WO2006057983A1 - Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of alzheimer's disease - Google Patents
Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of alzheimer's disease Download PDFInfo
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- WO2006057983A1 WO2006057983A1 PCT/US2005/042233 US2005042233W WO2006057983A1 WO 2006057983 A1 WO2006057983 A1 WO 2006057983A1 US 2005042233 W US2005042233 W US 2005042233W WO 2006057983 A1 WO2006057983 A1 WO 2006057983A1
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- thiazolyl
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- 0 *C(C**1)(*c2cc1nc(*)c2*)N Chemical compound *C(C**1)(*c2cc1nc(*)c2*)N 0.000 description 6
- YVDWFZIVIIKYBQ-UHFFFAOYSA-N Cc1nnc(C)[o]1 Chemical compound Cc1nnc(C)[o]1 YVDWFZIVIIKYBQ-UHFFFAOYSA-N 0.000 description 2
- YGDKDQQQHZSNGB-UHFFFAOYSA-N CC(CC(C1)=CC=CC1CCCCC(C1)=NC(N(C)S(C)(=O)=O)=CC1CO1)(C1=O)N Chemical compound CC(CC(C1)=CC=CC1CCCCC(C1)=NC(N(C)S(C)(=O)=O)=CC1CO1)(C1=O)N YGDKDQQQHZSNGB-UHFFFAOYSA-N 0.000 description 1
- PSOZJOZKEVZLKZ-UHFFFAOYSA-N Cc1c[o]c(C)n1 Chemical compound Cc1c[o]c(C)n1 PSOZJOZKEVZLKZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
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- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention is directed to the field of compounds which are inhibitors of the the activity of the ⁇ -secretase enzyme, and to the use of the compounds for the treatment of diseases in which the ⁇ - secretase enzyme is involved, such as Alzheimer's disease.
- Alzheimer's disease is characterized by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles.
- the rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein ( ⁇ A4, also referred to as A ⁇ , ⁇ -protein and ⁇ AP) which is a proteolytic product of a precursor protein of much larger size.
- the amyloid precursor protein (APP or A ⁇ PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail.
- the A ⁇ domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH 2 - and COOH-termini. At least two secretory mechanisms exist which release APP from the membrane and generate soluble, COOH-trancated forms of APP (APP S ). Proteases that release APP and its fragments from the membrane are termed
- secretases Most APP 5 is released by a putative ⁇ -secretase which cleaves within the A ⁇ protein to release ⁇ -APP s and precludes the release of intact A ⁇ . A minor portion of APP 3 is released by a ⁇ - secretase (“ ⁇ -secretase”), which cleaves near the NH 2 -terminus of APP and produces COOH-terminal fragments (CTFs) which contain the whole A ⁇ domain.
- ⁇ -secretase ⁇ -secretase
- CTFs COOH-terminal fragments
- the compoimds of the present invention are useful for treating Alzheimer's disease by inhibiting the activity of ⁇ -secretase or BACE, thus preventing the formation of insoluble A ⁇ and arresting the production of A ⁇ .
- the present invention is directed to novel macrocyclic aminopyridyl compounds represented by general formula (I)
- the invention is also directed to pharmaceutical compositions which include an effective amount of a compound of formula (T), or pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof, and a pharmaceutically acceptable carrier.
- the invention is also directed to methods of treating mammals for diseases in which the ⁇ -secretase enzyme is involved, such as Alzheimer's disease, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.
- the present invention is directed to compounds of formula (I):
- Y is selected from the group consisting of
- A is selected from the group consisting of
- aryl and heteroaryl groups are unsubstituted or substituted with one or more (i) halo, (Ii) -OH,
- Rl is selected from the group consisting of (1) -C6-10 arylene, or j ..' a "r -iu-,,> !!., « , complicat-,. « ceremoni5-!
- heteroarylene selected from the group consisting of divalent pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benziniidazolyl, indynyl and benzoxazolyl,
- arylene or heteroarylene is unsubstituted or substituted with one or more (a) halo
- R2 is selected from the group consisting of: (1) (R5-SO2)N(R6)-, wherein R5 is (a) -Ci-10 alkyl, (b) -C2-10 alkenyl, (c) -C2-IO alkynyl,
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl,
- alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one or more
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl, and said aryl and heteroaryl is unsubstituted or substituted with one or more (A) halo,
- R6 is selected from the group consisting of (a) hydrogen,
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl,
- alkyl, alkenyl, alkynyl, aryl or heteroaryl. is unsubstituted or substituted with one or more (i) halo, ( ⁇ ) -OH, (iii) -CN,
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl;
- R 5 and K.6 may be linked to form a group -CH2(CH2)pCH2 ⁇ ,
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl, wherein said heteroaryl is unsubstituted or substituted with one or more clergy ⁇ • . ⁇ i - i • - - -
- Q ⁇ is selected from the group consisting of (a) -CH2-
- Q3 is -CH- or -CH2CH-
- RY is selected from the group consisting of
- heteroaryl is selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl,
- alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl RY groups are unsubstituted or substituted with one or more (i) halo,
- Q4 is selected from the group consisting of
- R z is selected from the group consisting of (i) hydrogen,
- heteroaryl is selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl,
- R4 is -(CH 2 ) S -Q ⁇ -(CH2)t, wherein Q2 is selected from the group consisting of
- n 0, 1 or 2
- p is 1, 2 or 3
- q is 1, 2, 3, 4 or 5
- r is 0, 1 or 2
- s is 0 or 1
- t is 0 or 1
- u is 0, 1 or 2.
- Y is hydrogen
- Rl is unsubstituted or substituted -Cg-io arylene, preferably unsubstituted phenylene.
- R.4 is -(CH2) S -Q2 -(CEt ⁇ t, wherein Q2 is selected from the group consisting of
- A is selected from the group consisting of (1) hydrogen
- heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indynyl and benzoxazolyl.
- A is -Cl-10 alkyl
- alkyl (preferably methyl), wherein said alkyl is unsubstituted or substituted with one or more halo (preferably fiuoro).
- R2 is selected from the group consisting of (R 5 -S ⁇ 2)N(R6)-, wherein R5 is -C ⁇ . ⁇ alkyl, wherein said alkyl is unsubstituted or substituted with one or more
- R6 is selected from the group consisting of (a) hydrogen,
- R ⁇ group is-C6-10 ar yl 5 unsubstituted or substituted as described above.
- Preferred aryl groups are phenyl groups, unsubstituted or substituted with cyano.
- a preferred R2 substituent is shown below:
- R2 substituent is heteroaryl, either unsubstituted or substituted as described above.
- a preferred heteroaryl group is furanyl or oxazolyl, either unsubstituted or substituted as described above.
- a preferred furanyl or oxazolyl substituent is depicted below:
- Ql is selected from the group consisting of
- R x is preferably hydrogen, and n is preferably 1.
- Q3 is -O - and n is preferably 1.
- R ⁇ is preferably hydrogen, and n is preferably 1.
- the dotted line leading to RY is absent and Ry is selected from the group consisting of
- Q4 is CH2, m is preferably 1 and r is preferably 0.
- the invention is directed to compounds of Formula (JT):
- Another embodiment of the present invention includes a compound which is selected from the title compounds of the following Examples and pharmaceutically acceptable salts thereof.
- alkyl by itself or as part of another substituent, means a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., C i _ 10 alkyl means an alkyl group having from one to ten carbon atoms).
- Preferred alkyl groups for use in the invention are Cl-6 alkyl groups, having from one to six carbon atoms.
- Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
- alkylene by itself or as part of another substituent, means a saturated straight or branched chain divalent hydrocarbon radical having the number of carbon atoms designated.
- Co alkylene (for example, in the radical "-Coalkylene-C6-l ⁇ aryl") means that the alkylene group is absent.
- cycloalkyl by itself or as part of another substituent, means a saturated cyclic hydrocarbon radical having the number of carbon atoms designated (e.g., C3.8 cycloalkyl means a cycloalkyl group having from three to eight carbon atoms).
- exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. IU-.. ....J' ,
- alkenyl by itself of as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon double bond and having the number of carbon atoms designated (e.g., C2-10 alkenyl means an alkenyl group having from one to ten carbon atoms).
- Preferred alkenyl groups for use in the invention are C2-6 alkenyl groups, having from two to six carbon atoms.
- Exemplary alkenyl groups include ethenyl, n-propenyl, isopropenyl, butenyl, and the like.
- alkynyl by itself or as part of another substituent, means a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g., C2-10 alkynyl means an alkynyl group having from two to ten carbon atoms).
- Preferred alkynyl groups for use in the invention are C2-6 alkynyl groups, having from two to six carbon atoms.
- Exemplary alkynyl groups include ethynyl and propynyl.
- aryl by itself or as part of another substituent, means an aromatic or cyclic radical having the number of carbon atoms designated (e.g., Cg_io aryl means an aryl group having from six to ten carbons atoms).
- aryl includes multiple ring systems as well as single ring systems.
- Preferred aryl groups for use in the invention include phenyl and naphthyl.
- arylene by itself or as part of another substituent, means a divalent aromatic or cyclic radical, having the number of carbon atoms designated (e.g., C6-10 arylene means an arylene group having from six to ten carbons atoms).
- arylene includes multiple ring systems as well as single ring systems.
- Preferred arylene groups for use in the invention include phenylene and naphthylene.
- heteroaryl by itself or as part of another substituent, means an aromatic cyclic radical having at least one ring heteroatom (O, N or S).
- heteroaryl includes multiple ring systems as well as single ring systems.
- heteroaryl groups for use in the invention include furyl, pyranyl, benzofuranyl, isobenzofuranyl, chromenyl, thienyl, benzothiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, tetrazolyl, indazolyl, napthyridinyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indynyl and dihydroindolyl.
- the substituent When a heteroaryl group as defined herein is substituted, the substituent may be bonded to a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits substitution. Preferably, the substituent is bonded to a ring carbon atom.
- the point of attachment may be at a ring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has a valence which permits attachment.
- the attachment is at a ring carbon atom.
- heteroarylene by itself or as part of another substituent, means an aromatic cyclic divalent radical having at least one ring heteroatom (O, N or S).
- halo or “halogen” includes fluoro, chloro, bromo and iodo.
- the compounds of the instant invention have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the ir iL if . ⁇ • ''Li 1 ⁇ Ji iJ .”.3 ,.' ' ' rE".'. iC' J .,,"S
- racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
- the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
- the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
- the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
- the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
- any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
- the compounds of the present invention are prepared by the methods outlined in Schemes 1.1 to 5.8, below, and the intermediates and examples herein.
- the compounds of the present invention are prepared by the methods outlined in Schemes 1.1-5.8, illustrated below.
- Scheme 1.1 describes the preparation of derivatives of type 1.1a, as well as the corresponding trifiate analogs 1.1b and 1.1c.
- starting from glycine Schiff base more elaborated bromides of type l.ld and l.le were prepared. IUn il .'' 1 U '-Jt ⁇ !...!' ..ml! ,•" " I! Hv, St.,,, , n Vêt.
- Scheme 2.1 describes a sequence leading to 2,6-dichloro pyridine derivatives from 2,6- dichoroisonicotinate.
- Methyl ester hydrolysis gives acid 2.1a, which was transformed via a two step sequence to acylhydrazide 2.1b.
- Benzyl alcohol 2.1c is readily accessed via ester reduction, and was transformed to the corresponding benzyl bromide with CBr 4 /Ph 3 P.
- Homo-allylic amies of type 3.1b were prepared via conjugate addition of phthalimide to ⁇ , ⁇ -unsaturated aldehydes, followed by Wittig homologation to give compounds of type 3.1a, as described in Scheme 3.1 (See Bergman, E. D., Migron, Y. Organic Preparations and Procedures Int. 1976, 8, 75-80). Pthalimide deprotection with hydrazine gives primary amine 3.1b, which were Boc protected without further functionalization to afford 3.1c. Alternatively, 3.1b underwent a reductive amination followed by Boc protection to give amines of type 3.1d. Boc protected amine 3.1c can also be alkylated under basic conditions to afford 3.1d. . ,
- Scheme 3.2 describes an alternate synthesis of amines of type 3.1c and 3.1d.
- Scheme 3.4 shows the synthesis of alcohols 3.4a and 3.4b from intermediate 3.2b.
- Decarboxylation of 3.2b using conditions described by Krapcho, ester reduction and alcohol protection affords 3.4a.
- Lindlar reduction of the alkyne gives homoallylic alcohol 3.4b.
- Olefins of type 4.3c were accessed via two methods, as described in Scheme 4.3. Suzuki coupling of olefin 3.2f with 1.1b or 1.1 d, followed by oxidation and Wittig homologation gives the desired intermediate. Alternatively, hydroboration of excess 1,5 diene 4.3b, followed by Suzuki coupling enables direct access of 4.3c. Ester hydrolysis gives acid 4.3d, and reduction yields alcohol 4.3e.
- Etherification of benzylic bromides 2.1d or 2.2c with alcohol 4.1d was accomplished with silver trifluoromethanesulfonate.
- the azide functionality of adduct 5.1a was reduced under Staudinger conditions. Macroamination yields primary aminopyridine 5.1b. Reductive amination or mono alkylation of the primary amine prior to ring closure gave macroether adducts of type 5.1c.
- benzyl bromide 2.1d is used for this sequence, further elaboration of the macrocyclic chloroaminopyridines 5.1b and 5.2c is possible utilizing standard Negishi coupling conditions. Deprotection of the Boc group affords adducts 5.1d and 5.1e.
- Scheme 5.5 Described in Scheme 5.5 is the synthesis of macrocycles of type 5.5b and 5.5c, using a strategy similar to that of Scheme 5.1.
- the ring closure is accomplished through an intramolecular Heck reaction.
- Scheme 5.6 Described in Scheme 5.6 is the synthesis of macrocycles of type 5.6b and 5.6c, using a strategy similar to that of Scheme 5.1. The ring closure is accomplished through an intramolecular Heck reaction.
- Scheme 5.7 is the synthesis of macrocycles of type 5.7b and 5.7c, using a strategy similar to that of Scheme 5.1.
- the ring closure is accomplished through a palladium catalyzed intramolecular etherification reaction (for conditions, see: Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553-5566).
- Scheme 5.8 is the synthesis of macrocycles of type 5.8b and 5.8c, using a strategy similar to that of Scheme 5.1.
- the ring closure is accomplished through a palladium catalyzed intramolecular etherification reaction (for conditions, see: Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553-5566).
- 5.9c can be synthesized utilizing an alternate route.
- 1,5-pentadiene 3.5b monohydroboration followed by Suzuki coupling affords 5.10a.
- a second Suzuki coupling with 2.2f affords 5.9c through an alternate route.
- Described in Scheme 5.11 is the synthesis of macrocycles of type 5.11d and 5.11e.
- Acid l.lf is alkylated with benzyl bromide derivative 2.2e to afford adduct 5.11a.
- Bis allylation then gives 5.11b, which can undergo a ring closing metathesis reaction to afford 5.11c.
- Boc deprotection gives 5.11d.
- substantially pure means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
- the present invention is directed to the use of the compounds disclosed herein as inhibitors of ⁇ - secretase enzyme activity or ⁇ -site amyloid precursor protein-cleaving enzyme ("BACE") activity, in a patient or subject such as a mammal in need of such inhibition, comprising the administration of an effective amount of the compound.
- BACE ⁇ -secretase enzyme
- ⁇ -site amyloid precursor protein- cleaving enzyme and “BACE” are used interchangeably in this specification. Jh addition to humans, a variety of other mammals can be treated according to the method of the present invention.
- the present invention is further directed to a method for the manufacture of a medicament or a composition for inhibiting ⁇ -secretase enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
- the compounds of the present invention have utility in treating Alzheimer's disease.
- the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
- the compounds may also be useful in treating diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
- APP amyloid precursor protein
- Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
- the subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom inhibition of ⁇ -secretase enzyme activity is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which inhibition of ⁇ -secretase enzyme activity or treatment of the above noted disorders is desired.
- the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
- combinations of the compounds of the present invention with other drugs in either unit dose or kit form include combinations with anti-Alzheimer's agents, for example other beta-secretase inhibitors or gamma-secretase inhibitors; tau phosphorylation inhibitors; Ml receptor positive allosteric modulators; blockers of A ⁇ oligomer formation; 5-HT modulators, such as PRX-03140, GSK 742467, 1C !l
- NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies; anti-inflammatory compounds such as (R)-flurbiprofen, nitroflurbiprofen, rosiglitazone, ND-1251, VP-025, HT-0712 and EHT-202; CB-I receptor antagonists or CB-I receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine and neramexane; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phens
- NMDA N-methyl-D-aspartate
- composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for - , K ,, • " u Si O is -
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
- compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be formulated according to the known art, or may be administered in the form of suppositories for rectal administration of the drug.
- the compounds of the present invention may also be administered by inhalation, by way of inhalation devices known to those skilled in the art, or by a transdermal patch.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- administering a should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
- oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
- injectable dosage forms such as IV, IM, or IP, and the like
- transdermal dosage forms including creams, jellies, powders, or patches
- buccal dosage forms inhalation powders, sprays, suspensions, and the like
- rectal suppositories rectal suppositories.
- an effective amount or “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
- treatment refers to the treatment of the mentioned conditions, particularly in a patient who demonstrates symptoms of the disease or disorder.
- compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person adminstering the drug to the patient can - . .. • ⁇ -
- unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
- compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person adminstering the drug to the patient.
- kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
- the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
- the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
- the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
- Specific dosages of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 80 mg, 100 mg, 150mg, 300mg and 500 mg.
- Pharmaceutical compositions of the present invention may be provided in a formulation comprising about 0.5 mg to 1000 mg active ingredient; more preferably comprising about 0.5 mg to 500 mg active ingredient; or 0.5 mg to 250 mg active ingredient; or 1 mg to 100 mg active ingredient.
- Specific pharmaceutical compositions useful for treatment may comprise about 1 mg, 5 mg, 10 mg, 30 mg, 80 mg, 100 mg, 150 mg, 300mg and 500 mg of active ingredient.
- FRET fluorescence resonance energy transfer
- a homogeneous end point fluorescence resonance energy transfer (FRET) assay is employed with the substrate ([TAMRA-S-CO-EEISEVNLDAEF-NHQSY] QFRET), which is cleaved by BACE 1 to release the fluorescence from TAMRA.
- the Km of the substrate is not determined due to the limit of solubility of the substrate.
- a typical reaction contains approximately 30 nM enzyme, 1.25 ⁇ M of the substrate, and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mM deferoxamine) in a total reaction volume of 100 ⁇ l.
- the reaction is proceeded for 30 min and the liberation of TAMRA fragment is measured in a 96-well plate LJL Analyst AD using an excitation wavelength of 530 nm and an emission wavelength of 580 nm. Under these conditions, less than 10% of substrate is processed by BACE 1.
- the enzyme used in these studies is soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system.
- solutions of inhibitor in DMSO four concentrations of the inhibitors are prepared: ImM, 100 ⁇ M, 10 ⁇ M, 1 ⁇ M) are included in the reactions mixture (final DMSO concentration is 0.8%). All experiments are conducted at rt using the standard reaction conditions described above.
- HPLC assay A homogeneous end point HPLC assay is used with the substrate (coumarin-CO-REVNFEVEFR), which is cleaved by BACE 1 to release the N-terminal fragment attached with coumarin.
- the Km of the substrate is greater than 100 ⁇ M and can not be determined due to the limit of solubility of the substrate.
- a typical reaction contains approximately 2 nM enzyme, 1.0 ⁇ M of the substrate, and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mM deferoxamine) in a total reaction volume of 100 ⁇ l.
- the reaction is proceeded for 30 min and is stopped by the addition of 25 ⁇ L of 1 M Tris-HCl, pH 8.0.
- the resulting reaction mixture is loaded on the HPLC and the product is separated from substrate with 5 min linear gradient. Under these conditions, less than 10% of substrate is processed by BACE 1.
- the enzyme used in these studies is soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system.
- solutions of inhibitor in DMSO (12 concentrations of the inhibitors are prepared and the concentration rage is dependent on the potency predicted by FRET) are included in the reaction mixture (final DMSO concentration is 10 %). All experiments are conducted at rt using the standard reaction conditions described above.
- To determine the IC50 of the compound four parameters equation is used for curve fitting. The errors in reproducing the dissociation constants are typically less than two-fold.
- the compounds of the following examples had activity in inhibiting the beta- secretase enzyme in the aforementioned assay, generally with an IC50 from about 1 nM to 100 ⁇ M. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of the beta- secretase enzyme activity.
- HMDS hexamethyldisilazane
- BSA bovine serum albumin
- Methyl 2,6-dichloroisonicotinate (10 g, 48.5 mmol), methyl(propylsulfonyl)amine (7.99 g, 58.2 mmol), potassium phosphate (14.4 g, 68 mmol), Xantphos (1.69 g, 2.9 mmol) and tris(dibenzylideneacetone)dipalladium (0.89 g, 0.97 mmol) were added to a dry, argon flushed flask.
- Step A Sulfonamide reduction Performed as described in Step A of the synthesis of Intermediate H2.C.1, with mesyl methyl sulfonamide being used in place of propyl methyl sulfonamide.
- Step B Reduction Performed as described in Step B of the synthesis of Intermediate H2.C.1.
- Step C Silyl ether formation N-f ⁇ -chloro ⁇ -Oiydroxymethy ⁇ pyridin ⁇ -yy-N-methylmethanesulfonamide (2.8 g, 11.1 mmol) from Step B, imidazole (0.91 g, 13.4 mmol), and tert-butyldimethylsilyl chloride (1.85 g, 12.2 mmol) were dissolved in anhydrous methylene chloride (25 mL) and allowed to stir at 25 0 C for 16 hours.
- Step A Mono-esterif ⁇ cation of diacid 3-Phenylglutaric acid (5 g, 24 mmol) and cesium carbonate (3.9 g, 12 mmol) were dissolved in 200 mL of anhydrous DMF and cooled to 0 0 C. Methyl iodide (1.5 mL, 24 mmol) was added via syringe to the solution, which was allowed to slowly warm to 25 0 C over 16 hours. The reaction was diluted with water, and the pH was adjusted to ⁇ 9 with sat'd NaHCO3.
- 5-methoxy-5-oxo-3-phenylpentanoic acid (4.2 g, 19 mmol) was dissolved in 200 mL of anhydrous THF and cooled to 0 0 C.
- Borane (57 mL, 57 mmol, 1 M soln in THF) was added via syringe to the solution, which was allowed to slowly warm to 25 0 C over 16 hours.
- the reaction was then cooled to 0 0 C and quenched with methanol (25 mL), followed by water (25 mL), followed by saturated solution sodium bicarbonate (25 mL).
- the product was extracted into ethyl acetate, washed with brine, dried over sodium .
- Step C Iodination of Alcohol Triphenylphosphine (1.5 g, 5.8 mmol) and imidazole (0.39 g, 5.8 mmol) were added to a dried flask under argon atmoshphere. Anhydrous methylene chloride (50 mL) was added and the solution was cooled to 0 0 C. Iodine (1.45 g, 5.8 mmol) was added in one portion, and the resulting solution was stirred at 0 0 C for 0.5 h.
- Step A Suzuki Coupling To 0.70Og (2.25 mmol, 1 equiv.) of (but-3-en-l-yloxy)(tert-buryl)diphenylsilane was added 5.9 mL
- reaction was cooled to rt and filtered through a pad of celite, rinsing with EtOAc. Partitioned filtrate between EtOAc and brine, separated and washed organics with brine, dried over Na 2 SO 4 , filtered and concentrated. Purified residue using silica gel chromatography to isolate desired product as a viscous oil.
- Step B Silyl Deprotection ⁇ is .•• ⁇ " » »-,: B !? n- ...
- Step C Allylation To a solution of ⁇ 2-chloro-6-[methyl(methylsulfonyl)amino]pyridine-4-yl ⁇ methyl 3-b ⁇ omo-N-(tert- butoxycarbonyl)- ⁇ -methylphenylalaninate (400 mg, 0.68 mmol) and allyltributylstannane (0.48 mL, 1.6 mmol) in degassed DMF (4 mL) was added bis(triphenylphosphine)palladium( ⁇ ) dichloride (33 mg, 0.048 mmol). The reaction was heated to 120 0 C in a microwave for 0.5 h. Additional catalyst was added and heating was repeated 3x to drive the reaction to completion.
- Step C Macroamination To a solution of product from Step B (0.015 g, 0.025 mmol, 1 equiv) in 0.60 mL DMA was added
- Step B and Step C Macroamination and Boc deprotection
- Step A Zincate coupling of intermediate A and B
- Step B Reduction of Ester methyl 5- ⁇ 4-( ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ methyl)-6- ⁇ methyl(methylsulfonyl)amino]pyridin-2-yl ⁇ -3- phenylpentanoate (0.55 g, 1.05 mmol) from step A was dissolved in anhydrous THF (10 mL) and cooled to 0 0 C under argon atmosphere. Lithium borohydride (0.74 mL, 1.49 mmol, 2.0 M solution in THF) was slowly added via syringe. After addition was complete, the temperature was raised to 45 0 C and the reaction was allowed to stir at that temperature for 16 h.
- Step D Zincate coupling of intermediate I.l.c.l and scaffold r Ii ⁇ ⁇ >u? w 1 ⁇ u8 S ,. ⁇ -Ii ET « * C n »TMi"
- Step F Hydrolysis of Ester
- a IM solution of LiOH in water 0.145 mL (0.291 mmol) of a IM solution of LiOH in water. The solution was allowed to stir overnight at 45 0 C for 16 h.
- Step B Suzuki with product from Step A and intermediate 2.2f Prepared as described in Step A.
- Step C-F Silyl Deprotection, Ester hydrolysis, Mitsunobu macrolactonization and Boc deprotection sequence performed as described in the synthesis of Example 9.
- LC/MS [M+H] 446
- Step A Suzuki with 3 -Methyl- 1,4-pentadiene and 1.1.c.1 Prepared as Step A in the synthesis of Example 9.
Abstract
Description
Claims
Priority Applications (6)
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CA002587256A CA2587256A1 (en) | 2004-11-23 | 2005-11-18 | Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of alzheimer's disease |
US11/791,465 US7951949B2 (en) | 2004-11-23 | 2005-11-18 | Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of Alzheimer's disease |
JP2007543382A JP2008520727A (en) | 2004-11-23 | 2005-11-18 | Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of Alzheimer's disease |
AT05849049T ATE512147T1 (en) | 2004-11-23 | 2005-11-18 | MACROCYCLIC AMINIOPYRIDYL BETA SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
AU2005309708A AU2005309708A1 (en) | 2004-11-23 | 2005-11-18 | Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of Alzheimer's disease |
EP05849049A EP1817312B1 (en) | 2004-11-23 | 2005-11-18 | Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of alzheimer's disease |
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US63031904P | 2004-11-23 | 2004-11-23 | |
US60/630,319 | 2004-11-23 |
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PCT/US2005/042233 WO2006057983A1 (en) | 2004-11-23 | 2005-11-18 | Macrocyclic aminopyridyl beta-secretase inhibitors for the treatment of alzheimer's disease |
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US (1) | US7951949B2 (en) |
EP (1) | EP1817312B1 (en) |
JP (1) | JP2008520727A (en) |
CN (1) | CN101061119A (en) |
AT (1) | ATE512147T1 (en) |
AU (1) | AU2005309708A1 (en) |
CA (1) | CA2587256A1 (en) |
WO (1) | WO2006057983A1 (en) |
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WO2006055434A3 (en) * | 2004-11-17 | 2007-07-05 | Merck & Co Inc | Macrocyclic tertiary amine beta-secretase inhibitors for the treatment of alzheimer's disease |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
WO2008065141A1 (en) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
WO2008104580A1 (en) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP2073635A1 (en) * | 2006-10-06 | 2009-07-01 | Merck & Co., Inc. | Macrocyclic spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease |
WO2011029920A1 (en) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Heterocylcic derivatives as inhibitors of glutaminyl cyclase |
WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
WO2011110613A1 (en) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
US8183252B2 (en) | 2003-12-15 | 2012-05-22 | Schering Corporation | Heterocyclic aspartyl protease inhibitors |
WO2012123563A1 (en) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Benz imidazole derivatives as inhibitors of glutaminyl cyclase |
US8729071B2 (en) | 2009-10-08 | 2014-05-20 | Merck Sharp & Dohme Corp. | Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use |
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CN104263795A (en) * | 2014-08-22 | 2015-01-07 | 四川同晟生物科技有限公司 | Method for preparing chiral alpha-naphthenic glycine |
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WO2006015621A1 (en) * | 2004-08-09 | 2006-02-16 | Cellzome Ag | Treatment of neurodegenerative diseases by the use of scd4 inhibitors |
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WO2001051126A1 (en) * | 2000-01-12 | 2001-07-19 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
US6333410B1 (en) * | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
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EP1644322A1 (en) | 2003-06-16 | 2006-04-12 | Sunesis Pharmaceuticals, Inc. | Aspartyl protease inhibitors |
WO2005004802A2 (en) * | 2003-06-30 | 2005-01-20 | Merck & Co., Inc. | N-alkyl phenylcarboxamide beta-secretase inhibitors for the treatment of alzheimer's disease |
CA2530006A1 (en) * | 2003-07-01 | 2005-01-20 | Merck & Co., Inc. | Phenylcarboxylate beta-secretase inhibitors for the treatment of alzheimer's disease |
CA2535337A1 (en) * | 2003-08-14 | 2005-03-03 | Merck & Co., Inc. | Macrocyclic beta-secretase inhibitors for the treatment of alzheimer's disease |
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EP1689713B1 (en) | 2003-11-24 | 2011-07-27 | Merck Sharp & Dohme Corp. | Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer s disease |
CA2548849A1 (en) | 2003-12-19 | 2005-07-21 | Merck & Co., Inc. | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer's disease |
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2005
- 2005-11-18 EP EP05849049A patent/EP1817312B1/en not_active Not-in-force
- 2005-11-18 WO PCT/US2005/042233 patent/WO2006057983A1/en active Application Filing
- 2005-11-18 CA CA002587256A patent/CA2587256A1/en not_active Abandoned
- 2005-11-18 CN CNA2005800399218A patent/CN101061119A/en active Pending
- 2005-11-18 JP JP2007543382A patent/JP2008520727A/en active Pending
- 2005-11-18 US US11/791,465 patent/US7951949B2/en active Active
- 2005-11-18 AT AT05849049T patent/ATE512147T1/en not_active IP Right Cessation
- 2005-11-18 AU AU2005309708A patent/AU2005309708A1/en not_active Abandoned
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WO2006015621A1 (en) * | 2004-08-09 | 2006-02-16 | Cellzome Ag | Treatment of neurodegenerative diseases by the use of scd4 inhibitors |
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Also Published As
Publication number | Publication date |
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CA2587256A1 (en) | 2006-06-01 |
ATE512147T1 (en) | 2011-06-15 |
US20080015213A1 (en) | 2008-01-17 |
CN101061119A (en) | 2007-10-24 |
EP1817312A1 (en) | 2007-08-15 |
US7951949B2 (en) | 2011-05-31 |
EP1817312A4 (en) | 2009-11-04 |
AU2005309708A1 (en) | 2006-06-01 |
EP1817312B1 (en) | 2011-06-08 |
JP2008520727A (en) | 2008-06-19 |
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