CA2572287A1 - Carboranylporphyrins and uses thereof - Google Patents

Abstract

The present invention is directed to low toxicity boronated compounds and methods for their use in the treatment, visualization, and diagnosis of tumors. More specifically, the present invention is directed to low toxicity carborane-containing 5, 10,20-tetraphenylporphyrin compounds and methods for their use particularly in boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) for the treatment of tumors of the brain, head, neck, and surrounding tissue. The invention is also directed to using these carborane-containing tetraphenyl porphyrin compounds to methods of tumor imaging and/or diagnosis such as MRI SPECT, or PET.

Description

CARBORANYLPORPHYRINS AND USES THEREOF

[00011 The present invention was made with government support under Grant No.DE-AC02-98CH10886 awarded by the U.S. Department of Energy. The United States govemment has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0002] The efficacy of radiation and chemical methods in the treatment of cancers has been limited by a lack of selective targeting of tumor cells by the therapeutic agent. In an effort to spare normal tissue, current tumor treatment methods have therefore restricted radiation and/or chemical treatment doses to levels that are well below optimal or clinically adequate. Thus, designing compounds that are capable, either alone or as part of a therapeutic method, of selectively targeting. and destroying tumor cells, is a field of intense study.

[0003] Because of the known affinity of porphyrins to neoplastic tissues, there has been intense interest in using porphyrins as delivery agents in the treatment of neoplasms in the brain, head and neck, and related tumors. Porphyrins in general belong to a class of colored, aromatic tetrapyrrole compounds, some of which are found naturally in plants and animals, e.g., chlorophyll and heme, respectively.

[0004] Porphyrins and other tetrapyrroles with relatively long singlet lifetimes have already been used to treat malignant tumors using photodynamic therapy (PDT).
In PDT, the patient is first injected with a photosensitizing drug, typically a porphyrin. The tuinor cells, now photosensitized, are susceptible to destruction when exposed to an intense beam of laser red light. The biochemical mechanism of cell damage in PDT is believed to be mediated largely by singlet oxygen, which is produced by transfer of energy from the light-excited porphyrin molecule to an oxygen molecule. However, PDT has been limited predominantly by the photosensitizing compounds, which have lower than adequate selectivity to tumor cells and higher than optimal toxicity to normal tissue.

[0005] A promising new form of cancer therapy is boron neutron-capture therapy (BNCT). BNCT is a bimodal cancer treatment based on the selective accumulation of a stable nuclide of boron known as boron-10, or 1 B, in the tumor, followed by irradiation of the tumor with thermalized neutrons. The thermalized neutrons impinge on the boron-10, causing a nuclear fission (decay reaction). The nuclear fission reaction causes the highly localized release of vast amounts of energy in the form of high linear-energy-transfer (LET) radiation, which can kill cells more efficiently (higher relative biological effect) than low LET radiation, such as x-rays.

[0006] In BNCT, the boron-containing compound must be non-toxic or of low toxicity when administered in therapeutically effective amounts, as well as being capable of selectively accumulating in cancerous tissue. For example, clinical BNCT for malignant brain tumors was carried out at the Brookhaven National Laboratory Medical Department usingp-boronophenylalanine (BPA) as the boron carrier (Chanana et al., Neurosurgery, 44, 1182-1192, 1999). Although BPA has the advantage of low chemical.toxicity, it accumulates in critical normal tissues at levels that are less than desirable.
In particular, the tumor-to-normal brain and tumor-to-blood boron concentrations are in the ratio of approximately 3:1. Such low specificity limits the maximum dose of BPA to a tumor since the allowable dose to normal tissue will be the limiting factor.

[0007] A particular class of synthetic porphyrins, known as tetraphenyl porphyrins, have garnered intense interest in the design of new boron carrier compounds for BNCT.
Tetraphenylporphyrins (TPPs) contain four phenyl groups, typically on the 5, 10, 15, and 20 positions of the porphyrin ring. An advantage of TPPs is their ease of synthesis.

[0008] The solubility of TPPs can be controlled by the substituents, generally on the phenyl positions. Those TPPs containing sulfonates or carboxylates are water-soluble.

However, some of the carborane-containing TPPs have high lipophilic properties, which can require high amounts of non-aqueous excipients before administration into animals.
High amounts of excipients may reduce the biological effect of the porphyrin by, for example, changing the microlocalization within the tumor cell such that it may be bound to membranes instead of being homogeneously distributed throughout the cell.
In addition, the use of more hydrophilic bonds such as amide, ester, or urea bonds, although significantly more hydrophilic than carbon-carbon linkages, are known to hydrolyze under numerous types of conditions. Such hydrolysis is particularly problematic when such hydrophilic bonds are employed to attach the carboranyl group to the porphyrin molecule, since hydrolysis results in loss of the carbonyl group before reaching the target.

[0009] Therefore, there continues to be an effort to reduce the lipophilic behavior of TPPs while not compromising their chemical stability. For example, international Patent Application No. WO Ol/85736 by Vicente et al describes the synthesis and use of tetraphenylporphyrin compounds that contain hydrophilic groups. A salient feature of the Vicente compounds is the attachment of the carboranyl group to the phenyl group by, exclusively, a carbon-carbon linkage. Although such a carbon-carbon linkage is not prone to hydrolysis or other chemical attack, such a linkage is significantly hydrophobic.

[0010] Porphyrins also have the advantage of having the ability to chelate metal ions in its interior. Such chelated porphyrins can additionally function as visualization tools for real-time monitoring of porphyrin concentration and/or diagnostic agents. For example, when chelated to paramagnetic metal ions, porphyrins may function as contrast agents in magnetic resonance imaging (MRI), and when chelated to radioactive metal ions, porphyrins may function as irnaging agents for single photon emission computed tomography (SPECT) or positron emission tomography (PET).

[0011] In addition, by using chelated boron-containing porphyrins in BNCT, boron concentration and distribution in and around the tumor and all tissues within the irradiated treatment volume can be accurately and rapidly determined noninvasively before and during the irradiation. Such diagnostic information allows BNCT
treatment to be perfornned more quickly, accurately, and safely, by lowering exposures of epithermal neutrons in regions of tissues known to contain high levels of boron. Short irradiations would obviate the inconvenience and discomfort to the patient of long and often awkward positioning of the head at a reactor port. However, the anticipated use of accelerator-generated neutrons would lilcely produce a significantly lower flux and hence effect longer irradiation times, so that compounds that have longer tumor retention times would become critical.

[0012] Accordingly, there is a need for new compounds, especially boron-containing porphyrins, with long retention times in tumors, and that selectively target and destroy-tumor cells with minirhal damage to normal tissue. In addition, there is a need for more effective methods for the treatment of brain, head and neck, and related tumors, and more particularly, more effective BNCT treatments and boron-delivery compounds used therein.

SUMMARY OF THE INVENTION

[0013] The present invention is directed to low toxicity boronated compounds and methods for their use in the treatment, visualization, and diagnosis of tumors. More specifically, the present invention is directed to low toxicity boronated 5, 10, 15, 20-tetraphenylporphyrin compounds and methods for their use particularly in boron neutron capture therapy (BNCT) or photodynamic therapy (PDT) for the treatment of tumors of the brain, head and neck, and surrounding tissue.

[0014] Tn particular, the present invention is directed to boron-containing 5, 10, 15, 20-tetraphenyl porphyrins of the formula (y4)d (y5)k \(W4)h (Y')a .. ~ / ~ .
(Y$) w~ N W)e N-I N
lo ~I

(W3)g N (y6)I
(Y3) c~.~
(y7)u (W2) f \
(y2)b (1) wherein:

Y', Y2, Y3, and Y4 are independently on the ortho, meta or para position on the phenyl rings, and are independently hydrogen, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, or an alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, or heteroaryl group substituted with 1 to 4 hydrophilic groups selected from hydroxy, alkoxy, -C(O)ORS, -SOR6, -S02R6, nitro, amido, ureido, carbamato, -SR7, -NR$R9, or poly-alkyleneoxide; or a substituent represented by the formula [X2_(CR3R4)P D]m -X~-(CR'R2) n (2), wherein D represents independently, Z, hydrogen, or a substituent represented by the formula / [X3-(CR10R11)S D']q ~ V V ,n r5 )i (3), provided that at least one D is Z or is represented by fonnula (3);

wherein D' represents independently, Z, hydrogen, or a substituent represented by the formula [X4-(CR12R13)t Zlr &(W6), (4), provided that when q is 0, or when q is not zero and D' is solely hydrogen, then at least one D is represented by Z, or when q is not zero and D' is represented by formula (4) and r is zero, then at least one D is represented by Z;

Ys, Y6, Y7, and Yg are independently on the ortho, meta or para position on the phenyl rings, and are represented by the formula Xa-(CRaRb)v Z (5);

Wl, WZ, W3, W4, W5, and W6 are hydrophilic groups independently on the ortho, meta or para position on the phenyl rings, and are independently selected from hydroxy, alkoxy, -C(O)ORS, -SOR6, -S02R6, nitro, amido, ureido, carbamato, -SR7, -NR8R9, or polyalkylene oxide;

Xa, Xt, X2, X3, and X4 are independently oxygen or sulfur;

Ra, Rb, R', R2, Rs, R4, Rs, R6, R7, R8, R9, Rlo, R", RIZ, and R13 are independently selected from hydrogen and C t to C4 alkyl;

Z is a carborane cluster comprising at least two carbon atoms and at least three boron atoms, or at least one carbon atom and at least five boron atoms, within a cage structure;
n, p, s, t, and v independently represent 0, or an integer from 1 to 20;

m independently represents 1, 2, or 3;

q and r independently represent 0, 1, 2, or 3;
a, b, c, and d independently represent 1 or 2;

k, l, u, and w independently represent 0, 1, or 2;

e, f, g, h, i, and j independently represent 0, or an integer from 1 to 5;

provided that at least one of Yl, Y2, Y3, and Y4 represents formula (2); each of the sums a + e + k, b + f+1, c + g + u, h + d + w, q + i, r + j, independently represents an integer from 1 to 5; when any of k, 1, u, or w is not zero, then at least one of YI, Y2, Y3, and Y4 represents fo~-niila (2); and M is either two hydrogen ions; a single monovalent metal ion; two monovalent inetaI
ions; a divalent metal ion; a trivalent metal zon; a tetravalent metal ion;
apenta'vatent metal ion; a.hoxavalent rnetal ion; a radioactive metal ion useful in rad'zozsOtcape-znediated radiation therapy or imageable by single photon emission computed tomography (SPECT) or positron emission tomography (PET), a paramagnetic metal ion detectable by magnetic resoixance zrnaging (1~~~; a metal ion suitable for boron neutron capture therapy (BNCT) or phatodynairdc therapy (PDT); or a combination thereof;
wherein the.
porphyrin-metal complex derived from a single mo.n0valent metal ion is charge-balanced by a counter cation, and the porphyrin-metal complex dcrived from a trivalent, t~travalerzt. pentavalent, hexavalent metal ion is charge-balanced by an appropriate nu.mbex of counter anions, dianions, or trianions.

[00151 Z is preferably selected from the carboranes -C2)FIB91-Ija or -CzHBio Hi0, wherein -C,_:~91110 is nido ortho-, meta-, or para-carborane, and -Ca~~~~IO is closo oztho, meta-, or para-carborane.

_3_ 100161 M is preferably vanadium (V), manga-nese (Nln), iron (Fe), ruthenium.
(Ru), tedz:ta.etium (Tr,), eb.rcrrnium (Cr), pTatznuna (Pt), cobaJt (Co), nickel (Ni), copper (Cu), zinc (Zn), germanium (Ge), irAum (i:n), tin (Sn), yttrium (Y), gold (Au), barium (Ba), tungsten OAT), or gadolinium (Gd). In a more preferred embodiment, M is copper (C;u.) or nickel K).

~001, 71 In one embodiment, a, b, c, and d m 1, Y', Y~, "Y3, and y4 are represented by forrnula (2); D 's Z; Xt and ~e are 0; R', R~, W and R~ axe H; n and p are 1;
m is 2; Y', Y2, Y3, and Y4 are in the, meta position on the phenyl ring; the ..,K2")(GR~R)~-D
substituents are in the 3 and 5, or 3 and 4, positions on the phenyl ring, and e, f, g, h, k, 1, u, and w are 0.

[00181 In another enabcsdinxent, a, b, c, d, e, f,.g, and h are 1; k,1, u, and w are 0; Y', Y2, Y3, and'k'4 are in the para position on the phenyl r:ng, W1, V , W3, and W4 are in the meta position of the phenyl ring, W', W2, W~, and W4 a-re %ndependently, hydroxy or alkoxy, and the ,.Xk~CR3R4~,-D substituents are in the 3 mid 5, or 3 and 4, positions of the pheiiy1 ring, and D is Z. Preferably, alkoxy is raethoxy.

100191 In another embod'zme.nt, k,1, u, and w are 1; a, b, c, and d are 1, Y', Y2, Y~, an.d Y4 m represented by formula (2); Xl and X2 are 0; R', R.', R' and R~ are H; n an.d p are 1;
and m is -1; Y', Y2, Y', and Y4 are in the metap.~sifion on the phenyl Tings;
Y5, y6 , Yi, and Y4 are in the para position on the phenyl rings; the _X2..(CR?R) p D
substituents are in the 3 and 5, or 3 and 4, positions on the phenyl ring; D is Z; X' is t), W and R~ are H; v is 1,ande, f,g,andh are 0.

[0020) In yet another embodiment, a, b, c, and d are 2; 'Y'~, Y2, Y3, and 'Y4 are represented by fonnula (2); :Xl aarxd )e are (); .Rr, W, R.a and R~ are H; n and p a.re l; m. as 2, Y', y'', Y3, aad y4 are in the rneta positions on each phenyl ring; the ..x2-(c.R?R),D
substituents are in the 3 and 5, or 3 and 4, positions on the phenyl ring; D is Z; k,1, u, and w are 0; and e,f,g,andhare{}.

10Ã}21] In yet aTiother embodiment, a, b, c, atzd d are 1; c, f, g, h, k, 1, u, aiid w are 0; "Y~, Y2, Y'3, an.d. 'S''~ are represented by fOrxraula. (2); Xt and ~0 are 0; R', R~, R? and R~ aTe H;
n and pa.re 1; rn. is 2; Y', ~.~2, ~~, and y4 are in a meta position on each plienyl ring; the ..
)'-(CR~~~)p-D substituents are in the 3 and 5, or 3 and 4, positions on the phenyl ring; D
is accorciiiig to fonuuta (3), Nyherezn X' is tJ, R~~ a-nd R" are H, s is 1, D' is Z, q is 2, and i is 0. Sin.ce i is 0, V is not present.

[0022] In yet another embodiment, When the porphyarz-n compound requires a counter dianion, the counter dianion is a porg}iyrin compound containing a divalent negative charge. The porphyrin compound containing a divalent negative charge may be a carborane-containing porphyr.in canzpauaad of t.he presentinvention, with the proviso that M is absent.

[0023] The present invention also zzxelu.des methods of tumor imaging by SPECT, PET, or MRI, as well as metla.ods of bimodal cancer treatment su~li as BNCT and PDT
that require the adminktration to a subject ~~~ composition that co:rnpnses one or more of the porphyrin compounds described above. In a preferred embodiment, the composition is essentially one or more of the pc~~~iyz-in compounds described above.

DETAILED DEzCRIPTION OFT~~ INVENTION

[04241 The inventiOn. relates to boron-containing 5,10, 15, 20-tetraphonyl porph.yrins havzng, the formula ~~~~~ (Y5)k \(W4)h (/)(Y1 )a (8),~ /\J(WI)e N ~' ~ ~ .

N-M-N

(W3~~ (y6)I
(Y3 c (y7)u (~2)f 2~~

100251 Y', Y'~, Y~, and 'Y4 are independently on the ortho, meta or para position on the phenyl rizigs, and a, b, c, and d intioperldently represent 1 or 2. Y', Y2, Y, and y4 are independently hydrogen, alkyl, cycloa~.~yl, aryb alky-lary4, ary~~~kyl, heteroaryl, or an alkyl, cycloalkyl, aryl, alkylarA arylahkyl, or het~~oatyI group substituted With.1 to 4 liydraphilic groups selected from hydroxy, aikoxy, -C(C3)OW, -SOR~, -SOzR~, nitro, ami.do, ureido, carbamato, wSR7, -NR8R?, or poly alkyleneoxicle, or a substituent represented by the fo:cxnnla (X2-(CR 3 R'~)~ ~]m -X'-CI~'R2 ~ )n <

p.rov3.ded that at least one of Y', Y2, Y3, and Y' represents fO.rmula (2).
..~~..

100261 In fo:rtnula (2), X' and X2 are independently o-xygen or sulfur, and R', R..22 W, and R~ are independently selected from hydrogen and aI.kyl groups as defined below, except that the a~lcyi groups fcar R', R.x, W, mid R..~ contain 1 to 4 carbon atoms.
The subscripts n and p independently represent 0, or an integer from 1 to 20, and m independently rPpresents 1, 2, or 3.

10027] D represents independently, Z, hydrogen, or a suhsfituerzt represen.ted by the formula [X3~.~~(CR't~R"), D"Ja ~~ -W), (3), provided that at least one D is Z or is represented by fonnu1.a (3).

[00281 Sn formula (3), X3 is indepenc3ently oxygen or ~~~fur; R", and R" are xnd.epcndently selected from hyd.rogen and u1.k-yl groups as ~efined below, except that the alkyl groups for Rlo arzd R' 1 contain 1 to 4 carbon atoms; s ind.ependentl) represents 0, or an iriteger from 1 to 20; and q independently represents 0, 1, 2, or 3, provided that vvTien q is 0, or when q is not zero and D' is solely hydrogen, t:h.en. at 1east one D
is represented by Z, or Wh,en q is not zero and D' is represented by formula (4) and r is zero, then at least one D is represented by Z.

[00291 D' represents independently, Z, hydrogen, or a subsiituezit represented by the formula ~...,..,.~~fX4-(CR'2 R 13)f-Z]r (W6)j 100301 In formula (4), X4 is independently oxygen or sulfur; R,12 and R 13 are independently selected from hydrogen and alkyl groups as defined below, except that, the alkyl groups fax R" and R" contain I. to ~carbon atoms; t independently represents t?, ox an integer from I to 20; and xindependentSy represents 0, 1, 2, or 3.

[0031) Z is i cazborane cluster comprising at least two carbon atoins and at least three bc~ron atoms, or at least one =bcan atom and at least five boron atoms, within a cage sira:cttire, Some exanpl.es of carborane clusters in.c1,ude the regu..[ar polyhedral carbaTzne clusters, also known as cIoso structures, as weU as ionized fragments of the polyhedral clusters, also known as nida structures. Sonae examples of the preferred carboranes of the present invention include -~21-IBqHzo or -C2HBroH3o, Whereiia -C211B911Fo is nido aztho-, meta-, or para-carborane, and -C2H)3iOHza is closo ortho-, meta-, or para-carborane.

10032 ] Wz, W2, V, W4, Ws, and W6 are hydrophilic groups independently on the o-rtho, nseta or para position on the phenyl rings. W', W2, V, W4, W', and W" are independently selected frc~in hydroxy, alkoxy, -~(O)C3R', SOR~, SO~,R~, nitra, amido, ureido, =baznato, -SR.7, -WR.", or polyalkylene oxide. R~, R6, R', k', R~, are independently seIected fTam hydrogen and alkyl groups as defined below, except that the alkyl groups for R', R.~, k~, R~, R? contain 1 to 4 carbon atcizn.s, The subscripts e, f, g, h, i, and j independently represent 0, or an i-ateger from. 1 to 5.

[00331 Y, Y' ', "V7, and Y' are independently on the ortho, meta or para position on the -plienyl rings, and are represented by the fanmul~ ~" - (C1~~Rb)7- Z hl for.rnula. 5, V is independently oxygen or sulfur; V and e are independently selected from hydrogen and alkyl groups as defined below, except that the al.k.~l groups for R~ and e contain 1 to 4 carbon atonis; v independently represents 0, or an integer from 1 to 20;
k, 1, u, and w independently represent 0, 1, or 2; provided that each of the sums a + e + k, b + f+l, c + g + u, h + d + w, q + i, x+,j, independently represents an integer from 1 to 5;
when any of k, I, u, or r~~ is not zero, then at least one of Y~, Y~, Y", and Y'4 represents formula (2).

100341 When any of Y1, 'Y2, Y3, or Y4 is alkyi, a1kyl is a straight chain or branched alkyl ;xc~~a.~p contai-ning 1to 20 caTbon atoms inoiueling, optionally, up to three double or triple bonds. Some examples of alkyl groups include methyl, ethyI, n-propyl, isca_propyl, n..
butyl, iso-butyl, sec butyl, tert-butyl, propenyl, 2-butenyl, 3-butenyl, 3-butynyl, 2-methyl-2 -butenyl, u-pentyl7 dodecyl, hexadecyl, octadecyl, and eicosyl.

10035] The ~~~ group may be unsubstituted or substitu:tecl. with I to 4 bydroghilic groups. Some examples of suitable hytirc~pbilzc groups include bydroxy, alkoxy, -~(O)OR', -SOR~, -SO2R~, nitro, amido, ureido, c~bamato, wSR~, -WR9, and poly-alkyleneoxide. R, R~, R.~, R~, and R9 are independently selected frozn Ixydrogerz and alkyl groups as defined above, except that the aW groups for R.5, R.~, R7, R8 cc~ilta.in 1 to 4 carbon atoms.

10036] The carbon atoms of the a1ky1 group may also be substituted with I to 4 heteroatoms. In this specification, heteroatoms are 0, N, or S. The heteroatoms are not adjacent, aiad are separated by at least one carbon atoni.

[00371 NVhen any of Y', Y~ Y3, or Y4 is cyclo~.~rl, the cycloalkyl ring is a 4, 5, 6, or 7 member cycloalkyl ring. The ring may be saturated, or may contain I to 4 unsaturated (i.e., double or triple) bOnds. Some examples of satu.rti ted cycloalkyl nngs iiiclude cyciobu.i;ane, cyclopentane, cyclohexane, and ~~clopen.tane rings. Some examples of unsaturated cyc1oa1kyl rings include cyclobutene, cyclopen.tene, cyclohexene, and 1,3-cycloheptadiene rings.

100381 The cycloalkyl ring may optionally be substituted with 1 to 4 :heteroatoms of 0, N, or S. Some examples of cycloalkyl rings substituted with heteroatoms include pyrrolidine, piperidine, piperazine, tetrahydrofuran, furan, thiogbene, 1,3-axa.zolidin.e, imidazole, and pyrrole rings. The cycloalkyl rings may be optionally substituted with alkyl as defined above, or Wzta 1 to 4 hydrophilic groups, also as de~"zned above.

_ 1 4..

j0039) The cycloalkyl ring may be fused to 1 to 3addi.tzonal4, 5, 6, or 7 znezn.ber cycloalkyl or phenyl:ri.n.gs. Some examples of fused "cIoa11cy3 rinc,,,,s are bicyclo[3.3.01actan.e, bicyclo[4.3,01ncsn,w3-ene, triphenylene, and 1,2,3,4-tetraliydronaphtba1ene rings.

f0040] When any of Y~, +arY4 is aryl, aryl is a 5, 6, Ox'7 znember aromatic z-ing, preferably a plienyl arlng. The aryl rings may be optionally substituted with al.ltyl as defined above to produce Acyla~~ or arylalkyl groups. The ary1, alkylaryl, and ary1alkyl groups may be substituted with 1 to 4liydrc~~liili~ groups, as defined above.

f0041) The aryl ring may optionally be substituted With T. to 4lxeternatorns of 0, N, or S, resulting in a heteroaryl ring. SOine examples of heteroaryl rings include thicaphon.e, pyridine, oxazole, thiazole, oxazine, and pyrazine rings, The heter0aryl ri-ng may be substituted Wztli 1 to 4 hyerOphilicgrnu.ps, as defined above.

f00421 The aryl or heteroaryl ring may also be fused to 1 to 3 additional 5, 6, or 7 men-iber aryl or heteroaryl rings. Some examples of fused arvl and lieteroaxyl rings include napthalen.e, anthracene, phenanthrene, trzplien.ytene, chrysene, indoline, quinoline, and tetraazaz~plithalene (pteridine) rings.

[00431 In this specification, an a1koxy group contains an a.ll,.~1 portion as defined above.
Some examples of alkoxy groups include znothaxy, ethoxy, propoxy, n-butoxy, t-butoxy, and dodecyloxy.

[00441 Apolya2kylene oxide is defined according to the formula -(CHz)d-O-((CH2),-O-]"-[(GH2)f-C)-]y-(CH2)g7OR', wherein, independently, d is 0, or an integer from 1 to 10, c is 0, or aza, zn.teger from I to 10, f is 1to 10, g is 1 to 10, xand y aare each independently 1 or 0, and R' is either H or an alkyl group as defined previously, provided that when e is 0, then x is 0; when f is 0, then y is 0; W1ien e is not 0, then x is 1; and when f is not 0, then yis 1.

10045) A preferable polyalkylene oxide of the invention is polyetliylene oxide.
Pn1yethylene oxide is defined aoccarding to the formula -(CH2)a-O-[(GHx),w O-b-[(CH2)f-O-]y-(CH2)e"ORa, wherein, independently, d is 0 or 2, e is 0 or 2, f is 0 or 2, g is 2, x and y are eacla independently 1 or 0, and R' is either H or an ethyl group, Provic~ed that Whcn c is (?, then x is 0; when f is 0, then y is 0, Wlien e is not 0, then x is 1;
and V~hen f is not 0, khen y i.s 1.

[00461 In fonmula (1), M may be two hydrogen ions, a single:rza.onovalent metal ion, or two ziioiaovalezit n tal ions. Some examples of suitable monovalent metal ions inclur~~
~i+I, Na~z, K"" CU+I, Ag z, .A.u~% and Tl+', When M is a single monovalent metal ican.;
the resulting pmphyrin-naetaI complex anion is charge-balanced by a counter cation.
Some examples of counter cations zraclude any of the foregoing monovalent metal ions, and amnonium and phosphonzmn cations, such as tetramethylanun.oniu.rn, tetrabutylammonium, and tetraphenylamm,Onium. The counter cation may be either bound or associated in some form. Witli the pozphyrzn- zneta1 complex.

[00471 M may also be a divalent metal ion, Some examples or sua.t~ib1e divalent metal ions include V+2a 1VSn'"2> Fe"'x Re'2s Co+~> Ni+2a Cu+~a P&aa a ~:t'-z Zn~xa W2s Mg-12a Se">
and Ba~'.

10048J Altematively, M may be a trivalent, tetravalent, pentavalent, or hexavalent metal ion. Some examples of suitable trzvatent metal ions include Ge, Y+~, Ino, Cr ~, C"aa ~, AI'E'3, E-u4"-, and Dy 3. Some exatnpI~~ of suitable tetravalent metal ions include Tc+4, Ge'4, Sn*4, and Pt4". An exampI6 of a suitable pentavalent metal ion is 'T'c+s. Sorne examples of suitable hexavalent metal ions include W+5, Tc+, and Ma+6. The resulting porphyrin-metal complex cation is charge-balanced by an app.ro;przatemmmlaer of counter anions, dianions, or trzanions. For example, aporphyTx:n-rn.etal complex ca.txon derz,,fed from a trivalent nxctal ican may be charge-balanced by a single counter anion, and such a complex derived from a tetravalent metal ion may, for example, be charge-balanced by a single counter dianion or hvo counter anions, and so on.

- lfi -[00491 Some examples of suitable counter anions include chloride, perchlorate, sulfate, nitr~,~te, and tetrafluoroborate. Some Qxanples of suitable counter dianions include oxide, sulfide, or a poxphyrin compound containing a divalent negative charge. The porphyrin compound containing a divalent negative charge tnay be a porphyrin compound of the present invention with the prt~iiso that lvf is absent. An example of a suitable counter trianion includes phosphate.

tOO5E31 The counter ardon, dianion, or trianion may be either bound or associated in some form with a ca,ncorane-cantaini-ng porphyrin e~mpound of the present invention. The carborane-containing porphyrin compound may also be bound to or associated with neutrally charged molecules, such as molecules of solvation, for example, water, acetonitrile, methanol, and so on.

100511 In addition, M may be a radioactive metal ion i.rn:a.geab1e by single photon emission computed tomography (SPECT) or positron emission tomography (PET).
Some examples of radioactive metals suitable for SPECT are 'tu, 9"Tc, "'In, aiicl those for PET include54Cu, 55Co, M may also be a radioactive metal useful as a radiopharmaceutical fox therapy. Some examples o;~radioactive metals suitable for such theropy include OY3 "'Rey "7Cu.

j00521 M may also be a pararna;n.etzc metal ion detectable by magnetic xes~iiance imaging (MRI). Some examples of sucb meWs include Ma, Fe, Co, and Gd.

10053) In addition, M may be a metal ion suitable for boron neutron capture th.e.rapy (B~CT) or photodynamic therapy (PDT); or a combination thereoE The metal ions suitable for BNCT include those described thus far, Wzth the exclusian of those that aare photoactive, such as Zn and Sn. Such photoactive metals, and particularly those with lQng=-lzved triplet states, are preferable for PDT, Since the dosage for B~v~CT is 100 to 1000 tinies greater than the dosage for PDT, a significant accumulation of photoactive metal xn th.e* sk.i,n could result if such photoactive rnetals We:re used in BNCT. Such an accumulation ofphotoactive metal may cause biological damage.

10054] The invention also relates to methods of treating iuniors. Tn a preferred embodiment, the method of treating malignant tumors, especially brain tum.ors, is via BNCT. BNCT is a himodat cancer treatment based on the selective accuznulation of a stable nnelide of horon known as horon- 10, or 1013, in the tumor, fc+IloNved by irradiation of the tumor with fhernalized neutrons. The thermalized neutrons impinge on the boron-10, ~auszng a. nuelear fission. reactic-rz. The nuclear fisszon causes the highly localized release of vast amounts of eaergy in the form ofh:igh li.nearr-em~rgy-transfer (LET) radiation, ~ljich can more effectively kill cells than low LET radz'ation, such as x-rays.
[00551 BorOn-1(} undez:gaes te.folloWing nuclear reaction Avhen captured by a thermal neutron:

z~B+n ~-~- ~ B

~~B '7 Li + 'He+,y (478 keV) fOO56J In this nuclear reaction, a boron-10 nucleus captures a neutron forming the metastable nuclide I I B? which spontaneously and nearly instantaneously disintegrates into a 4He and Ii particle, Which together possess an average total k-a.netic energy a~2,34 MeV. These Mro ionized particles travel about 9 ~tm and 5 p.m (7 2 ttm) in opposite directions in soft tissue, respectively.

fflO571 The distances traveled by the 4He and Ii particles are comparable to the diameter of many tinn.ax and tumor-associated cellsr Therefore, the efficacy of BNCT
resides in the production of hig .,hly localized, hig.h. LET ionizing radiation within the tumor. The targeted tumor thus receives ala.rge dose of radiation while sparing surrounding normal tissue.

[0058] .xn the case ofhrain tumors, after administration oft.he boron compound, the pa.tient's head is ir.radi,ated in the general area of the brain tumor with an incident beam or field of epithermal (0.5 eV-10 keV) neutrons. The neutrons become progressively _~~_ tlaerm.alized. (average energy approximately 0:04 eV) as they penetrate deeper into the l'iead. As the ncutrvns become #hennalized, they aTe more readily captured by the boron-concentrated in the tumor eells and/or tumor supporting tissues, since'tie capture cross section is inversely proportional to the ueutrcan vel.ocity.

fOO591 In BNCT ofmaligzian.tbra.in tur.n.ors faHowzng the metierd of the present invention, the patient is first given an infusioji of a, carhorane-contaznzng porphyrin of formula (1), which is highly enriched in boxon-14. The caxborane-contain%ng porphyrin is then concentrated preferentially in the brain tumor Widii.n the effective :irradiation volume, which, for brain tumors may be a su.bstantial pmt of the brain. For example, tumors located in most or all ofonc hemisphere and some or all of the contralateral licr-n7sphere of the brain can accuzniilate boronated porphyrins.

[0060] The twmor area is then irradiated With the:rmalized neutrons (primary irradiation), some of wbich are captured by the boron-10 concentrated in the tuznor. The relative probability that the slow-moving thermal neutrons will be captured by the boron-10 nuclicie is high compared to the probability of capture by all of the other nuchcies normally present in mammalian tissues, provided that boran-10 concentrations in tumor tissues is greater than 30 4a, 100611 Since a minuscule proporti.on of the bcaron-1(} nuclei in. and axraund, a tn.moT
undergoes thenuclea.r reaction inunedaat~~y after capturing a neutron, a high concentration of bcaxon-1Q in the targeted tissue is necessary for BNCT to be clinically effective. Therefore, to maximize the concentration of boron-10 in the targeted tissue, the carborane clusters arehzghly enriched in boron-10, Specifically, the boron in the carborane cluster is ezuiched to at least 95 atom~'la in borOn 10.

[0062] An advantage of the present invention over the prior art for the t.reatznent of cancer is that the boron-containing porphyrins of the present hivendan selectively accumulate in neopJas.xns in mre preferred ratios than other known boron-containing compounds.

100631 Additionally, the porphyrin compounds of the present inve.ntion that have been tested in vivo are non-toxic at theoretically therapeutic effective doses. The higher selectivity and IoNv~r toxicity of the carborane-containing porphyrins of the present invention allow for the selective destTuction, of tumor tissue with n-Animal dzsnzption of normal tissues and tissue function, when irradiated.

10064) Another advantage of the earhorane-ccsntai.ning pozph,yrins of the present invention is their increased polarity, imparted by the hydrophilic groups Wz, W2, IV', W4, W5, and 'W' ; and/t~r the ether :tinkages. The greater polm.ity of such groups render the fietraplienyl porphyrin compounds less 'lipophihe, Which effects a reduction of the amount of an emulsifying co-solvent during acmzni..stratzon. TherefOxe, the microlocalization wifla.in the tum.or cell may be improved yielding a higher relative biological effect.

100651 hn addition, th.~ ether linkages in the carborane-containing porphyrins of the present in:ventican provide more chemical stahihty than, foz example, ester or amide linkages, which can much more easily hydrobqe, thereby catising the loss of the baron functio-ndlity. In fact, the ether linkages possess nearly the same resistance to hydrolysis and other ~'can'ns of chemical attack as a carbon-carbon linkage.

100661 It is significant that some of the ~~~fcrred carborane-containing porphyrins of the present invention contain in excess of 8 carbotane clusters (80 boron atoms).
In fact, the present invention provides for carborane-containing porphyrin molecules containing in excess of 16, 32, or even 64, ca.rborane. clusters, Which is higher than any carborane-containing porphyrins currently known.

100671 Since such. Iixgkz carbvtane-c0ntain%ng poxphyrzn molecules deliver more boron to a target, i.e., are more potent, they permit lower required molar doses of porphyrin as compared to the porphyrin compounds in the prior art. The lower molar dose of carboraza.e-con.taiza.ing porphyrin allows the amount of boron at the target to be significantly increased while keeping blood porphyrin concentrations well below toxic ftesho1d values.

10068) To accumulate the requisite amount of accampound of the present invention in a tumor, generally a systemically injected or infused dose of about 10-50 mzlligrams of boxon-10 per kg body weight in a pharmaceutically acceptable carrier is administered to a patient. The carrier may include sucli comrz Lerxcia.t~y available solvents as Cremophor EL, propylen:e gtyeo1, TNveea 80, polyethylene glycol, or liposomes. The compound is adrniWstered in one or more doses, the last dose being given between abaut 1 hour and one W~el- prior to the epithermal neutron irradiation.

[00691 The timing of the neutron e1posure, depends upon the coneentrati:on of the porphyrin in the blood, Nvhich decreases more rapidly with 1;.inie than the ~orphyrin concentration in the turnor. 'nie timing of the neutron exposure also depends on other factors that are well known to those st-i11ed in the art of clinical BNCT.
These other factors include the pharna~okin.etic behavior of thr: compound, (e.g., the rate of absorption of the compound into the tumor and into the tumor vasculature) and the rate of excretion from and/Ãar metabolism of the conipound in the tumor and various other tissues that absorb the compound.

100701 In anotherpxeferred enibodiment, the m.ethad, of treating malignant tumors of the present invention is via PDT. PDT is a birnodal cancer treatment based ozl the selective accumulation of a porphyrin in a tumor, followed by irracliatzon of the tumor Witli laser red light. Upon activation with light, an electron of the porphyrin is excited from the singlet goLtnci state to a singlet excited state. The electron ttien can eitlaer return to the singlet ground state with the emission of light causing fluorescence, or it can change its spin via intersystezn: crossing to the triplet state. In the decay of'the triplet back down to the ground state singdetx it can transfer energy to ground state triplet dioxygen NvhicIa fonns the higbly reactive singlet oxygen. Bian-iolecules that react most readily with singlet oxygen include unsaturated lipids and alpl.xa amino-acid residues, botli of which are major constituents of biological membranes. Beyond a certain reversible or repairable threshold, damage to znenibranes, especially to endothelial cell membranes, can lead to local vascular thrombosis and shutdown of blood circulation.

10{}71~ In using PDT in the present invention, ihe patient is first given an injection or infusion of a phatOsonsxtizzng carborane-containing porphyrin of fonrnula (1).
Fzber-csptzc probes are then used to iIlurnin:atc the tmnor tissne. For matipant tumors, it is preferable that the PDT photosensitizers have optical abserbance peaks at sufficiently long wavelengths for maxiimnm penetration to the depth of the fiumor, [0072] :tn a preferred embodiment, the tlierapeufic treatment of znalip, ant tumors is augrnentcd by the use of SPECT or PET, h-i SPECT, the patient is first given an infusion or i-njection of a cauipound of forxnu.la (1) WI ierezn M is a gamma-emitting radioactive metal ion. The patienVs head is then scanned noninvasively and the radionucfide concentration, and hence indirectly, the average boron concentration, in each pixel or voxel representing brain or brain tumor tissue is imaged. Contour lines representing zones of equal boron-1 0 cOncentratinn can thereby be drawn on each imagc, of the brain.
100731 SPECT of the brain is at least one order ofrnagnitude more sensitive to isotopic tracers than is conventional radiography or computerized tozno;~aphy. In.
addztzon, SPECT results, as opposed to results from canvQntional radiography, can be analyzed to provide quantitative information either in defined vnltunes or voxels of the brain iznages, in the concentrations of boron relevant to BNCT treatment planning and hnpleme-ntation.
SPECT scanning can indicate the p~~smce of a tumor in the patient, as well as its location in the brain or elseNvhere in the body. SPECT scanning is noninvasive, fast, and convenient.

[00741 However, the positron emitting PET-imageable radioisotope Cu-64, is more readily a.vailahle- than is Cu-67, used in SPECT. Because of the much greater availability of Cu-64, we have carried out preelinical PET studies usina a Cu-64 labeled pcrrphyrin.
[00751 In another preferred embodiment, the thezapmtic treatment of malignant t.unors is augniented by the use of 11W. In MRI, a patient is first given an infusion or injection of a , porphydn of fonnula (I) chelated to a suitable solution containing a carboxane-con.ta%n.ina paramagnetic metal ion. For a hrazn, tumor, the pa.tient's head is then scanned and the ?2 pararna.gnetic metal ion concentration, and tlZ.us, boron coiicentration in the brain is imaged and quantified. MRI. utilizing the conapounda of the present zn-vention may perrnit rapid enhanced targeting and treatment planning for nnutrOn irradiation in BNCT before, during and after infusion Wlien the boronated ctrxnpound is being redistributed in blood, tumor, and healthy tissne, 10076) The carborane-containing porphyrins of the present invention are synthesized through aserz~s of separate steps. Provided beloNy is first, a summary ofti.e spthetic steps required for the preparation of the preferred carbcarane-contain.iiig porphyrins a~the present invention. The synthetic summary provides general methods for synthesizing compounds of the invention, and is thereby meant to encompass nin-neraus ways for synthesizing each compounrt. For example, different startizig materials may be used to synthesize the same product, and each starting material may require a cli.ffercnt set of reaction conditions such 2s temperature, reaction time, solvents, and extraction and purification parocedures.

[00771 The specific examples describe a.prefezTed method for synthesizing the compounds of the present invention. The scope of this invention is not to be in any -VN-ay limited by the examples set forth herein. For example, assymmetric carborane-containing tetraplien.ylporphyzin compounds can be synthesized by using a rnzxture of different benzaJ.deh.yde or dibenzaldehyde starting materials and proceeding with a similar synthetic reaction as shown in Reaction Scheme S.

[0078] Reaction Scheme 1 HX ~H Coupling Agen;t~ '.,.~' x ~
I + R,.,~-- ~0. I
Solvent A reflux OH OH
where X is eitlxer 0 or S, solvent A. is preferably a polar nona-protic solvent such as acetone, and R is a haIog, gen, preferably Cl. The coupling agent is any compo-uzad, mixture, or sequence of compounds capable, of coupling a phenol or thiophenol and an dkyl halide to produce an ether. Some couptin~ agents may nofi require reflux conditioiis or a polar non-protic solvent. PxefeTabl~, the co~a..~ling agent is a mixt:ure afpotasszum.
carbonate aza.d potassium iodide (K,,C03/KJ).

10079] Reaction Scheme 2 x ~
~ ~ Acid Catalyst + R-C-O-C-R, ''.

OH OCR
O
where X is either 0 or S; and the R groups oii the arhyclride may be ttie same or different, and selected from alkyl, cycloal.k.~yl or aryl. A preferred anbydride is acetic anbydride wherein R is methyl. The acid catalyst may be any Bronsted-Lowry (proton donating) acid that does not interfere with conversion of the alcohol, to the ester product.
Preferably, the acid catalyst is sulfuric acid, HzSO4.

100801 Reaction Scheme 3 41~x x~~~ xll-~z Borane cluster so1vent B, reflux QC F~ O~R

where X is either 0 or S, solvent B is preferably a polar, aprotic solvent, preferably acetonit.rile, and R is as defn.ed in reaction scheme 2. The borane cluster is any cluster comprising at least three boron atoms within a cage structure. For example, the borau.e cluster can be decaborane, BIOH 14. The boz-ane cluster reacts with the triple bond of the propargyl starting material to ~'c~rm the carboranyl product. Thus, in the case of decaborane, Z represents the carborane -C2HBIOHIO. Z represents any carborane cluster comprising at least t~Nro darbon atoms and at least three boron a.toms, or at least one carbon atom and at least five boron atoms, Within a cagge structure. For exarzxple, the carboraixc cluster may be ~~zBBsHro rar -C2)HBjoHjo, wherein. -~2HB9Hj0 is iazdo ortho-, meta-, or para-carborane, and -~~~joHlo is cla,so ortho-, xneta-, or para-carborarae.
[0081] [Reaction Scheme 4 z .11~ X X.111~z zx X.-~ Z
Protonating Acid Protic Solvent OCR OH
a!

Wbere X, R, and Z are as defined above. The protonating acid is any acid, a.cid mixture, or sequence of acid additions capable ofconvez~g the, ester into the alcohol product.
Frefembly, the protonating acid is concentrated HCI. The protic solvent may be, for example, an alcohol such as methanol.

100821 Reaction Scheme ~

~ Halogenating Agent OH ~

where X and Z are as defined above, and D is a halogen. The haIogenatingr agent is any agent capable of converting the hydroxy substituent of the starting materia.l to a halogen.
Preferably, the halogenating agent is a 1:1 mixture of carbon tetrabromide and tzzph.eny1phosphinn, wherein D becomes a bromide. 'I'he reaction is performed preferably in an ether solvent, such as tetahydrofuar'a.n (TBF).

[0083] Reaction Schezne.6 x ~ ,. :X.z + HX Goupl:zng Agent Solvent C reflux OH
D
Z
~
x OH
x z Whez=e X, Z, and D are as cle;F.ined previously. Solvent C is preferably a polar, apratic solvent such as acetone. The coupling agent is any coznpound, mixture, or s~quen:ce, of compouinds capable of coupling a phenol or thiopheDal and an alkyl halide to produce an ether, Some coupling agents may not require reflux conditions or a poIara aprotic solvent.

Preferably, tlle coupling agent is a znixtur~ of pcstassiUxn carbonate aiid potassium iodide (~~COAP.

[00841 Reaction ~c_herne 7 z z x Y
Oxxdant OH Solvmt D CH
x z z where X and Z are as previously defined.. The oxidant is any oxidizing compound capable of,selective1y cobverting a primary alcohol to an aldehyde, preferably 2,3,.
d%chioro-5,6-dic}fano-1,4-benzoquinnne (DDQ) or pyridinium chicaxochroznate (P'Cq).
SciIve2 it D is a non-polar aprotic solvent, preferably clichloronieth.zne.

[0085) R.eactian Scli.eme fi z H
x N Coupliaa~ Systexn ~H Sc~I~rent E

0 y4 z YI

H
N N~~.
H
N
y3 Wherein yl, y2, yl, and y4 are represented by z -x Z. X and Z bave been previously defmed. The coupling, system preferably cOmpT.is~s a LoWZs acid (e1ectroii acceptor) such as boron tr.i.fluoride (a3F3) or trifluoraamfic acid (TFA) to form the intermediate porphyrinogen from the pyrrole, and ~enzaldehyde and an axidizung agent such as 2,3-cichloro-5,6-cl.icyarxes-1.4-benzoquin.one (DDQ) to oxidize the porphyrinogen to pozphyriu, Solvent E is a nonpolar aprotic solvent, prefexably dichloromethane.

100861 Reaction Sebeme 9 Y4 y4 Yi Y, ~ ~,tGtal salt of metal t~
i0a M
~
~tSalventF I
~~~~
H ~
. ~ N N ,~.
y3 3 -- ~ ~

y2 y2 Wh~~e Y', Y~, Y3, and y'' are as defined above. In a preferred embodixnent, M
is selected from the group consisting of vanadium (V), manganese (N4n), iron (Fe), ruthenium (Ru), technetiuin (Tc), chromium (Cr), platinum (Pt), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn)a ge.zmaniuzra. (Go), indium, (in), tin (Sn), yttrium (Y), gold (Au), barium (Ba), tm;sten (~), and gadolinium (Gd)~ In a more preferred embod%nient, M is copper (Cu) or nickel (Ni). The metal salt used contains the metal ion M chelated to the pozphyrin.
For example, for the compound where M is desired to be copper, copper acetate, i.e., Cu(O,Ac)2.H2O, may be used as the metal sa.lt. Solvent F is any solvent or solvent niixture capable of at least partially solubilizing the pozphyr%n and.mefial salt, and that does not interfere w'rth incorporating the metal into the porphyri-a.

100871 For example, using schemes 1-9, and as ~Nril1 be seen through examples 1-9, the S-carbarane-conta.ining porphyrin, i.e,, porphyrin (VII), ~~ be'en prepa~ed.
Porphyrin NrM
has the following structuxe-w29-O~-Ar / ~ ~

~-Ar 02HB10H1~3 ~ N 0-/
1 ~N N~ Ar H
Ar --~ NI-I
0. -\
~2HBIOHIO
. ~ ~

Ar-O
Porphyrin VM shoWn above. In this case, a, b, c, and d are 1, ''Y"~, Y2, Y"and y4 are represented by fo:rznula (2); D is Z, wherein Z is the -C2BBjoHta carborane;
Xl and 3e are 0; R~, R~, R~ and R~ are H; n and p are 1; m is 2; Y1, Y2a Y3, and Y4 are in the meta position on the phenyl ring=, the _X2w(CR3R),_D substituents are in the 3 and 5 positions on the phenyl ring, and e, f, g, hj k, 1, u, and w are 0.

[00881 Using similar reaction scheznes as shown above, the inventors predict facile syntheses ofPorphyrins A, B, C, and Dx which are shoWra beIow. In fact, starting materials for each o:f'tla:ese porphyrin compounds have either already. been synthesized or are presently in the process of being synth.eszzed.

f{?0891 Porphyrin A, an 8-carborane-containing porphyrin containing hydrophi:lic grou.ps Wi, W2, W3, and W4:

wQ Ar t ~ 2HB1OHIa A~-~ ~
W2 Ar H
N N q2HBIOHIO
H
N
w 4 wl W", ~~, W4 = QCH3 ,Ar Ar Su the case of Porphyrin A above, a, b, c, d, e, f, g, and h are 1; k,1, u, and w are 0; Y','Y'2, Y3, and Y''} (ze,, O-.fi~) are in the para position of each phenyl ring, the hydrophilic groups W', W~, V, and W4 ate in the meta position. of each phenyl ringõ Nvhcrein W' ,%F2, V, and NV4 are methoxy; the ~~O_(CR;.'~) p -1? substituents a,re in the 3 and 5pusations of the Ar phenyl rings; D is Z, wherein.Z is the -C2HBIOHz0 carborane.

- 31.

100901 Porphyfin B, a 12-catborane-containing porphyrin:

C2HB'10H1(l U-Ar /'_'C2HB,OHI0 O-Ar C2KBjDHjO
N
H
Nr ~ Ar - ~ ~
Ar -~ . N 0" ''l G2H~'31QH'10 .~õ--~
H'iOBI(#C2H,.-/ Ar_Q C> ) C2HB1qH'tfl In the case of Porphyrin B above, :, 1, u, and w are 1; a, b, c, and d are 1, Y', Y', Y~, aiid Y" are repx~~ented by fonnula (2); ~l and X2 are 0; R.~, R~, R3 an.d. R~ are H; n and p are 1; and m is 2;Y~, Y'', V, and Y4 (z~e., O-.A. c) are in the meta position of each pheziyl ring;
Y'', Y', Y7, and Y' (in this case, t~-CHz-C2:~ joHlcr) are in the para position of each phenyl ri.ng, the ..x2..(cWR),..D substituents are in the 3 and 5posztions of the .Ar pherz~l rings; D is Z, Nvherein Z is the ~~2HBIOHIO =boxane; X is 0; W and R~ are H; v is 1, and e, .f, g, and h. are 0.

jUO911 Porphyrin C, an 8-carborane-containing pazplzyTin.

O-Ar Ar-O

0 0 C2HBIaHIo Ar ~ Ar 0 N N I AX -H
~r N ~r 0~
0 '-- ~ ~ C) C2HBIOH10 O-Ar Ar-O

Tn the case of Porphyrin C above, a, b, c, and d a.re 2; Y', Y~, Y3, and Y4 (i.e., O-A.r) are represented by formula (~), X' and )0 are 0; R', R~, R3 and R~ are H; n and p are 1; m. is 2; ~,''', Y2:% ~.~'3, and y4 are in the two meta positions on each phenyl zing, the A'-(CR?R'~), D substituents are in the 3arr.d 5 positions on the Ar phenyl z ings, D is Z, wherein Z is the - C2HBj offl0 carborane; k, 1, u, and w are 0; and e, f, and h are 0.

_33..

j00921 Por h ~Ln D a.16-carborane coiitainin~ ~ lj 'n:

O-Ar HIÃr~~~~~H--\
...--~
~'= ~ . ~ -~ C2HB~it3H10 H Ar 0 H Ar Ar -~. N ~

Ar-O C~
~~~~~~C,?H~
hi the case of 1'orphyran D above, a, b, e, and cl are 1; e, f, g, h# k,1, u4 an.ci w are 0; Yl, Y2, Y3, and y'~ ~~ represented by fonnula (.2.); X~ and ~~' are' 0; R', R~, R.~
and R~ are H; n and p are 1; m is 2; Yl, ~.~2, V, aa.d Y' (i.e,, CJ-Ar) are in the meta positions on each phonyl ring; the ..XI-(CWR),-D substituents are in ;the 3 and 5 positions on the phenyl ring; D is according to fonnula (3), wherein X~ is 0, R' and R' 1 are H, s is 1, D' is ~t, Whexein Z is the -C2HB~ciH,o carborane; q is 2, and i is 0.

[0093] The reaction scheme that is curTent1y bei.ng, employed for flie attempted synthesis of the 16~carborane-containing Porphyriii above (Porphyrin D), is shown below:

I,Base 2. 0)eidation 0 + H~ ~ '~ 0/j/), Br-Ar ~. (see reaction H -OH schemes 6 & 7) ""O Ar 1. Pyrrole/Lewis acid 2. Oxidation (sc~e reaction scheme 8) Q ~r HIOBic~C2H~
~
0 0~
I _ _ ._._G2;uB
~ Ar H Ar o-Ar-O 0 HIa~~~C,2H"

~XAAWLES
[00941 Examples have beon set fortli below for the purpose of illustration and to describe the best mode of the invention at the present time. The scope of the invention is not to be in any way izniited by the examples set forth herein.

Example 1 Synthesis of 3,5-dipropar.gyloxyber~~la1caho1 (1) 104951 Finely powdered Ki_CO3, 14 grams (0.10 moles), and Ki, 17 grams (0.10 moles) were placed in a 540 niG rou.ud flask, and 200 mL acetone was added. Under a nitrogen atmosphere, 3,5-dihydrvxyben~lal.cohol, 4.2 grams (0.03 moles), and propargyl chloride, 5.3 grams (0.07 xno1es) were then added. The resulting mixture was refluxed overnight.
The results from thin layer cbroznatography shoNved no sta:rti.ng material (3,5-dihydroxyben.zylalc:taho1) as Avell as the presence of a neW compound. The solution was filtered, and the filtered sol.idwashed with acetone...The acetone of the xesu.Itzzi~ filtrate was removed by rotary evaporation, leaving an organic residue. T3ichIoromthane (50 mL) was acl.ded to dissolve the organic residue, and this Was washed with water (3OmL x 2), and then dried over anhydrous sodium sulfato. After filtering the organic phase, the solvents were removed by rotary evaporation leaving a yeIlow oi~, whzcb solidified upon standing. 6.3~ of product was obtained, which corresponds to a 97% yield.

[00961 The product had a melting point of 79-80 C and gave the following proton n.uclear magnetic res~jiance ('H NMR) spectrum in ppm (in CDCl3 solN~ent):
2.52 (triplet, M, al~.~yl); 2.15 (broad singlet, IK hydroxyl); 4.65 (dou3a1et, 4H, ,ArC~CH2)s 4.60 (sin,glet, 2H, .A.r~H:t); 6.52 (singlet, IH, aryI), 6.60 (singlet, 'k~, aryl).
The prcadu~~ gave the follc~Nving proton-decoupled carbon-13 nuclear magnetic resonance (13C
NMR) spectruni,in ppm (in CDC13 solvent): 56.1 (,ArOCHti)~ 65.1 (ArCH2); 75.9 (alkynyl); 78.6(alk.yny1)> 101.6 (ary1), 106.4 (aryl)x 143.8 (aryl), 159.0 (aryl). The mass spectrum (FAB) showed a parent ion peak of 217.5 that arnatch~d the molecular weight ofthe ccampound>

Exaniple 2 Synthesis of 3,5-ciipropargyloxybenzylacetate (11) 14097) 3,5-dipropargyloxbonzyIalcob.o1 (1), 6.3 grams (0.02:9 moles), was stzrred in 7:rriL
(0.07 moles) acetic an.tiydrs:de. Two drops of concentrated sulfuric acid was then added to the sc~lufion. The solution was stirred in a temperature range of 90-1 00 C
for three hours.
The results from thin layer cbaromatograpliy showed no starting ~~~erial (1) as well as the presenee of a new compou.nd, The solution was then poured into 50 mL of ice water.
Aqueous saturated sodium carbonate solution was add d, slorvly until the pH of the solution was afi.least 8, at which point there -vvas no finther release of carbon dioxide. The aqueous solution was extracted with 50 rnL x 2 of dicbioromethane, and the organic phase was Wasl-ted wi th water (50 nzL x 2) mid then dried with anhydrous sodium sulfate.
The desired product was purified using a pad of silica in a sintered glass funnel, the pad of silica then washed with 200 .n-L dichloromethane. 'fhe dichlaromeiluzra.e of the filtrate was removed by rotary evaporation, leaving a yellow oil, Wh:ich solidified upon standing.
7.2g o.fp.roduct was obtained, which corresponds to a 96% yield.

[00981 The product had a melting, point of 65-66 C and gave the following proton nucle~,r magnetic resonance (H NNM) spectrum in ppm (in CDCI3 solvent): 2.11 (singleta 3H, CH3); 2.54 (triplet, 2H, alkynyl); 4.67 (doublet, 4H, ATOCHj);
5.05 (singlet, 2H, ArCHz); 6.58 (singIet,1H, aryl); 6.61 (singlet, 2H, aryl). The product gave the foIlowing, Proton-decoupled 13C NMR spectrum in ppm (in CDC13 saiveut): 213 (CH3), 56.0 (ArOCH2); 66.2 (ArCHz), 76.2 (alk3xnyl), 78.6 (alkynyl); 1{}2.3 (aryl);
108.0 (aryl)>
138.8 (aryI);159.0 (aryl); 171.1 (CO). The mass spectrum (FAB) showed a parent ion peak of 259.5 that matched the molecular weight aft.h.e compound.

Example 3 Synthesis of 3,5-o-d.icarboranylna.ethoxylhenzylacetate (:11) 100991 T7ecahome, 2.70 grazns, (0.022 moles) was dissolved in 80 m.L dry toluene in a 200 xnL round-bottomed flask -a.nd starred at room temperature wider a nitrogen atmosphere. Acetonitrile, 12 mL (0.22 moles), was added to the solution by syringe. The solution was then stirred for three hours. A solution composed Of2.84 grams (0.011 moles) 3,5-d:ipr~pargylaxybenzyIacctate p in 80 mL of toluene was then added to the sÃal.u.tzon by *,ringe. Thd resultiug mixture was slowly heated to 80-90 C and stirred in that temperature range ~~rtwo days. The ~~sults from thin layer chromatography s:hoNved no starfing znateriaI (H) as well as the presence of a z~~Nv compound. The solvents were then removed by rotary evaporation, ~eav'mg m organic residue. The organic residue was dissolved in approximately 50 mL of methanol and allowed to stir at reflux for 1 hour to clecornpos~ excess decaborane. The rnethanv2 was then removed by rotary evaporation.
The organic residue'was dissolved in 50 mL d:ichlorometha.ne and then purified using a pad of silica in a sintered glass fuzunel. The pad of silica was washed with an additional 200 xnL of dichloromethane. The dichlo:romethar-.e of the f"il.trate was removed by rotary evaporati0.n,1~aAng a yellow oil, Nvhich solidified upon standing. 4.40 grams of product was rabtaiTied, Nvbich corresponds to aa, 81% yield.

10100] The product had a melting point of 1?22-123 C and gave the following proton nuclear magnctic, resonance (H NMR) spectrum in ppn-t (iu. CDC13 sol.vent~).
2.12 (singlet, 3H, CH3); 4.06 (singtet, 2H, CCI1Bjs~~j@> 4.39 (singlet, 4H, ArOCH2); 5.01 (singlet, 2H, ATCH2); 6.32 (singlet, IH, a.ryl); 6.52 (singtet, 2H, aryl). The prcrduct gave the following pxotozi-decoupled 13 C NMR spectrum in ppm (in CDC13 solvent):
21.4 (CH3); 58.3 (ArC?CHx)z 65.8 (ArCHz)x 69,6 (-CCBDX0Hjo); 71.5 ~~~CHBx~~-103 102.3 (aryl); 108.5 (aryl); 139.9 (aryI),158.6 (aryl); 171.0 (CO), The mass spectrum (FAB) showed a parent ion pe~. of 496.0 that matched the molecular weight of the compaun.d, Example 4 Synthesis of 3,5-o-dica.rboranylm.e-thaxylbenzylalcohcal (IV) 101011 Concentrated hydrochloric acid, 4.0 mL, Nvas added to a solution composed of 4.0 grmns (8.0 millimoles) 3,5-o-di.carbozanyloxymethvlt7enzyla~~tate (M) in 60 mL
of mefhanol. The mixture was refluxed for two hours, after Which time the results from than layer ~liramatography showed no sfiaz-tizig material (M) as well as the presence of a new compaund, The solvents were then renioved by rotary evaporation leaving a yellow oil.
On standing at room temperature, the oil solidified to a white solid. 3,4 grams.of product was obtained, Wia.ich cor~"responds to a 93% yield.

101021 The product bad a tnelting point of 267 -269 C and gave the follo~.~ag proton nucloa,r magzeti~ resanaan~e (H NNM) spectum in ppm (in. GDQ3 solvers.t): 2,54 (broad singlet, IH, hydroxyl); 4.04 (singlet, ~~~ ~CBBjaHjo)> 4.40 (singlet, 411, ArOCH2); 4.65 (singlet, 2H, ArCH2); 6.28 (singlet, IH, aryl); 6.54 (singkt, 2H, aryl). The product gave the follo-%ing protan-decoupled 13 C NMR spectrum in ppm (in CDC13 so1vent) .
58.0 (Ar(:~~H2); 64.7 (ArCH2); 69.4 (-~CHBjoHjo); 71.3 (-~CHBIOHiO)> 101.5 (aryl);
106.6 (aryl); 144.7 (aryl); 158.5 (ayl). The mass spectrum (FAB) showed a parent ion pealk of 453.0 that matched the m;olecu1aT weight of the compound.

Example 5 Synt.h.esis of 3,5-o-dicarboranylmethoxylbe:cazylbromi.cte (V) [01031 3.5-dica:rboranyhtaelhcaxylbenzylalcohoI {M, 0.454 grams (1.0 millimoIes), and carbon tetrabrozzizde, 0.398 graTns (1<2 mi1lirza.oles), were dissolved in approximately 2 mL afdry tetrahydr0furan. T'riphenylphosphine, 0.314 grams (1.2 millimoles), was added to the mixture, and the resulting mixture stirred under an argon atmosphere for 20 minutes. The mi-x,,tzre was then poured into water and the product extracted Nvzth dxchloromethane (7 rnl,, x 3). The dichlaxomethane extract was dried with anhydrous potassium carbonate and then purified using a silica pad. The silica pad was washed with additional cl.ichloromethane. The dichlorozuetharze filtrate was evaporated to dryness, leaving a white solid. 0,485 grmns of product was obtained, which correspcands to a 92 f, 3ieId.

[0104] The product had a melting point of 230-232 C and gave the following proton nuclear magnetic resonance (H NMR) spmtrurri in ppm (in CDC13 solvent)=. 4.0-7 (singl.et, 2111, C~~I~H-~~); 4.37 (singlet, 2H, ~H2Br); 4.39 (sing1et, 4H, Ar~~HZ)> 6.26 (singlet, IH, aryl); 6.55 (singlet, 2H, aryl). The product gave the fOllowzna proton-decoupl~~ ~~~ NMR sp'ectrum in ppm (in CDC13 solvezit): 32.4 (~472Br); 58.0 (A.rCJCH2)_ 69.5 (-~CHBtoHjo); 71A (-~CHBjcHjo), 102-3 (aryl); 109.2 (aryl); 141.2 (aryl);

(aryl). The mass spectrum (FAD) showed a parent ion peak of 516.5 that matched the molecular weight of the compound.

Example 6 Synthesis of 3-[3,5-o-dicarboranyhnethoxybf,.nzyloxy]benzylalcohOI (VI) [0105] K2CO.3, 0.210 grams (1.5 millimoles), and KI, 0.25 grams (1.5 znillimoles), were placed in a 50 mL round-bottomed .flask. 3,5-dicarboranyl- methoxylbenzyl bromide (NT), 0.410 grams (0.80 millimoles), 3-hydroxybenzylalcoho1, 0.100 grams (0.80 znzllinioles)>
and 20 mL acetone, were then added. The mixture was refluxed under an argon abnosphere for 24 hours. The solvent was removed by Totary evaporation, leaving an organic residue. The residue was extracted with 10 rnZ of dichlorcamethanes and t1ae organic phase was washed with water in a separatory funnel. Thc, organic phase was then dried over anhyclrous potassium carbonate. The diebloromethane Nvas removed by rotary evaporation, leaving a whitd soIid, 0.430 grams of product was obtained, which correspond.s to a 96% yield.

101061 The product had a me1tingpoint of 259-261'C and ga-ve the follow-zng proton nuclear magaetic resonance (H NUR) spec#run in ppm (in CDCI3 solvent): 1.70 (singlet, lH, hyriroxyI)x 4.04 (singlet, 2H, CCHBIoHla), 4.40 (singlet, 41-1, CH2C~CHBIr~jo); 4.67 (singlet, 2H, ArCH2OH)x 5.00 (singlet 2H, ~H,-Oa.r); 6.31 (singlet, IH, aryl); 6.60 (singlet, 2H, aryl); 6.87 (multiplet, IH, aryl);
7.00 (multiplet, 2H, aryl); 7.26 (multiplet, 1H, aryl). The product gave the following proton-decoupled 13C
NMR spectrum in ppm (in CDC13 s~~vent): 58.2 (CHXCHBIOHIo); 65.5 (.A.rCHzQH)x 69.6 (-~CHBzoHIo); 71.4 (-CCI-IBIaH-1o); 102.0 (aryl); 107.4 (azyl),11 3.6 (aryI); 114.3 (aryl); 120.2 (ary1); 130.2 (aryl); 141.2 (ar'yl), 143.1 (aryl.), 15,33 (aryl); 158.8 (aryl). The mass spectrum (FAB) showed a parent ion peak of 559.0 that matched the molecular Weight of tlie coxn.po-an.d.

Ex=pIe 7 Synthesis of 3-(3,5-ca-dicarbc~ranylmethoxybenzytoxyJben.za.idehyde (VII) ~OI07J Fyridinum chloxochromate (PCC), 0. 172 grams (0.80 millimotes), was dissolved zn. 10 nnL dichlor.omethane. The resultizig solution was cooled in an ice water bath. A
solution of 0.223 gra.rn.s (0.40 millimoles) of 3-[3,5-di.carhoranyImethoxy he:czyl]henzy1 alcohol (VI) dissolved i.n. 10 nL di.chloxomefih.ane was added dropwise to the PCC
s~lution, nie mixture was stirred fcsx hv0 hours. The results from thin layer chrona-atogzaphy showed no stuting material M as well as the presence of a neNNJ
compound. The major product was purifi:ed using a sintered glass funnel containing a 2 centzmeter-thick layer of silica. The flask and the layer of silica were washed thoroughly with excess dichloxomethan.e. The solvents were xemoved by rotary evaporation, leaving a white solid. 0.220 grams of product was obtained, which corresponds to a 99%
yield.
[OI081 The product had a melting point of 263-265 C and gave the following proton nuclear magnetic resonance (':~ ~UvIR) spectturn in ppm (in C53CIS sc~lvent);
4.04 (singlet, 21I. ~CHBIaHIo); 4.42 (singlet, 4H, AxOCH,,); 5.00 (singlet, M, ArC:~20);
6.33 (singlat, 1~, aryl); 6.61 (singlet, 2H, aryl), 7.23 (singlet,.1H, aryl);
7.44 (anultiplet, IR, aryl); 7.50 (multiplet, 2H, aryl); 9.99 (singlet, IH, CHO). The product gave the following proton-decoupled ~~C NMR spectraum in ppna (in CDC13 solvent): 5 8,4 (CH,.,CCHBIaHIo)a 69,5 (-CCHBzoHla); 69.7 (ArCH2C3A.r)x'711.2 (-MMIoHi0)>
102.0 (aryl); 107.4 (aryl); 112.8 (aryl); 122.4 (aryl); 124.8 (aryl); 130.6 (aryl);
138.1 (aryl);
138.~ (aryl); 140.3 (aryl); 158.6 (aryl); 192.1 (CHO). The i:nass spect:rum (FAB) showed a parent ion peak of 558.0 that matc-hed: the molecular weight of the compound.

Exatnple 8 Synthesis of m.escr5,1q,15,2.6-tet.rakas[3-(3,5-6-dicarborany:lm~thoxybenzyloxy)phenylI
porohyrin ~~

(01091 3-[3,5=o-di=baranylmetboxyben~~loxy]benzaldehycÃe (VU), 337 milligrams (0.60 millimoles), 100 naL of d.i:chloronaethane, and 420 microliters (0.60 milhmoles) of freshly distilled pyrrole, were sequentially transferred to a dry 300 :rnL
round-bottomed flask. The solution Wa.s deoxygenated by bubbling argon gas directly into the solution.
while stz~g for 15-20 minutes. BF3,Et2O, 72 microliters of aIM
dichlarometha,n.e solution (0.072 xnillzmoles), was then added. The solutian was allowed to stir under an argon atnnOspb,ere overnight, after which time the solution became reddish brown. 2,3-dicht.oro-5,6-di.c,yano-I.4-benzoqninone (DDQ),15Q milligrams {0.60 zni.llirrtotes) Nvas then add.ed, which immediately turned the solution very dark. The solution was stirred under reflux for one hour. The major product in the solution was then purified using a6(?
mL sintered glass Az,nneI containing about4O m:G of silzca, The resulting dark filtrate was rotary evaporated to dryness. The results from thin layer cbromatography confirmed the presence of the new puple product as well as some con.tamznants. The solid was redissolved in ciie.hloionzethane and then purified again using another short column of silica eluted with a 1: 1 solvent mixture of dich.loromethane to hexanes. The regults from tlxin layer chroznatograph.y,eonfircned the absence of the contaminants. The resulting dark filtrate was rotary evaporated to dryness, resulting in a purple product. 78 milligrams of pr0duct "Was obtained, Which corresponds to a 22% yield.

[01101 The product gave the following proton nu.ciear magnetic resonance (H
NMR) spectrum in ppm (in CDC13 solvent): -2.84 (singlet, ~~~~ NH); 3.97 (singlet, SH, CCHBjoHrO)> 4.35 (singlet, 16H, .ArOCHz)a 5.19 (singlet, $H, ArC.Hx)', 6.31 (singlet, 4H, myl); 6.65 (singlet, 811, aryl); 7.40 (singlet, 4H, aryl); 7.70 (nzultipi.et, 4H, aryl); 7.79 (multiplet, 4H, aryl); 7.86 (multipiet, 4H, aryl); 8.84 singlet, SH, pyrrole-H). The mass spectrum (FAB) showed apa.rent ion peak of 2418.3 that matched the molecular weight of the compound. The ultraviolet-visible absorbance spectrum of the product (dichlororneth.ane) showed the .i'alloNvi.ng peaks in nanometers of wavelength: 420, 516, 550, 5 89, and 645.
Example 9 Synthesis of copper rr~~so-5,1 t1,15,20-tefiralds[3-(3,5-o-dicancoranyl .m.ethoxybenzyloxY)phenyl1 porphyrin (IX) ~01111 Aso1ution of Cu(OAc)2 =H2Q (6 rn.i.iligrams, 0.{}30 mi.Ilitnoles) in 5mL:zuethanol Was added iz~~o a solution of porph}Tin compound (VMD (60 milligrams, 4.025 znilliznoIes in 20 mL d.ichloromethaue). The mixture was stirred for 20 minutes. The solvent was then removed by rotary evaporation. The resulting residue was dissolved in dichioror,aethane, washed with water and then dried over anhydrous sodiunn sulfate. The drying agent was filtered off. The solvent of the filtrate was removed by rotary evaporation, leaving a red solid residue. The solid was re-dissolved in diclilororn.ethane and purifi'ed using asilzca pad eluting with a 1: 1 solvent mixture of hexan.e and dichloromethane. The solvents were reniOved by rotary evaporation, leaving the red copper porphyrin coznpound, 57 milEgranls of product, which corresponds to a 92 ~'~
yield.

[01121 nie mass spectnwn (FAB) showed, a pareut ion pe~:. of 2479.9 that rn.atclied the znolecular ~~ei~ht of the cozzipaund. The ultraviolet-visible absorbance spectrum of the product shoA,ed the folloNving peaks in nanometers of wavelength (in dichtcrromethaa.e solvent): 416, 539.
Example 10 Preparation csfboronatQd porphyrin solutions ~01131 Porphyrin compound (IX) was ernulsified in 9% Cre-mophor EL and 18%
propylene glycol in saline to give a porphyrin concentration of approximately 2.9 mghnL. To prepare a solution of -2.9 mg1m:I1 porplxyri.n in 9% Cremophor EL
(CRM) and 18% prupylerz~ glydoI (PR.C), the porphyrin was dissolved in tetrahyd.rofuraTi (THF) (1.5% of the total volume) and then heated to 40 Cfor 15 ni.in. CRM (9% of total vcalunie) was then added and the mixture was heated to 601C for 2 hoursa,Arhich .removed.
most of the TBF. After cooling to room. temperature, PRG (18% of total volume) was added, followed by slom, dropwise addition of saline (?'1,5~'~ of tota.l valwn~) ~Nvith z,apid stirring. The sol-ution was t~~gass.ed by stirring under vacuum (-30 nun Hg) for 30 - 60 min and then filtered (Millipore, 8 Am).
Example 11 Biodistribution ofpesrph.yriu IX in mice beazing EMT-6 caccxn'omas [01141 :BAZ,$/c mice bearing subcutaneously im:pla-nted EMT-6 mammary carcinomas implanted on the dorsal thorax were given a total dose of 87 milligrams porphvnin compound (1X) per lcil.ogram, body weight (30 mg B/kg) in 3 intraperitoneal (z:p) injections over a period of 8 ho-urs. At two and four days after the last injection, mice were euthanized, and tumor, blood, brain, and liver were removed for boron a.nalyses.
The blood was first analyzed for hematOlagi.c parameters that indicate toxicity before it WO 2006/012140 _ PCT/US2005/022061 was arialyzed for boron. Table 1. below shoNvs the average horon conccntxations for different, types of tissue in five of the BALB/c n-ice in milligram of porphynn compound per kilogram body Weight.

Average boron concentrations (4glg) in vmious tissues in mice (n S) given 87 mg/kg parphyrin (a) (30 mg B/kg) in 3 %.p. injections over a period of 8 hours.

ime after last injection EMT-6 Tumor Blood Brain Liver [t~" B/g ~g B/g ~ B/g n BIg days 43.5 10.0 0.5 0.2 0.2+4.0 353+55 days 27.8+7.6 0.2+0.1 0.3 ~ 01 250:h 70 Example 12 Weight changes and hematologic paran.eiers from porphyrin (LX) Weight changes and hematologic parameters in mice given 87 mg/kg pozph.yrzn.
(IX) (30 mg Bl;.g) or solvent only (9'~r'~ Cremophor and 18% propyIeae glycol zn salino) at 2 or 4 days after the last injectzon, Values are reported as median. (and range).

onipound ime after u:rrzber of % Weight latelets yrnphocytes arzttlcacytes ast znjec'on rnice hange (103tmm~) {/' w B C} (% WBC) arphyrzn days 5 .4 (-4.9-2.5) 193 (51-432) 44 (37-5653 (42-60) conapound (IX) Solvent only days 4 1.3 (45-1.1) 640 (568-730) 68 (61-71) 8{26-32) orph}rri'a days 5 M ( 4.7w1.5) 917 (670~1128) 35 (30-39) 2 (5'7-67) com.pouzid O,,~

solvent oll2~ days 4 ~03 (2.2-2.1) . 27 (5(}0,615) 71 (70-72) 26(24-'?~) [01151 The results of the preliminary biodistribution study shcsvued that the tumor boron concentratxons m adequate for tl-ierapy, particularly at the two-day fiune-point. The tumor to blood boxon ratios are quztc highs Wh.ich are more than 80:1, and tumor to brain ratios are even h:igFa.er. The platelet data indicate a small but szgaificant decrease in the pozphyri.n-acrnini~tered mzco at the 2-day time point compared to the solvent-only rnice.
However, by the 4-day time point, the platelet counts have rebounded to a level greater fihan those from the solvent-only gratap. The Wei ;ht data indicate that the level o.~toxzcity is ,fe.ry low if it exists at all since there were no differences behveen porphyrin- and sc~lvent-injected mice. Thus, it is possible that the doses can be escalated significantly without affecting tox.icity, [0116] 'Thits, Wh.i.le thcre have been described the preferred embodiments of the present invention, those skilSed in the art wzE realize that other embodiments can be made without departing from the spirit of the inve:ntion, Nvhicli includes all such fuz-th:er modifications and changes as come within the true scope of the claims set forth lierein.

Claims (56)

1. A compound of the formula wherein:

Y1, Y2, Y3, and Y4 are independently on the ortho, meta or para position on the phenyl rings, and are independently hydrogen, alkyl, cycloalkyl, aryl, akylaryl, arylalkyl, heteroaryl, or an alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, or heteroaryl group substituted with 1 to 4 hydrophilic groups selected from hydroxy, alkoxy, -C(O)OR5, -SOR6, -SO2R6, nitro, amido, ureido, carbamato, -SR7, -NR8R9, or poly-alkyleneoxide, or a substituent represented by the formula wherein D represents independently, Z, hydrogen, or a substituent represented by the formula provided that at least one D is Z or is represented by formula (3);

wherein D' represents independently, Z, hydrogen, or a substituent represented by the formula provided that when q is 0, or when q is not zero and D' is solely hydrogen, then at least one D is represented by Z, or when q is not zero and D' is represented by formula (4) and r is zero, then at least one D is represented by Z;

Y5, Y6, Y7, and Y8 are independently on the ortho, meta or para position on the phenyl rings, and are represented by the formula -X a-(CR a R b)v-Z (5);
W1, W2, W3, W4, W5, and W6 are hydrophilic groups independently on the ortho, meta or para position on the phenyl rings, and are independently selected from hydroxy, alkoxy, -C(O)OR5, -SOR6, -SO2R6, nitro, amido, ureido, carbamato, -SIR7, -NR8R9, or polyalkylene oxide;

X a, X1, X2, X3, and X4 are independently oxygen or sulfur;

R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from hydrogen and C1 to C4 alkyl;

Z is -a carborane cluster comprising at least two carbon atoms and at least three boron atoms, or at least one carbon atom and at least five boron atoms, within a cage structure;
n, p, s, t, and v independently represent 0, or an integer from 1 to 20;

m independently represents 1, 2, or 3;

q and r independently represent 0, 1, 2, or 3;
a, b, c, and d independently represent 1 or 2;

k, l, u, and w independently represent 0, 1, or 2;

e, f, g, h, i, and j independently represent 0, or an integer from 1 to 5;

provided that at least one of Y1, Y2, Y3, and Y4 represents formula (27); each of the sums a + e + k, b + f +1, c + g + u, h + d + w, q + i, r + j, independently represents an integer from 1 to 5; when any of k, l, u, or w is not zero, then at least one of Y1, Y2, Y3, and Y4 represents formula (2); and M is either two hydrogen ions; a single monovalent metal ion; two monovalent metal ions; a divalent metal ion; a trivalent metal ion; a tetravalent metal ion; a pentavalent metal ion; a hexavalent metal ion; a radioactive metal ion useful in radioisotope-mediated radiation therapy or imageable by single photon emission computed tomography (SPECT) or positron emission tomography (PET); a paramagnetic metal ion detectable by magnetic resonance imaging (MRI); a metal ion suitable for boron neutron capture therapy (BNCT) or photodynamic therapy (PDT); or a combination thereof;
wherein the porphyrin-metal complex derived from a single monovalent metal ion is charge-balanced by a counter cation, and the porphyrin-metal complex derived from a trivalent, tetra-valent, pentavalent, hexavalent metal ion is charge-balanced by an appropriate number of counter anions, dianions, or trianions.

2. The compound according to claim 1 wherein Z is selected from the carboranes -C2HB9H10 or -C2HB10H10 wherein -C2HB9H10 is nido meta-, meta-, or para-carborane, and -C2HB10H10 is closo ortho-, meta-, or para-carborane.

3. The compound according to claim 1, wherein M is vanadium, manganese, iron, ruthenium, technetium, chromium, platinum, cobalt, nickel, copper, zinc, geranium, indium, tin, yttrium, gold, barium, tungsten, or gadolinium.

4. The compound according to claim 1 wherein a, b, c, and d are 1, and Y1, Y2, Y3, and Y4 are represented by

5. The compound according to claim 4 wherein D is Z, wherein Z is selected from the carboranes -C2HB9H10 or C2HB10 H10 wherein -C2HB9H10 is nido ortho-, meta-or para-carborane, and -C2HB10H10 is closo ortho-, meta-, or para-carborane.

6. The compound according to claim 5, wherein M is vanadium, manganese, iron, ruthenium, technetium, chromium, platinum, cobalt, nickel, copper, zinc, germanium, indium, tin, yttrium, gold, barium, tungsten, or gadolinium.

7. The compound according to claim 6, wherein X1 and X2 are O; R1, R2, R3 and R4 are H; n and p are 1; and m is 2.

8. The compound according to claim 7 wherein Y1, Y2, Y3 and Y4 are in a meta position on each phenyl ring.

9. The compound according to claim 8 wherein the -X2-(CR3R4)p-D
substituents are in the 3 and 5 positions on each phenyl ring.

10. The compound according to claim 8 wherein the -X2-(CR3R4)p-D
substituents are in the 3 and 4 positions on the phenyl ring.

11. The compound according to claim 9 wherein e, f, g, h, k, l, u, and w are 0.

12. The compound according to claim 7, wherein e, f, g, and h are 1 and k, l, u, and w are 0.

13. The compound according to claim 12, wherein W1, W2, W3, and W4 are independently, hydroxy or alkoxy.

14. The compound according to claim 13, wherein W1 W2, W3, and W4 are alkoxy.

15. The compound according to claim 14, wherein alkoxy is methoxy.

16. The compound according to claim 15, wherein Y1, Y2, Y3, and Y4 are in the para position on each phenyl ring.

17. The compound according to claim 16, wherein W1, W2 , W3, and W4 are in a meta position of each phenyl ring.

18. The compound according to claim 17 wherein the -X2-(C3R4)p-D
substituents are in the 3 and 5 positions of each phenyl ring.

19. The compound according to claim 17 wherein the -X2-(CR3R4)p-D
substituents are in the 3 and 4 positions of the phenyl ring.

20. The compound according, to claim 9 wherein k, l, u, and w are 1.

21. The compound according to claim 20, wherein Y5, Y6 Y7, and Y8 are in the para position on each phenyl ring.

22. The compound according to claim 21 wherein the -X a-(CR a R b)v-Z
substituents are in the 3 and 5 positions on each phenyl ring.

23. The compound according to claim 21 wherein the -X a-(CR a R b)v-Z
substituents are in the 3 and 4 positions on the phenyl ring.

24. The compound according to claim 22 or 23 wherein X a is O; R a and R b are H; v is 1, and Z is selected from the carboranes -C2HB9H10 or -C2HB10 H10, wherein -C2HB9H10 is nido ortho-, meta-, or para carborane, and -C2HB10H10 is closo ortho-, meta-, or para-carborane.

25. The compound according to claim 24, wherein e, f, g, and h are 0.

26. The compound according to claim 1 wherein a, b, c, and d are 2, and Y1, Y2, Y3, and Y4 are represented by

27. The compound according to claim 26 wherein D is Z, and Z is selected from the carboranes -C2HB9H10 or -C2HB10 H10 wherein -C2HB9H10 is nido ortho-, meta-, or para-carborane, and -C2HB10H10 is closo ortho-, meta-, or para-carborane.

28. The compound according to claim 27, wherein M is vanadium, manganese, iron, ruthenium, technetium, chromium, platinum, cobalt, nickel, copper, zinc, germanium, indium, tin, yttrium, gold, barium, tungsten, or gadolinium.

29. The compound according to claim 28, wherein X1 and X2 are O; R1, R2, R3 and R4 are H; and p are 1; and m is 2.

30. The compound according to c1aim 29, wherein Y1, Y2, Y3, and Y4 are in the two meta positions on each phenyl ring.

31. The compound according to claim 30, wherein the -X2-(CR3R4)p-D
substituents are in the 3 and 5 positions on each phenyl ring.

32. The compound according to claim 30, wherein the -X2-(CR3R4)p-D
substituents are in the 3 and 4 positions on the phenyl ring.

33. The compound according to claim 31 or 32, wherein k, l, u, and w are 0.

34, The compound according to claim 33, wherein e, f, g, and h are 0.

35. The compound according to claim 4, wherein X1 and X2 are O; R1, R2, R3 and R4 are H; n and p are 1; m is 2, and D is represented by

36. The compound according to claim 35, wherein X3 is O, R10 and R11 are H, s is 1, D' is Z, q is 2, and i is 0, wherein Z is selected from the carboranes -C2HB9H10 or C2HB10H10 wherein -C2HB9H10 is nido ortho-, meta-, or para-carborane, and -C2HB10H10 is closo ortho-, meta-, or para-carborane.

37. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 1; and the imaging of said subject.

38. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 11; and the imaging of said subject.

39. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 18; and the imaging of said subject.

40. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 25; and the imaging of said subject.

41. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 34; and the imaging of said subject.

42. A method of imaging a tumor and surrounding tissue in a subject comprising the administration to the subject of a composition comprising a compound according to claim 36; and the imaging of said subject.

43. The method according to any of claims 37, 38, 39, 40, 41, or 42 wherein said imaging is by a method selected from magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), or positron emission tomography (PET) methods.

44. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 1; and the irradiation of said subject.

45. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 11; and the irradiation of said subject.

46. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 18; and the irradiation of said subject.

47. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 25; and the irradiation of said subject.

48. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 34; and the irradiation of said subject.

49. A method of bimodal cancer treatment in a subject comprising the administration to the subject of a composition comprising a compound according to claim 36; and the irradiation of said subject.

50. The method according to any of claims 44, 45, 46, 47, 48, or 49 wherein said irradiation is by a method utilizing thermal or epithermal neutrons, or laser red light.

51. The method according to claim 44, wherein said bimodal cancer treatment comprises boron neutron capture therapy (BNCT).

52. The method according to claim 44, wherein said bimodal cancer treatment comprises photodynamic therapy (PDT).

53. The method according to claim 44, wherein said bimodal cancer treatment utilizes single photon emission computed tomography (SPECT) or positron emission tomography (PET) wherein M is a SPECT- and/or PET-imageable radioactive metal ion.

54. The method according to claim 44, wherein said bimodal cancer treatment utilizes magnetic resonance imaging (MRI) wherein M is a paramagnetic metal ion.

55. The compound according to claim 1 wherein the counter dianion is a porphyrin compound containing a divalent negative charge.

56. The compound according to claim 55, wherein the porphyrin compound containing a divalent negative charge is the compound of claim 1, with the proviso that M
is absent.