WO2002032896A1 - Derives de furazanyl-triazole destines au traitement de maladies - Google Patents

Derives de furazanyl-triazole destines au traitement de maladies Download PDF

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WO2002032896A1
WO2002032896A1 PCT/DK2001/000676 DK0100676W WO0232896A1 WO 2002032896 A1 WO2002032896 A1 WO 2002032896A1 DK 0100676 W DK0100676 W DK 0100676W WO 0232896 A1 WO0232896 A1 WO 0232896A1
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alkyl
pharmaceutical composition
compound
pharmaceutically acceptable
substituted
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PCT/DK2001/000676
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Preben Houlberg Olesen
Peter Kurtzhals
Helle Worsaae
Bo Falck Hansen
Anders Robert SØRENSEN
Andrew Neil Bowler
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Novo Nordisk A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to pharmaceutical compositions comprising 1-(furazan-3-yl)- [1 ,2,3]triazole derivatives for the treatment and/or prevention of disorders and diseases, wherein an inhibition of GSK-3 (glycogen synthase kinase-3) is beneficial, especially Alzheimer's disease, bipolar disorder, IGT (impaired glucose tolerance), Type 1 diabetes, Type 2 diabetes and obesity.
  • GSK-3 is a protein-serine kinase implicated in the hormonal control of several regulatory proteins. It was first discovered by virtue of its ability to phosphorylate and inactivate glycogen synthase, the regulatory enzyme of glycogen synthesis in mammals (Embi, N. et al. (1980), EUR J BIOCHEM 107, 519-527; Rylatt, D. B. et al. (1980), EUR J BIOCHEM 107, 529-537). Since then a number of other substrates have been identified, implicating the enzyme in the regulation of several physiological processes.
  • GSK-3 exists in two isoforms, termed GSK-3 ⁇ and GSK-3 ⁇ , which are derived from distinct genes and show 85% sequence identity. Unlike many protein kinases, both GSK-3 isoforms are constitutively active in resting cells, and are primarily regulated by inactivation. Thus, it has been shown that GSK-3 is inhibited by serine phosphorylation in response to insulin and growth factors such as IGF-1 and EGF via activation of the MAP kinase cascade or via PI3 kinase dependent activation of protein kinase B.
  • GSK-3 activity is useful in the treatment of diseases, disorders and conditions, wherein such an inhibition is beneficial, eg in diseases, disorders and conditions related to GSK-3, in diseases, disorders and conditions related to a dysfunction of GSK-3, in diseases, disorders and conditions in which growth factor induced inhibition of GSK-3 is insufficient and in diseases, disorders and conditions in which glycogen synthase is insuffi- ciently activated.
  • Type 1 diabetes also known as insulin dependent diabetes mellitus (IDDM)
  • IDDM insulin dependent diabetes mellitus
  • IDDM insulin dependent diabetes mellitus
  • 6230.204-WO diabetic remains susceptible to the long-term and devastating complications of diabetes, such as cardiovascular disease, retinopathy, nephropathy and neuropathy.
  • Type 2 diabetes also known as non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • Type 2 diabetes results from defects in both insulin secretion and insulin action, but the exact underlying mechanism(s) causing the disease are not known.
  • An elevation of hepatic glucose production contributes significantly to causing fasting hyperglycemia, whereas decreased insulin-mediated glucose uptake by muscle and fat is a major contributor to postprandial hy- perglycemia.
  • the metabolic fate of glucose taken up by muscle is not normal in people with Type 2 diabetes. For example muscle glycogen synthase activity and glycogen synthesis have been shown to be impaired in Type 2 diabetes.
  • the available treatments do not allow for a complete normalisation of the metabolic state and some of them are associated with side effects.
  • GSK-3 expression is elevated in muscle of people with Type 2 diabetes and that the GSK-3 expression is inversely correlated with both glycogen synthase activity and glucose disposal.
  • an increased GSK-3 expression may contribute to the impaired glycogen synthase activity and insulin resistance that occurs in Type 2 diabetes.
  • Other recent experiments have suggested a role for GSK-3 in attenuating insulin action via its phosphorylation of insulin receptor substrate 1.
  • GSK-3 inhibitors may be useful for the treatment of metabolic disorders, such as IGT, Type 1 diabetes and Type 2 diabetes.
  • GSK-3 is also involved in biological pathways relating to Alzheimer's disease and GSK-3 inhibitors may be useful in the treatment thereof.
  • Alzheimer's disease is characterized histopa- thologically by the presence of intraneuronal neurofibrillary tangles and the extracellular deposition of ⁇ amyloid in the brain, especially the hippocampus.
  • the neurofibrillary tangles are made up of paired helical filaments (PHFs), the major protein subunit of which is the abnormally phosphorylated and glycosylated microtubule associated protein tau ( ⁇ ).
  • PHFs paired helical filaments
  • ⁇ glycosylated microtubule associated protein tau
  • GSK-3 is one of several kinases that phosphorylates tau in vitro on the abnormal sites characteristic of PHF-tau and has also been demonstrated to do this in living cells. Furthermore, the GSK-3 inhibitor lithium blocks tau hyperphosphorylation in cells. Further evidence for a role of GSK-3 in Alzheimer's disease is provided by ia (i) the association of GSK-3 with presenellin 1 , (ii) reduced cytotoxicity of ⁇ amyloid protein in neuronal cells incubated with GSK-3 antisense and (iii) 50% increased expression of GSK-3 in postsynaptic supematants of Alzheimer's disease compared to normal brain tissue.
  • Lithium has been used for decades in the treatment of manic depression (bipolar disorder).
  • the mechanism of action of lithium as a mood-stabilizing agent remains unknown, although effects on biological membranes and synaptic neurotransmission have been suggested.
  • GSK-3 activity could be implicated in the etiology of bipolar disorder.
  • One mechanism by which lithium and other GSK-3 inhibitors may act to treat bipolar disorder is to increase the survival of neurons subjected to aberrantly high levels of excitation induced by the neurotransmitter glutamate. Glutamate may also be implicated in mediating neurodegenera- tion following acute damage, eg in cerebral ischemia, traumatic brain injury and bacterial, viral and prion infection.
  • GSK-3 inhibitors may be useful in the treatment of these and other neurodegenerative disorders.
  • lithium has a variety of biological effects that, if mediated
  • GSK-3 has been shown to phosphorylate the transcription factor NF-AT, which participates in the activation of early immune response genes. Phosphorylation prevents translocation of NF-AT to the nucleus and thus blocks early immune responses.
  • GSK- 3 inhibitors may prolong and potentiate the immunostimulatory effect of certain cytokines and such an effect could be beneficial in the use of cytokines for cancer or immunotherapy.
  • WO 98/16528 discloses purine derivates, which are stated to be effective as GSK-3 inhibitors.
  • WO 99/65897 discloses pyrimidine and pyridine derivates, which are stated to be effective as GSK-3 inhibitors.
  • WO 00/21927 discloses 3-amino-4-maleimide derivatives, which are stated to be effective as GSK-3 inhibitors.
  • WO 00/38675 discloses a method for the treatment and/or prophylaxis of conditions associated with a need for the inhibition of GSK-3 comprising the administration of different groups of known compounds, ia bisindole maleimide derivatives, indole aryl maleimides and indolocarbazole derivatives. These compounds differ structurally from the present compounds.
  • the identification of potent and specific GSK-3 inhibitors would be a highly desirable contribution to the art.
  • the present invention provides such a contribution to the art being based on the finding that the 1-(furazan-3-yl)-[1,2,3]triazole derivatives derivatives of the general formula (I) potently and specifically inhibit GSK-3.
  • the present compounds are accordingly useful in the treatment and/or prevention of a wide range of conditions and disorders in which an inhibition of GSK-3 is beneficial.
  • Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
  • C ⁇ -alkyl in the present context designates a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, n-pentyl, isopentyl, neopentyl, te/ ⁇ -pentyl, n-hexyl, isohexyl and the like.
  • C ⁇ -alkoxy in the present context designates a group -O-C ⁇ -alkyl, wherein C ⁇ -alkyl is as defined above.
  • Representative examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, fert-butoxy, n-pentoxy, isopentoxy, neopentoxy, fe/ ⁇ -pentoxy, n-hexoxy, isohexoxy and the like.
  • C ⁇ -alkoxycarbonyl in the present context designates a group -C ⁇ O-C ⁇ -alkyl, wherein C ⁇ -alkyl is as defined above.
  • Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, butoxycar- bonyl, isobutoxycarbonyl, sec-butoxycarbonyl, fe/ ⁇ -butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, terf-pentoxycarbonyl, n-hexoxycarbonyl, iso- hexoxycarbonyl and the like.
  • C 2 . 6 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
  • C 2 . 6 -aIkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
  • groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
  • C 3 . 8 -cycloalkyl represents a saturated carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C 3 . 8 -heterocyclyl represents a saturated 3 to 8 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • 6230.204-WO amples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahy- drofuranyl and the like.
  • aryl represents a carbocyclic aromatic ring system 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-dihydronaphthyI and the like.
  • heteroaryl represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3- triazolyl, 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 1,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like.
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above.
  • Non- limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • heteroarylamino represents a group -NH-heteroaryl, wherein heteroaryl has the above meaning.
  • 3 to 14 membered, mono-, bi- or tricyclic carbocyclic ring system represents a carbocyclic ring system which may optionally contain one or more double bonds.
  • Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopententyl, cyclohexenyl, cycloheptyl, cyclooctyl, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, 1,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • aryl or heteroaryl representative examples are 2,3-dihydroindolyl, 1 ,3- dihydroisoindolyl and the like.
  • Aryl-C ⁇ -alkyl "heteroaryl-C ⁇ -alkyl” etc. means C ⁇ -alkyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • GSK-3 as used herein is intended to mean GSK-3 ⁇ and/or GSK- ⁇ .
  • the invention relates to, a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound of the general formula (I):
  • R 6 is hydrogen or C- ⁇ _ 6 -alkyI
  • R 7 is hydrogen, d-e-alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, aryl, heteroaryl, C 3 - 8 -cycloalkyl, C 3 . 8 -heterocyclyl, aryl-d-e-alkyl, heteroaryl-C ⁇ e-alkyl, heteroarylamino-d-e-alkyl, C 3 . 8 -cycloalkyl-C ⁇ - 6 -alkyl, C 3 . 8 -heterocyclyl-d- 6 -alkyl, aryl-C 2 . 6 -alkenyl, heteroaryl-C 2 .
  • R 8 and R 9 independently are hydrogen or C ⁇ _ 6 -alkyl, or with two substituents in adjacent positions together forming a -0-(CH 2 ) m -0- radical, wherein m is 1 or 2,
  • R 6 and R 7 when attached to the same carbon atom, together with the said carbon atom may form a mono-, bi- or tricyclic, 3 to 14 membered ring system, which is optionally substituted with one to three substituents independently selected from halogen, nitro, cyano, oxo, trifluoromethyl, hydroxy, C ⁇ -alkoxy, carboxy, d- 6 -alkoxycarbonyl, C ⁇ . 6 -alkyl, -NR 8 R 9 ,
  • n 1 or 2
  • R 2 and R 3 independently are hydrogen, d-e-alkyl, aryl, heteroaryl, aryl-d-e-alkyl or hetero- aryl-C ⁇ profession 6 -alkyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 3 to 7 membered, heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, which ring may optionally be annelated with aryl or heteroaryl,
  • R 4 and R 5 independently are hydrogen or d-e-alkyl, or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3 to 7 membered, heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur,
  • R 7 is pyridyl, 1-benzotriazolylmethyl, phenyl or furanyl, which may optionally be substituted with one to three substituents selected from C ⁇ -alkoxy, hydroxy, Ci-e-alkyl, halogen and nitro or with two substituents in adjacent positions together forming a -0-(CH 2 ) m -0- radical, wherein m is 1 or 2.
  • R 7 is pyridyl
  • R 7 is phenyl, which may optionally be substituted with one to three substituents selected from d. 6 -alkoxy, hydroxy, d. 6 -alkyl, halogen and nitro or with two substituents in adjacent positions together forming a -0-(CH 2 ) m -0- radical, wherein m is 1 or 2.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n 1
  • R 2 and R 3 independently are selected from hydrogen, d-e-alkyl, aryl-d. 6 -alkyl, aryl, heteroaryI-d. 6 -alkyl and C 3 . 8 -cycloalkyl, wherein the cyclic moieties may optionally be substituted as defined for formula (I).
  • R 2 and R 3 independently are selected from hydrogen, d-e-alkyl, phenyl-d.6-alkyl, phenyl, pyridyl-d_ 6 -alkyl and C 3 . 8 -cycloalkyl, wherein the cyclic moieties optionally may be substituted with one to three substituents selected from d- 6 -alkyl, oxo, nitro, d. 6 -alkoxycarbonyl and d. 6 -alkyl substituted with hydroxy.
  • R 2 and R 3 are both d. 6 -alkyl.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a ring system selected from 1-perhydroazepinyl, 1-piperidinyl, 1-morpholinyl, 1 ,2,3,4-tetrahydroquinolin-1-yl, 1-pyrrolidinyl, 1-piperazinyl, 2,3-dihydroindol-1-yl, 1- benzotriazol-1-yl, 1,2,3,4-tetrahydroisoquinoIin-2-yl and 1,2,4-triazol-1-yl, which may optionally be substituted as defined for formula (I).
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a ring system selected from 1-perhydroazepinyl, 1-piperidinyl, 1-pyrrolidinyl and 1-morpholinyl, which may optionally be substituted with one to three substituents selected from d. 6 -alkyl, oxo, nitro, d-e-alkoxycarbonyl and d. 6 -alkyl substituted with hydroxy.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a ring selected from 1-perhydroazepinyl, 1-piperidinyl, 1-pyrrolidinyl and 1-mor- pholinyl.
  • R 4 and R 5 are both hydrogen.
  • the pharmaceutical composition is in unit dosage form and com- prises from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound of the general formula (I) or an optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
  • the invention relates to a compound of the general formula (I'):
  • n and R 2 to R 7 are as defined for formula (I) or in any one of the above embodi- ments, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound of the general formula (II):
  • R is hydrogen or d-e-alkyl
  • R 7 is hydrogen, d-e-alkyl, C 2 . 6 -alkenyl, C 2 . 6 -alkynyl, aryl, heteroaryl, C 3 . 8 -cycloalkyl, C 3 . 8 -heterocyclyl, aryl-d. 6 -alkyl, heteroaryl-d. 6 -alkyI, C 3 _ 8 -cycloalkyl-d-6-aIkyl, C 3 . 8 -hetero- cyclyl-d-e-alkyl, aryl-C 2 . 6 -alkenyl, heteroaryl-C 2 . 6 -aIkenyl, C 3 .
  • R 8 and R 9 independ- ently are hydrogen or d-e-alkyl, or with two substituents in adjacent positions together forming a -0-(CH 2 ) m -0- radical, wherein m is 1 or 2, and
  • R 6 and R 7 when attached to the same carbon atom, together with the said carbon atom may form a mono-, bi- or tricyclic, 3 to 14 membered ring system, which is optionally substi- tuted with one to three substituents independently selected from halogen, nitro, cyano, oxo, trifluoromethyl, hydroxy, d. 6 -alkoxy, carboxy, C ⁇ - 6 -alkoxycarbonyl, C ⁇ e-alkyl, -NR 8 R 9 ,
  • n 1 or 2
  • R 2 and R 3 independently are hydrogen, d combat 6 -alkyl, aryl, heteroaryl, aryl-C ⁇ e-alkyl or hetero- aryl-d- ⁇ -alkyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 3 to 7 membered, heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, which ring may optionally be annelated with aryl or heteroaryl,
  • R 4 and R 5 independently are hydrogen or d. 6 -alkyl, or R 4 and R 5 together with the nitrogen atom to which they are attached form a 3 to 7 membered, heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur,
  • R 7 is pyridyl, 1-benzotriazolylmethyl, phenyl or furanyl, which may optionally be substituted with one to three substituents selected from C ⁇ . 6 -alkoxy, hydroxy, oxo, Ci-e-alkyl, halogen and nitro or with two substituents in adjacent positions together forming a -O-
  • R 7 is pyridyl, which is unsubstituted, or R 7 is phenyl, which may optionally be substituted with one to three substituents selected from d-e-alkoxy, hydroxy, d- 6 -alkyl, halogen and nitro or with two substituents in adjacent positions together forming a -0-(CH 2 ) m -0- radical, wherein m is 1 or 2.
  • R 6 is hydrogen and R 7 is heteroaryl-C ⁇ _ 6 -alkyl or aryl-d. 6 -alkyl, which may be substituted as defined for formula (II).
  • n 1
  • R 2 and R 3 are independently selected from Ci-e-alkyl, aryl-C ⁇ . 6 -alkyl, aryl and C 3 . 8 -cycloalkyl, wherein the cyclic moieties may optionally be substituted as defined for formula (II). More preferably, R 2 and R 3 are independently selected from Ci-e-alkyl, phenyl-C ⁇ - 6 -alkyl, phenyl and C 3 . 8 -cycloalkyl, wherein the cyclic moieties optionally may be substituted with one to three substituents selected from Ci-e-alkyl, oxo, nitro, C . 6 - alkoxycarbonyl and Ci-e-alkyl substituted with hydroxy. Even more preferably, R 2 and R 3 are both Ci-e-alkyl.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a ring system selected from 1-perhydroazepinyl, 1-piperidinyl, 1-morpholinyl, 1,2,3,4-tetrahydroquinolin-l-yl, 1-pyrrolidinyl, 1-piperazinyl, 2,3-dihydroindol-1-yl, 1- benzotriazol-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl and 1,2,4-triazol-1-yl, which may option- ally be substituted as for formula (II).
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a ring system selected from 1-perhydroazepinyl, 1-piperidinyl, 1-pyrrolidinyl and 1-morpholinyl, which may optionally be substituted with one to three substituents selected from Ci-e-alkyl, oxo, nitro, d. 6 -alkoxycarbonyl and Ci-e-alkyl substituted with hydroxy. More preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a ring selected from 1-perhydroazepinyl, 1-piperidinyl, 1-pyrrolidinyl and 1- morpholinyl.
  • R 4 and R 5 are both hydrogen.
  • the invention relates to a compound of the general formula (IT):
  • n and R 2 to R 7 are as defined for formula (II) or in any one of the above embodiments, as well as any optical or geometric isomer or tautomeric form thereof including mix- tures of these or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention.
  • geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, 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, methane- sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,
  • benzenesulfonic, p-toluenesulfonic acids and the like are further examples of pharmaceutically acceptable inorganic or organic acid addition salts.
  • pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl- ammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethyl- ammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
  • 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 derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of the present compounds.
  • the present compounds inhibit GSK-3 and accordingly they may find use in the treatment and/or delaying or prevention of the progression of hyperglycemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, hyperiipidemia, cardiovascular diseases and hypertension. Furthermore, they may find use in the treatment and/or delaying or prevention of the progression of appetite regulation and energy expenditure disorders
  • 6230.204-WO such as eating disorders eg bulimia, and other conditions, wherein a weight reduction is required.
  • bipolar disorder manic depressive syndrome
  • mania Alzheimer's disease
  • bipolar disorder Huntington's chorea
  • Parkinson's disease amyotrophic lateral sclerosis
  • multiple sclerosis leukopenia
  • anxiety movement disorder
  • aggression psychosis
  • seizures panic attacks
  • hysteria or sleep disorders a group consisting of a wide range of diseases and conditions.
  • contraceptives cf WO 97/41854
  • the present compounds are used for the manufacture of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of diseases, disorders and conditions related to GSK-3.
  • the present compounds are used for the manufacture of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of diseases, disorders and conditions, wherein growth factor induced inhibition of GSK-3 is insufficient.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of diseases, disorders and conditions, wherein glycogen metabolism exhibits abnormalities.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of diseases, disorders and conditions, wherein glycogen synthase is insufficiently activated.
  • the present compounds are used for the preparation of a pharmaceutical composition for the lowering of blood glucose, both in the fasting and postprandial stage.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the
  • the present compounds are used for the prepa- ration of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of hyperglycemia.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progressive- sion of lGT.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non- insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of Type 1 diabetes.
  • a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of Type 1 diabetes.
  • Such treatment and/or delaying or prevention are normally accompanied by insulin therapy.
  • the present compounds may be used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of Alzheimer's disease.
  • the present compounds may be used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of bipolar disorder.
  • the present compounds may be used for the preparation of a pharmaceutical composition for the treatment and/or delaying or prevention of the progression of obesity.
  • the present compounds may also be used for the preparation of a pharmaceutical composi- tion for the treatment and/or delaying or prevention of the progression of an appetite regulation or energy expenditure disorder such as an eating disorder eg bulimia or binge eating.
  • an appetite regulation or energy expenditure disorder such as an eating disorder eg bulimia or binge eating.
  • the present compounds may be administered in combination with one or more further pharmacologically active substances eg selected from antidiabetic agents, antiobesity agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes, agents for the treatment of Alzheimer's disease and agents for the treatment of bipolar disorder.
  • pharmacologically active substances eg selected from antidiabetic agents, antiobesity agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes, agents for the treatment of Alzheimer's disease and agents for the treatment of bipolar disorder.
  • the present compounds are administered in combination with one or more further antidiabetic agents.
  • Suitable antidiabetic agents comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference as well as orally active hypoglycemic agents.
  • the orally active hypoglycemic agents preferably comprise sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (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 (Novo Nordisk A/S) which are incorporated herein by reference, insulin sensitizers, DPP-IV inhibitors, PTPase inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR and RXR agonists and
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sulfonylurea eg tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulfonylurea 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.
  • the present compounds are administered in combination with a thiazolidinedione eg troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 (Dr. Reddy's Research Foundation).
  • a thiazolidinedione eg troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 (Dr. Reddy's Research Foundation).
  • the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 (Dr. Reddy's Research Foundation).
  • 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, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, 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 sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • 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 (***e amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 agonists, orexin antagonists, H3 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 agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH agonists, UCP (uncoupling protein) 2 or 3 modulators, leptin agonists, DA agonists (bromo
  • the antiobesity agent is leptin.
  • the antiobesity agent is dexamphetamine or amphetamine.
  • the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • 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 converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing
  • the present compounds may be administered in combination with one or more agents for the treatment of Alzheimer's disease.
  • agents for the treatment of Alzheimer's disease examples include tacrine, done- pezil, haloperidol, olanzapine, quetiapine, risperidone, alprazolam, buspirone, diazepam, lorazepam, amitriptyline, bupropion, desipramine, fluoxetine, fluvoxamine, nefazodone, nor- triptyline, paroxetine, sertraline and trazodone.
  • the present compounds may also be administered in combination with one or more agents for the treatment of bipolar disorder.
  • agents for the treatment of bipolar disorder include lithium, valproate, divalproex, carbamazepine, antipsychotic drugs such as haloperidol and perphenazine, antianxiety agents such as lorazepam and clonazepam, antidepressants such as bupropion, fluoxetine, fluvoxamine, paroxetine, sertraline, mirtazepine, phenelzine, tranylcypromine, nefazodone, amitriptyline, desipramine, imipramine, nortriptyline and venlafaxine.
  • the present compounds may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin- gual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as cap- sules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to pro-
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syr- ups and elixirs.
  • 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 in- jectable formulations are also contemplated as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are in the order of about half the dose employed for oral administration.
  • the present compounds 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 formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and
  • 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 compounds of the formula (I) 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 em- ployed 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.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospho- lipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • Formulations of the present invention suitable for oral administration may be presented as dis- crete 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, emulsion, 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:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
  • R is different from H
  • the water phase was extracted with ether (2 x 75 ml).
  • the ether phase was extracted with 1N hydrochloric acid solution (3 x 50 ml).
  • the hydrochloric acid extracts were collected and made alkaline with a 30% ammonium hydroxide solution.
  • the title compound separated as an oil and was extracted with ether (3 x 50 ml).
  • the ether extracts were dried over magnesium sulphate and evaporated.
  • the crude compound was triturated with hexane, and the crystalline compound was filtered giving the title compound in 750 mg yield. Mp 123-124 °C.
  • Example 3 (general procedure (A), step 1 )
  • Example 11 (general procedure (A), step 5)
  • Example 12 (general procedure (A), step 5)
  • Example 14 (general procedure (A), step 4)
  • Example 16 (general procedure (A), step 4)
  • the title compound was prepared in exactly the same manner as example 14 starting from 1-(4-aminofurazan-3-yl)-5-piperidin-1-ylmethyl-1 - -[1 ,2,3]triazole-4-carboxylic acid and 2-(2- aminoethylamino)-5-nitropyridinepyridine.
  • the free base was precipitated as the oxalate salt from 2-propanol. Mp 179-182 °C.
  • Example 17 (general procedure (A), step 4)
  • the title compound was prepared in exactly the same manner as example 14 starting from 1-(4-aminofurazan-3-yl)-5-piperidin-1 -ylmethyl-1 H-[1 ,2,3]triazole-4-carboxylic acid and 4-(2- methylamino)ethyl)pyridine.
  • the free base was precipitated as the dioxalate salt from acetone. Mp 163-168 °C.
  • Example 18 (general procedure (A), step 4) 1 -(4-Aminofurazan-3-yl)-5-dimethylaminomethyl-1 H-[1 ,2,3]triazole-4-carboxylic acid (2- pyridin-4-ylethyl)amide dioxalate.
  • Example 19 (general procedure (A), step 4) 1 -(4-Aminofurazan-3-yl)-5-diethylaminomethyl-1 H-[1 ,2,3]triazole-4-carboxylic acid (2-pyridin- 4-ylethyl)amide dioxalate.
  • the title compound was prepared in exactly the same manner as example 14 starting from 1 -(4-aminofurazan-3-yl)-5-diethylaminomethyl-1 H-[1 ,2,3]triazole-4-carboxylic acid and 4-(2- aminoethyl)pyridine.
  • the free base was precipitated as the dioxalate salt from acetone. Mp 175-177 °C.
  • Example 20 (general procedure (A), step 4) 1 -(4-Aminofurazan-3-yl)-5-pyrrolidin-1 -ylmethyl-1 H-[1 ,2,3]triazole-4-carboxylic acid (2-pyridin- 4-ylethyl)amide dioxalate.
  • Example 21 (general procedure (A), step 4)
  • Example 22 (general procedure (A), step 4)
  • Example 23 (general procedure (A), step 4)
  • the title compound was prepared in exactly the same manner as example 14 starting from 1 -(4-aminofurazan-3-yl)-5-(isobutylaminomethyI)-1 H-[1 ,2,3]triazole-4-carboxylic acid and 4-(2-aminoethyl)pyridine.
  • the free base was precipitated as the dioxalate salt from ethanol.
  • Example 24 (general procedure (A), step 4)
  • the title compound was prepared in exactly the same manner as example 14 starting from 1-(4-aminofurazan-3-yl)-5-piperidin-1 -ylmethyl-1 /--[1,2,3]triazole-4-carboxylic acid and 4-(2- aminoethyl)benzenesulfonamide.
  • Example 26 (general procedure (A), step 4)
  • Example 28 (general procedure (A), step 4)
  • Example 30 (general procedure (A), step 4)
  • Example 34 (general procedure (A), step 7)
  • Example 35 (general procedure (A), step 7)
  • Example 36 (general procedure (A), step 7)
  • Example 90 Example 91
  • GSK-3 ⁇ was incubated with 32 ⁇ M substrate and varying concentrations of test compound in a buffer containing 0.1 mM 33 P-labeled ATP, 10 mM magnesium acetate, 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.1% dithiothreitol and 0.03% Triton-X100 for 60 min at room temperature.
  • the reaction was performed using 96-well filter plates. The reaction was terminated by filtration followed by addition of 25 ⁇ l 2% phosphoric acid to each well. All wells were then washed three times in 0.5% phosphoric acid to remove unreacted 33 P-labeled ATP, dried and radioactivity was counted in a Packard topcounter. Dose-response profiles were generated, and the IC 50 value for inhibition of GSK-3 by the test compound was calculated using a four-parameter logistic function.

Abstract

L'invention concerne des compositions pharmaceutiques comportant des dérivés de 1-(furazan-3-yl)-[1,2,3] triazole de la formule générale (I) dans laquelle R?1,R2,R3,R4,R5 ¿et n ont la notation donnée dans la description, destinées au traitement et/ou à la prévention de troubles et de maladies, et présentant une inhibition favorable de la GSK-3 (glycogène synthase kinase-3), en particulier pour le traitement de la maladie d'Alzheimer, d'un trouble bipolaire, de l'IGT (tolérance réduite au glucose), des diabètes de type 1 et de type 2, et de l'obésité.
PCT/DK2001/000676 2000-10-16 2001-10-12 Derives de furazanyl-triazole destines au traitement de maladies WO2002032896A1 (fr)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003027068A2 (fr) * 2001-09-24 2003-04-03 Elan Pharmaceuticals, Inc. Amines substituees pour le traitement de la maladie d'alzheimer
WO2005097119A3 (fr) * 2004-04-06 2006-01-26 Semafore Pharmaceuticals Inc Inhibiteurs de pten
JP2006522813A (ja) * 2003-04-09 2006-10-05 エクセリクシス， インク． Ｔｉｅ−２モジュレータと使用方法
JP2007512230A (ja) * 2003-08-20 2007-05-17 バーテックス　ファーマシューティカルズ　インコーポレイテッド プロテインキナーゼ阻害剤として有用な（４−アミノ−１，２，５−オキサジアゾール−４−イル）−ヘテロ芳香族化合物
WO2008064342A2 (fr) * 2006-11-21 2008-05-29 Omeros Corporation Inhibiteurs de la pde10 et compositions et procédés apparentés
WO2009009768A3 (fr) * 2007-07-12 2009-03-26 Acumen Pharmaceuticals Inc Procédés consistant à inhiber la formation de ligands diffusables d'amyloide-b utilisant des composés d'acylhydrazide
US7625890B2 (en) 2005-11-10 2009-12-01 Smithkline Beecham Corp. Substituted imidazo[4,5-c]pyridine compounds as Akt inhibitors
US7786139B2 (en) 2006-11-21 2010-08-31 Omeros Corporation PDE10 inhibitors and related compositions and methods
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
EP2502623A1 (fr) 2008-06-06 2012-09-26 Children's Medical Center Corporation Promotion de régénération d'axone dans le SNC des adultes par l'intermédiaire du contrôle de la translation de protéine
US8962677B2 (en) 2007-07-12 2015-02-24 Acumen Pharmaceuticals, Inc. Methods of restoring cognitive ability using non-peptidic compounds
US9006283B2 (en) 2007-07-12 2015-04-14 Acumen Pharmaceuticals, Inc. Methods of modifying amyloid β oligomers using non-peptidic compounds
US9217024B2 (en) 2007-12-18 2015-12-22 Acumen Pharmaceuticals, Inc. ADDL receptor polypeptides, polynucleotides and host cells for recombinant production
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998016528A1 (fr) * 1996-10-11 1998-04-23 Chiron Corporation Inhibiteurs puriques de glycogene synthase kinase 3 (gsk3)
WO1999065897A1 (fr) * 1998-06-19 1999-12-23 Chiron Corporation Inhibiteurs de glycogene synthase kinase 3

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998016528A1 (fr) * 1996-10-11 1998-04-23 Chiron Corporation Inhibiteurs puriques de glycogene synthase kinase 3 (gsk3)
WO1999065897A1 (fr) * 1998-06-19 1999-12-23 Chiron Corporation Inhibiteurs de glycogene synthase kinase 3

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE STN INTERNATIONAL file CHEMCATS, Chem. Div. Inc. Product Library; 26 April 2001 (2001-04-26), "RN 296792-97-7", XP002902274 *
DATABASE STN INTERNATIONAL file CHEMCATS, Screening collection; 28 March 2000 (2000-03-28), "RN 312497-11-3", XP002902273 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003027068A2 (fr) * 2001-09-24 2003-04-03 Elan Pharmaceuticals, Inc. Amines substituees pour le traitement de la maladie d'alzheimer
WO2003027068A3 (fr) * 2001-09-24 2004-04-08 Elan Pharm Inc Amines substituees pour le traitement de la maladie d'alzheimer
JP2006522813A (ja) * 2003-04-09 2006-10-05 エクセリクシス， インク． Ｔｉｅ−２モジュレータと使用方法
US8178570B2 (en) 2003-04-09 2012-05-15 Exelixis, Inc. Tie-2 modulators and methods of use
JP4881725B2 (ja) * 2003-04-09 2012-02-22 エクセリクシス， インク． Ｔｉｅ−２モジュレータと使用方法
JP2007512230A (ja) * 2003-08-20 2007-05-17 バーテックス　ファーマシューティカルズ　インコーポレイテッド プロテインキナーゼ阻害剤として有用な（４−アミノ−１，２，５−オキサジアゾール−４−イル）−ヘテロ芳香族化合物
WO2005097119A3 (fr) * 2004-04-06 2006-01-26 Semafore Pharmaceuticals Inc Inhibiteurs de pten
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
US7625890B2 (en) 2005-11-10 2009-12-01 Smithkline Beecham Corp. Substituted imidazo[4,5-c]pyridine compounds as Akt inhibitors
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
WO2008064342A3 (fr) * 2006-11-21 2008-10-09 Omeros Corp Inhibiteurs de la pde10 et compositions et procédés apparentés
US8278327B2 (en) 2006-11-21 2012-10-02 Omeros Corporation PDE10 inhibitors and related compositions and methods
US7786139B2 (en) 2006-11-21 2010-08-31 Omeros Corporation PDE10 inhibitors and related compositions and methods
WO2008064342A2 (fr) * 2006-11-21 2008-05-29 Omeros Corporation Inhibiteurs de la pde10 et compositions et procédés apparentés
US8962677B2 (en) 2007-07-12 2015-02-24 Acumen Pharmaceuticals, Inc. Methods of restoring cognitive ability using non-peptidic compounds
WO2009009768A3 (fr) * 2007-07-12 2009-03-26 Acumen Pharmaceuticals Inc Procédés consistant à inhiber la formation de ligands diffusables d'amyloide-b utilisant des composés d'acylhydrazide
US9006283B2 (en) 2007-07-12 2015-04-14 Acumen Pharmaceuticals, Inc. Methods of modifying amyloid β oligomers using non-peptidic compounds
US9217024B2 (en) 2007-12-18 2015-12-22 Acumen Pharmaceuticals, Inc. ADDL receptor polypeptides, polynucleotides and host cells for recombinant production
EP2502623A1 (fr) 2008-06-06 2012-09-26 Children's Medical Center Corporation Promotion de régénération d'axone dans le SNC des adultes par l'intermédiaire du contrôle de la translation de protéine
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille

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