HK1075650B - Acyl-3-carboxyphenylurea derivatives, method for production and use thereof - Google Patents
Acyl-3-carboxyphenylurea derivatives, method for production and use thereof Download PDFInfo
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Description
Technical Field
The present invention relates to acyl-3-carboxyphenylurea derivatives, their physiologically acceptable salts and physiologically functional derivatives.
Background
EP0193249(Duphar) discloses acylcarboxyphenylurea derivatives having antitumor activity.
Object of the Invention
It is an object of the present invention to provide compounds which can be used for the prevention and treatment of type II diabetes. In particular, the object of the present invention is to obtain new compounds with a significantly better effect than the compounds disclosed in EP 0193249.
Disclosure of Invention
The present invention therefore relates to compounds of the formula I,
wherein the content of the first and second substances,
r7, R8, R9 and R10 are each, independently of one another, H, F, Cl, Br, OH, NO2、CN、O-(C1-C6) Alkyl, O- (C)2-C6) Alkenyl, O- (C)2-C6) -alkynyl, O-SO2-(C1-C4) Alkyl radicals, (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl or (C)2-C6) -alkynyl, wherein alkyl, alkenyl and alkynyl may be substituted one or more times by F, Cl or Br;
r1 and R2 are each independently H, (C)1-C6) Alkyl, where the alkyl may be substituted by OH, O- (C)1-C4) -alkyl, NH2、NH(C1-C4) Alkyl or N [ (C)1-C6) -alkyl radical]2Substituted, O- (C)1-C6) Alkyl, CO- (C)1-C6) Alkyl, COO- (C)1-C6) Alkyl radicals, (C)1-C6) alkylene-COOH or (C)1-C6) -alkylene-COO- (C)1-C6) -an alkyl group;
r3 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r4 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, wherein alkyl, cycloalkyl andalkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r5 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r6 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r11 is H, (C)1-C8) Alkyl radicals, (C)2-C8) -alkenyl or (C)2-C8) Alkynyl, where alkyl, alkenyl and alkynyl may be substituted by F, Cl, Br, OH or O- (C)1-C4) -alkyl substitution one or more times;
r12 and R13 are each independently H, (C)1-C8) Alkyl radicals, (C)2-C8) -alkenyl, (C)2-C8) -alkynyl, (C)3-C7) -cycloalkyl, (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, COO- (C)1-C4) Alkyl, COO- (C)2-C4) Alkenyl, phenyl or SO2Phenyl, where the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、OCF3、COOH、COO-(C1-C6) -alkyl orCONH2Up to 2 substitutions;
or R12 and R13, together with the nitrogen atom to which they are bound, form a 3-to 7-membered saturated heterocyclic ring which may contain up to 2 further heteroatoms selected from N, O or S, wherein the heterocyclic ring may be interrupted by F, Cl, Br, OH, oxo, (C)1-C4) -alkyl or N (R14) (R15) substitution up to 4 times;
r14 and R15 are each independently H, (C)1-C8) Alkyl radicals, (C)2-C8) -alkenyl, (C)2-C8) -alkynyl, (C)3-C7) -cycloalkyl, (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, COO- (C)1-C4) Alkyl, COO- (C)2-C4) Alkenyl, phenyl or SO2Phenyl, where the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、OCF3、COOH、COO(C1-C6) -alkyl or CONH2Up to 2 substitutions;
r16 and R17 are each independently H, (C)1-C8) Alkyl radicals, (C)2-C8) -alkenyl, (C)2-C8) -alkynyl, (C)3-C7) -cycloalkyl, (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, COO- (C)1-C4) Alkyl, COO- (C)2-C4) Alkenyl, phenyl or SO2Phenyl, where the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、OCF3、COOH、COO-(C1-C6) -alkyl or CONH2Up to 2 substitutions;
or R16 and R17, together with the nitrogen atom to which they are bound, form a 3-to 7-membered saturated heterocyclic ring which may contain up to 2 further heteroatoms selected from N, O or S, wherein the heterocyclic ring may be interrupted by F, Cl, Br, OH, oxo, (C)1-C4) Alkyl or N (R1)4) (R15) up to 4 substitutions;
and physiologically acceptable salts thereof.
Preference is given to compounds of the formula I in which one or more radicals have the following meanings:
r7, R8, R9 and R10 are each, independently of one another, H, F, Cl, Br, OH, NO2、CN、(C1-C6) Alkyl or O- (C)1-C6) -an alkyl group;
r1 and R2 are H;
r3 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r4 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r5 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r6 is H, F, Cl, Br, NO2CN, O-R11, O-phenyl, S-R11, COOR11, N (R12) (R13), (C)1-C6) Alkyl radicals, (C)2-C6) -alkenyl, (C)2-C6) -alkynyl, (C)3-C7) -cycloalkyl or (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, where alkyl, cycloalkyl and alkynyl may be substituted one OR more times by F, Cl, Br, OR11, COOR11 OR N (R16) (R17);
r11 is H, (C)1-C8) Alkyl radicals, (C)1-C8) alkylene-O- (C)1-C8) -alkyl or (C)1-C8) -alkyl-OH, wherein alkyl may be substituted one or more times by F;
r12 and R13 are each independently H or (C)1-C8) -an alkyl group;
r14 and R15 are each independently H, (C)1-C8) Alkyl radicals, (C)2-C8) -alkenyl, (C)2-C8) -alkynyl, (C)3-C7) -cycloalkyl, (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, COO- (C)1-C4) Alkyl, COO- (C)2-C4) Alkenyl, phenyl or SO2Phenyl, where the phenyl ring may be substituted by F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、OCF3、COOH、COO(C1-C6) -alkyl or CONH2Up to 2 substitutions;
r16 and R17 are each independently H, (C)1-C8) Alkyl radicals, (C)2-C8) -alkenyl, (C)2-C8) -alkynyl, (C)3-C7) -cycloalkyl, (C)3-C7) -cycloalkyl- (C)1-C4) Alkylene, COO- (C)1-C4) Alkyl, COO- (C)2-C4) Alkenyl, phenyl or SO2-phenyl, wherein the phenyl ring may beBy F, Cl, CN, OH, (C)1-C6) Alkyl, O- (C)1-C6) -alkyl, CF3、OCF3、COOH、COO-(C1-C6) -alkyl or CONH2Up to 2 substitutions;
or R16 and R17, together with the nitrogen atom to which they are bound, form a 3-to 7-membered saturated heterocyclic ring which may contain up to 2 further heteroatoms selected from N, O or S, wherein the heterocyclic ring may be interrupted by F, Cl, Br, OH, oxo, (C)1-C4) -alkyl or N (R14) (R15) substitution up to 4 times;
and physiologically acceptable salts thereof.
Particular preference is given to compounds of the formula I in which one or more radicals have the following meanings:
r7, R8, R9 and R10 are independently H, F, Cl or CH3；
R1, R2, R4, R5 and R6 are H;
r3 is F, Cl, CF3O-R11 or O-phenyl;
r11 is H, (C)1-C8) Alkyl radicals, (C)1-C8) alkylene-O- (C)1-C8) -alkyl or (C)1-C8) -alkyl-OH;
and physiologically acceptable salts thereof.
If a group or substituent in formula I occurs more than once, for example-O-R11, they all have the meanings given independently of one another and may be identical or different.
The present invention relates to compounds of formula I in the form of racemates, racemic mixtures and pure enantiomers, as well as to their diastereomers and mixtures thereof.
The alkyl groups in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 may be linear or branched.
Pharmaceutically acceptable salts are particularly suitable for medical use due to their higher water solubility compared to the starting or base compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and salts of organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts containing non-pharmaceutically acceptable anions, such as trifluoroacetate, are also within the scope of the invention because they may be used as intermediates in the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic uses, such as in vitro applications.
The term "physiologically functional derivative" as used herein refers to any physiologically acceptable derivative of a compound of formula I according to the invention, for example an ester, which is capable of forming, directly or indirectly, a compound of formula I or an active metabolite thereof upon administration to a mammal, for example a human.
Physiologically functional derivatives also include prodrugs of the compounds of the invention, such as those disclosed in H.Okada et al, chem.pharm.Bull, 1994, 42, 57-61. Such prodrugs are metabolized in vivo to produce the compounds of the invention. These prodrugs may themselves be active or inactive.
The compounds of the present invention may also exist in different polymorphs, such as amorphous or crystalline polymorphs. All polymorphs of the compounds of the present invention are within the scope of the present invention and are a further aspect of the present invention.
Hereinafter, all references to "compounds of formula I" refer to the compounds of formula I described above and their salts, solvates and physiologically functional derivatives described herein.
Detailed Description
The compounds of the formula I can also be administered in combination with other active compounds.
The amount of a compound of formula I required to achieve a desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the nature of the administration and the clinical condition of the patient. The daily dose is usually 0.3mg to 100mg (typically 3mg to 50mg) per kg body weight per day, for example 3-10 mg/kg/day. The intravenous dose may range, for example, from 0.3mg to 1.0mg/kg, and such doses may advantageously be administered as an infusion of from 10ng to 100ng per kg per minute. Infusion solutions suitable for these purposes may contain, for example, from 0.1ng to 10mg, typically from 1ng to 10mg, per ml. A single dose may, for example, contain from 1mg to 10g of active compound. Thus, ampoules for injection may, for example, contain from 1mg to 100mg, whereas oral unit dosage forms, such as tablets or capsules, may, for example, contain from 1 to 1000mg, typically from 10 to 600 mg. Although the compounds of formula I may be used as such for the treatment of the above-mentioned diseases, they are preferably formulated in the form of pharmaceutical compositions together with acceptable excipients. The excipient must be acceptable in the sense that it is compatible with the other components of the composition and not deleterious to the health of the patient. Excipients may be solid, liquid or solid-liquid and are preferably formulated with the compound in unit dosage form, for example as tablets, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances, including other compounds of formula I, may also be present. The pharmaceutical compositions of the present invention may be prepared by a known pharmaceutical process which essentially comprises admixing the active ingredient with pharmacologically acceptable excipients and/or auxiliaries.
The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration will depend in each particular case on the nature and severity of the condition to be treated, on the nature of the compound of formula I used in each case. Coated formulations and coated sustained release formulations are also within the scope of the invention. Preferred dosage forms are acid and gastric juice resistant. Suitable coatings resistant to gastric juices include cellulose acetate phthalate, polyethylene acetate phthalate, hydroxypropyl methylcellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.
Pharmaceutical compounds suitable for oral administration can be isolated units, such as capsules, wafers, lozenges or tablets, which in each case contain a defined amount of a compound of the formula I; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical process comprising the step of bringing into contact the active compound and the excipients, which may consist of one or more additional components. In general, the compositions are prepared by uniformly and homogeneously mixing the active compound with liquid and/or finely divided solid excipients, and if desired molding the product. Thus, tablets may be prepared, for example, by compressing or molding a powder or granules of the compound, optionally together with one or more additional ingredients. Compressed tablets may be prepared by tableting the compound in free-flowing form (e.g. as a powder or granules), if appropriate in a suitable machine, together with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets may be prepared by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges comprising a compound of formula I and a flavouring agent, usually sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerol or sucrose and acacia.
Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I according to the invention, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although they may also be administered by subcutaneous, intramuscular, and intradermal injections. These formulations are preferably prepared by mixing the compound with water and sterilizing and isotonicizing the resulting solution with blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably unit dose suppositories. They may be prepared by mixing a compound of formula I with one or more conventional solid excipients, such as cocoa butter, and molding the resulting mixture.
Suitable pharmaceutical compositions for topical application to the skin are preferably ointments, creams, lotions, pastes, sprays, aerosols or oils. Excipients which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these. The concentration of active compound is generally from 0.1 to 15%, for example from 0.5 to 2% by weight of the composition.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal use may be plasters suitable for prolonged intimate contact with the dermis of a patient. Such plasters advantageously contain the active compound in an aqueous solution which is suitably buffered, dissolved and/or dispersed in an adhesive or dispersed in a polymer. Suitable active compound concentrations are about 1% to 35%, preferably about 3% to 15%. As a specific possibility, the active compound can be released by electromigration or iontophoresis, for example according to Pharmaceutical Research, 2 (6): 318 (1986).
The following substances are suitable as additional active compounds for the combined preparation:
all in Roten Liste Red directory]2001 chapter 12 hitsThe name of the antidiabetic medicine. They can be combined with the compounds of the formula I according to the invention, in particular to improve the synergistic effect. The active compound combination can be administered by separate administration of several active compounds to the patient or in the form of a combined preparation in which several active compounds are present in a single pharmaceutical preparation. Most of the active compounds listed below have been disclosed in USP Dictionary of USAN and International drug Names, US Pharmacopeia, Rockville 2001. Antidiabetic agents include insulin and insulin derivatives, e.g. Lantus*(see www.lantus.com) or HMR1964, rapid acting insulin (see US patent 6,221,633), GLP-1 derivatives such as those disclosed by NovoNordisk A/S in WO98/08871, and orally active hypoglycemic active compounds.
Orally active hypoglycemic compounds preferably include sulfonylureas, biguanides, glitazones (meglitinides), oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, calcium channel openers, such as those disclosed by Novo Nordisk a/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds that alter fat metabolism, such as anti-hyperlipidemic and anti-lipemic active compounds, compounds that reduce food intake, agonists of PPAR and PXR, and active compounds that act on the ATP-dependent potassium channel of beta cells.
In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin or rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, for example ezetimibe, tiquinan or pamoside.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR γ agonist, for example rosiglitazone, pioglitazone, JTT-501 or GI 262570.
In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR α agonist, for example GW 9578 or GW 7647.
In one embodiment of the invention, the compounds of the formula I are administered in combination with mixed α/γ agonists, for example GW 1536, AVE 8042, AVE 8134 or AVE 0847, or as disclosed in PCT/US11833, PCT/US 11490 or DE 10142734.4.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, for example fenofibrate, clofibrate or bezafibrate.
In one embodiment of the invention, the compounds of formula I are administered in combination with an MTP inhibitor, for example, implipide, BMS-201038 or R-103757.
In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid absorption inhibitor (see, e.g., U.S. patent 6,245,744 or 6,221,897), such as HMR 1741.
In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, e.g., JTT-705.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid absorber, for example cholestyramine or colesevelam.
In one embodiment of the invention, the compound of formula I is administered in combination with an LDL receptor inducer (see U.S. patent 6,342,512), such as HMR1171 or HMR 1586.
In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, e.g., avasimibe.
In one embodiment of the invention, the compounds of the formula I are applied in combination with antioxidants, for example OPC-14117.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, for example NO-1886.
In one embodiment of the invention, the compounds of formula I are administered in combination with an ATP citrate lyase inhibitor, e.g., SB-204990.
In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor, e.g. BMS-188494.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein antagonist, for example Cl-1027 or nicotinic acid.
In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example orlistat.
In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment, the compounds of the formula I are administered in combination with sulfonylureas, for example tolbutamide, glyburide, glipizide or glimepiride.
In one embodiment, the compound of formula I is administered in combination with a biguanide, for example metformin.
In one embodiment, the compounds of formula I are administered in combination with glitazones, for example repaglinide.
In one embodiment, the compounds of formula I are administered in combination with a thiazolidinedione, such as the compounds disclosed in WO97/41097 by the research foundation of troglitazone, ciglitazone, pioglitazone, rosiglitazone or Dr.Reddy, especially 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl ] methyl ] -2, 4-thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, for example miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in combination with active compounds which act on the ATP-dependent potassium channel of the beta cells, for example tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
In one embodiment, the compounds of formula I are administered in combination with a plurality of the above-mentioned compounds, for example in combination with sulfonylureas and metformin, sulfonylureas and acarbose, repaglinide and metformin, insulin and sulfonylureas, insulin and metformin, insulin and troglitazone, insulin and lovastatin, and the like.
In another embodiment, the compound of formula I is administered in combination with: CART modulators (see, "cocaine-amphetamine regulated transcription affects energy metabolism, anxiety and gastric emptying in mice," Asakawa, A, et al, M.: Hormone and Metabolic Research (2001), 33(9), 554-); NPY antagonists, such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide, hydrochloride salt (CGP 71683A)); MC4 agonists (e.g., 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3 a-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)); an obesity hormone (orexin) antagonist (e.g., 1- (2-methylbenzoxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea), hydrochloride salt (SB-334867-A)); an H3 agonist (3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) propan-1-one oxalate (WO 00/63208)); a TNF agonist; CRF antagonists (e.g., [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl ] dipropylamine (WO 00/66585)); CRF BP antagonists (e.g., urocortin); a urotensin agonist; a β 3-agonist (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol, hydrochloride salt (WO 01/83451)); MSH (hormone that stimulates melanocytes) agonists; CCK-A agonists (e.g. {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetic acid trifluoroacetate (WO 99/15525)); 5-hydroxytryptamine reuptake inhibitors (e.g., dexfenfluramine); a mixed 5-hydroxytryptamine compound and norepinephrine compound (e.g., WO 00/71549); 5HT agonists, such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111); bombesin agonists; galanin antagonists; growth hormone (e.g., human growth hormone); a growth hormone releasing compound (tert-butyl-6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)); TRH agonists (see, e.g., EP 0462884); uncoupling protein 2-or 3-modulators; leptin agonists (see, e.g., Lee, Daniel W.; Leinung, MatthewC.; Rozhavskaya-Arena, Marina; Grasso, Patricia, leptin agonists as a potential route for the treatment of obesity. Drugs of the Future (2001), 26(9), 873-); DA agonists (bromocriptine, doprexin); lipase/amylase inhibitors (e.g., WO 00/40569); PPAR modulators (e.g. WO 00/78312); RXR modulators or TR β -agonists.
In one embodiment of the invention, the additional active compound is leptin; see, e.g., "therapeutic application prospects for leptin" Salvador, Javier; Gomez-Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.
In one embodiment, the additional active compound is dextroamphetamine or amphetamine.
In one embodiment, the additional active compound is fenfluramine or dexfenfluramine.
In another embodiment, the additional active compound is sibutramine.
In one embodiment, the additional active compound is orlistat.
In one embodiment, the additional active compound is mazindol or mephenbutamine.
In one embodiment, the compound of formula I is administered in combination with a filler, preferably an insoluble filler (see, e.g., Carob/Caromax)*(Zunft H J; et al, carob bean milk products for the treatment of hypercholesterolemia, ADVANCES IN THERAPY: (9-10 months 2001), 18(5), 230-6), Caromax*Is Nutrinova, Nutrition Specialties&Food Ingredients GmbH, Industriaparik Hochst, 65926 Frankfurt/Main @) carob-containing products). And Caromax*Can be effected in a single formulation, or by separate administration of the compound of formula I and Caromax*To be implemented. In this respect, Caromax*It can also be administered in the form of a food product, for example in bread or a breakfast custard.
It is to be understood that each suitable combination of a compound of the invention with one or more of the above-mentioned compounds (and, if desired, with one or more other pharmacologically active substances) is within the scope of the present invention.
The following examples are given to illustrate the invention without limiting it.
Table 1: a compound of formula I
| Examples | R7，R8，R9，R10 | R1 | R2 | R3 | R4 | R5 | R6 | Salt (salt) | MS* |
| 1 | 2-Cl，4-Cl，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 2 | 2-Cl，H，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 3 | 2-Cl，4-Cl，H，H | H | H | OH | H | H | H | - | Ok |
| 4 | 2-Cl，4-Cl，H，H | H | H | F | H | H | H | - | Ok |
| 5 | 2-CH3，H，H，H | H | H | Cl | H | H | H | - | Ok |
| 6 | 2-Cl，5-Cl，H，H | H | H | Cl | H | H | H | - | Ok |
| 7 | 2-Cl，5-Cl，H，H | H | H | Cl | H | H | H | TRIS | Ok |
| 8 | 2-CH3，H，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 9 | 2-Cl，5-Cl，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 10 | 3-Cl，4-Cl，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 11 | 2-Cl，H，H，H | H | H | Cl | H | H | H | - | Ok |
| 12 | 2-Cl，4-Cl，H，H | H | H | Cl | H | H | H | - | Ok |
| 13 | 2-Cl，4-Cl，H，H | H | H | OCH2CH3 | H | H | H | - | Ok |
| 14 | 2-CH3，4-CH3，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 15 | 2-F，4-Cl，H，H | H | H | Cl | H | H | H | - | Ok |
| 16 | 2-F，4-Cl，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 17 | 2-F，4-F，H，H | H | H | Cl | H | H | H | - | Ok |
| 18 | 2-F，4-F，H，H | H | H | OCH3 | H | H | H | - | Ok |
| 19 | 2-Cl，4-Cl，H，H | H | H | OCH2CH2OH | H | H | H | - | Ok |
| 20 | 2-Cl，4-Cl，H，H | H | H | OCH2CH2CH3 | H | H | H | - | Ok |
| 21 | 2-Cl，4-Cl，H，H | H | H | OCH2CH2CH2CH3 | H | H | H | - | Ok |
| 22 | 2-Cl，4-Cl，H，H | H | H | OCH2CH2OCH3 | H | H | H | - | Ok |
| 23 | 2-Cl，4-Cl，H，H | H | H | O-phenyl | H | H | H | - | Ok |
| 24 | 2-Cl，4-Cl，H，H | H | H | O-phenyl | H | H | H | TRIS | Ok |
| 25 | 2-Cl，4-F，H，H | H | H | CF3 | H | H | H | - | Ok |
| 26 | 2-Cl，4-Cl，H，H | H | H | CF3 | H | H | H | - | Ok |
*The information "MS is Ok" means that mass spectrum or HPLC/MS is measured and a molecular peak (molar mass + H) is detected in the spectrum+)
Example 5 in synthetic EP0193249 was taken as comparative example a. Comparative example a had the following structure:
the compounds of formula I are characterized by a pronounced effect on sugar metabolism; in particular, they lower blood glucose levels and are suitable for the treatment of type II diabetes. These compounds can therefore be used alone or in combination with other hypoglycemic active compounds (antidiabetics).
The compounds of formula I are also suitable for the treatment of late-stage damage from diabetes, such as nephropathy, retinopathy, neuropathy and cardiac infarction, myocardial infarction, peripheral arterial occlusive disease, thrombosis, arteriosclerosis, syndrome X, obesity, inflammation, immunological diseases, autoimmune diseases, such as AIDS, asthma, osteoporosis, cancer, psoriasis, alzheimer's disease, schizophrenia and infectious diseases.
The activity of the compounds was tested as follows:
glycogen phosphorylase activity assay
The synthesis of glycogen from glucose-1-phosphate was examined by measuring the release of inorganic phosphate, and the effect of the compound on the activity of the active form of glycogen phosphorylase (GPa) was determined in the reverse direction. All reactions were assayed in duplicate on 96-well microtiter Plates (Half Area Plates, Costar No.3696) and the changes in absorbance due to the formation of reaction products were determined at the wavelengths specified below using Multiscan assay Elisa readers (Lab Systems, finland). In order to determine the enzymatic activity of GPa in the reverse direction, the conversion of glucose-1-phosphate into glycogen and inorganic phosphate was determined according to the general method of Engers et al (Engers H D, Shechosky S, Madsen NB, Can Jbiochem 1970 July; 48 (7): 746-754), but with the following modifications: human glycogen phosphorylase a (e.g., containing 0.76mg protein/ml (Aventis Pharma Deutschland GmbH) was dissolved in buffer solution E (25 mM. beta. -glycerophosphate, pH 7.0, 1mM EDTA and 1mM dithiothreitol) with buffer T (50mM Hepes, pH 7.0, 100mM KCl, 2.5mM EDTA, 2.5mM MgCl2·6H2O) and 5mg glycogen/ml is added to a concentration of 10. mu.g protein/ml. The test substances are prepared as 10mM DMSO solutions and bufferedT was diluted to 50. mu.M. To 10ml of this solution were added 10. mu.l of 37.5mM glucose dissolved in buffer solution T and 5mg/ml glycogen, 10. mu.l of a human glycogen phosphorylase a solution (10. mu.g protein/ml) and 20. mu.l of 2.5mM glucose-1-phosphate. The basal value of glycogen phosphorylase activity in the absence of test substance was determined by adding 10. mu.l of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes and the released inorganic phosphate was determined using the general method of Drueckes et al (DrueckesP, Schinzel R, Palm D, Anal Biochem 1955 Sep.1; 230 (10): 173-177) with the following modifications: mu.l of a stop solution containing 7.3mM ammonium molybdate, 10.9mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS was added to 50. mu.l of the enzyme mixture. After incubation at 45 ℃ for 60 minutes, the absorbance was measured at 820 nm. To determine the background of absorption, the stop solution was added immediately after the addition of the glucose-1-phosphate solution in a separate experiment. To determine the inhibition of glycogen phosphorylase a by the test substances in vitro, respectively, the test substance was used in a concentration of 10. mu.M.
TABLE 2 biological Activity
| Examples | % inhibition [ 10. mu.M] |
| 1 | 95 |
| 2 | 75 |
| 3 | 74 |
| 4 | 75 |
| 5 | 46 |
| 6 | 57 |
| 7 | 54 |
| 8 | 77 |
| 9 | 81 |
| 10 | 41 |
| 11 | 49 |
| 12 | 83 |
| 13 | 86 |
| Examples | % inhibition [ 10. mu.M] |
| 14 | 57 |
| 15 | 61 |
| 16 | 48 |
| 17 | 52 |
| 18 | 69 |
| 19 | 90 |
| 20 | 62 |
| 21 | 64 |
| 22 | 72 |
| 23 | 55 |
| 24 | 65 |
| 25 | 49 |
| 26 | 44 |
Control A exhibited 3% inhibition at 10. mu.M.
As can be seen from the table, the compounds of formula I inhibit the activity of glycogen phosphorylase a and are therefore suitable for lowering blood glucose levels. In particular, the compounds of formula I exhibited 14-32 times greater effects than control A.
The preparation of one embodiment is described in detail below;
the remaining compounds of formula I are obtained in a similar manner:
experimental part:
example 1:
a)2, 4-Dichlorobenzoyl isocyanate
2, 4-Dichlorobenzamide was dissolved in dichloromethane, then 1.5 equivalents of oxalyl chloride were added, and the mixture was heated under reflux for 16 hours. The reaction mixture was then concentrated under high vacuum and reacted directly in step b) without any further purification.
b)3- [3- (2, 4-dichlorobenzoyl) ureido ] -4-methoxybenzoic acid
20g (120mmol) of 3-amino-4-methoxybenzoic acid are reacted with 36g (168mmol) of the 2, 4-dichlorobenzoyl isocyanate from step a) in 400ml of acetonitrile for 2 hours at reflux. After cooling the mixture to room temperature, the precipitate is filtered off with suction and washed 2 times with 20ml of acetonitrile each time, dried by suction and dried under high vacuum. 44g (96%) of the expected product are obtained.
Melting point: 290 deg.c.
Claims (10)
1. A compound of the formula I,
wherein:
r7, R8, R9 and R10 independently of one another are H, F, Cl, Br or C1-C6An alkyl group;
r1, R2, R4, R5 and R6 are H;
r3 is F, Cl, Br, CF3O-R11 or O-phenyl;
r11 is H, C1-C8Alkyl radical, C1-C8alkylene-O-C1-C8Alkyl or C1-C8alkyl-OH; or a physiologically acceptable salt thereof.
2. A compound of formula I according to claim 1, wherein:
r7, R8, R9 and R10 are independently H, F, Cl or CH3；
R1, R2, R4, R5 and R6 are H;
r3 is F, Cl, CF3O-R11 or O-phenyl;
r11 is H, C1-C8Alkyl radical, C1-C8alkylene-O-C1-C8Alkyl or C1-C8alkyl-OH; or a physiologically acceptable salt thereof.
3. A medicament for lowering blood glucose or for treating type II diabetes and late stage diabetes injury comprising one or more compounds as claimed in claim 1 or 2.
4. A medicament containing one or more compounds as claimed in claim 1 or 2 and one or more hypoglycemic active compounds.
5. Use of a compound as claimed in claim 1 or 2 in the manufacture of a medicament for the treatment of type II diabetes.
6. Use of a compound as claimed in claim 1 or 2 for the manufacture of a medicament for lowering blood glucose.
7. Use of a compound as claimed in claim 1 or 2 in the manufacture of a medicament for the treatment of late stage diabetes injury.
8. Use of a compound as claimed in claim 1 or 2 in combination with at least one other hypoglycemic active compound for the preparation of a medicament for the treatment of type II diabetes.
9. Use of a compound as claimed in claim 1 or 2 in combination with at least one other hypoglycemic active compound for the preparation of a medicament for lowering blood glucose.
10. A process for the preparation of a medicament containing one or more compounds as claimed in claim 1 or 2, which comprises mixing the active compound with pharmaceutically suitable excipients and bringing this mixture into a form suitable for administration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10215908.4 | 2002-04-11 | ||
| DE10215908A DE10215908B4 (en) | 2002-04-11 | 2002-04-11 | Acyl-3-carboxyphenyl-urea derivatives and their use as medicaments |
| PCT/EP2003/003254 WO2003084923A1 (en) | 2002-04-11 | 2003-03-28 | Acyl-3-carboxyphenylurea derivatives, method for production and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1075650A1 HK1075650A1 (en) | 2005-12-23 |
| HK1075650B true HK1075650B (en) | 2006-11-17 |
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