WO2008016340A1 - Dérivés innovants de spiro-quinuclidinyle pour le traitement des troubles du système nerveux central - Google Patents

Dérivés innovants de spiro-quinuclidinyle pour le traitement des troubles du système nerveux central Download PDF

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Publication number
WO2008016340A1
WO2008016340A1 PCT/US2006/020924 US2006020924W WO2008016340A1 WO 2008016340 A1 WO2008016340 A1 WO 2008016340A1 US 2006020924 W US2006020924 W US 2006020924W WO 2008016340 A1 WO2008016340 A1 WO 2008016340A1
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compound
acid
isocyanate
prepared
aryl
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PCT/US2006/020924
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English (en)
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Yifang Huang
Michael H. Parker
Allen B. Reitz
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Janssen Pharmaceutica N.V.
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Priority to PCT/US2006/020924 priority Critical patent/WO2008016340A1/fr
Publication of WO2008016340A1 publication Critical patent/WO2008016340A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present invention is directed to novel spiro-quinuclidinyl derivatives, pharmaceutical compositions containing them and their use in the treatment of central nervous system disorders.
  • the compounds of the invention are useful for the treatment of central nervous system disorders, including Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.
  • AD Alzheimer's disease
  • senility dementia
  • dementia with Lewy bodies dementia with Lewy bodies
  • Down's syndrome dementia associated with Parkinson's disease
  • dementia associated with beta-amyloid dementia associated with beta-amyloid.
  • AD Alzheimer's Disease
  • AD patients suffer from cognition deficits and memory loss as well as behavioral problems such as anxiety. Over 90% of those afflicted with AD have a sporadic form of the disorder while less than 10% of the cases are familial or hereditary. In the United States, about 1 in 10 people at age 65 have AD while at age 85, 1 out of every two individuals are affected with AD. The average life expectancy from the initial diagnosis is 7-10 years, and AD patients require extensive care either in an assisted living facility which is very costly or by family members. With the increasing number of elderly in the population, AD is a growing medical concern. Currently available therapies for AD merely treat the symptoms of the disease and include acetylcholinesterase inhibitors to improve cognitive properties as well as anxiolytics and antipsychotics to control the behavioral problems associated with this ailment.
  • a ⁇ 1-42 forms oligomers and then fibrils, and ultimately amyloid plaques.
  • the fibrils are believed to be especially neurotoxic and may cause most of the neurological damage associated with AD.
  • agents that prevent the formation of A ⁇ i -42 fibrils, aggregates and / or plaques have the potential to be disease-modifying agents for the treatment of AD, mild cognitive impairment and dementia.
  • X is selected from the group consisting of O and NR A ; and Y is selected from the group consisting of O and NR B ; wherein R A and R B are each selected from the group consisting of hydrogen and lower alkyl; provided that when X is O, then Y is O; provided that when X is NR A and Y is NR B then R A and R B are each hydrogen;
  • R 1 is selected from the group consisting of alkyl, alkoxycarbonyl and aryl; wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, alkyl, alkoxy, nitro, cyano, NR C R D , halogenated lower alkyl, halogenated lower alkoxy, alkoxycarbonyl or -S(O)o- 2 -alkyl; wherein each R c and R D is independently selected from hydrogen or lower alkyl; provided that when X is NH and Y is O, then R 1 is other than methyl; or a pharmaceutically acceptable salt thereof.
  • the present invention is further directed to a compound of formula (II) wherein
  • R 1 is selected from the group consisting of alkyl, alkoxycarbonyl and aryl; wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, alkyl, alkoxy, nitro, cyano, NR C R D , halogenated lower alkyl, halogenated lower alkoxy, alkoxycarbonyl or -S(0)o- 2 -alkyl; wherein each R c and R D is independently selected from hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above.
  • An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Exemplifying the invention are methods of treating central nervous system disorders in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
  • An example of the invention is a method for a central nervous system disorder selected from the group consisting of Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, in a subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
  • AD Alzheimer's disease
  • mild cognitive impairment senility
  • dementia dementia with Lewy bodies
  • Down's syndrome dementia associated with Parkinson's disease
  • dementia associated with beta-amyloid dementia associated with beta-amyloid
  • Another example of the invention is the use of any of the compounds described above in the preparation of a medicament for treating: (a) Alzheimer's Disease (AD), (b) mild cognitive impairment, (c) senility, (d) dementia, (e) dementia with Lewy bodies, (f) Down's syndrome, (g) dementia associated with Parkinson's disease and (h) dementia associated with beta- amyloid, in a subject in need thereof.
  • AD Alzheimer's Disease
  • senility dementia
  • dementia with Lewy bodies dementia with Lewy bodies
  • f Down's syndrome
  • dementia associated with Parkinson's disease dementia associated with beta- amyloid
  • the present invention is directed to novel spiro-quinuclidinyl derivatives, compounds of formula (I) and compounds of formula (II)
  • the compounds of the present invention are useful for the treatment of central nervous system disorders, including but not limited to, Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.
  • AD Alzheimer's disease
  • the coimpounds of the present invention are useful in the treatment of Alzheimer's disease (AD), mild cognitive impairment or demetion, more preferably, Alzheimer's disease (AD) or mild cognitive impairment.
  • X is O and Y is O. In another embodiment of the present invention X is NH and Y is O. In yet another embodiment of the present invention X is NH and Y is NH.
  • R A and R B are each independently selected from hydrogen or methyl. Preferably R A and R B are each hydrogen.
  • R 1 is selected from the group consisting of lower alkyl, lower alkoxycarbonyl-(lower alkyl), aryl and substituted aryl; wherein the substituents on the aryl group are one to two independently selected from hydroxy, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, lower alkoxycarbonyl, lower alkylthio or lower alkylsulfonyl.
  • R 1 is selected from the group consisting of ethyl, ethoxycarbonylmethyl, phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2- fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 2-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 3-nitrophenyl, 3-cyanophenyl, 4-cyanophenyl, 3- ethoxycarbonylphenyl, 4-hydroxy-2-methylphenyl, 3-chloro-4-methylphenyl, 2- methyl-4-methoxyphenyl , 4-methoxy-2-methylphenyl, 2,3-dimethylphenyl, 2,5- dimethylphenyl, 3,4-dimethyl
  • R 1 is selected from the group consisting of lower alkyl, lower alkoxycarbonyl-(lower alkyl), aryl and substituted aryl; wherein the substituents on the aryl are one to two substituents independently selected from hydroxy, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano, lower alkoxycarbonyl, lower alkylthio or lower alkylsulfonyl.
  • R 1 is selected from the group consisting of ethyl, ethoxycarbonylmethyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, 2-methylphenyl, 4-methylphenyl, 2-isopropylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3- nitrophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-ethoxycarbonylphenyl, A- hydroxy-2-methylphenyl, 3-chloro-4-methylphenyl, 4-methoxy-2-methylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5- dimethylphenyl, 2,4-dimethoxphenyl
  • R 1 is selected from the group consisting of aryl and substituted aryl; wherein the substituents on the aryl are one to two independently selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkoxycarbonyl.
  • R 1 is selected from the group consisting of 2-fluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3- ethoxycarbonylphenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl, 2,4- dimethoxyphenyl, 3,5-bis(trifluoromethyl)phenyl and 1-naphthyl.
  • R 1 is selected from the group consisting of aryl and substituted aryl; wherein the substituents on the aryl are one to two independently selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or lower alkoxycarbonyl.
  • R 1 is selected from the group consisting of phenyl, 3-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3- ethoxycarbonylphenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl , 3,5-dimethylphenyl, 2,4-dimethoxyphenyl, 3,5- dimethoxyphenyl, 3-chloro-4-methylphenyl and 2-methyl-4-methoxyphenyl.
  • R 1 is other than methyl. In another embodiment of the present invention, when X is NH and Y is O, then R 1 is other than lower alkyl. Representative compounds of the present invention were prepared as listed in Tables 1 -3.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl whether used alone or as part of a substituent group, include straight and branched chains.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl and the like.
  • lower when used with alkyl means a carbon chain composition of 1 -4 carbon atoms.
  • alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless otherwise noted, “lower” when used with alkoxy means an oxygen ether radical 1 -4 carbon atoms.
  • halogenated lower alkyl shall mean any lower alkyl group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to -CF 3 , -CH 2 -CF 3 , -CF 2 -CF 2 - CF 2 -CF 3 , and the like.
  • halogenated lower alkoxy alkyl shall mean any lowerr alkoxy group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to -OCF 3 , -OCH 2 -CF 3 , -OCF 2 - CF 2 -CF 2 -CF 3 , and the like.
  • aryl shall refer to unsubstituted carbocyclic aromatic groups such as phenyl, naphthyl, and the like, preferably phenyl.
  • substituents preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
  • a "phenyl-Cr C 6 alkyl-aminocarbonyl-CrC 6 alkyl" substituent refers to a group of the formula
  • HPLC High Pressure Liquid Chromatography
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • composition means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate,
  • acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2- disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid,
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
  • the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • a compound of formula (II) as its corresponding HCI salt a known compound or compound prepared by known methods
  • a source of cyanide such as potassium cyanide, sodium cyanide, and the like
  • water at about 0°C
  • a compound of formula (II) is reacted with TMSCN, in an organic solvent such as dichloromethane, chloroform, dichloroethane, and the like, at about room temperature, to yield the corresponding compound of formula (III).
  • the compound of formula (III) is reacted with a suitably substituted isocyanate derivative, a compound of formula (III), a known compound or compound prepared by known methods, preferably in the presence of a catalyst such as CuCI, CuBr, CuI, in an organic solvent such as DMF, DMSO, and the like, preferably in a polar organic solvent which at least partially dissolves the catalyst, at a temperature greater than room temperature, preferably at a temperature in the range of about 60°C to about 120°C, more preferably at about 100°C, to yield the corresponding compound of formula (V).
  • a catalyst such as CuCI, CuBr, CuI
  • organic solvent such as DMF, DMSO, and the like
  • a polar organic solvent which at least partially dissolves the catalyst
  • the compound of formula (V) is reacted with an acid such as concentrated HCI, sulfonic acid, sulfuric acid, and the like, preferably at a temperature in the range of about 60°C to about 120°C, more preferably at about 100°C, to yield the corresponding compound of formula (Ia).
  • an acid such as concentrated HCI, sulfonic acid, sulfuric acid, and the like, preferably at a temperature in the range of about 60°C to about 120°C, more preferably at about 100°C, to yield the corresponding compound of formula (Ia).
  • a suitably substituted compound of formula (III) is reacted with a source of ammonia such as ammonium hydroxide, ammonia gas, and the like, in a polar organic solvent such as ethanol, methanol, dioxane, and the like, at a temperature greater than room temperature, preferably at a temperature of about 50°C, to yield the corresponding compound of formula
  • the compound of formula (V) is reacted with a suitably substituted isocyanate derivative, a compound of formula (III), a known compound or compound prepared by known methods, preferably in the presence of a catalyst such as CuCI, CuBr, CuI, in an organic solvent such as DMF, DMSO, and the like, preferably in a polar organic solvent which at least partially dissolves the catalyst, at about room temperature, to yield the corresponding compound of formula (VII).
  • a catalyst such as CuCI, CuBr, CuI
  • organic solvent such as DMF, DMSO, and the like, preferably in a polar organic solvent which at least partially dissolves the catalyst, at about room temperature, to yield the corresponding compound of formula (VII).
  • the compound of formula (VII) is reacted with an acid such as concentrated HCI, sulfonic acid, sulfuric acid, and the like, preferably at a temperature in the range of about 60°C to about 120°C, more preferably at about 100°C, to yield the corresponding compound of formula (Ib).
  • an acid such as concentrated HCI, sulfonic acid, sulfuric acid, and the like, preferably at a temperature in the range of about 60°C to about 120°C, more preferably at about 100°C, to yield the corresponding compound of formula (Ib).
  • the compound of formula (Ib) may optionally be reacted according to known methods, (for example by reacting the compound of formula (Ib) with a base and then with a suitably substituted electrophile) to yield the corresponding compound of formula (I) wherein X is NR A and R A is other than hydrogen.
  • a suitably substituted compound of formula (Vl) is reacted with a suitably substituted isocyanate derivative, a compound of formula (III), preferably in the presence of a catalyst such as CuCI, CuBr, CuI, in an organic solvent such as DMF, DMSO, and the like, preferably in a polar organic solvent which at least partially dissolves the catalyst, at about room temperature, to yield the corresponding compound of formula (Ic).
  • a catalyst such as CuCI, CuBr, CuI
  • the compound of formula (VIII) is reacted with a suitably substituted isocyanate derivative, a compound of formula (III), a known compound or compound prepared by known methods, preferably in the presence of a catalyst such as CuCI, CuBr, CuI, in an organic solvent such as DMF, DMSO, and the like, preferably in a polar organic solvent which at least partially dissolves the catalyst, at about room temperature, to yield the corresponding compound of formula (Ha).
  • the present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) and / or compounds of formula (II) with a pharmaceutically acceptable carrier.
  • compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.1-500 mg and may be given at a dosage of from about 0.1-100 mg/kg/day, preferably from about 0.5-100 mg/kg/day, more preferably from about 1.0-50 mg/kg/day.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition 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 novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits 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 with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the method of treating central nervous system disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.1 mg and 500 mg, preferably about 5 to 100 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of central nervous system disorders is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 500 mg/kg of body weight per day.
  • the range is from about 0.1 to about 100 mg/kg of body weight per day, more preferably, from about 0.5 to about 100 mg/kg of body weight per day, more preferably, from about 1.0 to about 50 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
  • Step A 3-Hydroxyquinuclidine-3-carbonitrile (following the procedure described in J. Heterocyclic Chem., 18, 1507(1981))
  • Step B 3'-(3-Trifluoromethylphenyl)-quinuclidine-3-spiro-5'-oxazolidine-2',4'- dione trifluoroacetate.
  • Example 15 Following the procedure of Example 15, with substitution of the compound prepared as in Example 3 for the compound prepared as in Example 14, the title compound was prepared as a white solid.
  • Step B 1 with substitution of 2- isopropylphenyl isocyanate for 3-trifluoromethylphenyl isocyanate, the title compound was prepared as a white solid.
  • Step A 3-Aminoquinuclidine-3-carbonitrile(Synthesis, 1994, 832-836) To a stirring solution of the compound prepared as in Example 1 , Step A: 3-Aminoquinuclidine-3-carbonitrile(Synthesis, 1994, 832-836) To a stirring solution of the compound prepared as in Example 1 , Step A: 3-Aminoquinuclidine-3-carbonitrile(Synthesis, 1994, 832-836) To a stirring solution of the compound prepared as in Example 1 , Step B
  • Step B 3'-(3-Trif luoromethylphenyO-quinuclidine-S-spiro- ⁇ '-hydantoins trifluoroacetate.
  • Step A 3-Hydroxyquinuclidine-3-methylnitrile(RWJ356576-300-A).
  • Step B 3'-(4-methoxyphenyl)-quinuclidine-3-spiro-4'-iminooxan-2-ones trifluoroacetate salt
  • Example 55 -A ⁇ Aggregation Assay A ⁇ s are known to form aggregates leading to the formation of amyloid plaques that are characteristic of Alzheimer's disease. This phenomenon can be demonstrated in vitro by using Synthaloid plates, coated with A ⁇ crystallization centers, and labelled A ⁇ s for detecting aggregation.
  • This aggregation assay was validated using both 125 l-A ⁇ i -4 o and fluo-A ⁇ 40 in a buffer containing 5O mM HEPES, pH 7.4, 0.1 % BSA, 10% FCS and protease inhibitors.
  • Example 56 - % Inhibition of AcH Release Assay Synaptosomes from guinea pig hippocampus were incubated with 0.1 ⁇ M 3 H-choline and then subjected to repeated washes with buffer to remove unincorporated 3 H-choline. The synaptosomes were then treated with 65 mM K + for 30 seconds to elicit 3H-acetylcholine release.
  • Both Ap 1-40 and Ap 1-42 at 100 pM are known to inhibited acetylcholine release from these preparations (33% inhibition for both APi -4 O and Ap 1-42 )-
  • the synaptosomes were pre-treated with 10 ⁇ M of the test compound prior to the K+ stimulation. The decrease or increase in acetylcholine release was then measured by superfusion.
  • the reagents and materials used in this assay were as follows: 50 mM Tris-HCI, 10 mM MgCI 2 , 1 mM EDTA, 0.375% BSA, pH 7.4 buffer; M1 human CHO receptor membranes (Amersham 6110503, 200 Units): 9.7 ⁇ g/ ⁇ l, vials of 1 ml; WGA SPA Beads (Amersham SPQ0031 , 12.5 grams): vials of 500 mg; Tritiated Scopolamine Ligand (Perkin Elmer NET-636 250 ⁇ Ci, 250 ⁇ l): 12 ⁇ M, vials of 250 ⁇ l; 30% DMSO in 5OmM Hepes pH 7.4; Assay Plates (Dynatech 96 well white flat bottom) and Seals (Clear- Zymark #74845, 3 rolls of 2000 seals)
  • the ligand was prepared as 5nM 48 ⁇ l 12 ⁇ M + 115 ml buffer (900 ⁇ l per well to a 2 ml deepwell).
  • Test compounds were diluted to 0.4 mM (30% DMSO in 5OmM HEPES, pH 7.4). The positive control was atropine.
  • the HTS assay was run as follows: SPA-beads were pre-coupled with membrane in binding buffer for at least 30 min at room temperature. 75 ⁇ !_ of buffer was added to each well of a Dynateh 96 well white flat bottom plates with 200 ⁇ l final volume. To each well was then added 5 ⁇ l of test compound or control (atropine). To each well was then added 20 ⁇ l of ligand and 100 ⁇ l of the membrane and bead complex. The plate was then incubated for 60 minutes at room temperature. The plate was clear sealed and centrifuged at 1200-1500 rpm for 5 min using a Beckman, Allegra 6K-R centrifuge. Each well was then measured by counting for 1 minute per well on TopCount with 1 min pre-read delay.
  • Nonspecific binding the mean of counts per minute (CPM) of the 10 ⁇ M Atropine wells 12E - 12H
  • Total Binding the mean of the wells with no Atropine 12A - 12D
  • % Inhibition for the test compounds [1 -(Sample CPM - NSB) X 100] / TB-NSB
  • Compounds which inhibit the M1 muscarinic receptor are useful for the treatment of for example, mild cognitive impairment, Alzheimer's disease, dementia, senility and the like.
  • an oral composition 100 mg of the Compound #1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés innovants de spiro-quinuclidinyle, des compositions pharmaceutiques qui les contiennent et leur utilisation pour le traitement des troubles du système nerveux central.
PCT/US2006/020924 2006-08-02 2006-08-02 Dérivés innovants de spiro-quinuclidinyle pour le traitement des troubles du système nerveux central WO2008016340A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5852029A (en) * 1990-04-10 1998-12-22 Israel Institute For Biological Research Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5852029A (en) * 1990-04-10 1998-12-22 Israel Institute For Biological Research Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity

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