WO2004080376A2 - Hydroxyethylamine compounds having asp2 inhibitory activity for the treatment of alzheimer’s disease - Google Patents
Hydroxyethylamine compounds having asp2 inhibitory activity for the treatment of alzheimer’s disease Download PDFInfo
- Publication number
- WO2004080376A2 WO2004080376A2 PCT/EP2004/002644 EP2004002644W WO2004080376A2 WO 2004080376 A2 WO2004080376 A2 WO 2004080376A2 EP 2004002644 W EP2004002644 W EP 2004002644W WO 2004080376 A2 WO2004080376 A2 WO 2004080376A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- equiv
- mmol
- amino
- aryl
- Prior art date
Links
- 0 C*C(C)(*)c1cccc(C*(CC(*)C(Cc2ccccc2)*C(c2cccc(*(c3cc(C#CC)ccc3)[Cn](C)(=O)=O)c2)=O)=C)c1 Chemical compound C*C(C)(*)c1cccc(C*(CC(*)C(Cc2ccccc2)*C(c2cccc(*(c3cc(C#CC)ccc3)[Cn](C)(=O)=O)c2)=O)=C)c1 0.000 description 3
- JFBLSBOXCYPKQC-WLRRAVMWSA-N CC(C=C)(c1cccc(CNC[C@H]([C@H](Cc2ccccc2)NC(c2cc(C)cc(N(c3ccccc3)S(C)(=O)=O)c2)=O)O)c1)F Chemical compound CC(C=C)(c1cccc(CNC[C@H]([C@H](Cc2ccccc2)NC(c2cc(C)cc(N(c3ccccc3)S(C)(=O)=O)c2)=O)O)c1)F JFBLSBOXCYPKQC-WLRRAVMWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/32—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/24—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to novel hydroxyethylamine compounds having Asp2 ( ⁇ - secretase, BACE1 or Memapsin) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits, particularly Alzheimer's disease.
- Asp2 ⁇ - secretase, BACE1 or Memapsin
- Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of ⁇ -amyloid (A ⁇ ) in the form of senile plaques represents a key pathological hallmark of the disease (Selkoe, D. J. (2001) Physiological Reviews 81: 741-766). The presence of senile plaques is accompanied by a prominent inflammatory response and neuronal loss.
- a ⁇ exists in soluble and insoluble, fibrillar forms and a specific fibrillar form has been identified as the predominant neurotoxic species (Vassar, R. and Citron, M. (2000) Neuron 27: 419-422).
- dementia correlates more closely with the levels of soluble amyloid rather than plaque burden (Naslund, J.
- a ⁇ is known to be produced through the cleavage of the beta amyloid precursor protein (also known as APP) by an aspartyl protease enzyme known as Asp2 (also known as ⁇ - secretase, BACE1 or Memapsin) (De Slrooper, B. and Konig, G. (1999) Nature 402: 471-472).
- Asp2 also known as ⁇ - secretase, BACE1 or Memapsin
- APP is cleaved by a variety of proteolytic enzymes (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
- the key enzymes in the amyloidogenic pathway are Asp2 ( ⁇ -secretase) and ⁇ -secretase both of which are aspartic proteinases and cleavage of APP by these enzymes generates A ⁇ .
- the non-amyloidogenic, ⁇ -secretase pathway which precludes A ⁇ formation, has been shown to be catalysed by a number of proteinases, the best candidate being ADAM10, a disintegrin and metalloproteinase.
- Asp1 has been claimed to show both - and ⁇ -secretase activity in vitro.
- Asp2 is most highly expressed in the pancreas and brain while Asp1 expression occurs in many other peripheral tissues.
- the Asp2 knockout mouse indicates that lack of Asp2 abolished A ⁇ production and also shows that in this animal model endogenous Asp1 cannot substitute for the Asp2 deficiency (Luo, Y. et al. (2001) Nat Neurosci. 4: 231-232; Cai, H. et. al. (2001) Nat Neurosci. 4: 233-234; Roberds, S. L. et al. (2001) Hum. Mol. Genet. 10: 1317-1324).
- said agent is a potent inhibitor of the Asp2 enzyme, but should ideally also be selective for Asp2 over other enzymes of the aspartyl proteinase family, e.g Cathepsin D (Connor, G. E. (1998) Cathepsin D in Handbook of Proteolytic Enzymes, Barrett, A. J., Rawlings, N. D., & Woesner, J. F. (Eds) Academic Press London. pp828- 836).
- Cathepsin D Connor, G. E. (1998) Cathepsin D in Handbook of Proteolytic Enzymes, Barrett, A. J., Rawlings, N. D., & Woesner, J. F. (Eds) Academic Press London. pp828- 836).
- WO 01/70672 WO 02/02512, WO 02/02505 and WO 02/02506 (Elan Pharmaceuticals Inc.) describe a series of hydroxyethylamine compounds having ⁇ -secretase activity which are implicated to be useful in the treatment of Alzheimer's disease.
- R 1 represents aryl or heteroaryl
- R 2 represents C 1-6 alkyl or C 3-8 cycloalkyl
- R 2a represents hydrogen, halogen, C 1-3 alkyl or C ⁇ alkoxy; n represents 0, 1 or 2;
- R 2b represents C 1-3 alkyl, C 2-4 alkenyl, halogen, C 1-3 alkoxy, amino, cyano or hydroxy;
- R 3 represents hydrogen, halogen, optionally substituted C ⁇ -6 alkyl, C 2-6 alkenyl, aryl, heteroaryl, heterocyclyl, -C 1-6 alkyl-aryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-heterocyclyl, -C 2- e alkenyl-aryl, -C 2-6 alkenyl-heteroaryl, -C 2-6 alkenyl-heterocyclyl, C 3-8 cycloalkyl, -C 1-6 alkyl-C 3 -8 cycloalkyl, cyano, azido, nitro, sulphoxide, -NR 7 R 8 , -NR 9 COR 10 , -NR 11 SO 2 R 12 , -
- COOR 19 -C 1-6 alkyl-NR 20 R 21 or -C ⁇ -6 alkyl-N 3 , or R 3 together with R 2b on adjacent carbon atoms may form a fused 5-7 membered saturated or partially saturated carbocyclic or heterocyclic ring optionally substituted by a C 1-6 alkyl group;
- R 4 represents optionally substituted C 1-6 alkyl, -C 1-6 alkyl-C 3 . 8 cycloalkyl, -C 1-6 alkyl-aryl, - C 1-e alkyl-heteroaryl or -C 1-6 alkyl-heterocyclyl;
- R 5 represents hydrogen, optionally substituted C ⁇ o alkyl, -C 3 . 8 cycloalkyl, -C 3-8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C 1-6 alkyl-C 3-8 cycloalkyl, -C 3 .
- R b and R d independently represent hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or -C 1-6 alkyl-SO 2 - C 1-6 alkyl or R a and R b , R c and R d , R 9 and R h , R 1 and R j , R k and R 1 and R and R n together with the carbon atom to which they are attached may form a C 3 . 8 cycloalkyl group; R 12 represents C 1-6 alkyl or C 3-a cycloalkyl; q represents 0 to 3; optional substituents for alkyl groups of R 3 , R 4 and R 5 include one or more (eg.
- halogen C 1-6 alkoxy, amino, cyano or hydroxy groups
- R 2 represents C 1-6 alkyl
- R 2a represents hydrogen, halogen or C 1-3 alkyl
- R 3 represents hydrogen, halogen, optionally substituted C 1-6 alkyl, C 2-6 alkenyl, aryl, heteroaryl, heterocyclyl, -C 1-6 alkyl-aryl, -C 1-6 alkyl-heteroaryl, -C 1-6 alkyl-heterocyclyl, -C 2- 6 alkenyl-aryl, -C 2-6 alkenyl-heteroaryl, -C 2-6 alkenyl-heterocyclyl, C 3-8 cycloalkyl, -C 1-6 alkyl-C 3-8 cycloalkyl, cyano, azido, nitro, sulphoxide, -NR 7 R 8 , -NR 9 COR 10 , -NR 11 SO 2 R 12 , - OR 13 , -SO 2 R 14 , -SR 15 , -C ⁇ CR 16 , -C 0
- R 11 , R a , R c , R e , R f , R 9 , R h , R 1 , R j , R k , R R m , R n , R° and R p independently represent hydrogen, d -6 alkyl or C 3-8 cycloalkyl; and q represents 1 to 3.
- references to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkenyl shall be interpreted similarly.
- references to C 3-8 cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl.
- references to 'aryl' include references to monocyclic carbocyclic aromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl) or carbocyclic benzofused rings (eg. C 3-8 cycloalkyl fused to a phenyl ring).
- references to 'heteroaryl' include references to mono- and bicyclic heterocyclic aromatic rings containing 1-4 hetero atoms selected from nitrogen, oxygen and sulphur.
- monocyclic heterocyclic aromatic rings include e.g. thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, tetrazolyl and the like.
- bicyclic heterocyclic aromatic rings include eg.
- quinolinyl isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
- references to 'heterocyclyl' include references to a 5-7 membered non-aromatic monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen.
- heterocyclic non-aromatic rings include e.g. morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxathianyl, dithianyl, dioxanyl, pyrrolidinyl, dioxolanyl, oxathiolanyl, imidazolidinyl, pyrazolidinyl and the like.
- R 1 represents aryl (eg. phenyl or naphthyl) or heteroaryl (eg. pyridyl) optionally substituted by one or more halogen (eg. fluorine or chlorine), cyano, -CF 3 , C 1-6 alkoxy (eg. methoxy) or-CONR 22 R 23 (eg. -CONH 2 ) groups. More preferably, R 1 represents aryl (eg. phenyl or naphthyl) or heteroaryl (eg. pyridyl) optionally substituted by one or more halogen (eg. fluorine or chlorine) atoms.
- halogen eg. fluorine or chlorine
- R 1 represents aryl, eg. unsubstituted phenyl or phenyl substituted by a halogen (eg. fluorine or chlorine), cyano, or C 1-6 alkoxy (eg. methoxy) group.
- a halogen eg. fluorine or chlorine
- cyano e.g. C 1-6 alkoxy
- R 2 represents methyl, ethyl, i-propyl or butyl, more preferably methyl.
- n is 0 or 1 , more preferably 1.
- R 2a is preferably C 1-3 alkyl (eg. methyl) or halogen (eg. fluorine), more preferably halogen (eg. fluorine).
- R 2a is preferably at the para position of the carbocyclic/heterocyclic ring with respect to the group B.
- R 2b is preferably: halogen (eg. chlorine or fluorine); or
- C 1-3 alkyl eg. methyl
- R 2b is more preferably fluorine.
- R 3 represents: halogen (eg. bromine);
- C 1-6 alkyl eg. ethyl, propyl, i-propyl or t-butyl
- C 3 . 8 cycloalkyl eg. cyclopentyl or cyclohexyl
- cyano aryl (eg. phenyl) optionally substituted by one or more C 1-6 alkyl (eg. methyl) groups
- heterocyclyl eg. pyrrolidinyl or isothiazolidinyl
- oxo groups eg. 2-oxopyrrolidinyl or 1,1-dioxo-isothiazolidinyl
- R 3 together with R 2b on adjacent carbon atoms forms a partially saturated heterocyclic (eg. pyrroline) group optionally substituted by a C ⁇ -6 alkyl group (eg. ethyl).
- a partially saturated heterocyclic eg. pyrroline
- a C ⁇ -6 alkyl group eg. ethyl
- R 3 represents: halogen (eg. bromine);
- C 1-6 alkyl eg. i-propyl
- C 3-8 cycloalkyl eg. cyclopentyl
- heterocyclyl eg. pyrrolidinyl
- oxo group eg. 2-oxopyrrolidinyl
- R 7 and R 8 independently represent: hydrogen;
- C 1-6 alkyl eg. methyl, ethyl, propyl, butyl, pentyl, i-propyl, i-butyl, ethylpropyl, dimethylpropyl or methylbutyl
- C 3-8 cycloalkyl eg. cyclopentyl or cyclohexyl
- aryl eg. phenyl
- -C ⁇ -6 alkyl-C 3-8 cycloalkyl eg. -CH 2 -cyclopropyl
- -C 1-6 alkyl-aryl eg. -CH 2 -phenyl or -(CH 2 ) 2 -phenyl
- -CO-C -6 alkyl eg. -COCH 3
- R 7 and R 8 independently represent hydrogen, C 1-6 alkyl (eg. methyl, ethyl or isopropyl) or -G ⁇ -6 alkyl-aryl (eg. -CH 2 -phenyl), especially hydrogen or C 1-6 alkyl.
- R 7 represents hydrogen and R 8 represents C 1-6 alkyl (eg. ethyl or isopropyl).
- R 13 represents C 1-6 alkyl (eg. ethyl or isopropyl).
- R 14 and R 15 independently represent C 1-6 alkyl (eg. methyl or ethyl).
- R 15 represents ethyl
- R 16 represents hydrogen or C ⁇ -6 alkyl (eg. methyl).
- R 17 and R 18 independently represent C 1-6 alkyl (eg. propyl).
- R 4 represents -C 1-6 alkyl-aryl (eg. benzyl) optionally substituted by one or two halogen atoms (eg. fluorine). More preferably, R 4 represents unsubstituted benzyl.
- R 5 represents: -C 1-10 alkyl (eg. 1 ,5-dimethylhexyl or 1 ,1 ,5-trimethylhexyl);
- cycloalkyl eg. cyclopropyl or cyclohexyl
- -C(R'R J )-aryl eg. benzyl or 1-phenyl-1-methylethyl
- optionally substituted eg. substituted at the 3 and 5 positions
- -C(R c R d )-CONH-C 3-8 cycloalkyl eg. C(R c R d )-CONH-cyclohexyl
- R 5 represents:
- -C(R'R J )-aryl eg. benzyl
- cycloalkyl eg. C(R c R d )-CONH-cyclohexyl
- R c and R d independently represent hydrogen or methyl, more preferably R c represents hydrogen and R d represents methyl.
- R 1 and R J independently represent hydrogen or C 1-6 alkyl (eg. methyl) or together with the carbon atom to which they are attached form a C 3-8 cycloalkyl group.
- Preferred compounds according to the invention includes examples E1-E90 as shown below, or a pharmaceutically acceptable salt thereof.
- the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic or organic acids e.g.
- the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
- the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate.
- This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water).
- Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
- the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
- the invention also extends to any tautomeric forms and mixtures thereof.
- compounds of formula (I) are in the form of a single enantiomer of formula (la):
- a process according to the invention for preparing a compound of formula (I) which comprises:
- R 4 and R 5 are as defined above;
- process (a) typically comprises treatment of said activated derivative with an amine (Ogliaruso, M.A.; Wolfe, J.F. in The Chemistry of Functional Groups (Ed. Fatal, S.) Suppl.
- amine Ogliaruso, M.A.; Wolfe, J.F. in The Chemistry of Functional Groups (Ed. Fatal, S.) Suppl.
- B The Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp 442-8; Beckwith, A.L.J. in The Chemistry of Functional Groups (Ed. Patai, S.) Suppl.
- process (a) typically comprises the use of water soluble carbodiimide, HOBT and a suitable base such as tertiary alkylamine or pyridine in a suitable solvent such as DMF and at a suitable temperature, eg. between 0°C and room temperature.
- Process (b) typically comprises the use of sodium borohydride triacetate in the presence of a suitable solvent, such as ethanol, dichloromethane and 1 ,2-dichloroethane and at a suitable temperature, e.g. between 0°C and room temperature.
- a suitable solvent such as ethanol, dichloromethane and 1 ,2-dichloroethane and at a suitable temperature, e.g. between 0°C and room temperature.
- Suitable amine protecting groups include aryl sulphonyl (e.g. tosyl), acyl (e.g. acetyl), carbamoyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate.
- aryl sulphonyl e.g. tosyl
- acyl e.g. acetyl
- carbamoyl e.g. benzyloxycarbonyl or t-butoxycarbonyl
- arylalkyl e.g. benzyl
- Suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis.
- Suitable hydroxy protecting groups would be silyl based groups such as t-butyldimethylsilyl, which may be removed using standard methods, for example use of an acid such as trifluoroacetic or hydrochloric acid or a fluoride source such as tetra n-butylammonium fluoride.
- Process (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, amide bond formation or removal and sulphonylation.
- a further example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R 3 represents - C 1-6 alkyl-N 3 to a corresponding compound of formula (I) wherein R 3 represents -C 1-6 alkyl-NH 2 , using standard hydrogenation or reductive conditions.
- a yet further example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R 3 represents a nitro group to a corresponding compound of formula (I) wherein R 3 represents NH 2 , using standard hydrogenation or reductive conditions.
- a yet further example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R 3 represents a halogen atom to a corresponding compound of formula (I) wherein R 3 represents a C 2-6 alkenyl group, using standard Suzuki coupling conditions.
- R 2a , n, A, B, R 1 and R 2 are as defined above, P 1 represents a suitable group such as C 1-6 alkyl, L 1 represents a suitable leaving group such as a halogen atom (eg. iodine, chlorine or bromine) and L 2 represents a suitable group such as boronic acid or a boronic ester.
- P 1 represents a suitable group such as C 1-6 alkyl
- L 1 represents a suitable leaving group such as a halogen atom (eg. iodine, chlorine or bromine)
- L 2 represents a suitable group such as boronic acid or a boronic ester.
- Step (i) typically comprises the use of a suitable solvent such as dichloromethane and suitable bases such as pyridine and dimethylaminopyridine at a suitable temperature, such as room temperature.
- a suitable solvent such as dichloromethane
- suitable bases such as pyridine and dimethylaminopyridine
- Step (ii) typically comprises the use of copper (II) acetate in the presence of a suitable solvent such as dichloromethane and a suitable base such as triethylamine at a suitable temperature, such as room temperature (Chan et al, (1998) Tetrahedron Letters 39, 2933-2936).
- a suitable solvent such as dichloromethane
- a suitable base such as triethylamine
- Step (iii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as the use of an appropriate hydroxide salt like lithium or sodium salt in an appropriate solvent such as methanol at an appropriate temperature such as room temperature.
- an appropriate acid such as trifluoroacetic acid in an appropriate solvent such as dichloromethane at an appropriate temperature such as O°C.
- Activated derivatives of compounds of formula (II) may then be prepared as described in process (a) above.
- R 2a , n, A, B, R 1 , R 2 , P 1 and L 1 are as defined above and L 3 represents a suitable leaving group such as a halogen atom (eg. bromine, chlorine or iodine), OSO 2 (CF 2 ) 0- 7 CF 3 .
- a halogen atom eg. bromine, chlorine or iodine
- Step (i) typically comprises the use of caesium carbonate, 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene and a suitable catalyst such as tris(dibenzylideneacetone)dipalladium(0) in the presence of a suitable solvent (eg. toluene) at a suitable temperature, eg. 100°C.
- a suitable solvent eg. toluene
- Step (ii) typically comprises the use of lithium diisopropylamide in the presence of a suitable solvent such as tetrahydrofuran at a suitable temperature, eg. heating from - 78°C to room temperature.
- a suitable solvent such as tetrahydrofuran
- Step (iii) typically comprises a standard procedure for conversion of a carboxylic ester to an acid, such as the use of an appropriate hydroxide salt such as lithium or sodium salt in an appropriate solvent such as methanol at an appropriate temperature such as room temperature.
- an appropriate hydroxide salt such as lithium or sodium salt
- an appropriate solvent such as methanol
- this conversion can be achieved by the use of an appropriate acid such as trifluoroacetic acid in an appropriate solvent such as dichloromethane at an appropriate temperature such as 0°C.
- Activated derivatives of compounds of formula (II) may then be prepared as described in process (a) above.
- R 4 and R 5 are as defined above and P 2 represents a suitable amine protecting group, such as t-butoxycarbonyl.
- Step (i) typically comprises the reaction of a compound of formula (X) with a compound of formula NH 2 R 5 in the presence of a suitable solvent, e.g. ethanol at a suitable temperature, e.g. reflux.
- a suitable solvent e.g. ethanol
- a suitable temperature e.g. reflux.
- Step (ii) typically comprises the use of suitable deprotection reactions as described above for process (c), eg. when P 2 represents t-butoxycarbonyl, deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane at a suitable temperature, e.g. between 0°C and room temperature.
- a suitable solvent such as dichloromethane
- R 1 , R 2 , R 2a , n, A, B, R 4 and P 2 are as defined above and P 3 represents a suitable amine protecting group different to P 2 , such as -COOCH 2 -phenyl.
- Step (i) typically comprises the reaction of a compound of formula (X) in aqueous ammonia in the presence of a suitable solvent, e.g. ethanol at a suitable temperature, e.g. reflux.
- a suitable solvent e.g. ethanol
- a suitable temperature e.g. reflux.
- step (ii) typically comprises the use of CICOOCH 2 -phenyl in the presence of a suitable base, e.g. triethylamine, a suitable solvent, e.g. dimethylformamide at a suitable temperature, e.g. between 0°C and room temperature.
- a suitable base e.g. triethylamine
- a suitable solvent e.g. dimethylformamide
- Step (iii) typically comprises the use of suitable deprotection reactions as described above for process (c), eg. when P 2 represents t-butoxycarbonyl, deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane at a suitable temperature, e.g. between 0°C and room temperature.
- a suitable solvent such as dichloromethane
- Step (iv) typically comprises reacting a compound of formula (Xlll) with a compound of formula (II) in the presence of water soluble carbodiimide and HOBT.
- Step (v) typically comprises the use of suitable deprotection reactions as described above for process (c), eg. when P 3 represents -COOCH 2 -phenyl, deprotection typically comprises the use of a suitable catalyst, eg. palladium in the presence of a suitable solvent, e.g. water and ethanol and in the presence of a suitable hydrogen source, e.g. ammonium formate at a suitable temperature, eg. 60°C.
- a suitable catalyst eg. palladium in the presence of a suitable solvent, e.g. water and ethanol
- a suitable hydrogen source e.g. ammonium formate at a suitable temperature, eg. 60°C.
- a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical, particularly in the treatment of patients with diseases characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits.
- a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with diseases characterised by elevated ⁇ - amyloid levels or ⁇ -amyloid deposits.
- a method for the treatment of a human or animal subject with diseases characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
- composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits.
- the compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in the therapy of diseases characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable diluents or carriers.
- diseases characterised by elevated ⁇ -amyloid levels or ⁇ - amyloid deposits include Alzheimer's disease, mild cognitive impairment, Down's syndrome, hereditary cerebral haemorrhage with ⁇ -amyloidosis of the Dutch type, cerebral ⁇ -amyloid angiopathy and various types of degenerative dementias, such as those associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration and diffuse Lewis body type of Alzheimer's disease.
- the disease characterised by elevated ⁇ -amyloid levels or ⁇ -amyloid deposits is Alzheimer's disease.
- Compounds of formula (I) may be used in combination with other therapeutic agents.
- suitable examples of such other therapeutic agents may be acetylcholine esterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), gamma secretase inhibitors, anti-inflammatory agents (such as cyclooxygenase II inhibitors), antioxidants (such as Vitamin E and ginkolidesor), statins or p-glycoprotein (P-gp) inhibitors (such as cyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E- TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11- methanodibenzosuberane, phenothiazines, acridine derivatives such as GF120918, FK506, VX-710, LY335979, PSC-833, GF
- the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
- the compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, enteral, parenteral, topical, sublingual, intrathecal or rectal administration, preferably for oral administration.
- Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid.
- the preparations may also contain buffer salts, flavouring, colouring and/or sweetening
- compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative.
- the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
- the compounds of the invention When the compounds of the invention are administered topically they may be presented as a cream, ointment or patch.
- composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
- suitable unit doses may be 0.05 to 3000 mg; and such unit doses may be administered more than once a day, for example one, two, three or four times per day (preferably once or twice); and such therapy may extend for a number of weeks, months or years.
- All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
- Description F13 was prepared in an analogous manner to the procedure described for Description F12 using cyclohexene instead of cyclopentene (470 ⁇ l, 4.7 mmol, 2 equiv) and using 3-bromo-5-(methanesulfonyl-phenyl-amino)-benzoic acid terf-butyl ester (C44) (1 g, 2.35 mmol, 1 equiv) which yielded 350 mg (40%) of a mixture of 3-cyclohex-1-enyl- 5-(methanesulfonyl-phenyl-amino)-benzoic ferf butyl ester, 3-cyclohex-2-enyl-5-
- NEt 3 (14.2 ml, 102 mmol, 1.3 equiv) and diphenylphosphoryl azide (22 ml, 102 mmol, 1.3 equiv) were added to a suspension of 5-ethoxy-isophthalic acid monomethyl ester (F29) (17.6 g, 78.6 mmol, 1 equiv) in toluene (250 ml) and the mixture heated at 80 ° C for 3 h. Benzyl alcohol (12 ml, 118 mmol, 1.5 equiv) was added and the resulting mixture was refluxed for 4 h, cooled to room temperature and concentrated in vacuo.
- F29 5-ethoxy-isophthalic acid monomethyl ester
- Benzyl alcohol (12 ml, 118 mmol, 1.5 equiv) was added and the resulting mixture was refluxed for 4 h, cooled to room temperature and concentrated in vacuo.
- D16 was obtained in an analogous manner to the procedure described in Description 17 from 5-amino-nicotinic acid ethyl ester (which was prepared in accordance with Jensen, H. . et al Chem. Europ. J 2002, 8 (5), 1218-1226).
- esters were prepared in an analogous manner to the procedure described for Ester 1 from the corresponding N-aryl sulphonamide and boronic acid starting materials:
- Ester 16 was prepared in an analogous manner to Ester 17 from 5- methanesulfonylamino-nicotinic acid ethyl ester (D16).
- esters were prepared in an analogous manner to the procedure described for Ester 1 from the corresponding N-aryl sulphonamide and boronic acid starting materials:
- esters were obtained in analogous manner to that described for Ester 27 from the appropriate diphenylamine using the appropriate alkylsulfonyl chloride:
- N-Methylbenzylamine (368 ⁇ l, 2.85 mmol, 1.5 equiv) was then added via syringe and the resulting mixture was stirred at 90°C for 2 h then N- methylbenzylamine (200 ⁇ l, 1.54 mmol, 0.8 equiv) was added. After 3 h, the mixture was cooled to room temperature, diluted with H 2 O and AcOEt. The layers were separated, the aqueous phase diluted with saturated aqueous NaHCO 3 solution and extracted with AcOEt. The combined organic phases were dried over MgSO 4 and concentrated in vacuo.
- Ester 54 was prepared according to an analogous procedure described for Ester 55, using (2-methylphenyl)boronic acid instead of 2.6-dimethylphenylboronic acid which yielded (methanesulfonyl-phenyl-amino)-methyl-biphenyl-3-carboxylic acid dimethyl-ethyl ester (C54) (130 mg, 63%) from 3-bromo-5-(methanesulfonyl-phenyl-amino)-benzoic acid ferf-butyl ester (C44) (200 mg, 0.47 mmol).
- Examples 2-79 were prepared in an analogous manner to Example 1 from the appropriate acid and amines indicated in the below table:
- Examples 81-83 were prepared in an analogous manner to Example 80 from Example 45 (E45) and the appropriate vinylcyclotriboroxane-pyridine complex (as described by F. Kerins and D. F. O' Shea in J. Org. Chem, 2002, 67, 4968-4971 ):
- Examples 89-90 were prepared in an analogous manner to Example 1 from the appropriate acid and amines indicated in the below table:
- Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 1h at room temperature and fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer ( 485nm excitation, 535nm emission).
- a) 1 ⁇ l of a DMSO solution of the test compound (IC 50 curve uses ten 1 in 2 serial dilutions from 500 ⁇ M).
- c) 10 ⁇ l enzyme solution This is prepared by diluting 1.6ml of a 200 unit/ml (in 10 mM HCI) enzyme solution into 398.4 ml of buffer (prepared as above).
- Blank wells (enzyme solution replaced by buffer) are included as controls on each plate. Wells are incubated for 1 h at room temperature and fluorescence read using a Tecan Ultra Fluorimeter/Spectrophotometer ( 485nm excitation, 535nm emission).
- the compounds of E1-E90 were tested in Assays (I) and (II) and exhibited inhibition within the following range: 1-5000 nM (Asp-2) and 50-25000 nM (CatD). More particularly, the compounds of E17, 25, 38, 41 , 46, 49, 50, 55-56, 60, 61 , 64, 77, 83 and 87 exhibited inhibition within the following range: 1-100 nM (Asp-2) and 200-2500 nM (CatD). Most particularly, the compounds of E38, 41 , 49, 55, 60, 64, 77 and 87 exhibited inhibition within the following range: 1-10 nM (Asp-2) and 400-1000 nM.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04719453A EP1611089A2 (en) | 2003-03-14 | 2004-03-11 | Hydroxyethylamine compounds having asp2 inhibitory activity for the treatment of alzheimer's disease |
US10/549,349 US20060211740A1 (en) | 2003-03-14 | 2004-03-11 | Novel compounds |
JP2006504685A JP2006520358A (en) | 2003-03-14 | 2004-03-11 | Hydroxyethylamine compounds having ASP2 inhibitory activity for the treatment of Alzheimer's disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0305918.5A GB0305918D0 (en) | 2003-03-14 | 2003-03-14 | Novel compounds |
GB0305918.5 | 2003-03-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004080376A2 true WO2004080376A2 (en) | 2004-09-23 |
WO2004080376A3 WO2004080376A3 (en) | 2004-11-11 |
Family
ID=9954818
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/002644 WO2004080376A2 (en) | 2003-03-14 | 2004-03-11 | Hydroxyethylamine compounds having asp2 inhibitory activity for the treatment of alzheimer’s disease |
Country Status (5)
Country | Link |
---|---|
US (1) | US20060211740A1 (en) |
EP (1) | EP1611089A2 (en) |
JP (1) | JP2006520358A (en) |
GB (1) | GB0305918D0 (en) |
WO (1) | WO2004080376A2 (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005113525A1 (en) * | 2004-05-21 | 2005-12-01 | Glaxo Group Limited | N, n’-substituted-1,3-diamino-2-oxopropane derivatives, their pharmaceutical compositions and use |
WO2006060109A1 (en) | 2004-10-29 | 2006-06-08 | Merck & Co., Inc. | 2-aminopyridine compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease |
WO2006064324A2 (en) * | 2004-12-14 | 2006-06-22 | Pfizer Products Inc. | Heterocycloalkyl-benzyl substituted hydroxyethlamines |
EP1697308A2 (en) * | 2003-12-19 | 2006-09-06 | Merck & Co., Inc. | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer s disease |
WO2006103088A1 (en) * | 2005-03-31 | 2006-10-05 | Glaxo Group Limited | Novel hydroxyethylamine and ketone compounds having asp2 inhibitory activity |
WO2007029587A1 (en) | 2005-09-05 | 2007-03-15 | Dainippon Sumitomo Pharma Co., Ltd. | β SECRETASE INHIBITOR |
WO2007061670A1 (en) | 2005-11-21 | 2007-05-31 | Amgen Inc. | Beta-secretase modulators and methods of use |
WO2007062007A1 (en) | 2005-11-21 | 2007-05-31 | Amgen Inc. | Beta-secretase modulators and methods of use |
WO2007061930A1 (en) | 2005-11-21 | 2007-05-31 | Amgen Inc. | Beta-secretase modulators and methods of use |
WO2008147544A1 (en) | 2007-05-25 | 2008-12-04 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
US7504420B2 (en) | 2005-04-08 | 2009-03-17 | Comentis, Inc. | Compounds which inhibit beta-secretase activity and methods of use |
US7803809B2 (en) | 2008-11-12 | 2010-09-28 | Amgen Inc. | Substituted pyrano [2,3-b] pyridinamine compounds as beta-secretase modulators and methods of use |
WO2011063233A1 (en) | 2009-11-23 | 2011-05-26 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
WO2011063272A1 (en) | 2009-11-23 | 2011-05-26 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
WO2011090911A1 (en) | 2010-01-19 | 2011-07-28 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
US8106236B2 (en) | 2006-04-21 | 2012-01-31 | Ortho-Mcneil Pharmaceutical, Inc. | Triaryl compounds and derivates thereof |
US8299267B2 (en) | 2007-09-24 | 2012-10-30 | Comentis, Inc. | (3-hydroxy-4-amino-butan-2-yl) -3- (2-thiazol-2-yl-pyrrolidine-1-carbonyl) benzamide derivatives and related compounds as beta-secretase inhibitors for treating |
TWI399362B (en) * | 2006-04-21 | 2013-06-21 | Cellzome Ltd | Substituted biphenyl carboxylic acids and derivatives thereof |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DOP2003000765A (en) * | 2002-11-27 | 2004-05-31 | Elan Fharmaceuticals Inc | SUBSTITUTED UREAS AND USEFUL CARBAMATES FOR THE TREATMENT OF ALZHEIMER'S DISEASE (SUBSTITUTED UREAS AND CARBAMATES USEFUL IN THE TREATMENT OF ALZHEIMER`S DISEASE |
US7745484B2 (en) | 2005-11-21 | 2010-06-29 | Amgen Inc. | Beta-secretase modulators and methods of use |
US8163909B2 (en) | 2007-05-25 | 2012-04-24 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
WO2009015369A2 (en) * | 2007-07-26 | 2009-01-29 | Comentis, Inc. | Compounds which inhibit beta-secretase activity and methods of use thereof |
FR2919285B1 (en) * | 2007-07-27 | 2012-08-31 | Sanofi Aventis | 1-OXO-ISOINDOLINE-4-CARBOXAMIDE AND 1-OXO-1,2,3,4-TETRAHYDROISOQUINOLEINE-5-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF |
KR20110073511A (en) * | 2008-09-11 | 2011-06-29 | 암젠 인크 | Spiro-tetracyclic ring compounds as betasecretase modulators and methods of use |
EP2358377A2 (en) * | 2008-11-24 | 2011-08-24 | Ramot at Tel-Aviv University Ltd. | Method for treating parkinson's disease using filamentous bacteriophage |
EP2547686B1 (en) | 2010-03-15 | 2014-01-22 | 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 |
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 |
EP2758406A1 (en) | 2011-09-21 | 2014-07-30 | Amgen Inc. | Amino-oxazines and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
US9725469B2 (en) | 2012-11-15 | 2017-08-08 | Amgen, Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
CN115784839B (en) * | 2022-11-11 | 2024-06-21 | 浙江工业大学 | Preparation method of 4-cyclohexyl-3- (trifluoromethyl) benzyl alcohol |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002002505A2 (en) * | 2000-06-30 | 2002-01-10 | Elan Pharmaceuticals, Inc. | Compounds to treat alzheimer's disease |
-
2003
- 2003-03-14 GB GBGB0305918.5A patent/GB0305918D0/en not_active Ceased
-
2004
- 2004-03-11 JP JP2006504685A patent/JP2006520358A/en active Pending
- 2004-03-11 EP EP04719453A patent/EP1611089A2/en not_active Withdrawn
- 2004-03-11 US US10/549,349 patent/US20060211740A1/en not_active Abandoned
- 2004-03-11 WO PCT/EP2004/002644 patent/WO2004080376A2/en active Search and Examination
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002002505A2 (en) * | 2000-06-30 | 2002-01-10 | Elan Pharmaceuticals, Inc. | Compounds to treat alzheimer's disease |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1697308A2 (en) * | 2003-12-19 | 2006-09-06 | Merck & Co., Inc. | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer s disease |
US7550481B2 (en) | 2003-12-19 | 2009-06-23 | Merck & Co., Inc. | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease |
EP1697308A4 (en) * | 2003-12-19 | 2007-08-22 | Merck & Co Inc | Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of alzheimer s disease |
WO2005113525A1 (en) * | 2004-05-21 | 2005-12-01 | Glaxo Group Limited | N, n’-substituted-1,3-diamino-2-oxopropane derivatives, their pharmaceutical compositions and use |
JP2008518969A (en) * | 2004-10-29 | 2008-06-05 | メルク エンド カムパニー インコーポレーテッド | 2-Aminopyridine compounds useful as β-secretase inhibitors for treating Alzheimer's disease |
US7932275B2 (en) | 2004-10-29 | 2011-04-26 | Merck, Sharp & Dohme Corp. | 2-aminopyridine compounds useful as β-secretase inhibitors for the treatment of alzheimer's disease |
EP1807396A1 (en) * | 2004-10-29 | 2007-07-18 | Merck & Co., Inc. | 2-aminopyridine compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease |
EP1807396A4 (en) * | 2004-10-29 | 2009-09-09 | Merck & Co Inc | 2-aminopyridine compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease |
WO2006060109A1 (en) | 2004-10-29 | 2006-06-08 | Merck & Co., Inc. | 2-aminopyridine compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease |
WO2006064324A3 (en) * | 2004-12-14 | 2006-08-17 | Pfizer Prod Inc | Heterocycloalkyl-benzyl substituted hydroxyethlamines |
WO2006064324A2 (en) * | 2004-12-14 | 2006-06-22 | Pfizer Products Inc. | Heterocycloalkyl-benzyl substituted hydroxyethlamines |
WO2006103088A1 (en) * | 2005-03-31 | 2006-10-05 | Glaxo Group Limited | Novel hydroxyethylamine and ketone compounds having asp2 inhibitory activity |
US7504420B2 (en) | 2005-04-08 | 2009-03-17 | Comentis, Inc. | Compounds which inhibit beta-secretase activity and methods of use |
WO2007029587A1 (en) | 2005-09-05 | 2007-03-15 | Dainippon Sumitomo Pharma Co., Ltd. | β SECRETASE INHIBITOR |
JP5030781B2 (en) * | 2005-09-05 | 2012-09-19 | 良明 木曽 | β-secretase inhibitor |
US7816387B2 (en) | 2005-09-05 | 2010-10-19 | Dainippon Sumitomo Pharma Co., Ltd. | β secretase inhibitor |
WO2007061670A1 (en) | 2005-11-21 | 2007-05-31 | Amgen Inc. | Beta-secretase modulators and methods of use |
WO2007061930A1 (en) | 2005-11-21 | 2007-05-31 | Amgen Inc. | Beta-secretase modulators and methods of use |
WO2007062007A1 (en) | 2005-11-21 | 2007-05-31 | Amgen Inc. | Beta-secretase modulators and methods of use |
US8106236B2 (en) | 2006-04-21 | 2012-01-31 | Ortho-Mcneil Pharmaceutical, Inc. | Triaryl compounds and derivates thereof |
TWI399362B (en) * | 2006-04-21 | 2013-06-21 | Cellzome Ltd | Substituted biphenyl carboxylic acids and derivatives thereof |
WO2008147544A1 (en) | 2007-05-25 | 2008-12-04 | Amgen Inc. | Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use |
US8299267B2 (en) | 2007-09-24 | 2012-10-30 | Comentis, Inc. | (3-hydroxy-4-amino-butan-2-yl) -3- (2-thiazol-2-yl-pyrrolidine-1-carbonyl) benzamide derivatives and related compounds as beta-secretase inhibitors for treating |
US7951838B2 (en) | 2007-11-14 | 2011-05-31 | Amgen Inc. | Substituted spirocyclic chromanamine compounds as Beta-Secretase modulators and methods of use |
US7803809B2 (en) | 2008-11-12 | 2010-09-28 | Amgen Inc. | Substituted pyrano [2,3-b] pyridinamine compounds as beta-secretase modulators and methods of use |
WO2011063233A1 (en) | 2009-11-23 | 2011-05-26 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
WO2011063272A1 (en) | 2009-11-23 | 2011-05-26 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
WO2011090911A1 (en) | 2010-01-19 | 2011-07-28 | Amgen Inc. | Amino heteroaryl compounds as beta-secretase modulators and methods of use |
Also Published As
Publication number | Publication date |
---|---|
WO2004080376A3 (en) | 2004-11-11 |
GB0305918D0 (en) | 2003-04-23 |
JP2006520358A (en) | 2006-09-07 |
EP1611089A2 (en) | 2006-01-04 |
US20060211740A1 (en) | 2006-09-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2004080376A2 (en) | Hydroxyethylamine compounds having asp2 inhibitory activity for the treatment of alzheimer’s disease | |
ZA200508041B (en) | Tricyclic indole derivatives and their use in the treatment of Alzheimer's disease | |
WO2005113525A1 (en) | N, n’-substituted-1,3-diamino-2-oxopropane derivatives, their pharmaceutical compositions and use | |
US6992103B2 (en) | Benzamide derivatives, processes for their preparation, and their pharmaceutical use | |
CA2515780C (en) | Phenylenediamine urotensin-ii receptor antagonists and ccr-9 antagonists | |
ES2584188T3 (en) | Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof | |
EP1567488A1 (en) | Hydroxyethylamine derivatives for the treatment of alzheimer's disease | |
EP1740573A1 (en) | Amides as bace inhibitors | |
SK283463B6 (en) | Indoline derivatives, process for their production, intermediates of this process and pharmaceutical compositions containing them | |
US7163942B2 (en) | Sulfonamide compounds for the treatment of neurodegenerative disorders | |
WO2005058915A1 (en) | Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease | |
KR20030011093A (en) | Bis-arylsulfones | |
KR20000005039A (en) | Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase | |
KR19990076817A (en) | Amidinoprotease inhibitor | |
WO2006103088A1 (en) | Novel hydroxyethylamine and ketone compounds having asp2 inhibitory activity | |
MXPA06011349A (en) | Thiazole sulfonamide compounds for the treatment of neurodegenerative disorders. | |
KR20010041341A (en) | Benzylpiperazinyl and benzylpiperidinyl ethanone derivatives, their preparation and their use as dopamine d4 receptor antagonists | |
HUT73436A (en) | Quinoxaline-2,3-dions pericondensed with heterocycles containing oxygen or sulphur atomes, process for preparing them and pharmaceutical compositions containing said compounds | |
JPH04283553A (en) | Hiv protease inhibitor having polyether substituent | |
US7160905B2 (en) | Hydroxyethylene compounds with Asp2 inhibitory activity | |
WO2004111022A1 (en) | 3-(1,1-DIOXOTETRAHYDRO-1,2-THIAZIN-2-YL) or 3-(1,1-DOXO-ISOTHIAZOLIDIN-2YL) SUBSTITUTED BENZAMIDE COMPOUNDS AS ASP2 INHIBITORS | |
KR20080018206A (en) | Alkyl sulfonamide derivatives | |
AU2004232475B2 (en) | Tricyclic indole derivatives and their use in the treatment of alzheimer's disease | |
WO2006040151A1 (en) | Subsituted hydroxyethylamine compounds for treating alzheimer’s disease | |
MXPA06006572A (en) | Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2004719453 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10549349 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006504685 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2004719453 Country of ref document: EP |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
WWP | Wipo information: published in national office |
Ref document number: 10549349 Country of ref document: US |