Human N-type calcium channel blockers
OwnerRobert Zelle, Pravin Chaturvediinventors
Life of this patent
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Abstract
This invention features a method for modulating human N-type calcium channel α1B+SFVG subunit activity. The method includes administering to a subject in need thereof an effective amount of a compound of formula (I), (II), or (III): 1
Claims24
A method for modulating human N-type calcium channel α1B+SFVG subunit activity, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), or (III):
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- wherein
- m is 0, 1 or 2, in which when m is 0, Z is O, when m is 1, Z is N, and when m is 2, Z is C;
- n is 0 or 1;
- each of X1 and X2, independently, is a linker;
- Y is H, OH, NH2, or an organic moiety of C1-C20, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S and halo;
- V is N or CH;
- W is O, S, NR or CR2, in which R is H or alkyl (C1-C6);
- Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings;
- Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic moieties, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic moiety and one substituted or unsubstituted aromatic or heteroaromatic moiety;
- each of I1 and I2, independently, is 0, 1, 2, 3, 4, or 5;
- I3 is 0 or 1;
- each of I4 and I5, independently, is 0, 1, 2, 3, or 4;
- I6 is 0or 1;
- each of R1, R2 and R3, independently, is alkyl (C1-C6), aryl (C6-C10) or arylalkyl (C7-C16) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S, or each of R1 and R2 may independently be halo, COOR, CONR2, CF3, CN or NO2, in which R is H or lower alkyl (C1-C4) or alkyl (C1-C6);
- each of R4, R5 and R6, independently, is alkyl (C1-C6), aryl (C6-C10) or arylalkyl (C7-C16) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S, or may independently be halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, CN or NO2, wherein R is H or alkyl (C1-C6), and
- the dotted lines represent optional π-bonds;
- or compounds of formulae (II) or (III) where (X2)n—Ar or (X2)n—Cy is replaced by alkyl (1-6C);
- with the proviso that Y is not a tropolone, a coumarin, or an antioxidant containing an aromatic group, and with the further proviso that if I3 is 0, and either I1 and I2 is 0 or 1 and if R1 and/or R2 represent F in the para position, Z cannot be N or C.
A method for modulating human N-type calcium channel α1B+SFVG subunit activity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (IV) or (V) or a pharmaceutically acceptable salt thereof:
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- wherein,
- Each Z is, independently, N or CH, at least one Z being N;
- n1 is 1 and n2 is 0 or 1;
- X1 and X2 are linkers;
- Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings;
- Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring;
- Each of Ya and Yb is two substituted or unsubstituted aromatic or heteroaromatic rings, or two substituted or unsubstituted aliphatic cyclic or heterocyclic rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring;
- l1 is 0 or 1;
- R1 is substituted or unsubstituted alkyl (C1-C6), substituted or unsubstituted aryl (C6-C10) or substituted or unsubstituted arylalkyl (C7-C16), each of which optionally further containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S;
- or is halo, OR, SR, NR2, OOCR, NROCR, COR, COOR, CONR2, CF3, OCF3, CN or NO2, wherein R is H or alkyl (C1-C6).
A method for modulating human N-type calcium channel α1B+SFVG subunit activity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt thereof:
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- wherein,
- Cy represents cyclohexyl;
- Y is CH═CHΦ, CHΦ2, Φ or Cy;
- X is divalent or trivalent straight-chain alkylene (C3-C10) or divalent or trivalent straight-chain 1-alkenylene (C3-C10) optionally substituted by oxo at the C adjacent N when n is 0 and Y is Φ2CH;
- and is otherwise divalent or trivalent straight-chain alkylene (C5-C10) or divalent or trivalent straight-chain 1-alkenylene (C5-C10) optionally substituted by oxo at the C adjacent N;
- Z is N, NCO, CHNCOR1 or CHNR1, wherein R1 is H or alkyl (C1-C6);
- and
- n is 0-5;
- wherein each Φ and Cy independently may optionally be substituted by alkyl (C1-C6) or by halo, CF3, OCF3, NO2, NR2, OR, SR, COR, COOR, CONR2, NROCR or OOCR where R is H or alkyl (C1-C4), or two substituents may form a 5-7 membered ring.
A method for modulating human N-type calcium channel α1B+SFVG subunit activity, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (VIII) or a pharmaceutically acceptable salt thereof:
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- wherein m is 0, 1 or 2;
- wherein when m is 0, Z is O, when m is 1, Z is N, and when m is 2, Z is C;
- Y is H, OH, NH2, or an organic moiety of C1-C20, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S. and halo;
- each l1 and l2 is independently 0-5;
- l3 is 0 or 1;
- each of R1, R2 and R3 is independently alkyl (C1-C6), aryl (C6-C10) or arylalkyl (C7-C16) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R1 and R2 may independently be halo, COOR, CONR2, CF3, CN or NO2, wherein R is H or lower alkyl (C1-C4) or alkyl (C1-C6);
- n is 0 or 1;
- and
- X is a linker.
A method for modulating human N-type calcium channel α1B+SFVG subunit activity, the method comprising administering to a subject in need thereof an effective amount of a compound comprising:
- a straight backbone carbon chain of C8-16C, optionally substituted with 1-15 alkyl groups (C1-C6);
- said chain optionally functionalized at one terminus with halo, —OR, SR, NR2, —OOCR, —NROCR wherein R is alkyl (C1-C6), or phosphate or pyrophosphate, or functionalized wherein a terminal carbon is optionally in the form or —COOR, —CONR2 or —COR wherein R is alkyl (C1-C16);
- and
- wherein said chain may optionally contain 1-4 π-bonds or the epoxides thereof.
Dependencies are inferred from the claim text.