Metallotexaphyrin derivatives

Details Metallotexaphyrin derivatives Metallotexaphyrin derivatives

2001-08-28

2003-10-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S410000, C540S145000, C540S465000, C540S472000, C534S010000, C534S015000, C534S016000

Reexamination Certificate

active

06638924

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods for modifying metallotexaphyrins to provide metallotexaphyrin derivatives (MTDs) having a wide range of physicochemical properties. In particular, the methods involve modifying the apical ligands associated with the central metal component of metallotexaphyrins. The invention also relates to the novel MTDs prepared by these methods, and their uses, and pharmaceutical compositions containing such compounds.
BACKGROUND INFORMATION
Porphyrins, the so-called “expanded porphyrins”, and related polypyrrole structures are members of a class of macrocycles capable of forming stable complexes with metals. The metal is constrained (as its cation) within a central binding cavity of the macrocycle (the “core”). The anions associated with the metal cation are found above and below the core; and are called apical ligands. Examples of this class of macrocycles are porphyrins, porphyrin isomers, porphyrin-like macrocycles, benzoporphyrins, texaphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
One preferred class of macrocycles is the texaphyrins. Texaphyrins are aromatic pentadentate macrocyclic compounds that have the ability to integrate metals within their core to form complexes known as “metallotexaphyrins”. Texaphyrins and metallotexaphyrins have been described as being useful as MRI contrast agents, fluorescent imaging agents for cancer, plaque, and retinal diseases, as radiosensitizers and as chemosensitizers in both oncology and atherosclerosis, and as photosensitizers in photodynamic therapy in oncology, atherosclerosis, and ophthamology. They have also been described as having the ability to hydrolytically cleave phosphate esters such as RNA, and to photolytically cleave RNA and DNA. Texaphyrins are aromatic benzannulene compounds containing both 18&pgr;- and 227&pgr;-electron delocalization pathways. Texaphyrin molecules absorb light strongly in the tissue-transparent 700-900 nm range, and they exhibit selective uptake (or biolocalization) in certain tissues, particularly regions such as liver, atheroma or tumor tissue, and neovascularized regions. Such selectivity can be detected by magnetic resonance imaging (for example with paramagnetic metal complexes) and by fluorescence.
Accordingly, advantage may be taken of this property to provide a means for selectively treating tumors, plaque caused by atherosclerosis, retinal diseases, and the like, as disclosed in the publications incorporated by reference below in the detailed description of the invention. Notwithstanding these properties, it has remained desired to provide new MTDs having a range of physicochemical properties, such, as improved solubility and/or lipophilicity, lower toxicity, and improved stability, but still retaining the basic attribute of selective localization.
One method of accomplishing these goals would be to change the properties of existing metallotexaphyrins by modifying the functional groups covalently attached to the macrocycle, and/or by changing the core metal. However, preparations of such MTDs require complicated syntheses, since each compound is necessarily made by a different synthetic route, and/or is derived from different starting materials. Accordingly, there remains a need for a convenient method for preparing a library of texaphyrin derivatives, which vary in their physicochemical properties, and can be synthesized easily and efficiently in high yield. The present invention provides such a method by modifying the apical ligands associated with the metal component of existing metallotexaphyrins to provide a library of MTDs having a wide range of physicochemical properties.
SUMMARY OF THE INVENTION
It is an object of this invention to provide novel metallotexaphyrin derivatives (MTDs). Accordingly, in a first aspect, the invention relates to compounds having the Formula I:
wherein:
M is a metal cation;
AL is an apical ligand;
with the proviso that AL is not derived from acetic acid, nitric acid, or hydrochloric acid; n is an integer of 1-5;
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
8
, and R
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
5
, R
10
, R
11
, and R
12
are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with the proviso that: halogen is other than iodide and haloalkyl is other than iodoalkyl.
Substituents R
1
-R
12
are further described in U.S. patents, PCT publications and allowed and pending patent applications, incorporated by reference in the Detailed Description.
M can be monovalent, divalent, trivalent, or tetravalent. Examples of monovalent metal cations are tellurium and technetium; an example of an appropriate tetravalent metal is thorium. Preferred are divalent and trivalent metals. Preferred divalent metal cations are Ca(II), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), Hg(III), Fe(II), Sm(II), or U(II). Preferred trivalent metal cations are Mn(III), Co(III), Ni(III), Fe(III), Ho(III), Ce(III), Y(III), In(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Er(III), Tm(III), Yb(III), Lu(III), La(III), or U(III). More preferred trivalent metal cations are Lu(III) or Gd(III). In some embodiments, in particular for use in neutron capture therapy, the metal can be present as a pure isotope of the metal, or be enriched in one or more of its isotopes. For example, gadolinium may be present as its
155
Gd or
157
Gd isotope, or “natural” gadolinium may be optionally enriched in the isotopes
155
Gd and/or
157
Gd. Similarly, cadmium may be present as the cadmium isotope
113
Cd, or “natural” cadmium enriched in
113
Cd; europium may be present as the europium isotope
115
Eu, or “natural” europium enriched in
151
Eu; mercury may be present as the mercury isotope
199
Hg, or “natural” mercury enriched in
199
Hg; and samarium may be present as the samarium isotope
149
Sm. or “natural” samarium enriched in
149
Sm. Particularly preferred for neutron capture therapy is the
157
Gd isotope of gadolinium, or “natural” gadolinium enriched in the isotope
157
Gd.
M or one of groups R
1
to R
12
can be radioactive, and are as described in the U.S. patents, PCT publications, and allowed and pending patent applications disclosed and incorporated by reference below.
Preferred apical ligands are formed, for example, from carboxylates of sugar derivatives, such as gluconic acid or glucoronic acid, cholesterol derivatives such as cholic acid and deoxycholic acid, polyethylene glycol (PEG) acids, or carboxylic acid derivatives, such as formic acid, propionic acid, butyric acid, pentanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic 2,5-dioxoheptanoic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid. Other preferred acids for forming apical ligands include methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, organophosphates, such as methylphosphonic acid and phenylphosphonic acid, phosphoric acid and the like.
A second aspect of the present invention relates to a preferred process f

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