Inhibitors of microsomal triglyceride transfer protein and method

• US 6,066,650 A
• Filed: 07/21/1997
• Issued: 05/23/2000
• Est. Priority Date: 09/03/1993
• Status: Expired due to Term

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• 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): Raymond, Richard L.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/898,303
• Time in Patent Office: 1,037 Days
• Field of Search: 514/248, 514/252, 514/266, 514/307, 514/314, 514/315, 514/318, 514/320, 514/321, 514/323, 514/322, 514/324, 514/326, 514/329, 544/235, 544/238, 544/277, 544/407, 546/146, 546/169, 546/194, 546/196, 546/197, 546/198, 546/199, 546/201, 546/202, 546/208, 546/209, 546/211, 546/213, 546/214, 546/224, 546/223
• US Class Current: 514/315
• 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 method for preventing, inhibiting or treating atherosclerosis;

pancreatitis secondary to hypertriglyceridemia;

hyperglycemia (1) by causing reduced absorption of dietary fat through MTP inhibition or (2) by lowering triglycerides through MTP inhibition of (3) by decreasing absorptiion of free fatty acids through MTP inhibition;

or obesity secondary to malabsorption of dietary fat, or a method of lowering serum lipid levels, cholesterol and/or triglycerides, or preventing and/or treating hyperlipidemia, or hypercholesterolemia in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound which has the structure ##STR734## wherein R¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl;

R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, heteroarylalkyl, alkylthio, arylthio;

with the proviso that when R⁵ is CH₃, R⁶ is not hydrogen; and

pharmaceutically acceptable salts thereof.

2. The method as defined in claim 1 where the compound employed is

N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-benzamide;

N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-pentamide;

4-methoxy-α

-(4-methoxyphenyl)-N-[1-(2-phenylethyl)-4-piperidinyl]benzeneacetamide;

N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2-methoxybenzamide;

N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2-methylbenzamide;

N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2-pyridinamide;

N-1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl-benzamide, and the monhydrochloride salts of each thereof.