JP2003503342A - Combinations of MTP inhibitors and HMG-CoA reductase inhibitors and their use in medicine - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of a combination of at least one selected MTP inhibitor (component A) and at least one HMG-CoA reductase inhibitor (component B) for controlling cardiovascular diseases. The invention also relates to medicaments containing this combination and their manufacture.

Description

Detailed Description of the Invention

The present invention relates to at least one selected MTP for the control of cardiovascular disease.
Inhibitor (Component A) and at least one HMG-CoA reductase inhibitor (Component B)
The use of the combination with, the agents comprising this combination and their manufacture.

The compound of component A is used as an ApoB secretion inhibitor in documents EP 705 831, EP.
779 279, EP 779 276, EP 802 198 and EP 779 828. However, no mention is made of combinations with HMG-CoA reductase inhibitors.

HMG-CoA reductase inhibitors are one of the lipid-lowering agents known to those skilled in the art. Preferred statins as HMG-CoA reductase inhibitors in the context of the present invention are described, for example, in EP 325 130 or US 5 177 080.

PCT WO 98/31366 and WO 98/03069 disclose combinations of MTP inhibitors with other cholesterol-lowering compounds. However, the MTP inhibitors actually listed therein are distinct in their chemical structure from the selected MTP inhibitors claimed in this invention.

The subject of the invention is a cardiovascular disease, preferably a cardiovascular disease associated with a metabolic disease or deficiency, eg a disorder of fat metabolism or carbohydrate metabolism, eg diabetes,
In formula (A1), which may be an isomeric form and salts thereof, in the prophylaxis and treatment of

[0006]

[Chemical 12]

[Wherein R ¹ and R ² together include a double bond connecting them and are together a phenyl or pyridyl ring or a formula

[0008]

[Chemical 13]

Wherein R ⁸ represents hydrogen or linear or branched alkyl having up to 4 carbon atoms, and R ³ and R ⁴ include the double bond connecting them. And together to form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene group, all ring systems mentioned for R ¹ / R ² and R ³ / R ⁴ are optionally Up to 3 times, identical or different, with halogen, trifluoromethyl, carboxyl, hydroxyl, respectively with linear or branched alkoxy or alkoxycarbonyl having up to 6 carbon atoms, or linear with up to 6 carbon atoms Alternatively, it may be substituted by branched alkyl, which for its part is by hydroxyl or by linear or branched alkoxy up to 4 carbon atoms. D may represent hydrogen, cycloalkyl having 4 to 12 carbon atoms or linear or branched alkyl having up to 12 carbon atoms, and E represents a -CO- or -CS- group. Embedded image L represents an oxygen or sulfur atom or a group of formula —NR ⁹ , wherein R ⁹ represents hydrogen or linear or branched alkyl with up to 6 carbon atoms, optionally with hydroxyl or phenyl. Optionally substituted R ⁵ represents phenyl or a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O; The system may be identical or different, up to 3 times, with nitro, carboxyl,
Optionally substituted by halogen, cyano, or by a straight-chain or branched alkenyl or alkoxycarbonyl having up to 6 carbon atoms, or by a straight-chain or branched alkyl having up to 6 carbon atoms. , It may be optionally substituted by hydroxyl, carboxyl or by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or the cyclic system is optionally of the formula —OR ¹⁰ or -NR ¹¹ R ¹² may be substituted, wherein R ¹⁰ represents hydrogen or linear or branched alkyl or alkenyl having up to 6 carbon atoms, and R ¹¹ and R ¹² are the same. Or different and phenyl, hydrogen, or 6 carbons
Up to linear or branched alkyl or up to 8 carbon atoms, linear or branched acyl, which may be optionally substituted by a group of the formula —NR ¹³ R ¹⁴ . Here, R ¹³ and R ¹⁴ are the same or different and represent hydrogen or linear or branched acyl having up to 8 carbon atoms, and R ⁶ is hydrogen, carboxyl or linear or branched having up to 5 carbon atoms. Represents a branched alkoxycarbonyl, or represents a 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. R ¹⁵ is optionally substituted up to 3 times, identical or different, with halogen, hydroxyl, or with a straight-chain or branched-chain alkyl having up to 5 carbon atoms. Phenyl, which may be optionally substituted, or linear or branched alkyl or alkenyl, each having up to 22 carbon atoms, each of which may optionally be substituted by a group of formula --OR ^16. Well, R ¹⁶ here represents hydrogen, benzyl, triphenylmethyl or a straight-chain or branched acyl having up to 6 carbon atoms, R ⁷ represents hydrogen or R ⁶ and R ⁷ together Represents a group of formula = O], or general formula (A2)

[0010]

[Chemical 14]

[0011] [In the formula, A is the formula

[0012]

[Chemical 15]

Wherein L and M are the same or different and are hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl having 3 to 6 carbon atoms, hydroxyl, phenyl or a straight chain having up to 6 carbon atoms each. Jo or branched alkyl, shows alkoxycarbonyl or alkoxy, Q is represents nitrogen atom or a -CH- radical, T is a group or an oxygen or sulfur atom of the formula -SO ₂ or -CO, V is oxygen Or a sulfur atom, R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and represent hydrogen, or linear or branched alkyl, benzyl or phenyl having up to 6 carbon atoms, Each optionally with halogen or with 6 carbon atoms
Up to may be substituted by straight-chain or branched alkyl, R ⁹ has trifluoromethyl, benzyl, or S, up to 3 heteroatoms from the group consisting of N and / or O 5 to 7-membered optionally represents a benzo-fused heterocycle, which may be up to 3 times, identical or different, with a halogen, phenyl, hydroxyl or straight-chain with up to 4 carbon atoms each. Or, it may be substituted by branched alkyl or alkoxy, or represents a group of the formula —S (O) _a —R ¹⁰ , in which a represents the number 0, 1 or 2, and R ¹⁰ is each Linear or branched alkyl or alkenyl of up to 8 carbon atoms, each of which is optionally by straight or branched acyl of up to 6 carbon atoms or May be substituted by aryl or aroyl of up to 0, they up to two times for some of them, identical or different,
It may be substituted by halogen, trifluoromethyl or by straight-chain or branched acyl having up to 5 carbon atoms, or represents aryl having 6-10 carbon atoms, which may optionally be halogen, hydroxyl,
It may be substituted by trifluoromethyl or a linear or branched alkyl or alkoxy each having up to 5 carbon atoms, D and E being the same or different and hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl. Or each represents a linear or branched alkyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms, Z represents an oxygen atom or a sulfur atom, R ¹ represents cycloalkyl having 3 to 10 carbon atoms or 1 to 1 carbon atoms. Represents 10 straight-chain or branched-chain alkyls, or optionally up to twice, the same or different, halogen, nitro, cyano, hydroxyl, each straight-chain or branched-chain having up to 4 carbon atoms It represents alkyl or phenyl optionally substituted by alkoxy, R ² is hydrogen or Or represents a straight-chain or branched alkyl having up to 3 carbon atoms, R ³ represents a straight-chain or branched alkyl having up to 5 carbon hydrogen or carbon,
Or represents a cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, Each of them may optionally be substituted up to 3 times, identical or different, with halogen, nitro, phenyl, hydroxyl or with a straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, R ⁴ represents hydrogen or a group of formula —CH ₂ —OH or CH ₂ O—CO—R ¹¹ , where R ¹¹ is hydrogen, linear or branched alkyl of up to 8 carbons, or optionally Up to 3 times, substituted with halogen, hydroxyl, cyano or linear or branched alkyl or alkoxy, each having up to 4 carbon atoms, which may be the same or different. Represents an optionally substituted phenyl], or general formula (A3)

[0014]

[Chemical 16]

[0015] [In the formula, D is the formula

[0016]

[Chemical 17]

Wherein T represents a nitrogen atom or a —CH— group, R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ are the same or different and are hydrogen, trifluoromethyl, halogen or each carbon number. 6 represents a straight-chain or branched alkyl or alkoxy up to 6 and R ⁵ , R ⁸ and R ⁹ are the same or different and are hydrogen, cycloalkyl having 3 to 6 carbons, phenyl, up to 6 carbons Straight-chain or branched alkoxycarbonyl or straight-chain or branched alkyl up to 6 carbon atoms, which may be optionally substituted by halogen,
Alternatively, when T represents a nitrogen atom, R ⁵ can also represent benzyl,
E and L are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or a linear or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and R ¹ is a carbon number. Represents a cycloalkyl having 3 to 10 or a linear or branched alkyl having 1 to 10 carbons, or optionally up to twice, the same or different, halogen, cyano, hydroxyl, each having up to 4 carbons. Represents a phenyl optionally substituted by linear or branched alkyl or alkoxy, R ² represents hydrogen or linear or branched alkyl having up to 3 carbon atoms, and R ³ represents Represents hydrogen or a linear or branched alkyl group having up to 5 carbon atoms,
Or represents a cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, Each of them may optionally be substituted up to 3 times, identical or different, with halogen, nitro, phenyl, hydroxyl or with a straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, R ⁴ represents hydrogen or a group of the formula —CH ₂ —OH or CH ₂ O—CO—R ¹² , where R ¹² is hydrogen, straight-chain or branched alkyl up to 8 carbons or optionally 3 Up to and including the same or different, substituted by halogen, hydroxyl, cyano or linear or branched alkyl or alkoxy each having up to 4 carbon atoms Optionally represents phenyl], or general formula (A4)

[0018]

[Chemical 18]

[0019] [In the formula, A is the formula

[0020]

[Chemical 19]

Wherein R ³ , R ⁴ , R ⁶ and R ⁷ are the same or different and represent hydrogen, cycloalkyl having 3 to 7 carbons or aryl having 6 to 10 carbons,
Or each represents a straight chain or branched alkyl or alkenyl having up to 8 carbon atoms, each of which may optionally be halogen, hydroxyl or 6 to 1 carbon atom.
Optionally substituted by 0 aryl, T, V, X and Y are the same or different and represent an oxygen or sulfur atom,
R ⁵ and R ⁸ are the same or different and represent hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or linear or branched alkyl or alkenyl having up to 8 carbon atoms, each of which is By C3-8 cycloalkyl or by S, N and / or O
5- to 6-membered aromatics having up to 3 heteroatoms from the group consisting of, optionally substituted by an optionally benzo-fused heterocycle or by aryl having 6 to 10 carbon atoms Alternatively, for some of them, the cyclic system may be up to 3 times, 5- to 6-membered, identical or different and having up to 3 heteroatoms from the group consisting of S, N and / or O. By an aromatic heterocycle, or phenyl,
It may be substituted by benzyl, halogen, hydroxyl, carboxyl or by linear or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or aryl having 6 to 10 carbon atoms or S, N. And / or 3 from the group consisting of O
5-7-membered aromatic optionally having benzo-fused heterocycles having up to 4 heteroatoms, each of which optionally up to 3 times, being identical or different, halogen, phenyl , Trifluoromethyl, hydroxyl, carboxyl or respectively substituted by a straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms or by a radical of the formula-(CO) _a --NR ⁹ R ^10. Where a represents the number 0 or 1 and R ⁹ and R ¹⁰ are the same or different and represent hydrogen, phenyl or a linear or branched alkyl or acyl each having up to 5 carbon atoms. , D and E are the same or different and are hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or each Represents a straight chain or branched chain alkyl, alkoxy, or alkoxycarbonyl having up to 6 carbon atoms, R ¹ represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or each represents straight chain having up to 8 carbon atoms. Or represents branched alkyl or alkenyl, each of which is optionally cycloalkyl having 3 to 6 carbons, phenyl,
Or optionally substituted by a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, or phenyl or S, N and / or O Represents a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of, the ring system optionally up to 3 times being identical or different, halogen, phenyl, trifluoromethyl or each It may be substituted by straight or branched chain alkyl or alkoxy having up to 5 carbon atoms, hydroxyl, or by a group of formula —NR ¹¹ R ¹² where R ¹¹ and R ¹² are as defined above. has the meaning of R ⁹ and R ¹⁰ and are identical or different and which was, L is an oxygen or sulfur atom, R ² is mercapto, hydroxyl, and linear up to 8 carbon atoms Ku is branched alkoxy or formula

[0022]

[Chemical 20]

Wherein R ¹³ represents hydrogen or linear or branched alkyl having up to 4 carbon atoms, and R ¹⁴ represents hydrogen, phenyl, or a group consisting of S, N and / or O. 5 represents a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms, wherein R ¹⁵ represents hydrogen or straight-chain or branched alkyl having up to 8 carbons, which is optionally Optionally substituted by hydroxyl], or general formula (A5)

[0024]

[Chemical 21]

[Wherein A, D, E, G, L and M are the same or different and each of hydrogen, halogen, trifluoromethyl, carboxyl and hydroxyl is a straight chain or branched chain having up to 6 carbon atoms. Represents an alkoxy or alkoxycarbonyl of or a linear or branched alkyl having up to 6 carbons, which is substituted in part by hydroxyl or by a linear or branched alkoxy having up to 4 carbons. R ¹ and R ² are the same or different and represent hydrogen, cycloalkyl having 3 to 8 carbons or linear or branched alkyl having up to 10 carbons, which may optionally be carbon. It may be substituted by cycloalkyl of the number 3 to 6, or optionally by halogen or trifluoromethyl. Or optionally substituted phenyl, or R ¹ and R ² together with the carbon atom form a 4- to 8-membered cycloalkyl ring, and R ³ represents phenyl, which is Optionally up to 3 times, identical or different, with nitro, carboxyl, halogen, cyano or respectively with a straight-chain or branched alkenyl or alkoxycarbonyl having up to 6 carbon atoms or with a straight-chain with up to 6 carbon atoms or It may be substituted by branched alkyl, which may optionally be substituted by hydroxyl, carboxyl or by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or optionally may be substituted by a group of the formula -OR ⁴ or -NR ⁵ R ^6, Where R ⁴ represents hydrogen or linear or branched alkyl or alkenyl having up to 6 carbon atoms, R ⁵ and R ⁶ are the same or different and are phenyl, hydrogen or linear alkyl having up to 6 carbon atoms. Represents a straight-chain or branched alkyl, or represents a straight-chain or branched acyl having up to 8 carbon atoms, which may be optionally substituted by a group of the formula —NR ⁷ R ⁸ . Here, R ⁷ and R ⁸ are the same or different and represent hydrogen or a linear or branched acyl having up to 8 carbon atoms], or a general formula (A6)

[0026]

[Chemical formula 22]

[Wherein A, D, E, G, L and M are the same or different and each of hydrogen, halogen, trifluoromethyl, carboxyl and hydroxyl is a linear or branched chain having up to 6 carbon atoms. Of alkoxy or alkoxycarbonyl or a straight-chain or branched-chain alkyl having up to 6 carbon atoms, which is partially substituted by hydroxyl or with a straight-chain or branched-chain alkoxy having up to 4 carbon atoms. R ¹ and R ² may be the same or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or linear or branched alkyl having up to 10 carbon atoms, which optionally has carbon atoms. Optionally substituted by 3-6 cycloalkyl, or optionally by halogen or trifluoromethyl Or optionally substituted phenyl, or R ¹ and R ² together with the carbon atom form a 4- to 8-membered cycloalkyl ring, and R ³ represents phenyl, which is Optionally up to 3 times, identical or different, with nitro, carboxyl, halogen, cyano or respectively with straight-chain or branched alkenyl or alkoxycarbonyl having up to 6 carbon atoms or with straight-chain having up to 6 carbon atoms Alternatively, it may be substituted by branched alkyl,
It may be optionally substituted by hydroxyl, carboxyl or by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or optionally of the formula —OR ⁴ or —NR ⁵ R ⁶ Wherein R ⁴ represents hydrogen or linear or branched alkyl or alkenyl having up to 6 carbon atoms, R ⁵ and R ⁶ are the same or different and are phenyl. , Hydrogen or straight-chain or branched-chain alkyl having up to 6 carbon atoms, or straight-chain or branched acyl having up to 8 carbon atoms, which optionally has the formula --NR ⁷ R ⁸ It may be substituted by a group, wherein R ⁷ and R ⁸ are identical or different and linear or hydrogen or up to 8 carbon atoms HMG-Co as the at least one MTP inhibitor and component B as the component A of the indicating branch chain acyl]
Use in combination with an A reductase inhibitor.

The present invention further relates to pharmaceutical formulations comprising the combination of components A and B and their manufacture.

Compounds of general formula (A1) are of great interest as combination partners of component A, and likewise the compounds of Examples 1 to 119 below, in particular the compounds of Examples 92 to 119, very particularly the Examples. The compounds of 48 and 80 are (2S) -2-cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl) -phenyl] -N- (2- (1R) -Hydroxy-1-phenyl-ethyl) -acetamide (Example 48) and (2S) -2-cyclopentyl-2- [4- (2,
4-Dimethyl-pyrimido [1,2-a] indol-10-ylmethyl) -phenyl
] -N- (2- (1R) -Hydroxy-1-phenyl-ethyl) -acetamide (Example 80) is also of particular importance.

In the concept of the present invention, the use of physiologically acceptable salts of the above MTP inhibitors is also claimed. Physiologically acceptable salts of the compounds according to the invention are, for example, salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts include, for example, 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, With fumaric acid, maleic acid or benzoic acid.

The physiologically acceptable salts of the MTP inhibitors mentioned above may also be metal or ammonium salts of the compounds according to the invention having a free carboxyl group. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine. Ammonium salts derived from ethylenediamine or 2-phenylethylamine.

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

The combination of selected MTP inhibitors such as formulas (A1)-(A6) as component A and HMG-CoA reductase inhibitors as component (B) is novel.

It has now been found that the combinations according to the invention have unexpectedly valuable pharmacological properties, in particular that they are suitable for the prevention and treatment of cardiovascular diseases associated with metabolic disorders.

In the context of the present invention, HMG-CoA reductase inhibitors generally represent all substance groups mentioned under the term in the prior art. The abbreviation "HMG-
“CoA” here stands for “3-hydroxy-3-methylglutaryl-coenzyme A”. Under this term, for example EP 247 633, US 5 006 530,
EP 33 538, US 4346 227, EP 22 478 or EP 11
Statins such as those described in 4027 are preferred.

[0036]   The following may preferably be mentioned: ・ Atorvastatin (product name from Parke-Davis)
Lipitor^(TM)Marketed as), ・ Cerivastatin (Product name Lipobay from Bayer) ^(TM) Or Bayco^(TM)Marketed as), ・ Fluvastatin (from Novartis)
scol)^(TM)Marketed as), Lovastatin (Product name Mevacor from Merck)^(TM)age
Are commercially available), Pravastatin (Bristol-Myers Squibb)
Myers Squibb) to product name Lipostat^(TM)Marketed as),
Simvastatin (Product name Zocor from Merck)^(TM)Marketed as
), Itavastatin ("Nisvastatin", NK-10
4, scientific name: [S- [R *, S *-(E)]]-7- [2-cyclopropyl-4-
(4-Fluorophenyl) -3-quinolinyl] -3,5-dihydroxy-6-hepte
Acid), ・ Dalvastatin, ・ Mevastatin, ・ Dihydrocompactin, .Compactin, and * (+)-(3R, 5S) -bis- (7- (4- (4-fluorophenyl) -6-isop
Ropyl-2- (N-methyl-N-methanesulfonylamino) -pyrimidin-5-i
) -3,5-Dihydroxy-6 (E) -heptenoic acid.

Statins are commonly used as lactones (see, eg, lovastatin), esters, or carboxylic acids themselves or salts of carboxylic acids (eg, cerivastatin sodium).

According to the invention, the statins can be used in all suitable forms, ie in the form of their respective salts, hydrates, alcoholates, esters, lactones and tautomers.

Among the statins, atorvastatin, cerivastatin, fluvastatin,
Lovastatin, pravastatin, itavastatin, simvastatin and (+)-
(3R, 5S) -bis- (7- (4- (4-fluorophenyl) -6-isopropyl-
2- (N-methyl-N-methanesulfonylamino) -pyrimidin-5-yl) -3,
Very particularly preferred are 5-dihydroxy-6 (E) -heptenoic acids, and their respective salts, hydrates, alcoholates, esters, lactones and tautomers.

Also among these, atorvastatin and especially cerivastatin, and their respective salts, hydrates, alcoholates, esters, lactones and tautomers are very particularly preferred.

For further details on the above statins, see Drugs of the Future 1994, 19
(6), pages 537-541, and 1995, 20 (6), page 611, and 1996, 21 (6), pa
Reference is made to the procedures in ges 642, the content of each of which is incorporated by reference in its entirety.

With regard to HMG-CoA reductase inhibitors, the term “salt” in the sense of the present invention
Means in each case physiologically acceptable salts of the compounds, for example, with mineral acids, carboxylic acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, It may be a salt with toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid, or a mixed salt thereof. However, it is also salts with common bases, for example alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonia or organic amines, for example diethylamine, triethylamine, Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1
-Ammonium salts derived from ephenamine or methyl-piperidine,
As well as mixed salts thereof may be meant.

Examples of statin salts that can be used in accordance with the present invention are fluindostatin (fluindostane).
atin) (fluvastatin monosodium salt), itavastatin monopotassium and calcium salts, and (+)-(3R, 5S) -bis (7- (4- (4-fluorophenyl) -6-isopropyl- 2- (N-methyl-N-methane-sulfonylamino
) -Pyrimidin-5-yl) -3,5-dihydroxy-6 (E) -heptenoic acid (“ZD4522” or “S4522” from Shionogi and AstraZeneca). Another example of statin salts that can be used in accordance with the present invention are cerivastatin, atorvastatin and pravastatin monosodium and monopotassium salts and calcium salts. The monosodium salt of cerivastatin (“cerivastatin sodium”) is very particularly preferably used.

Another preferred HMG-CoA reductase inhibitor is both Bayer AG
Are described in EP-A-0 325 130 and EP-A-0-491 226, the contents of which are incorporated herein by reference. EP-
The subject of A-0 325 130 is substituted pyridines, and EP-A-
0-491 226 describes substituted pyridyldihydroxyheptenoic acid derivatives and their salts, among which cerivastatin (EP-A-0 491 226, claim 6) is particularly preferred for the invention.

The statins mentioned in WO-A-99 / 11263 are likewise preferred according to the invention, the disclosure of which is incorporated by reference.

Reference Bioorganic & Medicinal Chemistry, Vol. 5, No. 2, pages 437-444 (1
The HMG-CoA reductase inhibitors listed in 997) are equally preferred according to the invention, the disclosures of which are incorporated herein by reference.

Another review of HMG-CoA reductase inhibitors is Pharmazie in unserer Ze.
It, 28th year, No. 3, pages 147-152 (1999).

[0048]   Preferred MTP inhibitors are the compounds shown in the table below:

[0049]

[Table 1]

[0050]

[Table 2]

[0051]

[Table 3]

[0052]

[Table 4]

[0053]

[Table 5]

[0054]

[Table 6]

[0055]

[Table 7]

[0056]

[Table 8]

[0057]

[Table 9]

[0058]

[Table 10]

[0059]

[Table 11]

[0060]

[Table 12]

[0061]

[Table 13]

[0062]

[Table 14]

[0063]

[Table 15]

[0064]

[Table 16]

[0065]

[Table 17]

[0066]

[Table 18]

[0067]

[Table 19]

[0068]

[Table 20]

[0069]

[Table 21]

[0070]

[Table 22]

[0071]

[Table 23]

[0072]   Particularly preferred MTP inhibitors are the compounds shown in the table below:

[0073]

[Table 24]

[0074]

[Table 25]

[0075]

[Table 26]

[0076]

[Table 27]

[0077]

[Table 28]

[0078]

[Table 29]

The combinations according to the invention show a broad and versatile range of activity. They are, for example, arteriosclerosis, stroke, angina, diseases of the coronary vessels of the heart, in particular arterial coronary vessels, heart failure, primary and secondary myocardial infarction, pathological changes in the vascular wall, impaired blood circulation, Impaired microcirculation, smooth muscle cell proliferation, increased lipoprotein levels in serum and possibly lipid metabolism disorders with fluctuations in the proportion of lipoproteins, elevated serum lipids, hyperlipoproteinemia, hypercholesterolemia, hyperlipidemia Triglyceridemia, elevated VLDL (very low density lipoprotein) and elevated serum cholesterol and serum triglycerides combined with elevated plasma chrysanthemum, insulin resistance, IGT (damaged glucose) Tolerance), diabetes, non-insulin-dependent diabetes mellitus (= type 2 diabetes), hyperglycemia, metabolic disorders such as disorders of lipid metabolism. Deficiency of acid lipase, storage disease, especially fat storage disease, phytosterolosis, hypertension, osteoporosis, obesity, X syndrome, thrombosis, pancreatitis, constipation (intestinal obstruction), brain dysfunction, cerebrovascular failure Disease, cerebral vascular circulation disorder, stroke,
It can be used for the treatment and / or prevention of transient ischemic attacks (TIA) and syncope.

Diseases affected or caused by more than one risk factor, such as arteriosclerosis, disorders of the heart coronary vessels, especially arterial coronary vessels, elevated serum lipids, hypercholesterolemia, hypertriglycerides Serum, elevated VLDL (very low density lipoproteins) or both serum cholesterol and serum triglycerides in combination with LDL (low density lipoproteins), and / or plasma chloasma Of particular interest is the treatment and prophylaxis of elevations such as chorrhea and syndrome X.

Combinations according to the invention may also be used, for example, for apolipoprotein E polymorphisms (eg apolipoprotein phenotype E4 / 4 or E3 / 4), obesity, choremia and chylous syndrome, renal failure, chronic kidney. It is also suitable for the treatment of secondary hypercholesterolemia and secondary hypertriglyceridemia associated with insufficiency, nephrotic syndrome, diabetes mellitus type II, and hepatoma and plasmacytoma.

A combination according to the invention of components A and B, in particular (2S) -2-cyclopentyl-2- [4- (2,4-dimethyl-pyrido [2,3-b] indol-9-ylmethyl.
Specific combinations of) -phenyl] -N- (2- (1R) -hydroxy-1-phenyl-ethyl) -acetamide and cerivastatin are associated with coronary heart failure, heart failure, cerebral dysfunction, stroke, impaired blood circulation and fat metabolism. Has proven to be surprisingly advantageous in the treatment of disorders. An example that may be mentioned is dyslipidaemias, which occurs not only in diabetes but also in patients who do not have diabetes. When using the combination according to the invention, an unexpected synergistic effect on the activity is observed, for example in lowering LDL (low density lipoprotein) levels. Therefore, the amount of components A and B used can be reduced compared to monotherapy.

MTP inhibitor and HM by the addition of one or more additional components, as appropriate.
It is convenient to supplement the combination according to the invention of G-CoA reductase inhibitors. Examples which may be mentioned are vitamins, preferably all fat-soluble vitamins,
, And especially vitamins A and E. These vitamins or other ingredients can be added individually or together. Another example of an additional ingredient that may be mentioned is acetylsalicylic acid.

“Dyslipidemia” here refers to either hypertriglyceridemia or hypercholesterolemia, especially mixed hyperlipidemia, ie elevated cholesterol levels (LDL).
And total cholesterol) and disease states with elevated triglyceride levels. This may be associated with a reduction in HDL (high density lipoprotein) cholesterol in plasma or a disturbed HD-C / LDL-C ratio.

In particular, the combinations according to the invention are also suitable for the treatment of dyslipidemia or insulin resistance and IGT (impaired glucose tolerance) in diabetes.

Due to their effect on serum lipid levels, the combinations according to the invention are also particularly suitable for the prevention and treatment of arteriosclerosis.

References to adverse effects, such as warnings about the combination of statins with lipid-lowering agents, are found in the literature, but the combinations according to the invention are further characterized by a surprisingly good tolerability.

The combinations according to the invention are preferably used in human medicine, but they 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 active compounds of components A and B can be converted into the customary preparations in a known manner and they can be liquid or solid preparations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices.

Since the combinations according to the invention are highly tolerated and active even at low dosages, it is possible to produce all kinds of formulation variants. Therefore, on the one hand, it is possible to formulate 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, in contrast, continuous intake may be advantageous for an optimal effect. In the case of this type of separate administration, it is suggested to combine the formulations of the two individual components, for example tablets or capsules, almost simultaneously in a suitable initial packaging.

Another formulation variant suitable for the combination according to the invention is preferably a fixed combination. "Fixed combination" is to be understood here to mean a pharmaceutical form in which the two components are present together in a fixed, quantitative ratio. Such a fixed combination can also be manufactured, for example, as an oral solution,
They are preferably solid oral pharmaceutical formulations, such as capsules or tablets.

The combinations according to the invention can be given up to three times a day, preference being given to combinations allowing once-a-day administration.

The combinations according to the invention are preferably from 0.01 to 20 mg / kg, in particular from 0.1 to 5 mg / kg, in each case orally administered per kg patient body weight, of the active compound of component A and 0.1. 001 to 30 mg / kg, especially 0.005 to 10 mg / k
g of component B active compound.

As appropriate, ie body weight or type of mode of administration, individual response to the drug,
Deviations from the above amounts may be necessary depending on the formulation method and the time or interval at which the administration is performed. Therefore, in some cases it may be appropriate to prescribe less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. For relatively large doses, it is recommended to divide these into multiple individual doses over the day.

The active compounds of components A and B are particularly suitable for the formulation of fixed combinations in solid oral dosage forms.

The reliability of ingestion in a patient's case obviously depends on the following factors: the number of dosage forms at the time of ingestion and the size and weight of the (solid oral) drug form. In order for the patient to ingest as much as possible, while maintaining full therapeutic ability,
The number of different drugs taken should therefore be as low as possible (advantage of a fixed combination), and the size and weight of the solid oral dosage form should be as low as possible. Therefore, fixed combinations can be manufactured in the form of solid oral pharmaceutical formulations with minimal size and minimal weight. Therefore, the fixed combination according to the invention provides the highest possible patient compliance, and thereby significantly improves the safety and reliability of the therapy.

The release of the active compound can be controlled by the combination of the two components A and B and the modification of the composition or function. For example, a delayed release of one component (delayed) makes it possible to achieve the above-mentioned temporary release at the onset of activity even in a fixed combination.

The solid oral dosage forms listed herein are manufactured by standard standard processes. The components are pharmaceutically acceptable and physiologically acceptable, for example, as a filler, a cellulose derivative (eg, microcrystalline cellulose), a sugar (eg, lactose), sugar alcohols (eg, mannitol, sorbitol), Inorganic filler (
(Eg calcium phosphate), binders (eg polyvinylpyrrolidone, gelatin, starch and cellulose derivatives), and all other excipients necessary for the preparation of pharmaceutical formulations with the desired properties, eg lubricants (magnesium stearate). , Disintegrants (eg crosslinked polyvinylpyrrolidone, sodium carboxymethylcellulose), wetting agents (eg sodium lauryl sulphate), retarders (eg cellulose derivatives, polyacrylic acid derivatives), stabilizers, fragrances, color pigments.

Liquid formulations are likewise prepared by standard methods using pharmaceutically customary excipients and either the active compound or the two active compounds in dissolved or suspended form. Contained in. Typical dosages of these drug formulations are 1-10 ml
Is. Examples of excipients in these liquid formulations are solvents (eg water, alcohol,
Natural and synthetic oils such as medium chain triglycerides), solubilizers (eg glycerol, glycol derivatives), wetting agents (eg polysulfates, sodium lauryl sulphate) and other additives necessary for the preparation of pharmaceutical formulations with the desired properties. Molding agents such as viscosity-increasing agents, pH-correcting agents, sweeteners and flavoring agents, antioxidants, stabilizers, preservatives.

The main constituent of the shell of the capsule formulation is, for example, gelatin or hydroxypropylmethylcellulose.

Pharmaceutical excipients well known to those skilled in the art are also described, for example, in the following book: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, PJ.
, American Pharmaceutical Association, Washington, 2nd Edition 1994. Example 0.03 mg cerivastatin / kg body weight (BW) or 4 mg Example 4
A% change in serum triglycerides of dogs was examined after 6 and 10 days of oral treatment with compounds according to 8 / kg body weight or a combination of 2 active compounds at this dose. The results are summarized in Table 1.

[0103]

[Table 30]

[0104]   The data was specifically measured as follows.

Serum triglyceride-lowering effects of substances can be demonstrated by both male and female dogs (beagle, breeding company,
Marshall Farms, Inc., North
Rose, New York, USA). Dogs (9 females and 9 males) were randomly assigned to groups, taking care to assign males and females equally to the groups. Control group: 3 male dogs and 2 female dogs Cerivastatin group: 2 male dogs and 2 female dogs Example 48 Group: 2 male dogs and 2 female dogs combined group (Cerivastatin + performed Example 48): 3 female dogs and 2 male dogs At the start of the experiment the dogs weighed 8.3 to 12.7 kg. For administration, the substances were mixed with canned food (Top Dog, Sniff, Soest, Germany) at a dose of 10 g / kg BW. 1) Control animals (n = 5) received corresponding amounts of canned food without substance. 2) Example 48 (n = 4) was mixed with canned food as a co-precipitate (20 mg / kg BW) corresponding to 4 mg active compound / kg BW. 3) Cerivastatin (n = 4) was administered at a dose of BW of 0.03 mg / kg. For this, cerivastatin was dissolved in a dose of 0.1 ml water / kg BW and the appropriate amount mixed with canned food. 4) In the combination (n = 5) both substances corresponding to a dose of 0.03 mg cerivastatin / kg BW and 4 mg Example 48 / kg BW were mixed in a canned food and administered to animals. did.

Dogs received these substances once daily in the morning, then animals received the dog's maintenance diet (Sniff HD-H, Soest, Germany) ad libitum.

Blood was taken from the jugular vein of the animals for triglyceride determination. Blood samples were taken directly before the first substance administration at about 09.00 (morning), on day 6 after the substance administration 23 hours after the treatment start and on day 10 after the last treatment 23 hours after the treatment start. Blood was collected in heparinized LH monovettes and centrifuged. Triglycerides in plasma were tested using a commercially available test kit (Boehringer Mannheim, Germany) with an EPOS analyzer (Eppendorf Geraetebau, Netheler unhins).
d Hinz), Hamburg, Germany). Individual differences in post-treatment plasma triglyceride concentrations relative to the corresponding preliminary test values before the first substance administration were calculated and these were averaged and presented as a percentage change from the preliminary test values.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/44 A61K 31/44 31/519 31/519 A61P 3/00 A61P 3/00 3/04 3 / 04 3/06 3/06 3/10 3/10 9/04 9/04 9/10 9/10 101 101 13/12 13/12 43/00 111 43/00 111 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM), A E, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI , GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ , UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Bisijov, Hilmer Germany Day-42113 Buttupertal Amrom 78 F Term (reference) 4C086 AA01 AA02 BA17 BC05 BC13 BC17 CB05 MA02 MA04 NA14 ZA37 ZA40 ZA45 ZA70 ZA81 ZC21 ZC33 ZC35 4C206 AA01 AA02 DB02 DB52 M A02 MA04 NA14 ZA37 ZA40 ZA45 ZA70 ZA81 ZC21 ZC33 ZC35

Claims (12)

[Claims] 1. A compound of the general formula (A1), which may be in any isomeric form and salts thereof, for the manufacture of a medicament for the prevention and / or treatment of cardiovascular diseases. [Wherein R ¹ and R ² together include the double bond connecting them and are together a phenyl or pyridyl ring or a compound of the formula Wherein R ⁸ represents hydrogen or linear or branched alkyl having up to 4 carbon atoms, R ³ and R ⁴ include a double bond connecting them, Taken together to form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene group, all ring systems mentioned under R ¹ / R ² and R ³ / R ⁴ optionally up to 3 times , Identical or different, with halogen, trifluoromethyl, carboxyl, hydroxyl, respectively with linear or branched alkoxy or alkoxycarbonyl having up to 6 carbon atoms, or linear or branched with up to 6 carbon atoms It may be substituted by chain alkyl, which is partially substituted by hydroxyl or by straight chain or branched chain alkoxy having up to 4 carbon atoms. Optionally, D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms or linear or branched alkyl having up to 12 carbon atoms, E represents -CO- or -CS- group, L represents an oxygen or sulfur atom or a group of the formula —NR ⁹ , wherein R ⁹ represents hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by hydroxyl or phenyl. R ⁵ may be phenyl or a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, wherein the cyclic system is Depending on the case, up to 3 times, the same or different, nitro, carboxyl,
Optionally substituted by halogen, cyano, or by a straight-chain or branched alkenyl or alkoxycarbonyl having up to 6 carbon atoms, or by a straight-chain or branched alkyl having up to 6 carbon atoms. , It may be optionally substituted by hydroxyl, carboxyl or by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or the cyclic system is optionally of the formula —OR ¹⁰ or -NR ¹¹ R ¹² may be substituted, wherein R ¹⁰ represents hydrogen or linear or branched alkyl or alkenyl having up to 6 carbon atoms, and R ¹¹ and R ¹² are the same. Or different and phenyl, hydrogen, or 6 carbons
Up to linear or branched alkyl or up to 8 carbon atoms, linear or branched acyl, which may be optionally substituted by a group of the formula —NR ¹³ R ¹⁴ . Here, R ¹³ and R ¹⁴ are the same or different and represent hydrogen or linear or branched acyl having up to 8 carbon atoms, and R ⁶ is hydrogen, carboxyl or linear or branched having up to 5 carbon atoms. Represents a branched alkoxycarbonyl, or represents a 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. R ¹⁵ is optionally substituted up to 3 times, identical or different, with halogen, hydroxyl, or with a straight-chain or branched-chain alkyl having up to 5 carbon atoms. Phenyl, which may be optionally substituted, or linear or branched alkyl or alkenyl, each having up to 22 carbon atoms, each of which may optionally be substituted by a group of formula --OR ^16. Well, R ¹⁶ here represents hydrogen, benzyl, triphenylmethyl or a straight-chain or branched acyl having up to 6 carbon atoms, R ⁷ represents hydrogen or R ⁶ and R ⁷ together Represents a group of formula = O], or general formula (A2): [Wherein A is the formula: Wherein L and M are the same or different and are hydrogen, halogen, trifluoromethyl, carboxyl, cycloalkyl having 3 to 6 carbon atoms, hydroxyl, phenyl or a linear or branched group having up to 6 carbon atoms, respectively. Branched-chain alkyl, alkoxycarbonyl or alkoxy, Q represents a nitrogen atom or a —CH— group, T represents a group of the formula —SO ₂ or —CO or an oxygen or sulfur atom, and V represents an oxygen or sulfur atom. R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and represent hydrogen, or straight or branched alkyl, benzyl or phenyl having up to 6 carbon atoms, each of which is By halogen or by 6 carbon atoms
Up to may be substituted by straight-chain or branched alkyl, R ⁹ has trifluoromethyl, benzyl, or S, up to 3 heteroatoms from the group consisting of N and / or O 5 to 7-membered optionally represents a benzo-fused heterocycle, which may be up to 3 times, identical or different, with a halogen, phenyl, hydroxyl or straight-chain with up to 4 carbon atoms each. Or, it may be substituted by branched alkyl or alkoxy, or represents a group of formula —S (O) _a —R ¹⁰ , in which a represents the number 0, 1 or 2, and R ¹⁰ is each Linear or branched alkyl or alkenyl having up to 8 carbon atoms, each of which is optionally by linear or branched acyl having up to 6 carbon atoms or having 1 carbon atom May be substituted by up to 0 aryl or aroyl, which may be the same or different up to twice for some of them,
It may be substituted by halogen, trifluoromethyl or by straight-chain or branched acyl having up to 5 carbon atoms, or represents aryl having 6-10 carbon atoms, which may optionally be halogen, hydroxyl,
It may be substituted by trifluoromethyl or a linear or branched alkyl or alkoxy each having up to 5 carbon atoms, D and E being the same or different and hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl. Or each represents a linear or branched alkyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms, Z represents an oxygen atom or a sulfur atom, R ¹ represents cycloalkyl having 3 to 10 carbon atoms or 1 to 1 carbon atoms. Represents 10 straight-chain or branched-chain alkyls, or optionally up to twice, the same or different, halogen, nitro, cyano, hydroxyl, each straight-chain or branched-chain having up to 4 carbon atoms It represents alkyl or phenyl optionally substituted by alkoxy, R ² is hydrogen or Or represents a straight-chain or branched alkyl having up to 3 carbon atoms, R ³ represents a straight-chain or branched alkyl having up to 5 carbon hydrogen or carbon,
Or represents a cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, Each of them may optionally be substituted up to 3 times, identical or different, with halogen, nitro, phenyl, hydroxyl or with a straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, R ⁴ represents hydrogen or a group of formula —CH ₂ —OH or CH ₂ O—CO—R ¹¹ , where R ¹¹ is hydrogen, linear or branched alkyl of up to 8 carbons, or optionally Up to 3 times, substituted with halogen, hydroxyl, cyano or linear or branched alkyl or alkoxy, each having up to 4 carbon atoms, which may be the same or different. Optionally present phenyl], or general formula (A3): [Wherein D is the formula: Wherein T represents a nitrogen atom or a —CH— group, R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ are the same or different and are hydrogen, trifluoromethyl, halogen or each of up to 6 carbon atoms. Represents a linear or branched alkyl or alkoxy, R ⁵ , R ⁸ and R ⁹ are the same or different and are hydrogen, cycloalkyl having 3 to 6 carbons, phenyl, linear having up to 6 carbons Or a branched alkoxycarbonyl or a linear or branched alkyl having up to 6 carbon atoms, which may be optionally substituted by halogen,
Alternatively, when T represents a nitrogen atom, R ⁵ can also represent benzyl,
E and L are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or a linear or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and R ¹ is a carbon number. Represents a cycloalkyl having 3 to 10 or a linear or branched alkyl having 1 to 10 carbons, or optionally up to twice, the same or different, halogen, cyano, hydroxyl, each having up to 4 carbons. Represents a phenyl optionally substituted by linear or branched alkyl or alkoxy, R ² represents hydrogen or linear or branched alkyl having up to 3 carbon atoms, and R ³ represents Represents hydrogen or a linear or branched alkyl group having up to 5 carbon atoms,
Or represents a cycloalkyl having 3 to 7 carbon atoms, or phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, Each of them may optionally be substituted up to 3 times, identical or different, with halogen, nitro, phenyl, hydroxyl or with a straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, R ⁴ represents hydrogen or a group of the formula —CH ₂ —OH or CH ₂ O—CO—R ¹² , where R ¹² is hydrogen, straight-chain or branched alkyl up to 8 carbons or optionally 3 Up to and including the same or different, substituted by halogen, hydroxyl, cyano or linear or branched alkyl or alkoxy each having up to 4 carbon atoms Optionally represent phenyl], or general formula (A4): [Wherein A is the formula: Wherein R ³ , R ⁴ , R ⁶ and R ⁷ are the same or different and represent hydrogen, cycloalkyl having 3 to 7 carbons or aryl having 6 to 10 carbons,
Or each represents a straight chain or branched alkyl or alkenyl having up to 8 carbon atoms, each of which may optionally be halogen, hydroxyl or 6 to 1 carbon atom.
Optionally substituted by 0 aryl, T, V, X and Y are the same or different and represent an oxygen or sulfur atom,
R ⁵ and R ⁸ are the same or different and represent hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or linear or branched alkyl or alkenyl having up to 8 carbon atoms, each of which is By C3-8 cycloalkyl or by S, N and / or O
5- to 6-membered aromatics having up to 3 heteroatoms from the group consisting of, optionally substituted by an optionally benzo-fused heterocycle or by aryl having 6 to 10 carbon atoms Alternatively, for some of them, the cyclic system may be up to 3 times, 5- to 6-membered, identical or different and having up to 3 heteroatoms from the group consisting of S, N and / or O. By an aromatic heterocycle, or phenyl,
It may be substituted by benzyl, halogen, hydroxyl, carboxyl or by linear or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or aryl having 6 to 10 carbon atoms or S, N. And / or 3 from the group consisting of O
5-7-membered aromatic optionally having benzo-fused heterocycles having up to 4 heteroatoms, each of which optionally up to 3 times, being identical or different, halogen, phenyl , Trifluoromethyl, hydroxyl, carboxyl or respectively substituted by a straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms or by a radical of the formula-(CO) _a --NR ⁹ R ^10. Where a represents the number 0 or 1 and R ⁹ and R ¹⁰ are the same or different and represent hydrogen, phenyl or a linear or branched alkyl or acyl each having up to 5 carbon atoms. , D and E are the same or different and are hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or each Represents a straight chain or branched chain alkyl, alkoxy, or alkoxycarbonyl having up to 6 carbon atoms, R ¹ represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or each represents straight chain having up to 8 carbon atoms. Or represents branched alkyl or alkenyl, each of which is optionally cycloalkyl having 3 to 6 carbons, phenyl,
Or optionally substituted by a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and / or O, or phenyl or S, N and / or O Represents a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of, the ring system optionally up to 3 times being identical or different, halogen, phenyl, trifluoromethyl or each It may be substituted by straight or branched chain alkyl or alkoxy having up to 5 carbon atoms, hydroxyl, or by a group of formula —NR ¹¹ R ¹² where R ¹¹ and R ¹² are as defined above. has the meaning of R ⁹ and R ¹⁰ and are identical or different and which was, L is an oxygen or sulfur atom, R ² is mercapto, hydroxyl, and linear up to 8 carbon atoms Clause of branched alkoxy or the formula: 9] Wherein R ¹³ represents hydrogen or linear or branched alkyl having up to 4 carbon atoms, R ¹⁴ represents hydrogen, phenyl or 3 from the group consisting of S, N and / or O. Represents a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms, R ¹⁵ represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, optionally substituted by hydroxyl. Or a compound represented by the general formula (A5): [Wherein A, D, E, G, L and M are the same or different and each of hydrogen, halogen, trifluoromethyl, carboxyl, hydroxyl, a linear or branched alkoxy group having up to 6 carbon atoms or Alkoxycarbonyl, or straight-chain or branched-chain alkyl having up to 6 carbon atoms, substituted in part by hydroxyl or by straight-chain or branched-chain alkoxy having up to 4 carbon atoms R ¹ and R ² may be the same or different and represent hydrogen, cycloalkyl having 3 to 8 carbon atoms or linear or branched alkyl having up to 10 carbon atoms, which optionally has 3 to 8 carbon atoms. 6 cycloalkyl, or optionally halogen or trifluoromethyl. Or even represent a phenyl, or R ¹ and R ^2, together with the carbon atom form a cycloalkyl ring of 4-～8- membered, and R ³ represents phenyl, which is optionally 3 times Up to the same or different, with nitro, carboxyl, halogen, cyano or with a straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or with a straight-chain or branched chain having up to 6 carbon atoms Of alkyl, which is optionally substituted by hydroxyl, carboxyl or by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, and / or It may be substituted by a group of the formula -OR ⁴ or -NR ⁵ R ⁶ by, wherein R ⁴ is Represents a linear or branched alkyl or alkenyl of up element or each carbon number 6, R ⁵ and R ⁶ are identical or different and phenyl, hydrogen or a linear or branched up to C 6 Represents an alkyl group, or represents a linear or branched acyl group having up to 8 carbon atoms, which may be optionally substituted by a group of the formula —NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are the same or different and represent hydrogen or linear or branched acyl having up to 8 carbon atoms], or a compound represented by the general formula (A6): [Wherein A, D, E, G, L and M are the same or different and each of hydrogen, halogen, trifluoromethyl, carboxyl, hydroxyl, a linear or branched alkoxy group having up to 6 carbon atoms or Alkoxycarbonyl or a straight-chain or branched-chain alkyl having up to 6 carbon atoms, which may be substituted on its part by hydroxyl or by a straight-chain or branched-chain alkoxy having up to 4 carbon atoms Often R ¹ and R ² are the same or different and represent hydrogen, cycloalkyl having 3 to 8 carbons or linear or branched alkyl having up to 10 carbons, which optionally has 3 to 6 carbons. Optionally substituted by cycloalkyl, or optionally by halogen or trifluoromethyl. Or even represent a phenyl, or R ¹ and R ^2, together with the carbon atom form a cycloalkyl ring of 4-～8- membered, and R ³ represents phenyl, which is optionally 3 times Up to, the same or different, with nitro, carboxyl, halogen, cyano, or with a linear or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms, or with a linear or branched chain having up to 6 carbon atoms Optionally substituted with a
It may be optionally substituted by hydroxyl, carboxyl or by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms and / or optionally of the formula —OR ⁴ or —NR ⁵ R ⁶ Wherein R ⁴ represents hydrogen or linear or branched alkyl or alkenyl having up to 6 carbon atoms, R ⁵ and R ⁶ are the same or different and 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 optionally has the formula --NR ⁷ R ⁸ It may be substituted by a group, wherein R ⁷ and R ⁸ are identical or different and linear or hydrogen or up to 8 carbon atoms At least one MTP inhibitors as component A shows a branch-chain acyl], HMG-C as component B
Use in combination with an oA reductase inhibitor. 2. Use of the combination according to claim 1 for the manufacture of a medicament for the control or prevention of cardiovascular diseases associated with metabolic diseases or deficiencies. 3. Atherosclerosis, coronary heart disease, elevated serum lipids, hypercholesterolemia, hypertriglyceridosis, and elevated VLDL or LD.
Use of a mixed form in combination with L and / or elevated chylomicrons, and the combination according to claim 2 for the inhibition of syndrome X. 4. Optionally, apolipoprotein E polymorphism, obesity, chylousemia and chylousemia syndrome, renal failure, chronic renal failure, nephrotic syndrome, diabetes mellitus type.
II, and the use of the combination according to claim 2 for the treatment of secondary hypercholesterolemia and secondary hypertriglyceridemia associated with hepatoma and plasmacytoma. 5. Use of the combination according to claim 2, characterized in that, as component A, it contains a compound of the general formula (A1). 6. Use of the combination according to claim 2, characterized in that it contains, as component A, the compounds of Examples 1-119. 7. Use of a combination according to claim 2, characterized in that it contains, as component A, the compounds of Examples 92-119. 8. Use of the combination according to claim 2, characterized in that it contains the compound of Example 48 or 80 as component A. 9. 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 further suitable components. Become a drug. 10. The active compound 2-cyclopentyl-2- [4] as the component A.
-(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] indol-10-ylmethyl) -phenyl] -N- (2-hydroxy-1-phenyl-ethyl) -acetamide, and As component B, the active compound atorvastatin (ator
vastatin), cerivastatin (cerivastatin), simvastatin (simvastatin), pravastatin (pravastatin), lovastatin, fluvastatin (fluv)
The drug according to claim 9, which comprises astatin, itavastatin or ZD4522. 11. A compound (2S) -2-cyclopentyl-2- as the component A.
Contains [4- (2,4-Dimethyl-pyrido [2,3-b] indol-9-ylmethyl) -phenyl] -N- (2- (1R) -hydroxy-1-phenyl-ethyl) -acetamide The drug according to claim 9, which is characterized in that: 12. Component A and B are converted into a suitable dosage form together with excipients and vehicles and, optionally, further components.
The method for producing the drug according to 1.