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WO1999066934A1 - COMPOSES D'ACIDES AMINES CYCLIQUES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT ET METHODES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE A L'AIDE DE CES COMPOSES - Google Patents

COMPOSES D'ACIDES AMINES CYCLIQUES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT ET METHODES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE A L'AIDE DE CES COMPOSES Download PDF

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WO1999066934A1
WO1999066934A1 PCT/US1999/014211 US9914211W WO9966934A1 WO 1999066934 A1 WO1999066934 A1 WO 1999066934A1 US 9914211 W US9914211 W US 9914211W WO 9966934 A1 WO9966934 A1 WO 9966934A1
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Prior art keywords
amino
group
dihydro
methyl
alkyl
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PCT/US1999/014211
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English (en)
Inventor
James E. Audia
Bruce A. Dressman
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 JP2000555620A priority Critical patent/JP2002518451A/ja
Priority to CA002324475A priority patent/CA2324475A1/fr
Priority to AU47104/99A priority patent/AU4710499A/en
Priority to EP99930600A priority patent/EP1093372A4/fr
Publication of WO1999066934A1 publication Critical patent/WO1999066934A1/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
    • C07D223/18—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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    • 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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    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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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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    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms
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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
    • C07D409/12—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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    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
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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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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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. 1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No.
  • ⁇ -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.
  • 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.
  • the present invention provides compounds of formula I and Ia:
  • 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 hetercyclic ring selected from the group consisting of aryl, cycloalkyl, heteroaryl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, and heterocyclic
  • ring B together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic
  • ring C together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring
  • Y is represented by the formula:
  • R 1 together with R' and the carbon and nitrogen atoms attached thereto, respectively, form a nitrogen containing heterocyclic in formula I or a nitrogen containing unsaturated heterocyclic or heteroaryl group in formula Ia;
  • R" is selected from the group consisting of hydrogen, alkyl, substimted alkyl and aryl; each R 2 is independently selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R 3 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl.
  • each R 4 is independently selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic;
  • R 5 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy. alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, substimted amino, aryl, aryloxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl. heteroaryl, heterocyclic. thioalkoxy and substimted thioalkoxy;
  • Q is selected from the group consisting of oxygen, sulfur, -S(O)-, -S(O),-. -C(O)- and -C(S)-:
  • X is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl.
  • This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the formula I or Ia above.
  • this invention is directed to a method for inhibiting ⁇ -amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I/Ia above effective in inhibiting the cellular release and/or synthesis of ⁇ -amyloid peptide.
  • this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable inert carrier and an effective amount of a compound or a mixture of compounds of formula I/Ia 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 acceptable inert carrier and an effective amount of a compound or a mixture of compounds of formula I/Ia above.
  • rings A and B may be the same or different and are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. More preferably, rings A and B are independently selected from the group consisting of aryl and cycloalkyl. Still more preferably, rings A and B are independently aryl.
  • Particularly preferred ⁇ and B rings include, by way of example, phenyl, substimted phenyl, including fluoro-substituted phenyl, cyclohexyl and the like.
  • Preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, morpholino and the like.
  • Preferred heterocycles defined by R 1 , R' and the nitrogen and carbon atoms attached thereto, respectively include by way of example, monocyclic nitrogen-containing heterocycles optionally substimted with 1 to 3 substituents selected from the group consisting of hydroxyl, keto, thioketo, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, aryl, aryloxy, cyano, cycloalkyl, substimted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro.
  • thiol thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy and the like; bicyclic heterocycles wherein the second cyclic group is selected from the group consisting of aryl.
  • cycloalkyl cycloalkenyl, heteroaryl and heterocyclic
  • the bicyclic group includes fused bicyclics, bridged bicyclics and spiro bicyclics and further wherein each ring is optionally substimted with 1 to 3 substiments selected from the group consisting of hydroxyl, keto, thioketo, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, aryl, aryloxy, cyano, cycloalkyl, substimted cycloalkyl, halo, heteroaryl, heteroaryloxy, nitro, thiol, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy and the like; and tricyclic heterocycles wherein the second and/or third cyclic group is independently selected from the group consisting of aryl, cycloalkyl, cycl
  • nitrogen-containing heterocycles defined by R 1 , R' and the nitrogen and carbon atoms attached thereto, respectively include by way of example, pyrrolidinyl, 4-hydroxypyrrolidinyl, azetidinyl, thiazolidinyl, piperidinyl, piperizinyl, dihydroindolyl (e.g., 2,3-dihydroindol-2-yl), tetrahydroquinolinyl (e.g.
  • l,2,3,4-tetrahydroquinolin-2-yl 1,2,3,4- tetrahydroquinolin- 1 -y 1 , 1 ,2 ,3 ,4-tetrahydroquinolin-3-yl , ) , morpholinyl , fhiomo ⁇ holinyl, 4-halopyrrolidinyl, 3-phenylpyrrolidinyl, 4-aminopyrrolidinyl, 3-methoxypyrrolidinyl, 4,4-dimethylpyrrolidinyl, 5,5-dimethylthiazolindin-4-yl. 2,3,4,5-tetrahydrooxazol-4-yl, perhydroindolyl-2-yl and the like.
  • Preferred nitrogen-containing heteroaryl groups defined by R 1 , R' and the nitrogen and carbon atoms attached thereto, respectively, include by way of example, monocyclic heteroaryls optionally substimted with 1 to 3 substiments selected from the group consisting of hydroxyl, alkyl, substimted alkyl, alkoxy, substimted alkoxy.
  • bicyclic heteroaryls wherein the second cyclic group is selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the bicyclic group includes fused bicyclics and bridged bicyclics and further wherein each ring is optionally substimted with 1 to 3 substiments selected from the group consisting of hydroxyl, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, aryl, aryloxy, cyano, cycloalkyl, substim
  • heteroaryls defined by R 1 , R' and the nitrogen and carbon atoms attached thereto, respectively include by way of example, pyridinyl, 2-quinoxalinyl, indolyl, N-methylindolyl, 3-amino-2-pyrazinyl, 3- amino-5,6-dichloro-2-pyrazinyl, 4-methoxyindolyl, 3-isoquinolinyl, and the like.
  • R 2 is preferably selected from the group consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
  • R 2 substiments include, by way of example, methyl, ethyl, n-propyl, wo-propyl, /2-butyl, iso-butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl- «-butyl, 6-fluoro-rt-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, /so-but-2-enyl, 3-methylpentyl, -CH 2 - cyclopropyl, -CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclohexyl, - CH 2 -indol-3-yl, /?-(phenyl)phenyl, o-fluorophenyl, -fluor
  • -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., 1- naphthyl and 2-naphthyl
  • -CH 2 -(N-mo ⁇ holino) /?-(N-mo ⁇ holino-CH 2 CH 2 O)- benzyl
  • benzo[b]thiophen-2-yl 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl
  • benzo[b]thiophen-3-yl 5- chlorobenzo[b]thiophen-3-yl
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
  • R 3 substiments include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3- dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • R 4 is preferably alkyl or substimted alkyl.
  • R 5 is preferably hydrogen; alkyl; substimted alkyl; phenyl; substimted phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl and the like; cycloalkyl, such as cyclohexyl and the like; or heteroaryl or heterocyclic, such as 1-piperdinyl, 2-pyridyl, 2-thiazyl, 2-thienyl and the like.
  • / is 0 or 1. More preferably, / is 0 and when/ is 0 then a methylene group or a methenylene group is defined.
  • n 1
  • W is a cyclic group of the formula:
  • each R 6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substimted alkenyl, alkoxy, substimted alkoxy, alkyl, substimted alkyl, alkynyl, substimted alkynyl, amino, substimted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substimted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -al
  • R 8 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, acyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic; p is an integer from 0 to 4; q is an integer from 0 to 4.
  • R b and R 7 are independently selected from the group consisting of alkoxy, substimted alkoxy, alkyl.
  • R 6 and R 7 are fluoro.
  • R 8 is preferably selected from the group consisting of hydrogen, alkyl, substimted alkyl, acyl, aryl, cycloalkyl and substimted cycloalkyl. More preferably, R 8 is selected from the group consisting of hydrogen, alkyl, substimted alkyl and cycloalkyl.
  • R 8 substiments include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3- dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • W is a cyclic group of the formula:
  • R 6 , R 7 , and p are as defined herein and r is an integer from 0 to 3.
  • W is a cyclic group of the formula:
  • R 6 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 and /? are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and/? are as defined herein; and each R 9 is independently selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic; and g is an integer from 0 to 2.
  • R 9 is preferably alkyl or substimted alkyl.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and /? are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein;
  • R 10 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl and heterocyclic.
  • W is a cyclic ring of the formula:
  • R 6 , R 10 and p are as defined herein;
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and p are as defined herein;
  • Q is oxygen, sulfur, -S(O)-, -S(0 -, -C(O)- or -C(S)-.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 8 is as defined herein.
  • W is a cyclic ring of the formula:
  • R 8 is as defined herein.
  • W is a cyclic ring of the formula:
  • R 8 is as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein.
  • W is a cyclic ring of the formula: wherein R 4 and R 8 are as defined herein.
  • W is a cyclic ring of the formula:
  • R 4 is as defined herein.
  • W is a cyclic ring of the formula:
  • R 4 , R 6 , R 8 and /? are as defined herein.
  • W is a cyclic ring of the formula:
  • R 4 , R 6 , R 8 and p are as defined herein.
  • 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 glyceraldehyde 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 pu ⁇ ose.
  • prodrugs of the compounds of formula I or Ia above including acylated forms of alcohols and thiols, aminals of one or more amines, and the like.
  • this invention relates to compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • ⁇ -amyloid peptide release and/or its synthesis relates to compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • ⁇ -amyloid peptide refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al. 1 including mutations and post-translational modifications of the normal ⁇ -amyloid peptide.
  • the ⁇ -amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the ⁇ -amyloid precursor protein (APP). Its 43-amino acid sequence is:
  • Alkyl refers to monovalent alkyl groups preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, /z-propyl, iso-propy ⁇ , rt-butyl, iso-butyl, n- hexyl, decyl, dodecyl, hexadecyl, and the like.
  • “Substimted alkyl” refers to an alkyl group, preferably of from 1 to 20 carbon atoms, having from 1 to 5 substiments, and preferably 1 to 3 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.
  • Alkylene refers to divalent alkylene 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 methylene (-CH 2 -), ethylene (-CH 2 CH : -), the propylene isomers (e.g. , -CH : CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Substimted alkylene refers to an alkylene group, preferably of from 1 to 20 carbon atoms and more preferably of from 1 to 6 carbon atoms, having from 1 to 3 substiments selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxy lalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO- alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -al
  • substimted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • fused cycloalkyl groups contain from 1 to 3 fused ring structures.
  • Substimted alkenylene refers to an alkenylene group, preferably of from 2 to 20 carbon atoms and more preferably of from 2 to 6 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, carboxy lalkyl, keto.
  • substimted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl. aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 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-" where "alkyl” is as defined above.
  • Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, s ⁇ -propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substituted alkoxy refers to the group “substimted alkyl-O-" where substituted alkyl is as defined above.
  • Alkylalkoxy refers to the group "-alkylene-O-alkyl” wherein alkylene and alkyl are as defined above and which includes by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH 2 CH 2 OCH 3 ), n- propylene-/s ⁇ -propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-r-butoxy (-CH 2 -O- C(CH 3 ),) and the like.
  • Alkylthioalkoxy refers to the group "-alkylene-S-alkyl” wherein alkylene and alkyl are as defined above and which includes by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy (-CH 2 CH 2 SCH 3 ), ⁇ -propy lene-thio- ⁇ o-propoxy (-CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ) , methylenethio-f-butoxy (-CH 2 SC(CH 3 ) 3 ) and the like.
  • alkenyl refers to alkenyl groups preferably having from 2 to 20 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
  • Substimted alkenyl refers to an alkenyl group as defined above having from 1 to 3 substiments selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxy 1, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxy lalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -
  • Alkynyl refers to alkynyl groups preferably having from 2 to 20 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
  • Preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH) and the like.
  • Substimted alkynyl refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkoxy, substimted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substimted amino.
  • aminoacyl aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, and -SO 2 -heteroaryl.
  • Acyl refers to the groups alkyl-C(O)-, substimted alkyl-C(O)-, cycloalkyl-C(O)-, substimted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Acylamino refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group, wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Amino refers to the group -NH 2
  • Substimted amino refers to the group -N(R), where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl. aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group. When both R groups are hydrogen, -N(R) 2 is an amino group. Examples of substimted amino groups include, by way of illustration, mono- and di-alkylamino, mono- and di-(substimted alkyl)amino, mono- and di-arylamino.
  • 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. Examples of suitable amino-blocking groups include, by way of illustration, terf-butoxycarbonyl (Boc), benzyloxycarbonyl
  • Tfa 2,4,6-trimethoxybenzyl
  • Tmob 2,4,6-trimethoxybenzyl
  • Trt trityl
  • 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 heterocyclic wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Aminoacyloxy refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substimted alkyl, aryl. heteroaryl and heterocyclic are as defined herein.
  • Alkyloxy refers to the groups alkyl-C(O)O-, substimted alkyl-C(O)O-, cycloalkyl-C(O)O-, substimted cycloalkyl-C(O)-, aryl-C(O)O-, heteroaryl- C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. , phenyl) or multiple condensed (fused) rings (e.g. , naphthyl or anthryl).
  • Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substimted with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substimted alkyl, substimted alkoxy, substimted alkenyl, substimted alkynyl, amino, substimted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO- heteroary
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substimted aryl groups as also defined above.
  • Carboxyalkyl refers to the groups “-C(O)Oalkyl” and “-C(O)O- substimted alkyl” where alkyl is as defined above.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms and preferably 3 to 12 carbon atoms having a single cyclic ring or multiple rings including condensed rings, bridged rings, spiro rings and combinations thereof.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • “Substimted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substiments selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxy lalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substimted alkyl, -SO-ary
  • Cycloalkenyl refers to cyclic alkenyl groups of from 4 to 20 carbon atoms and preferably 4 to 12 carbon atoms having a single cyclic ring or multiple rings including condensed rings, bridged rings, spiro rings and combinations thereof 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.
  • Substimted 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, substituted amino, aminoacyl, aminoacyloxy. oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxy lalkyl.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
  • heteroaryl groups can be optionally substimted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substimted alkyl, substimted alkoxy, substimted alkenyl, substimted alkynyl, amino, substimted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxy lalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, - SO-aryl, -SO-heteroaryloxy, -SO-alkyl, -SO-
  • heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple rings including condensed and bridged ring strucmres (e.g. , indolizinyl or benzothienyl).
  • “Monocyclic heteroaryls” refer to single ring heteroaryl groups which are exemplified by, for example, pyridyl, pyrrolyl and pyrimidine.
  • Bicyclic heteroaryls refer to heteroaryl groups comprised of two ring systems which may be fused 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 heterocyclic. Examples of fused bicyclic heteroaryl ring systems include, for instance, 3-isoquinoline and the like.
  • Tricyclic heteroaryls refer to heteroaryl groups comprised of three ring systems wherein each of the ring systems are independently fused 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 heterocyclic. When the remaining two rings are cycloalkyl, cycloalkenyl or heterocyclic, these rings may optionally be spiro linked.
  • Heteroaryloxy refers to the group “-O-heteroaryl”.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated or unsaturated group having a single ring or multiple rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
  • heterocyclic groups can be optionally substimted with 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, carboxy lalkyl, keto, thioketo, thiol, thioalkoxy, substimted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino.
  • heterocyclic groups can have a single ring or multiple rings including condensed rings, bridged rings. spiro rings and combinations thereof.
  • Preferred heterocyclics include mo ⁇ holino, piperidinyl, and the like.
  • Neitrogen containing heterocycles refer to heterocyclic groups described above (including samrated and unsamrated heterocyclic groups) wherein at least one of the heteroatoms in the heterocyclic group is nitrogen.
  • “Monocyclic heterocyclics” refer to single ring heterocycle groups which are exemplified by, for example, pyrrolidinyl, mo ⁇ holino, and the like.
  • Bicyclic heterocyclics refer to heterocyclic 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 heterocyclic.
  • fused bicyclic heterocyclic ring systems include, for instance, 3- (1,2,3,4-tetrahydro-isoquinolinyl) and the like.
  • Tricyclic heterocyclics refer to heterocyclic 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 heterocyclic. When the remaining two rings are cycloalkyl, cycloalkenyl or heterocyclic, 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, mo ⁇ holino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitro
  • Heterocyclooxy refers to the group “-O-heterocycle” .
  • Oxyacylamino refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Thioalkoxy refers to the group -S-alkyl.
  • Substituted 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.
  • 4,5,6 , 7-tetrahydro-3 , 7-methano-3H-3-benzazonin-2( 1 H)-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 or Ia which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium. and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.
  • protecting group or “blocking group” refers to any group which when bound to one or more amino, hydroxyl, thiol, carboxyl groups or other protectable functional group of the compounds which prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the unprotected functional group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substiments such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t- butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild hydrolysis conditions compatible with the nature of the product.
  • protected carboxylic acid 1 (where B 1 is an amino protecting group and R 2 is as defined herein) can be coupled with an amine compound, such as 2 (where R 6 , R 7 , R 8 , p and q are as defined herein), by conventional acylation reaction conditions well known in peptide chemistry to provide, after deprotection, intermediate 2-
  • 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 to provide for compounds of formula I.
  • amino acid 4 can be replaced with an unsamrated heterocyclic or heteroaryl amino acid, such as picolinic acid (pyrid-2-yl carboxylic acid) which would provide for compounds of formula Ia.
  • Intermediate 3 can then be acylated or coupled with a cyclic amino acid, e.g., 4 (where R', R" and R 1 are as defined herein), to provide compound 5.
  • a cyclic amino acid e.g., 4 (where R', R" and R 1 are as defined herein)
  • the amino group of cyclic amino acid 4 can be blocked with a removable blocking group such as with BOC, CBZ and the like and.
  • Both acylation reactions are typically conducted using conventional coupling reagents and procedures and at least a stoichiometric amount of intermediate 2 and carboxylic acid 1 in the first acylation reaction and intermediate 3_ and carboxylic acid 4 in the second acylation reaction.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1- hydroxybenzotriazole, etc. can be used to facilitate coupling.
  • the reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • the acid halide of compounds 1 and/or 4 can be employed in the acylation reactions of scheme (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmo ⁇ holine and the like.
  • compound 5 can be prepared by acylation of a compound of formula 6:
  • the compounds of this invention can be prepared merely by inco ⁇ orating a second acylation reaction which couples a compound of formula 1 with intermediate 3 followed by removal of the blocking group and then coupling amino acid 4 under conventional acylation conditions.
  • a triamino acid analogue of compound 6 can be prepared which is then coupled via conventional conditions, as discussed above, with amine 2, to afford compounds of formula I or Ia.
  • amino acids 1 and 4 employed in the above reactions are well known in the art and many of these amino acids are commercially available.
  • these amino acids 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.
  • Amino acids such as 1 and 4 can also be coupled to amines prepared by use of polymer supported forms of carbodiimide peptide coupling reagents.
  • a polymer supported form of EDC for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993)) 11 .
  • 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.
  • hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents.
  • these hydroxylated resins include the 4-hydroxymefhy ⁇ phenyl- 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 2. Scheme 2
  • PEPC is prepared by first reacting ethyl isocyanate with l-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
  • the carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45 °C, for from about 3 to 120 hours.
  • the product may be isolated by washing the reaction with CHCI 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.
  • cyclic compounds and amino-substituted derivatives thereof, such as 2. employed in the reactions described above are either known in the art or can be prepared by art-recognized procedures using commercially available starting materials and reagents.
  • 5,7-dihydro-6H-dibenz[b,d]azepin-6-one may be prepared by cyclizing a chloromethyl amide intermediate using the procedures set forth in R. F. C. Brown et al., Tetrahedron Letters 1971, 8, 667-670 12 and references cited therein.
  • This reaction is typically conducted by treating 18 with about 1.0 to about 2.1 equivalents of an alkyl lithium reagent, preferably sec-butyl lithium or tert-butyl lithium, in an inert diluent, such as THF, at a temperamre ranging from about -80°C to about -60°C for about 0.25 to about 1 hour.
  • the resulting lithium anion is then treated in situ with an excess, preferably 1.5 equivalents, of a trialkylborate, such as trimethylborate [(CH 3 O) 3 B] .
  • This reaction is initially conducted at -80 °C to about -60 °C and then allowed to warm to about 0°C to about 30 °C for about 0.5 to about 3 hours.
  • the resulting methyl boronate ester is typically not isolated, but is preferably converted in situ into the pinacol ester by treating the reaction 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 a groups are preferably joined together to form -C(CH 3 ) 2 C(CH 3 ) 2 -.
  • N-Boc-2-bromoaniline derivative 21 is converted into the N-Boc derivative 21 by treating 20 with about 1.0 to about 1.5 equivalents of di-tert-butyl-dicarbonate. Typically, this reaction is conducted at a temperamre ranging from 25 °C to about 100°C for about 12 to 48 hours to afford the N-Boc-2-bromoaniline derivative 21.
  • the 2-methylphenylboronate ester, 19, and the N-Boc-2-bromoaniline derivative 21 can then be coupled to form the biphenyl derivative 22.
  • This reaction is typically conducted by contacting 21 with about 1.0 to about 1.2 equivalents of 19 and about 1.0 to about 1.2 equivalents of potassium carbonate in the presence of a pallidium catalyst. preferably tetrakis(triphenylphosphine)pallidium(0).
  • a pallidium catalyst preferably tetrakis(triphenylphosphine)pallidium(0).
  • this coupling reaction is conducted in a diluent, preferably 20% water/dioxane, under an inert atmosphere at a temperamre ranging from about 50°C to about 100°C for about 6 to 24 hours.
  • Biphenyl derivative 22 is then readily converted into the 5,7-dihydro-6H- dibenz[b,d]azepin-6-one 23 by carboxylation of the 2-methyl group, followed by cyclization to form the e-caprolactam.
  • the carboxylation reaction is typically conducted by contacting 22 with about 2.0 to about 2.5 equivalents of a suitable base, such as sec-butyllithium, tert-butyllithium and the like, in an inert diluent, such as THF, at a temperamre ranging from about -100°C to about -20°C for about 0.5 to 6 hours.
  • THF inert diluent
  • the resulting dianion is then treated with excess anhydrous carbon dioxide to form the carboxylate.
  • Scheme 4 Preferred synthetic procedures for aminating a representative compound are illustrated in Scheme 4. It will be readily apparent to those of ordinary skill in the art that the synthetic procedure illustrated in Scheme 4 and the following reaction conditions can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other amino compounds suitable for use in this invention.
  • Scheme 4 As shown in Scheme 4, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 23, is optionally N-alkylated using conventional reagents and conditions to provide a 7- alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24.
  • this reaction is conducted by first contacting 23 with about 1.0 to 1.5 equivalents of a suitable base, such as sodium hydride, sodium bis(trimethysilyl)amide and the like, in an inert diluent, such as DMF, THF and the like, at a temperamre ranging from about -78°C to about 50°C for about 0.25 to about 6 hours.
  • a suitable base such as sodium hydride, sodium bis(trimethysilyl)amide and the like
  • an inert diluent such as DMF, THF and the like
  • the resulting anion is then treated in situ with an excess, preferably about 1.1 to about 2.0 equivalents, of an alkyl, substimted alkyl, cycloalkyl halide, etc., typically a chloride, bromide or iodide.
  • This reaction is typically conducted at a temperamre ranging from about 0°C to about 60 °C for about 1.0 to about 48 hours to afford the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative, 24. It is understood, however, that if a substimted alkyl or cycloalkyl halide is used in this reaction, the 7-substituent will be substimted alkyl or cycloalkyl rather than the alkyl group recited herein.
  • 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 temperamre ranging from about -10°C to about 20 °C for about 0.5 to about 6 hours to afford the 7-alkyl-5-oximo-5,7-dihydro-6H- dibenz[b,d]azepin-6-one derivative 25.
  • an inert diluent such as THF and the like
  • this reduction reaction is conducted by hydrogenating the oxime 25 in the presence of a catalyst, such as Raney nickel.
  • a catalyst such as Raney nickel.
  • This reaction is typically conducted under about 200 psi to about 600 psi of hydrogen at a temperamre of about 70 °C to about 120°C for about 8 to 48 hours in a diluent, preferably a mixture of ethanol and ammonia (about 20: 1).
  • the oxime may be reduced using 10% Pd/C and between about 30 to about 60 psi of hydrogen at a temperamre ranging from about 20°C to about 50°C for about 4 hours.
  • the resulting 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 26 is generally purified using well known procedures, such as recrystallization and/or chromatography.
  • the 5-iodo derivative 27 of 5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 23 can be prepared by first forming the 5-iodo derivative 27 of 5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 23. This reaction is typically conducted as described in A. O. King et al. 13 by treating 23 with an excess, preferably about 1.2 to about 2.5 equivalents, of trimethylsilyl iodide in the presence of an excess of a trialkyamine, such as triethylamine, diisopropylethylamine, TMEDA and the like, at a temperamre ranging from about -20 °C to about 0°C for about 3 to 30 minutes and then adding about 1.1 to about 2.0 equivalents of iodine (L).
  • a trialkyamine such as triethylamine, diisopropylethylamine, TMEDA and the like
  • the reaction is stirred at a temperamre ranging from about 0°C to about 20 °C for about 2 to about 4 hours to afford 5- iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 27.
  • Displacement of iodide from 27 using an alkali metal azide then affords 5- azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 28.
  • this reaction is conducted by contacting 27 with about 1.1 to about 1.5 equivalents of sodium azide in an inert diluent, such as DMF, at a temperamre ranging from about 0°C to about 50 °C for about 12 to about 48 hours.
  • the azido derivative 28 is then reduced to the corresponding amino derivative 29 using conventional procedures and reagents.
  • the azido group is preferably reduced by contacting 28 with an excess, preferably with about 3 equivalents, of triphenylphosphine in a diluent, preferably a mixmre of THF and water.
  • This reduction reaction is typically conducted at a 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-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 30.
  • Compound 30 is then optionally N-alkylated to afford, after de-blocking of the amino group, a 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,
  • the N-alkylation reaction is typically conducted by treating 30 with about 1.0 to 1.5 equivalents of an alkyl halide, a substimted alkyl halide or a cycloalkyl halide in the presence of about 1.0 to about 1.5 equivalents of a suitable base, such as cesium carbonate and the like.
  • This reaction is generally conducted in an inert diluent, such as DMF and the like, at a temperamre ranging from about 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.
  • the N-Boc protecting group is then removed using conventional procedures and reagents to afford the 5-amino-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 26.
  • This deblocking reaction is typically conducted by treating the N-Boc compound 30 with anhydrous hydrogen chloride in an inert diluent, such as 1,4-dioxane, at a temperamre ranging from about 0°C to about 50°C for about 2 to about 8 hours.
  • the resulting 5-amino-7-alkyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one 26 is generally purified using well known procedures, such as recrystallization and/or chromatography.
  • the 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones, 26, can also be prepared via an azide transfer reaction as illustrated in Scheme 5.
  • 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 23, is first N-alkylated as described above using conventional reagents and conditions to provide a 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 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 temperamre ranging from about -90 °C to about -60 °C for about 0.25 to about 2.0 hours.
  • a suitable base such as lithium diisopropylamine and the like
  • THF inert diluent
  • 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).
  • This reaction is typically conducted at a temperamre ranging from about -90°C to about -60°C for about 0.25 to about 2.0 hours.
  • the reaction mixmre is then typically treated with an excess of glacial acetic acid and the mixmre 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-amino-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 26.
  • 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 samrated 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 temperamre ranging from about 20 °C to about 100 °C for about 12 to 96 hours in a suitable diluent, such as ethyl acetate/acetic acid (1:1) and the like.
  • benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents .
  • a 2-aminobenzophenone can be readily coupled to ⁇ -(isopropylthio)-N- (benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2- aminobenzophenone in the presence of a base, such as 4-methylmo ⁇ holine, to afford the 2-[ ⁇ -(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzo- phenone.
  • a base such as 4-methylmo ⁇ holine
  • 2,3-dihydro-5-phenyl-lH-l,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-lH-l,4- benzodiazepin-2-ones are readily alkylated at the 1 -position using conventional procedures and reagents.
  • this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1 ,1,1,3,3,3- hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF.
  • a base such as sodium hydride, potassium tert-butoxide, potassium 1 ,1,1,3,3,3- hexamethyldisilazane, cesium carbonate
  • an inert diluent such as DMF.
  • This reaction is typically conducted at a 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 a temperam
  • 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5- benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-l,5-bis(alkyl)-2,4- dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepines. Such procedures are described in further detail in the example set forth below. The synthesis of additional ring strucmres is provided in the examples below.
  • the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixmre of R,S enantiomers.
  • a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained.
  • Such reaction protocols can involve inversion of the chiral center during synthesis.
  • the products of this invention are a mixmre of R,S enantiomers.
  • the chiral product corresponds to the L-amino acid derivative.
  • chiral products can be obtained via purification techniques which separates enantiomers from a R,S mixmre to provide for one or the other stereoisomer. Such techniques are well known in the art.
  • compositions When employed as pharmaceuticals, the compounds of formula I or Ia are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I or Ia above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • 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.
  • the 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 or Ia above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound acmally administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be inco ⁇ orated 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 masks tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the following formulation examples illustrate the pharmaceutical compositions of the present invention.
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • Lactose 95 The active ingredient is mixed with the lactose and the mixmre 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 poly vinyl-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.
  • Capsules each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/capsule)
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the samrated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixmre is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • 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.
  • 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 560 mg quantities.
  • a subcutaneous formulation may be prepared as follows: Ingredient Quantity
  • Active Ingredient 1.0 mg corn oil 1 mL (Depending on the solubility of the active ingredient in corn oil, up to about 5.0 mg or more of the active ingredient may be employed in this formulation, if desired).
  • a topical formulation may be prepared as follows: Ingredient Quantity
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the 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.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • 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 inco ⁇ orated by reference.
  • Indirect techniques which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lip id-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • Other suitable formulations for use in the present invention can be found in Remington 's
  • 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 inco ⁇ orated herein by reference.
  • compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.
  • Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
  • An amount adequate to accomplish this is defined as "prophylactically effective dose. " Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery pu ⁇ oses. Specifically, the compounds may be used in the diagnosis of cells releasing and/or synthesizing ⁇ -amyloid peptide. In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of ⁇ -amyloid peptide.
  • DIPEA diisopropylethylamine
  • HMDS 1,1,1 ,3 ,3,3 -hexamethyldisilazane
  • HOBT 1-hydroxybenzotriazole hydrate
  • Hunig's base diisopropylethylamine
  • Aldrich indicates that the compound or reagent used in the procedure is commercially available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA; the term “Fluka” indicates that the compound or reagent is commercially available from Fluka Chemical Co ⁇ . , 980 South 2nd
  • 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. Louis MO 63178 USA; the term “Chemservice” indicates that the compound or reagent is commercially available from Chemservice Inc. , Westchester, PA; the term “Bachem” indicates that the compound or reagent is commercially available from Bachem Biosciences Inc.
  • Advanced Chemtech indicates that the compound or reagent is commercially available from Advanced Chemtech, Louisville, KY; and the term “Pfaltz & Bauer” indicates that the compound or reagent is commercially available from Pfaltz & Bauer, Waterbury, CT, USA.
  • GENERAL PROCEDURE A First EDC Coupling Procedure To a 1: 1 mixmre of the corresponding carboxylic acid and the corresponding amine, amine hydrochloride or amino acid ester or amide in CH 2 C1 2 at 0°C was added 1.5 eq. triethylamine, followed by 2.0 eq. hydroxy benzotriazole monohy drate and then 1.25 eq. of ethyl-3-(3- dimethylamino)propyl carbodiimide HCl. The reaction mixmre was stirred overnight at room temperamre and then transferred to a separatory funnel.
  • the mixmre was washed with water, samrated aqueous NaHCO 3 , IN HCl and samrated aqueous NaCl, and then dried over MgSO 4 .
  • the resulting solution was stripped free of solvent on a rotary evaporator to yield the crude product.
  • GENERAL PROCEDURE F Coupling of an Acid Chloride with an Amino Acid Ester
  • 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 NaHCO 3 (1 or 2x), and brine (lx). Then, the organic phase was dried over either MgSO 4 or Na 2 SO 4 , filtered, concentrated to provide the crude product, which was either further purified or utilized without further purification.
  • Method A To a carboxylic ester compound in a 1:1 mixmre of CH 3 OH/H 2 O was added 2-5 equivalents of K 2 CO 3 . The mixmre was heated to 50°C for 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperamre and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ⁇ 2, and ethyl acetate was added to extract the product. The organic phase was then washed with samrated aqueous NaCl and dried over MgSO 4 . The solution was stripped free of solvent on a rotary evaporator to yield the product.
  • Method B The amino acid ester was dissolved in dioxane/water (4: 1) to which was added LiOH ( ⁇ 2 eq.) that was dissolved in water such that the total solvent after addition was about 2: 1 dioxane: water.
  • the reaction 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 SO 4 and the solvent was removed under reduced pressure after filtration.
  • the residue was purified by conventional methods (e.g., recrystallization).
  • Step A 1-Ethoxycarbonylamino-l ,3,4,5-tetrahydro-2H-3-benzazepin-2- one was prepared according to the procedure of Ben-Ishai et al., Tetrahedron,
  • Step B 1-Ethoxycarbonylamino-l ,3,4, 5-tetrahydro-2H-3-benzazepin-2- one (2.0 g, 100 M%) was dissolved in DMF (30 mL) and NaH (95 % , 0.17 g, 100M%) was added in one portion. The reaction mixmre was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and the mixmre was stirred for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were then washed with water (3x) and brine (lx).
  • Step C l-Ethoxycarbonylamino-3-alkyl-l ,3,4,5-tetrahydro-2H-3- benzazepin-2-one (l .Og, 100M%) was suspended in 30 mL of 30% HBr/HOAc and heated to 100 °C.
  • Step A 3-Amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from ⁇ -tetralone using the methods described in Armstrong et al. Tetrahedron Letters, 1994, 35, 3239. The following compounds were as prepared by this procedure for use in the following steps: 5-methyl-3-amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (from 4- methyl- ⁇ -tetralone (Aldrich)); and
  • Step B 3-Amino-l, 3,4, 5-tetrahydro-2H-l-benzazepin-2-one (4.43 g,
  • Step C BOC-protected 3-amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2- one (1.5 g, 100M%) was dissolved in DMF (20mL) and NaH (95% , 0.13g, 100M%) was added in one portion. The reaction mixmre was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and stirring was continued for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were washed with water (3x) and then brine (lx).
  • Step D The BOC-protected 3-amino-l-alkyl-l ,3,4,5-tetrahydro-2H-l- benzazepin-2-one (l.Og, 100M%) was suspended in 30 mL of 1:1 CH 2 Cl 2 /triflouroacetic acid and the mixmre was stirred for 4 hours. The reaction was then rotoevaporated to yield the 3-amino-l-alkyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100% yield).
  • Step B 3-Amino-5-methyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (9.3g 100M%) was dissolved in dioxane (300mL) and the solution was chilled to
  • Step C BOC-protected 3-amino-5-methyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100 M%) was dissolved in DMF (20mL) and NaH (95 %, 100 M%) was added in one portion and the reaction mixmre was stirred for 1 hour. Methyl iodide (300 M%) was added and this mixmre was stirred for 12 hours. The reaction was then poured into water and extracted with ethyl acetate (3x) then backwashed with water (3x) and then brine (lx).
  • Step D BOC-protected 3-amino-l, 5-dimethyl-l, 3,4, 5-tetrahydro-2H-l- benzazepin-2-one (100 M%) was suspended in 30 mL of 1: 1 CH 2 Cl 2 /triflouroacetic acid. The reaction mixmre was stirred for 4 hours. The reaction was then rotoevaporated to yield 3-amino-l, 5-dimethyl-l, 3,4, 5- tetrahydro-2H-l-benzazepin-2-one (100% yield).
  • Example 1-C Following the procedure of Example 2-1 and using 5-amino-3,3,7- trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 1-C), the title compound was prepared.
  • Step A GENERAL PROCEDURE N-Alkylation of Lactams
  • 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.
  • 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 temperature 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 2 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)-Amino-5-oxa-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-l -nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286.
  • 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.
  • Step A 3-(S)-Amino-5-oxa-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-l -nitrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorganic and Medicinal Chemistry
  • Step B Following 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.
  • Example 1-G 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., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286, followed by the General Procedure of Step A of Example 1-C.
  • Example 1-G 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., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286, followed by the General Procedure of Step A of Example 1-C.
  • Example 1-G Example 1-G
  • Step B Synthesis of 1.3.4.7.12.12a-hexahvdropyridor2.1- b] r31benzazepin-6(2H)-one Following General Procedure G and using N-chloroacetyl-2- benzylpiperidine, the title compound was prepared.
  • Step C Synthesis of 7-Oximo- 1.3.4.7.12.12a-hexahydropyrido [2.1- bl [31benzazepin-6(2Hy one Following General Procedure 3A (Step B) and using 1,3,4,7,12,12a- hexahydropyrido[2,l-b][3]benzazepin-6(2H)-one (from Step B above), the title compound was prepared.
  • Step B Synthesis of 4.5.6.7-Tetrahvdro-3.7-methano-3H-3- benzazonin-2( 1 H)-one Following General Procedure G and using N-chloroacetyl-3-phenyl- piperidine, the title compound was prepared.
  • Step E Synthesis of l-(N'-Boc-L-Alaninyl)amino-4.5.6.7- tetrahydro-3.7-methano-3H-3-benzazonin-2( 1 H -one Following General Procedure D and using N-tert-Boc-L-alanine (Aldrich) and the product from Step D above, the title compound was prepared.
  • Step F Synthesis of l-fl -L-Alaninyl amino-4.5.6.7-tetrahydro- 3.7-methano-3H-3-benzazonin-2( 1 H)-one
  • the resulting alcohol was oxidized as follows. To a stirred mixmre of oxalyl chloride (0.1.5 mL, 1.2 mmol) in 10 mL of dichloromethane cooled to -78°C was added DMSO (0.106 mL, 1.5 mmol) and the mixmre was stirred for 10 minutes. A solution of the alcohol (0.1828 g, 0.60 mmol) in 20 mL of chloroform was added dropwise. The reaction mixmre was stirred at -78 °C for 2 hours, and then 0.5 mL (3.6 mmol) of triethylamine was added.
  • the Boc group was removed using 2.0 M HCl/dioxane.
  • the title compound was isolated as an orange foam.
  • Step B The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixmre was cooled to 0°C in an ice bath. NaHMDS (1.1 eq. , 1M in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixmre was concentrated then acidified with IN HCl and extracted with EtOAc. The organic portion was dried and concentrated to yield a crude product which was purified by silica gel chromatography.
  • Step C The resulting oxime was dissolved in EtOH/NH 3 (20: 1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at 100°C for 10 hours. The resulting mixmre was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound.
  • the crude material was dissolved in methanol and the solution was samrated with HCl. The mixmre was heated at reflux for 12 hours then was allowed to cool. The mixmre was concentrated to provide crude lactam which was purified by chromatography or crystallization.
  • the resolved di-/?-toluoyl-D-tartaric salt was then dissolved in EtOAc and samrated NaHCO 3 until pH 9-10 was reached.
  • the layers were separated and the organic layer was washed again with samrated NaHCO,, H 2 O, and brine.
  • the organic layer was dried over MgSO 4 and the drying agent was removed by filtration.
  • the filtrate was concentrated in vacuo.
  • the free amine was dissolved in MeOH and HCl (12M, 1.0 eq.) was added.
  • the salt was concentrated in vacuo and the resulting film was triturated with EtOAc.
  • the HCl salt was filtered and rinsed with EtOAc. The ee was determined by chiral HPLC.
  • the oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Pan- apparatus at 35 psi over 10 % Pd/C (0.46 g) in 3 A ethanol. After 32 hours, the reaction mixture was filtered through a plug of celite, the filtrate evaporated to a foam and treated with a saturated solution of HCl (g) in Et 2 O. The resulting colorless solid was filtered, rinsed with cold Et 2 O and vacuum dried to give 0.66 g (61 %) of the title compound.
  • Boc-L-V aline (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), DIPEA (1.05 mL, 6.05 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 3- A). The temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Aldrich) and stirred 17 hours under N 2 .
  • Step B Synthesis of (SV and (RV5-(L-ValinylVamino-7-methyl-5.7- dihydro-6H-dibenz[b.d]azepin-6-one Hydrochloride
  • Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), DIPEA (1.05 mL, 6.05 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g,
  • Example 3-A 2.75 mmol
  • the temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred 17 hours under N 2 .
  • the reaction mixture was evaporated, the residue diluted with EtOAc/H 2 O, washed 1.0 N HCl, sat. NaHCO 3 , brine and dried over Na 2 SO 4 .
  • the diastereomers were separated on a Chiralcel OD column using 10% IPA heptane at 1.5 mL/minute.
  • Step B Synthesis of (SV and (RV5-(L-tert-LeucinylVamino-7- methyl-5.7-dihydro-6H-dibenz[b.d]azepin-6-one Hydrochloride
  • the iodide isolate above was dissolved in DMF and treated with 1.2 equivalents of NaN 3 . After stirring 17 hour at 23° C, the mixture was diluted with EtOAc/H 2 O, separated, washed with brine and dried over MgSO 4 . The title compound was triturated from hot EtOAc as a tan powder.
  • the azide was dissolved in THF/H 2 O 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 % HO Ac/toluene, separated, the aqueous layer extracted with toluene and evaporated to an oily residue. This was taken to pH 7.0 by the addition of 1 N NaOH, the resulting HO Ac salt was collected and vacuum dried. Finally, the compound was treated with Boc anhydride (1.05 equivalents) and Et 3 N (2.1 equivalents) in THF. After stirring for 5 hours at 23 °C, the reaction was filtered and the title compound isolated as a colorless powder.
  • Example 3-E (1.03, 3.08 mmol) (Example 3-E) in DMF was treated with Cs 2 CO 3 (1.10 g, 3.39 mmol) and warmed to 60° C. To the reaction mixture was added bromomethyl acetate (0.321 mL, 3.39 mmol) (Aldrich) and stirring continued for 17 hours.
  • Step B Synthesis of 5-Amino-7-f3.3-dimethyl-2-butanonyD-5.7- dihydro-6H-dibenz[b.d]azepin-6-one Hydrochloride
  • the compound isolated in Part A was deprotected in dioxane saturated with gaseous HCl.
  • the title compound was isolated as a colorless solid after evaporation and vacuum drying.
  • Example 3-1
  • Step B Following the General Procedure of Step B of Example 1-C and using the N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one, the title compound was prepared.
  • Other substituted N-t- Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.
  • Step A Following General Procedure D and using N-t-Boc-L-valine and 5- amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t-Boc-L-valinyl-5- amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
  • Step B Following the General Procedure of Step B of Example 1-C and using the N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one, the title compound was prepared.
  • Other substituted N-t-Boc-L-valinyl-5- amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure.
  • Step 2 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1 eq.) were stirred at 80 °C for 20 hours. The resulting mixture was allowed to cool and was directly distilled using house vacuum to provide N-t-Boc-2-bromoaniline.
  • Step 3 N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester (Step 1, 1.1 eq.), K 2 CO 3 (1.1 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.02 eq.) were stirred in 20% water/dioxane under nitrogen. The solution was heated at reflux for 10 hours. The mixture was allowed to cool then was concentrated. The resulting residue was partitioned between water and chloroform. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography using 1 :1 CH 2 Cl 2 /hexanes.
  • Step 4 Following General Procedure 3-B and using the substituted biphenyl from step 3, the 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
  • Step 5 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to provide a residue which was partitioned between EtOAc and water. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography to 9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one.
  • Step 6 Following General Procedure 3-A, Step B and 9-fluoro-7-mefhyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 5, 5-amino-9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.
  • Step 7 Following the procedure of Example 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-V Following the procedure of Example 3-J and using 5-amino-7-phenbutyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 3-U), the title compound was prepared.
  • Example 3-V Following the procedure of Example 3-J and using 5-amino-7-phenbutyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 3-U), the title compound was prepared.
  • Example 3-V Following the procedure of Example 3-J and using 5-amino-7-phenbutyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one
  • Step B Following the procedure of Example 3-J and using 5-amino-7- hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 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-A The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 3-A) was dissolved in a 1 :1 mixture of EtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at 60 °C under 60 psi of hydrogen.
  • Step B Synthesis of 8-Phenyl-l .2.3.4-tetrahydroquinoline
  • Step C Synthesis of l-ChIoromethylacetyl-8-phenyl-l .2.3.4- tetrahydroquinoline
  • the product from Step B (1.0 g, 4.78 mmol) was dissolved in CH 2 C1 2 (20 mL)/ H 2 O (20 mL) and treated with NaHCO 3 (0.602 g, 7.18 mmol) followed by chloroacetyl chloride (0.478 mL, 5.26 mmol). After stirring for 17 h at 23 °C, the reaction was diluted with CH 2 C1 2 , washed with saturated NaHCO 3 , dried over Na 2 SO 4 and purified by SiO 2 chromatography (CHC1 3 /Hexanes 9:1). The product was isolated as a colorless solid. Physical data were as follows:
  • A1C1 3 (0.87 g, 6.54 mmol) at 23°C and the mixture heated neat at 100°C for 5-7 minutes. After vigorous gas evolution, the molten mixture was allowed to cool and extracted with several portions of CH 2 Cl 2 /NaHCO 3 (sat). The combined organic layers were dried over Na 2 SO 4 and the title compound was purified by chromatography (SiO 2 , CHCl 3 /hexanes 9:1), yielding a colorless oil which solidified upon standing.
  • Step F Synthesis of 9-Amino-5.6-Dihydro-4H-quino[8.1- ab] [3 ] benzazepin- 8(9HVone
  • the product from Step E (0.360 g, 1.29 mmol) was hydrogenated over
  • Step B Synthesis of g-fN'-L-AlaninyDamino-S. ⁇ -dihydro ⁇ H- quinof ⁇ .1-ab] [3]benzazepin-8(9HVone Hydrochloride Following General Procedure E and using the product from Step A, the title compound was prepared. Physical data were as follows:
  • the HBr salt was partitioned between ethyl acetate and 1 M K 2 CO 3 .
  • the aqueous layer was back-extracted with ethyl acetate.
  • the combined organics were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • the azido derivative was prepared using the procedure described in John W. Butcher et al., Tet. Lett., 31, 6685-6688 (1996).
  • reaction mixture was stirred at -78 °C for 20 minutes and then quenched with acetic acid (4.0 eq.). The reaction mixture 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.
  • GENERAL PROCEDURE 4-F Azido Group Reduction The azido group was reduced to the corresponding primary amine using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).
  • GENERAL PROCEDURE 4-J BOC Removal Procedure To an N-Boc protected compound was added CH 2 C1 2 /TFA (4:1) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was extracted into dichloromethane and washed with water, saturated sodium bicarbonate, dried over Na 2 SO 4 , filtered and concentrated to give the free amine.
  • GENERAL PROCEDURE 4-K Azide Transfer Procedure This azide transfer procedure is a modification of the procedure described in Evans, D. A.; Britton, T. C; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc.
  • GENERAL PROCEDURE 4-L Azide Reduction to an Amine A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10% Pd/C (-1/3 by weight of the azide) was shaken in a Parr apparatus under H 2 (35-45 psi) at room temperature for 3-6 hours. The catalyst was removed by filtration through a plug of Celite, rinsing with absolute EtOH, and the filtrate concentrated to provide the crude amine product.
  • GENERAL PROCEDURE 4-M Amide Alkylation Using Cesium Carbonate This procedure is a modification of the procedure described in Claremon, D. A.; et al, PCT Application: WO 96/406555.
  • Step B Preparation of 1.2-Dihydro-3H-l-methyl-3-oximido-5-(l- piperidinyl V 1.4-benzodiazepin-2-one
  • Step D Preparation of 3-Amino-l .3-dihvdro-2H-l -methyl-5-(l- piperidinyl V 1 ,4-benzodiazepin-2-one
  • Step B Preparation of 3-[N'-(tert-Butylcarbamate -L-alaninyl]- amino-2.3-dihydro-l-methyl-5-phenyl-lH-1.4- benzodiazepin-2-one
  • Step B Preparation of 3-Amino-7-chloro-l ,3-dihydro-l -methyl-5- phenyl-2H- 1.4-benzodiazepin-2-one Following General Procedure 4-B using 3-(benzyloxycarbonyl)-amino-7- chloro-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C.
  • Step C Preparation of 3-[N'-tert-ButylcarbamateVL-alaninyl]- amino-7-chloro- 1.3-dihydro- 1 -methyl-5-phenyl-2H- 1.4- benzodiazepin-2-one
  • Step D Preparation of 3 -f L- Alaninyl)amino-7-chloro- 1.3-dihydro- 1 - methyl-5 -phenyl-2H- 1.4-benzodiazepin-2-one
  • Step C Preparation of 3-[N , -(/er/-Butylcarbamate -L-alaninyl]- amino-7-bromo-l .3-dihydro- 1 -methyl-5-f2-fluorophenylV 2H- 1.4-benzodiazepin-2-one
  • N-Boc-L-alanine Novo
  • 3- amino-7-bromo-l, 3-dihydro- l-methyl-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2- one the title intermediate was prepared as a white foam.
  • Step A Preparation of 3-[N Vtert-ButylcarbamateVN'-mefhyl-L- alaninyl]-amino-2.3-dihydro-l -methyl-5 -phenyl- 1 H-l .4- benzodiazepin-2-one Following General Procedure D and using (S)-3 -amino- 1,3 -dihydro- 1 - methyl-5 -phenyl-2H-l,4-benzodiazepin-2-one (Example 4-B) and N-tert-Boc-N- methyl-alanine (Sigma), the title intermediate was obtained as a white solid.
  • Step B Preparation of 3-fN'-Methyl-L-alaninylVamino-2.3-dihydro- l-methyl-5-phenyl-lH-1.4-benzodiazepin-2-one
  • Step C Preparation of 3-[N'-(tgr/-Butylcarbamate -L-alaninyl]- amino-7-chloro-l .3-dihydro-l -mefhyl-5-(2-chlorophenylV 2H-1 ,4-benzodiazepin-2-one
  • General Procedure D using N-Boc-L-alanine and 3-amino-7- chloro-1, 3-dihydro-l -methyl-5-(2-chlorophenyl)-2H-l,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam.
  • Step D Preparation of 3-fL-AlaninylVamino-7-chloro-l ,3-dihydro-
  • Step D Preparation of 3-(L-Alaninyl amino-5-cyclohexyl- 1.3- dihydro- 1 -methyl-2H- 1.4-benzodiazepin-2-one
  • the cooling bath was removed and the reaction stirred at ambient for 5 hours.
  • the reaction was diluted with methylene chloride and washed with 0.5 M citric acid, saturated aqueous NaHCO 3 , and brine.
  • the organic phase was dried over Na 2 SO 4 , filtered, and concentrated.
  • the residue was purified via preparative LC2000 eluting with a gradient of 15 ⁇ 20%> ethyl acetate/hexanes giving an off- white foam.
  • Step B Preparation of 2-[N-( -Amino)-N , -(benzyloxycarbonyl)- glycinyl]-amino-5-nitrobenzophenone Ammonia gas was bubbled into a solution 2-[N-( ⁇ -isopropylthio)-N'-

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  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des composés inhibant la libération du peptide β-amyloïde et/ou sa synthèse, et présentant par conséquent une utilité dans le traitement de la maladie d'Alzheimer. L'invention concerne également des compositions pharmaceutiques comprenant un composé inhibant la libération du peptide β-amyloïde et/ou sa synthèse ainsi que des méthodes de traitement de la maladie d'Alzheimer à la fois de façon prophylactique et thérapeutique avec ces compositions pharmaceutiques.
PCT/US1999/014211 1998-06-22 1999-06-22 COMPOSES D'ACIDES AMINES CYCLIQUES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT ET METHODES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE A L'AIDE DE CES COMPOSES WO1999066934A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000555620A JP2002518451A (ja) 1998-06-22 1999-06-22 環状アミノ酸化合物およびその医薬組成物、並びにそれら化合物を用いた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方法
CA002324475A CA2324475A1 (fr) 1998-06-22 1999-06-22 Composes d'acides amines cycliques, compositions pharmaceutiques les contenant et methodes d'inhibition de la liberation du peptide .beta.-amyloide et/ou de sa synthese a l'aide de ces composes
AU47104/99A AU4710499A (en) 1998-06-22 1999-06-22 Cyclic amino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use ofsuch compounds
EP99930600A EP1093372A4 (fr) 1998-06-22 1999-06-22 COMPOSES D'ACIDES AMINES CYCLIQUES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT ET METHODES D'INHIBITION DE LA LIBERATION DU PEPTIDE $g(b)-AMYLOIDE ET/OU DE SA SYNTHESE A L'AIDE DE CES COMPOSES

Applications Claiming Priority (4)

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US10250798A 1998-06-22 1998-06-22
US09/102,507 1998-06-22
US16445198A 1998-09-30 1998-09-30
US09/164,451 1998-09-30

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FR2908131A1 (fr) * 2006-11-03 2008-05-09 Univ Haute Alsace Etablissemen Derives d'aminobenzocycloheptene,leurs procedes de preparation et leur utilisation en therapeutique
US7671196B2 (en) 2005-07-26 2010-03-02 Wyeth Llc Diazepinoquinolines, synthesis thereof, and intermediates thereto
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WO2010084979A1 (fr) * 2009-01-23 2010-07-29 Banyu Pharmaceutical Co.,Ltd. Dérivés de benzodiazépin-2-one
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CN110483376A (zh) * 2019-09-11 2019-11-22 陈建江 一种中间体n-苯基-4-哌啶酮的合成方法

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AU4710499A (en) 2000-01-10
EP1093372A1 (fr) 2001-04-25

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