CA2418410A1 - Novel, water-soluble porphyrin platinum compounds with high tumor selectivity and their use for the treatment of benign and malignant tumor diseases - Google Patents
Novel, water-soluble porphyrin platinum compounds with high tumor selectivity and their use for the treatment of benign and malignant tumor diseases Download PDFInfo
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- CA2418410A1 CA2418410A1 CA002418410A CA2418410A CA2418410A1 CA 2418410 A1 CA2418410 A1 CA 2418410A1 CA 002418410 A CA002418410 A CA 002418410A CA 2418410 A CA2418410 A CA 2418410A CA 2418410 A1 CA2418410 A1 CA 2418410A1
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
Abstract
The invention relates to novel, water-soluble porphyrin platinum compounds of the tetraarylporphyrin platinum derivatives type or of the hematoporphyrin platinum derivatives type with high tumor selectivity and their use for the treatment of benign and malignant tumor diseases. In particular, the compounds are suitable for photodynamic anti-tumor therapy.
Description
Novel, water-soluble porphyrin platinum compounds with high tumor selectivity and their use for the treatment of benign and malignant tumor diseases Introduction The invention relates to novel, water-soluble porphyrin platinum compounds with high tumor selectivity and their use for the treatment of benign and malignant tumor diseases. In particular, the inventive compounds are suitable for photodynamic anti-lc tumor therapy in man and mammals.
Prior art Platinum(II) complexes with porphyrin ligands and their application as potent ~s cytostatic and phototoxic antitumor agents have already been described in the following publications.
W.M. Sharman, C.M. Allen and J.E. van Lier, DDT 4, (11 ) 507-517 (1 X799).
Photodynamic therapeutics: basic principles and clinical applications z0 T. Okunaka and H. Kato, Rev. Contemp. Pharmacother., 10, 59-68 (1999).
Potential Applications of Photodynamic Therapy.
H. Brunner, H. Obermeier and R.-M. Szeimie~, Chem. Ber., 1995, 128, 173-181.
2s Platinum(Il) complexes with porphyrin I~gands. synthesis and synergism during photodynamic therapy.
H. Brunner, K.-H. Schellerer and B. Treittinger, Inorg. Chim. Acta 1997, 264, 67-69.
Synthesis and in vitro testing of hematoporphyrin type ligands in platinum(II) ~o complexes as potent cytostatic and phototoxic antitumor agents.
Zentar~s AG
Description of the invention In the invention, novel porphyrin platinum derivatives are described, which have cytotoxic properties. Surprisingly, the compounds have good water solubility and a high selectivity. The compounds can be used for the treatment of cancer and, in particular, for the photodynamic treatment of tumors.
The general formulas of the claimed compounds of the tetraarylporphyrin platinum derivatives type are:
Formula I
O O
P~''~NHZ R3 O
X
I ~i O
R5 _ R6 R. ~ ~ O-~-CHZ CH2 O ~ n R4 n: 1-20 X: 0, S, NH, N-Alkyl R2IR3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R4: H, Alkyl, Aryl, Araikyl, Hetaryl. Hetarylalkyl, Cycloaikyl R5: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro. Cyano, Amino, subst. Amino R6: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro. Cyano, Amino, subst. Amino Zentaris AG
Formula II
NHZ R2~
'Z
'~ 'NHz R~'3 0 R.~
R7 _ R6 R: ~ ~ O--~-CH2 CHI O-'~R5 n: 1-20 X: O, S, NH, N-Alkyl R1IR2/R31R4: H, Alkyl, Aryl, Aralkyl. Hetaryl, Hetarylaikyt, Cycloalkyl oder R2-Z-R3, mit Z. (CHz)", n=0-6 R1IR4: H, -(CH~)"COORB, n=0-6 R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R6: H, Alkyf, 0-Alkyl. S-Alkyl, Halogen, Nit~o, Cyano, Amino, subst. Amino R7: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino RB: H, Alkyl The general tormuias of the claimed compounds of the hematoporphyrin platinum derivatives type are:
1:
Zentaris AG
Formula III
'H N ~ OR
/ N N ,_._ R4 i 0 ( 0 R= (CH,CH20)~Rs /NHS
R2 n= 1-20 R21R3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Het~rylalkyl, Cycloaikyl R4: H, Alkyl, Gycioalkyi R5: H, Alkyl, Cycloalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl Zentaris AG 5 Formula !1l R5 ~OR
'N
H \ ~ OR
N
_..- /
RS
O
O R= (CH2CH~0)nR7 O O n= 1-20 N- IPt~
NH
1 i~R3 R1/R21R3/R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, tietarylalkyl, Cycloalkyl oder R2-Z-R4, mit Z: (CHz)~, n=0-6 oder R11R3: H, -(CH2)~-COOR6. n=0-6 R4/R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycioalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyi, Cycloalkyl R7: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalky, Cycloalkyl If the inventive compounds have at least one center of asymmetry, they can be in the form of their race mates, their pure enantiomers and/or their diastereoisomers or in the form of mixtures of these enantiomers or diastereoisomers.
The inventive compounds exhibit cytatoxic activity in selected tumor cell lines. The antitumor activity is intensified by irradiating with electromagnetic radiation having a to wavelength of 600 to 730 nm. The invention accordingly relates to the chemical combination of the cytotoxic principle of the platinum compounds of the cis platinum type with a photodynamically ac;ive molecule of the porphyrin derivative type, in such a manner, that compounds of goon water solubility and high selectivity are obtained.
Zentaris AG
The inventive compounds can be administerE:d intraaterially, intracerebrally, intramuscularly, intraperitoneally, intrathecally, intravenously, orally, parenterally, intranasally, rectally, subcutaneously and/or topically in the form of tablets, film-coated tablets, capsules, coated tablets, powders, granulates, drops, syrups.
ointments, powders for inhalation, infusion solutions, drinking solutions or in some other suitable form.
The medicaments comprise one or more compounds in addition to customary physiologically tolerable carriers and/or diiuents or auxiliaries.
~o The process for the production of the medicament is characerized in that one or more compounds are processed to give pharmaceutical preparations or brought into a therapeutically administrable form using customary pharmaceutical carriers andlor diluents or other auxiliaries.
a The synthesis of the inventive compounds is described.
Tetraarvlporphyrin platinum derivatives zo Synthesis of the substituted benzaldehydes. For the reaction with 4-hydroxy-benzaldehyde the respective oligo- and polyethyleneglycol monornethylethers had to be activated at their alcohol terminus with tosyl chloride according to a literature procedure. The etherification was performed by refluxing the tosylated alcohols and 4-hydroxybenzaldehyde together with KZC03 in DMF. ?he substituted ~s benzaldehydes were separated by filtration and purified by column chromatography.
For platinum coordination to the tetraarylporphryrins 1o be synthesized it is necessary to introduce two adjacent carboxylic acid groups in one of the substituted benzaldehydes. Therefore, 4-hydroxybenzald~3hyde was etherified with diethyl 3~ bromomalonate under alkaline conmditions. The diethyl 2-(4-formylphenoxy)malonate was used together with the substituted benzaldehydes for the synthesis of asymmetric tetraarylporphyrins.
Zentarls AG 7 Synthesis of the porphyrin ligands. The synthesis of the asymmetric tetraarylporphyrins was performed using the Lindsey method. Pyrrol and the respective benzaldehydes were reacted under Lewis acid catalysis to porphyrinogens, which were oxidized with p-ch(oranil to the corresponding porphyrins. The tetraarylporphyrin esters were purified by severs! column chromatographies. The carboxylic acids, which were required for coordination to the platinum(II) fragments, were prepared by hydrolysis of the esters with a mixture of CHC13 and 20 % methanolic KOH solution or pure 20 % methanolic KOH solution io only.
Synthesis of the platinum fragments. 1,2-Diaminoethane, 1,3-diam~nopropane, traps-1,2-diaminocyclohexane and 2,2'-bipyridine were commercially available and used as ligands to prepare the corresponding dichioroplatinum(II) complexes ~s according to literature procedures. Ethyl DL-2,3-diaminopropionate dihydrochloride, ethyl L-2,4-diaminobutanoate dihydrochloride and diethyl rneso-4,5-diaminosuberate dihydrochloride were synthesized according to literature procedures and used as iigands for the preparation of the corresponding diiodoplatinurn(Il) complexes, 2c~ Synthesis of the platinum complexes. For the reaction with the porphyrincarboxylie acids cisplatin had to be activated by conversion into diammine(diaqua)platinum(ll) hydroxide. It was reacted with an equimolar amount of the porphyrin ligand in a mixture of CHC13, ethanol and water or, in the case of the water-soluble ligand, in pure water. The resulting diammine(malonato)platinum(II) a5 complexes precipitated. To the reaction mixture of the water-soluble complex CH2CI2 was added to remove neutral impurities. The aqueous hphase was evaporated to obtain the product.
The diamine(dichloro)platinum(II) fragments were activated by conversion into diamine(dihydroxy)platinum(II) species, which were reacted with an equimolar ?a amount of the respective porphyrin malonic acid in a mixture of CH2C12, ethanol and wafer or, in the case of the water-soluble ligand, in pure water. The complexes Zentaris AG 8 precipitated. To the water-soluble complex CHZCl2 was added to remove neutral impurities, before the aqueous phase was evaporated to obtain the product.
For the reaction with the porphyrinmalonic acids it was necessary to activate the - diamine(diiodo)platinum(II) complexes by conversion into diamine(dinitrato) platinum(II) species, which are water-soluble in this form they were reacted with an equimolar amount of the porphyrin ligands, in a mixture of CH2C12, ethanol and water. The water-insoluble complexes precipitated after concentrating the solutions.
to Hematoporphyrin platinum derivatives tvpe Synthesis of the parphyrin ligands and the platinum precursors. Hemin was transferred to protoporphyrin dimethylester, from which all the subsequent reactions started. First, protoporphyrin dimethylester was treated with 30 % hydrobromic acid is in acetic acid to give the labile Markownikoff adduct of HBr to the two vinyl double bonds, which was reacted with different types of alcohols to replace bromide by the corresponding alkoxides. As alcohols we chose hydrophilic oligo- and polyethyleneglycol monomethylethers. During the etherification the F-aBr formed catalyzed the transesterification of the methylesters into the esters of the Zo corresponding alcohols. The etherified hematoporphyrin esters were purified by column chromatography. The carboxylic acids, which were required for coordination to the platinum(11) moieties, were prepared by hydrolysis of the esters with methanolic KOH solution.
__ 1,2-Diaminoethane, 1,3-diaminopropane, trans-1-2-diaminocyclohexane and 2,2'-bi-pyridine were commercially available and used as ligands to prepare the corresponding dichloroplatinum(Il) complexes according to literature procedures.
Ethyl Dl--2,3-diaminopropionate dihydrochloride, ethyl L-2,4-diaminobutanoate dihydrochloride and diethyl meso-4,5-diaminosuberate cihydrochloride were ~e synthesized according to literature procedures and used as ligands for the preparation of the corresponding diiodoplatinum(Il) complexes.
Zentaris AG 9 Synthesis of the platinum complexes. Reaction of the porphyrin carboxylic acids with cisplatin did not result in the desired complexes. Therefore, cisplatin had to be activated by conversion into diammine(diaqua)platinum(II) hydroxide, which was reacted with an equimolar amount of the porphyrin ligand in a mixture of ethanol and wafer or, in the case of the water-soluble ligands, in pure water. The resulting diammine(dicarboxylato)plaiinum{11) complexes precipitated. To the reaction mixtures of the water-soluble complexes CH2Clz was added to remove neutral impurities before the aqueous phase was evaporated to obtain the products.
:o The diamine(dichloro)platinum(II) precursors were activated by conversion into diamine(dihydroxy)platinum(Ilj species, which were reacted with an equimolar amount of the respective porphyr~n carboxylic; acid in a mixture of ethanol and water or, in the case of the water-soluble ligands, in pure water. The complexes precipitated. To the water-soluble complex CH2C12 was added to remove neutral is impurities and the aqueous phase was evaporated to obtain the product.
For the reaction with the porphyrincarboxylic acids it is necessary to activate the diamine(diiodo)platinum{II) complexes by conversion into diamine(dinitrato) platinum(II) species, which are water-soluble. In this form they were reacted with an 2o equimolar amount of the porphyrin ligand in a mixture of ethanol and water or, in the case of the water-soluble ligand, in pure water. The water-insoluble complexes precipitated after concentrating the solution. The water-soluble complexes were isolated by chromatography on silica.
25 Exemplary embodiments The following examples are intended to explain the invention in more detail.
The inventive compounds are tetraarylporphyrin platinum derivatives, covered by way of example by examples 1 and 2, and hc:matoporphyrin platinum derivatives, 3o covered by way of example by examples 3, ~ and 5.
Examples:
Zent3rfs AG 10 Example 1 R
NH.
J
pi,.._NH
Prior art Platinum(II) complexes with porphyrin ligands and their application as potent ~s cytostatic and phototoxic antitumor agents have already been described in the following publications.
W.M. Sharman, C.M. Allen and J.E. van Lier, DDT 4, (11 ) 507-517 (1 X799).
Photodynamic therapeutics: basic principles and clinical applications z0 T. Okunaka and H. Kato, Rev. Contemp. Pharmacother., 10, 59-68 (1999).
Potential Applications of Photodynamic Therapy.
H. Brunner, H. Obermeier and R.-M. Szeimie~, Chem. Ber., 1995, 128, 173-181.
2s Platinum(Il) complexes with porphyrin I~gands. synthesis and synergism during photodynamic therapy.
H. Brunner, K.-H. Schellerer and B. Treittinger, Inorg. Chim. Acta 1997, 264, 67-69.
Synthesis and in vitro testing of hematoporphyrin type ligands in platinum(II) ~o complexes as potent cytostatic and phototoxic antitumor agents.
Zentar~s AG
Description of the invention In the invention, novel porphyrin platinum derivatives are described, which have cytotoxic properties. Surprisingly, the compounds have good water solubility and a high selectivity. The compounds can be used for the treatment of cancer and, in particular, for the photodynamic treatment of tumors.
The general formulas of the claimed compounds of the tetraarylporphyrin platinum derivatives type are:
Formula I
O O
P~''~NHZ R3 O
X
I ~i O
R5 _ R6 R. ~ ~ O-~-CHZ CH2 O ~ n R4 n: 1-20 X: 0, S, NH, N-Alkyl R2IR3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R4: H, Alkyl, Aryl, Araikyl, Hetaryl. Hetarylalkyl, Cycloaikyl R5: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro. Cyano, Amino, subst. Amino R6: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro. Cyano, Amino, subst. Amino Zentaris AG
Formula II
NHZ R2~
'Z
'~ 'NHz R~'3 0 R.~
R7 _ R6 R: ~ ~ O--~-CH2 CHI O-'~R5 n: 1-20 X: O, S, NH, N-Alkyl R1IR2/R31R4: H, Alkyl, Aryl, Aralkyl. Hetaryl, Hetarylaikyt, Cycloalkyl oder R2-Z-R3, mit Z. (CHz)", n=0-6 R1IR4: H, -(CH~)"COORB, n=0-6 R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R6: H, Alkyf, 0-Alkyl. S-Alkyl, Halogen, Nit~o, Cyano, Amino, subst. Amino R7: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino RB: H, Alkyl The general tormuias of the claimed compounds of the hematoporphyrin platinum derivatives type are:
1:
Zentaris AG
Formula III
'H N ~ OR
/ N N ,_._ R4 i 0 ( 0 R= (CH,CH20)~Rs /NHS
R2 n= 1-20 R21R3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Het~rylalkyl, Cycloaikyl R4: H, Alkyl, Gycioalkyi R5: H, Alkyl, Cycloalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl Zentaris AG 5 Formula !1l R5 ~OR
'N
H \ ~ OR
N
_..- /
RS
O
O R= (CH2CH~0)nR7 O O n= 1-20 N- IPt~
NH
1 i~R3 R1/R21R3/R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, tietarylalkyl, Cycloalkyl oder R2-Z-R4, mit Z: (CHz)~, n=0-6 oder R11R3: H, -(CH2)~-COOR6. n=0-6 R4/R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycioalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyi, Cycloalkyl R7: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalky, Cycloalkyl If the inventive compounds have at least one center of asymmetry, they can be in the form of their race mates, their pure enantiomers and/or their diastereoisomers or in the form of mixtures of these enantiomers or diastereoisomers.
The inventive compounds exhibit cytatoxic activity in selected tumor cell lines. The antitumor activity is intensified by irradiating with electromagnetic radiation having a to wavelength of 600 to 730 nm. The invention accordingly relates to the chemical combination of the cytotoxic principle of the platinum compounds of the cis platinum type with a photodynamically ac;ive molecule of the porphyrin derivative type, in such a manner, that compounds of goon water solubility and high selectivity are obtained.
Zentaris AG
The inventive compounds can be administerE:d intraaterially, intracerebrally, intramuscularly, intraperitoneally, intrathecally, intravenously, orally, parenterally, intranasally, rectally, subcutaneously and/or topically in the form of tablets, film-coated tablets, capsules, coated tablets, powders, granulates, drops, syrups.
ointments, powders for inhalation, infusion solutions, drinking solutions or in some other suitable form.
The medicaments comprise one or more compounds in addition to customary physiologically tolerable carriers and/or diiuents or auxiliaries.
~o The process for the production of the medicament is characerized in that one or more compounds are processed to give pharmaceutical preparations or brought into a therapeutically administrable form using customary pharmaceutical carriers andlor diluents or other auxiliaries.
a The synthesis of the inventive compounds is described.
Tetraarvlporphyrin platinum derivatives zo Synthesis of the substituted benzaldehydes. For the reaction with 4-hydroxy-benzaldehyde the respective oligo- and polyethyleneglycol monornethylethers had to be activated at their alcohol terminus with tosyl chloride according to a literature procedure. The etherification was performed by refluxing the tosylated alcohols and 4-hydroxybenzaldehyde together with KZC03 in DMF. ?he substituted ~s benzaldehydes were separated by filtration and purified by column chromatography.
For platinum coordination to the tetraarylporphryrins 1o be synthesized it is necessary to introduce two adjacent carboxylic acid groups in one of the substituted benzaldehydes. Therefore, 4-hydroxybenzald~3hyde was etherified with diethyl 3~ bromomalonate under alkaline conmditions. The diethyl 2-(4-formylphenoxy)malonate was used together with the substituted benzaldehydes for the synthesis of asymmetric tetraarylporphyrins.
Zentarls AG 7 Synthesis of the porphyrin ligands. The synthesis of the asymmetric tetraarylporphyrins was performed using the Lindsey method. Pyrrol and the respective benzaldehydes were reacted under Lewis acid catalysis to porphyrinogens, which were oxidized with p-ch(oranil to the corresponding porphyrins. The tetraarylporphyrin esters were purified by severs! column chromatographies. The carboxylic acids, which were required for coordination to the platinum(II) fragments, were prepared by hydrolysis of the esters with a mixture of CHC13 and 20 % methanolic KOH solution or pure 20 % methanolic KOH solution io only.
Synthesis of the platinum fragments. 1,2-Diaminoethane, 1,3-diam~nopropane, traps-1,2-diaminocyclohexane and 2,2'-bipyridine were commercially available and used as ligands to prepare the corresponding dichioroplatinum(II) complexes ~s according to literature procedures. Ethyl DL-2,3-diaminopropionate dihydrochloride, ethyl L-2,4-diaminobutanoate dihydrochloride and diethyl rneso-4,5-diaminosuberate dihydrochloride were synthesized according to literature procedures and used as iigands for the preparation of the corresponding diiodoplatinurn(Il) complexes, 2c~ Synthesis of the platinum complexes. For the reaction with the porphyrincarboxylie acids cisplatin had to be activated by conversion into diammine(diaqua)platinum(ll) hydroxide. It was reacted with an equimolar amount of the porphyrin ligand in a mixture of CHC13, ethanol and water or, in the case of the water-soluble ligand, in pure water. The resulting diammine(malonato)platinum(II) a5 complexes precipitated. To the reaction mixture of the water-soluble complex CH2CI2 was added to remove neutral impurities. The aqueous hphase was evaporated to obtain the product.
The diamine(dichloro)platinum(II) fragments were activated by conversion into diamine(dihydroxy)platinum(II) species, which were reacted with an equimolar ?a amount of the respective porphyrin malonic acid in a mixture of CH2C12, ethanol and wafer or, in the case of the water-soluble ligand, in pure water. The complexes Zentaris AG 8 precipitated. To the water-soluble complex CHZCl2 was added to remove neutral impurities, before the aqueous phase was evaporated to obtain the product.
For the reaction with the porphyrinmalonic acids it was necessary to activate the - diamine(diiodo)platinum(II) complexes by conversion into diamine(dinitrato) platinum(II) species, which are water-soluble in this form they were reacted with an equimolar amount of the porphyrin ligands, in a mixture of CH2C12, ethanol and water. The water-insoluble complexes precipitated after concentrating the solutions.
to Hematoporphyrin platinum derivatives tvpe Synthesis of the parphyrin ligands and the platinum precursors. Hemin was transferred to protoporphyrin dimethylester, from which all the subsequent reactions started. First, protoporphyrin dimethylester was treated with 30 % hydrobromic acid is in acetic acid to give the labile Markownikoff adduct of HBr to the two vinyl double bonds, which was reacted with different types of alcohols to replace bromide by the corresponding alkoxides. As alcohols we chose hydrophilic oligo- and polyethyleneglycol monomethylethers. During the etherification the F-aBr formed catalyzed the transesterification of the methylesters into the esters of the Zo corresponding alcohols. The etherified hematoporphyrin esters were purified by column chromatography. The carboxylic acids, which were required for coordination to the platinum(11) moieties, were prepared by hydrolysis of the esters with methanolic KOH solution.
__ 1,2-Diaminoethane, 1,3-diaminopropane, trans-1-2-diaminocyclohexane and 2,2'-bi-pyridine were commercially available and used as ligands to prepare the corresponding dichloroplatinum(Il) complexes according to literature procedures.
Ethyl Dl--2,3-diaminopropionate dihydrochloride, ethyl L-2,4-diaminobutanoate dihydrochloride and diethyl meso-4,5-diaminosuberate cihydrochloride were ~e synthesized according to literature procedures and used as ligands for the preparation of the corresponding diiodoplatinum(Il) complexes.
Zentaris AG 9 Synthesis of the platinum complexes. Reaction of the porphyrin carboxylic acids with cisplatin did not result in the desired complexes. Therefore, cisplatin had to be activated by conversion into diammine(diaqua)platinum(II) hydroxide, which was reacted with an equimolar amount of the porphyrin ligand in a mixture of ethanol and wafer or, in the case of the water-soluble ligands, in pure water. The resulting diammine(dicarboxylato)plaiinum{11) complexes precipitated. To the reaction mixtures of the water-soluble complexes CH2Clz was added to remove neutral impurities before the aqueous phase was evaporated to obtain the products.
:o The diamine(dichloro)platinum(II) precursors were activated by conversion into diamine(dihydroxy)platinum(Ilj species, which were reacted with an equimolar amount of the respective porphyr~n carboxylic; acid in a mixture of ethanol and water or, in the case of the water-soluble ligands, in pure water. The complexes precipitated. To the water-soluble complex CH2C12 was added to remove neutral is impurities and the aqueous phase was evaporated to obtain the product.
For the reaction with the porphyrincarboxylic acids it is necessary to activate the diamine(diiodo)platinum{II) complexes by conversion into diamine(dinitrato) platinum(II) species, which are water-soluble. In this form they were reacted with an 2o equimolar amount of the porphyrin ligand in a mixture of ethanol and water or, in the case of the water-soluble ligand, in pure water. The water-insoluble complexes precipitated after concentrating the solution. The water-soluble complexes were isolated by chromatography on silica.
25 Exemplary embodiments The following examples are intended to explain the invention in more detail.
The inventive compounds are tetraarylporphyrin platinum derivatives, covered by way of example by examples 1 and 2, and hc:matoporphyrin platinum derivatives, 3o covered by way of example by examples 3, ~ and 5.
Examples:
Zent3rfs AG 10 Example 1 R
NH.
J
pi,.._NH
R: ~ / O-~-CH~ CHZ O-~-CH~
n: 2 Diammine[2-(4-{10,15,20-tris[4-(1,4,7-trioxaoctyl)phenyl]porphyrin-5-yl}phenoxy)malonato]platinum(II) (No. 21 in Figure 1 ) The compound 2-(4-(10,15.20-Tris[4-(1,4,7-trioxaoctyl)phenyl]porphyrin-5-yl}phenoxy)malonic acid (109 mg, 0.100 mmol) was dissolved in 10 ml of CHCIS
and 20 ml of EtOH, combined with 0.100 mmol of the aqueous diammine(diaqua)platinum(1l) hydroxide solution and stirred for 20 h. Yield:
81.0 mg m (54.2 Irnol, 54 %) purpie powder, mp 213-214°C.
Anal. (C~2H66N60~4Pt ~10 H20, 1494,5) C: calcd. 49,83; found. 49,10. H, N:
calcd.
5,62; found 6.09.
Zentaris AG I 1 N liz'"1~ W
0 O. //
PI~
o NNz 0 , O
o-Z-CH2 cH2 o-~cr~~
n: 3 (~)-traps-1,2-Diaminocyclohexane[2-(4-{10,15.20-tris(4-(1,4,7,10-tetraoxaundecyl)phenyl]porphyrin-5-yi}phenoxy)maionato]platinum(i1) (No. 29 in Figure 1 }.
122 mg (0.100 mmol) Of the compound 2-(4-{10,15,20-Tris[4-(1,4,7,10-tetraoxaundecyl)phenyl]porphyrin-5-yl}phenoxy)malonic acid in 10 ml of CHzCl2 and is 20 ml of EtOH were reacted with 0.100 mmol of activated (~)-traps-1,2-diaminocyclohexane(dichloro)platinum(II). YiEald: 113 mg (73.9 ~mol, 74 %) purple solid, mp 208°C. Anal. (C~4HegNg017Ft, 1526.6) C, H, N.
Example 2 Ze~taris AG 12 OR
i2CH20)~CH~
i- , ,Pt H3N 1 n= 2 Diammine{7,12-bis[1-(1,4,7-trioxaoctyl)ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionato}platinum(II) (No. 21 in Figure 2) The compound 7,12-Bis[1-(1,4,7-trioxaoctyl)Eahylj-3,8,13,17-tetramethylporphyrin-2,18-dipropionic acid (80.3 mg, 0.100 mmol) was dissolved in 6 ml EiOH, combined with 0.100 mmol of the aqueous diammine(diaqua)platinum(II) hydroxide solution and stirred for 20 h. Yield: 23.0 mg (22.3 Irnol, 22 %) dark brown powder, mp >
to 250°C. Anal. (C~H62N60-pPt, 1030.1 ). C: calcd_ 51.30; found. 50.75.
H: calcd. 6.07;
found. 5.49. N
.s ~o Example 3 Zentaris AG 13 Example 4 OR
O
i2CH2O)r,CH, ~Pt U
NHS , n= 5 N H, s (~)-frans-1,2-Diaminocyclohexane{7,12-bis[1-(1,4,7,10,13,16-hexaoxaheptadecyl)ethylJ-3,8,13,17-tetrame;hylporphyrin-2,18-dipropionato)platinum(II) (No. 38 in Figure 2).
The compound 7,12-Bis[1,4,7,10,13,16-hexaoxaheptadecyi)ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionic acid (107 mg, 0.100 mmol) in 10 ml of EtOH
~o were rested with 0.100 mmol of activated (~)-frans-1,2-Diaminocyclohexane(dichloro)platinum(II).
Yield: 25.5 mg (17.2 Irnol, 17 %) reddish brown powder; mp 245°C
Anal.
(C62H94N6016Pt -6 H20, 1482,6). C: calcd. 50.23; found. 49.02. H' calcd. 7.21;
found. 6.33. N: calcd. 5,67; found. 6.41 Zentaris AG 14 Example 5 OR
O
~Pt~ ~ . ~ZCH20)~CH3 'N ~ n= 2 / Nw 2,2'-Bipyridyl{7,12-bis[1-(1,4,7-trioxaoctyl)ethyl]-3,8,13,17-tetramethylporphyrin-2,13-dipropionato)platinum(II) (No. 40a in Figure 2).
42.2 mg (0.100 mmol) of the compound 2,2'-8ipyridyl(dichloro)platinum(II) were suspended in 15 ml of H20. After 10 min ultrasonic treatment 34.0 mg (0.200 mmol) of AgN03 were added and the mixture was stirred for 4 h in the dark at room temperature. The precipitated AgCI was filtered off and washed with water. The filtrate containing the activated platinum(Il) complex was evaporated. The residue ~o was dissolved in 5 ml of H20 and combined with a solution of 80.3 mg (0.100 mmoi) 7,12-Bis[1-(1,4,7-trioxaoctyl)ethyl]-3,8," 3,17-tetramethylporphyrin-2,'~ 8-dipropionic acid in 10 ml of EtOH. After stirring for 20 h at 50°C and cooling to room temperature the precip;tated solid was filtered, washed with water and EtOH and dried in vacuo.
Yieldv 64.0 mg (55.5 ~rnol, 55 %) dark purple powder, mp > 250'C. Anal.
is (C54H64N60~OFt, 1152.2) C, H, N.
Biological data.
Zentarns AG 15 Data of the cytotoxic effect was obtained, for instance, on the human tumor cell lines TCC-SUP and J82. The effect of the compounds was investigated in the dark and under irradiation with light at a wavelength of G00 - 730 nm. Selected compounds s are clearly more activ cytotoxically under irradiation. There is a synergism between the cytotoxic effect of the platinum component and the photodynamic principle.
Cell lines and general procedures.
To determine the antiproliferative activity of the new porphyrin ligands and the ~o corresponding platinum complexes with different amine non-leaving groups two bladder cancer cell lines TCC-SUP and J82 were selected as in vifro models.
To discriminate between the cytotoxic and piiototoxic effects all experiments were carried out in duplicate. The cells were seeded into microplates and the test 1~ compounds were added after 48 h. One batch of the microplates was kept in the dark until the end o' the experiment, whereas the other microplates were irradiated 48 h after addition of the substances for 10 min with a light dose of 24 Jcm-2, before the plates were reincubated in the dark.
2o End-point chemosensitivity assay, Hematopog?hvrin platinum derivatives type.
At a dosage of 1 uM, both the dark- and phototoxicity of the porphyrin-platinum conjugates are influenced by the type of the non-leaving group. The platinum Ls complexes with 2,2'-bipyridyl (40, 41 ), ethyl ClL-2,3-diaminopropionate (42-46), ethyl DL-2,3-diaminobutanoate (47-51 ), diethyl meso-4,5-diaminosuberate (52-55) ligands were inactive at a concentration of 1 uM, botn in the dark and after irradiation. The compounds bearing 1,2-diaminoethane {27-30) and 1,2-diaminopropane (31-34) non-leaving groups were also inactive against TCC-SUP cells. The most interesting 3o porphyrin-platinum conjugates were those with the diammine (21-26) and the (~)-trans-1,2-diaminocyclohexane (35-39) iigands. Within these series of compounds the water-soluble complexes 26 and 39 were most active with TIC~o~~ of around 30 Zen;aris AG 1 G
Gnd 15 %, respectively. At 1 y~M concentration the reference cisplatin had a TIC~orr.
value of approximately 2 %, At this dosage there was no statistically significant enhancement of the cytotoxicity by irradiation of the bladder cancer cells.
An increase in the concentration of complexes 40-55 to 5 ~M resulted in no or only marginal augmentation of the dark toxicity (Figure 2). For most of these complexes the phototoxicity is not much higher than the c:ytotoxicity observed without irradiation.
However, for 42, 45, 47, 49, 50 and 53 there is a distinct effect and for 40 and 44 a very strong effect on the proliferativation of the TCC-SUP cells upon irradiation is ;o observed (Figure 2). The highest synergism was found for compound 52 resulting in the lysis of the tumor cells.
Apart from cisplatin, the highest antitumor activities were measured within the series of porphyrin-platinum conjugates bearing diammine (21-26) and (~)-trays-1,2-a s diaminocyclohexane (35-39) non-leaving groups. The differences between dark and light -induced toxicities were best for the water-soluble porphyrin-platinum complexes 26 and 39 with a side chain length of n - 17 in position 7 and 12 of the porphyrin leaving group. All the ethylenediamine and propylenediamine complexes 27-34 showed a remarkable light-induced toxicity (Figure 2).
Tetraarylporph~rin platinum derivatives type.
At a dosage of 1 ~cM and 5 ECM, both the dark- and phototoxicity of the tetraarylporphyrin-platinum conjugates 21-38 were highly influenced by the type of the non-leaving group the results agreeing with those of the hematoporphyrin-platinum complexes discussed above. 23, 2~ and 30 were the most active tetraarylporphyrin-platinum conjugates with TIC~orr. values of around 37 %, 57 and 63 %, respectively, at 1 iuM concentration. This is analogous to the 3o hemaioporphyrin-platinum complexes, the most active of which were those with the diammine or the (~)-traps-1,2-diaminocyclohexane non-leaving groups, At 1 pM
Zentans AG .?
concentration there was only a slight enhancement of the cytotoxicity of the tetraarylporphyrin-platinum conjugates with the side chain length n = 2 and n = 3 upon irradiation. On the average the light-induced TICoorr. values were by approximately 20 % Lower than the dark-only cytotoxicities (data not shown).
An increase in the concentration of the complexes to 5 ~M enhanced the dark effects and the phototoxicities as shown in Figure 1. Apart from cisplatin, the highest antitumor activities were measured for the tetraarylporphyrin-platinum conjugates bearing diammine (21-23) and (~)-trans-1,2-diaminocyclohexane (28-30) non-leaving groups. The differences betUreen dark and light-induced toxicities were best for the ~,o tetraarylporphyrin-platinum complexes 24, 27, 32-34, 36 and 38 with a side chain length of n = 2 or n = 3 (Figure l ).
n: 2 Diammine[2-(4-{10,15,20-tris[4-(1,4,7-trioxaoctyl)phenyl]porphyrin-5-yl}phenoxy)malonato]platinum(II) (No. 21 in Figure 1 ) The compound 2-(4-(10,15.20-Tris[4-(1,4,7-trioxaoctyl)phenyl]porphyrin-5-yl}phenoxy)malonic acid (109 mg, 0.100 mmol) was dissolved in 10 ml of CHCIS
and 20 ml of EtOH, combined with 0.100 mmol of the aqueous diammine(diaqua)platinum(1l) hydroxide solution and stirred for 20 h. Yield:
81.0 mg m (54.2 Irnol, 54 %) purpie powder, mp 213-214°C.
Anal. (C~2H66N60~4Pt ~10 H20, 1494,5) C: calcd. 49,83; found. 49,10. H, N:
calcd.
5,62; found 6.09.
Zentaris AG I 1 N liz'"1~ W
0 O. //
PI~
o NNz 0 , O
o-Z-CH2 cH2 o-~cr~~
n: 3 (~)-traps-1,2-Diaminocyclohexane[2-(4-{10,15.20-tris(4-(1,4,7,10-tetraoxaundecyl)phenyl]porphyrin-5-yi}phenoxy)maionato]platinum(i1) (No. 29 in Figure 1 }.
122 mg (0.100 mmol) Of the compound 2-(4-{10,15,20-Tris[4-(1,4,7,10-tetraoxaundecyl)phenyl]porphyrin-5-yl}phenoxy)malonic acid in 10 ml of CHzCl2 and is 20 ml of EtOH were reacted with 0.100 mmol of activated (~)-traps-1,2-diaminocyclohexane(dichloro)platinum(II). YiEald: 113 mg (73.9 ~mol, 74 %) purple solid, mp 208°C. Anal. (C~4HegNg017Ft, 1526.6) C, H, N.
Example 2 Ze~taris AG 12 OR
i2CH20)~CH~
i- , ,Pt H3N 1 n= 2 Diammine{7,12-bis[1-(1,4,7-trioxaoctyl)ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionato}platinum(II) (No. 21 in Figure 2) The compound 7,12-Bis[1-(1,4,7-trioxaoctyl)Eahylj-3,8,13,17-tetramethylporphyrin-2,18-dipropionic acid (80.3 mg, 0.100 mmol) was dissolved in 6 ml EiOH, combined with 0.100 mmol of the aqueous diammine(diaqua)platinum(II) hydroxide solution and stirred for 20 h. Yield: 23.0 mg (22.3 Irnol, 22 %) dark brown powder, mp >
to 250°C. Anal. (C~H62N60-pPt, 1030.1 ). C: calcd_ 51.30; found. 50.75.
H: calcd. 6.07;
found. 5.49. N
.s ~o Example 3 Zentaris AG 13 Example 4 OR
O
i2CH2O)r,CH, ~Pt U
NHS , n= 5 N H, s (~)-frans-1,2-Diaminocyclohexane{7,12-bis[1-(1,4,7,10,13,16-hexaoxaheptadecyl)ethylJ-3,8,13,17-tetrame;hylporphyrin-2,18-dipropionato)platinum(II) (No. 38 in Figure 2).
The compound 7,12-Bis[1,4,7,10,13,16-hexaoxaheptadecyi)ethyl]-3,8,13,17-tetramethylporphyrin-2,18-dipropionic acid (107 mg, 0.100 mmol) in 10 ml of EtOH
~o were rested with 0.100 mmol of activated (~)-frans-1,2-Diaminocyclohexane(dichloro)platinum(II).
Yield: 25.5 mg (17.2 Irnol, 17 %) reddish brown powder; mp 245°C
Anal.
(C62H94N6016Pt -6 H20, 1482,6). C: calcd. 50.23; found. 49.02. H' calcd. 7.21;
found. 6.33. N: calcd. 5,67; found. 6.41 Zentaris AG 14 Example 5 OR
O
~Pt~ ~ . ~ZCH20)~CH3 'N ~ n= 2 / Nw 2,2'-Bipyridyl{7,12-bis[1-(1,4,7-trioxaoctyl)ethyl]-3,8,13,17-tetramethylporphyrin-2,13-dipropionato)platinum(II) (No. 40a in Figure 2).
42.2 mg (0.100 mmol) of the compound 2,2'-8ipyridyl(dichloro)platinum(II) were suspended in 15 ml of H20. After 10 min ultrasonic treatment 34.0 mg (0.200 mmol) of AgN03 were added and the mixture was stirred for 4 h in the dark at room temperature. The precipitated AgCI was filtered off and washed with water. The filtrate containing the activated platinum(Il) complex was evaporated. The residue ~o was dissolved in 5 ml of H20 and combined with a solution of 80.3 mg (0.100 mmoi) 7,12-Bis[1-(1,4,7-trioxaoctyl)ethyl]-3,8," 3,17-tetramethylporphyrin-2,'~ 8-dipropionic acid in 10 ml of EtOH. After stirring for 20 h at 50°C and cooling to room temperature the precip;tated solid was filtered, washed with water and EtOH and dried in vacuo.
Yieldv 64.0 mg (55.5 ~rnol, 55 %) dark purple powder, mp > 250'C. Anal.
is (C54H64N60~OFt, 1152.2) C, H, N.
Biological data.
Zentarns AG 15 Data of the cytotoxic effect was obtained, for instance, on the human tumor cell lines TCC-SUP and J82. The effect of the compounds was investigated in the dark and under irradiation with light at a wavelength of G00 - 730 nm. Selected compounds s are clearly more activ cytotoxically under irradiation. There is a synergism between the cytotoxic effect of the platinum component and the photodynamic principle.
Cell lines and general procedures.
To determine the antiproliferative activity of the new porphyrin ligands and the ~o corresponding platinum complexes with different amine non-leaving groups two bladder cancer cell lines TCC-SUP and J82 were selected as in vifro models.
To discriminate between the cytotoxic and piiototoxic effects all experiments were carried out in duplicate. The cells were seeded into microplates and the test 1~ compounds were added after 48 h. One batch of the microplates was kept in the dark until the end o' the experiment, whereas the other microplates were irradiated 48 h after addition of the substances for 10 min with a light dose of 24 Jcm-2, before the plates were reincubated in the dark.
2o End-point chemosensitivity assay, Hematopog?hvrin platinum derivatives type.
At a dosage of 1 uM, both the dark- and phototoxicity of the porphyrin-platinum conjugates are influenced by the type of the non-leaving group. The platinum Ls complexes with 2,2'-bipyridyl (40, 41 ), ethyl ClL-2,3-diaminopropionate (42-46), ethyl DL-2,3-diaminobutanoate (47-51 ), diethyl meso-4,5-diaminosuberate (52-55) ligands were inactive at a concentration of 1 uM, botn in the dark and after irradiation. The compounds bearing 1,2-diaminoethane {27-30) and 1,2-diaminopropane (31-34) non-leaving groups were also inactive against TCC-SUP cells. The most interesting 3o porphyrin-platinum conjugates were those with the diammine (21-26) and the (~)-trans-1,2-diaminocyclohexane (35-39) iigands. Within these series of compounds the water-soluble complexes 26 and 39 were most active with TIC~o~~ of around 30 Zen;aris AG 1 G
Gnd 15 %, respectively. At 1 y~M concentration the reference cisplatin had a TIC~orr.
value of approximately 2 %, At this dosage there was no statistically significant enhancement of the cytotoxicity by irradiation of the bladder cancer cells.
An increase in the concentration of complexes 40-55 to 5 ~M resulted in no or only marginal augmentation of the dark toxicity (Figure 2). For most of these complexes the phototoxicity is not much higher than the c:ytotoxicity observed without irradiation.
However, for 42, 45, 47, 49, 50 and 53 there is a distinct effect and for 40 and 44 a very strong effect on the proliferativation of the TCC-SUP cells upon irradiation is ;o observed (Figure 2). The highest synergism was found for compound 52 resulting in the lysis of the tumor cells.
Apart from cisplatin, the highest antitumor activities were measured within the series of porphyrin-platinum conjugates bearing diammine (21-26) and (~)-trays-1,2-a s diaminocyclohexane (35-39) non-leaving groups. The differences between dark and light -induced toxicities were best for the water-soluble porphyrin-platinum complexes 26 and 39 with a side chain length of n - 17 in position 7 and 12 of the porphyrin leaving group. All the ethylenediamine and propylenediamine complexes 27-34 showed a remarkable light-induced toxicity (Figure 2).
Tetraarylporph~rin platinum derivatives type.
At a dosage of 1 ~cM and 5 ECM, both the dark- and phototoxicity of the tetraarylporphyrin-platinum conjugates 21-38 were highly influenced by the type of the non-leaving group the results agreeing with those of the hematoporphyrin-platinum complexes discussed above. 23, 2~ and 30 were the most active tetraarylporphyrin-platinum conjugates with TIC~orr. values of around 37 %, 57 and 63 %, respectively, at 1 iuM concentration. This is analogous to the 3o hemaioporphyrin-platinum complexes, the most active of which were those with the diammine or the (~)-traps-1,2-diaminocyclohexane non-leaving groups, At 1 pM
Zentans AG .?
concentration there was only a slight enhancement of the cytotoxicity of the tetraarylporphyrin-platinum conjugates with the side chain length n = 2 and n = 3 upon irradiation. On the average the light-induced TICoorr. values were by approximately 20 % Lower than the dark-only cytotoxicities (data not shown).
An increase in the concentration of the complexes to 5 ~M enhanced the dark effects and the phototoxicities as shown in Figure 1. Apart from cisplatin, the highest antitumor activities were measured for the tetraarylporphyrin-platinum conjugates bearing diammine (21-23) and (~)-trans-1,2-diaminocyclohexane (28-30) non-leaving groups. The differences betUreen dark and light-induced toxicities were best for the ~,o tetraarylporphyrin-platinum complexes 24, 27, 32-34, 36 and 38 with a side chain length of n = 2 or n = 3 (Figure l ).
Claims (15)
1. Porphyrin platinum derivatives of the (a) tetraarylporphyrin platinum derivatives type according to formula I
X: O, S, NH, N-Alkyl R2/R3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R5: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino R6: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino and according to formula II
X: O, S, NH, N-Alkyl R1/R2/R3/R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl oder R2-Z-R3, mit Z: (CH2)n, n=0-6 R1/R4: H, -(CH2)n-COOR8, n=0-6 R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R6: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino R7: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino R8: H, Alkyl and (b) hematoporphyrin platinum derivatives type according to formula III
R2/R3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R4: H, Alkyl, Cycloalkyl R5: H, Alkyl, Cycloalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl and according to formula IV
R1/R2/R3/R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl oder R2-Z-R4, mit Z: (CH2)n, n=0-6 oder R1/R3: H, -(CH2)-COOR6, n=0-6 R4/R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R7: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl
X: O, S, NH, N-Alkyl R2/R3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R5: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino R6: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino and according to formula II
X: O, S, NH, N-Alkyl R1/R2/R3/R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl oder R2-Z-R3, mit Z: (CH2)n, n=0-6 R1/R4: H, -(CH2)n-COOR8, n=0-6 R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R6: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino R7: H, Alkyl, O-Alkyl, S-Alkyl, Halogen, Nitro, Cyano, Amino, subst. Amino R8: H, Alkyl and (b) hematoporphyrin platinum derivatives type according to formula III
R2/R3: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R4: H, Alkyl, Cycloalkyl R5: H, Alkyl, Cycloalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl and according to formula IV
R1/R2/R3/R4: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl oder R2-Z-R4, mit Z: (CH2)n, n=0-6 oder R1/R3: H, -(CH2)-COOR6, n=0-6 R4/R5: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R6: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl R7: H, Alkyl, Aryl, Aralkyl, Hetaryl, Hetarylalkyl, Cycloalkyl
2. Compounds as shown in formulas I, II, III and IV according to claim 1, having one or more asymmetric carbon atoms, in the form of their racemates, their pure enantiomers and/or their diastereoisomers or in the form of mixtures of these enantiomers or diastereoisomers.
3 Use of the compounds as shown in formulas I, II, III and IV according to claims ~
and 2 as therapeutic active compounds for the production of medicaments for the treatment of cancer.
and 2 as therapeutic active compounds for the production of medicaments for the treatment of cancer.
4. Use of the compounds as shown in formulas I, II, III and IV according to claims 1 and 2 as therapeutic active compounds for the production of medicaments for the photodynamic treatment of tumors.
5. Particularly preferred use of the compounds as shown in formulas I, II, III
and IV
according to claims 1, 2 and 4 as therapeutic active compounds for the production of medicaments for the photodynamic treatment of tumors by irradiating with electromagnetic radiation having a wavelenght of 600 to 730 nm.
and IV
according to claims 1, 2 and 4 as therapeutic active compounds for the production of medicaments for the photodynamic treatment of tumors by irradiating with electromagnetic radiation having a wavelenght of 600 to 730 nm.
6. Medicaments comprising one or more compounds according to claims 1 and 2 in addition to customary physiologically tolerable carriers and/or diluents or auxiliaries.
7. Process for the production of a medicament according to claim 6, characterized in that one or more compounds according to claims 1 and 2 are processed to give pharmaceutical preparations or brought into a therapeutically administrable form using a customary pharmaceutical carriers and/or diluents or other auxiliaries.
8. Use of compounds of the formulas I, II, III or IV according to claims 1 and 2 and/or pharmaceutical preparations acording to claims 6 and 7 on their own or in combination with one another or in combination with carriers and/or diluents or other auxiliaries.
9. A porphyrin derivative which having one of the following formulae wherein X is O, S, or an NH, or N-alkyl residue R2/R3 are H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, or a cycloalkyl residue, R4 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, or cycloalkyl residue.
R5 is H, or an O-alkyl, S-alkyl, ha;ogen, nitro, cyano, amino, or subst. amino residue, R6 is H, or an alkyl, O-alkyl, S-alkyl, halogen;
nitro, cyano, amino, or subst.amino residue.
wherein:
X is O, S, or n NH or N-alkyl residue, R1/R2/R3/R4 are H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl; cycloaklyl, Or R2-Z-R3 with Z are a (CH2)n-COOR3; n=0-8 R5 is H. or an alkyl, aryl, aralkyl, heteroaryl, heterylaklyl, or cycloalkyl residue, R6 is H. or an alkyl, O-allyl, S-alkyl, halogen, nitro, cyano, amino, or subs. amino residue, R7 is H. or an alkyl, O-alkyl, S-alkyl, halogen, nitro, cyano, amino or subst. amino residue, and R8 is H or an alkyl residue.
wherein R2/R3 is H, or an aryl, aralkyl, heteroaryl, heterylaklyl, or cycloalkyl residue, R4 is H, or an alkyl or cycloakyl residue, R5 is H, or an alkyl, or cycloalkyl residue, R6 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, of cyanoalkyl residue.
wherein R1/R2/R3/R4 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl or cycloalkyl residue. or R2-Z-R4 with Z=(CH2)n,, where n=0-6, or R2/R3 is H or (CH2)n, where n=0-6, R4/R5 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, or cycloalkyl residue, R6 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, or cycloalkyl residue, and R7 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylaklyl, or cycloalkyl residue.
R5 is H, or an O-alkyl, S-alkyl, ha;ogen, nitro, cyano, amino, or subst. amino residue, R6 is H, or an alkyl, O-alkyl, S-alkyl, halogen;
nitro, cyano, amino, or subst.amino residue.
wherein:
X is O, S, or n NH or N-alkyl residue, R1/R2/R3/R4 are H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl; cycloaklyl, Or R2-Z-R3 with Z are a (CH2)n-COOR3; n=0-8 R5 is H. or an alkyl, aryl, aralkyl, heteroaryl, heterylaklyl, or cycloalkyl residue, R6 is H. or an alkyl, O-allyl, S-alkyl, halogen, nitro, cyano, amino, or subs. amino residue, R7 is H. or an alkyl, O-alkyl, S-alkyl, halogen, nitro, cyano, amino or subst. amino residue, and R8 is H or an alkyl residue.
wherein R2/R3 is H, or an aryl, aralkyl, heteroaryl, heterylaklyl, or cycloalkyl residue, R4 is H, or an alkyl or cycloakyl residue, R5 is H, or an alkyl, or cycloalkyl residue, R6 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, of cyanoalkyl residue.
wherein R1/R2/R3/R4 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl or cycloalkyl residue. or R2-Z-R4 with Z=(CH2)n,, where n=0-6, or R2/R3 is H or (CH2)n, where n=0-6, R4/R5 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, or cycloalkyl residue, R6 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylalkyl, or cycloalkyl residue, and R7 is H, or an alkyl, aryl, aralkyl, heteroaryl, heterylaklyl, or cycloalkyl residue.
10. The porphyrin derivative of claim 1, which is selected from the following compounds:
Porphyrin-2,2-diamino-5-phenoxy-[1,2,3] - Porphyrin-2,2-octahydro-1,3-oiaza-2--dioxaplatininane-4,6-dione platina-inden-2-yl spiro ester of phenoxy-[1,3,2]dioxapiatininane-4,6--dione Porphyrin-propionic acid 2--propionyloxy-octahydro--1,3-diaza-2-plating-inden-2-yl ester
Porphyrin-2,2-diamino-5-phenoxy-[1,2,3] - Porphyrin-2,2-octahydro-1,3-oiaza-2--dioxaplatininane-4,6-dione platina-inden-2-yl spiro ester of phenoxy-[1,3,2]dioxapiatininane-4,6--dione Porphyrin-propionic acid 2--propionyloxy-octahydro--1,3-diaza-2-plating-inden-2-yl ester
11. A process for intensifying the antitumor efficacy of a porphyrin derivative of claim 9, which comprises irradiating the derivative with electromagnetic radiation.
12. A process for treating a tumor, which comprises administering to a patient in need therefor a porphyrin derivative of claim 9.
13. A process for treating a tumor which comprises administering to a patient in need therefor a compound of claim 10.
14. The process of claim 12, wherein the tumor to be treated is photosensitive.
15. The process of claim 13, wherein the tumor to be treated is photosensitive.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35358502P | 2002-02-01 | 2002-02-01 | |
| US60/353,585 | 2002-02-01 |
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| CA2418410A1 true CA2418410A1 (en) | 2003-08-01 |
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| CA002418410A Abandoned CA2418410A1 (en) | 2002-02-01 | 2003-02-03 | Novel, water-soluble porphyrin platinum compounds with high tumor selectivity and their use for the treatment of benign and malignant tumor diseases |
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| US (1) | US7087214B2 (en) |
| EP (1) | EP1470139A2 (en) |
| JP (1) | JP2005522429A (en) |
| KR (1) | KR20040083098A (en) |
| CN (1) | CN1303090C (en) |
| AR (1) | AR038479A1 (en) |
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| HK (1) | HK1078585A1 (en) |
| HR (1) | HRP20040788A2 (en) |
| MX (1) | MXPA04007443A (en) |
| NO (1) | NO20043650L (en) |
| NZ (1) | NZ534541A (en) |
| PL (1) | PL373346A1 (en) |
| RU (1) | RU2004126637A (en) |
| TW (1) | TWI233929B (en) |
| UA (1) | UA78007C2 (en) |
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| US10766915B2 (en) | 2013-03-15 | 2020-09-08 | Sherri Ann McFARLAND | Metal-based coordination complexes as photodynamic compounds and their use |
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| US6995260B2 (en) * | 2004-05-20 | 2006-02-07 | Brookhaven Science Associates, Llc | Carboranylporphyrins and uses thereof |
| US8287839B2 (en) * | 2006-12-04 | 2012-10-16 | Brookhaven Science Associates, Llc | Carboranylporphyrins and uses thereof |
| EP1950217A1 (en) * | 2007-01-26 | 2008-07-30 | Université de Neuchâtel | Organometallic compounds for the treatment of cancer |
| US8444953B2 (en) * | 2007-03-22 | 2013-05-21 | Brookhaven Science Associates, Llc | Symmetric and asymmetric halogen-containing metallocarboranylporphyrins and uses thereof |
| US20080279781A1 (en) * | 2007-05-10 | 2008-11-13 | Brookhaven Science Associates, Llc | Glycosylated Carboranylporphyrins and Uses Thereof |
| JP5823413B2 (en) * | 2010-01-22 | 2015-11-25 | カウンシル オブ サイエンティフィック アンド インダストリアル リサーチ | Process for the preparation of novel porphyrin derivatives and their use as PDT agents and fluorescent probes |
| CN102408452B (en) * | 2011-12-13 | 2014-09-03 | 中山大学 | Tetrapyridylporphine bridged crossed tetra-palladium complexes, and preparation method and antitumor activity thereof |
| WO2019217606A1 (en) * | 2018-05-09 | 2019-11-14 | Virginia Commonwealth University | Near-ir activatable fluorescent small molecules with dual modes of cytotoxicity |
| CN109251206B (en) * | 2018-09-21 | 2022-02-08 | 上海大学 | Water-soluble platinum-porphyrin complex and preparation method thereof |
| CN110028513B (en) * | 2019-04-30 | 2020-12-11 | 北京太阳升高科医药研究股份有限公司 | Porphyrin derivatives and sonosensitizers |
| CN110590852B (en) * | 2019-08-29 | 2022-12-09 | 合肥学院 | Platinum complex with antitumor activity and preparation method thereof |
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| JPH0615545B2 (en) * | 1984-10-01 | 1994-03-02 | 東洋薄荷工業株式会社 | Metal pheophobide derivatives and metal porphyrin derivatives |
| ZA86704B (en) | 1985-02-23 | 1986-10-29 | Asta Werke Ag Chem Fab | Tumor retarding(1-benzyl-ethylenediamine9-platin(ii)-complexes |
| CA1311239C (en) * | 1985-10-23 | 1992-12-08 | Isao Sakata | Porphyrin derivatives, and their production and use |
| DE19824653A1 (en) | 1998-02-25 | 1999-08-26 | Schering Ag | Use of compounds concentrating in necrotic tissue as drug depots, e.g. for radiation therapy, pharmacotherapy, restenosis prevention and diagnosis |
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| US10766915B2 (en) | 2013-03-15 | 2020-09-08 | Sherri Ann McFARLAND | Metal-based coordination complexes as photodynamic compounds and their use |
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| Publication number | Publication date |
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| CN1639178A (en) | 2005-07-13 |
| BR0307400A (en) | 2004-12-21 |
| AR038479A1 (en) | 2005-01-19 |
| WO2003064424A3 (en) | 2004-01-15 |
| KR20040083098A (en) | 2004-09-30 |
| US7087214B2 (en) | 2006-08-08 |
| EP1470139A2 (en) | 2004-10-27 |
| WO2003064424A2 (en) | 2003-08-07 |
| UA78007C2 (en) | 2007-02-15 |
| TW200305571A (en) | 2003-11-01 |
| CN1303090C (en) | 2007-03-07 |
| RU2004126637A (en) | 2006-02-10 |
| ZA200405925B (en) | 2004-09-07 |
| HK1078585A1 (en) | 2006-03-17 |
| JP2005522429A (en) | 2005-07-28 |
| NZ534541A (en) | 2005-10-28 |
| HRP20040788A2 (en) | 2004-12-31 |
| PL373346A1 (en) | 2005-08-22 |
| TWI233929B (en) | 2005-06-11 |
| MXPA04007443A (en) | 2004-10-11 |
| NO20043650L (en) | 2004-10-29 |
| US20040023942A1 (en) | 2004-02-05 |
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