Substituted sapogenins and their use

A method according to claim 9, wherein in the general formula (III):

• R1═R2═R4═R5═R6═R7═R8═R10═R11═R9═R12═R13═R15═R16═R17═R18═R21═R22═R23═R24═R25═R26═R27═R28═R29═R30═R31═R32═R33═R34═R35═H,
• R14=methyl group in either the R or S configuration,
• R20═—OH or —OR where R=alkyl, acyl or carbohydrate and
• R19═H or is absent
• R37═H, —OH or ═O
• R36═H or —OH
• represents a single bond, and
• wherein in addition to the above
• at least one of R3 and R23 is a X radical, the possible remaining substituent being H, OH, ═O, and OR where R=alkyl or acyl group or absent,
• and X is chosen from the group consisting of:
• θ halo atom, particularly F, Cl or Br,
• θ (Me—S—), (Me—SO—), (Me—SO2—), and
• θ N3—, NH2—, MeSO2NH—,
• alkyl.

A method of treating or preventing cognitive dysfunction in a human or non-human animal suffering therefrom or susceptible thereto, which comprises administering to the said human or non-human animal an effective amount of a compound chosen from:

• substituted forms of sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin, anzurogenin-D, in which one or more carbon atom carries a substituent X chosen from the group consisting of
• θ halo atom, particularly F, Cl or Br,
• θ (Me—S—), (Me—SO—), (Me—SO2—), and
• θ N3—, NH2—, MeSO2NH—,
• alkyl;
• and their pharmaceutically acceptable pro-drugs and salts.

A method of treating or preventing a condition characterized by a deficiency in receptor number or function in a human or non-human animal suffering therefrom or susceptible thereto, or for the regulation of cellular activity in a human or non-human animal, which comprises administering to the said human or non-human animal an effective amount of a compound of general formula (I) or (II) or (III):

• 8
• including all stereoisomers and racemic mixtures thereof with the exception of stereoisomers at carbon atoms specifically identified by bonds illustrated to be out of the plane of the paper, or a pharmaceutically acceptable pro-drug or salt thereof,
• wherein in the general formula (I):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent, represents an optional double bond, and
• wherein in addition to the above
• at least one ofthe R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• wherein in the general formula (II):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R19, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of the R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• and wherein in the general formula (III):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R19, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R37 are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R14, R15, R16, R17, R25, R33 can be either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 R36, R37is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl.

A method of treating or preventing a condition characterized by a deficiency in receptor number or function in a human or non-human animal suffering therefrom or susceptible thereto, or for the regulation of cellular activity in a human or non-human animal, which comprises administering to the said human or non-human animal an effective amount of a compound chosen from:

• substituted forms of sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin, anzurogenin-D, in which one or more carbon atom carries a substituent X chosen from the group consisting of
• θ halo atom, particularly F, Cl or Br,
• θ (Me—S—), (Me—SO—), (Me—SO2—), and
• θ N3—, NH2—, MeSO2NH—,
• alkyl;
• and their pharmaceutically acceptable pro-drugs and salts.

A method of increasing the muscarinic, nicotinic or dopamine receptor number or enhancing the function of muscarinic, nicotinic or dopamine receptors in a human or non-human animal in need thereof, which comprises administering to the said human or non-human animal an effective amount of a compound of general formula (I) or (II) or (III):

• 9
• including all stereoi somers and racemic mixtures thereof with the exception of stereoi somers at carbon atoms specifically identified by bonds illustrated to be out of the plane of the paper, or a pharmnaceutically acceptable pro-drug or salt thereof,
• wherein in the general forrnula (I):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of the R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• wherein in the general formula (II):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35 are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R19, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one ofthe R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• and wherein in the general formula (III):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R19, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R37 are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R14, R15, R16, R17, R25, R33 can be either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 R36, R37 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl.

A method of increasing the muscarinic, nicotinic or dopamine receptor number or enhancing the function of muscarinic, nicotinic or dopamine receptors in a human or non-human animal in need thereof, which comprises administering to the said human or non-human animal an effective amount of a compound chosen from:

• substituted forms of sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin, anzurogenin-D, in which one or more carbon atom carries a substituent X chosen from the group consisting of
• θ halo atom, particularly F, Cl or Br,
• θ (Me—S—), (Me—SO—), (Me—SO2—), and
• θ N3—, NH2—, MeSO2NH—,
• alkyl;
• and their pharmaceutically acceptable pro-drugs and salts.

A method of treating or preventing a condition characterized by the presence of neurofibrillary tangles and/or β-amyloid plaques in a human or non-human animal suffering therefrom or susceptible thereto, which comprises administering to the said human or non-human animal an effective amount of a compound of general formula (I) or (II) or (III):

• 10
• including all stereoi somers and racemic mixtures thereof with the exception of stereoisomers at carbon atoms specifically identified by bonds illustrated to be out of the plane of the paper, or a pharmaceutically acceptable pro-drug or salt thereof,
• wherein in the general formula (I):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R25 are either a H. OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of the R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• wherein in the general formula (II):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R19, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one ofthe R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• and wherein in the general formula (III):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R19, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R37 are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R14, R15, R16, R17, R25, R33 can be either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 R36, R37 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl.

A method of treating or preventing a condition characterized by the presence of neurofibrillary tangles and/or β-amyloid plaques in a human or non-human animal suffering therefrom or susceptible thereto, which comprises administering to the said human or non-human animal an effective amount of a compound chosen from:

• substituted forms of sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin, anzurogenin-D, in which one or more carbon atom carries a substituent X chosen from the group consisting of
• θ halo atom, particularly F, Cl or Br,
• θ (Me—S—), (Me—SO—), (Me—SO2—), and
• θ N3—, NH2—, MeSO2NH—,
• alkyl;
• and their pharmaceutically acceptable pro-drugs and salts.

Compounds of general formula (I) or (II) or (III):

• 11
• including all stereoisomers and racemic mixtures thereof with the exception of stereoisomers at carbon atoms specifically identified by bonds illustrated to be out of the plane of the paper, or a pharmaceutically acceptable pro-drug or salt thereof,
• wherein in the general formula (I):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one ofthe R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• wherein in the general formula (II):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R15, R16, R17, R19, R25 are either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, ═O or OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one ofthe R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• and wherein in the general formula (III):
• R1, R2, R3, R4, R5, R6, R7, R8, R10, R13, R18, R19, R20, R21, R22, R23, R24, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R37 are, independently of each other, either H, OH, ═O, and OR where R=alkyl or acyl group or absent;
• R9, R11, R12, R14, R15, R16, R17, R25, R33 can be either a H, OH, OR where R=alkyl or acyl group or absent;
• R33, R14═H, alkyl group, OH, OR where R=alkyl or acyl group or absent,
• represents an optional double bond, and
• wherein in addition to the above
• at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35 R36, R37 is a X radical,
• wherein X is chosen from the group consisting of:
• halo atom, particularly F, Cl or Br,
• (Me—S—), (Me—SO—), (Me—SO2—),
• N3—, NH2—, MeSO2NH—, and
• alkyl;
• excluding compounds of general formula (I) and (II) in which
• one or both of R13 and R31 is chosen from Br and Cl;
• and excluding compounds of general formula (I) in which
• R1═R2═R4═R5═R6═R7═R8═R9═R10═R11═R12═R13═R15═R16═R17═R18═R21═R22═R23═R24═R25═R26═R27═R28═R29═R30═R31═R32═R33═R34═R35═H,
• R14=methyl in the S configuration,
• R23═OH,
• represents a single bond, and
• R3 is a methyl group in either the α or β orientation;
• and further excluding compounds of general formula (I) in which
• R1═R2═R4═R5═R6═R7═R8═R9═R10═R11═R12═R13═R15═R16═R17═R18═R21═R22═R23═R24═R25═R26═R27═R28═R29═R30═R31═R32═R33═R34═R35═H,
• R14=methyl in the R configuration,
• represents a single bond, and
• R3 is an amino group in the β orientation;
• and further excluding compounds of general formula (III) in which
• one or both of R13 and R31 is chosen from Br and Cl
• and further excluding compounds of general formula (III) in which
• one of R18 or R32 is alkyl.

A compound chosen from:

• substituted forms of sarsasapogenin, episarsasapogenin, smilagenin, epismilagenin, anzurogenin D, in which one or more carbon atom carries a substituent X chosen from the group consisting of:
• θ halo atom, particularly F, Cl or Br,
• θ (Me—S—), (Me—SO—), (Me—SO2—), and
• θ N3—, NH2—, MeSO2NH—,
• alkyl;
• and their pharmaceutically acceptable pro-drugs and salts;
• excluding 3β-amino-smilagenin.