1. A compound having the structure (B) or an N-oxide, N,N\u2032-dioxide, N,N\u2032,N\u2033-trioxide, or a pharmaceutically acceptable salt thereof:
wherein:
each of Z1, Z2 and Z3 is independently selected from a group consisting of N, and N\u2014R4, wherein R4 is hydrogen or lower alkyl,
X is absent or is NH; and
Y is absent or is selected from a group consisting of the following moieties:
R1 is an unsubstituted or a substituted C3-C12 heteroaryl having 1-3 heteroatoms;
R2 is selected from a group consisting of hydrogen, halogen, C1-C18 alkyl, \u2014OH, NO2, \u2014CN, C1-C18 alkoxy, \u2014NHSO2R5, \u2014SO2NHR5, \u2014NHCOR5, \u2014NH2, \u2014NR5R6, \u2014S(O)R5, S(O)2R5, \u2014CO2R5, \u2014CONR5R6, wherein R5 and R6 are independently selected from a group consisting of hydrogen, a C1-C18alkyl, and a substituted C1-C12 alkyl; and
R3 is selected from a group consisting of a C1-C18 alkyl, a substituted C1-C12 alkyl, a C1-C12 cycloalkyl, a substituted C1-C12 cycloalkyl, a substituted C3-C10 cycloalkyl having 0-3 heteroatoms, an C6-C12 aryl, a substituted C6-C12 aryl, a heterocycle, a substituted heterocycle, a C3-C12 heteroaryl having 1-3 heteroatoms, a substituted C3-C12 heteroaryl having 1-3 heteroatoms, a C7-C24 aralkyl, a substituted C7-C24 aralkyl, a C7-C24 alkylaryl, and a substituted C7-C24 alkaryl.
2. The compound of claim 1, wherein R1 is selected from the group consisting of:
R3 is selected from the group consisting of:
n is an integer selected from a group consisting of 0, 1, 2, and 3, and
R\u2032 is selected from a group consisting of hydrogen, a C1-C18 alkyl, and a substituted C1-C18 alkyl.
3. The compound of claim 1, wherein the compound having structure (B) is selected from a group consisting of compounds having the following formulae:
4. The compound of claim 3, wherein the compound has the formula:
5. The compound of claim 3, wherein the compound has the formula:
6. The compound of claim 3, wherein the compound has the formula:
7. The compound of claim 3, wherein the compound has the formula:
8. The compound of claim 3, wherein the compound has the formula:
9. The compound of claim 3, wherein the compound has the formula:
10. The compound of claim 3, wherein the compound has the formula:
11. The compound of claim 3, wherein the compound has the formula:
12. A pharmaceutical composition comprising a compound as set forth in claim 1, in a pharmaceutically acceptable carrier.
13. The compound of claim 1, wherein Y is
14. A compound represented by:
or pharmaceutically acceptable salts or N-oxides thereof.
15. A composition comprising the compound of claim 14, and a pharmaceutically acceptable excipient.
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 increasing a first specific productivity of a recombinant antibody or fragment thereof in a first cell, comprising co-expressing said antibody or fragment thereof with adenovirus GAM1 or a fragment andor variant thereof, wherein said first specific productivity is greater for said antibody or fragment thereof compared with a second specific productivity of the same antibody or fragment thereof expressed in a second cell, wherein said adenovirus GAM1 or fragment andor variant thereof is not expressed.
2. (canceled)
3. The method of claim 1, wherein said antibody is humanized or is fully human.
4. (canceled)
5. (canceled)
6. The method of claim 1, wherein said antibody is a domain antibody.
7. The method of claim 1, wherein said first cell is a mammalian cell.
8. (canceled)
9. The method of claim 7, wherein said first cell is a CHO cell.
10. The method of claim 1, wherein said first cell comprises an artificial chromosome.
11. The method of claim 1, wherein said first cell comprises episome DNA.
12. The method of claim 1, wherein said first and second cell are the same.
13. (canceled)
14. The method of claim 1, wherein adenovirus GAM1 is wild type.
15. The method of claim 14, wherein said adenovirus GAM1 is avian.
16. The method of claim 1, wherein said first cell is stably transfected with DNA encoding said antibody or antibody fragment and DNA encoding said adenovirus GAM1 or fragment andor variant thereof.
17. The method of claim 1, wherein said first cell is stably transfected with DNA encoding said antibody or antibody fragment and DNA encoding said adenovirus GAM1 or fragment andor variant thereof is expressed from a vector in said first cell.
18. The method of claim 1, wherein said adenovirus GAM1 or fragment andor variant thereof is present in more than one copy.
19. The method of claim 1, wherein said adenovirus GAM1 is a variant of wild type adenovirus GAM1.
20. The method of claim 19, wherein said variant of wild type adenovirus GAM1 increases the specific productivity of said monoclonal antibody or fragment thereof more than wild type adenovirus GAM1.
21. The method of claim 1, wherein said first cell is sequentially or simultaneously transfected with DNA encoding said antibody or antibody fragment and DNA encoding said adenovirus GAM1 or fragment andor variant thereof.
22. (canceled)
23. A method of increasing integral viable cells of a first cell culture comprising co-expressing an antibody or fragment thereof with adenovirus GAM1 or a fragment andor variant thereof in at least one cell of said first cell culture wherein said integral viable cells of said first cell culture is greater compared with the integral viable cells of a second cell culture, wherein said adenovirus GAM1 or fragment andor variant thereof is not expressed.
24-42. (canceled)
43. A method of creating an expression stable, viable cell line comprising transfecting at least one mammalian cell with DNA encoding adenovirus GAM1 or a variant andor fragment thereof wherein said expression stable, viable cell line comprises said at least one mammalian cell.
44. The method of claim 43, wherein said cell line remains viable and expression stable over at least about 60 passages.
45. The method of claim 44, wherein at least 1 passage occurs every 3 to 4 days.
46. The method of claim 43, wherein said cell line remains viable and expression stable for at least 210 days.
47. (canceled)
48. The method of claim 43, wherein said at least one mammalian cell is sequentially transfected with DNA encoding an antibody or fragment thereof.
49. The method of claim 43, wherein at least one mammalian cell is simultaneously or sequentially co-transfected with DNA encoding said adenovirus GAM1 or a fragment or variant thereof and DNA encoding an antibody or fragment thereof.
50-52. (canceled)
53. An expression stable, viable cell line comprising DNA encoding adenovirus GAM1 or a fragment andor a variant thereof and capable of producing a monoclonal antibody or fragment andor variant thereof.