CA2336306A1 - Indium photosensitizers for pdt - Google Patents
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Abstract
The invention disclosed herein involves a phototherapeutic pyrrolic core complexed with a non-radioactive Indium atom. Complexation of Indium by the pyrrolic core forms a metalopyrrolic compound which influences enables these compounds to localize at target sites a phototherapy. Such functionally aids in both detection and phototherapy of disease sites, or provides functionali ty that binds to site specific receptors of a target area such that the therapy is improved.
Description
INDIUM PHOTOSENSITIZERS FOR PDT.
BACKGROUND OF THE INVENTION
Porphyrins and related pyrrolic macrocycles, particularly tetrapyrrolic macrocycles, as well as many other light absorbing compounds are currently receiving a great deal of attention with regard to photosensitized medicine, especially in the field of Photodynamic therapy (PDT) . The therapy necessarily involves the localization of a photosensitizing agent at or near a site of disease. The sensitizer, upon illumination in the presence of oxygen, produces cytotoxic species of oxygen such as singlet oxygen or oxygen radicals, which destroy the diseased cells. As the sensitizer is innocuous at the therapeutic dose, and only becomes active on illumination with light of a specific wavelength, PDT offers the possibility of a level of control or selectivity in the treatment of diseases not found with other current methods (e.g. conventional chemotherapy).
Photodynamic therapy has wide application to modern medicine, targeting diseases such as cancers, cardiovascular restenosis and plaques, psoriasis, viral infections, benign t5 prostate hyperplasia and diabetic retinopathy. In addition, photodynamic therapy may also be useful for the sterilization of blood, an area of increasing concern, especially now with the advent of AIDS and the transmission of HIV through blood transfusions.
Most research on PDT has centered on a complex mixture consisting of ill-defined porphyrin dimers, trimers and oligomers', which is marketed under the designation 2o Photofrin II~. This complex mixture has recently been recommended for approval in the treatment of obstructed endobronchial tumors by the Food and Drug Administration Advisory Panel. Although the mixture has demonstrated the potential benefits of PDT, it has by virtue of its composition a number of associated disadvantages. For example, each of its components has varied subcellular localizations, depending on structure and inherent 25 differences in photophysical properties. This makes the interpretation of pharmacokinetic data difficult. In addition, the composition of the oligomers is often difficult to reproduce and changes, depending on the conditions under which a solution3 thereof is stored.
Hence, the true "active components" may vary considerably. The mixture has a less than optimal light absorption profile (630nm, g~3,000cni ~M-~). Numerous studies on light 3o penetration through tissues show that longer wavelength light penetrates deeper into tissues4. While not all applications of PDT require deep penetration of light, many applications of PDT require the maximum depth of light penetration possible (for example the treatment of brain tumors). The mixture has a severe adverse normal skin response to light, which often lasts for up to 12 weekss after therapy. During this time patients must avoid strong light, as otherwise severe burns and edema occur.
Several well characterized second generation sensitizers (SnET26, ZnPc~, BPDMAg, THPC9) are currently in phase I/II clinical trials and the continued development of new sensitizers that show improved therapeutic efficacy is crucial to the future progress of the therapy. The development of new photosensitizers that possess all the basic requirements to be effective PDT drugs is not an easy task. While the optimal photophysical properties of a second generation drug are well defined, the factors which aid in the localization of photosensitizers to tissues are not. Several investigators have attempted to ascertain structure-activity relationships in ring systems that lend themselves to chemical modification without dramatically influencing the photophysical properties of the compounds. Woodburn and coworkers, working on hematoporphyrin based analogues, have proposed that anionic compounds tend to localize in lysosomes, while cationic photosensitizers tend to localize in the mitochondria. Pandey and coworkers have ~5 suggested that the lipophilicity of the compound is important, and have demonstrated in a chlorophyll derived series that PDT effects vary with the length of the ether carbon chain.
Unfortunately, many of the correlation's found in one group of photosensitizing compounds do not transfer to different groups of photosensitizing compounds.
Thus, while structure-activity relationships are valuable for a particular class of compound whose ~c~ geometry and spatial arrangements vary only slightly, a different class of compound, that inherently has its own spatial and geometric parameters, must have its own structure-activity relationships investigated. This in itself is a large time consuming process with ultimately no guarantees of enhanced localization or improved PDT efficacy for the modified compound.
25 The instant invention is based upon the discovery of a single simple chemical modification of compounds having a pyrrolic core involving the coordination of a non-radioactive indium salt into the central cavity of the pyrrolic core to produce an indium pyrrolic complex, which markedly enhances the biological efficacy of compounds as photosensitizers for PDT.
3o Two isotopes of indium occur naturally: In~'3 and In"5; the former (natural abundance 4.23%) has no radioactivity, while the latter (natural abundance 95.77%) has a half life of 6 x 10''' years, and, as a result, is also considered to be non-radioactive. Other WO 00!00204 PCT/US98/13601 indium nuclides have half lives ranging from 50.0 days (for Ins ~4"') to 0.2 second (for In ~o9m ) THE PRIOR ART
Tetrapyrroles containing Indium ~ ~ ~ (half life 2.81 days) and other metals are known in the art, being disclosed, by way of example, in Japanese Kokai 3-261786, 1991, Mauclaire et al., US patent No. 5, 268,371 and in Maier et al., US patent No.
5,674,467, which also disclose their use for diagnostic imaging. The metal-tetrapyrrole compounds are all water soluble, and contain functional groups capable of coupling a biologically active molecule, such as an antibody, to the tetrapyrrolic nucleus. The compounds usually are prepared by reacting a porphyrin derivative with a solution of a salt of the metal to be complexed at a temperature and for a time sufficient to obtain the metal tetrpyrrole compound. For example, when a metal salt of indium ' ~ ~ is heated for three hours at 110°C. in a porphyrin solution to which a mixture of acetic acid and sodium acetate has been added, an Ins ~ ~porphyrin is produced. Although the preparation of such t5 metalloporphyrins is known and the compounds have been discussed in the context of radiocontrasting agents, surprisingly, so far as is known, there has been no report on the efficacy of indiumporphyrins as therapeutic photosensitizers. In view of the substantial prior art involving indium tetrapyrroles, it is indeed surprising to discover that complexes of non-radioactive indium with tetrapyrroles exhibit a marked improvement in their 2o cytocidal effect in vivo when compared with other metallotetrapyrrole complexes.
Sakata, US patent No. 4,849,207, discloses compounds having the following structure:
where:
R I, R2, R4 and R6 are methyl, R8, R 10, R 11 and R 12 are H, and R7 and R9 are CH~CH~COR 13 (where R 13 is a residue which results when H is removed from an amino acid), R3 and R5 are ethyl, and In is not radioactive, i.e., is Ins ~3 or Ins ~5.
Japanese Kokai 5-97857 discloses compounds having the following structure Where R1 is CH(OR)Me, R is alkyl, R2 is a residue derived by removing H from an t0 amino acid, and M is 2H, Ga, Zn, Pd, In or Sn The following references are cited above:
1. For an overview of photodynamic therapy see"Photodynamic Therapy o~
Neoplastic Disease", Vol. I and II. Ed. Kessel, D., CRC Press, 1990.
BACKGROUND OF THE INVENTION
Porphyrins and related pyrrolic macrocycles, particularly tetrapyrrolic macrocycles, as well as many other light absorbing compounds are currently receiving a great deal of attention with regard to photosensitized medicine, especially in the field of Photodynamic therapy (PDT) . The therapy necessarily involves the localization of a photosensitizing agent at or near a site of disease. The sensitizer, upon illumination in the presence of oxygen, produces cytotoxic species of oxygen such as singlet oxygen or oxygen radicals, which destroy the diseased cells. As the sensitizer is innocuous at the therapeutic dose, and only becomes active on illumination with light of a specific wavelength, PDT offers the possibility of a level of control or selectivity in the treatment of diseases not found with other current methods (e.g. conventional chemotherapy).
Photodynamic therapy has wide application to modern medicine, targeting diseases such as cancers, cardiovascular restenosis and plaques, psoriasis, viral infections, benign t5 prostate hyperplasia and diabetic retinopathy. In addition, photodynamic therapy may also be useful for the sterilization of blood, an area of increasing concern, especially now with the advent of AIDS and the transmission of HIV through blood transfusions.
Most research on PDT has centered on a complex mixture consisting of ill-defined porphyrin dimers, trimers and oligomers', which is marketed under the designation 2o Photofrin II~. This complex mixture has recently been recommended for approval in the treatment of obstructed endobronchial tumors by the Food and Drug Administration Advisory Panel. Although the mixture has demonstrated the potential benefits of PDT, it has by virtue of its composition a number of associated disadvantages. For example, each of its components has varied subcellular localizations, depending on structure and inherent 25 differences in photophysical properties. This makes the interpretation of pharmacokinetic data difficult. In addition, the composition of the oligomers is often difficult to reproduce and changes, depending on the conditions under which a solution3 thereof is stored.
Hence, the true "active components" may vary considerably. The mixture has a less than optimal light absorption profile (630nm, g~3,000cni ~M-~). Numerous studies on light 3o penetration through tissues show that longer wavelength light penetrates deeper into tissues4. While not all applications of PDT require deep penetration of light, many applications of PDT require the maximum depth of light penetration possible (for example the treatment of brain tumors). The mixture has a severe adverse normal skin response to light, which often lasts for up to 12 weekss after therapy. During this time patients must avoid strong light, as otherwise severe burns and edema occur.
Several well characterized second generation sensitizers (SnET26, ZnPc~, BPDMAg, THPC9) are currently in phase I/II clinical trials and the continued development of new sensitizers that show improved therapeutic efficacy is crucial to the future progress of the therapy. The development of new photosensitizers that possess all the basic requirements to be effective PDT drugs is not an easy task. While the optimal photophysical properties of a second generation drug are well defined, the factors which aid in the localization of photosensitizers to tissues are not. Several investigators have attempted to ascertain structure-activity relationships in ring systems that lend themselves to chemical modification without dramatically influencing the photophysical properties of the compounds. Woodburn and coworkers, working on hematoporphyrin based analogues, have proposed that anionic compounds tend to localize in lysosomes, while cationic photosensitizers tend to localize in the mitochondria. Pandey and coworkers have ~5 suggested that the lipophilicity of the compound is important, and have demonstrated in a chlorophyll derived series that PDT effects vary with the length of the ether carbon chain.
Unfortunately, many of the correlation's found in one group of photosensitizing compounds do not transfer to different groups of photosensitizing compounds.
Thus, while structure-activity relationships are valuable for a particular class of compound whose ~c~ geometry and spatial arrangements vary only slightly, a different class of compound, that inherently has its own spatial and geometric parameters, must have its own structure-activity relationships investigated. This in itself is a large time consuming process with ultimately no guarantees of enhanced localization or improved PDT efficacy for the modified compound.
25 The instant invention is based upon the discovery of a single simple chemical modification of compounds having a pyrrolic core involving the coordination of a non-radioactive indium salt into the central cavity of the pyrrolic core to produce an indium pyrrolic complex, which markedly enhances the biological efficacy of compounds as photosensitizers for PDT.
3o Two isotopes of indium occur naturally: In~'3 and In"5; the former (natural abundance 4.23%) has no radioactivity, while the latter (natural abundance 95.77%) has a half life of 6 x 10''' years, and, as a result, is also considered to be non-radioactive. Other WO 00!00204 PCT/US98/13601 indium nuclides have half lives ranging from 50.0 days (for Ins ~4"') to 0.2 second (for In ~o9m ) THE PRIOR ART
Tetrapyrroles containing Indium ~ ~ ~ (half life 2.81 days) and other metals are known in the art, being disclosed, by way of example, in Japanese Kokai 3-261786, 1991, Mauclaire et al., US patent No. 5, 268,371 and in Maier et al., US patent No.
5,674,467, which also disclose their use for diagnostic imaging. The metal-tetrapyrrole compounds are all water soluble, and contain functional groups capable of coupling a biologically active molecule, such as an antibody, to the tetrapyrrolic nucleus. The compounds usually are prepared by reacting a porphyrin derivative with a solution of a salt of the metal to be complexed at a temperature and for a time sufficient to obtain the metal tetrpyrrole compound. For example, when a metal salt of indium ' ~ ~ is heated for three hours at 110°C. in a porphyrin solution to which a mixture of acetic acid and sodium acetate has been added, an Ins ~ ~porphyrin is produced. Although the preparation of such t5 metalloporphyrins is known and the compounds have been discussed in the context of radiocontrasting agents, surprisingly, so far as is known, there has been no report on the efficacy of indiumporphyrins as therapeutic photosensitizers. In view of the substantial prior art involving indium tetrapyrroles, it is indeed surprising to discover that complexes of non-radioactive indium with tetrapyrroles exhibit a marked improvement in their 2o cytocidal effect in vivo when compared with other metallotetrapyrrole complexes.
Sakata, US patent No. 4,849,207, discloses compounds having the following structure:
where:
R I, R2, R4 and R6 are methyl, R8, R 10, R 11 and R 12 are H, and R7 and R9 are CH~CH~COR 13 (where R 13 is a residue which results when H is removed from an amino acid), R3 and R5 are ethyl, and In is not radioactive, i.e., is Ins ~3 or Ins ~5.
Japanese Kokai 5-97857 discloses compounds having the following structure Where R1 is CH(OR)Me, R is alkyl, R2 is a residue derived by removing H from an t0 amino acid, and M is 2H, Ga, Zn, Pd, In or Sn The following references are cited above:
1. For an overview of photodynamic therapy see"Photodynamic Therapy o~
Neoplastic Disease", Vol. I and II. Ed. Kessel, D., CRC Press, 1990.
2 ."Photodynamic Therapy of Neoplastic Disease", Vol. I and II. Ed. Kessel, D., CRC
Press, 1990 p 1- I 2.
Press, 1990 p 1- I 2.
3. Byrne, C.J., Ward, A.D., Marshallsay, C.J. Photochem. Photobiol., 46, 575, 1987.
4. a)Svaasand, L.O.> Ellingsen. R. Photochem. Photobiol. 41, 73, 1985:b) Bolin. F.P..
Preuss, L.E., Cain, B.W., in "Porphyrin Localization and Treatment of Tumours".
Eds. Doiron, D.R., Gomer., C.J. Alan Liss, New York, 211, 1984.
Preuss, L.E., Cain, B.W., in "Porphyrin Localization and Treatment of Tumours".
Eds. Doiron, D.R., Gomer., C.J. Alan Liss, New York, 211, 1984.
5. Razum, N., Balchum, O.J., Profio, A.E., Carstens, C. Photochem Photobiol.
46, 925, 1987.
46, 925, 1987.
6. Kessel, D., Morgan, A.R., Garbo, G.M., Photochem. Photobiol. , 54(2), 193, 1991.
7. Ginevra, F., Biffanti, S., Pagnan, A., Biolo, R., Reddi, E., Jori, G., Cancer Letters, 49, 59, 1990.
8. Aveline, B., Hasan, T., Redmond, R.W., Photochem. Photobiol. , 59(3), 328, 1994.
9. Bonnett, R., White, R.D., Winfield, U.. Berenbaum, M.C., Biochem. J., 26I, 277, 1989.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide pyrrolic compounds that absorb light at long wavelengths for use in photodynamic therapy and diagnosis of disease states.
It is another object to provide a reaction product of (A) P where P is a pyrrolic 5 derivative and (B) In";X3 and/or In"SX~ (where X is a charge balancing ion, either organic or inorganic) such as to provide the reaction product (C) PIn";~X"
and/orPIn"5"X", where indium is coordinated to the pyrrolic derivative and n =1, 2, 3.
It is yet another object of the invention to provide a reaction product of (C) PIn"j~X" and/or PIn"5"Xn with a neucleophile Y, such that a reaction product (D) to PIn"~nY"XZ and/or PIn"5"Y"XZ is obtained (where Y is a charge balancing ion, either organic or inorganic n=1,2,3 and z = 0, l, 2, 3).
It is still another object to provide compounds PIn"~X and/or PIn"5X that may be used to treat diseases such as atherosclerosis, restenosis, cancer, cancer pre-cursors, non-cancerous hyperproliferating diseases, psoriasis, macular degeneration, glaucoma and t5 viruses, benign prostate hyperplasia, rheumatoid arthritis and to aid in the diagnosis of these disease states.
DESCRIPTION OF THE PERFERRED EMBODIMENTS
2o The present invention provides derivatives of photoactivatable compounds, some of which are shown in the following Examples, in table l, and in Figs. 1- 5 via the introduction of non-radioactive indium into the macrocycle. The resulting products can be used to diagnose and treat disease states. Additionally, the ligand on the indium complex may then be further chemically or biochemically modit7ed ex-vivo or in-vdvo to form a 25 different pyrrolic indium complex which is capable of binding to important blood plasma components or cell transport proteins that enhance sensitizer uptake at the diseased tissue site.
Additional functionality around the pyrrolic structure can be used to attach biomolecules, examples of which may be antibodies, growth hormones and growth factors 30 or other disease specific molecules, or to aid such factors as water solubility, lipophilicity or hydrophobicity which are known factors that influence drug uptake in tumor disease tissue.
The following Examples are presented solely for the purpose of disclosing and illustrating the invention, and are not to be construed as limiting. In all of the procedures described in the examples, indium, where used, was the natural material, a mixture of abouit 4.23% In~~~ and 95.77% In~~S. The following abbreviations are used in the examples: mL means millilter or milliliters, g means gram or grams; mg means milligram or milligrams; ~tg means microgram or micrograms Example 1, Preparation of Indium Methyl pyropheophorbide from methyl pyropheophorhide:
M is 2H in methyl pyropheophorbide, and a mixture of Ins ~3 CI and Ins ~5 Cl in Indium methyl pyropheophorbide i0 Methyl pyropheophorbide (O.Sg) was dissolved in acetic acid (100mL); Indium chloride (O.Sg) and anhydrous sodium acetate (0.5 g) were added, and the solution was refluxed for 3 hrs. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane / water ( 100mL/ 100mL). The organic layer was washed several times with 0.5 N HCl/water (200mL), collected and dried over anhydrous sodium sulfate (20g). The organic layer was filtered and evaporated to dryness. The resulting residue was crystallized from methanol / dichloromethane. Yield 0.45g.
HC = CH2 WO 00/00204 ~ PCT/US98/13601 Example 2, preparation of Indium tert-butyl phthalocyanine:
'.
R~ ~ R2 R ~ ~ ' RI
, ;J' N
RI ~ RI
R Rd R4 R3 one of R2 and R3 is tert-butyl while the other and R l and R4 are H; and M is Inl1'~ Cl, In~IS Cl or a mixture of Inl l3 CI and In115 CI
4-tent-butyl-1,2-dicyanobenzene (2g) and Indium chloride (2.Og) were mixed thoroughly in a round bottom flask with stirring. The mixture was heated at 160°C for 2 hrs and the reaction vessel cooled to room temperature. The crude phthalocyanine was extracted from the resulting green solid using hot dichloroethane and the green solution evaporated by rotary evaporation. The resulting solid was dissolved in 7°lo acetone /
dichloromethane and chromatographed on silica using 7% acetone /
dichloromethane as eluent. The major green fraction was collected and recrystallized from methanol/
dichloromethane. Yield , 1.1 g.
Example 3, Preparation of Indium Benzoporphyrin derivative from Benzoporphyrin derivative dimethyl ester .
Where M is In~t~ Cl, In~~s Cl, or a mixture of Ins y~ Cl and In~ ~5 Cl in indium ben2oporphyrin derivative dimethyl ester and 2H in Ring B isomer benzopor-phyrin derivative dimethyl ester Ring B isomer, Benzoporphyrin derivative dimethyl ester ( 100mg) was dissolved in acetic acid (SOmL) and Indium chloride (0.2g) and anhydrous sodium acetate ,(0.2 g) were added: the solution was refluxed for 3 hrs. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane / water ( 100mL1 100mL). The organic layer was washed several times with 0.5 N HCl/water (200mL), collected and dried over anhydrous sodium sulfate (20g). The organic layer was filtered lp and evaporated to dryness. The resulting residue was chromatographed on silica using 5%
MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane /
dichloromethane. Yield SOmg.
Example 4, Preparation of Indium m-hydroxy tetraphenylchlorin:from Tetrakis (3-hydroxyphenyl)chlorin RI
R5 l ~ R2 n ,, ~ R3 R2 R-~ \ 'l '~ _~ R-~ R2 R1 /_\ \ N I vN / \ / R1 N N % \
R5 R4 ~~ ~~ / R4 R5 Where each R2 is OH, each Rl, R3, R4 and RS is Hydrogen, In is a mixture of Ins I~ C1 and In ~ 15 Cl, arid Z is Cl tp Tetrakis (3-hydroxyphenyl)chlorin ( 100mg) was dissolved in acetic acid and the solution purged with argon. Indium chloride (0.2g) and anhydrous sodium acetate (0.2 g) was added and the solution refluxed for 3 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane / water ( 100mL/ 100mL). The organic layer was washed several times with 0.5 N
HCl/water t5 (200mL), collected and dried over anhydrous sodium sulfate (20g). The organic layer was filtered and evaporated to dryness. The resulting residue was chromatographed on silica using 5% MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane /
dichloromethane. Yield 60mg.
WO 00/00204 ~ ~ PCT/US98/13601 Example 5, preparation of In Octaethylbenzochlorin (9) from Octaethylbenzochlorin (~~OEBC") Each of RI through R8 is ethyl.
In Octaethyl benzochlorin, M
is 2H, and in Indium octaethyl benzochlorin M is Ins" Z, Ins ~5 Z or a mixture of Int ~'~ Z and Ins ~5 Z;
Z is CI
Octaethylbenzochlorin ( 100mg) was dissolved in acetic acid and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution was refluxed for 3 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( IOmL). The resulting solution was chromatographed on silica using 5% MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid I o crystallized from hexane / dichloromethane. Yield 1 l Omg.
WO 00/00204 ~ ~ PCT/US98/13601 Example 6, preparation of InOEBCSOZNH(CH2)30H (10) from OEBCSOZNH(CHZ)30H
Each of R 1 through R8 is ethyl In Octaethyl benzochlorin, M
Is 2H, and in Indium Octaethyl benzochlorin M is a mixture of In~~3 Cl and In~~s CI
R is SO,NH(CHZ)30H
LO
OEBCSO~NH(CHZ)30H (100mg) was dissolved in dimethylformamide (DMF) (25mL) and InCl3 ( 100mg) was added. The solution was refluxed for 6 hrs and the DMF
was removed by rotary evaporation. The residue was dissolved in dichloromethane (IOmL) and the resulting solution was chromatographed on silica using 5°lo MeOH /
dichloromethane as eluent. A minor fore running green band was collected and discarded and the more polar major green fraction was collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane.
Yield 52mg.
WO 00/00204 '2 PCT/US98/13601 Example 7, Preparation of InOEBCS02I~CH2CH~OCH2CH~OCH2 H~OCH2CH~OCH~ (1~) from OEBCSO2N~H~CH20CH2CH20CH2CH~OCH~CH~OCH~
CH~CH20CH2CH20CH2CH20CH2CH~OCH~
Where each of R1 through R8 is ethyl M is In ~ t3 Z, In ~ ~5 Z, or a mixture of Ins ~~ Z and Ins ~5 Z
in In Octaethyl benzochlorin and 2H in Octaethyl benzochlorin ~H,CH=OCH=CH=OCH=CH,OCH,CH~OCHz R is SO,[~ ~
~H_CH=OCH=CH~OCH_CH,OCH_CH=OCHi Z is CI
OEBCSO N"'CH?CH20CH2CH20CH2CH20CH~CH~OCH~ (400 mg) was 2 ~CH2CH~OCH2CH20CH2CH20CH2CH20CH~
dissolved in acetic acid ( 150mL) and Indium chloride (0.4g) and anhydrous sodium acetate (0.3g) were added. The solution was refluxed for 3 hrs under argon.
The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( IOmL). The resulting solution was chromatographed on silica using 5%
acetone / dichloromethane as eluent and the major green fraction collected.
The solvent was removed by rotary evaporation and the solid crystallized from hexane l0 dichloromethane. Yield 420mg.
WO 00/00204 ~ 3 PCT/US98/13601 Example 8, Preparation of InOEBCSOZNHC(CH20H)3 (19) from OEBC
SOzNHC(CHZOH)3 Each of R1 through R8 is ethyl In Octaethyl benzochlorin, M
Is 2H, and in Indium Octaethyl benzochlorin VI is a mixture of Ins" Cl And Ins ~5 Cl R is SO,NHC(CH,OH)~
to OEBCSO~NHC(CH~OH)~ (100mg) was dissolved in bromobenzene (SOmL) and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution was refluxed for 5 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( l OmI,). The resulting solution was chromatographed on silica using 5% acetone / dichloromethane as eluent and the major 15 green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane. Yield lOSmg.
Example 9, preparation of InOEBCSO2NH (CHZ)4CH(NHZ)COZH (21) from OEBCS02NH (CHZ)4CH(NH2)COZH
Each of R1 through R8 is ethyl In Octaethyl benzochlorin, M
Is 2H, and in Indium Octaethyl Benzochlorin M is a mixture of In 113 Cl and In 115 C!
R is SOZNH (CHZ)4CH(NHZ)COZH
OEBCSOZNH (CHZ)4CH(NH2)COzH (100mg) was dissolved in acetic acid and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution refluxed for 3 hours under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( lOmL). The resulting solution was chromatographed on silica using 5% MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane. Yield 1 lOmg.
Example I0, Preparation of Indium 2-desvinyl-2-acetyl pyropheophorbide (26) from 2-desvinyl-2-acetyl pyropheophorbide (26) O=C-CH3 N N
,, , N,, N
'H
CH~OZC
M is 2H in 2-desvinyl-2-acetyl g Pyro heophorbide and a mixture of In~" CI and In~~S Cl in Indium-2-desvinyl-2-acetyl pyropheophorbide to 2-Desvinyl-2-acetyl pyrropheophorbide (100mg) was dissolved in acetic acid and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution was refluxed for 3 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( l OmL,). The resulting solution was chromatographed on silica using 5°lo acetone / dichloromethane as eluent and the major 15 green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane. Yield 100mg.
WO 00/00204 ' 6 PCT/US98/13601 Example 11, Preparation of Indium 2-desvinyl-2-formyl pyropheophorbide (27) from 2-desvinyl-2-formyl pyropheophorbide O=
N
N,, N
r'H
Hz CH~02C
M is 2H in 2-desvinyl-2-formyl Pyro~heophorbide and a mixture of In ~3 CI and In~~s CI in Indium-2-desvinyl-2-formyl pyropheophorbide 2-Desvinyi-2-formyl pyropheophorbide ( 100mg) was dissolved in acetic acid (20mL) and Indium chloride ( 100mg) was added. Diisopropylethylamine (0.3m1) was added and the solution refluxed until no more starting material remained by TLC (5%acetone i dichloromethane). The acetic acid was removed by rotary evaporation and the residue dissolved in dichloromethane and washed with 10% NHaCI (2 x SOmL). The organic phase was separated, dried over sodium sulfate filtered and rotoevaporated to dryness. The residue was dissolved in dichloromethane and purified by chromatography on silica using 5% acetone / dichloromethane as eluent followed by 20% acetone /
dichloromethane as eluent. A less polar green fraction was collected and recrystallized from dichloromethane /
2o hexane. A second more polar green fraction was collected and discarded.
Yield of (27) _ 62mg.
WO 00/00204 1 ~ PCT/US98/13601 Example 12, preparation of Indium Chlorin e6 trimethyl ester (28) from Chlorin e6 trimethyl ester N
N
CO~CH
CH~CO~CH~
M is 2H in Chlorin eb Trimethyl eater and a mixture of In~~3 Cl and In~~S CI in Indium-Chlorin e6 trimethyl ester Chlorin e6 trimethyl ester ( 150mg) was dissolved in acetic acid (20mL) and to Indium chloride (150mg) added. Diisopropylethylamine (0.3m1) was added and the solution refluxed until no more starting material remained by TLC (5%acetone /
dichloromethane). The acetic acid was removed by rotary evaporation and the residue dissolved in dichloromethane and washed with 10% NH~CI (2 x SOmL). The organic phase was separated, dried over sodium sulfate, filtered and rotoevaporated to dryness.
The residue was dissolved in dichloromethane and purified by chromatography on silica using 5% acetone / dichloromethane as eluent followed by '~0% acetone /
dichloromethane as eluent. The major green fraction was collected and re-purified by chromatography on silica using 5% acetone / dichloromethane as eluent. The major green fraction was collected and recrystalized from dichloromethane / hexane. Yield, 67mg 2o Various compounds comprised essentially of a non-radioactive indium atom complexed with the inner nitrogens of a pyrrolic core have been evaluated biologically as photosensitizers. The results of some of this evaluation are summarized below.
In Vitro Biological Evaluation of FunctionaIized Benzochlorins.
The in vitro biological evaluation of certain photosensitizers was determined, using standard procedures. Several of the photosensitizers had the following structure:
RT
where each of R 1 through R8 was ethyl and R and M had various meanings The identities of a first group of the compounds tested, all of which had the foregoing structure, of an arbitrary "Sensitizer Number" assigned for reference purposes, to and the Example (if any) where their preparation is described are set forth below:
SensitizerExampleIdentity Identity of R in Foregoing formula Number (if of any) M in Foregoing formula 2 2H SO,NH(CH ),OH
4 Zn H
Zn SO,NH(CH ),OH
7 Sn SO,NH(CH ),OH
g Sn CH
9 5 In H
6 In SO,NH(CH ),OH
11 In CH.
12 In SO,N(CH,CH,OH), 13 In SO,NH(CH,) OH
14 In See structure below In See structure below 16 In SO,NH(CH,),O(CH,),O(CH,),OCH
17 7 In SO,N [(CH,),O(CH,),O(CH,),O(CH,)OCH
], lg In SO,NH(CH,) SH
19 8 In See structure below In SO,NHCH,CO,H
21 9 In See structure below Sensitizer Number 14 SO2N ~ N(CH~)2 N(CH~)~
Sensitizer Number 15 SOZNHCH~CH2N~
OH
Sensitizer Number 19 S03NH OH
OH
Sensitizer Number 21 S02NH(CH2)4~HCOZH
The identities of a second group of compounds tested, all of which had the following structure, of an arbitrary "Sensitizer Number" assigned for reference purposes, and the Example, (if any) where their preparation is described are set forth below:
WO 00/00204 2o PCT/US98/13601 Sensitizer ExampleIdentity of Identity of Number lif M in fore- in foregoing any) going formula formula 22 2H Vinyl 23 SnCI, Vinyl to 24 InCI Vinyl 25 InCI Ethyl 26 10 InCI COCH
27 11 InCI CHO
28 12 Pd COCH
WO 00/00204 2~ PCT/US98/13601 A third group of the sensitizers had the folowing formula:
CI , -Sensitizer Example Identity of Identity of Identity R1 of R2 Number (if any) M in fore- in foregoing in foregoing going formula formula formula 29 a mixture of Vinyl CH~CO~CH3 Ins ~3 Cl and ~~ is Cl 30 a mixture of Ethyl CH~COZCH3 Ins l~ C1 and ~vs Cl 31 a mixture of Vinyl COZCH~
~1i3 Cl and y ~s Cl 32 a mixture of Ethyl COZCH3 Ins ~~ Cl and y is CI
For the Biological Evaluation, Chinese hamster lung fibroblasts (V-79) obtained from the American Tissue Culture Collection were grown in D-MEM supplemented with 10% fetal calf serum at 37°C, 5% C02~ and 95% humidity. These cells were used to evaluate the sensitizers for dark and light toxicity, and cellular uptake.
Medium was replaced with 5% fetal calf serum supplemented medium during sensitizer incubations.
In the first phase, the combination of intracellular and extracellular concentration of photosensitizer required for lethal damage to 50% of the cells in culture (DC(50)) on light exposure was determined by plating cells at a density of 100 cells / cm2 and incubating for 1-3 hours to allow attachment of the cells. Cells were incubated with various concentrations of sensitizer ([C]= 0.01-l.OpM) delivered in non-toxic concentrations of DMSO/ 5% dextrose solution or in some cases in egg yolk phosphatidase (EYP) for 16-24 hours. The cells were then irradiated with laser light using ~ o a tunable Lexel argon pumped dye laser at the band I absorption of the photosensitizer.
Total power density was adjusted to 12.5 mW/cm2 and a total light dose of 1.25 J/cm2 was applied. After treatment, cells were washed with HBSS, refed with 10% FBS
supplemented DMEM with phenol red and incubated far 3-S days to allow colony formation: Cells were fixed in methanol, stained with Giemsa, and colonies were counted.
~5 Plating efficiency was determined using a control colony and the mean percent survival fraction plotted against the sensitizer concentration and the DC50 established (Table 5).
Several photosensitizers were screened by a standard cellular uptake protocol.
A
IOp.M stock solution of photosensitizer in EYP was prepared by dilution of the photosensitizer stock (1mM) using 5% dextrose solution. Monolayer V-79 cells in the log 20 phase of growth in 12- well tissue culture plates were incubated with 0.2mL
of the IOpM
solution of photosensitizer for time periods of 0. 12, 36, 48hrs. Following incubation the cells were washed with PBS (1mL) three times, then washed with HBSS (1mL) and detached using 100p.L of trypsin. Individual wells containing cells were lysed by three freeze thaws.
25 ~ Spiking experiments were performed to confirm that the sensitizer could be adequately recovered using standard procedures. The sensitizer was then extracted from the cell debris with DMSO, centrifuged and the supernatant examined for fluorescence.
Sensitizer concentration was determined by comparison to a standard curve.
Results are expressed in ug / ug protein. Untreated monolayers are used to determine cell count.
3o Treated cells of each time point were used to determine the protein concentration using the BCA assay. The results for the photosensitizers studied are presented in Table 2. Results shown are the mean of the three experiments for each timepoint.
As can be clearly seen for the compounds tested, indium compounds had clearly a much lower DC(50)(light) values, regardless of the functionality attached to the chlorin.
In Vivo Assay of Photosensitizers on Tumors Female C3H/HeJ mice (8-9 weeks old} were subjected to trochar implantation of BA mammary carcinoma on the hind leg of the animals. Animals having tumors ca Smm in diameter were entered into the in vivo screen. For each new photosensitizes, a group of at least three mice were used to ascertain a drug dose that caused a response as described in table 3 when treated with the appropriate wavelength of light. Generally in this series, animals were injected with 1 p. .mole of sensitizes / Kg of body weight, formulated in egg yolk phosphatidate (EYP)> via the tail vein. At a defined time period later the animals were irradiated with light from a laser source tuned to the wavelength of activation of the sensitizes. The power density of the laser was set at 75mW ! cm' with a total light dose of 200J / cm''. The spot size was lcm diameter. Results for each photosensitizes are shown in Table 3.
Selected Kaplan-Meier curves for two different benzochlorin metal classes are shown below. The curves are identified by legend.
Table 2.
Photophysical measurements, DC(50)(light) and cellular uptake of Photosensitizers Compound 7~max ~ f DC (50) (light)Cellular uptake (Figure 16) (s M-~ cm's) (pM) (24hrs) (pmole/pg protein) ( l ) H2 658 (35,000)0.347 > 1.0 -(4) Zn 678 (57,000)0.150 > I .0 -(6) Sn 69l (54,000)0.044 0.08-0.16 0.501 (9) In 691 (53,000)0.028 0.1 0.336 (2) H2 665 (34.000)0.230 0.5-1.0 0.129 (5) Zn 678 (48,000)0.124 0.5 -1.0 0.093 (7) Sn 684 (52,000)0.040 0.5 -1.0 -(10) In 684 (52.00010.027 O.l-0.125 -(3) H2 658 (35.000)0.35 - -(8) Sn 694 (50.000)0.02 - -( I I ) In 687 (54,000)0.034 - -( I 2) In 684 (52.OOU)-0.03 0.04 -( l3) In 684 (52.000)-0.03 0.04 -( l4) In 684 (52.000)0.03 0.05 -( 15) In 684 (52,000)-0.03 0.05 -(16) In 684 (52,000)-0.03 0.04 -( 17) In 684 (52,000)-0.03 0.04 ( I 8) In 684 (52.000)-0.03 0.04 ( 19) In 684 (52,000-0.03 0.04 (20) In 684 (52,000-0.03 0.04 (21 ) In 684 (52,000-0.03 0.04 (22) H2 666 (45.000)- -(23) Sn 658 (74.000)- >1.0 (24) In 666 (45.000)- -(25) In 655 - 0.03 (26) In 672 - I 0.06 (27)In 683 - 0.05 (28) Pd 653 - 0.05 (29) In 641 0.05 (30) In 637 - 0.06 (3 l ) In 650 - 0.08 (32) In 642 - 0.07 -Table 3 Tumor tes for o cure free ra base, Ztnc, m an n mm Compounds Drug DoseTime of TreatmentLight % Cure (30 (Figure ( m / Post injectionDose days) 16) (M) K ) I n = i0 ( I ) H2 3 24 200 60%
(4) Zn 3 24 200 0%
(6) Sn 0.75 24 200 80%
(9) In U.l 24 200 70%
(2) H2 2. 5 24 200 80%
(5) Zn 2.25 24 200 100%
(7) Sn 1.5 24 200 0%
( 10) In 0. ! 24 200 100%
(3) H2 2.5 24 200 60%
(8) Sn 1.0 24 200 !00%
( 11 ) In 0.15 24 200 90%
(22) H2 10.6 3 200 50%
(23) Sn 2.0 24 or 6 200 0%
(24) In 0.2 6 or 8 20CI 80%
( l2) In 0.05 24 200 90%
( I 3) In 0.075 24 20U 80%
( l4) In 0.075 24 20C1 90%
l5) In 0.05 24 200 100%
( I6) In 0.05 24 200 80%
( l7) In 0.075 6 200 100%
(25) In 0.075 6 or 8 200 80%
(26) In 0.125 8 200 90%
(27) In 0.1 8 200 90%
28) Pd 0.2 8 200 80%
(29) In 0.15 6 200 70%
80 ~ ~ >! L. ~ wET-3E 'f 3E 3E 3E ~E~
\ ~W
i N ~N
60 r ~ , =.- 0.25urrYKg n=1 p) ~ ~S
i --~-- 0.35um/Kg ~n=9~ N ~ - N
--+-0.5um/Kg (n=5~
[Ji 40 r ~~ I ~ 0.75urNKg (n-1 ) 1 v 20 t-T' d I d' Chl Tins Days Post PDT
Kaplan-Meier survival Curves for SnOEBC
100 ~,, , ,I
8 0 tr h ~. v r~
40 r ~ -~ 0.075um/Kg (n=5) -~- 0.05um/Kg (n=3) -~--O.Ium/Kg (n=10, 2 lath ) Days Post PDT
Kaplan-Meier survival curves for InOEBC.
5 The procedures of Examples 1-12 can be modified to produce other phototherapeutic compositions according to the invention, each such composition being comprised essentially of a non-radioactive indium atom complexed with the inner nitrogens of a pyrrolic core composed of at least two pyrroles. The modification involves merely substituting an equivalent amount of the free base of another compound having a l o pyrrolic core composed of at least two pyrroles for the methyl pyropheophorbide, the benzoporphyrin derivative, the tetrakis (3-hydroxyphenyl)chlorin, the octaethylbenzo-chlorin of Examples 1, 3, 4, 5, and 6 or for the corresponding starting materials of Examples 7-12, or by substituting other dicyano compounds capable of forming functionalized phthalocyanines, functionalized naphthocyanines or the like for the 4-tert-is butyl-1,2-dicyano benzene of Example 2.
Examples of compounds having a pyrrolic core composed of at least two pyrroles, and which can be substituted as described in the preceding paragraph to produce additional compounds according to the instant invention are named in Table l, and defined by reference to Figures 1-58, which follow the Table.
WO 00/00204 2~ PCT/US98/13601 Table 1:
Pvrrole-derived macrocyclic compounds (Fig. l ).
Naturally occurring or synthetic porphyrins and derivatives thereof (Fig. 2) g Naturally occurring or synthetic chlorins and derivatives thereof (Figs. 3, 16, 17, 32-35 and 48-55) Bacteriochlorins and isobacteriochlorins (Figs. 4, 5 and 36-47)) Phthalocyanines, Naphthalocyanines and derivatives thereof (Figs. 6, 7, 15, 18-21. 24. 26. 29, 30, 31 and 56) Porphycenes and derivatives thereof ( Fig. 8) Porphycyanines and derivatives thereof (Fig.9) Pentaphyrins, sapphyrins and derivatives thereof (Figs. 10 and 11 ) Texaphyrins and derivatives thereof (Fig. 12) Benzochlorins and derivatives thereof (Fig. 13) Chlorophylls and derivatives thereof (Fig. l4) Corroles (Fig. 58) ~3 Ril R4 R3 RII R4 R3 R7 R4 ~ W \ RS R2 ~ ~ ~~ \ RS
N N _' N N \ ~ R10 ~ N~M N / R12 RIO ~ ~M. / R12 N N N N
R1 ~M\R8 R6 RI \ 1 / / R6 RI ~ / / R6 FIGURE t FIGURE 2 FIGURE 3 _ R4 RS
R3 R11 R4 R3 R11 R4 ~ 1 \ N\ \ ' R7 R? ~ ~ RS ~ ~ \~_ R5 RI ~ N N - R8 N W / N~ N N~ ~M iN
RIU ~ \M. / RI2 R10 N M.N / R12 R16 jl' 'N R9 N~ N
R1 1 / / R6 R1 / / / / R6 / \ N /
T RIS ~ ~ R1o R8 R9 R~ R8 ~9 R~ R13 R12 RII
~ ~ .
R7~ ~~ oz R11 R17 R4 N'~~i~ Rli ~ - \
RS
rN R12 ~ ~ N~ ,N-~ N ,M~
v_ :"1N i N~ N
R23 \ ~ N / Rl3 R14 Ri \ ~ _ / R6 R19 R18 ~ ' R15 R4 ~ R4 R3 R11 R13 R4 R-~ Rll ~ R12 ~ R11 % R12 ~IN' ~N \ RS ~ ~\~ ~ ~ R6 ~ ~\H \ i ~ R6 R10 ~ ~M M~ / Rt2 M-N I ~M-N I
R1 \ N ''N~ N R6 \ N ~ I \ ~ R~ RI \ N ,N\ ~ R7 / / Rl '- _ ~R9 Rt0 R8 R9 RIS R7 R8 Rl R13~ R8 R8 R13 R8 FIGURE 9 FIGURE 10 FIGURE 1 i iiR
R17 ~~ R12 R,~ \w \ \ R6 R3 \w \ \ R6 R16 / ~ N j ~ R6 N~ N' N. N-' M_ N I Rl2 \ M ~ R14 R12 \ M ~ R14 RI , N, ,N
RIS ~ N/ II ~ R7 N' /N / R7 Rl 1 / / R7 R 14 '-- ~ 9 R2 ~ ~ R2~
R1 [0 R l l ~ R9 R8 8~~
R4 RS R4 R13 RS R4 RI~ RS
R3 ~ N~ \ R6 R3 ~ ~ ~\ R6 R3 ~ ~ \ \ R6 N N- N N' N~ N-=..~ R12 ~ \M ~ R14 Rl2 ~ 'M ~ R14 N\ N,M'N ~y RI N, ~N R1 N, .N
R2 \ 1 N / R7 R2 ~~~=~ R2 RI1 ~ R8 R11~ R8 RI R8 R10 R9 R10/ 'R16IR159 Y. :X V ~ ~ ,U.
R2-U~V~ ~U~V~R7 R2 ~ RS ~ R2 R2-U~ ~ Y R18 X V~R7 \ N. \ y~ ' w \ \ I jt w \ \ y RI ~ N rN ~ R8 RI ~ ~' N~\RI Rl ~ N\ .N - ~R8 Nv :~ ~N Nv M ~N Nv :~ ~N
R17 N N R9 RI N~ ~N RI R17 N N R9 1 i X I 1 i 1 Y \ ' /
Y
R16-V U X N Y V,U-R10 R2 ~ N / R2 R16-V~U;X N Y; V,U-R10 ~R14 Rl3 RII 3 R4 R4 ~ R15 'R14 R13 RII
RIS
FIGURE 18 FIGURE l9 FIGURE 20 R4 RS R5 R4 R4 RS R8\ R9 A
R3 / '' R6R7R ' ~ I R3 R3-AD -C'F R6 R7~E fl~ C-Rl0 R2 ~ \ I R2 R2 ~ ~ N~ \~ Rll R1 ~ N \N~RI Rl ~ N N=.~ Rt2 N~ ~M ~N Nv :~ ~N
N ~N RI E~24 N N ~R13 Rl \ 1 1 N / ~ R2 R?-i E \ N / E D R l4 R2 ~ C _ -~
w ~F F \ v R3 I ~ R6 R 1 / R3 ~B ;p R19 R18 C;~ A-RIS
R22 ~A . i 4 RS RS R4 R21 R20 R17 ~16 WO 00/00204 3~ PCT/US98/13601 R~ O O
A
R3 / _C R6 R~.'D' ~ R10 X R2 R-~ X
A \ o -B A D
R2 ~ N ~ ~\ N \
D C~ A ~ ' B.
Rl ~ N' N R12 R~l ~ N .~ R4 ~'-=t N~ i.~N ~N /Ri3 R8, N~N ~N, ~~N RS
C \ N ~ ~ /R14 B \ N~A, p' C~ A O ~~ - ~B'' O
Rly R18 / R15 X~ R7 R6 R__ \
R~ i R_0 R 16 O O
FIGURE 2:i FIGURE 24 E' ~RS R8~ , D~ ~ ,RS R8~ I
R3-D F R6 R7 C ~ E-R I 0 E= F C = D~
C ~ B A~ p R3-D~ R6 R7~ ~g-R I O
~F
R? A ~ N' ~ B \RI1 R~ ~B N A ll \R11 RI ~ N N' \R12 A ~\ \ \ B~R12 ~ RI N' N"
N :1V1\ N
N\ N N ~N v R2?\A \ I / / A/ R I 3 R2n N N / R l :i " N~1 ~R14 1A ~ ~ ~ A
R2i-D~C;B' B~C R19-D~ ~N D~R14 I Rl9 Rjg D-R15 C'Bv ,B'E
R20 Ri~'E~ R18 R17 R16 R15 E-F R8 p._ E~ RS
R3-D' \ R6 R~\ ~C R3 C~ ~F-R6 7 R8 R9 C~B A~ iD_Ry -' ~.4=B C
N
RS A w ' \ B R2 B~ N I '~p-R10 BRIO A w ' \
RI N N- Rl ~j N N' F~E~RII
W ~ i ~' N N R I 2 R?(1 N N R I 1 R2.~ R24 \A 1 ~ .A t , F N N R 13 R19-C \ N / 1 iRl2 E~ ~ I ~ / .A~
=B B~C R22-D'' I ' N ~B-R14 D 'Rl7 R16 ' D-Rl-1 C BrA R18 R18 ~FrE R~.I R20 Rl9 -F, ~C_RIS
R15 R14 iE~D
R1~ Rl6 a~ ~n _ R6 fZlO R12 p~C B~ B,C~ ., R,~~ ~~-R8 D p Rl3 R3 ~R.1 RS R6 p ~ R9 ~ p _ ~V' Y R 18 X =~, R3-C' 1 \ N\ \ I ''C-R14 R2 U~ \ \ \ a 'R7 R2' B ~ \ ~ ~ B' ,RI ~ N, . N'--~ i Rt5 RI X \ ~ N~Y R8 R.' v :~ ~ R17 Nv :~ ~N
R3l,B'p N N plB~Rl8 R17 N N R9 R30-C~~ I \ N / ~ i,C-R 19 Y \ I N / X
p ~ R24 ~ p R16-V~ ,L'-R10 U:X' Y-V
R2 R'~,~, ,B \R2S DB_ ~p R21R_0 RIS R14 R13 Rl I
R27 R26 R2'I R22 \ ~\~\ \ ~ ~\ \~ \ \
N N" 1 N N'- 1 N~ N' 1 R3 \ ,Mv / R-~ \ My / R? \ IvI\ /
H N N H N N' H N N
1 / / I / / ~ / /
H R6 H R4 R6 H p~ X ~ B
R2 ~R4 R2 R2 w \ R~ \ \ R~ w \ R~ ~ \ R6 \ i v \ ! i \ I 1 \ I 1 N ,N' N, N-' N, N- N' N' RZ \ M~ / R3 \ M~ / ' R3 \ M\ / , R3 \ M\
H 'V N H N N H N N H N N
1 / / t / / 1 / / I / /
R8 H ~ R8 HA~X~B
H ~ H R4 R2 R4 X R' R4 R2 R2 R1 RS RI RS R6 R1 RS R6 Rl \ \ ~ \ \ \
\ ~ ~_ ~ \ ! ~ \ 1 l N .N v N' N' I N N' 1 R3 \ M\ / Rg \ M;
N N N N / R3 \ ~M' /
N N
H l / / H 1 / ~ H I / /
H ~ ft7 H
R4 R7 Hp~X~B
R1 RS R1 RS Rl R~
R6 \ ~~Y_ R6 \ N' ~N_ RS
R3 \ M' / R3 \ M\ / R3 \ M\ /
N N N N N N
H ~ R7 H R4 127 H A~, X'~ B
.1 RI Rl3 R3 RI R13 R4 2 R1 R4 i3 R2 \ R4 R2 \
_ w B' ~ Rg ~ B'Y ' RS ~
Rs \ \
N N~ N~ .N~ B~ ~C~
R6-A~ M ~C-R12 l2 R6-A' M ~C-R12 R6 \ ~M~ / R12 r 1 D R11 1 ~~Rll R7 R7 \ 1 ~ / R I I I I R7~ ~ / \ / /
D~ ~ D
Rg R9 R10 "" Rg R9 RIO Rg R9 RIO
,1 RIS RI R13 R15 Rl R13 I3 RI Rl3 Rl R4 2 ~ R4 R3 R2 R 14 R4 i 3 2 4 R5 ~ ~ ~ RS
\ ~ 1 _ 12 R6-A ~ N'IVI N C:-R l2 R6 \ B~M C / R 12 R6-A\ N'M N ~C-Rl2 I R7 \ N' ~N / R11 R \ A /D / R11 R7 \ N' ,N / RIl D~ D
Rg R9 RIO RS R9 RIO Rg R9 R10 FIGURE S l FIGURE 52 FIGURE 53 FIGURE 54 R4 ~ ~ RI R3-p E4 F ELS R6 R7\ :Cg R4 R3 RI
$ C-~ B A D-R9 RS ~ ' \ R13 R~ , ~ N~ \ " ~ ~ \ R13 RS
\ N' .N RA \ N. .~B R10 \ N' ~N~
R6-A~ ~M ~C-R12 N\ ,~ ~N M ~ RI2 N ~N R 8 N N N~ ~N
R7 \ I D / Rll ~A \ t ~~ II ~ R7 \ \ / R11 N _ R8 R9 RIO RI7 D.C:B~IS ~B'CD R1_ R8 R9 R10 R16 Rt'~ I~13 Examples and illustrations from the literature outlined in Table 1 and Figures 1 to 57 of types of photosensitizers that may be used in photodynamic therapy or imaging and are applicable to the insertion of indium into the central core are as follows:
Dipyrromethenes: (Figure 1 ).
Dipyrromethenes have been used widely as intermediates in. the synthesis of porphyries (for example "The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume II. 215-223; Volume I, Chapter IV, 101-234. References within these volumes provide actual experimental details. These compounds can be coordinated with metal salts to produce metallo complexes (for example A.W. Johnson, LT. Kay, R. Price, K.B.
Shaw, J.
Chem. Soc, Perkin Trans .I, 3416-3424, 1959; S.M. Bloam, P.P. Garcia; J.H.
Boyer, L.R.
Morgan US Patent 5,189,029; date of patent Feb 23, 1993; L.R. Morgan, J.H.
Boyer, U.S
Patent 5,446,157). As shown in Figure 1, these molecules can be synthesized such that a wide variety of functionality can be directly attached to the basic diyrromethene ring structure. Such functionality can be used to increase water solubility, lippophilicity, ~5 conjugation to biomolecules such as antibodies or proteins, to increase the wavelength of absorption of the molecules (by increasing the conjugation of the macrocycle).
As such, these molecules can be used for light activated photochemistry or diagnosis.
Porphyries: (Figure 2) Routes to the synthesis of the ubiquitous tetrapyrrolic macrocycles that contain in 2o their macrocyclic ring system 11 double bonds (excluding peripheral substituents), is outlined in detail in several books including "Porphyries and Metalloporphyrins" Ed.
K.M. Smith, Elsevier Publishing Company, New York, 1975, Chapter 2, p29-55;
chapter 19, p778-785 and "The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I.
References within these volumes provide actual experimental details. A very large number 25 of porphyrinic compounds have been synthesized. As they are prevalent in nature, a large number of studies on the chemical modification of these compounds have been undertaken ("The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I, p 289-339.).
A great deal of work has been undertaken on the synthesis of porphyries from mono-pyrrols ("The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I, chapter 3, 85-100;
chapter 30 4, 101-234, chapter S, 235-264; chapter 6, 265-288). Notable valuable examples of such work is in the synthesis of mono, di, tri and tetraphenyl porphyries ("The Porphyries" Ed.
D.Dolphin, Academic Press, 1978, Volume I, chapter 3, 88-90; Gunter, M.J., Mander, L.N., J. Org. Chem. 46, 4792-4795, 1981.). Such compounds can be widely functionalized as the aromatic rings may possess different substituents or have incorporated in them heteroatoms. Porphyrins also can be synthesized that possess annelated aromatic rings on the (3-pyrrole positions (T.D. Lash, C.Wijesinghe, A.T. Osuma, J.R. Patel, Tetrahedron Letters, 38(12), 2031-2034. 1997.) which can have the effect of extending conjugation and modifying the absorption and photophysical properties of the compounds.
Porphyrin type compounds have been synthesized from pyrroles and 5-membered ring heterocycles (such as thiophenes or furans for example) which incorporates one or more heteroatom besides nitrogen within the central porphyrin "core" ("Porphyrins and Metalloporphyrins" Ed.
K.M. Smith, Elsevier Publishing Company, New York, 1975, Chapter 18, 729-732).
Such compounds can be modified similarly to produce highly functionalized derivatives. In addition porphyrin dimers, trimers or oligomers have been synthesized with great abandon.( H. Meier, Y. Kobuke, S. Kugimiya, J. Chem. Soc. Chem. Commun., 923, 1989;
G.M. Dubowchik, A.D. Hamilton, J. Chem. Soc. Chem. Commun.,904, 1985; R.K.
Pandey, F-Y. Shaiu, C.J. Medforth, T.J. Dougherty, K.M. Smith, Tetrahedron Letters, 31, IS 7399, 1990; D.R. arnold, L.J. Nitschinsk, Tetrahedron Letters, 48, 8781, 1992; J.L.
Sessler, S. Piering, Tetrahedron Letters, 28, 6569, 1987; A. Osaku, F.
Kobayashi, K.
Maruyama, Bull. Chem. Soc. Jpn, 64, 1213, 1991 ).
Chlorins: (Figures 3, 16, 17, 31-34, 47-54) Chlorins or Hydroporphyrins are porphyrins that have only 10 double bonds in 2U their macrocyclic ring system (excluding peripheral substituents). The "reduction" of the porphyrin macrocycle has pronounced effects on both the absorption profile of the macrocycle and the photophysical properties of the compound. Many naturally occuring chlorins may be extracted from plants, seaweeds or algae (e.g. "Porphyrins and Metalloporphyrins" Ed. K.M. Smith, Elsevier Publishing Company, New York, 1975, 25 Section H, p774 -778.) and simple chemical modifications to pheophorbide can give pyrropheophorbides, chlorin e6, purpurin 18 and other chlorin ring systems.
Routes to the synthesis of chlorin macrocycles are outlined in "Porphyrins and Metalloporphyrins" Ed.
K.M. Smith, Elsevier Publishing Company, New York, :1975, Chapter 2, p61-116;
Chapter 19, 774-778, "The Porphyrins" Ed. D.Dolphin, Academic Press, 1978, Volume II, p 1-37, 3o p131-143. References within these volumes provide actual experimental details.
Considerable research has been directed toward the synthesis of chlorin derivatives from porphyrins. Catalytic hydrogenation and hydroboration (H.H. Inhoffen, J.W.
Buchler, R.
Thomas, Tetrahedon Letters, 1145, 1969;.), diimide reductions (H.W. Whitlock Jr., R
Hanauer, R., Oester, m.Y., B.K. Bower, J. Am. Chem. Soc. 91, 7585, 1969), osmium tetroxide (R. Bonnett, A.N. Nizhnick, M.C. Berenbaum, J. Chem. Soc. Chem.
Comm., 1822, 1989) and hydrogen peroxide (C,K, Chang, Biochemistry, 19, 1971, 1971.) , alkali metals and electrochemical reduction (N.S. Hush, J.R. Rowlands, J. Am. Chem.
Soc., 89, 5 2976. 1967), aromatic radicals ( G.L. Closs, L.E. Closs, J. Am. Chem. Soc, 85, 818, 1963) have all been successful at producing chlorins from porphyrins. The use of light as a reductive tool has also been extensively studied by several authors. The reaction of singlet oxygen on vinyl porphyrin has been used extensively to produce chlorins (H.H.
Inhoffen, H. Brockman, K.M. Bleisnerv, Ann. Chem. 730, 173, 1969; D. Brault, C. Vever-Bizet, to Mougee, C., Bensasson, R., Photochem. Photobioi.. 47 151, 1988). The reduction of free base and metalloporphyrins with light and and reducing agents (such as amines or ascorbates) (Y. Harel, J. Manassen, J. Am. Chem. Soc., 100, 6228. 1977: J.H.
Fuhrhop, T.
Lumbantobing, Tetrahedron Letters, 2815, 1970; D.G. Whitten, J.C., Yau., F.A.
Carol, J.
Am. Chem. Soc., 93, 2291, 1971.) also produces chlorins. Cyclization of meso-acrylate t5 containing porphyrins has been used extensively to produce purpurin derivatives (Figure 16 and 17) (A.R. Morgan, N.C. Tertel., J.Org. Chem., 51, 1347, 1986) while acid cyclization of meso-acrolein porphyrins has been used extensively to produce benzochlorins (Figure 13.) ( M.G.H, Vincente, LN. Rezzano, K.M. Smith, Tetrahedron Letters, 31, 1365, 1990; M.J. Gunter, B.C. Robinson, Tetrahedron., 47, 7853, 1991). Diels 20 alder addition of dienophiles with vinyl containing porphyrins has been used extensively to produce chlorins ( Figures 49-54) (R. Grigg, A.W. Johnson, A. Sweeney, Chem.
Commun., 697, 1968, H.J. Callot, A.W. Johnson, A. Sweeney, J. Chem. Soc.
Perkin Trans. I, 1424, 1973; V.S. Pangka, A.R. Morgan, D.Dolphin J.Org. Chem. 51, 1094, 1986;
P. Yon-Hin, T.P. Wijesekera, D.Dolphin, Tetrahedron Letters, 32, 2875, 1991;
P. Yon-25 Hin, T.P. Wijesekera, D.Dolphin, New. J. Chem, 16, 527, 1992; A.R. Morgan, D.Skalkos, G.M. Garbo, R.W. Keck, S.H. Selman J. Med. Chem. 34, 1991).
Acetamidoporphyrins can be cyclized to produce chlorins via a intramolecular Vilsmeier reaction (G.L.
Collier, A.H.
Jackson, G.W., Kenner, J. Chem. Soc., C., 564, 1969). Recently, chlorin analogues of Purpurin 18 based on purpurin 18, have been produced that possess nitrogens on the cyclic 30 "anhydride" ring system (Figure 35, A or B = NR) (A.N. Kosyrev, G. Zheng, E. Lazarou, T. J. Dougherty, K.M. Smith, R. Pandey, Tetrahedron Letters, 38, 3335, 1997).
Bacteriochlorins and isobacteriochlorins: (Figures 4, 5, 35 to 46) Bacteriochlorin and isobacteriochlorins are tetrahydroporphyrins. These derivatives have only nine double bonds in their macrocyclic ring system (excluding peripheral groups). The "double" reduction of the porphyrin nucleus at the pyrrole positions has a. pronounced effect on the absorption properties and photophysical properties. Typically bacteriochlorins absorb in the 720-850nm range while isobacteriochlorins absorb in the 500-650nm range ("The Porphyrins" Ed.
D.Dolphin, Academic Press, 1978, Volume III, Chapter 1; References within these volumes provide actual experimental details). Examples of the synthesis of bacteriochlorins and t0 isobacteriochlorins may be found in the following references; H, H
Inhoffen. P. Jager and R. Mahlhop and C.D. Mengler, Justus Liebigs Ann. Chem. 704, 188, 1967; H, H
Inhoffen, P. Jager and R. Mahlhop and C.D. Mengler, Justus Liebigs Ann. Chem.
704, 188, 1967; H. Mittenzwei, Hoppe-Seyler,s Z. Physiol. Chem. 275, 93, 1942; H.
Brockmann Jr., G . Knobloch, Arch. Mikrobiol, 85, 123, 1972; J.J. Katz, H.H., Strain, A.L., Harkness, M.H. Studier, W.A., Svec, T.R. Janson, B.T. Cope, J. Am. Chem Soc. 94, 7983, 1972; D. Dolphin C. Bruckner, Patent No: 5,648,485, Date of Patent Jul.
15, 1997;
D. Dolphin, P.Y. Hin, T. Wijesekera Patent No: 5,149,708, Date of Patent: Sept 22, 1992;
H.W. Whitlock, R. Hanauer, M.Y. Oester, B.K. Bower, J. Am. Chem Soc. 9I, 7485, 1969;
H, H Inhoffen, H. Sheer, Tetrahedron Letters, 1115, 1972; H, H Inhoffen, J.W.
Buchler, R.
Thomas, Tetrahedron Letters, 5145, 1969; J.H. Fuhrhop, T. Lumbantobing.
Tetrahedron Letters, 2815, 1970; A. Scherz, Y. Saloman, L. Fiedor European patent No:
0584,552 A2;
A. Scherz, Y. Saloman, L. Fiedor U.S patent No: 5,650,292; (A.N. Kosyrev, G.
Zheng, E.
Lazarus, T. J. Dougherty, K.M. Smith, R.Pandey, Tetrahedron Letters, 38, 3335, 1997).
In particular, osmium tetroxide has proved useful in the synthesis of ~3,~3 dihydroxy-bacteriochlorins and isobacteriochlorins from chlorins (R.K. Pandey, T.J.
Dougherty, K:M. Smith, F.Y. Shiau, U.S. Patent No: 5,591,847) and the acid rearrangement of these derivatives has produced numerous bacteriochlorin derivatives.
The treatment of porphyrins and chlorins with hydrogen peroxide has been used to produce bacteriochlorins and isobacteriochlorins (H.H. Tnhoffen, W. Nolte, Justus Liebigs Ann. Chem. 725, 167, 1969). Diets alder addition of dienophiles with porphyrins containing two ~i-vinyl substituents has been used extensively to produce bacteriochlorins and isobacteriochlorins (R. Grigg, A.W. 3ohnson, A. Sweeney, Chem. Commun., 697, 1968, H.J. Callot, A.W. Johnson, A. Sweeney, J. Chem. Soc. Perkin Trans. I, 1424, 1973. ;
P. Yon-Hin, T.P. Wijesekera, D.Dolphin, Tetrahedron Letters, 32, 2875, 1991;
A.R.
Morgan, D.Skalkos, G.M. Garbo, R.W. Keck, S.H. Selman J. Med. Chem. 34, 1991).
Phthalocyanines and Naphthalocyanines;, (Figure 6, 18, 21-24, 28-30) Phthalocyanines and phthalocyanine analogues are perhaps some of the most widely studied photosensitizers in the field of photodynamic therapy and are also widely used as optical recording media. As such the number of structurally different phthalocyanine derivatives is enormous. Not only can the peripheral functionality be widely varied which changes the electronic spectra and photophysics of the compounds, but metallation of the macrocycle also results in photophysical changes. In addition carbons in the aromatic rings may be substituted with heteroatoms (such as nitrogen, sulphur phosphorus) that change markedly the photophysical properties of the compounds.
Examples of references that disclose the formation of such compounds are;
"Phthalocyanines Properties and Applications, Eds. C.C. Leznoff, A.B.P. Lever, VCH
Publishers Inc., 1989; "The Phthalocyanines", Eds, F.H. Moser, A.L. Thomas, CRC Press, t5 Volumes I and II, 1983; "The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I, Chapter 9, p 374-380, References within these volumes provide actual experimental details; A.K. Sobbi, D.Wohrle, D. Schlettwein, J. Chem. Soc. Perkin Trans. 2, 481-488, 1993; J.H. Weber, D.H. Busch, Inorg. Chem. 192, 713, 1988.; R.P. Linstead, F.T. Weiss, J. Chem. Soc., 2975, 1950; M.E. Kenney, N.L. Oleinick, Patent No: 5,166,197, date of 2o patent Nov 24, 1992; M.E. Kenney, N.L. Oleinick, Patent No: 5,484,778, date of patent Jan 16. 1996; P. Gregory, S.J. Reynolds, R.L. White, Patent No: 5,484,915, date of patent:
Jan 16, 1996. A great number of binuclear phthalocyanines / napthalocyanines have been synthesised which share a common benzene or naphthalene ring (J. Yang, M.R.
Van De Mark, Tetrahedron Letters, 34, 5223, 1993; N. Kobayashi, HY. Higashi, T. Osa, 25 Chemistry letters, 1813, 1994.
Azoporphyrins: (Figures 18, 20, 21, 30, 55) Porphyries that possess at least one meso-nitrogen linking atom are called azoporphyrins. The number of meso-nitrogen linking atoms may be extended from one to four. Phthalocyanines and Naphthalocyanine may be regarded as tetraazoporphyrins with 30 extended conjugation due to annelated benzene and napthalene rings. The synthesis of mono, di, tri and tetraazoporphyrin analogues is discussed in "The Porphyries"
Ed.
D.Dolphin, Academic Press, 1978, Volume I, Chapter 9, p 365-388;
"Phthalocyanines Properties and Applications, Eds. C.C. Leznoff, A.B.P. Lever. VCH Publishers Inc., 1989;
WO 00/00204 PC'T/US98/13601 "The Phthalocyanines", Eds, F.H. Moser, A.L. Thomas, CRC Press, Volumes I and II, 1983. References within these volumes provide actual experimental details. The synthesis of a series of tetrabenzotriazoporphyrins and tetranapthotriazoporphyrins has recently been published (Y-H, Tse, A. Goel, M. Hue, A.B.P. Lever, C.C. Leznoff , Can. J.
Chem. 71, 742, 1993.) and clearly it can be envisaged that chemistry typical of phthalocyanine chemistry and porphyrin chemistry may be applied to these compounds, such that hetero atoms may be introduced into the annelated benzene or napthalene rings.
Unsymmetrical benzonaphthoporphyrazines (Figures 25-27, 57 ) Unsymmetrical tetraazoporphyrins that have both a benzene and a naphthalene to annelated unit in the macrocyclic ring system are loosely called benzonaphthoporphyrazines. The synthesis of these derivatives is carried out using classical phthalocyanine syntheses however, using mixed aromatic dinitriles (U.
Michelsen, H. Kliesch, G. Schnurpfeil, A.K. Sobbi, D. Wohrle, Photochem.
Photobiol, 64, 694, 1996; S.V. Kudrevich, H. Ali, J.E. Van Lier: Canadian Patent No:
2,130,853 Filed 25 t 5 / 8/ 1994). References to the synthesis of these macrocycles can also be found in "Phthalocyanines Properties and Applications, Eds. C.C. Leznoff, A.B.P. Lever, VCH
Publishers Inc., 1989; "The Phthalocyanines", Eds, F.H. Moser, A.L. Thomas, CRC Press, Volumes I and II, 1983.
Texaphyrins: (Figure 12) 2o Texaphyrins are tripyrrol dimethene derived "expanded porphyrin"
macrocycles who's central core is larger than that of a porphyrin. The reaction of diformyl tripyrranes with functionalized aromatic diamines in the presence of a metal, gives rise to functionalized metallated texaphyrins (J.L. Sessler, G.W. Hemmi, T.D. Mody, LT.S. Patent No: 5,252,720; J.L. Sessler, G.W. Hemmi, T. Murai, U.S. Patent No: 4,935,498;
D.
25 Magda, J.L Sessler, B. Iverson, P.L. Jansen, M. Wright, T D. Mody, G.W.
Hemmi, U.S.
Patent No: 5,567,687).
Pentaphyrins and Sapphyrins:_ (Figures 10,11).
Sapphyrins and pentaphyrins are fully conjugated macrocycles that possess five pyrrole units. Structural analogues of the sapphyrins and pentaphyrins are outlined in 30 "Porphyrins and Metalloporhyrins", Ed. K.M. Smith, Elsevier, Chapter 18, p750-751;
"The Porphyrins Ed. D Dolphin, Academic Press, NY, Chapter 10, p351-356;
Broadherst et al, J. Chem. Soc. Perkin Trans. I , 2111, 1972; J.L Sessler, V. Kral, U.S.
Patent 5,543,514).
Porphycenes: (Figure 8).
Porphycenes are isomeric analogues of porphyrins that have eleven double bonds in their macrocyclic core that are derived formally by a mere reshuffling of the pyrrole and methine moieties. Routes to the synthesis of functionalized porphycenes are outlined in the following references; E.Vogel, C. Richert, T. Benninghaus, M. Muller, A.D.
Cross.
U.S. patent 5,409,900; E.Vogel, C: Richert, T. Benninghaus, M. Muller, A.D.
Cross. U.S.
patent 5,262,401: E.Vogel, P.A. Koch, A. Rahbar, A.D. Cross. U.S. patent 5,244,671;
E.VoQel, M. Muller, A.D., O. Halpern, Cross. U.S. patent 5,610,175; E.Vogel, M. Muller, A.D.> O. Halpern, A.D. Cross. U.S. patent 5,637,608; E.Vogel, C. Richert, T.
Benninghaus, M. Muller, A.D. Cross. U.S. patent 5,179,120; D. Martire, N. Jux, P. F.
Armendia, R.M. Negri, J. Lex, S. E. Braslavsky, K. Schaffner, E. Vogel. J. Am.
Chem.
Soc.. 114, 1992; N. Jux, P. Koch, H. Schmickler, J.Lex, E.Vogel. Angew. Chem.
Int. Ed.
Engl. ?9, 1385, 1990.
Corroles; (Figure 57) is Corroles contain an aromatic 18 electron chromophore. The synthesis and structural modifications of these compounds (such as N-alkylation) are discussed in detail in "The Porphyrins" Ed. D.Dolphin, Academic Press, 1978, Volume I, Chapter 9, p 357-363 and in "Porphyrins and Metalloporphyrins" Ed. K.M. Smith, Elsevier Publishing Company, New York, 1975, Chapter 18, p730 -749.
2o It will be appreciated that various changes and modifications can be made from the specific details of the invention as disclosed above, and as described in the foregoing examples and that, in its essential details, the invention is a composition which is comprised essentially of a non-radioactive indium atom complexed with the inner nitroaens of a pyrrolic core composed of at least two pyrroles, with the proviso that fully 25 unsaturated porphyrins having the structures:
R3 R12 R.~
Z '~ ~ RS
R11 \ In RIO
N~ \N
RI ~ ~~ ~ ~ R6 R9 R8 Rl where R 1, R2, R4 and R6 are methyl, R8, R 10, R 11 and R 12 are hydrogen, and and R8 are CH~CH2COR 13 (where R 13 is a moiety which results from the removal of H from an amino acid), and where R 1 is CH(OH)Me, R is alkyl, and R'' is a residue derived by removing H
from an amino acid are excluded.
Preferably, the invention is a composition which is comprised essentially of a non-_ radioactive indium atom complexed with the inner nitrogens of a tetrapyrrolic core, with 10 the proviso that the fully unsaturated porphyrins identified above are excluded. A non-radioactive indium atom complexed with the inner nitrogens of a photosensitive compound having a dihydro or tetrahydro tetrapyrrolic core is another preferred composition of the invention.
Other preferred families of compounds according to the invention have the ~5 structures of Figs. 1 to 58> above. Specifically, one preferred family has the structure of Fig: 2, where each of R1 through R12 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, vinyl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 12R 12, CN, OH, OR 12, CHO, (CH,,)"OH, (CH.,}"SH, (CH2)"O-alkoxy, (CH2)"SR 12, (CH,,)"OR 12 (where n = l, 2, 3, 4, and R 12 is a functional group less than or 2o equal to 100000 daltons), (CH2)"C02R12 (where R12 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH~)nCONHR12, (CHZ)~CON(R12)" C02R12 (where R12 is a functional group less than or equal to 100000 daltons), SR12 (where R12 is a functional group less than or equal to 100000 daltons), S03H, S03R12, S02NHR12, 25 SOZN(R 12)x, SO~N(R 12)3+X' (where R 12 is a functianal group less than or equal to 100000 daltons and X is a charge balancing ion).
Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecuie, with the exclusions noted above when the pyrrolic core is fully unsaturated.
Still another preferred family has the following structure:
R
where each of R1 through R14 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)~C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, COCH3, (CH2)"OH, (CH,,)"SH, (CH,)"O-alkoxy, (CHZ)"SRIS, (CH2)"ORIS (where n = 1, 2, 3, 4, and R15 is a functional group less than or equal to 100000 daltons), (CHz)~CO.,R15 (where RIS is H, a physiologically acceptable salt, alkyl ( I-6 carbons), aryl, substituted aryl, alkenyi, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR15, (CH.,)~CON(R 15)x, CO~R 15, CONHR 15, CON(R 15)." (where R 15 is a functional groups less than or equal to 100000 daltons), SR 15 (where R 15 is a functional group less than or equal to 100000 daltons), .SO;H, SO~R 15, SO~NHR 15, SO~N(R 15)x, SO~N(R
15)3TX' (where RIS is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In"z, In"5 or a mixture of In"~ and In"5; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, proteins or biomolecules.
M in the foregoing formula can also be Pd, Sn, Pt, Al, Ru, Ga.
Another preferred family has the following structure:
Where each of R1 through R4 is selected from SO;H (or a salt thereof), SO~NHRS, CO~H
(or a salt thereof), CONHRS, OH, ORS (wherein RS is a alcohol or ether containing group), amide, N(CH3)~, N(Et)~ .
M is In"~, In"5 or a mixture of In"3 and In ~ 1 s Z is a halide, acetate, OH.
M in the foregoing formula can also be Pd, Sn, Pt, Al, Ru, Ga.
Another preferred family has the following structure:
=, D_ _D
Where each of A, B, C, D and E is C, N, N+R (where R is alkyl charged or uncharged) or combinations thereof;
M is In"3, In' ~5 or a mixture of In"3 and In''S and Z is a halide, acetate, OH.
M is the foregoing formula can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
B~C.D
i i A L' Still another preferred family has the structure:
R13 Rll RIO
R16 ~ ~M~ ~ R8 RI
R'i R4 RS R6 Where each of R1 through R16 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)~ X- (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), NR17R17, CN, OH, OR17, CHO, COCH;, CH(OR17)CH3, (CH2)~OH, (CH2)"SH, (CH2)"O-alkoxy, (CH2)"SR17, (CH2)"OR17 (where n = l, 2, 3, 4, and R17 is a functional groups less than or equal to 100000 daltons), (CH2)nC02R17 (where R17 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkyinyl, and n=1, 2, 3, 4), (CH2)nCONHR17, (CH2)nCON(R17)2" COZR17, CONHR17, CONR17R17, SR17 (where R17 is a functional groups less than or equal to 100000 daltons), ~5 SO~H. SO~R17, SO~NHR17, SO~N(R17)~, SO~N(R17)3+X- (where R17 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In ~ ~ ~> In ~ ~ s or a mixture of In ~ ~ ~ and In ~ ~ s; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkyne, or functional groups less than or equal to 100000 daltons, proteins or biomolecules.
Yet another family has the structure:
RI
Where each of Rl through R4 is S03H (or a salt thereof), SO~NHRS, CO~H (or a salt thereof), CONHRS, OH, ORS (wherein RS is a alcohol ar ether containing group), amide, N(CH3)~, N(Et)2.
M is In' i~', In' 15 or a mixture of In"3 and In"5 s Z is a halide, acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Still another family has the structure:
B~C.D
i ii A~,E
~Z
B=A \ N\ I ~N"' A=B' C, ~ ~ ~M ~ ~ ,C
D-E N ~N E-D
A
B
is Where each of A-E is C, N, or N+R (where R is a charged or uncharged alkyl group);
M is In"3, In"5 or a mixture of In"3 and In"5 Z is halide, acetate, or OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
~5 Another family has the structure:
R10 ~ R1 C9 ~ ~ ~ R'?
\ t 1 N Z N "' R3 ,,M\
~ R4 Where each of R 1 through R 10 is H, halide, alkyl, cyclic alkyl ( 1-6 carbons), aryl, 2o substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide; ester, CH=CHCH~N(CH;)~, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR11R11, CN, OH, OR11, CHO, COCH3, CH(OR 11 )CHI, (CH2)~OH, (CH~)"SH, (CHZ)~O-alkoxy, (CHZ)~SR 11, (CH2)nOR 11 (where n = 1, 2, 3, 4, and R11 is a functional groups less than or equal to 100000 daltons), (CH.,)nCO2R11 (where R11 is H, a physiologically acceptable salt, alkyl (1-6 carbons), 5 aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=l, 2, 3, 4), (CH~)~CONHR11, (CHZ}~CON(R11}." CO,,R11, CONHR11, CONR11R11, SR11 (where R11 is a functional groups less than or equal to 100000 daltons), S03H, S03R11, SO,,NHR11, SO.,N(R11)2, SO~N(R11)~+X- (where R11 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In"3, Inns or a mixture of In~~3 and In"5 ; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, proteins or biomolecules.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure immediately above, where each of R 1, R2, R6, R7 is CO~H (or a salt thereof), or COZR 11 (where R 11 is alkyl or aryl).
Each of R3 and R8 is methyl or ethyl.
Each of R4; R5, R9, R10 is methyl, ethyl alkyl, CH~CHZCO,H (or salts therof), or 2o CHzCH~COZRI l (where R11 is alkyl or aryl).
M is In"3, In' n or a mixture of In"i and In"5 and Z is a halide , acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Still another family of compounds has the structure:
R10 ~ ~ R1 ;9 ~ \~ ~~ ~ R2 M\
R8 N~~ N
R6--<~
WO OOI00204 PCT/US98/13b01 Where each of R 1-R 10 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)3 X~ (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), NR11R11, CN, OH, OR11, CHO, COCH3, CH(OR11)CH;, (CH,)~OH, (CHZ)~SH, (CH.,)~O-alkoxy, (CH~)nSRI l, (CH.,)~OR11 (where n = 1, 2, 3, 4, and R11 is a functional group less than or equal to 100000 daltons), (CH,)~CO.,R 11 (where R 11 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=I, 2, 3, 4), (CH,)~CONHR11. (CHz)nCON(R11)." CO,,R11, CONHRI 1, CONR11R11, SRI I
(where R11 is a functional groups less than or equal to 100000 daltons), S03H, S03R11, SO,NHR11, SO,N(R11)," SO~N(R11)~+X- (where R11 is a functional groups less than. or equal to 100000 daltons and X is a charge balancing ion); M is In"3, In"5 or a mixture of t5 In"' and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl; substituted alkynyl, or a functional group less than or equal to 100000 daltons, proteins or biomolecules.
Another family of compounds has the structure:
0 ~ ~~-Rl R9 ~ ~~ ~ ~R2 N\ Z,.N_' R3 M\
R8 N~~ N
R7 ~ / ~ R4 R6 ~
Where each of R1-R10 is H, halide, alkyl, cyclic alkyl (3-6 carbons}, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyil, amide, ester, CH=CHCH~N(CH3)~ , CH=CHCH,N+(CH;)~ X- (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), NR11R11, CN, OH, OR11, CHO, COCH3, CH(OR11)CH3, (CHZ)"OH, (CH2}~SH, (CH2)~O-alkoxy, (CH2)nSRll, (CH2)"OR11 (where n = l, 2, 3, 4, and R11 is a functional group less than or equal to 100000 daltons), to (CHZ)~CO.,R11 (where R11 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH,)~CONHRI 1, (CHZ)nCON(R11)2, C02R11, CONHR11, CONR11R11, SR11 (where RI1 is a functional group less than or equal to 100000 daltons), S03H, S03R11, SOZNHRl l, SO~N(R11)2, SO~N(R11)3+X- (where R11 is a functional groups less than or ~5 equal to 100000 daltons and X is a charge balancing ion); M is In~'3, In"5 or a mixture of In"3 and In"s ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family has the structure:
Ri where each of R 1, R2, R6, R7 is CO~H (or a salt thereof), COZR 11 (where R 11 is alkyl or aryl).
each of R3 and R8 is methyl or ethyl.
each of R4, R5, R9, R10 is methyl, ethyl, alkyl, CH~CH~CO~H (or a salt therof), or to CHZCH~CO~R11 (where R11 is alkyl or aryl).
M is In ~ ~ ~, In ~ 15 or a mixture of In ~ ~ ~ and In' ~ 5 ; and Z is a halide . acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Yet another family of compounds has the following structure;
R13 ~ N Z'N_ RS R4 ~ I ., M\
R11 R12 N~' N
RIO ~ / / R6 R9 ~ R7 l5 Where each of Rl-RI4 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl> substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH3); X- (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), NR 15R 15, CN, OH, OR 15, CHO, COCH3, 20 CH(OR15)CHj, (CH.,)nOH, (CH.,)"SH, (CH2)~O-alkoxy, (CH.,)~SR15, (CH2)nORlS
(where n = l, 2, 3, 4, and R 15 is a functional groups less than or equal to 100000 daltons), (CHZ)nCO.,R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4}, (CH2)~CONHR15, (CH.,)nCON(R15)." C02R15, CONHR15, CONR15R15, SR15 (where R15 is a functional group Iess than or equal to 100000 daltons), S03H, S03R15, SO~NHR15, SO~N(R15)." SO~N(R15)~+X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In"3, Ins ~5 or a mixture of Ins ~3 and In~'S ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
to Still another family of compounds has the structure:
14 ~R 1 ~I /'' R2 R13 ~ N\ Z''N- ~ R4 M\
R1l R12 N~~ N
R10 ~ / / R6 R8~ R7 Where each of R 1, R2, R3, R4, R8, R9, R 10, R 11 is CN
Each of RS and R 12 is methyl or ethyl.
Each of R6, R7, R13 and R14 is methyl, ethyl, alkyl, CH~CH~CO~H (or salts thereof), or CHZCH~CO~R 15 (where R 15 is alkyl, aryl).
M is Ins ~3, Ins ~5 or a mixture of Ins ~3 and Ins ~s.
2o Z is a halide , acetate, or OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure:
R7 ~ ~ ~~ N' Rl N~ Z,.N R2 O
O R6 \ N.,M~N /
~'N ~/~~~
5 Where each of R1-R8 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), NR9R9, CN, OH, OR9, CHO, COCH3, CH(OR9)CH~, (CH,)nOH, (CH.,)nSH, (CH.,)~O-alkoxy, (CH2)~SR9, (CH2)~OR9 (where n - 1, 2, 3. 4, and R9 is a functional group less than or equal to 100000 daltons), (CH2)nC02R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHZ)"CONHR9, (CH2)~CON(R9)2, C02R9, CONHR9, CONR9R9, SR9 (where R9 is a functional groups less than or equal to 100000 daltons}, S03H, S03R9, SOZNHR9, 15 SO.,N(R9)~, SO~N(R9)3+X- (where R9 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion): M is Ins ~3, Ins ~5 or a mixture of In~'3 and In"5 ; Z
is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
Another family of compounds has the structure:
R7 \ ~ ~ N R1 N\ Z,.N R2 O
M' R6 N~~ N
R5_N~~ ~/~~~
where each of R 1 and RS is alkyl or aryl.
Each of R2 and R6 is methyl or ethyl.
Each of R7, R8, R3, and R4 is methyl, ethyl alkyl, CH,CH~CO~H (or a salt therof), or CH~CH~COZR9 (where R9 is alkyl or aryl).
M is In~~~, In~~s or a mixture of In~'3 and In~ls.
to Z is a halide , acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Yet another family of compounds has the structure:
RI ~ ~T ~j ~ R4 N Z N '-~i;
R9 ~ M~ ~ R11 R8 N~, N
R7 ~ / / RS
i R6 Where each of R1-R14 is H, halide, methyl, ethyl, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)~C(X)3 (where X is a halogen), NR 15R 15, CN, OH, OR 15, CHO, COCH3, CH(OR15)CH3, (CH2)"OH, (CH2)"SH, (CH.,)"O-alkoxy, (CH2)nSRlS, (CHZ)nORlS
(where n = l, 2, 3, 4, and R15 is a functional groups less than or equal to 100000 daltons), (CH.,)nCO.,R15 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl. alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl and n=1, 2, 3, 4), (CH,)~CONHR15> (CH,)"CON(R15)." CO~R15, CONHR15, CONR15R15, SR15 (where R 15 is a functional group less than or equal to 100000 daltons and n=
i, 2, 3, 4), SO~H, SO~R15, SO,NHR15, SO,N(R15)" SO~N(R15)~+X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M
is In~'3, In ~ I 5 or a mixture of In ~ ~; and In I ~ 5 Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
M can also be Pd. Sn, Pt, Al, Zn, Ru, Ga.
IU
Another family of compounds has the structure:
RI ~ ~'~ ~' ' R4 N Z N"
M\
I / ~ RS
where each of R1-R8 is ethyl or methyl R9 is CH;, _SO,NH(CH.,CH.,O)nCH~ (n=1 to 1000), SO.,N((CH2CH,0)~CH~)., (n=1 to 1000); SO,NH(CH,)~OH (n=1 to 1000), CH~~ SO,N((CH,CH.,)nOH), (n=1 to 1000);
SO,NC((N(CH3}.,)., ; SO,NH(CH,)nN(CH~)., (n=1 to 1000); S02NH(CH,)nSH (n=1 to 1000); SO.,NHC(CH.,CH.,OH)~; SO,NHCH2CO,H (or salts thereof);
SOZNH(CH.,)~CH(NH.,)CO.,H (or salts thereof) (n=1 to 5); SO,,NHCH2COZR10 (R10 is alkyl, aryl); SO~NH(CH.,)nCH(NH~}CO,R10 (R10 is alkyl, aryl) (n=1 to 5) M is Ins ~;, Ins ~5 or a mixture of Ins ~~ and Ins ~5 Z is a halide > acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure:
RI ~ ~~ ~~ ~ R4 N Z N-R8 N ~, N
RS
where each of R1-R8 is ethyl or methyl.
to R9 is; CH2CO.,NH(CH.,CH~O)~~CH-~ (n=1 to 1000}, CH=CO.,N((CH.,CH.,O)nCHz)., (n=1 to 1000); CH,CO~NH(CH,)"OH (n=1 to 1000), CH,CO,N((CH,CH.,)~OH), (n=1 to 1000);
CH,CO,NC((N(CH~),)~ ; CH,CO,NH(CH.,)~N(CH~)., (n=I to 1000);
CH.,CO,NH(CH.,)~SH (n=1 to 1000); CH,,CO,NHC{CH.,CH~OH)a ;
CH,,CO,NHCH,CO,H _(or salts thereof); CH~CO~NH(CHZ)nCH(NH,)CO,H (or salts l5 thereof) (n=1 to 5); CH~CO,NHCH~C02R10 (R10 is alkyl or aryl);
CH2CO~NH(CH.,)"CH(NH.,)CO.,R10 (R10 is alkyl, aryl) (n=1 to 5) M is Inll~, Inl IS or a mixture of Inl l3 and Inl Is Z is a halide , acetate, OH.
M can also be Pd, Sn. Pt, Al, Zn, Ru, Ga.
20 Another family has the structure:
N
R' ~\~Z \ ~RS
N\I ~N
N~ /M\ ~N
N N
RI- ~ , i / Rb N
where each of R1-R8 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)~C(X)~ (where X is a halogen), NR9R9, -CN, OH, OR9, CHO, COCH~, (CH2)~OH, (CH.,)"SH, 25 CH(OR9)CH~, (CH,)"O-alkoxy> (CH,,)"SR9, (CH,,)"OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH,)~CO,R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl; alkynyl or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)"CONHR9, (CH,)"CON(R9),,, CO~R9, CONHR9, CONR9R9, SR9 (where R9 is a functional groups less than or equal to 100000 daltons), SO~H, SO~R9, SO~NHR9, SO,N(R9)2, s SO~N(R9)~+X- (where R9 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion); M is In"3, In ~'s or a mixture of In"3 and In" s;
Z is a halide , acetate, OH; alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl.
alkynyl, substituted alkyinyl, protein or biomolecule or functional group less than or equal to 100000 daitons.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
to Another family of compounds has the structure:
R3 R4 ~5 R6 p gyp; B.
C~R7 N' R1 ~ N ~;N=C Rg N~ ~1~ ~N
A
R16-C~ N ~B-R10 B; A' where each of R 1-R 17 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, 15 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester.
C(X),C(X)3 (where X is a halogen), NR18R _ -18, CN, OH, DRIB, CHO, COCH;, (CH.,)~OH, (CH.,)"SH, CH(OR18)CH~, (CH,)"O-alkoxy, (CH.,)~SR18, (CH,,)"OR18(where n = 1, 2, 3, 4, and R5 is a functional group less than or equal to 100000 daltons), (CHZ)"CO,,R 18 (where R 18 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, 20 substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR18, (CH.,)nCON(R18)~ , CO~R 18, CONHR 18, CONR 18R 18, SR 18 (where R 18 is a functional groups less than or equal to 100000 daltons), SOX, S03R18, SO~NHR18, SO~N(R18)2, SO~N(R18)3+X~ (where R18 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In"3, In"s or a mixture of Inl3 and In"s; Z
is a halide, 25 acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyil, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, or Ga.
Still another family has the structure:
R4 / ~ R8 R9 C D \A~B II RIO
R-;-" R6 R7 /A ~.E Fi Rll N
~F \ ~E~R12 \i N\I,~N
N\ M\ /N
R24 ',, N ~R13 ~ /R14 D~F F'/ -A
R22-C' ~ \R19 R18 ''~~ _ ~B-R15 B' A \ R20 R:17 Rl6 5 where each of R I-R24 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenvl: substituted alkenyl, alkynyl, substituted alkynyl, amide, ester.
C(X)~C(Xl~ (where X is ya halogen), NR25R25, CN, OH, OR25, CHO, COCH3 , (CH2)"OH, (CH2)~SH, CH(OR25)CH.~, (CH~)"O-alkoxy, (CH.,)"SR25, (CH2)"OR25 (where n = 1, 2, 3, 4, and R25 is a functional groups less than or equal to IQ0000 daltons), (CHz)nCO,,R25 (where 10 R25 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)nCONHR25; (CH.,)"CON(R25)~ , CO~R25, CONHR25, CONR25R25> SR25 (where R25 is a functional group less than or equal to 100000 daltons). SO~H. SO~R25, SO~NHR25, SO~N(R25)~, SO,N(R25)z~X- (where R25 is a functional group less than or t5 equal to 100000 daltons and X is a charge balancing ion); M is Inll~, In115 or a mixture of In' 13 and Inl Is ; A, B, C> D, E, F are; C, N, O+, O, S, Te, P, N+(R25)X-(where R25 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl> alkynyl, substituted alkynyl, protein or biomolecule or functional 2o group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
z NvI/N.
R3 ~ /M\
N N
H~ 11 t H
Ft4 X
where each of R1- RS is CH~CHj, CH=CHI, CH=CHCH~N(CH3)~ CH=CHCH~N+(CH3lz X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCH~, CO~H, CO~R6, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons), CH=CHCH20H, CH=CHCH~OR6, CH(OH)CH~, CH(OR6)CH~, H, halide, alkyl, cyclic alkyl (1-6 carbons}, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, OH, OR6, (CH,,)~OH, (CH2)"SH, (CHZ)~O-alkoxy, (CH2)~SR6, (CH2)"OR6 (where n = 1, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH.,)nCO.,R6 (where R6 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted ~5 alkynyl, and n=1, 2, 3, 4), (CH,)nCONHR6, (CH~)~CON(R6)~, CO~R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltonsj.
SO~H. SO~R6, SO~NHR6, SO~N(R6)~, SO~N(R6);+X- (where R6 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); X is . O, 2H, (H, OH), S, (H, OR6} or a ketone protecting group; M is In"3. In"5 or a mixture of In";
and In"5 ; Z
2o is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkyinyl, protein or biomolecule or functional group Iess than or equal to 100000 daltons.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Still another family of compounds has the structure:
wherein:
R 1 is CH=CHI, CHO, Et, COCH
R2 is CO~CH~ ,COSH, amide R3 and R4 are H
RS is CH;
XisO
to M is In' ", Ins ~5 or a mixture of Ins" and Ins ~5 Z is a halide, acetate or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Pt, Ru, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure:
RI
\ ' Z
20 R~ N' ~ ~N
M\
__ N N
where each of Rl- R6 is; CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)~
X~ (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH~, CO~H, CO~R7, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, 3o OR7 or is a functional group less than or equal to 100000 daltons), CH=CHCH~OH, CH=CHCH~OR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, OH, OR7, (CH,)"OH, (CH2)"SH, (CH2)"O-alkoxy, (CH2)"SR7, (CH,)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH,)~CO,R7 (where R7 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH,)"CONHR7, (CH2)"CON(R7)~, CO~R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), SO~H, SO~R7, SO,NHR7, SO~N(R7)~, SO~N(R7)~+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In~~~, In~~S or a mixture of In ~ ~' and In ~ ~ s ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, protein or biomolecuie or functional group less than or equal to 100000 daltons; with the proviso that when R2 =
CO,,NHR6, R6 can not be a mono- or di-carboxylic acid of an amino acid.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zr, preferably .Pd, Pt.
Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
where each of R1- R6 is; CH~CH~, CH=CHI, CH=CHCHZN(CH~)~, CH=CHCH~N+(CH~)3 X- (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH;, CO~H, CO~R7, CONHR7, CH=CHCHO, CHZY, (where Y = H, halogen, OH, OR7 or is a functional gro~lp less than or equal to 100000 daltons), CH=CHCH~OH, ~5 CH=CHCH~OR7, CH(OH)CH~, CH(OR7)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, OH, OR7, (CH,)~OH, (CH.,)~SH, (CH,)~O-alkoxy, (CHZ)"SR7, (CH,)"OR7 (where n = l, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH.,)~CO.,R7 (where R7 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH,)nCONHR7, (CH,)"CON(R7)~, COZR7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), S03H, S03R7, SO~NHR7, SO~N(R7),, SO~N(R7)~+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In~~~, In~~S or a mixture of Inl~3 and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than I U or equal to 100000 daltons.
Still another family of compounds has the following structure:
r Z r NvI~N
R'i ~ ~M\
__ N N
~ 5 wherein;
R 1 is CH=CHI, CHO, Et, COCH;
R2 is CO~CH
R3 is H
R4 is CH~CO~CH;, CO~CH3, CH~CO~H (or a salt thereof), CO~H (or a salt thereof).
20 RS is CH3 R6 is CO~H, CO,Me or an amide M is In~ ~~, In~ ~5 or a mixture of Ins i~ and Ins 15 Z is a halide, acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Nd, Pb, Pd, 25 Pr, Pt, Rh, Sb, Sc, Sm. Sn, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, Zn, or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the structure:
Rl _ \I/
R7 ~ /M\ ~ R 13 N y R8 \ ~ ~~ /~R12 Ry R10 R11 where each R1-R13 is H, halide, alkyl, vinyl, cyclic alkyl (3-6 carbons), aryl, substituted 5 aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)3 X~ (where X is a charge balancing ton), C(X)~C(X)~ (where X is a halogen), NR14R14, CN, OH, OR14, CHO, COCH; , (CH.,)"OH, (CH~)"SH, (CH~)~O-alkoxy, CH(OH)CH~, CH(OR14)CH3 (CH2)"SR14, (CH,,)"OR14 (where n = 1, 2, 3, 4, and R14 is a functional group less than or equal to 100000 daltons), (CHZ)"COZR14 (where R14 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, _and n=1, 2, 3, 4), (CH.,)"CONHR14, (CH2)~CON(R14)~, CO~R14, CONHR14, CONR 14R 14. SR 14 (where R 14 is a functional group less than or equal to daltons); SOX. SO,R14, SO~R14, SO~NHR14, SO~N(R14),, SO~N(R14)~TX- (where R14 15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion):
M is In ~ ~ ~, In ~ ~' or a mixture of In ~ ~ ~ and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, suibstituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Still another family of compounds has the, following structure:
where each of R1 and R2 is CO~R14 (where R.14 is alkyl or aryl), CO~H (or a salt therof), SO~Ph, or CN;
R3, R6, R8, and R 12 are Me.
RS is CH=CHZ, or CH(OR 14)CH~ (where R 14 is alkyl or aryl) R4, R7, R 13, R 10 are H
R9, R 11 are CH~CH~CO~R 15 (where R 15 is alkyl or H or a salt of the carboxylic acid) M is Ins ~3, Ins ~5 or a mixture of Ins ~~ and Ins ~5 ; Z is a halide , acetate, OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb. Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the following structure:
Rl RS R6 N.Z.N_ I
3 ~ M, /
H N N
/ /
H ~
2o where each of R 1- R7 is CH~CH~, CH=CHI, CH=CHCH~N(CH,)z , CH=CHCH~N+(CH;)3 X- (where X is a charge balancing ion), C(X)~C(X)z (where X is a halogen), CHO, 's a functional group less than or equal to 100000 daltons), CH~CO~RB, OR8 or i HRB, CH=CHCH~OH, CH=CHCH20R8, CH(OH)CH3, CH(OR8)CH3, H
CH~CON
1 c clic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, halide, alky , Y
substituted alkynyl, amide, ester, NR8R8, CN, OH. ORB, CHO, (CH~)"OH, alkynyl, H CH.,)"O-alkoxy, (CH~)~SRB, (CH2)"OR8 (where n = 1, 2, 3, 4, and R8 is a (CH.,)nS , ( 1 rou less than or equal to 100000 daltons), (CH~)~CO.,R8 (where R8 is H, a functiona g p 'call acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, physiologi y alken l, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)"CONHRB, substituted Y
CON(R8)~, CO~RB, CONHR8, CONR8R8, SR8 (where R8 is a functional group (CH~)n an or equal to 100000 daltons), S03H, S03R8. SO~NHRB, SOaN(R8)2, less th where R8 is a functional group less than or equal to 100000 daltons and X
SO~N(R8)~
r a balancing ion), protein or biomolecule or functional group less than or equal to is a cha g tons; X is O, H2, (H, OH), S, (H, OR8) or a ketone protecting group; M is 100000 dal ~'s or a mixture of In"3 and ~'~5; Z is a halide , acetate, OH, alkyl, aryl, In ' uted ar 1, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or t 5 substit Y
biomolecule or functional group less than or equal to 100000 daltons.
lso be A , Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Mcana g b Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y~ ~ or Zr, preferably Pd, Pt, Ga, Al or Ru.
Pt, Rh, S , 2p Still another family of compounds has the following structure:
\ N, Z ,N=
3 \ NMvN.
H. w I
H
X
wherein;
R 1 = COCH3 R3 and R5 = H, CHI
R~ = H or OH
25 R6 = Me or OH
R4 = H or CO~CH3 R2 = CO~R8 (where R8 is alkyl ) M is Ins ", In' 15 or a mixture of Ins ~~ and Ins ~5 Z is a halide, acetate, or OH.
X=O
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, A1 or Ru.
Another family of compounds has the structure:
R3_- R1 Rl3 R6 ~ A M~D ~ R 12 R7 \ ). i~/ R11 LO
werein each of R 1-R 13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH;)~ , CH=CHCH~N+(CH;)~ X' (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), NR 14R 14, CN, OH, OR 14, CHO, (CH.,)"OH, (CH,)"SH, (CH,)~O-alkoxy, CH(OH)CH~, CH(OR14)CH~ (CH,,)"SR14, (CH~)"OR14 (where n = 1, 2, 3, 4, and R14 is a functional group less than or equal to 100000 daltons), (CH,)"CO,,R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=l, 2, 3, 4), _(CH.,)"CONHR 14, (CH.,)~CON(R 14)?, CO?R 14, CONHR 14, CONK 14R 14, (where R 14 is a functional group less than or equal to 100000 daltons), S03H, SO~R 14, SO~NHR 14, SO~N(R 14)x, SO~N(R 14)~+X' (where R 14 is a functional group less than or equal to 2000 daltons and X is a charge balancing ion); A, B, C, D are; C, N, O+, O, S, Te, P or combinations thereof; M is In~~~, In~IS or a mixture of In~~3 and In~~S;
Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sn, Sm, Tb, Th, Ti, Tl, Tm, Lt, V, Y, Yb, Zn, Zr.
Still another family of compounds has the following structure:
RS ~ N Z N=--R6-A~ ~M~ ~C-R12 N N
R ~ ~ ~ ~ R1t D
Rg R9 810 were each of RI-813 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl> substituted alkynyl, amide, ester, CH=CHCH~N(CH~)a , CH=CHCH2N+(CH3)3 X (where X is a charge balancing ion), C(X}~C(X)~ (where X is a halogen), NR 14814, CN, OH, OR 14, CHO. (CH~)~OH, CH SH, (CH.,)n0-alkoxy, CH(OH)CH~, CH(OR14)CH3, (CH,,)"SR14, (CH,,)"OR14 ( ~)n _ (where n = 1, 2, 3, 4, and 814 is a functional group less than or equal to 100000 daltons), tp (CH2)nCO,,Rl4 (where 814 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4); (CH~)"CONHR14, (CH.,)"CON(R14)~, CO~R14, CONHR14, CONK14814, SR14 14 is a functional group less than or equal to 100000 daltons), SO~H, SO~R14, (where R
S02NHR14> SO~N(R14)~, SO~N(R14)~+X- (where 814 is a functional group less than or ~5 equal to 100000 daltons and X is a charge balancing ion); A, B, C, D are;
C, N, O+, O, S, Te, P or combinations thereof; M is In! ~~, Ins ~5 or a mixture of Ins ~3 and Ins ~5; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl>
substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
20 M can also be Ag, Al, Ce, Co, Cr, Cu, Dy. Er. Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sn, Sm, Tb. Th, Ti, Tl. Tm, U, V, Y, Yb, Zn or Zr.
Another family of compounds has the following structure:
.i.
R7 \ ,M, / R l3 N N
R \ ~ i~/ R12 were each of R 1-R 13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, 5 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CHz)~ , CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), NR 14R 14, CN, OH, OR 14, CHO, (CH~)"OH, (CH.,)nSH, (CH2)n0-alkoxy, CH(OH)CH3, CH(OR14)CH3 (CH~)"SR14, (CH2)nORl4 (where n = 1, 2, 3, ~4, and R 14 is a functional group less than or equal to 100000 daltons), l0 (CH,) CO~R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted- alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)~CONHR14, (CH2)nCONH(R14)~, CO~R14, CONHR14, CONR14R14, SR14 (where R14 is a functional group less than or equal to 100000 daltons), SO~H, SO~R14, SO~NHR14, SON{R14)~, SO~N(R14)3+X- (where R14 is a functional group less t5 than or equal to 100000 daltons and X is a charge balancing ion); M is In."~. In"5 or a mixture of In"; and In"5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, 20 Pd, Pr, Pt, Rh, Sb, Sc, Sn, Sm, Tb, Th, Ti, Tl, Tm, U, V,1', ~. Zn or Zr.
Another family of compounds has the following structure:
R6 ~ / 1 N. Z.N_ R7 ~ . ~M~ ~ R 13 N N
n . 11 _I ~ R12 Where each of R 1 and R2 is CO~R 14 (where R 14 is alkyl or aryl), CO~H (or a salt 5 thereof), SO~Ph, CN or a combination thereof;
Each of R3, R6, R8, R 12 is Me.
RS is CH=CHI, or CH(OR 14)CH~ (where R 14 is alkyl or aryl) Each of R4, R7, R 13, R 10 is H
R9 and R11 are CH~CH~CO~R15 (where R15 is alkyl or H or a salt of the carboxylic 10 acid).
M is In''3, Inns or a mixture of In''3 and ~"5 Z is a halide , acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R7 R6 R4 R i 1 ~ RS
N\Z/N_ R9 ~ ~1v1\ ~ Rl5 N N
R l 0 \ 1~ i~ / R 14 where each of R1-R15 is H, halide, alkyl, vinyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH~)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)2C(X)~ (where X is a halogen), NR 16R 16, CN, OH, OR 16, CHO, COCH3 , (CH2)"OH, (CH.,)nSH, (CH.,)"O-alkoxy, SO~Ph, CH(OH)CH~, CH(OR14)CH3 (CH,,)"SR 16, (CH2)"OR 16 (where n = 1, 2, 3, 4, and R 16 is a functional group less than or equal to 100000 daltons), (CH,)"CO,,R16 (where R16 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)"CONHR16, (CH2)~CON(R16)~, CO~R16, CONHR 16, CONR 16R 16, SR 16 (where R 16 is a functional group less than or equal to 100000 daltons), SOX, SO~R16, SOZNHR16, SON{R16)Z, SO~N(R16)~+X- (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion);
o M is In~~~, In~~S or a mixture of In~~3 and Inl'S ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Pt; Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R6 R4~~~ R 1 \ N\Z/y R9 ~ ~M~ ~ R15 N N
RIO ~ ~ ~~ / R14 Rll R12 R13 where each of R1, R2, R3 and R4 is CO~R16 (where R16 is alkyl or aryl), CO2H
(or a salt thereof) or SO~Ph, CN;
Each of R5, R8, R 10 and R 14 is Me.
R7 is CH=CHI or CH(OR 16)CH~ (where R 16 is alkyl or aryl) Each of R6, R9, R 12 and R 15 is H
Each of R 11 and R 13 is CH2CH~CO~R 16 (where R 16 is alkyl or H or a salt of the carboxylic acid), or an amide M is Ins ~~, Ins 15 or a mixture of Ins ~~ and Ins ~5 Z is a halide , acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd. Pb, Pd, Pr. Pt. Rh. Sb, Sc. Sm, Tb, Th. Ti. TI, Tm. U, V, Y. Yb or Zr. preferably Pd. Pt, Ga, Al. Ru. Sn or Zn.
Still another family of compounds has the following structure:
R5 ~ R3 t R7-A N\M N~C-R13 i N N
R ~ 1 ~ / Rl2 D
R9 Rip R11 Where each of RI-R13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, to alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH;)2 , CH=CHCH~N+(CH~)3 X' (where X is a charge balancing ion), C(X)zC(X); (where X is a halogen), NR14R14, CN, OH, OR14, CHO, (CH~)~OH, (CH,,)"SH, (CH~)n0-alkoxy, CH(OH)CH~, CH(OR14)CH3 (CHZ)"SR14, (CH,,)"OR14 (where n = l, 2, 3, 4, and R14 is a functional group less than or equal to 100000' daltons), (CH,)"CO,R 14 (where R 14 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4): (CH,)~CONHR 14, (CH,)"CON(R 14)x, CO~R 14, CONHR 14, CONR 14R 14. SR
(where R 14 is a functional group less than or equal to 100000 daltons). SO~H, S03R 14.
SO~NHR 14, SO~N(R 14)~> SO~N(R 14)3+X- (where R 14 is a functional group less than or 2o equal to 100000 daitons and X is a charge balancing ion); A, B, C, D are;
C, N, O+, O, S, Te, P or combinations thereof; M is In"3, Inns or a mixture of In~~3 and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf. Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the structure:
R3 R i i R4 R2 ~ B~ ~ R5 i R10-A N'M N C-Ri2 ~- N~ ~N'''~
Ri~ 11 _) ~R6 R9 ~ R7 R 14~R 13 Where each of R1-R14 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl> amide, ester, CH=CHCH~N(CH~)z , CH=CHCH~N+(CH~)3 X' (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), NR15R15, CN, OH, OR15, CHO, (CH2)"OH, (CH~)nSH, (CHZ)~O-alkoxy, CH(OH)CH3, CH(OR15)CH3 (CH,,)"SR15, (CH,,)"OR15 (where n = 1, 2, 3, 4, and R 15 is a functional group less than or equal to 100000 daltons), (CH2)"COZR15 (where R15 is H, a physiologically acceptable salt, alkyl {1-6 carbons), to aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)"CONHR 15, (CH2)"CON(R 15)z, COZR 15, CONHR 15, CONR 15R 15, SR
(where R15 is a functional group less than or equal to 100000 daltons), SO~H, S03R15, SO~NHR15, S02N(R15)~, SO~N(R15)3+X' (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); A, B, C, D are; C, N, O+, O, S, i5 Te, P or combinations thereof; M is In"3, In"5 or a mixture of In~'~ and In~~S ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, 2o Pd, Pr, Pt, Rh, Sb, Sc, 5m, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr.
Another family of compounds has the following structure:
R
5 Where each of Rl-R4 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)ZC(X)z (where X is a halogen), CHO, COCH~, CO~H, CO~RS, CONHRS, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, ORS or is a functional group less than or equal to 100000 daltons), CH2CO~R5, CHZCONHRS, CH=CHCH20H, CH=CHCH20R5, CH(OH)CH;, CH(ORS)CH3, H, l0 halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NRSRS, CN, OH, ORS, CHO, (CH2)"OH, (CH~)~SH, (CH,)~O-alkoxy, (CH.,)"SRS, (CHZ)nORS (where n = 1, 2, 3, 4, and R5 is a functional group less than or equal to 100000 daltons), (CHI) CO,,RS (where RS
is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, t5 substituted alkenyl, alkynyl, or substituted alkynyl, arid n=1, 2, 3, 4), (CHZ)"CONHRS, (CH~)"CON(RS)~ , CO~RS, CONHRS, CONR5R5, SRS (where RS is a functional group less than or equal to 100000 daltons), SO~H, S03R5, SO~NHRS, SO~N(RS)~, SO~N(RS)~+X' (where RS is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecules or functional groups less than or equal 2o to 100000 daltons; A and B are O, NH, NRS or combinations thereof; X is , O, NRS
(where R5 is H, alkyl ( 1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynylk, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); M is Ins ~'~, Ins ~5 or a mixture of Ins ~~
and Ins ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyi, substituted alkenyl, alkynyl, 25 substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Rt R4 M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R~C R R7 Where each of Ri- R8 is CH~CH;, CH=CH2, CH=CHCH2N(CHa)2, CH=CHCHZN+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, to COCH;, CO~H, CO~R9, CONHR9, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CHZC02R9, CH~CONHR9, CH=CHCH~OH, CH=CHCH~OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, OH, OR9, CHO, (CH2)"OH, ~ 5 (CH~)"SH, (CH,)"O-alkoxy, (CH.,)"SR9, (CH~~"OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH2)"C02R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH2}nCONHR9, (CH,)~CON(R9)2, CO~R9, CONHR9, CONR9R9, SR9 (where R9 is a functional group 20 less than or equal to 100000 daltons), S03H, SO~R9, SOZNHR9, S02N(R9)2, SO~N(R9)~+X- (where R9 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, HZ, (H, OH), (H, OR9), S, or a ketone protecting group; M is Ins ~3, Ins ~5 or a mixture of Ins ~3 and Ins ~5 ; Z is a halide , acetate, OH, alkyl, aryl, 25 substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkyinyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
N~ i ,N~
3 \ My /
H N N
HA~X~B
Where each of RI- R6 is CH~CH3, CH=CHI, CH=CHCH~N(CHj)~ , CH=CHCH~N''(CH3)~
X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCH3, C02H, CO~R7, CONHR7, CH=CHCHO, CHZY, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CHZC02R7, CHZCONHR7, CH=CHCH~OH, CH=CHCH20R7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, OH, OR7, CHO. (CH~)"OH, (CH2)"SH, (CH,,)"O-~5 alkoxy, (CH~)"SR7, (CH~)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH,,)nCO,,R7 (where R7 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHZ)"CONHR7, (CHZ)~CON(R7)2, CO~R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 20 100000 daltons), SO;H, SO~R7, SO~NHR7, SO~N(R7)2, SO~N(R7)3+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is , O, NR7 (where R7 is H, alkyl (1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, au amino acid ester or a functional 25 group less than or equal to 100000 daitons); A and B are O, NH, NR7 or combinations thereof; M is In113, In ~ ~ 5 or a mixture of In ~ ~ ~ and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, thereof; M is In ~ ~ ~, In ~ ~ 5 or a mixture of In ~ ~'~ and In ~ 15 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 dalions.
M can also be Ag, Ce, Co, Cr, Cu, Dy> Er, Fe, Hf, Ho, :La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc. Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
\ /RS
n R~ R6 \ ' Z ' N~i~N
N N
II .l HA~X~B
wherein;
R1 is CH=CHI, Et, CHO, or COCH, R2 is CO~CH~, CO~H, CO~R7 (R7 is an alkyl, phenyl), oz an amide R3isH
~ 5 R4 is Me Each of RS and R6 is OH
Each of A and B is O or NR7 ( R7 is alkyl).
X is O or NR7 (R7 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is Ins ~3; Ins is or a mixture of Ins ~3 and Ins ~5 Z is a halide , acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, AI, Ru, Sn or Zn.
Another family of compounds has the following structure:
RI
N Z N
.I.
H_ N N
H
where each of R 1- R6 is CH~CH~, CH=CHI, CH=CHCH~N(CH3)2 , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)ZC(X)~ (where X is a halogen), CHO, COCH~, CO~H, CO~R7, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH~CO~R7, CH~CONHR7. CH=CHCH~OH, CH=CHCHZOR7, CH(OH)CH3, CH(OR7)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, l0 alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, (CH2)"OH, (CH,)"SH, (CH,,)"O-alkoxy, (CHz)"SR7, (CH2)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH2)~C02R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH,)~CONR7, i 5 CO~R7, CONHR7, CONR l OR7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), S03H, S03R7, SO~NHR7, SOZN(R7}~, SO~N(R7)~+X' (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, HZ, (H, OH), (H, OR8) S, or a ketone protecting group; M is In~~3, Inls or a mixture of 2o In ~ ~ ~ and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu. Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, AI, Ru, 25 Sn or Zn,.
Another family of compounds has the following structure:
\ ~z~
N, ~ .N
3 \ ;~~ /
H N N
/ /
H
_ R4 X
wherein;
5 Rl is CH=CHI, Et, CHO, or COCH
R2 is CO~CH3, CO~H, COZR7 (R7 is an alkyl or phenyl group), or an amide R3 is H
R4 is H or COZCH3 RS is O or NR7 (where R7 is alkyl) R6 is Me XisO
M is In ~ ", In ~ ~ 5 or a mixture of In ~ " and In ~ ~ 5 Z is a halide , acetate or OH.
M can also be Ag, Ce, C'.o, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, ~5 Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R 1 ,~ R7 \ N,Z,N
3 \ My H~ N N
H ~ R8 2o where each of Rl- R8 is CH~CHa, CH=CHI, CH=CHCH~N(CH3)2, CH=CHCH~N+(CHj)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH;, CO~H, CO~R9, CONHR9, CH=CHCHO, CHzY, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CH2CO~R9, CH~CONHR9, CH=CHCH~OH, CH=CHCH~OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, O, S, NHR9, OH, OR9, CHO, (CH2)~OH, (CH.,)"SH, (CH,)~O-alkoxy, (CH,,)"SR9, (CH,,)"OR9 (where n = l, 2, 3, 4, and R9 is a functional groups less than or equal to 100000 daltons), (CH~)~CO.,R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHZ)~CONHR9, l0 (CH.,)~CON(R9)~, CO~R9, CONHR9, CONR I OR9, SR9 (where R9 is a functional groups less than or equal to 100000 daltons), S03H, SO;R9, SO~NHR9, SO~N(R9)~, SO~N(R9)~+X- (where R9 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In ~ ", In ~ ~ s or a mixture of In ~ 13 and In ~ ~ 5;
Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the following structure:
RI ~
~
~
Z .
N, i .N
\ /
My N
N
wherein;
RI is CH=CH2, Et, CHO, or COCH;
RS is O or NR7 (where R7 is alkyl) R7 is Me R3 is H
R4 and R8 are H, CO~CH~, CO~H (or a salt thereof), CO~R7 (R7 is an alkyl or phenyl group), an amide, CH~CO~CH~, CH~CO~H (or a salt thereof), CO~R9 (R9 is an alkyl or a phenyl group), or an amide R2 is CO~CH~, CO~H, CO~R9 (R9 is an alkyl or phenyl group), or an amide M is Ins ~;, Ins ~s or a mixture of Ins ~3 and Ins is Z is a halide , acetate, or OH.
M can also be Ag, Ce. Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
\ N'Z~N
M\
H 11 _I
H A~X~B
where each of Rl- RS is CH~CH3> CH=CHI, CH=CHCH~N(CH~)2, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen j, CHO, COCH~, CO~H, CO~R6, CONHR6, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons), CH2CO~R6, CH~CONHR6, CH=CHCH~OH, CH=CHCH~ORB, CH(OH)CH~, CH(OR6)CHa, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, 2o alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, O, S, NHR6, OH, OR6, CHO, (CH.,)~OH, (CH,)~SH, (CH~)"O-alkoxy, (CH~)"SR6, (CH2)~OR6 (where n = l, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH,,)nCO,,R6 (where R6 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH~)nCONR6, CO~R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltons), SO~H> SO~R6, SO~NHR6, S02N(R6)~, SO~N(R6)~+X- (where R6 is a functional group less than or equal to 100000 daltons), S03H, SO~R6, S02NHR6, SO~N(R6)~, SO~N(R6);+X' (where R6 is a functional group less than or equal to daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, NR6 (where R6 is H, alkyl ( 1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); A and B
are O, NH, NR6 or combinations thereof; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc. Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, AI, Ru, S
or Zn.
Another family of compounds has the following structure:
t5 \ ' Z ' N~M,N
H N y 11 l HA~X~B
Wherein:
Each of A and B is O or NR6 (where R6 is an alkyl or phenyl group) R 1 is CH=CHI, Et, CHO, or COCH3 20 R4 is O or NR6 (where R6 is alkyl) RS is Me R3 is H
R2 is CO~CH~, CO~H, CO~R6 (R6 is an alkyl or phenyl group), or an amide X is O, NR6 (R6 is alkyl, an amino acid, an alcohol containing group, or an ether 25 containing group) M is In ~ 1 ~, In ~ ~ 5 or a mixture of In ~ ~' and In ~ ~ 5 Z is a halide , acetate, OH.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm. Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
\ N. Z,N-'' H N N' H
Where each of Rl- R6 is CH~CHz, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH3, CO~H, CO~R7, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH,C02R7, CH~CONHR7, CH=CHCH~OH, CH=CHCHzOR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, ~5 (CH.,)~OH, (CH~)~SH, (CH,,)"O-alkoxy, (CH.,)"SR7, (CH~)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional groups less than or equal to 100000 daltons), (CH,)nCO,,R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)~CONR7, CO~R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 20 100000 daltons), SO~H, SO~R7, SO~NHR7, SO~N(R7)z, SO~N(R7)3+X' (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, HZ, (H, OH), (H, OR7), S, or a ketone protecting group; M is Ins ~~, In~ ~5 or a mixture of Ins ~3 and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted 25 alkenyl, alkynyl, substituted alkynyl, protein or biomolecules or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er. Fe, Ga. Hf, Ho, La. Lu. Mo, Mg, Nd, Pb. Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, ' Sn or Zn.
5 Another family of compounds has the structure:
\ N, Z.N:
.3 \ N M, N
H n .t H
wherein;
Rl is CH=CHI, Et, CHO, or COCH3 R6 is O or NR7 (where R7 is an alkyl group) RS is Me R3 is H
R4 is H or CO~CH
~ 5 R2 is CO~CHz, CO~H, CO~R7 (R7 is an alkyl, phenyl), or an amide XisO
M is Ins ~'. Ins ~5 or a mixture of Ins ~~ and Ins ~5 Z is a halide , acetate, or OH.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, 2o Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the structure:
N. Z.N
R3 ~
H~ N N
Where each of Rl- R7 is CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), CHO, COCH;, CO~H, CO~RB, CONHRB, CH=CHCHO, CH~Y,(where Y = H, halogen, OH, OR8 or is a functional group less than or equal to 100000 daltons), CH~CO~RB, CH~CONHRB, CH=CHCH20H, CH=CHCH~ORB, CH(OH)CH3, CH(OR8)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR8R8, CN, O, S, NHRB, OH, ORB, CHO, (CH?)~OH, (CH2)"SH, (CH2)"O-alkoxy, (CH2)"SRB, (CH2)"OR8 (where n = 1, 2, 3, 4, and R8 is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R8 (where R8 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl,substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH?)nCONRB, CO~RB, CONHRB, CONR8R8, SR8 (where R8 is a functional groups less than or equal to 100000 daltons), SO~H, SOzRB, SO~NaRB, SO~N(R8)2, SO~N(R8)3+X- (where R8 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecules or functional groups less than or equal to 100000 daltons; M is In"~, In"S or a mixture of In"j and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecules or functional groups less than or equal to 100000 daltons.
Another family of compounds has the structure:
~ ~TZ~ R6 N.,.N-R3 ~ M, /
H~ N N
H
wherein;
R 1 is CH=CHI, Et, CHO, or COCH
R6 is O, or NR8 (where R8 is alkyl) R5 is Me R3 is H
R4 and R7 are H, CO~CH~, CO~H (or a salt thereof), CO~R8 (R8 is alkyl or phenyl), an amide, CH~CO~CH3, CH~CO~H (or a salt thereof), CO~R8 (R8 is an alkyl or phenyl group) R2 is CO~CHz, CO~H, CO~R8 (R8 is alkyl or phenyl), or an amide to M is Ins ~3, Ins ~5 or a mixture of Ins ~3 and In~~s Z is a halide , acetate, OH.
M can also be Pd Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
IS
Another family of compounds has the following structure:
\ N,Z,N
H N N
HA~X~B
2o Wherein:
R 1 is CH=CHI, Et, CHO or COCH
R4 is Me R3 is H
R2 is CO~CH~, CO~H, COZRS (R5 is alkyl or phenyl), or an amide Each of A and B is O or NRS ( RS is alkyl) X is O, NRS (R5 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is In"~, In"5 or a mixture of In"3 and In"5 .
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, l0 Sn or Zn.
Another family of compounds has the structure:
n ~RR7 \ N, Z,N
.3 N N
Wherein: RI is CH=CHI, Et, CHO or COCH3 i 5 Each of R6 and R7 is H or OH
RS is Me R4 is CO~CH~, CO~H, CO~R9 (R9 is an alkyl or a phenyl group), an amide, CH~CO~CH~, CH~CO~H, or CH~CO~R9 (R9 is an alkyl or a phenyl group).
R3isH
2o each of R2 and R8 is CO~CH~, CO~H, CO~R9 (R9 is an alkyl or a phenyl group), or an amide M is In";, In"5 or a mixture of In"~ and In"5 Z is a halide , acetate, or OH.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, 25 Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the structure:
Rt R4 I Z ,I RS
N~ i ~ N--i~~ /
H N N
~i .r , H
X~ ~ B
wherein each of R1-RS is CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH;)~ X' (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH3, CO~H, CO~R6, CONHR6, CH=CHCHO, CH~Y, (where Y = H, halogen, OH or OR6 or is a functional group less than or equal to 100000 daltons), CHZCO~R6, CH~CONHR6, CH=CHCH~OH, CH=CHCH~OR6, CH(OH)CH~, to CH(OR6)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, O, S, NHR6, OH, OR6, CHO, (CH.,)"OH, (CH,)"SH, (CH.,)"O-alkoxy, (CH,,)"SR6, (CHZ)~OR6 (where n = 1, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH.,)~~CO.,R6 (where R6 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, ~5 substituted aryl, alkenyl, substituted alkenyl. alkynyl, or substituted alkynyl. and n=1, 2, 3, 4), (CH~)~CONR6, CO~R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltons), S03H, SO;R6, SO~NHR6, SO~N(R6)~, SO~N(R6)3+X- (where R6 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecule or functional group less than or equal to 20 100000 daltons; ; A and B are O, NH, NR6 or combinations thereof; X is , O, NR6 (where R6 is H, alkyl (1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); M is Ins ~'~, In' ~s or a mixture of Ins ~~ and Ins ~5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted 25 alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf> Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
5 Still another family of compounds has the structure:
Rl R4 RS
N~ ~ ,N'-\ ~Mv /
N N
HA~X~B
wherein:
R 1 is CH=CHI, Et, CHO or COCH
RS is O or NR6 (where R6 is alkyl) R4 is Me R3isH
R2 is CO~CH~, CO~H, CO~RS (RS is alkyl or phenyl), or an amide A and B are O or NR6 (R6 is an alkyl or a phenyl group) ~ 5 X is O, NR6 (R6 is alkyl), an amino acid, an alcohol containing group, or an ether or amine containing group M is In ~ ~ ~, In ~ ~ s or a mixture of In ~ ~ ~ and In ~ ~ 5 Z is a halide. acetate. or OH.
M can also be Ag, Ce, Co, Cr> Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd.
Pb, Pr or 2o Rh, preferably Ga, AI, Ru, Sn or Zn.
Still another family of compounds has the structure:
R8~
R_3 / R6 R7v A ~R 10 A~C D
R2 p w N, \ CC
Rl ~ N.2 N=( ~R12 N, .~ N
R~4 N N ,R13 C \ ' N~ ~ ~ ~R14 D C , _A
R22 \ p R19 R18 / Rl5 ~R20 Wherein each of R1- R24 is CH~CH~, CH=CHCH~N(CH3)2 , CH=CHCH~N+(CH;)3 X-(where X is a charge balancing ion), CH=CHI, C(X)~C(X)3 (where X is a halogen), CHO, COCH~, CO~H, CO~R25, CONHR25, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR25 or is a functional group less than or equal to 100000 daltons), CH~CO~R25, CHZCONHR25, CH=CHCH~OH, CH=CHCH~OR25, CH(OH)CH3, CH(OR25)CH3, H, to halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR25R25, CN, O, S, NHR25, OH, OR25, CHO, (CH,,)"OH, (CH.,)"SH, (CH~)"O-alkoxy, (CH~)~SR25, (CH2)"OR25 (where n =
1, 2, 3, 4, and R25 is a functional group less than or equal to 100000 daltons).
(CH~)~CO~R25 (where R25 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH~)~CON(R25)~, (CH2)"CONHR25, CO~R25, CONHR25, CONR25R25, SR25 (where R25 is a functional group less than or equal to 100000 daltons), S03H, S03R25, S02NHR25, SO~N(R25)2, SO~N(R25)3+X- (where R25 is a functional group less than or equal to 100000 daitons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D are: C, N, O+, O, S, Te, P, N+(R25)X- (where R2S is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), or combinations thereof; M is In ~''~, In"5 or a mixture of In'' and In"5; Z is %~ halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Yet another family of compounds has the structure:
O O
N ' , I~ N
O 'B _\ 1 N/ / A/ O
A B
X -~ \ R7 R6 ~ X
p O
Wherein each of R1-R8 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)~, a CH=CHCH~N+(CH;)~ X- (where X is a charge balancing ion), C(X)~C(X), (where X
is a halogen), CHO, COCH~, CO~H, CO~R9, CONHR9, CH=C:HCHO, CH~Y, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CH~COZR9, CH2CONHR9, CH=CHCH~OH, CH=CHCH~OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, O, S, NHR9, OH, OR9, CHO, (CH~)"OH, (CH.,)"SH, (CH,)"O-alkoxy, (CHZ)"SR9, (CHZ)"OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH.,)~CO.,R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, ~5 4), (CH~)~CONHR9, (CH~)~CON(R9)~, CO~R9, CONHR9, CONR.9R9, SR9 (where R9 is a functional group less than or equal to 100000 daltons), SO~H, SO~R9, SO~NHR9, SO~N(R9)~, SO~N(R9)~+X- (where R9 is a functional group less than or equal to daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons.
2o A, B, C, D are; C, N, O+, O, S, Te, P, N+(R9)X- (where R9 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof.; M
is In ~ ~ ~, In ~ ~ 5 or a mixture of In ~ 13 and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, X R2 R-~ X
i B Ar N
~A ~ Z. B
RI \ Ny N=~ 'R4 substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, NR9 (where R9 is H, alkyl ( 1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons).
M can also be Pd or Ga.
S
Yet another family of compounds has the structure:
RS Rg _ .D
R3- D E F R6 R7~ C ~ ~.E -R I 0 C_>=B A- ~ F
R2~ ~A ~ N~ \ B \R11 R1, ~ N, Z,N~ ~R12 N. ~ N
N N ~R13 R21- D \ N / A , R I 4 ~C
:B B
0 R19 R18 F. D-RIS
' E
wherein each of R1-R22 is CHzCH3, CH=CHI, CH=CHCHZN(CH3)z , l0 CH=CHCH~N'"(CH~); X~ (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH~, CO~H, CO~R23, CONHR23, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR23 or is a functional group less than or equal to 100000 daltons), CH~CO~R23, CH~CONHR23, CH=CHCH~OH, CH=CHCH~OR23, CH(OH)CH~, CH(OR23)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, is substituted alkenyl, aIkynyl, substituted alkynyl, amide, ester, NR23R23, CN, O, S, NHR23, OH, OR23, CHO, (CH,)~OH, (CHZ)"SH, (CH.,)~O-alkoxy, (CH,)"SR23, (CH,,)"OR23 (where n = l, 2, 3> 4, and R23 is a functional group less than or equal to 100000 daltons), (CH.,)~CO~R23 (where R23 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted 2o alkynyl, and n=1, 2, 3, 4)> (CH.,)~CONHR23, (CH~)~CON(R23)~, COZR23, CONHR23, CONR23R23, SR23 (where R23 is a functional group less than or equal to 100000 daltons), SO~H, SO~R23, SO~NHR23, SOzN(R23)~, SO~N(R23)~+X- (where R23 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, 25 D, E and F are C, N, O+, O, S, Te. P, N+(R23)X- (where R23 is a functional group less than or equal to 2000 daltons and X is a charge balancing ion), or combinations thereof; M
is In ~ ~;, In ~ ~ 5 or a mixture of In ~ ~ ~ and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
' ,R5 R3- D E F ~R6 R7\ R8 C ~ B '°' ~ C p -R9 R~ N ..
A ~' Z~ ~ B\
Rl ~ ~. I .N R10 ~N
R~ N N ~1 j A \ ~ ~ / A
R17-D,C_ B N B;C.D-R12 ~R15 R[4 R13 wherein each of R1-R18 is CHZCH3, CH=CHI, CH=CHCH~N(CH3)z , CH=CHCH~N+(CH3)~ X~ (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO. COCH~, CO~H, CO~R19, CONHR19, CH=CHCHO, CH~Y, (where Y =
H, halogen. OH, OR 19 or is a functional group less than or equal to 100000 daltons), CH~CO~R 19, CH~CONHR 19, CH=CHCH~OH, CH=CHCH~OR 19, CH(OH)CH3, CH(OR 19)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl.
substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR19R19, CN, O. S, NHR19, OH, OR19, CHO, (CHZ)"OH, (CH,,)"SH, (CHZ)~O-alkoxy, (CH,)~SR19, or (CH,)"OR19 (where n = l, 2, 3, 4, and R19 is a functional group less than or equal to 100000 daltons), (CH,)~CO,R19 (where R19 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)~CONHR19, (CH2)~CON(R19)Z, CO~R19, CONHR19, CONR 19R 19, SR 19 (where R 19 is a functional group less than or equal to 2000 daltons), SO~H, S03R19, SO~NHR19, SO~N(R19)~, SO~N(R19)~+X- (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E, F are CH, N, O+, O, S, Te, P, N+(R 19)X' (where R 19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In ~ ~ ~, In ~ ~5 or a mixture of In ~ ~' and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, 5 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
tt4 R3= D E F ~R6 R7~ R8 C-~ B ~'~C~D-R9 A ~ N~ B
RI ~ N, Z.N- ~R10 N ~ Ivl\ ~ N
N N ~R11 R19- C \ N / A ~R12 C
.D. B~R17 R16 ~ D-R13 R18 ,F' E, wherein each of Rl-R20 is CH~CH3, CH=CHI, CH=CHCH,N(CH3)~ , CH=CHCH~N+(CH~)z X- (where X is a charge balancing ion), C(X)~C(X), (where X
is a halogen), CHO, COCH~, CO~H, CO~R21, CONHR21, CH=CHCHO, CH~Y, (where Y =
is H, halogen, OH, OR21 or is a functional group less than or equal to 100000 daltons).
CH~CO~R21, CH~CONHR21, CH=CHCH~OH, CH=CHCH~OR21, CH(OH)CH~, CH(OR21 )CHI, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR21R21, CN, O, S, NHR21, OH, OR21, CHO, (CHZ)~OH, (CHZ)"SH, (CH,)"O-alkoxy, (CHZ)"SR21, (CH~)"OR21 (where n = 1, 2, 3, 4, and R21 is a functional group less than or equal to 100000 daltons), (CH.,)~~CO,R21 (where R21 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3> 4), {CH.,)~CONHR21, (CH,)nCON(R21)~, CO~R21, CONHR21, CONR21R21, SR21 (where R21 is a functional group less than or equal to 100000 daltons), SO;H, SO~R21, SO~NHR21, SO~N(R21)~, SO~N(R21)~+X- (where R21 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E, F are: C, N, O+, O, S, Te, P, N+(R21)X' (where R21 is a functional group less than or equal to 100000 daltons and X is a charge balancing ian), or combinations thereof; M is In ~ ~ j, In ~ 15 or a mixture of Iri ~ ~ 3 and In ~ ~ s; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
to Still another family of compounds has the following structure:
R~4 p~E~RS
R3-C' R9 ~F-R6 ~ R8 ' w A, B C, R2- A \ N\ ~ ~ ~ D-R 10 R1 ~ 1'1, j ,N=~ ~12~ R11 R24 N~ ;~ ~N
R2~E'F N N ~R13 R22-D~~ ~ ~ N / B-R14 C B~A~ RIS
R~21 R20 R19 E,D n-R15 where each of R1-R24 is CH~CH~, CH=CHI, CH=CHCH~N(CH;)~ , CH=CHCH~N+(CH~)~
X' (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCH~, COzH, CO~R25, CONHR25, CH=CHCHO, CHZY, (where Y = H, halogen, OH, OR25 or is a functional group less than or equal to 100000 daltons), CH~CO~R25, CHZCONHR25, CH=CHCHZOH, CH=CHCHZOR25, CH(OH)CH~, CH(OR25)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR25R25, CN, O, S, NHR25, OH, OR25, CHO, (CH,,)"OH, (CH~)"SH, (CH.,)~O-alkoxy, (CH~)"SR25, (CH~)"OR25 (where ri =
1, 2, 3, 4, and R25 is a functional group less than or equal to 100000 daltons), (CH.,)~CO.,R25 (where R25 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH~)"CONHR25, (CH~)"CON(R25)~, CO~R25, CONHR25, CONR25R25, SR25 (where 9'' R25 is a functional group less than or equal to 100000 daltons), SO~H, S03R25, SO~NHR25, SO,N(R25)a, SO~N(R25)~+X- (where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E, F are C, N, O+, O, S, Te, P, N+(R25)X- (where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In~l3, InlcS
or a mixture of Ins" and In~~S; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
1 o M can also be Pd or Ga.
Still another family of compounds has the structure:
R7 'R6 R10 ~11 ~C-B B'Cv R12 ~4~A ~ g ~ A ~t13 A w R ~ A
R3-C' ~ N ~ '~C-R14 \ , RrB ~ N, ~ ,N- ' B~RIS
R3l R_ 21 Nv N:~N ~N R17 ~R18 B -- 1 ~ B
R30-C\~ ~ \ N ~ , ,,C-R19 A .~ R24 ~ 'A
R29 / R~5 ~ ~ R20 A, ., A- R21 R28' C-B, ,B'C
R27 R'6 R23 ~22 !5 where each of R1-R32 is CH~CHz, CH=CHI, CH=CHCHZN(CHz)Z , CH=CHCH~N+(CH3)3 X~ (where X is a charge balancing ion), C(X)2C(X) ~ (where X is a halogen), CHO, COCH~, CO~H, CO,R33, CONHR33, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR33 or is a functional group less than or equal to 100000 daltons), CH~CO~R33, 20 CH~CONHR33, CH=CHCH~OH> CH=CHCH~OR33, CH(OH)CH~, CH(OR33)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR33R33, CN, O, S, NHR33, OH, OR33, CHO, (CH.,)"OH, (CH,,)"SH, (CH,)~O-alkoxy, (CHZ)~SR33, (CH~)"OR33 (where n =
1, 2, 3, 4, and R33 is a functional group less than or equal to 100000 daltons), (CH.,)nCOZR33 25 (where R33 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)"CONHR33, (CH~)~CON(R33}~, COZR33, CONHR33, CONR33R33, SR33 (where R33 is a functional group less than or equal to 100000 daltons), S03H, SO3R33, SO~NHR33, SO~N(R33)~, SO~N(R33)3+X- (where R33 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C are; C, N, O+, O, S, Te, P, N+(R33)X- (where R33 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is Ins 13, Im 15 or a mixture of In113 and In~ 15' Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, to alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Still another family of compounds has the structure:
l5 R3 R4 RS Rfi R2-U~V~ Y/ Rl8 \X'U iV_R7 \\ ~ ~ ~ Y\
~X
Rl ~ ~ i ~ R8 N\ M\ /N
R17 N~' N ~R9 \Y ~ ~ i ~ X
ll N U-R l0 R l6-V~
U~Xv /Y;V
Rl5 R14 R13 R.11 where each of R1-R18 is CH~CH~, CH=CH2, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)3 X' (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH;, CO~H, CO~R 19, CONHR 19, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, 2o OR19 or is a functional group less than or equal to 100000 daltons), CH~CO~R19, CH~CONHR 19, CH=CHCH~OH, CH=CHCH~OR 19, CH(OH)CH~, CH(OR 19)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 19R 19, CN, O, S, NHR 19, OH, OR 19, CHO; (CH2)"OH, (CH.,)nSH, (CH~)~O-alkoxy, (CH2)"SR19, (CH,,)"OR19 (where n =
1, 2, 25 3, 4, and R19 is a functional group less than or equal to 100000 daltons}, (CH,)~CO.,R19 (where R19 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4}, (CH.,)~CONHR 19, (CH.,)~CON(R 19)x, CO~R 19, CONHR 19, CONR l OR 19, SR 19 (where R19 is a functional group less than or equal to 100000 daltons), S03H, SO~R19, SO~NHR19, SO~N(R19)~, SO~N(R19)z+X' (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons. Lf, V, X, Y are C, N, O+, O, S, Te, P, N+(R 19}X' (where R 19 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), or combinations thereof; M is In~~~, In~~S or a mixture of In«
and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl. substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
~5 A
R2 ~ ~~ ~ ~ RS
N N"
RI M~ R6 R8 R~
where each of R1-R9 is CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), CHO, 2o COCH~, CO~H, CO~R 10, CONHR 10, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR10 or is a functional group less than or equal to 100000 daltons), CH~CO~R10, CHZCONHR 10, CH=CHCH~OH, CH=CHCH~OR 10, CH(OH)CH3, CH(OR 10)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR l OR 10, CN, OH, OR 10, CHO, (CHZ)"OH, 25 (CHZ)"SH, (CH,)"O-alkoxy, (CH,)"SR 10, (CH,)"OR 10 (where n = 1, 2, 3, 4, and R 10 is a functional group less than or equal to 100000 daltons), (CH,)nCO,R 10 (where R
10 is H, a physiologically acceptable salt, alkyl (I-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHz)~CONHR10, (CH,)~CON(R 10)x, CO~R 10, CONHR 10, CONR l OR 10, SR 10 (where R 10 is a functional group less than or equal to 100000 daltons), SO~H, SO;R10, S02NHR10, S02N(R10)2;
S02N(R10);+X- (where R10 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In ~ ~ ~, In ~ ~ s or a mixture of In ~ ~ 3 and In ~
~s .
5 M can also be Ga.
Still another family of compounds has the structure:
Rtt ~
R 12 I N\M/~ ~ R4 R 10 ~ ~ / -R5 -N N
R9 ~ ~/ R6 where each of R1-R12 is CH~CH~> CH=CH2, CH=CHCH~N(CH~)~ , CH=CHCH2N+(CH3)s X- (where X is a charge balancing ion), C(X)zC(X)~ (where X is a halogen), CHO, COCH;, C02H, C02R 13, CONHR 13, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR 13 or is a functional group less than or equal to 100000 daltons), CH2C02R
13, CH2CONHR 13, CH=CHCH20H, CH=CHCH20R 13, CH(OH)CH~, CH(OR 13)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, 15 alkynyl; substituted alkynyl, amide, ester, NR13R13, CN, OH, OR13, CHO, (CH2)"OH, (CH.,)"SH, (CH2)"O-alkoxy, (CH,,)"SR13, (CH,)~OR13 (where n = 1, 2, 3. 4, and R13 is a functional group less than or equal to 100000 daltons), (CH2)"CO,R13 (where R13 is H, a physiologically acceptable salt,- alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH2)"CONHR13, 20 (CH.,)"CON(R 13)2, C02R 13, CONHR 13, CONR 13R 13, SR 13 (where R 13 is a functional group less than or equal to 100000 daltons), SO~H, SO~R13, S02NHR13, S02N(R13)2, S02N(R 13);+X- (where R 13 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In ~ ~;, In ~ ~ s or a mixture of In ~ ~; and In ~ ~ s ; Z is a halide , acetate, 25 OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Yet another family of compounds has the structure:
-w R 11 ~ ~ M n~ N
N~ '~~ I R7 R1 ~ 1 N\
R10 RIS ~
Where each of R 1- R 15 is CH~CH~. CH=CHI, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)~ X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH~, CO~H, COZR16, CONHR16, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR16 or is a functional group less than or equal to 100000 daltons), CHZCO~R 16, CH2CONHR 16, CH=CHCH~OH, CH=CHCH20R 16, CH(OH)CH3, CH(OR16)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 16R 16, CN, O, S, NHR16, OH, OR16, CHO, (CH,,)"OH, (CH2)~SH, (CHZ)"O-alkoxy, (CH~)"SR16, (CH~)nORl6 (where n = 1, 2, 3, 4, and R16 is a functional group less than or equal to 100000 daltons), (CH,)nCO,Rl6 (where R16 is H, a physiologically acceptable salt, alkyl ~5 (1-6 carbons), aryl, substituted aryl, alkenyl; substituted alkenyl, alkynyl, or substituted alkynyl, _and n=1, 2, 3, 4), (CH~)nCONHR16, (CH.,)~CON(R16)~, CO~R16, CONHR16, CONR 16R 16, SR 16 (where R 16 is a functional group less than or equal to daltons), SO;H, S03R16, SO~NHR16, SO~N(R16)Z, S02N(R16)3+X- (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), 20 protein or biomolecule or functional group less than or equal to 100000 daltons; M is Ins ~3, In~ ~5 or a mixture of In"3 and In' ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be M is Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, 25 Pr or Rh, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Yet another family of compounds has the following structure:
R_i R 1 I j-,w( RS
~N ~ ~ R6 Nw M n+
_."' N
N , . ~,' ~ R7 R1 v ~l .Ns s where each of R 1-R 14 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)Z , CH=CHCH~N+(CH3)s X- (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH3, CO~H, CO~R 15, CONHR 15, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR15 or is a functional group less than or equal to 100000 daltons), CH~CO~R15, CH~CONHR 15, CH=CHCH~OH, CH=CHCH~OR 15, CH(OH)CH;, CH(OR 15)CH~, H, to halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR15R15, CN, O, S, NHR15, OH, OR15, CHO, (CH.,)"OH, (CH~)"SH, (CH2)"O-alkoxy, (CHZ)"SR15, (CHZ)"OR15 (where n = 1, 2, 3, 4, and R 15 is a functional group less than or equal to 100000 daltons), (CH2)~C02R 15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted 15 aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)~CONHR I S, (CH~),~CON(R 15)x, CO~R 15, CONHR I5, CONR I SR 15, SR 15 (where R15 is a functional group less than or equal to 100000 daltons), SO;H, S03R15, SO~NHRIS, SO~N(R15)~, SO~N(R1S)~+X- (where R15 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or 2o functional group less than or equal to 100000 daltons; M is In"3, In"5 or a mixture of In"3 and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyI, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr or 25 Rh, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the following stucture:
\~'N~~1' \
R_5 N~ , ,.N'-R10 ~ M~°~ ~ RI2 N~~ ; N
R i \ ~ . N / / R6 R8 R9 R 15 R~
where each of Rl-R15 is CH~CH3, CH=CHI, CH=CHCH~N(CH3)Z, CH=CHCH~N+(CH3)~
X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCHz, CO~H, CO~R16, CONHR16> CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR 16 or is a functional group less than or equal to 100000 daltons), CH~CO~R
16, CH~CONHR16, CH=CHCH~OH, CH=CHCH~OR16, CH(OH)CH3, CH(OR16)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 16R 16, CN, O, S, NHR 16, OH, OR 16, CHO, -(CHZ)"OH, (CH2)"SH, (CH2)"O-alkoxy, (CH,,)"SR16, (CH,,)"OR16 (where n =
1, 2, 3, 4, and R 16 is a functional group less than or equal to 100000 daltons), (CH2) COZR 16 (where R 16 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,),1CONHR16, (CH.,)~CON(R16)~, CO~R16, CONHR16, CONR16R16, SR16 (where R 16 is a functional group less than or equal to 100000 daltons), S03H, SO~R
16, SO~NHR16, SO~N(R16)~, SO~N(R16)~+X- (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or 2o functional group less than or equal to 100000 daltons; M is Inl~~, Ins ~5 or a mixture of Inl~3 and In~~s ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr> Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, or Rh> preferably Pd, Pt, Ga> Al, Ru, Sn or Zn.
Yet other families of compounds have the following structure:
N
R2 ~N' ~ .Z 1 R6 -M'N I
RI N - ~_ / R7 R10 ~-~ R11 Where each of R 1-R 12 is CHZCH3, CH=CHI, CH=CHCH~N(CH~)~, CH=CHCH~N+(CH;)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCHz, CO~H, CO~R13, CONHR13, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR13 or is a functional group less than or equal to 100000 daltons), CH~CO~R 13, CH~CONHR 13, CH=CHCH~OH, CH=CHCH~OR 13, CH(OH)CH3, to CH(OR13)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR13R13, CN, O, S, NHR13, OH, OR13, CHO, (CH2)~OH, (CH.,)"SH, (CHZ)"O-alkoxy, (CH2)"SR13, (CH,,)"OR 13 (where n = 1, 2, 3, 4, and R 13 is a functional group less than or equal to 100000 daltons), (CH~)~CO~R13 (where R13 is H, a physiologically acceptable salt, alkyl ~5 ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2. 3, 4), (CH.,)nCONHR13, (CHZ)nCON(R13)~, CO~R13, CONHR13, CONR13R13, SR13 (where R13 is a functional group less than or equal to 100000 daltons), SO~H, S03R13, SO~NHR13, SO~N(R13)Z, SOZN(R13);+X- (where R13 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), 2o protein or biomolecule or functional group less than or equal to 100000 daltons; M is In''3, In"5 or a mixture of In"~ and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, Pt, Ga or Al.
Another family of compounds has the following structure:
R4 ~ R8 N
R3.D.~A ~N. ~ ,Z 1 R9 ,C ~ .M-N I
R2 ~~$ N~~' N ~ R10 R13 'R12 Where each of R1-R14 is CH~CH~. CH=CHI, CH=CHCH~N(CH~)2, CH=CHCH~N+(CH~)z X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCHz, CO~H, CO~R15, CONHR15, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR15 or is a functional group less than or equal to 100000 daltons), CH~CO~R15, CH~CONHR15, CH=CHCH~OH, CH=CHCHZOR15, CH(OH)CH3, CH(OR15)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR15R15, CN, O, S, NHR15> _OH, OR15, CHO, (CHZ)"OH, (CH~)"SH, (CH.,)~O-alkoxy, (CH~)"SR15, (CH,)"OR 15 (where n = l, 2, 3, 4, and R 15 is a functional group less than or equal to 100000 daltons), (CH~)~CO,R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH~)nCONHRIS, (CHZ)~CON(R15)~, CO~R15, CONHR15, CONR 15R 15, S R 1 S (where R 15 is a functional group less than or equal to daltons), SO~H, S03R15, SO~NHR15, SO~N(R15)2, SO~N(R15)~+X~ (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D are; C, N, O+> O, S, Te, P, N+(R15)X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In~'3, Ins ~5 or a mixture of Ins ~3 and 1n~ ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, Pt, Ga or Al.
Yet another family of compounds has the following structure:
R13'B~C\ D RI '_' R4 I I
N
,A / ~N, ~ ~Z ~ RS
R15,H N'~ ; ~ R6 N
I I
~~ Ev RIO ~ ~7 R16 i R18 Where each of R1-R18 is CH~CH~, CH=CHI, CH=CHCH~N(CH;)2, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH3, CO~H, CO~R19, CONHR19, CH=CHCHO, CH~Y, (where Y =
1 o H, halogen, OH, OR 19 or is a functional group less than or equal to 100000 daltons), CH~CO~R 19, CH~CONHR 19, CH=CHCH~OH, CH=CHCHZOR 19, CH(OH)CH3, CH(OR 19)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR19R19, CN, O, S, NHR19, OH, OR19, CHO, (CHz)~OH, (CH2)"SH, (CHZ)"O-alkoxy, (CH2)"SR19, ~5 (CH,,)"OR19 (where n = l, 2, 3, 4, and R19 is a functional group less than or equal to' 100000 daltons), (CH.,)nCO~R 19 (where R 19 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl: and n=1. 2, 3, 4), (CH2)~CONHR19, (CH,,)nCON(R19)~, CO~R19, CONHR19, CONR 19R 19, SR 19 (where R 19 is a functional group less than or equal to 20 daltons), SO;H, S03R19, SO~NHR19, SO~N(R19)~, SO~N(R19)3+X~ (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E , F, G, H are; C, N, O+, O, S, Te, P, N+(R19)X- (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion) or combinations thereof;
25 M is Ins ~3, Ins ~5 or a mixture of Ins ~~ and Ins ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, Pt, Ga or Al.
Still another family of compounds has the following structure:
R1l ~ RS
R10 \ N~I~ N ~ R12 \ i N N
R 1 ~~ ~~ / R6 R8 ~ R7 Where each of Rl-R12 is CH~CH3, CH=CHI, CH=CHCH~N(CH3)~X, CH=CHCH~N~(CH~)3X- (where X is a charge balancing ion), C(X)~C(X}~ (where X is a halogen), CHO, COCH~, CO~H, CO~R13, CONHR13, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR13 or is a functional group less than or equal to 100000 daltons), CH~CO~R13, CH~CONHR13, CH=CHCH~OH, CH=CHCH~OR13, CH(OH)CH~, to CH(OR13)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR13R13, CN, O, S, NHR13, OH, OR13, CHO, (CH2)"OH, (CHZ)"SH, (CHZ)"O-alkoxy, (CHZ)"SR13, (CH~);,OR13 (where n = l, 2, 3, 4, and R13 is a functional group less than or equal to 100000 daltons), (CH,,)nCO,,Rl3 (where R13 is H, a physiologically acceptable salt, alkyl ~ 5 ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)~CONHR13, (CH,}nCON(R13)~, CO~R13, CONHR13, CONR 13R 13, SR 13 (where R 13 is a functional group less than or equal to daltons), SO~H, SO~R13, SO~NHR13, 502N(R13)~, SO~N(R13)z~X- (where R13 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), 2o protein or biomolecule or functional group less than or equal to 100000 daltons; Z is halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Another family of compounds has the following structure:
R2 ~ J ~ ~ ' RS
N~ Z N.
R13 ~ In' ~ R15 N N
R1 ~l ,l i R6 / ' R8 where each of R 1-R 15 is CH~CH;, CH=CHI, CH=CHCH~N(CH~}Z , CH=CHCH~N+(CH~)3 X- (where X is a charge balancing ion). C(X)~C(X)3 (where X is a halogen), CHO, COCH~, COZH, CO,R16, CONHR16, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR16 or is a functional group less than or equal to 100000 daltons), CH2COZR16, CH~CONHR 16, CH=CHCH~OH, CH=CHCH~OR 16, CH(OH)CH3, CH(OR 16)CH3, H, to halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 16R 16, CN, O, S, NHR 16. OH, OR 16, CHO, (CH,,)"OH, (CH.,)"SH, (CH2)"O-alkoxy, (CH2)"SR16, (CH2)"OR16 (where n =
1, 2, 3, 4, and R 16 is a functional group less than or equal to 100000 daltons), (CH~)~C02R 16 (where R16 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)nCONHR 16, (CH.,)~CON(R 16),, CO~R 16, CONHR 16, CONR 16R 16, SR 16 (where R16 is a functional group less than or equal to 100000 daltons), SO~H, S03R16, SO~NHR16, SO~N(R16)~, SO~N(R16)~+X~ (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; Z is halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Still another family of compounds has the following structure:
RS \\~~~ ~ R13 % \~/N_ R14/M~ ~ R12 ~N N
R7 ~ ~~ ~ ~ RI l where each of R I-R 14 can be CH~CH3, CH=CH2, CH=CHCH2N(CH3)2, s CH=CHCH~N+(CH~)~ X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH~, CO~H, CO~R15, CONHR15, CH=CHCHO. CH~Y. (where Y =
H, halogen, OH, OR15 or is a functional group less than or equal to 100000 daltons), CH~CO~R 15, CHZCONHR 15, CH=CHCH,OH, ('_H=CHCH~OR 15, CH(OH)CH3, CH(OR 15)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, 1 o substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 15R I
5, CN, O, S, NHR15, OH, OR15, CHO, (CHZ),;OH, (CH2)"SH, (CHZ)"O-alkoxy, (CH2)"SR15, (CH~)"OR15 (where n = 1, 2, 3, 4, and RI5 is a functional group less than or equal to 100000 daltons), (CH,)~CO.,R 15 (where R 15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted 15 alkynyl, and n=1, 2, 3, 4), (CH~)~CONHR15, (CHZ)~CON(R15)~, COZR15, CONHR15, CONR 1 SR I5, SR 15 (where R 1 S is a functional group less than or equal to daltons), SO~H, SO~R15, SO~NHR16, SO~N(R15)~, SO~N(R15)3~X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is Ins ls, 2o In ~ ~ 5 or a mixture of In ~ ~ ~ and In ~ ~ 5 ; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or' Zr, preferably Pd, Pt, Ga, Al, Ru, 25 Sn or Zn.
Still another family of compounds has the formula:
R3 Rll R2 ~ ~J Z~~ ' RS
N' yN"
R10 ~ In' ~ Rl N N
RI ~l ,l i R6 R8 1~ R7 Where In is In"~, In"5> or a mixture of In"j and In' ~5, each of R1-R12 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)~, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH~, CO~H, CO~R13, CONHR13, CH=CHCHO, CH~Y. (where Y = H, halogen, OH, OR13 or is a functional group less than or equal to I 00000 daltons), CH~CO~R 13, CH~CONHR 13, CH=CHCH~OH, CH=CHCH~OR13, CH(OH)CH~, CH(OR13)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, t0 amide, ester, NR13R13, CN, O, S, NHR13, OH, OR13, CHO, (CHZ)~OH, (CH,,)"SH, (CHz)"O-alkoxy, (CH2)"SR13, (CHZ)"OR13 (where n = 1, 2, 3, 4, and R13 is a functional group less than or equal to 100000 daltons), (CH~)~CO.,R13 (where R13 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and n=I, 2, 3, 4), (CH,)nCONHR13, IS (CH.,)nCON(R13)~, CO~R13, CONHR13, CONR13R13, SR13 (where R13 is a functional groups less than or equal to 100000 daltons), SO~H, SO~R13, SO~NHR13, SO~N(R13)~, SO~N(R 13)~+X- (where R 13 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; Z is halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, 2o substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional groups less than or equal to 100000 daltons.
l06 Two other families of compounds have the structures of Compound I and II, below:
X v X v c:ompounct 1 _.......r..~.... .~
wherein M is In ~ ~;, In ~ ~ 5 or a mixture of In ~ ~ 3 and In ~ u:
Rl, R2 and R3 can be the same or different, and each is C02H, CO~R4, CONR4, CH3Y', CONR4R4, NHS, N(R4)~, or N(R4)3+Z-, where Y' is halogen, OH, OR4, or a functional group having a molecular weight equal to or less than 100,000 daltons, R4 is a functional group having a molecular weight equal to or less than 100,000 daltons, and Z
is a physiologically acceptable charge balancing ion, with the proviso that R4 is not a mono-or di-carboxylic acid of an amino acid, RS is a methylene group or an ethylene group, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy. Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La.
Lu, Mn, Mo;
Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, and preferably is i 5 In, Pd, or Pt.
In still another aspect, the invention is a free base or a metal complex having the structure of one of Compounds III and IV, below:
X y X Y
Compound III Compound IV
wherein M is 2H or a metal cation, R1, R2 and R3 can be the same or different, and each is C:O~H, CO~R4, CONR4, CH3Y', CONR4R4, NHZ, N(R4)~, N(R4)3+Z~, or CONHR60R7 where R6 is a bivalent moiety composed of a number, n, of alkylene groups and (n minus 1 ) oxygens, each oxygen linking two alkylene groups through an ether linkage, CONHR60R7 where R6 is a bivalent moiety composed of a number, n, of alkylene groups and (n minus 1) oxygens, each oxygen linking two alkylene groups through an t o ether linkage, and R7 is alkyl, and Z is a physiologically acceptable charge balancing ion, with the proviso that there is at least one R6 group in the structure, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
t 5 In the foregoing definition, and elsewhere herein, the term "alkylene"
means a bivalent radical derived from an alkane with the free valences on different carbon carbon atoms, l.e., -C"H,"-.
Preferably, M is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La, Lu, Mn.
Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, most desirabl y Zn. Sn, In ~ ~ j, In ~ ~ 5, a mixture of In ~ " and In ~ ~ 5, Pd, or Pt.
In still another aspect, the invention is a metal complex having the structure of one of Compound V and VI, below:
X v X Y
Compound V Compound VI
wherein M is 2H, In ~ 13, Im ~ 5 or a mixture of In ~' 3 and 1n ~ ~ S, R1, R2 and R3 can be the same or different, and each is X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, most desirably Pd, Pt, Ins ~;, Ins ~5 or a mixture of Ins ~~ and Ins ~5 In the foregoing discussion of the invention and in the following claims, the term functional group having a molecular weight equal to or less than 100,000 daltons has been ~ 5 used. This term refers to such groups as monoclonal antibodies, proteins, saccharides, oligomeric nucleosides, peptides and the like. The terms alkyl, alkenyl, alkynyl, substituted alkenyl, substituted alkynyl and aryl, when used herein and in the appended claims to refer to substituents, preferably mean groups having 1 to 10, 2 to 10, 2 to 10, 2 to 10, 2 to 10 and 6 to 10 carbons, respectively.
It will be apparent that various changes and modifications can be made from the specific disclosure of the invention set forth herein without departing from the spirit and scope thereof as defined in the following claims.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide pyrrolic compounds that absorb light at long wavelengths for use in photodynamic therapy and diagnosis of disease states.
It is another object to provide a reaction product of (A) P where P is a pyrrolic 5 derivative and (B) In";X3 and/or In"SX~ (where X is a charge balancing ion, either organic or inorganic) such as to provide the reaction product (C) PIn";~X"
and/orPIn"5"X", where indium is coordinated to the pyrrolic derivative and n =1, 2, 3.
It is yet another object of the invention to provide a reaction product of (C) PIn"j~X" and/or PIn"5"Xn with a neucleophile Y, such that a reaction product (D) to PIn"~nY"XZ and/or PIn"5"Y"XZ is obtained (where Y is a charge balancing ion, either organic or inorganic n=1,2,3 and z = 0, l, 2, 3).
It is still another object to provide compounds PIn"~X and/or PIn"5X that may be used to treat diseases such as atherosclerosis, restenosis, cancer, cancer pre-cursors, non-cancerous hyperproliferating diseases, psoriasis, macular degeneration, glaucoma and t5 viruses, benign prostate hyperplasia, rheumatoid arthritis and to aid in the diagnosis of these disease states.
DESCRIPTION OF THE PERFERRED EMBODIMENTS
2o The present invention provides derivatives of photoactivatable compounds, some of which are shown in the following Examples, in table l, and in Figs. 1- 5 via the introduction of non-radioactive indium into the macrocycle. The resulting products can be used to diagnose and treat disease states. Additionally, the ligand on the indium complex may then be further chemically or biochemically modit7ed ex-vivo or in-vdvo to form a 25 different pyrrolic indium complex which is capable of binding to important blood plasma components or cell transport proteins that enhance sensitizer uptake at the diseased tissue site.
Additional functionality around the pyrrolic structure can be used to attach biomolecules, examples of which may be antibodies, growth hormones and growth factors 30 or other disease specific molecules, or to aid such factors as water solubility, lipophilicity or hydrophobicity which are known factors that influence drug uptake in tumor disease tissue.
The following Examples are presented solely for the purpose of disclosing and illustrating the invention, and are not to be construed as limiting. In all of the procedures described in the examples, indium, where used, was the natural material, a mixture of abouit 4.23% In~~~ and 95.77% In~~S. The following abbreviations are used in the examples: mL means millilter or milliliters, g means gram or grams; mg means milligram or milligrams; ~tg means microgram or micrograms Example 1, Preparation of Indium Methyl pyropheophorbide from methyl pyropheophorhide:
M is 2H in methyl pyropheophorbide, and a mixture of Ins ~3 CI and Ins ~5 Cl in Indium methyl pyropheophorbide i0 Methyl pyropheophorbide (O.Sg) was dissolved in acetic acid (100mL); Indium chloride (O.Sg) and anhydrous sodium acetate (0.5 g) were added, and the solution was refluxed for 3 hrs. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane / water ( 100mL/ 100mL). The organic layer was washed several times with 0.5 N HCl/water (200mL), collected and dried over anhydrous sodium sulfate (20g). The organic layer was filtered and evaporated to dryness. The resulting residue was crystallized from methanol / dichloromethane. Yield 0.45g.
HC = CH2 WO 00/00204 ~ PCT/US98/13601 Example 2, preparation of Indium tert-butyl phthalocyanine:
'.
R~ ~ R2 R ~ ~ ' RI
, ;J' N
RI ~ RI
R Rd R4 R3 one of R2 and R3 is tert-butyl while the other and R l and R4 are H; and M is Inl1'~ Cl, In~IS Cl or a mixture of Inl l3 CI and In115 CI
4-tent-butyl-1,2-dicyanobenzene (2g) and Indium chloride (2.Og) were mixed thoroughly in a round bottom flask with stirring. The mixture was heated at 160°C for 2 hrs and the reaction vessel cooled to room temperature. The crude phthalocyanine was extracted from the resulting green solid using hot dichloroethane and the green solution evaporated by rotary evaporation. The resulting solid was dissolved in 7°lo acetone /
dichloromethane and chromatographed on silica using 7% acetone /
dichloromethane as eluent. The major green fraction was collected and recrystallized from methanol/
dichloromethane. Yield , 1.1 g.
Example 3, Preparation of Indium Benzoporphyrin derivative from Benzoporphyrin derivative dimethyl ester .
Where M is In~t~ Cl, In~~s Cl, or a mixture of Ins y~ Cl and In~ ~5 Cl in indium ben2oporphyrin derivative dimethyl ester and 2H in Ring B isomer benzopor-phyrin derivative dimethyl ester Ring B isomer, Benzoporphyrin derivative dimethyl ester ( 100mg) was dissolved in acetic acid (SOmL) and Indium chloride (0.2g) and anhydrous sodium acetate ,(0.2 g) were added: the solution was refluxed for 3 hrs. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane / water ( 100mL1 100mL). The organic layer was washed several times with 0.5 N HCl/water (200mL), collected and dried over anhydrous sodium sulfate (20g). The organic layer was filtered lp and evaporated to dryness. The resulting residue was chromatographed on silica using 5%
MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane /
dichloromethane. Yield SOmg.
Example 4, Preparation of Indium m-hydroxy tetraphenylchlorin:from Tetrakis (3-hydroxyphenyl)chlorin RI
R5 l ~ R2 n ,, ~ R3 R2 R-~ \ 'l '~ _~ R-~ R2 R1 /_\ \ N I vN / \ / R1 N N % \
R5 R4 ~~ ~~ / R4 R5 Where each R2 is OH, each Rl, R3, R4 and RS is Hydrogen, In is a mixture of Ins I~ C1 and In ~ 15 Cl, arid Z is Cl tp Tetrakis (3-hydroxyphenyl)chlorin ( 100mg) was dissolved in acetic acid and the solution purged with argon. Indium chloride (0.2g) and anhydrous sodium acetate (0.2 g) was added and the solution refluxed for 3 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane / water ( 100mL/ 100mL). The organic layer was washed several times with 0.5 N
HCl/water t5 (200mL), collected and dried over anhydrous sodium sulfate (20g). The organic layer was filtered and evaporated to dryness. The resulting residue was chromatographed on silica using 5% MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane /
dichloromethane. Yield 60mg.
WO 00/00204 ~ ~ PCT/US98/13601 Example 5, preparation of In Octaethylbenzochlorin (9) from Octaethylbenzochlorin (~~OEBC") Each of RI through R8 is ethyl.
In Octaethyl benzochlorin, M
is 2H, and in Indium octaethyl benzochlorin M is Ins" Z, Ins ~5 Z or a mixture of Int ~'~ Z and Ins ~5 Z;
Z is CI
Octaethylbenzochlorin ( 100mg) was dissolved in acetic acid and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution was refluxed for 3 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( IOmL). The resulting solution was chromatographed on silica using 5% MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid I o crystallized from hexane / dichloromethane. Yield 1 l Omg.
WO 00/00204 ~ ~ PCT/US98/13601 Example 6, preparation of InOEBCSOZNH(CH2)30H (10) from OEBCSOZNH(CHZ)30H
Each of R 1 through R8 is ethyl In Octaethyl benzochlorin, M
Is 2H, and in Indium Octaethyl benzochlorin M is a mixture of In~~3 Cl and In~~s CI
R is SO,NH(CHZ)30H
LO
OEBCSO~NH(CHZ)30H (100mg) was dissolved in dimethylformamide (DMF) (25mL) and InCl3 ( 100mg) was added. The solution was refluxed for 6 hrs and the DMF
was removed by rotary evaporation. The residue was dissolved in dichloromethane (IOmL) and the resulting solution was chromatographed on silica using 5°lo MeOH /
dichloromethane as eluent. A minor fore running green band was collected and discarded and the more polar major green fraction was collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane.
Yield 52mg.
WO 00/00204 '2 PCT/US98/13601 Example 7, Preparation of InOEBCS02I~CH2CH~OCH2CH~OCH2 H~OCH2CH~OCH~ (1~) from OEBCSO2N~H~CH20CH2CH20CH2CH~OCH~CH~OCH~
CH~CH20CH2CH20CH2CH20CH2CH~OCH~
Where each of R1 through R8 is ethyl M is In ~ t3 Z, In ~ ~5 Z, or a mixture of Ins ~~ Z and Ins ~5 Z
in In Octaethyl benzochlorin and 2H in Octaethyl benzochlorin ~H,CH=OCH=CH=OCH=CH,OCH,CH~OCHz R is SO,[~ ~
~H_CH=OCH=CH~OCH_CH,OCH_CH=OCHi Z is CI
OEBCSO N"'CH?CH20CH2CH20CH2CH20CH~CH~OCH~ (400 mg) was 2 ~CH2CH~OCH2CH20CH2CH20CH2CH20CH~
dissolved in acetic acid ( 150mL) and Indium chloride (0.4g) and anhydrous sodium acetate (0.3g) were added. The solution was refluxed for 3 hrs under argon.
The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( IOmL). The resulting solution was chromatographed on silica using 5%
acetone / dichloromethane as eluent and the major green fraction collected.
The solvent was removed by rotary evaporation and the solid crystallized from hexane l0 dichloromethane. Yield 420mg.
WO 00/00204 ~ 3 PCT/US98/13601 Example 8, Preparation of InOEBCSOZNHC(CH20H)3 (19) from OEBC
SOzNHC(CHZOH)3 Each of R1 through R8 is ethyl In Octaethyl benzochlorin, M
Is 2H, and in Indium Octaethyl benzochlorin VI is a mixture of Ins" Cl And Ins ~5 Cl R is SO,NHC(CH,OH)~
to OEBCSO~NHC(CH~OH)~ (100mg) was dissolved in bromobenzene (SOmL) and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution was refluxed for 5 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( l OmI,). The resulting solution was chromatographed on silica using 5% acetone / dichloromethane as eluent and the major 15 green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane. Yield lOSmg.
Example 9, preparation of InOEBCSO2NH (CHZ)4CH(NHZ)COZH (21) from OEBCS02NH (CHZ)4CH(NH2)COZH
Each of R1 through R8 is ethyl In Octaethyl benzochlorin, M
Is 2H, and in Indium Octaethyl Benzochlorin M is a mixture of In 113 Cl and In 115 C!
R is SOZNH (CHZ)4CH(NHZ)COZH
OEBCSOZNH (CHZ)4CH(NH2)COzH (100mg) was dissolved in acetic acid and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution refluxed for 3 hours under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( lOmL). The resulting solution was chromatographed on silica using 5% MeOH / dichloromethane as eluent and the major green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane. Yield 1 lOmg.
Example I0, Preparation of Indium 2-desvinyl-2-acetyl pyropheophorbide (26) from 2-desvinyl-2-acetyl pyropheophorbide (26) O=C-CH3 N N
,, , N,, N
'H
CH~OZC
M is 2H in 2-desvinyl-2-acetyl g Pyro heophorbide and a mixture of In~" CI and In~~S Cl in Indium-2-desvinyl-2-acetyl pyropheophorbide to 2-Desvinyl-2-acetyl pyrropheophorbide (100mg) was dissolved in acetic acid and Indium chloride (0.2g) and anhydrous sodium acetate (0.2g) were added. The solution was refluxed for 3 hrs under argon. The solution was taken to dryness by rotary evaporation and the solid residue dissolved in dichloromethane ( l OmL,). The resulting solution was chromatographed on silica using 5°lo acetone / dichloromethane as eluent and the major 15 green fraction collected. The solvent was removed by rotary evaporation and the solid crystallized from hexane / dichloromethane. Yield 100mg.
WO 00/00204 ' 6 PCT/US98/13601 Example 11, Preparation of Indium 2-desvinyl-2-formyl pyropheophorbide (27) from 2-desvinyl-2-formyl pyropheophorbide O=
N
N,, N
r'H
Hz CH~02C
M is 2H in 2-desvinyl-2-formyl Pyro~heophorbide and a mixture of In ~3 CI and In~~s CI in Indium-2-desvinyl-2-formyl pyropheophorbide 2-Desvinyi-2-formyl pyropheophorbide ( 100mg) was dissolved in acetic acid (20mL) and Indium chloride ( 100mg) was added. Diisopropylethylamine (0.3m1) was added and the solution refluxed until no more starting material remained by TLC (5%acetone i dichloromethane). The acetic acid was removed by rotary evaporation and the residue dissolved in dichloromethane and washed with 10% NHaCI (2 x SOmL). The organic phase was separated, dried over sodium sulfate filtered and rotoevaporated to dryness. The residue was dissolved in dichloromethane and purified by chromatography on silica using 5% acetone / dichloromethane as eluent followed by 20% acetone /
dichloromethane as eluent. A less polar green fraction was collected and recrystallized from dichloromethane /
2o hexane. A second more polar green fraction was collected and discarded.
Yield of (27) _ 62mg.
WO 00/00204 1 ~ PCT/US98/13601 Example 12, preparation of Indium Chlorin e6 trimethyl ester (28) from Chlorin e6 trimethyl ester N
N
CO~CH
CH~CO~CH~
M is 2H in Chlorin eb Trimethyl eater and a mixture of In~~3 Cl and In~~S CI in Indium-Chlorin e6 trimethyl ester Chlorin e6 trimethyl ester ( 150mg) was dissolved in acetic acid (20mL) and to Indium chloride (150mg) added. Diisopropylethylamine (0.3m1) was added and the solution refluxed until no more starting material remained by TLC (5%acetone /
dichloromethane). The acetic acid was removed by rotary evaporation and the residue dissolved in dichloromethane and washed with 10% NH~CI (2 x SOmL). The organic phase was separated, dried over sodium sulfate, filtered and rotoevaporated to dryness.
The residue was dissolved in dichloromethane and purified by chromatography on silica using 5% acetone / dichloromethane as eluent followed by '~0% acetone /
dichloromethane as eluent. The major green fraction was collected and re-purified by chromatography on silica using 5% acetone / dichloromethane as eluent. The major green fraction was collected and recrystalized from dichloromethane / hexane. Yield, 67mg 2o Various compounds comprised essentially of a non-radioactive indium atom complexed with the inner nitrogens of a pyrrolic core have been evaluated biologically as photosensitizers. The results of some of this evaluation are summarized below.
In Vitro Biological Evaluation of FunctionaIized Benzochlorins.
The in vitro biological evaluation of certain photosensitizers was determined, using standard procedures. Several of the photosensitizers had the following structure:
RT
where each of R 1 through R8 was ethyl and R and M had various meanings The identities of a first group of the compounds tested, all of which had the foregoing structure, of an arbitrary "Sensitizer Number" assigned for reference purposes, to and the Example (if any) where their preparation is described are set forth below:
SensitizerExampleIdentity Identity of R in Foregoing formula Number (if of any) M in Foregoing formula 2 2H SO,NH(CH ),OH
4 Zn H
Zn SO,NH(CH ),OH
7 Sn SO,NH(CH ),OH
g Sn CH
9 5 In H
6 In SO,NH(CH ),OH
11 In CH.
12 In SO,N(CH,CH,OH), 13 In SO,NH(CH,) OH
14 In See structure below In See structure below 16 In SO,NH(CH,),O(CH,),O(CH,),OCH
17 7 In SO,N [(CH,),O(CH,),O(CH,),O(CH,)OCH
], lg In SO,NH(CH,) SH
19 8 In See structure below In SO,NHCH,CO,H
21 9 In See structure below Sensitizer Number 14 SO2N ~ N(CH~)2 N(CH~)~
Sensitizer Number 15 SOZNHCH~CH2N~
OH
Sensitizer Number 19 S03NH OH
OH
Sensitizer Number 21 S02NH(CH2)4~HCOZH
The identities of a second group of compounds tested, all of which had the following structure, of an arbitrary "Sensitizer Number" assigned for reference purposes, and the Example, (if any) where their preparation is described are set forth below:
WO 00/00204 2o PCT/US98/13601 Sensitizer ExampleIdentity of Identity of Number lif M in fore- in foregoing any) going formula formula 22 2H Vinyl 23 SnCI, Vinyl to 24 InCI Vinyl 25 InCI Ethyl 26 10 InCI COCH
27 11 InCI CHO
28 12 Pd COCH
WO 00/00204 2~ PCT/US98/13601 A third group of the sensitizers had the folowing formula:
CI , -Sensitizer Example Identity of Identity of Identity R1 of R2 Number (if any) M in fore- in foregoing in foregoing going formula formula formula 29 a mixture of Vinyl CH~CO~CH3 Ins ~3 Cl and ~~ is Cl 30 a mixture of Ethyl CH~COZCH3 Ins l~ C1 and ~vs Cl 31 a mixture of Vinyl COZCH~
~1i3 Cl and y ~s Cl 32 a mixture of Ethyl COZCH3 Ins ~~ Cl and y is CI
For the Biological Evaluation, Chinese hamster lung fibroblasts (V-79) obtained from the American Tissue Culture Collection were grown in D-MEM supplemented with 10% fetal calf serum at 37°C, 5% C02~ and 95% humidity. These cells were used to evaluate the sensitizers for dark and light toxicity, and cellular uptake.
Medium was replaced with 5% fetal calf serum supplemented medium during sensitizer incubations.
In the first phase, the combination of intracellular and extracellular concentration of photosensitizer required for lethal damage to 50% of the cells in culture (DC(50)) on light exposure was determined by plating cells at a density of 100 cells / cm2 and incubating for 1-3 hours to allow attachment of the cells. Cells were incubated with various concentrations of sensitizer ([C]= 0.01-l.OpM) delivered in non-toxic concentrations of DMSO/ 5% dextrose solution or in some cases in egg yolk phosphatidase (EYP) for 16-24 hours. The cells were then irradiated with laser light using ~ o a tunable Lexel argon pumped dye laser at the band I absorption of the photosensitizer.
Total power density was adjusted to 12.5 mW/cm2 and a total light dose of 1.25 J/cm2 was applied. After treatment, cells were washed with HBSS, refed with 10% FBS
supplemented DMEM with phenol red and incubated far 3-S days to allow colony formation: Cells were fixed in methanol, stained with Giemsa, and colonies were counted.
~5 Plating efficiency was determined using a control colony and the mean percent survival fraction plotted against the sensitizer concentration and the DC50 established (Table 5).
Several photosensitizers were screened by a standard cellular uptake protocol.
A
IOp.M stock solution of photosensitizer in EYP was prepared by dilution of the photosensitizer stock (1mM) using 5% dextrose solution. Monolayer V-79 cells in the log 20 phase of growth in 12- well tissue culture plates were incubated with 0.2mL
of the IOpM
solution of photosensitizer for time periods of 0. 12, 36, 48hrs. Following incubation the cells were washed with PBS (1mL) three times, then washed with HBSS (1mL) and detached using 100p.L of trypsin. Individual wells containing cells were lysed by three freeze thaws.
25 ~ Spiking experiments were performed to confirm that the sensitizer could be adequately recovered using standard procedures. The sensitizer was then extracted from the cell debris with DMSO, centrifuged and the supernatant examined for fluorescence.
Sensitizer concentration was determined by comparison to a standard curve.
Results are expressed in ug / ug protein. Untreated monolayers are used to determine cell count.
3o Treated cells of each time point were used to determine the protein concentration using the BCA assay. The results for the photosensitizers studied are presented in Table 2. Results shown are the mean of the three experiments for each timepoint.
As can be clearly seen for the compounds tested, indium compounds had clearly a much lower DC(50)(light) values, regardless of the functionality attached to the chlorin.
In Vivo Assay of Photosensitizers on Tumors Female C3H/HeJ mice (8-9 weeks old} were subjected to trochar implantation of BA mammary carcinoma on the hind leg of the animals. Animals having tumors ca Smm in diameter were entered into the in vivo screen. For each new photosensitizes, a group of at least three mice were used to ascertain a drug dose that caused a response as described in table 3 when treated with the appropriate wavelength of light. Generally in this series, animals were injected with 1 p. .mole of sensitizes / Kg of body weight, formulated in egg yolk phosphatidate (EYP)> via the tail vein. At a defined time period later the animals were irradiated with light from a laser source tuned to the wavelength of activation of the sensitizes. The power density of the laser was set at 75mW ! cm' with a total light dose of 200J / cm''. The spot size was lcm diameter. Results for each photosensitizes are shown in Table 3.
Selected Kaplan-Meier curves for two different benzochlorin metal classes are shown below. The curves are identified by legend.
Table 2.
Photophysical measurements, DC(50)(light) and cellular uptake of Photosensitizers Compound 7~max ~ f DC (50) (light)Cellular uptake (Figure 16) (s M-~ cm's) (pM) (24hrs) (pmole/pg protein) ( l ) H2 658 (35,000)0.347 > 1.0 -(4) Zn 678 (57,000)0.150 > I .0 -(6) Sn 69l (54,000)0.044 0.08-0.16 0.501 (9) In 691 (53,000)0.028 0.1 0.336 (2) H2 665 (34.000)0.230 0.5-1.0 0.129 (5) Zn 678 (48,000)0.124 0.5 -1.0 0.093 (7) Sn 684 (52,000)0.040 0.5 -1.0 -(10) In 684 (52.00010.027 O.l-0.125 -(3) H2 658 (35.000)0.35 - -(8) Sn 694 (50.000)0.02 - -( I I ) In 687 (54,000)0.034 - -( I 2) In 684 (52.OOU)-0.03 0.04 -( l3) In 684 (52.000)-0.03 0.04 -( l4) In 684 (52.000)0.03 0.05 -( 15) In 684 (52,000)-0.03 0.05 -(16) In 684 (52,000)-0.03 0.04 -( 17) In 684 (52,000)-0.03 0.04 ( I 8) In 684 (52.000)-0.03 0.04 ( 19) In 684 (52,000-0.03 0.04 (20) In 684 (52,000-0.03 0.04 (21 ) In 684 (52,000-0.03 0.04 (22) H2 666 (45.000)- -(23) Sn 658 (74.000)- >1.0 (24) In 666 (45.000)- -(25) In 655 - 0.03 (26) In 672 - I 0.06 (27)In 683 - 0.05 (28) Pd 653 - 0.05 (29) In 641 0.05 (30) In 637 - 0.06 (3 l ) In 650 - 0.08 (32) In 642 - 0.07 -Table 3 Tumor tes for o cure free ra base, Ztnc, m an n mm Compounds Drug DoseTime of TreatmentLight % Cure (30 (Figure ( m / Post injectionDose days) 16) (M) K ) I n = i0 ( I ) H2 3 24 200 60%
(4) Zn 3 24 200 0%
(6) Sn 0.75 24 200 80%
(9) In U.l 24 200 70%
(2) H2 2. 5 24 200 80%
(5) Zn 2.25 24 200 100%
(7) Sn 1.5 24 200 0%
( 10) In 0. ! 24 200 100%
(3) H2 2.5 24 200 60%
(8) Sn 1.0 24 200 !00%
( 11 ) In 0.15 24 200 90%
(22) H2 10.6 3 200 50%
(23) Sn 2.0 24 or 6 200 0%
(24) In 0.2 6 or 8 20CI 80%
( l2) In 0.05 24 200 90%
( I 3) In 0.075 24 20U 80%
( l4) In 0.075 24 20C1 90%
l5) In 0.05 24 200 100%
( I6) In 0.05 24 200 80%
( l7) In 0.075 6 200 100%
(25) In 0.075 6 or 8 200 80%
(26) In 0.125 8 200 90%
(27) In 0.1 8 200 90%
28) Pd 0.2 8 200 80%
(29) In 0.15 6 200 70%
80 ~ ~ >! L. ~ wET-3E 'f 3E 3E 3E ~E~
\ ~W
i N ~N
60 r ~ , =.- 0.25urrYKg n=1 p) ~ ~S
i --~-- 0.35um/Kg ~n=9~ N ~ - N
--+-0.5um/Kg (n=5~
[Ji 40 r ~~ I ~ 0.75urNKg (n-1 ) 1 v 20 t-T' d I d' Chl Tins Days Post PDT
Kaplan-Meier survival Curves for SnOEBC
100 ~,, , ,I
8 0 tr h ~. v r~
40 r ~ -~ 0.075um/Kg (n=5) -~- 0.05um/Kg (n=3) -~--O.Ium/Kg (n=10, 2 lath ) Days Post PDT
Kaplan-Meier survival curves for InOEBC.
5 The procedures of Examples 1-12 can be modified to produce other phototherapeutic compositions according to the invention, each such composition being comprised essentially of a non-radioactive indium atom complexed with the inner nitrogens of a pyrrolic core composed of at least two pyrroles. The modification involves merely substituting an equivalent amount of the free base of another compound having a l o pyrrolic core composed of at least two pyrroles for the methyl pyropheophorbide, the benzoporphyrin derivative, the tetrakis (3-hydroxyphenyl)chlorin, the octaethylbenzo-chlorin of Examples 1, 3, 4, 5, and 6 or for the corresponding starting materials of Examples 7-12, or by substituting other dicyano compounds capable of forming functionalized phthalocyanines, functionalized naphthocyanines or the like for the 4-tert-is butyl-1,2-dicyano benzene of Example 2.
Examples of compounds having a pyrrolic core composed of at least two pyrroles, and which can be substituted as described in the preceding paragraph to produce additional compounds according to the instant invention are named in Table l, and defined by reference to Figures 1-58, which follow the Table.
WO 00/00204 2~ PCT/US98/13601 Table 1:
Pvrrole-derived macrocyclic compounds (Fig. l ).
Naturally occurring or synthetic porphyrins and derivatives thereof (Fig. 2) g Naturally occurring or synthetic chlorins and derivatives thereof (Figs. 3, 16, 17, 32-35 and 48-55) Bacteriochlorins and isobacteriochlorins (Figs. 4, 5 and 36-47)) Phthalocyanines, Naphthalocyanines and derivatives thereof (Figs. 6, 7, 15, 18-21. 24. 26. 29, 30, 31 and 56) Porphycenes and derivatives thereof ( Fig. 8) Porphycyanines and derivatives thereof (Fig.9) Pentaphyrins, sapphyrins and derivatives thereof (Figs. 10 and 11 ) Texaphyrins and derivatives thereof (Fig. 12) Benzochlorins and derivatives thereof (Fig. 13) Chlorophylls and derivatives thereof (Fig. l4) Corroles (Fig. 58) ~3 Ril R4 R3 RII R4 R3 R7 R4 ~ W \ RS R2 ~ ~ ~~ \ RS
N N _' N N \ ~ R10 ~ N~M N / R12 RIO ~ ~M. / R12 N N N N
R1 ~M\R8 R6 RI \ 1 / / R6 RI ~ / / R6 FIGURE t FIGURE 2 FIGURE 3 _ R4 RS
R3 R11 R4 R3 R11 R4 ~ 1 \ N\ \ ' R7 R? ~ ~ RS ~ ~ \~_ R5 RI ~ N N - R8 N W / N~ N N~ ~M iN
RIU ~ \M. / RI2 R10 N M.N / R12 R16 jl' 'N R9 N~ N
R1 1 / / R6 R1 / / / / R6 / \ N /
T RIS ~ ~ R1o R8 R9 R~ R8 ~9 R~ R13 R12 RII
~ ~ .
R7~ ~~ oz R11 R17 R4 N'~~i~ Rli ~ - \
RS
rN R12 ~ ~ N~ ,N-~ N ,M~
v_ :"1N i N~ N
R23 \ ~ N / Rl3 R14 Ri \ ~ _ / R6 R19 R18 ~ ' R15 R4 ~ R4 R3 R11 R13 R4 R-~ Rll ~ R12 ~ R11 % R12 ~IN' ~N \ RS ~ ~\~ ~ ~ R6 ~ ~\H \ i ~ R6 R10 ~ ~M M~ / Rt2 M-N I ~M-N I
R1 \ N ''N~ N R6 \ N ~ I \ ~ R~ RI \ N ,N\ ~ R7 / / Rl '- _ ~R9 Rt0 R8 R9 RIS R7 R8 Rl R13~ R8 R8 R13 R8 FIGURE 9 FIGURE 10 FIGURE 1 i iiR
R17 ~~ R12 R,~ \w \ \ R6 R3 \w \ \ R6 R16 / ~ N j ~ R6 N~ N' N. N-' M_ N I Rl2 \ M ~ R14 R12 \ M ~ R14 RI , N, ,N
RIS ~ N/ II ~ R7 N' /N / R7 Rl 1 / / R7 R 14 '-- ~ 9 R2 ~ ~ R2~
R1 [0 R l l ~ R9 R8 8~~
R4 RS R4 R13 RS R4 RI~ RS
R3 ~ N~ \ R6 R3 ~ ~ ~\ R6 R3 ~ ~ \ \ R6 N N- N N' N~ N-=..~ R12 ~ \M ~ R14 Rl2 ~ 'M ~ R14 N\ N,M'N ~y RI N, ~N R1 N, .N
R2 \ 1 N / R7 R2 ~~~=~ R2 RI1 ~ R8 R11~ R8 RI R8 R10 R9 R10/ 'R16IR159 Y. :X V ~ ~ ,U.
R2-U~V~ ~U~V~R7 R2 ~ RS ~ R2 R2-U~ ~ Y R18 X V~R7 \ N. \ y~ ' w \ \ I jt w \ \ y RI ~ N rN ~ R8 RI ~ ~' N~\RI Rl ~ N\ .N - ~R8 Nv :~ ~N Nv M ~N Nv :~ ~N
R17 N N R9 RI N~ ~N RI R17 N N R9 1 i X I 1 i 1 Y \ ' /
Y
R16-V U X N Y V,U-R10 R2 ~ N / R2 R16-V~U;X N Y; V,U-R10 ~R14 Rl3 RII 3 R4 R4 ~ R15 'R14 R13 RII
RIS
FIGURE 18 FIGURE l9 FIGURE 20 R4 RS R5 R4 R4 RS R8\ R9 A
R3 / '' R6R7R ' ~ I R3 R3-AD -C'F R6 R7~E fl~ C-Rl0 R2 ~ \ I R2 R2 ~ ~ N~ \~ Rll R1 ~ N \N~RI Rl ~ N N=.~ Rt2 N~ ~M ~N Nv :~ ~N
N ~N RI E~24 N N ~R13 Rl \ 1 1 N / ~ R2 R?-i E \ N / E D R l4 R2 ~ C _ -~
w ~F F \ v R3 I ~ R6 R 1 / R3 ~B ;p R19 R18 C;~ A-RIS
R22 ~A . i 4 RS RS R4 R21 R20 R17 ~16 WO 00/00204 3~ PCT/US98/13601 R~ O O
A
R3 / _C R6 R~.'D' ~ R10 X R2 R-~ X
A \ o -B A D
R2 ~ N ~ ~\ N \
D C~ A ~ ' B.
Rl ~ N' N R12 R~l ~ N .~ R4 ~'-=t N~ i.~N ~N /Ri3 R8, N~N ~N, ~~N RS
C \ N ~ ~ /R14 B \ N~A, p' C~ A O ~~ - ~B'' O
Rly R18 / R15 X~ R7 R6 R__ \
R~ i R_0 R 16 O O
FIGURE 2:i FIGURE 24 E' ~RS R8~ , D~ ~ ,RS R8~ I
R3-D F R6 R7 C ~ E-R I 0 E= F C = D~
C ~ B A~ p R3-D~ R6 R7~ ~g-R I O
~F
R? A ~ N' ~ B \RI1 R~ ~B N A ll \R11 RI ~ N N' \R12 A ~\ \ \ B~R12 ~ RI N' N"
N :1V1\ N
N\ N N ~N v R2?\A \ I / / A/ R I 3 R2n N N / R l :i " N~1 ~R14 1A ~ ~ ~ A
R2i-D~C;B' B~C R19-D~ ~N D~R14 I Rl9 Rjg D-R15 C'Bv ,B'E
R20 Ri~'E~ R18 R17 R16 R15 E-F R8 p._ E~ RS
R3-D' \ R6 R~\ ~C R3 C~ ~F-R6 7 R8 R9 C~B A~ iD_Ry -' ~.4=B C
N
RS A w ' \ B R2 B~ N I '~p-R10 BRIO A w ' \
RI N N- Rl ~j N N' F~E~RII
W ~ i ~' N N R I 2 R?(1 N N R I 1 R2.~ R24 \A 1 ~ .A t , F N N R 13 R19-C \ N / 1 iRl2 E~ ~ I ~ / .A~
=B B~C R22-D'' I ' N ~B-R14 D 'Rl7 R16 ' D-Rl-1 C BrA R18 R18 ~FrE R~.I R20 Rl9 -F, ~C_RIS
R15 R14 iE~D
R1~ Rl6 a~ ~n _ R6 fZlO R12 p~C B~ B,C~ ., R,~~ ~~-R8 D p Rl3 R3 ~R.1 RS R6 p ~ R9 ~ p _ ~V' Y R 18 X =~, R3-C' 1 \ N\ \ I ''C-R14 R2 U~ \ \ \ a 'R7 R2' B ~ \ ~ ~ B' ,RI ~ N, . N'--~ i Rt5 RI X \ ~ N~Y R8 R.' v :~ ~ R17 Nv :~ ~N
R3l,B'p N N plB~Rl8 R17 N N R9 R30-C~~ I \ N / ~ i,C-R 19 Y \ I N / X
p ~ R24 ~ p R16-V~ ,L'-R10 U:X' Y-V
R2 R'~,~, ,B \R2S DB_ ~p R21R_0 RIS R14 R13 Rl I
R27 R26 R2'I R22 \ ~\~\ \ ~ ~\ \~ \ \
N N" 1 N N'- 1 N~ N' 1 R3 \ ,Mv / R-~ \ My / R? \ IvI\ /
H N N H N N' H N N
1 / / I / / ~ / /
H R6 H R4 R6 H p~ X ~ B
R2 ~R4 R2 R2 w \ R~ \ \ R~ w \ R~ ~ \ R6 \ i v \ ! i \ I 1 \ I 1 N ,N' N, N-' N, N- N' N' RZ \ M~ / R3 \ M~ / ' R3 \ M\ / , R3 \ M\
H 'V N H N N H N N H N N
1 / / t / / 1 / / I / /
R8 H ~ R8 HA~X~B
H ~ H R4 R2 R4 X R' R4 R2 R2 R1 RS RI RS R6 R1 RS R6 Rl \ \ ~ \ \ \
\ ~ ~_ ~ \ ! ~ \ 1 l N .N v N' N' I N N' 1 R3 \ M\ / Rg \ M;
N N N N / R3 \ ~M' /
N N
H l / / H 1 / ~ H I / /
H ~ ft7 H
R4 R7 Hp~X~B
R1 RS R1 RS Rl R~
R6 \ ~~Y_ R6 \ N' ~N_ RS
R3 \ M' / R3 \ M\ / R3 \ M\ /
N N N N N N
H ~ R7 H R4 127 H A~, X'~ B
.1 RI Rl3 R3 RI R13 R4 2 R1 R4 i3 R2 \ R4 R2 \
_ w B' ~ Rg ~ B'Y ' RS ~
Rs \ \
N N~ N~ .N~ B~ ~C~
R6-A~ M ~C-R12 l2 R6-A' M ~C-R12 R6 \ ~M~ / R12 r 1 D R11 1 ~~Rll R7 R7 \ 1 ~ / R I I I I R7~ ~ / \ / /
D~ ~ D
Rg R9 R10 "" Rg R9 RIO Rg R9 RIO
,1 RIS RI R13 R15 Rl R13 I3 RI Rl3 Rl R4 2 ~ R4 R3 R2 R 14 R4 i 3 2 4 R5 ~ ~ ~ RS
\ ~ 1 _ 12 R6-A ~ N'IVI N C:-R l2 R6 \ B~M C / R 12 R6-A\ N'M N ~C-Rl2 I R7 \ N' ~N / R11 R \ A /D / R11 R7 \ N' ,N / RIl D~ D
Rg R9 RIO RS R9 RIO Rg R9 R10 FIGURE S l FIGURE 52 FIGURE 53 FIGURE 54 R4 ~ ~ RI R3-p E4 F ELS R6 R7\ :Cg R4 R3 RI
$ C-~ B A D-R9 RS ~ ' \ R13 R~ , ~ N~ \ " ~ ~ \ R13 RS
\ N' .N RA \ N. .~B R10 \ N' ~N~
R6-A~ ~M ~C-R12 N\ ,~ ~N M ~ RI2 N ~N R 8 N N N~ ~N
R7 \ I D / Rll ~A \ t ~~ II ~ R7 \ \ / R11 N _ R8 R9 RIO RI7 D.C:B~IS ~B'CD R1_ R8 R9 R10 R16 Rt'~ I~13 Examples and illustrations from the literature outlined in Table 1 and Figures 1 to 57 of types of photosensitizers that may be used in photodynamic therapy or imaging and are applicable to the insertion of indium into the central core are as follows:
Dipyrromethenes: (Figure 1 ).
Dipyrromethenes have been used widely as intermediates in. the synthesis of porphyries (for example "The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume II. 215-223; Volume I, Chapter IV, 101-234. References within these volumes provide actual experimental details. These compounds can be coordinated with metal salts to produce metallo complexes (for example A.W. Johnson, LT. Kay, R. Price, K.B.
Shaw, J.
Chem. Soc, Perkin Trans .I, 3416-3424, 1959; S.M. Bloam, P.P. Garcia; J.H.
Boyer, L.R.
Morgan US Patent 5,189,029; date of patent Feb 23, 1993; L.R. Morgan, J.H.
Boyer, U.S
Patent 5,446,157). As shown in Figure 1, these molecules can be synthesized such that a wide variety of functionality can be directly attached to the basic diyrromethene ring structure. Such functionality can be used to increase water solubility, lippophilicity, ~5 conjugation to biomolecules such as antibodies or proteins, to increase the wavelength of absorption of the molecules (by increasing the conjugation of the macrocycle).
As such, these molecules can be used for light activated photochemistry or diagnosis.
Porphyries: (Figure 2) Routes to the synthesis of the ubiquitous tetrapyrrolic macrocycles that contain in 2o their macrocyclic ring system 11 double bonds (excluding peripheral substituents), is outlined in detail in several books including "Porphyries and Metalloporphyrins" Ed.
K.M. Smith, Elsevier Publishing Company, New York, 1975, Chapter 2, p29-55;
chapter 19, p778-785 and "The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I.
References within these volumes provide actual experimental details. A very large number 25 of porphyrinic compounds have been synthesized. As they are prevalent in nature, a large number of studies on the chemical modification of these compounds have been undertaken ("The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I, p 289-339.).
A great deal of work has been undertaken on the synthesis of porphyries from mono-pyrrols ("The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I, chapter 3, 85-100;
chapter 30 4, 101-234, chapter S, 235-264; chapter 6, 265-288). Notable valuable examples of such work is in the synthesis of mono, di, tri and tetraphenyl porphyries ("The Porphyries" Ed.
D.Dolphin, Academic Press, 1978, Volume I, chapter 3, 88-90; Gunter, M.J., Mander, L.N., J. Org. Chem. 46, 4792-4795, 1981.). Such compounds can be widely functionalized as the aromatic rings may possess different substituents or have incorporated in them heteroatoms. Porphyrins also can be synthesized that possess annelated aromatic rings on the (3-pyrrole positions (T.D. Lash, C.Wijesinghe, A.T. Osuma, J.R. Patel, Tetrahedron Letters, 38(12), 2031-2034. 1997.) which can have the effect of extending conjugation and modifying the absorption and photophysical properties of the compounds.
Porphyrin type compounds have been synthesized from pyrroles and 5-membered ring heterocycles (such as thiophenes or furans for example) which incorporates one or more heteroatom besides nitrogen within the central porphyrin "core" ("Porphyrins and Metalloporphyrins" Ed.
K.M. Smith, Elsevier Publishing Company, New York, 1975, Chapter 18, 729-732).
Such compounds can be modified similarly to produce highly functionalized derivatives. In addition porphyrin dimers, trimers or oligomers have been synthesized with great abandon.( H. Meier, Y. Kobuke, S. Kugimiya, J. Chem. Soc. Chem. Commun., 923, 1989;
G.M. Dubowchik, A.D. Hamilton, J. Chem. Soc. Chem. Commun.,904, 1985; R.K.
Pandey, F-Y. Shaiu, C.J. Medforth, T.J. Dougherty, K.M. Smith, Tetrahedron Letters, 31, IS 7399, 1990; D.R. arnold, L.J. Nitschinsk, Tetrahedron Letters, 48, 8781, 1992; J.L.
Sessler, S. Piering, Tetrahedron Letters, 28, 6569, 1987; A. Osaku, F.
Kobayashi, K.
Maruyama, Bull. Chem. Soc. Jpn, 64, 1213, 1991 ).
Chlorins: (Figures 3, 16, 17, 31-34, 47-54) Chlorins or Hydroporphyrins are porphyrins that have only 10 double bonds in 2U their macrocyclic ring system (excluding peripheral substituents). The "reduction" of the porphyrin macrocycle has pronounced effects on both the absorption profile of the macrocycle and the photophysical properties of the compound. Many naturally occuring chlorins may be extracted from plants, seaweeds or algae (e.g. "Porphyrins and Metalloporphyrins" Ed. K.M. Smith, Elsevier Publishing Company, New York, 1975, 25 Section H, p774 -778.) and simple chemical modifications to pheophorbide can give pyrropheophorbides, chlorin e6, purpurin 18 and other chlorin ring systems.
Routes to the synthesis of chlorin macrocycles are outlined in "Porphyrins and Metalloporphyrins" Ed.
K.M. Smith, Elsevier Publishing Company, New York, :1975, Chapter 2, p61-116;
Chapter 19, 774-778, "The Porphyrins" Ed. D.Dolphin, Academic Press, 1978, Volume II, p 1-37, 3o p131-143. References within these volumes provide actual experimental details.
Considerable research has been directed toward the synthesis of chlorin derivatives from porphyrins. Catalytic hydrogenation and hydroboration (H.H. Inhoffen, J.W.
Buchler, R.
Thomas, Tetrahedon Letters, 1145, 1969;.), diimide reductions (H.W. Whitlock Jr., R
Hanauer, R., Oester, m.Y., B.K. Bower, J. Am. Chem. Soc. 91, 7585, 1969), osmium tetroxide (R. Bonnett, A.N. Nizhnick, M.C. Berenbaum, J. Chem. Soc. Chem.
Comm., 1822, 1989) and hydrogen peroxide (C,K, Chang, Biochemistry, 19, 1971, 1971.) , alkali metals and electrochemical reduction (N.S. Hush, J.R. Rowlands, J. Am. Chem.
Soc., 89, 5 2976. 1967), aromatic radicals ( G.L. Closs, L.E. Closs, J. Am. Chem. Soc, 85, 818, 1963) have all been successful at producing chlorins from porphyrins. The use of light as a reductive tool has also been extensively studied by several authors. The reaction of singlet oxygen on vinyl porphyrin has been used extensively to produce chlorins (H.H.
Inhoffen, H. Brockman, K.M. Bleisnerv, Ann. Chem. 730, 173, 1969; D. Brault, C. Vever-Bizet, to Mougee, C., Bensasson, R., Photochem. Photobioi.. 47 151, 1988). The reduction of free base and metalloporphyrins with light and and reducing agents (such as amines or ascorbates) (Y. Harel, J. Manassen, J. Am. Chem. Soc., 100, 6228. 1977: J.H.
Fuhrhop, T.
Lumbantobing, Tetrahedron Letters, 2815, 1970; D.G. Whitten, J.C., Yau., F.A.
Carol, J.
Am. Chem. Soc., 93, 2291, 1971.) also produces chlorins. Cyclization of meso-acrylate t5 containing porphyrins has been used extensively to produce purpurin derivatives (Figure 16 and 17) (A.R. Morgan, N.C. Tertel., J.Org. Chem., 51, 1347, 1986) while acid cyclization of meso-acrolein porphyrins has been used extensively to produce benzochlorins (Figure 13.) ( M.G.H, Vincente, LN. Rezzano, K.M. Smith, Tetrahedron Letters, 31, 1365, 1990; M.J. Gunter, B.C. Robinson, Tetrahedron., 47, 7853, 1991). Diels 20 alder addition of dienophiles with vinyl containing porphyrins has been used extensively to produce chlorins ( Figures 49-54) (R. Grigg, A.W. Johnson, A. Sweeney, Chem.
Commun., 697, 1968, H.J. Callot, A.W. Johnson, A. Sweeney, J. Chem. Soc.
Perkin Trans. I, 1424, 1973; V.S. Pangka, A.R. Morgan, D.Dolphin J.Org. Chem. 51, 1094, 1986;
P. Yon-Hin, T.P. Wijesekera, D.Dolphin, Tetrahedron Letters, 32, 2875, 1991;
P. Yon-25 Hin, T.P. Wijesekera, D.Dolphin, New. J. Chem, 16, 527, 1992; A.R. Morgan, D.Skalkos, G.M. Garbo, R.W. Keck, S.H. Selman J. Med. Chem. 34, 1991).
Acetamidoporphyrins can be cyclized to produce chlorins via a intramolecular Vilsmeier reaction (G.L.
Collier, A.H.
Jackson, G.W., Kenner, J. Chem. Soc., C., 564, 1969). Recently, chlorin analogues of Purpurin 18 based on purpurin 18, have been produced that possess nitrogens on the cyclic 30 "anhydride" ring system (Figure 35, A or B = NR) (A.N. Kosyrev, G. Zheng, E. Lazarou, T. J. Dougherty, K.M. Smith, R. Pandey, Tetrahedron Letters, 38, 3335, 1997).
Bacteriochlorins and isobacteriochlorins: (Figures 4, 5, 35 to 46) Bacteriochlorin and isobacteriochlorins are tetrahydroporphyrins. These derivatives have only nine double bonds in their macrocyclic ring system (excluding peripheral groups). The "double" reduction of the porphyrin nucleus at the pyrrole positions has a. pronounced effect on the absorption properties and photophysical properties. Typically bacteriochlorins absorb in the 720-850nm range while isobacteriochlorins absorb in the 500-650nm range ("The Porphyrins" Ed.
D.Dolphin, Academic Press, 1978, Volume III, Chapter 1; References within these volumes provide actual experimental details). Examples of the synthesis of bacteriochlorins and t0 isobacteriochlorins may be found in the following references; H, H
Inhoffen. P. Jager and R. Mahlhop and C.D. Mengler, Justus Liebigs Ann. Chem. 704, 188, 1967; H, H
Inhoffen, P. Jager and R. Mahlhop and C.D. Mengler, Justus Liebigs Ann. Chem.
704, 188, 1967; H. Mittenzwei, Hoppe-Seyler,s Z. Physiol. Chem. 275, 93, 1942; H.
Brockmann Jr., G . Knobloch, Arch. Mikrobiol, 85, 123, 1972; J.J. Katz, H.H., Strain, A.L., Harkness, M.H. Studier, W.A., Svec, T.R. Janson, B.T. Cope, J. Am. Chem Soc. 94, 7983, 1972; D. Dolphin C. Bruckner, Patent No: 5,648,485, Date of Patent Jul.
15, 1997;
D. Dolphin, P.Y. Hin, T. Wijesekera Patent No: 5,149,708, Date of Patent: Sept 22, 1992;
H.W. Whitlock, R. Hanauer, M.Y. Oester, B.K. Bower, J. Am. Chem Soc. 9I, 7485, 1969;
H, H Inhoffen, H. Sheer, Tetrahedron Letters, 1115, 1972; H, H Inhoffen, J.W.
Buchler, R.
Thomas, Tetrahedron Letters, 5145, 1969; J.H. Fuhrhop, T. Lumbantobing.
Tetrahedron Letters, 2815, 1970; A. Scherz, Y. Saloman, L. Fiedor European patent No:
0584,552 A2;
A. Scherz, Y. Saloman, L. Fiedor U.S patent No: 5,650,292; (A.N. Kosyrev, G.
Zheng, E.
Lazarus, T. J. Dougherty, K.M. Smith, R.Pandey, Tetrahedron Letters, 38, 3335, 1997).
In particular, osmium tetroxide has proved useful in the synthesis of ~3,~3 dihydroxy-bacteriochlorins and isobacteriochlorins from chlorins (R.K. Pandey, T.J.
Dougherty, K:M. Smith, F.Y. Shiau, U.S. Patent No: 5,591,847) and the acid rearrangement of these derivatives has produced numerous bacteriochlorin derivatives.
The treatment of porphyrins and chlorins with hydrogen peroxide has been used to produce bacteriochlorins and isobacteriochlorins (H.H. Tnhoffen, W. Nolte, Justus Liebigs Ann. Chem. 725, 167, 1969). Diets alder addition of dienophiles with porphyrins containing two ~i-vinyl substituents has been used extensively to produce bacteriochlorins and isobacteriochlorins (R. Grigg, A.W. 3ohnson, A. Sweeney, Chem. Commun., 697, 1968, H.J. Callot, A.W. Johnson, A. Sweeney, J. Chem. Soc. Perkin Trans. I, 1424, 1973. ;
P. Yon-Hin, T.P. Wijesekera, D.Dolphin, Tetrahedron Letters, 32, 2875, 1991;
A.R.
Morgan, D.Skalkos, G.M. Garbo, R.W. Keck, S.H. Selman J. Med. Chem. 34, 1991).
Phthalocyanines and Naphthalocyanines;, (Figure 6, 18, 21-24, 28-30) Phthalocyanines and phthalocyanine analogues are perhaps some of the most widely studied photosensitizers in the field of photodynamic therapy and are also widely used as optical recording media. As such the number of structurally different phthalocyanine derivatives is enormous. Not only can the peripheral functionality be widely varied which changes the electronic spectra and photophysics of the compounds, but metallation of the macrocycle also results in photophysical changes. In addition carbons in the aromatic rings may be substituted with heteroatoms (such as nitrogen, sulphur phosphorus) that change markedly the photophysical properties of the compounds.
Examples of references that disclose the formation of such compounds are;
"Phthalocyanines Properties and Applications, Eds. C.C. Leznoff, A.B.P. Lever, VCH
Publishers Inc., 1989; "The Phthalocyanines", Eds, F.H. Moser, A.L. Thomas, CRC Press, t5 Volumes I and II, 1983; "The Porphyries" Ed. D.Dolphin, Academic Press, 1978, Volume I, Chapter 9, p 374-380, References within these volumes provide actual experimental details; A.K. Sobbi, D.Wohrle, D. Schlettwein, J. Chem. Soc. Perkin Trans. 2, 481-488, 1993; J.H. Weber, D.H. Busch, Inorg. Chem. 192, 713, 1988.; R.P. Linstead, F.T. Weiss, J. Chem. Soc., 2975, 1950; M.E. Kenney, N.L. Oleinick, Patent No: 5,166,197, date of 2o patent Nov 24, 1992; M.E. Kenney, N.L. Oleinick, Patent No: 5,484,778, date of patent Jan 16. 1996; P. Gregory, S.J. Reynolds, R.L. White, Patent No: 5,484,915, date of patent:
Jan 16, 1996. A great number of binuclear phthalocyanines / napthalocyanines have been synthesised which share a common benzene or naphthalene ring (J. Yang, M.R.
Van De Mark, Tetrahedron Letters, 34, 5223, 1993; N. Kobayashi, HY. Higashi, T. Osa, 25 Chemistry letters, 1813, 1994.
Azoporphyrins: (Figures 18, 20, 21, 30, 55) Porphyries that possess at least one meso-nitrogen linking atom are called azoporphyrins. The number of meso-nitrogen linking atoms may be extended from one to four. Phthalocyanines and Naphthalocyanine may be regarded as tetraazoporphyrins with 30 extended conjugation due to annelated benzene and napthalene rings. The synthesis of mono, di, tri and tetraazoporphyrin analogues is discussed in "The Porphyries"
Ed.
D.Dolphin, Academic Press, 1978, Volume I, Chapter 9, p 365-388;
"Phthalocyanines Properties and Applications, Eds. C.C. Leznoff, A.B.P. Lever. VCH Publishers Inc., 1989;
WO 00/00204 PC'T/US98/13601 "The Phthalocyanines", Eds, F.H. Moser, A.L. Thomas, CRC Press, Volumes I and II, 1983. References within these volumes provide actual experimental details. The synthesis of a series of tetrabenzotriazoporphyrins and tetranapthotriazoporphyrins has recently been published (Y-H, Tse, A. Goel, M. Hue, A.B.P. Lever, C.C. Leznoff , Can. J.
Chem. 71, 742, 1993.) and clearly it can be envisaged that chemistry typical of phthalocyanine chemistry and porphyrin chemistry may be applied to these compounds, such that hetero atoms may be introduced into the annelated benzene or napthalene rings.
Unsymmetrical benzonaphthoporphyrazines (Figures 25-27, 57 ) Unsymmetrical tetraazoporphyrins that have both a benzene and a naphthalene to annelated unit in the macrocyclic ring system are loosely called benzonaphthoporphyrazines. The synthesis of these derivatives is carried out using classical phthalocyanine syntheses however, using mixed aromatic dinitriles (U.
Michelsen, H. Kliesch, G. Schnurpfeil, A.K. Sobbi, D. Wohrle, Photochem.
Photobiol, 64, 694, 1996; S.V. Kudrevich, H. Ali, J.E. Van Lier: Canadian Patent No:
2,130,853 Filed 25 t 5 / 8/ 1994). References to the synthesis of these macrocycles can also be found in "Phthalocyanines Properties and Applications, Eds. C.C. Leznoff, A.B.P. Lever, VCH
Publishers Inc., 1989; "The Phthalocyanines", Eds, F.H. Moser, A.L. Thomas, CRC Press, Volumes I and II, 1983.
Texaphyrins: (Figure 12) 2o Texaphyrins are tripyrrol dimethene derived "expanded porphyrin"
macrocycles who's central core is larger than that of a porphyrin. The reaction of diformyl tripyrranes with functionalized aromatic diamines in the presence of a metal, gives rise to functionalized metallated texaphyrins (J.L. Sessler, G.W. Hemmi, T.D. Mody, LT.S. Patent No: 5,252,720; J.L. Sessler, G.W. Hemmi, T. Murai, U.S. Patent No: 4,935,498;
D.
25 Magda, J.L Sessler, B. Iverson, P.L. Jansen, M. Wright, T D. Mody, G.W.
Hemmi, U.S.
Patent No: 5,567,687).
Pentaphyrins and Sapphyrins:_ (Figures 10,11).
Sapphyrins and pentaphyrins are fully conjugated macrocycles that possess five pyrrole units. Structural analogues of the sapphyrins and pentaphyrins are outlined in 30 "Porphyrins and Metalloporhyrins", Ed. K.M. Smith, Elsevier, Chapter 18, p750-751;
"The Porphyrins Ed. D Dolphin, Academic Press, NY, Chapter 10, p351-356;
Broadherst et al, J. Chem. Soc. Perkin Trans. I , 2111, 1972; J.L Sessler, V. Kral, U.S.
Patent 5,543,514).
Porphycenes: (Figure 8).
Porphycenes are isomeric analogues of porphyrins that have eleven double bonds in their macrocyclic core that are derived formally by a mere reshuffling of the pyrrole and methine moieties. Routes to the synthesis of functionalized porphycenes are outlined in the following references; E.Vogel, C. Richert, T. Benninghaus, M. Muller, A.D.
Cross.
U.S. patent 5,409,900; E.Vogel, C: Richert, T. Benninghaus, M. Muller, A.D.
Cross. U.S.
patent 5,262,401: E.Vogel, P.A. Koch, A. Rahbar, A.D. Cross. U.S. patent 5,244,671;
E.VoQel, M. Muller, A.D., O. Halpern, Cross. U.S. patent 5,610,175; E.Vogel, M. Muller, A.D.> O. Halpern, A.D. Cross. U.S. patent 5,637,608; E.Vogel, C. Richert, T.
Benninghaus, M. Muller, A.D. Cross. U.S. patent 5,179,120; D. Martire, N. Jux, P. F.
Armendia, R.M. Negri, J. Lex, S. E. Braslavsky, K. Schaffner, E. Vogel. J. Am.
Chem.
Soc.. 114, 1992; N. Jux, P. Koch, H. Schmickler, J.Lex, E.Vogel. Angew. Chem.
Int. Ed.
Engl. ?9, 1385, 1990.
Corroles; (Figure 57) is Corroles contain an aromatic 18 electron chromophore. The synthesis and structural modifications of these compounds (such as N-alkylation) are discussed in detail in "The Porphyrins" Ed. D.Dolphin, Academic Press, 1978, Volume I, Chapter 9, p 357-363 and in "Porphyrins and Metalloporphyrins" Ed. K.M. Smith, Elsevier Publishing Company, New York, 1975, Chapter 18, p730 -749.
2o It will be appreciated that various changes and modifications can be made from the specific details of the invention as disclosed above, and as described in the foregoing examples and that, in its essential details, the invention is a composition which is comprised essentially of a non-radioactive indium atom complexed with the inner nitroaens of a pyrrolic core composed of at least two pyrroles, with the proviso that fully 25 unsaturated porphyrins having the structures:
R3 R12 R.~
Z '~ ~ RS
R11 \ In RIO
N~ \N
RI ~ ~~ ~ ~ R6 R9 R8 Rl where R 1, R2, R4 and R6 are methyl, R8, R 10, R 11 and R 12 are hydrogen, and and R8 are CH~CH2COR 13 (where R 13 is a moiety which results from the removal of H from an amino acid), and where R 1 is CH(OH)Me, R is alkyl, and R'' is a residue derived by removing H
from an amino acid are excluded.
Preferably, the invention is a composition which is comprised essentially of a non-_ radioactive indium atom complexed with the inner nitrogens of a tetrapyrrolic core, with 10 the proviso that the fully unsaturated porphyrins identified above are excluded. A non-radioactive indium atom complexed with the inner nitrogens of a photosensitive compound having a dihydro or tetrahydro tetrapyrrolic core is another preferred composition of the invention.
Other preferred families of compounds according to the invention have the ~5 structures of Figs. 1 to 58> above. Specifically, one preferred family has the structure of Fig: 2, where each of R1 through R12 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, vinyl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 12R 12, CN, OH, OR 12, CHO, (CH,,)"OH, (CH.,}"SH, (CH2)"O-alkoxy, (CH2)"SR 12, (CH,,)"OR 12 (where n = l, 2, 3, 4, and R 12 is a functional group less than or 2o equal to 100000 daltons), (CH2)"C02R12 (where R12 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH~)nCONHR12, (CHZ)~CON(R12)" C02R12 (where R12 is a functional group less than or equal to 100000 daltons), SR12 (where R12 is a functional group less than or equal to 100000 daltons), S03H, S03R12, S02NHR12, 25 SOZN(R 12)x, SO~N(R 12)3+X' (where R 12 is a functianal group less than or equal to 100000 daltons and X is a charge balancing ion).
Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecuie, with the exclusions noted above when the pyrrolic core is fully unsaturated.
Still another preferred family has the following structure:
R
where each of R1 through R14 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)~C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, COCH3, (CH2)"OH, (CH,,)"SH, (CH,)"O-alkoxy, (CHZ)"SRIS, (CH2)"ORIS (where n = 1, 2, 3, 4, and R15 is a functional group less than or equal to 100000 daltons), (CHz)~CO.,R15 (where RIS is H, a physiologically acceptable salt, alkyl ( I-6 carbons), aryl, substituted aryl, alkenyi, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR15, (CH.,)~CON(R 15)x, CO~R 15, CONHR 15, CON(R 15)." (where R 15 is a functional groups less than or equal to 100000 daltons), SR 15 (where R 15 is a functional group less than or equal to 100000 daltons), .SO;H, SO~R 15, SO~NHR 15, SO~N(R 15)x, SO~N(R
15)3TX' (where RIS is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In"z, In"5 or a mixture of In"~ and In"5; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, proteins or biomolecules.
M in the foregoing formula can also be Pd, Sn, Pt, Al, Ru, Ga.
Another preferred family has the following structure:
Where each of R1 through R4 is selected from SO;H (or a salt thereof), SO~NHRS, CO~H
(or a salt thereof), CONHRS, OH, ORS (wherein RS is a alcohol or ether containing group), amide, N(CH3)~, N(Et)~ .
M is In"~, In"5 or a mixture of In"3 and In ~ 1 s Z is a halide, acetate, OH.
M in the foregoing formula can also be Pd, Sn, Pt, Al, Ru, Ga.
Another preferred family has the following structure:
=, D_ _D
Where each of A, B, C, D and E is C, N, N+R (where R is alkyl charged or uncharged) or combinations thereof;
M is In"3, In' ~5 or a mixture of In"3 and In''S and Z is a halide, acetate, OH.
M is the foregoing formula can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
B~C.D
i i A L' Still another preferred family has the structure:
R13 Rll RIO
R16 ~ ~M~ ~ R8 RI
R'i R4 RS R6 Where each of R1 through R16 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)~ X- (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), NR17R17, CN, OH, OR17, CHO, COCH;, CH(OR17)CH3, (CH2)~OH, (CH2)"SH, (CH2)"O-alkoxy, (CH2)"SR17, (CH2)"OR17 (where n = l, 2, 3, 4, and R17 is a functional groups less than or equal to 100000 daltons), (CH2)nC02R17 (where R17 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkyinyl, and n=1, 2, 3, 4), (CH2)nCONHR17, (CH2)nCON(R17)2" COZR17, CONHR17, CONR17R17, SR17 (where R17 is a functional groups less than or equal to 100000 daltons), ~5 SO~H. SO~R17, SO~NHR17, SO~N(R17)~, SO~N(R17)3+X- (where R17 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In ~ ~ ~> In ~ ~ s or a mixture of In ~ ~ ~ and In ~ ~ s; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkyne, or functional groups less than or equal to 100000 daltons, proteins or biomolecules.
Yet another family has the structure:
RI
Where each of Rl through R4 is S03H (or a salt thereof), SO~NHRS, CO~H (or a salt thereof), CONHRS, OH, ORS (wherein RS is a alcohol ar ether containing group), amide, N(CH3)~, N(Et)2.
M is In' i~', In' 15 or a mixture of In"3 and In"5 s Z is a halide, acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Still another family has the structure:
B~C.D
i ii A~,E
~Z
B=A \ N\ I ~N"' A=B' C, ~ ~ ~M ~ ~ ,C
D-E N ~N E-D
A
B
is Where each of A-E is C, N, or N+R (where R is a charged or uncharged alkyl group);
M is In"3, In"5 or a mixture of In"3 and In"5 Z is halide, acetate, or OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
~5 Another family has the structure:
R10 ~ R1 C9 ~ ~ ~ R'?
\ t 1 N Z N "' R3 ,,M\
~ R4 Where each of R 1 through R 10 is H, halide, alkyl, cyclic alkyl ( 1-6 carbons), aryl, 2o substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide; ester, CH=CHCH~N(CH;)~, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR11R11, CN, OH, OR11, CHO, COCH3, CH(OR 11 )CHI, (CH2)~OH, (CH~)"SH, (CHZ)~O-alkoxy, (CHZ)~SR 11, (CH2)nOR 11 (where n = 1, 2, 3, 4, and R11 is a functional groups less than or equal to 100000 daltons), (CH.,)nCO2R11 (where R11 is H, a physiologically acceptable salt, alkyl (1-6 carbons), 5 aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=l, 2, 3, 4), (CH~)~CONHR11, (CHZ}~CON(R11}." CO,,R11, CONHR11, CONR11R11, SR11 (where R11 is a functional groups less than or equal to 100000 daltons), S03H, S03R11, SO,,NHR11, SO.,N(R11)2, SO~N(R11)~+X- (where R11 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In"3, Inns or a mixture of In~~3 and In"5 ; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, proteins or biomolecules.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure immediately above, where each of R 1, R2, R6, R7 is CO~H (or a salt thereof), or COZR 11 (where R 11 is alkyl or aryl).
Each of R3 and R8 is methyl or ethyl.
Each of R4; R5, R9, R10 is methyl, ethyl alkyl, CH~CHZCO,H (or salts therof), or 2o CHzCH~COZRI l (where R11 is alkyl or aryl).
M is In"3, In' n or a mixture of In"i and In"5 and Z is a halide , acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Still another family of compounds has the structure:
R10 ~ ~ R1 ;9 ~ \~ ~~ ~ R2 M\
R8 N~~ N
R6--<~
WO OOI00204 PCT/US98/13b01 Where each of R 1-R 10 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)3 X~ (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), NR11R11, CN, OH, OR11, CHO, COCH3, CH(OR11)CH;, (CH,)~OH, (CHZ)~SH, (CH.,)~O-alkoxy, (CH~)nSRI l, (CH.,)~OR11 (where n = 1, 2, 3, 4, and R11 is a functional group less than or equal to 100000 daltons), (CH,)~CO.,R 11 (where R 11 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=I, 2, 3, 4), (CH,)~CONHR11. (CHz)nCON(R11)." CO,,R11, CONHRI 1, CONR11R11, SRI I
(where R11 is a functional groups less than or equal to 100000 daltons), S03H, S03R11, SO,NHR11, SO,N(R11)," SO~N(R11)~+X- (where R11 is a functional groups less than. or equal to 100000 daltons and X is a charge balancing ion); M is In"3, In"5 or a mixture of t5 In"' and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl; substituted alkynyl, or a functional group less than or equal to 100000 daltons, proteins or biomolecules.
Another family of compounds has the structure:
0 ~ ~~-Rl R9 ~ ~~ ~ ~R2 N\ Z,.N_' R3 M\
R8 N~~ N
R7 ~ / ~ R4 R6 ~
Where each of R1-R10 is H, halide, alkyl, cyclic alkyl (3-6 carbons}, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyil, amide, ester, CH=CHCH~N(CH3)~ , CH=CHCH,N+(CH;)~ X- (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), NR11R11, CN, OH, OR11, CHO, COCH3, CH(OR11)CH3, (CHZ)"OH, (CH2}~SH, (CH2)~O-alkoxy, (CH2)nSRll, (CH2)"OR11 (where n = l, 2, 3, 4, and R11 is a functional group less than or equal to 100000 daltons), to (CHZ)~CO.,R11 (where R11 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH,)~CONHRI 1, (CHZ)nCON(R11)2, C02R11, CONHR11, CONR11R11, SR11 (where RI1 is a functional group less than or equal to 100000 daltons), S03H, S03R11, SOZNHRl l, SO~N(R11)2, SO~N(R11)3+X- (where R11 is a functional groups less than or ~5 equal to 100000 daltons and X is a charge balancing ion); M is In~'3, In"5 or a mixture of In"3 and In"s ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family has the structure:
Ri where each of R 1, R2, R6, R7 is CO~H (or a salt thereof), COZR 11 (where R 11 is alkyl or aryl).
each of R3 and R8 is methyl or ethyl.
each of R4, R5, R9, R10 is methyl, ethyl, alkyl, CH~CH~CO~H (or a salt therof), or to CHZCH~CO~R11 (where R11 is alkyl or aryl).
M is In ~ ~ ~, In ~ 15 or a mixture of In ~ ~ ~ and In' ~ 5 ; and Z is a halide . acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Yet another family of compounds has the following structure;
R13 ~ N Z'N_ RS R4 ~ I ., M\
R11 R12 N~' N
RIO ~ / / R6 R9 ~ R7 l5 Where each of Rl-RI4 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl> substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH3); X- (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), NR 15R 15, CN, OH, OR 15, CHO, COCH3, 20 CH(OR15)CHj, (CH.,)nOH, (CH.,)"SH, (CH2)~O-alkoxy, (CH.,)~SR15, (CH2)nORlS
(where n = l, 2, 3, 4, and R 15 is a functional groups less than or equal to 100000 daltons), (CHZ)nCO.,R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4}, (CH2)~CONHR15, (CH.,)nCON(R15)." C02R15, CONHR15, CONR15R15, SR15 (where R15 is a functional group Iess than or equal to 100000 daltons), S03H, S03R15, SO~NHR15, SO~N(R15)." SO~N(R15)~+X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In"3, Ins ~5 or a mixture of Ins ~3 and In~'S ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
to Still another family of compounds has the structure:
14 ~R 1 ~I /'' R2 R13 ~ N\ Z''N- ~ R4 M\
R1l R12 N~~ N
R10 ~ / / R6 R8~ R7 Where each of R 1, R2, R3, R4, R8, R9, R 10, R 11 is CN
Each of RS and R 12 is methyl or ethyl.
Each of R6, R7, R13 and R14 is methyl, ethyl, alkyl, CH~CH~CO~H (or salts thereof), or CHZCH~CO~R 15 (where R 15 is alkyl, aryl).
M is Ins ~3, Ins ~5 or a mixture of Ins ~3 and Ins ~s.
2o Z is a halide , acetate, or OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure:
R7 ~ ~ ~~ N' Rl N~ Z,.N R2 O
O R6 \ N.,M~N /
~'N ~/~~~
5 Where each of R1-R8 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), NR9R9, CN, OH, OR9, CHO, COCH3, CH(OR9)CH~, (CH,)nOH, (CH.,)nSH, (CH.,)~O-alkoxy, (CH2)~SR9, (CH2)~OR9 (where n - 1, 2, 3. 4, and R9 is a functional group less than or equal to 100000 daltons), (CH2)nC02R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHZ)"CONHR9, (CH2)~CON(R9)2, C02R9, CONHR9, CONR9R9, SR9 (where R9 is a functional groups less than or equal to 100000 daltons}, S03H, S03R9, SOZNHR9, 15 SO.,N(R9)~, SO~N(R9)3+X- (where R9 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion): M is Ins ~3, Ins ~5 or a mixture of In~'3 and In"5 ; Z
is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
Another family of compounds has the structure:
R7 \ ~ ~ N R1 N\ Z,.N R2 O
M' R6 N~~ N
R5_N~~ ~/~~~
where each of R 1 and RS is alkyl or aryl.
Each of R2 and R6 is methyl or ethyl.
Each of R7, R8, R3, and R4 is methyl, ethyl alkyl, CH,CH~CO~H (or a salt therof), or CH~CH~COZR9 (where R9 is alkyl or aryl).
M is In~~~, In~~s or a mixture of In~'3 and In~ls.
to Z is a halide , acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Yet another family of compounds has the structure:
RI ~ ~T ~j ~ R4 N Z N '-~i;
R9 ~ M~ ~ R11 R8 N~, N
R7 ~ / / RS
i R6 Where each of R1-R14 is H, halide, methyl, ethyl, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)~C(X)3 (where X is a halogen), NR 15R 15, CN, OH, OR 15, CHO, COCH3, CH(OR15)CH3, (CH2)"OH, (CH2)"SH, (CH.,)"O-alkoxy, (CH2)nSRlS, (CHZ)nORlS
(where n = l, 2, 3, 4, and R15 is a functional groups less than or equal to 100000 daltons), (CH.,)nCO.,R15 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl. alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl and n=1, 2, 3, 4), (CH,)~CONHR15> (CH,)"CON(R15)." CO~R15, CONHR15, CONR15R15, SR15 (where R 15 is a functional group less than or equal to 100000 daltons and n=
i, 2, 3, 4), SO~H, SO~R15, SO,NHR15, SO,N(R15)" SO~N(R15)~+X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M
is In~'3, In ~ I 5 or a mixture of In ~ ~; and In I ~ 5 Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
M can also be Pd. Sn, Pt, Al, Zn, Ru, Ga.
IU
Another family of compounds has the structure:
RI ~ ~'~ ~' ' R4 N Z N"
M\
I / ~ RS
where each of R1-R8 is ethyl or methyl R9 is CH;, _SO,NH(CH.,CH.,O)nCH~ (n=1 to 1000), SO.,N((CH2CH,0)~CH~)., (n=1 to 1000); SO,NH(CH,)~OH (n=1 to 1000), CH~~ SO,N((CH,CH.,)nOH), (n=1 to 1000);
SO,NC((N(CH3}.,)., ; SO,NH(CH,)nN(CH~)., (n=1 to 1000); S02NH(CH,)nSH (n=1 to 1000); SO.,NHC(CH.,CH.,OH)~; SO,NHCH2CO,H (or salts thereof);
SOZNH(CH.,)~CH(NH.,)CO.,H (or salts thereof) (n=1 to 5); SO,,NHCH2COZR10 (R10 is alkyl, aryl); SO~NH(CH.,)nCH(NH~}CO,R10 (R10 is alkyl, aryl) (n=1 to 5) M is Ins ~;, Ins ~5 or a mixture of Ins ~~ and Ins ~5 Z is a halide > acetate, OH.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure:
RI ~ ~~ ~~ ~ R4 N Z N-R8 N ~, N
RS
where each of R1-R8 is ethyl or methyl.
to R9 is; CH2CO.,NH(CH.,CH~O)~~CH-~ (n=1 to 1000}, CH=CO.,N((CH.,CH.,O)nCHz)., (n=1 to 1000); CH,CO~NH(CH,)"OH (n=1 to 1000), CH,CO,N((CH,CH.,)~OH), (n=1 to 1000);
CH,CO,NC((N(CH~),)~ ; CH,CO,NH(CH.,)~N(CH~)., (n=I to 1000);
CH.,CO,NH(CH.,)~SH (n=1 to 1000); CH,,CO,NHC{CH.,CH~OH)a ;
CH,,CO,NHCH,CO,H _(or salts thereof); CH~CO~NH(CHZ)nCH(NH,)CO,H (or salts l5 thereof) (n=1 to 5); CH~CO,NHCH~C02R10 (R10 is alkyl or aryl);
CH2CO~NH(CH.,)"CH(NH.,)CO.,R10 (R10 is alkyl, aryl) (n=1 to 5) M is Inll~, Inl IS or a mixture of Inl l3 and Inl Is Z is a halide , acetate, OH.
M can also be Pd, Sn. Pt, Al, Zn, Ru, Ga.
20 Another family has the structure:
N
R' ~\~Z \ ~RS
N\I ~N
N~ /M\ ~N
N N
RI- ~ , i / Rb N
where each of R1-R8 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)~C(X)~ (where X is a halogen), NR9R9, -CN, OH, OR9, CHO, COCH~, (CH2)~OH, (CH.,)"SH, 25 CH(OR9)CH~, (CH,)"O-alkoxy> (CH,,)"SR9, (CH,,)"OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH,)~CO,R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl; alkynyl or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)"CONHR9, (CH,)"CON(R9),,, CO~R9, CONHR9, CONR9R9, SR9 (where R9 is a functional groups less than or equal to 100000 daltons), SO~H, SO~R9, SO~NHR9, SO,N(R9)2, s SO~N(R9)~+X- (where R9 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion); M is In"3, In ~'s or a mixture of In"3 and In" s;
Z is a halide , acetate, OH; alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl.
alkynyl, substituted alkyinyl, protein or biomolecule or functional group less than or equal to 100000 daitons.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
to Another family of compounds has the structure:
R3 R4 ~5 R6 p gyp; B.
C~R7 N' R1 ~ N ~;N=C Rg N~ ~1~ ~N
A
R16-C~ N ~B-R10 B; A' where each of R 1-R 17 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, 15 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester.
C(X),C(X)3 (where X is a halogen), NR18R _ -18, CN, OH, DRIB, CHO, COCH;, (CH.,)~OH, (CH.,)"SH, CH(OR18)CH~, (CH,)"O-alkoxy, (CH.,)~SR18, (CH,,)"OR18(where n = 1, 2, 3, 4, and R5 is a functional group less than or equal to 100000 daltons), (CHZ)"CO,,R 18 (where R 18 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, 20 substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR18, (CH.,)nCON(R18)~ , CO~R 18, CONHR 18, CONR 18R 18, SR 18 (where R 18 is a functional groups less than or equal to 100000 daltons), SOX, S03R18, SO~NHR18, SO~N(R18)2, SO~N(R18)3+X~ (where R18 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In"3, In"s or a mixture of Inl3 and In"s; Z
is a halide, 25 acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyil, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, or Ga.
Still another family has the structure:
R4 / ~ R8 R9 C D \A~B II RIO
R-;-" R6 R7 /A ~.E Fi Rll N
~F \ ~E~R12 \i N\I,~N
N\ M\ /N
R24 ',, N ~R13 ~ /R14 D~F F'/ -A
R22-C' ~ \R19 R18 ''~~ _ ~B-R15 B' A \ R20 R:17 Rl6 5 where each of R I-R24 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenvl: substituted alkenyl, alkynyl, substituted alkynyl, amide, ester.
C(X)~C(Xl~ (where X is ya halogen), NR25R25, CN, OH, OR25, CHO, COCH3 , (CH2)"OH, (CH2)~SH, CH(OR25)CH.~, (CH~)"O-alkoxy, (CH.,)"SR25, (CH2)"OR25 (where n = 1, 2, 3, 4, and R25 is a functional groups less than or equal to IQ0000 daltons), (CHz)nCO,,R25 (where 10 R25 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)nCONHR25; (CH.,)"CON(R25)~ , CO~R25, CONHR25, CONR25R25> SR25 (where R25 is a functional group less than or equal to 100000 daltons). SO~H. SO~R25, SO~NHR25, SO~N(R25)~, SO,N(R25)z~X- (where R25 is a functional group less than or t5 equal to 100000 daltons and X is a charge balancing ion); M is Inll~, In115 or a mixture of In' 13 and Inl Is ; A, B, C> D, E, F are; C, N, O+, O, S, Te, P, N+(R25)X-(where R25 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl> alkynyl, substituted alkynyl, protein or biomolecule or functional 2o group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
z NvI/N.
R3 ~ /M\
N N
H~ 11 t H
Ft4 X
where each of R1- RS is CH~CHj, CH=CHI, CH=CHCH~N(CH3)~ CH=CHCH~N+(CH3lz X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCH~, CO~H, CO~R6, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons), CH=CHCH20H, CH=CHCH~OR6, CH(OH)CH~, CH(OR6)CH~, H, halide, alkyl, cyclic alkyl (1-6 carbons}, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, OH, OR6, (CH,,)~OH, (CH2)"SH, (CHZ)~O-alkoxy, (CH2)~SR6, (CH2)"OR6 (where n = 1, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH.,)nCO.,R6 (where R6 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted ~5 alkynyl, and n=1, 2, 3, 4), (CH,)nCONHR6, (CH~)~CON(R6)~, CO~R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltonsj.
SO~H. SO~R6, SO~NHR6, SO~N(R6)~, SO~N(R6);+X- (where R6 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); X is . O, 2H, (H, OH), S, (H, OR6} or a ketone protecting group; M is In"3. In"5 or a mixture of In";
and In"5 ; Z
2o is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkyinyl, protein or biomolecule or functional group Iess than or equal to 100000 daltons.
M can also be Pd, Sn, Pt, Al, Zn, Ru, Ga.
Still another family of compounds has the structure:
wherein:
R 1 is CH=CHI, CHO, Et, COCH
R2 is CO~CH~ ,COSH, amide R3 and R4 are H
RS is CH;
XisO
to M is In' ", Ins ~5 or a mixture of Ins" and Ins ~5 Z is a halide, acetate or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Pt, Ru, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Sn, Pt, Al, Zn, Ru, Ga.
Another family of compounds has the structure:
RI
\ ' Z
20 R~ N' ~ ~N
M\
__ N N
where each of Rl- R6 is; CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)~
X~ (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH~, CO~H, CO~R7, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, 3o OR7 or is a functional group less than or equal to 100000 daltons), CH=CHCH~OH, CH=CHCH~OR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, OH, OR7, (CH,)"OH, (CH2)"SH, (CH2)"O-alkoxy, (CH2)"SR7, (CH,)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH,)~CO,R7 (where R7 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH,)"CONHR7, (CH2)"CON(R7)~, CO~R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), SO~H, SO~R7, SO,NHR7, SO~N(R7)~, SO~N(R7)~+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In~~~, In~~S or a mixture of In ~ ~' and In ~ ~ s ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, protein or biomolecuie or functional group less than or equal to 100000 daltons; with the proviso that when R2 =
CO,,NHR6, R6 can not be a mono- or di-carboxylic acid of an amino acid.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zr, preferably .Pd, Pt.
Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
where each of R1- R6 is; CH~CH~, CH=CHI, CH=CHCHZN(CH~)~, CH=CHCH~N+(CH~)3 X- (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH;, CO~H, CO~R7, CONHR7, CH=CHCHO, CHZY, (where Y = H, halogen, OH, OR7 or is a functional gro~lp less than or equal to 100000 daltons), CH=CHCH~OH, ~5 CH=CHCH~OR7, CH(OH)CH~, CH(OR7)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, OH, OR7, (CH,)~OH, (CH.,)~SH, (CH,)~O-alkoxy, (CHZ)"SR7, (CH,)"OR7 (where n = l, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH.,)~CO.,R7 (where R7 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH,)nCONHR7, (CH,)"CON(R7)~, COZR7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), S03H, S03R7, SO~NHR7, SO~N(R7),, SO~N(R7)~+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In~~~, In~~S or a mixture of Inl~3 and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than I U or equal to 100000 daltons.
Still another family of compounds has the following structure:
r Z r NvI~N
R'i ~ ~M\
__ N N
~ 5 wherein;
R 1 is CH=CHI, CHO, Et, COCH;
R2 is CO~CH
R3 is H
R4 is CH~CO~CH;, CO~CH3, CH~CO~H (or a salt thereof), CO~H (or a salt thereof).
20 RS is CH3 R6 is CO~H, CO,Me or an amide M is In~ ~~, In~ ~5 or a mixture of Ins i~ and Ins 15 Z is a halide, acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Nd, Pb, Pd, 25 Pr, Pt, Rh, Sb, Sc, Sm. Sn, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, Zn, or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the structure:
Rl _ \I/
R7 ~ /M\ ~ R 13 N y R8 \ ~ ~~ /~R12 Ry R10 R11 where each R1-R13 is H, halide, alkyl, vinyl, cyclic alkyl (3-6 carbons), aryl, substituted 5 aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)3 X~ (where X is a charge balancing ton), C(X)~C(X)~ (where X is a halogen), NR14R14, CN, OH, OR14, CHO, COCH; , (CH.,)"OH, (CH~)"SH, (CH~)~O-alkoxy, CH(OH)CH~, CH(OR14)CH3 (CH2)"SR14, (CH,,)"OR14 (where n = 1, 2, 3, 4, and R14 is a functional group less than or equal to 100000 daltons), (CHZ)"COZR14 (where R14 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, _and n=1, 2, 3, 4), (CH.,)"CONHR14, (CH2)~CON(R14)~, CO~R14, CONHR14, CONR 14R 14. SR 14 (where R 14 is a functional group less than or equal to daltons); SOX. SO,R14, SO~R14, SO~NHR14, SO~N(R14),, SO~N(R14)~TX- (where R14 15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion):
M is In ~ ~ ~, In ~ ~' or a mixture of In ~ ~ ~ and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, suibstituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Still another family of compounds has the, following structure:
where each of R1 and R2 is CO~R14 (where R.14 is alkyl or aryl), CO~H (or a salt therof), SO~Ph, or CN;
R3, R6, R8, and R 12 are Me.
RS is CH=CHZ, or CH(OR 14)CH~ (where R 14 is alkyl or aryl) R4, R7, R 13, R 10 are H
R9, R 11 are CH~CH~CO~R 15 (where R 15 is alkyl or H or a salt of the carboxylic acid) M is Ins ~3, Ins ~5 or a mixture of Ins ~~ and Ins ~5 ; Z is a halide , acetate, OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb. Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the following structure:
Rl RS R6 N.Z.N_ I
3 ~ M, /
H N N
/ /
H ~
2o where each of R 1- R7 is CH~CH~, CH=CHI, CH=CHCH~N(CH,)z , CH=CHCH~N+(CH;)3 X- (where X is a charge balancing ion), C(X)~C(X)z (where X is a halogen), CHO, 's a functional group less than or equal to 100000 daltons), CH~CO~RB, OR8 or i HRB, CH=CHCH~OH, CH=CHCH20R8, CH(OH)CH3, CH(OR8)CH3, H
CH~CON
1 c clic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, halide, alky , Y
substituted alkynyl, amide, ester, NR8R8, CN, OH. ORB, CHO, (CH~)"OH, alkynyl, H CH.,)"O-alkoxy, (CH~)~SRB, (CH2)"OR8 (where n = 1, 2, 3, 4, and R8 is a (CH.,)nS , ( 1 rou less than or equal to 100000 daltons), (CH~)~CO.,R8 (where R8 is H, a functiona g p 'call acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, physiologi y alken l, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)"CONHRB, substituted Y
CON(R8)~, CO~RB, CONHR8, CONR8R8, SR8 (where R8 is a functional group (CH~)n an or equal to 100000 daltons), S03H, S03R8. SO~NHRB, SOaN(R8)2, less th where R8 is a functional group less than or equal to 100000 daltons and X
SO~N(R8)~
r a balancing ion), protein or biomolecule or functional group less than or equal to is a cha g tons; X is O, H2, (H, OH), S, (H, OR8) or a ketone protecting group; M is 100000 dal ~'s or a mixture of In"3 and ~'~5; Z is a halide , acetate, OH, alkyl, aryl, In ' uted ar 1, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or t 5 substit Y
biomolecule or functional group less than or equal to 100000 daltons.
lso be A , Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Mcana g b Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y~ ~ or Zr, preferably Pd, Pt, Ga, Al or Ru.
Pt, Rh, S , 2p Still another family of compounds has the following structure:
\ N, Z ,N=
3 \ NMvN.
H. w I
H
X
wherein;
R 1 = COCH3 R3 and R5 = H, CHI
R~ = H or OH
25 R6 = Me or OH
R4 = H or CO~CH3 R2 = CO~R8 (where R8 is alkyl ) M is Ins ", In' 15 or a mixture of Ins ~~ and Ins ~5 Z is a halide, acetate, or OH.
X=O
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, A1 or Ru.
Another family of compounds has the structure:
R3_- R1 Rl3 R6 ~ A M~D ~ R 12 R7 \ ). i~/ R11 LO
werein each of R 1-R 13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH;)~ , CH=CHCH~N+(CH;)~ X' (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), NR 14R 14, CN, OH, OR 14, CHO, (CH.,)"OH, (CH,)"SH, (CH,)~O-alkoxy, CH(OH)CH~, CH(OR14)CH~ (CH,,)"SR14, (CH~)"OR14 (where n = 1, 2, 3, 4, and R14 is a functional group less than or equal to 100000 daltons), (CH,)"CO,,R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=l, 2, 3, 4), _(CH.,)"CONHR 14, (CH.,)~CON(R 14)?, CO?R 14, CONHR 14, CONK 14R 14, (where R 14 is a functional group less than or equal to 100000 daltons), S03H, SO~R 14, SO~NHR 14, SO~N(R 14)x, SO~N(R 14)~+X' (where R 14 is a functional group less than or equal to 2000 daltons and X is a charge balancing ion); A, B, C, D are; C, N, O+, O, S, Te, P or combinations thereof; M is In~~~, In~IS or a mixture of In~~3 and In~~S;
Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sn, Sm, Tb, Th, Ti, Tl, Tm, Lt, V, Y, Yb, Zn, Zr.
Still another family of compounds has the following structure:
RS ~ N Z N=--R6-A~ ~M~ ~C-R12 N N
R ~ ~ ~ ~ R1t D
Rg R9 810 were each of RI-813 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl> substituted alkynyl, amide, ester, CH=CHCH~N(CH~)a , CH=CHCH2N+(CH3)3 X (where X is a charge balancing ion), C(X}~C(X)~ (where X is a halogen), NR 14814, CN, OH, OR 14, CHO. (CH~)~OH, CH SH, (CH.,)n0-alkoxy, CH(OH)CH~, CH(OR14)CH3, (CH,,)"SR14, (CH,,)"OR14 ( ~)n _ (where n = 1, 2, 3, 4, and 814 is a functional group less than or equal to 100000 daltons), tp (CH2)nCO,,Rl4 (where 814 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4); (CH~)"CONHR14, (CH.,)"CON(R14)~, CO~R14, CONHR14, CONK14814, SR14 14 is a functional group less than or equal to 100000 daltons), SO~H, SO~R14, (where R
S02NHR14> SO~N(R14)~, SO~N(R14)~+X- (where 814 is a functional group less than or ~5 equal to 100000 daltons and X is a charge balancing ion); A, B, C, D are;
C, N, O+, O, S, Te, P or combinations thereof; M is In! ~~, Ins ~5 or a mixture of Ins ~3 and Ins ~5; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl>
substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
20 M can also be Ag, Al, Ce, Co, Cr, Cu, Dy. Er. Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sn, Sm, Tb. Th, Ti, Tl. Tm, U, V, Y, Yb, Zn or Zr.
Another family of compounds has the following structure:
.i.
R7 \ ,M, / R l3 N N
R \ ~ i~/ R12 were each of R 1-R 13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, 5 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CHz)~ , CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), NR 14R 14, CN, OH, OR 14, CHO, (CH~)"OH, (CH.,)nSH, (CH2)n0-alkoxy, CH(OH)CH3, CH(OR14)CH3 (CH~)"SR14, (CH2)nORl4 (where n = 1, 2, 3, ~4, and R 14 is a functional group less than or equal to 100000 daltons), l0 (CH,) CO~R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted- alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)~CONHR14, (CH2)nCONH(R14)~, CO~R14, CONHR14, CONR14R14, SR14 (where R14 is a functional group less than or equal to 100000 daltons), SO~H, SO~R14, SO~NHR14, SON{R14)~, SO~N(R14)3+X- (where R14 is a functional group less t5 than or equal to 100000 daltons and X is a charge balancing ion); M is In."~. In"5 or a mixture of In"; and In"5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, 20 Pd, Pr, Pt, Rh, Sb, Sc, Sn, Sm, Tb, Th, Ti, Tl, Tm, U, V,1', ~. Zn or Zr.
Another family of compounds has the following structure:
R6 ~ / 1 N. Z.N_ R7 ~ . ~M~ ~ R 13 N N
n . 11 _I ~ R12 Where each of R 1 and R2 is CO~R 14 (where R 14 is alkyl or aryl), CO~H (or a salt 5 thereof), SO~Ph, CN or a combination thereof;
Each of R3, R6, R8, R 12 is Me.
RS is CH=CHI, or CH(OR 14)CH~ (where R 14 is alkyl or aryl) Each of R4, R7, R 13, R 10 is H
R9 and R11 are CH~CH~CO~R15 (where R15 is alkyl or H or a salt of the carboxylic 10 acid).
M is In''3, Inns or a mixture of In''3 and ~"5 Z is a halide , acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R7 R6 R4 R i 1 ~ RS
N\Z/N_ R9 ~ ~1v1\ ~ Rl5 N N
R l 0 \ 1~ i~ / R 14 where each of R1-R15 is H, halide, alkyl, vinyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH~)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)2C(X)~ (where X is a halogen), NR 16R 16, CN, OH, OR 16, CHO, COCH3 , (CH2)"OH, (CH.,)nSH, (CH.,)"O-alkoxy, SO~Ph, CH(OH)CH~, CH(OR14)CH3 (CH,,)"SR 16, (CH2)"OR 16 (where n = 1, 2, 3, 4, and R 16 is a functional group less than or equal to 100000 daltons), (CH,)"CO,,R16 (where R16 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)"CONHR16, (CH2)~CON(R16)~, CO~R16, CONHR 16, CONR 16R 16, SR 16 (where R 16 is a functional group less than or equal to 100000 daltons), SOX, SO~R16, SOZNHR16, SON{R16)Z, SO~N(R16)~+X- (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion);
o M is In~~~, In~~S or a mixture of In~~3 and Inl'S ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Pt; Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R6 R4~~~ R 1 \ N\Z/y R9 ~ ~M~ ~ R15 N N
RIO ~ ~ ~~ / R14 Rll R12 R13 where each of R1, R2, R3 and R4 is CO~R16 (where R16 is alkyl or aryl), CO2H
(or a salt thereof) or SO~Ph, CN;
Each of R5, R8, R 10 and R 14 is Me.
R7 is CH=CHI or CH(OR 16)CH~ (where R 16 is alkyl or aryl) Each of R6, R9, R 12 and R 15 is H
Each of R 11 and R 13 is CH2CH~CO~R 16 (where R 16 is alkyl or H or a salt of the carboxylic acid), or an amide M is Ins ~~, Ins 15 or a mixture of Ins ~~ and Ins ~5 Z is a halide , acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd. Pb, Pd, Pr. Pt. Rh. Sb, Sc. Sm, Tb, Th. Ti. TI, Tm. U, V, Y. Yb or Zr. preferably Pd. Pt, Ga, Al. Ru. Sn or Zn.
Still another family of compounds has the following structure:
R5 ~ R3 t R7-A N\M N~C-R13 i N N
R ~ 1 ~ / Rl2 D
R9 Rip R11 Where each of RI-R13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, to alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH~N(CH;)2 , CH=CHCH~N+(CH~)3 X' (where X is a charge balancing ion), C(X)zC(X); (where X is a halogen), NR14R14, CN, OH, OR14, CHO, (CH~)~OH, (CH,,)"SH, (CH~)n0-alkoxy, CH(OH)CH~, CH(OR14)CH3 (CHZ)"SR14, (CH,,)"OR14 (where n = l, 2, 3, 4, and R14 is a functional group less than or equal to 100000' daltons), (CH,)"CO,R 14 (where R 14 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4): (CH,)~CONHR 14, (CH,)"CON(R 14)x, CO~R 14, CONHR 14, CONR 14R 14. SR
(where R 14 is a functional group less than or equal to 100000 daltons). SO~H, S03R 14.
SO~NHR 14, SO~N(R 14)~> SO~N(R 14)3+X- (where R 14 is a functional group less than or 2o equal to 100000 daitons and X is a charge balancing ion); A, B, C, D are;
C, N, O+, O, S, Te, P or combinations thereof; M is In"3, Inns or a mixture of In~~3 and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf. Ho, In, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the structure:
R3 R i i R4 R2 ~ B~ ~ R5 i R10-A N'M N C-Ri2 ~- N~ ~N'''~
Ri~ 11 _) ~R6 R9 ~ R7 R 14~R 13 Where each of R1-R14 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl> amide, ester, CH=CHCH~N(CH~)z , CH=CHCH~N+(CH~)3 X' (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), NR15R15, CN, OH, OR15, CHO, (CH2)"OH, (CH~)nSH, (CHZ)~O-alkoxy, CH(OH)CH3, CH(OR15)CH3 (CH,,)"SR15, (CH,,)"OR15 (where n = 1, 2, 3, 4, and R 15 is a functional group less than or equal to 100000 daltons), (CH2)"COZR15 (where R15 is H, a physiologically acceptable salt, alkyl {1-6 carbons), to aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)"CONHR 15, (CH2)"CON(R 15)z, COZR 15, CONHR 15, CONR 15R 15, SR
(where R15 is a functional group less than or equal to 100000 daltons), SO~H, S03R15, SO~NHR15, S02N(R15)~, SO~N(R15)3+X' (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); A, B, C, D are; C, N, O+, O, S, i5 Te, P or combinations thereof; M is In"3, In"5 or a mixture of In~'~ and In~~S ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, 2o Pd, Pr, Pt, Rh, Sb, Sc, 5m, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr.
Another family of compounds has the following structure:
R
5 Where each of Rl-R4 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)ZC(X)z (where X is a halogen), CHO, COCH~, CO~H, CO~RS, CONHRS, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, ORS or is a functional group less than or equal to 100000 daltons), CH2CO~R5, CHZCONHRS, CH=CHCH20H, CH=CHCH20R5, CH(OH)CH;, CH(ORS)CH3, H, l0 halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NRSRS, CN, OH, ORS, CHO, (CH2)"OH, (CH~)~SH, (CH,)~O-alkoxy, (CH.,)"SRS, (CHZ)nORS (where n = 1, 2, 3, 4, and R5 is a functional group less than or equal to 100000 daltons), (CHI) CO,,RS (where RS
is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, t5 substituted alkenyl, alkynyl, or substituted alkynyl, arid n=1, 2, 3, 4), (CHZ)"CONHRS, (CH~)"CON(RS)~ , CO~RS, CONHRS, CONR5R5, SRS (where RS is a functional group less than or equal to 100000 daltons), SO~H, S03R5, SO~NHRS, SO~N(RS)~, SO~N(RS)~+X' (where RS is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecules or functional groups less than or equal 2o to 100000 daltons; A and B are O, NH, NRS or combinations thereof; X is , O, NRS
(where R5 is H, alkyl ( 1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynylk, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); M is Ins ~'~, Ins ~5 or a mixture of Ins ~~
and Ins ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyi, substituted alkenyl, alkynyl, 25 substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Rt R4 M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R~C R R7 Where each of Ri- R8 is CH~CH;, CH=CH2, CH=CHCH2N(CHa)2, CH=CHCHZN+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, to COCH;, CO~H, CO~R9, CONHR9, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CHZC02R9, CH~CONHR9, CH=CHCH~OH, CH=CHCH~OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, OH, OR9, CHO, (CH2)"OH, ~ 5 (CH~)"SH, (CH,)"O-alkoxy, (CH.,)"SR9, (CH~~"OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH2)"C02R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH2}nCONHR9, (CH,)~CON(R9)2, CO~R9, CONHR9, CONR9R9, SR9 (where R9 is a functional group 20 less than or equal to 100000 daltons), S03H, SO~R9, SOZNHR9, S02N(R9)2, SO~N(R9)~+X- (where R9 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, HZ, (H, OH), (H, OR9), S, or a ketone protecting group; M is Ins ~3, Ins ~5 or a mixture of Ins ~3 and Ins ~5 ; Z is a halide , acetate, OH, alkyl, aryl, 25 substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkyinyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
N~ i ,N~
3 \ My /
H N N
HA~X~B
Where each of RI- R6 is CH~CH3, CH=CHI, CH=CHCH~N(CHj)~ , CH=CHCH~N''(CH3)~
X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCH3, C02H, CO~R7, CONHR7, CH=CHCHO, CHZY, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CHZC02R7, CHZCONHR7, CH=CHCH~OH, CH=CHCH20R7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, OH, OR7, CHO. (CH~)"OH, (CH2)"SH, (CH,,)"O-~5 alkoxy, (CH~)"SR7, (CH~)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH,,)nCO,,R7 (where R7 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHZ)"CONHR7, (CHZ)~CON(R7)2, CO~R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 20 100000 daltons), SO;H, SO~R7, SO~NHR7, SO~N(R7)2, SO~N(R7)3+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is , O, NR7 (where R7 is H, alkyl (1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, au amino acid ester or a functional 25 group less than or equal to 100000 daitons); A and B are O, NH, NR7 or combinations thereof; M is In113, In ~ ~ 5 or a mixture of In ~ ~ ~ and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, thereof; M is In ~ ~ ~, In ~ ~ 5 or a mixture of In ~ ~'~ and In ~ 15 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 dalions.
M can also be Ag, Ce, Co, Cr, Cu, Dy> Er, Fe, Hf, Ho, :La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc. Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
\ /RS
n R~ R6 \ ' Z ' N~i~N
N N
II .l HA~X~B
wherein;
R1 is CH=CHI, Et, CHO, or COCH, R2 is CO~CH~, CO~H, CO~R7 (R7 is an alkyl, phenyl), oz an amide R3isH
~ 5 R4 is Me Each of RS and R6 is OH
Each of A and B is O or NR7 ( R7 is alkyl).
X is O or NR7 (R7 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is Ins ~3; Ins is or a mixture of Ins ~3 and Ins ~5 Z is a halide , acetate, or OH.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, AI, Ru, Sn or Zn.
Another family of compounds has the following structure:
RI
N Z N
.I.
H_ N N
H
where each of R 1- R6 is CH~CH~, CH=CHI, CH=CHCH~N(CH3)2 , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)ZC(X)~ (where X is a halogen), CHO, COCH~, CO~H, CO~R7, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH~CO~R7, CH~CONHR7. CH=CHCH~OH, CH=CHCHZOR7, CH(OH)CH3, CH(OR7)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, l0 alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, (CH2)"OH, (CH,)"SH, (CH,,)"O-alkoxy, (CHz)"SR7, (CH2)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH2)~C02R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH,)~CONR7, i 5 CO~R7, CONHR7, CONR l OR7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), S03H, S03R7, SO~NHR7, SOZN(R7}~, SO~N(R7)~+X' (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, HZ, (H, OH), (H, OR8) S, or a ketone protecting group; M is In~~3, Inls or a mixture of 2o In ~ ~ ~ and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu. Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, AI, Ru, 25 Sn or Zn,.
Another family of compounds has the following structure:
\ ~z~
N, ~ .N
3 \ ;~~ /
H N N
/ /
H
_ R4 X
wherein;
5 Rl is CH=CHI, Et, CHO, or COCH
R2 is CO~CH3, CO~H, COZR7 (R7 is an alkyl or phenyl group), or an amide R3 is H
R4 is H or COZCH3 RS is O or NR7 (where R7 is alkyl) R6 is Me XisO
M is In ~ ", In ~ ~ 5 or a mixture of In ~ " and In ~ ~ 5 Z is a halide , acetate or OH.
M can also be Ag, Ce, C'.o, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, ~5 Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
R 1 ,~ R7 \ N,Z,N
3 \ My H~ N N
H ~ R8 2o where each of Rl- R8 is CH~CHa, CH=CHI, CH=CHCH~N(CH3)2, CH=CHCH~N+(CHj)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH;, CO~H, CO~R9, CONHR9, CH=CHCHO, CHzY, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CH2CO~R9, CH~CONHR9, CH=CHCH~OH, CH=CHCH~OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, O, S, NHR9, OH, OR9, CHO, (CH2)~OH, (CH.,)"SH, (CH,)~O-alkoxy, (CH,,)"SR9, (CH,,)"OR9 (where n = l, 2, 3, 4, and R9 is a functional groups less than or equal to 100000 daltons), (CH~)~CO.,R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHZ)~CONHR9, l0 (CH.,)~CON(R9)~, CO~R9, CONHR9, CONR I OR9, SR9 (where R9 is a functional groups less than or equal to 100000 daltons), S03H, SO;R9, SO~NHR9, SO~N(R9)~, SO~N(R9)~+X- (where R9 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In ~ ", In ~ ~ s or a mixture of In ~ 13 and In ~ ~ 5;
Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the following structure:
RI ~
~
~
Z .
N, i .N
\ /
My N
N
wherein;
RI is CH=CH2, Et, CHO, or COCH;
RS is O or NR7 (where R7 is alkyl) R7 is Me R3 is H
R4 and R8 are H, CO~CH~, CO~H (or a salt thereof), CO~R7 (R7 is an alkyl or phenyl group), an amide, CH~CO~CH~, CH~CO~H (or a salt thereof), CO~R9 (R9 is an alkyl or a phenyl group), or an amide R2 is CO~CH~, CO~H, CO~R9 (R9 is an alkyl or phenyl group), or an amide M is Ins ~;, Ins ~s or a mixture of Ins ~3 and Ins is Z is a halide , acetate, or OH.
M can also be Ag, Ce. Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
\ N'Z~N
M\
H 11 _I
H A~X~B
where each of Rl- RS is CH~CH3> CH=CHI, CH=CHCH~N(CH~)2, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen j, CHO, COCH~, CO~H, CO~R6, CONHR6, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons), CH2CO~R6, CH~CONHR6, CH=CHCH~OH, CH=CHCH~ORB, CH(OH)CH~, CH(OR6)CHa, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, 2o alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, O, S, NHR6, OH, OR6, CHO, (CH.,)~OH, (CH,)~SH, (CH~)"O-alkoxy, (CH~)"SR6, (CH2)~OR6 (where n = l, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH,,)nCO,,R6 (where R6 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH~)nCONR6, CO~R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltons), SO~H> SO~R6, SO~NHR6, S02N(R6)~, SO~N(R6)~+X- (where R6 is a functional group less than or equal to 100000 daltons), S03H, SO~R6, S02NHR6, SO~N(R6)~, SO~N(R6);+X' (where R6 is a functional group less than or equal to daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, NR6 (where R6 is H, alkyl ( 1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); A and B
are O, NH, NR6 or combinations thereof; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc. Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, AI, Ru, S
or Zn.
Another family of compounds has the following structure:
t5 \ ' Z ' N~M,N
H N y 11 l HA~X~B
Wherein:
Each of A and B is O or NR6 (where R6 is an alkyl or phenyl group) R 1 is CH=CHI, Et, CHO, or COCH3 20 R4 is O or NR6 (where R6 is alkyl) RS is Me R3 is H
R2 is CO~CH~, CO~H, CO~R6 (R6 is an alkyl or phenyl group), or an amide X is O, NR6 (R6 is alkyl, an amino acid, an alcohol containing group, or an ether 25 containing group) M is In ~ 1 ~, In ~ ~ 5 or a mixture of In ~ ~' and In ~ ~ 5 Z is a halide , acetate, OH.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm. Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the following structure:
\ N. Z,N-'' H N N' H
Where each of Rl- R6 is CH~CHz, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH3, CO~H, CO~R7, CONHR7, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH,C02R7, CH~CONHR7, CH=CHCH~OH, CH=CHCHzOR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, ~5 (CH.,)~OH, (CH~)~SH, (CH,,)"O-alkoxy, (CH.,)"SR7, (CH~)"OR7 (where n = 1, 2, 3, 4, and R7 is a functional groups less than or equal to 100000 daltons), (CH,)nCO,,R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)~CONR7, CO~R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 20 100000 daltons), SO~H, SO~R7, SO~NHR7, SO~N(R7)z, SO~N(R7)3+X' (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, HZ, (H, OH), (H, OR7), S, or a ketone protecting group; M is Ins ~~, In~ ~5 or a mixture of Ins ~3 and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted 25 alkenyl, alkynyl, substituted alkynyl, protein or biomolecules or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er. Fe, Ga. Hf, Ho, La. Lu. Mo, Mg, Nd, Pb. Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, ' Sn or Zn.
5 Another family of compounds has the structure:
\ N, Z.N:
.3 \ N M, N
H n .t H
wherein;
Rl is CH=CHI, Et, CHO, or COCH3 R6 is O or NR7 (where R7 is an alkyl group) RS is Me R3 is H
R4 is H or CO~CH
~ 5 R2 is CO~CHz, CO~H, CO~R7 (R7 is an alkyl, phenyl), or an amide XisO
M is Ins ~'. Ins ~5 or a mixture of Ins ~~ and Ins ~5 Z is a halide , acetate, or OH.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, 2o Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Another family of compounds has the structure:
N. Z.N
R3 ~
H~ N N
Where each of Rl- R7 is CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), CHO, COCH;, CO~H, CO~RB, CONHRB, CH=CHCHO, CH~Y,(where Y = H, halogen, OH, OR8 or is a functional group less than or equal to 100000 daltons), CH~CO~RB, CH~CONHRB, CH=CHCH20H, CH=CHCH~ORB, CH(OH)CH3, CH(OR8)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR8R8, CN, O, S, NHRB, OH, ORB, CHO, (CH?)~OH, (CH2)"SH, (CH2)"O-alkoxy, (CH2)"SRB, (CH2)"OR8 (where n = 1, 2, 3, 4, and R8 is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R8 (where R8 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl,substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH?)nCONRB, CO~RB, CONHRB, CONR8R8, SR8 (where R8 is a functional groups less than or equal to 100000 daltons), SO~H, SOzRB, SO~NaRB, SO~N(R8)2, SO~N(R8)3+X- (where R8 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecules or functional groups less than or equal to 100000 daltons; M is In"~, In"S or a mixture of In"j and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecules or functional groups less than or equal to 100000 daltons.
Another family of compounds has the structure:
~ ~TZ~ R6 N.,.N-R3 ~ M, /
H~ N N
H
wherein;
R 1 is CH=CHI, Et, CHO, or COCH
R6 is O, or NR8 (where R8 is alkyl) R5 is Me R3 is H
R4 and R7 are H, CO~CH~, CO~H (or a salt thereof), CO~R8 (R8 is alkyl or phenyl), an amide, CH~CO~CH3, CH~CO~H (or a salt thereof), CO~R8 (R8 is an alkyl or phenyl group) R2 is CO~CHz, CO~H, CO~R8 (R8 is alkyl or phenyl), or an amide to M is Ins ~3, Ins ~5 or a mixture of Ins ~3 and In~~s Z is a halide , acetate, OH.
M can also be Pd Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
IS
Another family of compounds has the following structure:
\ N,Z,N
H N N
HA~X~B
2o Wherein:
R 1 is CH=CHI, Et, CHO or COCH
R4 is Me R3 is H
R2 is CO~CH~, CO~H, COZRS (R5 is alkyl or phenyl), or an amide Each of A and B is O or NRS ( RS is alkyl) X is O, NRS (R5 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is In"~, In"5 or a mixture of In"3 and In"5 .
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, l0 Sn or Zn.
Another family of compounds has the structure:
n ~RR7 \ N, Z,N
.3 N N
Wherein: RI is CH=CHI, Et, CHO or COCH3 i 5 Each of R6 and R7 is H or OH
RS is Me R4 is CO~CH~, CO~H, CO~R9 (R9 is an alkyl or a phenyl group), an amide, CH~CO~CH~, CH~CO~H, or CH~CO~R9 (R9 is an alkyl or a phenyl group).
R3isH
2o each of R2 and R8 is CO~CH~, CO~H, CO~R9 (R9 is an alkyl or a phenyl group), or an amide M is In";, In"5 or a mixture of In"~ and In"5 Z is a halide , acetate, or OH.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, 25 Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the structure:
Rt R4 I Z ,I RS
N~ i ~ N--i~~ /
H N N
~i .r , H
X~ ~ B
wherein each of R1-RS is CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH;)~ X' (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH3, CO~H, CO~R6, CONHR6, CH=CHCHO, CH~Y, (where Y = H, halogen, OH or OR6 or is a functional group less than or equal to 100000 daltons), CHZCO~R6, CH~CONHR6, CH=CHCH~OH, CH=CHCH~OR6, CH(OH)CH~, to CH(OR6)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, O, S, NHR6, OH, OR6, CHO, (CH.,)"OH, (CH,)"SH, (CH.,)"O-alkoxy, (CH,,)"SR6, (CHZ)~OR6 (where n = 1, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH.,)~~CO.,R6 (where R6 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, ~5 substituted aryl, alkenyl, substituted alkenyl. alkynyl, or substituted alkynyl. and n=1, 2, 3, 4), (CH~)~CONR6, CO~R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltons), S03H, SO;R6, SO~NHR6, SO~N(R6)~, SO~N(R6)3+X- (where R6 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecule or functional group less than or equal to 20 100000 daltons; ; A and B are O, NH, NR6 or combinations thereof; X is , O, NR6 (where R6 is H, alkyl (1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); M is Ins ~'~, In' ~s or a mixture of Ins ~~ and Ins ~5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted 25 alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf> Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
5 Still another family of compounds has the structure:
Rl R4 RS
N~ ~ ,N'-\ ~Mv /
N N
HA~X~B
wherein:
R 1 is CH=CHI, Et, CHO or COCH
RS is O or NR6 (where R6 is alkyl) R4 is Me R3isH
R2 is CO~CH~, CO~H, CO~RS (RS is alkyl or phenyl), or an amide A and B are O or NR6 (R6 is an alkyl or a phenyl group) ~ 5 X is O, NR6 (R6 is alkyl), an amino acid, an alcohol containing group, or an ether or amine containing group M is In ~ ~ ~, In ~ ~ s or a mixture of In ~ ~ ~ and In ~ ~ 5 Z is a halide. acetate. or OH.
M can also be Ag, Ce, Co, Cr> Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd.
Pb, Pr or 2o Rh, preferably Ga, AI, Ru, Sn or Zn.
Still another family of compounds has the structure:
R8~
R_3 / R6 R7v A ~R 10 A~C D
R2 p w N, \ CC
Rl ~ N.2 N=( ~R12 N, .~ N
R~4 N N ,R13 C \ ' N~ ~ ~ ~R14 D C , _A
R22 \ p R19 R18 / Rl5 ~R20 Wherein each of R1- R24 is CH~CH~, CH=CHCH~N(CH3)2 , CH=CHCH~N+(CH;)3 X-(where X is a charge balancing ion), CH=CHI, C(X)~C(X)3 (where X is a halogen), CHO, COCH~, CO~H, CO~R25, CONHR25, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR25 or is a functional group less than or equal to 100000 daltons), CH~CO~R25, CHZCONHR25, CH=CHCH~OH, CH=CHCH~OR25, CH(OH)CH3, CH(OR25)CH3, H, to halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR25R25, CN, O, S, NHR25, OH, OR25, CHO, (CH,,)"OH, (CH.,)"SH, (CH~)"O-alkoxy, (CH~)~SR25, (CH2)"OR25 (where n =
1, 2, 3, 4, and R25 is a functional group less than or equal to 100000 daltons).
(CH~)~CO~R25 (where R25 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH~)~CON(R25)~, (CH2)"CONHR25, CO~R25, CONHR25, CONR25R25, SR25 (where R25 is a functional group less than or equal to 100000 daltons), S03H, S03R25, S02NHR25, SO~N(R25)2, SO~N(R25)3+X- (where R25 is a functional group less than or equal to 100000 daitons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D are: C, N, O+, O, S, Te, P, N+(R25)X- (where R2S is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), or combinations thereof; M is In ~''~, In"5 or a mixture of In'' and In"5; Z is %~ halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Yet another family of compounds has the structure:
O O
N ' , I~ N
O 'B _\ 1 N/ / A/ O
A B
X -~ \ R7 R6 ~ X
p O
Wherein each of R1-R8 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)~, a CH=CHCH~N+(CH;)~ X- (where X is a charge balancing ion), C(X)~C(X), (where X
is a halogen), CHO, COCH~, CO~H, CO~R9, CONHR9, CH=C:HCHO, CH~Y, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CH~COZR9, CH2CONHR9, CH=CHCH~OH, CH=CHCH~OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, O, S, NHR9, OH, OR9, CHO, (CH~)"OH, (CH.,)"SH, (CH,)"O-alkoxy, (CHZ)"SR9, (CHZ)"OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH.,)~CO.,R9 (where R9 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, ~5 4), (CH~)~CONHR9, (CH~)~CON(R9)~, CO~R9, CONHR9, CONR.9R9, SR9 (where R9 is a functional group less than or equal to 100000 daltons), SO~H, SO~R9, SO~NHR9, SO~N(R9)~, SO~N(R9)~+X- (where R9 is a functional group less than or equal to daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons.
2o A, B, C, D are; C, N, O+, O, S, Te, P, N+(R9)X- (where R9 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof.; M
is In ~ ~ ~, In ~ ~ 5 or a mixture of In ~ 13 and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, X R2 R-~ X
i B Ar N
~A ~ Z. B
RI \ Ny N=~ 'R4 substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, NR9 (where R9 is H, alkyl ( 1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons).
M can also be Pd or Ga.
S
Yet another family of compounds has the structure:
RS Rg _ .D
R3- D E F R6 R7~ C ~ ~.E -R I 0 C_>=B A- ~ F
R2~ ~A ~ N~ \ B \R11 R1, ~ N, Z,N~ ~R12 N. ~ N
N N ~R13 R21- D \ N / A , R I 4 ~C
:B B
0 R19 R18 F. D-RIS
' E
wherein each of R1-R22 is CHzCH3, CH=CHI, CH=CHCHZN(CH3)z , l0 CH=CHCH~N'"(CH~); X~ (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH~, CO~H, CO~R23, CONHR23, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR23 or is a functional group less than or equal to 100000 daltons), CH~CO~R23, CH~CONHR23, CH=CHCH~OH, CH=CHCH~OR23, CH(OH)CH~, CH(OR23)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, is substituted alkenyl, aIkynyl, substituted alkynyl, amide, ester, NR23R23, CN, O, S, NHR23, OH, OR23, CHO, (CH,)~OH, (CHZ)"SH, (CH.,)~O-alkoxy, (CH,)"SR23, (CH,,)"OR23 (where n = l, 2, 3> 4, and R23 is a functional group less than or equal to 100000 daltons), (CH.,)~CO~R23 (where R23 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted 2o alkynyl, and n=1, 2, 3, 4)> (CH.,)~CONHR23, (CH~)~CON(R23)~, COZR23, CONHR23, CONR23R23, SR23 (where R23 is a functional group less than or equal to 100000 daltons), SO~H, SO~R23, SO~NHR23, SOzN(R23)~, SO~N(R23)~+X- (where R23 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, 25 D, E and F are C, N, O+, O, S, Te. P, N+(R23)X- (where R23 is a functional group less than or equal to 2000 daltons and X is a charge balancing ion), or combinations thereof; M
is In ~ ~;, In ~ ~ 5 or a mixture of In ~ ~ ~ and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
' ,R5 R3- D E F ~R6 R7\ R8 C ~ B '°' ~ C p -R9 R~ N ..
A ~' Z~ ~ B\
Rl ~ ~. I .N R10 ~N
R~ N N ~1 j A \ ~ ~ / A
R17-D,C_ B N B;C.D-R12 ~R15 R[4 R13 wherein each of R1-R18 is CHZCH3, CH=CHI, CH=CHCH~N(CH3)z , CH=CHCH~N+(CH3)~ X~ (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO. COCH~, CO~H, CO~R19, CONHR19, CH=CHCHO, CH~Y, (where Y =
H, halogen. OH, OR 19 or is a functional group less than or equal to 100000 daltons), CH~CO~R 19, CH~CONHR 19, CH=CHCH~OH, CH=CHCH~OR 19, CH(OH)CH3, CH(OR 19)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl.
substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR19R19, CN, O. S, NHR19, OH, OR19, CHO, (CHZ)"OH, (CH,,)"SH, (CHZ)~O-alkoxy, (CH,)~SR19, or (CH,)"OR19 (where n = l, 2, 3, 4, and R19 is a functional group less than or equal to 100000 daltons), (CH,)~CO,R19 (where R19 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)~CONHR19, (CH2)~CON(R19)Z, CO~R19, CONHR19, CONR 19R 19, SR 19 (where R 19 is a functional group less than or equal to 2000 daltons), SO~H, S03R19, SO~NHR19, SO~N(R19)~, SO~N(R19)~+X- (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E, F are CH, N, O+, O, S, Te, P, N+(R 19)X' (where R 19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In ~ ~ ~, In ~ ~5 or a mixture of In ~ ~' and In ~ ~ 5; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, 5 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
tt4 R3= D E F ~R6 R7~ R8 C-~ B ~'~C~D-R9 A ~ N~ B
RI ~ N, Z.N- ~R10 N ~ Ivl\ ~ N
N N ~R11 R19- C \ N / A ~R12 C
.D. B~R17 R16 ~ D-R13 R18 ,F' E, wherein each of Rl-R20 is CH~CH3, CH=CHI, CH=CHCH,N(CH3)~ , CH=CHCH~N+(CH~)z X- (where X is a charge balancing ion), C(X)~C(X), (where X
is a halogen), CHO, COCH~, CO~H, CO~R21, CONHR21, CH=CHCHO, CH~Y, (where Y =
is H, halogen, OH, OR21 or is a functional group less than or equal to 100000 daltons).
CH~CO~R21, CH~CONHR21, CH=CHCH~OH, CH=CHCH~OR21, CH(OH)CH~, CH(OR21 )CHI, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR21R21, CN, O, S, NHR21, OH, OR21, CHO, (CHZ)~OH, (CHZ)"SH, (CH,)"O-alkoxy, (CHZ)"SR21, (CH~)"OR21 (where n = 1, 2, 3, 4, and R21 is a functional group less than or equal to 100000 daltons), (CH.,)~~CO,R21 (where R21 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3> 4), {CH.,)~CONHR21, (CH,)nCON(R21)~, CO~R21, CONHR21, CONR21R21, SR21 (where R21 is a functional group less than or equal to 100000 daltons), SO;H, SO~R21, SO~NHR21, SO~N(R21)~, SO~N(R21)~+X- (where R21 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E, F are: C, N, O+, O, S, Te, P, N+(R21)X' (where R21 is a functional group less than or equal to 100000 daltons and X is a charge balancing ian), or combinations thereof; M is In ~ ~ j, In ~ 15 or a mixture of Iri ~ ~ 3 and In ~ ~ s; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
to Still another family of compounds has the following structure:
R~4 p~E~RS
R3-C' R9 ~F-R6 ~ R8 ' w A, B C, R2- A \ N\ ~ ~ ~ D-R 10 R1 ~ 1'1, j ,N=~ ~12~ R11 R24 N~ ;~ ~N
R2~E'F N N ~R13 R22-D~~ ~ ~ N / B-R14 C B~A~ RIS
R~21 R20 R19 E,D n-R15 where each of R1-R24 is CH~CH~, CH=CHI, CH=CHCH~N(CH;)~ , CH=CHCH~N+(CH~)~
X' (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCH~, COzH, CO~R25, CONHR25, CH=CHCHO, CHZY, (where Y = H, halogen, OH, OR25 or is a functional group less than or equal to 100000 daltons), CH~CO~R25, CHZCONHR25, CH=CHCHZOH, CH=CHCHZOR25, CH(OH)CH~, CH(OR25)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR25R25, CN, O, S, NHR25, OH, OR25, CHO, (CH,,)"OH, (CH~)"SH, (CH.,)~O-alkoxy, (CH~)"SR25, (CH~)"OR25 (where ri =
1, 2, 3, 4, and R25 is a functional group less than or equal to 100000 daltons), (CH.,)~CO.,R25 (where R25 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH~)"CONHR25, (CH~)"CON(R25)~, CO~R25, CONHR25, CONR25R25, SR25 (where 9'' R25 is a functional group less than or equal to 100000 daltons), SO~H, S03R25, SO~NHR25, SO,N(R25)a, SO~N(R25)~+X- (where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E, F are C, N, O+, O, S, Te, P, N+(R25)X- (where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In~l3, InlcS
or a mixture of Ins" and In~~S; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
1 o M can also be Pd or Ga.
Still another family of compounds has the structure:
R7 'R6 R10 ~11 ~C-B B'Cv R12 ~4~A ~ g ~ A ~t13 A w R ~ A
R3-C' ~ N ~ '~C-R14 \ , RrB ~ N, ~ ,N- ' B~RIS
R3l R_ 21 Nv N:~N ~N R17 ~R18 B -- 1 ~ B
R30-C\~ ~ \ N ~ , ,,C-R19 A .~ R24 ~ 'A
R29 / R~5 ~ ~ R20 A, ., A- R21 R28' C-B, ,B'C
R27 R'6 R23 ~22 !5 where each of R1-R32 is CH~CHz, CH=CHI, CH=CHCHZN(CHz)Z , CH=CHCH~N+(CH3)3 X~ (where X is a charge balancing ion), C(X)2C(X) ~ (where X is a halogen), CHO, COCH~, CO~H, CO,R33, CONHR33, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR33 or is a functional group less than or equal to 100000 daltons), CH~CO~R33, 20 CH~CONHR33, CH=CHCH~OH> CH=CHCH~OR33, CH(OH)CH~, CH(OR33)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR33R33, CN, O, S, NHR33, OH, OR33, CHO, (CH.,)"OH, (CH,,)"SH, (CH,)~O-alkoxy, (CHZ)~SR33, (CH~)"OR33 (where n =
1, 2, 3, 4, and R33 is a functional group less than or equal to 100000 daltons), (CH.,)nCOZR33 25 (where R33 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,)"CONHR33, (CH~)~CON(R33}~, COZR33, CONHR33, CONR33R33, SR33 (where R33 is a functional group less than or equal to 100000 daltons), S03H, SO3R33, SO~NHR33, SO~N(R33)~, SO~N(R33)3+X- (where R33 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C are; C, N, O+, O, S, Te, P, N+(R33)X- (where R33 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is Ins 13, Im 15 or a mixture of In113 and In~ 15' Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, to alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Still another family of compounds has the structure:
l5 R3 R4 RS Rfi R2-U~V~ Y/ Rl8 \X'U iV_R7 \\ ~ ~ ~ Y\
~X
Rl ~ ~ i ~ R8 N\ M\ /N
R17 N~' N ~R9 \Y ~ ~ i ~ X
ll N U-R l0 R l6-V~
U~Xv /Y;V
Rl5 R14 R13 R.11 where each of R1-R18 is CH~CH~, CH=CH2, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)3 X' (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH;, CO~H, CO~R 19, CONHR 19, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, 2o OR19 or is a functional group less than or equal to 100000 daltons), CH~CO~R19, CH~CONHR 19, CH=CHCH~OH, CH=CHCH~OR 19, CH(OH)CH~, CH(OR 19)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 19R 19, CN, O, S, NHR 19, OH, OR 19, CHO; (CH2)"OH, (CH.,)nSH, (CH~)~O-alkoxy, (CH2)"SR19, (CH,,)"OR19 (where n =
1, 2, 25 3, 4, and R19 is a functional group less than or equal to 100000 daltons}, (CH,)~CO.,R19 (where R19 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4}, (CH.,)~CONHR 19, (CH.,)~CON(R 19)x, CO~R 19, CONHR 19, CONR l OR 19, SR 19 (where R19 is a functional group less than or equal to 100000 daltons), S03H, SO~R19, SO~NHR19, SO~N(R19)~, SO~N(R19)z+X' (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons. Lf, V, X, Y are C, N, O+, O, S, Te, P, N+(R 19}X' (where R 19 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), or combinations thereof; M is In~~~, In~~S or a mixture of In«
and In ~ ~ 5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl. substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Another family of compounds has the structure:
~5 A
R2 ~ ~~ ~ ~ RS
N N"
RI M~ R6 R8 R~
where each of R1-R9 is CH~CH~, CH=CHI, CH=CHCH~N(CH3)~ , CH=CHCH~N+(CH3)3 X' (where X is a charge balancing ion), C(X)~C(X); (where X is a halogen), CHO, 2o COCH~, CO~H, CO~R 10, CONHR 10, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR10 or is a functional group less than or equal to 100000 daltons), CH~CO~R10, CHZCONHR 10, CH=CHCH~OH, CH=CHCH~OR 10, CH(OH)CH3, CH(OR 10)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR l OR 10, CN, OH, OR 10, CHO, (CHZ)"OH, 25 (CHZ)"SH, (CH,)"O-alkoxy, (CH,)"SR 10, (CH,)"OR 10 (where n = 1, 2, 3, 4, and R 10 is a functional group less than or equal to 100000 daltons), (CH,)nCO,R 10 (where R
10 is H, a physiologically acceptable salt, alkyl (I-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CHz)~CONHR10, (CH,)~CON(R 10)x, CO~R 10, CONHR 10, CONR l OR 10, SR 10 (where R 10 is a functional group less than or equal to 100000 daltons), SO~H, SO;R10, S02NHR10, S02N(R10)2;
S02N(R10);+X- (where R10 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In ~ ~ ~, In ~ ~ s or a mixture of In ~ ~ 3 and In ~
~s .
5 M can also be Ga.
Still another family of compounds has the structure:
Rtt ~
R 12 I N\M/~ ~ R4 R 10 ~ ~ / -R5 -N N
R9 ~ ~/ R6 where each of R1-R12 is CH~CH~> CH=CH2, CH=CHCH~N(CH~)~ , CH=CHCH2N+(CH3)s X- (where X is a charge balancing ion), C(X)zC(X)~ (where X is a halogen), CHO, COCH;, C02H, C02R 13, CONHR 13, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR 13 or is a functional group less than or equal to 100000 daltons), CH2C02R
13, CH2CONHR 13, CH=CHCH20H, CH=CHCH20R 13, CH(OH)CH~, CH(OR 13)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, 15 alkynyl; substituted alkynyl, amide, ester, NR13R13, CN, OH, OR13, CHO, (CH2)"OH, (CH.,)"SH, (CH2)"O-alkoxy, (CH,,)"SR13, (CH,)~OR13 (where n = 1, 2, 3. 4, and R13 is a functional group less than or equal to 100000 daltons), (CH2)"CO,R13 (where R13 is H, a physiologically acceptable salt,- alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH2)"CONHR13, 20 (CH.,)"CON(R 13)2, C02R 13, CONHR 13, CONR 13R 13, SR 13 (where R 13 is a functional group less than or equal to 100000 daltons), SO~H, SO~R13, S02NHR13, S02N(R13)2, S02N(R 13);+X- (where R 13 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In ~ ~;, In ~ ~ s or a mixture of In ~ ~; and In ~ ~ s ; Z is a halide , acetate, 25 OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd or Ga.
Yet another family of compounds has the structure:
-w R 11 ~ ~ M n~ N
N~ '~~ I R7 R1 ~ 1 N\
R10 RIS ~
Where each of R 1- R 15 is CH~CH~. CH=CHI, CH=CHCH~N(CH~)~ , CH=CHCH~N+(CH~)~ X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH~, CO~H, COZR16, CONHR16, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR16 or is a functional group less than or equal to 100000 daltons), CHZCO~R 16, CH2CONHR 16, CH=CHCH~OH, CH=CHCH20R 16, CH(OH)CH3, CH(OR16)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 16R 16, CN, O, S, NHR16, OH, OR16, CHO, (CH,,)"OH, (CH2)~SH, (CHZ)"O-alkoxy, (CH~)"SR16, (CH~)nORl6 (where n = 1, 2, 3, 4, and R16 is a functional group less than or equal to 100000 daltons), (CH,)nCO,Rl6 (where R16 is H, a physiologically acceptable salt, alkyl ~5 (1-6 carbons), aryl, substituted aryl, alkenyl; substituted alkenyl, alkynyl, or substituted alkynyl, _and n=1, 2, 3, 4), (CH~)nCONHR16, (CH.,)~CON(R16)~, CO~R16, CONHR16, CONR 16R 16, SR 16 (where R 16 is a functional group less than or equal to daltons), SO;H, S03R16, SO~NHR16, SO~N(R16)Z, S02N(R16)3+X- (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), 20 protein or biomolecule or functional group less than or equal to 100000 daltons; M is Ins ~3, In~ ~5 or a mixture of In"3 and In' ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be M is Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, 25 Pr or Rh, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Yet another family of compounds has the following structure:
R_i R 1 I j-,w( RS
~N ~ ~ R6 Nw M n+
_."' N
N , . ~,' ~ R7 R1 v ~l .Ns s where each of R 1-R 14 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)Z , CH=CHCH~N+(CH3)s X- (where X is a charge balancing ion), C(X)ZC(X)3 (where X is a halogen), CHO, COCH3, CO~H, CO~R 15, CONHR 15, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR15 or is a functional group less than or equal to 100000 daltons), CH~CO~R15, CH~CONHR 15, CH=CHCH~OH, CH=CHCH~OR 15, CH(OH)CH;, CH(OR 15)CH~, H, to halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR15R15, CN, O, S, NHR15, OH, OR15, CHO, (CH.,)"OH, (CH~)"SH, (CH2)"O-alkoxy, (CHZ)"SR15, (CHZ)"OR15 (where n = 1, 2, 3, 4, and R 15 is a functional group less than or equal to 100000 daltons), (CH2)~C02R 15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted 15 aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)~CONHR I S, (CH~),~CON(R 15)x, CO~R 15, CONHR I5, CONR I SR 15, SR 15 (where R15 is a functional group less than or equal to 100000 daltons), SO;H, S03R15, SO~NHRIS, SO~N(R15)~, SO~N(R1S)~+X- (where R15 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or 2o functional group less than or equal to 100000 daltons; M is In"3, In"5 or a mixture of In"3 and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyI, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr or 25 Rh, preferably Pd, Pt, Ga, Al, Ru, Sn or Zn.
Still another family of compounds has the following stucture:
\~'N~~1' \
R_5 N~ , ,.N'-R10 ~ M~°~ ~ RI2 N~~ ; N
R i \ ~ . N / / R6 R8 R9 R 15 R~
where each of Rl-R15 is CH~CH3, CH=CHI, CH=CHCH~N(CH3)Z, CH=CHCH~N+(CH3)~
X- (where X is a charge balancing ion), C(X)~C(X)3 (where X is a halogen), CHO, COCHz, CO~H, CO~R16, CONHR16> CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR 16 or is a functional group less than or equal to 100000 daltons), CH~CO~R
16, CH~CONHR16, CH=CHCH~OH, CH=CHCH~OR16, CH(OH)CH3, CH(OR16)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 16R 16, CN, O, S, NHR 16, OH, OR 16, CHO, -(CHZ)"OH, (CH2)"SH, (CH2)"O-alkoxy, (CH,,)"SR16, (CH,,)"OR16 (where n =
1, 2, 3, 4, and R 16 is a functional group less than or equal to 100000 daltons), (CH2) COZR 16 (where R 16 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH.,),1CONHR16, (CH.,)~CON(R16)~, CO~R16, CONHR16, CONR16R16, SR16 (where R 16 is a functional group less than or equal to 100000 daltons), S03H, SO~R
16, SO~NHR16, SO~N(R16)~, SO~N(R16)~+X- (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or 2o functional group less than or equal to 100000 daltons; M is Inl~~, Ins ~5 or a mixture of Inl~3 and In~~s ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr> Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, or Rh> preferably Pd, Pt, Ga> Al, Ru, Sn or Zn.
Yet other families of compounds have the following structure:
N
R2 ~N' ~ .Z 1 R6 -M'N I
RI N - ~_ / R7 R10 ~-~ R11 Where each of R 1-R 12 is CHZCH3, CH=CHI, CH=CHCH~N(CH~)~, CH=CHCH~N+(CH;)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCHz, CO~H, CO~R13, CONHR13, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR13 or is a functional group less than or equal to 100000 daltons), CH~CO~R 13, CH~CONHR 13, CH=CHCH~OH, CH=CHCH~OR 13, CH(OH)CH3, to CH(OR13)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR13R13, CN, O, S, NHR13, OH, OR13, CHO, (CH2)~OH, (CH.,)"SH, (CHZ)"O-alkoxy, (CH2)"SR13, (CH,,)"OR 13 (where n = 1, 2, 3, 4, and R 13 is a functional group less than or equal to 100000 daltons), (CH~)~CO~R13 (where R13 is H, a physiologically acceptable salt, alkyl ~5 ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2. 3, 4), (CH.,)nCONHR13, (CHZ)nCON(R13)~, CO~R13, CONHR13, CONR13R13, SR13 (where R13 is a functional group less than or equal to 100000 daltons), SO~H, S03R13, SO~NHR13, SO~N(R13)Z, SOZN(R13);+X- (where R13 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), 2o protein or biomolecule or functional group less than or equal to 100000 daltons; M is In''3, In"5 or a mixture of In"~ and In"5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, Pt, Ga or Al.
Another family of compounds has the following structure:
R4 ~ R8 N
R3.D.~A ~N. ~ ,Z 1 R9 ,C ~ .M-N I
R2 ~~$ N~~' N ~ R10 R13 'R12 Where each of R1-R14 is CH~CH~. CH=CHI, CH=CHCH~N(CH~)2, CH=CHCH~N+(CH~)z X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCHz, CO~H, CO~R15, CONHR15, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR15 or is a functional group less than or equal to 100000 daltons), CH~CO~R15, CH~CONHR15, CH=CHCH~OH, CH=CHCHZOR15, CH(OH)CH3, CH(OR15)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR15R15, CN, O, S, NHR15> _OH, OR15, CHO, (CHZ)"OH, (CH~)"SH, (CH.,)~O-alkoxy, (CH~)"SR15, (CH,)"OR 15 (where n = l, 2, 3, 4, and R 15 is a functional group less than or equal to 100000 daltons), (CH~)~CO,R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH~)nCONHRIS, (CHZ)~CON(R15)~, CO~R15, CONHR15, CONR 15R 15, S R 1 S (where R 15 is a functional group less than or equal to daltons), SO~H, S03R15, SO~NHR15, SO~N(R15)2, SO~N(R15)~+X~ (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D are; C, N, O+> O, S, Te, P, N+(R15)X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In~'3, Ins ~5 or a mixture of Ins ~3 and 1n~ ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, Pt, Ga or Al.
Yet another family of compounds has the following structure:
R13'B~C\ D RI '_' R4 I I
N
,A / ~N, ~ ~Z ~ RS
R15,H N'~ ; ~ R6 N
I I
~~ Ev RIO ~ ~7 R16 i R18 Where each of R1-R18 is CH~CH~, CH=CHI, CH=CHCH~N(CH;)2, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH3, CO~H, CO~R19, CONHR19, CH=CHCHO, CH~Y, (where Y =
1 o H, halogen, OH, OR 19 or is a functional group less than or equal to 100000 daltons), CH~CO~R 19, CH~CONHR 19, CH=CHCH~OH, CH=CHCHZOR 19, CH(OH)CH3, CH(OR 19)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR19R19, CN, O, S, NHR19, OH, OR19, CHO, (CHz)~OH, (CH2)"SH, (CHZ)"O-alkoxy, (CH2)"SR19, ~5 (CH,,)"OR19 (where n = l, 2, 3, 4, and R19 is a functional group less than or equal to' 100000 daltons), (CH.,)nCO~R 19 (where R 19 is H, a physiologically acceptable salt, alkyl ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl: and n=1. 2, 3, 4), (CH2)~CONHR19, (CH,,)nCON(R19)~, CO~R19, CONHR19, CONR 19R 19, SR 19 (where R 19 is a functional group less than or equal to 20 daltons), SO;H, S03R19, SO~NHR19, SO~N(R19)~, SO~N(R19)3+X~ (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; A, B, C, D, E , F, G, H are; C, N, O+, O, S, Te, P, N+(R19)X- (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion) or combinations thereof;
25 M is Ins ~3, Ins ~5 or a mixture of Ins ~~ and Ins ~5 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Pd, Pt, Ga or Al.
Still another family of compounds has the following structure:
R1l ~ RS
R10 \ N~I~ N ~ R12 \ i N N
R 1 ~~ ~~ / R6 R8 ~ R7 Where each of Rl-R12 is CH~CH3, CH=CHI, CH=CHCH~N(CH3)~X, CH=CHCH~N~(CH~)3X- (where X is a charge balancing ion), C(X)~C(X}~ (where X is a halogen), CHO, COCH~, CO~H, CO~R13, CONHR13, CH=CHCHO, CH~Y, (where Y =
H, halogen, OH, OR13 or is a functional group less than or equal to 100000 daltons), CH~CO~R13, CH~CONHR13, CH=CHCH~OH, CH=CHCH~OR13, CH(OH)CH~, to CH(OR13)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR13R13, CN, O, S, NHR13, OH, OR13, CHO, (CH2)"OH, (CHZ)"SH, (CHZ)"O-alkoxy, (CHZ)"SR13, (CH~);,OR13 (where n = l, 2, 3, 4, and R13 is a functional group less than or equal to 100000 daltons), (CH,,)nCO,,Rl3 (where R13 is H, a physiologically acceptable salt, alkyl ~ 5 ( 1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)~CONHR13, (CH,}nCON(R13)~, CO~R13, CONHR13, CONR 13R 13, SR 13 (where R 13 is a functional group less than or equal to daltons), SO~H, SO~R13, SO~NHR13, 502N(R13)~, SO~N(R13)z~X- (where R13 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), 2o protein or biomolecule or functional group less than or equal to 100000 daltons; Z is halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Another family of compounds has the following structure:
R2 ~ J ~ ~ ' RS
N~ Z N.
R13 ~ In' ~ R15 N N
R1 ~l ,l i R6 / ' R8 where each of R 1-R 15 is CH~CH;, CH=CHI, CH=CHCH~N(CH~}Z , CH=CHCH~N+(CH~)3 X- (where X is a charge balancing ion). C(X)~C(X)3 (where X is a halogen), CHO, COCH~, COZH, CO,R16, CONHR16, CH=CHCHO, CH~Y, (where Y = H, halogen, OH, OR16 or is a functional group less than or equal to 100000 daltons), CH2COZR16, CH~CONHR 16, CH=CHCH~OH, CH=CHCH~OR 16, CH(OH)CH3, CH(OR 16)CH3, H, to halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 16R 16, CN, O, S, NHR 16. OH, OR 16, CHO, (CH,,)"OH, (CH.,)"SH, (CH2)"O-alkoxy, (CH2)"SR16, (CH2)"OR16 (where n =
1, 2, 3, 4, and R 16 is a functional group less than or equal to 100000 daltons), (CH~)~C02R 16 (where R16 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=l, 2, 3, 4), (CH.,)nCONHR 16, (CH.,)~CON(R 16),, CO~R 16, CONHR 16, CONR 16R 16, SR 16 (where R16 is a functional group less than or equal to 100000 daltons), SO~H, S03R16, SO~NHR16, SO~N(R16)~, SO~N(R16)~+X~ (where R16 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; Z is halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Still another family of compounds has the following structure:
RS \\~~~ ~ R13 % \~/N_ R14/M~ ~ R12 ~N N
R7 ~ ~~ ~ ~ RI l where each of R I-R 14 can be CH~CH3, CH=CH2, CH=CHCH2N(CH3)2, s CH=CHCH~N+(CH~)~ X- (where X is a charge balancing ion), C(X)~C(X)~ (where X
is a halogen), CHO, COCH~, CO~H, CO~R15, CONHR15, CH=CHCHO. CH~Y. (where Y =
H, halogen, OH, OR15 or is a functional group less than or equal to 100000 daltons), CH~CO~R 15, CHZCONHR 15, CH=CHCH,OH, ('_H=CHCH~OR 15, CH(OH)CH3, CH(OR 15)CH;, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, 1 o substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR 15R I
5, CN, O, S, NHR15, OH, OR15, CHO, (CHZ),;OH, (CH2)"SH, (CHZ)"O-alkoxy, (CH2)"SR15, (CH~)"OR15 (where n = 1, 2, 3, 4, and RI5 is a functional group less than or equal to 100000 daltons), (CH,)~CO.,R 15 (where R 15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted 15 alkynyl, and n=1, 2, 3, 4), (CH~)~CONHR15, (CHZ)~CON(R15)~, COZR15, CONHR15, CONR 1 SR I5, SR 15 (where R 1 S is a functional group less than or equal to daltons), SO~H, SO~R15, SO~NHR16, SO~N(R15)~, SO~N(R15)3~X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is Ins ls, 2o In ~ ~ 5 or a mixture of In ~ ~ ~ and In ~ ~ 5 ; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
M can also be Ag, Ce, Co, Cr, Cu, Dy, Er, Fe, Ga, Hf, Ho, La, Lu, Mo, Mg, Nd, Pb, Pr, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or' Zr, preferably Pd, Pt, Ga, Al, Ru, 25 Sn or Zn.
Still another family of compounds has the formula:
R3 Rll R2 ~ ~J Z~~ ' RS
N' yN"
R10 ~ In' ~ Rl N N
RI ~l ,l i R6 R8 1~ R7 Where In is In"~, In"5> or a mixture of In"j and In' ~5, each of R1-R12 is CH~CH~, CH=CHI, CH=CHCH~N(CH~)~, CH=CHCH~N+(CH3)3 X- (where X is a charge balancing ion), C(X)~C(X)~ (where X is a halogen), CHO, COCH~, CO~H, CO~R13, CONHR13, CH=CHCHO, CH~Y. (where Y = H, halogen, OH, OR13 or is a functional group less than or equal to I 00000 daltons), CH~CO~R 13, CH~CONHR 13, CH=CHCH~OH, CH=CHCH~OR13, CH(OH)CH~, CH(OR13)CH~, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, t0 amide, ester, NR13R13, CN, O, S, NHR13, OH, OR13, CHO, (CHZ)~OH, (CH,,)"SH, (CHz)"O-alkoxy, (CH2)"SR13, (CHZ)"OR13 (where n = 1, 2, 3, 4, and R13 is a functional group less than or equal to 100000 daltons), (CH~)~CO.,R13 (where R13 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and n=I, 2, 3, 4), (CH,)nCONHR13, IS (CH.,)nCON(R13)~, CO~R13, CONHR13, CONR13R13, SR13 (where R13 is a functional groups less than or equal to 100000 daltons), SO~H, SO~R13, SO~NHR13, SO~N(R13)~, SO~N(R 13)~+X- (where R 13 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; Z is halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, 2o substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional groups less than or equal to 100000 daltons.
l06 Two other families of compounds have the structures of Compound I and II, below:
X v X v c:ompounct 1 _.......r..~.... .~
wherein M is In ~ ~;, In ~ ~ 5 or a mixture of In ~ ~ 3 and In ~ u:
Rl, R2 and R3 can be the same or different, and each is C02H, CO~R4, CONR4, CH3Y', CONR4R4, NHS, N(R4)~, or N(R4)3+Z-, where Y' is halogen, OH, OR4, or a functional group having a molecular weight equal to or less than 100,000 daltons, R4 is a functional group having a molecular weight equal to or less than 100,000 daltons, and Z
is a physiologically acceptable charge balancing ion, with the proviso that R4 is not a mono-or di-carboxylic acid of an amino acid, RS is a methylene group or an ethylene group, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy. Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La.
Lu, Mn, Mo;
Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, and preferably is i 5 In, Pd, or Pt.
In still another aspect, the invention is a free base or a metal complex having the structure of one of Compounds III and IV, below:
X y X Y
Compound III Compound IV
wherein M is 2H or a metal cation, R1, R2 and R3 can be the same or different, and each is C:O~H, CO~R4, CONR4, CH3Y', CONR4R4, NHZ, N(R4)~, N(R4)3+Z~, or CONHR60R7 where R6 is a bivalent moiety composed of a number, n, of alkylene groups and (n minus 1 ) oxygens, each oxygen linking two alkylene groups through an ether linkage, CONHR60R7 where R6 is a bivalent moiety composed of a number, n, of alkylene groups and (n minus 1) oxygens, each oxygen linking two alkylene groups through an t o ether linkage, and R7 is alkyl, and Z is a physiologically acceptable charge balancing ion, with the proviso that there is at least one R6 group in the structure, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
t 5 In the foregoing definition, and elsewhere herein, the term "alkylene"
means a bivalent radical derived from an alkane with the free valences on different carbon carbon atoms, l.e., -C"H,"-.
Preferably, M is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La, Lu, Mn.
Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, most desirabl y Zn. Sn, In ~ ~ j, In ~ ~ 5, a mixture of In ~ " and In ~ ~ 5, Pd, or Pt.
In still another aspect, the invention is a metal complex having the structure of one of Compound V and VI, below:
X v X Y
Compound V Compound VI
wherein M is 2H, In ~ 13, Im ~ 5 or a mixture of In ~' 3 and 1n ~ ~ S, R1, R2 and R3 can be the same or different, and each is X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
M can also be Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb or Zr, most desirably Pd, Pt, Ins ~;, Ins ~5 or a mixture of Ins ~~ and Ins ~5 In the foregoing discussion of the invention and in the following claims, the term functional group having a molecular weight equal to or less than 100,000 daltons has been ~ 5 used. This term refers to such groups as monoclonal antibodies, proteins, saccharides, oligomeric nucleosides, peptides and the like. The terms alkyl, alkenyl, alkynyl, substituted alkenyl, substituted alkynyl and aryl, when used herein and in the appended claims to refer to substituents, preferably mean groups having 1 to 10, 2 to 10, 2 to 10, 2 to 10, 2 to 10 and 6 to 10 carbons, respectively.
It will be apparent that various changes and modifications can be made from the specific disclosure of the invention set forth herein without departing from the spirit and scope thereof as defined in the following claims.
Claims (30)
1. A phototherapeutic compound composed of an atom of In113 or of In115 complexed with the inner nitrogens of a pyrrolic core composed of at least two pyrroles whose pyrrole linking atoms may be carbon or nitrogen or combinations thereof, with the proviso that fully unsaturated porphyrins having the structures:
where R1, R2, R4 and R6 are methyl, R8, R10, R11 and R12 are hydrogen, and R7 and R8 are CH2CH2COR13 (where R13 is a moiety which results from the removal of H
from an amino acid) and where R1 is CH(OR)Me, R is alkyl, R2 is a residue derived by removing H from an amino acid, and M is 2H, Ga, Zn, Pd, In or Sn are excluded.
where R1, R2, R4 and R6 are methyl, R8, R10, R11 and R12 are hydrogen, and R7 and R8 are CH2CH2COR13 (where R13 is a moiety which results from the removal of H
from an amino acid) and where R1 is CH(OR)Me, R is alkyl, R2 is a residue derived by removing H from an amino acid, and M is 2H, Ga, Zn, Pd, In or Sn are excluded.
2. A phototherapeutic compound as claimed in claim 1 wherein the core is a tetrapyrrolic core.
3. A phototherapeutic compound as claimed in claim 2 wherein the core is a dihydro or tetrahydro tetrapyrrolic core.
4. A phototherapeutic compound as claimed in claim 3 which has a tetrapyrrolic core whose linking atoms are carbon.
5. A phototherapeutic compound as claimed in claim 4 having the structure of one of Compound 1 and Compound II, below:
wherein M is In113Z, In115Z, or a mixture of In113Z and In115Z, R1, R2 and R3 can be the same or different, and each is CO2H, CO2R4, CONR4, CH3Y', CONR4R4, NH2, N(R4)2, or N(R4)3+Z-, where Y' is halogen, OH, OR4, or a functional group having a molecular weight equal to or less than 100,000 daltons, R4 is a functional group having a molecular weight equal to or less than 100,000 daltons, R5 is a methylene group or an ethylene group, X is H, vinyl, ethyl, acetyl or formyl, Y is methyl or formyl, and Z is a physiologically acceptable charge balancing ion.
wherein M is In113Z, In115Z, or a mixture of In113Z and In115Z, R1, R2 and R3 can be the same or different, and each is CO2H, CO2R4, CONR4, CH3Y', CONR4R4, NH2, N(R4)2, or N(R4)3+Z-, where Y' is halogen, OH, OR4, or a functional group having a molecular weight equal to or less than 100,000 daltons, R4 is a functional group having a molecular weight equal to or less than 100,000 daltons, R5 is a methylene group or an ethylene group, X is H, vinyl, ethyl, acetyl or formyl, Y is methyl or formyl, and Z is a physiologically acceptable charge balancing ion.
6. A free base or a metal complex having the structure of one of Compound III
and Compound IV, below:
wherein M is 2H or a metal cation and, associated with the metal cation, a physiologically acceptable charge balancing ion, R1, R2 and R3 can be the same or different, and each is CO2H, CO2R4, CONR4, CH3Y', CONR4R4, NH2, N(R4)2, N(R4)3+Z-, or CONHR6OR7 where R4 is an alkyl group, R6 is a bivalent moiety composed of a number, n, of alkylene groups and (n minus 1) oxygens, each oxygen linking two alkylene groups through an ether linkage and R7 is an alkylene group, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl with the proviso that the molecule includes at least one R6 group,
and Compound IV, below:
wherein M is 2H or a metal cation and, associated with the metal cation, a physiologically acceptable charge balancing ion, R1, R2 and R3 can be the same or different, and each is CO2H, CO2R4, CONR4, CH3Y', CONR4R4, NH2, N(R4)2, N(R4)3+Z-, or CONHR6OR7 where R4 is an alkyl group, R6 is a bivalent moiety composed of a number, n, of alkylene groups and (n minus 1) oxygens, each oxygen linking two alkylene groups through an ether linkage and R7 is an alkylene group, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl with the proviso that the molecule includes at least one R6 group,
7. A metal complex as claimed in claim 6 where M is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Gd, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr.
8. A metal complex as claimed in claim 7 where M Zn, Sn, Pd,, Pt, In113, In115 or a mixture of In113 and In115.
9. A phototherapeutic compound as claimed in claim 4 having the structure of one of Compound V and Compound VI, below:
wherein M is 2H, In113, In115 or a mixture of In113 and In115 and, associated with the In113, In115 or mixture of In113 and In115, a physiologically acceptable charge balancing ion, R1 and R3 can be the same or different, and each is CO2CH3, CO2H, CO2R4, or an amide, where R4 is an alkyl or a phenyl group, R2 is CO2CH3, CO2H, CO2R4, an amide, CH2CO2CH3, CH2CO2H, or CH2CO2R4, where R4 is an alkyl or a phenyl group, R5 is methylene or ethylene, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
wherein M is 2H, In113, In115 or a mixture of In113 and In115 and, associated with the In113, In115 or mixture of In113 and In115, a physiologically acceptable charge balancing ion, R1 and R3 can be the same or different, and each is CO2CH3, CO2H, CO2R4, or an amide, where R4 is an alkyl or a phenyl group, R2 is CO2CH3, CO2H, CO2R4, an amide, CH2CO2CH3, CH2CO2H, or CH2CO2R4, where R4 is an alkyl or a phenyl group, R5 is methylene or ethylene, X is H, vinyl, ethyl, acetyl or formyl, and Y is methyl or formyl.
10. A phototherapeutic compound as claimed in claim 4 which has the structure:
where R1 - R5 can be the same or different and each is CH2CH2, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3X1-, C(Y1)2C(Y1)3, CHO, COCH2, CO2H, CO2R6, CONHR6, CH=CHCHO, CH2Y, CH=CHCH2OH, CH=CHCH2OR6, CH(OH)CH3, CH(OR6)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, OH, OR6, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR6, (CH2)n OR6, (CH2)n CO2R6, (CH2)n CONHR6, (CH2)n CON(R6)2, CO2R6, CONHR6, CONR6R6, SR6, SO3H, SO3R6, SO2NHR6, SO2N(R6)2, SO2N(R6)3+X1-;
M is In113, In115 or a mixture of In113 and In115;
Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons;
Y1 is halogen;
Y is H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons;
R6 is a functional group less than or equal to 100000 daltons;
R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
X1 is a charge balancing ion; and X is O, 2H, (H, OH), S, (H, OR6) or a ketone protecting group.
where R1 - R5 can be the same or different and each is CH2CH2, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3X1-, C(Y1)2C(Y1)3, CHO, COCH2, CO2H, CO2R6, CONHR6, CH=CHCHO, CH2Y, CH=CHCH2OH, CH=CHCH2OR6, CH(OH)CH3, CH(OR6)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, OH, OR6, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR6, (CH2)n OR6, (CH2)n CO2R6, (CH2)n CONHR6, (CH2)n CON(R6)2, CO2R6, CONHR6, CONR6R6, SR6, SO3H, SO3R6, SO2NHR6, SO2N(R6)2, SO2N(R6)3+X1-;
M is In113, In115 or a mixture of In113 and In115;
Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons;
Y1 is halogen;
Y is H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons;
R6 is a functional group less than or equal to 100000 daltons;
R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
X1 is a charge balancing ion; and X is O, 2H, (H, OH), S, (H, OR6) or a ketone protecting group.
11. A phototherapeutic compound as claimed in claim 10 wherein:
R1 is CH=CH2, CHO, Et, COCH3 R2 is CO2CH3, CO2H, or an amide R3 and R4 are H
R5 is CH3 X is O
M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate or OH.
R1 is CH=CH2, CHO, Et, COCH3 R2 is CO2CH3, CO2H, or an amide R3 and R4 are H
R5 is CH3 X is O
M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate or OH.
12. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R17 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR18R18, CN, OH, OR18, CHO, COCH3, (CH2)nOH, (CH2)nSH, CH(OR18)CH3, (CH2)nO-alkoxy, (CH2)SR18, (CH2)nOR18(where n = 1, 2, 3, 4, and is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R18 (where R18 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR18, (CH2)nCON(R18)2 , CO1R18, CONHR18, CONR18R18, SR18 (where R18 is a functional group less than or equal to 100000 daltons). SO3X, SO3R18, SO2NHR18, SO2N(R18)2, SO2N(R18)3+X- (where R18 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); A, B, C and D are; C, N, O+, O, S, Te, P, N+(R19)X- (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In113, In115 or a mixture of In113 and In115 ; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1-R17 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR18R18, CN, OH, OR18, CHO, COCH3, (CH2)nOH, (CH2)nSH, CH(OR18)CH3, (CH2)nO-alkoxy, (CH2)SR18, (CH2)nOR18(where n = 1, 2, 3, 4, and is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R18 (where R18 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR18, (CH2)nCON(R18)2 , CO1R18, CONHR18, CONR18R18, SR18 (where R18 is a functional group less than or equal to 100000 daltons). SO3X, SO3R18, SO2NHR18, SO2N(R18)2, SO2N(R18)3+X- (where R18 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); A, B, C and D are; C, N, O+, O, S, Te, P, N+(R19)X- (where R19 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; M is In113, In115 or a mixture of In113 and In115 ; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
13. A phototherapeutic compound as claimed in claim 4 which has the structure:
were each of R1-R24 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR25R25, CN, OH, OR25, CHO, COCH3, (CH2)n OH, (CH2)n SH, CH(OR25)CH3, (CH2)n O-alkoxy, (CH2)n SR25, (CH2)n OR25 (where n = 1, 2, 3, 4, and R25 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R25 (where R25 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONHR25, (CH2)n CON(R25)2, CO2R25, CONHR25, CONR25R25, SR25 (where R25 is a functional group less than or equal to 100000 daltons), SO3H, SO3R25, SO2NHR25, SO2N(R25)2, SO2N(R25)3+X- (where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In113, In115 or a mixture of In113 and In115 ; A, B, C, D, E, F are; C, N, O+, O, S, Te, P, N+(R25)X-(where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; Z is a halide , acetate. OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a protein or biomolecule or functional group less than or equal to 100000 daltons.
were each of R1-R24 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR25R25, CN, OH, OR25, CHO, COCH3, (CH2)n OH, (CH2)n SH, CH(OR25)CH3, (CH2)n O-alkoxy, (CH2)n SR25, (CH2)n OR25 (where n = 1, 2, 3, 4, and R25 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R25 (where R25 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONHR25, (CH2)n CON(R25)2, CO2R25, CONHR25, CONR25R25, SR25 (where R25 is a functional group less than or equal to 100000 daltons), SO3H, SO3R25, SO2NHR25, SO2N(R25)2, SO2N(R25)3+X- (where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In113, In115 or a mixture of In113 and In115 ; A, B, C, D, E, F are; C, N, O+, O, S, Te, P, N+(R25)X-(where R25 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), or combinations thereof; Z is a halide , acetate. OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a protein or biomolecule or functional group less than or equal to 100000 daltons.
14. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each R1-R13 is H, halide, alkyl, vinyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR14R14, CN, OH, OR14, CHO, COCH3, (CH2)nOH, (CH2)nSH, (CH2)nO-alkoxy, CH(OH)CH3, CH(OR14)CH3 (CH2)n SR14, (CH2)nOR14 (where n = 1, 2, 3, 4, and R14 is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR14, (CH2)n CON(R14)2, CO2R14, CONHR14, CONR14R14, SR14 (where R14 is a functional group less than or equal to 100000 daltons), SO3X, SO3R14, SO2R14, SO2NHR14, SO2N(R14)2, SO2N(R14)3+X- (where R14 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion);
M is In113, In115 or a mixture of In113 and In115 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
where each R1-R13 is H, halide, alkyl, vinyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR14R14, CN, OH, OR14, CHO, COCH3, (CH2)nOH, (CH2)nSH, (CH2)nO-alkoxy, CH(OH)CH3, CH(OR14)CH3 (CH2)n SR14, (CH2)nOR14 (where n = 1, 2, 3, 4, and R14 is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR14, (CH2)n CON(R14)2, CO2R14, CONHR14, CONR14R14, SR14 (where R14 is a functional group less than or equal to 100000 daltons), SO3X, SO3R14, SO2R14, SO2NHR14, SO2N(R14)2, SO2N(R14)3+X- (where R14 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion);
M is In113, In115 or a mixture of In113 and In115 ; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
15. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH3)2 , CH=CHCH2N+(CH3)3X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR14R14. CN, OH, OR14, CHO, (CH2)nOH, (CH2)nSH, (CH2)nO-alkoxy, CH(OH)CH3, CH(OR14)CH; (CH2)nSR14, (CH2)"nOR14 (where n = 1, 2, 3, 4, and R14 is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR14, (CH2)nCONH(R14)2, CO2R14. CONHR14, CONR14R14, SR14 (where R14 is a functional group less than or equal to 100000 daltons), SO3H.
SO3R14, SO2NHR14, SO2N(R14)2, SO2N(R14)3+X- (where R14 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In113, In115 or a mixture of In113 and In115; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1-R13 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH3)2 , CH=CHCH2N+(CH3)3X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR14R14. CN, OH, OR14, CHO, (CH2)nOH, (CH2)nSH, (CH2)nO-alkoxy, CH(OH)CH3, CH(OR14)CH; (CH2)nSR14, (CH2)"nOR14 (where n = 1, 2, 3, 4, and R14 is a functional groups less than or equal to 100000 daltons), (CH2)nCO2R14 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)nCONHR14, (CH2)nCONH(R14)2, CO2R14. CONHR14, CONR14R14, SR14 (where R14 is a functional group less than or equal to 100000 daltons), SO3H.
SO3R14, SO2NHR14, SO2N(R14)2, SO2N(R14)3+X- (where R14 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); M is In113, In115 or a mixture of In113 and In115; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
16. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1 and R2 is CO2R14 (where R14 is alkyl or aryl), CO2H (or a salt therof), SO2Ph, CN or combinations thereof;
Each of R3, R6, R8, R12 is Me.
R5 is CH=CH2, or CH(OR14)CH3 (where R14 is alkyl or aryl) Each of R4, R7, R13, R10 is H
R9 and R11 are CH2CH2CO2R15 (where R15 is alkyl or H or a salt of the carboxylic acid).
M is In113 In115 or a mixture of In113 and In115.
Z is a halide ,acetate, or OH.
where each of R1 and R2 is CO2R14 (where R14 is alkyl or aryl), CO2H (or a salt therof), SO2Ph, CN or combinations thereof;
Each of R3, R6, R8, R12 is Me.
R5 is CH=CH2, or CH(OR14)CH3 (where R14 is alkyl or aryl) Each of R4, R7, R13, R10 is H
R9 and R11 are CH2CH2CO2R15 (where R15 is alkyl or H or a salt of the carboxylic acid).
M is In113 In115 or a mixture of In113 and In115.
Z is a halide ,acetate, or OH.
17. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of A, B, C, D and E is C, N, N+R (where R is alkyl charged or uncharged) or combinations thereof;
M is In113 In115 or a mixture of In113 and In115 and Z is a halide, acetate, OH.
where each of A, B, C, D and E is C, N, N+R (where R is alkyl charged or uncharged) or combinations thereof;
M is In113 In115 or a mixture of In113 and In115 and Z is a halide, acetate, OH.
18. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1 through R4 is SO3H (or a salt thereof), SO2NHR5, CO2H (or a salt thereof ), CONHR5, OH, OR5 (wherein R5 is an alcohol or ether containing group), amide, N(CH3)2, N(Et)2.
M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, OH.
where each of R1 through R4 is SO3H (or a salt thereof), SO2NHR5, CO2H (or a salt thereof ), CONHR5, OH, OR5 (wherein R5 is an alcohol or ether containing group), amide, N(CH3)2, N(Et)2.
M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, OH.
19. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R14 is H, halide, methyl, ethyl, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, COCH3, CH(OR15)CH3, (CH2)nOH, (CH2)nSH, (CH2)nO-alkoxy, (CH2)nSR15, (CH2)nOR15 (where n = 1, 2, 3, 4, and R15 is a functional groups less than or equal to 100000 daltons), (CH2)n CO2R15 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkyne and n=1, 2, 3, 4), (CH2)n CONHR15, (CH2)n CON(R15)2, CO2R15, CONHR15, CONR15R15, SR15 (where R15 is a functional groups less than or equal to 100000 daltons and n=1, 2, 3, 4), SO3H, SO3R15, SO2NHR15, SO2N(R15)2SO3N(R15)3+X- (where R15 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In113 In115 or a mixture of In113 and In115 Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons. a protein or a biomolecule.
where each of R1-R14 is H, halide, methyl, ethyl, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, COCH3, CH(OR15)CH3, (CH2)nOH, (CH2)nSH, (CH2)nO-alkoxy, (CH2)nSR15, (CH2)nOR15 (where n = 1, 2, 3, 4, and R15 is a functional groups less than or equal to 100000 daltons), (CH2)n CO2R15 (where R14 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkyne and n=1, 2, 3, 4), (CH2)n CONHR15, (CH2)n CON(R15)2, CO2R15, CONHR15, CONR15R15, SR15 (where R15 is a functional groups less than or equal to 100000 daltons and n=1, 2, 3, 4), SO3H, SO3R15, SO2NHR15, SO2N(R15)2SO3N(R15)3+X- (where R15 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In113 In115 or a mixture of In113 and In115 Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or a functional group less than or equal to 100000 daltons. a protein or a biomolecule.
20. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R8 is ethyl or methyl R9 is CH3, SO2NH(CH2CH2O)n CH3 (n=1 to 1000), SO2N((CH2CH2O)n CH3), (n=1 to 1000); SO2NH(CH2)n OH (n=1 to 1000), CH3, SO2N((CH2CH2)n OH)2 (n=1 to 1000);
SO2NC((N(CH3)2)2; SO2NH(CH2)n N(CH3)2 (n=1 to 1000); SO2NH(CH2)n SH (n=1 to 1000); SO2NHC(CH2CH2OH)3; SO2NHCH2CO2H (or salts thereof);
SO2NH(CH2)n CH(NH2)CO2H (or salts therof) (n=1 to 5); SO2NHCH2CO2R10 (R10 is alkyl, aryl); SO2NH(CH2)n CH(NH2)CO2R10 (R10 is alkyl, aryl) (n=1 to 5) M is In113 In115 or a mixture of In113 and In115 Z is a halide, acetate, OH.
where each of R1-R8 is ethyl or methyl R9 is CH3, SO2NH(CH2CH2O)n CH3 (n=1 to 1000), SO2N((CH2CH2O)n CH3), (n=1 to 1000); SO2NH(CH2)n OH (n=1 to 1000), CH3, SO2N((CH2CH2)n OH)2 (n=1 to 1000);
SO2NC((N(CH3)2)2; SO2NH(CH2)n N(CH3)2 (n=1 to 1000); SO2NH(CH2)n SH (n=1 to 1000); SO2NHC(CH2CH2OH)3; SO2NHCH2CO2H (or salts thereof);
SO2NH(CH2)n CH(NH2)CO2H (or salts therof) (n=1 to 5); SO2NHCH2CO2R10 (R10 is alkyl, aryl); SO2NH(CH2)n CH(NH2)CO2R10 (R10 is alkyl, aryl) (n=1 to 5) M is In113 In115 or a mixture of In113 and In115 Z is a halide, acetate, OH.
21. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R8 is ethyl or methyl.
R9 is; CH2CO2NH(CH2CH2O)n CH3 (n = 1 to 1000), CH2CO2 N((CH2CH2O)n CH3)2 (n=1 to 1000); CH2CO2NH(CH2)n OH (n=1 to 1000), CH2CO2N((CH2CH2)n OH)2 (n=1 to 1000);
CH2CO2NC((N(CH3)2)2 ; CH2CO2NH(CH2)n N(CH3)2 (n=1 to 1000); CH2CO2N(CH2)n SH
(n=1 to 1000); CH2CO2NHC(CH2CH2OH)3 ; CH2CO2NHCH2CO2H (or salts thereof);
CH2CO2NH(CH2)n CH(NH2)CO2H (or salts thereof) (n=1 to 5); CH2CO2NHCH2CO2R10 (R10 is alkyl, aryl); CH2CO2NH(CH2)n CH(NH2)CO2R10 (R10 is alkyl, aryl) (n=1 to 5) M is In113, In115 or a mixture of In113 and In115.
Z is a halide, acetate, OH.
where each of R1-R8 is ethyl or methyl.
R9 is; CH2CO2NH(CH2CH2O)n CH3 (n = 1 to 1000), CH2CO2 N((CH2CH2O)n CH3)2 (n=1 to 1000); CH2CO2NH(CH2)n OH (n=1 to 1000), CH2CO2N((CH2CH2)n OH)2 (n=1 to 1000);
CH2CO2NC((N(CH3)2)2 ; CH2CO2NH(CH2)n N(CH3)2 (n=1 to 1000); CH2CO2N(CH2)n SH
(n=1 to 1000); CH2CO2NHC(CH2CH2OH)3 ; CH2CO2NHCH2CO2H (or salts thereof);
CH2CO2NH(CH2)n CH(NH2)CO2H (or salts thereof) (n=1 to 5); CH2CO2NHCH2CO2R10 (R10 is alkyl, aryl); CH2CO2NH(CH2)n CH(NH2)CO2R10 (R10 is alkyl, aryl) (n=1 to 5) M is In113, In115 or a mixture of In113 and In115.
Z is a halide, acetate, OH.
22. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R14 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH3)2 , CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, CH(OH)CH3, CH(OR15)CH3 (CH2)n SR15, (CH2)n OR15 (where n = 1, 2, 3, 4, and R15 is a functional groups less than or equal to 100000 daltons), (CH2)n CO2R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkyne and n=1, 2, 3, 4), (CH2)n CONHR15, (CH2)n CON(R15)2, CO2R15, CONHR15, CONR15R15, SR15 (where R15 is a functional groups less than or equal to 100000 daltons), SO3H, SO3R15, SO2NHR15, SO2N(R15)2, SO2N(R15)3+X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); A, B, C, D are; C, N, O+, O, S, Te, P or combinations thereof; M is In113, In115 or a mixture of In113 and In115; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1-R14 is H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, CH=CHCH2N(CH3)2 , CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, CH(OH)CH3, CH(OR15)CH3 (CH2)n SR15, (CH2)n OR15 (where n = 1, 2, 3, 4, and R15 is a functional groups less than or equal to 100000 daltons), (CH2)n CO2R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkyne and n=1, 2, 3, 4), (CH2)n CONHR15, (CH2)n CON(R15)2, CO2R15, CONHR15, CONR15R15, SR15 (where R15 is a functional groups less than or equal to 100000 daltons), SO3H, SO3R15, SO2NHR15, SO2N(R15)2, SO2N(R15)3+X- (where R15 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion); A, B, C, D are; C, N, O+, O, S, Te, P or combinations thereof; M is In113, In115 or a mixture of In113 and In115; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
23. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1 through R14 is H, halide, alkyl, cyclic alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alklynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, COCH3, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR15, (CH2)n OR15 (where n = 1, 2, 3, 4, and R15 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONHR15, (CH2)n CON(R15)2, CO2R15, CONHR15, CON(R15)2, (where R15 is a functional group less than or equal to 100000 daltons), SR15 (where R15 is a functional group less than or equal to 100000 daltons), SO3H, SO3R15, SO2NHR15, SO2N(R15)2, SO2N(R15)3+X-(where R15 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In113, In115 or a mixture of In113 and In115; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
where each of R1 through R14 is H, halide, alkyl, cyclic alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alklynyl, amide, ester, C(X)2C(X)3 (where X is a halogen), NR15R15, CN, OH, OR15, CHO, COCH3, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR15, (CH2)n OR15 (where n = 1, 2, 3, 4, and R15 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R15 (where R15 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONHR15, (CH2)n CON(R15)2, CO2R15, CONHR15, CON(R15)2, (where R15 is a functional group less than or equal to 100000 daltons), SR15 (where R15 is a functional group less than or equal to 100000 daltons), SO3H, SO3R15, SO2NHR15, SO2N(R15)2, SO2N(R15)3+X-(where R15 is a functional groups less than or equal to 100000 daltons and X is a charge balancing ion); M is In113, In115 or a mixture of In113 and In115; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, or a functional group less than or equal to 100000 daltons, protein or biomolecule.
24. A phototherapeutic compound as claimed in claim 4 which has the structure:
wherein;
R1 is CH=CH2, Et, CHO, or COCH3 R4 is Me R3 is H
R2 is CO2CH3, CO2H, CO2R7 (R7 is an alkyl, phenyl), or an amide Each of A and B is O or NR5(R5 is alkyl), X is O or NR6 (R6 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, or OH.
wherein;
R1 is CH=CH2, Et, CHO, or COCH3 R4 is Me R3 is H
R2 is CO2CH3, CO2H, CO2R7 (R7 is an alkyl, phenyl), or an amide Each of A and B is O or NR5(R5 is alkyl), X is O or NR6 (R6 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, or OH.
25. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1- R6 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R7, CONHR7, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH2CO2R7, CH2CONHR7, CH=CHCH2OH, CH=CHCH2OR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR7, (CH2)n OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONR7, CO2R7, CONHR7, CONR10R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), SO3H, SO3R7, SO2NHR7, SO2N(R7)2, SO2N(R7)3+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, H2, (H, OH), (H, OR8) S, or a ketone protecting group; M is In113, In115 or a mixture of In113 and In115; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1- R6 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R7, CONHR7, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH2CO2R7, CH2CONHR7, CH=CHCH2OH, CH=CHCH2OR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR7, (CH2)n OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONR7, CO2R7, CONHR7, CONR10R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), SO3H, SO3R7, SO2NHR7, SO2N(R7)2, SO2N(R7)3+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, H2, (H, OH), (H, OR8) S, or a ketone protecting group; M is In113, In115 or a mixture of In113 and In115; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
26. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1-R8 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R9, CONHR9, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CH2CO2R9, CH2CONHR9, CH=CHCH2OH, CH=CHCH2OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, O, S, NHR9, OH, OR9, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR9, (CH2)n OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R9 (where R9 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONHR9, (CH2)n CON(R9)2, CO2R9, CONHR9, CONR10R9, SR9 (where R9 is a functional group less than or equal to 100000 daltons), SO3H, SO3R9, SO2NHR9, SO2N(R9)2, SO2N(R9)3+X- (where R9 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In113, In115 or a mixture of In113 and In115; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1-R8 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R9, CONHR9, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR9 or is a functional group less than or equal to 100000 daltons), CH2CO2R9, CH2CONHR9, CH=CHCH2OH, CH=CHCH2OR9, CH(OH)CH3, CH(OR9)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR9R9, CN, O, S, NHR9, OH, OR9, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR9, (CH2)n OR9 (where n = 1, 2, 3, 4, and R9 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R9 (where R9 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONHR9, (CH2)n CON(R9)2, CO2R9, CONHR9, CONR10R9, SR9 (where R9 is a functional group less than or equal to 100000 daltons), SO3H, SO3R9, SO2NHR9, SO2N(R9)2, SO2N(R9)3+X- (where R9 is a functional group less than or equal to 100000 daltons and X
is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; M is In113, In115 or a mixture of In113 and In115; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a protein or biomolecule or functional group less than or equal to 100000 daltons.
27. A phototherapeutic compound as claimed in claim 4 which has the structure:
wherein;
R1 is CH=CH2, Et, CHO, or COCH3 R5 is O or NR9 (where R9 is alkyl) R7 is Me R3 is H
R4 and R8 are H, CO2CH3, CO2H (or a salt thereof), CO2R10 (R10 is an alkyl or phenyl group), an amide, CH2CO2CH3, CH2CO2H (or a salt thereof), CO2R10 (R10 is an alkyl or a phenyl group), or an amide R2 is CO2CH3, CO2H, CO2R10 (R10 is an alkyl or phenyl group), or an amide M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, or OH.
wherein;
R1 is CH=CH2, Et, CHO, or COCH3 R5 is O or NR9 (where R9 is alkyl) R7 is Me R3 is H
R4 and R8 are H, CO2CH3, CO2H (or a salt thereof), CO2R10 (R10 is an alkyl or phenyl group), an amide, CH2CO2CH3, CH2CO2H (or a salt thereof), CO2R10 (R10 is an alkyl or a phenyl group), or an amide R2 is CO2CH3, CO2H, CO2R10 (R10 is an alkyl or phenyl group), or an amide M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, or OH.
28. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1- R5 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R6, CONHR6, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons), CH2CO2R6, CH2CONHR6, CH=CHCH2OH, CH=CHCH2OR8, CH(OH)CH3, CH(OR6)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, O, S, NHR6, OH, OR6, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR6, (CH2)n OR6 (where n = 1, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R6 (where R6 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONR6, CO2R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltons), SO3H, SO3R6, SO2NHR6, SO2N(R6)2, SO2N(R6)3+X- (where R6 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons: X is O, NR6 (where R6 is H, alkyl (1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); A and B are O, NH, NR6 or combinations thereof; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1- R5 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R6, CONHR6, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR6 or is a functional group less than or equal to 100000 daltons), CH2CO2R6, CH2CONHR6, CH=CHCH2OH, CH=CHCH2OR8, CH(OH)CH3, CH(OR6)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR6R6, CN, O, S, NHR6, OH, OR6, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR6, (CH2)n OR6 (where n = 1, 2, 3, 4, and R6 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R6 (where R6 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONR6, CO2R6, CONHR6, CONR6R6, SR6 (where R6 is a functional group less than or equal to 100000 daltons), SO3H, SO3R6, SO2NHR6, SO2N(R6)2, SO2N(R6)3+X- (where R6 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons: X is O, NR6 (where R6 is H, alkyl (1-10 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, an amino acid, an amino acid ester or a functional group less than or equal to 100000 daltons); A and B are O, NH, NR6 or combinations thereof; Z is a halide, acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
29. A phototherapeutic compound as claimed in claim 4 which has the structure:
wherein:
R1 is CH=CH2, Et, CHO, or COCH
R4 is O or NR6 (where R6 is alkyl) R5 is MeR3 is H
R2 is CO2CH3, CO2H, CO2R7 (R7 is an alkyl or phenyl group), or an amide X is O, NR6 (R6 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, OH, and A and B are O or NR6 where R 6 is alkyl.
wherein:
R1 is CH=CH2, Et, CHO, or COCH
R4 is O or NR6 (where R6 is alkyl) R5 is MeR3 is H
R2 is CO2CH3, CO2H, CO2R7 (R7 is an alkyl or phenyl group), or an amide X is O, NR6 (R6 is alkyl, an amino acid, an alcohol containing group, or an ether containing group) M is In113, In115 or a mixture of In113 and In115 Z is a halide, acetate, OH, and A and B are O or NR6 where R 6 is alkyl.
30. A phototherapeutic compound as claimed in claim 4 which has the structure:
where each of R1- R6 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R7, CONHR7, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH2CO2R7, CH2CONHR7, CH=CHCH2OH, CH=CHCH2OR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR7, (CH2)n OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONR7, CO2R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), SO3H, SO3R7, SO2NHR7, SO2N(R7)2, SO2N(R7)3+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, H2, (H, OH), (H, OR7), S, or a ketone protecting group; M is In113, In115 or a mixture of In113 and In115; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
where each of R1- R6 is CH2CH3, CH=CH2, CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3 X- (where X is a charge balancing ion), C(X)2C(X)3 (where X is a halogen), CHO, COCH3, CO2H, CO2R7, CONHR7, CH=CHCHO, CH2Y, (where Y = H, halogen, OH, OR7 or is a functional group less than or equal to 100000 daltons), CH2CO2R7, CH2CONHR7, CH=CHCH2OH, CH=CHCH2OR7, CH(OH)CH3, CH(OR7)CH3, H, halide, alkyl, cyclic alkyl (3-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, NR7R7, CN, O, S, NHR7, OH, OR7, CHO, (CH2)n OH, (CH2)n SH, (CH2)n O-alkoxy, (CH2)n SR7, (CH2)n OR7 (where n = 1, 2, 3, 4, and R7 is a functional group less than or equal to 100000 daltons), (CH2)n CO2R7 (where R7 is H, a physiologically acceptable salt, alkyl (1-6 carbons), aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, and n=1, 2, 3, 4), (CH2)n CONR7, CO2R7, CONHR7, CONR7R7, SR7 (where R7 is a functional group less than or equal to 100000 daltons), SO3H, SO3R7, SO2NHR7, SO2N(R7)2, SO2N(R7)3+X- (where R7 is a functional group less than or equal to 100000 daltons and X is a charge balancing ion), protein or biomolecule or functional group less than or equal to 100000 daltons; X is O, H2, (H, OH), (H, OR7), S, or a ketone protecting group; M is In113, In115 or a mixture of In113 and In115; Z is a halide , acetate, OH, alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, protein or biomolecule or functional group less than or equal to 100000 daltons.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1998/013601 WO2000000204A1 (en) | 1997-02-14 | 1998-06-29 | Indium photosensitizers for pdt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2336306A1 true CA2336306A1 (en) | 2000-01-06 |
Family
ID=22267408
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002336306A Abandoned CA2336306A1 (en) | 1998-06-29 | 1998-06-29 | Indium photosensitizers for pdt |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2002519327A (en) |
| AU (1) | AU761891B2 (en) |
| CA (1) | CA2336306A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7468434B2 (en) * | 2004-12-22 | 2008-12-23 | The University Of Hong Kong | Diazene-bridge crown ether lithium compounds and methods for their use |
| EP1871421A1 (en) * | 2005-04-07 | 2008-01-02 | Photo Diagnostic Devices (PDD) Ltd | Photosensitizers and mri enhancers |
| KR100707655B1 (en) * | 2005-07-18 | 2007-08-09 | 주식회사 라이트팜텍 | Porphyrin Metal complex compound derivatives |
-
1998
- 1998-06-29 JP JP2000556789A patent/JP2002519327A/en active Pending
- 1998-06-29 AU AU83794/98A patent/AU761891B2/en not_active Ceased
- 1998-06-29 CA CA002336306A patent/CA2336306A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002519327A (en) | 2002-07-02 |
| AU8379498A (en) | 2000-01-17 |
| AU761891B2 (en) | 2003-06-12 |
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