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EP0944580A2 - Esters de n-(aryl/heteroaryl) aminoacide, compositions pharmaceutiques et methodes pour inhiber la liberation du peptide beta-amyloide et/ou sa synthese - Google Patents

Esters de n-(aryl/heteroaryl) aminoacide, compositions pharmaceutiques et methodes pour inhiber la liberation du peptide beta-amyloide et/ou sa synthese

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Publication number
EP0944580A2
EP0944580A2 EP97952177A EP97952177A EP0944580A2 EP 0944580 A2 EP0944580 A2 EP 0944580A2 EP 97952177 A EP97952177 A EP 97952177A EP 97952177 A EP97952177 A EP 97952177A EP 0944580 A2 EP0944580 A2 EP 0944580A2
Authority
EP
European Patent Office
Prior art keywords
alanine
ester
group
dichlorophenyl
iso
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Withdrawn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
EP97952177A
Other languages
German (de)
English (en)
Inventor
James E. Audia
Beverly K. Folmer
Varghese John
Lee H. Latimer
Jeffrey S. Nissen
Jon K. Reel
Eugene D. Thorsett
Celia A. Whitesitt
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
Application filed by Elan Pharmaceuticals LLC, Eli Lilly and Co filed Critical Elan Pharmaceuticals LLC
Publication of EP0944580A2 publication Critical patent/EP0944580A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/16—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to compounds which inhibit /3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • AD Alzheimer's Disease
  • AD failureia
  • AD in aged humans and is believed to represent the fourth most common medical cause of death in the United States.
  • AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
  • the brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles.
  • senile or amyloid
  • amyloid angiopathy amyloid deposits in blood vessels
  • neurofibrillary tangles Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD.
  • Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D).
  • a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
  • amyloid angiopathy amyloid angiopathy characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the ⁇ -amyloid peptide ( / SAP) or sometimes A ⁇ , A / SP or p7A4.
  • ⁇ - Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al. 1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,829 2 .
  • ⁇ -amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans.
  • APP precursor protein
  • Knowledge of the structure of the gene encoding the APP has demonstrated that j6-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 / 3-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
  • a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the 3-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 /3-amyloid peptide fragment can cause AD.
  • the treatment methods would advantageously be based on drugs which are capable of inhibiting /3-amyloid peptide release and/or its synthesis in vivo.
  • This invention is directed to the discovery of a class of compounds which inhibit /3-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/ or in the treatment of patients with AD in order to inhibit further deterioration in their condition.
  • the class of compounds having the described properties are defined by formula I below:
  • R 1 is selected from the group consisting of: (a) a substituted phenyl group of formula II:
  • R c is selected from the group consisting of acyl, alkyl, alkoxy, alkoxycarbonyl, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R b and R c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
  • R b and R b' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that R b , R b' and R c are not all hydrogen and with the further proviso that when R c is hydrogen, then neither R b nor R b' are hydrogen;
  • R 2 is selected from the group consisting of hydrogen, alkyl of from 1 to
  • R 3 is selected from the group consisting of:
  • n is an integer of from 0 to 2
  • Y is selected from the group consisting of oxygen and sulfur
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, heteroaryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, and where R 4 and R 5 are joined to form a cycloalkyl group, a cycloalkenyl group, or a heterocyclic group;
  • R 1 is the substituted phenyl group of formula II above, R b' is hydrogen, R b and R c are chloro, and R 2 is methyl, then R 3 is not -OCH(CH 3 )- ⁇ ;
  • R 1 is the substituted phenyl group of formula II above
  • R b' is hydrogen
  • R b and R c are chloro
  • R 3 is -OCH 2 CH 3 then R 2 is not hydrogen
  • R 1 is the substituted phenyl group of formula II above, R b' is hydrogen, R b and R c are chloro, and R 3 is -OCH 2 CH(CH 3 ) 2 then R 2 is not -CH(CH 3 )CH 2 CH 3 ; and 4. when R 1 is N-methylindol-5-yl and R 2 is methyl, then R 3 is not
  • any substituents at the 2 and/or 6 positions or substituents at the 3, 4 and/or 5 positions, other than those specifically specified above, eliminate the ability of the resulting compounds to inhibit /3-amyloid peptide release and/or its synthesis.
  • this invention is directed to a method for inhibiting /3-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of /3-amyloid peptide.
  • this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
  • this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
  • R 1 substituted phenyls are preferably 4-substituted, 3,5-disubstituted or 3,4-disubstituted phenyl substituents wherein the substituents at the 3 and/or 5 positions are defined by R b , R b' as above and the substituent at the 4 position is defined by R c as above.
  • Particularly preferred 3,5-disubstituted phenyls include, by way of example, 3,5-dichlorophenyl, 3,5- difluorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, and the like.
  • preferred 3,4-disubstituted phenyls include, by way of example, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluorornefhyl)-4- chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, 3,4- methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, and the like.
  • Particularly preferred 4-substituted phenyls include, by way of example, 4-azidophenyl, 4- bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4- iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(l-ethoxy)ethylphenyl, 4- (ethoxycarbonyl)phenyl, and the like.
  • R 1 substituents include, by way of example, 2-naphthyl,
  • R 2 is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms and alkylthioalkoxy of from 1 to 4 carbon atoms.
  • Particularly preferred R 2 substituents include, by way of example, methyl, ethyl, n-propyl, wo-butyl, and the like.
  • This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of the formula I above.
  • Particularly preferred compounds for use in the methods and compositions of this invention include, by way of example, the following wherein the stereochemistry of the R 2 group (where appropriate) is derived from the L-amino acid: N-(3,4-dichlorophenyl)alanine ethyl ester; N-(3-trifluoromethyl-4-chlorophenyl)alanine ethyl ester;
  • N-(3,5-difluorophenyl)alanine iso-butyl ester; N-(3,4-dichlorophenyl)alanine O-acylacetamidoxime ester;
  • N-(naphth-2-yl)alanine methyl ester N-(benzothiazol-6-yl)alanine ethyl ester;
  • N-(2-napthyl)alanine O-acylisovaleramidoxime ester N-(2-napthyl)alanine O-acylbenzamidoxime ester;
  • R 1 is selected from the group consisting of: (a) a substituted phenyl group of formula II:
  • R c is selected from the group consisting of acyl, alkyl, alkoxy, alkoxycarbonyl, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and where R b and R c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
  • R b and R b' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that R b , R b' and R c are not all hydrogen and with the further proviso that when R c is hydrogen, then neither R b nor R b' are hydrogen;
  • R 2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms and alkylthioalkoxy of from 1 to 4 carbon atoms;
  • R 3 is selected from the group consisting of: (a) -Y(CH 2 ) n CHR 4 R 5 wherein n is an integer of from 0 to 2, Y is selected from the group consisting of oxygen and sulfur, R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, heteroaryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, and where R 4 and R 5 are joined to form a cycloalkyl group, a cycloalkenyl group or a heterocyclic group;
  • R 1 is the substituted phenyl group of formula II above, R b' is hydrogen, R b and R c are chloro, and R 2 is methyl, then R 3 is not -OCH(CH 3 )- ⁇ ;
  • R 1 is the substituted phenyl group of formula II above
  • R b' is hydrogen
  • R b and R c are chloro
  • R 3 is -OCH 2 CH 3 then R 2 is not hydrogen
  • R 1 is the substituted phenyl group of formula II above, R b' is hydrogen, R b and R c are chloro, and R 3 is -OCH 2 CH(CH 3 ) 2 then R 2 is not -CH(CH 3 )CH 2 CH 3 ; and 4. when R 1 is N-methylindol-5-yl and R 2 is methyl, then R 3 is not
  • N-(4-chlorophenyl)alanine ethyl ester N-(3,4-dichlorophenyl)alanine ethyl ester; N-(3,5-dichlorophenyl)alanine ethyl ester; N-(4-n-butylphenyl)alanine ethyl ester; N-(3,4-dinitrophenyl)alanine ethyl ester; N-(4-chlorophenyl)glycine heptenyl ester; N-(4-methylphenyl)glycine butyl ester; N-(3-nitrophenyl)glycine decyl ester; N-(3,4-difluorophenyl)alanine methyl ester; N-(3,4-difluoro- phenyl)alanine ethyl
  • Preferred compounds of formula I above include those set forth in Formula IV below:
  • this invention relates to compounds which inhibit /3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • this invention relates to compounds which inhibit /3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • /3-amyloid peptide refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al. 1 including mutations and post-translational modifications of the normal /3-amyloid peptide.
  • the /3-amyloid peptide is approximately a 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: 1
  • Alkyl refers to monovalent alkyl 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 methyl, ethyl, -propyl, w ⁇ -propyl, n-butyl, iso- butyl, n-hexyl, and the like.
  • 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.
  • Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • Alkoxy refers to the group “alkyl-O-" where alkyl is as defined herein. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, /z-propoxy, w ⁇ -propoxy, n-butoxy, terr-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Alkoxycarbonyl refers to the group “alkyl-O-C(O)-" wherein alkyl is as defined herein.
  • Such groups include, by way of example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, w ⁇ -propoxy carbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, H-pentoxycarbonyl, n-hexoxycarbonyl, and the like.
  • Alkylalkoxy refers to the group “-alkylene-O-alkyl” wherein alkylene and alkoxy are as defined herein.
  • groups include, by way of example, methylmethoxy (-CH 2 OCH 3 ), ethylmethoxy (-CH 2 CH 2 OCH 3 ), n-propyl-wo- propoxy (-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methyl- rt-butoxy (-CH 2 -O-C(CH 3 ) 3 ) and the like.
  • Alkylthioalkoxy refers to the group “-alkylene-S-alkyl” wherein alkylene and alkoxy are as defined herein.
  • groups include, by way of example, methylthiomethoxy (-CH 2 SCH 3 ), ethylthiomethoxy (-CH 2 CH 2 SCH 3 ), «-propyl-w ⁇ -thiopropoxy (-CH 2 CH 2 CH 2 SCH(CH 3 ) 2 ), methyl-t -thiobutoxy (-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.
  • 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.
  • Acyl refers to the groups alkyl-C(O)-, aryl-C(O)-, and heteroaryl-
  • aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen or alkyl where alkyl is as defined herein.
  • Acyloxy refers to the groups alkyl-C(O)O-, aryl-C(O)O-, heteroaryl- C(O)O-, and heterocyclic-C(O)O- where alkyl, 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 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 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, aryl, aryloxy, carboxyl, alkoxycarbonyl, acylamino, cyano, halo, nitro, heteroaryl, trihalomethyl and the like.
  • 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.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2- methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • 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 which can be optionally substituted with from 1 to 3 alkyl groups.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3- enyl, cyclooct-3-enyl and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either chloro or fluoro.
  • Heteroaryl refers to a monovalent aromatic group of from 2 to 8 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
  • heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy and the like.
  • 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.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 8 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 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy and the like.
  • heterocyclic groups can have a single ring (e.g., piperidinyl or tetrahydrofuryl) or multiple condensed rings (e.g., indolinyl, dihydrobenzofuran or quinuclidinyl).
  • Preferred heterocycles include piperidinyl, pyrrolidinyl and tetrahydrofuryl.
  • heterocycles and heteroaryls include, but are not limited to, furan, thiophene, thiazole, oxazole, pyrrole, 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, pyrrolidine, indoline and the like.
  • R b and R c can be fused to form a heteroaryl or heterocyclic ring with the phenyl ring. Fusion in this manner results in a fused bicyclic ring structure of the formula:
  • R b' is as defined above and A is the fused heteroaryl or heterocyclic group containing from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur wherein the two atoms of the phenyl ring are included in the total atoms present in the heteroaryl or heterocyclic group.
  • fused ring systems include, for instance, indol-5-yl, indol-6-yl, fhionaphthen-5-yl, fhionaphthen-6- yl, isothionaphthen-5-yl, isothionaphthen-6-yl, indoxazin-5-yl, indoxazin-6-yl, benzoxazol-5-yl, benzoxazol-6-yl, anthranil-5-yl, anthranil-6-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-6-yl, isoquinolin-7-yl, cinnolin-6-yl, cinnolin-7-yl, quinazolin-6-yl, quinazolin-7-yl, benzofuran-5-yl, benzofuran-6-yl, isobenzofuran-5-yl, isobenzofuran
  • Thiol refers to the group -SH.
  • Thioalkoxy refers to the group -S-alkyl.
  • Thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups as 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.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • a first synthetic method involves conventional coupling of a halo acetic acid with a primary amine to form the amino acid followed by conventional esterification as shown in reaction (1) below:
  • R 1 , R 2 , R 3 are as defined above and X is a halo group such as chloro or bromo.
  • leaving groups other than halo may be employed such as triflate, tosylate, mesylate and the like.
  • a suitable ester of 1 may be employed in this reaction.
  • the first step of reaction (1) involves coupling of a suitable haloacetic acid derivative 1 with a primary aryl/heteroarylamine 2 under conditions which provide for amino acid 3.
  • This reaction is described by, for example, Yates, et al. 10 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid 1 with primary aryl/heteroarylamine 2 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like.
  • DMSO dimethylsulfoxide
  • the reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction.
  • reaction is preferably conducted at from about 25 °C to about 100 °C until reaction completion which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety.
  • N-aryl/N-heteroaryl amino acid 3 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
  • N-aryl/N-heteroaryl amino acid 3 is next esterified with alcohol 4 by conventional esterification conditions to provide for the esterified N-aryl/N-heteroaryl amino acid 5 which is a compound of formula I.
  • esterification procedures for R 3 groups containing an ester group can be achieved by using the methods of Losse, et al. 11
  • the esterification reaction can optionally be conducted on haloacetic acid 1 prior to amination with aryl/heteroarylamine 2.
  • each of the reagents (haloacetic acid 1, primary aryl/heteroarylamine 2 and alcohol 3) are well known in the art with a plurality of each being commercially available.
  • the R 1 group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation.
  • a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a haloaryl compound, X-R 1 where X is a halo group such as fluoro, chloro or bromo and R 1 is as defined above.
  • a suitable diluent such as DMSO
  • X-R 1 where a halo group such as fluoro, chloro or bromo and R 1 is as defined above.
  • the reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction.
  • the reaction typically proceeds at from 15 °C to about 250°C and is complete in about 1 to 24 hours.
  • N-aryl amino acid ester is recovered by conventional methods including chromatography, filtration and the like.
  • esterified amino acids of formula I above can be prepared by reductive amination of a 2-oxocarboxylic acid ester (such as a pyruvate ester) ester in the manner illustrated in Reaction (2) below:
  • R 1 , R 2 , R 3 are as defined above.
  • reaction (2) approximately stoichiometric equivalents of pyruvate ester 6 and arylamine 2 are combined in an inert diluent such as methanol, ethanol and the like and the reaction solution treated under conditions which provide for imine formation (not shown).
  • the imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H 2 /palladium on carbon and the like to form the N-aryl amino acid ester 5.
  • the reducing agent is H 2 /palladium on carbon which is incorporated into the initial reaction medium which permits imine reduction in situ in a one pot procedure to provide for the N-aryl amino acid ester 5.
  • reaction is preferably conducted at from about 20 °C to about 80 °C at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours.
  • N-aryl amino acid ester 5 is recovered by conventional methods including chromatography, filtration and the like.
  • a further embodiment for preparing the compounds of formula I above includes aromatic nucleophilic substitution of fluorobenzenes by the amine group of an amino acid as set forth in the Examples below.
  • conventional transesterification techniques can be used to prepare a variety of different ester groups on the N-aryl amino acid esters 5.
  • Numerous techniques are known in the art to effect transesterification and each technique merely replaces the -OR 3 group on the ester of the N-aryl amino acid ester 5 with a different -OR 3 group derived from the corresponding alcohol (i.e., HOR 3 ) and, in some cases, a catalyst such as titanium (IV) wo-propoxide is used to facilitate reaction completion.
  • the alcohol HOR 3 is first treated with sodium hydride in a suitable diluent such as toluene to form the corresponding Na + " OR 3 which is then employed to effect transesterification with the N-aryl amino acid ester 5.
  • a suitable diluent such as toluene
  • the efficiency of this technique makes it particularly useful with high boiling and/or expensive alcohols.
  • the N-aryl amino acid ester 5 to be transesterified is placed in a large excess of the alcohol which effects transesterification.
  • a catalytic amount of sodium hydride is then added and the reaction proceeds quickly under conventional conditions to provide the desired transesterified product. Because this protocol requires the use of a large excess of alcohol, this procedure is particularly useful when the alcohol is inexpensive.
  • Transesterification provides a facile means to provide for a multiplicity of R 3 substituents on the compounds of formula I above.
  • the alcohols employed to effect transesterification are well known in the art with a significant number being commercially available.
  • Other methods for preparing the esters of this invention include, by way of example, first hydrolyzing the ester to the free acid followed by O-alkylation with a halo-R 3 group in the presence of a base such as potassium carbonate.
  • O-acyloxime esters include transesterification of the trichlorophenyl ester of a carboxylic acid with an oxime, and coupling of a carboxylic acid and an oxime using a carbodiimide coupling reagent.
  • methods for the preparation of pyrrole amides include conventional amidation techniques of the corresponding acid and pyrrole.
  • the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers.
  • a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained.
  • Such reaction protocols can involve inversion of the chiral center during synthesis.
  • the products of this invention are a mixture of R,S enantiomers.
  • the chiral product corresponds to the L-amino acid derivative.
  • chiral products can be obtained via purification techniques which separates enantiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art.
  • the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
  • Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh
  • Capsules each containing 40 mg of medicament are made as follows:
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Quantity Ingredient (mg/capsule)
  • a subcutaneous formulation may be prepared as follows: Ingredient Quantity Active Ingredient 5.0 mg
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds and pharmaceutical compositions of the invention are useful in inhibiting /3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease in mammals including humans.
  • the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
  • compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.
  • Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 0.1 to about 500 mg/kg/day.
  • compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
  • An amount adequate to accomplish this is defined as "prophylactically effective dose. " Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 0.1 to about 500 mg/kg/day.
  • the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. When aqueous solutions are employed, these may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5-9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • EDC l-(3-dimethyaminopropyl)-ethylcarbodiimide hydrochloride
  • Aldrich indicates that the compound or reagent used in the following procedures is commercially available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA; the term “Fluka” indicates the compound or reagent is commercially available from Fluka Chemical Corp. , 980 South 2nd Street, Ronkonkoma, NY 11779 USA; the term “Lancaster” indicates the compound or reagent is commercially available from Lancaster Synthesis, Inc., P.O. Box 100, Windham, NH 03087 USA; and the term “Sigma” indicates the compound or reagent is commercially available from Sigma, P.O. Box 14508, St. Louis, MO 63178 USA.
  • GENERAL PROCEDURE B First Transesterification Technique A solution of 1-5 equivalents of the desired alcohol was added to 1 equivalent of sodium hydride in toluene. After off-gassing had ceased, the compound to be transesterified, dissolved in toluene, was added. After 0.5 hours, the reaction was either heated to 40 °C and placed under house vacuum ( — 20 mmHg), or nitrogen was bubbled through the solution while it was heated at 90°C. The reaction was followed by tic, and when the reaction was complete the solution was cooled and quenched with water or 1M HCl, and in smaller scale reactions diluted with ethyl acetate.
  • the organic phase was extracted with saturated aqueous NaHCO 3 , then washed with saturated aqueous NaCl and dried over MgSO 4 .
  • the solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography. Alternatively, the reaction mixture was worked-up by evaporation of the solvents and direct chromatography of the crude mixture.
  • GENERAL PROCEDURE C Second Transesterification Technique
  • the compound to be transesterified was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of IN HCl, and after a few minutes of stirring saturated aqueous NaHCO 3 was added. The organic phase was washed with saturated aqueous NaCl and dried over MgSO «. The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography.
  • GENERAL PROCEDURE D Third Transesterification Technique
  • the compound to be transesterified was placed in a large excess of the desired alcohol.
  • a catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected.
  • the reaction was quenched with a few milliliters of IN HCl, and after a few minutes of stirring saturated aqueous NaHCO 3 was added.
  • the volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in ethyl acetate and additional water was added.
  • the organic phase was washed with saturated aqueous NaCl and dried over MgSO 4 .
  • the solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography.
  • This procedure is particularly employed in the case of low boiling, inexpensive alcohols, miscible with water.
  • GENERAL PROCEDURE E O-Alkylation Technique To a carboxylic acid compound (prepared, for example, by reductive amination via General Procedure A to provide for the N-aryl amino acid ester, followed by hydrolysis via Procedure F) in DMF was added 1.5 equivalents K 2 CO 3 , followed by 1 equivalent of alkylating agent (e.g. , tert-butyl bromoacetate). The reaction was stirred at room temperature for 2 hours, then was quenched with water and extracted into ethyl acetate. The organic phase was washed with saturated aqueous ⁇ aHCO,, water, and saturated aqueous NaCl, and was then dried over MgSO 4 . The solution was stripped free of solvent on a rotary evaporator to yield the crude product.
  • alkylating agent e.g. , tert-butyl bromoacetate
  • GENERAL PROCEDURE I Oxime or Amine Coupling Technique
  • the trichlorophenyl ester (1 eq) of a carboxylic acid was stirred in DMF or T ⁇ F.
  • the oxime or amine (1.2 eq) was added and the mixture was stirred at ambient temperature for 1-4 hours.
  • a suitable base such as N,N-diisopropylethylamine (1.2 eq) was also added.
  • the resulting mixture was concentrated under reduced pressure to yield a crude product which was used without purification or was purified by silica gel chromatography and/or crystallization.
  • GENERAL PROCEDURE J Alkylation Technique The amine (1 eq), the ⁇ -bromo ester (1.1 eq) and a suitable base (such as triethylamine) (2 eq) were stirred in chloroform. The resulting solution was heated at reflux for 4-12 hours. After cooling, the mixture was diluted with chloroform and washed with water. The organic portion was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography. GENERAL PROCEDURE K Oxime or Alcohol Coupling Technique The carboxylic acid (1 eq) was stirred in a suitable solvent (such as THF, dioxane or DMF).
  • a suitable solvent such as THF, dioxane or DMF
  • the ester to be transesterified was dissolved in a large excess of the alcohol and 0.3 equivalents of titanium(IV) isopropoxide (Aldrich) was added. The reaction was followed by tic until complete and then the volatiles were removed at reduced pressure. The resulting crude material was then chromatographed to obtain the desired product.
  • GENERAL PROCEDURE S Oxime Ester Formation The trichlorophenyl ester (1 eq.) was stirred in DMF or THF. The oxime (1.2 eq.) was added and the mixture was stirred at ambient temperature for 1 to 4 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography and/or crystallization.
  • N-(3,4- dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4- dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to 40°C and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days.
  • N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2- chloropropionic acid (Aldrich).
  • Example 20 Synthesis of N-(3-chloro-4-cyanophenyl)alanine iso-butyl ester Following General Procedure P above and using 2-chloro-4- fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example A above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
  • N-BOC-3-chloro-4-iodoaniline was prepared.
  • the reaction was heated to 100°C for 10 hours, cooled, diluted with dichloromethane and washed with cold IN HCl, water and brine.
  • N-(3,4- methylenedioxyphenyl)alanine methyl ester was prepared.
  • the methyl ester was then transesterified following General Procedure Q above and using iso- butanol to provide the title compound as an oil.
  • the titie compound was prepared as a solid having a melting point of 52-56°C.
  • N-(3,5-dimethoxyphenyl)alanine (crude, 454 mg) (prepared according to the procedure described in U.S. Patent No. 3,598,859 using 3,5-dimefhoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich)) was treated in dry iso-butanol
  • This mutation is commonly called the Swedish mutation and the cells, designated as “293 751 SWE", were plated in Corning 96-well plates at 1.5-2.5 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 /3-amyloid ELISA results within the linear range of the assay ( ⁇ 0.2 to 2.5 ng per mL).
  • Cytotoxic effects of the compounds were measured by a modification of the method of Hansen, et al. 13 .
  • To the cells remaining in the tissue culture plate was 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 of the /3-amyloid peptide ELISA were fit to a standard curve and expressed as ng/mL /3-amyloid peptide. In order to normalize for cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the results from a drug free control. All results are the mean and standard deviation of at least six replicate assays.
  • test compounds were assayed for /3-amyloid peptide production inhibition activity in cells using this assay.
  • the results of this assay demonstrate that, each of the compounds of Examples 1-59 inhibit the ⁇ - amyloid peptide production by at least 30% as compared to control.
  • Example 61 In Vivo Suppression of /3-Amyloid Release and/or Synthesis This example illustrates how the compounds of this invention could be tested for in vivo suppression of /3-amyloid release and/or synthesis.
  • 3 to 4 month old PDAPP mice are used [Games et al., (1995) Nature 373:523-527].
  • the compound is usually formulated at either 5 or 10 mg/ml.
  • the compounds may be formulated with various vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil; 2-hydroxypropyl-/3-cyclodextrin (Research Biochemicals International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis MO).
  • various vehicles such as corn oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil; 2-hydroxypropyl-/3-cyclodextrin (Research Biochemicals International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis MO).
  • 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 /3-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 ⁇ 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.
  • PBS phosphate buffered saline
  • the /3-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 /3-amyloid sandwich ELISA quantitating both /3-amyloid (aa 1- 40) and /3-amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) to ⁇ - amyloid.
  • the capture antibody, 266 [P. Seubert, Nature (1992) 359:325-327], is specific to amino acids 13 - 28 of /3-amyloid.
  • the antibody 3D6 [Johnson- Wood et al., PNAS USA (1997) 94: 1550-1555], which is specific to amino acids 1 - 5 of / 3-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 /3-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 /3-amyloid peptide at concentrations up to 1 ng/ml.
  • the configuration of the 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 21F12 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 of the 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.
  • 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 /3-amyloid assay (266 capture/3D6 reporter) described above for the brain assay except the specimen diluent was used instead of the casein diluents described.
  • Gly Ala lie lie Gly Leu Met Val Gly Gly Val Val lie Ala 30 35 40

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Abstract

L'invention concerne des composés qui inhibent la libération du peptide de β-amyloïde et/ou sa synthèse et qui sont donc utiles dans le traitement de la maladie d'Alzheimer. Elle porte aussi sur des compositions pharmaceutiques comprenant un composé qui inhibe la libération du peptide de β-amyloïde et/ou sa synthèse, ainsi que sur des méthodes de traitement de la maladie d'Alzheimer de manière thérapeutique et prophylactique à l'aide desdites compositions pharmaceutiques.
EP97952177A 1996-11-22 1997-11-20 Esters de n-(aryl/heteroaryl) aminoacide, compositions pharmaceutiques et methodes pour inhiber la liberation du peptide beta-amyloide et/ou sa synthese Withdrawn EP0944580A2 (fr)

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US75544496A 1996-11-22 1996-11-22
US755444 1996-11-22
PCT/US1997/020356 WO1998022441A2 (fr) 1996-11-22 1997-11-20 ESTERS DE N-(ARYL/HETEROARYL) AMINOACIDE, COMPOSITIONS PHARMACEUTIQUES ET METHODES POUR INHIBER LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU SA SYNTHESE

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HRP990246A2 (en) 1998-08-07 2000-06-30 Du Pont Pharm Co Succinoylamino benzodiazepines as inhibitors of a beta protein production
NZ509241A (en) 1998-08-07 2003-08-29 Du Pont Pharm Co Succinoylamino lactams as inhibitors of alpha-beta protein production
AU6278099A (en) 1998-09-30 2000-04-17 Elan Pharmaceuticals, Inc. Biological reagents and methods for determining the mechanism in the generation of beta-amyloid peptide
WO2000038618A2 (fr) 1998-12-24 2000-07-06 Du Pont Pharmaceuticals Company BENZODIAZEPINES SUCCINOYLAMINO UTILISEES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b)
CA2380359C (fr) * 1999-09-08 2011-11-29 Daiichi Pharmaceutical Co., Ltd. Procede de preparation de derives de benzoxazine et de leurs intermediaires
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
EP1222176A1 (fr) 1999-10-08 2002-07-17 Bristol-Myers Squibb Pharma Company AMINO SULFONAMIDES DE LACTAME UTILISES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b)
US6670399B2 (en) 1999-12-23 2003-12-30 Neurochem (International) Limited Compounds and methods for modulating cerebral amyloid angiopathy
CA2395862A1 (fr) 2000-02-17 2001-08-23 Hong Liu Carbocycles et heterocycles succinoylamino utilises en tant qu'inhibiteurs de la production de la proteine a.beta.
BR0110051A (pt) 2000-04-03 2004-12-07 Bristol Myers Squibb Pharma Co Composto, uso do composto, composição farmacêutica e método de tratamento do mal de alzheimer
JP2003535046A (ja) 2000-04-03 2003-11-25 デュポン ファーマシューティカルズ カンパニー Ａβタンパク質産生の阻害剤としての環状ラクタム
JP2004500419A (ja) 2000-04-11 2004-01-08 デュポン　ファーマシューティカルズ　カンパニー Ａβタンパク質産生阻害剤としての置換ラクタム
US6878363B2 (en) 2000-05-17 2005-04-12 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
WO2001092235A1 (fr) 2000-06-01 2001-12-06 Bristol-Myers Squibb Pharma Company Lactames substitues par des succinates cycliques en tant qu'inhibiteurs de la production de la proteine beta
US6432944B1 (en) 2000-07-06 2002-08-13 Bristol-Myers Squibb Company Benzodiazepinone β-amyloid inhibitors: arylacetamidoalanyl derivatives
JP4805909B2 (ja) * 2004-03-03 2011-11-02 スミスクライン ビーチャム コーポレーション 選択的アンドロゲン受容体モジュレーターとしてのアニリン誘導体
JP2008536868A (ja) * 2005-04-15 2008-09-11 スミスクライン・ビーチャム・コーポレイション シアノアリールアミン
BG110141A (en) 2008-05-23 2009-12-31 "Софарма" Ад GALANTAMINE DERIVATIVES, METHODS FOR THEIR PREPARATION AND USE

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