WO1998031225A1

WO1998031225A1 - A method of inhibiting or treating phytosterolemia with an mtp inhibitor

Info

Publication number: WO1998031225A1
Application number: PCT/US1998/000618
Authority: WO
Inventors: Richard E. Gregg
Original assignee: Bristol-Myers Squibb Company
Priority date: 1997-01-17
Filing date: 1998-01-13
Publication date: 1998-07-23
Also published as: AU6023298A

Abstract

A method is provided for inhibiting onset of or treating phytosterolemia by administering to a patient an MTP inhibitor, alone or optionally, in combination with another cholesterol lowering drug, such as pravastatin.

Description

A METHOD OF INHIBITING OR TREATING PHYTOSTEROLEMIA WITH AN MTP INHIBITOR

Field of the Invention The present invention related to a method for inhibiting onset of or treating phytosterolemia, by administering an MTP inhibitor alone or in combination with another cholesterol lowering drug, such as pravastatin.

Background of the Invention As indicated in Scriver, C.R. et al "Metabolic Basis of Inherited Diseases" Vol. II (1995), Chap. 65, Inborn Errors in Bile Acid Biosynthesis and Storage of Sterols Other than Cholesterol, Bjorkhe , I. and Boberg, K.M. , pp. 2073-2099, phytosterolemia (also referred to as sitosterolemia) is a rare inherited sterol storage disease involving increased intestinal absorption of phytosterol or shellfish sterols and decreased fecal secretion. It is characterized by "tendon and tuberous xanthomas and by a strong predisposition to premature coronary atherosclerosis.... Increased amounts of phytosterols (plant sterols) , such as sitosterol and campesterol and their 5α-stanols, are found in blood, plasma, erythrocytes, and different tissues, especially in the xanthomas and arteries of affected subjects. Increased serum cholesterol and cholesterol have also been found in many patients . " (p. 2073)

Patients afflicted with phytosterolemia have been found to have an increased incidence of coronary heart disease at an early age most likely due to early development of atherosclerosis at an early age. Bjorkhem et al, supra, indicate at page 2090 that "the mechanism behind the atherosclerosis is unexplained, but a high content of plant sterols in the circulating lipoproteins might promote their deposition in the arterial wall." The microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride (TG) , cholesteryl ester (CE) , and phosphatidylcholine (PC) between small unilamellar vesicles (SUV) . Wetterau & Zilversmit, Chem. Phvs. Lroids 38, 205-22 (1985) . When transfer rates are expressed as the percent of the donor lipid transferred per time, MTP expresses a distinct preference for neutral lipid transport (TG and CE) , relative to phospholipid transport. The microsomal triglyceride transfer protein from bovine liver has been isolated and extensively characterized (1) . This has led to the cloning of cDNA expressing the protein from several species, including humans (2) . MTP is composed of two subunits . The small subunit is the previously characterized multifunctional protein, protein disulfide isomerase. This is supported by biochemical analysis of the protein (3) as well as co-expression studies performed in insect Sf9 cells using the baculovirus expression system. Expression of soluble active MTP requires the co-expression of PDI and the unique large subunit of MTP (4) .

1: Wetterau, J.R. and Zilversmit, D.B. (1985) Chem. Phys. Lipids 38, 205-222.

Wetterau, J.R. , et al, (1990) J. Biol . Chem. 265, 9800-9807.

Wetterau, J.R., et al, (1991) Biochemistry 30, 4406- 4412.

Atzel, A., and Wetterau, J.R. (1993) Biochemistry

32, 10444-10450. Atzel, A., and Wetterau, J.R. (1994) Biochemistry

33, 15382-15388.

Jamil, H., et al, (1995) J. Biol. Chem. 270, 6549- 6554.

2. Sharp, D. et al, (1993) Nature 365, 65-69.

Lin, M.C.M., et al, J. Biol. Chem. 269, 29138-29145. Nakamuta, M. , et al, (1996) Genomics 33, 313-316. 3. Wetterau, J.R. , et al, (1990) J. Biol. Chem. 265, 9800-9807.

Wetterau, J.R. , et al, (1991) Biochemistry 30, 9728- 9735.

4. Ricci, B., et al, (1995) J. Biol. Chem. 270, 14281- 14285.

JEn vitro, MTP catalyzes the transport of lipid molecules between phospholipid membranes. Presumably, it plays a similar role in vivo , and thus plays some role in lipid metabolism. The subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. Wetterau & Zilversmit, Biochem. Bioohvs . Acta 875, 610-7 (1986) . The ability of MTP to catalyze the transport of TG between membranes is consistent with this hypothesis, and suggests that MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER.

Abetalipoproteinemia is an autosomal recessive disease characterized by a virtual absence of plasma lipoproteins which contain apolipoprotein B (apoB) . Kane & Havel in The Metabolic Basis of Inherited Disease, Sixth edition, 1139-64 (1989) . Plasma TG levels may be as low as a few mg/dL, and they fail to rise after fat ingestion. Plasma cholesterol levels are often only 20-45 mg/dL.

These abnormalities are the result of a genetic defect in the assembly and/or secretion of very low density lipoproteins (VLDL) in the liver and chylomicrons in the intestine. The molecular basis for this defect had not been previously determined. In subjects examined, triglyceride, phospholipid, and cholesterol synthesis appear normal. At autopsy, subjects are free of atherosclerosis. Schaefer et al . , Clin. Chem. 34, B9-12 (1988) . A link between the apoB gene and abetalipoproteinemia has been excluded in several families. Talmud et al . , J. Clin. Invest. 82, 1803-6 (1988) and Huang et al . , Am. J. Hum. Genet. 46, 1141-8 (1990) .

Recent reports (5) demonstrate that the defect causing abetalipoproteinemia is in the MTP gene, and as a result, the MTP protein. When examined, individuals with abetalipoproteinemia have no MTP activity, as a result of mutations in the MTP gene, some of which have been characterized. These results indicate that MTP is required for the synthesis of apoB containing lipoproteins, such as VLDL, the precursor to LDL. It therefore follows that inhibitors of MTP would inhibit the synthesis of VLDL and LDL, thereby lowering VLDL levels, LDL levels, cholesterol levels, and triglyceride levels in animals and man.

5. Wetterau, J.R., et al, (1992) Science 258, 999-1001. Sharp, D., et al, (1993) Nature 365, 65-69. Ricci, B., et al, (1995) J. Biol. Chem. 270, 14281-

14285.

Shoulders, C.C., et al, (1993) Hum. Mol . Genetics 2, 2109-2116.

Narcisi, T.M.E., et al, (1995) Am. J. Hum. Genet. 57, 1298-1310.

Rehberg, E.F., et al, J. Biol. Chem (in press) .

Canadian Patent Application No. 2,091,102 published March 2, 1994 (corresponding to U.S. application Serial No. 117,362, filed September 3, 1993 (file DC21b) ) which is incorporated herein by reference) , reports MTP inhibitors which also block apoB containing lipoprotein secretion in a human hepatic cell line (HepG2 cells) . This provides further support for the proposal that an MTP inhibitor would lower apoB containing lipoprotein and lipid levels in vivo . This Canadian patent application discloses a method for identifying the MTP inhibitors. The use of microsomal triglyceride transfer protein (MTP) inhibitors for decreasing serum lipids including cholesterol and triglycerides and their use in treating atherosclerosis, obesity, hyperglycemia, and pancreatitis is disclosed in WO 96/26205, published August 29, 1996, U.S. Application Serial No. 472,067, filed June 6, 1995 (file DC21e) , U.S. Application Serial No. 548,811, filed January 11, 1996 (file DC21h) , U.S. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a* ) , U.S. provisional application No. 60/017,253, filed May 10, 1996 (file HX82*), U.S. provisional application No. 60/017,254, May 10, 1996 (file HX84*) and U.S. provisional application No. 60/028,216, filed October 1, 1996 (file HX86*) •

All of the above U.S. applications are incorporated herein by reference.

Description of the Invention In accordance with the present invention, a method is provided for inhibiting onset of or treating phytosterolemia, in mammalian species, wherein a therapeutically effective amount of a microsomal triglyceride transfer protein (MTP) inhibitor is administered to a patient in need of treatment .

The MTP inhibitor may optionally be administered in combination with another cholesterol lowering drug or delipidating agent.

The MTP inhibitor alone or optionally in combination with another cholesterol lowering drug is administered systemically, such as orally or parenterally or transdermally, to patients in need of treatment.

In accordance with the present invention, the MTP inhibitor lowers plasma cholesterol (LDL-cholesterol) to at least about 50% of normal LDL blood level, preferably down to less than about 25% of normal, and lowers triglycerides to at least about 50% of normal triglyceride blood level, and preferably down to about 25% or less of normal, and thereby reduces plasma cholesterol and resulting atherosclerosis .

The terms "another cholesterol lowering drug or agent" or "another delipidating drug" will be employed interchangeably herein.

MTP inhibitors to be employed in the methods of the invention include MTP inhibitors disclosed in Canadian

Patent Application No. 2,091,102 described hereinbefore

(corresponding to U.S. Application Serial No. 117,362), WO 92/26205 published August 29, 1996, U.S. Application Serial

No. 472,067, filed June 6, 1995 (file DC21e) , U.S.

Application Serial No. 548,811, filed January 11, 1996

(file DC21h) , U.S. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a*), U.S. provisional application No. 60/017,253, filed May 10, 1996 (file

HX82*), U.S. provisional application No. 60/017,254, filed

May 10, 1996 (file HX84*), and U.S. provisional application

No. 60/028,216, filed October 1, 1996 (file HX86*).

Preferred are each of the preferred MTP inhibitors disclosed in each of the above applications.

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 DC21e) are piperidine compounds of the structure

or

or R¹

R⁵' ^Q /~

or

0 0

I I I I where Q is — c- - or — s— ;

II

0

X is: CHR⁸, ^■ - c I I— ' -CH— CH- or -^{c= c}- ; o 1

R⁹ _R10 R⁹ R¹⁰

R⁸, R⁹ and R¹⁰ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl , cycloalkyl, or cycloalkylalkyl;

Y is -(CH₂)_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, 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

R¹ is an indenyl-type group of the structure

Z¹ and Z² are the same or different and are independently a bond, 0, S,

(o),

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 preferably

(1) when R¹² is H, aryloxy, alkoxy or arylalkoxy, then Z² is

_{or a bond and}

(2) when Z² is a bond, R¹² cannot be heteroaryl or heteroarylalkyl ;

Z is a 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;

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; or R¹ is a group of the structure

R¹⁷

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, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyaIky1 , 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 ( If ) .

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 preferably 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 preferably 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) . The MTP inhibitors disclosed in U.S. application Serial No. 548,811 filed January 11, 1996 (file DC21h) , have the structure

including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, 0 or S; χl 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 R^ group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different.

The MTP inhibitors disclosed in U.S. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a*) have the structure

or XΛ IB including pharmaceutically acceptable salts thereof, wherein q is 0, 1 or 2; A is (1) a bond; (2) -0- ; or N

(3) R⁵ 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:

or (the above B is also referred to as a fluorenyl- type ring or moiety); or

B is an indenyl-type group of the structure

(the above B is also referred to as an indenyl-type ring or moiety);

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, heteroarylsulfonyl, -PO (R¹³) (R¹⁴) , (where R¹³ and R¹⁴ are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy) ; R¹ can also be 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, such as 1,3-dioxane or 1, 3-dioxolane, 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 have from one to four substituents, which can be any of the R³ groups or R¹ groups, and any of the preferred R¹ substituents set out below. R¹ may be substituted with the following preferred substituents: alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may 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: CHR 2^:3 —

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 preferred substituents may either be directly attached to R¹, or attached via an alkylene chain at an open position. R² is the same or different from R¹ and is independently any of the groups set out for R¹, H, polyhaloalkyl (such as CF₃CH₂, CF₃CF₂CH₂ or CF₃) or cycloheteroalkyl, and may be substituted with one to four of any of the groups defined for R³, or any of the substituents preferred 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 optionally substituted with alkyl or aryl, an oxo group; and may be substituted with one to five alkyl or halo groups (preferably F) . 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 R ' 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;

R^3a and R^3b 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 may contain 1 , 2 , 3 or 4 heteroatoms in the ring which are independently N, S or 0; and including N-oxides .

X (in the fluorenyl type ring) is a bond, or is one of the following groups:

(1) —s—

I

(0)_n,

(2) -o-

(7)

^Nτ>10 wherein

Y is 0, N-R⁶ or S; n' is 0, 1 or 2 ;

R⁶ is H, lower alkyl, aryl, -C(0)-R^1:L or -C(0)-0-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. The following provisos apply to formula I preferred compounds :

(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 IA and IB, R²L² cannot have an 0 or N atom directly attached to S=(0)_g or CR^x(OH) and for IA, RL² cannot be H.

With respect to preferred compounds of formula IA and IB, where R¹ is cycloheteroalkyl, R¹ is exclusive of 1-piper-idinyl, 1-pyrrolidinyl, 1-azetidinyl or 1- (2-oxo-pyrrolidinyl) .

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

I I

O I I O " where Q is — c — or — S —

I I

W is H , H or 0 ;

X is: CHR⁸, -

R⁸, R⁹ and R¹⁰ 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

R¹ is an indenyl-type group of the structure

Z¹ and Z² are the same or different and are independently a bond, 0, S,

S _f S ,-NH-C- , -N C- , -C- or -C- ,

0 0)₂ o alkyl 0 0 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

o -romix-ed a >rylene-alkylene (for example

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

arylalkoxy, then Z² is

or a bond; and (2) when Z² is a bond, R¹² cannot be heteroaryl or heteroarylalkyl;

Z is a bond, 0, 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;

R^15a and R^16a are independently any of the R¹⁵ or R¹⁶ groups except hydroxy, nitro, amino or thio; or R¹ is R¹⁷ (CH₂ ) _p-^

R¹⁸ 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

R²⁰

-.19.

<

-.21 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 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;

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

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

I I

R⁵' " N- (CH₂)_n— <^N-F I*

where Q is — c — or — S —

I I

O

X is: CHR⁸, -

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

R¹ is an indenyl-type group of the structure

Z¹ and Z² are the same or different and are independently a bond, 0, S,

H

S II , Sιι \ » __N«π_H__C«_ , —NI CI,— — c II- or — C-

O ^Oj_{2 0} alkyl 0 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 arylene-alkylene (for example

-ιQr^(CH2)«" ) where q is 1 to 6;

-NH-C- , -N C- -C- arylalkoxy, then Z² is O a^lky^l O ^» ° or a bond; and (2) when Z² is a bond, R¹² cannot be heteroaryl ■ or heteroarylalkyl;

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; R^15a and R¹⁶ are independently any of the R¹⁵ or R¹⁶ groups except hydroxy, nitro, amino or thio; or R¹ is

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 3.20

-.19 -

<

R ,2' 1 wherein R¹⁹ is aryl or heteroaryl; R²⁰ is aryl or heteroaryl;

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;

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

including pharmaceutically acceptable salts thereof. The MTP inhibitors disclosed in U.S. provisional application No. 60/028,216, filed October 1, 1996, have the structure

including pharmaceutically acceptable salts thereof, wherein

A is (1) a bond; (2) -O- ; or N

( 3 ) R⁵ 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:

or (the above B is also referred to as a fluorenyl- type ring or moiety); or

B is an indenyl-type group of the structure

(the above B is also referred to as an indenyl-type ring or moiety);

R¹ 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, cycloheteroalkylalkyl, 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; R² 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, heteroarylsulfonyl, -P0 (R¹³) (R¹⁴) , (where R¹³ and R¹⁴ are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy) ; R¹ can also be 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, such as 1,3-dioxane or 1, 3-dioxolane, connected to L¹ (or L² in the case of R²) at the 2-position) ; 1,3-dioxane or 1, 3-dioxolane connected to ¹ (or L² in the case of R²) at the 4-position. The R² group may have from one to four substituents, which can be any of the R³ groups or R² groups, and any of the preferred R² substituents set out below.

R² may be substituted with the following preferred substituents: alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino , alkoxycarbonylamino , aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may 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, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these preferred substituents may either be directly attached to R¹, or attached via an alkylene chain at an open position.

R³, R³ ' , R⁴ and R⁴' may be the same or different and are independently selected from H, halogen, CF , 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;

are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1 , 2 , 3 or 4 heteroatoms in the ring which -are independently N, S or 0; and including N-oxides.

X (in the fluorenyl type ring) is a bond, or is one of the following groups:

(i) —s— I

(0)_n. (2) -o-

(7)

R⁹ R¹⁰ wherein

Y is 0, N-R⁶ or S; n' is 0, 1 or 2;

R¹¹ is alky or aryl; R¹² is H, alkyl or aryl. 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 DC21h) and in U.S. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a*) . Thus, preferred compounds in U.S. patent application Serial No. 548,811 (file DC21h) for use herein are compounds where Z is a bond; X¹ and X² are H;

R⁵ is aryl such as phenyl substituted with

CH₃

(1) aryl such as phenyl , ^v— ' , ci _r

„, _he_{ter0aryl SUch as}

(3) halo such as Cl

R⁵ is heteroaryl such as

^or substituted with

(1) aroyl such as 7-Q—'

(2) arylthio such as

wherein the R⁵ substituent is preferably in the position

adjacent to the carbon linked to ^c . (CH₂)_X is -(CH₂)4- or

F

— CH₂— CH₂— C- CH₂— F

Most preferred is

9-[4-[4-[[2-(2,2,2-Trifluoroet oxy)benzoyl]amino]-1 -piperidinyl]butyl]- N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

Preferred compounds in U.S. provisional application

No. 60/017,224 (file HX79a*) for use herein are MTP inhibitor compounds of formula I that is

wherein A is NH, B is

X is a bond, oxygen or sulfur; R³ and R⁴ are independently H or F.

Preferred R¹ groups are aryl, preferably phenyl, heteroaryl, preferably imidazoyl or pyridyl (preferably substituted with one of the preferred R¹ substituents: arylcarbonylamino, heteroarylcarbonylamino, cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino) , PO(OAlkyl)₂/ heteroarylthio, benzthi-azole-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 P0(0Alkyl)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 ¹ 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 of the invention include those where B, L¹, L², R¹ and R² are as set out with respect to the preferred embodiments of the formula I compounds, q is 0 or 2 and R is H.

The other cholesterol lowering drugs or delipidating drugs which may be used in the method of the invention include HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, bile acid sequestrants, probucol, niacin, niacin derivatives and the like.

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, with pravastatin, lovastatin or simvastatin being preferred. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, cerivastatin, atorvastatin, 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, α-phosphonosulfonates 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 o o o o

II II II II

_R ^l — — CH ₂— P— O- R¹ — P— CF₂— P— 0" I I I I o- o- o- o-

I II

R¹

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, phosphmylphosphonates reported by McClard, R.W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. . , 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 (TH ) , istigmastanylphosphorylcholine (SPC, Roche) , aminocyclodextrin (Tanabe Seiyoku) , Ajinomoto AJ-814 (azulene derivative) , melinamide (Sumitomo) , Sandoz 58-035, American Cyanamid C -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.

The above-mentioned U.S. patents are incorporated herein by reference. The MTP inhibitor will be employed in a weight ratio to the other cholesterol lowering or delipidating agent (where present) , in accordance with the present invention, within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100. In carrying out the method of the present invention, the MTP inhibitor alone or optionally in combination with 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, antibacterial, bulking agent (such as mannitol) , 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.

The dosages and formulations for the MTP inhibitor will be as disclosed in the various patents and applications discussed above.

The dosages and formulations for the other delipidating agent to be employed, where applicable, will be as set out in the latest edition of the Physicians' Desk Reference.

For oral administration, a satisfactory result 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, one to four times daily.

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, one to four times daily.

For parenteral administration, the MTP inhibitor will be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, one to four times daily.

The other cholesterol lowering or delipidating agent will be employed in amounts set out in the latest edition of the Physician's Desk Reference (PDR) . For oral administration, a satisfactory result may be obtained employing an HMG CoA reductase inhibitor in dosages employed, for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin as indicated in the Physician's Desk Reference, 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 the HMG CoA reductase inhibitor in an amount of from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.

The 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.

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 (where present) in an amount of from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 50 mg. The MTP inhibitor and other cholesterol lowering drug 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 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 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 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 phytosterolemia exists . Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed. The following Examples represent preferred embodiments of the present invention. Examples 1 and 2

Formulations suitable for oral administration 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 form the following ingredients.

Example 1 Example 2 Amount (mg/ Amount (mg/

Ingredient Capsule) Capsule)

BMS-201038 (1) 1.1 56.9

Lactose, Hydrous, NF ca. 30.2 ca. 99.9

Lactose, Anhydrous, NF 47.3 0.0

Microcrystallme Cellulose, 10.0 50.0

NF

Pregelatinized Starch, NF 5.0 25.0

Sodium Starch Glycolate, NF 5.0 12.5

Colloidal Silicon Dioxide, 1.0 5.0

NF

Magnesium Stearate, NF 0.3 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 1000.0 250.0

(1) In Example 1, this amount is expressed in terms of the amount of methane sulfonic acid salt per capsule at 100% potency. In Example 2, this amount is expressed in terms of the free base. This is equivalent to 1 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, microcrystallme 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 Pravastatin tablets (10, 20 or 40 mg as described in the 1996 PDR) and MTP inhibitor (BMS 201,238) tablets may be administered as a combination in accordance with the teachings of the present invention. In addition, the pravastatin and MTP inhibitor tablets may be ground up into powders and used together in a single capsule.

Example 4 Tablets containing 500 mg clofibrate by itself or in combination with 10 mg BMS 201,038 may be employed in separate dosage forms or combined in a single capsule form.

Examples 5 , 6 and 7 Ciprofibrate, bezafibrate, gemfibrozil alone or in combination with an MTP inhibitor may also be prepared in a manner described hereinbefore in Examples 1 to 3.

Claims

What is claimed is:

1. A method for inhibiting onet of or treating phytosterolemia in a mammalian species, which comprises administering to a patient in need of treatment a therapeutically effective amount of an MTP inhibitor.

2. The method as defined in Claim 1 wherein the MTP inhibitor is employed in combination with another type of cholesterol lowering drug.

3. The method as defined in Claim 2 wherein the MTP inhibitor has the structure

R⁵

including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, 0 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.

4. The method as defined in Claim 3 where in the MTP inhibitor Z is a bond.

5. The method as defined in Claim 3 where the MTP inhibitor is a piperidine N-oxide.

6. The method as defined in Claim 3 where in the MTP inhibitor (CH₂)_X is optionally substituted with 1, 2 or 3 substituents which are the same or different and are alkyl or halo .

7. The method as defined in Claim 3 where in the

MTP inhibitor R⁵ is substituted with 1, 2, 3 or 4 substituents which may be the same or different and are halogen, monocyclic heteroaryl, bicyclic heteroaryl, heteroarylalkyl, cycloheteroalkyl, alkyl, alkoxy, cycloalkyl, aryl, aryloxy, substituted aryl, arylalkyloxy, heteroaryloxy, amino, alkylamino, alkyl (aryl ) amino , heteroarylamino, arylamino, alkylthio, arylthio, arylthioalkyl, heteroarylthio, arylsulfinyl or acyl.

8. The method as defined in Claim 7 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 method as defined in Claim 7 where in the

MTP inhibitor R⁵ is substituted with 1, 2, 3 or 4 of one or more of the following I, Cl, F, CF₃

where x is 1 to 5

alkyl, phenyl, phenyl substituted with halo, alkyl, CF 0,

.CF₃

H alkoxy, ^CI?3 , CF₃, or phenyl; NΓÇö (CH₂)_PCF₃- _{where p} is 1 to 5, -N(CH₃)C₆H₅;

CF₃

ΓÇö S-

-S-(CH₂)_PCF₃ where p is 1 to 5 , ^CF3 , -S-alkyl, o

-s -(CH₂)_p-S-C₆H₅ ΓÇö o-

II o -0-(CH₂)_p-CF₃, CF_? OCH₃ ;

-A3 -┬░^0 Cl cyclohexyl,

amino,

^CF3 , ^OCH₃

alkanoyl , alkoxycarbonyl , aroyl , heteroarylammocarbonyl , arylalkyloxycarbonyl ,

10. The method as defined in Claim 9 where in the MTP inhibitor R⁵ is phenyl substituted with haloalkylphenyl or heteroaryl.

11. The method as defined in Claim 10 where in the MTP inhibitor R⁵ is

12. The method as defined in Claim 9 where in the MTP inhibitor is

or

13. The method as defined in Claim 2 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) -0-; or N

(3) R⁵ where R⁵ is H or lower alkyl, or R⁵ together with R² forms a carbocyclic or heterocyclic ring system containing 4 to 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, heteroarylsulfonyl, -P0 (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

^Γûá nitrogen or carbon atom) , alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,

where J is : CHR²³ , ΓÇö C ΓÇö -CH ΓÇö CH- or -C= C-

I I

┬░ _R24 _R I 25 R ' 24 _RI 2. 5

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, Γûá 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;

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:

(i) ΓÇös

(0)ΓÇ₧. . (2 ) - o- .

( 3 ) N

R⁶

(4) ΓÇö c ΓÇö

(5)

_R9 _R10_R9 . ^ _R10 -

( 6 )

I R⁹" ,10" or

(7 )

9 _P10 wherein

Y is 0, N-R⁶ or S ; n' is 0, 1 or 2; R⁶ is H, lower alkyl, aryl, -C(0)-R^1:L or

-C(0)-0-R^1:L;

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;

14. The method as defined in Claim 13 wherein the

MTP inhibitor has the structure

.

15. The method as defined in Claim 14 wherein A is a bond.

16. The method as defined in Claim 14 wherein A is -0-.

17. The method as defined in Claim 14 wherein A is

ΓÇö NΓÇö

18. The method as defined in Claim 14 wherein B is a fluorenyl-type group.

19. The method as defined in Claim 14 having 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, P0(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.

20. The method as defined in Claim 1 wherein the

MTP inhibitor has the structure

including pharmaceutically acceptable salts thereof, N-oxides thereof, wherein

A is (1) a bond;

(2) -0-; or

(3) R⁵ 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 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, cycloheteroalkylalkyl, 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, alkynylammocarbonyl , alkylammocarbonyl , alkenylaminocarbonyl , alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonyl-amino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl ;

R² 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, alkylsul-fonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, -P0 (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 R² 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, ΓÇö CΓÇö -CHΓÇö CH- or -CΓÇö C- ; ╧Ç ' I I I I

O _{R24 R}25 R24_R25 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; 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, CF , 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, - ^Γûá 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;

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 :

(i) ΓÇös

(0)_n. . (2) -o- . ( 3 ) N

R

(4)

^^CN

(6)

┬╗9" ,10" or

wherein

Y is 0, N-R⁶ or S; n' is 0, 1 or 2;

R⁶ is H, lower alkyl, aryl, -C(0)-Rⁿ or -C(0)-0-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.

21. The method as defined in Claim 2 wherein the other cholesterol lowering drug is an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, probucol, a bile acid sequestrant, nicotinic acid or neomycin.

22. The method as defined in Claim 21 wherein the

HMG CoA reductase inhibitor is pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin.

23. The method as defined in Claim 2 wherein the cholesterol lowering drug is a fibric acid derivative which is gemfibrozil, fenofibrate, clofibrate, bezafibrate, ciprofibrate, clinofibrate, probucol, gemfibrozil, dextrothyroxine or its sodium salt, colestipol or its hydrochloride, cholestyramine, nicotinic acid, neomycin, p-aminosalicylic acid or aspirin.

24. The method as defined in claim 2 wherein the MTP inhibitor is present in a weight ratio to the other cholesterol lowering drug (where present) within the range from about 500:1 to about 1:500.

25. The method as defined in Claim 1 wherein the MTP inhibitor lowers plasma LDL-cholesterol to at least 50% of normal LDL blood levels, and lowers triglycerides to at least 50% of normal triglyceride blood levels.