U.S. patent application number 12/267896 was filed with the patent office on 2009-06-11 for phenylamino-benzoxazole substituted carboxylic acids, method for their production and use thereof as medicaments.
This patent application is currently assigned to SANOFI-AVENTIS. Invention is credited to Stefan Bartoschek, Elisabeth Defossa, Viktoria Dietrich, Markus Follmann, Guido Haschke, Andreas Herling, Gerhard Hessler, Thomas Klabunde, Siegfried Stengelin.
Application Number | 20090149519 12/267896 |
Document ID | / |
Family ID | 38371048 |
Filed Date | 2009-06-11 |
United States Patent
Application |
20090149519 |
Kind Code |
A1 |
Defossa; Elisabeth ; et
al. |
June 11, 2009 |
PHENYLAMINO-BENZOXAZOLE SUBSTITUTED CARBOXYLIC ACIDS, METHOD FOR
THEIR PRODUCTION AND USE THEREOF AS MEDICAMENTS
Abstract
This invention relates to a compound of formula I, ##STR00001##
wherein R1, R2, R6, R7, R8, R9, R10, m and X are as defined herein,
or a physiologically tolerated salt thereof, its pharmaceutical
composition and use for lowering blood glucose, treating diabetes,
or increasing insulin release.
Inventors: |
Defossa; Elisabeth;
(Frankfurt am Main, DE) ; Follmann; Markus;
(Wulfrath, DE) ; Klabunde; Thomas; (Frankfurt am
Main, DE) ; Dietrich; Viktoria; (Frankfurt am Main,
DE) ; Hessler; Gerhard; (Frankfurt am Main, DE)
; Stengelin; Siegfried; (Frankfurt am Main, DE) ;
Haschke; Guido; (Frankfurt am Main, DE) ; Herling;
Andreas; (Frankfurt am Main, DE) ; Bartoschek;
Stefan; (Frankfurt am Main, DE) |
Correspondence
Address: |
ANDREA Q. RYAN;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206, MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
SANOFI-AVENTIS
Paris
FR
|
Family ID: |
38371048 |
Appl. No.: |
12/267896 |
Filed: |
November 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/EP2007/003806 |
Apr 30, 2007 |
|
|
|
12267896 |
|
|
|
|
Current U.S.
Class: |
514/375 ;
548/222 |
Current CPC
Class: |
C07D 263/58 20130101;
A61K 31/423 20130101; C07D 413/12 20130101; A61P 3/00 20180101;
A61P 3/10 20180101; A61P 3/06 20180101; A61K 45/06 20130101 |
Class at
Publication: |
514/375 ;
548/222 |
International
Class: |
A61K 31/423 20060101
A61K031/423; C07D 263/48 20060101 C07D263/48; A61P 3/10 20060101
A61P003/10 |
Foreign Application Data
Date |
Code |
Application Number |
May 11, 2006 |
DE |
102006021878.7 |
Claims
1. A compound of formula I, ##STR00014## wherein: R1 is H or
(C.sub.1-C.sub.6)-alkyl; R6, R7, R8, R9 and R10 are, independently
of one another, H, F, Cl, Br, CN, CF.sub.3, OH, OCF.sub.3,
OCHF.sub.2, SCH.sub.3, SCF.sub.3, phenyl, O-phenyl, COOH,
COO--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl, OBn,
SO.sub.3H, SO.sub.2NR3R4, NR3R4 or SO.sub.2--N-piperidinyl, wherein
the alkyl and phenyl moieties are optionally substituted one or
more times by R2, or two of the radicals R6, R7, R8, R9 and R10, in
adjacent position on the phenyl ring may together form a radical
--O--CH.sub.2--O--, --O--(CH.sub.2).sub.2--O-- or
--CH.dbd.CH--CH.dbd.CH--; m is 0, 1, 2 or 3; X is bond,
(C.sub.2-C.sub.10)-alkylene, (C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.1-C.sub.8)-alkylene-(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.8-
)-alkylene,
(C.sub.1-C.sub.8)-alkylene-(C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.8)-alkylene,
(C.sub.2-C.sub.8)-alkenylene-(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub-
.8)-alkylene,
(C.sub.1-C.sub.8)-alkylene-(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.2-C.sub.8-
)-alkenylene,
(C.sub.2-C.sub.8)-alkenylene-(C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.2-C.sub.8)-alkenylene,
(C.sub.2-C.sub.10)-alkenylene or (C.sub.2-C.sub.10)-alkynylene,
wherein the alkylene, cycloalkyl, alkenylene and alkynylene
moieties are optionally substituted one or more times by R5; R2 is
OH, F, Cl, Br, CN, OCH.sub.3, OCF.sub.3, CH.sub.3, CF.sub.3,
(C.sub.1-C.sub.6)-alkyl or O--(C.sub.1-C.sub.6)-alkyl, wherein the
alkyl moiety is optionally substituted one or more times by OH, F,
Cl, Br or CN; R3 and R4 are, independently of one another, H or
(C.sub.1-C.sub.6)-alkyl, wherein the alkyl is optionally
substituted one or more times by OH, F, Cl or Br; and R5 is
NH.sub.2, NH(C.sub.1-C.sub.4)-alkyl,
N[(C.sub.1-C.sub.4)-alkyl].sub.2, F, Cl, Br, CN, OH,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl; or a
physiologically tolerated salt thereof.
2. The compound according to claim 1, wherein: R6, R7, R8, R9 and
R10 are, independently of one another, H, F, Cl, Br, CF.sub.3,
OCH.sub.3, OCF.sub.3, OCHF.sub.2, SCH.sub.3, SCF.sub.3, phenyl,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl or NR3R4,
wherein the alkyl and phenyl moieties are optionally substituted
one or more times by R2, or two of the radicals R6, R7, R8, R9 and
R10 in adjacent position on the phenyl ring may together form a
radical --CH.dbd.CH--CH.dbd.CH--; X is (C.sub.2-C.sub.10)-alkylene,
which is optionally substituted one or more times by R5; R2 is F,
Cl, Br, CN, OCH.sub.3, OCF.sub.3, CH.sub.3, CF.sub.3,
(C.sub.1-C.sub.6)-alkyl or O--(C.sub.1-C.sub.6)-alkyl, wherein the
alkyl moiety is optionally substituted one or more times by OH, F,
Cl, Br or CN; and R3 and R4 are, independently of one another, H or
(C.sub.1-C.sub.6)-alkyl; or a physiologically tolerated salt
thereof.
3. The compound according to claim 1, wherein: R1 is H; R6, R7, R8,
R9 and R10 are, independently of one another, H, F, Cl, Br,
CF.sub.3, OCH.sub.3, OCF.sub.3, OCHF.sub.2, SCH.sub.3, SCF.sub.3,
phenyl, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl or
NR3R4, wherein the alkyl and phenyl moieties are optionally
substituted one or more times by R2, or two of the radicals R6, R7,
R8, R9 and R10 in adjacent position on the phenyl ring may together
form a radical --CH.dbd.CH--CH.dbd.CH--; X is --(CH.sub.2).sub.2--;
R2 is F, Cl, Br, CN, OCH.sub.3, OCF.sub.3, CH.sub.3, CF.sub.3,
(C.sub.1-C.sub.6)-alkyl or O--(C.sub.1-C.sub.6)-alkyl, wherein the
alkyl moiety is optionally substituted one or more times by OH, F,
Cl, Br or CN; and R3 and R4 are, independently of one another, H or
(C.sub.1-C.sub.6)-alkyl; or a physiologically tolerated salt
thereof.
4. A pharmaceutical composition comprising the compound according
to claim 1 or a physiologically tolerated salt thereof, in
combination with a pharmaceutically acceptable excipient.
5. A pharmaceutical composition comprising the compound according
to claim 2 or a physiologically tolerated salt thereof, in
combination with a pharmaceutically acceptable excipient.
6. A pharmaceutical composition comprising the compound according
to claim 3 or a physiologically tolerated salt thereof, in
combination with a pharmaceutically acceptable excipient.
7. The pharmaceutical composition according to claim 4, further
comprising at least one additional active ingredient.
8. The pharmaceutical composition according to claim 5, further
comprising at least one additional active ingredient.
9. The pharmaceutical composition according to claim 6, further
comprising at least one additional active ingredient.
10. The pharmaceutical composition according to claim 7, wherein
the additional active ingredient is selected from the group
consisting of antidiabetics, hypoglycemic active ingredients,
HMGCoA reductase inhibitors, cholesterol absorption inhibitors,
PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and gamma
agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid
absorption inhibitors, CETP inhibitors, polymeric bile acid
adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants,
lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors,
squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A
receptor agonists, lipase inhibitors, insulins, sulfonylureas,
biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase
inhibitors, active ingredients which act on the ATP-dependent
potassium channel of the beta cells, glycogen phosphorylase
inhibitors, glucagon receptor antagonists, activators of
glucokinase, inhibitors of gluconeogenesis, inhibitors of
fructose-1,6-bisphosphatase, modulators of glucose transporter 4,
inhibitors of glutamine-fructose-6-phosphate amidotransferase,
inhibitors of dipeptidylpeptidase IV, inhibitors of
11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein
tyrosine phosphatase 1B, modulators of the sodium-dependent glucose
transporter 1 or 2, inhibitors of hormone-sensitive lipase,
inhibitors of acetyl-CoA carboxylase, inhibitors of
phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase
kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A
receptor antagonists, inhibitors of I kappaB kinase, modulators of
the glucocorticoid receptor, CART agonists, NPY agonists, MC4
agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,
CRF BP antagonists, urocortin agonists, .beta.3 agonists, CB1
receptor antagonists, MSH 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,
uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists,
lipase/amylase inhibitors, PPAR modulators, RXR modulators or
TR-.beta. agonists and amphetamines.
11. The pharmaceutical composition according to claim 8, wherein
the additional active ingredient is selected from the group
consisting of antidiabetics, hypoglycemic active ingredients,
HMGCoA reductase inhibitors, cholesterol absorption inhibitors,
PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and gamma
agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid
absorption inhibitors, CETP inhibitors, polymeric bile acid
adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants,
lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors,
squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A
receptor agonists, lipase inhibitors, insulins, sulfonylureas,
biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase
inhibitors, active ingredients which act on the ATP-dependent
potassium channel of the beta cells, glycogen phosphorylase
inhibitors, glucagon receptor antagonists, activators of
glucokinase, inhibitors of gluconeogenesis, inhibitors of
fructose-1,6-bisphosphatase, modulators of glucose transporter 4,
inhibitors of glutamine-fructose-6-phosphate amidotransferase,
inhibitors of dipeptidylpeptidase IV, inhibitors of
11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein
tyrosine phosphatase 1B, modulators of the sodium-dependent glucose
transporter 1 or 2, inhibitors of hormone-sensitive lipase,
inhibitors of acetyl-CoA carboxylase, inhibitors of
phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase
kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A
receptor antagonists, inhibitors of I kappaB kinase, modulators of
the glucocorticoid receptor, CART agonists, NPY agonists, MC4
agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,
CRF BP antagonists, urocortin agonists, .beta.3 agonists, CB1
receptor antagonists, MSH 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,
uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists,
lipase/amylase inhibitors, PPAR modulators, RXR modulators or
TR-.beta. agonists and amphetamines.
12. The pharmaceutical composition according to claim 9, wherein
the additional active ingredient is selected from the group
consisting of antidiabetics, hypoglycemic active ingredients,
HMGCoA reductase inhibitors, cholesterol absorption inhibitors,
PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and gamma
agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid
absorption inhibitors, CETP inhibitors, polymeric bile acid
adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants,
lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors,
squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A
receptor agonists, lipase inhibitors, insulins, sulfonylureas,
biguanides, meglitinides, thiazolidinediones, .alpha.-glucosidase
inhibitors, active ingredients which act on the ATP-dependent
potassium channel of the beta cells, glycogen phosphorylase
inhibitors, glucagon receptor antagonists, activators of
glucokinase, inhibitors of gluconeogenesis, inhibitors of
fructose-1,6-bisphosphatase, modulators of glucose transporter 4,
inhibitors of glutamine-fructose-6-phosphate amidotransferase,
inhibitors of dipeptidylpeptidase IV, inhibitors of
11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein
tyrosine phosphatase 1B, modulators of the sodium-dependent glucose
transporter 1 or 2, inhibitors of hormone-sensitive lipase,
inhibitors of acetyl-CoA carboxylase, inhibitors of
phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase
kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A
receptor antagonists, inhibitors of I kappaB kinase, modulators of
the glucocorticoid receptor, CART agonists, NPY agonists, MC4
agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,
CRF BP antagonists, urocortin agonists, .beta.3 agonists, CB1
receptor antagonists, MSH 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,
uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists,
lipase/amylase inhibitors, PPAR modulators, RXR modulators or
TR-.beta. agonists and amphetamines.
13. A method for lowering blood glucose, treating diabetes, or
increasing insulin release, in a patient in need thereof,
comprising administering to the patient a pharmaceutically
effective amount of the compound according to claim 1, or a
physiologically tolerated salt thereof.
14. A method for lowering blood glucose, treating diabetes, or
increasing insulin release, in a patient in need thereof,
comprising administering to the patient a pharmaceutically
effective amount of the compound according to claim 2, or a
physiologically tolerated salt thereof.
15. A method for lowering blood glucose, treating diabetes, or
increasing insulin release, in a patient in need thereof,
comprising administering to the patient a pharmaceutically
effective amount of the compound according to claim 3, or a
physiologically tolerated salt thereof.
16. A process for manufacturing a pharmaceutical composition
comprising the compound according to claim 1 or a physiologically
tolerated salt thereof, in combination with a pharmaceutically
acceptable excipient, which comprises mixing the compound according
to claim 1 or the physiologically tolerated salt thereof, with the
pharmaceutically acceptable excipient, and converting this mixture
into a form suitable for administration.
17. A process for manufacturing a pharmaceutical composition
comprising the compound according to claim 2 or a physiologically
tolerated salt thereof, in combination with a pharmaceutically
acceptable excipient, which comprises mixing the compound according
to claim 2 or the physiologically tolerated salt thereof, with the
pharmaceutically acceptable excipient, and converting this mixture
into a form suitable for administration.
18. A process for manufacturing a pharmaceutical composition
comprising the compound according to claim 3 or a physiologically
tolerated salt thereof, in combination with a pharmaceutically
acceptable excipient, which comprises mixing the compound according
to claim 3 or the physiologically tolerated salt thereof, with the
pharmaceutically acceptable excipient, and converting this mixture
into a form suitable for administration.
Description
[0001] This application is a Continuation of International
Application No. PCT/EP2007/003806, filed Apr. 30, 2007, which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to phenylaminobenzoxazole-substituted
carboxylic acids and their physiologically tolerated salts.
BACKGROUND OF THE INVENTION
[0003] Compounds of similar structure have been described in the
prior art (see WO 94/08962).
[0004] The invention was based on the object of providing compounds
which display a therapeutically utilizable effect. The object was
in particular to find novel compounds suitable for the treatment of
hyperglycemia and diabetes.
SUMMARY OF THE INVENTION
[0005] The invention therefore relates to compounds of the formula
I,
##STR00002##
in which the meanings are [0006] R1 H or (C.sub.1-C.sub.6)-alkyl;
[0007] R6, R7, R8, R9, R10, independently of one another H, F, Cl,
Br, CN, CF.sub.3, OH, OCF.sub.3, OCHF.sub.2, SCH.sub.3, SCF.sub.3,
phenyl, Ophenyl, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, OBn, SO.sub.3H, SO.sub.2NR3R4, NR3R4 or
SO.sub.2--N-piperidinyl, where alkyl and phenyl may be substituted
one or more times by R2, and where in each case two of the radicals
R6, R7, R8, R9, R10, in adjacent position on the phenyl ring may
together form a radical --O--CH.sub.2--O--,
--O--(CH.sub.2).sub.2--O-- or --CH.dbd.CH--CH.dbd.CH--; [0008] m 0,
1, 2 or 3; [0009] X bond, (C.sub.2-C.sub.10)-alkylene,
(C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.1-C.sub.8)-alkylene-(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.9-
)-alkylene,
(C.sub.1-C.sub.8)-alkylene-(C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub.8)-alkylene,
(C.sub.2-C.sub.8)-alkenylene-(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.1-C.sub-
.8)-alkylene,
(C.sub.1-C.sub.8)-alkylene-(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.2-C.sub.8-
)-alkenylene,
(C.sub.2-C.sub.8)-alkenylene-(C.sub.3-C.sub.12)-cycloalkyl,
(C.sub.3-C.sub.12)-cycloalkyl-(C.sub.2-C.sub.8)-alkenylene,
(C.sub.2-C.sub.10)-alkenylene or (C.sub.2-C.sub.10)-alkynylene,
where alkylene, cycloalkyl, alkenylene and alkynylene may be
substituted one or more times by R5; [0010] R2 OH, F, Cl, Br, CN,
OCH.sub.3, OCF.sub.3, CH.sub.3, CF.sub.3, (C.sub.1-C.sub.6)-alkyl
or O--(C.sub.1-C.sub.6)-alkyl, where alkyl may be substituted one
or more times by OH, F, Cl, Br or CN; [0011] R3, R4 independently
of one another H or (C.sub.1-C.sub.6)-alkyl, where alkyl may be
substituted one or more times by OH, F, Cl or Br; [0012] R5
NH.sub.2, NH(C.sub.1-C.sub.4)-alkyl,
N[(C.sub.1-C.sub.4)-alkyl].sub.2, F, Cl, Br, CN, OH,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl; and the
physiologically tolerated salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Preference is given to compounds of the formula I in which
one or more radicals have the following meanings: [0014] R1 H or
(C.sub.1-C.sub.6)-alkyl; [0015] R6, R7, R8, R9, R10, independently
of one another H, F, Cl, Br, CF.sub.3, OCH.sub.3, OCF.sub.3,
OCHF.sub.2, SCH.sub.3, SCF.sub.3, phenyl, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl or NR3R4, where alkyl and phenyl may be
substituted one or more times by R2, and where in each case two of
the radicals R6, R7, R8, R9, R10 in adjacent position on the phenyl
ring may together form a radical --CH.dbd.CH--CH.dbd.CH--; [0016] m
0; [0017] X (C.sub.2-C.sub.10)-alkylene, where alkylene may be
substituted one or more times by R5; [0018] R3, R4 independently of
one another H or (C.sub.1-C.sub.6)-alkyl; [0019] R5 NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl, N[(C.sub.1-C.sub.4)-alkyl].sub.2, F, Cl,
Br, CN, OH, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl; and the
physiologically tolerated salts thereof.
[0020] Particular preference is given to compounds of the formula I
in which one or more radicals have the following meanings: [0021]
R1 H; [0022] R6, R7, R8, R9, R10, independently of one another H,
F, Cl, Br, CF.sub.3, OCH.sub.3, OCF.sub.3, OCHF.sub.2, SCH.sub.3,
SCF.sub.3, phenyl, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl or NR3R4, where alkyl and phenyl may be
substituted one or more times by R2, and where in each case two of
the radicals R6, R7, R8, R9, R10 in adjacent position on the phenyl
ring may together form a radical --CH.dbd.CH--CH.dbd.CH--; [0023] m
0, 1, 2 or 3; [0024] X --(CH.sub.2).sub.2--; [0025] R2 F, Cl, Br,
CN, OCH.sub.3, OCF.sub.3, CH.sub.3, CF.sub.3,
(C.sub.1-C.sub.6)-alkyl or O--(C.sub.1-C.sub.6)-alkyl, where alkyl
may be substituted one or more times by OH, F, Cl, Br or CN; [0026]
R3, R4 independently of one another H or (C.sub.1-C.sub.6)-alkyl;
and the physiologically tolerated salts thereof.
[0027] If radicals or substituents may occur more than once in the
compounds of the formulae I, they may all independently of one
another have the stated meaning and be identical or different.
[0028] The alkyl, alkenyl, alkynyl, alkylene, alkenylene and
alkynylene radicals in the radicals X, R1, R2, R3, R4, R5, R6, R7,
R8, R9 and R10 may be either straight-chain or branched.
[0029] The invention relates to compounds of the formula I in the
form of their salts, racemates, racemic mixtures and pure
enantiomers, and diastereomers and mixtures thereof.
[0030] Physiologically tolerated 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 physiologically tolerated anion or cation.
Suitable physiologically tolerated acid addition salts of the
compounds of the invention are salts of inorganic acids such as
hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric,
sulfonic and sulfuric acids, and 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 acids. The chlorine salt is
particularly preferably used for medical purposes.
[0031] Suitable physiologically tolerated basic salts are ammonium
salts, alkali metal salts (such as sodium and potassium salts),
alkaline earth metal salts (such as magnesium and calcium salts),
zinc salts, and salts of trometamol
(2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine,
arginine, choline, meglumine or ethylenediamine salts.
[0032] Salts with a physiologically untolerated anion or cation
likewise belong within the framework of the invention as useful
intermediates for preparing or purifying physiologically tolerated
salts and/or for use in nontherapeutic, for example in vitro
applications.
[0033] A further aspect of this invention are prodrugs of the
compounds of the invention. Such prodrugs can be metabolized in
vivo to a compound of the invention. These prodrugs may themselves
be active or not.
[0034] The compounds of the invention may also exist in various
polymorphous forms, e.g. as amorphous and crystalline polymorphous
forms. All polymorphous forms of the compounds according to the
invention belong within the framework of the invention and are a
further aspect of the invention.
[0035] All references to "compound(s) of formula (I)" hereinafter
refer to compound(s) of the formula (I) as described herein, and
the salts and solvates thereof as described herein.
[0036] The compounds of the formula (I) and the physiologically
tolerated salts thereof represent ideal pharmaceuticals for the
treatment of elevated lipid concentrations in the blood, the
metabolic syndrome, diabetes, insulin resistance, dysregulation of
LDL, HLD and VLDL or cardiovascular disorders and lipid metabolism
disorders, especially hyperlipidemia.
[0037] The compound(s) of the formula (I) can also be administered
in combination with further active ingredients.
[0038] 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 0.1 mg to 100 mg (typically
from 0.1 mg to 50 mg) per day and per kilogram of body weight, for
example 0.1-10 mg/kg/day. Tablets or capsules may contain, for
example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. For the
prophylaxis or 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.
[0039] Pharmaceutical compositions of the invention are those
suitable for oral and peroral (for example sublingual)
administration, although the most suitable mode of administration
depends in each individual case on the nature and severity of the
condition to be treated and on the nature of the 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.
[0040] Suitable pharmaceutical compounds for oral administration
may be in the form of separate units such as, for example,
capsules, cachets, suckable tablets or tablets, each of which
contains 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.
[0041] 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.
Combinations with Other Medicaments
[0042] The compounds of the invention can be administered alone or
in combination with one or more further pharmacologically active
substances which have, for example, beneficial effects on metabolic
disturbances or disorders frequently associated therewith. Examples
of such medicaments are [0043] 1. medicaments which lower blood
glucose, antidiabetics, [0044] 2. active ingredients for the
treatment of dyslipidemias, [0045] 3. antiatherosclerotic
medicaments, [0046] 4. antiobesity agents, [0047] 5.
antiinflammatory active ingredients [0048] 6. active ingredients
for the treatment of malignant tumors [0049] 7. antithrombotic
active ingredients [0050] 8. active ingredients for the treatment
of high blood pressure [0051] 9. active ingredients for the
treatment of heart failure and [0052] 10. active ingredients for
the treatment and/or prevention of complications caused by diabetes
or associated with diabetes.
[0053] They can be combined with the compounds of the invention of
the formula I in particular for a synergistic improvement in the
effect. Administration of the active ingredient combination can
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.
[0054] Further examples of active ingredients suitable for
combination products are in particular: All antidiabetics which are
mentioned in the Rote Liste 2006, chapter 12; all weight-reducing
agents/appetite suppressants which are mentioned in the Rote Liste
2006, chapter 1; all lipid-lowering agents which are mentioned in
the Rote Liste 2006, chapter 58. They may be combined with the
compound of the invention of the formula I in particular for a
synergistic improvement in the effect. The active ingredient
combination can be administered 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 is
present in a pharmaceutical preparation. Most of the active
ingredients mentioned hereinafter are disclosed in the USP
Dictionary of USAN and International Drug Names, US Pharmacopeia,
Rockville 2001.
[0055] Antidiabetics include insulin and insulin derivatives such
as, for example, Lantus.RTM. (see www.lantus.com) or HMR 1964 or
those described in WO2005005477 (Novo Nordisk), fast-acting
insulins (see U.S. Pat. No. 6,221,633), inhalable insulins such as,
for example, Exubera.RTM. or oral insulins such as, for example,
IN-105 (Nobex) or Oral-lyn.TM. (Generex Biotechnology), GLP-1
derivatives such as, for example, exenatide, liraglutide or those
which have been disclosed in WO98/08871 or WO2005027978 of Novo
Nordisk A/S, in WO01/04156 of Zealand or in WO00/34331 of
Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin
Pharmaceuticals), and orally effective hypoglycemic active
ingredients.
[0056] The orally effective hypoglycemic active ingredients include
preferably sulfonylureas,
biguanidines, meglitinides, oxadiazolidinediones,
thiazolidinediones, glucosidase inhibitors, inhibitors of glycogen
phosphorylase, glucagon antagonists, glucokinase activators,
inhibitors of fructose-1,6-bisphosphatase, modulators of glucose
transporter 4 (GLUT4), inhibitors of glutamine-fructose-6-phosphate
amidotransferase (GFAT), GLP-1 agonists, potassium channel openers
such as, for example, those which have been disclosed in WO
97/26265 and WO 99/03861 of Novo Nordisk A/S, inhibitors of
dipeptidylpeptidase IV (DPP-IV), insulin sensitizers, inhibitors of
liver enzymes involved in stimulating gluconeogenesis and/or
glycogenolysis, modulators of glucose uptake, of glucose transport
and of glucose reabsorption, inhibitors of 11.beta.-HSD1,
inhibitors of protein tyrosine phosphatase 1B (PTP1B), modulators
of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2),
compounds which alter lipid metabolism such as antihyperlipidemic
active ingredients and antilipidemic active ingredients, compounds
which reduce food intake, compounds which increase thermogenesis,
PPAR and RXR modulators and active ingredients which act on the
ATP-dependent potassium channel of the beta cells.
[0057] In one embodiment of the invention, the compound of the
formula I is administered in combination with an HMGCoA reductase
inhibitor such as simvastatin, fluvastatin, pravastatin,
lovastatin, atorvastatin, cerivastatin, rosuvastatin or
L-659699.
[0058] In one embodiment of the invention, the compound of the
formula I is administered in combination with a cholesterol
absorption inhibitor such as, for example, ezetimibe, tiqueside,
pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate;
Forbes Medi-Tech, WO2005042692), MD-0727 (Microbia Inc.,
WO2005021497) or with compounds as described in WO2002066464
(Kotobuki Pharmaceutical Co. Ltd.), WO2005062824 (Merck & Co.)
or WO2005061451 and WO2005061452 (AstraZeneca AB).
[0059] In one embodiment of the invention, the compound of the
formula I is administered in combination with a PPAR gamma agonist
such as, for example, rosiglitazone, pioglitazone, JTT-501, G1
262570, R-483 or CS-011 (rivoglitazone).
[0060] In one embodiment of the invention, the compound of the
formula I is administered in combination with a PPAR alpha agonist
such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or
DRF-10945.
[0061] In one embodiment of the invention, the compound of the
formula I is administered in combination with a mixed PPAR
alpha/gamma agonist such as, for example, muraglitazar,
tesaglitazar, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042,
AVE 8134, AVE 0847, or as described in PCT/US 00/11833, PCT/US
00/11490, DE10142734.4 or in J. P. Berger et al., TRENDS in
Pharmacological Sciences 28(5), 244-251, 2005.
[0062] In one embodiment of the invention, the compound of the
formula I is administered in combination with a PPAR delta agonist
such as, for example, GW-501516.
[0063] In one embodiment of the invention, the compound of the
formula I is administered in combination with metaglidasen or with
MBX-2044 or other partial PPAR gamma agonists/antagonists.
[0064] In one embodiment of the invention, the compound of the
formula I is administered in combination with a fibrate such as,
for example, fenofibrate, clofibrate or bezafibrate.
[0065] In one embodiment of the invention, the compound of the
formula I is administered in combination with an MTP inhibitor such
as, for example, implitapide, BMS-201038, R-103757 or those
described in WO2005085226.
[0066] In one embodiment of the invention, the compound of the
formula I is administered in combination with a CETP inhibitor such
as, for example, torcetrapib or JTT-705.
[0067] In one embodiment of the invention, the compound of the
formula I is administered in combination with a bile acid
absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744,
U.S. Pat. No. 6,221,897 or WO00/61568), such as, for example, HMR
1741 or those as described in DE 10 2005 033099.1 and DE 10 2005
033100.9.
[0068] In one embodiment of the invention, the compound of the
formula I is administered in combination with a polymeric bile acid
adsorbent such as, for example, cholestyramine or colesevelam.
[0069] In one embodiment of the invention, the compound of the
formula I is administered in combination with an LDL receptor
inducer (see U.S. Pat. No. 6,342,512), such as, for example,
HMR1171, HMR1586 or those as described in WO2005097738.
[0070] In one embodiment of the invention, the compound of the
formula I is administered in combination with Omacor.RTM. (omega-3
fatty acids; highly concentrated ethyl esters of eicosapentaenoic
acid and of docosahexaenoic acid).
[0071] In one embodiment of the invention, the compound of the
formula I is administered in combination with an ACAT inhibitor
such as, for example, avasimibe.
[0072] In one embodiment of the invention, the compound of the
formula I is administered in combination with an antioxidant such
as, for example, OPC-14117, probucol, tocopherol, ascorbic acid,
.beta.-carotene or selenium.
[0073] In one embodiment of the invention, the compound of the
formula I is administered in combination with a vitamin such as,
for example, vitamin B6 or vitamin B12.
[0074] In one embodiment of the invention, the compound of the
formula I is administered in combination with a lipoprotein lipase
modulator such as, for example, ibrolipim (NO-1886).
[0075] In one embodiment of the invention, the compound of the
formula I is administered in combination with an ATP citrate lyase
inhibitor such as, for example, SB-204990.
[0076] In one embodiment of the invention, the compound of the
formula I is administered in combination with a squalene synthetase
inhibitor such as, for example, BMS-188494 or as described in
WO2005077907.
[0077] In one embodiment of the invention, the compound of the
formula I is administered in combination with a lipoprotein (a)
antagonist such as, for example, gemcabene (CI1027).
[0078] In one embodiment of the invention, the compound of the
formula I is administered in combination with an HM74A receptor
agonist such as, for example, nicotinic acid.
[0079] In one embodiment of the invention, the compound of the
formula I is administered in combination with a lipase inhibitor
such as, for example, orlistat or cetilistat (ATL-962).
[0080] In one embodiment of the invention, the compound of the
formula I is administered in combination with insulin.
[0081] In one embodiment of the invention, the compound of the
formula I is administered in combination with a sulfonylurea such
as, for example, tolbutamide, glibenclamide, glipizide or
glimepiride.
[0082] In one embodiment of the invention, the compound of the
formula I is administered in combination with a biguanide such as,
for example, metformin.
[0083] In another embodiment of the invention, the compound of the
formula I is administered in combination with a meglitinide such
as, for example, repaglinide or nateglinide.
[0084] In one embodiment of the invention, the compound of the
formula I is administered in combination with a thiazolidinedione
such as, for example, troglitazone, ciglitazone, pioglitazone,
rosiglitazone or the compounds disclosed in WO 97/41097 of Dr.
Reddy's Research Foundation, in particular
5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2-
,4-thiazolidinedione.
[0085] In one embodiment of the invention, the compound of the
formula I is administered in combination with an
.alpha.-glucosidase inhibitor such as, for example, miglitol or
acarbose.
[0086] In one embodiment of the invention, the compound of the
formula I is administered in combination with an active ingredient
which acts on the ATP-dependent potassium channel of the beta
cells, such as, for example, tolbutamide, glibenclamide, glipizide,
glimepiride or repaglinide.
[0087] In one embodiment of the invention, the compound of the
formula I is administered in combination with more than one of the
aforementioned compounds, e.g. in combination with a sulfonylurea
and metformin, a sulfonylurea and acarbose, repaglinide and
metformin, insulin and a sulfonylurea, insulin and metformin,
insulin and troglitazone, insulin and lovastatin, etc.
[0088] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
glycogen phosphorylase, such as, for example, PSN-357 or FR-258900
or those as described in WO2003084922, WO2004007455,
WO2005073229-31 or WO2005067932.
[0089] In one embodiment of the invention, the compound of the
formula I is administered in combination with glucagon receptor
antagonists such as, for example, A-770077, NNC-25-2504 or as
described in WO2004100875 or WO2005065680.
[0090] In one embodiment of the invention, the compound of the
formula I is administered in combination with activators of
glucokinase, such as, for example, RO-4389620, LY-2121260
(WO2004063179), PSN-105, PSN-110, GKA-50 or those as are described
for example by Prosidion in WO2004072031, WO2004072066, WO 05103021
or WO 06016178, by Roche in WO 00058293, WO 00183465, WO 00183478,
WO 00185706, WO 00185707, WO 01044216, GB 02385328, WO 02008209, WO
02014312, WO 0246173, WO 0248106, DE 10259786, WO 03095438, U.S.
Ser. No. 04/067,939 or WO 04052869, by Novo Nordisk in EP 1532980,
WO 03055482, WO 04002481, WO 05049019, WO 05066145 or WO 05123132,
by Merck/Banyu in WO 03080585, WO03097824, WO 04081001, WO 05063738
or WO 05090332, by Eli Lilly in WO 04063194, or by Astra Zeneca in
WO 01020327, WO 03000262, WO 03000267, WO 03015774, WO 04045614, WO
04046139, WO 05044801, WO 05054200, WO 05054233, WO 05056530, WO
05080359, WO 05080360 or WO 05121110.
[0091] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
gluconeogenesis, such as, for example, FR-225654.
[0092] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
fructose-1,6-bisphosphatase (FBPase), such as, for example,
CS-917.
[0093] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of glucose
transporter 4 (GLUT4), such as, for example, KST-48 (D. -O. Lee et
al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
[0094] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
glutamine-fructose-6-phosphate amidotransferase (GFAT), as are
described for example in WO2004101528.
[0095] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
dipeptidylpeptidase IV (DPP-IV), such as, for example, vildagliptin
(LAF-237), sitagliptin (MK-0431), saxagliptin (BMS-477118),
GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200,
GW-825964.times. or as are described in WO2003074500, WO2003106456,
WO200450658, WO2005058901, WO2005012312, WO2005012308,
PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002,
PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2 or DE 10
2005 012873.4.
[0096] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
11-beta-hydroxysteroid dehydrogenase 1 (11.beta.-HSD1), such as,
for example, BVT-2733 or those as are described for example in
WO200190090-94, WO200343999, WO2004112782, WO200344000,
WO200344009, WO2004112779, WO2004113310, WO2004103980,
WO2004112784, WO2003065983, WO2003104207, WO2003104208,
WO2004106294, WO2004011410, WO2004033427, WO2004041264,
WO2004037251, WO2004056744, WO2004065351, WO2004089367,
WO2004089380, WO2004089470-71, WO2004089896, WO2005016877 or
WO2005097759.
[0097] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of protein
tyrosine phosphatase 1B (PTP1B), as are described for example in
WO200119830-31, WO200117516, WO2004506446, WO2005012295,
PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151,
PCT/EP2005/or DE 10 2004 060542.4.
[0098] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of the
sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), such
as, for example, KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226
or as are described for example in WO2004007517, WO200452903,
WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630 or by A.
L. Handlon in Expert Opin. Ther. Patents (2005) 15(11),
1531-1540.
[0099] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
hormone-sensitive lipase (HSL) as described for example in
WO2005073199.
[0100] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
acetyl-CoA carboxylase (ACC), such as, for example, those as
described in WO199946262, WO200372197, WO2003072197 or
WO2005044814.
[0101] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
phosphoenolpyruvate carboxykinase (PEPCK), such as, for example,
those as described in WO2004074288.
[0102] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
glycogen synthase kinase 3 beta (GSK-3 beta), as described for
example in US2005222220, WO2005085230, PCT/EP2005/005346,
WO2003078403, WO2004022544, WO2003106410, WO2005058908,
US2005038023, WO2005009997, US2005026984, WO2005000836,
WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727
or WO2004046117.
[0103] In one embodiment of the invention, the compound of the
formula I is administered in combination with an inhibitor of
protein kinase C beta (PKC beta), such as, for example,
ruboxistaurin.
[0104] In one embodiment of the invention, the compound of the
formula I is administered in combination with an endothelin A
receptor antagonist such as, for example, avosentan (SPP-301).
[0105] In one embodiment of the invention, the compound of the
formula I is administered in combination with inhibitors of
"I-kappaB kinase" (IKK inhibitors), as are described for example in
WO2001000610, WO2001030774, WO2004022553 or WO2005097129.
[0106] In one embodiment of the invention, the compound of the
formula I is administered in combination with modulators of the
glucocorticoid receptor, like those described for example in
WO2005090336.
[0107] In a further embodiment of the invention, the compound of
the formula I is administered in combination with CART modulators
(see "Cocaine-amphetamine-regulated transcript influences energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A. et
al.: Hormone and Metabolic Research (2001), 33(9), 554-558);
NPY antagonists such as, for example, naphthalene-1-sulfonic acid
{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide
hydrochloride (CGP 71683A); peptide YY 3-36 (PYY3-36) or analogous
compounds, such as, for example, CJC-1682 (PYY3-36 conjugated with
human serum albumin via Cys34), CJC-1643 (derivative of PYY3-36
which conjugates in vivo to serum albumin) or those as are
described in WO2005080424; cannabinoid receptor 1 antagonists such
as, for example, rimonabant, SR147778 or those as are described for
example in EP 0656354, WO 00/15609, WO02/076949, WO2005080345,
WO2005080328, WO2005080343, WO2005075450, WO2005080357,
WO200170700, WO2003026647-48, WO200302776, WO2003040107,
WO2003007887, WO2003027069, U.S. Pat. No. 6,509,367, WO200132663,
WO2003086288, WO2003087037, WO2004048317, WO2004058145,
WO2003084930, WO2003084943, WO2004058744, WO2004013120,
WO2004029204, WO2004035566, WO2004058249, WO2004058255,
WO2004058727, WO2004069838, US20040214837, US20040214855,
US20040214856, WO2004096209, WO2004096763, WO2004096794,
WO2005000809, WO2004099157, US20040266845, WO2004110453,
WO2004108728, WO2004000817, WO2005000820, US20050009870,
WO200500974, WO2004111033-34, WO200411038-39, WO2005016286,
WO2005007111, WO2005007628, US20050054679, WO2005027837,
WO2005028456, WO2005063761-62, WO2005061509 or WO2005077897; 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)) or
LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141
or those that are described in WO2005060985, WO2005009950,
WO2004087159, WO2004078717, WO2004078716, WO2004024720,
US20050124652, WO2005051391, WO2004112793, WOUS20050222014,
US20050176728, US20050164914, US20050124636, US20050130988,
US20040167201, WO2004005324, WO2004037797, WO2005042516,
WO2005040109, WO2005030797, US20040224901, WO200501921,
WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251,
EP1538159, WO2004072076 or WO2004072077; orexin receptor
antagonists (e.g.
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea
hydrochloride (SB-334867-A) or those as are described for example
in WO200196302, WO200185693, WO2004085403 or WO2005075458);
histamine H3 receptor agonists (e.g.
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) or those as are
described in WO200064884, WO2005082893); 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 (such as, for example,
1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6--
yloxy)ethylamino]ethanol hydrochloride (WO 01/83451)); MSH
(melanocyte-stimulating hormone) agonists; MCH
(melanin-concentrating hormone) receptor antagonists (such as, for
example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71,
GW-803430 or compounds such as are described in WO2003/15769,
WO2005085200, WO2005019240, WO2004011438, WO2004012648,
WO2003015769, WO2004072025, WO2005070898, WO2005070925,
WO2004039780, WO2003033476, WO2002006245, WO2002002744,
WO2003004027 or FR2868780); CCK-A agonists (such as, for example,
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclo-hexylethyl)thiazol-2-ylca-
rbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid
salt (WO 99/15525), SR-146131 (WO 0244150) or SSR-125180);
serotonin reuptake inhibitors (e.g. dexfenfluramine); mixed
serotoninergic and noradrenergic compounds (e.g. WO 00/71549); 5-HT
receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic
acid salt (WO 01/09111); 5-HT2C receptor agonists (such as, for
example, APD-356, BVT-933 or those as are described in WO200077010,
WO20077001-02, WO2005019180, WO2003064423, WO200242304 or
WO2005082859); 5-HT6 receptor antagonists as are described for
example in WO2005058858; bombesin receptor agonists (BRS-3
agonists); galanin receptor antagonists; growth hormone (e.g. human
growth hormone or AOD-9604); growth hormone-releasing compounds
(tertiary butyl
6-benzyloxy-1-(2-diisopropyl-aminoethylcarbamoyl)-3,4-dihydro-1H-isoquino-
line-2-carboxylate (WO 01/85695)); growth hormone secretagogue
receptor antagonists (ghrelin antagonists) such as, for example,
A-778193 or those as are described in WO2005030734; 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 or Doprexin); lipase/amylase inhibitors (like those
described for example in WO 00/40569); inhibitors of diacylglycerol
O-acyltransferases (DGATs) as described for example in
US2004/0224997, WO2004094618, WO200058491, WO2005044250,
WO2005072740, JP2005206492 or WO2005013907; inhibitors of fatty
acid synthase (FAS) such as, for example, C75 or those as described
in WO2004005277; oxyntomodulin; oleoyl-estrone or thyroid hormone
receptor agonists such as, for example: KB-2115 or those as
described in WO20058279, WO200172692, WO200194293, WO2003084915,
WO2004018421 or WO2005092316.
[0108] In one embodiment of the invention, the further 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.
[0109] In one embodiment of the invention, the further active
ingredient is dexamphetamine or amphetamine.
[0110] In one embodiment of the invention, the further active
ingredient is fenfluramine or dexfenfluramine.
[0111] In another embodiment of the invention, the further active
ingredient is sibutramine.
[0112] In one embodiment of the invention, the further active
ingredient is mazindole or phentermine.
[0113] In one embodiment of the invention, the compound of the
formula I is 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.
[0114] It will be understood that every suitable combination of the
compounds of the invention with one or more of the aforementioned
compounds and optionally one or more further pharmacologically
active substances will be regarded as falling within the protection
conferred by the present invention.
##STR00003## ##STR00004## ##STR00005## ##STR00006## ##STR00007##
##STR00008## ##STR00009##
[0115] The invention further relates both to mixtures of
stereoisomers of the formula I and to the pure stereoisomers of the
formula I, and mixtures of diastereomers of the formula I and the
pure diastereomers. Separation of the mixtures takes place
chromatographically.
[0116] The examples detailed below serve to illustrate the
invention without, however, restricting it.
TABLE-US-00001 TABLE 1 I ##STR00010## Ex. R1 R6 R7 R8 R9 R10 X m
Linkage 1 H H H F H H --(CH.sub.2).sub.2-- 0 5 2 H H CF.sub.3 H H H
--(CH.sub.2).sub.2-- 0 5 3 H H H CF.sub.3 H H --(CH.sub.2).sub.2--
0 5 4 H H CF.sub.3 H CF.sub.3 H --(CH.sub.2).sub.2-- 0 5 5 H H H
NEt.sub.2 H H --(CH.sub.2).sub.2-- 0 5 6 H CN H H H H
--(CH.sub.2).sub.2-- 0 5 7 H H H SO.sub.2NH.sub.2 H H
--(CH.sub.2).sub.2-- 0 5 8 H H H OCHF.sub.2 H H
--(CH.sub.2).sub.2-- 0 5 9 H Ph H H H H --(CH.sub.2).sub.2-- 0 5 10
H H H SO.sub.2--N- H H --(CH.sub.2).sub.2-- 0 5 Pip 11 H H H
SO.sub.2--N- H H --(CH.sub.2).sub.2-- 0 5 Pip 12 H CF.sub.3 H H H H
--(CH.sub.2).sub.2-- 0 5 13 H F H F H H --(CH.sub.2).sub.2-- 0 5 14
H F H F H F --(CH.sub.2).sub.2-- 0 5 15 H F H H H F
--(CH.sub.2).sub.2-- 0 5 16 H H CF.sub.3 H H Cl
--(CH.sub.2).sub.2-- 0 5 17 H H CN H H H --(CH.sub.2).sub.2-- 0 5
18 H H Cl H H OMe --(CH.sub.2).sub.2-- 0 5 19 H H OMe OMe H H
--(CH.sub.2).sub.2-- 0 5 20 H H OMe OMe OMe H --(CH.sub.2).sub.2--
0 5 21 H H Ph H H OMe --(CH.sub.2).sub.2-- 0 5 22 H H H OCH.sub.2Ph
H H --(CH.sub.2).sub.2-- 0 5 23 H H CO.sub.2H H H H
--(CH.sub.2).sub.2-- 0 5 24 H H H CO.sub.2H H H
--(CH.sub.2).sub.2-- 0 5 25 H H H OCF.sub.3 H H
--(CH.sub.2).sub.2-- 0 5 26 H H OCH.sub.2Ph H H H
--(CH.sub.2).sub.2-- 0 5 27 H H H OPh H H --(CH.sub.2).sub.2-- 0 5
28 H OCF.sub.3 H H H H --(CH.sub.2).sub.2-- 0 5 29 H CF.sub.3 H Cl
H H --(CH.sub.2).sub.2-- 0 5 30 H H H SCF.sub.3 H H
--(CH.sub.2).sub.2-- 0 5 31 H H SCF.sub.3 H H H
--(CH.sub.2).sub.2-- 0 5 32 H H CF.sub.3 H H F --(CH.sub.2).sub.2--
0 5 33 H OCHF.sub.2 H H H H --(CH.sub.2).sub.2-- 0 5 34 H Me H H H
Me --(CH.sub.2).sub.2-- 0 5 35 H Br H Me H H --(CH.sub.2).sub.2-- 0
5 36 H H Br H H Br --(CH.sub.2).sub.2-- 0 5 37 H F F F F F
--(CH.sub.2).sub.2-- 0 5 38 H H H Br H H --(CH.sub.2).sub.2-- 0 5
39 H H H N(Et)-- H H --(CH.sub.2).sub.2-- 0 5 (CH.sub.2).sub.2-- OH
40 H H H (CH.sub.2).sub.2-- H H --(CH.sub.2).sub.2-- 0 5 OH 41 H H
H NMe.sub.2 H H --(CH.sub.2).sub.2-- 0 5 42 H H H SO.sub.3H H H
--(CH.sub.2).sub.2-- 0 5 43 H F F H F F --(CH.sub.2).sub.2-- 0 5 44
H H F H H F --(CH.sub.2).sub.2-- 0 5 45 H Cl Cl H H H
--(CH.sub.2).sub.2-- 0 5 46 H Cl Cl Cl H H --(CH.sub.2).sub.2-- 0 5
47 H H Cl Cl H Cl --(CH.sub.2).sub.2-- 0 5 48 H Cl H Cl H Cl
--(CH.sub.2).sub.2-- 0 5 49 H H Cl H H Cl --(CH.sub.2).sub.2-- 0 5
50 H H OMe H H OMe --(CH.sub.2).sub.2-- 0 5 51 H SMe H H H H
--(CH.sub.2).sub.2-- 0 5 52 H Me Me H H H --(CH.sub.2).sub.2-- 0 5
53 H H Me Me H Me --(CH.sub.2).sub.2-- 0 5 54 H Et H H H H
--(CH.sub.2).sub.2-- 0 5 55 H Me H H H Et --(CH.sub.2).sub.2-- 0 5
56 H Et H H H Et --(CH.sub.2).sub.2-- 0 5 57 H H Cl H Cl H
--(CH.sub.2).sub.2-- 0 5 58 H H CO.sub.2Me H H H
--(CH.sub.2).sub.2-- 0 5 59 H H Me H Me H --(CH.sub.2).sub.2-- 0 5
60 H OMe H H Me H --(CH.sub.2).sub.2-- 0 5 61 H
--CH.dbd.CH--CH.dbd.CH-- H H H --(CH.sub.2).sub.2-- 0 5 62 H
--CH.dbd.CH--CH.dbd.CH-- NMe.sub.2 H H --(CH.sub.2).sub.2-- 0 5 63
H H H H H H --(CH.sub.2).sub.2-- 0 5 64 H F H H H H
--(CH.sub.2).sub.2-- 0 5 65 H Cl H H H H --(CH.sub.2).sub.2-- 0 5
66 H Me H H H H --(CH.sub.2).sub.2-- 0 5 67 H H F H H H
--(CH.sub.2).sub.2-- 0 5 68 H H Cl H H H --(CH.sub.2).sub.2-- 0 5
69 H H Me H H H --(CH.sub.2).sub.2-- 0 5 70 H H H Cl H H
--(CH.sub.2).sub.2-- 0 5 71 H H H Me H H --(CH.sub.2).sub.2-- 0 5
72 H OMe H H H H --(CH.sub.2).sub.2-- 0 5 73 H H H OMe H H
--(CH.sub.2).sub.2-- 0 5 74 H i-Pr H H H H --(CH.sub.2).sub.2-- 0 5
75 H Me H Me H Me --(CH.sub.2).sub.2-- 0 5 76 H Me Cl H H H
--(CH.sub.2).sub.2-- 0 5 77 H H Cl Me H H --(CH.sub.2).sub.2-- 0 5
78 H H H CO.sub.2Et H H --(CH.sub.2).sub.2-- 0 5 79 H H H t-Bu H H
--(CH.sub.2).sub.2-- 0 5 80 H H H i-Pr H H --(CH.sub.2).sub.2-- 0 5
81 H H Me Me H H --(CH.sub.2).sub.2-- 0 5 82 H Cl H Cl H H
--(CH.sub.2).sub.2-- 0 5 83 H H Cl Cl H H --(CH.sub.2).sub.2-- 0 5
84 H Br H H H H --(CH.sub.2).sub.2-- 0 5 85 H H Br H H H
--(CH.sub.2).sub.2-- 0 5 86 H H Cl Br H H --(CH.sub.2).sub.2-- 0 5
87 H H Ac H H H --(CH.sub.2).sub.2-- 0 5 88 H Me H Br H Me
--(CH.sub.2).sub.2-- 0 5 89 H H F Me H H --(CH.sub.2).sub.2-- 0 5
90 H H F F H H --(CH.sub.2).sub.2-- 0 5 91 H Cl H CF.sub.3 H H
--(CH.sub.2).sub.2-- 0 5 92 H H CH.sub.2OH H H H
--(CH.sub.2).sub.2-- 0 5 93 H H CH(OH)--CH.sub.3 H H H
--(CH.sub.2).sub.2-- 0 5 94 H Cl H F H H --(CH.sub.2).sub.2-- 0 5
95 H F H Cl H H --(CH.sub.2).sub.2-- 0 5 96 H H Me Cl H H
--(CH.sub.2).sub.2-- 0 5 97 H Br H Br H H --(CH.sub.2).sub.2-- 0 5
98 H H F F H F --(CH.sub.2).sub.2-- 0 5 99 H F F H F H
--(CH.sub.2).sub.2-- 0 5 100 H Me F H H H --(CH.sub.2).sub.2-- 0 5
101 H Br H CF.sub.3 H H --(CH.sub.2).sub.2-- 0 5 102 H F Cl H H H
--(CH.sub.2).sub.2-- 0 5 103 H H Me F H H --(CH.sub.2).sub.2-- 0 5
104 H H OMe Cl H OMe --(CH.sub.2).sub.2-- 0 5 105 H H
--(CH.sub.2).sub.3-- H H --(CH.sub.2).sub.2-- 0 5 106 H Me H OMe H
H --(CH.sub.2).sub.2-- 0 5 107 H H Cl OMe H OMe
--(CH.sub.2).sub.2-- 0 5 108 H H Cl F H H --(CH.sub.2).sub.2-- 0 5
109 H H --O--CH.sub.2--O-- H H --(CH.sub.2).sub.2-- 0 5 110 H H Et
H H H --(CH.sub.2).sub.2-- 0 5 111 H H H CN H H
--(CH.sub.2).sub.2-- 0 5 112 H Me H Cl H H --(CH.sub.2).sub.2-- 0 5
113 H H CF.sub.3 Cl H H --(CH.sub.2).sub.2-- 0 5 114 H H H OEt H H
--(CH.sub.2).sub.2-- 0 5 115 H H H CO.sub.2Me H H
--(CH.sub.2).sub.2-- 0 5 116 H H H Ac H H --(CH.sub.2).sub.2-- 0 5
117 H H H Et H H --(CH.sub.2).sub.2-- 0 5 118 H H H n-Bu H H
--(CH.sub.2).sub.2-- 0 5 119 H H H SMe H H --(CH.sub.2).sub.2-- 0 5
120 H OEt H H H H --(CH.sub.2).sub.2-- 0 5 121 H Me H H Me H
--(CH.sub.2).sub.2-- 0 5 122 H H Cl H H Me --(CH.sub.2).sub.2-- 0 5
123 H Me H F H H --(CH.sub.2).sub.2-- 0 5 124 H H
--O--(CH.sub.2).sub.2--O H H --(CH.sub.2).sub.2-- 0 5 125 H H F H H
Br --(CH.sub.2).sub.2-- 0 5 126 H Br H F H H --(CH.sub.2).sub.2-- 0
5 127 H H OH H H H --(CH.sub.2).sub.2-- 0 5 128 H Cl H Cl H Me
--(CH.sub.2).sub.2-- 0 5 129 H Br H i-Pr H H --(CH.sub.2).sub.2-- 0
5 130 H H Cl H H F --(CH.sub.2).sub.2-- 0 5 131 H H F H F H
--(CH.sub.2).sub.2-- 0 5 132 H F F F H H --(CH.sub.2).sub.2-- 0 5
133 H H Cl OH Cl H --(CH.sub.2).sub.2-- 0 5 134 H F H Br H H
--(CH.sub.2).sub.2-- 0 5 135 H H CF.sub.3 F H H
--(CH.sub.2).sub.2-- 0 5 136 H H CF.sub.3 Me H H
--(CH.sub.2).sub.2-- 0 5 137 H H Me OH Me H --(CH.sub.2).sub.2-- 0
5 138 H Cl Cl H Cl Cl --(CH.sub.2).sub.2-- 0 5 139 H OCHF.sub.2 H
Me H H --(CH.sub.2).sub.2-- 0 5 140 H OCHF.sub.2 H H Me H
--(CH.sub.2).sub.2-- 0 5 141 H F H Me H H --(CH.sub.2).sub.2-- 0 5
142 H F H H Me H --(CH.sub.2).sub.2-- 0 5 143 H CO.sub.2H H H H H
--(CH.sub.2).sub.2-- 0 5 144 H Cl Cl H H H --(CH.sub.2).sub.2-- 0 6
145 H CF.sub.3 H Cl H H --(CH.sub.2).sub.2-- 0 6 146 H Cl H
CF.sub.3 H H --(CH.sub.2).sub.2-- 0 5
[0117] The activity of the compounds was tested as follows:
In Vitro FLIPR Assay with Recombinant Cells which Express the GPCR
GPR40
[0118] Function-testing assays were carried out by means of the
FLIPR technique ("Fluorescence Imaging Plate Reader", Molecular
Devices Corp.). For this purpose, agonist-induced changes in the
intracellular concentration of Ca.sup.2+ in recombinant HEK293
cells which expressed the GPCR GPR40 were determined.
[0119] For the investigations, cells were seeded in 96-well
microtiter plates (60 000 cells/well) and allowed to grow
overnight. The medium was removed and the cells were incubated in
buffer which contained the fluorescent dye fluo-4. After this
loading with dye, the cells were washed, test substance was added,
and changes in the intracellular Ca.sup.2+ concentration were
measured in the FLIPR instrument. Results have been presented as
percentage change relative to the control (0%: no test substance
added; 100%: 10 .mu.M reference agonist linoleic acid added).
TABLE-US-00002 TABLE 2 Biological activity Ex. % activation @ 100
.mu.M 29 92 36 97 45 111 48 111 82 90 91 100 97 96 101 96 129 89
138 100 144 87 145 79
[0120] It is evident from the table that the compounds of the
formula I activate the GPR40 receptor and thus are very suitable
for the treatment of hyperglycemia and of diabetes. Insulin release
is increased by the compounds of the formula I (see Itoh et al.,
Nature 2003, 422, 173-176).
[0121] The compounds of the formula I may also show a corresponding
effect on the GPR120 receptor.
[0122] The compounds of the formula I can be prepared for example
by reacting suitable starting materials of the formula II (the
syntheses are sufficiently well known in the literature) with
isothiocyanates of the formula III to give compounds of the formula
IV.
##STR00011##
[0123] This process is adequately described in the literature.
[0124] The compounds of the formula I can be prepared for example
by converting suitable starting materials (in the case of
substituted (2-hydroxyphenyl)thioureas) of the formula IV (the
syntheses are sufficiently well known in the literature) by a
choice of a suitable desulfurizing reagent such as, for example,
yellow HgO (Journal of Chemical Research, Synopses 2001, (4),
138-139), PbO (Journal of Pharmaceutical Sciences 1964, 53 (5),
538-44), AgNO.sub.3/NH.sub.4OH (Khimiya Geterotsiklicheskikh
Soedinenii 1981, (5), 604-7), KO.sub.2 (Chemistry Letters 1986,
(8), 1291-4), N,N'-dicyclohexylcarbonyldiimide (DE 3006671), methyl
iodide/s-collidine (Tetrahedron Letters 2001, 42 (34), 5853-5856),
or p-toluenesulfonyl chloride/NaOH (Tetrahedron 2004, 60,
9883-9888) into the corresponding 2-aminobenzoxazoles of the
formula I.
[0125] The compounds of the formula I can also be converted by the
synthesis described by Jong Yeon Hwang and Young-Dae Gong (J. Comb.
Chem. 2006, in press) of polymer-bound mercaptobenzoxazoles by
reacting 2-aminophenols of the formula II with CS.sub.2 and for
example Merrifield resin in the presence of
diisopropylcarbonyldiimide into the compounds of the formula V,
##STR00012##
subsequent oxidation of the sulfur to the sulfone and reaction with
anilines of the formula VI afford compounds of the formula I.
##STR00013##
[0126] The general preparation of the examples is described in
detail below:
Experimental section: General experimental protocol:
[0127] 0.25 mmol of an aminophenol is dissolved in 1.5 ml of 4:1
toluene/dimethylformamide, and 0.275 mmol of the appropriate
isocyanate is added. The mixture is then heated at 80.degree. C.
with stirring for 1 hour. After complete conversion into the
thiourea, 0.375 mmol of yellow HgO is added and stirring is
continued at 80.degree. C. for 2 hours. After conversion is
complete, the mixture is cooled and mixed with 0.3 g of thiol
scavenger (SiO.sub.2-bound propane thiol, Aldrich) and stirred at
room temperature for a further 12 hours. It is then filtered
through Celite, concentrated and purified by preparative HPLC
(Waters C.sub.18, X-Terra, 10 .mu.m, 30.times.100 mm,
acetonitrile/(water+0.1% TFA), 10% acetonitrile to 90% in 4
minutes).
[0128] The compounds were analyzed by LC/MS. The appropriate
molecular peak (M+H) was detectable by LC/MS with all the
examples.
* * * * *
References