Texaphyrin coordination compounds and uses thereof Number:7,160,873 from the United States Patent and Trademark Office (PTO) owispatent Novel coordination polymers, their pharmaceutical formulations, useful for treating atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress, are disclosed.<H coordination, Texaphyrin, Texaphyrin, coor, 7160873.html, Patent, pto, 7160873

Title: Texaphyrin coordination compounds and uses thereof

Abstract: Novel coordination polymers, their pharmaceutical formulations, useful for treating atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress, are disclosed.

Patent Number: 7,160,873 Issued on 01/09/2007 to Magda, et al.

Inventors: Magda; Darren (Cupertino, CA), Miles; Dale (Sunnyvale, CA), Gerasimchuk; Nikolay (Springfield, MO), Lepp; Cheryl (Mountain View, CA)
Assignee: Pharmacyclics, Inc. (Sunnyvale, CA)

Appl. No.: 11/033,431

Filed: January 7, 2005

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10415916		6919327
PCT/US01/43590	Nov., 2001
60249523	Nov., 2000

Current U.S. Class: 514/185 ; 514/410; 534/11; 534/15; 540/145; 540/465; 540/472

Current International Class: A61K 31/555 (20060101); C07D 487/22 (20060101)

Field of Search: 514/185,410 534/11,15 540/145,465,472

References Cited [Referenced By]

U.S. Patent Documents


5457183	October 1995	Sessler et al.

Primary Examiner: O'Sullivan; Peter
Attorney, Agent or Firm: Wilson, Sonsini, Goodrich & Rosati

Parent Case Text

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 10/415,916, filed Nov. 16, 2001, allowed on Jul. 19, 2005 now U.S. Pat. No. 6,919,327, of which the said application is the National Stage of International Application No. PCT/US01/43590, filed Nov. 16, 2001, published in English under PCT Article 21(2) as Publication No. WO 02/39953, on May 23, 2002, which claimed the benefit of priority from U.S. Provisional Application No. 60/249,523, filed Nov. 17, 2000, all of which are incorporated herein by reference.

Claims

What is claimed is:

1. A method for treating atherosclerotic inflammation in a mammal, said process comprising administering to the mammal: (a) a reducing agent; and (b) a compound of Formula I ##STR00041## its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein: M represents H or a metal cation; Q represents an integer of from about -5 to about +5; L represents a charge balancing species; n represents an integer of from 0 to +5; Z.sup.1, Z.sup.2 and Z.sup.3 independently represent N, O, CH or S; R.sup.1, R.sup.1a, R.sup.2, R.sup.3, R.sup.4, R.sup.4a, R.sup.7, and R.sup.8 are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, S--R.sup.31, SO--R.sup.31, SO.sub.2--R.sup.31, and the moiety X--Y; R.sup.6 and R.sup.9 are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, fluoro, chloro, bromo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, sulfanyl, sulfinyl, sulfonyl, and the moiety X--Y; R.sup.5, R.sup.10, R.sup.11 and R.sup.12 are independently selected from acyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, halo, hydrogen, hydroxy, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; X is a covalent bond or a linker; Y is a catalytic group, a chemotherapeutic agent or a site-directing group; R.sup.31 represents acyl, optionally substituted alkenyl, optionally substituted alky, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkynyl, optionally substituted aminocarbonyl, optionally substituted aryl, carboxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

2. A process of claim 1 wherein the compound of Formula I is represented by ##STR00042## its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein: M represents a metal cation selected from Gd(III) and Lu(III); Q represents an integer of 2; L represents a charge balancing species selected from OAc, NO.sub.2, Cl, and PO.sub.4; n represents an integer of 2; Z.sup.1, Z.sup.2 and Z.sup.3 independently represent N; R.sup.1 and R.sup.1a independently represent (CH.sub.2).sub.3OH; R.sup.2 and R.sup.3 independently represent C.sub.2H.sub.5; R.sup.4 and R.sup.4a independently represent CH.sub.3; R.sup.7 and R.sup.8 independently represent O--(CH.sub.2--CH.sub.2--O).sub.3--CH.sub.3; and R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 independently represent H.

3. A process of claim 2 wherein the reducing agent and the compound of Formula I ##STR00043## wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); and n represents an integer from 1 to 3; are intravenously administered to the host.

4. A process of claim 3 wherein the reducing agent is selected from ascorbic acid, dehydroascorbate, dihydrolipoate, NADH, folate, glyoxal, glyoxalate, oxamate, dimethyloxalate, oxamide, NADPH, glutathione, nacetylcystein and pyruvate.

5. A process of claim 4 wherein the reducing agent is administered at least about 30 minutes before administering a compound of Formula I.

6. A process of claim 5 wherein the reducing agent and a compound of Formula I are administered simultaneously to the host.

7. A process of claim 6 wherein the host is administered a mixture of the reducing agent and a compound Formula I.

8. A process of claim 7 wherein the host is administered the reducing agent after the administration of a compound of Formula I.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds and their pharmaceutical formulations, and their uses to treat atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress.

2. Background Information

Treatment of solid mammalian tumors with ionizing radiation involves the in situ generation of hydroxyl radicals and other reactive oxygen species that, due to the focusability of the ionizing radiation are primarily located in the tumor, i.e., in tumor cells. These reactive species possess extreme oxidizing properties which oxidize biomolecules in vivo thereby interfering with cellular metabolism, as discussed by Buettner, et al., Radiation Research, Catalytic Metals, Ascorbate and Free Radicals: Combinations to Avoid, 145:532 541 (1996).

Tumor treatment via the use of ionizing radiation can be enhanced by increasing the radio sensitivity of the tumor cells. One method suggested for enhancing radio sensitivity has been the external administration of a compound having a high affinity for electrons, which ideally localizes in the tumor. Proposed radiation sensitizers include compounds such as halogenated pyrimidines, nitroimidazoles and gadolinium (III) complexes of the pentadentate macrocycle Texaphyrin, as described by Sessler, et al., J. Phys. Chem. A, One-Electron Reduction and Oxidation Studies of the Radiations Sensitizer Gadolinium (III) Texaphyrin (PCI-120) and Other Water Soluble Metallotexaphyrins, 103: 787 794 (1999).

Texaphyrins are known to be useful as radiation sensitizers, and also for the treatment of plaque caused by atherosclerosis, retinal diseases, for the destruction of retroviruses, especially HIV and the like.

Efficacy of texaphyrins is dependent on its ability to penetrate cellular membranes and thereby increase its intracellular concentration. Thus intracellular availability of texaphyrin is a key to its biological activity and effectiveness. Texaphyrins are known to penetrate cell membranes and are known to have an effective intracellular concentration to have beneficial biological activity. An improvement in the ability of a drug substance to enter cellular membranes is however always welcome. It has been surprisingly discovered that premixing texaphyrins with an oxalate salt or an oxalate precursor, for example ascorbic acid, gives rise to a compound whose structure differs from that of a Texaphyrin, but is seen to accumulate more rapidly in tumor cells, plaque, etc.

SUMMARY OF THE INVENTION

This invention relates to a method of treating tumors and other neoplastic tissue, plaque caused by atherosclerosis, viruses, including HIV, and retinal diseases using the polymeric complex of the present invention.

The present invention also relates to polymeric complexes formed by treating texaphyrins with oxalate salts or oxalate precursors and their pharmaceutical compositions.

The present invention thus provides a method for treating a disease or condition in a mammal resulting from the presence of neoplastic tissue, neovascularization, or an atheroma, said method comprising:

(a) administering to a mammal in need of such treatment a therapeutically effective amount of a coordination polymer comprising structural units "A":

##STR00001## wherein: M is a trivalent metal cation; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and structural unit "B"

##STR00002##

Another aspect of the present invention provides a coordination polymer comprising structural units "A":

##STR00003## wherein: M is a trivalent metal cation; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and structural unit "B"

##STR00004##

Provided in yet another aspect is a coordination polymer wherein structural unit "A" is represented by

##STR00005## wherein M independently at each occurrence represents Gd(III) or Lu(III); and structural unit "B" is represented by

##STR00006##

Yet another aspect provides a process of making a coordination polymer comprising structural units "A":

##STR00007## wherein: M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11; and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; and structural unit "B"

##STR00008## said process comprising contacting a compound of Formula A

##STR00009## wherein M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, to form a coordination polymer comprising structural units "A" and "B".

Also provided is a coordination polymer prepared by contacting a compound of Formula A

##STR00010## wherein: M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, option ally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, optionally in the presence of oxygen.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts the time course showing changes in optical spectra occurring upon incubation of Motexafin Gadolinium (GdTex) with dihydroascorbate (DHA) in a buffer (see Example 2).

FIG. 2 refers to cellular uptake of GdTex oxalate complex as measured by absorbance (see Example 7).

FIG. 3 refers to cellular uptake of GdTex oxalate complex as measured by dichlorofluoroscin acetate (DCFA) oxidation to form dichlorofluoresin (DCF) (see Example 7).

FIG. 4 depicts uptake in A549 cells as measured using flow cytometry (see Example 8).

FIG. 5 depicts oxidation in A549 cells as measured using flow cytometry (see Example 8).

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus provides a method for treating a disease or condition in a mammal resulting from the presence of neoplastic tissue, neovascularization, or an atheroma, said method comprising:

(a) administering to a mammal in need of such treatment a therapeutically effective amount of a coordination polymer comprising structural units "A":

##STR00011## wherein: M is a trivalent metal cation; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and structural unit "B"

##STR00012##

A preferred embodiment provides a method wherein within structural unit "A" M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); R.sup.1 represents (CH.sub.2).sub.2-4--OH; R.sup.2 and R.sup.3 independently represent C.sub.1 C.sub.3-alkyl; R.sup.4 represents ethyl, methyl or propyl; R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 independently represent H or methyl; and R.sup.7 and R.sup.8 represent O--[(CH.sub.2).sub.2O].sub.3--C.sub.1-2-alkyl or O--(CH.sub.2).sub.2-4OH.

A further preferred embodiment provides a method of Claim 2 wherein structural unit "A" is represented by

##STR00013## wherein, M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III).

Another preferred embodiment provides a method wherein said method further comprises treating the area in proximity to the neoplastic tissue with a therapeutic energy means or with a chemotherapeutic agent, or treating the area in proximity to the neovascularization or atheroma with a therapeutic energy means; and wherein the optional therapeutic energy means is chosen from photoirradiation, ionizing radiation, neutron irradiation, and ultrasound.

Another aspect of the present invention provides a coordination polymer comprising structural units "A":

##STR00014## wherein: M is a trivalent metal cation; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl, and structural unit "B"

##STR00015## A preferred coordination polymer is one wherein within structural unit "A", M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); R.sup.1 represents (CH.sub.2).sub.2-4--OH; R.sup.2 and R.sup.3 independently represent C.sub.1 C.sub.3-alkyl; R.sup.4 represents ethyl, methyl or propyl; R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 independently represent H or methyl; and R.sup.7 and R.sup.8 represent O--[(CH.sub.2).sub.2O].sub.3--C.sub.1-2-alkyl or O--(CH.sub.2).sub.2-4OH.

A further preferred coordination polymer comprises structural unit "A" represented by

##STR00016## wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III).

A particularly preferred coordination polymer comprises a structural unit "A" is represented by

##STR00017## wherein M independently at each occurrence represents Gd(III) or Lu(III); and structural unit "B" is represented by

##STR00018## Another particularly preferred coordination polymer comprises a structural unit "A" represented by

##STR00019## wherein M represents Gd(III); and structural unit "B" is represented by

##STR00020## Yet another particularly preferred coordination polymer comprises structural unit "A" represented by

##STR00021## wherein M represents Lu(III); and structural unit "B" is represented by

##STR00022##

Another aspect of the present invention provides a process of making a coordination polymer comprising structural units "A":

##STR00023## wherein: M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; and structural unit "B"

##STR00024## said process comprising contacting a compound of Formula A

##STR00025## wherein M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, to form a coordination polymer comprising structural units "A" and "B".

A preferred process is one wherein within structural unit "A" M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); R.sup.1 represents (CH.sub.2).sub.2-4--OH; R.sup.2 and R.sup.3 independently represent C.sub.1 C.sub.3-alkyl; R.sup.4 represents ethyl, methyl or propyl; R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 independently represent H or methyl; and R.sup.7 and R.sup.8 represent O--[(CH.sub.2).sub.2O].sub.3--C.sub.1-2-alkyl or O--(CH.sub.2).sub.2-4OH.

A further preferred process is one wherein structural unit "A" is represented by

##STR00026## and compound of Formula A are represented by

##STR00027## wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); the process is carried out at ambient temperature and neutral pH; the oxalate or oxalate precursor is selected from ascorbate, dehydroascorbate, glyoxal and glyoxylate; and the process is carried out in the presence of oxygen.

Yet another aspect of the present invention provides a coordination polymer prepared by contacting a compound of Formula A

##STR00028## wherein: M is a trivalent metal cation; AL is an apical ligand; n is an integer of 1 5; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group --X--Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and R.sup.5, R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with an oxalate salt or an oxalate precursor, optionally in the presence of oxygen.

A preferred coordination polymer is one wherein within structural unit "A" M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); R.sup.1 represents (CH.sub.2).sub.2-4--OH; R.sup.2 and R.sup.3 independently represent C.sub.1 C.sub.3-alkyl; R.sup.4 represents ethyl, methyl or propyl; R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 independently represent H or methyl; and R.sup.7 and R.sup.8 represent O--[(CH.sub.2).sub.2O].sub.3--C.sub.1-2-alkyl or O--(CH.sub.2).sub.2-4OH; and wherein the oxalate precursor is selected from ascorbate, dehydroascorbate, glyoxal, glyoxalate, oxamate, dimethyloxalate, and oxamide.

Yet another preferred method is one wherein the compound of Formula A is represented by

##STR00029## wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); and n represents an integer from 1 to 3.

A particularly preferred process is one wherein the disease or condition in a mammal resulting from the presence of atheroma is atherosclerotic inflammation.

Another embodiment of the present invention provides a method for treating atherosclerotic inflammation in a mammal, said method comprising administering to the mammal: (a) a reducing agent; and (b) a compound of Formula I

##STR00030## its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein: M represents H or a metal cation; Q represents an integer of from about -5 to about +5; L represents a charge balancing species; n represents an integer of from 0 to +5; Z.sup.1, Z.sup.2 and Z.sup.3 independently represent N, O, CH or S; R.sup.1, R.sup.1a, R.sup.2, R.sup.3, R.sup.4, R.sup.4a, R.sup.7, and R.sup.8 are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, S--R.sup.31, SO--R.sup.31, SO.sub.2--R.sup.31, and the moiety X--Y; R.sup.6 and R.sup.9 are independently selected from acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, (optionally substituted alkoxy)carbonyloxy, (optionally substituted amino)carbonyloxy, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, fluoro, chloro, bromo, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydrogen, hydroxyl, nitro, optionally substituted azo, sulfanyl, sulfinyl, sulfonyl, and the moiety X--Y; R.sup.5, R.sup.10, R.sup.11 and R.sup.12 are independently selected from acyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, halo, hydrogen, hydroxy, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; X is a covalent bond or a linker; Y is a catalytic group, a chemotherapeutic agent or a site-directing group; R.sup.31 represents acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkynyl, optionally substituted aminocarbonyl, optionally substituted aryl, carboxy, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

A further preferred method of this embodiment is one wherein the atherosclerotic inflammation is in the form of plaque in an artery; the compound of Formula I is represented by

##STR00031## its hydrate, pharmaceutically acceptable salt or prodrug form thereof, wherein: M represents a metal cation selected from Gd(III) and Lu(III); Q represents an integer of 2; L represents a charge balancing species selected from OAc, NO.sub.2, Cl, and PO.sub.4; n represents an integer of 2; Z.sup.1, Z.sup.2 and Z.sup.3 independently represent N; R.sup.1 and R.sup.1a independently represent (CH.sub.2).sub.3OH; R.sup.2 and R.sup.3 independently represent C.sub.2H.sub.5; R.sup.4 and R.sup.4a independently represent CH.sub.3; R.sup.7 and R.sup.8 independently represent O--(CH.sub.2--CH.sub.2--O).sub.3--CH.sub.3; and R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11 and R.sup.12 independently represent H; and wherein the plaque is vulnerable plaque and is essentially present along walls of an artery.

A particularly preferred method is one wherein the vulnerable plaque has lipids and is inflamed; and wherein the coordination polymer is formed within a mammal by first administering to a mammal a compound of structural unit A followed by an oxalate or oxalate precursor selected from ascorbate, dehydroascorbate, glyoxal and glyoxylate.

Yet another embodiment provides a process wherein the reducing agent and the compound of Formula I

##STR00032## wherein M independently at each occurrence represents Gd(III), Lu(III), Eu(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), or Y(III); and n represents an integer from 1 to 3; are intravenously administered to the host.

A further preferred method is one wherein the reducing agent is administered at least about 30 minutes before administering a compound of Formula I. Another preferred method provides a process wherein the reducing agent and a compound of Formula I are administered simultaneously to the host. Yet another preferred embodiment provides a method wherein the host is administered a mixture of the reducing agent and a compound of Formula I. In yet another preferred embodiment is provided a method wherein the host is administered the reducing agent after the administration of a compound of Formula I.

It has now been discovered that mixing the texaphyrins with a reducing chemical entity selected from ascorbic acid, dehydroascorbate, dihydrolipoate, NADH, folate, glyoxal, glyoxalate, oxamate, dimethyloxalate, oxamide, NADPH, glutathione, nacetylcystein, pyruvate, and the like, forms a complex comprising texaphyrin and oxalate. These complexes have a characteristic UV absorption at 510 nm and 780 nm, which differ from that of the starting compound(s).

It has now been discovered that mixing the texaphyrins with a chemical entity selected from an oxalate, ascorbate, dehydroascorbate, glyoxylate, dimethyl oxalate, and the like, forms a complex comprising Texaphyrin and oxalate. These complexes have a characteristic UV absorptions at 510 nm and 780 nm, which differ from that of the starting compound(s).

This coordination complex, upon administration by injection, improves localization of the texaphyrin at the desired site (tumor, plaque, etc.) as compared to the previously known method of injecting texaphyrin alone, and thereby provides a more effective method of treatment.

As used herein, the following terms have the meanings as defined below.

The term "texaphyrin" refers to metal complexes of aromatic pentadentate macrocyclic "expanded porphyrins" which are considered as being an aromatic benzannulene containing both 18 .pi. and 22 .pi.-electron delocalization pathways. Such texaphyrins and their synthesis have been described, for example, by Sessler, et al., in U.S. Pat. No. 5,457,183; Sessler, et al., Accounts of Chem. Res., Texaphyrins: Synthesis and Applications, 27:43 50 (1994) and Hemmi, et al., U.S. Pat. No. 5,599,928 and are incorporated herein by reference.

The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl and the like.

The term "substituted alkyl" refers to an alkyl group as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyl amino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxylamine, alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and --SO.sub.2-heteroaryl.

The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. This term is exemplified by groups such as ethylene (--CH.sub.2CH.sub.2--), the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and --CH(CH.sub.3)CH.sub.2--) and the like.

The term "substituted alkylene" refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxylamine, alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and --SO.sub.2-heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures.

The term "alkoxy" refers to the groups alkyl-O--, alkenyl-O--, cycloalkyl-O-- and cycloalkenyl-O--, where alkyl, alkenyl, cycloalkyl, and cycloalkenyl are as defined herein. Preferred alkoxy groups are alkyl-O-- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

The term "substituted alkoxy" refers to the groups substituted alkyl-O--, substituted alkenyl-O--, substituted cycloalkyl-O-- and substituted cycloalkenyl-O--, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, and substituted cycloalkenyl are as defined herein. A preferred class of substituted alkoxy are polyoxyalkylene groups represented by the formula --O(R'O).sub.qR'' where R' is an alkylene group or a substituted alkylene group, R'' is selected from the group consisting of hydrogen, alkyl or substituted alkyl and q is an integer from 1 to 10. Preferably, in such groups, q is from 1 to 5 and most preferably 3.

The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1 6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2), iso-propenyl (--C(CH.sub.3).dbd.CH.sub.2), and the like.

The term "substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxylamine, alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and --SO.sub.2-heteroaryl.

The term "acyl" refers to the groups HC(O)--, alkyl-C(O)--, substituted alkyl-C(O)--, cycloalkyl-C(O)--, substituted cycloalkyl-C(O)--, cycloalkenyl-C(O)--, substituted cycloalkenyl-C(O)--, aryl-C(O)--, heteroaryl-C(O)-- and heterocyclic-C(O)-- where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "acylamino" refers to the group --C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "aminoacyl" refers to the group --NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "aminoacyloxy" refers to the group --NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "acyloxy" refers to the groups alkyl-C(O)O--, substituted alkyl-C(O)O--, cycloalkyl-C(O)O--, substituted cycloalkyl-C(O)O--, aryl-C(O)O--, heteroaryl-C(O)O--, and heterocyclic-C(O)O-- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused)rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl, --SO.sub.2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

The term "aryloxy" refers to the group aryl-O-- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.

The term "amino" refers to the group --NH.sub.2.

The term "substituted amino" refers to the group --NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic provided that both R's are not hydrogen.

The term "carboxyalkyl" refers to the groups "--C(O)O-alkyl", "--C(O)O-substituted alkyl", "--C(O)O-cycloalkyl", "--C(O)O-substituted cycloalkyl", "--C(O)O-alkenyl", and "--C(O)O-substituted alkenyl", where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl, are as defined herein.

The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxylamine, alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and --SO.sub.2-heteroaryl.

The term "cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.

The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxylamine, alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2substituted alkyl, --SO.sub.2-aryl and --SO.sub.2-heteroaryl.

The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

The term "heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl, --SO.sub.2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.

The term "heteroaryloxy" refers to the group heteroaryl-O--.

The term "heterocycle" or "heterocyclic" refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxylamine, alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and --SO.sub.2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.

Illustrative examples of nitrogen heterocycles and heteroaryls are pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.

The term "heterocyclooxy" refers to the group heterocyclic-O--.

The term "thioheterocyclooxy" refers to the group heterocyclic-S--.

The term "oxyacylamino" refers to the group --OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "thiol" refers to the group --SH.

The term "thioalkoxy" refers to the group --S-alkyl.

The term "substituted thioalkoxy" refers to the group --S-substituted alkyl.

The term "thioaryloxy" refers to the group aryl-S-- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.

The term "thioheteroaryloxy" refers to the group heteroaryl-S-- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.

The term "saccharide" refers to oxidized, reduced or substituted saccharides hexoses such as D-glucose, D-mannose, D-xylose, D-galactose, D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, sialyic acid, iduronic acid, L-fucose, and the like; pentoses such as D-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose; disaccharides such as sucrose, lactose, or maltose; derivatives such as acetals, amines, acylated, sulfated and phosphorylated sugars; oligosaccharides having from 2 to 10 saccharide units. For the purposes of this definition, these saccharides are referenced using conventional three letter nomenclature and the saccharides can be either in their open or preferably in their pyranose form.

As to any of the above groups that contain one or more substituents, it is understod of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this invention include all stereochemical isomers and mixtures thereof arising from the substitution of these compounds.

The term "treatment" or "treating" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms.

The term "effective amount", means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.

The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartarate, mesylate, acetate, maleate, oxalate and the like.

The term "thiol-depleting compound" refers to a compound which upon administration to a host or to a cell, results in a global lowering of the concentration of available reduced thiol (e.g., glutathione). Examples of thiol-depleting compounds include buthionine sulfoximine ("BSO", a known inhibitor of glutathione synthesis), diethyl maleate (a thiol reactive compound) dimethyl fumarate, N-ethyl maleimide, diamide (diazene dicarboxylic acid bis-(N,N'-dimethylamide)) and the like.

The term "ionizing radiation" refers to radiation conventionally employed in the treatment of tumors which radiation, either as a large single dosage or as repeated smaller dosages, will initiate ionization of water thereby forming reactive oxygen species. Ionizing radiation includes, by way of example, x-rays, electron beams, .gamma.-rays, and the like.

The term "oxalate" salts represents a dianion of oxalic acid, including its salts. Illustrative examples of oxalic acid salts include their sodium, potassium and ammonium salts. The term "oxalate precursors" represents compounds which undergo a chemical transformation (in the presence of a texaphyrin) to form the oxalic acid dianion, i.e., O.sub.2CCO.sub.2.sup.2-. Illustrative examples of oxalate precursors are oxalic acid esters, oxalic acid diesters, ascorbate, dehydroascorbate, glyoxal, oxamates, oxamide(s), glycolates, and oxalyl chloride. It is understood that the preceding oxalate precursors, especially acids, can exist as their corresponding salts such as sodium, potassium and ammonium salts.

The term "porphyrin derivative" refers to those molecules which contain as part of their chemical structure a polypyrrole macrocycle.

The term "DNA alkylators" refer to well known alkylating agents which alkylate DNA thereby interfering with cellular processes and leading to cell death. Suitable alkylating agents include nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, mephalan, chlorambucil and estramustine), etheleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitroureas (e.g., carmustine, lomusine, semustine, and streptozocin), and triazines (e.g., dacarbazine, procarbazine, and aziridine).

Experimental

Methods

The following examples describe the reaction of GdTex with dehydroascorbic acid in buffered solution to provide the oxalate coordination complex of the invention, and the reaction of GdTex with (di)sodium oxalate to provide the same product. The cellular uptake of GdTex in the presence of ascorbate is also described.

General Procedure: General Protocol to Test for Formation of M-Tex Oxalate Complex in Buffer

To a solution of motexafin gadolinium (131 .mu.M) in 400 .mu.L buffer (100 mM sodium chloride, 50 mM HEPES, pH 7.5) was added a 10-fold molar excess of neat (either solid or liquid) compound being tested as a source of oxalate. The UV-visible absorbance of the resulting solution was then monitored for 24 hours. The following species all resulted in formation of the characteristic absorbances at 510 nm and 780 nm: ascorbic acid, dehydroascorbic acid, oxalic acid, sodium oxalate, dimethyl oxalate, diethyl oxalate, dibutyl oxalate, di-tert-butyl oxalate, glyoxylic acid, glyoxal, oxamic acid, and oxamide (All compounds were purchased from Aldrich Chemical Co., Milwaukee, Wis., except for dehydroascorbic acid, which was obtained in dimeric form from Fluka Chemical Co., Milwaukee, Wis.).

General Description of Formation of M-Tex Oxalate Complexes in Buffer.

A 10 mM stock solution of sodium oxalate (Aldrich Chemical Co., Milwaukee, Wis.) in water was prepared by dissolving 13.4 mg in 10 mL of ACS grade water. Test solutions of various Texaphyrin metal cation complexes at 50 .mu.M concentration in buffer (5 mM HEPES, pH 7.5, 10 mM sodium chloride) and sodium oxalate (1 mM, all concentrations final) were prepared by combining stock sodium oxalate, buffer, and Texaphyrin complex solutions and adding ACS grade water to 1 mL final volume. Test solutions were stored in the dark for 24 hours, whereupon the UV-vis spectra were measured. Spectra of the following texaphyrins were observed to have altered to form new absorbances characteristic of oxalate complex formation: motexafin europium(III), motexafin gadolinium(III), motexafin terbium(III), motexafin dysprosium(III), motexafin holmium(III), motexafin erbium(III), and motexafin lutetium(III). Spectra for all Texaphyrin oxalate complexes displayed absorbance maxima at 510 nm and 780 nm, regardless of the initial absorbance wavelengths of the Texaphyrin complex starting materials, which ranged from 474 478 nm and 732 746 nm.

EXAMPLE 1

Reaction of Motexafin Gadolinium (Gd-Tex) with Ascorbic Acid in Buffered Solution

A solution of ascorbic acid (1.23 mM) in 50 mM HEPES buffer, pH 7.5, 100 mM NaCl (all concentrations final) was placed in a 1 mm quartz cuvette at ambient temperature. The UV-visible spectrum of this solution was recorded every 30 seconds following addition of a solution of Gd-Tex in ACS (American Chemical Society grade) water (62 .mu.M final, 0.05 eq.). Buffer was treated with Chelex 100.TM. (BioRad Labs, Hercules, Calif.) prior to use, to remove endogenous transition metal cation contaminants. Within an hour after addition of Gd-Tex, the absorbance of ascorbate at 266 nm was observed to decrease. Moreover, the absorbance maxima of Gd-Tex at 470 nm and 740 nm were converted to new absorbance maxima at 510 nm and 780 nm, corresponding to formation of the oxalate coordination polymer of Gd-Tex.

EXAMPLE 2

Reaction of Motexafin Gadolinium (Gd-Tex) with Dehydroascorbic Acid in Buffered Solution

Motexafin gadolinium (Gd-Tex, 50 mg, 43.6 .mu.mol) was placed in a 50 mL round bottom flask and dissolved at room temperature in ACS grade water (20 mL). Dehydroascorbic acid (DHA, 15.3 mg, 87.9 .mu.mol) (Aldrich Chemical, Milwaukee, Wis.) was placed in a 15 mL screw-cup vial and buffer (10 mL, 100 mM NaCl, 50 mM HEPES, pH=7.5) was added. Sonication for 10 min at 25.degree. C. produced very fine yellow suspension. This suspension was added at once to the above aqueous solution of Gd-Tex and agitated as it was heated to about 50.degree. C. using a water bath under ambient atmosphere. Progress of the reaction was followed by monitoring the increased absorbance in the UV-visible spectrum at 780 nm. After about 75 minutes, and after no further changes in the spectrum were observed, another portion of solid DHA (15.3 mg, 87.9 .mu.mol) was added to the reaction mixture, and the resulting reaction mixtur