Inhibitors of microsomal triglyceride transfer protein and method

• US 5,883,099 A
• Filed: 07/21/1997
• Issued: 03/16/1999
• Est. Priority Date: 09/03/1993
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lawrence, R. Michael, Sulsky, Richard B., Tino, Joseph A., Poss, Michael A., Magnin, David R., Lawson, John E., Biller, Scott A., Dickson, John K., Holava, Henry M., Partyka, Richard A.
• Primary Examiner(s): HUANG, EVELYN MEI
• Application Number:
  US08/896,872
• Time in Patent Office: 603 Days
• Field of Search: 544/391, 544/392, 514/255
• US Class Current: 514/255.01
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 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 211/58 attached in position 4
• CPC Class Codes: 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
• CPC Class Codes: C07D 211/94 Oxygen atom, e.g. piperidine N-oxide
• 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 419/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: G01N 2800/044 : Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity

Abstract

Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum lipids and treating atherosclerosis and related diseases. The compounds have the structure ##STR1## wherein R¹ to R⁷, Q, X and Y are as defined herein.

Claims

1. A compound which has the stricture ##STR444## wherein m is 2 or:

3;

R², R³, R⁴ are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxyl or haloalkyl;

R⁷ is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalky is optionally substituted with oxo ##STR445## or a pharmaceutically acceptable salt thereof;

with the provisos that

(1) where R², R³ and R⁴ are each H or where one of R², R³ and R⁴ is 6-fluoro, and the others are H, R⁷ will be other then 4-(2-methoxyphenyl); and

(2) where R², R³ and R⁴ are each H or where one of R², R³ and R⁴, is 6-fluoro, and the others are H, then where R⁷ is alkyl or arylalkyl, the alkyl by itself or as part of arylalkyl will not be substituted with oxo ##STR446##

2. The compound as defined in claim 1

wherein:

R², R³, R⁴ are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto.

5. The compound as defined in claim 1 wherein Y is ##STR451## .

6. The compound as defined in claim 1 wherein R⁷ is aryl.

7. The compound as defined in claim 1 wherein R⁷ is phenyl or phenyl substituted with alkoxy.

8. The compound as defined in claim 1 wherein R⁷ is phenyl or 2-methoxyphenyl.

3. A method for treating atherosclerosis;

pancreatitis obesity or hyperglycemia, responsive to a decrease in MTP activity, in a patient, which comprises administering to a patient in need of treatment an MTP activity decreasing amount of a compound of the structure ##STR447## wherein m is 2 or 3;

R², R³, R⁴ are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, axyl, arylalkyl, alkylmercapto, arylmercapto, cyoloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;

R⁷ is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo ##STR448## or a pharmaceutically acceptable salt thereof.

4. A method of lowering serum lipid levels, cholesterol or triglycerides, or treatins hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hyplrcholesterolemia or hypertriglyceridemia, responsive to a decrease in MTP activity, in a patient, which comprises administering to a patient in need of treatment an MTP activity decreasing amount of a compound of the structure ##STR449## wherein m is 2 or 3;

R², R³, R⁴ are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;

R⁷ is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo ##STR450## or a pharmaceutically acceptable salt thereof.

9. A compound which is 3,4-dihydro-3- 4-phenyl-1-piperazinyl!methyl!-1(2H)-naphthalenone;

or

3,4-dihydro-3- 4-(2-methoxyphenyl)-1-piperazinyl!-carbonyl!-1(2H) -naphthalenone.