A method of lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hyperglycemia and/or hypertriglyceridemia, and/or preventing, inhibiting or treating atherosclerosis, pancreatitis, noninsulin dependent diabetes, or obesity in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound having the structure
- including pharmaceutically acceptable salts thereof, N-oxides thereof,
- wherein
- A is
- (1) a bond;
- (2) —O—;
- or
- (3)
- where R5 is H or lower alkyl, or R5 together with R2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring;
- B is a fluorenyl-type group of the structure
- R1 is H, alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloheteroalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, —PO(R13) (R14) (where R13 and R14 are independently alkyl, aryl, alkoxy or aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy or cycloheteroalkylalkoxy);
- aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups);
- cyano, 1,1-(alkoxyl or aryloxy)2alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring connected to L1 (or L2 in the case of R2) at the 2-position);
- 1,3-dioxane or 1,3-dioxolane connected to L1 (or L2 in the case of R2) at the 4-position;
- the R1 group may optionally be substituted with 1, 2, 3 or 4 substituents, which can be any of the R3 or R1 groups, or alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may optionally be substituted with alkyl, aryl or heteroaryl), heterocyclylcarbonylamino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom), alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,
- where J is:
- CHR23,
- R23, R24 and R25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
- R20, R21, R22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkyl-alkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
- and these substituents may either be directly attached to R1, or attached via an alkylene at an open position;
- R2 is independently any of the groups set out for R1, polyhaloalkyl or cycloheteroalkyl, and may be optionally substituted with one to four of any of the substituents defined for R1;
- L1 is a linking group containing up from 1 to 10 carbons in a linear chain including alkylene, alkenylene or alkynylene, which may contain, within the linking chain any of the following:
- one or two alkenes, one or two alkynes, an oxygen, an amino group, an oxo group, and may be substituted with one to five alkyl or halo groups;
- L2 may be the same or different from L1 and may independently be any of the L1 groups set out above or a single bond;
- R3, R3′, R4 and R4′ may be the same or different and are independently selected from H, halogen, CF3, haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar;
- with the proviso that (1) at least one of R1 and R2 includes a cycloheteroalkyl, and/or (2) at least one of R1 and R2 includes a substituent which is
- and/or a heterocyclylcarbonylamino moiety, and/or (3) at least one of R3, R3′, R4 and R4′ includes a cycloheteroalkyl moiety;
- are the same or different and independently represent a 5 or 6 membered heteroaryl ring which contains 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O;
- and including N-oxides;
- X is a bond, or is one of the following groups:
- wherein
- Y is O, N—R6 or S;
- n′ is 0, 1 or 2;
- R6 is H, lower alkyl, aryl, —C(O)R11 or —C(O)—O—R11;
- R7 and R8 are the same or different and are independently H, alkyl, aryl, halogen, —O—R12, or
- R7 and R8 together can be oxygen to form a ketone;
- R9, R10, R9′ and R10′ are the same or different and are independently H, lower alkyl, aryl or —O—R11;
- R9″, and R10″ are the same or different and are independently H, lower alkyl, aryl, halogen or —O—R11;
- R11 is alkyl or aryl;
- R12 is H, alkyl or aryl;
- with the proviso that where R1 and/or R2 is cycloheteroalkyl, such R1 and/or R2 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo-pyrrolidinyl).