Note: Descriptions are shown in the official language in which they were submitted.
CA 02513286 2005-07-13
WO 2004!065356 PCT/EP2004/000041
Description
Carbonyl-amino substituted acyl phenyl urea derivatives, method for the
production and use thereof
The invention relates to carbonylamino-substituted acyl phenyl urea
derivatives, and also to their physiologically tolecated salts and
physiologically functional derivatives.
WO 9946236 (Novo Nordisk) describes carbonylamino-substituted acyl
phenyl urea derivatives (Example 1) which are effective in the event of type
2 diabetes.
WO 00/07991 (PCT/GB99/02489 Astra Zeneca) describes amide
derivatives as inhibitors of the formation of cytokines.
It is an object of the invention to provide compounds which make possible
prevention and treatment of type II diabetes. To this end, the compounds
should in particular exhibit a therapeutically utilizable blood sugar-lowering
action.
The invention therefore relates to compounds of the formula I
R4
R3 R~
o ~ i ' o
R8
N N \ N~R7
R9
R1 R2 R6
R10 R11
in which
R8, R9, R10, R11 are each independently H, F, CI, Br, OH, N02, CN,
O-(C~-Cg)alkyl, O-(C2-Cg)alkenyl, O-(C2-Cg)alkynyl,
O-S02-(C1-C4)-alkyl, (C~-Cg)-alkyl, (C2-Cg)-alkenyl or
(C2-Cg)aikynyi, where alkyl, alkenyl and alkynyl may be
polysubstituted by F, CI or Br;
CA 02513286 2005-07-13
WO 2004/065356 2 PCT/EP2004/000041
R1, R2 are each independently H, (C~-Cg)-alkyl, where alkyl may be
substituted by OH, O-(C~-C4)-alkyl, NH2, NH(C~-C4)-alkyl,
N[(C~-Cg)-alkyl]2, or are O-(C~-Cg)-alkyl, CO-(C~-Cg)-alkyl,
COO-(C~-Cg)-alkyl, (C~-Cg)-alkylene-COOH or (C~-Cg)-
alkylene-COO-(C~-Cg)-alkyl;
R3, R4, R5, R6 are each independently, H, F, CI, Br, NOZ, CN, O-R12,
O-phenyl, S-R12, COOR12, N(R13)(R14), (C~-Cg)-alkyl,
(C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Cg-C7)-cycloalkyl, (C3-C~)-
cycloalkyl-(C~-Cq.)-alkylene or O-(C~-C5)-alkyl-COOR12,
where alkyl, cycloalkyl, alkylene and alkynyl may be
polysubstituted by F, CI, Br, OR12, COOR12 or N(R13)(R14);
R7 is H, (C~-Cg)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-
(Ct-C4)-alkylene, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C~-Cg)-
alkylcarboxy-(C~-Cg)-alkylene, COOR12, (Cg-Cep)-aryl,
(Cg-Cep)-aryl-(C~-C4)-alkylene, heterocyclic radical,
heteroaryl-(C~-C4)-alkylene or heteroarylcarbonyl, where
alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be
polysubstituted by F, CI, Br, OR12, COOR12, CONH2,
CONH(C~-Cg)-alkyl, CON[(C~-Cg)-alkyl]2 or N(R13)(R14),
and where aryl and heteroaryi may be poiysubstituted by F,
CI, Br, N02, CN, O-R12, S-R12, COOR12, N(R13)(R14) or
(C~-Cg)-alkyl;
R12 is H, (C~-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)-alkynyl, where
alkyl, alkenyf and alkynyf may be polysubstituted by F, CI, Br,
OH or O-(C~-C4)-alkyl,
R13, R14 are each independently H, (C~-Cg)-alkyl, (C2-Cg)-alkenyl,
(C2-Cg)-alkynyl, (C3-C~)-cycloalkyl, (C3-C~)-cycloalkyl-
(C~-C~)-afkylene, COO-(Ct-C4)-alkyl, COO-(C2-C4)-alkenyl,
phenyl or S02-phenyl, where the phenyl ring may be up to
disubstituted by F, CI, CN, OH, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl,
CF3, OCF3, COOH, COO(C~-Cg)-alkyl or CONH2;
CA 02513286 2005-07-13
WO 2004/065356 3 PCT/EP2004/000041
where R13 and R14, together with the nitrogen atom to which they are
bonded, may form a 3-7 membered, saturated, heterocyclic
ring which may contain up to 2 further heteroatoms from the
group of N, O and S, where the heterocyclic ring may be up to
trisubstituted by F, CI, Br, OH, oxo, N(R21)(R22) or (C~-C4)-
alkyl;
R21, R22 are each independently H, (C~-Cg)-alkyl, (C2-Cg)-alkenyl,
(C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C~)-cycloalkyl-
(C~-C4)-alkylene, COO-(C~-C4)-alkyl, COO-(C2-C4)-alkenyl,
phenyl or S02-phenyl, where the phenyl ring may be up to
disubstituted by F, CI, CN, OH, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl,
CF3, OCF3, COOH, COO(C~-Cg)-alkyl or CONH2;
excluding compounds of the formula I in which the radicals are at the same
time defined as follows:
R5 is halogen or unsubstituted (C~-Cg)-alkyl, R7 is heterocyclic radical or
heteroaryl;
and their physiologically tolerated salts.
Preference is given to compounds of the formula I in which one or more
radicals are defined as follows:
R8, R9, R10, R11 are each independently H, F, Cl, Br, OH, N02, CN,
O-(C~-Cg)-alkyl, where alkyl may be polysubstituted by F, CI
or Br;
R1, R2 are each H;
R3, R4, R5, R6 are each independently, H, F, CI, Br, N02, CN, O-R12,
O-phenyl, S-R12, COOR12, N(R13)(R14), (C~-Cg)-alkyl,
(C2-Cg)-alkenyl, (CZ-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-
cycioalkyl-(C~-C4)-alkylene or O-(C~-C5)-alkyl-COOR12,
where alkyl, cycloalkyl, alkylene and alkynyl may be
polysubstituted by F, CI, Br, OR12, COOR12 or N(R13)(R14);
CA 02513286 2005-07-13
WO 2004/065356 4 PCT/EP2004/000041
R7 is H, (C~-Cg)-alkyl, (C3-C7)-cycloalkyl, (C2-Cg)-alkenyl,
(C2-Cg)-alkynyl, (C~-Cg)-alkylcarboxy-(C~-Cg)-alkylene,
COOR12, (Cg-Cep)-aryl, (Cg-Cep)-aryl-(C~-C4)-alkylene,
heteroaryl, heteroaryl-(C~-C4)-alkylene or heteroarylcarbonyl,
where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be
polysubstituted by F, CI, Br, OR12, COOR12, CONH2,
CONH(C~-Cg)-alkyl, CON[(C~-Cg)-alkyl]2 or N(R13)(R14),
and where aryl and heteroaryl may be polysubstituted by F,
CI, Br, N02, CN, O-R12, S-R12, COOR12, N(R13)(R14) or
(C~-Cg)-alkyl;
R12 is H, (C~-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)-alkynyl, where
alkyl, alkenyl and alkynyl may be polysubstituted by F, CI, Br,
OH or O-(C~-C4)-alkyl,
R13, R14 are each independently H, (C~-Cg)-alkyl, (C2-Cg)-alkenyl,
(C2-Cg)-alkynyl, (Cg-C7)-cycloalkyl, (C3-C~)-cycloalkyl-
(C~-C4)-alkylene, COO-(C~-C4)-alkyl, COO-(C2-C4)-alkenyl,
phenyl or S02-phenyl, where the phenyl ring may be up to
disubstituted by F, CI, CN, OH, (C~-Cg)-alkyl, O-(C~-Cg)-alkyl,
CF3, OCF3, COOH, COO(C~-C6)-alkyl or CONH2; where R13
and R14, together with the nitrogen atom to which they are
bonded, may form a 3-7 membered, saturated, heterocyclic
ring which may contain up to 2 further heteroatoms from the
group of N, O and S, where the heterocyclic ring may be up to
trisubstituted by F, CI, Br, OH, oxo, N(R21)(R22) or (C~-C4)-
alkyl;
R21, R22 ace each independently H, (C~-Cg)-alkyl;
excluding compounds of the formula I in which the radicals are at the same
time defined as follows:
R5 is halogen or unsubstituted (C~-Cg)-alkyl, R7 is heterocyclic radical or
heteroaryl;
and their physiologically tolerated salts.
CA 02513286 2005-07-13
WO 2004!065356 5 PCT/EP20041000041
Particular preference is given to compounds of the formula 1 in which one
or more radicals are defined as follows:
R8, R9, R10, R11 are each independently H, F or CI;
R1, R2, R4, R6 are each H;
R3, R5 are each independently H, CI, OR12, COOR12, N(R13)(R14)
or (C~-Cg)-alkyl;
R7 is (C~-Cg)-alkyl, where alkyl may be polysubstituted by F,
OR12, COOR12 or N(R13)(R14), or is (C3-Cg)-cycloalkyl,
(C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C~-C5)-alkylcarboxy-
(C~-Cg)-alkylene, COOR12, phenyl, where phenyl may be
polysubstituted by F, OMe or OCF3, or is benzyl whose
phenyl ring may be substituted by OMe, pyridyl, thienyl,
furanyl, indolylcarbonyl, benzofuranyl, where benzofuranyl
may be substituted by CI or OMe;
R12 is H or (C~-Cg)-alkyl, where alkyl may be polysubstituted by
F;
R13, R14 are each independently H or (C~-Cg)-alkyl; or
R13 and R14, together with the nitrogen atom to which they are bonded,
may form a 5-membered, saturated heterocyclic ring;
excluding compounds of the formula 1 in which the radicals are at the same
time defined as follows:
R5 is halogen or unsubstituted (C~-Cg)-alkyl, R7 is heterocyclic radical or
heteroaryl;
and their physiologically tolerated salts.
The invention relates to compounds of the formula I, in the form of their
racemates, racemic mixtures and pure enantiomers, and also to their
diastereomers and mixtures thereof.
CA 02513286 2005-07-13
WO 2004/065356 6 PCT/EP2004/000041
The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9,
R10, R11, R12, R13, R14, R21 and R22 may be either straight-chain or
branched.
When radicals or substituents can occur more than once in the compounds
of the formula I, for example O-R12, they may each independently be as
defined and be the same or different.
As a consequence of their higher water solubility compared to the starting
or basic compounds, pharmaceutically acceptable salts are particularly
suitable for medical applications. These salts have to have a
pharmaceutically acceptable anion or cation. Suitable pharmaceutically
acceptable 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, e.g. acetic acid, benzenesulfonic acid, benzoic acid, citric
acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,
isethionic acid, lactic acid, lactobionic acid, maieic acid, malic acid,
methanesuifonic acid, succinic acid, p-toluenesulfonic acid and tartaric
acid. Suitable pharmaceutically acceptable basic salts are ammonium salts,
alkali metal salts (such as sodium and potassium salts), alkaline earth
metal salts (such as magnesium and calcium salts), trometamol (2-amino-
2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or
ethylenediamine.
Salts having a pharmaceutically unacceptable anion, for example
trifluoroacetate, are likewise encompassed by the scope of the invention as
useful intermediates for the preparation or purification of pharmaceutically
acceptable salts and/or for use in nontherapeutic, for example in vitro,
applications.
The term "physiologically functional derivative" used herein refers to any
physiologically tolerated derivative of a compound of the formula I
according to the invention, e.g. an ester which is able, on administration to
a mammal, e.g. a human, to (directly or indirectly) form a compound of the
formula I or an active metabolite thereof.
CA 02513286 2005-07-13
WO 20041065356 7 PCT/EP2004/000041
The physiologically functional derivatives also include prodrugs of the
compounds according to the invention, for example as described in H.
Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be
metabolized in vivo to a compound according to the invention. These
prodrugs may or may not be active themselves.
The compounds according to the invention can also exist in different
polymorphous forms, for example as amorphous and crystalline
polymorphous forms. All polymorphous forms of the compounds according
to the invention ace encompassed by the scope of the invention and are a
further aspect of the invention.
Ail references given below to "compound(s) of formula I" refer to
compounds) of the formula I as described above, and also to their salts,
solvates and physiologically functional derivatives as described herein.
In this context, an aryl radical is a phenyl, naphthyl, biphenyl,
tetrahydronaphthyl, alpha- or beta-tetralon, indanyl or indan-1-onyl radical.
The terms "heterocyclic ring" and "heterocyclic radical" used herein relate
to heteroaryl radicals and heterocycloalkyl radicals which derive from 3 to
10 membered carbon rings in which one or more carbon atoms are
replaced by one or more atoms selected from the group of oxygen, sulfur
and nitrogen.
Suitable "heterocyclic rings" and "heterocyclic radicals" are acridinyl,
azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl,
benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
quinazolinyl, quinolinyl, 4H-quinolizinyi, quinoxalinyl, quinuclidinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-
dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolinyl,
indolizinyl,
indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyi,
isoindolyl, isoquinolinyl, (benzimidazolyl), isothiazolyl, isoxazolyl,
morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-
oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazoiyl,
oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl,
CA 02513286 2005-07-13
WO 2004/065356 8 PCT/EP2004/000041
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl,
pyrazinyl,
pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinofinyl,
tetrahydroquinolinyl, 6H-1,2;5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl,
triazolyl,
tetrazolyl and xanthenyl.
Pyridyl is either 2-, 3- or 4-pyridyl. Thienyl is either 2- or 3-thienyl.
Furyl is
either 2- or 3-furyl.
Also included are the corresponding N-oxides of these compounds, for
example 1-oxy-2-, 3- or 4-pyridyl.
Also included are one or more benzofused derivatives of these
heterocycles.
The compounds) of the formula (1) can also be administered in
combination with further active ingredient.
The amount of a compound of formula I which is required in order to
achieve the desired biological effect is dependent upon a series of factors,
for example the specific compound selected, the intended use, the mode of
administration and the clinical condition of the patient. The daily dose is
generally in the range from 0.3 mg to 100 mg (typically from 3 mg and
50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day.
An intravenous dose may, for example, be in the range from 0.3 mg to
1.0 mg/kg and may advantageously be administered as an infusion of from
10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for
these purposes may, for example, contain from 0.1 ng to 10 mg, typically
from 1 ng to 10 mg, per milliliter. Individual doses may contain, for
example, from 1 mg to 10 g of the active ingredient. Ampoules for injections
may therefore contain, for example, from 1 mg to 100 mg, and single dose
formulations which can be administered orally, for example tablets or
capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10
to 600 mg. The compounds of formula I may be used for therapy of the
abovementioned conditions as the compounds themselves, although they
CA 02513286 2005-07-13
WO 2004/065356 9 PCT/EP2004/000041
are preferably in the form of a pharmaceutical composition with an
acceptable carrier. The carrier of course has to be acceptable, in the sense
that it is compatible with the other constituents of the composition and is
not damaging to the health of the patient. The carrier may be a solid or a
liquid or both and is preferably formulated with the compound as a single
dose, for example as a tablet, which may contain from 0.05 to 95% by
weight of the active ingredient. Further pharmaceutically active substances
may likewise be present, including further compounds of formula 1. The
pharmaceutical compositions according to the invention may be produced
by one of the known pharmaceutical methods which consist essentially of
mixing the ingredients with pharmacologically acceptable carriers and/or
excipients.
Pharmaceutical compositions according to the invention are those which
are suitable for oral, rectal, topical, peroral (for example sublingual) and
parenteral (for example subcutaneous, intramuscular, intradermal or
intravenous) 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 type of the compound of formula I
used in each case. Coated formulations and coated slow-release
formulations are also encompassed by the scope of the invention.
Preference is given to acid- and gastric fluid-resistant formulations.
Suitable
gastric fluid-resistant coatings include cellulose acetate phthalate,
polyvinyl
acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic
polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the
form of separate units, for example capsules, cachets, lozenges or tablets,
each of which contains a certain amount of the compound of formula I; as
powder or granules; as solution or suspension in an aqueous or
nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These
compositions may, as already mentioned, be prepared by any suitable
pharmaceutical method which includes a step in which the active ingredient
and the carrier (which may consist of one or more additional ingredients)
. 35 are brought into contact. In general, the compositions are prepared by
uniform and homogeneous mixing of the active ingredient with a liquid
and/or finely divided solid carrier, after which the product is shaped if
necessary. For example, a tablet can be produced by compressing or
CA 02513286 2005-07-13
WO 2004/065356 10 PCT/EP2004/000041
shaping a powder or granules of the compound, optionally with one or more
additional ingredients. Compressed tablets can be prepared by tableting
the compound in free-flowing form, for example a powder or granules,
optionally mixed with a binder, lubricant, inert diluent and/or one (or more)
surfactants/dispersants in a suitable machine. Shaped tablets can be
prepared by shaping the pulverulent compound moistened with an inert
liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual)
administration include lozenges which contain the compound of formula I
with a flavoring, customarily sucrose, and gum arabic or tragacanth, and
pastilles which include the compound in an inert base such as gelatin and
glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration include
preferably sterile aqueous preparations of a compound of formula I which
are preferably isotonic with the blood of the intended recipient. These
preparations are preferably administered intravenously, although the
administration may also be subcutaneous, intramuscular or intradermal as
an injection. These preparations can preferably be produced by mixing the
compound with water and making the solution obtained sterile and isotonic
with the blood. The injectable compositions according to the invention
generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are
preferably in the fom-~ of single dose suppositories. These can be prepared
by mixing a compound of formula I with one or more conventional solid
carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical use on the skin are
preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or
oil. Useful carriers include petroleum jelly, lanolin, polyethylene glycofs,
alcohols and combinations of two or more of these substances. The active
ingredient is generally present in a concentration of from 0.1 to 15% by
weight of the composition, preferably from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical
compositions for transdermal applications may be in the form of single
CA 02513286 2005-07-13
WO 2004/065356 11 PCT/EP2004/000041
plasters which are suitable for long-term close contact with the epidermis of
the patient. Such plasters advantageously contain the active ingredient in
an optionally buffered aqueous solution, dissolved and/or dispersed in a
tackifier or dispersed in a polymer. A suitable active ingredient
concentration is from approx. 1 % to 35%, preferably from approx. 3 to 15%.
A particular means of releasing the active ingredient is by electrotransport
or iontophoresis, as described, for example, in Pharmaceutical Research,
2(6): 318 (1986).
Further useful active ingredients for combination products are as follows:
All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They can be
combined with the compounds of the formula I according to the invention,
in particular for synergistic enhancement of the action. The active
ingredient combination can be administered either by separately
administering the active ingredients to the patient or in the form of
combination products in which a plurality of active ingredients are present
in one pharmaceutical preparation. Most of the active ingredients listed
hereinbelow are disclosed in USP Dictionary of USAN and International
Drug Names, US Pharmacopeia, Rockville 2001.
Antidiabetics include insulin and insulin derivatives, for example Lantus~
(see www.lantus.com) or HMR 1964, fast-acting insulins (see US
6,221,633), GLP-1 derivatives, for example those disclosed in WO
98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active
ingredients.
The orally active hypoglycemic active ingredients preferably include
sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,
thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1
agonists, potassium channel openers, for example those disclosed in WO
97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers,
inhibitors of liver enzymes which are involved in the stimulation of
gluconeogenesis andlor 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 PXR agonists and active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an HMGCoA reductase inhibitor such as
CA 02513286 2005-07-13
WO 2004/065356 12 PCT/EP2004/000041
simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,
rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a cholesterol absorption inhibitor, for
example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula f are
administered in combination with a PPAR gamma agonist, for example,
rosigRtazone, piogRtazone, JTT-501, GI 262570.
fn one embodiment of the invention, the compounds of the formula 1 are
administered in combination with PPAR alpha agonist, for example,
GW 9578, 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, for
example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in
PCTIUS 11833, PCT/US 11490, DE10142734.4.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a fibrate, for example, fenofibrate,
clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an MTP inhibitor, for example,
implitapide, BMS-201038, R-103757.
fn one embodiment of the invention, the compounds of the formula I are
administered in combination with bile acid absorption inhibitor (see, for
example, US 6,245,744 or US 6,221,897), for example, HMR 1741.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a CETP inhibitor, for example, JT'T-705.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a polymeric bile acid adsorbent, for
example, cholestyramine, colesevelam.
CA 02513286 2005-07-13
WO 2004/065356 13 PCTlEP2004/000041
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), for example, HMR1171, HMR1586.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an ACAT inhibitor, for example,
avasimibe.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an antioxidant, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipoprotein lipase inhibitor, for example,
NO-1886.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with an ATP-citrate lyase inhibitor, for
example, SB-204990.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a squalene synthetase inhibitor, for
example, BMS-188494.
In one embodiment of the invention, the compounds of the formula I are
administered in combination with a lipoprotein(a) antagonist, for example,
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, for example, 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 I are administered in
combination with a sulfonylurea, for example, tolbutamide, glibenclamide,
glipizide or glimepiride.
In one embodiment, the compounds of the formula I are administered in
combination with a biguanide, for example, metFormin.
CA 02513286 2005-07-13
WO 2004/065356 14 PCT/EP2004/000041
In yet another embodiment, the compounds of the formula I are
administered in combination with a meglitinide, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with a thiazolidinedione, for example, troglitazone, ciglitazone,
pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of
Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-
methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination with an a-glucosidase inhibitor, for example, miglitol or
acarbose.
In one embodiment, the compounds of the formula I are administered in
combination with an active ingredient which acts on the ATP-dependent
potassium channel of the beta cells, for example, tolbutamide,
glibenclamide, glipizide, glimepiride or repaglinide.
fn one embodiment, the compounds of the formula 1 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 trogiitazone, insulin and lovastatin, etc.
In a further embodiment, the compounds of the formula 1 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-yfamino)methyl]cyciohexylmethyl}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-
oxo-ethyl]amide; (WO 01!91752)), orexin antagonists (e.g. 1-(2-
methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea 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]dipropylamine (WO 00/66585)),
CRF BP antagonists (e.g. urocortin), urocortin agonists, X33 agonists (e.g.
1-(4-chloro-3-methanesulfonylmethy!phenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-
yloxy)ethylamino]ethanol hydrochloride (WO 01/83451)), MSH
CA 02513286 2005-07-13
WO 2004!065356 15 PCT/EP2004/000041
(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 00171549), 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-
~ agonists.
In one embodiment of the invention, 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.
In one embodiment, the other active ingredient is dexamphatamine or
amphetamine.
In one embodiment, the other active ingredient is fenfluramine or
dexfenfluramine.
In another embodiment, the other active ingredient is sibutramine.
In one embodiment, the other active ingredient is orlistat.
In one embodiment, the other active ingredient is mazindof or phentermine.
In one embodiment, the compounds of the formula I are administered in
combination with dietary fiber materials, preferably insoluble dietary fiber
materials (see, for example, Carob/CaromaxC~ (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 supplied by Nutrinova, Nutrition Specialties & Food Ingredients
GmbH, Industriepark Hochst, 65926 FrankfurtlMain)). Combination with
CA 02513286 2005-07-13
WO 2004/065356 16 PCT/EP2004/000041
Caromax~ is possible in one preparation or by separate administration of
compounds of the formula I and Caromax~. Caromax~ can also be
administered in the form of foodstuffs, for example, in bakery products or
muesli bars.
It will be appreciated that any suitable combination of the compounds
according to the invention with one or more of the abovementioned
compounds and optionally one or more further pharmacologically active
substances is regarded as being covered by the scope of protection of the
present invention.
CA 02513286 2005-07-13
WO 2004/065356 17 PCT/EP2004/000041
CH_
/ O~CH3
OPC-14117
JTT-705 CI
,, o
~ v ~ oO
cl
Br I \ O sB-2oasso Ho off
/ N \ _CH~
O O
H ~ / \P~O CH
N 3
NO-1886 O OH
H3C OH O CH3
HOC O CHI
BMS-
p CI-1027
O
CH3
O / ~ ~OH
N ~ O \ ~ H \
O ~ /
GI 262570
O \
CH3
\ ~ ~ ~ / ~~o
N O O ~'NH
JTf-501
The examples recited hereinbelow serve to illustrate the invention, but
without restricting it.
CA 02513286 2005-07-13
WO 2004/065356 18 PCT/EP2004/000041
No example which is exactly analogous to compounds of the formula I is
cited in WO 9946236. Example A was therefore selected as the most
similar compound. The compounds of this application are distinguished
from Comparative Example A are distinguished by an increased activity on
glycogen phosphorylase a, see Table 2.
2004/065356 19 PCT/EP2004/000041
,~ O
z=
z
o / \ ~ -
\ /
N
=Z ~ Z - ~
Z- ~
O
/
O
a'
_N
7
E
O
N
~
_
N
O
N
x a
u~
E
a~ c~
_> x
r-'
a
c
..
m
Q
a~
0
~
U H
0
CA 02513286 2005-07-13
2004/065356 20 PCT/EP2004/000041
CA 02513286 2005-07-13
~ _ _ _= == = I2 = == I2 = =~=I2 = ='== 22 2= 2 2=
o
LLlLLLLLI1.LLLLlltLLLLLLLliLLLLlLLLLLlLLLLLtiLLtiLLti11LLlLlL
y n aimw wnu~u~~c7w nu u~u7w mm mn m ~n~n m m mn
tilililitititililitiLL.lLl1.LLLLLLLiLt.lilililitiLitiliLilt.lili
of~
~t~tvtst~~t~ ~tetet~t~ ~t~t~tv~ ~~ ~ ~t~ ~ ~~t~~ eh~~
~ U U UU UU U UU U UU UU U UU UU U UU U UU UU U UU
N N NN NN N NN N NN NN N NN NN N NN N NN NN N NN
~ U = = Z U 2
U O O
~ Z U2 ~ ~~ - _
O
O U U O ~U O p U=pOU OO V V= U Oc --~U o '~o
N NN Nf~N NN Ih N N tn ~ O O
U O
NN N N N _
= o == == = == o =o =o = == == o =o = =a te
U U UU UU U UU U UU UU U UU UU U UU U Uc%~c~U U c~U
cu
~ _ _ __ __ _ _= = == Z2 Z S
= Z2 = =Z 2 == =I 2 Z2
_ _ _ _
U U U U
N N N N
I I Z Z
=U U= U U= =
, 00 00 0 00 0
U U UU U == == = 00 00 0 00 0
= = == =O O OO O UU UU U UU UU U UU U 2= == 2 ==
~ _ _ == == Z 2= = =2 2=
= =Z 2= = == = == =2 2 ==
M
e~7m ~n,efo,e~,c~M roe,v,~,a7~,e,e~o,~e~,
_n,M e~~,n =_
U U UU U= = == = UU UU U UU UU U UU U UU UU U UU
O O OO OU U UU U 00 00 0 00 00 0 00 0 00 00 0 00
N
~ ~ InOh QD~ O rN f''7~tn(p1~00OO rN M ettnto1~OD~O r NCh
( r rr r rr rr r r(1~NN N NN N NN~N('~c'~C'~M
2004/065356 I 21
PCT/EP2004/000041
CA 02513286 2005-07-13
2 ZZ I 2Z Z ZI Z= Z ZZ Z ZZ Z ZZ 2Z 2 Z I
0 = 2=
LiLLLLLiLLLLLlti.LLL1LLLL.LLLLLLLLLLLlLLLLu.lLLL Li iL
r- tnIntL~LI~l0tntf~tntt7l0tntf~tnLf~tnIntl~lf~tnlt7tnlf~l~ Ll lL
tnL~tf7~
lilitl.u.tLLLu.LLLLlLLilLLLLLLLLLtiliLLtLLLLLLi L. Ltt
i
~tr1~t~t~ ~et~t~ et~t~ ~ ~et~t~~ V~ ~t ltiLl
W ~tet
t
~ U UU U UU U UU UU U UU U UU U UU UU U U UU
U
N NN N NN N NN NN N NN N NN N NN NN N
NN NN
N~ -
C
C~ t- G1
f0N
C OC ~ S -
~O
O~ _ X w
U
c - c - cv w - o m
U = d o N -
= ~ t co - s t O U E N ccr= -~ w
- c ,c _
0 00 00 0 00 ~ o ~ ~ O o NZ c~az Z ~U
~ ~ N U ~ _N C
m ~~ ~L 3 C~C ~O +.' 0 Z ~ '
' '
~ au.~ ~ ~ ~~ ~W i mm = N~ = i i
m
cy~en ui~ v c~_ U ri.'-c U Ua N UU ~U ~ mV uId
~ = 2= _ __ _ =2 == 2 =_ = 2= _ __
__ _ __ =2
u~
_ __ _ __ = 2= __ _ __ _ __ _ __ =2 = __ __
~ _ __ _ _= 2 == 22 = __ _ __ _
_= 2= _
_ _= S 2= _ __ __ _ __ _ __ _ =2 =2 =
__ __
U UU U UU U UU UU U UU U UU U UU UU U UU UU
0 00 0 00 0 00 00 0 00 0 00 0 00 00 0 00 00
N
lljc'~~MM C~C~7M ~ ~~'vttt~ ~ ~~ tt'~~ tl)1~1V71n~~ ~ ~ ~
~ CO
2004/065356 22 PCT/EP2004/000041
CA 02513286 2005-07-13
'C7
N
U
N
'D
U
fd
3
z
-
~ x x xx xx x xx xx x xx x xx zx x xx x= x xx xE
~i~i~iuuiu:univi~ivi~i~iW i ti W i vi~i~iii
2x x x= x
u m mw m m w m w w m n W
m w ~n
__ _ __ _
vivitiu.tiu.tititititivitita.~ u.u:UU U UU UtititiiitiU
ai~ ~ ~~ ~~ ~ ~~ ~i ~
~ ~ v ~~r~v ~ ~v vv ~ vv et~rv ~v v ~~ wt v ~v v
U U UU UU U UU UU U UU U UU UU U UU UU U UU U
E
N " NN "N " N" "N , ~~ , .N "" N "N "N " N" N
N N N N N N NN N N NN N N N N
'S
(6
N
Q
L
U
o = _ o o o E
_ N o
O =O V O V O O OO N= U UU
= UO x =O = O O OO xZ x xx OU =
N O U U U U O U UU U U UU U
U
U O O N
= = == O= = O= =Z 2 == Z 2= == = == 22 = ZO OC
U
U U UU UU U UU UU U UU U UU U U UU UU U UU Uto
~ x x =x xx x xx xx x xx x xx xx x xx x2 x xx x
N
I
U
O ~U
x x Ux xx x xx xx x xx x xx xx = xx xx x xx x(~
ca
~ x x xx xx x xx xx x xx x xx xx x xx xx x xx x
U
C_ C C ~ Z
_ .O .D ,'C ~- L
O'rO 'rO ~ U
c7tht~m P!f'7Pff~1'!1~ N ~ ~ ~L. t~(~
x x xu titLtitiIiu= x x x
. . U U ''
U U UU UU U UU UU U 0.U a Ua. ..
O O OO OO O OO OZ Z ZZ Z ZZ xx U U0 0U U UU U~ U
N
~ x x xx xx x xx xx x x2 x xx xx = xx xx = xx x
_ ~ N
C
~
x x 2x x= = xx xx x xx x xx xx x xx =x x x= =N E
1C~ N M~t~COI~00O Or N M~ l!7(Dt~OGO p ~N c7'V~ COI~CO
11,1(DO fD(O(DCD(OCD(~t~h-i~NI~1~P.t~.1~t~~poQ00GOo0GOo0CO00
~U
N
_N
E
x
a~
a~
s
L
0
CA 02513286 2005-07-13
WO 2004/065356 23 PCT/EP2004I000041
The effectiveness of the compounds was tested as follows:
Glycogen phophorylase 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 reactions were carried out as duplicate
determinations in 96-well microtiter plates (half area plates, Costar No.
3696), and the change in absorption as a consequence of the formation of
the reaction product was measured at the wavelength specified below in a
Multiskan Ascent Elisa Reader (Lab Systems, Finland).
In order to measure the GPa enzyme activity in the reverse direction, the
conversion of glucose 1-phosphate to glycogen and inorganic phosphate
was measured by the general method of Engers et al. (Engers HD,
Shechosky S, Madsen NB, Can J Biochem 1970 Ju1;48(7):746-754) with
the following modifications: human glycogen phosphorylase a (for example
containing 0.76 mg of protein / mf (Aventis Pharma Deutschland GmbH),
dissolved in buffer solution E (25 mM ~-glycerophosphate, pH 7.0, 1 mM
EDTA and 1 mM dithiotreitol) was diluted to a concentration of 10 Ng of
protein/ml with buffer T (50 mM Hepes, pH 7.0, 100 mM KCI, 2.5 mM
EDTA, 2.5 mM MgC12.6H20) and addition of 5 mglml of glycogen. Test
substances were prepared as a 10 mM solution in DMSO and diluted to 50
NM with buffer solution T. To 10 NI of this solution were added 10 NI of 37.5
mM glucose dissolved in buffer solution T and 5 mglml of glycogen, and
also 10 NI of a solution of human glycogen phosphorylase a (10 pg of
protein/ml) and 20 N! of 2.5 mM glucose 1-phosphate. The base value of
the activity of 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
released inorganic phosphate was determined by means of the general
method of Drueckes et ai. (Drueckes P, Schinzel R, Palm D, Anal Biochem
1995 Sep 1;230(1 ):173-177) with the following modifications: 50 NI of a
stop solution of 7.3 mM of ammonium molybdate, 10.9 mM of zinc acetate,
3.6°I° of ascorbic acid, 0.9% of 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. To determine the background absorption, the stop
solution was added immediately after the addition of the glucose 1-
CA 02513286 2005-07-13
WO 2004/065356 24 PCT/EP2004/000041
phosphate solution in a separate reaction. This test was carried out at a
concentration of 10 NM of the test substance, in order to determine the
respective inhibition of glycogen phosphorylase a by the test substance in
vitro.
Table 2: Biological activity
Ex. % inhibition Ex. % Inhibition
at10p.M at10pM
1 99 35 99
2 99 36 101
3 104 37 101
4 97 38 102
5 99 39 101
6 100 40 98
7 100 41 104
8 100 42 83
95 43 98
11 96 44 101 -
12 90 45 _
97
_
13 94 46 10_2
14 91 47 105
101 48 97
16 95 49 99
17 100 50 94
18 99 51 92
19 97 52 101
95 53 100
22 96 54 10
0
95 55 _
_
100
26 97 56 99
-
27 98 57 _
99
28 89 58 99
29 98 59 X03 -
101 60 103
31 98 61 10
0
32 102 62 _
101
33 96 64 101
34 97 ~-65 f ~$
CA 02513286 2005-07-13
WO 2004/065356 25 PCT/EP2004/000041
Ex. % Inhibition Ex. t Inhibition
at 10 ~M at 10 ~M
66 100 79 80
67 101 80 98
68 101 81 97
69 100 82 102
70 99 83 103
71 97 84 100
72 96 85 98
73 97 86 95
74 98 87 96
75 100 88 97
76 99
77 98
78 86
Comparative Example A exhibits no inhibition at a concentration of 10 ~M
and 11 % inhibition at a concentration of 100 ~M.
It can be seen from the Table that the compounds of the formula I inhibit
the activity of glycogenphosphorylase a and are therefore very suitable for
lowering the blood sugar level. In particular, the compounds of the formula I
exhibit distinctly increased action compared to Comparative Example A.
CA 02513286 2005-07-13
WO 2004!065356 26 PCT/EP2004/000041
The preparation of some examples is described in detail hereinbelow, and
the remaining compounds of the formula I were obtained in a similar
manner:
Experimental section:
Example 1: N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-
methoxyphenyl}acetamide
a) 2-Chloro-4,5-difluorobenzoyl isocyanate
2-Chloro-4,5-difluorobenzamide was dissolved in dichloromethane,
admixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours.
The reaction mixture was concentrated under high vacuum and reacted in
stage b without further purification.
b) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea
1 g (5.9 mmol) of 2-methoxy-5-nitroaniline were admixed with 1.3 g
(5.9 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate from stage a in 2 ml
of N-methylpyrrolidone and reacted at room temperature for one hour. The
precipitate was filtered off, washed twice with 5 ml of acetonitrile each time
and dried under high vacuum. 2.2 g of the desired product were obtained
which were used in stage c without further purification.
c) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(5-amino-2-methoxyphenyl)urea
2.2 g (5.7 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-
nitrophenyl)urea were heated to the boiling temperature in 50 ml of ethyl
acetate and admixed with 6.4 g (28.5 mmol) of SnCl2 monohydrate. After 1
hour, the mixture was allowed to cool to room temperature and the pH was
adjusted to 8 using 2 N sodium hydroxide solution. The precipitate which
formed was filtered off and washed with methanol, and the mother liquor
was washed twice with H20, dried and concentrated under reduced
pressure. The resulting product (1.4 g) was reacted in step d without further
purification.
CA 02513286 2005-07-13
WO 2004/065356 27 PCT/EP2004/000041
d) N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-
methoxyphenyl}acetamide
0.10 g (0.3 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(5-amino-2-
methoxyphenyl)urea was admixed with 1 ml of N-methylpyrrolidone, 0.11 g
(0.3 mmol) of acetic anhydride and stirred at room temperature for 2 hours.
The mixture was diluted with 20 ml of H20 and extracted three times with
20 ml of ethyl acetate each time. The combined organic phase was washed
with H20, concentrated and dried. The crude product was purified by
preparative HPLC (column: Waters XterraTM MS Cog, 5 p.m, 30 X 100 mm,
eluent: A: H20 + 0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5
minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 0.03 g of the
desired product was obtained.
Melting point 225-228°C.
In a similar manner to Example 1, Examples 2-8, 27-62 and 78-88 were
prepared from the corresponding nitroanilines and the corresponding
isocyanates, if necessary with the use of appropriate protecting group
techniques.
Example 64: N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-
trifluoromethoxyphenyf}acetamide
a) 3-Nitro-4-trifluoromethoxyaniline
Method according to Syn. Commun. 1988, 18 (16+17), 2161-2165
3.0 g (17 mmol) of 4-trifluoromethoxyaniline were dissolved in 10 ml of
conc. sulfuric acid, cooled to 0-10°C and admixed in portions with 2.1
g
(17 mmol) of urea nitrate, in such a way that the temperature did not
exceed 10°C. After the addition had ended, stirring was continued for
10
minutes and then the solution was poured into ice. The mixture was
extracted using dichloromethane, the combined organic phases were dried
and the solvent was distilled off under reduced pressure. The product was
used in the next stage without further purification (yield 2.8 g, 75%).
The 3-vitro-4-trifluoromethoxyaniline obtained in this way was reacted with
acetyl chloride in a similar manner to method d for Example 1,
CA 02513286 2005-07-13
WO 2004/065356 28 PCT/EP2004/000041
hydrogenated with hydrogen in the presence of Pd/C and reacted with 2-
chloro-4,5-difluorobenzoyl isocyanate to give the acyl urea.
Melting point 216-218°C
In a similar manner, Examples 65 to 70 were prepared by using other
acylating agents in accordance with Example 1 d.
Example 73: N-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-pyrrolidin-1-
yiphenyi}acetamide
a) N-(2-Fluoro-5-nitrophenyl)acetamide
5.0 g (32 mmol) of 2-fluoro-5-nitroaniline were admixed with 10 ml
(110 mmol) of acetic anhydride and 0.1 ml of conc, sulfuric acid and stirred
at 100°C for 1.5 hours. The solution was added to 100 ml of ice/water,
and
the precipitate which formed was filtered off and washed with water. The
crude product was purified by chromatography (1:1 ethyl acetate/heptane)
on silica get (yield 5.4 g, 85°1°).
Melting point 174-176°C
b) N-(5-Nitro-2-pyrrolidin-1-ylphenyl)acetamide
0.5 g (2.5 mmol) of N-(2-fluoro-5-nitrophenyl)acetamide was admixed in a
pressure reaction vessel with 1 ml (12.6 mmol) of pyrrolidine and stirred at
90°C for 2.5 hours. After the mixture had been cooled, it was diluted
with
20 ml of dichloromethane, adjusted to pH 4 using citric acid solution (10%)
and washed four times with water. After the organic phase had been dried,
the solvent was removed under reduced pressure: In the aqueous phase, a
solid is precipitated out. It was filtered off with suction and washed with
water, and combined with the residue from the organic phase (yield 0.58 g,
93°!°). The product was reacted in stage c without further
purification.
Melting point 210-213°C
c) 5-Nitro-2-pyrrolidin-1-ylaniline
0.58 g (2.3 mmol) of N-(5-vitro-2-pyrrolidin-1-ylphenyl)acetamide was
admixed with 12 ml of conc. hydrochloric acid and heated to reflux for 1.5
hours. The solution was added to 100 ml of ice/water, neutralized with 2 N
CA 02513286 2005-07-13
WO 2004/065356 29 PCT/EP20041000041
sodium hydroxide solution and admixed three times with ethyl acetate.
After the mixture had been dried, the solvent was distilled off under
reduced pressure to obtain the product quantitatively as a red solid which
was used for the reactions a-d described in Example 1 without further
purification (reaction with the aryl isocyanate, reduction with SnCl2 and
acylation with Ac20).
Melting point 175-180°C
In a similar manner to Example 73, Examples 71, 72 and 74-77 were
prepared from the corresponding amines and the particular acylating
agents, if necessary with the use of customary protecting group techniques.
In the synthesis of Examples 19-26 and 63, 4-amino-3-methoxybenzoic
acid was nitrated with urea nitrate in a similar manner to Example 64a. The
synthetic route which followed proceeded in a similar manner to that
described in Example 1.
To synthesize Examples 9-18, N-(4-methoxy-2-methylphenyl)acetamide or
N-(2-methoxy-4-methylphenyl)acetamide were nitrated under customary
conditions (HN03/HOAc), the amide was hydrolyzed using conc.
hydrochloric acid (in a similar manner to Example 73c) and reacted further
as described for Example 1.
