N-phenyl anthranilic acid derivatives and uses thereof
AssigneeRamot at Tel-Aviv University Ltd.
InventorsBernard Attali, Asher Peretz
Life of this patent
Estimating the term…
Abstract
Compounds that can be used as openers or blockers of voltage-dependent potassium channels, and which are useful in the treatment of conditions such as central or peripheral nervous system disorders through the modulation of potassium ion flux through voltage-dependent potassium channels and/or depressing or enhancing cortical and/or peripheral neuron activity, compositions containing same and methods utilizing same are disclosed. Also disclosed are modulators of voltage-dependent potassium channels, which exhibit blocking of a TRPV1 channel, and hence are useful in the treatment of TRPV1-related conditions.
Claims45
1-54. (canceled)
A compound having the general Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein:
- Z is an A-G(=K)—X—Y group,
- A is alkyl or absent;
- G is selected from the group consisting of C, S and PRa;
- K is selected from the group consisting of O and S;
- X is selected from the group consisting of O, S and NRb, or absent;
- and
- Y is selected from the group consisting of hydroxyalkyl and a polyalkylene glycol moiety,
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- each of R2, R3, R4, R5, R6, R7, R8, R9 and R10 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and —NR15R16, or, alternatively, at least two of R2, R3, R4, R5 and R6, and/or of R7, R8, R9 and R10 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
- and
- each of Ra and Rb, is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl,
- provided that at least one of R7, R8, R9 and R10 is an electron-withdrawing group.
A method of blocking a voltage-dependent potassium channel and/or enhancing a cortical and/or peripheral neuron activity, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound having a general Formula III:
- a pharmaceutically acceptable salt thereof,
- wherein:
- Z is an A-G(=K)—X—Y group,
- A is alkyl;
- G is selected from the group consisting of C, S and PRa;
- K is selected from the group consisting of O and S;
- X is selected from the group consisting of NRb, S or absent;
- and
- Y is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalicyclic and a positively charged group, with the proviso that Y does not contain a hydroxy group;
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- each of R2, R3, R4, R5, R6, R7, R8, R9 and R10, is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and —NR15R16, or, alternatively, at least two of R2, R3, R4, R5 and/or R6, of R7, R8, R9 and R10 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
- and
- each of Ra and Rb is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl.
A pharmaceutical composition comprising, as an active ingredient, a compound having a general Formula III:
- a pharmaceutically acceptable salt thereof,
- wherein:
- Z is an A-G(=K)—X—Y group,
- A is alkyl;
- G is selected from the group consisting of C, S and PRa;
- K is selected from the group consisting of O and S;
- X is selected from the group consisting of NRb, S or absent;
- and
- Y is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroalicyclic and a positively charged group, with the proviso that Y does not contain a hydroxy group;
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- each of R2, R3, R4, R5, R6, R7, R8, R9 and R10, is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and —NR15R16, or, alternatively, at least two of R2, R3, R4, R5 and/or R6, of R7, R8, R9 and R10 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
- and
- each of Ra and Rb is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl,
- the composition being packaged in a packaging material and identified in print, in or on said packaging material, for use in blocking a voltage-dependent potassium channel.
A method of blocking a voltage-dependent potassium channel, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of interacting with a hydrophobic binding pocket in a voltage sensitive domain of said potassium channel, while not interacting with at least one electrophilic binding site in said voltage sensitive domain.
A method of opening a voltage-dependent potassium channel, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of interacting with a hydrophobic binding pocket and with at least two electrophilic binding sites in a voltage sensitive domain of said potassium channel.
A method of blocking a transient receptor potential vanilloid 1 (TRPV1) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having general Formula IV:
- wherein:
- Z is an A-G(=K)—X—Y group,
- and wherein:
- A is alkyl or absent;
- G is selected from the group consisting of C, S and PRa;
- K is selected from the group consisting of O and S;
- X is selected from the group consisting of NRb, O, S or absent;
- and
- Y is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heteroalicyclic, aryl and a polyalkylene glycol residue,
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- each of R2, R3, R4, R5, R6, R7, R8, R9 and R10 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, an electron-withdrawing group, amino and —NR15R16, or, alternatively, at least two of R2, R3, R4, R5 and R6, of R7, R8, R9 and R10 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
- R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R15 and R16 form a five- or six-member heteroalicyclic ring;
- and
- each of said Ra and Rb is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl.
A pharmaceutical composition comprising a compound having general Formula IV:
- wherein:
- Z is an A-G(=K)—X—Y group,
- and wherein:
- A is alkyl or absent;
- G is selected from the group consisting of C, S and PRa;
- K is selected from the group consisting of O and S;
- X is selected from the group consisting of NRb, O, S or absent;
- and
- Y is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, aryl and a polyalkylene glycol residue,
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- each of R2, R3, R4, R5, R6, R7, R8, R9 and R10 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, an electron-withdrawing group, amino and —NR15R16, or, alternatively, at least two of R2, R3, R4, R5 and R6, of R7, R8, R9 and R10 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
- R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl and sulfonyl, or, alternatively R15 and R16 form a five- or six-member heteroalicyclic ring;
- and
- each of said Ra and Rb is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl.
- and a pharmaceutically acceptable carrier, the composition being packaged and identified in print, in or on said packaging material, for use in blocking Transient receptor potential vanilloid 1 (TRPV1).
A compound having the general Formula I:
- or a pharmaceutically acceptable salt thereof,
- wherein:
- Z is an A-G(=K)—X—Y group,
- A is alkyl or absent;
- G is selected from the group consisting of C, S and PRa;
- K is selected from the group consisting of O and S;
- X is selected from the group consisting of O, S and NRb, or absent;
- and
- Y is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, aryl and a polyalkylene glycol moiety,
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl or aryl;
- each of R2, R3, R4, R5, R6, R7, R8, R9 and R10 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, amino and —NR15R16, or, alternatively, at least two of R2, R3, R4, R5 and R6, and/or of R7, R8, R9 and R10 form a five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;
- and
- each of Ra and Rb, is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl,
- provided that at least one of R2, R3, R4, R5, R6, R7, R8, R9 and R10 is an electron-withdrawing group.
Dependencies are inferred from the claim text.