1. A method for monitoring tissue undergoing ablation, the method comprising:
transmitting microwave energy from a power source to a microwave antenna to form a tissue ablation zone;
monitoring reflected power associated with the microwave antenna to generate a reflected power signal;
calculating a derivative indicative of rise and fall portions of the reflected power signal, wherein when the derivative is taken during a rise portion of the reflected power signal the measured reflected power is assigned a positive value and when the derivative is taken during a fall portion of the reflected power signal the measured reflected power is assigned a negative value, the positive and negative values of the reflected power signal indicating when the microwave antenna and tissue in a near field of the ablation zone are approaching a respective steady-state condition or an impedance match between the microwave antenna and tissue in the near field;
communicating a control signal to the power source when a predetermined reflected power is reached at the microwave antenna; and
adjusting the amount of microwave energy from the power source to the microwave antenna.
2. The method according to claim 1, further comprising:
accessing at least one data look-up table including data pertaining to a control curve varying over time and being representative of at least one electrical parameter associated with the microwave antenna; and
generating a signal when a predetermined threshold value of the at least one electrical parameter is corresponding to the radius of the ablation zone.
3. The method according to claim 2, wherein the at least one electrical parameter is selected from the group consisting of impedance, power, voltage and current.
4. The method according to claim 3, further comprising correlating a reflected signal generated by the power source associated with the microwave antenna during transmission of microwave energy to the microwave antenna when the microwave antenna is in a near field state with the tissue ablation zone.
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 for treating cancer in a subject comprising administering an effective amount of a composition comprising one or more Thymidylate synthase inhibitor, wherein said one or more Thymidylate synthase inhibitor is a compound, or analog or derivative thereof, selected from:
wherein
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivative;
Hal represents a halogen group producing respective fluoro, chloro, bromo, and iodo; and
L1 and L2 represent linkage bridging the two carbons at the specified position surrounded by parentheses and is C1-C5 alkylene, C2-C5 alkenylene, amidino or ureido type of linkage.
2. The method of claim 1, wherein the one or more Thymidylate synthase inhibitor is selective for cancer cells.
3. The method of claim 1, wherein the one or more Thymidylate synthase inhibitor is a compound selected from the group consisting of:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl;
and derivative and analogs or derivatives of said compounds.
4. The method of claim 1, wherein the method further comprises administering radiation therapy andor at least one additional anti-cancer agent.
5. The method of claim 4, wherein the anti-cancer agent is a chemotherapeutic agent selected from anthracyclines, platinum-based chemotherapy drugs, pyrimidine analogues, biologic agents, kinase inhibitors, alkylating agents, or a combination thereof.
6. The method of claim 5, wherein the chemotherapeutic agent is:
a) an anthracycline selected from doxorubicin, epirubicin, daunorubicin, aclarubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin, carminomycin or detorubicin;
b) a platinum-based chemotherapy drug selected from carboplatin, cisplatin, nedaplatin, oxaliplatin, triplatin tetranitrate or satraplatin;
c) a pyrimidine analogue selected from 5-fluorouracil (5-FU), cytarabine or floxuridine;
d) an alkylating agent selected from cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan and bendamustine; nitrosourea compounds selected from carmustine, lomustine, semustine and streptozotocin; busulfan; dacarbazine; procarbazine; altretamine; mitozolomide; or temozolomi de;
e) biologic agents selected from epotin, opreleukin, filgrastim, pegfilgrastim, rituximab, trastuzumab, or aldesleukin; or
f) a tyrosine kinase inhibitor selected from the group consisting of sorafenib, sunitinib and imatini b.
7. The method of claim 1, wherein the cancer is acute lymphoblatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia, large cell immunoblastic lymphoma, plasmacytoma, multiple myeloma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, leukemia, brain cancer, lung cancer, central nervous system (CNS) cancer, melanoma, renal cancer, prostate cancer, colon cancer, ovarian cancer, or breast cancer.
8. The method of claim 7, wherein the cancer is triple negative breast cancer.
9. The method of claim 1, wherein the subject is human.
10. A method of reducing the growth, proliferation, or survival of a neoplastic cell comprising contacting the cell with a composition comprising an effective amount of one or more Thymidylate synthase inhibitor compound selected from the group consisting of:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl;
and derivative and analogs or derivatives of said compounds.
11. The method of claim 10, wherein the one or more Thymidylate synthase inhibitor compound is selective for neoplastic cells.
12. The method of claim 10, wherein the one or more Thymidylate synthase inhibitor compound is selected from the group consisting of:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, suiphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl;
and derivative and analogs or derivatives of said compounds.
13. The method of claim 12, wherein the method further comprises administering radiation therapy andor at least one additional anti-cancer agent.
14. The method of claim 13, wherein the anti-cancer agent is a chemotherapeutic agent selected from anthracyclines, platinum-based chemotherapy drugs, pyrimidine analogues, biologic agents, kinase inhibitors, alkylating agents, or a combination thereof.
15. The method of claim 14, wherein the chemotherapeutic agent is:
a) an anthracycline selected from doxorubicin, epirubicin, daunorubicin, aclarubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin, carminomycin or detorubicin;
b) a platinum-based chemotherapy drug selected from carboplatin, cisplatin, nedaplatin, oxaliplatin, triplatin tetranitrate or satraplatin;
c) a pyrimidine analogue selected from 5-fluorouracil (5-FU), cytarabine or floxuridine;
d) an alkylating agent selected from cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan and bendamustine; nitrosourea compounds selected from carmustine, lomustine, semustine and streptozotocin; busulfan; dacarbazine; procarbazine; altretamine; mitozolomide; or temozolomide;
e) biologic agents selected from epotin, opreleukin, filgrastim, pegfilgrastim, rituximab, trastuzumab, or aldesleukin; or
f) a tyrosine kinase inhibitor selected from the group consisting of sorafenib, sunitinib and imatinib.
16. The method of claim 10, wherein the cancer is acute lymphoblatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia, large cell immunoblastic lymphoma, plasmacytoma, multiple myeloma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, leukemia, brain cancer, lung cancer, central nervous system (CNS) cancer, melanoma, renal cancer, prostate cancer, colon cancer, ovarian cancer, or breast cancer.
17. The method of claim 16, wherein the cancer is triple negative breast cancer.
18. The method of claim 10, wherein the subject is human.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, one or more compound selected from the group consisting of:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl;
and derivative and analogs or derivatives of said compounds and, optionally, a chemotherapeutic agent.
20. The pharmaceutical composition of claim 19, wherein the compound is selected from:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl;
and derivative and analogs or derivatives of said compounds.
21. The pharmaceutical composition of claim 20, wherein the chemotherapeutic agent selected from anthracyclines, platinum-based chemotherapy drugs, pyrimidine analogues, kinase inhibitors, alkylating agents, or a combination thereof.
22. The pharmaceutical composition of claim 20, wherein the chemotherapeutic agent is:
a) an anthracycline selected from doxorubicin, epirubicin, daunorubicin, aclarubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin, carminomycin or detorubicin;
b) a platinum-based chemotherapy drug selected from carboplatin, cisplatin, nedaplatin, oxaliplatin, triplatin tetranitrate or satraplatin;
c) a pyrimidine analogue selected from 5-fluorouracil (5-fu), cytarabine or floxuridine;
d) an alkylating agent selected from cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan and bendamustine; nitrosourea compounds selected from carmustine, lomustine, semustine and streptozotocin; busulfan; dacarbazine; procarbazine; altretamine; mitozolomide; or temozolomide;
e) biologic agents selected from epotin, opreleukin, filgrastim, pegfilgrastim, rituximab, trastuzumab, or aldesleukin; or
f) a tyrosine kinase inhibitor selected from the group consisting of sorafenib, sunitinib and imatinib.
23. A method of treating a disease or disorder comprising the administering, to a subject having a disease or disorder responsive to inhibition of Thymidylate synthase, a therapeutically effective amount of one or more compound selected from the group consisting of:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl;
and derivative and analogs or derivatives of said compounds.
24. The method of claim 23, wherein said disease or disorder is associated with excessive activity of Thymidylate synthase.
25. The method of claim 23, wherein said disease or disorder is selected from the group consisting of Paget’s disease of the bone, Paget’s disease of the breast, and extramammary Paget’s disease.
26-30. (canceled)
31. A Thymidylate synthase inhibitor of formula:
wherein:
R1, R3, R4 and R5 are independently, a hydrogen atom, methyl, C1-C5 branched or unbranched alkyl, amino, nitro, amidino, sulpho, sulphonamido, carboxy, cyano, phenyl, thienyl, pyrril, pyrazolyl, imidazolyl, isoxazyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinazolyl, pyridyl, pyrimidyl group, C1-C5 alkenyl, C1-C5 alkylamino, C2-C10 dialkylamino, hydroxy C1-C5 alkyl, carbonyl, C3-C7 cycloalkyl or trifluoromethyl group;
R2 is a hydrogen atom, C1-C5 alkyl, hydroxy, amino, nitro, sulpho, sulphonamido, carboxy, or cyano group;
X is a carbon, nitrogen, oxygen or sulphur atom at the indicated position, producing respective alkyl, alkylamino, alkoxy, sulphaalkyl derivatives;
Y is a carbon, nitrogen or oxygen atom at the indicated position, producing respective alkyl alkylamino, alkoxy derivatives;
and derivative and analogs or derivatives of said compounds.