[go: up one dir, main page]

EP0553116A1 - Derives de prophyrine - Google Patents

Derives de prophyrine

Info

Publication number
EP0553116A1
EP0553116A1 EP19910916730 EP91916730A EP0553116A1 EP 0553116 A1 EP0553116 A1 EP 0553116A1 EP 19910916730 EP19910916730 EP 19910916730 EP 91916730 A EP91916730 A EP 91916730A EP 0553116 A1 EP0553116 A1 EP 0553116A1
Authority
EP
European Patent Office
Prior art keywords
esters
hpix
carboxyphenyl
ether
methanamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19910916730
Other languages
German (de)
English (en)
Inventor
Michel Ringuet
Roy H. Pottier
James C. Kennedy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Queens University at Kingston
Original Assignee
Queens University at Kingston
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Queens University at Kingston filed Critical Queens University at Kingston
Publication of EP0553116A1 publication Critical patent/EP0553116A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • This invention relates to a novel concept and technique for the chemical modification of lipophilic and amphiphilic drugs to increase their selective accumulation within malignant tissues, to a novel class of compounds having photochemo-therapeutic perties , to a method of making same, and to a method for treating tumours in patients.
  • Every cytotoxic agent used in the treatment of cancer causes damage to normal as well as malignant cells .
  • the maximum therapeutically useful dose is limited by toxicity to essential normal tissues , and in many cases it is not possible to give a dose large enough to destroy the cancer without als o killing the patient .
  • the concentration of the cytotoxic drug could be increased in the malignant tissues only , then the therapeutic effectiveness of the drug would be increased without a corresponding increase in toxicity.
  • hypoxic zones Many types of malignant tumors develop zones in which the blood supply is inadequate , resulting in poorly nourished and hypoxic cells and areas of necrosis .
  • the malignant cells in hypoxic zones normally are quiescent, but many retain the capacit o proliferate without limit or control and will do so if given a more adequate supply of oxygen and nutrients .
  • hypoxic cells often are relatively res istant to both radiation therapy and chemotherapy.
  • Hypoxic cells are relatively resistant to radiation therapy that involves X-rays or gamma-rays, since molecular oxygen is required for some of the radiochemical processes that eventually lead to cell death.
  • hypoxic or poorly nourished cells normally are not in the prolif erative cycle , and resting cells are relatively resistant also to the many chemotherapeutic agents whose toxic ity is restricted primarily to cells that are proliferating.
  • oxygen, nutrients, and drugs all reach cells by diffusion from adjacent capillaries , cells that are hypoxic or poorly nourished because they are too far from the nearest capillary may not be exposed to an adequate dose of chemotherapeutic agent. Failure to kill hypoxic or poorly nourished cells during attempts to eradicate a malignant tumor (by radiotherapy, chemotherapy. or any other form of therapy) may be followed by tumor recurrence.
  • Photodynamic therapy is an experimental form of treatment for cancer. It involves the localized or systemic administration of a photosensitizing compound or a metabolic precursor thereof , followed by exposure of the malignant tissue and adjacent normal tissues to photoactivating light.
  • tissue specificity of the resultant phototoxic damage is determined largely (though not entirely) by the relative concentrations of the photosensitizer in each tissue at the time of its exposure to the photoactivating light .
  • certain derivatives of porphyrins , phthalocyanines , and chlorins accumulate preferentially within malignant tissues .
  • photochemotherapeutic agents Like most drugs, photochemotherapeutic agents usually enter malignant tissues by diffusion from capillaries. As a result, zones of tissue that are poorly supplied with capillaries will be exposed to relatively low concentrations of the compound, perhaps too low to be therapeutically effective, unless the compound has a special affinity for hypoxic or necrotic tissue.
  • the primary mechanism by which most photosensitizers kill cells requires effective contact between a molecule of photosensitizer and a molecule of oxygen. The probability that enough such contacts will take place within hypoxic tissue will be reduced if the concentration of the photosensitizer is low, but will increase if the concentration of the photosensitizer in the hypoxic tissue is increased.
  • an object of the present invention to provide novel photochemotherapeutic agents of the porphyrin and chlorin type substituted with functionalized alkyl amide groups, which are good tissue photosensitizers, accumulate preferentially in necrotic and/or hypoxic areas of malignant tumors, show low systemic toxicity, clear rapidly from skin and most other normal tissues, and which show some degree of anti tumor activity even in the dark.
  • Z is selected from mono-, di-, and tri- hydroxyalkyl and mono-, di-, and tri- halogenoalkyl;
  • X is selected from substituted tetrapyroles in which the substituent is at least one of the group consisting of methyl, ethyl, vinyl, hydroxyethyl, alkoxyethyl, carboxymethyl, carboxyethyl, Z-substituted propylamide, phenyl and Z-substituted phenylamide, and
  • n is an integer from 1 to 8.
  • a method for treating malignant tissue abnormalities in a patient comprising administering to said patient an effective amount of a lipophilic or amphiphilic compound having water solubilizing groups attached thereto by amide bonds and exposing said tissue abnormality to light within the photoactivating spectrum of said lipophilic compound.
  • a method for treating malignant tissue abnormalities in a patient comprising administering to said patient an effective amount of a lipophilic or amphiphilic compound having water solubilizing groups attached thereto by bonds cleavable by a protease present in said malignant tissue, so as to cause selective accumulation of said compound in said malignant tissue.
  • novel compounds of the present invention can be characterized by the general formula (ZNHCO) n X where
  • Z mono-, di- or tri- hydroxyalkyl or mono-, di- or tri- halogenoalkyl
  • X substituted tetrapyrole, wherein the substituent group or groups are selected from methyl, ethyl, vinyl, hydroxyethyl, alkoxyethyl, carboxymethyl, carboxyethyl, Z-substituted propylamide, phenyl and Z-substituted phenylamide,
  • Preferred compounds may be derived from commercially available hematoporphyrin IX dihydrochloride HPIX.2HCl (Roussel, France) or mesoporphyrin IX dihydrochloride MPIX.2HCl (Aldrich Chemical Co. U.S.A.) or deuteroporphyrin IX dimethyl ester (Aldrich Chemical Co. U.S.A.) according to the following reaction scheme:
  • HPHEHE HPIX di(2-hydroxyethyl)ether di(2-hydroxyethyl ester)
  • Hexacarboxyporphyrin I & III both isomers
  • Heptacarboxyporphyrin I & III and their esters 5,10,15,20-tetra(y-carboxyphenyl)porphin and its esters
  • HPPEEA hematoporphyrin IX di-n-propyl ether diethanolamide
  • HPPEPE 1g; 1.30 mmol of HPPEPE was dissolved in 2-aminoethanol (10 ml; 166 mmol) and heated at 100-120°C for three hours to give HPPEEA which was extracted from the reaction mixture by precipitation in cold water, followed by centrifugation. The residue obtained was chromatographed on deactivated silica gel with a mixture of chloroform and methanol. After evaporating the solvent, the product was dissolved in a small amount of ethanol and precipitated in a mixture of ethyl ether - petroleum ether for final purification. Pure crystalline HPPEEA was recovered, in 76% yield from HPIX, by centrifugation.
  • HPPEPE hematoporphyrin di-n-propyl ether
  • Chemotherapeutic agents usually enter tissues via the blood, and malignant cells whose blood supply is inadequate may not receive a lethal dose.
  • the toxicity of many common chemotherapeutic agents is restricted primarily to cells that are in cell cycle . Consequently, malignant cells that are poorly nourished and/ or hypoxic may survive courses of radiotherapy and/ or chemotherapy that otherwise might have been curative. Such surviving cells may proliferate subsequently to cause a recurrence of the cancer.
  • a drug which shows suff icient preferential toxicity for hypoxic cells may be given in doses that should kill the hypoxic cells in tumors without caus ing unacceptable toxicity to the normally-oxygenated cells of non-malignant tissues.
  • a drug might not be curative if given as the sole therapy, since only some of the cells in tumors are hypoxic but it would be a very useful adjunct to radiotherapy and/or chemotherapy, since these tend to kill well oxygenated cells preferentially.
  • certain nitro-containing compounds accumulate preferentially in hypoxic tissues where they cause preferential toxicity for the hypoxic cells.
  • Phototoxic damage to hypoxic tissue can be increased either by increasing the tissue concentration of oxygen or by increasing the concentration of photosensitizer.
  • the former is not very effective but as the photosensitizers of the present invention tend to accumulate in necrotic/hypoxic tissue they selectively increase the intensity of the phototoxic reaction in such tissues.
  • mice bearing subcutaneous transitional cell carcinoma FCB were each injected intraperitoneally with 10 mg per kg body weight every other day for 10 days, for a total dose of 50 mg per kg body weight of a compound selected from: MPEA, MPDA, MPTA, HPMEEA, HPEEEA, HPPEEA and DPEA as defined herein above.
  • the mice were then killed and their tissues examined for porphyrin fluorescence under UV light 48 hours following the final injection. All of the compounds tested showed strong fluorescence in the necrotic areas of the tumor with little or no fluorescence in the adjacent healthy tumor.
  • Tissues that contained the modified mesoporphyrins MPEA, MPDA, and MPTA which showed porphyrin fluorescence at autopsy continued to do so for at least several weeks of storage in buffered formalin, but tissues containing HPPEEA or HPEEEA completely lost their original porphyrin fluorescence while stored in buffered formalin in the dark.
  • Example 6 The procedures of Example 6 were repeated on (B6D2) F1 mice bearing Lewis lung carcinoma. 100 mg of HPPEEA per kg body weight was injected over a 10 day period. At autopsy, intense porphyrin fluorescence was observed in the necrotic areas of the tumors with very little fluorescence in other locations except the pancreas. From the results of examples 6 and 7 it may be concluded that the unusual tissue specificity observed with the seven porphyrins tested is associated with the presence of an amide linkage between the propionic acids of the porphyrin and an alcohol-containing solubilizing group. It will be appreciated that mesoporphyrin
  • modified porphyrin molecules having a range of solubilities can be produced viz MPEA (mesoporphyrin diethanolamide) has 2 added alcohol groups.
  • MPEA mesoporphyrin diethanolamide
  • MPDA mesoporphyrin di(bis(hydroxymethyl) methanamide)
  • MPTA mesoporphyrin di (tris (hydroxymethyl)methanamide)
  • HPMEEA hematoporphyrin dimethylether diethanol-amide
  • HPEEEA hematoporphyrin diethylether diethanol-amide
  • HPPEEA hematoporphyrin di-n propyl ether diethanolamide
  • proteases are present in the blood and extracellular fluid of non-malignant tissues, such proteases normally show little activity.
  • malignant cells often release proteolytic enzymes and may induce the release or activation of such enzymes by normal cells.
  • Activated protease enzymes are often present in the necrotic areas of malignant tissues, derived from the dead cells and from the phagocytes that have been attempting to liquefy them.
  • drugs must dissolve in the plasma membrane, which is mostly lipid, in order to enter a cell.
  • drugs whose lipid/water partition ratio is high tend to enter cells more readily than those whose partition ratio is low (hydrophilic drugs).
  • a lipophilic drug is converted into a hydrophilic compound by linking it with a solubilizing group via an amide bond or an appropriate polypeptide chain, such a compound will not enter cells in normal tissues as readily as the original drug.
  • a solubilizing group via an amide bond or an appropriate polypeptide chain
  • the hydrophilic compound will be converted back to the lipophilic form of the drug by protease-mediated cleavage of the amide or peptide bonds, with consequent increased solubility in the plasma membranes of the cells.
  • HPPEEA at a concentration of 1.0mg HPPEEA per ml of 10%
  • DMSO in serum was injected intravenously into Skh:HR-1 mice bearing well-developed Adenocarcinoma 755 (a) in ascites form, or (b) as a solid tumor growing within the muscles of the thigh; and also into Skh:HR-1 mice bearing advanced subcutaneous tumors of FCB transitional cell carcinoma of the bladder.
  • the dose in each case was 10mg of HPPEEA per kg of body weight.
  • the mice were maintained in dim light following the HPPEEA injection, to minimize the possibility of photodynamic effects.
  • a small proportion of the injected mice showed rapid and complete regression of the cancer, such regression being maintained until termination of the experiment 10 weeks later. Cancers in control mice normally grew progressively.
  • the particular tumor/mouse combination used is not completely histocompatible and therefore may provide an unusually sensitive detection system for anti-tumor actiiity of HPPEEA in the dark.
  • HPPEEA Phototoxicity and Therapeutic Effectiveness of HPPEEA.
  • Lewis Lung Carcinoma was transplanted subcutaneously into the flank of Skh:HR-1 hairless mice, and allowed to grow until the tumor was approximately 10 mm in diameter.
  • a dose of 10mg HPPEEA per kg of body weight was then injected intraperitoneally.
  • the tumor and adjacent normal skin was exposed to a dose of 50 mWhr/cm 2 photoactivating light (wavelengths greater than 600 nm) at an intensity of 200 mW/cm 2 .
  • HPPEEA appears to have a clinically useful degree of tissue specificity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Agents photochimiothérapiques et procédé de fabrication. Composés lipophiles et amphiphiles qui sont des dérivés amide de porphyrine, présentant au moins une efficacité soit photosensible, soit radio-pharmaceutique ou immunologique et comportant des groupes de solubilisation aqueuse qui y sont fixés au moyen de liaisons sélectionnées à partir de liaisons amide et de liaisons peptide, pour une accumulation sélective dans des tissus malins de l'organisme.
EP19910916730 1990-10-05 1991-10-01 Derives de prophyrine Withdrawn EP0553116A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59386790A 1990-10-05 1990-10-05
US593867 1990-10-05

Publications (1)

Publication Number Publication Date
EP0553116A1 true EP0553116A1 (fr) 1993-08-04

Family

ID=24376530

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910916730 Withdrawn EP0553116A1 (fr) 1990-10-05 1991-10-01 Derives de prophyrine

Country Status (6)

Country Link
EP (1) EP0553116A1 (fr)
AU (1) AU655942B2 (fr)
CA (1) CA2093361C (fr)
MX (1) MX9101448A (fr)
NZ (1) NZ240057A (fr)
WO (1) WO1992006097A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5599924A (en) * 1992-08-14 1997-02-04 Trustees Of The University Of Pennsylvania Electron-deficient porphyrins and processes and intermediates for preparing same
US5817830A (en) * 1992-08-14 1998-10-06 Trustees Of The University Of Pennsylvania Pyrrolic compounds
US5371199B1 (en) * 1992-08-14 1995-12-26 Univ Pennsylvania Substituted porphyrins porphyrin-containing polymers and synthetic methods therefor
US5493017A (en) * 1992-08-14 1996-02-20 The Trustees Of The University Of Pennsylvania Ring-metalated porphyrins
CA2189967A1 (fr) * 1994-05-11 1995-11-23 Guy Jacques Felix Marchal Utilisation de composes a base d'un complexe de porphyrine ou d'un complexe de porphyrine etendue comme preparation diagnostique pour la localisation d'un infarctus
US6013241A (en) * 1995-01-23 2000-01-11 Schering Aktiengesellschaft Use of porphyrin-complex or expanded porphyrin-complex compounds as an infarction localization diagnosticum
US6492420B2 (en) 1995-03-10 2002-12-10 Photocure As Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
US6992107B1 (en) 1995-03-10 2006-01-31 Photocure Asa Esters of 5-aminolevulinic acid and their use as photosensitizing compounds in photochemotherapy
CZ291132B6 (cs) * 1995-03-10 2002-12-11 Photocure Asa Estery kyselin 5-aminolevulových a farmaceutický prostředek s jejich obsahem
US7530461B2 (en) 1995-03-10 2009-05-12 Photocure Asa Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
GB9700396D0 (en) 1997-01-10 1997-02-26 Photocure As Photochemotherapeutic compositions
GB0018528D0 (en) 2000-07-27 2000-09-13 Photocure Asa Compounds
US6838248B2 (en) 2000-11-17 2005-01-04 Biomoda, Inc. Compositions and methods for detecting pre-cancerous conditions in cell and tissue samples using 5, 10, 15, 20-tetrakis (carboxyphenyl) porphine
EP1401430A4 (fr) 2001-05-31 2005-10-19 Miravant Pharm Inc Derives porphyrine et azaporphyrine substitues et utilisation en therapie photodynamique, radioimagerie, et diagnostic par irm
EP2596348B1 (fr) 2009-07-17 2017-09-06 bioAffinity Technologies, Inc. Système et procédé d analyse d échantillons marqués au moyen de la 5, 10, 15, 20 tétrakis (4-carboxyphényle) porphine (tcpp)
WO2017218959A1 (fr) 2016-06-16 2017-12-21 Oncoselect Therapeutics, Llc Composés de porphyrine et compositions utiles pour le traitement du cancer

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675338A (en) * 1984-07-18 1987-06-23 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4693885A (en) * 1984-07-18 1987-09-15 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
WO1986001720A1 (fr) * 1984-09-13 1986-03-27 Cytogen Corporation Conjugues d'agents therapeutiques-anticorps
US4656186A (en) * 1985-04-30 1987-04-07 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4886484A (en) * 1989-06-02 1989-12-12 Litens Automotive Partnership Torsional spring tensioner with stabilizer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9206097A1 *

Also Published As

Publication number Publication date
AU8612291A (en) 1992-04-28
CA2093361A1 (fr) 1992-04-06
NZ240057A (en) 1994-07-26
CA2093361C (fr) 2002-04-23
MX9101448A (es) 1992-06-05
WO1992006097A1 (fr) 1992-04-16
AU655942B2 (en) 1995-01-19

Similar Documents

Publication Publication Date Title
AU655942B2 (en) Porphyrin derivatives
EP0168832B1 (fr) Composition pharmaceutique contenant un composé de tétrapyrrole comme composé actif et procédé pour la production de ce composé
EP0168831B1 (fr) Composés de tétrapyrrole, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0322795B1 (fr) Acides tétrapyrrole-aminocarboxyliques
US4656186A (en) Tetrapyrrole therapeutic agents
US4977177A (en) Tetrapyrrole polyaminomonocarboxylic acid therapeutic agents
US5591847A (en) Long wavelength absorbing photosensitizers related to purpurin-18, bacteriopurpurin-18 and related compounds with imide linkages
NZ338031A (en) Ethylene glycol esters of monohydrobenzoporphyrin derivatives as photoactive agents and their use in conducting photodynamic diagnosis
EP0210351B1 (fr) Utilisation de dérivés de la porphyrine dans la détection et le traitement de tumeurs
US5219878A (en) Tetrapyrrole hydroxyalkylamide photochemotherapeutic agents
WO1992012636A1 (fr) Derives de porphycene s'utilisant directement en therapie photodynamique ou comme intermediaires de synthese de colorants photoactivables appropries en therapie photodynamique
CN100439372C (zh) 卟啉衍生物
WO1998015271A1 (fr) Porphycenes 9-substitues

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930413

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19950810

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19951221