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US 2011/0300074 A1Published application
3,6-disubstituted xanthylium salts
AssigneeWisTa Laboratories Ltd.
InventorsScott Clunas, John Mervyn David Storey, Janet Elizabeth Rickard, David Horsley, Charles Robert Harrington, Claude Michel Wischik
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Abstract
This invention pertains generally to processes, uses, methods and materials utilising particular xanthylium compounds, including compounds of formula (I) and (II), as further defined herein. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease.
Claims70
A method of treatment or prophylaxis of a tauopathy condition or a disease of tau protein aggregation in a patient in need thereof comprising administering to the patient a compound of formula (I), (II) or (III):
- wherein:
- X− is a counter ion;
- where Z is present:
- Y is O, and Z is N or C—R5;
- or
- Y is NH, and Z is N;
- or
- Y is S, and Z is C—R5;
- where Z is absent:
- Y is O or S;
- —R1, and —R2 are each independently saturated C1-6alkyl,
- or R1 and R2, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R3 and —R4 are each independently saturated C1-6alkyl,
- or R3 and R4, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R9, and —R10 are each independently saturated C1-6alkyl;
- or —R9 and —R10, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R11 and —R12 are each independently saturated C1-6alkyl,
- or —R11 and —R12, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R5 is independently —H, or saturated C1-6alkyl, which is unsubstituted or substituted with one or more substituents —R5A, or phenyl, which is unsubstituted or substituted with one or more substituents —R5A;
- each —R5A is independently selected from —F, —Cl, —Br, —I, —OH, —OR6, —SH, —SR6, —CN, —NO2, —NH2, —NHR6, —NR62, —NHC(═O)R6, —NR6C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NH2, —C(═O)NHR6, and —C(═O)NR62, —C(═O)R6, —C(═O)OH, —S(═O)R6, —S(═O)2R6, and —S(═O)2OH;
- each —R6 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;
- —R7 and —R8 are each independently selected from:
- —H, saturated C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl;
- and
- additionally, when Z is C—R5 and R5 is phenyl, —R7 and —R8 may each independently be a bridging group, W, which is bonded to said R5;
- W is O, NR17, S, or C(R17)2 wherein each R17 is independently selected from H, saturated aliphatic C1-4 alkyl, and R5A;
- —R13a, —R13b, —R14a, —R14b, —R15a, —R15b, —R16a, and —R16b are each independently selected from H and saturated aliphatic C1-4 alkyl;
- with the proviso that the compound is not 3,6-bis-dimethylamino xanthylium chloride (DMAXC).
25 more elements
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A compound of formula (I):
- wherein
- X− is a counter ion;
- —R5 is independently —H, or saturated C1-6alkyl, which is unsubstituted or substituted with one or more substituents —R5A, or phenyl, which is unsubstituted or substituted with one or more substituents —R5A;
- each —R5A is independently selected from —F, —Cl, —Br, —I, —OH, —OR6, —SH, —SR6—CN, —NO2—NH2, —NHR6, —NR62, —NHC(═O)R6, —NR6C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NH2, —C(═O)NHR6, and —C(═O)NR62, —C(═O)R6, —C(═O)OH, —S(═O)R6, —S(═O)2R6, and —S(═O)2OH;
- each —R6 is independently aliphatic C1-4alkyl, phenyl, or benzyl;
- and
- —R13a, —R13b, —R14a, —R14b, —R15a, —R15b, —R16a, and —R16b are each independently selected from H and saturated aliphatic C1-4 alkyl;
- with the proviso that the compound is not:
- 2,3,6,7,12,13,16,17-octahydro-1H,5H,11H,15H-diquinolizino[1,9-bc:1′,9′-hi]xanthylium chloride (“compound A”);
- 8-(trifluoromethyl)-2,3,5,6,11,12,14,15-octahydro-1H,4H,10H,13H-diquinolizino[9,9a,1-bc;9′,9a′1′-hi]xanthylium perchlorate (“compound C”);
- or
- 2,3,6,7,12,13,16,17-octahydro-1H,5H,11H,15H-diquinolizino[1,9-bc:1′,9′-hi]xanthylium perchlorate (“compound X”).
9 more elements
A compound of formula (Ic):
- wherein
- X− is a counter ion;
- —R5 is independently —H, or saturated C1-6alkyl, which is unsubstituted or substituted with one or more substituents —R5A, or phenyl, which is unsubstituted or substituted with one or more substituents —R5A;
- each —R5A is independently selected from —F, —Cl, —Br, —I, —OH, —OR6, —SH, —SR6—CN, NO2—NH2, —NHR6, —NR62, —NHC(═O)R6, —NR6C(═O)R6, —C(═O)OR6, —OC(═O)R6, —(═O)NH2, —C(═O)NHR6, and —C(═O)NR62, —C(═O)R6, —C(═O)OH, —S(═O)R6, —S(═O)2R6, and —S(═O)2OH;
- each —R6 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;
- with the proviso that the compound is not:
- 2,3,6,7,12,13,16,17-octahydro-1H,5H,11H,15H-diquinolizino[1,9-bc:1′,9′-hi]xanthylium chloride (“compound A”);
- 8-(trifluoromethyl)-2,3,5,6,11,12,14,15-octahydro-1H,4H,10H,13H-diquinolizino[9,9a,1-bc;9′,9a′1′-hi]xanthylium perchlorate (“compound C”);
- or
- 2,3,6,7,12,13,16,17-octahydro-1H,5H,11H,15H-diquinolizino[1,9-bc:1′,9′-hi]xanthylium perchlorate (“compound X”).
7 more elements
A compound of formula (II):
- wherein
- X− is a counter ion;
- Y is O, and Z is N or C—R5;
- or
- Y is NH, and Z is N;
- or
- Y is S, and Z is C—R5;
- —R1, and —R2 are each independently saturated C1-6alkyl,
- or R1 and R2, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R3 and —R4 are each independently saturated C1-6alkyl,
- or R3 and R4, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R5 is independently —H, or saturated C1-6alkyl, which is unsubstituted or substituted with one or more substituents —R5A, or phenyl, which is unsubstituted or substituted with one or more substituents —R5A;
- each —R5A is independently selected from —F, —Cl, —Br, —I, —OH, —OR6, —SH, —SR6, —CN, —NO2, —NH2, —NHR6, —NR62, —NHC(═O)R6, —NR6C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NH2, —C(═O)NHR6, and —C(═O)NR62, —C(═O)R6, —C(═O)OH, —S(═O)R6, —S(═O)2R6, and —S(═O)2OH;
- each —R6 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;
- —R7 and —R8 are each independently selected from:
- —H, saturated C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl;
- and
- additionally, when Z is C—R5 and R5 is phenyl, —R7 and —R8 may each independently be a bridging group, W, which is bonded to said R5;
- W is O, NR17S or C(R17)2 wherein each R17 is independently selected from H, saturated aliphatic C1-4 alkyl, and R5A;
- with the proviso that the compound is not:
- 3,6-bis(dimethylamino)thioxanthylium zinc trichloride (“compound LZ”);
- 3,6-bis(dimethylamino)thioxanthylium perchlorate (“compound LP”);
- 3,7-bis(dimethylamino)phenazinium chloride (“compound MC”);
- 3,7-Bis(dimethylamino)phenazinium perchlorate (“compound MP”);
- 3,7-bis(dimethylamino)oxazinium chloride (“compound O”);
- 3,6-bis-diethylamino xanthylium chloride (“compound E”);
- 3,6-bis-diethylamino xanthylium iron tetrachloride (“compound G”);
- 3,6-bis-diethylamino xanthylium zinc trichloride (“compound Y”);
- 9-(2-carboxyethyl)-3,6-Bis-dimethylamino xanthylium chloride (“compound AA”);
- 3,6-bis-dimethylamino xanthylium chloride (DMAXC);
- 2,6,10-tris-diethylamino-4,8,12-trioxatrianguleum hexafluorophosphate (“compound AL”).
28 more elements
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A compound of formula (III):
- wherein
- X− is a counter ion;
- Y is O or S
- —R5 is independently —H, or saturated C1-6alkyl, which is unsubstituted or substituted with one or more substituents —R5A, or phenyl, which is unsubstituted or substituted with one or more substituents —R5A;
- each —R5A is independently selected from —F, —Cl, —Br, —I, —OH, —OR6, —SH, —SR6, —CN, —NO2, —NH2, —NHR6, —NR62, —NHC(═O)R6, —NR6C(═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)NH2, —C(═O)NHR6, and —C(═O)NR62, —C(═O)R6, —C(═O)OH, —S(═O)R6, —S(═O)2R6, and —S(═O)2OH;
- each —R6 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;
- —R9 and —R10 are each independently saturated C1-6alkyl;
- or —R9 and —R10 together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- —R11 and —R12 are each independently saturated C1-6alkyl,
- or —R11 and —R12, together with the nitrogen atom to which they are bound, form a saturated C3-7 heterocycle;
- with the proviso that the compound is not 3,6-bis-diethylamino xanthene dihydrochloride (“compound H”).
8 more elements
Dependencies are inferred from the claim text.