WO2001034639A2 - COMPOSES CONTENANT DES β-ACIDES AMINES UTILES POUR INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE - Google Patents

COMPOSES CONTENANT DES β-ACIDES AMINES UTILES POUR INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE Download PDF

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WO2001034639A2
WO2001034639A2 PCT/US2000/026277 US0026277W WO0134639A2 WO 2001034639 A2 WO2001034639 A2 WO 2001034639A2 US 0026277 W US0026277 W US 0026277W WO 0134639 A2 WO0134639 A2 WO 0134639A2
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alkyl
group
compound
substituted
methyl
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PCT/US2000/026277
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WO2001034639A3 (fr
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James Edmund Audia
Warren Jaye Porter
William Leonard Scott
Douglas Richard Stack
Richard Craig Thompson
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Eli Lilly And Company
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Priority to EP00978212A priority Critical patent/EP1235789A2/fr
Priority to AU15694/01A priority patent/AU1569401A/en
Priority to CA002388750A priority patent/CA2388750A1/fr
Publication of WO2001034639A2 publication Critical patent/WO2001034639A2/fr
Publication of WO2001034639A3 publication Critical patent/WO2001034639A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • 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
    • 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 ⁇ -aminoacid containing compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis and are useful in treating Alzheimer's disease.
  • Alzheimer's Disease 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.
  • Alzheimer's disease 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.
  • Alzheimer's disease 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. Alzheimer's disease is at present incurable. No treatment that effectively prevents Alzheimer's disease or reverses its symptoms and course is currently known.
  • the brains of individuals with Alzheimer's disease 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 Alzheimer's disease. 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 Alzheimer's disease.
  • 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 Alzheimer's disease 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 The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of Alzheimer's disease 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
  • ⁇ AP ⁇ - amyloid peptide
  • ⁇ -amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP) , that is normally produced by cells in many tissues of various animals, including humans.
  • APP amyloid precursor protein
  • Knowledge of the structure of the gene encoding APP has demonstrated that ⁇ -amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme (s) .
  • protease enzyme protease enzyme
  • the precise biochemical mechanism by which the ⁇ -amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown .
  • a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the ⁇ -amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles Alzheimer's disease is some patients but HCHWA-D in others.
  • the discovery of these and other mutations in APP in genetically based cases of Alzheimer's disease prove that alteration of APP and subsequent deposition of its ⁇ -amyloid peptide fragment can cause Alzheimer's disease.
  • 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 provides ⁇ -aminoacid containing compounds of formula I :
  • Ri is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
  • R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
  • R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
  • R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, alkaryl, substituted alkaryl, cycloalkyl, and substituted cycloalkyl;
  • X' is selected from the group consisting of hydrogen, hydroxy, and fluoro
  • X" is selected from the group consisting of hydrogen, hydroxy, and fluoro
  • W is selected from the group consisting of -OR 5 and -NR 6 R 7 wherein
  • R 5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, and alkaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, and alkaryl;
  • R 7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, and alkaryl; or
  • This invention also provides for novel pharmaceutical compositions comprising a compound of the formula I and a pharmaceutically acceptable diluent. Additionally, this invention provides a method for inhibiting ⁇ -amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of ⁇ -amyloid peptide. Because the in vivo generation of ⁇ -amyloid peptide is associated with the pathogenesis of Alzheimer's disease the t tSJ H 1
  • APP ⁇ -amyloid precursor protein
  • This term is exemplified by groups such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl .
  • Substituted alkyl refers to an alkyl group, preferably of from 1 to 10 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 alky
  • 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, -S0 2 -alkyl, -S0 2 -substit
  • 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-0-”. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1 , 2-dimethylbutoxy, and the like.
  • Substituted alkoxy refers to the group “substituted alkyl-O-" where substituted alkyl is as defined above.
  • 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, -S0 2 -alkyl, -S0 2 -substituted alkyl, - S0 2 -
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
  • Preferred alkynyl groups include ethynyl, propargyl , 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, -S0-alkyl, -S0 2 -substituted alkyl, -S0 2 -aryl
  • Acyl refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C (0) - , substituted cycloalkyl-C (0) - , aryl-C(O)-, heteroaryl-C (0) - and heterocyclic-C (0) - where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein .
  • Acylamino refers to the group -C(0)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.
  • a protecting group may also be a covalently attached to a solid support as is well known and appreciated in the art of peptide synthesis and combinatorial chemistry.
  • aminoacyl refers to the group -NRC(0)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(0)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 (0) 0- , substituted alkyl-C (0) 0- , cycloalkyl-C (0) 0- , substituted cycloalkyl-C (0) -, aryl-C(0)0-, heteroaryl-C (0) 0- , and heterocyclic-C (0) 0- 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 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 quininclidine, 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-he
  • Cycloalkenyl refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl , cyclopent-3-enyl , cyclooct-3-enyl and the like.
  • Substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 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,
  • 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, -SO-heteroaryl, -S0 2 -alky
  • 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.
  • 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,
  • heterocyclic groups can have a single ring or multiple condensed rings.
  • Preferred heterocyclics include morpholino, 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
  • 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.
  • Compounds in which Re and R 7 together with the nitrogen to which they are attached form a 3 to 7 membered cyclic group 3 to 7 membered cyclic group refers to groups such as a pyrrolido, piperidino, azepino, and the like or when R 6 and R 7 together with the nitrogen to which they are attached form a 6 to 7 membered group containing a heteroatom selected from the group consisting of 0, S, NR 8 wherein R 8 refers to groups such as morpholino, thiomorpholino, piperazino, 4-methylpiperazino, 4-ethylpiperazino, 4-phenyl piperazino, 4-benzylpiperazino, and the like.
  • pharmaceutically-acceptable addition salt refers to an acid addition salt
  • the compound of formula I and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • a pharmaceutically-acceptable addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66 , 2-19 (1977) which are known to the skilled artisan.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric , metaphosphoric , pyrophosphoric , and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1 , 4-dicarboxylate, hexyne-1 , 4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate, propionate,
  • compounds of formula I exist as stereoisomers.
  • the present invention relates to the stereoisomers of the compounds of formula I.
  • the Cahn-Prelog-Ingold designations of (R) - and (S)- and the designations of L- and D- for stereochemistry relative to the isomers of glyceraldehyde are used to refer to specific isomers where designated.
  • the specific isomers of the compounds of formula I can by prepared by stereospecific synthesis.
  • the compounds of formula I and the starting materials for their preparation can be resolved and recovered by techniques known in the art, such as, chromatography on chiral stationary phases, and fractional recrystallization of addition salts formed by reagents used for that purpose.
  • Useful methods of resolving and recovering specific stereoisomers are known in the art and described in Stereochemistry of Organic Compounds, E.L. Eliel and S.H. Wilen (Wiley-Interscience 1994), Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S.H. Wilen (Wiley-Interscience 1981), and European Patent Application No. EP-A-838448, published April 29, 1998. It is to be understood that the invention extends to each of the isomeric forms of the compounds of the present invention including the geometric, diastereomeric, enantiomeric, and racemic forms of the compound of formula I.
  • Ri is phenyl substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, alkyl, alkoxy, and halo are more preferred with 3 , 5-difluorophenyl being most preferred.
  • R 2 and R are hydrogen, alkyl, cycloalkyly, or aryl are preferred.
  • R 2 or R 3 are phenyl substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, alkyl, alkoxy, and halo are more preferred with phenyl being most preferred.
  • R 4 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and alkaryl are preferred, with aryl being more preferred and phenyl being most preferred.
  • W is -OR 5 in which R 5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl are preferred.
  • W is -OR 5 in which R 5 is C 1 -C4 alkyl being more preferred and methyl, isopropyl, sec-butyl, isobutyl, t-butyl being most preferred.
  • W is -NR6R7 in which Rs is hydrogen, alkyl, or cycloalkyl; and R 7 is hydrogen, alkyl, or alkaryl are preferred.
  • W is -NR 6 R in which R 6 and R 7 together with the nitrogen to which they are attached form a 3 to 7 membered cyclic group in which the cyclic group is pyrrolidino or piperidino are preferred.
  • W is - R6R7 in which R 6 and R 7 together with the nitrogen to which they are attached form a 6 to 7 membered group containing a heteroatom selected from the group consisting of 0, S, NR 8 wherein R 8 is selected from the group consisting of hydrogen, alkyl, aryl, and alkaryl in which the cyclic group is morpholino, piperazino, 4-methylpiperazino, 4-phenyl piperazino, 4-benzylpiperazino, are preferred.
  • Reaction Scheme A.l, step a depicts the coupling reaction of an appropriate amino-protected ⁇ -amino acid of formula (1) and an appropriate compound of formula (2) .
  • Appropriate amino-protected ⁇ -amino acids are ones in which R 2 and R 3 are as desired in the final product of formula I and readily available to the person skilled in the art and can be prepared as described herein.
  • An appropriate compound of formula (1) may also have the stereochemistry that is desired in the final compound of formula I.
  • An appropriate compound of formula (2) is one in which W' is W as desired in the final compound of formula I.
  • an appropriate compound of formula (2) is one in which is a protecting group which after removal and esterification or amidation give rise to W as desired in the final product of formula I.
  • an appropriate compound of formula (2) may also have the stereochemistry that is desired in the final compound of formula I.
  • Compounds of formula (2) are readily available to the skilled person.
  • an appropriate compound of formula (2) is one in which W' is W as desired in the final compound is readily prepared by esterification or amidation of amino protected amino acids, followed by deprotection to give a compound of formula (2) .
  • the coupling reaction depicted in Reaction Scheme A.l, step a involves a reaction which is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1- hydroxybenzotriazole, etc.
  • the reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
  • the acid halide of compound (1) can be employed in the reaction and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
  • Suitable bases include, by way of example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and the like.
  • the reaction is preferably conducted at from about 0 2 C to about 60 2 C until reaction completion which typically occurs within 1 to about 24 hours.
  • the product .of formula (3) is recovered by conventional methods including precipitation, chromatography, filtration and the like or alternatively is deprotected to the corresponding amine of formula (4) without purification and/or isolation other than conventional work-up (e.g., aqueous extraction, etc.).
  • Reaction Scheme A.l, step b depicts the deprotection of a compound of formula (3) to give a compound or formula (4) .
  • Reaction Scheme A.l, step c depicts the coupling reaction of an appropriate compound of formula (5), R ⁇ CX'X"C (0) -OH, and a compound of formula (4) .
  • Appropriate compounds of formula (5) are compounds in which Ri , X' and X" are as desired in the final product of formula I and are well known in the art and available as described herein.
  • An appropriate compound of formula (5) may also have the stereochemistry that is desired in the final compound of formula I.
  • the coupling reaction depicted in step c is carried out using the acid of formula (5) or the acid halide derived therefrom, in a manner similar to those taught in Reaction Scheme A.l, step a.
  • an acid addition salt is formed using a pharmaceutically- acceptable acid.
  • the formation of acid addition salts is well known and appreciated in the art.
  • step a depicts the coupling reaction of an appropriate carboxy-protected ⁇ -amino acid of formula (6) and an appropriate compound of formula (5), as described above, to give a compound of formula (7) .
  • Appropriate carboxy-protected ⁇ -amino acids are ones in which R 2 and R 3 are as desired in the final product of formula I and readily available to the person skilled in the art and can be prepared as described herein.
  • An appropriate compound of formula (6) may also have the stereochemistry that is desired in the final compound of formula I.
  • This coupling reaction is carried out using the acid of formula (5) or the acid halide derived therefrom, in a manner similar to those taught in Reaction Scheme A.l, step a.
  • Reaction Scheme A.2, step b depicts the deprotection of a compound of formula (7) to give a compound or formula (8) .
  • Such deprotections of carboxy protecting groups is well known and appreciated in the art.
  • step c depicts the coupling reaction of an appropriate compound of formula (2), as described above, and a compound of formula (8) .
  • Appropriate compounds of formula (2) are the coupling reaction depicted in step c are taught in Reaction Scheme A.l, step a.
  • an acid addition salt is formed using a pharmaceutically- acceptable acid.
  • the formation of acid addition salts is well known and appreciated in the art.
  • BEMP refers to 2-tert-butylimino-2-diethylamino-l, 3- dimethylperhydro-1 , 3 , 2-diazaphosphorine
  • Boc refers to t- butoxycarbonyl
  • BOP refers to benzotriazol-1-yloxy- tris (dimethyla ino) phosphonium hexafluorophosphate
  • bd refers to broad doublet
  • bs refers to broad singlet
  • d refers to doublet
  • dd refers to doublet of doublets
  • DIC refers to diisopropyl carbodiimide
  • DMF refers to dimethylformamide
  • DMAP refers to 4-dimethylaminopyridine
  • DMSO refers to dimethylsulfoxide
  • EDC refers to ethyl-l-(3- dimethyaminopropyl )
  • EtOAc refers to ethyl acetate
  • g refers to grams
  • h refers to hours
  • HOBT refers to 1- hydroxybenzotriazole hydrate
  • Hunig's base refers to N,N- diisopropylethylamine
  • L refers to liter
  • m refers to multiplet
  • M refers to molar
  • max refers to maximum
  • meq refers to milliequivalent
  • mg refers to milligram
  • mL refers to milliliter
  • mm refers to millimeter
  • mmol refers to millimole
  • MOC refers to methoxyoxycarbonyl
  • N refers to normal
  • N/A refers to not available
  • ng refers to nanogram
  • nm refers to nanometers
  • OD refers to optical density
  • PEPC refers to 1- (3- (1-pyrrolidinyl) propyl) -3-ethylcarbodiimide
  • the mixture was washed with water, saturated aqueous NaHC0 3 , IN HC1 and saturated aqueous NaCl, and then dried over MgS0 4 .
  • the resulting solution was stripped free of solvent on a rotary evaporator to yield the crude product.
  • the reaction mixture stirred at room temperature for 10-20 hours under an atmosphere of nitrogen.
  • the mixture was diluted with EtOAc and washed with 0.1 M HCl (1 x 10 L) , saturated NaHC0 3 (1 x 10 mL) , H 2 0 (1 x 10 mL) , and brine and dried over MgS0 4 .
  • the drying agent was removed by filtration and the filtrate was concentrated in vacuo.
  • the residue was purified by flash column chromatography on silica gel followed by trituration from EtOAc and hexanes .
  • the cooling bath was removed and the mixture allowed to warm to room temperature for 10-24 hours.
  • the solution or mixture was diluted with EtOAc, in a 3-5 volume multiple of the initial THF volume, and washed with 0.1-1.0 M aq. HCl (1 or 2x) , dilute NaHC0 3 (1 or 2x) , and brine
  • 1H NMR data was as follows: 1H NMR (400 MHz, CD30D) ⁇ 7.35-7.24 (5H m) , ⁇ 4.80 (0.5H s) , ⁇ 4.71 ( 0.5H s) , ⁇ 4.35-4.30 (0.5 H m) , ⁇ 3.61-3.47 ( 0.5H m) , ⁇ 2.71 (1.5H s), ⁇ 2.69 (1.5H s), ⁇ 1.29-0.80 (10H m) .
  • PREPARATRION 4 Synthesis of (R/S) -N-Boc- ⁇ -methyl- ⁇ -alanine.
  • This mutation is commonly called the Swedish mutation and the cells, designated as "293 751 SWE" , were plated in Corning 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 ⁇ -amyloid ELISA results within the linear range of the assay (-0.2 to 2.5 ng per mL) . Following overnight incubation at 37 2 C in an incubator equilibrated with 10% carbon dioxide, media were removed and replaced with 200 ⁇ L of a compound of formula I (drug) containing media per well for a two hour pretreatment period and cells were incubated as above. Drug stocks were prepared in 100% dimethyl sulfoxide such that at the final drug concentration used in the treatment, the concentration of dimethyl sulfoxide did not exceed 0.5% and, in fact, usually equaled 0.1%.
  • 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 5-diphenyltetrazolium bromide
  • Example Bio-2 In Vivo Suppression of ⁇ -Amyloid Release and/or Synthesis This example illustrates how the 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) .
  • the compound is usually formulated at between 1 and 10 mg/mL. Because of the low solubility factors of the compounds, they may be formulated with various vehicles, such as corn oil
  • 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 2 C.
  • each brain region is homogenized in 10 volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 rtiM 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 2 C prior to quantitation of ⁇ -amyloid.
  • 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), is specific to amino acids 13 - 28 of ⁇ -amyloid.
  • the antibody 3D6 Johnson-Wood et al . , PNAS USA (1997) 94:1550-1555), 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 of the sandwich ELISA quantitating the level of ⁇ -amyloid employs the mAb 21F12 (Johnson-Wood et al . , PNAS USA (1997) 94:1550-1555) (which recognizes amino acids 33-42 of ⁇ -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 21F12 capture mAbs are coated at 10 ⁇ g/ml into 96 well immunoassay plates (Costar, Cambridge 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 2 C until use.
  • the plates are dehydrated 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.
  • the 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.
  • the EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/1 sodium phosphate- H0 (monobasic), 2.16 gm/1 sodium phosphate -7 H 2 0 (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) .
  • specimen diluent 0.2 gm/1 sodium phosphate- H0 (monobasic), 2.16 gm/1 sodium phosphate -7 H 2 0 (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 capture/3D6 reporter) 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% corn oil or, alternatively, in a solution containing 80% corn 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.
  • 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% corn oil or, alternatively, in a solution containing 80% corn 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.
  • the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal . These compounds are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art .
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 g, 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 prefor ulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid prefor ulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the following formulation examples illustrate the pharmaceutical compositions of the present invention.
  • Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: Quantity
  • Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • 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:
  • Lactose 95 The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient (mg/tablet)
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50 2 to 60 2 C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg .
  • Quantity Ingredient (mg/capsule)
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No . 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.
  • a subcutaneous formulation may be prepared as follows: Ingredient Quantity Active Ingredient 1.0 mg corn oil 1 mL
  • a topical formulation may be prepared as follows:
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts .
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds and pharmaceutical compositions of the invention are useful in inhibiting ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans.
  • the compounds described herein are suitable for use in a variety of drug delivery systems described above. 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 Alzheimer's disease 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 "therapeutally 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 Alzheimer's disease in the patient, the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • compositions are administered to a patient at risk of developing Alzheimer's disease (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
  • An amount adequate to accomplish this is defined as “prophylactically effective dose.” Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day .
  • the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery purposes.
  • the compounds may be used in the diagnosis of cells releasing and/or synthesizing ⁇ -amyloid peptide.
  • the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of ⁇ -amyloid peptide.

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Abstract

Composés contenant des β-acides aminés de formule (I) qui inhibent la libération et/ou la synthèse du peptide β-amyloïde et qui sont utiles pour traiter la maladie d'Alzheimer et pour favoriser les processus cognitifs.
PCT/US2000/026277 1999-11-09 2000-10-26 COMPOSES CONTENANT DES β-ACIDES AMINES UTILES POUR INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE WO2001034639A2 (fr)

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EP00978212A EP1235789A2 (fr) 1999-11-09 2000-10-26 COMPOSES CONTENANT DES $g(b)-ACIDES AMINES UTILES POUR INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE $g(b)-AMYLOIDE
AU15694/01A AU1569401A (en) 1999-11-09 2000-10-26 Beta-aminoacid compounds useful for inhibiting beta-amyloid peptide release and/or its synthesis
CA002388750A CA2388750A1 (fr) 1999-11-09 2000-10-26 Composes contenant des .beta.-acides amines utiles pour inhiber la liberation et/ou la synthese du peptide .beta.-amyloide

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099210A2 (fr) 2007-02-12 2008-08-21 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
WO2009128057A2 (fr) 2008-04-18 2009-10-22 UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al Produits psycho-pharmaceutiques
EP2489656A1 (fr) 2007-12-21 2012-08-22 Ligand Pharmaceuticals Inc. Modulateurs de récepteurs androgènes sélectifs (sarm) et leurs utilisations
US9833420B2 (en) 2003-02-27 2017-12-05 JoAnne McLaurin Methods of preventing, treating, and diagnosing disorders of protein aggregation
EP3613418A1 (fr) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022494A2 (fr) * 1996-11-22 1998-05-28 Elan Pharmaceuticals, Inc. METHODES ET COMPOSES DESTINES A INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022494A2 (fr) * 1996-11-22 1998-05-28 Elan Pharmaceuticals, Inc. METHODES ET COMPOSES DESTINES A INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9833420B2 (en) 2003-02-27 2017-12-05 JoAnne McLaurin Methods of preventing, treating, and diagnosing disorders of protein aggregation
WO2008099210A2 (fr) 2007-02-12 2008-08-21 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
EP2489656A1 (fr) 2007-12-21 2012-08-22 Ligand Pharmaceuticals Inc. Modulateurs de récepteurs androgènes sélectifs (sarm) et leurs utilisations
US9675583B2 (en) 2007-12-21 2017-06-13 Ligand Pharmaceuticals Incorporated Selective androgen receptor modulators (SARMS) and uses thereof
US10106500B2 (en) 2007-12-21 2018-10-23 Ligand Pharmaceuticals Incorporated Selective androgen receptor modulators (SARMs) and uses thereof
US10730831B2 (en) 2007-12-21 2020-08-04 Ligand Pharmaceuticals Incorporated Selective androgen receptor modulators (SARMs) and uses thereof
US11358931B2 (en) 2007-12-21 2022-06-14 Ligand Pharmaceuticals Incorporated Selective androgen receptor modulators (SARMs) and uses thereof
WO2009128057A2 (fr) 2008-04-18 2009-10-22 UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al Produits psycho-pharmaceutiques
EP3613418A1 (fr) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones

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