CA2133284A1 - Octacarboxy substituted tetra(2,3-pyrazino)porphyrazines and their derivatives - Google Patents
Octacarboxy substituted tetra(2,3-pyrazino)porphyrazines and their derivativesInfo
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- CA2133284A1 CA2133284A1 CA002133284A CA2133284A CA2133284A1 CA 2133284 A1 CA2133284 A1 CA 2133284A1 CA 002133284 A CA002133284 A CA 002133284A CA 2133284 A CA2133284 A CA 2133284A CA 2133284 A1 CA2133284 A1 CA 2133284A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/08—Copper compounds
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- 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
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/06—Zinc compounds
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/005—Compounds of elements of Group 5 of the Periodic System without metal-carbon linkages
Abstract
Disclosed herein are water-soluble octacarboxy substituted tetra(2,3-pyrazino)porphyrazines of the following formula:
(I) wherein M is HH, Cu, VO, Co, Ni or Zn;
and R is C2H5, n-C4H9, n-C6H13, n-C8H17 or ONa.
The present invention discloses photoinactivators and more particularly a novel class of water soluble azaphathalocyanines (AzaPc's), functionalized on the macrocyle with carboxy substituents to yield octacarboxy substituted tetra(2,3-pyrazino)porphyrazines (TTPA's). The invention also relates to processes for their preparation and the use thereof for the photodynamic therapy of cancer and the inactivation of viruses or bacteria in stored blood products.
(I) wherein M is HH, Cu, VO, Co, Ni or Zn;
and R is C2H5, n-C4H9, n-C6H13, n-C8H17 or ONa.
The present invention discloses photoinactivators and more particularly a novel class of water soluble azaphathalocyanines (AzaPc's), functionalized on the macrocyle with carboxy substituents to yield octacarboxy substituted tetra(2,3-pyrazino)porphyrazines (TTPA's). The invention also relates to processes for their preparation and the use thereof for the photodynamic therapy of cancer and the inactivation of viruses or bacteria in stored blood products.
Description
TITLB
Water-soluble Octacarboxy Substituted Tetra(2 3-pyrazino~por~hyrazines, Pre~aration and Use thereof FIBLD OF THB lNV~ lON
The present invention relates to photoinactivators and more particularly to a novel class of water soluble azaphathalocyanines (AzaPc's), functionalized on the macrocyle with carboxy substituents to yield octacarboxy substituted tetra(2,3-pyrazino)porphyrazines (TPPA's). The invention also relates to processes for their preparation and the use thereof for the photodynamic therapy of cancer and the inactivation of viruses or bacteria in stored blood products.
DESCRIPTION OF THB lNV~N ~ ION
Background of the invention Aza analogues of phthalocyanine (AzaPc's) are photoinactivators with known applications, for example, as photo-bleaching agents for textiles, control agents to reduce the growth of microorganisms, electrocatalysts for oxygen reduction, catalysts for thiols and cumene autooxidation, materials for electrochromic displays, and media for optical data storage. Reference is made to GB 2,159,516 A, US
Patents 3,922,967, 4,033,718, 4,166,718 and 4,094,806.
213~284 However, there remains a strong need for novel AzaPc's with improved properties and over the prior art.
The potential efficiency of water soluble and thermally stable AzaPc's in different oxidative processes, such as oxidation of alkanes to alcohols and conversion of alkenes to epoxides, is yet to be discovered. Furthermore, these compounds are potential catalysts in oxidation processes to remove organic environmental pollutants. Accordingly, for many important potential applications, water solubility combined with the above capabilities are particularly sought after properties.
In another field of art, phthalocyanines (Pc's) and their various derivatives are beginning to receive attention as photoinactivators in biological systems. This is due to the ability of certain Pc derivatives to efficiently inactivate cancer cells in vivo and inactivate in vitro viruses or bacteria in stored blood products. In this regard, water soluble Pc's are receiving particular attention.
Most Pc derivatives, which have been evaluated for photodynamic therapy of cancer to date, carry substituents either on the benzene rings of the macrocycle or on the central atom as axial ligands. In contrast, the AzaPc's of the present invention, which feature additional nitrogen atoms in the macrocycle, have received very little attention as sensitizers for photodynamic therapy. (TEUCHNER, K. et al., 21332~
Spectroscopic Properties of Potential Sensitizers for the New Photodynamic Therapy Start Mechanisms via Two-Step Excited Electronic State, (1993), Photochemistry and Photobiology, Vol. 57, No. 3, 465).
It is also known that certain derivatives of phthalocyanine (Pc), including AzaPc's, exhibit liquid crystalline behaviour, in particular the formation of so-called columnar discotic mesophases. This adds a new dimension to their range of potential applications, for example in electronic devices. (CAMMIDGE, Andrew N. et al., Synthesis and Characterisation of some 1 4 8 11 15 18 22 25-Octa(alkoxymethyl)-phthalocyanines: a New Series of Discotic Liquid Crystals, J. CHEM. SOC. PERKIN TRANS. I, (1991) 3053).
Mesophase behaviour has been reported for metal-free and metallated phthalocyanines substituted with eight long chained alkyl, alkoxy or alkoxymethyl groups either at peripheral or at the non-peripheral sites.
It is known that long chain substituted tetrapyrazinoporphyrazine (TPPA) and its copper (II) complex, exhibit columnar mesomorphism different from their carbocyclic analogues. (OHTA, Kazuchika et al., Synthesis and Columnar MesomorPhism of Octa(dodecyl)tetrapyrazinoporphyraxine and its Copper(II) ComPlex, J. CHEM. SOC., CHEM. COMMUN.,(1989) 1611). The pyrazine derivatives are unique 7r-acceptors whereas all long-chain substituted Pc derivatives are ~r-donor columnar mesogens.
Consequently, there is a strong need for the development and new preparation routes of long-chain substituted Aza-Pc's which can optionally feature mesophase behaviour.
BUMMARY OF THB lNv~N~ION
The invention provides a compound of the formula RO2C~ CO2R
RO2C~N N~CO2R
CO2R ( I) CO2R
wherein M is HH, Cu, VO, Co, Ni or Zn;
a d R is C2H5, n-C4H9, n-C6H13~ n~CsHt7 or ONa-Also disclosed in a process for thepreparation of the novel compounds and uses therefor.
Other features and advantages of the invention will become apparent to those of ordinary skill in the art upon review of the following detailed description, schematic diagrams and claims.
DBTAI~BD DB8CRIPTION OF T~E lNv~h.ION
The preparation of the tetrapyrazinoporphyrazines (TPPA) of the present invention will now be described in relation to a preferred embodiment and for illustrative purposes only. The tetrapyrazinoporphyrazines (TPPA) of the present invention have the following formula 1-6:
RO2C~, "~CO2R
\_N~ ~/
RO2C~ N~CO2R
~02R CO2R
1 M 2 HH 2 M z Cu 3 M = VO 4 M = Co 5 N = Ni 6 M = Zn for 1-6a, R = C~g b, R = n-C4H9 c, R = n-C6H13 d, R = n-C8H17 for 2-6e, R = ONa A process for the preparation of the above compounds is also included in the scope of the present invention.
In order to construct the precursors of AzaPc's la-d - 6a-d, it was surprisingly found that an established protocol could be ingeniously adapted for the preparation of 2,3-dicyano derivatives (LINSTEAD et al. J. Chem. Soc. 1937, 911; ROTHKOPF, H.W. et al., G.
Chem. Ber. 1975, vol 108, 875; GALPERN, M.G. et al., I.G. Khim. Geterotsikl. Soedin. 1993, 58).:
NC$2 O~CO2R ~ ~,CO2R
NC H2 CO2R EIOH N~N~CO2R
5548%
for 8.9a, R = C2H5 b, R = n-C~H9 c, R = n-C6H13 d R = n-C8H~7 Scheme (I) Condensation of diaminomaleodinitrile 7 with dialkyldioxosuccinates 8a-d, in the presence of acetic acid, gave o-dinitriles 9a-d in 55-68% yield.
_ 7 _ 213 328 4 Compounds 8a-d were prepared from disodium dihydroxytartrate and an appropriate alcohol, using Fox's method (Fox H.H., J. Org. Chem., 1947, 12, 535).
It is to be noted that compounds 8c-d are novel and are included within the scope of the present invention as key intermediates. Compounds 9a-d were purified chromatographically on silica gel. Accordingly, compounds 9a-d are precursors to the compounds of the present invention.
PREPARATION OF H2TTPA la-d Free base octaalkoxycarbonyl TPPA la-d were synthesized from 9a-d by refluxing in ethanol (buthanol) with 1,8-diazabicyclo t5.4.0] undec-7-ene (DBU). Compounds la-d are soluble in chloroform. The purification was accomplished by chromatography on silica gel and recrystallization from tetrahydrofuran.
The yields of H2TPPA's vary from 12 to 27%. The synthesis route is schematically illustrated as follows:
DBU
9a-d > H2TppA(la-d) EtOH(BuOH)12-27%
Scheme (II) PREPARATION OF THE METAL COMPLEXES OF TPPA
The metal complexes of octaalkoxycarbonyl TPPA 2a-d - 6a-d were obtained by complexation of o-dinitriles 9a-d with the appropriate metal salts in quinoline. Reactions of 9a-d with metal salts at 160-170 proceed unusually fast (ca. 5 min.) and further heating results in a decrease in the yield of the metal complexes. Lowering the temperature slows the reaction down, but does not increase the product yield. Varying the reaction conditions showed that formation of the metal complexes requires the presence of basic solvents to neutralize the liberated acid. Accordingly, the possible synthesis routes can be schematically illustrated as follows:
DBU
9a-d ---------> H2TPPA(la-d) Scheme (II) EtOH(BuOH) 12-27%
I ~x.
Quinol ine MTPPA 32-60~
Water-soluble Octacarboxy Substituted Tetra(2 3-pyrazino~por~hyrazines, Pre~aration and Use thereof FIBLD OF THB lNV~ lON
The present invention relates to photoinactivators and more particularly to a novel class of water soluble azaphathalocyanines (AzaPc's), functionalized on the macrocyle with carboxy substituents to yield octacarboxy substituted tetra(2,3-pyrazino)porphyrazines (TPPA's). The invention also relates to processes for their preparation and the use thereof for the photodynamic therapy of cancer and the inactivation of viruses or bacteria in stored blood products.
DESCRIPTION OF THB lNV~N ~ ION
Background of the invention Aza analogues of phthalocyanine (AzaPc's) are photoinactivators with known applications, for example, as photo-bleaching agents for textiles, control agents to reduce the growth of microorganisms, electrocatalysts for oxygen reduction, catalysts for thiols and cumene autooxidation, materials for electrochromic displays, and media for optical data storage. Reference is made to GB 2,159,516 A, US
Patents 3,922,967, 4,033,718, 4,166,718 and 4,094,806.
213~284 However, there remains a strong need for novel AzaPc's with improved properties and over the prior art.
The potential efficiency of water soluble and thermally stable AzaPc's in different oxidative processes, such as oxidation of alkanes to alcohols and conversion of alkenes to epoxides, is yet to be discovered. Furthermore, these compounds are potential catalysts in oxidation processes to remove organic environmental pollutants. Accordingly, for many important potential applications, water solubility combined with the above capabilities are particularly sought after properties.
In another field of art, phthalocyanines (Pc's) and their various derivatives are beginning to receive attention as photoinactivators in biological systems. This is due to the ability of certain Pc derivatives to efficiently inactivate cancer cells in vivo and inactivate in vitro viruses or bacteria in stored blood products. In this regard, water soluble Pc's are receiving particular attention.
Most Pc derivatives, which have been evaluated for photodynamic therapy of cancer to date, carry substituents either on the benzene rings of the macrocycle or on the central atom as axial ligands. In contrast, the AzaPc's of the present invention, which feature additional nitrogen atoms in the macrocycle, have received very little attention as sensitizers for photodynamic therapy. (TEUCHNER, K. et al., 21332~
Spectroscopic Properties of Potential Sensitizers for the New Photodynamic Therapy Start Mechanisms via Two-Step Excited Electronic State, (1993), Photochemistry and Photobiology, Vol. 57, No. 3, 465).
It is also known that certain derivatives of phthalocyanine (Pc), including AzaPc's, exhibit liquid crystalline behaviour, in particular the formation of so-called columnar discotic mesophases. This adds a new dimension to their range of potential applications, for example in electronic devices. (CAMMIDGE, Andrew N. et al., Synthesis and Characterisation of some 1 4 8 11 15 18 22 25-Octa(alkoxymethyl)-phthalocyanines: a New Series of Discotic Liquid Crystals, J. CHEM. SOC. PERKIN TRANS. I, (1991) 3053).
Mesophase behaviour has been reported for metal-free and metallated phthalocyanines substituted with eight long chained alkyl, alkoxy or alkoxymethyl groups either at peripheral or at the non-peripheral sites.
It is known that long chain substituted tetrapyrazinoporphyrazine (TPPA) and its copper (II) complex, exhibit columnar mesomorphism different from their carbocyclic analogues. (OHTA, Kazuchika et al., Synthesis and Columnar MesomorPhism of Octa(dodecyl)tetrapyrazinoporphyraxine and its Copper(II) ComPlex, J. CHEM. SOC., CHEM. COMMUN.,(1989) 1611). The pyrazine derivatives are unique 7r-acceptors whereas all long-chain substituted Pc derivatives are ~r-donor columnar mesogens.
Consequently, there is a strong need for the development and new preparation routes of long-chain substituted Aza-Pc's which can optionally feature mesophase behaviour.
BUMMARY OF THB lNv~N~ION
The invention provides a compound of the formula RO2C~ CO2R
RO2C~N N~CO2R
CO2R ( I) CO2R
wherein M is HH, Cu, VO, Co, Ni or Zn;
a d R is C2H5, n-C4H9, n-C6H13~ n~CsHt7 or ONa-Also disclosed in a process for thepreparation of the novel compounds and uses therefor.
Other features and advantages of the invention will become apparent to those of ordinary skill in the art upon review of the following detailed description, schematic diagrams and claims.
DBTAI~BD DB8CRIPTION OF T~E lNv~h.ION
The preparation of the tetrapyrazinoporphyrazines (TPPA) of the present invention will now be described in relation to a preferred embodiment and for illustrative purposes only. The tetrapyrazinoporphyrazines (TPPA) of the present invention have the following formula 1-6:
RO2C~, "~CO2R
\_N~ ~/
RO2C~ N~CO2R
~02R CO2R
1 M 2 HH 2 M z Cu 3 M = VO 4 M = Co 5 N = Ni 6 M = Zn for 1-6a, R = C~g b, R = n-C4H9 c, R = n-C6H13 d, R = n-C8H17 for 2-6e, R = ONa A process for the preparation of the above compounds is also included in the scope of the present invention.
In order to construct the precursors of AzaPc's la-d - 6a-d, it was surprisingly found that an established protocol could be ingeniously adapted for the preparation of 2,3-dicyano derivatives (LINSTEAD et al. J. Chem. Soc. 1937, 911; ROTHKOPF, H.W. et al., G.
Chem. Ber. 1975, vol 108, 875; GALPERN, M.G. et al., I.G. Khim. Geterotsikl. Soedin. 1993, 58).:
NC$2 O~CO2R ~ ~,CO2R
NC H2 CO2R EIOH N~N~CO2R
5548%
for 8.9a, R = C2H5 b, R = n-C~H9 c, R = n-C6H13 d R = n-C8H~7 Scheme (I) Condensation of diaminomaleodinitrile 7 with dialkyldioxosuccinates 8a-d, in the presence of acetic acid, gave o-dinitriles 9a-d in 55-68% yield.
_ 7 _ 213 328 4 Compounds 8a-d were prepared from disodium dihydroxytartrate and an appropriate alcohol, using Fox's method (Fox H.H., J. Org. Chem., 1947, 12, 535).
It is to be noted that compounds 8c-d are novel and are included within the scope of the present invention as key intermediates. Compounds 9a-d were purified chromatographically on silica gel. Accordingly, compounds 9a-d are precursors to the compounds of the present invention.
PREPARATION OF H2TTPA la-d Free base octaalkoxycarbonyl TPPA la-d were synthesized from 9a-d by refluxing in ethanol (buthanol) with 1,8-diazabicyclo t5.4.0] undec-7-ene (DBU). Compounds la-d are soluble in chloroform. The purification was accomplished by chromatography on silica gel and recrystallization from tetrahydrofuran.
The yields of H2TPPA's vary from 12 to 27%. The synthesis route is schematically illustrated as follows:
DBU
9a-d > H2TppA(la-d) EtOH(BuOH)12-27%
Scheme (II) PREPARATION OF THE METAL COMPLEXES OF TPPA
The metal complexes of octaalkoxycarbonyl TPPA 2a-d - 6a-d were obtained by complexation of o-dinitriles 9a-d with the appropriate metal salts in quinoline. Reactions of 9a-d with metal salts at 160-170 proceed unusually fast (ca. 5 min.) and further heating results in a decrease in the yield of the metal complexes. Lowering the temperature slows the reaction down, but does not increase the product yield. Varying the reaction conditions showed that formation of the metal complexes requires the presence of basic solvents to neutralize the liberated acid. Accordingly, the possible synthesis routes can be schematically illustrated as follows:
DBU
9a-d ---------> H2TPPA(la-d) Scheme (II) EtOH(BuOH) 12-27%
I ~x.
Quinol ine MTPPA 32-60~
2 M = Cu 3 M = VO 4 M = Co 5 M = Ni 6 M = Zn for 2-6a, R = C2H5 b, R = n-C4H9 c, R = n-C6H13 d, R = n-C8H17 Scheme (III) g The compounds 2a-d - 6a-d were purified by silica gel chromatography. The yields are good, 32-60~.
The compounds of the formula la-d - 6a-d, symmetrically substituted with eight long chain alkoxycarbonyl groups, may exhibit a discotic liquid crystalline phase and could be used in electronic devices.
Also included in the scope of the present invention is a process for hydrolysis of the ester groups of complexes 2a - 6a. Initial attempts to hydrolyse the ethoxycarbonyl groups under either mild or extreme acidic conditions failed. Hydrolysis did proceed in alkaline aqueous solutions; however, instability of the solubilized products made it difficult to recover the octacarboxy derivatives. It is possible to stop decomposition by quick acidification to pH 2-3, resulting in precipitation of the carboxylic products, however, in the procedure both composition and yield of the product are unpredictable.
It was surprisingly discovered that appropriate conditions could be obtained when using very mild alkaline hydrolysis, have been established for the preparation of these compounds. Since Pc-carboxylic salts are insoluble in methanol, esters 2a -6a ere treated with a mixture of 3 parts of NaOH-saturated methanol an 1 part water resulting in instantaneous dissolution of the complexes followed by precipitation of the salts 2e - 6e. The hydrolysis method can be schematically illustrated as follows:
NaOH
2a - 6a --------> 2e - 6e 100%
S MeOH-H20 Scheme IV
The reaction was monitored by HPLC analysis of the redissolved precipitate. Complexes 2e - 6e were obtained as single isomeric compounds in quantitative yields. They have Q-band maxima in the W -vis spectra around 640 nm (in water). The sharp Q-band maxima are indicative of substantial monomerization of the dye molecules in solution. Furthermore, their extinction coefficients are comparable to those of compounds 2a -6a in organic solvents. Interestingly, in vivo thesedyes require light of 650-700 nm to promote tumour regression in a mouse-tumour model, suggesting a substantial red-shift of the Q-band due to association with biomolecules. It is the in vivo red-shift that renders this class of compounds of particular interest for photodynamic therapy of medical conditions since the 650-700 nm band provides a window with little absorbance of endogenous biological molecules resulting in optimal light penetration in tissues and biological samples.
These derivatives constitute a novel class of water soluble AzaPc's, functionalized on the macrocyle with carboxy substituents. This is an alternative class of photosensitizers, with a different pKa to those currently available, for photodynamic therapy of cancer and inactivation of viruses in stored blood products.
EXPERIMENTAL:
The following examples illustrate but do not limit the invention.
Example 1 5.6 Diethoxycarbonyl-2,3-dicyanopyrazine (9a):
A mixture of 7 (1.08g, 0.01 mol) and 8a (1.46 g, 0.01 mol) in glacial AeOH (10 mL), and EtOH (250 mL) was stirred at 70-80C for 2 h. The solvent was evaporated and the crude product was flash chromatographed (silica gel, CHCl3) affording 1.42 g (52%) of compound 9a.
Example 2 Tetra-2~3-(5~6-dibutoxycarbonylpyrazino)porPhyrazine (lb):
5,6-Dibutoxycarbonyl-2,3-dicyanopyrazine 9b (0.66 g, 2 mmol) was dissolved in n-butanol (25 mL).
The catalytic amount of 1.8-diazabicyclo[5.4.0] undec-7-ene(DBU) was added and the mixture was refluxed for 4 h under the nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, CHCl3 - acetone) affording compound lb (0.18 g, 27%).
Exam~le 3 Metal com~lexes of tetra-2 3-(5 6-dialkoxycarbonyl pyrazino)porphyrazine (2a-d - 6a-d): General Procedure:
A mixture of o-dinitrile 9a-d, a metal salt (in molar ratio 1:1, CuCl for 2a-d, VCl3 for 3a-d, CoCl2 for 4a-d, NiCl2 for 5a-d, and Zn(OAc) 2- 2H20 for 6a-d), and freshly distilled quinoline (l mL per 100 mg of o-dinitrile) was quickly heated to 170C. The heating was discontinued after an intense greenish-blue colour appeared (ca. 5 min.), and the resulting mixture was allowed to cool. Metal complexes 2a-d - 6a-d were extracted with CHCl3 or acetone. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, CHCl3 - acetone). The yields of compounds 2a-d - 6a-d vary from 32% to 60%.
ExamPle 4 Metal complexes of tetra-2~3-(5~6-dicarboxYpyrazino) por~hyrazine (2e - 6e); General procedure:
Complex 2a - 6a (120 mg) was added under stirring to a mixture of NaOH-saturated MeOH (45 mL) and water (15 mL). A precipitate appeared immediately.
The mixture was stirred for 30 min (reaction progress 213328~
was monitored by analytical HPLC), whereafter the solid was filtered, washed with 25% aqueous MeOH and dissolved in distilled water (30 mL). This solution was neutralized to pH 6 - 7 with several drops of lN
HCl, filtered, and a little amount of EtOH was added to precipitate the salt 2e -6e. The solid was centrifuged, washed with 25% aqueous MeOH and dried for 4 h at 60C in vacuo (10 mm Hg). The yield of the salts 2e - 6e was quantitative.
TEST EXPERIMENTS
Example 5 Tumour regression after PDT with 6e:
Photosensitizer. Zinc octacarboxytetrapyrazino porphyrazine (6e) (MW 1113) in sterile, physiological saline (0.154 M) at a concentration of 0.12S mM.
Tumour model. Male Balb/c mice (6-7 weeks old, Charles River Inc.) were inoculated in the right hind thigh with 2 x 105 EMT-6 murine mammary tumour cells suspended in 0.05 ml of Waymouth's medium (Gibco Inc.). At 6 days postinoculation the tumors were 2-3 mm in diameter and this time point were selected for therapeutic intervention.
Treatment protocol. Tumour bearing mice (n =
lO) were i.v. injected with 0.2 ml of 6e (formulated as above), to give an administered dose of 1.0 ~mol/kg (l.l mg/kg). Twenty-four hours after dye injection tumors were exposed to an 8 mm circular red light beam (400 J/cm2 at a fluence rate of 200 mW/cm2, 600-700 nm) delivered by a 1000 W Xenon lamp, equipped with a 10 cm water filter and LS700 and LL650 Corion~ filters.
Under these conditions no hyperthermia occurred during illumination.
Tumour response. Complete tumour necrosis in 100% of treated animals were observed within 3 days following PDT. When the same light dose was delivered over a 600-650 nm band, partial tumour response occurred, indicating the in vivo action spectrum of the drug was red-shifted relative to its A~x = 640 nm in homogenous solution. This is an important and unexpected property of this drug since biological samples including blood and most tissues, are more transparent > 640 nm due to the absence of endogenous chromophores at these wavelengths, thus facilitating the penetration depth of therapeutic light. Another unique observation with this drug following PDT, is the absence of any noticeable response (redness, edema) to the tissue/skin surrounding the tumour, even after augmenting the administered drug dose from 1 to lOmg/kg, indicative of the high tumour-selectivity of the drug.
Accordingly, this invention also relates to therapeutic compositions useful in the photodynamic therapy of cancer in mammals, one active ingredient therein being the tetrapyrazinoporphyrazines (TPPA) of the present invention, described herein, together with a pharmaceutically suitable diluent or carrier. Any appropriate form of administration may be envisaged but dosage is generally lower than for similar photodynamic agents because of its high activity and because its activity is strong at wavelengths where mammalian skin is most transparent.
Although the invention has been described above with respect with one specific form, it will be evident to a person skilled in the art that it may be modified and refined in various ways. It is therefore wished to have it understood that the present invention should not be limited in scope, except by the terms of the following claims.
The compounds of the formula la-d - 6a-d, symmetrically substituted with eight long chain alkoxycarbonyl groups, may exhibit a discotic liquid crystalline phase and could be used in electronic devices.
Also included in the scope of the present invention is a process for hydrolysis of the ester groups of complexes 2a - 6a. Initial attempts to hydrolyse the ethoxycarbonyl groups under either mild or extreme acidic conditions failed. Hydrolysis did proceed in alkaline aqueous solutions; however, instability of the solubilized products made it difficult to recover the octacarboxy derivatives. It is possible to stop decomposition by quick acidification to pH 2-3, resulting in precipitation of the carboxylic products, however, in the procedure both composition and yield of the product are unpredictable.
It was surprisingly discovered that appropriate conditions could be obtained when using very mild alkaline hydrolysis, have been established for the preparation of these compounds. Since Pc-carboxylic salts are insoluble in methanol, esters 2a -6a ere treated with a mixture of 3 parts of NaOH-saturated methanol an 1 part water resulting in instantaneous dissolution of the complexes followed by precipitation of the salts 2e - 6e. The hydrolysis method can be schematically illustrated as follows:
NaOH
2a - 6a --------> 2e - 6e 100%
S MeOH-H20 Scheme IV
The reaction was monitored by HPLC analysis of the redissolved precipitate. Complexes 2e - 6e were obtained as single isomeric compounds in quantitative yields. They have Q-band maxima in the W -vis spectra around 640 nm (in water). The sharp Q-band maxima are indicative of substantial monomerization of the dye molecules in solution. Furthermore, their extinction coefficients are comparable to those of compounds 2a -6a in organic solvents. Interestingly, in vivo thesedyes require light of 650-700 nm to promote tumour regression in a mouse-tumour model, suggesting a substantial red-shift of the Q-band due to association with biomolecules. It is the in vivo red-shift that renders this class of compounds of particular interest for photodynamic therapy of medical conditions since the 650-700 nm band provides a window with little absorbance of endogenous biological molecules resulting in optimal light penetration in tissues and biological samples.
These derivatives constitute a novel class of water soluble AzaPc's, functionalized on the macrocyle with carboxy substituents. This is an alternative class of photosensitizers, with a different pKa to those currently available, for photodynamic therapy of cancer and inactivation of viruses in stored blood products.
EXPERIMENTAL:
The following examples illustrate but do not limit the invention.
Example 1 5.6 Diethoxycarbonyl-2,3-dicyanopyrazine (9a):
A mixture of 7 (1.08g, 0.01 mol) and 8a (1.46 g, 0.01 mol) in glacial AeOH (10 mL), and EtOH (250 mL) was stirred at 70-80C for 2 h. The solvent was evaporated and the crude product was flash chromatographed (silica gel, CHCl3) affording 1.42 g (52%) of compound 9a.
Example 2 Tetra-2~3-(5~6-dibutoxycarbonylpyrazino)porPhyrazine (lb):
5,6-Dibutoxycarbonyl-2,3-dicyanopyrazine 9b (0.66 g, 2 mmol) was dissolved in n-butanol (25 mL).
The catalytic amount of 1.8-diazabicyclo[5.4.0] undec-7-ene(DBU) was added and the mixture was refluxed for 4 h under the nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, CHCl3 - acetone) affording compound lb (0.18 g, 27%).
Exam~le 3 Metal com~lexes of tetra-2 3-(5 6-dialkoxycarbonyl pyrazino)porphyrazine (2a-d - 6a-d): General Procedure:
A mixture of o-dinitrile 9a-d, a metal salt (in molar ratio 1:1, CuCl for 2a-d, VCl3 for 3a-d, CoCl2 for 4a-d, NiCl2 for 5a-d, and Zn(OAc) 2- 2H20 for 6a-d), and freshly distilled quinoline (l mL per 100 mg of o-dinitrile) was quickly heated to 170C. The heating was discontinued after an intense greenish-blue colour appeared (ca. 5 min.), and the resulting mixture was allowed to cool. Metal complexes 2a-d - 6a-d were extracted with CHCl3 or acetone. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, CHCl3 - acetone). The yields of compounds 2a-d - 6a-d vary from 32% to 60%.
ExamPle 4 Metal complexes of tetra-2~3-(5~6-dicarboxYpyrazino) por~hyrazine (2e - 6e); General procedure:
Complex 2a - 6a (120 mg) was added under stirring to a mixture of NaOH-saturated MeOH (45 mL) and water (15 mL). A precipitate appeared immediately.
The mixture was stirred for 30 min (reaction progress 213328~
was monitored by analytical HPLC), whereafter the solid was filtered, washed with 25% aqueous MeOH and dissolved in distilled water (30 mL). This solution was neutralized to pH 6 - 7 with several drops of lN
HCl, filtered, and a little amount of EtOH was added to precipitate the salt 2e -6e. The solid was centrifuged, washed with 25% aqueous MeOH and dried for 4 h at 60C in vacuo (10 mm Hg). The yield of the salts 2e - 6e was quantitative.
TEST EXPERIMENTS
Example 5 Tumour regression after PDT with 6e:
Photosensitizer. Zinc octacarboxytetrapyrazino porphyrazine (6e) (MW 1113) in sterile, physiological saline (0.154 M) at a concentration of 0.12S mM.
Tumour model. Male Balb/c mice (6-7 weeks old, Charles River Inc.) were inoculated in the right hind thigh with 2 x 105 EMT-6 murine mammary tumour cells suspended in 0.05 ml of Waymouth's medium (Gibco Inc.). At 6 days postinoculation the tumors were 2-3 mm in diameter and this time point were selected for therapeutic intervention.
Treatment protocol. Tumour bearing mice (n =
lO) were i.v. injected with 0.2 ml of 6e (formulated as above), to give an administered dose of 1.0 ~mol/kg (l.l mg/kg). Twenty-four hours after dye injection tumors were exposed to an 8 mm circular red light beam (400 J/cm2 at a fluence rate of 200 mW/cm2, 600-700 nm) delivered by a 1000 W Xenon lamp, equipped with a 10 cm water filter and LS700 and LL650 Corion~ filters.
Under these conditions no hyperthermia occurred during illumination.
Tumour response. Complete tumour necrosis in 100% of treated animals were observed within 3 days following PDT. When the same light dose was delivered over a 600-650 nm band, partial tumour response occurred, indicating the in vivo action spectrum of the drug was red-shifted relative to its A~x = 640 nm in homogenous solution. This is an important and unexpected property of this drug since biological samples including blood and most tissues, are more transparent > 640 nm due to the absence of endogenous chromophores at these wavelengths, thus facilitating the penetration depth of therapeutic light. Another unique observation with this drug following PDT, is the absence of any noticeable response (redness, edema) to the tissue/skin surrounding the tumour, even after augmenting the administered drug dose from 1 to lOmg/kg, indicative of the high tumour-selectivity of the drug.
Accordingly, this invention also relates to therapeutic compositions useful in the photodynamic therapy of cancer in mammals, one active ingredient therein being the tetrapyrazinoporphyrazines (TPPA) of the present invention, described herein, together with a pharmaceutically suitable diluent or carrier. Any appropriate form of administration may be envisaged but dosage is generally lower than for similar photodynamic agents because of its high activity and because its activity is strong at wavelengths where mammalian skin is most transparent.
Although the invention has been described above with respect with one specific form, it will be evident to a person skilled in the art that it may be modified and refined in various ways. It is therefore wished to have it understood that the present invention should not be limited in scope, except by the terms of the following claims.
Claims (12)
1. A compound of the formula (I) wherein M is HH, Cu, VO, Co, Ni or Zn;
and R is C2H5, n-C4-H9, n-C6H13, n-C8H17 or ONa.
and R is C2H5, n-C4-H9, n-C6H13, n-C8H17 or ONa.
2. The compound of claim 1 with the proviso that if M is HH, then R is not ONa.
3. A precursor compound to the compound of claim 1, said precursor compound having the formula (II) (II) wherein R is C2H5, n-C4H9, n-C6H13 or n C8H17.
4. A precursor compound to the compound of claim 1, said precursor compound having the formula (IV) (IV) wherein R is n-C6H13 or n-C8H17.
5. A process for preparing the compound of claim 1 having formula (I), wherein M is HH and R is C2H5, n-C4H9, n-C6H13, or n-C8H17;
said process comprising the following steps:
(a) condensing diaminomaleodinitrile of formula (III) with dialkyldioxosuccinates of formula (IV), in the presence of acetic acid to produce o-dinitriles of formula (II) as shown below;
+ ? (III) (IV) (II) (b) refluxing in ethanol or butanol, in the presence of undec-7-ene (DBU) the compound of formula (II) to yield the compound of formula (I);
(I) (c) recovering and purifying the desired product.
said process comprising the following steps:
(a) condensing diaminomaleodinitrile of formula (III) with dialkyldioxosuccinates of formula (IV), in the presence of acetic acid to produce o-dinitriles of formula (II) as shown below;
+ ? (III) (IV) (II) (b) refluxing in ethanol or butanol, in the presence of undec-7-ene (DBU) the compound of formula (II) to yield the compound of formula (I);
(I) (c) recovering and purifying the desired product.
6. A process for preparing the compound of claim 1 having formula (I), wherein M is Cu, VO, Co, Ni or Zn, and R is C2H5, n-C4H9, n-C6H13, or n-C8H17;
said process comprising the following steps:
(a) condensing diaminomaleodinitrile of formula (III) with dialkyldioxosuccinates of formula (IV), in the presence of acetic acid to produce o-dinitriles of formula (II) as shown below;
+ ? (III) (IV) (II) (b) complexation of the compound of formula (II) with the appropriate metal salt, in a basic solvent, to yield the compound of formula (I);
(I) (c) recovering and purifying the desired product.
said process comprising the following steps:
(a) condensing diaminomaleodinitrile of formula (III) with dialkyldioxosuccinates of formula (IV), in the presence of acetic acid to produce o-dinitriles of formula (II) as shown below;
+ ? (III) (IV) (II) (b) complexation of the compound of formula (II) with the appropriate metal salt, in a basic solvent, to yield the compound of formula (I);
(I) (c) recovering and purifying the desired product.
7. The process of claim 2 wherein for step (b) said basic solvent consists of quinoline.
8. A process for preparing the compound of claim 1 having formula (I), wherein M is Cu, VO, Co, Ni or Zn, and R is ONa;
said process comprising the following steps:
(a) condensing diaminomaleodinitrile of formula (III) with dialkyldioxosuccinates of formula (IV), in the presence of acetic acid to produce o-dinitriles of formula (II) as shown below;
+ ? (III) (IV) (II) (b) complexation of compound of formula (II) with the appropriate metal salt in a basic solvent to yield compound of formula (I) wherein M is Cu, VO, Co, Ni or Zn, and R is C2H5, n-C4H9, n-C6H13, or n-C8H17;
(c) hydrolysing the compound of step (b) to yield a compound of formula (I) as defined in the preceding claims but wherein R is ONa;
(d) recovering and purifying the desired product.
said process comprising the following steps:
(a) condensing diaminomaleodinitrile of formula (III) with dialkyldioxosuccinates of formula (IV), in the presence of acetic acid to produce o-dinitriles of formula (II) as shown below;
+ ? (III) (IV) (II) (b) complexation of compound of formula (II) with the appropriate metal salt in a basic solvent to yield compound of formula (I) wherein M is Cu, VO, Co, Ni or Zn, and R is C2H5, n-C4H9, n-C6H13, or n-C8H17;
(c) hydrolysing the compound of step (b) to yield a compound of formula (I) as defined in the preceding claims but wherein R is ONa;
(d) recovering and purifying the desired product.
9. The process of claim 8 wherein step (c) is conducted by hydrolysing the compound of step (b) in a mixture of about 3 parts NaOH saturated in methanol for 1 part of water resulting in the dissolution of the compound of step (b) and precipitation of the compound of formula (I) wherein R is ONa.
10. The use of the compound of claim 1 in the photodynamic therapy of cancer in mammals.
11. The use of the compound of claim 1 in the photoinactivation of viruses or bacteria in blood products.
12. Therapeutical compositions for the photodynamic therapy of cancer in mammals, the principal active ingredient therein being a sufficient amount of the compound according to claim 1, together with an appropriate diluent or carrier.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002133284A CA2133284A1 (en) | 1994-09-29 | 1994-09-29 | Octacarboxy substituted tetra(2,3-pyrazino)porphyrazines and their derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002133284A CA2133284A1 (en) | 1994-09-29 | 1994-09-29 | Octacarboxy substituted tetra(2,3-pyrazino)porphyrazines and their derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2133284A1 true CA2133284A1 (en) | 1996-03-30 |
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ID=4154427
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002133284A Abandoned CA2133284A1 (en) | 1994-09-29 | 1994-09-29 | Octacarboxy substituted tetra(2,3-pyrazino)porphyrazines and their derivatives |
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| CA (1) | CA2133284A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10766915B2 (en) | 2013-03-15 | 2020-09-08 | Sherri Ann McFARLAND | Metal-based coordination complexes as photodynamic compounds and their use |
-
1994
- 1994-09-29 CA CA002133284A patent/CA2133284A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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