U.S. patent application number 10/679550 was filed with the patent office on 2004-08-12 for carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments.
This patent application is currently assigned to Aventis Pharma Deutschland GmbH. Invention is credited to Burger, Hans-Joerg, Defossa, Elisabeth, Enhsen, Alfons, Herling, Andreas, Kadereit, Dieter, Klabunde, Thomas, Schoenafinger, Karl, Von Roedern, Erich, Wendt, Karl-Ulrich.
Application Number | 20040157922 10/679550 |
Document ID | / |
Family ID | 32830166 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040157922 |
Kind Code |
A1 |
Defossa, Elisabeth ; et
al. |
August 12, 2004 |
Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and
their use as medicaments
Abstract
Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and
their use as medicaments The invention relates to
acyl-carboxyphenylurea derivatives and to their physiologically
tolerated salts and physiologically functional derivatives.
Compounds of the formula I, 1 in which the radicals have the stated
meanings, and the physiological tolerated salts thereof and
processes for preparing them are described. The compounds are
suitable for example for the treatment of type II diabetes.
Inventors: |
Defossa, Elisabeth;
(Idstein, DE) ; Kadereit, Dieter; (Kelkheim,
DE) ; Klabunde, Thomas; (Frankfurt, DE) ;
Burger, Hans-Joerg; (Morristown, NJ) ; Herling,
Andreas; (Bad Camberg, DE) ; Wendt, Karl-Ulrich;
(Frankfurt, DE) ; Von Roedern, Erich;
(Hattersheim, DE) ; Schoenafinger, Karl; (Alzenau,
DE) ; Enhsen, Alfons; (Buttleborn, DE) |
Correspondence
Address: |
ROSS J. OEHLER
AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
Aventis Pharma Deutschland
GmbH
Industriepark Hoechst
Frankfurt am Main
DE
D-65929
|
Family ID: |
32830166 |
Appl. No.: |
10/679550 |
Filed: |
October 6, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60444890 |
Feb 4, 2003 |
|
|
|
Current U.S.
Class: |
514/522 ;
514/542; 560/34 |
Current CPC
Class: |
C07C 275/54
20130101 |
Class at
Publication: |
514/522 ;
514/542; 560/034 |
International
Class: |
A61K 031/277; A61K
031/235 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 4, 2002 |
DE |
10246434.0-42 |
Sep 22, 2003 |
WO |
PCT/EP03/10501 |
Claims
1. A compound of the formula I, 8in which R1 is H,
(C.sub.1-C.sub.6)-alkyl or (C.sub.0-C.sub.6)-alkyl-phenyl wherein
the phenyl ring is optionally mono- or disubstituted with F, Cl,
Br, CN, OH, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
CF.sub.3, OCF.sub.3, COOH, COO(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2; R2 is H, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl or (C.sub.0-C.sub.6)-alkylene-COOH; R3
is H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkyl; and n is 1,
2, 3, 4, 5, 6, 7 or 8; and pharmaceutically acceptable salts
thereof.
2. The compound of claim 1 wherein R1 is H or
(C.sub.1-C.sub.6)-alkyl; R2 is H, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl or (C.sub.0-C.sub.6)-alkylene-COOH; R3
is H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkyl; and n is 1,
2, 3, 4, 5, 6, 7 or 8; and pharmaceutically acceptable salts
thereof.
3. The compound of claim 2, wherein R1 is H or
(C.sub.1-C.sub.6)-alkyl; R2 is H, COO--(C.sub.1-C6)-alkyl or
--COOH; R3 is H or F; and n is 1, 2, 3 or 4; and pharmaceutically
acceptable salts thereof.
4. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and one or more compounds of claim 1.
5. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier, one or more compounds of claim 1, and at least
one other active ingredient.
6. The pharmaceutical composition of claim 5, wherein the other
active ingredient comprises one or more antidiabetics, hypoglycemic
active ingredients, antiobesics, anorexia, HMG-CoA reductase
inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists,
PPAR alpha agonists, PPAR alpha/gamma agonists, PPAR delta
agonists, fibrates, MTP inhibitors, bile acid absorption
inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL
receptor inducers, cholesterol absorption inhibitors (ezetimibe),
ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors,
ATP-citrate lyase inhibitors, ACC inhibitors, squalene synthetase
inhibitors, lipoprotein(a) antagonists, lipase inhibitors,
insulins, sulfonylureas, biguanides, glitinides,
thiazolidinediones, .alpha.-glucosidase inhibitors,
glucagon-receptor antagonists, active ingredients which act on the
ATP-dependent potassium channel of the beta cells, CART agonists,
NPY agonists, GLP1 agonists, GIP agonists, MC4 agonists, MCH
antagonists, orexin agonists, H3 agonists, TNF agonists, CRF
agonists, CRF BP antagonists, urocortin agonists, .beta.3 is
agonists, MSH (melanocyte-stimulating hormone) agonists, CCK
agonists, serotonin reuptake inhibitors, mixed serotoninergic and
noradrenergic compounds, 5HT agonists, bombesin agonists, galanin
antagonists, growth hormones, growth hormone-releasing compounds,
TRH agonists, LXR modulators, FXR modulators, uncoupling protein 2
or 3 modulators, leptin agonists, DA agonists (bromocriptine,
Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR
modulators, TR-.beta. agonists or amphetamines.
7. A method of reducing blood glucose comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound of claim 1.
8. A method of treating type II diabetes comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of claim 1.
9. A method of treating disturbances of lipid and carbohydrate
metabolism comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1.
10. A method of treating symptoms associated with arteriosclerosis
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1.
11. A method of treating insulin resistance comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
12. A process for producing a pharmaceutical composition comprising
one or more of the compounds of claim 1 comprising mixing said
compound of claim 1 with a pharmaceutically suitable carrier and
converting this mixture into a form suitable for
administration.
13. A method of treating or preventing acute and chronic damage and
disorders of the heart, peripheral organs and limbs which are
caused by ischemic events or by reperfusion events comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
14. A method of treating or preventing diseases caused by ischemic
states comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1.
15. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment or prophylaxis of acute and chronic
damage and disorders of the heart which are caused by ischemic
events or by reperfusion events, and for the treatment or
prevention of myocardial infarction.
16. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment or prophylaxis of angina
pectoris.
17. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment or prophylaxis of ischemic states of
the heart.
18. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment or prevention of ischemic states of
the peripheral and central nervous system and of stroke.
19. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment or prevention of ischemic states of
the peripheral organs and limbs.
20. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment of oncosis.
21. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment of oncosis in which the tumor growth
is dependent on glycogen phosphorylase activity.
22. The use of a compound of claim 1 for producing a pharmaceutical
composition for the treatment of cancer of the lung, breast and
bowel.
Description
DOMESTIC PRIORITY CLAIM
[0001] This application claims priority under 35 U.S.C. .sctn. 119
of U.S. Provisional Application No. 60/444,890 filed on Feb. 4,
2003.
PRIORITY CLAIM
[0002] This application claims priority under 35 U.S.C. .sctn. 119
of German Application No. 10246434.0-42 filed on Oct. 4, 2002.
[0003] The invention relates to acyl-carboxyphenylurea derivatives
and to their physiologically tolerated salts and physiologically
functional derivatives.
[0004] Acylphenylurea derivatives have already been described as
antitumor or antidiabetic agents in the prior art (EP 0 193 249 and
WO 01/94300).
[0005] The invention was based on the object of providing compounds
which display a therapeutically utilizable blood glucose-lowering
effect. In particular, it was an object to find novel compounds
which, compared to the compounds described in WO 01/94300 show
better blood glucose-lowering effect.
[0006] The invention therefore relates to compounds of the formula
I, 2
[0007] in which
[0008] R1 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkyl-phenyl, wherein the phenyl ring is
optionally mono- or disubstituted with F, Cl, Br, CN, OH,
(C.sub.1-C.sub.6)-alkyl, O-(C.sub.1-C.sub.6)-alkyl, CF.sub.3,
OCF.sub.3, COOH, COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0009] R2 is H, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl or
(C.sub.0-C.sub.6)-alkylene-COOH;
[0010] R3 is H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkyl; and
[0011] n is 1, 2, 3, 4, 5, 6, 7 or 8;
[0012] and pharmaceutically acceptable salts thereof.
[0013] Preference is given to compounds of the formula I in
which
[0014] R1 is H or (C.sub.1-C.sub.6)-alkyl;
[0015] R2 is H, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl or
(C.sub.0-C.sub.6)-alkylene-COOH;
[0016] R3 is H, F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkyl;
[0017] n is 1, 2, 3, 4, 5, 6, 7 or 8;
[0018] and pharmaceutically acceptable salts thereof.
[0019] Particularly preference is given to compounds of the formula
I in which
[0020] R1 is H or (C.sub.1-C.sub.6)-alkyl;
[0021] R2 is H, COO--(C.sub.1-C.sub.6)-alkyl or --COOH;
[0022] R3 is H or F; and
[0023] n is 1, 2, 3 or 4;
[0024] and pharmaceutically acceptable salts thereof.
[0025] 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.
[0026] The alkyl radicals in the substituents R1, R2 and R3 may be
both straight-chain and branched.
[0027] Pharmaceutically acceptable salts are, because their
solubility in water is greater than that of the initial or basic
compounds, particularly suitable for medical applications. These
salts must have a pharmaceutically acceptable anion or cation.
Suitable pharmaceutically acceptable acid addition salts of the
compounds of the invention are salts of inorganic acids such as
hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric
and sulfuric acid, and of organic acids such as, for example,
acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic,
fumaric, gluconic, glycolic, isethionic, lactic, lactobionic,
maleic, malic, methanesulfonic, succinic, p-toluenesulfonic 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), and salts of trometamol
(2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine
or ethylenediamine.
[0028] Salts with a pharmaceutically unacceptable anion such as,
for example, trifluoroacetate likewise belong within the framework
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.
[0029] The term "physiologically functional derivative" used herein
refers to any physiologically tolerated derivative of a compound of
the formula I of the invention, for example an ester, which on
administration to a mammal such as, for example, a human is able to
form (directly or indirectly) a compound of the formula I or an
active metabolite thereof.
[0030] Physiologically functional derivatives include prodrugs of
the compounds of 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 a compound of the invention. These
prodrugs may themselves be active or not.
[0031] The compounds of the invention may also exist in various
polymorphous forms, for example as amorphous and crystalline
polymorphous forms. All polymorphous forms of the compounds of the
invention belong within the framework of the invention and are a
further aspect of the invention.
[0032] As used herein, the following definitions apply:
[0033] "Patient" means a warm blooded animal, such as for example
rat, mice, dogs, cats, guinea pigs, and primates such as
humans.
[0034] "Treat" or "treating" means to alleviate symptoms, eliminate
the causation of the symptoms either on a temporary or permanent
basis, or to prevent or slow the appearance of symptoms of the
named disorder or condition.
[0035] "Therapeutically effective amount" means a quantity of the
compound which is effective in treating the named disorder or
condition.
[0036] "Pharmaceutically acceptable carrier" is a non-toxic
solvent, dispersant, excipient, adjuvant or other material which is
mixed with the active ingredient in order to permit the formation
of a pharmaceutical composition, i.e., a dosage form capable of
administration to the patient. One example of such a carrier is a
pharmaceutically acceptable oil typically used for parenteral
administration.
[0037] "Pharmaceutically acceptable salts" means either an acid
addition salt or a basic addition salt which is compatible with the
treatment of patients for the intended use.
[0038] "Pharmaceutically acceptable acid addition salt" is any
non-toxic organic or inorganic acid addition salt of the base
compounds represented by Formula I or any of its intermediates.
Illustrative inorganic acids which form suitable salts include
hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid
metal salts such as sodium monohydrogen orthophosphate and
potassium hydrogen sulfate. Illustrative organic acids which form
suitable salts include the mono-, di- and tri-carboxylic acids.
Illustrative of such acids are, for example, acetic, glycolic,
lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic,
tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,
hydroxybenzoic, phenylacetic, cinnamic, salicyclic,
2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as
methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the
mono- or di-acid salts can be formed, and such salts can exist in
either a hydrated, solvated or substantially anhydrous form. In
general, the acid addition salts of these compounds are more
soluble in water and various hydrophilic organic solvents and which
in comparison to their free base forms, generally demonstrate
higher melting points.
[0039] "Pharmaceutically acceptable basic addition salts" means
non-toxic organic or inorganic basic addition salts of the
compounds of Formula (I) or any of its intermediates. Examples are
alkali metal or alkaline-earth metal hydroxides such as sodium,
potassium, calcium, magnesium or barium hydroxides; ammonia, and
aliphatic, alicyclic, or aromatic organic amines such as
methylamine, trimethylamine and picoline. The selection criteria
for the appropriate salt will be known to one skilled in the
art.
[0040] "Oncosis" means a condition characterized by the formation
of one or more neoplasms or tumors.
[0041] All references to "compound(s) of formula I" hereinafter
refer to compound(s) of the formula I as described above, and their
salts, solvates and physiologically functional derivatives as
described herein.
[0042] The compound(s) of formula (I) may also be administered in
combination with other active ingredients.
[0043] The amount of a compound of formula I necessary to achieve
the desired biological effect depends on a number of factors, for
example the specific compound chosen, the intended use, the mode of
administration and the clinical condition of the patient. The daily
dose is generally in the range from 0.3 mg to 100 mg (typically
from 3 mg to 50 mg) per day and per kilogram of bodyweight, for
example 3-10 mg/kg/day. An intravenous dose may be, for example, in
the range from 0.3 mg to 1.0 mg/kg, which can suitably be
administered as infusion of 10 ng to 100 ng per kilogram and per
minute. Suitable infusion solutions for these purposes may contain,
for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg,
per milliliter. Single doses may contain, for example, from 1 mg to
10 g of the active ingredient. Thus, ampoules for injections may
contain, for example, from 1 mg to 100 mg, and single-dose
formulations which can be administered orally, such as, for
example, capsules or tablets, may contain, for example, from 1.0 to
1000 mg, typically from 10 to 600 mg. For the therapy of the
abovementioned conditions, the compounds of formula I may be used
as the compound itself, but they are preferably in the form of a
pharmaceutical composition with an acceptable carrier. The carrier
must, of course, be acceptable in the sense that it is compatible
with the other ingredients of the composition and is not harmful
for the patient's health. The carrier may be a solid or a liquid or
both and is preferably formulated with the compound as a single
dose, for example as a tablet, which may contain from 0.05% to 95%
by weight of the active ingredient. Other pharmaceutically active
substances may likewise be present, including other compounds of
formula I. The pharmaceutical compositions of the invention can be
produced by one of the known pharmaceutical methods, which
essentially consist of mixing the ingredients with
pharmacologically acceptable carriers and/or excipients.
[0044] Pharmaceutical compositions of the invention are those
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 nature of the compound of formula I used in each case.
Coated formulations and coated slow-release formulations also
belong within the framework of the invention. Preference is given
to acid- and gastric juice-resistant formulations. Suitable
coatings resistant to gastric juice comprise cellulose acetate
phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic polymers of
methacrylic acid and methyl methacrylate.
[0045] Suitable pharmaceutical compounds for oral administration
may be in the form of separate units such as, for example,
capsules, wafers, suckable tablets or tablets, each of which
contain a defined amount of the compound of formula I; as powders
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) are brought into contact. The compositions
are generally produced 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. Thus, for
example, a tablet can be produced by compressing or molding a
powder or granules of the compound, where appropriate with one or
more additional ingredients. Compressed tablets can be produced by
tableting the compound in free-flowing form such as, for example, a
powder or granules, where appropriate mixed with a binder, glidant,
inert diluent and/or one or more surface-active/dispersing agent(s)
in a suitable machine. Molded tablets can be produced by molding
the compound, which is in powder form and is moistened with an
inert liquid diluent, in a suitable machine.
[0046] Pharmaceutical compositions which are suitable for peroral
(sublingual) administration comprise suckable tablets which contain
a compound of formula I with a flavoring, normally sucrose and gum
arabic or tragacanth, and pastilles which comprise the compound in
an inert base such as gelatin and glycerol or sucrose and gum
arabic.
[0047] Pharmaceutical compositions suitable for parenteral
administration comprise 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 administration may also take
place by subcutaneous, intramuscular or intradermal injection.
These preparations can preferably be produced by mixing the
compound with water and making the resulting solution sterile and
isotonic with blood. Injectable compositions of the invention
generally contain from 0.1 to 5% by weight of the active
compound.
[0048] Pharmaceutical compositions suitable for rectal
administration are preferably in the form of single-dose
suppositories. These can be produced by mixing a compound of the
formula I with one or more conventional solid carriers, for example
cocoa butter, and shaping the resulting mixture.
[0049] Pharmaceutical compositions suitable for topical use on the
skin are preferably in the form of ointment, cream, lotion, paste,
spray, aerosol or oil. Carriers which can be used are petrolatum,
lanolin, polyethylene glycols, 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, for example from 0.5 to 2%.
[0050] Transdermal administration is also possible. Pharmaceutical
compositions suitable for transdermal uses can be in the form of
single plasters which are suitable for long-term close contact with
the patient's epidermis. Such plasters suitably contain the active
ingredient in an aqueous solution which is buffered where
appropriate, dissolved and/or dispersed in an adhesive or dispersed
in a polymer. A suitable active ingredient concentration is about
1% to 35%, preferably about 3% to 15%. A particular possibility is
for the active ingredient to be released by electrotransport or
iontophoresis as described, for example, in Pharmaceutical
Research, 2(6): 318 (1986).
[0051] Further active ingredients suitable for combination products
are: all antidiabetics mentioned in the Rote Liste 2001, chapter
12. They may be combined with the compounds of the formula I of the
invention in particular for a synergistic improvement of the
effect. Administration of the active ingredient combination may
take place either by separate administration of 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
below are disclosed in the USP Dictionary of USAN and International
Drug Names, US Pharmacopeia, Rockville 2001.
[0052] Antidiabetics include insulin and insulin derivatives such
as, for example, Lantus.RTM. (see www.lantus.com) or HMR 1964,
fast-acting insulins (see U.S. Pat. No. 6,221,633), GLP-1
derivatives such as, for example, those disclosed in WO 98/08871 of
Novo Nordisk A/S, and orally effective hypoglycemic active
ingredients.
[0053] The orally effective hypoglycemic active ingredients
include, preferably, sulfonylureas, biguanides, meglitinides,
oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,
glucagon antagonists, GLP-1 agonists, potassium channel openers
such as, for example, those disclosed in WO 97/26265 and WO
99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of
liver enzymes involved in the stimulation of gluconeogenesis and/or
glycogenolysis, modulators of glucose uptake, compounds which alter
lipid metabolism, such as antihyperlipidemic active ingredients and
antilipidemic active ingredients, compounds which reduce food
intake, PPAR and PXR agonists and active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
[0054] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an HMG-CoA reductase
inhibitor such as simvastatin, fluvastatin, pravastatin,
lovastatin, atorvastatin, cerivastatin, rosuvastatin.
[0055] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a cholesterol
absorption inhibitor such as, for example, ezetimibe, tiqueside,
pamaqueside.
[0056] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a PPAR gamma
agonist, such as, for example, rosiglitazone, pioglitazone,
JTT-501, GI 262570.
[0057] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a PPAR alpha
agonist, such as, for example, GW 9578, GW 7647.
[0058] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a mixed PPAR
alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE
8134, AVE 0847, or as described in PCT/US00/11833, PCT/US00/11490,
DE10142734.4.
[0059] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a fibrate such as,
for example, fenofibrate, clofibrate, bezafibrate.
[0060] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an MTP inhibitor
such as, for example, implitapide, BMS-201038, R-103757.
[0061] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a bile acid
absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744 or
U.S. Pat. No. 6,221,897), such as, for example, HMR 1741.
[0062] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a CETP inhibitor,
such as, for example, JTT-705.
[0063] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a polymeric bile
acid adsorbent such as, for example, cholestyramine,
colesevelam.
[0064] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an LDL receptor
inducer (see U.S. Pat. No. 6,342,512), such as, for example,
HMR1171, HMR1586.
[0065] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an ACAT inhibitor,
such as, for example, avasimibe.
[0066] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an antioxidant, such
as, for example, OPC-14117.
[0067] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a lipoprotein lipase
inhibitor, such as, for example, NO-1886.
[0068] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an ATP-citrate lyase
inhibitor, such as, for example, SB-204990.
[0069] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a squalene
synthetase inhibitor, such as, for example, BMS-188494.
[0070] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a lipoprotein(a)
antagonist, such as, for example, CI-1027 or nicotinic acid.
[0071] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a lipase inhibitor,
such as, for example, orlistat.
[0072] In another embodiment of the invention, the compounds of the
formula I are administered in combination with insulin.
[0073] In another embodiment, the compounds of the formula I are
administered in combination with a sulfonylurea such as, for
example, tolbutamide, glibenclamide, glipizide or glimepiride.
[0074] In another embodiment, the compounds of the formula I are
administered in combination with a biguanide, such as, for example,
metformin.
[0075] In another further embodiment, the compounds of the formula
I are administered in combination with a meglitinide, such as, for
example, repaglinide.
[0076] In another embodiment, the compounds of the formula I are
administered in combination with a thiazolidinedione, such as, 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]pheny-
l]methyl]-2,4-thiazolidinedione.
[0077] In another embodiment, the compounds of the formula I are
administered in combination with an a-glucosidase inhibitor, such
as, for example, miglitol or acarbose.
[0078] In another 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, such as, for
example, tolbutamide, glibenclamide, glipizide, glimepiride or
repaglinide.
[0079] In another embodiment, the compounds of the formula I are
administered in combination with more than one of the
aforementioned compounds, e.g. in combination with a sulfonylurea
and metformin, with a sulfonylurea and acarbose, repaglinide and
metformin, insulin and a sulfonylurea, insulin and mefformin,
insulin and troglitazone, insulin and lovastatin, etc.
[0080] In a further 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., in: Hormone and Metabolic Research (2001), 33(9), 554-558),
NPY antagonists, e.g. naphthalene-1-sulfonic acid
{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclo- hexylmethyl}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-ylure- a
hydrochloride (SB-334867-A)), H3 agonists
(3-cyclohexyl-1-(4,4-dimethyl--
1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic
acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.
[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropyla-
mine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin
agonists, .beta.3 agonists (e.g.
1-(4-chloro-3-methanesulfonylmethylpheny-
l)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanol
hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)
agonists, CCK-A agonists (e.g.
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-
thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid
trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake
inhibitors (e.g. dexfenfluramine), mixed serotoninergic and
noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.
1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO
01/09111), bombesin agonists, galanin antagonists, growth hormone
(e.g. human growth hormone), growth hormone-releasing compounds
(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1-
H-isoquinoline-2-carboxylic acid tertiary butyl ester (WO
01/85695)), TRH agonists (see, for example, EP 0 462 884),
uncoupling protein 2 or 3 modulators, leptin agonists (see, for
example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena,
Marina; Grasso, Patricia. Leptin agonists as a potential approach
to the treatment of obesity. Drugs of the Future (2001), 26(9),
873-881), DA agonists (bromocriptine, Doprexin), lipase/amylase
inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312),
RXR modulators or TR-.beta.agonists.
[0081] In another 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.
[0082] In another embodiment, the other active ingredient is
dexamphetamine or amphetamine.
[0083] In another embodiment, the other active ingredient is
fenfluramine or dexfenfluramine.
[0084] In another embodiment, the other active ingredient is
sibutramine.
[0085] In another embodiment, the other active ingredient is
mazindol or phentermine.
[0086] In another embodiment, the compounds of the formula I are
administered in combination with bulking agents, preferably
insoluble bulking agents (see, for example, carob/Caromax.RTM.
(Zunft H J; et al., Carob pulp preparation for treatment of
hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October),
18(5), 230-6.) Caromax is a carob-containing product from
Nutrinova, Nutrition Specialties & Food Ingredients GmbH,
Industriepark Hochst, 65926 Frankfurt/Main)). Combination with
Caromax.RTM. is possible in one preparation or by separate
administration of compounds of the formula I and Caromax.RTM..
Caromax.RTM. can in this connection also be administered in the
form of food products such as, for example, in bakery products or
muesli bars.
[0087] It will be appreciated that every suitable combination of
the compounds of the invention with one or more of the
aforementioned compounds and optionally one or more other
pharmacologically active substances is regarded as falling within
the protection conferred by the present invention. 34
[0088] The examples detailed below serve to illustrate the
invention without, however, restricting it. The measured
solidification or decomposition points have not been corrected and
generally depend on the heating rate
1TABLE 1 Examples 5 Example m.p. No. X R R2 n [.degree. C.] MS 1 H
H H 1 180-181 ok 2 H H COOH 1 279-281 ok 3 F H H 1 179-180 ok 4 F
Me COOMe 1 268 ok 5 F H COOH 1 294-297 ok 6 F H H 3 168 ok 7 F Me H
3 228 ok 8 F Me COOMe 3 209 ok 9 F H COOH 3 194 ok 10 F Me COOH 3
227 0k 11 H H H 4 197 ok 12 H H COOH 4 253-254 ok 13 F H H 4 164 ok
14 F H COOH 4 293-296 ok 15 F Me COOH 4 220 ok * The statement "MS
is ok" means that a mass spectrum was recorded and the molecular
peak (molecular mass + H.sup.+) was detected therein
[0089] The compounds of the formula I are distinguished by
beneficial effects on lipid and carbohydrate metabolism, they lower
in particular the blood glucose level and they are suitable for the
treatment of type 2 diabetes, of insulin resistance, of
dyslipidemias and of the metabolic syndrome/syndrome X. The
compounds are additionally suitable for the prophylaxis and
treatment of arteriosclerotic manifestations. The compounds can be
employed alone or in combination with other blood glucose-lowering
active ingredients. The compounds of the formula I are also
outstandingly suitable because of their pharmacological properties
(see J. L. Treadway, P. Mendys, D. J. Hoover, Exp. Opin. Invest.
Drugs 2001, 10(3), 439-454) as cardioprotective medicaments for the
prophylaxis of infarction and the treatment of infarction, and for
the treatment of angina pectoris, where they also preventively
inhibit or greatly reduce the pathophysiological processes
associated with the development of ischemia-induced damage, in
particular in the triggering of ischemia-induced cardiac
arrhythmias. The compounds can be employed alone or in combination
with other cardioprotective or antiarrhythmic active ingredients.
The compounds of the formula I are also because of their
pharmacological properties of suitable for the treatment oncoses.
It was possible to show in various investigations of this that
there is a direct connection between the glycogen level and various
parameters of tumor growth and tumor development (see M. Rousset,
E. Dussauix, G. Chevalier, A. Zweibaum, J. Natl. Cancer Inst. 1980,
65(5), 885-889; K. Yano, S. Ohoshima, Y. Shimizu, T. Moriguchi, H.
Katayama, Cancer Letters 1996, 110(1,2), 29-34; L. Skwarski, Z.
Namiot, J. Stasiewicz, A. Kemona, M. Kralisz, J. Gorski, Cancer
Letters 1998, 127(1,2), 123-128; S. Takahashi, A. Satomi, K. Yano,
H. Kawase, T. Tanimizu, Y. Tuji, S. Murakami, R. Hirayama, J.
Gastroenterology 1999, 34(4), 474-480). It is thus also possible to
reduce tumor growth through manipulation of the amount of glucose
released. The compounds of the formula I can for this purpose be
employed where appropriate also in conjunction with other antitumor
medicaments.
[0090] The efficacy of the compounds was tested as follows:
[0091] Analysis of Test Substances for Their Inhibitory Potency on
Glycogenolysis in Primary Cultures of Rat Hepatocytes
[0092] Hepatocytes were isolated from the livers of fed rats
(Sprague-Dawley or Wistar, bodyweight 220-240 g) by means of a
standard 2-stage perfusion first with calcium-free buffer solution
followed by perfusion with collagenase-containing solution to break
up the tissue assembly (Seglen et al, 1979). The cells were
incubated in an incubator with 90% humidity at 37.degree. C. and an
atmosphere with 5% CO.sub.2 in air. The cultivation normally took
place with Williams' medium E supplemented with 20 mM glucose, 0.1
mM fructose, 1 .mu.M dexamethasone and 100 nM insulin.
Glycogenolysis was induced by changing the culture medium to
prewarmed carbogen-gassed Krebs-Henseleit bicarbonate Hepes (20 mM)
buffer, pH 7.4, supplemented with 100 nM glucagon (time 0 min). The
test substances were normally added at time 0 min as
100.times.stock solution in DMSO. The final DMSO concentration was
not higher than 1% (v/v). The amount of glucose in the culture
supernatant was determined after addition of glucagon in the
presence and absence of test substance by removing small aliquots
of the cell culture supernatant at times 0, 30, 60 and 90 min. The
glucose concentration (mM) was determined by enzymatic methods in a
biochemical analysis laboratory of Aventis Pharma Deutschland. The
glucose production rate was found by linear regression of the
glucose concentration at times 30, 60 and 90 min using the
following formula:
Glucose production rate (mM/h)=mM glucose (90 min)-mM glucose (30
min).
[0093] The percent inhibition was calculated using the following
formula: 1 Percentage inhibition = 100 .times. [ 1 - glucose
production rate in the presence of test substance glucose
production rate in the absence of test substance ]
[0094] IC.sub.50 values (IC.sub.50: the concentration (.mu.M) of
test substance which brings about a reduction of 50% in the glucose
production rate) was estimated by standard curve fitting methods
using the percent inhibitions obtained at relevant concentrations
of test substance.
2TABLE 2 Biological activity Example No. IC50 on hep. 1 1.161 2
1.46 3 0.776 4 1.191 5 0.407 6 0.134 7 0.226 8 0.069 9 <0.1 10
0.106 11 0.156 12 0.34 13 0.113 14 0.312 15 0.032
[0095] It is evident from the table that the compounds of the
formula I inhibit glycogenolysis in rat hepatocytes and thus bring
about a reduction in the blood glucose level.
[0096] Two compounds disclosed in WO 01/94300 were tested as
comparison examples.
3TABLE 2 Biological activity of comparison examples IC.sub.50 nm
hep. Structure MW [.mu.M] Example No. 105 from WO 01/94300 491.73
17.524 6 Example No. 116 from WO 01/94300 457.28 13.522 7
[0097] It is evident from the table that the compounds of the
formula I show an increased pharmacological effect. The effect of
the compounds of the formula I is 11 to 548 fold higher than the
effect of the comparison examples.
[0098] The preparation of some examples is described in detail
below, and the other compounds of the formula I were obtained
analogously:
[0099] Experimental Part:
EXAMPLE 1
2-[3-(2-Chloro-4-fluorobenzoyl)ureido]phenoxyacetic acid
a) tert-Butyl 2-nitrophenoxyacetate
[0100] 2.8 g (14.4 mmol) of tert-butyl bromoacetate and 2.6 g (7.9
mmol) of cesium carbonate are added to a solution of 1.0 g (7.2
mmol) of 2-nitrophenol in 20 ml of acetone. The suspension is
heated to reflux for 48 hours. Then 50 ml of water are added, and
the mixture is extracted twice with 50 ml of ethyl acetate each
time. The combined organic phases are washed with water, dried over
Na.sub.2SO.sub.4 and concentrated in a rotary evaporator. The
product is employed without purification in the next step. Crude
yield: 2.4 g
b) tert-Butyl 2-aminophenoxyacetate
[0101] 0.5 g of crude material from a) are dissolved in methanol
and, after addition of 0.3 g of Raney Ni, hydrogenated with
hydrogen at room temperature. The reaction is monitored by
LC-MS.
[0102] After reduction is complete, the mixture is filtered with
suction through Celite and washed with methanol. The filtrate is
concentrated in a rotary evaporator, and the product is employed
without purification in step d). Crude yield: 0.34 g
c) 2-Chloro-4-fluorobenzoyl isocyanate
[0103] 2-Chloro-4-fluorobenzamide was dissolved in dichloromethane
and, after addition 1.5 eq. of oxalyl chloride, heated to reflux
for 16 hours, The reaction mixture was concentrated under high
vacuum and employed without further purification in stage d).
d) tert-Butyl
2-[3-(2-chloro-4-fluorobenzoyl)ureido]phenoxyacetate
[0104] A solution of 230 mg (1.2 mmol) of 2-chloro-4-fluorobenzoyl
isocyanate in 5 ml of acetonitrile is added at room temperature to
a solution of 129 mg (0.6 mmol) of tert-butyl 2-aminophenoxyacetate
in 5 ml of dry acetonitrile under a protective gas atmosphere. The
mixture is heated to reflux for 4 hours and cooled to room
temperature. The solvent is distilled out in a rotary evaporator,
and the resulting residue is employed without further purification
in the next step. Crude yield: 0.33 g.
e) tert-Butyl
2-[3-(2-chloro-4-fluorobenzoyl)ureido]phenoxyacetate
[0105] 0.33 g of crude material from stage d) are taken up in 10 ml
of methylene chloride and, after addition of 10 ml of
trifluoroacetic acid, stirred at room temperature for two hours.
The solution is then concentrated after addition of 3 ml of toluene
twice in a rotary evaporator, and the residue obtained in this way
is purified in a preparative HPLC system (column: Waters Xterra
.TM.MS C.sub.18, 5 .mu.m, 30.times.100 mm, mobile phases: A:
H.sub.2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5
minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 88 mg (0.23 mmol)
of the desired product are obtained.
[0106] Melting point: 180-181.degree. C.
[0107] Example 3 was prepared in accordance with this method.
EXAMPLE 2
3-Carboxymethoxy-4-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic
acid
a) Methyl 3-methoxycarbonylmethoxy-4-nitrobenzoate
[0108] 0.77 g (5.1 mmol) of methyl bromoacetate and 0.91 g (2.8
mmol) of cesium carbonate are added to a solution of 0.50 g (2.5
mmol) of methyl 3-hydroxy-4-nitrobenzoate in 10 ml of acetone. The
suspension is heated to reflux for 48 hours. Then 50 ml of water
are added, and the mixture is extracted twice with 50 ml of ethyl
acetate each time. The combined organic phases are washed with
water, dried over Na.sub.2SO.sub.4 and concentrated in a rotary
evaporator. Crude yield: 0.64g
b) 3-Carboxymethoxy-4-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic
acid
[0109] The crude product from step a) is converted in analogy to
examples 1b) to 1d) into methyl
3-methoxycarbonylmethoxy-4-[3-(2-chloro-4-fluorobe-
nzoyl)ureido]-benzoate, of which 50 mg (0.11 mmol) are dissolved in
5 ml of THF, and 1 ml of water is added. To this are added 27 mg
(1.1 mmol) of LiOH, and the reaction is stirred at room temperature
until the precursor has reacted completely. The reaction is
monitored by LC-MS. After completion of the reaction, the mixture
is acidified with dilute hydrochloric acid and extracted twice with
20 ml of ethyl acetate each time. The combined organic phases are
dried over Na.sub.2SO.sub.4, filtered and concentrated in a rotary
evaporator, and the residue obtained in this way is purified in a
preparative HPLC system (column: Waters Xterra TMMS C.sub.18, 5
.mu.m, 30.times.100 mm, mobile phases: A: H.sub.2O+0.2%
trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90%
A/10% B to 17.5 minutes 10% A/90% B). 28 mg (0.068 mmol) of the
desired product are obtained.
[0110] Melting point: 279-281.degree. C.
[0111] Examples 4-9 and 11-14 were prepared in analogy to this
method.
EXAMPLE 10
4-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-3-(3-methoxycarbonylpropoxy)ben-
zoic acid
a) Benzyl 3-hydroxy-4-nitrobenzoate
[0112] 2.0 g (11 mmol) of 3-hydroxy-4-nitrobenzoic acid are
suspended in 25 ml of toluene, and 1.8 g (16 mmol) of benzyl
alcohol and 0.2 g (1.1 mmol) of p-toluenesulfonic acid are added.
The reaction is heated to reflux using a water trap until no
further water separates out. After the reaction is complete, the
solution is evaporated in a rotary evaporator and the crude product
is purified by chromatography. Yield 1.6 g (5.9 mmol).
b)
4-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-3-(3-methoxycarbonylpropoxy)-
-benzoic acid
[0113] The benzyl 3-hydroxy-4-nitrobenzoate from step a) was
alkylated in analogy to method 2a) to form benzyl
3-(3-methoxycarbonylpropoxy)-4-nitro- benzoate. 450 mg (1.2 mmol)
of the benzyl ester are dissolved in 20 ml of methanol and, after
addition of 13 mg (0.1 mmol) of palladium on activated carbon
(10%), hydrogenated at room temperature. The reaction is monitored
by LC-MS. After the reduction is complete, the mixture is filtered
with suction through Celite and washed with methanol. The filtrate
is concentrated in a rotary evaporator, and the product is reacted
without previous purification in analogy to method 1d) to give
4-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-3-(3-methoxycarbonylpropoxy)-b-
enzoic acid. The final purification takes place by preparative HPLC
(column: Waters Xterra .TM.MS C.sub.18, 5 .mu.m, 30.times.100 mm,
mobile phases: A: H.sub.2O+0.2% trifluoroacetic acid, B:
acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10%
A/90% B). Yield: 0.51 mg (0.11 mmol)
[0114] Melting point: 227.degree. C.
[0115] Example 15 was prepared in analogy to this method.
* * * * *
References