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WO2009133127A1 - Composés bicycliques fusionnés et utilisations de ceux-ci comme inhibiteurs de p13k - Google Patents

Composés bicycliques fusionnés et utilisations de ceux-ci comme inhibiteurs de p13k Download PDF

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WO2009133127A1
WO2009133127A1 PCT/EP2009/055172 EP2009055172W WO2009133127A1 WO 2009133127 A1 WO2009133127 A1 WO 2009133127A1 EP 2009055172 W EP2009055172 W EP 2009055172W WO 2009133127 A1 WO2009133127 A1 WO 2009133127A1
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Dominique Swinnen
Catherine Jorand-Lebrun
Tania Grippi-Vallotton
Patrick Gerber
Jerome Gonzalez
Jeffrey P. Shaw
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Merck Serono SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to novel compounds of formula I and related formulae, their use as medicament and their use for treating autoimmune diseases, inflammatory disorders, multiple sclerosis and other diseases such as cancers.
  • the invention relates to compounds of formula I:
  • U denotes CR C , CH, or S
  • V denotes C or N
  • W denotes N or CR 1
  • R a denotes perfluoroalkyl, A, NH-A, -NH-(CH 2 ) P -A, Het-alkyl.or if X denotes a bond, also CO-Het, CO-N(H) 2-m (A) m , COOA, CO, CS, or if X denotes CO, SO, CS, also H, or if V denotes C or if U denotes S, also Ar or Het.
  • R b denotes Ar, Het 2 ,
  • R c denotes H, alkyl, Ar, Het Ar denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by, Hal, CF 3 , OCF 3 , NO 2 , CN, perfluoroalkyl, A, OH, NH 2 , COH, CONH 2 ,-NHCOA, -NHSO 2 A, -NHSO 2 - N(H) 2-m (A) m , N(H) 1-q A q COA, N(H) 1-q ASO 2 -N(H) 2-m (A) m , N(H) 1- q A q CON(H) 2-m (A) m , COOA, -SO 2 A, -SO 2 N(H) 2-m (A) m , -SO 2 Het, or
  • X denotes CO, SO, CS or a bond
  • Het denotes a monocyclic or bicyclic saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms which is unsubstituted or monosubstituted, disubstituted or trisubstituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, Hal,
  • CF 3 OCF 3 , NO 2 , CN, perfluoroalkyl, A, OA, OH, amino, CONH 2 , - NHCOA, -NHSO 2 -N(H) 2-m (A) m , COOA, -SO 2 A, -SO 2 N(H) 2-m (A) m , - SO 2 Het, or SO 2 Het 2 .
  • Het 2 denotes a monocyclic saturated, unsaturated or aromatic heterocyclic ring having 1 N, O or S atoms which is unsubstituted, monosubstituted, disubstituted or trisubstituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, Hal, CF 3 , OCF 3 , NO 2 , CN, perfluoroalkyl, OA, OH, CONH 2 , -NHCOA, -NHSO 2 -N(H) 2-m (A) m , COOA, -SO 2 N(H) 2-m (A) m , -SO 2 Het, SO 2 J, wherein J denotes an alkyl group having 1 to 6 carbon atoms, or Het 2 denotes one of the following groups:
  • n 0, 1 or 2;
  • p denotes 0, 1 , 2, 3, 4;
  • R 1 , R 2 are each independently H, Hal, CF 3 , A; Ar or Het
  • R 3 is H or Hal
  • R , R denote each independently H, Ar, Het, or A, and if R'or R" is bond to a C atom also OA.
  • R 6 is H, a branched or linear alkyl or hydroxyalkyl having 1 to 12 C-atoms and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
  • R a and R b are as defined above.
  • the present invention also relates to compounds of Formula (I)
  • R a denotes perfluoroalkyl, A 1 , NH-A, -NH-(CH 2 )p-A, Het-alkyl,or if X denotes a bond, also CO-Het, CO-N(H) 2-m (A) m , COOA, CO, CS, or if X denotes CO, SO, CS, also H, or if V denotes C or if U denotes S, also Ar or
  • R b denotes Ar, Het
  • the compounds of formula I and related formulae modulate activity of Phosphoinositide 3-kinases such as Pi3K ⁇ and Pi3K ⁇ or other isoforms Phosphoinositide 3-kinases (PI3Ks) have a critical signalling role in cell proliferation, cell survival, vascularization, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (Cantley, 2000, Science, 296, 1655-1657).
  • Phosphoinositide 3-kinases such as Pi3K ⁇ and Pi3K ⁇ or other isoforms Phosphoinositide 3-kinases (PI3Ks) have a critical signalling role in cell proliferation, cell survival, vascularization, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (Cantley, 2000, Science, 296, 1655-1657).
  • PI3K is given to a family of lipid kinases which, in mammals, consists in eight identified PI3Ks that are divided into three sub-families according to their structure and their substrate specificity.
  • the present invention provides a kit or a set consisting of separate packs of
  • Class I group of PI3Ks consists in two sub-groups, Class IA and Class IB.
  • Class IA are a family of heterodimehc lipid kinases consisting in a 85 kDa regulatory unit (responsible for protein-protein interactions via the interaction of Src homology 2 (SH2) domain with phosphotyrosine residues of other proteins) and a catalytic sub-unit of 11 OkDa that generate second messenger signals downstream of tyrosine kinases, thereby controlling cell metabolism, growth, proliferation, differentiation, motility and survival.
  • Three catalytic forms p110a, p110 ⁇ and p110 ⁇
  • five regulatory isoforms p85 ⁇ , p85 ⁇ , p55 ⁇ , p55 ⁇ and p50 ⁇
  • Class IB are stimulated by G protein ⁇ sub-units of heterodimeric G proteins.
  • the only characterized member of Class IB is PI3K ⁇ (p110 ⁇ catalytic sub-unit complex with a 101 -kDa regulatory protein, p101 ).
  • Class 1A PI3Ks comprises ⁇ , ⁇ and ⁇ isoforms, which are approximately of 170 kDa and characterized by the presence of a C-terminal C2 domain.
  • Class III PI3Ks includes the phosphatidylinositol specific 3-kinases.
  • the evolutionary conserved isoforms p110a and ⁇ are ubiquitously expressed, while ⁇ and ⁇ are more specifically expressed in the haematopoetic cell system, smooth muscle cells, myocytes and endothelial cells ⁇ Vanhaesebroeck et al., 2001, Annu. Rev. Biochem., 70, 535-602). Their expression might also be regulated in an inducible manner depending on the cellular-, tissue type and stimuli as well as disease context.
  • PI3Ks are enzymes involved in phospholipid signalling and are activated in response to a variety of extra-cellular signals such as growth factors, mitogens, integhns (cell-cell interactions) hormones, cytokines, viruses and neurotransmitters and also by intra-cellular cross regulation by other signalling molecules (cross-talk, where the original signal can activate some parallel pathways that in a second step transmit signals to PI3Ks by intra-cellular signalling events), such as small GTPases, kinases or phosphatases for example.
  • extra-cellular signals such as growth factors, mitogens, integhns (cell-cell interactions) hormones, cytokines, viruses and neurotransmitters and also by intra-cellular cross regulation by other signalling molecules (cross-talk, where the original signal can activate some parallel pathways that in a second step transmit signals to PI3Ks by intra-cellular signalling events), such as small GTPases, kinases or phosphatases for example.
  • Phosphatidylinositol is the basic building block for the intracellular inositol lipids in eukaryotic cells, consisting of D-myo-inositol-1 -phosphate (Insi P) linked via its phosphate group to diacylglycerol.
  • the inositol head group of Ptdlns has five free hydroxy groups and three of these are found to be phosphorylated in cells in different combinations.
  • Ptdlns and its phosphorylated derivatives are collectively referred as inositol phospholipids or phosphoinositides (PIs).
  • PIs all reside in membranes and are substrates for kinases, phosphatases and lipases.
  • PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring in three different substrates: phosphatidylinositol (Ptdlns), phosphatidylinositol-4- phosphate (PI(4)P) and phosphatidylinositol-4,5-biphosphate (PI(4,5)P2), respectively generating three lipid products, namely phosphatidylinositol 3- monophosphate (PI(3)P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P 2 ) and phosphatidylinositol 3,4,5-thsphosphate (PI(3,4,5)P3(see Scheme A below).
  • PI(3)P Phosphatidylinositol 3-monophosphate
  • Class I PI3Ks The preferred substrate for Class I PI3Ks is PI(4,5)P 2 .
  • Class Il PIKs have a strong prefererence for Ptdlns as substrate over PI(4)P and PI(4,5)P2
  • Class III PI3Ks can only use Ptdlns as substrate in vivo and are likely to be responsible for the generation of most PI(3)P in cells (Vanhaesebroeck et al., 2001, above).
  • the phosphoinositides intracellular signalling pathway begins with the binding of a signalling molecule (extracellular ligands, stimuli, receptor dimidiation, transactivation by heterologous receptor (e.g. receptor tyrosine kinase)) to a G-protein linked transmembrane receptor integrated into the plasma membrane resulting in the activation of PI3Ks.
  • a signalling molecule extracellular ligands, stimuli, receptor dimidiation, transactivation by heterologous receptor (e.g. receptor tyrosine kinase)
  • heterologous receptor e.g. receptor tyrosine kinase
  • PI3Ks convert the membrane phospholipid PI(4,5)P2 into PI(3,4,5)P3 which in turn can be further converted into another 3' phosphorylated form of phosphoinositides by 5'-specific phosphoinositide phosphatases, thus PI3K enzymatic activity results either directly or indirectly in the generation of two 3'-phosphoinositide sub-types that function as second messengers in intra-cellular signal transduction (Joker et ai, 2002, Cell MoI. Life Sci. 59(5) 761-79).
  • the role as second messengers of phosphorylated products of Ptdlns act is involved in a variety of signal transduction pathways, including those essential to cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes, vesicle trafficking and metabolic pathway ⁇ Stein, 2000, MoI. Med. Today 6(9) 347-57).
  • Chemotaxis the directed movement of cells toward a concentration gradient of chemical attractants, also called chemokines is involved in many important diseases such as inflammation/auto-immunity, neurodegeneration, angiogenesis, invasion/metastasis and wound healing (Wyman et ai, 2000, Immunol Today 21(6) 260-4 and Gerard et ai, 2001, Nat Immunol. 2(2) 108-15).
  • PI3-kinase activation is therefore believed to be involved in a range of cellular responses including cell growth, differentiation, migration and apoptosis ⁇ Parker et ai, 1995, Current Biology, 5, 577-99; Yao et ai, 1995, Science, 267, 2003-05).
  • PI3Ks appear to be involved in a number of aspects of leukocyte activation.
  • a p85-associated PI3-kinase activity has been shown to physically associate with the cytoplasmic domain of CD28, which is an important co-stimulatory molecule for the activation of T-cells in response to antigen.
  • CD28 interleukin-2
  • Fraser et ai an important T cell growth factor
  • PI3Ks Cellular processes in which PI3Ks play an essential role include suppression of apoptosis, reorganization of the actin skeleton, cardiac myocyte growth, glycogen synthase stimulation by insulin, TNF ⁇ -mediated neutrophil priming and superoxide generation, and leukocyte migration and adhesion to endothelial cells.
  • Class I PI3Ks e.g. Class IB isoform
  • PI3K ⁇ are dual-specific kinase enzymes, i.e. they display both lipid kinase activity (phosphorylation of phospho-inositides) as well as protein kinase activity, as they are able to induce the phosphorylation of other protein as substrates, including auto-phosphorylation as intra-molecular regulatory mechanism.
  • PI3K ⁇ relays inflammatory signals through various G(i)-coupled receptors (Laffargue et al., 2002, Immunity 16(3) 441-51) and its central to mast cell function, stimuli in context of leukocytes, immunology includes cytokines, chemokines, adenosines, antibodies, integhns, aggregation factors, growth factors, viruses or hormones for example ⁇ Lawlor et al., 2001, J. Cell. ScL, 114 (Pt 16) 2903-10).
  • thromboembolism is a major cause of a variety of pathological processes such as artherosclerosis, occlusion of vascular grafts, or acute restenosis after angioplasty Emilio Hirsch et al.The FASEB journal vol.15 September 2001 2019-2021 ). Also the severity of Secretagogue-lnduced Acute pancreatitis is reduced in Mice lacking PI3K ⁇ .pancreatic damage and neutrophil infiltration resulted significantly reduced in PI3K ⁇ " ⁇ compared to wild-type mice.
  • tissue mast cells are key regulators in allergy and inflammation and release histamine upon clustering of their IgE receptors.
  • researchers have demonstrated that murine mast cell responses are exacerbated in vitro and in vivo by autocrine signals, and require functional PI3K gamma.
  • Adenosine acting through the A(3) adenosine receptor, as well as other agonists of G(alpha i)-coupled receptors, transiently increased Ptdlns(3,4,5) P (3) exclusively via PI3K ⁇ (Wymann MP et al. Biochem Soc Trans. 2003 Feb;31 (Pt 1 ):275-80.).
  • PI3K ⁇ gene deletion or pharmacologic inhibition of PI3K ⁇ leads to perturbations of critical innate immune responses of the lung to challenge with S. pneumoniae. These data are of clinical relevance for the treatment of chronic inflammatory diseases where pharmacologic inhibition of PI3K ⁇ signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.
  • PI3K ⁇ Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions. Capillahzation and arteriogenesis were reduced in PI3K ⁇ (" ⁇ ) ischemic muscles resulting in delayed reperfusion compared with WT, whereas reparative neovascularization was preserved in PI3K ⁇ (kDa/kDa). In PI3K ⁇ (" ⁇ ) muscles, endothelial cell proliferation was reduced, apoptosis was increased, and interstitial space was infiltrated with leukocytes but lacked cKit(+) progenitor cells that in WT muscles typically surrounded arterioles.
  • PI3Kgamma is constitutively expressed by WT EPCs, with expression levels being upregulated by hypoxia.
  • PI3Kgamma(-/-) EPCs showed a defect in proliferation, survival, integration into endothelial networks, and migration toward SDF-1.
  • the dysfunctional phenotype was associated with nuclear constraining of FOXO1 , reduced Akt and eNOS phosphorylation, and decreased nitric oxide (NO) production.
  • Pretreatment with an NO donor corrected the migratory defect of PI3K ⁇ (" ⁇ ) EPCs.
  • PI3K ⁇ (kDa/kDa) EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration consequently PI3K ⁇ modulates angiogenesis, artehogenesis, and vasculogenesis by mechanisms independent from its kinase activity (Paolo Madeddu et al. Artehoscler Thromb Vase Biol. 2007 Oct 25).
  • PI3-kinase inhibitors Two compounds, LY294002 and Wortmannin (cf.hereinafter), have been widely used as PI3-kinase inhibitors. These compounds are non-specific PI3K inhibitors, as they do not distinguish among the four members of Class I PI3- kinases.
  • IC 5 O values of Wortmannin against each of the various Class I PI3-kinases are in the range of 1 -10 nM and IC 5 O values for LY294002 against each of these PI3-kinases are about 15-20 ⁇ M (Fruman et al., 1998, Ann. Rev. Biochem.,
  • Wortmannin is a fungal metabolite which irreversibly inhibits PI3K activity by binding covalently to the catalytic domain of this enzyme. Inhibition of PI3K activity by Wortmannin eliminates the subsequent cellular response to the extracellular factor ⁇ Thelen et al., 1994, Proc. Natl. Acad. Sci. USA, 91, 4960- 64).
  • PI3K activity in cells of hematopoietic lineage is involved in many of the non-memory immune response associated with acute and chronic inflammation.
  • PI3-kinase function is also required for some aspects of leukocyte signalling through G- protein coupled receptors (Thelen et ai, 1994, above).
  • Wortmannin and LY294002 block neutrophil migration and superoxide release.
  • PI3K inhibitors in general have been developed: thiazole derivatives (WO 2005/021519; and WO 04/078754), thiazolidine derivatives (WO 2004/007491 and WO 2004/056820) and quinazolinones derivatives (WO 03
  • Immunosuppressive agents are further useful in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. They are also useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias. It has been found that the compounds of the present invention are modulating PI3K inhibitor with improved pharmacological and/ or other properties.
  • the present invention preferably comprises compounds which are inhibitors of the PI3K receptor, especially having selectivity for the PI3K ⁇ receptor.
  • a PI3K ⁇ receptor selective inhibitor has advantages over current therapies and extends the therapeutic window of lymphocyte sequestration agents, allowing better tolerability with higher dosing and thus improving efficacy.
  • the inventions further relates to the use of compounds according to formula I in combination with immunomodulating agents for example Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281 , ASM981 , rapamycin, 40- O-(2-hydroxy)ethyl-rapamycin etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15-deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathiophne; basiliximab; beclometasone dipropionate; betamethasone; betamethas
  • CTLA41g or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists.
  • a preferred composition is with Cyclosporin A, FK506, rapamycin or 40-(2-hydroxy)ethyl-rapamycin and Fingolimod.
  • the compounds according to formula I and related formulae 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, stoechiometry 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 the person skilled in the art, using routine optimisation procedures.
  • ACN acetonithle
  • BINAP 2,2'-bis(disphenylphosphino)-1 ,1 '-binaphthalene
  • BOC tert-butoxy-carbonyl
  • CBZ carbobenzoxy
  • CDCI 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CH 3 CN acetonitrile
  • c-hex cyclohexane
  • DCC dicyclohexyl carbodiimide
  • DCM diichloromethane
  • DIC diisopropyl carbodiimide
  • DIEA diisopropylethyl-amine
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DMSO-d ⁇ deuterated dimethylsulfoxide
  • EDC 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide
  • the compounds according to formula I and related formulae of this invention may be prepared from readily available starting materials. If such starting materials are not commercially available they may be prepared by standard synthetic techniques. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of formula I and related formulae.
  • the compounds according to Formula (I) 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, stoechiometry of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Generally, the compounds according to the general
  • Formula (I) may be obtained by several processes using both solution-phase and/or solid-phase chemistry protocols. Examples of synthetic pathways for the preparation of compounds according to the general Formula (I) will be described. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures.
  • the compounds according to Formula (I) may be prepared following the synthetic pathways described in the general scheme 1.
  • L 1 , L 2 , L 3 , L 4 , L 5 are leaving groups.
  • the term leaving group preferably denotes Cl, Br, I or a reactively modified OH group.
  • a reactively modified OH group can be for example, an ester, an imidazolide, an aryloxy or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl- or p tolylsulfonyloxy).
  • the term leaving group can denote a reactively modified OH group that can be prepared in situ by reaction of the carboxylic acid with peptide coupling reagents such as HATU, EDC, PyBOP, DCC, TBTU, possibly in the presence of HOBt or N-hydroxysuccinimide.
  • L 1 is preferably chloride, bromide, iodide or triflate.
  • L 2 is preferably chloride or carboxylate (from anhydride or mixte anhydride).
  • L 3 is preferably chloride, bromide, iodide or triflate.
  • L 4 is preferably chloride, imidazoyl, thchloromethoxy or para-nitrophenyloxy.
  • L 5 is preferably chloride, trichloromethoxy or imidazoyl.
  • R denotes independently each other H, Ar, Het, OA or A
  • compounds of Formula (I) may be prepared from the corresponding derivatives of Formula (II), by a cross- coupling reaction such as a Suzuki type cross-coupling reaction.
  • Preferred conditions consist in the treatment of compounds of Formula (II) with a boronic acid or ester of Formula (RO) 2 B-R b wherein R is a branched or linear alkyl having 1 to 12 C-atoms and R b is as defined above, in presence of a base such as cesium fluoride and a catalyst such as PdCl2(PPh 3 ) 2 in a suitable solvent such as a mixture of dioxane and water at temperature between about 80 0 C and about 100 0 C.
  • a cross- coupling reaction such as a Suzuki type cross-coupling reaction.
  • Preferred conditions consist in the treatment of compounds of Formula (II) with a boronic acid or ester of Formula (RO) 2 B-R b wherein R is a branched or linear alkyl having 1 to 12 C-atom
  • Compounds of Formula (II) wherein, X is a carbonyl group and R a is as above defined may be prepared by a coupling reaction between the corresponding derivatives of Formula (III) with L 2 -X-R a wherein X is a carbonyl group, and R a is a group linked to X by a carbon atom.
  • Preferred conditions consist in the treatment of compounds of Formula (III) with an acyl chloride or an acyl anhydride in the presence of a base such as pyridine as solvent, with or without an additional suitable solvent such as DCM at temperature between about 0° to about 60 0 C.
  • Compounds of Formula (II) wherein X is a carbonyl group and R a is an amino group NR R may be prepared from compounds of Formula (V) wherein X is a carbonyl group, by treatment with an amine of Formula HNR R .
  • Compounds of Formula (V) wherein X is a carbonyl group may be prepared from compounds of Formula (III) by treatment with reagents of Formula L 5 -X-L 4 wherein L 4 and L 5 are as defined above.
  • An alternative pathway for the synthesis of compounds of Formula (I) from compounds of Formula (I I) consists in the preparation of boron ic acid derivatives of Formula (IV) wherein R 2 , R 3 are hydrogen or alkyl groups.
  • Preferred conditions consist in the treatment of compounds of Formula (II) with bis(pinacolato)diboron in presence of a base such as potassium acetate and a catalyst such as 1 ,1 '-bis(diphenylphosphino)ferrocenedichloro palladium(ll) in a suitable solvent such as DMSO at temperature between around 80 0 C to around 100°C.
  • a second step consists of the transformation of compounds of Formula (IV) in compounds of Formula (I) by a Suzuki type cross coupling reaction with derivatives of Formula L 3 -R b wherein L 3 and R b are as defined above.
  • Preferred conditions consist in the treatment of compounds of Formula (IV) with an aryl or heteroaryl bromide of Formula Br-R b in presence of a base such as cesium fluoride and a catalyst such as PdCI 2 (PPh 3 ) 2 in a suitable solvent such as a mixture of dioxane and water at temperature between around 80 0 C and around 100°C.
  • An alternative pathway for the synthesis of compounds of Formula (I) from compounds of Formula (III) consists to start with a cross-coupling reaction to give compounds of Formula (l-l).
  • Preferred conditions consist in the treatment of compounds of Formula (III) with a boronic acid or ester of Formula (RO) 2 B-
  • R b wherein R is a branched or linear alkyl having 1 to 12 C-atoms and R b is as defined above, in presence of a base such as cesium fluoride and a catalyst such as PdCl2(PPh 3 ) 2 in a suitable solvent such as a mixture of dioxane and water at temperature between around 80 0 C and around 100 0 C.
  • a base such as cesium fluoride
  • a catalyst such as PdCl2(PPh 3 ) 2
  • a suitable solvent such as a mixture of dioxane and water at temperature between around 80 0 C and around 100 0 C.
  • a second step consists in the transformation of compounds of Formula (l-l) in compounds of Formula (I) wherein, X is a carbonyl group and R a is as above defined (with the exception of R a is NR R , for which one the pathway described in the next paragraph is generally preferred), by treatment with a reagent of Formula L 2 - X-R a wherein L 2 is as above defined.
  • Preferred conditions consist in the treatment of compounds of Formula (l-l) with an acyl chloride in the presence of a base such as pyridine, with or without an additional suitable solvent such as DCM at temperature between around 0° to around 60 0 C.
  • Compounds of Formula (I) wherein X is a carbonyl group and R a is an amino group NR R may be prepared from compounds of Formula (Vl) wherein X is a carbonyl group and L 4 is as above defined, by treatment with an amine of Formula HNR R " .
  • Preferred conditions consist in the treatment of compounds of Formula (Vl) with an amine of Formula HNR R in a suitable solvent such as DMF at temperature between RT and around 100°C, in the presence of an additional base such as Et 3 N in case of salified amine of Formula HNR R .
  • Compounds of Formula (Vl) wherein X is a carbonyl group may be prepared from compounds of Formula (l-l) wherein by treatment with reagents of
  • Preferred conditions consist in the treatment of compounds of Formula (l-l) with 1 ,1 '- carbonyldiimidazole in a suitable solvent such as ACN at temperature between RT to around 60°C.
  • Compounds of Formula (III) and reagents of Formulae (RO) 2 B-R b , L 2 -X-R a , L 3 - R b , L 5 -X-L 4 and HNR R may be obtained either from commercial sources or they may be prepared from known compounds using procedures such as those described hereinafter in the examples, or conventional procedures, well known by one skilled in the art.
  • Compounds of Formulae (I), (II), (III) and (Vl) may be converted to alternative compounds of Formulae (I), (II), (III) and (Vl) respectively, using suitable interconversion procedures such as those described hereinafter in the examples, or conventional interconversion procedures, well known by one skilled in the art.
  • the pharmaceutically acceptable anionic salts of the compounds of Formula (I), which contain a basic center may be prepared in a conventional manner.
  • a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • the pharmaceutically acceptable cationic salts of the compounds of Formula (I), which contain an acidic center may be prepared in a conventional manner.
  • a solution of the free acid may be treated with a suitable base, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • salts can be prepared by mixing a solution of the acid with a solution of an alkali or earth alkali salt (such as sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired alkali or earth alkali salt of the compounds of formula (I) precipitates, or can be otherwise isolated by concentration and addition of a non-solvent. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • reaction times are generally between a few minutes and 14 days.
  • the reaction temperature is between about -30 0 C and about 140 0 C, normally between -10°C and 90 0 C, in particular between about 0°C and 70°C.
  • Compounds of the formula I and related formulae can furthermore be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino- protecting group instead of an H atom bonded to an N atom, in particular those which carry an R*-N group, in which R* denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR ** group, in which R ** denotes a hydroxyl-protecting group, instead of a -COOH group.
  • amino-protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1- 8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert- butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
  • Preferred amino-protecting groups are BOC and Mtr, furthermore
  • hydroxyl-protecting group is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • the nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1 -20, in particular 1 -10, carbon atoms.
  • hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
  • the compounds of the formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • strong inorganic acids such as hydrochloric acid, perchloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio
  • reaction temperatures for the cleavage are advantageously between about 0 and about 50 0 C, preferably between 15 and 30 0 C (room temperature).
  • the BOC, OtBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or pipehdine in DMF at 15- 30 0 C.
  • Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1 -10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as thchloroethylene, 1 ,2-dichloroethane, tetrachloromethane, trifluoro- methylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacet
  • Esters can be hydrolysed, for example, using HCI, H 2 SO 4 , or using LiOH,
  • Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60 0 C and +30°C.
  • an inert solvent such as dichloromethane or THF
  • a base such as triethylamine or pyridine
  • the formula I and related formulae also encompasses the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
  • pharmaceutically usable derivatives is taken to mean, for example, the salts of the compounds of the formula I and so-called prodrug compounds.
  • prodrug derivatives is taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds.
  • prodrug as of the compounds of formula I, refers to derivative compounds that are rapidly transformed in vivo to yield the parent compound of the formula I, as for example by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro- drugs as Novel Delivery Systems", VoI 14 of the A.C.S. Symposium Series,
  • esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York (1987). It is intended that these references, and any others cited throughout this specification, are incorporated herein by reference.
  • biodegradable polymer derivatives of the compounds according to the invention as described, for example, in Int. J. Pharm. 115, 61 -67 (1995).
  • the formula I and related formulae also encompasses mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 or 1 :1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • the invention also relates to compounds of Formula (I) wherein U, V, W, R 2 , R 3 are as above defined, R b is Ar or Het, X denotes CO, SO, SO 2 , CS or a bond, and wherein R a denotes perfluoroalkyl, A, NH-A, -NH-(CH 2 ) P -A, Ar, Het, Het-alkyl, or if X denotes a bond, also CO-Het, CO-N(H) 2-m (A) m , COOA, CO, CS, or if X denotes CO, SO, SO 2 , CS, also H.
  • R a denotes perfluoroalkyl, A, NH-A, -NH-(CH 2 ) P -A, Ar, Het, Het-alkyl, or if X denotes a bond, also CO-Het, CO-N(H) 2-m (A) m
  • Ar also denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or mono- substituted, disubstituted or trisubstituted by, Hal, CF 3 , OCF 3 , NO 2 , CN, perfluoroalkyl, A, OA, OH, NH 2 , COH, CONH 2 ,-NHCOA, -NHSO 2 A, -NHSO 2 - N(H) 2-m (A) m , N(H) 1-q A q COA, N(H) 1-q ASO 2 -N(H) 2-m (A) m , N(H) 1-q A q CON(H) 2- m (A) m , COOA, -SO 2 A, -SO 2 N(H) 2-m (A) m , -SO 2 Het, or SO 2 Het 2
  • U preferably denotes CR C or S
  • V preferably denotes C
  • W preferably denotes CR 1
  • R 2 and R 3 are preferably simultaneously H.
  • R 3 is preferably H or F, more preferably H.
  • R a preferably denotes Alkyl, Ar or Het, and more preferably one of the following groups: H, methyl, ethyl, CF 3 , NH 2 , COOEt, (CH 2 ) 2 CO 2 Et, (CH 2 ) 3 CO 2 Et, NH(CH2) 2 CO 2 Et, NH(CH 2 ) 3 CO 2 Et, NH(CH 2 ) 2 NHCOMe, NH(CH 2 )CONMe 2 , NH(CH 2 ) 2 COOtBu, NH(CH 2 ) 2 CO 2 Me, NH(CH 2 ) 3 OtBu,
  • R b preferably denotes Ar or Het, especially substituted or unsubstituted pyridine.
  • R b more particularly denotes a group of the following formula:
  • R x and R y are each independantly H, Ci-Ce Alkyl, d-Cs hydroxyalkyl, Het.
  • R x and R y together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring. More preferably R b denotes one of the following groups.
  • Alkyl preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1 ,1 -, 1 ,2- or 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1 ,1 -, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or
  • Cycloalkyl are cyclic alkyl containing 3 to 12 carbon atoms.
  • Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Cycloalkylalkylene preferably denotes cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene or cycloheptyl methylene.
  • Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
  • Perfluoroalkyl preferably denotes CF 3 .
  • Hal denotes Cl, Br, I, F and preferably F, Cl or Br.
  • Alkoxy is branched or linear and preferably denotes a group -O-(CH 2 ) n -CH 3 . Most preferably alkoxy is Methoxy or Ethoxy.
  • Carboxy denotes a group -COOH.
  • Carboxyalkyl denotes an ester group, preferably an alkyl ester, such as COOMe or COOEt.
  • Sulfonyl denotes a group -SO 2 - Het-alkyl denotes a branched or linear carbon chain having 1 to 6 carbon atoms and wherein 1 H atom is replaced by Het.
  • Alkylsulfonyl denotes a group -SO 2 -alkyl, preferably Methylsulfonyl or
  • Acyl denotes a group -C(O)R, wherein R can be A, Ar, Het as defined above.
  • R can be A, Ar, Het as defined above.
  • Acyl denotes acetyl (-C(O)CH 3 ).
  • Amino denotes the group -NR'R"where each R', R" is independently hydrogen, alkyl, Ar, Het or A. R and R " , together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring.
  • Amido refers to the group -C(O)NR 1 R" where each R', R" is independently hydrogen, a branched or linear alkyl having 1 to 12 C-atoms, Ar, Het or A, and where R and R " , together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered Het ring.
  • Ar denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, Hal, CF 3 , OCF 3 , NO 2 , CN, perfluoroalkyl, A, OA, OH, amino, CONH 2 ,- NHCOA, -NHSO 2 -N(H) 2-m (A) m , COOA, -SO 2 A, -SO 2 N(H) 2-m (A) m , -SO 2 Het
  • Ar is one of the following groups:
  • R 4 , R 5 denote independently each other Ar, Het, OA or A.
  • R 4 preferably denotes OA, -SO 2 NHA, -SO 2 N(A) 2 , or -SO 2 -A and R 5 is preferably OH 1 Cl Or CF 3 .
  • Ar is unsubtituted or
  • Het is preferably a 6 to 14 membered ring system and denotes, not withstanding further substitutions, for example, 2- or 3-furyl, 2- or 3-thienyl, 1 -,
  • 2- or 3-pyrrolyl 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-,
  • Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5- dihydro-2-, -3-, -A- or -5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-i -, -2-, -3-, -4- or -5-pyrrolyl, 2,5- dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-
  • R 4 and R 5 denote independently each other Ar, Het, OA or A.
  • R 4 preferably denotes OA, -SO 2 NHA, -SO 2 N(A) 2 , NHSO 2 A, Or -SO 2 -A and R 5 is preferably OH, Cl or CF 3 .
  • R a also denotes Ar or Het when V is N or U is CR c or CH.
  • X also denotes SO2.
  • R b denotes Het.
  • the invention provides compounds of formula
  • R a denotes Perfluoroalkyl, A, -NH-A, Het, R b denotes Ar, Het;
  • the invention provides compounds of formula I wherein R a denotes A, -NH-A, wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by OR 6 , N(R 6 ) 2 , Het, or denotes cycloalkyl, R b denotes Ar, Het;
  • the invention provides compounds of formula I wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H or Me;
  • the invention provides compounds of formula I wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino,wherein n and m are as defined above;
  • R a denotes Perfluoroalkyl, A, -N-A wherein A is a branched or linear alkyl having 1 to 5 C-atoms, wherein one or more, preferably 1 to 7 H-atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH, OA, -SO 2 -N(H) 2-m (A)m, -SO 2 -Het or NO 2 ,wherein n and m are as defined above;
  • the invention provides compounds of formula I wherein R a denotes methyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH, OMe, -SO 2 -NHMe and -SO 2 -NH- CH 2 -CH 2 -OH;
  • the invention provides compounds of formula l-a wherein R a denotes Perfluoroalkyl, A, -NHA, Het, R b denotes Ar, Het;
  • the invention provides compounds of formula Ia wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het;
  • the invention provides compounds of formula l-a wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H or Me;
  • the invention provides compounds of formula l-a wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalky
  • the invention provides compounds of formula l-a wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 5 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH,
  • the invention provides compounds of formula l-a wherein R a denotes methyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH, OMe, -SO 2 -NHMe and -SO 2 -NH-
  • the invention provides compounds of formula l-b wherein R a denotes Perfluoroalkyl, A, -NHA, Het, R b denotes Ar, Het;
  • the invention provides compounds of formula l-b wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het;
  • the invention provides compounds of formula l-b wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H;
  • the invention provides compounds of formula l-b wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino,wherein n amd m are as defined above;
  • the invention provides compounds of formula l-b wherein R a denotes Perfluoroalkyl, A, -NH-A, wherein A is a branched or linear alkyl having 1 to 5 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH,
  • the invention provides compounds of formula l-b wherein R a denotes methyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH, OMe, -SO 2 -NHMe and -SO 2 -NH- CH 2 -CH 2 -OH;
  • the invention provides compounds of formula l-c wherein R a denotes Perfluoroalkyl, A, -NHA, Het, R b denotes Ar, Het;
  • the invention provides compounds of formula l-d wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het;
  • the invention provides compounds of formula l-c wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H;
  • the invention provides compounds of formula l-c wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino,wherein n amd m are as defined above;
  • the invention provides compounds of formula l-c wherein R a denotes Perfluoroalkyl, A, -NH-A wherein A is a branched or linear alkyl having 1 to 5 C-atoms, wherein one or more, preferably 1 to 7 H- atoms may be replaced by OR 6 , Het, or denotes cycloalkyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 )n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH, OA, -SO 2 -N(H) 2-m (A)m, -SO 2 -Het or NO 2 ,wherein n amd m are as defined above;
  • the invention provides compounds of formula l-c wherein R a denotes methyl, R b denotes Ar, Het wherein Ar and Het may be unsubstituted or substituted by a group selected from (R 4 ) n and/or (R 5 ) n , wherein R 6 is H, wherein Ar is phenyl, Het is imidazolyl, pyridinyl, morpholino, wherein R 4 and/or R 5 are selected from OH, OMe, -SO 2 -NHMe and -SO 2 -NH- CH 2 -CH 2 -OH;
  • the starting materials can also be formed in situ so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
  • the starting compounds for the preparation of compounds of formula I and related formulae are generally known. If they are novel, they can, however, be prepared by methods known per se.
  • the reactions are preferably carried out in an inert solvent.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as thchloroethylene, 1 ,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or
  • the invention also relates to the preparation of the compounds of formula (I), (II), (Vl) and (V) and salts thereof, as described in scheme 2.
  • the invention relates, in particular, to the use of formula I and related formulae as defined above, as a medicament.
  • the invention relates, in particular, to the use of compounds of the formula I and related formulae as defined above, for the preparation of pharmaceutical formulation for the prevention and/or the treatment of multiple sclerosis, cancers and related disorders such as monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, acute myelotic leukaemia, chronic myelotic leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia, glioblastomas and breast carcinoma and colon carcinoma, tumour of the blood and immune system, tumours of the squamous epithelium, of the bladder, of the stomach, of the kidneys, of head and neck, of the oesophagus, of the cervix, of the thyroid, of the intestine, of the liver, of the brain, of the prostate, of the urogenital tract, of the lymphatic system, of the larynx and/or of the lung,
  • cancers and related disorders such as monocytic le
  • the said compounds of the formula I and related formulae can be used in their final non-salt form.
  • the present invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.
  • Pharmaceutically acceptable salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I and related formulae contains an acidic center, such as a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base-addition salt.
  • Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example sodium- or potassium methoxide and sodium or potassiumpropoxide, alkalihydhdes, such as sodium- or potassiumhydride; and various organic bases, such as pipehdine, diethanolamine and N-methyl-glutamine, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benethamine, diethylamine, piperazine and tromethamine.
  • the aluminium salts of the compounds of the formula I and related formulae are likewise included.
  • acid-addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoaryl-sulfonates, such as ethanesulfonate, toluenesulfonate and benzene-sulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoro-acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
  • organic and inorganic acids for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoary
  • pharmaceutically acceptable acid-addition salts of the compounds of the formula I and related formulae include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzene-sulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor-sulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclo-pentane-propionate, digluconate, dihydrogen-phosphate, dinitrobenzoate, dodecyl-sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluco-nate, glutamate, glycerophosphate, hemi-succinate, hemisulfate, heptanoate, hexanoate, hippurate, hydro-chloride,
  • the base salts of the compounds of the formula I and related formulae include aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium, magne-sium, manganese(lll), manganese(ll), potassium, sodium and zink salts, but this is not intended to represent a restriction.
  • Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N 1 N'- dibenzyl-ethylen-ediamine (benzathine), dicyclohexylamine, diethanol-amine, diethyl-amine, 2-diethyl-amino-ethanol, 2-dimethyl-amino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl-pipehdine, glucamine, glucosamine, histidine, hydrabamine, isopropyl-amine, lido-caine, lysine, meglumine (N-methyl-D-glucamine), morpholine, pipe
  • Compounds of the formula I and related formulae of the present invention which contain basic nitrogen-containing groups can be quaternised using agents such as (Ci-C 4 )-alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(Ci-C 4 )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Cio-Ci 8 )alkyl halides, for example decyl, do-decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl-(Ci-C 4 )alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds of the formula I can be prepared using such salts.
  • the above-mentioned pharmaceutical salts which are preferred include acetate, thfluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stea-rate, sulfate, subsalicylate, tartrate, thiomalate, tosylate and tro-meth-amine, but this is not intended to represent a restriction.
  • the acid-addition salts of basic compounds of the formula I and related formulae are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner.
  • the free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner.
  • the free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free base forms thereof.
  • the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N,N'-dibenzylethylenediannine, chloroprocaine, choline, diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base-addition salts of acidic compounds of the formula I and related formulae are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner.
  • the free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free acid forms thereof.
  • a compound of the formula I and related formulae contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the formula I also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di-phosphate, disodium and trihydrochloride, but this is not intended to represent a restriction.
  • the term "pharmaceutically acceptable salt” in the present connection is taken to mean an active ingredient which comprises a compound of the formula I and related formulae in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • the compounds of the formula I and related formulae can be chiral and can accordingly occur in various enantiomeric forms. They can therefore exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active resolving agent.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartahc acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N- benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids.
  • chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally dehvatised methacrylate polymers immobilised on silica gel).
  • optically active resolving agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally dehvatised methacrylate polymers immobilised on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
  • the invention furthermore relates to the use of compounds of formula I and related formulae in combination with at least one further medicament active ingredient, preferably medicaments used in the treatment of multiple sclerosis such as cladribine or another co-agent, such as interferon, e.g. pegylated or non-pegylated interferons, preferably interferon beta and/or with compounds improving vascular function or in combination with immunomodulating agents for example Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g.
  • multiple sclerosis such as cladribine or another co-agent, such as interferon, e.g. pegylated or non-pegylated interferons, preferably interferon beta and/or with compounds improving vascular function or in combination with immunomodulating agents for example Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs,
  • cyclosporin A cyclosporin G, FK-506, ABT- 281 , ASM981 , rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.
  • corticosteroids cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolate mofetil; 15-deoxyspergualine; diflucortolone valerate; difluprednate; Alclometasone dipropionate; amcinonide; amsacrine; asparaginase; azathioprine; basiliximab; beclometasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone phosphate sodique; betamethasone valerate; budesonide; captopril; chlormethine chlorhydrate; cladribine; clobet
  • CTLA41g or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including Selectin antagonists and VLA-4 antagonists.
  • a preferred composition is with Cyclosporin A, FK506, rapamycin or 40-(2-hydroxy)ethyl-rapamycin and Fingolimod.
  • These further medicaments, such as interferon beta may be administered concomitantly or sequentially, e.g. by subcutaneous, intramuscular or oral routes.
  • the invention furthermore relates to the use of compounds of formula I and related formulae in combination with at least one further medicament active ingredient, preferably medicaments used in the treatment of cancer wherein said antitumoral compounds are selected from those well known by the one skilled in the related art.
  • These compositions can be used as medicaments in human and veterinary medicine.
  • compositions can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit.
  • a unit can comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit.
  • Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • compositions adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water- in-oil liquid emulsions.
  • the active-ingredient component in the case of oral administration in the form of a tablet or capsule, can be combined with an oral, non- toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like.
  • an oral, non- toxic and pharmaceutically acceptable inert excipient such as, for example, ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol.
  • a flavour, preservative, dispersant and dye may likewise be present.
  • Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith.
  • Glidants and lubricants such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation.
  • a disintegrant or solubiliser such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica-ment after the capsule has been taken.
  • suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • the disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or dry- pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets.
  • a powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate.
  • a binder such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone
  • a dissolution retardant such as, for example, paraffin
  • an absorption accelerator such as, for example, a quaternary salt
  • an absorbant such as, for example, bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve.
  • a binder such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials
  • the powder mixture can be run through a tableting machine, giving lumps of nonuniform shape which are broken up to form granules.
  • the granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets.
  • the active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps.
  • a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
  • Oral liquids such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds.
  • Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle.
  • Suspensions can be for-mulated by dispersion of the compounds in a non-toxic vehicle.
  • Solubilisers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.
  • the dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules.
  • the formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
  • the compounds of the formula I and related formulae and salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for exam-pie, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the formula I and related formulae and the salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled to soluble polymers as targeted medicament carriers.
  • Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidophenol, polyhydroxyethylaspartamido- phenol or polyethylene oxide polylysine, substituted by palmitoyl radicals.
  • the compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyhc acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a medicament for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyhc acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient.
  • the active ingredient can be delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as topical ointment or cream.
  • the active ingredient can be employed either with a paraffinic or a water-miscible cream base.
  • the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or sus-pended in a suitable carrier, in particular an aqueous solvent.
  • compositions adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose.
  • suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
  • compositions adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insuf-flators.
  • compositions adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners.
  • the formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dhed (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.
  • Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
  • formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours.
  • a therapeutically effective amount of a compound of the formula I and related formulae and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet.
  • an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same.
  • An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
  • the present invention furthermore relates to a method for treating a subject suffering from a PI3K related disorder, comprising administering to said subject an effective amount of a compound of formula I and related formulae.
  • the present invention preferably relates to a method, wherein the PI3K associated disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer.
  • the present invention furthermore relates to a method of treating a subject suffering from an immunerogulatory abnomality, comprising administering to said subject a compound of formula I and related formulae in an amount that is effective for treating said immunoregulatory abnormality.
  • the present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma.
  • ALS amyotrophic lateral sclerosis
  • systemic lupus erythematosus chronic rheumatoid arthritis
  • type I diabetes mellitus inflammatory bowel disease
  • biliary cirrhosis uveitis
  • the present invention furthermore relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft-versus-host disease.
  • the present invention furthermore relates to a method wherein the immunoregulatory abnormality is selected from the group consisting of: transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, sebor
  • cancer diseases are associated with a tumor from the group of tumours of the squamous epithelium, of the bladder, of the stomach, of the kidneys, of head and neck, of the oesophagus, of the cervix, of the thyroid, of the intestine, of the liver, of the brain, of the prostate, of the urogenital tract, of the lymphatic system, of the stomach, of the larynx and/or of the lung.
  • tumour originates from the group of monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma and colon carcinoma or of the blood and immune system.
  • Preferred compounds of formula I and related formulae exhibit a IC 5 O for the binding to PI3K ⁇ of less than about 5 ⁇ M, preferably less than about 1 ⁇ M and even more preferred less than about 0,010 ⁇ M.
  • any individual compound of formula I and related formulae will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
  • Compounds of this invention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent.
  • the pharmaceutically acceptable acid addition salts of the compounds of formula I and related formulae which contain a basic center may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • Base addition salts may be obtained in an analogous manner by treating a solution of compound of formula I and related formulae, which contain an acid center, with a suitable base. Both types of salts may be formed or interconverted using ion-exchange resin techniques.
  • the compounds of invention have been named according the standards used in the program "ACD/Name Batch” from Advanced Chemistry Development Inc., ACD/Labs (7.00 Release). Product version: 7.10, build: 15 Sep 2003.
  • NMR Bruker DPX-300, using residual signal of deuterated solvent as internal reference.
  • HPLC Waters Alliance 2695, column Waters XBridge C8 3.5 ⁇ m 4.6x50 mm, conditions: solvent A (H 2 O with 0.1 % TFA), solvent B (ACN with 0.05% TFA), gradient 5% B to 100% B over 8 min, UV detection with PDA Water 996 (230-
  • the microwave chemistry is performed on a single mode microwave reactor EmrysTM Optimiser from Personal Chemistry.
  • Acetic anhydride (4.95 ml_, 52.4 mmol) was added to a solution of 2-amino-6- bromobenzothiazole (3.00 g, 13.2 mmol) in anhydrous pyridine (30 ml) at 0 0 C. The resulting mixture was stirred at RT for 48 hours. The reaction mixture was poured into water (300 ml_) and stirred for 30 minutes. Then the precipitate was washed with water (5x) and dried under reduced pressure to give the title compound as a white powder (3.44 g, 97%). HPLC, Rt: 3.3 min (purity: 99.1 %). UPLC/MS, M+(ESI): 270.1 and 272.1 , M-(ESI): 269.1 and 271.1.
  • Trifluoroacetic anhydride (24 ml_) was added slowly to a stirred suspension of 2-[(2Z)-5-bromo-2- ⁇ [(4-methyl phenyl )sulfonyl]imino ⁇ pyridin-1 (2H)-yl]acetamide (4.8 g, 12.5 mmol) in anhydrous DCM (60 ml_). After being refluxed for 3 hours, the reaction mixture was concentrated under reduced pressure and the resulting yellow solid was suspended in a saturated aqueous solution of sodium bicarbonate, stirred for 15 min and filtered off.
  • reaction mixture was cooled at RT and filtered, and then diluted with EtOAc (4-10 volumes compare to dioxane). The aqueous layer was removed. The organic layer was washed with brine and dried (MgSO 4 ), optionally treated with activated charcoal, and then the solvents were removed under reduced pressure. The residue was purified by precipitation from an adequate solvent mixture (usually MeOH with or without additional amount of DCM, Et 2 O or dioxane) or by flash chromatography on silica (using an adequate solvent mixture (such as cHex/EtOAc or DCM/MeOH) or by reverse chromatography (such as using AutoPrep system) to give the expected compound. Work-up B: for final compounds soluble in reaction mixture at RT.
  • the title compound (5) was obtained as an off-white powder (77 mg, 36%).
  • the title compound was prepared following procedure described in Method B (work-up C) starting from 4-bromo-1 -methyl-2-(methylsulfonyl)benzene.
  • the title compound (14) was obtained as a pale orange powder (13 mg, 23%).
  • the title compound was prepared following procedure described in Method A s t a r t i n g f r o m 2-amino-6-bromobenzothiazole and (3- methylsulfonylphenyl)boronic acid.
  • the reaction mixture was diluted with water and extracted with EtOAc (2x). The organic layers were combined and the solvents were removed under reduced pressure.
  • the crude was taken up with EtOAc and extracted with a 1 N aqueous solution of HCI (2x). The acidic aqueous layers were combined, basified until pH 12 with a 5N aqueous solution of NaOH and extracted with EtOAc (2x). The organic layers were combined, dried (MgSO 4 ) and the solvent was removed under reduced pressure.
  • Nicotinoyl chloride hydrochloride (178 mg, 1.00 mmol) was added to a solution of 6-[3-(methylsulfonyl)phenyl]-1 ,3-benzothiazol-2-amine (60 mg, 0.20 mmol) and pyridine (80 ⁇ l_, 1.00 mmol) in anhydrous DCM (2 ml_). The reaction mixture was stirred at RT for one hour. The reaction mixture was diluted with water and cyclohexane. The precipitate was filtered off. The residue was crystallized from DMSO to give the title compound (20) as a white powder (67 mg, 83%). HPLC, Rt: 3.3 min (purity: 98.9%). UPLC/MS, M+(ESI): 410.2, M- (ESI): 408.3.
  • Example 26 Formation of ⁇ /-[2-(1-isopropyl-1H-imidazol-4-yl)ethyl]- ⁇ /'- ⁇ 6- [3-(methylsulfonyl)phenyl]-1 ,3-benzothiazol-2-yl ⁇ urea (26)
  • Step 1) Formation of N- ⁇ 6-[3-(methylsulfonyl)phenyl]-1 ,3-benzothiazol-2-yl ⁇ - 1 H-imidazole- 1 -carboxamide
  • Example 30 Formation of N-[6-(3- ⁇ [(2-morpholin-4- ylethyl)amino]sulfonyl ⁇ phenyl)-1,3-benzothiazol-2-yl]acetamide (30) Step 1) Formation of 3-bromo-N-(2-morpholin-4-ylethyl)benzenesulfonamide
  • Step 2) Formation of N-[6-(4-chloro-3- ⁇ [(2- hydroxyethyl)amino]sulfonyl ⁇ phenyl)-1,3-benzothiazol-2-yl]acetamide
  • Step 1) Formation of 1-[(4,5-dibromo-2-thienyl)sulfonyl]piperidin-4-ol
  • a suspension of 4,5-dibromothiophene-2-sulfonyl chloride (10.0 g, 29.4 mmol) was prepared in anhydrous DCM (200 ml) and cooled at 0 0 C.
  • Et 3 N (20.4 ml_, 147 mmol) was added, followed by 4-hydroxypipehdine (5.94 g, 58.8 mmol). The resulting mixture was stirred at 0 0 C for one hour.
  • Step 1 Formation of 3-[(3-bromophenyl)thio]propan-1 -ol
  • 3-bromothiophenol 5.0 g, 26.4 mmol
  • 3-bromo-propan-1-ol 4.4 g, 31.6 mmol
  • cesium carbonate (17.2 g, 52.8 mmol) in anhydrous DMF (30 ml_) was heated at 50 0 C for 12 hours.
  • the solvent was removed under reduced pressure.
  • the residue was taken up with DCM and washed with water and brine.
  • the organic layer was dried (Na2SO 4 ) and the solvent was removed under reduced pressure to give the title compound as a pale yellow oil (6.4 g, 98%).
  • Step 1) Formation of 3-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide bis(3-aminopropane-1 ,2-diol) hydrochloride mixture
  • Step 2) Formation of N-[6-(3- ⁇ [(2,3-dihydroxypropyl)amino]sulfonyl ⁇ phenyl)- 1 ,3-benzothiazol-2-yl]acetamide
  • the title compound was prepared following procedure described in Example 23 Step 1 ), but starting from 3-bromobenzenesulfonyl chloride and 4- hydroxypipehdine. The title compound was obtained as a white powder.
  • Step 2) Formation of N-(6- ⁇ 3-[(4-hydroxypiperidin-1 -yl)sulfonyl]phenyl ⁇ -1 ,3- benzothiazol-2-yl)acetamide
  • Step 2 Formation of 2-[(3-bromophenyl)sulfonyl]ethanol m-Chloroperbenzoic acid (12.2 g, 70.7 mmol) was added to a solution of 2-[(3- bromophenyl)thio]ethanol (5.5 g, 23.5 mmol) in anhydrous DCM (75 ml_). The reaction mixture was stirred at RT for 5 hours. The solid formed was filtered and washed with cold DCM. The filtrate was washed with a 10% aqueous solution of NaOH, water and brine. The organic layer was dried (Na2SO 4 ) and the solvent was removed under reduced pressure.
  • Step 3 Formation of 3- ⁇ 2-[( ⁇ [2-(3-isopropyl-1,2,4-oxadiazol-5- yl)ethyl]amino ⁇ carbonyl)amino]-1,3-benzothiazol-6-yl ⁇ -N,N- dimethylbenzenesulfonamide
  • Step 1) Formation of tert-butyl N- ⁇ [(6-bromo-1 ,3-benzothiazol-2- yl)amino]carbonyl ⁇ -beta-alaninate
  • Step 2) Formation of tert-butyl N- ⁇ [(6- ⁇ 3-[(dimethylamino)sulfonyl]phenyl ⁇ -1,3- benzothiazol-2-yl)amino]carbonyl ⁇ -beta-alaninate
  • Step 2) Formation of N-[6-(4-hydroxy-3-methoxyphenyl)-1,3-benzothiazol-2- yl]-N-(2-morpholin-4-yl-2-oxoethyl)urea
  • Example 65 ⁇ /-(6- ⁇ 3-[(ethylamino)sulfonyl]phenyl ⁇ imidazo[1 ,2-a]pyridin- 2-yl)-2,2,2-trifluoroacetamide (65)
  • A/-(6-chloro-imidazo[1 ,2-b]pyndazin-2-yl)-2,2,2-trifluoro-acetamide (1.0 g, 3.78 mmol), (3-methylsulfonylphenyl)boronic acid (1.13 g, 5.67 mmol), dichlorobis(triphenylphosphine)palladiunn(ll) (270 mg, 0.38 mmol) and cesium fluoride (1.72 g, 11.3 mmol) were flushed with nitrogen in a sealed vial. Dioxane (20 ml_) and water (10 ml_) were then added and the reaction mixture was heated at 90 0 C for 3 hours.
  • Example 70 /V- ⁇ 6-[3-(methylsulfonyl)phenyl]imidazo[1 ,2-b]pyridazin-2- yl ⁇ acetamide (70)
  • the efficacy of compounds of the invention in inhibiting the PI3K induced-lipid phosphorylation may be tested in the following binding assay.
  • the assay combines the scintillation proximity assay technology (SPA, Amersham) with the capacity of neomycin (a polycationic antibiotic) to bind phospholipids with high affinity and specificity.
  • SPA scintillation proximity assay technology
  • neomycin a polycationic antibiotic
  • the Scintillation Proximity Assay is based on the properties of weakly emitting isotopes (such as 3H, 1251, 33P).
  • Coating SPA beads with neomycin allows the detection of phosphorylated lipid substrates after incubation with recombinant PI3K and radioactive ATP in the same well, by capturing the radioactive phospholipids to the SPA beads through their specific binding to neomycin.
  • the assay is further incubated at room temperature for 60 minutes with gentle agitation to allow binding of phospholipids to neomycin-SPA beads. After settle the neomycin-coated PVT SPA for ⁇ hours, radioactive Ptdlns(3)P is quantified by scintillation counting in a Wallac MicroBeta TM plate counter.
  • the efficacy of compounds of the invention in inhibiting the PI3K induced-lipid phosphorylation may be tested in the following binding assay.
  • the assay combines the scintillation proximity assay technology (SPA,
  • neomycin a polycationic antibiotic
  • the Scintillation Proximity Assay is based on the properties of weakly emitting isotopes (such as 3H, 1251, 33P). Coating SPA beads with neomycin allows the detection of phosphorylated lipid substrates after incubation with recombinant PI3K and radioactive ATP in the same well, by capturing the radioactive phospholipids to the SPA beads through their specific binding to neomycin.
  • the following assay components are added: 1) 10 ⁇ l of lipid micelles 2) 20 ⁇ l of Kinase buffer ([33P] ⁇ ATP75 ⁇ M/1 00 nCi, MgCI2 12.5mM, DTT 2.5mM, Na3VO4 250 ⁇ M in Hepes 40 mM, pH 7.4, CHAPS 0.125%, Sodium Cholate 0.25%) and 3) 10 ⁇ l (100ng) of Human recombinant GST-PI3gamma (in Hepes
  • the efficacy of compounds of the invention in inhibiting the PI3K induced-lipid phosphorylation may be tested in the following binding assay.
  • the assay combines the scintillation proximity assay technology (SPA, Amersham) with the capacity of neomycin (a polycationic antibiotic) to bind phospholipids with high affinity and specificity.
  • SPA scintillation proximity assay technology
  • neomycin a polycationic antibiotic
  • the Scintillation Proximity Assay is based on the properties of weakly emitting isotopes (such as 3H, 1251, 33P).
  • Coating SPA beads with neomycin allows the detection of phosphorylated lipid substrates after incubation with recombinant PI3K and radioactive ATP in the same well, by capturing the radioactive phospholipids to the SPA beads through their specific binding to neomycin.
  • the following assay components are added: 1) 10 ⁇ l of lipid micelles 2) 20 ⁇ l of Kinase buffer ([33P] ⁇ ATP175 ⁇ M/300 nCi, MgCI2 1 OmM, DTT 2.5mM, Na3VO4 250 ⁇ M, Sodium cholate 0.5% in Hepes 40 mM, pH 7.4) and 3) 10 ⁇ l (100ng) of
  • radioactive Ptdlns(3)P is quantified by scintillation counting in a Wallac MicroBeta TM plate counter.
  • Table I refers to the IC50 ( ⁇ M) with respect to PI3K, i.e. the amount necessary to achieve 50 % inhibition of said target. Said values show a considerable inhibitory potency of the compounds with regard to PI3K.
  • PI3K Alpha refers to the IC50 ( ⁇ M) with respect to PI3K, i.e. the amount necessary to achieve 50 % inhibition of said target. Said values show a considerable inhibitory potency of the compounds with regard to PI3K.
  • the efficacy of compounds of the invention in inhibiting the PI3K induced-lipid phosphorylation may be tested in the following binding assay.
  • the assay combines the scintillation proximity assay technology (SPA, Amersham) with the capacity of neomycin (a polycationic antibiotic) to bind phospholipids with high affinity and specificity.
  • SPA scintillation proximity assay technology
  • neomycin a polycationic antibiotic
  • the Scintillation Proximity Assay is based on the properties of weakly emitting isotopes (such as 3H, 1251, 33P).
  • Coating SPA beads with neomycin allows the detection of phosphorylated lipid substrates after incubation with recombinant PI3K and radioactive ATP in the same well, by capturing the radioactive phospholipids to the SPA beads through their specific binding to neomycin.
  • the following assay components are added: 1) 10 ⁇ l of lipid micelles 2) 20 ⁇ l of Kinase buffer ([33P] ⁇ ATP250 ⁇ M/300 nCi, MgCI2 25mM, DTT 2.5mM, Na3VO4 0.25mM in Hepes 40 mM, pH 7.4) and 3) 10 ⁇ l (100ng) of Human recombinant GST-PI3alpha (in Hepes 4OmM, pH 7.4, ethylenglycol 2.5%).
  • the reaction is stopped by addition of 200 ⁇ l of a solution containing 150 ⁇ g of neomycin-coated PVT SPA beads, ATP 6mM and EDTA 6mM in PBS.
  • the assay is further incubated at room temperature for 60 minutes with gentle agitation to allow binding of phospholipids to neomycin-SPA beads. After settle the neomycin-coated PVT
  • radioactive Ptdlns(3)P is quantified by scintillation counting in a Wallac MicroBeta TM plate counter.
  • Table I refers to the IC50 ( ⁇ M) with respect to PI3K, i.e. the amount necessary to achieve 50 % inhibition of said target. Said values show a considerable inhibitory potency of the compounds with regard to PI3K.

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Abstract

L'invention porte sur des composés de formule (I) pour la régulation d'une activité phosphoinositides 3-kinases et des maladies apparentées.
PCT/EP2009/055172 2008-04-30 2009-04-29 Composés bicycliques fusionnés et utilisations de ceux-ci comme inhibiteurs de p13k Ceased WO2009133127A1 (fr)

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US8729074B2 (en) 2009-03-20 2014-05-20 Amgen Inc. Inhibitors of PI3 kinase
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