USRE39094E1 - Pyropheophorbides and their use in photodynamic therapy - Google Patents

Pyropheophorbides and their use in photodynamic therapy Download PDF

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USRE39094E1
USRE39094E1 US10/384,895 US38489503A USRE39094E US RE39094 E1 USRE39094 E1 US RE39094E1 US 38489503 A US38489503 A US 38489503A US RE39094 E USRE39094 E US RE39094E
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pyropheophorbide
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Ravindra K. Pandey
Thomas J. Dougherty
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Health Research Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates generally to photosensitive therapeutic compounds and photodynamic therapy (PDT). More particularly, the invention relates to pyropheophorbides, formulations that contain such and their use is the treatment of cancer.
  • porphyrin related compounds accumulate at higher concentrations in tumor tissue as compared to normal tissue and that irradiation of these compounds using light of the proper wavelength results in a energized form which, upon decay, results in cytotoxicity. It is believed that excitation of the porphyrin or related material results in the formation of singlet oxygen which is in fact the toxic agent. However, the compounds administered apparently do not degrade in this process.
  • hematoporphyrin derivative“(HPD) describes this process utilizing a preparation obtained when hematoporphyrin dichloride is treated using the procedure of Lipson, R. L., et al, J National Cancer Inst (1961) 26:1-8. More recently, it has been shown that if this hematoporphyrin derivative is treated at a suitable pH, aggregation occurs and the active material in the mixture can be prepared in crude form as a size segregated aggregate (see, for example, U.S. Pat. No. 4,649,151, incorporated herein by reference). This preparation is commercially available under the trademark Photofrin.
  • the preparation marketed as the Photofrin composition is a mixture.
  • the mixture contains porphyrins joined by ether linkage (Dougherty, T. J., et al, Adv Exp Med Bio (1983)160:3-13), and more recently, Kessel, D., et al Photochem Photobiol (1987) 46:463-568, has shown that ester linked porphyrins are contained in this mixture as well.
  • Scourides, P. A., et al, Cancer Res (1987) 47:3439-3445 have synthesized an oligomeric mixture of ether linked porphyrins starting from hematoporphyrin dimethyl esters. The mixture was active in PDT, but was a complex a mixture as the Photofrin preparation.
  • Dimers of hematoporphyrin joined by ester linkages have also been prepared by Pandey, R. K., et al, Cancer Res (in press) and the dimers prepared were shown to be absent from the mixture in the Photofrin composition as well as inactive in an in vitro assay.
  • Pyropheophorbide compounds and pharmaceutical compositions containing such compounds can be used in methods or photodynamic therapy.
  • the pyropheophorbides are encompassed by the following general structural formula I or II. wherein R 1 CH 2 OR 2 is —CH 2 OR 2 where R 2 is a primary or secondary ary alkyl containing 1 to 20 carbons; and R 3 is —CO 2 R 4 —CH 2 CH 2 CO 2 R 4 where R 4 is H or an alkyl containing 1 to 20 carbons.
  • R 5 is —OR 6 when R 6 is a primary or secondary ary alkyl containing 1 to 20 carbons and R 7 is —CO 2 R 8 —CH 2 CH 2 CO 2 R 8 where R 8 is H or an alkyl containing 1 to 20 carbons.
  • Particularly preferred compounds are where R 5 is —O— hexyl and R 7 is —CO 2 H or —CO 7 H 3 .
  • the pyropheophorbides of the invention are combined with excipients to provide pharmaceutically acceptable formulations suitable for use in photodynamic therapy.
  • the invention also includes methods of synthesizing compounds of formula I and II.
  • the invention includes injectable pharmaceutical compositions containing the pyropheophorbide compounds of the invention an active ingredients and to methods of conducting photodynamic therapy using the compounds and compositions of the invention.
  • the invention also includes the pyropheophorbide compounds of the invention conjugated to a ligand which is capable of binding a specific receptor such as a cellular receptor, or as antibody which it capable of binding to a particular antigen and to compositions containing these conjugates and methods of conducting photodynamic therapy using the conjugates and their compositions.
  • a primary object of the invention is to provide pyropheophorbide compounds, pharmaceutical compositions containing such compounds and method of treatment carried out wing such compounds in a photodynamic therapy.
  • Another objects are to provide methods of treating humans with tumor cells which cells replicate abnormally fast, treating atherosclerosis or inactivating bacteria or virus infections.
  • a feature of the present invention is that the pyropheophorbide compounds of the invention absorb light further into the red portion of the spectrum so compared with conventional compounds used ice photodynamic therapy.
  • An advantage of the present invention is that the pyropheophorbide compounds and pharmaceutical composition of the invention optimize tissue penetration and are retained in the skin for relatively short periods of time as compared with other compounds used in photodynamic therapy.
  • Another advantage of the present invention is that the pyropheophorbide compounds of the invention have a greater toxicity with respect to tumor cells and diseased tissue as compared with the toxicity of conventional compounds used in photodynamic therapy.
  • pyropheophorbides can be synthesized as free acids (e.g. in formula I and II when R 3 or R 7 are —CO 2 H) allowing case in formulation without the need for liposomes or detergents.
  • Another advantage of the invention is the pyropheophorbide of the invention are active at very low doses of injected material as compared to conventional photosensitizers used in photodynamic therapy.
  • FIG. 1 is a FAB mass spectrum of the compound of formula II(a).
  • the essence of the invention is the disclosure of novel compounds and pharmaceutical compositions containing such compounds which have been found to be highly effective in the treatment of cancer when used in connection with a photodynamic therapy. More specifically, the compounds are pyropheophorbide compounds which are encompassed by the following general structural formulae I and II. wherein R 1 is CH 2 OR 2 —CH 2 OR 2 where R 2 is a primary or secondary ary alkyl containing 1 to 20 (preferably 5-20) carbons; and R 3 is —COR 4 —CH 2 CH 2 CO 2 R 4 where R 4 is H or an alkyl containing 1 to 20 carbons.
  • R 1 is —CO 2 —O—hexyl —CH 2 —O—hexyl and R 3 is —CO 2 CH 3 —CH 2 CH 2 CO 2 CH 3 or —CO 2 H —CH 2 CH 2 CO 2 H .
  • Other compounds of the invention are encompassed by formula II as follows: wherein R 5 is —OR 6 where R 5 is a primary or secondary alkyl containing 1 to 20 (preferably 5-20) carbons and R 7 is —CO 2 R 8 —CH 2 CH 2 CO 8 where R 8 is H or an alkyl containing 1 to 20 carbons.
  • Particularly preferred compounds are where R 5 is —O—hexyl and R 7 is —CO 2 H —CH 2 CH 2 CO 2 H or —CO 2 CH 3 —CH 2 CH 2 CO 2 CH 3 .
  • the pyropheophorbide compounds of structural formulae I and II can be formulated into pharmaceutical compositions and administered to patients in therapeutically effective amounts in order to treat cancer.
  • the starting material for preparation of the red light-absorbing compounds is methyl pheophorbide-a, which is isolated from Spirulina destridratada by the method of Smith and Golf (D. Goff, Ph.D. Thesis, Univ. of Calif., Davis, CA 95616. 1994 incorporated herein by reference). Briefly, 500 gm dried Spirulina was slurried in a large volume of acetone and then liquid nitrogen was added to form a frozen slush. The slush was transferred to a 3-necked, 5-liter round bottom flask and heated to reflux under nitrogen with stirring for 2 hours. The mixture was filtered through Whatman paper on a Buchner funnel with extensive acetone washing. The extraction and filtration process was repeated 2 more times; all green color could not be removed from the solid.
  • the green filtrate was evaporated and purified by flash chromatography on Grade V neutral Alumina, eluting first with n-hexane to remove a fast running yellow band and then with dichloromethane to obtain the major blue/gray peak containing pheophytin-a.
  • Treatment of pheophytin-a with 500 ml sulfuric acid in methanol for 12 hours at room temperature in the dark under nitrogen was followed by dilution with dichloromethane.
  • the reaction mixture was rinsed with water and then 10% aqueous sodium bicarbonate and the organic layer was dried, evaporated, and the residue recrystallized from dichloromethane/methanol to obtain 1.8 gm methyl pheophorbide-a.
  • Methyl pheophorbide-a appears to be inactive in the in vivo tumorcidal activity assay when injected at a done of 5 mg/kg.
  • compositions which consist essentially of the above-defined compounds or preparations an active ingredient, it is possible to sue derivatized forms in order to provide a specific targeting mechanism.
  • target-specific components include monoclonal antibodies and ligands which bind to a cellular receptor.
  • the compositions can also be conveniently labeled.
  • the target-specific component can then be, for example, an immunoglobulin or portion thereof or a ligand specific for a particular receptor.
  • the immunoglobulin component can be made of a variety of materials. It may be derived from polyclonal or monoclonal antibody preparations and may contain whole antibodies or immunologically reactive fragments of then antibodies such as F(ab′)2, FAB, or FAB′ fragments. Use of such immunologically reactive fragments as substitutes for whole antibodies is well known in the art. See, for example, Spiegelberg, H. L., in “Immunoassays in the Clinical Laboratory” (1978) 3:1-23 incorporated herein by reference.
  • Polyclonal anti-sera are prepared in conventional ways by injecting a suitable mammal with antigen to which antibody is desired, assaying the antibody level in serum against the antigen, and preparing anti-sera when the titers are high.
  • Monoclonal antibody preparations may also be prepared conventionally such as by the method of Koehler and Milstein using peripheral blood lymphocytes or spleen cells from immunized animals and immortalizing these cells either by viral infection, by fusion with myelomas, or by other conventional procedures, and screening for production of the desired antibodies by isolated colonies. Formation of the fragments from either monoclonal a polyclonal preparations is effected by conventional means as described by Spiegelberg, H. L., supra.
  • Particularly useful antibodies include the monoclonal antibody preparation CAMALI which can be prepared as described by Malcolm, A., et al, Ex Hematol (1984) 12:539-547; polyclonal or monoclonal preparations of anti-MI antibody as described by New, D. et al, J Immunol (1983) 130:1473-1477 (supra) and B16G antibody which is prepared as described by Maier, T., et al, J Immunol (1913) 131:1843; Steel, J. K., et al, Cell Immunol (1984) 90:303 all of which publications are incorporated by reference.
  • CAMALI monoclonal antibody preparation
  • B16G antibody which is prepared as described by Maier, T., et al, J Immunol (1913) 131:1843; Steel, J. K., et al, Cell Immunol (1984) 90:303 all of which publications are incorporated by reference.
  • the ligand specific for receptor refers to a moiety which binds a receptor at cell surfaces, and thus contains contacts and charge patterns which are complementary to those of the receptor. It is well understood that a wide variety of cell types have specific receptors designed to bind hormones, growth factors, or neurotransmitters. However, while these embodiments of ligands specific for receptor are known and understood, the phrase “ligand specific for receptor,” as used herein, refers to any substance, natural of synthetic, which binds specifically to a receptor.
  • each ligands include the steroid hormones, such as progesterone, estrogen, androgens, and the adrenal cortical hormones; growth factors, such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and so forth; other protein hormones, such as human growth hormone, parathyroid hormone, and so forth; and neurotransmitters, such as acetylcholine, serotonin, and dopamine. Any analog of these substances which succeeds in binding to the receptor is also included.
  • steroid hormones such as progesterone, estrogen, androgens, and the adrenal cortical hormones
  • growth factors such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and so forth
  • other protein hormones such as human growth hormone, parathyroid hormone, and so forth
  • neurotransmitters such as acetylcholine, serotonin, and dopamine. Any analog of these substances which succeeds in binding to the receptor is also included.
  • the conjugation of the target-cell-specific component to the compounds of the invention can be effected by any convenient means.
  • proteins such Ig and certain receptor ligand
  • a direct covalent bond between these moieties may be effected, for example, using a dehydrating agent such as a carbodiimide.
  • a particularly preferred method of covalently binding the compounds of the invention to the immunoglobulin moiety is treatment with 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDCI) in the presence of a reaction medium consisting essentially of dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • dehydrating agents such as dicyclohexylcarbodiimide or diethylcarbodilmide could also be used as well as conventional aqueous and partially aqueous media.
  • Nonprotein receptor ligands can be conjugated to be dimers and trimers according to their relevant functional groups by means known in the art.
  • the active moieties of the conjugate may also be conjugated through linker compounds which are bifunctional, and are capable of covalently binding each of the two active components.
  • linker compounds which are bifunctional, and are capable of covalently binding each of the two active components.
  • linkers are either homoor heterobifunctional moieties and include functionalities capable of forming disulfides, amides, hydrazones, and a wide variety of other linkages.
  • linkers include polymers such a polyamines, polyethers, polyamine alcohols, derivatized to the components by moms of ketones, acids, aldehydes, isocyanates, or a variety of usher groups.
  • the techniques employed in conjugating the active moieties of the conjugate to the target-specific component include any standard mean and the method for conjugation does as form part of the invention. Therefore, any effective technique knows in the art to produce such conjugates falls within the scope of the invention, and the linker moiety is accordingly broadly defined only as being either a covalent bond or any linker moiety available is the art or derivable therefrom using standard techniques.
  • the compounds of the invention per se or the conjugates may be further derivatized to a compound or ion which labels the drug.
  • labeling moieties can be used, including radioisotopes and fluorescent labels. Radioisotope labeling is preferred, as it can be readily detected in vivo.
  • the compounds which are alone or are conjugates with a specific binding substance can be labeled with radioisotopes by coordination of a suitable radioactive cation in the porphyrin system.
  • Useful cations include technetium and indium.
  • the specific binding substances can also be linked to label.
  • the pyropheophorbide compounds of the invention are administered to a host such as a human suffering from cancer in therapeutically effective amounts by any suitable means such as injection which may be IV or IM or may be administered transdermally.
  • the pyropheophorbide compounds of the invention accumulate in tumor cells to a much higher degree than they accumulate in surrounding normal tissues. After being provided with sufficient time so as to accumulate in the tumor tissue, the pyropheophorbide compounds are exposed to a particular wavelength of light which causes the compounds to become cytotoxic, thus destroying the tumor or diseased tissue which the pyropheophorbide compounds have accumulated in. This is accomplished without causing irreversible damage to surrounding normal tissues wherein there has not been an accumulation of the pyropheophorbide compounds.
  • the compounds and their conjugates with target-specific substances of the invention are useful, in general, in the manner known in the art for hematoporphyrin derivative and for Photofrin II compositions. These compositions are useful in sensitizing neoplastic cells or other abnormal tissue to destruction by irradiation using visible light—upon photoactivation, the compositions have no direct effect, nor are they entered into any biological event; however the energy of photoactivation is believed to be transferred to endogenous oxygen to convert it to singlet oxygen. This singlet oxygen is thought to be responsible for the cytotoxic effect.
  • the photoactivated forms of porphyrin fluorescence which fluoresce can aid in localizing the tumor.
  • the dimer and trimer compounds of the invention are not consumed or altered in exerting their biological effects.
  • Typical indications include destruction of tumor tissue in solid tumors, dissolution of plaques in blood vessels (see, eg., U.S. Pat. No. 4,517,762), treatment of tropical conditions such as acne, athlete's foot, warts, papilloma, and psoriasis and treatment of biological products (such as blood for transfusion) for infectious agents, since the presence of a membrane in such agents promotes the accumulation of the drug.
  • Other uses include treating humans suffering from atherosclerosis and inactivating bacterial or viral infections.
  • compositions are formulated into pharmaceutical compositions for administration to the subject or applied to an in vitro target using techniques known in the art generally. A summery of such pharmaceutical compositions may be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.
  • the compositions, labeled or unlabeled can be administered systemically, in particular by injection or can be used topically.
  • Injection may be intravenous, subcutaneous, intra-muscular, or even intraperitoneal.
  • Injectables in be prepared in conventional forms, either as liquid solutions or suspensions, solid form suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients normal for example, water, saline, dextrose, glycerol and the like.
  • these compositions may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and so forth.
  • Systemic administration can also be implemented through implantation of a slow release or sustained release system, by suppository, or, if properly formulated, orally.
  • Formulations for these mode of administration are well known in the art, and a summary of such methods may be found, for example, in Remington's Pharmaceutical Sciences (supra).
  • compositions may be typically administered using standard topical compositions involving lotions, suspensions, or pastes.
  • the quantity of compound to be administered depends on the choice of active ingredient, the condition to be treated, the mode of administration, the individual subject, and the judgment of the practitioner. Depending on the specificity of the preparation, smaller or larger doses may be needed. For compositions which are highly specific to target tissue, such as those which comprise conjugates with a highly specific monoclonal immunoglobulin preparation or specific receptor ligand, dosages in the range of 0/05-1 mg/kg are suggested. For compositions which are less specific to the target tissue, larger doses, up to 1-10 mg/kg may be needed. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large and considerable excursions from these recommended values are expected. Further, because of slight solubility in water, certain compounds of the invention may be administered directly in saline or 5% glucose solution, thus avoiding the complications of detergents or other solubilizing agents.
  • the present invention will be better able to determine an appropriate dosage and overall dosage regime when taking a number of factors into consideration. For example, the size, weight and condition of the patient must be considered as must be the responsiveness of the patient and their disease to the particular therapy. It is believed that even relatively small doses administered a single time can have a beneficial effect Further, extremely large doses could of course, be toxic.
  • Methyl pyropheophorbide-a (2) Methyl pheophorbide-a (1, 1.0 g) was obtained from alga Spirulina destridratada by following the procedure described in K. M. Smith, D. A. Golf and D. J. Simpson, J. Am. Chem. Soc, 1985, 107, 4941-4954; and R. R. Pandey, D. A. Bellnier, K. M. Smith and T. J. Dougherty, Photochem. Photobiol, 1991, 53, 65-72 both of which are incorporated herein by reference The methyl pheophorbide-a was heated under reflux in collidine (100 ml) for 90 min during slow passage of a stream of nitrogen.
  • Methyl-2- ⁇ 1((0-hexyl)ethyl)-devinyl pyropheophorbide (4); pyropheophorbide-a 200 mg) was dissolved in 30% HBr/acetic acid (5.0 ml) and the reaction mixture was stirred in a glass stoppered flask (rubber septum can also be used) at room temperature for 2.5 hours. The solvent was removed under high vacuum (1 mm Hg) and the resulting 1-bromo ethyl derivative was washed with water (3 ⁇ 200 ml) till the aqueous phase is neutral and then dried over anhydrous sodium sulfate.
  • mice with 0.4-0.5 mm diameter subcutaneous SMT-F tumors in the axilla are injected intravenously with 0.3 mg/kg body weight of the above solution (after diluting in HBSS so that the injected volume per mouse is approximately 0.2 ml).
  • the tumor area (having been shaved and depilated prior to tumor implant) is exposed to laser light at 660-670 nm for 30 min at a power of 75 m W /cm 2 to deliver 135 Joules/cm 2 .
  • a Xenon arc lamp filtered to emit a broader band width near 670 nm and approximately 283 Joules/cm 2 can be used.
  • mice Six albino Swiss mice (HalCR) are injected intravenously with a doe of 0.1 mg/kg body weight of the compound of formula IIa prepared as is Example 1. After approximately 24 h, the hind foot of the animal is exposed to the same dose or either laser light at 660-670 nm (135 Joules/cm 2 ) or the Xenon arc lamp (283 Joules/cm 2 ) as above The reaction of the foot is scored for damage over the next few days to determine the maximum effect, which in this case is a value 0.3 equivalent to slight edema. If the internal between the injection and light treatment is extended to approximately 48 h, the foot reaction is zero (no damage incurred), indicating either clearance or metabolism of the sensitizer.
  • the data of Table 1 show compounds of the invention clear skin over a period or 24-48 hours after administration. This is a desirable feature in that the patient is not subjected to prolonged cutaneous photosensitivity.
  • the data of Table 1 also show that the hexyl ethers of formula II are preferred over methyl ethers in terms of effecting tumor growth when used in photodynamic therapy.

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US07/597,786 US5093349A (en) 1988-07-20 1990-10-15 Photosensitizing agents
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US20100056983A1 (en) * 2007-09-27 2010-03-04 Health Research, Inc. Treatment of cancer using photodynamic therapy
US20100144820A1 (en) * 2007-01-09 2010-06-10 Health Research, Inc. Therapeutic hpph dosage for pdt
US7820143B2 (en) 2002-06-27 2010-10-26 Health Research, Inc. Water soluble tetrapyrollic photosensitizers for photodynamic therapy
WO2014056270A1 (zh) 2012-10-08 2014-04-17 浙江海正药业股份有限公司 靶向胸苷激酶光敏剂及其药物组合物与治疗癌症的用途

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