WO2003011843A1 - Nouveaux derives de la 2,4-diaminothiazole - Google Patents

Nouveaux derives de la 2,4-diaminothiazole Download PDF

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Publication number
WO2003011843A1
WO2003011843A1 PCT/DK2002/000508 DK0200508W WO03011843A1 WO 2003011843 A1 WO2003011843 A1 WO 2003011843A1 DK 0200508 W DK0200508 W DK 0200508W WO 03011843 A1 WO03011843 A1 WO 03011843A1
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alkyl
aryl
alkoxy
heteroaryl
och
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PCT/DK2002/000508
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English (en)
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Andrew Neil Bowler
Bo Falck Hansen
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Novo Nordisk A/S
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Priority to BR0211626-0A priority Critical patent/BR0211626A/pt
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to CA002455753A priority patent/CA2455753A1/fr
Priority to IL15996502A priority patent/IL159965A0/xx
Priority to MXPA04000906A priority patent/MXPA04000906A/es
Priority to KR10-2004-7001686A priority patent/KR20040029393A/ko
Priority to JP2003517035A priority patent/JP2004538315A/ja
Priority to HU0401403A priority patent/HUP0401403A3/hu
Priority to EA200400260A priority patent/EA200400260A1/ru
Priority to EP02750845A priority patent/EP1417188A1/fr
Publication of WO2003011843A1 publication Critical patent/WO2003011843A1/fr
Priority to IS7131A priority patent/IS7131A/is
Priority to US10/770,705 priority patent/US20040210063A1/en
Priority to NO20040913A priority patent/NO20040913L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel 2,4-diaminothiazole derivatives of the general formula (I) which inhibit GSK-3 (glycogen synthase kinase-3), to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds and to methods of treatment employing these compounds and compositions.
  • the present compounds may be useful for the treatment of disorders, syndromes, diseases and conditions, wherein an inhibition of GSK-3 is beneficial, especially IGT (impaired glucose tolerance), type 1 diabetes, type 2 diabetes, obesity, Alzheimer's disease and bipolar disorder.
  • 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. 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 in- sulin 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 inhibition are useful in the treatment of diseases, disorders, syndromes and conditions, wherein such an inhibition is beneficial, eg in diseases, disorders, syndromes and conditions related to GSK-3, in diseases, disorders, syndromes and conditions related to a dysfunction of GSK-3, in diseases, disorders, syndromes and conditions in which growth factor induced inhibition of GSK-3 is insufficient, in diseases, disorders, syndromes and conditions in which glycogen synthase is insufficiently activated and in situations wherein GSK-3 inhibition could counter-regulate unwanted cellular events.
  • Type 1 diabetes also known as insulin dependent diabetes mellitus (IDDM)
  • IDDM insulin dependent diabetes mellitus
  • IDDM insulin dependent diabetes mellitus
  • 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 hyperglycemia.
  • 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 severely impaired in type 2 diabetes.
  • the available treatments do not allow for a complete normalisation of the metabolic state and most of them are associated with side effects.
  • 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 histopathologically 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 PHFs (paired helical filaments), 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 supernatants 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 sug- gested.
  • 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 neurodegen- eration 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 through the inhibition of GSK-3, could provide an even broader application of GSK-3 inhibitors.
  • 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 immu- notherapy.
  • WO 99/21845 discloses 4-aminothiazole derivatives and their use as inhibitors of cyclin-dependent kinases (CDKs).
  • CDKs cyclin-dependent kinases
  • Table I discloses one compound (l(6)), of the following structure:
  • WO 00/75120 discloses diaminothiazoles and their use for inhibiting protein kinases.
  • the compounds are stated to be useful for the treatment of disease conditions associated with tumor growth, cell proliferation or angiogenesis, such as cancer.
  • the compounds differ structurally from the present compounds.
  • the present compounds are accordingly useful in the treatment of a wide range of disorders, syndromes, diseases and conditions 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 1-6 -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, tert- butyl, n-pentyl, isopentyl, neopentyl, terf-pentyl, n-hexyl, isohexyl and the like.
  • C 1-6 -alkoxy in the present context designates a group -O-C ⁇ _3-alkyl, wherein C 1-6 -alkyl is as defined above.
  • Representative examples include, but are not limited to, meth- oxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, terf-butoxy, n-pentoxy, isopentoxy, neopentoxy, ferf-pentoxy, n-hexoxy, isohexoxy and the like.
  • C 2-6 -alkenyl as used herein represents a 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, isopropenyl, 1 ,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyI, 2,4-hexadienyl, 5-hexenyl and the like.
  • C 2-6 -alkynyl 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-propynyI, 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 sulphur.
  • Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azirid- inyl, tetrahydrofuranyl 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-dihydronaphthyl and the like.
  • heteroaryl as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, 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-oxadiazoIyl, 1 ,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazoly
  • 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.
  • Aryl-C ⁇ -alkyl means C 1-6 -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- ⁇ .
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder, syndrome or condition.
  • the term is in- tended to include the delaying of the progression of the disease, disorder, syndrome or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder, syndrome or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the present invention relates to a compound of the general formula (I):
  • A is a valence bond or C 1-6 -alkylene
  • R 1 and R 2 together with the nitrogen atom to which they are attached, form a 5 to 7 mem- bered non-aromatic ring, which ring may optionally contain a double bond, and which ring may optionally contain a further nitrogen atom, and to which ring is attached two groups R 4 and R 5 which are independently selected from
  • R 6 and R 7 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 8 and R 9 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 3 is hydrogen
  • R 10 is C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyI, which may optionally be substituted with one or two substituents independently selected from
  • R 11 and R 12 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 2 and R 3 are connected to form, together with A and the nitrogen atom and carbon atom, respectively, to which they are attached, a 5 to 7 membered non-aromatic ring to which ring is attached two groups R 13 and R 14 which are independently selected from
  • R 15 and R 16 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 15 and R 16 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • ring moieties may optionally be substituted with one to three substituents independently selected from
  • R 17 and R 18 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 17 and R 18 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 20 and R 21 which may be the same or different independently are selected from hydrogen and C ⁇ -6 -alkyl, or R 20 and R 21 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 3 is hydrogen
  • R 22 and R 23 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 22 and R 23 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • aryl C 3-8 -cycloalkyl, heteroaryl, C 3-8 -heterocyclyl, aryI-C ⁇ -6 -alkyl, C 3-8 -cycloalkyl- C 1-6 -alkyl, heteroaryl-d-e-alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, aryl-C 1-6 -alkoxy, C 3 .
  • ring moieties may optionally be substituted with one to three substituents selected from
  • R 26 and R 27 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 26 and R 27 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • ring moieties may optionally be substituted with one to three sub- stituents selected from hydroxy, halogen, cyano, nitro, -NR 30 R 31 ,
  • R 30 and R 31 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 30 and R 31 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 3 is hydrogen, and R 1 and R 2 , together with the ni- trogen atom to which they are attached, form a ring
  • R 4 and R 5 are as defined for formula (I).
  • R 4 and R 5 are in- dependently selected from hydrogen, C 1-6 -alkyl, phenyl-Ci-e-alkyl and oxo.
  • R 4 is hydrogen or C 1-6 -alkyl
  • R 5 is hydrogen or oxo.
  • R 3 is hydrogen, and R 1 and R 2 , together with the nitrogen atom to which they are attached, form a ring
  • R 2 and R 3 together with A and the nitrogen atom and the carbon atom, respectively, to which they are attached, form a ring
  • R 1 , R ld and R 14 are as defined for formula (I).
  • R 2 and R 3 together with A and the nitrogen atom and the carbon atom, respectively, to which they are attached, form a ring
  • R , R and R are as defined for formula (I).
  • R , R and R are hydrogen.
  • A is C 1-6 -alkylene. In an embodiment thereof A is methylene or ethylene. In yet a further embodiment thereof A is ethylene.
  • D is C 3 . 8 -cycloalkyl, heteroaryl or aryl, which may optionally be substituted as defined for formula (I).
  • D is C 3-8 -cycloalkyl, heteroaryl or aryl, which may optionally be substituted as defined for formula (I), but not in the positions adjacent to the point of attach- ment of D to B.
  • D is cyclopropyl, thienyl or phenyl, which may optionally be substituted as defined for formula (I).
  • D is cyclopropyl. In yet another embodiment thereof D is thienyl, which is substituted with halogen.
  • D is phenyl, which is optionally substituted with
  • D is phenyl which is optionally substituted with halogen or benzyloxy, wherein the ring moiety of benzyloxy is optionally substi- tuted as defined for formula (I).
  • D is phenyl, which is substituted with benzyloxy.
  • 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. Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule 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, sulphuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulphonic, ethanesulphonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulphonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-amino- benzoic, glutamic, benzenesulphonic, p-toluenesulphonic acids and the like.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hy- droxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • 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 synthe- sis.
  • 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 sol- vates 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 are useful for the treatment of hyperglycemia; IGT; Syn- drome X; type 1 diabetes; type 2 diabetes; conditions with dyslipidemia including diabetic dyslipidemia; and obesity.
  • they may be useful for the treatment of albuminuria; polycystic ovary syndrome, cardiovascular diseases such as cardiac hypertrophy, hypertension and arteriosclerosis including atherosclerosis; gastrointestinal disorders; acute pancreatitis; and appetite regulation or energy expenditure disorders.
  • 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 compound of the general formula (I'):
  • A is a valence bond or C 1-6 -alkylene
  • R 1 and R 2 together with the nitrogen atom to which they are attached, form a 5 to 7 membered non-aromatic ring, which ring may optionally contain a double bond, and which ring may optionally contain a further nitrogen atom, and to which ring is attached two groups R 4 and R 5 which are independently selected from
  • R 6 and R 7 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen, • aryl, C 3-8 -cycloalkyl, heteroaryl, C 3-8 -heterocyclyl, aryl-d- 6 -alkyl, C 3 . 8 -cycloalkyl-
  • R 8 and R 9 which may be the same or different independently are selected from hydrogen and C ⁇ -6 -alkyI, or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 3 is hydrogen
  • R 10 is C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, which may optionally be substituted with one or two substituents independently selected from
  • R 11 and R 12 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen, and R 2 and R 3 are connected to form, together with A and the nitrogen atom and carbon atom, respectively, to which they are attached, a 5 to 7 membered non-aromatic ring to which ring is attached two groups R 13 and R 4 which are independently selected from
  • R 15 and R 16 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 15 and R 16 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • ring moieties may optionally be substituted with one to three substituents independently selected from
  • R 17 and R 18 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 17 and R 18 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 19 is C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, which may optionally be substituted with one or two substituents independently selected from
  • R 20 and R 21 which may be the same or different independently are selected from hydrogen and d -6 -alkyl, or R 20 and R 21 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 3 is hydrogen
  • R 24 and R 25 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 24 and R 25 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • ring moieties may optionally be substituted with one to three substituents selected from
  • R 26 and R 27 which may be the same or different independently are se- lected from hydrogen and C 1-6 -alkyl, or R 26 and R 27 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • R 28 and R 29 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 28 and R 29 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • aryl C 3-8 -cycloaIkyl, heteroaryl, C 3-8 -heterocyclyl, aryl-C 1-6 -alkyl, C 3-8 -cyclo- alkyl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, C 3-8 -heterocyclyl-C 1-6 -alkyl, aryl-
  • R 30 and R 31 which may be the same or different independently are selected from hydrogen and C 1-6 -alkyl, or R 30 and R 31 , together with the nitrogen atom to which they are attached, form a 3 to 8 membered cyclic ring optionally containing one or two further heteroatoms selected from oxygen, sulphur and nitrogen,
  • the compounds of the general formula (I') are used for the manufacture of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions related to GSK-3.
  • the present compounds of the general formula (I') are used for the manufacture of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein growth factor induced inhibition of GSK-3 is insufficient.
  • the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein glycogen metabolism exhibits abnormalities.
  • the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions, wherein glycogen synthase is insufficiently activated.
  • the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of diseases, disorders, syndromes and conditions involving elevated blood glucose.
  • the compounds are effective in lowering both fasting and postprandial blood glucose.
  • the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of hyperglycemia. In yet a further preferred embodiment of the invention the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of IGT.
  • the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes.
  • Such treatment includes ia the delaying of the progression from IGT to type 2 diabetes as well as the delaying of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
  • the present compounds of the general formula (I') are used for the preparation of a pharmaceutical composition for the treatment of type 1 diabetes. Such treatment is normally accompanied by insulin therapy.
  • present compounds of the general formula (I') may be used for the preparation of a pharmaceutical composition for the treatment of obesity.
  • the present compounds of the general formula (I') may be used for the preparation of a pharmaceutical composition for the treatment of Alz- heimer's disease.
  • the present compounds of the general formula (I') may be used for the preparation of a pharmaceutical composition for the treatment of bipolar disorder.
  • the present compounds are administered in com- bination with diet and/or exercise.
  • the present compounds are administered in combination with one or more further pharmacologically active substances in any suitable ratios.
  • Such further active agents may be selected from antidiabetic agents, antihyper- lipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
  • they may be administered in combination with one or more further pharmacologically active substances selected from agents for the treatment of Alzheimer's disease and agents for the treatment of bipolar disorder.
  • Such combined administration may be in separate preparations or in a single preparation, as appropriate.
  • Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise imidazolines, sulpho- nylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitiz- ers, ⁇ -glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the ⁇ -cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nord- isk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00
  • the present compounds are administered in combination with insulin.
  • the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibencla- mide, glipizide, glimepiride, glicazide or glyburide.
  • the present compounds are administered in combination with a biguanide eg metformin. In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
  • the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
  • a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120,
  • the present compounds are administered in combination with an insulin sensitizer eg such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, 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, BTS-67582 or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in com- bination with more than one of the above-mentioned compounds eg in combination with met- formin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulphonylurea, metformin and troglitazone; insulin and a sulphonylurea; insulin and metformin; insulin, metformin and a sulphonylurea; insulin and troglitazone; insulin and lovastatin; etc.
  • the present compounds are 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 amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita
  • Iactogen growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase in- hibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR ⁇ agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists such as those disclosed in WO 00/42023, WO 00/63208 and WO 00/64884 (Novo Nordisk A S and Boehringer Ingelheim International GmbH), which are incorporated herein by reference, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
  • opioid antagonists such as naltrexone
  • exendin-4 exendin-4
  • GLP-1
  • the antiobesity agent is leptin. In another embodiment the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine. In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
  • the present compounds are adminis- tered 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.
  • ⁇ -blockers such as alprenolol, atenolol, timolo
  • the present compounds are administered in combination with one or more agents for the treatment of Alzheimer's disease.
  • agents for the treatment of Alzheimer's disease are tacrine, donepezil, haloperidol, olanzapine, quetiapine, risperidone, alprazolam, buspirone, diazepam, lorazepam, amitriptyline, bupropion, desipramine, fluoxetine, fluvoxam- ine, nefazodone, nortriptyline, paroxetine, sertraline and trazodone.
  • the present compounds are 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, antide- pressants such as bupropion, fluoxetine, fluvoxamine, paroxetine, sertraline, mirtazepine, phenelzine, tranylcypromine, nefazodone, amitriptyline, desipramine, imipramine, nortriptyline and venlafaxine.
  • any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances are considered to be within the scope of the present invention.
  • 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 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 sublingual), 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.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups 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.
  • De- pot injectable 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 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 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 organic acids. Representative examples are mentioned above.
  • Physiologically acceptable salts of a compound with a hydroxy group include the an- ion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be em- ployed.
  • 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.
  • 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, phospholipids, 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.
  • the pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. 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. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, 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 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.
  • Sciex AP1 100 single quadropole mass spectrometer, Applied Biosystems 785A UV detector, Sedex 55 evaporative light scattering detector.
  • R 1 and R 2 are both hydrogen the amino group formed should be protected with a suitable protecting group, such as Boc, before carrying out step A.
  • a suitable protecting group such as Boc
  • the protecting group can be removed in a conventional manner to form the compounds of the formula (la) wherein R 1 and R 2 are both hydrogen.
  • the starting material 4-isothiocyanatopiperidine-1 -carboxylic acid terf-butyl ester, was first prepared, from the corresponding amine using di-2-pyridylthionocarbonate, according to the method of Kim, S. and Yi, K. Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661- 1664).
  • the title compound was obtained after chromatography using ethyl acetate/heptane (1 :1) as eluant.
  • the starting material 1-(3-benzyloxyphenyl)-2-bromoethanone, was first prepared, from the corresponding ketone using copper (II) bromide, according to the method of King, L. C. et al (J. Org. Chem., 1964, 29, pp 3459-3461).
  • the title compound was obtained after chromatography using ethyl acetate/heptane (1 :1) as eluant.
  • the starting material 1-(3-isothiocyanatopropyl)pyrrolidin-2-one, was first prepared, from the corresponding amine, using di-2-pyridylthionocarbonate, according to the method of Kim, S. and Yi, K. Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664).
  • the product was found to precipitate from the reaction mixture. This was filtered off and stirred in hot ethanol before warm filtration offered the title compound in 40% yield.
  • the starting material 1-(3-isothiocyanatopropyl)-4-methylpiperazine, was first prepared, from the corresponding amine, using di-2-pyridylthionocarbonate, according to the method of Kim, S. and Yi, K. Y. (Tetrahedron Lett., 26 (13), 1985, pp. 1661-1664).
  • M.p. 210-212 °C; HPLC-MS (ESI): m/z 401 [M+H] + ; R t 1.65 min (Method B).
  • reaction was performed according to Example 6, with the ring-opened intermediate first being isolated after addition of water to the reaction mixture. This was dissolved in hot ethanol and treated with 1.2 equivalents of triethlyamine. After 2 hours, reaction was cooled and filtered to furnish the title compound in 32% yield as a white solid.
  • the title compound was obtained as a hydrochloride salt, starting from [2-(4-amino- 5-cycIopropanecarbonylthiazol-2-ylamino)ethyl]carbamic acid terf-butyl ester and using the method described in Example 11.
  • the title compound was obtained as a TFA salt, starting from 4-[4-amino-5-(3- benzyloxybenzoyl)thiazol-2-ylamino]piperidine-1 -carboxylic acid terf-butyl ester, and using the method described in Example 13.
  • the title compound was obtained as a TFA salt, starting from ⁇ 3-[4-amino-5-(3- benzyloxybenzoyl)thiazol-2-ylamino]propyl ⁇ carbamic acid terf-butyl ester, and using the method described in Example 13.
  • GSK-3 ⁇ was incubated with 35 ⁇ 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 plates. The reaction was ter- minated by adding 13 ⁇ l 2% phosphoric acid to each well, and 10 ⁇ l was spotted onto P30 paper which was washed 4 times in 0.5% phosphoric acid to remove non-incorporated 33 P-labeled ATP. After drying the radioactivity was counted in a Wallac. 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. The following compounds inhibited GSK-3 with an IC 50 value lower than 1 ⁇ M:

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Abstract

L'invention porte: sur de nouveaux dérivés de la 2,4-diaminothiazole de formule générale (I) inhibiteurs de la GSK-3 (glycogène synthase kinase-3), sur l'utilisation de ces composés comme médicaments; sur des préparations pharmaceutiques les contenant et sur des procédés de traitement utilisant lesdits composés et compositions. Lesdits composés peuvent servir à traiter des troubles, syndromes, maladies et états où l'inhibition de la GSK-3 (glycogène synthase kinase-3) est bénéfique, et spécialement: la diminution de la tolérance au glucose, le diabète de type 1, le diabète de type 2, l'obésité, la maladie d'Alzheimer et les troubles bipolaires.
PCT/DK2002/000508 2001-08-03 2002-07-22 Nouveaux derives de la 2,4-diaminothiazole WO2003011843A1 (fr)

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JP2003517035A JP2004538315A (ja) 2001-08-03 2002-07-22 新規の２，４−ジアミノチアゾール誘導体
CA002455753A CA2455753A1 (fr) 2001-08-03 2002-07-22 Nouveaux derives de la 2,4-diaminothiazole
IL15996502A IL159965A0 (en) 2001-08-03 2002-07-22 Novel 2,4-diaminothiazole derivatives
MXPA04000906A MXPA04000906A (es) 2001-08-03 2002-07-22 Nuevos derivados de 2,4-diaminotiazol.
KR10-2004-7001686A KR20040029393A (ko) 2001-08-03 2002-07-22 신규한 2,4-디아미노티아졸 유도체
BR0211626-0A BR0211626A (pt) 2001-08-03 2002-07-22 Composto, uso do mesmo, composição farmacêutica, e, método para o tratamento de doenças, distúrbios, sìndromes e condições
HU0401403A HUP0401403A3 (en) 2001-08-03 2002-07-22 2,4-diaminothiazole derivatives, their use and pharmaceutical compositions containing them
EA200400260A EA200400260A1 (ru) 2001-08-03 2002-07-22 Новые производные 2,4-диаминотиазола
EP02750845A EP1417188A1 (fr) 2001-08-03 2002-07-22 Nouveaux derives de la 2,4-diaminothiazole
IS7131A IS7131A (is) 2001-08-03 2004-01-29 Nýjar 2,4-díamínóþíasól afleiður
US10/770,705 US20040210063A1 (en) 2001-08-03 2004-02-03 Novel 2,4-diaminothiazole derivatives
NO20040913A NO20040913L (no) 2001-08-03 2004-03-02 Nye 2,4-diaminotiazolderivater

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WO2005014593A1 (fr) * 2003-08-12 2005-02-17 F. Hoffmann-La Roche Ag Derives de thiazole utiles comme antagonistes de npy *
WO2005099673A1 (fr) * 2004-04-13 2005-10-27 Icagen, Inc. Thiazoles polycyliques utilises en tant que modulateurs du canal des ions potassium
WO2006005508A1 (fr) * 2004-07-15 2006-01-19 F.Hoffmann-La Roche Ag Nouveaux derives de 2,4-diaminothiazol-5-one
WO2006117212A2 (fr) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques
WO2006117221A1 (fr) * 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Utilisation d'azapaullones pour la prevention et le traitement de troubles auto-immunes du pancreas
KR100670974B1 (ko) * 2006-09-18 2007-02-28 (주) 리드제넥스 티아졸 유도체의 조합화학적 방법에 의한 분자다양성구축기술
US7253197B2 (en) 2002-08-07 2007-08-07 Hoffmann-La Roche Inc. Aminothiazole derivatives
EP1814551A2 (fr) * 2004-09-20 2007-08-08 Xenon Pharmaceuticals Inc. Derives de pyridazine destines a l'inhibition du desaturase-coa-stearoyl de l'humain
JP2008522199A (ja) * 2004-12-03 2008-06-26 ロード アイランド ホスピタル アルツハイマー病の診断および治療
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
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
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
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
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors

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US6686381B2 (en) * 2002-02-28 2004-02-03 Hoffmann-La Roche Inc. Thiazole derivatives
WO2003072577A1 (fr) * 2002-02-28 2003-09-04 F.Hoffmann-La Roche Ag Derives thiazoles utilises comme antagonistes du recepteur npy
US7253197B2 (en) 2002-08-07 2007-08-07 Hoffmann-La Roche Inc. Aminothiazole derivatives
WO2005014593A1 (fr) * 2003-08-12 2005-02-17 F. Hoffmann-La Roche Ag Derives de thiazole utiles comme antagonistes de npy *
CN100393718C (zh) * 2003-08-12 2008-06-11 霍夫曼-拉罗奇有限公司 作为npy拮抗剂的噻唑衍生物
US7265109B2 (en) 2003-08-12 2007-09-04 Hoffmann-La Roche Inc. Thiazole derivatives
WO2005099673A1 (fr) * 2004-04-13 2005-10-27 Icagen, Inc. Thiazoles polycyliques utilises en tant que modulateurs du canal des ions potassium
JP2008505950A (ja) * 2004-07-15 2008-02-28 エフ．ホフマン−ラ　ロシュ　アーゲー 新規２，４−ジアミノチアゾール−５−オン誘導体
CN1976910B (zh) * 2004-07-15 2010-07-21 霍夫曼-拉罗奇有限公司 2,4-二氨基噻唑-5-酮衍生物
WO2006005508A1 (fr) * 2004-07-15 2006-01-19 F.Hoffmann-La Roche Ag Nouveaux derives de 2,4-diaminothiazol-5-one
US7423053B2 (en) 2004-07-15 2008-09-09 Hoffmann-La Roche Inc. 4-Aminothiazole derivatives
KR100908591B1 (ko) * 2004-07-15 2009-07-22 에프. 호프만-라 로슈 아게 신규 2,4-디아미노티아졸-5-온 유도체
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
EP1814551A2 (fr) * 2004-09-20 2007-08-08 Xenon Pharmaceuticals Inc. Derives de pyridazine destines a l'inhibition du desaturase-coa-stearoyl de l'humain
EP2316458A1 (fr) * 2004-09-20 2011-05-04 Xenon Pharmaceuticals Inc. Derives de pyridazine destines a l'inhibition du desaturase-coa-stearoyl de l'humain
JP2008522199A (ja) * 2004-12-03 2008-06-26 ロード アイランド ホスピタル アルツハイマー病の診断および治療
WO2006117212A3 (fr) * 2005-05-04 2007-02-15 Develogen Ag Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques
WO2006117221A1 (fr) * 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Utilisation d'azapaullones pour la prevention et le traitement de troubles auto-immunes du pancreas
WO2006117212A2 (fr) 2005-05-04 2006-11-09 Develogen Aktiengesellschaft Utilisation des inhibiteurs gsk-3 dans la prevention et le traitement des maladies auto-immunes pancreatiques
US7968535B2 (en) 2005-05-04 2011-06-28 Develogen Atkiengesellschaft Use of azapaullones for preventing and treating pancreatic autoimmune disorders
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
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
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
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
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
KR100670974B1 (ko) * 2006-09-18 2007-02-28 (주) 리드제넥스 티아졸 유도체의 조합화학적 방법에 의한 분자다양성구축기술
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
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar

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JP2004538315A (ja) 2004-12-24
HUP0401403A3 (en) 2005-11-28

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