WO2006138265A2 - Heterocyclic aspartyl protease inhibitors, preparation and use thereof - Google Patents
Heterocyclic aspartyl protease inhibitors, preparation and use thereof Download PDFInfo
- Publication number
- WO2006138265A2 WO2006138265A2 PCT/US2006/022919 US2006022919W WO2006138265A2 WO 2006138265 A2 WO2006138265 A2 WO 2006138265A2 US 2006022919 W US2006022919 W US 2006022919W WO 2006138265 A2 WO2006138265 A2 WO 2006138265A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- heteroaryl
- arylalkyl
- Prior art date
Links
- 0 CC1=N*CC(*)(*)CN1C Chemical compound CC1=N*CC(*)(*)CN1C 0.000 description 7
- GIZZYXYMDUIPLS-UHFFFAOYSA-N CCOC(c1ccccc11)=NC1c1ccccc1 Chemical compound CCOC(c1ccccc11)=NC1c1ccccc1 GIZZYXYMDUIPLS-UHFFFAOYSA-N 0.000 description 1
- NYPXJMCLORDOTF-IDQNONRSSA-N CCS(N[C@H]1NNC1O)=O Chemical compound CCS(N[C@H]1NNC1O)=O NYPXJMCLORDOTF-IDQNONRSSA-N 0.000 description 1
- UCTCPQSYOGLOSH-UHFFFAOYSA-N CCc1cc(-c2cc(C#N)ccc2)c[s]1 Chemical compound CCc1cc(-c2cc(C#N)ccc2)c[s]1 UCTCPQSYOGLOSH-UHFFFAOYSA-N 0.000 description 1
- ORMKHLRTSBLBSK-FFFFSGIJSA-N C[C@](C(C1=NCCCN11)Br)(c2cc(Br)c[s]2)NC1=N Chemical compound C[C@](C(C1=NCCCN11)Br)(c2cc(Br)c[s]2)NC1=N ORMKHLRTSBLBSK-FFFFSGIJSA-N 0.000 description 1
- FNTLAUMGKABLPH-MYIOLCAUSA-N C[C@](C1C(N2C)=NCC1)(c1cc(Br)c[s]1)NC2=N Chemical compound C[C@](C1C(N2C)=NCC1)(c1cc(Br)c[s]1)NC2=N FNTLAUMGKABLPH-MYIOLCAUSA-N 0.000 description 1
- UAMHBGORKBCRLU-SFHVURJKSA-N C[C@](CC(N1NC2=O)=C2Br)(c2cc(-c3cccc(C#N)c3)c[s]2)NC1=N Chemical compound C[C@](CC(N1NC2=O)=C2Br)(c2cc(-c3cccc(C#N)c3)c[s]2)NC1=N UAMHBGORKBCRLU-SFHVURJKSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P25/28—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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
-
- 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
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- 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
- AD extracellular ⁇ -amyloid
- a ⁇ extracellular ⁇ -amyloid
- intracellular neurofibrillary tangles comprised of abnormally phosphorylated protein tau.
- Individuals with AD exhibit characteristic A ⁇ deposits, in brain regions known to be important for memory and cognition. It is believed that A ⁇ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioral decline.
- Amyloid plaques consist predominantly of A ⁇ peptides comprised of 40 - 42 amino acid residues, which are derived from processing of amyloid precursor protein (APP). APP is processed by multiple distinct protease activities.
- APP amyloid precursor protein
- R 3 and R 4 together with the carbon to which they are attached, form a 3- to 8-membered cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl or heteroaryl ring having O to 3 heteroatoms independently selected from the group consisting of O, N, S, and -N(R)-
- M is independently -(CH 2 )-, -S-, -N(R >1 ⁇ 9 a ⁇ ) ⁇ , -O-, -S(O)-, -S(O) 2 -, or -C(O)-; q is 0, 1 , or 2;
- a and B are independently aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl; E is aryl or heteroaryl; and
- R 27 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, -NO 2 , halo, -CF 3 , -CN, alkyl-CN, - C(O)R 28 , -C(O)OH, -C(O)OR 28 , -C(O)NHR 29 , -C(O)N(alkyl) 2) -C(O)N(alkyl)(aryl),
- the invention comprises the method of treating Alzheimer's disease comprising administering to a patient in need of such treatment a combination of at least one compound of formula I and/or Il and a cholinesterase inhibitor or a modulator of muscarinic receptors, such as, but not limited to, a muscarinic m2 antagonist or an ml muscarinic agonist.
- Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
- Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
- Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
- Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
- Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
- “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
- suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
- Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
- Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one to four of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
- the "heteroaryl” can be optionally substituted by one or more R 21 substituents which may be the same or different, and are as defined herein.
- the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
- Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond.
- the cycloalkenyl ring can be optionally substituted with one or more R 21 substituents which may be the same or different, and are as defined above.
- Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
- suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
- Non- limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
- Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
- Arylheterocycloalkyl means a group derived from a fused aryl and heterocycloalkyl as defined herein.
- Preferred arylcycloalkyls are those wherein aryl is phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms.
- the arylheterocycloalkyl can be optionally substituted by 1-5 R 21 substituents.
- suitable arylheterocycloalkyls include
- arylcycloalkylalkyl "heteroarylcycloalkylalkyl", “arylheterocycloalkylalkyl", “heteroarylheterocycloalkylalkyl", “heteroarylheterocycloalkyl”, “arylcycloalkenyl”, “heteroarylcycloalkenyl”,
- Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
- suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.
- the bond to the parent moiety is through the ether oxygen.
- Arylalkynyl means a group derived from an aryl and alkenyl as defined herein. Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more R 27 substituents. The bond to the parent moiety is through a non-aromatic carbon atom.
- substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group.
- variables can be the same or different.
- R 21 and R 22 are, for example, -N(R 15 )C(O)N(R 16 )(R 17 ) and R 15 and R 16
- a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 - Ci 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(Ci-C 8 )alkyl, (C 2 - Ci 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4
- a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C-i-C 6 )alkanoyloxymethyl, 1-((C 1 - Ce)alkanoyloxy)ethyl, 1 -methyl-1 -((Ci-C 6 )alkanoyloxy)ethyl, (C 1 - C 6 )alkoxycarbonyloxymethyl, N-(CrC 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 - C 6 )alkanoyl, ⁇ -amino(CrC4)alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH
- Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting aspartyl protease and/or inhibiting BACE-1 and thus producing the desired therapeutic effect in a suitable patient.
- salts which are also within the scope of this invention.
- Reference to a compound of formula I or Il herein is understood to include reference to salts thereof, unless otherwise indicated.
- a compound of formula I or Il contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term "salt(s)" as used herein.
- Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-
- All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.
- enantiomeric forms which may exist even in the absence of asymmetric carbons
- rotameric forms which may exist even in the absence of asymmetric carbons
- atropisomers rotameric forms
- diastereomeric forms are contemplated within the scope of this invention.
- a compound of Formula (I) or (II) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within
- some of the compounds of Formula (I) or (II) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. Polymorphic forms of the compounds of formula I or II, and of the salts, solvates and prodrugs of the compounds of formula I or II, are intended to be included in the present invention
- lsotopically labelled compounds of formula (I) or (II) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
- R 3 , R 4 , R 6 , R 6 , R 7 and R 7 are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -O-Si(R 9 )(R 10 )(R 19 ), -SH, -CN, -OR 9 , -C(O)R 8 , -C(O)OR 9 , -C(O)N(R 11 XR 12 ), -SR 19 , -S(O)N(R 11 )(R 12 ), -S(O) 2 N(R 11 )(R 12 ), -N(R 11 )(R 12 ), -N(R 11 )C(O)R 8 , -N(R 11 )S(O)R 10
- R 3 , R 4 , R 6 , R 6' , R 7 and R 7' are preferably selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.
- R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
- Additional groups of preferred compounds of formula I include those where: a) LMs -C(R 6 XR 7 )-
- Q is a bond
- R 3 , R 4 H or alkyl
- Y is C Z is C; or e) T is -C(R 6' )(R 7' )-
- Y is C
- Z is C; and ring A including Y and Z is
- R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl; and
- R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 - cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 - heterocycloalkyl or R 21 -heterocycloalkylalkyl.
- R 2 is H.
- R 3 and R 4 are independently H, alkyl, aryl or heteroaryl; and R 6 'and R 7 are H, alkyl, aryl or heteroaryl.
- An even more preferred group of compounds of formua III is those of the formula:
- R 21 include phenyl wherein the phenyl moiety is optionally substituted by alkyl, optionally substituted phenyl or optionally substituted heteroaryl, wherein the optional substituents on the optionally substituted phenyl or optionally substituted heteroaryl are alkyl, halo, CN or -OR 24 , where R 24 is H, alkyl, aryl or heteroaryl.
- N,N-dimethylformamide DMF
- N-bromosuccinimide NBS ethyl acetate: EtOAc
- MeOH trifluoroacetic acid TFA polymer-bound triphenylphosphine-Pd (0): PS-Ph 3
- P-Pd meta chloroperbenzoic acid mCPBA trimethylsilyl cyanide: TMSCN lithium diisopropylamide: LDA
- the compounds in the invention may be produced by variety of processes known to those skilled in the art and by known processes analogous thereto.
- the following reaction schemes serve as examples of these processes and illustrate routes to prepare specific embodiments; the practitioner is not limited to these methods.
- One skilled in the art will recognize that one route will be optimized depending on the choice appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatability.
- the prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy and IR spectra.
- reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents.
- solvent or reagent it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme and in the preparations and examples described below.
- each variable may be any moiety within that variable's definition.
- the compounds of formula IA can be synthesized according to Reaction Scheme I.
- Compound 1 is reacted with HCO 2 H and HCONH 2 to yield compound 2.
- Compound 2 is then reacted with Et 3 OBF 4 to give compound 3.
- Compound 3 is then reacted with sodium hydride and the halide R 4 X, where X may be, for example Br or I to yield compound 4.
- Compound IA is formed by reacting compound 4 with ammonia and methanol.
- Compounds of formula 1C can be prepared following Reaction Scheme 3 by starting with ketone 10 and reacting it with 2-methyl-2-propanesulfinamide and titanium (IV) ethoxide give compound 11.
- Compound 11 is then reacted with compound 12 and CITi(O-JPr) 3 to give compound 13, which is then reacted with a mineral acid, such as HCI to yield compound 14.
- Compound 14 is reacted with ethyl chlorooxoacetate and a base such as pyridine to yield compound 15, which is then cyclized in base such as sodium ethoxide in ethanol to form compound 16.
- Compound 16 is reacted with H 2 NNHR to give compound 17.
- the compounds of formula 1D can be made following the synthesis outlined in Reaction Scheme 4.
- PG is a protecting group, such as TBDMS ("t- butyldimethylsilyl”) moiety.
- Compound 22 is then reacted with 2-methyl-2- propanesulfinamide and titanium (IV) ethoxide to give compound 23. Reacting compound 23 with R 7 MgBr yields compound 24.
- the compounds of formula Il can be prepared as outlined in Scheme 11.
- the hydroxyl group of 55 can be converted to an azide 56 by treatment with azide under Mitsunobu conditions.
- B5 2 A mixture of B5 (30mg, 0.10 mmol), 3-cyanophenylboronic acid (22 mg, 0.15 mmol), K 2 CO 3 (28 mg, 0.20 mmol), and PS-Ph 3 P-Pd (0.1 mmol/g, 50mg, 0.005 mmol) in ethanol (1 mL) and H 2 O (0.1 mL) was degassed with N 2 and then heated in a microwave reactor at 110 0 C for 20 min. The mixture was filtered and concentrated. The residue was purified by PTLC (10% (2M NH 3 MeOH)/CH 2 CI 2 ) to give 2 (23 mg, 71%).
- Solution B was slowly cannulated to solution A over 20 min. The resulting mixture was stirred at -78 0 C for 3 h, followed by slow warm-up to 0 0 C. Saturated aq. Na 2 SO 4 solution was added dropwise until gas was no longer evolved upon addition. Dry MgSO 4 powder was then added and the mixture was stirred for 10 min before it was filtered and rinsed with EtOAc. The filtrate was concentrated and the residue was purified on silica gel chromatography (1 :1 EtOAc/hexane) to give 2.1 g (62%) of 12 as a brown oil.
- Example 20 A mixture of Example 20 (16 mg, 0.05 mmol), 3-cyanophenylboronic acid (16 mg, 0.11 mmol), Pd(PPh 3 J 4 (8 mg, 0.007 mmol), and K 3 CO 3 (0.5 mL, 1M aq. solution, 0.5 mmol, 10 eq) in 1.5 mL of EtOH was heated at 110 0 C in a microwave reactor for 15 min. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC to afford 7 mg (42%) of Example 21 as a white solid.
- Example 22 Compound K4 (0.002 g, 0.005 mmol) was treated with 20% TFA/CH 2 CI 2 for 1 h. The solution was concentrated, and the residue was purified by reverse phase HPLC to yield Example 22 (0.001 g, 0.003 mmol, 67% yield). MS m/e: 327.2 (M+H).
- the following assays may be used to evaluate the biological properties of the inventive compounds.
- the assay is run in a 3OuI final volume using a 384 well Nunc black plate. 8 concentrations of compound are pre-incubated with enzyme for 30mins at 37C followed by addition of substrate with continued incubation at 37C for 45 mins. The rate of increase in fluorescence is linear for over 1 h and is measured at the end of the incubation period using a Molecular Devices FLEX station plate reader. Kis are interpolated from the IC50s using a Km value of 4uM and the substrate concentration of 2.5uM.
- Pepstatin is used as a control inhibitor (Ki-0.5nM) and is available from Sigma. Nunc 384 well black plates
- Compound is diluted to 3x final concentration in assay buffer containing 3% DMSO. 1OuI of compound is added to 1OuI of 2.25nM enzyme(3x) diluted in assay buffer without DMSO, mixed briefly, spun, and incubated at 37C for 30mins. 3x substrate (7.5uM) is prepared in 1x assay buffer without DMSO. 1OuI of substrate is added to each well mixed and spun briefly to initiate the reaction. Assay plates are incubated at 37 C for 45mins and read on 384 compatible fluorescence plate reader using a 328nm Ex and 393nm Em. BACE-1 Cloning, Protein Expression and Purification.
- a predicted soluble form of human BACE1 (sBACEI , corresponding to amino acids 1-454) is generated from the full length BACE 1 cDNA (full length human BACE1 cDNA in pCDNA4/mycHisA construct; University of Toronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, CA).
- a Hindlll/Pmel fragment from pCDNA4-sBACE1myc/His is blunt ended using Klenow and subcloned into the Stu I site of pFASTBACI(A) (Invitrogen).
- a sBACEI mycHis recombinant bacmid is generated by transposition in DHIOBac cells(GIBCO/BRL).
- Proteins are eluted from the Q-sepharose column with Buffer B (20 mM HEPES, pH 8.0, 500 mM NaCI). The protein peaks from the Q-sepharose column are pooled and loaded onto a Ni-NTA agarose column. The Ni-NTA column is then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCI). Bound proteins are then eluted with Buffer D (Buffer C+250 mM imidazole). Peak protein fractions as determined by the Bradford Assay (Biorad, CA) are concentrated using a Centricon 30 concentrator (Millipore).
- sBACEI purity is estimated to be ⁇ 90% as assessed by SDS-PAGE and Commassie Blue staining. N-terminal sequencing indicated that greater than 90% of the purified sBACEI contained the prodomain; hence this protein is referred to as sproBACEL
- KTEEISEVNLDAEFRHDKC-biotin CIS-Bio International, France
- 5 ⁇ M unlabeled APPsw peptide KTEEISEVNLDAEFRHDK
- 7 nM sproBACEl 20 mM PIPES pH 5.0, 0.1%Brij-35 (protein grade, Calbiochem, San Diego, CA)
- 10% glycerol are preincubated for 30 min at 30°C. Reactions are initiated by addition of substrate in a 5 ⁇ l aliquot resulting in a total volume of 25 ⁇ l.
- the Kj values of the compounds of Examples 1 to 9 and 12 to 20 were determined.
- the Ki values ranged from 1 to 1 ,000,000 nM, with some preferred compound exhibiting Kj values of less than 100 nM.
- Human mature Renin enzyme assay :
- Human Renin is cloned from a human kidney cDNA library and C-terminally epitope- tagged with the V5-6His sequence into pCDNA3.1.
- pCNDA3.1-Renin-V5-6His is stably expressed in HEK293 cells and purified to >80% using standard Ni-Affinity chromatography.
- the prodomain of the recombinant human renin-V5-6His is removed by limited proteolysis using immobilized TPCK-trypsin to give mature-human renin.
- acetyl- and/or butyrylchlolinesterase inhibitors can be used.
- cholinesterase inhibitors are tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, rivastigmine and galantamine being preferred.
- beta secretase inhibitors include beta secretase inhibitors; HMG-CoA reductase inhibitors, such as atorvastatin, lovastatin, simvistatin, pravastatin, fluvastatin and rosuvastatin; non-steroidal anti-inflammatory agents, such as ibuprofen, N-methyl-D-aspartate receptor antagonists, such as memantine, anti- amyloid antibodies including humanized monoclonal antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB 1 receptor antagonists; antibiotics, e.g., docycycline; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity, and cholesterol absorption inhibitors;
- inert, pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
- the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
- Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
- Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
- Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
- the compounds of the invention may also be deliverable transdermally.
- the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
- the compound is administered orally.
- the pharmaceutical preparation is in a unit dosage form.
- the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
- the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
- the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
- a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses.
- Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
- Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
- Tablet- refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents.
- the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
- Oral gels- refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
- Powders for constitution - refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
- Diluent - refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose.
- the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
- Pisi ⁇ tegrants - refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
- Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures.
- the amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
- Binders - refers to substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent.
- Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
- the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
- Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
- Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- AIDS & HIV (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0612545-0A BRPI0612545A2 (en) | 2005-06-14 | 2006-06-12 | protease inhibiting compounds, pharmaceutical compositions and their use |
MX2007016183A MX2007016183A (en) | 2005-06-14 | 2006-06-12 | The preparation and use of compounds as protease inhibitors. |
AU2006259573A AU2006259573A1 (en) | 2005-06-14 | 2006-06-12 | Heterocyclic aspartyl protease inhibitors, preparation and use thereof |
EP06784808A EP1896032B1 (en) | 2005-06-14 | 2006-06-12 | The preparation and use of compounds as protease inhibitors |
CA002610828A CA2610828A1 (en) | 2005-06-14 | 2006-06-12 | Heterocyclic aspartyl protease inhibitors, preparation and use thereof |
JP2008516998A JP4896972B2 (en) | 2005-06-14 | 2006-06-12 | Heterocyclic aspartyl protease inhibitors, their preparation and use |
IL187455A IL187455A0 (en) | 2005-06-14 | 2007-11-18 | Heterocyclic aspartyl protease inhibitors, preparation and use thereof |
NO20080186A NO20080186L (en) | 2005-06-14 | 2008-01-11 | Heterocyclic aspartyl protease inhibitors, preparation and use thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US69054105P | 2005-06-14 | 2005-06-14 | |
US60/690,541 | 2005-06-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006138265A2 true WO2006138265A2 (en) | 2006-12-28 |
WO2006138265A3 WO2006138265A3 (en) | 2007-03-01 |
Family
ID=37467438
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2006/022919 WO2006138265A2 (en) | 2005-06-14 | 2006-06-12 | Heterocyclic aspartyl protease inhibitors, preparation and use thereof |
Country Status (19)
Country | Link |
---|---|
US (2) | US8722708B2 (en) |
EP (2) | EP2345411B1 (en) |
JP (2) | JP4896972B2 (en) |
KR (1) | KR20080028881A (en) |
CN (1) | CN101394852A (en) |
AR (1) | AR056865A1 (en) |
AU (1) | AU2006259573A1 (en) |
BR (1) | BRPI0612545A2 (en) |
CA (1) | CA2610828A1 (en) |
EC (1) | ECSP078004A (en) |
ES (1) | ES2436795T3 (en) |
IL (1) | IL187455A0 (en) |
MX (1) | MX2007016183A (en) |
NO (1) | NO20080186L (en) |
PE (1) | PE20070321A1 (en) |
RU (1) | RU2008100164A (en) |
TW (1) | TW200716643A (en) |
WO (1) | WO2006138265A2 (en) |
ZA (1) | ZA200710385B (en) |
Cited By (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007149033A1 (en) | 2006-06-22 | 2007-12-27 | Astrazeneca Ab | Substituted isoindoles as bace inhibitors and their use |
WO2008073370A1 (en) * | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors containing a tricyclic ring system |
WO2009005470A1 (en) * | 2007-07-05 | 2009-01-08 | Astrazeneca Ab | Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors |
WO2009005471A1 (en) * | 2007-07-05 | 2009-01-08 | Astrazeneca Ab | Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors |
WO2009022961A1 (en) * | 2007-05-15 | 2009-02-19 | Astrazeneca Ab | Pyrrolopyridine derivatives and their use as bace inhibitors |
WO2009032277A1 (en) | 2007-09-06 | 2009-03-12 | Schering Corporation | Gamma secretase modulators |
US7592348B2 (en) | 2003-12-15 | 2009-09-22 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7700603B2 (en) | 2003-12-15 | 2010-04-20 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
WO2010056196A1 (en) * | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 578 |
WO2010056194A1 (en) * | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | 5h-pyrrolo [ 3, 4-b] pyridin derivatives and their use |
WO2010056195A1 (en) * | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 575 |
WO2010056849A1 (en) | 2008-11-13 | 2010-05-20 | Schering Corporation | Gamma secretase modulators |
WO2010075204A2 (en) | 2008-12-22 | 2010-07-01 | Schering Corporation | Gamma secretase modulators |
WO2010075203A1 (en) | 2008-12-22 | 2010-07-01 | Schering Corporation | Gamma secretase modulators |
US7759354B2 (en) | 2005-06-14 | 2010-07-20 | Schering Corporation | Bicyclic guanidine derivatives as asparyl protease inhibitors, compositions, and uses thereof |
US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
WO2010147973A1 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
WO2010147975A1 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
WO2010147969A2 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
US7868000B2 (en) | 2005-06-14 | 2011-01-11 | Schering Corporation | Aspartyl protease inhibitors |
EP2281824A1 (en) | 2009-08-07 | 2011-02-09 | Noscira, S.A. | Furan-imidazolone derivatives, for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders |
WO2011044181A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2011044187A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2011044185A2 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
WO2011115938A1 (en) | 2010-03-15 | 2011-09-22 | Amgen Inc. | Spiro-tetracyclic ring compounds as beta - secretase modulators |
WO2011115928A1 (en) | 2010-03-15 | 2011-09-22 | Amgen Inc. | Amino -dihydrooxazine and amino - dihydrothiazine spiro compounds as beta - secretase modulators and their medical use |
US8071766B2 (en) | 2008-02-01 | 2011-12-06 | Takeda Pharmaceutical Company Limited | HSP90 inhibitors |
US8093254B2 (en) | 2006-12-12 | 2012-01-10 | Schering Corporation | Aspartyl protease inhibitors |
WO2012019056A1 (en) | 2010-08-05 | 2012-02-09 | Amgen Inc. | Amino-iso-indole, amino-aza-iso-indole, amino-dihydroisoquinoline and amino-benzoxazine compounds as beta-secretase modulators and methods of use |
WO2012038438A1 (en) | 2010-09-22 | 2012-03-29 | Janssen Pharmaceutica Nv | 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
US8168630B2 (en) | 2007-04-24 | 2012-05-01 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
US8168641B2 (en) | 2006-06-12 | 2012-05-01 | Schering Corporation | Aspartyl protease inhibitors |
WO2012057247A1 (en) | 2010-10-29 | 2012-05-03 | 塩野義製薬株式会社 | Fused aminodihydropyrimidine derivative |
US8173642B2 (en) | 2005-10-25 | 2012-05-08 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
WO2012069428A1 (en) | 2010-11-22 | 2012-05-31 | Noscira, S.A. | Bipyridine sulfonamide derivatives for the treatment of neurodegenerative diseases or conditions |
WO2012071279A1 (en) | 2010-11-23 | 2012-05-31 | Amgen Inc. | Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use |
WO2012109165A1 (en) | 2011-02-07 | 2012-08-16 | Amgen Inc. | 5-amino-oxazepine and 5-amino-thiazepane compounds as beta-secretase antagonists and methods of use |
WO2012112462A1 (en) | 2011-02-15 | 2012-08-23 | Amgen Inc. | Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use |
WO2012138734A1 (en) | 2011-04-07 | 2012-10-11 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2013028670A1 (en) | 2011-08-22 | 2013-02-28 | Merck Sharp & Dohme Corp. | 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use |
WO2013044092A1 (en) | 2011-09-21 | 2013-03-28 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
US8426447B2 (en) | 2008-09-11 | 2013-04-23 | Amgen Inc. | Spiro-tricyclic ring compounds as beta-secretase modulators and methods of use |
US8426595B2 (en) | 2007-12-11 | 2013-04-23 | Xianhai Huang | Gamma secretase modulators |
US8487099B2 (en) | 2007-11-05 | 2013-07-16 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
US8557826B2 (en) | 2009-10-08 | 2013-10-15 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use |
WO2014062549A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2014062553A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2014078314A1 (en) | 2012-11-15 | 2014-05-22 | Amgen Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
WO2014127881A1 (en) * | 2013-02-25 | 2014-08-28 | Merck Patent Gmbh | 2-amino -3,4-dihydro-quinazoline derivatives and the use thereof as cathepsin d inhibitors |
US9145426B2 (en) | 2011-04-07 | 2015-09-29 | Merck Sharp & Dohme Corp. | Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
US9346811B2 (en) | 2011-03-01 | 2016-05-24 | Janssen Pharmaceutica Nv | 6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
US9580433B2 (en) | 2013-06-12 | 2017-02-28 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-5,6-dihydroimidazo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
US9650371B2 (en) | 2008-06-13 | 2017-05-16 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity |
US9656974B2 (en) | 2009-12-11 | 2017-05-23 | Shionogi & Co., Ltd. | Oxazine derivatives |
US9751886B2 (en) | 2013-06-12 | 2017-09-05 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
US9758513B2 (en) | 2012-10-24 | 2017-09-12 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity |
US9828350B2 (en) | 2010-06-09 | 2017-11-28 | Janssen Pharmaceutica Nv | 5,6-dihydro-2H-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (BACE) |
US9834559B2 (en) | 2013-06-12 | 2017-12-05 | Janssen Pharmaceutica Nv | 4-Amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-3(2H)-one derivatives as inhibitors of beta-secretase (BACE) |
US9840507B2 (en) | 2010-12-22 | 2017-12-12 | Janssen Pharmaceutica, Nv | 5,6-dihydro-imidazo[1,2-a]pyrazin-8-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
US9845326B2 (en) | 2011-03-09 | 2017-12-19 | Janssen Pharmaceutica Nv | Substituted 3,4-dihydropyrrolo[1,2-A]pyrazines as beta-secretase (BACE) inhibitors |
US10106524B2 (en) | 2014-12-18 | 2018-10-23 | Janssen Pharmaceutica Nv | 2,3,4,5-tetrahydropyridin-6-amine and 3,4-dihydro-2H-pyrrol-5-amine compound inhibitors of beta-secretase |
EP3607946A1 (en) | 2012-03-19 | 2020-02-12 | Buck Institute for Research on Aging | App specific bace inhibitors (asbis) and uses thereof |
EP3653609A1 (en) | 2013-02-12 | 2020-05-20 | Buck Institute for Research on Aging | Hydantoins that modulate bace-mediated app processing |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8653067B2 (en) | 2007-04-24 | 2014-02-18 | Shionogi & Co., Ltd. | Pharmaceutical composition for treating Alzheimer's disease |
CN102186841A (en) | 2008-10-22 | 2011-09-14 | 盐野义制药株式会社 | 2-aminopyridin-4-one and 2-aminopyridine derivative both having bace1-inhibiting activity |
JP5816630B2 (en) | 2010-10-29 | 2015-11-18 | 塩野義製薬株式会社 | Naphthyridine derivatives |
JPWO2012147763A1 (en) | 2011-04-26 | 2014-07-28 | 塩野義製薬株式会社 | Oxazine derivatives and BACE1 inhibitors containing the same |
RU2642246C2 (en) * | 2014-12-30 | 2018-01-24 | Федеральное государственное бюджетное научное учреждение "Институт экспериментальной медицины" (ФГБНУ "ИЭМ") | Application of probiotic strain of enterococcus faecium l-3 microorganism for neurodegenerative diseases treatment |
WO2018118829A1 (en) * | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Heterocyclic compounds as hiv protease inhibitors |
JOP20180094A1 (en) | 2017-10-18 | 2019-04-18 | Hk Inno N Corp | Heterocyclic compound as a protein kinase inhibito |
CN110563631B (en) * | 2018-06-05 | 2023-05-23 | 爱斯特(成都)生物制药股份有限公司 | IDO inhibiting compound and application thereof |
Family Cites Families (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1077204A (en) | 1912-11-20 | 1913-10-28 | John Bonner Semple | Tracer for projectiles. |
US3632814A (en) * | 1968-11-25 | 1972-01-04 | Velsicol Chemical Corp | Phosphoramidate esters |
JPS5013951B1 (en) * | 1969-05-23 | 1975-05-23 | ||
DE2430354A1 (en) | 1974-06-25 | 1976-01-15 | Basf Ag | NEW SUBSTITUTED 1-AMINO-ISOINDOLES, PROCESS FOR THEIR MANUFACTURING AND THESE PHARMACEUTICAL PREPARATIONS |
DE2757982C2 (en) * | 1977-12-24 | 1980-02-21 | Basf Ag, 6700 Ludwigshafen | Compounds of the isoindoline series and process for the production of pigments with improved application properties |
DE3371618D1 (en) * | 1982-02-27 | 1987-06-25 | Asahi Chemical Ind | Coloring method and color-forming material |
IL92011A0 (en) * | 1988-10-19 | 1990-07-12 | Abbott Lab | Heterocyclic peptide renin inhibitors |
WO1993004047A1 (en) | 1991-08-16 | 1993-03-04 | Merck & Co., Inc. | Quinazoline derivatives as inhibitors of hiv reverse transcriptase |
DE4419849A1 (en) * | 1994-06-07 | 1995-12-14 | Hoechst Ag | Isoindoline pigments |
US5629322A (en) * | 1994-11-15 | 1997-05-13 | Merck & Co., Inc. | Cyclic amidine analogs as inhibitors of nitric oxide synthase |
JP3666922B2 (en) * | 1995-02-21 | 2005-06-29 | 山本化成株式会社 | Carboxylate, method for producing the same, and thermosensitive recording material using the salt compound |
US5889006A (en) | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
IL117149A0 (en) | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
DE19516804A1 (en) * | 1995-05-08 | 1996-11-14 | Hoechst Ag | Isoindoline pigments based on aminoquinoxalinediones |
US5935958A (en) | 1996-07-01 | 1999-08-10 | Schering Corporation | Muscarinic antagonists |
US5952349A (en) | 1996-07-10 | 1999-09-14 | Schering Corporation | Muscarinic antagonists for treating memory loss |
US5977138A (en) | 1996-08-15 | 1999-11-02 | Schering Corporation | Ether muscarinic antagonists |
WO1999011622A1 (en) * | 1997-09-03 | 1999-03-11 | Guilford Pharmaceuticals Inc. | Amino-substituted compounds, methods, and compositions for inhibiting parp activity |
WO1999033795A1 (en) * | 1997-12-24 | 1999-07-08 | Vertex Pharmaceuticals Incorporated | Prodrugs of aspartyl protease inhibitors |
US6066636A (en) | 1998-06-30 | 2000-05-23 | Schering Corporation | Muscarinic antagonists |
US6420364B1 (en) * | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
HUP0302380A2 (en) * | 1999-09-13 | 2004-03-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | Novel spiroheterocyclic compounds useful as reversible inhibitors of cysteine proteases, process for their preparation and pharmaceutical compositions containing them |
US6294554B1 (en) | 1999-09-22 | 2001-09-25 | Schering Corporation | Muscarinic antagonists |
PE20020276A1 (en) * | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | SUBSTITUTE AMINE COMPOUNDS AS ß-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER |
MXPA03005743A (en) | 2000-12-22 | 2003-09-05 | Schering Corp | Muscarinic antagonists. |
AU2002306734A1 (en) | 2001-03-15 | 2002-10-03 | The Johns Hopkins University | Inhibitors of plasmepsins |
AR034390A1 (en) | 2001-08-03 | 2004-02-25 | Schering Corp | DERIVATIVES OF 1-SULFONIL-TETRAHIDRO REPLACED KINOLINES, PHARMACEUTICAL COMPOSITIONS AND THE USE OF THE SAME FOR THE PREPARATION OF MEDICINES AS INHIBITORS OF THE SECRET RANGE |
ES2269774T3 (en) | 2001-10-10 | 2007-04-01 | Schering Corporation | PIPERIDINE COMPOUNDS AS MUSCARINIC ANTAGONISTS. |
RS52883B (en) * | 2003-12-15 | 2014-02-28 | Merck Sharp & Dohme Corp. | Heterocyclic aspartyl protease inhibitors |
US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
PE20060299A1 (en) * | 2004-06-16 | 2006-05-18 | Wyeth Corp | DIPHENYLIMIDAZOPYRIMIDINE AND -IMIDAZOLE AMINES AS ß-SECRETASE INHIBITORS |
ATE444962T1 (en) | 2004-06-16 | 2009-10-15 | Wyeth Corp | AMINO-5,5-DIPHENYLIMIDAZOLONE DERIVATIVES FOR BETA SECRETASE INHIBITION |
JP4898677B2 (en) | 2004-08-06 | 2012-03-21 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 2-Amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
WO2006017844A1 (en) | 2004-08-06 | 2006-02-16 | Janssen Pharmaceutica, N.V. | NOVEL 2-AMINO-QUINAZOLINE DERIVATIVES USEFUL AS INHIBITORS OF β-SECRETASE (BACE) |
US8436006B2 (en) | 2004-08-06 | 2013-05-07 | Jansssen Pharmaceutica N.V. | 2-amino-quinazoline derivatives useful as inhibitors of β-secretase (BACE) |
WO2006044497A2 (en) | 2004-10-13 | 2006-04-27 | Merck & Co., Inc. | Spiropiperidine compounds useful as beta-secretase inhibitors for the treatment of alzhermer’s disease |
WO2006044492A2 (en) | 2004-10-14 | 2006-04-27 | Ingenious Targeting Laboratory, Inc. | Methods for generating rat embryo-derived cell lines and genetic modification of rat genome |
WO2006041404A1 (en) | 2004-10-15 | 2006-04-20 | Astrazeneca Ab | Substituted amino-compounds and uses thereof |
CN101084198A (en) | 2004-10-15 | 2007-12-05 | 阿斯利康(瑞典)有限公司 | Substituted amino-pyrimidones and uses thereof |
KR20070095948A (en) | 2005-01-14 | 2007-10-01 | 와이어쓰 | AMINO-IMIDAZOLONES FOR THE INHIBITION OF beta;-SECRETASE |
US7812013B2 (en) * | 2005-06-14 | 2010-10-12 | Schering Corporation | Macrocyclic heterocyclic aspartyl protease inhibitors |
US8110682B2 (en) * | 2005-06-14 | 2012-02-07 | Schering Corporation | Preparation and use of compounds as aspartyl protease inhibitors |
TW201004961A (en) * | 2005-06-14 | 2010-02-01 | Schering Corp | Aspartyl protease inhibitors |
TW200738683A (en) | 2005-06-30 | 2007-10-16 | Wyeth Corp | Amino-5-(5-membered)heteroarylimidazolone compounds and the use thereof for β-secretase modulation |
WO2007005404A1 (en) | 2005-06-30 | 2007-01-11 | Wyeth | AMINO-5-(6-MEMBERED)HETEROARYLIMIDAZOLONE COMPOUNDS AND THE USE THEREOF FOR ß-SECRETASE MODULATION |
TW200730523A (en) | 2005-07-29 | 2007-08-16 | Wyeth Corp | Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation |
CA2623245A1 (en) | 2005-09-26 | 2007-04-05 | Wyeth | Amino-5- [4- (difluoromethoxy) phenyl] -5-phenylimidazolone compounds as inhibitors of the beta-secretase (bace) |
PL1966198T3 (en) | 2005-10-25 | 2011-07-29 | Janssen Pharmaceutica Nv | 2-amino-3,4-dihydro-pyrido[3,4-d]pyrimidine derivatives useful as inhibitors of beta-secretase (bace) |
EP2612854B1 (en) | 2005-10-25 | 2015-04-29 | Shionogi&Co., Ltd. | Aminothiazolidine and aminotetrahydrothiazepine derivatives as BACE 1 inhibitors |
PE20070531A1 (en) | 2005-10-27 | 2007-07-13 | Schering Corp | HETEROCYCLIC COMPOUNDS AS INHIBITORS OF ASPARTILE PROTEASES |
CN101351460A (en) | 2005-10-31 | 2009-01-21 | 先灵公司 | Aspartyl protease inhibitors |
TW200804290A (en) | 2005-11-15 | 2008-01-16 | Astrazeneca Ab | Compounds and uses thereof |
AR058381A1 (en) | 2005-12-19 | 2008-01-30 | Astrazeneca Ab | COMPOUNDS DERIVED FROM 2-AMINOPIRIDIN-4-ONAS AND A PHARMACEUTICAL COMPOSITION |
US7776882B2 (en) | 2006-02-06 | 2010-08-17 | Baxter Ellen W | 2-amino-3,4-dihydro-quinoline derivatives useful as inhibitors of β-secretase (BACE) |
WO2007092854A2 (en) | 2006-02-06 | 2007-08-16 | Janssen Pharmaceutica N.V. | 2-AMINO-QUINOLINE DERIVATIVES USEFUL AS INHIBITORS OF β-SECRETASE (BACE) |
WO2007092839A2 (en) | 2006-02-06 | 2007-08-16 | Janssen Pharmaceutica N.V. | Macrocycle derivatives useful as inhibitors of beta-secretase (bace) |
WO2007100536A1 (en) | 2006-02-24 | 2007-09-07 | Wyeth | DIHYDROSPIRO[DIBENZO[A,D][7]ANNULENE-5,4'-IMIDAZOL] COMPOUNDS FOR THE INHIBITION OF β-SECRETASE |
WO2007114771A1 (en) | 2006-04-05 | 2007-10-11 | Astrazeneca Ab | 2-AMINOPYRIMIDIN-4-ONES AND THEIR USE FOR TREATING OR PREVENTING Aβ-RELATED PATHOLOGIES |
KR20090015967A (en) | 2006-06-12 | 2009-02-12 | 쉐링 코포레이션 | Heterocyclic aspartyl protease inhibitors |
TW200815449A (en) | 2006-06-14 | 2008-04-01 | Astrazeneca Ab | Novel compounds II |
US20080051420A1 (en) | 2006-06-14 | 2008-02-28 | Astrazeneca Ab | New Compounds 317 |
TW200808796A (en) | 2006-06-14 | 2008-02-16 | Astrazeneca Ab | New compounds III |
TW200815443A (en) | 2006-06-14 | 2008-04-01 | Astrazeneca Ab | Novel compounds I |
TW200815447A (en) | 2006-06-14 | 2008-04-01 | Astrazeneca Ab | Novel compounds IV |
TW200815349A (en) | 2006-06-22 | 2008-04-01 | Astrazeneca Ab | New compounds |
TW200817406A (en) | 2006-08-17 | 2008-04-16 | Wyeth Corp | Imidazole amines as inhibitors of β-secretase |
WO2008063114A1 (en) | 2006-11-20 | 2008-05-29 | Astrazeneca Ab | Amino- imidazolones and their use as medicament for treating cognitive impairment alzheimer disease, neurodegeneration and dementia |
CA2672295A1 (en) | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors containing a tricyclic ring system |
WO2008073365A1 (en) | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors |
TW200831484A (en) | 2006-12-20 | 2008-08-01 | Astrazeneca Ab | New compounds |
US8653067B2 (en) | 2007-04-24 | 2014-02-18 | Shionogi & Co., Ltd. | Pharmaceutical composition for treating Alzheimer's disease |
ES2476605T3 (en) | 2007-04-24 | 2014-07-15 | Shionogi & Co., Ltd. | Aminohydrotiazine derivatives substituted with cyclic groups |
TW200902499A (en) | 2007-05-15 | 2009-01-16 | Astrazeneca Ab | New compounds |
UY31083A1 (en) | 2007-05-15 | 2009-01-05 | Astrazeneca Ab | SULFOXIMINAL DERIVATIVES FOR THE INHIBITION OF B-SECRETASE |
WO2009005470A1 (en) | 2007-07-05 | 2009-01-08 | Astrazeneca Ab | Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors |
WO2009005471A1 (en) | 2007-07-05 | 2009-01-08 | Astrazeneca Ab | Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors |
CA2687750C (en) | 2007-07-06 | 2016-10-18 | Boehringer Ingelheim International Gmbh | Substituted amino-quinazolinones, medicaments comprising said compound, their use and their method of manufacture |
MY160690A (en) | 2008-01-18 | 2017-03-15 | Eisai R&D Man Co Ltd | Condensed aminodihydrothiazine derivative |
CL2009000119A1 (en) | 2008-01-22 | 2010-03-05 | Boehringer Ingelheim Int | Compounds derived from substituted amino-benzimidazoles; pharmaceutical composition; and its use in the treatment of Alzheimer's. |
EP2238111B1 (en) | 2008-01-28 | 2013-01-16 | Janssen Pharmaceutica NV | 6-substituted-thio-2-amino-quinoline derivatives useful as inhibitors of -secretase (bace) |
ES2397682T3 (en) | 2008-01-29 | 2013-03-08 | Janssen Pharmaceutica Nv | 2-Amino-quinoline derivatives useful as beta-secretase inhibitors (BACE) |
BRPI0907563A2 (en) | 2008-02-18 | 2015-08-04 | Hoffmann La Roche | 4,5-Dihydroxazol-2-ylamine derivatives |
WO2009108550A1 (en) | 2008-02-28 | 2009-09-03 | Merck & Co., Inc. | 2-aminoimidazole beta-secretase inhibitors for the treatment of alzheimer's disease |
AR072952A1 (en) | 2008-04-22 | 2010-10-06 | Schering Corp | 2-IMINO-3-METHYL-PIRROLOPIRIMIDINONA PHENYL-REPLACED COMPOUNDS AS BACE-1 INHIBITORS, COMPOSITIONS AND THEIR USE |
TWI431004B (en) | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Bace inhibitors |
JP5490692B2 (en) | 2008-06-13 | 2014-05-14 | 塩野義製薬株式会社 | Sulfur-containing heterocyclic derivatives having β-secretase inhibitory action |
WO2010013302A1 (en) | 2008-07-28 | 2010-02-04 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Spiroaminodihydrothiazine derivative |
CA2731209A1 (en) | 2008-07-28 | 2010-02-04 | Eisai R&D Management Co., Ltd. | Spiroaminodihydrothiazine derivatives |
CN102171221B (en) | 2008-09-30 | 2013-11-06 | 卫材R&D管理有限公司 | Novel fused aminodihydrothiazine derivative |
CN102186841A (en) | 2008-10-22 | 2011-09-14 | 盐野义制药株式会社 | 2-aminopyridin-4-one and 2-aminopyridine derivative both having bace1-inhibiting activity |
WO2010056195A1 (en) | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 575 |
US20100125081A1 (en) | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 574 |
CA2744425A1 (en) | 2008-11-20 | 2010-05-27 | Purdue Research Foundation | Quinazoline inhibitors of bace 1 and methods of using |
-
2006
- 2006-06-12 JP JP2008516998A patent/JP4896972B2/en not_active Expired - Fee Related
- 2006-06-12 BR BRPI0612545-0A patent/BRPI0612545A2/en not_active IP Right Cessation
- 2006-06-12 WO PCT/US2006/022919 patent/WO2006138265A2/en active Application Filing
- 2006-06-12 CN CNA2006800209186A patent/CN101394852A/en active Pending
- 2006-06-12 AR ARP060102462A patent/AR056865A1/en not_active Application Discontinuation
- 2006-06-12 CA CA002610828A patent/CA2610828A1/en not_active Abandoned
- 2006-06-12 KR KR1020077029569A patent/KR20080028881A/en not_active Application Discontinuation
- 2006-06-12 RU RU2008100164/04A patent/RU2008100164A/en not_active Application Discontinuation
- 2006-06-12 AU AU2006259573A patent/AU2006259573A1/en not_active Abandoned
- 2006-06-12 ES ES11157371.3T patent/ES2436795T3/en active Active
- 2006-06-12 EP EP11157371.3A patent/EP2345411B1/en active Active
- 2006-06-12 MX MX2007016183A patent/MX2007016183A/en active IP Right Grant
- 2006-06-12 US US11/451,065 patent/US8722708B2/en active Active
- 2006-06-12 EP EP06784808A patent/EP1896032B1/en active Active
- 2006-06-13 TW TW095120997A patent/TW200716643A/en unknown
- 2006-06-13 PE PE2006000660A patent/PE20070321A1/en not_active Application Discontinuation
-
2007
- 2007-11-18 IL IL187455A patent/IL187455A0/en unknown
- 2007-11-29 ZA ZA200710385A patent/ZA200710385B/en unknown
- 2007-12-12 EC EC2007008004A patent/ECSP078004A/en unknown
-
2008
- 2008-01-11 NO NO20080186A patent/NO20080186L/en not_active Application Discontinuation
-
2011
- 2011-07-11 JP JP2011153202A patent/JP5454956B2/en not_active Expired - Fee Related
-
2014
- 2014-03-26 US US14/226,338 patent/US9382242B2/en active Active
Non-Patent Citations (1)
Title |
---|
None |
Cited By (107)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8937093B2 (en) | 2003-12-15 | 2015-01-20 | Merck Sharp & Dohme Corp. | Heterocyclic aspartyl protease inhibitors |
US9416108B2 (en) | 2003-12-15 | 2016-08-16 | Merck Sharp & Dohme Corp. | Heterocyclic aspartyl protease inhibitors |
US7763609B2 (en) | 2003-12-15 | 2010-07-27 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7592348B2 (en) | 2003-12-15 | 2009-09-22 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7700603B2 (en) | 2003-12-15 | 2010-04-20 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US8178513B2 (en) | 2003-12-15 | 2012-05-15 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
US7868000B2 (en) | 2005-06-14 | 2011-01-11 | Schering Corporation | Aspartyl protease inhibitors |
US7759354B2 (en) | 2005-06-14 | 2010-07-20 | Schering Corporation | Bicyclic guanidine derivatives as asparyl protease inhibitors, compositions, and uses thereof |
US8173642B2 (en) | 2005-10-25 | 2012-05-08 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
US9029358B2 (en) | 2005-10-25 | 2015-05-12 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
US8629155B2 (en) | 2006-06-12 | 2014-01-14 | Merck Sharp & Dohme, Corp. | Aspartyl protease inhibitors |
US8168641B2 (en) | 2006-06-12 | 2012-05-01 | Schering Corporation | Aspartyl protease inhibitors |
JP2009541311A (en) * | 2006-06-22 | 2009-11-26 | アストラゼネカ・アクチエボラーグ | Substituted isoindoles as BACE inhibitors and their use |
EP2035378A4 (en) * | 2006-06-22 | 2012-01-25 | Astrazeneca Ab | Substituted isoindoles as bace inhibitors and their use |
WO2007149033A1 (en) | 2006-06-22 | 2007-12-27 | Astrazeneca Ab | Substituted isoindoles as bace inhibitors and their use |
US7855213B2 (en) | 2006-06-22 | 2010-12-21 | Astrazeneca Ab | Compounds |
EP2035378A1 (en) * | 2006-06-22 | 2009-03-18 | AstraZeneca AB | Substituted isoindoles as bace inhibitors and their use |
US8093254B2 (en) | 2006-12-12 | 2012-01-10 | Schering Corporation | Aspartyl protease inhibitors |
WO2008073370A1 (en) * | 2006-12-12 | 2008-06-19 | Schering Corporation | Aspartyl protease inhibitors containing a tricyclic ring system |
US8168630B2 (en) | 2007-04-24 | 2012-05-01 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
WO2009022961A1 (en) * | 2007-05-15 | 2009-02-19 | Astrazeneca Ab | Pyrrolopyridine derivatives and their use as bace inhibitors |
US7629356B2 (en) | 2007-05-15 | 2009-12-08 | Astrazeneca Ab | Substituted pyrrolo[3,4-b]pyridinamines and pharmaceutical compositions |
US20100324072A1 (en) * | 2007-05-15 | 2010-12-23 | Astrazeneca Ab | Pyrrolopyridine derivatives and their use as bace inhibitors |
WO2009005470A1 (en) * | 2007-07-05 | 2009-01-08 | Astrazeneca Ab | Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors |
WO2009005471A1 (en) * | 2007-07-05 | 2009-01-08 | Astrazeneca Ab | Aryl and heteroaryl substituted isoindole derivatives as bace inhibitors |
WO2009032277A1 (en) | 2007-09-06 | 2009-03-12 | Schering Corporation | Gamma secretase modulators |
US8487099B2 (en) | 2007-11-05 | 2013-07-16 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
US8426595B2 (en) | 2007-12-11 | 2013-04-23 | Xianhai Huang | Gamma secretase modulators |
US8071766B2 (en) | 2008-02-01 | 2011-12-06 | Takeda Pharmaceutical Company Limited | HSP90 inhibitors |
US8618290B2 (en) | 2008-02-01 | 2013-12-31 | Takeda Pharmaceutical Company Limited | HSP90 inhibitors |
US9650371B2 (en) | 2008-06-13 | 2017-05-16 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity |
US8426447B2 (en) | 2008-09-11 | 2013-04-23 | Amgen Inc. | Spiro-tricyclic ring compounds as beta-secretase modulators and methods of use |
WO2010056849A1 (en) | 2008-11-13 | 2010-05-20 | Schering Corporation | Gamma secretase modulators |
WO2010056196A1 (en) * | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 578 |
CN102282140A (en) * | 2008-11-14 | 2011-12-14 | 阿斯利康(瑞典)有限公司 | New compounds 578 |
US8030500B2 (en) | 2008-11-14 | 2011-10-04 | Astrazeneca Ab | Substituted isoindoles for the treatment and/or prevention of Aβ- related pathologies |
WO2010056195A1 (en) * | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | New compounds 575 |
WO2010056194A1 (en) * | 2008-11-14 | 2010-05-20 | Astrazeneca Ab | 5h-pyrrolo [ 3, 4-b] pyridin derivatives and their use |
WO2010075203A1 (en) | 2008-12-22 | 2010-07-01 | Schering Corporation | Gamma secretase modulators |
WO2010075204A2 (en) | 2008-12-22 | 2010-07-01 | Schering Corporation | Gamma secretase modulators |
JP2012513400A (en) * | 2008-12-22 | 2012-06-14 | シェーリング コーポレイション | γ-secretase modulator |
WO2010147969A2 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
WO2010147975A1 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
WO2010147973A1 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
WO2011015646A2 (en) | 2009-08-07 | 2011-02-10 | Noscira, S.A. | Furan-imidazolone derivatives, for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders |
EP2281824A1 (en) | 2009-08-07 | 2011-02-09 | Noscira, S.A. | Furan-imidazolone derivatives, for the treatment of cognitive, neurodegenerative or neuronal diseases or disorders |
WO2011044181A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US9029362B2 (en) | 2009-10-08 | 2015-05-12 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use |
US9687494B2 (en) | 2009-10-08 | 2017-06-27 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
US9475785B2 (en) | 2009-10-08 | 2016-10-25 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use |
US9428475B2 (en) | 2009-10-08 | 2016-08-30 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
US8729071B2 (en) | 2009-10-08 | 2014-05-20 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use |
EP3034080A1 (en) | 2009-10-08 | 2016-06-22 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US8569310B2 (en) | 2009-10-08 | 2013-10-29 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use |
WO2011044187A1 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US8940748B2 (en) | 2009-10-08 | 2015-01-27 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
WO2011044185A2 (en) | 2009-10-08 | 2011-04-14 | Schering Corporation | Pentafluorosulfur imino heterocyclic compounds as bace-1 inhibitors, compositions, and their use |
US8557826B2 (en) | 2009-10-08 | 2013-10-15 | Merck Sharp & Dohme Corp. | Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use |
US8563543B2 (en) | 2009-10-08 | 2013-10-22 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US9656974B2 (en) | 2009-12-11 | 2017-05-23 | Shionogi & Co., Ltd. | Oxazine derivatives |
US9012446B2 (en) | 2010-03-15 | 2015-04-21 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
US8883782B2 (en) | 2010-03-15 | 2014-11-11 | Amgen Inc. | Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use |
WO2011115928A1 (en) | 2010-03-15 | 2011-09-22 | Amgen Inc. | Amino -dihydrooxazine and amino - dihydrothiazine spiro compounds as beta - secretase modulators and their medical use |
WO2011115938A1 (en) | 2010-03-15 | 2011-09-22 | Amgen Inc. | Spiro-tetracyclic ring compounds as beta - secretase modulators |
US8497264B2 (en) | 2010-03-15 | 2013-07-30 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
US9828350B2 (en) | 2010-06-09 | 2017-11-28 | Janssen Pharmaceutica Nv | 5,6-dihydro-2H-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (BACE) |
US8921363B2 (en) | 2010-08-05 | 2014-12-30 | Amgen Inc. | Derivatives of 1 H-isoindol-3-amine, 1 H-iso-aza-indol-3amine, 3,4-dihydroisoquinolin-1-amine, and 1,4-dihydroisoquinolin-3-amine as beta-secretase inhibitors |
WO2012019056A1 (en) | 2010-08-05 | 2012-02-09 | Amgen Inc. | Amino-iso-indole, amino-aza-iso-indole, amino-dihydroisoquinoline and amino-benzoxazine compounds as beta-secretase modulators and methods of use |
JP2013540740A (en) * | 2010-09-22 | 2013-11-07 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 4,7-Dihydro-pyrazolo [1,5-a] pyrazin-6-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
AU2011306941B2 (en) * | 2010-09-22 | 2014-06-12 | Janssen Pharmaceutica Nv | 4,7-dihydro-pyrazolo[1,5-a] pyrazin-6-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
CN103097389B (en) * | 2010-09-22 | 2015-10-14 | 詹森药业有限公司 | As 4,7-dihydro-pyrazol also [1,5-a] pyrazine-6-yl amine derivatives of beta-secretase (BACE) inhibitor |
US8609660B2 (en) | 2010-09-22 | 2013-12-17 | Janssen Pharmaceutica Nv | 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
CN103097389A (en) * | 2010-09-22 | 2013-05-08 | 詹森药业有限公司 | 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine derivatives useful as inhibitors of beta-secretase (bace) |
EA021723B1 (en) * | 2010-09-22 | 2015-08-31 | Янссен Фармацевтика Нв | 4,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
WO2012038438A1 (en) | 2010-09-22 | 2012-03-29 | Janssen Pharmaceutica Nv | 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
WO2012057247A1 (en) | 2010-10-29 | 2012-05-03 | 塩野義製薬株式会社 | Fused aminodihydropyrimidine derivative |
WO2012069428A1 (en) | 2010-11-22 | 2012-05-31 | Noscira, S.A. | Bipyridine sulfonamide derivatives for the treatment of neurodegenerative diseases or conditions |
WO2012071279A1 (en) | 2010-11-23 | 2012-05-31 | Amgen Inc. | Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use |
US9840507B2 (en) | 2010-12-22 | 2017-12-12 | Janssen Pharmaceutica, Nv | 5,6-dihydro-imidazo[1,2-a]pyrazin-8-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
WO2012109165A1 (en) | 2011-02-07 | 2012-08-16 | Amgen Inc. | 5-amino-oxazepine and 5-amino-thiazepane compounds as beta-secretase antagonists and methods of use |
US9346827B2 (en) | 2011-02-07 | 2016-05-24 | Amgen Inc. | 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use |
US8962859B2 (en) | 2011-02-15 | 2015-02-24 | Amgen Inc. | Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use |
WO2012112462A1 (en) | 2011-02-15 | 2012-08-23 | Amgen Inc. | Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use |
US9346811B2 (en) | 2011-03-01 | 2016-05-24 | Janssen Pharmaceutica Nv | 6,7-dihydro-pyrazolo[1,5-a]pyrazin-4-ylamine derivatives useful as inhibitors of beta-secretase (BACE) |
US9845326B2 (en) | 2011-03-09 | 2017-12-19 | Janssen Pharmaceutica Nv | Substituted 3,4-dihydropyrrolo[1,2-A]pyrazines as beta-secretase (BACE) inhibitors |
US9221839B2 (en) | 2011-04-07 | 2015-12-29 | Merck Sharp & Dohme Corp. | C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
WO2012138734A1 (en) | 2011-04-07 | 2012-10-11 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US9145426B2 (en) | 2011-04-07 | 2015-09-29 | Merck Sharp & Dohme Corp. | Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use |
WO2013028670A1 (en) | 2011-08-22 | 2013-02-28 | Merck Sharp & Dohme Corp. | 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use |
US9181236B2 (en) | 2011-08-22 | 2015-11-10 | Merck Sharp & Dohme Corp. | 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use |
US9296759B2 (en) | 2011-09-21 | 2016-03-29 | Amgen Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
WO2013044092A1 (en) | 2011-09-21 | 2013-03-28 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
US9777019B2 (en) | 2011-09-21 | 2017-10-03 | Amgen Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
EP3607946A1 (en) | 2012-03-19 | 2020-02-12 | Buck Institute for Research on Aging | App specific bace inhibitors (asbis) and uses thereof |
WO2014062553A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
WO2014062549A1 (en) | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | Tricyclic substituted thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
US9758513B2 (en) | 2012-10-24 | 2017-09-12 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity |
US9725469B2 (en) | 2012-11-15 | 2017-08-08 | Amgen, Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
WO2014078314A1 (en) | 2012-11-15 | 2014-05-22 | Amgen Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
EP3653609A1 (en) | 2013-02-12 | 2020-05-20 | Buck Institute for Research on Aging | Hydantoins that modulate bace-mediated app processing |
US9663475B2 (en) | 2013-02-25 | 2017-05-30 | Merck Patent Gmbh | 2 amino-3,4-dihydrcquinazoline derivatives and the use thereof as cathepsin D inhibitors |
WO2014127881A1 (en) * | 2013-02-25 | 2014-08-28 | Merck Patent Gmbh | 2-amino -3,4-dihydro-quinazoline derivatives and the use thereof as cathepsin d inhibitors |
AU2014221010B2 (en) * | 2013-02-25 | 2018-06-14 | Merck Patent Gmbh | 2-amino -3,4-dihydro-quinazoline derivatives and the use thereof as cathepsin D inhibitors |
US9751886B2 (en) | 2013-06-12 | 2017-09-05 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
US9834559B2 (en) | 2013-06-12 | 2017-12-05 | Janssen Pharmaceutica Nv | 4-Amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-3(2H)-one derivatives as inhibitors of beta-secretase (BACE) |
US9580433B2 (en) | 2013-06-12 | 2017-02-28 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-5,6-dihydroimidazo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
US10106524B2 (en) | 2014-12-18 | 2018-10-23 | Janssen Pharmaceutica Nv | 2,3,4,5-tetrahydropyridin-6-amine and 3,4-dihydro-2H-pyrrol-5-amine compound inhibitors of beta-secretase |
Also Published As
Publication number | Publication date |
---|---|
JP4896972B2 (en) | 2012-03-14 |
NO20080186L (en) | 2008-03-14 |
CN101394852A (en) | 2009-03-25 |
JP2008546696A (en) | 2008-12-25 |
AU2006259573A1 (en) | 2006-12-28 |
ZA200710385B (en) | 2008-11-26 |
EP2345411B1 (en) | 2013-10-02 |
EP1896032A2 (en) | 2008-03-12 |
US9382242B2 (en) | 2016-07-05 |
KR20080028881A (en) | 2008-04-02 |
EP1896032B1 (en) | 2012-10-31 |
ES2436795T3 (en) | 2014-01-07 |
AR056865A1 (en) | 2007-10-31 |
EP2345411A1 (en) | 2011-07-20 |
ECSP078004A (en) | 2008-01-23 |
BRPI0612545A2 (en) | 2010-11-23 |
CA2610828A1 (en) | 2006-12-28 |
US20140206715A1 (en) | 2014-07-24 |
TW200716643A (en) | 2007-05-01 |
IL187455A0 (en) | 2008-02-09 |
US20080176868A1 (en) | 2008-07-24 |
JP2011251978A (en) | 2011-12-15 |
WO2006138265A3 (en) | 2007-03-01 |
US8722708B2 (en) | 2014-05-13 |
PE20070321A1 (en) | 2007-04-16 |
MX2007016183A (en) | 2008-03-10 |
RU2008100164A (en) | 2009-07-20 |
JP5454956B2 (en) | 2014-03-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2345411B1 (en) | Heterocyclic aspartyl protease inhibitors, preparation and use thereof | |
EP1896430B1 (en) | The preparation and use of compounds as aspartyl protease inhibitors | |
EP1891021B1 (en) | Aspartyl protease inhibitors | |
EP1896477B1 (en) | Aspartyl protease inhibitors | |
EP2644600B1 (en) | Heterocyclic aspartyl protease inhibitors | |
US7560451B2 (en) | Aspartyl protease inhibitors | |
EP1902057B1 (en) | Macrocyclic heterocyclic aspartyl protease inhibitors | |
WO2006138230A2 (en) | The preparation and use of protease inhibitors | |
AU2006259572A1 (en) | Aspartyl protease inhibitors | |
CA2672293A1 (en) | Aspartyl protease inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680020918.6 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 187455 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12007502605 Country of ref document: PH Ref document number: 2006259573 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2610828 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 07129343 Country of ref document: CO |
|
ENP | Entry into the national phase |
Ref document number: 2008516998 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2007/016183 Country of ref document: MX Ref document number: 5757/CHENP/2007 Country of ref document: IN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020077029569 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 565027 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008100164 Country of ref document: RU Ref document number: 2006784808 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0612545 Country of ref document: BR Kind code of ref document: A2 Effective date: 20071214 |