WO2005003101A2 - Pyrazine and pyridine derivatives as rho kinase inhibitors - Google Patents

Pyrazine and pyridine derivatives as rho kinase inhibitors Download PDF

Info

Publication number
WO2005003101A2
WO2005003101A2 PCT/GB2004/002849 GB2004002849W WO2005003101A2 WO 2005003101 A2 WO2005003101 A2 WO 2005003101A2 GB 2004002849 W GB2004002849 W GB 2004002849W WO 2005003101 A2 WO2005003101 A2 WO 2005003101A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
ethyl
hydroxy
benzyl
methyl
Prior art date
Application number
PCT/GB2004/002849
Other languages
French (fr)
Other versions
WO2005003101A3 (en
Inventor
Veronique Birault
John C. Harris
Original Assignee
Biofocus Discovery Limited
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 Limited filed Critical Biofocus Discovery Limited
Priority to EP04743195A priority Critical patent/EP1644365A2/en
Priority to US10/561,914 priority patent/US20090163515A1/en
Priority to CA002530389A priority patent/CA2530389A1/en
Priority to JP2006518333A priority patent/JP2007516196A/en
Publication of WO2005003101A2 publication Critical patent/WO2005003101A2/en
Publication of WO2005003101A3 publication Critical patent/WO2005003101A3/en

Links

Classifications

    • 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).

Abstract

The present invention relates to a compound and a group of compounds of formula (I) and (II) with the definitions of R1 -R6 according to claim 1 which are inhibitors of Rho kinase (ROK, ROCK). In addition, 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.

Description

COMPOUNDS WHICH BIND TO THE ACTIVE SITE OF PROTEIN KINASE ENZYMES
The present invention relates to a compound and a group of compounds capable of binding to the active site of protein kinase enzymes. In particular, 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). In addition, 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.
The kinase gene family
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.
One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals across the membrane that, in turn, modulate biochemical pathways within the cell. Protein phosphorylation represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are highly regulated and often overlapping as evidenced by the existence of many protein kinases as well as phosphatases. It is currently believed that a number of disease states and/or disorders are a result of either aberrant activation or functional mutations in the molecular components of kinase cascades. In humans, 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.
Three potential mechanisms for inhibition of protein kinases have been identified thus far. These include a pseudo-substrate mechanism, an adenine mimetic mechanism and the locking of the enzyme into an inactive conformation by using surfaces other than the active site. The majority of inhibitors identified/designed to date act at the ATP-binding site. Such ATP-competitive inhibitors have demonstrated selectivity by virtue of their ability to target the more poorly conserved areas of the ATP-binding site.
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^
The 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 α (ROCK2) and β (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. Numerous substrates of this kinase have been identified: myosin-binding subunit of yosin light-chain phosphatase; ERM (ezrin, radixin, moesin); adducin; intermediate filament (vimentin); the Na+-H+-exchanger, and LIM-kinase.
The 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. Through the modulation of its target effectors/substrates ROK plays an important role in various cellular functions including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility and gene expression.
Therapeutic Potential of ROK inhibitors
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. Furthermore, short-term administration of Y-27632 preferentially reduces systemic blood pressure in various models of systemic hypertension.
By virtue of ROK's role in mediating a number of cellular functions perceived to be associated with the pathogenesis of arteriosclerosis, inhibitors of this kinase may also be useful for the treatment or prevention of various arteriosclerotic cardiovascular diseases, including angina pectoris, myocardial infarction, hypertensive vascular disease, stroke, heart failure, and arteriosclerosis obliterans. 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.
In summary the early generation ROK inhibitors have shown promising efficacy in a variety of disease areas. The development of further ROK inhibitors with improved activity, selectivity and pharmacokinetic profiles is therefore needed to fully exploit the clinical potential of this target.
The invention addresses or ameliorates at least one of the disadvantages of the prior art, or provides a useful alternative.
Thus, in a first aspect the invention provides a compound selected from the specific group of compounds that comprises or consists of compounds of formula (I) or (II):
Figure imgf000006_0001
(I) (π)
wherein:
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- dimethoxy-phenyl)-piperazin-l-yl; 4-pyridin-2-yl-piperazin-l-yl; 4-(2- hydroxy-ethyl)-piperazin-l-yl; 4-(furan-3-carbonyl)-piperazin-l-yl; 4-(2- pyrrolidin-l-yl-ethyl)-piperazin-l-yl; 2-(2-hydroxy-ethyl)-pyrrolidin-l-yl; or
RI is H; and
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, 1-hydroxymethyl-propyl, 2-morpholin-4-yl-ethyl, furan-2-yl-methyl; C3-C6 optionally substituted cycloalkyl preferably cyclohexane; 5 to 7 membered optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen, preferably piperazine ring, [l,4]diazepane or a pyrrolidine ring; R2 is optionally linked to the scaffold by a linker which includes 1 to 3 carbon atoms;
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-yl; 2-methoxy-5-isopropyl-phenyl; 3-hydroxymethyl- phenyl; 3-pyridyl; hex-1-enyl; 4-cyano-phenyl; thiophen-3-yl; 3-nitro- phenyl; 3-chloro-phenyl; 2-methoxy-phenyl; 4-isopropyl-phenyl;
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-
[l,4]diazepan-l-yl; N-(2-dimethylamino-ethyl)-N-methyl-; 4-(3,4- dimethoxy-phenyl)-piperazin-l-yl; 4-pyridin-2-yl-piperazin-l-yl; 4-(2- hydroxy-ethyl)-piperazin-l-yl; 4-(furan-3-carbonyl)-piperazin-l-yl; 4-(2- pyrrolidin-l-yl-ethyl)-piperazin-l-yl; 2-(2-hydroxy-ethyl)-pyrrolidin-l-yl; or
R4 is H or Methyl; and
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; phenyl; 3-chloro-phenyl; 2-naphtyl; pyridin-3-yl-methyl; pyridin-4-yl-methyl; quinolin-3-yl-methyl; 4- isopropyl-phenyl; 4-chloro-benzyl; 3,4-methoxy-benzyl; 3-fluoro-4-chloro- phenyl; 4-trifluoromethoxy-phenyl; 4-cyano-phenyl; 4-metoxy benzyl, 4- methoxy-3-hydroxy benzyl; pyridin-4-yl-ethyl; piperidine-1-carboxylic acid benzyl ester 3-yl-methyl ; cyclohexane-methyl; 4-chlorobenzoyl; pyrrolidine-2-yl-methyl; 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, 1- hydroxymethyl-propyl, 2-morpholin-4-yl-ethyl, furan-2-yl-methyl; C3-C8 optionally substituted cycloalkyl preferably cyclohexane; 5 to 7 membered optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen, preferably piperazine ring, [l,4]diazepane or a pyrrolidine ring; R5 is optionally linked to the scaffold by a linker which includes 1 to 3 carbon atoms;
R6 is 3-carbamoyl-phenyl; 4-hydroxy-phenyl; 4-amino-phenyl; 3-amino- phenyl; phenyl; lH-Indol-5-yl; 4-pyridyl; 3-hydoxy-phenyl;
Benzo[l,3]dioxol-5-yl; 3-(2-Hydroxy-ethylcarbamoyl)-phenyl; 3- hydroxymethyl-phenyl; 3-acetylamino-phenyl; 4-hydroxymethyl-phenyl; 3-(2-dimethylamino-ethylcarbamoyl)-phenyl; thiophene-3-yl; 3-pyridyl; 3,4-methoxy-phenyl; 6-Bromo-l-carboxylic acid tert-butyl ester-indol-2- yl; 3-(2-hydroxy-ethylcarbamoyl)-phenyl; 3-Methanesulfonylamino- phenyl; 3-trifluoromethoxy-phenyl; 4-hydroxymethyl-phenyl; 4- methanesulfonyl-phenyl; quinolin-3-yl; 5-methoxy-pyridin-3-yl;4- carbamoyl-phenyl; 4-acetylamino-phenyl; 4-Methylcarbamoyl-phenyl; 4- (2-Hydroxy-ethylcarbamoyl)-phenyl; quinolin-4-yl; quinolin-5-yl; isoquinoliπ-4-yl; lH-pyrazol-4-yl; 3-chloro-pyridin-4-yl; 3-methoxy- pyridin-5-yl; 4-methoxy-pyridin-5-yl; 2-methyl-pyridin-4-yl; benzothiophene-2-yl; 3-chloro-pyridine-4-yl; lH-pyrazol-3-yl; isoquinolin- 3-yl; 4-carbamoyl-phenyl; 4-carbamoyl-phenyl; 3-(2-Hydroxy- ethylcarbamoyl)-phenyl; More preferably, RI is hydrogen;
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.
Most preferably a compound according to an embodiment of the invention has the structure of a compound of Table A or B below.
Any known compound having a structural formula identical to any one of the compounds covered by the formulae of scaffolds and permitted substitutions described herein is hereby explicitly disclaimed per se.
In a second aspect 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.
In a third aspect 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.
Preferably, 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.
In a fourth aspect 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.
In a further aspect the invention provides an assay comprising a group of compounds, or one or more compounds according to the invention.
In a further aspect the invention provides use of an assay according to an embodiment of the invention for identifying a compound that has therapeutic affect.
In a further aspect 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.
In a further aspect the invention provides a compound according to an embodiment of the invention for use in therapy.
In a further aspect 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.
In a further aspect 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.
In a further aspect 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.
In a further aspect 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.
Compounds of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier. As used herein the language "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. Examples of 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.
Pharmaceutical 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. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, 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. In many cases, it will be preferable to include 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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.
For administration by inhalation, 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. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such 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. For transdermal administration, 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.
In one embodiment, 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. 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.
It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein 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. For any compound used in the method of the invention, 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. Such information can be used to more accurately determine useful doses in humans. 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.
The invention will now be described in detail with reference to specific examples of compounds and methods for their production.
Within this specification embodiments have been described in a way that enables a clear and concise specification to be written, but it will be appreciated that embodiments may be variously combined or separated without parting from the invention.
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. Examples of 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. Examples of 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. Such 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; Λ/-methylglucosamine; Λ/-methylpiperazine; morpholine; ethylenediamine; Λ/-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
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. Where a compound of the invention contains an acidic function, 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.
The invention will now be described in detail with reference to particular embodiments and examples of the invention. Within the following table activity is presented as +, ++, or ++ + representing active, more active and very active based on assays conducted at 1 - 100 μM. Table A
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0003
An embodiment of a compound according to the invention can be produced according to the following scheme.
General Scheme for synthesising compounds of formula (I)
Figure imgf000026_0001
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). General Procedures:
Typical example of compound of formula (B), as described in the general reaction scheme; (5-Bromo-pyrazin-2~yl)-(2-pyridin-4-yl-ethyl)-amine
Figure imgf000026_0002
To a solution of (A) in 3ml of n-butanol was added 0.61g of 2-pyridine-4- yl-ethylamine and 0.65 g of Hunigs base. The mixture was heated at 150°C in a microwave for 0.5 hr. The mixture was poured into dichloromethane. The organic phase was washed with water and brine before being dried on magnesium sulfate. The mixture was filtrate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using petroleum ether and ethyl acetate as a eluent.
XH (270MHz, CDCI3) 2.91-2.96 (2H, t, J 6.8), 3.62-3.70 (2H, m), 7.14-7.16 (2H, m), 7.64-7.65 (1H, d, J 1.2), 8.10-8.11 (1H, d, J 1.2), 8.52-8.55 (2H, m); HPLC 82%; m/z (ES) 279 [M+H]+.
General procedure for the synthesis of compounds of formula (1). To a solution of the required intermediates (B) in DMF (0.3mmol, 0.5ml) was added a solution of boronic acid in DMF (0.36mmol, 0.6ml) and 1.5M Na2CO3(aq.) solution (0.75mmol, 0.5ml) under nitrogen. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was added. The reaction was then heated at 80°C with agitation for 16h under nitrogen. The reaction mixtures were filtered and purified by preparative reverse phase HPLC or on silicagel by flash chromatography.
Typical example of compound of formula (I), (5-Benzo[b]thiophen-2-yl- pyrazin-2-yl)-(2-pyridin-4-yl-ethyl)-amine
Figure imgf000028_0001
A mixture of 138 g of benzothiophene-2-boronuc acid, 130 mg of (5- Bromo-pyrazin-2-yl)-(2-pyridin-4-yl-ethyl)-amine , 22 mg of palladium acetate and 37 mg of triphenylphosphine in 3 ml of DMF and 1.5 ml and 2M aqueous sodium carbonate solution was prepared at room temperature. The stirred mixture was heated at 100°C in a Discovery microwave CEM for 0.5 hr. The reaction mixture was filtered through celite, then diluted with water, extracted with ether. The ether extracts were dried over magnesium sulfate, then concentrated to dryness. The crude product was purified by flash chromatography using petroleum ether and ethyl actetate as a eluent.
XH (270MHz, CDCI3) 2.3(2H, t), 3.7 (2H, q), 4.95 (1H, bs), 7.15 (lH,s), 7.35 (2H, m), 7.45 (1H, m), 7.65 (1H, m), 7.75 (1H, m), 7.85(1H, m), 7.9 (1H, s), 8.55 (3H, m) ;HPLC 96.8%; m/z (ES) 333 [M + H]+.
Scheme for synthesising compounds of formula (II) - (Ha and lib ) Na
Figure imgf000029_0001
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). Alternatively, 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).
General Procedures:
Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(3-nitro-phenyl)-amine.
Figure imgf000029_0002
3-Amino-5-bromopyridine (3.11g, lδmmol), 3-nitrophenylboronic acid (6.28g, 36mmol), copper(II) acetate (1.63g, 9mmol), 4A" molecular sieves (3g) and pyridine (2.9 ml, 36mmol) in DCM (50ml) was stirred vigorously in an open top vessel for 18h. The reaction was filtered and the residue was washed with methanol. Si02 (10g) was added to the solution and concentrated in vacuo to dryness. The resultant solid was chromatographed (SiO2, 20%-50% EtOAc in hexane) to afford the desired product as a bright yellow solid. XH (270MHz, CDCI3) 6.08(1H, br.s, NH), 7.39-7.40(lH, m, r), 7.45-7.60(lH, m, Ar), 7.62(1H, s, Ar), 7.83-7.89(2H, m, Ar), 8.34-8.37 (2H, m, Ar); HPLC: Rt 2.06 (77.89%); m/z (ES): 294(100%, M+).
Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-phenyl-amine.
Figure imgf000030_0001
*H (250MHz, CDCI3) 5.87 (IH, br.s), 7.07-7.53 (6H, m), 8.16-8.24 (2H, m); HPLC 92%; m/z (ES) 249 [M+H]+.
Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(4-methoxy-phenyl)-amine .
Figure imgf000030_0002
*H (250MHz, CDCI3) 3.82 (3H, s) 5.61 (IH, br.s), 6.89-6.92 (2H, d, J 8.9) 7.07-7.11 (2H, d, J 8.9), 7.27-7.29 (IH, m) 8.06-8.11 (2H, m); HPLC 100%; m/z (ES) 279 [M+H]+. Typical example of compound of formula (D), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(4-chloro~phenyl)-amine .
Figure imgf000031_0002
XH (250MHz, CDCI3) 6.11 (IH, br.s), 7.02-7.06 (2H, d, J 8.8) 7.27-7.31 (2H, d, J 8.8), 7.48-7.50 (IH, m) 8.18-8.24 (2H, m); HPLC 90%; m/z (ES) 283 [M+H]+.
General procedure for the synthesis of compounds of formula (Ha). To a solution of the required intermediates (D) in DMF (0.3mmol, 0.5ml) was added under nitrogen a solution of boronic acid in DMF (0.36mmol, 0.6ml) and 1.5M Na2CO3(aq.) solution (0.75mmol, 0.5ml). Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4- dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was then added to reaction mixture under nitrogen. The reaction mixture was heated at 80°C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC or purified on silicagel by flash chromatography.
Typical example of compound of formula (Ila), as described in the general reaction scheme; [5-(4-methanesulphoylphenyl)pyridin-3-yl]-phenylamine
Figure imgf000031_0001
XH (250MHz, CDCI3) 3.86 (3H, s), 6.23-6.43 (6H, m) 7.63-7.71 (3H, m), 7.95-7.96 (2H, ), 8.33-8.34 (2H, m); HPLC 100%; m/z (ES) 325 [M+H]+.
Typical example of compound of formula (Ila), as described in the general reaction scheme; phenyl-(5-quinolin-3-yl-pyridin-3-yl)amine .
Figure imgf000032_0001
H (250MHz, CDCI3) 7.16-7.24 (3H, m), 7.38-7.44 (2H, m) 7.71-7.77 (IH, m), 7.7.86-7.93 (IH, m), 7.99-8.04 (2H, m), 8.24-8.27 (IH, m), 8.44-8.45 (IH, m), 8.53-8.56 (2H, m), 9.23-9.24 (IH, m); HPLC 98%; m/z (ES) 298 [M + H]+.
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(4-chloro-benzyl)-amine .
Figure imgf000032_0002
3-Amino-5-bromopyridine (2.04g, 13mmol), 4-chlorobenzaldehyde (1.83g, 13mmol) and sodium triacetoxyborohydride (3.86g, 18.2mmol) in DCM (40ml) was stirred at room temperature for 16h. The reaction was taken up in DCM. The solution was washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The resultant solid was recrystallised from hexane/DCM to afford the desired product as an off-white solid. XH (270MHz, CDCI3) 4.24-4.68(3H, m, NH, CH2), 6.98- 7.00(1H, m, Ar), 7.25-7.36(4H, m, Ar), 7.95-8.02(2H, m, Ar); HPLC: Rt 1.94 (98.70%); m/z (ES): 297(100%, M+).
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-furan~3-ylmethyl-amine.
Figure imgf000033_0001
XH (250MHz, CDCI3) 4.12-4.16 (3H, m), 6.39-6.40 (IH, m) 7.04-7.06 (IH, m), 7.42-7.43 (2H, m) 7.95-8.01 (2H, m); HPLC 98%; m/z (ES) 253 [M+H]+.
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-py din-3-yl)-(3,4-difluoro-benzyl)-amine .
Figure imgf000033_0002
XY\ (250MHz, CDCI3) 4.30-4.44 (3H, m), 6.97-7.20 (4H, m) 7.95-8.01 (2H, m); HPLC 95%; m/z (ES) 299 [M+H]+.
Typical example of compound of formula (E), as described in the general reaction scheme; (5-bromo-pyridin-3-yl)-(3,4-dichloro-benzyl)-amine .
Figure imgf000034_0001
XH (250MHz, CDCI3) 4.30-4.42 (3H, m), 6.97-6.98 (IH, m), 7.13-7.20 (IH, m), 7.39-7.47 (2H, m), 7.92-8.01 (2H, m); HPLC 75%; m/z (ES) 331 [M+H]+.
Typical example of compound of formula (E), as described in the general rea ctio n scheme; (5-bromo-pyridin -3-yl)-(3-hydroxy-benzyl)-amine.
Figure imgf000034_0002
XH (250MHz, CDCI3) 9.35 (IH, s), 7.84 (IH, s), 7.68 (IH, s), 7.04-7.00 (IH, m), 6.96-6.94 (IH, m), 6.74-6.71 (IH, m), 6.66-6.32 (2H, m), 6.54- 6.52 (IH, m), 4.12-4.11 (2H, m); LCMS 97%; m/z (CI) [M+H]+ 279.
General procedure for the synthesis of compounds of the formula (lib) To a solution of the required intermediates (E) in DMF (0.3mmol, 0.5ml) was added a solution of boronic acid in DMF (0.36mmol, 0.6ml) and 1.5M Na2CO3(aq.) solution (0.75mmol, 0.5ml). The reaction was performed under nitrogen. Two solutions of palladium acetate (95mg) and triphenylphosphine (335mg) in 1,4-dioxane (15ml) were freshly prepared and placed in a sonication bath for 2min. The palladium catalyst (0.3ml) was added to reaction mixture under nitrogen. The reaction mixture was heated at 80°C with agitation for 16h. The reaction mixtures were filtered and purified by preparative reverse phase HPLC or purified by flash chromatography on silicagel.
Typical example of compound of formula (lib), as described in the general reaction scheme; (5'-methoxy-[3,3']bipyridinyl-5-yl)-naphthalen-2- ylmethyl-amine.
Figure imgf000035_0001
l (250MHz, CDCI3) 3.83(3H, s), 4.66 (2H, s), 7.24-7.26 (IH, m) 7.40- 7.53 (4H, m), 7.79-7.89 (4H, m), 8.11-8.12 (IH, m), 8.34-8.42 (3H, m); HPLC 100%; m/z (ES) 342 [M + H]+.
Typical example of compound of formula (lib), as described in the general reaction scheme; naphthalen-2-ylmethyl-(5-pyrimidin-5-yl-pyridin-3-yl)- amine.
Figure imgf000035_0002
*H (250MHz, CDCI3) 4.72 (2H, s), 7.13-7.15 (IH, m) 7.62-7.68 (IH, m), 7.78-7.90 (2H, m), 8.20-8.22 (2H, m), 8.30-8.31 (2H, m),8.89 (2H, s), 9.08-9.09 (IH, m), 9.25 (IH, s); HPLC 100%; m/z (ES) 314 [M+H]+. Typical example of compound of formula (lib), as described in the general rea cti o n sche e; (5- (4 '-hydroxy -phenyl) -pyridin-3-yl) - (3-hydroxy- benzyl)~amine
Figure imgf000036_0001
X (250MHz, CDCI3) 9.46 (IH, s), 9.20 (IH, s), 7.83 (IH, s), 7.76-7.75 (IH, m), 7.28-7.26 (2H, m), 7.00-6.97 (IH, m), 6.88-6.87 (IH, m), 6.71- 6.65 (4H, m), 6.50-6.48 (IH, m), 6.40-6.37 (IH, m), 4.16-4.14 (2H, m); LCMS 97%; m/z (ES) [M+H] + 293.
Typical example of compound of formula (lib), as described in the general rea cti o n scheme; 3- [5- (3-Hydroxy-benzylamino) -pyridin -3-yl]-benzamide
Figure imgf000036_0002
*H (250MHz, CDCI3) 9.23 (IH, s), 7.99 (3H, s), 7.89-7.88 (IH, m), 7.78- 7.57 (IH, m), 7.64-7.62 (IH, m), 7.45-7.42 (IH, m), 7.35 (IH, s), 7.07- 7.01 (2H, m), 6.72-6.68 (2H, m), 6.53-6.50 (2H, m), 4.22-4.20 (2H, m); LCMS 99%; m/z (CI) [M+H]+ 320. Typical example of compound of formula (lib), as described in the general reaction scheme [3,4']Bipyridinyl-5-yl-(4-chloro-benzyl)-amine
Figure imgf000037_0001
H (250MHz, CDCI3) 8.80-8.78 (2H, m), 8.32 (IH, s), 8.22-8.21 (IH, m), 7.81-7.79 (2H, m), 7.60-7.55 (4H, m), 7.38-7.37 (IH, m), 6.95-6.92 (IH, m), 4.57-4.56 (2H, m); LCMS 100%; m/z (ES) [M+H]+ 296.
Other examples of compounds of general formula (I), (Ila) or (lib) prepared by the above procedures are recorded in Table B. Compounds were characterised by mass spectrometry using single quadrupole instrumentation with an electrospray source. Table B
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0001
It will be appreciated by those skilled in the art that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognise apparent modifications and variations that may be made without departing from the spirit of the invention. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.

Claims

A compound selected from the specific group of compounds that comprises or consists of compounds of formula (I) or (II):
Figure imgf000046_0001
(I) (π) wherein:
RI and R2 are joined to form a ring system; or
RI is H; and 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, eg including ethyl, propyl, 3-hydroxy-2,2-dimethyl-propyl, 3- hydroxy-propyl, 2-methoxy-ethyl, 2-hydroxy-ethyl, 2- hydroxymethyl-3-methyl-butyl, 1-hydroxymethyl-propyl, 2- morpholin-4-yl-ethyl, furan-2-yl-methyl; C3-C6 optionally substituted cycloalkyl eg including cyclohexane; 5 to 7 membered optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen, preferably piperazine ring, [l,4]diazepane or a pyrrolidine ring; R2 is optionally linked to the scaffold by a linker which includes 1 to 3 carbon atoms; 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-yl; 2-methoxy-5- isopropyl-phenyl; 3-hydroxymethyl-phenyl; 3-pyridyl; hex-1-enyl; 4-cyano-phenyl; thiophen-3-yl; 3-nitro-phenyl; 3-chloro-phenyl; 2- methoxy-phenyl; 4-isopropyl-phenyl;
R4 and R5 are joined to form a ring system; or
R4 is H or methyl; and R5 is 3-hydroxy-phenyl; 3-hydroxybenzoyl; 4-bromo-benzyl; 4-methoxybenzyl; 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; phenyl; 3-chloro-phenyl; 2-naphtyl; pyridin-3-yl-methyl; pyridin-4-yl-methyl; quinolin-3-yl-methyl; 4-isopropyl-phenyl; 4- chloro-benzyl; 3,4-methoxy-benzyl; 3-fluoro-4-chloro-phenyl; 4- trifluoromethoxy-phenyl; 4-cyano-phenyl; 4-metoxy benzyl, 4- methoxy-3-hydroxy benzyl; pyridin-4-yl-ethyl; piperidine-1- carboxylic acid benzyl ester 3-yl-methyl ; cyclohexane-methyl; 4- chlorobenzoyl; pyrrolidine-2-yl-methyl; C1-C6 optionally substituted alkyl, eg including ethyl, propyl, 3-hydroxy-2,2-dimethyl-propyl, 3- hydroxy-propyl, 2-methoxy-ethyl, 2-hydroxy-ethyl, 2- hydroxymethyl-3-methyl-butyl, 1-hydroxymethyl-propyl, 2- morpholin-4-yl-ethyl, furan-2-yl-methyl; C5-C7 optionally substituted cycloalkyl eg including cyclohexane; 5 to 7 membered optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen, eg including a piperazine ring, [l,4]diazepane or a pyrrolidine ring; and R5 is optionally linked to the scaffold by a linker which includes 1 to 3 carbon atoms;
R6 is 3-carbamoyl-phenyl; 4-hydroxy-phenyl; 4-amino-phenyl; 3- amino-phenyl; phenyl; lH-Indol-5-yl; 4-pyridyl; 3-hydoxy-phenyl; Benzo[l,3]dioxol-5-yl; 3-(2-Hydroxy-ethylcarbamoyl)-phenyl; 3- hydroxymethyl-phenyl; 3-acetylamino-phenyl; 4-hydroxymethyl- phenyl; 3-(2-dimethylamino-ethylcarbamoyl)-phenyl; thiophene-3- yl; 3-pyridyl; 3,4-methoxy-phenyl; 6-Bromo-l-carboxylic acid tert- butyl ester-indol-2-yl; 3-(2-hydroxy-ethylcarbamoyl)-phenyl; 3- Methanesulfonylamino-phenyl; 3-trifluoromethoxy-phenyl; 4- hydroxymethyl-phenyl; 4-methanesulfonyl-phenyl; quinolin-3-yl; 5- methoxy-pyridin-3-yl;4-carbamoyl-phenyl; 4-acetylamino-phenyl; 4-Methylcarbamoyl-phenyl; 4-(2-Hydroxy-ethylcarbamoyl)-phenyl; quinolin-4-yl; quinolin-5-yl; isoquinolin-4-yl; lH-pyrazol-4-yl; 3- chloro-pyridin-4-yl; 3-methoxy-pyridin-5-yl; 4-methoxy-pyridin-5- yl; or 2-methyl-pyridin-4-yl; benzothiophene-2-yl; 3-chloro- pyridine-4-yl; lH-pyrazol-3-yl; isoquinolin-3-yl; 4-carbamoyl- phenyl; 4-carbamoyl-phenyl; 3-(2-Hydroxy-ethylcarbamoyl)-phenyl.
2. A compound according to claim 1, wherein RI and R2 form a 5 to 7 membered ring optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen.
3. A compound according to claim 2 wherein 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-dimethoxy-phenyl)-piperazin-l-yl; 4-pyridin-2-yl-piperazin- 1-yl; 4-(2-hydroxy-ethyl)-piperazin-l-yl; 4-(furan-3-carbonyl)- piperazin-1-yl; 4-(2-pyrrolidin-l-yl-ethyl)-piperazin-l-yl; or 2-(2- hydroxy-ethyl)-pyrrolidin-l-yl.
4. A compound according to claim 1 wherein R4 and R5 form a 5 to 7 membered ring optionally substituted containing 1 to 3 heteroatoms selected from nitrogen and oxygen.
5. A compound according to claim 4 wherein 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-dimethoxy-phenyl)-piperazin-l-yl; 4-pyridin-2-yl-piperazin- 1-yl; 4-(2-hydroxy-ethyl)-piperazin-l-yl; 4-(furan-3-carbonyl)- piperazin-1-yl; 4-(2-pyrrolidin-l-yl-ethyl)-piperazin-l-yl; or 2-(2- hydroxy-ethyl)-pyrrolidin-l-yl.
6. A compound according to claim 1, wherein:
RI is hydrogen;
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.
7. A compound according to claim 1 that is selected from the group of compounds named in Table A or Table B.
8. A method for making a compound according to any one of claims 1 to 7, which method comprises at least one step or a series of consecutive steps from the scheme defined herein.
9. A group of two or more 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.
10. A group of two or more compounds according to claim 9 which comprises compounds according to any one of claims 1 to 7, and said group has all or substantially all of the permitted substitutions represented by compounds therein.
11. A method for making a group of compounds according to claim 10, which method comprises at least one step or a series of consecutive steps from the scheme defined herein.
12. An assay comprising a group of compounds according to claim 9, or one or more compounds according to any one of claims 1 to 7.
13. Use of an assay according to claim 12 for identifying a compound that has therapeutic affect.
14. A pharmaceutical composition that comprises a compound according to any one of claims 1 to 7 or a compound identified in an assay according to claim 12.
15. A compound according to any one of claims 1 to 7 for use in therapy.
16. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for treatment or prophylaxis of a condition characterised by abnormal kinase activity.
17. Use according to claim 16 wherein the medicament is 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.
18. A method of treatment of a condition characterised by abnormal kinase activity that comprises administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 7.
19. A method of treatment according to claim 18 wherein the condition is selected from cardiovascular disease (coronary vasospasm, hypertensive disease, arteriosclerosis), stroke, cancer, erectile dysfunction, asthma, osteoporosis, glaucoma and AIDS.
0. A compound, method of production, selection of compounds, assay, pharmaceutical composition, use or method of treatment substantially as described herein.
PCT/GB2004/002849 2003-07-02 2004-07-01 Pyrazine and pyridine derivatives as rho kinase inhibitors WO2005003101A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP04743195A EP1644365A2 (en) 2003-07-02 2004-07-01 Pyrazine and pyridine derivatives as rho kinase inhibitors
US10/561,914 US20090163515A1 (en) 2003-07-02 2004-07-01 Compounds Which Bind to the Active Site of Protein Kinase Enzymes
CA002530389A CA2530389A1 (en) 2003-07-02 2004-07-01 Pyrazine and pyridine derivatives as rho kinase inhibitors
JP2006518333A JP2007516196A (en) 2003-07-02 2004-07-01 Pyrazine and pyralidine derivatives as Rho kinase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0315494.5 2003-07-02
GBGB0315494.5A GB0315494D0 (en) 2003-07-02 2003-07-02 Compounds which bind to the active site of protein kinase enzymes
GB0328497.3 2003-12-09
GB0328497A GB2403721A (en) 2003-07-02 2003-12-09 Compounds which bind to the active site of protein kinase enzymes

Publications (2)

Publication Number Publication Date
WO2005003101A2 true WO2005003101A2 (en) 2005-01-13
WO2005003101A3 WO2005003101A3 (en) 2005-03-24

Family

ID=33566546

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/002849 WO2005003101A2 (en) 2003-07-02 2004-07-01 Pyrazine and pyridine derivatives as rho kinase inhibitors

Country Status (4)

Country Link
EP (1) EP1644365A2 (en)
JP (1) JP2007516196A (en)
CA (1) CA2530389A1 (en)
WO (1) WO2005003101A2 (en)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006010637A2 (en) * 2004-07-30 2006-02-02 Gpc Biotech Ag Pyridinylamines
WO2006051311A1 (en) * 2004-11-12 2006-05-18 Galapagos Nv Nitrogen heteroaromatic compounds which bind to the active site of protein kinase enzymes
WO2006067466A2 (en) * 2004-12-22 2006-06-29 The Wellcome Trust Limited Pyrazines and pyridines and derivatives thereof as therapeutic compounds
WO2006072792A2 (en) * 2005-01-07 2006-07-13 Galapagos Nv Compounds which bind to the active site of protein kinase enzymes
WO2007026920A2 (en) * 2005-09-02 2007-03-08 Astellas Pharma Inc. Amide derivatives as rock inhibitors
JP2007513093A (en) * 2003-12-03 2007-05-24 サイトピア・リサーチ・ピーティーワイ・リミテッド Tubulin inhibitor
WO2007076360A1 (en) * 2005-12-22 2007-07-05 Alcon Research, Ltd. (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)- pyrazines for treating rho kinase-mediated diseases and conditions
EP1848435A2 (en) * 2005-01-25 2007-10-31 Synta Pharmaceuticals Corporation Compounds for inflammation and immune-related uses
WO2008011560A2 (en) * 2006-07-20 2008-01-24 Mehmet Kahraman Benzothiophene inhibitors of rho kinase
WO2009028631A1 (en) 2007-08-29 2009-03-05 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
JP2010520276A (en) * 2007-03-06 2010-06-10 アストラゼネカ・アクチエボラーグ Novel 2-heteroaryl-substituted benzothiophenes and benzofurans 709
US7799807B2 (en) 2003-09-22 2010-09-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8158796B2 (en) 2008-06-18 2012-04-17 Inspire Pharmaceuticals, Inc. Process for the preparation of Rho-kinase inhibitor compounds
US8247576B2 (en) 2003-12-23 2012-08-21 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical 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
WO2013086236A2 (en) 2011-12-06 2013-06-13 Advanced Cell Technology, Inc. Method of directed differentiation producing corneal endothelial cells, compositions thereof, and uses thereof
WO2013100208A1 (en) 2011-12-28 2013-07-04 京都府公立大学法人 Normalization of culture of corneal endothelial cells
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
WO2014090692A1 (en) * 2012-12-10 2014-06-19 F. Hoffmann-La Roche Ag Novel bi-ring phenyl-pyridines/pyrazines for the treatment of cancer
US8846687B2 (en) 2008-03-19 2014-09-30 Novartis Ag Pyrazine compounds as PI3 kinase inhibitors
US20140309237A1 (en) * 2011-06-10 2014-10-16 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2015016371A1 (en) 2013-07-30 2015-02-05 京都府公立大学法人 Corneal endothelial cell marker
WO2015041533A1 (en) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut Rock in combination with mapk-pathway
WO2015064768A1 (en) 2013-10-31 2015-05-07 京都府公立大学法人 Therapeutic drug for diseases related to endoplasmic reticulum cell death in corneal endothelium
WO2015080297A1 (en) 2013-11-27 2015-06-04 Kyoto Prefectural Public University Corporation Application of laminin to corneal endothelial cell culture
CN104837842A (en) * 2012-12-10 2015-08-12 霍夫曼-拉罗奇有限公司 Novel bi-ring phenyl-pyridines/pyrazines for treatment of cancer
WO2015200920A1 (en) 2014-06-27 2015-12-30 The Regents Of The University Of California Cultured mammalian limbal stem cells, methods for generating the same, and uses thereof
US9309267B2 (en) 2008-08-29 2016-04-12 Astrazeneca Ab Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
WO2016161192A1 (en) 2015-04-03 2016-10-06 Propagenix Inc. Ex vivo proliferation of epithelial cells
WO2017064119A1 (en) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion
WO2017141926A1 (en) 2016-02-15 2017-08-24 Kyoto Prefectural Public University Corporation Human functional corneal endothelial cell and application thereof
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10066201B2 (en) 2015-09-11 2018-09-04 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10100285B2 (en) 2015-04-03 2018-10-16 Propagenix Inc. Ex vivo proliferation of epithelial cells
JP2018199664A (en) * 2017-05-26 2018-12-20 日本化薬株式会社 Pyrazine compound
IT201800003040A1 (en) * 2018-02-26 2019-08-26 Univ Pisa New activators of the SIRT1 enzyme for the treatment of cardiovascular and cardiometabolic diseases
EP3553168A1 (en) 2010-11-12 2019-10-16 Georgetown University Immortalization of epithelial cells and methods of use
WO2020041065A1 (en) 2018-08-20 2020-02-27 Propagenix Inc. Epithelial cell spheroids
WO2020045642A1 (en) 2018-08-31 2020-03-05 学校法人同志社 Composition and method for preserving or culturing ocular cells
WO2020047229A1 (en) 2018-08-29 2020-03-05 University Of Massachusetts Inhibition of protein kinases to treat friedreich ataxia
WO2020071438A1 (en) 2018-10-02 2020-04-09 学校法人同志社 Method and vessel for preserving corneal endothelial cells
WO2020084580A1 (en) 2018-10-26 2020-04-30 Novartis Ag Methods and compositions for ocular cell therapy
WO2021172554A1 (en) 2020-02-27 2021-09-02 京都府公立大学法人 Functional human corneal endothelial cells and application thereof
WO2021220132A1 (en) 2020-04-27 2021-11-04 Novartis Ag Methods and compositions for ocular cell therapy
WO2022235586A1 (en) 2021-05-03 2022-11-10 Astellas Institute For Regenerative Medicine Methods of generating mature corneal endothelial cells
EP4088719A1 (en) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion
WO2023067394A2 (en) 2021-10-22 2023-04-27 Evia Life Sciences Inc. Methods for making extracellular vesicles, and compositions and methods of use thereof
WO2023069949A1 (en) 2021-10-18 2023-04-27 Evia Life Sciences Inc. Compositions and methods of use thereof for treating liver fibrosis

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0428514D0 (en) * 2004-12-31 2005-02-09 Prosidion Ltd Compounds
WO2009107391A1 (en) * 2008-02-27 2009-09-03 武田薬品工業株式会社 Compound having 6-membered aromatic ring
JP2019019124A (en) * 2017-07-19 2019-02-07 日本化薬株式会社 Pyrazine compound

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017995A1 (en) * 1999-09-10 2001-03-15 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors
WO2002024681A2 (en) * 2000-09-20 2002-03-28 Ortho-Mcneil Pharmaceutical, Inc. Pyrazine derivatives as modulators of tyrosine kinases
WO2002094814A1 (en) * 2001-05-08 2002-11-28 Schering Aktiengesellschaft 3,5-diamino-1,2,4-triazoles as kinase inhibitors
WO2003051366A2 (en) * 2001-12-13 2003-06-26 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
WO2003062227A1 (en) * 2002-01-23 2003-07-31 Bayer Pharmaceuticals Corporation Rho-kinase inhibitors
WO2003099796A1 (en) * 2002-05-23 2003-12-04 Cytopia Pty Ltd Protein kinase inhibitors
WO2004016597A2 (en) * 2002-08-14 2004-02-26 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors and uses thereof
WO2004085409A2 (en) * 2003-03-28 2004-10-07 Biofocus Discovery Ltd Compounds and libraries of pyridines, pyrazines, imidazo[1,2-a]pyrazines and 1h-imidazo[4,5-b]pyrazin-2-ones and first and second medical uses thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017995A1 (en) * 1999-09-10 2001-03-15 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors
WO2002024681A2 (en) * 2000-09-20 2002-03-28 Ortho-Mcneil Pharmaceutical, Inc. Pyrazine derivatives as modulators of tyrosine kinases
WO2002094814A1 (en) * 2001-05-08 2002-11-28 Schering Aktiengesellschaft 3,5-diamino-1,2,4-triazoles as kinase inhibitors
WO2003051366A2 (en) * 2001-12-13 2003-06-26 Abbott Laboratories 3-(phenyl-alkoxy)-5-(phenyl)-pyridine derivatives and related compounds as kinase inhibitors for the treatment of cancer
WO2003062227A1 (en) * 2002-01-23 2003-07-31 Bayer Pharmaceuticals Corporation Rho-kinase inhibitors
WO2003099796A1 (en) * 2002-05-23 2003-12-04 Cytopia Pty Ltd Protein kinase inhibitors
WO2004016597A2 (en) * 2002-08-14 2004-02-26 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors and uses thereof
WO2004085409A2 (en) * 2003-03-28 2004-10-07 Biofocus Discovery Ltd Compounds and libraries of pyridines, pyrazines, imidazo[1,2-a]pyrazines and 1h-imidazo[4,5-b]pyrazin-2-ones and first and second medical uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BOWMAN, R. E. ET AL: "Preparation and cyclization of 3-aza-1,5-diketones" XP002308867 retrieved from STN Database accession no. 1973:29148 & JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY (1972-1999) , (22), 2878-82 CODEN: JCPRB4; ISSN: 0300-922X, 1972, *
JEANJOT P ET AL: "N-(alkyl)-2-amino-1,4-pyrazine derivatives: Synthesis and antioxidative properties of 3- and 3,5-p-hydroxyphenyl-substituted compounds" SYNTHESIS, GEORG THIEME VERLAG. STUTTGART, DE, no. 4, 7 March 2003 (2003-03-07), pages 513-522, XP002287849 ISSN: 0039-7881 *
LUMMA W C ET AL: "Piperazinylpyrazines with central serotoninmimetic activity" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 21, no. 6, 1978, pages 536-542, XP002287850 ISSN: 0022-2623 *

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964606B2 (en) 2003-09-22 2011-06-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8129388B2 (en) 2003-09-22 2012-03-06 Purde Pharma L.P. Therapeutic agents useful for treating pain
US7799807B2 (en) 2003-09-22 2010-09-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US9139560B2 (en) 2003-12-03 2015-09-22 Ym Biosciences Australia Pty Ltd. Substituted pyrazines as tubulin inhibitors
JP2011093930A (en) * 2003-12-03 2011-05-12 Ym Biosciences Australia Pty Ltd Tubulin inhibitor
JP4772690B2 (en) * 2003-12-03 2011-09-14 ワイエム・バイオサイエンシズ・オーストラリア・ピーティーワイ・リミテッド Tubulin inhibitor
US9732046B2 (en) 2003-12-03 2017-08-15 Ym Biosciences Australia Pty Ltd. Substituted 1,2,4-triazines as tubulin inhibitors
JP2007513093A (en) * 2003-12-03 2007-05-24 サイトピア・リサーチ・ピーティーワイ・リミテッド Tubulin inhibitor
US8691806B2 (en) 2003-12-23 2014-04-08 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US9283226B2 (en) 2003-12-23 2016-03-15 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8247576B2 (en) 2003-12-23 2012-08-21 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
WO2006010637A2 (en) * 2004-07-30 2006-02-02 Gpc Biotech Ag Pyridinylamines
WO2006010637A3 (en) * 2004-07-30 2006-08-31 Gpc Biotech Ag Pyridinylamines
WO2006051311A1 (en) * 2004-11-12 2006-05-18 Galapagos Nv Nitrogen heteroaromatic compounds which bind to the active site of protein kinase enzymes
WO2006067466A3 (en) * 2004-12-22 2007-07-05 Wellcome Trust Ltd Pyrazines and pyridines and derivatives thereof as therapeutic compounds
WO2006067466A2 (en) * 2004-12-22 2006-06-29 The Wellcome Trust Limited Pyrazines and pyridines and derivatives thereof as therapeutic compounds
US7737152B2 (en) 2004-12-22 2010-06-15 The Wellcome Trust Limited 6-carboaryl-oxy-pyrazin-2-yl-carboaryl-amines and compositions comprising said compounds
WO2006072792A3 (en) * 2005-01-07 2007-01-11 Galapagos Nv Compounds which bind to the active site of protein kinase enzymes
WO2006072792A2 (en) * 2005-01-07 2006-07-13 Galapagos Nv Compounds which bind to the active site of protein kinase enzymes
US9090570B2 (en) 2005-01-25 2015-07-28 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8518950B2 (en) 2005-01-25 2013-08-27 Synta Pharmaceuticals Corp. 2-amido pyrazines for inflammation and immune related uses
EP1848435A4 (en) * 2005-01-25 2010-09-29 Synta Pharmaceuticals Corp Compounds for inflammation and immune-related uses
US9493427B2 (en) 2005-01-25 2016-11-15 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
EP1848435A2 (en) * 2005-01-25 2007-10-31 Synta Pharmaceuticals Corporation Compounds for inflammation and immune-related uses
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical compounds
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
US8211919B2 (en) 2005-09-02 2012-07-03 Astellas Pharma Inc. Amide derivatives as rock inhibitors
JP2009506979A (en) * 2005-09-02 2009-02-19 アステラス製薬株式会社 New compounds
WO2007026920A2 (en) * 2005-09-02 2007-03-08 Astellas Pharma Inc. Amide derivatives as rock inhibitors
WO2007026920A3 (en) * 2005-09-02 2007-06-28 Astellas Pharma Inc Amide derivatives as rock inhibitors
WO2007076360A1 (en) * 2005-12-22 2007-07-05 Alcon Research, Ltd. (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)- pyrazines for treating rho kinase-mediated diseases and conditions
US7655662B2 (en) 2005-12-22 2010-02-02 Alcon Research, Ltd. (Indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)-pyrazines for treating glaucoma and controlling intraocular pressure
WO2008011560A3 (en) * 2006-07-20 2008-03-27 Mehmet Kahraman Benzothiophene inhibitors of rho kinase
WO2008011560A2 (en) * 2006-07-20 2008-01-24 Mehmet Kahraman Benzothiophene inhibitors of rho kinase
JP2010520276A (en) * 2007-03-06 2010-06-10 アストラゼネカ・アクチエボラーグ Novel 2-heteroaryl-substituted benzothiophenes and benzofurans 709
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
US11633404B2 (en) 2007-08-29 2023-04-25 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
US11839618B2 (en) 2007-08-29 2023-12-12 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
WO2009028631A1 (en) 2007-08-29 2009-03-05 Senju Pharmaceutical Co., Ltd. Agent for promoting corneal endothelial cell adhesion
US8846687B2 (en) 2008-03-19 2014-09-30 Novartis Ag Pyrazine compounds as PI3 kinase inhibitors
US8158796B2 (en) 2008-06-18 2012-04-17 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
US9309267B2 (en) 2008-08-29 2016-04-12 Astrazeneca Ab Compounds suitable as precursors to compounds that are useful for imaging amyloid deposits
EP3553168A1 (en) 2010-11-12 2019-10-16 Georgetown University Immortalization of epithelial cells and methods of use
US20140309237A1 (en) * 2011-06-10 2014-10-16 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10106529B2 (en) 2011-06-10 2018-10-23 Calcimedia, Inc. Compounds that modulate intracellular calcium
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2013086236A2 (en) 2011-12-06 2013-06-13 Advanced Cell Technology, Inc. Method of directed differentiation producing corneal endothelial cells, compositions thereof, and uses thereof
EP3517604A1 (en) 2011-12-06 2019-07-31 Astellas Institute for Regenerative Medicine Method of directed differentiation producing corneal endothelial cells, compositions thereof, and uses thereof
EP3553169A1 (en) 2011-12-28 2019-10-16 Kyoto Prefectural Public University Corporation Normalization of culture of corneal endothelial cells
WO2013100208A1 (en) 2011-12-28 2013-07-04 京都府公立大学法人 Normalization of culture of corneal endothelial cells
US20150266878A1 (en) * 2012-12-10 2015-09-24 Hoffmann-La Roche Inc. Novel bi-ring phenyl-pyridines/pyrazines for the treatment of cancer
CN104837842A (en) * 2012-12-10 2015-08-12 霍夫曼-拉罗奇有限公司 Novel bi-ring phenyl-pyridines/pyrazines for treatment of cancer
WO2014090692A1 (en) * 2012-12-10 2014-06-19 F. Hoffmann-La Roche Ag Novel bi-ring phenyl-pyridines/pyrazines for the treatment of cancer
WO2015016371A1 (en) 2013-07-30 2015-02-05 京都府公立大学法人 Corneal endothelial cell marker
WO2015041533A1 (en) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut Rock in combination with mapk-pathway
WO2015064768A1 (en) 2013-10-31 2015-05-07 京都府公立大学法人 Therapeutic drug for diseases related to endoplasmic reticulum cell death in corneal endothelium
EP3804760A1 (en) 2013-10-31 2021-04-14 Kyoto Prefectural Public University Corporation Therapeutic drug for diseases related to endoplasmic reticulum cell death in corneal endothelium
WO2015080297A1 (en) 2013-11-27 2015-06-04 Kyoto Prefectural Public University Corporation Application of laminin to corneal endothelial cell culture
WO2015200920A1 (en) 2014-06-27 2015-12-30 The Regents Of The University Of California Cultured mammalian limbal stem cells, methods for generating the same, and uses thereof
US9790471B2 (en) 2015-04-03 2017-10-17 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10711250B2 (en) 2015-04-03 2020-07-14 Propagenix Inc. Ex vivo proliferation of epithelial cells
WO2016161192A1 (en) 2015-04-03 2016-10-06 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10100285B2 (en) 2015-04-03 2018-10-16 Propagenix Inc. Ex vivo proliferation of epithelial cells
US11680246B2 (en) 2015-04-03 2023-06-20 Propagenix Inc. Ex vivo proliferation of epithelial cells
EP3822339A1 (en) 2015-04-03 2021-05-19 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10711251B2 (en) 2015-04-03 2020-07-14 Propagenix Inc. Ex vivo proliferation of epithelial cells
US9963680B2 (en) 2015-04-03 2018-05-08 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10119121B2 (en) 2015-04-03 2018-11-06 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10514163B2 (en) 2015-09-11 2019-12-24 Propagenix Inc. Ex vivo proliferation of epithelial cells
EP3892717A1 (en) 2015-09-11 2021-10-13 Propagenix Inc. Ex vivo proliferation of epithelial cells
EP3892718A1 (en) 2015-09-11 2021-10-13 Propagenix Inc. Ex vivo proliferation of epithelial cells
US11060715B2 (en) 2015-09-11 2021-07-13 Propagenix Inc. Ex vivo proliferation of epithelial cells
US10066201B2 (en) 2015-09-11 2018-09-04 Propagenix Inc. Ex vivo proliferation of epithelial cells
WO2017064119A1 (en) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion
EP4088719A1 (en) 2015-10-13 2022-11-16 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods and pharmaceutical compositions for the treatment of retinal capillary non-perfusion
EP4218773A1 (en) 2016-02-15 2023-08-02 Kyoto Prefectural Public University Corporation Human functional corneal endothelial cell and application thereof
WO2017141926A1 (en) 2016-02-15 2017-08-24 Kyoto Prefectural Public University Corporation Human functional corneal endothelial cell and application thereof
JP2018199664A (en) * 2017-05-26 2018-12-20 日本化薬株式会社 Pyrazine compound
WO2019162911A1 (en) * 2018-02-26 2019-08-29 Universita' Di Pisa Fnew activators of sirt1 enzyme for the treatment of cardiovascular and cardiometabolic pathologies
IT201800003040A1 (en) * 2018-02-26 2019-08-26 Univ Pisa New activators of the SIRT1 enzyme for the treatment of cardiovascular and cardiometabolic diseases
WO2020041065A1 (en) 2018-08-20 2020-02-27 Propagenix Inc. Epithelial cell spheroids
WO2020047229A1 (en) 2018-08-29 2020-03-05 University Of Massachusetts Inhibition of protein kinases to treat friedreich ataxia
WO2020045642A1 (en) 2018-08-31 2020-03-05 学校法人同志社 Composition and method for preserving or culturing ocular cells
WO2020071438A1 (en) 2018-10-02 2020-04-09 学校法人同志社 Method and vessel for preserving corneal endothelial cells
WO2020084580A1 (en) 2018-10-26 2020-04-30 Novartis Ag Methods and compositions for ocular cell therapy
WO2021172554A1 (en) 2020-02-27 2021-09-02 京都府公立大学法人 Functional human corneal endothelial cells and application thereof
WO2021220132A1 (en) 2020-04-27 2021-11-04 Novartis Ag Methods and compositions for ocular cell therapy
WO2022235586A1 (en) 2021-05-03 2022-11-10 Astellas Institute For Regenerative Medicine Methods of generating mature corneal endothelial cells
WO2023069949A1 (en) 2021-10-18 2023-04-27 Evia Life Sciences Inc. Compositions and methods of use thereof for treating liver fibrosis
WO2023067394A2 (en) 2021-10-22 2023-04-27 Evia Life Sciences Inc. Methods for making extracellular vesicles, and compositions and methods of use thereof

Also Published As

Publication number Publication date
JP2007516196A (en) 2007-06-21
WO2005003101A3 (en) 2005-03-24
EP1644365A2 (en) 2006-04-12
CA2530389A1 (en) 2005-01-13

Similar Documents

Publication Publication Date Title
WO2005003101A2 (en) Pyrazine and pyridine derivatives as rho kinase inhibitors
CA2585490A1 (en) Nitrogen heteroaromatic compounds which bind to the active site of protein kinase enzymes
US20080194584A1 (en) Nitrogen Heteroaromatic Compounds Which Bind To The Active Site Of Protein Kinase Enzymes
AU2006282456B2 (en) Novel pyridine derivative and pyrimidine derivative (3)
US6730672B2 (en) Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
AU2011249167B2 (en) Picolinamide and pyrimidine-4-carboxamide compounds, process for preparing and pharmaceutical composition comprising the same
RU2283835C2 (en) Heterocyclic compound derivatives and pharmaceutical agents
WO2005082854A1 (en) Novel pyridine derivative and pyrimidine derivative (1)
KR20070026357A (en) Indole derivatives and use thereof as kinase inhibitors in particular ikk2 inhibitors
CA2504766A1 (en) 2-pyridone derivatives as inhibitors of neutrophile elastase
EA018065B1 (en) Pyridines and pyrazines as pi3k inhibitors (phosphatidylinositol 3-kinase)
JPH0233705B2 (en)
WO2002102778A1 (en) Phenylpyridine carbonyl piperazine derivative
KR20140001904A (en) Substituted 6-amino-nicotinamides as kcnq2/3 modulators
WO2006072792A2 (en) Compounds which bind to the active site of protein kinase enzymes
US7763614B2 (en) Isoquinoline potassium channel inhibitors
JP2021070688A (en) Pharmaceutical composition for prevention and/or treatment of hearing loss
US20090163515A1 (en) Compounds Which Bind to the Active Site of Protein Kinase Enzymes
RU2283306C2 (en) Piperidine- and piperazine-substituted n-hydroxyformamides as inhibitors of metalloproteinases
KR20010102072A (en) Heterocyclic derivatives as inhibitors of factor xa
EP3640242B1 (en) Rock-inhibiting compound and uses thereof
KR20230092870A (en) compound
MXPA06008080A (en) Indole derivatives and use thereof as kinase inhibitors in particular ikk2 inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2004743195

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2530389

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2006518333

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2004743195

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10561914

Country of ref document: US