# US 8,772,494 B2 · N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein b

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- Number: US 8,772,494 B2
- Document ID: US8772494B2
- Status: Granted
- Kind: B2
- Application number: 10/580,530
- Filed: 2004-12-06
- Published: 2007-05-03
- Granted: 2014-07-08
- Earliest claimed: 2003-12-09
- Assignees: Janssen Pharmaceutica NV
- Applicants: Lieven Meerpoel; Marcel Viellevoye; Joannes Theodorus Maria Linders
- Inventors: Lieven Meerpoel; Marcel Viellevoye; Joannes Theodorus Maria Linders
- Web page: https://patentgrep.com/patent/US8772494B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/34: with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

N-aryl piperidine substituted biphenylcarboxamides compounds of formula (I) methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.

## Claims

### Claim 1

A compound of formula (I)
the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R1 is hydrogen, C1-4alkyl, halo, or polyhaloC1-4alkyl;
R2 is hydrogen, C1-4alkyl, halo, or polyhaloC1-4alkyl;
R3 is hydrogen or C1-4alkyl;
R4 is hydrogen, C1-4alkyl, or halo;
n is an integer 0, or 1;
X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon;
or X1 is carbon and X2 is nitrogen;
X3 is carbon or nitrogen;
Y represents O, or NR6 wherein R6 is hydrogen or C1-4alkyl;
R5 represents a radical of formula
wherein
m is an integer 0, 1, or 2;
Z is O or NH;
R7 is hydrogen,
C1-6alkyl;
C1-6alkyl substituted with hydroxy, amino, mono- or di(C1-4alkyl)amino, C1-4alkyloxycarbonyl, aminocarbonyl, aryl or heteroaryl;
C1-4alkyl-O—C1-4alkyl;
C1-4alkyl-S—C1-4alkyl; or
aryl;
R8 is hydrogen or C1-6alkyl;
R9 is C1-4alkyl;
or when Y represents NR6 the radicals R5 and R6 may be taken together with the nitrogen to which they are attached to form pyrrolidinyl substituted with C1-4alkyloxycarbonyl and optionally further substituted with hydroxy; or piperidinyl substituted with C1-4alkyloxycarbonyl;
aryl is phenyl; phenyl substituted with one, two or three substituents each independently selected from C1-4alkyl, C1-4alkyloxy, halo, hydroxy, nitro, cyano, C1-4alkyloxycarbonyl, trifluoromethyl, or trifluoromethoxy; or benzo[1,3]dioxolyl;
and
heteroaryl is imidazolyl, thiazolyl, indolyl, or pyridinyl.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein X1, X2 and X3 are carbon.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1) wherein m is the integer 0.

### Claim 4 (depends on 1)

A compound as claimed in claim 1 wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1) wherein m is the integer 1.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-2) wherein m is the integer 1.

### Claim 6 (depends on 1)

A compound as claimed in claim 1 wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 and R5 and R6 are taken together with the nitrogen to which they are attached to form pyrrolidinyl substituted with C1-4alkyloxycarbonyl and optionally further substituted with hydroxy, or piperidinyl substituted with C1-4alkyloxy-carbonyl.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 1.

### Claim 8 (depends on 1, 7)

A process for preparing a pharmaceutical composition as claimed in claim 7 wherein a therapeutically active amount of a compound as claimed in claim 1 is intimately mixed with a pharmaceutically acceptable carrier.