EP1117665A1 - Photosensibilisants pour applications photodynamiques - Google Patents

Photosensibilisants pour applications photodynamiques

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Publication number
EP1117665A1
EP1117665A1 EP98952052A EP98952052A EP1117665A1 EP 1117665 A1 EP1117665 A1 EP 1117665A1 EP 98952052 A EP98952052 A EP 98952052A EP 98952052 A EP98952052 A EP 98952052A EP 1117665 A1 EP1117665 A1 EP 1117665A1
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Prior art keywords
ethyl
amino acid
alkyl
carbon atoms
composition
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German (de)
English (en)
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Alan R. Morgan
Michael E. Menes
Ruizheng Wang
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Lambda Pharmaceuticals Inc
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Lambda Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to benzochlorin derivatives that can be used as photosensitizers in photodynamic therapy ("PDT"). More particularly, the present invention relates to pharmaceutically acceptable formulations of benzochlorin and benzochlorin imine derivatives and to the use of these new benzochlorin and benzochlorin imine compositions for the selective destruction of cells and tissues in PDT.
  • PDT is an emerging technology for the selective destruction of cells and/or tissues. The process requires the presence of a photosensitizing agent which is capable of being taken up by target cells and tissues and which, on irradiation by light of a particular wavelength, generates species which are toxic to those cells and tissues.
  • Photofrin ® a porphyrin-derived preparation known as Photofrin ®
  • a photosensitizing agent when applied to a human or animal body is taken up by certain cells and tissues.
  • the cells and tissues containing the photosensitizing agent can then be exposed to light of a certain wavelength.
  • the light is generated and directed to the target cells and/or tissue by the use of lasers, photodiode arrays or lamps. If the target cells and tissues are located deeper into the body, light is delivered by the use of fiber-optic systems, endoscopic devices and catheters.
  • Photofrin ® a certain amount of time after it is administered, is retained in greater concentrations in certain types of cells .
  • the time period for such "selective" accumulation is 24-48 hours.
  • Cells that show such selectivity have been characterized as hyperproliferating cells, i.e., cells which are growing at a faster rate than normal.
  • Such cells are representative of many diseased tissues and states, including but not limited to cancer, dermatological disease such as psoriasis, cardiovascular disease such as atherosclerosis and restenosis and diseases which are characterized by a rapid growth of blood vessels, for example, as is the case in ophthalmologic conditions such as age-related macular degeneration.
  • certain cells associated with immunological functions have been shown to selectively retain photosensitizing agents.
  • photodynamic therapy to reduce the potential for graft rejection and for autoimmune disease such as rheumatoid arthritis has been reported.
  • Photodynamic therapy has advantages over many other conventional therapies due to the selectivity of the photodynamic process.
  • therapies such as chemotherapy and radiation therapy are known to have significant side-effects and are toxic to normal as well as abnormal cells. Consequently these treatments are associated with the destruction of a significant amount of normal cells and tissues.
  • the increased affinity of the photosensitizing agent for hyperproliferating cells such as those found in tumors reduces the potential for destruction of normal cells and tissues while increasing the potential for destruction of the lesion.
  • the ability to direct the light specifically onto the target cells and tissues by the use of fiber-optic technology or the ability to protect adjacent normal cells or tissues by the use of filters further increases the selectivity of the photodynamic process.
  • the biological response can also be controlled by the amount of light given, thus, the greater the amount of light, the greater the biological response. More light can be given by increasing the time of irradiation, by increasing the intensity of the light or by both. Such a regimen is useful for the treatment of diseases including but not limited to benign prostatic hypertrophy and endometriosis .
  • Photofrin as a photosensitizer in photodynamic therapy for the treatment of certain esophageal tumors and lung cancer.
  • the use of Photofrin has been approved for photodynamic treatment of a variety of cancers including lung, stomach and cervical; in Canada the same procedure has been approved for use in treatment of bladder cancer and in the Netherlands, France, Italy and Germany, approval has been granted for use in esophageal cancer.
  • Photodynamic therapy may also result in activation of a process known as apoptosis, which is defined as programmed cell death and is the mechanism by which cells die naturally.
  • apoptosis which is defined as programmed cell death and is the mechanism by which cells die naturally.
  • photodynamic therapy may also be advantageous in that the mechanism of cell death may involve processes that biological systems use in their natural state to remove cells that are no longer useful.
  • a second mechanism by which the photodynamic effect may be generated involves not the generation of singlet oxygen, but the generation of radical species.
  • radical species can be generated by the interaction of the photoactivated photosensitizer with oxygen to produce radical species such as superoxide and/or hydroxyl radical that are known to be toxic to cells.
  • the photoactivated photosensitizer can itself react directly with cellular components to generate a free-radical type reaction which again results in loss of cell integrity and thus, of cell viability.
  • photodynamic therapy has advantages over many current day procedures. The process appears to have minimum side-effects and a greater degree of selectivity for target cells and tissues.
  • photodynamic therapy can be used in conjunction with other treatment modalities as well as in a stand-alone treatment.
  • Photofrin 0 is the only photosensitizer to have gained approval anywhere in the world to date, however a number of photosensitizers have been proposed for use in photodynamic therapy and are in pre-clinical or clinical trials for the treatment of various indications including cancer, dermatology, cardiovascular, immunology, ophthalmology and urology.
  • photosensitizers which have received attention include Purpurins, Benzoporphyrin Derivatives, Porphycenes, Texaphyrins Pheophorbides and Phthalocyanines
  • Purpurins Benzoporphyrin Derivatives
  • Porphycenes Porphycenes
  • Texaphyrins Pheophorbides Phthalocyanines
  • US Patent 5,789,586 discloses benzochlorins of general Figs. IA and IB where R 12 is S0 2 R, S0 2 NHR or S0 3 X, where R is a compound containing a reactive carboxyl or amine group and X is halide.
  • the present invention is directed to a family of photoreactive benzochlorin derivatives and their metallo- analogs having the structures set forth in Figs. IA and IB and identified by legend thereafter.
  • the present invention is also directed to photoreactive benzochlorin derivatives and their metallo-analogs which are used in photodynamic therapy.
  • Ri to R 10 can be the same or different and each is :
  • R 1 is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms
  • R 2 is H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 2 can be the same or different
  • R x is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms and where R 2 is H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 2 can be the same or different,
  • A is a physiologically acceptable anion
  • R is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms
  • R 2 is H or an amino acid residue, a carbohydrate residue or an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms
  • R is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms
  • R 2 is NH 2 , an amino acid group or a polyhydroxyamino moiety having from 1 to 6 hydroxyl groups
  • OR 3 where R 3 is H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms, an amino acid group or a polyhydroxyamino moiety having from 1 to 6 hydroxyl groups or a carbohydrate residue, or
  • R 1 is an amino acid residue, polyhydroxyamino moiety having from 1 to 6 hydroxyl groups or a carbohydrate residue
  • R X1 and R 13 are H.
  • R 12 is:
  • R 2 can be H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 2 can be the same or different,
  • R 2 can be H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 2 can be the same or different and A " is a physiologically acceptable anion, or -OR 2 where R 2 can be H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms, an amino acid residue or a carbohydrate residue
  • R 14 is as defined for R 1 to R 10 and also may be:
  • R x can be H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 1 can be the same or different and A is a physiologically acceptable anion, or,
  • R can be H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue or where R x is OH, an amino acid group, a polyhydroxyamino moiety having from 1 to 6 hydroxyl groups or a carbohydrate residue .
  • M is any metal which results in a photodynamically active molecule but is preferentially selected from the group, Al, Zn, Sn, Ge, Cu.
  • the present invention is further directed to a pharmaceutical composition wherein the active ingredient is a composition having the structure of one of Figs. IA or IB above .
  • the present invention is even further directed to methods for destroying cells and tissues through a photodynamic process comprising the steps of administering to a human or animal patient, or to fluids such as blood, plasma, bone marrow, from a human or animal patient one of the compositions of Figs. IA or IB and supplying sufficient light to generate a cytotoxic effect.
  • Fig. IA is a structural formula for a family of benzochlorins, including the present invention.
  • Fig. IB is a structural formula for metal complexes of a family of benzochlorins including the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • Example 1 describes the synthesis of bromooctaethylbenzochlorin (Fig. IA where R 1 to R 8 are ethyl, R 9/ R 10 , R X1 , R 13 and R 14 are H, and R 12 is Br) , a key compound for the subsequent generation of many of the other compounds disclosed in this invention.
  • Example 1 can be used to produce a wide variety of bromo-benzochlorins .
  • bromobenzochlorins By exchanging the octaethylporphyrin reactant in Example 1 with a wide variety of porphyrins, bromobenzochlorins in which R ⁇ to R 8 can be varied according to the invention, are produced.
  • the requisite porphyrins are generated using standard procedures, which involve production of the necessary intermediate pyrroles followed by condensations and other known reactions, to produce the porphyrin products.
  • standard procedures which involve production of the necessary intermediate pyrroles followed by condensations and other known reactions, to produce the porphyrin products.
  • Example 2a illustrates the method for introduction of a halogen at R 10 and at R 14 of the bromobenzochlorin prepared in Example 1.
  • Example 2b illustrates a method for the production of a bromobenzochlorin halogenated at R 10 and
  • Example 2c illustrates a method for the production of a bromobenzochlorin halogenated at R 14 .
  • R 10 , R 117 R 13 and R 14 are H, and, R 12 is Br in dichloromethane.
  • the reaction was refluxed while stirring for 2 hrs, neutralized with aqueous sodium bicarbonate and the combined organic fractions were chromatographed (Hexanes/CH 2 C1 2 ) .
  • the isolated dichlorinated product (Fig. IA) where R 1 to R 8 are ethyl, R 9 , R 117 R 13 are H, R 10 and R 14 is Cl, and, R 12 is Br) was recrystallized from methanol : dichloromethane.
  • the structure was confirmed by visible spectroscopy which gave a characteristic 689nm absorption maximum and by H NMR where a distinguishing 0. lppm resonance was also observed.
  • Example 2a The above dichlorinated bromobenzochlorin prepared in Example 2a was treated with SnCl 2 in dimethyl formamide at reflux temperature for 45 minutes. The resulting solution was poured into water, washed with aqueous hydrochloric acid and then extracted into dichloromethane. The solvent was removed and the residue chromatographed on silica using dichloromethane-hexanes as eluant. The major fraction was collected and was found to be the monochloro-monobromo- benzochlorin (Fig. IA) , where R x to R 8 are ethyl, R 9 , R X1 , R 13 , R 14 are H, R10 is Cl, and, R 12 is Br. Visible spectroscopy gave a maximum absorption at 663nm while NMR showed a characteristic resonance at 0.02 ppm.
  • the second fraction of dichlorobromobenzochlorin was treated with SnCl 2 in acetic acid at reflux and the reaction progress monitored by visible spectroscopy. Once the absorption at 675nm had reached maximum intensity, the reaction was stopped, the solvent removed and the residue taken up in dichloromethane and washed with aqueous hydrochloric acid. The organic fraction was collected and purified by silica gel chromatography using dichloromethane-hexanes as eluant. The major product was collected and shown to be bromochlorobenzochlorin (Fig. IA) where R x to R 8 are ethyl, R 9 , R 1X , R 13 , R 10 are H, R 14 is Cl , and, R 12 is Br. Visible spectroscopy gave a maximum absorption at 675nm while NMR gave a characteristic resonance at 0.30 ppm.
  • Example 3 illustrates the method by which metals can be inserted into the benzochlorin cavity.
  • Zinc was inserted into bromobenzochlorin (Fig. IA) where R x to R 8 are ethyl, R 9 , R 10 , R X1 , R 13 and R 14 are H, and, R 12 is Br by addition of zinc acetate to the bromobenzochlorin in dimethylformamide .
  • the mixture was then heated to reflux for 1 hr.
  • the reaction mixture was added to water, extracted with dichloromethane and chromatographed with a combination of hexanes/dichloromethane . After recrystalization in methanol/dichloromethane the structure, according to Fig.
  • Examples 4a and 4b illustrate the preparation of aminobenzochlorins from bromo-benzochlorins such as that prepared in Example 1.
  • Nickel bromobenzochlorin (Fig. IB) where R x to R 8 are ethyl, R 9 , R 10 , R X1 , R 13 and R 14 are H, R 12 are Br, and, M is
  • Ni was taken up in dimethyl acetamide and copper (I) iodide and potassium phthalimide added. The resulting mixture was refluxed for 20 hours. The solvent was then removed and the residue chromatographed on silica using hexanes- dichloromethane. The major band was collected and shown to be the nickel phthalimidobenzochlorin (Fig. IB) where R x to R 8 are ethyl, R 9 , R 10 , R 11# R 13 and R 14 are H, R 12 is Phthalimido, and, M is Ni . Demetallation was achieved by adding concentrated sulfuric aid to the nickel phthalimidobenzochlorin at room temperature. After 1 hour, the solution was neutralized with aq.
  • Phthalimidobenzochlorin (Fig. IA) prepared in Example 4a was treated with excess hydrazine hydrate in ethanol, at reflux, for 3 hours. The mixture was then acidified with cone. Hydrochloric acid and refluxed a further 30 minutes. After cooling, the mixture was filtered and the filtrate concentrated. The concentrate was neutralized with sodium bicarbonate and extracted with dichloromethane . The organic layer was collected and the solvent removed. The residue was recrystallized from dichloromethane-hexanes to give aminobenzochlorin (Fig. IA) where R x to R 8 are ethyl, R 9 , R 10 , R X1 , R 13 and R 14 are H, and, R 12 is NH 2 . NMR gave a characteristic resonance at 0.14ppm while visible spectroscopy gave an absorption at 657nm.
  • Example 5 illustrates the preparation of a quarternized aminobenzochlorin.
  • Aminobenzochlorin (Fig. IA) where R to R 8 are ethyl, R 9 , R 10 , R ll R 13 and R 14 are H, and, R 12 is NH 2 was treated with nickel acetate using the method of Example 3. The product of this reaction was treated with excess methyl iodide at 50°C for 2 hours and then the solvent removed. The product was taken up in concentrated sulfuric acid for 1 hour. The resulting solution was then neutralized with sodium bicarbonate and extracted with dichloromethane. The organic layer was collected, the solvent removed and the residue purified by chromatography on silica gel using dichloromethane-methanol . The product (Fig. IA) where R to R 8 are ethyl, R 9 , R 10 , R ll R 13 and R 14 are H, and, R 12 is NH 2 was treated with nickel acetate using the method of Example 3. The product of this reaction was treated with excess methyl iodide at 50°C for 2 hours and then the solvent removed. The
  • R x to R 8 are ethyl
  • R 9 , R 10 , R llf R 13 and R 14 are H
  • R 12 is NMe 3 + I " was collected and characterized by visible spectroscopy (absorption band at 654nm) .
  • Example 6 illustrates the preparation of a formyl bromobenzochlorin.
  • Nickel bromobenzochlorin (Fig. IB) where R to R 8 are ethyl, R 9 , R 10 , R 1X , R 13 and R 14 is H, R 12 is Br, and, M is Ni was taken up in dichloromethane and an excess of Vilsmeier reagent (prepared from P0C1 3 and DMF) added. The resulting solution was refluxed for 1 hour. After cooling, aq. sodium acetate was added and the mixture refluxed a further 1 hour. The organic layer was collected and concentrated. Sulfuric acid was added to the residue at room temperature. After 2 hours, the resulting mixture was neutralized with aq. sodium bicarbonate and extracted into dichloromethane. The organic layer was collected and concentrated.
  • Examples 7a and 7b illustrates the preparation of a hydrazone derivative of formylbromobenzochlorin.
  • R to R 8 is ethyl
  • R 9 , R 10 , R X1 , R 13 are H
  • R 12 is Br
  • the product was characterized by a visible absorption band at 668nm and a resonance at 5. ppm in the NMR spectrum.
  • R x to R 8 is ethyl
  • R 9 , R 10 , R llf R 13 is H
  • R 12 is Br
  • the product was characterized by a visible absorption band at 668nm and a resonance at 0.03ppm in the NMR spectrum.
  • Example 8a-c illustrates the method by which iminium derivatives of benzochlorins can be generated.
  • Example 8a The copper iminium salt prepared in Example 8a was treated with concentrated sulfuric acid at room temperature for 24 hours. The mixture was neutralized with aq. sodium bicarbonate and extracted with dichloromethane . The organic layer was collected and the solvent removed. The residue was purified using silica gel chromatography using methanol -dichloromethane. The resulting product was recrystallized using hexane-dichloromethane . A characteristic visible absorption band at 784nm was observed.
  • Example 8b The iminium salt prepared in Example 8b was treated with zinc acetate according to the procedure described in Example 2.
  • the product (Fig. IB) where R x to R 8 are ethyl, R 9 , R 10 , R ll t R 13 are H, R 12 is Br, R 14 is CH NMe 2 + Cl " , and, M is Zn was characterized by a visible absorption band at 738nm.
  • Example 9 illustrates the synthesis of nitrobenzochlorins .
  • Nickel benzochlorin prepared as described in Morgan et al, (Photochem. Photobiol. 1992, 55, 133) was treated with a mixture of concentrated nitric and sulfuric acid for 2 hours at room temperature. The mixture was neutralized with aq. sodium bicarbonate and extracted with dichloromethane. The organic layer was collected and the solvent removed. The residue was purified using silica gel chromatography using methanol-dichloromethane . The resulting product was recrystallized using hexane- dichloromethane. The nitrobenzochlorin (Fig.
  • R to R 8 are ethyl
  • R 9 , R 10 , R ll r R 13 , R 14 are H
  • R 12 is Br was characterized by a resonance at 0.03ppm in the NMR spectrum and an absorption at 661nm in the visible spectrum.
  • Example 1 The procedure of Example 1 can be used to produce a wide variety of bromo-benzochlorins .
  • bromobenzochlorins in which R to R 8 can be varied according to the invention are produced.
  • the requisite porphyrins are generated using standard procedures, which involve production of the necessary intermediate pyrroles followed by condensations and other known reactions, to produce the porphyrin products.
  • a comprehensive overview of this technology has been described in " The Porphyrins" Volume 1, Structure and Synthesis, Part A, Academic Press, New York, San Francisco and London 1978.
  • Example 2 introduces halogens into the benzochlorin nucleus, specifically chloro- by use of thionyl chloride but also bromo- when thionyl bromide is used.
  • Example 3 demonstrates the process for metal insertion into the benzochlorin cavity with the replacement of zinc acetate for other metal salts, such as copper acetate, tin chloride, and the like. This generates the corresponding metallo-derivative .
  • Example 4a illustrates introduction of a phthalimido group. Use of substituted phthalimido groups such as 4-nitrophthalimide in this reaction will generate benzochlorins bearing the nitrophthalimido- moiety.
  • Reaction of the nitro group, for example, by reduction to the amine can generate further benzochlorin derivatives which may also be further derivatized using standard methods for organic group transformations to produce compounds of this invention.
  • the generation of an aminobenzochlorin is also described in Example 4b. It will be appreciated that condensation of the amino- functionality with a large number of carboxylates or acyl chlorides can readily be effected to generate additional compounds of this invention.
  • Preferred reactants in such transformations are amino acids such as lysine, glutamic acid, aspartic acid, serine, cystine and arginine .
  • Suitable reactants include carbohydrates such as ribose that can be condensed at the carbohydrate anomeric center or carbohydrates bearing a carboxylate function, such as sialic acid, gluconic acid, galactaric acid and mannonic acid.
  • Example 5 demonstrates a standard procedure for generation of quaternary ammonium salts at the amino functionality of the aminobenzochlorin. While methyl iodide is the preferred reagent in this process, nevertheless, other reagents may be substituted to generate additional salt derivatives.
  • quaternization of the amino functionality of other amino groups attached to the benzochlorin nucleus arising, for example, through condensation of an aminobenzochlorin with the carboxylate function of an amino acid can be effected through a similar procedure, leading to other quaternary ammonium salt analogs.
  • the introduction of a formyl group into the benzochlorin nucleus is illustrated in Example 6. This general process can be used to formylate a large number of benzochlorins and the formyl group so introduced can then be reacted using standard organic chemistry procedures. For example, the formyl group can be treated with Grignard or alkyl lithium reagents to generate alcohols that may condense to form alkenes.
  • Example 7 Addition of cyanohydrin in a similar fashion will generate the cyanohydrin which may undergo further transformation.
  • Particularly useful reactions are those illustrated in Example 7 in which a hydrazone is generated or that illustrated in Example 8 where an iminium functionality is generated.
  • Hydrazones that are favored for reaction as described in Example 7 include hydrazine hydrate itself since the -NH 2 terminus generated can undergo additional reactions as described above for aminobenzochlorins .
  • a second hydrazine which is useful for further derivatization is phenylhydrazine-4- sulfonic acid as outlined in Example 7b.
  • the terminus S0 3 H group can be converted to S0 2 C1 by reaction with a number of chlorinating agents including PC1 5 , S0 2 C1 and P0C1 3 /DMF and the sulfonyl chloride so formed reacted with an amine to produce a sulfonamide.
  • Preferred amines include amino acids or aminoalcohols .
  • the iminium salt of Example 8 is formed by use of P0C1 3 /DMF and the iminium group is thus substituted with two methyl groups .
  • Example 9 illustrates how the nitro group can be added to form nitrobenzochlorins .
  • Other nitrating agents can also be used to produce nitrobenzochlorins, for example, NaN0 2 /TFA, N0 2 + BF 4 " , N0 2 + CF 3 S0 3 " . Since the nitro group is inert to many reagents, the above chemistry to insert and alter functionality at R 14 of the benzochlorin nucleus is also applicable to nitrobenzochlorins. Alternatively, the nitro group can be reduced, thus forming an alternative route to aminobenzochlorins.
  • R x to R 10 can be the same or different and each is H, Br,
  • R x is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms and where R 2 is H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 2 can be the same or different,
  • R x is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms and where
  • R 2 is H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms or an amino acid residue or a carbohydrate residue and each R 2 can be the same or different
  • A is a physiologically acceptable anion, -R-,OR 2 where R is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms, and R 2 is H or an amino acid residue, a carbohydrate residue or an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms, -R 1 COR 2 where R ⁇ is an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms, R 2 is NH 2 , an amino acid group or a polyhydroxyamino moiety having from 1 to 6 hydroxyl groups, OR 3 where R 3 is H, an alkyl or alkenyl hydrocarbon radical having from 1 to 6 carbon atoms, an amino acid group or a polyhydroxyamino moiety having from 1 to 6 hydroxyl groups or a
  • the compounds of the invention are useful as photosensitizers and can be used to destroy cells and tissues following activation by light.
  • the benzochlorin derivatives are administered in a therapeutic amount to a human or animal patient in whom it is desired to destroy certain cells or tissues.
  • the administration may be intravenous, intramuscular or topical.
  • the target cells and tissues are exposed to light of a wavelength that causes the photosensitizer to become cytotoxic.
  • the process may also be applied to an in vi tro situation where, for example, blood or blood products collected from a human or animal patient can be treated photodynamically and then readministered to the same or to another human or animal patient .
  • compositions are formulated into pharmaceutical compositions for administration using techniques which are well known to those skilled in the art and which are described in general in texts such as Remington ' s Pharmaceutical Sciences . More specifically, the preferred formulations are those prepared in conventional forms in which suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like or emulsions based on medium chain triglycerides, non-ionic solubilizers such as Cremophor or Tween 80 or phospholipids such as EYP.
  • suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like or emulsions based on medium chain triglycerides, non-ionic solubilizers such as Cremophor or Tween 80 or phospholipids such as EYP.
  • compositions may be topically administered using standard topical compositions involving penetrating solvents, or in the form of lotions, creams, gels or ointments. It is necessary only for the solution or emulsion to be one which is physiologically acceptable and of a suitable concentration or dilutable to a suitable concentration for administration. An indefinitely large number of such solutions and emulsions will be apparent to those skilled in the relevant art from the foregoing disclosures. Typical indications for which these compositions have utility include, but are not limited to, cancer, dermatological applications, cardiovascular applications, urology applications, ophthalmologic applications, immunology applications, treatment of viral and fungal conditions and treatment of blood or blood products.
  • the benzochlorin derivative (identified below) is dissolved in saline containing 1% ethanol to give a solution with a final photosensitizer concentration of approximately 0.5mg/ml .
  • the solution is filtered through a 0.22 micron Millipore filter.
  • Ten C3H/HeJ mice with 0.5mm diameter subcutaneous RIF tumors in the flank are injected IV with 2.5 mg/kg body weight of the above solution. After 24 hours, the tumor area is exposed to light at for 30 min at a power density of lOOmW/cm 2 .
  • the light source is a Xenon arc lamp filtered to remove IR radiation and all wavelengths below 620nm.
  • the treatment site appears cyanotic in nature and tumors are seen to become flat and non-palpable. An eschar forms over the treatment site.
  • 100% of animals are shown to have responded to the photodynamic therapy.
  • thirty days post treatment some of the animals remain tumor free. Normal tissue surrounding the tumor and included in the treatment site is shown to be minimally affected by the photodynamic treatment, indicating a selectivity for response in the tumorous tissue.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne une famille de dérivés du chlorobenzène, dont les formules sont illustrées dans les figures (IA) et (IB), qui peuvent être utilisés comme photosensibilisants en thérapie photodynamique. Les solutions desdits dérivés de chlorobenzène, qui sont acceptées sur le plan physiologique, provoquent une destruction cellulaire et tissulaire sélective. L'invention concerne également un procédé qui permet de détruire les cellules et les tissus par une technique photodynamique, qui consiste à administrer à l'homme ou à l'animal les dérivés de chlorobenzène de formules (IA) et (IB), puis à exposer ledit animal ou homme à une lumière suffisante pour générer un effet cytotoxique.
EP98952052A 1998-10-05 1998-10-05 Photosensibilisants pour applications photodynamiques Withdrawn EP1117665A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1998/020854 WO2000020419A1 (fr) 1998-10-05 1998-10-05 Photosensibilisants pour applications photodynamiques

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EP1117665A1 true EP1117665A1 (fr) 2001-07-25

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EP98952052A Withdrawn EP1117665A1 (fr) 1998-10-05 1998-10-05 Photosensibilisants pour applications photodynamiques

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EP (1) EP1117665A1 (fr)
JP (1) JP2002526543A (fr)
CA (1) CA2345580A1 (fr)
WO (1) WO2000020419A1 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1341460C (fr) * 1988-01-11 2004-10-19 The Medical College Of Ohio Fabrication et utilisation de derives de la prophyrine, ainsi que des compostions compremant ces derives
EP0644759A4 (fr) * 1992-06-19 1998-04-01 Univ Toledo Production et utilisation d'imines de porphyrines.
CA2225214A1 (fr) * 1995-06-20 1997-01-09 Miravant Pharmaceuticals, Inc. Fonctionnalisation efficace de derives de porphyrine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0020419A1 *

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CA2345580A1 (fr) 2000-04-13
JP2002526543A (ja) 2002-08-20
WO2000020419A1 (fr) 2000-04-13

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