WO2011161065A1 - Composé macrocyclique tétrapyrrolique de la famille des porphyrines, des chlorines et des bactériochlorines comme photosensibilisateurs pour thérapie photodynamique - Google Patents

Composé macrocyclique tétrapyrrolique de la famille des porphyrines, des chlorines et des bactériochlorines comme photosensibilisateurs pour thérapie photodynamique Download PDF

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Publication number
WO2011161065A1
WO2011161065A1 PCT/EP2011/060256 EP2011060256W WO2011161065A1 WO 2011161065 A1 WO2011161065 A1 WO 2011161065A1 EP 2011060256 W EP2011060256 W EP 2011060256W WO 2011161065 A1 WO2011161065 A1 WO 2011161065A1
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group
compound
hydroxyphenyl
macrocyclic
porphyrins
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PCT/EP2011/060256
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English (en)
Inventor
António Manuel d'Albuquerque ROCHA GONSALVES
Maria Filomena Botelho
Arménio Coimbra SERRA
Marta Pineiro
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Fundação Padre Antonio Vieira
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Publication of WO2011161065A1 publication Critical patent/WO2011161065A1/fr

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Macrocyciic tetrapyrrolic compound of the family of porphyrins, chlorins and bacteriochlorins as photosensitizers for photodynamic therapy
  • This invention discloses new macrocyciic pyrrolic compounds with appropriate amphiphilicity and halogen substituents which have proved to optimize the photo- physical, photochemical and pharmacological properties of these compounds so that they may be used and are particularly efficient in photodynamic therapy (PDT) and photodiagnosis.
  • the compounds of this invention proved to be useful in PDT against human cancer cells.
  • the present invention also includes a new advantageous synthetic process for the preparation of the dypyrrylmethanes, which are the precursors of this kind of macrocyciic.
  • the included structures are 5,15-bisphenylchlorins and 5,15- bisphenylbacteriochlortns with a hydroxy! group in the meta position and bromine or chlorine in the ortho positions of the phenyl rings.
  • the substituents in positions 2,3,7,8,12,13,17 and 18 may be hydrogen, halogen atoms or alkyl, vinyl, carboxyl, carboxylalkyi, alkoxycarbonyl, aikoxycarbonylalkyl, alkoxycarbonyiaryl, acetoxy or hydroxyalkyl groups.
  • the invention also comprises the use of these compounds in photodynamic therapy and photodiagnosis.
  • Photodynamic therapy is presently a well established technique allowing very useful oncological and non-oncological therapeutics involving the irradiation of the affected areas with visible light after a sensitizer that has been administered localizes itself preferentially in the target cells.
  • PSD photosensitizer
  • the sensitizer is therefore a species without pharmacological activity and its function consists in the production of true active species from inactive species present in the medium.
  • the referred species is oxygen which is converted from its natural triplet state into harmful oxygen species, mainly the oxygen singlet state.
  • the sensitizer does not have the function of a common pharmaceutical compound but, through the interaction with light, basically generates the species that will carry out the pharmacological function.
  • some specific properties must be present, such as:
  • Non-oncologicai applications include vascular applications of photochemotherapy: an example is the ophthalmologic problem of age related macular degeneration (AMD) which requires sensitizers with absorption values at wavelengths higher than 700 nm; another example is the use of PDT for the prevention of restenosis.
  • AMD age related macular degeneration
  • PDT for the prevention of restenosis.
  • Relatively to oncological applications the use of PDT in the destruction of large tumours appears to have unsatisfactory results except in a few cases of brain tumors in which the blood-brain barrier favors the concentration of the sensitizer in the tumor tissue relatively to the healthy tissues. In this case light diffusion through brain tissue also seems to be better than through others.
  • glyoblastoms an "orphelin" pathology that has a very short survival prognosis, about one year or less.
  • glyoblastoms an "orphelin" pathology that has a very short survival prognosis, about one year or less.
  • the mouth leucodisplasies very common in developing countries, which can be promptly and easily treated by PDT contrary to the present situation where treatment is not made for being too expen- sive
  • pre-cancerous lesions such as Barrett mucosa, with increasing cases in industrialized countries, can be cured by PDT with minimal invasive treatments
  • prostate and bladder cancer and actinic keratosis with a growing number of cases due to aging of the population and increasing solar exposure, showed complete cure by PDT therapy.
  • WO 03/064427 A1 describes 5,15-bis(2-bromo-5-hydroxyphenyl)porphyrin used as photodynamic agent.
  • the invention relates to macrocyclic tetrapyrrolic compounds of the family of porphyrins, chlorins and bacteriochlorins of the general formula (I)
  • R 1 and R 2 are a substituted phenyl group, wherein the substituent at the phenyl group is a halogen atom in ortho or para position of the phenyl ring and a hydroxyl group in meta position of the phenyl ring;
  • positions 2, 3, 7, 8, 12, 13, 17 and/or 18 of the macrocycle are substituted with a group selected from hydrogen atom, halogen atom, alky! group, vinyl group, carboxy group, carboxyalkyl group, alkoxycarbonyl group, alkoxycar- bonylalkyl group, alkoxycarbonylaryl group, acetoxy group or hydroxyalkyl group; wherein the compound 5,15-bis (2-bromo-5-hydroxyphenyl) porphyrin is excluded.
  • the macrocyclic tetrapyrrolic is a chlorin having a double bond between position 7 and 8 and a single bond between position 17 and18 of the porphyrin ring.
  • the macrocyclic tetrapyrrolic compounds is a bacteriochlorin having a single bond between position 7 and 8 and a single bond between position17 and 18 of the porphyrin ring. The most preferred compounds are:
  • the compounds according to the invention are used as a medicament, preferably for use in the photodynamic therapy and photodiagnosis.
  • the medicament according to the invention can contain appropriate additives.
  • Disclosure of the invention is based on the modulation of the structure of the photosensitizer relatively to its photophysical and pharmacological properties.
  • the type of sub- stituents that have been incorporated into the macrocycles was selected with the aim of maximizing the required properties for PDT application.
  • the selection of the adequate pattern of substitution is sustained by our own studies and knowl- edge of photochemical, photophysical and biological properties and the capacity to exploit our expertise in organic synthesis 22"26 .
  • the synthetic methods were specifically established to allow efficient preparation of the required sensitizers.
  • the synthetic methods were specifically established to allow efficient preparation of the required sensitizers.
  • halogen atoms and their location on the macrocycle require a specific tuning to ensure the maximum singlet oxygen quantum yield.
  • Other positions of the porphyrin macrocycle that lack halogen atoms can accommodate substitu- ents such as alkyl, vinyl, carboxyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbon- ylalkyl, alkoxycarbonylaryl, acetoxy or hydroxyalkyl groups in order to grant am- phiphilic characteristics to the porphyrins.
  • Groups that are present in natural porphyrins will be chosen in order to improve the selectivity for different kinds of tumor cells and cellular components and to provide the correct lifetime in order to allow enough time for light treatment, but not so long as to make elimination difficult.
  • the time that the photosensitizer is located in the specific cellular structures has to be long enough to ensure the success of the treatment and short enough to guarantee the elimination from the body and avoid unnecessary tissue accumulation.
  • the correlation between the structure of the photosensitizer and the ability to interact with light is decisive for the success of the photodynamic treatment.
  • Light to be used in the photodynamic processes must have a wavelength higher than 600 nm. At these wavelengths the tissues are more light-transparent and light has more capacity of tissue penetration 8 . Therefore it is essential that macrocycles present absorption bands with strong absorption coefficients in this region of the spectrum.
  • the photosensitizers object of this patent besides the presence of halogen and hydroxyl groups to maximize photophysical characteristics and biological requirements, belong to the chiorin and bacteriochlorin type macrocycles which have absorption bands in the red zone of the spectrum with much higher absorption coefficients than porphyrins.
  • the present invention discloses the use of compounds of the diarylchlorin type (PS1 ,PS2) and corresponding diarylbacteriochlorins for application in phototherapy of tumors and other lesions, having the general formula (II) and (III) described below.
  • chlorins PS1 and PS2 and bacteriochlorins PSbd and PSbc2 which are new compounds.
  • the advantage of these classes of compounds is that they present an intense absorption band at higher wavelengths which is a favorable situation to clinical photodynamic applications.
  • PS1 and PS2 also have favorable photo- physical characteristics as illustrated in Table 1.
  • the absorption spectra of photosensitizers PS1 and PS2 show the typical Soret (B(0-0) band) at 408 nm and three Q-bands with the Qy(0-0) band of 5,15- diarylsubstituted chlorins at 646 nm.
  • these chlorins present a 20 nm shift to the red region and an increase of one hundred times in the absorption coefficient of the band with ⁇ >600 nm, which is a much more favorable situation considering the application of these compounds in PDT.
  • the fluorescence quantum yields for the 5,15-diarylchlorins PS1 and PS2 ( ⁇ ⁇ ) have the same order of magnitude of those of the corresponding porphyrins 28 .
  • the more favorable characteristics of PS1 and PS2 is that the maximum wave- length of the fluorescence band occurs at ca. 650 nm which is a very encouraging property for the use of PS1 and PS2 in photodiagnosis applications.
  • Figure 2 shows the A375 melanoma cancer cells viability after photodynamic treatment when incubated with different concentrations of photosensitizers PS1 PS2 and photofrin.
  • Figure 3 shows the WiDr adenocarcinoma cells viability after photodynamic treatment when incubated with different concentrations of photosensitizers PS1 , PS2 and photofrin.
  • Photofrin R is a sodium profimer of the following formula shown in Fig 4.
  • compositions which can be administered to humans or animals. These compositions can be run via enteric, parenteric or transdermic way, and can also be presented as tablets, pills, capsules, suspensions or solutions (oral and intravenous), dermic ointment or transdermic band-aid, in which the com- pound can be associated with additives and/or excipients usually employed in the pharmaceutical art.
  • the doses can be comprised between 0.1 and 20 mg/kg body weight.
  • the cell culture conditions are as follows.
  • the human colon carcinoma cell line WiDr and the human melanoma cell line A375 were purchased from American Type Culture Collection.
  • the cell lines were cultured with Dul- becco's modified Eagle medium (Sigma D-5648; Sigma-Aldrich, Inc.) supplemented with 10% heat-inactivated fetal bovine serum (Gibco 2010-04; Gibco Invi- trogen Life Technologies), 1% penicillin-streptomycin (Gibco Invitrogen Life Technologies; 100 U/mL penicillin and 10 g/mL streptomycin-Gibco 15140-122) and 100 ⁇ Sodium Piruvate (Gibco 1360; Gibco Invitrogen Life Technologies) at 37°C, in a humidified incubator with 95% air and 5% C0 2 .
  • Photodynamic treatment For each experiment, cells were plated in 48 muftiwells (Corning Costar Corp) at a concentration of 40 000 cells/mL) and kept in the incubator overnight, in order to allow the attachment of the cells.
  • the formulation of these sensitizers consisted in a 1 mg mL " solution in a ternary mixture of H 2 0:PEG 4 oo:Ethanol (50:30:20, v v), the desired concentrations being achieved by successive dilutions.
  • the sensitizers were administered in several concentrations (50 nM, 250 nM, 500 nM, 1 ⁇ , 5 ⁇ and 10 ⁇ ) and cells were incubated for 24 h.
  • the demethylation was carried out as follows.
  • the porphyrin (100 mg, 0.13 mmol) was dissolved in dichloromethane (15 mL), the solution cooled to -25°C and 1 mL of BBr 3 solution was slowly added. The mixture was left overnight at room temperature and was diluted with ethyl acetate and treated with methanol and triethylamine. The organic phase was carefully washed with water, dried with sodium sulfate and evaporated in vacuum to give 80 mg (84%) of 5,15-i>/s(2-chloro-5- hydroxyphenyl)porphyrin (PSp2).
  • the resulting solid product was redissolved in ethyl acetate and the organic phase was washed with water and dried over anhydrous Na 2 S0 4 . After filtration, p-cloranil (80 mg) was added in small portions to the stirred organic solution at room temperature until the absorption peak of the bacteriochlorin had disappeared. The solution was washed with NaHS0 4 (5%), distilled water and saturated bicarbon- ate. The resulting solution was stirred with a solution of 2M HCI for 30 min. The organic layer was separated, dried (MgS04) and concentrated on a rotary evaporator.

Abstract

La présente invention se rapporte à des composés macrocycliques tétrapyrroliques de la famille des porphyrines, des chlorines et des bactériochlorines substitués en positions 5 et 15 du macrocycle porphyrine par deux groupes phényles ayant des atomes de brome ou de chlore en position ortho et un groupe hydroxyle en position meta du cycle phényle ; dans ces composés, les positions 2, 3, 7, 8, 12, 13, 17 et/ou 18 du macrocycle sont substituées par des atomes d'hydrogène ou d'halogène ou des groupes alkyle, vinyle, carboxy, carboxyalkyle, alkoxycarbonyle, alkoxycarbonylalkyle, alkoxycarbonylaryle, acétoxy ou hydroxyalkyle. Les composés de cette invention se sont avérés utiles en thérapie photodynamique contre des cellules de cancer humain.
PCT/EP2011/060256 2010-06-25 2011-06-20 Composé macrocyclique tétrapyrrolique de la famille des porphyrines, des chlorines et des bactériochlorines comme photosensibilisateurs pour thérapie photodynamique WO2011161065A1 (fr)

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PT105173B 2010-06-25
PT10517310 2010-06-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9371555B2 (en) 2012-06-01 2016-06-21 Concordia Laboratories Inc. Lighting systems and methods of using lighting systems for in vitro potency assay for photofrin

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9371555B2 (en) 2012-06-01 2016-06-21 Concordia Laboratories Inc. Lighting systems and methods of using lighting systems for in vitro potency assay for photofrin
US10247723B2 (en) 2012-06-01 2019-04-02 Concordia Laboratories Inc. Lighting systems and methods of using lighting systems for in virto potency assay for photofrin
US11726079B2 (en) 2012-06-01 2023-08-15 Concordia Laboratories, Inc. Lighting systems and methods of using lighting systems for in vitro potency assay for Photofrin

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