ZA200504647B - Carbonyl-amino substituted acyl phenyl urea derivatives method for the production and use thereof - Google Patents

Carbonyl-amino substituted acyl phenyl urea derivatives method for the production and use thereof Download PDF

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ZA200504647B
ZA200504647B ZA200504647A ZA200504647A ZA200504647B ZA 200504647 B ZA200504647 B ZA 200504647B ZA 200504647 A ZA200504647 A ZA 200504647A ZA 200504647 A ZA200504647 A ZA 200504647A ZA 200504647 B ZA200504647 B ZA 200504647B
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alkyl
alkylene
alkenyl
alkynyl
cycloalkyl
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ZA200504647A
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Elisabeth Defossa
Thomas Klabunde
Andreas Herling
Erich Von Roedern
Alfons Ehnsen
Dieter Kadereit
Hans-Joerg Burger
Karl-Ulrich Wendt
Karl Schoenafinger
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Sanofi Aventis Deutschland
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Abstract

The invention relates to compounds of formula (I) wherein the radicals have the cited meaning, in addition to the physiologically compatible salts thereof. The compounds, for example, can be used as medicaments for preventing and treating type 2 diabetes.

Description

bs
Ct WO 2004/065356 PCT/EP2004/000041
Description
Carbonyl-amino substituted acyl phenyl urea derivatives, method for the production and use thereof
The invention relates to carbonylamino-substituted acyl phenyl urea } derivatives, and also to their physiologically tolerated salts and physiologically functional derivatives.
WO 9946236 (Novo Nordisk) describes carbonylamino-substituted acyl phenyl urea derivatives (Example 1) which are effective in the event of type 2 diabetes.
WO 00/07991 (PCT/GB99/02489 Astra Zeneca) describes amide derivatives as inhibitors of the formation of cytokines.
It is an object of the invention to provide compounds which make possible prevention and treatment of type Il diabetes. To this end, the compounds should in particular exhibit a therapeutically utilizable blood sugar-lowering action.
The invention therefore relates to compounds of the formula
R4
R5
RS oO 0) R3 0
NN a
R9 I H
R1 R2 Ré6
R10 R11 [ : 25 in which
R8, R9, R10, R11 are each independently H, F, CI, Br, OH, NO2, CN,
O-(C1-Ceg)alkyl, O-(C2-Cg)alkenyl, 0O-(C2-Cg)alkynyl,
O-S02-(C1-Cy)-alkyl, (C1-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl or Br;
oe WO 2004/065356 2 PCT/EP2004/000041 ®
R1, R2 are each independently H, (C1-Cg)-alkyl, where alkyl may be substituted by OH, O-(C4-C4)-alkyl, NH2, NH(C4-Cg4)-alkyl,
N[(C1-Cg)-alkyl]2, or are O-(C4-Cg)-alkyl, CO-(C1-Cg)-alkyl,
COO-(C1-Cpg)-alkyl, (C1-Cg)-alkylene-COOH or (Cq-Cg)- alkylene-COO-(C1-Cg)-alkyl;
R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO2, CN, O-R12,
O-phenyl, S-R12, COOR12, N(R13)(R14), (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkyl-(C1-C4)-alkylene or O-(C1-Cs)-alkyl-COOR12, : where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, CI, Br, OR12, COOR12 or N(R13)(R14);
R7 is H, (C4-Cg)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-Cg4)-alkylene, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C1-Ceg)- alkylcarboxy-(C1-Cg)-alkylene, n COOR12, (Cg-C1qp)-aryl, (Ce-C1p)-aryl-(C1-C4)-alkylene, heterocyclic radical, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12, CONHo,
CONH(C1-Cg)-alkyl, CON[(C1-Cg)-alkyl]z or N(R13)(R14), and where aryl and heteroaryl may be polysubstituted by F,
Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14) or (C1-Cg)-alkyl;
R12 is H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Ci, Br,
OH or O-(C1-C4)-alkyl,
R13, R14 are each independently H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-Cy)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyi, phenyl or SO2-phenyl, where the phenyl ring may be up to disubstituted by F, CI, CN, OH, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl,
CF3, OCF3, COOH, COO(C1-Cg)-alkyl or CONH?2;
Ce WO 2004/065356 3 PCT/EP2004/000041 ® where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the group of N, O and S, where the heterocyclic ring may be up to trisubstituted by F, CI, Br, OH, oxo, N(R21)(R22) or (C4-Ca4)- alkyl;
R21, R22 are each independently H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynvyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-C4)-alkylene, COO-(C1-Cy)-alkyl, COO-(C2-Cy)-alkenyl, phenyl or SO2-phenyl, where the phenyl ring may be up to disubstituted by F, CI, CN, OH, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl,
CF3, OCF3, COOH, COO(C1-Cg)-alkyl or CONHp2; excluding compounds of the formula | in which the radicals are at the same time defined as follows:
R5 is halogen or unsubstituted (C1-Cg)-alkyl, R7 is heterocyclic radical or heteroaryl; and their physiologically tolerated salts.
Preference is given to compounds of the formula | in which one or more radicals are defined as follows:
RS8, R9, R10, R11 are each independently H, F, Cl, Br, OH, NO2, CN, 0-(C4-Cg)-alkyl, where alkyl may be polysubstituted by F, Cl or Br;
R1, R2 are each H;
R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO2, CN, O-R12,
O-phenyl, S-R12, COOR12, N(R13)(R14), (C1-Ceg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkyl-(C1-C4)-alkylene or O-(C4-Cs)-alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12 or N(R13)(R14);
Ce WO 2004/065356 4 PCT/EP2004/000041 ®
R7 is H, (C1-Cg)-alkyl, (C3-C7)-cycloalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C1-Ceg)-alkylcarboxy-(C1-Cg)-alkylene,
COOR12, (Ce-C1p)-aryl, (Cg-C1p)-aryl-(C1-C4)-alkylene, heteroaryl, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, CI, Br, OR12, COOR12, CONHy,
CONH(C1-Cg)-alkyl, CONI[(C1-Cpg)-alkyl]z or N(R13)(R14), and where aryl and heteroaryl may be polysubstituted by F,
Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14) or (C1-Ceg)-alky!;
R12 is H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl, Br,
OH or O-(C1-Cy)-alkyl,
R13, R14 are each independently H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-Cg4)-alkylene, COO-(C1-C4)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, where the phenyl ring may be up to disubstituted by F, CI, CN, OH, (C4-Cg)-alkyl, O-(C1-Cg)-alkyl,
CF3, OCF3, COOH, COO(C1-Cg)-alkyl or CONH2; where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the group of N, O and S, where the heterocyclic ring may be up to trisubstituted by F, CI, Br, OH, oxo, N(R21)(R22) or (C1-C4)- alkyl;
R21, R22 are each independently H, (C1-Cg)-alkyl; excluding compounds of the formula | in which the radicals are at the same time defined as follows:
RS is halogen or unsubstituted (C1-Cg)-alkyl, R7 is heterocyclic radical or heteroaryl; and their physiologically tolerated salts.
Ce WO 2004/065356 5 PCT/EP2004/000041
Particular preference is given to compounds of the formula | in which one or more radicals are defined as follows:
R8, R9, R10, R11 are each independently H, F or CI,
R1, R2, R4, R6 are each H;
R3, RS are each independently H, Cl, OR12, COOR12, N(R13)(R14) or (C1-Ceg)-alkyl;
R7 is (C1-Cg)-alkyl, where alkyl may be polysubstituted by F,
OR12, COOR12 or N(R13)(R14), or is (C3-Cg)-cycloalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C1-Cs)-alkylcarboxy- (C4-Ceg)-alkylene, COOR12, phenyl, where phenyl may be polysubstituted by F, OMe or OCF3, or is benzyl whose phenyl ring may be substituted by OMe, pyridyl, thienyi, furanyl, indolylcarbonyl, benzofuranyl, where benzofuranyl may be substituted by Cl or OMe;
R12 is H or (C1-Cg)-alkyl, where alkyl may be polysubstituted by
F,
R13, R14 are each independently H or (C1-Cg)-alkyl; or
R13 and R14, together with the nitrogen atom to which they are bonded, may form a 5-membered, saturated heterocyclic ring; excluding compounds of the formula | in which the radicals are at the same time defined as follows:
RS5 is halogen or unsubstituted (C41-Cg)-alkyl, R7 is heterocyclic radical or heteroaryl, and their physiologically tolerated salts.
The invention relates to compounds of the formula |, in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof.
®
The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, RS,
R10, R11, R12, R13, R14, R21 and R22 may be either straight-chain or branched.
When radicals or substituents can occur more than once in the compounds of the formula I, for example O-R12, they may each independently be as defined and be the same or different.
As a consequence of their higher water solubility compared to the starting or basic compounds, pharmaceutically acceptable salts are particularly suitable for medical applications. These salts have to have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also of organic acids, e.g. acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, : methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and caicium salts), trometamol (2-amino- 2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts having a pharmaceutically unacceptable anion, for example trifluoroacetate, are likewise encompassed by the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound of the formula according to the invention, e.g. an ester which is able, on administration to a mammal, e.g. a human, to (directly or indirectly) form a compound of the formula | or an active metabolite thereof.
®
The physiologically functional derivatives also include prodrugs of the compounds according to the invention, for example as described in H.
Okada et al.,, Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may or may not be active themselves.
The compounds according to the invention can also exist in different polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention are encompassed by the scope of the invention and are a further aspect of the invention.
All references given below to “compound(s) of formula I” refer to compound(s) of the formula | as described above, and also to their salts, solvates and physiologically functional derivatives as described herein.
In this context, an aryl radical is a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon, indanyl or indan-1-onyl radical.
The terms “heterocyclic ring” and “heterocyclic radical” used herein relate to heteroaryl radicals and heterocycloalkyl radicals which derive from 3 to 10 membered carbon rings in which one or more carbon atoms are replaced by one or more atoms selected from the group of oxygen, sulfur and nitrogen.
Suitable “heterocyclic rings” and “heterocyclic radicals” are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,52- dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2 3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl,
® phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl. Pyridyl is either 2-, 3- or 4-pyridyl. Thienyl is either 2- or 3-thienyl. Fury! is either 2- or 3-furyl.
Also included are the corresponding N-oxides of these compounds, for example 1-oxy-2-, 3- or 4-pyridyl.
Also included are one or more benzofused derivatives of these heterocycles.
The compound(s) of the formula (I) can also be administered in combination with further active ingredient.
The amount of a compound of formula | which is required in order to achieve the desired biological effect is dependent upon a series of factors, for example the specific compound selected, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day per kilogram of bodyweight, for example 3-10 mg/kg/day.
An intravenous dose may, for example, be in the range from 0.3 mg to 1.0 mg/kg and may advantageously be administered as an infusion of from 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Individual doses may contain, for example, from 1 mg to 10 g of the active ingredient. Ampoules for injections may therefore contain, for example, from 1 mg to 100 mg, and single dose formulations which can be administered orally, for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. The compounds of formula | may be used for therapy of the abovementioned conditions as the compounds themselves, although they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier of course has to be acceptable, in the sense that it is compatible with the other constituents of the composition and is not damaging to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05 to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including further compounds of formula |. The pharmaceutical compositions according to the invention may be produced by one of the known pharmaceutical methods which consist essentially of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the type of the compound of formula used in each case. Coated formulations and coated slow-release formulations are also encompassed by the scope of the invention.
Preference is given to acid- and gastric fluid-resistant formulations. Suitable gastric fluid-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylimethylceliulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the form of separate units, for example capsules, cachets, lozenges or tablets, each of which contains a certain amount of the compound of formula |; as powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. For example, a tablet can be produced by compressing or
® shaping a powder or granules of the compound, optionally with one or more additional ingredients. Compressed tablets can be prepared by tableting the compound in free-flowing form, for example a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or one (or more) surfactants/dispersants in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain the compound of formula with a flavoring, customarily sucrose, and gum arabic or tragacanth, and pastilles which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration include preferably sterile aqueous preparations of a compound of formula | which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations can preferably be produced by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. The injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably in the form of single dose suppositories. These can be prepared by mixing a compound of formula | with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Useful carriers include petroleum jelly, lanolin, polyethylene 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, preferably from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be in the form of single plasters which are suitable for long-term close contact with the epidermis of the patient. Such plasters advantageously contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in a tackifier or dispersed in a polymer. A suitable active ingredient concentration is from approx. 1% to 35%, preferably from approx. 3 to 15%.
A particular means of releasing the active ingredient is by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).
Further useful active ingredients for combination products are as follows:
All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They can be combined with the compounds of the formula | according to the invention, in particular for synergistic enhancement of the action. The active ingredient combination can be administered either by separately 16 administering the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed hereinbelow are disclosed in USP Dictionary of USAN and International
Drug Names, US Pharmacopeia, Rockville 2001.
Antidiabetics include insulin and insulin derivatives, for example Lantus® (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221,633), GLP-1 derivatives, for example those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients.
The orally active hypoglycemic active ingredients preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, for example those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes which are involved in the stimulation of gluconeogenesis 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.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an HMGCoA reductase inhibitor such as
® simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a cholesterol absorption inhibitor, for example, ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a PPAR gamma agonist, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570.
In one embodiment of the invention, the compounds of the formula | are administered in combination with PPAR alpha agonist, for example,
GW 9578, GW 7647.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a mixed PPAR alpha/gamma agonist, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in : PCT/US 11833, PCT/US 11490, DE10142734 4.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a fibrate, for example, fenofibrate, clofibrate, bezafibrate.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an MTP inhibitor, for example, implitapide, BMS-201038, R-103757.
In one embodiment of the invention, the compounds of the formula | are administered in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), for example, HMR 1741.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a CETP inhibitor, for example, JTT-705.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a polymeric bile acid adsorbent, for example, cholestyramine, colesevelam.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an LDL receptor inducer (see
US 6,342,512), for example, HMR1171, HMR 1586.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an ACAT inhibitor, for example, avasimibe.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an antioxidant, for example, OPC-14117.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a lipoprotein lipase inhibitor, for example,
NO-1886.
In one embodiment of the invention, the compounds of the formula | are administered in combination with an ATP-citrate lyase inhibitor, for example, SB-204990.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a squalene synthetase inhibitor, for example, BMS-188494.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a lipoprotein(a) antagonist, for example,
CI-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of the formula | are administered in combination with a lipase inhibitor, for example, orlistat.
In one embodiment of the invention, the compounds of the formula | are administered in combination with insulin.
In one embodiment, the compounds of the formula | are administered in combination with a sulfonylurea, for example, tolbutamide, glibenclamide, (glipizide or glimepiride.
In one embodiment, the compounds of the formula | are administered in combination with a biguanide, for example, metformin.
®
In yet another embodiment, the compounds of the formula | are administered in combination with a meglitinide, for example, repaglinide.
In one embodiment, the compounds of the formula | are administered in combination with a thiazolidinedione, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of
Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3- methyl-4-oxo-2-quinazolinylmethoxy]phenyllmethyl]-2,4-thiazolidinedione.
In one embodiment, the compounds of the formula | are administered in combination with an a-glucosidase inhibitor, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula | are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of the formula | are administered in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
In a further embodiment, the compounds of the formula | are administered in combination with CART modulators (see "Cocaine-amphetamine- regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M..Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexyimethyl}amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3 4- tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo- 2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2- oxo-ethyllamide; (WO 01/91752)), orexin antagonists (e.g. 1-(2- methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB- 334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7- tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6- trimethylphenyl)-9H-1,3,9-triazafluoren-4-ylldipropylamine (WO 00/66585)),
CRF BP antagonists (e.g. urocortin), urocortin agonists, 3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6- yloxy)ethylaminojethanol ~~ hydrochloride (WO 01/83451)), MSH

Claims (11)

What is claimed is:
1. Compounds of the formula R4 R5 RS oO 0] R3 oO _— Nr R9 | H R1 R2 R6 R10 R11 in which R8, R9, R10, R11 are each independently H, F, Cl, Br, OH, NO2, CN, O-(C1-Cg)alkyl, O-(C2-Cg)alkenyl, O-(Co-Cg)alkynyl, 0-S02-(C1-Cyg)-alkyl, (C41-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, Cl or Br; R1,R2 are each independently H, (C1-Cg)-alkyl, where alkyl may be substituted by OH, O-(C1-Cg4)-alkyl, NH2, NH(C1-C4)-alkyl, N[(C1-Cg)-alkyl]2, or are O-(C4-Cg)-alkyl, CO-(C1-Cg)-alkyl, COO-(C1-Cg)-alkyl, (C4-Cg)-alkylene-COOH or (C1-Cg)- alkylene-COO-(C1-Cg)-alkyl; R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO2, CN, O-R12, O-phenyl, S-R12, COOR12, N(R13)(R14), (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkyl-(C1-C4)-alkylene or O-(C1-Cs)-alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, CI, Br, OR12, COOR12 or N(R13)(R14); R7 is H, (Cq1-Cg)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-Cg4)-alkylene, (C2-Cg)-alkenyl, (Co-Cg)-alkynyl, (C1-Ceg)- alkylcarboxy-(C1-Cg)-alkylene, COOR12, (Cg-C1p)-aryl, (Ces-C1p)-aryl-(C1-Cy)-alkylene, heterocyclic radical, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where
® alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, Cl, Br, OR12, COOR12, CONHpy, CONH(C1-Cg)-alkyl, CON[(C1-Cg)-alkyllz or N(R13)(R14), and where aryl and heteroaryl may be polysubstituted by F, Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14) or (C1-Ce)-alkyl, R12 is H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, CI, Br, OH or O-(C1-Cy)-alkyl, R13, R14 are each independently H, (C1-Cg)-alkyl, (C»-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-C4)-alkylene, COO-(C1-Cg)-alkyl, COO-(C2-Cg4)-alkenyl, phenyl or SO2-phenyl, where the phenyl ring may be up to disubstituted by F, CI, CN, OH, (C1-Cg)-alkyl, O-(C1-Cg)-alkyl, CF3, OCF3, COOH, COO(C1-Cg)-alkyl or CONH>; where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the group of N, O and S, where the heterocyclic ring may be up to trisubstituted by F, Cl, Br, OH, oxo, N(R21)(R22) or (C1-C4)- alkyl;
R21,R22 are each independently H, (C1-Cg)-alkyl, (C2-Cg)-alkenyt, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-Cy)-alkylene, COO-(C1-Cy)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, where the phenyl ring may be up to disubstituted by F, CI, CN, OH, (C4-Cg)-alkyl, O-(C1-Cg)-alkyl, CF3, OCF3, COOH, COO(C1-Cg)-alkyl or CONH2; excluding compounds of the formula | in which the radicals are at the same time defined as follows: RS is halogen or unsubstituted (C1-Cg)-alkyl, R7 is heterocyclic radical or heteroaryl;
® and their physiologically tolerated salts.
2. Compounds of the formula | as claimed in claim 1, wherein R8,R9, R10, R11 are each independently H, F, Cl, Br, OH, NO2, CN, O-(C1-Cg)-alkyl, where alkyl may be polysubstituted by F, CI or Br; R1, R2 are each H; R3, R4, R5, R6 are each independently, H, F, Cl, Br, NO2, CN, O-R12, O-phenyl, S-R12, COOR12, N(R13)(R14), (C4-Cg)-alkyl, (C2-Ceg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)- cycloalkyl-(C1-C4)-alkylene or O-(C1-Cs)-alkyl-COOR12, where alkyl, cycloalkyl, alkylene and alkynyl may be polysubstituted by F, CI, Br, OR12, COOR12 or N(R13)(R14); R7 is H, (Cq1-Cg)-alkyl, (C3-C7)-cycloalkyl, (C2-Cg)-alkenyl, (C2-Ceg)-alkynyl, (C1-Cg)-alkylcarboxy-(C1-Cg)-alkylene, COOR12, (Cg-C1p)-aryl, (Cg-C10)-aryl-(C1-C4)-alkylene, heteroaryl, heteroaryl-(C1-C4)-alkylene or heteroarylcarbonyl, where alkyl, cycloalkyl, alkylene, alkenyl and alkynyl may be polysubstituted by F, CI, Br, OR12, COOR12, CONHo, CONH(C4-Cg)-alkyl, CONI[(C1-Cg)-alkyl]z or N(R13)(R14), and where aryl and heteroaryl may be polysubstituted by F, Cl, Br, NO2, CN, O-R12, S-R12, COOR12, N(R13)(R14) or (C1-Ce)-alkyl; R12 is H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl or (C2-Cg)-alkynyl, where alkyl, alkenyl and alkynyl may be polysubstituted by F, CI, Br, OH or O-(C1-Cg4)-alkyl, R13, R14 are each independently H, (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-Cy)-alkylene, COO-(C1-Cy)-alkyl, COO-(C2-C4)-alkenyl, phenyl or SO2-phenyl, where the phenyl ring may be up to disubstituted by F, CI, CN, OH, (C4-Cg)-alkyl, O-(C1-Cg)-alkyl,
® CF3, OCF3, COOH, COO(C1-Cg)-alkyl or CONHjy; where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 3-7 membered, saturated, heterocyclic ring which may contain up to 2 further heteroatoms from the group of N, O and S, where the heterocyclic ring may be up to trisubstituted by F, Cl, Br, OH, oxo, N(R21)(R22) or (C1-C4)-alkyl; R21, R22 are each independently H, (C1-Cg)-alkyl; excluding compounds of the formula | in which the radicals are at the same time defined as follows: R5 is halogen or unsubstituted (C1-Cg)-alkyl, R7 is heterocyclic radical or heteroaryl, and their physiologically tolerated salts.
3. Compounds of the formula | as claimed in claim 1 or 2, where R8,R9, R10, R11 are each independently H, F or CI; R1, R2, R4, R6 are each H; R3, R5 are each independently H, Cl, OR12, COOR12, N(R13)(R14) or (C1-Cg)-alkyl; R7 is (C1-Cg)-alkyl, where alkyl may be polysubstituted by F, OR12, COOR12 or N(R13)(R14), or is (C3-Cg)-cycloalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C1-Cs)-alkylcarboxy- (C1-Cg)-alkylene, COOR12, phenyl, where phenyl may be polysubstituted by F, OMe or OCF3, or is benzyl whose phenyl ring may be substituted by OMe, pyridyl, thienyl, furanyl, indolyicarbonyl, benzofuranyl, where benzofuranyl may be substituted by Cl or OMe; R12 is H or (C1-Cg)-alkyl, where alkyl may be polysubstituted by F;
R13, R14 are each independently H or (C1-Cg)-alkyl; and where R13 and R14, together with the nitrogen atom to which they are bonded, may form a 5-membered, saturated heterocyclic ring; excluding compounds of the formula | in which the radicals are at the same time defined as follows: RS is halogen or unsubstituted (C1-Cg)-alkyl, R7 is heterocyclic radical or heteroaryl; and their physiologically tolerated salts. 4, A pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3.
5. A pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3 and one or more blood sugar- reducing active ingredients.
6. A pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3 and one or more statins.
7. The use of the compounds as claimed in one or more of claims 1 to 3 for producing a medicament for treating type 2 diabetes.
8. The use of the compounds as claimed in one or more of claims 1 to 3 for producing a medicament for lowering blood sugar.
9. The use of the compounds as claimed in one or more of claims 1 to 3 in combination with at least one further blood sugar-reducing active ingredient for producing a medicament for treating type 2 diabetes
10. The use of the compounds as claimed in one or more of claims 1 to 3 in combination with at least one further blood sugar-reducing active ingredient for producing a medicament for lowering blood sugar.
®
11. A process for producing a pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 3, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and bringing this mixture into a form which is suitable for administration.
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