WO2002088095A1 - Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) - Google Patents
Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) Download PDFInfo
- Publication number
- WO2002088095A1 WO2002088095A1 PCT/GB2002/002029 GB0202029W WO02088095A1 WO 2002088095 A1 WO2002088095 A1 WO 2002088095A1 GB 0202029 W GB0202029 W GB 0202029W WO 02088095 A1 WO02088095 A1 WO 02088095A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- dihydro
- pyrrolo
- dichlorophenyl
- compounds
- Prior art date
Links
- 0 Cc1c(*)c(I)nc(*)n1 Chemical compound Cc1c(*)c(I)nc(*)n1 0.000 description 7
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0463—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0465—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- 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
- A61P27/14—Decongestants or antiallergics
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to bicyclic derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy.
- CRF corticotropin-releasing factor
- CRF In addition to its role in stimulating the production of ACTH and POMC, CRF appears to be one of the pivotal central nervous system neurotransmitters and plays a crucial role in integrating the body's overall response to stress.
- CRF receptor antagonists may represent novel antidepressant and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
- the first CRF receptor antagonists were peptides (see, e.g., Rivier et al., U.S. Patent No. 4,605,642; Rivier et al., Science 224: 889,1984). While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported.
- WO 95/10506 describes inter alia compounds of general formula (A) with general CRF antagonist activity
- Y may be CR29; V and Z may be nitrogen and carbon, R3 may correspond to an amine derivative and R4 may be taken together with R29 to form a 5-membered ring and is - CH(R28) when R29 is-CH(R30).
- R3 may correspond to an amine derivative
- R4 may be taken together with R29 to form a 5-membered ring and is - CH(R28) when R29 is-CH(R30).
- a and Y may be nitrogen and carbon and B may correspond to an amine derivative.
- A may be nitrogen
- G may be nitrogen or carbon
- B may be an amino derivative and the other groups have the meanings as defined.
- CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
- the invention relates to novel compounds which are potent and specific antagonists of corticotropin-releasing factor (CRF) receptors.
- CCF corticotropin-releasing factor
- the present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof
- R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, -COR_ t , nitro, -NR 9 R, 0 cyano, and a group R 5 ; Ri is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo Cl-
- R 2 is hydrogen, C3-C7 cycloalkyl, or a group R ⁇ ;
- R 3 has the same meanings as R 2 , but R 2 and R 3 may not be simultaneously hydrogen; or R 2 and R 3 together with N form a saturated or unsaturated heterocycle, which may be substituted by 1 to 3 R 7 groups; or
- R 2 and R 3 together with N form a 5-10 membered heteroaryl group, in which the 5-membered heteroaryl group contains at least one heteroatom selected from oxygen, sulphur or nitrogen and the 6-10 membered heteroaryl group contains from 1 to 3 nitrogen atoms and wherein said 5-10 membered heteroaryl may be substituted by 1 to 3 R 7 groups;
- R4 is a Cl-C4 alkyl, -OR 9 or -NR 9 Ri 0 ;
- R 5 is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by
- Re is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloCl-C6 alkoxy, hydroxy, haloCl-C6 alkyl;
- R 7 is a group R5, a group Rg, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 9 R ⁇ 0 , phenyl which may be substituted by 1 to 4 R 8 groups;
- R 8 is C1-C6 alkyl, halo C1-C2 alkyl, halogen, nitro, C1-C6 alkoxy or cyano;
- R 9 is hydrogen or C1-C6 alkyl;
- Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, malic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, p-toluensulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.
- the solvates may, for example, be hydrates.
- references hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.
- prodrugs are also included within the context of this invention.
- Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
- Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
- Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
- prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I).
- esters may be employed, such as methyl esters, ethyl esters, and the like.
- the compounds of structure (I) may have chiral centers and may occur as recemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
- C1-C6 alkyl refers to a linear or branched alkyl group containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl.
- C3-C7 cycloalkyl group means a non aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; while unsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and the like.
- halogen refers to a fluorine, chlorine, bromine or iodine atom.
- halo C1-C6 alkyl, or halo C1-C2 alkyl means an alkyl group having one or more carbon atoms and wherein at least one hydrogen atom is replaced with halogen such as for example a trifluoromethyl group and the like.
- C2-C6 alkenyl defines straight or branched chain hydrocarbon radicals containing one or more double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl and the like.
- C1-C6 alkoxy group may be a linear or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
- halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as defined before substituted with at least one halogen, preferably fluorine, such as OCHF 2 , or OCF 3 .
- C2-C6 alkynyl defines straight or branched chain hydrocarbon radicals containing one or more triple bond and having from 2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-pentynyl, 3 -methyl- 1-butynyl and the like.
- aryl means an aromatic carbocyclic moiety such as phenyl, biphenyl or naphthyl.
- heteroaryl means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems.
- heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, and quinazolinyl.
- heterocycle means a 5 to 7-membered monocyclic, or 7-to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings.
- the heterocycle may be attached via any heteroatom or carbon atom.
- Heterocycles include heteroaryls as defined above.
- heterocycles also include (but are not limited to) mo ⁇ holinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- 5-6 membered heterocycle means, according to the above definition, a 5-6 monocyclic heterocyclic ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
- Heterocycles include heteroaryls as defined above. The heterocycle may be attached via any heteroatom or carbon atom.
- the term include (but are not limited to) mo ⁇ holinyl, pyridinyl, pyrazinyl, pyrazolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- the CRF receptor antagonists of this invention have structure (la), and, when n is 2, then the CRF receptor antagonists of this invention have structure (lb), wherein R, Ri, R 2 and R 3 are defined as above.
- R 2 and R 3 together with N form a saturated or unsaturated heterocycle, which may be substituted by 1 to 3 R 7 groups or R 2 and R 3 together with N form a 5-10 membered heteroaryl group, in which the 5- membered heteroaryl group contains at least one heteroatom selected from oxygen, sulphur or nitrogen and the 6-10 membered heteroaryl group contains from 1 to 3 nitrogen atoms and wherein said 5-10 membered heteroaryl may be substituted by 1 to 3 R 7 groups, such R 7 groups are defined as above.
- the CRF receptor antagonists of this invention include compounds having the following structures (Ia-1), (Ia-2), (Ib-1), (Ib-2).
- More specific embodiments of the invention include, but are not limited to, compounds of general formula (Ia-1), (Ia-2), (Ib-1), and (Ib-2), in which the group NR 2 R 3 represents a secondary amine or a tertiary amine.
- compounds of formula (1-1), (1-2), (1-3), (1-4), (1-5), (2-1), (2-2), (2-3), (3-1), (3-2), (3-3), (4-1), (4-2) are preferred
- R 1; R 2 , R have the meanings as defined before. Examples of such compounds are reported in the Experimental Part.
- inventions include, but are not limited to, compounds of the formula (Ia-1), (Ia-2), (Ib-1) and (Ib-2), in which the group NR 2 R 3 represents a 5-6 membered heterocycle.
- R b R and R 7 have the meanings as defined before. Examples of such compounds are reported in the Experimental Part.
- Even more preferred embodiments of the invention include, but are not limited to, compounds of the formula (I); (la), (lb), (Ic), (Id); (Ia-1), (Ia-2), (Ib-1), (Ib-2), (Ic-1), (Ic-2), (Id-1), (Id-2), (1-1), (1-2), (1-3), (1-4), (1-5), (1-6), (1-7), (1-8), (1-9), (1-10), (1-11), (1-12), (2-1), (2-2), (2-3), (2-4), (2-5), (3-1), (3-2), (3-3), (3-4), (4-1), and (4-2) wherein:
- Ri is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl;
- R is an aryl group selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2- chloro-4-trifiuoromethyl, 2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4- dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4- trifluoromethyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2- methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4- isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4- isopropylphenyl, 2-meth
- Preferred compounds according to the invention are:
- the compounds of structure (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples.
- Compounds of formula (I) may be prepared by reaction of a compound of formula (II), wherein L is a leaving group selected in a group consisting from halogens (preferably
- reaction can be optionally carried out in an aprotic solvent such NN-dimethylformamide in the presence, if desired, of a strong base such as sodium hydride and with heating.
- aprotic solvent such NN-dimethylformamide
- compounds (II) may react with hydrazine to give the corresponding hydrazino derivatives and then they may be cyclised to the desired final compound (I).
- Compounds of formula (II), wherein X is nitrogen are equivalent to compounds of formula (Ila), may be prepared by cyclisation of a compound of formula (IV), wherein p is 1 or 2 and Ra is a suitable protecting group for the amino group.
- the activation of the hydroxy group is performed by conversion into a suitable leaving group, such as mesylate.
- the deprotection of the amino protecting group can be performed, for example, using an acid, such as trifluoroacetic acid, in an aprotic solvent, like dichloromethane.
- the cyclisation may take place in an aprotic solvent such as tetrahydrofuran and in the presence of a tertiary amine such as triethyl amine.
- an aprotic solvent such as tetrahydrofuran
- a tertiary amine such as triethyl amine
- the oxidation is carried out, for example, with ozone at low temperature, e.g. -78°C, in a solvent such as dichloromethane.
- the reduction takes places using for example sodium borohydride in a solvent such as methanol.
- Compounds of formula (IV), wherein p is 2 may be prepared by reduction of an aldehyde of formula (VII) with a suitable reducing agent, such as diisobutylaluminumhydride in usual conditions (aprotic solvent such as dichloromethane at low temperature, e.g. 0°C).
- a suitable reducing agent such as diisobutylaluminumhydride in usual conditions (aprotic solvent such as dichloromethane at low temperature, e.g. 0°C).
- VHI Aldehydes
- the oxidation is carried out in the presence of ozone at low temperature, e.g. -78°C, in a solvent such as dichloromethane.
- compounds of formula (IVc) may be prepared by reaction of a compound of formula (DC) with amine (X), in which Rb is a suitable protecting group for the hydroxy group.
- reaction preferably takes place in an aprotic solvent such as dichlorometane or N,N- dimethyl formamide optionally in the presence of a tertiary amine (e.g. triethylamine).
- a tertiary amine e.g. triethylamine.
- Compounds (IVc) may be subjected to deprotection and then activation of the hydroxy group (e.g mesylate) as described before followed by in situ cyclisation
- Compounds of formula (XI) may be prepared from compounds of formula (XII) by conversion of the hydroxy groups in suitable leaving groups.
- the halogenation reaction may be carried out using conventional methods known in the art.
- the reaction may be carried out by treatment with PO(Hal)3, wherein Hal is preferably chlorine.
- the reaction preferably takes place in an aprotic solvent such as tetrahydrofuran, dichlorometane or N,N-dimethylformamide in the presence of a strong base such sodium hydride and by heating.
- an aprotic solvent such as tetrahydrofuran, dichlorometane or N,N-dimethylformamide
- the halogenation reaction may be carried out using conventional methods known in the art.
- the reaction may be carried out by treatment with PO(Hal)3, wherein Hal is preferably chlorine.
- the reaction is carried out in the presence of an alkaline organic base C1-C4 (e.g. sodium methoxide) in a solvent such as methyl alcohol.
- an alkaline organic base C1-C4 e.g. sodium methoxide
- a solvent such as methyl alcohol.
- the cyclisation may be carried out in the presence of an organic alkaline C1-C4 alkoxyde
- Compounds of formula (XVII) can be prepared by reaction of a compound of formula (XVi ⁇ ) with a compound of formula (XIX), wherein L is preferably a bromine or iodine atom.
- the reaction is carried out in aprotic solvent such as an ether e.g. tetrahydrofuran at low temperature, e.g. -78°C, and in the presence of a strong base such as Lithium diisopropylamide .
- aprotic solvent such as an ether e.g. tetrahydrofuran at low temperature, e.g. -78°C
- a strong base such as Lithium diisopropylamide .
- compounds of formula (XVIa), corresponding to compounds of formula (XVI) when n is 2, may be prepared according to the following scheme from cyclohexanone. It can be converted to its reactive enol ether (such as a triflate, as in Lai and McAllister; Synth.Commun.; 29; 3; 1999; p 409), then coupled with an organic metallic derivative of R (such as a boronic acid derivative, as in Suzuki, Akira; J.Org.Chem.; 58; 8; 1993; p 2201) to give the substituted cyclohexene, which can be epoxidised, using for example chloro- peroxybenzoic acid, and converted to a carbonyl group under acidic conditions (using, for example, sulfuric acid, as in Crotti, P.
- R organic metallic derivative of R
- the ketone thus obtained can be carboxymethylated, using a strong base (such as lithium diisopropyl amide) and an acylating agent (such as ethyl cyanoformate).
- a strong base such as lithium diisopropyl amide
- an acylating agent such as ethyl cyanoformate
- compounds of formula (XVIb), corresponding to compounds of formula (XVI) when n is 1, may be prepared according to the following scheme from 2- chloro-cyclopentanone, by reaction with a suitable Grignard derivative of the group R and then carboxymethylated as described above.
- Pharmaceutical acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.
- the compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation or evaporation of an appropriate solvent to give the corresponding solvates.
- the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formulas I and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
- Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are inco ⁇ orated, are useful in drug and/or substrate tissue distribution assays.
- Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
- U C and 8 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
- substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
- Isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- the CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site including CRF 1 and CRF 2 receptors and may be used in the treatment of conditions mediated by CRF or CRF receptors.
- Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with CRF.
- a compound of structure (I) may be assessed for activity as a CRF antagonist by one or more generally accepted assays for this pu ⁇ ose, including (but not limited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7: 88,1987) and Battaglia et al. (Synapse 1 : 572,1987).
- the CRF receptors-binding assay was performed by using the homogeneous technique of scintillation proximity (SPA).
- SPA scintillation proximity
- the ligand binds to recombinant membrane preparation expressing the CRF receptors which in turn bind to wheatgerm agglutinin coated SPA beads.
- SPA scintillation proximity
- CRF receptor antagonists of this invention have a Ki less than 10 ⁇ m.
- a CRF receptor antagonist has a Ki comprised in a range from 0.1 nM and 10 ⁇ m.
- the value of Ki is less than 1 ⁇ m and more preferably less than 0.1 ⁇ m.
- the Ki values of representative compounds of this invention were assayed by the methods set forth in Example 5.
- Preferred compounds having a Ki of less than 1 ⁇ m are compound numbers 1-10-9, 1-10-11, 1-10-16, 1-10-19, 1-10-23, 1-10-24, 1-10-31, 1-10-32, 1-10-33, 1-10-40, 1-11-2, 2-2-5, 2-3-5, 2-3-6 and 2-5-2.
- More preferred compounds having a Ki less than 0.1 ⁇ m are compound numbers 1-1-1, 1-1-2, 1-1-3, 1-2-1, 1-2-2, 1-2-3, 1-2-4, 1-4-1, 1-4-2, 1-4-3, 1-4-4, 1-6-3, 1-7-3, 1-10-1, 1-10-2, 1-10- 6, 1-10-7, 1-10-15, 1-10-18, 1-10-30, 2-5-1, 3-1-1, 3-2-1 and 3-3-1.
- Compounds of the invention may be useful in the treatment of central nervous system disorders where CRF receptors are involved.
- major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, the treatment of anxiety and the treatment of panic disorders.
- Major depressive disorders include dysthymic disorder with early or late onset and with or without atypical features, neurotic depression, post traumatic stress disorders and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.
- Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
- Compounds of the invention are useful as analgesics.
- traumatic pain such as postoperative pain
- traumatic avulsion pain such as brachial plexus
- chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis
- neuropathic pain such as post-he ⁇ etic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain
- various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain
- Compounds of the invention are also useful for the treatment of dysfunction of appetite and food intake and in circumstances such as anorexia, anorexia nervosa and bulimia.
- Compounds of the invention are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy, and circadiananderic disorders. Compounds of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
- compounds of the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.
- Compounds of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidine like compounds), or in the treatment of tolerance to and dependence on opiates (e.g. cannabis, heroin, mo ⁇ hine) or benzodiazepines; in the treatment of cocaine, sedative ipnotic, amphetamine or amphetamine- related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof.
- opiates e.g. cannabis, heroin, mo ⁇ hine
- benzodiazepines e.g. cocaine, sedative ipnotic, amphetamine or amphetamine- related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof.
- Compounds of the invention are also useful as anti-inflammatory agents.
- they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD) and non- steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as he ⁇ es and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation.
- IBD inflammatory bowel disease
- Compounds of the invention are also useful in the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
- Emesis i.e. nausea, retching and vomiting.
- Emesis includes acute emesis, delayed emesis and anticipatory emesis.
- the compounds of the invention are useful in the treatment of emesis however induced.
- emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.
- cytarabine methotrexate and 5- fluorouracil
- vinca alkaloids e.g. etoposide, vinblastine and vincristine
- others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof
- radiation sickness e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g.
- gastritis or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g.
- opioid analgesics such as mo ⁇ hine
- gastro-oesophageal reflux disease acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
- Compounds of the invention are of particular use in the treatment of gastrointestinal disorders such as irritable bowel syndrome (IBS); skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
- IBS irritable bowel syndrome
- skin disorders such as psoriasis, pruritis and sunburn
- vasospastic diseases such as angina, vascular headache and Reynaud's disease
- cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrh
- Compounds of the invention are of particular use in the treatment of depressive states, in the treatment of anxiety and of panic disorders.
- Depressive states include major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, dysthymic disorder with early or late onset and with or without atypical features, neurotic depression and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type.
- Compounds of the invention are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia, anoxia, perinatal asphyxia cardiac arrest.
- the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.
- a method for the treatment of a mammal including man, in particular in the treatment of condition mediated by CRF, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
- compositions which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route.
- Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
- compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
- the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
- binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
- fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
- lubricants e.g. magnesium stearate, talc or silica
- disintegrants e.g. potato starch or sodium starch glycollate
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
- the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
- Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
- composition may take the form of tablets or formulated in conventional manner.
- the compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- the compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
- Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
- the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
- a proposed dose of the compounds of the invention is 1 to about lOOOmg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian.
- the dosage will also depend on the route of administration and the particular compound selected. Thus for parenteral administration a daily dose will typically be in the range of 1 to about 100 mg, preferably 1 to 80 mg per day. For oral administration a daily dose will typically be within the range 1 to 300 mg e.g. 1 to 100 mg.
- EtOAc ethyl acetate
- cHex cyclohexane
- CH2CI2 dichloromethane
- Et2 ⁇ dietyl ether
- DMF N,N'-dimethylformamide
- DIPEA N,N-diisopropylethylamine
- MeOH methanol
- Et3N triethylamine
- TFA trifluoroacetic acid
- THF tetrahydrofuran
- DIBAL-H diisobutylaluminium hydride
- DMAP dimethylaminopyridine
- LHMDS lithiumhexamethyldisilazane
- Tic refers to thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate
- r.t. (RT) refers to room temperature.
- reaction mixture was first flushed with oxygen and then with nitrogen for 10 min.
- NaBH 4 90 mg
- temperature was allowed to warm up to 22°C.
- the solution was stirred for 3 hr at r.t..
- the reaction mixture was acidified with glacial AcOH, diluted with EtOAc and washed with water (2x20 mL) and with diluted aqueous NaHC0 3 (2x20 mL) and dried over anh. Na 2 S0 4 .
- the solids were filtered and the solvent evaporated.
- the title compound was obtained as a pale yellow oil (1 g, 3.48 mmol, 85%), as a mixture of two diastereoisomers in a 7:3 ratio and was used in the following step without further purification.
- Acetamidine hydrochloride 50 mg, 2.3 eq. was added to a solution of freshly prepared MeONa (37 mg, 2.3 eq.) in anh. MeOH (1 mL). The resulting suspension was filtered and added to a flask containing intermediate 42 (65 mg, 0.23 mmol) in anh. MeOH (1 mL). The reaction mixture was stirred for 1 day and then a second portion of the free acetamidine was prepared as described above and added to the reaction flask. After stirring for 2 days, the solution was concentrated in vacuo and the crude oil was purified by flash chromatography (silica gel, 100% EtOAc).
- example 1-2-5 The sequence for the preparation of example 1-2-5 is similar to the preparation of example 1- 2-1 (intermediate 1 to intermediate 8) except that 2,2,2-trifluoroacetamidine hydrochloride was used instead of acetamidine hydrochloride in the first step (intermediate 1).
- the compounds 1-10-35 and 1-10-38 whose analytical data are reported in the following Table 1-10, were prepared analogously using lH-pyrazole-3-carboxylic acid ethyl ester instead of 2-(lH-pyrazol-3-yl)-thiazole.
- the ester group was then transformed into the corresponding N-methyltriazole and oxadiazole following procedures known in the literature (J.Het.Chem., 1986, 1391).
- Compound 1-10-36 whose analytical data are reported in the following Table 1-10, was prepare by methylation of compound 1-10-37 using NaH as a base and methyl iodide as a methylating agent.
- 3-Bromopyrazole (21 mg) was added to a suspension of Na ⁇ 80%/oil (4 mg) in anh. DMF (300 ⁇ L). After stirring for 30 min at r.t., intermediate 8 (15 mg) was added at and the resulting mixture was heated at 110° C for 3 hr. The reaction was then concentrated in vacuo and the residue was diluted with ⁇ 2 0 and extracted with CH 2 C1 2 (3x5mL). The combined organic extracts were dried over anh. Na 2 S0 4 , the solids were filtered and the solvent evaporated. The tilte compound was obtained as a white solid (3.5 mg) after two chromatographic purifications (silica gel, EtOAc/cHex 95:5).
- 3-(3-chloro phenyl) pyrazole (3 eq, 0.19 mmol) was added to a solution of Na ⁇ 80%/oil (6 mg, 3eq) in anh. DMF (0.5 mL) at 0°C. After 10 min, intermediate 8 (20 mg, 0.064mmol) was added and the solution was heated in a sealed vial at 100°C for 3 hr. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were dried over anh. Na 2 S0 , the solids were filtered and the solvent evaporated.
- 4-1-1 and 4-2- 1 ( 1 -bromo-2,4-dimethoxybenzene), 4-1-2 and 4-2-2 (2-bromo-5-fluoro-toluene) and 4-2-3 (2-bromo-5-methyl-toluene).
- CRF binding affinity has been determined in vitro by the compounds' ability to displace 125 I- oCRF and 125 I-Sauvagine for CRFl and CRF2 SPA, respectively, from recombinant human CRF receptors expressed in Chinese Hamster Ovary (CHO) cell membranes.
- CHO cells from confluent T-flasks were collected in SPA buffer (HEPES/KOH 50mM, EDTA 2mM; MgCl 2 lOmM, pH 7.4.) in 50mL centrifuge tubes, homogenized with a Polytron and centrifuged (50'000g for 5min at 4°C: Beckman centrifuge with JA20 rotor). The pellet was resuspended, homogenized and centrifuged as before.
- the SPA experiment has been carried out in Optiplate by the addition of 100 ⁇ L the reagent mixture to l ⁇ L of compound dilution (100%o DMSO solution) per well.
- the assay mixture was prepared by mixing SPA buffer, WGA SPA beads (2.5 mg/mL), BSA (1 mg/mL) and membranes (50 and 5 ⁇ g of protein/mL for CRFl and CRF2 respectively) and 50 pM of radioligand.
- Compounds of the invention were characterised in a functional assay for the determination of their inhibitory effect.
- Human CRF-CHO cells were stimulated with CRF and the receptor activation was evaluated by measuring the accumulation of cAMP.
- CHO cells from a confluent T-flask were resuspended with culture medium without G418 and dispensed in a 96-well plate, 25'000c/well, 100 ⁇ L/well and incubated overnight. After the incubation the medium was replaced with 100 ⁇ L of cAMP IBMX buffer warmed at 37°C (5mM KCl, 5mM NaHC0 3 , 154mM NaCl, 5mM HEPES, 2.3mM CaCl 2 , ImM MgCl 2 ; lg/L glucose, pH 7.4 additioned by lmg/mL BSA and ImM IBMX) and l ⁇ L of antagonist dilution in neat DMSO.
- cAMP IBMX buffer warmed at 37°C
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA03009938A MXPA03009938A (es) | 2001-04-30 | 2002-04-30 | Pirimidinas fusionadas como antagonistas del factor liberador de corticotropina. |
CA002446514A CA2446514A1 (en) | 2001-04-30 | 2002-04-30 | Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) |
DE60225127T DE60225127T2 (de) | 2001-04-30 | 2002-04-30 | Kondensierte pyrimidine als antagonisten des corticotropin releasing factor (crf) |
EP02722478A EP1383747B1 (en) | 2001-04-30 | 2002-04-30 | Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) |
US10/476,368 US7279474B2 (en) | 2001-04-30 | 2002-04-30 | Substituted pyrrolo[2,3-d]pyrimidines as antagonists of the corticotropin releasing factor (CRF) |
ES02722478T ES2301633T3 (es) | 2001-04-30 | 2002-04-30 | Pirimidinas condensadas como antagonistas del factor de liberacion de corticotropina (crf). |
JP2002585397A JP2004528349A (ja) | 2001-04-30 | 2002-04-30 | 副腎皮質刺激ホルモン放出因子(crf)のアンタゴニストとしての縮合ピリミジン類 |
KR10-2003-7014160A KR20040015206A (ko) | 2001-04-30 | 2002-04-30 | 코르티코트로핀 방출 인자 (crf)의 길항제로서의 접합피리미딘 |
BR0209267-0A BR0209267A (pt) | 2001-04-30 | 2002-04-30 | Pirimidinas fundidas como antagonistas do fator de liberação de corticotropina (crf) |
IL15806202A IL158062A0 (en) | 2001-04-30 | 2002-04-30 | Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) |
AU2002253357A AU2002253357B2 (en) | 2001-04-30 | 2002-04-30 | Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) |
HU0304054A HUP0304054A2 (hu) | 2001-04-30 | 2002-04-30 | A kortikotropin-realising faktor (CRF) antagonistáiként alkalmazható kondenzált pirimidinek, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények |
NO20034836A NO20034836D0 (no) | 2001-04-30 | 2003-10-29 | Sammensmeltede pyrimidiner som antagonister av kortikotropinfrigivelsesfaktoren (CRF) |
Applications Claiming Priority (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0110569A GB0110569D0 (en) | 2001-04-30 | 2001-04-30 | Chemical compounds |
GB0110567A GB0110567D0 (en) | 2001-04-30 | 2001-04-30 | Chemical compounds |
GB0110569.1 | 2001-04-30 | ||
GB0110567.5 | 2001-04-30 | ||
GB0110570A GB0110570D0 (en) | 2001-04-30 | 2001-04-30 | Chemical compounds |
GB0110570.9 | 2001-04-30 | ||
GB0117420.0 | 2001-07-17 | ||
GB0117401A GB0117401D0 (en) | 2001-07-17 | 2001-07-17 | Chemical compounds |
GB0117420A GB0117420D0 (en) | 2001-07-17 | 2001-07-17 | Chemical compounds |
GB0117399A GB0117399D0 (en) | 2001-07-17 | 2001-07-17 | Chemical compounds |
GB0117401.0 | 2001-07-17 | ||
GB0117399.6 | 2001-07-17 | ||
GB0203201A GB0203201D0 (en) | 2002-02-11 | 2002-02-11 | Chemical compounds |
GB0203201.9 | 2002-02-11 | ||
GB0206834.4 | 2002-03-22 | ||
GB0206834A GB0206834D0 (en) | 2002-03-22 | 2002-03-22 | Chemical compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002088095A1 true WO2002088095A1 (en) | 2002-11-07 |
Family
ID=27571152
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2002/002029 WO2002088095A1 (en) | 2001-04-30 | 2002-04-30 | Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) |
Country Status (19)
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004094420A1 (en) * | 2003-04-09 | 2004-11-04 | Sb Pharmco Puerto Rico Inc | Condensed n-heterocyclic compounds and their use as crf receptor antagonists |
WO2004099209A1 (en) * | 2003-05-05 | 2004-11-18 | F. Hoffmann-La-Roche Ag | Fused pyrimidine derivatives with crf activity |
WO2005014557A1 (en) * | 2003-08-12 | 2005-02-17 | F.Hoffmann-La Roche Ag | Tetrahydroquinazoline derivatives as cfr antagonists |
WO2005085253A1 (en) * | 2004-03-05 | 2005-09-15 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine derivatives |
WO2006001501A1 (en) * | 2004-06-25 | 2006-01-05 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with tetrahydropyridine as crf antagonists |
JP2006515334A (ja) * | 2003-01-16 | 2006-05-25 | エスビー ファームコ プエルト リコ インコーポレーテッド | CRF受容体アンタゴニストとしてのヘテロアリール置換ピロロ[2,3−b]ピリジン誘導体 |
US7135476B2 (en) | 2003-08-12 | 2006-11-14 | Roche Palo Alto Llc | Spiro tetrahydroquinazolines and dihydrocyclopentapyrimidines as CRF antagonists |
JP2007517793A (ja) * | 2004-01-06 | 2007-07-05 | 大正製薬株式会社 | 環状アミノ基によって置換されたチエノピリミジン及びチエノピリジン誘導体 |
WO2009107767A1 (ja) * | 2008-02-29 | 2009-09-03 | 大日本住友製薬株式会社 | H4受容体アンタゴニスト作用を有する新規2環性ピリミジン誘導体 |
US8178543B2 (en) | 2004-06-02 | 2012-05-15 | Takeda Pharmaceutical Company Limited | Bi- and tricyclic fused pyrimidines as tyrosine kinase inhibitors |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
US9533984B2 (en) | 2013-04-19 | 2017-01-03 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9611267B2 (en) | 2012-06-13 | 2017-04-04 | Incyte Holdings Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US9708318B2 (en) | 2015-02-20 | 2017-07-18 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9890156B2 (en) | 2015-02-20 | 2018-02-13 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10611762B2 (en) | 2017-05-26 | 2020-04-07 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002100863A1 (en) * | 2001-06-12 | 2002-12-19 | Glaxo Group Limited | Corticotropin releasing factor antagonists |
GB0117396D0 (en) * | 2001-07-17 | 2001-09-05 | Glaxo Group Ltd | Chemical compounds |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
CN1938309B (zh) * | 2003-12-22 | 2011-11-09 | 史密斯克莱.比奇曼(科克)有限公司 | Crf受体拮抗剂及其相关方法 |
ATE430746T1 (de) * | 2004-10-19 | 2009-05-15 | Smithkline Beecham Cork Ltd | Crf-rezeptor-antagonisten und zugehörige verfahren |
GB0519957D0 (en) * | 2005-09-30 | 2005-11-09 | Sb Pharmco Inc | Chemical compound |
US8088779B2 (en) * | 2005-09-30 | 2012-01-03 | Smithkline Beecham (Cork) Limited | Pyrazolo [1,5-alpha] pyrimidinyl derivatives useful as corticotropin-releasing factor (CRF) receptor antagonists |
US9303040B2 (en) | 2006-07-06 | 2016-04-05 | Array Biopharma Inc. | Substituted piperazines as AKT inhibitors |
CA2656618C (en) * | 2006-07-06 | 2014-08-26 | Array Biopharma Inc. | Cyclopenta [d] pyrimidines as akt protein kinase inhibitors |
US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
JP5231410B2 (ja) | 2006-07-06 | 2013-07-10 | アレイ バイオファーマ、インコーポレイテッド | Aktプロテインキナーゼ阻害剤としてのジヒドロフロピリミジン |
EP2043744A2 (en) * | 2006-07-13 | 2009-04-08 | SmithKline Beecham Corporation | Chemical compounds |
DE102007004303A1 (de) | 2006-08-04 | 2008-02-07 | Osram Opto Semiconductors Gmbh | Dünnfilm-Halbleiterbauelement und Bauelement-Verbund |
CA3089569C (en) | 2007-06-04 | 2023-12-05 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
EP2173723B3 (en) * | 2007-07-05 | 2014-11-19 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as akt protein kinase inhibitors |
US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
TWI450720B (zh) | 2007-07-05 | 2014-09-01 | Array Biopharma Inc | 作為akt蛋白質激酶抑制劑之嘧啶環戊烷 |
US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
JP5539225B2 (ja) * | 2008-01-09 | 2014-07-02 | アレイ バイオファーマ、インコーポレイテッド | Aktタンパク質キナーゼ阻害剤としての水酸化されたピリミジルシクロペンタン |
EP2247578B1 (en) * | 2008-01-09 | 2013-05-22 | Array Biopharma, Inc. | Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors |
JP2011522828A (ja) | 2008-06-04 | 2011-08-04 | シナジー ファーマシューティカルズ インコーポレイテッド | 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト |
EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
EP2694073B1 (en) | 2011-04-01 | 2018-08-08 | Genentech, Inc. | Combinations of akt and mek inhibitors for treating cancer |
RS56759B1 (sr) | 2011-04-01 | 2018-04-30 | Genentech Inc | Kombinacija akt inhibitor jedinjenja i abiraterona za upotrebu pri terapeutskim tretiranjima |
CN108707151B (zh) | 2011-08-23 | 2022-06-03 | 阿萨纳生物科技有限责任公司 | 嘧啶并-哒嗪酮化合物及其用途 |
US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
WO2014145576A2 (en) | 2013-03-15 | 2014-09-18 | Northwestern University | Substituted pyrrolo(2,3-d)pyrimidines for the treatment of cancer |
CN104193745B (zh) * | 2014-07-30 | 2016-09-28 | 斯芬克司药物研发(天津)股份有限公司 | 一种咪唑并嘧啶羧酸类化合物及其制备方法 |
WO2019198692A1 (en) | 2018-04-09 | 2019-10-17 | Raqualia Pharma Inc. | Fused cyclic urea derivatives as crhr2 antagonist |
WO2021247862A1 (en) * | 2020-06-03 | 2021-12-09 | Yumanity Therapeutics, Inc. | Bicyclic heteroarenes and methods of their use |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995033750A1 (en) * | 1994-06-08 | 1995-12-14 | Pfizer Inc. | Corticotropin releasing factor antagonists |
WO1998008846A1 (en) * | 1996-08-27 | 1998-03-05 | Pfizer Inc. | Substituted 6,6-hetero-bicyclic derivatives |
EP1082960A2 (en) * | 1999-08-27 | 2001-03-14 | Pfizer Products Inc. | Use of CRF antagonists and related compositions for treating depression and modifying the circadian rhytm |
EP1097709A2 (en) * | 1999-10-29 | 2001-05-09 | Pfizer Products Inc. | Use of corticotropin releasing factor antagonists for treating syndrome X |
EP1149583A2 (en) * | 2000-04-13 | 2001-10-31 | Pfizer Products Inc. | Combinations of corticotropin releasing factor antagonists and growth hormone secretagogues |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9022644D0 (en) | 1990-10-18 | 1990-11-28 | Ici Plc | Heterocyclic compounds |
US6403599B1 (en) | 1995-11-08 | 2002-06-11 | Pfizer Inc | Corticotropin releasing factor antagonists |
JP2000038350A (ja) | 1998-05-18 | 2000-02-08 | Yoshitomi Pharmaceut Ind Ltd | 糖尿病治療薬 |
EP1040831A3 (en) | 1999-04-02 | 2003-05-02 | Pfizer Products Inc. | Use of corticotropin releasing factor (CRF) antagonists to prevent sudden death |
US6387894B1 (en) | 1999-06-11 | 2002-05-14 | Pfizer Inc. | Use of CRF antagonists and renin-angiotensin system inhibitors |
AU780052B2 (en) | 1999-09-17 | 2005-02-24 | Abbott Gmbh & Co. Kg | Pyrazolopyrimidines as therapeutic agents |
NZ517575A (en) | 1999-09-30 | 2004-04-30 | Neurogen Corp | Certain alkylene diamine-substituted heterocycles |
-
2002
- 2002-04-30 ES ES02722478T patent/ES2301633T3/es not_active Expired - Lifetime
- 2002-04-30 IL IL15806202A patent/IL158062A0/xx unknown
- 2002-04-30 AT AT02722478T patent/ATE386727T1/de not_active IP Right Cessation
- 2002-04-30 EP EP02722478A patent/EP1383747B1/en not_active Expired - Lifetime
- 2002-04-30 WO PCT/GB2002/002029 patent/WO2002088095A1/en active IP Right Grant
- 2002-04-30 US US10/476,368 patent/US7279474B2/en not_active Expired - Fee Related
- 2002-04-30 CN CNA028107462A patent/CN1649848A/zh active Pending
- 2002-04-30 AU AU2002253357A patent/AU2002253357B2/en not_active Ceased
- 2002-04-30 JP JP2002585397A patent/JP2004528349A/ja active Pending
- 2002-04-30 MX MXPA03009938A patent/MXPA03009938A/es active IP Right Grant
- 2002-04-30 CA CA002446514A patent/CA2446514A1/en not_active Abandoned
- 2002-04-30 HU HU0304054A patent/HUP0304054A2/hu unknown
- 2002-04-30 DE DE60225127T patent/DE60225127T2/de not_active Expired - Fee Related
- 2002-04-30 CZ CZ20032946A patent/CZ20032946A3/cs unknown
- 2002-04-30 BR BR0209267-0A patent/BR0209267A/pt not_active IP Right Cessation
- 2002-04-30 KR KR10-2003-7014160A patent/KR20040015206A/ko not_active Application Discontinuation
- 2002-04-30 AR ARP020101597A patent/AR033295A1/es unknown
- 2002-04-30 PL PL02366934A patent/PL366934A1/xx not_active Application Discontinuation
-
2003
- 2003-10-29 NO NO20034836A patent/NO20034836D0/no not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995033750A1 (en) * | 1994-06-08 | 1995-12-14 | Pfizer Inc. | Corticotropin releasing factor antagonists |
WO1998008846A1 (en) * | 1996-08-27 | 1998-03-05 | Pfizer Inc. | Substituted 6,6-hetero-bicyclic derivatives |
EP1082960A2 (en) * | 1999-08-27 | 2001-03-14 | Pfizer Products Inc. | Use of CRF antagonists and related compositions for treating depression and modifying the circadian rhytm |
EP1097709A2 (en) * | 1999-10-29 | 2001-05-09 | Pfizer Products Inc. | Use of corticotropin releasing factor antagonists for treating syndrome X |
EP1149583A2 (en) * | 2000-04-13 | 2001-10-31 | Pfizer Products Inc. | Combinations of corticotropin releasing factor antagonists and growth hormone secretagogues |
Non-Patent Citations (2)
Title |
---|
CHRISTOS ET AL: "Corticotropin-releasing factor antagonists", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 8, no. 2, February 1998 (1998-02-01), pages 143 - 152, XP002109498, ISSN: 1354-3776 * |
MCCARTHY J R ET AL: "RECENT ADVANCES WITH THE CRF1 RECEPTOR: DESIGN OF SMALL MOLECULE INHIBITORS, RECEPTOR SUBTYPES AND CLINICAL INDICATIONS", CURRENT PHARMACEUTICAL DESIGN, BENTHAM SCIENCE PUBLISHERS, SCHIPHOL, NL, vol. 5, no. 5, 1999, pages 289 - 315, XP000882142, ISSN: 1381-6128 * |
Cited By (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006515334A (ja) * | 2003-01-16 | 2006-05-25 | エスビー ファームコ プエルト リコ インコーポレーテッド | CRF受容体アンタゴニストとしてのヘテロアリール置換ピロロ[2,3−b]ピリジン誘導体 |
JP2006522799A (ja) * | 2003-04-09 | 2006-10-05 | エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド | 縮合n−ヘテロサイクリック化合物およびcrf受容体アンタゴニストとしてのその使用 |
WO2004094420A1 (en) * | 2003-04-09 | 2004-11-04 | Sb Pharmco Puerto Rico Inc | Condensed n-heterocyclic compounds and their use as crf receptor antagonists |
JP4866722B2 (ja) * | 2003-04-09 | 2012-02-01 | スミスクライン ビーチャム (コーク) リミテッド | 縮合n−ヘテロサイクリック化合物およびcrf受容体アンタゴニストとしてのその使用 |
AU2004232551C1 (en) * | 2003-04-09 | 2010-06-17 | Neurocrine Biosciences Inc | Condensed N-heterocyclic compounds and their use as CRF receptor antagonists |
EP2186813A1 (en) * | 2003-04-09 | 2010-05-19 | SmithKline Beecham (Cork) Limited | Condensed N-heterocyclic compounds and their use as CRF receptor antagonists |
US7427630B2 (en) | 2003-04-09 | 2008-09-23 | Sb Pharmaco Puerto Rico Inc. | Condensed N-heterocyclic compounds and their use as CRF receptor antagonists |
AU2004232551B2 (en) * | 2003-04-09 | 2008-09-11 | Neurocrine Biosciences Inc | Condensed N-heterocyclic compounds and their use as CRF receptor antagonists |
WO2004099209A1 (en) * | 2003-05-05 | 2004-11-18 | F. Hoffmann-La-Roche Ag | Fused pyrimidine derivatives with crf activity |
CN100372851C (zh) * | 2003-05-05 | 2008-03-05 | 弗·哈夫曼-拉罗切有限公司 | 具有crf活性的稠合的嘧啶衍生物 |
JP2006525261A (ja) * | 2003-05-05 | 2006-11-09 | エフ.ホフマン−ラ ロシュ アーゲー | Crf活性を有する縮合ピリミジン誘導体 |
KR100767272B1 (ko) * | 2003-05-05 | 2007-10-17 | 에프. 호프만-라 로슈 아게 | Crf 활성을 갖는 융합 피리미딘 유도체 |
US7307082B2 (en) | 2003-05-05 | 2007-12-11 | Roche Palo Alto Llc | Heterocyclic derivatives as CRF antagonists |
US7135476B2 (en) | 2003-08-12 | 2006-11-14 | Roche Palo Alto Llc | Spiro tetrahydroquinazolines and dihydrocyclopentapyrimidines as CRF antagonists |
US7223767B2 (en) | 2003-08-12 | 2007-05-29 | Roche Palo Alto Llc | Tetrahydroquinazolines and dihydrocyclopentapyrimidines as CRF antagonists |
WO2005014557A1 (en) * | 2003-08-12 | 2005-02-17 | F.Hoffmann-La Roche Ag | Tetrahydroquinazoline derivatives as cfr antagonists |
CN100398524C (zh) * | 2003-08-12 | 2008-07-02 | 弗·哈夫曼-拉罗切有限公司 | 作为crf拮抗剂的四氢喹唑啉衍生物 |
JP2007517793A (ja) * | 2004-01-06 | 2007-07-05 | 大正製薬株式会社 | 環状アミノ基によって置換されたチエノピリミジン及びチエノピリジン誘導体 |
WO2005085253A1 (en) * | 2004-03-05 | 2005-09-15 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine derivatives |
US8178543B2 (en) | 2004-06-02 | 2012-05-15 | Takeda Pharmaceutical Company Limited | Bi- and tricyclic fused pyrimidines as tyrosine kinase inhibitors |
WO2006001501A1 (en) * | 2004-06-25 | 2006-01-05 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with tetrahydropyridine as crf antagonists |
WO2009107767A1 (ja) * | 2008-02-29 | 2009-09-03 | 大日本住友製薬株式会社 | H4受容体アンタゴニスト作用を有する新規2環性ピリミジン誘導体 |
US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US10213427B2 (en) | 2010-12-22 | 2019-02-26 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US10813930B2 (en) | 2010-12-22 | 2020-10-27 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US11053246B2 (en) | 2012-06-13 | 2021-07-06 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US11840534B2 (en) | 2012-06-13 | 2023-12-12 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US9611267B2 (en) | 2012-06-13 | 2017-04-04 | Incyte Holdings Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US10131667B2 (en) | 2012-06-13 | 2018-11-20 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
US9745311B2 (en) | 2012-08-10 | 2017-08-29 | Incyte Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
US10947230B2 (en) | 2013-04-19 | 2021-03-16 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US10450313B2 (en) | 2013-04-19 | 2019-10-22 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9533984B2 (en) | 2013-04-19 | 2017-01-03 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11530214B2 (en) | 2013-04-19 | 2022-12-20 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US10040790B2 (en) | 2013-04-19 | 2018-08-07 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11173162B2 (en) | 2015-02-20 | 2021-11-16 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9890156B2 (en) | 2015-02-20 | 2018-02-13 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10632126B2 (en) | 2015-02-20 | 2020-04-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10738048B2 (en) | 2015-02-20 | 2020-08-11 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9801889B2 (en) | 2015-02-20 | 2017-10-31 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10251892B2 (en) | 2015-02-20 | 2019-04-09 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9708318B2 (en) | 2015-02-20 | 2017-07-18 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11014923B2 (en) | 2015-02-20 | 2021-05-25 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11667635B2 (en) | 2015-02-20 | 2023-06-06 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10214528B2 (en) | 2015-02-20 | 2019-02-26 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10016438B2 (en) | 2015-02-20 | 2018-07-10 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11472801B2 (en) | 2017-05-26 | 2022-10-18 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
US10611762B2 (en) | 2017-05-26 | 2020-04-07 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
Also Published As
Publication number | Publication date |
---|---|
BR0209267A (pt) | 2004-06-15 |
HUP0304054A2 (hu) | 2004-04-28 |
NO20034836L (no) | 2003-10-29 |
EP1383747A1 (en) | 2004-01-28 |
CA2446514A1 (en) | 2002-11-07 |
EP1383747B1 (en) | 2008-02-20 |
DE60225127D1 (en) | 2008-04-03 |
ES2301633T3 (es) | 2008-07-01 |
KR20040015206A (ko) | 2004-02-18 |
IL158062A0 (en) | 2004-03-28 |
NO20034836D0 (no) | 2003-10-29 |
AU2002253357B2 (en) | 2006-08-24 |
US20040176400A1 (en) | 2004-09-09 |
MXPA03009938A (es) | 2005-09-07 |
PL366934A1 (en) | 2005-02-07 |
US7279474B2 (en) | 2007-10-09 |
CZ20032946A3 (en) | 2004-05-12 |
CN1649848A (zh) | 2005-08-03 |
AR033295A1 (es) | 2003-12-10 |
JP2004528349A (ja) | 2004-09-16 |
DE60225127T2 (de) | 2009-02-19 |
ATE386727T1 (de) | 2008-03-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2002253357B2 (en) | Fused pyrimidines as antagonists of the corticotropin releasing factor (crf) | |
AU2002253357A1 (en) | Fused pyrimidines as antagonists of the corticotropin releasing factor (CRF) | |
US7427630B2 (en) | Condensed N-heterocyclic compounds and their use as CRF receptor antagonists | |
US20070219232A1 (en) | Chemical Compounds | |
AU2002328899A1 (en) | Hetero-bicyclic CRF antagonists | |
US7462622B2 (en) | Pyrrolo[2, 3-d] pyrimidine derivatives as corticotropin releasing factor antagonists | |
AU2002354916B2 (en) | Chemical compounds | |
AU2002354916A1 (en) | Chemical compounds | |
US20070021429A1 (en) | Condensed n-heterocyclic compounds and their use as crf receptor antagonists | |
US7273871B2 (en) | Phenyl-5,6,6A,7,8,9-hexahydro-4H-1,4,9-triaza-phenalene derivatives as CRF antagonists | |
ZA200307367B (en) | Fused pyrimidines as antagonists of the corticotropin releasing factor (CRF). | |
JP2004528342A (ja) | Crf受容体アンタゴニスト |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE 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 | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 01499/DELNP/2003 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003/07367 Country of ref document: ZA Ref document number: 158062 Country of ref document: IL Ref document number: 200307367 Country of ref document: ZA Ref document number: 528365 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002253357 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002722478 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1-2003-501064 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/009938 Country of ref document: MX Ref document number: PV2003-2946 Country of ref document: CZ Ref document number: 1020037014160 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002585397 Country of ref document: JP Ref document number: 2446514 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 028107462 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2002722478 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10476368 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-2946 Country of ref document: CZ |
|
WWR | Wipo information: refused in national office |
Ref document number: PV2003-2946 Country of ref document: CZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 2002253357 Country of ref document: AU |
|
WWG | Wipo information: grant in national office |
Ref document number: 2002722478 Country of ref document: EP |