WO2005014553A1 - Novel gamma-secretase inhibitors - Google Patents
Novel gamma-secretase inhibitors Download PDFInfo
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- WO2005014553A1 WO2005014553A1 PCT/GB2004/003277 GB2004003277W WO2005014553A1 WO 2005014553 A1 WO2005014553 A1 WO 2005014553A1 GB 2004003277 W GB2004003277 W GB 2004003277W WO 2005014553 A1 WO2005014553 A1 WO 2005014553A1
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- SXIDTPCGGYEWQF-UHFFFAOYSA-N COc1ccc(CN(C(CN2CC(F)(F)F)(C(CC3)C4)C3CC(Cl)=C4C=O)S2(=O)=O)cc1 Chemical compound COc1ccc(CN(C(CN2CC(F)(F)F)(C(CC3)C4)C3CC(Cl)=C4C=O)S2(=O)=O)cc1 SXIDTPCGGYEWQF-UHFFFAOYSA-N 0.000 description 1
- CYMPOVGPYPUEOJ-FGJOEMFESA-N C[n]1nc(/C=C/C(CC(CC[C@H]2C3)C2N)=C3Cl)cc1-c(cc1)ccc1F Chemical compound C[n]1nc(/C=C/C(CC(CC[C@H]2C3)C2N)=C3Cl)cc1-c(cc1)ccc1F CYMPOVGPYPUEOJ-FGJOEMFESA-N 0.000 description 1
- OJVVHOZBBZNLDJ-SDDHYBKLSA-N C[n]1nc(/C=C/C(C[C@@H](CC[C@H]2C3)C22OCCO2)=C3Cl)cc1-c(cc1)ccc1F Chemical compound C[n]1nc(/C=C/C(C[C@@H](CC[C@H]2C3)C22OCCO2)=C3Cl)cc1-c(cc1)ccc1F OJVVHOZBBZNLDJ-SDDHYBKLSA-N 0.000 description 1
- CLYQBOFKZLDRQX-UHFFFAOYSA-N Fc1ccc(C2OC(CP(C[Cl-])(c3ccccc3)(c3ccccc3)c3ccccc3)=NC2)cc1 Chemical compound Fc1ccc(C2OC(CP(C[Cl-])(c3ccccc3)(c3ccccc3)c3ccccc3)=NC2)cc1 CLYQBOFKZLDRQX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to a novel class of compounds, their salts, pharmaceutical compositions comprising them, processes for making them and their use in therapy of the human body.
- the invention relates to novel sulphonamide and sulphamide derivatives which inhibit the processing of APP by ⁇ - secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.
- Alzheimer's disease is the most prevalent form of dementia. Although primarily a disease of the elderly, affecting up to 10% of the population over the age of 65, AD also affects significant numbers of younger patients with a genetic predisposition.
- a ⁇ amyloid peptide
- secretases including the putative ⁇ -secretase, in the processing of amyloid precursor protein (APP) to form A ⁇
- APP amyloid precursor protein
- WO 01/70677 There are relatively few reports in the literature of compounds with inhibitory activity towards ⁇ -secretase, as measured in cell-based assays. These are reviewed in WO 01/70677.
- WO 01/70677 and WO 02/36555 disclose, respectively, sulphonamido- and sulphamido-substituted bridged bicycloalkyl derivatives which are believed to be useful in the treatment of Alzheimer's disease, but do not disclose or suggest compounds in accordance with the present invention.
- the present invention provides a novel class of bridged bicycloalkyl sulphonamide and sulphamide derivatives which show a particularly strong inhibition of the processing of APP by the putative ⁇ -secretase, and thus are useful in the treatment or prevention of AD.
- a compound of formula 1 I wherein n is 0 or 1 ; X completes a 5- or 6-membered heteroaromatic ring bearing the group Ar as a substituent, and also the group R 5 as a substituent when n is 1 ; R 5 represents a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms; Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF 3 , CHF 2 , CH F, NO 2 , CN, OCF 3 , C ⁇ - 6 alkyl and C ⁇ - 6 alkoxy; Y represents a bond or NR ; R 1 represents H, or when Y represents NR 3 , R 1 and R 3 may together represent - CH 2 -; R 2 represents a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 3 halogen atoms, or heteroary
- Such groups may comprise linear, branched or cyclic structures, singly or in any combination consistent with the indicated maximum number of carbon atoms, and may be saturated or unsarurated, including aromatic when the indicated maximum number of carbon atoms so permits.
- the expression "Ci- X alkyl" where x is an integer greater than 1 refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x.
- Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
- C 2 - 6 alkenyl such as "C 2 - 6 alkenyl”, “hydroxyC ⁇ - 6 alkyl”, “heteroaryl -ealkyl”, “C 2 - 6 alkynyl” and “C ⁇ - 6 alkoxy” are to be construed in an analogous manner. Most suitably, the number of carbon atoms in such groups is not more than 6.
- C 3 - 6 cycloalkyl refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
- cycloalkylalkyl as used herein includes groups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
- the compounds of formula I may be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be foraied by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- a pharmaceutically acceptable salt may be formed by neutralisation of said acidic moiety with a suitable base.
- Examples of pharmaceutically acceptable salts thus formed include alkali metal salts such as sodium or potassium salts; ammonium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic bases, such as amine salts (including pyridinium salts) and quaternary ammonium salts.
- alkali metal salts such as sodium or potassium salts
- ammonium salts such as sodium or potassium salts
- alkaline earth metal salts such as calcium or magnesium salts
- salts formed with suitable organic bases such as amine salts (including pyridinium salts) and quaternary ammonium salts.
- X completes a 5- or 6-membered heteroaromatic ring bearing the group Ar as a substituent, and optionally the group R 5 as a substituent.
- Five-membered rings completed by X preferably comprise at least one heteroatom, selected from O, N and S, in addition to the nitrogen atom shown in formula 1. Suitable five-membered rings include pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, oxadiazole and thiadiazole, of which pyrazole, oxazole, thiazole, imidazole and 1,2,4-triazole are preferred.
- Suitable 6- membered rings include pyridine, pyrimidine and pyrazine, of which pyridine is preferred.
- the optional substituent R 5 is a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms, and thus may comprise cyclic or acyclic hydrocarbon residues or combinations thereof, saturated or unsaturated, up to a maximum of 5 carbon atoms in total.
- the hydrocarbon group represented by R 5 is preferably unsubstituted or is substituted with up to 3 fluorine atoms
- Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl and allyl.
- Preferred examples include methyl, ethyl and 2,2,2-trifluoroethyl.
- R 5 represents methyl.
- R 5 may be attached to a ring carbon atom or to a ring nitrogen atom when valency constraints so permit, including to the nitrogen atom shown in formula I although this is not preferred.
- Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF 3 , CHF 2 , CH 2 F, NO 2 , CN, OCF , C ⁇ - 6 alkyl and C ⁇ - 6 alkoxy.
- suitable 6-membered heteroaryl groups represented by Ar include pyridyl, pyrazmyl, pyrimidinyl, pyridazinyl and triazinyl, of which pyridyl is a preferred example.
- the phenyl or heteroaryl ring bears 0 to 2 substituents.
- Preferred substituents include halogen (especially chlorine and fluorine), CN, C ⁇ - 6 alkyl (especially methyl), C ⁇ - 6 alkoxy (especially methoxy), OCF 3 and CF 3 . If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl.
- groups represented by Ar include phenyl, monohalophenyl, dihalophenyl, trihalophenyl, cyanophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, monohalopyridyl and trifluoromethylpyridyl, wherein "halo" refers to fluoro or chloro.
- Suitable specific values for Ar include 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4,5- trifluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- (trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoiOmethoxy)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 5-methylpyridin-2-yl, 5- fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-(trifluoromethyl
- Preferred examples include 2-fluorophenyl, 2- chlorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-(trifluoromethyl)phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
- Ar represents 4-fluorophenyl.
- Ar may be attached to a ring carbon or ring nitrogen, preferably in a 1,3- relationship to the double bond which links the ring completed by X to the remainder of the molecule.
- Preferred examples of heteroaryl groups completed by X include 5-aryl-l- methylpyrazol-3-yl, 5-aryloxazol-2-yl, 4-arylpyridin-2-yl, l-arylimidazol-4-yl, and 1- aryl-[l,2,4]triazol-3-yl, where "aryl” refers to the group Ar having the definition and preferred identities indicated above.
- a particularly preferred example is 5-(4- fluorophenyl)- 1 -methylpyrazol-3-yl.
- R 4 represents halogen (especially CI, Br or I) or C ⁇ - 4 alkyl, such as methyl, ethyl, isopropyl, n-propyl or n-butyl.
- R represents CI or methyl.
- R 4 represents CI.
- Y represents a bond or NR 3 .
- R 3 optionally combines with R 1 to form a -CH 2 - group. Otherwise, R 1 is H.
- R 1 and R 3 combine in this manner, the result is a spiro-linked cyclic sulfamide of formula II:
- R 2 represents an optionally-substituted hydrocarbon group as defined previously.
- Suitable hydrocarbon groups represented by R 2 include alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl and benzyl groups optionally bearing up to 3 halogen substituents, the preferred halogen substituent being fluorine or chlorine, especially fluorine.
- Said alkyl, cycloalkyl, cycloalkylalkyl and alkenyl groups typically comprise up to 6 carbon atoms.
- hydrocarbon and fluorinated hydrocarbon groups represented by R 2 include 4-fluorophenyl, benzyl, n-propyl, 2,2-dimethylpropyl, n- butyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl, 3,3,3-trifiuoropropyl, allyl, 2- methylpropen-3-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclopropylmethyl.
- Heteroaryl groups represented by R 2 are either 5-membered or 6-membered and are optionally substituted as defined previously.
- Preferred 5-membered heteroaryl groups include those containing a sulphur atom, such as thienyl, thiathiazolyl and isothiazolyl.
- Preferred 6-membered heteroaryl groups include pyridyl, in particular 3- pyridyl.
- Preferred substituents include halogen (especially chlorine or fluorine), CF 3 and alkyl (such as methyl). If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl.
- Preferred heteroaryl groups are unsubstituted or monosubstituted with halogen.
- R 2 represents an optionally substituted phenyl or heteroaryl group
- Y is preferably a bond.
- R 2 may combine with R 3 to complete a heterocyclic ring of up to 6 members which is optionally substituted as defined previously.
- Said ring preferably comprises at most one heteroatom selected from O, N and S in addition to the nitrogen to which R 2 and R 3 are mutually attached.
- Suitable rings include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
- Preferred substituents include CF 3 , halogen (especially chlorine or fluorine) and alkyl such as methyl. If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl..
- R 3 may alternatively represent H or C ⁇ - 4 alkyl, such as methyl.
- R 3 represents H or completes a ring with R 2 or with R 1 .
- Y is a bond and R 2 is hydrocarbon of up to 6 carbon atoms, optionally bearing up to 3 fluorine or chlorine substituents, or 5- or 6-membered heteroaryl which is optionally substituted as described previously.
- suitable identities for R 2 include methyl, n- butyl, 4-fluorophenyl, 2-thienyl, 5-chloro-2-thienyl, 5-isothiazolyl and 6-chloro-3- pyridyl.
- R 2 examples include 6-chloro-3 -pyridyl.
- Y is NH and R 2 represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.
- preferred identities for R 2 include n-propyl, n-butyl, 2-methylpropen-3-yl, cyclobutyl and 2,2,2- trifluoroethyl.
- Y represents NR 3 and R 2 and R 3 complete a heterocyclic ring as described previously, in particular a pyrrolidine ring.
- a fourth subset of the compounds of formula I is defined by formula II above in which R 2 represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.
- suitable identities for R include, n-propyl, 2,2-dimethylpropyl, n-butyl, isopropyl, t- butyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, allyl, cyclobutyl and cyclopropylmethyl, in particular allyl, cyclopropylmethyl, n-propyl, n-butyl, cyclobutyl and 2,2,2-trifluoroethyl.
- Individual compounds in accordance with the invention are illustrated in the Examples section later herein.
- the compounds of the present invention have an activity as inhibitors of ⁇ secretase.
- compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier.
- these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- the principal active ingredient typically is mixed with a pharmaceutical carrier, e.g.
- a tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This preforaiulation 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.
- Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
- 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.
- a variety of materials can be used for such 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.
- the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, liquid- or gel- filled capsules, 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, poly(ethylene glycol), poly(vinylpyrrolidone) or gelatin.
- the present invention also provides a compound of the invention or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human body.
- the treatment is for a condition associated with the deposition of ⁇ - amyloid.
- the condition is a neurological disease having associated ⁇ - amyloid deposition such as Alzheimer's disease.
- the present invention further provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease. Also disclosed is a method of treatment of a subject suffering from or prone to Alzheimer's disease which comprises administering to that subject an effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof. For treating or preventing Alzheimer's disease, a suitable dosage level is about
- reaction may be carried out in DMSO at 100°C in a sealed tube.
- the compounds of formula II may be obtained by sequential treatment of an aziridine of formula (lb) with an amine R 2 NH 2 and then -SrH 2 SO NH 2 .
- Reaction of (lb) with the amine may be carried out in refluxing dichloromethane in the presence of zinc iodide, and reaction of the resulting diamine may with sulfamide may be carried out in refluxing pyridine.
- Aziridines (la) may be prepared by condensation of ketones (2) with Me 2 NSO 2 NH 2 and reaction of the resulting sulphimine with trimethylsulfoxonium iodide:
- n, X, R 4 , R 5 and Ar have the same meanings as before.
- the condensation may be carried out in refluxing THF in the presence of Ti(OEt) 4 , while reaction to form the aziridine (1) takes place in DMSO at ambient temperature in the presence of sodium hydride.
- Aziridines (lb) may be prepared in the same manner, substituting tBuSONH 2 for Me 2 NSO 2 NH 2 . • 1 7
- Compounds of formula I in which R is H may be prepared by reaction of R - Y-SO Cl with an amine of fomiula (3):
- R 2 N, n, X, R 4 , R 5 and Ar have the same meanings as before.
- the reaction may be carried out in an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine.
- amine (3) may be treated sequentially with catechol sulphate and R 2 R 3 NH, in the manner described in WO 02/36555.
- Amines (3) may be prepared by condensation of ketones (2) with tBuSONH 2 as described above, followed by reduction of the resulting sulfmimide with sodium borohydride (e.g. in methanol solution at 0°C), then hydrolysis of the resulting sulfmamide (e.g.
- ketones (2) may be prepared by reaction of aldehydes (4) with phosphonium salts (5) in the presence of strong base, followed by hydrolysis of the cyclic ketal group:
- Hal represents halogen (preferably CI, Br or I) and n, X, Ar, R 4 and R 5 have the same meanings as before.
- the reaction may be carried out in an aprotic solvent such as THF at 0°C in the presence of n-BuLi.
- Hydrolysis of the cyclic ketal may be effected by treatment with dilute HC1 in THF at 60°C.
- Aldehydes (4) in which R 4 is CI may be prepared by reaction of ketone (6) with POCl 3 and dimethylformamide (DMF):
- the alkylcopper reagent may be prepared in situ by pre- reaction of the corresponding alkyllithium with Cul at 0°C.
- Ketone (6) may be obtained from bicyclo[4,2,l]non-3-en-9-one (7) by (i) formation of the cyclic ketal, (ii) hydroboration, and (iii) oxidation of the of the resulting cycloalkanols, as described in the Examples included herein.
- Aldehydes (10) may be prepared by conventional techniques of heterocyclic synthesis, as illustrated in the Examples section.
- the novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as chiral HPLC, or 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.
- optically active acid such as di-p-toluoyl-D-tartaric acid and/or di- p-toluoyl-L-tartaric acid
- the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by cbromatographic separation and removal of the chiral auxiliary. Alternatively, such techniques may be carried out on racemic synthetic precursors of the compounds of interest.
- the starting materials and reagents used in the above-described synthetic schemes may be prepared by conventional means.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- the compounds of the present invention show unexpectedly high affinities as measured by the above assays.
- the following Examples all had an ED 50 of less than lOOnM, typically less than lOnM, and frequently less than lnM in at least one of the above assays.
- the compounds also exhibit good oral bioavailability and/or brain penetration, and are largely free from undesirable biological interactions likely to lead to toxic side effects.
- the following examples illustrate the present invention.
- Step 3 [5-(4-fluorophenyl - 1 -methyl- iH- pyrazol-3 -yll -methyltriphenylphosphonium chloride
- the aldehyde from Step 2 (2.3g, 1 lmmol) was dissolved in ethanol and sodium borohydride (0.832g, 22mmol) added, and the reaction stirred at 25°C for lh.
- the reaction was quenched with ammonium chloride solution, the ethanol removed in vacuo and the aqueous extracted into ethyl acetate (2X), washed with brine and concentrated to give a yellow oil.
- the crude alcohol was dissolved in dichloromethane (20mL) , thionyl chloride ( 1.6mL, 22mmol) was added and the reaction stirred at 25°C for lh. Water was added and the product extracted into dichloromethane (2X), dried over MgSO 4 , concentrated and azeotroped with toluene to give a solid.
- the solid was dissolved in xylene (50mL) and triphenylphosphine (2.62g, lOmmol) added and the reaction heated to reflux for 16h. The solid formed was filtered off and washed with xylene. The filtrate was heated to reflux for a further 16h and the solid formed was filtered and washed with xylene.
- Trimethylsulfoxonium iodide (151.3g, 0.69mol) was dissolved in anhydrous DMSO (660mL) under nitrogen and sodium hydride (60% dispersion in oil, 27.5g,
- Step 1 The product of Step 1 ( 6.6g, 0.021mol) was dissolved in acetone (lOOmL) and potassium carbonate ( 4.3g, 0.03 lmol) was added, followed by tetra-n- butylammonium iodide (0.760g, 2.05mmol) and p-methoxybenzyl chloride (6.4g, 0.041mol). The reaction was stirred at 25°C under nitrogen for 36h., filtered and the filtrate was concentrated in vacuo. The residue was recrystallised from ethyl acetate/hexane to obtain a white solid (tetra-n-butylammonium iodide).
- Step 2 The product of Step 2 ( 5.65g, 0.013mol) was dissolved in anhydrous THF, cooled to 0°C and borane (1M solution in THF, 26mL, 0.026mol) was added dropwise. The reaction was warmed to 25°C and then heated to reflux for 2h. The flask was once again cooled to 0°C and NaOH (4M, 19.5mL, 0.078mol) was added dropwise, followed by hydrogen peroxide (35% w/w, 7.6mL, 0.078mol). The reaction was stirred at 25 °C for 16h.
- reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried over MgSO 4 , and the solvent evaporated.
- the residual oil was chromatographed on silica eluting with 50%-60% ethyl acetate/hexane to provide the title compound (mixture of epimers) as a colourless oil.
- Step 4 9-e?.Jol 2 ⁇ 3 ⁇ 4 ⁇ 5'-Tetrahvdro-2'-(4-methoxybenzyl)-5'-(2,2,2-trifluoroethvnspiror3- oxobicyclor4.2.11non-3-ene)9,3'-ri,2,51thiadiazol-lM '-dioxide
- Step 3 The product of Step 3 (4.6g, O.Olmol) was dissolved in dichloromethane (200mL) and molecular sieves (4A, 2.5g) were added followed by N-methylmorpholine N-oxide (1.8g, 0.015mol) and tetrapropylammonium perruthenate (0.151g, 0.042mmol). The reaction mixture was stirred under nitrogen for 1.5h, diluted with ethyl acetate and filtered through a pad of silica with further washings with ethyl acetate.
- Step 6 The product of Step 6 (0.04g, O.OO ⁇ mmol) was treated with trifluoroacetic acid (3mL) and the mixture was stirred at 25 °C for 2h.
- the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicabonate solution.
- the organic layer was collected, washed with brine, dried over MgSO 4 and evaporated.
- the residue was chromatographed on silica eluting with 50%-70% ethyl acetate/hexanes to obtain the product as a white solid.
- Step 1 ⁇ 9-end ⁇ 2'.3 ',4',5'- Tetrahydro-2 '-(4-methoxybenzyl -5' -(2,2,2- trifluoroethv spiro(4-methyl-3-formylbicyclor4.2.11non-3-ene)9,3'-ri,2,51thiadiazol- l',l '-dioxide
- Step 6 f 3-Chloro-4- ⁇ (E)-2-r5-(4-fluorophenvn- 1 -methyl- lH-pyrazol-3- yl] vinyl ⁇ bicyclor4.2.1 lnon-3-en-9-yl amine
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (6)
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AU2004263353A AU2004263353B2 (en) | 2003-08-05 | 2004-07-29 | Novel gamma-secretase inhibitors |
DE602004007808T DE602004007808T2 (en) | 2003-08-05 | 2004-07-29 | NEW GAMMA SECRETASE INHIBITORS |
JP2006522390A JP4714686B2 (en) | 2003-08-05 | 2004-07-29 | Novel γ-secretase inhibitor |
US10/566,486 US7452899B2 (en) | 2003-08-05 | 2004-07-29 | Gamma-secretase inhibitors |
EP04743604A EP1658272B1 (en) | 2003-08-05 | 2004-07-29 | Novel gamma-secretase inhibitors |
CA002534057A CA2534057A1 (en) | 2003-08-05 | 2004-07-29 | Novel gamma-secretase inhibitors |
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GBGB0318447.0A GB0318447D0 (en) | 2003-08-05 | 2003-08-05 | Therapeutic agents |
GB0318447.0 | 2003-08-05 |
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WO2005014553A1 true WO2005014553A1 (en) | 2005-02-17 |
Family
ID=27839748
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PCT/GB2004/003277 WO2005014553A1 (en) | 2003-08-05 | 2004-07-29 | Novel gamma-secretase inhibitors |
Country Status (11)
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US (1) | US7452899B2 (en) |
EP (1) | EP1658272B1 (en) |
JP (1) | JP4714686B2 (en) |
CN (1) | CN100475792C (en) |
AT (1) | ATE368031T1 (en) |
AU (1) | AU2004263353B2 (en) |
CA (1) | CA2534057A1 (en) |
DE (1) | DE602004007808T2 (en) |
ES (1) | ES2289537T3 (en) |
GB (1) | GB0318447D0 (en) |
WO (1) | WO2005014553A1 (en) |
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- 2003-08-05 GB GBGB0318447.0A patent/GB0318447D0/en not_active Ceased
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- 2004-07-29 WO PCT/GB2004/003277 patent/WO2005014553A1/en active IP Right Grant
- 2004-07-29 DE DE602004007808T patent/DE602004007808T2/en active Active
- 2004-07-29 JP JP2006522390A patent/JP4714686B2/en not_active Expired - Fee Related
- 2004-07-29 EP EP04743604A patent/EP1658272B1/en active Active
- 2004-07-29 US US10/566,486 patent/US7452899B2/en not_active Expired - Fee Related
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- 2004-07-29 ES ES04743604T patent/ES2289537T3/en active Active
- 2004-07-29 CA CA002534057A patent/CA2534057A1/en not_active Abandoned
- 2004-07-29 AU AU2004263353A patent/AU2004263353B2/en not_active Ceased
- 2004-07-29 AT AT04743604T patent/ATE368031T1/en not_active IP Right Cessation
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GB0318447D0 (en) | 2003-09-10 |
US7452899B2 (en) | 2008-11-18 |
AU2004263353A1 (en) | 2005-02-17 |
ATE368031T1 (en) | 2007-08-15 |
DE602004007808T2 (en) | 2008-04-17 |
ES2289537T3 (en) | 2008-02-01 |
JP4714686B2 (en) | 2011-06-29 |
EP1658272A1 (en) | 2006-05-24 |
CA2534057A1 (en) | 2005-02-17 |
CN100475792C (en) | 2009-04-08 |
JP2007501206A (en) | 2007-01-25 |
EP1658272B1 (en) | 2007-07-25 |
CN1832927A (en) | 2006-09-13 |
US20060189666A1 (en) | 2006-08-24 |
AU2004263353B2 (en) | 2009-11-26 |
DE602004007808D1 (en) | 2007-09-06 |
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