EP1296681A2

EP1296681A2 - Use of microsomal triglyceride transfer protein (mtp) inhibitors for reducing the number of postprandial triglyceride-rich lipoprotein particles (pptrl)

Info

Publication number: EP1296681A2
Application number: EP01951571A
Authority: EP
Inventors: Rudi Grützmann; Ulrich Müller; Hilmar Bischoff; Siegfried Zaiss
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2000-06-21
Filing date: 2001-06-08
Publication date: 2003-04-02
Also published as: WO2001097787A3; US20040014748A1; AU2001272461A1; US20060166999A1; WO2001097787A2; CA2413277A1; JP2003535888A; DE10030375A1

Abstract

The invention relates to the use of inhibitors of the microsomal triglyceride transfer protein (MTP) for reducing the number of postprandial triglyceride-rich lipoprotein particles (ppTRL) or for reducing their decomposition products i.e. the cholesterol-rich "small remnant particle" (remnants). Said particles are associated with apolipoprotein B-48 (ApoB-48) and are designated as "ppTRL" in the further course of events.

Description

Use of MTP inhibitors to lower ppTRL

The invention relates to the use of inhibitors of microsomal triglyceride transfer protein (MTP) for lowering the postprandial triglyceride-rich lipoprotein particles (ppTRL) or for lowering their breakdown products

Small cholesterol-rich "small remnant particle" (remnants). The particles mentioned are associated with apolipoprotein B-48 (ApoB-48) and are referred to in the following as "ppTRL".

Substances that inhibit the release of ApoB-100 associated lipoproteins are well known to those skilled in the art. Such compounds are described for example in the publications EP 705 831, EP 779279, EP 779276, EP 802 198 and EP 799 828. These compounds, which lower the plasma serum levels of the ApoB-100-associated lipoproteins, are MTP inhibitors. In these cited applications a rat test is also described, with which the effect of some substances on the intestinal triglyceride absorption was determined. In this rat test, the substances reduced the postprandial increase in serum triglycerides.

In Zaiss et al., Circulation 100 (18, Suppl. I): 258 Abstr. 1343 (1999) describes results of a mouse test. According to this test, the MTP inhibitor hnplitapide prevents the formation of atherosclerotic plaques.

The prophylaxis and treatment of metabolic disorders, in particular those which affect lipoprotein or lipid metabolism and are associated with cardiovascular diseases or neuronal degeneration, is still an essential goal of modern drug research. In the literature, for example, alleles of the apoE genes are discussed, which both represent risk factors for the development of coronary heart diseases and are associated with the development of Alzheimer's disease (Rubinsztein, DC and Easton, DF; Apolipoprotein E genetic Variation and Alzheimers disease. A meta -analysis; dementia. Geriatr. Cogn. Disord., 1999; 10 (3): pp. 199-209; Nakayama S. and Kuzuhara S .; Apolipoprotein E phenotypes in healthy normal controls and demented subjects with Alzheimers disease and vascular dementia in Mie Prefecture of Japan; Psychiatry Clin. Neurosci. 1999; 53 (6): pp. 643-648; Fullerton SM, Strittmatter WJ. and Matthew WD; Peripheral sensory nerve defects in apolipoprotein E knockout mice;

Exp. Neurol. 1998; 153 (1): pp. 156-163). ApoE is a component of the "very low density lipoprotein" (VLDL), which is formed in the liver, and the chylomicrons, which are synthesized in the intestine. ApoE mediates a high affinity binding of the chylomicrons and of VLDL to special receptors on cells. This enables Metabolism and uptake of the above-mentioned particles into the corresponding cells, which ultimately prevents the accumulation of cholesterol-rich remnants and ppTRL in the plasma The homozygous inactivation of the apoE genes, as is the case in apoE knockout mice, has the consequence that In the serum of these animals no apoE can be detected.The animals initially develop normally after birth, but show an impaired lipoprotein or lipid metabolism, which can be associated, for example, with up to five times higher levels of plasma cholesterol these animals spontaneously experience neuronal degeneration and atherosclerotic lesions. This is similar to People who have an apoE variant that can only bind weakly or not at all to cellular receptors. ApoE is also involved in the regulation of the immune system, the regeneration of nerve cells and the differentiation of muscles (Masliah E, Mallory M, Ge N, Alford M, Neinbergs I, Roses AD Νeurodegeneration in the central nervous system of apoE-deficient mice. Exp. Neurol. 1995; 136 (2): 107-122; Masliah E, Samuel W, Neinbergs I, Mallory M, Mante M, Saitoh T „odeurodegeneration and cognitive impairment in apoE- deficient mice is ameliorated by infusion of recombinant apoE "Brain Res 1997; 751 (2): 307-314; Chen Y, Lomnitski L, Michaelson DM, Shohami E" Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury "Νeuroscience 1997: 1255-1262; Fullerton SM, Strittmatter WJ, Matthew WD. "Peripheral sensory nerve defects in apolipoprotein E knockout mice" Exp Neurol

1998; 153 (1): 156-63; Mato M, Ookawara S, Mashiko T, Sakamoto A, Mato TK, MaedaN, Kodama T Anat Rec 1999; 256 (2): 165-176 "Regional difference of lipid distribution in brain of apolipoprotein E deficient mice").

The pathological effects of a disturbed lipoprotein or lipid metabolism are therefore not only limited to atherosclerosis. The apoE knockout

Mouse is therefore suitable as an animal model to investigate the effects of medicinal products on the lipoprotein or lipid metabolism, atherosclerosis and damage to the nervous system in a multi-factorial manner with the aim of intervening in these complex pathological processes.

The more recent literature also describes that ppTRL and its breakdown products in particular play an important role in diabetes (Howard, BN; Insulin resistance and lipid metabolism; Am. J. Cardiol., 1999; 84 (1A): pp. 28J- 32J; Mero, Ν., Malmstrom, R., Steiner, G., Taskinen, M., Syvanne, M .; Postprandial metabolism of apolipoprotein B-48- and B-100-containing particles in type 2 diabetes mellitus: relations to angiographically verified severity of coronary artery disease. Atherosclerosis, 2000; 150 (1): pp. 167-177). It is therefore of great importance to find ways to lower the ppTRL level in the blood plasma.

It has now surprisingly been found that MTP inhibitors the ppTRL in

Reduce plasma, e.g. after fat exposure. The invention therefore relates to the use of MTP inhibitors for reducing or lowering the ppTRL in the plasma. Lowering ppTRL by inhibiting MTP has a beneficial impact on morbidity and mortality, particularly with regard to neurodegenerative and cardiovascular diseases. MTP inhibitors are therefore suitable for favorably influencing these disease courses.

Surprisingly, it was also found that the reduction in ppTRL, in particular after ingestion of fatty foods, already occurred at doses of the MTP inhibitor at which there was no significant or only a slight lowering

Effect on serum triglyceride or serum cholesterol concentration in the fasting state (about 12 hours after the last meal) is seen. In the same way, the liver-derived LDL particles, which are only ApoB-100-associated lipoprotein particles in humans, are largely unaffected. As a minor effect, a reduction in the plasma triglyceride or plasma cholesterol concentration or

Lowering the ApoB-100-associated lipoproteins by less than 20%, preferably less than 10% or less. "Sober plasma values" means that measurements must not be taken in postprandial plasma or serum, ie after ingestion of food containing lipids, but in sober plasma or serum, which is obtained about 12 hours after the last ingestion of food.

Due to the effect on ppTRL, the MTP inhibitors can also be used to inhibit or reduce intestinal cholesterol absorption.

Surprisingly, the targeted lowering of the plasma ppTRL with a low dose of an MTP inhibitor, combined with better tolerability, is already sufficient to prolong patient survival. Since a disturbed lipoprotein or lipid metabolism, as explained above, can lead to complex degenerative diseases, lowering the ppTRL makes an important therapeutic contribution to the treatment of such complex clinical pictures.

MTP inhibitors are described, for example, in the following documents: Wetterau et al. Science 282, 751 (1998), J Lipid Res 37, 1468 (1996), Bristol-Myers-

Squibb: EP-A-584 446, EP-A-643 057, WO 96/26205, WO 97/26240, WO 97/43255, WO 97/43257, WO 98/27979, US 5 760 246, US 5 827 875 , WO 99/21564; Pfizer: WO 96/40 640, WO 98/23593, EP-A 887 345, WO 97/41111; Glaxo-Wellcome: WO 98/16526, WO 98/47877, WO 98/56790; Janssen: WO 96/13499, WO 96/33193; Novartis: WO 00/05201; Meji Seika Kaisha: WHERE

98/54135, Japan Tobacco: WO 99/31085; Advanced Medicine: WO 99/63929. In The following documents from Bayer AG describe substances which inhibit the release of ApoB-100-associated lipoproteins; these substances are MTP inhibitors: EP-A 716 082, EP-A 719 763, EP-A 705 831, EP-A 753 517, EP-A 765 878, EP-A 764 647, EP-A 779 279, EP-A 779 276, EP-A 799 828, EP-A 802 198, EP-A 802 186, EP- A 802 188, EP-A 802 192,

EP-A 802 197. The disclosure of the aforementioned documents disclosing MTP inhibitors is hereby fully incorporated by reference.

Some examples of the MTP inhibitors described there are listed below:

Preferred MTP inhibitors which can be used according to the invention are: Compounds of the general formula (AI)

in which

Rl and R ^ together with the double bond connecting them together a phenyl or pyridyl ring or a ring of the formula form what

R denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R3 and R ^ together with the double bond connecting them form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical,

where all ring systems listed under Rl / R ^ and RNR4 optionally up to 3 times the same or different by halogen, trifluoromethyl, carboxy, hydroxy, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms are substituted, which in turn can be substituted by hydroxy or by straight-chain or branched alkoxy having up to 4 carbon atoms,

D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms or straight-chain or branched alkyl having up to 12 carbon atoms,

E represents the -CO or -CS group,

L represents an oxygen or sulfur atom or represents a group of the formula -NR ⁹ ,

wherein

R ^{9 is} hydrogen or straight-chain or branched alkyl with up to 6 Carbon atoms, which is optionally substituted by hydroxy or phenyl,

R ^ represents phenyl or a 5- to 7-membered saturated or unsaturated heterocycle with up to 3 heteroatoms from the series S, N and or O,

where the cycles are optionally up to 3 times the same or different by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which are optionally substituted is substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or the cycles are optionally substituted by a group of the formula -OR "or - RHR12,

wherein

RIO is hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms,

RU or Rl2 are the same or different and are phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms

or straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula -NR ¹³ R ¹⁴ ,

wherein Rl3 and Rl4 are identical or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

R6 represents hydrogen, carboxy or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms,

or represents straight-chain or branched alkyl having up to 6 carbon atoms, optionally by hydroxyl or by a group of the formula

-O-CO-R ^{15 is} substituted,

wherein

R ¹ denotes phenyl which is optionally substituted up to 3 times identically or differently by halogen, hydroxyl or by straight-chain or branched alkyl having up to 5 carbon atoms,

or straight-chain or branched alkyl or alkenyl each having up to 22 carbon atoms, which may be replaced by a

Group of the formula -OR16 are substituted,

wherein

R * 6 denotes hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl with up to 6 carbon atoms,

R represents hydrogen or

R6 and R? together represent the group of the formula = O, or the general formula (A2)

in which

for a rest of the formula

embedded image in which

L and M are the same or different and

Hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl having 3 to 6 carbon atoms, hydroxy, phenyl or straight-chain or are branched alkyl, alkoxycarbonyl or alkoxy each having up to 6 carbon atoms,

Q represents a nitrogen atom or the -CH group,

T represents a group of the formula -SO2 or -CO or an oxygen or sulfur atom,

V represents an oxygen or sulfur atom,

R5, R6, R7 and R8 are the same or different and

Is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which are optionally substituted by halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,

R ⁹ trifluoromethyl, benzyl or a 5- to 7-membered, optionally benzocondensed heterocycle with up to 3 heter atoms from the

Row S, N and / or O means, which is optionally substituted up to 3 times identically or differently by halogen, phenyl, hydroxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or a group of the formula -S (O) _a -R ^ means

wherein

a represents a number 0, 1 or 2,

IO means straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be replaced by straight-chain or branched acyl having up to 6 carbon atoms. Substance atoms or are substituted by aryl or aroyl each having up to 10 carbon atoms, which in turn can be substituted up to 2 times the same or different by halogen, trifluoromethyl or by straight-chain or branched acyl having up to 5 carbon atoms, or aryl with 6 to 10 Is carbon atoms which is optionally substituted by halogen, hydroxy, trifluoromethyl or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,

D and E are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,

Z represents an oxygen or sulfur atom,

Rl stands for cycloalkyl with 3 to 10 carbon atoms or for straight-chain or branched alkyl with 1 to 10 carbon atoms, or stands for phenyl which may optionally be identical or different up to 2 times through halogen, nitro, cyano, hydroxy, straight-chain or branched alkyl or Alkoxy is each substituted with up to 4 carbon atoms,

R ^ represents hydrogen or straight-chain or branched alkyl with up to 3

Carbon atoms,

R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle up to 3 heteroatoms from the series S, N and / or O, which are optionally substituted up to 3 times identically or differently by halogen, nitro, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,

R4 represents hydrogen or a group of the formula -CH2-OH or CH2O-CO- R ¹¹ ,

wherein

U is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, cyano or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,

or the general formula (A3)

in which

D for a residue of the formula

stands in what T represents a nitrogen atom or the -CH group,

R6, R7, R10 and R11 are the same or different and

Is hydrogen, trifluoromethyl, halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,

5, R8 and R ^{9 are the} same or different and

Is hydrogen, cycloalkyl with 3 to 6 carbon atoms, phenyl, straight-chain or branched alkoxycarbonyl with up to 6 carbon atoms or straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by halogen,

or in the case that T represents a nitrogen atom, R ^ can also mean benzyl,

E and L are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,

Rl stands for cycloalkyl with 3 to 10 carbon atoms or for straight-chain or branched alkyl with 1 to 10 carbon atoms, or for phenyl, which may optionally be identical or different up to 2 times through halogen, cyano, hydroxy, straight-chain or branched alkyl or alkoxy up to 4 carbon atoms is substituted,

R ^ represents hydrogen or straight-chain or branched alkyl with up to 3

Carbon atoms, R3 represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O, which are optionally substituted up to 3 times identically or differently by halogen, nitro, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,

R4 represents hydrogen or a group of the formula -CH2-OH or CH2O-CO- R ¹² ,

embedded image in which

Rl2 is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, cyano or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,

or the general formula (A4)

in which

A for a residue of the formula stands,

wherein

R ³ , R4 ₅ R6 and R ^ are the same or different and

Is hydrogen, cycloalkyl having 3 to 7 carbon atoms or aryl having 6 to 10 carbon atoms, or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally substituted by halogen, hydroxy or aryl having 6 to 10 carbon atoms,

T, V, X and Y are the same or different and represent an oxygen or sulfur atom,

R5 and R8 are the same or different and

Hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally by cycloalkyl having 3 to 8 carbon atoms, or by a 5- to 6-membered, aromatic, optionally benzo-condensed heterocycle are substituted by up to 3 heteroatoms from the series S, N and / or O, or by aryl having 6 to 10 carbon atoms, the cycles in turn being identical or different up to 3 times by a 5- to 6-membered aromatic heterocycle up to 3 heteroatoms from the series S, N and / or O, or by phenyl, benzyl, halogen, hydroxy, carboxyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each having up to 6 carbon atoms, can be substituted, or

Aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-fused

Heterocycle with up to 3 heteroatoms from the series S, N and / or O, which are optionally up to 3 times the same or different by halogen, phenyl, trifluoromethyl, hydroxy, carboxyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl with each up to 6

Carbon atoms or are substituted by a group of the formula - (CO) _a -NR ⁹ R ¹⁰ ,

wherein

a number means 0 or 1,

R ⁹ and RIO are the same or different and

Is hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms,

Rl represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be by cycloalkyl having 3 to 6

Carbon atoms, phenyl or by a 5- to 6-membered aromatic Heterocycle are substituted with up to 3 heteroatoms from the series S, N and / or O, or represents phenyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where the ring systems optionally up to 3 times the same or different by halogen,

Phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms, hydroxyl or substituted by a group of the formula -NRl 1R 2,

wherein

Rl 1 and Rl2 have the meaning given above of R ⁹ and RIO and are the same or different with this,

L represents an oxygen or sulfur atom,

R ² for mercapto, hydroxy, straight-chain or branched alkoxy having up to 8 carbon atoms or for the group of the formula

R 14

-NR ¹³ ^ H ^> R 15,

wherein

Rl-3 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R ¹⁴ denotes hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, R15 is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxy,

or the general formula (A5)

in which

A, D, E, G, L and M are the same or different and represent hydrogen, halogen, trifluoromethyl, carboxy, hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms which in turn can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,

Rl and R ^{2 are the} same or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represent phenyl, which is optionally substituted by Halogen or trifluoromethyl is substituted, or l and R ² together with the carbon atom form a 4-8 membered cycloalkyl ring

and

R ^{3 represents} phenyl, which is optionally up to 3 times identical or different by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms. lenstoffatomen is substituted, which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and or is optionally substituted by a group of the formula -OR ⁴ or - R ^ R ^Ö ,

wherein

R ⁴ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms,

R5 or R6 are identical or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or mean straight-chain or branched acyl having up to 8 carbon atoms, which is optionally replaced by a group of the formula -

NR ⁷ R ^{8 is} substituted,

embedded image in which

R ⁷ and R8 are the same or different and

Hydrogen or straight-chain or branched acyl with up to 8 carbon atoms mean

or the general formula (A6)

in which

R * and R ^{2 are} identical or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represent phenyl, which is optionally is substituted by halogen or trifluoromethyl, or

Rl and R ² together with the carbon atom form a 4-8 membered cycloalkyl ring and

R ^{3 represents} phenyl, which is optionally up to 3 times identical or different by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 Carbon atoms, which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or is optionally substituted by a group of the formula -OR ⁴ or -NR ^ RO,

wherein

R5 or R6 are the same or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or mean straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula - NR ⁷ R ⁸ .

wherein

R ⁷ and R ^{8 are the} same or different and

Is hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

optionally in an isomeric form and their salts. The compounds of the general formula (AI) are of great interest as MTP inhibitors; the compounds of Examples 1 to 119 below are also of particular importance, in particular the compounds of Examples 92 to 119, very particularly the compounds of Examples 48 and 80 , (2S) -2-Cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2- (IR) -hydroxy- l-ρhenyl-ethyl) -acetamide (Example 48) and (2S) -2-cycloρentyl-2- [4- (2,4-dimethyl-pyrimido [l, 2-a] indol-10-ylmethyl) -ρhenyl] -N- (2- (IR) -hydroxy-1-phenyl-ethyl) -acetamide (Example 80).

In the context of the present invention, the use of the physiologically acceptable salts of the MTP inhibitors listed above is also claimed. Physiologically acceptable salts of the compounds according to the invention are e.g. Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts of the MTP inhibitors listed above can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, and also ammonium salts derived from ammonia, or organic amines, such as ethylamine, di- or triethylamine, ethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The MTP inhibitors according to the invention can be in stereoisomeric forms, which are either like image and mirror image (enantiomers), or which are not like image and

Mirror image (diastereomers) behave, exist. The invention relates to both Enantiomers as well as diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.

Because of their effect, especially on the ppTRL plasma levels, the

MTP inhibitors are used for the prophylaxis and treatment of diseases that are associated with increased plasma levels of ppTRL and its remnants. The following may be mentioned as: diseases of the cardiovascular system, such as As atherosclerosis or myocardial infarction, further such diseases that can be attributed to neuronal degeneration and are associated with disorders in the metabolism of lipoproteins or lipids, z. B. dementia or Alzheimer's disease. Disorders of carbohydrate metabolism, such as Diabetes or IGT (impaired glucose tolerance), associated with elevated and prolonged ppTRL levels. Therefore, these diseases can also be treated with MTP inhibitors.

The lowering of the ppTRL also leads to a reduced formation of its degradation products, the remnants. Since the ppTRL and the remnants are associated with ApoB-48, the MTP inhibitors not only lower the ppTRL but also the remnants and ApoB-48 or ApoB-48-associated lipoproteins.

Preferred MTP inhibitors are the compounds listed in the following table:

Particularly preferred MTP inhibitors are the compounds listed in the table below

According to the invention, the MTP inhibitors can be used, for example, for the treatment and / or prophylaxis of diseases which are particularly associated with disorders of the postprandial lipoprotein or lipid metabolism. Such disorders are to be understood here: accumulation and / or prolonged residence time of ppTRL, chylomicrons and cholesterol are sufficient remnants in the plasma as well as increased or prolonged postprandial plasma lipid levels.

Diseases associated with this are e.g. in addition to cardiovascular diseases, primarily neurodegenerative deficiency symptoms. Neuropathological changes in the brain and their consequences are particularly noteworthy here: neurodegeneration such as Alzheimer's disease, progressive brain atrophy, morphological changes in the brain during normal aging (presenile dementia), cortical cholinergic system disorders, memory disorders, orientation disorders, aphasia, word finding disorders, agnosia, apraxia, euphoria, depression, Binswanger disease, pick Niemann disease

Pick's disease, cerebrovascular insufficiency.

Examples of cardiovascular diseases which are associated with disorders of the postprandial lipoprotein or lipid metabolism are: arteriosclerosis, stroke, angina, diseases of the coronary arteries, in particular the arterial coronary arteries, heart failure, primary and secondary myocardial infarction, pathological changes in the vascular wall, disorders of blood circulation and microcirculation.

Likewise, carbohydrate metabolism disorders are associated with elevated and prolonged ppTRL levels, such as Insulin resistance, IGT (impaired glucose tolerance), diabetes, especially type 11 diabetes, metabolic syndrome. Therefore, these diseases can also be treated with MTP inhibitors.

It may be advantageous to use the MTP inhibitors in combination with other suitable active ingredients. The following may be mentioned: acetylcholinesterase Inhibitors, for example metrifonate, tacrine and donepezil, substances which inhibit the abnormal cleavage of the amyloid precursor protein, estrogens such as for example estradiol, synthetic estrogen receptor agonists, nitamine E,

The targeted reduction in plasma ppTRL levels also leads to an improved tolerance of the MTP inhibitors. Especially through lower ones

Dosages avoid side effects that can occur at high dosages. Furthermore, no or only minor mechanism-related effects in the liver are to be expected at low doses; consequently, no mechanism-related side effects can be induced in the liver.

The MTP inhibitors are preferably used in human medicine, but are also suitable for veterinary medicine, especially for the treatment of mammals.

The combinations according to the invention can be administered parenterally or, preferably, orally.

The MTP inhibitors can be converted into the customary formulations in a known manner, which can be liquid or preferably solid formulations. Examples are tablets, dragees, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices.

When administered orally, the MTP inhibitors are preferably used in doses of 0.01 to 20 mg / kg, in particular 0.1 to 5 mg of active ingredient per kg of body weight of the patient.

It may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place. In some cases, it may be sufficient to make do with less than the aforementioned minimum quantity, while in others it is sufficient upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

The solid oral dosage forms listed here are manufactured according to the general standard procedures. Ingredients are those that are pharmaceutically accepted and are physiologically harmless, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugar (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders ( eg polyvinylpyrrolidone, gelatin, starch and cellulose derivatives), as well as all other auxiliaries which are required for the preparation of pharmaceutical formulations of the desired properties, for example Lubricants (magnesium stearate), e.g. Disintegrants (e.g. cross-linked polyvinyl pyrrolidone, sodium carboxymethyl cellulose), e.g. Wetting agents (e.g. sodium lauryl sulfate) e.g. Retardants (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. Stabilizers, e.g. Flavors, e.g. Color pigments.

Liquid formulations are also produced by standard methods with pharmaceutically customary auxiliaries and contain the active ingredient or the two active ingredients either dissolved or suspended. Typical application volumes of these pharmaceutical preparations are 1 to 10 ml.Examples of auxiliaries in these liquid formulations are: solvents (e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglcerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium lauryl sulfate) ), as well as other auxiliary substances that are required for the production of pharmaceutical formulations with the desired properties, eg viscosity increasing agents, e.g. pH corrections, e.g. Sweeteners and flavors, e.g. Antioxidants, e.g. Stabilizers, e.g. Preservative.

The main components of the capsule formulations are, for example, gelatin or hydroxypropylethylcellulose. Pharmaceutical auxiliaries, as are known to the person skilled in the art, are also described, for example, in the following manual: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, PJ, American Pharmaceutical Association, Washington, 2nd edition 1994.

example

Long-term feeding trial with ApoE knockout mice

ApoE knockout mice were on a fatty diet (0.15% cholesterol,

21.4% crude fat, 19% casein; The treated group was administered the compound according to Example 48 with the feed in a proportion of 5 ppm, while the control group received the feed without active ingredient. After 13 months, over half of the untreated mice were dead during 23 out of 25 animals were still alive in the treated group.

It is known from the literature that the ApoE knockout mice used die from heart attacks and neuronal degeneration symptoms [Caligiuri, G., et al., Proc. Natl. Acad. Be. USA, 96: 6920-6924 (1999); Walker, L.C. Am.J.Pathol., 151, (5), 1371-137781997)].

Claims

Patentansprfiche

1. Use of MTP inhibitors for the production of medicaments for lowering the ppTRL plasma level.

2. Use of MTP inhibitors for the manufacture of medicaments for reducing intestinal cholesterol absorption.

3. Use according to claim 1 or 2, characterized in that the MTP inhibitor is used in a concentration at which at most a slight decrease in the fasting values of the plasma triglycerides or the plasma cholesterol is caused.

4. Use according to one of claims 1 to 3, characterized in that a compound of general is used as the MTP inhibitor

Formula (AI)

in which

R1 and R2 together with the double bond connecting them together form a phenyl or pyridyl ring or a ring of the formula

^{Form 0} , embedded image in which

R ^{8 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R3 and R ^{4 together} with the double bond connecting them form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical,

where all ring systems listed under RI / R ^ and R3 / R4 optionally up to 3 times the same or different by halogen, trifluoromethyl, carboxy, hydroxy, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl are substituted with up to 6 carbon atoms, which in turn by

Hydroxy or can be substituted by straight-chain or branched alkoxy having up to 4 carbon atoms,

E represents the -CO or -CS group,

L represents an oxygen or sulfur atom or a group of

Formula -NR ⁹ stands,

wherein

R ^{9 is} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally by Hydroxy or phenyl is substituted,

R5 represents phenyl or a 5- to 7-membered saturated or unsaturated heterocycle with up to 3 heteroatoms from the series S, N and / or O,

where the cycles are optionally substituted up to 3 times identically or differently by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or alkoxycarbonyl, each having up to 6 carbon atoms, and / or the cycles, if appropriate, by a group of the formula -

OR ¹⁰ or -NR ⁿ R ^{12 are} substituted,

wherein

RIO is hydrogen or straight-chain or branched alkyl or

Alkenyl each having up to 6 carbon atoms,

RU or Rl2 are the same or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms

or straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula -NR13R14,

embedded image in which Rl3 and Rl are identical or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

or represents straight-chain or branched alkyl having up to 6 carbon atoms, which may be by hydroxyl or by a

Group of the formula -O-CO-R 5 is substituted,

wherein

Rl5 is phenyl which is optionally substituted up to 3 times identically or differently by halogen, hydroxyl or by straight-chain or branched alkyl having up to 5 carbon atoms,

or straight-chain or branched alkyl or alkenyl each having up to 22 carbon atoms, which are optionally substituted by a group of the formula -OR ^,

embedded image in which

R ^ stands for hydrogen or R ° ^" and R ^ together represent the group of the formula = O,

or the general formula (A2)

in which

for a rest of the formula

stands,

wherein L and M are the same or different and

Are hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl having 3 to 6 carbon atoms, hydroxy, phenyl or straight-chain or branched alkyl, alkoxycarbonyl or alkoxy each having up to 6 carbon atoms,

Q represents a nitrogen atom or the -CH group,

T represents a group of the formula -SO2 or -CO or an oxygen or sulfur atom,

V represents an oxygen or sulfur atom,

R5, R6 ₅ R7 and R ^{8 are the} same or different and are hydrogen, straight-chain or branched alkyl with up to 6

Are carbon atoms, benzyl or phenyl, which are optionally substituted by halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,

R ⁹ trifluoromethyl, benzyl or a 5- to 7-membered, optionally benzocondensed heterocycle with up to 3

Heteratoms from the series S, N and or O means, which is optionally substituted up to 3 times identically or differently by halogen, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or a group of the formula -S (O) _a -R ^ means

wherein a represents a number 0, 1 or 2,

RIO means straight-chain or branched alkyl or alkenyl, each having up to 8 carbon atoms, which may be straight-chain or branched

Acyl with up to 6 carbon atoms or with aryl or aroyl with up to 10 carbon atoms each, which in turn can be substituted up to 2 times by the same or different means by halogen, trifluoromethyl or by straight-chain or branched acyl having up to 5 carbon atoms, or Aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,

Z represents an oxygen or sulfur atom,

Rl stands for cycloalkyl with 3 to 10 carbon atoms or for straight-chain or branched alkyl with 1 to 10 carbon atoms, or stands for phenyl which may optionally be identical or different up to 2 times through halogen, nitro, cyano, hydroxy, straight-chain or branched alkyl or Alkoxy is each substituted with up to 4 carbon atoms, R ^{2 represents} hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R ^ represents hydrogen or straight-chain or branched alkyl with up to 5

Represents carbon atoms, or stands for cycloalkyl with 3 to 7 carbon atoms, or for phenyl or for a 5- to 7-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which optionally represents up to 3- are identical or differently substituted by halogen, nitro, phenyl, hydroxy or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,

R ^{4 represents} hydrogen or a group of the formula -CH2-OH or

CH ₂ O-CO-R ⁿ is

wherein

Rl 1 is hydrogen, straight-chain or branched alkyl having up to 8

Is carbon atoms or phenyl which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, cyano or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,

or the general formula (A3)

in which for a rest of the formula

stands where

T represents a nitrogen atom or the -CH group,

R6, R7, RIO and R * 1 are identical or different and are hydrogen, trifluoromethyl, halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,

R5, R ⁸ and R ^{9 are} identical or different and are hydrogen, cycloalkyl having 3 to 6 carbon atoms,

Phenyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen,

or in the case that T represents a nitrogen atom, R ^ can also mean benzyl,

E and L are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, R * represents cycloalkyl having 3 to 10 carbon atoms or straight-chain or branched alkyl having 1 to 10 carbon atoms, or represents phenyl which may be up to 2 times identical or different by halogen, cyano, hydroxyl, straight-chain or branched alkyl or alkoxy is each substituted with up to 4 carbon atoms,

R ^{2 represents} hydrogen or straight-chain or branched alkyl with up to 3

Carbon atoms,

R3 represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which are optionally substituted up to 3 times identically or differently by halogen, nitro, phenyl, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms,

R ^{4 represents} hydrogen or a group of the formula -CH2-OH or CH ₂ O-CO-R ¹² ,

wherein

R12 is hydrogen, straight-chain or branched alkyl with up to 8

Carbon atoms or phenyl means that optionally up to 3 times the same or different by halogen, hydroxy,

Cyano or straight chain or branched alkyl or alkoxy is each substituted with up to 4 carbon atoms,

or the general formula (A4)

in which

A for a residue of the formula

stands,

embedded image in which

R3, R ⁴ , R6 and R ^{7 are the} same or different and

T, V, X and Y are the same or different and represent an oxygen or sulfur atom, R ^ and R ^{8 are the} same or different and

Are hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which are optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by a 5- to 6-membered aromatic optionally benzocondensed heterocycle with up to 3 heteroatoms from the series S, N and / or O, or by aryl

10 are substituted with 6 to 10 carbon atoms, the cycles in turn up to 3 times the same or different by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, or by phenyl , Benzyl, halogen,

15 hydroxy, carboxyl or can be substituted by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or aryl having 6 to 10 carbon atoms or a 5- to

20 7-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, which are optionally up to 3 times the same or different by halogen, phenyl, trifluoromethyl, hydroxy, carboxyl

25 or by straight-chain or branched alkyl,

Alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or substituted by a group of the formula - (CO) _a -NR ⁹ R ¹⁰ ,

30 in which a represents a number 0 or 1,

R ⁹ and RIO are the same or different and

Hydrogen, phenyl or straight-chain or branched alkyl or acyl, each with up to

5 carbon atoms mean

Rl represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, optionally by cycloalkyl having 3 to 6 carbon atoms, phenyl or by a 5- to 6-membered aromatic heterocycle are substituted with up to 3 heteroatoms from the series S, N and / or O, or represents phenyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, where the Ring systems optionally substituted up to 3 times, identically or differently, by halogen, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms, hydroxy or by a group of the formula -NRUR ² ,

wherein

R ¹ 1 and R ^{2 have} the meaning of R ⁹ and R ⁱ⁰ given above and are the same or different with it,

L represents an oxygen or sulfur atom,

stands,

wherein

R13 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

Rl ⁴ denotes hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O,

R15 is hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally by

Hydroxy is substituted,

or the general formula (A5)

in which

Rl and R ² together with the carbon atom form a 4-8 membered cycloalkyl ring

and

R ^ is phenyl, which may be up to 3 times the same or variously substituted by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or Alkoxycarbonyl, each having up to 6 carbon atoms, and or optionally substituted by a group of the formula -OR ⁴ or - NR ⁵ R ⁶ ,

embedded image in which

R5 or R6 are the same or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or mean straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula -NR ^ R ⁸ .

embedded image in which

R ^ and R ^{8 are the} same or different and

Is hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

or the general formula (A6)

in which

Rl and R ^{2 are the} same or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or represent phenyl, which is optionally substituted by Halogen or trifluoromethyl is substituted, or

R ¹ and R ² together with the carbon atom form a 4-8 membered cycloalkyl ring

and

R3 is phenyl, which may be up to 3 times the same or variously substituted by nitro, carboxy, halogen, cyano or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, carboxy or by straight-chain or branched alkoxy or Alkoxycarbonyl, each having up to 6 carbon atoms, and or optionally substituted by a group of the formula -OR ⁴ or - NR ⁵ R ⁶ ,

wherein

5 or R ^ are identical or different and represent phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or mean straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula -NR ^ R ⁸ is

embedded image in which

R? and R ^{8 are the} same or different and

Is hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

optionally in an isomeric form and their salts.

5. Use according to one of claims 1 to 4, characterized in that a compound of Examples 1-119 is used as the MTP inhibitor.

6. Use according to one of claims 1 to 4, characterized in that a compound of Examples 92-119 is used as the MTP inhibitor.

7. Use according to claim 5, characterized in that Example 48 or 80 is used as MTP inhibitor.

8. Use according to one of claims 1 to 7 for the manufacture of medicaments for the prophylaxis and / or control of cardiovascular diseases.

9. Use according to one of claims 1 to 7 for the production of

Medicines for the prophylaxis and / or control of neurodegenerative deficiency symptoms.

10. Use according to one of claims 1 to 7 for the manufacture of medicaments for the therapy of insulin resistance, IGT, diabetes, in particular

Type π diabetes.

11. Use according to one of claims 1 to 7 for the manufacture of medicaments for the prophylaxis and / or control of the metabolic syndrome.

12. Use according to one of claims 1 to 7 for the manufacture of medicaments for the prophylaxis and / or control of obesity.