EP1042298A1 - Polycyclic alpha-amino-epsilon-caprolactams and related compounds - Google Patents

Polycyclic alpha-amino-epsilon-caprolactams and related compounds

Info

Publication number
EP1042298A1
EP1042298A1 EP98956198A EP98956198A EP1042298A1 EP 1042298 A1 EP1042298 A1 EP 1042298A1 EP 98956198 A EP98956198 A EP 98956198A EP 98956198 A EP98956198 A EP 98956198A EP 1042298 A1 EP1042298 A1 EP 1042298A1
Authority
EP
European Patent Office
Prior art keywords
substituted
amino
dihydro
azepin
dibenz
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98956198A
Other languages
German (de)
French (fr)
Inventor
James E. Audia
Thomas E. Mabry
Jeffrey S. Nissen
Stacey L. Mcdaniel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Elan Pharmaceuticals LLC
Eli Lilly and Co
Original Assignee
Elan Pharmaceuticals LLC
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/996,422 external-priority patent/US6635632B1/en
Application filed by Elan Pharmaceuticals LLC, Eli Lilly and Co filed Critical Elan Pharmaceuticals LLC
Publication of EP1042298A1 publication Critical patent/EP1042298A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • This invention relates to polycyclic ⁇ -amino-e-caprolactams and related compounds which are useful as synthetic intermediates in the preparation of inhibitors of ⁇ -amyloid peptide release and/or its synthesis.
  • AD Alzheimer's Disease
  • AD is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death.
  • AD is a very common cause of progressive mental failure (dementia) 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
  • HCVWA-D Hemorrhage with Amyloidosis ofthe Dutch Type
  • the principal chemical constituent ofthe amyloid plaques and vascular amyloid deposits (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 ofthe 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 ofthe cerebral and meningeal blood vessels is currently unknown.
  • a mutation at amino acid 693 ofthe 770-amino acid isoform of APP has been identified as the cause ofthe ⁇ -amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others.
  • the discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its ⁇ -amyloid peptide fragment can cause AD.
  • the treatment methods would advantageously be based on drugs which are capable of inhibiting ⁇ -amyloid peptide release and/or its synthesis in vivo.
  • This invention is directed to the discovery of a class of intermediates which are useful in the preparation the cycloalkyl, lactam, lactone and related compounds described in U.S. Patent Application Serial No. 08/996,422, which compounds inhibit ⁇ -amyloid peptide release and/or its synthesis. Accordingly, in one of its composition aspects, this invention is directed to a compound of formula I:
  • ring A together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
  • ring B together with the atoms of the e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
  • ring C together with the atoms ofthe e-caprolactam to which it is attached, forms a heteroaryl or heterocyclic ring;
  • R 1 is selected from the group consisting of hydrogen and an amino- blocking group
  • each R 2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl and heterocyclic;
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; m is an integer from 0 to 2; n is an integer from 0 to 2; and salts thereof.
  • R 1 is hydrogen or tert-butoxycarbonyl (Boc).
  • R 2 substituents include, by way of example, hydrogen, methyl, ethyl, rt-propyl, isopropyl, H-butyl, isobutyl, sec-butyl, tert- butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl- «-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, wo-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, ⁇ -fluorophenyl, m-fluorophenyl,
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
  • Particularly preferred R 3 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • R 4 is preferably alkyl or substituted alkyl.
  • n is 0 or 1. More preferably, m is 0.
  • W is preferably a substituted e-caprolactam selected from the group consisting of:
  • A, B, R , R and m are as defined herein.
  • Wx ' s a substituted e-caprolactam ofthe formula:
  • this invention is also directed to compounds of formula I wherein W is independently selected from each ofthe substituted e-caprolactams illustrated above.
  • Rings A and B may be the same or different and are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. More preferably, rings A and B are independently selected from the group consisting of aryl and cycloalkyl. Still more preferably, rings A and B are independently aryl.
  • Particularly preferred A and B rings include, by way of example, phenyl, substituted phenyl, including fluoro-substituted phenyl, cyclohexyl and the like.
  • the A and B rings are fused to one another, they preferably form a naphthyl or sustituted naphthyl ring.
  • Particularly preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, mo ⁇ holino and the like.
  • each R 5 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, and
  • R 7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; p is an integer from 0 to 4; q is an integer from 0 to 4; and salts thereof.
  • R 5 and R 6 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
  • R 5 and R 6 are fluoro.
  • R 7 is preferably selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. More preferably, R 7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
  • R 7 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • Wis a substituted e- caprolactam of the formula:
  • R 5 , R 6 , and ? are as defined herein and r is an integer from 0 to 3; and salts thereof.
  • R 5 , and p are as defined herein; and salts thereof.
  • R 5 and/? are as defined herein; and salts thereof.
  • Preferred substituted e-caprolactams include, by way of example, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-(2-methylpropyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-(methoxyacetyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-(3,3-dimethylbutan-2-onyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-yl, 7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one- yl, 7-cyclopropymethyl-5
  • Compounds of this invention include, by way of example, the following: 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
  • Preferred compounds include those defined by the formulas as set forth in Tables I, II, III, IN and V below and salts thereof.
  • this invention is directed a compound of formula II:
  • W is a substituted e-caprolactam selected from the group consisting of:
  • ring A together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
  • ring B together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
  • ring C together with the atoms of the e-caprolactam to which it is attached, forms a heteroaryl or heterocyclic ring;
  • R 1 is selected from the group consisting of hydrogen and an amino- blocking group
  • Y is represented by the formula:
  • each R 2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl and heterocyclic;
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; a is an integer from 2 to 6; m is an integer from 0 to 2; n is an integer from 0 to 2; and salts thereof.
  • Y in formula II is the group -(CHR 2 ) a -NH-, the integer a is preferably 2, 3 or 4, more preferably 2 or 4, and still more preferably a is equal to 2.
  • Y has the formula -CHR -CH,-NH-, where R 2 is as defined herein.
  • R 1 , R 2 , R 3 , R 4 , A, B, C, W, m, n and the like in formula II are the same as those described herein for compounds of formula I.
  • Preferred compounds include those defined by the formulas as set forth in Tables VI below and salts thereof.
  • ⁇ -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 ofthe protein described by Glenner, et al. 1 including mutations and post- translational modifications ofthe 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, «-propyl, zs ⁇ -propyl, «-butyl, wo-butyl, n-hexyl, decyl and the like.
  • Substituted alkyl refers to an alkyl group, preferably of from 1 to 20 carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO- substitute
  • Alkylene refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Substituted alkylene refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, - SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -
  • substituted alkylene groups include those where 2 substituents 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.
  • Substituted alkenylene refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, - SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl,
  • Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 8 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • Alkoxy refers to the group “alkyl-O-”. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, ⁇ -propoxy, wo-propoxy, n-butoxy, tert-butoxy, sec-butoxy, «-pentoxy, H-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substituted alkoxy refers to the group “substituted alkyl-O-" where substituted alkyl is as defined above.
  • Alkylalkoxy refers to the group “-alkylene-O-alkyl” which includes by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH 2 CH 2 OCH 3 ), n-propylene-wo-propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene- t-butoxy (-CH 2 -O-C(CH 3 ) 3 ) and the like.
  • Alkylthioalkoxy refers to the group “-alkylene-S-alkyl” which includes by way of example, methylenethiomethoxy (-CH 2 SCH 3 ), ethylenethiomethoxy (-CH 2 CH 2 SCH 3 ), «-propylene-thio-t5o-propoxy (-CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ), methylenethio-t-butoxy (-CH 2 SC(CH 3 ) 3 ) and the like.
  • alkenyl refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
  • Substituted alkenyl refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 - substituted alkyl, -SO 2 -aryl, and -SO
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
  • Preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH) and the like.
  • Substituted alkynyl refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 - substituted alkyl, -SO 2 -aryl, and
  • Acyl refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted 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, substituted alkyl, aryl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group, wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -N(R) 2 where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group.
  • both R groups are hydrogen
  • -N(R) 2 is an amino group.
  • substituted amino groups include, by way of illustration, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di- heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like.
  • amino-blocking group or “amino-protecting group” refers to any group which, when bound to an amino group, prevents undesired reactions from occurring at the amino group and which may be removed by conventional chemical and or enzymatic procedures to reestablish the amino group. Any known amino- blocking group may be used in this invention. Typically, the amino-blocking group is selected so as to render the resulting blocked-amino group unreactive to the particular reagents and reaction conditions employed in a subsequent predetermined chemical reaction or series of reactions. After completion ofthe reaction(s), the amino-blocking group is selectively removed to regenerate the amino group.
  • Suitable amino-blocking groups include, by way of illustration, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, 1-(1 '- adamantyl)-l-methylethoxycarbonyl (Acm), allyloxycarbonyl (Aloe), benzyloxymethyl (Bom), 2- ?-biphenylisopropyloxycarbonyl (Bpoc), tert- butyldimethylsilyl (Bsi), benzoyl (Bz), benzyl (Bn), 9-fluorenyl- methyloxycarbonyl (Fmoc), 4-methylbenzyl, 4-methoxybenzyl, 2- nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmob),
  • Aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyloxy refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Alkyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
  • Carboxyalkyl refers to the groups “-C(O)Oalkyl” and "-C(O)O- substituted alkyl” where alkyl is as defined above.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • Substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-hetero
  • Cycloalkenyl refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
  • Substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
  • heteroaryl groups can have a single ring
  • heteroaryls include pyridyl, pyrrolyl and furyl.
  • Heteroaryloxy refers to the group “-O-heteroaryl”.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
  • heterocyclic groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO
  • 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, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Thioalkoxy refers to the group -S-alkyl.
  • 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 substituted aryl groups also defined above.
  • Thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
  • 4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-2(lH)-one refers to a polycyclic e-caprolactam ring system having the formula:
  • salt(s) refers to salts of a compound of formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • protecting group or “blocking group” refers to any group which when bound to one or more hydroxyl, thiol, carboxyl or other protectable functional group ofthe compound prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical and/or enzymatic steps to reestablish the unprotected functional group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, tert- butyldiphenylsilyl 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 ofthe product.
  • substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, tert- butyldiphenylsilyl 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 ofthe product.
  • Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, tert-butyl, etc. which can be removed by mild hydrolysis conditions compatible with the nature of the product.
  • polycyclic ⁇ -amino-e-caprolactarns and related compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, 8 and references cited therein.
  • the compound of this invention are prepared by first aminating a polycyclic e-caprolactam to provide a polycyclic ⁇ - amino-e-caprolactam. If desired, the amino group ofthe polycyclic ⁇ -amino-e- caprolactam can then be coupled with a mono- or diamino acid derivative to provide compounds of formula I wherein n is 1 or 2.
  • polycyclic e-caprolactams employed as starting materials in this invention are either commercially available or can be prepared from commercially available materials using conventional procedures 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 9 and references cited therein.
  • This reaction is typically conducted by treating 1 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 temperature ranging from about -80 °C to about -60 °C for about 0.25 to about 1 hour.
  • an alkyl lithium reagent preferably sec-butyl lithium or tert-butyl lithium
  • an inert diluent such as THF
  • the resulting methyl boronate ester is typically not isolated, but is preferably converted in situ into the pinacol ester by treating the reaction mixture with an excess, preferably about 2.0 equivalents, of pinacol.
  • This reaction is typically conducted at ambient temperature for about 12 to about 24 hours to afford the 2- methylphenylboronate ester, 2, in which both R a groups are preferably joined together to form -C(CH 3 ) 2 C(CH 3 ) 2 -.
  • the amino group of a 2-bromoaniline derivative, 3, is converted into the N-Boc derivative 4 by treating 3 with about 1.0 to about 1.5 equivalents of di-tert-butyl-dicarbonate.
  • this reaction is conducted at a temperature ranging from 25 °C to about 100°C for about 12 to 48 hours to afford the N-Boc-2-bromoaniline derivative 4.
  • the 2-methylphenylboronate ester, 2, and the N-Boc-2-bromoaniline derivative 4 can then be coupled to form the biphenyl derivative 5.
  • This reaction is typically conducted by contacting 4 with about 1.0 to about 1.2 equivalents of 2 and about 1.0 to about 1.2 equivalents of potassium carbonate in the presence of a pallidium catalyst, preferably tetrakis(triphenylphosphine)pallidium(0).
  • a pallidium catalyst preferably tetrakis(triphenylphosphine)pallidium(0).
  • this coupling reaction is conducted in a diluent, preferably 20% water/dioxane, under an inert atmosphere at a temperature ranging from about 50°C to about 100°C for about 6 to 24 hours.
  • Biphenyl derivative 5 is then readily converted into the 5,7-dihydro-6H- dibenz[b,d]azepin-6-one 6 by carboxylation ofthe 2-mefhyl group, followed by cyclization to form the e-caprolactam.
  • the carboxylation reaction is typically conducted by contacting 5 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 temperature ranging from about -100°C to about -20 °C for about 0.5 to 6 hours.
  • a suitable base such as sec-butyllithium, tert-butyllithium and the like
  • an inert diluent such as THF
  • 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 6, 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, 7.
  • this reaction is conducted by first contacting 6 with about 1.0 to 1.5 equivalents of a suitable base, such as sodium hydride, sodium bis(trimethysilyl)amide and the like, in an inert diluent, such as DMF, THF and the like, at a temperature ranging from about -78 °C to about 50°C for about 0.25 to about 6 hours.
  • a suitable base such as sodium hydride, sodium bis(trimethysilyl)amide and the like
  • an inert diluent such as DMF, THF and the like
  • the resulting anion is then treated in situ with an excess, preferably about 1.1 to about 2.0 equivalents, of an alkyl, substituted alkyl, cycloalkyl halide, etc., typically a chloride, bromide or iodide. This reaction is typically conducted at a temperature ranging from about
  • the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 7 is then oximated by contacting 7 with an excess, preferably with about 1.0 to 1.5 equivalents of a suitable base, such as sodium bis(trimethysilyl)amide and the like, in the presence of about 1.0 to about 2.0 equivalents of an alkyl nitrite.
  • a suitable base such as sodium bis(trimethysilyl)amide and the like
  • This reaction is typically conducted in an inert diluent, such as THF and the like, at a temperature ranging from about -10°C to about 20 °C for about 0.5 to about 6 hours to afford the 7-alkyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6- one derivative 8.
  • an inert diluent such as THF and the like
  • this reduction reaction is conducted by hydrogenating the oxime 8 in the presence of a catalyst, such as Raney nickel.
  • a catalyst such as Raney nickel.
  • This reaction is typically conducted under about 200 psi to about 600 psi of hydrogen at a temperature of about 70 °C to about 120°C for about 8 to 48 hours in a diluent, preferably a mixture of ethanol and ammonia (about 20:1).
  • the oxime may be reduced using 10% Pd/C and between about 30 to about 60 psi of hydrogen at a temperature 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 9 is generally purified using well known procedures, such as recrystallization and/or chromatography.
  • the reaction is stirred at a temperature 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, 10.
  • Displacement of iodide from 10 using an alkali metal azide then affords 5- azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 11.
  • this reaction is conducted by contacting 10 with about 1.1 to about 1.5 equivalents of sodium azide in an inert diluent, such as DMF, at a temperature ranging from about 0°C to about
  • the azido derivative 11 is then reduced to the corresponding amino derivative 12 using conventional procedures and reagents.
  • the azido group is preferably reduced by contacting 11 with an excess, preferably with about 3 equivalents, of triphenylphosphine in a diluent, preferably a mixture of THF and water.
  • This reduction reaction is typically conducted at a temperature ranging from about 0°C to about 50°C for about 12 to 48 hours to afford 5-amino-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one, 12.
  • the amino group of 12 is then protected or blocked using a conventional amino blocking group.
  • compound 12 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 temperature 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, 13.
  • Compound 13 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, 9.
  • the N-alkylation reaction is typically conducted by treating 13 with about 1.0 to 1.5 equivalents of an alkyl halide, a substituted alkyl halide or a cycloalkyl halide in the presence of about 1.0 to about 1.5 equivalents of a suitable base, such as cesium carbonate and the like.
  • This reaction is generally conducted in an inert diluent, such as DMF and the like, at a temperature ranging from about 25 °C to about 100°C for about 12 to about 48 hours.
  • alkyl, substituted 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, 1 -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, 9.
  • This deblocking reaction is typically conducted by treating the N-Boc compound 13 with anhydrous hydrogen chloride in an inert diluent, such as 1,4- dioxane, at a temperature 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 9 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, 9, can also be prepared via an azide transfer reaction as illustrated in Scheme 3.
  • the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 7 is then reacted with an azide transfer reagent to afford 5-azido-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 14.
  • this reaction is conducted by first contacting 7 with an excess, preferably with about 1.0 to 1.5 equivalents of a suitable base, such as lithium diisopropylamine and the like, in an inert diluent such as THF, at a temperature ranging from about -90°C to about -60°C for about 0.25 to about 2.0 hours.
  • the resulting anion is then treated with an excess, preferably with about 1.1 to about 1.2 equivalents, of an azide transfer reagent, such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide).
  • an azide transfer reagent such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide).
  • This reaction is typically conducted at a temperature ranging from about -90 °C to about -60 °C for about 0.25 to about 2.0 hours.
  • the reaction mixture is then typically treated with an excess of glacial acetic acid and the mixture is allowed to warm to ambient temperature and then heated at about 35 °C to about 50 °C for about 2 to 4 hours to afford the 5-azido-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative 14.
  • the aryl rings of 5-amino-7-alkyl-5,7-dihydro-6H- dibenz[b,d]aze ⁇ in-6-ones, 9, and related compounds may be partially or fully saturated by treatment with hydrogen in the presence of a hydrogention catalyst.
  • this reaction is conducted by treating 9 with hydrogen at a pressure of about 10 to about 100 psi in the presence of a catalyst, such as rhodium on carbon.
  • a catalyst such as rhodium on carbon.
  • This reaction is typically conducted at a temperature ranging from about 20°C to about 100°C for about 12 to 96 hours in a suitable diluent, such as ethyl acetate/acetic acid (1:1) and the like.
  • a suitable diluent such as ethyl acetate/acetic acid (1:1) and the like.
  • the ⁇ -amino group may be coupled with a mono- or dipeptide derivative (i.e., an amino acid derivative) to prepared compounds of formula I, wherein n is 1 or 2.
  • Scheme 4 illustrates the coupling of a representative polycyclic ⁇ -amino-e-caprolactam, i.e., 9, with a mono- or dipeptide derivative 15, wherein R 2 and n are as defined above and R 1' is an amino-blocking group.
  • the coupling of 5-amino-7-alkyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-ones, 9, with a mono- or dipeptide 15 affords the amide 16.
  • This reaction is typically conducted by reacting at least a stoichiometric amount ofthe amino compound 9 and the mono- or dipeptide 15 with a standard coupling reagent, typically in the presence of a trialkylamine, such as ethyldiisopropylamine, under conventional coupling reaction conditions.
  • a trialkylamine such as ethyldiisopropylamine
  • well-known coupling promoters such N-hydroxysuccinimide, 1- hydroxybenzotriazole and the like, may be employed in this reaction.
  • this coupling reaction is conducted at a temperature ranging from about 0°C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF, to afford the
  • Suitable coupling reagents include, by way of example, carbodiimides, such as ethyl-3-(3-dimethylamino)propylcarboiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and the like, and other well-known coupling reagents, such as N,N' -carbonyl diimidazole, 2-ethoxy-l-ethoxycarbonyl- 1,2-dihydroquinoline (EEDQ), benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and the like.
  • the coupling reagent may also be bound to a solid support. For example, a polymer supported form of EDC is described in Tetrahedron Letters 1993, 34(48), 7685.”
  • PEPC l-(3-(l-pyrrolidinyl)propyl-3-ethylcarbodiimide
  • PEPC l-(3-(l-pyrrolidinyl)propyl-3-ethylcarbodiimide
  • PEPC can be 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 reacting
  • the mono- or dipeptide derivatives employed in the coupling reaction are commercially available or can be prepared using conventional procedures and reagents from commercially available starting materials.
  • the mono- and dipeptide derivatives may be derived from naturally-occurring and non-natural amino acids.
  • suitable monopeptide derivatives include, by way of illustration, N-Boc-glycine, N-Boc-L-alanine, N-Boc-L-valine, N-Boc-L-leucine, N-Boc-L-isoleucine, N-Boc-tert-L-leucine, N-Boc-L-methionine, N-Boc-L-phenylalanine, N-Boc-L-phenylglycine, N-Boc-L-aspartic acid ⁇ -tert- butyl ester, N-Boc-L-glutamic acid ⁇ -tert-butyl ester, N-Boc- ⁇ e-Cbz-L-lysine, N- Boc-norleucine and the like.
  • Exemplary dipeptides include, for pu ⁇ oses of illustration only, ⁇ -Boc-glycinyl-L-alanine, ⁇ -Boc-L-alaninyl-L-alanine, ⁇ -Boc- L-alaninyl-L-valine, ⁇ -Boc-glycinyl-L-phenylglycine, ⁇ -Boc-L-phenylglycinyl-L- valine and the like.
  • the amino-blocking group R 1 is typically removed to reestablish the amino group.
  • the N-Boc group can be removed by treating 16 with anhydrous hydrogen chloride in an inert diluent, such as 1 ,4-dioxane. This reaction is typically conducted at a temperature ranging from about -10°C to about 15°C while hydrogen chloride gas is introduced into the reaction mixture, and then at a temperature ranging from about 10°C to about 60 °C for about 1 to about 24 hours.
  • Other amino-blocking groups can be removed using well-known art recognized procedures.
  • the deoxy derivatives of formula II can also be prepared using conventional reagents and procedures.
  • the synthesis of such compounds is described more fully in U.S. Patent Application Serial No. / , filed on even date herewith (Attorney Docket No. 002010-136) and entitled "Deoxyamino Acid Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting ⁇ -Amyloid Peptide Release, and/or its Synthesis by Use of Such Compounds," the disclosure of which is inco ⁇ orated herein by reference in its entirety, and in the Examples set forth below.
  • the polycyclic ⁇ -amino-e- caprolactams of this invention may contain one or more chiral centers.
  • such compounds will be prepared as a racemic mixture.
  • such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) ofthe polycyclic ⁇ -amino-e-caprolactams of formula I are included within the scope of this invention.
  • Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the compounds ofthe invention are useful as synthetic intermediates in the preparation of inhibitors of ⁇ -amyloid peptide release and/or its synthesis. Accordingly, the intermediates of this inventions have utility in the preparation of compounds which are useful, for example, for diagnosing and treating Alzheimer's disease in mammals, including humans.
  • Boc tert-butoxycarbonyl
  • HOBt 1-hydroxybenzotriazole hydrate
  • Hunig's base diisopropylethylamine
  • PEPC l-(3-(l-pyrrolidinyl)propyl)-3-ethylcarbodiimide
  • UV ultraviolet
  • Step A To a stirred solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one
  • Step B The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) from Step A was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture was cooled to 0°C in an ice bath.
  • Step C The resulting oxime from Step B was dissolved in EtOH/NH 3 (20: 1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at
  • the resolved di-/?-toluoyl-D-tartaric salt was then dissolved in EtOAc and saturated NaHCO 3 until pH 9-10 was reached.
  • the layers were separated and the organic layer was washed again with saturated NaHCO 3 , 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. This General Procedure can also be used to resolve other 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones.
  • a stream of anhydrous HCl gas was passed through a stirred solution ofthe N-Boc compound in 1,4-dioxane (0.03-0.09 M), chilled in a ice bath to ⁇ 10°C under ⁇ 2 , for 10-15 minutes.
  • the cooling bath removed and the solution was allowed to warm to room temperature with stirring for 2-24 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 ofthe residual dioxane). The residue was typically used without further purification.
  • Step B Synthesis of 7-Methyl-5-oximo-5,7-dihydro-6H- dihenz[b,d]azepin-6-one
  • the product from Step A (0.700 g, 3.14 mmol) was dissolved in 20 mL of toluene and treated with butyl nitrite (0.733 mL, 6.28 mmol).
  • the reaction temperature was lowered to 0°C and the solution was treated with KHMDS (9.42 mL, 0.5 M) under N 2 atmosphere. After stirring for 1 h the reaction was quenched with a saturated solution of NaHSO 4 , diluted with CH 2 C1 2 and separated.
  • the organic layer was dried over Na 2 SO 4 and the title compound purified by chromatography (SiO 2 , 98:2 CHCl 3 /MeOH) giving 0.59 g (80 %) as a colorless solid.
  • Step B Synthesis of 5- A7ido-5.7-dihvdro-6H-diben7[h.d]a7epin-6-
  • Step C Synthesis of 5-(N-Boc-AminoY- 7-Hihyrim-fiW 7W- dihen7[h,d]a7epin-6-one
  • the product from Step B was dissolved in THF/H 2 O and stirred at 23 °C for
  • Step B Synthesis of 5-Amino-7-(2-rnethylpropy1)-5,7-dihydro-6H- dihen7[h,d]azepin-6-one Hydrochloride
  • the product from Step A was deprotected using General Procedure E to provide the title compound as a slightly colored solid after neutralization and extraction with ethyl acetate, drying over Na 2 SO 4 and vacuum drying.
  • Step B Synthesis of 5-Amino-7-fmethoxycarhony1methyn- 1 7- dihyriro-6H-dihenz[b.d]azepin-6-one HyHror.h1r>ri e
  • Example 3 (0.2 g, 0.617 mmol) (Example 3) in DMF was treated with Cs 2 CO 3 (0.3 g, 0.925 mmol) and warmed to 60 °C. To this reaction mixture was added l-chloro-3,3- dimethyl-2-butanone (0.096 mL, 0.74 mmol) (Aldrich) and stirring was continued for 17 h. After cooling to 23 °C, the mixture was diluted with CH 2 C1 2 , washed with several portions of brine and dried over ⁇ a ⁇ O,,. The title compound was isolated as a colorless solid.
  • Step C Synthesis of 5- Amino-7-phenhuty1-5 r 7-dihydro-6H- dibenz[h,d]azepin-6-one
  • Step B Synthesis of 5-Hydroxyirmno-7-cyclopropy1rnethyl-S,7- dihydro-6H-dihenz[b,d]azepin-6-one
  • Step B Synthesis of ⁇ /-Boc-2-bromoaniline 2-Bromoaniline (1 eq.) (Aldrich) and di-tert-butyl-dicarbonate (1.1 eq.)
  • N-Boc-2-bromoaniline (1 eq.) (Step B), the arylboronate ester (1.1 eq.) (Step A), 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 D Synthesis of 9-Fh ⁇ oro-5 -dihydro-6H-riihen7[h,d]a7epin-6-
  • Step E Synthesis of 9-Flnoro-7-methy1-5,7-dihyHrn-r H- dihen7[b,d]azepin-6-one 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) (Step D), 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 provide the title compound. Physical data were as follows:
  • Step F Synthesis of 5- Amino-9-fluoro-7-methyl-5,7-dihydro-6H- riihenz[b,d]a7ftnin-6-one
  • Step E the title compound was prepared.
  • Step F Synthesis of 5- Amino- 10-fiuoro-7-methyl-5,7-dihydro-6H- dihen7.[b r d]a7epin-6-one
  • Step D Synthesis of 1 -Fluoro-5.7-dihydro-6H-dihen7[h,d]a7epin-6- one
  • Step F Synthesis of 5-Amino-l 3-fluoro-7-methy1-5,7-dihydro-6H- dihen7[b,d]a7e ⁇ in-fi-one Gen. Proc.
  • Example 1 Example 1 was dissolved in a 1:1 mixture of EtOAc/HOAc. Rhodium on carbon (5%) was added and the mixture was stirred at 60°C under 60 psi of hydrogen for 3 days. The reaction mixture was then filtered and the filtrate was concentrated to provide an oil which was purified by SCX-cation exchange chromatography to yield the title compound.
  • N-Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.305 g, 2.26 mmol), and 5-amino-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89 mmol) (Example 1). The temperature was lowered to 0°C and the reaction mixture was treated with EDC
  • Step B Synthesis of (S - and ⁇ -5-fL-A1aniny1)am ⁇ no-7-mt » rhy1-
  • Step A Synthesis of (S and ⁇ tt-5-(N-Boc-T ⁇ Va1iny1)ami ⁇ n-7- methy1-5,7-dihydrn-fiH-dihen7[b r d]azepin-fi-nne N-Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), DLPEA (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 1).
  • Step B Synthesis of fSV and fRV5-rL-Va1iny1Vaminn-7-methy1- ,7- dihydrn-6H-dibenz[b r d]azepin-6-one Hydroch1nriHe
  • each ofthe isomers from Step A was dissolved in dioxane and treated with excess HCl(g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
  • Step A Synthesis of (S)- and (R)-5-(V-Boc-L-tert-Leuciny1)-amino- 7-methy1-5 r 7-Hihydrn-6H-diben7[b.d]a7epin-6-nne
  • N-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), DLPEA (1.05 mL, 6.05 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
  • Example 1 (0.75 g, 2.75 mmol) (Example 1). The temperature was lowered to 0°C and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred for 17 hours under ⁇ 2 . The reaction mixture was then evaporated and the residue diluted with EtOAc/H 2 O, washed 1.0 N HCl, sat. NaHCO 3 , brine and dried over Na ⁇ O ⁇ The diastereomers were separated on a Chiralcel OD column using 10% IP A/heptane at 1.5 mL/minute.
  • Step B Synthesis of CSV and fRV5-fL-tert-T .eucinynamino-7- methyl-5 r 7-dihydro-6H-dibenz[b r d]azepin-fi-one Hydrochloride
  • each ofthe isomers from Step A was dissolved in dioxane and treated with excess HCl(g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
  • Step A Synthesis of 5-(/V-Boc-L-A1aniny1)amino-7-methy1-5,7-
  • Step B Synthesis nf 5-tT .- Alaninynaminn ⁇ -methyl-S -dihydrn-fiH- diben7[h,d]a7epin- ⁇ -one Hydrochloride
  • Step B Synthesis of - .-Valinynamino ⁇ -methyl- ⁇ -dihydrn-fiH- diben7[h,d]a7epin-fi-one Hydrochloride
  • Step B Synthesis of 5-(T -A1aniny1)amino-9-fluoro-7-methy1-5,7- dihydro-6H-dihen7[h r d]azepin-6-one Hydrochloride
  • Step A Synthesis of 5-(/V-Boc-L-A1aninyl nino-10-fluoro-7- methy1-5,7-dihydro-6H-diben7[b r d]a7epin-fi-one
  • Step B Synthesis of 5-(T ,- A1aniny11amino-1 -flnnrn-7-methy1-5, 7- dihydro-6H-dibenz[b.d3azepin-6-one Hydroch1nridR
  • Step B Synthesis of -(T -A1aninynamino-1 -f1nnrn-7-methy1-5,7- dihydro-fiH-dihen7[h.d]azepin-6-one Hydrochloride
  • Step A Synthesis of 5-(A/ ' -Boc-T.-A1aninynaminn-7- cvc1npropv1methv1-5_7-dihvdro-fiH-Hihen7[h r ]a7epin-fi-nne
  • Step B Synthesis of -n,- A1aninynamino-7-cyr.1npropy1methy1-5, 7- dihvdro-6H-dihenz[b.d1azepin-6-one Hydrorh1nriHe
  • Step B Synthesis of 5-(T,-A1aniny1)amino-7-phenhuty1-5,7-dihydro-
  • Step B Synthesis of 5-(L-Va1iny amino-7- y 1opropy1methy1- , 7- dihydro-6H-dibenz[b.d]azepin-6-one Hydrochloride
  • Step B Synthesis of 5-(L-Va1inynamino-7-phenh ⁇ ty1-5,7-Hihydrn- fiH-diben7[h,d]a7epin-6-one Hydrochloride
  • Step A Synthesis of -f ⁇ -Roc-T.-Valiny1 ⁇ a ⁇ ninn-7-he ⁇ y1- 7- dihydro-6H-dibenz[b r d]azepin-fi-one
  • Step B Synthesis of 5-(L-Va1iny1)amino-7-hexy1-5,7-di hydro-fiH- diben7[b,d]a7epin-6-one Hydrochloride
  • Step A Synthesis of 5-(V-Boc-L-Va1inynamino-9-flunrn-7-methyl- 5,7-dihydro-fiH-dihen7[b,d]azepin-fi-one
  • Step B Synthesis of -(T ,-Valinyl inn-9-flnoro-7-rnethy1-5,7- dihydro-6H-dihen7.[b r d]a7epin-6-one Hydrochloride
  • Step A Synthesis of 5-(V-Boc-L-Va1iny1)arnino-10-flnoro-7-methyl-
  • Step B Synthesis of 5-(T,-Va1invnamino-1 0-fh ⁇ oro-7-methy1-5,7- dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
  • Step B Synthesis of 5-fT.-Valinynamino-13-flnnro-7-methy1-5,7- dihydro-6H-dibenz[b r d]azepin-6-one Hydrochloride
  • Step D Synthesis of 9 r 1 -Difh ⁇ oro-5.7-dihydro-6H- dihen7[b t d]a7epin-fi-one
  • Example 33
  • Step D Synthesis of 1 r n-Difluoro-5,7-dihydro-fiH- dihen7[h,d]a7epin-6-one
  • Step F Synthesis of 5-Amino-10.1 3-difluoro-7-methyl-5.7-dihydro-
  • Step E Synthesis of 9-Oximo-5 ⁇ fi-Dihydro-4H-qnino[8 ⁇ 1 - ah][3]he ⁇ za7epin-8(9H)-one
  • Step F Synthesis of 9- A ⁇ nino-5,6-Dihydro-4H-q ⁇ ino[8, 1 - ah][3]hen7a7epin-8t9H)-one
  • the product from Step E (0.360 g, 1.29 mmol) was hydrogenated over Ra Ni (0.05 g) in EtOH (50 mL)/ NH 3 (anhydrous) (5.0 mL) at 100°C and 500 psi for 10 h.
  • the catalyst was removed by filtration and the resulting filtrate chromatographed over SiO 2 (CHCl 3 /MeOH, 98:2) yielding the titled compound as a colorless oil which solidified upon standing.
  • Step A Synthesis of 9-fN'-Boc-L- Alaninyllamino-S. ⁇ -Dihydro ⁇ H- quino[8 r 1-ah][3]ben7azepin-8(9H)-one Following General Procedure D and using N-Boc- Alanine (Aldrich) and
  • Step B Synthesis of 9-fN / -L-AlaninyPamino-5.6-dihydro-4H- quino[8,1-ab][3]ben7a7epin-8(9H)-one Hydrochloride Following General Procedure E and using the product from Step A, the title compound was prepared. Physical data were as follows:
  • Step B Synthesis of 1 ,3 4,7, 17, 12a-hexahvdropvrido[2.1 -b][3]ben7a7epin-
  • Step C Synthesis of 7-Oximo-l .3.4.7.12.1 ?.a-heyahydropyridn[2, 1 - h][3]henza7epin-6(2H)-one Following General Procedure A (Step B) and using 1,3,4,7,12,12a- hexahydropyrido[2,l-b][3]benzazepin-6(2H)-one (from Step B), the title compound was prepared.
  • Step D Synthesis of 7- Amino-1.3.4.7.12 r 12a-hexahydropyrido[?., 1 - h][3]henza7epin-6(2H)-one
  • Step B Synthesis of 4.5.6.7-Tetrahydro-3,7-methann-3H-3- benzazQnin-2(lH)-one Following General Procedure G and using N-chloroacetyl-3- phenylpiperidine, the title compound was prepared. Physical data were as follows:
  • Step C Synthesis of 1 -Oximo-4.5 r 6.7-tetrahydro-3,7-methano-3H-3- benzazonin-2( 1 H)-one Following General Procedure A (Step B) and using the product from Step
  • Step D Synthesis of 1 -Amino-4 r 5.fi.7-tet ⁇ ahydro-3 r 7-methano-3H-3- ben7a7onin-2(1 HVone Following General Procedure A (Step C) and using the product from Step
  • Step E Synthesis of 1-r ⁇ '-Boc-L-Alaninvnamino-4.5.6.7- tetrahydro-3,7-methano-3H-3-ben7a7onin-2(1 H)-one
  • reaction mixture was stirred for 5 minutes before 6.5 mL triethylamine (46.6 mmol, 6.0 eq) was added and the reaction warmed to room temperature for 10 minutes.
  • the reaction was quenched with 200 mL 0.1 N aqueous HCl, and this was extracted with 2 x 100 mL CH 2 C1 2 .
  • the combined organic layers were washed with 100 mL saturated NaHCO 3 followed by
  • Step B Synthesis of SS-
  • Step C Synthesis of 5S-(2S-aminopropyl)-arnino-7-rnethy1-5,7- dihydro-6H-dihenz[h,d]azepin-6-one HCl (g) was bubbled through a solution of 317 mg of 5S-[N'-(tert- butyloxycarbonyl)-2S-aminopropyl]amino-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one (0.8 mmol) (from Step B) in 30 mL dioxane for 15 minutes. This was stirred at room temperature for 17 hours at which time the solvent was removed in vacuo to yield 248 mg (94 %) of a white solid. This was used without further purification.
  • Step D Synthesis of 5S-[N 2S-hydroxy-3-methy1hutyryn-2S- aminopropy1]amino-7-methyl-5.7-dihydro-6H- dihen7[h,d]azepin-6-one
  • Example 39 Cellular Screen for the Detection of Inhibitors of ⁇ -Amyloid Production
  • compounds can be assayed for their ability to inhibit ⁇ -amyloid production in a cell line possessing the Swedish mutation.
  • This mutation is commonly called the Swedish mutation and the cells, designated as “293 751 SWE", are plated in Coming 96- well plates at 2-4 x 10 4 cells per well in Dulbecco's minimal essential media (Sigma, St. Louis, MO) plus 10% fetal bovine serum. Cell number is important in order to achieve ⁇ -amyloid ELISA results within the linear range ofthe assay (-0.2 to 2.5 ng per mL).
  • Drug stocks are prepared in 100% dimethyl sulfoxide such that at the final drug concentration used in the treatment, the concentration of dimethyl sulfoxide does not exceed 0.5% and, in fact, usually equals 0.1%.
  • the media are again removed and replaced with fresh drug containing media as above and cells are incubated for an additional two hours.
  • plates are centrifuged in a Beckman GPR at 1200 ⁇ m for five minutes at room temperature to pellet cellular debris from the conditioned media. From each well, 100 ⁇ L of conditioned media or appropriate dilutions thereof are transferred into an ELISA plate precoated with antibody 266 [P. Seubert, Nature (1992) 359:325-327 17 ] against amino acids 13-28 of ⁇ -amyloid peptide as described in International Patent Application Publication No. 94/10569 15 and stored at 4°C overnight.
  • An ELISA assay employing labeled antibody 3D6 [P.
  • Cytotoxic effects ofthe compounds are measured by a modification ofthe method of Hansen, et al. 18 .
  • To the cells remaining in the tissue culture plate is added 25 ⁇ L of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis, MO) stock solution (5 mg/mL) to a final concentration of 1 mg/mL.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • results ofthe ⁇ -amyloid peptide ELISA are fit to a standard curve and expressed as ng/mL ⁇ -amyloid peptide. In order to normalize for cytotoxicity, these results are divided by the MTT results and expressed as a percentage ofthe results from a drug free control. All results are the mean and standard deviation of at least six replicate assays.
  • test compounds are assayed for ⁇ -amyloid peptide production inhibition activity in cells using this assay.
  • the results of this assay can be used to demonstrate that the compounds prepared from the intermediates of this invention inhibit ⁇ -amyloid peptide production by at least 30% as compared to control when employed at 10 ⁇ g/mL.
  • This example illustrates how the compounds prepared from the intermediate compounds of this invention could be tested for in vivo suppression of ⁇ -amyloid release and/or synthesis.
  • 3 to 4 month old PDAPP mice are used [Games et al., (1995) Nature 373:523-527 19 ].
  • the compound is usually formulated at between 1 and 10 mg/mL. Because ofthe low solubility factors of the compounds, they may be formulated with various vehicles, such as com oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil; 2-hydroxypropyl- ⁇ -cyclodextrin (Research Biochemicals International, ⁇ atick MA); and carboxy-methyl-cellulose
  • mice are dosed subcutaneously with a 26 gauge needle and 3 hours later the animals are euthanized via CO 2 narcosis and blood is taken by cardiac puncture using a 1 cc 25G 5/8" tuberculin syringe/needle coated with solution of 0.5 M EDTA, pH 8.0.
  • the blood is placed in a Becton-Dickinson vacutainer tube containing EDTA and spun down for 15 minutes at 1500 xg at 5 °C.
  • the brains of the mice are then removed and the cortex and hippocampus are dissected out and placed on ice.
  • each brain region is homogenized in 10 volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher, Pittsburgh PA). The homogenates are gently rocked on a rotating platform for three to four hours at room temperature and stored at -20 ° C prior to quantitation of ⁇ -amyloid.
  • ice cold guanidine buffer 5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0
  • the brain homogenates are diluted 1 :10 with ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 ⁇ g/mL aprotinin, 5 mM EDTA, pH 8.0, 10 ⁇ g/mL leupeptin], thereby reducing the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 xg for 20 minutes at 4°C. Samples are further diluted, if necessary, to achieve an optimal range for the ELISA measurements by the addition of casein buffer with 0.5 M guanidine hydrochloride added.
  • the ⁇ -amyloid standards (1-40 or 1-42 amino acids) were prepared such that the final composition equaled 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).
  • the total ⁇ -amyloid sandwich ELISA quantitating both ⁇ -amyloid (aa 1- 40) and ⁇ -amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) to ⁇ - amyloid.
  • the capture antibody, 266 [P. Seubert, Nature (1992) 359:325-327 17 ], is specific to amino acids 13 - 28 of ⁇ -amyloid.
  • the antibody 3D6 [Johnson- Wood et al., RN S USA (1997) 94:1550-1555 20 ], which is specific to amino acids 1 - 5 of ⁇ - amyloid, is biotinylated and served as the reporter antibody in the assay.
  • the 3D6 biotinylation procedure employs the manufacturer's (Pierce, Rockford IL) protocol for NHS-biotin labeling of immunoglobulins except that 100 mM sodium bicarbonate, pH 8.5 buffer is used.
  • the 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP but detects only ⁇ -amyloid species with an amino terminal aspartic acid.
  • the assay has a lower limit of sensitivity of -50 pg/mL (11 pM) and shows no cross-reactivity to the endogenous murine ⁇ -amyloid peptide at concentrations up to 1 ng/mL.
  • the configuration ofthe sandwich ELISA quantitating the level of ⁇ - amyloid (aa 1 -42) employs the mAb 2 IF 12 [Johnson- Wood et al., PNAS USA
  • Biotinylated 3D6 is also the reporter antibody in this assay which has a lower limit of sensitivity of -125 pg/mL (28 pM).
  • the 266 and 2 IF 12 capture mAbs are coated at 10 ⁇ g/mL into 96 well immunoassay plates (Costar, Cambidge MA) overnight at room temperature. The plates are then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature, then stored desiccated at 4°C until use. The plates are rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use. The samples and standards are added to the plates and incubated overnight at 4°C. The plates are washed ⁇ 3 times with wash buffer between each step ofthe assay.
  • wash buffer Tris-buffered saline, 0.05% Tween 20
  • biotinylated 3D6 diluted to 0.5 ⁇ g/mL in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is incubated in the well for 1 hour at room temperature.
  • Avidin-HRP Vector, Burlingame CA
  • diluted 1 :4000 in casein incubation buffer is added to the wells for 1 hour at room temperature.
  • the colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA) is added and allowed to react for 15 minutes, after which the enzymatic reaction is stopped with addition of 2 N H 2 SO 4 .
  • Reaction product is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) measuring the difference in absorbance at 450 nm and 650 nm. 2. Blood Assay
  • the EDTA plasma is diluted 1 : 1 in specimen diluent (0.2 gm/1 sodium phosphate»H 2 O (monobasic), 2.16 gm/1 sodium phosphate »7H 2 O (dibasic), 0.5gm/l thimerosal, 8.5 gm 1 sodium chloride, 0.5 mL Triton X-405, 6.0 g/1 globulin-free bovine serum albumin; and water).
  • the samples and standards in specimen diluent are assayed using the total ⁇ -amyloid assay (266 caprure/3D6 reporter) described above for the brain assay except the specimen diluent was used instead ofthe casein diluents described.
  • Formulations other than those described above can also be used for oral delivery and intravenous delivery to a mammal.
  • the compound can be mixed with either 100% com oil or, alternatively, in a solution comtaining 80% com oil, 19.5% oleic acid and 0.5% labrafil.
  • the compound can be mixed with the above solutions in concentrations ranging from 1 mg/mL to 10 mg/mL.
  • the compound in solution is preferably administered orally to the mammal at a dose volume of 5 mL/kg of body weight.
  • the compound is preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% saline.
  • the compound is preferably mixed with the above solution in concentrations ranging from 0.25 mg/mL to 5 mg/mL.
  • the compound in solution is preferably administered by IV to the mammal at a dose volume of 2 mL/kg of body weight.

Abstract

Disclosed are polycyclic alpha -amino- ELEMENT -caprolactams and related compounds which are useful as synthetic intermediates in the preparation of inhibitors of beta -amyloid peptide release and/or its synthesis.

Description

POLYCYCLIC α-AMINO-e-CAPROLACTAMS AND RELATED COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Patent Application No. 08/996,422, filed December 22, 1997 (Attorney Docket No. 002010-062) and entitled "Cycloalkyl, Lactam, Lactone and Related Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting β-Amyloid Peptide
Release and/or its Synthesis by Use of Such Compounds", which application claims the benefit of U.S. Provisional Application No. 60/064,851, which was converted pursuant to 37 C.F.R. § 1.53(b)(2)(ii) from U.S. Patent Application No. 08/780,025, filed December 23, 1996. Each of these applications are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
1. Field ofthe Invention
This invention relates to polycyclic α-amino-e-caprolactams and related compounds which are useful as synthetic intermediates in the preparation of inhibitors of β-amyloid peptide release and/or its synthesis.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
i Glenner, et al., Biochem. Biophys. Res. Commun. (1984) 120:885- 890. 2 U.S. Patent No. 4,666,829, issued May 19, 1987, to G. G. Glenner et al., entitled "Polypeptide Marker for Alzheimer's Disease and Its Use for Diagnosis." 3 Selkoe, Neuron. (1991) 6:487-498.
4 Goate, et al, Nature (1990) 349:704-706.
5 Chartier Harlan, et al., Nature (1989) 353:844-846.
6 Murrell, et al, Science (1991) 254:97-99.
7 Mullan, et al, Nature Genet. (1992) 1:345-347.
8 T. W. Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York (1991).
9 R. F. C. Brown et al., Tetrahedron Letters 1971, 8, 667-670.
10 A. O. King et al., J. Org. Chem. 1993, 58, 3384-3386.
11 Tetrahedron Letters 1993, 34(48), 7685. n U.S. Provisional Application Serial No. 60/019,790, filed June 14,
1996.
13 U.S. Patent Application Serial No. 08/996,442, filed December 19, 1997.
1 R. D. Clark et al., Tetrahedron 1993, 49(7), 1351-1356.
15 Schenk, et al., International Patent Application Publication No. WΟ 94/10569, "Methods and Compositions for the Detection of Soluble β-Amyloid Peptide", published 11 May 1994.
16 Citron, et al., Nature (1992) 360:672-674.
17 P. Seubert, Nature (1992) 359:325-327.
18 Hansen, et al, J. Immun. Meth.(\9S9) 119:203-210.
19 Games et al., Nature (1995) 373:523-527. 20 Johnson- Wood et al, PNAS USA (1997) 94:1550-1555.
All ofthe above publications, patents and patent applications are herein incoφorated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incoφorated by reference in its entirety.
3. State ofthe Art Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) 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. 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 ofthe Dutch Type (HCHWA-D). At present, 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.
The principal chemical constituent ofthe amyloid plaques and vascular amyloid deposits (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 β-amyloid peptide (βAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No.
4,666,8292.
Molecular biological and protein chemical analyses have shown that the β- 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. Knowledge of the structure ofthe gene encoding APP has demonstrated that β-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the β-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls ofthe cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of β- amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595- methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 ofthe 770-amino acid isoform of APP has been identified as the cause ofthe β-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its β-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other β-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment ofthe disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting β-amyloid peptide release and/or its synthesis in vivo.
Compounds which inhibit β-amyloid peptide release and/or its synthesis in vivo are disclosed in U.S. Patent Application Serial No. 08/996,422, filed December 22, 1997 (Attorney Docket No. 002010-062) and entitled "Cycloalkyl, Lactam, Lactone and Related Compounds, Pharmaceutical Compositions
Comprising Same, and Methods for Inhibiting β-Amyloid Peptide Release, and/or its Synthesis by Use of Such Compounds," the disclosure of which is incoφorated herein by reference in its entirety. The present invention is directed to intermediates useful in the preparation of such compounds.
SUMMARY OF THE INVENTION This invention is directed to the discovery of a class of intermediates which are useful in the preparation the cycloalkyl, lactam, lactone and related compounds described in U.S. Patent Application Serial No. 08/996,422, which compounds inhibit β-amyloid peptide release and/or its synthesis. Accordingly, in one of its composition aspects, this invention is directed to a compound of formula I:
wherein
Wis a substituted e-caprolactam selected from the group consisting of:
wherein ring A, together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring B, together with the atoms of the e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring C, together with the atoms ofthe e-caprolactam to which it is attached, forms a heteroaryl or heterocyclic ring;
R1 is selected from the group consisting of hydrogen and an amino- blocking group; each R2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl and heterocyclic;
R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; m is an integer from 0 to 2; n is an integer from 0 to 2; and salts thereof.
Preferably, R1 is hydrogen, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, l-( -adamantyl)-l-methylethoxycarbonyl (Acm), allyloxycarbonyl (Aloe), benzyloxymethyl (Bom), 2- -biphenylisopropyloxycarbonyl (Bpoc), tert- butyldimethylsilyl (Bsi), benzoyl (Bz), benzyl (Bn), 9-fluorenyl- methyloxycarbonyl (Fmoc), 4-methylbenzyl, 4-methoxybenzyl, 2- nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmob), trityl (Trt), and the like. More preferably, R1 is hydrogen or tert-butoxycarbonyl (Boc). When n is one or two, each R2 is preferably (and independently for n = 2) selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
Particularly preferred R2 substituents include, by way of example, hydrogen, methyl, ethyl, rt-propyl, isopropyl, H-butyl, isobutyl, sec-butyl, tert- butyl, -CH2CH(CH2CH3)2, 2-methyl-«-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, wo-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3 -yl, ?-(phenyl)phenyl, ø-fluorophenyl, m-fluorophenyl, -fluorophenyl, m -methoxyphenyl, /?-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, /?-hydroxybenzyl, -nitrobenzyl, m-trifluoromethylphenyl, ?-(CH3)2NCH2CH2CH2O-benzyl, 7-(CH3)3COC(O)CH2O-benzyl, -(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N- moφholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl,
-CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2( 1 -methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(O)O-t-butyl, -CH2- C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(O-t-butyl)CH3, -
CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., 1- naphthyl and 2-naphthyl), -CH2-(4-moφholinyl), -(4-moφholinyl-CH2CH2O)- 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, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, - CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like.
Preferably, R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl. Particularly preferred R3 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
When present, R4 is preferably alkyl or substituted alkyl.
Preferably, m is 0 or 1. More preferably, m is 0.
W is preferably a substituted e-caprolactam selected from the group consisting of:
wherein A, B, R , R and m are as defined herein.
More preferably, Wx's a substituted e-caprolactam ofthe formula:
wherein A, B, and R3 are as defined herein. In separate preferred embodiments, this invention is also directed to compounds of formula I wherein W is independently selected from each ofthe substituted e-caprolactams illustrated above.
Rings A and B may be the same or different and are preferably independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic. More preferably, rings A and B are independently selected from the group consisting of aryl and cycloalkyl. Still more preferably, rings A and B are independently aryl.
Particularly preferred A and B rings include, by way of example, phenyl, substituted phenyl, including fluoro-substituted phenyl, cyclohexyl and the like. When the A and B rings are fused to one another, they preferably form a naphthyl or sustituted naphthyl ring.
Particularly preferred C rings include, by way of example, pyrrolidinyl, piperidinyl, moφholino and the like.
In one preferred embodiment of this invention, Wis a substituted e- caprolactam ofthe formula:
wherein each R5 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; each R6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
-SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl;
R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; p is an integer from 0 to 4; q is an integer from 0 to 4; and salts thereof.
Preferably, R5 and R6 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
More preferably, when present, R5 and R6 are fluoro.
R7 is preferably selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. More preferably, R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
Particularly preferred R7 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like. In another preferred embodiment of this invention, Wis a substituted e- caprolactam of the formula:
wherein R5, R6, and ? are as defined herein and r is an integer from 0 to 3; and salts thereof.
In still another preferred embodiment of this invention, Wis a substituted e-caprolactam ofthe formula:
wherein R5, and p are as defined herein; and salts thereof.
In yet another preferred embodiment of this invention, Wis a substituted e- caprolactam of the formula:
wherein R5 and/? are as defined herein; and salts thereof.
Preferred substituted e-caprolactams (i.e., W) include, by way of example, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-(2-methylpropyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-(methoxyacetyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-(3,3-dimethylbutan-2-onyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-yl, 7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one- yl, 7-cyclopropymethyl-5 ,7-dihydro-6H-dibenz[b,d] azepin-6-one-yl, 7-(2 ' ,2 ' ,2 ' - trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-yl, 7-cyclohexyl-5,7- dihydro-6H-dibenz[b,d] azepin-6-one-5 -yl, 7-hexyl-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 9-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 13-fluoro-7-rnethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl and 7-methyl-l,2,3,4,5,7-hexahydro-6H- dicyclohexyl[b,d]azepin-6-one-5-yl.
Compounds of this invention include, by way of example, the following: 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-amino)-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-amino)-7-(methoxycarbonymethyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-amino-7-(methoxycarbonylmethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(N-Boc-amino)-7-(3 ,3-dimethyl-butanonyl)-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-(2 ' ,2 ' ,2 ' -trifluoroethyl)-5 ,7-dihydro-6H-dibenz[b,d] azepin-6- one
5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-methyl-l,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6- one
5-(N-Boc-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-(L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(L-valinyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-tert-leucinyl)amino-7-methyl-5,7-dihydro-6H- dibenz[b ,d] azepin-6-one
5-(L-tert-leucinyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(N-Boc-L-alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d] azepin-6-one 5-(L-alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
6-one
5-(N-Boc-L-alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-(N-Boc-L-alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-alaninyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-alaninyl)amino-7-phenbutyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d] azepin-6-one
5-(L-valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-(L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(L-valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-valinyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one 5-(N-Boc-L-valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d] azepin-6-one
5-(L-valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-(N-Boc-L-valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-(L-valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-amino-9,13-difluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5 -amino- 10,13 -difluoro-7-methyl-5 ,7-dihydro-6H-dibenz[b,d] azepin-6-one
5-aminohexahydropyrido[a]benz[d]azepin-6-one
9-amino-5,6-Dihydro-4H-quino[8, 1 -ab] [3]benzazepin-8(9H)-one
9-(N'-Boc-L-alaninyl)amino-5,6-Dihydro-4H-quino[8,l-ab][3]benzazepin- 8(9H)-one
9-(N'-L-alaninyl)amino-5,6-dihydro-4H-quino[8,l-ab][3]benzazepin-
8(9H)-one
7-amino- 1 ,3 ,4,7, 12, 12a-hexahydropyrido [2, 1 -b] [3 ]benzazepin-6(2H)-one l-amino-4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-2(lH)-one l-(N'-Boc-L-alaninyl)amino-4,5,6,7-tetrahydro-3,7-methano-3H-3- benzazonin-2( 1 H)-one l-(N'-L-alaninyl)amino-4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-
2(lH)-one and salts thereof.
Preferred compounds include those defined by the formulas as set forth in Tables I, II, III, IN and V below and salts thereof.
Table I
Boc = tert-butoxycarbonyl = (CH3)3COC(O)-
Table II
Table III
Table IV
Table V
10
15
Boc = tert-butoxycarbonyl = (CH3)3COC(O)-
20 Deoxy derivatives ofthe compounds described in U.S. Patent Application Serial No. 08/996,422 have also been discovered to inhibit β-amyloid peptide release and/or its synthesis in vivo. Such compounds are disclosed in U.S. Patent
Application Serial No. __/__, , filed on even date herewith (Attorney Docket No. 002010-136) and entitled "Deoxyamino Acid Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting β-Amyloid Peptide Release, and or its Synthesis by Use of Such Compounds," the disclosure of which is incoφorated herein by reference in its entirety.
Accordingly, in another of its composition aspects, this invention is directed a compound of formula II:
wherein
W is a substituted e-caprolactam selected from the group consisting of:
wherein ring A, together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring B, together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring C, together with the atoms of the e-caprolactam to which it is attached, forms a heteroaryl or heterocyclic ring;
R1 is selected from the group consisting of hydrogen and an amino- blocking group;
Y is represented by the formula:
provided that at least one Y is -(CHR2)a-NH-; each R2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl and heterocyclic;
R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; a is an integer from 2 to 6; m is an integer from 0 to 2; n is an integer from 0 to 2; and salts thereof.
When Y in formula II is the group -(CHR2)a-NH-, the integer a is preferably 2, 3 or 4, more preferably 2 or 4, and still more preferably a is equal to 2. In a preferred embodiment, Y has the formula -CHR -CH,-NH-, where R2 is as defined herein. The preferred embodiments for R1, R2, R3, R4, A, B, C, W, m, n and the like in formula II are the same as those described herein for compounds of formula I.
Compounds of this invention include, by way of example, the following:
5-[N'-Boc-2S-aminopropyl]amino-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(2S-aminopropyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
and salts thereof.
Preferred compounds include those defined by the formulas as set forth in Tables VI below and salts thereof.
Table VI
Boc = tert-butoxycarbonyl = (CH3)3COC(O)- DETAILED DESCRIPTION OF THE INVENTION
For puφoses of describing this invention in all its aspects, the following terms have the followings meanings unless otherwise indicated. All other terms have their conventional art-recognized meanings.
Definitions
The term "β-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 ofthe protein described by Glenner, et al.1 including mutations and post- translational modifications ofthe normal β-amyloid peptide. In whatever form, the β-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the β-amyloid precursor protein (APP). Its 43-amino acid sequence is:
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr
11
Glu Val His His Gin Lys Leu Val Phe Phe
21
Ala Glu Asp Val Gly Ser Asn Lys Gly Ala
21 lie He Gly Leu Met Val Gly Gly Val Val
41
He Ala Thr (SEQ ID NO: 1) or a sequence which is substantially homologous thereto.
"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, «-propyl, zsσ-propyl, «-butyl, wo-butyl, n-hexyl, decyl and the like. "Substituted alkyl" refers to an alkyl group, preferably of from 1 to 20 carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, - SO2-aryl, and -SO2 -heteroaryl.
"Alkylene" refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.
"Substituted alkylene" refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, - SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2- heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused cycloalkyl groups contain from 1 to 3 fused ring structures.
"Alkenylene" refers to divalent alkenylene groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH2CH=CH- and -C(CH3)=CH-) and the like.
"Substituted alkenylene" refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, - SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2- heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents 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 8 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
"Alkoxy" refers to the group "alkyl-O-". Preferred alkoxy groups include, by way of example, methoxy, ethoxy, π-propoxy, wo-propoxy, n-butoxy, tert-butoxy, sec-butoxy, «-pentoxy, H-hexoxy, 1,2-dimethylbutoxy, and the like.
"Substituted alkoxy" refers to the group "substituted alkyl-O-" where substituted alkyl is as defined above.
"Alkylalkoxy" refers to the group "-alkylene-O-alkyl" which includes by way of example, methylenemethoxy (-CH2OCH3), ethylenemethoxy (-CH2CH2OCH3), n-propylene-wo-propoxy (-CH2CH2CH2OCH(CH3)2), methylene- t-butoxy (-CH2-O-C(CH3)3) and the like. "Alkylthioalkoxy" refers to the group "-alkylene-S-alkyl" which includes by way of example, methylenethiomethoxy (-CH2SCH3), ethylenethiomethoxy (-CH2CH2SCH3), «-propylene-thio-t5o-propoxy (-CH2CH2CH2SCH(CH3)2), methylenethio-t-butoxy (-CH2SC(CH3)3) and the like.
"Alkenyl" refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), tso-propenyl (-C(CH3)=CH2), and the like.
"Substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2- substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.
"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH) and the like.
"Substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2- substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.
"Acyl" refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, substituted 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, substituted alkyl, aryl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group, wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Amino" refers to the group -NH2.
"Substituted amino" refers to the group -N(R)2 where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted 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 substituted amino groups include, by way of illustration, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di- heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like.
The term "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 predetermined chemical reaction or series of reactions. After completion ofthe 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, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, 1-(1 '- adamantyl)-l-methylethoxycarbonyl (Acm), allyloxycarbonyl (Aloe), benzyloxymethyl (Bom), 2- ?-biphenylisopropyloxycarbonyl (Bpoc), tert- butyldimethylsilyl (Bsi), benzoyl (Bz), benzyl (Bn), 9-fluorenyl- methyloxycarbonyl (Fmoc), 4-methylbenzyl, 4-methoxybenzyl, 2- nitrophenylsulfenyl (Nps), 3-nitro-2-pyridinesulfenyl (NPys), trifluoroacetyl (Tfa), 2,4,6-trimethoxybenzyl (Tmob), trityl (Trt), and the like. If desired, 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, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Aminoacyloxy" refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted 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.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl and trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
"Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
"Carboxyalkyl" refers to the groups "-C(O)Oalkyl" and "-C(O)O- substituted alkyl" where alkyl is as defined above.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
"Substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2- substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.
"Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
"Substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, - SO2-aryl, and -SO2-heteroaryl.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
"Heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
-SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl,
-SO2-heteroaryl and trihalomethyl. Such heteroaryl groups can have a single ring
(e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
"Heteroaryloxy" refers to the group "-O-heteroaryl".
"Heterocycle" or "heterocyclic" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, - SO2-aryl, and -SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocychcs include moφholino, piperidinyl, and the like.
Examples of 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, moφholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.
"Heterocyclooxy" refers to the group "-O-heterocycle".
"Keto" or "oxo" refers to the group "=O".
"Oxyacylamino" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
"Thiol" refers to the group -SH.
"Thioalkoxy" refers to the group -S-alkyl.
"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 substituted aryl groups also defined above.
"Thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
"Thioketo" refers to the group "=S".
As to any ofthe above defined groups which contain 1 or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and or synthetically non-feasible.
The term "5,7-dihydro-6H-dibenz[b,d]azepin-6-one" refers to a polycyclic e-caprolactam ring system having the formula:
wherein, for nomenclature puφoses, the atoms and bonds are numbered and lettered, respectively, as shown.
The term "5,6-dihydro-4H-quino[8,l-ab][3]benzazepin-8(9H)-one" refers to a polycyclic e-caprolactam ring system having the formula:
wherein, for nomenclature puφoses, the atoms and bonds are numbered and lettered, respectively, as shown. The term " 1 ,3,4,7, 12, 12a-hexahydropyrido[2, 1 -b][3]benzazepin-6(2H)-one" refers to a polycyclic e-caprolactam ring system having the formula:
wherein, for nomenclature puφoses, the atoms and bonds are numbered and lettered, respectively, as shown.
The term "4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin-2(lH)-one" refers to a polycyclic e-caprolactam ring system having the formula:
wherein, for nomenclature puφoses, the atoms and bonds are numbered and lettered, respectively, as shown.
The term "salt(s)" refers to salts of a compound of formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, thiol, carboxyl or other protectable functional group ofthe compound prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical and/or enzymatic steps to reestablish the unprotected functional group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, tert- butyldiphenylsilyl 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 ofthe product.
Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, tert-butyl, etc. which can be removed by mild hydrolysis conditions compatible with the nature of the product.
Compound Preparation
The polycyclic α-amino-e-caprolactarns and related compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991,8 and references cited therein.
In a preferred method of synthesis, the compound of this invention are prepared by first aminating a polycyclic e-caprolactam to provide a polycyclic α- amino-e-caprolactam. If desired, the amino group ofthe polycyclic α-amino-e- caprolactam can then be coupled with a mono- or diamino acid derivative to provide compounds of formula I wherein n is 1 or 2.
The polycyclic e-caprolactams employed as starting materials in this invention are either commercially available or can be prepared from commercially available materials using conventional procedures and reagents. For example, 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, 667-6709 and references cited therein.
Additionally, the synthesis of a representative polycyclic e-caprolactam, i.e., a 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, is illustrated in Scheme 1. As will be readily apparent to those of ordinary skill in the art, the synthetic procedure illustrated in Scheme 1 and the reaction conditions described below can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other polycyclic e-caprolactams.
Scheme 1
As shown in Scheme 1, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivatives, 6, wherein R5, R6, p and q are as defined above, can be readily prepared in several steps from a 2-bromotoluene derivative 1 and a 2-bromoaniline derivative 4. In this synthetic procedure, the 2-bromotoluene derivative, 1, is first converted into the corresponding 2-methylphenylboronate ester, 2. This reaction is typically conducted by treating 1 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 temperature ranging from about -80 °C to about -60 °C for about 0.25 to about 1 hour. The resulting lithium anion is then treated in situ with an excess, preferably 1.5 equivalents, of a trialkylborate, such as trimethylborate. This reaction is initially conducted at -80 °C to about -60 °C and then allowed to warm to about 0°C to about 30°C for about 0.5 to about 3 hours. The resulting methyl boronate ester is typically not isolated, but is preferably converted in situ into the pinacol ester by treating the reaction mixture with an excess, preferably about 2.0 equivalents, of pinacol. This reaction is typically conducted at ambient temperature for about 12 to about 24 hours to afford the 2- methylphenylboronate ester, 2, in which both Ra groups are preferably joined together to form -C(CH3)2C(CH3)2-.
In a separate reaction, the amino group of a 2-bromoaniline derivative, 3, is converted into the N-Boc derivative 4 by treating 3 with about 1.0 to about 1.5 equivalents of di-tert-butyl-dicarbonate. Typically, this reaction is conducted at a temperature ranging from 25 °C to about 100°C for about 12 to 48 hours to afford the N-Boc-2-bromoaniline derivative 4.
As further illustrated in Scheme 1, the 2-methylphenylboronate ester, 2, and the N-Boc-2-bromoaniline derivative 4 can then be coupled to form the biphenyl derivative 5. This reaction is typically conducted by contacting 4 with about 1.0 to about 1.2 equivalents of 2 and about 1.0 to about 1.2 equivalents of potassium carbonate in the presence of a pallidium catalyst, preferably tetrakis(triphenylphosphine)pallidium(0). Generally, this coupling reaction is conducted in a diluent, preferably 20% water/dioxane, under an inert atmosphere at a temperature ranging from about 50°C to about 100°C for about 6 to 24 hours.
Biphenyl derivative 5 is then readily converted into the 5,7-dihydro-6H- dibenz[b,d]azepin-6-one 6 by carboxylation ofthe 2-mefhyl group, followed by cyclization to form the e-caprolactam. The carboxylation reaction is typically conducted by contacting 5 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 temperature ranging from about -100°C to about -20 °C for about 0.5 to 6 hours. The resulting dianion is then treated with excess anhydrous carbon dioxide to form the carboxylate. Treatment ofthe carboxylate with excess hydrogen chloride in a suitable diluent, such as methanol, at a temperature ranging from about 25°C to about 100°C then affords the 5,7-dihydro-6H- dibenz[b,d]azepin-6-one 6. Various other polycyclic e-caprolactam compounds can be prepared by routine modifications ofthe above described procedures.
Preferred synthetic procedures for aminating a representative polycyclic e- caprolactam compound are illustrated in Scheme 2. It will be readily apparent to those of ordinary skill in the art that the synthetic procedure illustrated in Scheme 2 and the following reaction conditions can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other polycyclic α- amino-e-caprolactams of this invention.
Scheme 2
As shown in Scheme 2, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 6, 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, 7. Typically, this reaction is conducted by first contacting 6 with about 1.0 to 1.5 equivalents of a suitable base, such as sodium hydride, sodium bis(trimethysilyl)amide and the like, in an inert diluent, such as DMF, THF and the like, at a temperature ranging from about -78 °C to about 50°C for about 0.25 to about 6 hours. The resulting anion is then treated in situ with an excess, preferably about 1.1 to about 2.0 equivalents, of an alkyl, substituted alkyl, cycloalkyl halide, etc., typically a chloride, bromide or iodide. This reaction is typically conducted at a temperature 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, 7.
The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 7 is then oximated by contacting 7 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. Suitable alkyl nitrites for use in this reaction include, by way of example, butyl nitrite, isoamyl nitrite and the like. This reaction is typically conducted in an inert diluent, such as THF and the like, at a temperature ranging from about -10°C to about 20 °C for about 0.5 to about 6 hours to afford the 7-alkyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6- one derivative 8.
Reduction of 8 using conventional reagents and conditions then affords the 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 9. Preferably, this reduction reaction is conducted by hydrogenating the oxime 8 in the presence of a catalyst, such as Raney nickel. This reaction is typically conducted under about 200 psi to about 600 psi of hydrogen at a temperature of about 70 °C to about 120°C for about 8 to 48 hours in a diluent, preferably a mixture of ethanol and ammonia (about 20:1). Alternatively, in another preferred procedure, the oxime may be reduced using 10% Pd/C and between about 30 to about 60 psi of hydrogen at a temperature 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 9 is generally purified using well known procedures, such as recrystallization and/or chromatography.
Alternatively, 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones,
9, can be prepared by first forming the 5-iodo derivative 10 of 5,7-dihydro-6H- dibenz[b,d]azepin-6-one, 6. This reaction is typically conducted as described in A. O. King et al.10 by treating 6 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 temperature 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 (I2). Typically, after addition ofthe iodide, the reaction is stirred at a temperature 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, 10.
Displacement of iodide from 10 using an alkali metal azide then affords 5- azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 11. Typically, this reaction is conducted by contacting 10 with about 1.1 to about 1.5 equivalents of sodium azide in an inert diluent, such as DMF, at a temperature ranging from about 0°C to about
50 °C for about 12 to about 48 hours.
The azido derivative 11 is then reduced to the corresponding amino derivative 12 using conventional procedures and reagents. For example, the azido group is preferably reduced by contacting 11 with an excess, preferably with about 3 equivalents, of triphenylphosphine in a diluent, preferably a mixture of THF and water. This reduction reaction is typically conducted at a temperature ranging from about 0°C to about 50°C for about 12 to 48 hours to afford 5-amino-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one, 12.
The amino group of 12 is then protected or blocked using a conventional amino blocking group. Preferably, compound 12 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 temperature 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, 13.
Compound 13 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, 9. The N-alkylation reaction is typically conducted by treating 13 with about 1.0 to 1.5 equivalents of an alkyl halide, a substituted alkyl halide or a cycloalkyl halide in the presence of about 1.0 to about 1.5 equivalents of a suitable base, such as cesium carbonate and the like. This reaction is generally conducted in an inert diluent, such as DMF and the like, at a temperature ranging from about 25 °C to about 100°C for about 12 to about 48 hours.
Representative alkyl, substituted 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, 1 -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, 9. This deblocking reaction is typically conducted by treating the N-Boc compound 13 with anhydrous hydrogen chloride in an inert diluent, such as 1,4- dioxane, at a temperature 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 9 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, 9, can also be prepared via an azide transfer reaction as illustrated in Scheme 3.
Scheme 3
As shown in Scheme 3, 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, 6, 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, 7.
The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 7 is then reacted with an azide transfer reagent to afford 5-azido-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 14. Typically, this reaction is conducted by first contacting 7 with an excess, preferably with about 1.0 to 1.5 equivalents of a suitable base, such as lithium diisopropylamine and the like, in an inert diluent such as THF, at a temperature ranging from about -90°C to about -60°C for about 0.25 to about 2.0 hours. The resulting anion is then treated with an excess, preferably with about 1.1 to about 1.2 equivalents, of an azide transfer reagent, such as 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide). This reaction is typically conducted at a temperature ranging from about -90 °C to about -60 °C for about 0.25 to about 2.0 hours. The reaction mixture is then typically treated with an excess of glacial acetic acid and the mixture is allowed to warm to ambient temperature and then heated at about 35 °C to about 50 °C for about 2 to 4 hours to afford the 5-azido-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative 14.
Reduction of 14 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 9.
If desired, the aryl rings of 5-amino-7-alkyl-5,7-dihydro-6H- dibenz[b,d]azeρin-6-ones, 9, and related compounds may be partially or fully saturated by treatment with hydrogen in the presence of a hydrogention catalyst.
Typically, this reaction is conducted by treating 9 with hydrogen at a pressure of about 10 to about 100 psi in the presence of a catalyst, such as rhodium on carbon.
This reaction is typically conducted at a temperature ranging from about 20°C to about 100°C for about 12 to 96 hours in a suitable diluent, such as ethyl acetate/acetic acid (1:1) and the like.
After preparing the polycyclic α-amino-e-caprolactam, the α-amino group may be coupled with a mono- or dipeptide derivative (i.e., an amino acid derivative) to prepared compounds of formula I, wherein n is 1 or 2. Scheme 4 illustrates the coupling of a representative polycyclic α-amino-e-caprolactam, i.e., 9, with a mono- or dipeptide derivative 15, wherein R2 and n are as defined above and R1' is an amino-blocking group.
As illustrated in Scheme 4, the coupling of 5-amino-7-alkyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-ones, 9, with a mono- or dipeptide 15 affords the amide 16. This reaction is typically conducted by reacting at least a stoichiometric amount ofthe amino compound 9 and the mono- or dipeptide 15 with a standard coupling reagent, typically in the presence of a trialkylamine, such as ethyldiisopropylamine, under conventional coupling reaction conditions. Optionally, well-known coupling promoters, such N-hydroxysuccinimide, 1- hydroxybenzotriazole and the like, may be employed in this reaction. Typically, this coupling reaction is conducted at a temperature ranging from about 0°C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF, to afford the amide 16.
Suitable coupling reagents include, by way of example, carbodiimides, such as ethyl-3-(3-dimethylamino)propylcarboiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and the like, and other well-known coupling reagents, such as N,N' -carbonyl diimidazole, 2-ethoxy-l-ethoxycarbonyl- 1,2-dihydroquinoline (EEDQ), benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and the like. The coupling reagent may also be bound to a solid support. For example, a polymer supported form of EDC is described in Tetrahedron Letters 1993, 34(48), 7685."
Additionally, l-(3-(l-pyrrolidinyl)propyl-3-ethylcarbodiimide (PEPC) and its corresponding polymer supported forms may be used as a coupling reagent. Briefly, PEPC can be 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 reacting
PEPC with an appropriate resin, such as chloromethyl ated styrene/divinylbenzene resins (Merrifield's resins) under standard conditions to give the desired reagent. Such methods are described more fully in U.S. Provisional Application Serial No. 60/019,790, filed June 14, 1996,12 which application is incoφorated herein by reference in its entirety.
The mono- or dipeptide derivatives employed in the coupling reaction are commercially available or can be prepared using conventional procedures and reagents from commercially available starting materials. The mono- and dipeptide derivatives may be derived from naturally-occurring and non-natural amino acids.
For example, suitable monopeptide derivatives (i.e., amino acid derivatives) include, by way of illustration, N-Boc-glycine, N-Boc-L-alanine, N-Boc-L-valine, N-Boc-L-leucine, N-Boc-L-isoleucine, N-Boc-tert-L-leucine, N-Boc-L-methionine, N-Boc-L-phenylalanine, N-Boc-L-phenylglycine, N-Boc-L-aspartic acid β-tert- butyl ester, N-Boc-L-glutamic acid β-tert-butyl ester, N-Boc-Νe-Cbz-L-lysine, N- Boc-norleucine and the like. Exemplary dipeptides include, for puφoses of illustration only, Ν-Boc-glycinyl-L-alanine, Ν-Boc-L-alaninyl-L-alanine, Ν-Boc- L-alaninyl-L-valine, Ν-Boc-glycinyl-L-phenylglycine, Ν-Boc-L-phenylglycinyl-L- valine and the like.
After forming amide 16, the amino-blocking group R1 , is typically removed to reestablish the amino group. For example, when R1 is a tert- butoxycarbonyl group, the N-Boc group can be removed by treating 16 with anhydrous hydrogen chloride in an inert diluent, such as 1 ,4-dioxane. This reaction is typically conducted at a temperature ranging from about -10°C to about 15°C while hydrogen chloride gas is introduced into the reaction mixture, and then at a temperature ranging from about 10°C to about 60 °C for about 1 to about 24 hours. Other amino-blocking groups can be removed using well-known art recognized procedures.
If desired, the deoxy derivatives of formula II can also be prepared using conventional reagents and procedures. The synthesis of such compounds is described more fully in U.S. Patent Application Serial No. / , filed on even date herewith (Attorney Docket No. 002010-136) and entitled "Deoxyamino Acid Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting β-Amyloid Peptide Release, and/or its Synthesis by Use of Such Compounds," the disclosure of which is incoφorated herein by reference in its entirety, and in the Examples set forth below.
As will be apparent to those skilled in the art, the polycyclic α-amino-e- caprolactams of this invention may contain one or more chiral centers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) ofthe polycyclic α-amino-e-caprolactams of formula I are included within the scope of this invention. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
Utility
The compounds ofthe invention are useful as synthetic intermediates in the preparation of inhibitors of β-amyloid peptide release and/or its synthesis. Accordingly, the intermediates of this inventions have utility in the preparation of compounds which are useful, for example, for diagnosing and treating Alzheimer's disease in mammals, including humans.
For example, the use of various compounds of this invention in the preparation of inhibitors of β-amyloid peptide release and/or its synthesis is described in U.S. Patent Application No. 08/996,422, filed December 19, 1997,13 the disclosure of which is incoφorated herein by reference in its entirety.
The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention.
EXAMPLES In the examples below, the following abbreviations have the following meanings, unless otherwise indicated. All other abbreviations have their generally accepted meaning.
BEMP — 2-tert-butylimino-2-diethylamino-l,3- dimethylperhydro-l,3,2-diazaphosphorine
Boc = tert-butoxycarbonyl
BOP = benzotriazol- 1 -yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate bd = broad doublet (spectral) bs = broad singlet (spectral)
°C = degrees Celsius calcd = calculated δ = chemical shift in parts per million downfield from tetramethylsilane d = doublet (spectral) dd = doublet of doublets (spectral)
DIC = diisopropylcarbodiimide
DΓPEA = diisopropylethylamine
DMF = dimethylformamide
DMAP = dimethylaminopyridine
DMSO = dimethyl sulfoxide
EDC = ethyl- 1 -(3-dimethyaminopropyl)carbodiimide ee = enantiomeric excess eq. = equivalents Et = ethyl
EtOAc = ethyl acetate g = gram(s) h = hour(s)
HMDS ~" 1,1,1,3,3,3-hexamethyldisilazane or bis(trimethylsilyl)amine
HOAc = acetic acid
HOBt = 1-hydroxybenzotriazole hydrate
HPLC = high-performance liquid chromatography
Hunig's base = diisopropylethylamine
IPA = isopropyl alcohol
L = liter m = multiplet (spectral)
M = moles per liter max = maximum
Me = methyl meq = milliequivalent mg = milligram mL = milliliter mm = millimeter mmol = millimole
MW = molecular weight
N = normal ng = nanogram nm = nanometers
NMR = nuclear magnetic resonance
OD = optical density
PEPC = l-(3-(l-pyrrolidinyl)propyl)-3-ethylcarbodiimide
PP-HOBT = piperidine-piperidine- 1 -hydroxybenzotrizole psi = pounds per square inch
Φ = phenyl q = quartet (spectral) quint. = quintet (spectral) φm = rotations per minute s = singlet (spectral) t = triplet (spectral)
TFA = trifluoroacetic acid
THF = tetrahydrofuran tic or TLC = thin layer chromatography μL = microliter
UV = ultraviolet
Additionally, the following abbreviations are used to indicate the commercial source for certain compounds and reagents: Aldrich Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA
Fluka Fluka Chemical Coφ., 980 South 2nd Street, Ronkonkoma NY 11779 USA
Lancaster Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087 USA
Sigma Sigma, P.O. Box 14508, St. Louis MO 63178 USA
Bachem Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA
Novabiochem Calbiochem-Novabiochem Coφ. 10933 North Torrey Pines Road, P.O. Box 12087, La Jolla CA 92039-2087
In the examples below, all temperatures are in degrees Celsius (unless otherwise indicated). The following General Procedures were used as indicated to prepare the compounds set forth in the examples below.
GENERAL PROCEDURE A
Preparation of
5 - Amino-7-alkyl-5 ,7-dihydro-
6H-dibenz[h,d]a7epin-6-one Derivatives
Step A: To a stirred solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(30 mmol) in DMF (150 mL) was added in portions 97% NaH (1.08g, 45 mmol).
Bubbling occurred immediately and was followed by heavy precipitation. After 10 min., an alkyl halide (33 mmol) was added. The precipitate dissolved quickly and in about 10 min. a clear solution was obtained. The reaction mixture was stirred overnight and then evaporated as completely as possible on a rotovap at 30 °C.
Ethyl acetate (100 mL) was added to the residue and this mixture was washed with water, brine, and dried over magnesium sulfate. After filtration and concentration, the residue was typically chromatographed to provide the 7-alkyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one. Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) from Step A was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture was cooled to 0°C in an ice bath. NaHMDS (1.1 eq., IM in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture 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 from Step B was dissolved in EtOH/NH3 (20: 1) and hydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at
100°C for 10 hours. The resulting mixture was filtered and concentrated to provide a crude product which was purified by silica gel chromatography to yield the title compound.
GENERAL PROCEDURE B
Preparation of Fluoro-Substituted 5,7-Dihydro-6H- dibenz[h,d]azepin-6-one Derivatives
A modification ofthe procedure of Robin D. Clark and Jahangir, Tetrahedron 1993, 49(7), 1351-135614 was used. Specifically, an appropriately substituted N-Boc-2-amino-2'-methylbiphenyl was dissolved in THF and cooled to
-78 °C. sec-Butyllithium (1.3M in cyclohexane, 2.2 eq.) was added slowly so that the temperature remained below -65 °C. The resulting mixture was allowed to warm to -25 °C and was stirred at that temperature for 1 hour. The mixture was cooled to -78°C. Dry CO2 was bubbled through the mixture for 30 seconds. The mixture was allowed to warm to ambient temperature then was carefully quenched with water. The mixture was concentrated under reduced pressure then was adjusted to pH 3 with IN HCl. The mixture was extracted with EtOAc and the organic portion was dried and concentrated to yield a crude material. The crude material was dissolved in methanol and the solution was saturated with HCl. The mixture was heated at reflux for 12 hours then was allowed to cool. The mixture was concentrated to provide crude lactam which was purified by chromatography or crystallization.
GENERAL PROCEDURE C Resolution of
5-Amino-7-methy1-5,7-dihydro-6H-dibenz[b.d]a7epin-ή-nnff
In a round bottom flask was added the racemic freebase amine (1.0 eq.) in methanol followed by di- ?-toluoyl-D-tartaric acid monohydrate (1.0 eq.). The mixture was concentrated in vacuo to a residue and redissolved in a moderate volume of methanol and allowed to stir at room temperature open to the atmosphere (8-72 hours). The solid was removed by filtration. The enantiomeric excess was determined by chiral HPLC (Chiracel ODR) using 15% acetonitrile and 85% H2O with 0.1% trifluoroacetic acid and a flow rate of 1.0 mL/min at 35 °C. The resolved di-/?-toluoyl-D-tartaric salt was then dissolved in EtOAc and saturated NaHCO3 until pH 9-10 was reached. The layers were separated and the organic layer was washed again with saturated NaHCO3, H2O, and brine. The organic layer was dried over MgSO4 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. This General Procedure can also be used to resolve other 5-amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones.
GENERAL PROCEDURE D FDC Coupling Procedure
A round bottom flask was charged with a carboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) and an amine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in ethyl acetate (or similar solvent) and water, washed with saturated aqueous sodium bicarbonate solution, IN HCl, brine, dried over anhydrous sodium sulfate and the solvent removed at reduced pressure to provide the product.
GENERAL PROCEDURE E N-Bo Removal Procedure
A stream of anhydrous HCl gas was passed through a stirred solution ofthe N-Boc compound in 1,4-dioxane (0.03-0.09 M), chilled in a ice bath to ~10°C under Ν2, for 10-15 minutes. The cooling bath removed and the solution was allowed to warm to room temperature with stirring for 2-24 hours, monitoring by TLC for the consumption of starting material. The solution was concentrated (and in some instances dissolved in CH2C12 then re-concentrated and placed in vacuum oven at 60-70 °C to remove most ofthe residual dioxane). The residue was typically used without further purification.
GENERAL PROCEDURE F
Reduction of Pyridines and Subsequent Acylation Step A - Reduction of Pyridines
A substituted pyridine hydrochloride was dissolved in ethanol. Rhodium on alumina was added and the mixture was shaken under 60 psi atmosphere of hydrogen at 40 °C for 6 to 18 hours. The mixture was filtered and concentrated to provide a crude product used in Step B.
Step B - Acylation of Piperidines
The crude product from Step A was vigorously stirred in a mixture of chloroform and saturated aqueous sodium bicarbonate. Chloroacetyl chloride
(about 1.1 equivalents) was added dropwise. The resulting mixture was stirred for one hour. The organic portion was separated, dried and concentrated to provide a crude product which was purified by silica gel chromatography. GENERAL PROCEDURE G Fridel-Crafτs Alkylation An appropriately substituted chloroacetamide (1 equivalent) and aluminum trichloride (2.4 equivalents) were stirred in ø-dichlorobenzene. The mixture was heated to between 150°C and the refluxing temperature for between one and four hours. The mixture was allowed to cool and then was poured onto ice. The mixture was extracted with methylene chloride and the organic portion was dried and concentrated to yield a crude product which was purified either by crystallization or by chromatography.
GENERAL PROCEDURE H Azide Transfer The lactam starting material was dissolved in THF and the stirred solution was cooled to -78 °C. An appropriate base, such as lithium diisopropylamine (1.1 eq.), was slowly added. The mixture was stirred for 30 minutes. A solution of trisyl azide (1.1 eq.) in THF was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes. Glacial acetic acid (4.2 eq.) was added and the mixture was allowed to warm to room temperature. The mixture was heated to 40 °C and stirred at that temperature for between 2 and 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic portion was dried and concentrated to provide a crude product which was purified by silica gel chromatography.
GENERAL PROCEDURE I Azide Reduction
The azide starting material (1 eq.) was dissolved in 4% water/THF. Triphenylphosphine (2.8 eq.) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was extracted with dilute aqueous hydrochloric acid. The aqueous portion was washed with ether and then adjusted to pH 9 - 10 with aqueous sodium hydroxide. The mixture was extracted with methylene chloride. The organic portion was dried and concentrated to provide the crude amine which was purified by silica gel chromatography. Example 1
Synthesis of
5-Amino-7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride Step A - Synthesis of 7-Methyl-5τ7-dihydro-6H-dihenz[h,d]a7epin-ή- one
A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 mL of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepin-6- one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, prepared as described in R. F. C. Brown, et. al., Tetrahedron Letters 1971, 8, 667-6709 and references cited therein). After stirring at 60 °C for 1 h, the solution was treated with methyl iodide (1.16 mL, 18.6 mmol) and stirring continued for 17 h with the exclusion of light. After cooling, the reaction was diluted with CH2Cl2/H2O, washed with NaHSO4 solution, H2O, and dried over Na^O^ Evaporation and flash chromatography (SiO2, CHC13) gave 0.885 g (63%) ofthe title compound as a colorless solid.
Physical data were as follows:
'H-NMR (CDC13): δ = 7.62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H), 3.32 (s, 3H).
C15H13NO (MW = 223.27); mass spectroscopy (MH+) 223. Anal. Calcd for C15H13NO; C, 80.69 H, 5.87 N, 6.27. Found: C, 80.11 H,
5.95 N, 6.23.
Step B - Synthesis of 7-Methyl-5-oximo-5,7-dihydro-6H- dihenz[b,d]azepin-6-one The product from Step A (0.700 g, 3.14 mmol) was dissolved in 20 mL of toluene and treated with butyl nitrite (0.733 mL, 6.28 mmol). The reaction temperature was lowered to 0°C and the solution was treated with KHMDS (9.42 mL, 0.5 M) under N2 atmosphere. After stirring for 1 h the reaction was quenched with a saturated solution of NaHSO4, diluted with CH2C12 and separated. The organic layer was dried over Na2SO4 and the title compound purified by chromatography (SiO2, 98:2 CHCl3/MeOH) giving 0.59 g (80 %) as a colorless solid.
Physical data were as follows: C15H12N2O2(MW = 252.275); mass spectroscopy (MH+) 252. Anal. Calcd for C15H,,N2O2; C, 71.42 H, 4.79 N, 11.10. Found: C, 71.24 H, 4.69 N, 10.87.
Step C - Synthesis nf 5- Amino-7-Methv1- 7-Hir Hrn-fflr. dihen?[h,d3azepin-6-one Hydrochloride
The product from Step B (0.99 g, 3.92 mmol) was hydrogenated in a Parr apparatus at 35 psi over 10% Pd C (0.46 g) in 3 A ethanol. After 32 h the reaction mixture was filtered through a plug of Celite, the filtrate evaporated to a foam and treated with a saturated solution of HCl(g) in Et2O. The resulting colorless solid was filtered, rinsed with cold Et2O and vacuum dried to give 0.66 g (61%) of the title compound.
Physical data were as follows:
'H-NMR (DMSO-rf6): δ = 9.11 (bs, 3H), 7.78-7.41 (m, 8H), 4.83 (s, IH), 3.25 (s, 3H).
C,jH14N2O»HCl (MW = 274.753); mass spectroscopy (MH+ free base) 238.
Anal. Calcd for C15Hl4N2O»HCl; C, 65.57 H, 5.50 N, 10.19 Found: C, 65.27 H, 5.67 N, 10.13.
Example 2
Synthesis of
5-(S)-Amino-7-methyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Following General Procedure C using racemic 5-amino-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) and di-/?-toluoyl-D-tartaric acid monohydrate (1.0 eq.) in methanol, the title compound was prepared as a solid.
The product was collected by filtration. Enantiomeric excess was determined by chiral HPLC]
Physical data were as follows: Enantiomer l: Retention time = 9.97 minutes.
Enantiomer 2: Retention time = 8.62 minutes.
NMR data was as follows: 'H-NMR (CDC13): δ = 9.39 (s, 2H), 7.75-7.42 (m, 8H), 4.80 (s, IH), 3.30 (s, 3H).
CI5H15ClN2O (MW = 274.75); mass spectroscopy (MH*) 239.1. Anal Calcd for C15H15ClN2O3; C, 65.57; H, 5.50; N, 10.20; Found: C, 65.51, H, 5.61; N, 10.01.
Example 3
Synthesis of 5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one Step A - Synthesis of 5-Iodo-5t7-dihydro-6H-dihen7[h,d]a7epin-ή-
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (prepared as described in R. F. C. Brown, et. al., Tetrahedron Letters 1971, 8, 667- 6709 and references cited therein) and Et3N ( 2.66 mL, 19.12 mmol) were stirred for 5.0 minutes at -15°C in CH2C12 and treated with TMSI (1.36 mL, 9.54 mmol).
After stirring for 15 minutes, I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10°C over 3 h. The reaction was quenched with sat. NajSOj, diluted with CH2C12 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration or could be chromatographed (SiO2, CHCl3/MeOH, 99:1) to provide a yellow solid. Physical data were as follows:
'H-nmr (CDC13): δ = 8.05 (bs, IH), 7.64-7.58 (m, 2H), 7.52-7.45 (m, 2H), 7.38-7.32 (m, 3H), 7.11 (d, IH), 5.79 (s, IH).
C14H10INO(MW = 335.139); mass spectroscopy (MH+) 336. Anal. Calcd for C14H10INO; C, 50.17 H, 3.01 N, 4.18. Found: C, 49.97 H, 3.01 N, 4.06. .
Step B - Synthesis of 5- A7ido-5.7-dihvdro-6H-diben7[h.d]a7epin-6-
The product from Step A was dissolved in DMF and treated with 1.2 equivalents of NaN3. After stirring 17 h at 23°C, the mixture was diluted with EtOAc/H2O, separated, washed with brine and dried over MgSO . Trituration from hot EtOAc provided the title compound as a tan powder.
Physical data were as follows:
Η-nmr (DMSO- 6): δ = 10.51 (s, IH), 7.72 (m, IH), 7.63 (m, IH), 7.48 (m, 4H), 7.30 (m, IH), 7.24 (m, IH) 5.27 (s, IH).
C14H10N4O (MW = 250.13); mass spectroscopy (MH+) 251.
Step C - Synthesis of 5-(N-Boc-AminoY- 7-Hihyrim-fiW 7W- dihen7[h,d]a7epin-6-one The product from Step B was dissolved in THF/H2O and stirred at 23 °C for
17 h in the presence of 3.0 equivalents of Ph3P. The reaction was diluted with 50
% HO Ac/toluene, separated, the aqueous layer extracted with toluene and evaporated to an oily residue. The pH ofthe residue was adjusted to pH 7.0 by the addition of IN ΝaOH and the resulting HO Ac salt was collected and vacuum dried. This salt was treated with di-tert-butyl dicarbonate (1.05 equivalents) (Aldrich) and
Et3Ν (2.1 equivalents) in THF. After stirring for 5 h at 23 °C, the reaction was filtered and the title compound was isolated as a colorless powder.
Physical data were as follows:
Η-nmr (CDC13): δ = 7.69-7.31 (m, 8H), 7.1 1 (m, IH), 6.22 (m, IH), 5.12 (m, IH), 1.47 (s, 9H).
C19H20N2O3 (MW = 324.16); mass spectroscopy (MH+) 325.
Example 4
Synthesis of 5-Amino-7-(2-methylpropyl)-5,7-dihydro-
6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A - Synthesis of 5-(Λ/-Boc- Arnino)-7-(2-mefhylpropy1)-5r7- dihyriro-6H-dihenz[hrd]azepin-6-one
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2g, 0.617 mmol) (Example 3) in DMF was treated with Cs2CO3 (0.22 g, 0.678 mmol) and warmed to 60 °C. To the reaction mixture was added l-iodo-2- methylpropane (0.078 mL, 0.678 mmol) and stirring continued for 17 h. After cooling to 23 °C, the mixture was diluted with CH2C12, washed with several portions of brine and dried over Na^O^ The title compound was purified by chromatography (SiO2, CHCl3/MeOH 9:1).
Physical data were as follows:
C23H28N2O3 (MW = 380.41); mass spectroscopy (MH+) 381. Anal. Calcd for C23H28N2O3; C, 72.61 H, 7.42 N, 7.36. Found: C, 72.31 H,
7.64 N, 7.17.
Step B - Synthesis of 5-Amino-7-(2-rnethylpropy1)-5,7-dihydro-6H- dihen7[h,d]azepin-6-one Hydrochloride The product from Step A was deprotected using General Procedure E to provide the title compound as a slightly colored solid after neutralization and extraction with ethyl acetate, drying over Na2SO4 and vacuum drying.
Physical data were as follows:
'H-nmr (CDC13): δ = 7.63-7.31 (m, 8H), 4.35 (bs, IH), 4.27 (m, IH), 3.30 (m, IH), 2.02 (bs, 2H), 0.55 (d, 3H), 0.29 (d, 3H).
C18H20N2O (MW = 280.17); mass spectroscopy (MH+) 281.
Example 5
Synthesis of 5-Amino-7-(methoxycarbonylmethyl)-5,7-dihydro-
6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A- Synthesis of 5-(V-Boc-Amino)-7-(methoxycarhony1methyl)-
5,7-riihydro-6H-dihenz[brd3azepin-6-one
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.03, 3.08 mmol) (Example 3) in DMF was treated with Cs2CO3 (1.10 g, 3.39 mmol) and warmed to 60 °C. To this reaction mixture was added methyl bromoacetate (0.321 mL, 3.39 mmol) (Aldrich) and stirring was continued for 17 h. After cooling to 23 °C, the mixture was diluted with CH2C12, washed with several portions of brine and dried over ΝajSO,. The title compound was purified by chromatography (SiO2, CHC13).
Physical data were as follows:
C22H24Ν2O5 (MW = 396.44); mass spectroscopy (MH+) 397 Anal. Calcd for C22H2 N2O5; C, 66.65 H, 6.10 N, 7.07. Found: C, 66.28 H, 5.72 N, 6.50.
Step B - Synthesis of 5-Amino-7-fmethoxycarhony1methyn- 17- dihyriro-6H-dihenz[b.d]azepin-6-one HyHror.h1r>ri e
The product from Step A was deprotected using General Procedure E to provide the title compound as a colorless solid after evaporation and vacuum drying.
Physical data were as follows: 'H-nmr (DMSO-d6): δ = 7.72-7 '.42 (m, 8H), 4.92 (s, IH), 4.53 (m, 2H),
3.52 (s, 3H).
C17H16N2O3«HCl (MW = 332.78); mass spectroscopy (MH+ free base) 297.
Example 6 Synthesis of
5-Amino-7-(3,3-dimethyl-2-butanonyl)- 5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A- Synthesis of 5-(Λt-Boc-Amino)-7-(3,3-dimethy1-hutanony1V
5 7-Hihyrirr>-6H-dibenz[h.d]a7epin-6-one A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
(0.2 g, 0.617 mmol) (Example 3) in DMF was treated with Cs2CO3 (0.3 g, 0.925 mmol) and warmed to 60 °C. To this reaction mixture was added l-chloro-3,3- dimethyl-2-butanone (0.096 mL, 0.74 mmol) (Aldrich) and stirring was continued for 17 h. After cooling to 23 °C, the mixture was diluted with CH2C12, washed with several portions of brine and dried over Νa^O,,. The title compound was isolated as a colorless solid.
Physical data were as follows:
C25H30Ν2O4 (MW = 422.522); mass spectroscopy (MH+) 423.
Anal. Calcd for C25H30N2O4 -0.6825 mol H2O; C, 69.05 H, 7.27 N, 6.44. Found: C, 69.03 H, 7.27 N, 6.60. Step B - Synthesis of -Amino^-G^-dimethyl^.-hiitflnonylVS,?- dihyriro-6H-dibenz[bfd]azepin-6-one Hydrochloride
The product from Step A was deprotected using General Procedure E to provide the title compound as a colorless solid after evaporation and vacuum drying.
Physical data were as follows:
'H-nmr (OMSO-d6): δ = 9.14 (bs, 3H), 7.76-7.32 (m, 8H), 4.99 (d, IH), 4.98 (s, IH), 4.69 (d, IH), 1.15 (s, 9H).
C20H22N2O2 HCl (MW = 358); mass spectroscopy (MH+ free base) 323.
Example 7
Synthesis of 5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Following General Procedure A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron
Letters, No. 8, 667-670, (1971) and references cited therein) and l-chloro-4- phenylbutane (Aldrich), the title compound was prepared.
Physical data were as follows:
Step B: Synthesis of 5-Hydroxyirnino-7-phenhuty1-5,7-dihydro-6H- dihenz[h,d]a7epin-6-one lH-nmr (CDC13): δ = 2.37 (m,2H), 3.65 (m, IH), 4.50 (m, IH) .
Cl5H13NO (MW = 370.45); mass spectroscopy (MH+) 371.2.
Step C: Synthesis of 5- Amino-7-phenhuty1-5r7-dihydro-6H- dibenz[h,d]azepin-6-one
Η-nmr (CDC13): δ = 2.27 (m, 2H), 3.55 (m, IH), 4.33 (m, IH) .
(MW = 356.47); mass spectroscopy (MH+) 357.3.
Example 8 Synthesis of
5-Amino-7-cyclopropymethyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one
Following General Procedure A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in R. F. C. Brown, et. al., Tetrahedron Letters 1971, 8, 667-6709 and references cited therein) and
(bromomethyl)cyclopropane (Aldrich), the title compound was prepared.
Physical data were as follows:
Step B: Synthesis of 5-Hydroxyirmno-7-cyclopropy1rnethyl-S,7- dihydro-6H-dihenz[b,d]azepin-6-one
Η-nmr (CDC13): δ = 3.6 (m, IH), 4.15 (m, IH).
(MW = 292.34); mass spectroscopy (MH+) 293.2.
Example 9 Synthesis of
5-Amino-7-(2',2',2'-trifluoroethyl)-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one
Following General Procedure A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in R. F. C. Brown, et. al., Tetrahedron Letters 1971, 8, 667-6709 and references cited therein) and 1-bromo-
2,2,2-trifluoroethane (Aldrich), the title compound was prepared.
Physical data were as follows:
Step A: Synthesis of 7-(?., I?., r2,-Trifluoroethyn-5.7-dihydro-6H- dibenz[h,d]azepin-6-one 'H-nmr (CDC13): δ = 3.46 (d,lH), 3.63 (d,lH), 4.07 (m, IH), 5.06(m,lH).
Step B: Synthesis of 5-Hydroxyιmino-7-(2',2,,2'-trifluoroethyl)-5,7- dihydro-6H-dihenz[btd3azepin-6-one lH-nmr (CDC13): δ = 4.13 (m, IH), 5.27 (m,lH ). (MW = 320.27); mass spectroscopy (MH+) 321.2.
Example 10
Synthesis of
5-Amino-7-cyclohexyl-5,7-dihydro-
6H-dibenz[b,d] azepin-6-one Following General Procedure A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in R. F. C. Brown, et. al., Tetrahedron Letters 1971, 8, 667-6709 and references cited therein) and bromocyclohexane (Aldrich), the title compound was prepared. Physical data were as follows: Step A: Synthesis of 7-Cvc1ohexyl-5.7-riihydτ-n-6H- dihen7[hrd]azepin-6-one 'H-nmr (CDC13): δ = 3.35 (d,lH), 3.47 (d,lH), 4.03 (m, IH).
Example 11
Synthesis of
5-Amino-7-hexyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Following General Procedure A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in R. F. C. Brown, et. al.,
Tetrahedron Letters 1971, 8, 667-6709 and references cited therein) and 1- bromohexane (Aldrich), the title compound was prepared.
Example 12 Synthesis of
5-Amino-9-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A - Synthesis of 4-Fluoro-2-methylphenylhoronate Pinacol Fster
2-Bromo-5-fluorotoluene (1.0 eq.) (Aldrich) was stirred in THF at -78°C. sec-Butyllithium (1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture was stirred for 45 minutes. Trimethylborate (1.5 eq) (Aldrich) was then added and the mixture was allowed to warm to ambient temperature. After stirring for 1 hour, pinacol (2 eq.) (Aldrich) was added. The mixture was stirred for 16 hours then was concentrated under reduced pressure. The resulting residue was slurried in CH2C12 and filtered through Celite. The filtrate was concentrated to yield an oil which was purified by chromatography on deactivated silica gel (Et3N) to yield the title compound.
Step B - Synthesis of Λ/-Boc-2-bromoaniline 2-Bromoaniline (1 eq.) (Aldrich) and di-tert-butyl-dicarbonate (1.1 eq.)
(Aldrich) were stirred at 80 °C for 20 hours. The resulting mixture was allowed to cool and was directly distilled using house vacuum to provide the title compound. Step C - Synthesis of N-Boc-2-amino-4'-fluoro-2'-mefhylbiphenyl
N-Boc-2-bromoaniline (1 eq.) (Step B), the arylboronate ester (1.1 eq.) (Step A), K2CO3 (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 CH2Cl2/hexanes.
Step D - Synthesis of 9-Fhιoro-5 -dihydro-6H-riihen7[h,d]a7epin-6-
Following General Procedure B and using the product from Step C, the title compound was prepared.
Physical data were as follows: (MW = 227.24); mass spectroscopy (MH+) 228.0.
Step E - Synthesis of 9-Flnoro-7-methy1-5,7-dihyHrn-r H- dihen7[b,d]azepin-6-one 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) (Step D), 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 provide the title compound. Physical data were as follows:
'H-nmr (CDC13): δ = 3.33 (s,3H), 3.42 (d,lH), 3.54 (d, IH).
(MW = 241.27); mass spectroscopy (MH+) 242.0.
Step F - Synthesis of 5- Amino-9-fluoro-7-methyl-5,7-dihydro-6H- riihenz[b,d]a7ftnin-6-one
Following General Procedure A, Steps B and C, and using the product from
Step E, the title compound was prepared.
Physical data were as follows: Gen. Proc. A Step B: Synthesis of S-Hydroxyimino^-fliioro^-rnei-hyl- ,?. dihydro-6H-diben7[brd]a7epin-6-one 'H-nmr (CDC13): δ = 3.44, 3.47 (singlets, 3H) .
(MW = 270.26); mass spectroscopy (MH+) 271.4.
Gen. Proc. A/Step C: Synthesis of 5-Amino-9-fhιoro-7-rnethy1-5r7- dihydro-6H-diben7[b.d]a7epin-ή-nne lH-nmr (CDC13): δ = 2.08 (s,2H); 3.34 (s,3H); 4.30 (s,lH).
(MW =256.3 ); mass spectroscopy (MH+) 257.0.
Example 13
Synthesis of
5-Amino-10-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride
Following the procedure of Example 12 and using 2-bromo-4-fluorotoluene (Lancaster) in Step A, the title compound was prepared.
Physical data were as follows:
Step D: Synthesis of 1 -Fluoro-5,7-dihydro-6H-dibenz[h,d]a7eρin-6- one Η-nmr (CDCl3/DMSO-c?6): δ = 3.34 (q,2h); 9.91(s,lH). (MW = 227.24); mass spectroscopy (MH+) 228.0.
Step E: Synthesis of 1 -F1noro-7-methy1-5,7-dihydro-6H- diben7[h,d]azepin-6-one 'H-nmr (CDC13): δ = 3.33 (s,3H), 3.42 (d,lH), 3.57 (d, IH).
(MW = 241.27); mass spectroscopy (MH+) 242.0. Step F: Synthesis of 5- Amino- 10-fiuoro-7-methyl-5,7-dihydro-6H- dihen7.[brd]a7epin-6-one
Gen. Proc. A/Step B: Synthesis of 5-Hydroxyimino-10-flιιoro-7- methy1-5r7-dihydro-6H-dibenz[h,d]a7epin-6- one
Η-nmr (CDC13): δ = 3.43, 3.47 (singlets, 3H).
(MW = 270.26); mass spectroscopy (MH+) 271.4.
Gen. Proc. A/Step C: Synthesis of 5-Amino-l 0-fluoro-7-methyl- ,7-dihydro-6H-dihen7.[b,d]a7epin-6-one Η-nmr (CDC13): δ = 2.06 (s, 2H); 3.34 (s,3H); 4.28 (s, IH).
(MW = 256.3); mass spectroscopy (MH+) 257.0. Example 14
Synthesis of
5-Amino-13-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Following the procedure of Example 12 and using 2-bromo-4-fluoroaniline
(Lancaster) in Step B, and ø-tolylboronic acid (Aldrich) in Step C, the title compound was prepared.
Physical data were as follows:
Step D: Synthesis of 1 -Fluoro-5.7-dihydro-6H-dihen7[h,d]a7epin-6- one
Η-nmr (CDC13): δ = 3.5 (bm, 2H).
(MW = 227.24); mass spectroscopy (MH+) 227.8.
Step E: Synthesis of 1 -F1uoro-7-methv1-5.7-dihydrn-.fiH- diben7[b,d]a7epin-6-one Η-nmr (OMSO-d6): δ = 3.33 (s,3H), 3.35 (d,lH), 3.52 (d, IH).
(MW = 241.27); mass spectroscopy (MH+) 241.8.
Step F: Synthesis of 5-Amino-l 3-fluoro-7-methy1-5,7-dihydro-6H- dihen7[b,d]a7eρin-fi-one Gen. Proc. A/Step B: Synthesis of 5-Hydroxyimino-l -flnnrn-7-methy1- l7-HihyHrn-fiH-dibenz[b.d]azepin-fi-nne Η-nmr (CDC13): d = 3.39, 3.44 (singlets, 3H) .
(MW = 270.26); mass spectroscopy (M+) 270.1.
Gen. Proc. A/Step C: Synthesis nf 5-Amino-l 3-fluoro-7-methy1-5,7- dihydrn-6H-dihen7.[b,d]a7epin-fi-nne lH-nmr (CDC13): δ = 2.06 (bs,2H); 3.33 (s,3H); 4.35(s,lH).
Rf (5% methanol/chloroform) = 0.3.
Example 15 Synthesis of
5-Amino-7-methyl-l,2,3,4,5,7-hexahydro- 6H-dicyclohexyl[b,d]azepin-6-one
5- Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride
(Example 1) was dissolved in a 1:1 mixture of EtOAc/HOAc. Rhodium on carbon (5%) was added and the mixture was stirred at 60°C under 60 psi of hydrogen for 3 days. The reaction mixture was then filtered and the filtrate was concentrated to provide an oil which was purified by SCX-cation exchange chromatography to yield the title compound.
Physical data were as follows:
(MW = 250.38); mass spectroscopy (MH+) 251.3.
Example 16
Synthesis of (S)- and (R)-5-(L-Alaninyl)amino-7-methyI- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Step A - Synthesis nf (S)- and tRV5-tW-Boc- -A1aninynamino-7- methyl-5,7-dihydro-6H-dibenz[brd]azepin-6-nne
N-Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.305 g, 2.26 mmol), and 5-amino-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89 mmol) (Example 1). The temperature was lowered to 0°C and the reaction mixture was treated with EDC
(0.449 g, 2.26 mmol) (Alrich) and stirred for 17 hours under Ν2. The reaction mixture was then evaporated and the residue diluted with EtOAc/H2O, washed 1.0
N HCl, sat. NaHCO3, brine and dried over Na2SO4. The resulting diastereomers were separated on a Chiralcel OD column using 10% LP A/heptane at 1.5 mL/minute.
Isomer 1: Retention time 3.37 minutes.
NMR data was as follows:
'H-NMR (CDC13): δ = 7.62-7.33 (m, 9H), 5.26 (d, IH), 5.08 (m, IH), 4.34
(m, IH), 3.35 (s, 3H), 1.49 (s, 9H), 1.40 (d, 3H). Optical Rotation: [α]20 = -96 @ 589 nm (c = 1 , MeOH).
C23H27N3O4 (MW = 409.489); mass spectroscopy (MH+) 409.
Anal. Calcd for C23H27N3O4; C, 67.46 H, 6.64 N, 10.26. Found: C, 68.42 H,
7.02 N, 9.81.
Isomer 2: Retention time 6.08 minutes. NMR data was as follows:
Η-NMR (CDC13): δ = 7.74 (bd, IH), 7.62-7.32 (m, 8H), 5.28 (d, IH), 4.99
(m, IH), 4.36 (m, IH), 3.35 (s, 3H), 1.49 (s, 9H), 1.46 (d, 3H).
Optical Rotation: [α]20 = 69 @ 589 nm (c = 1, MeOH). C23H27N3O4 (MW = 409.489); mass spectroscopy (MH+) 409. Anal. Calcd for C23H27N3O4; C, 67.46 H, 6.64 N, 10.26. Found: C, 67.40 H, 6.62 N, 10.02.
Step B - Synthesis of (S - and π -5-fL-A1aniny1)amιno-7-mt»rhy1-
5r7-dihydro-6H-dihenz[b.d]azepin-6-one Hydrnch1nride
In separate reaction flasks, each isomer from Step A was dissolved in dioxane and treated with excess HCl(g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying. Isomer 1:
CI8H19N3O2»HCl (MW = 345.832); mass spectroscopy (MH+ free base) 309.
Optical Rotation: [α]20 = -55 @ 589 nm (c = 1, MeOH).
Isomer 2: ClgH19N3O2«HCl (MW = 345.832); mass spectroscopy (MH+ free base)
309.
Optical Rotation: [α]20 = +80 @ 589 nm (c = 1, MeOH).
Example 17 Synthesis of
(S)- and (R)-5-(L-Valinyl)amino-7-methyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Step A - Synthesis of (S and πtt-5-(N-Boc-T^Va1iny1)amiτιn-7- methy1-5,7-dihydrn-fiH-dihen7[brd]azepin-fi-nne N-Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), DLPEA (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 1). The temperature was lowered to 0°C and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred for 17 hours under Ν2. The reaction mixture was then evaporated and the residue diluted with EtOAc/H2O, washed 1.0 N HCl, sat. NaHCO3, brine and dried over NajSO.,. The resulting diastereomers were separated on a Chiralcel OD column using 10% IP A/heptane at 1.5 mL/minute. Isomer 1 : Retention time 3.23 minutes. Optical Rotation: [ ]20 = -120 @ 589 nm (c = 1, MeOH). C25H31N3O4 (MW = 437.544); mass spectroscopy (MH+) 438 Isomer 2: Retention time 6.64 minutes. Optical Rotation: [ ]20 = +50 @ 589 nm (c = 1 , MeOH).
C25H31N3O4 (MW = 437.544); mass spectroscopy (MH+) 438
Step B - Synthesis of fSV and fRV5-rL-Va1iny1Vaminn-7-methy1- ,7- dihydrn-6H-dibenz[brd]azepin-6-one Hydroch1nriHe In separate reaction flasks, each ofthe isomers from Step A was dissolved in dioxane and treated with excess HCl(g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1 :
C20H23N3O2»HC1 (MW = 373.88); mass spectroscopy (MH+ free base) 338. Optical Rotation: [α]20 = -38 @ 589 nm (c = 1 , MeOH).
Isomer 2:
C20H23N3O2-HC1 (MW = 373.88); mass spectroscopy (MH+ free base) 338.
Optical Rotation: [α]20 = +97 @ 589 nm (c = 1, MeOH).
Example 18
Synthesis of
(S)- and (R)-5-(L-tert,-Leucinyl)amino-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Step A - Synthesis of (S)- and (R)-5-(V-Boc-L-tert-Leuciny1)-amino- 7-methy1-5r7-Hihydrn-6H-diben7[b.d]a7epin-6-nne
N-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), DLPEA (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 1). The temperature was lowered to 0°C and the reaction mixture was treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred for 17 hours under Ν2. The reaction mixture was then evaporated and the residue diluted with EtOAc/H2O, washed 1.0 N HCl, sat. NaHCO3, brine and dried over Na^O^ The diastereomers were separated on a Chiralcel OD column using 10% IP A/heptane at 1.5 mL/minute.
Isomer 1 : Retention time 3.28 minutes.
Optical Rotation: [α]20 = -128 @ 589 nm (c = 1, MeOH). C26H33N3O4 (MW = 451.571); mass spectroscopy (MH+) 452
Isomer 2: Retention time 5.52 minutes.
Optical Rotation: [α]20 = +26 @ 589 nm (c = 1, MeOH).
C26H33N3O4 (MW = 451.571); mass spectroscopy (MH+) 452
Step B - Synthesis of CSV and fRV5-fL-tert-T .eucinynamino-7- methyl-5r7-dihydro-6H-dibenz[brd]azepin-fi-one Hydrochloride
In separate reaction flasks, each ofthe isomers from Step A was dissolved in dioxane and treated with excess HCl(g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying.
Isomer 1 :
C21H25N3O2-HCl (MW = 387.91); mass spectroscopy (MH+ free base) 352.
Optical Rotation: [α]20 = -34 @ 589 nm (c = 1, MeOH).
Isomer 2: C21H25N3O2»HCl (MW = 387.91); mass spectroscopy (MH+ free base) 352.
Optical Rotation: [α]20 = +108 @ 589 nm (c = 1, MeOH).
Example 19
Synthesis of 5-(L-Alaninyl)amino-7-methyl-5,7-dihydro-
6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A - Synthesis of 5-(/V-Boc-L-A1aniny1)amino-7-methy1-5,7-
Hihydro-fiH-dihenz[h.d]azepin-fi-one
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 1), the title compound was prepared. Step B - Synthesis nf 5-tT .- Alaninynaminn^-methyl-S -dihydrn-fiH- diben7[h,d]a7epin-ή-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared.
Example 20
Synthesis of 5-(L-Valinyl)amino-7-methyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one Hydrochloride Step A - Synthesis of 5-(V-Boc-L- Va1inynamino-7-methy1- ,7- dihydro-6H-dibenz[b,d]azepin-6-Qne
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 1), the title compound was prepared.
Step B - Synthesis of - .-Valinynamino^-methyl- ^-dihydrn-fiH- diben7[h,d]a7epin-fi-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared.
Example 21
Synthesis of
5-(L-Alaninyl)amino-9-fiuoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Step A - Synthesis of 5-( V- oc-T,-A1aninynamino- -f^lIorn-7-m thy1- 7-dihydrn-fiH-dihen7[h.d]azepin-fi-one
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and
5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example
12), the title compound was prepared.
Step B - Synthesis of 5-(T -A1aniny1)amino-9-fluoro-7-methy1-5,7- dihydro-6H-dihen7[hrd]azepin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared. Example 22
Synthesis of
5-(L-Alaninyl)amino-10-fluoro-7-rnethyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - Synthesis of 5-(/V-Boc-L-A1aninyl nino-10-fluoro-7- methy1-5,7-dihydro-6H-diben7[brd]a7epin-fi-one
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and
5 -amino- 10-fluoro-7-methyl-5 ,7-dihydro-6H-dibenz[b,d] azepin-6-one (Example
13), the title compound was prepared.
Step B - Synthesis of 5-(T ,- A1aniny11amino-1 -flnnrn-7-methy1-5, 7- dihydro-6H-dibenz[b.d3azepin-6-one Hydroch1nridR
Following General Procedure E and using the product from Step A, the title compound was prepared.
Example 23
Synthesis of
5-(L-AlaninyI)amino-13-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Step A - Synthesis of 5-( V-Boc-L-A1aninyl)amino-1 -fluoro-7- methy1-5,7-dihydro-fiH-dibenz[brd]azepin-fi-one
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and
5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example
14), the title compound was prepared.
Step B - Synthesis of -(T -A1aninynamino-1 -f1nnrn-7-methy1-5,7- dihydro-fiH-dihen7[h.d]azepin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared. Example 24
Synthesis of
5-(L-AIaninyl)amino-7-cyclopropylmethyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - Synthesis of 5-(A/'-Boc-T.-A1aninynaminn-7- cvc1npropv1methv1-5_7-dihvdro-fiH-Hihen7[hr ]a7epin-fi-nne
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and
5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example
8), the title compound was prepared.
Step B - Synthesis of -n,- A1aninynamino-7-cyr.1npropy1methy1-5, 7- dihvdro-6H-dihenz[b.d1azepin-6-one Hydrorh1nriHe
Following General Procedure E and using the product from Step A, the title compound was prepared.
Example 25
Synthesis of
5-(L-Alaninyl)amino-7-phenbutyI-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Step A - Synthesis of 5-(Λ/-Boc-T,-A1aninynamino-7-phenhnty1-5r7- dihydro-6H-dihen7[brd]azepin-fi-one
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and
5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7), the title compound was prepared.
Step B - Synthesis of 5-(T,-A1aniny1)amino-7-phenhuty1-5,7-dihydro-
6H-dihen7[h,d]a7epin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared. Example 26
Synthesis of
5-(L-VaIinyl)amino-7-cyclopropylmethyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - Synthesis of 5-(N-Boc-T, Nalinynamino-7- πyclopropylmethy1-5,7-dihydro-6H-diben7[h.d]a7epin-6-one
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 8), the title compound was prepared.
Step B - Synthesis of 5-(L-Va1iny amino-7- y 1opropy1methy1- , 7- dihydro-6H-dibenz[b.d]azepin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared.
Example 27
Synthesis of
5-(L-Valinyl)amino-7-phenbutyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Step A - Synthesis of 5-(V-Boc-T.-Valinynamino-7-phenhιιry1-5,7- dihydro-fiH-dibenz[brd]azepin-6-one
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7), the title compound was prepared.
Step B - Synthesis of 5-(L-Va1inynamino-7-phenhιιty1-5,7-Hihydrn- fiH-diben7[h,d]a7epin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared. Example 28
Synthesis of
5-(L-Valinyl)amino-7-hexyl-5,7-dihydro-
6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - Synthesis of -fΛ -Roc-T.-Valiny1 ιaτninn-7-heγy1- 7- dihydro-6H-dibenz[brd]azepin-fi-one
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 11), the title compound was prepared.
Step B - Synthesis of 5-(L-Va1iny1)amino-7-hexy1-5,7-di hydro-fiH- diben7[b,d]a7epin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared. Physical data were as follows:
'H-nmr (DUSO-d6): δ = 2.17 (bm, IH); 3.98, 4.07 (doublets, IH); 4.27 (m,
IH); 5.24, 5.33 (doublets, IH).
(MW = 407.55, free base); mass spectroscopy (MH+) 408.1.
Example 29
Synthesis of
5-(L-Valinyl)amino-9-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A - Synthesis of 5-(V-Boc-L-Va1inynamino-9-flunrn-7-methyl- 5,7-dihydro-fiH-dihen7[b,d]azepin-fi-one
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 12), the title compound was prepared.
Step B - Synthesis of -(T ,-Valinyl inn-9-flnoro-7-rnethy1-5,7- dihydro-6H-dihen7.[brd]a7epin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared.
Physical data were as follows: Η-nmr (DMSO- 6): δ = 2.05 - 2.27 (bm, IH); 3.96, 4.07 (doublets, IH); 5.26, 5.32 (doublets, IH).
(MW = 355.41, free base); mass spectroscopy (MH+) 356.3. Anal. Calcd for C20H22FN3O2.HC1; C, 61.30 H, 5.92 N, 10.72. Found: C, 61.15 H, 6.22 N, 10.69.
Example 30
Synthesis of 5-(L-ValinyI)amino-10-fluoro-7-methyI- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Step A - Synthesis of 5-(V-Boc-L-Va1iny1)arnino-10-flnoro-7-methyl-
5,7-dihydro-6H-dibenz[brd]azepin-6-one
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 13), the title compound was prepared.
Step B - Synthesis of 5-(T,-Va1invnamino-1 0-fhιoro-7-methy1-5,7- dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared.
Physical data were as follows:
'H-nmr (DMSO- 6): δ = 2.05 - 2.30 (bm, IH); 3.97, 4.06 (doublets, IH);
5.23, 5.32 (doublets, IH).
(MW = 355.41, free base); mass spectroscopy (MH+) 356.3. Anal. Calcd for C20H22FΝ3O2.HC1; C, 61.30 H, 5.92 N, 10.72. Found: C,
61.04 H, 5.90 N, 11.01. Example 31
Synthesis of
5-(L-Valinyl)amino-13-fluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride
Step A - Synthesis of 5-(/V-Boc-T.Na1iny1)amino-1 -fluoro-7-methyl-
5r7-dihydro-6H-diben7[brd]azepin-fi-one
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5- amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 14), the title compound was prepared.
Step B - Synthesis of 5-fT.-Valinynamino-13-flnnro-7-methy1-5,7- dihydro-6H-dibenz[brd]azepin-6-one Hydrochloride
Following General Procedure E and using the product from Step A, the title compound was prepared. Physical data were as follows:
Η-nmr (DMSO-rf6): δ = 2.05 - 2.28 (bm, IH); 3.98, 4.07 (doublets, IH);
5.27, 5.34 (doublets, IH).
(MW = 355.41, free base); mass spectroscopy (MH+) 356.4.
Anal. Calcd for C20H22FΝ3O2.HC1; C, 61.30 H, 5.92 N, 10.72. Found: C, 61.24 H, 6.07 N, 10.86.
Example 32
Synthesis of 5-Amino-9,13-difiuoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d] azepin-6-one
Following the procedure of Example 12 and using 2-bromo-4-fluoroaniline
(Lancaster) in Step B, the title compound was prepared.
Physical data were as follows:
Step D: Synthesis of 9r1 -Difhιoro-5.7-dihydro-6H- dihen7[btd]a7epin-fi-one
(MW = 245.23); mass spectroscopy (MH+) 246.0.
Step F: Synthesis of 5-Amino-9.13-difluoro-7-methyl-5,7-dihydro- fiH-dihen7[h.d]a7epin-6-one Η-nmr (CDC13): δ = 2.14 (s, 2H); 3.31 (s, 3H); 4.32 (s, IH). (MW = 274.3 ); mass spectroscopy (MH+) 275.0. Example 33
Synthesis of
5-Amino-10,13-difluoro-7-methyl-
5,7-dihydro-6H-dibenz[b,d]azepin-6-one Following the procedure of Example 12 and using 2-bromo-4-fiuorotoluene
(Lancaster) in Step A and 2-bromo-4-fluoroaniline (Lancaster) in Step B, the title compound was prepared.
Physical data were as follows:
Step D: Synthesis of 1 rn-Difluoro-5,7-dihydro-fiH- dihen7[h,d]a7epin-6-one
(MW = 245.23 ); mass spectroscopy (MH+) 246.0.
Step E: Synthesis of 1 .1 -Difluoro-7-methy1-5,7-dihydrn-fiH- diben7[h,d]azepin-6-one Η-nmr (CDC13): δ = 3.30 (s,3H), 3.35 (d,lH), 3.58 (d, IH). Step F: Synthesis of 5-Amino-10.1 3-difluoro-7-methyl-5.7-dihydro-
6H-dibenz[b,d]azepin-6-Qne Η-nmr (CDC13): δ = 2.06 (s, 2H); 3.32 (s, 3H); 4.27 (s, IH).
(MW = 274.3); mass spectroscopy (MH+) 275.0.
Example 34
Synthesis of 9-Amino-5,6-dihydro-4H-quino[8,l-ab][3]benzazepin-8(9H)-one
Hydrochlororide
Step A - Synthesis of 8-Phenylφιinnline
A degassed solution of 8-bromoquinoline (1.0 g, 4.81 mmol) (Aldrich) in dioxane (50 mL)/H2O (10 mL) was treated with phenylboronic acic (0.64 g, 5.29 mmol) (Aldrich), Pd(Ph3P)4 (0.050 g, 0.04 mmol) and K2CO3 (0.73 g, 5.29 mmol). After refiuxing for 4 h under a N2 atmosphere the reaction was allowed to cool, diluted with EtOAc and separated. After drying over Na2SO4 and SiO2 chromatography (95:5 Hexanes/EtOAc) the titled compound was isolated as a colorless oil.
Physical data were as follows:
Η-nmr (CDC13): δ = 8.97 (d, IH), 8.22 (dd, IH), 7.87-7.39 (m, 9H). Cl5HuN (MW = 205); mass spectroscopy (MH+ ) 206. Step B - Synthesis of 8-Phenyl-l ,2, ,4-tetrahydroquinoline
The product from Step A (0.99 g, 4.82 mmol) was hydrogenated according to the procedure described by Honel, M., et. al., J.C.S. Perkin I, (1980), 1933-1938.
Physical data were as follows: Η-nmr (CDC13): δ = 7.46 (m, 3H), 7.38 (m, 2H), 6.98 (m, 2H), 6.70 (m,
IH), 3.27 (t, 2H), 2.86 (t, 2H), 1.96 (m, 2H).
C15H15N (MW = 209); mass spectroscopy (MH+ ) 210.
Step C - Synthesis of l -Chloromethvlacetvl-K-phenyl-l 7,3,4- tetrahydroquinoline
The product from Step B (1.0 g, 4.78 mmol) was dissolved in CH2C12 (20 mL)/ H2O (20 mL) and treated with NaHCO3 (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 CH2C12, washed with saturated NaHCO3, dried over Na2SO4 and purified by SiO2 chromatography (CHCL/Hexanes 9:1). The product was isolated as a colorless solid.
Physical data were as follows:
C17H16ClNO (MW = 286.77); mass spectroscopy (MH+ ) 287.
Anal. Calcd for C17H16ClNO; C, 71.45 H, 5.64 N, 4.90. Found: C, 71.63 H, 5.60 N, 4.87.
Step D - Synthesis of 5lfi-nihvdro-4H-quino[8.1 -ah][ ]hen7a7epin-
8(9H)-one The product from Step C (0.89 g, 3.11 mmol) was mixed thoroughly with A1C13 (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 CH2Cl2/NaHCO3 (sat). The combined organic layers were dried over Na2SO4 and the title compound was purified by chromatography (SiO2, CHCl3/hexanes 9:1), yielding a colorless oil which solidified upon standing.
Physical data were as follows:
CI7H15NO (MW = 249.312); mass spectroscopy (MH+ ) 250. Anal. Calcd for C17H15NO; C, 81.90 H, 6.06 N, 5.62. Found: C, 81.75 H, 6.11 N, 5.86.
Step E - Synthesis of 9-Oximo-5τfi-Dihydro-4H-qnino[8ι1 - ah][3]heπza7epin-8(9H)-one
The product from Step D (0.490 g, 1.97 mmol) was dissolved in THF and butyl nitrite (0.46 mL, 3.93 mmol) and treated with KHMDS (0.5 M, 4.52 mL,
2.26 mmol) at 0°C. After stirring for 1 h, the reaction was quenched with cold 1 N
HCl, extracted with EtOAc, the combined organic layers dried over NajSO,, and the product purified by SiO2 chromatography (CHCl3/MeOH, 99: 1). The title compound was isolated as a colorless solid.
Physical data were as follows:
C17H14N2O2 (MW = 278.3); mass spectroscopy (MH+ ) 279.
Anal. Calcd for CI7H14N2O2.0.3317 mol H2O; C, 71.82 H, 5.19 N, 9.85. Found: C, 71.85 H, 5.09 N, 9.59.
Step F - Synthesis of 9- Aτnino-5,6-Dihydro-4H-qιιino[8, 1 - ah][3]hen7a7epin-8t9H)-one The product from Step E (0.360 g, 1.29 mmol) was hydrogenated over Ra Ni (0.05 g) in EtOH (50 mL)/ NH3 (anhydrous) (5.0 mL) at 100°C and 500 psi for 10 h. The catalyst was removed by filtration and the resulting filtrate chromatographed over SiO2 (CHCl3/MeOH, 98:2) yielding the titled compound as a colorless oil which solidified upon standing.
Physical data were as follows: C17H16N2O (MW = 264.326); mass spectroscopy (MH+ ) 266.
Anal. Calcd for CI7H16N2O; C, 77.25 H, 6.10 N, 10.60. Found: C, 77.23 H,
6.15 N, 10.49. Example 35
Synthesis of
9-(N'-L-Alaninyl)amino-5,6-dihydro-
4H-quino[8,l-ab] [3]benzazepin-8(9H)-one Hydrochloride
Step A - Synthesis of 9-fN'-Boc-L- Alaninyllamino-S.ό-Dihydro^H- quino[8r1-ah][3]ben7azepin-8(9H)-one Following General Procedure D and using N-Boc- Alanine (Aldrich) and
9-amino-5,6-dihydro-4H-quino[8,l-ab][3]benzazepin-8(9H)-one (from Example 34), the title compound was prepared.
Physical data were as follows:
C25H29N3O4 (MW = 435.521); mass spectroscopy (MH+ ) 436.
Anal. Calcd for C25H29N3O4.0.4102 mol H2O; C, 67.79 H, 6.79 N, 9.49;
Found: C, 67.83 H, 6.91 N, 9.29.
Step B - Synthesis of 9-fN/-L-AlaninyPamino-5.6-dihydro-4H- quino[8,1-ab][3]ben7a7epin-8(9H)-one Hydrochloride Following General Procedure E and using the product from Step A, the title compound was prepared. Physical data were as follows:
C20H21N3O2.HC1 (MW = 371.6); mass spectroscopy (MH+ free base ) 335.
Example 36
Synthesis of 7-Amino-l,3,4,7,12,12a-hexahydropyrido[2,l-b][3]benzazepin-6(2H)-one
Step A - Synthesis of /V-Chloroacetyl-2-benzylpiperidine
Following General Procedure F and using 2-benzylpyridine, the title compound was prepared.
Physical data were as follows: (MW = 251.8); mass spectroscopy (MH+) 252.0.
Step B - Synthesis of 1 ,3 4,7, 17, 12a-hexahvdropvrido[2.1 -b][3]ben7a7epin-
6(2H)-one Following General Procedure G and using N-chloroacetyl-2- benzylpiperidine, the title compound was prepared. Physical data were as follows:
Η-nmr (CDC13): δ = 1.3-1.9 (6H); 2.42 (t, IH); 3.08 (m, 2H); 3.47 (m, IH);
3.96 (q, 2H); 4.66 (d, IH); 7.2 (m, 4H).
(MW = 215.3); mass spectroscopy (MH+) 216.1.
Step C - Synthesis of 7-Oximo-l .3.4.7.12.1 ?.a-heyahydropyridn[2, 1 - h][3]henza7epin-6(2H)-one Following General Procedure A (Step B) and using 1,3,4,7,12,12a- hexahydropyrido[2,l-b][3]benzazepin-6(2H)-one (from Step B), the title compound was prepared.
Physical data were as follows:
(MW = 244.3); mass spectroscopy (MH+) 245.0.
Step D - Synthesis of 7- Amino-1.3.4.7.12r 12a-hexahydropyrido[?., 1 - h][3]henza7epin-6(2H)-one
Following General Procedure A (Step C) and using 7-oximo- l,3,4,7,12,12a-hexahydropyrido[2,l-b][3]benzazepin-6(2H)-one (from Step C), the title compound was prepared.
Physical data were as follows: 'H-nmr (CDC13): δ = 1.3-1.9 (6H); 2.42 (t, IH); 3.08 (m, 2H); 3.47 (m,
IH); 3.96 (q,2H); 4.66 (d,lH); 7.2 (m,4H).
(MW = 230.3); mass spectroscopy (MH+) 231.1.
Example 37 Synthesis of
1 -(N '-L-Alaninyl)amino-4,5,6,7-tetrahydro- 3,7-methano-3H-3-benzazonin-2(lH)-one
Step A - Synthesis of Λ/-Ch1oroacety1-3-pheny1piperidine
Following General Procedure F and using 3-phenylpyridine hydrochloride (Aldrich), the title compound was prepared. Step B - Synthesis of 4.5.6.7-Tetrahydro-3,7-methann-3H-3- benzazQnin-2(lH)-one Following General Procedure G and using N-chloroacetyl-3- phenylpiperidine, the title compound was prepared. Physical data were as follows:
'H-nmr (CDC13): d = 1.32-1.57 (2H); 2.08 (m, 2H); 2.81 (t, IH); 3.13 (bs,
IH); 3.37 (m, 2H); 4.36 (m, 2H); 4.50 (d, IH).
(MW = 201.3); mass spectroscopy (MH+) 202.1.
Step C - Synthesis of 1 -Oximo-4.5r6.7-tetrahydro-3,7-methano-3H-3- benzazonin-2( 1 H)-one Following General Procedure A (Step B) and using the product from Step
B, the title compound was prepared.
Step D - Synthesis of 1 -Amino-4r5.fi.7-tetτahydro-3r7-methano-3H-3- ben7a7onin-2(1 HVone Following General Procedure A (Step C) and using the product from Step
C, the title compound was prepared.
Physical data were as follows: 'H-nmr (CDC13): δ = 2.86 (t, IH); 3.17 (bs, IH); 3.39 (dd, IH); 4.40 (d,
IH); 4.50 (d, IH); 5.39 (s, IH).
(MW = 216.3); mass spectroscopy (MH+) 217.4.
Step E - Synthesis of 1-rΝ'-Boc-L-Alaninvnamino-4.5.6.7- tetrahydro-3,7-methano-3H-3-ben7a7onin-2(1 H)-one
Following General Procedure D and using N-tert-Boc-L-alanine (Aldrich) and the product from Step D, the title compound was prepared.
Physical data were as follows:
(MW = 387.48); mass spectroscopy (MH+) 388.1.
Step F - Synthesis of l-fΝ'-L-AlaninyDamino-4.5.6.7-tetrahydro-3.7- τnethano-3H-3-hen7a7onin-2n HVone Following General Procedure E and using the product from Step E, the title compound was prepared. Physical data were as follows: Η-nmr (CDC13): δ = 2.85 (t, IH); 3.16 (bs, IH); 3.40 (dd, IH); 3.67 (m, IH); 4.35 (d, IH); 4.56 (d, IH); 6.40 (d, IH).
(MW = 287.4); mass spectroscopy (MH+) 288.1.
Example 38
Synthesis of
5S-[N'-(2S-hydroxy-3-methylbutyryl)-2S-aminopropyl]amino-
7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
Step A - Synthesis of A/-Boc-T,-A1aninal
Methylene chloride (50 mL) was added to a flask equipped with an addition funnel and cooled to -78°C before adding 1.6 mL oxalyl chloride (18.3 mmol, 2.4 eq). This was stirred for 5 minutes, at which time 1.8 mL dimethyl sulfoxide (25.4 mmol, 3.3 eq) dissolved in 20 mL CH2Cl2was added over 5 minutes. This was stirred for an additional 5 minutes before adding 1.4 g N-Boc-L-alaninol (7.8 mmol, 1.0 eq) in 20 mL CH2C12. The reaction mixture was stirred for 5 minutes before 6.5 mL triethylamine (46.6 mmol, 6.0 eq) was added and the reaction warmed to room temperature for 10 minutes. The reaction was quenched with 200 mL 0.1 N aqueous HCl, and this was extracted with 2 x 100 mL CH2C12. The combined organic layers were washed with 100 mL saturated NaHCO3 followed by
100 mL saturated NaCl, then dried over Na^O,, and removed in vacuo. The remaining oil was passed through a silica gel plug with ethyl acetate (EtOAc). The solvent was removed in vacuo to yield 1.14 g (85%) of the desired product. NMR data was as follows: Η NMR (300 MHz, CDC13): δ = 9.56 (s, IH, CHO), 5.06 (bs, IH, NH),
4.24 (bq, IH, CH), 1.45 (s, 9H, C(CH3)3), 1.33 (d, 3H, J= 7.2 Hz, CHCH3). M+ (ionspray) Calcd for CgΗ15 NO3 173.2, Obs. 174.2 (M + IH).
Step B - Synthesis of SS-|NyterNhιιtylnxyrarhnτιy1 -?S- aminopropy1]-amino-7-methyl-5.7-dihydro-fiH- dihenz[b,d]azepin-6-one To a solution of 620 mg of 5S-amino-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one (2.6 mmol, 1.0 eq) (from Example 1) in 50 mL methanol was added 653 mg of N-Boc-L-alaninal (3.8 mmol, 1.4 eq) (from Step A), followed by 74 mg of sodium cyanoborohydride (1.2 mmol, 0.5 eq). This was stirred at room temperature for 1 hour after which the solvent was removed. The resulting solid was dissolved in 50 mL methylene chloride and washed with 50 mL aqueous saturated NaHCO3. The aqueous layer was re-extracted with 50 mL methylene chloride. The combined organic solvents were dried over Na2SO4 and removed in vacuo. The crude product was purified by flash chromatography (1:1 hexanes:ethyl acetate) to yield 309 mg (30%) ofthe desired product.
NMR data was as follows:
Η NMR (300 MHz, CDC13): δ = 7.64-7.31 (m, 8H, aromatic Hs), 4.04 (bs, IH, CHN), 3.73 (bs, IH, CHCH3), 3.34 (s, 3H, NCH3), 2.78 (dd, IH, J= 4.9, 12.0
Hz, CHHN), 2.48 (dd, IH, J= 6.8, 12.0 Hz, CHHN), 1.43 (s, 9Η, CCH3), 1.17 (d, 3H, J= 6.8 Hz, CHCH3).
M+ (ionspray) Calcd for C23Η29N3O3 395.5, Obs. 396.1 (M + IH).
Step C - Synthesis of 5S-(2S-aminopropyl)-arnino-7-rnethy1-5,7- dihydro-6H-dihenz[h,d]azepin-6-one HCl (g) was bubbled through a solution of 317 mg of 5S-[N'-(tert- butyloxycarbonyl)-2S-aminopropyl]amino-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one (0.8 mmol) (from Step B) in 30 mL dioxane for 15 minutes. This was stirred at room temperature for 17 hours at which time the solvent was removed in vacuo to yield 248 mg (94 %) of a white solid. This was used without further purification.
NMR data was as follows:
'H NMR (300 MHz, CD3OD) 7.73-7.45 (m, 8H, aromatic Hs), 3.76 (m, IH, CHCH3), 3.38 (m, 5H, NCH3 and CH2N), 1.46 (d, 3H, J= 6.4 Hz, CHCH3).
M* (ionspray) Calcd for C18Η2IN3O 295.4, Obs. 296.4 (M + IH).
Step D - Synthesis of 5S-[N 2S-hydroxy-3-methy1hutyryn-2S- aminopropy1]amino-7-methyl-5.7-dihydro-6H- dihen7[h,d]azepin-6-one
To a solution of 240 mg 5S-(2S-aminopropyl)-amino-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one (0.8 mmol, 1.0 eq) (from Step C) in 25 mL
4:1 tetrahydrofuran (THF): dimethylformamide (DMF) was added 125 mg of 2- hydroxy-3-methylbutyric acid (1.1 mmol, 1.3 eq), 184 mg of N-ethyl-N'-(3- dimethylaminopropyl)-carbodiimide (1.0 mmol, 1.2 eq), 139 mg 1- hydroxybenzotriazole hydrate (0.9 mmol, 1.1 eq), and 0.5 mL of diisopropylethylamine (2.9 mmol, 3.5 eq). The reaction mixture was stirred at room temperature for 20 hours. The solvent was removed and the remaining oil diluted with 30 mL CH2Cl2and washed with 25 mL 0.1 N aqueous HCl. The aqueous layer was back extracted with 25 mL CH2C12. The combined orgainc layers were dried over NajSO,, and removed in vacuo. The crude product was purified by flash column chromatography (ethyl acetate) to yield 38 mg (12 %) of the desired product as a white solid.
NMR data was as follows:
Η NMR (300 MHz, CDC13): δ = 7.62-7.37 (m, 8H, aromatic Hs), 6.67 (d, IH, J= 9.0 Hz, NHCO) 4.61 (m, IH, CHCH3), 4.40 (bs, IH, CHNH), 4.13 (d, 1Η, J= 3.8 Ηz, CHOΗ), 3.38 (s, 3Η, NCH3), 2.95 (m, 2H, CH2NH), 2.10 (m, IH, CH(CH3)2), 1.26 (d, 3H, J= 6.4 Hz, CHCH3), 1.06 (d, 3Η, J= 6.8 Hz, CH(CH3)2),
0.93 (d, 3Η, J= 6.8 Hz, CH(CH3)2).
M (ionspray) Calcd for C23Η29N3O3 395.5, Obs. 396.1 (M + IH).
Anal. Calcd for C23H29N3O3 C, 69.85; H, 7.39; N, 10.62. Found: C, 69.63; H, 7.44; N, 10.32.
The following examples illustrate how a compound prepared from a synthetic intermediate of this invention could be assayed to determine its ability to inhibit β-amyloid production in a cell or tested to determine its ability to suppress β-amyloid release and/or synthesis in vivo.
Example 39 Cellular Screen for the Detection of Inhibitors of β-Amyloid Production
Using the procedure of this example, compounds can be assayed for their ability to inhibit β-amyloid production in a cell line possessing the Swedish mutation. This screening assay employs cells (K293 = human kidney cell line) which are stably transfected with the gene for amyloid precursor protein 751 (APP751) containing the double mutation Lys651Met652 to Asn651Leu652 (APP751 numbering) in the manner described in International Patent Application Publication No. 94/1056915 and Citron et al.16. This mutation is commonly called the Swedish mutation and the cells, designated as "293 751 SWE", are plated in Coming 96- well plates at 2-4 x 104 cells per well in Dulbecco's minimal essential media (Sigma, St. Louis, MO) plus 10% fetal bovine serum. Cell number is important in order to achieve β-amyloid ELISA results within the linear range ofthe assay (-0.2 to 2.5 ng per mL).
Following overnight incubation at 37°C in an incubator equilibrated with 10% carbon dioxide, media are removed and replaced with 200 μL of a compound to be tested (drug) containing media per well for a two hour pretreatment period and cells are incubated as above. Drug stocks are prepared in 100% dimethyl sulfoxide such that at the final drug concentration used in the treatment, the concentration of dimethyl sulfoxide does not exceed 0.5% and, in fact, usually equals 0.1%.
At the end ofthe pretreatment period, the media are again removed and replaced with fresh drug containing media as above and cells are incubated for an additional two hours. After treatment, plates are centrifuged in a Beckman GPR at 1200 φm for five minutes at room temperature to pellet cellular debris from the conditioned media. From each well, 100 μL of conditioned media or appropriate dilutions thereof are transferred into an ELISA plate precoated with antibody 266 [P. Seubert, Nature (1992) 359:325-32717] against amino acids 13-28 of β-amyloid peptide as described in International Patent Application Publication No. 94/1056915 and stored at 4°C overnight. An ELISA assay employing labeled antibody 3D6 [P.
Seubert, Nature (1992) 359:325-32717] against amino acids 1-5 of β-amyloid peptide is run the next day to measure the amount of β-amyloid peptide produced.
Cytotoxic effects ofthe compounds are measured by a modification ofthe method of Hansen, et al.18. To the cells remaining in the tissue culture plate is added 25 μL of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis, MO) stock solution (5 mg/mL) to a final concentration of 1 mg/mL. Cells are incubated at 37°C for one hour, and cellular activity is stopped by the addition of an equal volume of MTT lysis buffer (20% w/v sodium dodecylsulfate in 50% dimethylformamide, pH 4.7). Complete extraction is achieved by overnight shaking at room temperature. The difference in the OD562nm and the OD650nm is measured in a Molecular Device's UNmax microplate reader as an indicator ofthe cellular viability.
The results ofthe β-amyloid peptide ELISA are fit to a standard curve and expressed as ng/mL β-amyloid peptide. In order to normalize for cytotoxicity, these results are divided by the MTT results and expressed as a percentage ofthe results from a drug free control. All results are the mean and standard deviation of at least six replicate assays.
The test compounds are assayed for β-amyloid peptide production inhibition activity in cells using this assay. The results of this assay can be used to demonstrate that the compounds prepared from the intermediates of this invention inhibit β-amyloid peptide production by at least 30% as compared to control when employed at 10 μg/mL.
Example 40
In Vivo Suppression of β-Amyloid Release and/or Synthesis
This example illustrates how the compounds prepared from the intermediate compounds of this invention could be tested for in vivo suppression of β-amyloid release and/or synthesis. For these experiments, 3 to 4 month old PDAPP mice are used [Games et al., (1995) Nature 373:523-52719]. Depending upon which compound is being tested, the compound is usually formulated at between 1 and 10 mg/mL. Because ofthe low solubility factors of the compounds, they may be formulated with various vehicles, such as com oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil; 2-hydroxypropyl-β-cyclodextrin (Research Biochemicals International, Νatick MA); and carboxy-methyl-cellulose
(Sigma Chemical Co., St. Louis MO). The mice are dosed subcutaneously with a 26 gauge needle and 3 hours later the animals are euthanized via CO2 narcosis and blood is taken by cardiac puncture using a 1 cc 25G 5/8" tuberculin syringe/needle coated with solution of 0.5 M EDTA, pH 8.0. The blood is placed in a Becton-Dickinson vacutainer tube containing EDTA and spun down for 15 minutes at 1500 xg at 5 °C. The brains of the mice are then removed and the cortex and hippocampus are dissected out and placed on ice.
1. Brain Assay To prepare hippocampal and cortical tissue for enzyme-linked immunosorbent assays (ELIS As) each brain region is homogenized in 10 volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher, Pittsburgh PA). The homogenates are gently rocked on a rotating platform for three to four hours at room temperature and stored at -20 ° C prior to quantitation of β-amyloid.
The brain homogenates are diluted 1 :10 with ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 μg/mL aprotinin, 5 mM EDTA, pH 8.0, 10 μg/mL leupeptin], thereby reducing the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 xg for 20 minutes at 4°C. Samples are further diluted, if necessary, to achieve an optimal range for the ELISA measurements by the addition of casein buffer with 0.5 M guanidine hydrochloride added. The β-amyloid standards (1-40 or 1-42 amino acids) were prepared such that the final composition equaled 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).
The total β-amyloid sandwich ELISA, quantitating both β-amyloid (aa 1- 40) and β-amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) to β- amyloid. The capture antibody, 266 [P. Seubert, Nature (1992) 359:325-32717], is specific to amino acids 13 - 28 of β-amyloid. The antibody 3D6 [Johnson- Wood et al., RN S USA (1997) 94:1550-155520], which is specific to amino acids 1 - 5 of β- amyloid, is biotinylated and served as the reporter antibody in the assay. The 3D6 biotinylation procedure employs the manufacturer's (Pierce, Rockford IL) protocol for NHS-biotin labeling of immunoglobulins except that 100 mM sodium bicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP but detects only β-amyloid species with an amino terminal aspartic acid. The assay has a lower limit of sensitivity of -50 pg/mL (11 pM) and shows no cross-reactivity to the endogenous murine β-amyloid peptide at concentrations up to 1 ng/mL.
The configuration ofthe sandwich ELISA quantitating the level of β- amyloid (aa 1 -42) employs the mAb 2 IF 12 [Johnson- Wood et al., PNAS USA
(1997) 94:1550-155520] (which recognizes amino acids 33-42 of β-amyloid) as the capture antibody. Biotinylated 3D6 is also the reporter antibody in this assay which has a lower limit of sensitivity of -125 pg/mL (28 pM).
The 266 and 2 IF 12 capture mAbs are coated at 10 μg/mL into 96 well immunoassay plates (Costar, Cambidge MA) overnight at room temperature. The plates are then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature, then stored desiccated at 4°C until use. The plates are rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use. The samples and standards are added to the plates and incubated overnight at 4°C. The plates are washed ≥ 3 times with wash buffer between each step ofthe assay. The biotinylated 3D6, diluted to 0.5 μg/mL in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is incubated in the well for 1 hour at room temperature. Avidin-HRP (Vector, Burlingame CA) diluted 1 :4000 in casein incubation buffer is added to the wells for 1 hour at room temperature. The colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA), is added and allowed to react for 15 minutes, after which the enzymatic reaction is stopped with addition of 2 N H2SO4. Reaction product is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) measuring the difference in absorbance at 450 nm and 650 nm. 2. Blood Assay
The EDTA plasma is diluted 1 : 1 in specimen diluent (0.2 gm/1 sodium phosphate»H2O (monobasic), 2.16 gm/1 sodium phosphate »7H2O (dibasic), 0.5gm/l thimerosal, 8.5 gm 1 sodium chloride, 0.5 mL Triton X-405, 6.0 g/1 globulin-free bovine serum albumin; and water). The samples and standards in specimen diluent are assayed using the total β-amyloid assay (266 caprure/3D6 reporter) described above for the brain assay except the specimen diluent was used instead ofthe casein diluents described.
Formulations other than those described above can also be used for oral delivery and intravenous delivery to a mammal. For oral delivery, the compound can be mixed with either 100% com oil or, alternatively, in a solution comtaining 80% com oil, 19.5% oleic acid and 0.5% labrafil. The compound can be mixed with the above solutions in concentrations ranging from 1 mg/mL to 10 mg/mL. The compound in solution is preferably administered orally to the mammal at a dose volume of 5 mL/kg of body weight. For IV delivery, the compound is preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% saline. The compound is preferably mixed with the above solution in concentrations ranging from 0.25 mg/mL to 5 mg/mL. The compound in solution is preferably administered by IV to the mammal at a dose volume of 2 mL/kg of body weight.
From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope ofthe appended claims are intended to be included therein.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I:
wherein W is a substituted e-caprolactam selected from the group consisting of:
wherein ring A, together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring B, together with the atoms ofthe e-caprolactam to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; ring C, together with the atoms of the e-caprolactam to which it is attached, forms a heteroaryl or heterocyclic ring;
R1 is selected from the group consisting of hydrogen and an amino- blocking group; each R2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl and heterocyclic;
R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; m is an integer from 0 to 2; n is an integer from 0 to 2; and salts thereof.
2. The compound of Claim 1 wherein R1 is selected from the group consisting of hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, 1-(1 '- adamantyl)-l-methylethoxycarbonyl, allyloxycarbonyl, benzyloxymethyl, 2-p- biphenylisopropyloxycarbonyl, tert-butyldimethylsilyl, benzoyl, benzyl, 9- fluorenylmethyloxycarbonyl, 4-methylbenzyl, 4-methoxybenzyl, 2- nitrophenylsulfenyl, 3-nitro-2-pyridinesulfenyl, trifluoroacetyl, 2,4,6- trimethoxybenzyl and trityl.
3. The compound of Claim 2 wherein R1 is selected from the group consisting of hydrogen and tert-butoxycarbonyl.
4. The compound of Claim 1 wherein each R2 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
5. The compound of Claim 4 wherein each R2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, /.-butyl, isobutyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6- fluoro-H-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, z'sø-but- 2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2- cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, ?-(phenyl)phenyl, o- fluorophenyl, m-fluorophenyl, ^-fluorophenyl, m-rnethoxyphenyl, -rnethoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, 7-hydroxybenzyl, -nitrobenzyl, m-trifluoromethylphenyl, p- (CH3)2NCH2CH2CH2O-benzyl, ?-(CH3)3COC(O)CH2O-benzyl, ?-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, -(N- moφholino-CH2CH2O)-benzyl, -CH2CH2C(O)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, - CH2-C(O)O-t-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2,
-2-methylcyclopentyl; -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3, -CH,OH, -CH(OH)CH3, -CH(0-t-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl, pyridyl, -CH2-naphthyl,
-CH2-(4-moφholinyl), ?-(4-moφholinyl-CH2CH2O)-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, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl.
6. The compound of Claim 1 wherein R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
7. The compound of Claim 6 wherein R3 is selected from the group consisting of hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl and cyclohexyl.
8. The compound of Claim 1 wherein Wis a substituted e-caprolactam selected from the group consisting of:
9. The compound of Claim 8 wherein rings A and B are the same or different and each is independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic.
10. The compound of Claim 9 wherein rings A and B are independently selected from the group consisting of aryl and cycloalkyl.
11. The compound of Claim 10 wherein rings A and B are independently aryl.
12. The compound of Claim 8 wherein Wis a substituted e-caprolactam ofthe formula:
13. The compound of Claim 12 wherein rings A and B are the same or different and each is independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic.
14. The compound of Claim 13 wherein rings A and B are independently selected from the group consisting of aryl and cycloalkyl.
15. The compound of Claim 14 wherein rings A and B are independently aryl.
16. The compound of Claim 12 wherein Wis a substituted e- caprolactam ofthe formula:
wherein each R5 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; each R6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; p is an integer from 0 to 4; q is an integer from 0 to 4; and salts thereof.
17. The compound of Claim 16 wherein R5 and R6 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
18. The compound of Claim 16 wherein R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl.
19. The compound of Claim 18 wherein R7 is selected from the group consisting of hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl,
3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl and cyclohexyl.
20. The compound of Claim 16 wherein Wis a substituted e- caprolactam selected from the group consisting of 5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl, 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one- 5-yl, 7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 7- (methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 7-(3,3- dimethylbutan-2-onyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-yl, 7-phenbutyl- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one-yl, 7-cyclopropymethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-yl, 7-(2',2',2'-trifluoroethyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-yl, 7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one-5-yl, 7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 9-fluoro-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 10-fluoro-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one-5-yl, 13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one-5-yl and 7-methyl-l,2,3,4,5,7-hexahydro-6H- dicyclohexyl[b,d]azepin-6-one-5-yl.
21. The compound of Claim 8 wherein W is a substituted e-caprolactam ofthe formula:
22. The compound of Claim 21 wherein rings A and B are the same or different and each is independently selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic.
23. The compound of Claim 22 wherein rings A and B are independently selected from the group consisting of aryl and cycloalkyl.
24. The compound of Claim 23 wherein rings A and B are independently aryl.
25. The compound of Claim 24 wherein Wis a substituted e- caprolactam of the formula:
wherein each R5 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; each R6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, - SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; p is an integer from 0 to 4; r is an integer from 0 to 3; and salts thereof.
26. The compound of Claim 25 wherein R5 and R6 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
27. The compound of Claim 8 wherein fTis a substituted e-caprolactam ofthe formula:
28. The compound of Claim 27 wherein ring A is selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic.
29. The compound of Claim 22 wherein ring A is selected from the group consisting of aryl and cycloalkyl.
30. The compound of Claim 29 wherein ring A is aryl.
31. The compound of Claim 30 wherein W is a substituted e- caprolactam ofthe formula:
wherein each Rs is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; p is an integer from 0 to 4; and salts thereof.
32. The compound of Claim 31 wherein R5 is selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
33. The compound of Claim 8 wherein Wis a substituted e-caprolactam ofthe formula:
34. The compound of Claim 33 wherein ring A is selected from the group consisting of aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic.
35. The compound of Claim 34 wherein ring A is selected from the group consisting of aryl and cycloalkyl.
36. The compound of Claim 35 wherein ring A is aryl.
37. The compound of Claim 36 wherein Wis a substituted e- caprolactam ofthe formula:
wherein each R5 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl; p is an integer from 0 to 4; and salts thereof.
38. The compound of Claim 37 wherein R5 is selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy.
39. A compound selected from the group consisting of: 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-amino)-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-amino)-7-(methoxycarbonymethyl)-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-amino-7-(methoxycarbonylmethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5 -(N-Boc-amino)-7-(3 ,3 -dimethyl-butanonyl)-5 ,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-(2,,2',2'-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-amino-7-methyl-l,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6- one 5-(N-Boc-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(N-Boc-L-valinyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(L-valinyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-(N-Boc-L-tert-leucinyl)amino-7-methyl-5 ,7-dihydro-6H- dibenz[b,d]azeρin-6-one
5-(L-tert-leucinyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(N-Boc-L-alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-(L-alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-(N-Boc-L-alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-alaninyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-alaninyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-alaninyl)amino-7-phenbutyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-(L-alaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one 5-(L-valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-(L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6- one
5-(L-valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-(N-Boc-L-valinyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-valinyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one 5-(N-Boc-L-valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one
5-(N-Boc-L-valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one
5-(L-valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-
6-one
5-amino-9,13-difluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5-amino-10,13-difluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one
5-aminohexahydropyrido[a]benz[d]azepin-6-one
9-amino-5,6-Dihydro-4H-quino[8,l-ab][3]benzazepin-8(9H)-one
9-(Ν'-Boc-L-alaninyl)amino-5,6-Dihydro-4H-quino[8,l-ab][3]benzazepin- 8(9H)-one
9-(N'-L-alaninyl)amino-5,6-dihydro-4H-quino[8,l-ab][3]benzazepin- 8(9H)-one
7-amino-l ,3,4,7, 12, 12a-hexahydropyrido[2, 1 -b][3]benzazepin-6(2H)-one l-amino-4,5,6,7-tetrahydro-3)7-methano-3H-3-benzazonin-2(lH)-one l-(N'-Boc-L-alaninyl)amino-4,5,6,7-tetrahydro-3,7-methano-3H-3- benzazonin-2( 1 H)-one l-(N'-L-alaninyl)amino-4,5,6,7-tetrahydro-3,7-methano-3H-3-benzazonin- 2(lH)-one and salts thereof.
EP98956198A 1997-12-22 1998-10-29 Polycyclic alpha-amino-epsilon-caprolactams and related compounds Withdrawn EP1042298A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US996422 1997-12-22
US08/996,422 US6635632B1 (en) 1996-12-23 1997-12-22 Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US10272698A 1998-06-22 1998-06-22
US102726 1998-06-22
PCT/US1998/022637 WO1999032453A1 (en) 1997-12-22 1998-10-29 POLYCYCLIC α-AMINO-⊂-CAPROLACTAMS AND RELATED COMPOUNDS

Publications (1)

Publication Number Publication Date
EP1042298A1 true EP1042298A1 (en) 2000-10-11

Family

ID=26799672

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98956198A Withdrawn EP1042298A1 (en) 1997-12-22 1998-10-29 Polycyclic alpha-amino-epsilon-caprolactams and related compounds

Country Status (9)

Country Link
EP (1) EP1042298A1 (en)
JP (1) JP2003521438A (en)
KR (1) KR20010033408A (en)
AU (1) AU1277799A (en)
BR (1) BR9812773A (en)
CA (1) CA2307221A1 (en)
HU (1) HUP0100294A3 (en)
IL (1) IL135564A0 (en)
WO (1) WO1999032453A1 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ525513A (en) 1998-08-07 2004-09-24 Pont Pharmaceuticals Du Succinoylamino lactams as inhibitors of Abeta protein production
BR9917082A (en) 1998-12-24 2001-11-06 Du Pont Pharm Co Compounds that inhibit the production of "beta" proteins, a method of treating neurological disorders associated with the production of "beta" -amyloid, pharmaceutical composition and, method of inhibiting y-secretase activity
WO2001002358A2 (en) * 1999-07-06 2001-01-11 Vertex Pharmaceuticals Incorporated Cyclized amide derivatives for treating or preventing neuronal damage
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
BR0014269A (en) * 1999-09-13 2002-07-02 Bristol Myers Squibb Pharma Co Lactam compounds, their pharmaceutically acceptable salts and prodrugs, pharmaceutical composition, method of treating neurological disorders associated with the production of "beta" -amyloid, method of inhibiting "alpha" -secretase activity and uses of the compounds
EP1222176A1 (en) 1999-10-08 2002-07-17 Bristol-Myers Squibb Pharma Company AMINO LACTAM SULFONAMIDES AS INHIBITORS OF A$g(b) PROTEIN PRODUCTION
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
IL151576A0 (en) 2000-04-03 2003-04-10 Bristol Myers Squibb Pharma Co Cyclic lactams as inhibitors of a-beta protein production
AU2001253108A1 (en) 2000-04-03 2001-10-15 Bristol-Myers Squibb Pharma Company Cyclic lactams as inhibitors of a-beta protein production
US6632812B2 (en) 2000-04-11 2003-10-14 Dupont Pharmaceuticals Company Substituted lactams as inhibitors of Aβ protein production
CA2379445C (en) 2000-06-01 2007-08-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of a.beta. protein production
US6432944B1 (en) 2000-07-06 2002-08-13 Bristol-Myers Squibb Company Benzodiazepinone β-amyloid inhibitors: arylacetamidoalanyl derivatives

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4666829A (en) * 1985-05-15 1987-05-19 University Of California Polypeptide marker for Alzheimer's disease and its use for diagnosis
ATE247282T1 (en) * 1992-10-26 2003-08-15 Elan Pharm Inc METHOD FOR IDENTIFYING INHIBITORS OF BETA-AMYLOID PEPTIDE PRODUCTION
NZ264143A (en) * 1993-08-09 1996-11-26 Lilly Co Eli Use of an aspartyl protease inhibitor to inhibit beta-amyloid peptide production
US5580979A (en) * 1994-03-15 1996-12-03 Trustees Of Tufts University Phosphotyrosine peptidomimetics for inhibiting SH2 domain interactions
US6251928B1 (en) * 1994-03-16 2001-06-26 Eli Lilly And Company Treatment of alzheimer's disease employing inhibitors of cathepsin D
ZA9711537B (en) * 1996-12-23 1998-06-25 Athena Neurosciences Inc Eli L Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting ß-amyloid peptide release and/or its synthesis by use of such compounds.
HRP980093A2 (en) * 1997-02-28 1998-12-31 Lilly Co Eli Heterocyclic compounds, pharmaceutical compositions comprising same, and methods for inhibiting "beta"-amyloid peptide release and/or its synthesis by use of such compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9932453A1 *

Also Published As

Publication number Publication date
CA2307221A1 (en) 1999-07-01
HUP0100294A3 (en) 2003-04-28
JP2003521438A (en) 2003-07-15
AU1277799A (en) 1999-07-12
WO1999032453A1 (en) 1999-07-01
KR20010033408A (en) 2001-04-25
BR9812773A (en) 2000-10-10
HUP0100294A2 (en) 2001-09-28
IL135564A0 (en) 2001-05-20

Similar Documents

Publication Publication Date Title
US6509331B1 (en) Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US8188069B2 (en) Azepine derivatives as gamma-secretase inhibitors
JP2002518481A (en) Compounds for inhibiting the release of β-amyloid peptide and / or its synthesis
JP2002518451A (en) Cyclic amino acid compound and pharmaceutical composition thereof, and method of inhibiting release of β-amyloid peptide and / or synthesis thereof using the compound
JP2000511932A (en) Cycloalkyls, lactams, lactones and related compounds and pharmaceutical compositions thereof, and methods for inhibiting β-amyloid peptide release and / or synthesis using the compounds
EP1089980A1 (en) Compounds for inhibiting beta-amyloid peptide release and/or its synthesis
EP1042298A1 (en) Polycyclic alpha-amino-epsilon-caprolactams and related compounds
US6974829B2 (en) Succinoyl aminopyrazoles and related compounds
EP1089981A1 (en) Compounds for inhibiting beta-amyloid peptide release and/or its synthesis.
WO2003064396A1 (en) Hydroxyalkanoyl aminopyrazoles and related compounds
CA2390376A1 (en) .beta.-aminoacid compounds useful for inhibiting .beta.-amyloid peptide release and/or its synthesis
CA2528496C (en) Acylated amino acid amidyl pyrazoles and related compounds
US6958330B1 (en) Polycyclic α-amino-ε-caprolactams and related compounds
US6838455B2 (en) Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
CA2388750A1 (en) .beta.-aminoacid compounds useful for inhibiting .beta.-amyloid peptide release and/or its synthesis
US6696438B2 (en) Cyclic amino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6774125B2 (en) Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6906056B2 (en) Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
MXPA00005540A (en) POLYCYCLIC&agr;-AMINO-?-CAPROLACTAMS AND RELATED COMPOUNDS
US20050192265A1 (en) Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000605

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20000605;LT PAYMENT 20000605;LV PAYMENT 20000605;MK PAYMENT 20000605;RO PAYMENT 20000605;SI PAYMENT 20000605

17Q First examination report despatched

Effective date: 20020624

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030108