1. A compound of the formula:
30
wherein Ar is phenyl, a six-membered or five-membered ring which is heteroaromatic or a fused aromatic or heteroaromatic system, each of which may optionally be substituted with one or more non-interfering substituents;
X1 is a linker containing 1-5 members;
n is 0 or 1;
each R1-R3 is independently a non-interfering non-hydrogen substituent;
each 1 is independently 0-5;
m is 0-4;
X2 is a linker comprising a chain of at least 5 members;
A is H, OR, SR, NR2, or halo wherein R is H or lower alkyl (1-6C);
with the proviso that
(a) Ar is a five- or six-membered heteroaryl substituent or an optionally substituted fused aromatic or heteroaromatic substituent; andor
(b) n is 0; andor
(c) m is 1-4; andor
(d) X2 is alkylene substituted by O, OR, SR, NR2 andor halo; andor
(e) X2 is a chain of at least 6 members; andor
(f) X2 contains at least one heteroatom selected from N, S and O; andor
(g) A is OR, SR, NR2 or halo, wherein R is H or lower alkyl (1-6C) andor
(h) Ar is substituted with at least one t-butyl moiety or at least one substituted alkoxy; andor
(i) X1 includes at least one heteroatom selected from O, N and S.
2. The compound of claim 1 which is of the formula
31
wherein Ar, R1-R3, l, m, X2 and A are as defined above, het is a heteroatom selected from O, S and N, and wherein X1 is defined as X1 but lacking one chain member.
3. The compound of claim 1 which is of the formula
32
wherein Ar, X1, R1-R3, l, m, n, A and Ar are defined as above, and X2 is defined as X2 but lacking one chain member.
4. The compound of claim 1 which is of the formula
33
wherein R4 is O, or a carboxylic acid group or ester or amide thereof and Ar, R2-R3, X1, l, n, X2 and A are defined as above.
5. The compound of claim 1, wherein each non-interfering substituent is independently alkyl (1-10C), alkenyl (2-10C), alkynyl (2-10C), aryl (6-10C), arylalkyl (7-16C) or arylalkenyl (7-16C) each optionally further containing 1-4 heteroatoms (N, O or S) each further optionally substituted, or is independently O, halo, CF3, OCF, NO2, NH2, OH, or SH wherein S may optionally be oxidized.
6. The compound of claim 1, wherein the phenyl groups represented by A and B are linked through a bond, one or more CR2 moieties wherein each R is H or lower alkyl (1-6C) wherein one or more of said CR2 may be replaced by NR, O or S.
7. The compound of claim 1, wherein each l is independently 0 or 1.
8. The compound of claim 1, wherein X2 is substituted by O adjacent the piperazine ring.
9. The compound of claim 1, wherein X1 is substituted by O at the position next to the piperazine ring.
10. The compound of claim 1, wherein each of R2 and R3 is independently alkoxy, halo, or alkyl.
11. The compound of claim 1, wherein m is 1 and R1 is O or a carboxylic acid group or ester or amide thereof.
12. The compound of claim 1, wherein Ar is optionally substituted phenyl.
13. The compound of claim 12, wherein said phenyl is unsubstituted or is substituted by one or more tert-butyl, methoxy, substituted alkoxy, hydroxy andor halo.
14. The compound of claim 13, wherein the substituted alkoxy is substituted by an amino group.
15. The compound of claim 1, wherein Ar is optionally substituted pyrimidyl, pyridyl, benzothiazole, benzimidazole or indole.
16. The compound of claim 1, which is
6,6-Bis-(4-fluoro-phenyl)-1-4-(2-phenylsulfanyl-ethyl)-piperazin-1-yl-hexan-1-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-2-(4-fluoro-phenoxy)-ethyl-piperazine;
1-4-2-(Benzo1,3dioxol-5-yloxy)-ethyl-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(2-phenylsulfanyl-ethyl)-piperazine;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-2-(4-methoxy-phenoxy)-ethyl-piperazine;
1-4-2-(2,4-Difluoro-phenoxy)-ethyl-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
6,6-Bis-(4-fluoro-phenyl)-1-4-(2-phenoxy-ethyl)-piperazin-1-yl-hexan-1-one;
1-4-2-(2,4-Dichloro-phenoxy)-ethyl-piperazin-1-yl -6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
6,6-Bis-(4-fluoro-phenyl)-1-4-2-(4-methoxy-phenoxy)-ethyl-piperazin-1-yl-hexan-1-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(2-phenoxy-ethyl)-piperazine;
6,6-Bis-(4-fluoro-phenyl)-1-4-2-(3,4,5-trimethoxy-phenoxy)-ethyl-piperazin-1-yl-hexan-1-one;
1-4-2-(Benzothiazol-2-ylsulfanyl)-ethyl-piperazin-1-yl -6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
4-(2-4-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-piperazin-1-yl-ethoxy)-2,3,6-trimethyl-phenyl-carbamic acid tert-butyl ester;
4-(2-4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-yl-ethoxy)-2,3,6-trimethyl-phenylamine;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-2-(2,4-dichloro-phenoxy)-ethyl-piperazine;
2-(4-4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-ylmethyl-2,6-di-tert-butyl-phenoxy)-ethyl-dimethyl-amine;
4-4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-ylmethyl-2,6-di-tert-butyl-phenol;
1-4-(3,5-Di-tert-butyl-4-methoxy-benzoyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-4-(3,5-Di-tert-butyl-4-methoxy-benzyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(3,5-di-tert-butyl-4-methoxy-benzyl)-piperazine;
4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-yl-(3,5-di-tert-butyl-4-methoxy-phenyl)-methanone;
1-4-3,5-Di-tert-butyl-4-(2-dimethylamino-ethoxy)-benzoyl-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-Benzo1,3dioxol-5-ylmethyl-4-6,6-bis-(4-fluoro-phenyl)-hexyl-piperazine;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(3,5-di-tert-butyl-benzyl)-piperazine;
4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-yl-(3,5-di-tert-butyl-4-hydroxy-phenyl)-methanone;
1-4-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-4-(3,5-Dibromo-4-hydroxy-benzoyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-4-(3,5-Di-tert-butyl-4-hydroxy-benzoyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-4-(3,5-Di-tert-butyl-benzoyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(4-tert-butyl-benzyl)-piperazine;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(9H-thioxanthen-9-yl)-piperazine;
2-4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-yl-benzothiazole;
6,6-Bis-(4-fluoro-phenyl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-hexan-1-one;
2-4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-yl -pyrimidine;
6,6-Bis-(4-fluoro-phenyl)-1-4-(9H-thioxanthen-9-yl)-piperazin-1-yl-hexan-1-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(3,4,5-trimethoxy-benzyl)-piperazine-2-carboxylic acid ethyl ester;
6,6-Bis-(4-fluoro-phenyl)-1-4-2-(3,4,5-trimethoxy-benzylamino)-ethyl-piperazin-1-yl-hexan-1-one;
9,9-Bis-(4-fluoro-phenyl)-1-4-(3,4,5-trimethoxy-benzyl)-piperazin-1-yl-nonan-1-one;
(2-4-6,6-Bis-(4-fluoro-phenyl)-hexyl-piperazin-1-yl-ethyl)-phenyl-amine;
1-9,9-Bis-(4-fluoro-phenyl)-nonyl-4-(3,4,5-trimethoxy-benzyl)-piperazine;
(4-4-Bis-(4-fluoro-phenyl)-methoxy-butyl-piperazin-1-yl)-(3,4,5-trimethoxy-phenyl)-methanone;
6,6-Bis-(4-fluoro-phenyl)-1-4-(4-trifluoromethoxy-benzoyl)-piperazin-1-yl-hexan-2-one;
1-4-(4-Bromo-benzoyl)-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one;
6,6-Bis-(4-fluoro-phenyl)-5-hydroxy-1-4-(3,4,5-trimethoxy-benzoyl)-piperazin-1-yl-hexan-1-one;
1-4-Bis-(4-fluoro-phenyl)-methoxy-butyl-4-(3,4,5-trimethoxy-benzyl)-piperazine;
6,6-Bis-(4-fluoro-phenyl)-6-hydroxy-1-4-(3,4,5-trimethoxy-benzoyl)-piperazin-1-yl-hexan-1-one;
4-6,6-Bis-(4-fluoro-phenyl)-hexyl-1-(3,4,5-trimethoxy-benzyl)-piperazine-2-carboxylic acid;
4-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-1-(3,4,5-trimethoxy-benzyl)-piperazin-2-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-4-(3,5-di-tert-butyl-4-methoxy-benzoyl)-piperazin-2-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(3,4,5-trimethoxy-benzoyl)-piperazin-2-one;
4-6,6-Bis-(4-fluoro-phenyl)-hexyl-1-(3,4,5-trimethoxy-benzyl)-piperazin-2-one;
4-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-1-(3,5-di-tert-butyl-4-methoxy-benzyl)-piperazin-2-one;
4-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-1-2-(4-fluoro-phenoxy)-ethyl-piperazin-2-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(3,5-di-tert-butyl-4-methoxy-benzoyl)-piperazin-2-one;
4-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-piperazin-2-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-(3,5-di-tert-butyl-4-methoxy-benzyl)-piperazin-2-one;
1-6,6-Bis-(4-fluoro-phenyl)-hexanoyl-4-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-piperazin-2-one;
6,6-Bis-(4-fluoro-phenyl)-1-4-(3,4,5-trimethoxy-benzoyl)-piperazin-1-yl-hex-5-en-1-one;
1-4-2-(3,4-Dimethoxy-phenoxy)-ethyl-piperazin-1-yl-6,6-bis-(4-fluoro-phenyl)-hexan-1-one; or
1-6,6-Bis-(4-fluoro-phenyl)-hexyl-4-2-(3,4-dimethoxy-phenoxy)-ethyl-piperazine.
17. A pharmaceutical composition for use in treating conditions characterized by calcium channel activity which composition comprises, in admixture with a pharmaceutically acceptable excipient, a unit dosage amount of at least one compound of claim 1.
18. A method to treat conditions associated with calcium channel activity in a subject which method comprises administering to a subject in need of such treatment at least one compound of claim 1 or a pharmaceutical composition thereof.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of recovering a purified product from a load fluid, comprising the steps of:
passing the load fluid through a medium at operating conditions which cause the medium to bind at least 1 mg of product per 1 mL of medium; and
recovering the purified product from column effluent.
2. A method of recovering a purified product from a load fluid, comprising the steps of:
passing the load fluid through a medium at operating conditions defined by a partition coefficient of at least 0.1; and
recovering the purified product from column effluent.
3. The method of claim 1, wherein the operating conditions cause the medium to bind at least 10 mg of product per mL of medium.
4. The method of claim 2, wherein the value of the partition coefficient is in the range of about 0.2 to about 10.0.
5. The method of claim 1, further comprising the step of recovering the purified product from the medium using an essentially isocratic wash.
6. The method of claim 2, further comprising the step of recovering the purified product from the medium using an essentially isocratic wash.
7. The method of claim 1, wherein the purified product is a protein selected from the group consisting of fusion proteins, Fc-containing proteins, immunoconjugates, cytokines, interleukins, hormones, and therapeutic enzymes.
8. The method of claim 2, wherein the purified product is a protein selected from the group consisting of fusion proteins, Fc-containing proteins, immunoconjugates, cytokines, interleukins, hormones, and therapeutic enzymes.
9. The method of claim 1, wherein the operating conditions comprise a pH of 7.5-8.2 and a chloride concentration of 12 mM-55 mM.
10. The method of claim 2, wherein the operating conditions comprise a pH of 7.5-8.2 and a chloride concentration of 12 mM-55 mM.