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WO2004111031A1 - Carbamates de pyridinyle utilises en tant qu'inhibiteurs de la lipase hormono-sensible - Google Patents

Carbamates de pyridinyle utilises en tant qu'inhibiteurs de la lipase hormono-sensible Download PDF

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Publication number
WO2004111031A1
WO2004111031A1 PCT/DK2004/000391 DK2004000391W WO2004111031A1 WO 2004111031 A1 WO2004111031 A1 WO 2004111031A1 DK 2004000391 W DK2004000391 W DK 2004000391W WO 2004111031 A1 WO2004111031 A1 WO 2004111031A1
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Prior art keywords
methyl
ester
phenyl
pyridin
carbamic acid
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PCT/DK2004/000391
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English (en)
Inventor
Johannes Cornelis De Jong
Poul Jacobsen
Søren EBDRUP
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Novo Nordisk A/S
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Publication date
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Priority to BRPI0411255-5A priority Critical patent/BRPI0411255A/pt
Priority to MXPA05013224A priority patent/MXPA05013224A/es
Priority to CA002526204A priority patent/CA2526204A1/fr
Priority to EP04736303A priority patent/EP1636205A1/fr
Priority to AU2004247319A priority patent/AU2004247319A1/en
Priority to JP2006515703A priority patent/JP2006527210A/ja
Publication of WO2004111031A1 publication Critical patent/WO2004111031A1/fr
Priority to US11/301,224 priority patent/US20060160865A1/en
Priority to NO20060168A priority patent/NO20060168L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel substituted pyridinyl carbamates, to pharma- ceutical compositions comprising these compounds, to the use of these compounds as pharmaceutical compositions, and to methods of treatment employing these compounds and compositions.
  • the present compounds show inhibition of hormone sensitive lipase. As a result, the compounds are useful for the treatment and/or prevention of diseases and disorders related to hormone sensitive lipase.
  • the overall energy homeostasis of a mammalian system requires a high degree of regulation to ensure the availability of the appropriate substrate at the appropriate time.
  • Plasma glucose levels rise during the post-prandial state, to return to pre-prandial levels within 2-3 hours. During these 2-3 hours, insulin promotes glucose uptake by skeletal muscle and adipose tissue and decreases the release of free fatty acids (FFA) from adipocytes, to ensure that the two substrates do not compete with each other.
  • FFA free fatty acids
  • HSL Hormone-sensitive lipase
  • adipocytes HSL catalyses the conversion of triglycerides to glycerol and fatty acids. It is through the regulation of this enzyme that the levels of circulating FFA are modulated. Insulin leads to the inactivation of HSL with a subsequent fall in plasma FFA levels during the post-prandial state, followed by the activation of the enzyme when the insulin concen- tration falls and catecholamines rise during the post-absorptive period.
  • HSL The activation of HSL leads to an increase in plasma FFA, as they become the main source of energy during fasting.
  • the activation-inactivation of HSL is primarily mediated through the cAMP-protein kinase A and AMP-dependent kinase pathways.
  • cAMP-protein kinase A a cAMP-protein kinase A and AMP-dependent kinase pathways.
  • nicotinic acid and its derivatives that decrease the activation of HSL via these pathways and cause a decrease in lipolysis that leads to a reduction in the FFA levels.
  • These drugs have a beneficial effect in the utilization of glucose and in the normalization of the excess triglyceride synthesis seen in patients with elevated FFA. However, since these pathways are used by other processes in the body, these drugs have severe side effects.
  • HSL inhibitors WO 01/87843, WO 01/17981, WO 01/66531, WO 01/83497, and WO 01/26664.
  • HSL inhibitors disclosed in these publications contain pyridinyl and carbamate substructures as in the compounds of the present invention.
  • potent pyridinyl carbamate compounds that specifically inhibit the lipolytic activity of HSL and which may be expected to decrease plasma FFA levels. These compounds can be used to treat disorders where a decreased level of plasma FFA is de- sired, such as insulin resistance, syndrome X, dyslipidemia, abnormalities of lipoprotein metabolism.
  • One object of the present invention is to provide compounds and pharmaceutical compositions that inhibit the lipolytic activity of HSL.
  • a further object is to provide compounds which have good pharmaceutical properties such as solubility, bioavailability, specificity etc.
  • halogen in the present context designates an atom selected from the group consisting of F, Cl, Br and I.
  • C 1-6 -alkyI in the present context designates a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms.
  • C 2-6 -alkyI in the present context designates a saturated, branched or straight hydrocarbon group having from 2 to 6 carbon atoms.
  • Representative examples in- dude but are not limited to, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, n- pentyl, isopentyl, neopentyl, ferf-pentyl, n-hexyl, isohexyl and the like.
  • C 1-6 -alkoxy in the present context designates a group -O-C-i- ⁇ -alkyl wherein d- 6 -alkyI is as defined above.
  • Representative examples include, but are not limited to, meth- oxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ferf-butoxy, n-pentoxy, isopentoxy, neopentoxy, terf-pentoxy, n-hexoxy, isohexoxy and the like.
  • C 2-6 -alkenyl as used herein, represent an olefinically unsaturated branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2- propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.
  • C 3-10 -cycloalkyl as used herein represents a saturated mono-, bi-, tri- or spirocarbocyclic group having from 3 to 10 carbon atoms.
  • Ca ⁇ -heterocyclyl represents a saturated 3 to 8 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azirid- inyl, tetrahydrofuranyl and the like.
  • aryl represents a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • heteroaryl represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazoIyl, 1 ,2,4- triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadia
  • Heteroaryl is also intended to include the partially hydrogen- ated derivatives of the heterocyclic systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, 3,4-dihydroisoquinolinyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • perhalomethyl designates a methyl moiety substituted with three halogen atoms.
  • Non-limiting examples of perhalomethyl are CF 3 , CCI 3 , and CF 2 CI.
  • perhalomethoxy designates a perhalomethyl linked via an oxygen atom, e.g. -0-CF 3 , -0-CCl 3 , and -0-CF 2 Cl
  • ring system includes aromatic as well as non-aromatic ring moieties, which may be monocyclic, bicyclic or polycyclic, and they encompass moieties with zero, one or more hetereatoms selected from nitrogen, oxygen and sulphur.
  • Non-limiting examples of such ring systems are aryl, C 3 ⁇ -heterocyclyl and heteroaryl.
  • heterocyclic system as used herein includes aromatic as well as non- aromatic ring moieties, which may be monocyclic, bicyclic or polycyclic, and containing in their ring structure one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non- limiting examples of such heterocyclic systems are C 3-8 -heterocyclyl and heteroaryl.
  • the term "optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
  • the terms "disease”, “condition” and “disorder” as used herein are used interchangeably to specifiy a state of a patient which is not the normal physiological state of man.
  • treatment as used herein means the management and care of a patient having developed a disease, condition or disorder, as well as the management and care of an individual at risk of developing the disease, condition or disorder prior to the clinical onset of said disease, condition or disorder.
  • treatment is to combat the disease, condition or disorder, as well as to to combat the development of the disease, condition or disorder.
  • Treatment includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the dis- ease, condition or disorder.
  • effective amount means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.
  • modulate means to influence, i.e. to modulate a parameter means to influence that parameter in a desired way. Examples are to modulate insulin secretion from beta cells and to modulate the plasma level of free fatty acids.
  • medicament means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.
  • pharmaceutically acceptable means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.
  • the present invention relates to a compound of the general formula (I)
  • R 1 and R 2 are independently selected from hydrogen, hydroxy, sulfanyl, amino, amide, urea, thiourea, benzamide, thioamide, halogen, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, amino, amide, urea, thiourea, benzamide, thioamide, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, het- eroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, thio
  • R 3 , and R 4 are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl and C 3-1o -cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -CyClOaIkYl, wherein
  • R 2 is selected from hydrogen, hydroxy, amino, halogen, Ci -6 - alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C ⁇ -heterocyclyl, amide, urea and thiourea and C 3-10 -CyClOaIRyI, wherein each of hydroxy, amino, C 1-6 -aikyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3 ⁇ -heterocyclyl, amide, urea and thiourea and Cs-io-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C
  • R 4 is selected from hydrogen, halogen, C 1-6 -alkyl, C 2-6 - alkenyl, wherein each of C 1-6 -alkyl, C 2-6 -alkenyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, Cs- ⁇ -heterocyclyl and C ⁇ o-cycloalkyl.
  • R 4 is selected from hydrogen, halogen and C 1-6 -alkyl.
  • R 4 is hydrogen
  • R 4 is halogen
  • R 3 is selected from hydrogen, hydroxy, halogen, C 1-6 -alkyl, C 2-6 -alkenyl, wherein each of hydroxy, C 1-6 -alkyl, C 2-6 -alkenyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-6 -alkyl, C 2-6 - alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl.
  • R 3 is selected from halogen, C 1-6 -alkyl, methoxy, perha- lomethyl and perhalomethoxy.
  • R 3 is selected from halogen, methyl, ethyl, isopropyl, meth- oxy and perhalomethyl.
  • R 3 is selected from halogen, methyl, methoxy and perhalomethyl.
  • the present invention relates to a compound of the general for- mula (I) : wherein
  • R 1 and R 2 are independently selected from hydrogen, hydroxy, sulfanyl, amino, amide, urea, thiourea, halogen, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl and wherein each of hydroxy, sulfanyl, amino, amide, urea, thiourea, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2 -6-alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, Ci -alkyl, C 1-6 -alkoxy, C 2 .
  • R 3 , and R 4 are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, d- 6 -alkyl, C 2-6 -aIkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and Cs-io-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C 1-6 -aIkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl and Cs-io-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycIoalkyl,
  • R 2 is selected from hydrogen, hydroxy, amino, halogen, C 1-6 - alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl, amide, urea and thiourea and C 3-10 -cycloalkyl, wherein each of hydroxy, amino, Ci -6 -alkyl, Ci -6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl, amide, urea and thiourea and C 3-10 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, Cs- ⁇ -hetero
  • R 2 is halogen or hydrogen.
  • R 4 is selected from hydrogen, halogen, C 1-6 -alkyl, C 2-6 - alkenyl, wherein each of C 1-6 -alkyl, C 2-6 -alkenyl is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-6 -alkyl, C 2- 6-alkenyl, aryl, het- eroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl.
  • R 4 is selected from hydrogen, halogen and C 1-6 -alkyl.
  • R 4 is hydrogen. ; In another embodiment R 4 is halogen.
  • R 3 is selected from hydrogen, halogen, C 1-6 -alkyl, C 2-6 - alkenyl, wherein each of , d -6 -alkyl, C 2-6 -alkenyI is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, het- eroaryl, Cs-s-heterocyclyl and In another embodiment R 3 is selected from halogen, d- ⁇ -alkyl, perhalomethyl and perhalomethoxy.
  • R 3 is selected from halogen, methyl, ethyl, isopropyl and perhalomethyl.
  • R 3 is selected from halogen, methyl or perhalomethyl.
  • the present invention relates to a compound of the general formula (I) :
  • R 1 and R 2 are independently selected from hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 - cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl and C 3- i 0 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl,
  • the present invention is related to a compound of the general formula (I)
  • R 2 is H and R 1 is
  • each R 5 is independently selected from hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, Ci -6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C ⁇ s-heterocyclyl and C 3-10 -cycloalkyl may optionally be substituted with one or more sub- stituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 - alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8
  • R 3 , and R 4 are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, Ci -6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl and C 3-10 -cycloalkyl is optionally substituted with one or more substituents inde- pendently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3 .
  • each of hydroxy, sulfanyl, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, Ci -6 -alkyl, perhalomethyl and perhalomethoxy;
  • Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4- chloro-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-methoxy- benzoylamino)-pyridin-2-yl ester, as well as diastereomers, enantiomers or tautomeric forms thereof including mixtures of these, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.
  • the present invention is related to a compound of the general formula (I) :
  • R 2 is H and R 1 is
  • each R 5 is independently selected from hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2- e-alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, Ci_ 6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3 - 8 -heterocyclyl and C 3- i 0 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, Ci -6 - alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl,
  • R 3 , and R 4 are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C 1-6 -aIkyl, C 2-6 -alkenyl, aryl, heteroaryl, Cs ⁇ -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C 1-6 -alkyl, C 2- 6-alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl and C 3- i 0 -cycIoalkyl is optionally substituted with one or more substituents inde- pendently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl, Cs- ⁇ -heterocyclyl and C 3- i 0 -cycl
  • Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4- chloro-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-methoxy- benzoylamino)-pyridin-2-yl ester, as well as diastereomers, enantiomers or tautomeric forms thereof including mixtures of these, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.
  • the present invention is related to a compound of the general formula (I) :
  • R 2 is H and R 1 is
  • each R 5 is independently selected from hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, Ci -6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3 ⁇ -heterocyclyl and C 3 .
  • each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyl, C 1-6 -aIkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Ca-s-heterocyclyl and C 3- i 0 -cycloalkyl may optionally be substituted with one or more sub- stituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 - alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs-a-heterocyclyl, and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, C 3-8
  • R 3 , and R 4 are hydrogen
  • the present invention is related to a compound of the general formula (I) :
  • R 2 is H and R 1 is
  • each R 5 is independently selected from hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, Ci -6 -alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C ⁇ -heterocyclyl and C 3-10 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 - alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs-s-heterocycl
  • R 3 , and R 4 are hydrogen
  • Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4- chloro-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-methoxy- benzoylamino)-pyridin-2-yl ester, as well as diastereomers, enantiomers or tautomeric forms thereof including mixtures of these, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.
  • the present invention is related to a compound of the general formula (I) :
  • R 2 is H and R 1 is
  • each R 5 is independently selected from hydrogen, hydroxy, amino, halogen, C 1-6 -alkyl, C 1-6 - alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and Ca-io-cycloalkyl, wherein each of hydroxy, d -6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 - cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyI, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl, and Ca.-m-cycloalkyl,
  • R 3 and R 4 are hydrogen
  • the present invention is related to a compound of the general formula (I)
  • R 2 is H and R 1 is
  • each R 5 is independently selected from hydrogen, hydroxy, amino, halogen, C 1-6 -alkyl, C 1-6 - alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs- ⁇ -heterocyclyl and C M o-cycloalkyl, wherein each of hydroxy, amino, C 1-6 -alkyl, Ci -6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl and C 3- 10 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, Ci -6 -alkyl, Ci -6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C ⁇ -heterocyclyl, and C 3-10 -cycloalkyl,
  • R 3 and R 4 are hydrogen
  • Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4- chloro-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-methoxy- benzoylamino)-pyridin-2-yl ester, as well as diastereomers, enantiomers or tautomeric forms thereof including mixtures of these, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.
  • the invention is related to a compound wherein R 2 is selected from from hydrogen, hydroxy, amino, halogen, Ci -6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl and C 3-10 -cycloalkyl, wherein each of hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 - alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3-10 -cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3 ⁇ -heterocyclyl, and C 3-10 - cycloalkyl, where
  • the invention is related to a compound wherein R 3 is selected from fluor, chlor, methyl, perhalomethyl or perhalomethoxy.
  • the invention is related to a compound wherein R 2 is hydrogen. In another embodiment the invention is related to a compound wherein R 2 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • each Rx is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, d-e-alkyl, C 1-6 -alkoxy, C 2 -6-alkenyl, aryl, heteroaryl, C 3 ⁇ -heterocyclyl, and C 3-10 -CyClOaIRyI, wherein each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, Cs-s-heterocyclyl and C 3-10 -cycloalkyl may optionally be substituted with one or more sub- stituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perha- lomethyl, perhalomethoxy, C 1-6 -alkyl, C 1-6 -alkoxy,
  • R 2 is selected from the group consisting of where each Rx is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl, and C 3-10 -CyClOaIKyI;
  • R 2 is selected from the group consisting of
  • each Rx is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, Ci -6 -alkoxy, C 2- 6-alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl, and C 3-10 -cycloaIkyl, wherein each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 -heterocyclyl and C 3- i 0 -cycloalkyl may optionally be substituted with one or more sub- stituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, Ci -6 -alkyl, C 1-6 -alkoxy, C 2-6
  • R 2 is selected from the group consisting of
  • each Rx is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl, and C 3-10 -cycloalkyl;
  • R 2 is selected from the group consisting of
  • the invention is related to a compound wherein R 2 is selected from the group consisting of
  • the invention is related to a compound wherein R 2 is selected from the group consisting of
  • the invention is related to a compound wherein R 1 is selected from the group consisting of
  • the invention is related to a compound wherein R 1 is selected from the group consisting of
  • the invention is related to a compound wherein R 1 is selected from the group consisting of
  • the invention is related to a compound wherein R 1 is selected from the group-consisting of
  • R 1 is selected from the group consisting of
  • each Rx is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3 ⁇ -heterocyclyl, and Cs-io-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C 1-6 -alkyI, Ci -6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C ⁇ s-heterocyclyl and Cs-io-cycloalkyl may optionally be substituted with one or more sub- stituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perha- lomethyl, perhalomethoxy, C 1-6 -alkyl, C 1-6 -aikoxy, C 2
  • each Rx is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, Ci -6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, aryl, heteroaryl, C 3-8 - heterocyclyl, and C 3- io-cycloalkyl;
  • R 1 is selected from the group consisting of
  • each Rx is independently selected from halogen, perhalomethyl, perhalomethoxy, C 1-
  • R 4 is selected from fluor, chlor, methyl, perhalomethyl or perhalomethoxy.
  • the invention is concerned with compounds, having one free -
  • the invention is concerned with compounds having one free amino group, or one monosubstituted amino group or one disubstituted amino group. In another embodiment the invention is concerned with compounds having one substituted or unsubstituted pyridine ring.
  • the invention is concerned with compounds having one substituted or unsubstituted imidazole ring. In another embodiment the invention is concerned with compounds wherein the molar weight of said compound is less than 650 g/mole.
  • the property cLog P of a compound which has no ionisable group is calculated using Sybyl 6.6 from Tripos Corporation, version 4.0 (provided by Biobyte Corp., Claremont CA, USA).
  • the invention is concerned with compounds wherein the compound contains no ionisable group and wherein cLog P is in the range from 1.0 to 6.0.
  • the invention is concerned with compounds wherein the compound contains no ionisable group and wherein cLog P is in the range from 1.0 to 5.0.
  • the invention is concerned with compounds wherein the compound contains no ionisable group and wherein cLog P is in the range from 1.0 to 4.0.
  • the invention is concerned with compounds wherein the compound contains no ionisable group and wherein cLog P is in the range from 2.0 to 4.0.
  • Tripos Corporation i.e. the number of H-bond donors, the number of H-bond acceptors, the number of rotatable bonds.
  • the polar surface area (PSA) is calculated using the SAVoI program Based on SAVoI 3.7 using Allinger vdw radii.
  • Polar atoms are oxygens, nitrogens, plus hydrogens attached to O and N developed by R. S. Pearlman, J. M. Skell and F. Deanda, Laboratory for Molecular Graphics and Theoretical Modeling, College of Pharmacy, University of Texas, Austin, TX 78712, U.S.A.
  • the invention is concerned with compounds wherein the ACD LogD is in the range from 0.8 to 3.0. In another embodiment the invention is concerned with compounds wherein the number of H-bond donors is 0, 1 , 2 or 3.
  • the invention is concerned with compounds wherein the number of H-bond donors is 0, 1 , or 2.
  • the invention is concerned with compounds wherein the number of H-bond acceptors is in the range from 4 to 9. In another embodiment the invention is concerned with compounds wherein the number of H-bond acceptors is in the range from 6 to 8.
  • the invention is concerned with compounds wherein the number of rotatable bonds of said compound is in the range from 4 to 14. In another embodiment the invention is concerned with compounds wherein the number of rotatable bonds of said compound is in the range from 8 to 12. In another embodiment the invention is concerned with compounds wherein the polar surface area (PSA) is in the range from 50 A 2 to120 A 2 .
  • PSA polar surface area
  • the invention is concerned with compounds wherein the polar surface area (PSA) is in the range from 60 A 2 to100 A 2 .
  • PSA polar surface area
  • Methyl-phenyl-carbamic acid 5-(4-dimethylaminomethyl-benzoylamino)-pyridin-2-yl es- ter.Methyl-phenyl-carbamic acid 5-(4-diethylaminomethyl-benzoylamino)-pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-(4-pyrrolidin-1-ylmethyl-benzoyIamino)-pyridin-2-yl ester,
  • Methyl-phenyl-carbamic acid 5-[(piperidine-1-carbothioyl)-amino]-pyridin-2-yl ester
  • Methyl-phenyl-carbamic acid 5-[(4-methyl-piperidine-1-carbothioyl)-amino]-pyridin-2-yl ester
  • Methyl-p-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2/-/-[1 ,3']bipyridinyl-6'- yl ester,
  • Methyl-m-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2/-/-[1,3']bipyridinyl-6'- yl ester,
  • Methyl-(3-trifluorornethyl-phenyl)-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro- 2H-[1 ,3']bipyridinyl-6'-yl ester, (3-Bromo-phenyl)-methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2/-/- [1.S'Jbipyridinyl- ⁇ '-yl ester,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • the invention is concerned with a pharmaceutical composition in unit dosage form, comprising from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferable from about 1.0 to about 100 mg of said compound according to the invention or pharmaceutically acceptable salt thereof.
  • the invention is concerned with a pharmaceutical composition for use as a medicament for inhibiting the lipolytic activity of hormone-sensitive lipase against triacyl- glycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters, said composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • the invention is concerned with a pharmaceutical composition which is for oral administration. In another embodiment the invention is concerned with a pharmaceutical composition which is for nasal, transdermal, pulmonal, or parenteral administration.
  • the present invention relates to use of a compound according to the invent- tion for the preparation of a pharmaceutical composition.
  • the invention is concerned with use of a compound according to the invention for inhibition of hormone sensitive lipase.
  • the invention is concerned with use of a compound according to the invention for preparation of a pharmaceutical composition for inhibition of the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters.
  • the invention is concerned with use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment or prevention of any disorder where it is desirable to modulate the plasma level of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and/or glucose; and/or modulate intracellular triacylglycerol and cholesterol ester stores, intracellular level of fatty acids, fatty acid esters such as diacylglycerols, phosphatidic acids, long chain acyl-CoA's as well as citrate or malonyl-CoA; and/or increase insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic ⁇ cells; and/or modulate insulin secretion from pancreatic ⁇ cells.
  • fatty acid esters such as diacylglycerols, phosphatidic acids, long chain acyl-CoA's as well as citrate or malonyl-CoA
  • the invention is concerned with the above use wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 , diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atheroschlerosis, hypertension, abnormalities of lipoprotein metabolism and any combination thereof.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of dyslipidemia.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of hyperlipidemia.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of hyperglycemia.
  • the invention is concerned with the use of a compound according to the invention for lowering HbA 10 .
  • the invention is concerned with the preparation of a pharmaceutical composition for the treatment and/or prevention of diabetes type 2.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention impaired glucose tolerance.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of metabolic syndrome X.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of atheroschlerosis.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for delaying or prevention of the progression from impaired glucose tolerance to diabetes type 2.
  • the invention is concerned with the use of a compound according to the invention for the preparation of a pharmaceutical composition for delaying or prevention of the progression from non-insulin requiring diabetes type 2 to insulin requiring diabetes type 2.
  • the invention is concerned with the use according to above indica- tionns wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is used.
  • the invention is concerned with the use according to above indications, wherein metformin is also used.
  • the present invention is related to a method of treating a disorder of a patient where modulation of the activity of hormone-sensitive lipase is desired, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
  • the invention is concerned with a method of treating a disorder of a patient where lowering of the activity of hormone-sensitive lipase is desired, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof.
  • the invention is concerned with the above methods wherein said administration is carried out by the oral, nasal, transdermal, pulmonal, or parenteral route.
  • the invention is concerned with the above methods wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 , diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atherosclerosis, hypertension, abnormalities of lipoprotein metabolism and any combination thereof.
  • the invention is concerned with the above methods wherein the therapeutically effective amount of the compound is from about 0.05 to about 2000 mg, pref- erably from about 0.1 to about 500 mg and even more preferable from about 1.0 to about 100 mg of said compound per day.
  • the invention is concerned with the above methods wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is administered to the patient.
  • the invention is concerned with above methods wherein metformin is also administered to the patient.
  • the present invention is related to a process P 1 for the preparation of a compound of the invention or its pharmaceutically acceptable salt, which comprises reacting the appropriate alcohol with the appropriate carbamoylating reagent in a solvent according to the reaction scheme P 1 and isolating the disubstituted carbamate product.
  • said solvent is selected from the group consisting of tetrahydrofurane, dimethylformamide and N-methylpyrolidone.
  • said base is selected from the group consisting of triethylamine, N,N-diisopropyl-N-ethylamine and DABCO.
  • the present invention relates to a process P 2 for the preparation of a compound of the invention, said process comprising the treatment of the appropriate amine with the appropriate acylating reagent in a solvent and in the presence of a base according to the reaction scheme P 2
  • Lv is CI.
  • said solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and dichloromethane.
  • said base is selected from the group consisting of trimethylamine, triethylamine, ethyl-diisopropyl-amine and 1 ,4-diazabicyclo[2.2.2]octane.
  • said base is present as a functionality in one or both of the substituents R 3 and R 4 , thus forming a salt with the acid H-Lv.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, parnoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycero
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, di- methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetrame- thylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula I 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 like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.
  • Organic bases like lysine, arginine, diethanolamine, choline
  • acid addition salts wherever 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, ascorbic
  • 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 preferred methods include use of microbial resolution, enzymatic 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, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
  • the compound of formula I 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 I may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of compound of general formula I forming part of this invention may be prepared by crystallization of compound of formula I 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 encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug de- rivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
  • the invention relates to the use of compounds of the general formula I or their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically ac- ceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders where a decreased level of plasma FFA is desirable, such as the conditions mentioned above.
  • the present invention relates to a method of treating and/or preventing type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
  • the present invention relates to the use of one or more compounds of the general formula I, or pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
  • the present compounds are useful for the delaying or prevention of the progression from impaired glucose tolerance to type 2 diabetes.
  • the present compounds are useful for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the present compounds reduce triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity.
  • the compounds of general formula I are useful for the treatment of hy- perglycemia, elevated HbA 10 level, hyperinsulinemia, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome X, insulin resistance, impaired lipid tolerance, cystic fibrosis related diabetes, polycystic ovarian syndrome, and gestational diabetes.
  • the compounds of general formula I are useful for the treatment of obesity, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, essential hypertension, acute hypertensive emergency, arteriosclerosis, atherosclerosis, restenosis, intermittent claudication (atherosclerosis oblitterens), cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary artery disease, heart insufficiency, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, acute coronary syndrome, angina pectoris, unstable angina, cardiac bypass re- occlusion, diastolic dysfunction, systolic dysfunction, non-Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, and
  • the compounds of general formula I may be useful for the treatment of diabetic retinopathy, background retinopathy, preproliferative retinopathy, prolif- erative retinopathy, macular edema, cataracts, nephropathy, nephrotic syndrome, diabetic nephropathy, microalbuminuria, macroalbuminuria, neuropathy, diabetic neuropathy, distal symmetrical sensorimotor polyneuropathy, and diabetic autonomic neuropathy.
  • the compounds of general formula I are useful for increasing the number of beta-cells in a patient, increasing the size of beta-cells in a patient or stimulating beta-cell proliferation, modulating beta-cell function and insulin secretion in a patient in need thereof, which method comprises administration of an effective amount of a compound of formula I to a patient in need thereof.
  • the compounds of the invention are also believed to be useful for reducing body weight in a patient in need thereof.
  • the compounds of the invention are also believed to be useful for weight neutral treatment of above mentioned diseases.
  • the compounds of the invention are also believed to be useful for redistributing fat in a pa- tient in need thereof.
  • the compounds of the invention are also believed to be useful for redistributing central fat in a patient in need thereof.
  • the compounds of the invention are also believed to be useful for reducing or preventing central obesity.
  • the compounds of the invention are also believed to be useful for reducing postprandial serum lipid excursions.
  • the compounds of the invention are also believed to be useful for the treatment of fatty acid oxidation disorders such as MCAD.
  • the compounds of general formula I are believed to be useful for the treatment of a disease, condition or disorder wherein cholesterol is a precursor.
  • diseases, conditions or disorders may relate to testosterone, e.g. male contraception, excessive testosterone levels, PCOS and prostate cancer. They may also relate to Cortisol or cortico- tropin, e.g. Cushing disease.
  • the compounds of the invention are also believed to be useful for the treatment of cancer.
  • the compounds of the general formula I may be useful for the treatment of insulinoma (pancreatic islet cell tumors), e.g. malignant insulinomas and multiple insulinomas, adipose cell carcinomas, e.g. lipocarconoma.
  • insulinoma pancreatic islet cell tumors
  • adipose cell carcinomas e.g. lipocarconoma
  • the compounds of the invention are also believed to be useful for the treatment of phaechromocytoma and other diseases with increased catecholamine incretion.
  • the compounds of the invention are also believed to be useful for the treatment of prostate cancer, e.g. adenocarcinoma.
  • the compounds of general formula I may be useful for the treatment of hepatic steatosis.
  • the compounds of general formula I may be useful for the treatment of cirrhosis. In still another aspect, the compounds of general formula I may be useful for the treatment of AIDS or an AIDS related diseases, condition or disorders
  • the compounds of general formula I may be useful for the treatment of lipodystrophy
  • the compounds of general formula I may be useful for the treatment of lactic acidosis.
  • the compounds of the present invention are expected to be useful for the treatment of CNS diseases, conditions or disorders.
  • the compound of the present invention may be used for the treatment of Parkinsons disease, Alzheimers disease, ADHD (Attention Deficit Hyperactivity Disorder), feeding disorders such as bulimia and anorexia, depression, anxiety, cognitive memory disorders, age related cognitive decline, mild cognitive impairment and schizophrenia.
  • the compounds of the present invention may be useful for the treatment of inflammatory disorders, e.g. rheumatoid arthritis, psoriasis, systemic inflammatory response syndrome, sepsis and the like.
  • the present compounds may also be administered in combination with one or more further pharmacologically active substances eg., selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications re- suiting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • further pharmacologically active substances eg., selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications re- suiting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine am- phetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, se- rotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone
  • the antiobesity agent is leptin.
  • the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • Suitable antidiabetics comprise insulin, exendin-4, GLP-1 (glucagon like peptide-1) and derivatives thereof such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potas- sium channel of the ⁇ -
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide eg. metformin.
  • the present compounds are administered in combination with a meglitinide eg. repaglinide or senaglinide.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg. miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor eg. miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofi- brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin con- verting enzyme) inhibitors such as benazepril, captopril, alatriopril, enalapril, fosinopril, lisi- nopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition,
  • the present invention also relates to processes according to reaction schemes P 1 and P 2 for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceu- tically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacol 9 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route be- ing preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropri- ate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • the therapeutic dose of the compound will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • the composition in unit dosage form comprises from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg of the compound of formula I pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is for oral, nasal, transdermal, pulmonal, or parenteral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • solutions of the present compounds in sterile aqueous solution aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • 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.
  • compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may con- veniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emul- sion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • the compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the present compounds may be administered in combination with further pharmacologically active substances e.g. an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prevention of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism.
  • the compounds according to the invention may be administered in combination with antiobesity agents or appetite regulating agents.
  • Step A Thionyl chloride (100 mL) was added to a stirred solution of (6-methoxy-pyridin-3- yl)-methanol (31.0 g, 223 mmol) in chloroform (300 mL). After refluxing for 2 hours, the solvent and excess thionyl chloride were removed by evaporation in vacuo. The residue was stripped with toluene, dissolved in dichloromethane (400 mL) and extracted with a saturated aqueous sodium bicarbonate solution (200 mL). The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo, yielding a yellow oil.
  • Step D During 5 minutes HCI-gas was bubbled into a solution of 1-[2-(6-methoxy-pyridin-3- yl)-ethyl]-4,4-dimethyl-piperidine-2,6-dione (1.15 g, 4.18 mmol) in tetrahydrofuran (25 mL). Ether (200 mL) was added and the solvent was evaporated in vacuo. The residue was heated for 5 minutes at 180 0 C. After cooling to room temperature the solid was dissolved in dichloromethane (10 mL).
  • Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (1.22 g, 5.00 mmol) was added in portions to a stirred solution of di-2-pyridyl thionocarbonate (1.16 g, 5.00 mmol) in 1 ,2-dichIoropropane (15 mL).
  • alpha- aminoisobutyric acid methyl ester hydrochloride (0.77 g, 5.00 mmol
  • triethylamine 0.7 mL
  • DL-alpha-amino-n-butyric acid methyl ester hydrochloride (2.00 mmol, 307 mg) was added to a solution of methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.00 mmol) in 1,2-dichloropropane (5 mL). A small amount of methanol was added to get a clear solution. Triethylamine (0.28 mL, 2.00 mmol) was added and the solution was stirred overnight at room temperature. Dichloromethane was added and the reaction mixture was extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo.
  • O-M3utyl-D-serine acid methyl ester hydrochloride (2.00 mmol, 307 mg) was added to a solution of methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.00 mmol) in dichloromethane (10 ml_). Triethylamine (0.28 mL, 2.00 mmol) was added and the solution was stirred for 7 days at room temperature. Part of the solvent was removed by evaporation in vacuo.
  • Phosgene (5 mL, 20% in toluene) was added to a stirred suspension of 6'-hydroxy- 4,4-dimethyl-4,5-dihydro-3/-/-[1 ,3']bipyridinyl-2,6-dione (0.47 g, 2.00 mmol) and triethylamine (0.29 mL, 2.00 mmol) in dichloromethane (10 mL). After stirring for 0.75 h at room temperature, the solvent and excess phosgene were evaporated under reduced pressure, yielding a white solid.
  • Morpholine (0.144 mL, 1.65 mmol) was added to a stirred suspension of methyl- phenyl-carbamic acid 5-(4-formyl-benzoylamino)-pyridin-2-yl ester (0.56 g, 1.5 mmol) in methanol (15 mL). The solution was warmed carefully to get the starting material into solution. After stirring for 0.5 hours at room temperature sodium cyanoborohydride (104 mg, 1.65 mmol) was added and stirring was continued at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography (SiO 2 ), yielding the title compound (38 mg, 6% yield).
  • Example 46 Using the procedure as described in Example 46 and starting from 4,4- dimethylpiperidine hydrochloride (0.22 g, 1.50 mmol), ⁇ /-ethyldiisopropylamine (0.52 ml_, 3.00 mmol) and methyl-phenyl-carbamic acid 5-(4-chloromethyl-benzoylamino)-pyridin-2-yl ester (0.40 g, 1.00 mmol) and stirring for 3 days yielded the title compound (341 mg, 72% yield) as a white solid.
  • Example 46 Using the procedure as described in Example 46 and starting from 4-ketopiperidine hydrate hydrochloride (154 mg, 1.00 mmol), /V-ethyldiisopropylamine (259 mg, 2.00 mmol) and methyl-phenyl-carbamic acid 5-(4-chloromethyl-benzoylamino)-pyridin-2-yl ester (0.40 g, 1.00 mmol) and stirring for 2 days yielded the title compound (358 mg, 78% yield).
  • Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.73 g, 3.00 mmol) was added to a solution of di-2-pyridyl thionocarbonate (0.70 g, 3.00 mmol) in dichloromethane (15 mL). After stirring for 2 hours 2-amino-2-methyl-1-propanol (0.27 g, 3.00 mmol), dissolved in a small amount of dichloromethane, was added in one portion. Stirring was continued overnight at room temperature. The product was purified by flash column chromatography (SiO 2 , gradient of 80-100% ethyl acetate in heptane). Crystallisation from ethyl ace- tate/heptane yielded the title compound (907 mg, 81 % yield) as a white solid.
  • Methyl-phenyl-carbamic acid 5-amino-pyridin-2 ⁇ yl (243 mg, 1.00 mmol) was added to a solution of di-2-pyridyl thionocarbonate (232 mg, 1.00 mmol) in dichloromethane (5 mL).
  • Step A A solution of 4-aminophenethylalcohol (2.03 g, 14.8 mmol) in ethyl formate (15 mL) was heated at reflux overnight. After cooling to room temperature heptane was added to the reaction mixture. The solvent was decanted from the oil and the last traces of solvent were removed in vacuo. Dichloromethane was added to the residue and the precipitate was isolated by suction, yielding ⁇ /-[4-(2-hydroxyethyl)-phenyl]-formamide (1.95 g, 80% yield), which was used without further purification in the next step
  • Step B Under a nitrogen atmosphere, a solution of ⁇ /-[4-(2-hydroxyethyl)-phenyl]-formamide
  • Compounds of formula I may be evaluated in vitro for their efficacy and potency to inhibit HSL, and such evaluation may be performed as described below.
  • HSL Hormone-sensitive lipase
  • the Hormone-sensitive lipase was provided by Dr. Cecilia Holm, from Lund University Sweden or produced and purified by Novo Nordisk (NN) using the reagents and protocols used by Dr. Holm.
  • the substrates used are: 3 H-Iabeled triolein (TO) from Amersham, Buckinghamshire, U.K. cat No. TRA191 ; 5-20 Ci/mmol dissolved in toluene, triolein (Sigma, Cat. No.
  • PC phosphatidyl choline
  • Pl phosphatidyl inositol
  • a lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration of highly purified HSL (12 ⁇ g/mL initial concentration corresponding to 600ng/mL final concentration). BSA is added as product acceptor.
  • the transfer of the fluorochrome from the lipid phase to the water (BSA) phase changes the fluo- rescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450nm and an emission wavelength of 545nm.
  • Compound and HSL (20 ⁇ L compound, 10 ⁇ l_ enzyme and 70 ⁇ L PED-BSA buffer) is pre-incubated for 30min at 25 0 C before addition of substrate (100 ⁇ l_). Amount of formed product is measured after 120min incubation at 37 0 C.
  • Results are given as percent activity relative to a non-inhibited sample (no compound).
  • 3190.2 Assay for determination of IC 50 value for the inhibition of hormone sensitive lipase by compound. Standard concentrations of compound are 100//M and 5-fold dilutions (initial concentration corresponding to 10//M final concentration and 5-fold).
  • a lipid emulsion with fluorochrome-iabeled triacylglyceride and phospholipid is used as substrate with a standard concentration of highly purified HSL (12 ⁇ g/mL initial concentration corresponding to 600ng/mL final concentration).
  • BSA is added as product acceptor.
  • the transfer of the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450nm and an emission wavelength of 545nm.
  • Compound and HSL (20 ⁇ L compound, 10 ⁇ L enzyme and 70 ⁇ L PED-BSA buffer) is pre-incubated for 30min at 25 0 C before addition of substrate (1 OO ⁇ L). Amount of formed product is measured after 120min incubation at 37 0 C.
  • Results are given as IC 50 values after 4PL fit of obtained activity data.

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Abstract

L'invention concerne de nouveaux carbamates de pyridinyle substitués de formule (I), des compositions pharmaceutiques les contenant, ainsi que l'utilisation desdits composés pour traiter et/ou prévenir des maladies et des troubles liés à la lipase hormono-sensible. Les composés selon l'invention servent notamment à traiter et/ou prévenir des maladies et des troubles pour lesquel(le)s la modulation de l'activité de la lipase hormono-sensible est bénéfique.
PCT/DK2004/000391 2003-06-12 2004-06-08 Carbamates de pyridinyle utilises en tant qu'inhibiteurs de la lipase hormono-sensible WO2004111031A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BRPI0411255-5A BRPI0411255A (pt) 2003-06-12 2004-06-08 composto, composição farmacêutica, uso de um composto, métodos de tratar um distúrbio de um paciente, e, processo para a preparação de um composto
MXPA05013224A MXPA05013224A (es) 2003-06-12 2004-06-08 Piridinilcarbamatos como inhibidores de lipasa sensible a hormonas.
CA002526204A CA2526204A1 (fr) 2003-06-12 2004-06-08 Carbamates de pyridinyle utilises en tant qu'inhibiteurs de la lipase hormono-sensible
EP04736303A EP1636205A1 (fr) 2003-06-12 2004-06-08 Carbamates de pyridinyle utilises en tant qu'inhibiteurs de la lipase hormono-sensible
AU2004247319A AU2004247319A1 (en) 2003-06-12 2004-06-08 Pyridinyl carbamates as hormone-sensitive lipase inhibitors
JP2006515703A JP2006527210A (ja) 2003-06-12 2004-06-08 ホルモン感受性リパーゼ阻害剤としてのピリジニルカルバメート
US11/301,224 US20060160865A1 (en) 2003-06-12 2005-12-12 Pyridinyl carbamates
NO20060168A NO20060168L (no) 2003-06-12 2006-01-12 Pyridinylkarbamater som hormonsensitive lipaseinhibitorer

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DKPA200300879 2003-06-12
DKPA200300879 2003-06-12
US47852603P 2003-06-13 2003-06-13
US60/478,526 2003-06-13

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Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006087308A1 (fr) * 2005-02-15 2006-08-24 Novo Nordisk A/S Ester et sels d'acide methylphenylcarbamique 5-(4-isobutyl-2,6,-dioxopiperazine-l-yl) pyridinyle-2-yl comme inhibiteurs de lipase hormonosensible
WO2007106525A1 (fr) * 2006-03-13 2007-09-20 The Regents Of The University Of California Inhibiteurs d'uree a conformation restreinte d'epoxyde hydrolase soluble
US20080139634A2 (en) * 2006-03-29 2008-06-12 Regents Of The University Of California Diarylthiohydantoin compounds
JP2009506125A (ja) * 2005-08-29 2009-02-12 ジェラルド・エム・ハウシー セラミューテイン・モジュレーター
US7662910B2 (en) 2004-10-20 2010-02-16 The Regents Of The University Of California Inhibitors for the soluble epoxide hydrolase
EP2004181A4 (fr) * 2006-03-27 2010-11-10 Univ California Modulateur de récepteur androgène pour le traitement du cancer de la prostate et de maladies associées au récepteur androgène
US8173669B2 (en) 2007-02-09 2012-05-08 Sanofi-Aventis Azabicycloalkane derivatives, preparation thereof and use thereof in therapy
US8183274B2 (en) 2005-05-13 2012-05-22 The Regents Of The University Of California Treatment of hyperproliferative disorders with diarylhydantoin compounds
US8455652B2 (en) 2003-04-03 2013-06-04 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Inhibitors for the soluble epoxide hydrolase
US8513302B2 (en) 2003-04-03 2013-08-20 The Regents Of The University Of California Reducing nephropathy with inhibitors of soluble epoxide hydrolase and epoxyeicosanoids
US8680291B2 (en) 2007-10-26 2014-03-25 The Regents Of The University Of California Diarylhydantoin compounds
WO2015089137A1 (fr) 2013-12-11 2015-06-18 Karos Pharmaceuticals, Inc. Acylguanidines comme inhibiteurs de la tryptophan hydroxylase
US9108944B2 (en) 2010-02-16 2015-08-18 Aragon Pharmaceuticals, Inc. Androgen receptor modulators and uses thereof
US9199994B2 (en) 2013-09-06 2015-12-01 Karos Pharmaceuticals, Inc. Spirocyclic compounds as tryptophan hydroxylase inhibitors
AU2013205325B2 (en) * 2006-03-27 2016-03-24 The Regents Of The University Of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
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US9340524B2 (en) 2013-01-15 2016-05-17 Aragon Pharmaceuticals, Inc. Androgen receptor modulator and uses thereof
WO2016109501A1 (fr) 2014-12-30 2016-07-07 Karos Pharmaceuticals, Inc. Composés amides utilisés en tant qu'inhibiteurs de la tryptophane hydroxylase
AU2016201061B2 (en) * 2006-03-27 2017-03-02 The Regents Of The University Of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
US9611201B2 (en) 2015-03-05 2017-04-04 Karos Pharmaceuticals, Inc. Processes for preparing (R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol and 1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanone
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9884054B2 (en) 2012-09-26 2018-02-06 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
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US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10377741B2 (en) 2011-12-28 2019-08-13 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10501469B2 (en) 2016-01-11 2019-12-10 Janssen Pharmaceutica Nv Substituted thiohydantoin derivatives as androgen receptor antagonists
WO2020099929A1 (fr) 2018-11-14 2020-05-22 Roivant Sciences Gmbh Inhibiteur de composé spirocyclique cristallin de tryptophane hydroxylase 1 (tph1) pour le traitement de maladies ou de troubles associés à la sérotonine périphérique
US10683285B2 (en) 2018-11-19 2020-06-16 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US10702508B2 (en) 2017-10-16 2020-07-07 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007298539B2 (en) * 2006-09-21 2013-05-02 Piramal Enterprises Limited Pyridine derivatives for the treatment of metabolic disorders related to insulin resistance or hyperglycemia
EP3722290B1 (fr) 2013-04-12 2023-06-21 VALENTA-INTELLEKT Limited Dérivé de glutarimide, son utilisation, composition pharmaceutique basée sur celui-ci et procédés de production du dérivé de glutarimide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10010968A1 (de) * 2000-03-07 2001-09-13 Aventis Pharma Gmbh Substituierte 3-Phenyl-5-alkoxi-1,3,4-oxdiazol-2-one, ihre Herstellung und Verwendung in Arzneistoffen
WO2001087843A1 (fr) * 2000-05-15 2001-11-22 Novo Nordisk A/S Composes destines au traitement de troubles dans lesquels une diminution du niveau d'agl du plasma est voulue
WO2003051841A2 (fr) * 2001-12-14 2003-06-26 Novo Nordisk A/S Composes ralentissant l'activite de la lipase hormono-sensible

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10063008A1 (de) * 2000-12-16 2002-06-20 Merck Patent Gmbh Carbonsäureamidderivate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10010968A1 (de) * 2000-03-07 2001-09-13 Aventis Pharma Gmbh Substituierte 3-Phenyl-5-alkoxi-1,3,4-oxdiazol-2-one, ihre Herstellung und Verwendung in Arzneistoffen
WO2001087843A1 (fr) * 2000-05-15 2001-11-22 Novo Nordisk A/S Composes destines au traitement de troubles dans lesquels une diminution du niveau d'agl du plasma est voulue
WO2003051841A2 (fr) * 2001-12-14 2003-06-26 Novo Nordisk A/S Composes ralentissant l'activite de la lipase hormono-sensible

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T.R.KELLY ET AL.: "Facile metal-assisted hydrolysis of a urethane", ORGANIC LETTERS, vol. 3, no. 24, 2001, pages 3895 - 3898, XP002294791 *

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EP1636205A1 (fr) 2006-03-22
KR20060017791A (ko) 2006-02-27
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