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Claims for Patent: 5,712,279

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Claims for Patent: 5,712,279

Title: Inhibitors of microsomal triglyceride transfer protein and method
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, X.sup.1, X.sup.2, x and R.sup.5 are as defined herein.
Inventor(s): Biller; Scott A. (Hopewell, NJ), Dickson; John K. (Eastampton, NJ), Lawrence; R. Michael (Yardley, PA), Magnin; David R. (Hamilton, NJ), Poss; Michael A. (Lawrenceville, NJ), Robl; Jeffrey A. (Newtown, PA), Sulsky; Richard B. (Franklin Park, NJ), Tino; Joseph A. (Lawrenceville, NJ)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:08/548,811
Patent 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;

X.sup.1 and X.sup.2 are independently selected from H or halo;

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

R.sup.5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R.sup.5 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 X.sup.1 and X.sup.2 is H.

5. The compound as defined in claim 1 wherein (CH.sub.2).sub.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 R.sup.5 is adjacent to the carbon attached to the ##STR267## group.

8. The compound as defined in claim 1 wherein R.sup.5 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 R.sup.5 is independently substituted with 1, 2, 3 or 4 of the following

I, Cl, F, CF.sub.3, ##STR268## where x is 1 to 5 ##STR269## alkyl, phenyl, phenyl substituted with halo, alkyl, CF.sub.3 O, alkoxy, ##STR270## CF.sub.3, or phenyl; ##STR271## where p is 1 to 5, --N(CH.sub.3)C.sub.6 H.sub.5 ; --S--(CH.sub.2).sub.p CF.sub.3 where p is 1 to 5, ##STR272## --S--alkyl, ##STR273## OCH.sub.3 ; cyclohexyl, ##STR274## amino; ##STR275## alkanoyl, alkoxycarbonyl, aroyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, --CH.sub.2 --S--C.sub.6 H.sub.5, ##STR276##

10. The compound as defined in claim 9 wherein (CH.sub.2).sub.x is (CH.sub.2).sub.4 or ##STR277## Z is a bond; X.sup.1 and X.sup.2 are H;

R.sup.5 is aryl, which is substituted with trifluoromethylphenyl, heteroaryl, halo and/or aryl or

R.sup.5 is heteroaryl

wherein the R.sup.5 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.

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

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

R.sup.5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R.sup.5 group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different wherein a substituent on R.sup.5 is adjacent to a ring carbon attached to the ##STR283## group.

17. The compound as defined in claim 16 wherein R.sup.5 is phenyl substituted with haloalkylphenyl or heteroaryl.

18. The compound as defined in claim 17 wherein R.sup.5 is ##STR284##

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