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WO2000023417A1 - Nouveaux composes, leur preparation et leur utilisation - Google Patents

Nouveaux composes, leur preparation et leur utilisation Download PDF

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Publication number
WO2000023417A1
WO2000023417A1 PCT/DK1999/000574 DK9900574W WO0023417A1 WO 2000023417 A1 WO2000023417 A1 WO 2000023417A1 DK 9900574 W DK9900574 W DK 9900574W WO 0023417 A1 WO0023417 A1 WO 0023417A1
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Prior art keywords
ethoxy
phenyl
dibenzo
cyclohepten
propionic acid
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PCT/DK1999/000574
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English (en)
Inventor
Lone Jeppesen
Paul Stanley Bury
Per Sauerberg
Original Assignee
Novo Nordisk A/S
Dr. Reddy's Research Foundation
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Publication date
Application filed by Novo Nordisk A/S, Dr. Reddy's Research Foundation filed Critical Novo Nordisk A/S
Priority to EP99950504A priority Critical patent/EP1123269A1/fr
Priority to JP2000577145A priority patent/JP2002527503A/ja
Priority to AU63258/99A priority patent/AU6325899A/en
Publication of WO2000023417A1 publication Critical patent/WO2000023417A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/12—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing them, methods for preparing the compounds and their use as medicaments. More specifically, compounds of the invention can be utilised in the treatment of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
  • PPAR Peroxisome Proliferator-Activated Receptors
  • the present compounds reduce blood glucose and triglyceride levels and are accordingly useful for the treatment of ailments and disorders such as diabetes and obesity.
  • the present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the compounds are useful for the treatment and/or prophylaxis of insulin resistance (type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hyperglycaemia, atherosclerosis, hyperlipide- mia, coronary artery disease and other cardiovascular disorders.
  • the compounds of the present invention are also useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis. These compounds may also be useful for improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) and prevention and treatment of bone loss, e.g. osteoporosis.
  • PCOS polycystic ovarian syndrome
  • Coronary artery disease is the major cause of death in type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the 'deadly quartet' category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity ).
  • the hypoiipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in type 2 diabetic or metabolic syndrome patients.
  • the thiazolidinediones also potently lower circulating glucose levels of type 2 diabetic animal models and humans.
  • the fibrate class of compounds are without beneficial effects on glycaemia.
  • thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key-players in regulation of plasma triglyceride content.
  • Fibrates on the one hand, are PPAR ⁇ activators, acting primarily in the liver.
  • Thiazolidinediones on the other hand, are high affinity ligands for PPAR ⁇ acting primarily on adipose tissue.
  • Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates.
  • Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation.
  • white adipose tissue is the result of a continuous differentiation process throughout life.
  • Much evidence points to the central role of PPAR ⁇ activation in initiating and regulating this cell differentiation.
  • Several highly specialised proteins are induced during adipocyte differentiation, most of them being involved in lipid storage and metabolism. The exact link from activation of PPAR ⁇ to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified.
  • a possible link is via free fatty acids such that activation of PPAR ⁇ induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue.
  • LPL Lipoprotein Lipase
  • FATP Fatty Acid Transport Protein
  • ACS Acyl-CoA Synthetase
  • PPAR ⁇ is involved in stimulating ⁇ -oxidation of fatty acids.
  • a PPAR ⁇ -mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents.
  • the phenomenon of peroxisome proliferation is not seen in man.
  • PPAR ⁇ is also involved in the control of HDL cholesterol levels in rodents and humans. This effect is, at least partially, based on a PPAR ⁇ -mediated transcriptional regulation of the major HDL apolipoproteins, apo A-l and apo A-ll.
  • the hypotriglyceridemic action of fibrates and fatty acids also involves PPAR ⁇ and can be summarised as follows: (I) an increased lipoiysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-lll levels, (II) a stimulation of cellular fatty acid uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (III) an induction of fatty acid b-oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production.
  • both enhanced catabolism of triglyceride- ch particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
  • the present invention relates to compounds of the general formula (la):
  • R 1 , R 2 , R 3 , and R 4 independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, or C ⁇ alkyl, C ⁇ -alkenynyl, C 2 . 12 -alkenyl, C 2 . 12 -alkynyl, C 1-12 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC,.
  • R 11 and R 12 independently of each other are selected from hydroxy, halogen, perhalomethyl, C 1-6 alkoxy or amino optionally substituted with one or more C h alky!, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 may form a cyclic ring containing from 5 to 7 carbon atoms optionally substituted with one or more C 6 alkyl;
  • ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, or C ⁇ alkyl, C 4-12 - alkenynyl, C 2 . 12 -alkenyl, C 2 .
  • Z is -CH 2 -, -O-, -S-, >SO 2 ⁇ , >NR 15 , wherein R 15 is hydrogen, halogen, hydroxy, nitro, cyano, formyl, C ⁇ zaikyl, C 1-12 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, C ⁇ zalkyl-amino, arylamino, aralkylamino, aminoC ⁇ alkyl, C,_ 12 alkoxycarbonyl, aryloxycarbonyl, araikoxycarbonyl, C 1 .
  • Q is -O-, -S-, >NR 18 wherein R 18 is hydrogen or C ⁇ alkyl
  • Ar represents arylene, heteroarylene, or a divalent heterocyclic group optionally substituted with one or more C 1-6 alkyl or aryl;
  • R 5 represents hydrogen, hydroxy, halogen, d. 12 alkoxy, C 1-12 alkyl, C ⁇ -alkenynyl, C 2 . 12 - aikenyl, C 2 . 12 -alkynyl or aralkyl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 5 forms a bond together with R 6 , R 6 represents hydrogen, hydroxy, halogen, C 1-12 alkoxy, d. 12 alkyl, C 4 .
  • R 6 forms a bond together with R 5 , R 7 represents hydrogen, d. 12 alkyl, C 4 . 12 -alkenynyl, C 2 . 12 -aikenyl, C 2 . 12 -alkynyl, aryl, aralkyl, d_ 12 alkoxyd. 12 aikyl, C 1-12 alkoxycarbonyl, aryloxycarbonyl, d.
  • R 8 represents hydrogen, d. 12 alkyl, d. 12 -alkenynyl, C 2 . 12 -aikenyl, C 2 . 12 -alkynyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;
  • Y represents oxygen, sulphur or NR 10 , where R 10 represents hydrogen, C 1-12 alkyl, aryl, hy- droxyd.
  • R 8 and R 10 may form a 5 or 6 membered nitrogen containing ring, optionally substituted with one or more d. 6 alkyl; n is an integer ranging from 1 to 4; or a pharmaceutically acceptable salt thereof.
  • the present invention is concerned with compounds of formula I wherein R 1 , R 2 , R 3 , and R 4 independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, d. 7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC,.
  • R 11 and R 2 independently of each other are selected from hydroxy, perhalomethyl, C 1-6 alkoxy or amino optionally substituted with one or more C 1- ⁇ alkyl, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano; or R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 may form a cyclic ring containing from 5 to 7 carbon atoms optionally substituted with one or more C 1-6 alkyl.
  • the present invention is concerned with compounds of formula I wherein R ⁇ R 2 , R 3 , and R 4 independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, cyano, or C 1 . 7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, d- 7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, hydroxyC 1-7 alkyl, amino, acylamino, d.
  • the present invention is concerned with compounds of formula I wherein R 1 , R 2 , R 3 , and R 4 independently of each other represent hydrogen, halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, d. 7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, hydroxyd. 7 alkyl, amino, d_ 7 alkyl-amino, arylamino, aralkylamino, d. 7 alkoxyd. 7 alkyl, aryloxyC,. 7 alkyl, aralkoxyC 1-7 alky or C 1-7 alkylthio.
  • the present invention is concerned with compounds of formula I wherein R ⁇ R 2 , R 3 , and R 4 independently of each other represent hydrogen, halogen, perhalomethyl, or C 1 . 7 alkyl, C ⁇ -alkenynyl, C 2 . 7 -aikenyl, C 2-7 -alkynyl, aryl, aralkyl, hy- droxyC 1-7 alkyl, C ⁇ alkoxyC ⁇ alkyl, aryloxyC 1-7 alkyl or aralkoxyC 1-7 alkyl.
  • the present invention is concerned with compounds of formula I wherein R ⁇ R 2 , R 3 , and R 4 independently of each other represent hydrogen, halogen or C,. 7 alkyl.
  • the present invention is concerned with compounds of formula I wherein R ⁇ R 2 , R 3 , and R 4 independently of each other represent hydrogen, chlorine or methyl.
  • the present invention is concerned with compounds of formula I wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano or C 1-7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 .
  • R 11 and R 2 independently of each other are selected from hydroxy, perhalomethyl, C 1-6 alkoxy or amino optionally substituted with one or more d. 6 alkyl, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy or cyano.
  • the present invention is concerned with compounds of formula I wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, hydroxyd. 7 alkyl, amino, acylamino, d.
  • the present invention is concerned with compounds of formula I wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano, or C 1-7 alkyl, d. 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, d. 7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, hydroxyd. 7 alkyl, amino, C 1-7 alkyl-amino, arylamino, aralkylamino, d. 7 alkoxyC 1-7 alkyl, aryloxyC 1 . 7 alkyl, aralkoxyC 1-7 alkyl or C 1-7 alkylthio.
  • the present invention is concerned with compounds of formula I wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl or d. 7 alkyl, d. 7 - alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, d. 7 alkoxy, aryl, aralkyl, hydroxyC 1-7 alkyl, d- 7 alkoxyC 1-7 alkyl, aryloxyd. 7 alkyl or aralkoxyd. 7 alkyl.
  • the present invention is concerned with compounds of formula I wherein ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more chlorine or methyl groups.
  • the present invention is concerned with compounds of formula I wherein X is a valence bond, -(CHR 9 )-, -(CHR 9 )-CH 2 -, -
  • the present invention is concerned with compounds of formula I wherein X is a valence bond, -(CHR 9 )-, -(CHR 9 )-CH 2 -, -
  • the present invention is concerned with compounds of formula I wherein Z is -CH 2 -, -O-, -S-, , >NR 15 , wherein R 15 is hydrogen, d. 12 alkyl, C,. 7 alkoxy, aralkyl, aralkoxy, hydroxyalkyl, aminod. 7 aikyl, d- 12 alkoxyd. 7 alkyl, aryloxyd. 7 alkyl or aralkoxyC 1-7 alkyl.
  • the present invention is concerned with compounds of formula I wherein Z is -CH 2 -, -0-, -S- or >NR 15 , wherein R 15 is hydrogen.
  • the present invention is concerned with compounds of formula I wherein Z is -0-.
  • the present invention is concerned with compounds of formula I wherein Q is -O-, -S- or >NR 18 wherein R 18 is hydrogen or methyl.
  • the present invention is concerned with compounds of formula I wherein Q is -O- or >NR 18 wherein R 18 is methyl.
  • the present invention is concerned with compounds of formula I wherein Ar represents arylene optionally substituted with one or more d. 6 alkyl or aryl.
  • the present invention is concerned with compounds of formula I wherein Ar represents phenyl.
  • the present invention is concerned with compounds of formula I wherein R 5 represents hydrogen, hydroxy, halogen, C 1-7 alkoxy, C 1-7 alkyl, C 4 . 7 - alkenynyl, C 2-7 -alkenyl, C 2 . 7 -alkynyl or aralkyl, or R 5 forms a bond together with R 6 .
  • the present invention is concerned with compounds of formula I wherein R 5 represents hydrogen or R 5 forms a bond together with R 6 .
  • the present invention is concerned with compounds of formula I wherein R 5 represents hydrogen, hydroxy, halogen, C 1-7 alkoxy, C 1-7 alkyl, C 4 . 7 - alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl or aralkyl, or R 5 forms a bond together with R 6 .
  • the present invention is concerned with compounds of formula I wherein R 5 represents hydrogen or R 5 forms a bond together with R 6 .
  • the present invention is concerned with compounds of formula I wherein R 7 represents hydrogen, d. 7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2-7 -alkynyl, aryl, aralkyl, C ⁇ alkoxyd ⁇ alkyl, d. 7 alkoxycarbonyl, aryloxycarbonyl, d. 7 alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups.
  • the present invention is concerned with compounds of formula I wherein R 7 represents hydrogen, C 1 . 7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl or C 2 . 7 - alkynyl.
  • the present invention is concerned with compounds of formula I wherein R 7 represents d. 2 alkyl.
  • the present invention is concerned with compounds of formula I wherein R 8 represents hydrogen, C 1-7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano.
  • the present invention is concerned with compounds of formula I wherein R 8 represents hydrogen, C 1-7 alkyl, C 4 . 7 -alkenynyi, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, aryl or aralkyl.
  • the present invention is concerned with compounds of formula I wherein R 8 represents hydrogen or C 1-2 alkyl.
  • the present invention is concerned with compounds of formula I wherein Y represents oxygen, sulphur or NR 10 , where R 10 represents hydrogen, d_ 7 alkyl, aryl, hydroxyC 1 . 7 aikyl or aralkyl groups.
  • the present invention is concerned with compounds of formula I wherein Y represents oxygen.
  • the present invention is concerned with compounds of formula I wherein n is an integer ranging from 2 to 3.
  • the present invention is concerned with compounds of formula I wherein A is benzo.
  • the present invention is concerned with compounds of formula I wherein A is a five membered ring containing S.
  • the present invention is concerned with compounds of formula I wherein X is -(CHR 9 )-CH 2 -, wherein R 9 is H.
  • the present invention is concerned with compounds of formula I wherein X is -O-(CHR 9 )-, wherein R 9 is H.
  • the present invention is concerned with compounds of formula I wherein X is -S-(CHR 9 )-, wherein R 9 is H.
  • the present invention is concerned with compounds of formula I wherein X is -O-CH 2 -O-.
  • the present invention is concerned with compounds of formula I wherein Q is -O-.
  • the present invention is concerned with compounds of formula I wherein Q is -S-.
  • the present invention is concerned with compounds of formula I wherein Q is >NR 18 , wherein R 18 is C 1-6 -alkyl, preferably methyl. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein Z is -O-.
  • the present invention is concerned with compounds of formula I wherein n is 2.
  • the present invention is concerned with compounds of formula I wherein Q is -O-.
  • the present invention is concerned with compounds of formula I wherein Ar is phenylene.
  • the present invention is concerned with compounds of formula I wherein R 5 is H.
  • the present invention is concerned with compounds of formula I wherein R 6 is H.
  • the present invention is concerned with compounds of formula I wherein R 7 is ethyl.
  • the present invention is concerned with compounds of formula I wherein R 8 is H.
  • Preferred compounds of the invention are:
  • d. 12 -alkyr as used herein, alone or in combination is intended to include those al- kyl groups of the designated length in either a linear or branched or cyclic configuration, represents e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like. Typical d.
  • 6 -alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like.
  • C 2 . n .-alkenyl wherein n' can be from 3 through 15, as used herein, represents an oiefinically unsaturated branched or straight group having from 2 to the specified number of carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-proppenyl, 1 ,3-butadienyl, 1-butenyl, hex- enyl, pentenyl, and the like.
  • C 2 . n -alkynyl wherein n' can be from 3 through 15, as used herein, represent an unsaturated branched or straight group having from 2 to the specified number of carbon at- oms and at least one triple bond.
  • groups include, but are not limited to, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
  • C 4 . ⁇ .-alkenynyl wherein n' can be from 5 through 15, as used herein, represent an unsaturated branched or straight hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne, 1 ,3- hexadiene-5-yne and the like.
  • C 1-12 -alkoxy as used herein, alone or in combination is intended to include those d_ 12 -alkyl groups of the designated length in either a linear or branched or cyclic configuration linked thorugh an ether oxygen having its free valence bond from the ether oxygen.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • branched alkoxy are isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • C ⁇ -alkoxycarbonyloxy is intended to include the above defined C ⁇ -alkoxy groups attached to a carbonyloxy moiety, eg. ethoxycarbonyloxy, ethoxycarbonyloxy, etc..
  • C 4 . 12 -(cycloalkylalkyl) represents a branched or straight alkyl group substituted at a carbon with a cycloalkyl group.
  • examples of such groups include, but are not limited to, cyclopropylethyl, cyclobutylmethyl, 2-(cyclohexyl)ethyl, cyclohexylmethyl, 3- (cyclopentyl)-l-propyl, and the like.
  • d. 12 -alkylthio refers to a straight or branched or cyclic monovalent substituent comprising a C 1-12 -alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 12 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio.
  • cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio and cyclohexylthio.
  • d. 12 alkylamino refers to a straight or branched or cyclic monovalent substituent comprising a C 1-12 -alkyl group linked through amino having a free valence bond from the nitrogen atom e.g. methylamino, ethylamino, propylamino, butylamino, pentylamino.
  • cyclic alkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino.
  • hydroxyC 1 . 12 alkyl refers to a C 1-12 alkyl as defined herein whereto is attached a hydroxy group, e.g. hydroxyethyl, 1-hydroxypropyl, 2- hydroxypropyl etc..
  • arylamino refers to an aryl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. phenylamino, naphthylamino, etc..
  • aralkylamino refers to an aralkyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. benzylamino, phenethylamino, 3-phenylpropylamino, 1-naphtylmethylamino, 2-(1- naphtyl)ethylamino and the like.
  • aminod. ⁇ alkyl refers to a C 1-12 alkyl as defined herein whereto is attached an amino group, e.g. aminoethyl, 1-aminopropyl, 2- aminopropyl etc..
  • aryloxycarbonyl refers to an aryloxy as defined herein linked through a carbonyl having a free valence bond from the carbon atom, e.g. phenoxycarbonyl, 1-naphthyloxycarbonyl or 2-naphthyloxycarbonyl, etc..
  • araikoxycarbonyl refers to an aralkoxy as defined herein linked through a carbonyl having a free valence bond from the carbon atom, e.g. benzyioxycarbonyl, phenethoxycarbonyl, 3-phenylpropoxycarbonyl, 1- naphthylmethoxycarbonyl, 2-(1-naphtyl)ethoxycarbonyl, etc..
  • d. ⁇ alkoxyd. ⁇ alkyl refers to a C 1-12 alkyl as defined herein whereto is attached a C 1-12 alkoxy as defined herein, e.g. methoxy methyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc..
  • aryloxyd. 12 alkyl refers to a C 1-12 alkyl as defined herein whereto is attached an aryloxy as defined herein, e.g. phenoxymethyl, phenoxydodecyl, 1-naphthyloxyethyl, 2-naphthyloxypropyl, etc..
  • aralkoxyd. 12 alkyl refers to a C 1-12 alkyl as defined herein whereto is attached an aralkoxy as defined herein, e.g. benzyloxymethyl, phenethoxydodecyl, 3-phenylpropoxyethyl, 1-naphthylmethoxypropyl, 2-(1- naphtyl)ethoxymethyl, etc..
  • thiod. 12 alkyl refers to a C 1-12 alkyl as defined herein whereto is attached a group of formula -SR'" wherein R'" is hydrogen, C,. 6 alkyl or aryl, e.g. thiomethyl, methylthiomethyl, phenylthioethyl, etc..
  • d. 12 alkoxycarbonylamino refers to a d- 12 alkoxycarbonyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. methoxycarbonylamino, carbethoxyamino, propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonyiamino, etc.
  • aryloxycarbonylamino refers to an aryloxycarbonyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. phenoxycarbonylamino, 1-naphthyloxycarbonylamino or 2- naphthyloxycarbonylamino, etc..
  • aralkoxycarbonylamino refers to an araikoxycarbonyl as defined herein linked through amino having a free valence bond from the nitrogen atom e.g. benzyloxycarbonylamino, phenethoxycarbonylamino, 3- phenylpropoxycarbonylamino, 1 -naphthylmethoxycarbonylamino, 2-( 1 - naphtyl)ethoxycarbonylamino, etc..
  • aryl is intended to include aromatic rings, such as carboxylic aromatic rings selected from the group consisting of phenyl, naphthyl, (1-naphtyl or 2-naphtyl) optionally substituted with halogen, amino, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy.
  • arylene is intended to include divalent aromatic rings, such as carboxylic aromatic rings selected from the group consisting of phenylene, naphthylene, optionally substituted with halogen, amino, hydroxy, C 1-6 -alkyl or C 1-6 -alkoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • C 1-6 -dialkylamino refers to an amino group wherein the two hydrogen atoms independently are substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms; such as dimethylamino, N- ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n- pentyl)amino, and the like.
  • acyl refers to a monovalent substituent comprising a C 1-6 -alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, and the like.
  • acyloxy refers to acyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, and the like.
  • d. 12 -alkoxycarbonyr refers to a monovalent substituent comprising a d. 12 -alkoxy group linked through a carbonyl group; such as e.g. methoxycarbonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
  • a cyclic ring containing from 5 to 7 carbon atoms refers to a monocyclic saturated or unsaturated or aromatic system, wherein the ring may be cyclopentyl, cyclopentenyl, cyclohexyl, phenyl or cycloheptyl.
  • the term "bicycioalkyl” as used herein refers to a monovalent substituent comprising a bicyclic structure made of 6-12 carbon atoms such as e.g. 2-norbornyl, 7-norbornyl, 2- bicyclo[2.2.2]octyl and 9-bicyclo[3.3.1]nonanyl.
  • heteroaryl refers to a monovalent substituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
  • heteroarylene refers to a divalent group comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
  • heteroaryloxy refers to a heteroaryl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom e.g. pyrrole, imidazole, pyrazoie, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine linked to oxygen.
  • oxygen atom e.g. pyrrole, imidazole, pyrazoie, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, qui
  • aralkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy or 2-naphthyioxy.
  • aralkoxy refers to a C 1-6 -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1- naphtyl)ethoxy and the like.
  • heteroarylkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2- furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl- 1-(2-pyrimidyl)ethyl and the like.
  • heteroaralkoxy refers to a heteroaralkyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2- pyrimidyl)ethyl linked to oxygen.
  • d ⁇ -alkylsuifonyl refers to a monovalent substituent comprising a C 1-6 -alkyl group linked through a sulfonyl group such as e.g. methyfsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert- butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl and 2,2-
  • C 1 . 6 -monoalkylaminosulfonyl refers to a monovalent substituent comprising a d. 6 -monoalkylamino group linked through a sulfonyl group such as e.g.
  • methylaminosulfonyl methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n- butylaminosulfonyl, sec-butylaminosulfonyi, isobutylaminosulfonyl, tert-butylaminosulfonyl, n- pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl, n- hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopentylaminosulfonyl, n- hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
  • d.e-dialkylaminosulfonyl refers to a monovalent substituent comprising a d. 6 -dialkylamino group linked through a sulfonyl group such as dimethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, N-(n-butyl)-N-methylaminosulfonyi, di(n-pentyl)aminosulfonyl, and the like.
  • acylamino refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group, such as e.g. acetamido, propionamido, isopropylcar- bonylamino, and the like.
  • (C 3 ⁇ -cycloalkyl)C 1 . 6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubsti- tuted with a C ⁇ -cycloalkyl group, the cycloalkyl group optionally being mono- or polysubsti- tuted with C 1-6 -alkyl, halogen, hydroxy or C ⁇ -alkoxy; such as e.g. cyclopropylmethyl, (1- methylcyclopropyl)methyl, 1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • arylthio refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio, and the like.
  • arylsulfonyl refers to an aryl group linked through a sulfonyl group, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C,. 6 -alkoxy; such as e.g. phenylsulfonyl, tosyl, and the like.
  • C 1 _ 6 -monoalkylaminocarbonyl refers to a monovalent substituent comprising a C ⁇ -monoalkylamino group linked through a carbonyl group such as e.g.
  • C ⁇ -dialkylaminocarbonyl refers to a monovalent substituent com- prising a C ⁇ -dialkylamino group linked through a carbonyl group such as dimethylaminocar- bonyl, N-ethyl-N-methylaminocarbonyi, diethylaminocarbonyl, dipropylaminocarbonyl, N-(n- butyl)-N-methylaminocarbonyl, di(n-pentyl)aminocarbonyl, and the like.
  • C ⁇ -monoalkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a C 1-6 -monoalkylaminocarbonyl group, e.g. methylaminocarbonylamino, ethylamino-carbonylamino, n-propylaminocarbonylamino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec-butylaminocarbonylamino, isobutylaminocarbonyiamino, tert-butylaminocarbonylamino, and 2- methylbutylaminocarbonylamino,
  • C ⁇ -dialkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a C ⁇ -dialkylaminocarbonyl group, such as di- methylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethylaminocarbony- lamino, dipropylaminocarbonylamino, N-(n-butyl)-N-methylaminocarbonylamino, di(n- pentyl)aminocarbonylamino, and the like.
  • heterocyclyl means a monovalent saturated or unsaturated group being monocyclic and containing one or more, such as from one to four carbon atom(s), and from one to four N, O or S atom(s) or a combination thereof.
  • heterocyclyl includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline); 5-membered heterocycles having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g.
  • pyrazoline pyrazolidine, 1 ,2-oxathiolane, imidazolidine, imidazoline, 4- oxazolone
  • 5-membered heterocycles having three heteroatoms e.g. tetrahydrofurazan
  • 5- membered heterocycles having four heteroatoms 6-membered heterocycles with one het- eroatom (e.g. piperidine); 6-membered heterocycles with two heteroatoms (e.g. piperazine, morpholine); 6-membered heterocycles with three heteroatoms; and 6-membered heterocycles with four heteroatoms.
  • a divalent heterocyclic group means a divalent saturated or unsaturated system being monocyclic and containing one or more, such as from one to four carbon atom(s), and one to four N, O or S atom(s) or a combination thereof.
  • the phrase a divalent heterocyclic group includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline); 5-membered heterocycles having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g.
  • pyrazoline pyrazolidine, 1 ,2-oxathiolane, imidazolidine, imi- dazoline, 4-oxazolone
  • 5-membered heterocycles having three heteroatoms e.g. tetrahy- drofurazan
  • 5-membered heterocycles having four heteroatoms 6-membered heterocycles with one heteroatom (e.g. piperidine); 6-membered heterocycles with two heteroatoms (e.g. piperazine, morpholine); 6-membered heterocycles with three heteroatoms; and 6- membered heterocycles with four heteroatoms.
  • a 5-6 membered cyclic ring means an unsaturated or saturated or aromatic system containing one or more carbon atoms and optionally from one to four N, O or S atom(s) or a combination thereof.
  • the phrase “a 5-6 membered cyclic ring” includes, but is not limited to, e.g.
  • cyclopentyl cyclohexyl, phenyl, cyclohexenyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1 ,3-dioxolanyl, 1 ,4-dioxolanyl, 5-membered heterocycles having one hetero atom (e.g.
  • 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines
  • 5-membered heterocycles having three heteroatoms e.g. triazoles, thiadiazoles
  • 5-membered heterocycles having four heteroatoms 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthridine, cyclohepta[b]pyridine); 6-membered heterocycles with two heteroatoms (e.g.
  • pyridazines cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines, morpholines
  • 6-membered heterocycles with three heteroatoms e.g. 1 ,3,5- triazine
  • 6-membered heterocycles with four heteroatoms e.g.
  • 5- or 6-membered nitrogen containing ring refers to a monovalent substituent comprising a monocyclic unsaturated or saturated or aromatic system containing one or more carbon, nitrogen, oxygen or sulfur atoms or a combination thereof and having 5 or 6 members, e.g.
  • pyrrolidinyl pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyi, morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1 ,3-dioxolanyl and 1 ,4-dioxolanyl.
  • Pharmaceutically acceptable salts forming part of this invention include salts of the carboxylic acid moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanola- mine, choline and the like, ammonium or substituted ammonium salts, aluminum salts.
  • alkali metal salts like Li, Na, and K salts
  • alkaline earth metal salts like Ca and Mg salts
  • salts of organic bases such as lysine, arginine, guanidine, diethanola- mine, choline and the like
  • ammonium or substituted ammonium salts aluminum salts.
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succi- nates, palmoates, methanesulplionates, benzoates, salicylates, hydroxynaphthoates, ben- zenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceuti- cally acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (la) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents lilke ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanoiamine, choline, guandine and their derivatives etc. may also be used.
  • acid addition salts whereever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascor
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the pre- ferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • the compound of formula (la) may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the dia- stereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (la) may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of compound of general formula (la) forming part of this invention may be prepared by crystallization of compound of formula (la) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calo- rimetry, powder X-ray diffraction or such other techniques.
  • the invention also relate to methods of preparing the above mentioned compounds, comprising:
  • L is a leaving group such as halogen, p-toluenesulfonate, methanesulfonate and the like and wherein n, Z, Ar, R 5 -R 8 are defined as above except that R 8 is not H, to obtain a compound of formula (la) wherein n, Z, Ar, R 1 -R 8 , A, X and Q are defined as above except that R 8 is not H.
  • Z, Ar and R 5 -R 8 are defined as above except that R 8 is not H, by using suitable coupling agents such as dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD (Diethylazodicarboxylate) and the like, to obtain a compound of formula (la), wherein n, Ar, R 1 -R 8 , A, X, Z and Q are defined as above except that R 8 is not H, and Z is not e.
  • suitable coupling agents such as dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD (Diethylazodicarboxylate) and the like, to obtain a compound of formula (la), wherein n, Ar, R 1 -R 8 , A, X, Z and Q are defined as above except that R 8 is not H, and Z is not e.
  • L is a leaving group such as halogen, p-toluenesulfonate, methanesulfonate and the like and wherein R 1 -R 4 , A, X , Q and n are defined as above, with an compound of formula V
  • R -R 4 , A, X , Q, Z, Ar, and n are defined as above, with an compound of formula VIII
  • R 6 -R 8 are defined as above except that R 8 is not H, to obtain the ⁇ -hydroxy aldol product, which may be dehydroxylated or dehydrated to obtain a compound of formula (la) wherein n, Ar, R 1 -R 8 , A, X, Z and Q are defined as above except that R 8 is not H.
  • R 7 and R 8 are defined as above except that R 8 is not H, and wherein R 11 is a lower alkyl group to obtain a compound of formula (la) wherein n, Ar, R 1 -R 4 , R 7 - R 8 , A, X, Z and Q are defined as above except that R 8 is not H and wherein R 5 forms a bond together with R 6 . f) hydrogenation of a compound of formula X
  • n, Ar, R 1 -R 4 , R 7 -R 8 , A, X , Z and Q are defined as above except that R 8 is not H, to obtain a compound of formula (la) wherein n, Ar, R 1 -R 4 , R 7 - R 8 , A, X, Z and Q are defined as above except that R 8 is not H and wherein R 5 and R 6 is hydrogen.
  • L is a leaving group such as halogen and R 1 -R 8 , A, X , Q, Z and n are defined as above except that R 8 is not H, with an alcohol of formula XII
  • R 7 is defined as above, to obtain a compound of formula (la) wherein n, Ar, R 1 -R 8 , R 7 , A, X, Z and Q is defined as above except that R 8 is not H.
  • n, Ar, R 1 -R 6 , A, X, Z and Q is defined as above and wherein R 8 is defined as above except that R 8 is not H, with a compound of formula XIV
  • Hal— R 7 XIV wherein R 7 is defined as above and wherein "Hal” represents Cl, Br, or I to obtain a compound of formula (la) wherein n, Ar, R 1 - R 8 , A, X , Z and Q is defined as above except that R 8 is not H.
  • L is a leaving group such as halogen, p-toluenesulfonate, methanesulfonate and the like and wherein R 1 -R 4 , A, X , Q and n are defined as above, with a nucleophilic compound of formula XV
  • Metal is a metal such as zinc or copper, carrying suitable ligands chosen preferentially from trifluoro-methanesulfonate, halide or C r C 6 alkyl, to obtain a compound of formula (la) wherein n, Ar, R 1 -R 8 , R 7 , A, X and Q is defined as above except that R 8 is not H, and Z is C.
  • n, Ar, R 1 -R 8 , A, X , Z and Q is defined as above except that R 8 is not H, to obtain a compound of formula (la) wherein n, Ar, R 1 -R 7 , A, X, Z and Q is defined as above and wherein R 8 is H.
  • the starting materials are commercially available or readily prepared by methods familiar to those skilled in the art.
  • the PPAR gene transcription activation assays were based on transient transfection into human HEK293 cells of two piasmids encoding a chimeric test protein and a reporter protein respectively.
  • the chimeric test protein was a fusion of the DNA binding domain (DBD) from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR proteins.
  • the GAL4 DBD will force the fusion protein to bind only to Gal4 enhancers (of which none existed in HEK293 cells).
  • the reporter plasmid contained a Gal4 enhancer driving the expression of the firefly luciferase protein.
  • HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein.
  • the fusion protein will in turn bind to the Gal4 enhancer controlling the luciferase expression, and do nothing in the absence of ligand.
  • luciferase protein Upon addition to the cells of a PPAR ligand, luciferase protein will be produced in amounts corresponding to the activation of the PPAR protein. The amount of luciferase protein is measured by light emission after addition of the appropriate substrate.
  • HEK293 cells were grown in DMEM + 10% FCS, 1% PS. Cells were seeded in 96-well plates the day before transfection to give a confluency of 80 % at transfection. 0,8 ⁇ g DNA per well was transfected using FuGene transfection reagent according to the manufacturers instructions (Boehringer-Mannheim). Cells were allowed to express protein for 48 h followed by addition of compound.
  • Plasmids Human PPAR ⁇ and ⁇ was obtained by PCR amplification using cDNA templates from liver, intestine and adipose tissue respectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. The LBD from each isoform PPAR was generated by PCR (PPAR ⁇ : aa 167 - C-term; PPAR ⁇ : aa 165 - C-term) and fused to GAL4-DBD by subcloning fragments in frame into the vector pM1 generating the plasmids pMl ⁇ LBD and pMl ⁇ LBD. Ensuing fusions were verified by sequencing. The reporter was constructed by inserting an oligonucleotide encoding five repeats of the Gal4 recognition sequence into the pGL2 vector (Promega).
  • Luciferase assay Medium including test compound was aspirated and 100 ⁇ l PBS incl. 1 mM Mg++ and Ca++ was added to each well. The luciferase assay was performed using the Lu- cLite kit according to the manufacturers instructions (Packard Instruments). Light emission was quantified by counting SPC mode on a Packard Instruments top-counter. PHARMACEUTICAL COMPOSITIONS
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula (la) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of formula (la) or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryi monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transder- mal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula (la) dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxyiated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain: Core:
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar.
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non- domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg of the compounds of formula (la) admixed with a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to a method of treating and/or preventing type I or type II diabetes.
  • the present invention relates to the use of one or more compounds of the general formula (la) or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prevention of type I or type II diabetes.
  • Dibenzosuberenol (2.08 g, 10 mmol) was dissolved in dry THF (20 mL) at 0 °C.
  • Sodium hy- dride (1.0 g of 50 % mineral oil dispersion, 20 mmol) was added.
  • tert- butylbromoacetate (4.0 g, 20.0 mmol) was added over a period of 20 min and then stirred for 1 h.
  • the reaction mixture was quenched with water at 0 °C and the product extracted with ethyl acetate. The combined extracts were dried (MgSO 4 ), and concentrated in vacuo.

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Abstract

L'invention concerne des composés représentés par la formula (Ia). Ces composés sont utiles pour traiter et/ou prévenir des états induits par des récepteurs nucléaires, en particulier, les récepteurs activés par le proliférateur du peroxisome (PPAR).
PCT/DK1999/000574 1998-10-21 1999-10-19 Nouveaux composes, leur preparation et leur utilisation WO2000023417A1 (fr)

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JP2000577145A JP2002527503A (ja) 1998-10-21 1999-10-19 新規化合物類、それらの調製及び使用
AU63258/99A AU6325899A (en) 1998-10-21 1999-10-19 New compounds, their preparation and use

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WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
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WO2000035437A3 (fr) * 1998-12-17 2000-11-09 Mindset Biopharmaceuticals Usa Utilisation accrue de glucose par le cerveau
WO2000035437A2 (fr) * 1998-12-17 2000-06-22 Mindset Biopharmaceuticals (Usa), Inc. Utilisation accrue de glucose par le cerveau
EP1634605A2 (fr) 2000-03-08 2006-03-15 Novo Nordisk A/S Traitement de la dyslipidémie chez un patient souffrant de diabète de type 2
US7041837B2 (en) 2001-07-26 2006-05-09 Cadilla Healthcare Limited Heterocyclic compounds having hypolipidemic, hypocholesteremic activities process for their preparation and pharmaceutical compositions containing them and their use in medicine
US7323491B2 (en) 2001-07-26 2008-01-29 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
US8558009B2 (en) 2001-07-26 2013-10-15 Cadila Healthcare Limited Pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine
US8110598B2 (en) 2001-07-26 2012-02-07 Cadila Healthcare Limited Heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine
WO2003031432A1 (fr) 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
EP2243776A1 (fr) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Piperidines substituées et leur utilisation dans le traitement de maladies liées au recepteur histaminique H3
EP2305648A1 (fr) 2001-12-21 2011-04-06 Novo Nordisk A/S Dérivés d'amide en tant qu'activateurs de la glucokinase
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
US7015345B2 (en) 2002-02-21 2006-03-21 Asahi Kasei Pharma Corporation Propionic acid derivatives
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WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
WO2004101505A1 (fr) 2003-05-14 2004-11-25 Novo Nordisk A/S Nouveaux composes pour le traitement de l'obesite
WO2005030797A2 (fr) 2003-09-30 2005-04-07 Novo Nordisk A/S Nouveaux agonistes du recepteur de la melanocortine
EP2298337A2 (fr) 2003-12-09 2011-03-23 Novo Nordisk A/S Régulation des préférences alimentaires en utilisant des agonistes du GLP-1
EP2444397A1 (fr) 2004-01-06 2012-04-25 Novo Nordisk A/S Hétéroaryl-urées et leur utilisation en tant qu'activateurs de glucokinase
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2005105785A2 (fr) 2004-05-04 2005-11-10 Novo Nordisk A/S Nouveaux derives d'indole
EP2316446A1 (fr) 2004-06-11 2011-05-04 Novo Nordisk A/S Remède contre l'obésité induite par les médicaments au moyen d'agonistes GLP-1
WO2006053906A1 (fr) 2004-11-22 2006-05-26 Novo Nordisk A/S Formulations solubles stables contenant de l'insuline et un sel de protamine
WO2006058923A1 (fr) 2004-12-03 2006-06-08 Novo Nordisk A/S Composés hétéroaromatiques activants de glucokinase
EP2386554A1 (fr) 2005-07-04 2011-11-16 High Point Pharmaceuticals, LLC Composés actives sur le recepteur histamine H3
EP2233470A1 (fr) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Antagonists du receptor histamine H3
EP2377856A1 (fr) 2005-07-14 2011-10-19 Novo Nordisk A/S Activateurs de la glucokinase d'urée
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