WO2012168164A1 - Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors - Google Patents
Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors Download PDFInfo
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- WO2012168164A1 WO2012168164A1 PCT/EP2012/060457 EP2012060457W WO2012168164A1 WO 2012168164 A1 WO2012168164 A1 WO 2012168164A1 EP 2012060457 W EP2012060457 W EP 2012060457W WO 2012168164 A1 WO2012168164 A1 WO 2012168164A1
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- compound
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- alkoxy
- halogen
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
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- A—HUMAN NECESSITIES
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Definitions
- pharmaceutically acceptable carrier and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.
- aromatic denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).
- a certain embodiment of the invention provides a compound of formula I as described herein, wherein R is F.
- a certain embodiment of the invention provides a compound of formula I as described herein, wherein R is fluoro-Ci-6-alkyl.
- a certain embodiment of the invention provides a compound of formula I as described herein for the use as inhibitor of BACE1 activity.
- a certain embodiment of the invention provides a compound of formula I as described herein for the use as inhibitor of BACE2 activity.
- a certain embodiment of the invention provides a compound of formula I as described herein for the use as inhibitor of BACE1 and BACE2 activity.
- a certain embodiment of the invention provides a compound of formula I as described herein for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diabetes.
- a certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease.
- a certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
- a certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of type 2 diabetes.
- a certain embodiment of the invention provides the use of a compound of formula I as described herein for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of amyotrophic lateral sclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases, cancer such as breast cancer, cardiovascular diseases such as myocardial infarction and stroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases, Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple mieloma, rhe
- the alcohol of formula E4 can be prepared by the reduction of an ethylester of formula E3 with an alkali hydride, particularly lithium borohydride or lithium aluminum hydride, in a solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
- an alkali hydride particularly lithium borohydride or lithium aluminum hydride
- a solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
- the aminooxazine of formula F6 can be prepared by reaction of an aminoalcohol of formula F5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.
- the stable cell line "INS-TMEM27” represents an INSle-derived cell line with inducible expression (using the TetOn system) of full-length hTMEM27 in a doxycycline-dependent manner.
- the cells are cultured throughout the experiment in RPMI1640 + Glutamax (Invitrogen) Penicillin/Streptomycin, 10% Fetal bovine serum, 100 mM pyruvate, 5 mM beta- mercatptoethanol, 100 micrograms/ml G418 and 100 micro gram/ml hygromycin and are grown inadherent culture at 37 °C in a standard C0 2 cell culture incubator.
- the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Transplantation (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2012266544A AU2012266544A1 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as BACE1 and/or BACE2 inhibitors |
KR1020147000274A KR20140041687A (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
EA201391786A EA023261B1 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
US14/116,043 US8987255B2 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as BACE1 and/or BACE2 inhibitors |
JP2014514010A JP2014516063A (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as BACE1 and / or BACE2 inhibitors |
BR112013031098A BR112013031098A2 (en) | 2011-06-07 | 2012-06-04 | haloalkyl-1,3 oxazines as inhibitors of bace1 and / or bace2 |
NZ617507A NZ617507B2 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
MX2013013692A MX2013013692A (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors. |
CN201280027493.7A CN103717592A (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as BACE1 and/or BACE2 inhibitors |
CA2837252A CA2837252A1 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
EP12725743.4A EP2718286A1 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
IL229686A IL229686A0 (en) | 2011-06-07 | 2013-11-28 | Halogen -alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
MA36584A MA35193B1 (en) | 2011-06-07 | 2013-12-18 | Halogeno-1,3-alkyl oxazines as inhibitors of bace1 and / or bace2 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11169007 | 2011-06-07 | ||
EP11169007.9 | 2011-06-07 |
Publications (1)
Publication Number | Publication Date |
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WO2012168164A1 true WO2012168164A1 (en) | 2012-12-13 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/060457 WO2012168164A1 (en) | 2011-06-07 | 2012-06-04 | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
Country Status (18)
Country | Link |
---|---|
US (1) | US8987255B2 (en) |
EP (1) | EP2718286A1 (en) |
JP (1) | JP2014516063A (en) |
KR (1) | KR20140041687A (en) |
CN (1) | CN103717592A (en) |
AU (1) | AU2012266544A1 (en) |
BR (1) | BR112013031098A2 (en) |
CA (1) | CA2837252A1 (en) |
CL (1) | CL2013003472A1 (en) |
CO (1) | CO6811854A2 (en) |
CR (1) | CR20130588A (en) |
EA (1) | EA023261B1 (en) |
EC (1) | ECSP13013068A (en) |
IL (1) | IL229686A0 (en) |
MA (1) | MA35193B1 (en) |
MX (1) | MX2013013692A (en) |
PE (1) | PE20140623A1 (en) |
WO (1) | WO2012168164A1 (en) |
Cited By (29)
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US8541408B2 (en) | 2007-04-24 | 2013-09-24 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
US8546380B2 (en) | 2005-10-25 | 2013-10-01 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives |
US8563543B2 (en) | 2009-10-08 | 2013-10-22 | 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 |
US8637504B2 (en) | 2008-06-13 | 2014-01-28 | Shionogi & Co., Ltd. | Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity |
US8653067B2 (en) | 2007-04-24 | 2014-02-18 | Shionogi & Co., Ltd. | Pharmaceutical composition for treating Alzheimer's disease |
US20140080819A1 (en) * | 2011-06-07 | 2014-03-20 | Hoffmann-La Roche Inc. | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
US8703785B2 (en) | 2008-10-22 | 2014-04-22 | Shionogi & Co., Ltd. | 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity |
WO2014065434A1 (en) * | 2012-10-24 | 2014-05-01 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having bace1 inhibitory activity |
WO2014114532A1 (en) * | 2013-01-22 | 2014-07-31 | F. Hoffmann-La Roche Ag | Fluoro-[1,3]oxazines as bace1 inhibitors |
WO2014134341A1 (en) | 2013-03-01 | 2014-09-04 | Amgen Inc. | Perfluorinated 5,6-dihydro-4h-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use |
WO2014138484A1 (en) | 2013-03-08 | 2014-09-12 | Amgen Inc. | Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use |
US8883779B2 (en) | 2011-04-26 | 2014-11-11 | Shinogi & Co., Ltd. | Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them |
US8927721B2 (en) | 2010-10-29 | 2015-01-06 | Shionogi & Co., Ltd. | Naphthyridine derivative |
US8999980B2 (en) | 2009-12-11 | 2015-04-07 | Shionogi & Co., Ltd. | Oxazine derivatives |
US9018219B2 (en) | 2010-10-29 | 2015-04-28 | Shionogi & Co., Ltd. | Fused aminodihydropyrimidine derivative |
WO2015156421A1 (en) | 2014-04-11 | 2015-10-15 | Shionogi & Co., Ltd. | Dihydrothiazine and dihydrooxazine derivatives having bace1 inhibitory activity |
US9163011B2 (en) | 2011-08-25 | 2015-10-20 | Novartis Ag | Oxazine derivatives and their use in the treatment of disease |
WO2016001266A1 (en) | 2014-07-04 | 2016-01-07 | F. Hoffmann-La Roche Ag | Fluoro-[1,3]oxazines as bace1 inhibitors |
WO2016075063A1 (en) * | 2014-11-10 | 2016-05-19 | H. Lundbeck A/S | 2-amino-6-(difluoromethyl)- 5,5-difluoro-6-phenyl-3,4,5,6-tetrahydropyridines as bace1 inhibitors |
WO2016075064A1 (en) * | 2014-11-10 | 2016-05-19 | H. Lundbeck A/S | 2-amino-5,5-difluoro-6-(fluoromethyl)-6-phenyl-3,4,5,6-tetrahydropyridines as bace1 inhibitors |
JP2016515638A (en) * | 2013-04-11 | 2016-05-30 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | BACE1 inhibitor |
US9353084B2 (en) | 2014-02-19 | 2016-05-31 | H. Lundbeck A/S | 2-amino 3,5,5-trifluoro-3,4,5,6-tetrahydropyridines as BACE1 inhibitors for treatment of Alzheimer's disease |
WO2016150785A1 (en) | 2015-03-20 | 2016-09-29 | F. Hoffmann-La Roche Ag | Bace1 inhibitors |
US9550762B2 (en) | 2014-08-08 | 2017-01-24 | Amgen, Inc. | Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use |
US10004738B2 (en) | 2015-08-10 | 2018-06-26 | H. Lundbeck A/S | Combination treatment comprising administration of 2-amino-3,5,5-trifluoro-3,4,5,6-tetrahydropyridines |
US10011596B2 (en) | 2015-08-12 | 2018-07-03 | H. Lundbeck A/S | 2-amino-3-fluoro-3-(fluoromethyl)-6-methyl-6-phenyl-3,4,5,6-tetrahydropyridines as BACE1 inhibitors |
US10059669B2 (en) | 2014-11-10 | 2018-08-28 | H. Lundbeck A/S | 2-amino-3,5-difluoro-3,6-dimethyl-6-phenyl-3,4,5,6-tetrahydropyridines as BACE1 inhibitors for treating alzheimer's disease |
US11629154B2 (en) | 2018-04-27 | 2023-04-18 | Shionogi & Co., Ltd. | Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998057925A1 (en) | 1997-06-16 | 1998-12-23 | American Home Products Corporation | Elevation of hdl cholesterol by 2-[(aminothioxomethyl)-hydrazono]-2-arylethyl carbamates |
WO2006034093A2 (en) * | 2004-09-21 | 2006-03-30 | Elli Lilly And Company | 3- (2-acylamino-1-hydroxyethyl)- morpholine derivatives and their use as bace inhibitors |
US20110046122A1 (en) * | 2009-08-19 | 2011-02-24 | Matteo Andreini | 3-amino-5-phenyl-5,6-dihydro-2h-[1,4]oxazines |
WO2011071135A1 (en) * | 2009-12-11 | 2011-06-16 | 塩野義製薬株式会社 | Oxazine derivative |
WO2011070029A1 (en) * | 2009-12-10 | 2011-06-16 | F. Hoffmann-La Roche Ag | Amino oxazine derivatives |
WO2011069934A1 (en) * | 2009-12-11 | 2011-06-16 | F. Hoffmann-La Roche Ag | 2-amino-5, 5-difluoro-5, 6-dihydro-4h-oxazines as bace 1 and/or bace 2 inhibitors |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA06001559A (en) * | 2003-08-08 | 2006-05-15 | Schering Corp | Cyclic amine bace-1 inhibitors having a benzamide substituent. |
MXPA06001558A (en) * | 2003-08-08 | 2006-05-15 | Schering Corp | Cyclic amine base-1 inhibitors having a heterocyclic substituent. |
CN1968945A (en) * | 2004-06-16 | 2007-05-23 | 惠氏公司 | Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase |
TW200730523A (en) * | 2005-07-29 | 2007-08-16 | Wyeth Corp | Cycloalkyl amino-hydantoin compounds and use thereof for β-secretase modulation |
CN103936690B (en) | 2005-10-25 | 2016-06-08 | 盐野义制药株式会社 | Aminodihydrothiazinederivative derivative |
US8168630B2 (en) | 2007-04-24 | 2012-05-01 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivatives substituted with a cyclic group |
AR077328A1 (en) * | 2009-07-24 | 2011-08-17 | Novartis Ag | DERIVATIVES OF OXAZINE AND ITS USE IN THE TREATMENT OF NEUROLOGICAL DISORDERS |
NZ603427A (en) | 2010-06-09 | 2013-08-30 | Janssen Pharmaceutica Nv | 5,6-dihydro-2h-[1,4]oxazin-3-yl-amine derivatives useful as inhibitors of beta-secretase (bace) |
CA2807393C (en) * | 2010-08-05 | 2019-03-26 | Nestec S.A. | Frozen confectionary product with a natural stabiliser |
JP2012250933A (en) * | 2011-06-03 | 2012-12-20 | Shionogi & Co Ltd | Pharmaceutical composition containing oxazine derivative for treating or preventing alzheimer's disease |
EA023261B1 (en) * | 2011-06-07 | 2016-05-31 | Ф.Хоффманн-Ля Рош Аг | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
-
2012
- 2012-06-04 EA EA201391786A patent/EA023261B1/en not_active IP Right Cessation
- 2012-06-04 PE PE2013002764A patent/PE20140623A1/en not_active Application Discontinuation
- 2012-06-04 CN CN201280027493.7A patent/CN103717592A/en active Pending
- 2012-06-04 MX MX2013013692A patent/MX2013013692A/en not_active Application Discontinuation
- 2012-06-04 AU AU2012266544A patent/AU2012266544A1/en not_active Abandoned
- 2012-06-04 WO PCT/EP2012/060457 patent/WO2012168164A1/en active Application Filing
- 2012-06-04 CA CA2837252A patent/CA2837252A1/en not_active Abandoned
- 2012-06-04 EP EP12725743.4A patent/EP2718286A1/en not_active Withdrawn
- 2012-06-04 JP JP2014514010A patent/JP2014516063A/en active Pending
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998057925A1 (en) | 1997-06-16 | 1998-12-23 | American Home Products Corporation | Elevation of hdl cholesterol by 2-[(aminothioxomethyl)-hydrazono]-2-arylethyl carbamates |
WO2006034093A2 (en) * | 2004-09-21 | 2006-03-30 | Elli Lilly And Company | 3- (2-acylamino-1-hydroxyethyl)- morpholine derivatives and their use as bace inhibitors |
US20110046122A1 (en) * | 2009-08-19 | 2011-02-24 | Matteo Andreini | 3-amino-5-phenyl-5,6-dihydro-2h-[1,4]oxazines |
WO2011070029A1 (en) * | 2009-12-10 | 2011-06-16 | F. Hoffmann-La Roche Ag | Amino oxazine derivatives |
WO2011071135A1 (en) * | 2009-12-11 | 2011-06-16 | 塩野義製薬株式会社 | Oxazine derivative |
WO2011069934A1 (en) * | 2009-12-11 | 2011-06-16 | F. Hoffmann-La Roche Ag | 2-amino-5, 5-difluoro-5, 6-dihydro-4h-oxazines as bace 1 and/or bace 2 inhibitors |
Non-Patent Citations (49)
Title |
---|
"Compendium of Chemical Terminology", 1997, BLACKWELL SCIENTIFIC PUBLICATIONS |
BARBIERO L., EXP NEUROL., vol. 182, no. 2, August 2003 (2003-08-01), pages 335 - 345 |
BASSET C. ET AL., SCAND J IMMUNOL., vol. 51, no. 3, March 2000 (2000-03-01), pages 307 - 311 |
BIOCHEM. PHARMACOL., vol. 22, 1973, pages 3099 |
BROCKHAUS ET AL., NEUROREPORT, vol. 9, 1998, pages 1481 - 1486 |
DESNUES B. ET AL., CLIN VACCINE IMMUNOL., vol. 13, no. 2, February 2006 (2006-02-01), pages 170 - 178 |
E. HASLAM: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS |
G FINZI; F FRANZI; C PLACIDI; F ACQUATI ET AL.: "BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells", ULTRASTRUCT PATHOL., vol. 32, no. 6, 2008, pages 246 - 251 |
GATCHEL J.R. ET AL., PROC NATL ACAD SCI U S A, vol. 105, no. 4, 29 January 2008 (2008-01-29), pages 1291 - 1296 |
GREENBERG S.A. ET AL., ANN NEUROL., vol. 57, no. 5, 2005, pages 664 - 678 |
GREENBERG S.A. ET AL., NEUROL, vol. 57, no. 5, 2005, pages 664 - 678 |
GREWAL P.K., MOL CELL BIOL., vol. 26, no. 13, July 2006 (2006-07-01), pages 4970 - 4981 |
HARDY ET AL.: "The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics", SCIENCE, vol. 297, no. 5580, 19 July 2002 (2002-07-19), pages 353 - 356 |
HEDLUND M., CANCER RES., vol. 68, no. 2, 15 January 2008 (2008-01-15), pages 388 - 394 |
HODGES A. ET AL., HUM MOL GENET, vol. 15, no. 6, 8 February 2006 (2006-02-08), pages 965 - 977 |
HOFFMEISTER A., JOP, vol. 10, no. 5, 4 September 2009 (2009-09-04), pages 501 - 506 |
I HUSSAIN; D POWELL; D HOWLETT; G CHAPMAN ET AL.: "ASP1 (BACE2) cleaves the amyloid precursor protein at the ?-secretase site", MOL CELL NEUROSCI., vol. 16, 2000, pages 609 - 619, XP002589910, DOI: doi:10.1006/MCNE.2000.0884 |
J. ORG. CHEM., vol. 71, no. 9, 2006, pages 3545 |
K FUKUI; Q YANG; Y CAO; N TAKAHASHI ET AL.: "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", CELL METAB., vol. 2, 2005, pages 373 - 384, XP055002289, DOI: doi:10.1016/j.cmet.2005.11.003 |
KIHARA Y. ET AL., PROC NATL ACAD SCI U S A., vol. 106, no. 51, 22 December 2009 (2009-12-22), pages 21807 - 21812 |
KILJANSKI J., THYROID, vol. 15, no. 7, July 2005 (2005-07-01), pages 645 - 652 |
KIM Y.J. ET AL., NEUROBIOL DIS., vol. 22, no. 2, 19 January 2006 (2006-01-19), pages 346 - 356 |
KOISTINEN H. ET AL., MUSCLE NERVE., vol. 34, no. 4, October 2006 (2006-10-01), pages 444 - 450 |
KONDOH K. ET AL., BREAST CANCER RES TREAT., vol. 78, no. 1, March 2003 (2003-03-01), pages 37 - 44 |
LAGOS D. ET AL., BLOOD, vol. 109, no. 4, 15 February 2007 (2007-02-15), pages 1550 - 1558 |
LI Q.X. ET AL., AGING CELL, vol. 5, no. 2, April 2006 (2006-04-01), pages 153 - 165 |
LICHTENTHALER S.F. ET AL., J BIOL CHEM., vol. 278, no. 49, 5 December 2003 (2003-12-05), pages 48713 - 48719 |
LL BAGGIO; DJ DRUCKER: "Therapeutic approaches to preserve islet mass in type 2 diabetes", ANNU. REV. MED., vol. 57, 2006, pages 265 - 281 |
LUO ET AL.: "Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation", NAT NEUROSCI., vol. 4, no. 3, March 2001 (2001-03-01), pages 231 - 232, XP002350002, DOI: doi:10.1038/85059 |
M PRENTKI; C J NOLAN: "Islet beta-cell failure in type 2 diabetes.", J. CLIN. INVESTIG, vol. 116, no. 7, 2006, pages 1802 - 1812 |
MAUGERI N. ET AL., SRP ARH CELOK LEK., vol. 138, no. 1, January 2010 (2010-01-01), pages 50 - 52 |
MCCONLOGUE ET AL.: "Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice", J BIOL CHEM., vol. 282, no. 36, 7 September 2007 (2007-09-07), pages 26326, XP055244703, DOI: doi:10.1074/jbc.M611687200 |
MERTEN M. ET AL., Z KARDIOL., vol. 93, no. 11, November 2004 (2004-11-01), pages 855 - 863 |
P AKPINAR; S KUWAJIMA; J KRIITZFELDT; M STOFFEL: "Tmem27: A cleaved and shed plasma membrane protein that stimulates pancreatic 0 cell proliferation", CELL METAB., vol. 2, 2005, pages 385 - 397 |
P KUHN; E MARJAUX; A IMHOF; B DE STROOPER ET AL.: "Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase", J. BIOL. CHEM., vol. 282, no. 16, 2007, pages 11982 - 11995 |
P ZIMMET; KGMM ALBERTI; J SHAW: "Global and societal implications of the diabetes epidemic", NATURE, vol. 414, 2001, pages 782 - 787, XP055047466, DOI: doi:10.1038/414782a |
ROBERDS ET AL.: "BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics", HUM MOL GENET., vol. 10, no. 12, 1 June 2001 (2001-06-01), pages 1317 - 1324, XP002228077, DOI: doi:10.1093/hmg/10.12.1317 |
S WILD; G ROGLIC; A GREEN; R.SICREE; H KING: "Global prevalence of diabetes", DIABETES CARE, vol. 27, no. 5, 2004, pages 1047 - 1053 |
SELKOE: "Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease", ANNU REV CELL BIOL., vol. 10, 1994, pages 373 - 403 |
SUGIMOTO I ET AL., J BIOL CHEM., vol. 282, no. 48, 30 November 2007 (2007-11-30), pages 34896 - 34903 |
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC. |
T.P. TANG; J.A. ELLMAN, J. ORG. CHEM., vol. 64, 1999, pages 12 |
T.W. GREENE: "Protective Groups in Organic Synthesis", 1981, JOHN WILEY AND SONS |
TALANTOV D. ET AL., CLIN CANCER RES., vol. 11, no. 20, 15 October 2005 (2005-10-15), pages 7234 - 7242 |
TETRAHEDRON, vol. 61, no. 19, 2005, pages 4671 |
TOEGEL S., OSTEOARTHRITIS CARTILAGE, vol. 18, no. 2, 22 September 2009 (2009-09-22), pages 240 - 248 |
VASSAR ET AL.: "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE", SCIENCE, vol. 286, no. 5440, 22 October 1999 (1999-10-22), pages 735, XP000914811, DOI: doi:10.1126/science.286.5440.735 |
VATTEMI G. ET AL., LANCET, vol. 358, no. 9297, 8 December 2001 (2001-12-08), pages 1962 - 1964 |
WOODARD-GRICE A.V. ET AL., J BIOL CHEM., vol. 283, no. 39, 23 July 2008 (2008-07-23), pages 26364 - 26373 |
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CN103717592A (en) | 2014-04-09 |
JP2014516063A (en) | 2014-07-07 |
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CA2837252A1 (en) | 2012-12-13 |
PE20140623A1 (en) | 2014-05-30 |
CO6811854A2 (en) | 2013-12-16 |
CR20130588A (en) | 2014-02-18 |
KR20140041687A (en) | 2014-04-04 |
EP2718286A1 (en) | 2014-04-16 |
ECSP13013068A (en) | 2014-01-31 |
US8987255B2 (en) | 2015-03-24 |
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