EP0735821A1 - Procedes permettant de traiter ou de prevenir les pathologies associees aux peptides amylo dogenes - Google Patents

Procedes permettant de traiter ou de prevenir les pathologies associees aux peptides amylo dogenes

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Publication number
EP0735821A1
EP0735821A1 EP95906018A EP95906018A EP0735821A1 EP 0735821 A1 EP0735821 A1 EP 0735821A1 EP 95906018 A EP95906018 A EP 95906018A EP 95906018 A EP95906018 A EP 95906018A EP 0735821 A1 EP0735821 A1 EP 0735821A1
Authority
EP
European Patent Office
Prior art keywords
ethoxy
benzoyl
phenyl
benzo
methoxyphenyl
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Withdrawn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
EP95906018A
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German (de)
English (en)
Other versions
EP0735821A4 (fr
Inventor
William Henry Walker Lunn
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Eli Lilly and Co
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Eli Lilly and Co
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Publication date
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Publication of EP0735821A1 publication Critical patent/EP0735821A1/fr
Publication of EP0735821A4 publication Critical patent/EP0735821A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen 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
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Proteinaceous deposits (called "amyloid”) appear as neurofibrillary tangles, amyloid plaque cores, and amyloid of the congophilic angiopathy. [For a review, see. D.J. Selkoe, Neuron, 6:487-498 (1991)]
  • ⁇ -arayloid peptide is proteolytically derived from a transmembrane protein, the amyloid precursor protein.
  • Different splice forms of the amyloid precursor protein are encoded by a widely expressed gene. see, e. ⁇ .. K. Beyreuther and B. M ⁇ ller-Hill, Annual Reviews in Biochemistry.
  • ⁇ -amyloid peptide consists, in its longest forms, of 42 or 43 amino acid residues. J. Kang, et al.. Nature (London) . 325:733-736 (1987). These peptides, however, vary as to their amino-termini. C. Hilbich, et al. , Journal of Molecular Biology. 218:149-163 (1991). Because senile plaques are invariably surrounded by dystrophic neurites, it was proposed early that ⁇ -amyloid peptide is involved in the loss of neuronal cells that occurs in Alzheimer's disease. B.
  • Down's syndrome is also characterized by an accumulation of ⁇ -amyloid peptide.
  • the ⁇ - amyloid peptide is the primary constituent of senile plaques and cerebrovascular deposits.
  • CSF cerebrospinal fluid
  • a possible correlation to the plaque pathology has been developed by several groups demonstrating the direct ⁇ - amyloid peptide-induced neurotoxicity toward cultured neurons.
  • TGF- ⁇ beta transforming growth factor
  • the beta transforming growth factors are multifunctional cytokines produced by many types of cells, including hematopoietic, neural, heart, fibroblast, and tumor cells, that can regulate the growth and differentiation of cells from a variety of tissue origins. Sporn, et al.. Science. 233:532 (1986). There are at least five isoforms of TGF- ⁇ currently identified.
  • TGF- ⁇ has been shown to have numerous regulatory actions on a wide variety of both normal and neoplastic cells. This protein is multifunctional, as it can either stimulate or inhibit cell proliferation, differentiation, and othr critical processes in cell function.
  • This protein is multifunctional, as it can either stimulate or inhibit cell proliferation, differentiation, and othr critical processes in cell function.
  • amyloidogenic peptide In addition to Alzheimer's Disease and other conditions associated with the amyloidogenic peptide ⁇ -amyloid peptide, there exist conditions associated with other amyloidogenic peptides which are structurally similar to ⁇ -amyloid peptide but which share no sequence homology with the ⁇ -amyloid peptide. Recent studies have demonstrated the functional interchangeability of many of these amyloidogenic peptides with regard to neurotoxicity. P.C.
  • Human amylin also known as diabetes-associated peptide and islet amyloid polypeptide
  • islet amyloid polypeptide is a 37 amino acid peptide first isolated from amyloid deposits in the pancreas of non-insulin-dependent diabetic individuals. C.J.S. Cooper al.. Proceedings of the National Academy of Sciencs ( SA) .
  • the rat homologue of amylin is 95% similar in primary sequence to human amylin but has amino acid substitutions in the region conferring ⁇ -pleated secondary structure which render it non-amyloidogenic. See. e. ⁇ .. J. Asai et al. > Biochemical and Biophysical Research
  • ⁇ 2 -microglobulin is another protein unrelated to ⁇ - amyloid peptide but capable of forming amyloid deposits in the kidney, [for recent review, see. J.M. Campistol and M.
  • This nonpolymorphic peptide is homologous to the C3 domain of the immunoglobulin class IgG and is one subunit of class I major histocompatibility antigens.
  • This invention provides compounds efficacious in the treatment and prevention of these disorders.
  • This invention encompasses a method for the inhibition of a physiological disorder associated with an amyloidogenic peptide, which method comprises administering to a mammal in need thereof an effective amount of a compound of Formula I
  • X is a bond or C1-C4 alkylidenyl
  • R 2 is a group of the formula
  • R 4 and R 5 are independently Ci-Cg alkyl or combine to form, along with the nitrogen to which they are attached, a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazino, heptamethyleneiminyl, 4-methylpiperidinyl, imidazolinyl, piperidinyl, pyrrolidinyl, or morpholinyl;
  • R is hydroxy, halo, hydrogen, C 3 -C 8 cycloalkyl, C 2 ⁇ C7 alkanoyloxy, Ci-C ⁇ alkoxy, or phenyl, said phenyl being optionally substituted with one, two, or three moieties selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, chloro, fluoro, trifluoromethyl -OSO 2 -(C 1 -C 10 alkyl) O -OCN-R 3 or H
  • R 1 is hydroxy, halo, hydrogen, C 3 -C 8 cycloalkyl, C2- C7 alkanoyloxy, Ci-C ⁇ alkoxy, or phenyl, said phenyl being optionally substituted with one, two, or three moieties selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro. chloro, fluoro, trifluoromethyl -OSO 2 - (C 1 -C 1 0 alkyl)
  • each R 3 is independently C -C ⁇ alkyl, C 3 -C8 cycloalkyl, unsubstituted or substituted phenyl where the substituent is halo, C ⁇ -C 6 • alkyl or Ci-Cg alkoxy;
  • R and R 1 are not both selected from the group consisting of hydroxy, methoxy, and C 2 -C 7 alkanoyloxy;
  • the present invention also provides a method of inhibiting amyloidogenic peptide production comprising administering to a mammal in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of increasing TGF- ⁇ expression in the brain, comprising administering to a human in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention also provides a method of inhibiting the inflammatory response associated with Alzheimer's Disease comprising administering to a human in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • amyloidogenic peptide refers to those peptides which have the ability to self-associate into higher ordered aggregates and eventually assemble into an amyloid plaque.
  • An especially preferred amyloidogenic peptide target in methods of this invention is the ⁇ -amyloid peptide.
  • the term “inhibit” or “inhibiting” includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
  • physiological disorder associated with an amyloidogenic peptide includes diseases related to the inappropriate or undesirable deposition, such as in the brain, liver, kidney, or other organ, of at least one amyloidogenic peptide, and as such includes Alzheimer's Disease (including familial Alzheimer's Disease), Down's Syndrome, advanced aging of the brain, hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (HCHWA-D) , and the like.
  • an amyloidogenic peptide or inhibit amyloidogenic production or deposition, or inhibit Alzheimer's Disease, as the case may be.
  • conservative variant refers to amino acid substitutions which alter the primary sequence of the peptide but do not alter its secondary structure or diminish its amyloidogenic properties.
  • human amylin(20-29) refers to amino acids 20-29 of the human amylin peptide as defined in SEQ ID NO:3 or amino acids 1-43 of the ⁇ -amyloid peptide as defined in SEQ ID NO:l. In all such references, the first number listed is the amino-terminus of this peptide sequence.
  • ⁇ -amyloid peptide naturally occurs as a series of peptides which are 39 to 43 amino acids long, with the shorter, more soluble forms being present in cerebrovascular deposits and the longer forms being found primarily in senile plaques.
  • F. Prelli, $t al, , Journal of Neurochemistrv. 51 : 648-651 ( 1988 ) The primary structure of the 43 amino acid long peptide ( ⁇ l-43 ) is depicted in SEQ ID NO : l :
  • Amylin is a 37 amino acid peptide having the primary sequence
  • SEQ ID NO:3 SEQ ID NO:3.
  • the peptide ⁇ 2-microglobulin has a molecular weight of about 11,000 Daltons. It can be readily purified from urine samples using known techniques. See, e.g.. I. Berggard, et al.. Journal of Biological Chem try. 243:4095 (1968).
  • C1-C6 alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C ⁇ -Cs alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
  • the term "C 1 -C6 alkoxy” includes within its definition the term "C 1 -C 4 alkoxy".
  • Ci-C ⁇ alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • the term "Ci-C ⁇ alkyl” includes within its definition the term “C 1 -C 4 alkyl”.
  • the current invention concerns the discovery that a select group of substituted benzofurans, benzothiophenes, indoles, naphthalenes, and dihydronaphthalenes, those of Formula I, are useful as in treating or preventing physiological disorders associated with an amyloidogenic peptide.
  • C 1 -C 10 alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 10 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • C 1 -C 10 alkyl includes within its definition the terms “C 1 -C 4 alkyl” and "Ci-Ce alkyl”.
  • "Ci-C ⁇ alkoxy” represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
  • the term "C ⁇ -C 6 alkoxy” includes within its definition the term “C 1 -C alkoxy”.
  • C1-C6 alkylidenyl refers to a straight or branched, divalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, and the like.
  • C 1 -C 4 alkylidenyl is encompassed within the term “C 1 -C 6 alkylidenyl”.
  • halo encompasses chloro, fluoro, bromo and iodo.
  • leaving group refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction.
  • the term “leaving group” as used in this document encompasses, but is not limited to, activating groups.
  • activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -0-CO-(C 4 -C 7 alkyl).
  • Some of the compounds of the present invention are derivatives of benzo[b]thiophene which are named and numbered according to the RING INDEX as follows.
  • R 1 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or -OSO2- (C 1 -C 1 0 alkyl) ; d) X is a bond or methylene; and e) R 2 is piperidinyl, hexamethyleneiminyl, pyrrolidinyl, or -NR 4 R 5 , where R 4 and R 5 are C 1 -C 4 alkyl; and the pharmaceutically acceptable acid addition salts and solvates.
  • the most preferred compounds employed in the methods of this invention are those compounds of Formula I wherein a) A is -S-; b) R is hydrogen, hydroxy, C 1 -C3 alkoxy, or -OSO 2 - (C 1 -C 1 0 alkyl) ; c) R 1 is hydrogen, hydroxy, C1-C 3 alkoxy, or -OSO 2 -
  • R 2 is piperidinyl, hexamethyleneiminyl, pyrrolidinyl, or -NR 4 R 5 , where R 4 and R 5 are C 1 -C4 alkyl; and f) at least one of R and R 1 is -OSO 2 - (C 1 -C 10 alkyl); and the pharmaceutically acceptable acid addition salts and solvates thereof.
  • the compounds of the present invention can be prepared by a variety of procedures well known to those of ordinary skill in the art.
  • the particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties.
  • A Preparation of Dihydronapthalenyl Compounds
  • naphthalenes and dihydronaphthalenes employed in the methods of the instant invention may be prepared by reacting a tetralone of Formula II
  • R c is hydrogen, Ci-C ⁇ alkoxy, or benzyloxy with a phenyl benzoate of Formula III
  • Y 1 is methoxy, benzyloxy, or -O-(CH 2 ) n -NR a R b , where n is 1-6, and -NR a R b is R 2 .
  • This reaction is generally carried out in the presence of a moderately strong base such as sodium amide and at room temperature or below.
  • the product which is obtained is a substituted tetralone of Formula IV.
  • R l is hydrogen, Ci-C ⁇ alkoxy, or benzyloxy and Y a is a bond, methylene, or ethylene.
  • a compound of Formula V can be treated with pyridine hydrochloride at reflux to produce the corresponding hydroxy compound. Under these conditions, should R c or R la be alkoxy or benzyloxy, these groups will also be cleaved, resulting in hydroxy groups.
  • the group at Y 1 can be selectively cleaved by treating a compound of
  • Formula V with an equivalent of sodium thioethoxide in N,N- dimethylformamide at a moderately elevated temperature of about 80°C to about 90°C.
  • the process of the selective cleavage may be monitored by periodic thin layer chromatography analysis. The reaction is complete when little or no starting material remains.
  • L is a good leaving group such as halo, especially chloro.
  • alkylation will be effected at each of the unprotected hydroxy groups which are present in the molecule. This can be avoided, and alkylation at the 4-benzoyl groups alone can be achieved, by carrying out the reaction in the presence of an excess of finely powdered potassium carbonate and using an equivalent or slight excess of the compound of Formula VII.
  • the compound containing the substituent of Formula VII can then be further treated with an additional quantity of sodium thioethoxide in N,N-dimethylformamide as aforedescribed to effect cleavage of any remaining alkoxy or benzyloxy groups, thereby providing another sequence for achieving formation of those compounds employed in this invention in which R 1 and/or R 2 are hydroxy.
  • R 1 and/or R 2 are hydroxy.
  • R 2a is -H or C ⁇ -C 6 alkoxy
  • Y c is Ci-C ⁇ alkoxy- substituted phenyl or benzyl
  • a tetralone as described above, or a salt thereof, is acylated using standard Friedel Crafts conditions to provide a highly enolized diketone of formula
  • R 2a is -H or C ⁇ -C 6 alkoxy.
  • R a is as defined above.
  • R 2 and Y c are as defined above.
  • R 2b is -H or -OH and Y d is phenyl, benzyl, hydroxyphenyl, or hydroxybenzyl.
  • the compounds of Formula Vlf can be substituted using standard means,- if desired, to produce the corresponding dihydronaphthenyl compounds of Formula I.
  • naphthalenes are readily prepared from the corresponding dihydronaphthalenyl compounds.
  • Selective dehydrogenation of the dihydronaphthalene structure to produce specifically the corresponding naphthalene can be accomplished by treatment with 2,3-dichloro-5, 6-dicyano-l, 4-benzoquinone (DDQ) at a temperature of from about 50°C to about 100°C
  • DDQ 2,3-dichloro-5, 6-dicyano-l, 4-benzoquinone
  • the naphthalene which is produce may be further converted to other naphthalene compounds by means of the derivatizing reactions described supra.
  • the title compound was prepared as described in United States Patent 4,230,862. To a suspension of sodium amide (15.2 g, 0.38 mol) in 250 ml of tertrahydrofuran were added 50 grams (0.34 mol) of ⁇ -tetralone. The mixture was stirred for 15-20 minutes, and 78 grams of phenyl p- methoxybenzoate dissolved in tetrahydrofuran were added. The temperature of the reaction mixture was maintained below 10°C, and the mixture was then stirred at room temperature overnight. The reaction mixture was concentrated and the water was added to the residue. The aqueous mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and concentrated.
  • a mixture of 11.1 grams (0.03 mol) of the above dimethoxy product, 7.2 grams of sodium hydride (50 percent in oil) , and 11 ml of ethyl mercaptan in N,N-dimethylformamide was prepared.
  • the mixture was heated to 65-70°C and maintained at that temperature for about two hours.
  • the mixture was then cooled and conetrated.
  • the concentrate was acidified and extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated.
  • the residue was extracted with hexanes, the insoluble portion was dissolved in ethyl acetate, and the ethyl acetate solution was extracted with 1 N hydrochloric acid.
  • the acid extract was rendered alkaline, and then was extracted with ethyl acetate.
  • the ethyl acetate extract was washed and concentrated.
  • One equivalent of citric acid in acetone then was added to the concentrate, and the mixture was concentrated to dryness.
  • the residue was dissolved in a large volume of methyl ethyl ketone.
  • the title product was prepared as described iin United States Patent 4,230,862.
  • To 300 ml of N,N- dimethylformamide were added 107 grams of phenyl p- hydroxybenzoate and 26 grams of sodium hydride (50 percent in oil) .
  • the mixture was heated to 60°C and maintained at this temperature for about two hours.
  • To this mixture was added l-chloro-2-pyrrolidin-l-ylethane (67 g) , and the mixture was stirred overnight at 85°C.
  • the bulk of the N,N- dimethylformamide then was evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate.
  • the ethyl acetate extract was concentrated, and the residue was dissolved in a 1:1 mixture of ether and ethyl acetate.
  • the organic solution was then extracted with 2 N hydrochloric acid, and the acid extract was added dropwise to 2 N sodium hydroxide.
  • the resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and then dried over magnesium sulfate.
  • the ethyl acetate was concentrated to obtain 110 grams of crude phenyl p-(2-pyrrolidin-l-ylethoxy)benzoate.
  • the resulting mixture was poured into a mixture of ice and hydrochloric acid, and the acid mixture was extracted with ethyl acetate.
  • the ethyl acetate extract was washed, dried, and concentrated to obtain 10.5 grams of a red-brown oil.
  • the oil was added to 500 ml of acetic acid, and the mixture was heated on a steam bath for about 30 minutes. The acid was stripped off, and water as added to the residue.
  • the aqueous mixture was rendered alkaline by addition of base, and the alkaline mixture was extracted with ethyl acetate. The extract was dried and concentrated to obtain 8.7 grams of product which was dissolved in acetone, and one equivalent of citric acid was added to the mixture. The acetone was stripped off, and methyl ethyl ketone was added to the residue. The mixture was maintained at 0°C overnight, and the crystals which formed were collected by filtration and washed with cold methyl ethyl ketone and vacuum dried. The solid was recrystallized from acetone to obtain the title compound in the form of its citrate salt, mp 98-100°C Analysis of C36H39NO 1 0
  • the ethyl acetate extract was dried over magnesium sulfate an evaporated to give an oil which was further purified by chromatography on a silica column, using benzene to elute impurities. The product was then eluted with ethyl acetate to give, upon evaporation of the ethyl acetate, 1.69 grams of 3-phenyl-4-(4-hydroxybenzoyl) -1,2-dihydronaphthalene as a clear pale yellow oil.
  • the resulting mixture was added at about 10°C to a mixture of 20 ml of N,N-dimethylformamide containing 120 mg (5.0 mmol) of sodium hydride and 800 mg of l-chloro-2-(pyrrolidin-1-yl)ethane.
  • the mixture was heated to 80°C and maintained at that temperature for about three hours, during which time sodium chloride precipitated.
  • the mixture was cooled and evaporated to dryness.
  • the resulting residue was partitioned between water and ethyl acetate.
  • the organic fraction was washed with brine (5 x 25 ml) .
  • the organic fraction was dried and evaporated to give 1.62 grams of l-[4- [2- (pyrrolidin-l-yl)ethoxy]benzoyl]-2-phenylnaphthalene as a yellow oil.
  • the title compound was prepared as described in United States Patent 4,230,862. To 50 ml of acetone were added 4.0 grams (11.2 mmol) of 3-(4-methoxypheny1) -A-(4- hydroxybenzoyl)-1,2-dihydronaphthalene, prepared as described in Example 1, 1.81 grams (16.8 mmol) of l-chloro-2- dimethylaminoethane (freshly prepared from the hydrohloride) , and 2.32 grams (16.8 mol) of finely powdered potassium chloride. The resulting mixture was refluxed under nitrogen with stirring for about 72 hours. The progress of the reaction was monitored by thin layer chromatography.
  • the acylation of this invention is a Friedel-Crafts acylation, and is carried out in the usual way, using aluminum chloride or bromide, preferably the chloride, as the acylation catalyst.
  • the acylation is ordinarily carried out in a solvent, and any inert organic solvent which is not significantly attacked by the conditions may be used.
  • halogenated solvents such as dichloromethane, 1,2- dichloroethane, chloroform, and the like may be used, as can aromatics such as benzene, chlorobenzene, and the like. It is preferred to use a halogenated solvent, especially dichloromethane.
  • toluene is rather easily acylated under the conditions used in the Friedel-Crafts acylation, and so it is important, when toluene is used in an earlier step of the process, to remove it as completely as possible from the protected starting compound, to avoid wasting the acylating agent.
  • the acylations may be carried out at temperatures from about -30 * C to about 100'C, preferably at about ambient temperature, in the range of from about 15 * C to about 30'C
  • the acylating agent is an active form of the appropriate benzoic acid of Formula VIII
  • R a is chloro or bromo.
  • the preferred acylating agents are those wherein R a is chloro.
  • the most highly preferred individual acylating agents are 4-[2- (piperidin-1- yDethoxy]benzoyl chloride, 4-[2-(hexamethyleneimin-1- yDethoxy]benzoyl chloride, 4-[2-(pyrrolidin-1- yDethoxy]benzoyl chloride, 4-[2-(dimethylamino)ethoxy]- benzoyl chloride, 4-[2-(diethylamino)ethoxy]benzoyl chloride, and 4-[2-(diisopropylamino)ethoxy]benzoyl chloride.
  • the acyl chloride used as an acylating agent may be prepared from the corresponding carboxylic acid by reaction with a typical chlorinating agent such as thionyl chloride. Care must be taken to remove any excess chlorinating agent from the acyl chloride. Most conveniently, the acyl chloride is formed in situ, and the excess chlorinating agent is distilled off under vacuum. It is generally preferred that an equimolar amount of the compounds of Formula VII and VIII are reacted together. If desired, a small excess of either reactant may be added to assure the other is fully consumed. It is generally preferred to use a large excess of the acylation catalyst, such as about 2-12 moles per mole of product, preferably about 5-10 moles of catalyst per mole of product.
  • the acylation is rapid. Economically brief reaction times, such as from about 15 minutes to a few hours provide high yields of the acylated intermediate. Longer reaction times may be used if desired, but are not usually advantageous. As usual, the use of lower reaction temperatures call for relatively longer reaction times.
  • the acylation step is ended and the optional demethylation step is begun by the addition of a sulfur compound selected from the group consisting of methionine and compounds of the formula
  • X 1 is hydrogen or unbranched C 1 -C 4 alkyl
  • Y ⁇ is C 1 -C 4 alkyl or phenyl.
  • the sulfur compounds are, preferably, the alkylthiols, such as methanethiol, ethanethiol, isopropanethiol, butanethiol, and the like; dialkyl sulfides, such as diethyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide, and the like; benzenethiol; methionine; and alkyl phenyl sulfides, such as methyl phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide, and the like.
  • the demethylation reaction goes well at about ambient temperature, in the range of from about 15'C to about 30 * C, and such operation is preferred.
  • the demethylation may be carried out, however, at temperatures in the range of from about -30'C to about 50"C if it is desired to do so. Short reaction times, in the range of about one hour, have been found to be sufficient.
  • the product After the product has been demethylated, it is recovered and isolated by conventional means. It is customary to add water to decompose the complex of the acylation catalyst. Addition of dilute aqueous acid is advantageous. The product precipitates in many instances, or may be extracted with an organic solvent according to conventional methods. The examples below further illustrate the isolation.
  • Lower alkyl alcohols are usually added to the non-polar solvent so as to retain more of the hydrochloric acid created in situ, with ethanol and methanol being especially preferred.
  • the reaction is performed at temperatures ranging from ambient temperature up to the reflux temperature of the mixture. This reaction results in the synthesis of a compound of Formula X
  • the intermediate of Formula X may be isolated or may preferably be converted to the compound of Formula IX in the same reaction vessel.
  • the ether of the compounds of Formula I is then produced by the substitution of the hydrogen on the hydroxy group by an alkyl or halide.
  • Those compounds of Formula I in which "A" equals -NtR 11 )- are prepared in essentially the same manner as the substituted benzofurans described supra.
  • Example 33, infra, provides one such protocol for synthesizing the substituted indoles of this invention.
  • Those compounds of Formula I in which m is one or two may be prepared by oxidation of the corresponding benzothiophene in which m is zero. Oxidation may be carried out by treating the benzothiophene with an oxidizing agent, for example, m-chloroperbenzoic acid, or the like, for a time sufficient to achieve formation of the sulfoxide group. The progress of the oxidation reaction may be monitored by thin layer chromatography methods.
  • an oxidizing agent for example, m-chloroperbenzoic acid, or the like
  • the compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, ethylbenzoate, 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, hydrochloride, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate,
  • a preferable salt is the hydrochloride salt.
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of Formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
  • Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides and carbonates, as well as aliphatic and aromatic amines, aliphatic diamines and hydroxy alkyla ines.
  • Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, calcium hydroxide, methylamine, diethylamine, ethylene diamine, cyclohexylamine and ethanolamine.
  • the pharmaceutically acceptable salts frequently have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • reaction mixture was cooled and the reaction mixture was partitioned by the addition of water. The organic phase was removed and the aqueous layer was washed with 2-butanone. The organic layers were then combined, dried over magnesium sulfate, and the solvents were removed in vacuo to yield 31.1 grams of a yellow oil. The yellow oil was further purified by chromatography, the fractions containing the desired product were then crystallized. All of the crystalline fractions were combined and then dissolved in 80 ml of hot ethanol.
  • ethanethiol (0.95 ml, 1.288 mmol) was dissolved in 10 ml of anhydrous N,N- dimethylformamide.
  • n-butyllithium (0.60 ml of a 1.6 M in hexane solution, 0.966 mmole) followed by the addition of 2-(4-methoxyphenyl) -3- (4-methoxybenzoyl) - 6-methoxybenzofuran (250 mg, 0.644 mole), prepared as described in Preparation 3, supra.
  • the reaction mixture was then heated to 80'C and allowed to remain at that tempeature for about 16 hours.
  • Method B Alkylation of 2- (4-methoxyphenyl) -3- (4- hydroxybenzoyl) -6-methoxybenzofuran.
  • the N,N-dimethylformamide was evaporated and the residue was dissolved in ethyl acetate and water.
  • the ethyl acetate layer was removed and the aqueous layer was washed with more ethyl acetate.
  • the organic fractions were combined, dried over magnesium sulfate, and the solvents were removed in vacuo, yielding 13.3 g of a yellow oil which crystallized upon standing.
  • the product was recrystallized from methanol cooled to -30'C prior to filtration, yielding 11.4 g (84%) of the desired product as pale yellow crystals. mp 87-89'C.
  • Example la supra.
  • ethylene chloride 50 ml
  • aluminum trichloride 9.60 g, 72 mmol
  • ethanethiol 6.39 g, 103 mmol
  • To this liquid was then added the product of Example la (5.00 g, 10.3 mmol) in a gradual fashion.
  • a red oil precipitated and the mixture was stirred for about 20 minutes.
  • 100 ml of tetrahydrofuran was added and the mixture was allowed to stir until all of the oil had gone into solution.
  • the title compound is prepared essentially as described in the process for preparing the compound of Example 18 except that 4-[2- (pyrrolidin-1-yl)ethoxy]benzoyl chloride is employed in the synthesis of Method A in place of 4-[2- (piperidin-1-yl)ethoxy]benzoyl chloride or 2- (pyrrolidin-1-yl)ethyl chloride is employed in the synthesis of Method B in place of the 2- (piperidin-1-yl)ethyl chloride.
  • the title compound was prepared by reacting the compound of Preparation 4a supr .
  • 2- (4-methoxyphenyl) -3- (4- hydroxybenzoyl) -6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with an equimolar amount of 2- (N,N-diethylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06 g, 80.2 mmol).
  • the mixture was heated to 100 * C and was maintained at that temperature for about two hours.
  • the reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
  • the title compound was prepared by reacting the compound of Preparation 4a supra.
  • 2- (4-methoxyphenyl) -3- (4- hydroxybenzoyl) -6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with 2-(N,N- diisopropylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06g, 80.2 mmol) .
  • the mixture was heated to 100'C and was maintained at that temperature for about two hours.
  • the reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
  • the 2-(4-hydroxyphenyl) -3-[4-[2-(piperidin-1- yl)ethoxy]benzoyl]benzofuran was prepared essentially as described in Example 19, except that phenol was used as a starting material in the synthesis described in Preparation 2a instead of 3-methoxy phenol.
  • the hydrochloride salt of this substituted benzofuran was prepared essentially as described in Example 30, supra.
  • Zinc chloride (66.5 g, 0.49 mole) was added to a 3- neck round bottom flask under a nitrogen atmosphere. The flask and its contents were then heated to 200 * C at which time the hydrazone (26.4 g, 0.098 mole) prepared supra was added. The mixture was stirred for about 17 minutes, resulting in the formation of a brown tar and the evolution of some gas. The brown tar was then poured into two liters of 0.075 N hydrochloric acid and this mixture was stirred for about 48 hours, resulting in the formation of a yellow solid. The solids were removed by filtration and were then recrystallized from methanol. The solids were again removed by filtration and the solvents were removed in vacuo to yield the desired 2-(4-methoxyphenyl)-6-methoxyindole (5.50 g, 22% yield) as a white crystalline product.
  • the 2-(4-methoxyphenyl)-6-methoxyindole (2.0 g, 8 mmol) was dissolved in 40 milliliters of N,N- dimethylformamide. This solution was added dropwise to a solution of sodium hydride (0.48 g, 12 mmol) in ten milliliters of N,N-dimethylformamide. This reaction mixture was then stirred at room temperature for 1 hour at which time a solution of ethyl iodide (1.9 g, 12 mmol) in N,N- dimethylforma ide (10 ml) was added dropwise over five minutes. This mixture was then stirred at room temperature for about two hours.
  • the reaction was quenched by the addition of methanol.
  • the volume of the solvents was reduced by vacuum, leaving a brown oil.
  • This oil was diluted with chloroform, washed with 5 N sodium hydroxide (3 x 75 ml), followed by washing with water (2 x 200 ml) .
  • the organic layer was dried over sodium sulfate and the solvents were removed in vacuo leaving 2.3 g of the desired intermediate l-ethyl-2-(4- methoxyphenyl)-6-methoxyindole as white crystals.
  • the preceding intermediate was acylated at the 3- position by first placing N,N-dimethyl-4-methoxybenzamide (1.43 g, 8 mmol), in a 100 ml flask cooled to O'C To this was then added phosphorous oxychloride (6.1 g, 40 mmol) dropwise at such a rate that the reaction temperature never exceeded 20'C The reaction mixture was allowed to warm to room temperature and was stirred for about 30 minutes. The reaction mixture was then cooled to O'C and the l-ethyl-2-(4- methoxyphenyl) -6-methoxyindole (1.5 g, 5.33 mmol) prepared supra. was added and the reaction mixture was then heated to 75 * C and maintained at this temperature for about three hours.
  • reaction mixture was poured over ice and diluted with water. The layers were separated and the organic phase was washed with water (150 ml) . The organic layer was dried over sodium sulfate and the oslvents were removed in vacuo to yield a dark brown/black oil. This oil was taken up in 50 milliliters of methanol and cooled to O'C. This solution was then basified by the dropwise addition of 2N sodium hydroxide (50 ml) . The mixture was then heated to reflux for about 5 minutes, then cooled overnight at 4'C
  • This intermediate (1.0 g, 1.82 mmol) was dissolved in dichloromethane (10 ml) and cooled to O'C. To this mixture was then added the Lewis acid aluminum chloride (1.2 g, 9 mmol) and the reaction mixture was then stirred for five minutes. Ethanol (3 ml) were then added and the reaction mixture was stirred on ice for about 15 minutes. The temperature of the reaction mixture was slowly raised to reflux and maintained at reflux for about 1.5 hours.
  • reaction mixture was then cooled to O'C and this temperature was maintained as tetrahydrofuran (5 ml) was added.
  • To this mixture was then added 20% hydrochloric acid in water (5 ml) and the reaction mixture was cooled back to O'C at which time five milliliters of water was then added, resulting in the formation of a yellow gum.
  • This suspension was then placed at -40'C and kept at this temperature for about 48 hours, after which time a grayish material was removed from the mixture by filtration. Thin layer chromatography confirmed this precipitate as the desired title product.
  • R or R 1 are -OSO 2 -(Ci-Cio alkyl) or
  • O -OCN-R 3 were made essentially as described in European
  • X 1 is a leaving group, preferably a chloro or bromo group.
  • This reaction is usually performed in a basic environment in the presence of a coupling catalyst such as 4- dimethylaminopyridine (DMAP) .
  • DMAP 4- dimethylaminopyridine
  • Most preferred solvents include the lower alkyl amines, especially triethylamine. While this thioester formation reaction may be performed at equal molar ratios of the two reactants, it is usually preferred to employ a 2-3 molar excess of the alkyl sulfonyl compound so as to complete the reaction.
  • the reaction mixture was placed under a nitrogen atmosphere and allowed to warm slowly to room temperature and continued for 72 hours.
  • the reaction mixture was filtered and evaporated to an oil.
  • the oily residue was dissolved in chloroform and chromatographed on a silica gel column and eluted with a linear gradient of chloroform to chloroform-methanol (19:1; V:V) .
  • the desired fractions were combined and evaporated to dryness to afford 5.60 g of the title compound as a tan amorphous powder.
  • the reaction was allowed to proceed at room temperature and under nitrogen for eighteen hours.
  • the reaction mixture was filtered and the volatiles were removed j i vacuo.
  • the resulting material was dissolved in a small amount of chloroform and chromatographed (HPLC) on a silica gel column eluted with a linear gradient starting with chloroform and ending with chloroform-methanol (19:1 v/v) .
  • the desired fractions were determined by thin layer chromatography, combined and evaporated down to afford 3.82 g of the title compound as thick oil.
  • the reaction was allowed to proceed at room temperature and under nitrogen for 3 days.
  • the reaction mixture was evaporated down in vacuo and resuspended in ethyl acetate and washed with water.
  • the organic layer was dried by filtering it through anhydrous sodium sulfate and evaporated to a yellow oil.
  • the oil was dissolved in chloroform and chromatographed (HPLC) on a silica gel column and eluted with a linear gradient starting with chloroform and ending with chloroform-methanol (19:1 v/v) .
  • the desired fractions were determined by thin layer chromatography, combined and evaporated down to afford 3.14 g of the title compound as a thick oil.
  • the reaction was allowed to proceed for eighteen hours at room temperature and under nitrogen. The reaction was quenched with the addition of 25 ml methanol and volume reduced in vacuo. The crude product was chromatographed on a silica gel column, eluted with chloroform-methanol (19:1 v/v) . The desired fractions were determined by thin layer chromatography, combined, and evaporated to a tan oil.
  • the reaction mixture was stirred for eighteen hours at room temperature and under a nitrogen atmosphere.
  • the reaction mixture was evaporated to a gum in vacuo.
  • the crude product was suspended in 100 ml of ethyl acetate and washed with sodium bicarbonate solution and subsequently with water.
  • the organic layer was dried by filteration through anhydrous sodium sulfate and evaporated to a yellow oil.
  • the final product was crystallized from hot ethyl acetate-hexane to afford 410 mg of the title compound.
  • n-butylsulfonylchloride (0.04 mol) was dissolved in 25 ml of tetrahydrofuran and slowly added to the reaction mixture over a period of twenty minutes. The reaction was allowed to continue for 5 days at room temperature and under nitrogen atmosphere. The reaction mixture was evaporated to a gum and suspended in ethyl acetate. The ethyl acetate mixture was washed successively with water, dilute sodium bicarbonate, and water. The ethyl acetate solution was dried by filteration through anhydrous sodium sulfate and evaporated to an amorphous solid.
  • This compound was prepared by substantially following the procedures of Example 75 to afford 3.58 g of the title compound as a white crystalline powder.
  • Two cell lines [human kidney cell line 293 and Chines hamster ovary cell line (CHO)] were stably transfected with the gene for amyloid precursor protein (APP-751) containing the double mutation ys65i ⁇ Met65 2 to Asng5i- eu652 • (APP-751 numbering system) commonly called the Swedish mutation using the method described in Citron, et al.. Nature (London) . 360:672-674 (1992).
  • the transfected cell lines wre designated as 293 751 SWE and CHO 751 SWE, and were plated in 96-well plates at an initial density of 2.5 x 10 4 and 1 x 10 4 cells per well, respectively, in Dulbecco's Minimal Essential Media (DMEM) supplemented with 10% fetal bovine serum. Following overnight incubation at 37"C in an incubator equilibrated with 10% carbon dioxide, the media was removed and replaced with 200 ⁇ l per well of DMEM containing test compound at various concentration. Controls were also performed in which no test compound was added to the media in the wells. After a two hour pretreatment period, the media werew again removed and replaced with fresh media supplemented with the test compound and the cells were incubated for an additional two hours.
  • DMEM Dulbecco's Minimal Essential Media
  • test compound stocks were prepared in dimethylsulfoxide (DMSO) such that, at the highest conentration of tet compound, the concentration of DMSO in the wells never exceeded 0.5%.
  • DMSO dimethylsulfoxide
  • ELISA enzyme- linked immunosorbent assay
  • ⁇ -amyloid ELISA results were fit to a standard curve and expressed as ng/ml of ⁇ -amyloid peptide.
  • the ⁇ -amyloid concentrations were divided by the MTT results and expressed as a percentage of the results from the drug-free controls.
  • the compounds of Formula I were very active in the inhibition of ⁇ -amyloid production in the above assay while not causing significant cytotoxicity.
  • the aggregation of ⁇ -amyloid peptide results in the activation of immune and inflammatory responses in affected areas of the brain.
  • the ⁇ -amyloid peptide upon assuming the conformation necessary for aggregation, also potentiates cytokine secretion, especially interleukin-6 and interleukin-8 release.
  • the compounds of Formula I in preventing the formation of ⁇ - a yloid aggregates, inhibit this cytokine release and, thereby, ameliorate the inflammatory component of Alzheimer's Disease.
  • the compounds of Formula I are usually administered in the form of pharmaceutical compositions.
  • compositions which contain, as the active ingredient, the compounds of Formula I 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, cachet, paper or other container.
  • the excipient when it serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, lozenges, 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, 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 propylhydroxybenzoates; 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 form refers to physically discrete units suitable as unitary dosages 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.
  • dosages per day normally fall within the range of about 0.05 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
  • 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, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • the compounds of Formula I are administered to a host susceptible to Alzheimer's Disease or another physiological condition associated with an amyloidogenic peptide, but not necessarily already suffering from such disease.
  • a host susceptible to Alzheimer's Disease or another physiological condition associated with an amyloidogenic peptide may be identified by genetic screening and clinical analysis, as described in the medical literature. See e.g.. Goate, Nature, 349:704-706 (1991).
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from 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 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 solutiona, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • 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 U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • the active ingredient, cellulose, 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:
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • Capsules each containing 15 mg of medicament, are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • 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.
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • 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 incorporated 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 or prodrugs.
  • 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.

Abstract

Procédés permettant de traiter ou de prévenir les dysfonctionemments physiologiques associés à un peptide amyloïdogène, selon lesquels on administre une série d'indoles de benzothiophènes, de benzofurannes, de dihydronaphtalènes, de naphtalènes substitués ou leurs sels ou solvates pharmaceutiquement acceptables. Sont également décrits des procédés permettant de traiter ou de prévenir la maladie d'Alzeimer ou le syndrome de Down, qui consistent à administrer ces mêmes benzofurannes ou benzothiophènes, ou leurs sels pharmaceutiquement acceptables.
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CA2176127A1 (fr) 1995-06-29
AU1440395A (en) 1995-07-10
EP0735821A4 (fr) 1998-04-01
ZA9410036B (en) 1996-06-18
JPH09507071A (ja) 1997-07-15
WO1995017095A1 (fr) 1995-06-29

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