WO1999067220A1 - Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide - Google Patents

Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide Download PDF

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WO1999067220A1
WO1999067220A1 PCT/US1999/014007 US9914007W WO9967220A1 WO 1999067220 A1 WO1999067220 A1 WO 1999067220A1 US 9914007 W US9914007 W US 9914007W WO 9967220 A1 WO9967220 A1 WO 9967220A1
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Prior art keywords
substituted
group
alkyl
phenyl
heteroaryl
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PCT/US1999/014007
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English (en)
Inventor
James E. Audia
Richard C. Thompson
Stephen C. Wilkie
Thomas C. Britton
Warren J. Porter
George W. Huffman
Lee H. Latimer
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Elan Pharmaceuticals, Inc.
Eli Lilly And Company
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Application filed by Elan Pharmaceuticals, Inc., Eli Lilly And Company filed Critical Elan Pharmaceuticals, Inc.
Priority to EP99937164A priority Critical patent/EP1089981A1/fr
Priority to JP2000555874A priority patent/JP2002518482A/ja
Priority to CA002325388A priority patent/CA2325388A1/fr
Priority to AU52047/99A priority patent/AU5204799A/en
Publication of WO1999067220A1 publication Critical patent/WO1999067220A1/fr

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    • 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
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • 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
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • This invention relates to compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. 5
  • AD Alzheimer's Disease
  • AD failureia
  • AD in aged humans and is believed to represent the fourth most common medical cause of death in the United States.
  • AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
  • the brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles.
  • senile or amyloid
  • amyloid angiopathy amyloid deposits in blood vessels
  • neurofibrillary tangles Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD.
  • Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D).
  • a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
  • amyloid angiopathy amyloid angiopathy characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the ⁇ -amyloid peptide ( ⁇ AP) or sometimes A ⁇ , A ⁇ P or ⁇ /A4.
  • ⁇ AP ⁇ -amyloid peptide
  • ⁇ -Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al. 1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,829 2 .
  • ⁇ -amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans.
  • APP amyloid precursor protein
  • Knowledge of the structure of the gene encoding APP has demonstrated that ⁇ -amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s).
  • protease enzyme(s) The precise biochemical mechanism by which the ⁇ -amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
  • a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the ⁇ -amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others.
  • the discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its ⁇ -amyloid peptide fragment can cause AD.
  • the treatment methods would advantageously be based on drugs which are capable of inhibiting ⁇ -amyloid peptide release and/or its synthesis in vivo.
  • This invention is directed to the discovery of a class of compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition.
  • W is a cyclic group selected from the group consisting of:
  • ring A together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic
  • ring B together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic
  • ring C together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;
  • Y is represented by the formula:
  • R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, substimted cycloalkyl, substimted cycloalkenyl, aryl, heteroaryl and heterocyclic;
  • R 2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R 2' is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; R 3 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; each R 4 is independently selected from the group consisting of al
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substimted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substimted thioalkoxy;
  • Q is oxygen, sulfur, -S(O)- or -S O ;
  • Z is represented by the formula -T-CX'X"C(O)-, wherein T is selected from the group consisting of a bond covalently linking R 1 to -CX'X"-, oxygen, sulfur and -NR 6 , wherein R 6 is hydrogen, acyl, alkyl, aryl or heteroaryl group;
  • X' is hydrogen, hydroxy or fluoro
  • X is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; a is an integer from 2 to about 6; / is an integer from 0 to 2; m is an integer equal to 0 or 1 ; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof.
  • This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the formula I above.
  • this invention is directed to a method for inhibiting ⁇ -amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of fo ⁇ nula I above effective in inhibiting the cellular release and/or synthesis of ⁇ -amyloid peptide.
  • this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixmre of compounds of formula I above.
  • this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixmre of compounds of formula I above.
  • rings A and B may be the same or different and are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl. heteroaryl and heterocyclic. More preferably, rings A and B are independently selected from the group consisting of aryl and cycloalkyl. Still more preferably, rings A and B are independently aryl.
  • Particularly preferred A and B rings include, by way of example, phenyl, substimted phenyl, including fluoro-substimted phenyl, cyclohexyl and the like.
  • Preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, mo ⁇ holino and the like.
  • R 1 is preferably aryl (including substituted aryl) or heteroaryl (including substituted heteroaryl).
  • R 1 groups include
  • R b wherein R c is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R b and R c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
  • R b and R b are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R c is hydrogen, then R b and R b are either both hydrogen or both substituents other than hydrogen,
  • substituted heteroaryl containing 1 to 3 substiments selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the -NH group, and
  • particularly preferred substimted phenyl R 1 groups include mono-, di- and tri-substituted phenyl groups including 3,5-disubstituted phenyls such as 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)- phenyl, etc.; 3,4-disubstituted phenyls such as 3, 4-dichlorophenyl, 3,4- difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3- chloro-4-iodophenyl, 3, 4-methy lenedioxyphenyl, etc.; 4-substituted phenyls such as 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4- ethylphenyl, 4-fluorophenyl
  • R 1 groups for when m is zero include 3, 4-dichlorophenyl, 4- phenylfurazan-3-yl, and the like.
  • R 1 substituents include, by way of example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, 5- indolyl, phenyl, and the like.
  • R 1 groups include unsubstituted aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc. ; substimted aryl groups such as monosubstimted phenyls (preferably substiments at 3 or 5 positions); disubstituted phenyls (preferably substituents at 3 and 5 positions); and trisubstituted phenyls (preferably substituents at the 3,4,5 positions).
  • the substituted phenyl groups do not include more than 3 substituents.
  • substimted phenyls include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2- bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methy lphenyl, 2- methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethy lphenyl, 4-fluorophenyl, 4- chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methy lphenyl, 4-hydroxyphenyl,
  • R 1 groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, wo-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso- valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1- enyl, cyclopent-2-enyl, cyclohex-1-enyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, - CH 2 -cyclohexyl, -CH 2 -cyclopentyl, -CH 2 CH 2 -cyclopropy
  • R 2 is preferably selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
  • Each R 2' is preferably (and independently) selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
  • R 2 and R 2' substiments include, by way of example, methyl, ethyl, n-propyl, ⁇ r ⁇ -propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-n-butyl, 6- fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso- but-2-enyl, 3-methylpentyl, -CH 2 -cyclopropyl, -CH 2 -cyclohexyl, -CH 2 CH 2 - cyclopropyl, -CH 2 CH 2 -cyclohexyl, -CH 2 -indol-3-yl, /?-(phenyl)phenyl,
  • R 2' is methyl.
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
  • R 3 is alkyl, substimted alkyl or aryl. More preferably, R 3 is alkyl.
  • R 3 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3- dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • R 4 is preferably alkyl or substimted alkyl.
  • R 5 is preferably alkyl; substituted alkyl; phenyl; substituted phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl and the like; cycloalkyl, such as cyclohexyl and the like; or heteroaryl or heterocyclic, such as 1-piperdinyl, 2-pyridyl, 2-thiazyl, 2-thienyl and the like.
  • / is 0 or 1. More preferably, / is 0.
  • Y is the group -(CHR 2' ) a -NH-
  • the integer a is preferably 2, 3 or 4, more preferably 2 or 4, and still more preferably a is equal to 2.
  • Y has the formula -CHR 2 -CH 2 -NH-, where R 2' is as defined herein, including the described preferred embodiments.
  • W is a cyclic group of the formula:
  • each R 6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substimted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substimted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -
  • each R 7 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substimted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, - SO-aryl,
  • R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, acyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic; p is an integer from 0 to 4; q is an integer from 0 to 4.
  • R 6 and R 7 are independently selected from the group consisting of alkoxy, substimted alkoxy, alkyl, substimted alkyl, amino, substimted amino, carboxyl, carboxyalkyl, cyano. halo, nitro, thioalkoxy and substimted thioalkoxy. More preferably, when present, R 6 and R 7 are fluoro.
  • R 8 is preferably selected from the group consisting of hydrogen, alkyl, substimted alkyl, acyl, aryl, cycloalkyl and substimted cycloalkyl. More preferably, R 8 is selected from the group consisting of hydrogen, alkyl, substimted alkyl and cycloalkyl.
  • R 8 substiments include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3- dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • W is a cyclic group of the formula:
  • R 6 , R 7 , and p are as defined herein and r is an integer from 0 to 3.
  • W is a cyclic group of the formula:
  • R 6 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein; and each R 9 is independently selected from the group consisting of alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic; and g is an integer from 0 to 2.
  • R 9 is preferably alkyl or substimted alkyl.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and /? are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , each R 8 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 9 (R 9 ) c wherein R 6 , each R 8 , R 9 , g and /? are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein;
  • R 10 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substimted alkynyl, substimted amino, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substimted thioalkoxy.
  • W is a cyclic ring of the formula:
  • R 6 , R 10 and p are as defined herein;
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and p are as defined herein; and Q is oxygen, sulfur, -S(O)- or -S(O) 2 -.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • the products of this invention include mixtures of R,S enantiomers at any stereochemical center.
  • the chiral product corresponds to the L-amino acid derivative.
  • a mixture of R,S enantiomers at the stereochemical center is sometimes indicated by a squiggly line as per convention. Othertimes, no stereochemical designation is made at the stereochemical center and this also infers that a mixture of enantiomers is present.
  • prodrugs of the compounds of formula I above including acylated forms of alcohols and thiols, aminals of one or more amines, and the like.
  • this invention relates to compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • ⁇ -amyloid peptide release and/or its synthesis relates to compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • ⁇ -amyloid peptide refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al. 1 including mutations and post-translational modifications of the normal ⁇ -amyloid peptide.
  • the ⁇ -amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the ⁇ -amyloid precursor protein (APP). Its 43-amino acid sequence is:
  • Alkyl refers to monovalent alkyl groups preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, iso-butyl, n- hexyl, and the like.
  • Substimted alkyl refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents,.
  • substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, - SO-substimted alkyl, -SO-aryl,-SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl
  • Alkylene refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g. , -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Substimted alkylene refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substiments selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted
  • substimted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • fused cycloalkyl groups contain from 1 to 3 fused ring structures.
  • Substimted alkenylene refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substiments selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted
  • Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 8 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • Alkoxy refers to the group “alkyl-O-" .
  • Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, /s ⁇ -propoxy, n-butoxy, tert-butoxy, 5ec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substimted alkoxy refers to the group “substimted alkyl-O-" where substimted alkyl is as defined above.
  • Alkylalkoxy refers to the group “-alkylene-O-alkyl” which includes by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH 2 CH 2 OCH 3 ), n-propylene- ⁇ r ⁇ -propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (-CH 2 -O-C(CH 3 ) 3 ) and the like.
  • Alkylthioalkoxy refers to the group “-alkylene-S-alkyl” which includes by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy
  • alkenyl refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
  • Substituted alkenyl refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substimted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
  • Preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH) and the like.
  • Substimted alkynyl refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2
  • Acyl refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substimted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic -C(O)- where alkyl, substituted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Acylamino refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group, wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Amino refers to the group -NH 2 .
  • Substimted amino refers to the group -N(R) 2 where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group.
  • both R groups are hydrogen
  • -N(R) 2 is an amino group.
  • substituted amino groups include, by way of illustration, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di- heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like.
  • amino-blocking group or “amino-protecting group” refers to any group which, when bound to an amino group, prevents undesired reactions from occurring at the amino group and which may be removed by conventional chemical and/or enzymatic procedures to reestablish the amino group. Any known amino-blocking group may be used in this invention. Typically, the amino-blocking group is selected so as to render the resulting blocked-amino group unreactive to the particular reagents and reaction conditions employed in a subsequent pre -determined chemical reaction or series of reactions. After completion of the reaction(s), the amino-blocking group is selectively removed to regenerate the amino group.
  • Suitable amino-blocking groups include, by way of illustration, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, l-(l'-adamantyl)-l-methylethoxycarbonyl (Acm), allyloxycarbonyl (Aloe), benzyloxymethyl (Bom), 2- -biphenylisopropyloxycarbonyl (Bpoc), tert- butyldimethylsilyl (Bsi), benzoyl (Bz), benzyl (Bn), 9-fluorenyl- methyloxycarbonyl (Fmoc), 4-methy lbenzyl, 4-methoxybenzyl, 2- nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmo
  • Aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyloxy refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Alkyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)-, aryl-C(O)O-, heteroaryl- C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 5 substiments selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substimted alkyl, substimted alkoxy, substituted alkenyl, substituted alkynyl, amino, substimted amino, aminoacyl, acylamino. alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino.
  • thioalkoxy substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl.
  • Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substimted aryl groups as also defined above.
  • Carboxyalkyl refers to the groups “-C(O)Oalkyl” and “-C(O)O- substimted alkyl” where alkyl is as defined above.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • “Substimted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substiments selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-
  • Cycloalkenyl refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • Suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
  • Substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substiments selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
  • -SO-alkyl -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 - substituted alkyl, -SO 2 -aryl, and -SO 2 -heteroaryl.
  • Halo or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
  • heteroaryl groups can be optionally substimted with 1 to 5 substiments selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substimted alkyl, substimted alkoxy, substimted alkenyl, substimted alkynyl, amino, substimted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -
  • heteroaryl groups can have a single ring
  • heteroaryls include pyridyl, pyrrolyl and furyl.
  • Heteroaryloxy refers to the group “-O-heteroaryl”.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated or unsamrated group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
  • heterocyclic groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
  • heterocycles and heteroaryls include, but are not limited to, pyrrole, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole.
  • Heterocyclooxy refers to the group “-O-heterocycle”.
  • Oxyacylamino refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Thioalkoxy refers to the group -S-alkyl.
  • Substimted thioalkoxy refers to the group -S-substituted alkyl.
  • Thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
  • Thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substimted aryl groups as also defined above.
  • 4,5,6 , 7-tetrahy dro-3 , 7-methano-3H-3-benzazonin-2( 1 H)-one refers to a polycyclic e-caprolactam ring system having the fo ⁇ nula:
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.
  • protecting group or “blocking group” refers to any group which when bound to one or more hydroxyl, thiol, carboxyl groups or other protectable functional group of the compounds which prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the unprotected functional group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substiments such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t- butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild hydrolysis conditions compatible with the nature of the product.
  • a protected aldehyde or ketone J (where B 1 is a protecting group and R 2' and a are as defined herein) can be coupled with an amine compound, such as 2 (where R 6 , R 7 , R 8 , p and q are as defined herein), by conventional reductive amination to provide, after deprotection, intermediate 3.
  • amine 2 is merely representative and those skilled in the art will recognize that amino derivatives of any of the other ring systems described herein may be employed in this reaction.
  • this reaction is conducted by contacting amine 2 with an excess of 1, preferably with 1.1 to 2 equivalents of J., and an excess, preferably 1.1 to 1.5 equivalents, of a reducing agent, such as sodium cyanoborohydride.
  • a reducing agent such as sodium cyanoborohydride.
  • this reaction is conducted in an essentially inert diluent, such as methanol, at a temperamre ranging from about 0°C to about 50°C, preferably at ambient temperamre, for about 0.5 to 3 hours. Removal of the amine protecting group using conventional procedures and reagents then affords intermediate 3.
  • Intermediate 3 can then be acylated or coupled with a carboxylic acid, e.g. , 4 (where R 1 , T, X' and X" are as defined herein), to provide compound 5.
  • This reaction is typically conducted using conventional coupling reagents and procedures and at least a stoichiometric amount of intermediate 3 and carboxylic acid 4.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1- hydroxy benzotriazole, etc. can be used to facilitate coupling.
  • reaction (1) is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • the acid halide of compound 4 can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, triethylamine, diisopropylethylamine, N- methylmo ⁇ holine and the like.
  • compound 5 can be prepared by reductive amination of a compound of formula 6:
  • R 1 , R 2 , T, X', X" and a are as defined herein, with amine 2, using conventional reagents and procedures.
  • B 2 is a suitable amine protecting group and R 1 , R 2 and a are as defined herein, with amine 2, followed by deprotection using conventional procedures.
  • the compounds of formula I can be prepared by further reductive alkylation of intermediate 3 with, for example, compound 6 or 7, using conventional reagents and procedures.
  • intermediate 3 can be reductively alkylated with protected aldehyde or ketone 1 and the resulting intermediate deprotected and acylated using procedures similar to those described above.
  • R 1 , R 2 , Z and m are as defined herein, using conventional coupling reagents and procedures such as those described above, to afford compounds of fo ⁇ nula I.
  • compounds of formula I can be prepared by first coupling an amine, such as 2, with a protected carboxylic acid 9, and then, after deprotection, reductively alkylating the resulting intermediate 10 as illustrated in Scheme 2.
  • the aldehyde, ketone or carboxylic acid units may also be coupled together prior to reaction with an amine using the reductive amination or acylation procedures described above, as appropriate.
  • the resulting intermediate is then coupled to the amine, such as 2, to afford compounds of formula I.
  • aldehyde, ketone and carboxylic acids employed in the above reactions can be readily prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether m is zero or one, whether n is one or two, etc.
  • the aldehyde and ketone compounds, e.g. 1, 6 and 7, employed in this invention can be readily prepared by oxidizing the corresponding alcohol using conventional oxidizing agents.
  • Swern oxidation of N-protected amino primary alcohols affords the corresponding aldehyde.
  • this reaction is conducted by contacting the alcohol with a mixture of oxalyl chloride and dimethyl sulfoxide in the presence of a tertiary amine, such as triethylamine.
  • a tertiary amine such as triethylamine.
  • this reaction is conducted in an inert diluent, such as dichloromethane, at an intial temperature of about -78 °C and then at ambient temperamre for about 0.25 to 2 hours to afford the aldehyde.
  • the alcohols employed in this reaction are either commercially available or can be prepared using conventional reagents and procedures.
  • suitable alcohols can be prepared by reduction of the corresponding amino acids or amino
  • the carboxylic acids of fo ⁇ nula 8, where m is 0, can be prepared by various conventional procedures. For example, reaction of a halo acetic acid 11
  • a suitable haloacetic acid derivative JJ is reacted with a primary amine 12 under conditions which provide for amino acid J3.
  • This reaction is described by, for example, Yates, et al. 10 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid JJ with primary amine 12 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like.
  • DMSO dimethylsulfoxide
  • the reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction.
  • the reaction is preferably conducted at from about 25 °C to about 100°C until reaction completion which typically occurs within 1 to about 24 hours.
  • N- substimted amino acid 13 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
  • Each of the reagents employed in this reaction e.g. , haloacetic acid 11. and primary amine J2
  • haloacetic acid 11. and primary amine J2 are well known in the art with a plurality of each being commercially available.
  • the R 1 group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation.
  • a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a halo-R 1 compound, Z'-R 1 where Z' is a halo group such as chloro or bromo and R 1 is as defmed above.
  • the reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction.
  • the reaction typically proceeds at from 15 °C to about 250°C and is complete in about 1 to 24 hours.
  • N-substituted amino acid ester is recovered by conventional methods including chromatography, filtration and the like. This ester is then hydrolyzed by conventional methods to provide for carboxylic acid 8, where m is 0.
  • ester ified amino acids of formula 8, where m is 0, can be prepared by reductive amination of a suitable pyruvate ester J4 (where R is typically an alkyl group and R 2 is as defined above) with a primary amine J2 (where R 1 is as defined herein) in the manner illustrated in Scheme 4.
  • the reaction shown in Scheme 4 is typically conducted by combining approximately stoichiometric equivalents of pyruvate ester J4 and amine J2 in an inert diluent such as methanol, ethanol and the like under conditions which provide for imine formation (not shown).
  • the imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H 2 /palladium on carbon and the like to form the N-substituted amino acid ester J5.
  • the reducing agent is H 2 /palladium on carbon which is inco ⁇ orated into the initial reaction medium which permits imine reduction in situ in a one pot procedure to provide for the N- substimted amino acid ester J5.
  • reaction is preferably conducted at from about 20 °C to about 80 °C at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours.
  • N-substituted amino acid ester 15 is recovered by conventional methods including chromatography, filtration and the like. Subsequent hydrolysis of the ester J5 leads to the corresponding carboxylic acid derivative 8, where m is 0.
  • the carboxylic acids of formula 8, where m is 1, can be prepared by conventional coupling of an acetic acid derivative 4 (where R 1 , T, X' and X" are as defined herein) with a primary amine of an esterified amino acid (where R is typically an alkyl group and R 2 is as defined herein) as illustrated in Scheme 5.
  • this reaction merely involves coupling of a suitable acetic acid derivative 4 with the primary amine of amino acid ester 16 under conditions which provide for the N-acetyl derivative J7.
  • This reaction is conventionally conducted as described for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters J7 of this invention.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as ⁇ - hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling.
  • the reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • the acid halide of compound 4 can be employed and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
  • Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N- methylmo ⁇ holine and the like.
  • the coupling reaction of 4 and J6 is preferably conducted at from about 0°C to about 60 °C until reaction completion which typically occurs within 1 to about 24 hours.
  • reaction completion N-acetyl amino acid ester J7 is recovered by conventional methods including precipitation, chromatography, filtration and the like or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up (e.g., aqueous extraction, etc.).
  • reagents e.g., acetic acid derivative 4 and amino acid ester 16
  • acetic acid derivative 4 and amino acid ester 16 are well known in the art with a plurality of each being commercially available.
  • Carboxylic acids such as 4 can also be coupled to amines prepared by use of polymer supported forms of carbodiimide peptide coupling reagents.
  • a polymer supported form of EDC for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993)) 11 .
  • PEPC polymer supported form of EDC
  • Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts.
  • a suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group.
  • the polymer's backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.
  • hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents.
  • hydroxylated resins include the 4-hydroxymethylphenyl- acetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see
  • Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield 's resins and are available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in Scheme 6.
  • PEPC is prepared by first reacting ethyl isocyanate with l-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
  • the carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45 °C, for from about 3 to 120 hours.
  • the product may be isolated by washing the reaction with CHC ⁇ and concentrating the remaining organics under reduced pressure.
  • isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
  • cyclic compounds and amino-substituted derivatives thereof, such as 2, employed in the reactions described above are either known in the art or can be prepared by art-recognized procedures using commercially available starting materials and reagents.
  • 5,7-dihydro-6H-dibenz[b,d]azepin-6-one may be prepared by cyclizing a chloromethyl amide intermediate using the procedures set forth in R. F. C. Brown et al. , Tetrahedron Letters 1971, 8, 667-670 12 and references cited therein.
  • This reaction is typically conducted by treating 18 with about 1.0 to about 2.1 equivalents of an alkyl lithium reagent, preferably sec-butyl lithium or tert-butyl lithium, in an inert diluent, such as THF, at a temperamre ranging from about -80 °C to about -60 °C for about 0.25 to about 1 hour.
  • the resulting lithium anion is then treated in situ with an excess, preferably 1.5 equivalents, of a trialkylborate, such as trimethylborate.
  • This reaction is initially conducted at - 80 °C to about -60 °C and then allowed to warm to about 0°C to about 30 °C for about 0.5 to about 3 hours.
  • the resulting methyl boronate ester is typically not isolated, but is preferably converted in situ into the pinacol ester by treating the reaction mixmre with an excess, preferably about 2.0 equivalents, of pinacol.
  • This reaction is typically conducted at ambient temperamre for about 12 to about 24 hours to afford the 2-methylphenylboronate ester, 19, in which both R 3 groups are preferably joined together to form -C(CH 3 ) 2 C(CH 3 ) r .
  • N-Boc-2-bromoaniline derivative 21 is converted into the N-Boc derivative 21 by treating 20 with about 1.0 to about 1.5 equivalents of di-tert-butyl-dicarbonate. Typically, this reaction is conducted at a temperamre ranging from 25 °C to about 100°C for about 12 to 48 hours to afford the N-Boc-2-bromoaniline derivative 21.
  • the 2-methylphenylboronate ester, 19, and the N-Boc-2-bromoaniline derivative 21 can then be coupled to form the biphenyl derivative 22.
  • This reaction is typically conducted by contacting 21 with about 1.0 to about 1.2 equivalents of 19 and about 1.0 to about 1.2 equivalents of potassium carbonate in the presence of a pallidium catalyst, preferably tetrakis(triphenylphosphine)pallidium(0).
  • a pallidium catalyst preferably tetrakis(triphenylphosphine)pallidium(0).
  • this coupling reaction is conducted in a diluent, preferably 20% water/dioxane, under an inert atmosphere at a temperature ranging from about 50 °C to about 100°C for about 6 to 24 hours.
  • Biphenyl derivative 22 is then readily converted into the 5,7-dihydro-6H- dibenz[b,d]azepin-6-one 23 by carboxylation of the 2-methyl group, followed by cyclization to form the e-caprolactam.
  • the carboxylation reaction is typically conducted by contacting 22 with about 2.0 to about 2.5 equivalents of a suitable base, such as sec-butyllithium, tert-butyllithium and the like, in an inert diluent, such as THF, at a temperamre ranging from about -100°C to about -20°C for about 0.5 to 6 hours.
  • THF inert diluent
  • the resulting dianion is then treated with excess anhydrous carbon dioxide to form the carboxylate.
  • 5,7-dihydro-6H-dibenz[b,d]aze ⁇ in-6-one, 23, is optionally N-alkylated using conventional reagents and conditions to provide a 7- alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24.
  • this reaction is conducted by first contacting 23 with about 1.0 to 1.5 equivalents of a suitable base, such as sodium hydride, sodium bis(trimethysilyl)amide and the like, in an inert diluent, such as DMF, THF and the like, at a temperature ranging from about -78°C to about 50°C for about 0.25 to about 6 hours.
  • a suitable base such as sodium hydride, sodium bis(trimethysilyl)amide and the like
  • an inert diluent such as DMF, THF and the like
  • the resulting anion is then treated in situ with an excess, preferably about 1.1 to about 2.0 equivalents, of an alkyl, substimted alkyl, cycloalkyl halide, etc., typically a chloride, bromide or iodide.
  • This reaction is typically conducted at a temperamre ranging from about 0°C to about 60 °C for about 1.0 to about 48 hours to afford the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24.
  • the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 24 is then oximated by contacting 24 with an excess, preferably with about 1.0 to 1.5 equivalents of a suitable base, such as sodium bis(trimethysilyl)amide and the like, in the presence of about 1.0 to about 2.0 equivalents of an alkyl nitrite.
  • a suitable base such as sodium bis(trimethysilyl)amide and the like
  • This reaction is typically conducted in an inert diluent, such as THF and the like, at a temperature ranging from about -10°C to about 20°C for about 0.5 to about 6 hours to afford the 7-alkyl-5-oximo-5,7-dihydro-6H- dibenz[b,d]azepin-6-one derivative 25.
  • an inert diluent such as THF and the like
  • this reduction reaction is conducted by hydrogenating the oxime 25 in the presence of a catalyst, such as Raney nickel.
  • a catalyst such as Raney nickel.
  • This reaction is typically conducted under about 200 psi to about 600 psi of hydrogen at a temperamre of about 70 °C to about 120°C for about 8 to 48 hours in a diluent, preferably a mixture of ethanol and ammonia (about 20:1).
  • the oxime may be reduced using 10% Pd/C and between about 30 to about 60 psi of hydrogen at a temperamre ranging from about 20 °C to about 50 °C for about 4 hours.
  • the resulting 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 26 is generally purified using well known procedures, such as recrystallization and/or chromatography.
  • the 5-iodo derivative 27 of 5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 23 can be prepared by first forming the 5-iodo derivative 27 of 5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 23. This reaction is typically conducted as described in A. O. King et al. 13 by treating 23 with an excess, preferably about 1.2 to about 2.5 equivalents, of trimethylsilyl iodide in the presence of an excess of a trialkyamine, such as triethylamine, diisopropylethylamine, TMEDA and the like, at a temperamre ranging from about -20 °C to about 0°C for about 3 to 30 minutes and then adding about 1.1 to about 2.0 equivalents of iodine (L).
  • a trialkyamine such as triethylamine, diisopropylethylamine, TMEDA and the like
  • the reaction is stirred at a temperamre ranging from about 0°C to about 20 °C for about 2 to about 4 hours to afford 5- iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 27.
  • Displacement of iodide from 27 using an alkali metal azide then affords 5- azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 28.
  • this reaction is conducted by contacting 27 with about 1.1 to about 1.5 equivalents of sodium azide in an inert diluent, such as DMF, at a temperamre ranging from about 0°C to about 50 °C for about 12 to about 48 hours.
  • the azido derivative 28 is then reduced to the corresponding amino derivative 29 using conventional procedures and reagents.
  • the azido group is preferably reduced by contacting 28 with an excess, preferably with about 3 equivalents, of triphenylphosphine in a diluent, preferably a mixmre of THF and water.
  • This reduction reaction is typically conducted at a temperature ranging from about 0°C to about 50 °C for about 12 to 48 hours to afford 5-amino-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 29.
  • the amino group of 29 is then protected or blocked using a conventional amino blocking group.
  • compound 29 is treated with about 1.0 to about 1.1 equivalents of di-tert-butyl dicarbonate in the presence of an excess, preferably about 2 to about 3 equivalents, of a trialkylamine, such as triethylamine.
  • This reaction is typically conducted in an inert diluent, such as
  • THF at a temperamre ranging from about 0°C to about 50°C for 3 to about 24 hours to provide 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 30.
  • Compound 30 is then optionally N-alkylated to afford, after de-blocking of the amino group, a 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 26.
  • the N-alkylation reaction is typically conducted by treating 30 with about 1.0 to 1.5 equivalents of an alkyl halide, a substimted alkyl halide or a cycloalkyl halide in the presence of about 1.0 to about 1.5 equivalents of a suitable base, such as cesium carbonate and the like.
  • This reaction is generally conducted in an inert diluent, such as DMF and the like, at a temperamre ranging from about
  • alkyl, substimted alkyl and cycloalkyl halides suitable for use in this N-alkylation reaction include, by way of illustration, l-iodo-2- methylpropane, methyl bromoacetate, l-chloro-3,3-dimefhyl-2-butanone, 1- chloro-4-phenylbutane, bromomethylcyclopropane, l-bromo-2,2,2- trifluoroethane, bromocyclohexane, 1-bromohexane and the like.
  • N-Boc protecting group is then removed using conventional procedures and reagents to afford the 5-amino-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 26.
  • This deblocking reaction is typically conducted by treating the N-Boc compound 30 with anhydrous hydrogen chloride in an inert diluent, such as 1,4-dioxane, at a temperamre ranging from about 0°C to about 50°C for about 2 to about 8 hours.
  • the resulting 5-amino-7-alkyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one 26 is generally purified using well known procedures, such as recrystallization and/or chromatography.
  • the 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones, 26, can also be prepared via an azide transfer reaction as illustrated in Scheme 9.
  • the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 24 is then reacted with an azide transfer reagent to afford 5-azido-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 31.
  • this reaction is conducted by first contacting 24 with an excess, preferably with about 1.0 to 1.5 equivalents of a suitable base, such as lithium diisopropylamine and the like, in an inert diluent such as THF, at a temperature ranging from about -90 °C to about -60 °C for about 0.25 to about 2.0 hours.
  • the resulting anion is then treated with an excess, preferably with about 1.1 to about 1.2 equivalents, of an azide transfer reagent, such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide).
  • an azide transfer reagent such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide).
  • This reaction is typically conducted at a temperature ranging from about -90°C to about -60°C for about 0.25 to about 2.0 hours.
  • the reaction mixture is then typically treated with an excess of glacial acetic acid and the mixture is allowed to warm to ambient temperature and then heated at about 35 °C to about 50 °C for about 2 to 4 hours to afford the 5-azido-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative 31.
  • Reduction of 31 as described above using conventional reagents and conditions then affords the 5-a
  • the aryl rings of 5-amino-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-ones, 26, and similar or related compounds may be partially or fully saturated by treatment with hydrogen in the presence of a hydrogention catalyst.
  • this reaction is conducted by treating 26 with hydrogen at a pressure of about 10 to about 100 psi in the presence of a catalyst, such as rhodium on carbon.
  • This reaction is typically conducted at a temperature ranging from about 20°C to about 100°C for about 12 to 96 hours in a suitable diluent, such as ethyl acetate/acetic acid (1 : 1) and the like.
  • benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents.
  • a 2-aminobenzophenone can be readily coupled to ⁇ -(isopropylthio)-N- (benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2- aminobenzophenone in the presence of a base, such as 4-methy lmo ⁇ holine, to afford the 2-[ ⁇ -(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]- aminobenzophenone.
  • a base such as 4-methy lmo ⁇ holine
  • 2,3-dihydro-5-phenyl-lH-l,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-lH-l,4- benzodiazepin-2-ones are readily alkylated at the 1 -position using conventional procedures and reagents.
  • this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3- hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF.
  • a base such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3- hexamethyldisilazane, cesium carbonate
  • an inert diluent such as DMF.
  • This reaction is typically conducted at a temperature ranging from about -78°C to about 80 °C for about 0.5 to about 6 hours.
  • the resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide.
  • this reaction is conducted at a temperamre of about 0°C
  • 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5- benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1 ,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-l,5-bis(alkyl)-2,4- dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepines. Such procedures are described in further detail in the example set forth below.
  • the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixmre of R,S enantiomers.
  • a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained.
  • Such reaction protocols can involve inversion of the chiral center during synthesis.
  • the products of this invention are a mixmre of R,S enantiomers.
  • the chiral product corresponds to the L-amino acid derivative.
  • chiral products can be obtained via purification techniques which separates enantiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art.
  • compositions When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound acmally administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablet)
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixmre is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50° to 60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • a subcutaneous formulation may be prepared as follows: Ingredient Quantity
  • a topical formulation may be prepared as follows: Ingredient Quantity
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds and pharmaceutical compositions of the invention are useful in inhibiting ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans.
  • the compounds described herein are suitable for use in a variety of drug delivery systems described above.
  • the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871 , 4,501,728 and 4,837,028 each of which is inco ⁇ orated herein by reference.
  • compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.
  • Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
  • An amount adequate to accomplish this is defined as "prophylactically effective dose. " Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery pu ⁇ oses. Specifically, the compounds may be used in the diagnosis of cells releasing and/or synthesizing ⁇ -amyloid peptide. In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of ⁇ -amyloid peptide.
  • ⁇ L microliter
  • Aldrich indicates that the compound or reagent used in the procedure is commercially available from Aldrich Chemical Company, Inc. , 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA; the term “Fluka” indicates that the compound or reagent is commercially available from Fluka Chemical Co ⁇ ., 980 South 2nd Street, Ronkonkoma NY 11779 USA; the term “Lancaster” indicates that the compound or reagent is commercially available from Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087 USA; the term “Sigma” indicates that the compound or reagent is commercially available from Sigma, P.O. Box 14508, St.
  • TCI indicates that the compound or reagent is commercially available from TCI America, 9211 North Harborgate Street, Portland OR 97203
  • Alfa indicates that the compound or reagent is commercially available from Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, MA 01835-0747
  • Novabiochem indicates that the compound or reagent is commercially available from Calbiochem-Novabiochem Co ⁇ . 10933 North Torrey Pines Road, P.O.
  • GENERAL PROCEDURE A First EDC Coupling Procedure To a 1 : 1 mixture of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH 2 C1 2 at O°C was added 1.5 equivalents triethylamine, followed by 2.0 equivalents hydroxy benzotriazole monohydrate and then 1.25 equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimide HCl. The reaction mixmre was stirred overnight at room temperamre and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO 3 , IN HCl and saturated aqueous NaCl, and then dried over MgSO 4 .
  • the mixmre was diluted with EtOAc and washed with 0.1 M HCl (1 x 10 mL), saturated NaHCO 3 (1 x 10 mL), H 2 O (1 x 10 mL), and brine and dried over MgSO 4 .
  • the drying agent was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel followed by trituration from EtOAc and hexanes.
  • the solution or mixture was diluted with EtOAc, in a 3-5 volume multiple of the initial THF volume, and washed with 0.1-1.0 M aq. HCl (1 or 2x), dilute NaHCO 3 (1 or 2x), and brine (lx). Then, the organic phase was dried over either MgSO 4 or Na 2 SO 4 , filtered, concentrated to provide the crude product, which was either further purified or utilized without further purification.
  • GENERAL PROCEDURE II-A Ester Hydrolysis to Free Acid Ester hydrolysis to the free acid was conducted by conventional methods. Below are two examples of such conventional de-esterification methods.
  • Method A To a carboxylic ester compound in a 1: 1 mixmre of CH 3 OH/H 2 O was added 2-5 equivalents of K 2 CO 3 . The mixture was heated to 50°C for 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ⁇ 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO 4 . The solution was stripped free of solvent on a rotary evaporator to yield the product.
  • Method B The amino acid ester was dissolved in dioxane/water (4: 1) to which was added LiOH ( ⁇ 2 eq.) that was dissolved in water such that the total solvent after addition was about 2: 1 dioxane: water.
  • the reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure.
  • the residue was dissolved in water and washed with ether.
  • the layers were separated and the aqueous layer was acidified to pH 2.
  • the aqueous layer was extracted with ethyl acetate.
  • the ethyl acetate extracts were dried over Na 2 SO 4 and the solvent was removed under reduced pressure after filtration.
  • the residue was purified by conventional methods (e.g., recrystallization).
  • Step B Preparation of N-(Cyclopentylacetyl)-L-phenylglvcine
  • Methyl ( ⁇ )-3,5-difluoromandelate was separated via preparative chiral HPLC to give a white solid having a melting point of 70-71 °C.
  • Step A To (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF cooled to -
  • Step B To a solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone in THF at -78°C was added LiHMDS (1.05 eq.) (Aldrich) dropwise. The reaction mixture was allowed to stir at -78 °C for 30 min. and then a precooled solution of di-tert-butyl-azodicarboxylate (Aldrich) was added via a cannula. After 5 min. 2.6 eq. of acetic acid was added. The reaction mixture was then extracted with dichloromethane and the organic layer was washed with 1M potassium phosphate.
  • LiHMDS 1.05 eq.
  • Aldrich di-tert-butyl-azodicarboxylate
  • Step C To the product from Step B (1.0 g, 2.16 mM) in THF (34 mL) and water (13 mL), cooled to 0°C, was added a 30% solution of H 2 O 2 (0.734 mL, 6.4 mM) and LiOH (57 mg, 2.37 mM). The reaction mixture was stirred at ambient temperature for 1.5 h and then quenched with 1.5 N Na 2 SO 3 (15 mL). A saturated solution of sodium bicarbonate (48 mL) was added and the mixture was pardoned between dichloromethane and water. The aqueous layer was acidified with 10% citric acid and extracted into dichloromethane. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to give the title compound (390 mg, 60%) as a colorless glass which was used without further purification.
  • Step A Ethyl 3,5-difluorophenyl- ⁇ -oxoacetate was prepared from 1- bromo-3.5-difluorobenzene (Aldrich) according to the procedure described in J.
  • Step B Ethyl 3,5-difluorophenyl- ⁇ -oxoacetate was hydrolyzed using General Procedure II-A (Method B) to afford 3,5-difluorophenyl- ⁇ -oxoacetic acid.
  • Example P Ethyl 3,5-difluorophenyl- ⁇ -oxoacetic acid.
  • N-(3,4- dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4- dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2- chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to 40 °C and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days.
  • N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
  • Step A l-Ethoxycarbonylamino-l,3,4,5-tetrahydro-2H-3-benzazepin-2- one was prepared according to the procedure of Ben-Ishai et al., Tetrahedron,
  • Step B l-Ethoxycarbonylamino-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one (2.0 g, 100 M%) was dissolved in DMF (30 mL) and NaH (95%, 0.17 g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and the mixture was stirred for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were then washed with water (3x) and brine (lx).
  • Step C l-Ethoxycarbonylamino-3-alkyl-l,3,4,5-tetrahydro-2H-3- benzazepin-2-one (l .Og, 100M%) was suspended in 30 mL of 30% HBr/HOAc and heated to 100°C. The reaction mixture was stirred for 5 hours at this temperature and then the reaction was cooled and rotoevaporated to yield l-amino-3-alkyl- 1,3,4, 5-tetrahydro-2H-3-benzazepin-2-one as the hydrobromide salt (100% yield).
  • Step A 3-Amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from ⁇ -tetralone using the methods described in Armstrong et al. Tetrahedron Letters, 1994, 35, 3239. The following compounds were as prepared by this procedure for use in the following steps:
  • Step B 3-Amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (4.43 g, 100M%) was suspended in t-butanol (30mL) and BOC-anhydride (7.5 mL, 130M%) was added dropwise. The reaction was stirred for 2 hours and then it was rotoevaporated to a residue which was chromatographed with 60% ethyl acetate/hexanes to yield BOC-protected 3-amino-l ,3,4,5-tetrahydro-2H-l- benzazepin-2-one in 87% yield.
  • Step C BOC-protected 3-amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2- one (1.5 g, 100M%) was dissolved in DMF (20mL) and NaH (95%, 0.13g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and stirring was continued for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were washed with water (3x) and then brine (lx).
  • Step D The BOC-protected 3-amino-l-alkyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (l.Og, 100M%) was suspended in 30 mL of 1 : 1 CH 2 Cl 2 /triflouroacetic acid and the mixmre was stirred for 4 hours. The reaction was then rotoevaporated to yield the 3-amino-l-alkyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100% yield).
  • Step A 3- Amino-5-methy 1- 1 ,3,4 , 5-tetrahydro-2H- 1 -benzazepin-2-one was prepared from 4-methyl- ⁇ -tetralone using the methods described in
  • Step B 3-Amino-5-methy 1- 1 , 3 ,4 , 5-tetrahydro-2H- 1 -benzazepin-2-one (9.3g 100M%) was dissolved in dioxane (300mL) and the solution was chilled to 0°C. BOC-anhydride (13.89g 130M%) was added and the ice bath was removed allowing the solution to come to room temperature and stirring was continued for 16 hours. The solution was rotory evaporated to remove dioxane to provide an off white solid. This solid was recrystallized from CHCk to yield BOC- protected 3-amino-5-methyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one in 55 % yield.
  • Step C BOC-protected 3-amino-5-methyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100 M%) was dissolved in DMF (20mL) and NaH (95%, 100 M%) was added in one portion and the reaction mixmre was stirred for 1 hour. Methyl iodide (300 M%) was added and this mixmre was stirred for 12 hours. The reaction was then poured into water and extracted with ethyl acetate (3x) then backwashed with water (3x) and then brine (lx).
  • Step D BOC-protected 3-amino-l,5-dimethyl-l ,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100 M%) was suspended in 30 mL of 1 : 1 CH 2 Cl 2 /triflouroacetic acid. The reaction mixmre was stirred for 4 hours. The reaction was then rotoevaporated to yield 3-amino-l ,5-dimethyl-l ,3,4,5- tetrahydro-2H-l-benzazepin-2-one (100% yield).
  • Example 6-C Following the procedure of Example 7-1 and using 5-amino-3,3,7- trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared.
  • Step A Following General Procedure 5-A and using N-t-Boc-5-amino-
  • Step A 3-(S)-Amino-5-oxa-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-l -nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry
  • Step B Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
  • Step A 3-(S)-Amino-5-oxa-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-l -nitrobenzene (Aldrich) using the method of R. J. DeVita et al. , Bioorganic and Medicinal Chemistry
  • Step B Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
  • Example 6-F Following General Procedure 5-A and using the product from Step A, the title compound was prepared.
  • Step B Synthesis of 1.3.4.7.12.12a-hexahvdropyridor2.1- b] r31benzazepin-6(2H)-one Following General Procedure G and using N-chloroacetyl-2- benzylpiperidine, the title compound was prepared.
  • Step C Synthesis of 7-Oximo-l .3.4.7.12.12a- hexahydropyrido[2.1-b]
  • Step D Synthesis of 7-Amino-1.3.4.7.12.12a- hexahydropyridor2.1-b][31benzazepin-6(2H)-one Following General Procedure A (Step C) and using 7-oximo- l,3,4,7,12,12a-hexahydropyrido[2,l-b][3]benzazepin-6(2H)-one (from Step C), the title compound was prepared.
  • Step B Synthesis of 4.5.6.7-Tetrahydro-3.7-methano-3H-3- benzazonin-2(lH)-one Following General Procedure G and using N-chloroacetyl-3- phenylpiperidine, the title compound was prepared.
  • Step E Synthesis of l-fN'-Boc-L-Alaninyl)amino-4.5.6.7- tetrahydro-3.7-methano-3H-3-benzazonin-2(lH)-one Following General Procedure D and using N-tert-Boc-L-alanine (Aldrich) and the product from Step D, the title compound was prepared.
  • Step F Synthesis of l-(A-L-Alaninyl)amino-4.5.6.7-tetrahydro-
  • Step A Following General Procedure 5-A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one and an alkyl halide, the 7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one was prepared.
  • Step B The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixmre was cooled to 0°C in an ice bath. NaHMDS (1.1 eq., 1M in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixmre was concentrated then acidified with IN HCl and extracted with EtOAc. The organic portion was dried and concentrated to yield a crude product which was purified by silica gel chromatography.
  • Step C The resulting oxime was dissolved in EtOH/NH 3 (20: 1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at 100°C for 10 hours. The resulting mixmre was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound.
  • the oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parr apparatus at 35 psi over 10 % Pd/C (0.46 g) in 3 A ethanol. After 32 h the reaction mixture was filtered through a plug of celite, the filtrate evaporated to a foam and treated with a saturated solution of HCl (g) in Et 2 O. The resulting colorless solid was filtered, rinsed with cold Et 2 O and vacuum dried to give 0.66 g (61 %) of the title compound.
  • Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.305 g, 2.26 mmol). and 5-amino-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89 mmol) (Example 7-A).
  • the temperature was lowered to 0°C and the reaction mixture treated with EDC (0.449 g, 2.26 mmol) (Alrich) and stirred 17 hours under N 2 .
  • the reaction mixture was evaporated, the residue diluted with EtOAc/H 2 O, washed 1.0 N HCl, sat. NaHCO 3 , brine and dried over Na 2 SO4.
  • the diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
  • Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol) and 5- amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol)(Alrich) and stirred 17 hours under N 2 .
  • the reaction mixture was evaporated, the residue diluted with EtOAc/H 2 O, washed 1.0 N HCl, sat. NaHCO 3 , brine and dried over Na 2 SO 4 .
  • the diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute.
  • Step B Synthesis of (S)- and (R)-5-(L-Valinyl)-amino-7-methyl-
  • Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol) and 5- amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred 17 hours under N 2 .
  • the reaction mixture was evaporated, the residue diluted with EtOAc/H 2 O, washed 1.0 N HCl, sat. NaHCO 3 , brine and dried over Na 2 SO .
  • the diastereomers were separated on a Chiralcel OD column using 10% IPA heptane at 1.5 ml/minute.
  • Step B Synthesis of 5-Azido-5.7-dihydro-6H-dibenz[b.d]azepin-6- one
  • the iodide isolate above was dissolved in DMF and treated with 1.2 equivalents of NaN 3 . After stirring 17 h at 23 °C the mixture was diluted with
  • Example 7-E 6-one (0.2g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs 2 CO 3 (0.22 g,
  • Example 7-E (1.03. 3.08 mmol) (Example 7-E) in DMF was treated with Cs 2 CO 3 (1.10 g, 3.39 mmol) and warmed to 60°C. To the reaction mixture was added bromomethyl acetate (0.321 ml. 3.39 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23 °C the mixture was diluted with CH 2 CL, washed with several portions of brine and dried over Na 2 SO 4 . The title compound was purified by chromatography (SiO 2 , CHC1J.
  • Step A Following General Procedure D and using N-t-Boc-L-alanine and
  • Step B Following General Procedure 8-N and using the N-t-Boc-L- alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.
  • Other substituted N-t-Boc-L-alaninyl-5-amino-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.
  • Step A Following General Procedure D and using N-t-Boc-L-valine and
  • Step B Following General Procedure 8-N and using the N-t-Boc-L- valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.
  • Other substituted N-t-Boc-L-valinyl-5-amino-7-mefhyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.
  • Step 1 2-Bromo-5-fluorotoluene was stirred in THF at -78C.
  • s-BuLi (1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture was stirred for 45 minutes.
  • Trimethylborate ( 1.5 eq) was added and the mixture was allowed to warm to ambient temperature. After sti ⁇ ing for 1 hour, pinacol (2 eq.) was added.
  • Step 2 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1 eq.) were stirred at 80 °C for 20 hours. The resulting mixture was allowed to cool and was directly distilled using house vacuum to provide N-t-Boc-2-bromoaniline.
  • Step 3 N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester (Step 1, 1.1 eq.), K 2 CO 3 (1.1 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.02 eq) were stirred in 20% water/dioxane under nitrogen. The solution was heated at reflux for 10 hours. The mixture was allowed to cool then was concentrated. The resulting residue was partitioned between water and chloroform. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography using 1 : 1 CH 2 CL/hexanes.
  • Step 4 Following General Procedure 7-B and using the substituted biphenyl from step 3, the 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
  • Step 5 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to provide a residue which was partitioned between EtOAc and water. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography to 9-fluoro-7-mefhyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
  • Step 6 Following General Procedure 7-A, Step B and 9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 5, 5-amino-9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
  • Step 7 Following the procedure of Example 7-1 and using 5-amino-9- fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 6, the title compound was prepared.
  • Example 7-S Following the procedure of Example 7-1 and using 5-amino-7- cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared.
  • Example 7-S
  • Example 7-L Following the procedure of Example 7-J and using 5-amino-7- cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared.
  • Step A Following General Procedure 7-A and using 5,7-dihydro-6FI- dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron
  • Step B Following the procedure of Example 7-J and using 5-amino-7- hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared.
  • Example 7-J Following the procedure of Example 7-J and using 5-amino-10-fluoro-7- mefhyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example T ⁇ -Q), the title compound was prepared.
  • Example 7-O Following the procedure of Example 7-J and using the 5-amino-9-fluoro-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 7-O), the title compound was prepared.
  • Example 7-A The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-A) was dissolved in a 1 :1 mixture of EtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at 60 °C under 60 psi of hydrogen. After 3 days, the mixture was filtered and the filtrate was concentrated to provide an oil which was purified by SCX-cation exchange chromatography to yield the title compound.
  • Desired enantiomer 1 retention time of 9.97 minutes.
  • Undesired enantiomer 2 retention time of 8.62 minutes.
  • Step C Synthesis of l -Chloromethylacetyl-8-phenyl-l .2.3.4- tetrahvdroquinoline
  • the product from Step B (1.0 g. 4.78 mmol) was dissolved in CH 2 CL (20 mL)/ H 2 O (20 mL) and treated with NaHCO 3 (0.602 g, 7.18 mmol) followed by chloroacetyl chloride (0.478 ml, 5.26 mmol). After stirring for 17 h at 23°C, the reaction was diluted with CH 2 CL, washed with saturated NaHCO 3 , dried over
  • Step E Synthesis of 9-Oximo-5.6-Dihydro-4H-quino[8.1 - ab][3]benzazepin-8(9H)-one
  • the product from Step D (0.490 g, 1.97 mmol) was dissolved in THF and butyl nitrite (0.46 mL, 3.93 mmol) and treated with KHMDS (0.5 M. 4.52 mL,
  • Step F Synthesis of 9-Amino-5.6-Dihydro-4H-quino[8.1- ab][3]benzazepin-8(9H)-one
  • the product from Step E (0.360 g, 1.29 mmol) was hydrogenated over
  • Step A Synthesis of 9-(N'-Boc-L-Alaninyl)amino-5.6-Dihvdro-4H- quino[8.1-ab][3]benzazepin-8(9H)-one Following General Procedure D and using N-Boc -Alanine (Aldrich) and 9-amino-5,6-dihydro-4H-quino[8, l-ab][3]benzazepin-8(9H)-one (from
  • Example 7-AC the title compound was prepared.
  • Step B Synthesis of 9-(N'-L-Alaninyl)amino-5.6-dihydro-4H- quinof8. l-ab][31benzazepin-8(9H)-one Hydrochloride Following General Procedure E and using the product from Step A, the title compound was prepared.
  • GENERAL PROCEDURE 8-A N- 1 -Methy lation of Benzodiazepines A solution of benzodiazepine (1 eq.) in DMF (0.1 M concentration) at 0°C was treated with potassium tert-butoxide (1.0 eq., 1.0 M solution in THF). After stirring for 30 minutes at 0°C, iodomethane (1.3 eq.) was added and stirring continued for 25 minutes. The mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na 2 S0 4 , filtered, and concentrated. The crude product was then either purified by trituration with 1 : 1 ether/hexanes or chromatographed via HPLC using ethyl acetate/hexanes as the eluent.
  • the HBr salt was partitioned between ethyl acetate and 1 M K 2 CO 3 .
  • the aqueous layer was back-extracted with ethyl acetate.
  • the combined organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • GENERAL PROCEDURE 8-C Boc Removal Procedure A solution of Boc-protected amine (1 eq.) in methylene chloride (0.15 M concentration) was cooled to 0°C and treated with trifluoroacetic acid (30 eq.). After 10 minutes at 0°C, the cooling bath was removed and stirring continued at ambient for 20 minutes to 1 hour. The mixture was concentrated in vacuo to remove excess trifluoroacetic acid. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO 3 or 1 M K 2 CO 3 and brine. The organic layer was dried over Na 2 SO , filtered, and concentrated.
  • GENERAL PROCEDURE 8-F Azido Group Reduction The azido group was reduced to the corresponding primary amine using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996). GENERAL PROCEDURE 8-G

Abstract

L'invention concerne des composés qui inhibent la libération et/ou la synthèse de peptide bêta-amyloïde et qui, de ce fait, sont utiles dans le traitement de la maladie d'Alzheimer. L'invention concerne également des compositions renfermant un composé qui inhibe la libération et/ou la synthèse de peptide bêta-amyloïde, ainsi que des procédés relatifs au traitement de la maladie d'Alzheimer par le biais desdites compositions, à des fins prophylactiques et thérapeutiques.
PCT/US1999/014007 1998-06-22 1999-06-21 Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide WO1999067220A1 (fr)

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EP99937164A EP1089981A1 (fr) 1998-06-22 1999-06-21 Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide
JP2000555874A JP2002518482A (ja) 1998-06-22 1999-06-21 β−アミロイドペプチド放出および／またはその合成を阻害する化合物
CA002325388A CA2325388A1 (fr) 1998-06-22 1999-06-21 Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide
AU52047/99A AU5204799A (en) 1998-06-22 1999-06-21 Compounds for inhibiting beta-amyloid peptide release and/or its synthesis

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US6432944B1 (en) 2000-07-06 2002-08-13 Bristol-Myers Squibb Company Benzodiazepinone β-amyloid inhibitors: arylacetamidoalanyl derivatives
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
WO2004031154A1 (fr) * 2002-10-03 2004-04-15 Astrazeneca Ab Nouvelles lactames et utilisations de ces dernieres
US6794381B1 (en) 1998-08-07 2004-09-21 Bristol-Myers Squibb Company Succinoylamino lactams as inhibitors of aβ protein
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
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7153491B2 (en) 1998-11-12 2006-12-26 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
WO2007053725A3 (fr) * 2005-11-01 2007-07-19 Univ Michigan Nouvelles 1,4-benzodiazépine-2,5-diones dotées de propriétés thérapeutiques
WO2008125008A1 (fr) * 2007-04-12 2008-10-23 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composés de cyclohepta[b]pyridine, leur procédé de préparation et leur usage ainsi que compositions pharmaceutiques contenant les composés
WO2010095766A1 (fr) * 2009-02-17 2010-08-26 Banyu Pharmaceutical Co.,Ltd. Dérivés de 1,4-benzodiazépine-2-on
US9126978B2 (en) 2009-11-17 2015-09-08 The Regents Of The University Of Michigan 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties

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