+

WO2005113525A1 - Derives -1,3-diamino-2-oxopropane n, n'-substitue et compositions pharmaceutique de ces composes et utilisation - Google Patents

Derives -1,3-diamino-2-oxopropane n, n'-substitue et compositions pharmaceutique de ces composes et utilisation Download PDF

Info

Publication number
WO2005113525A1
WO2005113525A1 PCT/EP2005/005586 EP2005005586W WO2005113525A1 WO 2005113525 A1 WO2005113525 A1 WO 2005113525A1 EP 2005005586 W EP2005005586 W EP 2005005586W WO 2005113525 A1 WO2005113525 A1 WO 2005113525A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
amino
aryl
heterocyclyl
Prior art date
Application number
PCT/EP2005/005586
Other languages
English (en)
Inventor
Emmanuel Hubert Demont
Sally Redshaw
Daryl Simon Walter
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2005113525A1 publication Critical patent/WO2005113525A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • 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
    • 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
    • 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
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • 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

Definitions

  • the present invention relates to novel ketone compounds having Asp2 ( ⁇ -secretase, BACE1 or Memapsin 2) 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 2
  • Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of 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, ⁇ -amyloid (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).
  • 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 2) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472).
  • Asp2 also known as ⁇ -secretase, BACE1 or Memapsin 2
  • 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. er a/. (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 04/014843 (Takeda) describes a series of ketones having ⁇ -secretase activity which are implicated to be useful in the treatment of Alzheimer's disease.
  • WO 01/70672, WO 02/02512, WO 02/02505, WO 02/02506 and WO 03/040096 (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 C ⁇ . 6 alkyl, C 2 . 6 alkenyl, halogen, C 1-6 alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;
  • R 2a represents hydrogen, C 1-3 alkyl, C 1-3 alkoxy or halogen; m and n independently represent 0, 1 or 2; X represents CO, SO or SO 2 ; p represents an integer from 1 to 3;
  • R 2b represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, halogen, C 1-6 alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;
  • R 3 represents halogen, C 1-6 alkyl, C 2 . 6 alkenyl, aryl, heteroaryl, heterocyclyl, -C ⁇ -6 alkyl-aryl, - C ⁇ - 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 .
  • R 4 represents -C 2 . 6 alkynyl, -C ⁇ alkyl-aryl, -C ⁇ -6 alkyl-heteroaryl or -C 1-6 alkyl-heterocyclyl;
  • R 5 represents hydrogen, -C 1-10 alkyl, -C 3 . ⁇ 0 cycloalkyl, -C 3-10 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C ⁇ -6 alkyl-C 3 - 10 cycloalkyl, -C3.10 cycloalkyl-CL.10 alkyl, -C 3 .
  • R 7 , R 8 , R 9 , R 10 , R 13 , R 14 , R 5 , R 16 , R 17 , R 18 , R 19 , R 20 and R 2 independently represent hydrogen
  • R 1 , R 12 , R a , R c , R e and R f independently represent hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl;
  • R b and R d independently represent hydrogen, C 1-6 alkyl, C 3 _s cycloalkyl or -Ci -6 alkyl-SO 2 -C 1-6 alkyl; q represents 1 to 3; wherein said alkyl groups may be optionally substituted by one or more (eg. 1, 2 or 3) halogen, C ⁇ -6 alkyl, C 1-6 alkoxy, C 2 . 6 alkenoxy, C 3-8 cycloalkyl, amino, cyano or hydroxy groups; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (eg.
  • -COOR 22 , -SO 2 R 22 , -C 1-6 alkyl-NR 22 R 23 (wherein R 22 and R 23 independently represent hydrogen or C 1-6 alkyl), -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkanol or hydroxy groups; or a pharmaceutically acceptable salt or solvate thereof.
  • 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 and alkenoxy shall be interpreted similarly. It will also be appreciated that when an alkenyl or alkenoxy group is attached to an O, N or S atom the double bond is not at the alpha position relative to said O, N or S atom.
  • haloC 1-6 alkyl include references to both straight chained and branched chain aliphatic isomers of C 1-6 alkyl in which one or more hydrogen atoms are substituted by halogen atoms (eg. fluorine, chlorine or bromine).
  • halogen atoms eg. fluorine, chlorine or bromine.
  • Examples of haloC 1-6 alkyl groups include - CH 2 CF 3 and -CF 3 .
  • references to cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl.
  • a cycloalkyl group is substituted by two or more C 1-6 alkyl groups, said cycloalkyl groups together with any two alkyl groups may form a bridged cycloalkyl group which includes bicycloheptyl, adamantyl, bicyclo-octyl and the like.
  • 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, such as dihydroindenyl or tetrahydronaphthalenyl).
  • monocyclic carbocyclic aromatic rings eg. phenyl
  • bicyclic carbocyclic aromatic rings e.g. naphthyl
  • carbocyclic benzofused rings eg. C 3- 8 cycloalkyl fused to a phenyl ring, such as dihydroindenyl or tetrahydronaphthalenyl.
  • references to 'heteroaryl' include references to mono- and bicyclic heterocyclic aromatic rings which monocyclic or bicyclic rings contain 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.
  • quinolinyl isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benziso
  • 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.
  • references to 'benzofused heterocyclyl or heteroaryl ring' include quinolinyl, isoquinolinyl, indolyl, indazolyl, dihydroindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, dihydrochromene, benzotriazolyl, tetrahydroquinoxalinyl and the like.
  • m is 0 or 1. In a more particular aspect, m is 0. In one embodiment in which m represents 1 , R 1 is aryl (eg. phenyl).
  • n is 0 or 1. In a more particular embodiment, n is 1.
  • R 2a is C 1-3 alkoxy (eg. methoxy) or halogen (eg. fluorine). In a more particular embodiment, R 2a is halogen (eg. fluorine).
  • R 2a is in the position ortho to the sultam or lactam substituent of the phenyl ring.
  • p is 1 , 2 or 3. In a more particular embodiment in which X represents SO 2 , p is 2.
  • p is 1 or 2. In a more particular embodiment in which X represents CO, p is 1.
  • R 2b is : hydrogen; halogen (eg. chlorine or fluorine); C 1-6 alkyl (eg. methyl); C 1-6 alkoxy (eg. methoxy); or heterocyclyl (eg. pyrrolidinyl) optionally substituted by an oxo group (eg. 2- oxopyrrolidin-1-yl).
  • halogen eg. chlorine or fluorine
  • C 1-6 alkyl eg. methyl
  • C 1-6 alkoxy eg. methoxy
  • heterocyclyl eg. pyrrolidinyl
  • an oxo group eg. 2- oxopyrrolidin-1-yl
  • R 2b is hydrogen or halogen (eg. fluorine), particularly hydrogen.
  • R 3 represents: C 1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl) optionally substituted by one or more (eg. 1 , 2 or 3) hydroxy, halogen (eg. fluorine) or C 1-6 alkoxy groups (eg. methoxy or ethoxy); C- 2 . 6 alkenyl (eg. propenyl); C 3-8 cycloalkyl (eg.
  • cyclopentyl or cyclohexyl cyano
  • heterocyclyl eg. piperidinyl, pyrrolidinyl or isothiazolidinyl
  • -NR 7 R 8 a compound selected from the group consisting of cyclopentyl or cyclohexyl
  • -OR 13 e.g. cyclopentyl or cyclohexyl
  • -SR 15 e.g. -CONR 17 R 18 .
  • R 3 represents: C 1-6 alkyl (eg. n-propyl); -NR 7 R 8 ; C 3-8 cycloalkyl (eg. cyclopentyl or cyclohexyl); -OR 13 ; or -CONR 17 R 18 .
  • R 3 represents d -6 alkyl (eg. n-propyl), -NR 7 R 8 or -OR 13 .
  • R 3 and R 2b together with the phenyl group which they are attached represent indolyl, indazolyl, dihydroindolyl, benzofuranyl, dihydrochromenyl, benzotriazolyl, benzimidazolyl or tetrahydroquinoxalinyl, optionally substituted by one or two C 1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl or pentyl) groups. More particularly, R 3 and R 2b together with the phenyl group which they are attached represent benzimidazolyl or indolyl substituted by a C ⁇ -6 alkyl group (eg. ethyl).
  • R 7 and R 8 independently represent: hydrogen; C 1-6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, i-propyl, i-butyl, -CH 2 C(CH 3 ) 3 , -CH(CH 2 CH 3 )CH 2 CH 3 or -(CH 2 ) 2 CH(CH 3 ) 2 ); C 3 . 8 cycloalkyl (eg. cyclopentyl or cyclohexyl); aryl (eg.
  • C 1-6 alkyl eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, i-propyl, i-butyl, -
  • phenyl ); -C 1-6 alkyl-C 3-8 cycloalkyl (eg. -CH 2 -cyclopropyl); -C 1-6 alkyl-aryl (eg. -CH 2 -phenyl or -(CH 2 ) 2 -phenyl); or -CO-C 1-6 alkyl (eg. -COCH 3 ).
  • R 7 represents hydrogen and R 8 represents C ⁇ alkyl (particularly ethyl or isopropyl).
  • R 13 represents C ⁇ . 6 alkyl (eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl or pentyl) optionally substituted by a hydroxy or C 1 -6 alkoxy (eg. methoxy) group, more particularly R 13 represents ethyl or i-propyl. In a most particular embodiment R 13 represents ethyl.
  • R 15 represents C ⁇ . 6 alkyl (eg. methyl or ethyl).
  • R 17 and R 18 both represent C ⁇ . 6 alkyl (eg. both represent propyl or one represents propyl and the other represents methyl).
  • R 4 represents -C ⁇ -6 alkyl-aryl (eg. benzyl) or -C 1-6 alkyl-heteroaryl (eg. - CH 2 -pyridinyl, -CH 2 -thiazolyl, -CH 2 -furanyl, -CH 2 -thienyl or -CH 2 -pyrazolyl) optionally substituted by one or two halogen atoms (eg. chlorine or fluorine).
  • R 4 represents -C ⁇ . 6 alkyl-aryl (eg. benzyl) optionally substituted by one or two halogen atoms (eg. chlorine or fluorine).
  • R 4 represents unsubstituted benzyl.
  • cyclopropyl optionally substituted by one or more C 1 - 6 alkyl (eg. methyl, ethyl or propyl) or halogen (eg. fluorine) groups; -C ⁇ -6 alkyl-C 3 . ⁇ o cycloalkyl (eg. -CH 2 -cyclohexyl or -CH 2 -cyclopropyl); -aryl (eg.
  • phenyl, dihydroindenyl or tetrahydronaphthalenyl optionally substituted by one or more hydroxy or C ⁇ -6 alkoxy (eg. methoxy) groups; -C ⁇ -6 alkyl-aryl (eg. benzyl, -ethyl-phenyl, -ethyl-naphthyl, -propyl-phenyl, -C(H)(Me)- phenyl, -C(H)(Et)-phenyl -C(Me)(Me)-benzyl or -C(Me)(Me)-phenyl) optionally substituted by one or more halogen (eg.
  • haloC ⁇ -6 alkyl eg. - CH 2 CF 3 or -CF 3
  • C 1 - 6 alkyl eg. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t- butyl
  • C 2-6 alkenyl eg. ethenyl
  • C 2-6 alkynyl C 1 . 6 alkoxy (eg. methoxy, ethoxy, propoxy, isopropoxy or methylethoxy)
  • cyano, nitro, -COOR 22 eg.
  • tetrahydropyranyl or tetrahydrothiopyranyl tetrahydropyranyl or tetrahydrothiopyranyl
  • -C ⁇ _ 5 alkyl-heterocyclyl eg. -CH 2 -tetrahydropyranyl
  • -C 3 . 10 cycloalkyl-d. 10 alkyl eg.
  • -cyclopropyl-CH 2 -phenyl optionally substituted by one or more halogen (eg. chlorine) atoms; -C 3 .i 0 cycloalkyl-aryl (eg. -cyclopropyl-phenyl) optionally substituted by one or more halogen (eg. chlorine, bromine or fluorine), hydroxy, -OCF 3 , haloC ⁇ . 6 alkyl (eg. -CH 2 CF 3 or - CF 3 ), C ⁇ -6 alkyl (eg.
  • R 5 represents: -C 1 - 1 0 alkyl (eg. i-propyl); -Q3. 10 cycloalkyl (eg. cyclohexyl); -C 1 - 6 alkyl-aryl (eg. benzyl) optionally substituted by one or more halogen (eg. chlorine, bromine or fluorine), C 1 - 6 alkoxy (eg. methoxy), -OCF 3 or haloC ⁇ alkyl (eg. -CF 3 ) groups; -C ⁇ . 6 alkyl-heteroaryl (eg.
  • -CH 2 -thienyl, -CH 2 -pyrazolyl or -CH 2 -isoxazolyl optionally substituted by one or more C ⁇ . 6 alkyl (eg. methyl, ethyl, isopropyl, propyl or butyl) or haloC ⁇ alkyl (eg. CH 2 CF 3 ) groups; -heterocyclyl (eg. tetrahydropyranyl such as tetrahydropyran-4-yl); or -C(R c R d )-CONH-C 3-10 cycloalkyl (eg. C(R c R d )-CONH-cyclohexyl).
  • C ⁇ . 6 alkyl eg. methyl, ethyl, isopropyl, propyl or butyl
  • haloC ⁇ alkyl eg. CH 2 CF 3
  • -heterocyclyl eg.
  • R 5 represents: -C 1 .10 alkyl (eg. i-propyl), particularly unsubstituted -C 1-10 alkyl; -C 3 . ⁇ o cycloalkyl (eg. cyclohexyl), particularly unsubstituted -C 3 . 10 cycloalkyl; - -6 alkyl-aryl (eg. benzyl) optionally substituted by one or more C ⁇ -6 alkoxy (eg. methoxy), -OCF 3 or haloC 1-6 alkyl (eg. -CF 3 ) groups; -heterocyclyl (eg.
  • tetrahydropyran-4-yl particularly unsubstituted heterocyclyl; or -C(R c R d )-CONH-C 3 .i 0 cycloalkyl (eg. C(R c R d )-CONH-cyclohexyl).
  • the aryl group may be substituted at the 3 position by C 1-6 alkoxy (eg. methoxy), -OCF 3 or haloC ⁇ . 6 alkyl (eg. -CF 3 ) groups.
  • q represents 1 or 2.
  • R a represents hydrogen or C ⁇ -6 alkyl (methyl).
  • R b and R d independently represent C 1 - 6 alkyl (eg. methyl, ethyl, propyl or butyl) or -C 1 .6 alkyl-SO 2 -d. 6 alkyl (eg. -CH 2 CH 2 SO 2 CH 3 ) optionally substituted by one or more hydroxy groups.
  • R b and R independently represent d ⁇ alkyl (eg. methyl).
  • R c represents hydrogen or d -6 alkyl (methyl), particularly hydrogen.
  • R e and R f both represent C ⁇ . 6 alkyl (eg. methyl).
  • the invention provides a compound of formula (I) wherein: m represents 0; n represents 0 or 1 ;
  • R 2a represents C ⁇ . 3 alkoxy or halogen
  • R 2 is hydrogen or halogen
  • R 3 represents C ⁇ . 6 alkyl, -NR 7 R 8 or -OR 13 ;
  • R 4 represents unsubstituted benzyl.
  • R 5 represents -d- 1 0 alkyl, -C 3 . ⁇ 0 cycloalkyl,-C ⁇ -6 alkyl-aryl, -heterocyclyl or -C(R c R d )-CONH-C 3 .
  • cycloalkyl wherein said alkyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) groups selected from halogen, amino, cyano, hydroxy, C 1-6 alkyl and C ⁇ -6 alkoxy; and wherein said cycloalkyl, aryl or heterocyclyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) groups selected from halogen, amino, cyano, hydroxy, d- ⁇ alkyl, d.
  • alkyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) groups selected from halogen, amino, cyano, hydroxy, C 1-6 alkyl and C ⁇ -6 alkoxy
  • cycloalkyl, aryl or heterocyclyl groups may be optionally substituted by one or more (eg. 1 , 2 or 3) groups selected from halogen, amino, cyano, hydroxy, d- ⁇ alkyl,
  • Compounds according to the invention include the compounds of examples E1-E12 or pharmaceutically acceptable salts thereof..
  • Particular compounds of the invention include the following compounds, or pharmaceutically acceptable salts 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.
  • prodrugs of compounds of formula (I) also includes within its scope prodrugs of compounds of formula (I).
  • prodrug means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H.
  • Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • 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): (la)
  • a process according to the invention for preparing a compound of formula (I) which comprises:
  • R 1 , m, X, p, R 2a , n, R 2 , R 3 , R 4 and R 5 are as defined above and P 1 represents a suitable protecting group such as -COOC(CH 3 ) 3 , followed by a deprotection reaction; or
  • Process (a) typically comprises treatment of compounds of formula (II) with a suitable oxidising agent such as Dess-Martin periodinane in the presence of a suitable solvent, such as dichloromethane, and at a suitable temperature e.g. between 0°C and room temperature, followed by removal of the P 1 group with hydrogen chloride, formic acid or p-toluenesulfonic acid in the presence of a suitable solvent such as dioxane and at a suitable temperature, e.g. between 0°C and room temperature.
  • a suitable oxidising agent such as Dess-Martin periodinane
  • a suitable solvent such as dichloromethane
  • 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 t fluoroacetyl (-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 (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, amide bond formation or removal and sulphonylation.
  • An example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R 3 represents a C 2 . 6 alkenyl containing group to a corresponding compound of formula (I) wherein R 3 represents a C ⁇ . 6 alkyl containing group, using standard hydrogenation or reductive conditions.
  • a further example of such an interconversion reaction may include interconversion of a compound of formula (I) wherein R 3 represents - C ⁇ .
  • 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 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.
  • a pharmaceutical 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.
  • a pharmaceutical 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 and PSC-833).
  • 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.
  • the mixture was stirred at room temperature for 1 hr and then treated with a saturated aqueous solution of sodium hydrogen carbonate containing 10% w/v sodium thiosulphate (5 ml) for 0.5 hr.
  • the organic layer was then separated and evaporated in-vacuo.
  • Example 2-12 (E2-12) The following compounds have been obtained from the appropriate intermediates according to the general procedure described for the synthesis of Example 1 (E1). In examples 2-5, the deprotection was carried out using tosic acid (ca 30 equivalents) in acetonitrile. The compound of Example 2 was purified using mass-directed auto purification (MDAP) using aqueous acetonitrile and formic acid for the elution.
  • MDAP mass-directed auto purification
  • Aminomethyl fluorescein (FAM) and tetramethyl rhodamine (TAMRA) are fluorescent molecules which co-operate to emit fluorescence at 535nm upon cleavage of the SEVNLDAEFK peptide.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne ce nouveaux composés cétone possédant une activité inhibitrice Asp2 (?-secrétase, BACE1 ou Memapsine 2), des processus de préparation de ces composés, des compositions contenant ces composés et leur utilisation dans le traitement de maladies caractérisées par des taux d'amyloïdes B élevés ou des dépôts d'amyloïdes ?, la maladie d'Alzheimer, en particulier.
PCT/EP2005/005586 2004-05-21 2005-05-19 Derives -1,3-diamino-2-oxopropane n, n'-substitue et compositions pharmaceutique de ces composes et utilisation WO2005113525A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0411404.7 2004-05-21
GBGB0411404.7A GB0411404D0 (en) 2004-05-21 2004-05-21 Novel compounds

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11/093,203 A-371-Of-International US7093903B2 (en) 1998-08-13 2005-03-28 Winged headrest with safety features for vehicular use
US13/314,983 Continuation US8969278B2 (en) 2005-11-09 2011-12-08 Composition with surface modifying properties

Publications (1)

Publication Number Publication Date
WO2005113525A1 true WO2005113525A1 (fr) 2005-12-01

Family

ID=32607758

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/005586 WO2005113525A1 (fr) 2004-05-21 2005-05-19 Derives -1,3-diamino-2-oxopropane n, n'-substitue et compositions pharmaceutique de ces composes et utilisation

Country Status (2)

Country Link
GB (1) GB0411404D0 (fr)
WO (1) WO2005113525A1 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504420B2 (en) 2005-04-08 2009-03-17 Comentis, Inc. Compounds which inhibit beta-secretase activity and methods of use
US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8329897B2 (en) 2007-07-26 2012-12-11 Vitae Pharmaceuticals, Inc. Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8440658B2 (en) 2007-12-11 2013-05-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040096A2 (fr) * 2001-11-08 2003-05-15 Elan Pharmaceuticals, Inc. Derives 1,3-diamino-2-hydroxypropane n-n'-substitues
WO2004014843A1 (fr) * 2002-08-09 2004-02-19 Takeda Chemical Industries, Ltd. Composés amino substitués et utilisation de ces composés
WO2004050619A1 (fr) * 2002-12-05 2004-06-17 Glaxo Group Limited Derives d'hydroxyethylamine utilises pour le traitement de la maladie d'alzheimer
WO2004080376A2 (fr) * 2003-03-14 2004-09-23 Glaxo Group Limited Nouveaux composes
WO2004094430A1 (fr) * 2003-04-23 2004-11-04 Glaxo Group Limited Derives d'indole tricycliques et leur utilisation dans le cadre du traitement de la maladie d'alzheimer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040096A2 (fr) * 2001-11-08 2003-05-15 Elan Pharmaceuticals, Inc. Derives 1,3-diamino-2-hydroxypropane n-n'-substitues
WO2004014843A1 (fr) * 2002-08-09 2004-02-19 Takeda Chemical Industries, Ltd. Composés amino substitués et utilisation de ces composés
WO2004050619A1 (fr) * 2002-12-05 2004-06-17 Glaxo Group Limited Derives d'hydroxyethylamine utilises pour le traitement de la maladie d'alzheimer
WO2004080376A2 (fr) * 2003-03-14 2004-09-23 Glaxo Group Limited Nouveaux composes
WO2004094430A1 (fr) * 2003-04-23 2004-11-04 Glaxo Group Limited Derives d'indole tricycliques et leur utilisation dans le cadre du traitement de la maladie d'alzheimer

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504420B2 (en) 2005-04-08 2009-03-17 Comentis, Inc. Compounds which inhibit beta-secretase activity and methods of use
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8329897B2 (en) 2007-07-26 2012-12-11 Vitae Pharmaceuticals, Inc. Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8440658B2 (en) 2007-12-11 2013-05-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8202857B2 (en) 2008-02-11 2012-06-19 Vitae Pharmaceuticals, Inc. 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8138178B2 (en) 2008-05-01 2012-03-20 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8569292B2 (en) 2008-05-01 2013-10-29 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8242111B2 (en) 2008-05-01 2012-08-14 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8114868B2 (en) 2008-07-25 2012-02-14 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8883778B2 (en) 2009-07-01 2014-11-11 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders

Also Published As

Publication number Publication date
GB0411404D0 (en) 2004-06-23

Similar Documents

Publication Publication Date Title
WO2005113525A1 (fr) Derives -1,3-diamino-2-oxopropane n, n'-substitue et compositions pharmaceutique de ces composes et utilisation
ZA200508041B (en) Tricyclic indole derivatives and their use in the treatment of Alzheimer's disease
US6992103B2 (en) Benzamide derivatives, processes for their preparation, and their pharmaceutical use
EP1611089A2 (fr) Composes hydroxyethylamines ayant une activite inhibitrice asp2 pour le traitement de la maladie d' alzheimer
EP1692143B1 (fr) Derives d'indole hydroxyethylamine tricycliques et leur utilisation dans le traitement de la maladie d'alzheimer
KR101945139B1 (ko) 선택적 bace1 억제제
JP7414820B2 (ja) ヒストンデアセチラーゼの阻害剤
KR20140051823A (ko) 결정질 옥사진 유도체 및 bace 억제제로서의 그의 용도
EP0549666B1 (fr) Nouveaux derives d'aminobenzosultame utilises comme inhibiteurs de la lipoxygenase
WO2006103088A1 (fr) Nouveaux composes hydroxyethylamine et cetone possedant une activite inhibitrice de asp2
US7160905B2 (en) Hydroxyethylene compounds with Asp2 inhibitory activity
WO2004111022A1 (fr) Composes de benzamide a substitution 3-(1,1-dioxotetrahydro-1,2-thiazin-2-yl) ou 3-(1,1-doxo-isothiazolidin-2yl) utilises comme inhibiteurs de l'enzyme asp2
EP0228035A2 (fr) Composés antimicrobiens de l'acide 1-thiényl-4-oxoquinoléine-3-carboxylique
WO2006040148A1 (fr) Derives indoliques tricycliques pour le traitement de la maladie d'alzheimer
WO2006040151A1 (fr) Composes d'hydroxyethylamine substitues pour le traitement de la maladie d'alzheimer
WO2006040149A1 (fr) Composes heterocycliques de cetones pour traiter la maladie d'alzheimer
AU2004232475B2 (en) Tricyclic indole derivatives and their use in the treatment of alzheimer's disease
MXPA06006572A (en) Tricyclic indole hydroxyethylamine derivatives and their use in the treatment of alzheimer's disease
EP0966473B1 (fr) Thiazolobenzoheterocycles, leur preparation et les medicaments les contenant
CN110467611B (zh) 亚氨基噻二嗪二氧化物衍生物及其用途
JPH0321542B2 (fr)
IE65214B1 (en) Movel aminobenzosultam derivatives as lipoxygenase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR 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 KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM 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: A1

Designated state(s): BW GH GM KE LS MW MZ NA 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 IS IT LT 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
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载