TEXAPHYRIN DERIVATIVES FOR MANGANESE CHEMOTHERAPY, PHOTOACOUSTIC IMAGING, AND PHOTOTHERMAL THERAPY
20250034158 ยท 2025-01-30
Inventors
- Jonathan L. Sessler (Austin, TX)
- Adam C. SEDGWICK (Austin, TX, US)
- Gregory Thiabaud (Austin, TX)
- Jonathan Arambula (Austin, TX)
Cpc classification
C07D487/22
CHEMISTRY; METALLURGY
A61K41/0052
HUMAN NECESSITIES
A61K49/221
HUMAN NECESSITIES
International classification
C07D487/22
CHEMISTRY; METALLURGY
A61K31/555
HUMAN NECESSITIES
A61K41/00
HUMAN NECESSITIES
Abstract
The present disclosure relates to manganese containing texaphyrin compounds of the formula (I). Wherein the variables are as described herein. The present disclosure also provides pharmaceutical compositions of the compounds. Also, provided herein are methods of using the compounds in the treatment of cancer including platinum resistant cancer.
##STR00001##
Claims
1. A compound of the formula: ##STR00070## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00071## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6), or ##STR00072## wherein m is 1-8 and R.sub.b is hydroxy, alkoxy.sub.(C6), substituted alkoxy.sub.(C6), alkylamino.sub.(C6), substituted alkylamino.sub.(C6), dialkylamino.sub.(C6), substituted dialkylamino.sub.(C6), or a sugar moiety; A.sub.1 and A.sub.2 are each hydrogen, halo, hydroxy, alkyl.sub.(C8), substituted alkyl.sub.(C8), aryl.sub.(C8), or substituted aryl.sub.(C8); Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently hydrogen, halo, hydroxy, alkyl.sub.(C8), or substituted alkyl.sub.(C8); X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof, or a platinum(IV) chelating group; provided at least one of X.sub.1-X.sub.6 is a platinum(IV) chelating group, wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00073## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00074## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; L.sub.1 is a monovalent anionic group; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 further defined as: ##STR00075## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00076## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6), or ##STR00077## wherein m is 1-8 and R.sub.b is hydroxy, alkoxy.sub.(C6), substituted alkoxy.sub.(C6), alkylamino.sub.(C6), substituted alkylamino.sub.(C6), dialkylamino.sub.(C6), substituted dialkylamino.sub.(C6), or a sugar moiety; A.sub.1 and A.sub.2 are each hydrogen, halo, hydroxy, alkyl.sub.(C8), substituted alkyl.sub.(C8), aryl.sub.(C8), or substituted aryl.sub.(C8); X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof, or a platinum(IV) chelating group; provided at least one of X.sub.1-X.sub.6 is a platinum(IV) chelating group, wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00078## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00079## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; L.sub.1 is a monovalent anionic group; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 further defined as: ##STR00080## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00081## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6), or ##STR00082## wherein m is 1-8 and R.sub.b is hydroxy, alkoxy.sub.(C6), substituted alkoxy.sub.(C6), alkylamino.sub.(C6), substituted alkylamino.sub.(C6), dialkylamino.sub.(C6), substituted dialkylamino.sub.(C6), or a sugar moiety; X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof, or a platinum(IV) chelating group; provided at least one of X.sub.1-X.sub.6 is a platinum(IV) chelating group, wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00083## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00084## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; L.sub.1 is a monovalent anionic group; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 further defined as: ##STR00085## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00086## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof, or a platinum(IV) chelating group; provided at least one of X.sub.1-X.sub.6 is a platinum(IV) chelating group, wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00087## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00088## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; L.sub.1 is a monovalent anionic group; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 further defined as: ##STR00089## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00090## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); X.sub.1, X.sub.3, X.sub.4, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof; X.sub.2 and X.sub.5 are each independently alkyl.sub.(C8), substituted alkyl.sub.(C8), a platinum(IV) chelating group; provided either X.sub.2 or X.sub.5 is a platinum(IV) chelating group, wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00091## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00092## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; and L.sub.1 is a monovalent anionic group; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 further defined as: ##STR00093## wherein: R.sub.a and R.sub.a are each independently hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); o and p are each independent 1, 2, 3, or 4; X.sub.1, X.sub.3, X.sub.4, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof; X.sub.2 and X.sub.5 are each independently alkyl.sub.(C8), substituted alkyl.sub.(C8), a platinum(IV) chelating group; provided either X.sub.2 or X.sub.5 is a platinum(IV) chelating group, wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00094## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00095## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; and L.sub.1 is a monovalent anionic group; or a pharmaceutically acceptable salt thereof.
7.-26. (canceled)
27. The compound of claim 1, wherein X.sub.1, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each alkyl.sub.(C8) or substituted alkyl.sub.(C8).
28. (canceled)
29. (canceled)
30. The compound of claim 1, wherein X.sub.2 is a platinum(IV) chelating group.
31. The compound of claim 1, wherein A.sub.3 is alkanediyl.sub.(C8), Y.sub.5 is NR.sub.dC(O), and A.sub.4 is alkanediyl.sub.(C8).
32.-38. (canceled)
39. The compound of claim 1, wherein L.sub.2 is halide, or ammonia, or L.sub.2 and L.sub.3 are taken together and are diaminocycloalkane.sub.(C18) or substituted diaminocycloalkane.sub.(C18), or L.sub.2 and L.sub.3 are taken together and are alkyldicarboxylate.sub.(C18) or substituted alkyldicarboxylate.sub.(C18), or L.sub.3 is halide or ammonia, or L.sub.4 is halide or ammonia, or L.sub.4 and L.sub.5 are taken together and are diaminocycloalkane.sub.(C18) or substituted diaminocycloalkane.sub.(C18), or L.sub.4 and L.sub.5 are taken together and are alkyldicarboxylate.sub.(C18) or substituted alkyldicarboxylate.sub.(C18), or L.sub.5 is halide or ammonia.
40.-62. (canceled)
63. The compound of claim 1, wherein L.sub.6 is hydroxy, alkylcarboxylate.sub.(C12), substituted alkylcarboxylate.sub.(C12), or halo.
64.-77. (canceled)
78. The compound of claim 1, wherein X.sub.5 is a platinum(IV) chelating group.
79.-120. (canceled)
121. The compound of claim 1, wherein L.sub.1 is nitrate, alkylcarboxylate.sub.(C12), or substituted alkylcarboxylate.sub.(C12).
122.-124. (canceled)
125. The compound of claim 1 further defined as: ##STR00096## ##STR00097## ##STR00098## wherein: L.sub.1 is a monovalent anionic group; and each L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.
126. The compound of claim 125 further defined as: ##STR00099## ##STR00100## ##STR00101## or a pharmaceutically acceptable salt thereof.
127. A pharmaceutical composition comprising: (A) a compound of claim 1; and (B) an excipient.
128.-131. (canceled)
132. A method of treating a disease comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.
133. The method of claim 132, wherein the disease is cancer.
134.-141. (canceled)
142. A method of obtaining an image of a patient comprising administering to the patient an effective amount of a compound or a pharmaceutical composition comprising a compound of the formula: ##STR00102## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00103## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6), or ##STR00104## wherein m is 1-8 and R.sub.b is hydroxy, alkoxy.sub.(C6), substituted alkoxy.sub.(C6), alkylamino.sub.(C6), substituted alkylamino.sub.(C6), dialkylamino.sub.(C6), substituted dialkylamino.sub.(C6), or a sugar moiety; A.sub.1 and A.sub.2 are each hydrogen, halo, hydroxy, alkyl.sub.(C8), substituted alkyl.sub.(C8), aryl.sub.(C8), or substituted aryl.sub.(C8); Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently hydrogen, halo, hydroxy, alkyl.sub.(C8), or substituted alkyl.sub.(C8); X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof, or a platinum(IV) chelating group; wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00105## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00106## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; L.sub.1 is a monovalent anionic group; and imaging the patient to obtain the image of the patient.
143.-163. (canceled)
164. A method of treating a patient comprising administering a compound of the formula: ##STR00107## wherein: R.sub.1 and R.sub.2 are each independently hydroxy, alkoxy.sub.(C12), substituted alkoxy.sub.(C12), ##STR00108## wherein n is 1-8 and R.sub.a is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6), or ##STR00109## wherein m is 1-8 and R.sub.b is hydroxy, alkoxy.sub.(C6), substituted alkoxy.sub.(C6), alkylamino.sub.(C6), substituted alkylamino.sub.(C6), dialkylamino.sub.(C6), substituted dialkylamino.sub.(C6), or a sugar moiety; A.sub.1 and A.sub.2 are each hydrogen, halo, hydroxy, alkyl.sub.(C8), substituted alkyl.sub.(C8), aryl.sub.(C8), or substituted aryl.sub.(C8); Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently hydrogen, halo, hydroxy, alkyl.sub.(C8), or substituted alkyl.sub.(C8); X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, and X.sub.6 are each independently hydrogen, alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), alkynyl.sub.(C8), aryl.sub.(C8), heteroaryl.sub.(C8), heterocycloalkyl.sub.(C8), or a substituted version thereof, or a platinum(IV) chelating group; wherein the platinum(IV) chelating group is further defined as:
-A.sub.3-Y.sub.5-A.sub.4-R.sub.c wherein: A.sub.3 and A.sub.4 are each independently selected from alkanediyl.sub.(C8), substituted alkanediyl.sub.(C8), or ##STR00110## wherein p is 1-8; Y.sub.5 is C(O)NR.sub.d or NR.sub.dC(O); R.sub.d is hydrogen, alkyl.sub.(C6), or substituted alkyl.sub.(C6); R.sub.c is a group of the formula: ##STR00111## wherein: R.sub.6 is carboxy; L.sub.2-L.sub.5 are each independently selected or two or more may be taken together from ammonia, halide, diaminocycloalkane.sub.(C12), substituted diaminocycloalkane.sub.(C12), alkyldicarboxylate.sub.(C18), or substituted alkyldicarboxylate.sub.(C18); L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; L.sub.1 is a monovalent anionic group; to a patient in need thereof and exposing the patient to an electromagnetic radiation.
165.-179. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0158] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
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DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0201] The present disclosure relates to Mn containing texaphyrin compounds which may be used to image a patient either through photoacoustic imaging or MRI or used to treat the patient using photothermal therapy or delivery a therapeutic compound to a target tissue in the patient. These compounds may have one or more benefits. For example, the compounds may show more favorable photoacoustic imaging properties such as lower photobleaching or greater optical absorbance. Furthermore, the compounds that are described herein may also produce few side effects or generate fewer by-products such as singlet oxygen. Finally, the present compounds may have a more favorable toxicity profile than those known in the art. These and are more benefits of the claimed compounds are described herein.
A. CHEMICAL DEFINITIONS
[0202] When used in the context of a chemical group: hydrogen means H; hydroxy means OH; oxo means O; carbonyl means C(O); carboxy means C(O)OH (also written as COOH or CO.sub.2H); halo means independently F, Cl, Br or I; amino means NH.sub.2; hydroxyamino means NHOH; nitro means NO.sub.2; imino means=NH; cyano means CN; isocyanyl means NCO; azido means N.sub.3; in a monovalent context phosphate means OP(O)(OH).sub.2 or a deprotonated form thereof; in a divalent context phosphate means OP(O)(OH)O or a deprotonated form thereof; mercapto means SH; and thio means S; thiocarbonyl means C(S); sulfonyl means S(O).sub.2; and sulfinyl means S(O).
[0203] In the context of chemical formulas, the symbol means a single bond, = means a double bond, and means triple bond. The symbol --- represents an optional bond, which if present is either single or double. The symbol represents a single bond or a double bond. Thus, the formula
##STR00052##
covers, for example,
##STR00053##
And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol , when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol , when drawn perpendicularly across a bond (e.g.,
##STR00054##
for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol means a single bond where the group attached to the thick end of the wedge is out of the page. The symbol
means a single bond where the group attached to the thick end of the wedge is into the page. The symbol
means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.
[0204] When a variable is depicted as a floating group on a ring system, for example, the group R in the formula:
##STR00055##
then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a variable is depicted as a floating group on a fused ring system, as for example the group R in the formula:
##STR00056##
then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals CH), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter y immediately following the R enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.
[0205] For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: Cn or C=n defines the exact number (n) of carbon atoms in the group/class. Cn defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question. For example, it is understood that the minimum number of carbon atoms in the groups alkyl.sub.(C8), alkanediyl.sub.(C8), heteroaryl.sub.(C8), and acyl.sub.(C8) is one, the minimum number of carbon atoms in the groups alkenyl.sub.(C8), alkynyl.sub.(C8), and heterocycloalkyl.sub.(C8) is two, the minimum number of carbon atoms in the group cycloalkyl.sub.(C8) is three, and the minimum number of carbon atoms in the groups aryl.sub.(C8) and arenediyl.sub.(C8) is six. Cn-n defines both the minimum (n) and maximum number (n) of carbon atoms in the group. Thus, alkyl.sub.(C2-10) designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms C.sub.1-4-alkyl, C1-4-alkyl, alkyl.sub.(C1-4), and alkyl.sub.(C4) are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino.sub.(C12) group; however, it is not an example of a dialkylamino.sub.(C6) group. Likewise, phenylethyl is an example of an aralkyl.sub.(C=8) group. When any of the chemical groups or compound classes defined herein is modified by the term substituted, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl.sub.(C1-6). Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.
[0206] The term saturated when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded. When the term saturated is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.
[0207] The term aliphatic signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).
[0208] The term aromatic signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n+2 electrons in a fully conjugated cyclic system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:
##STR00057##
is also taken to refer to
##STR00058##
Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic system, two non-limiting examples of which are shown below:
##STR00059##
[0209] The term alkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups CH.sub.3 (Me), CH.sub.2CH.sub.3 (Et), CH.sub.2CH.sub.2CH.sub.3 (n-Pr or propyl), CH(CH.sub.3).sub.2 (i-Pr, .sup.iPr or isopropyl), CH.sub.2CH.sub.2CH.sub.2CH.sub.3 (n-Bu), CH(CH.sub.3)CH.sub.2CH.sub.3 (sec-butyl), CH.sub.2CH(CH.sub.3).sub.2 (isobutyl), C(CH.sub.3).sub.3 (tert-butyl, t-butyl, t-Bu or .sup.tBu), and CH.sub.2C(CH.sub.3).sub.3 (neo-pentyl) are non-limiting examples of alkyl groups. The term alkanediyl refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups CH.sub.2 (methylene), CH.sub.2CH.sub.2, CH.sub.2C(CH.sub.3).sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2 are non-limiting examples of alkanediyl groups. The term alkylidene refers to the divalent group CRR in which R and R are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: CH.sub.2, CH(CH.sub.2CH.sub.3), and C(CH.sub.3).sub.2. An alkane refers to the class of compounds having the formula HR, wherein R is alkyl as this term is defined above.
[0210] The term cycloalkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: CH(CH.sub.2).sub.2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term cycloalkanediyl refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The group
##STR00060##
is a non-limiting example of cycloalkanediyl group. A cycloalkane refers to the class of compounds having the formula HR, wherein R is cycloalkyl as this term is defined above.
[0211] The term alkenyl refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: CHCH.sub.2 (vinyl), CHCHCH.sub.3, CHCHCH.sub.2CH.sub.3, CH.sub.2CHCH.sub.2 (allyl), CH.sub.2CHCHCH.sub.3, and CHCHCHCH.sub.2. The term alkenediyl refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups CHCH, CHC(CH.sub.3)CH.sub.2, CHCHCH.sub.2, and CH.sub.2CHCHCH.sub.2 are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms alkene and olefin are synonymous and refer to the class of compounds having the formula HR, wherein R is alkenyl as this term is defined above. Similarly, the terms terminal alkene and -olefin are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.
[0212] The term alkynyl refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups CCH, CCCH.sub.3, and CH.sub.2CCCH.sub.3 are non-limiting examples of alkynyl groups. An alkyne refers to the class of compounds having the formula HR, wherein R is alkynyl.
[0213] The term aryl refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, C.sub.6H.sub.4CH.sub.2CH.sub.3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term arenediyl refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include:
##STR00061##
An arene refers to the class of compounds having the formula HR, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.
[0214] The term aralkyl refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
[0215] The term heteroaryl refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term N-heteroaryl refers to a heteroaryl group with a nitrogen atom as the point of attachment. A heteroarene refers to the class of compounds having the formula HR, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. The term heteroarenediyl refers to a divalent aromatic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroarenediyl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroarenediyl groups include:
##STR00062##
[0216] The term heterocycloalkyl refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings are fused. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term N-heterocycloalkyl refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group. The term heterocycloalkanediyl refers to a divalent cyclic group, with two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as the two points of attachment, said atoms forming part of one or more ring structure(s) wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings are fused. As used herein, the term heterocycloalkanediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl groups include:
##STR00063##
[0217] The term acyl refers to the group C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, CHO, C(O)CH.sub.3 (acetyl, Ac), C(O)CH.sub.2CH.sub.3, C(O)CH(CH.sub.3).sub.2, C(O)CH(CH.sub.2).sub.2, C(O)C.sub.6H.sub.5, and C(O)C.sub.6H.sub.4CH.sub.3 are non-limiting examples of acyl groups. A thioacyl is defined in an analogous manner, except that the oxygen atom of the group C(O)R has been replaced with a sulfur atom, C(S)R. The term aldehyde corresponds to an alkyl group, as defined above, attached to a CHO group.
[0218] The term alkoxy refers to the group OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: OCH.sub.3 (methoxy), OCH.sub.2CH.sub.3 (ethoxy), OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2 (isopropoxy), or OC(CH.sub.3).sub.3 (tert-butoxy). The terms cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, heterocycloalkoxy, and acyloxy, when used without the substituted modifier, refers to groups, defined as OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term alkylthio and acylthio refers to the group SR, in which R is an alkyl and acyl, respectively. The term alcohol corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term ether corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.
[0219] The term alkylamino refers to the group NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: NHCH.sub.3 and NHCH.sub.2CH.sub.3. The term dialkylamino refers to the group NRR, in which R and R can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: N(CH.sub.3).sub.2 and N(CH.sub.3)(CH.sub.2CH.sub.3). The term amido (acylamino), when used without the substituted modifier, refers to the group NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is NHC(O)CH.sub.3. The terms cycloalkylamino, alkenylamino, alkynylamino, arylamino, aralkylamino, heteroarylamino, heterocycloalkylamino, and alkoxyamino when used without the substituted modifier, refers to groups, defined as NHR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non-limiting example of an arylamino group is NHC.sub.6H.sub.5. The terms dicycloalkylamino, dialkenylamino, dialkynylamino, diarylamino, diaralkylamino, diheteroarylamino, diheterocycloalkylamino, and dialkoxyamino, refers to groups, defined as NRR, in which R and R are both cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. Similarly, the term alkyl(cycloalkyl)amino refers to a group defined as NRR, in which R is alkyl and R is cycloalkyl. The amine versions of these compounds are compounds represent the compounds as noted above wherein the group is defined as: NNRR. The term alkylaminodiyl when used without the substituted modifier refers to a divalent unsaturated aliphatic group, with zero, one, or two carbon atoms as points of attachment with the remaining points of attachment being nitrogen atoms, a linear or branched, a linear or branched acyclic structure containing at least one nitrogen atom in the chain, no nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon, nitrogen and hydrogen. The term alkylaminodiyl does not preclude the attachment of one or more additional alkyl groups on the nitrogen atoms to form tertiary amines carbon limit permitting.
[0220] When a chemical group is used with the substituted modifier, one or more hydrogen atom has been replaced, independently at each instance, by OH, F, Cl, Br, I, NH.sub.2, NO.sub.2, CO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3, CN, SH, OCH.sub.3, OCH.sub.2CH.sub.3, C(O)CH.sub.3, NHCH.sub.3, NHCH.sub.2CH.sub.3, N(CH.sub.3).sub.2, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, OC(O)CH.sub.3, NHC(O)CH.sub.3, S(O).sub.2OH, or S(O).sub.2NH.sub.2. For example, the following groups are non-limiting examples of substituted alkyl groups: CH.sub.2OH, CH.sub.2Cl, CF.sub.3, CH.sub.2CN, CH.sub.2C(O)OH, CH.sub.2C(O)OCH.sub.3, CH.sub.2C(O)NH.sub.2, CH.sub.2C(O)CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OC(O)CH.sub.3, CH.sub.2NH.sub.2, CH.sub.2N(CH.sub.3).sub.2, and CH.sub.2CH.sub.2Cl. The term haloalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. F, Cl, Br, or I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, CH.sub.2Cl is a non-limiting example of a haloalkyl. The term fluoroalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups CH.sub.2F, CF.sub.3, and CH.sub.2CF.sub.3 are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups, C(O)CH.sub.2CF.sub.3, CO.sub.2H (carboxyl), CO.sub.2CH.sub.3 (methylcarboxyl), CO.sub.2CH.sub.2CH.sub.3, C(O)NH.sub.2 (carbamoyl), and CON(CH.sub.3).sub.2, are non-limiting examples of substituted acyl groups. The groups NHC(O)OCH.sub.3 and NHC(O)NHCH.sub.3 are non-limiting examples of substituted amido groups.
[0221] The term effective, as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result. Effective amount, Therapeutically effective amount or pharmaceutically effective amount when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to the patient or subject, is sufficient to effect such treatment or prevention of the disease as those terms are defined below.
[0222] An excipient is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as bulking agents, fillers, or diluents when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.
[0223] As used herein, the term IC.sub.50 refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
[0224] As used herein, the term ligand references to a chemical group which coordinates to a metal center through a bond. The bond between the ligand and the metal center in some cases is either an ionic or a coordination bond. A ligand can be monovalent, divalent, trivalent or have a greater valency. In some cases, a ligand may be negatively charged. Some exemplary examples of ligands include, but are not limited to, halide (F.sup., Cl.sup., Br.sup., or I.sup.), a carbonate (CO.sub.3.sup.2), bicarbonate (HCO.sub.3.sup.), hydroxide (.sup.OH), perchlorate (ClO.sub.4.sup.), nitrate (NO.sub.3.sup.), sulfate (SO.sub.4.sup.2), acetate (CH.sub.3CO.sub.2.sup.), trifluoroacetate (CF.sub.3CO.sub.2.sup.), acetylacetonate (CH.sub.3COCHCOCH.sub.3.sup.), trifluorosulfonate (CF.sub.3SO.sub.2.sup.), or phosphate (PO.sub.4.sup.3). A ligand could also be a neutral species that contains a lone pair of electrons. Some examples of neutral ligands include but are not limited to aqua (H.sub.2O) or ammonia (NH.sub.3). Additionally, a neutral ligand can include groups such as an alkylamine or a dialkylamine.
[0225] As used herein, the term patient or subject refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses.
[0226] As generally used herein pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
[0227] Pharmaceutically acceptable salts means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
[0228] Prevention or preventing includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
[0229] Prodrug means a compound that is convertible in vivo metabolically into an active pharmaceutical ingredient of the present invention. The prodrug itself may or may not have activity in its prodrug form. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Non-limiting examples of suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis--hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, and esters of amino acids. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
[0230] A repeat unit is the simplest structural entity of certain materials, for example, frameworks and/or polymers, whether organic, inorganic or metal-organic. In the case of a polymer chain, repeat units are linked together successively along the chain, like the beads of a necklace. For example, in polyethylene, [CH.sub.2CH.sub.2].sub.n, the repeat unit is CH.sub.2CH.sub.2. The subscript n denotes the degree of polymerization, that is, the number of repeat units linked together. When the value for n is left undefined or where n is absent, it simply designates repetition of the formula within the brackets as well as the polymeric nature of the material. The concept of a repeat unit applies equally to where the connectivity between the repeat units extends three dimensionally, such as in metal organic frameworks, modified polymers, thermosetting polymers, etc.
[0231] In the context of this application, selectively means that greater than 50% of the activity of the compound is exhibited in the noted location. On the other hand, preferentially means that greater than 75% of the activity of the compound is exhibited in the noted location.
[0232] A stereoisomer or optical isomer is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. Enantiomers are stereoisomers of a given compound that are mirror images of each other, like left and right hands. Diastereomers are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2.sup.n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that for tetrahedral stereogenic centers the stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase substantially free from other stereoisomers means that the composition contains 15%, more preferably 10%, even more preferably 5%, or most preferably 1% of another stereoisomer(s).
[0233] Treatment or treating includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
[0234] The term unit dose refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.
[0235] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.
B. COMPOUNDS OF THE PRESENT DISCLOSURE
[0236] The compounds of the present disclosure are shown, for example, above, in the summary of the invention section, and in the claims below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & DevelopmentA Guide for Organic Chemists (2012), which is incorporated by reference herein.
[0237] All the compounds of the present disclosure may in some embodiments be used for the prevention and treatment of one or more diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and/or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such unless explicitly stated to the contrary, all the compounds of the present invention are deemed active compounds and therapeutic compounds that are contemplated for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices.
[0238] In some embodiments, the compounds of the present disclosure have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.
[0239] Compounds of the present disclosure may contain one or more asymmetrically substituted carbon or nitrogen atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.
[0240] Chemical formulas used to represent compounds of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.
[0241] In addition, atoms making up the compounds of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include .sup.13C and .sup.14C.
[0242] In some embodiments, compounds of the present disclosure function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the disclosure may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.
[0243] In some embodiments, compounds of the present disclosure exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.
[0244] It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. Where the solvent is water, the complex is known as a hydrate. It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present invention.
C. TEXAPHYRIN COMPOUNDS
[0245] In some aspects, the present disclosure provides compositions and methods comprising a texaphyrin compound with a platinum chelating group directly bound to the macrocycle, wherein the texaphyrin is a macrocycle of the formula:
##STR00064##
wherein: [0246] Y.sub.1-Y.sub.4 are each independently selected from: hydrogen, amino, cyano, halo, hydroxy, or hydroxyamino, [0247] alkyl.sub.(C12), cycloalkyl.sub.(C12), alkenyl.sub.(C12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), aryl.sub.(C12), aralkyl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), acyl.sub.(C12), alkoxy.sub.(C12), acyloxy.sub.(C12), aryloxy.sub.(C12), heteroaryloxy.sub.(C12), heterocycloalkoxy.sub.(C12), amido.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), alkylthio.sub.(C12), arylthio.sub.(C12), alkylsulfinyl.sub.(C12), arylsulfinyl.sub.(C12), alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of any of these groups; or [0248] R.sub.1-R.sub.6 are each independently selected from: hydrogen, amino, cyano, halo, hydroxy, hydroxyamino, or nitro, [0249] alkyl.sub.(C12), cycloalkyl.sub.(C12), alkenyl.sub.(C12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), aryl.sub.(C12), aralkyl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), acyl.sub.(C12), alkoxy.sub.(C12), acyloxy.sub.(C12), aryloxy.sub.(C12), heteroaryloxy.sub.(C12), heterocycloalkoxy.sub.(C12), amido.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; or [0250] a PEG moiety wherein the PEG moiety is of the formula: (OCH.sub.2CH.sub.2).sub.nOR.sub.8; wherein: [0251] n is 1-20; and [0252] R.sub.8 is hydrogen, alkyl.sub.(C8), or substituted alkyl.sub.(C8); or [0253] a platinum(IV) chelating group; [0254] R.sub.7 is hydrogen, [0255] alkyl.sub.(C8), cycloalkyl.sub.(C8), alkenyl.sub.(C8), cycloalkenyl.sub.(C8), alkynyl.sub.(C8), alkoxy.sub.(C8), or a substituted version of any of these groups, or [0256] an amino protecting group; [0257] X.sub.1-X.sub.4 are each independently selected from: hydrogen, amino, cyano, halo, hydroxy, hydroxyamino, or nitro, [0258] alkyl.sub.(C12), cycloalkyl.sub.(C12), alkenyl.sub.(C12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), aryl.sub.(C12), aralkyl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), acyl.sub.(C12), alkoxy.sub.(C12), acyloxy.sub.(C12), aryloxy.sub.(C12), heteroaryloxy.sub.(C12), heterocycloalkoxy.sub.(C12), amido.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; or [0259] a PEG moiety wherein the PEG moiety is of the formula: (OCH.sub.2CH.sub.2).sub.nOR.sub.8; wherein: [0260] n is 1-20; and [0261] R.sub.8 is hydrogen, alkyl.sub.(C8), or substituted alkyl.sub.(C8); or [0262] a platinum(IV) chelating group; [0263] L.sub.1 and L.sub.2 are each independently absent, a neutral ligand, or an anionic ligand; and [0264] M is a manganese ion; [0265] provided that L.sub.1 and L.sub.2 are present or absent in a manner sufficient to balance the charge on the metal ion; [0266] or a pharmaceutically acceptable salt or tautomer thereof.
[0267] In some embodiments, the platinum(IV) chelating group is further defined as:
##STR00065## [0268] wherein: [0269] R.sub.6 is carboxy; [0270] L.sub.2-L.sub.5 are each independently selected from ammonia, halide, alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; [0271] L.sub.6 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate, [0272] alkylamine.sub.(C12), cycloalkylamine.sub.(C12), dialkylamino.sub.(C18), dicycloalkylamine.sub.(C18), arylamine.sub.(C12), diarylamine.sub.(C18), diaminoalkane.sub.(C12), diaminocycloalkane.sub.(C12), diaminoarene.sub.(C12), heteroarene.sub.(C12), alkylcarboxylate.sub.(C12), alkyldicarboxylate.sub.(C18), arylcarboxylate.sub.(C12), aryldicarboxylate.sub.(C18), or a substituted version of any of these groups; and
[0273] Additional non-limiting examples of texaphyrins are taught by U.S. Pat. Nos. 4,935,498, 5,252,270, 5,272,142, 5,292,414, 5,369,101, 5,432,171, 5,439,570, 5,504,205, 5,569,759, 5,583,220, 5,587,463, 5,591,422, 5,633,354, 5,776,925, 5,955,586, 5,994,535, 6,207,660, 7,112,671, 8,410,263, and 10,406,167 which are all incorporated herein by reference. When the term, texaphyrin compound is used herein it can refer to a texaphyrin in both its oxidized and reduced forms, a metallotexaphyrin, or any of these groups. As would be known by a person of skill in the art, texaphyrins are known to undergo oxidation upon complexation of a metal ion. This phenomenon is described in U.S. Pat. No. 5,504,205, Shimanovich, et al., 2001 and Hannah, et al., 2001, all of which are incorporated herein by reference. As this process is linked with the metalation of the texaphyrin compound, these compounds are referenced to herein as an oxidized metallated derivative of the reduced macrocycle formula.
[0274] In some aspects, the present disclosure provides compositions and methods of use of the metallated form of the texaphyrin compound. In some embodiments, the metal of the metallated form is a transition metal. In some embodiments, the metal is a metal ion in the 2+ oxidation state or the 3+ oxidation state. The compounds described herein may contain a manganese atom in the complex. In some aspects, the texaphyrin compound is administered simultaneously with a reducing agent. In some embodiments, the reducing agent is a two electron donor. In some embodiments, the reducing agent is sodium ascorbate, thioredoxin reductase, a platinum(II) ion or complex, or a biological thiol, including but not limited to cysteine, homocysteine, or glutathione. A photoreduction may also be used in conjunction with the texaphyrin compound.
D. HYPERPROLIFERATIVE DISEASES
[0275] While hyperproliferative diseases can be associated with any medical disorder that causes a cell to begin to reproduce uncontrollably, the prototypical example is cancer. One of the key elements of cancer is that the normal apoptotic cycle of the cell is interrupted and thus agents that lead to apoptosis of the cell are important therapeutic agents for treating these diseases. As such, the Mn texaphyrin analogues described in this disclosure may be effective in treating cancers.
[0276] Cancer cells that may be treated with the compounds according to the embodiments include but are not limited to cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, pancreas, testis, tongue, cervix, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. In certain aspects, the tumor may comprise an osteosarcoma, angiosarcoma, rhabdosarcoma, leiomyosarcoma, Ewing sarcoma, glioblastoma, neuroblastoma, or leukemia.
E. PHOTOACOUSTIC IMAGING
[0277] Photoacoustic imaging (PAI) is an emerging biomedical imaging modality based on the photoacoustic effect. In PAI, light pulses (often from a laser) are delivered to a target locus (situs) in or on a sample. Some of the pulse energy is absorbed at the situs and converted into heat. The transient heating causes a corresponding transient thermoelastic expansion of the situs, which produces a corresponding wideband ultrasonic emission from the situs. The generated ultrasonic waves are detected using one or more ultrasonic transducers that convert the detected waves into corresponding electrical pulses that are processed into corresponding images. The optical absorption of light by a biological sample is closely associated with certain physiological properties such as hemoglobin concentration and/or oxygen saturation. As a result, the magnitude of ultrasonic emission (the photoacoustic signal, which is proportional to the local energy deposition) from the situs reveals physiologically specific optical absorption contrast that facilitate formation of 2-D or 3-Dl images of the situs. Blood usually exhibits greater absorption than surrounding tissues, which provides sufficient endogenous contrast to allow PAI of blood vessels and tissues containing same. For example, PAI can produce high-contrast images of breast tumors in situ due to the greater optical absorption by the increased blood supply provided by the body to the tumor. Whereas conventional X-ray mammography and ultrasonography produce images of benign features as well as pathological features, PAI can produce information more specific to the malignant condition, such as enhanced angiogenesis at the tumor site.
[0278] Significant challenges currently limit PAI from widespread clinical use including both in the imaging systems as well as contrast agents. The development of contrast agents has been carried out in order to assist in generating images using PAI. Examples of contrast agents include organic based contrast agents such as cyanine dyes, nanoparticles, polyhydroxy-fullerene and carbon nanotubes. However, the photoacoustic contrast that is achieved using the contrast agents has often been low, resulting in poor spatial resolution of the images. Therefore, the development of new PAI contrast agents could result in useful in making PAI clinically useful.
F. PHOTOTHERMAL THERAPY
[0279] Additionally, photothermal therapy is a technique for treating cancer or related diseases by transferring a substance (photothermal material) capable of absorbing light to generate heat to a lesion site and then irradiating light to generate heat. This photothermal therapy is a method of selectively killing only cancer cells that relies on the fact that cancer cells are typically less resistant to heat than normal cells. Photothermal therapy is currently one of the more extensively researched technologies in the field of cancer treatment. Near-infrared rays are used as light used for photothermal treatment, since the encompass wavelengths that are relatively harmless to normal cells.
[0280] However, one of challenges associated with photothermal treatment is that the photothermal material administered in vivo to absorb light and generate beat may not be cleared out of the body in a timely manner. The field of photothermal treatment often makes use of metal nanoparticles to absorb light and generate heat. However, such inorganic materials are often not smoothly discharged when administered in vivo, potentially posing safety concerns. Therefore, compounds that may be used in photothermal treatments which have improved safety profiles would address an unmet need.
Pharmaceutical Formulations and Routes of Administration
[0281] For administration to a mammal in need of such treatment, the Mn texaphyrin analogues of the present disclosure are ordinarily combined with one or more excipients appropriate to the indicated route of administration. The Mn texaphyrin analogues of the present disclosure may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration. Alternatively, the Mn texaphyrin analogues of the present disclosure may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other excipients and modes of administration are well and widely known in the pharmaceutical art.
[0282] The pharmaceutical compositions useful in the present disclosure may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical carriers and excipients such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
[0283] The Mn texaphyrin analogues of the present disclosure may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, intraperitoneal, etc.). Depending on the route of administration, the novel conjugates may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. They may also be administered by continuous perfusion/infusion of a disease or wound site.
[0284] To administer the therapeutic compound by other than parenteral administration, it may be necessary to coat the Mn texaphyrin analogues of the present disclosure with or co-administer the Mn texaphyrin analogues of the present disclosure with, a material to prevent its inactivation. For example, the therapeutic compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes. Additionally, Trapasol, Travasol, cyclodextrin, and other drug carrier molecules may also be used in combination with the Mn texaphyrin analogues of the present disclosure. It is contemplated that the compounds of the present disclosure may be formulated with a cyclodextrin as a drug carrier using an organic solvent such as dimethylaceamide with a polyethylene glycol and a poloxamer composition in an aqueous sugar solution. In some embodiments, the organic solvent is dimethylsulfoxide, dimethylformamide, dimethylacetamide, or other biologically compatible organic solvents. Additionally, the composition may be diluted with a polyethylene glycol polymer such as PEG100, PEG200, PEG250, PEG400, PEG500, PEG600, PEG750, PEG800, PEG900, PEG1000, PEG2000, PEG2500, PEG3000, or PEG4000. Additionally, the composition may further comprise one or more poloxamer composition wherein the poloxamer contains two hydrophilic polyoxyethylene groups and a hydrophobic polyoxypropylene or a substituted version of these groups. This mixture may be further diluted using an aqueous sugar solution such as 5% aqueous dextrose solution.
[0285] The Mn texaphyrin analogues of the present disclosure may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
[0286] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion are also envisioned. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
[0287] Sterile injectable solutions can be prepared by incorporating Mn texaphyrin analogues of the present disclosure in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
[0288] The Mn texaphyrin analogues of the present disclosure can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the Mn texaphyrin analogues of the present disclosure in such therapeutically useful compositions is such that a suitable dosage will be obtained.
[0289] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of the Mn texaphyrin analogues of the present disclosure calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the Mn texaphyrin analogues of the present disclosure and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient.
[0290] The therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.
[0291] The Mn texaphyrin analogues of the present disclosure describe in this disclosure are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of the Mn texaphyrin analogues of the present disclosure can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in humans, such as the model systems shown in the examples and drawings.
[0292] The actual dosage amount of the Mn texaphyrin analogues of the present disclosure comprising the compounds of the present disclosure administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual physician in the event of any complication.
[0293] In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg/kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference):
HED(mg/kg)=Animal dose(mg/kg)(Animal K.sub.m/Human K.sub.m)
Use of the K.sub.m factors in conversion results in HED values based on body surface area (BSA) rather than only on body mass. K.sub.m values for humans and various animals are well known. For example, the K.sub.m for an average 60 kg human (with a BSA of 1.6 m.sup.2) is 37, whereas a 20 kg child (BSA 0.8 m.sup.2) would have a K.sub.m of 25. K.sub.m for some relevant animal models are also well known, including: mice K.sub.m of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K.sub.m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K.sub.m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K.sub.m of 12 (given a weight of 3 kg and BSA of 0.24).
[0294] Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation.
[0295] An effective amount typically will vary from about 1 mg/kg to about 50 mg/kg, in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). In some particular embodiments, the amount is less than 5,000 mg per day with a range of 10 mg to 4500 mg per day.
[0296] The effective amount may be less than 10 mg/kg/day, less than 50 mg/kg/day, less than 100 mg/kg/day, less than 250 mg/kg/day. It may alternatively be in the range of 1 mg/kg/day to 250 mg/kg/day.
[0297] In other non-limiting examples, a dose may also comprise from about 0.1 mg/kg/body weight, about 1 mg/kg/body weight, about 10 g/kg/body weight, about 50 g/kg/body weight, or more per administration, and any range derivable therein. In non-limiting examples of a derivable range from the numbers listed herein, a range of about 1 mg/kg/body weight to about 50 mg/kg/body weight, about 5 g/kg/body weight to about 10 g/kg/body weight, etc., can be administered, based on the numbers described above.
[0298] In certain embodiments, a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a compound described in the present disclosure. In other embodiments, the compound of the present disclosure may comprise between about 0.25% to about 75% of the weight of the unit, or between about 25% to about 60%, or between about 1% to about 10%, for example, and any range derivable therein.
[0299] Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the agents are administered once a day.
[0300] The compounds may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other embodiments, the invention provides that the agent(s) may take orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agents can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
G. COMBINATION THERAPY
[0301] In addition to being used as a monotherapy, the Mn texaphyrin analogues of the present disclosure may also find use in combination therapies. Effective combination therapy may be achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition includes a Mn texaphyrin analogues and compositions, and the other includes the second agent(s). The other therapeutic modality may be administered before, concurrently with, or following administration of the Mn texaphyrin analogues of the present disclosure. The therapy using the Mn texaphyrin analogues of the present disclosure may precede or follow administration of the other agent(s) by intervals ranging from minutes to weeks. In embodiments where the other agent and the compounds or compositions of the present disclosure are administered separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that each agent would still be able to exert an advantageously combined effect. In such instances, it is contemplated that one would typically administer the Mn texaphyrin analogues of the present disclosure and the other therapeutic agent within about 12-24 hours of each other and, more preferably, within about 6-12 hours of each other, with a delay time of only about 12 hours being most preferred. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.
[0302] It also is conceivable that more than one administration of a Mn texaphyrin analogues of the present disclosure or the other agent will be desired. In this regard, various combinations may be employed. By way of illustration, where the compounds of the present disclosure are A and the other agent is B, the following permutations based on 3 and 4 total administrations are exemplary: [0303] A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/B [0304] A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A [0305] A/A/A/B B/A/A/A A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B
[0306] Other combinations are likewise contemplated. Non-limiting examples of pharmacological agents that may be used in the present invention include any pharmacological agent known to be of benefit in the treatment of a cancer or hyperproliferative disorder or disease. In some embodiments, combinations of the Mn texaphyrin analogues of the present disclosure with a cancer targeting immunotherapy, radiotherapy, chemotherapy, or surgery are contemplated. Also contemplated is a combination of the Mn texaphyrin analogues of the present disclosure with more than one of the above-mentioned methods including more than one type of a specific therapy. In some embodiments, it is contemplated that the immunotherapy is a monoclonal antibody which targets HER2/neu such trastuzumab (Herceptin), alemtuzumab (Sampath), bevacizumab (Avastin), cetuximab (Eribitux), and panitumumab (Vectibix) or conjugated antibodies such as ibritumomab tiuxetan (Zevalin), tositumomab (Bexxar), brentuximab vedotin (Adcetris), ado-trastuzumab emtansine (Kadcyla), or denileukin dititox (Ontak) as well as immune cell targeting antibodies such as ipilimumab (Yervoy), tremelimumab, anti-PD-1, anti-4-1-BB, anti-GITR, anti-TIM3, anti-LAG-3, anti-TIGIT, anti-CTLA-4, or anti-LIGHT. Furthermore, in some embodiments, the texaphyrin-platinum(IV) conjugate the composition of a Mn texaphyrin analogues of the present disclosure are envisioned to be used in combination therapies with dendritic cell-based immunotherapies such as Sipuleucel-T (Provenge) or adoptive T-cell immunotherapies.
[0307] Furthermore, it is contemplated that the methods described herein may be used in combination with a chemotherapeutic agent such as PR-171 (Kyprolis), bortezomib (Velcade), anthracyclines, taxanes, methotrexate, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, vinorelbine, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, Pt(IV) complexes, topotecan, ifosfamide, cyclophosphamide, epirubicin, gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine, pemetrexed, melphalan, capecitabine, oxaliplatin, BRAF inhibitors, and TGF-beta inhibitors. In some embodiments, the combination therapy is designed to target a cancer such as those listed above.
[0308] In some aspects, it is contemplated that the Mn texaphyrin analogues of the present disclosure may be used in conjunction with radiation therapy. Radiotherapy, also called radiation therapy, is the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation deposits energy that injures or destroys cells in the area being treated by damaging their genetic material, making it impossible for these cells to continue to grow. Although radiation damages both cancer cells and normal cells, the latter are able to repair themselves and function properly.
[0309] Radiation therapy used according to the present disclosure may include, but is not limited to, the use of y-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors induce a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 weeks), to single doses of 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
[0310] Additionally, it is contemplated Mn texaphyrin analogues of the present disclosure are used in combination with sonodynamic therapy. The use of texaphyrins in sonodynamic therapy is described in U.S. Pat. No. 6,207,660 incorporated herein by reference. A Mn texaphyrin analogues of the present disclosure is administered before administration of the sonodynamic agent. The compound may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time. Parenteral administration is typical, including by intravenous and interarterial injection. Other common routes of administration can also be employed.
[0311] Ultrasound is generated by a focused array transducer driven by a power amplifier. The transducer can vary in diameter and spherical curvature to allow for variation of the focus of the ultrasonic output. Commercially available therapeutic ultrasound devices may be employed in the practice of the disclosure. The duration and wave frequency, including the type of wave employed may vary, and the preferred duration of treatment will vary from case to case within the judgment of the treating physician. Both progressive wave mode patterns and standing wave patterns have been successful in producing cavitation of diseased tissue. When using progressive waves, the second harmonic can advantageously be superimposed onto the fundamental wave.
[0312] Preferred sonodynamic agents employed in the present disclosure is ultrasound, particularly is low intensity, non-thermal ultrasound, i.e., ultrasound generated within the wavelengths of about 0.1 MHz and 5.0 MHz and at intensities between about 3.0 and 5.0 W/cm.sup.2.
[0313] Furthermore, it is contemplated that the compounds of the present disclosure can be used in combination with photodynamic therapy: By way of example, a texaphyrin is administered in solution containing 2 mg/ml optionally in 5% mannitol, USP. Dosages of about 1.0 or 2.0 mg/kg to about 4.0 or 5.0 mg/kg, preferably 3.0 mg/kg may be employed, up to a maximum tolerated dose that was determined in one study to be 5.2 mg/kg. The texaphyrin is administered by intravenous injection, followed by a waiting period of from as short a time as several minutes or about 3 hours to as long as about 72 or 96 hours (depending on the treatment being effected) to facilitate intracellular uptake and clearance from the plasma and extracellular matrix prior to the administration of photoirradiation.
[0314] The co-administration of a sedative (e.g., benzodiazapenes) and narcotic analgesic are sometimes recommended prior to light treatment along with topical administration of Emla cream (lidocaine, 2.5% and prilocaine, 2.5%) under an occlusive dressing. Other intradermal, subcutaneous and topical anesthetics may also be employed as necessary to reduce discomfort. Subsequent treatments can be provided after approximately 21 days. The treating physician may choose to be particularly cautious in certain circumstances and advise that certain patients avoid bright light for about one week following treatment.
[0315] When employing photodynamic therapy, a target area is treated with light at about 73216.5 nm (full width half max) delivered by LED device or an equivalent light source (e.g., a Quantum Device Qbeam Q BMEDXM-728 Solid State Lighting System, which operates at 728 nm) at an intensity of 75 mW/cm.sup.2 for a total light dose of 150 J/cm.sup.2. The light treatment takes approximately 30 minutes.
[0316] The optimum length of time following texaphyrin administration until light treatment can vary depending on the mode of administration, the form of administration, and the type of target tissue. Typically, the texaphyrin persists for a period of minutes to hours, depending on the texaphyrin, the formulation, the dose, the infusion rate, as well as the type of tissue and tissue size.
[0317] After the photosensitizing texaphyrin has been administered, the tissue being treated is photoirradiated at a wavelength similar to the absorbance of the texaphyrin, usually either about 400-500 nm or about 700-800 nm, more preferably about 450-500 nm or about 710-760 nm, or most preferably about 450-500 nm or about 725-740 nm. The light source may be a laser, a light-emitting diode, or filtered light from, for example, a xenon lamp; and the light may be administered topically, endoscopically, or interstitially (via, e.g., a fiber optic probe). Preferably, the light is administered using a slit-lamp delivery system. The fluence and irradiance during the photoirradiating treatment can vary depending on type of tissue, depth of target tissue, and the amount of overlying fluid or blood. For example, a total light energy of about 100 J/cm.sup.2 can be delivered at a power of 200 mW to 250 mW depending upon the target tissue.
[0318] One aspect of the present invention is that the compounds of the present disclosure can additionally be used to image the localization of the therapeutic agent. The texaphyrin core allows for the use of MRI to determine the location of the compound with the patient and determine the specific location and margin of the tumor to which it has localized. In some aspects, the ability to determine the location of the texaphyrin core may be advantageous for more or additional therapeutic methods such as surgery or radiation therapy.
H. EXAMPLES
[0319] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
Example 1: Synthesis of Compounds
A. Materials and Methods
[0320] Starting materials were purchased from Fisher Scientific or Sigma Aldrich and used without further purification unless otherwise specified. Oxaliplatin (IV) prodrug (1) was synthesized according to our previously reported procedure (1). Indocyanine green (ICG) was purchased from by Dandong Yichuang Pharmaceutical Co., Ltd. Solvents were purified using a solvent purifier system (Vacuum Atmospheres). Analytical RP-HPLC analyses for MMn, MGd and MLu were performed on a Thermo scientific Dionex Ultimate 3000 equipped with a PDA detector. The analytical column was a Syncronis C18 column, 5 m, 4.6250 mm (Thermo Scientific); the mobile phase consisted of an increasing gradient (from 10% to 99% in 20 min) of acetonitrile into water, both containing 0.1% acetic acid. In this case the flow rate was 1.2 mL/min. Texaphyrins were monitored at 254, 470, and 740 nm. MMn, MGd, and MLu were purified on reverse phase-t C18 SPE (Waters Sep-Pak, Waters) columns containing 10 g of C-18 using an increasing gradient of acetonitrile in either 0.1 M ammonium acetate/1% acetic acid aqueous solution or 0.1 M potassium nitrate aqueous solution as the eluent, depending on which counter anion (AcO.sup. or NO.sub.3.sup.) was desired as the ancillary ligand. Mass spectrometric analyses were carried out in The University of Texas at Austin Mass Spectrometry Facility. Low-resolution and high-resolution electro-spray mass spectrometric (ESI-MS) analyses were carried out using Thermo Finnigan LTQ and Qq-FTICR (7 Telsa) instruments, respectively. UV-Vis spectra were recorded using a Varian Cary 5000 spectrophotometer at room temperature. The UV-Vis absorption and fluorescence emission spectra of the resulting solutions were measured by a Varian Cary 500 UV-Vis spectrophotometer and Varian Cary eclipse fluorescence spectrophotometer, respectively. A quartz cuvette with a cell length of 10 mm was used in all UV-Vis and fluorescence studies. The purity of the texaphyrin derivatives, MMnNH.sub.2, Mono-MMn, Bis-MMn, MMn, MLu, and MGd was checked by reverse phase-HPLC before use. For those known compounds, MMn, MLu, and MGd matched previously reported analysis (Brewster et al., 2020). LogP values and the protocol for their determination can be found in the previous report by Brewster et al (2020).
B. Synthesis and Characterizations of MGd, MLu and MMn
[0321] MGd was prepared as described in Sessler et al., 1993. MLu and MMn were synthesized using literature protocols (Blumenkranz et al., 2000; Shimanovich et al., 2001; Sessler et al., 1993). [0322] i.
##STR00066##
[0323] MMn was synthesized according to a previously reported procedure (Shimanovich et al., 2001). Upon reaction completion, MMn was purified via silica column chromatography (DCM/MeOH100/0 to 95/5 then 80/20). Further purification was performed using reverse phase tC18 SPE (Waters Sep-Pak, Waters) columns containing 10 g of the C18 support using an increasing gradient of acetonitrile and 0.1% acetic acid aqueous solution. Final step of purification, Sep-Pak loaded MMn was washed with a 0.1 M potassium nitrate aqueous solution three times followed by a final wash of deionized H.sub.2O. MMn was eluted using MeOH and the solvent was removed in vacuo to afford MMn as a crystalline green solid. [0324] ii.
##STR00067##
[0325] MMn(NH.sub.2) and MMn(NH.sub.2).sub.2 were synthesized following a previously published procedure for MGd(NH.sub.2) derivatives but modified for MMn derivatives (Thiabaud et al., 2020). In brief, MMn and 3 equiv. of each of the reagents (triphenylphosphine, phthalimide and diisopropylazodicarboxylate) in DCM was used to form the corresponding pthalimide derivatives. Upon achieving the desired ratios of intermediates, the reaction was subjected to a short silica column (DCM/MeOH100/0 to 95/5 then 80/20). Phthalimide deprotection using methylamine (40% in water) was used to achieve a mixture of mono-, bis-NH.sub.2, and unreacted MMn. These three compounds were separated on reverse phase silica gel chromatography column using reverse phase tC18 SPE with an increasing gradient of acetonitrile and 0.1% acetic acid aqueous solution. Final step of purification, Sep-Pak loaded MMn derivative was washed with a 0.1 M potassium nitrate aqueous solution three times followed by a final wash of deionized H.sub.2O. MMn derivative was eluted using MeOH and the solvent was removed in vacuo to afford the desired product as a crystalline green solid. [0326] iii.
##STR00068##
[0327] Mono-MMn was synthesized following a similar protocol published protocol (Thiabaud et al., 2014). In brief, 1.5 equiv. of NHS, 1 and EDC in H.sub.2O was stirred for 20 minutes. Activated 1 was then added to a solution of 1 equiv. of DIPEA and MMn(NH.sub.2) in MeCN and the reaction was stirred for approx. 6 hours. Mono-MMn was then purified via reverse phase tC18 SPE with an increasing gradient of acetonitrile and 0.1% acetic acid aqueous solution. Final step of purification, Sep-Pak loaded Mono-MMn was washed with deionized H.sub.2O and eluted using MeOH and the solvent was removed in vacuo to afford the desired product as a crystalline green solid. High Resolution ESI-MS m/z 1482.5212 (MonoMMnOAc).sup.+iv.
##STR00069##
[0328] Bis-MMn was synthesized using similar protocol published protocol (Thiabaud et al., 2014). For the synthesis, 3 equiv. of NHS, 1 and EDC in H.sub.2O was stirred for 20 minutes. Activated 1 was then added to a solution of 2 equiv. of DIPEA and lequiv. of MMn(NH.sub.2).sub.2 in MeCN and the reaction was stirred for approx. 6 hours. Bis-MMn was then purified via reverse phase tC18 SPE with an increasing gradient of acetonitrile and 0.1% acetic acid aqueous solution. Final step of purification, Sep-Pak loaded Mono-MMn was washed with deionized H.sub.2O and eluted using MeOH and the solvent was removed in vacuo to afford the desired product as a crystalline green solid. High Resolution ESI-MS m/z 1482.5212 (BisMMnOAc).sup.+
Example 2: Photoacoustic Imaging with Manganese Compounds
A. Methods and Materials
i. Cell Culture Imaging Protocol
[0329] RAW 264.7 cells were purchased from a commercial source and cultured in Dulbecco's Modified Eagle Medium (DMEM) (Life Technologies, NY, USA) supplemented with 10% fetal bovine serum (FBS; HyClone, UT, USA). Cells were incubated at 37 C. in a humidified atmosphere containing 5% CO.sub.2. The cells were then divided into 4 groups and cultured in culturing bottle (75 mL); MMn, MLu and MGd were mixed in the cell media (no FBS) at a concentration of 500 M and incubated with cells for 30 mins. The old media was then discarded, and the cells were washed with PBS three times and collected by centrifugation (2000 rpm, 2 mins; or 3000-5000 rpm, 1 min). The collected cells were then added into the plastic tube for PA measurements.
ii. In Vivo Imaging Protocol
[0330] Male BALB/c nude mice (182 g, 4-6 weeks old) were purchased from a commercial source and used according to standard animal guidelines for the care and use of laboratory animals with appropriate ethical oversight board approval.
[0331] Human prostate cancer cell lines C4-2 were purchased from commercial sources and cultured in Dulbecco's Modified Eagle Medium (DMEM) (Life Technologies, NY, USA) supplemented with 10% fetal bovine serum (FBS; Cyclone, UT, USA). Cells were incubated at 37 C. in a humidified atmosphere containing 5% CO.sub.2. For C4-2 tumor inoculation, C4-2 cells (110.sup.6) suspended in PBS were injected under the nude mice epidermis of the right flank. Animals were observed every day for any behavioral abnormalities. Approximately after 12 days, the tumors were a suitable size for PAI experiments (diameter of tumor: 8-12 mm). Before each PAI experiment, the tumor site was gently wiped with alcohol and the tumor was first coated with an ultrasonic coupling adhesive and then a polyethylene plastic film, which held water was directly placed above the tumor. This protocol was important as the acoustic impedance mismatch between tissue and air would prevent the ultrasound information being received
iii. Photoacoustic Computed Tomography (PACT) System for In Vivo Experiments
[0332] An optical parametric oscillator (OPO) laser source (Innolas GmbH, Bonn, Germany) emitting 8 ns pulsed lasers was coupled to a multimode optical fiber with a 1500 m core diameter for the photoacoustic signal excitation. The use of this nanosecond pulsed laser on the tumor tissue resulted in very small thermal expansions. This led to the vibration of the tissue, which generated ultrasonic waves that could be recorded by a commercial 128-element linear array transrectal ultrasound transducer. For a model apparatus, see
iv. ICP-MS Analysis Protocol
[0333] MMn or MGd were mixed in cell media (no FBS, 15 mL, Cytiva HyClone DMEM, SH300243.01) to achieve a concentration of 100 M for each texaphyrin and incubated (37 C., 95% air, 5% CO.sub.2) with RAW 264.7 cells for 30 mins in a 75 mL culture flask. The old media was discarded, and the cells were washed with PBS three times. The cells were detached using trypsin and then collected by centrifugation (2000 rpm, 2 min). The collected cells were then added into a centrifuge tube. Nitric acid (1 mL; 65%-68%) was then added to the tube dropwise which was then held in a water bath at 90 C. for 1 hour with the tube sealed. Upon cooling to room temperature, 300 L H.sub.2O.sub.2 (30%) was added to the tube, which was unsealed and placed in a water bath at 90 C. for an additional 1 hour. The tubes were then cooled to room temperature and the contents filtered using a 0.45 um filter membrane. The filtrate was then subject to ICP-MS analysis (Thermo Scientific, iCAP Q).
B. Photoacoustic Properties of Manganese Derivatives
[0334] The attributes of MGd such as attractive safety profile, MRI enhancement, (Young et al., 1996) (Sedgwick et al., 2020) and tumor localization (Hashemy et al., 2007; Khuntia 2007), coupled with a strong absorptivity in the near-IR region >700 nm (
[0335] As PAI utilizes the nonradiative conversion of light energy, (Liu et al., 2019) a desired feature of a PA contrast agent is a low fluorescent quantum yield (Borg et al., 2018). Therefore, without wishing to be bound by any theory, it is believed that the superior performance observed for MMn comparison to MGd and MLu reflects that the compound has being essentially non-fluorescent (
[0336] A preferred PA contrast agent for clinical applications should avoid production of singlet oxygen (.sup.1O.sub.2). Surprisingly, MMn resulted in minimal production of .sup.1O.sub.2, as reflected in a standard 1,3-diphenylisobenzofuran (DPBF)-based assay (
[0337] Photostability is also relevant factor to consider for a potential PA contrast agent for clinical applications. Consistent with previous observations, (Mindt et al., 2018) ICG demonstrated poor photostability upon photoirradiation (100 M, 20 minutes, 780 nm, fluence 18 mJ/cm.sup.2) as inferred from the change in color from dark turquoise to a pale turquoise (cf.
[0338] The intracellular PAI capabilities of MMn and MGd were evaluated in RAW 264.7 cells, a cell line commonly used in imaging assays (Sedgwick et al., 2018). As can be seen from an inspection of
TABLE-US-00001 TABLE 1 ICP-MS analysis of the cellular uptake of either Mn or Gd in RAW264.7 cells Concentration Concentration Intensity Category average RSD average .sup.55Mn (KED) 220.413 ppb 0.5% 1,566,566 cps .sup.157Gd (KED) 91.783 ppb 0.5% 2,823,850 cps
[0339] To test further the PA imaging potential of MMn, in vivo experiments were performed using a prostate tumor mouse model as shown in
[0340] No significant increase in the PA signal at the tumor site was observed after the tail vein injection of ICG (500 M, 200 L 5 mol/kg)
[0341] To confirm the in vivo stability of MMn for PA imaging, MMn was injected directly at the tumor site and the PA signal was measured over time (0-60 mins) with concurrent US imaging. ICG was used as a positive control. As seen in
[0342] Using the PA imaging data obtained from MMn-treated tumor bearing mouse (injection concentration: 500 M, 200 L, (5 mol/kg); tail vein administration), a 3D image of the tumor was constructed. As can be seen from an inspection of
Example 3: Photothermal Therapy with Manganese Compounds
A. Methods and Materials
i. Photothermal Experiments of MMn and MMn Platinum Drug Conjugates
[0343] A549 cells (ATCC: CCL-185) were counted and seeded in transparent 96 well plates at a cell density of 1410.sup.4/mL (100 L in F12 medium (Gibco, Grand Island, NY, USA) with 10% fetal bovine serum (FBS, Gibco), penicillin and streptomycin (ps, 0.1%, Gibco)). Each plate was placed in the incubator at 37 C. and contained 5% CO.sub.2 overnight. After 24 h, each experimental group was prepared using F12 medium (Gibco, Grand Island, NY, USA) with 10% fetal bovine serum (FBS, Gibco), penicillin and streptomycin (0.1%, Gibco) with blank (fill up with DMSO of 0.3%), MMn, MMn+HSA, Mono-MMn, Mono-MMn+HSA, Bis-MMn, Bis-MMn+HSA added. Additionally, MGd and MMn were tested. For the groups containing HSA, 10 M of HSA was added to each corresponding solution and compound. The resulting solution was mixed for 10 minutes. The experimental groups were used and performed in triplicates. 100 L of each solution was added to each well and then placed in the incubator for 4 h. For PTT experiments, each plate was then subjected to laser irradiation (Changchun New Industry Optoelectronic Technology Co., Ltd., MDL-N-808(FC)-10W, 808 nm laser wavelength, power: 1 W/cm.sup.2) for 15 minutes
ii. Cytotoxicity
[0344] A solution of MTS: PMS was prepared at a ratio of 20:1 in EP tube, and directly added to each well, (10 L per well), placed in the incubator for 4 hours, and then the absorbance at 490 nm is measured by the Spectra Max multifunctional microplate reader (Molecular Devices, US) to calculate the cell survival rate.
B. Photothermal Therapy of Manganese Derivatives
[0345] The photothermal effects of MMn were determined and compared to MGd. See
[0346] Next, the generation of reactive oxygen species (ROS) with Bis-MMn was analyzed. After irradiation for 5 minutes per well with a 750 nm 2 W light source, the Bis-MMn showed the generation of ROS after irradiation with light. Samples that were not irradiated did not result in the generation of ROS.
[0347] Finally, similar results were obtained when the compounds were formulated into liposomes. See.
[0348] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of certain embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
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