WO2004000843A1 - NOVEL PURINE- OR PYRROLOL[2,3-d]PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY - Google Patents

NOVEL PURINE- OR PYRROLOL[2,3-d]PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY Download PDF

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Publication number
WO2004000843A1
WO2004000843A1 PCT/SE2003/001079 SE0301079W WO2004000843A1 WO 2004000843 A1 WO2004000843 A1 WO 2004000843A1 SE 0301079 W SE0301079 W SE 0301079W WO 2004000843 A1 WO2004000843 A1 WO 2004000843A1
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WO
WIPO (PCT)
Prior art keywords
carbonitrile
chlorophenyl
purine
alkyl
moφholin
Prior art date
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Ceased
Application number
PCT/SE2003/001079
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English (en)
French (fr)
Inventor
Andrew Bailey
Garry Pairaudeau
Anil Patel
Stephen Thom
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AstraZeneca AB
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AstraZeneca AB
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
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to JP2004515329A priority Critical patent/JP2005533804A/ja
Priority to EP03761002A priority patent/EP1532148B1/en
Priority to US10/518,815 priority patent/US7439240B2/en
Priority to AU2003243096A priority patent/AU2003243096A1/en
Priority to DE60311272T priority patent/DE60311272T2/de
Publication of WO2004000843A1 publication Critical patent/WO2004000843A1/en
Anticipated expiration legal-status Critical
Priority to US12/024,375 priority patent/US20080125426A1/en
Priority to US12/024,423 priority patent/US20080119469A1/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Novel purine- or pyrrolo[2,3-d]pyrum ' dine-2-carbomtiles for treating diseases associated with cysteine protease activity.
  • the present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity.
  • the compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S.
  • this invention also discloses processes for the preparation of such inhibitors.
  • Cathepsin S is a member of the papain superfamily of cysteine proteases which also encompasses Cathepsins B, H, L, O and K. Cathepsin S plays a key role in the processing of invariant chain in MHC class II complexes allowing the complex to associate with antigenic peptides. MHC class II complexes are then transported to the surface of the cell for presentation to effector cells such as T cells. The process of antigen presentation is a fundamental step in initiation of the immune response. In this respect inhibitors of cathepsin S could be useful agents in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cathepsin S has also been implicated in a variety of other diseases involving extracellular proteolysis such as the development of emphysema in COPD through degradation of elastin and in Alzheimers disease.
  • Cathepsins notably K and L have been shown to degrade bone collagen and other bone matrix proteins. Inhibitors of these cysteine proteases would be expected to be useful in the treatment of diseases involving bone resorption such as osteoporosis.
  • the present invention therefore provides a compound of formula (I)
  • X is N, NH, :CH or CH 2 ;
  • Y is N, :CH, CO, CH 2 or :CNR 2 R 3 , where R 2 and R 3 are independently hydrogen,
  • R is aryl or heteroaryl optionally substituted by halogen, amino, hydroxy, cyano, nitro, trifluoromethyl, carboxy, CONR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , NHSO 2 R 4 , NHCOR 4 , ethylenedioxy, methylenedioxy, C ⁇ .
  • R4 is hydrogen, C ⁇ -6 alkyl or C 3-6 cycloalkyl
  • R 5 and R 6 are independently hydrogen, C ⁇ -6 alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR 4 group
  • R is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl both of which can optionally contain one or more O, S or NR 4 groups
  • R 1 is a group Y(CH 2 )pR 7 where p is 0, 1 or 2 and Y is O or NR 8 where R 8 is hydrogen, C ⁇ -6 alkyl or C 3-6 cycloalkyl; and R 7 is a 5- or 6-membered saturated ring containing one or more O, S or N atoms, aryl or a heteroaryl group containing one to four heteroatoms selected from O, S or N, the saturated ring, aryl and heteroaryl groups all being optionally substituted by halogen, amino, hydroxy, cyano, nitro, trifluoromethyl, carboxy, CONR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , NHSO 2 R 4 , NHCOR 4 , C 1-6 alkyl, C ⁇ -6 alkoxy, SR 4 or NR 5 R 6 where R4 is hydrogen, C ⁇ -6 alkyl or C 3 .
  • R 5 and R 6 are independently hydrogen, C ⁇ -6 alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR 4 group; or R 1 is a group NR 9 R 10 where R 9 and R 10 are independently hydrogen or C ⁇ -6 alkyl optionally containing one or more O, S or NR 4 groups, or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated ring optionally containing a further O, S or N atom and optionally substituted by NR 9 R 10 , CO 2 C ⁇ -6 alkyl, CONR 1 'R 12 where R 1 ' and R 12 are independently hydrogen or C ⁇ -6 alkyl, aryl or heteroaryl group optionally substituted by halogen, amino, hydroxy, cyano, nitro, trifluoromethyl, carboxy, CONR 5 R 6 , SO 2 NR 5 R 6 ,
  • an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched.
  • Aryl groups include phenyl and naphthyl.
  • Heteroaryl groups include 5- or 6-membered, 5,6- or 6,6-fused aromatic rings containing one or more heteroatoms selected from N, S, O. Examples include pyridine, pyrimidine, pyrazine, pyridazine thiazole, oxazole, pyrazole, imidazole, furan and thiophene, quinoline, isoquinoline, benzimidazole, benzofuran, benzothiophene, indole.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • X is N and Y is :CH, X and Y are:CH or X and Y are CH 2
  • R is Ci ⁇ alkyl, or phenyl substituted by halogen, in particular chloro, SO 2 Me, Ci- ⁇ alkoxy, in particular methoxy, in particular methyl or propyl.
  • R 1 is a group Y(CH 2 )pR 7 where p is 0 and Y is NR 8 where R 8 is hydrogen and R 7 is substituted phenyl.
  • R 7 is phenyl substituted by halogen, especially chloro; or
  • R 1 is NR 9 R 10 where R 9 and R 10 are hydrogen or C ⁇ -3 alkyl or together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated ring optionally containing a O, S or NR 4 .
  • Preferred compounds of the invention include: l-[9-(4-Chlorophenyl)-2-cyano-9H-purin-6-yl]-L-prolinamide, 9-(4-Chlorophenyl)-6-(4-pyrrolidin- 1 -ylpiperidin- 1 -yl)-9H-purine-2-carbonitrile, 9-(4-Chlorophenyl)-6-[(3-pyrrolidin-l-ylpropyl)amino]-9H-purine-2-carbonitrile, 6-(4-Aminopiperidin- 1 -yl)-9-(4-chlorophenyl)-9H-purine-2-carbonitrile, 6-[(2-Aminoethyl)amino]-9-(4-chlorophenyl)-9H-purine-2-carbonitrile, 9-(4-Chlorophenyl)-6-(dimethylamino)-9H-purine-2-carbonitrile, 9-(
  • the present invention further provides a process for the preparation of a compound of formula (I) which comprises
  • LI and L2 represent a leaving group (e.g. halide, sulphide, sulfoxide or sulphone group), preferably the sulphide is oxidised to a sulphoxide or sulphone group before displacement.
  • An oxidising agent such as a peracid may be used, for example meta- chloroperbenzoic acid in dichloromethane at room temperature.
  • LI may be displaced by R 1 where R 1 is defined in formula (I) and L2 may be displaced by cyanide, preferably using a salt (e.g. lithium, sodium or potassium cyanide).
  • a salt e.g. lithium, sodium or potassium cyanide.
  • the sequence of displacement of LI, L2 may be varied.
  • Compounds of formula (II) may also be prepared from compound of formula (LV) by reaction with a group R-Z, where R is defined in formula (I) and Z is a leaving group (e.g. halide, activated alcohol).
  • R-Z where R is defined in formula (I) and Z is a leaving group (e.g. halide, activated alcohol).
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent for use as a therapeutic agent.
  • a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man.
  • the compounds of the invention are useful in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, COPD, multiple sclerosis, Crohn's disease, Alzheimers and pain, such as neuropathic pain.
  • inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, COPD, multiple sclerosis, Crohn's disease, Alzheimers and pain, such as neuropathic pain.
  • the compounds of the invention are used to treat pain, especially neuropathic pain.
  • the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin S in a warm blooded animal, such as man.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 1 mgkg "1 to 100 mgkg "1 of the compound, preferably in the range of 5 mgkg *1 to 20 mgkg '1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • Examples 2-12 were prepared according to the general method of example 1 using the appropriate amines.
  • Examples 14-18 were prepared according to the general method of example 13 using the appropriate amines.
  • Triphosgene (0.09g) was added to a mixture of the product from example 20 step (iii) (0.4g) and pyridine (0.4ml) in dichloromethane (30ml) and the mixture stirred at room temperature. After lh more triphosgene (0.02g) was added, stirred for a further lh, water added and the solid filtered. The solid was washed with water, diethylether and dried. Yield 0.14g
  • step (iii) and phosphorus oxychloride (30ml) was heated at 100°C for 3h.
  • the excess reagent was removed under reduced pressure, the residue quenched with ice- water, extracted with ethyl acetate, dried(MgSO ) and evaporated to an oil.
  • the oil was purified by chromatography on silica eluting with isohexane:diethylether(4: 1) to give a brown oil (0.36g).
  • Examples 29-32 were prepared according to the method of example 28 steps(vi)-(viii).
  • QFRET Technology Quenched Fluorescent Resonance Energy Transfer
  • Synthetic substrate 20 ⁇ M [f ⁇ nal]Z-Val-Val-Arg-AMC in phosphate buffer were added to a 96 well black Optiplate.
  • the assay plates were pre-read for compound auto fluorescence on SpectraMax Gemini at 355nM excitation and 460nM emission.
  • 250pM [final] rHuman Cathepsin S in phosphate buffer was added and incubated for 2h at room temperature on the SpectraMax Gemini, taking readings every 20min at 355nM excitation and 460nM emission.
  • Activity Based template (5PTB-8) used the auto fluorescent corrected data to calculate the percentage inhibition for each compound concentration using the relevent plate controls. This data was used to construct inhibition curves and pICso estimated by non-linear regression using a 4 parameter logistic model.

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  • Health & Medical Sciences (AREA)
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  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
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  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/SE2003/001079 2002-06-24 2003-06-23 NOVEL PURINE- OR PYRROLOL[2,3-d]PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY Ceased WO2004000843A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2004515329A JP2005533804A (ja) 2002-06-24 2003-06-23 システイン・プロテアーゼ活性に関係する疾患を処置するための新規プリン−もしくはピロール−［２，３−ｄ］ピリミジン−２−カルボニトリル
EP03761002A EP1532148B1 (en) 2002-06-24 2003-06-23 Novel purine- or pyrrolol(2,3-d)pyrimidine-2-carbonitiles for treating diseases associated with cysteine protease activity
US10/518,815 US7439240B2 (en) 2002-06-24 2003-06-23 Purine-or pyrrolol[2,3-d]pyrimidine-2-carbonitiles for treating diseases associated with cysteine protease activity
AU2003243096A AU2003243096A1 (en) 2002-06-24 2003-06-23 NOVEL PURINE- OR PYRROLOL(2,3-d)PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY
DE60311272T DE60311272T2 (de) 2002-06-24 2003-06-23 Neue purin- oder pyrrolol(2,3-d)pyrimidin-2-carbonsäurenitrile zur behandlung von mit cysteinproteaseaktivität assoziierten krankheiten
US12/024,375 US20080125426A1 (en) 2002-06-24 2008-02-01 Novel Compounds
US12/024,423 US20080119469A1 (en) 2002-06-24 2008-02-01 Novel Compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0201980-0 2002-06-24
SE0201980A SE0201980D0 (sv) 2002-06-24 2002-06-24 Novel compounds

Related Child Applications (2)

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US12/024,375 Division US20080125426A1 (en) 2002-06-24 2008-02-01 Novel Compounds
US12/024,423 Division US20080119469A1 (en) 2002-06-24 2008-02-01 Novel Compounds

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PCT/SE2003/001079 Ceased WO2004000843A1 (en) 2002-06-24 2003-06-23 NOVEL PURINE- OR PYRROLOL[2,3-d]PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY

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US (3) US7439240B2 (https=)
EP (1) EP1532148B1 (https=)
JP (1) JP2005533804A (https=)
AU (1) AU2003243096A1 (https=)
DE (1) DE60311272T2 (https=)
ES (1) ES2279162T3 (https=)
SE (1) SE0201980D0 (https=)
WO (1) WO2004000843A1 (https=)

Cited By (46)

* Cited by examiner, † Cited by third party
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WO2004065380A1 (en) * 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2005007658A3 (en) * 2003-07-14 2005-06-16 Arena Pharm Inc Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2005085210A1 (ja) * 2004-03-10 2005-09-15 Ono Pharmaceutical Co., Ltd. ニトリル化合物およびその化合物を有効成分として含有する医薬組成物
US7112589B2 (en) 2001-08-30 2006-09-26 Novartis Ag Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases
WO2007039470A1 (en) * 2005-09-23 2007-04-12 N.V. Organon 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives
WO2007080191A1 (en) * 2006-01-16 2007-07-19 N.V. Organon 6-phenyl-1h-imidazo[4, 5-c]pyridine-4-carbonitrile derivatives as cathepsin k and s inhibitors
US7253284B2 (en) 2001-07-17 2007-08-07 Giaxo Group Limited Chemical compounds
WO2007148064A1 (en) * 2006-06-23 2007-12-27 Astrazeneca Ab Pteridine derivatives and their use as cathespin inhibitors
US7326715B2 (en) 2005-09-23 2008-02-05 N.V. Organon 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives
EP1927594A1 (en) 2003-01-14 2008-06-04 Arena Pharmaceuticals, Inc. 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
WO2008107368A1 (en) * 2007-03-02 2008-09-12 Glaxo Group Limited Purines as cysteine protease inhibitors
US7427630B2 (en) 2003-04-09 2008-09-23 Sb Pharmaco Puerto Rico Inc. Condensed N-heterocyclic compounds and their use as CRF receptor antagonists
EP1972630A1 (en) * 2007-03-02 2008-09-24 Glaxo Group Limited Purines as cysteine protease inhibitors
US7470699B2 (en) 2003-07-11 2008-12-30 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2009010491A1 (en) * 2007-07-16 2009-01-22 N.V. Organon 6-phenyl-1h-imidazo[4,5-c]pyridine-4-carbonitrile derivatives as cathepsin inhibitors
US7589095B2 (en) 2004-06-11 2009-09-15 N.V. Organon 4-phenyl-pyrimidine-2-carbonitrile derivatives
US7687515B2 (en) 2006-01-17 2010-03-30 N.V. Organon 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
WO2010059418A1 (en) * 2008-11-19 2010-05-27 The Government Of The U.S.A. As Represented By The Secretary Of The Dept. Of Health & Human Services Substituted triazine and purine compounds, methods of inhibiting cruzain and rhodesain and methods of treating chagas disease and african trypanosomiasis
WO2010081859A1 (en) 2009-01-16 2010-07-22 N.V. Organon 6-phenyl-lh-imidazo [4, 5-c] pyridine-4-carbonitrile derivatives as cathepsin s and/or cathepsin k inhibitors
WO2011045561A2 (en) 2009-10-13 2011-04-21 Syngenta Limited Herbicidal compounds
US7932251B2 (en) 2007-07-16 2011-04-26 N.V. Organon 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
WO2011086125A1 (en) 2010-01-15 2011-07-21 N.V. Organon 1H-[1,2,3]TRIAZOLO[4,5-c]PYRIDINE-4-CARBONITRILE DERIVATIVES
US8026236B2 (en) 2009-01-16 2011-09-27 N.V. Organon 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
WO2012045905A2 (es) 2010-10-06 2012-04-12 Fundació Privada Institut De Recerca Biomèdica Método para el diagnóstico, pronóstico y tratamiento de la metástasis de cáncer de mama
WO2013153458A2 (en) 2012-04-09 2013-10-17 Inbiomotion S.L. Method for the prognosis and treatment of cancer metastasis
WO2013182912A2 (en) 2012-06-06 2013-12-12 Fundacio Privada Institut De Recerca Biomedica Method for the diagnosis, prognosis and treatment of lung cancer metastasis
WO2014140933A2 (en) 2013-03-15 2014-09-18 Fundacio Privada Institut De Recerca Biomedica Method for the prognosis and treatment of cancer metastasis
WO2014184679A2 (en) 2013-03-15 2014-11-20 Inbiomotion S.L. Method for the prognosis and treatment of renal cell carcinoma metastasis
CN104284895A (zh) * 2012-04-17 2015-01-14 安斯泰来制药株式会社 含氮双环式芳香族杂环化合物
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