Note: Descriptions are shown in the official language in which they were submitted.
CA 02481817 2004-10-07
WO 03/084922 1 PCTIEP03103251
Description
Acyl-4-carboxyphenylurea derivatives, processes for preparing them and
their use
The invention relates to acyl-4-carboxyphenylurea derivatives and to their
physiologically tolerated salts and physiologically functional derivatives.
EP 0 193 249 (Duphar) describes acylcarboxyphenylurea derivatives which
possess antitumor activity.
The invention was based on the object of providing compounds which can
be used for preventing and treating diabetes type 2. In particular, the object
was to make available novel compounds which have an effect which is
markedly superior to that of the compounds disclosed in EP 0 193 249.
The invention therefore relates to compounds of the formula l,
R4
OR3 / RS
R8 N ~ I OH
I I
R1 R2 R6 O
R9 R10
in which
R7, R8, R9 and R10 are, independently of each other, H, F, CI, Br, OH,
NO2, CN, O-(C~-C6)-alkyl, O-(CZ-C6)-alkenyl, O-(C2-C6)-
alkynyl, O-SOZ-(C~-C4)-alkyl, (C~-C6)-alkyl, (C2-C6)-alkenyl or
(C2-C6)-alkynyl, where alkyl, alkenyl and alkynyl can be
substituted, once or more than once, by F, CI or Br;
R1 and R2 are, independently of each other, H, (C~-C6)-alkyl, where alkyl
can be substituted by OH, O-(C~-C4)-alkyl, NH2, NH(C~-C4)-
alkyl or N[(C,-C6)-alkyl]2, O-(C~-C6)-alkyl, CO-(C~-C6)-alkyl,
CA 02481817 2004-10-07
2
COO-(C~-C6)-alkyl, (C~-C6)-alkylene-COOH or (C~-C6)-
alkylene-COO-(C~-C6)-alkyl;
R3 is H, F, CI, Br, N02, CN, O-R11, unsubstituted O-phenyl,
S-R11, COOR11, N(R12)(R13), (C~-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C~)-cycloalkyl-
(C~-C4)-alkylene, where alkyl, cycloalkyl and alkynyl can be
substituted, once or more than once, by F, CI, Br, OR11,
COOR11 or N(R16)(R17);
R4 is H, F, CI, Br, N02, CN, O-R11, unsubstituted O-phenyl,
S-R11, COOR11, N(R12)(R13), (C~-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-
(C~-C4)-alkylene, where alkyl, cycloalkyl and alkynyl can be
substituted, once or more than once, by F, CI, Br, OR11,
COOR11 or N(R16)(R17);
R5 is H, F, CI, Br, N02, CN, O-R11, unsubstituted O-phenyl,
S-R11, COOR11, N(R12)(R13), (C~-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C~)-cycloalkyl-
(C~-C4)-alkylene, where alkyl, cycloalkyl and alkynyl can be
substituted, once or more than once, by F, CI, Br, OR11,
COOR11 or N(R16)(R17);
R6 is H, F, CI, Br, NOZ, CN, O-R11, unsubstituted O-phenyl,
S-R11, COOR11, N(R12)(R13), (C~-C6)-alkyl, (C2-C6)-alkenyl,
(C2-C6)-alkynyl, (C3-C~)-cycloalkyl or (C3-C~)-cycloalkyl-
(C~-C4)-alkylene, where alkyl, cycloalkyl and alkynyl can be
substituted, once or more than once, by F, CI, Br, OR11,
COOR11 or N(R16)(R17);
R11 is H, (C~-C$)-alkyl, (C2-C8)-alkenyl or (C2-Ca)-alkynyl, where
alkyl, alkenyl and alkynyl can be substituted, once or more
than once, by F, CI, Br, OH or O-(C~-C4)-alkyl;
R12 and R13 are, independently of each other, H, (C~-C8)-alkyl, (Cz-Ca)-
alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-
(C~-C4)-alkylene, COO-(C~-C4)-alkyl, COO-(C2-C4)-alkenyl,
phenyl or SOZ-phenyl, where the phenyl ring can be
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3
substituted, up to two times, by F, CI, CN, OH, (C~-C6)-alkyl,
O-(C~-C6)-alkyl, CF3, OCF3, COOH, COO-(C~-C6)-alkyl or
CONH2;
or R12 and R13 form, together with the nitrogen atom to which they are
bonded, a 3-7-membered, saturated heterocyclic ring which
can contain up to 2 further heteroatoms from the group N, O
or S and where the heterocyclic ring can be substituted, up to
four times, by F, Ci, Br, OH, Oxo, (C~-C4)-alkyl or
N(R14)(R15);
R14 and R15 are, independently of each other, H, (C~-Ca)-alkyl, (C2-C$)-
alkenyl, (C2-C8)-alkynyl, (C3-C~)-cycloalkyl, (C3-C7)-cycloalkyl-
(C,-C4)-alkylene, COO-(C,-C4)-alkyl, COO-(C2-C4)-alkenyl,
phenyl or S02-phenyl, where the phenyl ring can be
substituted, up to two times, by F, CI, CN, OH, (C~-C6)-alkyl,
O-(C~-C6)-alkyl, CF3, OCF3, COOH, COO(C~-C6)-alkyl or
CONH2;
R16 and R17are, independently of each other, H, (C~-C$)-alkyl, (C2-C8)-
alkenyl, (C2-C8)-alkynyl, (C3-C~)-cycloalkyl, (C3-C7)-cycloalkyl
(C~-C4)-alkylene, COO-(C~-C4)-alkyl, COO-(CZ-C4)-alkenyl,
phenyl or SOz-phenyl, where the phenyl ring can be
substituted, up to two times, by F, CI, CN, OH, (C~-C6)-alkyl,
O-(C~-C6)-alkyl, CF3, OCF3, COOH, COO-(C~-Cs)-alkyl or
CONH2;
or R16 and R17 form, together with the nitrogen atom to which they are
bonded, a 3-7-membered, saturated heterocyclic ring which
can contain up to 2 further heteroatoms from the group N, O
or S and where the heterocyclic ring can be substituted, up to
four times, by F, CI, Br, OH, Oxo, (C~-C4)-alkyl or
N(R14)(R15);
it always being the case that at least one of the radicals R3, R7, R8, R9
and R10 is not hydrogen,
and the physiologically tolerated salts thereof.
Preference is given to compounds of the formula I in which one or more
radicals have the following meaning:
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R7, R8, R9 and R10 are, independently of each other, H, F, CI, Br,
OH, NO2, CN, (C~-C6)-alkyl or O-(C~-C6)-alkyl, where alkyl
can be substituted, once or more than once, by F;
R1 and R2 are H;
R3 is H, F, CI, Br, N02, CN, O-R11, unsubstituted O-phenyl,
S-R11, COOR11, N(R12)(R13), (C~-C6)-alkyl, (C2-C6)-alkenyl,
(CZ-C6)-alkynyl, (C3-C7)-cycloalkyl or (C3-C~)-cycloalkyl-
(C~-C4)-alkylene, where alkyl, cycloalkyl and alkynyl can be
substituted, once or more than once, by F, CI, Br, OR11 or
COOR11;
R4 is H, F, CI, N02, O-R11, N(R12)(R13) or (C~-Cs)-alkyl, where
alkyl, can be substituted, once or more than once, by F;
R5 is H, F, CI, N02, O-R11, N(R12)(R13) or (C1-C6)-alkyl, where
alkyl can be substituted, once or more than once, by F;
R6 is H, F, CI, N02, O-R11, N(R12)(R13) or (C~-Cs)-alkyl where
alkyl can be substituted, once or more than once, by F;
R11 is H, (C~-C8)-alkyl, (C~-C8)-alkylene-O-(C~-Ca)-alkyl or
(C~-C8)-alkyl-OH, where alkyl can be substituted, once or
more than once, by F;
R12 and R13 are, independently of each other, H or (C~-C8)-alkyl;
or R12 and R13 form, together with the nitrogen atom to which they are
bonded, a 3-7-membered, saturated heterocyclic ring which
can contain up to 2 further heteroatoms from the group N, O
or S and where the heterocyclic ring can be substituted, up to
four times, by F, CI, Br, OH, Oxo, (C~-C4)-alkyl or
N(R14)(R15);
R14 and R15 are, independently of each other, H, (C1-Ca)-alkyl, (C2-Cs)-
alkenyl, (C2-C8)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-
(C~-C4)-alkylene, COO-(C~-C4)-alkyl, COO-(C2-C4)-alkenyl,
phenyl or SOZ-phenyl, where the phenyl ring can be
CA 02481817 2004-10-07
substituted, up to two times, by F, CI, CN, OH, (C~-C6)-alkyl,
O-(C~-C6)-alkyl, CF3, OCF3, COOH, COO(C~-C6)-alkyl or
CONH2;
5 and the physiologically tolerated salts thereof.
Very particular preference is given to compounds of the formula I in which
one or more radicals have the following meaning:
R7, R8, R9 and R10 are, independently of each other, H, F, CI, Br,
CH3 or CF3;
R1, R2, R5 are H;
R3 is H, F, CI, N02, O-R11, N(R12)(R13) or (C~-C6)-alkyl, where
alkyl can be substituted once or more than once by F;
R4 is H, F, CI, N02, O-R11, N(R12)(R13) or (C~-C6)-alkyl, where
alkyl can be substituted once or more than once by F;
R6 is H, F, CI, N02, O-R11, N(R12)(R13) or (C~-C6)-alkyl, where
alkyl can be substituted once or more than once by F;
R11 is H or (C~-C8)-alkyl, where alkyl can be substituted once or
more than once by F,
R12 and R13 are H or (C~-C$)-alkyl;
or the two radicals R12 and R13 form, together with the nitrogen atom to
which they are bonded, a 5-6-membered, saturated
heterocyclic ring which can contain a further oxygen atom;
and the physiologically tolerated salts thereof.
Very particular preference is furthermore given to compounds of the
formula I in which one or more radicals have the following meaning:
R7, R8, R9 and R10 are, independently of each other, H, F, CI, Br,
CH3 or CF3;
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R1, R2, R4, R5 and R6 are H;
R3 is H, F, CI, N02, O-R11, N(R12)(R13) or (C~-C6)-alkyl, where
alkyl can be substituted once or more than once by F;
R11 is H or (C~-Ca)-alkyl, where alkyl can be substituted once or
more than once by F,
R12 and R13 are H or (C~-C$)-alkyl;
or the two radicals R12 and R13 form, together with the nitrogen atom to
which they are bonded, a 5-6-membered, saturated
heterocyclic ring which can contain a further oxygen atom;
and the physiologically tolerated salts thereof.
Preference is furthermore given to compounds of formula I in which R3 is
not H.
R3 is particularly preferably -OCF3.
Preference is given to compounds of formula I in which at least one of the
radicals R7, R8, R9 and R10 is not hydrogen.
Particular preference is given to compounds of formula I in which at least
one of the radicals R7, R8, R9 and R10 has the meaning F or CI.
Very particular preference is given to compounds of formula I in which at
least two of the radicals R7, R8, R9 and R10 have the meaning F or CI.
Very particular preference is given to compounds of formula I in which the
radicals R7, R8, R9 and R10 have the meanings 2-CI, 4-F, 5-F and H.
If radicals or substituents can occur more than once in the compounds of
the formula I, such as -O-R11, they can then all, independently of -each
other, have the given meanings and be identical or different.
The invention relates to compounds of the formula I, in the form of their
racemates, racemic mixtures and pure enantiomers, and to their
diastereomers and mixtures thereof.
The alkyl radicals in the substituents R1, R2, R3, R4, R5, RG, R7, R8, R9,
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R10, R11, R12, R13, R14, R15, R16 and R17 can be either straight-chain
or branched.
Because of their higher solubility in water as compared with the starting
compounds or basal compounds, pharmaceutically tolerated salts are
particularly suitable for medical applications. These salts must possess a
pharmaceutically tolerated anion or cation. Suitable pharmaceutically
tolerated acid addition salts of the compounds according to the invention
are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid,
phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also
of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid,
citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,
isethionic acid, lactic acid, lactobionic acid, malefic acid, malic acid,
methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric
acid. Suitable pharmaceutically tolerated basic salts are ammonium salts,
alkali metal salts (such as sodium salts and potassium salts), alkaline earth
metal salts (such as magnesium salts and calcium salts), trometamol
(2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or
ethylenediamine.
Particular preference is given to the tromethamol salts (also termed TRIS,
tris(hydroxymethyl)methylamine) of the compounds of formula I. They
exhibit a higher bioavailability than do the corresponding free acids.
HzN
HO ~OH
OH
Salts which contain an anion which is not pharmaceutically tolerated, such
as trifluoroacetate, also belong within the scope of the invention as useful
intermediates for preparing or purifying pharmaceutically tolerated salts
andlor for use in nontherapeutic, for example in-vitro, applications.
The term "physiologically functional derivative" which is used here denotes
any physiologically tolerated derivative of a compound according to the
invention of the formula I, e.g. an ester which is able, on being
administered to a mammal, such as a human, to form (directly or indirectly)
a compound of the formula I or an active metabolite thereof.
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The physiologically functional derivatives also include prodrugs of the
compounds according to the invention, as described, for example, in H.
Okada et al., Chem. Pharm. Bull, 1994, 42, 57-61. Such prodrugs can be
metabolized in vivo to give a compound according to the invention. These
prodrugs may or may not themselves be active.
The compounds according to the invention can also be present in different
polymorphic forms, e.g. as amorphous and crystalline polymorphous forms.
All polymorphous forms of the compounds according to the invention
belong within the scope of the invention and are another aspect of the
invention.
In that which follows, all references to "compound(s) according to formula 1"
refer to compounds) of the formula I as described above and to their salts,
solvates and physiologically functional derivatives as described herein.
The compounds) of the formula (I) can also be administered in
combination with other active compounds.
The quantity of a compound according to Formula I which is required in
order to achieve the desired biological effect depends on a number of
factors, e.g. the specific compound which is selected, the intended use; the
nature of administration and the clinical condition of the patient. In
general,
the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to
50 mg) per day per kilogram of bodyweight, e.g. 3-10 mg/kg/day. An
intravenous dose can, for example, be in the range from 0.3 mg to
1.0 mg/kg, which dose can expediently be administered as an infusion of
from 10 ng to 100 ng per kilogram per minute. Infusion solutions which are
suitable for these purposes can, for example, contain from 0.1 ng to 10 mg,
typically from 1 ng to 10 mg, per milliliter. Individual doses can, for
example, contain from 1 mg to 10 g of the active compound. Thus,
ampoules for infections can, for example, contain from 1 mg to 100 mg, and
orally administrable individual dose formulations, such as tablets or
capsules, can, for example, contain from 1.0 to 1000 mg, typically from 10
to 600 mg. While, for the therapy of the abovementioned conditions, the
compounds according to formula I can be used themselves as compounds,
they are preferably present, together with a tolerated excipient, in the form
of a pharmaceutical composition. The excipient naturally has to be
tolerated in the sense that it is compatible with the other components of the
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composition and is not harmful to the health of the patient. The excipient
can be a solid or a liquid or both and is preferably formulated together with
the compound as an individual dose, for example as a tablet, which can
contain from 0.05% to 95% by weight of the active compound. Other
pharmaceutically active substances can also be present, including other
compounds according to formula I. The pharmaceutical compositions
according to the invention can be prepared using one of the known
pharmaceutical methods, which essentially consist in the constituents being
mixed with pharmacologically tolerated excipients andlor auxiliary
substances.
Pharmaceutical compositions according to the invention are those which
are suitable for oral, rectal, topical, peroral (e.g. sublingual) and
parenteral
(e.g. subcutaneous, intramuscular, intradermal or intravenous)
administration, even though 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 compound according to
formula I which is employed in each case. Coated formulations and coated
delayed-release formulations also belong within the scope of the invention.
Preference is given to formulations which are acid-resistant and gastric
juice-resistant. Suitable gastric juice-resistant coatings include cellulose
acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl
cellulose phthalate and anionic polymers of methacrylic acid and methyl
methacrylate.
Suitable pharmaceutics! compounds for oral administration can be present
in separate units, such as capsules, cachets, sucking tablets or tablets
which in each case contain a defined quantity of the compound according
to formula I; 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. As already mentioned, these compositions can be prepared
using any suitable pharmaceutical method which comprises a step in which
the active compound and the excipient (which can be composed of one or
more additional constituents) are brought into contact. In general, the
compositions are prepared by uniformly and homogeneously mixing the
active compound with a liquid andlor finely divided solid excipient, after
which the product is molded, if required. Thus, a tablet, for example, can be
prepared by pressing or molding a powder or granulate of the compound,
where appropriate together with one or more additional constituents.
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Pressed tablets can be prepared by tableting the compound in freely
flowing form, such as a powder or granulate, where appropriate mixed with
a binding agent, lubricant, inert diluent and/or a (several) surface-
active/dispersing agents) in a suitable machine. Molded tablets can be
5 prepared by molding the pulverulent compound, which is moistened with an
inert liquid diluent, in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual)
administration include sucking tablets, which contain a compound
10 according to formula I together with a flavoring agent, usually sucrose and
gum arabic or tragacanth, and lozenges, which comprise the compound in
an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration
preferably include sterile aqueous preparations of a compound according to
formula l which are preferably isotonic with the blood of the intended
recipient. These preparations are preferably administered intravenously,
even though the administration can also take place as an injection
subcutaneously, intramuscularly or intradermally. These preparations can
preferably be prepared by mixing the compound with water and making the
resulting solution sterile and isotonic with the blood. In general, injectable
compositions according to the invention comprise from 0.1 to 5% by weight
of the active compound.
Suitable pharmaceutical compositions for rectal administration are
preferably present as individual dose suppositories. These can be prepared
by mixing a compound according to formula i with one or more
conventional solid excipients, for example cocoa butter, and molding the
resulting mixture.
Suitable pharmaceutical compositions for topical use on the skin are
preferably present as an ointment, cream, lotion, paste, spray, aerosol or
oil. Excipients which can be used are vaseline, lanolin, polyethylene
glycols, alcohols and combinations of two or more of these substances.
The active compound is generally present at a concentration of from 0.1 to
15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical
compositions for transdermal uses can be present as individual plasters
CA 02481817 2004-10-07
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which are suitable for long-term intimate contact with the epidermis of the
patient. Such plasters expediently contain the active compound in an
aqueous solution, which is, where appropriate, buffered, dissolved andlor
dispersed in an adhesive or dispersed in a polymer. A suitable active
compound concentration is from approx. 1 % to 35%, preferably from
approx. 3% to 15%. As a particular possibility, the active compound can, as
described, for example, in Pharmaceutical Research, 2(6): 318 (1986), be
released by means of electrotransport or iontophoresis.
The following are suitable for use as additional active compounds for the
combination preparations:
All antidiabetics which are named in the Roten Liste [Red List] 2001,
Chapter 12. They can be combined with the compounds according to the
invention of the formula I, particularly for improving the effect
synergistically. The active compound combination can be administered
either by administering the active compounds separately to the patient or in
the form of combination preparations in which several active compounds
are present in one pharmaceutical preparation. Most of the active
compounds which are listed below are disclosed in USP Dictionary of
USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
Antidiabetics include insulin and insulin derivatives, such as Lantus~ (see
www.lantus.com) or HMR 1964, rapidly acting insulins (see US 6,221,633),
GLP-1 derivatives, such as those which were disclosed in WO 98/08871 by
Novo Nordisk A/S, and hypoglycemic active compounds which are effective
orally.
The hypoglycemic active compounds which are effective orally preferably
include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,
thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1
agonists, calcium channel openers, such as those which were disclosed by
Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers,
inhibitors of liver enzymes which are involved in stimulating
gluconeogenesis andlor glycogenolysis, modulators of glucose uptake,
compounds, such as antihyperlipidemic active compounds and
antilipidemic active compounds, which alter fat metabolism, compounds
which decrease the intake of foodstuffs, agonists of PPAR and PXR, and
active compounds which act on the ATP-dependent potassium channel of
the beta cells.
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in one embodiment of the invention, the compounds of the formula I are
administered in combination with an HMGCoA reductase inhibitor, such as
simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin
or
rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a cholesterol absorption inhibitor, such as
ezetimibe, tiqueside or pamaqueside.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a PPAR gamma agonist, such as
rosiglitazone, pioglitazone, JTT-501 or GI 262570.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a PPAR alpha agonist, such as GW 9578
or GW 7647.
in one embodiment of the invention, the compounds of the formula I are
administered in combination with a mixed PPAR alpha/gamma agonist,
such as GW 1536, AVE 8042, AVE 8134 or AVE 0847, or as described in
PCT/US 11833, PCT/US 11490 or DE10142734.4.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a fibrate, such as fenofibrate, clofibrate or
bezafibrate.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an MTP inhibitor, such as implitapide,
BMS-201038 or R-103757.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a bile acid absorption inhibitor (see, for
example, US 6,245,744 or US 6,221,897), such as HMR 1741.
In one embodiment of the invention, the compounds of the formula i are
administered in combination with a CETP inhibitor, such as JTT-705.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a polymeric bile acid adsorber, such as
CA 02481817 2004-10-07
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cholestyramine or colesevelam.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an LDL receptor inducer (see US
6,342,512), such as HMR1171 or HMR1586.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an ACAT inhibitor, such as avasimibe.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an antioxidant, such as OPC-14117.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipoprotein lipase inhibitor, such as NO-
1886.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an ATP citrate lyase inhibitor, such as
SB-204990.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a squalene synthetase inhibitor, such as
BMS-188494.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipoprotein(a) antagonist, such as CI-
1027 or nicotinic acid
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipase inhibitor, such as orlistat.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with insulin.
In one embodiment, the compounds of the formula f are administered in
combination with a sulfonylurea, such as tolbutamide, glibenclamide,
glipizide or glimepiride.
In one embodiment, the compounds of the formula I are administered in
combination with a biguanide, such as metformin.
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In yet another embodiment, the compounds of the formula I are
administered in combination with a meglitinide, such as repaglinide.
In one embodiment; the compounds of the formula I are administered in
combination with a thiazolidinedione, such as troglitazone, ciglitazone,
pioglitazone, rosiglitazone or the compounds which are disclosed by
Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-
dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thia-
zolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination with an a-glucosidase inhibitor, such as miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in
combination with an active compound which acts on the ATP-dependent
potassium channel of the beta cells, such as tolbutamide, glibenclamide,
glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with more than one of the abovementioned compounds, for
example 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.
In another embodiment, the compounds of the formula I are 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-ylamino)methyl]cyclohexylmethyl}amide; hydrochloride
(CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-
tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-
2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-
oxoethyl]amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2-
methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea]; hydrochlorides (SB-
334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyi-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]dipropylamine (VllO 00/66585)),
CRF BP antagonists (e.g. urocortin), urocortin agonists, [i3-agonists (e.g.
1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-
yloxy)ethylamino]ethanol; hydrochloride (WO 01/83451)), MSH
CA 02481817 2004-10-07
~5
(melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-
chioro-2,5-dimethoxyphenyi)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-
5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99115525));
serotonin reuptake inhibitors (e.g. dexfenfluramines), mixed serotonin
compounds and noradrenergic compounds (e.g. WO 00/71549), 5HT
agonists, e.g. 1-(3-ethylbenzofuran-7-yi)piperazine oxalic acid salt (WO
01/09111 ), bombesin agonists, galanin antagonists, growth hormone (e.g.
human growth hormone), growth hormone-releasing compounds (tert-butyl
6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1 H-
isoquinoline-2-carboxylate (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), lipaselamylase
inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR
modulators or TR ~-agonists.
In one embodiment of the invention, the additional active compound is
leptin; see, e.g., "Perspectives in the therapeutic use of leptin", Salvador,
Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on
Pharmacotherapy (2001 ), 2(10), 1615-1622.
In one embodiment, the additional active compound is dexamphetamine or
amphetamine.
!n one embodiment, the additional active compound is flenfluramine or
dexfenfluramine.
In yet another embodiment, the additional active compound is sibutramine.
In one embodiment, the additional active compound is oriistat.
In one embodiment, the additional active compound is mazindol or
phentermine.
In one embodiment, the compounds of the formula I are administered in
combination with bulk materials, preferably insoluble bulk materials (see,
e.g., Carob/Caromax~ (Zunft H J; et al., Carob pulp preparation for
treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-
Oct), 18(5), 230-6), Caromax is a carob-containing product from Nutrinova,
Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst,
65926 FrankfurtlMain)). The combination with Caromax~ can be effected in
CA 02481817 2004-10-07
16
one preparation or by administering compounds of the formula I and
Caromax~ separately. fn this connection, Caromax~ can also be
administered in the form of foodstuffs, such as in bakery products or muesli
bars.
It will be understood that each suitable combination of the compounds
according to the invention with one or more of the abovementioned
compounds and, as desired, one or more further pharmacologically active
substances, is regarded as coming within the protective scope of the
present invention.
CA 02481817 2004-10-07
17
CH3
O ~N / O~CH3
CH~
OH HN~N
O NH CH3 HaC /. ~ CHa
CH3 \ CH3 OPC-14117
O CHa
JTT-705 CI
O
00
CI
\ O SB-204990 HO OH
\ CHa
O P~O~../
/ ~O~CHa
N
NO-1886 O OH
HaC OH O CHa
H3C O CHa
O CI-1027
HO~ //
\ / S\ H3C CHa
O O O
/ O \ ~ /P/ \/ CHa
i
HaC'O/CH3
BMS-188494 v ~ ~CHa
O O
CHa
OOH
\ ( H
\'_~N O \
O O ~ /
CH3
O 61262570
O \ 'i~
N O / O H \
JTT-501
The examples which are adduced below serve to explain the invention
without, however, limiting it.
CA 02481817 2004-10-07
O.
N
~C ~C.'L.Y ~C~CY Y ~C 'C.Y ~C
O O O O O O O O O O O O
,,.
~
i ~ i i ~ ~ ~ ~ ~ i
I =
Z Z Z Z 2 Z Z S Z Z Z I
-
~
'
Z 2 Z 2 Z 2 Z Z Z I Z I
N
Z-~
U
e~O O O = = U U U
~ Z Z Z O O U O O U U O O
o
Z Z
Z I Z Z Z Z Z Z I I
G:Z Z I Z Z Z Z Z Z Z I T
o~
0
Z Z Z Z T Z Z
Z = Z Z =
= U U = U = = U U U U Z
= v v z v = z ~tv
U U U U U U U U U U U vi
N N N N N N N N N N N N
7C~ N M ~ tntDI~ CO~ ~
T T
L
X
W
N
cB
H
CA 02481817 2004-10-07
a
i I
T
x x x ~cY ~c.~cx x Y x x ~c.x ~cx x x x~x
0 0 0 0 0 0 0 o 0 o O o 0 0 o O o o O
t jo
L
j
'
" " " " " " " " " "
~ w = z z z z = z z z zl z z z z z z z z z
z z z z z z z z z z z z z z z z z z z z
1 ,
z z z z z z Iz z z z z z T z z z z z z z
I
c~= z i z z z z z z z
U U U U U U U U U U U U U U U U U U U U
O O O O O O O O O O
2 z I z z z z Z Z z z Z z z Z I z Z ~=I
f
Z z z z I z z T z z z z z Z Z z z Z ~zZ
-
i
z = ~
I
0
'- Z z = = L ~, ~zz _ ,_ z
~ z
Z = _ = z = z Z z = _ = U U = = z = z
z = U U z U z T = Z ,U z v v U IU I~II y
= z W n = ~ _ = I= T ~ = I 2 '~~t ~t~ 'r
Q'~ U U U ti U U ii'u.U ,U U U U ~u,u._~tiu~ i
, v U
c~ c~7N N ~ c'~N N M M c~ N N N N N N ~
tiU ~
N
N
N
X ~M ~ Lf~Cflt~ O~~~O ~r N C'7~'tn GD~~C~O~rC~L
[(,/r Ir~r jr r ~Ir ~N IN~N ~N ~N
Ir ,N ~ I ~N IN
~i ~N
i ,N
'M
~M
~M
I
,:
CA 02481817 2004-10-07
r op N D to - ~ N
N N c N ~ c N N
N r N
.
x
~C ,G~L Y ~C ~L~C ~C~C 'S~C aC3C Y 3G ~LY Y 1C ~G
O O O O O O O O O O O O O O O O O . O O
( I O
N co
N 1--~ ~ ~ ~ ~ ~ ~ W - ~ ~ ~ ~ ~ . t-
Z Z Z
O O O O O = _ _ _ _ _ _ _ _ _ _ = Z
,
fnP1 1hN7 ihM M P7a M fH
= Z Z Z U U U U U U U . U U U ! U U I
O O O O O U O O U O O
O O
I I Z ~=Z Z Z = I Z Z Z Z Z ~ I Z I Z Z
I Z I Z I Z I 2 I Z Z I Z Z Z Z Z Z Z
Z
o Z 2 Z I S I
Z = S = _ _ _ = = Z Z ~ ti titi ~;Z Z
of a ui= = Z V in W n ~ Z S
u: S = U ~i U u. L
m ts:u=U tiV co~i ti~i U u. u.
sj-= I '~~t d'W n ~ ~ <t ~t~ = et ~ ~t ettt~st
U U U U U U U U U U u. U U U U U U U
U ~ ,
N ;-N N N N N N N N N N N N N N N N N N
N
M ~tsn C~t~ a~0 0 r lNC'~~i'~ COt~-o00 0 s N
c'~M ~M C~~M M M I~t~~t~~'et ~ ~J'd'et d vt ~ ~ tn
CA 02481817 2004-10-07
O
toO c0 c~ D
/ M N
N N N N C N
~
Y
O O O O O O O O O O O O O O O O O O O
I I ,
i
N
, , , , , , , , , , , , , , ~ , , , ,
T M
N I
O U
Z Z I O O Z O I I Z Z I Z 2 Z O 2 Z Z
~
Z 2 Z Z I I Z Z S Z Z 2 Z Z I I Z Z =
_ U O
Z Z I Z Z 2 Z ti tLU U O Z I ZI =
y ~ U
i U Z ~
U N U N
Z Z Z _ _
U U U U I I Z = _ = O O U U U
O O O O O O
I
Z I Z I Z Z I Z = I I Z Z Z Z Z Z Z ~_
Z I I= Z Z I I Z 2 I 2 Z I I Z 2 Z Z I
1
z z I== = _ z z z z z i I
u_U u_ = ~n ~ ~ ~n~.n~n ~.n ti ii
ti t~ titi titi ti u_uW i u_ tili
~ , , , , , = , , , ~ , , , , , , , , ,
~r ~ d-~r ~ ~ ~ ~ ~ ~ ~ ~r ~t ~ d-
U _ __ _ __ m _. __ __ _ _ _ _ _ __ _ _
IY U U U U U U IUU U U ' U U U U U U
, , , , , , , , , , , , U , , , ,
N N N N N N N N N N N N , N N ~NN N N
N _
~< M .~ ~ ICflt~ a0 l00 r-N C'~~ ~ CO 1~-~ O~ CO ~
f ~ ~ I ~ I ! I I ; ~__
CA 02481817 2004-10-07
a
O O
N N
* N N N
.Y Y Y Y .aL Y .Y Y X .~G Y ~C Y ~C .Y
O ,O O O O O O O O O O O O O O p p
, , , , , , , , , , , , , , ,
Q.' _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ = Z
____________
0000000oooooZoo
~ _ ====I=====______
o z = = z r
_ = v z = _ _ _ ~ = r = i z = z
,
c° " _ _ ,~ _ ~ _ _ = U U = ~i tL
_ - ti ~ = a M = W n
v ~t ~t u~ V ~ ~ ~t co ~3 ti ti ~i l~ ti
._ ~' ~ ~ ~ c$ cfl ~ d' v~
U U U m m m ti U U U U U U U U U U
N N N N N N N ~ N N N N N N N (V N
UJ N ~ ~ f~ ~ ~ ~~ O r
O O ~ ~ ~ O ~ O O
CA 02481817 2004-10-07
I
0 0 ; ' i
~N ~ t ' 1~ i '~ i
~ ! , ( ;
*
x ~ ~~ ~ X I~ x ,~
O ~ O O O O O ~ O ' O i O O O O I~ O
jj x
i
1 1 I 1 ~ 1 , 1 , t , 1 ~ 1 1 I . (
i
z ~z z z z z z z z z z z z
(z ~z z z z z z z z z jz z z
N
f3! z z z z z z z z ~z ~z z z z
t'~ N
O z _M
m M c , c~~ c~~ r~ r~ c-z z m U
z z iz z z z z z U z z
U U U U U U U U z U U
0 o to o '0 0 0 o z o 0
i
z z ~z z z z z z z z z z z
I , i
v z z z z z z z Iz z z (z 1z z
Iz
° _ _ = z z = _ ;_ ;z ~= z z
OC ,~ ~ _ ~ ~ , = I ~ ' z s ! u,' uW..~
z z z ~ ,, ~ '
m ~ _.. U ,~: ~~ 'ts: U
u_ t~ d- m U ~.n u~ d- ~ ti u_ u.
I i ~ 1 1 ~ ~ i 1 1
' M
s
U ~U ~U U m U 'U ~ U U U U 'U
C3: N CV N N N ~N ~N ~N (N N ~N N N
r I I ;
i
o ~ ~- I N c~ I d- y ~ c~ r~ a~ ~ c~ o 0
co o~ o~ o~ ~ o~ ~ a~ o~ ~ ~ m ~ O~ o~ ~ .~-- rt- I.
~ I ~ ~ x
CA 02481817 2004-10-07
L
L
O
C
L
U
J
Z
L
O
7
U
N
Q
N
d' v~
N
f~
f~
C
I~
N
U
O
O
O
N
O U
N
C
O N
U
L
.Y
0 ,C
N
.- O
_ O
C
I~
3
° ~ +~
c
o ~- +
U O U
N
CA 02481817 2004-10-07
Example 5 from EP 0 193 249 was synthesized as comparative example A.
Example A has the structure:
0
0 0 ~' I o'~
N_ -N
I I
F H H
5
The compounds of the formula I are characterized by advantageous effects
on sugar metabolism; in particular, they lower the blood sugar level and are
suitable for treating type 2 diabetes. The compounds can therefore be used
on their own or in combination with other blood sugar-lowering active
10 compounds (antidiabetics).
20
The compounds of formula I are furthermore suitable for treating late
damage in diabetes, such as nephropathy, retinopathy, neuropathy and
cardiac infarction, myocardial infarction, peripheral arterial occlusion
diseases, thromboses, arteriosclerosis, syndrome X, obesity,
inflammations, immune diseases, autoimmune diseases, such as AIDS,
asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease,
schizophrenia and infectious diseases.
The activity of the compounds was tested as follows:
Glycogen phosphorylase a activity test
The effect of compounds on the activity of the active form of glycogen
phosphorylase (GPa) was measured in the reverse direction by monitoring
the synthesis of glycogen from glucose 1-phosphate by determining the
release of inorganic phosphate. All the reactions were carried out as
duplicate determinations in 96-well microtiter plates (Half Area Plates,
Costar No. 3696), with the change in absorption due to the formation of the
reaction product being measured, at the wavelength specified below, in a
Multiscan Ascent Elisa Reader (Lab Systems, Finland). In order to measure
the enzymic activity of GPa in the reverse direction, the conversion of
glucose 1-phosphate into glycogen and inorganic phosphate was
measured in accordance with the general method of Engers et al. (Engers
HD, Shechosky S, Madsen NB, Can J Biochem 1970 Ju1;48(7): 746-754)
CA 02481817 2004-10-07
26
but with the following modifications: Human glycogen phosphorylase a (for
example containing 0.76 mg of protein/ml (Aventis Pharma Deutschland
GmbH), dissolved in buffer solution E (25 mM ~3-glycerophosphate, pH 7.0,
1 mM EDTA and 1 mM dithiothreitol), was diluted with buffer T (50 mM
Hepes, pH 7.0, 100 mM KCI, 2.5 mM EDTA, 2.5 mM MgCl2~6H20), and
addition of 5 mg of glycogenlml; to a concentration of 10 Ng of proteinlml.
Test substances were prepared as a 10 mM solution in DMSO and diluted
down to 50 NM with buffer solution T. 10 NI of 37.5 mM glucose, dissolved
in buffer solution T and 5 mg/ml of glycogen, and also 10 pl of a solution of
human glycogen phosphorylase a (10 Ng of protein/ml) and 20 NI of
glucose 1-phosphate, 2.5 mM, were added to 10 mi of the solution. The
basal value of the activity of the glycogen phosphorylase a in the absence
of test substance was determined by adding 10 Ni of buffer solution T
(0.1 % DMSO). The mixture was incubated at room temperature for 40
minutes and the inorganic phosphate which was released was measured
using the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm
D, Anal Biochem 1955 Sep 1;230(10):173-177) but with the following
modifications: 50 NI of a stop solution of 7.3 mM ammonium molybdate,
10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 NI of
the enzyme mixture. After 60 minutes of incubation at 45°C, the
absorption
was measured at 820 nm. In order to determine the background
absorption, the stop solution was added immediately after adding the
glucose 1-phosphate solution in a separate assay. This test was carried out
using a 10 NM concentration of the test substance in order to determine the
respective inhibition of glycogen phosphorylase a by the test substance in
vitro.
CA 02481817 2004-10-07
27
Table 2: Biological activity
Ex. % inhibition Ex. % inhibition
at10 M at10 M
71 52 96
2 85 53 93
3 g3 54 91
4 56 55 100
80 56 96
6 89 57 99
7 93 58 91
8 96 59 92
g 100 60 41
95 61 85
11 95 62 59
12 82 63 92
13 74 64 40
14 70 65 56
90 66 97
16 89 67 92
17 75 68 54
18 64 69 99
1g 94 70 100
85 71 95
21 81 72 99
22 79 73 85
23 59 74 47
24 87 75 84
82 76 98
26 81 77 96
27 90 78 69
2g g1 79 58
2g 72 80 65
95 81 49 '
31 ' 98 82 40
32 ~ 98 83 34
33 ~ 100 84 98
34 ~ 59 85 98
CA 02481817 2004-10-07
28
Ex. % inhibition Ex. % inhibition
at 10 M at 10 M
35 94 86 99
36 96 87 102
37 91 88 gg
38 103 89 102
39 98 90 95
40 92 91 94
41 101 92 95
42 99 93 96
43 100 94 88
44 101 95 96
45 96 96 90
46 92 97 97
47 98 98 95
48 99 99 95
49 103 100 95
50 108 101 100
51 96
Comparative Example A exhibits 3% inhibition at 10 NM.
It can be seen from the table that the compounds of the formula I inhibit the
activity of glycogen phosphorylase a and are therefore well suited for
lowering the blood sugar level. In particular, the compounds of formula I
exhibit an effect which is from 14- to 36-fold higher than that of comparative
example A.
The preparation of one example is described in detail below;
The remaining compounds of formula I were obtained in an analogous
manner, where appropriate using customary protective-group techniques:
CA 02481817 2004-10-07
29
Experimental section:
Example 1:
a) 2- Chlorobenzoyl isocyanate
1.03 g (6.6 mmol) of 2-chlorobenzamide were suspended in 3 ml of
dichloromethane. After 1.17 g (9.2 mmol) of oxalyl chloride had been
added, the mixture was heated to reflux for 17 hours. The reaction mixture
was then concentrated under high vacuum and reacted in step b without
any further purification.
b) 3-[3-(2,4-Dichlorobenzoyl)ureido]-4-methoxybenzoic acid
2-Chlorobenzoyl isocyanate (step a) was taken up in 8 ml of acetonitrile,
and a suspension of 1.1 g (6 mmol) of 4-amino-3-nitrobenzoic acid in 24 ml
of acetonitrile was added. The mixture was heated to reflux for 3.5 hours
and, after it had been cooled down, the precipitate was filtered off, washed
with acetonitrile and dried in vacuo. 1.68 g (77%) of the desired product
were obtained.
M.p.: 240°C (decomposition)
Example 2:
a) 4-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-3-trifluoromethoxybenzoic
acid
The compound was prepared in a one-pot reaction.
30.0 g (155.8 mmol) of 2-chloro-4,5-difluorobenzoic acid were initially
introduced, under a protective gas atmosphere, in a 1 I round-bottomed
flask fitted with a gastight mechanical stirrer and a distillation head. After
300 ml of toluene had been added, 29.01 ml of thionyl chloride were added
while stirring and the mixture was heated to 60°C. At 60°C, the
reaction
mixture was subsequently stirred for 1.5 h, after which 0.1 ml of pyridine
was added. After a further 1.5 h at 60°C, 90 ml of liquid were
distilled off
from the mixture under normal pressure (maximum bath temperature,
125°C). The reaction solution was then cooled down to 20°C and
ammonia
gas was passed in at 20-35°C (cooling with an ice bath) until the
solution
was saturated. After that, 160 ml of THF and 120 ml of deionized water
CA 02481817 2004-10-07
were added to the mixture at 20°C. The aqueous phase was separated off
and the organic phase was washed with a 5% aqueous solution of sodium
hydrogen carbonate. The organic phase was then azeotropically dried by
distilling off 250 ml of liquid in vacuo at 50°C. 17 ml of oxalyl
chloride were
5 added to the reaction suspension, which had been cooled down to 20°C.
The mixture was subsequently stirred at 20°C for 2 h and then
stirred at
50°C for 4 h. 200 ml of liquid were distilled off from the mixture in
vacuo at
50°C, after which 200 ml of toluene were added and 200 ml of liquid
were
once again distilled off in vacuo at 50°C. The mixture was cooled down
to
10 20°C and a solution of 26.49 g (119.8 mmol) of 4-amino-3-(trifluoro-
methoxy)benzoic acid in 75 ml of THF was added. The product was
separated off by filtration through a glass suction filter and dried to
constant
weight in vacuo at 50°C. 52.6 g of the desired product were obtained.
M.p.: 236°C
b) 4-[3-(2-Chloro-4,5-difiuorobenzoyl)ureido]-3-trifluoromethoxybenzoic
acid TRIS salt
A mixture of 10.0 g (22.79 mmol) of 4-[3-(2-chloro-4,5-difluorobenzoyl)-
ureido]-3-trifluoromethoxybenzoic acid and 3.0 g of a,a,a-tris(hydroxy-
methyl)methylamine were heated to reflux in 400 ml of 2-propanol until a
clear solution was formed. The solution was filtered in the hot and
concentrated down to a volume of 310 ml. The product crystallized from the
solution on cooling down to 20°C. 10.4 g of the desired product were
obtained.
M.p.: 176°C
The compounds or' formula I can be prepared by reacting ureas of the
formula 2 or aniline derivatives of the formula 3 with aroyl isocyanates, with
reactive acid derivatives, with acid chlorides or with anhydrides, of the
formula 4,
CA 02481817 2004-10-07
31
R4 O R4 O
O
pR3 ~ OH R3 / OH R$ R7
I
HN~N \ R6 HN \ R6
R1 R2 R5 ~ RrJ R9 r R10
4
in which R1 to R6 have the abovementioned meanings. The resulting free
acids of the formula I can then be converted, with the corresponding bases,
into the corresponding physiologically tolerated salts of the compounds of
the formula I.
For clarification: if formula 4 is an acid chloride, Y is CI, if 4 is an
isocyanate, Y is N=C=O, and if 4 is an anhydride, Y is
O
Rg R7
v
R9 R10
Preference is given to the method of preparing the compounds of the
formula I by way of the aroyl isocyanate 4a, as depicted in the following
scheme:
CA 02481817 2004-10-07
32
for example:
R~ O 1, SOCI2,toluene
R8 2. NH
3(g)
?~ ~OH
3. THF, N20
R9 R10 '~~ NaHC03(a4>
4b
O
R8 R7 O CI CI .
R8 R7 O
~NHZ O ( ~N=~C,,=O
toluene
R9 R10 R9 R10
4a
4c
not isolated
forexample:
1.Toluene /THI=
OH 2. H20
H2N~ Y ~R6
3a
R4 O
forexampl_e:
HO OH 0 OR3 ~ i OH
__~ R8 R7
N"N ~ Rfi
H2N OH ~ ' R1 RZ R5
for example: R9 R10
2-Propanol
R4 O
R8 R7 O OR3 / ) OH
N_ _N ~ R6
R1 R2 R5
R9 R10
HO--~~OH
I
HZN O H
The preparation of I can, in a general manner, take pace in a one-pot
CA 02481817 2004-10-07
33
process, thereby greatly simplifying its industrial-scale preparation. For
this,
4b is converted into the acid chloride in a suitable solvent, for example
toluene, using a suitable reagent, such as thionyl chloride or oxalyl
chloride. As required, a suitable catalyst, such as pyridine, NMP or DMF, is
added for the purpose of completing the reaction. After the unreacted
reagent (such as thionyl chloride) has been removed, the acid chloride is
converted into the acid amide 4b using suitable reagents, such as passing
ammonia gas into the reaction solution or adding a solution of ammonia in
a suitable solvent, such as THF. Sufficient water and a suitable solvent,
such as THF, are added to the reaction mixture to ensure that any solid
goes into solution. After the phases have separated, washing takes place
with sodium hydrogen carbonate solution and the organic phase is
subsequently dried. The acid amide 4b is converted into the aroyl
isocyanate 4a by adding oxalyi chloride and then heating. After the
unreacted oxaiyl chloride has been removed, the aniline 3a is dissolved in
a suitable solvent, such as THF, and added to the solution of the aroyl
isocyanate 4a, with the reaction product precipitating from the solution. The
compound of the formula I is separated off by filtration. The TRIS salt of the
compound of the formula I crystallizes after the compound of the formula I
has been dissolved with TRIS at boiling heat in a suitable solvent, such as
2-propanol, when the solution is subsequently cooled.
