US20040116404A1 - Sulphones which modulate the action of gamma secretase - Google Patents

Sulphones which modulate the action of gamma secretase Download PDF

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Publication number
US20040116404A1
US20040116404A1 US10/473,727 US47372703A US2004116404A1 US 20040116404 A1 US20040116404 A1 US 20040116404A1 US 47372703 A US47372703 A US 47372703A US 2004116404 A1 US2004116404 A1 US 2004116404A1
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United States
Prior art keywords
mmol
alkyl
ethyl acetate
halogen
nmr
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Abandoned
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US10/473,727
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English (en)
Inventor
Jose Pineiro
Ian Churcher
Kevin Dinnell
Timothy Harrison
Sonia Kerrad
Alan Nadin
Paul Oakley
Andrew Owens
Duncan Shaw
Martin Teall
Susannah William
Brian Williams
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Organon Pharma UK Ltd
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Individual
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Publication of US20040116404A1 publication Critical patent/US20040116404A1/en
Assigned to MERCK SHARP & DOHME LTD. reassignment MERCK SHARP & DOHME LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HARRISON, TIMOTHY, CHURCHER, IAN, WILLIAMS, SUSANNAH, DINNELL, KEVIN, KERRAD, SONIA, NADIN, ALAN JOHN, OAKLEY, PAUL JOSEPH, OWENS, ANDREW PATE, PINEIRO, JOSE LUIS CASTRO, SHAW, DUNCAN EDWARD, TEALL, MARTIN RICHARD, WILLIAMS, BRIAN JOHN
Priority to US11/788,888 priority Critical patent/US7598386B2/en
Priority to US12/151,296 priority patent/US7595344B2/en
Abandoned legal-status Critical Current

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
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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 sulphones which modulate the processing of APP by ⁇ -secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.
  • AD Alzheimer's disease
  • AD 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. It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers.
  • plaques mainly comprise fibrillar aggregates of ⁇ -amyloid peptide (A ⁇ ), and although the exact role of the plaques in the onset and progress of AD is not fully understood, it is generally accepted that suppressing or attenuating the secretion of A ⁇ is a likely means of alleviating or preventing the condition.
  • a ⁇ ⁇ -amyloid peptide
  • a ⁇ is a peptide comprising 39-43 amino acid residues, formed by proteolysis of the much larger amyloid precursor protein.
  • the amyloid precursor protein (APP or A ⁇ PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail.
  • Different isoforms of APP result from the alternative splicing of three exons in a single gene and have 695, 751 and 770 amino acids respectively.
  • the A ⁇ domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH 2 - and COOH-termini. At least two secretory mechanisms exist which release APP from the membrane and generate the soluble, COOH-truncated forms of APP (APP s ). Proteases which release APP and its fragments from the membrane are termed “secretases”. Most APP s is released by a putative ⁇ -secretase which cleaves within the A ⁇ domain (between residues Lys 6 and Leu 17 ) to release ⁇ -APP s and precludes the release of intact A ⁇ .
  • CTFs COOH-terminal fragments
  • Japanese Patent Publication No. 56 026847 discloses certain 4-aryl-4-arylsulphonylcyclohexanone derivatives as intermediates in the synthesis of substituted salicylic acids.
  • the present invention provides a novel class of non-peptidic compounds which are useful in the treatment or prevention of AD by modulating the processing of APP by the putative ⁇ -secretase, thus arresting the production of A ⁇ .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of formula I:
  • A represents the atoms necessary to complete a saturated or unsaturated ring containing 4, 5, 6 or 7 ring atoms, at most 2 of which are selected from nitrogen, oxygen and sulphur, the remainder being carbon, said ring bearing, in addition to Ar 2 and Ar 1 SO 2 , 0-3 substituents independently selected from ⁇ X, halogen, CN, NO 2 , N 3 , R 2 , CF 3 , N(R 1 ) 2 , OR 1 , COR 1 , CO 2 R 1 , CON(R 1 ) 2 , OCOR 1 , OCO 2 R 2 , OCON(R 1 ) 2 , N(R 1 )COR 2 , N(R 1 )CO 2 R 2 , OSO 2 R 2 and N(R 1 )SO 2 R 2 ;
  • X represents C(R 1 ) 2 , CHCO 2 R 1 , O, S, NOR 1 , CHCON(R 1 ) 2 , NNHCOR 2 , or the atoms necessary to complete a spiro-linked 5- or 6-membered carbocyclic or heterocyclic ring;
  • Ar 1 represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, OCF 3 , C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;
  • Ar 2 represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, OCF 3 , C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, No 2 , CF 3 , OH and C 1-4 alkoxy;
  • R 1 represents H or R 2 , or two R 1 groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-3 substituents selected from ⁇ O, ⁇ S, ⁇ NOR 1 , halogen, CN, NO 2 , R 2 , CF 3 , N(R 1a ) 2 , OR 1 , COR 1 , CO 2 R 1 and CON(R 1a ) 2 ;
  • R 1a represents H or R 2 , or two R 1a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-3 substituents selected from ⁇ O, ⁇ S, halogen, C 1-4 alkyl CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr;
  • R 2 represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C-heterocyclyl, any of which may bear up to 3 substituents independently selected from halogen, CN, NO 2 , N 3 , CF 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , COR 2a , OCOR 2a , CON(R 2a ) 2 , OCON(R 2a ) 2 , CONR 2a (OR 2a ), CONHC( ⁇ NOH)R 2a , CON(R 2a )N(R 2a ) 2 , heterocyclyl, phenyl and heteroaryl, said heterocyclyl, phenyl and heteroaryl substituents themselves bearing 0-3 substituents selected from halogen, CN, NO 2 , CF 3 , OR 2a , N
  • R 2a represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 -cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OR 2b , CO 2 R 2b , N(R 2b ) 2 , CON(R 2b ) 2 , Ar and COAr; or R 2a represents Ar; or two R 2a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-4 substituents independently selected from ⁇ O, ⁇ S, halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and
  • R 2b represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr; or R 2b represents Ar; or two R 2b groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-4 substituents independently selected from ⁇ O, ⁇ S, halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, CO 2 H, amino, C 1-4 alkylamino,
  • Ar represents phenyl or heteroaryl bearing 0-3 substituents selected from halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, C 1-4 alkylcarbamoyl and di(C 1-4 alkyl)carbamoyl;
  • heterocyclyl at every occurrence thereof means a cyclic or polycyclic system of up to 10 ring atoms selected from C, N, O and S, wherein none of the constituent rings is aromatic and wherein at least one ring atom is other than C;
  • heteroaryl at every occurrence thereof means a cyclic or polycyclic system of up to 10 ring atoms selected from C, N, O and S, wherein at least one of the constituent rings is aromatic and wherein at least one ring atom of said aromatic ring is other than C;
  • A represents the atoms necessary to complete a saturated or unsaturated ring containing 5, 6 or 7 ring atoms, at most 2 of which are selected from nitrogen, oxygen and sulphur, the remainder being carbon, said ring bearing 0-3 substituents independently selected from ⁇ C(R 1 ) 2 , ⁇ CHCO 2 R 1 , ⁇ O, ⁇ S, ⁇ NOR 1 , halogen, CN, NO 2 , N 3 , R 2 , CF 3 , N(R 1 ) 2 , OR 1 , COR 1 , CO 2 R 1 , CON(R 1 ) 2 , OCOR 1 , OCO 2 R 2 , N(R 1 )COR 2 , N(R 1 )CO 2 R 2 , OSO 2 R 2 and N(R 1 )SO 2 R 2 ;
  • Ar 1 represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;
  • Ar 2 represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;
  • R 1 represents H or R 2 , or two R 1 groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-3 substituents selected from ⁇ O, ⁇ S, ⁇ NOR 1 , halogen, CN, NO 2 , R 2 , CF 3 , N(R 1a ) 2 , OR 1 , COR 1 , CO 2 R 1 and CON(R 1a ) 2 ;
  • R 1a represents H or R 2 , or two R 1a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-3 substituents selected from ⁇ O, ⁇ S, halogen, C 1-4 alkyl CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr,
  • R 2 represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C-heterocyclyl, any of which may bear a substituent selected from halogen, CN, NO 2 , CF 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , COR 2a , CON(R 2a ) 2 , heterocyclyl, phenyl and heteroaryl, said heterocyclyl, phenyl and heteroaryl substituents themselves bearing 0-3 substituents selected from halogen, CN, NO 2 , CF 3 , OR 2a , N(R 2 a ) 2 , CO 2 R 2a , COR 2a , CON(R 2a ) 2 and C 1-4 alkyl, or R 2 represents Ar;
  • R 2a represents H, C 1-4 alkyl, or Ar; or two R 2a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group bearing 0-3 substituents selected from ⁇ O, ⁇ S, halogen, C 1-4 alkyl CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, Ar and COAr, and
  • Ar represents phenyl or heteroaryl bearing 0-3 substituents selected from halogen, C 1-4 alkyl, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, carbamoyl, C 1-4 alkylcarbamoyl and di(C 1-4 alkyl)carbamoyl.
  • the invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof, with the proviso that if A represents —CH 2 —CH(CO 2 R)—CO—CH 2 CH 2 — or —CH ⁇ C(CO 2 R)—CO—CH 2 CH 2 —, where R represents methyl, ethyl, n-propyl or n-butyl, and Ar 1 represents phenyl, 4-methylphenyl or 4-chlorophenyl, then Ar 2 does not represent phenyl, 4-halophenyl or 2,4-dihalophenyl where the halogens are independently Cl or F.
  • C 1-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 include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Derived expressions such as “C 2-6 alkenyl”, “hydroxyC 1-6 alkyl”, “heteroaryl”C 1-6 alkyl, “C 2-6 alkynyl” and “C 1-6 alkoxy” are to be construed in an analogous manner.
  • C 3-9 cycloalkyl refers to nonaromatic monocyclic or fused bicyclic hydrocarbon ring systems comprising from 3 to 9 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and bicyclo[2.2.1]heptyl.
  • C 3-6 cycloalkylC 1-6 alkyl as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • C 6-10 aryl as used herein includes phenyl and naphthyl.
  • heterocyclyl as used herein means a cyclic or polycyclic system of up to 10 ring atoms selected from C, N, O and S, wherein none of the constituent rings is aromatic and wherein at least one ring atom is other than carbon. Preferably not more than 3 ring atoms are other than carbon.
  • heterocyclyl groups include azetidinyl, pyrrolidinyl, terahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-aza-5-oxabicyclo[2.2.1]heptyl and 1,4-dioxa-8-azaspiro[4.5]decanyl.
  • heterocyclyl groups may be bonded through a ring carbon atom or a ring nitrogen atom where present. “C-heterocyclyl” indicates bonding through carbon, while “N-heterocyclyl” indicates bonding through nitrogen.
  • heteroaryl as used herein means a cyclic or polycyclic system of up to 10 ring atoms selected from C, N, O and S, wherein at least one of the constituent rings is aromatic and wherein at least one ring atom is other than carbon. Where a heteroaryl ring comprises two or more atoms which are not carbon, not more than one of said atoms may be other than nitrogen.
  • heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analogues thereof.
  • Further examples of heteroaryl groups include tetrazole, 1,2,4-triazine and 1,3,5-triazine.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
  • the compounds of formula I may advantageously 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 formed 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, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic 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.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • A completes a saturated or unsaturated ring system containing 4, 5, 6 or 7 ring atoms, at most 2 of which are selected from nitrogen, oxygen or sulphur, the remainder being carbon, which optionally bears up to 3 additional substituents as defined previously.
  • A completes a 4-, 5-, 6-, or 7-membered ring in which at most 1 ring atom is oxygen or nitrogen and the remainder carbon, and in certain embodiments when A completes a 4-membered ring, said ring is carbocyclic.
  • rings completed by A include cycloheptane, cyclohexane, cyclohexene, cyclopentane, cyclopentene, cyclobutane, piperidine, pyrrolidine and pyran, with cycloheptarie, cyclohexane, cyclohexene, cyclopentane, cyclopentene and pyran preferred.
  • the ring completed by A may bear up to 3 substituents in addition to those shown in formula I, but when A completes a 4-membered ring, said ring typically bears at most 2 additional substituents, preferably at most 1 additional substituent. Where three additional substituents are present, two of them are preferably attached to the same ring carbon atom.
  • Preferred substituents include ⁇ X; halogen; azide; hydroxy or alkoxy represented by OR 1 ; alkylsulphonyloxy represented by OSO 2 R 2 ; amino or N-heterocyclyl represented by N(R 1 ) 2 ; optionally substituted alkyl, alkenyl, aryl or heteroaryl represented by R 2 ; carboxylic acid or alkoxycarbonyl represented by CO 2 R 1 ; carbamoyl represented by CON(R 1 ) 2 ; carbamoyloxy represented by OCON(R 1 ) 2 ; and amido represented by N(R 1 )COR 2 .
  • Typical embodiments of ⁇ X include alkylidene represented by ⁇ C(R 1 ) 2 , ⁇ CHCON(R 1 ) 2 or ⁇ CHCO 2 R 1 ; oxo represented by ⁇ O; oximino or alkoximino represented by ⁇ NOR 1 ; ⁇ N—NHCOR 2 ; or the atoms necessary to complete a spiro-linked 5- or 6-membered carbocyclic or heterocyclic ring such as:
  • the ring positions adjacent to the carbon bonded to the Ar 1 SO 2 group are occupied by unsubstituted methylene groups.
  • fragments represented by A include, but are not limited to:
  • n is an integer in the range 4-6;
  • p and q are both 0-4 such that p+q is an integer in the range 2-4;
  • r and s are 0-5 such that r+s is an integer in the range 2-5, and
  • Y represents OR 1 , N(R 1 ) 2 , N(R 1 )COR 2 , OCOR 2 , OCON(R 1 ) 2 , CO 2 R 1 , CON(R 1 ) 2 or CN.
  • each of p, q, r and s is at least 1.
  • p+q is 2 or 3, most preferably 3.
  • r+s is 3 or 4, most preferably 4.
  • R 1 represents H or R 2 , or two R 1 groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group.
  • N-heterocyclyl groups represented by N(R 1 ) 2 include pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl and 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, each optionally bearing up to 3 substituents as defined previously.
  • such heterocyclyl groups bear at most 2 substituents selected from ⁇ O, CF 3 , OH, R 2 , CO 2 R 1 and N(R 1a ) 2 .
  • R 1a represents H or R 2 , or two R 1a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group, optionally substituted as defined previously, an example being piperidin-1-yl.
  • R 2 represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C-heterocyclyl (any of which is optionally substituted as defined previously), or Ar.
  • two OR 2 groups attached to adjacent carbon atoms may complete a 1,3-dioxolane ring such as 2,2-dimethyl-1,3-dioxolane.
  • Preferred substituents on groups represented by R 2 include CN, phenyl, heteroaryl (such as imidazolyl, furyl, thiazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl and pyridyl), C-heterocyclyl (such as 1-t-butoxycarbonylpyrrolidin-2-yl), COR 2a , OR 2a , N(R 2a ) 2 , CO 2 R 2a , CON(R 2 ) 2 , OCON(R 2a ) 2 , CONR 2a (OR 2a ), and CON(R 2a )N(R 2a ) 2 . Typically, not more than 2 substituents are present on R 2 .
  • R 2a represents H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 2-6 alkenyl, any of which optionally bears a substituent as defined previously; or R 2a represents Ar; or two R 2a groups together with a nitrogen atom to which they are mutually attached may complete an N-heterocyclyl group which is optionally substituted as defined previously.
  • R 2a include H, aryl (such as phenyl), heteroaryl (such as pyridyl), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl and cyclopentyl), C 3-6 cycloalkylC 1-6 alkyl (such as cyclopropylmethyl), C 2-6 alkenyl (such as allyl), and linear or branched C 1-6 alkyl which is optionally substituted with CF 3 , Ar, OR 2b , N(R 2b ) 2 , CO 2 R 2b or CON(R 2b ) 2 .
  • aryl such as phenyl
  • heteroaryl such as pyridyl
  • C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl and cyclopentyl
  • C 3-6 cycloalkylC 1-6 alkyl such as cyclopropylmethyl
  • C 2-6 alkenyl such as
  • N-heterocyclyl groups represented by N(R 2a ) 2 include piperidin-1-yl (optionally substituted with OH, CO 2 H, CO 2 C 1-4 alkyl, Me or Ph), piperazin-1-yl (optionally substituted with Me or Ph), morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl, 2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-pyridin-1-yl, and 2-oxo-pyrrolidin-1-yl.
  • R 2b typically represents H or C 1-4 alkyl.
  • R 2 represents C 2-6 alkenyl (such as allyl) or C 1-6 alkyl, such as methyl, ethyl, n-propyl or t-butyl, which is optionally substituted as described above.
  • Ar 1 represents C 6-10 aryl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy.
  • Ar 1 represents optionally substituted phenyl or heteroaryl.
  • Typical heteroaryl embodiments of Ar 1 include optionally substituted pyridyl, in particular optionally substituted 3-pyridyl.
  • Ar 1 bears 0-2 substituents, more preferably 1 or 2 substituents, and most preferably 1 substituent which is preferably in the para-position relative to the sulphone group.
  • Typical substituents include halogen (especially chlorine, bromine and fluorine), C 1-4 alkyl (such as methyl), C 1-4 alkoxy (such as methoxy), and CF 3 .
  • groups represented by Ar 1 include 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl and 6-chloro-3-pyridyl.
  • Ar 1 represents 4-chlorophenyl, 4-bromophenyl or 4-trifluoromethylphenyl.
  • Ar 2 represents C 6-10 aryl or heteroaryl bearing 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , OH, C 1-4 alkoxy or C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy.
  • Ar 2 represents phenyl bearing 1 or 2 substituents as indicated, and most preferably, Ar 2 represents 2,5-disubstituted phenyl.
  • Preferred substituents include halogen (especially bromine, chlorine and fluorine) and substituted alkyl, such as hydroxymethyl.
  • Examples of groups represented by Ar 2 include 2,5-dichlorophenyl, 2,5-difluorophenyl, 2-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 5-iodo-2-fluorophenyl and 2-hydroxymethyl-5-fluorophenyl. Very aptly, Ar 2 represents 2,5-difluorophenyl.
  • a subclass of the compounds of the invention comprises the compounds of formula II:
  • v is 1 and w is 0, 1 or 2, or v is 2 and w is 0 or 1;
  • bond a (indicated by the dotted line) may be single or double;
  • R 3 represents H, OR 1 , N(R 1 ) 2 or N(R 1 )COR 2 ;
  • R 4 represents H, R 2 , OR 1 , OCOR 2 , CN, CO 2 R 1 or CON(R 1 ) 2 ;
  • Ar 1 , Ar 2 , R 1 and R 2 have the same meanings as before.
  • bond a is preferably single and R 4 is preferably H.
  • R 3 may be cis or trans relative to Ar 1 SO 2 —, but is preferably cis.
  • Examples of compounds within this subclass include those wherein Ar 1 represents 4-chlorophenyl, Ar 2 represents 2,5-difluorophenyl, v is 1 and w, a, R 3 and R 4 are as indicated in the following table: w Bond a R 3 R 4 0 Single H H 0 Double H H H 0 Single OH H 1 Single H H 1 Double OH H 1 Double OH CO 2 Me 1 Double O-allyl CO 2 Me 1 Double O—CH 2 Ph CO 2 Me 1 Single OH CH 2 OH 1 Double OMe CO 2 Me 1 Double OH CONH 2 1 Single NH 2 H 1 Single NMe 2 H 1 Single NHCH 2 Ph H 1 Single morpholin-4-yl H 1 Single thiomorpholin-4-yl H 1 Single NHCH 2 CO 2 Me H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single H 1 Single
  • a subset of the compounds of formula II are those in which v is 2, bond a is single and R 3 is H.
  • Particular examples of compounds within this subset include those in which w is 0 and Ar 1 , Ar 2 and R 4 have the identities shown in the following table: Ar 1 Ar 2 R 4 3,4-di-Cl—C 6 H 3 2,5-di-F—C 6 H 3 H 4-Cl—C 6 H 4 2-F—C 6 H 4 H 4-Cl—C 6 H 4 2,5-di-F—C 6 H 3 CO 2 Me 4-Cl—C 6 H 4 2,5-di-F—C 6 H 3 OCOMe 4-Cl—C 6 H 4 2,5-di-F—C 6 H 3 1,2,3-triazol-1-yl 4-Br—C 6 H 4 2,5-di-F—C 6 H 3 H 4-F—C 6 H 4 2,5-di-F—C 6 H 3 H 4-Cl—C 6 H 4 2-Br-5-F—C 6 H 3 H 4-
  • Z represents halogen, CN, NO 2 , N 3 , CF 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , OCOR 2a , COR 2a , CON(R 2a ) 2 , OCON(R 2a ) 2 , CONR 2a (OR 2a ), CON(R 2a )N(R 2a ) 2 , CONHC( ⁇ NOH)R 2a , heterocyclyl, phenyl or heteroaryl, said heterocyclyl, phenyl or heteroaryl bearing 0-3 substituents selected from halogen, CN, NO 2 , CF 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , COR 2a , CON(R 2a ) 2 and C 1-4 alkyl;
  • R 1b represents H, C 1-4 alkyl or OH
  • R 1c represents H or C 1-4 alkyl
  • Ar 1 , Ar 2 and R 2a have the same meanings as before;
  • Z preferably represents optionally substituted phenyl or heteroaryl.
  • Ar 1 is typically selected from phenyl groups substituted in the 4-position with halogen, methyl or trifluoromethyl and phenyl groups substituted in the 3- and 4-positions by halogen; and Ar 2 is typically selected from phenyl groups substituted in the 2- and 5-positions by halogen.
  • Ar 1 is 4-chlorophenyl or 4-trifluoromethylphenyl and Ar 2 is 2,5-difluorophenyl.
  • R 1b typically represents H, methyl or OH, preferably H.
  • R 1c typically represents H or methyl, preferably H.
  • Z is typically selected from CN, N 3 , OR 2a , N(R 2a ) 2 , CO 2 R 2a , COR 2a , CON(R 2a ) 2 , OCON(R 2a ) 2 , CONR 2a (OR 2a ), CON(R 2a )N(R 2a ) 2 , and optionally substituted phenyl or heteroaryl.
  • R 2a aptly represents H, Ar (especially heteroaryl such as pyridyl), alkyl (such as methyl, ethyl, propyl or butyl), or substituted alkyl (especially CH 2 Ar such as benzyl or pyridylmethyl).
  • Ar especially heteroaryl such as pyridyl
  • alkyl such as methyl, ethyl, propyl or butyl
  • substituted alkyl especially CH 2 Ar such as benzyl or pyridylmethyl
  • N-heterocyclyl groups aptly complete an N-heterocyclyl group which is optionally substituted as described above.
  • Preferred substituents include ⁇ O and methyl.
  • Specific examples of N-heterocyclyl groups represented by Z include morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 5,5-dimethyl-2,2-dioxo-oxazolidin-3-yl, 2,5-dioxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-pyridin-1-yl, and 2-oxo-pyrrolidin-1-yl.
  • R 2a aptly represents H or alkyl (such as methyl, ethyl, propyl or butyl).
  • R 2a aptly represents Ar, especially heteroaryl, and in particular 5-membered heteroaryl such as 1,2,4-triazol-3-yl.
  • R 2a groups independently represent H or optionally substituted alkyl, cycloalkyl, cycloalkylalkyl or alkenyl, or together complete an N-heterocyclyl group.
  • one R 2a represents H and the other represents alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or 1-ethylpropyl), alkenyl (such as allyl), cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl), cycloalkylalkyl (such as cyclopropylmethyl) or substituted alkyl (such as alkyl substituted with Ar, especially 2-pyridylethyl, 3-(imidazol-1-yl)propyl or 2-phenylethyl; or alkyl substituted with CF 3 , CO 2 R 2b , or CON(R 2b ) 2 , especially 2,2,2-trifluoromethyl, methoxycarbonylmethyl or carbamoylmethyl).
  • alkyl such as methyl, ethyl, n-
  • the two R 2a groups complete an N-heterocyclyl group, such as morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, 4-methylpiperazine, 4-phenylpiperazine, piperidine, 4-hydroxypiperidine or piperidine which is substituted in the 3- or 4-position with CO 2 R 2b and/or C 1-4 alkyl, especially 3- or 4-carboxypiperidine, 3- or 4-ethoxycarbonylpiperidine, 3-carboxy-3-methylpiperidine and 3-ethoxycarbonyl-3-methylpiperidine.
  • N-heterocyclyl group such as morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, 4-methylpiperazine, 4-phenylpiperazine, piperidine, 4-hydroxypiperidine or piperidine which is substituted in the 3- or 4-position with CO 2 R 2b and/or C 1-4 alkyl, especially 3- or 4-carboxypiperidine, 3-
  • each R 2a aptly represents H or alkyl, such as methyl.
  • each R 2a aptly represents H or alkyl. Specific examples include CONHNH 2 and CONHNH t Bu.
  • R 2a aptly represents alkyl such as methyl or ethyl.
  • Heteroaryl groups represented by Z are very aptly 5-membered, such as tetrazole, triazole, thiazole, thiadiazole, oxadiazole, pyrazole and imidazole, which are typically unsubstituted or substituted with methyl or hydroxy groups.
  • the keto-tautomers of hydroxy-substituted heteroaryl groups are to be considered interchangeable with the enol forms.
  • Specific examples include 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-2-yl, 1,2,3,4-tetrazol-5-yl, 3-hydroxy-1,2,4-triazol-5-yl, 1,2,4-triazol-3-yl, 5-methyl-1,2,4-triazol-3-yl, 2,5-dimethyl-1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, imidazol-2-yl, imidazol-1-yl, 4-methylthiazol-2-yl, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, and 1,2,3-triazol-2-yl.
  • a second subclass of the compounds of the invention comprises the compounds of formula III:
  • v is 1 and w is 0, 1 or 2, or v is 2 and w is 0 or 1;
  • X represents C(R 1 ) 2 , CHCO 2 R 1 , O, NOR 1 , CHCON(R 1 ) 2 , NNHCOR 2 , or the atoms necessary to complete a spiro-linked 5- or 6-membered carbocyclic or heterocyclic ring;
  • R 5 represents H, CO 2 R 1 or CON(R 1 ) 2 ;
  • R 1 , R 2 , Ar 1 and Ar 2 have the same meanings as before.
  • v is 1 and w is 0 or 1. Most preferably, v and w are both 1.
  • Examples of compounds within this subclass include those wherein Ar 1 represents 4-chlorophenyl, Ar 2 represents 2,5-difluorophenyl, v and w are both 1 and X, R 1 and R 5 are as indicated in the following table: ⁇ X R 1 R 5 ⁇ 0 H H ⁇ 0 CH 2 Ph CO 2 Me ⁇ 0 H CONH 2 ⁇ 0 H CO 2 Me ⁇ 0 Me CO 2 Me ⁇ 0 allyl CO 2 Me ⁇ N—OH H H ⁇ N—OMe H H ⁇ N—OCH 2 Ph H H ⁇ N—OCH 2 CH ⁇ CH 2 H H ⁇ N—O t Bu H H H H H H H H H H H H H H H H H H H H H H H H H H H H ⁇ N—NH—COMe H H ⁇ CHCH 2 CH 2 CO 2 Et H H ⁇ N—O—CH 2 CO 2 H H H H H H H H H H H H ⁇ N—NH—COMe H H ⁇ CHCH 2 CH 2 CO 2 Et H H
  • a third subclass of the compounds of the invention is defined by formula IV and the pharmaceutically acceptable salts thereof:
  • W represents —NR 6 —(CH 2 ) t —, —O—CHR 7 —, or —CF 2 CH 2 —;
  • R 6 represents R 1 , COR 2 or CO 2 R 2 ;
  • R 7 represents H or OR 1 ;
  • t is 0 or 1
  • Ar 1 , Ar 2 , R 1 and R 2 have the same meanings as before.
  • Examples of groups represented by R 6 include H, optionally substituted C 1-6 alkyl (such as methyl, ethyl, benzyl and CH 2 CO 2 Me), C 2-6 alkenyl (such as allyl), t-butoxycarbonyl, and acyl (such as COCH 2 CH 2 CO 2 Me).
  • a fourth subclass of the compounds of the invention is defined by formula V and the pharmaceutically acceptable salts thereof:
  • R 1 aptly represents H, C 1-6 alkyl such as methyl, ethyl or propyl, any of which is optionally substituted with OR 2a , CO 2 R 2a or CON(R 2a ) 2 , where R 2a has the same meaning as before, or C 2-6 alkenyl such as allyl.
  • the compounds of formula I have an activity as modulators of the processing of APP by ⁇ secretase.
  • compositions comprising one or more compounds of formula I or the pharmaceutically acceptable salts thereof 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.
  • a pharmaceutical carrier e.g.
  • 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.
  • 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.
  • 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 and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the present invention also provides a compound of formula I 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 formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease.
  • 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, poly(vinylpyrrolidone) or gelatin.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and especially about 0.01 to 10 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.
  • the compounds of formula I may be synthesised by a variety of routes starting from the benzyl sulphones:
  • the sulphones (1) are prepared by oxidation of thioethers Ar 2 —CH 2 —SAr 1 (2), which in turn are formed by reaction of thiols Ar 1 SH (3) with benzyl derivatives Ar 2 CH 2 -L (4), where L is a leaving group such as chloride or bromide and Ar 1 and Ar 2 have the same meanings as before.
  • v, w, L, Ar 1 and Ar 2 have the same meanings as before.
  • the alkylations take place at ambient temperature in an aprotic solvent such as DMF or THF in the presence of strong base such as sodium hydride or potassium t-butoxide.
  • Suitable catalysts for the cyclisation of (6) to (7) include bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride, the reaction taking place at room temperature in an inert solvent such as dichloromethane.
  • R 2 , Ar 1 and Ar 2 have the same meanings as before.
  • the products are believed to exist predominantly as the enols (9).
  • the reaction may be carried out at ambient temperature in an inert solvent such as THF in the presence of strong base such as potassium t-butoxide.
  • A, Ar 1 and Ar 2 have the same meanings as before.
  • the styrenes (27) are available by reaction of the triflates (28) with Ar 2 —B(OH) 2 in the presence of a Pd(0) catalyst, and the triflates may be formed by treatment of the ketones (29) with N-phenyl triflamide and strong base such as lithium di-isopropylamide at low temperatures under anhydrous conditions:
  • Tf represents trifluoromethanesulphonyl
  • A Ar 1 and Ar 2 have the same meanings as before.
  • the compounds of formulae (9) or (10) may be reacted with R 2 -L in the presence of base to provide a mixture of O-alkyl and C-alkyl derivatives (14) and (15):
  • esters (9), (10), (14) and (15) may be hydrolysed to the corresponding carboxylic acids, which may be coupled with amines to provide the corresponding amides, or with alcohols to provide alternative esters. Alternatively, the esters (9), (10), (14) and (15) themselves may be reacted with amines or alcohols to provide amides or alternative esters.
  • cycloalkenes (7) may be reduced to the corresponding cycloalkanes (17):
  • v, w, Ar 1 and Ar 2 have the same meanings as before.
  • the reaction is typically carried out by hydrogenation over Pd/C. at 45 psi. in a solvent such as ethyl acetate.
  • the cycloalkenes (7) may be treated sequentially with borane in THF and alkaline hydrogen peroxide to provide the alkanols (18):
  • v, w, Ar 1 and Ar 2 have the same meanings as before.
  • the alkanols may be reacted with methanesulphonyl chloride to provide the corresponding mesylates, which may be subjected to nucleophilic displacement by a variety of nucleophiles such as halide, cyanide and azide (e.g. at 90° C. in DMF solution). Azides formed in this way may be reduced to the primary amines (19):
  • v, w, Ar 1 and Ar 2 have the same meanings as before.
  • the reduction may be effected by treatment with triphenylphosphine in refluxing aqueous THF.
  • alkanols (18) may also be oxidised to ketones (20):
  • v, w, Ar 1 and Ar 2 have the same meanings as before.
  • ketones (20) react with R 1 —ONH 2 to form oximes and alkoximes (21):
  • R 1 , v, w, Ar 1 and Ar 2 have the same meanings as before.
  • the reaction may be carried out in a mixture of pyridine and ethanol at 80° C.
  • ketones (20) may alternatively be converted to the amines (22) by reaction with (R 1 ) 2 NH and sodium triacetoxyborohydride:
  • R 1 , v, w, Ar 1 and Ar 2 have the same meanings as before.
  • the reaction takes place at ambient temperature in dichloromethane, and is particularly suitable for the synthesis of secondary and tertiary amines wherein at least one of the R 1 groups is other than H.
  • ketones (20) may converted to the difluorides (23) by reaction with (diethylamino)sulphur trifluoride:
  • v, w, Ar 1 and Ar 2 have the same meanings as before.
  • the reaction may be carried out in dichloromethane at ambient temperature.
  • ketones (20) may alternatively be condensed with ylides such as Ph 3 P ⁇ CH(R 1 ) 2 and Ph 3 P ⁇ CHCO 2 R 2 to form alkylidene derivatives (24) and (25):
  • v, w, R 1 , R 2 , Ar 1 and Ar 2 have the same meanings as before.
  • the ylides are formed by treatment of the corresponding phosphonium bromides with butyllithium in an aprotic solvent at low temperature, and are reacted in situ with the ketones (20).
  • the primary amines (19) may be alkylated and/or acylated in accordance with standard techniques. In particular, they may be coupled with acids R 2 CO 2 H to form the amides (26) using any of the well known processes for amide bond formation:
  • R 2 , v, w, Ar 1 and Ar 2 have the same meanings as before.
  • Suitable processes include conversion of the carboxylic acid to the acid chloride prior to reaction with amine (19), and the use of coupling agents such as dimethylaminopyridine, hydroxybenzotriazole, dicyclohexylcarbodiimide, carbonyldiimidazole and the like.
  • Compounds of formula IIA in which m is 0 and Z is CO 2 R 2a , CON(R 2a ) 2 , CONR 2a (OR 2a ), CON(R 2a )N(R 2a ) 2 or CONHC( ⁇ NOH)R 2a may be prepared by coupling of a carboxylic acid (30) with (respectively) R 2a OH, HN(R 2a ) 2 , HNR 2a (OR 2a ), HN(R 2a a)N(R 2a ) 2 or H 2 NC( ⁇ NOH)R 2a ,
  • Ar 1 , Ar 2 , R 1c and R 2a have the same meanings as before.
  • Any of the standard coupling techniques may be used, including the use of coupling agents such as dimethylaminopyridine, hydroxybenzotriazole, dicyclohexylcarbodiimide, carbonyldiimidazole and the like.
  • the acid is converted to the corresponding acid chloride (e.g. by treatment with oxalyl chloride in DMF solution) and reacted directly with the desired nucleophile.
  • the acid is converted to an active ester derivative such as the pentafluorophenol ester (e.g. by coupling with the phenol in the presence of dicyclohexyl carbodiimide), and this intermediate is reacted with the desired nucleophile.
  • the acids (30) are available by hydrolysis of the esters (31), typically under alkaline conditions such as treatment with LiOH in ethanol solution:
  • R 1 is typically methyl or ethyl.
  • the reduction may be carried out using sodium borohydride and nickel(II) chloride in ethanol, while the optional alkylation may be effected by treating the ester (31, R 1c ⁇ H)) with strong base (e.g. sodium bis(trimethylsilyl)amide) in an aprotic solvent at low temperature, followed by treatment with (C 1-4 alkyl)-L and warming to room temperature.
  • strong base e.g. sodium bis(trimethylsilyl)amide
  • Compounds of formula IIA in which m is 0 and Z is COR 2c may be prepared by treatment of the corresponding compounds in which Z is CONR 2c (OR 2c ) with R 2c —Li, where R 2c represents R 2a which is other than H.
  • the reaction is typically carried out in an aprotic solvent at low temperature, and is particularly useful when R 2c in COR 2c represents aryl or heteroaryl.
  • subsequent reduction of the carbonyl group e.g. using sodium borohydride
  • L 1 represents a sulphonate leaving group (such as mesylate, tosylate or triflate) and Ar 1 , Ar 2 and R 2a have the same meanings as before.
  • the displacement reaction may be carried out in DMF at elevated temperature, e.g. about 80° C.
  • the nucleophile is R 2a OH, HN(R 2a ) 2 or heteroaryl comprising NH in the ring, it is advantageous to generate the corresponding anion by treatment with sodium hydride prior to reaction with (32).
  • the sulphonates (32) are prepared by reaction of the alcohols (33) with the appropriate sulphonyl chloride (e.g. under anhydrous conditions at low temperature in the presence of a tertiary amine).
  • the alcohols (33) are available from the hydroboration of alkylidenes (24) in which one of the R 1 groups is H and the other is H or C 1-4 alkyl.
  • the process typically involves reaction with borane in THF at room temperature, followed by treatment with alkaline hydrogen peroxide and separation of the desired cis isomer by chromatography.
  • the hydrolysis is typically carried out under acid conditions (e.g. in a mixture of acetic acid and conc. HCl at 110° C.) and the reduction is conveniently carried out by sequential treatment with isobutyl chloroformate and borohydride in THF.
  • Compounds of formula IIA in which m is 0 and Z represents aryl or heteroaryl bonded through C may be prepared by reaction of a sulphonyl derivative (32) with the appropriate aryllithium or heteroaryllithium.
  • Z represents a functional group such as CN, CO 2 H, CONH 2 , CONHNH 2 or CONHC( ⁇ NOH)R 2a
  • Examples of such conversions include:
  • Compounds of formula V may be obtained by treatment of the sulphones (1) with an alkyllithium (e.g. BuLi) and epichlorohydrin, and optional alkylation of the resulting cyclobutanol with R 1 -L, where R 1 and L have the same meanings as before.
  • the reaction of (1) with epichlorohydrin is typically carried out at low temperature in THF, and the optional alkylation is typically effected by treatment of the cyclobutanol with sodium hydride in DMF and reaction of the resulting alkoxide with R 1 -L.
  • Certain compounds according to the invention may exist as optical isomers due to the presence of one or more chiral centres or because of the overall asymmetry of the molecule. Such compounds may be prepared in racemic form, or individual enantiomers may be prepared ither by enantiospecific synthesis or by resolution.
  • the novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative 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-1-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • a typical assay which can be used to determine the level of activity of compounds of the present invention is as follows:
  • Mouse neuroblastoma neuro 2a cells expressing human app695 are cultured at 50-70% confluency in the presence of sterile 10 mM sodium butyrate.
  • redox dye reduction To determine if compounds are cytotoxic, cell viability following compound administration is assessed by the use of redox dye reduction.
  • a typical example is a combination of redox dye MTS (Promega) and the electron coupling reagent PES. This mixture is made up according to the manufacturer's instructions and left at room temperature.
  • the Examples of the present invention all had an ED 50 of less than 10 ⁇ M, preferably less than 1 ⁇ M and most preferably less than 100 nM in at least one of the above assays.
  • reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (3 ⁇ 50 ml), and the combined organics washed with brine (sat., 100 ml), dried (Mg SO 4 ) and evaporated to dryness, giving an orange oil (506 mg).
  • This material was chromatographed on silica, eluting with 0-5% ethyl acetate in hexanes to give product 199 mg.
  • reaction mixture was extracted with ethyl acetate (2 ⁇ 25 ml) and the combined organics were washed with brine (sat., 30 ml), dried (MgSO 4 ) and evaporated in vacuo to give 116 mg crude product. This was chromatographed on silica, eluting with 30% ethyl acetate in hexanes to give product. 78 mg.
  • n-Butyllithium (1.6M solution in hexanes, 15.6 mL) was added slowly to a stirred, cooled (0° C.) suspension of methyl triphenylphosphonium bromide (9.26 g, 26.0 mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at room temperature for 3 h. The mixture was cooled to 0° C. and ketone from Ex. 2 (4 g, 10.4 mmol) in tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 1 h. then under reflux for 3 h. The mixture was cooled, poured into water and extracted with ethyl acetate.
  • Methanesulfonyl chloride (77 ⁇ L, 0.998 mm 1) was added to a solution of the cis and trans alcohol mixture from Example 44 (200 mg, 0.499 mmol) and triethylamine (208 ⁇ L, 1.50 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with aqueous citric acid (10%), aqueous sodium hydroxide (1M), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure.
  • Morpholine (91 ⁇ L, 1.04 mmol) was added to a solution of the cis-mesylate from Example 45 (50 mg, 0.104 mmol) in acetonitrile (2 mL) and the mixture was stirred at 80° C. for 3 days. The mixture was cooled and the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with aqueous sodium hydroxide (1M), dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane:EtOAc (1:1), to give the product as a white foam (30 mg, 61%).
  • Ethyl (diethoxyphosphinyl)acetate (5.16 mL, 26 mmol) was added dropwise to a slurry of sodium hydride (60% dispersion in mineral oil, 988 mg, 24.7 mmol) in tetrahydrofuran (60 mL) and the mixture was stirred at room temperature for 1 h.
  • the ketone from Example 2 (5 g, 13 mmol) in tetrahydrofuran (50 mL) was added dropwise over 20 min. and the mixture was stirred at room temperature for 18 h. Water was added and the mixture was extracted with ethyl acetate.
  • Lithium hydroxide (132 mg, 5.5 mmol) was added to a solution of the unsaturated ester from Example 47 (500 mg, 1.1 mmol) in ethanol (40 mL). The mixture was degassed and stirred at room temperature under nitrogen gas for 24 h. The mixture was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The organic extract was dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give the product as a white solid (430 mg, 92%).
  • Lithium hydroxide (350 mg, 14.57 mmol) was added to a solution of the cis-ester from Example 48, (1.33 g, 2.91 mmol) in ethanol (40 mL). The mixture was degassed and stirred at room temperature under nitrogen gas for 5 h. The mixture was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The organic extract was dried (MgSO 4 ) and the solvent was evaporated under reduced pressure to give a white solid which was then crystallized from IPA to give the product as a white solid (950 mg, 76%).
  • Lithium hydroxide (20 mg, 0.833 mmol) was added to a solution of Example 57 (95 mg, 0.167 mmol) in ethanol (12 ml) and water (4 ml). The mixture was degassed and stirred at room temperature under nitrogen gas for 18 h. The mixture was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The organic extract was dried MgSO 4 ) and the solvent was evaporated under reduced pressure to give the product as a white solid (75 mg, 83%).
  • reaction mixture was extracted with ethyl acetate (2 ⁇ 100 ml), and the combined organics washed with brine (sat., 100 ml), dried (MgSO 4 ) and evaporated in vacuo to giv 415 mg mixture of 4 isomers.
  • the isomers were separated by chromatography on silica, eluting with 30-50% ethyl acetate in hexanes. Fractions rich in 3-hydroxy isomers (198 mg) were purified by preparative t.l.c, eluting with 30% ethyl acetate in hexanes followed by two crystallisations from diethyl ether in hexanes to give the cis-3-alcohol product.
  • Cis-3-mesylate (52 mg) was purified by preparative t.l.c., eluting with 100% dichloromethane to give product. 48 mg.
  • Cis-3-mesylate from Example 94 (66 mg, 0.142 mmol) in N,N-dimethylformamide (2 ml) was treated with sodium azide (14 mg, 0.213 mmol) and the mixture heated to 95° C. for 16 hours. A further portion of sodium azide (9 mg, 0.142 mmol) was added and stirring at 95° C. continued for a further 24 hours. The reaction was diluted with water (40 ml), extracted with 20% ethyl acetate in diethyl ether (3 ⁇ 60 ml) and the combined organics washed with brine (sat., 100 ml), dried (MgSO 4 ) and evaporated in vacuo to give 46 mg crude product.
  • trans-acetate fraction from Example 97 (220 mg) was purified by chromatography on silica, eluting with 100% dichloromethane, then 20% ethyl acetate in hexanes to give 90 mg material which was further purified by preparative t.l.c., eluting with 5% ethyl acetate in dichloromethane to give product. 49 mg.
  • Cis-3-alcohol (Example 93) (49 mg, 0.128 mmol) in tetrahydrofuran (2 ml) was dripped into a stirring suspension of sodium hydride (5.6 mg, 60% w/w in mineral oil, 0.140 mmol) in tetrahydrofuran (1 ml) and the mixture heated to reflux for 2 hours. After cooling to 0° C., bromoethane (38 ⁇ l, 0.512 mmol) was added, the mixture stirred at room temperature for 16 hours, then further portions of sodium hydride (11 mg, 60% w/w in mineral oil, 0.256 mmol) and bromoethane (29 ⁇ l, 0.384 mmol) were added.
  • Example R MS (MH+) 104 Dimethylaminomethyl 470 (472) 105 2-(piperidin-1-yL)ethyl 525 (527) 106 3-(dimethylamino)propyl 499 (501) 107 (1H-imidazol-5-yl)methyl 493 (495)
  • reaction mixture was extracted with ethyl acetate (3 ⁇ 100 ml), and the combined organics were washed with brine (sat., 200 ml), dried (MgSO 4 ) and evaporated in vacuo to give 1.31 g mixture of isomeric cycloheptanols.
  • reaction was then cooled, further portions of sodium hydride (27.1 mg, 60% w/w in mineral oil, 0.678 mmol) and ethyl bromoacetate (75.2 ⁇ l, 0.678 mmol) added, and heated again to 90° C. After 4 hours at this temperature, reaction was cooled, diluted with water (150 ml) and extracted with ethyl acetate (3 ⁇ 100 ml). Combined organics were washed with brine (sat., 250 ml), dried (MgSO 4 ) and evaporated in vacuo to give crude (263 mg).
  • reaction mixture was diluted with sodium hydrogen sulfite (sat., aq., 16 ml) then extracted with ethyl acetate (3 ⁇ 15 ml). Combined organics were washed with brine (sat., 50 ml), dried (MgSO 4 ) and evaporated in vacuo to give product (88:12 cis:trans) (509 mg, 94%).
  • Example No. NR 2 m/z 198 294 [M—ArSO 2 —]+ 199 292 [M—ArSO 2 —]+ 200 275 [M—ArSO 2 —]+451 [MH]+ 201 302 [M—ArSO 2 —]+478 [MH]+ 202 321 [M—ArSO 2 —]+497 [MH]+ 203 307 [M—ArSO 2 —]+483 [MH]+ 204 *** 205* 452 [MH]+ 206* 452 [MH]+ 207 451 [MH]+ 208** 453 [MH]+ 209** 453 [MH]+ 210 482 [MH]+

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US20040122050A1 (en) * 2002-10-04 2004-06-24 Ian Churcher Cyclohexyl sulphone derivatives as gamma-secretase inhibitors
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US20070225520A1 (en) * 2004-02-20 2007-09-27 Brands Karel M J Stereoselective Synthesis of a 4,4-Disubstituted Cyclohexanepropanoic Acid
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WO2002081435A1 (en) 2002-10-17
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ATE498608T1 (de) 2011-03-15
US20070213329A1 (en) 2007-09-13
CA2442882A1 (en) 2002-10-17
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