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WO2001074771A1 - Derives de pyrrole-2, 5-dione destines au traitement du diabete - Google Patents

Derives de pyrrole-2, 5-dione destines au traitement du diabete Download PDF

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WO2001074771A1
WO2001074771A1 PCT/EP2001/003687 EP0103687W WO0174771A1 WO 2001074771 A1 WO2001074771 A1 WO 2001074771A1 EP 0103687 W EP0103687 W EP 0103687W WO 0174771 A1 WO0174771 A1 WO 0174771A1
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formula
compound
substituted
diabetes
ring
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David Haigh
Brian Peter Slingsby
David Glynn Smith
Robert William Ward
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 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 other ring carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/12—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 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
    • C07D417/02—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

Definitions

  • This invention relates to a novel method for the treatment and/or prophylaxis of conditions associated with a need for inhibition of glycogen synthase kinase-3 (GSK-3), especially diabetes, and chronic neurodegenerative conditions including dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, manic depression, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, and immunodeficiency; and to certain novel inhibitors of GSK-3 for use in such a method.
  • GSK-3 is a serine/threonine protein kinase composed of two isoforms ( ⁇ and ⁇ ) which are encoded by distinct genes.
  • GSK-3 is one of several protein kinases which phosphorylates glycogen synthase (GS) (Embi et al Eur. J. Biochem. (107) 519-527 ( 1980)).
  • the ⁇ and ⁇ isoforms have a monomeric structure and are both found in mammalian cells. Both isoforms phosphorylate muscle glycogen synthase (Cross et al Biochemical Journal (303) 21-26 (1994)) and these two isoforms show good homology between species (e.g. human and rabbit GSK-3 ⁇ are 96% identical).
  • Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus. NIDDM) is a multifactorial disease. Hyperglycaemia is due to insulin resistance in the liver, muscle and other tissues coupled with inadequate or defective secretion of insulin from pancreatic islets. Skeletal muscle is the major site for insulin-stimulated glucose uptake and in this tissue, glucose removed from the circulation is either metabolised through glycolysis and the TCA cycle, or stored as glycogen. Muscle glycogen deposition plays the more important role in glucose homeostasis and Type II diabetic subjects have defective muscle glycogen storage. The stimulation of glycogen synthesis by insulin in skeletal muscle results from the dephosphorylation and activation of glycogen synthase (Villar-Palasi C. and Larner J. Biochim.
  • GSK-3 is responsible for phosphorylation and deactivation of GS, while glycogen bound protein phosphatase 1 (PP1G) dephosphorylates and activates GS. Insulin both inactivates GSK-3 and activates PP1G (Srivastava A K and Pandey S K Mol. and Cellular Biochem. (182) 135-141 (1998)).
  • GSK-3 ⁇ and constitutively active GSK-3 ⁇ (S9A, S9E) mutants in HEK-293 cells resulted in suppression of glycogen synthase activity (Eldar-Finkelman et al., PNAS (93) 10228-10233 (1996)) and overexpression of GSK-3 ⁇ in CHO cells, expressing both insulin receptor and insulin receptor substrate 1 (IRS-1), resulted in an impairment of insulin action (Eldar-Finkelman and Krebs PNAS (94) 9660-9664 (1997)).
  • GSK-3 has been shown to phosphorylate other proteins in vitro including the eukaryotic initiation factor eIF-2B at Serine 540 (Welsh et al., FEBS Letts (421) 125-130 (1998)). This phosphorylation results in an inhibition of eIF-2B activity and leads to a reduction in this key regulatory step of translation. In disease states, such as diabetes, where there is elevated GSK-3 activity this could result in a reduction of translation and potentially contribute to the pathology of the disease.
  • GSK-3 functions and regulation in addition to modulation of glycogen synthase activity indicate that inhibitors of this enzyme may be effective in treatment of disorders of the central nervous system.
  • GSK-3 activity is subject to inhibitory phosphorylation by PI 3 kinase-mediated or Wnt-1 class-mediated signals that can be mimicked by treatment with lithium, a low mM inhibitor of GSK-3 (Stambolic N., Ruel L. and Woodgett J.R. Curr. Biol. 1996 6(12): 1664-8).
  • GSK-3 inhibitors may be of value as neuroprotectants in treatment of acute stroke and other neurotraumatic injuries. Roles for PI 3-kinase signalling through PKB/akt to promote neuronal cell survival are well established, and GSK-3 is one of a number of PKB/akt substrates to be identified that can contribute to the inhibition of apoptosis via this pathway (Pap & Cooper, (1998) J. Biol. Chem. 273: 19929-19932). Evidence suggests that astrocytic glycogen can provide an alternative energy source to facilitate neuronal survival under conditions of glucose deprivation (for example see Ransom, B.R. and Fern, R. (1997) Glia 21: 134-141 and references therein).
  • Lithium is known to protect cerebellar granule neurons from death (DTvlello et al., (1994) Exp. Cell Res. 211: 332-338 and Volonte et al (1994) ⁇ eurosci. Letts. 172: 6-10) and chronic lithium treatment has demonstrable efficacy in the middle cerebral artery occlusion model of stroke in rodents ( ⁇ onaka and Chuang, (1998) ⁇ euroreport 9(9): 2081-2084). Wnt- induced axonal spreading and branching in neuronal culture models has been shown to correlate with GSK-3 inhibition (Lucas & Salinas, ( 1997) Dev. Biol. 192: 31-44) suggesting additional value of GSK-3 inhibitors in promoting neuronal regeneration following neurotraumatic insult.
  • Tau and ⁇ -catenin, two known in vivo substrates of GSK-3, are of direct relevance in consideration of further aspects of the value of GSK-3 inhibitors in relation to treatment of chronic neurodegenerative conditions.
  • Tau hyperphosphorylation is an early event in neurodegenerative conditions such as Alzheimer's disease (AD), and is postulated to promote microtubule disassembly.
  • AD Alzheimer's disease
  • Lithium has been reported to reduce the phosphorylation of tau, enhance the binding of tau to microtubules, and promote microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D.C., Klein P.S. and Lee N.M. J.Biol. Chem. 1997 272(40) 25326-32).
  • ⁇ -catenin is phosphorylated by GSK-3 as part of a tripartite complex with axin, resulting in ⁇ -catenin being targetted for degradation (Ikeda et al., (1998) EMBO J. 17: 1371-1384). Inhibition of GSK-3 activity is a key mechanism by which cytosolic levels of catenin are stabilised and hence promote ⁇ -catenin-LEF-1/TCF transcriptional activity (Eastman, Grosschedl (1999) Curr. Opin. Cell Biol. 11: 233). Rapid onset AD mutations in presenilin-1 (PS-1) have been shown to decrease the cytosolic ⁇ -catenin pool in transgenic mice.
  • PS-1 presenilin-1
  • WO 00/17184 discloses certain hydroflavone derivatives as Tau protein kinase-1 (TPK-1) inhibitors, where Tau protein kinase is a synonym for GSK-3 ⁇ .
  • Co-pending International Patent Application No. WO 00/18758 Mitsubishi Chemical Corporation discloses certain pyrimidona derivatives as TPK-1 inhibitors.
  • Co-pending International Patent Applications Nos. WO 00/21927 and WO 00/38675 disclose certain pyrrole-2,5-dione derivatives as GSK-3 inhibitors.
  • Co- pending International Patent Application No. WO 01/09106 discloses certain 1,2,4-triazole derivatives as GSK-3 inhibitors.
  • 3-amino-4-arylmaleimides are particularly potent and selective inhibitors of GSK-3. These compounds are indicated to be useful for the treatment and/or prophylaxis of conditions associated with a need for inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and manic depression, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, inflammation and immunodeficiency.
  • diabetes conditions associated with diabetes
  • chronic neurodegenerative conditions including dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and manic depression, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, inflammation and immunodeficiency.
  • the present invention provides a method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and manic depression, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, inflammation and immunodeficiency, which method comprises the administration of a pharmaceutically effective, non-toxic amount of a compound of formula (I):
  • R ! is a substituted or unsubstituted carbocychc or heterocyclic aromatic ring, which ring may be fused to a substituted or unsubstituted carbocychc or heterocyclic aromatic or non-aromatic ring;
  • R2 is a substituted or unsubstituted carbocychc or heterocyclic aromatic ring, which ring may be fused to a substituted or unsubstituted carbocychc or heterocyclic aromatic ring, with the proviso that R ⁇ is not 3-indolyl or a fused-ring derivative of 3- indolyl;
  • R3 is hydrogen, or,
  • R 1 and R ⁇ together with the nitrogen atom to which they are attached form a fused substituted or unsubstituted heterocylic ring; to a human or non-human mammal in need thereof.
  • R S a substituted or unsubstituted carbocychc aromatic ring
  • examples include phenyl.
  • RMs a substituted or unsubstituted heterocyclic aromatic ring
  • examples include pyridinyl.
  • RMs a substituted or unsubstituted carbocychc aromatic ring which ring is fused to a substituted or unsubstituted carbocychc non-aromatic ring
  • examples include indanyl.
  • R ! is a substituted or unsubstituted carbocychc aromatic ring which ring is fused to a substituted or unsubstituted heterocyclic aromatic or non-aromatic ring
  • examples include benzothiazolyl, benzoxazolyl, indolinyl, quinolinyl, indolyl, benzothiazolinonyl, benzimidazolyl, benzimidazolinonyl, benzothiophenyl, benzofuranyl, indolinonyl, benzoxazinonyl, and benzoxazolinonyl.
  • R2 is a substituted or unsubstituted carbocychc aromatic ring
  • examples include phenyl.
  • R ! and R ⁇ together with the nitrogen atom to which they are attached form a fused substituted or unsubstituted heterocylic ring examples include indolinyl and tetrahydroquinolinyl.
  • suitable substituents include up to five groups independently selected from the list consisting of hydroxy, Cj.galkoxy, di-(C ⁇ _6alkyl)amino, cyano, substituted or unsubstituted Chalky], carboxy, Cj.galkoxycarbonyl, C ⁇ alkylaminocarbonyl, halo, carboxyC j.galkyloxy, C ⁇ alkylamino, morpholinyl, hydroxyCi.galkylaminocarbonyl, (di-C ⁇ _5alkylamino)carbonyl, Ci. ⁇ alkoxyCi.
  • alkylaminosulphonyl Cj_ galkylaminosulphonyl, Cj.galkylcarbonyl, C ⁇ alkylcarbonylamino, (perfluoroCj. galkyl)carbonylamino, Cj.galkylthio, amino, perfluoroCj. ⁇ alkyl, aminocarbonyl, nitro, aminocarbonylC2-6 a lkenyl, C ⁇ alkoxyCi.galkylcarbonylamino, C ⁇ _ 6alkylcarbonylaminoC _5alkylcarbonylamino, hydroxyC _ 0 alkylcarbonylamino, C j _ ⁇ alkoxycarbonylC j .galkylcarbonylamino, carboxyC j _5alkylcarbonylamino, aminosulphonyl, carboxyC2-6alkenyl, aminocarbonylCi.galkylcarbonylamino, C [ .
  • galkylaminocarbonylC ⁇ alkoxy phenoxy, carboxyC i .galkyl, carboxycarbonylamino, thiazolidindionylC ⁇ _6alkyl, C j _5alkylcarbonylhydrazocarbonylC [ .galkyl, C i _ 5alkylcarbonylaminoC ⁇ . ⁇ alkyl, C ⁇ _galkylsulphonylaminoC ⁇ _6alkyl, (C ⁇ .
  • Q is a bond or a bivalent linking group
  • Ar represents a carbocychc or heterocyclic aromatic ring
  • Rl2 represents hydrogen or one or more substituent, suitably up to five, independently selected from the list consisting of carboxyC2-6 a lkenyl, C ⁇ _ galkylcarbonylamino, amino, halo, cyano, C ⁇ _ 5alkoxy, Ci .galkoxycarbonyl, (di-Cj.galky aminocarbonyl, carboxyC i .galkyl, Cj_ 6alkylaminocarbonyl, carboxy, hydroxy, aminocarbonyl, Cj.galkoxyCi.
  • Ar is a heterocyclic aromatic ring
  • examples include oxazolyl, benzothiazolyl, quinolinyl, oxadiazolyl, pyrimidinyl, pyrazinyl, dihydropyridazinonyl, pyrazolyl, imidazolyl, pyrazinonyl, dihydro-oxadiazinonyl, pyridazinonyl, and pyridinyl.
  • Examples of Q include -[CONH], -[(CH 2 ) ⁇ _6 ⁇ ]-, -[CONH(CH 2 ) ⁇ _6_-, -[( CH 2 ) 1 _ 6 CONH(CH 2 ) 1 _ 6 )]-, -[S]-, -[O]-, -[(CH 2 )i- 6 CONH]-, -[CO]-, -[O(CH 2 ) . _ 6 ]-, - [NHCO]-, -[NHSO 2 ]-, -[(CH 2 ) ⁇ _ 6 NHCO(CH 2 ) .
  • Suitable substituents for any alkyl group include cyano, Cj.galkylaminocarbonyl, aminosulphonyl, Cj.galkoxy, Ci .galkylsulphonylamino, hydroxy, carboxy, phenylaminocarbonyl, phenylCj.galkylaminocarbonyl, phenylcarbonylamino, phenylCj.
  • galkoxycarbonylCj.galkylcarbonylamino, hydroxyCj.galkylcarbonylamino, and (di-C i _ 6alkylamino)sulphonyl Suitable substituents for any piperazinyl group include C i .galkyl.
  • R' is unsubstituted phenyl or phenyl substituted with; 4-[S-(3-CH 2 CO 2 H)Ph], 4-[S-(3-CONHMe)Ph], 4-[O-(3-CO 2 H)Ph], 3-CO 2 H, 3- [CH 2 CONHPh], 4-[CH 2 CONHPh], 3-COPh, 3-OCH 2 Ph, 4-[NHCO-(2-OH)Ph], 3- CO 2 Et, 4-[S-(2-CO 2 H)Ph], 4-[O-(3-CONHMe)Ph], 4-[O-(3-CONH 2 )Ph], 4-[S-(3- CONH 2 )Ph], 4-[O-(4-CONHMe)Ph], 4-[NHCOPh], 4-[S-[3-CONH(CH 2 ) 2 OMe]Ph], 4- [S-(2-CO 2 H)Ph], 4-[NHCOCH 2 Ph], 3-[NHCOCH 2 Ph], 3-CONHPh, 4-[O-[O-
  • R 1 is phenyl substituted with 4-[S-(3-CH2CU2H)Ph].
  • R 1 is pyridin-5-yl substituted with 2-[(CH 2 ) 3 CN]-3-Me, 2- [(CH 2 ) 2 CO 2 H]-, 2-[(CH 2 ) 4 CO 2 H]-, 2-[(CH 2 ) 3 CN]-3-CO 2 Et, or 2-[OPh].
  • R 1 is pyridin-3-yl substituted with 2-Me, or 2-[(CH 2 ) 3 CN].
  • Suitable substituents for either ring include carboxyC j.galkylthio and esters thereof, halo, aminocarbonyl, hydroxy, aryloxy, arylthio, arylamino, Cj.galkyl, Ci_galkylcarbonyl, Cj.
  • R' is indolin-5-yl unsubstituted or substituted with l-(SO 2 Me), or 1-
  • R ⁇ is indan-5-yl.
  • R ⁇ is quinolin-6-yl.
  • R ⁇ is indol-5-yl unsubstituted or substituted with [l-Me-2-CONH2], 1- Me, or [l-Me-2-CO 2 H].
  • R is benzoxazol-5-yl substituted with 2-Me.
  • R ⁇ is unsubstituted benzoxazol-6-yl, or benzoxazol-6-yl substituted with 2-Me.
  • R ⁇ is benzothiazol-5-yl substituted with 2-Me.
  • R* is unsubstituted benzothiazol-6-yl or benzothiazol-6-yl substituted with 2-[NHCOMe], 2-NH 2 , 2-NHiPr, 2-[NHEt], 2-[mo ⁇ holin-4-yl], 2- [NH(CH 2 ) 3 N(Me) 2 ], 2-[(CH 2 )4CO 2 H], 2-[(CH 2 )4CO 2 Me], 2-NHPh, 2- [S(CH 2 ) 3 CO 2 H], 2-Ph, 2-NHMe, 2-N(Me) 2 , 2-CI, 2-SMe, 2-Me, 2-(SCH 2 CO 2 Me), or 2-(SCH 2 CO 2 H).
  • R ⁇ is benzthiazolinon-6-yl unsubstituted or substituted with 3- CH 2 CO 2 Me, 3-[3-F-Ph], 3-[4-OMe-Ph], 3-[CH 2 Ph], 3-[3-NHCOMe-Ph], 3- [(CH 2 ) 3 N(Me) ], 3-Me, 3-CH 2 CO 2 H.
  • R 1 is benzoxazolinon-6-yl.
  • R 1 is benzoxazolinon-5-yl.
  • R 1 is benzimidazol-5-yl substituted with 2-Me.
  • R 1 is benzimidazolinon-5-yl unsubstituted or substituted with 1,3-di-Me
  • ⁇ 1 is benzothiophen-5-yl.
  • R 1 is benzofuran-5-yl substituted with 2-CO 2 H.
  • R 1 is indolin-2-on-5-yl.
  • R 1 is 2H- 1 ,4-benzothiazin-3(4H)-on-7-yl.
  • R* is unsubstituted benzoxazolinon-6-yl.
  • R' is unsubstituted benzthiazolinon-6-yl.
  • R ! is unsubstituted indolin-2-on-5-yl.
  • R ! is benzothiazol-6-yl substituted with a 2-amino group.
  • R2 is a substituted carbocychc or heterocyclic aromatic ring
  • suitable substituents include up to five groups independently selected from the list consisting of hydroxyCj.galkyl, carboxy, cyano, aminocarbonyl, halo, Cj. ⁇ alkoxy, nitro, perfluoroCj. galkyl, benzoyl, C j .galkoxycarbonyl, Cj.galkylsulphonyl, hydroxy, -O(CH 2 ) w O- where w is 1 to 4, phenoxy, benzyloxy, C j .galkoxyCi.galkyl, perfluoroCi.galkoxy, C j .
  • galkylS- perfluoroCj.galkylS-, (diCj.galkyON-, amino, Ci_galkylcarbonylamino, substituted or unsubstituted ureido, phenylcarbonylamino, benzylcarbonylamino, styrylcarbonylamino, Cj. ⁇ alkyl, and phenyl.
  • Suitable substituents for ureido include fluorophenyl, phenylCj.galkyl-, cyclohexyl, Cj.galkenyl, Cj.galkyl, and Cj.galkoxyphenyl.
  • R is unsubstituted phenyl or phenyl substituted with 4-NO 2 , 4- NHCOMe, 4-1, 2,3-di-F, 3-CN, 2,3,6-tri-F, 3-CO 2 H, 3-CH 2 OH, 2,3,5-tri-F, 3,5-di-Me, 3- F, 2-C1-5-F, 2-C1, 2-F-3-C1, 2-C1-3-F, or 4-C1.
  • R ⁇ is phenyl substituted with 2,3-di-F.
  • suitable substituents include hydroxyCj.galkyl and Cj.galkoxyC galkyl.
  • R! and R ⁇ form indolinyl substituted with 2-(hydroxymethyl) or 2- (methoxymethyl).
  • R ⁇ and R ⁇ form tetrahydroquinolinyl.
  • Preferred compounds of formula (I) are selected from the list consisting of
  • Rl, R2, and R ⁇ are as defined in formula (I), with the proviso that formula (O does not include the following compound:
  • the present invention also provides a compound of formula (T) or a derivative thereof.
  • Preferred compounds of formula (1 ⁇ are selected from the list consisting of Example Al in Table A. and Example B IO, Example B 16, Example B47, and Example B49 in Table B.
  • RI represents hydrogen or one or more substituents, suitably up to five, independently selected from the list consisting of halo and cyano
  • RU represents hydrogen or one or more substituents, suitably up to four, independently selected from the list consisting of carboxy, Cj.galkoxycarbonyl, C ⁇ _ galkylaminocarbonyl, halo, and Cj.galkyl;
  • Q represents a bond or a bivalent linking group.
  • Examples of Q include -[CONH]-, -[(CH 2 )!_ 6 O]-, -[CONH CH ⁇ .g]-, -[( CH ⁇ CONH CH ⁇ )]-, -[S]-, -[O]-, -[(CH 2 ) 1 . 6 CONH]-, -[CO]-, -[O(CH 2 )!_ 6 ]-,
  • R ⁇ 2 represents hydrogen or one or more substituent, suitably up to five, independently selected from the list consisting of Ci .galkylcarbonylamino, amino, Cj. galkylamino, (di-Cj.galky amino, halo, cyano, Cj.galkoxy, Cj.galkoxycarbonyl, (di- Ci .galky aminocarbonyl, hydrogen, carboxyC galkyl, Cj.galkylaminocarbonyl, carboxy, hydroxy, aminocarbonyl, Ci.galkoxyCj.galkylaminocarbonyl, C ⁇ _ galkylaminocarbonylC j .galkyl, mo ⁇ holinylC ⁇ . ⁇ alkylaminocarbony 1C ⁇ .galkyl, C [ .
  • R 10 represents hydrogen, 2,3-di-F, 3-CN, 2-F-3-C1, 2,3,6-tri-F, 2-C1-3- F, and 4-Cl.
  • RlO represents 2,3-di-F.
  • R u represents hydrogen, 3-CO 2 H, 3-CO 2 Et, 3-CONHMe, 3-Me, or 3- Cl.
  • Q represents 4-[S]-, 4-[O]-, 3-[CH 2 CONH]-, 4-[CH 2 CONH]-, 3-[CO]-, 3-[OCH 2 ]-, 4-[NHCO]-, 4-[NHCOCH 2 ]-, 3-[NHCOCH 2 ]-, 3-[NHCO]-, 4-
  • Q represents 4-[S]-.
  • R 12 represents hydrogen, 4-CH 2 CO 2 H, 4-CH 2 CH 2 CO 2 H, 4-CH 2 OH, 3-NMe 2 , 4-NH , 4-NMe 2 , (3-Cl-4-mo ⁇ holin-4-yl), 4-CH CN, 4-OCH 2 -(l-Me- piperidin-4-yl), 3-CH 2 CO 2 H, 3-CONHMe, 3-CO 2 H, 2-OH, 2-CO 2 H, 3-CONH 2 , 4- CONHMe, 3-[CONH(CH 2 ) 2 OMe], 4-CO 2 H, 4-CONH 2 , 3- [CH 2 CONH(CH 2 )2mo ⁇ holin-4-yl], 4-Me, 3-CH 2 CONH 2 , 3-CH CONHOH, 2- CH 2 CO 2 Me, 2-CONHMe, 3-CH 2 CONHMe, 2-CONH , 4-Ph, 4-CH 2 CH 2 OH, 4- mo ⁇ holin-4-yl, 4-piperidin-l-yl, 4-CH 2 NHCOMe, 3-NH
  • R ⁇ represents 3-CH2CO2H.
  • a compound of formula (IA) is Example Al of Table A.
  • the compounds of formula (IA) are novel. Accordingly, the present invention also provides a compound of formula (IA) or a derivative thereof.
  • RIO represents hydrogen or one or more substituents, suitably up to five, selected from the list consisting of cyano, halo, carboxy, and hydroxyCj.galkyl; Rl3 represents hydrogen;
  • R 10 represents hydrogen, 3-CN, 2,3-di-F, 2,3,6-tri-F, 3-CO2H, 2-F-3- Cl, 2-C1-3-F, or 3-CH 2 OH.
  • R ⁇ represents 2,3-di-F.
  • R ⁇ 3 represents hydrogen.
  • W represents 3,4-[CH2CONH]-.
  • W represents 3,4-[O-C(O)-NH]-.
  • W represents 3,4-[S-C(O)-NH]-.
  • a compound of formula (IB) is selected from the list consisting of Examples B IO, B 16, B47, and B49 of Table B.
  • the compounds of formula (IB) are novel. Accordingly, the present invention also provides a compound of formula (IB) or a derivative thereof.
  • R ' O represents hydrogen or one or more, suitably up to five, substituents selected from the list consisting of halo, Cj.galkyl, cyano, carboxy, nitro, Cj. galkylcarbonylamino, and hydroxyC j .galkyl;
  • Rl4 represents hydrogen or one or more, suitably up to five, substituents selected from the list consisting of carboxycarbonylamino, unsubstituted or substituted Cj.galkyl, halo, Cj.galkylaminocarbonyl, C ⁇ _ 0 alkylamino, mo ⁇ holinyl, Ci.galkoxyCj.
  • Cj.galkyl 6alkoxyaminocarbonylC2-6alkenyl, aminoCi.galkyl, and Cj.galkylaminocarbonylCi. galkoxy.
  • Suitable substituents for Cj.galkyl include Cj.galkylcarbonylhydrazocarbonyl, thiazolidindionyl, (piperazinyl)carbonyl wherein the piperazinyl moiety may be unsubstituted or substituted, (mo ⁇ holinyl)carbonyl, (piperidinyl)carbonyl, hydroxyC].
  • Suitable substituents for piperazinyl include Cj.galkyl.
  • R 10 " represents hydrogen, 2-F-3-C1, 2-C1-3-F, 4-NO 2 , 4-1, 2-C1, 4- NHCOMe, 2,3,5-tri-F, 3,5-di-Me, 2,3,6-tri-F, 2,3-di-F, 3-CN, 3-F, 2-C1-5-F, 3-CO 2 H, or 3-CH 2 OH.
  • R 14 represents hydrogen, 3-[CH2-(l ,3-thiazolidine-2,4-dion-5-yl)], 3,5- di-F, 3-CI, 3-OCH 2 CO 2 H, 3-CONHMe-4-NHMe, 4-[CH 2 CO(4-Me-piperazin-l-yl)], 2- (mo ⁇ holin-4-yl), 3-[CH 2 CO(mo holin-4-yl)], 3-[CH 2 CO(piperidin-l-yl)], 4- [CH 2 CO(piperidin-l-yl)], 4-[CH 2 CONH(CH 2 ) 2 OH], 4-[CH 2 CONMe 2 ], 3-CONHMe-4- CI, 3-SO 2 NH(CH 2 ) 2 OMe, 3-SO 2 NHnBu, 3-COMe, 3-CH CO 2 H, 3-NHCOMe, 4- NHCOCF 3 , 2-Me, 2-Me-4-F, 2-Me-5-F, 3-Me, 2-SMe, 3-CF 3
  • RIO ' and R 4 ' are as defined for RlO" and R ⁇ 4 respectively in formula (IC), with the proviso that formula (IC) does not include 3-phenylamino-4-phenyl- 1 H-pyrrole-2,5-dione.
  • RIO represents hydrogen or one or more, suitably up to five, substituents selected from the list consisting of halo and Cj.galkyl;
  • X-Y represents -[CH((CH 2 ) 1 . 6 OH)-(CH 2 ) 1 . 4 ]-, -[CH 2 ] ⁇ _4-, or -[CH((CH 2 )i-
  • Ri5a represents hydrogen
  • Rl5b represents hydrogen
  • R 15° represents hydrogen
  • Rl5d represents hydrogen
  • R ⁇ ⁇ represents hydrogen, 2,3-di-F, 2,3,6-tri-F, 3,5-di-Me, or 2-C1.
  • X-Y represents -[CH(CH 2 OH)CH 2 ]-, -[(CH 2 ) 2 ]-, -[(CH 2 ) 3 ]-, or - [CH(CH 2 OMe)CH 2 ]-. It is considered that compounds of formula (ID) are novel. Accordingly, the present invention also provides a compound of formula (ID) or a derivative thereof.
  • R ' is substituted pyridinyl
  • R2" is substituted phenyl
  • Suitable substituents for pyridinyl include aryloxy, Cj ⁇ galkyl, cyanoCj.galkyl, carboxyC ⁇ _galkyl, or Cj.galkoxycarbonyl.
  • Suitable substituents for phenyl include halo.
  • R ⁇ ' is 2-[(CH 2 ) 3 CN]-3-Me-pyridin-5-yl, 2-Me-pyridin-3-yl, 2- [(CH 2 ) 2 CO 2 H]-pyridin-5-yl, 2-[(CH 2 ) 3 CN]-3-(CO 2 Et)-pyridin-5-yl, 2-[(CH 2 ) 4 CO 2 H]- pyridin-5-yl, 2-OPh-pyridin-5-yl, or 2-[(CH ) 3 CN]-pyridin-3-yl.
  • R 2" is 2,3-difluorophenyl.
  • R ⁇ ⁇ represents hydrogen or one or more, suitably up to five, substituents selected from the list consisting of halo;
  • Rl 1 represents hydrogen or hydroxy
  • Q represents a bond, -[O]-, -[(CH 2 ) 1 _ 6 CONH]-, -[(CH 2 ) 1 . 6 CO 2 (CH 2 ) 1 _ 6 ]- > - [O(CH 2 ) 1 . 6 N(C ⁇ _ 6 alkyl)]-, -[O(CH 2 ) ⁇ _ 6 ]-, -[S(CH 2 )j. 6 ]-, -[(CH 2 ) 1 .
  • Ar 2 represents oxazolyl, benzothiazolyl, quinolinyl, oxadiazolyl, pyrimidinyl, pyrazinyl, dihydropyridazinonyl, pyrazolyl, imidazolyl, pyrazinonyl, dihydro- oxadiazinonyl, pyridazinonyl, and pyridinyl.
  • Suitable substituents for oxazolyl include Cj.galkyl.
  • Suitable substituents for benzothiazolyl include Cj.galkyl.
  • Suitable substituents for oxadiazolyl include C ⁇ .galkyl.
  • Suitable substituents for pyrimidinyl include hydroxy.
  • Suitable substituents for dihydropyridazinonyl include Cj.galkyl.
  • Suitable substituents for pyrazinyl include Cj.galkoxy.
  • Suitable substituents for pyridinyl include Cl j.galkyl, Cj.galkoxy, and amino.
  • R l ° '"" represents 2,3-di-F.
  • Q represents a bond at position 3, 4-[NHCO(CH 2 ) 2 ]-, 4-[O], 3-[bond], 3-[CH 2 CONH], 3-[CH 2 CO 2 CH 2 ], 4-[O(CH 2 ) 2 NMe], 4-[OCH 2 ], 4-[SCH ], 3- [CH2SO2NH], or a bond at position 4.
  • the position of the linking moiety Q is defined with respect to the atom numbering depicted in formula (IF).
  • Ar 2 represents 5-oxazolyl, 3-pyridinyl, 5-Me-2-oxazolyl, 2-Me-4- oxazolyl, 6-Me-benzothiazol-2-yl, 3-pyridinyl, benzothiazol-2-yl, quinolin-3-yl, 3-Me- l,2,4-oxadiazol-5-yl, 2-Me-pyridin-3-yl, 5-Me-pyridin-3-yl, 2-OMe-pyridin-5-yl, 3-NH2- pyridin-2-yl, pyridin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, 2-OH-pyrimidin-5-yl, 5-Me-4,5- dihydro-2H-pyridazin-3-on-6-yl, 2,5-di-Me-4,5-dihydro-2H-pyridazin-3-on-6-yl, 1 H- pyrazol-3-yl
  • Certain of the compounds of formula (I) may contain chiral atoms and/or multiple bonds, and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the isomeric forms of the compounds of formula (I) whether as individual isomers or as mixtures of isomers, including geometric isomers, tautomers, and racemic modifications.
  • Alkyl groups referred to herein, including those forming part of other groups, include straight or branched chain alkyl groups containing up to twelve, suitably up to six carbon atoms. These alkyl groups may be optionally substituted with up to five, suitably up to three, groups selected from the list consisting of aryl, heterocyclyl, alkylthio, alkenylthio, alkynylthio, arylthio, heterocyclylthio, alkoxy, arylalkoxy, arylalkylthio, amino, mono- or di-alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, phosphonic acid and esters thereof, mono- or dialkylaminosulphonyl, aminosulphonyl, cyano, alkylcarbonylamino, arylcarbonylamino, arylaminocarbonyl, arylalkylaminocarbonyl, arylalkylcarbony
  • Alkenyl and alkynyl groups referred to herein include straight and branched chain groups containing from two to twelve, suitably from two to six, carbon atoms. These alkenyl and alkynyl groups may be optionally substituted with up to five, suitably up to three, groups including those substituents described hereinbefore for the alkyl groups.
  • the term "carbocychc” includes aromatic carbocychc rings, for example aryl groups, and non-aromatic carbocychc groups, for example cycloalkyl and cycloalkenyl groups, and fused carbocychc ring systems wherein the carbocychc rings may be aromatic or non-aromatic, for example indanyl.
  • Cycloalkyl and cycloalkenyl groups referred to herein include groups having between three and eight ring carbon atoms. These cycloalkyl and cycloalkenyl groups may be optionally substituted with up to five, suitably up to three, groups including those substituents hereinbefore described for the alkyl groups.
  • aryl includes phenyl, naphthyl, and biphenyl groups, especially phenyl.
  • substituents for any aryl group include up to five substituents selected from the list consisting of alkylbenzothiazolyl, pyridinyloxy, benzothiazolyl, quinolinylaminocarbonylalkyl, alkyloxadiazolyl, (alkyl )pyridinylaminocarbonylalkyl, (alkoxy)pyridinylaminocarbonylalkyl, pyridinylaminocarbonylalkyl, (amino)pyridinylalkoxycarbonylalkyl, (pyridinyl)(alkyl)aminoalkoxy, pyridinylalkoxy, pyrimidinylaminocarbonylalkyl, pyrazinylaminocarbonylalkyl, hydroxypyrimidinyl, mono or dialkyldihydro-2H-pyridazinonyl, lH-pyrazolyl, lH-imidazolylal
  • heterocyclyl and “heterocyclic” suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur. Each ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. These heterocyclyl and heterocyclic rings may be unsubstituted or substituted by up to five substituents.
  • a fused heterocyclic ring system may include carbocychc rings and need include only one heterocyclic ring.
  • heterocyclyl and heterocyclic rings include pyridyl, indolinyl, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, benzothiazolinonyl, benzimidazolinonyl, benzothiophenyl, benzofuranyl, indolinonyl, benzoxazinonyl, quinolinyl, oxadiazolyl, pyrimidinyl, pyrazinyl, dihydropyridazinonyl, pyrazolyl, imidazolyl, pyrazinonyl, dihydro-oxadiazinonyl, pyridazinonyl, benzoxazolinonyl, is benzimidazolyl, benzimidazolinonyl, benzothiophenyl, benzofuranyl, indolinonyl, 2H-benzothiazin-3(4H)-onyl, and be
  • Substituents for any heterocyclyl or heterocyclic group are suitably selected from aryloxy, cyano, carboxyalkoxy, mo ⁇ holinyl, hydroxyalkylaminocarbonyl, alkoxyalkylaminosulphonyl, alkylaminosulphonyl, arylcarbonylamino, aralkylcarbonylamino, aralkenylcarbonylamino, perhalocarbonylamino, perhaloalkyl, aminocarbonyl, nitro, aminocarbonylalkenyl, alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino, hydroxyalkylcarbonylamino, carboxyalkenyl, aminocarbonylalkylcarbonylamino, alkylaminocarbonylalkoxy, aryl, arylcarbonyl, alkylenedioxy, aryloxy, aralkyloxy, perhaloalkylthio,
  • halogen or tialo' include iodo, bromo, chloro or fluoro, especially chloro or fluoro.
  • Suitable derivatives of the compounds of the invention are pharmaceutically acceptable derivatives.
  • Suitable derivatives of the compounds of the invention include salts and solvates.
  • Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
  • Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2- hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N - bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, al
  • Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.
  • Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.
  • Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, ⁇ -keto glutarate and -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • diabetes mellitus especially Type 2 diabetes, and conditions associated with diabetes mellitus.
  • condition associated with diabetes includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.
  • condition associated with the pre-diabetic state' includes conditions such as insulin resistance, impaired glucose tolerance and hyperinsulinaemia.
  • diabetes mellitus itself include hyperglycaemia, insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance.
  • the term 'complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy. Renal diseases associated with Type II diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
  • a further aspect of the invention provides a process for the preparation of a compound of formula (1 , which process comprises reaction of a compound of formula
  • R 2a is as defined for R 2 in formula (I) and L is a leaving group, with a compound of formula (III) ,3a
  • R ⁇ a and R ⁇ a are as defined for R ⁇ and R ⁇ respectively in formula (I), and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (H to a further compound of formula (10; (ii) removing any necessary protecting group; (iii) preparing an appropriate derivative of the compound so formed.
  • suitable leaving groups, L are chloro, bromo, triflate, and hydroxy.
  • reaction between the compounds of formulae (II) and (III) is carried out in any suitable solvent, for example l-methyl-2-pyrrolidinone, tetrahydrofuran, or methanol, under conventional amination conditions at any temperature providing a suitable rate of formation of the required product, generally an elevated temperature, over a suitable reaction time.
  • suitable solvent for example l-methyl-2-pyrrolidinone, tetrahydrofuran, or methanol
  • Suitable reaction temperatures include those in the range of 60°C to 220°C and, as appropriate, the reflux temperature of the solvent.
  • the reaction may be assisted by, for example, using temperatures at the upper end of this range, generating the anion of the compound of formula (III) in situ using, for example, sodium hydride, or by using a basic catalyst such as triethylamine.
  • Conventional methods of heating also include the use of microwave heating devices, for example a microwave reactor, such as a 100 watt reactor.
  • reaction products are isolated using conventional methods. Typically, the reaction mixture is cooled, the residue acidified and the products extracted using solvent extraction, suitably using an organic solvent.
  • reaction products are purified by conventional methods, such as chromatography and trituration.
  • Crystalline product may be obtained by standard methods.
  • a solution of the compound of formula (II) and a compound of formula (III) in methanol is heated to reflux from between 1 to 4 days, then cooled and concentrated.
  • the residue is then acidified with hydrochloric acid, and extracted with ethyl acetate.
  • the organic extracts are then washed with water, brine, dried with anhydrous magnesium sulphate, and the solvent is removed.
  • the product is then purified by standard methods such as trituration or chromatography, on silica gel, to afford the desired compound.
  • a solution of the compound of formula (II) and a compound of formula (III) in l-methyl-2-pyrrolidinone is heated at 69°C from between 1 to 4 days, then cooled and concentrated.
  • the residue is then acidified with hydrochloric acid, and extracted with ethyl acetate.
  • the organic extracts are then washed with water, brine, dried with anhydrous magnesium sulphate, and the solvent is removed.
  • the product is then purified by standard methods such as trituration or chromatography, on silica gel, to afford the desired compound.
  • conversions (i) to (iii) may be carried out using any appropriate method under conditions determined by the particular groups chosen.
  • suitable conversions of one group R ! ' into another group R I ' include converting a group Rl I which represents carboxy into a group R ! I which represents alkylaminocarbonyl; such conversion may be carried out using a conventional procedure for the formation of amide bonds, for example treating an appropriately protected compound of formula (I) with an amine in the presence of suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide.
  • Suitable conversions of one group R ⁇ into another group R ⁇ 2 include: (a), converting a group R ⁇ 2 which contains a carboxy group into a group R ⁇ 2 which contains an alkylaminocarbonyl group; such a conversion may be carried out using a conventional procedure for the formation of amide bonds, for example treating an appropriately protected compound of formula (I) with an amine in the presence of suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide.
  • suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide.
  • suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • the derivatives of the compounds of formula (I), including salts and/or solvates, may be prepared and isolated according to conventional procedures.
  • the compounds of formula (II) are known compounds or they may be prepared using methods analogous to those used to prepare compounds such as those described in International Patent Application, Publication Number WO97/34890 and Wiley, R.H. and Slaymaker, S.C. J. Am. Chem. Soc. (80) 1385 (1958).
  • the compounds of formula (II) may be inter-converted in an analogous manner to the above mentioned inter-conversions of the compounds of formula (I).
  • the compounds of formula (III) are either commercially available, or are reported in the chemical literature, or are prepared by analogy with known conventional literature procedures, for example those disclosed in J. Org. Chem 1998, 63, 6338, Eet. Lett. 1984, 25, 3383, Synlett. 1997, 133, Synth. Commun. 1995, 25, 1077, Bioorg. Med. Chem. Lett. 1997, 7, 1345, Synthesis 1994, 1413, and Chem. Pharm. Bull. 1982, 30, 3580, J. Het. Chem. 1992, 29, 1069, or in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience. 3-Phenylamino-4-phenyl-lH-pyrrole-2,5-dione may be prepared according to procedures disclosed in J. Amer. Chem. Soc. 1958, 80, 1385.
  • the compounds of formula (I), or pharmaceutically acceptable derivatives thereof are indicated to be useful as inhibitors of glycogen synthase kinase-3.
  • the present invention further provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use as an inhibitor of glycogen synthase kinase-3, and especially for use in the treatment of conditions associated with a need for the inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and manic depression, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, inflammation and immunodeficiency.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of conditions associated with a need for the inhibition of GSK-3, such as diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and manic depression, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, inflammation and immunodeficiency.
  • dementias such as Alzheimer's disease, neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and manic depression, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, traumatic brain injury, cancer, inflammation and immunodeficiency.
  • the compounds of formula (I), or pharmaceutically acceptable derivatives thereof are administered as pharmaceutically acceptable compositions.
  • the invention also provides a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
  • Neurotraumatic diseases include both open or penetrating head trauma, such as caused by surgery, or a closed head trauma injury, such as caused by an injury to the head region, ischaemic stroke including acute stroke, particularly to the brain area, transient ischaemic attacks following coronary by-pass and cognitive decline following other transient ischaemic conditions.
  • the active compounds are usually administered as the sole medicament agent but they may be administered in combination with other medicament agents as dictated by the severity and type of disease being treated.
  • a compound of formula (I), or a pharmaceutically acceptable derivative thereof may be used in combination with other medicament agents, especially antidiabetic agents such as insulin secretagogues, especially sulphonylureas, insulin sensitisers, especially glitazone insulin sensitisers (for example thiazolidinediones), or with biguanides or alpha glucosidase inhibitors or the compound of formula (I), or a pharmaceutically acceptable derivative thereof, may be administered in combination with insulin.
  • the said combination comprises co-administration of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and an additional medicament agent or the sequential administration of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent.
  • Co-administration includes administration of a pharmaceutical composition which contains both a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent or the essentially simultaneous administration of separate pharmaceutical compositions of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent.
  • compositions of the invention are preferably adapted for oral administration. However, they may be adapted for other modes of administration.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • a composition of the invention is in the form of a unit dose.
  • compositions are in unit dosage form.
  • a unit dose will generally contain from 0.1 to 1000 mg of the active compound.
  • an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
  • active compounds will typically be administered once or more times a day for example 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 800 mg/kg/day.
  • Suitable dose forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch,
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Suitable methods for preparing and suitable unit dosages for the additional medicament agent, such as the antidiabetic agent mentioned herein include those methods and dosages described or referred to in the above mentioned reference texts.
  • Types of GSK-3 assay used to test the compounds of the invention include the following: Type 1: The GSK-3 specific peptide used in this assay was derived from the phosphorylation site of glycogen synthase and its sequence is: YRRAAVPPSPSLSRHSSPHQ(S)EDEEE. (S) is pre-phosphorylated as is glycogen synthase in vivo and the three consensus sites for GSK-3 specific phosphorylation are underlined.
  • the buffer used to make up the glycogen synthase peptide and [ ⁇ -33p] ATP consisted of MOPS 25mM, EDTA 0.2mM, MgAcetate lOmM, Tween-20 0.01% and mercaptoethanol 7.5mM at pH 7.00.
  • the compounds were dissolved in dimethyl sulphoxide (DMSO) to a final concentration of lOOmM.
  • DMSO dimethyl sulphoxide
  • Various concentrations were made up in DMSO and mixed with the substrate (GSK-3 peptide) solution (to a final concentration 20uM) described in the above section along with rabbit or human GSK-3 ⁇ and GSK-3 ⁇ (final concentration 0.5U/ml enzyme).
  • the reactions were initiated with the addition of [ ⁇ - ⁇ P] ATP (500cpm/pmole) spiked into a mixture of ATP (final concentration of lO ⁇ M). After 30 min at room temperature the reaction was terminated by the addition of lO ⁇ l of H PO4/ 0.01% Tween-20 (2.5%).
  • a volume (lO ⁇ l) of the mixture was spotted onto P-30 phosphocellulose paper (Wallac & Berthold, EG&G Instruments Ltd, Milton Keynes).
  • the paper was washed four times in H 3 PO4 (0.5%), 2 mins for each wash, air dried and the radioactive phosphate inco ⁇ orated into the synthetic glycogen synthase peptide, which binds to the P-30 phosphocellulose paper, was counted in a Wallac microbeta scintillation counter.
  • Type 2 This protocol is based on the ability of the kinase to phosphorylate a biotinylated 26 mer peptide, Biot- KYRRAANPPSPSLSRHSSPHQ(S)EDEEE, the sequence of which is derived from the phosphorylation site of glycogen synthase, where (S) is a pre-phosphorylated serine as in glycogen synthase in vivo and the three consensus sites for GSK-3 specific phosphorylation are underlined.
  • the phosphorylated biotinylated peptide is then captured onto Streptavidin coated SPA beads (Amersham Technology), where the signal from the 33p j s amplified via the scintillant contained in the beads.
  • GSK-3 was assayed in 50 mM MOPS buffer, pH 7.0, containing 5% glycerol, 0.01 % Tween-20, 7.5 mM 2-mercaptoethanol, 10 mM magnesium acetate, 8 uM of the above peptide, and 10 uM [33p]-ATP. After incubation at room temperature, the reaction was stopped by addition of 50 mM EDTA solution containing the Streptavidin coated SPA beads to give a final 0.2 mgs. Following centrifugation, the microtitre plates are counted in a Trilux 1450 microbeta liquid scintillation counter (Wallac). IC50 values are generated for each compound by fitting to a four parameter model.
  • the most potent compounds of the present invention show IC50 values in the range of 1 to 100 nM.
  • Example C97 A mixture of 3-(3,5-difluorophenylamino)-4-(4-nitrophenyl)-lH-pyrrole-2,5- dione (Table C, Example C91, 0.012 g, 0.035 mmol), stannous chloride dihydrate (0.023 g, 0.105 mmol) and ethanol (5 mL) was stirred at 70°C overnight before being evaporated and suspended in dichloromethane. The resulting precipitate was collected and suspended in dichloromethane (5 mL) and treated with acetic anhydride (10 uL, 0.1 mmol).
  • Example Syntheses 1 to 22 themselves are shown as Example Compounds in the following Tables according to the list below:
  • the positions of substitution of R 1 ', R 12 and Q are defined with reference to formula (Z-2) and the values of R 10 , R 11 , R 12 and Q are listed in Table A.
  • the group R 3 of formula (I) is hydrogen.
  • the values of R 10 , R 13 and W are listed in Table B.
  • Q represents a linking moiety and Ar 1 represents an aromatic heterocyclic group as hereinbefore defined.
  • the positions of substitution of R 11 and Q are defined with reference to formula (Z-8) and the values of R 10 , R n , Q and Ar 1 are listed in Table F.

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Abstract

L'invention concerne un procédé visant à traiter des affections associées à un besoin d'inhibition de GSK-3, ce procédé comportant l'administration à un mammifère humain ou non humain nécessitant un tel traitement d'une quantité pharmaceutiquement efficace non toxique d'un composé représenté par la formule (I), ou d'un dérivé pharmaceutiquement acceptable de celui-ci. Dans la formule, R1 représente un noyau aromatique carbocyclique ou hétérocyclique substitué ou non substitué, ce noyau pouvant être condensé avec un noyau aromatique ou non aromatique carbocyclique ou hétérocyclique substitué ou non substitué; R2 représente un noyau aromatique carbocyclique ou hétérocyclique substitué ou non substitué, ce noyau pouvant être condensé avec un noyau aromatique carbocyclique ou hétérocyclique substitué ou non substitué, à condition que R2 ne représente pas 3-indolyle ou un dérivé de 3-indolyle à noyaux condensés; R3 représente hydrogène, ou R1 et R3 forment ensemble avec l'atome d'azote auquel ils sont liés un noyau hétérocyclique condensé substitué ou non substitué.
PCT/EP2001/003687 2000-04-04 2001-04-02 Derives de pyrrole-2, 5-dione destines au traitement du diabete Ceased WO2001074771A1 (fr)

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WO2003011843A1 (fr) * 2001-08-03 2003-02-13 Novo Nordisk A/S Nouveaux derives de la 2,4-diaminothiazole
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WO2004072022A1 (fr) * 2003-02-12 2004-08-26 Galderma Research & Development, Snc Composes fonctionnant comme modulateurs de recepteurs de type ppar et leur utilisation dans des compositions cosmetiques ou pharmaceutiques
WO2005030716A1 (fr) * 2003-09-25 2005-04-07 Wyeth Acides ou esters d'indoles-2-carboxylique heterocyclique ou aryloxy, -thio ou -amino substitues en tant que pai-1
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WO2006073363A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives de 1,1-dioxydes d'isothiazol-3(2h)-one utilises comme modulateurs du recepteur x du foie
WO2006073365A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives non aniliques d'isothiazol-3(2h)-thione 1,1-dioxides servant de modulateurs de recepteurs nucleaires hepatiques
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WO2006073366A1 (fr) * 2005-01-10 2006-07-13 Astrazeneca Ab Derives non aniliques d'isothiazol-3(2h)-one 1,1-dioxides servant de modulateurs de recepteurs nucleaires hepatiques
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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
EP2294050A2 (fr) * 2008-05-14 2011-03-16 Biolipox AB Composes bis-aryles destines a etre utilises en tant que medicaments
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
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
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WO2003011843A1 (fr) * 2001-08-03 2003-02-13 Novo Nordisk A/S Nouveaux derives de la 2,4-diaminothiazole
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FR2850967A1 (fr) * 2003-02-12 2004-08-13 Galderma Res & Dev NOUVEAUX COMPOSES MODULATEURS DES RECEPTEURS DE TYPE PPARs ET LEUR UTILISATION DANS DES COMPOSITIONS COSMETIQUES OU PHARMACEUTIQUES
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