WO2001009106A1 - Composes diamino-1,2,4-triazole-acide carboxylique et derives de ces derniers utiles en tant qu'inhibiteurs de gsk-3 - Google Patents

Composes diamino-1,2,4-triazole-acide carboxylique et derives de ces derniers utiles en tant qu'inhibiteurs de gsk-3 Download PDF

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WO2001009106A1
WO2001009106A1 PCT/EP2000/007423 EP0007423W WO0109106A1 WO 2001009106 A1 WO2001009106 A1 WO 2001009106A1 EP 0007423 W EP0007423 W EP 0007423W WO 0109106 A1 WO0109106 A1 WO 0109106A1
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triazole
amino
anilino
formula
compound
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PCT/EP2000/007423
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English (en)
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David Glynn Smith
Robert William Ward
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Smithkline Beecham P.L.C.
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Priority to AU69898/00A priority Critical patent/AU6989800A/en
Priority to JP2001514309A priority patent/JP2003506362A/ja
Priority to EP00958343A priority patent/EP1200415A1/fr
Publication of WO2001009106A1 publication Critical patent/WO2001009106A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel compositions, especially pharmaceutical compositions, processes for the preparation of compounds, the use of these compounds in medicine, and to certain novel compounds.
  • GSK-3 is a serine/threonine protein kinase having a 47kDa monomeric structure. It is one of several protein kinases which phosphorylates glycogen synthase (GS) (Embi et al. Eur. J. Biochem. (107) 519-527 (1980)). Two isoforms are found in mammalian cells: and ⁇ . 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 2 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 2 diabetic subjects have defective muscle glycogen storage.
  • glycogen synthase The stimulation of glycogen synthesis by insulin in skeletal muscle results from the dephosphorylation and activation of glycogen synthase (Villar-Palasi C. and Lamer 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).
  • GSK-3 has been shown to phosphorylate other proteins in vitro, e.g. tau protein, which is hyperphosphorylated in Alzheimer's disease, and the eukaryotic initiation factor eIF-2B at Serine ⁇ O GSK-3 is known to be inhibited by lithium (Stambolic V., Ruel L.and Woodgett J.R. Curr. Biol. 1996 6(12): 1664-8) and lithium reduces the phosphorylation of tau, enhances the binding of tau to microtubules, and promotes microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D.C., Klein P.S. and Lee V.M. J.Biol. Chem. 1997 272(40) 25326-32).
  • United States patent 2,456,090 discloses 3,5-diamino-2-benzoyl-l,2,4-triazole as a precursor in the production of synthetic resins.
  • Blank B. et al. J. Med. Chem. 15(6) 694 (1972) discloses certain 1,2,4-triazoles as potential hypoglycaemic agents.
  • Certain 1,2,4-triazoles are also known from the Maybridge Chemical Company Ltd., Trevillett, Tintagel, Cornwall, PL34 0HW, UK.
  • triazole compounds including a series of novel compounds, are particularly potent and selective inhibitors of GSK-3. These compounds are therefore indicated to be useful for the treatment of conditions associated with a need for the inhibition of GSK-3 such as diabetes, especially Type 2 diabetes, dementias, such as Alzheimer's disease, and manic depression.
  • composition which composition comprises a compound of formula (I)
  • R 3 CZ- moiety may be attached to the nitrogen atom at position 1 or the nitrogen atom at position 2;
  • R 1 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic;
  • R is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R and R together with the nitrogen atom to which they are attached may form a heterocychc ring which ring may be unsubstituted or substituted;
  • R 3 is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalkyl, ahcyclylalkyl, diarylalkyl, or NR 6 R 7 ;
  • R 4 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic;
  • R 5 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R 4 and R together with the nitrogen atom to which they are attached may form a heterocychc ring which ring may be unsubstituted or substituted;
  • R 6 is hydrogen, aryl or alicyclic
  • R 7 is hydrogen, aryl or alicyclic, and
  • Z is oxygen or sulphur.
  • R 1 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C
  • R 1 is phenyl either unsubstituted or substituted with up to three of methyl, methoxy, or chloro.
  • R " is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of Cj-C ⁇ alkyl, Cj-C 6 alkoxy Cj-C ⁇ alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro.
  • R " is hydrogen
  • R is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted benzyl, unsubstituted or substituted thienylmethyl, unsubstituted or substituted phenylthiomethyl, unsubstituted or substituted naphthylmethyl, unsubstituted or substituted furylethenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted pyridyl, unsubstituted or substituted indolylmethyl, unsubstituted or substituted phenylcarbonylethyl, unsubstituted or substituted cyclopentenylmethyl, unsubstituted or substituted phenylpropyl, unsubstituted or substituted diphenylethyl, wherein the substituents for the R " aryl groups are selected from - O(
  • R 3 is phenyl either unsubstituted or substituted with up to three of chloro, bromo, phenyl, trifluoromethyl, nitro, benzoyl, phenoxy, acetyl, or 3,4-OCH 2 O-; naphthyl; benzyl either unsubstituted or substituted with up to three of phenyl or fluoro; 2-thienylmethyl; phenylthiomethyl 2-naphthylmethyl; cyclohexyl; 3-pyridyl; 3-indolylmethyl; phenylcarbonylethyl; cyclopent-2- enylmethyl; phenylpropyl; 2,2-diphenylethyl; or 2-furylethenyl; or NR 6 R 7 where R 6 and R 7 are each independently hydrogen, phenyl either unsubstituted or substituted with up to three of chloro, phenyl, phenoxy, methyl, bro
  • R 6 is unsubstituted or substituted aryl or unsubstituted or substituted alicyclic.
  • R 6 is cyclohexyl, naphthyl or phenyl which phenyl group may be either unsubstituted or substituted with up to three of chloro, bromo, phenyl, methyl, phenoxy, nitro or methoxy.
  • R is hydrogen.
  • the pharmaceutical composition provided by the invention comprises a compound of formula (I) selected from the list consisting of:
  • 3-amino-5-anilino-l,2,4-triazole-2-carboxylic acid (l-naphthyl)amide; 3-amino-5-anilino-l,2,4-triazole-2-carboxylic acid (3-nitrophenyl)amide, and; 3-amino-5-anilino- 1 ,2,4-triazole-2-carboxylic acid (3-methoxyphenyl)amide.
  • Certain of the compounds of formulae (IA) and (IB) may exist in one or more stereoisomeric forms, including geometric isomers.
  • the present invention encompasses all of the isomeric forms of the compounds of formulae (IA) and (IB), including geometric isomers, whether as individual isomers or as mixtures of isomers, including racemates.
  • Alkyl groups referred to herein include straight or branched chain alkyl groups containing up to six carbon atoms, said carbon atoms being optionally substituted with up to five, suitably up to three, groups selected from the list consisting of carboxy and esters and amides thereof, hydroxamic acids and esters thereof, hydroxy, halogen, amino, alkylamino, and dialkylamino.
  • Alkenyl groups referred to herein include straight and branched chain alkenyl groups containing from two to six carbon atoms, said carbon atoms being optionally substituted with up to five, suitably up to three, groups including those substituents described hereinbefore for the alkyl group.
  • Alicyclic groups referred to herein include cycloalkyl and cycloalkenyl groups having between three and eight ring carbon atoms, which carbon atoms are optionally substituted with up to five, suitably up to three, groups including those substituents described hereinbefore for the alkyl group.
  • aryl when used herein includes phenyl and naphthyl, especially phenyl.
  • Suitable optional substituents for any aryl group include up to three substituents selected from the list consisting of 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, carbamoylalkyl, mono- and di-N-alkylcarbamoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxy
  • heterocyclyl and “heterocychc” when used herein 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, which rings, may be unsubstituted or substituted by, for example, up to three substituents.
  • Each ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocychc ring system may include carbocyclic rings and need include only one heterocychc ring.
  • Substituents for any heterocyclyl or heterocychc group are suitably selected from halogen, alkyl, arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxy, amino, mono- and di-N-alkyl-amino, acylamino, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-alkylcarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, heterocyclyl, heterocyclylalkyl, and hydroxamic acids or esters thereof.
  • tialo' includes 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-b-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,
  • 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, alpha-keto glutarate and alpha-glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • treatment of diabetes includes treatment of 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 (I), wherein Z is O and R is other than NR R , or a derivative thereof, which process comprises the reaction of a compound of formula (II)
  • R 3A is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalkyl, ahcyclylalkyl, diarylalkyl, or a protected form thereof, and X is a suitable acylating group such as -COL, wherein L is a hydroxy group which has been activated by esterification with, for example, 1-hydroxybenzotriazole, or L is a suitable leaving group such as chloro, and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I), wherein Z is O and R is other than NR 6 R 7 , to a further compound of formula (I), wherein Z is O and R is other than NR 6 R 7 ;
  • Y is at position 1 or position 2.
  • reaction between the compounds of formulae (II) and (III) may be carried out in any suitable solvent, for example dimethyl formamide, under suitable acylation conditions, for example using an active ester of a carboxylic acid in the presence of a peptide coupling agent, at any temperature providing a suitable rate of formation of the required product, generally ambient temperature, over a suitable reaction time, generally 24 hours.
  • suitable solvent for example dimethyl formamide
  • suitable acylation conditions for example using an active ester of a carboxylic acid in the presence of a peptide coupling agent, at any temperature providing a suitable rate of formation of the required product, generally ambient temperature, over a suitable reaction time, generally 24 hours.
  • Suitable reaction temperatures include those in the range of 0-30°C. Conventional methods of heating and cooling such as thermostatically controlled electric heating mantles and ice baths may be employed.
  • the reaction products are isolated using conventional methods. Typically, water is added and the resultant solid product removed by filtration. The reaction products are purified by conventional methods, such as chromatography, recrystallisation, and trituration.
  • X is -COL, wherein L is a hydroxy group which has been activated by esterification with 1-hydroxybenzotriazole.
  • a mixture of a compound of formula (II), a compound of formula (III) wherein L is hydroxy, 1-hydroxybenzotriazole, and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dry dimethylformamide, wherein the carbodiimide is added last, is stirred at ambient temperature for about 24 hours. Water is then added and the resulting solid product is isolated by filtration, washed with water and dried in vacuo.
  • a further aspect of the invention provides a process for the preparation of a compound of formula (I), wherein Z is O and R 3 is NHR 6 , or a derivative thereof, which process comprises the reaction of a compound of formula (II) as hereinbefore defined with a compound of formula (IV)
  • R 6A is R 6 as hereinbefore defined, or a protected form thereof, and T is a suitable aminocarbonylating group such as isocyanate, and thereafter, if required, carrying out one or more of the following optional steps:
  • Y is at position 1 or position 2.
  • reaction between the compounds of formulae (II) and (IV) may be carried out in any suitable solvent, for example dimethyl formamide, under conventional aminocarbonylating conditions at any temperature providing a suitable rate of formation of the required product, generally ambient temperature, over a suitable reaction time, generally 48 hours.
  • suitable solvent for example dimethyl formamide
  • Suitable reaction temperatures include those in the range of 20-30°C. Conventional methods of heating and cooling such as thermostatically controlled electric heating mantles and ice baths may be employed.
  • reaction products are isolated using conventional methods. Typically, water is added and the resultant solid product removed by filtration.
  • the reaction products are purified by conventional methods, such as chromatography, recrystallisation, and trituration.
  • T is isocyanate.
  • a mixture of the isocyanate of formula (IV) and the compound of formula (II) in dry dimethyl formamide is stirred for about 48 hours and water added.
  • the resulting solid product is isolated by filtration, washed with water and dried in vacuo.
  • a further aspect of the invention provides a process for the preparation of a compound of formula (I), wherein Z is S and R 3 is other than NR R 7 , or a derivative thereof, which process comprises the reaction of a compound of formula (II) as hereinbefore defined with a compound of formula (V) (V)
  • R 3A is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalkyl, ahcyclylalkyl, diarylalkyl, or a protected form thereof, and W is a suitable thioacylating group such as -
  • a further aspect of the invention provides a process for the preparation of a compound of formula (I), wherein Z is S and R 3 is NHR 6 , or a derivative thereof, which process comprises the reaction of a compound of formula (II) as hereinbefore defined with a compound of formula (VI)
  • R 6A is R 6 as hereinbefore defined, or a protected form thereof, and U is a suitable aminothiocarbonylating group such as isothiocyanate, and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I), wherein Z is S and R is NHR , to a further compound of formula (I), wherein Z is S and R is NHR ; (ii) removing any necessary protecting group; (iii) preparing a derivative of the compound so formed.
  • Y is at position 1 or position 2.
  • reaction between the compounds of formulae (II) and (VI) may be carried out using procedures similar to those described in Reiter J et al J. Heterocycl. Chem. 24(6) 1685-1695 (1987).
  • (I) may be prepared as individual isomers using conventional chemical 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 (III) are known, commercially available compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in standard reference texts of synthetic methodology such as March J. Advanced Organic Chemistry 3rd Edition (1985) Wiley Interscience.
  • Amidotriazoles wherein the amido nitrogen atom is disubstituted are known for example in Banks. R et al. J. Chem. Soc. Perkin Trans. 1 ( 19) 1836- 1840 (1975). As stated above, the compounds of formula (I), or derivatives thereof, are indicated to be useful as inhibitors of GSK-3.
  • the present invention provides a compound of formula (I), or a derivative thereof, for use in the treatment of conditions associated with the need for the inhibition of GSK-3 such as diabetes, especially Type 2 diabetes, dementias such as Alzheimer's disease and manic depression.
  • the present invention provides the use of a compound of formula (I), or a derivative thereof, for the manufacture of a medicament for the treatment of conditions associated with the need for the inhibition of GSK-3 such as diabetes, especially Type 2 diabetes, dementias such as Alzheimer's disease and manic depression.
  • the present invention provides a method for the treatment of conditions associated with the need for the inhibition of GSK-3 such as diabetes, especially Type 2 diabetes, dementias such as Alzheimer's disease and manic depression, which method comprises the administration of a pharmaceutically effective, non-toxic amount of a compound of formula (I) or a derivative thereof.
  • the compounds of formula (I), or a derivative thereof are usually administered as the sole medicament 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 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 derivative thereof, may be administered in combination with insulin.
  • the said combination comprises co-administration of a compound of formula (I), or a derivative thereof, and an additional medicament agent or the sequential administration of a compound of formula (I), or a 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 derivative thereof, and the additional medicament agent or the essentially simultaneous administration of separate pharmaceutical compositions of a compound of formula (I), or a 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.
  • the composition 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. 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.
  • 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 star
  • 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, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or
  • fluid unit dosage forms are prepared utilising 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 sterilised 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 sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised 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.
  • 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.
  • 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 [ ⁇ - 33 P] ATP consisted of MOPS 25mM, EDTA 0.2mM, magnesium acetate 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 [ ⁇ - 3 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 3 PO 4 / 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 PO (0.5%), 2 mins for each wash, air dried and the radioactive phosphate incorporated 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-
  • KYRRAAVPPSPSLSRHSSPHQ(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 8.
  • EDTA solution containing the Streptavidin coated SPA beads to give a final 0.2 mgs.
  • 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 IC 5 0 values in the range of from between 10 to 100 nM.
  • Benzoyl chloride (0.33 mL, 2.85 mmol) was added dropwise with stirring to an ice-bath cooled solution of 3-amino-5-anilino-l,2,4-triazole (0.5g. 2.85 mmol) in a mixture of acetone (24 mL) and pyridine (0.29 mL). After stirring for 1 hour at bath temperature the mixture was allowed to warm to room temperature and then stirred for a further 8 hours. After storing in a refrigerator at about 4°C for two days, the mixture was poured into water (100 mL) and the resulting solid washed with water and dried in vacuo. Recrystallisation from ethanol afforded the title compound as a crystalline solid.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant des composés de formule (I), ou un dérivé pharmaceutiquement acceptable de ces derniers et un support pharmaceutiquement acceptable. Dans la formule, la fraction R3CZ- peut être attachée à l'atome d'azote en position 1 ou à l'atome d'azote en position 2; R1 représente hydrogène, alkyle, aryle, aralkyle, aralcényle ou un élément alicyclique; R2 représente hydrogène, alkyle, aryle, aralkyle, aralcényle ou un élément alicyclique, ou R1 et R2 peuvent former ensemble, avec l'atome d'azote auquel ils sont attachés, un anneau hétérocyclique qui peut être substitué ou non substitué; R3 représente alkyle, aryle, aralkyle, aryl(Q)alkyle, où Q représente O ou S, aralcényle, un élément alicyclique, hétéroaryle, hétéroaralkyle, arylcarbonylalkyle, alicyclyalkyle, diarylalkyle, ou NR6R7; R4 représente hydrogène, alkyle, aryle, aralkyle, aralcényle ou un élément alicyclique; R5 représente hydrogène, alkyle, aryle, aralkyle, aralcényle ou un élément alicyclique, ou R4 et R5 peuvent former, avec l'atome d'azote auquel ils sont attachés, un anneau hétérocyclique qui peut être substitué ou non substitué; R6 représente hydrogène, aryle ou un élément alicyclique; R7 représente hydrogène, aryle ou un élément alicyclique, et; Z représente oxygène ou soufre. Ces compositions sont utiles dans le traitement des pathologies associées à la nécessité de l'inhibition de GSK-3.
PCT/EP2000/007423 1999-08-02 2000-07-31 Composes diamino-1,2,4-triazole-acide carboxylique et derives de ces derniers utiles en tant qu'inhibiteurs de gsk-3 WO2001009106A1 (fr)

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AU69898/00A AU6989800A (en) 1999-08-02 2000-07-31 Diamino-1,2,4-triazole-carboxylic and derivatives as gsk-3 inhibitors
JP2001514309A JP2003506362A (ja) 1999-08-02 2000-07-31 Ｇｓｋ−３阻害剤としてのジアミノ−１，２，４−トリアゾール−カルボン酸誘導体
EP00958343A EP1200415A1 (fr) 1999-08-02 2000-07-31 Composes diamino-1,2,4-triazole-acide carboxylique et derives de ces derniers utiles en tant qu'inhibiteurs de gsk-3

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WO2001085685A1 (fr) * 2000-05-11 2001-11-15 Consejo Superior Investigaciones Cientificas Inhibiteurs heterocycliques de la glycogene synthase kinase gsk-3
WO2002057240A1 (fr) * 2000-12-22 2002-07-25 Ortho Mc Neil Pharmaceutical, Inc. Derives de triazole diamine substitues inhibiteurs de kinases
WO2002062387A1 (fr) * 2001-02-07 2002-08-15 Smithkline Beecham P.L.C. Traitement de pathologies necessitant l'inhibition de gsk-3
WO2003011843A1 (fr) * 2001-08-03 2003-02-13 Novo Nordisk A/S Nouveaux derives de la 2,4-diaminothiazole
WO2003027275A1 (fr) 2001-09-27 2003-04-03 Alcon, Inc. Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
JP2003532708A (ja) * 2000-05-11 2003-11-05 コンセホ・スペリオル・インヴェスティガシオンズ・シエンティフィカス グリコーゲンシンターゼキナーゼｇｓｋ−３の複素環インヒビター
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WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
US8012965B2 (en) 2006-12-29 2011-09-06 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
US8349838B2 (en) 2008-07-09 2013-01-08 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8431594B2 (en) 2008-07-09 2013-04-30 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as AXL inhibitors
US8546433B2 (en) 2009-01-16 2013-10-01 Rigel Pharmaceuticals, Inc. Axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer
US8906922B2 (en) 2006-12-29 2014-12-09 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as AXl inhibitors
US9629826B2 (en) 2004-09-24 2017-04-25 Gen Pharma Holdings, Llc CAI-based systems and methods for the localized treatment of uveitis

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2352944A (en) * 1942-07-04 1944-07-04 Gen Electric Triazole derivatives
EP0162217A1 (fr) * 1984-03-16 1985-11-27 Ciba-Geigy Ag Dérivés de 1,2,4-triazacycloalcadiène
WO2000010563A1 (fr) * 1998-08-20 2000-03-02 Smithkline Beecham Corporation Nouveaux composes de triazole substitues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2352944A (en) * 1942-07-04 1944-07-04 Gen Electric Triazole derivatives
EP0162217A1 (fr) * 1984-03-16 1985-11-27 Ciba-Geigy Ag Dérivés de 1,2,4-triazacycloalcadiène
WO2000010563A1 (fr) * 1998-08-20 2000-03-02 Smithkline Beecham Corporation Nouveaux composes de triazole substitues

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US7666885B2 (en) 2000-05-11 2010-02-23 Consejo Superior De Investigaciones Cientificas Enzyme inhibitors
WO2001085685A1 (fr) * 2000-05-11 2001-11-15 Consejo Superior Investigaciones Cientificas Inhibiteurs heterocycliques de la glycogene synthase kinase gsk-3
US6872737B2 (en) 2000-05-11 2005-03-29 Consejo Superior De Investigaciones Cientificas Heterocyclic inhibitors of glycogen synthase kinase GSK-3
JP4897179B2 (ja) * 2000-05-11 2012-03-14 コンセホ・スペリオル・デ・インヴェスティガシオネス・シエンティフィカス グリコーゲンシンターゼキナーゼｇｓｋ−３の複素環インヒビター
JP2003532708A (ja) * 2000-05-11 2003-11-05 コンセホ・スペリオル・インヴェスティガシオンズ・シエンティフィカス グリコーゲンシンターゼキナーゼｇｓｋ−３の複素環インヒビター
EP1712550A2 (fr) * 2000-12-22 2006-10-18 Ortho-McNeil Pharmaceutical, Inc. Dérivés de triazole diamine substitués comme inhibiteurs de kinases
US6924302B2 (en) 2000-12-22 2005-08-02 Ortho Mcneil Pharmaceutical, Inc. Substituted triazole diamine derivatives as kinase inhibitors
CN100357278C (zh) * 2000-12-22 2007-12-26 奥索-麦克尼尔药品公司 作为激酶抑制剂的取代的三唑二胺衍生物
WO2002057240A1 (fr) * 2000-12-22 2002-07-25 Ortho Mc Neil Pharmaceutical, Inc. Derives de triazole diamine substitues inhibiteurs de kinases
EP1712550A3 (fr) * 2000-12-22 2009-07-15 Ortho-McNeil Pharmaceutical, Inc. Dérivés de triazole diamine substitués comme inhibiteurs de kinases
US7317031B2 (en) 2000-12-22 2008-01-08 Ortho-Mcneil Pharmaceutical, Inc. Substituted triazole diamine derivatives as kinase inhibitors
WO2002062387A1 (fr) * 2001-02-07 2002-08-15 Smithkline Beecham P.L.C. Traitement de pathologies necessitant l'inhibition de gsk-3
WO2003011843A1 (fr) * 2001-08-03 2003-02-13 Novo Nordisk A/S Nouveaux derives de la 2,4-diaminothiazole
US7598288B2 (en) 2001-09-27 2009-10-06 Alcon, Inc. Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
EP1430120A4 (fr) * 2001-09-27 2007-06-20 Alcon Inc Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
WO2003027275A1 (fr) 2001-09-27 2003-04-03 Alcon, Inc. Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
EP2281560A1 (fr) 2001-09-27 2011-02-09 Alcon, Inc. Inhibiteurs de la glycogène synthase kinase-3 (GSK-3) pour traiter la neuropathie optique du glaucome
EP1430120A1 (fr) * 2001-09-27 2004-06-23 Alcon, Inc. Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
WO2006037106A3 (fr) * 2004-09-24 2006-12-21 Rfe Pharma Llc Systemes bases sur cai et methodes de traitement localise de maladies oculaires et autres
US9629826B2 (en) 2004-09-24 2017-04-25 Gen Pharma Holdings, Llc CAI-based systems and methods for the localized treatment of uveitis
US8614235B2 (en) 2004-09-24 2013-12-24 Rfe Pharma Llc CAI-based systems and methods for the localized treatment of ocular and other diseases
US7888380B2 (en) 2004-10-08 2011-02-15 Janssen Pharmaceutica, N.V. 1,2,4-Triazolylaminoaryl (heteroaryl) sulfonamide derivatives
US8299082B2 (en) 2004-10-08 2012-10-30 Janssen Pharmaceutica, N.V. 1,2,4-triazolylaminoaryl (heteroaryl) sulfonamide derivatives
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
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EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
US8389557B2 (en) 2005-09-07 2013-03-05 Rigel Pharmaceuticals, Inc. Triazole derivatives useful as Axl inhibitors
WO2007030680A2 (fr) * 2005-09-07 2007-03-15 Rigel Pharmaceuticals, Inc. Derives de triazole utiles comme inhibiteurs d'axl
US7884119B2 (en) 2005-09-07 2011-02-08 Rigel Pharmaceuticals, Inc. Triazole derivatives useful as Axl inhibitors
WO2007030680A3 (fr) * 2005-09-07 2007-05-18 Rigel Pharmaceuticals Inc Derives de triazole utiles comme inhibiteurs d'axl
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
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US8618331B2 (en) 2006-12-29 2013-12-31 Rigel Pharmaceuticals Inc. Polycyclic heteroaryl substituted triazoles useful as axl inhibitors
US9353124B2 (en) 2006-12-29 2016-05-31 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
US10166216B2 (en) 2006-12-29 2019-01-01 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as Axl inhibitors
US9650391B2 (en) 2006-12-29 2017-05-16 Rigel Pharmaceuticals Inc. N3-heteroaryl substituted triazoles and N5-heteroaryl substituted triazoles useful as Axl inhibitors
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US7872000B2 (en) 2006-12-29 2011-01-18 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8906922B2 (en) 2006-12-29 2014-12-09 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as AXl inhibitors
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US8658669B2 (en) 2008-07-09 2014-02-25 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8933080B2 (en) 2008-07-09 2015-01-13 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
US9079898B2 (en) 2008-07-09 2015-07-14 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
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US9206161B2 (en) 2008-07-09 2015-12-08 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8431594B2 (en) 2008-07-09 2013-04-30 Rigel Pharmaceuticals, Inc. Bridged bicyclic heteroaryl substituted triazoles useful as AXL inhibitors
US8349838B2 (en) 2008-07-09 2013-01-08 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
US8546433B2 (en) 2009-01-16 2013-10-01 Rigel Pharmaceuticals, Inc. Axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar

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