Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION TREATMENT OF OBESITY INVOLVING SELECTIVE CBS.-ANTAGONISTS AND
LIPASE
INHIBITORS
The present invention relates to a novel therapeutic and/or prophylactic
treatment
of obesity by administering a combination of CBS-antagonistic compounds
together with a further active principle, and to pharmaceutical compositions
containing at least one of these CBS-antagonistic compounds in
combinatiowrvith
said further active principle for the treatment and/or prophylaxis of obesity.
The
combination provided by the present invention of a compound showing potent
Cannabis-1 (CBS) receptor antagonistic activity with said further active
principle
are of particular utility for treating of obesity.
Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been
used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog.
Med. Chem. 1987, 24, 159). However, only within the past ten years the
research
in the cannabinoid area has revealed pivotal information on cannabinoid
receptors and their (endogenous) agonists and antagonists. The discovery and
the subsequent cloning of two different subtypes of Cannabinoid receptors (CBS
and CB2) stimulated the search for novel cannabinoid receptor antagonists
(Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L.A.;
Bonner, T.I. Cannabinoid Receptors, Pertwee, R.G. Ed. 1995, 117, Academic
Press, London). 1n addition, pharmaceutical companies became interested in the
development of cannabinoid drugs for the treatment of diseases connected with
disorders of the cannabinoid system. The wide distribution of CBS receptors in
the
brain, in combination with the strictly peripheral localization of the CBz
receptor,
makes the CBS receptor a very interesting molecular target for CNS-directed
drug
discovery in the areas of both psychiatric and neurological disorders
(Consroe, P.
Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS
Investigational DiUgs 1999, 7, 587. Greenberg, D.A. Drug News Perspect.
1999, 72, 458). Hitherto, three types of distinct CBS receptor antagonists are
known. Sanofi disclosed their diarylpyrazole congeners as selective CBS
receptor
antagonists. A representative example is SR-141716A, which is currently
undergoing Phase l! clinical development for psychotic disorders (Dutta, A.K.;
Sard, H.; Ryan, W.; Razdan, R.K.; Compton, D.R.; Martin, B.R. Med. Chem. Res.
1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S.R.; McCallion,
D.;
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2
Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769. Nakamura-Palacios,
E.M.; Moerschbaecher, J.M.; Barker, L.A. CNS Drug Rev. 1999, 5, 43).
Aminoalkylindoles have been disclosed as CBS receptor antagonists. A
representative example is lodopravadoline (AM-630), which was introduced in
1995. AM-630 is a CBS receptor antagonist, but sometimes behaves as a weak
partial agonist (Hosohata, K.; Quock, R.M.; Hosohata, Y.; Burkey, T.H.;
Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.i. Life Sc. 1997, 67,
PL115). More recently, researchers from Eli Lilly described aryl-aroyl
substituted
benzofurans as selective CBS receptor antagonists (e.g. LY -320135) (Felder,
C,C.; Joyce, K.E.; Bri(ey, E.J.; Glass, M.; Mackie, K.P.; Fahey, K.J.;
Cullinan,
G.J.; Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M.
J. Pharmacol. Exp. Ther. 1998, 284, 291 ). Recently, 3-alkyl-5,5'-
diphenylimidazolidinediones were described as cannabinoid receptor ligands,
which were indicated to be cannabinoid antagonists (Kanyonyo, M.; Govaerts,
S.J.; Hermans, E.; Poupaert, J.H., Lambent, D.M. 8iorg. Med,Chem. Lett. 1999,
9,
2233). Interestingly, many CBS receptor antagonists have been reported to
behave as inverse agonists in vitro (i_andsman, R,S.; Burkey, T.H.; Consroe,
P.;
Roeske, W.R.; Yamamura, H.I. Eur. J. PharmacoL 1997 , 334, R1 ). Recent
reviews provide a nice overview of the current status in the cannabinoid
research
area (Mechoulam, R.; Hanus, L.; Fride, E. Prog, Med. Chem. 1998, 35, 199.
Lambent, D.M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, .R.; Fride, E.; Di
Marzo, V. Eur. J. Pharmacol. 1998 , 359, 1 ). From the international patent
application WO 01/70700 4,5-dihydro-1 H-pyrazole compounds are known which
exhibit potent and selective cannabis CBS-receptor antagonistic activity.
It is an objective of the invention to provide improved methods of treatment
and/or prophylaxis for the treatment of obesity, particularly methods of
treatment
and/or prophylaxis for the treatment of obesity suitable in patient groups
with
enhanced need of safety and tolerability, e.g . in particular such as juvenile
obesity patients and/or patients subject to long term treatment, e.g. in drug
induced obesity in juvenile or adolescent patients.
It has now surprisingly been found that selective CBS-antagonists in general,
prodrugs thereof, tautomers thereof' and salts thereof, show a unigue
pharmacological profile and therefore are particularly suited in combination
with
at least one lipase inhibiting compound (lipase inhibitor) for the use in the
manufacture of a medicaments for the treatment and/or prophylaxis of obesity
in
patients of any age, and in particular also for the treatment and/or
prophylaxis of
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3
obesity in juvenile patients and/or drug induced obesity in juvenile, as well
as
adolescent, patients. In this regard combinations of at least one CBS
antagonistic
compound with at least one lipase inhibiting compound are highly valuable in
providing medicaments for the treatment and/or prophylaxis of obesity in
general,
e.g. in adolescent patients of any age, and particularly also in pediatric or
juvenile
obesity, and also in drug induced obesity in adolescent and juvenile patients.
Therefore, the invention also pertains to the combination of a CBS
antagonistic
compound, which is a potent and selective antagonist of the cannabis CB~-
receptor, or a prodrug, tautomer or salt thereof, with at least one lipase
inhibiting
compound. In a variant, the invention pertains to the combination, wherein the
combination is in a medicament for the treatment and/or prophylaxis of
obesity,
including in particular the treatment and/or prophylaxis of obesity in
juvenile
patients andlor drug induced obesity in juveniie as well as adolescent
patients.
The term "selective" means that preferably there is no substantial other
activity
than the CBS-receptor antagonistic activity, or that at least the CB1-receptor
antagonistic activity is substantially overcompensating any other activity.
The outstanding unique pharmacological profile of selective CBS-antagonistic
compounds includes particularly high safety and tolerability which make the
compounds particularly suitable in combination with lipase inhibiting
compounds
in patient groups with enhanced need of safety and tolerability, in particular
such
as juvenile patients and/or patients subject to long term treatment, e.g. in
drug
induced obesity.
Due to the potent and selective CBS antagonistic activity the compounds (CBS
antagonists) used according to the invention are suitable also in combination
with
other drugs, in particular in combination with lipase inhibiting compounds
according to the present invention. Thus the CBS antagonistic compounds in
combination with lipase inhibiting compounds are particuiariy suitable also in
patient groups with enhanced need of safety and tolerability, in particular
such as
juvenile patients and/or patients subject to long term treatment, e.g. in drug
induced obesity.
This safety and tolerability of CBS antagonistic compounds in combination with
lipase inhibiting compounds is advantageous in the treatment and/or
prophylaxis
of obesity in those patient populations where a single treatment is not
sufificientiy
effective and a combination treatment and/or prophylaxis involving different
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4
medical or metabolic mechanisms is desired or required for achieving and
stabilizing a defined degree of weight loss.
Hence, combination of CBS antagonistic compounds with lipase inhibiting
compounds according to the present invention is expected to be very is
advantageous in the treatment and/or prophylaxis of obesity in general, e.g.
of
obesity in adolescent patients of any age, and particularly also in pediatric
or
juvenile obesity, and in drug induced obesity.
The CB1 receptor modulating activity of the compounds of the invention makes
them particularly useful in the treatment of obesity, juvenile obesity and
drug
induced obesity, when used in combination with lipase inhibitors. Specific
examples of lipase inhibiting compounds which can be used in such combination
preparations are (but not restricted to) the synthetic Lipase inhibitor
orlistat,
panclicins, lipase inhibitors isolated from micro organisms such as lipstatin
(from
Streptomyces toxytricini~, ebelactone B (from Strepfomyces aburaviensis),
synthetic derivatives of these compounds, 2-oxy-4H-3,1-benzoxazin-4-one
derivatives like ATL-962 and structurally related compounds, 2 -amino-4H-3,1-
benzoxazin-4-one derivatives, as well as extracts of plants known to possess
lipase inhibitory activity, for instance extracts of Alpinia officinarum Hance
or
compounds isolated from such extracts like 3-methylethergalangin (from A.
otficinarum). The lipase inhibiting compound may also be a lipase inhibiting
polymer. These lipase inhibiting compounds and their manufacture are well
known in the state of the art.
As indicated already above, the invention also pertains to a combination of a
CBS
antagonistic compound, which is a potent and selective antagonist of the
cannabis CBS-receptor, or a prodrug, tautomer or salt thereof, with at least
one
lipase inhibiting compound; and in a further variant, the invention pertains
to a
combination, wherein the combination is in a medicament for the treatment
and/or prophylaxis of obesity, including in particular the treatment andlor
prophylaxis of obesity in juvenile patients and/or drug induced obesity in
juvenile
as well as adolescent patients. In these combinations according to the
invention
the CBS receptor antagonistic compound is selected from the group of
1 ) Diarylpyrazole selective CBS receptor antagonists, preferably the
compounds SR-141716A, rimonabant and related compounds, SR-
147778, SR-140098 and/or WIN-54461;
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2) Aminoalkylindoles selective CBS receptor antagonists, preferably the
compound lodopravadoline (AM-630);
3) Aryl-aroyl substituted benzofuran compounds with selective CBS receptor
antagonistic activity, preferably the compound LY-320135;
5 4) Selective CBS rec eptor antagonistic compounds AM251 and/or AM281,
and substituted imidazolyl compounds with selective CBS receptor
antagonistic activity;
5) Azetidine derivatives with selective CBS receptor antagonistic activity;
6) The compound CP-55940;
7) Diaryl-pyrazine-amide with selective CBS receptor antagonistic activity;
8) The compounds ACPA and ACEA;
9) Pyrazole derivatives with selective CBS receptor antagonistic activity;
10) The compounds HU-210 and/or HU-243;
11 ) The compounds O-585, O-823, O-689, O-1 D72, andior O-2093;
12) 3-Alkyl-5,5'-diphenylimidazolidinediones with selective CBS receptor
antagonistic activity
13) CB1 antagonistic compounds with selective CB1 receptor antagonistic
activity.
In yet a further variant, the invention pertains to a combination, wherein the
CBS
receptor antagonistic compound is in combination with at least one lipase
inhibiting compound selected from the group of lipase inhibiting polymers,
orlistat,
panclicins, ATL-962 and lipstatin.
The selective CBS antagonistic compounds used in the present the invention can
be obtained according to known methods. Suitable ways of synthesis for the
compounds used according to the present invention are described in the state
of
the art, e.g. in the documents cited in the present application and
incorporated by
reference.
Examples of selective C8~ antagonistic compounds being relevant in the context
of the present invention and incorporated by reference are for example (but
not
being limited thereto):
1 ) Diarylpyrazole congeners disclosed by Sanofi as selective CBS receptor
antagonists, e.g. as representative example the compound SR-141716A,
rimonabant and related compounds described e.g. in EP 0969835, SR-
147778, SR-140098 (Central mediation of the cannabinoid cue: activity of
a selective CB1 antagonist, SR 141716A Perio A, Rinaldi-Carmona M,
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6
Maruani J Behavioural Pharmacology 1996, 7:1 (65-71)
); WIN-54461
disclosed by Sanofi-Winthrop (Cannabinoid receptor
ligands : Clinical and
neuropharmacological considerations relevant to future
drug discovery
and development. Pertwee RG, Expert Opinion on Investigational
Drugs
1996, 5:10 (1245-1253) )
2) Aminoalkylindoles having been disclosed as CBS receptor
antagonists,
e.g. as a representative example the compound iodopravadofine
(AM-
630),
3) Aryl-aroyl substituted benzofurans described by Eli
Lilly as selective CBS
receptor antagonists, e.g.LY-320135 (Cannabinoid
receptor ligands
Clinical and neuropharmacological considerations
relevant to future drug
discovery and development. Pertwee RG, Expert Opinion
on
Investigational Drugs 1996, 5:10 (1245-1253) ),
4) Compounds described by Merck & Co, e.g. AM 251 and
AM 281
(Conference: 31 st Annual Meeting of the Society
for Neuroscience, San
Diego, USA, 10-15.11.2001 ), and substituted imidazolyl
derivatives
disclosed e.g. in US 2003-114495 or WO 03/007887,
5) Azetidine derivatives described by Aventis Pharma
e.g. in WO 02/28346
or EP 1328269,
6) CP-55940 from Pfizer Inc. (Comparison of the pharmacology
and signal
transduction of the human cannabinoid CB1 and CB2
receptors, Felder
CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond
O, Lai Y, Ma AL,
Mitchell RL, Molecular Pharmacology 1995, 48:3 (443)
),
7) Diaryl-pyrazine-amide derivatives from Astra Zeneca
described e.g. in the
WO 03/051851,
8) ACPA and ACEA from Med. Coll. Wisconsin (Univ. Aberdeen),
("Effects of
AM 251 & AM 281, cannabinoid CB1 antagonists, on
palatable food
intake in lewis rats" J.PharmacoLExp.Ther. 289, No3,
1427-33, 1999),
9) Pyrazole derivatives described by the University
of Conneticut e.g. in the
WO 01 /29007,
10) HU-210
(internationai
Association
for the Study
of Pain -
Ninth Worid
Congress (Part II) Vienna, Austria, Dickenson AH,
Carpenter K, Suzuki R,
IDDB MEETING REPORT 1999, August 22-27) and HU-243
(Cannabinoid receptor agonists and antagonists, Barth
F, Current Opinion
in Therapeutic Patents 1998, 8:3 (301-313)) from
Yissum R&D Co
Hebrew Univ. of Jerusalem,
11 ) O-823
from Organix
Inc. (Drug
development
pipeline:
O-585, O-823,
0-
689, O-1072, nonamines, Orgaix, Altropane Organix
inc, Company
Communication 1999, August 10; IDDb database) and
O-2093 from
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r
Consiglio Nazionale delle Ricerche ("A structure/activity relationship study
on arvanil, endocannabinoid and vanilloid hybrid.", Marzo DV, Griffin G,
Petrocellis L, Brandi I, Bisogno T, Journal of Pharmacology and
Experimental Therapeutics 2002, 300:3 (984-991 ) ),
12) 3-Alkyl-5,5'-diphenylimidazolidinediones which were described as
cannabinoid receptor ligands,
13) CB~ antagonistic compounds currently under development by Bayer AG
(IDDb database: company communication 2002, February 28 ).
Lipase inhibiting compounds used in the combinations according to the present
invention may be any lipase inhibiting compound suitable for pharmaceutical
use,
e.g. in particular inhibitors of pancreatic lipases. Lipases are key enzymes
in the
digestive system which break down tri- and diglycerides, which are too large
to be
absorbed by the small intestine into fatty acids which can be absorbed. Since
lipases are responsible for the hydrolysis of fat, a consequence of their
inhibition
is a reduction in fat hydrolysis and absorption. Therefore, inhibition of
lipases
results in a reduction in the absorption of fat. The lipase inhibiting
compound is
preferably the synthetic lipase inhibitor orlistat and structurally related
compounds, panclicins, lipase inhibitors isolated from micro organisms such as
lipstatin, ebelactone B, or synthetic derivatives of these compounds, 2-oxy-4H-
3,1-benzoxazin-4-one derivatives like ATL-962 and structurally related
compounds, 2-amino-4H-3,1-benzoxazin-4-one derivatives, however may also be
a lipase inhibiting polymer. Most preferred are orlistat, panclicins, ATL-962
and
lipstatin.
Orlistat (tetrahydrolipstatin) and lipstatin are described in the US-patent US
4,598,089 and its European equivalent EP 0 129 748 B1 in more detail. The
compounds are 2-hexyl-3-hydroxy-hexadecanoic acid lactone derivatives with the
chemical names (2S,3S,5S,7Z,10Z)-5-((S)-2-formamido-4-methylvaleryloxy)-2-
hexyl-3-hydroxy-7,10-hexadecadienoic acid lactone (lipstatin) and (2S,3S,5S)-5-
((S)-2-4-methylvaleryioxy)-2-heyi-3-hydroxy-hexadecanoic acid 4actone (tetra-
hydrolipstatin). The compounds are known to be inhibitors of pancreas lipase
which can be used for the prevention of treatment of obesity and
hyperlipaemia,
for which purpose they can be formulated as medicaments or incorporated into
industrially prepared foodstuffs. Inhibition of pancreas lipase prevents the
hydrolysis of dietary fats to give absorbable free fatty acids and
monoglycerides,
so that the fats are excreted unchanged. IC50's for lipstatin and
tetrahydrolipstatin for inhibition of hydrolysis of triolein by porcine
pancrease
lipase are 0.07 and 0.18 mcg/ml, respectively.
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8
Furthermore, there are suitable lipase inhibitors which are structurally
related to
orlistat and/or lipstatin and which are known as panclicins. These panclicines
are
derived from orlistat and contain a 4-ring lactone (Mutoh M; Nakada N;
Matsukima S; Ohshima S; Yoshinari K; Watanabe J Location: Kanagawa, Japan
Issue Date: 19-JAN-1995 Journal: J.Antibiot., 47, No. 12, 1369-75, 1994). The
biological data of these panclicins may be summarized as fofiows: Panciicins
A,
B, C, D and E, structural analogs of tetrahydrolipstatin (THL), dose-
dependently
inhibited hydrolysis of triolein of fatty acids by porcine pancreatic lipase,
with IC50
values of 2.9, 2.6, 0.62, 0.66 and 0.89 microM, respectively. The inhibitory
activity
of panclicins A and B (alanine moiety in place of leucine in THL) was 2-3-fold
weaker than that of THL; in contrast, the inhibitory activity of panclicins C,
D and
E (glycine moiety in place of leucine in THL) was 2-fold stronger than that of
THL.
Panclicins A, B, C, D and E also potently inhibited plasma iipases with iC50
values of 1.0, 1.2, 0.29, 0.25 and 0,15 microM, respectively. Panclicins A and
B
inhibited plasma lipases with the same potency as THL, while panclicins C, D
and
E had a 3-6-fold greater inhibitory activity than THL. Panclicins A, B, C, D
and E
inhibited bacterial and fungal lipases with profiles similar to those for
porcine
pancreatic lipase. Panclicins inhibited pancreatic lipase irreversibly, but
less
irreversibly than THL. Panclicins A, B, C, D and E irreversibly inhibit
pancreatic
lipase.
Ebelactone B is described in the US-patent US 4,358,602 and its German
equivalent DE 3 109 335 C1. Ebelactone A and ebelactone B belong to a group
of compounds that exhibit activity to enhance the cell mediated immune
response
in living animals and they also inhibit inflammations in living animals. Thus
they
may be used in the immunological treatment of tumours and for enhancing anti-
tumour agents such as bleomycins. The compounds have anti-esterase activity
and anti-formylmethionine aminopeptidase activity. Admininistration to mice of
these compounds at a dosage of 0.781-50 mg/kg (i.p.) or 0.5 mglkg (per os)
enhances the development of DTH response and the compounds show a
potentiating effect on cell-mediated immunity. Ebelactone B reduces
carragheenin-induced swelling in mice.
In the context of the present invention the lipase inhibitors administered in
combination with the selective CBS antagonistic compounds to a patient for
treating obesity may be also a polymer that has been substituted with or
comprises one or more groups which can inhibit a lipase. Such lipase
inhibiting
polymers are described in the US patents US 6572850, US 6558657, US
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9
6352692, US 6267952 and in the international patent application WO 99/34786.
In one embodiment, the lipase inhibiting group can be a "suicide substrate"
which
inhibits the activity of the lipase by forming a covalent bond with the enzyme
either at the active site or elsewhere. In another embodiment, the lipase
inhibiting
group is an isosteric inhibitor of the enzyme.
1n a first aspect of the present invention when using lipase inhibiting
polymers in
addition to the selective CBS antagonistic compounds, the lipase inhibiting
group
inactivates a lipase such as gastric, pancreatic and lingual lipases.
Inactivation
can result by forming a covalent bond such that the enzyme is inactive. The
covalent bond can be formed with an amino acid residue at or near the active
site
of the enzyme, or at a residue which is distant from the active site provided
that
the formation of the covalent bond results in inhibition of the enzyme
activity.
Lipases contain a catalytic triad which is responsible for the hydrolysis of
lipids
into fatty acids. The catalytic triad consists of a serine, aspartate and
histidine
amino acid residues. This triad is also responsible for the hydrolysis of
amide
bonds in serine proteases, and it is expected that compounds that are serine
protease inhibitors will also inhibit lipases. Therefore, serine protease
inhibitors
that can be covalently linked to a polymer are preferred lipase inhibiting
groups.
For example, a covalent bond can be formed between the lipase inhibiting group
and a hydroxyl at or the catalytic site of the enzyme. For instance, a
covalent
bond can be formed with serine. Inactivation can also result from a lipase
inhibiting group forming a covalent bond with an amino acid, for example
cysteine, which is at some distance from the active site. In a second aspect
of the
present invention when using lipase inhibiting polymers in addition to the CBS
antagonistic compounds, non-covalent interaction between the lipase inhibiting
group and the enzyme can also result in inactivation of the enzyme. For
example,
the lipase inhibiting group can be an isostere of a fatty acid, which can
interact
non-covalently with the catalytic site of the lipase. In addition, the lipase
inhibiting
group can compete for lipase hydrolysis with natural triglycerides.
A variety of polymers can be employed in the invention described herein. The
polymers can be aliphatic, alicyclic or aromatic or synthetic or naturally
occurring.
However, aliphatic and alicyclic synthetic polymers are preferred.
Furthermore,
the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic
and/or
hydrophilic monomers. The polymer can be non-ionic (e.g., neutral), anionic or
cationic, in whole or in part. Furthermore, the polymers can be manufactured
from olefinic or ethylenic monomers (such as vinylalcohoi) or condensation
polymers. For example, the polymers can be a polyvinylalcohol, polyvinylami
ne,
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poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine,
polyalkylenimine,
polyethylene, polypropylene, polyether, polyethylene oxide, polyamide,
polyacrylic acid, polyalkylacrylate, polyacrylamide, polymethacrylic acid,
polyalkylmethacrylate, polymethacrylamide, poly-N-alkylacrylamide, poly-N-
5 alkylmethacrylamide, polystyrene, vinylnaphthalene, ethylvinylbenzene,
aminostyrene, vinylbiphenyl, vinylanisole, vinylimidazolyl, vinylpyridinyl,
dimethylaminomethylstyrene, trimethylammoniumethyfmethacryfate,
trimethylammoniumethylacrylate, carbohydrate, protein and substituted
derivatives of the above (e.g., fluorinated monomers thereof) and copolymers
10 thereof. Preferred polymers include polyethers, such as polyalkylene
glycols.
The polymers employed in the methods described herein as well as intermediates
and methods for preparing the polymers are described in detail in the US
patents
US 6572850, US 6558657, US 6352692, US 6267952 and in the international
patent application WO 99/34786, which are all incorporated by reference into
the
present invention.
Recently, in the international patent application WO 03/072555 new 5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of formula (A) are described to
be pancreatic lipase inhibitors useful for treating metabolic diseases,
cardiovascular diseases or especially obesity.
R5
R4 /
~ ~ ~N R1 (A)
R3 ~ ~N ~~O
R2 /~-~ O
O
Such oxadiazolones of formula (A) and their salts and acid addition salts are
also
suitable for combinations with the CBS antagonistic compounds used according
to
the present invention. In formula (A) the substituents may be as follows:
R1 may be 7-22C alkyl; 2-4C alkyl substituted by 4-20C alkoxy, 6-10C aryl, 6-
10C
aryloxy or (4-12C) alkoxy-(2-4C) alkoxy (where aryl can be substituted by one
or more of halogen, 1-4C alkyl, 1-4C alkoxy, N02 or CF3); 7-20C alkenyl; or
phenyl substituted by 6-12C alkyl or by phenoxy; and
R2 to R5 each may be H, halogen, N02, 1-4C alkyl, 1-4C alkoxy, CF3 or OCF3;
or (6-10C) aryl-(1-4C) alkoxy, 6-10C aryloxy, 6-10C aryl, 3-8C cycloalkyl or 3-
8C cycloalkoxy (optionally substituted by halogen, CF3, 1-4C alkoxy or 1-4C
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11
alkyl).
These 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones are described to have
pharmacological properties as anorectic, antidiabetic, hypotensive or
cardiant,
with mechanism of action as pancreatic lipase inhibitors. For example 5-
dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one had IC50
0.03 microM for inhibition of porcine pancreatic lipase. Hence, these 5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones may be used as medicaments,
especially for the treatment of obesity . As pancreatic lipase inhibtors, the
5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones inhibit the resorption of the
fat
content of foods and thus reduce fat uptake and body weight (or prevent
increase in body weight). Furthermore, the 5-hydrocarbyloxy-3-phenyl-1,3,4-
oxadiazol-2-ones are reported to also have a beneficial effect in the
treatment of
metabolic disorders (e.g. diabetes) or cardiovascular disorders (e.g.
hypertension
and cardiac infarction). The lipase inhibiting compounds of formula (A) are
described in more detail in the WO 03/072555 and can be obtained according to
known methods. A suitable synthesis for the lipase inhibiting compounds of
formula (A) is described also in the international patent application WO
03/072555. The whole content of the international patent application WO
03/072555 is incorporated by reference into the present application regarding
the
disclosure of lipase inhibitors of formula (A).
In addition, in the international patent application WO 03/072098 further 5 -
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of formuia (A) are described to
be pancreatic lipase inhibitors useful for treating of obesity or diabetes
mellitus
type 1 and 2. Such oxadiazolones of formula (A) as described in WO 03/072098
and their salts and acid addition salts are also suitable for combinations
with the
CBS antagonistic compounds used according to the present invention. In formula
(A) the substituents may be as follows:
R1 may be 1-6C alkyl; 3-9C-cycloalkyl, both groups optionally may be
substituted
by phenyl, 1-4C alkoxy, S-1-4C alkyl, N(1-4C-alkyl)2; and phenyl optionally
may be also substituted by halogen, 1-4C alky, 1-4C-alkyloxy, nitro or CF3;
and
R2 to R5 each may be independently H, halogen, N02, 1-4C alkyl, 1-9C alkoxy
which is substituted by F, 6-10C-aryl, amino or1-4C alkyl amino;
6-1 OC-aryl-1-4C-alkyloxy, 6-1 OC-aryloxy, 6-1 OC-aryl, 6-1 OC-aryloxy-1-4C-
alkyl, 3-8C cycloalkyl or O(3-8 cycloalky), which may optionally be
substituted
by halogen, CF3, 1-4 alkyloxy or 1-4C alkyl;
S02-NH-(1-6C alkyl), optionally substituted by N(1-6C alkyl)2, S02-NH-
(2,2,6,6-tetramethylpiperidin-4-yl), S02-NH-(3-8C cycloalkyl), optionally
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12
substituted by 1-4C alkyl, S02-N(1-6Calkyl)2 or COX;
2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7
with the proviso that R2, R3, R4 and R5 are not H at the same time when
X is O(1-6C alkyl), NH(1-6C alkyl), NH(3-8C cycloalkyl or
N(1-6C alkyl)2 and
N(1-6C alkyl)2 may be also pyrrolidino, piperidino, morpholino,
thiomorpholino or piperazino, which optionally substituted
by 1-4C alkyl,
benzyl, 6-10C aryl, CO-(1-4 alkyl), CO-(6-10 aryl), CO-O-(1-4C
alkyl),
S02-(1-4C alkyl) or S02-(6-10C aryl);
R6 is H, 1-4C alkyl or 6~10C-aryl-1-4C-alkyl, wherein aryl
may be substitutet
by halogen, CF3, 1-8C alkyloxy or 1-4C alkyl;
A is a single bond, COn, SOn or CONH;
n is 1 oder2:
R7 is H; 1-18C alkyl or 2-18G aikenyl, which may up to three
times substituted
by 1-4C alkyl, halogen, CF3, 1-4C alkyloxy, N(1-4C alkyl)2,
-COOH, 1-4C
alkyloxycarbonyl, 6-12C aryl, 6-12C aryloxy, 6-12C arylcarbonyl,
6-10-aryl-
1-4C-alkyloxy or oxo, wherein aryl itself may be optionally
substituted by
halogen, 1-4C alkyl, aminosulfonyl or methylmercapto;
6-10C-aryl-1-4C-alkyl, 5-8C-cycloalkyl-1-4C-alkyl, 5-8C
cycloalkyl, 6-10-
aryl-2-6C-alkenyl, 6-10C aryl, biphenylyl, diphenyl-(1-4
alkyl), indanyl,
which may be optionally substituted by 1-18C alkyl, 1-18C
alkyloxy, 3-8C
cycloalkyl, COOH, hydroxy, 1-4C alkylcarbonyl, 6-10C-aryl-1-4C
alkyl, 6-
10C-aryl-1-4C-alkyloxy, 6-10C aryloxy, nitro, cyano, 6-10C
aryl,
fluorsulfonyl, 1-6C alkyloxycarbonyl, 6-10 arylsulfonyloxy,
pyridyl, NHS02-
(6-10 aryl), halogen, CF3 or OCF3, wherein alkyl may be
additionally
substituted by 1-4C alkyloxycarbonyl, CF3 or carboxy and
aryl by halogen,
CF3 or 1-4C alkyloxy;
or the group Het-(CH2)r- with r = 0, 1, 2 or 3 and Het =
saturated or
unsaturated 5-7-membered heterocyclus, which may be optionally
benzo
anellated and substituted by 1-4C alkyl, 6-10C aryl, halogen,
1-4C
alkyloxy, 1-4C alkyloxycarbonyl, 6-10C-aryl-1-4Calkyl, 6-10C-aryl-1-4C-
alkylmercapto or nitro, wherein benzo anellated aryl may
be substituted by
halogen, 1-4C alkyloxy or GF3 and alkyl in arylalkyl may
be substituted by
methoxy and CF3.
The lipase inhibiting compounds of formula (A) are described in more detail in
the
WO 03/072098 and can be obtained according to known methods. A suitable
synthesis for the lipase inhibiting compounds of formula (A) is described also
in
the international patent application WO 03/072098. The whole content of the
international patent application WO 03/072098 is incorporated by reference
into
the present application regarding the disclosure of lipase inhibitors of
formula (A).
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WO 2005/039579 PCT/EP2004/052643
13
In addition, in the US patent US 6,624,161 and its corresponding international
patent application WO 00/040569 and WO 00/40247 further lipase inhibiting
compounds are described which are also suitable in the context of the present
invention for combination with CB1 antagonistic compounds described herein.
These patent documents US 6,624,161 and WO 00/040569 describe a series of
compounds which are 2-oxy-4H-3,1-benzoxazin-4-one derivatives, including ATL-
962, and their use in obesity and obesity-related disorders, including type 2
diabetes. The 2-oxy-4H-3,1-benzoxazin-4-one derivatives have the formula (B)
or
are or a pharmaceutically acceptable salt, ester, amide or prodrug thereof:
R9a ~ O
/R,a (B)
R~oa ~ ~ N O
R~~a
wherein:
R1 a is
(i) a C10-30 branched or unbranched alkyl , optionally substituted by one or
more independently of C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl,
heteroaryl, reduced heteroaryl, --C(O)R13, --C02R13, --SOR13, --
S02R13, --NR13R14, --OR13,
--SR13, --C(O)NR13R14, --NR14C(O)R13, halogen, cyano, and vitro
and/or optionally interrupted by one or more oxygen atoms with the
proviso that any hetero atom in R1 a must be separated from the
exocyclic oxygen atom (or from any other heteroatom) by at least two
carbon atoms;
(ii) C2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl,
heteroaryl-C2-25 alkenyl, reduced heteroaryl, reduced heteroaryl-C1-25
alkyl or a substituted derivative of any of the foregoing groups wherein
the substituents are one or more independently of C1-6 alkyl,
halosubstituted C1-6 alkyl, aryl, aryl-C1-6 alkyl, heteroaryl, reduced
heteroaryl, reduced heteroaryl-C1-6 alkyl, C1-6 alkoxy, aryl-C1-6 alkoxy, -
-C(O)R13, --C02R13, --SOR13, --S02R13, --NR13R14, --OR13, --SR13,
--C(O)NR13R14, --NR14C(O)R13, halogen, cyano, and vitro, with the
proviso that any hetero atom in R1 a must be separated from the
exocyclic oxygen atom (or from any other heteroatom) by at least two
carbon atoms;
(iii) a C2-9 alkyl group interrupted by one or more oxygen atoms and
optionally substituted by one or more independently of C3-6 cycioalkyl,
C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, --C(O)R13, --
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14
C02R13, -SOR13, -S02R13, NR13R14, OR13, SR13, -C(O)NR13R14,
-NR14C(O)R13, halogen, cyano and nitro with the proviso that any
hetero atom in R1 a must be separated from the exocyclic oxygen atom
(or from any other heteroatom) by at least two carbon atoms; or
(iv) a C1-9 alkyl group substituted by a group selected from --C(O)R13, -
C02R13, SOR13, S02R13, NR13R14, OR13, SR13, C(O)NR13R14,
NR14C(O)R13; tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, halogen,
cyano, nitro, bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic
reduced heteroaryl, monocyclic heteroaryl other than imidazolyl;
(v) a phenyl group substituted by a group selected from OR17, --COR13, --
C02R13, SORB, S02R13, CONR13R14, NR14C(O)R13 ;
halosubstituted C1-6 alkyl, aryl, arylC1-6 alkyl, heteroaryl and
heteroarylC1-6 alkyl; or
(vi) a bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced
heteroaryl, or monocyciic heteroaryi group other than imidazoiyl,
optionally substituted by a group selected from OR17, --COR13, --
C02R13, SOR13, S02R13, CONR13R14,
NR14 C(O)R13; halosubstituted C1-6 alkyl, aryl, arylC1-6 alkyl, heteroaryl
and heteroarylC1-6 alkyl;
where R13 and R14 each independently represents hydrogen, C1-10
alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C3-6
cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl,
reduced heteroaryl or reduced heteroaryl,
C1-10 alkyl, and R17 represents hydrogen or C2-10 alkenyl, C2-10
alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, arylC1-10 alkyl,
heteroaryl, heteroarylC1-10 alkyl, reduced heteroaryl or reduced
heteroarylC1-10 alkyl
and RBa, R9a, R10a and R11a
are each independently hydrogen, halo, hydroxy, amino, nitro, cyano, thiol, C1-
10
alkyl,
C1-10 alkoxy, C1-10 cycloalkyl, C1-10 cycloalkoxy, C(O)R15, C(O)NR15R16,
S(O)R15 or haloC1-10 alkyl;
where R15 and R16 each independently represent hydrogen or C1-10 alkyl with
the proviso that when R8a, R9a, R1 Oa, and R11 a are H, R1 a is not CH2CH2CI
or
C3 alkenyl.
Furthermore in the international patent application WO 00/40247 reiated 2-
amino-4H-3,1-benzoxazin-4-one derivatives are described as lipase inhibiting
compounds for the treatment of obesity. In formula (B) then the -OR1a
substituent is replaced by a -NR1R2 group with the definitions for R1 and R2
as
given in the WO 00140247.
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WO 2005/039579 PCT/EP2004/052643
The above group of structurally related compounds include ATL-962, an oral non-
absorbed synthetic lipase inhibitor derived from Alizyme's pancreatic lipase
inhibitor research program, is under development for the potential treatment
of
obesity and the potential management of type 2 diabetes. ATL-962 has the
5 chemical name 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one. Preclinical
studies showed that ATL-962 had similar efficacy to orlistat and no toxicity
was
observed. Clinical data for these compounds is also available in the public
domain, e.g. resulting from clinical studies with ATL-962 in obesity.
10 Thus, the results from a phase Ib program with ATL-962 were presented at
the
International Congress of Obesity in Sao Paulo, Brazil. The three phase Ib
trials
involved a total of 99 healthy male volunteers in groups of seven or nine,
given
one of several doses of ATL-962 (66 subjects) or placebo (24 subjects), tid
with
food for 5 days. In one group the nine subjects were given orlistat (qv) 120
mg
15 tid. Overall, ATL-962 was safe and well toierated and showed evidence of
efficacy as indicated by an increase in excretion of fat from the diet.
Subjects
given doses between 50 mg and 300 mg ATL-962 bid with meals excreted fat at
an average of between 4.9 (+/-4.3) and 11.2 (+/-6.9) g/day compared to 1.4 (+/-
1.0) glday on placebo and 5.6 (+/-3.8) g/day on orlistat. Compared to placebo,
55% of subjects who received ATL-962 (50 mg to 300 mg) demonstrated a 3-fold.
or greater increase in fat excretion and 27% of subjects demonstrated a 7-fold
or
greater increase. There was evidence of dose-dependency. Adverse events and
their frequency were similar between ATL-962 and placebo and were mainly
gastrointestinal, with the predominant event being oily stool.
The results of a multicenter, randomized, double-blind, parallel-group trial
(phase
Ilb study), involving 370 clinically obese patients, was being performed in
specialist clinics in 5 European countries, and in September 2003 preliminary
results were reported. All dose levels of ATL-962 (60, 120 and 240 mg)
demonstrated a significant reduction in weight, compared to placebo, for all
treatment groups. There was no difference in the extent of weight loss between
treatment groups. LDL-cholesterol decreased in the treatment groups, but not
for
placebo. There was no difference in HDL-cholesterol levels in the treatment
groups, whilst it increased in placebo-treated patients. Total cholesterol
decreased in the treatment groups, whilst placebo showed an increase. ATL-962
was safe and generally well tolerated.
The lipase inhibiting compounds of formula (B) like ATL-962 and structuraliy
related compounds are described in more detail in the US patent US 6,624,161
and its corresponding international'patent application WO 00/040569, and can
be
obtained according to known methods. A suitable synthesis for the lipase
inhibiting compounds of formula (B) is described also in the US 6,624,161 and
international patent application WO 00/040569. The whole content of the US
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WO 2005/039579 PCT/EP2004/052643
16
6,624,161 and international patent application WO 00/040569 is incorporated by
reference into the present application regarding the disclosure of lipase
inhibitors
of formula (B). The whole content of the international patent application WO
00/040247 is also incorporated by reference into the present application
regarding the disclosure of lipase inhibitors described therein, with related
2-
amino-4H-3,1-benzoxazin-4-one compound structure.
The whole content of the literature mentioned in the description of the
present
invention is incorporated by reference into the present application regarding
the
disclosure of the CBS antagonistic compounds as well as the lipase inhibitors
used according to the present invention in combination.
Pharmaceutically acceptable salts, hydrates and solvates, and prodrugs of all
the
above described lipase inhibiting compounds may also be used in the context of
the present invention.
The CBS antagonistic compound indicated above, which is a potent and selective
antagonist of the cannabis CBS-receptor, or a prodrug, tautomer or salt
thereof,
and the lipase inhibiting compound used according to the invention can be
brought into forms suitable for treatment and/or prophylaxis of obesity, e.g.
for
adolescent or pediatric administration, as well as for the administration in
treating
drug induced obesity by means of usual processes using pharmaceutical
excipients, auxiliary substances and/or liquid or solid carrier materials. As
therapeutic agents, the selective CBS antagonistic compound and/or the lipase
inhibiting compounds may be contained together with (conventional)
pharmaceutical excipients, adjuvants and/or auxiliaries in pharmaceutical
preparations such as tablets, capsules, suppositories or solutions. These
pharmaceutical preparations may be prepared according to known methods,
using conventional solid or liquid vehicles such as lactose, starch or talc,
or liquid
paraffins andlor using (conventional) pharmaceutical excipients, adjuvants
and/or
auxiliaries, such as tablet disintegrating agents, solubilisers or
preservatives.
Hence, in a further aspect the invention also pertains to a pharmaceutical
composition containing at least one selective CBS antagonistic compound as
indicated above, or a prodrug, tautomer or salt thereof, in combination with
at
least one lipase inhibiting compound. A preferred pharmaceutical composition
according to the invention contains as active components at least one CBS
antagonistic compound, preferably the CBS antagonistic as defined above, or a
prodrug, tautomer or salt thereof, and at least one lipase inhibiting compound
for
the treatment and/or prophylaxis of obesity in adolescent or in juvenile
patients
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17
and/or for the treatment and/or prophylaxis of drug induced obesity in
juvenile as
well as adolescent patients. Particular pharmaceutical compositions according
to
the invention, are characterized in that the at least one CBS antagonistic
compound as defined above, or the prodrug, tautomer or salt thereof, and the
at
least one lipase inhibiting compound each are present in an amount effectively
suited for the treatment and/or prophylaxis of obesity in a juvenile patient
in need
of such treating. in a further embodiment of the invention said antagonistic
compound and the lipase inhibiting compound are each present in the
pharmaceutical composition in an amount effectively suited for the treatment
and/or prophylaxis of drug induced obesity in juvenile as well as adolescent
patients in need of such treating. In the pharmaceutical compositions
according
to the invention the above defined selective CBS antagonistic compound, or the
prodrug, tautomer or salt thereof, is used preferably in combination with at
least
one lipase inhibiting compound selected from the group of lipase inhibiting
polymers, orlistat, panclicins, ATL-962 and lipstatin.
The invention also pertains to a pharmaceutical product containing as a
medicament a CBS antagonistic compound as defined above, or a prodrug,
tautomer or salt thereof, and a leafilet indicating that said CBS antagonistic
compound may be administered in combination with a lipase inhibiting compound
for simultaneous, separate or step-wise administration in the treatment and/or
prophylaxis of obesity.
Finally the invention also includes a method of treatment and/or prophylaxis
of
obesity, e.g. in adolescent or in juvenile patients and/or for the treatment
and/or
prophylaxis of drug induced obesity in juvenile as well as adolescent
patients,
characterized in that a CBS antagonistic compound as defined above, which is a
potent and selective antagonist of the cannabis CBS-receptor, or a prodrug,
tautomer or salt thereof, is administered in combination with at least one
lipase
inhibiting compound to a patient in need of such treating. The method of
treatment and/or prophyiaxis of obesity according to the present invention may
be directed to obesity in adolescent or in juvenile patients and/or to drug
induced
obesity in juvenile as well as adolescent patients. In a variant of the
invention the
method of treatment and/or prophylaxis is characterized in that the treating
is
directed to obesity in juvenile patients. In a further variant of the
invention the
method of treatment and/or prophylaxis is characterized in that the treating
is
directed to drug induced obesity in juvenile or adolescent patients. In the
method
of treatment and/or prophylaxis according to the invention the selective CBS
antagonistic compound as defined above, or a prodrug, tautomer or salt
thereof,
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WO 2005/039579 PCT/EP2004/052643
18
is administered preferably in combination with at least one lipase inhibiting
compound selected from the group of lipase inhibiting polymers, orlistat,
panclicins, ATL-962 and lipstatin.
According to the invention the above defined selective CBS antagonistic
compound, or a prodrug, tautomer or salt thereof, is administered in
combination
with the lipase inhibiting compound by simultaneous, separate or step-wise
administration route.
The compounds used in the combinations or compositions according to the
present invention each are preferably administered to a patient in need
thereof
and in a quantity sufficient to prevent and/or treat the symptoms of the
condition,
disorder or disease, e.g. obesity. For all aspects of the invention,
particularly
medical ones, the administration of a compound or composition has a dosage
regime which will ultimately be determined by the attending physician and will
take into consideration such factors such as the compound being used, animal
type, age, weight, severity of symptoms, method of administration, adverse
reactions and/or other contraindications. Specific defined dosage ranges can
be
determined by standard design clinical trials with patient progress and
recovery
being fully monitored. Such trials may use an escalating dose design using a
low
percentage of the maximum tolerated dose in animals as the starting dose in
man.
The physiologically acceptable compounds used in the combinations or
compositions according to the present invention each are will normally be
administered in a daily dosage regimen (for an adult patient) of, for example,
an
oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000
mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or
intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg
and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a
physiologically acceptable salt thereof calculated as the free base, the
compound
being administered 1 to 4 times per day. Suitably the compounds will be
administered for a period of continuous therapy, for example for a week or
more.
For a juvenile patient usually a part of the oral dose for an adult patient is
administered, e.g. 1 fifth to 1 half of the oral dose described before for an
adult
patient.
Preferably, in one embodiment of the invention the method of treatment and/or
prophylaxis is directed to the treating of obesity in juvenile patients. In
another
preferred embodiment of the invention the method of treatment andlor
prophylaxis is directed to the treating of drug induced obesity in juvenile or
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19
adolescent patients. This drug induced obesity may be in particular caused by
drugs like atypical antipsychotics.
In one embodiment of the invention the method of treatment and/or prophylaxis
is
directed to the treating of obesity in juvenile patients. Thus, it is
advantageous
that Cannabinoid antagonists are suitable for the treatment of Childhood
Obesity
and related Comorbidities as for example Type 2 Diabetes. There is a clear
medical need for improved therapy as obesity has become an increasingly
important medical problem not only in the adult population but increasingly in
children and (young and older) adolescents. In national surveys from the 1960s
to the 1990s in the United States, the prevalence of overweight in children
grew
from 5% to 11 % (Sorof and Daniels 2002). In Canada as another example
childhood obesity has tripled in the past 20 years (Spurgeon 2002). Obesity in
childhood causes a wide range of serious complications, and increases the risk
of
premature illness and death later in life, raising public-health concerns
(Ebbeling,
Pawlak et al. 2002). Over the last decades a tremendous increase of cases of
type 2 diabetes was observed, especially also in children. This epidemic trend
is
clearly reflecting the increasing rates of obesity. Type-2-diabetes was in the
past
considered a disease of adults and older individuals, not a pediatric
condition
(Arslanian 2002). One of the main risk factor of pediatric type 2 diabetes is
obesity.
Type 2 diabetes in children (as is in adults) is part of the insulin
resistance
syndrome (Rosenbloom 2002) that includes hypertension, dyslipidemia and other
atherosclerosis risk factors, and hyperandrogenism seen as premature
adrenarche and polycystic ovary syndrome. Other outcomes related to childhood
obesity include left ventricular hypertrophy, nonalcoholic steatohepatitis,
obstructive sleep apnea, orthopedic problems, and severe psychosocial
problems. .
In addition primary hypertension has become increasingly common in children
again associated obesity as a major independent risk factor. Obese children
are
at approximately a 3-fold higher risk for hypertension than non-obese children
(Sorof and Daniels 2002). The benefits of weight loss for blood pressure
reduction in children have been demonstrated in both observational and
interventional studies.
Public concerns are rising because of a rapid development of the childhood
obesity epidemic in genetically stable populations. Driving factors are
assumed to
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WO 2005/039579 PCT/EP2004/052643
be mainly adverse environmental factors for which straightforward
recommendations of life style modifications exists. Obesity and it's related
co-
morbidities are very serious medical conditions and state of the art measures
and
treatment of obesity and especially childhood obesity remain largely
ineffective at
5 the time being (Ebbeling, Pawlak et al. 2002). The management of type 2
diabetes in is also especially difficult in children and the adolescent age
group
(Silink 2002). Craving for and over consumption of palatable food is one of
the
important factors of life-style related obesity in humans and especially also
in
children and adolescents, Treatment of type 2 diabetes and other co-morbid
10 conditions by the degree of metabolic derangement and symptoms: The only
data on the use of oral hypoglycemic agents in children with type 2 diabetes
has
been with metformin (Rosenbloom 2002).
Thus, CBS antagonists used according to the present invention in combination
15 with lipase inhibitors offer a unique opportunity for the treatment of
obesity by
interacting with these "driving forces". They are superior to current medical
treatments and especially suited for adolescent as well as for pediatric
treatment
because of their outstanding safety profile and/or tolerability and
surprisingly
beneficial combination effects. Besides efficacy, the treatment of obesity,
20 especially the treatment of childhood obesity, dictated by safety.
Obesity in childhood is a medical condition that is likely to require long-
term
management. The safety profile of CBS antagonists used according to the
present invention in combination with lipase inhibitors are suggested to be
superior to current standard medications, and these CBS antagonists in
combination with lipase inhibitors will be especially suited for the treatment
and
prevention of obesity in adolescents and childhood obesity and related co-
morbidities.
Literature:
Arslanian, S. (2002). "Type 2 diabetes in children: clinical aspects and risk
factors." Horm Res 57 Suppl 1: 19-28.
Ebbeling, C. B., D. B. Pawlak, et al. (2002). "Childhood obesity: public-
health
crisis, common sense cure." Lancet 360(9331): 473-82.
Rosenbloom, A. L. (2002). "Increasing incidence of type 2 diabetes in children
and adolescents: treatment considerations." Paediatr Druas 4(4): 209-21.
Silink, M. (2002). "Childhood diabetes: a global perspective." Horm Res 57
Suppl
1: 1-5.
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WO 2005/039579 PCT/EP2004/052643
21
Sorof, J. and S. Daniels (2002). "Obesity hypertension in children: a problem
of
epidemic proportions." Hypertension 40(4): 441-7.
Spurgeon, D. (2002). "Childhood obesity in Canada has tripled in past 20
years."
Bm~ 324(7351 ): 1416.
In another embodiment of the invention the method of treatment and/or
prophylaxis is directed to the treating of drug induced obesity in juvenile or
adolescent patients. Drug induced weight gain is also of major concern and
subject to high medical need of improved treatments. Again, in this context
the
CBS antagonists according to the present invention are suggested to be
superior
to current standard medications, and these CBS antagonists will be especially
suited for the treatment and prevention of drug induced obesity in juvenile as
well
as in adolescent patients.
Regarding drug induced weight gain, it is reported by ~immermann, U., T.
Kraus,
et al. (2003, "Epidemiology, impiications and mechanisms underlying drug-
induced weight gain in psychiatric patients." J Psychiatr Res 37(3): 193-220)
that
body weight gain frequently occurs during drug treatment of psychiatric
disorders
and is often accompanied by increased appetite or food craving. While
occurrence and time course of this side effect are difficult to predict, it
ultimately
results in obesity and the morbidity associated therewith in a substantial
part of
patients, often causing them to discontinue treatment even if it is effective.
Weight gain appears to be most prominent in patients treated with some of the
second generation antipsychotic drugs and with some mood stabilizers. Marked
weight gain also frequently occurs during treatment with most tricyclic
antidepressants.
Very large weight gains are associated with drugs like for example the
atypical
antipsychotics clozapine and olanzapine. Some atypical antipsychotics,
however,
tend to cause significant weight gain, which may lead to poor compliance and
other adverse health effects (Nasrallah, H. (2003). "A review of the effect of
atypical antipsychotics on weight." Psychoneuroendocrinology 28 Suppl 1: 83-
96.). The mechanisms invaived in antipsychotic drug-re4ated weight gain are as
yet uncertain, although serotoninergic, histaminic, and adrenergic affinities
have
been implicated along with other metabolic mechanisms. The atypical
antipsychotics vary in their propensity to cause weight change with long-term
treatment. Follow-up studies show that the largest weight gains are associated
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22
with clozapine and olanzapine, and the smallest with quetiapine and
ziprasidone.
Risperidone is associated with modest weight changes that are not dose
related.
Given the equivalent efficacy of atypical antipsychotics, weight-gain profile
is a
legitimate factor to consider when constructing an algorithm for treatment due
to
the serious medical consequences of obesity. In this regard co-administration
of
a CBS antagonist as defined above in combination with lipase inhibitors
according
to the invention is suggested to work beneficiafiy.
Experimental protocol for study of
CBS antagonistic compound plus lipase inhibitor effects on obesity
The beneficial pharmacological effects of the combination of a CBS antagonist
with a lipase inhibitor according to the invention can be shown by standard
experimental animal models by measuring the influence of the administered
combination of a CBS antagonist with a lipase inhibitor on the driving and
characteristic parameters associated with obesity.
For investigation of the influence of the combination of a CBS antagonist with
a
lipase inhibitor on obesity the body weight gain in rats may be measured as a
pharmacological indicator. Here fore, the following experimental protocol for
rats
may be applied:
The rats will have unlimited access to feed for two 2.5h periods per day,
during
the dark phase of a reversed 12h/12h light cycle, e.g. lights are put on at
21.15h
and put off at 09.15h. The rats will be offered a high fat, high sucrose diet
(Western diet). The lipase inhibitor will be dosed immediately before the rats
are
fed. The CBS antagonist will be dosed 1 h before the lipase inhibitor is
administered.
As an example, the following daily dosing schedule is applicable for a given
period of e.g. days, weeks or months:
The CBS antagonist, in particular the CBS antagonisic compound of formula (I)
as
defined above, or a vehicle dose is administered (po) in the morning at ca.
07.45
to 08.00 h. The lipase inhibitor, e.g. in particular orlistat, or a vehicle
dose is
administered (po) ca. 08.45 to 09.00 h. After medication the rats are set to
ad-
libitum feed from 09.15 to 11.45h, followed by feed removal from about 11.45
to
CA 02543197 2006-04-20
WO 2005/039579 PCT/EP2004/052643
23
14.45 h. Another dose of lipase inhibitor, e.g. in particular orlistat, or
vehicle
(Labrasol) dose is administered (po) in the afternoon at about 14.15 to
14.30h,
followed by ad-libitum feed from 14.45 to 17.15 h. Thereafter, the rats are
set to
feed deprivation from 17.15 - 09.15 h.
The experimental protocol results will compare daily food intake and body
weight
gain as indicators for the effects of the combination treatment on obesity
during
the experimental phase. In addition to the before given parameters it may be
desired to also collect faeces and to estimate fat digestibility. Eventually
it may be
also desired to perform a carcass analysis.
Furthermore, after finishing the experimental feeding and administering phase,
biochemical parameters may be measured at slaughter of the rats.
For investigating the effects the total number of rats subject to the
experimental
protocol is divided into the following groups with approximately the same
number
of rats in each group:
1 ) Control group: The rats receive only vehicle according to the protocol to
simulate administration (placebo group).
,20 2) CBS group: The rats receive a CBS antagonist in a vehicle.
3) LI group: The rats receive as lipase inhibitor ("LI") e.g. the compound
orlistat in a vehicle.
4) CBS+LI group (combination group): The rats receive a CBS antagonist in a
vehicle and as lipase inhibitor ("LI") e.g. the compound orlistat in a
vehicle.
The results of this protocol and the respective investigations show the
beneficial
suitability of the combination of a CBS antagonist as defined above and a
lipase
inhibitor in the treatment and / or prophylaxis of obesity.
