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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/32—Oxygen atoms
  • C07D209/34—Oxygen atoms in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the invention relates to compounds which are activators of AMP-activated protein kinase (AMPK) and which are useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
• AMPK AMP-activated protein kinase
• Obesity and type 2 diabetes, hypertension and cardiovascular disease are diseases that feature serious disturbances in glucose and lipid metabolism that severely affect the health and quality of life of affected individuals. The increasing prevalence of these diseases makes finding new drug targets for treating this syndrome an urgent task.
• AMP-activated protein kinase acts as a cellular energy sensor and regulator. It is activated by an increase in the cellular AMP:ATP ratio induced by metabolic stress. Once activated, AMPK switches on catabolic pathways that generate ATP and switches off ATP-consuming anabolic pathways by acute regulation of the activity of key enzymes in metabolism and chronic regulation of the expression of pivotal transcription factors (Hardie, D G. Nature Reviews 8 (2007b), 774-785; Woods, A et al. Molecular and Cellular Biology 20 (2000), 6704-6711). The growing evidence of AMPK regulatory effects on glucose and lipid metabolism makes it a potential drug target for treatment of diabetes and metabolic syndrome (Carling, D. Trends Biochem Sci 29(2004), 18-24; Hardie, D G.
• Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activation of AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing PEPCK and G6Pase expression, whereas the administration of dominant negative ⁇ 1 adenovirus reverses the effect in vivo (Yamauchi, T et al. Nature Medicine 8 (2002), 1288-1295).
• AMPK AMPK as a potential target for treating metabolic syndrome
• thiazolidinediones Rosiglitazone, troglitazone and pioglitazone
• biguanides metalformin and phenformin
• Rosiglitazone is traditionally considered to be a PPAR ⁇ agonist and exerts its antidiabetic effects through differentiation of adipocytes (Semple, R K et al. The Journal of clinical investigation 116 (2006), 581-589).
• the compounds of the present invention are potent AMPK activators.
• the compounds of the invention are therefore useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
• the present invention relates to a compound of formula (I),
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, and a therapeutically inert carrier.
• the invention also relates to a process for the manufacture of these novel compounds and medicaments containing them.
• the compounds of the invention have an activation effect on AMP (adenosine monophosphate)-activated protein kinase, which results in lowered blood glucose.
• AMP adenosine monophosphate
• the invention thus also concerns the use of such compounds for the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes.
• the present invention relates to a compound of formula (I),
• the compounds of the invention have an activation effect on AMP (adenosine monophosphate)-activated protein kinase, which results in lowered blood glucose.
• AMP adenosine monophosphate
• alkyl alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl and tert-butyl.
• Preferred “alkyl” groups are methyl, ethyl, isopropyl and tert-butyl.
• alkoxy alone or in combination signifies a group alkyl-O—, wherein the “alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy and t-butoxy.
• Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.
• cycloalkyl alone or in combination refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• a preferred cycloalkyl group is cyclohexyl.
• halogen means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine or chlorine.
• carbonyl alone or in combination refers to the group —C(O)—.
• amino alone or in combination refers to primary (—NH 2 —), secondary (—NH—) or tertiary amino (—N—).
• alkylsulfanyl alone or in combination refers to the group —S-alkyl.
• sulfonyl alone or in combination refers to the group —S(O) 2 —.
• the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
• pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
• Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
• Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
• the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R. J., et. al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).
• “Pharmaceutically acceptable esters” means that compounds of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention. Preferred are the methyl and ethyl esters of the compounds of formula (I).
• R 1 is selected from the group consisting of: hydrogen, halogen and alkoxy.
• R 1 is selected from the group consisting of: hydrogen, fluoro and chloro.
• Still further preferred is a compound of formula (I) wherein R 1 is hydrogen.
• a compound of formula (I) wherein R 2 is selected from the group consisting of: hydrogen, halogen and alkoxy is preferred.
• R 3 is selected from the group consisting of: hydrogen, halogen and alkoxy.
• R 3 is selected from the group consisting of: hydrogen, fluoro, chloro and methoxy is also preferred.
• R 4 is selected from the group consisting of: hydrogen, halogen and alkoxy.
• a compound of formula (I) wherein R 4 is hydrogen or fluoro is preferred.
• R 5 is selected from the group consisting of: phenyl, chlorophenyl, methoxyphenyl, methylphenyl, cyanophenyl, trifluoromethylphenyl, chlorofluorophenyl, trimethoxyphenyl, difluorophenyl, dichlorophenyl, bromophenyl, chlorotrifluoromethylphenyl, methylsulfanylphenyl, aminosulfonylphenyl, methylsulfonylphenyl, thiophenyl, fluorophenyl, pyridinyl, bis(trifluoromethyl)phenyl, isopropylphenyl, neopentyl, isopentyl, methylcarbonylphenyl and tert-butyl.
• R 5 is halophenyl or cyanophenyl.
• a compound of formula (I) wherein R 5 is chlorophenyl or cyanophenyl is also preferred.
• R 6 is selected from the group consisting of: alkyl, hydroxyalkyl, cycloalkyl, phenyl and halophenyl.
• R 6 is selected from the group consisting of: methyl, phenyl, methoxyphenyl, chlorophenyl, neopentyl, isopropyl, cyclohexyl, hydroxypropyl and tert-butyl.
• R 7 is selected from the group consisting of: substituted phenyl, substituted pyridinyl, substituted thiazolyl and carboxy, wherein said substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, and said substituted pyridinyl and said substituted thiazolyl are, respectively, pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy.
• R 7 is selected from the group consisting of: carboxyphenyl, alkoxycarbonylphenyl and carboxypyridinyl.
• R 7 is selected from the group consisting of: carboxyphenyl, methoxycarbonylphenyl and carboxypyridinyl is further preferred.
• R 7 is selected from the group consisting of: ethoxycarbonylphenyl, methoxycarbonylmethylphenyl, phenyl substituted with methyl and methoxycarbonyl, carboxy, methoxycarbonylphenyl, ethoxycarbonylmethoxyphenyl, isopropylaminocarbonylphenyl, methoxycarbonylpyridinyl, ethoxycarbonylthiazolyl, methoxyphenyl, trihydroxyphenyl, hydroxyphenyl, carboxyphenyl, carboxymethoxyphenyl, carboxythiazolyl, carboxypyridinyl and methylsulfonylminocarbonylphenyl.
• the compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds are provided in the examples. Generally, compounds of formula (I) can be prepared according to the schemes illustrated below.
• Ar is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, thiazolyl or substituted thiazolyl, wherein substituted phenyl is phenyl substituted with one to three substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein substituted pyridinyl and substituted thiazolyl are pyridinyl and thiazolyl substituted with alkoxycarbonyl or carboxy.
• R 8 is independently selected from the group consisting of alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and alkylcarbonyl as mono-substituent, bi-substituent or tri-substituent.
• R 1 to R 7 are as defined above unless otherwise indicated.
• intermediate IV can be prepared by a condensation reaction between the substituted oxindole II and the substituted acetophenone III.
• the reaction can be carried out in the presence of an organic base such as piperidine or pyrrolidine, in an organic solvent such as methanol, ethanol, toluene or the mixture thereof, under reflux overnight.
• the intermediate IV couples with the aryl halide V to afford the compound of formula Ia.
• the coupling reaction can be carried out in the presence of a copper catalyst such as copper(I) iodide (CuI), in combination with a ligand such as 2,2′-bipyridine, proline, N,N′-dimethyl glycine or ethylene glycol, and a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable organic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidinone or
• reaction can be carried out at elevated temperature such as 80° C. for a longer reaction time without microwave irradiation (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
• the compound of formula Ib can be prepared according to Scheme 2.
• the condensation reaction between the compound IV and the commercially available reagent VI gives the intermediate VII, which subsequently undergoes a hydrolysis reaction to afford the compound of formula Ib.
• starting material IV can be obtained through the synthetic method illustrated in Scheme 1.
• the intermediate VII can be prepared by an alkylation reaction between VI and IV when using base such as sodium hydride, potassium carbonate or cesium carbonate in organic solvent such as tetrahydrofuran, N,N-dimethylformamide or the mixture thereof, at room temperature for several hours.
• hydrolysis of the methyl ester VII affords the compound Ib.
• Hydrolysis of the methyl ester can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours.
• an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
• a solvent such as methanol, 1,4-dioxane or tetrahydrofuran
• the compound of formula Ic can be prepared according to Scheme 3. This approach is based on a highly efficient palladium-catalyzed synthesis of asymmetrically substituted 3-(diarylmethylenyl)indolinone from readily accessible starting materials. This reaction can be carried out successfully in the presence of catalytic amount of Pd(OAc) 2 , using N,N-dimethylformamide as solvent and NaOAc as a base. The reaction usually takes place at 110° C. and needs several hours to complete (Artur Pinto et al., Org. Lett. 4927, 2006).
• the amide X can be prepared by the coupling reaction between aniline VIII and carboxylic acid IX in the presence of coupling reagent such as 1,3-dicyclohexylcarbodiimide.
• Intermediate XII can be prepared by alkylation reaction between XI and X.
• the reaction usually needs sodium hydride, potassium carbonate or cesium carbonate as a base and is carried out at room temperature for several hours in organic solvent such as tetrahydrofuran or N,N-dimethylformamide.
• XIV can be prepared by the method described in Scheme 3. Treatment of XIV with boron tribromide in dichloromethane successfully affords Id.
• XV can be prepared by the method described in Scheme 3. Hydrolysis of XV in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acid Ie.
• a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours
• an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acid Ie.
• the starting material XVI can be prepared according to the method described in Scheme 3.
• the compounds of formula Ih and Ii can be prepared according to Scheme 7. Hydrolysis of If and Ig in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acids Ih and Ii.
• a solvent such as methanol, 1,4-dioxane or tetrahydrofuran
• the compounds of formula Ij can be prepared according to Scheme 8.
• the key step is the palladium catalyzed Heck-Carbocyclization/Suzuki-Coupling Reaction between iodide XVIII and boronic acid XIX in the presence of catalytic amount of Pd(PPh 3 ) 4 .
• This reaction proceeds smoothly when using CsF or copper thiophene-2-carboxylic acid as base (Reiko, Y. et al., J. Org. Chem. 70, 6972, 2005; Wing S. Cheung, et al., J. Org. Chem. 70, 3741, 2005).
• the starting material XVIII can be prepared according to the procedure described in Scheme 3.
• the compounds of formula Ik can be prepared according to Scheme 9.
• the key step is the palladium catalyzed Heck-Carbocyclization/Suzuki-Coupling Reaction between iodide XXVI and boronic acid XXVII in the presence of catalytic amount of Pd(PPh 3 ) 4 .
• This reaction proceeds smoothly when using CsF or copper thiophene-2-carboxylic acid as base (Reiko, Y. et al., J. Org. Chem. 70, 6972, 2005; Wing S. Cheung, et al., J. Org. Chem. 70, 3741, 2005).
• the amide XXVI can be prepared by the alkylation between amide XXIV and benzyl bromide XXV as described in Scheme 3.
• Amide XXIV can be prepared by reacting isocyanate XXII with lithium reagent XXIII generated from n-butyl lithium and acetylene.
• the isocyanate XXII can be prepared by treating 2-iodo-anilines XXI with triphosgene in organic solvent such as dichloromethane in the presence of saturated aqueous sodium bicarbonate solution.
• the compounds of formula II can be prepared according to Scheme 10. Hydrolysis of ester Ik in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acid I1.
• a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature for several hours
• an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide successfully affords acid I1.
• the compounds of formula Im can be prepared according to Scheme 11. Treatment of acid I1 with methylsulfonamide in the presence of coupling reagent such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and organic base such as DMAP for hours successfully affords compound Im.
• coupling reagent such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and organic base such as DMAP for hours successfully affords compound Im.
• the invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:
• R 1 to R 7 are as defined above, wherein Ar is selected from the group consisting of: phenyl, substituted phenyl, pyridinyl and thiazolyl, wherein substituted phenyl is phenyl substituted with one or two substituents independently selected from the group consisting of: alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonylalkyl, alkylaminocarbonyl, carboxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkoxy and alkylsulfonylaminocarbonyl, wherein R 10 is phenyl substituted with one to three substituents independently selected from the group consisting of: alkyl, alkoxy, halogen, cyano, haloalkyl, alkylsulfanyl, aminosulfonyl, alkylsulfonyl, haloalkoxy and al
• R 9 is preferably methyl or ethyl.
• R 11 is preferably selected from the group consisting of: C 1 -C 4 alkyl, preferably methyl and ethyl, more preferably methyl.
• the reaction of step (a) can be carried out in the presence of coupling reagent, such as a copper catalyst, such as copper(I) iodide (CuI), in combination with a ligand such as 2,2′-bipyridine, proline, N,N′-dimethyl glycine or ethylene glycol, and a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable organic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidinone or a mixture thereof.
• a copper catalyst such
• the reaction temperature can be for example between 100 and 180° C., e.g. for 15 to 60 minutes under microwave irradiation.
• the reaction can be carried out at a elevated temperature such as 80° C. for a longer reaction time without microwave irradiation.
• step (b) can be carried out in the presence of catalytic amount of Pd(OAc) 2 , using N,N-dimethylformamide as solvent and NaOAc as a base.
• the reaction usually takes place at 110° C. and may need several hours to complete.
• Step (c) is preferably carried out in dichloromethane.
• Step (e) can be carried out in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran, e.g. at room temperature for several hours.
• the base is preferably an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
• step (f) can be carried out in the presence of catalytic amount of Pd(PPh 3 ) 4 .
• a base is preferably employed. This reaction proceeds smoothly when using CsF or copper thiophene-2-carboxylic acid as base.
• step (g) can be achieved in the presence of coupling reagent such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as DMAP.
• coupling reagent such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as DMAP.
• the invention also relates to a compound of formula (I) for use as therapeutically active substance.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
• the invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 diabetes or type 2 diabetes, in particular type 2 diabetes.
• Said medicaments e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
• the above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers.
• Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, can be used as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
• Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• the pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
• the doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several administrations.
• a compound of formula (I) when manufactured according to the above process is also an object of the invention.
• the invention also relates to a method for the treatment or prophylaxis of diseases that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I).
• the invention further relates to a method for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 diabetes or type 2 diabetes, in particular type 2 diabetes, which method comprises administering an effective amount of a compound of formula (I).
• the invention also relates to a compound of formula (I) for the preparation of medicaments useful in the treatment of cancers that are related to AMPK regulation and provides a method for the treatment of cancers that are related to AMPK regulation.
• Acidic condition A: 0.1% formic acid in H 2 O; B: 0.1% formic acid in acetonitrile;
• Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) + .
• the microwave assisted reactions were carried out in a Biotage Initiator Sixty.
• Oxindole (0.1332 g, 1 mmol) and acetophenone (1.4 ml, 1.2 mmol) were mixed in toluene; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture refluxed for 3 hand monitored by TLC. When the reaction was finished the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 10-25% ethyl acetate in petroleum ether) to give 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one as yellow powder (200 mg, 85%).
• Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22 g, 22 mmol) were dissolved in dichloromethane (50 ml) and 1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one portion at 0° C. The mixture was stirred room temperature for 14 h. The mixture was poured into water and extracted with dichloromethane (3 ⁇ 15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenylamide 2.7 g (62%).
• the organic layer was washed with aqueous HCl solution (4%, 10 ml), brine (3 ⁇ 10 ml). The aqueous layer was back-extracted with ethyl acetate (3 ⁇ 10 ml). The combined organic layer was dried over anhydrous sodium sulfate.
• the title compound was prepared in analogy to Example 84 starting from phenylboronic acid (commercially available) and 3- ⁇ [(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-acetyl-phenylboronic acid (commercially available) and 3- ⁇ [(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-chloro-phenylboronic acid (commercially available) and 3- ⁇ [(3-cyclohexyl-propynoyl)-(2-iodo-phenyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-trifluoromethyl-phenylboronic acid (commercially available) and 3- ⁇ [(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-chloro-phenylboronic acid (commercially available) and 3- ⁇ [(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-cyano-phenylboronic acid (commercially available) and 3- ⁇ [(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-chloro-phenylboronic acid (commercially available) and 3- ⁇ [(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-cyano-phenylboronic acid (commercially available) and 3- ⁇ [(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• the title compound was prepared in analogy to Example 84 starting from 4-chloro-phenylboronic acid (commercially available) and 3- ⁇ [(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl ⁇ -benzoic acid methyl ester.
• This method evaluates endogenous expression and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase (ACC) in L6 cell line using Western blot analysis. It is used to determine the potency and efficacy of small molecular AMPK modulators.
• L6 cells (ATCC) are cultured and maintained at DMEM (high glucose, Gibco, BRL) with 10% fetal bovine serum (FBS, Hyclone). In an assay, cells are plated at 3 ⁇ 10 6 per plate in 10 ml on a 10 cm dish and they reach subconfluent of 70-80% within 24 hrs. The cells are serum starved overnight prior to be treated with an AMPK modulator.
• the compound concentration typically ranges from 0 to 100 uM and treat the cells for 1-4 hrs.
• the medium is aspirated and the cell layer is gently rinsed with 2 ml of ice-cold PBS.
• 500 ⁇ l of lysis buffer containing 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM NaF, 2 mM Na 3 VO 4 , 1 mg/ml of Pefabloc, 1% Triton X-100, and a Roche Complete Protease Inhibitor Tablet is added and incubated on ice for 10 min.
• the cell lysate is harvested and subsequently centrifugated at 12,000 rpm for 10 min at 4° C.
• the supernatant is saved and its protein concentration is determined using Quick Start Bradford protein quantification kit (Bio-Rad).
• 40 jug is loaded for 7.5% SDS-PAGE analysis and subsequently blotted to PVDF membrane following a standard procedure.
• the membrane is treated with a blocking buffer (5% nonfat milk) for 1 h at room temperature in agitation.
• the levels of phospho-AMPK and phospho-ACC are determined using phospho-AMPK ⁇ (Thr172)(40H9) rabbit mAb (Cell Signaling) and phospho-acetyl CoA carboxylase(Ser79) antibody (Cell Signaling) as primary antibodies by incubating the blot at 4° C. overnight.
• the blots are stripped and re-probed using acetyl CoA carboxylase (C83B10) rabbit mAb (Cell signaling), AMPK ⁇ (23A3) rabbit mAb (Cell Signaling), and ⁇ -actin antibody (Cell Signaling) to determine the whole protein level of ACC, AMPK and ⁇ -actin, respectively.
• Each protein band in a blot is visualized via ECL Plus Western blotting detection kit (Amersham) and quantified by the scan analysis.
• the EC 50 value defined as an activator concentration that produces half of the maximal activation effect, and Emax, defined as the maximal activation effect at the infinite activator concentration, are determined semi-quantitatively and recorded. All the compounds of formula (I) are active in the foregoing AMPK and ACC phosphorylation assay.
• Recombinant human AMPK ⁇ 1 ⁇ 1 ⁇ 1, ⁇ 2 ⁇ 1 ⁇ 1 or AMPK ⁇ subunit truncations al(1-335), ⁇ 1(1-394) and ⁇ 2(1-394) were constructed, expressed and purified as described previously (Pang, T., Zhang, Z. S., Gu, M., Qiu, B. Y., Yu, L. F., Cao, P. R., Shao, W., Su, M. B., Li, J. Y., Nan, F. J., and Li, J. (2008)).
• Rat liver AMPK heterotrimer enzyme was obtained from Upstate (Billerica, Mass., U.S.A.).
• SPA Scintillation Proximity Assay
• Reactions were initiated by the addition of 50 nM recombinant AMPK proteins to the reaction solutions and incubated at 30° C. for 2 hr. After that, reactions were terminated by the addition of 40 ⁇ l stop solution containing 80 ⁇ g streptavidin-coated SPA beads per well, 50 mM EDTA, 0.1% Triton X-100 in PBS, pH 7.5 and incubated for 1 hr. Finally, a 160 ul suspension solution containing 2.4 M CsCl, 50 mM EDTA, and 0.1% Triton X-100 in PBS (pH 7.5) was added to the reaction solution to suspend SPA beads completely.
• SPA signals were determined with a Wallac MicroBeta plate counter (PerkinElmer) 30 min later for calculation of the amount of product formed.
• the amount of products formed in 2 hr was plotted against activator concentrations to determine the effective concentration of the activator (EC50) required for 50% of maximal enzyme activity.
• Compounds as described above have EC50 values between 0.5 uM and 50 uM, preferred compounds have EC50 values between 0.5 uM and 10 uM, particularly preferred compounds have EC50 values between 0.5 uM and 1 uM.
• a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
• a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

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