Aryl piperidine and piperazine derivatives as inducers of ldl-receptor expression

• US 20040077654A1
• Filed: 11/11/2003
• Published: 04/22/2004
• Est. Priority Date: 01/15/2001
• Status: Abandoned Application

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Bombrun, Agnes, Congreve, Miles Stuart, Bouillot, Anne Marie Jeanne, Dumaitre, Bernard Andre, Ramsden, Nigel Grahame, Gosmini, Romain Luc
• Application Number:
  US10/250,713
• Publication Number:
  US 20040077654A1
• Time in Patent Office: Days
• US Class Current: 514/252.13
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention concerns Use of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof, in the manufacture of a medicament for the treatment of diseases ameliorated by LDL-r upregulation, to novel compounds and pharmaceutical compositions within the scope of formula (I).

Claims

1. Use of a compound of formula (I)

2. Use according to claim 1 where Ar₁ represents an optionally substituted phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or bicyclic heteroaromatic group, where optional substitution is effected by R¹.

3. Use according to claim 1 or 2 where substitution on Ar₁ is represented by methylenedioxy or one, two or three groups independently selected from C_1-4 alkylhydroxy, C_1-4 alkoxy, —

O—

C_0-4alkylene-R², where R² represents C_1-4 perfluoroalkyl, a 5-6 membered heteroaromatic group, e.g. pyridyl or a C_3-8cycloalkyl.

4. Use according to any one of claims 1 to 3 where A is —

C(H)—

.

5. Use according to any one of claims 1 to 4 where Z is a direct link, —

NH—

, NSO₂Ph- or —

O—

.

6. Use according to any one of claims 1 to 5 where Integers o and n are 1 and 2 respectively.

7. Use according to any one of claims 1 to 6 where E is an n-butylene group.

8. Use according to any one of claims 1 to 7 where G is Y—

Ar₃.

9. Use according to claim 8 where Y is an —

N(H)CO—

group or a direct link.

10. Use according to any one of claims 1 to 9 where Ar₂ is a bicyclic heteroaromatic group selected from benzofuranyl or indolyl, optionally substituted by C_1-4alkyl.

11. Use according to any one of claims 1 to 10 where Ar₃ is phenyl or a pyridyl group, substituted by a halogen, nitrile or C_1-4perfluoroalkyl.

12. Use of a compound of formula (Ia)

13. Use of a compound selected from:

4-(4-chloro-benzoylamino)-N-{4-[4-(2,4-dimethoxy-phenyl)-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-{4-4-(2-ethoxy-4-methyl-phenyl)-piperidin-1-yl]butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-{4-[4-(2-ethoxy-4-ethyl-phenyl)-pipeddin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-{4-[4-(4-ethyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-{4-[4-(4-isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-{4-[4-(2-ethoxy-4-isopropyl-phenyl)-piperidin-1-yl]-butyl}-benzamide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid (4-{4-[2,5-dimethyl-4-(pyridin-2-ylmethoxy)-phenyl]-piperidin-1-yl}-butyl)-amide;

4-(4-chloro-benzoylamino)-N-[4-(4-benzo[1,3]dioxol-5-yl-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-[4-(4-naphthalen-2-yl-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N{4-[4-(5,6,7,8-tetrahydro-naphthalen-2-yl)-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-[4-(4-naphthalen-1-yl-piperidin-1-yl]-butyl}-benzamide;

4-(4-chloro-benzoylamino)-N-{4-[4-(2-trifluoroethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl}-benzamide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(2-methylsulfanyl-phenyl)-piperidin-1-yl]-butyl}-amide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(1-methyl-1H-indol-3-yl)-piperidin-1-yl]-butyl}-amide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyl}-amide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid [4-(4-benzo[b]thiophen-3-yl-piperidin-1-yl)-butyl]-amide;

4-(4-chloro-benzoylamino)-N-4-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-butyl}-benzamide;

4-(4-Chloro-benzoylamino)-N-{4-[4-(2,4-dimethoxy-phenyl)-[1,4]diazocan-1-yl]-butyl}-benzamide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(2-ethoxy-4-methyl-phenylamino)-piperidin-1-yl]-butyl}-amide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid (4-{4-[benzenesulfonyl-(2-ethoxy-4-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide;

4′

-Trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(naphtalen-1-yloxy)-piperidin-1-yl]-butyl}-amide;

4-(4-chloro-benzoylamino)-N-{4-[4-(2-methoxy-4-methyl-phenyl)-piperazin-1-yl]-butyl}-benzamide;

4′

-Trifluoromethyl-biphenyl-4-sulfonic acid {4-[4-(2-ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl}-amide;

5-[4-(2-Ethoxy-4-methyl-phenyl)-piperidin-1-yl]-pentanoic acid (4′

-trifluoromethyl-biphenyl-4-yl)-amide;

4′

-{5-[4-(1-Methoxy-naphtalen-2-yl)-piperidin-1-yl]-pentyloxy}-biphenyl-4-carbonitrile;

4′

-{4-[4-(1-Methoxy-naphtalen-2-yl)-piperidin-1-yl]-butoxy}-biphenyl-4-carbonitrile;

4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid {4-[4-(4-isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-amide;

2-(4-Chloro-phenyl)-1-methyl-1H-indole-5-carboxylic acid {4-[4-(2-ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl}-amide;

2-(4-Trifluoromethyl-phenyl)-benzofuran-5-carboxylic acid {4-[4-(2-ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl}-amide;

2-(4-Chloro-phenyl)-benzofuran-5-carboxylic acid {4-[4-(2-ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl}-amide;

2-(3,4-Dichloro-phenyl)-benzofuran-5-carboxylic acid {4-[4-(1-cyclopropylmethoxy-5,6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-amide;

2-(6-Trifluoromethyl-pyridin-3-yl)-benzofuran-5-carboxylic acid {4-[4-(1-cyclopropylmethoxy-5,6,7,8-tetrahydronaphtalen-2-yl)-piperidin-1-yl]-butyl}-amide;

N-{4-[4-(2-Ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl}4-[2-(4-trifluoromethyl-phenyl)-vinyl]-benzamide;

N-{4-[4-(2-Ethoxy-4-methyl-phenyl)-piperidin-1-yl]-butyl)-4-(4-trifluoromethyl-benzyloxy)-benzamide;

4-[2-(3,5-dichloro-phenyl)-ethenyl]-N-4-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-butyl}-benzamide;

4-[2-(3,5-dichloro-phenyl)-ethyl]-N-{4-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-butyl}-benzamide;

4-(4-Benzoyl)-N-{4-[4-(4-isopropyl-2-methoxy-phenyl)-piperidin-1-yl]-butyl}-benzamide;

4′

-trifluoromethyl-biphenyl-4-carboxylic acid {4-[4-(2,4-diethoxy-benzyl)-piperidin-1-yl]-butyl}-amide;

4-(4-chloro-benzoylamino)-N-{4-[4-(2,4-dimethoxy-benzoyl)-piperidin-1-yl]-butyl}-benzamide;

4′

-Cyano-biphenyl-4-carboxylic acid {4-[4-(1-methyl-1H-indol-3-yl)-piperidin-1-yl]-butyl}-amide;

4(4-chloro-benzoylamino)-N-{4-[4-(5-methyl-2-piperidin-4-yl-phenol)]-butyl}-benzamide;

1-(4-chloro-benzoylamino)-N-{4-[4-(5-ethyl-2-piperidin-4-yl-phenol)]-butyl}-benzamide;

4-(4-Chloro-benzoylamino)-N-{4-[4-(1-hydroxy-5,6,7,8-tetrahydro-naphtalen-2-yl)-piperidin-1-yl]-butyl}-benzamide;

4-(4-Chloro-benzoylamino)-N-(4-[4-(1-hydroxy-naphtalen-2-yl)-piperidin-1-yl]-butyl}-benzamide;

or a physiologically acceptable salt, solvate or derivative thereof, in the manufacture of a medicament for the treatment of diseases ameliorated by LDL-r upregulation.

14. Use of a compound according to claim 13 in human medicine.

15. Use of a compound according to claim 13 or a physiologically acceptable salt solvate or derivative thereof in the preparation of a medicament for use in'"'"'the treatment of conditions resulting from elevated circulating levels of LDL-cholesterol.

16. A method for the treatment of a mammal, including man, of conditions resulting from elevated circulating levels of LDL-cholesterol, comprising administration of an effective amount of a compound according to claim 13 or a physiologically acceptable salt or solvate thereof.

17. A pharmaceutical composition which comprises at least one compound according to claim 13 or a physiologically acceptable-salt solvate or derivative thereof, with one or more pharmaceutically acceptable carriers or excipients and optionally one or more further physiologically active agents.

13-1. A compound of formula (IC)

18. A process for the preparation of compound of formula (Ib) comprising:

(A) reaction of a compound of formula (II) with a compound of formula (III)

where Xa and Xb are suitable reactants to form a group X;

(B) reaction of a compound of formula (IV) with a compound of formula (XIII)

where E-C₁ (‘

E minus C₁’

) means that the chain length of group E is one carbon less than that in the resulting compound (I), under standard reductive amination conditions;

or

(C) reaction of a different compound of formula (I).