WO2005051908A1 - Nouveaux derives d'indole a utiliser comme agents decouplants chimiques - Google Patents

Nouveaux derives d'indole a utiliser comme agents decouplants chimiques Download PDF

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WO2005051908A1
WO2005051908A1 PCT/DK2004/000303 DK2004000303W WO2005051908A1 WO 2005051908 A1 WO2005051908 A1 WO 2005051908A1 DK 2004000303 W DK2004000303 W DK 2004000303W WO 2005051908 A1 WO2005051908 A1 WO 2005051908A1
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nitro
alkyl
cyano
halogen
haloalkyl
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PCT/DK2004/000303
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Lise Brown Christiansen
Tina Møller TAGMOSE
Preben Houlberg Olesen
Thomas Kruse Hansen
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Novo Nordisk A/S
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Priority to JP2006540163A priority Critical patent/JP2007512263A/ja
Priority to EP04730958A priority patent/EP1689710A1/fr
Publication of WO2005051908A1 publication Critical patent/WO2005051908A1/fr
Priority to US11/440,935 priority patent/US20070010559A1/en

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Definitions

  • the present invention provides novel indolevinyl derivatives, which are effective in increasing the mitochondrial respiration and may thus be useful in the treatment of obesity and related diseases and states.
  • Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, type 2 diabetes (non-insulin dependent diabe- tes mellitus (NIDDM)), dyslipidemia, coronary heart disease, and osteoarthritis and various malignancies. It also causes considerable problems through reduced motility and decreased quality of life. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world.
  • the term obesity implies an excess of adipose tissue. In this context obesity is best viewed as any degree of excess adiposity that imparts a health risk.
  • This process may be counteracted by increasing the energy expenditure (for instance via exercise) or decreasing the energy intake (for instance by dieting).
  • Pharmacological treatment available up to date only consists of Sibutramine (acting via serotonergic mechanisms, Abbott) and Orlistat (reducing fat uptake from the gut, Roche Pharm) neither reducing body weight effectively nor acceptably.
  • One way of increasing energy expenditure is by increasing the metabolic rate. Oxi- dative phosphorylation in mitochondria, the energy from glucose metabolism and free fatty acids oxidation is used to drive the phosphorylation of ADP to ATP.
  • Chemical uncouplers are compounds, which can transport protons across membranes, and when protons are transported across the inner mitochondrial membrane, the ATP synthase is bypassed. At the (alkaline) matrix side the proton is released and the deprotonated uncoupler returns to the inter-membrane space where it picks up another proton.
  • Compounds, such as chemical uncouplers, which act by increasing the metabolic rate may thus be useful for treating obesity, but also for treating other conditions such as atherosclerosis, hypertension, diabetes, especially type 2 diabetes (NIDDM (non-insulin dependent diabetes mellitus)), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as endometrial, breast, prostate and colon can- cers and the risk for premature death as well as other conditions, such as diseases and disorders, which conditions are improved by a reduced mitochondrial potential.
  • NIDDM non-insulin dependent diabetes mellitus
  • dyslipidemia CAD
  • coronary heart disease gallbladder disease
  • osteoarthritis various types of cancer
  • endometrial, breast, prostate and colon can- cers and the risk for premature death as well as other conditions, such as diseases and disorders, which conditions are improved by a reduced mitochondrial potential.
  • ROS reactive oxygen species
  • ROS reactive oxygen species
  • DNP is the best known chemical uncoupler; but many other compounds are known to induce uncoupling.
  • DNP derivatives such as 4,6-dinitro-o-cresol (Victoria Yellow) and 2,4- dinitro-1-naphtol (Martius Yellow) as well as structurally unrelated compounds such as 2,6-di- f-butyl-4-(2',2'-dicyanovinyl)phenol) (SF6847) (also known as 2-(3,5-di-tert-butyl-4-hydroxy- benzylidene)-malononitrile), carbonylcyanide m-chlorophenylhydrazone (CCCP) and carbon- ylcyanide ptrifluoromethoxy-phenylhydrazone (FCCP) (Miyoshi H et al.
  • CCCP carbonylcyanide m-chlorophenylhydrazone
  • FCCP carbon- ylcyanide ptrifluoromethoxy-phenylhydrazone
  • WO00/06143 to Texas Pharmaceuticals Inc. relates to a method for inducing intra- cellular hyperthermia comprising a step of administering a mitochondrial uncoupling agent, such as 2,4-dinitrophenol.
  • a mitochondrial uncoupling agent such as 2,4-dinitrophenol.
  • US 4,673,691 to Bachynsky relates to the use of 2,4-dinitrophenol for treating obesity.
  • Various indolvinyl derivatives have been disclosed in the literature.
  • WO 95/26341 discloses a range of 3-[2-cyano-2-amide viny ndol derivatives, such as e.g. N-substituted 3-indolyl- ⁇ -cyanoacrylamide. The compounds are said to inhibit tyrosine kinase and to be useful in the treatment of certain cancer forms.
  • WO 95/19169 discloses various indole vinyl derivatives wherein the indole ring has been substituted in the 2-position with substituted alkyl, and wherein the vinyl group has been substituted with cyano and heteroaryl, keto or amides.
  • the compounds are effective inhibitors of platelet-derived growth factor. Matsuoka in Molecular Crystals and Liquid Crystals, (1990), 182A, 71-9 teaches that 3-[2-cyano-2-ethoxycarbonyl ethenyljindole exhibits good 2 nd harmonic generation efficiency.
  • the compounds are inhibitors of EGF receptor tyrosine kinase, and useful in the treatment of e.g. psoriasis and atherosclerosis.
  • US 5,981 ,569, WO 95/24190 and WO 96/40629 all disclose phenylvinyl derivatives, wherein the vinyl is substituted with cyano and sulfonyl derivatives.
  • the compounds are tyrosine kinase inhibitors useful in treatment of proliferative disorders.
  • R1 , R2, R3, R4 independently represents hydrogen, nitro, cyano, halogen, alkyl, alkenyl, al- kynyl, aryl, heteroaryl, haloalkyl, alkoxy, alkylamino, -C(0)OR9, -C(O)NR9R10, -S(0) 2 OR9, -S(0) ⁇ R9, -OC(0)R9, -NHC(0)R9 or -N(C(0)R9) 2 ;
  • R5 represents hydrogen, nitro, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy .alkylamino;
  • R6 represents -S(0) 2 OR9, -S(0) r R9, -S(O) 2 N(R9R10), -P(0)(OR9) 2 or -B(OR9) 2 ;
  • R7 represents cyano;
  • R8 represents hydrogen, nitro, cyano, halogen, haloalkyl, alkoxy, alkylamino, -C(0)OR9, -C(O)NR9R10, -S(0) 2 OR9, -S(0) n R9, -OC(0)R9, -NHC(0)R9 or -N(C(0)R9) 2 or alkyl, alkenyl, alkynyl, aryl, heteroaryl, all of which are optionally substituted with one or more substituents selected from the list consisting of alkyl, alkenyl, alkynyl, halogen, hydroxyl, cyano, nitro, carboxyl, oxo, haloalkyl, -0-R9, -S(0) n R9, -S(0) 2 OR9, -0-C(0)R9, -C(0)-0-R9, -C(0)-R9, -C(O)-N(R9)(R10), -N(R9)(
  • R9 and R10 represent hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, all of which are optionally substituted with a number substituents which is lower than the total number of hydrogens which could be substituted, and which substituents are selected from the list consisting of alkyl, halogen, hydroxyl, cyano, nitro, carboxyl, haloalkyl, -0-R11 , -S(0) n R11 , -0-C(0)R11 , -C(0)-0-R11 , -C(0)-R11 , -C(0)-N(R11)(R12), -N(R11)(R12), -(CH 2 ) P -N(R12)-C(0)-R11 , -B(OR11)(OR12), -(CH 2 ) p -0-R11 , -N(R11)-C(0)R12, N(R11)-S(0)
  • R11 and R12 independently represent hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl; or R11 and R12 when bound to nitrogen together with said nitrogen constitute a 5, 6, 7 or 8 membered ring, which may be saturated, either partly or fully or unsaturated, and wherein said ring is optionally substituted with one or more substituents selected from the list consisting of alkyl, halogen, hydroxyl, cyano and nitro;
  • R13 and R14 independently represent hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl; p represents 0, 1 or 2; r is 1 or 2; n is O, 1 or 2; and pharmaceutically acceptable salts, solvates and prodrugs thereof.
  • the present invention also relates to the use of compounds of formula I in therapy, and in particular to pharmaceutical compositions comprising said compounds.
  • the invention relates to therapeutic methods comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof.
  • the invention relates to the use of compounds of formula l in the manufacture of medicaments.
  • alkyl is intended to indicate a straight or branched chain saturated monovalent hydrocarbon radical having from one to twelve carbon atoms, also denoted as C 1-12 -alkyl.
  • Typical alkyl groups are alkyl groups with from one to eight or from one to six carbon atoms, also denoted as C 1-8 -alkyl and C 1-6 -alkyl respectively.
  • Typical C 1-8 -alkyl groups include, but are not limited to e.g.
  • C 1-8 -alkyl groups include the same groups as well as alkyl groups having seven or eight carbon atoms, such as heptyl, octyl, 2,2-dimethylhexyl and the like.
  • C ⁇ -6 -alkyl as used herein also includes secondary C 3 . 6 -alkyl and tertiary C 4-6 -alkyl.
  • C ⁇ -alky! as used herein also includes secondary C 3-8 -alkyl and tertiary C 4 . 8 -alkyl.
  • C 1-12 -alkyl as used herein also includes secondary C 3-12 -alkyl and tertiary C -12 -alkyl.
  • alkenyl is intended to indicate a straight or branched chain monovalent hydrocarbon radical having from two to six carbon atoms and at least one carbon-carbon double bond, for example C 3-5 -alkenyl.
  • Typical C 3-5 -alkenyl groups include vinyl, allyl, 1-propenyl, 1 ,3 butadiene-1-yl, and the like.
  • conjuggated alkenyl refers to an alkenyl having consecutive double bonds, such as for instance 1,3 butadiene-1-yl.
  • alkynyl is intended to indicate a straight or branched chain monovalent hydrocarbon radical having from two to six carbon atoms and at least one carbon-carbon triple bond and optionally one or more carbon-carbon double bonds. Examples include ethynyl, propynyl and 3,4-pentadiene-1-ynyl.
  • halogen is intended to indicate members of the seventh main group of the periodic system, i,e, fluoro, chloro, bromo and iodo.
  • aryl is intended to indicate a carbocyclic aromatic ring radical which may optionally be fused to another ring, which may be aromatic or nonaro- matic, aromatic or non-aromatic.
  • Typical aryl groups include phenyl, biphenylyl, indenyl, fluo- rene, naphthyl (1-naphthyl, 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), 1 ,2,3,4-tetrahydro quinolyl, 1 ,2,3,4-tetrahydro naphthyl, and the like.
  • heteroaryl refers to an aromatic ring radical with for instance 5 to 7 member atoms, or to a fused aromatic ring system radical with for instance from 7 to 18 member atoms, wherein at least on ring is aromatic, and which ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur heteroa- toms, wherein N-oxides and sulfur monoxides and sulfur dioxides are permissible het- eroaromatic substitutions.
  • Examples include furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothia- zolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, ben- zothiophenyl, indolyl, and indazolyl, thienyl (2-thienyl, 3-thienyl), furanyl (2-furanyl, 3-furanyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolinyl
  • fused ring system refers to a carbocyclic or heterocyclic ring radical fused to another carbocyclic or heterocyclic ring radical, the two rings having two atoms in common.
  • Typical fused aromatic ring systems include, but are not limited to napthalene, quinoline, isoquinoline, indole, and isoindole.
  • cycloalkyl is intended to indicate a cyclic saturated monovalent hydrocarbon radical having 3, 4, 5, 6, 7 or 8 ring carbon atoms.
  • alkoxy is intended to indicate a radical of the formula -OR', wherein R' represents alkyl as indicated above.
  • haloalkoxy is intended to indicate an alkoxy as defined above substituted with one or more halogen, such as fluoro, chloro, bromo or iodo.
  • alkylamino is intended to indicate a radical of the formula -NH-R' or -N(R') 2 , wherein each R' represents alkyl as indicated above.
  • nitro shall mean the radical -N0 2 .
  • cyano shall mean the radical -CN.
  • haloalkyl is intended to indicate an alkyl, as defined above, substituted with one or more halogens, as defined above.
  • solvate is a complex of defined stoichiometry formed by a solute (in casu, a compound according to the present invention) and a solvent. Solvents may be, by way of example, water, ethanol, or acetic acid.
  • prodrug includes biohydrolyzable amides and biohydro- lyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound according to the present invention, and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances according to the present invention.
  • these functional groups include 1 ,4-dihydropyridine, N-alkylcarbonyl-1 ,4-dihydropyridine, 1 ,4-cyclohexadiene, tert-butyl, and the like.
  • salts are intended to indicate salts which are not harmful to the patient.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hy- droiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cin- namic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hy- droxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • a “therapeutically effective amount” of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimen- tation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.
  • treatment and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
  • the patient to be treated is preferably a mammal, in particular a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs.
  • the invention relates to a compound according to formula I of the formula la
  • R1 , R2, R3, R4, R5, R6, R7 and R8 are as defined above.
  • R1 , R2, R3 and R4 represent hydrogen.
  • either R1 , R2, R3 or R4 represent nitro, and in particular R3 may represent nitro.
  • R1 may represent C 1-6 alkyl, such as methyl.
  • R5 represents hydrogen.
  • R6 represents -S(0) 2 OR9, -S(0) r R9 or -S(O)2N(R9R10), and particular mentioning is made of R6 representing -S(0) 2 R9, wherein R9 represents C 1-6 alkyl, aryl or heteroaryl, all of which may optionally be substituted.
  • R9 examples include methyl, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 1-methyl-2-imidazolyl and 2-thienyl.
  • R8 represents hydrogen or halogen, or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, all of which are optionally substituted.
  • R8 include hydrogen chloro, methyl, 2-phenyl-ethenyl, and 2-phenyl-ethynyl.
  • R8 represents optionally substituted aryl, and particular examples include phenyl and biphenylyl, both optionally substituted with a substituent selected from halogen, nitro, cyano and C 1-4 haloalkyl; or R8 represents radicals with the following structures
  • R is selected from the list consisting of hydrogen, methyl, CF 3 , Cl, Br, F, methoxy, ethoxy, methylcarbonyl, nitro, cyano, and phenyl, wherein said phenyl may optionally be substituted with Cl, Br, F, CF 3 or methoxy.
  • R8 include phenyl, biphenylyl, 4-chloro-phenyl, 4-nitro-phenyl, 4-cyanophenyl, 4-CF 3 -phenyl, 2-CF 3 -phenyl, 3- fluoro-4-bromo-phenyl and 2-fluoro-biphenyl-4-yl.
  • R8 represents an optionally substituted heteroaryl, and particular mentioning is made of wherein R is selected from the list consisting of hydrogen, methyl, CF 3 , Cl, Br, F, methoxy, ethoxy, methylcarbonyl, nitro, cyano, and phenyl, wherein said phenyl may optionally be substituted with Cl, Br, F, CF 3 or methoxy. Particular examples include 5-chloro-thienyl.
  • the invention relates to compounds of formula I selected from the list consisting of
  • Compounds according to formula I may comprise chiral carbon atoms or carbon- carbon double bonds which may give rise to stereo isomeric forms, e.g. enatiomers, di- astereomers and geometric isomers.
  • the present invention relates to all such isomers, either in pure form or as mixtures thereof.
  • Pure isomeric forms may either be prepared from intermediates which are pure isomers themselves, by purification of a mixture of isomers after the synthesis, or by a combination of the two methods. Purification of isomeric forms are well- known in the art, e.g. as described by Jaques in Enantiomers, Racemates and Resolution, Wiley, 1981.
  • the compounds of the present invention are useful in the treatment of diseases or states that benefit from an increase in the mitochondrial respiration.
  • the compounds of the present invention are believed to be particular well-suited for the treatment of obesity as such or preventing weight gain and for the treatment of diseases or disorders where obesity is involved in the etiology.
  • the invention thus provides a method of treating the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurode- generative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, atherosclerosis, hypertension, coronary heart disease, gallbladder disease, osteoarthritis, and cancer.
  • Such conditions include the metabolic syndrome, type 2 diabetes (especially in obese patients), diabetes as a consequence of obesity, insulin resistance, hy- perglycemia, prandial hyperglycemia, hyperinsulinemia, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia (especially in obese patients), diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia,, micro-/macroalbuminuria, neph- ropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, con-sumal heart failure, stroke, myocardial infarction, arrythmia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle ca- tabolism, osteoporosis, decreased linear growth,
  • cancer is intended to include forms such as hematological cancer, such as leukemia, acute myeloide leukemia, chronic myeloide leukemia, chronic lymphatic leukemia, myelo- dysplasia, multiple myeloma, Hodgkin's disease, or solid tumor forms, such as fibrosarcom, small or non-small cell long carcinoma, gastric, intestinal or colorectal cancer, prostate, en- dometrial, ovarian or breast cancer, brain, head or neck cancer, cancer in the urinary tract, such as kidney or bladder cancer, malignant melanoma, liver cancer, uterine and pancreatic cancer.
  • hematological cancer such as leukemia, acute myeloide leukemia, chronic myeloide leukemia, chronic lymphatic leukemia, myelo- dysplasia, multiple myeloma, Hodgkin's disease, or solid tumor forms, such as fibrosarcom, small or non-small cell long carcinoma, gastric, intestinal or colore
  • the invention relates to the use of a chemical uncoupler ac- cording to the present invention for maintaining a weight loss.
  • Use of the compounds according to the present invention in the treatment of obesity may very likely reduce or eliminate the side effects such as irritation of the skin, glaucoma etc. known from treatment of obesity with DNP and other chemical uncouplers with narrow safety windows.
  • Uncouplers may also reduce insulin release from ⁇ -cells and may thus be useful in providing ⁇ -cell rest. Inducing ⁇ -cell rest may be useful in connection with ⁇ -cell transplantation, and it has also been described that inducing ⁇ -cell rest may be useful in preventing diabetes.
  • Obesity drugs which regulate the appetite and reduce food intake often suffer from lack of long-term efficiency in terms of body weight loss because the body in response to the treatment lowers the rate of the metabolism.
  • the compounds of the present invention increases the metabolism, and they are therefore believed to be particular suited for maintaining a weight loss.
  • the compounds of the present invention are also believed to be particular well- suited for the treatment of diseases or disorders where reactive oxygen species are involved in the etiology, and wherein a reduction in the amount of reactive oxygen species are beneficial.
  • the invention thus provides a method of treating, and in particular preventing ageing and damages to the heart, endothelial cells and neuronal tissue, diabetic microvascular diseases in the retina, the renal glomerus and the peripheral nerve cells, the method comprising administering to a patient in need thereof a therapeutically effective amount of one or more compound of the present invention to a patient need thereof.
  • the subject may be any mammal suffering from a condition benefiting from increased mitochondrial respiration.
  • Such mammals may include, for instance, horses, cows, sheep, pigs, mice, rats, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably, humans.
  • the compounds of the present invention may be administered alone or in combination with other therapeutically active compounds, either concomitantly or sequentially, and at any suitable ratios.
  • Such further active compounds may be selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
  • Suitable antidiabetic agents include insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycemic agents.
  • Suitable orally active hypoglycemic agents preferably include imidazolines, sulfony- lureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, ⁇ -glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the pancreatic ⁇ -cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, potassium channel openers, such as ormitiglinide, potassium channel blockers such as nateglinide or BTS-67582, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), all of which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO
  • the compound of the present invention may be administered in combination with insulin or insulin analogues.
  • the compound of the present invnetion may be administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibencla- mide, glipizide, glimepiride, glicazide or glyburide.
  • the compound of the present invnetion may be administered in combination with a biguanide eg metformin.
  • the compound of the present invnetion may be administered in combination with a meglitinide eg repaglinide or senaglinide/nateglinide.
  • the compound of the present invention may be administered in combination with a thiazolidinedione insulin sensitizer, e.g. troglitazone, ciglitazone, pioglita- zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097 (e.g.
  • the compound of the present may be administered in combina- tion with an insulin sensitizer e.g.
  • the compound of the present invention may be administered in combination with an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • the compound of the present invnetion may be administered in combination with a glycogen phosphorylase inhibitor eg the compounds described in WO 97/09040.
  • the compound of the present may be administered in combination with a glucokinase activator.
  • the compound of the present invention may be administered in combination with an agent acting on the ATP-dependent potassium channel of the pancreatic ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • the compound of the present invention may be administered in combination with nateglinide.
  • the compound of the present invention may be administered in combination with an antihyperlipidemic agent or a antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothy- roxine.
  • the compound of thenpresent may be administered in combination with more than one of the above-mentioned compounds e.g. in combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
  • metformin and a sulphonylurea such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • the compound of the present invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC3 (melano- cortin 3) agonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecys), C
  • sibutramine 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR ⁇ agonists, adrenergic CNS stimulating agents, AGRP (agouti related protein) inhibitors, H3 histamine antagonists such as those disclosed in WO 00/42023, WO 00/63208 and WO 00/64884, which are incorporated herein by reference, exendin-4, GLP-1 agonists and ciliary neurotrophic factor.
  • 5HT serotonin
  • antiobesity agents are bupropion (antidepressant), topi- ramate (anticonvulsant), ecopipam (dopamine D1/D5 antagonist), naltrexone (opioid antagonist), and peptide YY 3-36 (Batterham et al, Nature 418, 650-654 (2002)).
  • the antiobesity agent is leptin.
  • the antiobesity agent is a lipase inhibitor eg orlistat.
  • the antiobesity agent is an adrenergic CNS stimulating agent eg dexamphetamine, amphetamine, phentermine, mazindol phendimetrazine, diethylpropion, fenfluramine or dexfenfluramine.
  • the compounds of the present invention may be adminis- tered in combination with one or more antihypertensive agents.
  • antihypertensive agents examples include ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol; ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril; calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil; and ⁇ - blockers such as doxazosin, urapidil, prazosin and terazosin.
  • ACE angiotensin converting enzyme
  • calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, d
  • the present invention also provides pharmaceutical compositions comprising as an active ingredient, at least one compound of the present invention, preferably in a therapeutically effective amount, suitable for any of the methods according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
  • Said pharmaceutical compositions may also comprise any of the further active compounds as indicated above
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of a compound suitable for any of the methods described above.
  • the present invention also relates to the use of a compound according to formula I for the manufacture of a medicament for the treatment of diseases benefiting from an increase in mitochondrial metabolism or a decrease in the amount of reactive oxygen species, as exemplified above.
  • the present invention relates to a method of treating obe- sity, hypertension, type 2 diabetes, osteoarthritis, gallbladder diseases, or preventing of weight gain or maintaining a weight loss, or treating diabetic microvascular diseases in the retina, renal glomerulus or peripheral nerve cell apoptosis, the method comprising administering to a subject in need thereof an effective amount of a first compound according to formula II wherein the wedged bonds to R16 and R17 indicate that R16 and R17 is either cis or trtans to R5;
  • R1 , R2, R3, R4 independently represents hydrogen, nitro, cyano, halogen, alkyl, alkenyl, al- kynyl, aryl, heteroaryl, haloalkyl, alkoxy, alkylamino, -C(0)OR9, -C(O)NR9R10, -S(0) 2 OR9, -S(0) n R9, -OC(0)R9, -NHC(0)R9 or -N(C(0)R9) 2 ;
  • R5 represents hydrogen, nitro, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy .alkylamino
  • R16 represents nitro, halogen, haloalkyl, -C(0)R9, -C(0)OR9, -C(O)N(R9R10) ,-S(0) 2 OR9, -S(0) r R9, -S(O) 2 N(R9R10), -P(0)(OR9) 2 or -B(OR6) 2
  • R17 represents cyano, nitro, halogen, haloalkyl, -C(0)R9, -C(0)OR9, -C(O)N(R9R10) , -S(0) 2 OR9, -S(0) r R9, -S(O) 2 N(R9R10), -P(0)(OR9) 2 or -B(OR6) 2
  • R8 represents hydrogen, nitro, cyano, halogen, haloal
  • R11 and R12 independently represent hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl; or R11 and R12 when bound to nitrogen together with said nitrogen constitute a 5, 6, 7 or 8 membered ring, which may be saturated, either partly or fully or unsaturated, and wherein said ring is optionally substituted with one or more substituents selected from the list consisting of alkyl, halogen, hydroxyl, cyano and nitro
  • R13 and R14 independently represent hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl; p represents 0, 1 or 2; r is 1 or 2 n is 0, 1 or 2; and pharmaceutically acceptable salts, solvates and prodrugs thereof, optionally in combination with one or more other therapeutically active compound, to a patient in need thereof, wherein said other compound may be admissered sequentially or concomitantly.
  • the present invention relates to the use of a compound according to formula II
  • R1 , R2, R3, R4 independently represents hydrogen, nitro, cyano, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, haloalkyl, alkoxy, alkylamino, -C(0)OR9, -C(O)NR9R10, -S(0) 2 OR9, -S(0) n R9, -OC(0)R9, -NHC(0)R9 or -N(C(0)R9) 2 ;
  • R5 represents hydrogen, nitro, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino;
  • R16 represents nitro, halogen, haloalkyl, -C(0)R9, -C(0)OR9, -C(O)N(R9R10) ,-S(0) 2 OR9, -S(0) r R9, -S(O) 2 N(R9R10), -P(0)(OR9) 2
  • R17 represents cyano, nitro, halogen, haloalkyl, -C(0)R9, -C(0)OR9, -C(O)N(R9R10) , -S(0) 2 OR9, -S(0) r R9, -S(O) 2 N(R9R10), -P(0)(OR9) 2 or -B(OR6) 2 ;
  • R8 represents hydrogen, nitro, cyano, halogen, haloalkyl, alkoxy, alkylamino, -C(0)OR9, -C(O)NR9R10, -S(0) 2 OR9, -S(0) n R9, -OC(0)R9, -NHC(0)R9 or -N(C(0)R9) 2 or alkyl, alkenyl, alkynyl, aryl, heteroaryl, all of which are optionally substituted with one or more substituents selected from the list consisting of alkyl, alkenyl, alkynyl,
  • R9 and R10 represents hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, all of which are optionally substituted with a number substituents which is lower than the total number of hydrogens which could be substituted, and which substituents are selected from the list consisting of alkyl, halogen, hydroxyl, cyano, nitro, carboxyl, haloalkyl, -0-R11, -S(0) n R11 , -0-C(0)R11 , -C(0)-0-R11 , -C(0)-R11 , -C(0)-N(R11)(R12), -N(R11)(R12), -(CH 2 ) P -N(R12)-C(0)-R11, -B(OR11)(OR12), -(CH 2 ) p -0-R11, -N(R11)-C(0)R12, -N(R11)-S(0) n
  • R9 and R10 when bound to nitrogen together with said nitrogen constitute a 5, 6, 7 or 8 membered ring, which may be saturated, either partly or fully or unsaturated, and wherein said ring is optionally substituted with one or more substituents selected from the list consisting of alkyl, halogen, hydroxyl, cyano and nitro
  • R11 and R12 independently represent hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl; or R11 and R12 when bound to nitrogen together with said nitrogen constitute a 5, 6, 7 or 8 membered ring, which may be saturated, either partly or fully or unsaturated, and wherein said ring is optionally substituted with one or more substituents selected from the list consisting of alkyl, halogen, hydroxyl, cyano and nitro
  • R13 and R14 independently represent hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl; p represents 0, 1 or 2; r is 1 or 2 n is 0, 1 or 2; and pharmaceutically acceptable salts, solvates and prodrugs thereof, in the manufacture of a medicament for the treatment of obesity, hypertension, type 2 diabetes, osteoarthritis, gallbladder diseases, or preventing of weight gain or maintaining a
  • R1 , R2, R3 and R4 represent hydrogen.
  • R5 represents hydrogen.
  • R17 represents cyano.
  • R16 represents -C(0)-0- R9 or -C(0)-R9, wherein R9 represents optionally substituted alkyl or phenyl. Particular examples of R9 include ethyl, tert-butyl or 3,4-dichloro phenyl.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Sci- ence and Practice of Pharmacy, 20 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 2000.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including sub- cutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
  • Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as ster- ile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
  • the compounds for use according to the present invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid.
  • salts refers to non-toxic salts of the compounds for use according to the present invention which salts are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • a compound for use according to the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid.
  • a compound for use according to the present invention contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the inven- tion and these form a further aspect of the invention.
  • solutions of the compounds for use according to the present invention in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composi- tions formed by combining the compounds for use according to the present invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or so- dium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the compound for use according to the present invention in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, me- thylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tra- gacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phos- phatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occ
  • the aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspen- sion by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavouring, and colouring agents may also be present.
  • the pharmaceutical compositions comprising compounds for use according to the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • compositions may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • any bland fixed oil may be employed using synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials in- elude cocoa butter and polyethylene glycols, for example.
  • creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the invention are contemplated.
  • topical applications shall include mouth washes and gargles.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.
  • a pharmaceutical composition comprising a compound for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liq- uid suspension or solution.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite®IRP88* 1.0 mg Magnesii stearas Ph. Eur. q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg
  • the pharmaceutical composition comprising a compound for use according to the present invention may comprise a compound for use according to the present invention in combination with further active substances such as those described in the foregoing.
  • the present invention also provides methods for the preparation of compounds for use according to the present invention.
  • the compounds can be prepared readily according to the following general procedures (in which all variables are as defined before, unless so specified) using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • HPLC-MS (Method A) The following instrumentation is used: • Hewlett Packard series 1100 G1312A Bin Pump • Hewlett Packard series 1100 Column compartment • Hewlett Packard series 1100 G1315A DAD diode array detector • Hewlett Packard series 1100 MSD • Sedere 75 Evaporative Light Scattering detector The instrument is controlled by HP Chemstation software. The HPLC pump is connected to two eluent reservoirs containing: A: 0.01% TFA in water B: 0.01% TFA in acetonitrile The analysis is performed at 40°C by injecting an appropriate volume of the sample
  • the title compound was prepared from N-butyloxycarbonyl-7-methyl-indole (prepared as described by G. Bartoli, G. Palmieri, M. Bosco, R. Dalpozzo Tetrahedron Lett. 30, 2129-2132, (1989)) and 4-chlorobromobenzene as described in EXAMPLE B.
  • Step A The title compound was prepared from 2-chloro-3-formyl-indole 4- chlorophenylsulfonylacetonitrile in 35 % yield.
  • Step A The title compound was prepared from 2-chloro-3-formyl-indole and ethyl cyanoace- tic acid in 11 % yield.
  • Step A The title compound was prepared from 5-nitro-3-formyl-indole and methanesulfon- ylacetonitrile in 87 % yield.
  • Example 4 2-(4-Chloro-benzenesulfonyl)-3-(5-nitro-1 H-indol-3-yl)-acrylonitrile.
  • Step A The title compound was prepared from 5-nitro-3-formyl-indole and 4- chlorophenylsulfonylacetonitrile in 72 % yield.
  • Step A The title compound was prepared from 5-nitro-3-formyl-indole and 1-Methyl-1H- imidazole-2-sulfonylacetonitrile in 93 % yield.
  • Step A The title compound was prepared from 5-nitro-3-formyl-indole and thiophene-2- sulfonylacetonitrile in 90 % yield.
  • Step A The title compound was prepared from 5-nitro-3-formyl-indole and 4-chloro- phenylmethanesulfonylacetonitrile in 83 % yield.
  • Step A The title compound was prepared from 2-methyl-5-nitro-3-formyl-indole and 4- chlorophenylsulfonylacetonitrile in 50 % yield.
  • Step A The title compound was prepared from 2-methyl-5-nitro-3-formyl-indole and methanesulfonylacetonitrile in 85 % yield.
  • Example 10 3-(2-Phenyl-indol-3-yl)-4-chlorophenylsulphonylacrylonitrile Step A: The title compound was prepared from 2-phenyl-3-formyl-indole and 4- chlorophenylsulfonylacetonitrile in 92 % yield.
  • Step A The title compound was prepared from 2-phenyl-3-formyl-indole and 2-tert- butylcarbonylacetonitrile in 18 % yield.
  • Example 12 (General procedure (A)) 2-(4-Chloro-benzenesulfonyl)-3-[2-(4-chloro-phenyl)-1 H-indol-3-yl]-acrylonitrile Step A: The title compound was prepared from 2-(4-chlorophenyl)-3-formyl-indole and 4- chlorophenylsulfonylacetonitrile in 40 % yield.
  • Step A The title compound was prepared from 2-(4-chlorophenyl)-3-formyl-indole and ethyl cyanoacetic acid in 72 % yield.
  • Example 14 (General procedure (A)) 3-[2-(4-Chloro-phenyl)-1H-indol-3-yl]-2-(3,4-dichloro-benzoyl)-acrylonitrile Step A: The title compound was prepared from 2-(4-chlorophenyl)-3-formyl-indole and 3-(3,4- dichloro-phenyl)-3-oxo-propionitrile in 11 % yield.
  • Step A The title compound was prepared from 2-(4-nitrophenyl)-3-formyl-indole and ethyl cyanoacetic acid in 52 % yield.
  • Step A The title compound was prepared from 2-(4-trifluoromethylphenyl)-3-formyl-indole and ethyl cyanoacetic acid in 52 % yield.
  • Example 18 (General procedure (A)) 2-Cyano-3-(7-methyl-2-(4-chlorophenyl)-indol-3-yl)-propenoic acid ethylester Step A: The title compound was prepared from 2-(4-chlorophenyl)-3-formyl-7-methylindole and ethyl cyanoacetic acid in 44 % yield.
  • Step A The title compound was prepared from 2-biphenyl-3-yl-1 H-indole-3-carbaldehyde and 4-chlorophenylsulfonylacetonitrile in 28 % yield.
  • Step B The title compound was prepared from 2-(2-trifluoromethylphenyl)-1H-indole-3- carbaldehyde and 4-chlorophenylsulfonylacetonitrile in 56 % yield.
  • Step B The title compound was prepared from 2-phenylethynyl-1H-indole-3-carbaldehyde and 4-chlorophenylsulfonylacetonitrile in 39 % yield.
  • Example 22 (General procedure (A)) 2-(4-Chlorobenzenesulfonyl)-3-(2-(E)-styryl-1 H-indol-3-yl)acrylonitrile Step A: The title compound was prepared from (E) 2-styryl-1 H-indole-3-carbaldehyde and 4- chlorophenylsulfonylacetonitrile in 32 % yield.
  • Example 23 (General procedure (A)) 2-(4-Chlorobenzenesulfonyl)-3-[2-(5-chlorothiophen-2-yl)-1 H-indol-3-yl]acrylonitrile
  • Step A The title compound was prepared from 2-(5-chlorothiophen-2-yl)-1H-indole-3- carbaldehyde and 4-chlorophenylsulfonylacetonitrile in 46 % yield.
  • Example 24 (General procedure (A)) 3-[2-(4-Bromo-3-fluorophenyl)-1 H-indol-3-yl]-2-(4-chlorobenzenesulfonyl)acrylonitrile
  • Step A The title compound was prepared from 2-(4-bromo-3-fluorophenyl)-1 H-indole-3- carbaldehyde and 4-chlorophenylsulfonylacetonitrile in 25 % yield.
  • Step A The title compound was prepared from 2-(2-fluorobiphenyl-4-yl)-1 H-indole-3- carbaldehyde and 4-chlorophenylsulfonylacetonitrile in 36 % yield.
  • Example 27 (General procedure (A)) 4-[3-(2-Benzenesulfonyl-2-cyanovinyl)-1 H-indol-2-yl]benzonitrile Step A: The title compound was prepared from 4-(3-formyl-1 H-indol-2-yl)benzonitrile and benzenesulfonylacetonitrile in 50 % yield.
  • Example 28 (General procedure (A)) 4- ⁇ 3-[2-(4-Chlorobenzenesulfonyl)-2-cyanovinyl]-1H-indol-2-yl ⁇ benzonitrile
  • Step B The title compound was prepared from 4-(3-formyl-1 H-indol-2-yl)benzonitrile and 4-chlorophenylsulfonylacetonitrile in 37 % yield.
  • the assay measures indirectly the activity of the respiratory chain in FSK-4 cells by using D-(6- 3 H(N))-glucose.
  • the 3 H-proton will first be released in the TCA cyclus and trans- ported to the respiratory chain where it will be incorporated into water.
  • the water is thereafter separated from the D-(6- 3 H(N))-glucose by evaporation. Finally, the radioactivity in the water is determined using a Topcounter.
  • FSK-4 cells obtained from ATCC (Maryland, USA), are cultured in growth medium (McCoy ' s medium with the following addition 100 units/ml penicillin and streptomycin and 10 % FCS (fetal calf serum)) at 37°C and 5% C0 2 . All media are obtained by Gibco (Life Technologies, Maryland, USA) where not otherwise mentioned.
  • the cells are harvested using trypsin-EDTA and washed in assay medium (MEM medium with the following addition 1x non-essential amino acids (M7145, 2 mM glutamin, 100 units/ml pencillin and streptomycin, 0.0075% sodium bicarbonate, 1 mM so- dium pyrovate and 2 % horse serum) using centrifugation.
  • M7145 1x non-essential amino acids
  • the cells are plated into single StripPlates wells (Corning B.V.Life Sciences, The Netherlands) that are placed into 24-well plates (Corning B.V.Life Sciences, The Netherlands) with a concentration of 1 ,5x10 4 cells/100 ⁇ l assay medium/well.
  • the cells are then incubated at 37°C and 5% C0 2 overnight.
  • the compounds to be tested are diluted to different concentrations in
  • DMSO dimethyl methoxysulfoxide
  • assay medium containing 10 ⁇ Ci/ml D-(6- 3 H(N))-glucose (PerkinElmer Life Sciences Inc., Boston, USA).
  • the medium is removed from the cells and 200 ⁇ l of the compound dilutions are added in duplicates.
  • the cells are then incubated for another 24 hours at 37°C and 5% C0 2 .
  • the cells are lysed by adding 50 ⁇ l 10% TCA (tri- chloroacetate). 300 ⁇ l of sterile water is then added to the 24-wells that surrounds the Strip- Plate wells.
  • the plate is sealed with Top-seal-tape (Packard, PerkinElmer Life Sciences Inc., Boston, USA) and the plate is incubated in a heating cupboard at 50°C to equilibrium the radioactive water formed in the respiratory chain into the water in the 24-well plate by evapo- rate.
  • the plates incubate for 8 hours where the heating cupboard is turned off.
  • the top seal is removed when the samples have reached room temperature.
  • One ml scintillation liquid (Packard Microscient, PerkinElmer Life Sciences Inc., Boston, USA) is added to all the samples and the radioactivity is determined using a Topcounter (Packard, PerkinElmer Life Sciences Inc., Boston, USA).
  • Non-specific activity is determined by evaporating 200 ⁇ l of the di- lution medium containing the D-(6- 3 H(N))-glucose into 300 ⁇ l sterile water, and total radioactivity is determined by counting 5 ⁇ l assay medium with 10 ⁇ Ci/ml D-(6- 3 H(N))-glucose.
  • the half maximal concentration (EC 50 ) and maximal efficacy (E maX) are calculated using the Hill equation in GraphPad Prism 3.0 (GraphPad software, Inc.). In studies where the linear slope is determined the following concentration of the compound is used; 5x, 3x, 2x, 1 ,5x, 1 ,25x, 1x, 0.85x, 0.7x, 0.5x, 0.3x, 0.2x and Ox EC 50 . From the percentage increase in glucose utilisation the linear slope is calculated using the Michaelis-Menten equation.
  • rotenone an inhibitor of clomplex 1

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Abstract

Les dérivés 3-vinylsulfonyl indoles de formule (I) sont des agents découplants utiles, par exemple, pour le traitement de l'obésité.
PCT/DK2004/000303 2003-11-25 2004-05-04 Nouveaux derives d'indole a utiliser comme agents decouplants chimiques WO2005051908A1 (fr)

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US11/440,935 US20070010559A1 (en) 2003-11-25 2006-05-25 Indole derivatives for use as chemical uncoupler

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WO2005105785A3 (fr) * 2004-05-04 2006-01-19 Novo Nordisk As Nouveaux derives d'indole
US9034849B2 (en) 2010-02-03 2015-05-19 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
US9108989B2 (en) 2006-10-10 2015-08-18 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005105785A3 (fr) * 2004-05-04 2006-01-19 Novo Nordisk As Nouveaux derives d'indole
US9108989B2 (en) 2006-10-10 2015-08-18 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9034849B2 (en) 2010-02-03 2015-05-19 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
US9951089B2 (en) 2010-02-03 2018-04-24 Infinity Pharmaceuticals, Inc. Methods of treating a fatty acid amide hydrolase-mediated condition

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