U.S. patent application number 10/225841 was filed with the patent office on 2003-08-21 for combination product of a 1,4-benzothiepine 1,1-dioxide compound with at least on.
Invention is credited to Frick, Wendelin, Glombik, Heiner, Kramer, Werner, Schafer, Hans-Ludwig.
Application Number | 20030158119 10/225841 |
Document ID | / |
Family ID | 26009944 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030158119 |
Kind Code |
A1 |
Glombik, Heiner ; et
al. |
August 21, 2003 |
Combination product of a 1,4-benzothiepine 1,1-dioxide compound
with at least on
Abstract
The present invention is directed to a 1,4-benzothiepine
1,1-dioxide compound of formula I 1 in which the radicals have the
meanings defined herein, or a pharmaceutically acceptable salt or
physiologically functional derivative thereof, with at least one
other active ingredient, or a pharmaceutically acceptable salt or
physiologically functional derivative thereof. The invention is
also directed to the use of the combination product, pharmaceutical
composition comprising the combination product and method for
preparing the pharmaceutical composition.
Inventors: |
Glombik, Heiner; (Hofheim,
DE) ; Frick, Wendelin; (Hunstetten-Beuerbach, DE)
; Schafer, Hans-Ludwig; (Hochheim, DE) ; Kramer,
Werner; (Mainz-Laubenheim, DE) |
Correspondence
Address: |
ROSS J. OEHLER
AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Family ID: |
26009944 |
Appl. No.: |
10/225841 |
Filed: |
August 22, 2002 |
Current U.S.
Class: |
514/5.9 ;
514/10.7; 514/11.2; 514/11.3; 514/12.6; 514/17.4; 514/19.7;
514/397; 514/414; 514/42; 514/422; 514/431; 514/5.2; 514/5.8;
514/6.9; 514/7.4; 530/330; 530/331; 536/18.7; 548/311.4; 548/454;
548/525; 549/12 |
Current CPC
Class: |
A61P 3/06 20180101; A61P
3/04 20180101; A61K 45/06 20130101; A61P 43/00 20180101; A61K 31/55
20130101; A61P 9/10 20180101; A61K 31/395 20130101; A61K 31/395
20130101; A61K 2300/00 20130101; A61K 31/55 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/18 ; 514/19;
514/42; 514/397; 514/414; 514/431; 530/331; 536/18.7; 548/311.4;
548/454; 548/525; 549/12; 530/330; 514/422 |
International
Class: |
A61K 038/06; A61K
038/05; A61K 038/04; A61K 031/7052; A61K 031/4178; A61K 031/405;
A61K 031/401; A61K 031/38; C07K 005/04; C07K 005/06; C07D
49/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 22, 2001 |
DE |
10140169.8 |
Aug 31, 2001 |
DE |
10142456.6 |
Claims
We claim:
1. A composition of matter comprising a compound of formula I 18in
which R.sup.1 is methyl, ethyl, propyl, or butyl; R.sup.2 is H,
--OH, --NH.sub.2, or --NH--(C.sub.1-C.sub.6)-alkyl; R.sup.3 is a
saccharide residue, disaccharide residue, trisaccharide residue, or
tetrasaccharide residue, wherein the saccharide residue,
disaccharide residue, trisaccharide residue or tetrasaccharide
residue is optionally substituted one or more times by a saccharide
protective group; or amino acid residue, diamino acid residue,
triamino acid residue, or tetraamino acid residue, wherein the
amino acid residue, diamino acid residue, triamino acid residue or
tetraamino acid residue is optionally substituted one or more times
by an amino acid protective group; R.sup.4 is methyl, ethyl,
propyl, or butyl; R.sup.5 is methyl, ethyl, propyl, or butyl; Z is
--(C.dbd.O).sub.n--C.sub.0-C.sub.16-alkyl-,
--(C.dbd.O).sub.n--C.sub.0-C.sub.16-alkyl-NH--,
--(C.dbd.O).sub.n--C.sub.- 0-C.sub.16-alkyl-O--,
--(C.dbd.O).sub.n--C.sub.1-C.sub.16-alkyl-(C.dbd.O).- sub.m--, or a
covalent bond; n is 0 or 1; and m is 0 or 1; or a pharmaceutically
acceptable salt or physiologically functional derivative thereof,
with at least one other active ingredient, or a pharmaceutically
acceptable salt or physiologically functional derivative
thereof.
2. The composition of matter according to claim 1, wherein R.sup.1
ethyl, propyl, or butyl; and R.sup.3 is a saccharide residue, or
disaccharide residue, wherein the saccharide residue or
disaccharide residue is optionally substituted one or more times by
a saccharide protective group; or amino acid residue, or diamino
acid residue, wherein the amino acid residue or diamino acid
residue is optionally substituted one or more times by an amino
acid protective group; or a pharmaceutically acceptable acid
addition salt thereof.
3. The composition of matter according to claim 1, wherein R.sup.1
ethyl; R.sup.2 OH; R.sup.3 is a saccharide residue, wherein the
saccharide residue is optionally substituted one or more times by a
saccharide protective group; diamino acid residue, wherein the
diamino acid residue is optionally substituted one or more times by
an amino acid protective group; R.sup.4 methyl; R.sup.5 methyl; and
Z --(C.dbd.O)--C.sub.0-C.sub.4- -alkyl, a covalent bond; or a
pharmaceutically acceptable acid addition salt thereof.
4. The composition of matter according to one of claims 1 to 3,
wherein the other active ingredient is an antidiabetic,
hypoglycemic active ingredient, HMG-CoA reductase inhibitor,
cholesterol absorption inhibitor, PPAR gamma agonist, PPAR alpha
agonist, PPAR alpha/gamma agonist, fibrate, MTP inhibitor, bile
acid absorption inhibitor, CETP inhibitor, polymeric bile acid
adsorbent, LDL receptor inducer, ACAT inhibitor, antioxidant,
lipoprotein lipase inhibitor, ATP-citrate lyase inhibitor, squalene
synthetase inhibitor, lipoprotein(a) antagonist, lipase inhibitor,
insulin, sulfonylurea, biguanide, meglitinide, thiazolidinedione,
(x-glucosidase inhibitor, active ingredient acting on the
ATP-dependent potassium channel of the beta cells, CART agonist,
NPY agonist, MC4 agonist, orexin agonist, H3 agonist, TNF agonist,
CRF agonist, CRF BP antagonist, urocortin agonist, .beta.3 agonist,
MSH (melanocyte-stimulating hormone) agonist, CCK agonist,
serotonin reuptake inhibitor, mixed serotoninergic and
noradrenergic compound, 5HT agonist, bombesin agonist, galanin
antagonist, growth hormone, growth hormone-releasing compound, TRH
agonist, uncoupling protein 2 or 3 modulator, leptin agonist, DA
agonist, lipase/amylase inhibitor, PPAR modulator, RXR modulator,
TR-.beta. agonist or amphetamine.
5. The composition of matter according to one of claims 1 to 3,
wherein the other active ingredient is a compound that normalizes
lipid metabolism.
6. The-composition of matter according to one of claims 1 to 3,
wherein the other active ingredient is a compound that normalizes
lipid metabolism selected from the group consisting of statins,
glitazones, PPAR alpha agonists, cholestyramine, colestipol,
colesevelam, adsorbent resins, fibrates, gemfibrozil, cholesterol
absorption inhibitors, ezetimibe, tiqueside, pamaqueside, CETP
inhibitors, MTP inhibitors, LDL receptor inducers, lipase
inhibitors, and orlistat.
7. The composition of matter according to one of claims 1 to 3,
wherein the other active ingredient is a cholesterol absorption
inhibitor.
8. The composition of matter according to claim 7, wherein the
cholesterol absorption inhibitor is ezetimibe, tiqueside or
pamaqueside.
9. The composition of matter according to one of claims 1 to 3,
comprising Caromax.RTM. as other active ingredient.
10. A method for effecting the prophylaxis or treatment of a lipid
metabolism disorder or metabolic syndrome in a patient comprising
administering a pharmaceutically effective amount of the
composition of matter according to one of claims 1 to 3 to the
patient.
11. The method of claim 10 wherein the pharmaceutically effective
amount of the composition of matter is provided for by the
combination of a pharmaceutically effective amount or a subclinical
pharmaceutically effective amount of the compound of formula I and
a pharmaceutically effective amount or a subclinical
pharmaceutically effective amount of the other active ingredient of
the composition of matter, such that the combination results in the
amount of the composition of matter being pharmaceutically
effective.
12. A method for effecting the prophylaxis or treatment of
hyperlipidemia in a patient comprising administering a
pharmaceutically effective amount of the composition of matter
according to one of claims 1 to 3 to the patient.
13. The method of claim 12 wherein the pharmaceutically effective
amount of the composition of matter is provided for by the
combination of a pharmaceutically effective amount or a subclinical
pharmaceutically effective amount of the compound of formula I and
a pharmaceutically effective amount or a subclinical
pharmaceutically effective amount of the other active ingredient of
the composition of matter, such that the combination results in the
amount of the composition of matter being pharmaceutically
effective.
14. A method for effecting the prophylaxis or treatment of
arteriosclerotic manifestations in a patient comprising
administering a pharmaceutically effective amount of the
composition of matter according to one of claims 1 to 3 to the
patient.
15. The method of claim 14 wherein the pharmaceutically effective
amount of the composition of matter is provided for by the
combination of a pharmaceutically effective amount or a subclinical
pharmaceutically effective amount of the compound of formula I and
a pharmaceutically effective amount or a subclinical
pharmaceutically effective amount of the other active ingredient of
the composition of matter, such that the combination results in the
amount of the composition of matter being pharmaceutically
effective.
16. A method for effecting the prophylaxis or treatment of a
physiological condition as described herein in a patient comprising
administering a pharmaceutically effective amount of the
composition of matter according to one of claims 1 to 3 to the
patient whereby the administering is effected by administering the
compound of formula I and the other active ingredient of the
composition of matter closely in time.
17. The method of claim 16 wherein closely in time means within 10
minutes.
18. A method for effecting the prophylaxis or treatment of a lipid
metabolism disorder in a patient comprising administering a
pharmaceutically effective amount of the composition of matter
according to one of claims 1 to 3 to the patient whereby the
administering is effected by administering the compound of formula
I and the other active ingredient of the composition of matter
closely in time.
19. The method of claim 18 wherein closely in time means within 10
minutes.
20. A pharmaceutical composition comprising, a pharmaceutically
acceptable carrier, and a pharmaceutically effective amount or a
subclinical pharmaceutically effective amount of the compound of
formula I according to one of claims 1 to 3 and a pharmaceutically
effective amount or a subclinical pharmaceutically effective amount
of the other active ingredient of the composition of matter, such
that the combination results in the amount of the composition of
matter being pharmaceutically effective.
21. A process for producing a pharmaceutical composition of the
composition of matter as claimed in one of claims 1 to 3,
comprising mixing the compound of formula I and the other active
ingredient of the composition of matter with a pharmaceutically
suitable carrier and converting this mixture into a form suitable
for administration.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a combination product of a
1,4-benzothiepine 1,1-dioxide compound of formula I, with at least
one other active ingredient
BACKGROUND OF THE INVENTION
[0002] 1,4-Benzothiepine 1,1-dioxide compounds and the use thereof
for the treatment of hyperlipidemia and of arteriosclerosis and
hypercholesterolemia have been described in U.S. Pat. No.
6,221,897].
[0003] Antidiabetics are described in the Rote Liste 2001, chapter
12. More specifically, the antidiabetics include insulin and
insulin derivatives such as, for example, Lantus.RTM. (see
www.lantus.com) or fast-acting insulins (see U.S. Pat. No.
6,221,633), GLP-1 derivatives such as, for example, those disclosed
in WO 98/08871, and orally active hypoglycemic active ingredients.
The orally active hypoglycemic active ingredients include,
preferably, sulfonylureas, biguanides, meglitinides,
oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,
glucagon antagonists, GLP-1-agonists, potassium channel openers
such as, for example, those disclosed in WO 97/26265 and WO
99/03861, insulin sensitizers, inhibitors of liver enzymes involved
in the stimulation of gluconeogenesis and/or glycogenolysis,
modulators of glucose uptake, compounds which alter lipid
metabolism, such as antihyperlipidemic active ingredients and
antilipidemic active ingredients, compounds which reduce food
intake, PPAR and RXR agonists and active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
SUMMARY OF THE INVENTION
[0004] The present invention is directed to a 1,4-benzothiepine
1,1-dioxide compound of formula I 2
[0005] in which
[0006] R.sup.1 is methyl, ethyl, propyl, or butyl;
[0007] R.sup.2 is H, --OH, --NH.sub.2, or
--NH--(C.sub.1-C.sub.6)-alkyl;
[0008] R.sup.3 is a saccharide residue, disaccharide residue,
trisaccharide residue, or tetrasaccharide residue, wherein the
saccharide residue, disaccharide residue, trisaccharide residue or
tetrasaccharide residue is optionally substituted one or more times
by a saccharide protective group; or
[0009] amino acid residue, diamino acid residue, triamino acid
residue, or tetraamino acid residue, wherein the amino acid
residue, diamino acid residue, triamino acid residue or tetraamino
acid residue is optionally substituted one or more times by an
amino acid protective group;
[0010] R.sup.4 is methyl, ethyl, propyl, or butyl;
[0011] R.sup.5 is methyl, ethyl, propyl, or butyl;
[0012] Z is --(C.dbd.O).sub.n--C.sub.0-C.sub.16-alkyl-,
--(C.dbd.O).sub.n--C.sub.0-C.sub.16-alkyl-NH--,
--(C.dbd.O).sub.n--C.sub.- 0-C.sub.16-alkyl-O--,
--(C.dbd.O).sub.n--C.sub.1-C.sub.16-alkyl-(C.dbd.O).- sub.m--, or a
covalent bond;
[0013] n is 0 or 1; and
[0014] m is 0 or 1; or
[0015] a pharmaceutically acceptable salt or physiologically
functional derivative thereof, with at least one other active
ingredient, or a pharmaceutically acceptable salt or
physiologically functional derivative thereof. The invention is
also directed to the use of the combination product, pharmaceutical
composition comprising the combination product and method for
preparing the pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Definitions of Terms
[0017] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings.
[0018] "Pharmaceutically acceptable salt", because of its greater
solubility in water compared with the initial compound, means a
salt that is particularly suitable for medical applications. The
salt must have a pharmaceutically acceptable anion or cation. A
suitable pharmaceutically acceptable salt as an acid addition salt
of a compound of the invention, for example, is a salt of an
inorganic acid such as hydrochloric acid, hydrobromic, phosphoric,
metaphosphoric, nitric, sulfamic or sulfuric acid, or of organic
acids such as, for example, acetic, benzenesulfonic, benzoic,
citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic,
lactic, lactobionic, maleic, malic, methanesulfonic, succinic,
p-toluenesulfonic, tartaric or trifluoroacetic acid. The chloride
salt is particularly preferably used for medical purposes. A
suitable pharmaceutically acceptable salt as a base addition salt
of a compound of the invention, for example, is an ammonium, alkali
metal (such as sodium and potassium) and alkaline earth metal (such
as magnesium and calcium) salt.
[0019] A salt with a pharmaceutically unacceptable anion likewise
belongs in the scope of the invention as useful intermediates for
the preparation or purification of a pharmaceutically acceptable
salt or for use in nontherapeutic, for example in vitro,
applications.
[0020] "Patient" means a mammal including a human.
[0021] "Physiologically functional derivative" means any
physiologically tolerated derivative of a compound of the
invention, e.g., a prodrug such as an ester that is able on
administration to a patient, to form (directly or indirectly) such
a compound or an active metabolite thereof.
[0022] A prodrug of the compounds according to the invention are
another aspect of this invention. Such prodrugs can be metabolized
in vivo to give a compound according to the invention. These
prodrugs may or may not be active themselves.
[0023] The a compound of formula I can also exist in various
polymorphous forms, for example as amorphous and crystalline
polymorphous forms. All the polymorphous forms of the compounds
according to the invention are included in the scope of the
invention and are a further aspect of the invention.
[0024] All references to "compound(s) according to formula I" in
the following text relate to compound(s) of the formula I as
described above and their salts, solvates and physiologically
functional derivatives as described herein.
[0025] "Saccharide residue" means a compound derived from an aldose
and ketose which has 3 to 7 carbon atoms and may belong to the D or
L series; these include an amino saccharide, sugar alcohol or
saccharic acid. Examples of saccharide residues are glucose,
mannose, fructose, galactose, ribose, erythrose, glyceraldehyde,
sedoheptulose, glucosamine, galactosamine, glucuronic acid,
galacturonic acid, gluconic acid, galactonic acid, mannonic acid,
glucamine, 3-amino-1,2-propanediol, glucaric acid and galactaric
acid. The saccharide residue may also be substituted or
protected.
[0026] "Di-, tri, or tetrasaccharide" means a saccharide composed
respectively of two, three or four saccharide units. Di-, tri-, or
tetrasaccharides are produced by acetal-like linkage with 2 or more
sugars. The linkages may moreover occur in the .alpha. or .beta.
form. Examples of the polysaccharides are lactose, maltose and
cellobiose.
[0027] "Substituted or protected saccharide" means a saccharide
substituted or protected preferably on the hydrogen atom of an OH
group of the saccharide. A suitable protective group for a hydroxyl
group of a saccharide include the following: benzyl, acetyl,
benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl, benzylidene,
cyclohexylidene and isopropylidene protective group.
[0028] "Amino acid" means, e.g., the stereoisomeric forms, i.e., D
or L forms, of the following compounds:
1 alanine glycine proline cysteine histidine glutamine aspartic
acid isoleucine arginine glutamic acid lysine serine phenylalanine
leucine threonine tryptophan methionine valine tyrosine asparagine
2-aminoadipic acid 2-aminoisobutyric acid 3-aminoadipic acid
3-aminoisobutyric acid beta-alanine 2-aminopimelic acid
2-aminobutyric acid 2,4-diaminobutyric acid 4-aminobutyric acid
desmosine piperidic acid 2,2-diaminopimelic acid 6-aminocaproic
acid 2,3-diaminopropionic acid 2-aminoheptanoic acid N-ethylglycine
2-(2-thienyl)-glycine 3-(2-thienyl)-alanine penicillamine sarcosine
N-ethylasparagine N-methylisoleucine hydroxylysine 6-N-methyllysine
allo-hydroxylysine N-methylvaline 3-hydroxyproline norvaline
4-hydroxyproline norleucine isodesmosine ornithine allo-isoleucine
N-methylglycine.
[0029] Abbreviated names for the amino acids follow the generally
customary names (cf. Schroder, Lubke, The Peptides, Vol. I, New
York 1965, pages XXII-XXIII; Houben-Weyl, Methoden der Organischen
Chemie [Methods of Organic Chemistry], Volume XV/1 and 2, Stuttgart
1974). The amino acid pGlu is pyroglutamyl, Nal is
3-(2-naphthyl)alanine, azagly-NH2 is a compound of the formula
NH2-HN--CONH2 and D-Asp is the D form of aspartic acid. According
to their chemical nature, peptides are amides and decompose into
amino acids on hydrolysis.
[0030] "Di-, tri-, and tetraamino acid residue" mean peptides
composed of 2 to 4 of the abovementioned amino acids.
[0031] A suitable "amino acid protective group" (see, for example,
T. W. Greene, "Protective Groups in Organic Synthesis", 2.sup.nd
Edition, John Wiley and Sons, New York 1991) for an amino acid are
represented in the parentheses after the following abbreviated
amino acid:
[0032] Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzl),
Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl), Glu(OBut),
His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(C1-2), Lys(Boc),
Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO),
Tyr(Br-Z), Tyr(Bzl) or Tyr(but). Furthermore, amino protective
groups used are preferably the benzyloxycarbonyl(Z) radical that is
removable by catalytic hydrogenation, the
2-(3,5-dimethyloxyphenyl)prop-2-yloxycarbonyl (Ddz) or trityl (Trt)
radical that is removed by a weak acid and the
9-fluorenylmethyloxycarbonyl (Fmoc) radical that is removed by a
secondary amine.
[0033] "Other active ingredient" that is suitable for the
combination products means:
[0034] all antidiabetics such as those mentioned in the Rote Liste
2001, chapter 12. Most of the other active ingredients listed below
are disclosed in the USP Dictionary of USAN and International Drug
Names, US Pharmacopeia, Rockville 2001. More specifically, the
antidiabetics include insulin and insulin derivatives such as, for
example, Lantus.RTM. (see www.lantus.com) or fast-acting insulins
(see U.S. Pat. No. 6,221,633), GLP-1 derivatives such as, for
example, those disclosed in WO 98/08871, and orally active
hypoglycemic active ingredients. The orally active hypoglycemic
active ingredients include, preferably, sulfonylureas, biguanides,
meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase
inhibitors, glucagon antagonists, GLP-1-agonists, potassium channel
openers such as, for example, those disclosed in WO 97/26265 and WO
99/03861, insulin sensitizers, inhibitors of liver enzymes involved
in the stimulation of gluconeogenesis and/or glycogenolysis,
modulators of glucose uptake, compounds which alter lipid
metabolism, such as antihyperlipidemic active ingredients and
antilipidemic active ingredients, compounds which reduce food
intake, PPAR and RXR agonists and active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
[0035] Embodiments
[0036] A preferred embodiment of the invention is where the
1,4-benzothiepine 1,1-dioxide compound of formula I and other
active ingredient of the combination product displays an activity
that is synergistic. Further preferred is where the hypolipidemic
activity of the 1,4-benzothiepine 1,1-dioxide compound of formula I
in the combination product is increased synergistically to a
disproportionately large extent by the other active ingredient.
[0037] Another preferred embodiment of the invention is where the
other active ingredient is an orally active hypoglycemic.
[0038] Another preferred embodiment of the invention is where the
combination product comprises the compound of formula I
wherein:
[0039] R.sup.1 ethyl, propyl, or butyl; and
[0040] R.sup.3 is a saccharide residue, or disaccharide residue,
wherein the saccharide residue or disaccharide residue is
optionally substituted one or more times by a saccharide protective
group; or amino acid residue, or diamino acid residue, wherein the
amino acid residue or diamino acid residue is optionally
substituted one or more times by an amino acid protective group;
or
[0041] a pharmaceutically acceptable acid addition salt
thereof.
[0042] A further preferred embodiment of the invention is where the
combination product comprises the compound of formula I in
which:
[0043] R.sup.1 ethyl;
[0044] R.sup.2 OH;
[0045] R.sup.3 is a saccharide residue, wherein the saccharide
residue is optionally substituted one or more times by a saccharide
protective group;
[0046] diamino acid residue, wherein the diamino acid residue is
optionally substituted one or more times by an amino acid
protective group;
[0047] R.sup.4 methyl;
[0048] R.sup.5 methyl; and
[0049] Z --(C.dbd.O)--C.sub.0-C.sub.4-alkyl, a covalent bond;
or
[0050] a pharmaceutically acceptable acid addition salts
thereof.
[0051] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an
HMG-CoA reductase inhibitor such as simvastatin, fluvastatin,
pravastatin, lovastatin, atorvastatin, cerivastatin, or
rosuvastatin.
[0052] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
cholesterol absorption inhibitor such as, for example, ezetimibe,
tiqueside, or pamaqueside.
[0053] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a PPAR
gamma agonist such as, for example, rosiglitazone, pioglitazone,
JTT-501 (see Table II), or GI 262570 (see Table II).
[0054] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with PPAR
alpha agonists such as, for example, GW 9578 (see Table I), or GW
7647 (see Table I).
[0055] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a mixed
PPAR alpha/gamma agonist such as, for example, GW 1536 (see Table
I), AVE 8042, AVE 8134, or AVE 0847, or as described in PCT/US
11833, PCT/US 11490, or DE10142734.4.
[0056] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a fibrate
such as, for example, fenofibrate, clofibrate, or bezafibrate.
[0057] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an MTP
inhibitor such as, for example, implitapide, BMS 201038 (see Table
I), or R 103757 (see Table I).
[0058] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with bile acid
absorption inhibitors (see, for example, U.S. Pat. No. 6,245,744 or
U.S. Pat. No. 6,221,897) such as, for example, HMR 1741.
[0059] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a CETP
inhibitor such as, for example, JTT-705 (see Table II).
[0060] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
polymeric bile acid adsorbent such as, for example, cholestyramine,
or colesevelam.
[0061] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an LDL
receptor inducer (see U.S. Pat. No. 6,342,512) such as, for
example, HMR1171, or HMR1586.
[0062] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an ACAT
inhibitor such as, for example, avasimibe.
[0063] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an
antioxidant such as, for example, OPC 14117 (see Table II).
[0064] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
lipoprotein lipase inhibitor such as, for example, NO 1886 (see
Table II).
[0065] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an
ATP-citrate lyase inhibitor such as, for example, SB 204990 (see
Table II).
[0066] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
squalene synthetase inhibitor such as, for example, BMS 188494 (see
Table II).
[0067] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
lipoprotein(a) antagonist such as, for example, CI 1027 (see Table
II) or nicotinic acid.
[0068] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a lipase
inhibitor such as, for example, orlistat.
[0069] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with
insulin.
[0070] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
sulfonylurea such as, for example, tolbutamide, glibenclamide,
glipizide or glimepiride.
[0071] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
biguanide such as, for example, metformin.
[0072] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
meglitinide such as, for example, repaglinide.
[0073] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with a
thiazolidinedione such as, for example, troglitazone, ciglitazone,
pioglitazone, rosiglitazone or the compounds disclosed in WO
97/41097, in particular
5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]pheny-
l]methyl]-2,4-thiazolidinedione.
[0074] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an
x-glucosidase inhibitor such as, for example, miglitol or
acarbose.
[0075] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with an active
ingredient which acts on the ATP-dependent potassium channel of the
beta cells, such as, for example, tolbutamide, glibenclamide,
glipizide, glimepiride or repaglinide.
[0076] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with more than
one of the aforementioned compounds, e.g., in combination with a
sulfonylurea and metformin, a sulfonylurea and acarbose,
repaglinide and metformin, insulin and a sulfonylurea, insulin and
metformin, insulin and troglitazone, insulin and lovastatin,
etc.
[0077] Another further particular embodiment of the invention is
where the compound of formula I is administered in combination with
CART modulators (see "Cocaine-amphetamine-regulated transcript
influences energy metabolism, anxiety and gastric emptying in mice"
Asakawa, A, et al., M.:Hormone and Metabolic Research (2001),
33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid
{4-[(4-aminoquinazolin-2-yl- amino)methyl]cyclohexylmethyl}amide;
hydrochloride (CGP 71683A)), MC4 agonists (e.g.
1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acids
[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-
-5-yl)-1-(4-chlorophenyl)-2-oxo-ethyl]amide; (WO 01/91752)), orexin
antagonists (e.g.
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylure- a;
hydrochloride (SB-334867-A)), H3 agonists
(3-cyclohexyl-1-(4,4-dimethyl-
-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic
acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.
[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropyla-
mine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin
agonists, .beta.3-agonists (e.g.
1-(4-chloro-3-methanesulfonylmethylpheny-
l)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol;
hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)
agonists, CCK-A agonists (e.g.
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-
thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid
trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake
inhibitors (e.g. dexfenfluramine), mixed serotoninergic and
noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.
1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO
01/09111), bombesin agonists, galanin antagonists, growth hormone
(e.g. human growth hormone), growth hormone-releasing compounds
(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1-
H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)),
TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2
or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.;
Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia.
Leptin agonists as a potential approach to the treatment of
obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists
(bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO
00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or
TR-.beta. agonists.
[0078] Another particular embodiment of the invention is where the
other active ingredient is leptin, see, for example, "Perspectives
in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001),
2(10), 1615-1622.
[0079] Another particular embodiment of the invention is where the
other active ingredient is dexamphetamine or amphetamine.
[0080] Another particular embodiment of the invention is where the
other active ingredient is fenfluramine or dexfenfluramine.
[0081] Another particular embodiment of the invention is where the
other active ingredient is sibutramine.
[0082] Another particular embodiment of the invention is where the
other active ingredient is orlistat.
[0083] Another particular embodiment of the invention is where the
other active ingredient is mazindol or phentermine.
[0084] Another particular embodiment of the invention is where the
compound of formula I is administered in combination with dietary
fiber materials, preferably insoluble dietary fiber materials (see,
for example, Carob/Caromax.RTM. (Zunft H J; et al., Carob pulp
preparation for treatment of hypercholesterolemia, ADVANCES IN
THERAPY (2001 September-October), 18(5), 230-6.) Caromax is a
carob-containing product supplied by Nutrinova, Nutrition
Specialties & Food Ingredients GmbH, Industriepark Hochst,
65926 Frankfurt/Main)). Combination with Caromax.RTM. is possible
in one preparation or by a separate administration of a compound of
formula I and Caromax.RTM.. Caromax.RTM. can moreover be
administered in the form of foodstuffs such as, for example, in
bakery products or muesli bars. Combination of a compound of
formula I with Caromax.RTM. not only improves the effect, in
particular in LDL-cholesterol lowering, compared with the
individual active ingredients, but is also tolerated better.
2TABLE I 3 GW-9578 4 GW-7647 5 GW-1536 6 Implitapide 7 R-103757 8
BMS-201038
[0085]
3TABLE II 9 JTT-705 10 OPC-14117 11 NO-1886 12 SB-204990 13
BMS-188494 14 CI-1027 15 JTT-501 16 GI 262570
[0086] The amount of a compound of formula I and of the other
active ingredient necessary to achieve the desired biological
effect with the combination product depends on a number of factors,
e.g., the specific compound of formula I or other active ingredient
chosen, the intended use, the mode of administration and the
clinical condition of the patient. The daily dose is generally in
the range from 0.1 to 100 mg (typically from 0.1 to 50 mg) per day
per kilogram of body weight, e.g. 0.1-10 mg/kg/day. Tablets or
capsules may contain, for example, from 0.01 to 100 mg, typically
from 0.02 to 50 mg. In the case of a pharmaceutically acceptable
salt, the aforementioned weight data are based on the weight of the
compound of formula I or other active ingredient derived from the
salt. The compound of formula I or other active ingredient of the
combination product, however, is preferably in the form of a
pharmaceutical composition with a convertible carrier. The carrier
must, of course, be compatible in the sense that it is compatible
with the compound of formula I or other active ingredient of the
combination product and is not harmful for the patient's health.
The carrier may be a solid or a liquid or both and is preferably
formulated with the compound as single dose, for example as a
tablet, which contain from 0.05% to 95% by weight of the other
active ingredient. Other pharmaceutically active substances may
likewise be present, including other compound of formula I. The
pharmaceutical combination product of the invention can be produced
by one of the known pharmaceutical methods which consist
essentially of mixing the compound of formula I or other active
ingredient with pharmacologically acceptable carriers and/or
excipients.
[0087] Pharmaceutical combination product of the invention is one
suitable for oral and peroral (e.g. sublingual) administration,
although the most suitable mode of administration depends in each
individual case on the nature and severity of the condition to be
treated and on the nature of the particular compound of formula I
used. Coated formulations and coated slow-release formulations of
the combination product are also within the scope of the invention.
Acid- and gastric juice-resistant formulations are preferred.
Suitable gastric juice-resistant coatings comprise cellulose
acetate phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of
methacrylic acid and methyl methacrylate.
[0088] Suitable pharmaceutical compositions comprising the compound
of formula I or other active ingredient for oral administration may
be in the form of separate units such as, for example, capsules,
cachets, lozenges or tablets, each of which contain a defined
amount of the compound of the formula (I) and of the other active
ingredient; as powders or granules; as a solution or suspension in
an aqueous or nonaqueous liquid; or as an oil-in-water or
water-in-oil emulsion. The combination product may, as already
mentioned, be prepared by any suitable pharmaceutical method which
includes a step in which the compound of formula I or other active
ingredient and the carrier (which may consist of one or more
additional ingredients) are brought into contact. The combination
product is generally produced by a uniform and homogeneous mixing
of the compound of formula I or other active ingredient with a
liquid and/or finely divided solid carrier, after which the product
is shaped if necessary. Thus, for example, a tablet can be produced
by compressing or shaping a powder or granules of the compound, and
the other ingredient. Compressed tablets may be produced by
tableting the compound of formula I or other active ingredient in
free-flowing form, such as, for example, a powder or granules,
where appropriate mixed with a binder, glidant, inert diluent
and/or one (or more) surface-active/dispersing agent in a suitable
machine. Shaped tablets can be produced by shaping the compound of
formula I or other active ingredient which is in powder form and
has been moistened with an inert liquid diluent in a suitable
machine.
[0089] Pharmaceutical composition of combination products suitable
for peroral (sublingual) administration include lozenges which
contain a cderivature of formula I and the other active ingredient
with a flavoring, normally sucrose and gum arabic or tragacanth,
and pastilles which comprise the compound of formula I or other
active ingredient in an inert base such as gelatin and glycerol or
sucrose and gum arabic.
[0090] Other active ingredients may be combined with a compound of
formula I in particular for synergistic improvement of the effect.
Administration of the other active ingredient combination and the
compound of formula I can also take place either by separate
administration of the other active ingredient and the compound of
formula I to the patient, i.e., an in vivo formation of a
combination product, or in the form of a combination product in
which the other active ingredient and compound of formula I are
present in one pharmaceutical preparation. When the administration
of the other active ingredient combination and the compound of
formula I takes place by separate administration such
administration should be undertaken so that the effects of each
combine additively or synergistically, preferably synergistically.
Thus, the separate administration is preferably undertaken closely
in time, e.g., within 10 minutes of each other.
[0091] The combined use of the compound of formula I and the other
active ingredient are used for the therapeutic purposes noted
herein in a patient, such that the combination is present in a
pharmaceutically effective amount. That pharmaceutically effective
amount arises from the use of the compound of formula I and the
other active ingredient wherein each is used in a pharmaceutically
effective amount, or by virtue of additive or synergistic effects
arising from the combined use, each can also be used in a
subclinical pharmaceutically effective amount, i.e., an amount
that, if used alone, provides for reduced or ineffective
pharmaceutical effectiveness for the therapeutic purposes noted
herein, provided that the combined use is pharmaceutically
effective. In addition, the present invention encompasses the use
of the combination of the compound of formula I and the other
active ingredient as described herein, where the compound of
formula I or the other active ingredient is present in a
pharmaceutically effective amount, and the other is present in a
subclinical pharmaceutically effective, provided that the combined
use is pharmaceutically effective owing to their additive or
synergistic effects. As used herein, the term "additive effect"
describes the combined effect of two (or more) pharmaceutically
active agents that is equal to the sum of the effect of each agent
given alone. A syngergistic effect is one in which the combined
effect of two (or more) pharmaceutically active agents is greater
than the sum of the effect of each agent given alone. It is
self-evident that every suitable combination of a compound of
formula I with one or more of the aforementioned other active
ingredients and optionally with one or more other pharmacologically
active substances is to be regarded as covered by the scope of
protection of the present invention.
[0092] The combination products comprising a compound of formula I
represent ideal medicaments for the treatment of lipid metabolism
disorders and/or carbohydrate metabolism disorders, especially
hyperlipidemia or metabolic syndrome. The combination products are
likewise suitable for modulating the decrease of the serum
cholesterol level or for the prevention or treatment of
arteriosclerotic manifestations.
[0093] The following preparations serve to illustrate the invention
without, however, restricting it.
EXAMPLE A
[0094] Soft gelatin capsules containing 100 mg of the compound of
formula I and other active ingredient per capsule:
4 per capsule the compound of formula I and other active ingredient
100 mg triglyceride mixture fractionated from coconut fat 400 mg
capsule contents 500 mg
EXAMPLE B
[0095] Emulsion containing 60 mg of the compound of formula I and
other active ingredient per 5 ml:
5 per 100 ml of emulsion the compound of formula I and other active
ingredient 1.2 g neutral oil q.s. sodiumcarboxymethylcellulose 0.6
g polyoxyethylene stearate q.s. glycerol, pure 0.2 to 2.0 g
flavoring q.s. water (deionized or distilled) ad 100 ml
EXAMPLE C
[0096] Rectal drug form containing 40 mg of the compound of formula
I and other active ingredient per suppository:
6 per suppository the compound of formula I and other active
ingredient 40 mg suppository base ad 2 g
EXAMPLE D
[0097] Tablets containing 40 mg of the compound of formula I and
other active ingredient per tablet:
7 per tablet the compound of formula I and other active ingredient
40 mg lactose 600 mg corn starch 300 mg soluble starch 20 mg
magnesium stearate 40 mg 1000 mg
EXAMPLE E
[0098] Coated tablets containing 50 mg of the compound of formula I
and other active ingredient per coated tablet:
8 per coated tablet the compound of formula I and other active
ingredient 50 mg corn starch 100 mg lactose 60 mg sec. calcium
phosphate 30 mg soluble starch 5 mg magnesium stearate 10 mg
colloidal silica 5 mg 260 mg
EXAMPLE F
[0099] The following formulations are suitable for producing the
contents of hard gelatin capsules:
9 a) the compound of formula I and other active ingredient 100 mg
corn starch 300 mg 400 mg b) the compound of formula I and other
active ingredient 140 mg lactose 180 mg corn starch 180 mg 500
mg
EXAMPLE G
[0100] Drops can be produced using the following formulation (100
mg of the compound of formula I and other active ingredient in 1
ml=20 drops):
10 the compound of formula I and other active ingredient 10 g
methyl benzoate 0.07 g ethyl benzoate 0.03 g ethanol, 96% 5 ml
demineralized water ad 100 ml
[0101] Experimental
[0102] The synergistic activity of the combination product of a
compound of formula I with the other active ingredient was tested
in an animal experiment. For this purpose, compound V1 from the
compound of formula I was tested: 17
[0103] Hamsters were used for the biological testing of the
combination product of the invention. Male Syrian hamsters
(Mesocricetus auratus) from 8 to 10 weeks of age were used for the
experiment. The animals received a standard feed (Teklad 8604M)
supplemented with 0.1% cholesterol. An additional normal control
group received only standard feed.
[0104] The test substances were administered orally by gavage once
a day on 10 consecutive days, and the control group was treated
with the vehicle.
[0105] Feces were collected on days 5 and 6 of the experiment for
bile acid analysis. Retroorbital blood was taken from the animals
on day 10 of the experiment, and the lipid levels in the plasma
were determined. Radioactive tracers were administered orally to
the animals on day 9 of the experiment to determine the cholesterol
absorption in analogy to the method described by Zilversmith et al.
On day 11 of the experiment, the animals were sacrificed, and the
animals' livers were removed for cholesterol analysis and
preparation of microsomes. The 7.alpha.-hydroxylase activity was
determined in the liver microsomes ex vivo by a modified method of
Hylemon et al.
[0106] Effect of Ezetimibe (K00 04513) Plus C1 on Cholesterol
Absorption
[0107] Ezetimibe (K00 04513) is a Cholesterol Absorption Inhibitor
from Schering Plough
11 1 Teklad Normal ctr. n = 5 2 Teklad +0.1% CH Cholesterol ctr. n
= 5 3 Teklad +0.1% CH 0.1 mg/kg/d Ezetimibe (K004513) n = 5 4
Teklad +0.1% CH 0.1 mg/kg/d V1 n = 5 5 Teklad +0.1% CH 0.3 mg/kg/d
V1 n = 5 6 Teklad +0.1% CH 1 mg/kg/d V1 n = 5 7 Teklad +0.1% CH 0.1
mg/kg/V1 + 0.1 mg/kg/d K0004513 n = 5 8 Teklad +0.1% CH 0.1
mg/kg/V1 + 0.3 mg/kg/d K0004513 n = 5 9 Teklad +0.1% CH 0.1
mg/kg/V1 + 1 mg/kg/d K0004513 n = 5
[0108] K0004513 employed as stock solution (1 mg/ml in EtOH)
[0109] Substances are dissolved in 2% EtOH in a final concentration
of 5%.
[0110] The solutions are then suspended with 0.4% potato
starch.
[0111] Administration takes place 1.times. in the morning with 10
ml/kg
[0112] Feed:
[0113] Teklad 8604M CH: 032201M
[0114] Experimental Animals:
[0115] Male Syrian hamsters (Mesocricetus auratus) supplied by
Harlan
[0116] 100-120 g at the start of adaptation
[0117] Measured Parameters:
[0118] Feed consumption
[0119] Animal weight (weekly)
[0120] Liver weight
[0121] Safety parameters (CH; TG; ALAT/ASAT; AP; HDL/LDL)
[0122] Liver cholesterol (HPLC)=1.times.500 mg in EtOH/KOH
[0123] CYP7 activity (liver microsomes as group pool of 0.5 g
each-preparation on day of experiment)
[0124] Feces collected on day 5-7 for bile acid determination
12 Plasma-parameter Cholesterol Triglycerides LDL Group
Feed/Product mmol/L STD % mmol/L STD % mmol/L 1 Normal ctr. 2.84
.+-.0.09 81 2.01 .+-.0.23 124 0.60 2 Cholesterol ctr. 3.50 .+-.0.27
100 1.62 .+-.0.54 100 1.12 +0.1% CH 3 +0.1% CH 3.44 .+-.0.64 98
1.63 .+-.0.36 100 1.04 0.1 mg/kg/d Ezetimibe (K0004513) 4 +0.1% CH
4.20 .+-.146 120 1.87 .+-.0.30 115 1.06 0.1 mg/kg/d V1 5 +0.1% CH
4.01 .+-.0.89 114 1.75 .+-.0.23 108 1.18 0.3 mg/kg/d V1 6 +0.1% CH
3.23 .+-.0.19 92 2.02 .+-.0.57 124 0.92 1 mg/kg/d V1 7 +0.1% CH
3.62 .+-.0.18 103 2.08 .+-.0.12 128 1.04 0.1 mg/kg/d V1 + 0.1
mg/kg/d Ezetimibe 8 +0.1% CH 3.56 .+-.0.94 101 2.11 .+-.0.58 130
0.99 0.3 mg/kg/d V1 + 0.1 mg/kg/d Ezetimibe 9 +0.1% CH 2.82
.+-.0.05 81 1.84 .+-.0.23 113 0.76 1 mg/kg/d V1 + 0.1 mg/kg/d
Ezetimibe It is evident from the table that the compounds of the
formula I in combination with ezetimibe show a synergistic effect
on the plasma parameters.
[0125] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof.
* * * * *
References