WO2000015645A1 - Derives d'esters phosphoniques et leur procede de production - Google Patents

Derives d'esters phosphoniques et leur procede de production Download PDF

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Publication number
WO2000015645A1
WO2000015645A1 PCT/JP1999/004913 JP9904913W WO0015645A1 WO 2000015645 A1 WO2000015645 A1 WO 2000015645A1 JP 9904913 W JP9904913 W JP 9904913W WO 0015645 A1 WO0015645 A1 WO 0015645A1
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Prior art keywords
ring
optionally substituted
integer
carbon atoms
group
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PCT/JP1999/004913
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English (en)
Japanese (ja)
Inventor
Yasushi Kono
Takayuki Sawada
Masahiro Nomura
Yukie Takahashi
Takeshi Tsubuki
Yasuhiko Sakoe
Kazuhiko Kuriyama
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to AU56485/99A priority Critical patent/AU5648599A/en
Publication of WO2000015645A1 publication Critical patent/WO2000015645A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to a phosphonate derivative having an activity of inhibiting the binding between cell adhesion molecules and being useful as an immunosuppressant, an anti-inflammatory, an antiallergic, or a cancer metastasis inhibitor, and a method for producing the same.
  • adhesion between vascular endothelial cells and leukocytes is a very important process (Mebio, No. 5, Vol. 10 (1993)).
  • the main adhesion molecules on the vascular endothelial cell side involved in this adhesion include ICAM—
  • ICAM-1 and VCAM-1 adhesion to leukocytes via ICAM_1 and VCAM-1 which are expressed in large amounts in the long term is the strongest, and these two adhesion molecules play an important role even in actual various diseases It is said that. Therefore, I CAM-1 and V CAM—
  • adhesion molecules such as 1, chronic It is considered to be effective as a remedy for autoimmune diseases such as rheumatoid arthritis, nephritis and knee osteoarthritis and allergic diseases such as chronic inflammatory diseases, asthma and dermatitis, and as a cancer metastasis inhibitor.
  • Cell adhesion inhibitors that have been reported up to now, so-called expression inhibitors that inhibit adhesion by suppressing the expression of adhesion molecules, and inhibit adhesion by inhibiting the binding between adhesion molecules It is classified as a so-called binding inhibitor.
  • Most of the cell adhesion inhibitors related to IC AM-1 and VC AM_1 are expression inhibitors (Japanese Patent Application Laid-Open Nos. 9-111, 689, 8-28, 156, and 8-8,156). 198,752, JP-A-7-304,667, JP-A-7-258,168), and binding inhibitors, such as antibodies and ligands of adhesion molecules. Except for macromolecules, only non-peptide low molecular weight compounds have been reported in J. Med.
  • Expression inhibitors often act on the intracellular signal transduction system, and may suppress functions other than expression of adhesion molecules. Unlike such expression suppressors, binding inhibitors only inhibit the binding between adhesion molecules, so they are considered to be excellent drugs in terms of safety, but they are still satisfactory It is not something.
  • the present invention provides excellent immunosuppressants, anti-inflammatory agents, and the like by providing a substance that inhibits an adhesion pathway mediated by ICAM-1 and VCAM-1 that plays a central role in cell adhesion molecules.
  • An object of the present invention is to provide an antiallergic agent and a cancer metastasis inhibitor. Disclosure of the invention
  • the present inventors inhibit the binding of human monocyte-like cell line (U933) to human umbilical vein-derived vascular endothelial cells (HUVEC) 24 hours after IL-11 stimulation.
  • U933 human monocyte-like cell line
  • VCAM human umbilical vein-derived vascular endothelial cells
  • a novel phosphonate ester derivative with a different structure from the known cell adhesion inhibitors is capable of binding between cells via ICAM1-1 and VCAM-1 without inhibiting the expression of adhesion molecules.
  • the inventors have found that the present invention inhibits the present invention and completed the present invention.
  • the present invention relates to the general formula (1)
  • W is a thiazole ring, an optionally substituted benzothiazolyl ring, a pyridothiazolyl ring, an optionally substituted pyridin ring, an optionally substituted quinoline ring, a substituted Optionally substituted pyridazine ring, optionally substituted phthalazine ring, optionally substituted quinoxaline ring, optionally substituted pyrimidine ring, optionally substituted quinazoline ring An optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, and an optionally substituted indole ring, X Is
  • Pharmaceutically acceptable salts of the compound represented by the general formula (1) in the present invention include acids such as hydrochloride, hydrobromide, methanesulfonate, citrate and tartrate. Addition salts, and metal salts such as sodium salts and potassium salts.
  • the “lower alkyl group” such as a lower alkyl group, a lower alkoxycarbonyl group and a lower alkoxyphosphoryl group means, for example, a straight chain such as methyl, ethyl, propyl, isopropyl, etc.
  • the compound represented by the general formula (1) is produced by condensing the compound represented by the general formula (2) and the compound represented by the general formula (3). Can be.
  • W is a thiazolyl ring, an optionally substituted benzothiazolyl ring, a pyridothiazolyl ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, An optionally substituted pyridazine ring, an optionally substituted phthalazine ring, an optionally substituted quinoxaline ring, an optionally substituted pyrimidine ring, an optionally substituted quinazoline ring X represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, or an optionally substituted indole ring;
  • R 3 represents a hydroxy group or a halogen atom]
  • R 1 is a hydrogen atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms
  • R 2 is a lower alkyl group having 1 to 4 carbon atoms
  • n is 0.
  • an acid halide in which R 3 in the formula (2) is a halogen atom methylene chloride and 1,4-dioxane are present in the presence of an organic base such as triethylamine or pyridine. And the like can be used as a solvent at 0 ° C. to room temperature.
  • R 3 in the formula (2) is a hydroxy group, it can be produced by a mixed acid anhydride method or an active ester method used in a usual peptide bond formation reaction, and preferably a condensing agent.
  • the method using is suitable. Reactions include dicyclohexyl carpoimide (DCC), diisopropyl carbodiimide (DIPC), diphenylphosphonyl azide (DPPA), getylphosphonyl cyanide (DEPC), 1-ethyl 3- (3-dimethylaminopropyl pill)
  • a condensing agent such as 1-carbodiimide (WSC), 4-dimethylaminoviridine (DMAP) may optionally be added as a catalyst and the reaction solvent used as a reaction solvent.
  • the reaction can be performed using tetrahydrofuran (THF), methylene chloride, dimethylsulfoxide (DMSO), or dimethylformamide (DMF) at a reaction temperature of 0
  • the reaction is carried out using methylene chloride, 1,4-dioxane or the like as a solvent in the presence of an organic base such as triethylamine or pyridine.
  • the reaction can be performed at 0 ° C. to room temperature.
  • R ; i in the formula (8) is a hydroxy group, it can be produced by a mixed acid anhydride method or an active ester method used in a general peptide bond formation reaction, and preferably by condensation. A method using an agent is suitable.
  • the reaction may be carried out in the presence of a condensing agent such as DCC; DIPC; DPPA, DEPC, WSC, etc., in some cases, by adding DMAP as a catalyst, and using THF, methylene chloride, DMSO, Using DMF, The reaction can be carried out at a temperature of 0 ° C to room temperature.
  • a condensing agent such as DCC; DIPC; DPPA, DEPC, WSC, etc.
  • the compound represented by the above general formula (7) can be produced by the following synthetic route.
  • V represents an amino group or a nitro group
  • Y, Z, R ′, R 2 , and n are as described above.
  • the compound represented by the general formula (3) The compound can be produced by condensing a compound represented by the general formula (4) with a compound represented by the general formula (4).
  • R 3 in the formula (4) is a halogen atom
  • methylene chloride, 1,4-dioxane or the like is used as a solvent in the presence of an organic base such as triethylamine or pyridine. It can be performed at 0 ° C to room temperature.
  • R : 3 in the formula (4) is a hydroxy group, it can be produced by a mixed acid anhydride method or an active ester method used for a usual peptide bond formation reaction, and is preferably used. A method using a condensing agent is suitable.
  • the reaction may be carried out in the presence of a condensing agent such as DCC, DIPC, DPPA, DEPC; or WSC, in some cases, by adding DMAP as a catalyst, and using THF, methylene chloride, DMSO, DMF as the reaction solvent.
  • a condensing agent such as DCC, DIPC, DPPA, DEPC; or WSC
  • DMAP as a catalyst
  • THF methylene chloride
  • DMSO methylene chloride
  • DMF DMF
  • the compound can also be produced by reducing the compound represented by (6).
  • the reaction is carried out in a hydrogen atmosphere in the presence of Pd / C, Raney nickel, platinum oxide, etc., using methanol, ethanol, DMF, 1,4-dioxane, THF, etc. as a solvent, and heating from room temperature to room temperature. Can react.
  • the reaction can be carried out from room temperature to under heating using acetic acid, a mixed solution of ethanol and water, a mixture of THF and the like as a solvent in the presence of iron, zinc and tin tetrachloride.
  • R 1 is a carboxyl group A compound of the general formula (11)! I)
  • R 4 represents a lower alkyl group having 1 to 4 carbon atoms, and W, X, Y, Z, R 2 and n are as described above]
  • the reaction is carried out using a solvent such as methanol, ethanol, DMSO, DMF, etc., and an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of lithium hydroxide, etc., and the reaction temperature is adjusted.
  • a solvent such as methanol, ethanol, DMSO, DMF, etc.
  • the reaction temperature is adjusted.
  • the reaction can be performed at 0 ° C to room temperature.
  • the obtained thiourea (1.30 g ) was dissolved in THF (50 ml), 4-ethyl acetylacetate (5.00 g) and DMAP (0.05 g) were added, and the mixture was heated under reflux for 20 hours.
  • the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained powder, and the mixture was extracted with ethyl acetate.
  • the organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. did.
  • the obtained crystals were recrystallized from THF-isopropyl ether-isopropyl alcohol to give the desired product (0.60 g) as milky white needles.
  • WSC (0.86 g) was added to a DMF (20 ml) solution of 2-cyclopyridine pyridin-5-carboxylic acid (0.47 g) and ethyl 4-ethylaminocinnamate (() .63 g), and the mixture was brought to room temperature. And stirred for 8 hours. Water is added to the reaction solution, and the precipitated crystals are filtered. The crystals were taken out, washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried.
  • the desired product was obtained as a yellow powder by reacting with 5-ethylamine 1-phenylindole-12-carboxylic acid and ethyl 4-ethylaminocinnamate in the same manner as in Reference Example 92.
  • Reference example 9 4
  • Example 18 The compound of 50 (50 mg ) was added to a mixed solution of ethanol (1 ml) and a 1N aqueous sodium hydroxide solution ((.13 ml)), and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was poured into water, adjusted to pH 3 with diluted hydrochloric acid, and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was solidified by adding ethyl persulfate and isopropyl ether, and the precipitated crystals were collected by filtration.
  • the adhesion inhibition effect of the test compound is mainly It can be evaluated whether it is due to inhibition of molecule binding or suppression of expression of adhesion molecules.
  • Experimental example 1 Binding inhibition test of adhesion molecule
  • HUVEC suspended in M199 medium (for culture) containing 20% fetal serum and 1 ng / ml vascular endothelial cell growth factor (ECGF) was applied to a 96-well collagen-coated plate (flat bottom).
  • X 1 0 4 / Ueru not a One were seeded and cultured in 3 7 ° C, 5% C 0 2 below.
  • HUV ECs were washed twice with M199 medium (for washing) containing no fetal serum and ECGF.
  • HUVECs were washed three times with M199 medium for washing.
  • the test compound was dissolved in dimethylsulfoxide, and diluted 100-fold with M-99 medium for culture, and added at a concentration of 801 / well.
  • a fluorescence-labeled U933 cell suspension was added at a rate of 201 / well (final concentration of the test compound was 10 / well).
  • the HUVE C were suspended in M 1 9 9 culturing medium was inoculated by Ueru 9 6 well collagen Coat Topure preparative (flat bottom), were cultured in 3 7 ° C, 5% C 0 2 below. After culturing for about 24 hours, HUVEC was washed twice with M199 medium for washing. Test compound is dimethylsulfoxy The cells were dissolved in a culture medium and diluted 100-fold with M199 medium for culture, added at 801 / well, and cultured for 1 hour. Next, a culture medium containing IL-1? was added to the culture medium at a concentration of 20 ⁇ ⁇ / ⁇ , and cultured for 24 hours (final concentration of IL-11? Was 10 U / m1.
  • Adhesion percentage (%): Number of cells of test compound — '1
  • a female female rat (Japanese charles 'river'), 8 or 9 weeks old, was divided into 5 animals per group.
  • the rat was injected with .05 ml of 0.6 mg bacterium (Difco) killed in liquid paraffin intradermally into the foot of the right hind limb suspended in liquid paraffin.
  • the back was shaved with an electric hair clipper, and the skin thickness of the back (two places on the left and right) was measured using a dial thickness gauge (Ozaki Seisakusho).
  • the antigen solution 5 () 1 was injected intradermally into the skin thickness measurement part.
  • test compounds were 3% arabia gum aqueous solution (Example No. 18 2) containing () .5% ethanol and (). 1% Tween 20 ('No. 18%) or 3% arabia gum aqueous solution (Example No.
  • the control group received a solvent of the same composition as used for the preparation of the test compound.
  • the results are shown as the increase in skin thickness of the test compound relative to the increase in skin thickness in the control group. Expressed as a percentage of the weight. Table 5 shows the results
  • the compound of the present invention represented by the general formula (1) does not exhibit the effect of suppressing the expression of cell adhesion molecules such as ICAM-1 and VCAM-1 and inhibits the binding between cells mediated by these compounds. Inhibition and its efficacy were also observed in delayed type hypersensitivity reaction tests.

Abstract

L'invention porte sur des dérivés d'esters phosphoniques de formule générale (1) et sur leurs sels pharmacocompatibles agissant comme inhibiteurs des liaisons entre molécules à adhésion cellulaire, et utiles de ce fait comme immunosuppresseurs, comme agents anti-inflammatoires, comme agent anti-allergique, et comme inhibiteurs des métastases cancéreuses.
PCT/JP1999/004913 1998-09-11 1999-09-10 Derives d'esters phosphoniques et leur procede de production WO2000015645A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56485/99A AU5648599A (en) 1998-09-11 1999-09-10 Phosphonic ester derivatives and process for producing the same

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JP10/258841 1998-09-11
JP25884198 1998-09-11

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WO2000015645A1 true WO2000015645A1 (fr) 2000-03-23

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010854A1 (fr) * 1999-08-09 2001-02-15 Ciba Specialty Chemicals Holding Inc. Composes a base de benzothiazole et leur utilisation en tant qu'azureurs optiques
WO2001021598A1 (fr) * 1999-09-23 2001-03-29 Astrazeneca Ab Composes therapeutiques de quinazoline
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
US6787542B2 (en) 2000-06-29 2004-09-07 Icos Corporation Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6878697B2 (en) * 2001-06-21 2005-04-12 Ariad Pharmaceuticals, Inc. Phenylamino-pyrimidines and uses thereof
US6878700B1 (en) 1998-12-29 2005-04-12 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
WO2005007672A3 (fr) * 2003-06-20 2005-09-15 Coley Pharm Gmbh Antagonistes des recepteurs toll (tlr) pour petites molecules
USRE39197E1 (en) 1998-12-29 2006-07-18 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
US7214704B2 (en) 2004-11-15 2007-05-08 Bristol-Myers Squibb Company 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7223786B2 (en) 2004-11-15 2007-05-29 Bristol-Myers Squibb Company 2-aminonaphthalene derivatives and related glycogen phosphorylase inhibitors
US7226942B2 (en) 2004-11-15 2007-06-05 Bristol-Myers Squibb Company 2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7365061B2 (en) 2004-11-15 2008-04-29 Bristol-Myers Squibb Company 2-Amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
CN1809357B (zh) * 2003-06-20 2010-12-22 科勒制药有限公司 小分子Toll样受体(TLR)拮抗剂
US20110092499A1 (en) * 2007-11-15 2011-04-21 Ym Biosciences Australia Pty Ltd N-containing heterocyclic compounds
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US8188254B2 (en) 2003-10-30 2012-05-29 Coley Pharmaceutical Gmbh C-class oligonucleotide analogs with enhanced immunostimulatory potency
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2014066659A1 (fr) * 2012-10-25 2014-05-01 Tetra Discovery Partners, Llc. Inhibiteurs hétéroaryle de pde4
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878700B1 (en) 1998-12-29 2005-04-12 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
USRE39197E1 (en) 1998-12-29 2006-07-18 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
WO2001010854A1 (fr) * 1999-08-09 2001-02-15 Ciba Specialty Chemicals Holding Inc. Composes a base de benzothiazole et leur utilisation en tant qu'azureurs optiques
WO2001021598A1 (fr) * 1999-09-23 2001-03-29 Astrazeneca Ab Composes therapeutiques de quinazoline
US6399603B1 (en) 1999-09-23 2002-06-04 Astrazeneca Ab Therapeutic heterocycles
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
US6787542B2 (en) 2000-06-29 2004-09-07 Icos Corporation Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US7129247B2 (en) 2000-06-29 2006-10-31 Abbott Laboratories Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6878697B2 (en) * 2001-06-21 2005-04-12 Ariad Pharmaceuticals, Inc. Phenylamino-pyrimidines and uses thereof
CN1809357B (zh) * 2003-06-20 2010-12-22 科勒制药有限公司 小分子Toll样受体(TLR)拮抗剂
WO2005007672A3 (fr) * 2003-06-20 2005-09-15 Coley Pharm Gmbh Antagonistes des recepteurs toll (tlr) pour petites molecules
US8188254B2 (en) 2003-10-30 2012-05-29 Coley Pharmaceutical Gmbh C-class oligonucleotide analogs with enhanced immunostimulatory potency
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7365061B2 (en) 2004-11-15 2008-04-29 Bristol-Myers Squibb Company 2-Amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7223786B2 (en) 2004-11-15 2007-05-29 Bristol-Myers Squibb Company 2-aminonaphthalene derivatives and related glycogen phosphorylase inhibitors
US7214704B2 (en) 2004-11-15 2007-05-08 Bristol-Myers Squibb Company 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7226942B2 (en) 2004-11-15 2007-06-05 Bristol-Myers Squibb Company 2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US8765755B2 (en) 2007-11-15 2014-07-01 Ym Biosciences Australia Pty Ltd. N-containing heterocyclic compounds
US20110092499A1 (en) * 2007-11-15 2011-04-21 Ym Biosciences Australia Pty Ltd N-containing heterocyclic compounds
US9499560B2 (en) 2007-11-15 2016-11-22 Ym Biosciences Australia Pty Ltd N-containing heterocyclic compounds
US8354408B2 (en) * 2007-11-15 2013-01-15 Ym Biosciences Australia Pty Ltd N-containing heterocyclic compounds
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9242963B2 (en) 2008-06-27 2016-01-26 Novartis Ag Organic compounds
US8791141B2 (en) 2008-06-27 2014-07-29 Novartis Ag Organic compounds
US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
JP2016505512A (ja) * 2012-10-25 2016-02-25 テトラ ディスカバリー パートナーズ エルエルシー Ｐｄｅ４のヘテロアリール阻害剤
US9221843B2 (en) 2012-10-25 2015-12-29 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US9777024B2 (en) 2012-10-25 2017-10-03 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
WO2014066659A1 (fr) * 2012-10-25 2014-05-01 Tetra Discovery Partners, Llc. Inhibiteurs hétéroaryle de pde4
US10093686B2 (en) 2012-10-25 2018-10-09 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US10364258B2 (en) 2012-10-25 2019-07-30 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
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