WO2001074771A1 - Pyrrole-2,5-dione derivatives for the treatment of diabetes - Google Patents

Pyrrole-2,5-dione derivatives for the treatment of diabetes Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
substituted
diabetes
ring
Prior art date
Application number
PCT/EP2001/003687
Other languages
French (fr)
Inventor
David Haigh
Brian Peter Slingsby
David Glynn Smith
Robert William Ward
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU2001262153A priority Critical patent/AU2001262153A1/en
Publication of WO2001074771A1 publication Critical patent/WO2001074771A1/en

Links

Classifications

    • 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.

Abstract

A method for the treatment of conditions associated with a need for inhibition of GSK-3, which method comprises the administration of a pharmaceutically effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein R1 is a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring, which ring may be fused to a substituted or unsubstituted carbocyclic or heterocyclic aromatic or non-aromatic ring; R2 is a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring, which ring may be fused to a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring, with the proviso that R2 is not 3-indolyl or a fused-ring derivative of 3-indolyl; R3 is hydrogen, or R?1 and R3¿ 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.

Description

PYR OLE-2 , 5-DIONE DERIVATIVES FOR THE TREATMENT OF DIABETES
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 (α and β) 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 α and β 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-3α 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. Biophys. Acta (39) 171-173 (1960), Parker P J et al., Eur. J. Biochem. (130) 227-234 ( 1983), and Cohen P. Biochem. Soc. Trans. (21) 555-567 ( 1993)). The phosphorylation and dephosphorylation of GS are mediated by specific kinases and phosphatases. 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)).
Chen et al Diabetes (43) 1234-1241 (1994) found that there was no difference in the mRNA abundance of PP1G between patients with Type II diabetes and control patients, suggesting that an increase in GSK-3 activity might be important in Type II diabetes. It has also recently been demonstrated that GSK-3 is overexpressed in Type II diabetic muscle and that an inverse correlation exists between skeletal muscle GSK-3α activity and insulin action (Nikoulina et al Diabetes 2000, 49 263-271 ). Overexpression of GSK-3β and constitutively active GSK-3β (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-3β 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)). Recent evidence for the involvement of elevated GSK-3 activity and the development of insulin resistance and type II diabetes in adipose tissue has emerged from studies undertaken in diabetes and obesity prone C57BL/6J mice (Eldar-Finkelman et al., Diabetes (48) 1662- 1666 (1999)).
GSK-3 has been shown to phosphorylate other proteins in vitro including the eukaryotic initiation factor eIF-2B at Serine540 (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. Several aspects of 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) Νeurosci. Letts. 172: 6-10) and chronic lithium treatment has demonstrable efficacy in the middle cerebral artery occlusion model of stroke in rodents (Νonaka and Chuang, (1998) Νeuroreport 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 β-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. 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). β-catenin is phosphorylated by GSK-3 as part of a tripartite complex with axin, resulting in β-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 β-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 β-catenin pool in transgenic mice. Further evidence suggests that such a reduction in available β- catenin may increase neuronal sensitivity to amyloid mediated death through inhibition of β-catenin-LEF-1/TCF transcriptional regulation of neuroprotective genes (Zhang et al., (1998) Nature 395: 698-702). A likely mechanism is suggested by the finding that mutant PS-1 protein confers decreased inactivation of GSK-3 compared with normal PS- 1 (Weihl, C.C., Ghadge, G D., Kennedy, S.G., Hay, N., Miller, R.J. and Roos, R.P.(1999) J. Neurosci. 19: 5360-5369).
International Patent Application Publication Number WO 97/41854 (University of Pennsylvania) discloses that an effective drug for the treatment of manic depression is lithium, but that there are serious drawbacks associated with this treatment. Whilst the precise mechanism of action of this drug for treatment of manic depression remains to be fully defined, current models suggest that inhibition of GSK-3 is a relevant target that contributes to the modulation of AP-1 DNA binding activity observed with this compound (see Manji et al., (1999) J. Clin. Psychiatry 60 (suppl 2): 27-39 for review). GSK-3 inhibitors may also be of value in treatment of schizophrenia. Reduced levels of β-catenin have been reported in schizophrenic patients (Cotter D, Kerwin R, al- Sarraji S, Brion JP, Chadwich A, Lovestone S, Anderton B, and Everall I. 1998 Neuroreport 9: 1379-1383 ) and defects in pre-pulse inhibition to startle response have been observed in schizophrenic patients (Swerdlow et al ( 1994) Arch. Gen. Psychiat. 51: 139-154). Mice lacking the adaptor protein dishevelled- 1, an essential mediator of Wnt- induced inhibition of GSK-3, exhibit both a behavioural disorder and defects in pre-pulse inhibition to startle response (Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K, Stevens KE, Maccaferri G, McBain CJ, Sussman DJ, and Wynshaw-Boris A. (1997) Cell 90: 895-905). Together, these findings implicate deregulation of GSK-3 activity as contributing to schizophrenia. Hence, small molecule inhibitors of GSK-3 catalytic activity may be effective in treatment of this mood disorder.
The finding that transient β-catenin stabilisation may play a role in hair development (Gat et al Cell (95) 605-614( 1998)) suggests that GSK-3 inhibitors could be used in the treatment of baldness. Studies on fibroblasts from the GSK-3β knockout mouse (Hoeflich KP et al.,
Nature 2000, 406, 86-90) support a role for this kinase in positively regulating the activity of NFkB. This transcription factor mediates cellular responses to a number of inflammatory stimuli. Therefore, pharmacologic inhibition of GSK-3 may be of use in treating inflammatory disorders through the negative regulation of NFkB activity. International Patent Application Number WO 98/16528 (Chiron Corporation) discloses certain purine derivatives as GSK-3 inhibitors. WO 99/47522 (University of British Colombia) discloses certain granulatimide derivatives as GSK-3β inhibitors. WO 99/65897 (Chiron Corporation) discloses certain pyrimidine and pyridine derivatives as GSK-3 inhibitors. WO 00/17184 (Mitsubishi Chemical Corporation) discloses certain hydroflavone derivatives as Tau protein kinase-1 (TPK-1) inhibitors, where Tau protein kinase is a synonym for GSK-3β. 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 (SmithKline Beecham Pic) discloses certain 1,2,4-triazole derivatives as GSK-3 inhibitors.
Certain substitued 3-amino-4-arylmaleimides are disclosed in J Amer Chem Soc 1958, 80, 1385 which compounds have no disclosed pharmaceutical utility. WO 00/06564 (Japan Tobacco Inc.) discloses certain 3-amino-4-(3-indolyl) maleimide derivatives as PKC-beta inhibitors.
We have now discovered that a series of 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.
Accordingly, in a first aspect, 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):
Figure imgf000005_0001
or a pharmaceutically acceptable derivative thereof, wherein; 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.
When R S a substituted or unsubstituted carbocychc aromatic ring, examples include phenyl.
When RMs a substituted or unsubstituted heterocyclic aromatic ring, examples include pyridinyl.
When RMs a substituted or unsubstituted carbocychc aromatic ring which ring is fused to a substituted or unsubstituted carbocychc non-aromatic ring, examples include indanyl.
When 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.
When R2 is a substituted or unsubstituted carbocychc aromatic ring, examples include phenyl.
When 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.
When RMs a substituted carbocychc aromatic ring or a substituted heterocyclic aromatic ring, suitable substituents include up to five groups independently selected from the list consisting of hydroxy, Cj.galkoxy, di-(Cι_6alkyl)amino, cyano, substituted or unsubstituted Chalky], carboxy, Cj.galkoxycarbonyl, C^alkylaminocarbonyl, halo, carboxyC j.galkyloxy, C^alkylamino, morpholinyl, hydroxyCi.galkylaminocarbonyl, (di-Cι_5alkylamino)carbonyl, Ci.βalkoxyCi. alkylaminosulphonyl, Cj_ galkylaminosulphonyl, Cj.galkylcarbonyl, C^alkylcarbonylamino, (perfluoroCj. galkyl)carbonylamino, Cj.galkylthio, amino, perfluoroCj.^alkyl, aminocarbonyl, nitro, aminocarbonylC2-6alkenyl, C^alkoxyCi.galkylcarbonylamino, C{_ 6alkylcarbonylaminoC _5alkylcarbonylamino, hydroxyC _0alkylcarbonylamino, C j _ βalkoxycarbonylC 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 } .βalkyl, C \ _galkylsulphonylaminoC \ _6alkyl, (C \ . galkyloxy)hydroxyphosphinylC \ _5alkyl, aminosulphonylC \ .galkyl, C \ _ 6alkoxyaminocarbonylCι_6alkyl, hydroxyaminocarbonylC^alkyl, Cι _ 6alkoxyaminocarbonylC2-6alkenyl, aminoC t .galkyl, and moiety (IN)
Figure imgf000006_0001
wherein;
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 carboxyC2-6alkenyl, Cι _ galkylcarbonylamino, amino,
Figure imgf000007_0001
halo, cyano, Cι _ 5alkoxy, Ci .galkoxycarbonyl, (di-Cj.galky aminocarbonyl, carboxyC i .galkyl, Cj_ 6alkylaminocarbonyl, carboxy, hydroxy, aminocarbonyl, Cj.galkoxyCi. 5alkylaminocarbonyl, C \ _6alkylaminocarbonylC \ .galkyl, mo holinylC \ _ galkylaminocarbonylCi.galkyl, Ci-galkyl, aminocarbonylC]_6alkyl, hydroxyaminocarbonylCi.galkyl, Ci.galkoxycarbonylCi.galkyl, phenyl, hydroxyCj. 6alkyl, moφholinyl, piperidinyl, cyanoC i .galkyl, (Ci.galkylpiperidinyljC i .galkoxy, (C j _6alkylcarbonyl)(C j _6alkyl)amino, C ι .galkylcarbonylaminoC \ .galkyl, (di-C \ . galkyl)aminoCι _5alkyl, aminosulphonyl, ureido, and Ci.galkylsulphonylamino. When Ar is a carbocychc aromatic ring, examples include phenyl. When 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], -[(CH2)ι_6θ]-, -[CONH(CH2) ι _6_-, -[( CH2) 1_6CONH(CH2)1_6)]-, -[S]-, -[O]-, -[(CH2)i-6CONH]-, -[CO]-, -[O(CH2) . _6]-, - [NHCO]-, -[NHSO2]-, -[(CH2)ι _6NHCO(CH2) . _6]-, -[SO2NH]-, -[(CH2)ι _ 6NHSO2(CH2)1_6]-, -[NHCO(CH2)!.6]-, a bond, -[(CH2)1.6NHCO]-I -[(CH2)i-
6NHSO2]-, -fNH]-, -[CH2O]-, -[(CH2) . _6SO2NH]-, -[(CH2)1.6CO2(CH2)1.6SO2]-, - [(CH2) i _6CONHNHCO]-, -[(CH2) i .6CO2(CH2) i _6]-,-[O(CH2) 1.6N(C i _6alkyl)]-, - [S(CH2)ι_6]-, and -[SO2]-.
Suitable substituents for any alkyl group include cyano, Cj.galkylaminocarbonyl, aminosulphonyl, Cj.galkoxy, Ci .galkylsulphonylamino, hydroxy, carboxy, phenylaminocarbonyl, phenylCj.galkylaminocarbonyl, phenylcarbonylamino, phenylCj. galkylcarbonylamino, thiazolidinedionyl, piperazinylcarbonyl where the piperazinyl group may be substituted or unsubstituted, morpholinylcarbonyl, piperidinylcarbonyl, hydroxyCi.galkylaminocarbonyl, (di-Cι_6alkylamino)carbonyl, Cj_ galkylaminosulphonyl, aminocarbonyl, (di-Cι_6alkylamino)C ι _6alkylaminocarbonyl, Cj.galkoxycarbonylamino, Cj.galkylcarbonylamino, Cι_6alkoxyCι_ galkylcarbonylamino, C j .galkylcarbonylaminoC \ .galkylcarbonylamino, C j . galkoxycarbonylCj.galkylcarbonylamino, hydroxyCj.galkylcarbonylamino, and (di-C i _ 6alkylamino)sulphonyl. Suitable substituents for any piperazinyl group include C i .galkyl.
Suitably, R' is unsubstituted phenyl or phenyl substituted with; 4-[S-(3-CH2CO2H)Ph], 4-[S-(3-CONHMe)Ph], 4-[O-(3-CO2H)Ph], 3-CO2H, 3- [CH2CONHPh], 4-[CH2CONHPh], 3-COPh, 3-OCH2Ph, 4-[NHCO-(2-OH)Ph], 3- CO2Et, 4-[S-(2-CO2H)Ph], 4-[O-(3-CONHMe)Ph], 4-[O-(3-CONH2)Ph], 4-[S-(3- CONH2)Ph], 4-[O-(4-CONHMe)Ph], 4-[NHCOPh], 4-[S-[3-CONH(CH2)2OMe]Ph], 4- [S-(2-CO2H)Ph], 4-[NHCOCH2Ph], 3-[NHCOCH2Ph], 3-CONHPh, 4-[O-(4-CO2H)Ph], 4-SPh, 4-[CH2NHCOCH2Ph], 3-CONHMe, 4-[O-(4-CONH2)Ph], 4-[S-(3- CH2CONHMe)Ph], 4-[S-[3-CH2CONH(CH )2(morpholin-4-yl)]Ph], 3-SO2NHPh, 3- CH2NHCOPh, 4-[NHSO (4-Me)Ph], 3-CH2NHCOCH2Ph, 4-[NHCO(CH )2Ph], 4-[S- (3-CH2CONH2)Ph], 4-[S-(3-CO2H)Ph], 4-[S-(3-CH2CONHOH)Ph], 4-[O-(2- CO2H)Ph], 4-Ph, 4-[S-(2-CH2CO2Me)Ph], 4-[S-(4-CONH2)Ph], 4-[S-(4-CO2H)Ph], 4- [O-(2-CONHMe)Ph], 4-[CH2CONH-(3-CO2H)Ph], 4-[O-(3-CH2CO2H)Ph], 4-[S-(2- CO2H)Ph], 4-[O-(2-CONH2)Ph], 3-[CH2(l,3-thiazolidine-2,4-dion-5-yl)], 3,5-di-F, 3-C1, 3-OCH2CO2H, 3-CONHMe-4-NHMe, 4-[CH2CO(4-Me-piperazin- 1 -yl)], 2-[morpholin- 4-yl], 3-[CH2CO(morpholin-4-yl)], 3-[CH2CO(piperidin-l-yl)], 4-[CH2CO(piperidin-l- yl], 4-[CH2CONH(CH2)2OH], 4-[CH2CONMe2], 3-[CONHMe]-4-Cl, 3- SO2NH(CH2)2OMe, 3-SO2NHn-Bu, 3-COMe, 3-CH2CO2H, 3-NHCOMe, 4- NHCOCF3, 2-Me, 2-Me-4-F, 2-Me-5-F, 3-Me, 2-SMe, 3-CF3-4-NH2, 3-CF3-4- NHCOMe, 4-CH2SO2NHMe, 4-CH2CH2CONH2, 4-Me, 3-[CH2CONH(CH2)2NMe2], 4-NH2, 3-NO2, 3-NH2, 2,3,4-tri-F, 3-F-5-CF3, 4-[O(CH2)3CO2H], 4-CH2NHCO2t-Bu, trans-4-[CH=CHC(O)NH2], 4-[NHCOCH OMe], 4-[NHCOCH2NHCOMe], 4- CH2NHCOn-Pr, 4-[NHCOCH2OH], 3-[NHCOCH2OMe], 4-[NHCOCH2CO2t-Bu], 3- [NHCOCH2NHC(O)Me], 4-[NHCOn-Pr], 4-[NHCOCH2CO H], 4- [CH2NHCOCH OMe], 4-[CH2NHCOCH2NHCOMe], 4-[(CH2)3CO2H], 3-
[CH2NHCO2t-Bu], 4-[CH2NHCOCH2OH], 4-[NHCOMe], 3-[NHCOCH2OH], 3-OH-4- [NHCOMe], 4-[CH2NHCOCH2CO2t-Bu], 3-[CH2CONH2], 3-[SO2NH2], 3- [CH2NHCOCH2OMe], 3-[CH2NHCOCH2NHCOMe], 3-[CH2NHCOCH OH], trans-4- [CH=CHCO2H], 4-[NHCO(CH2)2CONH2], 4-O(CH2)3CONHMe, 4-[NHCOMe], 4- [CH2SO2NHMe], 4-[CH2SO2NMe2], 3-[CH2CONH2], 4-[CH2SO2NHMe], 4-
[CH2(l,3-thiazolidine-2,4-dion-5-yl)], 3-[oxazol-5-yl], 4-[NHCO(CH2)2(3-pyridinyl)], 4-[5-Me-2-oxazolyl], 4-[2-Me-4-oxazolyl], 4-[S-(2-CONH2)Ph], 4-[S-(2-CONHMe)Ph], 4-[CH2CONH-(4-CO2H)Ph], 3-[CH2CONH-(4-CO2H)Ph], 3-CO2H-4-[O-Ph], 3- CO2H-4-[O-(4-Ph)Ph], 3-[CONH-(4-CO2H)Ph], 3-[CH2O-(4-CO2H)Ph], 4- [CH2SO2NH-Ph], 4-[O-(4-CO2H)Ph], 3-[O-(4-CO2H)Ph], 3-[O-(4-CH2CO2H)Ph], 4- [O-(4-CH2CO2H)Ph], 3-[CH2CONH-(4-CH2CH2OH)Ph], 3-[O-(3-CO2H)Ph], 3-[O-(4- CH2CH2CO2H)Ph], 3-[CH2CONH-(4-(moφholin-4-yl)Ph], 3-[CH2CONH-(4- (piperidin-l-yl)Ph], 3-[CH2CONH-(4-CH2OH)Ph], 4-[O-(3-NMe2)Ph], 3-[OCH -(4- CO2H)Ph], 3-[CH2CO2CH2CH2SO2-(4-NH2)Ph], 3-[CH2CONH-(4-NMe2)Ph], 3- [CH CONH-(3-Cl-4-(moφholin-4-yl)Ph], 3-[CH2CONH-(4-CH2CN)Ph], 3- [CH2CONH-4-(OCH2( l-methylpiperidin-4-yl)Ph)], 3-[O-(3-NH2)Ph], 4-[O-4- NHCOMe)Ph], 3-Me-4-[O-(4-CH2CO2H)Ph], 4-[CH2SO2NH-(4-CO2H)Ph], 4-[O-(3- NHCOMe)Ph], 3-[CH2CONH-(3-NHCOMe)Ph], 3-[CH2CONH-(4-NHCOMe)Ph], 3- [CH2CONH-(4-N(Me)COMe)Ph], 3-[CH2CONH-(3-CONH2)Ph], 3-[CH2CONH-(2- CONH2)Ph], 3-[CH2CONH-(3-NMe )Ph], 4-[CH SO2NH-(4-CH2CO2H)Ph], 4- [CH2Sθ2NH-(3-CH2CO2H)Ph], 4-[CH2Sθ2NH-(3-CO2H)Ph], 3-Cl-4-[O-(4- CH2CO2H)Ph], 3-Cl-4-[O-(4-CO2H)Ph], 3-[CH2CONH-(3-CO2H)Ph], 3- [CH2CONHCH2-(4-NMe )Ph], 3-[CH2CONHNHCO-(4-NH2)Ph], 4-[O-(4- CH2NHCOMe)Ph], 3-CO2H-4-[O-(4-Cl)Ph], 3-[O-(4-NHCOMe)Ph], 3-[CH2CONH-(4- CONH2)Ph], 4-[O-(3-NHCONH2)Ph], 4-[O-(4-CH2CH2NMe2)Ph], 3-[CH2CONH-(3- NH2)Ph], 3-[CH2CONH-(4-NH2)Ph], 3-[CH2CONHNHCO-Ph], 3-[CH2CONH-(4- SO2NH2)Ph], 3-[CH2CONH-(3-CH2OH)Ph], 3-[CH2CONH(CH2)2-(4-NH2)Ph], 3- [CH2CONHNHCO-(3-NH2)Ph], 3-[CH2SO2NH-Ph], 3-[CH2SO2NH-(3-CO2H)Ph], 3- [CH2CONH-(4-NHSO?Me)Ph], 3-[CH2SO2NH-(4-CO2H)Ph], 3-[SO2-(3-NH2)Ph], 4- [O-(4-SO2NH2)Ph], 4-[O-(4-NH2)Ph], 4-[CH2SO2NH-(4-NHSO2Me)Ph], 4- [CH2SO2NH-(4-NHCOMe)Ph], 4-[6-Me-2-benzothiazolyl], 4-[O-(3-pyridinyl)], 3-[2- benzothiazolyl], 3-[CH2CONH(3-quinolinyl)], 4-[3-Me-l,2,4-oxadiazol-5-yl], 3- [CH2CONH(2-Me-pyridin-3-yl)], 3-[CH2CONH(5-Me-pyridin-3-yl)], 3-[CH CONH(2- OMe-pyridin-5-yl)], 3-[CH2CONH(pyridin-3-yl)], 3-[CH2CO2CH2(3-NH2-pyndin-2- yl)], 4-[O(CH2)2NMe(pyridin-2-yl)], 4-[OCH2(pyridin-3-yl)], 3-[CH2CONH(pyrimidin- 4-yl)], 3-[CH2CONH(pyrazin-2-yl)], 4-[O-(pyridin-2-yl)], 4-[2-OH-pyrimidin-5-yl)], 4- [5-Me-4,5-dihydro-2H-pyridazin-3-on-6-yl)], 4-[2,5-di-Me-4,5-dihydro-2H-pyridazin-3- on-6-yl)], 4-[lH-pyrazol-3-yl], 4-[SCH2(lH-imidazol-4-yl)], 3-[CH2SO NH(pyridin-3- yl)], 4-[2-OMe-pyrazin-5-yl)], 4-[lH-pyrazin-2-on-5-yl)], 4-[5,6-dihydro-4H-[ 1,3,4]- oxadiazin-5-on-2-yl)], 4-[4,5-dihydro-2H-pyridazin-3-on-6-yl)], 4-[2H-pyridazin-3-on-6- yl)], 3-CH2CH2CO2H, 4-CH2CH2CH2CO H, 4-CH2CH2CH2CO2H, 4-OH, 3,5-di-Cl- 4-OH, 4-(CH2)2CO H, 3-F-4-OCH2CO2H, 4-NHCOCO2H, 3-Me-4-tra«_-- CH=CHCO2H, 3-CH CONHNHCOMe, 4-(CH2)4NHCOMe, 4-(CH2)4NHSO2Me, 3- CH2NHSO2Me, 4-CH2CH2P(O)(OEt)OH, 4-CH2CH2SO2NH2, 3-CH2SO2NH2, 3- CH2CONHOMe, 3-CH2CONHOH, 4-trans-CH=CHCONHOMe, 4-CH2NH2, or 3- CH2NH2-
Favourably, R1 is phenyl substituted with 4-[S-(3-CH2CU2H)Ph].
Suitably, R1 is pyridin-5-yl substituted with 2-[(CH2)3CN]-3-Me, 2- [(CH2)2CO2H]-, 2-[(CH2)4CO2H]-, 2-[(CH2)3CN]-3-CO2Et, or 2-[OPh].
Suitably, R1 is pyridin-3-yl substituted with 2-Me, or 2-[(CH2)3CN].
When RMs a substituted or unsubstituted carbocychc aromatic ring which ring is fused to a substituted or unsubstituted heterocyclic aromatic or non-aromatic ring, suitable substituents for either ring include carboxyC j.galkylthio and esters thereof, halo, aminocarbonyl, hydroxy, aryloxy, arylthio, arylamino, Cj.galkyl, Ci_galkylcarbonyl, Cj. galkylsulphonyl, Cj.galkylthio, Ci .galkoxy, Cj.galkoxycarbonyl, carboxy, carboxyC j_ galkyl, substituted or unsubstituted aryl, arylCj.galkyl, amino, dHC j.galkyDamino, di- (C j _6alkyl)aminoC j .galkyl, C j .galkoxycarbonylC \ .galkyl, di-(C j .galkyOaminoC \ _ galkylamino, moφholinyl, Cj.galkylcarbonylamino, and Ci-βalkylamino. Suitably, R' is indolin-5-yl unsubstituted or substituted with l-(SO2Me), or 1-
CO t-Bu.
Suitably, R^ is indan-5-yl.
Suitably, R^ is quinolin-6-yl.
Suitably, R^ is indol-5-yl unsubstituted or substituted with [l-Me-2-CONH2], 1- Me, or [l-Me-2-CO2H].
Suitably, R is benzoxazol-5-yl substituted with 2-Me.
Suitably, R^ is unsubstituted benzoxazol-6-yl, or benzoxazol-6-yl substituted with 2-Me.
Suitably, R^ is benzothiazol-5-yl substituted with 2-Me. Suitably, R* is unsubstituted benzothiazol-6-yl or benzothiazol-6-yl substituted with 2-[NHCOMe], 2-NH2, 2-NHiPr, 2-[NHEt], 2-[moφholin-4-yl], 2- [NH(CH2)3N(Me)2], 2-[(CH2)4CO2H], 2-[(CH2)4CO2Me], 2-NHPh, 2- [S(CH2)3CO2H], 2-Ph, 2-NHMe, 2-N(Me)2, 2-CI, 2-SMe, 2-Me, 2-(SCH2CO2Me), or 2-(SCH2CO2H). Suitably, R^ is benzthiazolinon-6-yl unsubstituted or substituted with 3- CH2CO2Me, 3-[3-F-Ph], 3-[4-OMe-Ph], 3-[CH2Ph], 3-[3-NHCOMe-Ph], 3- [(CH2)3N(Me) ], 3-Me, 3-CH2CO2H.
Suitably, R1 is benzoxazolinon-6-yl. Suitably^1 is benzoxazolinon-5-yl. Suitably, R1 is benzimidazol-5-yl substituted with 2-Me. Suitably, R1 is benzimidazolinon-5-yl unsubstituted or substituted with 1,3-di-Me Suitably^1 is benzothiophen-5-yl.
Sui tably, R1 is benzofuran-5-yl substituted with 2-CO2H. Sui tably, R1 is indolin-2-on-5-yl. Suitably, R1 is 2H- 1 ,4-benzothiazin-3(4H)-on-7-yl. Favourably, R* is unsubstituted benzoxazolinon-6-yl. Favourably, R' is unsubstituted benzthiazolinon-6-yl. Favourably, R ! is unsubstituted indolin-2-on-5-yl. Favourably, R ! is benzothiazol-6-yl substituted with a 2-amino group.
When 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.βalkoxy, nitro, perfluoroCj. galkyl, benzoyl, Cj.galkoxycarbonyl, Cj.galkylsulphonyl, hydroxy, -O(CH2)wO- where w is 1 to 4, phenoxy, benzyloxy, Cj.galkoxyCi.galkyl, perfluoroCi.galkoxy, Cj. galkylS-, perfluoroCj.galkylS-, (diCj.galkyON-, amino, Ci_galkylcarbonylamino, substituted or unsubstituted ureido, phenylcarbonylamino, benzylcarbonylamino, styrylcarbonylamino, Cj.βalkyl, and phenyl.
Suitable substituents for ureido include fluorophenyl, phenylCj.galkyl-, cyclohexyl, Cj.galkenyl, Cj.galkyl, and Cj.galkoxyphenyl.
Suitably, R is unsubstituted phenyl or phenyl substituted with 4-NO2, 4- NHCOMe, 4-1, 2,3-di-F, 3-CN, 2,3,6-tri-F, 3-CO2H, 3-CH2OH, 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.
Favourably, R^ is phenyl substituted with 2,3-di-F. When R and R^ form substituted indolinyl, suitable substituents include hydroxyCj.galkyl and Cj.galkoxyC galkyl.
Suitably, R! and R^ form indolinyl substituted with 2-(hydroxymethyl) or 2- (methoxymethyl).
Suitably, R^ and R^ form tetrahydroquinolinyl. Preferred compounds of formula (I) 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.
There is a sub-group of compounds, falling wholly within formula (I), and being of formula (H
wherein;
Rl, R2, and R^ are as defined in formula (I), with the proviso that formula (O does not include the following compound:
3-phenylamino-4-phenyl- 1 H-pyrrole-2,5-dione.
It is considered that the compounds of formula (O are novel. Accordingly, 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.
There is a subgroup of compounds falling wholly within formula (O being of formula (IA)
Figure imgf000011_0002
wherein;
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 ι _ galkylaminocarbonyl, halo, and Cj.galkyl;
Q represents a bond or a bivalent linking group.
Examples of Q include -[CONH]-, -[(CH2)!_6O]-, -[CONH CH^.g]-, -[( CH^CONH CH^^)]-, -[S]-, -[O]-, -[(CH2)1.6CONH]-, -[CO]-, -[O(CH2)!_6]-,
[NHCO]-, -[NHSO2]-, -[(CH^NHCO CH^.^-, -[SO2NH]-, -[(CH2)ι_
6NHSO2(CH2)i-6_-, -[NHCO(CH2)ι_6]-, a bond, -[(CH2)i-6NHCO]-, -[(CH2)i-
6NHSO2]-, -[NH]-, -[(CH2)i-6SO2NH]-, -[(CH2)1.6CO2(CH2)1.6SO2]-, -[(CH2)ι_
6CONHNHCO]-, and -[SO2]-. 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, Cι _ galkylaminocarbonylC j .galkyl, moφholinylC \ .βalkylaminocarbony 1C \ .galkyl, C [ . galkyl, aminocarbonylCi.galkyl, hydroxyaminocarbonylCj.galkyl, C\. galkoxycarbonylCi.galkyl, phenyl, hydroxyCj.galkyl, moφholinyl, piperidinyl, cyanoC \ .galkyl, (methylpiperidinyl)C \ .galkoxy , (C \ .galkylcarbonylXC [ .galkyljamino, Ct .galkoxyaminoCi.galkyl, (di-Ci .galky aminoCi.galkyl, aminosulphonyl, C\_ galkylcarbonylaminoC j.galkyl, ureido, and Cj.galkylsulphonylamino.
Suitably, R10 represents hydrogen, 2,3-di-F, 3-CN, 2-F-3-C1, 2,3,6-tri-F, 2-C1-3- F, and 4-Cl.
Favourably, RlO represents 2,3-di-F.
Suitably, Ru represents hydrogen, 3-CO2H, 3-CO2Et, 3-CONHMe, 3-Me, or 3- Cl.
Suitably, Q represents 4-[S]-, 4-[O]-, 3-[CH2CONH]-, 4-[CH2CONH]-, 3-[CO]-, 3-[OCH2]-, 4-[NHCO]-, 4-[NHCOCH2]-, 3-[NHCOCH2]-, 3-[NHCO]-, 4-
[CH2NHCOCH2]-, 3-[SO2NH]-, 3-[CH NHCO]-, 4-[NHSO2]-, 3-[CH2NHCOCH2]-, 4- [NHCOCH2CH2]-, a bond at position 4, 3-[CONH]-, 3-[CH2O]-, 4-[CH2SO2NH]-, 3- [O]-, 3-[CH2CONHNHCO]-, 3-[CH CONH(CH2)2]-, 3-[CH2CONHCH2]-, 3- [CH2CO (CH2)2SO2]-, 3-[SO2]-, 3-[CH2SO2NH]-, or 4-[CH2SO2NH]-. The position of the linking moiety Q is defined with respect to the atom numbering depicted in formula (IA).
Favourably, Q represents 4-[S]-.
Suitably, R12 represents hydrogen, 4-CH2CO2H, 4-CH2CH2CO2H, 4-CH2OH, 3-NMe2, 4-NH , 4-NMe2, (3-Cl-4-moφholin-4-yl), 4-CH CN, 4-OCH2-(l-Me- piperidin-4-yl), 3-CH2CO2H, 3-CONHMe, 3-CO2H, 2-OH, 2-CO2H, 3-CONH2, 4- CONHMe, 3-[CONH(CH2)2OMe], 4-CO2H, 4-CONH2, 3- [CH2CONH(CH2)2moφholin-4-yl], 4-Me, 3-CH2CONH2, 3-CH CONHOH, 2- CH2CO2Me, 2-CONHMe, 3-CH2CONHMe, 2-CONH , 4-Ph, 4-CH2CH2OH, 4- moφholin-4-yl, 4-piperidin-l-yl, 4-CH2NHCOMe, 3-NH2, 4-NHCOMe, 3-NHCOMe, 4- N(Me)COMe, 4-CH NHCOMe, 4-C1, 3-NHCONH2, 4-CH2NHCOMe, 4- CH2CH2NMe2, 4-SO2NH2,3-CH2OH, or 4-NHSO2Me.
Favourably, R^ represents 3-CH2CO2H.
Preferably, a compound of formula (IA) is Example Al of Table A.
It is considered that the compounds of formula (IA) are novel. Accordingly, the present invention also provides a compound of formula (IA) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I') being of formula (IB)
Figure imgf000013_0001
wherein;
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;
W represents -[S-CH=N]-, -[(CH2)2.4N(SO2C1_6alkyl)]-, -[(CH2)3_5]-, - [N^C^alky^-S]-, -[S-C(C1_6alkyl)=N]-, -[O-C(C1_6alkyl)=N]-, -[N=C(Cι_6alkyl)- O]-, -[O-CH=N]-, -[CH=CH-N(C1.6alkyl)]-, -[O-CO-NH]-, -[S-C(S(CH2)ι.6CO C1_ 6alkyl)=N]-, -[S-C(S(CH2)ι_6CO2H)=N]-, -[CH=CH-CH=N]-, -[S-CO-NH]-, -[N^. 6alkyl)-CH=N], -[S-C(halo)=N], -[S-C(SC1.6alkyl)=N], -[NHCONH], -[S-C(Ph)=N], - [S-QNHC i _6alkyl)=N], -[S-C(N(C j .6alkyl)2)=N], -[S-C(=O)N((CH2) ι_6CO2C j . 6alkyl)], -[S-C(=O)N((CH2)!.6CO2H)], -[CH=CH-S], -[S(CH2) 1.6CO2H]=N], -[S- C(NHPh)=N], -[N(C1_6alkyl)CON(C1.6alkyl)], -[S-CO-N C . ^alkyl)], -[S-C[(CH2)j_
Figure imgf000013_0002
-[CH=C(CO2H)-O], -[S- C[NH(CH2) 1.6N(C < _6alkyl)2]=N], -[S-CO-N[(CH2) i _6N(C i -6alkyl)2], -[S- C(Moφholin-4-yl)=N], -[S-CO-N(unsubstituted or substituted Ph)], -[S-CO-N((CH2)i- 6Ph)], -[CH=C(CO2H)-N(C1_6alkyI)]> -[(CH2)2^N(CO2Cι.6alkyl)], -[(CH2)2^NH], - [(CH2)i-3CONH], -[S-C(NHC1.6alkyl)=N], -[S-C(NH2)=N], [NH-CO-O], - [CH=C(CONH2)-N(Cι.6alkyl)], -[O(CH2)ι_2CONH], or -[S-C(NHCOC!_6alkyl)=N]. Suitably, R10' 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-CH2OH.
Favourably, R^ represents 2,3-di-F. Suitably, R^3 represents hydrogen. Suitably, W represents 3,4-[S-CH=N]-, 3,4-[CH2CH2N(SO2Me)]-, 3,4-
[CH2CH2CH2]-, 3,4-[N=C(Me)-S]-, 3,4-[S-C(Me)=N]-, 3,4-[O-C(Me)=N]-, 3,4- [N=C(Me)-O]-, 3,4-[O-CH=N]-, 3,4-[CH=CH-N(Me)]-, 3,4-[O-C(O)-NH]-, 3,4-[S- C(SCH2CO2Me)=N]-, 3,4-[S-C(SCH2CO2H)=N]-, 3,4-[CH=CH-CH=N]-, 3,4-[S-C(O)- NH]-, 3,4-[N(Me)-CH=N], 3,4-[S-C(Cl)=N], 3,4-[S-C(SMe)=N], 3,4-[NHCONH], 3,4- [S-C(Ph)=N], 3,4-[S-C(NHMe)=N], 3,4-[S-C(NMe2)=N], 3,4-[S-
C(=O)N(CH2CO2Me)], 3,4-[S-C(=O)N(CH2CO2H)], 3,4-[CH=CH-S], 3,4-[S- C[S(CH2)3CO2H]=N], 3,4-[S-C(NHPh)=N], 3,4-[N(Me)CON(Me)], 3,4-[S-CO-N(Me)], 3,4-[S-C[(CH2)4CO2Me]=N], 3,4-[S-C[(CH2)4CO2H]=N], 3,4-[CH=C(CO2H)-O], 3,4- [S-C[NH(CH2) NMe2]=N], 3,4-[S-CO-N[(CH2)3NMe2]], 3,4-[S-C(Mθφholin-4- yl)=N], 3,4-[S-CO-N(3-F-Ph)], 3,4-[S-CO-N(4-OMe-Ph)], 3,4-[S-CO-N(CH2Ph)], 3,4- [S-CO-N(3-NHCOMe-Ph], 3,4-[CH=C(CO2H)-N(Me)], 3,4-[CH2CH2N(CO2t-Bu)], 3,4-[CH2CH2NH], 3,4-[CH2CONH], 3,4-[S-C(NHEt)=N], 3,4-[S-C(NH2)=N]-, 3,4-[S- C(NHi-Pr)=N], 3,4-[NH-CO-O], 3,4-[CH=C(CONH2)-N(Me)], 3,4-[OCH2CONH], or 3,4-[S-C(NHCOMe)=N].
Favourably, W represents 3,4-[S-C(NH2)=N]-.
Favourably, W represents 3,4-[CH2CONH]-. Favourably, W represents 3,4-[O-C(O)-NH]-.
Favourably, W represents 3,4-[S-C(O)-NH]-.
Preferably, a compound of formula (IB) is selected from the list consisting of Examples B IO, B 16, B47, and B49 of Table B.
It is considered that the compounds of formula (IB) are novel. Accordingly, the present invention also provides a compound of formula (IB) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IC)
Figure imgf000014_0001
wherein;
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 hydroxyCj.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 ι _0alkylamino, moφholinyl, Ci.galkoxyCj. galkylaminosulphonyl, Cj.galkylaminosulphonyl, Cj.galkylcarbonyl, Cj_ galkylcarbonylamino, (perfluoroCi.galkyOcarbonylamino, Cj.galkylthio, amino, nitro, perfluoroCι_6alkyl, aminocarbonylC2-6alkenyl, Ci.galkoxyCi.galkylcarbonylamino,
C j .galkylcarbonylaminoC \ .galkylcarbonylamino, hydroxyC } .galkylcarbony lamino, C j _ galkoxycarbonylC i .galkylcarbonylamino, carboxyC \ .galkylcarbonylamino, hydroxyC j . galkylcarbonylamino, hydroxy, aminosulphonyl, carboxyC2-6alkenyl, aminocarbonylCi . galkylcarbonylamino, carboxyC j.galkyl, thiazolidindionylCj.galkyl, C\. galkylcarbonylaminoC \ .galkyl, C \ .galkylsulphonylaminoC .galkyl, (C \ .
5alkoxy)hydroxyphosphinylC [ .galkyl, aminosulphonylC j .galkyl, C j . galkoxy aminocarbony IC j -6alkyl , hydroxy aminocarbonylC i .galky 1 , C j .
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, (moφholinyl)carbonyl, (piperidinyl)carbonyl, hydroxyC]. galkylaminocarbonyl, (di-Cι_6alkylamino)carbonyl, carboxy, Cι _6alkylaminosulphonyl, aminocarbonyl, (di-Cι_6alkylamino)Cι_6alkylaminocarbonyl, C . galkoxycarbony lamino, C \ .galkylcarbonylamino, C \ .galkoxyC \ .galkylcarbonylamino, C j .galkylcarbonylaminoC \ .galkylcarbonylamino, hydroxyC j .galkylcarbonylamino, C j _ galkoxycarbonylC j .galkylcarbonylamino, C j.galkoxyC \ .galkylcarbonylamino, hydroxyC i.galkylcarbonylamino, Ci.galkylaminosulphonyl, and (di-Ci. 5alkylamino)sulphonyl.
Suitable substituents for piperazinyl include Cj.galkyl.
Suitably, R10" represents hydrogen, 2-F-3-C1, 2-C1-3-F, 4-NO2, 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-CO2H, or 3-CH2OH.
Suitably, R14 represents hydrogen, 3-[CH2-(l ,3-thiazolidine-2,4-dion-5-yl)], 3,5- di-F, 3-CI, 3-OCH2CO2H, 3-CONHMe-4-NHMe, 4-[CH2CO(4-Me-piperazin-l-yl)], 2- (moφholin-4-yl), 3-[CH2CO(mo holin-4-yl)], 3-[CH2CO(piperidin-l-yl)], 4- [CH2CO(piperidin-l-yl)], 4-[CH2CONH(CH2)2OH], 4-[CH2CONMe2], 3-CONHMe-4- CI, 3-SO2NH(CH2)2OMe, 3-SO2NHnBu, 3-COMe, 3-CH CO2H, 3-NHCOMe, 4- NHCOCF3, 2-Me, 2-Me-4-F, 2-Me-5-F, 3-Me, 2-SMe, 3-CF3-4-NH2, 3-CF3-4- NHCOMe, 4-CH2SO2NHMe, 4-CH2CH2CONH2, 4-Me, 3-[CH2CONH(CH2)2NMe2], 4-NH2, 3-NO2, 3-CI, 3-NH2, 2,3,4-tri-F, 3-F-5-CF3, 4-O(CH2)3CO2H, 4- CH2NHCO2tBu,
Figure imgf000015_0001
4-NHCOCH2OMe, 4-NHCOCH2NHCOMe, 4-CH NHCOnPr, 4-NHCOCH2OH, 3-NHCOCH2OMe, 4-NHCOCH2CO tBu, 3- NHCOCH2NHCOMe, 4-NHCOπPr, 4-NHCOCH2CO2H, 4-CH2NHCOCH2OMe, 4- CH2NHCOCH2NHCOMe, 4-(CH2)3CO2H, 4-(CH2)3CO2H, 3-CH2NHCO2tBu, 4- CH2NHCOCH2OH, 4-NHCOMe, 3-NHCOCH2OH, 3-OH-4-NHCOMe, 4- CH2NHCOCH2CO2tBu, 3-CH2CONH2, 3-SO2NH2, 3-CH2NHCOCH2OMe, 3- CH2NHCOCH2NHCOMe, 3-CH2NHCOCH2OH,
Figure imgf000015_0002
4- NHCO(CH2)2CONH2, 4-O(CH2)3CONHMe, 4-CH SO2NMe2, 4-[CH2-(l,3- thiazolidine-2,4-dion-5-yl)], 3-CH CH2CO H, 4-CH2CH2CH CO H, 4-OH, 3,5-di-Cl- 4-OH, 4-(CH2)2CO2H, 3-F-4-OCH2CO2H, 4-NHCOCO2H, 3-Me-4-tr_./z_- CH=CHCO2H, 3-CH2CONHNHCOMe, 4-(CH2)4NHCOMe, 4-(CH2)4NHSO2Me, 3- CH2NHSO2Me, 4-CH2CH2P(O)(OEt)OH, 4-CH2CH2SO2NH2, 3-CH2SO2NH2, 3- CH2CONHOMe, 3-CH CONHOH, 4-trans-CH=CHCONHOMe, 4-CH2NH2, or 3- CH2NH2.
There is a sub-group of compounds falling wholly within formula (O and being of formula (IC)
Figure imgf000015_0003
wherein;
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.
It is considered that compounds of formula (IC) are novel. Accordingly, the present invention also provides a compound of formula (IC) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (1^ being of formula (ID)
Figure imgf000016_0001
wherein;
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((CH2)1.6OH)-(CH2)1.4]-, -[CH2] ι_4-, or -[CH((CH2)i-
6(OC1.6alkyl))-(CH2)ι.4]-;
Ri5a represents hydrogen;
Rl5b represents hydrogen; R 15° represents hydrogen;
Rl5d represents hydrogen.
Suitably, Rι υ represents hydrogen, 2,3-di-F, 2,3,6-tri-F, 3,5-di-Me, or 2-C1. Suitably, X-Y represents -[CH(CH2OH)CH2]-, -[(CH2)2]-, -[(CH2)3]-, or - [CH(CH2OMe)CH2]-. 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.
There is a subgroup of compounds falling wholly within formula (V) being of formula (IE)
Figure imgf000016_0002
wherein;
R ' is substituted pyridinyl;
R2" is substituted phenyl;
Suitable substituents for pyridinyl include aryloxy, Cjμgalkyl, cyanoCj.galkyl, carboxyC ι_galkyl, or Cj.galkoxycarbonyl.
Suitable substituents for phenyl include halo.
Suitably, R^' is 2-[(CH2)3CN]-3-Me-pyridin-5-yl, 2-Me-pyridin-3-yl, 2- [(CH2)2CO2H]-pyridin-5-yl, 2-[(CH2)3CN]-3-(CO2Et)-pyridin-5-yl, 2-[(CH2)4CO2H]- pyridin-5-yl, 2-OPh-pyridin-5-yl, or 2-[(CH )3CN]-pyridin-3-yl. Suitably, R2" is 2,3-difluorophenyl.
It is considered that compounds of formula (IE) are novel. Accordingly, the present invention also provides a compound of formula (IE) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (O being of formula (IF)
Figure imgf000017_0001
wherein;
Rι υ 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]-, -[(CH2)1_6CONH]-, -[(CH2) 1.6CO2(CH2) 1_6]-> - [O(CH2)1.6N(Cι_6alkyl)]-, -[O(CH2)ι_6]-, -[S(CH2)j.6]-, -[(CH2)1.6SO2NH]-, or - [NHCO(CH2)1_6]-; Ar2 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. Suitably, R l °'"" represents 2,3-di-F.
Suitably, Q represents a bond at position 3, 4-[NHCO(CH2)2]-, 4-[O], 3-[bond], 3-[CH2CONH], 3-[CH2CO2CH2], 4-[O(CH2)2NMe], 4-[OCH2], 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).
Suitably, Ar2 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, lH-imidazol-4-yl, 2-OMe-pyrazin-5-yl, lH-pyrazin-2-on-5-yl, 5,6-dihydro- 4H-[l ,3,4]-oxadiazin-5-on-2-yl], 4,5-dihydro-2H-pyridazin-3-on-6-yl, or 2H-pyridazin-3- on-6-yl.
It is considered that compounds of formula (IF) are novel. Accordingly, the present invention also provides a compound of formula (IF) or a derivative thereof.
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, arylalkylcarbonylamino, thiazolidinedionyl, piperazinylcarbonyl wherein the piperazine may be unsubstituted or substituted, moφholinylcarbonyl, piperidinylcarbonyl, hydroxyalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl, dialkylaminoalkylaminocarbonyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino, alkylaminocarbonyl, aminosulphonyl, arylsulphonylamino, alkylsulphonylamino, hydroxy, moφholinylalkylaminocarbonyl, hydroxyaminocarbonyl, and halogen.
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. As used herein 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. As used herein, the term "aryl" includes phenyl, naphthyl, and biphenyl groups, especially phenyl.
Suitably optional 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-imidazolylalkylthio, pyridinylaminosulphonylalkyl, alkoxypyrazinyl, pyrazinonyl, dihydro-4H-oxadiazinonyl, dihydro-2H-pyridazinonyl, 2H-pyridazinonyl, aryl, hydroxyalkyl, moφholinyl, piperidinyl, cyanoalkyl, (alkylpiperidinyl)alkoxy, (alkylcarbonyl)(alkyl)amino, alkylcarbonylaminoalkyl, (dialkyl)aminoalkyl, aminosulphonyl, alkylsulphonylamino, carboxyalkyl, carboxyalkoxy, (thiazolidindionyl)alkyl, alperhaloalkyl, arylaminocarbonyl, aralkyaminocarbonyl, hydroxyalkylaminocarbonyl, arylamino, aminosulphonyl, alkylsulphonylamino, mono- and di-alkylamino, mono- and di- alkylaminocarbonyl, arylaminocarbonylalkyl, arylcarbonyl, aralkoxy, arylcarbonylamino, alkoxyalkylaminocarbonyl, aralkylcarbonylamino, aralkylcarbonylaminoalkyl, aminocarbonyl, moφholinylalkylaminocarbonylalkyl, arylaminosulphonyl, arylcarbonylaminoalkyl, arylsulphonylamino, aminocarbonylalkyl, hydroxyaminocarbonylalkyl, aryl, alkylaminocarbonyl, thiazolidinedionylalkyl, carboxyalkoxy, (alkylpiperazinyl)carbonylalkyl, moφholinyl, moφholinylcarbonylalkyl, piperidinylcarbonylalkyl, hydroxyalkylaminocarbonylalkyl, mono- and di- alkylaminocarbonylalkyl, alkoxyalkylaminosulphonyl, alkoxyamino, perhaloalkylcarbonylamino, alkylaminosulphonylalkyl, mono- and di- alkylaminoalkylaminocarbonylalkyl, carboxyalkoxy, alkoxycarbonylaminoalkyl, aminocarbonylalkenyl, alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino, alkylcarbonylaminoalkyl, hydroxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino, carboxyalkylcarbonylamino, alkoxyalkylcarbonylaminoalkyl, alkylcarbonylaminoalkylcarbonylaminoalkyl, hydroxyalkylcarbonylaminoalkyl, carboxyalkenyl, aminocarbonylalkylcarbonylamino, alkylaminocarbonylalkoxy, alkylaminosulphonylalkyl, aminocarbonylalkyl, oxazolyl, pyridinylalkylcarbonylamino, alkyloxazolyl, alkylthio, alkylaminocarbonylalkyl, halo, alkyl, alkenyl, substituted alkenyl, arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkyloxy, hydroxy, hydroxyalkyl, nitro, amino, cyano, cyanoalkyl , mono- and di-N-alkylamino, acyl, acylamino, N- alkylacylamino, acyloxy, carboxy, carboxyalkyl, carboxyalkylcarbonyl, carboxyalkenyl, ketoalkylester, carbamoyl, carbamoyl alkyl, mono- and di-N-alkylcarbamoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxy, arylthio, aralkyloxy, aryloxycarbonyl, ureido, guanidino, moφholino, adamantyl, oxazolyl, aminosulphonyl, alkylaminosulphonyl, alkylthio, haloalkylthio, alkylsulphinyl, alkylsulphonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, trityl, substituted trityl, mono- or bis- alkylphosphonate or mono- or bis-alkylphosphonateC^.galkyl or any two adjacent substituents on the phenyl ring together with the carbon atoms to which they are attached form a carbocychc ring or a heterocyclic ring.
As used herein the terms "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. Examples of 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 benzoxazolinonyl.
Substituents for any heterocyclyl or heterocyclic group are suitably selected from aryloxy, cyano, carboxyalkoxy, moφholinyl, hydroxyalkylaminocarbonyl, alkoxyalkylaminosulphonyl, alkylaminosulphonyl, arylcarbonylamino, aralkylcarbonylamino, aralkenylcarbonylamino, perhalocarbonylamino, perhaloalkyl, aminocarbonyl, nitro, aminocarbonylalkenyl, alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino, hydroxyalkylcarbonylamino, carboxyalkenyl, aminocarbonylalkylcarbonylamino, alkylaminocarbonylalkoxy, aryl, arylcarbonyl, alkylenedioxy, aryloxy, aralkyloxy, perhaloalkylthio, alkylcarbonyl, alkoxycarbonylalkylthio, carboxyalkylthio, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonyl, halogen, alkyl, arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxy, amino, mono- and di-N-alkylamino, acylamino, carboxy and salts and esters thereof, carbamoyl, mono- and di-N-alkylaminocarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, heterocyclyl and heterocyclylalkyl.
As used herein the terms "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-β-phenethylamine, dehydroabietylamine, N,N - bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
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, α-keto glutarate and -glycerophosphate.
Suitable pharmaceutically acceptable solvates include hydrates. For the avoidance of doubt when used herein the term "diabetes " includes diabetes mellitus, especially Type 2 diabetes, and conditions associated with diabetes mellitus.
The term 'conditions associated with diabetes' includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.
The term 'conditions associated with the pre-diabetic state' includes conditions such as insulin resistance, impaired glucose tolerance and hyperinsulinaemia.
The term 'conditions associated with 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
(ID
Figure imgf000021_0001
wherein;
R2a is as defined for R2 in formula (I) and L is a leaving group, with a compound of formula (III) ,3a
H- .R
N
(III)
wherein; 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. Examples of suitable leaving groups, L, are chloro, bromo, triflate, and hydroxy.
The 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 reaction temperatures include those in the range of 60°C to 220°C and, as appropriate, the reflux temperature of the solvent. When the compound of formula (III) is a weak nucleophile, then 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.
The 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.
The reaction products are purified by conventional methods, such as chromatography and trituration.
Crystalline product may be obtained by standard methods.
In a preferred aspect, 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.
In a further preferred aspect, 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.
The above mentioned conversion of a compound of formula (1 into another compound of formula (O includes any conversion which may be effected using conventional procedures, but in particular the said conversions include any combination of:
(i) for a compound of formula (IA), converting one group R^ * into another group RU;
(ii) for a compound of formula (IA), converting one group R 2 into another group R12, and;
(iii) for a compound of formula (IC), converting one group R ^ into another group Rl4.
The above mentioned conversions (i) to (iii) may be carried out using any appropriate method under conditions determined by the particular groups chosen. For a compound of formula (IA); suitable conversions of one group R ! ' into another group R I ' , as in conversion (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, as in conversion (ii), 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.
(b). converting a group R*2 which contains a carboxy group into a group R^2 which contains an aminocarbonyl 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 the ammonium salt of N- hydroxysuccinimide in the presence of a suitable activating agent such as 1,3- dicyclohexylcarbodiimide.
(c). converting a group R^ which contains a carboxy group into a group R^ which contains a hydroxyaminocarbonyl 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 O-(t- butyldimethylsilyl)hydroxylamine in the presence of suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide. For a compound of formula (IC); suitable conversions of one group Rl4 into another group R^, as in conversion (iii), include:
(a), converting a group Rl4 which represents nitro into a group Rl4 which represents amino; such a conversion may be carried out using a conventional reduction procedure, for example hydrogenating an appropriately protected compound of formula (I).
(b). converting a group R l4 which represents amino into a group Rl4 which represents acylamino; 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 a carboxylic acid in the presence of suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide. (c). converting a group Rl4 which represents aminoalkyl into a group R 4 which represents acylaminoalkyl; 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 a carboxylic acid in the presence of suitable activating agents such as a mixture of 1-hydroxybenzotriazole and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide.
The above mentioned conversions may as appropriate be carried out on any of the intermediate compounds mentioned herein.
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. Thus for example 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.
Where appropriate individual isomeric forms of the compounds of formula (I) may be prepared as individual isomers using conventional procedures.
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.
As stated above, the compounds of formula (I), or pharmaceutically acceptable derivatives thereof, are indicated to be useful as inhibitors of glycogen synthase kinase-3. Thus 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.
In a further aspect of this invention, there is provided a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use as an active therapeutic substance.
Preferably, the compounds of formula (I), or pharmaceutically acceptable derivatives thereof, are administered as pharmaceutically acceptable compositions.
Accordingly, 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. For example in the treatment of diabetes, especially Type 2 diabetes, 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.
The 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. In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Preferably the composition are in unit dosage form. A unit dose will generally contain from 0.1 to 1000 mg of the active compound. Generally 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. However, 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.
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.
For parenteral administration, 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. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The formulations mentioned herein are carried out using standard methods such as those described or referred to in reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) or the above mentioned publications.
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.
GSK-3 Assays
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 [γ-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. 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-3α and GSK-3β (final concentration 0.5U/ml enzyme). The reactions were initiated with the addition of [γ-~ P] ATP (500cpm/pmole) spiked into a mixture of ATP (final concentration of lOμM). After 30 min at room temperature the reaction was terminated by the addition of lOμl of H PO4/ 0.01% Tween-20 (2.5%). A volume (lOμl) 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 H3PO4 (0.5%), 2 mins for each wash, air dried and the radioactive phosphate incoφorated into the synthetic glycogen synthase peptide, which binds to the P-30 phosphocellulose paper, was counted in a Wallac microbeta scintillation counter. Analysis of Data: Nalues for IC50 for each inhibitor were calculated by fitting a four- parameter logistic curve to the model : cpm=lower+(upper-lower) /(l + (concentration/ IC50) s'ope).
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 js amplified via the scintillant contained in the beads. Using microtitre plates, 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.
No adverse toxicological effects are expected for the compounds of the invention, when administered in accordance with the invention. The following Syntheses illustrate the invention, but do not limit it in any way.
Synthesis 1
3-[4-[3-(Carboxymethyl)phenylthio]phenyIamino]-4-(2,3-difluorophenyl)-lH- pyrrole-2,5-dione (Example Al) A mixture of 3-(4-Aminophenylthio)phenylacetic acid (0.500 g, 1.93 mmol), 3- chloro-4-(4-chlorophenyl)-lH-pyrrole-2,5-dione (0.200 g, 0.80 mmol) and l-methyl-2- pyrrolidinone (4.0 mL) was heated in a sealed tube in a hotblock set at 69°C for 28.5 hours. The mixture was diluted with aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organics were washed with brine (2x10 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was chromatographed on silica gel using a gradient of dichloromethane-methanol as eluent to give a solid.
JH NMR (DMSO-d6): 63.55 (2H,s), 66.82 (3H, m), 67.09 (8H, m), 69.88 (1H, s), 610.98 (lH, s), 612.39 (lH, bs). MS (APCI +ve): [M+H]+ at m/z 467 (C24H16F2N2O4S requires [M+H]+ at m/z 467.
Synthesis 2
3-[4-[3-(MethyIaminocarbonyImethyl)phenylthio]phenylamino]-4-(2,3- difluorophenyl)-lH-pyrroIe-2,5-dione (Example A2) Methylamine (0.08mL, 2M in tetrahydrofuran, 0.17mmol) was added to a solution of 3- [4-[3-(carboxymethyl)phenylthio]phenylamino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5- dione (Table A, Example Al; 0.070 g, 0.16 mmol), 1-hydroxybenzotriazole (0.022 g, 0.17 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.031 g, 0.17 mmol in dichloromethane (2.5 mL). The mixture was stirred at ambient temperature for 18h. Saturated aqueous sodium bicarbonate (5 mL) was added, stirring continued for 5 minutes and the organic layer transferred directly onto a column of silica gel. Elution with dichloromethane-methanol gave the product as a solid. iH NMR (DMSO-d6): 62.54 (3H, d), 53.36 (2H, s), 66.80 (3H, m), 67.14 (8H, m), 67.94 (IH, bq), 69.88 (IH, s), 610.98 (IH, s).
MS (APCI +ve): [M+H]+ at m z 480 (C25H19F2N3O3S requires [M+H]+ at 480).
Synthesis 3
3-[4-[3-(Aminocarbonylmethyl)phenylthio]phenylamino]-4-(2,3-difluorophenyI)-lH- pyrrole-2,5-dione (Example A3)
A solution of N-hydroxysuccinimide ( l .Og, 8.70 mmol) in methanol ( 15mL) was treated with methanolic ammonia and the resulting ammonium salt was collected by filtration and dried in vacuo. A mixture of this ammonium salt (0.035 g, 0.27 mmol) and 3-[4-[3-(Carboxymethyl)phenylthio]phenylamino]-4-(2,3-difluorophenyl)-lH-pyrrole- 2,5-dione (Table A, Example Al ; 0.100 g, 0.20 mmol) in dimethylformamide (5 mL) was cooled to 0°C and 1,3-dicyclohexylcarbodiimide (0.057 g, 0.27 mmol) was added. The mixture was allowed to warm to ambient temperature and stirred for 18 h. The dimethylformamide was removed in vacuo, the residue taken up in ethyl acetate (5 mL) and the insoluble material removed by filtration. The filtrate was concentrated and the residue chromatraphed on silica gel using a gradient of dichloromethane-methanol as eluent to give a solid. lH NMR (DMSO-d6): 63.34 (2H, s), 66.77 (3H, m), 66.79 ( IH, bs), 67.09 (8H, m), 67.42 ( IH, bs), 69.88 (IH, s), 610.98 (IH, s). MS (APCI +ve): [M+H]+ at m/z 466 (C24H17F2N3O S requires [M+H]+ at m/z 466).
Synthesis 4
3-[4-[3-(N-Hydroxyaminocarbonylmethyl)phenyIthio]phenylamino]-4-(2,3- difluorophenyI)-lH-pyrroIe-2,5-dione (Example A4) O-(tert-Butyldimethylsilyl)hydroxylamine (0.029 g, 0.20 mmol) was added to a solution of 3-[4-[3-(Carboxymethyl)phenylthio]phenylamino]-4-(2,3-difluorophenyl)-lH-pyrrole- 2,5-dione (Table A, Example Al; 0.100 g, 0.20 mmol), 1-hydroxybenzotriazole (0.027 g, 0.20 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.041 g, 0.20 mmol in dichloromethane (5 mL). The mixture was stirred at ambient temperature for 18h. Water (5 mL) was added and the mixture extracted into ethyl acetate (3x10 mL). Concentration of the organic solutions gave a residue which was purified by chromatography on silica gel, eluting with a gradient of dichloromethane-methanol to give a solid.
*H NMR (DMSO-d6): 63.30 (2H, s), 66.78 (3H, m), 67.10 (8H, m), 68.85 (IH, s), 69.88 (IH, s), 610.63 (IH, s), 610.98 (IH, bs). MS (APCI +ve): [M+H]+ at m/z 482 (C24H17F2N3O4S requires [M+H]+ at m/z 482).
Synthesis 5
3-[3-[(l,3-ThiazoIidin-2,4-dion-5-yI)methyl]phenyIamino]-4-(2,3,5-trifluorophenyl)- lH-pyrrole-2,5-dione (Example Cl)
A solution of 5-[(3-aminophenyl)methyl]-l,3-thiazolidine-2,4-dione (277mg, 1.25 mmol) and 3-chloro-4-(2,3,5 trifluorophenyl)-lH-pyrrole-2,5-dione ( 131mg, 0.5mmol) in methanol (2 mL) was heated at 69°C for 5 days. EtOAc (6ml) was added and heating continued for a further lhr. The mixture was acidified with aqueous hydrochloric acid (IM, lOmL) and extracted with ethyl acetate (10 mL). The organic solution was washed with water (3 x lOmL), brine, dried with magnesium sulphate, evaporated and the residue chromatographed on silica gel using dichloromethane-diethyl ether (gradient from 100:0 to 75:25 v/v) as eluent to afford the title compound, a solid. *H NMR (DMSO-d6): 62.75 ( IH, dd), 63.05 (IH, dd), 64.67 (IH, dd), 66.60-7.40 (6H, m), 69.95 (IH, s), 61 1.00 (lH, s) and 612.05 (lH, br). MS (APCI +ve): [M+H]+ at m z 448 (C oHi2F3N3O4S requires [M+H]+ at m/z 448).
Synthesis 6 3-[[2-(2-Carboxyethyl)pyridin-5-yl]amino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5- dione (Example El)
A mixture of 3-chloro-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (0.100 g, 0.41 mmol), 3-(5-aminopyridin-2-yl)propanoic acid (0.170 g, 1.02 mmol) and l-methyl-2- pyrrolidinone (2.0 mL) was heated in a sealed tube in a hotblock set at 69°C for 14 days. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2x60 mL). The combined organics were washed with water (80 mL), brine (80 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was triturated with a mixture of dichloromethane-hexane (80:20 v/v) to afford the title compound, a solid. !H NMR (DMSO-d6): 62.44-2.50 (2H, m), 62.69-2.80 (2H, m), 66.85-7.09 (4H, m), 67.16-7.26 ( IH, m), 67.96 (IH, s), 69.83 (IH, s), 610.95 (lH,s) and 612.05 (IH, br). MS (APCI +ve): [M+H]+ at m/z 374 (Ci8H13F2N O4 requires [M+H]+ at m z 374).
Synthesis 7 3-(3-Aminophenylamino)-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (Example C38)
3-(3-Nitrophenylamino)-4-(2,3-difluorophenyl)- 1 H-pyrrole-2,5-dione (Table C, Example C36; 0.350 g, 1.01 mmol) and 10% Pd/C (50 mg) in ethanol (40 mL) was hydrogenated at atmospheric temperature and pressure for 2 hours. The reaction mixture was filtered through Kieselguhr and the filtrate concentrated in vacuo to give a solid which was triturated with a mixture of dichloromethane-hexane (20:80 v/v) to afford the title compound, a solid. *H NMR (DMSO-d6): 64.88 (2H, s), 65.77 (IH, d), 66.10-6.13 (2H, m), 66.50 (IH, t), 66.88-7.06 (2H, m), 67.13-7.23 (IH, m), 69.55 ( IH, s), 610.82 (IH, t). MS (APCI +ve): [M+H]+ at m/z 316 (C16HnF N3O2 requires [M+H]+ at m z 316).
Synthesis 8
3-[4-(Benzoylamino)phenylamino]-4-(2,3-difluorophenyI)-lH-pyrrole-2,5-dione (Example A18)
A mixture of 3-(4-aminophenylamino)-4-(2,3-difluorophenyl)-lH-pyrrole-2,5- dione (Table C, Example C35; 0.100 g, 0.31 mmol), benzoic acid (0.042 g, 0.35 mmol), l-hydroxybenzotriazole (0.047 g, 0.34 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.067 g, 0.34 mmol) in dimethylformamide (3 mL) was shaken on an orbital shaker for 72 hours. The mixture was diluted with aqueous hydrochloric acid (IM, 100 mL), and extracted with ethyl acetate (2x60 mL). The combined organic solutions were washed with saturated aqueous sodium bicarbonate ( 100 mL), brine ( 100 mL), dried over anhydrous magnesium sulphate and evaporated.
Trituration of the residue with dichloromethane-hexane (20:80 v/v) gave the title product, a solid.
*H NMR (DMSO-d6): 66.77 (2H, d), 66.96-7.17 (2H, m), 67.17-7.27 ( IH, d), 67.40-7.60 (5H, m), 67.88 (2H, d), 69.75 ( IH, s), 610.00 (IH, s), 610.85 ( IH, br). MS (APCI -ve): [M-H]" at m z 418 (C23H j sF2N3O3 requires [M-H]- at m/z 418)
Synthesis 9
3-[4-(tert-ButoxycarbonylmethyIcarbonyla_nino)phenyIamino]-4-(2,3- difluorophenyl)-lH-pyrrole-2,5-dione (Example C49) A mixture of 3-(4-aminophenylamino)-4-(2,3-difluorophenyl)-lH-pyrrole-2,5- dione (Table C, Example C35; 0.100 g, 0.31 mmol), mono-tert-butyl malonate (0.056 g, 0.35 mmol), 1-hydroxybenzotriazole (0.047 g, 0.34 mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.067 g, 0.34 mmol) in dimethylformamide (3 mL) was shaken on an orbital shaker for 72 hours. The mixture was diluted with dilute hydrochloric acid ( 100 mL), and extracted with ethyl acetate (2x60 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane-diethyl ether (90: 10 v/v) as eluent to afford the the title product, a solid. l NMR (DMSO-d6): 61.40 (9H, s), 63.27 (2H, s), 66.72 (2H, d), 66.93-7.09 (2H, m), 67.16-7.24 (3H, m), 69.75 (IH, br), 610.00 (IH, s), 610.85 (IH, br). MS (APCI -ve): [M-H]" at m/z 456 (C23H21F2N3O5 requires [M-H]" at m/z 456).
Synthesis 10 3-[4-(Carboxymethylcarbonylamino)phenylamino]-4-(2,3-difluorophenyl)-lH- pyrrole-2,5-dione (Example C53)
A mixture of 3-[4-(tert-butoxycarbonylmethylcarbonylamino)phenyl- -amino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (Table C, Example C49; 0.040 g, 0.087 mmol), trifluoroacetic acid (30 mL) and dichloromethane (50 mL) was stirred at room temperature for 40 minutes. The mixture was evaporated and the residue was diluted with water (80 mL), basified to ca. pH 3-4 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2x70 mL). The combined organic solutions were quickly washed with saturated aqueous sodium bicarbonate (40 mL), brine (100 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was triturated with a mixture of dichloromethane-hexane (20:80 v/v) to afford the title compound as a solid.
1H NMR (DMSO-d6): 63.27 (2H, s), 66.72 (2H, d), 66.93-7.09 (2H, m), 67.17-7.26 (3H, m), 69.75 (IH, s), 610.03 (IH, s), 610.87 (IH, s), 612.60 (lH,br). MS (APCI -ve): [M-H-CO2]" at m/z 356 (C19H13F2N3O5 requires [M-H-CO2]" at m/z 356).
Synthesis 11
3-(2,3,4-Trifluorophenylamino)-4-(2,3-difluorophenyI)-lH-pyrrole-2,5-dione (Example C39)
A mixture of 2,3,4-trifluoroaniline (0.184 g, 1.25 mmol) and 3-chloro-4-(2,3- difluorophenyl)-lH-pyrrole-2,5-dione (0.122 g, 0.5 mmol) in l-methyl-2-pyrrolidinone (2 mL) was heated in a sealed tube in a hotblock set at 69°C for 20 hours then at 90°C for a further 4 days. The mixture was diluted with aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (20 mL). The organics were washed with hydrochloric acid (20 mL), water (3x20 mL), and evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane then dichloromethane-diethyl ether (50: 1 v/v) as eluent to afford the title compound as a solid. ! H NMR (DMSO-d6): 66.7 - 7.3 (6H, m), 69.8 ( IH, br), 610.95( 1H, br). MS (APCI +ve): [M+H]+ at m/z 355 (C16H7F5N2O2 requires [M+H]+ at m/z 355).
Synthesis 12
3-[(2-Methylbenzoxazol-6-yl)amino]-4-(2,3-difluorophenyI)-lH-pyrrole-2,5-dione (Example B6) and 3-[(4-acetamido-3-hydroxyphenyl)amino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5- dione (Example C63)
A mixture of 6-amino-2-methylbenzoxazole (0.185 g, 1.25 mmol) and 3-chloro-4- (2,3-difluorophenyl)-lH-pyrrole-2,5-dione (0.122 g, 0.5 mmol) in methanol (3mL) was heated in a sealed tube in a hotblock set at 69°C for 20 hours. The mixture was diluted with aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (20 mL). The organics were washed with water (3x10 mL), and evaporated to dryness. The residue was triturated with diethyl ether to afford a solid which was dissolved in dichloromethane/methanol and chromatographed on silica gel using dichloromethane- diethyl ether (25: 1 v/v) as eluent to afford 3-[(2-methylbenzoxazol-6-yl)amino]-4-(2,3- difluorophenyl)-lH-pyrrole-2,5-dione (Table B, Example B6) as a solid.
JH NMR (DMSO-d6): 62.50 (3H, s, obscured by DMSO solvent peak), 66.7 - 7.3 (6H, m), 610.0 (IH, br), 610.8(1H, br).
MS (APCI +ve): [M+H]+ at m z 356 (C18HπF2N3O3 requires [M+H]+ at m/z 356). Further elution of the chromatography column afforded 3-(3-hydroxy-4- acetamidophenylamino)-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (Table C, Example C63) as a byproduct.
Synthesis 13
3-(3-TrifluoromethyI-4-acetamidophenyIamino)-4-(2,3-difluorophenyl)-lH-pyrroIe- 2,5-dione (Example C28) and
3-(3-trifluoromethyl-4-aminophenylamino)-4-(2,3-difluorophenyl)-lH-pyrroIe-2,5- dione (Example C27) A solution of 3-trifluoromethyl-4-acetamidoaniline (273mg, 1.25 mmol) and 3- chloro-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione ( 122mg, 0.5mmol) in methanol (2 mL) was heated at 69°C for 3 days. EtOAc (6ml) was added and heating continued for a further lhr. The mixture was acidified with aqueous hydrochloric acid (IM, lOmL) and extracted with ethyl acetate (10 mL). The organic solution was washed with water (3 x lOmL), brine, dried with magnesium sulphate, evaporated and the residue chromatographed on silica gel using dichloromethane-diethyl ether (gradient from 100:0 to 75:25 v/v) as eluent to afford 3-(3-trifluoromethyl-4-acetamidophenylamino)-4-(2,3- difluorophenyl)-lH-pyrrole-2,5-dione (Table C, Example C28) as a solid. 1H NMR (DMSO-d6): 61.97 (3H, s), 66.7-7.3 (6H, m), 69.37 ( IH, s), 610.00 (IH, br), 610.92 ( lH, br).
MS (APCI +ve): [M+H]+ at m z 426 (C19H12F5N3O3 requires [M+H] + at m/z 426). Earlier fractions from the chromatography column yielded 3-(3-trifluoromethyl-4- aminophenylamino)-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (Table C, Example C27) as a byproduct.
Synthesis 14
3-[2-(MethoxymethyI)indoIin-l-yI]-4-(2,3-di_luorophenyl)-lH-pyrrole-2,5-dione (Example D6)
A solution of 3-chloro-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione ( 195 mg, 0.80 mmol.), 2-(methoxymethyl)indoline (198 mg, 1.00 mmol.) and triethylamine (0.34 mL, 2.44 mmol.) in dry l-methylpyrrolidin-2-one (3 mL) was heated under argon at 65 C for 3 days. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic solutions were washed with brine (2 x 20 mL), dried with magnesium sulphate, evaporated and the residue chromatographed on silica using a mixture of dichloromethane and diethyl ether as eluant to afford the title compound as a solid.
ΪH NMR (DMSO-d6): 6 1 1.05 (IH, br), 7.36-7.13 (4H, m), 6.79 (IH, t), 6.61 (IH, t), 5.86 (IH, d), 5.26 (IH, m), 3.69 (IH, m), 3.35 (2H, m), 3.26 (3H, s), 3.00 (IH, dd). MS (APCI+ve): [M+H]+ at m/z 371 (C2θHi6N2O3F2 requires [M+H]+ at m z 371). Synthesis 15
3-[3-(4-Carboxyphenylaminocarbonylmethyl)phenylamino]-4-(2,3-difluorophenyl)- lH-pyrrole-2,5-dione (Example A50)
A mixture of 4-(3-aminophenylacetylamino)benzoic acid (0.277 g, 1.03 mmol), 3- chloro-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (0.100 g, 0.41 mmol) and 1-methyl- 2-pyrrolidinone (2 mL) was heated at 1 10°C overnight before being diluted with dilute hydrochloric acid (2M, 150 mL) and extracted with ethyl acetate (3 x 80 mL). The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and evaporated. The residual solid was chromatographed on silica gel using dichloromethane-methanol (96:4 v/v) as eluent to afford the title compound, a solid.
1H NMR (DMSO-d6): 63.30 (2H, s), 66.65-7.20 (7H, m), 67.66 (2H, d), 67.85 (2H, d),
69.75 (IH, s), 610.30 (IH, s), 610.85 (IH, s) and 612.62 (IH, s).
MS (AP-ve): [M]" at m z 477 (C25H17F2N3O5 requires [M]" at m/z 477).
Synthesis 16
3-[2-(Ethylamino)benzothiazol-6-ylamino]-4-(2,3-difIuorophenyI)-lH-pyrrole-2,5- dione (Example B48)
A solution of 2-ethylaminobenzothiazol-6-ylamine (316mg, 1.63mmol) and 3- chloro-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (158mg, 0.65mmol) in l-methyl-2- pyrrohdinone (2mL) was allowed to stand at room temperature overnight. The mixture was diluted with aqueous hydrochloric acid (25mL) and extracted with ethyl acetate (35 mL). The organics were washed with water (3x25mL), and evaporated to dryness. The residue was triturated with dichloromethane to give a solid. • H NMR (DMSO-d6): 61.16 (3H,t), 63.31 (2H, m), 66.73 (IH, m), 66.95 (4H, m), 67.1 ( IH, m), 67.86 (IH, t), 69.70(1H, bs), 610.80 (IH, bs).
MS (APCI +ve): [M+H]+ at m z 401 ( 9HHF2N4O2S requires [M+H]+ at m/z 401.
Synthesis 17 3-[3-(4-PyrimidyIaminocarbonylmethyl)phenyIamino]-4-(2,3-difluorophenyl)-lH- pyrrole-2,5-dione (Example F17)
A mixture of 4-aminopyrimidine (48mg, 0.5mmol), 3-[3-(carboxymethyl)-phenylamino]- 4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (prepared by analogy with Example Synthesis 1, 179mg, 0.5mmol), 1-hydroxybenzotriazole (68mg, 0.5mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96mg, 0.5mmol) was dissolved in dimethylformamide (2mL). The solution was allowed to stand at room temperature for 5 days. Ethyl acetate (8mL), water (4mL) and saturated aqueous sodium bicarbonate (2 mL) were added, the layers separated and the organic layer washed with water then brine and evaporated to dryness. The residue was chromatographed on silica gel eluting with dichloromethane-methanol to give the product as a solid. !H NMR (DMSO-d6): 63.39 (2H, m), 66.6 - 7.2 (7H,m), 68.00 (IH, m), 68.6 (IH, m), 68.85 (IH, s), 69.76 (IH, s), 610.9 (IH, s) and 611.0 (IH, s). MS (APCI +ve): [M+H]+ at m/z 436 (C 2Hi5F2N5O3 requires [M+H]+ at 436).
Synthesis 18 3-[3-(3-CarboxyphenylaminocarbonyImethyI)phenyIamino]-4-(2,3-difluorophenyI)- lH-pyrrole-2,5-dione (Example A91)
A mixture of 3-[3-(carboxymethyl)phenylamino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5- dione (prepared by analogy with Example Synthesis l,179mg, 0.5mmol), 1- hydroxybenzotriazole (68mg, 0.5mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (96mg, 0.5mmol) was dissolved in dimethylformamide (2mL). After standing at room temperature for 1 hour, 3-aminobenzoic acid (69mg, 0.5mmol) was added and the resulting solution was allowed to stand at room temperature for 2 days. Ethyl acetate (8mL) and water (6mL) were added, the layers separated and the organic layer washed with water (3x6mL) and evaporated to a gum which was triturated with dichloromethane/methanol to give the product as a solid. lH NMR (DMSO-d6): 63.28 (2H, s), 56.73 (2H,m), 66.95 (4H, m), 57.15 (IH, m), 67.41(1H, m), 67.60 (IH, m), 57.80(1H, m), 68.19 (IH, s), 59.77 (IH, s), 610.2 (IH, s), 610.9(lH, s), 512.9 (lH, bs). MS (APCI -ve): [M]" at m/z 477 (C25H17F2N3O5 requires [M]" at 477).
Synthesis 19
3-(3,5-DifluorophenyIamino)-4-(4-acetylaminophenyl)-lH-pyrroIe-2,5-dione
(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). The mixture was stirred for 70 hours then chromatographed on silica gel using dichloromethane-methanol (90: 10 v/v) as eluent to afford the title compound, a solid. lU NMR (DMSO-d6): 62.02 (3H,s), 66.33 (2H, m), 66.65 ( IH, m), 66.98 (2H, d), 67.41
(2H, s), 69.60 (IH, bs), 69.90 (IH, s) and 610.90 (IH, s).
MS (AP-ve): [M]" at m/z 357 (CιgH13F2N2θ3 requires [M]" at m/z 357).
Synthesis 20
3-(Indolin-5-yIamino)-4-(2,3-difluorophenyI)-lH-pyrroIe-2,5-dione (Example B46) A mixture of 3-(N-t-butoxycarbonylindolin-5-ylamino)-4-(2,3-difluorophenyl)- lH-pyrrole-2,5-dione (Table B, Example B45, 0.100 g, 0.22 mmol), trifluoroacetic acid (0.5 mL) and dichloromethane (9.5 mL) was stirred at room temperature for 2 hours, then evaporated. The residue was azeotroped from dichloromethane (x3) to afford the product, a solid. lU NMR (DMSO-d6): 62.73 (2H, t), 63.55 (2H, t), 63.98 (IH, br), 66.60-7.30 (6H, m),
69.77 (IH, s), and 610.90 (IH, s). MS (AP+ve): [M+H]+ at m/z 342 (C18Hι3F2N3O2 requires [M+H]+ at m/z 342).
Synthesis 21
3-[3-(N-HydroxylaminocarbonylmethyI)phenylamino]-4-(2,3-difluorophenyI)-lH- pyrrole-2,5-dione (Example C106) A mixture of O-(tert-butyldimethylsilyl)hydroxylamine (221mg, 1.5mmol), 3-[3- (carboxymethyl)phenylamino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione (prepared by analogy with Example Synthesis 1, 179mg, 0.5mmol), 1 -hydroxy-7-azabenzotriazole (136mg, lmmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144mg, 0.75mmol) was dissolved in dimethylformamide (2mL). The solution was allowed to stand at room temperature for 4 days. Ethyl acetate (8mL) and water (8mL) were added and the mixture acidified to pH3 with dilute hydrochloric acid. The layers were separated and the organic layer washed with water (2x8mL), saturated aqueous sodium bicarbonate (8mL) then water (2x8mL) and evaporated to dryness. The residue was chromatographed on silica gel eluting with dichloromethane-methanol to give a solid (38mg). This was dissolved in tetrahydrofuran (3mL), tetrabutylammonium fluoride trihydrate (49mg, 0.156mmol) added and the solution stirred at room temperature for 30 mins. The resulting suspension was evaporated to dryness, the residue dissolved in ethyl acetate (lOmL) and water (lOmL) and acidified to pH3 with dilute hydrochloric acid. The layers were separated and the organic layer washed with water (2x1 OmL) and evaporated to give the product as a solid. lH NMR (DMSO-d6): 62.87 (2H, s), 66.61 (l H,s), 56.71 (I H, m), 66.81 (I H. m), 57.0 (3H, m), 57.15 (IH, m), 68.74 (IH, bs) and 69-1 1 (3H, broad). MS (APCI -ve): [M-H]" at m z 372 (C18H13F2N3O4 requires [M-H]" at 372).
Synthesis 22
3-[3-(2-(4-AminophenylsuIphonyl)ethoxycarbonylmethyI)phenyIamino]-4-(2,3- difluorophenyI)-lH-pyrrole-2,5-dione (Example A70) A mixture of 2-(4-aminophenylsu_phonyl)ethanol hydrochloride (119mg, 0.5mmol), 3-[3- (carboxymethyl)phenylamino]-4-(2,3-difluorophenyl)-lH-pyrrole-2,5-dione ( 179mg, 0.5mmol), 1-hydroxybenzotriazole (68mg, 0.5mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (96mg, 0.5mmol) and triethylamine (lOlmg, lmmol) in dimethylformamide (2mL) was well shaken then allowed to stand at room temperature for 3days. Ethyl acetate (8mL), water (4mL) and saturated aqueous sodium bicarbonate (2 mL) were added, the layers separated and the organic layer washed with water then brine and evaporated to dryness. The residue was chromatographed on silica gel eluting with dichloromethane-methanol to give the product as a solid. JH NMR (DMSO-d6): 62.99 (2H, s), 53.57 (2H,t), 54.23 (2H, t), 65.69 (2H, s), 56.49 (IH, s), 66.75 (2H, m), 56.8-7.1 (6H, m), 67.1-7.3 (2H, m) 59.73 (IH, s), 510.9 (IH, s). MS (APCI +ve): [M+H]+ at m/z 542 (C26H2lF2N3O6 S requires [M+H]+ at 542). The following additional methods (Methods 1 and 2) serve to illustrate a typical preparation of a non-commercial aniline by a method analogous to that described in Synthesis 1994, 1413.
Method 1
3-[(4-Nitrophenyl)thio]benzoic acid
A suspension of potassium carbonate (18g) in acetone (140 mL) at ambient temperature was treated with 3-mercaptobenzoic acid (lOg, 64.4 mmol, 1 eq) followed by 4- nitrofluorobenzene (18g, 127.7 mmol, 2 eq). The resultant mixture was stirred for 18h and then poured onto saturated sodium bicarbonate and washed with ethyl acetate. The basic aqueous layer was acidified with 5N HC1 and extracted into ethyl acetate (3x100 mL). The combined organics were dried with anhydrous sodium sulphate and concentrated in vacuo to give the product as a solid. *H NMR (DMSO): 67.35 (2H, d), 7.66 (IH, t), 7.81 (IH, m), 8.06 (2H, m), 8.16 (2H, d), and 13.31 (IH. bs). MS (APCI-ve): [M-H]" at m/z 274 (Cι3H9NO4S requires [M-H]" at m/z 274)
Method 2 3-[(4-Aminophenyl)thio]benzoic acid
A mixture of 3-[(4-nitrophenyl)thio]benzoic acid ( 1 1.2g, 40.7 mmol) and 10% Pd/C (0.5g) in ethanol (250 mL) was hydrogenated at atmospheric temperature and pressure for 24h. The mixture was filtered through Celite and concentrated in vacuo to give the required aniline as a solid. ]H NMR (DMSO): 65.59 (2H, bs), 6.64 (2H, d), 7.28 (3H, m), 7.37 (IH, t), 7.52 (IH, s), 7.65 (IH, d), and 12.32 (IH, bs).MS (APCI+ve): [M+H]+ at m z 246 (C13HπNO2S requires [M+H]+ at m/z 246).
The further examples described herein were prepared according to the methods disclosed herein, with particular reference to Example Syntheses 1 to 22 above. Example Syntheses 1 to 22 themselves are shown as Example Compounds in the following Tables according to the list below:
Figure imgf000038_0001
Table A
Encompassing compounds of general formula (Z-1), wherein group R2 of formula (I) is a phenyl ring, optionally substituted by one or more substituents R10 and the moiety NR*R3 of formula (I) is represented by a moiety of general formula (Z-2), optionally substituted by one or more substituents R1 ' and one or more substituents R12, and Q represents a linking moiety as hereinbefore defined. The positions of substitution of R1 ', R12 and Q are defined with reference to formula (Z-2) and the values of R10, R11, R12 and Q are listed in Table A.
Figure imgf000039_0001
( Z- 1 ) ( Z- 2 )
Figure imgf000039_0002
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Table B
Encompassing compounds of general formula (Z-3), wherein group R2 of formula (I) is a phenyl ring, optionally substituted by one or more substituents R10 and the group R1 is represented by a benzene ring fused to an additional ring wherein the moiety W represents the atoms which, when taken together with the atoms of the benzene ring to which they are attached, form the fused ring. The position of the fusion of the two rings is defined with reference to the atom numbering depicted in formula (Z-3), for example in the case of compound Bl, the moiety W has the value 3,4-[S-CH=N] and is defined as having the sulphur atom of the moiety attached at position 3 and the nitrogen atom attached at position 4 to form a 5-membered thiazole ring. Additionally, the benzene ring may be optionally substituted by one or more additional substituents R13. The group R3 of formula (I) is hydrogen. The values of R10, R13 and W are listed in Table B.
Figure imgf000047_0001
(Z-3)
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Table C
Encompassing compounds of general formula (Z-4), wherein group R of formula (I) is a phenyl ring, optionally substituted by one or more substituents R10, group R1 of formula (I) is a phenyl ring, optionally substituted by one or more substituents R14 and group R3 of formula (I) is hydrogen, and substituents R10 and R14 are listed in Table C.
Figure imgf000051_0001
(Z-4)
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Table D
Encompassing compounds of general formula (Z-5), wherein group R2 of formula (I) is a phenyl ring, optionally substituted by one or more substituents R10 and the moiety - NR'R3 of formula (I) represents a heterocyclyl moiety of general formula (Z-6), optionally substituted by substituents R15a, R,5b, R15c and Rl5d and substituents R10, R15a, R15b, R15c, RI5d and X-Y are listed in Table D.
Figure imgf000056_0001
(Z-5) (Z-6)
Figure imgf000056_0002
Table E
Encompassing compounds of general formula I, and substituents R . 1 r R2 a „n_dj r R>3 are listed in Table E.
Figure imgf000057_0001
(I)
Figure imgf000057_0002
Table F
Encompassing compounds of general formula (Z-7), wherein group R2 of formula (I) is a phenyl ring, optionally substituted by one or more substituents R10 and the moiety NR'R3 of formula (I) is represented by a moiety of general formula (Z-8), optionally substituted by one or more substituents R1 '. Q represents a linking moiety and Ar1 represents an aromatic heterocyclic group as hereinbefore defined. The positions of substitution of R11 and Q are defined with reference to formula (Z-8) and the values of R10, Rn, Q and Ar1 are listed in Table F.
Figure imgf000058_0001
( Z- 7 ) ( Z- 8 )
Figure imgf000058_0002
Figure imgf000059_0001
Figure imgf000060_0001

Claims

Claims
1. 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):
Figure imgf000061_0001
or a pharmaceutically acceptable derivative thereof, wherein;
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 R2 is not 3-indolyl or a fused-ring derivative of 3- indolyl;
R is hydrogen, or,
R! 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.
2. A compound of formula (I1)
Figure imgf000061_0002
wherein;
R1, R2, and R are as defined in formula (I) in claim 1, with the proviso that formula (I1) does not include the following compound: 3-phenylamino-4-phenyl- 1 H-pyrrole-2,5-dione.
3. A process for the preparation of a compound of formula (I'), which process comprises reaction of a compound of formula (II)
Figure imgf000062_0001
wherein;
R2 is ^ defined for R2 in formula (I) in claim 1 and L is a leaving group, with a compound of formula (III)
Figure imgf000062_0002
wherein; Rl& and R a are as defined for R! and R3 respectively in formula (I) in claim 1, and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I1) to a further compound of formula (I');
(ii) removing any necessary protecting group;
(iii) preparing an appropriate derivative of the compound so formed.
4. A compound of formula (I) as defined in claim 1, 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.
5. Use of a compound of formula (I) as defined in claim 1, 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.
6. A compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable derivative thereof, for use as an active therapeutic substance.
7. A pharmaceutical composition which comprises a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
PCT/EP2001/003687 2000-04-04 2001-04-02 Pyrrole-2,5-dione derivatives for the treatment of diabetes WO2001074771A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001262153A AU2001262153A1 (en) 2000-04-04 2001-04-02 Pyrrole-2,5-dione derivatives for the treatment of diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0008264.4A GB0008264D0 (en) 2000-04-04 2000-04-04 Novel method and compounds
GB0008264.4 2000-04-04

Publications (1)

Publication Number Publication Date
WO2001074771A1 true WO2001074771A1 (en) 2001-10-11

Family

ID=9889171

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/003687 WO2001074771A1 (en) 2000-04-04 2001-04-02 Pyrrole-2,5-dione derivatives for the treatment of diabetes

Country Status (3)

Country Link
AU (1) AU2001262153A1 (en)
GB (1) GB0008264D0 (en)
WO (1) WO2001074771A1 (en)

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062387A1 (en) * 2001-02-07 2002-08-15 Smithkline Beecham P.L.C. Treatment of conditions with a need of gsk-3 inhibition
WO2003011843A1 (en) * 2001-08-03 2003-02-13 Novo Nordisk A/S Novel 2,4-diaminothiazole derivatives
FR2850967A1 (en) * 2003-02-12 2004-08-13 Galderma Res & Dev New Peroxisome Proliferator-Activated Receptor modulators useful in treatment of dermatological, lipid metabolism, inflammatory and immune system disorders, cancerous and pre-cancerous states, diabetes, and hypertension
WO2004072022A1 (en) * 2003-02-12 2004-08-26 Galderma Research & Development, Snc Compounds which are modulators of the ppar-type receptors and their use in cosmetic or pharmaceutical compositions
EP1490093A1 (en) * 2002-03-01 2004-12-29 Chiron Corporation Methods and compositions for the treatment of ischemia
WO2005030716A1 (en) * 2003-09-25 2005-04-07 Wyeth Heterocyclic- or aryloxy, -thio or -amino substituted indoles-2-carboxylic acids or esters as pai-1
WO2005085230A1 (en) * 2004-03-02 2005-09-15 Sanofi-Aventis Deutschland Gmbh 4-benzimidazol-2-yl-pyridazine-3-one-derivatives, production and use thereof in medicaments
WO2006052722A1 (en) * 2004-11-09 2006-05-18 Smithkline Beecham Corporation Glycogen phosphorylase inhibitor compounds and pharmaceutical compositions thereof
WO2006073365A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2h)-thione 1,1-dioxides as liver x receptor modulators
WO2006073367A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab 5-thioxo-1,5-dihydro-2h-pyrrol-2-one derivatives as liver x receptor modulators
WO2006073366A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2h)-one 1,1-dioxides as liver x receptor modulators
WO2006073364A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Derivatives of isothiazol-3 (2h)-thione 1,1-dioxides as liver x receptor modulators
WO2006073363A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Derivatives of isothiazol-3(2h)-one 1,1-dioxides as liver x receptor modulators
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7279576B2 (en) 2002-12-31 2007-10-09 Deciphera Pharmaceuticals, Llc Anti-cancer medicaments
JPWO2005087710A1 (en) * 2004-03-15 2008-01-24 武田薬品工業株式会社 Aminophenylpropanoic acid derivatives
US7432288B2 (en) 2003-07-11 2008-10-07 Astrazeneca Ab Pyrrole-2,5-dione derivatives as Liver X receptor modulators
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
EP2258357A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2275096A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis via modulation of the muscarinic receptors
EP2294050A2 (en) * 2008-05-14 2011-03-16 Biolipox AB Bis-aryl compounds for use as medicaments
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
EP2377530A2 (en) 2005-10-21 2011-10-19 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
EP2377531A2 (en) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenesis by modulating angiotensin
WO2012062210A1 (en) * 2010-11-09 2012-05-18 Zhejiang Beta Pharma Inc. Compound for increasing kinase active and application thereof
US8207168B2 (en) 2006-07-25 2012-06-26 Cephalon, Inc. Pyridazinone derivatives
AU2006325294B2 (en) * 2005-10-31 2012-10-11 Merck Sharp & Dohme Corp. CETP inhibitors
US8394828B2 (en) 2003-02-03 2013-03-12 Janssen Pharmaceutica, Nv Quinoline-derived amide modulators of vanilloid VR1 receptor
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
WO2020163812A1 (en) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Valproic acid compounds and wnt agonists for treating ear disorders
WO2020177952A1 (en) * 2019-03-01 2020-09-10 Ac Immune Sa Novel compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3340263A (en) * 1964-02-14 1967-09-05 Ciba Geigy Corp Amino-pyrroles
EP0328026A1 (en) * 1988-02-10 1989-08-16 F. Hoffmann-La Roche Ag Substituted pyrroles
WO1991013070A1 (en) * 1990-02-26 1991-09-05 Boehringer Mannheim Gmbh Novel trisubstituted maleinimides, process for their production and medicaments containing these compounds
WO1999047522A1 (en) * 1998-03-13 1999-09-23 The University Of British Columbia Granulatimide derivatives for use in cancer treatment
WO1999065897A1 (en) * 1998-06-19 1999-12-23 Chiron Corporation Inhibitors of glycogen synthase kinase 3
WO2000006564A1 (en) * 1998-07-30 2000-02-10 Japan Tobacco Inc. Disubstituted maleimide compounds and medicinal utilization thereof
WO2000021927A2 (en) * 1998-10-08 2000-04-20 Smithkline Beecham Plc Pyrrole-2,5-diones as gsk-3 inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3340263A (en) * 1964-02-14 1967-09-05 Ciba Geigy Corp Amino-pyrroles
EP0328026A1 (en) * 1988-02-10 1989-08-16 F. Hoffmann-La Roche Ag Substituted pyrroles
WO1991013070A1 (en) * 1990-02-26 1991-09-05 Boehringer Mannheim Gmbh Novel trisubstituted maleinimides, process for their production and medicaments containing these compounds
WO1999047522A1 (en) * 1998-03-13 1999-09-23 The University Of British Columbia Granulatimide derivatives for use in cancer treatment
WO1999065897A1 (en) * 1998-06-19 1999-12-23 Chiron Corporation Inhibitors of glycogen synthase kinase 3
WO2000006564A1 (en) * 1998-07-30 2000-02-10 Japan Tobacco Inc. Disubstituted maleimide compounds and medicinal utilization thereof
EP1120414A1 (en) * 1998-07-30 2001-08-01 Japan Tobacco Inc. Disubstituted maleimide compounds and medicinal utilization thereof
WO2000021927A2 (en) * 1998-10-08 2000-04-20 Smithkline Beecham Plc Pyrrole-2,5-diones as gsk-3 inhibitors

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CHEM. BIOL. (2000), 7(10), 793-803 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; AUGUSTIN, M. ET AL: "Reactions of 2,3-dichloromaleimides with methylene-active compounds", XP002175374, retrieved from STN Database accession no. 92:93863 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; COGHLAN, MATTHEW P. ET AL: "Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription", XP002175371, retrieved from STN Database accession no. 134:112113 *
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MAHBOOBI, S. ET AL: "Synthesis and biological evaluation of 4,4-dimethyl-5,5-di(1- methylethyl)-2,3,4,5-tetrahydro-1H-dipyrrolo[3,4-d:2,1- f][1,2]azasiline-1,3-dione and other pyrrolediones as new antibacterial active agents", XP002175373, retrieved from STN Database accession no. 132:64128 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACT SERVICE, COLUMBUS, OHIO, US; XP002175372, retrieved from STN *
J. PRAKT. CHEM. (1979), 321(5), 787-96 *
PHARMAZIE (1999), 54(10), 730-733 *
PIERS, EDWARD ET AL: "Improved Synthesis of Isogranulatimide, a G2 Checkpoint Inhibitor. Syntheses of Didemnimide C, Isodidemnimide A, Neodidemnimide A, 17-Methylgranulatimide, and Isogranulatimides A-C", J. ORG. CHEM. (2000), 65(2), 530-535, 28 January 2000 (2000-01-28), XP002175370 *
SMITH D G ET AL: "3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 11, no. 5, 12 March 2001 (2001-03-12), pages 635 - 639, XP004230079, ISSN: 0960-894X *

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062387A1 (en) * 2001-02-07 2002-08-15 Smithkline Beecham P.L.C. Treatment of conditions with a need of gsk-3 inhibition
WO2003011843A1 (en) * 2001-08-03 2003-02-13 Novo Nordisk A/S Novel 2,4-diaminothiazole derivatives
EP1490093A1 (en) * 2002-03-01 2004-12-29 Chiron Corporation Methods and compositions for the treatment of ischemia
EP1490093A4 (en) * 2002-03-01 2007-04-11 Novartis Vaccines & Diagnostic Methods and compositions for the treatment of ischemia
US7342037B2 (en) 2002-12-31 2008-03-11 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7279576B2 (en) 2002-12-31 2007-10-09 Deciphera Pharmaceuticals, Llc Anti-cancer medicaments
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
US8394828B2 (en) 2003-02-03 2013-03-12 Janssen Pharmaceutica, Nv Quinoline-derived amide modulators of vanilloid VR1 receptor
FR2850967A1 (en) * 2003-02-12 2004-08-13 Galderma Res & Dev New Peroxisome Proliferator-Activated Receptor modulators useful in treatment of dermatological, lipid metabolism, inflammatory and immune system disorders, cancerous and pre-cancerous states, diabetes, and hypertension
WO2004072022A1 (en) * 2003-02-12 2004-08-26 Galderma Research & Development, Snc Compounds which are modulators of the ppar-type receptors and their use in cosmetic or pharmaceutical compositions
US7432288B2 (en) 2003-07-11 2008-10-07 Astrazeneca Ab Pyrrole-2,5-dione derivatives as Liver X receptor modulators
WO2005030716A1 (en) * 2003-09-25 2005-04-07 Wyeth Heterocyclic- or aryloxy, -thio or -amino substituted indoles-2-carboxylic acids or esters as pai-1
JP2007506772A (en) * 2003-09-25 2007-03-22 ワイス Heterocyclic or aryloxy, -thio or -amino substituted indole-2-carboxylic acids or esters as PAI-1
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7727989B2 (en) 2004-03-02 2010-06-01 Sanofi-Aventis Deutschland Gmbh 4-benzimidazol-2-yl-pyridazine-3-one-derivatives, production and use thereof in medicaments
WO2005085230A1 (en) * 2004-03-02 2005-09-15 Sanofi-Aventis Deutschland Gmbh 4-benzimidazol-2-yl-pyridazine-3-one-derivatives, production and use thereof in medicaments
JP4875978B2 (en) * 2004-03-15 2012-02-15 武田薬品工業株式会社 Aminophenylpropanoic acid derivatives
JPWO2005087710A1 (en) * 2004-03-15 2008-01-24 武田薬品工業株式会社 Aminophenylpropanoic acid derivatives
WO2006052722A1 (en) * 2004-11-09 2006-05-18 Smithkline Beecham Corporation Glycogen phosphorylase inhibitor compounds and pharmaceutical compositions thereof
JP2008519761A (en) * 2004-11-09 2008-06-12 スミスクライン ビーチャム コーポレーション Glycogen phosphorylase inhibiting compound and pharmaceutical composition thereof
WO2006073367A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab 5-thioxo-1,5-dihydro-2h-pyrrol-2-one derivatives as liver x receptor modulators
WO2006073363A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Derivatives of isothiazol-3(2h)-one 1,1-dioxides as liver x receptor modulators
US7582629B2 (en) 2005-01-10 2009-09-01 Astrazeneca Ab Derivatives of isothiazol-3(2H)-one 1,1-dioxides as liver X receptor modulators
US7723333B2 (en) 2005-01-10 2010-05-25 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2H)-one 1,1-dioxides as liver X receptor modulators
WO2006073364A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Derivatives of isothiazol-3 (2h)-thione 1,1-dioxides as liver x receptor modulators
WO2006073366A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2h)-one 1,1-dioxides as liver x receptor modulators
WO2006073365A1 (en) * 2005-01-10 2006-07-13 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2h)-thione 1,1-dioxides as liver x receptor modulators
US7960380B2 (en) 2005-01-10 2011-06-14 Astrazeneca Ab Non-anilinic derivatives of isothiazol-3(2H)-one 1,1-dioxides as liver X receptor modulators
EP2275096A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis via modulation of the muscarinic receptors
EP2258359A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
EP2275095A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2258358A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2258357A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2377530A2 (en) 2005-10-21 2011-10-19 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
US8334290B2 (en) 2005-10-31 2012-12-18 Merck Sharp & Dohme Corp. CETP inhibitors
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
AU2006325294B2 (en) * 2005-10-31 2012-10-11 Merck Sharp & Dohme Corp. CETP inhibitors
EP2377531A2 (en) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenesis by modulating angiotensin
EP2382975A2 (en) 2006-05-09 2011-11-02 Braincells, Inc. Neurogenesis by modulating angiotensin
US8207168B2 (en) 2006-07-25 2012-06-26 Cephalon, Inc. Pyridazinone derivatives
US8586588B2 (en) 2006-07-25 2013-11-19 Cephalon, Inc. Aryl pyridazinone derivatives and their use as H3 receptor ligands
US8673916B2 (en) 2006-07-25 2014-03-18 Cephalon, Inc. Methods of treating disorders mediated by histamine H3 receptors using pyridazinone derivatives
US8247414B2 (en) 2006-07-25 2012-08-21 Cephalon, Inc. Pyridizinone derivatives and the use thereof as H3 inhibitors
EP2492263A1 (en) * 2006-07-25 2012-08-29 Cephalon, Inc. Pyridizinone Derivatives
EP2502918A1 (en) * 2006-07-25 2012-09-26 Cephalon, Inc. Pyridizinone Derivatives
EP2294050A2 (en) * 2008-05-14 2011-03-16 Biolipox AB Bis-aryl compounds for use as medicaments
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
CN103502244A (en) * 2010-11-09 2014-01-08 福建海西新药创制有限公司 Compound for increasing kinase active and application thereof
JP2014500252A (en) * 2010-11-09 2014-01-09 フチェン ハイシ ファーマシューティカルズ，インク． Compounds for increasing kinase activity and their applications
CN103502244B (en) * 2010-11-09 2014-10-08 福建海西新药创制有限公司 Compound for increasing kinase active and application thereof
US9409900B2 (en) 2010-11-09 2016-08-09 Fujian Haixi Pharmaceuticals, Inc. Compound for increasing kinase active and application thereof
WO2012062210A1 (en) * 2010-11-09 2012-05-18 Zhejiang Beta Pharma Inc. Compound for increasing kinase active and application thereof
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US8940756B2 (en) 2012-06-07 2015-01-27 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
WO2020163812A1 (en) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Valproic acid compounds and wnt agonists for treating ear disorders
JP7232931B2 (en) 2019-03-01 2023-03-03 エイシー イミューン ソシエテ アノニム Novel compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
JP2022521968A (en) * 2019-03-01 2022-04-13 エイシー イミューン ソシエテ アノニム New compounds for the treatment, alleviation, or prevention of disorders associated with tau aggregates
WO2020177952A1 (en) * 2019-03-01 2020-09-10 Ac Immune Sa Novel compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
US11426390B2 (en) 2019-08-12 2022-08-30 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11344536B1 (en) 2019-08-12 2022-05-31 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11813251B2 (en) 2019-08-12 2023-11-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11433056B1 (en) 2019-08-12 2022-09-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11529336B2 (en) 2019-08-12 2022-12-20 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11534432B2 (en) 2019-08-12 2022-12-27 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11576904B2 (en) 2019-08-12 2023-02-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11918564B1 (en) 2019-12-30 2024-03-05 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11844788B1 (en) 2019-12-30 2023-12-19 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11576903B2 (en) 2019-12-30 2023-02-14 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11793795B2 (en) 2019-12-30 2023-10-24 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11801237B2 (en) 2019-12-30 2023-10-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11612591B2 (en) 2019-12-30 2023-03-28 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11850240B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11850241B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11896585B2 (en) 2019-12-30 2024-02-13 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11903933B2 (en) 2019-12-30 2024-02-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11911370B1 (en) 2019-12-30 2024-02-27 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Also Published As

Publication number Publication date
AU2001262153A1 (en) 2001-10-15
GB0008264D0 (en) 2000-05-24

Similar Documents

Publication Publication Date Title
WO2001074771A1 (en) Pyrrole-2,5-dione derivatives for the treatment of diabetes
US7105532B2 (en) Pyrazolo[3,4-c]pyridines as gsk-3 inhibitors
JP5517935B2 (en) Indole and indazole compounds as cell necrosis inhibitors
JP6371786B2 (en) Compositions and methods for improving proteasome activity
EP1119548B1 (en) 3-(3-chloro-4-hydroxyphenylamino)-4-(2-nitrophenyl)-1h-pyrrole-2,5-dione as glycogen synthase kinase-3 inhibitor (gsk-3)
US10442782B2 (en) Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US5614520A (en) 2-arylthiazole derivatives and pharmaceutical composition thereof
US5958950A (en) Benzimidazole compounds useful for the treatment of inflammatory disease, atherosclerosis, restenosis or inhibiting lipoxygenase
Bekhit et al. Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents
EP2813498B1 (en) Compounds for Alzheimer&#39;s disease
EP2546242B1 (en) Cannabinoid receptor ligands
US5326770A (en) Monoamine oxidase-B (MAO-B) inhibitory 5-substituted 2,4-thiazolidinediones useful in treating memory disorders of mammals
KR20080081099A (en) Substituted thiazolidinedione derivatives
JP2009535320A (en) N- (2-thiazolyl) amide derivatives as GSK-3 inhibitors
KR20080012304A (en) Pyrazole compound and therapeutic agent for diabetes comprising the same
CA2408448A1 (en) Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation
WO2008049856A2 (en) Methods of treating pain using cdk inhibitors
EP3442948A1 (en) Ppar agonists, compounds, pharmaceutical compositions, and methods of use thereof
KR20140068243A (en) Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders
WO2020117877A1 (en) Compounds, compositions and methods of use
IL144229A (en) Novel 2-(n-cyanoimino) thiazolidin-4-one derivatives
WO2015047982A2 (en) Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
WO2003080609A1 (en) Pyrazolopyrimidines derivatives
KR20080003924A (en) New thiazolidinones without basic nitrogen, their production and use as pharmaceutical agents
JPH08231521A (en) 2-amino-1,3-thizepine and method of using same as inhibitor against nitrogen monoxide synthetase

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP