WO1999067219A1 - Composes destines a inhiber la liberation et/ou la synthese du peptide beta-amyloide - Google Patents

Composes destines a inhiber la liberation et/ou la synthese du peptide beta-amyloide Download PDF

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Publication number
WO1999067219A1
WO1999067219A1 PCT/US1999/014096 US9914096W WO9967219A1 WO 1999067219 A1 WO1999067219 A1 WO 1999067219A1 US 9914096 W US9914096 W US 9914096W WO 9967219 A1 WO9967219 A1 WO 9967219A1
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Prior art keywords
substimted
methyl
amino
dihydro
alkyl
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PCT/US1999/014096
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English (en)
Inventor
James E. Audia
Warren J. Porter
Richard C. Thompson
Stephen C. Wilkie
Douglas R. Stack
Qing Shi
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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 EP99930566A priority Critical patent/EP1089977A1/fr
Priority to JP2000555873A priority patent/JP2002518481A/ja
Priority to CA002324474A priority patent/CA2324474A1/fr
Priority to AU47079/99A priority patent/AU4707999A/en
Publication of WO1999067219A1 publication Critical patent/WO1999067219A1/fr

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    • 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
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
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    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
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    • 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
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    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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    • 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
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    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D401/14—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 three or more hetero rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • 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
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    • 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
    • C07D471/04—Ortho-condensed systems
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    • 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
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    • 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
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-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.
  • 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. 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.
  • AD (familial) form of AD (Goate. et al. 4 ; Chartier Harlan. et al.5 ; and Murrell, et al. ) and is referred to as the Swedish variant.
  • a double mutation changing lysine -methionine to asparagine -leucine (with reference to the 695
  • 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. Accordingly, in one of its composition aspects, the present invention provides compounds of formula I:
  • 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 heterocychc ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocychc
  • ring B together with the atoms to which it is attached, forms a carbocyclic or heterocychc ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocychc
  • ring C together with the atoms to which it is attached, forms a heteroaryl or heterocychc ring
  • Y is represented by the formula:
  • R is selected from the group consisting of alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocychc;
  • R is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl. substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocychc;
  • each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl. alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocychc;
  • each R is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocychc:
  • R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl. heterocychc, thioalkoxy and substituted thioalkoxy;
  • Q is oxygen, sulfur, -S(O)-, -S(O) 2 -, -C(O)- or -C(S)- ;
  • Z is represented by the formula -T-CX'X"V-, wherein T is selected from the group consisting of a bond covalently linking R to -CX'X"-, oxygen, sulfur and -NR -, wherein R is hydrogen, acyl. alkyl, aryl or heteroaryl;
  • X' is hydrogen, hydroxy or fluoro
  • X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; and V is selected from the group consisting of alkylene or substituted alkylene. or R and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl. heterocychc or substituted heterocychc
  • X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl. substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkenyl, heteroaryl and heterocychc: or X and one of R 4 and the atoms to which they are attached form a double bond; t is an integer from 0 to 2;
  • / is an integer from 0 to 2; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof provided that neither of X' and X" can be hydroxy or fluoro when T is other than a covalent bond linking R to - CX'X"-.
  • this invention also provides for novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the formula I above. Additionally, m one of its method aspects, 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 formula 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 tor developing AD which method comprises administering to said patient a pharmaceutical composition comp ⁇ sing a pharmaceutically inert carrier and an effective amount of a compound or a mixture 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 mixture 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 heterocychc 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, substituted phenyl, including fluoro-substituted phenyl, cyclohexyl and the like.
  • Preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, morpholino and the like.
  • R groups include unsubstituted aryl groups such as phenyl, 1- naphthyl, 2-naphthyl. etc. ; substituted aryl groups such as monosubstituted phenyls (preferably substiments at 3 or 5 positions); disubstituted phenyls (preferably substiments at 3 and 5 positions); and trisubstimted phenyls (preferably substituents at the 3,4,5 positions).
  • the substituted phenyl groups do not include more than 3 substiments.
  • substimted phenyls include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2- nitrophenyl, 2-methylphenyl, 2 -methoxy phenyl, 2 -phenoxyphenyl, 2- trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4- ethoxyphenyl. 4-butoxyphenyl, 4-wo-propylphenyl, 4-phenoxyphenyl, 4- trifluoromethylphenyl.
  • R groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl- ⁇ -butyl, methyl, ethyl, ⁇ -propyl, iso- propyl, wo-butyl, 5ec-butyl, tert-butyl, n-pentyl, zso-valeryl, A2-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclohex- en-l-yl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclohexyl, -CH 2 -cyclopentyl, -CH 2 CH 2 -cyclopropyl.
  • -CH 2 CH 2 -cyclobutyl -CH 2 CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopentyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, fluoropyridyls (including 5- fluoropyridin-3-yl), chloropyridyls (including 5-chloropyridin-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl.
  • 2-(4-nitrophenyl)ethyl 2-(4-methoxyphenyl)- ethyl, norboran-2-yl, (4-methoxyphenyl)-methyl, (2-methoxyphenyl)methyl, (3- methoxyphenyl)methyl, (3-hydroxyphenyl)-methyl, (4-hydroxyphenyl)methyl, (4- methoxyphenyl)methyl, (4-methylphenyl)-methyl, (4-fluorophenyl)methyl, (4- fluorophenoxy)methyl, (2,4-dichlorophenoxy)-ethyl, (4-chlorophenyl)methyl, (2- chlorophenyl)methyl, (l-phenyl)ethyl, (l-( -chlorophenyl)ethyl, (1- trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH 3 OC(0)CH 2 -, benzylthiomethyl, 5-(methoxycarbony
  • CH 3 C( NHOH)CH 2 -, 4-CH 3 - ⁇ -NHC(O)CH 2 CH 2 -, ⁇ C(0)CH( ⁇ )CH 2 -, (CH 3 ) 2 CHC(O)NHCH( ⁇ )-.
  • R is preferably selected from the group consisting of alkyl, substimted alkyl, alkenyl, cycloalkyl, aryl. heteroaryl and heterocychc.
  • R" substiments include, by way of example, methyl, ethyl, ft-propyl, so-propyl, /i-butyl. iso-buty ⁇ , sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl- «-butyl, 6-fluoro-rc-hexyl. phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, sobuten-2-yl.
  • 3-methylpentyl -CH 2 - cyclopropyl, -CH -cyclohexyl, -CH CH 2 -cyclopropyl, -CH 2 CH 2 -cyclohexyl, -CH 2 -indol-3-yl, -(phenyl)phenyl, o-fluorophenyl, -fluorophenyl, p- fluorophenyl, -methoxyphenyl, -methoxyphenyl, phenethyl.
  • benzyl m- hydroxy benzyl, ?-hydroxy benzyl, -nitrobenzyl, -trifluoromethylphenyl, p- (CH 3 ) 2 NCH 2 CH 2 CH 2 O-benzyl, J p-(CH 3 ) 3 COC(O)CH 2 O-benzyl, p- (HOOCCH 2 O)-benzyl, 2-aminopyridin-6-yl, /?-(N-morpholino-CH 2 CH 2 O)-benzyl, -CH 2 CH 2 C(O)NH 2 , -CH 2 -imidazol-4-yl, -CH 2 -(3-tetrahydrofuranyl), -CH 2 - thiophen-2-yl, -CH 2 (l-methyl)cyclopropyl, -CH 2 -thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH 2 -C(O)
  • -CH 2 -pyridyl e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pyridyl (2- pyridyl, 3-pyridyl and 4-pyridyl)
  • -CH 2 -naphthyl e.g.
  • R is selected from the group consisting of hydrogen, alky] substimted alkyl and cycloalkyl.
  • R substiments include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxy carbonylmethyl, 3.3-dimethyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2.2,2-trifluoroethyl, cyclohexyl, and the like.
  • R is preferably alkyl or substimted alkyl.
  • R is preferably alkyl; substimted alkyl; aryl; substimted aryl, such as
  • / is 0 or 1. More preferably, / is 0.
  • n is 1.
  • W is a cyclic group of the formula:
  • each R is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl. substimted alkenyl, alkoxy, substimted alkoxy, alkyl, substimted alkyl, alkynyl, substimted alkynyl, amino, substimted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocychc, nitro, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, -SO- aryl, -SO-heteroaryl. -S0 2 -alkyl, -S0 2 -substituted alkyl. -S0 2 -
  • each R is independently selected from the group consisting of acyl, acylamino, acyloxy. alkenyl. substimted alkenyl, alkoxy, substimted alkoxy, alkyl, substimted alkyl, alkynyl, substimted alkynyl, amino, substimted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substimted cycloalkyl, halo, heteroaryl, heterocychc, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl.
  • R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocychc;
  • p is an integer from 0 to 4; and q is an integer from 0 to 4.
  • R and R are independently selected from the group consisting of alkoxy, substimted alkoxy, alkyl. substimted alkyl, amino, substimted amino, carboxyl, carboxyalkyl. cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
  • R is preferably selected from the group consisting of hydrogen, alkyl. substimted alkyl, acyl. aryl, cycloalkyl and substimted cycloalkyl. More preferably. R is selected from the group consisting of hydrogen, alkyl, substimted alkyl and cycloalkyl.
  • R substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimefhyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • W is a cyclic group of the formula:
  • W is a cyclic group of the formula
  • W is a cyclic ring of the formula
  • W is a cyclic ring of the formula
  • R , R and p are as defined herein, and
  • each R is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocychc; and g is an integer from 0 to 2.
  • R is preferably alkyl or substimted alkyl.
  • W is a cyclic ring of the formula:
  • R , R , R , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R , R , R , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • R , R and p are as defined herein; and R is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substimted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocychc.
  • W is a cyclic ring of the formula:
  • R , R and p are as defined herein;
  • W is a cyclic ring of the formula:
  • R , R , R , 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 , R and p are as defined herein.
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • W is a cyclic ring of the formula:
  • R . R , R and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R . R , R and p are as defined herein.
  • Compounds of this invention include, by way of example, the following: 5-(S)-(N'-(2-(3,5-difluorophenyl)ethyl)-L-alaninyl)-amino-7-methyl-
  • compounds of the present invention exist as isomers.
  • the Cahn-Prelog-Ingold designations of (R)- and (S)- and. for amino acid derived portions of the compounds the L- and D- designations of stereochemistry relative to the isomers of glvceraldehyde are used to refer to specific isomers where designated.
  • the specific isomers can be prepared by stereospecific synthesis or can be resolved and recovered by techniques known in the art. such as. chromatography on chiral stationary phases, and fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and described, for example, in Stereochemistry of Organic Compounds.
  • 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. 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, wo-propyl, n-butyl, /so-butyl, n-hexyl, and the like.
  • Substituted alkyl refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substiments, and preferably 1 to 3 substiments, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl. substimted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy.
  • 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.
  • Substituted alkylene refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocychc, heterocyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, - SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl
  • substituted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocychc 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, substimted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto. thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl.
  • heterocychc heterocyclooxy. nitro -SO-alkyl, -SO-substituted alkyl, - SO-aryl. -SO-heteroaryl, -SO 2 -alkyl. -S0 2 -substituted alkyl, -SO 2 -aryl. and -SO-heteroaryl.
  • substimted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocychc or heteroaryl groups fused to the alkylene group.
  • 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, ⁇ r ⁇ -propoxy, n-butoxy, tert-butoxy, sec-butoxy. r ⁇ -pentoxy, rc-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substituted alkoxy refers to the group “substimted alky 1-0- " where substituted 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-wo-propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (-CH 2 -0-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 (-CH 2 CH 2 SCH 3 ) , n-propy lene-thio-wo-propoxy (-CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ) , methylenethio-r-butoxy (-CH 2 SC(CH 3 ) 3 ) and the like.
  • 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, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substimted cycloalkoxy, acyl, acylamino.
  • acyloxy amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocychc, heterocyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, and -SO 2 -heteroaryl .
  • 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 substiments selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxy, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl.
  • Acyl refers to the groups alkyl-C(O)-. substimted alkyl-C(O)-. cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocychc 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, substituted alkyl, aryl, heteroaryl, heterocychc and where both R groups are joined to form a heterocychc group, wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocychc 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, substimted cycloalkyl, heteroaryl, heterocychc and where both R groups are joined to form a heterocychc group. When both R groups are hydrogen, -N(R) 2 is an amino group.
  • substimted 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 substiments selected from alkyl, substimted alkyl. aryl, heteroaryl and heterocychc, 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-butoxy carbonyl (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-methylbenzyl, 4-methoxybenzyl, 2- nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmob), trityl (Trt), and the like.
  • amino- blocking groups covalently attached to a solid support may also be employed.
  • Aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, or heterocychc wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocychc are as defined herein.
  • Aminoacyloxy refers to the group -NRC(0)OR where each R is independently hydrogen, alkyl. substituted alkyl, aryl, heteroaryl. or heterocychc wherein alkyl. substimted alkyl, aryl, heteroaryl and heterocychc are as defined herein.
  • Alkyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)0-, substimted cycloalkyl-C(O)O-, aryl-C(0)0-, heteroaryl- C(O)0-, and heterocyclic-C(0)0- wherein alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl, and heterocychc 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.
  • 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, substituted alkyl.
  • alkoxy substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocychc, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, -SO 2 -heteroaryl and trihalomethyl.
  • Preferred substituents include alkyl, alkoxy, halo, cyano. nitro, trihalomethyl, and thioal
  • 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(0)0-alkyl” and “-C(0)0- 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, including bridged, fused and spiro rings and combinations thereof.
  • the cycloalkyl ring may optionally be fused to an aryl, heteroaryl, or heterocycle ring.
  • Such cycloalkyl groups include, by way of example, single ring strucmres such as cyclopropyl, cyclobutyl. cyclopentyl, cyclooctyl, and the like, or multiple ring strucmres such as adamantanyl, and the like.
  • Substimted cycloalkyl refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) 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, heterocychc, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-he
  • 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, 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.
  • 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 substituted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substimted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl.
  • acylamino alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocychc, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, -SO 7 -heteroaryl and trihalomethyl.
  • heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • Heteroaryloxy refers to the group “-O-heteroaryl” .
  • Heterocycle or “heterocychc” refers to a monovalent saturated or unsamrated group having a single ring or multiple condensed rings having from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within at least one ring.
  • heterocychc groups can be optionally substituted with 1 to 5 substiments selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino. acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyacylamino. cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto. thioketo.
  • heterocychc groups can have a single ring or multiple condensed rings.
  • Preferred heterocyclics include morpholino, piperidinyl, and the like.
  • “Monocyclic heterocyclics” refer to single ring heterocycle groups which are exemplified by, for example, pyrrolidinyl, morpholino, and the like.
  • “Bicyclic heterocyclics” refer to heterocychc groups comprised of two ring systems which may be fused, spiro or bridged wherein at least one of the rings contains a heteroatom and the other ring is selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocychc. Examples of fused bicyclic heterocychc ring systems include, for instance, 3-
  • Tricyclic heterocyclics refer to heterocychc groups comprised of three ring systems wherein each of the ring systems is independently fused, spiro or bridged wherein at least one of the rings contains a heteroatom and the remaining two rings are selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocychc. When the remaining two rings are cycloalkyl, cycloalkenyl or heterocychc, these rings may optionally be spiro linked.
  • heterocycles and heteroaryls include, but are not limited to, pyrrole, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole. indazole, purine. quinolizine, isoquinoline, quinoline, phthalazine. naphthylpyridine, quinoxaline. quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine. acridine, phenanthroline, isothiazole, phenazine.
  • isoxazole phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.
  • 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 heterocychc wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocychc 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 substimted 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.
  • 1,3,4,7,12, 12a-hexahydropy rido [2 , 1 -b] [3]benzazepin-6(2H)- one refers to a polycyclic e-caprolactam ring system having the formula:
  • 4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-2(lH)-one refers to a polycyclic e-caprolactam ring system having the formula:
  • “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 refers to any group which when bound to one or more hydroxyl, thiol, carboxyl groups or other protectable functional group of the compounds 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, r-butyl, etc. , which can be removed by mild hydrolysis conditions compatible with the nature of the product.
  • amine compound such as 2 (where R , R , R , p and q are as defined herein), by conventional acylation reactions 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 using conventional coupling reagents and procedures and at least a stoichiometric amount of amino acid 1 and amine 2.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole. etc.
  • Acid 1 can also be coupled to amine 2 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)) .
  • a new carbodiimide coupling reagent. PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of such compounds.
  • 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.
  • Certain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents.
  • hydroxylated resins examples include the 4-hydroxymethylphenyl- acetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see Advanced Chemtech 1993-1994 catalog, page 115).
  • the hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.
  • 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 1A below.
  • PEPC is prepared by first reacting ethyl isocyanate with l-(3-aminopropyl)pyrrolidine. The resulting urea is treated with
  • 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 CHC1 3 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.
  • the acid halide of compound 1 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-methylmorpholine and the like. Removal of the amine protecting group using conventional procedures and reagents then affords intermediate 3.
  • this reaction is conducted in an essentially inert diluent, such as methanol. at a temperature ranging from about 0°C to about 50°C, preferably at ambient temperature, for about 0.5 to 3 hours.
  • an essentially inert diluent such as methanol.
  • a compound of Formula I can be prepared by reacting an acid of formula 5:
  • the aldehyde, 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 precursors of the compounds of formula I.
  • the compounds of formula I may also be prepared by any one of the following methods by conventional means as known to one of ordinary skill in the art. Some such methods are described below (a) reductive alky lation. as shown in Scheme 3 below:
  • R . T, X' , X" , Y, W and Z are as defined herein and is described in detail in Scheme 1 above;
  • R . Y, W and Z are as defined herein, and X is a leaving group such as halogen, tosylate, mesylate, triflate, and the like, as known to one of ordinary skill in the art.
  • Epoxide ring opening reactions provide for ⁇ -hydroxyl groups ( ⁇ to the amine).
  • the conditions employed for such reactions are well known in the art.
  • nucleophilic displacement reactions provide for facile methods for reacting, e.g. , a primary amine with, for example, an -haloacetic acid derivative, to provide for an amino acid derivative which reaction is described in detail in International Patent Application Publication No. WO98/22441.
  • aldehyde 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 n is one or two, etc.
  • the aldehyde of formula 4, employed in this invention can be readily prepared by oxidizing the corresponding alcohol using conventional oxidizing agents. For example, Swern oxidation of primary alcohols affords the corresponding aldehyde. Typically, 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. Generally, this reaction is conducted in an inert diluent, such as dichloromethane, at an initial temperature of about -
  • 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 acid esters using conventional reducing agents such as lithium aluminum hydride and the like.
  • the carboxylic acids of formula 1 are commercially available or they can be prepared by esterification of corresponding alpha amino acids by methods well known in the art.
  • the acid of formula 5, can be prepared by conventional coupling of an aldehyde of formula 4 with the amino group of an esterified alpha- amino acid under reductive amination reaction conditions described above.
  • 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 12 R. F. C. Brown et al., Tetrahedron Letters 1971, 8, 667-670 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 terr-butyl lithium, in an inert diluent, such as THF, at a temperature ranging from about -80°C to about -60°C for about 0.25 to about 1 hour.
  • an alkyl lithium reagent preferably sec-butyl lithium or terr-butyl lithium
  • an inert diluent such as THF
  • the resulting methyl boronate ester is typically not isolated, but is preferably converted in situ into the pinacol ester by treating the reaction mixture 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 groups are preferably joined together to form -C(CH 3 ) 2 C(CH 3 ) 2 -.
  • the amino group of a 2-bromoaniline derivative, 20, 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.
  • this reaction is conducted at a temperature 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(triphenylphospnine)palhdium(0).
  • a pallidium catalyst preferably tetrakis(triphenylphospnine)palhdium(0).
  • this coupling reaction is conducted in a diluent, preferably 20% water/dioxane, under an inert atmosphere at a temperamre ranging from about 50°C to about 100°C for about
  • 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.
  • 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 temperature 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 .
  • trimethylsilyl iodide 2.5 equivalents, of trimethylsilyl iodide in the presence of an excess of a trialkylamine, 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 (I 2 ).
  • a trialkylamine 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 temperature 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 mixture of THF and water.
  • This reduction reaction is typically conducted at a temperamre 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-(/V-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 temperature ranging from about 25 °C to about 100°C for about 12 to about 48 hours.
  • 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-dimethyl-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
  • 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 8.
  • 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 temperamre 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-
  • 2.3-dihydro-5-phenyl-lH-1.4-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 rert-butoxide, potassium 1 , 1,1,3,3,3- hexamethyldisilazane. or cesium carbonate, in an inert diluent, such as DMF.
  • a base such as sodium hydride, potassium rert-butoxide, potassium 1 , 1,1,3,3,3- hexamethyldisilazane. or cesium carbonate
  • an inert diluent such as DMF.
  • This reaction is typically conducted at a temperamre 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
  • 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 examples 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 separate enantiomers from a R,S mixmre to provide for one or the other stereoisomer. Such techniques are well known in the art.
  • 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.
  • This invention also includes pharmaceutical 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 a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient when it 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.
  • the 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 actually 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 be separated by an 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
  • an 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
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. as well as elixirs and similar pharmaceutical vehicles
  • 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 mask, 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:
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Formulation Example 4 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.
  • 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.
  • Quantity Ingredient (mg/capsule)
  • 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 incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixmre 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.
  • the construction and use of 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 incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5.011.472 which is herein incorporated by reference.
  • 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, carboxyl. 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. Additionally, in order to enhance the in vivo serum half-life of the administered compound, 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 incorporated 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 a "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 to 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 purposes. 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.
  • DIPEA diisopropylethylamine
  • HMDS 1,1,1 ,3 ,3 , 3-hexamethyldisilazane
  • HOBT 1-hydroxybenzotriazole hydrate
  • Hunig's base diisopropy lethy lamine
  • PEPC l-(3-(l-pyrrolidinyl)propyl)-3-ethylcarbodiimide
  • UV __ ultra-violet In the examples below, all temperatures are in degrees Celsius (unless otherwise indicated). The compounds set forth in the examples below were prepared using the following general procedures as indicated.
  • 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 Corp. , 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, USA
  • Alfa indicates that the compound or reagent is commercially available from Johnson Matthey Catalog Company, Inc. 30 Bond Street. Ward Hill, MA 01835-0747, USA
  • Novabiochem indicates that the compound or reagent is commercially available from Calbiochem-Novabiochem Corp. , 10933 North Torrey Pines Road, P.O.
  • GENERAL PROCEDURE B Second EDC Coupling Procedure A mixmre of the corresponding acid (1 eqv), N-l -hydroxybenzotriazole (1.6 eqv), the corresponding amine (1 eqv), N-methylmorpholine ( 3 eqv) and dichloromethane (or DMF for insoluble substrates) was cooled in an ice-water bath and stirred until a clear solution was obtained. EDC (1.3 eqv) was then added to the reaction mixture. The cooling bath was then allowed to warm to ambient temperamre over 1-2 h and the reaction mixmre was stirred overnight. The reaction mixmre was then evaporated to dryness under vacuum.
  • the mixmre was diluted with EtOAc and washed with 0.1 M HCl (1 x 10 mL), samrated NaHC0 3 (1 x 10 mL), H 2 0 (1 x 10 mL), and brine and dried over MgS0 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 mixmre 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 NaHC0 3 (1 or 2x), and brine (lx). Then, the organic phase was dried over either MgS0 or Na 2 S0 4 , filtered, concentrated to provide the crude product, which was either further purified or utilized without further purification.
  • 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 mixmre 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 S0 4 and the solvent was removed under reduced pressure after filtration.
  • the residue was purified by conventional methods (e.g.. recrystallization).
  • 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.
  • reaction mixmre was stirred for 5 hours at this temperamre and then the reaction was cooled and rotoevaporated to yield l-amino-3-alkyl-l, 3,4,5- tetrahydro-2H-3-benzazepin-2-one as the hydrobromide salt (100% yield).
  • 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, incorporated herein by reference. The following compounds were as prepared by this procedure for use in the following steps: 5-methyl-3-amino-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one (from 4- methyl- -tetralone (Aldrich)); and
  • Step A 3-Amino-5-methyl-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from 4-methyl- ⁇ -tetralone using the methods described in Armstrong et al.
  • N-t-Boc-5-amino-3,3-dimethyl- 5,7-dihydro-6H-benz[b]azepin-6-one (General Procedure 1-B, followed by Boc protection) and methyl iodide.
  • N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H- benz[b]azepin-6-one was prepared.
  • a stream of anhydrous HCl gas was passed through a stirred solution of the N-t-Boc protected amino acid in 1 ,4-dioxane (0.03-0.09 M), chilled in a ice bath to ⁇ 10 °C under N 2 , for 10-15 minutes.
  • the solution was capped, the cooling bath removed, and the solution was allowed to warm to room temperamre with stirring for 2-8 hours, monitoring by TLC for the consumption of starting material.
  • the solution was concentrated (and in some instances dissolved in CH 2 C1 then re-concentrated and placed in vacuum oven at 60-70 °C to remove most of the residual dioxane) and used without further purification.
  • Step A 3-(S)-Am ⁇ no-5-oxa-l,3,4,5-tetrahydro-2H-l-benzazepm-2-one was prepared from N-Boc-serme (Bachem) and 2-fluoro-l -nitrobenzene (Aldrich) using the method of R J DeVita et al , Bioorgamc and Medicinal Chemistry Lett 1995,
  • Step B Following the General Procedure of Step A of Example 1-C and using the product from Step A of this example, the title compound was prepared
  • the title compound was prepared from N-Boc-cystine (Novabio) and 2- fluoro-1 -nitrobenzene (Aldrich) using the method of R J DeVita et al ,
  • Step D Synthesis of l-Amino-4.5.6.7-tetrahydro-3.7-methano-3H-3- benzazonin-2( 1 HVone
  • Step E Synthesis of l ⁇ N'-Boc-L-AlaninyDamino ⁇ .S. ⁇ -tetrahydro-S - methano-3H-3-benzazonin-2(l HVone Following General Procedure D and using JV-tert-Boc-L-alanine (Aldrich) and the product from Step D above, the title compound was prepared.
  • Step B Synthesis of 5-Amino-5.7-dihydro-6H-dibenzofa.c]-cyclohepten-6-ol Hydrochloride
  • the compound isolated above (0.489 g, 2.04 mmol) was dissolved in THF and added drop-wise to a well-stirred mixture of LAH (10.2 mL, 10.2 mmol)/THF. After heating to reflux for 25 hours under N 2 atmosphere the solution was quenched and worked-up according to Fieser's method. The resulting solid was rinsed with NH 3 sat/CHCl 3 , the filtrate evaporated and the title compound purified by chromatography (Si0 , CHC1 3 ).
  • the compound was prepared as a tan foam.
  • Step A Following the General Procedure of Step A of Example 1-C 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 Following the General Procedure of Step A of Example 1-C 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.
  • the enantiomeric excess was determined by chiral HPLC (Chiracel ODR) using 15% acetonitrile and 85% H 2 O with 0.1 % trifluoroacetic acid and a flow rate of 1.0 mL/minute at 35 °C.
  • the resolved di- -toluoyl-D-tartaric salt was then dissolved in EtOAc and saturated NaHC0 3 until pH 9-10 was reached.
  • the layers were separated and the organic layer was washed again with samrated NaHC0 3 , H 2 0, and brine.
  • the organic layer was dried over MgS0 and the drying agent was removed by filtration. The filtrate was concentrated in vacuo.
  • 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 3A ethanol. After 32 hours, the reaction mixmre was filtered through a plug of celite, the filtrate evaporated to a foam and treated with a samrated solution of HCl (g) in Et->0. The resulting colorless solid was filtered, rinsed with cold Et 2 0 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 (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 3-A).
  • the temperamre was lowered to 0°C and the reaction mixmre treated with EDC (0.449 g. 2.26 mmol) (Aldrich) and stirred 17 hours under N 2 .
  • the reaction mixmre was evaporated, the residue diluted with EtOAc/H 2 0, washed 1.0 N HCl, sat.
  • Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt (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,
  • Step B Synthesis of CSV and (RV5-(L-Valinyl)-amino-7-methyl-5.7- dihydro-6H-dibenz b.dlazepin-6-one Hydrochloride
  • the compounds isolated in Step A were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
  • Example 3-A Example 3-A and Et 3 N ( 2.66 mL, 19.12 mmol) was stirred for 5.0 minutes at -15 °C in CH 2 C1 2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I 2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10 °C over 3 h. The reaction was quenched with sat. Na 2 S0 3 , diluted with CH 2 C1 2 and separated. The organics were washed with Na 2 S0 3 and NaHS0 3 and dried over MgS0 4 .
  • the azide was dissolved in THF/H 2 0 and stirred at 23 °C for 17 hours in the presence of 3.0 equivalents of Ph 3 P.
  • the reaction was diluted with 50 %
  • Example 3-E (0.2g, 0.617 mmol) (Example 3-E) in DMF was treated with Cs 2 C0 3 (0.22 g,
  • Step A The compound isolated in Step A was deprotected in dioxane samrated with gaseous HCl.
  • the title compound was isolated as a slightly colored solid after evaporation and vacuum drying.
  • Example 3-E (1.03, 3.08 mmol) (Example 3-E) in DMF was treated with Cs 2 C0 3 (1.10 g, 3.39 mmol) and warmed to 60 °C. To the reaction mixmre was added bromomethyl acetate (0.321 mL, 3.39 mmol) (Aldrich) and stirring continued for 17 hours.
  • Step A The compound isolated in Step A was deprotected in dioxane samrated with gaseous HCl.
  • the title compound was isolated as a colorless solid after evaporation and vacuum drying.
  • Step A The compound isolated in Step A was deprotected in dioxane samrated with gaseous HCl.
  • the title compound was isolated as a colorless solid after evaporation and vacuum drying.
  • N-t-Boc-L-alanine and 5-amino- 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one N-t-Boc-L-alaninyl-5-amino-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
  • 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 substimted 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.
  • 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 substimted N-t-Boc-L-valinyl-5-amino-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.
  • N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester (Step 1, 1.1 eq.), K 2 C0 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.
  • Step F Following General Procedure 3-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 G Following the procedure of Example 3-1 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 3-L Following the procedure of Example 3-J and using 5-amino-7- cyclopropylmethyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 3-L), the title compound was prepared.
  • Example 3-Q Following the procedure of Example 3-J and using 5-amino-10-fluoro-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 3-Q), the title compound was prepared.
  • Example 3-0 Following the procedure of Example 3-J and using the 5-amino-9-fluoro-7- methyl-5.7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 3-0), the title compound was prepared.
  • Desired enantiomer 1 retention time of 9.97 minutes.
  • Undesired enantiomer 2 retention time of 8.62 minutes.
  • Step B Synthesis of 9-(N'-L-Alaninyl)amino-5.6-dihydro-4H-quinof8.1- abl [31benzazepin-8(9H)-one Hydrochloride Following General Procedure E and using the product from Step A, the title compound was prepared.
  • Example 3-F 5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 3-F), the compound was prepared as a tan foam. The resulting Boc group was removed using 2.0 M HCl/dioxane. The title compound was isolated as a slightly colored solid after evaporation and vacuum drying.
  • the HBr salt was partitioned between ethyl acetate and 1 M K 2 C0 3 .
  • the aqueous layer was back-extracted with ethyl acetate.
  • the combined organics were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated.
  • 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 mixmre was concentrated in vacuo to remove excess trifluoroacetic acid. The residue was dissolved in methylene chloride and washed with samrated aqueous NaHC0 3 or 1 M K 2 C0 3 and brine. The organic layer was dried over Na 2 S0 4 , filtered, and concentrated.
  • -78°C was added n-butyl lithium (1.6M in hexane) (1.1 eq.) dropwise maintaining the reaction temperamre at -78 °C.
  • the reaction mixmre was stirred for 30 minutes at -78 °C and then the lactam (0.471 mM) was added dropwise as a solution in 1 mL of dry THF.
  • the reaction mixture was stirred at -78 °C for 30 minutes and then a pre-cooled solution of trisyl azide (1.2 eq.) was added as a solution in 1 mL of dry THF.
  • the reaction mixmre was stirred at -78 °C for 20 minutes and then quenched with acetic acid (4.0 eq.).
  • reaction mixmre was then stirred at 40 °C for 2 hours.
  • the reaction was then poured into EtOAc and washed with water, sodium bicarbonate and brine, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC 2000 chromatography.
  • 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), incorporated herein by reference.
  • the mixmre was diluted with EtOAc, in a 2-5 volume multiple of the initial THF volume, and washed with dilute aq. NaHC0 3 (l-2x), 0.1-1.0 M aq. HCl (0-2x), and brine (lx).
  • the organic phase was then dried over MgS0 . filtered, and concentrated to provide the crude product.
  • Step B Preparation of 1.2-Dihydro-3H-l-methyl-3-oximido-5-(l- piperidinyl)-1.4-benzodiazepin-2-one
  • Potassium tert-butoxide 2.5 eq was added in two portions to a -20 °C solution of l ,2-dihydro-3H-l-methyl-5-(l-piperidinyl)-l ,4-benzodiazepin-2-one (1 eq.) in toluene.
  • isoamyl nitrite 1.2 eq. ; Aldrich
  • the reaction was stirred at -20 °C for 5 hours at which time the reaction was done by TLC.
  • the cooling bath was removed and the reaction quenched with 0.5 M citric acid.
  • diethyl ether was added.
  • the suspension was stirred at ambient temperamre overnight then filtered washing with ether.
  • the resultant cream colored solid had a melting point of 197-200°C.
  • Step C Preparation of 3-[N'-tert-Butylcarbamate)-L-alaninyll-amino-7- chloro-1.3-dihydro-l-methyl-5-phenyl-2H-1.4-benzodiazepin-2-one
  • Step B Preparation of 3-(N '-Methyl-L-alaninylVamino-2.3-dihydro- 1- methyl-5-phenyl-lH-1.4-benzodiazepin-2-one Following General Procedure 4-C and using 3-[N'-(tert-butylcarbamate)- N' -methy l-L-alaniny ll-amino-2 , 3-dihydro- 1 -methy 1-5-pheny 1- 1 H- 1 ,4- benzodiazepin-2-one, the title intermediate was prepared as a white foam.
  • Step C Preparation of 3-fN'-(tert-Butylcarbamate)-L-alaninyll-amino-7- chloro-1.3-dihydro-l-methyl-5-(2-chlorophenyl)-2H-l .4- benzodiazepin-2-one

Abstract

L'invention concerne des composés représentés par la formule (I): dans laquelle W représente un groupe cyclique du type (2); (3); et Y est représenté par la formule (II). Ces composés inhibent la libération et/ou la synthèse du peptide bêta-amyloïde, et sont donc utiles dans le traitement de la maladie d'Alzheimer. L'invention concerne également des compositions pharmaceutiques comprenant un composé qui inhibe la libération et/ou la synthèse du peptide bêta-amyloïde, ainsi que des méthodes de traitement de la maladie d'Alzheimer, de manière thérapeutique et prophylactique, à l'aide desdites compositions pharmaceutiques.
PCT/US1999/014096 1998-06-22 1999-06-22 Composes destines a inhiber la liberation et/ou la synthese du peptide beta-amyloide WO1999067219A1 (fr)

Priority Applications (4)

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EP99930566A EP1089977A1 (fr) 1998-06-22 1999-06-22 Composes destines a inhiber la liberation et/ou la synthese du peptide beta-amyloide
JP2000555873A JP2002518481A (ja) 1998-06-22 1999-06-22 β−アミロイドペプチドの放出および／またはその合成を阻害するための化合物
CA002324474A CA2324474A1 (fr) 1998-06-22 1999-06-22 Composes destines a inhiber la liberation et/ou la synthese du peptide beta-amyloide
AU47079/99A AU4707999A (en) 1998-06-22 1999-06-22 Compounds for inhibiting beta-amyloid peptide release and/or its synthesis

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US10250798A 1998-06-22 1998-06-22
US16275798A 1998-09-30 1998-09-30
US09/102,507 1998-09-30
US09/162,757 1998-09-30

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WO2002047671A2 (fr) * 2000-11-17 2002-06-20 Eli Lilly And Company Composé de lactam
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CA2324474A1 (fr) 1999-12-29
JP2002518481A (ja) 2002-06-25
AU4707999A (en) 2000-01-10

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