WO2001019797A2 - HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b) - Google Patents

HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b) Download PDF

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Publication number
WO2001019797A2
WO2001019797A2 PCT/US2000/024967 US0024967W WO0119797A2 WO 2001019797 A2 WO2001019797 A2 WO 2001019797A2 US 0024967 W US0024967 W US 0024967W WO 0119797 A2 WO0119797 A2 WO 0119797A2
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WO
WIPO (PCT)
Prior art keywords
phenyl
substituted
methyl
alkyl
occurrence
Prior art date
Application number
PCT/US2000/024967
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English (en)
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WO2001019797A3 (fr
Inventor
Richard Eric Olson
Hong Liu
Lorin Andrew Thompson, Iii
Original Assignee
Du Pont Pharmaceuticals Company
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 Du Pont Pharmaceuticals Company filed Critical Du Pont Pharmaceuticals Company
Priority to BR0014269-7A priority Critical patent/BR0014269A/pt
Priority to AU74797/00A priority patent/AU783914B2/en
Priority to CA002377221A priority patent/CA2377221A1/fr
Priority to JP2001523377A priority patent/JP2003509411A/ja
Priority to MXPA02001813A priority patent/MXPA02001813A/es
Priority to IL14777400A priority patent/IL147774A0/xx
Priority to EP00963374A priority patent/EP1212306A2/fr
Publication of WO2001019797A2 publication Critical patent/WO2001019797A2/fr
Publication of WO2001019797A3 publication Critical patent/WO2001019797A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

Definitions

  • the present invention provides a novel compound of Formula (I):
  • p 0, 1, 2, 3, or 4;
  • R 11 substituents on adjacent atoms may be combined to form C 3 -C 6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S; wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R 13 ;
  • R 2 is H, methyl, ethyl, propyl, or butyl
  • R 5 is H, OR 14 ;
  • R 5 and R 5a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5c ;
  • Z is H, halo
  • X is a bond; phenyl substituted with 0-3 R xb ;
  • R 9 and R 9a are independently selected from H, F, methyl, and ethyl;
  • Q 1 is C ⁇ -C 6 alkyl substituted with 0-3 R la ; C 2 -C 6 alkenyl substituted with 0-3 R l ; C -C ⁇ alkynyl substituted with 0-3 R la ;
  • R llb at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 16 , CF 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C ⁇ -C 2 haloalkoxy;
  • R 5a is H
  • the present invention provides a compound of Formula of Formula (Ic) ;
  • Z is H, F, Cl, Br,
  • Q 1 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 ,
  • R 13 at each occurrence, is independently selected from H, MeO, F, and Cl .
  • the present invention provides all herein disclosed embodiments with the proviso that when R 5 is C 1 -C 3 alkyl, then Q is not phenyl substituted by 0 , 1 or 2 R la .
  • the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer's Disease.
  • Haloalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2- trifluoroethoxy, and the like.
  • Halothioalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge .
  • Cycloalkyl is intended to include saturated ring groups, having the specified number of carbon atoms. For example, "C 3 -C 6 cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • aryl As used herein, the term "aryl”, “C 6 -C 10 aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl.
  • lactam ring B represents the lactam ring B of Formula (I) .
  • Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula.
  • the additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur.
  • Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven.
  • lactam ring B include:
  • Sulfoxides and sulfones are prepared from the corresponding sulfide by oxidation. See M. Hudlicky,
  • Examples Chemical abbreviations used in the Examples are defined as follows: "DMPU” for 1, 3-dimethyl-3 , 4, 5 , 6- tetrahydro-2 (IH) -pyrimidone; "TBTU” for O- (lH-benzotriazol- 1-yl) -N,N,N' , N' -tetramethyluronium tetrafluoroborate; "BOP” for benzotriazol-1-yloxytris-dimethylamino) - phosphonium hexafluorophosphate; "Bu 2 BOTf” for dibutylboron triflate; "EDC” for 1- [3- (dimethylamine) propyl] -3- ethylcarbodiimide hydrochloride; "HOBt” for 1- hydroxybenzotriazole; and "TEA” for triethylamine.
  • DMPU for 1, 3-dimethyl-3 , 4, 5 , 6- tetrahydro-2 (I
  • the reaction mixture was quenched by the addition of 4 mL of a pH 7 aqueous phosphate buffer and 12 mL of methanol. To this cloudy solution was added 8 mL of methanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as to keep the internal temperature below 10°C. After the solution was stirred for one additional hour, the volatile material was removed in a rotary evaporator. The resulting slurry was extracted with three 20 mL portions of diethyl ether. The combined organic layers was washed with 20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example 43 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (azapan-1-yl) -l-methyl-2 , 3-dihydro-lH- 1, 4-benzodiazepin-2-one.
  • Example 46 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5- (4-methoxyphenyl) l-methyl-2, 3-dihydro-lH- 1, 4-benzodiazepin-2-one.
  • Example 48 3- (S) - (4-cyclopentyl-2- (R) -cyclopropylmethyl- 3- (S) -hydroxyl-1-oxobutyl) amino-1-methyl-5-phenyl-2 , 3- dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 50 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxohept-6-enyl) amino-l-methyl-5- (4-trifluoromethyl-phenyl) - 2,3-dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 514 (M+H). Chromatography Note i. Example 51.
  • Example 64 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-7-methoxy-l-methyl-5-phenyl-2 , 3-dihydro-lH- l,4-benzodiazepin-2-one.
  • Example 84 3- (S) - (2- (R) -ethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-1-methyl-5-phenyl-2 , 3 -dihydro-lH-1, 4- benzodiazepin-2-one. MS (ESI) : 422 (M+H) .
  • Example 85 3- (S) - (2- (R) -propyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5-phenyl-2 , 3-dihydro-l, 4- benzodiazepin-2-one.
  • MS (ESI) 436 (M+H) .
  • Example 103 3- (2- (S) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-l-methyl-5- (4-trifluoromethylphenyl) -2,3- dihydro-lH-l,4-benzodiazepin-2-one.
  • Example 102 Followinged the synthetic sequence of Example 102, except the opposite enantiomer of the chiral auxiliary was used.
  • Example 120 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-1- oxoheptyl) amino-5-benzyl-l-methyl-2 , 3-dihydro-lH-l, 4- benzodiazepin-2-one.
  • Chromatography Note b and Note c The benzodiazepine was made from 1- (2-aminophenyl) -2- phenylethanone (see M. W. Partridge et al . , J. Chem . Soc . 1964, 3673) following the synthetic sequence from: R. G. Sherrill, J. Org. Chem. 1995, 60, 734.

Abstract

L'invention porte sur de nouveaux lactames de formule (I), sur leurs préparations pharmaceutiques, et sur leurs procédés d'utilisation. Ces nouveaux composés inhibent le processus de la protéine précurseur de l'amyloïde et plus spécifiquement la production du peptide Aβ, empêchant par là la formation de dépôts neurologiques de protéines amyloïdes. L'invention porte plus particulièrement le traitement des troubles neurologiques liés à production de l'amyloïde β, tels que la maladie d'Alzheimer et le syndrome de Down.
PCT/US2000/024967 1999-09-13 2000-09-13 HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b) WO2001019797A2 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
BR0014269-7A BR0014269A (pt) 1999-09-13 2000-09-13 Compostos de lactamas, seus sais e pró-drogas farmaceuticamente aceitáveis, composição farmacêutica, método de tratamento de disfunções neurológicas associadas com a produção de "beta"-amilóide, método de inibição da atividade da "alfa"-secretase e usos dos compostos
AU74797/00A AU783914B2 (en) 1999-09-13 2000-09-13 Hydroxyalkanoyl aminolactams and related structures as inhibitors of a beta protein production
CA002377221A CA2377221A1 (fr) 1999-09-13 2000-09-13 Hydroxyalkanoyl aminolactames et structures associees, inhibiteurs de la production de la proteine a.beta.
JP2001523377A JP2003509411A (ja) 1999-09-13 2000-09-13 Ａβタンパク質の産生阻害剤としてのヒドロキシアルカノイルアミノラクタムおよび関連構造体
MXPA02001813A MXPA02001813A (es) 1999-09-13 2000-09-13 Hidroxialcanoilaminolactamas y estructuras relacionas como inhibidores de la produccion de la proteina abeta.
IL14777400A IL147774A0 (en) 1999-09-13 2000-09-13 Hydroxyalkanoyl aminolactams and related structures as inhibitors of as protein production
EP00963374A EP1212306A2 (fr) 1999-09-13 2000-09-13 HYDROXYALKANOYL AMINOLACTAMES ET STRUCTURES ASSOCIEES, INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US15351199P 1999-09-13 1999-09-13
US60/153,511 1999-09-13
US22438800P 2000-08-09 2000-08-09
US60/224,388 2000-08-09

Publications (2)

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WO2001019797A2 true WO2001019797A2 (fr) 2001-03-22
WO2001019797A3 WO2001019797A3 (fr) 2002-04-11

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Country Status (9)

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EP (1) EP1212306A2 (fr)
JP (1) JP2003509411A (fr)
CN (1) CN1399634A (fr)
AU (1) AU783914B2 (fr)
BR (1) BR0014269A (fr)
CA (1) CA2377221A1 (fr)
IL (1) IL147774A0 (fr)
MX (1) MXPA02001813A (fr)
WO (1) WO2001019797A2 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074784A1 (fr) * 2000-04-03 2001-10-11 Dupont Pharmaceuticals Company Lactames cycliques utiles en tant qu'inhibiteurs de la production de proteine a-beta
WO2001077086A1 (fr) * 2000-04-11 2001-10-18 Dupont Pharmaceuticals Company LACTAMES SUBSTITUES UTILISES EN TANT QU'INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)
WO2001090084A1 (fr) * 2000-05-24 2001-11-29 Merck Sharp & Dohme Limited Derives de benzodiazepine utilises comme modulateurs de la proteine precurseur amyloide (app)
WO2002002512A2 (fr) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes utiles pour traiter la maladie d'alzheimer
US6737420B2 (en) 2000-03-23 2004-05-18 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
US6878363B2 (en) 2000-05-17 2005-04-12 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
JPWO2003055850A1 (ja) * 2001-12-27 2005-05-12 第一製薬株式会社 βアミロイド蛋白産生・分泌阻害剤
US6974829B2 (en) 2002-05-07 2005-12-13 Elan Pharmaceuticals, Inc. Succinoyl aminopyrazoles and related compounds
JP2006503862A (ja) * 2002-10-03 2006-02-02 アストラゼネカ・アクチエボラーグ 新規なラクタムおよびその使用
EP1666452A2 (fr) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Composés pour le traitement de la maladie d'Alzheimer
US7112583B2 (en) 1999-09-13 2006-09-26 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
WO2008099210A2 (fr) 2007-02-12 2008-08-21 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
WO2009128057A2 (fr) 2008-04-18 2009-10-22 UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al Produits psycho-pharmaceutiques
EP2489656A1 (fr) 2007-12-21 2012-08-22 Ligand Pharmaceuticals Inc. Modulateurs de récepteurs androgènes sélectifs (sarm) et leurs utilisations
EP2511267A1 (fr) 2003-06-05 2012-10-17 Elan Pharmaceuticals Inc. 3-((aminoacyl n-acylé)amino)pyrazoles comme inhibiteurs de la production de peptide beta-amyloide utiles pour le traitement de la maladie d'alzheimer
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
EP3613418A1 (fr) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones

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WO2000007995A1 (fr) 1998-08-07 2000-02-17 Du Pont Pharmaceuticals Company SUCCINOYLAMINO LACTAMES COMME INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)
WO2000038618A2 (fr) 1998-12-24 2000-07-06 Du Pont Pharmaceuticals Company BENZODIAZEPINES SUCCINOYLAMINO UTILISEES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b)

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CN1238760A (zh) * 1996-11-22 1999-12-15 伊兰药品公司 N－(芳基/杂芳基/烷基乙酰基)氨基酸酰胺类，含有这类化合物的药物组合物，及用这类化合物抑制β－淀粉样肽释放和或合成的方法
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Cited By (26)

* Cited by examiner, † Cited by third party
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US7112583B2 (en) 1999-09-13 2006-09-26 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US7423033B2 (en) 1999-09-13 2008-09-09 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of aβ protein production
US7342008B2 (en) 1999-09-13 2008-03-11 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6737420B2 (en) 2000-03-23 2004-05-18 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
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AU783914B2 (en) 2005-12-22
MXPA02001813A (es) 2004-03-19
AU7479700A (en) 2001-04-17
IL147774A0 (en) 2002-08-14
CA2377221A1 (fr) 2001-03-22
CN1399634A (zh) 2003-02-26
WO2001019797A3 (fr) 2002-04-11
JP2003509411A (ja) 2003-03-11
BR0014269A (pt) 2002-07-02
EP1212306A2 (fr) 2002-06-12

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