1. A specimen observing method, comprising the steps of:
irradiating a specimen supplied with a negative voltage with an electron beam to generate secondary electrons from the specimen,
forming a negative potential field such that the secondary electrons are retarded,
deflecting and detecting the retarded secondary electrons to obtain a specimen image on the basis of the retarded secondary electrons, and
adjusting the negative voltage so as to cancel charge-up of the specimen.
2. A specimen observing method according to claim 1, wherein the step of adjusting the negative voltage is so performed that the specimen image has a given image contrast.
3. A specimen observing method according to claim 1, wherein the step of adjusting the voltage is performed while monitoring an output of a secondary electron detector detecting the generated secondary electrons so that the output shows a maximum.
4. A specimen observing method, comprising the steps of:
irradiating a specimen supplied with a negative voltage with an electron beam to generate secondary electrons from the specimen,
forming a negative potential field such that the secondary electrons are retarded,
deflecting and detecting the retarded secondary electrons to obtain a specimen image on the basis of the retarded secondary electrons, and
adjusting the negative voltage while monitoring an output of a secondary electron detector detecting the secondary electrons to determine a value of the negative voltage at which the output has a maximum value.
5. A scanning electron microscope which comprises:
an electron source emitting a primary electron beam,
a focusing lens focusing the primary electron beam,
a deflector deflecting the primary electron beam to irradiate a specimen with the focused primary electron beam so as to generate secondary electrons from the specimen;
a detector detecting the secondary electrons;
a negative voltage supplying source supplying the specimen and the deflector with a negative voltage such that the secondary electrons are retarded, and
a controller adjusting the negative voltage to determine a value thereof at which the output shows a maximum.
6. A scanning electron microscope according to claim 5, wherein the secondary electron detector comprises a secondary electron multiplier and the controller adjusts the negative voltage while monitoring an output of the secondary electron multiplier.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. An active compound selected from the group consisting of a structure:
59
wherein s is an integer from about 1 to about 3;
A is selected from the group consisting of A1 and A3;
A1 is a group of the formula
60
wherein each R1 is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
x is 0 to about 10;
R2 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
D1 and D2 are each independently selected from the group consisting of C(O) and NR3
wherein R3 is selected from the group consisting of a hydrogen atom and R2, and with the proviso that optionally, R2 and R3 may be bonded together thereby forming a ring selected from the group consisting of heterocyclic groups and substituted heterocyclic groups;
y is 0 or 1 and z is 0 or 1,
with the provisos that when y is 0, z is 1 and when y is 1, z is 0,
when y is 0 and D1 is NR3, then D2 is C(O),
when y is 0 and D2 is NR3, then D1 is C(O), and
when x is 0, D1 is C(O), y is 0, D2 is NR3, and
D3 is C(O) or S(O)2, then R2 is selected from the group consisting of a hydrocarbon group and a substituted hydrocarbon group, wherein the substituted hydrocarbon group is substituted with an aromatic group; and
A2 is a group of the formula
61
wherein u is 0 to about 10; p is 0 to about 10; v is 0 or 1;
D3 is selected from the group consisting of-S(O)2, C(O), and CR1(OH), with the provisos that
when D3 is S(O)2, then D1 is C(O), D2 is NR3, and R2 and R3 are bonded together to form the ring structure, and
when D3 is C(O), v is 0, and R5 contains a C(O) group, then p is not 0;
R5 is selected from the group consisting of a substituted hydrocarbon groups of at least 2 carbon atoms and substituted heterogeneous groups of at least 2 member atoms, wherein R5 is substituted with at least one group selected from the group consisting of aromatic groups, heteroaromatic groups, substituted aromatic groups, and substituted heteroaromatic groups;
A3 has the formula
62
wherein t is about 1 to about 6;
D4 is selected from the group consisting of C(O) and CHR1, and
D5 is selected from the group consisting of NR6(R7), OrR6, and C(O)R6
wherein r is 0 or 1;
R6 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; and
R7 is selected from the group consisting of a hydrogen atom and R6, with the proviso that when u is 0, D3 and D4 are not both C(O); and
an optical isomer, a diastereomer, an enantiomer, a pharmaceutically-acceptable salt, a biohydrolyzable amide, a biohydrolyzable ester, and a biohydrolyzable imide of the structure.
2. The compound of claim 1, wherein u is about 1 to about 3, p is about 1 to about 3, and v is 1.
3. The compound of claim 2, wherein D3 is CR1(OH).
4. The compound of claim 3, wherein R5 is a heteroaromatic group of the formula:
63
wherein each X is independently selected from the group consisting of CH and a heteroatom, with the proviso that at least one X is a heteroatom.
5. The compound of claim 4, wherein A is A1, R2 and R3 are bonded together and the ring structure has 4 to 6 members in the ring.
6. The compound of claim 5, wherein the compound has a formula selected from the group consisting of:
64
7. The compound of claim 4, wherein A is A1, D1 is C(O), and D2 is NR3.
8. The compound of claim 7, wherein the compound has a formula selected from the group consisting of:
65
9. The compound of claim 4, wherein A is A3.
10. The compound of claim 9, wherein the compound has the formula:
66
11. The compound of claim 1, wherein D1 is C(O), y is 1, and z is 0.
12. The compound of claim 1, wherein D1 is NR3 and D2 is C(O).
13. The compound of claim 12, wherein R3 is selected from the group consisting of hydrogen and a hydrocarbon group.
14. The compound of claim 1, wherein R2 is selected from the group consisting of
an aromatic group;
a substituted aromatic group;
a heteroaromatic group;
a substituted heteroaromatic group;
a substituted hydrocarbon group, wherein the substituted hydrocarbon group is substituted with a group selected from the group consisting of an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; and
a substituted heterogenous group, wherein the substituted heterogenous group is substituted with a group selected from the group consisting of an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group.
15. The compound of claim 1, wherein u is 0, and R5 is selected from the group consisting of an aromatic group;
a substituted aromatic group;
a heteroaromatic group;
a substituted heteroaromatic group;
a hydrocarbon group;
a substituted hydrocarbon group, wherein the substituted hydrocarbon group is substituted with a group selected from the group consisting of an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; and
a substituted heterogenous group, wherein the substituted heterogenous group is substituted with a group selected from the group consisting of an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group.
16. The compound of claim 15, wherein p is 0, and D3 is SO2.
17. The compound of claim 1, wherein D4 is C(O), t is 0, and D5 is and C(O)R6.
18. The compound of claim 1, wherein D4 is C(O) and D5 is OrR6.
19. The compound of claim 1, wherein D4 is CH(R1) and D5 is OrR6 .
20. The compound of claim 1, wherein D4 is CH(R1) and D5 is NR6(R7).
21. The compound of claim 1, wherein D4 is C(O) and D5 is NR6(R7).
22. A composition for treating multidrug resistance comprising:
(A) a compound selected from the group consisting of a structure:
67
wherein s is an integer from about 1 to about 3;
A is selected from the group consisting of A1 and A3;
A1 is a group of the formula
68
wherein each R1 is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
x is 0 to about 10;
R2 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
D1 and D2 are each independently selected from the group consisting of C(O) and NR3
wherein R3 is selected from the group consisting of a hydrogen atom and R2, and with the proviso that optionally, R2 and R3 may be bonded together thereby forming a ring selected from the group consisting of heterocyclic groups and substituted heterocyclic groups;
y is 0 or 1 and z is 0 or 1,
with the provisos that when y is 0, z is 1 and when y is 1, z is 0,
when y is 0 and D1 is NR3, then D2 is C(O),
when y is 0 and D2 is NR3, then D1 is C(O), and
when x is 0, D1 is C(O), y is 0, D2 is NR3, and
D3 is C(O) or S(O)2, then R2 is selected from the group consisting of a hydrocarbon group and a substituted hydrocarbon group, wherein the substituted hydrocarbon group is substituted with an aromatic group; and
A2 is a group of the formula
69
wherein u is 0 to about 10; p is 0 to about 10; v is 0 or 1;
D3 is selected from the group consisting of S(O)2, C(O), and CR1(OH), with the provisos that
when D3 is S(O)2, then D1 is C(O), D2 is NR3, and R2 and R3 are bonded together to form the ring structure, and
when D3 is C(O), v is 0, and R5 contains a C(O) group, then p is not 0;
R5 is selected from the group consisting of a substituted hydrocarbon groups of at least 2 carbon atoms and substituted heterogeneous groups of at least 2 member atoms, wherein R5 is substituted with at least one group selected from the group consisting of aromatic groups, heteroaromatic groups, substituted aromatic groups, and substituted heteroaromatic groups;
A3 has the formula
70
wherein t is about 1 to about 6;
D4 is selected from the group consisting of C(O) and CHR1, and
D1 is selected from the group consisting of NR6(R7), OrR6 , and C(O)R6
wherein r is 0 or 1;
R6 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; and
R7 is selected from the group consisting of a hydrogen atom and R6, with the proviso that when u is 0, D3 and D4 are not both C(O); and
an optical isomer, a diastereomer, an enantiomer, a pharmaceutically-acceptable salt, a biohydrolyzable amide, a biohydrolyzable ester, and a biohydrolyzable imide of the structure, and combinations thereof; and
(B) a carrier.
23. The composition of claim 22, further comprising:
component (C) a therapeutic agent selected from the group consisting of
(i) a cancer therapeutic agent,
(ii) an antibacterial agent,
(iii) an antiviral agent,
(iv) an antifungal agent, and combinations thereof.
24. A method for inhibiting transport protein activity comprising administering, to a subject, a compound selected from the group consisting of a structure:
71
wherein s is an integer from about 1 to about 3;
A is selected from the group consisting of A1 and A3;
A1 is a group of the formula
72
wherein each R1 is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
x is 0 to about 10;
R2 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
D1 and D2 are each independently selected from the group consisting of C(O) and NR3
wherein R3 is selected from the group consisting of a hydrogen atom and R2, and with the proviso that optionally, R2 and R3 may be bonded together thereby forming a ring selected from the group consisting of heterocyclic groups and substituted heterocyclic groups;
y is 0 or 1 and z is 0 or 1,
with the provisos that when y is 0, z is 1 and when y is 1, z is 0,
when y is 0 and D1 is NR3, then D2 is C(O),
when y is 0 and D2 is NR3, then D1 is C(O), and
when x is 0, D1 is C(O), y is 0, D2 is NR3, and
D3 is C(O) or S(O)2, then R2 is selected from the group consisting of a hydrocarbon group and a substituted hydrocarbon group, wherein the substituted hydrocarbon group is substituted with an aromatic group; and
A2 is a group of the formula
73
wherein u is 0 to about 10; p is 0 to about 10; v is 0 or 1;
D3 is selected from the group consisting of S(O)2, C(O), and CR1(OH), with the provisos that
when D3 is S(O)2, then D1 is C(O), D2 is NR3, and R2 and R3 are bonded together to form the ring structure, and
when D3 is C(O), v is 0, and R5 contains a C(O) group, then p is not 0;
R5 is selected from the group consisting of a substituted hydrocarbon groups of at least 2 carbon atoms and substituted heterogeneous groups of at least 2 member atoms, wherein R5 is substituted with at least one group selected from the group consisting of aromatic groups, heteroaromatic groups, substituted aromatic groups, and substituted heteroaromatic groups;
A3 has the formula
74
wherein t is about 1 to about 6;
D4 is selected from the group consisting of C(O) and CHR1, and
D5 is selected from the group consisting of NR6(R7), OrR6, and C(O)R6
wherein r is 0 or 1;
R6 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group; and
R7 is selected from the group consisting of a hydrogen atom and R6, with the proviso that when u is 0, D3 and D4 are not both C(O); and
an optical isomer, a diastereomer, an enantiomer, a pharmaceutically-acceptable salt, a biohydrolyzable amide, a biohydrolyzable ester, and a biohydrolyzable imide of the structure; and combinations thereof.
25. The method of claim 24, further comprising coadministering component (C) a therapeutic agent.
26. The method of claim 25, wherein component (C) is coadministered at a time selected from the group consisting of before, during, and after administration of component (A); and
combinations thereof.