WO2000023416A1 - Nouveaux composes, leur preparation et leur utilisation - Google Patents

Nouveaux composes, leur preparation et leur utilisation Download PDF

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Publication number
WO2000023416A1
WO2000023416A1 PCT/DK1999/000572 DK9900572W WO0023416A1 WO 2000023416 A1 WO2000023416 A1 WO 2000023416A1 DK 9900572 W DK9900572 W DK 9900572W WO 0023416 A1 WO0023416 A1 WO 0023416A1
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alkyl
anyone
compound according
chr
ethoxy
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PCT/DK1999/000572
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Lone Jeppesen
Paul Stanley Bury
Per Sauerberg
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Novo Nordisk A/S
Dr. Reddy's Research Foundation
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Priority to JP2000577144A priority Critical patent/JP2002527502A/ja
Priority to EP99950502A priority patent/EP1123268A1/fr
Priority to AU63256/99A priority patent/AU6325699A/en
Publication of WO2000023416A1 publication Critical patent/WO2000023416A1/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
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    • 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
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • 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
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    • 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
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    • 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 hypolipidaemic 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 lipolysis 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-rich 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,- 12 alkyl, C 4 . 12 -alkenynyl, C 2 - 12 -alkenyl, C 2 . 12 -alkynyl, C ⁇ alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyC,.
  • ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, or C 1-12 alkyl, C 4 . 12 - alkenynyl, C 2 . 12 -alkenyl, C 2 .
  • R 1 and R 12 independently of each other are selected from hydroxy, halogen, perhalomethyl, C,. 6 alkoxy or amino optionally substituted with one or more C ⁇ alkyl, perhalomethyl or aryl; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;
  • Q is -O-, -S-, >NR 18 , wherein R 18 is hydrogen, halogen, hydroxy, nitro, cyano, formyl, C,. 12 alkyl, C ⁇ alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, C ⁇ alkyl- amino, arylamino, aralkylamino, aminoC ⁇ alkyl, C ⁇ alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, d- ⁇ alkoxyd- ⁇ alkyl, aryloxyd- ⁇ 2 alkyl, aralkoxyC ⁇ alkyl, C ⁇ alkylthio, thiod- 12 alkyl, C ⁇ alkoxycarbonylamino, aryloxycarbonyla
  • R 5 represents hydrogen, hydroxy, halogen, C ⁇ alkoxy, d- ⁇ alkyl, d- ⁇ -alkenynyl, C 2 . 12 - alkenyl, 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 . 12 -alkenynyl, C 2 . 12 - alkenyl, C 2 .
  • d-i alkoxycarbonyl, aryloxycarbonyl, C 1-12 alkylaminocarbonyl, arylamino- carbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano;
  • R 8 represents hydrogen, d. ⁇ alkyl, C 4 . 12 -alkenynyl, C 2 . 12 -alkenyl, 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, d- ⁇ 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 C ⁇ alkyl; n is an integer ranging from 1 to 4, p is an integer ranging from 0 to 1 , 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 d- 7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 .
  • 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 d-yalkyl, 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, hydroxyd. 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 d-yalkyl, 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, aralkoxyC 1 . 7 alky or
  • 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 d- 7 alkyl, C 4 - 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, aryl, aralkyl, hy- droxyC,- 7 alkyl, aryloxyd- 7 alkyl or aralkoxyd- 7 alkyl.
  • 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 or C,. 7 alkyl.
  • the present invention is concerned with compounds of formula I wherein R 1 , R 2 , R 3 , and R 4 represent hydrogen.
  • 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 d. 7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 .
  • 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 d- 7 alkyl, C 4-7 -alkenynyl, C 2 . 7 -alkenyl, C 2 .
  • 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 d-yalkyl, C 4 - 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyI, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, hydroxyd.
  • ring A represents a 5-6 membered cyclic ring, optionally substituted with one or more halogen, perhalomethyl, hydroxy, cyano, or d-yalkyl, C 4 - 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyI, C 1-7 alkoxy, aryl, aryloxy, aralkyl, aralk
  • 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 C 1 . 7 alkyl, C 4 . 7 - g alkenynyl, C 2 . 7 -alkenyl, C 2 - 7 -alkynyl, C 1-7 alkoxy, aryl, aralkyl, hydroxyd- 7 alkyl, d- 7 alkoxyd- 7 alkyl, aryloxyC 1 - 7 alkyl or aralkoxyC 1 - 7 alkyl.
  • the present invention is concerned with compounds of formula I wherein ring A represents a 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 ring A represent a phenyl ring.
  • the present invention is concerned with compounds of formula I wherein X is -S-.
  • the present invention is concerned with compounds of formula I wherein T is >C ⁇
  • the present invention is concerned with compounds of formula I wherein Z is >N-.
  • the present invention is concerned with compounds of formula I wherein Q is -O-, -S-, >NR 18 , wherein R 18 is hydrogen or d- 7 alkyl.
  • the present invention is concerned with compounds of formula I wherein Q is >NR 18 , wherein R 18 is hydrogen.
  • the present invention is concerned with compounds of formula I wherein Ar represents arylene optionally substituted with one or more d combat 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, d_ 7 alkoxy, C t - 7 alkyl, d- 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,- 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, C 1 . 7 alkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl, C 2 . 7 -alkynyl, aryl, aralkyl, d.yalkoxyd-yalkyl, d- 7 alkoxycarbonyl, aryloxycarbonyl, d-yalkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups.
  • the present invention is concerned with compounds of formula I wherein R 7 represents hydrogen, d-yalkyl, C 4 . 7 -alkenynyl, C 2 . 7 -alkenyl or C 2 . 7 - alkynyl. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein R 7 represents C 1 . 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, d_ 7 alkyl, C 4 . 7 -alkenynyl, 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 d- 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 alkyl 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 p is 1.
  • 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 X is -O-. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein X is -S-.
  • the present invention is concerned with compounds of formula I wherein Z is -S- and p is 1.
  • the present invention is concerned with compounds of formula I wherein Z is -CH 2 - and p is 1.
  • the present invention is concerned with compounds of formula I wherein T is >CH-.
  • the present invention is concerned with compounds of formula I wherein T is >C ⁇ .
  • 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 H.
  • the present invention is concerned with compounds of formula I wherein n is 2. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein U 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.
  • the present invention is concerned with compounds of formula I wherein p is 0.
  • 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. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein X is -O-CH 2 -O-.
  • Preferred compounds of the invention are: 2-Ethoxy-3- ⁇ 4-[2-(11H-5-oxa-10-thia-dibenzo[a,cQcyclohepten-11-yloxy)-ethoxy]-phenyl ⁇ - propionic acid,
  • preferred compounds of the invention are: 2-Ethoxy-3- ⁇ 4-[2-(11H-5-oxa-10-thia-dibenzo[a,c/]cyclohepten-11-yloxy)-ethoxy]-phenyl ⁇ - propionic acid,
  • d- ⁇ -alky 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 olefinically 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 atoms and at least one triple bond.
  • examples of such groups include, but are not limited to, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
  • C 4 . n .-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.
  • d- 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.
  • d. 6 -alkoxycarbonyloxy is intended to include the above defined d- 6 -alkoxy groups attached to a carbonyloxy moiety, eg. methoxycarbonyloxy, 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, cyclohexyimethyl, 3- (cyclopentyl)-l-propyl, and the like.
  • d- 12 -alkylthio refers to a straight or branched or cyclic monovalent substituent comprising a d- 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 d- 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.
  • hydroxyd. 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 d- 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, -naphthyloxycarbonyl or 2-naphthyloxycarbonyl, etc..
  • aralkoxycarbonyl refers to an aralkoxy as defined herein linked through a carbonyl having a free valence bond from the carbon atom, e.g. benzyloxycarbonyl, phenethoxycarbonyl, 3-phenylpropoxycarbonyl, 1- naphthylmethoxycarbonyl, 2-(1-naphtyl)ethoxycarbonyl, etc..
  • d. ⁇ alkoxyd- ⁇ alkyl refers to a d- 12 alkyl as defined herein whereto is attached a d- 12 alkoxy as defined herein, e.g. methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc..
  • aryloxyd-yalkyl 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 d- 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,- 12 alkyl as defined herein whereto is attached a group of formula -SR'" wherein R'" is hydrogen, d- 6 alkyl or aryl, e.g. thiomethyl, methylthiomethyl, phenylthioethyl, etc..
  • C 1-12 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-butoxycarbonylamino, 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 aralkoxycarbonyl 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 ⁇ -alkyl or d. 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, d_ 6 -alkyl or d. 6 -alkoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • perhalomethyl means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
  • d. 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 d. 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 -alkoxycarbonyl 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 monocydic saturated or unsaturated or aromatic system, wherein the ring may be cyclopentyl, cyclopentenyl, cyclohexyl, phenyl or cycloheptyl.
  • bicycloalkyl refers to a monovalent substituent comprising a bicyclic structure made of 6-12 carbon atoms such as e.g. 2-norbornyl, 7-norbomyl, 2- bicyclo[2.2.2]octyl and 9-bicyclo[3.3.1]nonanyl.
  • heteroaryl refers to a monovalent substituent comprising a 5-6 membered monocydic 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 monocydic 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, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothi- azole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine linked to oxygen.
  • oxygen atom e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothi- azole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline
  • 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-naphtyimethyl, 2-(1-naphtyl)ethyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy or 2-naphthyloxy.
  • aralkoxy refers to a d- 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-e-alkylsulfonyl refers to a monovalent substituent comprising a d. 6 -alkyl group linked through a sulfonyl group such as e.g. methylsulfonyl, 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-
  • d-e-monoalkylaminosulfonyl refers to a monovalent substituent comprising a d-e-monoalkylamino group linked through a sulfonyl group such as e.g.
  • methylaminosulfonyl methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n- butylaminosulfonyl, sec-butylaminosulfonyl, isobutyla inosulfonyl, tert-butylaminosulfonyl, n- pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl, n- hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopentylaminosulfonyl, n- hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.
  • d- 6 -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-methylaminosulfonyl, 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 - 6 -cycloalkyl)d. 6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubsti- tuted with a d-e-cycloalkyl group, the cycloalkyl group optionally being mono- or polysubsti- tuted with C 1 - 6 -alkyl, halogen, hydroxy or d-e-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 d- 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 d-e-alkyl, halogen, hydroxy or d_ 6 -alkoxy; such as e.g. phenylsulfonyl, tosyl, and the like.
  • d-e-monoalkylaminocarbonyl refers to a monovalent substituent comprising a C ⁇ -monoalkylamino group linked through a carbonyl group such as e.g. methy- laminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n- butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl, n- hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neopentylaminocarbonyl, n- hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl
  • d. 6 -dialkylaminocarbonyr refers to a monovalent substituent comprising a d. 6 -dialkylamino group linked through a carbonyl group such as dimethylaminocar- bonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-(n- butyl)-N-methylaminocarbonyl, di(n-pentyl)aminocarbonyl, and the like.
  • d-e-monoalkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a d-g-monoalkylaminocarbonyl group, e.g. methylaminocarbonylamino, ethylamino-carbonylamino, n-propylaminocarbonylamino, isopropylaminocarbonylamino, n-butylaminocarbonylamino, sec-butylaminocarbonylamino, isobutylaminocarbonylamino, tert-butylaminocarbonylamino, and 2- methylbutylaminocarbonylamino.
  • a d-g-monoalkylaminocarbonyl group e.g. methylaminocarbonylamino, ethylamino-carbonylamino, n-propylaminocarbonylamino, isopropylaminocarbon
  • C ⁇ -dialkylaminocarbonylamino refers to an amino group wherein one of the hydrogen atoms is substituted with a d-e-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.
  • a d-e-dialkylaminocarbonyl group such as di- methylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethylaminocarbony- lamino, dipropylaminocarbonylamino, N-(n-butyl)-N-methylaminocarbonylamino, di(n
  • heterocyclyl means a monovalent saturated or unsaturated group being monocydic 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 heterocydes having one hetero atom (e.g. pyrrolidine, pyrroline); 5-membered heterocydes having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g.
  • pyrazoline pyrazolidine, 1 ,2-oxathiolane, imidazolidine, imidazoline, 4- oxazolone
  • 5-membered heterocydes having three heteroatoms e.g. tetrahydrofurazan
  • 5- membered heterocydes having four heteroatoms 6-membered heterocydes with one heteroatom (e.g. piperidine); 6-membered heterocydes with two heteroatoms (e.g. piperazine, morpholine); 6-membered heterocydes with three heteroatoms; and 6-membered heterocy- cles with four heteroatoms.
  • a divalent heterocydic group means a divalent saturated or unsaturated system being monocydic 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 heterocydic group includes, but is not limited to, 5-membered heterocydes having one hetero atom (e.g. pyrrolidine, pyrroline); 5-membered heterocydes having two heteroatoms in 1,2 or 1,3 positions (e.g.
  • pyrazoline pyrazolidine, 1 ,2-oxathiolane, imidazolidine, imidazoline, 4-oxazolone
  • 5-membered heterocydes having three heteroatoms e.g. tetrahydrofurazan
  • 5-membered heterocydes having four heteroatoms 6-membered heterocydes with one heteroatom (e.g. piperidine); 6-membered heterocydes with two heteroatoms (e.g. piperazine, morpholine); 6-membered heterocydes with three heteroatoms; and 6- membered heterocydes 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 heterocydes having one hetero atom (e.g.
  • 5-membered heterocydes having two heteroatoms in 1 ,2 or 1 ,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocydes having three heteroatoms (e.g. triazoles, thiadiazoles); 5-membered heterocydes having four heteroatoms; 6-membered heterocydes with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthridine, cyclohepta[b]pyridine); 6-membered heterocydes with two heteroatoms (e.g.
  • pyridazines cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines, morpholines
  • 6-membered heterocydes with three heteroatoms e.g. 1 ,3,5- triazine
  • 6-membered heterocydes with four heteroatoms e.g. 1 ,3,5- triazine
  • 5- or 6-membered nitrogen containing ring refers to a monovalent substituent comprising a monocydic 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, pyridazinyl, 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 carbox- ylic 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.
  • Pharmaceutically 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 Nike ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of sol- vents may be used. Organic bases like lysine, arginine, diethanolamine, 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, pal- mitic 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, as
  • stereoisomers of the compounds forming part of this invention may be prepared by us- ing 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 preferred 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; conven- tional 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:
  • R -R 4 , A, X, Z, p and Q are defined as above, with a compound of formula
  • L is a leaving group such as halogen, p-toluenesulfonate, methanesulfonate and the like and wherein n, U, 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, p, Ar, R 1 -R 8 , A, X, Z, U and Q are defined as above except that R 8 is not H.
  • R 1 -R 4 , A, X , Z, Q, p and n are defined as above, with a compound of formula V
  • L is a leaving group such as halogen, p-toluenesulfonate, methanesulfonate and the like and wherein R 1 -R 4 , A, X ,Z, Q, p and n are defined as above, with an compound of formula V
  • R 1 -R 4 , A, X, Z, Q, U, Ar, p, 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, p, Ar, R 1 -R 8 , A, X, Z, U 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, p, Ar, R 1 -R 4 , R 7 - R 8 , A, X, Z , U and Q are defined as above except that R 8 is not H and wherein R 5 forms a bond together with R 6 .
  • n, p, Ar, R 1 -R 4 , R 7 -R 8 , A, X , Z , U and Q are defined as above except that R 8 is not H, to obtain a compound of formula (la) wherein n, p, Ar, R 1 -R 4 , R 7 - R 8 , A, X, Z, U 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, U, p 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, p, Ar, R 1 - R 8 , R 7 , A, X, Z , U and Q is defined as above except that R 8 is not H.
  • n, p, Ar, R 1 -R 6 , A, X, Z, U 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
  • R 7 is defined as above and wherein "Hal” represents Cl, Br, or I to obtain a compound of formula (la) wherein n, p, Ar, R 1 - R 8 , A, X , Z, U 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, Z, p 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 preferen- tially from trifluoro-methanesulfonate, halide or C r C 6 alkyl, to obtain a compound of formula (la) wherein n, p, Ar, R 1 -R 8 , R 7 , A, X and Q is defined as above except that R 8 is not H, and U is C.
  • n, p, Ar, R 1 -R 8 , A, X , Z, U 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 plasmids 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 subdoning 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. 1mM 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.
  • 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
  • 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 glyceryl 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.
  • 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 polyhydroxylated 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 cap- sules 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:
  • 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 hydride (1.0 g of 50 % mineral oil dispersion, 20 mmol) was added. After 10 min.
  • 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.
  • the com- bined extracts were dried (MgSO 4 ), and concentrated in vacuo.
  • the product was redissolved in ether and added dropwise to an ether (15 mL) suspension of lithium aluminium hydride (190 mg, 5.0 mmol).
  • the reaction was stirred 16 h at room temperature, quenched with water, cooled, and filtered through Decalit.
  • the ether solution was washed with saturated NaCl, dried, and purified by chromatography eluting with ethyl acetate/dichloromethan (1 :10) to give 850 mg (63%) of 2-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxy)-ethanol.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Reproductive Health (AREA)
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  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrane Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés représentés par la formule (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/DK1999/000572 1998-10-21 1999-10-19 Nouveaux composes, leur preparation et leur utilisation WO2000023416A1 (fr)

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JP2000577144A JP2002527502A (ja) 1998-10-21 1999-10-19 新規化合物、それらの調製及び使用
EP99950502A EP1123268A1 (fr) 1998-10-21 1999-10-19 Nouveaux composes, leur preparation et leur utilisation
AU63256/99A AU6325699A (en) 1998-10-21 1999-10-19 New compounds, their preparation and use

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WO2000035437A2 (fr) * 1998-12-17 2000-06-22 Mindset Biopharmaceuticals (Usa), Inc. Utilisation accrue de glucose par le cerveau
WO2003002508A1 (fr) * 2001-06-28 2003-01-09 Dr. Reddy's Research Foundation Derives d'acide para-ethoxy-phenillactique
WO2003031432A1 (fr) 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
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
US6916809B2 (en) 2001-12-21 2005-07-12 Bristol-Myers Squibb Company Heterocyclic acridone inhibitors of IMPDH enzyme
WO2005105785A2 (fr) 2004-05-04 2005-11-10 Novo Nordisk A/S Nouveaux derives d'indole
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
US7015345B2 (en) 2002-02-21 2006-03-21 Asahi Kasei Pharma Corporation Propionic acid derivatives
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
WO2007006814A1 (fr) 2005-07-14 2007-01-18 Novo Nordisk A/S Activateurs de l'uree glucokinase
WO2007015805A1 (fr) 2005-07-20 2007-02-08 Eli Lilly And Company Composés joints en position 1-amino
WO2007110364A1 (fr) 2006-03-28 2007-10-04 High Point Pharmaceuticals, Llc Benzothiazoles presentant une activité sur le récepteur h3 de l'histamine
WO2007123581A1 (fr) 2005-11-17 2007-11-01 Eli Lilly And Company Antagonistes des récepteurs du glucagon, leur préparation et leurs utilisations thérapeutiques
WO2007137968A1 (fr) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc Benzodioxolylcyclopropylpipérazinylpyridazines
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
WO2008059025A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouvelles 2-(2-hydroxyphényl) benzothiadiazines utilisées pour traiter l'obésité et le diabète
WO2008059026A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouveaux 2-(2-hydroxyphényl)benzimidazoles utilisés pour traiter l'obésité et le diabète
WO2008084044A1 (fr) 2007-01-11 2008-07-17 Novo Nordisk A/S Activateurs de l'urée glucokinase
EP2233470A1 (fr) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Antagonists du receptor histamine H3
EP2298337A2 (fr) 2003-12-09 2011-03-23 Novo Nordisk A/S Régulation des préférences alimentaires en utilisant des agonistes du GLP-1
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
WO2011104378A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides de traitement de l'obésité
WO2011104379A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides pour le traitement de l'obésité
WO2011117416A1 (fr) 2010-03-26 2011-09-29 Novo Nordisk A/S Nouveaux analogues du glucagon
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
EP2444397A1 (fr) 2004-01-06 2012-04-25 Novo Nordisk A/S Hétéroaryl-urées et leur utilisation en tant qu'activateurs de glucokinase
WO2012130866A1 (fr) 2011-03-28 2012-10-04 Novo Nordisk A/S Nouveaux analogues de glucagon
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
WO2018167194A1 (fr) 2017-03-15 2018-09-20 Novo Nordisk A/S Composés bicycliques aptes à se lier au récepteur de mélanocortine 4
US10130684B2 (en) 2011-02-03 2018-11-20 Pharmedica Ltd. Oral dissolving films for insulin administration, for treating diabetes
WO2019219714A1 (fr) 2018-05-15 2019-11-21 Novo Nordisk A/S Composés capables de se lier au récepteur de la mélanocortine 4
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
WO2020053414A1 (fr) 2018-09-14 2020-03-19 Novo Nordisk A/S Composés bicycliques aptes à se lier aux agonistes du récepteur de la mélanocortine 4

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ATE515494T1 (de) * 2004-05-05 2011-07-15 High Point Pharmaceuticals Llc Neue verbindungen, deren herstellung und verwendung

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Cited By (49)

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Publication number Priority date Publication date Assignee Title
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
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
WO2003002508A1 (fr) * 2001-06-28 2003-01-09 Dr. Reddy's Research Foundation Derives d'acide para-ethoxy-phenillactique
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
US6916809B2 (en) 2001-12-21 2005-07-12 Bristol-Myers Squibb Company Heterocyclic acridone inhibitors of IMPDH enzyme
US7312209B2 (en) 2001-12-21 2007-12-25 Bristol-Myers Squibb Company Acridone inhibitors of IMPDH enzyme
US7015345B2 (en) 2002-02-21 2006-03-21 Asahi Kasei Pharma Corporation Propionic acid derivatives
WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
EP2471533A1 (fr) 2002-06-27 2012-07-04 Novo Nordisk A/S Dérivés d'aryle carbonyle en tant qu'agents thérapeutiques
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
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
EP2233470A1 (fr) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Antagonists du receptor histamine H3
EP2386554A1 (fr) 2005-07-04 2011-11-16 High Point Pharmaceuticals, LLC Composés actives sur le recepteur histamine H3
WO2007006814A1 (fr) 2005-07-14 2007-01-18 Novo Nordisk A/S Activateurs de l'uree glucokinase
EP2377856A1 (fr) 2005-07-14 2011-10-19 Novo Nordisk A/S Activateurs de la glucokinase d'urée
WO2007015805A1 (fr) 2005-07-20 2007-02-08 Eli Lilly And Company Composés joints en position 1-amino
WO2007123581A1 (fr) 2005-11-17 2007-11-01 Eli Lilly And Company Antagonistes des récepteurs du glucagon, leur préparation et leurs utilisations thérapeutiques
WO2007110364A1 (fr) 2006-03-28 2007-10-04 High Point Pharmaceuticals, Llc Benzothiazoles presentant une activité sur le récepteur h3 de l'histamine
WO2007137968A1 (fr) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc Benzodioxolylcyclopropylpipérazinylpyridazines
EP2402324A1 (fr) 2006-05-29 2012-01-04 High Point Pharmaceuticals, LLC Benzodioxolylcyclopropylpipérazinylpyridazines
WO2008059026A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouveaux 2-(2-hydroxyphényl)benzimidazoles utilisés pour traiter l'obésité et le diabète
WO2008059025A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouvelles 2-(2-hydroxyphényl) benzothiadiazines utilisées pour traiter l'obésité et le diabète
WO2008084044A1 (fr) 2007-01-11 2008-07-17 Novo Nordisk A/S Activateurs de l'urée glucokinase
WO2011104378A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides de traitement de l'obésité
WO2011104379A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides pour le traitement de l'obésité
WO2011117416A1 (fr) 2010-03-26 2011-09-29 Novo Nordisk A/S Nouveaux analogues du glucagon
WO2011117415A1 (fr) 2010-03-26 2011-09-29 Novo Nordisk A/S Nouveaux analogues du glucagon
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
US10130684B2 (en) 2011-02-03 2018-11-20 Pharmedica Ltd. Oral dissolving films for insulin administration, for treating diabetes
WO2012130866A1 (fr) 2011-03-28 2012-10-04 Novo Nordisk A/S Nouveaux analogues de glucagon
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
US9486505B2 (en) 2011-09-23 2016-11-08 Novo Nordisk A/S Glucagon analogues
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US9751927B2 (en) 2013-04-18 2017-09-05 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
WO2018167194A1 (fr) 2017-03-15 2018-09-20 Novo Nordisk A/S Composés bicycliques aptes à se lier au récepteur de mélanocortine 4
WO2019219714A1 (fr) 2018-05-15 2019-11-21 Novo Nordisk A/S Composés capables de se lier au récepteur de la mélanocortine 4
WO2020053414A1 (fr) 2018-09-14 2020-03-19 Novo Nordisk A/S Composés bicycliques aptes à se lier aux agonistes du récepteur de la mélanocortine 4

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