Use of microsomal triglyceride transfer protein (MTP) inhibitors for reducing the number of postprandial triglyceride-rich lipoprotein particles (PPTRL)

• US 20060166999A1
• Filed: 03/24/2006
• Published: 07/27/2006
• Est. Priority Date: 06/21/2000
• Status: Abandoned Application

• Current Assignee: Bayer AG
• Original Assignee: Bayer AG
• Inventors: Muller, Ulrich, Grutzmann, Rudi, Bischoff, Hilmar, Zaiss, Siegfried
• Application Number:
  US11/388,810
• Publication Number:
  US 20060166999A1
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

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

Claims

1. The use of MTP inhibitors for producing medicaments for reducing the ppTRL plasma level.

3. The use as claimed in claim 1 or 2, characterized in that the MTP inhibitor is employed in a concentration with which no more than a slight reduction in the fasting levels of plasma triglycerides or of plasma cholesterol is induced.

4. The use as claimed in any of claims 1 to 3, characterized in that the MTP inhibitor employed is a compound of the general formula (A1)

in which

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

in which

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

R³ and R⁴ together form, with inclusion of the double bond connecting them, a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene residue,

where all ring systems mentioned under R¹/R² and R³/R⁴ optionally have up to 3 identical or different halogen, trifluoromethyl, carboxyl, hydroxyl substituents, straight-chain or branched alkoxy or alkoxycarbonyl substituents each having up to 6 carbon atoms, or straight-chain or branched alkyl substituents which have up to 6 carbon atoms and which in turn may be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,

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

E is the —

CO—

or —

CS—

group,

L is an oxygen or sulfur atom or is a group of the formula —

NR⁹,

in which

R⁹ is hydrogen or straight-chain or branched alkyl which has up to 6 carbon atoms and which is optionally substituted by hydroxyl or phenyl,

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

where the rings optionally have up to 3 identical or different nitro, carboxyl, halogen, cyano substituents or straight-chain or branched alkenyl or alkoxycarbonyl substituents each having up to 6 carbon atoms or straight-chain or branched alkyl substituents which have up to 6 carbon atoms and which are optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,

 

and/or the rings are optionally substituted by a group of the formula —

OR¹⁰ or —

NR¹¹R¹²,

in which

R¹⁰ is hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms,

R¹¹ and R¹² are identical or different and are phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

or straight-chain or branched acyl which has up to 8 carbon atoms and which is optionally substituted by a group of the formula —

NR¹³R¹⁴,

in which

R¹³ and R¹⁴ are identical or different and are hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,

R⁶ is hydrogen, carboxyl or is straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms,

or is straight-chain or branched alkyl which has up to 6 carbon atoms and which is optionally substituted by hydroxyl or by a group of the formula —

O—

CO—

R¹⁵,

in which

R¹⁵ is phenyl which optionally has up to 3 identical or different halogen, hydroxyl substituents or straight-chain or branched alkyl substituents having up to 5 carbon atoms,

or straight-chain or branched alkyl or alkenyl which each have up to 22 carbon atoms and which are optionally substituted by a group of the formula —

OR¹⁶,

in which

R¹⁶ is hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl having up to 6 carbon atoms,

R⁷ is hydrogen or

R⁶ and R⁷ together are the group of the formula ═

O,

or of the general formula (A2)

in which

A is a radical of the formula

in which

L and M are identical or different and are

 

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

Q is a nitrogen atom or the —

CH group,

T is a group of the formula —

SO₂ or —

CO or

 

an oxygen or sulfur atom,

V is an oxygen or sulfur atom,

R⁵, R⁶, R⁷ and R⁸ are identical or different and are

 

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,

R⁹ is trifluoromethyl;

benzyl or a 5- to 7-membered, optionally benzo-fused heterocycle having up to 3 heteroatoms from the series S, N and/or O and optionally having up to 3 identical or different halogen, phenyl, hydroxyl substituents or straight-chain or branched alkyl or alkoxy substituents each having up to 4 carbon atoms, or is

 

a group of the formula —

S(O)_a—

R¹⁰,

in which

a is a number 0, 1 or 2,

R¹⁰ is straight-chain or branched alkyl or alkenyl which each have up to 8 carbon atoms and which are optionally substituted by straight-chain or branched acyl having up to 6 carbon atoms or by aryl or aroyl each of which have up to 10 carbon atoms and which may in turn have up to 2 identical or different halogen, trifluoromethyl substituents or straight-chain or branched acyl substituents having up to 5 carbon atoms, or is

 

aryl which has 6 to 10 carbon atoms and 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 identical or different and are

 

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

Z is an oxygen or sulfur atom,

R¹ is cycloalkyl having 3 to 10 carbon atoms or is

 

straight-chain or branched alkyl having 1 to 10 carbon atoms, or is phenyl which optionally has up to 2 identical or different halogen, nitro, cyano, hydroxyl substituents or straight-chain or branched alkyl or alkoxy substituents each having up to 4 carbon atoms,

R² is hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R³ is hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or is

 

cycloalkyl having 3 to 7 carbon atoms, or is

 

phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, which optionally have up to 3 identical or different halogen, nitro, phenyl, hydroxyl substituents or straight-chain or branched alkyl or alkoxy substituents having up to 6 carbon atoms,

R⁴ is hydrogen or is a group of the formula —

CH₂—

OH or CH₂O—

CO—

R¹¹,

in which

R¹¹ is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl which optionally has up to 3 identical or different halogen, hydroxyl, cyano substituents or straight-chain or branched alkyl or alkoxy substituents each having up to 4 carbon atoms,

or of the general formula (A3)

in which

D is a radical of the formula

in which

T is a nitrogen atom or the —

CH group,

R⁶, R⁷, R¹⁰ and R¹¹ are identical or different and are

 

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

R⁵, R⁸ and R⁹ are identical or different and are

 

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

or, in the case where T is a nitrogen atom, R⁵ can also be a benzyl,

E and L are identical or different and are

 

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

R¹ is cycloalkyl having 3 to 10 carbon atoms or is

 

straight-chain or branched alkyl having 1 to 10 carbon atoms, or is phenyl which optionally has up to 2 identical or different halogen, cyano, hydroxyl substituents or straight-chain or branched alkyl or alkoxy substituents each having up to 4 carbon atoms,

R² is hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R³ is hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or is

 

cycloalkyl having 3 to 7 carbon atoms, or is

 

phenyl or a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, which optionally have up to 3 identical or different halogen, nitro, phenyl, hydroxyl substituents or straight-chain or branched alkyl or alkoxy substituents having up to 6 carbon atoms,

R⁴ is hydrogen or is a group of the formula —

CH₂—

OH or CH₂O—

CO—

R¹²,

in which

R¹² is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl which optionally has up to 3 identical or different halogen, hydroxyl, cyano substituents or straight-chain or branched alkyl or alkoxy substituents each having up to 4 carbon atoms,

or of the general formula (A4)

in which

A is a radical of the formula

in which

R³, R⁴, R⁶ and R⁷ are identical or different and are

 

hydrogen, cycloalkyl having 3 to 7 carbon atoms or aryl having 6 to 10 carbon atoms,

 

or straight-chain or branched alkyl or alkenyl which each have up to 8 carbon atoms and which are optionally substituted by halogen, hydroxyl or aryl having 6 to 10 carbon atoms,

T, V, X and Y are identical or different and are

 

an oxygen or sulfur atom,

R⁵ and R⁸ are identical or different and are

 

hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl which each have up to 8 carbon atoms and which are optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by a 5- to 6-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the series S, N and/or O, or by aryl having 6 to 10 carbon atoms, where the rings in turn may have up to 3 identical or different 5- to 6-membered aromatic heterocyclic substituents having up to 3 heteroatoms from the series S, N and/or O, or phenyl, benzyl, halogen, hydroxyl, carboxyl substituents or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl substituents 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 having up to 3 heteroatoms from the series S, N and/or O, which optionally have up to 3 identical or different halogen, phenyl, trifluoromethyl, hydroxyl, carboxyl substituents or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl substituents each having up to 6 carbon atoms, or a substituent group of the formula —

(CO)_a—

NR⁹R¹⁰,

in which

a is a number 0 or 1,

R⁹ and R¹⁰ are identical or different and are

 

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

D and E are identical or different and are

 

hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or are straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,

R¹ is hydrogen or cycloalkyl having 3 to 8 carbon atoms, or is straight-chain or branched alkyl or alkenyl which each have up to 8 carbon atoms and which are optionally substituted 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, or is

 

phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, where the ring systems optionally have up to 3 identical or different halogen, phenyl, trifluoromethyl substituents or straight-chain or branched alkyl or alkoxy substituents each having up to 5 carbon atoms, hydroxyl substituents or a substituent group of the formula —

NR¹¹R¹²,

in which

R¹¹ and R¹² have the abovementioned meaning of R⁹ and R¹⁰ and are identical to or different from the latter,

L is an oxygen or sulfur atom,

R² is mercapto, hydroxyl, straight-chain or branched alkoxy having up to 8 carbon atoms or the group of the formula

in which

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

R¹⁴ is 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 which has up to 8 carbon atoms and is optionally substituted by hydroxyl,

or of the general formula (A5)

in which

A, D, E, G, L and M are identical or different and are

 

hydrogen, halogen, trifluoromethyl, carboxyl, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or straight-chain or branched alkyl which has up to 6 carbon atoms and which in turn may be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,

R¹ and R² are identical or different and are

 

hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl which has up to 10 carbon atoms and which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or are phenyl which is optionally substituted by halogen or trifluoromethyl, or

R¹ and R² form, together with the carbon atom, a 4-8-membered cycloalkyl ring,

and

R³ is phenyl which optionally has up to 3 identical or different nitro, carboxyl, halogen, cyano substituents or straight-chain or branched alkenyl or alkoxycarbonyl substituents each having up to 6 carbon atoms, or straight-chain or branched alkyl substituents which have up to 6 carbon atoms and which are optionally substituted by hydroxyl, carboxyl 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 —

OR⁴ or —

NR⁵R⁶,

in which

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

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

NR⁷R⁸,

in which

R⁷ and R⁸ are identical or different and are

 

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

or of the general formula (A6)

in which

A, D, E, G, L and M are identical or different and are

 

hydrogen, halogen, trifluoromethyl, carboxyl, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or straight-chain or branched alkyl which has up to 6 carbon atoms and which in turn may be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,

R¹ and R² are identical or different and are

 

hydrogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl which has up to 10 carbon atoms and which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, or are phenyl which is optionally substituted by halogen or trifluoromethyl, or

R¹ and R² form, together with the carbon atom, a 4-8-membered cycloalkyl ring,

and

R³ is phenyl which optionally has up to 3 identical or different nitro, carboxyl, halogen, cyano substituents or straight-chain or branched alkenyl or alkoxycarbonyl substituents each having up to 6 carbon atoms, or straight-chain or branched alkyl substituents which have up to 6 carbon atoms and which are optionally substituted by hydroxyl, carboxyl 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 —

OR⁴ or —

NR⁵R⁶,

in which

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

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

NR⁷R⁸,

in which

R⁷ and R⁸ are identical or different and are

 

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

where appropriate in an isomeric form and the salts thereof.

5. The use as claimed in any of claims 1 to 4, characterized in that a compound of Examples 1-119 is employed as MTP inhibitor.

6. The use as claimed in any of claims 1 to 4, characterized in that a compound of Examples 92-119 is employed as MTP inhibitor.

7. The use as claimed in claim 5, characterized in that Example 48 or 80 is employed as MTP inhibitor.

8. The use as claimed in any of claims 1 to 7 for producing medicaments for the prophylaxis and/or control of cardiovascular disorders.

9. The use as claimed in any of claims 1 to 7 for producing medicaments for the prophylaxis and/or control of manifestations of neurodegenerative deficits.

10. The use as claimed in any of claims 1 to 7 for producing medicaments for the therapy of insulin resistence, IGT, diabetes, especially type II diabetes.

11. The use as claimed in any of claims 1 to 7 for producing medicaments for the prophylaxis and/or control of metabolic syndrome.

12. The use as claimed in any of claims 1 to 7 for producing medicaments for the prophylaxis and/or control of obesity.

2. The use of MTP inhibitors for producing medicaments for diminishing intestinal cholesterol absorption.