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EP1644365A2 - Composes se liant au site actif d'enzymes proteine kinases - Google Patents

Composes se liant au site actif d'enzymes proteine kinases

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Publication number
EP1644365A2
EP1644365A2 EP04743195A EP04743195A EP1644365A2 EP 1644365 A2 EP1644365 A2 EP 1644365A2 EP 04743195 A EP04743195 A EP 04743195A EP 04743195 A EP04743195 A EP 04743195A EP 1644365 A2 EP1644365 A2 EP 1644365A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
ethyl
hydroxy
benzyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04743195A
Other languages
German (de)
English (en)
Inventor
Veronique BioFocus Discovery Limited BIRAULT
John C. BioFocus Discovery Limited HARRIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galapagos NV
Original Assignee
Biofocus Discovery Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0315494.5A external-priority patent/GB0315494D0/en
Application filed by Biofocus Discovery Ltd filed Critical Biofocus Discovery Ltd
Publication of EP1644365A2 publication Critical patent/EP1644365A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a compound and a group of compounds capable of binding to the active site of protein kinase enzymes.
  • the invention relates to a compound and a group of compounds which are inhibitors of a serine/ threonine kinase more particularly Rho kinase (ROK, ROCK).
  • ROK Rho kinase
  • the invention relates to methods of treatment and use of the compounds in the manufacture of a medicament for application to a number of therapeutic indications including cardiovascular disease (coronary vasospasm, hypertensive disease, arteriosclerosis), stroke, cancer, erectile dysfunction, asthma, osteoporosis, glaucoma and AIDS.
  • the compounds can be used in screening programmes against protein kinases.
  • the invention also provides methods for making compounds and libraries that include these compounds.
  • Protein kinases are a family of enzymes that catalyse the phosphorylation of hydroxyl groups in proteins. Approximately 2% of the genes encoded by the human genome are predicted to encode protein kinases. The reversible phosphorylation of specific tyrosine, serine, or threonine residues on a target protein can dramatically alter its function in several ways including activating or inhibiting enzymatic activity; creating or blocking binding sites for other proteins; altering subcellular localisation or controlling protein stability. Consequently protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, differentiation and survival. Of the many different cellular functions know to require the actions of protein kinases, some represent targets for therapeutic intervention for certain disease states.
  • protein tyrosine kinases are known to have a significant role in the development of many disease states including diabetes, cancer and have also been linked to a wide variety of congenital syndromes.
  • Serine threonine kinases also represent a class of enzymes, inhibitors of which are likely to have relevance to the treatment of cancer, diabetes and a variety of inflammatory cardiovascular disorders and AIDS.
  • Modulation of protein kinase activity therefore represents an attractive area for the design of new therapeutic agents. Protein kinases therefore represent a targeted intervention point in the treatment of a wide range of diseases.
  • Rho kinases ROK ⁇
  • Rho family of small GTP binding proteins contains at least 10 members including Rho A-E and G, Rac 1 and 2, Cdc42, and TC10.
  • the effector domains of RhoA, RhoB, and RhoC have the same amino acid sequence appear to have similar intracellular targets.
  • Rho kinase operates as a primary downstream mediator of Rho and exists as two isoforms ⁇ (ROCK2) and ⁇ (ROCK1).
  • ROK has a catalytic (kinase) domain in its N-terminal domain, a coiled-coil domain in its middle portion, and a putative pleckstrin-homology (PH) domain in its C-terminal domain.
  • the Rho-binding domain of ROK is localized in the C-terminal portion of the coiled-coil domain and the binding the GTP-bound form of Rho results in enhancement of kinase activity.
  • myosin-binding subunit of yosin light-chain phosphatase ERM (ezrin, radixin, moesin); adducin; intermediate filament (vimentin); the Na + -H + -exchanger, and LIM-kinase.
  • Rho/Rho-kinase-mediated pathway plays an important role in the signal transduction initiated by many agonists, including angiotensin II, serotonin, thrombin, endothelin-1, norepinephrine, platelet-derived growth factor, ATP/ADP and extracellular nucleotides, and urotensin II.
  • ROK plays an important role in various cellular functions including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility and gene expression.
  • ROK inhibitor fasudil
  • Y-27632 compound The apparent contribution of ROK to the pathogenesis of certain disorders has highlighted this kinase as a target for therapeutic intervention in a number of disease areas.
  • the first generation ROK inhibitor, fasudil and the more recent Y-27632 compound has provided proof of concept in a variety of model systems.
  • Rho-kinase inhibitors have potential utility for the treatment of disorders caused by vascular smooth muscle hyper-constriction, including cerebral vasospasm, coronary vasospasm and hypertension.
  • the beneficial effects of fasudil in the inhibition of cerebral and coronary vasospasm have been documented and there is accumulating evidence that ROK is involved in the pathogenesis of such events.
  • ROK levels of expression and activity are significantly enhanced prior to development of symptoms in spontaneously hypertensive rats suggesting that this kinase is also involved in the pathogenesis of hypertension.
  • short-term administration of Y-27632 preferentially reduces systemic blood pressure in various models of systemic hypertension.
  • ROK has also been shown to be involved in endothelial contraction and enhancement of endothelial permeability which is thought to progress atherosclerosis.
  • the strategy of inhibiting ROK may also be useful for the treatment of other disorders associated with smooth muscle hyper-reactivity, such as bronchial asthma and glaucoma. Indeed, it has been recently demonstrated that ROK is involved in bronchial smooth muscle contraction and the regulation of aqueous humor outflow.
  • ROK is also thought to play a role in the negative regulation of bone marrow formation and that its inhibition may prove to be an appropriate new strategy for treatment of osteoporosis. Based upon rat model data, ROK inhibitors may also be useful for treatment of erectile dysfunction resulting from cavernosal smooth muscle relaxation. ROK inhibitors have also been implicated in treatment of AIDS through the proposed inhibition of HIV replication.
  • Inhibitors of this kinase have also been strongly implicated in the future treatment of cancer. It is known that constitutive activation of the Rho/ROK pathway contributes to the Ras transformation phenotype and mutations of Ras are thought to occur in as many as 25% of human tumours. Indeed pharmacological inhibition of ROK has been demonstrated to reduce both focus formation generated by Ras mutants and anchorage-independent growth in some colorectal cell lines. Evidence also exists to support a critical role for ROK in tumour cell invasion. To this end a ROK therapeutic has the potential for broad applicability to a wide range of cancer types.
  • the invention addresses or ameliorates at least one of the disadvantages of the prior art, or provides a useful alternative.
  • the invention provides a compound selected from the specific group of compounds that comprises or consists of compounds of formula (I) or (II):
  • RI and R2 are joined to form a ring system, wherein the ring is preferably a 5 to 7 membered ring optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen. More preferably, the ring is selected from 2-(2-hydroxy-ethyl)-piperidin-l-yl or 4-(2-hydroxy-ethyl)- piperazin-1-yl; 4-methyl-piperazin-l-yl; 4-pyridin-4-yl-piperazin-l-yl; 4- (2-dimethylamino-ethyl)-piperazin-l-yl; 4-(2-diethylamino-ethyl)- piperazin-1-yl; morpholin-4-yl; 4-(2-cyano-phenyl)-piperazin-l-yl; 4- methyl-[l,4]diazepan-l-yl; N-(2-dimethylamino-ethyl)-N-methyl-; 4-(3,4-
  • RI H
  • R2 is 2-pyridin-4-yl-ethyl; 3-chloro-benzyl; benzo[l,3]dioxol-4-ylmethyl; 4-sulfonamide-benzyl; benzyl; thiophen-2-ylmethyl; 1-phenyl-ethyl; 4-(4- amino-benzoylamino)-phenyl; 4-methoxy-benzyl; l-hydroxymethyl-2- methyl-propyl; 2-Pyridin-3-yl-ethyl; 4-phenoxy-phenyl; 4-fluoro-phenyl; 4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl; C1-C6 optionally substituted alkyl, preferably ethyl, propyl, 3-hydroxy-2,2-dimethyl-propyl, 3-hydroxy- propyl, 2-methoxy-ethyl, 2-hydroxy-ethyl, 2 ⁇ hydroxymethyl-3-methyl- butyl
  • R3 is benzofuran-2-yl; naphthalen-2-yl; 3-4-methoxy-phenyl; 4- thiomethyl-phenyl; benzothiophen-2-yl; 4-pyridyl; 4-methoxy-phenyl; quinolin-3-yl; benzo[l,3]dioxol-5-yl; 4-hydroxy-phenyl; 4- trifluoromethoxy-phenyl; 3-chloro-4-pyridyl; 3-4-5-methoxy-phenyl; 5- acetyl-thiophen-2-yl; 3-trifluoromethoxy-phenyl; 4-hydroxymethyl-phenyl; N-(4-Methoxy-phenyl)-benzamide-4-yl; 3-fluoro-4-chloro-phenyl; N-(2- Hydroxy-ethyl)-4- benzamide-4-yl; 3-hydroxy-phenyl; 3-acetylamino- phenyl; quinolin-7-
  • R4 and R5 are joined to form a ring system, wherein the ring is preferably 5 to 7 membered optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen. More preferably, the ring is selected from 2-(2-hydroxy-ethyl)-piperidin-l-yl or 4-(2-hydroxy-ethyl)-piperazin- 1-yl; 4-methyl-piperazin-l-yl; 4-pyridin-4-yl-piperazin-l-yl; 4-(2- dimethylamino-ethyl)-piperazin-l-yl; 4-(2-diethylamino-ethyl)-piperazin- 1-yl; morpholin-4-yl; 4-(2-cyano-phenyl)-piperazin-l-yl; 4-methyl-
  • R4 is H or Methyl
  • R5 is 3-hydroxy-phenyl; 3-hydroxybenzoyl; 4-bromo-benzyl; 4- methoxy benzyl; 2,5-hydroxybenzyl; 3-hydroxy-4 ⁇ methoxy-benzyl; 3- chloro-benzyl; 3-fluoro-4-chloro-benzyl; 3-amino-benzyl; 3- trifluoromethoxy-benzyl; 4-hydroxy-benzyl; 4-amino-benzyl; lH-Indol-6- yl; 3-hydroxy-benzyl; naphthalen-2-yl-methyl; benzo[l,3]dioxol-4- ylmethyl; 3,4-fluoro-benzyl; 3,4-chloro-benzyl; furan-3-yl-methyl; 4- methoxy-phenyl; 4-chloro-benzyl; 3-nitro-phenyl; 3,4-methoxy-phenyl; 3- bromo-phenyl; 4-chloro-phenyl; phen
  • R6 is 3-carbamoyl-phenyl; 4-hydroxy-phenyl; 4-amino-phenyl; 3-amino- phenyl; phenyl; lH-Indol-5-yl; 4-pyridyl; 3-hydoxy-phenyl;
  • R2 is 2-pyridin-4-yl-ethyl; thiophen-2-ylmethyl; 4-sulfonamide-benzyl; or 3-chloro-benzyl;
  • R3 is benzothiophen-2-yl; naphthalen-2-yl; 3-4-methoxy-phenyl; or 4- pyridyl; R4 is hydrogen;
  • R5 is 3-hydroxy-benzyl; 4-chloro-benzyl; naphthalen-2-yl-methyl; benzo[l,3]dioxol-4-ylmethyl; 3,4-fluoro-benzyl; 3,4-chloro-benzyl; or furan-3-yl-methyl; and
  • R6 is 3-carbamoyl-phenyl; 4-hydroxy-phenyl; or 4-pyridyl.
  • a compound according to an embodiment of the invention has the structure of a compound of Table A or B below.
  • the invention provides a method for making a compound according to a first aspect of the invention, which method comprises at least one step or a series of consecutive steps from the scheme defined herein below.
  • the invention provides a group of at least two compounds comprising or consisting of a set of structurally related compounds having a core chemical structure (scaffold) of a general formula selected from the group consisting of formula I or II.
  • an embodiment of a group of compounds according to the invention comprises compounds according to the first aspect of the invention, and said group of compounds has all or substantially all of the permitted substitutions represented by compounds therein.
  • the invention provides a method for making a group of compounds according to an aspect of the invention, which method comprises at least one step or a series of consecutive steps from the scheme defined herein below.
  • the invention provides an assay comprising a group of compounds, or one or more compounds according to the invention.
  • the invention provides use of an assay according to an embodiment of the invention for identifying a compound that has therapeutic affect.
  • the invention provides a pharmaceutical composition that comprises a compound according to an embodiment of the invention or a compound identified in an assay according to an embodiment of the invention.
  • the invention provides a compound according to an embodiment of the invention for use in therapy.
  • the invention provides use of a compound according to an embodiment of the invention in the manufacture of a medicament for treatment or prophylaxis of a condition characterised by abnormal kinase activity.
  • the invention provides use of a compound according to an embodiment of the invention in the manufacture of a medicament for treatment or prophylaxis of a condition selected from cardiovascular disease (coronary vasospasm, hypertensive disease, arteriosclerosis), stroke, cancer, erectile dysfunction, asthma, osteoporosis glaucoma and AIDS.
  • cardiovascular disease coronary vasospasm, hypertensive disease, arteriosclerosis
  • stroke cancer
  • erectile dysfunction asthma
  • asthma osteoporosis glaucoma
  • AIDS AIDS
  • the invention provides a method of treatment of a condition characterised by abnormal kinase activity that comprises administering a pharmaceutically effective amount of a compound according to an embodiment of the invention.
  • the invention provides a method of treatment of a condition selected from cardiovascular disease (coronary vasospasm, hypertensive disease, arteriosclerosis), stroke, cancer, erectile dysfunction, asthma, osteoporosis glaucoma and AIDS that comprises administering a pharmaceutically effective amount of a compound according to an embodiment of the invention.
  • cardiovascular disease coronary vasospasm, hypertensive disease, arteriosclerosis
  • stroke cancer
  • erectile dysfunction asthma
  • osteoporosis glaucoma osteoporosis glaucoma
  • AIDS a condition selected from cardiovascular disease (coronary vasospasm, hypertensive disease, arteriosclerosis), stroke, cancer, erectile dysfunction, asthma, osteoporosis glaucoma and AIDS that comprises administering a pharmaceutically effective amount of a compound according to an embodiment of the invention.
  • compositions suitable for administration typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • a compound according to an embodiment of the invention may be provided as a salt, preferably as a pharmaceutically acceptable salt of compounds of formula I or II.
  • pharmaceutically acceptable salts of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form salts.
  • Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; ⁇ /-methylglucosamine; ⁇ /-methylpiperazine; morpholine; ethylenediamine; ⁇ /-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
  • amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; ⁇ /-methylglucosamine; ⁇ /-methylpiperazine; morpholine;
  • Salts of compounds according to an embodiment of the invention may be prepared in a conventional manner using methods well known in the art.
  • Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.
  • a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation.
  • the compounds of this invention may also exist in solvated or hydrated forms.
  • the invention also extends to prodrug of a compound according to an embodiment of the invention such as an ester or amide thereof.
  • a prodrug is a compound that may be converted under physiological conditions or by solvolysis to a compound according to an embodiment of the invention or to a pharmaceutically acceptable salt of a compound according to an embodiment of the invention.
  • a prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
  • a compound for use according to the invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms.
  • a compound according to an embodiment of the invention may be in trans or cis form.
  • 2,5-Dibromopyrazine (A) can be aminated with amines.
  • the resultant compounds (B) can then be reacted with the boronic acids to yield the final compounds of formula (I).
  • 3-Amino-5-bromopyridine (C) can be subjected to a copper mediated N- arylation with boronic acids, and the resultant compounds (D) then subjected to Suzuki cross coupling reaction using further boronic acids to yield final compounds of formula (Ila).
  • compounds with the general structure (E) can be synthesised through a reductive amination. Functionalisation at C5 with the boronic acids yields final compounds with the general formula (lib).

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Abstract

La présente invention concerne un composé et un groupe de composés inhibiteurs de la Rho kinase (ROK, ROCK). Cette invention concerne également des méthodes de traitement et l'utilisation de ces composés dans la production d'un médicament présentant un certain nombre d'indications thérapeutiques parmi lesquelles figurent la maladie cardiovasculaire (vasospasme coronaire, affection hypertensive, artériosclérose), l'accident vasculaire cérébral, le cancer, la dysérection, l'asthme, l'ostéoporose, le glaucome et le SIDA. Ces composés peuvent être utilisés dans des programmes de criblage contre des protéine kinases. Ladite invention concerne également des procédés de production desdits composés ainsi que des bibliothèques comportant ces composés.
EP04743195A 2003-07-02 2004-07-01 Composes se liant au site actif d'enzymes proteine kinases Withdrawn EP1644365A2 (fr)

Applications Claiming Priority (3)

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GBGB0315494.5A GB0315494D0 (en) 2003-07-02 2003-07-02 Compounds which bind to the active site of protein kinase enzymes
GB0328497A GB2403721A (en) 2003-07-02 2003-12-09 Compounds which bind to the active site of protein kinase enzymes
PCT/GB2004/002849 WO2005003101A2 (fr) 2003-07-02 2004-07-01 Composes se liant au site actif d'enzymes proteine kinases

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Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004276251B2 (en) 2003-09-22 2008-02-07 Euro-Celtique S.A. Phenyl - carboxamide compounds useful for treating pain
ATE497949T1 (de) * 2003-12-03 2011-02-15 Ym Biosciences Australia Pty Tubulininhibitoren
MXPA06007326A (es) 2003-12-23 2007-01-26 Astex Therapeutics Ltd Derivados de pirazol como moduladores de proteina cinasa.
US20090196912A1 (en) * 2004-07-30 2009-08-06 Gpc Botech Ag Pyridinylamines
JP2008519814A (ja) * 2004-11-12 2008-06-12 ガラパゴス・ナムローゼ・フェンノートシャップ プロテインキナーゼ酵素の活性部位と結合する窒素複素環式芳香族化合物
GB0428082D0 (en) * 2004-12-22 2005-01-26 Welcome Trust The Ltd Therapeutic compounds
GB0428514D0 (en) * 2004-12-31 2005-02-09 Prosidion Ltd Compounds
GB0500226D0 (en) * 2005-01-07 2005-02-16 Biofocus Discovery Ltd Compounds which bind to the active site of protein kinase enzymes
MX2007008957A (es) 2005-01-25 2007-12-06 Synta Pharmaceuticals Corp Compuestos para usos relacionados a inflamacion de inmunidad.
EP1902032A1 (fr) 2005-06-22 2008-03-26 Astex Therapeutics Limited Composes pharmaceutiques
EP1933832A2 (fr) 2005-06-23 2008-06-25 Astex Therapeutics Limited Combinaisons pharmaceutiques comprenant des derives de pyrazole en tant que modulateurs de proteine kinase
JP5212101B2 (ja) * 2005-09-02 2013-06-19 アステラス製薬株式会社 新規化合物
ZA200804497B (en) 2005-12-22 2009-10-28 Alcon Res Ltd (Indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)-pyrazines for treating rho kinase-mediated diseases and conditions
US20080021217A1 (en) * 2006-07-20 2008-01-24 Allen Borchardt Heterocyclic inhibitors of rho kinase
TW200901998A (en) * 2007-03-06 2009-01-16 Astrazeneca Ab Novel 2-heteroaryl substituted benzothiophenes and benzofuranes
GB0704932D0 (en) 2007-03-14 2007-04-25 Astex Therapeutics Ltd Pharmaceutical compounds
KR20220151013A (ko) 2007-08-29 2022-11-11 센주 세이야꾸 가부시키가이샤 각막 내피 세포 접착 촉진제
EP2253618A1 (fr) * 2008-02-27 2010-11-24 Takeda Pharmaceutical Company Limited Composé contenant un cycle aromatique à 6 chaînons
US8268834B2 (en) * 2008-03-19 2012-09-18 Novartis Ag Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme
AU2009260628A1 (en) 2008-06-18 2009-12-23 Inspire Pharmaceuticals, Inc. Process for the preparation of Rho-kinase inhibitor compounds
US8410147B2 (en) 2008-06-26 2013-04-02 Inspire Pharmaceuticals, Inc. Method for treating diseases associated with alterations in cellular integrity using Rho kinase inhibitor compounds
US8193363B2 (en) 2008-08-29 2012-06-05 Astrazeneca Ab Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
DK2638149T3 (da) 2010-11-12 2019-08-12 Univ Georgetown Immortalisering af epitelceller og fremgangsmåder til anvendelse
US20120316182A1 (en) * 2011-06-10 2012-12-13 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
HUE041929T2 (hu) 2011-12-06 2019-06-28 Astellas Inst For Regenerative Medicine Eljárás szaruhártya endotél sejtek irányított differenciálására
JP6218229B2 (ja) 2011-12-28 2017-10-25 京都府公立大学法人 角膜内皮細胞の培養正常化
WO2014090692A1 (fr) * 2012-12-10 2014-06-19 F. Hoffmann-La Roche Ag Nouvelles phénylpyridines/pyrazines à deux cycles pour le traitement du cancer
CN104837842A (zh) * 2012-12-10 2015-08-12 霍夫曼-拉罗奇有限公司 新型二环苯基-吡啶/吡嗪用于治疗癌症
JP6548576B2 (ja) 2013-07-30 2019-07-24 京都府公立大学法人 角膜内皮細胞マーカー
WO2015041533A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut Association de rock et de la voie mapk
CA2927898C (fr) 2013-10-31 2021-11-16 Kyoto Prefectural Public University Corporation Medicament therapeutique pour des maladies associees a la mort cellulaire du reticulum endoplasmique dans l'endothelium de la cornee
RU2704984C1 (ru) 2013-11-27 2019-11-01 Киото Прифекчурал Паблик Юниверсити Корпорэйшн Применение ламинина в культуре клеток эндотелия роговицы
CA2953524A1 (fr) 2014-06-27 2015-12-30 The Regents Of The University Of California Cellules souches limbiques de mammiferes en culture, leurs methodes de production et leurs utilisations
WO2016161192A1 (fr) 2015-04-03 2016-10-06 Propagenix Inc. Prolifération ex vivo de cellules épithéliales
US10100285B2 (en) 2015-04-03 2018-10-16 Propagenix Inc. Ex vivo proliferation of epithelial cells
EP3892717A1 (fr) 2015-09-11 2021-10-13 Propagenix Inc. Prolifération de cellules épithéliales ex vivo
WO2017064119A1 (fr) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement de la non-perfusion des capillaires de la rétine
EP4088719A1 (fr) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Procédés et compositions pharmaceutiques pour le traitement de non-perfusion capillaire rétinienne
JP7008337B2 (ja) 2016-02-15 2022-02-10 京都府公立大学法人 ヒト機能性角膜内皮細胞およびその応用
JP7013213B2 (ja) * 2017-05-26 2022-01-31 日本化薬株式会社 ピラジン化合物
JP2019019124A (ja) * 2017-07-19 2019-02-07 日本化薬株式会社 ピラジン化合物
IT201800003040A1 (it) * 2018-02-26 2019-08-26 Univ Pisa Nuovi attivatori dell’enzima SIRT1 per il trattamento delle patologie cardiovascolari e cardiometaboliche
WO2020041065A1 (fr) 2018-08-20 2020-02-27 Propagenix Inc. Sphéroïdes de cellules épithéliales
EP3843845A4 (fr) 2018-08-29 2022-05-11 University Of Massachusetts Inhibition de protéines kinases pour traiter la maladie de friedreich
JPWO2020045642A1 (ja) 2018-08-31 2021-08-12 学校法人同志社 眼細胞を保存または培養するための組成物および方法
KR102797964B1 (ko) 2018-10-02 2025-04-22 학교법인 도시샤 각막 내피 세포를 보존하기 위한 방법 및 용기
UY38427A (es) 2018-10-26 2020-05-29 Novartis Ag Métodos y composiciones para terapia con células oculares
CA3173725A1 (fr) 2020-02-27 2021-09-02 Kyoto Prefectural Public University Corporation Cellule endotheliale corneenne fonctionnelle humaine, et application associee
EP4142879A1 (fr) 2020-04-27 2023-03-08 Novartis AG Procédés et compositions pour une thérapie cellulaire oculaire
KR20240005837A (ko) 2021-05-03 2024-01-12 아스텔라스 인스티튜트 포 리제너러티브 메디슨 성숙한 각막 내피 세포의 생성 방법
CA3235384A1 (fr) 2021-10-18 2023-04-27 Takahiro Ochiya Compositions et leurs procedes d'utilisation pour le traitement de la fibrose hepatique
AU2022369459A1 (en) 2021-10-22 2024-05-30 Evia Life Sciences Inc. Methods for making extracellular vesicles, and compositions and methods of use thereof
AU2022385051A1 (en) 2021-11-11 2024-06-20 Actualeyes Inc. Cryopreservation preparation for corneal endothelial cells and method for producing said cryopreservation preparation

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3892296B2 (ja) * 1999-09-10 2007-03-14 メルク エンド カムパニー インコーポレーテッド チロシンキナーゼ阻害薬
HUP0301117A3 (en) * 2000-02-17 2004-01-28 Amgen Inc Thousand Oaks Imidazole derivatives kinase inhibitors, their use, process for their preparation and pharmaceutical compositions containing them
EP1330452B1 (fr) * 2000-09-20 2008-11-26 Ortho-McNeil Pharmaceutical, Inc. Derives de pyrazine tenant lieu de modulateurs de tyrosine kinase
DE10123586A1 (de) * 2001-05-08 2002-11-28 Schering Ag 3,5-Diamino-1,2,4-triazole als Kinase Inhibitoren
US20030187026A1 (en) * 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
ATE381557T1 (de) * 2002-01-23 2008-01-15 Bayer Pharmaceuticals Corp Rho-kinase inhibitoren
CN100558715C (zh) * 2002-05-23 2009-11-11 西托匹亚有限公司 蛋白激酶抑制剂
US7304071B2 (en) * 2002-08-14 2007-12-04 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors and uses thereof
GB2400101A (en) * 2003-03-28 2004-10-06 Biofocus Discovery Ltd Compounds capable of binding to the active site of protein kinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005003101A2 *

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