[1,2,4]-dithiazoli(di)ne derivatives, inducers of gluthathione-S-transferase and NADPH quinone oxido-reductase, for prophylaxis and treatment of adverse conditions associated with cytotoxicity in general and apoptosis in particular

A pharmaceutical composition comprising, at least one pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, and a pharmacologically active amount of at least one compound of formula (I):

• or a tautomer, stereoisomer, or N-oxide thereof, or a pharmacologically acceptable salt of any of the foregoing,
• wherein the compound of formula (I) has anti-apoptotic activity, and
• wherein the dotted lines represent single or double bonds, and wherein the compound of formula (I) is chosen from the compounds listed below:
• R1
• R2
• R3
• R4
• CH3
• CH3
• 2-pyridyl
• —
• CH3
• CH3
• 3-pyridyl
• —
• CH3
• CH3
• 2-F-phenyl
• —
• CH3
• CH3
• 2-CH3-phenyl
• —
• CH3
• CH3
• 2-CF3-phenyl
• —
• CH3
• CH3
• 2-CH3CH2-phenyl
• —
• CH3
• CH3
• 2-(i-Pr)-phenyl
• —
• CH3
• CH3
• 2-CH3O-phenyl
• —
• CH3
• CH3
• 2-CH3S-phenyl
• —
• CH3
• CH3
• 2-benzyl-phenyl
• —
• CH3
• CH3
• 2,6-Cl2-phenyl
• —
• CH3
• CH3
• 2,6-(CH3)2-phenyl
• —
• CH3
• CH3
• 3-Cl-phenyl
• —
• CH3
• CH3
• 3-CH3-phenyl
• —
• CH3
• CH3
• 3-NO2-phenyl
• —
• CH3
• CH3
• 4-F-phenyl
• —
• CH3
• CH3
• 4-CH3O-phenyl
• —
• CH3
• CH3
• 4-(n-Bu)-phenyl
• —
• —(CH2)4—
• 2-CH3-phenyl
• —
• —(CH2)4—
• 2-CH3-phenyl
• —
• —(CH2)5—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• phenyl
• —
• —(CH2)2O(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CF3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3O-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3S-phenyl
• —
• —(CH2)2O(CH2)2—
• 3-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-F-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3O-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2N(CH3)(CH2)2—
• 2-CH3-phenyl
• —
• CH3
• —
• Cl
• CH3
• CH3
• —
• CH3
• CH3
• CH3
• —
• 2-(i-Pr)-phenyl
• CH3
• CH3
• —
• 2-CH3O-phenyl
• CH3
• CH3
• —
• 2,6-Cl2-phenyl
• CH3
• CH3
• —
• 3-F-phenyl
• CH3
• CH3
• —
• 4-F-phenyl
• CH3.

A medicament comprising a compound of formula (I)

• or a tautomer, stereoisomer, or N-oxide thereof, or a pharmacologically acceptable salt of any of the foregoing,
• wherein the compound of formula (I) has anti-apoptotic activity, and
• wherein the dotted lines represent single or double bonds, and wherein the compound of formula (I) is chosen from the compounds listed below:
• R1
• R2
• R3
• R4
• CH3
• CH3
• 2-pyridyl
• —
• CH3
• CH3
• 3-pyridyl
• —
• CH3
• CH3
• 2-F-phenyl
• —
• CH3
• CH3
• 2-CH3-phenyl
• —
• CH3
• CH3
• 2-CF3-phenyl
• —
• CH3
• CH3
• 2-CH3CH2-phenyl
• —
• CH3
• CH3
• 2-(i-Pr)-phenyl
• —
• CH3
• CH3
• 2-CH3O-phenyl
• —
• CH3
• CH3
• 2-CH3S-phenyl
• —
• CH3
• CH3
• 2-benzyl-phenyl
• —
• CH3
• CH3
• 2,6-Cl2-phenyl
• —
• CH3
• CH3
• 2,6-(CH3)2-phenyl
• —
• CH3
• CH3
• 3-Cl-phenyl
• —
• CH3
• CH3
• 3-CH3-phenyl
• —
• CH3
• CH3
• 3-NO2-phenyl
• —
• CH3
• CH3
• 4-F-phenyl
• —
• CH3
• CH3
• 4-CH3O-phenyl
• —
• CH3
• CH3
• 4-(n-Bu)-phenyl
• —
• —(CH2)4—
• phenyl
• —
• —(CH2)4—
• 2-CH3-phenyl
• —
• —(CH2)5—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• phenyl
• —
• —(CH2)2O(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CF3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3O-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3S-phenyl
• —
• —(CH2)2O(CH2)2—
• 3-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-F-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3O-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2N(CH3)(CH2)2—
• 2-CH3-phenyl
• —
• CH3
• —
• Cl
• CH3
• CH3
• —
• CH3
• CH3
• CH3
• —
• 2-(i-Pr)-phenyl
• CH3
• CH3
• —
• 2-CH3O-phenyl
• CH3
• CH3
• —
• 2,6-C12-phenyl
• CH3
• CH3
• —
• 3-F-phenyl
• CH3
• CH3
• —
• 4-F-phenyl
• CH3.

A method for preparing a pharmaceutical composition comprising

• (i) combining a pharmacologically active amount of a compound of formula (I):
• or a tautomer, stereoisomer, or N-oxide thereof, or a pharmacologically acceptable salt of any of the foregoing,
• wherein the compound of formula (I) has anti-apoptotic activity, and
• wherein the dotted lines represent single or double bonds, and wherein the compound of formula (I) is chosen from the compounds listed below:
• R1
• R2
• R3
• R4
• CH3
• CH3
• 2-pyridyl
• —
• CH3
• CH3
• 3-pyridyl
• —
• CH3
• CH3
• 2-F-phenyl
• —
• CH3
• CH3
• 2-CH3-phenyl
• —
• CH3
• CH3
• 2-CF3-phenyl
• —
• CH3
• CH3
• 2-CH3CH2-phenyl —
• CH3
• CH3
• 2-(i-Pr)-phenyl
• —
• CH3
• CH3
• 2-CH3O-phenyl
• —
• CH3
• CH3
• 2-CH3S-phenyl
• —
• CH3
• CH3
• 2-benzyl-phenyl
• —
• CH3
• CH3
• 2,6-Cl2-phenyl
• —
• CH3
• CH3
• 2,6-(CH3)2-phenyl
• —
• CH3
• CH3
• 3-Cl-phenyl
• —
• CH3
• CH3
• 3-CH3-phenyl
• —
• CH3
• CH3
• 3-NO2-phenyl
• —
• CH3
• CH3
• 4-F-phenyl
• —
• CH3
• CH3
• 4-CH3O-phenyl
• —
• CH3
• CH3
• 4-(n-Bu)-phenyl
• —
• —(CH2)4—
• 2-CH3-phenyl
• —
• —(CH2)4—
• 2-C H3-phenyl
• —
• —(CH2)5—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• phenyl
• —
• —(CH2)2O(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CF3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3O-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3S-phenyl
• —
• —(CH2)2O(CH2)2—
• 3-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-F-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3O-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2N(CH3)(CH2)2—
• 2-CH3-phenyl
• —
• CH3
• —
• Cl
• CH3
• CH3
• —
• CH3
• CH3
• CH3
• —
• 2-(i-Pr)-phenyl
• CH3
• CH3
• —
• 2-CH3O-phenyl
• CH3
• CH3
• —
• 2,6-Cl2-phenyl
• CH3
• CH3
• —
• 3-F-phenyl
• CH3
• CH3
• —
• 4-F-phenyl
• CH3
• with at least one pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance;
• and
• (ii) formulating the combination formed in (i) into a suitable form for administration.

A method of treating neurodegenerative diseases and other diseases characterized by free radical mediated cell degeneration and/or cell death (apoptosis) chosen from ischemic stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, senile dementia, spinal cord injury, restless legs syndrome, Huntington's disease, Parkinson's disease, irritable bowel disease and inflammatory bowel diseases, Crohn's disease, ulcerative colitis, alcoholic hepatitis, liver cirrhosis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, acute and chronic rejection of heart-, lung-, kidney-, skin-, corneal-, bone marrow- or liver-transplants and tissue rejection, the method comprising administering a pharmaceutical composition comprising a pharmacologically active amount of a compound of formula (I)

• or a tautomer, stereoisomer, or N-oxide thereof, or a pharmacologically acceptable salt of any of the foregoing,
• wherein the compound of formula (I) has anti-apoptotic activity, and
• wherein the dotted lines represent single or double bonds, and wherein the compound of formula (I) is chosen from the compounds listed below:
• R1
• R2
• R3
• R4
• CH3
• CH3
• 2-pyridyl
• —
• CH3
• CH3
• 3-pyridyl
• —
• CH3
• CH3
• 2-F-phenyl
• —
• CH3
• CH3
• 2-CH3-phenyl
• —
• CH3
• CH3
• 2-CF3-phenyl
• —
• CH3
• CH3
• 2-CH3CH2-phenyl —
• CH3
• CH3
• 2-(i-Pr)-phenyl
• —
• CH3
• CH3
• 2-CH3O-phenyl
• —
• CH3
• CH3
• 2-CH3S-phenyl
• —
• CH3
• CH3
• 2-benzyl-phenyl
• —
• CH3
• CH3
• 2,6-Cl2-phenyl
• —
• CH3
• CH3
• 2,6-(CH3)2-phenyl
• —
• CH3
• CH3
• 3-Cl-phenyl
• —
• CH3
• CH3
• 3-CH3-phenyl
• —
• CH3
• CH3
• 3-NO2-phenyl
• —
• CH3
• CH3
• 4-F-phenyl
• —
• CH3
• CH3
• 4-CH3O-phenyl
• —
• CH3
• CH3
• 4-(n-Bu)-phenyl
• —
• —(CH2)4—
• 2-CH3-phenyl
• —
• —(CH2)4—
• 2-CH3-phenyl
• —
• —(CH2)5—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• phenyl
• —
• —(CH2)2O(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CF3-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3O-phenyl
• —
• —(CH2)2O(CH2)2—
• 2-CH3S-phenyl
• —
• —(CH2)2O(CH2)2—
• 3-CH3-phenyl
• —
• —(CH2)2O(CH2)2—
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-F-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3O-phenyl
• —
• —CH2—CH(CH3)OCH(CH3)—CH2—
• 2-CH3CH2-phenyl —
• —(CH2)2S(CH2)2—
• 2-F-phenyl
• —
• —(CH2)2S(CH2)2—
• 2-CH3CH2-phenyl
• —
• —(CH2)2N(CH3)(CH2)2—
• 2-CH3-phenyl
• —
• CH3
• —
• Cl
• CH3
• CH3
• —
• CH3
• CH3
• CH3
• —
• 2-(i-Pr)-phenyl
• CH3
• CH3
• —
• 2-CH3O-phenyl
• CH3
• CH3
• —
• 2,6-Cl2-phenyl
• CH3
• CH3
• —
• 3-F-phenyl
• CH3
• CH3
• —
• 4-F-phenyl
• CH3
• to a patient in need of such treatment.

A method of treating neurodegenerative diseases and other diseases characterized by free radical mediated cell degeneration and/or cell death (apoptosis) chosen from ischemic stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, senile dementia, spinal cord injury, restless legs syndrome, Huntington's disease, Parkinson's disease, irritable bowel disease and inflammatory bowel diseases, Crohn's disease, ulcerative colitis, alcoholic hepatitis, liver cirrhosis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, acute and chronic rejection of heart-, lung-, kidney-, skin-, corneal-, bone marrow- or liver-transplants and tissue rejection, the method comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmacologically active amount of a compound of formula (I):

• or a tautomer, stereoisomer, or N-oxide thereof, or a pharmacologically acceptable salt of any of the foregoing,
• wherein the compound of formula (I) has anti-apoptotic activity, and
• wherein the dotted lines between carbon atom number 5 and its neighboring nitrogen atoms represent single or double bonds, with the proviso that one of the two bonds is a single bond and one is a double bond, and with the proviso that when the double bond is between carbon atom number 5 and nitrogen atom number 4, R4 does not exist and when the double bond is between carbon atom number 5 and the exo-nitrogen atom, R2 does not exist,
• R1, R2, R3 and R4 independently are chosen from a branched or unbranched alkyl(C1-4 group, optionally containing sulphur atoms or sulphoxide, amide, ketone, thioketone or sulfone groups, and optionally substituted with halogen, cyano, mono- or dialkyl(C1-4)amino, trifluoromethyl, (C1-4-alkoxy or hydroxyl groups;
• or
• R1 and R2 together with the nitrogen atom to which they are attached, form a 4 to 8 membered ring system wherein the ring system optionally comprises other (substituted) hetero atoms chosen from N, O and S, and which ring system may be optionally substituted with branched or unbranched alkyl(C1-4, halogen, cyano, mono- or dialkyl(C1-4)amino, trifluoromethyl, (C1-4-alkoxy or hydroxyl or which ring system contains amide, ketone, thioketone, sulfone or sulfoxide functions;
• R3 is chosen from a hydrogen atom, and a branched or unbranched alkyl(C1-4 group, optionally containing sulphur atoms or sulphoxide, amide, ketone, thioketone or sulfone groups, and optionally substituted with halogen, cyano, mono- or dialkyl(C1-4-amino, trifluoromethyl, (C1-4alkoxy, S-alkyl(C1-4, SH or hydroxyl groups;
• or
• R3 is an aryl group, optionally substituted with branched or unbranched alkyl(C1-4), aryl, alkyl(C1-4aryl, SH, S-alkyl(C1-4, halogen, cyano, mono- or dialkyl(C1-4)amino, CF3, OCF3, SCF3, nitro, hydroxy or (C1-4alkoxy groups.