WO2005085189A2 - Composes - Google Patents

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WO2005085189A2
WO2005085189A2 PCT/GB2005/000808 GB2005000808W WO2005085189A2 WO 2005085189 A2 WO2005085189 A2 WO 2005085189A2 GB 2005000808 W GB2005000808 W GB 2005000808W WO 2005085189 A2 WO2005085189 A2 WO 2005085189A2
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conh
compound according
cor
alkyl
compound
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PCT/GB2005/000808
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WO2005085189A3 (fr
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Ian Gilbert
Shane Sellarajah
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Medical Research Council
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C07C39/215—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring containing, e.g. diethylstilbestrol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring

Definitions

  • the present invention relates to chemical analogues of the diazo compound known as Congo Red. More specifically, the invention relates to compounds that are useful in the treatment or prevention of transmissible spongiform encephalopathies.
  • TSE Transmissible spongiform encephalopathies
  • GSS Gerstmann- Staussler-Scheinker Syndrome
  • FFI Familial Fatal Insomnia
  • BSE Bovine Spongiform Encephalopathy
  • PrP-res misfolded prion protein form
  • PrP-res normal cellular prion protein form
  • Compounds shown to have anti-prion activity include sulphated polysaccharides such as pentosan polysulfate, Congo Red and other azo dyes, amphotericin B and analogues, anthracyclines, phthalocyanines and porphyrins, inorganic ions, branched polyamines, and antagonists of the N-methyl-D-aspartate (NMD A) receptor such as memantine. 6 Recently there has been interest in quinacrine and other acridine derivatives.
  • the azo-dye Congo Red has been shown to have in vivo anti-prion activity against various models of TSEs, including a cell free polymerisation assay, 11 cellular assays 12 ' 13 and in vivo activity against golden Syrian hamsters. 14
  • the molecule itself has a number of shortfalls. 15 Firstly, it has a lack of specificity. In addition it does not have significant permeability through the blood brain barrier 16 ' 17 presumably due to its charged nature, primarily caused by the presence of two sulfonate groups. Toxicity is also a problem as the diazo bonds in Congo Red can be cleaved by enzymes present in the mammalian gut and intestines. ' The most common side product of this cleavage is benzidine, a highly carcinogenic compound strongly associated with urinary bladder cancer. 20 However, unlike many of the other compounds reported to have activity in various models of TSEs, Congo Red is a small molecule, which is amenable to chemical synthesis and structure activity relationship studies, with the aim of producing a low molecular weight therapeutic agent.
  • the present invention seeks to provide small molecule analogues of Congo Red, paricularly those which may have therapeutic applications in the treatment of TSEs. Ideally, the invention seeks to provide low molecular weight compounds which are specific in the interaction with PrP Sc , have good cellular uptake, good penetration of the blood brain barrier, and which exhibit low toxicity.
  • a first aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof,
  • R 1"5 are each independently selected from H, OH, OR 6 , CO 2 H, CO 2 R 7 , NO 2 , CN CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 , CONHCHR 17 COR 18 ;
  • the replacement of the diazo group of Congo Red with sulphonamide, amide, imine, aminomethylene and alkene bonds prevents the molecule being broken down to benzidine.
  • a second aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as defined above admixed with a pharmaceutically acceptable diluent, excipient or carrier.
  • a third aspect of the invention relates to use of a compound of formula II, or a pharmaceutically acceptable salt thereof,
  • X is selected from
  • R 1"5 are each independently selected from H, OH, OR 6 , CO 2 H, CO 2 R 7 , NO 2 , CN CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) ⁇ CO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 , CONHCHR 17 COR 18 ; ⁇ R 6"18 are each independently hydrocarbyl; n, m, p and q are each independently 1, 2, 3 or 4. in the preparation of a medicament for treating transmissible spongiform encephalopathy (TSE).
  • TSE transmissible spongiform encephalopathy
  • a fourth aspect of the invention relates to a method of treating, or preventing the onset of, transmissible spongiform encephalopathy (TSE) in a subject, said method comprising administering to a the subject a compound of formula II as defined above.
  • TSE transmissible spongiform encephalopathy
  • a fifth aspect of the invention relates to the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, in an assay for identifying further candidate compounds capable of inhibiting the polymerisation of PrP by PrP-res.
  • a sixth aspect of the invention relates to the use of a compound of formula LT, or a pharmaceutically acceptable salt thereof, in an assay for identifying further candidate compounds capable of inl ibiting the infectivity of the abnormal form of prion protein (PrP Sc ).
  • hydrocarbyl refers to a group comprising at least C and H that may Optionally comprise one or more other suitable substituents.
  • substituents may include OH, COOH, halo-, alkoxy-, nitro-, an alkyl group, or a cyclic group.
  • a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain heteroatoms.
  • heteroatoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen, oxygen, phosphorus and silicon.
  • the hydrocarbyl group is an aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or alkenyl group, more preferably, an aryl or alkyl group, more preferably still, an alkyl group.
  • alkyl includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted.
  • the alkyl group is a C ⁇ - 2 o alkyl group, more preferably a C MS , more preferably still a C ⁇ - ⁇ 2 alkyl group, more preferably still, a C ⁇ _ 6 alkyl group, more preferably a C ⁇ - 3 alkyl group.
  • Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
  • Suitable substituents include, for example, one or more halo-, OH, alkoxy-, nitro-, COOH, CF 3 , or alkyl groups.
  • cycloalkyl refers to a cyclic alkyl group which may be substituted (mono- or poly-) or unsubstituted.
  • the cycloalkyl group is a C 3 _ ⁇ 2 cycloalkyl group.
  • Suitable substituents include those listed above for alkyl.
  • alkenyl refers to a group containing one or more carbon-carbon double bonds, which may be branched or unbranched, substituted (mono- or poly-) or unsubstituted.
  • the alkenyl group is a C - 20 alkenyl group, more preferably a C 2 . ⁇ 5 alkenyl group, more preferably still a C 2 . ⁇ 2 alkenyl group, or preferably a C 2 . 6 alkenyl group, more preferably a C 2 . 3 alkenyl group.
  • Suitable substituents include those listed for alkyl above.
  • aryl refers to a C 6 _ ⁇ 2 aromatic group which may be substituted (mono- or poly-) or unsubstituted. Typical examples include phenyl and naphthyl etc. Suitable substituents include those listed for alkyl above.
  • heteroaryl refers to a C . ⁇ 2 aromatic, substituted (mono- or poly- ) or unsubstituted group, which comprises one or more heteroatoms.
  • Preferred heteroaryl groups include pyrrole, pyrazole, pyrimidine, pyrazine, pyridine, quinoline, thiophene and furan. Again, suitable substituents include those listed for alkyl above.
  • aralkyl includes, but is not limited to, a group having both aryl and alkyl functionalities.
  • the term includes groups in which one of the hydrogen atoms of the alkyl group is replaced by an aryl group, e.g. a phenyl group optionally having one or more substituents such as halo, alkyl, alkoxy, hydroxy, and the like.
  • Typical aralkyl groups include benzyl, phenethyl and the like.
  • R " are each independently alkyl or aryl, more preferably alkyl.
  • one of R 1"5 is selected from H, OH and OR 6 ; one of R 1"5 is selected from OH, CO 2 H, CN, CO 2 -alkyl and CONH-alkyl; and the remainder of R 1"5 are H.
  • R 3 is CN, OH or CO 2 H, and R 1 , R 2 , R 4 and R 5 are all H;
  • R 1 is OH, R 3 is CO 2 H, CO 2 R 7 or H, and R 2 , R 4 and R 5 are all H;
  • R 1 is OR 6 , R 4 is CO 2 R 7 or CO 2 H, and R 2 , R 3 and R 5 are all H;
  • R 2 and R 4 are CO 2 R 7 , and R 1 , R 3 and R 5 are all H;
  • R 3 is CO 2 R 7 , R 4 is OH or OR 6 , and R 1 , R 2 and R 5 are all H; or
  • R 3 is OH
  • R 4 is CO 2 R 7 or CO 2 H
  • R 1 , and R 2 and R 5 are all H.
  • R 3 is CN, OH or CO 2 H, and R 1 , R 2 , R 4 and R 5 are all H;
  • R 1 is OH, R 3 is CO 2 H, CO 2 Me or H, and R 2 , R 4 and R 5 are all H;
  • R 1 is OMe, R 4 is CO 2 Me or CO 2 H, and R 2 , R 3 and R 5 are all H; (iv) R 2 and R 4 are CO 2 Me, and R 1 , R 3 and R 5 are all H;
  • R 3 is CO 2 Me or CO 2 Et, R 4 is OH or OMe, and R 1 , R 2 and R 5 are all H; or
  • R 3 is OH
  • R 4 is CO 2 Me, CO 2 Et or CO 2 H
  • R 1 , and R 2 and R 5 are all H.
  • said compound is of formula la, or a pharmaceutically acceptable salt thereof
  • R 1 is OH
  • R 3 is CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) classroomCO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 2 , R 4 and R 5 are all H; or (ii) R 1 is OR 6 , R 5 is CO 2 H, CO 2 R 7 CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R n , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 2"4 are all H.
  • R 1 is OH
  • R 3 is CO 2 R 7
  • R 2 , R 4 and R 5 are all H
  • R 1 is OR 6
  • R 5 is CO 2 H or CO 2 R 7
  • R 2"4 are all H.
  • R 1 is OH, R 3 is CO 2 alkyl, and R 2 , R 4 and R 5 are all H; or (ii) R 1 is O-alkyl, R 5 is CO 2 H or CO 2 -alkyl, and R 2"4 are all H.
  • R 1 is OH, R 3 is CO 2 Me, and R 2 , R 4 and R 5 are all H; or (ii) R 1 is OMe, R 5 is CO 2 H or CO 2 Me, and R 2"4 are all H.
  • the compound is of formula lb, or a pharmaceutically acceptable salt thereof
  • R 1 is OH
  • R 3 is CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 2 , R 4 and R 5 are H;
  • R 2 is OR 6
  • R 3 is CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R 11 , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 1 , R 4 and R 5 are H;
  • R 1 is OH, R 3 is CO 2 R 7 , and R 2 , R 4 and R 5 are H;
  • R 2 is OR 6 , R 3 is CO 2 R 7 , and R 1 , R 4 and R 5 are H;
  • R 2 is CO 2 R 7 , R 3 is OH, and R 1 , R 4 and R 5 are H.
  • R 1 is OH, R 3 is CO 2 -alkyl, and R 2 , R 4 and R 5 are H;
  • R 2 is O-alkyl, R 3 is CO 2 -alkyl, and R 1 , R 4 and R 5 are H;
  • R 2 is CO 2 -alkyl, R 3 is OH, and R 1 , R 4 and R 5 are H.
  • R 1 is OH, R 3 is CO 2 Me, and R 2 , R 4 and R 5 are H;
  • R 2 is OMe, R 3 is CO 2 Me, and R 1 , R 4 and R 5 are H;
  • R 2 is CO 2 Me, R 3 is OH, and R 1 , R 4 and R 5 are H.
  • the compound according to claim 1 is of formula Ic, or a pharmaceutically acceptable salt thereof
  • R 1"5 are as defined above.
  • R 3 is CN, and R 1 , R 2 , R 4 and R 5 are H;
  • R 2 and R 4 are CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 1 , R 3 and R 5 are H; or (iv) R 1 is OH, R 3 is COR 7 and R 2 , R 4 and R 5 are all H.
  • R and R are CO 2 R , and R , R and R are H.
  • R 2 and R 4 are CO 2 -alkyl, and R 1 , R 3 and R 5 are H, or R 1 is OH, R 3 is CO 2 -alkyl and R 2 , R 4 and R 5 are all H.
  • R 2 and R 4 are CO Me, and R 1 , R 3 and R 5 are H, or R 1 is OH, R 3 is CO 2 Me and R 2 , R 4 and R 5 are all H.
  • the compound is of formula Id, or a pharmaceutically acceptable salt thereof Id
  • R 1"5 are as defined above.
  • R 3 is CO 2 H, CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R n , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , R 1 is OH, and R 2 , R 4 and R 5 are H; or
  • R 3 is OH, and R 1 , R 2 , R 4 and R 5 are H;
  • R 3 is CO 2 H, or CO 2 R 7 , R 1 is OH, and R 2 , R 4 and R 5 are H.
  • R 3 is CO 2 H, or CO 2 -alkyl, R 1 is OH, and R 2 , R 4 and R 5 are H.
  • R 3 is CO 2 H, or CO 2 Me, R 1 is OH, and R 2 , R 4 and R 5 are H.
  • the compound is of formula le, or a pharmaceutically acceptable salt thereof
  • R 1 is OR 6 , R 5 is CO 2 H, CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R 11 , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 2 , R 3 and R 4 are H; (ii) R 1 is OH, R 3 is CO 2 H or H, and R 2 , R 4 and R 5 are H; (iii) R 3 is CN or CO 2 H, and R 1 , R 2 , R 4 and R 5 are H;
  • R 2 is CO 2 H, CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R 11 , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , R 3 is OH, R 1 , R 4 and R 5 are H; or (v) R 2 is OH, R 3 is CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R ⁇ , CO 2 (CH 2 ) ra O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 1 , R 4 and R 5 are
  • R 1 is OR 6 , R 5 is CO 2 H or CO 2 R 7 , and R 2 , R 3 and R 4 are H; (ii) R 2 is CO 2 H or CO 2 R 7 , R 3 is OH, R 1 , R 4 and R 5 are H; or (iii) R 2 is OH, R 3 is CO 2 R 7 , and R 1 , R 4 and R 5 are H.
  • R 1 is O-alkyl
  • R 5 is CO 2 H or CO 2 -alkyl
  • R 2 , R 3 and R 4 are H
  • R 2 is CO 2 H or CO 2 alkyl
  • R 3 is OH
  • R 1 , R 4 and R 5 are H
  • R 2 is OH
  • R 3 is CO 2 -alkyl
  • R 1 , R 4 and R 5 are H.
  • R 1 is OMe, R 5 is CO 2 H or CO 2 Me, and R 2 , R 3 and R 4 are H;
  • R 2 is CO 2 H or CO 2 Et, R 3 is OH, R 1 , R 4 and R 5 are H; or
  • R 2 is OH, R 3 is CO 2 Et, and R 1 , R 4 and R 5 are H.
  • the compound is of formula If, or a pharmaceutically acceptable salt thereof
  • R 1 is OH
  • R 3 is H, CO 2 H, CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) n CO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18 , and R 2 , R 4 and R 5 are H; or
  • R 1 is OR 6
  • R 4 is CO 2 R 7 , CONR 8 R 9 , CONHR 10 , CO 2 (CH2) n CO 2 R 11 , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 , CONH(CH 2 ) p CO 2 R 15 , CONH(CH 2 ) q O(CO)R 16 or CONHCHR 17 COR 18
  • R 2 , R 3 and R 5 are H.
  • R 1 is OH, R 3 is H, CO 2 H or CO 2 -alkyl, and R 2 , R 4 and R 5 are H; or (ii) R 1 is O-alkyl, R 4 is CO 2 -alkyl, and R 2 , R 3 and R 5 are H.
  • R 1 is OH, R 3 is H, CO 2 H or CO 2 Me, and R 2 , R 4 and R 5 are H; or (iii) R 1 is OMe, R 4 is CO 2 Me, and R 2 , R 3 and R 5 are H.
  • the compound is of formula Ig, or a pharmaceutically acceptable salt thereof
  • R is OH, and R 1 , ⁇ R»2 , ⁇ R>4 and R are H.
  • the compound is selected from those set forth in Tables 1-8.
  • sulphonamide analogues of the invention can be synthesised from the readily available 4-4'-biphenyldisulfonyl chloride 8 and the appropriate amine utilising DMAP as a catalyst 15. and anhydrous pyridine as the solvent.
  • biphenyl amide analogues of the invention can be synthesised either by the reaction of the corresponding acid chloride with the appropriate aniline derivative in the presence of triethylamine or using TBTU, a uronium based peptide coupling reagent (Scheme 3).
  • Scheme 3 a uronium based peptide coupling reagent
  • the amount of triethylamine used in the coupling reaction is varied, specifically if the hydrochloride salt of the amine is to be used for coupling, a further equivalent of base (triethylamine) isbe needed to optimise the reaction.
  • the imine analogues of the invention can be made by condensation of the corresponding aldehyde with the appropriate amine.
  • the products (imines) are generally insoluble in ethanol and precipitate from solution: filtration and washing generally provides the compounds in good yield.
  • the biphenyl analogues prove less soluble but also the reaction time is longer in these cases.
  • the mono-phenyl imines (series 5) can be synthesised from the commerically available terephthalaldehyde, whereas the biphenyl analogues (series 4) require 4-4 '-biphenyl dialdehyde to be made first.
  • the amines of the invention can be synthesised by reduction of the imines with sodium borohydride.
  • the only limiting factor is the initial solubility of the imines, many of which prove insoluble in any solvent once formed.
  • the reduction is favourable in a methanol / dichloromethane mixture.
  • Transition metal chemistry plays a part in the synthesis of the alkenes of the invention (Scheme 7); the Heck reaction is preferred, so as to achieve only one of the stereoisomers, the tr ⁇ r ⁇ -stereoisomer.
  • the reaction is sensitive to the choice of solvent.
  • a 17:3 DMF:water mixture is optimal, the water being a crucial element.
  • 1,4-divinylbenzene can be purchased commercially but only as a mixture with 1,2-divinylbenzene, therefore it is preferable to synthesise this compound from terephthaldehyde using a Wittig reaction.
  • X is selected from
  • R 1"5 are each independently selected from H, OH, OR 6 , CO 2 H, CO 2 R 7 , NO 2 , CN CONR 8 R 9 , CONHR 10 , CO 2 (CH 2 ) conflictCO 2 R ⁇ , CO 2 (CH 2 ) m O(CO)R 12 , CO 2 CHR 13 COR 14 ,
  • R 6"18 are each independently hydrocarbyl; n, m, p and q are each independently 1, 2, 3 or 4. in the preparation of a medicament for treating transmissible spongiform encephalopathy (TSE).
  • TSE transmissible spongiform encephalopathy
  • said compound of formula II is as defined above for compounds of formula I.
  • said compound is as defined above for compounds of formula Ig and wherein:
  • R 3 is OH, and R 1 , R 2 , R 4 and R 5 are H; or
  • R J is OH, R >2 4 i ⁇ s CO 2 H, and R 1 1 , r R>4 4 and R D are H
  • preparation of a medicament includes the use of compounds of formula II directly as the medicament in addition to their use in a screening programme for identifying further therapeutic agents or in any stage of the manufacture of such a medicament.
  • Another aspect of the invention relates to a method of treating, or preventing the onset of, transmissible spongiform encephalopathy (TSE) in a subject, said method comprising administering to the subject a compound of formula II as defined above.
  • TSE transmissible spongiform encephalopathy
  • the TSE is selected from Creutzfeldt Jakob Disease (CJD), Gerstmann- Staussler-Scheinker Syndrome (GSS), Familial Fatal Insomnia (FFI), Kuru, variant CJD, Bovine Spongiform Encephalopathy (BSE) and scrapie.
  • CJD Creutzfeldt Jakob Disease
  • GSS Gerstmann- Staussler-Scheinker Syndrome
  • FCI Familial Fatal Insomnia
  • Kuru variant CJD
  • Bovine Spongiform Encephalopathy BSE
  • the compound of formula II is administered in an amount sufficient to inhibit the infectivity of the abnormal form of prion protein (PrP Sc ).
  • the compound of formula II is administered in an amount sufficient to inhibit the polymerisation of PrP by PrP-res.
  • the compounds of the invention are active in both the cellular and polymerisation assay described in the accompanying Examples section. Without wishing to be bound by theory, it is believed that these compounds probably prevent PrP-res formation in cells by preventing polymerisation of PrP c .
  • Preferred compounds falling into this category include, for example, WSP677, 905, 1008, 795, 1011 718 and 798.
  • the compounds of the invention are active in the polymerisation assay, but not in the cellular assay. Without wishing to be bound by theory, it is possible that these compounds are too weak at inhibition of polymerisation to be active in cellular assays, or they are inactivated in a cellular system, or they are unable to access the molecular target.
  • Preferred compounds falling into this category include, for example, WSP675, 676, 678, 917, 1012, 794, 738, 741, 742, 760, 980 and 759.
  • the compounds of the invention are active in the cellular assay, but not the polymerisation assay. Without wishing to be bound by theory, it is possible that these compounds preventPrP-res formation in the SMB cells by a mode of action other than inhibition of polymerisation. Preferred compounds falling into this category include, for example, WSP 1009, 906, 915, 740 and 911.
  • Both the cellular and polymerisation assay provide useful information in the context of a drug discovery programme.
  • the polymerisation assay can identify most, but not all molecules which reduce PrP-res formation in cellular assays. Thus, on its own it is not a useful screen to select out compounds for cellular assays.
  • the cellular assay employed on its own also has limitations. The assay does not identify all compounds that prevent polymerisation. These compounds may be a useful source of information for future rounds of drug design.
  • the polymerisation assay also provides information on the possible modes of action of compounds.
  • the biphenyl amides showed the most promise; WSP677 is of particular interest.
  • WSP677 is of particular interest.
  • the biphenyl amides without wishing to be bound by theory, there seems to be some correlation between prevention of PrP-res formation in cell culture and prevention of polymerisation of PrP c . This suggests that the anti-TSE activity of at least some of the compounds may be related to their ability to prevent polymerisation.
  • the sulfonamides appeared less active than the biphenyl amides (Series 2).
  • the sulfonamide group is a bioisostere of the amide group.
  • the NH of the sulfonamides is ionisable and may well be ionised at physiological pH. Whilst ionisation may well increase the solubility of these compounds, interaction with the prion protein may be also be prevented, hi spite of this, some of the sulfonamides still showed weak activity in a cellular model and inhibition of polymerisation.
  • Imines are normally readily subject to hydrolysis.
  • the imines of the present invention are highly conjugated, which stablises them to hydrolysis.
  • any hydrolysis should not give rise to benzidene or its analogues.
  • the biphenyl imines (Series 4) showed higher activity than the monophenyl imines (Series 5) in the cellular assay, although several of the monophenyl imines showed potent inhibition of polymerisation.
  • these compounds tended to be those with carboxylates on the terminator, e.g. WSP738, WSP741, WSP742, WSP760.
  • the aminomethylene compounds (Series 6) show very promising activity, particularly in the cellular assay, but also in the polymerisation assay.
  • Structure activity relationships indicate that the most active compounds in cellular assays preferably have a methyl carboxylate attached to the terminator and either a hydroxy or methoxy group.
  • the terminator found in compound found in WSP677 is active in both the cellular and polymerisation assays. However other regio-isomers are also active (WSP905, 1009). Some compounds containing a carboxylic acid on the terminator are active in inhibition of polymerisation, but not in the cellular assay. Conversely, compounds which are active in the cellular assay and contain a methyl ester are not be active in the polymerisation assay (WSP1009, 906, 740).
  • Another aspect of the invention relates to the use of compounds of formula I, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating Alzheimer's disease.
  • a fourth aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as defined for said first aspect admixed with one or more pharmaceutically acceptable diluents, excipients or carriers.
  • the compounds of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and- polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the compounds of formula I or II can be present as salts or esters, in particular pharmaceutically acceptable salts or esters.
  • salts of the compounds of the invention include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • sulphuric acid, phosphoric acid or hydrohalic acids with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C ⁇ -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid.
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C ⁇ -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-tol
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • the invention includes, where appropriate all enantiomers and tautomers of compounds of formula I or II.
  • the man skilled in the art will recognise compounds that possess an optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art. STEREO AND GEOMETRIC ISOMERS
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of those inhibitor agents, and mixtures thereof.
  • the tenns used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).
  • the present invention also includes all suitable isotopic variations of the agents or pharmaceutically acceptable salts thereof.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. SOLVATES
  • the present invention also includes the use of solvate forms of the compounds of the present invention.
  • the terms used in the claims encompass these forms.
  • the invention furthermore relates to the compounds of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
  • the invention further includes the compounds of the present invention in prodrug form.
  • Such prodrugs are generally compounds of formula I or II wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject.
  • Such reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo.
  • compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • parenteral intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • intramuscular intraperitoneal
  • intraarterial intrathecal
  • intrabronchial subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • Injectable forms may contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose.
  • compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • one or more doses of 10 to 150 mg/day will be administered to the patient for the treatment of TSE.
  • the one or more compounds of the invention are administered in combination with one or more other agents, for example, existing drugs available on the market.
  • the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.
  • Drugs in general are often more effective when used in combination.
  • combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s).
  • the major advantages of combining drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance in cells which would have been otherwise responsive to initial therapy with a single agent.
  • Beneficial combinations may be suggested by studying the activity of the test compounds with agents known or suspected of being valuable in the treatment of a particular disorder.
  • This procedure can also be used to determine the order of administration of the agents, i.e. before, simultaneously, or after delivery. Such scheduling may be a feature of all the agents identified herein.
  • Another aspect of the invention relates to the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, as defined above, in an assay for identifying candidate compounds capable of inhibiting the polymerisation of PrP c by PrP-res.
  • Yet another aspect relates to the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, as defined above, in an assay for identifying candidate compounds capable of inhibiting the infectivity of the abnormal form of prion protein (PrP Sc ).
  • the assay is a competitive binding assay.
  • One aspect of the invention relates to a process comprising the steps of: (a) performing an assay method described hereinabove;
  • Another aspect of the invention provides a process comprising the steps of: (a) performing an assay method described hereinabove; (b) identifying one or more candidate compounds capable of inhibiting the polymerisation of PrP c by PrP-res or inhibiting the infectivity of the abnormal form of prion protein (PrP Sc ); and
  • Another aspect of the invention provides a process comprising the steps of:
  • the invention also relates to a candidate compound identified by the method described hereinabove.
  • Yet another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a candidate compound identified by the method described hereinabove.
  • Another aspect of the invention relates to the use of a candidate compound identified by the method described hereinabove in the preparation of a pharmaceutical composition for use in the treatment or prevention of a TSE.
  • said candidate compound is generated by conventional SAR modification of a compound of the invention.
  • conventional SAR modification refers to standard methods known in the art for varying a given compound by way of chemical derivatisation.
  • Figure 1 shows the cell viability of cerebellar neurones isolated from mice when incubated with WSP677 and WSP1012.
  • WSP676 (0.1 OOg, 0.156mmol) was placed in a 10ml round bottomed flask, NaOH
  • WSP675 (0.086g, 0.14mmol) was reacted with aqueous NaOH (0.023g, 0.56mmol) in water (4ml) and the product WSP679 was isolated as a light brown solid.
  • WSP906 (0.250g, 0.456mmo ⁇ ) was reacted with aqueous NaOH (0.291g, 0.729mmol) in water (4ml) and the product WSP907 was isolated as a light grey solid.
  • WSP908 was isolated as a white solid.
  • This compound was made via an identical preparation to the preparation of WSP677 (alternative procedure). 2-aminophenol (0.234g, 2.15mmol) and triethylamine (0.45ml, 3.21mmol) was reacted with 4-4'-biphenyldicarboxyl chloride (0.300g, 1.07mmol) in anhydrous THF (10ml). An identical work-up procedure was employed, the pure product WSP912 was isolated as an off-white solid.
  • WSP905 (0.1 OOg, 0.176mmol) was reacted with aqueous NaOH (0.070g, 1.76mmol) in water (1ml) and THF (5ml).
  • the product WSP971 was isolated as a brown solid.
  • This compound was made via an identical preparation to the preparation of WSP677 (alternative procedure), with the exception of adding DMAP as a catalyst (0.009g, 0.689mmol). 2-amino-5-nitrophenol (1.062g, 6.89mmol) and triethylamine (0.45ml, 3.21mmol) was reacted with terephthaloyl chloride (0.700g, 3.44mmol) in anhydrous THF (15ml). An identical work-up procedure was employed, the pure product WSP974 was isolated as an orange solid.
  • terephthalaldehyde (0.200g, 1.49mmol) and methyl-4-amino-3-hydroxy-benzoate (0.498g, 2.98mmol).
  • Ethanol (15ml) was added and the reaction mixture heated to 55°C for 5 hours under a nitrogen atmosphere.
  • the precipitate which forms was filtered tlirough a sinter funnel and washed with ethanol (40ml).
  • the precipitate, the product WSP714 was isolated as a yellow powder and dried under high vacuum. No further purification was necessary.
  • WSP714 (0.300g, 0.693mmol) was dissolved in dichloromethane (10ml) and reacted with sodium borohydride (0.158g, 4.16mmol) in methanol (5ml). In this case water (20ml) was added to precipitate the product, which was washed further with water (20ml) and dichloromethane (20ml).
  • the product WSP740 was isolated as a light brown solid.
  • WSP740 Into a 25ml round bottomed flask was placed WSP740 (0.075g, 0.171mmol). A solution of NaOH (0.070g, 1.71mmol) in water (6ml) was added dropwise and the reaction mixture was left stirring at room temperature for 45 minutes. 2N HCl (8ml) was added dropwise to the reaction mixture till a neutral pH was achieved. A solid precipitated which was filtered and washed with water (20ml). The product WSP798 was obtained as a white solid without further need for purification.
  • Drug treatment Drugs were resuspended in DMSO at a stock concentration of lOmM.
  • SMB cells were plated at 50% confluency per well in 6-well plates. Cells were left for 24h to allow for attachment. Media was then replaced with fresh media containing the appropriate dilution of the lOmM drug stock. 4 days after the addition of drug the media was removed and the protein extracted.
  • the MTT formazan product was released from cells by addition of dimethylsulphoxide (Sigma) and measured at 570 mn in a spectrophotometer (Bio50, Cary). Relative survival in comparison to control treated with the DMSO vehicle could then be determined.
  • SMB cells are persistently scrapie-infected mouse cells, cloned from a scrapie-infected mouse brain, but of non-neuronal origin. ' ' ' These cells are highly phagocytic and may mimic cells involved in the initial uptake and replication of the agent in peripheral infection. 12 In addition these cells show stable persistent scrapie-infection over many passages, suggesting that they are suitable for drug screening. 23 hideed, this cell line has been 10 1 ⁇ successfully used to screen many derivatives of Congo Red.
  • Tables 1-7 The results from these assays are shown in Tables 1-7, for the seven series of compounds: sulfonamides (Table 1); amides with a biphenyl linker (Table 2); amides with a phenyl linker (Table 3); imines with a biphenyl linker (Table 4); imines with a phenyl linker (Table 5); amines with a phenyl linker (Table 6); and alkenes with a phenyl linker (Table 7).
  • Compound WSP979 which is a regioisomer of WSP677 and WSP1009 was inactive. This suggests that the relative orientation of the ester and they hydroxyl group are important in the terminator.
  • Compound WSP971 which is the analogue of WSP905 with the free carboxylate did not show activity, indicating that the ester has a role, perhaps as a prodrug.
  • Other compounds with the methyl carboxylate removed or replaced (WSP912, 916, 971, 978, 1013) were inactive in the cell culture assay. This suggests that the ester may have a role in the activity of the molecule; by altering the structure of the ester it may be possible to modify the potency and physicochemical properties of the compounds.
  • the compounds of series 3 were the amides with a phenyl core (Table 3).
  • Compound 27 showed activity and following a fuller dose-response experiment, the ED 50 was found to be 250nM.
  • WSP759 is X- 34, a compound used by Klunk for diagnosis of Alzheimer's disease. 24 ' 25 This compound showed no activity at lO ⁇ M, but weak activity at 50 ⁇ M.
  • WSP762 showed activity at 2 ⁇ M, the mechanism of action is unknown, but may well differ from that of the other molecules described herein. It is possible that this molecule could be acting through an antioxidant mode of action.
  • WSP794 and WSP795 show some inhibition of polymerisation.
  • the two compounds which inhibit polymerisation are the two compounds which also have some effect in cell culture assays, indicating that the mode of action of these compounds, may include inhibition of polymerisation.
  • the terminator group on WSP794 is the same as that on WSP677 and that on WSP795 differs only in the carboxylate ester being replaced by a free carboxylate group.
  • the compounds of Series 5 are those with a phenyl linker and an imine bond (Table 5). A number of these show inliibition of PrP c polymerisation; WSP716, 738, 741, 742, 760, 980.
  • the terminator group found in WSP677 is not active in this series of compounds (compound WSP714).
  • the presence of a carboxylate group (either as the free acid or as an ester) seems to be important for activity.
  • Compounds not containing these functionalities are not active in this assay.
  • Compound WSP739 is a direct homologue of WSP738 (one of the most active compounds) except it has an extra methylene between the terminator and the imine. WSP739 is inactive, suggesting that conjugation with the terminator is an important feature.
  • WSP759 (Table 7) shows some inhibition of polymerisation.
  • the efficacy of the compounds of the invention against Alzheimer's disease was investigated by performing a beta-amyloid assay to measure amyloid aggregation in accordance with the methodology set forth in Fernanda G. De Felice et al, FASEB Journal, 2001, vol 15, 1297-1299.
  • the effect of the compounds on Alzheimer beta- amyloid peptide (Abeta) polymerization and the growth of amyloid fibrils was investigated using the methodology disclosed in Kuner et al, Journal of Biological Chemistry, 2000, vol 275, 1673-1687.
  • Prusiner S. B. Prions. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 13363-13383.
  • WSP number Entry R MW Yield Inhibition Polymerof PrP-res isation formation (% of control) in SMB cells at lO ⁇ M WSP905 2b Me0 2 C— ⁇ X ⁇ - 568.57 46 +ve 70 MeO WSP912 2c 424.45 14 -ve 430 OH precipitated WSP916 2d VJ 392.45 48 -ve 171 WSP971 2e 540.52 32 -ve 472
  • Phenyl Imines Synthetic Yield, Inhibition of PrP-res formation in SMB cells at lO ⁇ M and Inhibition of Polymerisation at lOO ⁇ M. J ⁇ ⁇ - N-R
  • Phenyl amines Synthetic Yield, Inhibition of PrP-res formation in SMB cells at lO ⁇ M and Inhibition of Polymerisation at lOO ⁇ M.
  • Phenyl alkenes Synthetic Yield, Inhibition of PrP-res formation in SMB cells at lO ⁇ M and inhibition of Polymerisation at lOO ⁇ M.
  • WSP Entry R MW Yield hihibition of PrP- Polymer- number res formation in isation SMB cells at (% of control) lO ⁇ M WSP762 7b HO 314.4 (+ve 2 ⁇ M)
  • Table 8 ED50 values of compounds in SMB cells showing activity ⁇ 10 ⁇ M. WSP number Entry Structure Polymerisation (% of control) nM

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Abstract

L'invention concerne des composés représentés par la formule (I) ou des sels pharmaceutiquement acceptables de ces composés. Dans la formule (I), X est choisi dans le groupe constitué de (II) et (III), Y est choisi dans le groupe constitué de (I) SO2NH, CONH, CH=N, CH2NH and CH=CH ; R1-5 sont chacun indépendamment choisis dans le groupe constitué de H, OH, OR6, CO2H, C02R7, NO2, CN CONR8R9, CONHR10, CO2(CH2)nCO2R11, CO2(CH2)mO(CO)R12, CO2CHR13COR14, CONH(CH2)pCO2R15, CONH(CH2)qO(CO)R16, CONHCHRI7COR18 ; R6-18 représentent chacun indépendamment hydrocarbyle ; n, m, p et q représentent chacun indépendamment 1, 2, 3 ou 4 ; à la condition que lorsque X représente phényle, Y représente CH=CH, R3 représente OH et R1, R4 et R5 représentent H, R2 est différent de COON. Dans d'autres aspects, l'invention concerne l'utilisation de ces composés dans la préparation d'un médicament destiné au traitement et à la prévention des encéphalopathies spongiformes transmissibles et les compositions pharmaceutiques comprenant les composés selon l'invention.
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EP2041067A2 (fr) * 2006-07-11 2009-04-01 Emory University Antagonistes de cxcr4 comprenant des structures de diazine et de triazine pour le traitement de troubles médicaux
EP2332528A1 (fr) * 2009-12-14 2011-06-15 Grünenthal GmbH Médicament contenant un amide d'acide de dicarbone aromatique substitué
US8008312B2 (en) 2005-01-07 2011-08-30 Emory University CXCR4 antagonists for the treatment of HIV infection
US8207167B2 (en) 2008-09-19 2012-06-26 Pimco 2664 Limited Aryl-phenyl-sulfonamide-phenylene compounds and their use
US8435968B2 (en) 2008-09-19 2013-05-07 Pimco 2664 Limited Aryl-phenyl-sulfonamido-cycloalkyl compounds and their use
WO2014055644A2 (fr) * 2012-10-02 2014-04-10 New York University Compositions pharmaceutique et traitement de maladies génétiques associées à une désintégration d'arn à médiation non-sens
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US9624167B2 (en) 2013-06-26 2017-04-18 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamides and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)benzenesulfonamides and their therapeutic use
US10005733B2 (en) 2014-12-17 2018-06-26 Pimco 2664 Limited N-(4-hydroxy-4-methyl-cyclohexyl)-4-phenyl-benzenesulfonamide and N-(4-hydroxy-4-methyl-cyclohexyl)-4-(2-pyridyl)-benzenesulfonamide compounds and their therapeutic use
WO2021007474A1 (fr) * 2019-07-11 2021-01-14 Cura Therapeutics, Llc Composés de phényle et compositions pharmaceutiques associées, et leurs applications thérapeutiques
US11701334B2 (en) 2018-01-10 2023-07-18 Cura Therapeutics, Llc Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications

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