Inhibitors of microsomal triglyceride transfer protein and method

• US 6,034,098 A
• Filed: 07/21/1997
• Issued: 03/07/2000
• Est. Priority Date: 09/03/1993
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lawson, John E., Holava, Henry M., Partyka, Richard A., Lawrence, R. Michael, Sulsky, Richard B., Tino, Joseph A., Poss, Michael A., Magnin, David R., Biller, Scott A., Dickson, John K.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/898,304
• Time in Patent Office: 960 Days
• Field of Search: 514/290, 514/309, 514/318, 514/323, 546/111, 546/141, 546/194, 546/200
• US Class Current: 514/309
• 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 structure ##STR641## R⁸, R⁹ and R¹⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;

R¹ is a fluorenyl-type group of the structure ##STR642## R¹ is an indenyl-type group of the structure ##STR643## Z¹ and Z² are the same or different and are independently a bond, O,S, ##STR644## with the proviso that with respect to B, at least one of Z¹ and Z² will be other than a bond;

R¹¹ is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms;

arylene or mixed arylene-alkylene;

R¹² is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, theteroaryl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the proviso that

when R¹² is H, aryloxy, alkoxy or arylalkoxy, then Z² is ##STR645## Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms;

R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkyl-carbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;

R^15a and R^16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;

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

##STR646## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and

a pharmaceutically acceptable salt thereof.

2. The compound as defined in claim 1 having the formula ##STR647## and a pharmaceutically acceptable salt thereof.

3. The compound as defined in claim 1 wherein R¹ is ##STR648##

4. The compound as defined in claim 3, wherein R¹ is Z is a bond, O or S;

R¹³, R¹⁴, R¹⁵ and R¹⁶ are each H or one of R¹⁵ and R¹⁶ and one of R¹³ and R¹⁴ are halogen;

Z¹ is a bond or C═

O;

R¹¹ is alkylene or alkenylene;

R¹² -Z² is ##STR649## R^12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl.

5. The compound as defined in claim 1 having the structure ##STR650## Z is O, S or a bond;

R¹³ and R15 are independently H or F;

Z¹ is a bond;

R¹¹ is alkylene;

R¹² -Z² is ##STR651## and R^12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl.

6. The compound as defined in claim 5 wherein R¹¹ is --(CH₂)₄ --, Z¹ is a bond, and R¹² -Z² is ##STR652##

7. The compound as defined in claim 5 having the structure where R¹³ and R¹⁵ are independently H or F, and R¹² is trifluoromethylalkyl or alkyl.

8. The compound as defined in claim 1 having the structure ##STR653## where R¹² is alkyl, and R¹³ and R¹⁵ are independently H or F.

9. The compound as defined in claim 1 wherein R¹ is an indenyl-type group of the structure ##STR654##10.

10. The compound as defined in claim 1 wherein R¹ is a group of the structure

11. The compound as defined in claim 1 having the structure Z is O, S or a bond;

R¹³ and R¹⁵ are independently H or F;

Z¹ is a bond;

R¹¹ is alkylene;

R¹² -Z² is ##STR655## and R^12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl.

12. The compound as defined in claim 1 which is:

2-[1-[2-(9H-fluoren-9-yl)ethyl]-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one;

2,3-dihydro-2-[1-[2-[9-(2-propylenyl)-9H-fluoren-9-yl]ethyl]-4-piperidinyl]-1H-isoindol-1-one;

(Z)-2-[1-[4-(9H-fluoren-9-yl)-2-butenyl]-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one;

(Z)-2,3-dihydro-2-[1-[4-[9-(2-propenyl)-9H-fluoren-9-yl]-2-butenyl]-4-piperidinyl]-1H-isoindol-1-one;

and a pharmaceutically acceptable salt of any of the above and an N-oxide of any of the above.

13. The compound as defined in claim 1 which is ##STR656## 9-[3-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]propyl]-N-propyl-9H-fluorene-9-carboxamide;

2,3-dihydro-2-[1-[4-oxo-4-(9-propyl-9H-fluoren-9-yl)butyl]-4-piperidinyl]-1H-isoindol-1-one or its monohydrochloride salt;

(E)-9-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]-2-butenyl]-2,7-difluoro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

9-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

(Z)-9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]-2-butenyl]-N-propyl-9H-fluorene-9-carboxamide;

2,3-dihydro-2-[1-[2-oxo-2-(9-propyl-9H-fluoren-9-yl)ethyl]-4-piperidinyl]-1H-isoindol-1-one;

(E)-9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]-2-butenyl]-N-propyl-9H-fluorene-9-carboxamide;

9-[3-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]propyl]-N-propyl-9H-fluorene-9-carboxamide;

##STR657## N-[2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]-ethyl]-9-propyl-9H-fluorene-9-carboxamide

9-[5-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]pentyl]-N-propyl-9H-fluorene-9-carboxamide;

9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

9-[2-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]-ethyl]-N-propyl-9H-fluorene-9-carboxamide;

N-ethyl-9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide;

9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-2,2,2-trifluoroethyl-9H-xanthene-9-carboxamide;

9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]-butyl]-N-propyl-9H-xanthene-9-carboxamide;

9-[4-[4-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide;

9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-indeno[2,1-b]pyridine-9-carboxamide;

2,3-dihydro-2-[1-[4-hydroxy-4-(9-propyl-9H-fluoren-9-yl)butyl]-4-piperidinyl]-1H-isoindol-1-one;

15. The compound as defined in claim 1 which is

2,3-dihydro-1-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-1H-indene-1-carboxamide;

trans-2,3-dihydro-1-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-2-phenyl-N-propyl-1H-indene-1-carboxamide;

1-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-2-phenyl-N-propyl-1H-indene-1-carboxamide;

2-1-[4-[9-(butylsulfonyl)-9H-fluoren-9-yl]butyl]-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one;

9-[4-[[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1-piperidinyl]butyl]-2,7-difluoro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

2,3-dihydro-2-[1-[4-[9-(1-oxopentyl)-9H-fluoren-9-yl]butyl]-4-piperidinyl]-1H-isoindol-1-one;

9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;

9-[4-(4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-9H-fluorene-9-carboxamide;

1-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-2-methyl-N-(2,2,2-trifluoroethyl)-1H-indene-1-carboxamide;

9-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,3,3,3-pentafluoro-propyl)-9H-fluorene-9-carboxamide;

1-[4-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-1H-indene-1-carboxamide;

and a pharmaceutically acceptable salt of any of the above and an N-oxide of any of the above.

17. A method for preventing, inhibiting or treating atherosclerosis;

pancreatitis secondary to hypertriglyceridemia;

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

or obesity secondary to malabsorption of dietary fat in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

18. 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.

14. 3-dihydro-2-[1-[3-[(9-propyl-9H-fluoren-9-yl)thio]propyl]-4-piperidinyl]-1H-isoindol-1-one;

2,3-dihydro-2-[1-[3-[(9-propyl-9H-fluoren-9-yl)sulfonyl]propyl]-4-piperidinyl]-1H-isoindol-1-one;

and a pharmaceutically acceptable salt of any of the above and an N-oxide of any of the above.

16. A compound which has the structure ##STR658## R⁸, R⁹ and R¹⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;

R¹ is a fluorenyl-type group of the structure ##STR659## R¹ is an indenyl-type group of the structure ##STR660## Z¹ and Z² are the same or different and are independently a bond, O, S, ##STR661## with the proviso that with respect to B, at least one of Z¹ and Z² will be other than a bond;

R¹¹ is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms;

arylene or mixed arylene-alkylene;

R¹² is hydrogen, alkyl, alkenyl, aryl, haloalkyl, arylalkyl, arylalkenyl, cycloalkyl, trihaloalkyl, trihaloalkylalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the proviso that

when R¹² is H, aryloxy, alkoxy or arylalkoxy, then Z² is ##STR662## and Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms, R¹³, R¹⁴, R¹⁵, and R¹⁶ are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, carboxy, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;

R^15a and R^16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;

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

##STR663## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members;

or

a pharmaceutically acceptable salt thereof.