Title of Invention

"N-ARYL PIPERIDINE SUBSTITUTED BIPHENYLCARBOXAMIDES AS INHIBITORS OF APOLIPOPROTE IN B"

Abstract A n-aryl piperidine substituted biphenylcarboxamide compounds of formula (I) the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R1, R2, R3, R4, R5, X1, X2, X3, Y and n are as described in specification and claims.
Full Text The present invention is concerned with novel N-aryl piperidine substituted biphenylcarboxamide compounds having apolipoprotein B inhibiting activity and concomitant lipid lowering activity. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.
Obesity is the cause of a myriad of serious health problems like the adult onset of diabetes and heart disease. In addition, the loss of weight is getting an obsession among an increasing proportion of the human population.
The causal relationship between hypercholesterolemia, particularly that associated with increased plasma concentrations of low density lipoproteins (hereinafter referred as LDL) and very low density lipoproteins (hereinafter referred as VLDL), and premature atherosclerosis and/or cardiovascular disease is now widely recognized. However, a limited number of drugs are presently available for the treatment of hyperlipidemia.
Drugs primarily used for the management of hyperlipidemia include bile acid sequestrant resins such as cholestyramine and colestipol, fibric acid derivatives such as bezafibrate, clofibrate, fenofibrate, ciprofibrate and gemfibrozil, nicotinic acid and cholesterol synthesis inhibitors such as HMG Co-enzyme-A reductase inhibitors. There still remains a need for new lipid lowering agents with improved efficiency and/or acting via other mechanisms than the above mentioned drugs.
Plasma lipoproteins are water-soluble complexes of high molecular weight formed from lipids (cholesterol, triglyceride, phospholipids) and apolipoproteins. Five major classes of lipoproteins that differ in the proportion of lipids and the type of apolipoprotein, all having their origin in the liver and/or the intestine, have been defined according to their density (as measured by ultracentrifugation). They include LDL, VLDL, intermediate density lipoproteins (hereinafter referred as IDL), high density lipoproteins (hereinafter referred as HDL) and chylomicrons. Ten major human plasma apolipoproteins have been identified. VLDL, which is secreted by the liver and contains apolipoprotein B (hereinafter referred as Apo-B), undergoes degradation to LDL which transports 60 to 70% of the total serum cholesterol. Apo-B is also the main protein component of LDL. Increased LDL-cholesterol in serum, due to oversynthesis

or decreased metabolism, is causally related to atherosclerosis. In contrast high density
lipoproteins (hereinafter referred as HDL), which contain apolipoprotein Al, have a
protective effect and are inversely correlated with the risk of a coronary heart disease.
The HDL/LDL ratio is thus a convenient method of assessing the atherogenic potential
of an individual's plasma lipid profile.
The two isoforms of apolipoprotein (apo) B, apo B-48 and apo B-100, are important
proteins in human lipoprotein metabolism. Apo B-48, so named because it appears to
be about 48% the size of apo B-100 on sodium dodecyl sulfate-polyacrylamide gels, is
synthesized by the intestine in humans. Apo B-48 is necessary for the assembly of
chylomicrons and therefore has an obligatory role in the intestinal absorption of dietary
fats. Apo B-100, which is produced in the liver in humans, is required for the synthesis
and secretion of VLDL. LDL, which contain about 2/3 of the cholesterol in human
plasma, are metabolic products of VLDL. Apo B-100 is virtually the only protein
component of LDL. Elevated concentrations of apo B-100 and LDL cholesterol in
plasma are recognized risk factors for developing atherosclerotic coronary artery
disease.
A large number of genetic and acquired diseases can result in hyperlipidemia. They
can be classified into primary and secondary hyperlipidemic states. The most common
causes of the secondary hyperlipidemias are diabetes mellitus, alcohol abuse, drugs,
hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasis and bulimia.
Primary hyperlipidemias have also been classified into common hypercholesterolaemia,
familial combined hyperlipidaemia, familial hypercholesterolaemia, remnant
hyperlipidaemia, chylomicronaemia syndrome and familial hyper-triglyceridaemia.
Microsomal triglyceride transfer protein (hereinafter referred as MTP) is known to
catalyze the transport of triglyceride and cholesteryl ester by preference to
phospholipids such as phosphatidylcholine. It was demonstrated by D.Sharp et al.,
Nature (1993) 365:65 that the defect causing abetalipoproteinemia is in the MTP gene.
This indicates that MTP is required for the synthesis of Apo B-containing lipoproteins
such as VLDL, the precursor to LDL. It therefore follows that an MTP inhibitor would
inhibit the synthesis of VLDL and LDL, thereby lowering levels of VLDL, LDL,
cholesterol and triglyceride in humans.
One of the goals of the present invention is to provide an improved treatment for
patients suffering from obesity or atherosclerosis, especially coronary atherosclerosis
and more generally from disorders which are related to atherosclerosis, such as
ischaemic heart disease, peripheral vascular disease and cerebral vascular disease.
Another goal of the present invention is to cause regression of atherosclerosis and
inhibit its clinical consequences, particularly morbidity and mortality.
MTP inhibitors have been disclosed in WO-00/32582, WO-01/96327 and
WO-02/20501.
The present invention is based on the unexpected discovery that a class of novel N-aryl
piperidine substituted biphenylcarboxamide compounds is acting as selective MTP
inhibitors, i.e. is able to selectively block MTP at the level of the gut wall in mammals,
and is therefore a promising candidate as a medicine, namely for the treatment of
hyperlipidemia. The present invention additionally provides several methods for
preparing such N-aryl piperidine substituted biphenylcarboxamide compounds, as well
as pharmaceutical compositions including such compounds. Furthermore, the invention
provides a certain number of novel compounds which are useful intermediates for the
preparation of the therapeutically active N-aryl piperidine substituted biphenylcarboxamide
compounds, as well as methods for preparing such intermediates. Finally,
the invention provides a method of treatment of a condition selected from
atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia,
hyperlipidemia, diabetes and type n diabetes, comprising administering a
therapeutically active amount of a compound of formula (I) to a mammal.
The present invention relates to a family of novel compounds of formula (I)
the JV-oxides, the pharmaceutically acceptable acid addition salts and the
stereochemically isomeric forms thereof, wherein
R1 is hydrogen, Chalky!, halo, orpolyhaloCMalkyl;
R2 is hydrogen, Cualkyl, halo, or polyhaloCi_4alkyl;
R3 is hydrogen or Calkyl;
R4 is hydrogen, CMalkyl, or halo;
n is an integer 0, or 1;
X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon;
or X1 is carbon and X2 is nitrogen;
X3 is carbon or nitrogen;
Y represents 0, or NR6 wherein R6 is hydrogen or C1-4 alkyl;
R5 represents a radical of formula
(Figure Removed) wherein
m is an integer 0,1, or 2;
ZisOorNH;
R7is hydrogen;
Calkyl;
Calkyl substituted with hydroxy, amino, mono- or di(C1-4 alkyl)amino,
C1-4 alkyloxycarbonyl, aminocarbonyl, aryl or heteroaryl;
C1-.4 alkyl-O-C1-4alkyl;
C1-4 alkyl-S-C1-4 alkyl; or
aryl;
R8 is hydrogen of Chalky!;
R9 is hydrogen, C1-4 alkyl, aryl1, or Chalky! substituted with aryl1;
or when Y represents NR6 the radicals R5 and R6 may be taken together with the
nitrogen to which they are attached to form pyrrolidinyl substituted with
Cjalkyloxycarbonyl and optionally further substituted with hydroxy; or
piperidinyl substituted with C1-4 alkyloxycarbonyl;
aryl is phenyl; phenyl substituted with one, two or three substituents each
independently selected from C1-4 alky!, C1-4 alkyloxy, halo, hydroxy, nitro,
cyano, C1-4 alkyloxycarbonyl, trifluoromethyl, or trifluoromethoxy; or
benzo[ 1,3 ] dioxolyl;
aryl1 is phenyl; phenyl substituted with one, two or three substituents each
independently selected from C1-4 alkyl, C1-4 alkyloxy, halo, hydroxy, nitro,
cyano, C1-4 alkyloxycarbonyl, trifluoromethyl, or trifluoromethoxy; and
-5-
heteroaiyl is imidazolyl, thiazolyl, indolyl, or pyridinyl.
Unless otherwise stated, as used in the foregoing definitions and hereinafter:
- halo is generic to fluoro, chloro, bromo and iodo;
- C1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having
from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, n-butyl,
1-methylethyl, 2-methylpropyl, 1,1-dimethylethyl and the like;
- C1-6 alkyl is meant to include Chalky! (as hereinabove defined) and the higher
homologues thereof having 5 or 6 carbon atoms, such as for instance 2-methylbutyl,
n-pentyl, dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl and the like;
- polyhaloCMalkyl is defined as Chalky! substituted with 2 to 6 halogen atoms such
as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like;
- C1-4 alkylamino defines secondary amino radicals having from 1 to 4 carbon atoms
such as, for example, methylamino, ethylamino, propylamino, isopropylamino,
butylamino, isobutylamino and the like;
- di(C1-4 alkyl)amino defines tertiary amino radicals having from 1 to 4 carbon atoms
such as, for example, dimethylamino, diethylamino, dipropylamino,
diisopropylamino, N-memyl-N,-ethylamino, A^-ethyl-^-propylamino and the like.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are
meant to comprise the therapeutically active non-toxic acid addition salt forms which
the compounds of formula (1) are able to form. The pharmaceutically acceptable acid
addition salts can conveniently be obtained by treating the base form with such
appropriate acid. Appropriate acids comprise, for example, inorganic acids such as
hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and
the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic,
lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid),
maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,
benzenesulfonic,/?-toluenesulfonic, cyclamic, salicylic, P-aminosalicylic, pamoic and
the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into
the free base form.
The term addition salt as used hereinabove also comprises the solvates which the
compounds of formula (I) as well as the salts thereof, are able to form. Such solvates
are for example hydrates, alcoholates and the like.
The N-o\ide forms of the compounds of formula (I), which may be prepared in artknown
manners, are meant to comprise those compounds of formula (I) wherein a
nitrogen atom is oxidized to the TV-oxide. In particular said TV-oxide forms are
compounds of formula (I) wherein the nitrogen of the piperidinyl group is oxidized.
The term "stereochemically isomeric forms" as used hereinbefore defines all the
possible isomeric forms which the compounds of formula (I) may possess. Unless
otherwise mentioned or indicated, the chemical designation of compounds denotes the
mixture of all possible stereochemically isomeric forms, said mixtures containing all
diastereomers and enantiomers of the basic molecular structure. More in particular,
stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic
(partially) saturated radicals may have either the cis- or trans-configuration. Unless
otherwise mentioned or indicated, the chemical designation of compounds denotes the
mixture of all possible stereoisomeric forms, said mixtures containing all diastereomers
and enantiomers of the basic molecular structure. The same applies to the intermediates
as described herein, used to prepare end products of formula (I).
The terms cis and trans are used herein in accordance with Chemical Abstracts
nomenclature and refer to the position of the substituents on a ring moiety.
The absolute stereochemical configuration of the compounds of formula (I) and of the
intermediates used in their preparation may easily be determined by those skilled in the
art while using well-known methods such as, for example, X-ray diffraction.
Furthermore, some compounds of formula (I) and some of the intermediates used in
their preparation may exhibit polymorphism. It is to be understood that the present
invention encompasses any polymorphic forms possessing properties useful in the
treatment of the conditions noted hereinabove.
In an embodiment the present invention concerns the compounds of formula (I), the
TV-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically
isomeric forms thereof, wherein
R1 is hydrogen, Chalky!, halo, or polyhaloC1-4 alkyl;
R2 is hydrogen, Cnalkyl, halo, or polyhaloCMalkyl;
R3 is hydrogen or C1-4 alkyl;
R4 is hydrogen, C1-4 alkyl, or halo;
n is an integer 0, or 1;
X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon;
or X1 is carbon and X2 is nitrogen;
X3 is carbon or nitrogen;
Y represents O, or NR6 wherein R6 is hydrogen or
R5 represents a radical of formula
(Figure Removed)wherein
m is an integer 0, 1, or 2;
ZisOorNH;
R7 is hydrogen;
substituted with hydroxy, amino, mono- or di(Ci^aIkyl)arnino,
Calkyloxycarbonyl, aminocarbonyl, aryl or heteroaryl;
CMaIkyl-S-C1-4alkyl; or
aryl;
R8 is hydrogen of C1-4 alkyl;
R9 is C1-4 alkyl, phenyl or benzyl;
or when Y represents NR6 the radicals R5 and R6 may be taken together with the
nitrogen to which they are attached to form pyrrolidinyl substituted with
C1-4 alkyloxycarbonyl and optionally further substituted with hydroxy; or
piperidinyl substituted with C1-4 alkyloxycarbonyl;
aryl is phenyl; phenyl substituted with one, two or three substituents each
independently selected from C1-4 alkyl, C1-4 alkyloxy, halo, hydroxy, nitro,
cyano, C1-4 alkyloxycarbonyl, trifluoromethyl, or trifluoromethoxy; or
benzo[l,3]dioxolyl; and
heteroaryl is imidazolyl, thiazolyl, indolyl, or pyridinyl.
In another embodiment the present invention concerns compounds of formula (I) the
W-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically
isomeric forms thereof, wherein
R1 is polyhaloCualkyl;
R2 is hydrogen,
R3 is hydrogen or CMalkyl;
R4 is hydrogen;
n is an integer 0, or 1;
X1 is carbon and X2 is carbon; or X1 is nitrogen and X2 is carbon;
or X1 is carbon and X2 is nitrogen;
X3 is carbon or nitrogen;
Y represents O, or NR6 wherein R6 is hydrogen or C1-4 alkyl;
R5 represents a radical of formula
(Figure Removed)wherein
m is an integer 0, or 1;
ZisOorNH;
R7 is hydrogen; CMalkyl; C].6alkyl substituted with amino,
Ci^alkyloxycarbonyl, aryl or heteroaryl; Cj^alkyl-S-C^alkyl; or aryl;
R8 is hydrogen of CMalkyl;
R9isCMalkyl;
or when Y represents NR6 the radicals R5 and R6 may be taken together with the
nitrogen to which they are attached to form pyrrolidinyl substituted with
. Ci^alkyloxycarbonyl and optionally further substituted with hydroxy; or
piperidinyl substituted with C1-4 alkyloxycarbonyl;
aryl is phenyl; phenyl substituted with hydroxy; or benzo[l,3]dioxolyl;
heteroaryl is imidazolyl.
A group of interesting compounds consists of those compounds of formula (I) wherein
one or more of the following restrictions apply :
a) R1 is terf-butyl or trifluoromethyl;
b) R2 is hydrogen or C 1-4 alkyl;
c) R3 is hydrogen;
d) R4 is hydrogen;
e) Y represents NR6 wherein R6 is hydrogen or methyl;
f) Z represents 0;
g) R8 represents hydrogen;
h) R9 represents CMalkyl.
A first particular group of compounds are those compounds of formula (I) wherein X1,
X2 and X3 are carbon.
A second particular group of compounds are those compounds of formula (I) wherein
X1 is carbon, X2 is nitrogen, and X3 is carbon.
A third particular group of compounds are those compounds of formula (T) wherein X1
is nitrogen, X2 is carbon, and X3 is carbon.
A fourth particular group of compounds are those compounds of formula (I) wherein
X1 is carbon, X2 is nitrogen, and X3 is nitrogen.
A fifth particular group of compounds are those compounds of formula (I) wherein n is
the integer 1.
A first preferred group of compounds are those compounds of formula (I) wherein R1 is
trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are
carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5
is a radical of formula (a-1) wherein m is the integer 0.
A second preferred group of compounds are those compounds of formula (I) wherein
R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3
are carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and
R5 is a radical of formula (a-1.) wherein m is the integer 1.
A third preferred group of compounds are those compounds of formula (I) wherein R1
is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are
carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5
is a radical of formula (a-2) wherein m is the integer 1.
A fourth preferred group of compounds are those compounds of formula (I) wherein R1
is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are
carbon; n is the integer 1; Y represents NR6 and R5 and R6 are taken together with the
nitrogen to which they are attached to form pyrrolidinyl substituted with C1-4 alkyloxycarbonyl
and optionally further substituted with hydroxy, or piperidinyl substituted
with C1-4 alkyloxycarbonyl.
Particular groups of compoimds are those preferred groups of compounds wherein R8
represents hydrogen and R9 represents Cj^alkyl.
A first process for preparing compounds of formula (I) is a process wherein an
intermediate of formula (II)
(Figure Removed)wherein R3, R4, R5, Y, n, X1, X2 andX3 are as defined in formula (I), is reacted with a
biphenylcarboxylic acid or halide having the formula (ffl),
wherein R1 and R2 are as defined in formula (I) and Q1 is selected from hydroxy and
halo, in at least one reaction-inert solvent and optionally in the presence of a suitable
base, the said process further optionally comprising converting a compound of formula
(I) into an addition salt thereof, and/or preparing stereochemically isomeric forms
thereof. In case Q1 is hydroxy, it may be convenient to activate the biphenylcarboxylic
acid of formula (III) by adding an effective amount of a reaction promoter. Nonlimiting
examples of such reaction promoters include carbonyldiimidazole, diimides
such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(3'-dimethylamuiopropyl)-
carbodiimide (EDCI), and functional derivatives thereof. For this type of acylation
procedure, it is preferred to use a polar aprotic solvent such as, for instance,
dichloromethane. Suitable bases for carrying out this first process include tertiary
amines such as triethylamine, triisopropylamine and the like. Suitable temperatures for
carrying out the first process of the invention typically range from about 20°C to about
140°C, depending on the particular solvent used, and will most often be the boiling
temperature of the said solvent.
A second process for preparing compound of the present invention is a process wherein
an intermediate having the formula (IV)
(Figure Removed)wherein R1, R2, R3, R4, n, X1, X2 and X3 are as defined in formula (I) and Q2 is
selected from halo and hydroxy, is reacted with an intermediate (V) of the formula
H-NR5R6, wherein R5 and R6 are as defined for compounds of formula (I), in at least
one reaction-inert solvent and optionally in the presence of at least one suitable
coupling reagent and/or a suitable base, the said process further optionally comprising
converting a compound of formula (I) into an addition salt thereof, and/or preparing
stereochemically isomeric forms thereof. In case Q2 is hydroxy, it may be convenient to
activate the carboxylic acid of formula (IV) by adding an effective amount of a reaction
promoter. Non-limiting examples of such reaction promoters include carbonyldiimidazole,
diimides such as DCC, EDCI, hydroxybenzotriazole, benzotriazol-1-yl-Noxytris-(
dimethylamino)phosphonium hexafluorophosphate (BOP), tetrapyrrolidinophosphonium
hexafluorophosphate, bromotripyrrolidinophosphonium
hexafluorophosphate, or a functional derivative thereof, such as disclosed in "Solid-
Phase Synthesis: A Practical Guide", edited by Steven A. Kates and Fernando
Albericio, Marcel Dekker, Inc., 2000 (ISBN: 0-8247-0359-6) on pages 306 to 319.
A third process for preparing a compound according to the present invention is a
process wherein an intermediate having the formula (VI)
R2 (VI),
wherein R1, R2, R3, R4, X1, X2 and X3 are as defined in formula (I) and Q3 is selected
from halo, B(OH)2, alkylboronates and cyclic analogues thereof, is reacted with a
reactant having the formula (VII)
(Figure Removed)wherein n, R5 and Y are as defined in formula (I), in at least one reaction-inert solvent
and optionally in the presence of at least one transition metal coupling reagent and/or at
least one suitable ligand, the said process further optionally comprising converting a
compound of formula (I) into an addition salt thereof, and/or preparing
stereochemically isomeric forms thereof. This type of reaction being known in the art
as the Buchwald reaction, reference to the applicable metal coupling reagents and/or
suitable ligands, e.g. palladium compounds such as palladium tetra(triphenylphosphine),
tris(dibenzylidene-acetone dipalladium, 2,2>-bis(diphenylphosphino)-l,rbinaphtyl
(BINAP) and the like, may be found for instance in Tetrahedron Letters,
(1996), 37(40), 7181-7184 and J.Am.Chem.Soc., (1996), 118:7216. If Q3 is B(OH)2, an
alkylboronate or a cyclic analogue thereof, then cupric acetate should be used as the
coupling reagent, according to Tetrahedron Letters, (1998), 39:2933-6.
Compounds of formula (I-a), defined as compounds of formula (T) wherein Y represent
NH and R3 represents hydrogen, can conveniently be prepared using solid phase
synthesis techniques as depicted in Scheme 1 below. In general, solid phase synthesis
involves reacting an intermediate in a synthesis with a polymer support. This polymer
supported intermediate can then be carried on through a number of synthetic steps.
After each step, impurities are removed by filtering the resin and washing it numerous
times with various solvents. At each step the resin can be split up to react with various
intermediates in the next step thus allowing for the synthesis of a large number of
compounds. After the last step hi the procedure the resin is treated with a reagent or
process to cleave the resin from the sample. More detailed explanation of the
techniques used in solid phase chemistry are described in for example "Handbook of
Combinatorial Chemistry: Drugs, Catalysts, Materials" edited by K. C. Nicolaou, R.
Hanko, and W. Hartwig, volumes 1 and 2, Wiley (ISBN: 3-527-30509-2).
Scheme 1 :
(Figure Removed)The substituents R1, R2, R4, R4, R5, n, X1, X2 and X3 are as defined for compounds of
formula (I). PO represents a protecting group such as, e.g. Cj^alkyloxycarbonyl,
phenylmethyloxycarbonyl, f-butoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and
the like. The following abbreviations are used: "NMP" means W-methyl-2-
pyrrolidone, "DIPEA" means diisopropylethylamine, "TFA" means trifluoroacetic acid;
and "TIS" means triisopropylsilane.
Compounds of formula (I-b), defined as compounds of formula (I) wherein R3
represents hydrogen, may be prepared using a solid phase synthesis route as outlined in
Scheme 2.
(Figure Removed)The substituents R1, R2, R4, R4, R5, Y, n, X1, X2 and X3 are as defined for compounds
of formula (I). The following abbreviations are used: "NMP" means ^V-methyl-2-
pyrrolidone, "DIPEA" means diisopropylethylamine, "TFA" means trifluoroacetic acid,
"TIS" means triisopropylsilane, "DMAP" means dimethylaminopyridine, and "BINAP"
means 2,2 '-bis(diphenylphosphino)-1,1 '-binaphtyl.
The compounds of formula (I) as prepared in the hereinabove described processes may
be synthesized in the form of racemic mixtures of enantiomers which can be separated
from one another following art-known resolution procedures. Those compounds of
formula (I) that are obtained in racemic form may be converted into the corresponding
diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric
salt forms are subsequently separated, for example, by selective or fractional
crystallization and the enantiomers are liberated therefrom by alkali. An alternative
manner of separating the enantiomeric forms of the compounds of formula (I) involves
liquid chromatography using a chiral stationary phase. Said pure stereochemically
isomeric forms may also be derived from the corresponding pure stereochemically
isomeric forms of the appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably if a specific stereoisomer is desired, said compound will
be synthesized by stereospecific methods of preparation. These methods will
advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable
salts and stereoisomeric forms thereof possess favourable apolipoprotein B inhibiting
activity and concomitant lipid lowering activity. Therefore the present compounds of
formula (I) are useful as a medicine especially in a method of treating patients suffering
from hyperlipidemia, obesity, atherosclerosis or type II diabetes. In particular the
present compounds may be used for the manufacture of a medicine for treating
disorders caused by an excess of very low density lipoproteins (VLDL) or low density
lipoproteins (LDL), and especially disorders caused by the cholesterol associated with
said VLDL and LDL.
-16-
The principal mechanism of action of the compounds of formula (I) appears to involve
inhibition of MTP (microsomial triglyceride transfer protein) activity in hepatocytes
and intestinal epithelial cells, resulting in decreased VLDL and chylomicron
production, respectively. This is a novel and innovative approach to hyperlipidemia,
and is expected to lower LDL-cholesterol and triglycerides through reduced hepatic
production of VLDL and intestinal production of chylomicrons.
A large number of genetic and acquired diseases can result in hyperlipidemia. They
can be classified into primary and secondary hyperlipidemic states. The most common
causes of the secondary hyperlipidemias are diabetes mellitus, alcohol abuse, drugs,
hypothyroidism, chronic renal failure, nephrotiojsyndrome, cholestasis and bulimia.
Primary hyperlipidemias are common hypercholesterolaemia, familial combined
hyperlipidaemia, familial hypercholesterolaemia, remnant hyperlipidaemia, chylomicronaemia
syndrome, familial hypertriglyceridaemia. The present compounds may
also be used to prevent or treat patients suffering from obesitas or from atherosclerosis,
especially coronary atherosclerosis and more in general disorders which are related to
atherosclerosis, e.g. ischaemic heart disease, peripheral vascular disease, and cerebral
vascular disease. The present compounds may cause regression of atherosclerosis and
inhibit the clinical consequences of atherosclerosis, particularly morbidity and
mortality.
In view of the utility of the compounds of formula (I), it follows that the present
invention also provides a method of treating warm-blooded animals, rncludingjiumans,
(generally called herein patients) suffering from disorders caused by an excess of very
low density lipoproteins (VLDL) or low density lipoproteins (LDL), and especially
disorders caused by the cholesterol associated with said VLDL and LDL. Consequently
a method of treatment is provided for relieving patients suffering from conditions, such
as, for example, hyperlipidemia, obesity, atherosclerosis or type n diabetes.
Apo B-48, synthetized by the intestine, is necessary for the assembly of chylomicrons
and therefore has an obligatory role in the intestinal absorption of dietary fats. The
present invention provides biphenylcarboxamide compounds which are acting as
selective MTP inhibitors at the level of the gut wall.
Additionally the present invention provides pharmaceutical compositions comprising at
least one pharmaceutically acceptable carrier and a therapeutically effective amount of
a compound of formula (I).
-17-
In order to prepare the pharmaceutical compositions of this invention, an effective
amount of the particular compound, in base or addition salt form, as the active
ingredient is combined in intimate admixture with at least one pharmaceutically
acceptable carrier, which carrier may take a wide variety of forms depending on the
form of preparation desired for administration. These pharmaceutical compositions are
desirably in unitary dosage form suitable, preferably, for oral administration, rectal
administration, percutaneous administration or parenteral injection.
For example in preparing the compositions in oral dosage form, any of the usual liquid
pharmaceutical carriers may be employed, such as for instance water, glycols, oils,
alcohols and the like in the case of oral liquid preparations such as suspensions, syrups,
elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin,
lubricants, binders, disintegrating agents and the like in the case of powders, pills,
capsules and tablets. Because of their easy administration, tablets and capsules
represent the most advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. For parenteral injection compositions,
the pharmaceutical carrier will mainly comprise sterile water, although other
ingredients may be included in order to improve solubility of the active ingredient
Injectable solutions may be prepared for instance by using a pharmaceutical carrier
comprising a saline solution, a glucose solution or a mixture of both. Injectable
suspensions may also be prepared by using appropriate liquid carriers, suspending
agents and the like. In compositions suitable for percutaneous administration, the
pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with minor proportions of suitable
additives which do not cause a significant deleterious effect to the skin. Said additives
may be selected in order to facilitate administration of the active ingredient to the skin
and/or be helpful for preparing the desired compositions. These topical compositions
may be administered in various ways, e.g., as a transdermal patch, a spot-on or an
ointment. Addition salts of the compounds of formula (I), due to their increased water
solubility over the corresponding base form, are obviously more suitable in the
preparation of aqueous compositions.
It is especially advantageous to formulate the pharmaceutical compositions of the
invention in dosage unit form for ease of administration and uniformity of dosage.
"Dosage unit form" as used herein refers to physically discrete units suitable as unitary
dosages, each unit containing a predetermined amount of active ingredient calculated to
produce the desired therapeutic effect in association with the required pharmaceutical
carrier. Examples of such dosage unit forms are tablets (including scored or coated
tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions,
teaspoonfuls, tablespoonrals and the like, and segregated multiples thereof.
For oral administration, the pharmaceutical compositions of the present invention may
take the form of solid dose forms, for example, tablets (both swallowable and chewable
forms), capsules or gelcaps, prepared by conventional means with phannaceutically
acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize
starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g.
lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g.
magnesium stearate, talc, silica and the like), disintegrating agents (e.g. potato starch,
sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and
the like. Such tablets may also be coated by methods well known in the art.
Liquid preparations for oral administration may take the form of e.g. solutions, syrups
or suspensions, or they may be formulated as a dry product for admixture with water
and/or another suitable liquid carrier before use. Such liquid preparations may be
prepared by conventional means, optionally with other phannaceutically acceptable
additives such as suspending agents (e.g. sorbitol syrup, methylcellulose,
hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g.
lecithin or acacia), non-aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol),
sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl
p-hydroxybenzoates or sorbic acid). '"'
Phannaceutically acceptable sweeteners useful in the pharmaceutical compositions of
the invention comprise preferably at least one intense sweetener such as aspartame,
acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener,
monellin, stevioside sucralose (4,r,6-trichloro-4,l',6'-trideoxygalactosucrose) or,
preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk
sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose,
hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are
conveniently used in low concentrations. For example, in the case of sodium saccharin,
the said concentration may range from about 0.04% to 0.1% (weight/volume) of the
final formulation. The bulk sweetener can effectively be used in larger concentrations
ranging from about 10% to about 35%, preferably from about 10% to 15%
(weight/volume).
The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients
in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry,
black currant or strawberry flavour. A combination of two flavours may yield very
good results. In the high-dosage formulations, stronger pharmaceutically acceptable
flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like.
Each flavour may be present in the final composition in a concentration ranging from
about 0.05% to 1% (weight/volume). Combinations of said strong flavours are
advantageously used. Preferably a flavour is used that does not undergo any change or
loss of taste and/or color under the circumstances of the formulation.
The compounds of formula (I) may be formulated for parenteral administration by
injection, conveniently intravenous, intra-muscular or subcutaneous injection, for
example by bolus injection or continuous intravenous infusion. Formulations for
injection may be presented in unit dosage form, e.g. in ampoules or multi-dose
containers, including an added preservative. They may take such forms as suspensions,
solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents
such as isotonizing, suspending, stabilizing and/or dispersing agents. Alternatively, the
active ingredient may be present in powder form for mixing with a suitable vehicle, e.g.
sterile pyrogen-free water, before use.
The compounds of formula (I) may also be formulated in rectal compositions such as
suppositories or retention enemas, e.g. containing conventional suppository bases such
as cocoa butter and/or other glycerides.
The compounds of formula (I) may be used in conjunction with other pharmaceutical
agents, in particular the pharmaceutical compositions of the present invention may
further comprise at least one additional lipid-lowering agent, thus leading to a so-called
combination lipid-lowering therapy. The said additional lipid-lowering agent may be,
for instance, a known drug conventionally used for the management of hyperlipidaemia
such as e.g. a bile acid sequestrant resin, a fibric acid derivative or nicotinic acid as
previously mentioned in the background of the invention. Suitable additional lipidlowering
agents also include other cholesterol biosynthesis inhibitors and cholesterol
absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA
synthase inhibitors, HMG-CoA reductase gene expression inhibitors, CETP inhibitors,
ACAT inhibitors, squalene synthetase inhibitors and the like.
Any HMG-CoA reductase inhibitor may be used as the second compound in the
combination therapy aspect of this invention. The term "HMG-CoA reductase
inhibitor" as used herein, unless otherwise stated, refers to a compound which inhibits
the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acid as
catalyzed by the enzyme HMG-CoA reductase. Such "HMG-CoA reductase inhibitors"
are, e.g., lovastatin, simvastatin, fluvastatin, pravastatin, rivastatin, and atorvastatin.
Any HMG-CoA synthase inhibitor may be used as the second compound in the
combination therapy aspect of this invention. The term "HMG-CoA synthase inhibitor"
as used herein, unless otherwise stated, refers to a compound which inhibits the
biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and
acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase
Any HMG-CoA reductase gene expression inhibitor may be used as the second
compound in the combination therapy aspect of this invention. These agents may be
HMG-CoA reductase trancription inhibitors that block the transcription of DNA or
translation inhibitors that prevent translation of mRNA coding for HMG-CoA
reductase into protein. Such inhibitors may either affect trancription or translation
directly or may be biotransformed into compounds having the above-mentioned
attributes by one or more enzymes in the cholesterol biosynthetic cascade or may lead
to accumulation of a metabolite having the above-mentioned activities.
Any CETP inhibitor may be used as the second compound in the combination therapy
aspect of this invention. The term "CETP inhibitor" as used herein, unless otherwise
stated, refers to a compound which inhibits the cholesteryl ester transfer protein
(CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to
LDL and VLDL.
Any ACAT inhibitor may be used as the second compound in the combination therapy
aspect of this invention. The term "ACAT inhibitor" as used herein, unless otherwise
stated, refers to a compound which inhibits the intracellular esterification of dietary
cholesterol by the enzyme acyl CoA:cholestcrol acyltransferase.
Any squalene synthetase inhibitor may be used as the second compound in the
combination therapy aspect of this invention. The term "squalene synthetase inhibitor"
as used herein, unless otherwise stated, refers to a compound which inhibits the
condensation of two molecules of famesylpyrophosphate to form squalene, catalyzed
by the enzyme squalene synthetase.
Those of skill in the treatment of hyperlipidemia will easily determine the
therapeutically effective amount of a compound of formula (I) from the test results
presented hereinafter. In general it is contemplated that a therapeutically effective dose
will be from about 0.001 mg/kg to about 5 mg/kg of body weight, more preferably from
about 0.01 mg/kg to about 0.5 mg/kg of body weight of the patient to be treated. It may
be appropriate to administer the therapeutically effective dose in the form of two or
more sub-doses at appropriate intervals throughout the day. Said sub-doses may be
formulated as unit dosage forms, for example each containing from about 0.1 mg to
about 350 mg, more particularly from about 1 to about 200 mg, of the active ingredient
per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound
of formula (I) used, the particular condition being treated, the severity of the condition
being treated, the age, weight and general physical condition of the particular patient as
well as the other medication (including the above-mentioned additional lipid-lowering
agents), the patient may be taking, as is well known to those skilled in the art.
Furthermore, said effective daily amount may be lowered or increased depending on
the response of the treated patient and/or depending on the evaluation of the physician
prescribing the biphenylcarboxamide compounds of the instant invention. The effective
daily amount ranges mentioned hereinabove are therefore only guidelines.
Experimental part
In the procedures described hereinafter the following abbreviations were used:
'TS-DIEA" which stands for N,N-(diisopropyl)aminomethylpolystyrene resin was
obtained from Argonaut (New Road, Hengoed, Mid Glamorgan CF82 8AU, United
Kingdom) with product code 800279. "PS-DCC" is a N-cyclohexcylcarbodiimide
N'-methyl polystyrene resin which was obtained from Calbiochem-Novabiochem AG,
(Weidenmattweg 4, CH-4448 Lfiufelfingen, Switzerland) with product code
Novabiochem 01 -64-0211. 'THF* stands for tetrahydrofuran.
A. Synthesis of the intermediates
Example A.I
a) Preparation of y f _> « intermediate (1)
4'-(Trifluoromethyl)-[l,r-biphenyl]-2-carboxylic acid (0.0069 mol) was dissolved in
dichloromethane (400 ml) together with oxalyl chloride (0.069 mol) and dimethylformamide
(one drop) at 0°C. Further 4'-(trifluoromethyl)-[l,r-biphenyl]-2-carboxylic
acid (0.0621 mol) was added portionwise under a stream of nitrogen. Oxalyl chloride
(0.069 mol) and dimethylformamide (one drop) were added and the reaction mixture
was stirred for 2 hours at 0°C. The reaction mixture was filtered, the residue was
dissolved in dichloromethane (100 ml) and the resulting mixture was added dropwise at
0°C to a mixture of l-(4-aminophenyl)-4-piperidineacetic acid ethyl ester (0.069 mol)
in triethylamine (17.5 ml) and dichloromethane (300 ml). The reaction mixture was
allowed to reach room temperature in 90 minutes. The resulting reaction mixture was
washed with water, dried, and the solvent was evaporated. The residue was stirred hi a
!.,.
hot mixture of hexane and ethyl acetate and the resulting precipitate was filtered off hot
over celite. The filtrate was cooled and the resulting precipitate was filtered off,
washed with ether and dried, yielding 31 g of intermediate (1) (mp. 160- 162°C).
b) Preparation of j j? « intermediate (2)
A mixture of intermediate (1) (0.015 mol) in a concentrated HC1 solution (50 ml) was
stirred and refluxed for 90 minutes. The resulting precipitate was filtered off, washed
with water and dried. The precipitate (0.008 mol) was dissolved in a mixture of a
NaOH solution (1 N, 50 ml) and 2-propanol (100 ml) and stirred for 1 hour at 50°C.
The reaction mixture was cooled to room temperature and HC1 (1 N, 70 ml) was added
and the mixture was extracted twice with dichloromethane. The extracts were
combined, evaporated and the resulting residue was triturated under dichloromethane,
yielding 4.1 g of intermediate (2).
Examole A.2
a) Preparation of y intermediate (3)
6-Methyl-4'-(trifluoromethyl)- [l,l'-biphenyl]-2-carboxylic acid (0.0025 mol) was
dissolved in dry dichloromethane (140 ml) along with ethanedioyl dichloride (2.4 ml)
and a few drops of dimethylformamide, at 0°C. Then, all remaining 6-methyl-4-
(trifluoromethyl)- [l,l'-biphenyl]-2-carboxylic acid (0.0225 mol) was added in
portions, under a stream of nitrogen. The reaction mixture was heated gently to 40°C
until an homogeneous solution resulted and gas evolution had stopped. The mixture
was allowed to cool to room temperature, then filtered off over a Buchner filter. The
filter residue was dissolved in dichloromethane, then added dropwise at 0°C to a
solution of l-(4-aminophenyl)-4-piperidineacetic acid, ethyl ester (1 equiv, 0.025 mol)
and triethylamine (3 g) in dry dichloromethane (140 ml). The reaction mixture was
allowed to warm to room temperature over 90 minutes. The precipitate was filtered off
and dried, yielding 13.65 g of intermediate (3) (mp. 150-151°C).
b) Preparation of intermediate (4)
Sodium hydroxide (1 N, 100 ml) was added to a solution of intermediate (3) (0.0334
mol) in methanol (300 ml), then the reaction mixture was stirred for 2 hours at 50°C
and for 20 hours at room temperature. Water (300 ml) was added and the mixture was
acidified with IN HCL Dichloromethane (200 ml) was added and the reaction mixture
was stirred for 2 hours, then Hie resulting precipitate was filtered off, washed with
water and with dichloromethane and finally dried, yielding 17.1 g of intermediate (4),
isolated as a 1 : 1 hydrochloric acid salt.
Example A. 3
a) Preparation of intermediate (5)
A mixture of 4-piperidinecarboxylic acid ethyl ester (0.03 mol), l-fluoro-4-nitrobenzene
(0.03 mol) and potassium carbonate (4.5 g) in dimethylformamide (50 ml) was
reacted for 4 hours at 60°C, then the solvent was evaporated under reduced pressure
and the obtained residue was stirred in water. The obtained yellow solid was filtered off
and taken up in dichloromethane (100 ml). The organic layer was dried and the solvent
was evaporated. The resulting oil was crystallised from hexane and the desired product
was collected, yielding 7 g of intermediate (5) (m.p. 70-7 1°C).
b) Preparation of intermediate (6)
A mixture of intermediate (5) (0.025 mol) in ethanol (150 ml) was hydrogenated under
pressure (30 bar = 3.106 Pa)) overnight at 25°C with Pd/C 10% (0.5 g) as a catalyst.
After uptake of hydrogen (3 equivalents), the reaction mixture was filtered off and the
solvent was evaporated under reduced pressure, yielding 6 g of intermediate (6).
c) Preparation of intermediate (7)
Reaction under nitrogen: 0.2 g of 4'-(trifluoromethyl)- [l,l'-biphenyl]-2-carboxylic acid
in dichloromethane (50 ml) was reacted with ethanedioyl dichloride (0.01 mol) at 0°C
and then the reaction was initiated with dimemylformamide (1 drop). The remaining of
4'-(trifluoromethyl)- [l,1-biphenyl]-2-carboxylic acid (1.8 g) was added portionwise
and an extra amount of ethanedioyl dichloride was added. The reaction mixture was
stirred for 2 hours at 0°C (no acid present when sample of reaction mixture was taken
up hi methanol for TLC-analyses) and dichloromethane and the excess of ethanedioyl
dichloride was evaporated under reduced pressure. The obtained residue was taken up
in dichloromethane (50 ml) and added dropwise to a mixture of intermediate (6)
(0.0075 mol) and triethylamine (0.0075 mol) hi dichloromethane (50 ml) at 0°C. The
resulting mixture was stirred for 1 hour at room temperature, then the organic layer was
washed with water, dried and the solvent was evaporated under reduced pressure. The
obtained residue was crystallised from methanol and the desired product was collected,
yielding 2.9 g of intermediate (7) (mp. 190-192°C).
d) Preparation of | | intermediate (8)
Intermediate (7) (0.006 mol) was added to a solution of NaOH (0.018 mol) hi ethanol
(20 ml) and water (20 ml) and then the reaction mixture was warmed to 60°C. The
resulting solution was kept at 60°C for 1 hour and was cooled. The mixture was
acidified with 4N HC1 and stirred for 1 hour, then the resulting precipitate was filtered
off and washed with water, yielding 2.7 g of intermediate (8) (mp. 260-262°C).
Example A.4
A mixture of nitromalonaldehyde sodium salt hydrate (CAS 53821-72-0) (0.06 mol),
carbamimidothioic acid, methyl ester, sulfate (2:1) (0.03 mol) and 4-piperidine-
25-
carboxylic acid ethyl ester (0.047 mol) in water (200 ml) was stirred for 2 hours at
80°C or until the methanethiol-gas evolution stopped, then the resulting precipitate was
filtered off and washed with water. The solids were stirred in a minimum amount of
methanol, then filtered off again and washed with ether, yielding 4.8 g of intermediate
A mixture of intermediate (9) (0.017 mol) in ethanol (100 ml) was hydrogenated for
4 hours at 60°C with palladium-on-carbon 10% (0.5 g) as a catalyst. After uptake of
hydrogen (3 equivalents), the reaction mixture was filtered off and the solvent was
evaporated. The obtained residue was purified by column chromatography (eluent:
ethyl acetate/hexane 1/2). The product fractions were collected and the solvent was
evaporated, yielding 3 g of intermediate (10).
c) Preparation of J £ , _ ,, intermediate (1 1)
Reaction under nitrogen: 0.3 g of 4'-(trifluoromethyl)- [l,r-biphenyl]-2-carboxylicacid
in dichloromethane (50 ml) was reacted with ethanedioyl dichloride (0.01 mol) at 0°C
and then the reaction was initiated with dimethylformamide (1 drop). The remaining of
4'-(trifluoromethyl)- [l,l'-biphenyl]-2-carboxylic acid (2.7 g) was added portionwise
(no acid present when reaction mixture was taken up in methanol for TLC-analyses)
and the solvent was evaporated under reduced pressure. The obtained residue was taken
up in dichloromethane (50 ml) and added dropwise to a mixture of intermediate (10)
(0.01 1 mol) and triethylamine (0.01 1 mol) in dichloromethane (50 ml) at 0°C. The
resulting mixture was stirred for 30 minutes and was further purified by column
chromatography over silica gel (eluent: ethyl acetate/hexane 1/4, 1/2). The product
fractions were collected and the solvent was evaporated, yielding 2.9 g of intermediate
d) Preparation of I? N p intermediate (12)
Intermediate (11) (0.006 mol) was added to a solution of NaOH (0.018 mol) in ethanol
(20 ml) and water (20 ml), then the reaction mixture was heated for 1 hour at 60°C,
cooled and acidified with 4N HC1. The resulting precipitate was filtered off, washed
with water and dried, yielding 2.6 g of intermediate (12) (mp. 231-233°C).
Example A.5
a) Preparation of ^^-N ^~//- A mixture of 2-chloro-5-nitro- pyridine (0.0227 mol), 4-piperidineacetic acid, ethyl
ester (0.0227 mol) and sodium carbonate (0.091 mol) in dimethylsulfoxide (40 ml) was
heated at 60°C and stirred for 2 hours, then the reaction mixture was cooled to room
temperature and poured out into ice-water. The resulting precipitate was filtered off and
washed with water. The crude solid was purified by crystallisation from ethyl
acetate/hexane and the resulting precipitate was collected, yielding 3.2 g of
intermediate (13) (mp. 99-101°C).
b) Preparation of intermediate (14)
A mixture of intermediate (13) (0.0102 mol) in THF (50 ml) was hydrogenated for
30 minutes at 50°C with palladium-on-carbon 10% (0.3 g) as a catalyst. After uptake of
hydrogen (3 equivalents), the reaction mixture was cooled and the catalyst was filtered
off, then the filtrate was evaporated, yielding 2.6 g of intermediate (14).
c) Preparation of intermediate (15)
A solution of 6-methyl-4'-(trifluoromethyl)- [l,l'-biphenyl]-2-carboxylic acid (0.005
mol) in 1,4-dioxane (5 ml) was added to a solution of intermediate (14) (0.005 mol) and
triethylamine (0.005 mol) in 1,4-dioxane (15 ml) at 10°C, then the reaction mixture was
•Li-" • , . "
stirred at rObin temperature for 60 hours. The mixture was diluted with water and
extracted with ethyl acetate (100 ml). The product was washed with brine, dried and the
solvent was evaporated. The residue was purified by column chromatography (eluent:
ethyl acetate/hexane 1/4). The product fractions were collected and the solvent was
evaporated, yielding 1.7 g of intermediate (15) (mp.l34-137°C).
-27-
d) Preparation of intermediate (16)
A solution of NaOH (0.01 14 mol) in water (20 ml) was added to a mixture of
intermediate (15) (0.0038 mol) in ethanol (20 ml) and then the reaction mixture was
stirred for 2 hours at 60°C. After cooling to room temperature, the mixture was
acidified with cone. HC1 and the solvent was evaporated. The obtained residue was
stirred in diethyl ether and the desired product was collected, yielding 2.2 g of
intermediate (16).
Example A.6
a) Preparation of intermediate (17)
Aqueous formaldehyde 37% solution (0.0072 mol) and palladium-on-carbon (10%,
0.15 g) were added to a solution of l-(4-aminophenyl)-4-piperidineacetic acid, ethyl
ester (0.0057 mol) in ethyl acetate (40 ml) and then the reaction mixture was
hydrogenated for 5 hours. After uptake of hydrogen (1 equivalent), the catalyst was
filtered over celite and the celite was washed with ethyl acetate (40 ml). The filtrate
was evaporated and the obtained residue was combined with the residue analogously
obtained. The resulting residue was purified by Flash column chromatography (eluent:
ethyl acetate/hexane 30/70). The product fractions were collected, then the solvent was
evaporated and the obtained residual oil was dried, yielding 1.6 g of intermediate (17).
b) Preparation of intermediate (18)
A mixture of 4'-(trifluoromethyl)- [l,r-biphenyl]-2-carboxylic acid (0.0058 mol) in
dichloromethane (40 ml) was stirred at 0°C and under nitrogen, then ethanedioyl
dichloride (0.0087 mol) was added, followed by dimethylformamide (2 drops). The
resulting mixture was warmed to 15°C for 1 hour and then to 30-35°C for 1 hour. The
solvent was evaporated and the obtained yellow solid was dissolved in dichloromethane.
This solution was added to a solution of intermediate (17) (0.0058 mol) and
triethylamine (0.0087 mol) in dichloromethane under nitrogen and then the reaction
mixture was stirred for 16 hours at room temperature. The mixture was diluted with
ethyl acetate (100 ml) and washed with IN HC1 (50 ml), with a saturated NaHC03
solution (50 ml) and with brine (50 ml). The organic layer was dried and the solvent
was evaporated. The obtained oil was further purified by flash column chromatography
(eluent: ethyl acetate/hexane 30/70). The product fractions were collected and the
solvent was evaporated, yielding 1.6 g of intermediate (18).
c) Preparation of J intermediate (19)
Reaction performed under nitrogen : intermediate (18) (0.0029 mol) was dissolved in
ethanol (20 ml) at 20°C and then a mixture of NaOH (0.0087 mol) in water (20 ml) was
added. The resulting emulsion was stirred for 16 hours at 20°C and for 1 hour at 60°C.
The reaction mixture was neutralised with 2N HC1 and a suspension was formed,
Ethanol was evaporated, then the aqueous concentrate was cooled to 0°C and the
resulting solids were filtered off. Dichloromethane was added to the previously
obtained filtrate and then the emulsion was separated into its layers. Finally, the solvent
was evaporated, yielding 1 g of intermediate (19).
Example A. 7
a) Preparation of N= intermediate (20)
A mixture of 4-piperidineacetic acid, ethyl ester, hydrochloride (0.025 mol), 5-bromo-
2-nitro- pyridine (0.03 mol) and potassium carbonate (0.06 mol) in dimethylformamide
(100 ml) was heated for two days at 60°C and then the solvent was evaporated under
reduced pressure. The obtained residue was stirred in water and filtered. The filter
residue was taken up in dichloromethane (100 ml), dried and the solvent was
evaporated. The residue was purified by flash column chromatography over silica
gel(eluent: ethyl acetate/hexane 1/5, 1/3). The product fractions were collected and the
solvent was evaporated, yielding 3.3 g of intermediate (20).
b) Preparation of intermediate (21)
A mixture of intermediate (20) (0.01 mol) in ethanol (100 ml) was hydrogenated
overnight in autoclave (30 bar = 3.106 Pa) at 30°C with palladium-on-carbon (10%,
0.5 g) as a catalyst. After uptake of hydrogen (3 equivalents), the reaction mixture was
filtered off and the filtrate was evaporated, yielding 2.8 g of intermediate (21).
c) Preparation of intennediate (22)
Reaction at 0°C and under nitrogen: ethanedioyl dichloride (0.01 mol) and dimethylformamide
(2 drops) were added to a part of 6-methyl-4'-(trifluoromethyl)- [1,1'-
biphenyl]-2-carboxylic acid (0.2 g) in dichloromethane (100 ml) and then the
remaining of 6-methyl-4'-(trifluoromethyl)- [l,l'-biphenyl]-2-carboxylic acid (1.9 g)
was added portionwise (no acid present when reaction mixture was taken up in
methanol for TLC-analyses). The reaction mixture was stirred for 2 hours at 0°C and
the solvent was removed by evaporation. The residue was taken up in dichloromethane
(25 ml) and the mixture was added dropwise to a stirring solution of intermediate (21)
(0.0075 ml) and triethylamine (0.75 g) in dichloromethane (25 ml). After stirring
overnight, the reaction mixture was washed with water, dried and the solvent was
evaporated. The residue was purified by flash column chromatography (eluent: ethyl
acetate/hexane 1/3). The product fractions were collected and the solvent was
evaporated, yielding 1.5 g of intennediate (22).
d) Preparation of I /~ intermediate (23)
A mixture of NaOH (0.008 mol) in water (20 ml) was added to a mixture of
intermediate (22) (0.003 mol) in ethanol (20 ml) and then the reaction mixture was
stirred for 2 hours at 50°C. After cooling, the mixture was acidified with concentrated
HC1, filtered and washed with water. The filter residue was taken up in diethyl ether,
dried and the solvent was evaporated, yielding 1 g of intermediate (23).
Example A. 8
Preparation of intennediate (24)
Water (28 ml) and lithium hydroxide (0.7 g) were added to a solution of compound
(46) (0.013 mol) in THF (84 ml) and the reaction mixture was stirred at room
-30-
temperature until the reaction was completed. The mixture was filtered and then the
almost dry filter residue was taken up in a small amount of water. The resulting mixture
was washed with dichloromethane and the aqueous layer was acidified carefully to a
pH of 7. The resulting precipitate was filtered off and dried in a desiccator, yielding
6.9 g of intermediate (24) (mp.l70-172°C).
Example A.9
a) Preparation of intermediate (25)
A mixture of intermediate (14) (0.008 mol), aqueous formaldehyde solution (37%, 0.01
mol) and platinum-on-carbon (5%, 0.1 g) in ethyl acetate (100 ml) was stirred under
hydrogen for 2 hours and then an extra portion of aqueous formaldehyde solution
(37%, 0.01 mol) was added. The reaction mixture was stirred for 24 hours and was then
heated overnight at 40°C. The filtrate was evaporated and the obtained residue was
purified by column chromatography over silica gel (eluent: ethyl acetate/hexane 1/1).
The product fractions were collected and the solvent was evaporated, yielding 1.7 g of
intermediate (25).
b) Preparation of intermediate (26)
Reaction at 0°C and under nitrogen: 0.18 g of 6-methyl-4'-(trifluoromethyl)- [1,1'-
biphenyl]-2-carboxylic acid was stirred in dichloromethane (50 ml) with ethariedioyl
dichloride (0.008 mol) and then the mixture was initiated with dimethylformamide
(1 drop). The remaining of 6-methyl-4'-(trifluoromethyl)- [l,r-biphenyl]-2-carboxylic
acid (1.62 g) was added portionwise and the resulting mixture was stirred for 2 hours.
Dichloromethane was evaporated under reduced pressure, to give Residue (I). A
mixture of intermediate (25) (0.0065 mol) and triethylamine to dichloromethane (50
ml) was cooled under nitrogen to 0°C and a solution of Residue (I) in dichloromethane
(20 ml) was added dropwise. The reaction mixture was stirred for 3 hours at room
temperature and was diluted with water. The organic layer was separated, washed with
water, dried and the solvent was evaporated. The obtained residue was purified by flash
column chromatography (eluent: ethyl acetate/hexane 1/3). The product fractions were
collected and the solvent was evaporated, yield 1.2 g of intermediate (26).
c) Preparation of intermediate (27)
Intermediate (26) (0.0022 mol) was added to a solution of sodium hydroxide (0.0066
mol) in water (16 ml) and ethanol (30 ml) and then the reaction mixture was stirred for
18 hours at 30°C. The solvent was evaporated under reduced pressure and the obtained
residue was acidified with 4N HCL Finally, solvent was evaporated, yielding 1.2 g of
intermediate (27).
Example A. 10
a) Preparation of intermediate (28)
A mixture of intermediate (4) (0.0019 mol) and potassium carbonate (0.0053 mol) in
dimethylformamide (30 ml) was heated for 30 minutes at 45°C, then bromo acetic acid,
phenylmethyl ester (0.0029 mol) was added and the reaction mixture was heated for
3 hours at 45°C. The mixture was poured out into water (75 ml) and dichloromethane
(75 ml) and stirred, then the dichloromethane layer was separated and concentrated,
yielding 0.9 g of intermediate (28).
b) Preparation of intermediate (29)
A solution of intermediate (28) (0.0014 mol) in ethyl acetate (40 ml) and ethanol (40
ml) was hydrogenated at atmospheric temperature and at room temperature for 16
hours with palladium-on-carbon (10%, 0.100 g) as a catalyst. After uptake of hydrogen
(1 equivalent), the reaction mixture was filtered over celite and the filtrate was
evaporated, yielding 0.600 g of intermediate (29).
-32-
B. Preparation of the final compounds
Example B.I
Intermediate (2) (0.0001 mol) was dissolved in dichloromethane (2 ml) and PS-DEEA
(0.03 g) was added. The resulting suspension was shaken overnight at room
temperature and filtered. PS-DCC (0.08 g) was added to the filtrate of the previous
step and 2-(ethoxycarbonyl)piperidine (0.0001 mol) dissolved in dimethylformamide
(2 ml) was added. The reaction mixture was stirred for 20 hours at room temperature
and filtered. The filtrate was evaporated and purified by reverse-phase HPLC, yielding
0.001 g of compound (1).
Example B.2
JV-(ernylcarbonimidoyl)-N-dimethyl-1,3-propanediamine, monohydrochloride
(0.0015 mol) was added to a mixture of intermediate (8) (0.001 mol), l-hydroxy-l/ybenzotriazole
(0.0015 mol), 4-methyhnorpholine (0.004 mol) and D-alanine, ethyl
ester, hydrochloride (0.001 mol) in dichloromethane (50 ml) and the reaction mixture
was stirred overnight under nitrogen. The mixture was washed with IN HC1 (20 ml),
with a saturated NaHCOs solution (20 ml) and with brine, then dried and filtered off.
The solvent was evaporated under reduced pressure and the obtained residue was
stirred in hexane, yielding 0.470 g of compound (38) (mp. 213-215°C).
Example B.3
Intermediate (4) (0.002 mol), dimethylformamide (50 ml) and^-ethyl-JVr-(lmethylethyl)-
2-propanamine (0.5 ml) were stirred until complete dissolution, then
1 -[bis(dimethylamino)methylene]- l#-benzotriazolium, hexafluorophosphate(l -)>
3-oxide (0.0033 mol) was added and the mixture was stirred for 15 minutes. L-glutamic
acid, diethyl ester, hydrochloride (0.003 mol) was added and the reaction mixture was
stirred overnight. The mixture was poured out into water and extracted with ethyl
acetate ( triturated under diisopropyl ether with 3 drops of 2-propanol. The resulting precipitate
was filtered off and purified by column chromatography over reverse phase silica
(eluent: dichloromethane). The product fractions were collected and the solvent was
evaporated, yielding 0.6 g of compound (52).
The compounds (2) to (34) were prepared by reacting intermediate (1) with one of the
following reagents : 2-(R)-piperidine-carboxylic acid methyl ester hydrochloride, 2-(S)-
piperidinecarboxylic acid methyl ester hydrochloride, 3-(ethoxycarbonyl)piperidine,
(S)-3-piperidinecarboxylic acid ethyl ester, (R)-3-piperidinecarboxylic acid ethyl ester,
ethyl D-prolinate hydrochloride, 4-trans-hydroxy-L-proline ethyl ester hydrochloride,
4-trans-hydroxy-L-proline methyl ester hydrochloride, 4-cis-hydroxy-L-proline methyl
ester hydrochloride, (±)-alanine methyl ester hydrochloride, ethyl (S)-alaninate hydrochloride,
ethyl (R)-alam'nate hydrochloride, (±)-valine methyl ester hydrochloride, (S)-
valine ethyl ester hydrochloride, (R)-valine ethyl ester hydrochloride, (R)-phenylglycine
ethyl ester hydrochloride, (S)-phenylglycine ethyl ester hydrochloride, (±)-
phenylalanine methyl ester hydrochloride, (S)-phenylalanine ethyl ester, (R)-phenylalanine
ethyl ester, 3-aminopropionic acid ethyl ester hydrochloride, ethyl N-methyllycinate
hydrochloride, diethyl L-glutamate hydrochloride, (S)-2-amino-4-[[(l,ldimethyl-
ethoxy)carbonyl]amino]-butanoic acid methyl ester hydrochloride, N5-[(l,ldimethyl-
emoxy)carbonyl]-L-omithine methyl ester hydrochloride, N6-[(l,l-dimethylethoxy)
carbonyl]-Ilysine methyl ester hydrochloride, alanine ethyl ester hydrochloride,
(S)-leucine ethyl ester hydrochloride, tryptophan ethyl ester hydrochloride,
S-methionine ethyl ester hydrochloride, (S)-tyrosine ethyl ester hydrochloride,
(S)-proline ethyl ester hydrochloride, or 3-amino-3-benzo[l,3]dioxol-5-yl-propionic
acid ethyl ester hydrochloride.
Table F-l lists the compounds that were prepared according to the one of the above
Examples.
Table F-l
(Table Removed)Compound identification
The compound (8) to (34) were identified by LC/MS using a gradient elution system on
a reversed phase HPLC. The compounds are identified by their specific retention time
5 and their protonated molecular ion MH+ peak. The HPLC gradient was supplied by a
Waters Alliance HT 2790 system with a columnheater set at 40°C. Flow from the
column was split to a Waters 996 photodiode array (PDA) detector and a Waters-
Micromass ZQ mass spectrometer with an electrospray ionization source operated in
positive and negative ionization mode. Reversed phase HPLC was carried out on a
10 Xterra MS C18 column (3.5 urn, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three
mobile phases (mobile phase A 95% 25mM ammoniumacetate + 5% acetonitrile;
mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a
gradient condition from 100 % A to 50% B and 50% C in 10 minute, to 100 % B in 1
minute, 100% B for 3 minute and reequilibrate with 100 % A for 2.5 minutes. An
15 injection volume of 10 uL was used.
Mass spectra were acquired by scanning from 100 to 1000 in Is using a dwell time of
0.1 s. The capillary needle voltage was 3kV and the source temperature was maintained
at 140°C . Nitrogen was used a the nebulizer gas. Cone voltage was 10 V for positive
ionzation mode and 20 V for negative ionization mode. Data acquisition was performed
-39-
with a Waters-Micromass MassLynx-Openlynx data system.
Table F-2 : retention time (RT in minutes) and molecular weight as the MH+
(Table Removed)C. Pharmacological examples
C.I. Quantification of the secretion of ApoB
HepG2 cells were cultured in 24-well plates in MEM Rega 3 containing 10 % fetal calf
serum. At 70 % confluency, the medium was changed and the test compound or carrier
(DMSO, 0.4 % final concentration) was added. After 24 hours of incubation, the
medium was transferred to Eppendorf tubes and cleared by centrifugation. A sheep
antibody directed against either apoB was added to the supernatant and the mixture was
kept at 8°C for 24 hours. Then, rabbit anti-sheep antibody was added and the immune
complex was allowed to precipitate for 24 hours at 8°C. The immunoprecipitate was
pelleted by centrifugation for 25 minutes at 1320 g and washed twice with a buffer
containing 40 mM Mops, 40 mM NaH2PO4,100 mM NaF, 0.2 mM DTT, 5 mM
EDTA, 5 mM EGTA, 1 % Triton-X-100,0.5 % sodium deoxycholate (DOC), 0.1 %
-40-
SDS, 0.2 uM leupeptin and 0.2 uM PMSF. Radioactivity in the pellet was quantified
by liquid scintillation counting.
Resulting IC$Q values are enumerated in Table C.I. When the calculated IC5Q was
below 6, not enough data points were available at the tested concentrations to calculate
an IC50 value.
(Table Removed)MTP activity was measured using an assay similar to one described by J.R. Wetterau
and D.B. Zilversmit in Chemistry and Physics ofLipids, 38,205-222 (1985). To
prepare the donor and acceptor vesicles, the appropriate lipids in chloroform were put
into a glass test tube and dried under a stream of Nz. A buffer containing 15 mM Tris-
HC1 pH 7.5,1 mM EDTA, 40 mM NaCl, 0.02 % NaN3 (assay buffer) was added to the
dried lipid. The mixture was vortexed briefly and the lipids were then allowed to
hydrate for 20 min on ice. Vesicles were then prepared by bath sonication (Branson
2200) at room temperature for maximum 15 min. Butylated hydroxytoluene was
included in all vesicle preparations at a concentration of 0.1%, The lipid transfer assay
mixture contained donor vesicles (40 nmol phosphatidylcholine, 7.5 mol % of
cardiolipin and 0.25 mol % glycerol tri [l-14C]-oleate), acceptor vesicles (240 nmol
phosphatidylcboline) and 5 mg BSA in a total volume of 675 ul in a 1.5 ml
microcentrifuge tube. Test compounds were added dissolved in DMSO (0.13 % final
concentration). After 5 minutes of pre-incubation at 37 °C, the reaction was started by
the addition of MTP in 100 ul dialysis buffer. The reaction was stopped by the addition
of 400 ul DEAE-52 cellulose pre-equilibrated in 15 mM Tris-HCl pH 7.5,1 mM
EDTA, 0.02 % NaN3 (1:1, vol/vol). The mixture was agitated for 4 min and centrifuged
for 2 min at maximum speed in an Eppendorf centrifuge (4°C) to pellet the DEAE-52-
bound donor vesicles. An aliquot of the supernatant containing the acceptor liposomes
was counted and the [14C]-counts were used to calculate the percent triglyceride
transfer from donor to acceptor vesicles. The percent triglyceride transfer from donor
to acceptor vesicles measured results in a "%C" value (% control) of 100 % when the
test compound did not inhibit MTP activity and a lower %C value when the test
compound did inhibit the activity of MTP.
Resulting IC50 values are enumerated in Table C.2. When the calculated IC50 was
below 7, not enough data points were available at the tested concentrations to calculate
an IC5Q value. (Table Removed)

We Claim:

1. A n-aryl piperidine substituted biphenylcarboxamide compounds of formula (I)
(Formula Removed)
the N-oxides, the pharmaceutically acceptable acid addition salts and the
stereochemically isomeric forms thereof, wherein
R1 is hydrogen, C1-4alkyl, halo, or polyhalo C1-4alkyl;
R2 is hydrogen, C1-4alkyl, halo, or polyhalo C1-4alkyl;
R3 is hydrogen or C1-4alkyl;
R4 is hydrogen, C1-4alkyl, or halo;
n is the integer 1;

X 1is carbon and X is carbon; or X 1is nitrogen and X2 is carbon;
or X1 is carbon and X2 is nitrogen;
X3 is carbon or nitrogen;
Y represents O, or NR6 wherein R6 is hydrogen or C1-4alkyl;
R5 represents a radical of formula
(Formula Removed)

wherein
m is an integer 0, 1 or 2;
Z is O or NH;
R7 is hydrogen,
C1-6alkyl;

C1-6alkyl substituted with hydroxyl, amino, mono- or di( C1-4alkyl)amino, C1-4alkyloxy
carbonyl, aminocarbonyl, aryl or heteroaryl;
C1-4alkyl-0- C1-4alkyl;
C1-4alkyl-S- C1-4alkyl; or
Aryl;
R8 is hydrogen or C1-6alkyl;
R9 is hydrogen, C1-4alkyl, aryl1, or C1-4alkyl substituted with aryl1;
or when Y represents NR6 the radicals R5 and R6 may be taken together with the nitrogen
to which they are attached to form pyrrolidinyl substituted with C1-4alkyloxycarbonyl and
optionally further substituted with hydroxy; or piperidinyl substituted with
C1-4alkyloxycarbonyl;
aryl is phenyl; phenyl substituted with one, two or three substituents each independently
selected from C1-4alkyl, C1-4alkyloxy, halo, hydroxy, nitro, cyano, C1-4alkyloxycarbonyl,
trifluoromethyl, or trifluoromethoxy; or benzo[l,3]dioxolyl;
aryl1 is phenyl; phenyl substituted with one, two or three substituents each independently
selected from C1-4alkyl, C1-4alkyloxy, halo, hydroxy, nitro, cyano, C1-4alkyloxycarbonyl,
trifluoromethyl, or trifluoromethoxy; and heteroaryl is imidazolyl, thiazolyl, indolyl, or
pyridinyl.
2. A compound as claimed in claim 1 wherein X1, X2 and X3 are carbon.
3. A compound as claimed in claim 1 wherein R is trifluoromethyl; R is hydrogen; R is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1) wherein m is the integer 0.
4. A compound as claimed in claim 1 wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-1) wherein m is the integer 1.
5. A compound as claimed in claim 1 wherein R1 is trifluoromethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6

wherein R6 is hydrogen or methyl; and R5 is a radical of formula (a-2) wherein m is the integer 1.

6. A compound as claimed in claim 1 wherein R is triflurormethyl; R2 is hydrogen; R3 is hydrogen; R4 is hydrogen; X1, X2 and X3 are carbon; n is the integer 1; Y represents NR6 and R5 and R6 are taken together with the nitrogen to which they are attached to form pyrrolidinyl substituted with C1-4alkyloxycarbonyl and optionally further substituted with hydroxyl, or piperidinyl substituted with C1-4alkyloxycarbonyl.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any of claims 1 to 6.
8. A process for preparing a compound of formula (I) as claimed in claim 1 wherein
a) an intermediate of formula (II), wherein R3, R4, R5, Y, n, X1, X2 and X3 are defined as in claim 1,

(Formula Removed)

is reacted with a biphenylcarboxylic acid or halide having the formula (III), wherein R and R2 are as defined in formula (I) and Q1 is selected from hydroxyl and halo, in at least one reaction-inert solvent and optionally in the presence of a suitable base

Documents:

3243-DELNP-2006-Abstract-(10-07-2009).pdf

3243-delnp-2006-abstract.pdf

3243-DELNP-2006-Claims-(10-07-2009).pdf

3243-delnp-2006-claims.pdf

3243-DELNP-2006-Correspondence-Others-(03-08-2010).pdf

3243-DELNP-2006-Correspondence-Others-(19-05-2010).pdf

3243-delnp-2006-correspondence-others-1.pdf

3243-delnp-2006-correspondence-others.pdf

3243-DELNP-2006-Corresponence-Others-(10-07-2009).pdf

3243-DELNP-2006-Description (Complete)-(10-07-2009).pdf

3243-delnp-2006-description (complete).pdf

3243-delnp-2006-form-1.pdf

3243-delnp-2006-form-18.pdf

3243-DELNP-2006-Form-2-(10-07-2009).pdf

3243-delnp-2006-form-2.pdf

3243-DELNP-2006-Form-3-(10-07-2009).pdf

3243-delnp-2006-form-3.pdf

3243-delnp-2006-form-5.pdf

3243-DELNP-2006-GPA-(10-07-2009).pdf

3243-delnp-2006-gpa.pdf

3243-delnp-2006-pct-210.pdf

3243-delnp-2006-pct-237.pdf

3243-delnp-2006-pct-304.pdf

3243-DELNP-2006-Petition-137-(10-07-2009).pdf

3243-DELNP-2006-Petition-138-(10-07-2009).pdf

abstract.jpg


Patent Number 243281
Indian Patent Application Number 3243/DELNP/2006
PG Journal Number 41/2010
Publication Date 08-Oct-2010
Grant Date 01-Oct-2010
Date of Filing 06-Jun-2006
Name of Patentee JANSSEN PHARMACEUTICA N.V.
Applicant Address TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM.
Inventors:
# Inventor's Name Inventor's Address
1 LIEVEN MEERPOEL C/O JANSSEN PHARMACEUTICA N.V., TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM.
2 MARCEL VIELLEVOYE TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM
3 JOANNES THEODORUS MARIA LINDERS TURNHOUTSEWEG 30, B-2340 BEERSE, BELGIUM
PCT International Classification Number C07D 211/60
PCT International Application Number PCT/EP2004/053280
PCT International Filing date 2004-12-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03104601.4 2003-12-09 EUROPEAN UNION