Inhibitors of microsomal triglyceride transfer protein and method

• US 5,712,279 A
• Filed: 01/11/1996
• Issued: 01/27/1998
• Est. Priority Date: 02/21/1995
• 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., Robl, Jeffrey A., Magnin, David R., Biller, Scott A., Dickson, John K.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): WONG, KING
• Application Number:
  US08/548,811
• Time in Patent Office: 747 Days
• Field of Search: 546/208, 546/202, 546/198, 546/193, 546/189, 546/201, 514/325, 514/324, 514/321, 514/318, 514/316, 514/259, 514/235.5, 514/255, 514/228.8, 514/323, 514/252, 544/287, 544/130, 544/360, 544/88, 544/405
• US Class Current: 514/253.01
• 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 Z, X¹, X², x and R⁵ are as defined herein.

Claims

1. A compound having the structure ##STR265## including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond or S;

X¹ and X² are independently selected from H or halo;

x is an integer from 2 to 6, (CH₂)_x is optionally substituted with 1, 2 or 3 substituents which are the same or different and are alkyl or halo;

R⁵ is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R⁵ group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different, wherein one substituents is optionally attached to a ring carbon in the position adjacent to the carbon linked to ##STR266##

2. The compound as defined in claim 1 wherein Z is a bond.

3. The compound as defined in claim 1 which is a piperidine N-oxide.

4. The compound as defined in claim 1 wherein each of X¹ and X² is H.

5. The compound as defined in claim 1 wherein (CH₂)_x is substituted with 1, 2 or 3 substituents which are the same or different and are alkyl or halo.

6. The compound as defined in claim 5 wherein the halo substituent is F.

7. The compound as defined in claim 1 wherein the substituent on R⁵ is adjacent to the carbon attached to the ##STR267## group.

8. The compound as defined in claim 1 wherein R⁵ is substituted with 1, 2, 3 or 4 substituents which may be the same or different and are bicyclic heteroaryl, aryl, alkylamino, alkyl(aryl)amino, heteroarylamino, arylamino, or acyl.

9. The compound as defined in claim 1 wherein R⁵ is independently substituted with 1, 2, 3 or 4 of the following

I, Cl, F, CF₃, ##STR268## where x is 1 to 5 ##STR269## alkyl, phenyl, phenyl substituted with halo, alkyl, CF₃ O, alkoxy, ##STR270## CF₃, or phenyl;

##STR271## where p is 1 to 5, --N(CH₃)C₆ H₅ ;

--S--(CH₂)_p CF₃ where p is 1 to 5, ##STR272## --S--alkyl, ##STR273## OCH₃ ;

cyclohexyl, ##STR274## amino;

##STR275## alkanoyl, alkoxycarbonyl, aroyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, --CH₂ --S--C₆ H₅, ##STR276##

10. The compound as defined in claim 9 wherein (CH₂)_x is (CH₂)₄ or ##STR277## Z is a bond;

X¹ and X² are H;

R⁵ is aryl, which is substituted with trifluoromethylphenyl, heteroaryl, halo and/or aryl or

R⁵ is heteroaryl

wherein the R⁵ includes a substituent attached to a carbon adjacent to the carbon linked to ##STR278##

11. The compound as defined in claim 1 which is ##STR279## the monohydrochloride thereof, the dihydrochloride thereof or the pharmaceutically acceptable salt thereof.

12. The compound as defined in claim 1 which is ##STR280## the monohydrochloride thereof, the dihydrochloride thereof or other pharmaceutically acceptable salt thereof.

14. A method for preventing or treating atherosclerosis;

pancreatitis secondary to hypertriglyceridemia;

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

or obesity by causing a reduced absorption of dietary fat through MTP, in a mammal species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1 or 13.

15. A method of lowering serum lipid levels, cholesterol and/or triglycerides, or preventing and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1 or 13.

13. A compound of the structure ##STR281## or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof.

16. A compound having the structure ##STR282## including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof,

R⁵ is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R⁵ group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different wherein a substituent on R⁵ is adjacent to a ring carbon attached to the ##STR283## group.

17. The compound as defined in claim 16 wherein R⁵ is phenyl substituted with haloalkylphenyl or heteroaryl.

18. The compound as defined in claim 17 wherein R⁵ is ##STR284##

19. The compound as defined in claim 16 having the structure ##STR285##