EP1229907A1 - Prevention de la rupture de plaques par inhibiteurs de l'acat - Google Patents
Prevention de la rupture de plaques par inhibiteurs de l'acatInfo
- Publication number
- EP1229907A1 EP1229907A1 EP00973608A EP00973608A EP1229907A1 EP 1229907 A1 EP1229907 A1 EP 1229907A1 EP 00973608 A EP00973608 A EP 00973608A EP 00973608 A EP00973608 A EP 00973608A EP 1229907 A1 EP1229907 A1 EP 1229907A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- methylethyl
- bis
- sulfamic acid
- phenyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- ACAT inhibitors Compounds that inhibit acyl-coenzyme A: cholesterol acyltransferase are known as ACAT inhibitors. Certain ACAT inhibitors and the methods for preparing them are taught in United States Patent 5,491 , 172 and its divisional
- United States Patent 5,441,975 teaches ACAT inhibitors, especially N-[2,6-Bis(l-methylethyl)phenyl]-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- acetamide.
- ACAT inhibitors especially N-[2,6-Bis(l-methylethyl)phenyl]-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl- acetamide.
- This and other United States Patents in the same patent family — 5,646,170; 5,693,657; and 5,366,987 — are hereby incorporated by reference.
- the use of the compounds is treatment of hypercholesterolemia and atherosclerosis.
- PCT/US99/13948 filed June 18, 1999, teaches coadministration of ACAT and MMP inhibitors for the reduction of both macrophage and smooth muscle cell components of atherosclerotic lesions.
- the patent application is hereby incorporated by reference. The application teaches methods of preventing plaque rupture and promoting lesion regression.
- cholesteryl ester An integral process in the pathogenesis of atherosclerosis is the cholesteryl ester (CE) enrichment of the arterial wall. Cholesteryl ester enrichment can occur by passive influx and extracellular deposition of plasma lipoproteins, active cellular metabolism, and active intracellular storage. In man, arterial CE content increases from approximately 2% to 50% of total vessel lipid over 70 years (Small D., Arteriosclerosis. 1988;8:103-129) with a change in the cholesteryl oleate/linoleate ratio from 0.8 to 2.9 (Smith E.B., Evans P.H. and Downham M.D., J. Atheroscler. Res.. 1967;7:171-186).
- the change in fatty acyl pattern is a reflection of a change in the relative amounts of lipoprotein-derived CE, cholesteryl linoleate, and ACAT-derived cholesteryl oleate (Smith E.B., Evans P.H. and Downham M.D., J. Atheroscler. Res.. 1967;7:171-186). Brown and Goldstein have shown that in the 2 compartment model of cholesteryl ester cycling in the macrophage, lipoprotein-derived cholesteryl linoleate is hydrolyzed and the free cholesterol is reesterified with oleoyl-CoA by ACAT to form intracellular cholesteryl oleate enriched lipid droplets (Brown M.S.
- acyl-CoA:cholesterol O-acyltransferase ACAT
- ACAT inhibitors were administered in a cholesterol-containing diet, and shown to limit the development of the macrophage enriched fatty streak or fibrofoamy lesions.
- ACAT inhibitor sulfamic acid, [[2,4,6-tris(l-methylethyl)phenyl]acetyl-2,6-bis(l- methylethyl)phenyl ester] (hereinafter Avasimibe) in a model in which advanced fibrous plaque-like lesions develop.
- Monocyte-macrophage foam cells have recently been implicated in atherosclerotic lesion destabilization and rupture (Galis Z.S., Sukhova G.K., Kranzhoefer R., Clark S. and Libby P., Proc. Natl. Acad. Sci. USA. 1995;92:402-406).
- atherosclerotic lesion development there is an increase in the expression of matrix metalloproteinase (MMP-1, MMP-3, MMP-7 and
- MMPs have been shown to be catalytically active when evaluated by gelatin or casein zymography and both the gelatinolytic and caseinolytic activity has been localized to the shoulders of atherosclerotic lesions in areas of monocyte-macrophage accumulation (Galis Z.S., Sukhova
- a further surprising and beneficial result of the invention is that administration of an ACAT inhibitor alone is sufficient to reduce MMP expression in atherosclerotic lesions in the absence of an MMP inhibitor.
- This invention provides methods of treating atherosclerosis in a mammal, particularly a human, comprising administration of a therapeutically effective amount of an ACAT inhibitor sufficient to inhibit the accumulation of monocyte-macrophages and reduce expression of matrix metalloproteinases in atherosclerotic lesions.
- the invention provides methods for preventing destabilization and/or rupture of atherosclerotic lesions or plaques. Still further, the invention provides a method of treating unstable angina.
- This invention provides methods of treating atherosclerosis comprising administration of an ACAT inhibitor. More particularly, the invention provides methods of inhibiting the accumulation of monocyte-macrophages in atherosclerotic lesions in a mammal, particularly a human, by administering a therapeutically effective amount of an ACAT inhibitor. The invention also provides methods for preventing destabilization and/or rupture of atherosclerotic lesions or plaques.
- ACAT inhibitors suitable for administration and their pharmaceutical compositions are disclosed.
- the present invention is directed to new methods of use of an ACAT inhibitor. Further, the present invention is directed to methods of use of compounds of formula
- X and Y are selected from oxygen, sulfur and (CR'R") wherein n is an integer of from 1 to 4 and R' and R' are each independently hydrogen, Cj-C6 alkyl, C ⁇ -Cg alkoxy, halogen, hydroxy, C2-C6 acyloxy, C3-C10 cycloalkyl, phenyl optionally substituted or R' and R" together form a C3-C10 cycloalkyl or a carbonyl; R is hydrogen, a straight or branched alkyl of from 1 to 8 carbon atoms or benzyl;
- R ⁇ and R2 are each independently selected from
- phenyl or phenoxy each of which is unsubstituted or is substituted with 1 to 5 substituents selected from phenyl, an alkyl group having from 1 to 6 carbon atoms and which is straight or branched, an alkoxy group having from 1 to 6 carbon atoms and which is straight or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl,
- R4 is selected from hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms
- alkyl has from 1 to 4 carbon atoms and is straight or branched, -(CH2)pNR3R4 wherein p, R3 and R4 have the meanings defined above; (c) arylalkyl;
- Preferred compounds of the instant invention are those of Formula I: wherein R ⁇ is phenyl or is phenyl disubstituted in the 2,6-positions, wherein R2 is phenyl or is phenyl disubstituted in the 2,6-positions, wherein each of Rj and R2 is phenyl, wherein each phenyl is disubstituted in the 2,6-position, wherein R ⁇ is phenyl disubstituted in the 2,6-positions and R2 is phenyl trisubstituted in the 2,4,6-positions, wherein Ri is 2,6-bis(l-methylethyl)phenyl and R2 is
- t and w are independently an integer of from 0 to 4 with the proviso that the sum oft and w is not greater than 5;
- R5 and R5 are each independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when R5 is hydrogen, R5 can be selected from the groups defined for R7; and
- R7 is phenyl or phenyl substituted with from 1 to 3 substituents selected from a straight or branched alkyl group having from 1 to 6 carbon atoms, straight or branched alkoxy group having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl, wherein alkyl has from 1 to 4 carbon atoms, or -(CH2)pNR3R4 wherein substituted phenyl p, R3 and R4 have the meanings as defined above.
- Another preferred embodiment are compounds of Formula I wherein:
- X is oxygen, sulfur or (CR'R") n ;
- Y is oxygen, sulfur or (CR'R") n , with the proviso that at least one of X or Y is
- n is an integer of from 1 to 4 and R' and R" are each independently hydrogen, straight or branched alkyl of from 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, Cj-Cg alkoxy, C2-C6 acyloxy, C3-C10 cycloalkyl, or R' and R" are taken together with the carbon atom to which they are attached form a carbonyl or a cycloalkyl group of from 3 to 10 carbons; R is hydrogen; R ⁇ is optionally substituted phenyl, straight or branched alkyl of from 4 to
- R2 is optionally substituted phenyl, straight or branched alkyl of from 4 to
- R ⁇ is optionally substituted phenoxy only if X is (CR'R") n and R2 is optionally substituted phenoxy only if Y is (CR'R") n , and with the further proviso that at least one of R ⁇ and R2 is optionally substituted phenyl or phenoxy.
- R ⁇ and R2 are independently selected from substituted phenyl, straight or branched alkyl of from 4 to 10 carbon atoms, cycloalkyl of from 3 to
- R ⁇ is optionally substituted phenyl
- R2 is selected from substituted phenyl, substituted phenoxy, or R5
- R5 and R6 are each independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when R5 is hydrogen, R5 can be selected from the groups defined for R7; and R7 is phenyl or phenyl substituted with from 1 to 3 substituents selected from a straight or branched alkyl group having from 1 to 6 carbon atoms, straight or branched alkoxy group having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, -COOH, -COOalkyl, wherein alkyl has from 1 to 4 carbon atoms, or -(CH2)pNR 3 R4;
- X is oxygen
- Y is (CR'R") n ;
- R is hydrogen wherein n is an integer of 1 or 2, and substituted phenyl, p, R3, R4, R', and R" have the meanings as defined above.
- n 0, 1 or 2; wherein R ⁇ is selected from
- phenyl which is unsubstituted or is substituted with from 1 to 3 substituents selected from: alkyl having from 1 to 4 carbon atoms and which is straight or branched, alkoxy having from 1 to 3 carbon atoms and which is straight or branched, alkylthio having from 1 to 3 carbon atoms and which is straight or branched, hydroxy, phenyl, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, -COOH,
- alkyl has from 1 to 4 carbon atoms and which is straight or branched
- R7 is a lower alkyl group having from 1 to 3 carbon atoms and is straight or branched; (d) the group
- Rg and R9 are straight or branched alkyl having from 1 to
- RJQ is a straight or branched hydrocarbon group having from 1 to 18 carbon atoms which is saturated or is unsaturated containing 1 double bond or 2 nonadjacent double bonds; phenyl; phenyl substituted with from 1 to 3 substituents selected from straight or branched alkyl having 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 3 carbon atoms, hydroxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched or -(CH2)mNR5R6 wherein m, R5, and Rg are as defined above; or a heteroaryl group selected from 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8
- — denotes a single or double bond
- Y and Z are each independently hydrogen, a straight or branched alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or halogen
- X is oxygen or 2 hydrogen atoms
- R ⁇ ⁇ is hydrogen or a straight or branched alkyl group of 1 to
- n' is zero or 1 ;
- substituents selected from straight or branched 5 alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbon atoms, alkythio, straight or branched having 1 to 4 carbon atoms, hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, nitro, phenyl, or 10 (CH2) m NR5R wherein m, R5, and R5 have the meanings defined above;
- R3 20 is a heteroaryl selected from a 5- or 6-membered monocyclic or fused bicyclic group containing at least 1 to 4 heteroatoms in at least one ring, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heteroaryl group being 25 unsubstituted or substituted with an alkyl group having from 1 to 4 carbon atoms and the N-oxides thereof;
- alkyl having from 1 to 4 carbon atoms and which is straight or branched, alkoxy having from 1 to 3 carbon atoms and which is straight or branched; wherein R4 is a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and is saturated or is unsaturated and has 1 double bond or has 2 nonadjacent double bonds or is alkylthio having 1 to 20 carbon atoms and is saturated; or a pharmaceutically acceptable salt or individual enantiomeric isomer thereof.
- Preferred compounds of Formula II are those: wherein: R4 is in the 2-position of the tetrazole ring, wherein: n is 0; wherein: R4 is straight or branched alkyl containing from 8 to 18 carbon atoms, wherein: one of R2 or R3 is optionally substituted phenyl, wherein R ⁇ is optionally substituted phenyl, wherein R ⁇ is phenyl optionally disubstituted in the 2,6-positions, wherein Rj is phenyl optionally trisubstituted in the 2,4,6-positions.
- R ⁇ is optionally substituted phenyl
- R2 and R3 are each independently hydrogen, cycloalkyl containing from 3 to 8 carbon atoms, optionally substituted phenyl or optionally substituted phenylalkyl wherein the alkylene diradical is from 1 to 4 carbon atoms;
- R4 is a straight or branched alkyl containing from 8 to 18 carbon atoms and is attached in the 2-position of the tetrazole ring; and
- n is 0 or 1.
- Another preferred embodiment of compounds of Formula II is wherein:
- R ⁇ is phenyl disubstituted in the 2,6-positions or trisubstituted in the
- R2 and R3 are each independently hydrogen or optionally substituted phenyl
- R4 is a straight or branched alkyl containing from 8 to 18 carbon atoms and is attached in the 2-position of the tetrazole ring; and n is 0.
- Figure 1 is a gelatin zymography of MMP-2 and -9 and a casein zymography of MMP-1 or -3 after treatment with avasimibe.
- Figure 2 is a line graph with error bars showing mean plasma total cholesterol levels over the time course of the study.
- Figure 3 is a bar graph showing mean plasma cholesterol exposure during the final 7-week treatment phase of the study.
- Figure 4 is a gelatin zymography showing MMP-2 and -9 expression in the aortic arch of hypercholesterolemic rabbits treated with 25 mg/kg of avasimibe.
- Figure 5 is a casein zymography showing MMP-1 or -3 expression in the aortic arch of hypercholesterolemic rabbits treated with 25 mg/kg of avasimibe.
- Figure 6 is a bar graph showing the density of the various MMP zymogen bands.
- Figure 7 is a Northern blot of MMP-2 mRNA expression in the aortic arch of progression control and avasimibe-treated animals.
- Figure 8 is a Northern blot of MMP-9 mRNA expression in the aortic arch of progression control and avasimibe-treated animals.
- Figure 9 is a Northern blot of TIMP-1 mRNA expression in the aortic arch of progression control and avasimibe-treated animals.
- Figure 10 is a Northern blot of TIMP-2 mRNA expression in the aortic arch of progression control and avasimibe-treated animals.
- Figure 11 is a bar graph depicting a morphometric evaluation of the extent of atherosclerosis within the thoracic aorta and the cross-sectional lesion and macrophage area within the aortic arch.
- Figure 12 is a bar graph depicting a morphometric evaluation of the iliac- femoral cross-section lesion and macrophage area.
- ACAT inhibitors can inhibit development and destabilization of atherosclerotic lesions or plaques.
- ACAT inhibitors have been shown to reduce the accumulation of monocyte-macrophages within atherosclerotic lesions of cholesterol-fed rabbits.
- monocyte-macrophages have been reported to secrete such matrix metalloproteinases as MMP-7 and -9 while smooth muscle cells are noted to secrete MMP-1* -2, and -3.
- Inhibition of ACAT while directly reducing the accumulation of lipid-filled monocyte-macrophages will decrease a substantial source of MMPs in atherosclerotic lesions.
- administering will inhibit cellular accumulation and development of atherosclerotic lesions as well as prevent destabilization and/or rupture of mature and developing lesions by reducing the number of lipid-filled monocyte- macrophages, a source of the matrix-degrading MMPs.
- the method is practiced by administering a chemical compound effective in inhibiting the biological activity of the enzyme acyl-coenzyme Axholesterol acyltransferase or ACAT.
- ACAT inhibitors are useful in the practice of this invention.
- An "ACAT inhibitor” as used herein is any chemical compound that inhibits by at least 5 percent the catalytic activity of the enzyme ACAT at an inhibitor concentration of ⁇ 1000 ⁇ M.
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 3 carbon atoms, also known as a C1-C3 alkyl, include methyl, ethyl, 1 -propyl, and 2-propyl.
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 4 carbon atoms also known as a C1-C4 alkyl
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 6 carbon atoms, also known as a Cj-Cg alkyl include groups defined for C ⁇ to C4 alkyl and 1-pentyl, 2-pentyl, 3-pentyl, 2,2-dimethylpropyl,
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 8 carbon atoms also known as a Cj-Cg alkyl, include groups defined for C to C alkyl and 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 5-methyl-l- hexyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 6-methyl-l-heptyl, and 5,5- dimethylhexyl.
- Illustrative examples of a straight or branched alkyl group or radical having from 4 to 10 carbon atoms include 1 -butyl, 2-butyl, 2-methyl- 1 -propyl, 1,1-dimethylethyl, 1-pentyl, 2-pentyl, 3-pentyl, 2,2- dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl- 1-pentyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 5-methyl- 1-hexyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 6-methyl- l-heptyl, 5,5-dimethylhexyl, 1-nonyl, 2-nonyl, 1-decyl, and 2-decyl.
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 12 carbon atoms, also known as a C1-C12 alkyl include groups defined for Cj-Cg alkyl and 1-nonyl, 2-nonyl, 1-decyl, 2-decyl, 1-undecyl,
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 18 carbon atoms also known as a Ci-Cjg alkyl, include groups defined for C ⁇ to C12 alkyl and 1-tridecyl, 1-tetradecyl, 1-pentadecyl, 1- hexadecyl, 1-heptadecyl, and 1-octadecyl.
- Illustrative examples of a straight or branched alkyl group or radical having from 8 to 18 carbon atoms, also known as a Cg-Cjg alkyl, include 1-octyl,
- Illustrative examples of a straight or branched alkyl group or radical having from 1 to 20 carbon atoms, also known as a C1-C20 alkyl, include groups defined for C ⁇ to Cjg alkyl and 1-nonadecyl and 1-decadecyl.
- An adamantyl group or radical includes 1 -adamantyl and 2-adamantyl.
- alkenyl group or radical having from 2 to 6 carbon atoms also known as a C2 to C alkenyl
- alkenyl group or radical having from 2 to 6 carbon atoms also known as a C2 to C alkenyl
- alkenyl group or radical having from 2 to 6 carbon atoms also known as a C2 to C alkenyl
- alkenyl group or radical having from 2 to 6 carbon atoms also known as a C2 to C alkenyl
- Illustrative examples of a straight or branched hydrocarbon chain having from 1 to 18 carbon atoms and having from 1 or 2 nonadjacent double bonds include ethenyl, 2-propenyl, 2-butenyl, 3-pentenyl, 2-octenyl, 5-nonenyl, 4-undecenyl, 5-heptadecenyl, 3-octadecenyl, 9-octadecenyl, 2,2-dimethyl-l l- eicosenyl, and 9,12-octadecadienyl,
- Illustrative examples of a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and having from 1 to 3 double bonds include ethenyl,
- cycloalkyl group or radical having from 3 to 8 carbon atoms also known as a C3-Cg cycloalkyl
- cyclopropyl also known as a C3-Cg cycloalkyl
- cyclobutyl also known as a C3-Cg cycloalkyl
- cyclopentyl cyclohexyl
- cycloheptyl cycloheptyl
- cycloalkyl group or radical having from 3 to 10 carbon atoms also known as a C3-C10 cycloalkyl, include groups defined for
- a spirocycloalkyl group or radical which is a bicyclic group consisting of two rings sharing one and only one atom, having from 5 to 11 carbon atoms, also known as a C5-C1 ⁇ spirocycloalkyl, include bicyclo[2.2.1]pentanyl, bicyclo[3.2.1]hexanyl, bicyclo[3.3.1]heptanyl, and bicyclo[5.5.1 ]undecanyl.
- an aryl group or radical include phenyl,
- alkylene group or diradical which is a divalent radical, having from 1 to 4 carbon atoms, also known as a C1-C4 alkylene group or diradical, include -CH 2 -, -CH 2 CH -, -CH CH 2 CH2-, -CH2CH2CH2CH2-, and -CH(CH 3 )CH 2 CH2-.
- arylalkyl group or radical which is an aryl group or radical bonded to an C1-C4 alkylene group or diradical, wherein aryl and
- C to C4 alkylene have the meanings as defined above, include benzyl,
- a phenylalkyl group or radical which is a phenyl group or radical bonded to a C ⁇ to C4 alkylene group or diradical, wherein Cj to
- C4 alkylene has the meaning as defined above, include benzyl, 2-phenylethyl, 3- phenylpropyl, 4-phenylbutyl, and 3-methyl-3-phenylpropyl.
- An alkylidene group or diradical is a divalent radical formed by removal of one hydrogen atom from the same carbon atom of an alkyl group or radical.
- Illustrative examples of a straight or branched alkoxy group or radical having from 1 to 4 carbon atoms, also known as a C1-C4 alkoxy, include groups defined for C ⁇ to C3 alkoxy and 1-butoxy, 2-butoxy, 2-methyl- 1-propoxy, and 1,1-dimethylethoxy.
- Illustrative examples of a straight or branched alkoxy group or radical having from 1 to 6 carbon atoms also known as a Cj-Cg alkoxy, include groups defined for C ⁇ to C4 alkoxy and 1-pentoxy, 2-pentoxy, 3-pentoxy, 2,2- dimethylpropoxy, 1-hexoxy, 2-hexoxy, 3-hexoxy, and 4-methyl- 1-pentoxy.
- Phenoxy means a phenyl-O- group or radical.
- Illustrative examples of a straight or branched acyloxy group or radical having from 2 to 6 carbon atoms include acetyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, and 4-methylpentanoyloxy.
- Illustrative examples of a straight or branched alkylthio group or radical having from 1 to 3 carbon atoms also known as a C1-C3 alkylthio and which is a
- C1-C3 alkyl-S- group or radical include methylthio, ethylthio, 1-propylthio, and
- Illustrative examples of a straight or branched alkylthio group or radical having from 1 to 4 carbon atoms also known as a C1-C4 alkylthio and which is a C1-C4 alkyl-S- group or radical, include groups defined for C1-C3 alkylthio and
- Illustrative examples of a straight or branched alkylthio group or radical having from 1 to 20 carbon atoms also known as a C1-C20 alkylthio and which is a C1-C20 alkyl-S- group or radical, include groups defined for C1-C4 alkylthio and 1-pentylthio, 2-pentylthio, 3-pentylthio, 2,2-dimethylpropylthio, 1-hexylthio, 2-hexylthio, 3-hexylthio, 4-methyl- 1-pentylthio, 1-heptylthio, 2-heptylthio, 3-heptylthio, 4-heptylthio, 1-octylthio, 2-octylthio, 3-octylthio, 4-octylthio, 6- methyl- 1-heptylthio, 5,5-dimethylhexylthio, 1-nonylthio, 2-non
- a cycloalkylthio group or radical having from 3 to 10 carbon atoms also known as a C3-C10 cycloalkylthio
- a cycloalkylthio group or radical having from 3 to 10 carbon atoms also known as a C3-C10 cycloalkylthio
- cyclopropylthio also known as a C3-C10 cycloalkylthio
- cyclobutylthio also known as a C3-C10 cycloalkylthio
- cyclopentylthio cyclohexylthio
- cycloheptylthio cyclooctylthio
- cyclononylthio and cyclodecylthio.
- cycloalkylthio group or radical having from 5 to 7 carbon atoms also known as a C5-C7 cycloalkylthio
- cyclopentylthio cyclohexylthio
- cycloheptylthio cycloheptylthio
- phenylalkylthio group or radical which is a phenyl group or radical bonded to a C1-C4 alkylene-S- group or diradical, wherein C ⁇ to C4 alkylene has the meaning as defined above, include benzylthio,
- Phenylthio means a phenyl-S- group or radical.
- a heteroatom is nitrogen, oxygen, or sulfur.
- a fused bicyclic group or radical is a group wherein two ring systems share two and only two atoms.
- a fused tricyclic group or radical is a group wherein three ring systems share four and only four atoms.
- a heteroaryl group or radical is a 5- or 6-membered, monocyclic aromatic ring group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, an 8- to 12-membered fused bicyclic ring group wherein at least one ring is aromatic and contains from 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 12- to 14-membered fused tricyclic ring group wherein at least one ring is aromatic and contains from 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur.
- Illustrative examples of monocyclic heteroaryl include 2- or 3-thienyl, 2- or 3-furanyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 4-imidazolyl,
- tricyclic heteroaryl include 1-, 2-, 3- or 4-dibenzofuranyl, 1-, 2-, 3- or
- a heterocycloalkyl group or radical is a 3-, 4-, 5-, 6- or 7-membered, monocyclic nonaromatic ring group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, a 9- to 12-membered fused bicyclic ring group wherein at least one ring is nonaromatic and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, or a 12- to 15-membered fused tricyclic ring group wherein at least one ring is nonaromatic and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur.
- monocyclic heterocycloalkyl examples include 2- or 3-tetrahydrofuranyl, 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 2-, 3-, or 4-tetrahydropyranyl, 2-dioxanyl, 1-, 2-, 3- or 4-azacycloheptanyl, 1- or 2-aziridinyl, or 1- or 2-piperazinyl.
- bicyclic heterocycloalkyl examples include 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-(l, 2,3,4- tetrahydroquinolinyl), 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-(l, 2,3,4- tetrahydroisoquinolinyl), 1-, 2-, 3-, 4-, 5-, 6- or 7-indolinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolinyl, and 2-, 3-, 4-, 5-, 6- or 7-(2,3-dihydrobenzofuranyl).
- tricyclic heterocycloalkyl examples include 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-(9,10- dihydroacridinyl) and 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-xanthenyl. All with the proviso that when bonded to a heteroatom, the heterocycloalkyl group or radical is connected via a carbon atom.
- a heteroaryloxy group or radical is a heteroaryl-O- group wherein heteroaryl has the meaning as defined above.
- a heteroarylthio group or radical is a heteroaryl-S- group wherein heteroaryl has the meaning as defined above.
- Halogen means bromine, chlorine, fluorine, or iodine.
- Pharmaceutically acceptable salts of the compounds of Formula I and II are also included as a part of the present invention.
- the base salts may be generated from compounds of Formula I or II by reaction of the latter with one equivalent of a suitable nontoxic, pharmaceutically acceptable base followed by evaporation of the solvent employed for the reaction and recrystallization of the salt, if required.
- the compounds of Formula I or II may be recovered from the base salt by reaction of the salt with an aqueous solution of a suitable acid such as hydrobromic, hydrochloric, or acetic acid.
- Suitable bases for forming base salts of the compounds of this invention include amines such as triethylamine or dibutylamine, or alkali metal bases and alkaline earth metal bases.
- Preferred alkali metal hydroxides and alkaline earth metal hydroxides as salt formers are the hydroxides of lithium, sodium, potassium, magnesium, or calcium.
- the class of bases suitable for the formation of nontoxic, pharmaceutically acceptable salts is well-known to practitioners of the pharmaceutical formulation arts. See, for example, Berge S.N., et al, J. Pharm. Sci, 1977;66:1-19.
- Suitable acids for forming acid salts of the compounds of this invention containing a basic group include, but are not necessarily limited to acetic, benzoic, benzenesulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, pamoic, salicylic, stearic, succinic, sulfuric, and tartaric acids.
- the acid addition salts are formed by procedures well-known in the art.
- the compounds of the present invention may also exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compound.
- the present invention contemplates all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures.
- the compounds of this invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
- the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
- ACAT inhibitors of Formula I useful in the practice of this invention may be selected from:
- Sulfamic acid (cyclohexylacetyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid (diphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester, Sulfamic acid (triphenylacetyl)-2,6-bis(l-methylethyl)phenyl ester,
- ACAT inhibitors of Formula II useful in the practice of this invention may be selected from:
- ACAT inhibitors useful in the practice of this invention may be selected from: 4-Hexadecylamino-benzoic acid monosodium salt;
- Octadeca-9,12-dienoic acid (l-phenyl-ethyl)-amide; 3 -( 1 H-Indol-3 -yl)-2-octadec-9-enoylamino-propionic acid ethyl ester;
- mice Male New Zealand White rabbits from Kuiper Farms (Gary, IN) weighing 1.2 to 1.5 kg were meal-fed a chow diet (Purina 5321) supplemented with 0.5% cholesterol, 3% peanut oil, and 3% coconut oil diet for a total of 9 weeks followed by a 0% cholesterol, 3% peanut oil, and 3% coconut oil diet (chow/fat diet) for 6 weeks prior to a 7- to 8-week administration of the ACAT inhibitor, avasimibe, in the chow/fat diet.
- the dietary regimen consisted of feeding 30 g for the first week, 40 g for 2 weeks, 50 g for 2 weeks, 60 g for 4 weeks, 70 g for the next 6 weeks, and 80 g for the final 7 to 8 weeks.
- a chronic endothelial injury was induced in the abdominal aorta and femoral artery by surgically inserting a sterile, indwelling, 18-cm nylon monofilament with a diameter of 200 ⁇ m into the lumen of the right femoral artery.
- Surgical procedures were performed on animals anesthetized with 10 mg/kg xylazine from MILES (Shawnee Mission, KS) and 33 mg/kg ketamine HCL from Fort Dodge Laboratories (Fort Dodge, IA) in accordance with a vertebrate use form approved by the Parke-Davis institutional review board.
- the drug diet was prepared fresh on a biweekly basis.
- Plasma total cholesterol and triglyceride levels were measured enzymatically throughout the study on an Abbott VP Series II Bichromatic Analyzer (Chicago, IL) with the Boehringer-Mannheim total cholesterol reagent (Indianapolis, IN) and the Abbott triglyceride reagent (Chicago, IL). The lipid measurements were made monthly or biweekly throughout the study on plasma samples collected 24 hours post-meal. Plasma and vascular avasimibe concentrations were obtained in a group of
- Plasma samples from avasimibe-treated animals were obtained after 7 weeks of dosing at 0, 1, 2, 4, 8, and 24 hours post-dose, and plasma concentrations were determined using a liquid chromatographic mass spectrometric assay.
- Avasimibe and the internal standard were extracted from plasma using diethyl ether. The ether layer was evaporated to dryness and the residue reconstituted in acetonitrile:water (70:30).
- the chromatography conditions consisted of using 2.1 x 150 mm x 5 ⁇ m Zorbax RX-C 18 column with a mobile phase of acetonitrile: 5 mM ammonium acetate buffer (70:30) at a flow rate of 0.2 mL/min. Analytes were detected by mass spectrometry. Vascular avasimibe levels were quantified in a similar manner to that noted above for plasma; however, 100 to 200 mg of aortic arch tissue was homogenized in 2 to 4 mL of water prior to extraction with diethyl ether. Aortic arch samples were collected 24 hours post- dose after 8 weeks of 25 mg/kg avasimibe.
- a 3 -cm segment of the iliac-femoral artery adjacent to that collected for histologic evaluation and the descending thoracic aorta were assayed for their total cholesterol, CE, free cholesterol, and total phospholipid content as previously described.
- the lipids were extracted in chloroform:methanol (2: 1) by the procedure of Folch I., Lees M., Sloane-Stanley G.H., J. Biol. Chem., 1957;226:497-509.
- the lipid composition of the iliac-femoral artery and descending thoracic aorta was measured with an Iatroscan TH-10 Mark IV TLC-FID analyzer from RSS Inc. (thin-layer chromatography-flame ionization detection; Jackson, TN) attached to a Hewlett-Packard 3390 A integrator
- Macrophage Cell Culture Methods The IC50 of avasimibe against macrophage ACAT was evaluated in cultured human monocyte-derived macrophages.
- Human monocyte-derived macrophages supplied by Advanced Biotechnology, Inc. Colder than Eagle's medium (Bassham) were elutriated from blood of normal adult donors as previously described. Frozen but viable monocytes (20 x 10 ⁇ cells/vial) were thawed and plated into 6-well plates containing RPMI 1640 media, 10%
- FBS obtained from HyCll Laboratories (Logan, UT), 1 ng/mL GM-CSF from R&D Systems (Minneapolis, MN) for 10 days to promote monocyte differentiation. On Day 10, the cells were washed and incubated with RPMI 1640, 1% Hu-Nutridoma from Boehringer Mannheim (Indianapolis, IN) and 1 ng/mL GM-CSF for an additional 24 hours. The culture media was changed from
- Avasimibe was dissolved in DMSO and was added at concentrations of 10 to 1000 nM for 1 hour prior to addition of 37 ⁇ g/mL acetylated LDL supplied by Perlmmune, Inc. (Rockville, MD). After a 24 hour incubation, the internal standard,
- MMP activity was assessed by gelatin zymography.
- Aortic matrix metalloproteinase expression was assessed in the aortic arch of 4 to 6 animals from the progression control and avasimibe treatment group. Specimens of aortic arch were stored at -70°C prior to extraction of tissue MMPs according to the procedure described by Galis et al. Tissue samples were minced and homogenized in ice-cold 10 mM sodium phosphate buffer (pH 7.2) containing 150 mM sodium chloride, 1% Triton X-100, 0.1% SDS, 0.5%) sodium deoxycholate, and 0.2%> sodium azide. Tissue homogenates were centrifuged at 14000 RPM for 10 minutes at 4°C and the supernatant collected.
- tissue homogenate containing 30 ⁇ g protein was mixed with 1 part 2X sodium dodecyl sulfate (SDS) sample buffer from Novex (San Diego, CA) and molecular weight markers were added. Each sample was loaded on either a 10% polyacrylamide gel containing 0.1% gelatin purchased precast from Novex
- RNA (20 ⁇ g) was electrophoresed in 1% formaldehyde/agarose gel and blotted onto a nylon membrane (S&S, Keene, NH) in 20 x SSC by using capillary transfer overnight.
- the Northern blot was baked at 80°C for 20 minutes, UV-cross-linked, and prehybridized.
- Blots were hybridized at 65°C with a radiolabeled ( ⁇ - 32 P dCTP) cDNA probes for rabbit MMP-2, MMP-9, TIMP-1, TIMP-2 and, as an internal control, human S9 ribosomal cDNA (0.9 kb).
- the probes were generated by reverse transcriptase-polymerase chain reaction (RT- PCR) from rabbit tissue RNA using sense and antisense primers.
- RT- PCR reverse transcriptase-polymerase chain reaction
- the membranes were washed at 65°C in 1% SDS/2 x SSC and quantified the signals using a Storm 860 phosphoimager and ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
- the rabbit-specific sense and antisense primers used above were prepared for MMP-1 (Fini M.E. et al., Biochemistry. 1987;26:6156-6165), MMP-2 (Matsumoto S. et al., Biochimica et Biophvsica Acta. 1996;1307:137-139), MMP-3 (Fini M.E. et al., Arthritis and Rheumatism. 1987;30(11):1254-1264), MMP-9 (Tezuka K. et al., J. Biol. Chem.. 1994;269:15006-15009), TIMP-1
- Tm range of 60°C to 80°C, scale of 50 nmol and desalted purity.
- These primer sets were used with a One-Step RT-PCR procedure in order to generate the PCR products used above for MMP-1 (1,200 bp), MMP-2 (500 bp), MMP-3 (700 bp), MP-9 (600 bp), TIMP-1 (650 bp), and TIMP-2 (600 bp). Cytochemical Methods.
- the first 1-cm segment of the iliac-femoral artery distal to the aortic-iliac bifurcation and ascending aorta distal to the aortic valves, respectively, were fixed in 10% neutral buffered formalin for 24 hours.
- the vessels were dehydrated, cleared in xylene, and infiltrated with molten paraffin ( ⁇ 60°C) using a Miles Scientific Tissue Tek VIP autoprocessor (Elkhart, IN).
- the tissue segments were embedded in paraffin and sectioned at 5 ⁇ m with a Reichert-Jung microtome purchased from Baxter (McGraw Park, IL).
- the cellular composition of lesions was determined using anti-RAM 11 antibody to rabbit monocyte-macrophages from DAKO (Carpinteria, CA) and anti-HHF35 smooth muscle cell antibody from ENZO Diagnostics (New York, NY). The immuno-cytochemical staining of monocyte-macrophages and SMC was performed as described previously.
- the morphometric analyses of the iliac-femoral artery were performed on a Power Macintosh 8100/80AV computer using the public domain NIH Image program (written by Wayne Rasband at the US National Institute of Health and available from the Internet by anonymous ftp from zippy.nimh.nih.gov or on floppy disk from NTIS, 5285 Port Royal Road, Springfield, VA 22161, Part PB93-504868).
- Morphometric analyses of the aortic arch and thoracic aorta were performed using a PGT Imagist II image analysis system (Princeton, NJ) as previously described.
- RAM-11 (+) staining and number of nuclei associated with the immunoprecipitate were quantified and average monocyte-macrophage cell area was calculated.
- Iliac-femoral and aortic arch lesion and macrophage areas and aortic arch macrophage size were determined for each specimen, and the average per group was calculated based on the mean specimen area. The percent lesion coverage of the thoracic aorta was also determined for each group.
- Plasma avasimibe Cmax and AUC(o_24h) levels were 178 ng/mL and 2525 ng-h/mL, respectively, after 7 weeks of 25 mg/kg avasimibe.
- the IC50 against human monocyte- macrophage ACAT was 12 ng/mL when determined in the absence of albumin and aortic arch avasimibe levels were 25 ng/gm wet weight.
- Plasma total cholesterol levels rose to between 1500 and 2000 mg/dL but decreased to approximately 500 mg/dL during the subsequent 6-week dietary normalization phase ( Figure 2).
- mean plasma total cholesterol levels were reduced 70% by avasimibe; however, no significant changes were noted at previous time points.
- plasma total cholesterol exposure as measured by the area under the cholesterol time curve was similar between control and avasimibe groups, i.e., 117792 and 104422 mg-day/dL, respectively.
- Avasimibe had no effect on plasma total cholesterol exposure during the final 8-week treatment phase (Figure 3). Plasma triglyceride levels were unaffected by avasimibe treatment and mean values ranged from between 46 and 169 mg/dL.
- Plasma avasimibe Cmax determined in a subset of animals treated with 25 mg/kg avasimibe for 7 weeks but comparably fed the fat diet was 178 (31) ng/mL (Mean ⁇ %RSD) while the plasma AUC(Q_24) was 2525 (33) ng-hr/mL.
- avasimibe concentrations were 25 ng/gm tissue wet weight.
- avasimibe In cultured human monocyte-macrophages, avasimibe reduced the intracellular CE concentration in a dose-dependent manner while free cholesterol and triglyceride concentrations were relatively unchanged over the range of 10 to 1000 nM avasimibe.
- the IC50 of avasimibe against isolated cultured primary human monocyte-macrophage ACAT was 25 ⁇ 9 nM or 12 ⁇ 4.5 ng/mL (Mean ⁇
- Thoracic aortic and iliac-femoral CE content were reduced 39% and 36%, respectively, by avasimibe relative to the untreated control and 25% and 39%, respectively, when compared to time zero, i.e., initiation of drug intervention (Table 1).
- Thoracic aortic free cholesterol content was reduced 39%; however, no change in total phospholipid content or free cholesterol was noted in the iliac- femoral artery.
- Aortic arch MMP levels as measured by gelatin and casein zymography were reduced following avasimibe treatment ( Figures 4 and 5).
- the density of the zymogen bands associated with 92 kD gelatinase (latent MMP-9) and 88 kD gelatinase (active MMP-9) was reduced 65% and 33%, respectively.
- Density of bands associated with 72 kD gelatinase (latent MMP-2) and 66 kD gelatinase (active MMP-2) were modestly reduced 7 to 20% but such changes were not statistically significant.
- Latent MMP-9 and MMP-2 was present in differentiated non-CE enriched Hmdm and no change in the amount of catalytic activity was noted following incubation with acetyl-LDL for 24 hours. The catalytic activity was inhibited by incubation with EDTA. Direct incubation of up to 1000 nM avasimibe with cultured human monocyte- macrophages had no effect on latent MMP-9 and MMP-2 catalytic activity. Changes in aortic arch MMP and TIMP expression as measured by
- the macrophages were located both superficially and within the deep intimal regions of the lesion while in the iliac-femoral artery the macrophages were predominantly deep intimal and medial.
- the degree of lesion complexity as evidenced by the incidence of fibrous plaques and fibrofoamy lesions varied with the vascular region and treatment group. Fibrous plaque lesions were identified as containing areas of basophilia and intimal necrosis, cholesterol clefts, and/or calcium deposition. Fibrofoamy lesions were characterized as macrophage- and
- Avasimibe reduced the percent lesion coverage of the thoracic aorta from 34% in the control animals to 20%.
- Avasimibe decreased the cross-sectional lesion area and monocyte-macrophage content of the aortic arch by 35% and 27%, respectively (Figure 11).
- Monocyte-macrophage size within the aortic arch was unaffected by avasimibe treatment (Table 3).
- avasimibe decreased the monocyte-macrophage content of the lesions by 77% and the ratio of RAM-11(+) cell area/lesion area from 0.22 to 0.05 (Figure 12).
- avasimibe decreased thoracic aortic and iliac-femoral CE content 39% and 36%, respectively. Since cholesteryl ester is the end product of the ACAT reaction, these data suggest that vascular ACAT was inhibited.
- Aortic arch MMP activity as measured zymographically was reduced 33% to 65% and aortic arch MMP-9, TIMP-1 and TIMP-2 mRNA levels were decreased 28% to 39%. Both groups of changes were associated with reductions in aortic arch macrophage area.
- reductions in monocyte-macrophage accumulation within atherosclerotic lesions or alterations in the phenotype of the monocyte-macrophages further limits the expression of pro-atherosclerotic molecules.
- ACAT inhibitors directly limit macrophage accumulation in developing atherosclerotic plaques, resulting in mainly fibromuscular lesions. Additionally, ACAT inhibitors prevent destabilization and/or rupture of pre-established atherosclerotic lesions by reducing MMP expression within the lesion.
- the compounds to be employed in the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms for treating and preventing atherosclerosis.
- the compounds can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
- the compounds can be administered by inhalation, for example, intranasally.
- the compounds can be administered transdermally.
- the following dosage forms may comprise as the active component, either a compound as a free base, acid, or a corresponding pharmaceutically acceptable salt of such compound.
- the active compound generally is present in a concentration of about 5% to about 95% by weight of the formulation.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from 5% or 10% to about 70% of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
- the active component is dispersed homogeneously therein, as by stirring.
- the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
- Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
- liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
- viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
- liquid forms include solutions, suspensions, and emulsions.
- These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the pharmaceutical preparation is preferably in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- the quantity of active component in a unit-dose preparation may be varied or adjusted from 1 to 1000 mg, preferably 10 to 100 mg according to the particular application and the potency of the active component.
- the composition can, if desired, also contain other compatible therapeutic agents.
- the compounds utilized in the pharmaceutical method of this invention are administered at a dose that is effective to inhibit esterification activity of ACAT. Such effective amounts are those which prevent monocyte-macrophage accumulation.
- the compounds can also be used prophylactically at the same dose levels.
- the initial dosage of about 1 mg to about 100 mg per kilogram daily will be effective to prevent and treat atherosclerosis.
- a daily dose range of about 5 to about 75 mg is preferred.
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.
- Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. Typical dosages will be from about 0.1 to about 500 mg/kg, and ideally about 25 to about 250 mg/kg.
- the ACAT inhibitor, lactose, and cornstarch (for mix) are blended to uniformity.
- the cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
- the paste is used to granulate the mixed powders.
- the wet granules are passed through a No. 8 hand screen and dried at 80°C.
- the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
- Such tablets can be administered to a human from 1 to 4 times a day for prevention of atherosclerotic plaque destabilization and/or rupture.
- the sorbitol solution is added to 40 mL of distilled water, and the ACAT inhibitor is dissolved therein.
- the saccharin, sodium benzoate, flavor, and dye are added and dissolved.
- the volume is adjusted to 100 mL with distilled water.
- Each milliliter of syrup contains 4 mg of invention compound.
- N 16 in the time zero and progression group and 8 in the avasimibe treatment group. Value in parentheses represents percent change from progression control.
- N 16 in the time zero and progression group and 8 in the avasimibe treatment group. a Data are expressed as mean ⁇ SEM. No statistically significant differences in average macrophage size were noted at p ⁇ 0.05.
- FIGURES Figures are provided to illustrate data in various visual formats.
- Figure 1 is a gelatin zymography showing avasimibe failed to inhibit
- Figure 2 is a line graph with error bars showing mean plasma total cholesterol levels over the time course of the study for drug-treated animals versus untreated progression controls. In both groups, plasma total cholesterol levels rose during the hypercholesterolemia phase of the study (Week 0 to Week 9), then decreased during the subsequent 6-week dietary normalization phase (Week 9 to Week 15).
- Figure 3 is a bar graph showing mean plasma cholesterol exposure during the final 7-week treatment phase of the study. Avasimibe had no effect on plasma total cholesterol levels during Weeks 15 to 22 relative to untreated progression controls.
- Figure 4 is a gelatin zymography showing MMP-2 and -9 expression in the aortic arch of hypercholesterolemic rabbits treated with 25 mg/kg of avasimibe. MMP-2 and -9 levels were reduced relative to untreated progression controls.
- Figure 5 is a casein zymography showing MMP-1 or -3 expression in the aortic arch of hypercholesterolemic rabbits treated with 25 mg/kg of avasimibe. MMP-1 or -3 levels were reduced relative to untreated progression controls.
- Figure 6 is a bar graph showing mean densitometry measurements of the latent and active zymogen bands of the MMP-9, -2, and -1 and-3. Reduction in levels of latent and active forms of MMP-9 and -1 and -3 were statistically significant while those for MMP-2 were not compared to untreated progression controls.
- Figure 7 is a Northern blot of MMP-2 mRNA expression in the aortic arch. Aortic arch MMP-2 mRNA levels increased in avasimibe-treated animals versus untreated progression controls.
- Figure 8 is a Northern blot of MMP-9 mRNA expression in the aortic arch. Aortic arch MMP-9 mRNA levels decreased in avasimibe-treated animals versus untreated progression controls.
- Figure 9 is a Northern blot of MMP-1 mRNA expression in the aortic arch. Aortic arch TIMP-1 mRNA levels decreased in avasimibe-treated animals versus untreated progression controls.
- Figure 10 is a Northern blot of TIMP-2 mRNA expression in the aortic arch. Aortic arch TIMP-2 mRNA levels decreased in avasimibe-treated animals versus untreated progression controls.
- Figure 11 is a bar graph depicting a morphometric evaluation of the extent of atherosclerosis within the thoracic aorta and the cross-sectional lesion and macrophage area within the aortic arch. Relative to drug initiation, thoracic aortic, aortic arch, and iliac-femoral lesion size or extent and monocyte-macrophage enrichment increased in untreated progression control animals administered the chow/fat diet alone.
- Figure 12 is a bar graph depicting a morphometric evaluation of the iliac-femoral cross-section lesion and macrophage area. Avasimibe decreased the monocyte-macrophage content of the lesions and the ratio of RAM-11(+) cell area/lesion area relative to untreated progression controls.
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Abstract
Cette invention est l'administration d'un inhibiteur de l'ACAT afin de prévenir l'accumulation de monocytes-macrophages et l'expression MMP dans des lésions athéroscléreuses. De plus, cette invention concerne des méthodes d'inhibition de la déstabilisation et/ou la rupture de plaques athéroscléreuses et de traitement de l'angor instable.
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AU2012329045A1 (en) | 2011-10-26 | 2014-04-17 | Dow Agrosciences Llc | Pesticidal compositions and processes related thereto |
US9708288B2 (en) | 2012-04-27 | 2017-07-18 | Dow Agrosciences Llc | Pesticidal compositions and processes related thereto |
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US20130291227A1 (en) | 2012-04-27 | 2013-10-31 | Dow Agrosciences Llc | Pesticidal compositions and processes related thereto |
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CN105636442B (zh) | 2013-10-17 | 2018-04-27 | 美国陶氏益农公司 | 制备杀虫化合物的方法 |
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US9801383B2 (en) | 2013-10-22 | 2017-10-31 | Dow Agrosciences Llc | Synergistic pesticidal compositions and related methods |
WO2015061140A1 (fr) | 2013-10-22 | 2015-04-30 | Dow Agrosciences Llc | Compositions pesticides synergiques et méthodes associées |
JP2016535739A (ja) | 2013-10-22 | 2016-11-17 | ダウ アグロサイエンシィズ エルエルシー | 農薬組成物および関連する方法 |
MX2016005317A (es) | 2013-10-22 | 2016-08-12 | Dow Agrosciences Llc | Composiciones pesticidas y metodos relacionados. |
RU2016119368A (ru) | 2013-10-22 | 2017-11-28 | ДАУ АГРОСАЙЕНСИЗ ЭлЭлСи | Синергетические пестицидные композиции и связанные с ними способы |
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AR098096A1 (es) | 2013-10-22 | 2016-05-04 | Dow Agrosciences Llc | Composiciones plaguicidas sinérgicas y métodos relacionados |
JP2016535024A (ja) | 2013-10-22 | 2016-11-10 | ダウ アグロサイエンシィズ エルエルシー | 相乗的有害生物防除組成物および関連する方法 |
NZ719688A (en) | 2013-10-22 | 2017-06-30 | Dow Agrosciences Llc | Pesticidal compositions and related methods |
KR20160074582A (ko) | 2013-10-22 | 2016-06-28 | 다우 아그로사이언시즈 엘엘씨 | 상승작용적 살충 조성물 및 관련 방법 |
WO2015061163A1 (fr) | 2013-10-22 | 2015-04-30 | Dow Agrosciences Llc | Compositions pesticides et procédés associés |
JP2016538266A (ja) | 2013-10-22 | 2016-12-08 | ダウ アグロサイエンシィズ エルエルシー | 相乗的有害生物防除組成物および関連する方法 |
MX2016005323A (es) | 2013-10-22 | 2016-08-12 | Dow Agrosciences Llc | Composiciones pesticidas y metodos relacionados. |
KR20170038785A (ko) | 2014-07-31 | 2017-04-07 | 다우 아그로사이언시즈 엘엘씨 | 3-(3-클로로-1h-피라졸-1-일)피리딘의 제조 방법 |
BR112017000565A2 (pt) | 2014-07-31 | 2017-11-07 | Dow Agrosciences Llc | processo para a preparação de 3-(3-cloro-1h-pirazol-1-il)piridina |
JP2017523168A (ja) | 2014-07-31 | 2017-08-17 | ダウ アグロサイエンシィズ エルエルシー | 3−(3−クロロ−1h−ピラゾール−1−イル)ピリジンの製造方法 |
WO2016028328A1 (fr) | 2014-08-19 | 2016-02-25 | Dow Agrosciences Llc | Procédé de préparation de 3-(3-chloro-1h-pyrazol-1-yl)pyridine |
US9085552B1 (en) | 2014-09-12 | 2015-07-21 | Dow Agrosciences Llc | Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine |
EP3209671B8 (fr) * | 2014-10-21 | 2019-07-31 | Council of Scientific and Industrial Research | Esters de phosphonate d'alkylidène en tant qu'inducteurs de p-glycoprotéine |
PE20190656A1 (es) * | 2016-07-29 | 2019-05-08 | Lupin Ltd | Compuestos de tiazolo-piridina sustituida como inhibidores de malt1 |
WO2018093966A1 (fr) | 2016-11-16 | 2018-05-24 | Purdue Research Foundation | Compositions et procédés de régulation du poids corporel et des syndromes métaboliques |
US10233155B2 (en) | 2016-12-29 | 2019-03-19 | Dow Agrosciences Llc | Processes for the preparation of pesticide compounds |
CN110139853B (zh) | 2016-12-29 | 2023-06-16 | 美国陶氏益农公司 | 用于制备杀有害生物化合物的方法 |
AU2018354777A1 (en) | 2017-10-27 | 2020-04-16 | Bayer Aktiengesellschaft | Novel Pyrazolo-pyrrolo-pyrimidine-dione derivatives as P2X3 inhibitors |
WO2020113094A1 (fr) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Composés pyrrole et pyrazole et leurs procédés d'utilisation |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU654688B2 (en) * | 1990-10-30 | 1994-11-17 | Warner-Lambert Company | Oxysulfonyl carbamates |
IL109431A (en) * | 1993-05-14 | 2001-01-11 | Warner Lambert Co | Pharmaceutical compositions containing n-acyl sulfamic acid esters (or thioesters), n-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters), for regulating plasma cholesterol concentration, and certain such novel compounds |
IT1270976B (it) * | 1993-08-06 | 1997-05-26 | Pierrel Spa | Composti inibitpri di acil enzima-a-colesterolo-o-acil transferasi ad attivita' terapeutica, loro uso e composizioni farmaceutiche che li contengono |
JPH11510184A (ja) * | 1995-08-04 | 1999-09-07 | ワーナー−ランバート・コンパニー | リポ蛋白レベルを低下させるための医薬の製造用スルファミン酸誘導体、アシルスルホンアミドまたはスルホニルカルバメートの使用 |
CN1217656C (zh) * | 1995-11-02 | 2005-09-07 | 沃尼尔·朗伯公司 | 用于调节脂浓度的方法和药物组合物 |
IL140982A0 (en) * | 1998-07-21 | 2002-02-10 | Warner Lambert Co | Coadministration of acat and mmp inhibitors for the treatment of atherosclerotic lesions |
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2000
- 2000-10-17 CN CN00812939A patent/CN1414848A/zh active Pending
- 2000-10-17 TR TR2002/01204T patent/TR200201204T2/xx unknown
- 2000-10-17 HU HU0203160A patent/HUP0203160A3/hu unknown
- 2000-10-17 PL PL00355148A patent/PL355148A1/xx not_active Application Discontinuation
- 2000-10-17 EP EP00973608A patent/EP1229907A1/fr not_active Withdrawn
- 2000-10-17 IL IL14914500A patent/IL149145A0/xx unknown
- 2000-10-17 KR KR1020027005801A patent/KR20020050257A/ko not_active Application Discontinuation
- 2000-10-17 CA CA002382676A patent/CA2382676A1/fr not_active Abandoned
- 2000-10-17 JP JP2001536127A patent/JP2003513909A/ja active Pending
- 2000-10-17 AU AU12104/01A patent/AU1210401A/en not_active Abandoned
- 2000-10-17 WO PCT/US2000/028705 patent/WO2001034127A1/fr not_active Application Discontinuation
- 2000-10-25 SV SV2000000207A patent/SV2001000207A/es unknown
- 2000-11-01 PA PA20008506101A patent/PA8506101A1/es unknown
- 2000-11-03 PE PE2000001173A patent/PE20011027A1/es not_active Application Discontinuation
- 2000-11-03 UY UY26427A patent/UY26427A1/es not_active Application Discontinuation
- 2000-11-03 AR ARP000105803A patent/AR026354A1/es unknown
- 2000-11-03 CO CO00083934A patent/CO5270017A1/es not_active Application Discontinuation
- 2000-11-03 GT GT200000193A patent/GT200000193A/es unknown
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2002
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See references of WO0134127A1 * |
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KR20020050257A (ko) | 2002-06-26 |
PA8506101A1 (es) | 2002-10-28 |
ZA200201755B (en) | 2003-08-27 |
PL355148A1 (en) | 2004-04-05 |
GT200000193A (es) | 2002-04-27 |
WO2001034127A1 (fr) | 2001-05-17 |
AR026354A1 (es) | 2003-02-05 |
CO5270017A1 (es) | 2003-04-30 |
HUP0203160A2 (hu) | 2003-01-28 |
AU1210401A (en) | 2001-06-06 |
IL149145A0 (en) | 2002-11-10 |
HUP0203160A3 (en) | 2006-02-28 |
CA2382676A1 (fr) | 2001-05-17 |
SV2001000207A (es) | 2001-10-16 |
PE20011027A1 (es) | 2001-10-16 |
CN1414848A (zh) | 2003-04-30 |
UY26427A1 (es) | 2000-12-29 |
TR200201204T2 (tr) | 2002-08-21 |
JP2003513909A (ja) | 2003-04-15 |
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