WO2004009602A1 - Inhibiteurs de kinase sous forme de pyrazolopyrimidines - Google Patents

Inhibiteurs de kinase sous forme de pyrazolopyrimidines Download PDF

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WO2004009602A1
WO2004009602A1 PCT/US2003/022716 US0322716W WO2004009602A1 WO 2004009602 A1 WO2004009602 A1 WO 2004009602A1 US 0322716 W US0322716 W US 0322716W WO 2004009602 A1 WO2004009602 A1 WO 2004009602A1
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pyrazolo
mmol
methoxyphenyl
alkyl
nmr
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PCT/US2003/022716
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English (en)
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Matthew Lee Brown
Mui Cheung
Scott Howard Dickerson
Dulce Maria Garrido
Wendy Yoon Mills
Yasushi Miyazaki
Andrew James Peat
Jennifer Poole Peckham
Terrence L Smalley
Stephen Andrew Thomson
James Marvin Veal
Jayme Lyn Roark Wilson
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Smithkline Beecham Corporation
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Priority to AU2003261204A priority Critical patent/AU2003261204A1/en
Priority to EP03765825A priority patent/EP1551841A1/fr
Priority to JP2004523200A priority patent/JP2005536517A/ja
Publication of WO2004009602A1 publication Critical patent/WO2004009602A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates generally to inhibitors of the kinases, such as
  • the present invention provides compounds that are useful pharmacological agents for disease states that are mediated, for example alleviated, through the inhibition or antagonism, of protein kinases.
  • the present invention relates to compounds that demonstrate protein tyrosine kinase and/or protein serine/threonine kinase inhibition.
  • the protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function (Hanks, et al., Science, 1988, 241, 42-52). The loss of control over cellular regulation can often lead to aberrant cell function or death, often resulting in a disease state in the parent organism.
  • a partial list of such kinases includes ab1 , ATK , bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRafl , CSF1 R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK3, Hck, IGF-1 R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, TIE1, TIE2, TRK, Yes, and Zap70.
  • kinase therapy examples include, but should not be limited to: (1) inhibition of c-Src (Brickell, Critical Reviews in Oncogenesis 1992, 3, 401-46; Courtneidge, Seminars in Cancer Biology 1994, 5, 239-46), raf (Powis, Pharmacology Et Therapeutics 1994, 62, 57-95) and the cydin-dependent kinases (CDKs) 1 , 2 and 4 in cancer (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger, et al., Proceedings of the National Academy of Science USA 1995, 92, 2258-62), (3) inhibition of CDK5 and GSK3 kinases for Alzheimer's (Hosoi, et al., Journal of Biochemistry (Tokyo) 1995,
  • Inhibitors of certain kinases may also have utility in the treatment of diseases when the kinase is not misregulated, but is nonetheless essential for maintenance of the disease state. In this case, inhibition of the kinase activity would act either as a cure or palliative for these diseases.
  • many viruses such as human papiUoma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle (Vousden, FASEB Journal 1993, 7, 872-9). Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as though kinase inhibition, may disrupt the virus life cycle by preventing virus replication.
  • This same principle may be used to protect normal cells of the body from toxicity of cycle-specific chemotherapeutic agents (Stone, et al., Cancer Research 1996, 56, 3199-202; Kohn, et al., Journal of Cellular Biochemistry 1994, 54, 440-52).
  • GSK3 glycogen synthase kinase
  • GSK3 inhibits glycogen synthase by direct phosphorylation.
  • GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events.
  • Type II diabetes otherwise known as Non-Insulin Dependent Diabetes Mellitus (NIDDM)
  • NIDDM Non-Insulin Dependent Diabetes Mellitus
  • IIDDM Non-Insulin Dependent Diabetes Mellitus
  • Increased insulin levels are caused by increased secretion from the pancreatic beta cells in an attempt to overcome the insulin resistance.
  • the resulting hyperinsulinemia is associated with a variety of cardiovascular complications. As insulin resistance worsens, the demand on the pancreatic beta cells steadily increases until the pancreas can no longer provide adequate levels of insulin, thereby resulting in elevated levels of glucose in the blood.
  • diabetes causes impaired glucose transport into skeletal muscle and increased hepatic glucose production, in addition to inadequate insulin response.
  • the disorders and conditions associated with hyperglycemia and hyperlipidemia include cardiovascular disease, renal failure, and blindness.
  • GSK3 inhibition stimulates insulin-dependent processes and is consequently useful in the treatment of diseases and conditions, such as type II diabetes, that are mediated by GSK3 activity, or, more specifically, characterized by a need for the inhibition of GSK3.
  • GSK3 is a proline-directed serine/threonine kinase.
  • GSK3 mediated diseases or conditions include, without limitation, obesity, various CNS disorders such as Alzheimer's Disease, bipolar disorder, and schizophrenia, neurotraumatic injuries such as acute stroke, immune potentiation, baldness or hair loss, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, ischemia, brain trauma or injury, immunodeficiency, and cancer. See, for example, published PCT application WO 00/38675, the background of which is herein incorporated by reference " .
  • TIE tyrosine kinases containing Ig and EGF homology domains.
  • TIE is used to identify a class of receptor tyrosine kinases, which are exclusively expressed in vascular endothelial cells and early hemopoietic cells.
  • Angiopoieten 1 (Angl) a ligand for the endothelium-specific receptor tyrosine kinase TIE-2, is an angiogenic factor. See, Davis et al, Cell, 1996, 87:1 161-1 169; Partanen et al, Mol.
  • Ang1 and its receptor TIE-2 function in the later stages of vascular development, i.e., during vascular remodeling (remodeling refers to formation of a vascular lumen) and maturation. See, Yancopoulos et al., Cell, 1998, 93:661-664; Peters, K.G., Circ. Res., 1998, 83(3):342-3; Suri et ⁇ /., Cell, 87, 1 171-1 180 (1996).
  • TIE-2 would be expected to disrupt remodeling and maturation of new vasculature initiated by angiogenesis thereby disrupting the angiogenic process.
  • inhibition of TIE-2 should prevent tumor angiogenesis and serve to retard or eradicate tumor growth. Accordingly, a treatment for cancer or other disorders associated with inappropriate angiogenesis could be provided.
  • angiogenesis is defined as involving (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravisation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vii) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels.
  • Normal angiogenesis is activated during tissue growth, from embryonic development through maturity, and then enters a period of relative quiescence during adulthood.
  • angiogenesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate angiogenesis has been associated with several disease states including various retinopathies; ischemic disease; atherosclerosis; chronic inflammatory disorders; and cancer. The role of angiogenesis in disease states is discussed in Fan et al., Trends in Pharmacol Sci. 16:54-66; Shawver et al., DDT Vol. 2, No. 2 February 1997; Folkmann, 1995, Nature Medicine, 1 :27-31.
  • the growth of solid tumors has been shown to be angiogenesis dependent. See Folkmann, J., J. Nat'l. Cancer Inst, 1990, 82, 4-6. Consequently, the targeting of pro-angiogenic pathways in cancer treatment is a strategy being widely pursued in order to provide new therapeutics in these areas of great, unmet medical need.
  • the role of tyrosine kinases involved in angiogenesis and in the vascularization of solid tumors may prove useful in the creation of effective mediacaments.
  • the compounds of the present invention are believed useful is a variety of disease states, each of which may be characterized as mediated by inhibition or antagonism of protein kinases.
  • the present invention includes compounds of Formula (I)
  • A is H, alkyl, or aryl
  • R 1 is D 1 , D 2 , D 3 , D 4 , or D 5 ,
  • R 3 and R 4 are each independently H, alkyl, alkylsuifonyl, or -C(0)-(CH 2 )x-R 5 ,
  • R 5 is alkyl, acyl, alkoxy, -(0)-(CH 2 )x-(0)-alkyl, or -NR 6 R 7 ,
  • R 6 and R 7 are each independently H or alkyl, or 2004/009602
  • R 6 and R 7 combine to form a 5- or 6-membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted one or more times with alkyl, hydroxy, carboxy, acyl, alkoxy, or halogen,
  • R 3 and R 4 combine to form a 5- or 6-membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted one or more times with alkyl, hydroxy, carboxy, alkoxy, acyl, or halogen;
  • R 8 is alkyl, or -NR 9 R 10 ,
  • R 9 and R 10 are each independently selected from H, alkyl, or -(CH 2 )x-
  • R 6 and R 7 are each independently H or alkyl
  • R 6 and R 7 combine to form a 5- or 6-membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted one or more times with alkyl, hydroxy, carboxy, acyl, alkoxy, or halogen;
  • the dashed line represents an optional double bond
  • R 11 is -(CH 2 )x, the optional dashed double bond does not exist, and R 12 is alkylsuifonyl or -NR 13 R 14 ,
  • R 13 and R 14 are each independently selected from H, alkyl, - (CH 2 ) ⁇ -R 17 , where R 17 is alkoxy or -NR 15 R 16 ,
  • R 15 and R 16 are each independently H or alkyl
  • R 13 and R 14 combine to form a 5- or 6-membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted one or more times with alkyl or -(CH 2 )x-0H;
  • R 12 is -(CH)- C(0)-OH
  • R 17 is hydroxy, alkoxy, or -NR 18 R 19 ,
  • R 18 and R 19 are each independently selected from H, alkyl, -(CH2)x-R 20 ,
  • R 20 is alkylsuifonyl, hydroxy, aryl said aryl optionally substituted with hydroxy or alkoxy, heteroaryl, or -NR 21 R 22 , 2004/009602
  • R 21 and R 22 are each independently selected from H, acyl, alkyl,
  • R 21 and R 22 combine to form a 5- or 6-membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted with alkyl or -(CH 2 )x-0H;
  • R 18 and R 19 combine to form a 5- or 6-membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted with -(CH2)x-R 23 ,
  • R 23 is alkoxy, hydroxy, -C(0)-R 24 , where R 24 is a 5- or 6- membered ring optionally containing one or more heteroatoms and optionally containing one or more degrees of unsaturation, or -NR 25 R 26 , where R 25 and R 26 are each independently H or alkyl;
  • a 5- or 6- membered ring optionally containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, optionally fused with an additional 5- or 6- membered ring that optionally contains one or more heteroatoms and optionally contains one or more degrees of unsaturation,
  • ring or fused ring system may be optionally substituted one or more times with halogen, alkyl, haloalkyl, alkylsuifonyl, alkylthio, hydroxy, alkoxy, oxo, sulfonyl, sulfate ion, nitro, cyano, carboxy, al oxycarbonyl, aryl where said aryl may be optionally substituted with sulfamoyl, heteroaryl where said heteroaryl may be optionally substituted with alkyl, or -NR 27 R 28 , where R 27 and R 28 are each independently H, alkyl, acyl, alkoxy, alkoxycarbonyl, carboxy, or -(CH 2 )x-NR 29 R 30 , where R 29 and R 30 are each independently selected from H and alkyl,
  • R 27 and R 28 combine to form a 5- or 6- membered ring, optionally containing one or more additional heteroatoms, optionally containing one or more degrees of unsaturation, and optionally substituted one or more times with alkyl, hydroxy, carboxy, acyl, alkoxy, or halogen,
  • R 31 is hydroxy, alkoxy, haloalkyl, aryl optionally substituted with halogen, or -NR 27 R 28 , where R 27 and R 28 are as defined above;
  • x independently is 0, 1 , 2, or 3;
  • y independently is 0 or 1;
  • R 2 is phenyl, substituted one or more times with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or -NR 31 R 32 ,
  • R 31 and R 32 are each independently selected from H, alkyl, acyl, or -(CH ⁇ Jz-
  • R 33 is cycloalkyl
  • R 1 is D 5 . More preferably, D 5 is pyridyl. More preferably D 5 is 4-pyridyl.
  • R 2 is phenyl substituted with alkoxy. More preferably the alkoxy is methoxy. Preferably R 2 is
  • said alkyl is Ci-Ce alkyl.
  • the stereochemical configuration is cis.
  • stereochemical configuration is trans.
  • A is H.
  • A is alkyl. More preferably, A is G-ealkyl. More preferably A is selected from propyl or isopropyl.
  • Another aspect of the present invention includes a pharmaceutical composition that includes a therapeutically effective amount of a compound of the present invention.
  • the pharmaceutical composition further includes one or more pharmaceutically acceptable carrier(s), diluent(s), or excipient(s).
  • Another aspect of the present invention includes a method of treating a disorder in a mammal, where the disorder is characterized by misregulation of one or more protein kinase through the administration to said mammal a . therapeutically effective amount of a compound of the present invention.
  • the kinase is a serine/threosine kinase. More preferably the kinase is GSK3.
  • the kinase may be a tyrosine kinase. In such case, preferably the kinase is TIE2.
  • Another aspect of the present invention includes a compound of the present invention for use in therapy. Another aspect includes the use of a compound of the present invention in the preparation of a medicament for use in the treatment of a disorder characterized by misregulation of one or more protein kinase.
  • Another aspect of the present invention includes a method of treating type 2 diabetes, hyperlipidemia, obesity, CNS disorders, neurotraumatic injuries, immune potentiation, baldness or hair loss, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, ischemia, immunodeficiency, and cancer, through the administration to said mammal of a therapeutically effective amount of a compound of the present invention.
  • Another aspect of the present invention includes a method of treating type II diabetes, through the administration to said mammal therapeutically of effective amounts of a compound of the present invention and at least one additional anti- diabetic agent.
  • Another aspect of the present invention includes intermediates such as compounds of Formula (II): '
  • A is H, alkyl, or aryl
  • R a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or -NR b R c ,
  • R b and R c are each independently selected from H, alkyl, acyl, or -(CH2)z- R d ,
  • R d is cycloalkyl. Additionally, another aspect of the present invention includes compounds of formula (III)
  • A is H, alkyl, or aryl
  • R a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or -NR b R c , wherein R b and R c are each independently selected from H, alkyl, acyl, or -(CH2) Z
  • R d where z is O, 1 , or 2;
  • R d is cycloalkyl
  • Another aspect of the present invention includes compounds of formula (IV)
  • A is H, alkyl, or aryl
  • R a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or -NR b R c , wherein R b and R c are each independently selected from H, alkyl, acyl, or -(CH2)z- R d ,
  • R d is cycloalkyl
  • Another aspect of the present invention includes compounds of formula (V)
  • A is H, alkyl, or aryl
  • R a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or -NR b R c , wherein R b and R c are each independently selected from H, alkyl, acyl, or -(CH2)z R d ,
  • R d is cycloalkyl; and R e is H or -C(0)-(0)-C-(CH 3 ) 3 .
  • alkyl refers to a straight or branched chain hydrocarbon that may be optionally substituted, with multiple degrees of substitution being allowed.
  • Examples of “alkyl” include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl, isopropyl, and the like.
  • Cx-Cy alkyl refers to an alkyl group, as defined above, containing the specified number of carbon atoms.
  • alkylene refers to a straight or branched chain unsaturated aliphatic hydrocarbon radical that may be optionally substituted, with multiple degrees of substitution being allowed.
  • alkylene include, but are not limited to methylene, ethyiene, n-propylene, n-butylene, and the like.
  • aryl refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or naphthalene ring systems.
  • aryl groups include, but are not limited to phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substituted derivatives thereof.
  • aralkyl further refers to groups of -RaRb, where Ra is an alkylene as defined herein and Rb is an aryl as defined herein.
  • aralkyl groups include G-ealkylene-aryl, such as benzyl.
  • heteroaryl refers to a monocyclic aromatic ring system, or to a fused bicyclic aromatic ring system comprising two or more aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N- oxides and sulfur oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted, with multiple degrees of substitution being allowed.
  • heteroaryl groups used herein include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, and substituted versions thereof.
  • heteroarylkyl further refers to groups of -RaRb, where Ra is an alkylene as defined herein and Rb is a heteroaryl as defined herein.
  • acyl refers to the group -C(0)Ra, where Ra is H, alkyl, or aryl.
  • Non-limiting examples of “acyl” groups include formyl, acetyl, benzoyl, and the like.
  • alkoxy refers to the group -ORa, where Ra is alkyl as defined above.
  • Non-limiting examples of “alkoxy” groups include methoxy, ethoxy, and the like.
  • hydroxy refers to the group -OH.
  • carboxy refers to the group -COOH.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group, as defined herein, that is substituted with at least one halogen.
  • Non-limiting examples of “haloalkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and/or iodo.
  • haloalkyl should be interpreted to include such substituents as perfluoroalkyl and the like.
  • haloalkoxy refers to the group -ORa, where Ra is haloalkyl as defined above.
  • sulfonyl shall refer to the group -S(0)2-.
  • alkylsuifonyl refers to the group -S(0)2Ra, where Ra is alkyl as defined above.
  • alkylthio refers to the group -SRa, where Ra is alkyl as defined above.
  • sulfamoyl refers to a group -SO2-NH2.
  • carboxylate refers to the group -C(0)NH2.
  • carboxylate refers to the group -C(0)N(R a )2, where
  • Ra is alkyl or aryl as defined herein.
  • alkoxycarbonyl refers to the group -C(0)0Ra, where Ra is alkyl or aryl as defined herein.
  • the compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism.
  • polymorphs Such polymorphic forms (“polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure, or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics that are known in the art such as x- ray diffraction patterns, solubility, and melting point.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers, or enantiomerically or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds, as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • the present invention includes salts, solvates, and pharmaceutically functional derivatives of the compounds of the present invention.
  • Salts include addition salts, metal salts, or optionally alkylated ammonium salts. Examples of such salts include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, mandelic, benzoic, cinnamic, methane sulphonic, ethane sulphonic, picric, and the like. Further salts include lithium, sodium, potassium, magnesium, and the like. Reference is also made to Journal of Pharmaceutical Science, 1997, 66, 2, incorporated herein by reference, as relevant to salts.
  • solvate refers to a complex of variable stoichiometry formed by a solute or a salt or pharmaceutically functional derivative thereof and a solvent.
  • solvents for the purpose of the invention should not interfere with the biological activity of the solute.
  • solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
  • pharmaceutically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching pharmaceutically functional derivatives. While it is possible that compounds of the present invention may be administered as the raw chemical, preferably the compounds of the present invention are presented as an active ingredient within a pharmaceutical formulation, as are known in the art.
  • the present invention further includes a pharmaceutical formulation comprising a compound of the present invention, or salt, solvate, or functional derivative thereof together with one or more pharmaceutically acceptable carriers.
  • a pharmaceutical formulation comprising a compound of the present invention, or salt, solvate, or functional derivative thereof together with one or more pharmaceutically acceptable carriers.
  • other therapeutic and/or prophylactic ingredients may be included in the pharmaceutical formulation.
  • the compounds of the present invention may be combined with other agents, such as, without limitation, one or more other anti-diabetic agent such as insulin, alpha glucosidase inhibitors, biguanides, insulin secretagogues such as sulphonylureas, insulin senstizers such as thiazolidinediones, and/or dipeptidyl peptidase inhibitors.
  • Formulations of the present invention include those especially formulated for oral, buccal, parental, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration.
  • oral administration typically is preferred.
  • tablets, capsules, and caplets may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, and/or wetting agents.
  • binding agents include syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, or polyvinylpyrrolidone (PVP).
  • Non-limiting examples of fillers include, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol.
  • Non-limiting examples of lubricants include, for example, magnesium sterate, stearic acid, talc, polyethylene glycol or silica.
  • Non-limiting examples of disintegrants include, for example, potato starch or sodium starch glycollate.
  • a non-limiting example of a wetting agent includes sodium lauryl sulfate.
  • the tablets additionally may be coated according to methods known in the art.
  • the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs.
  • formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Liquid preparations may contain conventional additives.
  • Non-limiting examples of such additives include suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum sterate gel or hydrogenated edible fats.
  • emulsifying agents such as lecithin, sorbitan mono-oleate or acacia
  • non-aqueous vehicles which may include edible oils
  • preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid, may be incorporated into the preparation.
  • Such preparations may also be formulated as suppositories, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
  • formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.
  • the formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation, for example, subcutaneously or intramuscularly, or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials, such as an emulsion in an acceptable oil, ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials such as an emulsion in an acceptable oil, ion exchange resins, or as sparingly soluble derivatives, such as a sparingly soluble salt.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain certain amounts of a compound of the present invention depending on the condition being treated, the route of administration, and the age, weight and condition of the patient.
  • Preferred unit dosage formulations are those containing a predetermined dose, such as a daily dose, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • a "therapeutically effective amount" of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration. Therapeutic effectiveness ultimately will be at the discretion of the attendant physician or veterinarian.
  • An effective amount of a salt or solvate, or pharmaceutically functional derivative thereof, may be determined as a proportion of the effective amount of a compound of the present invention per se.
  • M molar
  • mM millimolar
  • i. v. intravenous
  • Hz Hertz
  • Tr retention time
  • RP reverse phase
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran
  • DCE dichloroethane
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • HOAc acetic acid
  • EDC ethylcarbodiimide hydrochloride
  • mCPBA metal-chloroperbenzoic acid
  • TIPS triisopropylsilyl
  • T BS t-butyldimethylsilyl
  • MS mass spectra
  • TUPAC names are included to further identify particular compounds of the present invention.
  • the IUPAC names stated herein should in no way limit the scope of the present invention.
  • the mixture was filtered and partitioned between methylene chloride and aqueous sodium bicarbonate to give the crude product.
  • the crude product was purified by silica gel chromatography (1 :3 ethyl acetate:hexanes) to give the product (60 mg, 35 %).
  • the mixture was filtered and partitioned between methylene chloride and aqueous sodium bicarbonate to give the crude product.
  • the crude product was purified by silica gel chromatography (1 :3 ethyl acetate:hexanes) to give the product (65 mg, 39 %).
  • Ethoxymethylenemalononitrile (1.12 g, 9.21 mmol) was added 1 to a solution of 3- ethoxyphenylhydrazine (1.40 g, 9.21 mmol) in 50 mL of absolute ethanol. The mixture was heated at reflux for 1 hour. A crystalline solid formed upon cooling to room temperature. The mixture was refrigerated overnight, filtered, and the crystals washed with hexane and dried under vacuum to give 1.20 g (57%) of pure product.
  • N.N-dimethylethylenediamine (3.40 mL; 31.10 mmol) was added to a solution of 4- cyanobenzenesulfonyl chloride (2.50 g; 12.40 mmol) in THF (25 mL) at RT. After 16h, saturated NaHC0 3 (100 mL) and ethylacetate (250 mL) were added. The organic layer was separated, dried over Na2S0 4 , filtered and concentrated to give the title compound (3.00 g; 96%).
  • Triethylamine (610 ⁇ L, 4.39 mmol) was added and the reaction was stirred at this temperature for 5 min and then warmed to RT. The mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (Na2S0 4 ) and concentrated, and the residue purified by silica gel flash chromatography (4% methanol in dichloromethane) to provide product as a yellow oil (112 mg, 34°/o yield).
  • Methoxyacetyl chloride (0.6 mL, 6.36 mmol) was added to a mixture of 4-(l ,3- dioxolan-2-yl)aniline (500 mg, 3.03 mmol) and pyridine (0.6 mL, 6.36 mmol) in diethyl ether (10 mL) at 0 °C. The reaction was stirred at this temperature for 20 min and then partitioned between ethyl acetate and satd. aq. NaHC0 3 .
  • the aqueous layer was extracted with ethyl acetate (1 x 50 mL) and the combined organics were dried (MgS04) and concentrated.
  • the crude product was purified by silica gel chromatography to provide the product as a red oil (3.49 g, 79%).
  • Nicotinaldehyde (0.031 mL, 0.33 mmol) and two drops of pyrrolidine were added to a suspension of 1 -(3-bromophenyl)-4-hydrazino-1 r/-pyrazolo[3,4-c(]pyrimidine hydrochloride (Intermediates Example B) (0.095 g, 0.28 mmol) in 15 mL of absolute ethanol. The mixture was heated at reflux for 3 hours. After cooling to room temperature, diethyl ether was added and the precipitated solid was collected by filtration and dried under vacuum to give 0.081 g (67%) of product as a white solid.
  • Nicotinaldehyde [1 -(2-methoxyphenyl)-1 /-pyrazolo[3,4-clpy ⁇ midin-4- yljhydrazone
  • the title compound was prepared according to the general procedure for nicotinaldehyde [l-(3-methylphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]hydrazone (Example 1) from ⁇ /-[3-(4-hydrazino-1 /-pyrazolo[3,4-d]pyrimidin-1 - yl)phenyl]benzamide hydrochloride (Intermediates Example G) (65 mg, 0.17 mmol) and isonicotinaldehyde (100 mg, 0.94 mmol) to give the product as a white solid (35 mg, 47o/o).
  • the title compound was prepared according to the general procedure for isonicotinaldehyde [1 -(2-methoxyphenyl-1 ⁇ -pyrazolo[3,4-d]pyrimidin-4-yl)hydrazone (Example 17) from 3-(4-hydrazino-1 f/-pyrazolo[3,4-d]pyrimidin-1 -yl)- ⁇ /-pentylaniline hydrochloride (Intermediates Example H) (42 mg, 0.12 mmol) and isonicotinaldehyde (50 mg, 0.47 mmol) to give impure product as a green solid. The crude product was purified by silica gel chromatography (3% methanol in methylene chloride) to give the pure product (21 mg, 44 %).
  • the title compound was prepared according to the general procedure for nicotinaldehyde [1 -(3-methylphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]hydrazone (Example 1) from ⁇ /-(cyclopropylmethyl)-3-(4-hydrazino-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)aniline hydrochloride (Intermediates Example I) (48 mg, 0.14 mmol) and isonicotinaldehyde (55 mg, 0.52 mmol) to give the product as a tan solid (37 mg, 69%).
  • the title compound was prepared according to the general procedure for nicotinaldehyde [1 -(3-methylphenyl)-1 r/-pyrazolo[3,4-d]pyrimidin-4-yl]hydrazone (Example 1) from 3-(4-h ⁇ drazino-1 /-pyrazolo[3,4-c(]pyrimidin-1 -yl)- ⁇ /-propylaniline hydrochloride (Intermediates Example J) (51 mg, 0.16 mmol) and isonicotinaldehyde (55 mg, 0.52 mmol) to give the product as a tan solid (41 mg, 69%).
  • the title compound was prepared according to the general procedure for nicotinaldehyde [1 -(3-methylphenyl)-1 H-pyrazolo[3,4-cdpyrimidin-4-yl]hydrazone (Example 1) from 3-(4-hydrazino-1 r/-pyrazolo[3,4-d]pyrimidin-1-yl)-/V- isobutylaniline hydrochloride (Intermediates Example K) (60 mg, 0.18 mmol) and isonicotinaldehyde (60 mg, 0.57 mmol) to give the product as a tan solid (44 mg, 63%).
  • Nicotinaldehyde (0.22 mL, 2.34 mmol) was added to a suspension of 4-hydrazino-1- (3-methoxyphenyl)-1 /-pyrazolo[3,4-d]pyrimidine (Intermediates Example T) (0.200 g, 0.78 mmol) in 10 mL of absolute ethanol. The mixture was heated at reflux for two hours. After cooling to room temperature the solid product was collected by filtration, washed with ethanol, and dried under vacuum to give 0.241 g (91%) of a white solid.
  • Trifluoroacetic acid (3 mL) was added to a suspension of tert-butyl 5- ⁇ (£)-[l-(3- methoxyphenyl-1 f/-pyrazolo[3,4-d]pyrimidin-4-yl)hydrazono]methyl ⁇ pyridin-2- ylcarbamate (Example 74) (0.070 g; 0.15 mmol) in C ⁇ 2CI2 (5 mL). The mixture was stirred at RT for 3 days then solvent removed to give the title compound (0.075 g) as a white solid (100o/o).
  • the title compound was prepared according to the general procedure for nicotinaldehyde [l-(3-methoxyphenyl)-1 /V-pyrazolo[3,4-Gflpyrimidin-4-yl]hydrazone (Example 72) from 4-hydrazino-1 -(3-methoxyphenyl)-1 /-pyrazolo[3,4-d]pyrimidine (Intermediates Example T) (100 mg, 0.39 mmol) and isonicotinaldehyde 1 -oxide (85 mg, 0.69 mmol) to give the product as a orange solid (127 mg, 90%).

Abstract

L'invention concerne des inhibiteurs de kinase et, plus particulièrement, de nouveaux composés de pyrazolopyrimidine.
PCT/US2003/022716 2002-07-23 2003-07-21 Inhibiteurs de kinase sous forme de pyrazolopyrimidines WO2004009602A1 (fr)

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EP03765825A EP1551841A1 (fr) 2002-07-23 2003-07-21 Inhibiteurs de kinase sous forme de pyrazolopyrimidines
JP2004523200A JP2005536517A (ja) 2002-07-23 2003-07-21 キナーゼインヒビターとしてのピラゾロピリミジン

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WO2006076455A2 (fr) * 2005-01-13 2006-07-20 Arena Pharmaceuticals, Inc. Procedes de preparation d'ethers de pyrazolo[3,4-d]pyrimidine
US7132426B2 (en) 2003-07-14 2006-11-07 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
EP2004649A2 (fr) * 2006-03-24 2008-12-24 The Feinstein Institute for Medical Research Inhibiteurs hydrazones phenoliques du facteur d'inhibition de la migration des macrophages
JP2009502801A (ja) * 2005-07-22 2009-01-29 サネシス ファーマシューティカルズ， インコーポレイテッド Ａｕｒｏｒａキナーゼインヒビターとして有用なピラゾロピリミジン
US7745446B2 (en) 2004-09-06 2010-06-29 Bayer Schering Pharma Aktiengesellschaft Pyrazolo[1,5-c]pyrimidines
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2287149A1 (fr) * 2009-08-20 2011-02-23 Max-Delbrück-Centrum Für Molekulare Medizin Activateurs de dégradation de protéine
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
CN104016985A (zh) * 2013-03-01 2014-09-03 华东理工大学 一种吡唑并嘧啶化合物及其用途
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
EP2655653B1 (fr) * 2010-12-20 2015-11-18 University College Cardiff Consultants Limited Procédés et composés pour détecter un cancer
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

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WO2001019829A2 (fr) * 1999-09-17 2001-03-22 Basf Aktiengesellschaft Pyrazolopyrimidines en tant qu'agents therapeutiques
WO2002050065A2 (fr) * 2000-12-21 2002-06-27 Vertex Pharmaceuticals Incorporated Composes de pyrazole presentant une grande utilite comme inhibiteurs de proteine kinase
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US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US7132426B2 (en) 2003-07-14 2006-11-07 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7625906B2 (en) 2003-07-14 2009-12-01 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7745446B2 (en) 2004-09-06 2010-06-29 Bayer Schering Pharma Aktiengesellschaft Pyrazolo[1,5-c]pyrimidines
EA013968B1 (ru) * 2005-01-13 2010-08-30 Арена Фармасьютикалз, Инк. СПОСОБЫ ПОЛУЧЕНИЯ ПИРАЗОЛО[3,4-d]ПИРИМИДИНОВЫХ ЭФИРОВ
US7425630B2 (en) 2005-01-13 2008-09-16 Arena Pharmaceuticals, Inc. Processes for preparing pyrazolo[3,4-d]pyrimidine ethers
WO2006076455A3 (fr) * 2005-01-13 2006-12-07 Arena Pharm Inc Procedes de preparation d'ethers de pyrazolo[3,4-d]pyrimidine
WO2006076455A2 (fr) * 2005-01-13 2006-07-20 Arena Pharmaceuticals, Inc. Procedes de preparation d'ethers de pyrazolo[3,4-d]pyrimidine
JP2009502801A (ja) * 2005-07-22 2009-01-29 サネシス ファーマシューティカルズ， インコーポレイテッド Ａｕｒｏｒａキナーゼインヒビターとして有用なピラゾロピリミジン
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
EP2004649B1 (fr) * 2006-03-24 2012-07-04 The Feinstein Institute for Medical Research Inhibiteurs hydrazones phenoliques du facteur d'inhibition de la migration des macrophages
US8193247B2 (en) 2006-03-24 2012-06-05 The Feinstein Institute For Medical Research Phenolic hydrazone macrophage migration inhibitory factor inhibitors
EP2004649A2 (fr) * 2006-03-24 2008-12-24 The Feinstein Institute for Medical Research Inhibiteurs hydrazones phenoliques du facteur d'inhibition de la migration des macrophages
US8742173B2 (en) 2006-03-24 2014-06-03 The Feinstein Institute For Medical Research Phenolic hydrazone macrophage migration inhibitory factor inhibitors
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
WO2011020883A1 (fr) * 2009-08-20 2011-02-24 Max-Delbrück-Centrum für Molekulare Medizin Agents renforçant la dégradation de protéines
EP2287149A1 (fr) * 2009-08-20 2011-02-23 Max-Delbrück-Centrum Für Molekulare Medizin Activateurs de dégradation de protéine
US9512066B2 (en) 2009-08-20 2016-12-06 Max-Delbruck-Centrum Fur Molekulare Medizin Enhancers of protein degradation
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
EP2655653B1 (fr) * 2010-12-20 2015-11-18 University College Cardiff Consultants Limited Procédés et composés pour détecter un cancer
CN104016985A (zh) * 2013-03-01 2014-09-03 华东理工大学 一种吡唑并嘧啶化合物及其用途
CN104016985B (zh) * 2013-03-01 2017-11-03 华东理工大学 一种吡唑并嘧啶化合物及其用途
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis

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