Anti-epileptogenic agents
AssigneeQueen's University at Kingston
InventorsDonald F. Weaver, Paul H. Milne, Christopher Y.K. Tan, John R. Carran
Life of this patent
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Abstract
Methods and compounds useful for the inhibition of convulsive disorders, including epilepsy, are disclosed. The methods and compounds of the invention inhibit or prevent ictogenesis and epileptogenesis. Methods for preparing the compounds of the invention are also described.
Claims67
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject in need thereof an effective amount of an agent which modulates a process in a pathway associated with epileptogenesis such that epileptogenesis is inhibited in the subject.
A method for inhibiting epileptogenesis in a subject, comprising administering to a subject in need thereof an effective amount of an agent which antagonizes an NMDA receptor and augments endogenous GABA inhibition, such that epileptogenesis is inhibited in the subject.
A method for inhibiting epileptogenesis, comprising administering to a subject in need thereof an effective amount of a compound of the formula:
- 63
- in which
- A is an anionic group at physiological pH;
- R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl;
- and
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- or a pharmaceutically acceptable salt thereof;
- such that epileptogenesis is inhibited.
A method for inhibiting epileptogenesis, comprising administering to a subject in need thereof an effective amount of a compound represented by the formula:
- 64
- in which
- the dashed line represents an optional single/double bond;
- A is an anionic group at physiological pH;
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, alkoxy, aryloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl;
- or R4 and R5, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having from 5 to 15 atoms in the ring;
- or a pharmaceutically acceptable salt thereof;
- such that epileptogenesis is inhibited.
A method of inhibiting a convulsive disorder, comprising administering to a subject in need thereof an effective amount of a β-amino anionic compound such that the convulsive disorder is inhibited;
- with the proviso that the β-amino anionic compound is not β-alanine or taurine.
An anti-epileptogenic compound of the formula
- 65
- in which
- A is an anionic group at physiological pH;
- R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl;
- and
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- or a pharmaceutically acceptable salt thereof;
- wherein the anti-epileptogenic compound has anti-epileptogenic activity.
A pharmaceutical composition for treatment of epileptogenesis, comprising an anti-epileptogenic-effective amount of a compound of the formula
- 66
- in which
- A is an anionic group at physiological pH;
- R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl;
- and
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- or a pharmaceutically acceptable salt thereof;
- and a pharmaceutically-acceptable carrier.
A dioxapiperazine compound of the formula
- 67
- in which
- Ar represents an unsubstituted or substituted aryl group;
- R6 and R6′ are each independently hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl;
- and
- R7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or —(CH2)n—Y, in which n is an integer from 1 to 4 and Y is hydrogen or a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl;
- with the proviso that if Ar is an unsubstituted phenyl group, R7 is not hydrogen, methyl or phenyl;
- or a pharmaceutically-acceptable salt thereof.
A method for inhibiting a convulsive disorder in a subject, comprising:
- administering to a subject in need thereof an effective amount of an agent which a) blocks sodium or calcium ion channels, or opens potassium or chloride ion channels;
- and
- b) has at least one activity selected from the group consisting of
- NMDA receptor antagonism;
- augmentation of endogenous GABA inhibition;
- calcium binding;
- iron binding;
- zinc binding;
- NO synthase inhibition;
- and
- antioxidant activity;
- such that epileptogenesis and ictogenesis is inhibited in the subject.
A method for inhibiting a convulsive disorder, comprising administering to a subject in need thereof an effective amount of a compound represented by the formula:
- 68
- in which
- Ar represents an unsubstituted or substituted aryl group;
- R6 and R6′ are each independently hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl;
- and
- R7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or —(CH2)n—Y, in which n is an integer from 1 to 4 and Y is hydrogen or a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl;
- with the proviso that if Ar is unsubstituted phenyl, R7 is not hydrogen, methyl or unsubstituted phenyl;
- or a pharmaceutically acceptable salt thereof;
- such that the convulsive disorder is inhibited.
A compound of the formula
- 69
- in which
- Ar represents an unsubstituted or substituted aryl group;
- R6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl;
- R6′ is selected from the group consisting of an antioxidant moiety, an NMDA antagonist, an NO synthase inhibitor, an iron chelator moiety, a Ca(II) chelator moiety, and a Zn(II) chelator moiety;
- and
- R7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or —(CH2)n—Y, in which n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl;
- or a pharmaceutically-acceptable salt thereof.
A pharmaceutical composition comprising a compound of the formula
- 70
- in which
- Ar represents an unsubstituted or substituted aryl group;
- R6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl;
- R6′ is selected from the group consisting of an antioxidant moiety, an NMDA antagonist, an NO synthase inhibitor, an iron chelator moiety, a Ca(II) chelator moiety, and a Zn(II) chelator moiety;
- and
- R7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or —(CH2)n—Y, in which n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl;
- or a pharmaceutically-acceptable salt thereof;
- and a pharmaceutically-acceptable carrier.
A method for concomitantly inhibiting epileptogenesis and ictogenesis, comprising administering to a subject in need thereof an effective amount of a compound of the formula:
- 71
- in which
- Ar represents an unsubstituted or substituted aryl group;
- R6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl;
- R6′ is selected from the group consisting of an antioxidant moiety, an NMDA antagonist, an NO synthase inhibitor, an iron chelator moiety, a Ca(II) chelator moiety, and a Zn(II) chelator moiety;
- and
- R7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or —(CH2)n—Y, in which n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl;
- or a pharmaceutically-acceptable salt thereof;
- such that epileptogenesis is inhibited.
A method for treating a disorder associated with NMDA receptor antagonism, comprising administering to a subject in need thereof an effective amount of a compound of the formula:
- 72
- in which
- Ar represents an unsubstituted or substituted aryl group;
- R6 is hydrogen or alkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or aryloxycarbonyl;
- R6′ is an NMDA antagonist moiety;
- R7 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or —(CH2)n—Y, in which n is an integer from 1 to 4 and Y is a heterocyclic moiety selected from the group consisting of thiazolyl, triazolyl, and imidazolyl;
- or a pharmaceutically-acceptable salt thereof, and
- such that the disorder associated with NMDA receptor antagonism is treated.
A method for preparing a β-amino carboxyl compound represented by formula VI:
- 73
- in which
- the dashed line represents an optional single/double bond;
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carboxyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R4 and R5, taken together form a substituted or unsubstituted carbocyclic or heterocyclic ring having from 5 to 15 atoms in the ring;
- and
- R8 is hydrogen, alkyl, aryl, or an organic or inorganic salt-forming cation;
- the method comprising:
- reacting a compound of formula VII
- 74
- in which
- the dashed lines each represent an optional single bond;
- X is nitro, azido, or NR2R3, wherein R2 and R3 are defined above;
- W is —CN or —COOR8;
- R4 and R5 are as defined above;
- and
- R8 is hydrogen, alkyl, aryl, or an organic or inorganic salt-forming cation;
- under reductive desulfurization conditions such that the β-amino carboxyl compound is formed.
A method for preparing a β-amino carboxyl compound represented by formula VIII:
- 75
- in which
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, alkoxy, aryloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl;
- or R4 and R5, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having from 5 to 15 atoms in the ring;
- and
- R8 is hydrogen, alkyl, aryl, or an organic or inorganic salt-forming cation;
- the method comprising reacting a compound of formula IX
- 76
- in which
- the dashed lines each represent an optional single/double bond;
- X is nitro, azido, or NR2R3, wherein R2 and R3 are defined above;
- W is —CN or —COOR8;
- R8 is hydrogen, alkyl, aryl, or an organic or inorganic salt-forming cation;
- and
- R4 and R5 are as defined above;
- under reductive desulfurization conditions such that the β-amino carboxyl compound of Formula VIII is formed;
- with the proviso that if W is —CN, the method comprises the further step of acidification.
A method for inhibiting epileptogenesis and ictogenesis in a subject, comprising administering to a subject in need thereof an effective amount of an agent represented by the formula A-B, in which
- A is a domain having sodium or calcium ion channel blocking activity, or A has potassium or chloride channel opening activity;
- and
- B is a domain having has at least one activity selected from the group consisting of
- NMDA receptor antagonism;
- augmentation of endogenous GABA inhibition;
- calcium binding;
- iron binding;
- zinc binding;
- NO synthase inhibition;
- and
- antioxidant activity;
- such that epileptogenesis is inhibited in the subject.
A method for inhibiting epileptogenesis, comprising the step of administering to a subject in need thereof an effective amount of a compound represented by the formula:
- 77
- in which
- A is an anionic group at physiological pH;
- R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R2 and R3, taken together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring;
- R4 and R5 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, alkoxy, aryloxy, carboxyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R4 and R5, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having from 5 to 15 atoms in the ring;
- or a pharmaceutically acceptable salt thereof;
- such that epileptogenesis is inhibited.
A method for inhibiting a neurological condition in a subject, the method comprising administering to a subject in need thereof an effective amount of an agent which antagonizes an NMDA receptor and augments endogenous GABA inhibition, such that the neurological condition is inhibited in the subject, wherein the neurological condition is selected from the group consisting of stroke, Alzheimer's disease, cancer, and neurodegenerative disease.
A method for preparing a β-aryl-β-alanine compound, comprising:
- reacting an aryl aldehyde with a malonate compound and an ammonium compound, under conditions such that a β-aryl-β-alanine compound is formed.
A method for inhibiting epileptogenesis, the method comprising the step of administering to a subject in need thereof an effective amount of a compound represented by the formula:
- 78
- in which
- R9 and R10 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, thiol, alkylthiol, nitro, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy and aminocarbonyl;
- or R9 and R10, together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring;
- and
- R11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or R10 and R11, together with the carbon atom and nitrogen atom to which they are respectively attached, are joined to form a heterocyclic ring having from 4 to 8 members in the ring;
- and R12 is selected from the group consisting of hydrogen, alkyl, aryl and a carbohydrate;
- or a pharmaceutically acceptable salt thereof;
- such that epileptogenesis is inhibited.
A method for inhibiting epileptogenesis, comprising the step of administering to a subject in need thereof an effective amount of a compound represented by the formula:
- 79
- in which
- R9a, R9b, R10a, R10b are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, thiol, alkylthiol, nitro, cyano, halogen, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy and aminocarbonyl;
- or
- R9a and R9b, together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring;
- or R10a and R10b, together with the two-carbon unit to which they are attached, are joined to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring;
- or
- one of R9a and R9b is joined with one of R10a and R10b, together with the two-carbon unit to which they are attached, to form a carbocyclic or heterocyclic ring having from 4 to 8 members in the ring;
- R11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
- or one of R10b and R10b is joined with R11, together with the carbon atom and nitrogen atom to which they are respectively attached, to form a heterocyclic ring having from 4 to 8 members in the ring;
- and
- R12 is selected from the group consisting of hydrogen, alkyl, aryl and a carbohydrate (such as a sugar, e.g., ribose or deoxyribose);
- or a pharmaceutically acceptable salt thereof;
- such that epileptogenesis is inhibited.
Dependencies are inferred from the claim text.