What is claimed:
1. A compound of Formula I:
13
wherein:
each Z is independently A or R1;
each A is independently:
14
J is a single bond or CH(Y);
X is D or R2-D;
Y is H, alkyl, or R3-D;
D is OH, SH, SR4, or NR4R5;
each R1 is independently C3-8 alkylene;
each R2, R3, R6, and R7 is independently C1-6 alkylene;
R4 is H or lower alkyl;
R5 is H, lower alkyl, or R6-D;
Q is H, lower alkyl, or R7-SR4;
k is an integer from 2 to about 16;
or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.
2. A compound of claim 1, wherein each A is independently:
15
3. A compound of claim 1, wherein each A is independently:
16
4. A compound of claim 2, wherein Y is H or R3-D.
5. A compound of claim 4, wherein Y is H.
6. A compound of claim 4, wherein Y is R3-D.
7. A compound of claim 5, wherein X is D.
8. A compound of claim 5, wherein X is R2-D.
9. A compound of claim 6, wherein X is D.
10. A compound of claim 6, wherein X is R2-D.
11. A compound of claim 2, wherein k is an integer from 2 to 8.
12. A compound of claim 2, wherein k is an integer from 9 to about 16.
13. A compound of claim 2, wherein k is an integer from 9 to 12.
14. A compound of claim 2, wherein k is 2.
15. A compound of claim 2, wherein k is 3.
16. A compound of claim 2, wherein k is 4.
17. A compound of claim 2, wherein k is 5.
18. A compound of claim 2, wherein k is 6.
19. A compound of claim 2, wherein k is 7.
20. A compound of claim 2, wherein k is 8.
21. A compound of claim 2, wherein:
k is the integer 2;
each R1 is butylene;
X is D, D is-NR4R5, R4 is H, and R5 is ethyl; and
Q is ethyl.
22. A compound of claim 2, wherein:
k is the integer 8;
each R1 is butylene;
X is D, D is-NR4R5, R4 is H, and R5 is ethyl; and
Q is ethyl.
23. A compound of claim 2, wherein:
k is the integer 2;
each R1 is butylene;
X is D, and D is SH; and
Q is ethyl.
24. A compound of claim 2, wherein:
k is the integer 4;
each R1 is butylene;
X is D, and D is SH; and
Q is ethyl.
25. A compound of claim 2, wherein:
k is the integer 6;
each R1 is butylene;
X is D, and D is SH; and
Q is ethyl.
26. A compound of claim 2, wherein:
k is the integer 8;
each R1 is butylene;
X is D, and D is SH; and
Q is ethyl.
27. A compound of claim 2, wherein:
k is the integer 4;
each R1 is butylene;
X is D, D is NR4R5, R4 is H, and R5 is methyl; and
Q is ethyl.
28. A compound of claim 4 wherein Q is H or lower alkyl.
29. A compound of claim 3, wherein Y is H or R3-D.
30. A compound of claim 29, wherein Y is H.
31. A compound of claim 29, wherein Y is R3-D.
32. A compound of claim 30, wherein X is D.
33. A compound of claim 30, wherein X is R2-D.
34. A compound of claim 31, wherein X is D.
35. A compound of claim 31, wherein X is R2-D.
36. A compound of claim 3, wherein k is an integer from 2 to 8.
37. A compound of claim 3, wherein k is an integer from 9 to about 16.
38. A compound of claim 3, wherein k is an integer from 9 to 12.
39. A compound of claim 3, wherein k is 2.
40. A compound of claim 3, wherein k is 3.
41. A compound of claim 3, wherein k is 4.
42. A compound of claim 3, wherein k is 5.
43. A compound of claim 3, wherein k is 6.
44. A compound of claim 3, wherein k is 7.
45. A compound of claim 3, wherein k is 8.
46. A compound of claim 29 wherein Q is H or lower alkyl.
47. A compound of claim 3 wherein J is a single bond.
48. A compound of claim 3 wherein J is CH(Y).
49. A pharmaceutical preparation for reducing or preventing hair loss, dermatitis, mucositis or gastrointestinal distress caused by treatment with a chemotherapeutic agent or radiation therapy, which comprises at least one compound of Formula I and a topical delivery vehicle for locally delivering the compound to dermal or mucosal cells of skin, scalp, mouth, nasoesophageal, gastrointestinal or urogenital system, wherein Formula I is
17
wherein:
each Z is independently A or R1;
each A is independently:
18
J is a single bond or CH(Y);
X is D or R2-D;
Y is H, alkyl, or R3-D;
D is OH, SH, SR4, or NR4R5;
each R1 is independently C3-8 alkylene;
each R2, R3, R6, and R7 is independently C1-6 alkylene;
R4 is H or lower alkyl;
R5 is H, lower alkyl, or R6-D;
Q is H, lower alkyl, or R7SR4;
k is an integer from 2 to about 16;
or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.
50. The pharmaceutical preparation of claim 49, which further comprises at least one other agent that reduces or prevents hair loss, dermatitis, mucositis or gastrointestinal distress caused by treatment with a chemotherapeutic agent or radiation therapy.
51. The pharmaceutical preparation of claim 50, wherein the other agent is an anti-proliferative agent.
52. The pharmaceutical preparation of claim 50, wherein the other agent is a chemoprotective inducing agent.
53. The pharmaceutical preparation of claim 50, wherein the other agent is a free radical scavenger.
54. The pharmaceutical preparation of claim 49, wherein the topical delivery vehicle comprises one or more of liposomes, lipid droplet emulsions, oils, aqueous emulsions of polyoxyethylene ethers, aqueous alcohol mixtures, aqueous ethanol mixtures containing propylene glycol, aqueous ethanol mixtures containing phosphatidyl choline, lysophosphatidyl choline and triglycerides, xanthan gum in aqueous buffer, hydroxypropymethylcellulose in aqueous buffer or aqueous alcohol mixtures, diethylene glycol monoethyl ether in aqueous buffer, and biodegradable microparticles.
55. The pharmaceutical preparation of claim 54, formulated for topical delivery to skin or hair follicles, wherein the delivery vehicle comprises an aqueous alcohol mixture.
56. The pharmaceutical preparation of claim 55, wherein the delivery vehicle further comprises propylene glycol.
57. The pharmaceutical preparation of claim 56, formulated as a cream, lotion, ointment or gel.
58. The pharmaceutical preparation of claim 54, formulated for topical delivery to the oral cavity or naso-esophageal passages, wherein the delivery vehicle comprises a mucoadhesive substance.
59. The pharmaceutical preparation of claim 58, formulated as an aerosol, oral rinse, ointment or gel.
60. The pharmaceutical preparation of claim 54, formulated for vaginal or rectal delivery, wherein the delivery vehicle comprises a mucoadhesive substance.
61. The pharmaceutical preparation of claim 60, formulated as a cream, ointment, lotion, gel, foam or suppository.
62. The pharmaceutical preparation of claim 54, formulated for topical delivery to the gastrointestinal tract, wherein the delivery vehicle comprises one or more of nonionic liposomes and mucoadhesive substances.
63. The pharmaceutical preparation of claim 62, formulated as a liquid for coating the surface of the gastrointestinal tract.
64. A method for reducing or preventing hair loss dermatitis, mucositis or gastrointestinal distress in a patient undergoing treatment with a chemotherapeutic agent or radiation therapy, which comprises administering to the patient a prophylactically or therapeutically effective amount of a pharmaceutical preparation comprising at least one compound of Formula I and a topical delivery vehicle for locally delivering the compound to dermal or mucosal cells of skin, scalp, mouth, nasoesophageal, gastrointestinal or urogenital system, wherein Formula I is:
19
wherein:
each Z is independently A or R1;
each A is independently:
20
J is a single bond or CH(Y);
X is D or R2-D;
Y is H, alkyl, or R3-D;
D is OH, SH, SR4, or NR4R5;
each R1 is independently C3-8 alkylene;
each R2, R3, R1, and R7 is independently C1-6 alkylene;
R4 is H or lower alkyl;
R5 is H, lower alkyl, or R6-D;
Q is H, lower alkyl, or R7SR4;
k is an integer from 2 to about 16;
or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt thereof.
65. The method of claim 64, wherein the pharmaceutical preparation is administered beginning at least one day prior to chemotherapy or radiation therapy.
66. The method of claim 65, wherein the pharmaceutical preparation is administered beginning at least five days prior to chemotherapy or radiation therapy.
67. The method of claim 64, wherein the pharmaceutical preparation is administered after initiation of chemotherapy or radiation therapy.
68. The method of claim 64, wherein the pharmaceutical preparation is administered throughout a course of chemotherapy or radiation therapy.
69. The method of claim 64, wherein the pharmaceutical preparation is administered following termination of a course of chemotherapy or radiation therapy.
70. The method of claim 64, which further comprises administering to the patient at least one other agent that reduces or prevents hair loss, dermatitis, mucositis or gastrointestinal distress caused by treatment with a chemotherapeutic agent or radiation therapy.
71. The pharmaceutical preparation of claim 70, wherein the other agent is an anti-proliferative agent.
72. The pharmaceutical preparation of claim 70, wherein the other agent is a chemoprotective inducing agent.
73. The pharmaceutical preparation of claim 70, wherein the other agent is a free radical scavenger.
74. A method of treating cancer that increases a patient’s tolerance to high doses of a chemotherapeutic’agent or radiation therapy, the method comprising:
a) administering the high dose of the chemotherapeutic agent or radiation therapy to the patient; and
b) administering one or more pharmaceutical preparations for reducing or preventing one or more of chemotherapy- or radiation therapy-induced hair loss, dermatitis, mucositis or gastrointestinal distress, in an amount and for a time to reduce or prevent the one or more of the chemotherapy- or radiation therapy-induced hair loss, dermatitis, mucositis or gastrointestinal distress, thereby increasing the patient’s tolerance to the high dose of the chemotherapeutic agent or radiation therapy, wherein the pharmaceutical preparation comprises compound of Formula I and a topical delivery vehicle for locally delivering the compound to dermal or mucosal cells of skin, scalp, mouth, nasoesophageal, gastrointestinal or urogenital system, wherein Formula I is:
21
wherein:
each Z is independently A or R1;
each A is independently:
22
J is a single bond or CH(Y);
X is D or R2-D;
Y is H, alkyl, or R3-D;
D is OH, SH, SR4, or NR4R5;
each R1 is independently C3-8 alkylene;
each R2, R3, R6, and R7 is independently C1-6 alkylene;
R4 is H or lower alkyl;
R5 is H, lower alkyl, or R6-D;
Q is H, lower alkyl, or R7SR4;
k is an integer from 2 to about 16;
or a stereoisomer, prodrug, pharmaceutically acceptable salt, or mono or polyprotonated acid salt 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 computer system, comprising:
a plurality of computers including a first computer, a second computer, and a third computer; and
a storage device coupled to the plurality of computers via a network,
the first computer including a first interface coupled to the network, a first processor coupled to the first interface, and a first memory coupled to the first processor,
the second computer including a second interface coupled to the network, a second processor coupled to the second interface, and a second memory coupled to the second processor,
the third computer including a third interface coupled to the network, a third processor coupled to the third interface, and a third memory coupled to the third processor, wherein:
the first computer is configured to:
execute, upon reception of an access request to a storage area of the storage device from a client computer coupled to the plurality of computers, the requested access; and
transmit to the client computer a response to the access request;
the second computer is configured to:
judge whether a failure has occurred in the first computer;
obtain load information of the second computer;
obtain load information of the third computer from the third computer; and
transmit a change request to the third computer when the obtained load information satisfies a predetermined condition; and
the third computer is configured to judge whether a failure has occurred in the first computer when the change request is received from the second computer.
2. The computer system according to claim 1, wherein the second computer is further configured to:
transmit the change request to the third computer when a failure occurs in the first computer;
execute, upon reception of an access request to the storage area of the storage device from the client computer, the requested access; and
transmit to the client computer a response to the access request.
3. The computer system according to claim 2, wherein the second computer is further configured to set to the second computer, when it is judged that a failure has occurred in the first computer, an address that is the same as an address set to the first computer as a destination of the access request from the client computer.
4. The computer system according to claim 1, wherein the third computer is further configured to:
judge whether a failure has occurred in the second computer; and
judge whether a failure has occurred in the first computer when it is judged that a failure has occurred in the second computer.
5. The computer system according to claim 1, wherein the second computer is further configured to compare the load information of the third computer with the load information of the second computer, and judge that the obtained load information satisfies the predetermined condition when a load of the third computer is smaller than a load of the second computer.
6. The computer system according to claim 5, wherein:
the plurality of computers further include a fourth computer,
the fourth computer including a fourth interface coupled to the network, a fourth processor coupled to the fourth interface, and a fourth memory coupled to the fourth processor;
the second computer is further configured to:
obtain load information of the fourth computer from the fourth computer;
compare the load information of the fourth computer with the load information of the third computer; and
transmit the change request to the third computer when it is judged that the load of the third computer is smaller than a load of the fourth computer and the load of the third computer is smaller than the load of the second computer; and
the fourth computer is configured to judge whether a failure has occurred in the first computer upon reception of the change request from the second computer.
7. The computer system according to claim 6, wherein:
the second computer is further configured to transmit, when it is judged that the load of the third computer is smaller than the load of the fourth computer, priority information containing information for identifying the third computer to the third computer and the fourth computer; and
the third computer is further configured to:
judge whether a failure has occurred in the second computer; and
judge whether a failure has occurred in the first computer when it is judged that a failure has occurred in the second computer and the last priority information received from the second computer contains the information for identifying the third computer.
8. The computer system according to claim 7, wherein;
the first computer is further configured to transmit a predetermined signal at a predetermined timing;
the second computer is further configured to:
judge that a failure has occurred in the first computer when the predetermined signal cannot be received at the predetermined timing; and
obtain the load information of the third computer and the load information of the fourth computer by transmitting a load information acquisition request to the third computer and the fourth computer at a predetermined timing and receiving a response containing the load information from the third computer and the fourth computer; and
the third computer is further configured to judge that a failure has occurred in the second computer when the load information acquisition request cannot be received at the predetermined timing.
9. The computer system according to claim 1, further comprising, as one of the plurality of computers, a fourth computer including a fourth interface coupled to the network, a fourth processor coupled to the fourth interface, and a fourth memory coupled to the fourth processor,
wherein the fourth computer is configured to:
transmit load information of the fourth computer to the second computer; and
judge, upon reception of the change request from the second computer, whether a failure has occurred in the first computer.
10. The computer system according to claim 1, wherein:
the first computer provides a first service that is provided by responding to the access request made with respect to a first storage area of the storage device by a first user;
the second computer is further configured to:
transmit a first failure monitor request to the first computer providing the first service; and
judge that a failure has occurred in the first computer when a response to the first failure monitor request cannot be received from the first computer at a predetermined timing; and
when one of the plurality of computers receives an instruction to provide a second service that is provided by responding to the access request made with respect to a second storage area of the storage device by a second user, the one of the plurality of computers that has received the instruction is configured to:
transmit a second failure monitor request to at least one of the plurality of computers providing the second service;
obtain load information of at least one computer among the plurality of computers;
transmit, when a response to the second failure monitor request cannot be received at a predetermined timing, the change request to a computer having the smallest load among the at least one computer; and
provide the second service.
11. The computer system according to claim 1, wherein:
the load information of each of the plurality of computers contains a value indicating a load of each of the plurality of computers; and
the value indicating the load of each of the plurality of computers includes at least one of a usage ratio of the processor included in each of the plurality of computers, a usage ratio of the memory included in each of the plurality of computers, a usage ratio of the network used by each of the plurality of computers, the number of times each of the plurality of computers accesses the storage device, and the number of processes operated in each of the plurality of computers.
12. A control method in a computer system including:
a plurality of computers including a first computer, a second computer, and a third computer; and
a storage device coupled to the plurality of computers via a network,
the first computer including a first interface coupled to the network, a first processor coupled to the first interface, and a first memory coupled to the first processor,
the second computer including a second interface coupled to the network, a second processor coupled to the second interface, and a second memory coupled to the second processor,
the third computer including a third interface coupled to the network, a third processor coupled to the third interface, and a third memory coupled to the third processor,
the method comprising the steps of:
executing, by the first computer, upon reception of an access request to a storage area of the storage device from a client computer coupled to the plurality of computers, the requested access;
transmitting, by the first computer, a response to the access request to the client computer;
judging, by the second computer, whether a failure has occurred in the first computer;
obtaining, by the second computer, load information of the second computer;
obtaining, by the second computer, load information of the third computer from the third computer;
judging, by the second computer, whether the obtained load information satisfies a predetermined condition;
transmitting, by the second computer, a change request to the third computer when the obtained load information satisfies the predetermined condition; and
judging, by the third computer, whether a failure has occurred in the first computer when the change request is received from the second computer.
13. The method according to claim 12, further comprising the steps of:
transmitting, by the second computer, the change request to the third computer when a failure occurs in the first computer;
setting, by the second computer, to the second computer, when a failure occurs in the first computer, an address that is the same as an address set to the first computer as a destination of the access request from the client computer;
executing, by the second computer, upon reception of an access request with the address set to the second computer as the destination, the requested access; and
transmitting, by the second computer, a response to the access request to the client computer.
14. The method according to claim 12, further comprising the steps of:
judging, by the third computer, whether a failure has occurred in the second computer; and
judging, by the third computer, when it is judged that a failure has occurred in the second computer, whether a failure has occurred in the first computer.
15. The method according to claim 12, wherein the step of judging, by the second computer, whether the obtained load information satisfies the predetermined condition includes comparing the load information of the third computer and the load information of the second computer and judging that the obtained load information satisfies the predetermined condition when it is judged that a load of the third computer is smaller than a load of the second computer.
16. The method according to claim 15, wherein:
the plurality of computers further include a fourth computer,
the fourth computer including a fourth interface coupled to the network, a fourth processor coupled to the fourth interface, and a fourth memory coupled to the fourth processor;
the method further comprises the steps of:
obtaining, by the second computer, load information of the fourth computer from the fourth computer; and
comparing, by the second computer, the load information of the fourth computer with the load information of the third computer; and
the step of transmitting, by the second computer, the change request to the third computer is executed when it is judged that the load of the third computer is smaller than a load of the fourth computer and the load of the third computer is smaller than the load of the second computer.
17. The method according to claim 16, further comprising the steps of:
transmitting, by the second computer, when it is judged that the load of the third computer is smaller than the load of the fourth computer, priority information containing information for identifying the third computer to the third computer and the fourth computer;
judging, by the third computer, whether a failure has occurred in the second computer; and
judging, by the third computer, whether a failure has occurred in the first computer when it is judged that a failure has occurred in the second computer and the last priority information received from the second computer contains the information for identifying the third computer.
18. The method according to claim 12, further comprising the step of, when the computer system further includes as one of the plurality of computers a fourth computer having a fourth interface coupled to the network, a fourth processor coupled to the fourth interface, and a fourth memory coupled to the fourth processor, transmitting, by the fourth computer, load information of the fourth computer to the second computer.
19. The method according to claim 12, wherein:
the first computer provides a first service that is provided by responding to the access request made with respect to a first storage area of the storage device by a first user; and
the method further comprises the steps of:
transmitting, by the second computer, a first failure monitor request to the first computer providing the first service;
judging, by the second computer, that a failure has occurred in the first computer when the second computer cannot receive a response to the first failure monitor request from the first computer at a predetermined timing;
transmitting, when one of the plurality of computers receives an instruction to provide a second service that is provided by responding to the access request made with respect to a second storage area of the storage device by a second user, by the one of the plurality of computers that has received the instruction, a second failure monitor request to at least one of the plurality of computers providing the second service;
obtaining, by the one of the plurality of computers that has received the instruction, load information of at least one computer among the plurality of computers;
transmitting, by the one of the plurality of computers that has received the instruction, when the one of the plurality of computers that has received the instruction cannot receive a response to the second failure monitor request at a predetermined timing, the change request to a computer having the smallest load among the at least one computer; and
providing, by the one of the plurality of computers that has received the instruction, the second service.
20. A computer system, comprising:
a plurality of computers including a first computer, a second computer, a third computer, and a fourth computer; and
a storage device coupled to the plurality of computers via a network,
the first computer including a first interface coupled to the network, a first processor coupled to the first interface, and a first memory coupled to the first processor,
the second computer including a second interface coupled to the network, a second processor coupled to the second interface, and a second memory coupled to the second processor,
the third computer including a third interface coupled to the network, a third processor coupled to the third interface, and a third memory coupled to the third processor,
the fourth computer including a fourth interface coupled to the network, a fourth processor coupled to the fourth interface, and a fourth memory coupled to the fourth processor, wherein:
the first computer is configured to:
provide a first service of executing, upon reception of an access request to a storage area of the storage device from a first user of a client computer coupled to the plurality of computers, the requested access, and transmitting to the client computer a response to the access request; and
transmit, upon reception of a first failure monitor request to the first computer providing the first service from the second computer, a response to the first failure monitor request to the second computer;
the second computer is configured to:
judge that a failure has occurred in the first computer when the response to the first failure monitor request cannot be received at a predetermined timing;
obtain load information of the second computer;
obtain load information of the third computer and load information of the fourth computer by transmitting a load information acquisition request to the third computer and the fourth computer at a predetermined timing and receiving a response containing the load information from the third computer and the fourth computer;
compare the load information of the fourth computer with the load information of the third computer;
compare the load information of the third computer with the load information of the second computer when it is judged that a load of the third computer is smaller than a load of the fourth computer;
transmit a change request to the third computer when it is judged that the load of the third computer is smaller than a load of the second computer;
transmit, when it is judged that the load of the third computer is smaller than the load of the fourth computer, priority information containing information for identifying the third computer to the third computer and the fourth computer;
set, when it is judged that a failure has occurred in the first computer, an address same as an address set as a destination of the access request from the client computer to the second computer;
execute, upon reception of an access request with the set address as the destination, the requested access; and
transmit a response to the access request to the client computer;
the third computer is configured to:
transmit the load information of the third computer to the second computer;
judge whether a failure has occurred in the first computer when the change request is received from the second computer;
judge that a failure has occurred in the second computer when the load information acquisition request cannot be received at the predetermined timing; and
judge whether a failure has occurred in the first computer when it is judged that a failure has occurred in the second computer and the last priority information received from the second computer contains the information for identifying the third computer;
the fourth computer is configured to:
transmit the load information of the fourth computer to the second computer; and
judge whether a failure has occurred in the first computer when the change request is received from the second computer;
when the computer system further includes as one of the plurality of computers a fifth computer having a fifth interface coupled to the network, a fifth processor coupled to the fifth interface, and a fifth memory coupled to the fifth processor, the fifth computer is configured to:
transmit load information of the fifth computer to the second computer; and
judge whether a failure has occurred in the first computer when the change request is received from the second computer;
when one of the plurality of computers receives an instruction to provide a second service that is provided by responding to the access request made with respect to a second storage area of the storage device by a second user, the one of the plurality of computers that has received the instruction is configured to:
transmit a second failure monitor request to at least one of the plurality of computers providing the second service;
obtain load information of at least one computer among the plurality of computers;
transmit, when a response to the second failure monitor request cannot be received at a predetermined timing, the change request to a computer having the smallest load among the at least one computer; and
provide the second service;
the load information of each of the plurality of computers contains a value indicating a degree of load of each of the plurality of computers; and
the value indicating the degree of load of each of the plurality of computers includes at least one of a usage ratio of the processor included in each of the plurality of computers, a usage ratio of the memory included in each of the plurality of computers, a usage ratio of the network used by each of the plurality of computers, the number of times each of the plurality of computers accesses the storage device, and the number of processes operated in each of the plurality of computers.