WO2001000183A2

WO2001000183A2 - COMBINATION OF MTP INHIBITORS AND HMG-CoA REDUCTASE INHIBITORS AND THE USE THEREOF IN MEDICAMENTS

Info

Publication number: WO2001000183A2
Application number: PCT/EP2000/005410
Authority: WO
Inventors: Rudi Grützmann; Ulrich Müller; Hilmar Bischoff
Original assignee: Bayer Aktiengesellschaft
Priority date: 1999-06-25
Filing date: 2000-06-13
Publication date: 2001-01-04
Also published as: EP1196194A2; AU5680900A; UY26218A1; SV2004000109A; GT200000099A; AR028996A1; WO2001000183A3; CA2376881A1; JP2003503342A; DOP2000000022A; DE19929065A1; PE20010302A1

Abstract

The invention relates to the use of a combination consisting of at least one selected MTP inhibitor (constituent A) and of at least one HMG-CoA reductase inhibitor (constituent B) for fighting cardiovascular diseases. The invention also relates to medicaments containing this combination and to the production thereof.

Description

Combination of MTP inhibitors and HMG-CoA reductase inhibitors and their use in drugs

The invention relates to the use of a combination of at least one selected MTP inhibitor (component A) and an HMG-CoA reductase inhibitor (component B) for combating cardiovascular diseases, medicaments containing this combination and their preparation.

The compounds of component A have already been described as ApoB secretion inhibitors in publications EP 705 831, EP 779 279, EP 779 276, EP 802 198 and

EP 799 828. However, there is no evidence of a combination with HMG-CoA reductase inhibitors.

HMG-CoA reductase inhibitors are a class of lipid-lowering agents well known to the person skilled in the art. Statins preferred as HMG-CoA reductase inhibitors in the context of this invention are e.g. described in EP 325 130 or US 5,177,080.

Combinations of MTP inhibitors with other cholesterol-lowering compounds are known from PCT WO 98/31366 and WO 98/03069. The MTP inhibitors specifically mentioned there, however, clearly differ in their chemical

Structure of the selected MTP inhibitors claimed in the present invention.

The present invention relates to the use of a combination of at least one MTP inhibitor as component A 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 ^u in which

R8 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R ^ 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 R ^ / R ^ 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 are substituted by straight-chain or branched alkyl having up to 6 carbon atoms, 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 a group of the formula

-NR ⁹ stands, embedded image in which

R is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which may be 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 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 is 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 -NR ¹ R ¹² ,

embedded image in which

R ^Ϊ O 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 with up to 8 carbon mean atoms which is optionally substituted by a group of the formula -NR ¹³ R ¹⁴ ,

wherein

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

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, which is optionally substituted by hydroxyl or by a group of the formula -O-CO-R ¹⁵ ,

embedded image in which

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 are optionally substituted by a group of the formula -OR ¹ ^,

embedded image in which

Rl6 is hydrogen, benzyl, trϊphenylmethyl or straight-chain or branched acyl having up to 6 carbon atoms, R ^ stands for hydrogen or

R6 and R? together represent the group of the formula = O,

or the general formula (A2)

in which

A for a residue of the formula

stands,

embedded image in which L and M are the same or different and

Hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl with 3 to

6 carbon atoms, hydroxy, phenyl or straight-chain or branched alkyl, alkoxycarbonyl or alkoxy, each with up to 6

Carbon atoms mean

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 is} trifluoromethyl, benzyl or a 5- to 7-membered, optionally benzocondensed heterocycle with up to 3 heteratoms from the series S, N and / or O, which may be up to 3 times the same or different by halogen, phenyl, hydroxy or by straight-chain or branched alkyl or alkoxy, each with up to 4

Is substituted carbon atoms, or denotes a group of the formula -S (O) _a -R ^,

embedded image in which

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 by straight-chain or branched acyl having up to 6 carbon atoms or by aryl or aroyl each having up to 10

Carbon atoms are substituted, which in turn may 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 having 6 to 10 carbon atoms, optionally 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,

R ^{1 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, hydroxyl, straight-chain or branched alkyl or alkoxy is substituted in each case with up to 4 carbon atoms,

R ^{2 represents} hydrogen or straight-chain or branched alkyl having 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 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, 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 CH2O-CO-

R ¹ 1 stands.

Wonn

R ^{1 1 is} hydrogen, straight-chain or branched alkyl with 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

D for a residue of the formula

stands where

T represents a nitrogen atom or the -CH group,

R ", R ^, R ¹ ^ and R 1 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,

R- \ 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,

represents cycloalkyl having 3 to 10 carbon atoms or straight-chain or branched alkyl having 1 to 10 carbon atoms, or represents phenyl which is optionally substituted up to 2 times identically or differently by halogen, cyano, hydroxy, straight-chain or branched alkyl or alkoxy each having 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 CH2O-CO- R ¹ ,

wherein

Rl2 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, each with up to 4

Carbon atoms is substituted,

or the general formula (A4)

in which

for a rest of the formula

stands.

embedded image in which

R ³ , R ⁴ , 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

Is 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 may be replaced by cycloalkyl having 3 to 8 carbon atoms atoms, or by a 5- to 6-membered, aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, or by aryl with 6 to 10 carbon atoms, the cycles in turn being substituted 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, hydroxy, carboxyl or by straight-chain or branched alkyl, Alkoxy or alkoxycarbonyl can each be substituted with up to 6 carbon atoms, 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, hydroxyl, carboxyl or by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by a group of the formula - (CO) _a -NR ⁹ R ¹⁰ ,

embedded image in which

a represents a number 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,

R ^{1 represents} hydrogen or cycloalkyl having 3 to 8 carbon atoms, or 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 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, hydroxy or by one

Group of the formula -NR! R ^{12 are} substituted,

embedded image in which

Rl 1 and R ^{12 have} the meaning given above of R ⁹ and R ^ 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 with up to 8

Carbon atoms or for the group of formula

, 14

stands, Wonn

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

R * 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,

R! 5 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

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

and

R3 represents phenyl, which is 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 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 ^ R ",

embedded image in which

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

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 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 ,

Wonn

R? and R8 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

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,

R ¹ 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 represents phenyl which is optionally 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 through nitro, carboxy, halogen, cyano or through straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or through straight-chain or branched alkyl with 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 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 R ^{8 are} identical or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

optionally in an isomeric form and their salts

with HMG-CoA reductase inhibitors as component B in prophylaxis and

Treatment of cardiovascular diseases, preferably those cardiovascular diseases associated with metabolic diseases or deficits, e.g. Disorders of fat metabolism or carbohydrate metabolism, e.g. Diabetes.

The invention further relates to pharmaceutical preparations containing these combinations of components A and B and their preparation.

The compounds of the general formula (AI) are of great interest as combination partners of component A, and the compounds of examples 1 to 119 below, in particular the compounds of examples 92 to 119, very particularly the compounds of the examples, are also of particular importance 48 and 80, (2S) -2-cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2- (IR) -hydroxy-l-phenyl-ethyl) -acetamide (Example 48) and (2S) -2-cycloρentyl-2- [4- (2,4-dimethyl-pyrimido [1,2-a] indol-10-ylmethyl) phenyl] -

N- (2- (IR) -hydroxy-l-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. Particularly preferred are, for example, 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, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The MTP inhibitors and HMG-CoA reductase inhibitors according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers and also diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.

The combinations of the selected MTP inhibitors according to the general formulas (AI) - (A6) as component A and HMG-CoA reductase inhibitors as component (B) is new.

It has now been found that the combinations according to the invention have unexpected valuable pharmacological properties, in particular they are suitable for the prophylaxis and treatment of diseases of the cardiovascular system which are associated with metabolic disorders. HMG-CoA reductase inhibitors are generally within the scope of the invention for all classes of substances listed in the prior art under this term. The abbreviation "HMG-CoA" stands for "3-hydroxy-3-methylglutaryl-coenzyme A". Preference is given to statins as described, for example, in EP 247 633, US 5 006 530, EP 33 538, US 4346 227, EP 22 478 or EP 114 027.

May be mentioned:

Atorvastatin (commercially available under the name Lipitor® from Parke-

Davis);

• Cerivastatin (commercially available under the name Lipobay® or Baycol® from Bayer);

• fluvastatin (commercially available under the name Lescol® from Novartis); Lovastatin (commercially available under the name Mevacor® from Merck);

• Pravastatin (commercially available under the name Lipostat® from Bristol-Myers Squibb);

• Simvastatin (commercially available under the name Zocor® from Merck);

• Itavastatin (also called "Nisvastatin"; NK-104; systematic name: [S- [R *, S * - (E)]] - 7- [2-Cycloproρyl-4- (4-fluo henyl) -3- quinolinyl] -3,5-dihydroxy-6-heptenoic acid);

• Dalvastatin;

• mevastatin;

• dihydrocompactin; • Compactin; and

• (+) - (3R, 5S) -Bis- (7- (4- (4-fluoφhenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl) - 3,5-dihydroxy-6 (e) heptenoic acid.

Statins are usually used as lactones (see, for example, lovastatin), esters or as carboxylic acids or as salts of the carboxylic acid (see, for example, cerivastatin sodium). According to the invention, the statins can be used in all suitable forms, ie in the form of the respective salts, hydrates, alcoholates, esters, lactones and tautomers.

Atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, itavastatin, simvastatin and (+) - (3R, 5S) -Bis- (7- (4- (4-fluoφhenyl) -6-isopropyl-2 - (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl) -3,5-dihydroxy-6 (E) -heptenoic acid and their respective salts, hydrates, alcoholates, esters, lactones and tautomers.

Of these, atorvastatin and in particular cerivastatin and their respective salts, hydrates, alcoholates, esters, lactones and tautomers are very particularly preferred.

For further details on the aforementioned statins, reference is made to the

Treatises in Drugs of the Futur e 1994, 19 (6), pages 537 - 541 and 1995, 20 (6), page 611 and 1996, 21 (6), page 642, the respective contents of which are included in their entirety by reference.

With regard to the HMG-CoA reductase inhibitors, the term “salt” means in the

According to the present invention, physiologically acceptable salts of the compounds in question: Salts with mineral acids, carboxylic acids or sulfonic acids, in particular 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 or mixed salts thereof. However, they can also be salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmoφholin, dihydro-abietylamine, 1-ephenamine or methyl-piperidine and mixed salts thereof. Examples of statin salts which can be used according to the invention are fluindostatin (the monosodium salt of fluvastatin); the monopotassium salt and the calcium salt of itavastatin; as well as the calcium salt of (+) - (3R, 5S) -Bis- (7- (4- (4-fluoφhenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidine) 5-yl) -3,5-dihydroxy-6 (E) - heptenoic acid ("ZD 4522" or "S 4522" from Shionogi or AstraZeneca). Further examples of statin salts which can be used according to the invention are the monosodium and the Monopotassium salts and the calcium salts of cerivastatin, atorvastatin and pravastatin The monosodium salt of cerivastatin ("cerivastatin sodium") is very particularly preferably used.

Further preferred HMG-CoA reductase inhibitors are described in EP-A-0 325 130 and in EP-A-0-491 226, both in the name of Bayer AG, the content of which is hereby incorporated by reference. EP-A-0 325 130 relates to substituted pyridines, and EP-A-0-491 226 describes substituted pyridyl-dihydroxyheptenoic acid derivatives and their salts, including in particular the cerivastatin particularly preferred according to the invention (claim 6 of EP-A-0 491 226).

Also preferred according to the invention are those mentioned in WO-A-99/11263

Statins, the disclosure of which is incorporated by reference.

Likewise preferred according to the invention are the HMG-CoA reductase inhibitors, which are described in Bioorganic & Medicinal Chemistry, Vol. 2, pages 437-444 (1997), the disclosure of which is hereby fully incorporated by reference.

A further overview of HMG-CoA reductase inhibitors can be found in pharmacy in our time, 28th year, No. 3, pages 147-152 (1999).

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

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

The combinations according to the invention show a broad and varied spectrum of action. They can be used, for example, for the treatment and / or prophylaxis of arteriosclerosis, stroke, angina, diseases of the coronary arteries of the heart, especially arterial coronary arteries, heart failure, primary and secondary myocardial infarction, pathological changes in the vascular wall, circulatory disorders, disorders of microcirculation, proliferation smooth muscle cells, lipid metabolism disorders with increased concentration of lipoproteins in the serum and possibly a shift in the lipoprotein content, increased serum lipids, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, increase in both serum cholesterol and serum triglyceride combined with increased VLDL (very low density lipoprotein ) and increase in plasma chylomicrons, insulin resistance, IGT (impaired glucose tolerance), diabetes, non-insulin-dependent diabetes mellitus (= type 2 diabetes), hyperglycaemia, metabolic disorders such as lipid meta disorders bolism, deficiency of acid lipase, storage diseases, especially fat storage diseases,

Phytosterolaemia, high blood pressure, osteoporosis, obesity, syndrome X, thrombosis, pancreatitis, constipation (constipation), brain dysfunction, cerebrovascular insufficiency, cerebral circulatory disorders, apoplexy, transient ischemic attacks (TLA) and fainting.

Of particular interest is the treatment and prophylaxis of diseases that are influenced or caused by more than one risk factor, e.g. Arteriosclerosis, diseases of the coronary arteries of the heart, in particular the arterial coronary arteries, increased serum lipids, hypercholesterolemia, hypertriglyceridemia, increases in both serum cholesterol and serum triglycerides combined with increased VLDL (very low density lipoprotein) or LDL (low density lipoprotein) and / or increasing the chylomicrons e.g. Chylomicronemia, in plasma and syndrome X.

Furthermore, the combinations according to the invention are suitable for the treatment of secondary hypercholesterolemias and secondary hypertriglyceridemias which, for example are associated with apolipoprotein E-polymorphism (e.g. apolipoprotein phenotype E 4/4 or E 3/4), obesity, chylomicronemia and chylomicronemia syndrome, renal failure, chronic renal failure, nephrotic syndrome, diabetes mellitus type II and with hepatomas and plasmacytomas.

The combinations of components A and B according to the invention, in particular the special combination of (2S) -2-cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl) - phenyl] -N- (2- (1 R) -hydroxy-1 -phenyl-ethyl) -acetamide and cerivastatin, have been found to be surprisingly advantageous in the treatment of coronary heart diseases, heart failure, impaired brain performance, apoplexy,

Circulatory disorders and disorders of fat metabolism. An example is dyslipidemia, which occurs in diabetics but also in patients who do not suffer from diabetes. When using the combinations according to the invention, an unexpected synergistic effect is observed, for example when lowering the LDL (low density lipoprotein) level. The amounts of components A and B used can thus be reduced in comparison to monotherapy.

If appropriate, it may be expedient to supplement the combination of MTP inhibitors and HMG-CoA reductase inhibitors according to the invention by adding one or more further components. Vitamins, preferably all fat-soluble ones, in particular vitamins A and E, may be mentioned as an example. These vitamins or other components can be added individually or together. Another example of an additional component is acetylsalicylic acid.

“Dyslipidemia” here means either hypertriglyceridemia or hypercholesterolemia, but especially mixed hyperlipidemia, ie a disease state with an elevated cholesterol level (LDL and total cholesterol) and an increased triglyceride level. This may be associated with a decrease in plasma HDL (high density lipoprotein) cholesterol or a disturbed HDL-C / LDL-C ratio. The combinations according to the invention are also particularly suitable for the treatment of dyslipidemia in diabetics or insulin resistance and IGT (impaired glucose tolerance).

Because of their effect on serum lipid levels, the combinations according to the invention are furthermore particularly suitable for the prophylaxis and treatment of arteriosclerosis.

Furthermore, the combinations according to the invention are surprisingly well tolerated, although there are indications of adverse effects in the literature, such as e.g. Warnings about combining statins with lipid-lowering drugs.

The combinations according to the invention are preferably used in human medicine, but are also suitable for veterinary medicine, in particular for the treatment of mammals.

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

The active ingredients of components A and B can be converted into the customary formulations in a known manner, which can be liquid or solid formulations. Examples are tablets, dragees, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices.

Since the combinations according to the invention are well tolerated and are effective even in low doses, a wide variety of formulation variants can be implemented. On the one hand, there is the possibility of formulating the individual components separately. In this case, the two individual components A and B do not necessarily have to be taken at the same time; staggered intake may be beneficial to achieve optimal effects. In the case of such a separate administration, it makes sense to combine the formulations of the two individual components, for example tablets or capsules, simultaneously in a suitable primary packaging agent.

Fixed combinations are also suitable as a further formulation variant for the combinations according to the invention. “Fixed combination” is to be understood here to mean medicinal forms in which the two components are present together in a fixed quantitative ratio. Such fixed combinations can be implemented, for example, as oral solutions, but are preferably solid oral medicinal preparations, for example capsules or tablets.

The combinations according to the invention are dosed up to 3 times a day; preference is given to those combinations which permit one daily application.

The combinations according to the invention preferably contain 0.01 to 20 mg / kg, in particular 0.1 to 5 mg / kg of active ingredient of component A and 0.001 to 30 mg / kg, in particular 0.005 to 10 mg / kg of active ingredient of component B, in each case based on kg Body weight of the patient with oral application.

It may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of route of administration, 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 other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses over the day. The active ingredients of components A and B are particularly suitable for being formulated in a fixed combination in the form of a fixed oral dosage form. It is generally known that the reliability of compliance (compliance) in patients depends to a large extent on the factors number of dosage forms per time of intake and size and weight of the (fixed oral)

Drug form is dependent. Therefore, the number of different medicinal products to be taken separately should be as small as possible (advantage of a fixed combination), and the size and weight of a fixed oral dosage form should be as small as possible with full therapeutic potency in order to ensure that the patient can take the medicinal product to be as comfortable as possible. This enables fixed combinations in the form of solid oral pharmaceutical formulations to be implemented with a minimal size and minimal weight. The fixed combinations according to the invention accordingly offer the highest possible patient compliance and thereby decisively improve the safety and reliability of a therapy.

The drug release can be controlled by combining the two components A and B and modifying the composition or functionality. For example, by delaying the release of active ingredient (retardation) of a component, the above-mentioned temporal decoupling of the onset of action can also be achieved in fixed combinations.

The solid oral dosage forms listed here are manufactured according to the general standard procedures. Ingredients are those that are pharmaceutically accepted and 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 (e.g. polyvinylpyrrolidone, gelatin, starch and cellulose derivatives), as well as all other auxiliaries that are required for the production of pharmaceutical formulations with the desired properties, e.g. lubricants (magnesium stearate), e.g. Disintegrants (e.g. cross-linked polyvinylpyrrolidone, 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 using 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 triglycerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium lauryl sulfate) ), and others

Excipients required for the preparation of pharmaceutical formulations with the desired properties, e.g. 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 hydroxypropylmethyl cellulose.

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, P.J., American Pharmaceutical Association, Washington, 2nd edition 1994.

example

The changes in the serum triglycerides of dogs in% after 6 and 10 days of oral treatment with 0.03 mg cerivastatin / kg or 4 mg / kg body weight (KG) of the compound according to Example 48 or with the combination of the two active compounds in this dosage were investigated. The results are summarized in Table 1. Table 1

The data were determined in detail as follows:

The serum triglyceride-lowering effect of the substances was tested in dogs of both sexes (Beagle, breeder: Marshall Farms, Inc. North Rose NY, USA). The dogs (9 female and 9 male) were randomly assigned to the groups, taking care to assign the genders evenly to the groups.

Control group: 3 male and 2 female dogs

Cerivastatin group: 2 male and 2 female dogs

Example 48 group: 2 male and 2 female dogs

Combination group (Cerivastatin + Ex. 48): 3 female and 2 male dogs

The body weights of the dogs were 8.3 to 12.7 kg at the start of the experiment. For application, the substances were mixed with canned food (Top Dog, Sniff, Soest, Germany) in an application volume of 10 g / kg body weight. 1) The control animals (n = 5) received the corresponding amount of canned food without substances

2) Example 48 (n = 4) was mixed with the canned feed as coprecipitate (20 mg / kg body weight corresponding to an active ingredient dose of 4 mg / kg body weight). 3) Cerivastatin (n =) was administered in a dose of 0.03 mg / kg body weight. For this purpose, cerivastatin was dissolved in an application volume of 0.1 ml water / kg body weight and the corresponding amount was mixed with the canned food.

4) In the combination (n = 5), both substances corresponding to a dose of 0.03 mg cerivastatin / kg body weight and 4 mg, for example, 48 / kg body weight were mixed into the canned feed and administered to the animals.

The dogs received the substances once a day in the morning, then the animals were given an ad libitum dog diet (Sniff HD-H, Soest, Germany).

Blood was taken from the jugular vein to determine the triglyceride.

The blood samples were taken immediately before the first substance application at 9:00 a.m. (morning), on day 6 after the start of treatment 23 hours after the substance application and on day 10 after the start of treatment 23 hours after the last treatment. The blood was taken up in heparinized Monovettes LH and centrifuged. The triglycerides in the plasma were determined enzymatically using a commercially available test kit (Boehringer Mannheim, Germany) on an EPOS analyzer (Eppendorf Gerätebau, Netheler and Hinz, Hamburg, Germany). The individual differences between the plasma triglyceride concentrations after treatment and the corresponding pre-values before the first were calculated

Substance application, these were averaged and given as a percentage change from the previous value.

Claims

Patentansprflche

1. Use of a combination of at least one MTP inhibitor as component A of the general formula (AI)

in which

Rl and R ^{2 together} with the double bond connecting them together form a phenyl or pyridyl ring or a ring of the formula

form, bliss

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

where all ring systems listed under R ^ / R ² 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 with up to 6 carbon atoms. are atoms or substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn can be substituted by hydroxy or 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 for phenyl or for a 5- to 7-membered saturated or unsaturated heterocycle with up to 3 heteroatoms from the

Row S, N and / or O stands,

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 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 ¹⁰ or -NR ¹ ! R ¹² ,

embedded image in which

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

RU or R ^ ^{2 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 -NR ¹³ R ¹⁴ is

embedded image in which

for hydrogen, carboxy or for straight-chain or branched

Alkoxycarbonyl with up to 5 carbon atoms, or stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by hydroxyl or by a group of the formula -O-CO-R15,

wherein Rl5 means 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

Rl6 denotes hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl with up to 6 carbon atoms,

R? stands for 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

stands,

embedded image in which

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, R ^, R6, R? and R ^ are the same or different and

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 Group of the formula -S (O) _a -R ^ means

embedded image in which

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 by straight-chain or branched acyl having up to 6 carbon atoms or by aryl or

Aroyl are each substituted with 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 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,

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 with 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 substituted with up to 4 carbon atoms in each case,

R ^{2 represents} hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R ^{3 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- several times the same or different by halogen, nitro, phenyl, hydroxy or by straight-chain or mixed branched alkyl or alkoxy with up to 6 carbon atoms are substituted,

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

embedded image in which

R1 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, hydroxyl, 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 where

T represents a nitrogen atom or the -CH group, RÖ, R7, RIO and R * * are the same or different and

R5, R8 and R ^{9 are the} same or different and

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

Is 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,

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 ^{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 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 CH ₂ O-CO-R ¹² ,

embedded image in which

R12 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,

embedded image in which

R ³ , R4, R6 and R ^ 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 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, 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 each having up to 6 carbon atoms or by a group of the formula - (CO) _a -NR ⁹ R ¹⁰ ,

embedded image in which

a represents a number 0 or 1,

R ⁹ and RIO are the same or different and are 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 having up to 3 heteroatoms from the series S, N and / or O are substituted, or represents phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and / or O, the ring systems optionally being up to 3 times identical 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 -NRURI,

Wonn

Rl 1 and R * ^{2 have} the meaning of R ⁹ and R ^ O given above and are identical 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

, 14

-NR ³ 'H ^" 15

R stands

embedded image in which Ri3 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R 14 represents hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle having 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

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, 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 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 is optionally substituted by a group of the formula -OR ^ or - NR ⁵ R ⁶ ,

Wonn

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

R5 and R6 are the same or different and are phenyl, hydrogen or mean 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 ^ RS,

wherein

R 'and R ° 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

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, 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

R * 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 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 Is substituted by 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 ^ or -NR ⁵ R ⁶ ,

wherein

R4 is hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms,

R5 and R6 are the same or different and are phenyl, hydrogen or mean 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 ^,

embedded image in which

R ^ and R8 are the same or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

optionally in an isomeric form and their salts

with HMG-CoA reductase inhibitors as component B for the production of

Medicines for the prophylaxis and / or treatment of cardiovascular diseases.

2. Use of a combination according to claim 1 for the production of medicaments for combating or prophylaxis of cardiovascular diseases which are associated with metabolic diseases or deficits.

3. Use of a combination according to claim 2 for combating arteriosclerosis, diseases of the coronary arteries, increased serum lipids,

Hypercholesterolemia, hypertriglyceridemia and mixed forms, which are combined with increased VLDL or LDL and / or increased chylomicrons, and syndrome X.

4. Use of a combination according to claim 2 for the treatment of secondary hypercholesterolemia and secondary hypertriglyceridemia, who may be associated with apoliprotein E polymoism, obesity, chylomicronemia and chylomicronemia syndrome, kidney failure, chronic kidney failure, nephrotic syndrome, type II diabetes mellitus and with hepatomas and plasma cytomas.

5. Use of a combination according to claim 2, characterized in that it contains as component A a compound of the general formula (AI).

6. Use of a combination according to claim 2, characterized in that it contains as component A a compound of Examples 1-119.

7. Use of a combination according to claim 2, characterized in that it contains as component A a compound of Examples 92-119.

8. Use of a combination according to claim 2, characterized in that it contains as component A a compound of Examples 48 or 80.

9. Medicament containing a combination of an MTP inhibitor as component A and an HMG-CoA reductase inhibitor as component

B according to claim 1 and optionally one or more other suitable components.

10. Medicament according to claim 9, characterized in that it contains, as component A, the active ingredients 2-cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl) phenyl] - N- (2-hydroxy-1-phenyl-ethyl) -acetamide or 2-cyclopentyl-2- [4- (2,4-dimethyl-pyrimido [1, 2-a] indole-10-ylmethyl) -pheny 1] - N- (2-hydroxy-l-phenyl-ethyl) -acetamide and contains as components B the active ingredients atorvastatin, cerivastatin, simvastatin, pravastatin, lovastatin, fluvastatin, itavastatin or ZD 4522.

11. Medicament according to claim 9, characterized in that it contains as component A the compound (2S) -2-cyclopentyl-2- [4- (2,4-dimethylpyrido [2,3-b] indol-9-ylmethyl ) -phenyl] -N- (2- (IR) -hydroxy-1-phenyl-ethyl) -acetamide contains.

12. A process for the preparation of medicaments according to claim 9, characterized in that components A and B are converted into auxiliaries and excipients and, if appropriate, with further components into a suitable form of administration.