WO2011069298A1 - Nouveaux dérivés de cyclopropane indolinone - Google Patents

Nouveaux dérivés de cyclopropane indolinone Download PDF

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Publication number
WO2011069298A1
WO2011069298A1 PCT/CN2009/075500 CN2009075500W WO2011069298A1 WO 2011069298 A1 WO2011069298 A1 WO 2011069298A1 CN 2009075500 W CN2009075500 W CN 2009075500W WO 2011069298 A1 WO2011069298 A1 WO 2011069298A1
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Prior art keywords
cyclopropane
indoline
oxospiro
methyl
chlorophenyl
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PCT/CN2009/075500
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English (en)
Inventor
Li Chen
Mengwei Huang
Lichun Feng
Yun He
Hongying Yun
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F. Hoffmann-La Roche Ag
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Priority to PCT/CN2009/075500 priority Critical patent/WO2011069298A1/fr
Priority to US12/959,408 priority patent/US8354443B2/en
Priority to KR1020127017856A priority patent/KR20120114297A/ko
Priority to CA2781839A priority patent/CA2781839A1/fr
Priority to BR112012013847A priority patent/BR112012013847A2/pt
Priority to ES10790751.1T priority patent/ES2464044T3/es
Priority to MX2012006180A priority patent/MX2012006180A/es
Priority to PCT/EP2010/069111 priority patent/WO2011070039A1/fr
Priority to EP10790751.1A priority patent/EP2509946B1/fr
Priority to RU2012126987/04A priority patent/RU2012126987A/ru
Priority to CN2010800558075A priority patent/CN102656147A/zh
Priority to JP2012542526A priority patent/JP2013513569A/ja
Publication of WO2011069298A1 publication Critical patent/WO2011069298A1/fr
Priority to US13/709,104 priority patent/US20130102604A1/en

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    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • 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
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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
  • the invention relates in particular to a compound of formula (I)
  • R 1 and R 2 are independently selected from hydrogen, alkyl, pyridinyl, phenyl,
  • R 3 is hydrogen, pyridinyl, piperidinyl, carboxypyridinyl, tetrahydropyranyl,
  • alkylsulfonylpiperazinylcarbonyl alkylpyrrolidinylalkylaminocarbonyl, alkyl- 1H- pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl, oxo-imidazolidinyl, morpholinylalkylaminocarbonyl, alkylaminoalkylpiperazinylcarbonyl, cycloalkyl- lH-pyrazolylaminocarbonyl and cycloalkylsulfonylaminocarbonyl;
  • R 4 is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof.
  • the invention also relates to a process for the manufacture of these novel compounds and medicaments containing them.
  • the compounds of the invention have 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.
  • Obesity and type 2 diabetes, hypertension, cancer, and cardiovascular disease are diseases that feature serious disturbances in glucose or 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 these syndromes 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, hormone and nuturient signals. 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, DG. 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
  • 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 l 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 PPARy agonist and exerts its antidiabetic effects through differentiation of adipocytes (Semple, RK et al. The Journal of clinical investigation 116 (2006), 581-589).
  • alkyl 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, tert-butyl and the like.
  • Preferred “alkyl” groups are methyl, ethyl, isopropyl, tert-butyl.
  • alkoxy signifies a group alkyl-O-, wherein the "alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy and the like.
  • Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.
  • cycloalkyl 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, cycloheptyl and the like.
  • Preferred cycloalkyl groups are cyclopropyl and cyclopentyl, cyclopropyl being particularly preferred.
  • halogen or "halo”, alone or in combination, means fluorine, chlorine, bromine or iodine.
  • Halogen is preferably fluorine, chlorine or bromine.
  • halophenyl means phenyl substituted by halogen.
  • carboxy alone or in combination, refers to the group -COOH.
  • carbonyl alone or in combination, refers to the group -C(O)-.
  • amino alone or in combination, refers to primary (- H 2 -), secondary (- H-) or tertiary amino (-N-).
  • hydroxy alone or in combination, refers to the group -OH.
  • sulfonyl alone or in combination, refers to the group -S(0) 2 -
  • 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 general 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 and R 2 are independently selected from hydrogen, alkyl, pyridinyl, phenyl,
  • R 3 is pyridinyl, carboxypyridinyl, tetrahydropyranyl, dialkylamino, morpholinyl,
  • alkylsulfonylpiperazinylcarbonyl alkylpyrrolidinylalkylaminocarbonyl, alkyl- 1H- pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl and oxo- imidazolidinyl;
  • R 4 is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl; and n is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof.
  • R 1 and R 2 are selected from hydrogen and alkyl and the other one is selected from pyridinyl, halophenyl, alkylsulfonylphenyl, cyanophenyl and trifluoromethylphenyl, or R 1 and R 2 , together with the carbon atom to which they are attached form cycloalkyl or tetrahydropyranyl;
  • R 1 and R 2 are selected from hydrogen and isopropyl and the other one is selected from pyridinyl, fluorophenyl, chlorophenyl, cyanophenyl, methylsulfonylphenyl and trifluoromethylphenyl.
  • Preferred is a compound according of formula (I) wherein R 3 is pyridinyl
  • alkylpiperazinylcarbonyl alkylsulfonylpiperazinylcarbonyl
  • alkylpyrrolidinylalkylaminocarbonyl alkyl- lH-pyrazolylaminocarbonyl, oxo-oxazolidinyl, oxo-pyrrolidinyl and oxo-imidazolidinyl.
  • R 3 is carboxypyridinyl, carboxyalkyl- lH-imidazolyl, carboxyphenyl or phenyl substituted with carboxy and oxo- oxazolidinyl.
  • R 4 is hydrogen, halogen, cyano, trifluoromethyl or alkylsulfonyl is also preferred.
  • a compound of formula (I) wherein R 4 is hydrogen, halogen, carboxy, cyano, trifluoromethyl or alkylsulfonyl is also preferred.
  • R 4 is hydrogen, halogen or carboxy.
  • R 4 is hydrogen, fluoro or chloro.
  • a compound of formula (I) wherein n is 0 or 1 is preferred.
  • R 5 is hydrogen, halogen, oxo-oxazolidinyl, oxo-imidazolidinyl.
  • R 6 and R 7 are independently selected from hydrogen, alkyl, cycloalkyl, alkylsulfonyl, cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl.
  • R 1 , R 2 , R 3 , R 4 and n are as defined above unless otherwise indicated.
  • the compounds of formula la and lb can be prepared according to Scheme 1.
  • Intermediate III is prepared as by the condensation reaction between II and different aldehydes or ketones. Cyclopropanation of III affords the intermediate IV. Alkylation between IV and bromide V affords the ester VI.
  • Ester VII can be obtained by introducing R 5 to the intermediate VI under copper salts catalysts. Hydrolysis of the methyl ester VII gives the corresponding acid la.
  • Amide lb can be prepared by the coupling reaction between the acid la and amine VIII.
  • the condensation reaction between II and different aldehydes is carried out in refluxing toluene or refluxing alcohol overnight when using base such as piperidine or pyrrolidine as catalyst.
  • Cyclopropanation of III is carried out in organic solvents such as DMSO at 50°C for several hours by treating trimethylsulfoxoniumiodide with sodium hydride to generate sulfurylide in situation.
  • introduction of R 5 to the methyl ester VI can be carried out in the presence of a copper source such as copper(I) iodide (Cul), in combination with a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a copper source such as copper(I) iodide (Cul)
  • a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol
  • a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxid
  • the reaction can be carried out in a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone at a temperature between 100°C and 180°C for 15 to 60 minutes under microwave irradiation.
  • a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone
  • a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone
  • Hydrolysis of the methyl esters VII 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 to give the stereoisomers of la.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane or tetrahydrofuran
  • the reaction is typically carried out in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), o- (lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or 1- ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt) or N,N-dimethylaminopyridine (DMAP), in the presence of a base such as trie
  • the reaction can be carried out in a solvent such as dichloromethane or N,N-dimethylformamide at room temperature for several hours (Montalbetti, C. A. G. N. et a/., Tetrahedron 61 (2005) 10827).
  • a solvent such as dichloromethane or N,N-dimethylformamide
  • the compounds of formula Ic and Id can be prepared according to Scheme 2.
  • the diazo compound X can be obtained by treating the isatin IX with /?-toluenesulfonyl hydrazide under basic conditions. Cyclopropanation of alkene XI with diazo compound X by Rh catalyst affords the intermediate XII. Alkylation or arylation of XII with the bromide V afforded the methyl ester XIII. Introduction of R 5 to XIII by using copper salts as catalyst gave intermediate XIV. Hydrolysis of the methyl ester gives the corresponding acids Ic.
  • the hydrolysis 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. Conversion of the acids Ic to the corresponding amides Id with suitable amines VIII can be easily accomplished using methods well known to someone skilled in the art.
  • the reaction is typically carried out in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC), benzotriazol- 1 -yl-oxy-tris-pyrrolidinophosphonium
  • hexafluorophosphate PyBop
  • HATU o-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU o-(lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EDCI l-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt
  • HABt hydroxybenzotriazole
  • DMAP N,N- dimethylaminopyridine
  • a base such as triethylamine or N,N- diisopropyl ethylamine.
  • the reaction can be carried out in a solvent such as
  • the compounds of formula Ie can be prepared according to Scheme 3. Alkylation of IV with the alkyl halide XV by using a base such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvent such as THF or DMF at room temperature for several hours affords the formula of Ie.
  • the compounds of formula If can be prepared according to Scheme 4. Alkylation of IV with the bromide XVI by using a base such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvent such as THF or DMF at room temperature for several hours affords the bromide XVII. If can be obtained by treating XVII with amine VIII under basic condition such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvent such as THF or DMF at room temperature.
  • alkylation between IV and the iodide XVIII can be carried out by using bases such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvents such as THF, DMF at room temperature for several hours.
  • Reductive amination of XX with different amines VIII can be carried out in organic solvents such as DCM, THF by using reducing reagents such as NaBH 4 or NaHB(OAc) 3 at room temperature to afford formula Ig.
  • the compounds of formula Ih and Ii can be prepared according to Scheme 6.
  • Ih and Ii can be obtained by alkylation of IV with XXI by using bases such as NaH, K 2 C0 3 or Cs 2 C0 3 in organic solvents such as THF or DMF at room temperature for several hours.
  • the compounds of formula Ij and Ik can be prepared according to Scheme 7.
  • the coupling between IV and idoimidazole XXII followed by deprotection in the presence of TFA affords Ij.
  • Subsequent alkylation with XXIII affords formula XXIV.
  • hydrolysis of the methyl esters XXIV provides the corresponding acids Ik.
  • the coupling reaction can be carried out in the presence of a copper source such as copper(I) iodide (Cul), in combination with a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a copper source such as copper(I) iodide (Cul)
  • a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol
  • a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert
  • the reaction can be carried out in a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone at a temperature between 100°C and 180°C for 15 to 60 minutes under microwave irradiation.
  • a suitable solvent like acetonitrile, dichloromethane, tetrahydrofuran, toluene, benzene, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone
  • the reactions can be carried out without the use of a microwave at a raised temperature such as 80°C for a longer reaction time (Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
  • Deprotection can be carried out in organic solvent such as DCM or THF with TFA at room temperature to afford stereoisomers Ij .
  • organic solvent such as DCM or THF with TFA at room temperature to afford stereoisomers Ij .
  • the alkylation of Ij with bromide XXIII is carried out by using bases such as NaH, K 2 C0 3 or CS2CO 3 in organic solvents such as THF or DMF at room temperature for several hours.
  • hydrolysis of the methyl ester gives the compounds Ik.
  • the hydrolysis 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.
  • Scheme 8 The compounds of formula IL can be prepared according to Scheme 8. The alkylation between IV and ethylene dibromide XXV affords the bromides XXVI.
  • nucleophilic substitution reaction between the ester XXVII and the bromide XXVI gives the methyl esters XXVIII. Hydrolysis of the methyl esters furnishes the corresponding acids IL.
  • the condensation between IV and ethylene dibromide can be carried out in organic solvents (THF or DMF) by using bases such as NaH, K 2 CO 3 or Cs 2 C0 3 at room temperature for several hours .
  • the substitution reaction between the imidazole XXVII and XXVI can be carried out in organic solvents such as THF or DMF by using bases such as NaH, K 2 C0 3 or Cs 2 C0 3 at room temperature for several hours.
  • hydrolysis of the methyl ester XXVII can afford the compounds IL.
  • the reaction can be carried out in the presence of an aqueous inorganic bases 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 bases 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.
  • the invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps: a) the reaction of a compound of formula (A)
  • R 1 , R 2 , R 3 , R 4 and n are defined as in any one of claims 1 to 8; wherein R 5 is hydrogen, halogen, oxo-oxazolidinyl or oxo-imidazolidinyl; wherein R 6 and R 7 are independently selected from hydrogen, alkyl, cycloalkyl, alkylsulfonyl,
  • cycloalkylsulfonyl, aminoalkyl and aminocycloalkyl wherein X is carbon or nitrogen; wherein Y is Br, I, or OTs; wherein Q is Br or I; and wherein R is alkyl.
  • the coupling reagent is for example dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), o- (lH-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or 1- ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI).
  • DCC dicyclohexyl carbodiimide
  • PyBop benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
  • Step (a) can be carried out in the presence or absence of hydroxybenzotriazole (HOBt) or N,N- dimethylaminopyridine (DMAP), in the presence of a base such as triethylamine or N,N- diisopropyl ethylamine.
  • the reaction of step (a) can be carried out in a solvent such as dichloromethane or N,N-dimethylformamide. The reaction can be carried out at room temperature for several hours.
  • the base can be for example NaH, K 2 C0 3 or Cs 2 C0 3 .
  • Step (b) can be carried out in an organic solvent such as THF or DMF. This reaction can proceed at room temperature for several hours.
  • the base can be for example NaH, K 2 C0 3 or Cs 2 C0 3 .
  • Step (c) can be done in an organic solvent such as THF or DMF. The reaction can proceed at room temperature.
  • step (d) can be carried out in an organic solvent such as DCM or THF.
  • the reducing agent of step (d) can be for example NaBH 4 or NaHB(OAc) 3 .
  • the reaction can proceed at room temperature.
  • the base in step (e), can be for example NaH, K 2 C0 3 or Cs 2 C0 3 .
  • the solvent can be an organic solvent such as THF or DMF. The reaction can be carried out at room temperature for several hours.
  • the base in step (f), can be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the solvent of step (f) can be for example methanol, 1,4-dioxane or tetrahydrofuran. The reaction can proceed at room temperature for several hours.
  • the base in step (g), can be an inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the solvent of step (g) can be for example methanol, 1,4-dioxane or tetrahydrofuran. The reaction can proceed at room temperature for several hours.
  • the invention also relates to a compound of formula (I) for use as therapeutically active substance.
  • the invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
  • the use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to AMPK regulation is an object of the invention.
  • 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, hyperglycemia, dyslipidemia, type 1 or type 2 diabetes, in particular type 2 diabetes.
  • Said medicaments e.g. in the form of pharmaceutical preparations, can be
  • 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 can be used, for example, as such carriers for tablets, coated tablets, dragees 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, hyperglycemia, dyslipidemia, type 1 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 cancer that are related to AMPK regulation and provides a method for the treatment of cancer that are related to AMPK regulation.
  • Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • Basic condition A: 0.01% NH 3 H 2 0 in H 2 0; B: acetonitrile;
  • Oxindole (0.13 g, 1 mmol), 4-chlorobenzaldehyde (0.17 g, 1.2 mmol) were mixed in alcohol; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture was refluxed for 3 hours. The formed precipitates was collected by filtration and washed with alcohol twice to give the title compound as yellow powder (0.24 g, 92 %).
  • CisHioClNO 255 observed(M+H) + : 256.1.
  • a solution of dimethylsulfoxoniummethylide was prepared as under argon from a 60% NaH mineral oil dispersion (88 mg, 2.2 mmol), trimethylsulfoxoniumiodide (484 mg, 2.2 mmol), and DMSO (10 mL). After 20 min, a solution of (Z)-3-(4-chloro-benzylidene)-l, 3-dihydro- indol-2-one (510 mg, 2 mmol) in THF (5 mL) was added dropwise over 20 min. After stirring for 1 hour at room temperature and another 1 hour at 50°C, the solution was poured into ice-cold water (20 mL) and extracted with ether (3 x 20 mL).
  • the tosylhydrazone (38.1 mmol) was treated with a solution of NaOH (76.1 mmol) in water 375 mL.
  • the reaction mixture was stirred for 15 hours in a water bath at 50 "C and then allowed to cool to room temperature.
  • the reaction mixture was neutralized by addition of dry ice whereupon diazo compound was precipitated. (5.94 g, 88%).
  • the tile compounds were obtained by separation of the stereoisomers of (I S, 2S) and (1R, 2R)-3 -((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 32) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
  • tile compounds were obtained by separation of the stereoisomers of (I S, 2S) and (1R, 2R)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[cyclopropane-l,3'-indoline]- l'-yl)methyl)benzoic acid (Example 35) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol. (+)-3-((2-(4-chlorophenyl)-5'-fluoro-2-isopropyl-2'-oxospiro[[(irans)-cyclo
  • Example 40 and Example 41 (-)-3-((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro[(irans)-cyclopropane-l,3'-indoline]- l'-yl)methyl)benzoic acid and (+)-3-((2-(4-chlorophenyl)-2-isopropyl-2'- oxospirol ⁇ ran ⁇ -cyclopropane-l ⁇ '-indolinel-l'-y ⁇ methy ⁇ benzoic acid
  • the tile compounds were obtained by separation of the stereoisomers of (I S, 2S) and (IR, 2R)-3 -((2-(4-chlorophenyl)-2-isopropyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 27) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
  • the tile compounds were obtained by separation of the stereoisomers of (1R, 2S) and (I S, 2R)-3 -((2-(4-chlorophenyl)-2-methyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 42) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
  • Example 46 and Example 47 (+)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(cis)-cyclopropane-l,3 , -indoline]-l'- yl)methyl)benzoic acid and (-)-3-((2-(4-chlorophenyl)-2-methyl-2'-oxospiro[(ciV)- cyclopropane-l,3'-indoline]-l'-yl)methyl)benzoic acid
  • the tile compounds were obtained by separation of the stereoisomers of (1R, 2R) and (I S, 2 S)-3 -((2-(4-chlorophenyl)-2-methyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl)benzoic acid (Example 45) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
  • the tile compounds were obtained by separation of the stereoisomers of (1R, 2S) and (I S, 2R)- 3 -((2-(4-cyanophenyl)-5 '-fluoro-2-methyl-2'-oxospiro [cyclopropane- 1 , 3 '-indoline] - 1 '- yl)methyl) benzoic acid (Example 48) by chiral preparative HPLC (Chiralpak AD) eluting with a mixture of n-heptane / 5% isopropanol.
  • Racemic (I S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-l,3'-indolin]-2'-one and (1R, 2S)- 2-(4-chlorophenyl)spiro[cyclopropane-l,3'-indolin]-2'-one 270 mg, 1.0 mmol, 1.0 equiv.
  • a stirred solution of sodium hydride 60 %, 60 mg, 1.5 mmol
  • Example 72 (IS, 2R) and (1R, 2S)-2-(4-chlorophenyl)-l'-(2-morpholinoethyl)spiro[cyclopropane- l,3'-indolin]-2'-one
  • Example 77 (IS, 2R)-2-(4-chlorophenyl)-l'-(2-((R)-3-(dimethylamino)pyrrolidin-l- yl)ethyl)spiro[cyclopropane-l,3'-indolin]-2'-one and (IR, 2S)-2-(4-chlorophenyl)-l'- (2-((R)-3-(dimethylamino)pyrrolidin-l-yl)ethyl)spiro[cyclopropane-l,3'-indolin]-2'- one
  • Example 80 (IS, 2R) and (1R, 2S)-2-(4-(2-(4-chlorophenyl)-2'-oxospiro[cyclopropane-l,3'- indoline] - 1 '-yl)- lH-imidazol- l-yl)acetic acid

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Abstract

L'invention concerne un composé de formule (I), ainsi qu'un de ses sels pharmaceutiquement acceptables, dans laquelle R1 à R4 ont la signification donnée dans la revendication 1, qui peut être utilisé en tant que médicament.
PCT/CN2009/075500 2009-12-11 2009-12-11 Nouveaux dérivés de cyclopropane indolinone WO2011069298A1 (fr)

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PCT/CN2009/075500 WO2011069298A1 (fr) 2009-12-11 2009-12-11 Nouveaux dérivés de cyclopropane indolinone
US12/959,408 US8354443B2 (en) 2009-12-11 2010-12-03 Cyclopropane indolinone derivatives
ES10790751.1T ES2464044T3 (es) 2009-12-11 2010-12-08 Espirol indol-ciclopropano indolinonas útiles como moduladores de AMPK
CA2781839A CA2781839A1 (fr) 2009-12-11 2010-12-08 Spiro-indole-cyclopropane-indolinones utiles en tant que modulateurs d'ampk
BR112012013847A BR112012013847A2 (pt) 2009-12-11 2010-12-08 novos derivados de indolinona ciclopropano
KR1020127017856A KR20120114297A (ko) 2009-12-11 2010-12-08 Ａｍｐｋ 조절제로서 유용한 스파이로 인돌-사이클로프로판 인돌린온
MX2012006180A MX2012006180A (es) 2009-12-11 2010-12-08 Espiro indol-ciclopropano indolinonas utiles como moduladores de proteina cinasa activada por monofosfato de adenosina.
PCT/EP2010/069111 WO2011070039A1 (fr) 2009-12-11 2010-12-08 Spiro-indole-cyclopropane-indolinones utiles en tant que modulateurs d'ampk
EP10790751.1A EP2509946B1 (fr) 2009-12-11 2010-12-08 Spiro-indole-cyclopropane-indolinones utiles en tant que modulateurs d'ampk
RU2012126987/04A RU2012126987A (ru) 2009-12-11 2010-12-08 Спироиндолциклопропаниндолиноны в качестве модуляторов амрк
CN2010800558075A CN102656147A (zh) 2009-12-11 2010-12-08 可用作ampk调节剂的螺吲哚-环丙烷二氢吲哚酮
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BR112012013847A2 (pt) 2016-05-10
US8354443B2 (en) 2013-01-15
JP2013513569A (ja) 2013-04-22
WO2011070039A1 (fr) 2011-06-16
US20110144106A1 (en) 2011-06-16
ES2464044T3 (es) 2014-05-30
RU2012126987A (ru) 2014-01-20
EP2509946A1 (fr) 2012-10-17
KR20120114297A (ko) 2012-10-16

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