Canadian Patents Database / Patent 2233558 Summary

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(12) Patent: (11) CA 2233558
(54) English Title: METHOD AND PHARMACEUTICAL COMPOSITION FOR REGULATING LIPID CONCENTRATION
(54) French Title: PROCEDE ET COMPOSITION PHARMACEUTIQUE VISANT A REGULER LA CONCENTRATION LIPIDIQUE
(51) International Patent Classification (IPC):
  • A61K 31/4418 (2006.01)
  • A61K 31/165 (2006.01)
  • A61K 31/17 (2006.01)
  • A61K 31/215 (2006.01)
  • A61K 31/22 (2006.01)
  • A61K 31/255 (2006.01)
  • A61K 31/366 (2006.01)
  • A61K 31/40 (2006.01)
  • A61K 31/41 (2006.01)
  • A61K 45/06 (2006.01)
(72) Inventors :
  • BOCAN, THOMAS MICHAEL ANDREW (United States of America)
(73) Owners :
  • WARNER-LAMBERT COMPANY (United States of America)
(71) Applicants :
  • WARNER-LAMBERT COMPANY (United States of America)
(74) Agent: MACRAE & CO.
(74) Associate agent: MACRAE & CO.
(45) Issued: 2005-12-06
(86) PCT Filing Date: 1996-10-02
(87) Open to Public Inspection: 1997-05-09
Examination requested: 2001-07-11
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country/Territory Date
60/006,155 United States of America 1995-11-02

English Abstract





The present invention is a combination of an ACAT inhibitor for example,
sulfamic acid, [[2,4,6; tris(1-methylethyl)phenyl]acetyl]-,
2,6-bis(1-methylethyl)phenyl ester, and an HMG-CoA-reductase inhibitor, for
example, atorvastatin, effective for lipid regulation. The
combination of agents results in a greater reduction in plasma VLDL and LDL
cholesterol and increases HDL cholesterol than either alone
resulting in a less atherogenic lipoprotein profile. The combination is useful
in the treatment of patients with or at risk of developing
ischemic syndromes in order to restore endogenous vascular endothelium-
dependent activities.


French Abstract

La présente invention se rapporte à une combinaison d'un inhibiteur d'ACAT tel que l'acide sulfamique, [[2,4,6,-tris(1-méthyléthyl)phényl]acétyl]-, 2,6-bis(1-méthyléthyl) phényl ester, et d'un inhibiteur de HMG-CoA-réductase tel que l'atorvastatine, efficace dans la régulation des lipides. La combinaison de ces agents entraîne une meilleure diminution du VLDL et LDL cholestérol plasmatique et élève davantage le taux de HDL cholestérol que l'un ou l'autre de ces agents administrés isolément, ce qui permet d'obtenir un profil lipoprotéinique moins athérogène. La combinaison est utilisée dans le traitement de patients présentant ou risquant de développer des syndromes ischémiques en vue de rétablir les activités endogènes dépendant de l'endothélium vasculaire.


Note: Claims are shown in the official language in which they were submitted.




-15-

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition for regulating lipid
concentration in a mammal comprising a therapeutically
effective amount of an aryl-CoA cholesterol O-
acyltransferase (ACAT) inhibitor and an HMG-CoA reductase
inhibitor together with a pharmaceutically acceptable
carrier.

2. A pharmaceutical composition according to Claim 1 wherein
the ACAT inhibitor is one or more compounds selected
from:
Sulfamic acid, [[2,4,6-tris(1-methylethyl)
phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl] ester;
2,6-bis(1-methyl-ethyl)phenyl[[2,6-
bis(1-methylethyl)phenyl]sulfonyl]carbamate monosodium
salt;
N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid
dodecyl-ester;
N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-
2H-tetrazol-5-yl)-2-phenyl-acetamide;
2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)-
docecanamide; and
N-[2,6-bis(1-methylethyl)-phenyl]-N'-
[[1-[4-(dimethylamino)phenyl]-cyclopentyl]methyl]
urea monohydrochloride;
and the HMG-CoA reductase inhibitor is one or more
compounds selected from rivastatin, lovastatin,
simvastatin, pravastatin, fluvastatin, and atorvastatin.

3. A pharmaceutical composition according to Claim 1 wherein
the ACAT inhibitor is one or more compounds selected from
2,6-bis(1-methylethyl)-phenyl[[2,4,6-tris(1-methylethyl)
phenyl]-acetyl]sulfamate, N-(2,6-diiso-propyl-phenyl)-



-16-

2-phenyl-malonamic acid dodecyl-ester, and
N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)
-2-phenyl-acetamide; and the HMG-CoA reductase inhibitor
is one or more compounds selected from rivastatin,
lovastatin, simvastatin, pravastatin, fluvastatin, and
atorvastatin.

4. A pharmaceutical composition according to Claim 1
wherein the ACAT inhibitor is 2,6-bis(1-methyl-
ethyl)phenyl[[2,4,6-tris(1-methylethyl)phenyl]-
acetyl]sulfamate and the HMG-CoA reductase inhibitor is
selected from rivastatin, lovastatin, simvastatin,
pravastatin, fluvastatin, and atorvastatin.

5. A pharmaceutical composition for regulating lipid
concentrations in a mammal comprising a therapeutically
effective amount of 2,6-bis(1-methylethyl)phenyl[[2,4,6-
tris(1-methylethyl)phenyl]acetyl]sulfamate and of
atorvastatin together with a pharmaceutically acceptable
carrier.

6. For use in restoring endogenous vascular endothelium-
dependent activities selected from preventing coagulation
of platelets, decreasing the adherent properties of blood
vessel walls, and inducing vasodilation to modulate
vascular tone and blood flow in a mammal in need of said
treatment, a composition comprising a therapeutically
effective amount of one or more ACAT inhibiting compounds
and one or more HMG-CoA reductase inhibitors.

7. The composition of Claim 6 wherein the ACAT inhibitor is
selected from: sulfamic acid, [[2,4,6-tris(1-methyl-
ethyl)phenyl]acetyl]-2,6-bis(1-methylethyl)phenyl] ester;
2,6-bis(1-methyl-ethyl)phenyl[[2,6-bis(1-methylethyl)-
phenyl]sulfonyl]carbamate monosodium salt;



-17-

N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid
dodecyl-ester; 2,2-dimethyl-N-(2,4,6-trimethoxy-
phenyl)-docecanamide; and N-[2,6-bis(1-methyl-
ethyl)-phenyl]-N'-[[1-[4-(dimethylamino)phenyl]-
cyclopentyl]methyl] urea monohydrochloride; and the HMG-
CoA reductase inhibitor is one or more compounds selected
from rivastatin, lovastatin, simvastatin, pravastatin,
fluvastatin, and atorvastatin.

8. The composition of Claim 6 wherein the ACAT inhibitor is
2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-
methylethyl)phenyl]acetyl]sulfamate, and the HMG-CoA
reductase inhibitor is one or more compounds selected
from rivastatin, lovastatin, simvastatin, pravastatin,
fluvastatin, and atorvastatin.

9. The composition of Claim 6 wherein the ACAT inhibitor is
2,6-bis(1-methylethyl)phenyl[[2,4,6-tris-(1-
methylethyl)phenyl]acetyl]sulfamate and the HMG-CoA
reductase inhibitor is selected from simvastatin and
atorvastatin.

10. The composition of Claim 6 wherein the therapeutically
effective amount of ACAT inhibitor is 50 to 1500 mg per
day, and the therapeutically effective amount of HMG-CoA
reductase inhibitor is about 5 to about 80 mg/day.

11. For use in the prevention of coagulation of platelets, a
composition comprising a therapeutically effective amount
of one or more ACAT inhibiting compounds and one or more
HMG-CoA reductase inhibitors.

12. For use in decreasing the adherent properties of blood
vessel walls, a composition comprising a therapeutically
effective amount of one or more ACAT inhibiting compounds




-18-

and one or more HMG-CoA reductase inhibitors.

13. For use in inducing vasodilation to modulate vascular
tone and blood flow, a composition comprising a
therapeutically effective amount of one or more ACAT
inhibiting compounds and one or more HMG-CoA reductase
inhibitors.

14. For use in preventing or treating diseases associated
with endothelial dysfunction selected from: angina
pectoris, myocardial infarctions, coronary artery
disease, hypertension, cerebrovascular accidents,
transient ischemic attacks, chronic obstructive pulmonary
disease, chronic hypoxic lung disease, pulmonary
hypertension, renal hypertension, chronic renal disease,
microvascular complications of diabetes, and vaso-
occlusive complications of sickle cell anemia, a
composition comprising a therapeutically effective amount
of one or more ACAT inhibiting compounds and one or more
HMG-CoA reductase inhibitors.

15. A composition according to Claim 14 which comprises one
or more ACAT inhibiting compounds selected from the group
consisting of: sulfamic acid, [[2,4,6-tris(1-methylethyl)
phenyl]acetyl]-2,6-bis (1-methylethyl)phenyl] ester;
2,6-bis(1-methyl-ethyl)phenyl[[2,6-bis(1-
methylethyl)phenyl]sulfonyl]carbamate monosodium
salt; N-(2,6-diisopropyl-phenyl)-2-phenyl-
malonamic acid dodecyl-ester; 5-methoxy-3-
(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[6]-
thiopheno-2-carboxamide monosodium salt; 2,2-
dimethyl-N-(2,4,6-trimethoxyphenyl)-docecanamide;
and N-[2,6-bis(1-methylethyl)-phenyl]-N'-
[[1-[4-(dimethylamino)phenyl]-cyclopentyl]methyl]
urea monohydrochloride; and one or more HMG-CoA reductase



-19-

inhibitors selected from the group consisting of:
rivastatin, lovastatin, simvastatin, pravastatin,
fluvastatin, and atorvastatin.

16. A composition according to Claim 14 which comprises one
or more ACAT inhibiting compounds selected from the group
consisting of: 2,6-bis(1-methylethyl)-phenyl[[2,4,6-
tris(1-methylethyl)phenyl]-acetyl]sulfamate,
N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid
dodecyl-ester, and N-(2,6-diisopropyl-phenyl)-
2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide: and
one or more HMG-CoA reductase inhibitors selected from
the group consisting of rifastatin, lovastatin,
simvastatin, pravastatin, fluvastatin, and atorvastatin.

17. For use in stabilizing atherosclerotic lesion and
preventing plaque rupture in a mammal with
atherosclerosis, a composition comprising therapeutically
effective amounts of an acyl-CoA cholesterol O-
acyltransferase (ACAT) inhibitor and an HMG-CoA reductase
inhibitor.

18. A composition according to Claim 17 which comprises one
or more ACAT inhibiting compounds selected from the group
consisting of: sulfamic acid, [[2,4,6-tris(1-methylethyl)
phenyl]acetyl]-2,6-bis (1-methylethyl)phenyl] ester;
2,6-bis(1-methyl-ethyl)phenyl[[2,6-bis(1-
methylethyl)phenyl]sulfonyl]carbamate monosodium
salt; N-(2,6-diisopropyl-phenyl)-2-phenyl-
malonamic acid dodecyl-ester; 5-methoxy-3-
(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[6]-
thiopheno-2-carboxamide monosodium salt: 2,2-
dimethyl-N-(2,4,6-trimethoxyphenyl)-docecanamide;
and N-[2,6-bis(1-methylethyl)-phenyl]-N'-
[[1-[4-(dimethylamino)phenyl]-cyclopentyl]methyl]




-20-

urea monohydrochloride; and one or more HMG-CoA reductase
inhibitors selected from the group consisting of:
rivastatin, lovastatin, simvastatin, pravastatin,
fluvastatin, and atorvastatin.

19. A composition according to Claim 17 which comprises one
or more ACAT inhibiting compounds selected from the group
consisting of: 2,6-bis(1-methylethyl)-phenyl[[2,4,6-
tris(1-methylethyl)phenyl]-acetyl]sulfamate,
N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid
dodecyl-ester, and N-(2,6-diisopropyl-phenyl)-
2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide; and
one or more HMG-CoA reductase inhibitors selected from
the group consisting of rifastatin, lovastatin,
simvastatin, pravastatin, fluvastatin, and atorvastatin.

20. For use in preventing ischemic sudden death in a patient
at risk of the same, a composition comprising
therapeutically effective amounts of an acyl-CoA
cholesterol O-acyltransferase (ACAT) inhibitor and an
HMG-CoA reductase inhibitor.

21. A composition according to Claim 20 which comprises one
or more ACAT inhibiting compounds selected from the group
consisting of: sulfamic acid, [[2,4,6-tris(1-methylethyl)
phenyl]acetyl]-2,6-bis (1-methylethyl)phenyl] ester;
2,6-bis(1-methyl-ethyl)phenyl[[2,6-bis(1-
methylethyl)phenyl]sulfonyl]carbamate monosodium
salt; N-(2,6-diisopropyl-phenyl)-2-phenyl-
malonamic acid dodecyl-ester; 5-methoxy-3-
(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[6]-
thiopheno-2-carboxamide monosodium salt; 2,2-
dimethyl-N-(2,4,6-trimethoxyphenyl)-docecanamide;
and N-[2,6-bis(1-methylethyl)-phenyl]-N'-
[[1-[4-(dimethylamino)phenyl]-cyclopentyl]methyl]




-21-

urea monohydrochloride; and one or more HMG-CoA reductase
inhibitors selected from the group consisting of:
rivastatin, lovastatin, simvastatin, pravastatin,
fluvastatin, and atorvastatin.

22. A composition according to Claim 20 which comprises one
or more ACAT inhibiting compounds selected from the group
consisting of: 2,6-bis(1-methylethyl)-phenyl[[2,4,6-
tris(1-methylethyl)phenyl]-acetyl]sulfamate,
N-(2,6-diiso-propyl-phenyl)-2-phenyl-malonamic acid
dodecyl-ester, and N-(2,6-diisopropyl-phenyl)-
2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide; and
one or more HMG-CoA reductase inhibitors selected from
the group consisting of rifastatin, lovastatin,
simvastatin, pravastatin, fluvastatin, and atorvastatin.

23. A composition according to Claim 1 wherein the ACAT
inhibitor is 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-
methylethyl)phenyl]acetyl]sulfamate and the HMG-CoA
reductase inhibitor is selected from rivastatin,
lovastatin, simvastatin, pravastatin, fluvastatin, and
atorvastatin.

24. A composition according to Claim 1 comprising 2,6-
bis(1-methylethyl)phenyl[[2,4,6-tris(1-methyl-
ethyl)phenyl]acetyl]sulfamate and atorvastatin.

25. A commercial package comprising a composition according
to Claim 1, 2, 3, 4 or 5 and written matter which states
that the composition is for use in regulating lipid
concentration in a mammal.

26. A commercial package comprising a composition according
to Claim 6, 7, 8, 9 or 10 and written matter which states


-22-
that the composition is for use in restoring endogenous
vascular endothelium-dependant activity in a mammal.
27. A commercial package comprising a composition according
to Claim 11 and written matter which states that the
composition is for use in preventing coagulation of
platelets.
28. A commercial package comprising a composition according
to Claim 12 and written matter which states that the
composition is for use in decreasing the adherent
properties of blood vessel walls.
29. A commercial package comprising a composition according
to Claim 13 and written matter which states that the
composition is for use in inducing vasodilation to
modulate vascular tone and blood flow.
30. A commercial package comprising a composition according
to Claim 14, 15 and 16 and written matter which states
that the composition is for use in preventing or treating
a disease associated with endothelial dysfunction.
31. A commercial package comprising a composition according
to Claim 17, 18 and 19 and written matter which states
that the composition is for use in stabilizing
atherosclerotic lesion and preventing plaque rupture in a
mammal with atherosclerosis.
32. A commercial package comprising a composition according
to Claim 20, 21 and 22 and written matter which states
that the composition is for use in preventing ischemic
sudden death in a mammal.

Note: Descriptions are shown in the official language in which they were submitted.


CA 02233558 1998-03-31
WO 97/16184 PCTJUS96/15854
-1-
METHOD AND PHARMACEUTICAL COMPOSITION FOR
REGULATING LIPID CONCENTRATION
BACKGROUND OF THE INVENTION
The treatment of patients with or at risk of
developing ischemic syndromes with doses of an HMG-CoA


reductase inhibitor to lower total and LDL cholesterol


is known. This is done in order to restore endogenous


vascular endothelium-dependent activities including,


but not limited to vasodilatory responses modulating


vascular tone and blood flow, antiadherent properties


of the blood vessel wall, and anticoagulation of


platelets (International Publication Number


WO 95/13063).


There is evidence from animal models that


compounds which inhibit the enzyme, acyl-coenzyme


A:cholesterol acyltransferase (ACAT) will be effective


anti-atherosclerotic agents,(Curr. Med. h r",


1994;1:204-225). It is well-established that when the


majority of cholesterol in plasma is carried on


apolipoprotein B-containing lipoproteins, such as low-


density lipoproteins (LDL-C) and very-low-density


lipoproteins (VLDL-C), the risk of coronary artery


disease in man is increased (Circulation, 1990;81:1721-


1733). Conversely, high levels of cholesterol carried


in high-density lipoproteins (HDL-C) is protective


against coronary artery disease (Am. J. Med.,


1977;62:707-714). Thus, a drug which reduces the


levels of atherogenic LDL-C and VLDL-C and elevates


levels of protective HDL-C will produce a less


atherogenic lipoprotein profile and thus a beneficial


effect on atherosclerotic disease and its
i


complications. This beneficial effect was demonstrated


in man in the Helsinki Heart Study with the lipid


regulator gemfibrozil which decreased LDL-C, increased




CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854 -
-2-
HDL-C, and reduced the incidence of coronary artery
disease (N. Engl. J. Med., 1987;317:1237-1245).
SUMMARY OF THE INVENTION ,
We have now shown that a combination of ACAT
inhibitor and HMG-CoA reductase inhibitor when
administered in a chow/fat diet results in a greater
reduction in apo B-containing liproprotein than either
alone and that a normalization of the plasma
lipoprotein profile can be achieved. This means the
combination treatment results in plasma lipoprotein
profile associated with a decreased risk of coronary
artery disease.
We have also shown that a combination of ACAT
inhibitors and HMG-CoA reductase inhibitors reduces the
cholesteryl esters (CE) enrichment of pre-existing
atherosclerotic lesions to the same extent as the
HMG-CoA reductase inhibitor alone but that the
histologic character of the atherosclerotic lesions is
less complicated. This means that the lesions are less
prone to induce myocardial infarction.
DETAILED DESCRIPTION OF THE INVENTION
The novel method of treatment of this invention
and the novel pharmaceutical compositions comprise the
administration to a patient at risk of developing
atherosclerosis or a patient in whom the disease has
been diagnosed with an ACAT inhibitor and HMG-CoA
reductase inhibitor which will restore endogenous
vascular endothelium-dependent activities including
improving the normal dilation capacity of the
endothelium. This method may be used to induce


CA 02233558 1998-03-31
WO 97/16184 PCTIUS96/15854 -
-3-
vasodilation to modulate vascular tone and blood flow.
Other improvements in vascular endothelium-dependent
activities include decreasing the adherent properties
of the blood vessel walls and decreasing the
coagulation of platelets. Suitable subjects for the
method of the present invention include those
individuals who currently exhibit symptoms of
atherosclerosis and those who are at risk of developing
various acute ischemic syndromes including individuals
with high blood pressure, diabetes, or hyperlipidemia,
and individuals who smoke.
The various acute ischemic syndromes that may be
treated by the method of the present invention include:
angina pectoris, coronary artery disease (CAD),
hypertension, cerebrovascular accidents, transient
ischemic attacks, chronic,obstructive pulmonary
disease, chronic hypoxic lung disease, pulmonary
hypertension, renal hypertension, chronic renal
disease, microvascular complications of diabetes, and
vaso-occlusive complications of sickle cell anemia.
An HMG-CoA reductase inhibitor for use in the
novel method may be selected from atorvastatin,
lovastatin, simvastatin, pravastatin, fluvastatin, and
rivastatin; preferably atorvastatin, lovastatin, or
simvastatin; most preferably atorvastatin.
HMG-CoA reductase inhibitors are known to function
as antihypercholesterolemic agents. They reduce
hepatic cholesterol biosynthesis by inhibiting the
enzyme HMG-CoA reductase which catalyzes the early,
rate-limiting step in the biosynthesis of cholesterol,
the conversion of hydroxymethylglutarate to mevalonate.
Known HMG-CoA reductase inhibitors include atorvastatin
MEVACOR~ (lovastatin), ZOCOR~ (simvastatin), PRAVACHOL~
(pravastatin), LESCOL~ (fluvastatin), and rivastatin.

CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854
°4-
H3C\ / CH3
O ;H ;H O
\ NHC iCH~ ~CH~ iC~
~ CH2 CH2 O
Ca 2+ w
Atorvastatin
H H C ///~ O ,
'H
3 H3C CH3~ H ,.H CH
3
/ /
H3C
Lovastatin Simvastatin
OH
Na00C
2 0 O HO
~~ H
O
H3C~i H .H
CH3 CH3
C02 Na+
/ /
HO
Pravastatin
Fluvastatin
Na+
F
~H3
H~
r
__
3 5 Rivastatin


CA 02233558 1998-03-31
WO 97/16184 PCT/LTS96/15854
-5-
The doses of HMG-CoA reductase inhibitor
contemplated for use in this invention are about 5 to
80 mg per day, preferably given in single or divided
doses.
Preferably, the patient is placed on a prudent
r
lipid-lowering diet during the treatment with the
HMG-CoA reductase inhibitors.
Lipid lowering therapy with HMG-CoA reductase


inhibitors normalizes vascular function in patients


with hypercholesterolemia and/or coronary artery


disease without the requirement for significant


regression of the atherosclerotic lesions. The


coronary microcirculation, which demonstrates


significantly impaired endothelium dependent dilatory


responses in the presence of hypercholesterolemia and


atherosclerotic disease, but is usually free of


atheroma, is likely to show marked improvement


demonstrating the ability of lipid lowering therapy to


halt the progression and/or promote regression of


atherosclerosis in epicardial arteries in humans.


Atorvastatin is disclosed in United States Patent


Number 5,273,995. Related compounds are disclosed in


United States Patent Number 4,681,893.


Lovastatin and related compounds are disclosed


in United States Patent Number 4,231,938; simvastatin


and related compounds are disclosed in United States


Patent Number 4,450,171 and United States Patent


Number 4,346,227; pravastatin and related compounds are


disclosed in United States Patent Number 4,346,227 and


fluvastatin and related compounds are disclosed in


United States Patent Number 4,739,073; rivastatin and


related compounds are disclosed in United States


Patents Numbers 5,177,080 and 5,006,530.


Compounds which effectively inhibit the enzyme,


acyl-coenzyme A:cholesterol acyltransferase (ACAT)


prevent the intestinal absorption of dietary




CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854
-6-
cholesterol into the blood stream or the reabsorption
of cholesterol which has been previously released into
the intestine through the body's own regulatory action.
The ACAT inhibiting compounds provide treatment of
hypercholesterolemia and atherosclerosis. Such
i
compounds include, for example, a compound of Formula I
O O
~.0 R1-X- ii -~-C-Y-R' 1
O R
or a pharmaceutically acceptable salt thereof wherein:
X and Y are selected from oxygen, sulfur and (CR'R")n,
wherein n is an integer of from 1 to 4 and R' and
R" are each independently hydrogen, alkyl, alkoxy,
halogen, hydroxy, acyloxy, cycloalkyl, phenyl
optionally substituted or R' and R" together form
a spirocycloalkyl or a carbonyl;
with the proviso at least one of X and Y is
(CR'R")n and with the further proviso when X and Y
are both (CR'R")n and R' and R" are hydrogen and n
is one, R1 and R2 are aryl;
R is hydrogen, a straight or branched alkyl of from
1 to 8 carbon atoms or benzyl;
R1 and R2 are each independently selected from
(a) 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,


CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854 -
chlorine,


bromine,


nitro,


trifluoromethyl,


-COON,



-COOalkyl wherein alkyl has from 1 to 4 carbon


atoms and is straight or branched,


-(CH2)pNR3R4 wherein p is zero or one, and each of


R3 and R4 is selected from hydrogen or a


straight or branched alkyl group having 1 to


4 carbon atoms;


(b) 1- or 2-naphthyl unsubstituted or substituted


with from 1 to 3 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;


hydroxy,


phenoxy,


fluorine,


chlorine,


bromine,


vitro,


trifluoromethyl,


-COOH,


-COOalkyl wherein 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;


(d) a straight or branched alkyl chain having


from 1 to 20 carbon atoms and which is saturated or


,, contains from 1 to 3 double bonds; or


(e) adamantyl or a cycloalkyl group wherein the


cycloalkyl moiety has from 3 to 6 carbon atoms;




CA 02233558 2001-11-28
WO 97/16184 PC'T/US96/15854 -
-g-
with the provisos:
(i) where X is (CH2)n, Y is oxygen, and R1 is a
substituted phenyl. then R2 is a
substituted phenyl;
(ii) where Y is oxygen, X is (CH2)n, R2 is
phenyl or aaphthyl, then R1 is not a
straight or branched alkyl chain; and
(iii) the following compounds are excluded:
X Y R R1 R2
CH2 O H (CH2)2CH3 Ph
CH2 O H CH3 Ph
CH2 O H Me i i-Pr
The ACAT inhibitor for use in the novel method may
be selected from any effective compound, especially
compounds of Fonaula I above, especially sulfamic acid,
([2,4,6-tris ~ ethylethyl)-phenyl]acetyl]-, 2,6-bis~(1-
methylethyl)phenyl ester; 2,6-bis(1-methylethyl)phenyl-
[[2,6-bis(1-methylethyl)-phenyl]sulfonyl]carbamate
monosodium salt; N-(2.6-di-isopropyl-phenyl)-2-pheayl-
malonamic acid dodecyl ester; N-(2,6-diisopropyl-
phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-
acetamide; 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)-
docecanamide; and N-[2,6-bis(1-methylethyl)phenyl]-
N'-[[1-(4-(dimethyl-amino)phenyl]cyclopentyl]methyl
urea monohydrochloride.
The doses of ACAT inhibitor contemplated for use
in this invention an about 50 to 1500 mg per day,
preferably given in single or divided doses.
One especially useful ACAT inhibitor is
2,6-bis(1-methylethyl)phenyl [[2,4.6-tris(1-
methylethyl)phenyl]acetyl]sulfamate disclosed in United


CA 02233558 2001-07-11
WO 97/16184 , PCT/US96/15854 -
_g_
States Patent Number 5,491,172.
Other ACAT inhibitors are 2,6-bis-(1-methylethyl)-
phenyl[[2,6-bis(1-methylethyl)phenoxy]-sulfonyl]-
carbamate monosodium salt; and similar compounds are
disclosed in United States Patent Number 5,245,068;
N-(2,6-diisopropyl-phenyl)-2-phenyl-malonamic acid
dodecyl ester; and similar compounds are disclosed in
United States Patent Number 5,420,339; N-(2,6-diiso-
propyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-
acetamide; and similar compounds are disclosed in
United States Patent Number 5,366,987 and divisional
5,441,975; N-[2,6-bis(1-methylethyl)phenyl]-N'-[[1-[4-
(dimethylamino)phenyl.]cyclo-penty]methyl]urea
monohydrochloride disclosed in United States Patent
Number 5,015,644 and 2,2-dimethyl-N-(2,4,6-
trimethoxyphenyl) docecanamide and similar compounds
disclosed in United States Patent Number 4,716,175.
The lipid modifying and antiatherosclerotic action
of 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-
methylethyl)phenyl]acetyl]sulfamate, atorvastatin, and
the combination of both compounds was assessed in a
rabbit model of atherosclerosis in which the
combination of hypercholesterolemia and chronic
endothelial denudation of the iliac-femoral artery
promotes lesion development.
The model of atherosclerosis consists of a lesion
induction phase of 15 weeks followed by an 8-week drug
intervention phase. A main feature of the protocol is
that after 9 weeks of a 0.5% cholesterol (C), 3% peanut
(PNO), 3% coconut (CNO) oil diet plasma, cholesterol
levels are normalized by feeding a 0% C, 3% PNO, 3% CNO
diet prior to drug administration. The animals are
randomized based on their mean plasma total cholesterol
levels and administered the 0% C, 3% PNO, 3% CNO diet


CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854 -
-10-
either alone or containing N-(2,6-diisopropyl-phenyl)-
2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-acetamide at
mg/kg, atorvastatin at 5 mg/kg, or N-(2,6-diiso-
propyl-phenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-phenyl-
5 acetamide + atorvastatin at 10 + 5 mg/kg for the next ,
8 weeks.
Relative to the untreated, cholesterol-fed
control, plasma total cholesterol levels were unchanged
by 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-
10 methylethyl)phenyl]acetyl]sulfamate but reduced 43~ and
67~ with atorvastatin and 2,6-bis(1-methylethyl)-
phenyl[[2,4,6-tris(1-methylethyl)phenyl]acetyl]-
sulfamate + atorvastatin, respectively. Associated
with the changes in plasma total cholesterol were
marked alterations in the plasma lipoprotein
distribution. 2,6-Bis(1-methylethyl)phenyl[[2,4,6-
tris(1-methylethyl)phenyl]acetyl]sulfamate reduced
VLDL-cholesterol (VLDL-C) and increased
LDL-cholesterol (LDL-C); atorvastatin had limited
effect; and upon combination treatment ~ VLDL-C and
LDL-C were reduced, and ~ HDL-cholesterol was
increased.
Results are summarized in Table I below.
r


CA 02233558 1998-03-31
WO 97/16184 PCT/LTS96/15854 -
-11-
TABLE I. Lipoprotein Distribution Expressed as
Percent of Total Plasma Cholesterol
VLDL LDL HDL


Progression Control 16 60 24


' 5 2,6-bis(1-methylethyl)- 5 73 22


phenyl[[2,4,6-tris(1-


methylethyl)phenyl]-


acetyl]sulfamate (10 mg/kg)


Atorvastatin (5 mg/kg) 14 48 3$


2,6~-bis(1-methylethyl)- 4 35 60


phenyl[[2,4,6-tris(1-


methylethyl)phenyl]-


acetyl]sulfamate +


Atorvastatin (10 + 5 mg/kg)



Analysis of the vascular cholesteryl ester (CE)
enrichment, incidence of complex atherosclerotic
lesions, gross extent of thoracic aortic
atherosclerosis, and size and composition of the
iliac-femoral lesion have also been performed. 2,6-
Bis(1-methylethyl)phenyl[[2,4,6-tris(1-methylethyl)-
phenyl]acetyl]sulfamate had no effect on the CE
enrichment of the thoracic aorta and iliac-femoral
artery and on the gross extent of lesion coverage in
the thoracic aorta; however, the incidence of complex
fibrous plaques within the iliac-femoral artery was
reduced from 50~ to 14~. Atorvastatin reduced the CE
enrichment of both vascular regions by 27~ to 41~
without changing the gross extent of thoracic lesions
and incidence of fibrous plaques. 2,6-Bis(1-
methylethyl)phenyl[[2,4,6-tris(1-methylethyl)-
phenyl]acetyl]sulfamate + atorvastatin had no effect on
the CE enrichment of the thoracic aorta and gross
extent of thoracic aortic lesions; however, the
iliac-femoral CE content was reduced 23~ and incidence


CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854 -
-12-
of fibrous plaques was decreased to 17~. Comparison of
the data relative to the time zero control, i.e., prior
to drug administration, atorvastatin alone and in
combination with 2,6-bis(1-methylethyl)phenyl[[2,4,6-
tris(1-methylethyl)phenyl]acetyl]sulfamate ,
significantly reduced the CE enrichment of the
iliac-femoral artery. Morphometric analysis of the
iliac-femoral artery revealed that atorvastatin reduced
the lesion size, while the combination of atorvastatin
and 2,6-bis(1-methylethyl)phenyl[[2,4,6-tris(1-
methylethyl)-phenyl]acetyl]sulfamate significantly
decreased the monocyte-macrophage content of the lesion
without changing lesion size. 2,6-Bis(1-
methylethyl)phenyl[[2,4,6-tris(1-methylethyl)-
phenyl]acetyl]sulfamate alone had no effect on the
iliac-femoral lesion size or composition.
Therefore, it is clear that a combination of
N-(2,6-diisopropyl-phenyl)-2-(2-dodecyl-2H-tetrazol-
5-yl)-2-phenyl-acetamide and atorvastatin administered
in a chow/fat diet results in a greater reduction in
plasma apo B-containing lipoprotein than either alone
and that a normalization of the plasma lipoprotein
distribution is achieved. Atorvastatin not only blunts
the cholesteryl ester enrichment of the vasculature but
also decrease the lipid enrichment of a pre-existing
atherosclerotic lesion. 2,6-Bis(1-
methylethyl)phenyl[[2,4,6-tris(1-methylethyl)-
phenyl]acetyl]sulfamate + atorvastatin reduces the CE
enrichment of pre-existing atherosclerotic lesions to
the same extent as atorvastatin alone, but the
atherosclerotic lesions are less complicated with
respect to their histologic character.
For preparing the pharmaceutical compositions from
the compounds of this invention, inert, pharmaceu- a
tically acceptable carriers can be either solid or


CA 02233558 1998-03-31
WO 97/16184 PCT/ITS96/15854 -
-13-
liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, and cachets.
A solid carrier can be one or more substances
which may also act as diluents, flavoring agents,
solubilizers, lubricants, suspending agents, binders,
or tablet disintegrating agents; it can also be an
encapsulating material.
In powders, the carrier is a finely divided solid
which is in a mixture with the finely divided active
component. In tablets, the active component is mixed
with the carrier having the necessary binding
properties in suitable proportions and compacted in the
shape and size desired.
Powders and tablets preferably contain between
about 5$ to about 70$ by weight of the active
ingredient. Suitable carriers are magnesium
dicarbonate, magnesium stearate, talc, lactose, sugar,
pectin, dextrin, starch, tragacanth, methyl cellulose,
sodium carboxymethyl cellulose, 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. In a similar manner cachets or transdermal
systems are also included.
Tablets, powders, cachets, and capsules can be
used as solid dosage forms suitable for oral
administration.
Liquid form preparations include solutions,
suspensions, or emulsions suitable for oral
administration. Aqueous solutions for oral
~ administration can be prepared by dissolving the active
compound in water and adding suitable flavorants,
coloring agents, stabilizers, and thickening agents as


CA 02233558 1998-03-31
WO 97/16184 PCT/US96/15854
-14-
desired. Aqueous suspensions for oral use can be made
by dispersing the finely divided active component in
water together with a viscous material such as natural -
or synthetic gums, resins, methyl cellulose, sodium
carboxymethylcellulose, and other suspending agents
known to the pharmaceutical formulation art.
Preferably, the pharmaceutical preparation is in
unit dosage form. In such form, the preparation is
divided into unit doses containing appropriate
quantities of the active component. The unit dosage
form can be a packaged preparation containing discrete
quantities of the preparation, for example, packeted
tablets, capsules, and powders in vials or ampoules.
The unit dosage form can also be a capsule, cachet, or
tablet itself, or it can be the appropriate number of
these packaged forms.
The dosage forms are well within the skill of a
physician who will be familiar with such factors as
time of day and other pertinent considerations.

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Admin Status

Title Date
Forecasted Issue Date 2005-12-06
(86) PCT Filing Date 1996-10-02
(87) PCT Publication Date 1997-05-09
(85) National Entry 1998-03-31
Examination Requested 2001-07-11
(45) Issued 2005-12-06
Lapsed 2009-10-02

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of Documents $100.00 1998-03-31
Filing $300.00 1998-03-31
Maintenance Fee - Application - New Act 2 1998-10-02 $100.00 1998-09-28
Maintenance Fee - Application - New Act 3 1999-10-04 $100.00 1999-09-24
Maintenance Fee - Application - New Act 4 2000-10-02 $100.00 2000-09-27
Request for Examination $400.00 2001-07-11
Maintenance Fee - Application - New Act 5 2001-10-02 $150.00 2001-09-27
Maintenance Fee - Application - New Act 6 2002-10-02 $150.00 2002-09-26
Maintenance Fee - Application - New Act 7 2003-10-02 $150.00 2003-09-24
Maintenance Fee - Application - New Act 8 2004-10-04 $200.00 2004-09-23
Final Fee $300.00 2005-08-10
Maintenance Fee - Application - New Act 9 2005-10-03 $200.00 2005-09-23
Maintenance Fee - Patent - New Act 10 2006-10-02 $250.00 2006-09-20
Maintenance Fee - Patent - New Act 11 2007-10-02 $250.00 2007-09-21
Current owners on record shown in alphabetical order.
Current Owners on Record
WARNER-LAMBERT COMPANY
Past owners on record shown in alphabetical order.
Past Owners on Record
BOCAN, THOMAS MICHAEL ANDREW
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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Claims 2001-11-28 8 334
Claims 2004-08-19 8 336
Description 1998-03-31 14 527
Description 2001-07-11 14 528
Claims 2001-08-15 8 315
Description 2001-11-28 14 531
Claims 1998-03-31 8 276
Abstract 1998-03-31 1 45
Cover Page 1998-07-14 1 43
Cover Page 2005-11-09 1 35
Prosecution-Amendment 2004-08-19 8 277
Assignment 1998-03-31 6 211
PCT 1998-03-31 10 333
PCT 1997-08-01 4 124
Prosecution-Amendment 2001-07-11 4 116
Prosecution-Amendment 2001-07-11 1 33
Prosecution-Amendment 2001-08-15 9 349
Prosecution-Amendment 2001-11-28 19 766
Prosecution-Amendment 2004-02-19 2 83
Correspondence 2005-08-10 1 30