ^c , A ^c a bond, an oxygen atom, a -CH ₂ -, - NH-, -N (C _1-3 alkyl) -, -NH-CO-, -CO-NH or carbonyl group, wherein a heteroatom of group A ^{c is} not linked to a nitrogen atom of a 5-membered heteroaryl group of group R ^c and E ^{c is} a 5-membered heteroarylene group which is bonded via two carbon atoms or via a carbon atom and an imino nitrogen atom, the imino nitrogen atom of the heteroarylene group not being linked to a hetero atom of the group A ^c and the heteroarylene group being one an 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 an optionally substituted by a C _1-3 Alkyl group substituted imino group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, or a 6-membered heteroarylene group containing one or two nitrogen atoms, the above-mentioned 5- and 6-membered heteroarylene radicals in the carbon skeleton by a fluorine, chlorine - or bromine atom, through a C _1-4 alkyl group, through a C ₃ _ ₇ cycloalkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino , Acetylamino, acetyl, C _1-3 alkoxy-carbonyl, aminocarbonyl, C _1-3 alkylamino-carbonyl or cyano group may be substituted, or R ⁶ and R ⁷ together form an n-alkylene bridge represent ke with 4 or 5 carbon atoms, in which a hydrogen atom can be replaced by a C _1-3 alkyl group or / and a -CH ₂ -CH ₂ group can be replaced by a 1,2-linked phenylene group which can be replaced by a Fluorine, chlorine or bromine atom, through a C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, acetyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl or cyano group or by one in the phenyl part, optionally by a fluorine, chlorine or bromine atom, through a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino , Acetylamino or cyano group substituted phenyloxy or phenyl-C _1-3 -alkyl group, or the carbon atom in position 3 of an n-pentylene group by a terminally substituted by an amino, C _1-3 -alkylamino, di- ( C _1-3 alkyl) amino or a 5- to 7-gli noble cycloalkyleneimino group substituted C _1-3 alkyl group, monosubstituted by a phenyl, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 alkylamino carbonyl or di (C _1-3 alkyl) aminocarbonyl group or may be disubstituted by a phenyl group and a cyano group or the methylene group in position 3 of an n-pentylene group by an oxygen atom, by a sulfonyl group or by an imino group which is optionally substituted by a C _1-3 -alkyl or C _1-3 -alkyl-carbonyl group may be replaced, mean, the phenyl groups mentioned in the definition of the abovementioned radicals as unsubstituted or monosubstituted as well as aromatic or heteroaromatic molecular parts, unless stated otherwise, in the carbon structure optionally additionally by a fluorine, chlorine or bromine atom, by a C. ₁ _ ₃ alkyl group, through a trifluoromethyl, hydroxy, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino -, Acetyl, C _1-3 -alkoxy-carbonyl, aminocarbonyl, C _1-3 -alkylamino-carbonyl or cyano group, which may be used in the definition of the abovementioned radicals and in the alkyl and alkoxy groups mentioned in groups of the formula I defined above and containing alkyl parts with more than two carbon atoms may be straight-chain or branched, unless stated otherwise, the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions or / and the amino and imino groups mentioned in the definition of the abovementioned radicals in each case by an in vivo removable residue may be substituted, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. Use according to claim 4, wherein the MTP inhibitor is a compound of the general formula I in which X _{1 is} the group CR ¹ , X _{2 is} the group CR ² , X _{3 is} the group CR ³ and X _{4 is} the group CR ⁴ or one of the Groups X ₁ to X _{4 represent} a nitrogen atom and the rest of the groups X ₁ to X ₄ three of the groups CR ¹ to CR ⁴ , where R ¹ , R ² , R ³ and R ⁴ each have a hydrogen atom or one or two of the groups R ¹ to R ⁴ each independently of the other a fluorine, chlorine or bromine atom, a C _1-3 alkyl group, a trifluoromethyl, amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group represent and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom, where R ⁴ together with R ^{5 may} additionally 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 _1-3 -alkyl) -, sulfonyl or carbonyl group or one via the carbon or Schwefela -NH-CH ₂ -, -NH-CO-, -NH-SO ₂ - group which is linked to the group R ^a in formula (I), a hetero atom of group A ^a not having a nitrogen atom of a 5-membered heteroaryl group of Group R ^a linked R ^{a is} a phenyl or pyridinyl group, a pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or thiazolyl group bonded via a carbon or nitrogen atom, a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 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 _1-3 alkyl, trifluoromethyl, C _{1- 3} -alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or cyano group, a 5- to 7-membered cycloalkyleneimino group in which the methylene group in position 4 of a 6-membered cycloalkyleneimino group may be substituted by a methyl group or may be replaced by an oxygen or sulfur atom or by an imino group optionally substituted by a C _1-3 alkyl group or in a piperidino group by one -CH ₂ - group linked to the imino nitrogen atom can be replaced by a carbonyl group or a - (CH ₂ ) ₂ group linked to the imino nitrogen atom can be replaced by a -CO-NR ⁸ group or a linkage linked to the imino nitrogen atom - (CH ₂ ) ₃ - group can be replaced by a -CO-NR ⁸ -CO- group, where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group, R ^{5 represents} a hydrogen atom or a C _1-3 alkyl group, Het a two carbon atoms-bonded 5-membered heteroarylene group which contains an imino group substituted by the group R ⁹ , an oxygen or sulfur atom or an imino group substituted by the group R ⁹ or an oxygen or sulfur atom and additionally a nitrogen atom, where R ^{9 is} a hydrogen atom, a C _1-3 alkyl group, a terminally substituted by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or C _1-4 alkoxycarbonylamino group -C ₂ _ ₃ -alkyl group, a carboxy-C _1-3 -a Alkyl, C _1-3 alkoxy-carbonyl-C _1-3 alkyl or C _1-3 alkylcarbonyl group or R ⁹ together with R ^{6 represents} a - (CH ₂ ) _p bridge, in which p is the number 2 or 3, or a pyridinylene or pyrimidinylene group, the abovementioned heteroarylene radicals in the carbon structure being replaced 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 _1-3 alkyl) amino, acetylamino or cyano group, R ^{6 can be} a hydrogen atom or a C ₁ _ ₃ alkyl group, R ⁷ a C _1-6 alkyl group, a straight-chain C ₂ _ ₆ alkyl group which is terminally substituted by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group, one by a C ₃ _ ₇ cycloalkyl substituted C _1-4 alkyl group, wherein a hydrogen atom in the 4-position of a cyclohexyl radical by C _1-5 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, phenyl-C _1-3 alkoxy-methyl, phenyl-C _1-3 -alkylamino-, phenyl-C _1-2 -alkyl-carbonylamino-, benzoylamino-, phenylaminocarbonyl, phenyl-C _1-3 -alkyl-aminocarbonyl, carboxy or C _1-3 -alkoxy-carbonyl group can be replaced or in a cyclopentyl radical, one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bi- or tricyclic ring system formed in this way the hydrogen atom bonded to the saturated carbon atom in position 1 by a C _{1- 3} -Alkylamino-carbonyl or di- (C _1-3 -alkyl) amino-carbonyl group, in which terminal methyl groups can in each case be wholly or partly fluorinated, can be replaced, a C ₁ optionally substituted by a C ₃ _ ₅ -cycloalkyl group _-6 -Alkylgruppe through a carboxy or C _1-3 -alkoxycarbonyl group or by a phenyl, 1-naphthyl, 2-naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group, where a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl or trifluoromethyl group and the phenyl group and the heteroaromatic groups mentioned above in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _{1- 4} -alkyl-, trifluoromethyl-, C _1-3 -alkoxy-, fluoromethoxy-, difluoromethoxy-, trifluoromethoxy-, C _1-4 -alkoxy-carbonylamino-C _1-3 -alkyl-, amino-, C _1-3 - Alkylamino, di (C _1-3 alkyl) amino or cyano group may be substituted, is substituted by a phenyl radical and a carboxy or C _1-3 alkoxy-carbonyl group, a C _1-6 alkyl group Phenyl-C ₂ _ ₃ -alkynylene-CH ₂ group in which a hydrogen atom of the methylene group in position 1 is replaced by a methyl group tetz can be and independently of the phenyl part by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, trifluoromethyl, C _1-3 alkoxy, phenyl or cyano group, which can be substituted in the C _1-3 -alkyl part optionally substituted by a methyl group R ^b -A ^b -E ^b -C _1-3 -alkyl-, in which R ^b one optionally by a fluorine, chlorine or bromine atom, by a C _1-3 -Alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoro methoxy, trifluoromethoxy, carboxy or C _1-3 alkoxy-carbonyl substituted phenyl group, a 5-membered heteroaryl group, which a carbon atom or, if A ^{b represents} a bond, can also be bonded via a nitrogen atom and which has an imino group optionally substituted by a C _1-3 alkyl group, an oxygen or sulfur atom, or an optionally substituted by a C _1-3 alkyl group Imino group or an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, a 6-membered heteroaryl group containing one or two nitrogen atoms, the above-mentioned heteroaryl radicals in the carbon structure being substituted by a fluorine -, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy, trifluoromethoxy, amino, C ₁ _ ₃ alkylamino, di (C _{1 -3-} alkyl) -amino or acetylamino group monosubstituted or, with the exception of 5-membered heteroaryl radicals containing more than two heteroatoms, by a C _1-4 alkyl group and a substituent selected from fluorine, chlorine, bromine, C _1-3 - Alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy and trifluoromethoxy can also be disubstituted, a C _3-6 cycloalkyl group, 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 cyclohex yl group can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group, a 5- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be condensed with a phenyl ring or a hydrogen atom by a C _1-3 -Alkylgruppe can be replaced and / or in each case the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group by a 4- to 7-membered cycloalkylenimino, phenyl or 4- (C _1-3 alkyl) -1.2 , 4-triazol-3-yl group can be substituted 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 by an n-butylene, n-pentylene or 1,2-ethylenedioxy group can be replaced, A ^{b is} a bond, an oxygen atom, a -CH ₂ -, -NH-, -O-CH ₂ -, carbonyl, -NH-CO or -CO-NH group, in which a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a C _1-3 alkyl group, E ^b a optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alk oxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino or C _1-3 alkoxycarbonyl group are substituted phenylene groups, or the group R ^c -A ^c -E ^c -C _1-3 alkyl-, in which R ^{c is} optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy -, Trifluoromethoxy-, carboxy- or C _1-3 -alkoxy-carbonyl group substituted phenyl group or a 5- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be condensed with a phenyl ring or a hydrogen atom replaced by a C _1-3 alkyl group may be 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 be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group , A ^{c is} a bond, E ^{c is} a 5-membered heteroarylene group bonded via two carbon atoms, one of which may have a ch a C _1-3 alkyl group substituted imino 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 an optionally substituted by a C _1-3 alkyl group contains substituted imino group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, or a pyridinylene, pyridazinylene or pyrimidinylene group, the abovementioned 5- and 6-membered heteroarylene radicals in the carbon skeleton being represented by a fluorine, chlorine or bromine atom, by one C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, C _1-3 alkoxycarbonyl or cyano group may be substituted , means, or R ⁶ and R ⁷ together represent an n-alkylene bridge with 4 or 5 carbon atoms, in which a hydrogen atom can be replaced by a C _1-3 alkyl group or / and a -CH ₂ -C H ₂ group may be replaced by a 1,2-linked phenylene group optionally substituted by a phenyloxy or benzyl group, the phenyloxy or benzyl group in the aromatic part 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 _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino, C _1-3 alkoxycarbonyl or cyano group may be substituted, or the carbon atom in position 3 of an n-pentylene group by a terminal by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) -amino-, acetylamino or N- (methyl) -acetylamino group or a 5- to 7-membered cycloalkyleneimino group substituted C _1-3 -alkyl group may be monosubstituted or may be disubstituted by a phenyl group and a cyano group, which in the definition of the aforementioned radicals mentioned phenyl groups, unless stated otherwise was, by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl group, by a trifluoromethyl, C ₁ _ ₃ alkoxy, trifluoromethoxy, phenyl, amino, C _1-3 alkylamino , Acetylamino, C _1-3 alkoxy-carbonyl or cyano group may be substituted, the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl moieties with more than two carbon atoms contained in the groups of formula I defined above, straight-chain or may be branched, unless stated otherwise, the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions or / and those which are used in the definition of the above-mentioned radicals mentioned amino and imino groups can each be substituted by a radical which can be split off in vivo, the tautomers, the diastereomers, the en enantiomers, their mixtures and their salts. Use according to claim 5, wherein the MTP inhibitor is a compound of the general formula I in which X _{1 is} the group CR ¹ , X _{2 is} the group CR ² , X _{3 is} the group CR ³ and X _{4 is} the group CR ⁴ or one of the Groups X ₁ to X _{4 represent} a nitrogen atom and the rest of the groups X ₁ to X ₄ three of the groups CR ¹ to CR ⁴ , where R ¹ , R ² , R ³ and R ⁴ each have a hydrogen atom or one or two of the groups R ¹ to R ⁴ each independently of the other a fluorine, chlorine or bromine atom, a C _1-3 alkyl group, a trifluoromethyl, amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group represent and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom, where R ⁴ together with R ^{5 can} additionally have the meaning of a - (CH ₂ ) _n bridge _, in which n represents the number 1, 2 or 3, and A ^a a bond, an oxygen atom, a -CH2-, - (CH ₂ ) ₂ -, -NH-, -N (C _1-3 -alkyl) -, sulfonyl or carbonyl group or one via the carbon or sulfur atom of the group R ^a in formula (I) -NH-CH ₂ -, -NH-CO-, -NH-SO ₂ group, wherein a hetero atom of group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group of group R ^{a is} linked, R ^{a is} a phenyl or pyridinyl group, a pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl or thiazolyl group bonded via a carbon or nitrogen atom, a nitrogen atom of the pyrrolyl, Pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl group and the phenyl group and the aforementioned heteroaromatic Gr groups in the carbon skeleton 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 _1-3 alkyl) amino or cyano group may be substituted, a 5- to 7-membered cycloalkyleneimino group in which the methylene group in position 4 of a 6-membered cycloalkyleneimino group is substituted by a methyl group or by an oxygen or sulfur atom or by a can optionally be replaced by a C _1-3 alkyl group substituted imino group or in a piperidino group a -CH ₂ - group linked to the imino nitrogen atom can 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 one with the imino nitrogen atom linked - (CH ₂ ) ₃ - group can be replaced by a -CO-NR ⁸ -CO- group, where R ^{8 represents} a hydrogen atom or a C _1-3 alkyl group, R ^{5 represents} a hydrogen atom or a C _1-3 - Alkyl group, Het is a 2,4-linked pyrrolylene or imidazolylene group which are each bonded via position 2 to the adjacent carbonyl group of the formula I and which are substituted on a nitrogen atom by a C _1-3 alkyl group and in the carbon skeleton by a C _1-3 alkyl group or a trifluoromethyl group may be substituted, R ^{6 is} a hydrogen atom or a C _1-3 alkyl group, R ^{7 is} a C _1-4 alkyl group which is terminally substituted by a C _3-7 cycloalkyl radical, a hydrogen atom in 4 a cyclohexyl radical position by a C _1-5 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, phenyl-C _1-3 alkoxy-methyl, phenyl-C _1-3 alkylamino, Phenyl-C _1-2 -alkyl-carbonylamino-, benzoylamino-, phenylaminocarbonyl-, phenyl-C _1-3 -alkyl-aminocarbonyl-, carboxy- or C _{1 -3} -alkoxy-carbonyl group can be replaced or in a cyclopentyl radical one or two single bonds separated by at least one bond and from position 1 can each be condensed with a phenyl radical, in a bicyclic or tricyclic ring system formed in this way the saturated Carbon atom bonded in position 1 by a C _1-3 alkylamino-carbonyl or di- (C _1-3 alkyl) amino-carbonyl group, in which terminal methyl groups may each be partially or completely fluorinated; may be replaced, a C _1-6 -alkyl group optionally substituted by a C _3-5 cycloalkyl group, which is replaced by a phenyl, 1-naphthyl, 2-naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, furanyl, Thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl group, where a nitrogen atom of the pyrrolyl, pyrazolyl and imidazolyl group can be substituted by a C _1-3 alkyl or trifluoromethyl group and the phenyl group and that The aforementioned heteroaromatic groups in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, trifluoromethyl, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C _1-4 -Alkoxy-carbonylamino-C _1-3 alkyl, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or cyano group, one is substituted by a phenyl radical and a carboxy or C _1-3 -alkoxy-carbonyl-substituted C _1-6 alkyl group, a phenyl-C _2- alkynylene _{3-CH 2} group in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and, independently thereof, the phenyl part by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, trifluoromethyl, C _{1- 3} -Alkoxy-, phenyl or cyano group can be substituted, which in the C _1-3 alkyl part optionally substituted by a methyl group R ^b -A ^b -E ^b -C _1-3 -alkyl-, in which R ^b one optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, hydroxy, C _1-3 alkoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, carboxy or C _1-3 -Alkoxy-carbonyl-substituted phenyl group, a 5-membered heteroaryl group which is bonded via a carbon atom or, if A ^{b is} a bond, also via a nitrogen atom and an 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 one optionally substituted by a C _{1 -3-} alkyl group substituted imino group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, a 6-membered heteroaryl group containing one or two nitrogen atoms, the above-mentioned heteroaryl radicals in the carbon skeleton being represented by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino - or acetylamino group monosubstituted or, with the exception of more than two heteroatoms containing 5-membered heteroaryl radicals, by a C _1-4 alkyl group and a substituent selected from fluorine, chlorine, Br om, C _1-3 alkyl, trifluoromethyl, phenyl, C _1-3 alkoxy and trifluoromethoxy can also be disubstituted, a C _3-6 cycloalkyl group, the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in 3- or 4-position of a cyclohexyl group can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group, a 5- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be fused with a phenyl ring or a hydrogen atom a C _1-3 alkyl group can be replaced or / and in each case the carbon atom in position 4 of a 6- or 7-membered cycloalkyleneimino group can be replaced by a 4- to 7-membered cycloalkylenimino, phenyl or 4- (C _1-3 alkyl) ) -1,2,4-triazol-3-yl group 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 by an n-butylene group, n-pentylene or 1,2-ethyl endioxy group can be replaced, A ^{b is} a bond, an oxygen atom, a -CH ₂ -, -NH-, -O-CH ₂ -, carbonyl, -NH-CO- or -CO-NH group, in which a a nitrogen atom-bonded hydrogen atom can in each case be replaced by a C _1-3 alkyl group, E ^b optionally 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 _1-3 alkyl) amino, acetylamino or C _1-3 alkoxycarbonyl group are substituted phenylene groups, or the group R ^c - a ^c E ^c -C _1-3 alkyl, where R ^c is an optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _{1- 3} alkoxy , Trifluoromethoxy, carboxy or C _1-3 alkoxycarbonyl group substituted phenyl group or a 5- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be fused with a phenyl ring or a hydrogen atom can be replaced by a C _1-3 alkyl group can 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 can be replaced by an n-butylene, n-pentylene or 1,2-ethylenedioxy group , A ^{c is} a bond, E ^{c is} a 5-membered heteroarylene group bonded via two carbon atoms, which has an 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 contains an oxygen or sulfur atom and additionally a nitrogen atom or an imino group optionally substituted by a C _1-3 alkyl group and two nitrogen atoms or an oxygen or sulfur atom and two nitrogen atoms, or a pyridinylene, pyridazinylene or pyrimidinylene group, the above mentioned 5- and 6-membered heteroarylene residues in the carbon skeleton by a fluorine, chlorine or bromine atom, durc h a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, amino, C _1-3 alkylamino, acetylamino, C _1-3 alkoxycarbonyl or cyano group means, or R ⁶ and R ⁷ together represent an n-alkylene bridge with 4 or 5 carbon atoms, in which a hydrogen atom can be replaced by a C _1-3 alkyl group or / and a -CH ₂ -CH ₂ - Group can be replaced by a 1,2-linked phenylene group optionally substituted by a phenyloxy or benzyl group, the phenyloxy or benzyl group in the aromatic part 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 _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino-, acetylamino-, C _1-3 -Alkoxy-carbonyl or cyano group substi can be tuiert, or the carbon atom in position 3 of an n-pentylene group by a terminal by an amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, acetylamino or N- ( Methyl) acetylamino group or a 5- to 7-membered cycloalkyleneimino group substituted C _1-3 alkyl group may be monosubstituted or may be disubstituted by a phenyl group and a cyano group, the phenyl groups mentioned in the definition of the abovementioned radicals, unless stated otherwise , by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl group, by a trifluoromethyl, C _1-3 alkoxy, trifluoromethoxy, phenyl, amino, C _1-3 alkylamino, Acetylamino, C _1-3 alkoxy-carbonyl or cyano group may be substituted, the alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals or in the alkyl groups contained in the groups of formula I defined above with more than two carbon atoms straight-chain o which may be branched, unless stated otherwise, the carboxy groups mentioned in the definition of the abovementioned radicals can be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, and / or those in the definition of the above-mentioned residues mentioned amino and imino groups can each be substituted by a residue which can be split off in vivo, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. Use according to claim 6, wherein the MTP inhibitor is a compound of the general formula I in which X _{1 is} the group CR ¹ , X _{2 is} the group CR ² , X _{3 is} the group CR ³ and X _{4 is} the group CR ⁴ , where R ¹ , R ² , R ³ and R ⁴ each represent a hydrogen atom or one of the groups R ¹ to R ^{4 is} a fluorine, chlorine or bromine atom, a C _1-3 alkyl group or a trifluoromethyl group and the rest of the groups R ¹ to R ⁴ each represent a hydrogen atom, A ^{a is} a bond, an oxygen atom, a -CH ₂ -, - (CH ₂ ) ₂ -, -NH-, or -N (C _1-3 -alkyl) group, a nitrogen atom the group A ^{a is} not linked to a nitrogen atom of a 5-membered heteroaryl group from the group R ^a , R ^{a is} a phenyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl group, a 1-pyrrolyl, 2-pyrrolyl , 3-pyrrolyl, 2-thienyl or 3-thienyl group, where the nitrogen atom of the pyrrolyl group may be substituted by a C _1-3 alkyl group and the phenyl group and the above gena Neither heteroaromatic groups in the carbon skeleton can be substituted by a fluorine, chlorine or bromine atom, by a C _1-3 -alkyl or trifluoromethyl group, a pyrrolidino, piperidino or morpholino group R ^{5 is} a hydrogen atom, Het is a 2,4-linked one Pyrrolylene or imidazolylene group, which are each bonded via position 2 to the adjacent carbonyl group of the formula I and which are substituted on a nitrogen atom by a C _1-3 alkyl group and substituted in the carbon skeleton by a C _1-3 alkyl group or a trifluoromethyl group R ^{6 can be} a hydrogen atom or a C _1-3 alkyl group, R ⁷ the group R ^d -CH ₂ - or R ^d -CH ₂ -CH ₂ -, in which a hydrogen atom of the methylene group in position 1 is replaced by a C _{1 -3-} alkyl group or a cyclopropyl group can be replaced and in which R ^{d is} phenyl, 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl or 5-pyrimidinyl group, the phen yl group and the above-mentioned heteroaromatic groups in the carbon skeleton can be substituted by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, trifluoromethyl, C _1-3 alkoxy or fluoromethoxy group, means a phenyl C≡C-CH ₂ group, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and, independently thereof, the phenyl part by a fluorine, chlorine or bromine atom, by a C _1-4 alkyl, trifluoromethyl - Or phenyl group may be substituted, the group R ^b -A ^b -E ^b -CH ₂ -, in which a hydrogen atom of the methylene group in position 1 can be replaced by a methyl group and in which R ^b one optionally by a fluorine or chlorine - or bromine atom, by means of a C _1-3 alkyl, Trifluoromethyl, hydroxyl, methoxy, carboxy or methoxycarbonyl group substituted phenyl group, a pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl bonded via a carbon atom or, if A ^{b represents} a bond, also via a nitrogen atom -, Isothiazolyl-, Oxadiazol- or Thiadiazolyl group in which a hydrogen atom bonded to a nitrogen atom can be replaced by a C _1-3 alkyl group, a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl , 5-pyrimidinyl, 3-pyridazinyl or 4-pyridazinyl group, the abovementioned 5- and 6-membered heteroaryl radicals in the carbon structure being replaced by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl , Phenyl, amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino or acetylamino group monosubstituted or, with the exception of 5-membered heteroaryl radicals containing more than two heteroatoms, by a C _{1 -3-} alkyl group and a substituent selected from fluorine, chlorine, bromine, C _1-3 alkyl, trifluoromethyl, phenyl, may also be disubstituted, a C _{5- 6} cycloalkyl 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 by an n-butylene, n-pentylene or 1,2-ethyl ndioxygruppe can be replaced, or a 5- to 6-membered cycloalkyleneimino group in which the cycloalkylene with one optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl or C _1-3 - Alkoxy group substituted, phenyl ring can be condensed or a hydrogen atom can be replaced by a C _1-3 alkyl group or / and the two hydrogen atoms of the methylene group in position 3 of the 5-membered or in position 4 of the 6-membered cycloalkyleneimino group by an n-butylene -, n-pentylene or 1,2-ethylenedioxy group can be replaced, A ^{b is} a bond, a -CH ₂ -, -NH-, -O-CH ₂ -, -NH-CO or -CO-NH group , in which a hydrogen atom bonded to a nitrogen atom can in each case be replaced by a methyl group, E ^{b is} a 1,4-linked, optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, C _1-3 alkoxy or trifluoromethoxy group substituted phenylene group, or he the group R ^c -A ^c -E ^c -C _1-3 alkyl-, in which R ^c one optionally by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl, methoxy -, carboxy or methoxycarbonyl group substituted phenyl group, A ^c a bond, E ^c a pyrrolylene, pyrazolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, [bonded via two carbon atoms in the relative positions 1,3 1,3,4] -oxadiazole or [1,3,4] thiadiazole group, in which a hydrogen atom bonded to a nitrogen atom can be replaced by a C _1-3 alkyl group, or a 1,4-linked pyridinylene group, Pyridazinylene or pyrimidinylene group, where the abovementioned 5- and 6-membered heteroarylene radicals in the carbon skeleton can be substituted by a fluorine, chlorine or bromine atom, by a C _1-3 alkyl, trifluoromethyl or methoxy group, where the alkyl and A mentioned in the definition of the above radicals If the alkoxy groups or in the alkyl parts contained in the groups of formula I defined above have more than two carbon atoms, they may be straight-chain or branched, unless stated otherwise, the carboxy groups mentioned in the definition of the abovementioned radicals by a group which can be converted into a carboxy group in vivo or can be replaced by a group which is negatively charged under physiological conditions or / and the amino and imino groups mentioned in the definition of the abovementioned radicals can each be substituted by a radical which can be split off in vivo, their tautomers, their diastereomers, their enantiomers, their Mixtures and their salts. Use according to claim 7, wherein the MTP inhibitor is one of the following compounds of general formula I: (a) N- [3- (biphenyl-4-yl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl -2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (b) N- [4- (1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) phenylmethyl] -4 - (4'-Trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2 = carboxamide, (c) N- [4- (3-aza-spiro [5.5] undec-3-yl) -phenylmethyl] -4 - (4'-Trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (d) N- [4- (6-methylpyridazin-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl -2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (e) N- (4'-hydroxybiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl- pyrrole-2-carboxamide, (f) N- [4- (1,4-Dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrol-2- carboxamide, (g) N- (4'-methylbiphenyl-4-yl) methyl-4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (h) N- [3- (4-isopropylphenyl) prop-2-ynyl] -4- (4'-trifluoromethyl-biphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (i) N- [3- (4-biphenyl ) -prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide, (j) N- [3- (4-trifluoromethylphenyl) prop-2- inyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazole-2-carboxamide and (k) N- [4- (4-propylpiperidino) phenylmethyl] -4- (4 ' -trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide and their salts. Use according to claim 8, wherein the MPT inhibitor is one of the following compounds of the general Formula I is: (a) N- [3- (biphenyl-4-yl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (c) N- (4- (3-aza-spiro [5.5] undec-3-yl) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxamide, (f) N- [4- (1,4-Dioxa-spiro [4.5] dec-8-yl) phenylmethyl] -4- (4'-tri-fluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole- 2-carboxylic acid amide-, (I) N- [3- (4-biphenyl) prop-2-ynyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-imidazol-2-carboxamide and k) N- [4- (4-Propylpiperidino) phenylmethyl] -4- (4'-trifluoromethylbiphenyl-2-carbonylamino) -1-methyl-pyrrole-2-carboxylic acid amide such as their salts. Use according to claim 1 or 2, wherein the MTP inhibitor from the group consisting of 9- {4- [4- (4-trifluoromethylphenylacetyl) piperazino] butyl} -9H-fluorene-9-carboxylic acid (2.2 , 2-trifluoro-ethyl) -amide, 9- [4- (4-phenylacetyl-piperazino) butyl] -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoro-ethyl) -amide, 9- (4- {4- [2-phenyl-butyryl] piperazino} butyl) -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoro-ethyl) -amide, 9- (4- {4- (3-phenylpropionyl) piperazino} butyl) -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoro-ethyl) -amide, 9- {4 -. [4 = (4-phenyl-butyryl) -piperazino] -butyl} -9H-fuoren-9-carboxylic acid- (2,2,2-trifluoro-ethyl) -amide, 9- (4- {4- (4- (4- (pyridin-2-yl-acetyl) - piperazino} -butyl) -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoro-ethyl) -amide, 9- (4- {4- [2-oxo-2-phenyl-acetyl] -piperazino} -butyl) -9H-fluorene-9-carboxylic acid- (2,2,2-trifluoro-ethyl) -amide, 9- (4- {4 - [(2,4-dichlorophenyl) acetyl] piperazino} butyl ) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoro-ethyl) -amide, 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] - N- ( 2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide, 9- [4- [2,5-dimethyl-4 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -2 -yl] carbonyl] amino] -1H-benzimidazol-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluoren-9-carboxamide, 2 (S) -cyclopentyl-2- (4- (2,4-dimethyl-9H-pyrido [2,3-b] indol-9-ylmethyl) phenyl) -N- (2-hydroxy-1 (R) -phenylethyl) acetamide, 2-cyclopentyl-2 - {4 - [(2,4-dimethyl-9H-pyrido [2,3-b] indol-9-yl) methyl] phenyl} -2'-phenylacetohydrazide, 2- {4 - [(2,4-dimethylpyrimido [1,2-a] indol-10-yl) methyl] phenyl} -3-methyl-2'-phenylbutane hydrazide, (-) - [2S- [2α, 4α (S *)]] - 4- [ 4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1,2,4-triazol-3-yl) thio] methyl] -1,3- dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one, (-) - [2S- [2α, 4α (S *)]] - 4- [4- [4- [4 - [[2- (4-chlorophenyl) -2 - [[(4-methyl-4H-1,2, 4-triazol-3-yl) sulfonyl] methyl] -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3 -1,2,4-triazol-3-one, (S) -6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid ure- (2-methylsulfonylamino-indan-5-yl) amide, (R) -6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylamino-indan-5-yl) amide, (S) -6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid- (2-methoxycarbonylamino-indan-5-yl) -amide, (R) -4-fluoro-4'-trifluoromethylbiphenyl-2-carboxylic acid- (2-methylsulfonylamino- indan-5-yl) -amide, (S) -4-fluoro-4 '= trifluoromethylbiphenyl-2-carboxylic acid- (2-methylsulfonylamino-indan-5-yl) -amide, 6-methyl-4'-trifluoromethylbiphenyl-2 -carboxylic acid- (2-dimethylaminocarbonylamino-indan-5-yl) -amide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2H- [1,2,4] triazol-3-ylmethyl) -1, 2,3,4-tetrahydro-isoquinolin-6-yl] amide and 4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylamino-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide and their tautomers, their diastereomers, their enantiomers, their mixtures and their salts is selected. Use according to claim 10, wherein the MTP inhibitor from the group consisting of 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluorene-9-carboxamide, 9- [4- [2,5-dimethyl-4 - [[[4 '- (trifluoromethyl) [1,1'-biphenyl] -2-yl] carbonyl] amino] -1H-benzimidazol-1-yl] butyl ] -N- (2,2,2-trifluoro-ethyl) -9H-fluorene-9-carboxamide, 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide and 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2-acetylamino-ethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] -amide such as their tautomers, their diastereomers, their enantiomers, their mixtures and their salts selected is. Use of bezafibrate to reduce liver toxicity of 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H fluorene-9-carboxamide. Pharmaceutical composition containing one MTP inhibitor in combination with a fibrate. Pharmaceutical composition according to claim 6 containing at least one MTP inhibitor in combination with a) bezafibrate; b) ciprofibrate, c) clofibrate, d) fenofibrate or e) Gemfibrozil. Pharmaceutical composition according to claim 13 or 14, wherein one of the MTP inhibitors mentioned in one of claims 3 to 7 is used. Pharmaceutical composition according to one of claims 13 or 14, wherein one of the MTP inhibitors mentioned in one of claims 8 or 9 is used. Pharmaceutical composition according to one of claims 13 or 14, wherein one of the MTP inhibitors mentioned in one of claims 10 or 11 is used. Pharmaceutical preparation containing 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluoren-9 -carboxamide in combination with bezafibrate. Pharmaceutical composition according to one of claims 13 to 18 for oral administration. Products containing an MTP inhibitor and a fibrate as a combination preparation for simultaneous, separate or graduated use for lowering lipids. Product according to claim 20, wherein the fibrate from the group consisting of a) bezafibrate, b) ciprofibrate, c) clofibrate, d) fenofibrate and e) Gemfibrozil selected is. Product according to claim 20 or 21, wherein one of the MTP inhibitors mentioned in one of claims 3 to 7 is used. Product according to claim 20 or 21, wherein one of the MTP inhibitors mentioned in one of claims 8 or 9 is used. Product according to claim 20 or 21, wherein one of the MTP inhibitors mentioned in one of claims 10 or 11 is used. Product according to claim 20 containing 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluoren-9- carboxamide in combination with bezafibrate. Product according to one of claims 20 to 25 for oral use. Use of a fibrate for the manufacture of a medicinal product containing one or more MTP inhibitors, with the addition of fibrate the liver toxicity of the MTP inhibitor is reduced. Use according to claim 27, the fibrate from the group consisting of a) bezafibrate, b) ciprofibrate, c) clofibrate, d) fenofibrate and e) Gemfibrozil selected is. Use according to claim 27 or 28, wherein one of the MTP inhibitors mentioned in one of claims 3 to 7 is used. Use according to claim 27 or 28, wherein one of the MTP inhibitors mentioned in one of claims 8 or 9 is used. Use according to claim 27 or 28, wherein one of the MTP inhibitors mentioned in one of claims 10 or 11 is used. Use of bezafibrate in the manufacture of a medicinal product containing 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) -9H-fluorene-9-carboxamide, with the addition of bezafibrate the liver toxicity of 9- [4- [4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl] butyl] -N- (2,2,2-trifluoro-ethyl) - 9H-fluorene-9-carboxamide is reduced. Use according to a of claims 27 to 32, the drug being intended for oral administration is. Use of a combination of at least one MTP inhibitor of the general formula I according to claim 3, in which the radicals X ₁ , X ₂ , X ₃ , X ₄ , R ^a , A ^a , R ⁵ , Het, R ⁶ and R ⁷ as are defined in one of claims 3 to 7 mentioned, with a fibrate for the treatment of diseases. Use a combination of at least one MTP inhibitor according to one of claims 8 or 9 with a fibrate for the treatment of diseases. Use of a combination of one of claims 34 or 35 with a fibrate according to claim 2 for the treatment of hyperlipidemia, dyslipidemia, Atherosclerosis, diabetes mellitus, obesity or pancreatitis. Use of a combination of one of claims 34 or 35 with a fibrate according to claim 2 for the manufacture of a medicament for the treatment of hyperlipidemia, dyslipidemia, atherosclerosis, Diabetes mellitus, obesity or pancreatitis. Process for the manufacture of a pharmaceutical Composition according to a of claims 13 to 19, characterized in that an MTP inhibitor and a Fibrate with auxiliaries and carriers in transferred a suitable form of application.