EP1667995A1 - Benzimidazole acetonitriles - Google Patents

Benzimidazole acetonitriles

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Publication number
EP1667995A1
EP1667995A1 EP04766767A EP04766767A EP1667995A1 EP 1667995 A1 EP1667995 A1 EP 1667995A1 EP 04766767 A EP04766767 A EP 04766767A EP 04766767 A EP04766767 A EP 04766767A EP 1667995 A1 EP1667995 A1 EP 1667995A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
benzimidazol
dihydro
ylidene
acetonitrile
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04766767A
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German (de)
English (en)
French (fr)
Inventor
Mattias Schwarz
Pascale Gaillard
Patrick Page
Jean-Pierre Gotteland
Russel J. Thomas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Serono SA
Original Assignee
Applied Research Systems ARS Holding NV
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Publication date
Application filed by Applied Research Systems ARS Holding NV filed Critical Applied Research Systems ARS Holding NV
Priority to EP04766767A priority Critical patent/EP1667995A1/en
Publication of EP1667995A1 publication Critical patent/EP1667995A1/en
Withdrawn legal-status Critical Current

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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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is related to benzimidazole acetonitriles, as well as pharmaceutical compositions containing such benzimida_.ole acetonitriles.
  • the compounds ofthe present invention axe useful in the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
  • the compounds ofthe present invention are inhibitors of Glycogen Synthase Kinase 3 (GSK3).
  • the present invention furthermore relates to methods for the preparation of benzimidazole acetonitriles.
  • Diabetes mellitus is a serious metabolic disease that is defined by the presence of chemically elevated levels of blood glucose (hyperglycemia).
  • diabetes mellitus encompasses several different hyperglycemic states. These states include Type 1 (insulin- dependent diabetes mellitus or IDDM) and Type 2 (non- insulin dependent diabetes mellitus or NIDDM) diabetes.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non- insulin dependent diabetes mellitus
  • the hyperglycemia present in individuals with Type 1 diabetes is associated with deficient, reduced, or nonexistent levels of insulin that are insufficient to maintain blood glucose levels within the physiological range.
  • Type 1 diabetes is treated by administration of replacement doses of insulin, generally by a parenteral route.
  • Type 2 diabetes is an increasingly prevalent disease of aging. It is initially characterized by decreased sensitivity to insulin and a compensatory elevation in circulating insulin concentrations, the latter of which is required to maintain normal blood glucose levels. As described below, GSK3 inhibition stimulates insulin-dependent processes and is consequently viewed to be useful in the treatment of type 2 diabetes. Recent data obtained using lithium salts provides evidence for this notion.
  • Hyperinsulinemia may be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in TDDM subjects, as a consequence of over injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.
  • NIDDM diabetic diabetic
  • PCOS Polycystic Ovary Syndrome
  • Type II diabetes mellitus is currently treated with sulfonylureas, biguanides, such as Metformin and thiazolidenediones, such as Troglitazone, Rosiglitazone or Pioglitazone, as oral hypoglycemic agents.
  • biguanides such as Metformin
  • thiazolidenediones such as Troglitazone, Rosiglitazone or Pioglitazone
  • Glycogen synthase kinase 3 is a serine/threonine kinase for which two isoforms, and ⁇ , have been identified (Trends Biochem. Sci., 16 p.177-81 (1991) by Woodgett et al.). Both GSK3 isoforms are constitutively active in resting cells. GSK3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such glucose transport.
  • GSK3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine Mnases (RTKs).
  • RTKs receptor tyrosine Mnases
  • Examples of such signalling molecules include IGF-1 and EGF.
  • GSK3 beta activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3 beta phosphorylates and thereby regulates the functions of many metabolic, signalling and structural proteins. Notable among the signalling proteins regulated by GSK3 beta are the many transcription factors, including activator protein- 1 cells, Myc, beta-catenin, CCAAT/enhancer binding protein, and NFkappaB.
  • GSK3 inhibitors e.g. WO 02/20495, Chiron Corporation; WO 02/10141, Pfizer Products Inc.; WO 02/22608, Vertex Pharmaceuticals Inc.).
  • WO 01/47920 discloses benzazoles of formula (A) in particular for the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.
  • the present invention relates to benzimidazole acetonitriles of formula (I)
  • the present invention relates to the use of compounds of formula (I) as medicament, in particular for the treatment and/or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, such as diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
  • metabolic disorders mediated by insulin resistance or hyperglycemia such as diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
  • Ci-C ⁇ -alkyl refers to alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).
  • Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
  • C ⁇ -C6-alkyl aryl refers to Ci-Ce-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
  • Heteroaryl refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group.
  • Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadia- zolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3- dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl,
  • Ci-C ⁇ -alkyl heteroaryl refers to Ci-C ⁇ -alkyl groups having a heteroaryl substituent, including 2--_urylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)et__yl and the like.
  • C 2 -C6-alkenyl aryl refers to Gj-C ⁇ -alkenyl groups having an aryl substituent, including 2- phenylvinyl and the like.
  • C 2 -C 6 -alkenyl heteroaryl refers to C 2 -C 6 -alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
  • C 2 -C 6 -alkyny_ refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • C 2 -C6-alkynyl aryl refers to C 2 -C 6 -aIkynyl groups having an aryl substituent, including phenylethynyl and the like.
  • C 2 -C6-alkynyl heteroaryl refers to C 2 -C6-alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
  • C 3 -C 8 -cycloalkyl refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).
  • Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
  • Ci-C ⁇ -alkyl cycloalkyl refers to Ci-C 6 -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
  • heterocycloalkyl refers to a C 3 -Cs-cycloalkyl group according to the definition above, in which 1 to 3 carbon atoms are replaced by hetero atoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or Ci-C- ⁇ alkyl.
  • Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.
  • Ci-C ⁇ -alkyl heterocycloalkyl refers to C ⁇ -C 6 -alkyl groups having a heterocycloalkyl substituent, including 2-(l-pyrro_idiny_)ethyl, 4-mo holinylmethyl, (l-methyl-4- piperidinyl)methyl and the like.
  • Carboxy refers to the group -C(0)OH.
  • Ci-C ⁇ -alkyl carboxy refers to Ct-C ⁇ -alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like.
  • Acyl refers to the group -C(0)R where R includes H, "Ci- -alkyl”, “C 2 -C 6 -alkenyl”, “C 2 -C6-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 - Ce-alkynyl aryl”, “C -C 6 -alkynylhetcroaryl", “C ⁇ -C 5 -alkyl cycloalkyl", “C]-C 5 -alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl acyl refers to Ci-C ⁇ -alkyl groups having an acyl substituent, including 2- acetylethyl and the like.
  • Aryl acyl refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.
  • Heteroaryl acyl refers to hetereoaryl groups having an acyl substituent, including 2- acetylpyridyl and the like.
  • C 3 -C 8 -(hetero)cycloalkyl acyl refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.
  • Acyloxy refers to the group -OC(0)R where R includes H, "C ⁇ -C 6 -alkyl", “C 2 -C 6 - alkenyl", “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylhetero_ ⁇ ry_", “d-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl acyloxy refers to Ci
  • Alkoxy refers to the group -O-R where R includes "C ⁇ -C 6 -alkyl”, “C 2 -C 6 -alkenyl”, “C 2 - Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 - Ce-alkynyl aryl", “C2-C 6 -alkynylheteroaryl", “C ⁇ -C 6 -alkyl cycloalkyl", “C ⁇ -C 6 -alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl alkoxy refers to Ci-Cg-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
  • Alkoxycarbonyl refers to the group -C(0)OR where R includes "C ⁇ -C 6 -alkyl", “C 2 -C 6 - alkenyl", “C 2 -C 5 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “CfCg-alkyl aryl” or "C.-C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “d-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl alkoxycarbonyl refers to C ⁇ -C6-alkyl groups having an alkoxycarbonyl substituent, including 2-(ben..yloxycarbonyl)ethyl and the like.
  • Aminocarbonyl refers to the group -C(0)NRR' where each R, R' includes independently hydrogen, "C ⁇ -C 5 -alkyl", “C 2 -C 6 -alkenyl", “C2-C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C,-C 6 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl", “Ci-C ⁇ -alkyl cycloalkyl", “Ci-C ⁇ -alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl aminocarbonyl refers to Ci-C ⁇ -alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
  • ⁇ cylamino refers to the group -NRC(0)R' where each R, R' is independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", "C 2 -C 6 -alkynyl aryl", “Cz-Ce-al
  • C ⁇ -C6-alkyl acylamino refers to Ci-C ⁇ -alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
  • “Ureido” refers to the group -NRC(0)NR'R” where each R, R', R" is independently hydrogen, "C 2 -C 6 -alkenyl", “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 5 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 - alkynylheteroaryr', "Ci-C ⁇ -alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”, and where R' and R", together with the nitrogen atom to which they are
  • C ⁇ -C6-alkyl ureido refers to C ⁇ -C 6 -alkyl groups having an ureido substituent, including 2- (iV-methylureido)ethyl and the like. ⁇
  • “Carbamate” refers to the group -NRC(0)OR' where each R, R' is independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", “Ca-Ce-alkenyl aryl", “C 2 -C 5 -alkenyl heteroaryl", “C 2 -C 6 -alkvnyl aryl", “C 2 -C 6 - alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “C ⁇ -C 6 -alkyl heterocycloalkyl”.
  • Amino refers to the group -NRR' where each R, R' is independently hydrogen, "Ci-Ce- alkyl", “d-Ce-alkenyl”, “C 2 -C 6 -alkvnyl", “d-Cg-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “d-C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", “d-Ce-alkenyl aryl”, “C 2 -C 6 - alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “C ⁇ -C 6 -alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”, and where R and R ⁇ together with the nitrogen atom to which they are attached, can optionally form a 3-8
  • C ⁇ -C6-alkyl amino refers to Ci-Ce-alkyl groups having an amino substituent, including 2- (l-pyrrolidinyl)ethyl and the like.
  • Ammonium refers to a positively charged group -N + RR'R", where each R, R ⁇ R" is independently, “Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “Ca-Ce-alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “C ⁇ -C 6 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “d-Ce-alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “Ci-C ⁇ -alkyl heterocycloalkyl”, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a
  • C ⁇ -C6-alkyl ammonium refers to Ci-Ce-alkyl groups having an ammonium substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
  • Halogen refers to fluoro, chloro, bromo and iodo atoms.
  • “Sulfonyloxy” refers to a group -OS0 2 -R wherein R is selected from H, "Ci-Ce-alkyl", “Ci-Ce-alkyl” substituted with halogens, e.g., an -0S0 2 -CF 3 group, "C 2 -C 6 -alkenyl", “C 2 - Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl", “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -a_kenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 - Ce-alkynyl aryl”, “C2-C6-alkynylheteroaryl", "C,-C 6 -alkyl cyclo
  • C ⁇ -C_ -alkyl sulfonyloxy refers to C ⁇ -C6-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
  • “Sulfonyl” refers to group “-SO 2 -R" wherein R is selected from H, "aryl", “heteroaryl”, “Ci-C ⁇ -alkyl", “Ci-Ce-alkyl” substituted with halogens, e.g., an -S0 2 -CF 3 group, "C 2 -C 6 - alkenyl”, “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl”, “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C -C 6 -alkenyl axyl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -Ce-alkynyl aryl”, “C 2 -Ce-alkynylheteroaryl", "C
  • Ci-C ⁇ -alkyl sulfonyl refers to Ci-C ⁇ -alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
  • “Sulfinyl” refers to a group “-S(0)-R” wherein R is selected from H, "Ci-Ce-alkyl", “Ci- C6-alkyl” substituted with halogens, e.g., an -SO-CF3 group, "C2-C6-alkenyl”, “C2-C6- alkynyl”, “d-Cg-cycloalkyl", “heterocycloalkyl”, “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -Ce-alkenyl heteroaryl", “C 2 -C 6 - alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", "Ci-Ce-
  • Ci-C ⁇ -alkyl sulfinyl refers to C ⁇ -C6-alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.
  • Sulfanyl refers to groups -S-R where R includes H, "Ci-Ce-alkyl", “C_ -C 6 -alkyl” substituted with halogens, e.g., an -SO-CF3 group, "C 2 -C6-alkenyl”, “C 2 -Ce-alkynyl”, “C 3 - C 8 -cycloalkyl", "heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “Ca-Ce-alkynyl aryl", “C 2 - C 6 -alkynylheteroaryl”, “C ⁇ -C 6 -alkyl cycloalkyl", "Ci-Ce-al
  • C ⁇ -C6-alkyl sulfanyl refers to Ci-C ⁇ -alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
  • “Sulfonylamino” refers to a group -NRS0 2 -R' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 3 -alkenyl", “d-Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “d -C 6 -alkyl aryl” or “Ci -C 6 -alkyl heteroaryl", “d-Ce-alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -Ce-alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “d-Ce-alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl sulfonylamino refers to Ci-C ⁇ -alkyl groups having a sulfonylamino substituent, including 2 ⁇ (ethylsulfonylamino)ethyl and the like.
  • Aminosulfonyl refers to a group -S0 2 -NRR' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “d-Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “d-Ce-alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “d-Ce-alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl”, “Ci-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl aminosulfonyl refers to C ⁇ -C 6 -alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)e_hyl and the like.
  • cycloalkyl "heterocycloalkyl”, “C ⁇ -C 6 -alkyl aryl”, “C ⁇ -C 6 -alkyl heteroaryl", “C ⁇ -C 6 - alkyl cycloalkyl”, “Ci-C ⁇ -alkyl heterocycloalkyl”, "amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “ureido”, “carbamate”, "aryl”, “heteroaryl”, “sulfinyl”, “sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”, “carboxy”, trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.
  • said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal i ⁇ tnctional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
  • “Pharmaceutically acceptable salts or complexes” refers to salts or complexes ofthe below- identified compounds of formula (I) that retain the desired biological activity.
  • Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, methanesulfonic acid and poly-galacturonic acid.
  • Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt ofthe formula - NR,R',R" + Z " , wherein R, R R" is independently hydrogen, alkyl, or benzyl, C ⁇ -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C ⁇ -C 6 -alkyl aryl, Ci-C ⁇ -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, as
  • “Pharmaceutically active derivative” refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
  • Enantiomeric excess refers to the products that are obtained by an asymmetric synthesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
  • a first aspect ofthe invention consists in benzimidazole acetonitriles of formula I
  • G is an unsubstituted or substituted pyrimidinyl.
  • G may be either ofthe substituted pyrimidinyl moieties
  • L is an amino group, or an unsubstituted or a substituted 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, O, S or L is an acylamino moiety.
  • R 1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, amino carbonyl, unsubstituted or substituted C ⁇ -C6-alkyl, unsubstituted or substituted C 2 -C6-alkenyl, unsubstituted or substituted d-Ce-alkynyl or Ci-C ⁇ -alkoxy, unsubstituted or substituted aryl (e.g. phenyl), halogen, cyano or hydroxy.
  • aryl e.g. phenyl
  • R 1 is II or C ⁇ -C 3 alkyl (e.g. a methyl or ethyl group).
  • R 2 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C ⁇ -C 6 -alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted cycloalkyl or Ci-Ce-alkoxy.
  • R 2 is a Ci-d alkyl (e.g. an ethyl group).
  • R 3 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Ci-C ⁇ -alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted d-Ce-alkynyl, unsubstituted or substituted cycloalkyl or C ⁇ -C6-alkoxy.
  • aryl e.g. phenyl
  • R 3 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Ci-C ⁇ -alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted d-Ce-alkynyl, unsubstituted or substituted cycloalkyl or
  • R 3 is hydrogen or a C 1 -C 3 alkyl (e.g. a methyl or an ethyl group).
  • the compounds ofthe present invention also comprises their tautomers, their geometrical isomers, their optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof.
  • Preferred pharmaceutically acceptable salts ofthe formula (I) are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, trifluoroacetate, and/. ⁇ r ⁇ -toluenesulfonate salts.
  • the benzimidazole acetonitriles ofthe present invention comprise the tautomeric forms, e.g. the below ones :
  • a specific embodiment of he present invention consists in benzimidazole acetonitriles of formula (la) in its tautomeric forms, e.g. the below ones :
  • R 1 , R 2 , R 3 and L are as defined for formula (I).
  • the moiety L is an amino group ofthe formula - NR 5 R 6 wherein R 5 and R 6 are each independently from each other H, unsubstituted or substituted Ci-Ce-alkyl, unsubstituted or substituted C 2 -C6-alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted Ci-C ⁇ -alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8- membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubsti
  • R 3 is hydrogen or a methyl or ethyl or propyl group and R 6 is selected from the group consisting of unsubstituted or substituted Ci-C ⁇ -alkyl, unsubstituted or substituted Ci-C ⁇ alkyl-aryl, unsubstituted or substituted Ci-Ce-alkyl- heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl or heteroaryl and unsubstituted or substituted 4-8 membered saturated or unsaturated cycloalkyl.
  • R 5 is H and R 6 is selected from the group consisting of Ci-d alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, heteroaryl, Ci-Ce-alkyl heteroaryl, C ⁇ -C 6 -alkyl cycloalkyl, C ⁇ -C 6 -alkyl heterocycloalkyl.
  • Examples of cycloalkyl are cyclopropyl, cyclopentyl or cyclohexyl.
  • R 6 may be a d- alkyl, in particular an ethylene or propylene moiety, optionally substituted with an imsubstituted or substituted heteroaryl group, e.g., an unsubstituted or substituted pyridyl or a 2-pyrrolidinone (2-oxopyrrolidine) or a triazolyl moiety.
  • an imsubstituted or substituted heteroaryl group e.g., an unsubstituted or substituted pyridyl or a 2-pyrrolidinone (2-oxopyrrolidine) or a triazolyl moiety.
  • the moiety L is an acylamino moiety of the formula -NR 5 C(0)R 6 wherein R 5 andR 6 are each independently from each other H, unsubstituted or substituted C ⁇ -C6-alkyl, unsubstituted or substituted d-d-a-kenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted C ⁇ -C6-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8-membered heterocycloalkyl, unsubstituted or substituted Ci-d-alkyl aryl, unsubstituted or substituted Ci-d-all yl heteroaryl, unsubstituted or substituted Ci-d- al
  • the compounds of formula (I) are useful in inhibiting Glycogen Synthase Kinase 3
  • Still a further object ofthe present invention is a process for preparing the benzimidazole acetonitriles according to formula I.
  • benzimidazole acetonitriles exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimisation procedures.
  • the benzimidazole acetonitriles derivatives according to the general formula I may be obtained by several processes using solution-phase chemistry protocols.
  • the benzimidazole acetonitrile derivative VI with R 1 being as above defined - is reacted with the electrophile VII (e.g. alkyl chloride) to give the corresponding benzimidazole compounds IV.
  • the intermediate IV is treated with a bis-chloro derivative V, wherein G is as above defined, to give the intermediate of synthesis II.
  • the intermediate II may be treated with an amine III, whereby the substituents R 5 , R 6 are as above defined to give the final benzimidazole acetonitrile derivatives I, utilizing well known solution-phase chemistry protocols, such as those described in the Examples and shown in Scheme 2, below :
  • Electrophiles VII as well as bis-chloro derivative V and amines III are commercially available.
  • the benzimidazole acetonitriles derivatives according to the general formula I may be obtained in 2-6 subsequent steps depending the availability of starting materials and building blocks. As shown in Scheme 3.
  • the benzimidazole acetonitriles derivatives IV are isolated after condensation ofthe benzimidazole compound VT with an electrophile VII, whereby R 2 is as above defined.
  • Several reaction conditions may be utilised for performing this first reaction step, e.g.
  • PS-TBD (7-methyl-l,5,7- triazabicyclo[4.4.0]dec-5-en' on polystyrene HL) a polymer immobilised reagent as a base in presence of various electrophihc reactants such as alkyl chlorine, bromide, iodide or also activated alcohol through mesylate formation.
  • This reaction may be performed in solvents like DCM or DCM/dioxane.
  • This reaction can be performed at various temperature depending of he intrinsic reactivity of compounds VI and VH, by traditional thermal method, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • the benzimidazole acetonitriles derivatives II whereby the substituents R 1 and R 2 are as above defined, are isolated after condensation ofthe benzimidazole compound IV with bis-chloro derivative V.
  • This reaction step is performed, using, e.g. lithium hydride or sodium hydride, cesium carbonate or similar reagents in an appropriate solvent such as Dioxane, THF, DMA or DMF.
  • This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compoimds IV and V, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • the chloro benzimidazole acetonitriles derivatives II may treated with various nucleophiles, e.g. an amine III, to give the expected benzimidazole acetonitriles I.
  • the nucleophilic displacement ofthe chloro atom ofthe pyrimidinyl moiety by the amine HI is accomplished by treatment with several equivalents ofthe nucleophile, e.g. the amine III, in presence or absence of e.g. sodium iodine as catalyst and a base such as triethylamine of diisopropylethylamine or similar reagents.
  • This reaction can be performed at various temperatures depending of the intrinsic reactivity of compounds II and III, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • the benzimidazole derivatives I may be obtained by treatment ofthe intermediate I' with either an acyl chloride, a carboxylic acid or a sulfonyl chloride using standard conditions well known to the person skilled in the art, such as amide bond formation protocols or sulfonamide formation using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating agents e.g, HOBt, EDC or similar reagents in an appropriate solvent such as THF or DMF.
  • This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compounds lb and VIII, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • R 1 A specific functional moiety (R 1 ) may be converted into a different one (R 1 ), using any known functional group interconversion protocols.
  • any known functional group interconversion protocols As illusttated in Scheme 7, the choice of the best synthetic strategy will be governed by the nature ofthe functional groups to be interconverted, and the compatibility of he required reaction conditions with other functional groups present in the corresponding compounds, as will be well appreciated by the person skilled in the art.
  • starting materials I, ⁇ and IV and VII are those wherein R 1 is -Br, -CI, -I, -OH, -NH2, -CH 2 OH, -CHO, -COOH, -N0 2 , and/or -CH 2 COOH, which are either obtained from commercial sources or made by one of the numerous processes described in the literature. From the intermediates (XXI, XXV,
  • XXV ⁇ derived thereof, in which R is as defined in Scheme 7, a wide range of derivatives, such as e.g. (XXII)-(XXXV), in which R 9 , R 10 , R 11 , R 7 , are as defined below, can be obtained by reaction sequences including oxidations, reductions, O- and N-alkylations, reductive alkylations and aminations, chain-elongations, Mitsunobu reactions, acylation, debocylation, Wittig reactions, acylations, sulfonylations, Stille, Suzuki, Sonogashira and any other appropriate transformations leading to functional group interconversions, some of which being exemplified in Scheme 8.
  • reaction sequences including oxidations, reductions, O- and N-alkylations, reductive alkylations and aminations, chain-elongations, Mitsunobu reactions, acylation, debocylation, Wittig reactions, acylations,
  • R 9 , R 10 , R 11 , R 7 are each independently from each other H, unsubstituted or substituted Ci- d-alky], unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -Ce- alkynyl, unsubstituted or substituted Ci-Ce-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8-membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubstituted or substituted Ci-C ⁇ -alkyl aryl
  • the benzimidazole acetonitriles derivatives according to the general formula I may be obtained in 2-6 subsequent steps depending the availability of starting materials and building blocks.
  • Scheme 9 the benzimidazole acetonitriles derivatives II' are isolated after condensation ofthe benzimidazole compound II with a solution of ammonium hydroxide.
  • This reaction may be performed in solvents like DMA, isopropanol or solution containing both solvents in various ratio.
  • This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compounds II, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples
  • the benzimidazole acetonitriles derivatives according to the general formula I can be further isolated from the intermediate III', whereby L is the moiety— C(0)R 6 , with R 6 is as above defined, as shown in Scheme 10.
  • the benzimidazole derivatives I may be obtained by treatment of the intermediate II' with either an acyl chloride or a carboxylic acid using standard conditions well known to the person skilled in the art, such as amide bond formation protocols using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating agents e.g, HOBt, EDC, Mukayama reagent or similar reagents in an appropriate solvent such as DCM, THF or DMF.
  • This reaction can be performed at various temperature depending of the intrinsic reactivity of compounds II' and III', by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention.
  • a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention.
  • a person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of he active ingredient commensurate with the intended daily dosage range to be employed.
  • benzimidazole acetonitriles of this invention are typically administered in the foim of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount.
  • the amount ofthe compound actually administered will typically be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response ofthe individual patient, the severity ofthe patient's symptoms, and the like.
  • compositions of these inventions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intra- thecal, intraperitoneal and intranasal.
  • the compoimds are preferably formulated as either injectable, topical or oral compositions.
  • the compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes ofthe liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the benzimidazole acetonitrile compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum ttagacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dio- xide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum ttagacanth or gelatine
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the benzimidazole acetonitriles of formula I in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can also be found in the incorporated materials in Remington 's Pharmaceutical Sciences.
  • a further aspect ofthe present invention is related to a pharmaceutical composition composition a comprising a benzimidazole derivative according to formula (I) and at least one further drug (in particular an anti-diabetes agent).
  • the further diabetes agents are selected from the group comprising or consisting of insulin (or insulin mimicks), aldose reductase inhibitors, alpha-glucosidase inhibitors, sulfonyl urea agents, biguanides (e.g. metformin), thiazolidines (e.g. pioglitizone, rosiglitazone, cf. WO 02/100396), a PTP1B inhibitor, a PPAR agonists or a GSK-3 inhibitor.
  • Insulins useful with the method ofthe present invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combination of intermediate and rapid acting insulins.
  • aldose reductase inhibitors of this invention are minalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopofrestat, Epalrestat, Zenarestat, Imirestat and Ponalrestat or the pharmaceutically acceptable salt forms thereof.
  • alpha-glucosidase inhibitors useful for the method ofthe present invention include miglitol or acarbose, or the pharmaceutically acceptable salt form thereof.
  • Sulfonylurea agents useful with the method ofthe present invention include glipizide, Glyburide (Ghbenclamide), Clorpropamide, Tolbutamide, Tolazamide and Glimepiride, or the pharmaceutically acceptable salt forms thereof.
  • said supplementary pharmaceutically active agent is selected from the group consisting of a rapid acting insulin, an intermediate acting insulin, a long acting insulin, a combination of intermediate and rapid acting insulins, Inalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat, Ponalrestat, ONO-2235, GP- 1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M- 16209, NZ-314, M-79175, SPR-210, ADN 138, or SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, Tolbutamide, Tolazamide, or Glimepriride.
  • HPLC column Waters Symmetry C8 50 x 4.6 mm, Conditions: MeC ⁇ /H 2 0, 5 to 100% (8 min), max plot 230-400 nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD (ES); 1H-NMR: Bruker DPX-300MHz.
  • the purifications were obtained as followed: Preparative HPLC Waters Prep LC 4000 System equipped with columns Prep Nova-Pak ® HR CI 86 ⁇ m 6 ⁇ A, 40x30mm (up to lOOmg) or 40x300 mm (up to lg). All the purifications were performed with a gradient of MeCN/H 2 0 0.09% TFA.
  • Example 1 General procedure for the solution-phase synthesis of benzimidazoles acetonitriles derivatives of general formula I. with G and L as above defined (Schemes 1- 6.: f2ZVri-ethyl-1.3-dihvdro-2H-benzimidazol-2-ylidene ⁇ 2-ir3- ⁇ H-pyrazol-l- yl ⁇ ropyl]amino ⁇ pyrimidin-4-yl)acetonitrile
  • the isopropanol was evaporated and the residue redissolved in 3mL of DCM.
  • This solution was loaded onto a lOg SCX- SPE syringe (O ⁇ mmol.g "1 ) and eluted with DCM, then DCM:MeOH (1:1), 0.1M NH 3 in MeOH and 1M NH 3 in MeOH.
  • he 4 fraction were analyzed by HPLC and LC-MS and the fractions contained the product were mixed together.
  • the solvents were evaporated and the residue redissolved in DCM and washed with NaHC03 sat. and brine.
  • the organic layer was dried over MgS0 , filtered and the solvent evaporated.
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- cWoro-5-me ylpyrimidin-4-yl)(l -ethyl-2,3-dihydro- 1 H-benzimidazol-2-yl)acetonitrile (intermediate 6), and3-(lH- ⁇ yrazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 82% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-rne ylpyrin ⁇ idm-4-yl)(l-ethyl-2,3-cfihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and N-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 77% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l -ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), andN-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l -ethyl-2,3-(Mhydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and 3-(lH-l,2,4-triazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l -ethyl-2,3 -dihydro- lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and3-(lH-l,2,4-triazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 78% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzi ⁇ nidazol-2-yl)acetonitrile (intermediate 6), and cyclopentylamine, the title compound was isolated, as a yellow solid in 69% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memyl ⁇ yrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 3 -(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 69% yield (96% purity by HPLC).
  • Example 14 1.3-dihydro-2H-benzimidazol-2-ylidene(5-methyl-2- ⁇ [3-(2-oxopyrrolidin-l- vDpropyl lamino ⁇ p yrimidin-4- vPacetonitrile
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l-cyclobutyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 18), andN-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpy ⁇ midin-4-yl)(l-ethy]-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and isobutylamine, the title compound was isolated, as a yellow solid in 72% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpy ⁇ imidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and histamine base, the title compound was isolated, as a yellow solid in 69% yield (93% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-methylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 2-(N,N-dimemylan ino)-5-aminoethyl ⁇ yridine, the title compound was isolated, as a yellow solid in 68% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-y])(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclopropylamine, the title compound was isolated, as a yellow solid in 75% yield (96% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpy ⁇ imidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and2-(2-aminoethyl)pyridine), the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and (+/-)-2-aminopentane, the title compound was isolated, as a yellow solid in 70% yield (92% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpvrin ⁇ idin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1 -(2 I -aminoethyl)pyrazole), the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-me ylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and2-(imidazol-l-yl)-ethylamine, the title compound was isolated, as a yellow solid in 60% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (6- chloropyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 11), and 3-(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 72% yield (88% purity by HPLC).
  • Example 48 (1 -etfayl-lH-penzimidazol-2-yl)[2-(4-e ⁇ hylpi ⁇ erazin-l -yl -5-methyl ⁇ yrimidin- 4-yl]acetonitrile-
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1 -ethylpiperazine, the title compound was isolated, as a yellow solid in 76% yield (99% purity by HPLC). MS(ESI + ): 390.5; MS(ESF): 388.4.
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memyl ⁇ yrimidin-4-yl)(l-ethyl-2,3-dihydro-lII-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclohexylamine, the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidm-4-yl)(l,3-die1hyl-2,3-dihydro-lH-benzimidazol-2-yl)acetoniteile (intermediate 15), and cyclopentylamine, the title compound was isolated, as a yellow solid in 80% yield (97% purity by HPLC). MS(EST): 389.2; MSfESF): 387.3.
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- cMoro-5-inethylpyriinidin-4-yl)(l-ethyl-2,3-chhydro-lH-benziniidazol-2-yl)acetonitrile (intermediate 6), and 4 -amino- 1 -piperidine, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI 4 : 376.2; MS(ESF): 374.3.
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-methylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzinfidazol-2-yl)acetonitrile (intermediate 6), and 1 -amino-3-(N-piperidino)propane, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI + ): 418.6; MS(ESF): 416.2.
  • Example 56 General procedure for the solution-phase synthesis of benzimidazoles acetonitriles derivatives of general formula I. with G and L as above defined (Schemes 10): tert-bu1yl (4S)-4-[( ⁇ 4-r(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene.methyl]- 5 -methylpyrimidin-2- yl amino)cafbonyl] -1.3 -thiazolidine-3 -carboxylate
  • reaction mixture was diluted with DCM (50mL), washed with NH4C1, NaHC03 and brine and dried over MgS0 .
  • the solvent was removed by evporation and the residue purified by FC using a gradient AcOE CycloH (4:6) to neat AcOEt then to AcOEt:MeOH (7:3) for lhour.
  • Example 61 ⁇ S.5S.7SVN-U-rfZVcvanofl-ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl ⁇ -6.8-dioxa-3-azabicyclo
  • Example 62 4-tert-butyl l-(9H-fluoren-9-ylmethyl. 2-[( ⁇ 4-[(Z)-cyanofl-ethyl-l-3-dihvdro- 2H-benzimidazol-2-ylidene)memyl]-5-n ethylpyr-midm-2-yl ⁇ --mino)carbonyl]pi ⁇ erazine- 1 ,4-dicarboxylate
  • Example 63 4-tert-butyl 1-(9H- fluoren-9-ylmethyl) 2-[( ⁇ 4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl ⁇ amino)carbonyl] ⁇ iperazine- 1 ,4-dicarboxylate (Example 63), the title compound was isolated, as a yellow solid in 90% yield (91% purity by HPLC).
  • Example 64 tert-butyl (2S)-2-[( ⁇ 4-[(Z)-cyano(l-eti ⁇ yl-13-dihydro-2H-benzimidazol-2- ylidene .methyl]-5-methylpyrimidin-2-yl ⁇ amino)carbonyl]-5-oxopyrrolidine- 1 -carboxylate
  • Example 65 N-(4-f Z)-cvano(l -ethyl-1.3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- ine ylpyrimidin-2-yl ⁇ -5-oxo-L-prolinamide
  • Example 66 tert-butyl (4R)-4-[( ⁇ 4-[(Z)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)memyl1-5-methylpyrimidin-2-yl ⁇ amino)carbonyl]-1.3-thiazolidine-3-carboxylate
  • Example 68 (lS.4S.5S.7RVN- ⁇ 4-[(Z)-cvano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)me yl1-5-methyl ⁇ yrimidin-2-yl ⁇ -4-methyl-6.8-dioxa-3-azabicyclo[3.2.1]octane-7- carboxamide
  • Example 70 N ⁇ l — ⁇ 4-[(Z)-cyano(l -ethyl-1.3 -dihydro-2H-benzimidazol-2- ylidene)memyl1-5-methylpyrimidin-2-yl ⁇ -N ⁇ 3 ⁇ .N ⁇ 3 ⁇ -dimethyl-beta-alaninamide
  • Example 72 N- ⁇ 4-[TZ)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrin idin-2-yl ⁇ cyclopentanecarboxamide
  • Example 73 tert-butyl r4-( ⁇ 4-r(Z -cvano(l-ethyl-L3-dihvdro-2H-benzimidazol-2- ylidene)n emyl]-5-n e1hyl ⁇ yrimidin-2-yl ⁇ ajmno)-4-oxobutyl]carban ⁇ ate
  • Example 74 4-amino-N- ⁇ 4-[(Z -cyano(l-ethyl-1.3-dihydro-2FI-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-yl ⁇ butanamide
  • Example 75 tert-butyl 4-[( ⁇ 4-[(Z)-cyano(l-ethyl-l,3-d-hvdro-2H-benzimidazol-2- ylidene)me yl]-5-methylpyrimidin-2-yl ⁇ amino)carbonyl]piperidine-l-carboxylate
  • Example 77 N- ⁇ 4- . (Z -cyano( 1 -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidenetoethyl] -5- methylpyrimidin-2-yl ⁇ -1 -methylpiperidine-4-carboxamide
  • Example 78 1 -acetyl-N- ⁇ 4- [(Z)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidene)me yll-5-methylpyrimidin-2-yl ⁇ piperidine-4-carboxan ide
  • Example 80 tert-butyl (2S)-2-[( ⁇ 4-[(Z)-cyano(l-eti ⁇ yl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-y] ⁇ amino)carbonyl]-2.5-dihydro-lH-pyrrole-l- carboxylate
  • Example 80 Following the general method as outlined in Example 56, starting from tert-butyl (2S)-2- [( ⁇ 4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyri ⁇ mdin-2-yl ⁇ amino)carbonyl]-2,5-dihydro-lH-pyrrole-l -carboxylate (Example 80), the title compound was isolated, as a yellow solid in 95% yield (96% purity by HPLC). MS(ESI + ): 388.5; MS(ESF): 386.6.
  • Example 82 tert-butyl 3-[( ⁇ 4-f(Z)-cvano(l -ethyl-1.3 -dihvdro-2H-benzimidazol-2- ylidene)me yll-5-methylp ⁇ midin-2-yI ⁇ amino carbonyl] ⁇ yrrolidine-l-carboxylate
  • Example 84 tert-butyl 2-[( ⁇ 4-[(Z)-cyanofl -ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)me yll-5-methylpyrimidin-2-yl ⁇ arnino carbonyl morpholine-4-carboxylate
  • Example 84 Following the general method as outlined in Example 56, starting from tert-butyl 2-[( ⁇ 4- [(Z)-cyano(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-yhdene)me yl]-5-methylpyrimidin-2- yl ⁇ amino)carbonyl]morpholine-4-carboxylate (Example 84), the title compound was isolated, as a yellow solid in 95% yield (99% purity by HPLC). MS(ESI + ): 406.6; MS(ESF): 404.7
  • Example 86 Following the general method as outlined in Example 56, starting from tert-butyl [2-( ⁇ 4- [(Z)-cy-mo(l-ethyl-l,3-dihydro-2H-ben_ midazol-2-yhdene)methyl]-5-memylpyri ⁇ r ⁇ din-2- yl ⁇ amino)-2-oxoethyl]methylcarbamate (Example 86), the title compound was isolated, as a yellow sohd in 98% yield (97% purity by HPLC). MS(ESI + ): 364.5; MS(ESF): 362.5.
  • Example 88 N ⁇ f4-. fZ.-cvanof 1 -ethyl-1 ,3-dihvcfro-2H-benz-midazol-2-V-idene)methyl 1-5- methyl ⁇ yrimidin-2-yl ⁇ - 1 -methyl ⁇ iperidine-3 -carboxamide
  • Example 90 tert-butyl 4-[2-( ⁇ 4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidm-2-yl ⁇ amino)-2-oxoethyl]piperidine-l-carboxylate
  • Example 90 Following the general method as outlined in Example 57, starting from tert-butyl 4-[2-( ⁇ 4- [(Z)-cy-mo(l-ethyl-l,3-chhydro-2H-bcnzimidazol-2-yhdene)methyl]-5-mc ⁇ ylpyrin idin-2- yl ⁇ amino)-2-oxoethyl]piperidine-l -carboxylate (Example 90), the title compound was isolated, as a yellow solid in 98% yield (97% purity by HPLC). MS(EST): 418.6; MS(ESF>: 416.3.
  • Example 93 tert-butyl 3-[( ⁇ 4-[(Z)-cyano(l -ethyl- 1.3-dihydro-2H-benzimic-azol-2- ylidene)memyl1-5-methylpyrimidin-2-yl ⁇ amino)carbonyllpiperidine-l-carboxylate
  • Example 93 Following the general method as outlined in Example 57, starting from tert-butyl 3-[( ⁇ 4- [(Z)-cyano(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-yhdene)methyl]-5-memylpyrimidin-2- yl ⁇ amino)carbonyl]piperidine-l -carboxylate (Example 93), the title compound was isolated, as a yellow solid in 95% yield (97% purity by HPLC). MS(ESI + ): 404.9; MS(ESF): 402.6.
  • Example 96 4-acetyl-N- ⁇ 4- [(Z)-cyano(l -ethyl- 1.3-dihydro-2H-benzimidazol-2- ylidene memyl]-5-methylpyrimidm-2-yl ⁇ mo ⁇ holine-2-carboxamide
  • Example 100 N- ⁇ 4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl1-5- methylpyrimidin-2-yl ⁇ -2-( 1.1 -dioxidothiomorpholin-4-yl)acetamide
  • a benzimidazole acetonitrile of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ration. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active benzimidazole acetonitrile compound per tablet) in a tablet press.
  • a benzimidazole acetonitrile of formula I is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active benzimidazole acetonitrile compound per capsule).
  • a benzimidazole acetonitrile of formula I (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
  • a benzimidazole acetonitrile of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active benzimidazole acetonitrile compound) in a tablet press. Formulation 5 - Injection
  • a benzimidazole acetonitrile of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
  • the compounds ofthe present invention may be subjected to the following assays :
  • GSK3 ⁇ (h) (5-10mTJ) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20 ⁇ M YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (being the
  • GSK3 substrate aphospho GS2 peptide
  • lOmM Mg Acetate aphospho GS2 peptide
  • [ ⁇ - 33 P-ATP] Specific activity approx. 500cpm/pmol, concentration as required.
  • the reaction is initiated by the addition of Mg 2+ [ ⁇ -33p_ATP].
  • the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution. 1 O ⁇ l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 50mM phosphoric acid and once in methanol prior to drying and the degree of phosphorylation of the substrate is determined by scintillation counting.
  • the tested compounds according to formula I display an inhibition (IC50) with regard to GSK3 of less than 20 ⁇ M, preferably less than 10 and even more preferred less than 1 ⁇ M.
  • binding affinities ofthe compounds of formula (I) were assessed using the above described in vitro biological assay. Representative values for some example compounds are given in Tables 1 and 2 below.
  • Table 1 In vitro potency of benzimidazole derivatives on human GSK3 beta
  • I ⁇ vivo assay Experimental model of type II diabetes (oral postprandial glvcemia in db/db mice)
  • the following assay aims at determining the anti-diabetic effect ofthe test compounds of formula (I) in a model of postprandial glycemia in db/db mice, in vivo.
  • the assay was performed as follows :
  • mice A total of 24 db/db mice (about 8-9 weeks; obtained from IFFACREDO, l'Arbreste, France) were fasted during 20 hours.
  • Group 1 The animals were administered (per os) a dose of 10 mg/kg of vehicle.
  • Group 2 The animals were administered (per os) a dose of 50 mg/kg ofthe test compound according to formula (I).
  • mice After oral administration of the compounds of formula (I) solubilized or suspended in CarboxyMethylCellulose (0.5%), Tween 20 (0.25%) and water as vehicle, the animals had access to commercial food (D04, UAR, Villemoisson/Orge, France) ad libitum. The diabetic state ofthe mice was verified by determining the blood glucose level before drug administration. Blood glucose and serum insulin levels were then determined 4 hrs after drug administration.
  • the determination ofthe blood glucose level was performed using a glucometer (Precision Q.I.D., Medisense, Abbot, ref. 212.62.31).
  • the determination ofthe Insulin level was performed using an ELISA kit (Crystal CHEM, Ref. INSK R020). Changes in blood glucose and serum insulin of drug treated mice were expressed as a percentage of control (group 1 : vehicle treated mice).

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