CA2286341A1

CA2286341A1 - Mtp inhibitors and fat soluble vitamin therapeutic combinations to lower serum lipid levels

Info

Publication number: CA2286341A1
Application number: CA002286341A
Authority: CA
Inventors: John R. Ii Wetterau; Richard E. Gregg
Original assignee: Individual
Current assignee: Bristol Myers Squibb Co
Priority date: 1997-05-01
Filing date: 1998-04-23
Publication date: 1998-11-12
Also published as: AU7155998A; WO1998050028A1; AU748608B2; JP2001527551A; EP1024804A1; EP1024804A4

Abstract

A pharmaceutical combination formed of an MTP inhibitor and a fat soluble vitamin such as Vitamins E, A, K and/or D, and optionally another cholesterol lowering drug, is provided which is employed in a method for lowering serum lipids, cholesterol and/or triglycerides and thereby inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia and/or obesity.

Description

MTP INHIBITORS AND FAT SOLUBLE VITAMIN THERAPEUTIC
COMBINATIONS TO LOWER SERUM LIPID LEVELS.
Field of the Invention The present invention relates to a combination of an MTP inhibitor and a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering drug, for example, an HMG CoA
reductase inhibitor, such as pravastatin, lovastatin or simvastatin, and to a method for lowering serum lipids, cholesterol and/or triglycerides in mammalian species by administering such combination.
Background of the Invention The use of microsomal triglyceride transfer protein (MTP) inhibitors for decreasing serum lipids including cholesterol and triglycerides and their use in treating atherosclerosis, obesity and pancreatitis is disclosed in Canadian Patent Application No. 2,091,102 (corresponding to U.S. Application Serial No. 117,362), U.S. Application Serial No. 472,067, filed June 6, 1995 (file DC2le), U.S.
Application Serial No. 548,811, filed January 11, 1996 (file DC2lh), U.S. Application Serial No. 08/767,923, filed December 17, 1996 (file HX79c*), U.S. provisional application No. 60/017,253, (file HX82*) and U.S.
provisional application No. 60/017,254, (file HX84*).
All of the above U.S. applications are incorporated herein by reference.
Description of the Invention In accordance with the present invention, a novel combination is provided which includes an MTP inhibitor and a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering agent.

In addition, in accordance with the present invention, a method for preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia, or obesity is provided, wherein an MTP inhibitor in combination with a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K
and/or Vitamin D, and optionally another cholesterol lowering drug, is administered in therapeutically effective amounts to lower LDL cholesterol and triglycerides.
Furthermore, in accordance with the present invention, a method is provided for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia, wherein a combination of an MTP
inhibitor and a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering drug, is administered in therapeutically effective amounts.
MTP inhibitors inhibit the production of triglyceride rich plasma lipoproteins, very low density lipoproteins (VLDL) and chylomicrons. Vitamins E, A, K and D are fat soluble vitamins which are, in part, transported throughout the body on these lipoproteins, or lipoproteins which are metabolic products of these lipoproteins.
Because MTP inhibitors block lipoprotein production, they may interfere with the normal absorption and transport of fat soluble vitamins. Abnormal absorption of fat soluble vitamins has been observed in abetalipoproteinemic subjects who lack MTP due to a genetic defect in the gene encoding MTP. Fat soluble vitamin supplements in abetalipoproteinemic subjects ameliorate most if not all the complications associated with fat soluble vitamin deficiencies (Kane, J.P., et al, "Disorders of the Biogenesis and Secretion of Lipoproteins Containing the B
Apolipoproteins", Chapter 57, pp. 1853-1885, "The Metabolic and Molecular Bases of Inherited Disease", 7th Ed., Vol. 11 (1995)). Thus, Vitamins E, A, K, and/or D supplements in subjects treated with an MTP inhibitor will ameliorate adverse effects of MTP inhibitors associated with fat soluble vitamin deficiencies.
Cholesterol lowering drugs or drugs which are inhibitors of cholesterol biosynthesis which may optionally be used in combination with the MTP inhibitor and the fat soluble vitamin include F~iG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, bile acid sequestrants, probucol, niacin, niacin derivatives, neomycin, aspirin, and the like.
It is believed that the combination of MTP inhibitor and other cholesterol lowering drug, which works by a mechanism other than inhibiting MTP, together with a fat soluble vitamin is a surprising and unique concept in treating diseases involved with elevated cholesterol and/or triglycerides and atherosclerosis, hyperglycemia, obesity and/or pancreatitis, in that the combination may provide additional anti.cholesterolemic effects over that which may be obtained using each of the cholesterol lowering components of the combination alone. It is expected that reduced levels of each of the MTP inhibitor and other cholesterol lowering drug may be employed to achieve desired results, albeit with reduced side effects.
Detailed Descrit~tion of the Invention The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term "MTP" refers to a polypeptide or protein complex that (1) if obtained from an organism (e. g., cows, humans, etc.), can be isolated from the microsomal fraction of homogenized tissue; and (2) stimulates the transport of triglycerides, cholesterol esters, or phospholipids from synthetic phospholipid vesicles, membranes or lipoproteins . 35 to synthetic vesicles, membranes, or lipoproteins and which is distinct from the cholesterol ester transfer protein [Drayna et al., Nature 327, 632-634 (1987)] which may have similar catalytic properties.
The phrase "treating atherosclerosis" as employed herein includes stabilizing atherosclerosis and/or causing the regression of atherosclerosis.
The phrase "stabilizing" atherosclerosis as used herein refers to slowing down the development of and/or inhibiting the formation of new atherosclerotic lesions.
The phrase "causing the regression of"
atherosclerosis as used refers to reducing and/or eliminating atherosclerotic lesions.
The term "fat soluble vitamin" as employed herein refers tb Vitamin E, Vitamin A, Vitamin K or Vitamin D, including combinations of any two or more of the above vitamins.
The term "pancreatitis" as employed herein refers to pancreatitis which is secondary to hypertriglyceridemia.
The phrase preventing, inhibiting or treating hyperglycemia as employed herein refers to preventing, inhibiting or treating hyperglycemia or diabetes (Type I or II) by (1) causing reduced absorption of dietary fat through MTP inhibition or (2) lowering triglycerides through MTP inhibition or (3) decreasing absorption of free fatty acids through MTP inhibition.
The term preventing, inhibiting or treating "obesity" as employed herein refers to preventing, inhibiting or treating obesity by causing reduced malabsorption of dietary fat through MTP inhibition.
The pharmaceutical combination of the invention will preferably include Vitamin E in an amount within the range from about 100 to about 15,000 mg/day, preferably from about 200 to about 5,000 mg/day.
Where present, Vitamin A will be employed in an amount within the range from about 1,000 to about 50,000 International Units (IU)/day, preferably from about 10,000' to about 35,000 IU/day.
G~here present, Vitamin K will be employed in an . amount within the range from about 0.1 to about 25 mg/day, preferably from about 5 to about 15 mg/day.
Where present, Vitamin D will be employed in an amount within the range from about 50 to about 1,000 IU/day, preferably from about 100 to about 400 IU/day.
Preferred combinations of vitamins include Vitamin E
and Vitamin A in amounts of each as set out above.
Vitamin K and Vitamin E in amounts of each as set out above.
Vitamin D and Vitamin E in amounts of each as set out above.
The combination of the MTP inhibitor and other cholesterol lowering drug will be employed in a weight ratio to each other within the range of from about 1000:1 to about 0.001:1 and preferably from about 100:1 to about 0.05:1.
MTP inhibitors to be employed in the methods of the invention include MTP inhibitors disclosed in Canadian Patent Application No. 2,091,102 (corresponding to U.S.
Application Serial No. 117,362), U.S. Application Serial No. 472,067, filed June 6, 1995 (file DC2le), U.S.
Application Serial No. 548,811 filed January 11, 1996 (file DC2lh), U.S. Application Serial No. 08/767,923, filed December 17, 1996 (file HX79c*), U.S. provisional application No. 60/017,253, (file HX82*) and U.S.
provisional application No. 60/017,254, (file HX84*).
All of the above U.S. applications are incorporated herein by reference.
The MTP inhibitors disclosed in U.S. Application Serial No. 472,067, filed June 6, 1995 (file DC2le) are piperidine compounds of the structure R
,\
R3. ~_ / N~N_ R1 X
R°

or or or or Rz O R~
Ra~ I / -N~
~X
Ra Rs~ Q_ /~
fl--( N- Rt Rs Rt Rs~ O_ N
Rs J
O
Rz, ~ ~N.~
R3 ~ ~ -_ i Y~N
Ra O O
where O is - C- or - S- ;
O
X is: CHR8, - C- ~ -CH- CH- or -~= C- ;
O R9 Rto Re Rto R8, R9 and R1~ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
Y is -(CHg)m or -C-O
wherein m is 2 or 3;
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, azylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least 2 carbons, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo;
or R1 is a fluorenyl-type group of the structure R1~~~ R15 R16 ~ R15 1 ~ 15 R\ / R
_ R11 _ R11 _ Zi v y _ R11_ Zi z or z or Z
R12 ~ ~ R12_ Z2 ~ ~ R12- Z2 Het _ R13 ~-''~ R14 R13 ~~ R14 13 R14 A s R1s R1s Het 1 or R1z- Zz Z
Het 2 R13 R1a .
or D
R1 is an indenyl-type group of the structure R R13~,~~ R
_ R11_ Z1 or - R11- Z1 \ / or Riz_ Zz ~ ~ Risa i2 z ~ Risa RlSa (CH2 a R - Z
Rl5a _E
(a = 2,3 or 4) F

R13 R1a R14 Het ) Het _ R11_ Z1 or _ R11_ Z1 R1z_ Zz ~ Rl6a R12_ Z2 ~ Rl6a Rlsa (CHz)a RlSa Z1 and ZZ are the same or different and are independently a bond, O, S, SUBSTITUTE SHEET (RULE 26) H
S S - NH- C- ~ -N C- ~ - C- or - C- , O ~ ~0~2 ~ p alkyl O O OH
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 arylenealkylene; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1} when R12 is H, aryloxy, alkoxy or arylalkoxy, -NH-C- , -N C- -C-i then Z2 is O alkyl O ° O or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
Z is bond, 0, 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, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;
Rl5a and Rl6a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarboriyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
or R1 is a group of the structure ( cH2 ) D

wherein p is 1 to 8 and R1~ and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R1~ and R18 being other than H;
_g_ or R1 is a group of the structure R2o - Rta wherein R19 is aryl or heteroaryl;
R2~ is aryl or heteroaryl;
R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
R2, R3, R4~are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl,,alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cyclohetero-alkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroazylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, aryisulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all optionally substituted with l, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 set out above;
R~ is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted wi th oxo f ~ f ~ f Het Het 1 and Het 2 are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and O
~~r'i~ Rt N-oxides thereof, and pharmaceutically acceptable salts thereof;
with the provisos that where in the first formula X
is CH2, and R2, R3 and R4 are each H, then R1 will be other than 3,3-diphenylpropyl, and in the fifth formula, where one of R2, R3 and R4 is 6-fluoro, and the others are H, R~
will be other than 4-(2-methoxyphenyl).
The MTP inhibitors disclosed in U.S. application Serial No. 548,811 filed January 11, 1996 (file DC2lh), have the structure xi ~ o ~i H
C- N- CHy - CFg Z O
( CH2 ) X N~ H- C- RS

including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, O or S;
X1 and X2 are independently selected from H or halo;
x is an integer from 2 to 6;
R5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R5 group being optionally substituted with l, 2, 3 or 4 substituents which may be the same or different.
The MTP inhibitors disclosed in U.S. Application Serial No. 08/767,923, filed December 17, 1996 (file HX79c*) have the structure o (o)Q oa La ~ Ll Ra ,S L1 Raw ~ L1 Ray ~A B~ ~Rl ~La ~B~ w 1 La B~ ~Ri R Rx or or I ~ IB
including pharmaceutically acceptable salts thereof, N-oxides thereof, wherein q is 0, 1 or 2;
A is (1) a bond;
(2) -O-; or -N
IS
( 3 ) R
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 f R4, Ra R4, 1 /, Or Het ~ /~ Or X ~ 3. X
Rs, Ra R Ra w R3 a' R
Net 1 Het 2 or Rs, X Ra B is an indenyl-type group of the structure R3, R3 R3, Or R3b ~ / or , s (CH~
R i~ "~
(a = 2,3 or 4) Raa R3, R3 R3, Het Het ) f J' or R3b R3b v Raa (CH2)a R3a RX is H, alkyl or aryl;
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, heteroazylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloheteroalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, -PO(R13)(R14)~
(where R13 and R14 are independently alkyl, aryl, alkoxy, 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, l,l-(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 RZ) 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, R2o O
R2~- I_ \
R~
inhere J is: CHRa3, -C- -CH-CH- pr -C=C- ;
' I I
Rze g2s g~a Ras R23, R24 and R25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycioalkyl, or cycloalkylalkyl;
R2o~ R21~ R22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, 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, H, polyhaloalkyl, or cycloheteroalkyl, and may be optionally substituted with one to four of any of the groups defined for R3 or substituents defined for R1;
L1 is a linking group containing 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 singe 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, IO 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;
R3a and R3b are the same or different and are independently any of the R3 groups except hydroxy, nitro, amino or thio;
f ~ f ~ f Het lief 1 and Het 2 are the same or different and independently represent a 5 or 6 membered heteroazyl ring which contains l, 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:
(i) -s-l ) '°- ;
(3) - I-Rs (4) ~C~
R' R8 ;
(s) -c ~' R9 ~ R10R9 ~ ~ R10 ~

(6) - C C-R9" Rl~" ~ Or (7) ~C~ Y
R9 Ri0 wherein ~ 5 Y is O, N-R6 or S;
n' is 0, 1 or 2;
R6 is H, lower alkyl, aryl, -C(0)-R11 or -C ( O ) -0-R11;
R~ and R8 are the same or different and are independently H, alkyl, aryl, halogen, -O-R12, or R~ and R8 together can be oxygen to form a ketone;
R9, Rlo, Rg' and Rl~' are the same or different and are independently H, lower alkyl, aryl or -O-R11;
R9" and R1~" are the same or different and are independently H, lower alkyl, aryl, halogen or -O-R11;
R11 is alky or aryl;
R12 is H, alkyl or aryl;
with the following provisos for compound of the LZ ~ Li Ray ~A g~ ~Rl structure (a) when R1 is unsubstituted alkyl or unsubstituted arylalkyl, L1 cannot contain amino;
(b) when R1 is alkyl, L1 cannot contain amino and oxo in adjacent positions (to form an amido group);
(c) when R2L2A- is H2N-, R1L1 cannot contain amino;
(d} when R1 is cyano, L1 must have more than 2 carbons;
(e) R1L1 must contain at least 3 carbons;
with respect to compounds of formulas I, IA and IB, where R1 or R2 is cycloheteroalkyl, R1 or R2 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo-pyrrolidinyl);

with respect to the sulfur containing compounds and alcohols, R2L2 cannot have an O or N atom directly attached to S=(O)q or CRX(OH), and for IA, R2L2 cannot be H.
The MTP inhibitors disclosed in U.S. provisional application No. 60/017,253, filed May 10, 1996, (file HX82*) are pyrrolidine compounds and have the structure I
II
O
R
.\
or Rs. ~ / X'N N_ R~
Ra W
Rs~ O~ N
Rs N- R~
W
O O
where O is - C- or - S- ;
O
W is H,H or O;
X is: CHRB, - C- ~ -CH- CH- or -~= C- ;
O Rs Rto R9 Rto R8, R9 and R1~ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons); all of the aforementioned R1 groups being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo; or R1 is a fluorenyl-type group of the structure Ris R1s R1s R1s Rls~ R1s _ R11 _ R11_ Zi v _ R11_ Z1 Z or Z
or Z
R12 ~ ~ R12_ Z2 ~ ~ R12 Z2 Het R13 ~_--~~ R14 R13 u~ R14 13 R14 g R1s R1s Het 1 -X11-Zi or R12- Z2 Z
Het 2 R13 R14 .
or a R1 is an indenyl-type group of the structure p13\~/ R14 _ R11_ Z1 or - R11- Z1 ~ ~ or _ ~ Rlsa R12 ZRis (CH2 a R12- Z2 Rlsa Rl6a (a o 2,3 or 4) _F
Rt3 Het ) Het _ R11_ Z1 or _ R11_ Z1 R12- Z2 ~ ~ Rl6a R12_ Z2 ~ 16a Rlsa (CH2)a G H Rlsa Z1 and Z2 are the same or different and are independently a bond, 0, S, ~ , - NH- C- ~ -N C- , - C- or - C- , O ~OJ2 p alkyl O O OH

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 (for example ) ~ , or mixed azylene-alkylene (for example O-«a)a ) where n is 1 to 6;
R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the provisos that (1) when R12 is H, aryloxy, alkoxy or - NH- C- , - N C- - C-arylalkoxy, then Z2 is O alkyl O ~ O or a bond;
and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroazylalkyl;
Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene of 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, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
Rl5a and Rl6a are independently any of the R15 or R16 groups except hydroxy, nitro, amino or thio;
or R1 is - ( CH2 ) p~
Ria wherein p is 1 to 8 and R1~ and Rl8 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R1~ and R18 being other than H;

or R1 is R2o .- R19 wherein R19 is aryl or heteroaryl;
R2~ is aryl or heteroaryl;
R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
R2, R3, R4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 is alkyl , alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryloxy, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all of the R5 substituents and R6 substituents (set out hereinafter) being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino (wherein the amino includes 1 or 2 substituents which are alkyl, aryl or heteroaryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. Where R5 is phenyl, aryl, heteroaryl or cycloalkyl; this group preferably includes an ortho hydrophobic substituent such as alkyl, haloalkyl (with up to 5 halo groups), alkoxy, haloalkoxy (with up to 5 halo groups), aryl, aryloxy or arylalkyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl;
f ~ f ~ f Het Het 1 and Het 2 are the same or different and are independently selected from heteroaryl containing 5- or &-ring members; and including N-oxides of the formulae I and II
compounds, that is f ana including pharmaceutically acceptable salts thereof.
The MTP inhibitors disclosed in U.S. provisional application No. 60/017,254, filed May 10, 1996, (file HX84*) are azetidine compounds which have the structure I

R '~ I ~N-(CHZ)e -~N-R~ , ox ' X
R°
I I
RS~O~N-(CHZ)o ""~N-R' Is R
O O
n m where Q is - ~- or - S- ;
o X is: CHRe, - C- , -CH- CH- or -C= C- ;
i i o Rs R1o Rs R1o n is 0 or 1;
R8, R9 and R1~ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons); all of the aforementioned R1 groups being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroaryl-alkyl, hydroxy or oxo; or R1 is a fluorenyl-type group of the structure R1s Rts Rts R1s Rt\,~/ Rts - Ri 1 _ R11 _ Z1 _ Rt1_ Zt Z or Z or ~Z
Rt2 ~ ~ Rt2_ Z2 ~ ~ R12_ Z2 HEt R13 ~ R14 R13 ~~ R14 13 R14 A B C
R1s Rt5 Het 1 or R12- Z2 Z
Het 2 R13 R1a .
or a R1 is an indenyl-type group of the structure WO 98!50028 PCT/US98/08269 R R13~,~~ R
_ R11_ Z1 or - R11 _ Zi ~ ~ or R12_ Z2 ~ Risa / tsa Rt5a (CH~ R12- Z2 R
RlSa {a = 2,3 or 4) _F

Het ) Het _ R11_ Zi or _ R11 _ Zi R12_ Z2 / ~ Rlsa Riz_ Z2 ~ Rlsa Rl5a (CHq)a H Risa Z1 and Z2 are the same or different and are independently a bond, 0, S, H
- NH- C- ~ -N C- , - C- or - C- , O ~0~2 p alkyl O O OH

with t he proviso thatwith respect to B_, least one of at Z1 and Z2 will be other than a bond;

R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms,arylene (for example ) or mixed arylene-alkylene (for example -~O--(C8a)Q ) where q is 1 to 6;
R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the provisos that (1) when R12 is H, aryloxy, alkoxy -N-C_ -C-- NH- C- ~ i " , or arylalkoxy, then Z2 is O , alkyl O ~ O or a bond;

and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene of from 1 to 5 carbon atoms;
S R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thin, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
Rl5a and Rl6a are independently any of the R15 or R16 groups except hydroxy, vitro, amino or thio;
or R1 is (CHZ)v~

wherein p is 1 to 8 and R1~ and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R1~ and R18 being other than H;
or R1 is R2o - R1 s wherein Rl9 is aryl or heteroaryl;
R2~ is aryl or heteroaryl;
R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
R2, R3, R4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 is alkyl , alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, hetero-arylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryloxy, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all of the R5 substituents and R6 substituents (set out hereinafter) being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, vitro, cyano, amino, substituted amino (wherein the amino includes 1 or 2 substituents which are alkyl, aryl or heteroaryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. Where R5 is phenyl, aryl, heteroaryl or cycloalkyl; this group preferably includes an ortho hydrophobic substituent such as alkyl, haloalkyl (with up to 5 halo groups), alkoxy, haloalkoxy (with up to 5 halo groups), aryl, aryloxy or arylalkyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl;
f ~ f Het Het 1 and Het 2 are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and including N-oxides of the formulae I and II
compounds, that is \ ~ p ; and including pharmaceutically acceptable salts thereof.
Compounds disclosed as preferred in each of the above applications are preferred for use in the present invention.
Most preferred MTP inhibitors to be employed in accordance with the present invention include preferred MTP
inhibitors as set out in U.S. patent application Serial No.
548,811, filed January 11, 1996 (file DC2lh) and in U.S.
Application Serial No. 08/767,923, filed December 17, 1996 (file HX79c*}.
Thus, preferred compounds in U.S. patent application Serial No. 548,811 (file DC2lh) for use herein are compounds where Z is a bond;
X1 and X2 are H;
R5 is aryl such as phenyl substituted with (1) aryl such as phenyl, , c1, S 'N
~N
/ , (2} heteroaryl such as (3) halo such as C1 /~ /
R5 is heteroaryl such as S °= S substituted with (1) aroyl such as , -s~ c1 (2) arylthio such a ~./s wherein the R5 substituent is preferably in the position adjacent to the carbon linked to c.

(CH2)x is -(CH2)4- or F
- Cg2- C~j2 _ C_ Cg2 F
Most preferred is BMS 201,038, that is 9-[4-[4-[[2-(2,2,2-Trifiuoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide O
N~ Cp3 CF3 H
Iw N
Preferred compounds in U.S. Application Serial No.
08/767,923 (file HX79c*) for use herein are MTP inhibitor compounds of formula I that is ~ Ri wherein A is NH, B is f R3 Ra x X is a bond, oxygen or sulfur; R3 and R4 are independently H or F.
Preferred Rl groups in Application Serial No.
08/767,923 are aryl, preferably phenyl, heteroaryl, preferably imidazoyl, benzimidazolyl, indolyl, or pyridyl {preferably substituted with one of the preferred R1 substituents: arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroaryl-sulfonylamino), PO(OAlkyl)2, heteroarylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, or alkenyl, cycloalkyl such as cyclohexyl, or 1,3-dioxan-2-yl.
Preferred R2 groups are alkyl, polyfluoroalkyl (such as 1,1,1-trifluoroethyl), alkenyl, aryl or heteroaryl (preferably substituted with one of the preferred R1 substituents above), or PO(OAlkyl)2.
If R2 is alkyl, 1,1,1-trifluoroethyl, or alkenyl, it is preferred that R1 is other than alkyl or alkenyl.
It is preferred that L1 contains 1 to 5 atoms in the linear chain and L2 is a bond or lower alkylene.
Preferred embodiments of formula IA and formula IB
compounds in Application Serial No. 08/767,923 include those where B, L1, L2, R1 and R2 are as set out with respect to the preferred embodiments of the formula I
IS compounds, q is 0 or 2 and RX is H.
Also preferred are compounds of the structure ~a ~ Li Rai wA $i ~Ri where B is S

, A is NH, L2 is a bond, R2 is CF3CH2 , , L1 is -CH2CH2CH2- or -CH2CH2CH2CH2-, and R1 is heteroaryl which is a 5-membered aromatic ring which includes 2 nitrogens, which ring is fused to an aryl ring and is substituted on the aryl moiety. Examples of preferred R1 groups include substituted benzimidazole groups including \

/
O= C / CF3 ( CFg / N /
\
~N
/
/ \ ~ ~ ~ cF

CHgO \ N ~ O

I
C=O CH3 /
/ ~ ~ ~ CF3 \
_ N
CF3 \ ~ ~ CF3 a ~O C
N$

~~ --CHg \ N
Preferred are compounds of the structure 2) I \
O NN ' ~ CF3 O NH I ~ CFa I /
~N ~ ~ \ N
cONhCH~C~3 ~ CONycH~Cpa \ 4 \ ) I / \
O NH I / CF3 O NH~CF3 ,/
N ~ \ N
(BMS 122,212) cONHCH?Cp3 CONHCHZCp3 , O NH
~N I /
O
H I /

) ' O

N~ N CF3 _ \- \
O ~ /
H
or a pharmaceutically acceptable salt thereof, with compound 3) being the most preferred.
Most preferred pharmaceutical combinations of the invention include an MTP inhibitor (such as a preferred MTP
inhibitor as set out above) in combination with Vitamin E.
Other preferred pharmaceutical combinations of the invention include a preferred MTP inhibitor in combination with Vitamin E and Vitamin A.
The other cholesterol lowering drug to be used in combination with the MTP inhibitor in accordance with the present invention is preferably an HI~IG CoA reductase inhibitor.
The HMG CoA reductase inhibitors suitable for use herein include, but are not limited to, mevastatin and related compounds as disclosed in U.S. Patent No.
3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No.
4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171, and atorvastatin, with pravastatin, atorvastatin, lovastatin or simvastatin being preferred. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, cerivastatin, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Patent No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivatives thereof as disclosed in U.S. Patent No.
4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO
86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-di-substituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S.
Patent No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Patent No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No. 0,142,146 A2, as well as other known HMG
CoA reductase inhibitors.
In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
The squalene synthetase inhibitors suitable for use herein include, but are not limited to, oc-phosphono-sulfonates disclosed in U.S. application Serial No.
08/266,888, filed July 5, 1994 (HX59b), those disclosed by Biller et al, J. Med. Chem. 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates such as those of the formula II II II
Rl- ~ - CRa- i _ O- Ri- i - Cg2 i - O-O' O- O' O' =Z

a / /
/ / /
/ / /
d / /
including the triacids thereof, triesters thereof and tripotassium and trisodium salts thereof as well as other squalene synthetase inhibitors disclosed in U.S. Patent Nos. 4,871,721 and 4,924,024 and in Biller et al, J. Med.
Chem., 1988, Vol. 31, No. 10, pp 1869 to 1871.
In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem.; 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R.W.
et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T.L., PhD dissertation, June, 1987, Dept. Med.
Chem. U. of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51, Summary.
Preferred are pravastatin, lovastatin or simvastatin.

All of the above U.S. applications are incorporated herein by reference.
Other cholesterol lowering drugs suitable for use herein include, but are not limited to, antihyperlipoproteinemic agents such as fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Patent No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex~', Polidexide~), as well as clofibrate, lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Patent No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents.
In carrying out the method of the present invention, the MTP inhibitor in combination with the fat soluble vitamin, namely, Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally the other cholesterol lowering drug, may be administered to mammalian species, such as monkeys, dogs, cats, rats, humans, etc., and, as such, may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable. The above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, anti-bacterial, bulking agent (such as mennitol), anti-oxidants (ascorbic acid of sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well.
The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
For oral administration, a satisfactoryresult may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg; and the fat soluble vitamin as set out hereinbefore.
A preferred oral dosage form, such as tablets or capsules; will contain the MTP inhibitor in an amount of from about 5 to about 500 mg, preferably from about 10 to about 400 mg, and more preferably from about 20 to about 250 mg; and the fat soluble vitamins will be employed as f ollows where present, Vitamin E will be employed in an amount within the range preferably to provide from about 200 to about 5,000 mg/day;
Vitamin A will be employed in an about within the range preferably to provide from about 10,000 to about 35,000 IU;
Vitamin K will be employed in an amount within the range preferably to provide from about 5 to about 15 mg/day; and, Vitamin D will be employed in an amount within the range preferably to provide from about 100 to about 400 IU/day.
For parenteral administration, the MTP inhibitor will be employed in an amount within the range from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, while the fat soluble vitamin will be employed in amounts conventionally used in parental administration of such vitamins.
For oral administration, a satisfactory result may be obtained employing the HMG CoA reductase inhibitor in dosages employed, for example, for pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and lovastatin, as indicated in the Physician's Desk Reference, or in the patents which disclose these compounds, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
The squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
A preferred oral dosage form, such as tablets or capsules, will contain MTP inhibitor in an amount of from about 10 to about 400 mg, and the HMG CoA reductase inhibitor in an amount of from about 0.1 to about 100 mg, IS preferably from about 5 to about 80 mg, and more preferably from about 10 to about 50 mg.
The other serum cholesterol lowering drugs when present will be employed in dosages normally employed as indicated in the Physician's Desk Reference, for each of such agents such as in an amount within the range of from about 2 mg to about 7500 mg and preferably from about 2 mg to about 4000 mg.
The MTP inhibitor and other cholesterol lowering agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
The compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
Tablets of various sizes can be prepared, e.g., of about 2 to 2000 mg in total weight, containing one or both of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can, of course, be scored to provide for fractional doses. Gelatin capsules can be similarly formulated.
Liquid formulations can also be prepared by dissolving or suspending one or the combination of active substances in a conventional liquid vehicle acceptable for pharmaceutical administration so as to provide the desired dosage in one to four teaspoonsful.
Such dosage forms can be administered to the patient on a regimen of one to four doses per day.
According to another modification, in order to more finely regulate the dosage schedule, the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances. The respective substances can be individually formulated in separate unit dosage forms in a manner similar to that described above.
Fixed combinations of MTP inhibitor and fat soluble vitamin, and optionally other cholesterol lowering drug are more convenient and are preferred, especially in tablet or capsule form for oral administration.
In formulating the compositions, the active substances, in the amounts described above, are compounded according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type of unit dosage form.
Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrating agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, aspartame, lactose or saccharin; a flavoring agent such as __-_..___.T__.__. _ orange, peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compound, water, alcohol or the like as - the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange.
Some of the active substances described above form commonly known, pharmaceutically acceptable salts such as alkali metal and other common basic salts or acid addition salts, etc. References to the base substances are therefore intended to include those common salts known to be substantially equivalent to the parent compound.
The formulations as described above will be administered for a prolonged period, that is, for as long as the potential for elevated cholesterol and/or triglycerides and/or atherosclerosis and other diseases set out above remains or the symptoms continue. Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed. A dosing period of at least one to two weeks are required to achieve minimal benefit.
The following Examples represent preferred embodiments of the present invention.
Examples 1 and 2 Formulations suitable for oral administration for reducing serum cholesterol are prepared as described below.
Capsules each containing about 5 mg MTP inhibitor BMS 201,038 (Example 1) and capsules each containing about 50 mg BMS 201,038 (Example 2) are produced from the following ingredients.

Example 1 Example 2 Amount (mg/ Amount (mg/
Incrredient capsule) Capsule) BMS-201038-methane sulfonic5.7 56.9 acid salt (1) Lactose, Hydrous, NF ca. 151.1 ca. 99.9 Microcrystalline Cellulose,50.0 50.0 NF

Pregelatinized Starch, NF 25.0 25.0 Sodium Starch Glycolate, 12.5 12.5 NF

Colloidal Silicon Dioxide, 5.0 5.0 NF

Magnesium Stearate, NF 0.6 0.6 Purified Water, USP or q.s. q.s.

Water for Injection, USP q.s. q.s.

Gray, Opaque, Size #0 One Capsule One Capsule Capsule Shell about about Total Fill Weight 250.0 250.0 (1) This amount is expressed in terms of the amount of methane sulfonic acid salt per capsule at 100 potency.
This is equivalent to 5 mg and 50 mg (Examples 1 and 2, respectively) of the free base.
The MTP inhibitor BMS 201,038, and colloidal silicon dioxide are blended in a suitable blender with~lactose hydrous, microcrystalline cellulose, pregelatinized starch and a portion of sodium starch glycolate. The resulting blend is wet granulated with water. The wet granulation is dried in a suitable dryer. The remaining portion of sodium starch glycolate is added to the granulation and mixed therein. Magnesium stearate is added to the granulation and mixed therein. The resulting blend is filled into capsules.

Example 3 and 4 MTP inhibitor (BMS 201,238) tablets and Vitamin E, Vitamin A, Vitamin K and/or Vitamin D in tablet or capsule form may be administered as a combination in accordance with the teachings of the present invention to lower serum cholesterol and to treat the various disease states mentioned above. In addition, the vitamins and MTP
inhibitor may be used together in a single capsule.
Example 5 1) Pravastatin tablets (10, 20 or 40 mg as described in the 1997 PDR), 2) atorvastatin tablets, 3) lovastatin tablets, 4) simvastatin tablets, 5) fluvastatin tablets, or 6) cerivastatin tablets, (2) to 6) being used in amounts as described in the PDR), MTP inhibitor (BMS 201,238) tablets and fat soluble vitamins, such as Vitamin E, A, K and/or D
tablets or capsules may be administered as a combination in accordance with the teachings of the present invention to lower serum cholesterol and to treat the various disease states mentioned above. In addition, the pravastatin or any of the statins 2)-6), vitamins and MTP inhibitor tablets may be ground up into powders and used together in a single capsule.
Examgle 6 Tablets containing 500 mg clofibrate in combination with 10 mg BMS 201,038 and fat soluble vitamin may be employed in separate dosage forms or combined in a single capsule form to lower serum cholesterol and to treat the various disease states mentioned above in accordance with the present invention.

Examples 7, 8, 9 and 10 Ciprofibrate, bezafibrate, or fenofibrate, gemfibrozil in combination with fat soluble vitamins and an MTP inhibitor may also be prepared in a manner described hereinbefore in Examples 1 to 5 to treat the various diseases mentioned above.

Claims

What is claimed is:

1. A pharmaceutical combination comprising an MTP
inhibitor and a fat soluble vitamin.

2. The pharmaceutical combination as defined in Claim 1 wherein the fat soluble vitamin is Vitamin E, Vitamin A, Vitamin K, Vitamin D or a combination of two or more thereof.

3. The pharmaceutical combination as defined in Claim 1 wherein the fat soluble vitamin is Vitamin E and/or Vitamin A.

4. The pharmaceutical combination as defined in Claim 1 wherein the MTP inhibitor has the structure where Q is ;
X is: R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;

Y is -(CH2), or wherein m is 2 or 3;
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least 2 carbons, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo;
or R1 is a fluorenyl-type group of the structure or R1 is an indenyl-type group of the structure Z1 and Z2 are the same or different and are independently a bond, O, S, 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, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1) alkoxy or arylalkoxy, then Z2 or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl;
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, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;
R15a and R16a 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;
or R1 is a group of the structure wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R17 and R18 being other than H;
or R1 is a group of the structure wherein R19 is aryl or heteroaryl;
R20 is aryl or heteroaryl;
R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
R2, R3, R4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cyclohetero-alkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 set out above;
R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo and are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and N-oxides thereof; and pharmaceutically acceptable salts thereof; with the provisos that where in the first formula X is CH2, and R2, R3 and R4 are each H, then R1 will be other than 3,3-diphenylpropyl, and in the fifth formula, where one of R2, R3 and R4 is 6-fluoro, and the others are H, R7 will be other than 4-(2-methoxyphenyl).

5. The pharmaceutical combination as defined in Claim 4 wherein the MTP inhibitor has the formula

6. The pharmaceutical combination as defined in Claim 5 where in the MTP inhibitor R1 is

7. The pharmaceutical combination as defined in Claim 4 wherein the MTP inhibitor has the structure including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, O or S;
X1 and X2 are independently selected from H or halo;
x is an integer from 2 to 6;
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.

8. The pharmaceutical combination as defined in Claim 4 where in the MTP inhibitor the R5 includes a substituent attached to a carbon in the position adjacent to the carbon linked to .

9. The pharmaceutical combination as defined in Claim 4 where in the MTP inhibitor R5 is

10. The pharmaceutical combination as defined in Claim 4 where in the MTP inhibitor is

11. The pharmaceutical combination as defined in Claim 1 wherein the MTP inhibitor has the structure including pharmaceutically acceptable salts thereof, N-oxides thereof, wherein q is 0, 1 or 2;
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 B is an indenyl-type group of the structure R x is H, alkyl or aryl;
R1 is 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, heteroarylthio, heteroarylsulfinyl, hetero-arylsulfonyl, -PO(R13)(R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, 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: CMR23, 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, cycloalkylalkyl, 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, H, polyhaloalkyl, or cycloheteroalkyl, and may be optionally substituted with one to four of any of the groups defined for R3 or substituents defined for R1;
L1 is a linking group containing 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 singe 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;
R3a and R3b are the same or different and are independently any of the R3 groups except hydroxy, nitro, amino or thio;
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 alky or aryl;
R12 is H, alkyl or aryl;
with the following provisos for compound of the structure (a) when R1 is unsubstituted alkyl or unsubstituted arylalkyl, L1 cannot contain amino;
(b) when R1 is alkyl, L1 cannot contain amino and oxo in adjacent positions (to form an amido group);
(c) when R2L2A- is H2N-, R1L1 cannot contain amino;
(d) when R1 is cyano, L1 must have more than 2 carbons;
(e) R1L1 must contain at least 3 carbons;
with respect to compounds of formulas I, IA and IB, where R1 is cycloheteroalkyl, R1 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo-pyrrolidinyl);
with respect to the sulfur containing compounds and alcohols, R2L2 cannot have an O or N atom directly attached to S=(O)q or CR X(OH), and for IA, R2L2 cannot be H.

12. The pharmaceutical combination as defined in Claim 11 wherein the MTP inhibitor has the structure

13. The pharmaceutical combination as defined in Claim 11 wherein B is a fluorenyl-type group.

14. The pharmaceutical combination as defined in Claim 11 wherein the MTP inhibitor has the formula wherein B is A is NH;
X is a bond, oxygen or sulfur;
R3 and R4 are the same or different and are H or F;
R1 is aryl, phenyl, heteroaryl, imidazolyl, pyridyl, cyclohexyl, PO(R13)(R14), heteroarylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, alkenyl or 1,3-dioxan-2-yl, wherein each of the above is optionally substituted;
R2 is alkyl, polyfluoroalkyl, alkenyl, aryl, phenyl, heteroaryl, imidazolyl or pyridyl, wherein each of the above is optionally substituted;
L1 is a chain containing 1 to 5 atoms in a linear chain;
L2 is a bond or lower alkylene.

15. The pharmaceutical combination as defined in Claim 11 wherein the MTP inhibitor is or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical combination as defined in Claim 1 further including another cholesterol lowering agent.

17. The pharmaceutical combination as defined in Claim 16 wherein the other cholesterol lowering drug is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.

18. The pharmaceutical combination as defined in Claim 17 wherein said inhibitor of the enzyme HMG CoA
reductase is lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin.

19. The pharmaceutical combination as defined in Claim 16 wherein the other cholesterol lowering drug is a fibric acid derivative which is gemfibrozil, fenofibrate, clofibrate, bezafibrate, ciprofibrate or clinofibrate, probucol, dextrothyroxine or its sodium salt, colestipol or its hydrochloride, cholestyramine, nicotinic acid, neomycin, p-aminosalicylic acid or aspirin.

20. The pharmaceutical combination as defined in Claim 2 wherein the fat soluble vitamin is Vitamin E
employed in an amount within the range from about 100 to about 15,000 mg/day, and/or Vitamin A employed in an amount within the range from about 1,000 to about 50,000 IU/day, and/or Vitamin K employed in an amount within the range from about 0.1 to about 25 mg/day, and/or Vitamin D
employed in an amount within the range from about 50 to about 1,000 IU/day.

21. The pharmaceutical combination as defined in Claim 1 wherein the MTP inhibitor is BMS 201,038 and the fat soluble vitamin is Vitamin E.

22. A method for preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia or obesity in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical combination as defined in Claim 1.

23. A method of lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia, and/or preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia or obesity, in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical combination as defined in Claim 1; and optionally another cholesterol lowering agent.

24. The method as defined in Claim 22 further including administering another cholesterol lowering agent.