WO1999067249A1 - Alkyl ether analogs of chlorins having an n-substituted imide ring - Google Patents
Alkyl ether analogs of chlorins having an n-substituted imide ring Download PDFInfo
- Publication number
- WO1999067249A1 WO1999067249A1 PCT/US1999/004924 US9904924W WO9967249A1 WO 1999067249 A1 WO1999067249 A1 WO 1999067249A1 US 9904924 W US9904924 W US 9904924W WO 9967249 A1 WO9967249 A1 WO 9967249A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compounds
- light
- chlorins
- tumor
- wavelength
- Prior art date
Links
Classifications
-
- 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
- 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
- porphyrins and related tetrapyrrolic compounds e.g. chlorins and
- bacteriochlorins tend to be retained in malignant tumors in higher concentrations than
- an excited state may occur and a singlet oxygen atom may be
- the tumor may then be exposed to the appropriate substance
- the release of singlet oxygen may be the cytotoxic species which, along with various others
- Photofiin® (a porphyrin derivative), has been studied in most detail and is currently being used all over the world for treatment of various types of cancers. Despite the fact that it has already been approved for commercialization in Canada, Japan, and the United States, Photofiin photosensitizing agent has some disadvantages. In particular, it both photosensitizes the skin and lacks rapid normal tissue clearance, so patients must avoid exposure to sunlight for an extended period after its use. Further, it is a complex mixture of ether and ester linked dimers and higher oligomers, making it difficult to study mechanistically.
- Photofiin photosensitizing agent also absorbs at a short wavelength making deep tissue penetration difficult and sometimes not possible. It is well established that both absorption and scattering of light by tissue increases as the wavelength decreases, and the most efficient photosensitizers are those which have strong absorption bands at the red end of the visible spectrum and the near IR region. Heme proteins accounts for most of the absorption of light in the visible region. Since this drops off rapidly beyond 550 nm, the effective depth of penetration doubles from 550 to 630 nm (where Photofiin® is activated) and doubles again in going to 700 nm, followed by 10% increase in penetration by moving into the near IR region (800 nm).
- FIGURE 1 is a schematic equation showing a method for preparation of compounds of the invention.
- FIGURE 2 is a curve showing uptake in tumor versus skin fold of a purpurin- imide of the invention where R 1 is heptyl, R 2 is hexyl and R 3 is methyl.
- the uptake is measured by optical density at the desired wavelength at 24 hours post injection.
- a new series of compounds is therefore provided, which have good antitumor activity and which absorb at relatively long wave lengths of light.
- R 1 , R 2 , and R 3 are independently alkyl of 3 through about 10 carbon atoms; provided that, R 1 and R 2 together contain at least six carbon atoms.
- R 3 is preferably methyl or ethyl and R 2 and R 3 are preferably alkyl of 3 through 8 carbon atoms.
- alkyl ether derivatives of pyropheophorbide-a it has been shown that the biological activity increased by increasing the length of the carbon chain, being maximum with n-hexyl and n-heptyl analogs, further increase in the length of carbon chain reduced the in vivo efficacy.
- R is alkyl of 3 through about 10 and preferably 3 to 8 carbon atoms.
- R is alkyl of 3 through about 10 carbon atoms and preferably 3 to 8 carbon atoms.
- R 3 is methyl or ethyl.
- R and R together contain at least 6 carbon atoms.
- the alkyl groups may be linear or branded chain and may be substituted with other groups, e.g., alkoxy, halogen, ester or aromatic substituents.
- Methylpheophorbide-a was isolated from the alga Spirulina Pacifica, and reacted with alkyl amines.
- the intermediate amides as carboxylic acid analogs were converted to the corresponding methyl esters, which on stirring with methanolic KOH at room temperature (5-10 min) produced the N-alkyl imide derivatives in 65-70% yield.
- the vinyl groups were then converted to various alkyl ether analogs by first reacting with 30% HBr/AcOH, and then with the desired alcohol (for example 4 to 6, Figure 1).
- the desired compounds (Table 1) were prepared in high yield (70-75%).
- the methyl ester group e.g., heptyl ether analog of N-hexyl purpurin imide 4
- the methyl ester group can be hydrolyzed to the corresponding carboxylic acid.
- REF Radiation induced fibrosarcoma
- mice were implanted subcutanaceously into the axilla of 5-7 week old female C3H mice. When tumors grew to about 5mm in diameter, the mice were injected with various doses of the photosensitizers. The mice (6 mice per group) were restrained in aluminum holders and each tumor illuminated with 135 J/cm 2 of light from a laser tuned at the longest wavelength abso ⁇ tion maximum of the photosensitizers at 705nm. The percentage of short term control was recorded daily.
- mice/group (RIF tumor). 1.0 ⁇ mol/kg. 705 nm, 135J/cm 2 (24h post injection)
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99909878A EP1090006A4 (en) | 1998-06-22 | 1999-03-05 | Alkyl ether analogs of chlorins having an n-substituted imide ring |
CA002335514A CA2335514C (en) | 1998-06-22 | 1999-03-05 | Alkyl ether analogs of chlorins having an n-substituted imide ring |
JP2000555901A JP2002518502A (en) | 1998-06-22 | 1999-03-05 | Alkyl ether analog of chlorin having N-substituted imide ring |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/102,394 US5952366A (en) | 1996-03-08 | 1998-06-22 | Alkyl ether analogs of chlorins having an N-substituted imide ring |
US09/102,394 | 1998-06-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999067249A1 true WO1999067249A1 (en) | 1999-12-29 |
Family
ID=22289615
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/004924 WO1999067249A1 (en) | 1998-06-22 | 1999-03-05 | Alkyl ether analogs of chlorins having an n-substituted imide ring |
Country Status (5)
Country | Link |
---|---|
US (1) | US5952366A (en) |
EP (1) | EP1090006A4 (en) |
JP (1) | JP2002518502A (en) |
CA (1) | CA2335514C (en) |
WO (1) | WO1999067249A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002020389A (en) * | 2000-06-12 | 2002-01-23 | Health Res Inc | Long wavelength absorption bacteriochlorin alkyl ether analogue |
EP1256586A1 (en) * | 2001-05-09 | 2002-11-13 | Health Research, Inc. | Galectin recognized photosensitizers for photodynamic therapy |
US6534040B2 (en) | 1999-12-23 | 2003-03-18 | Health Research, Inc. | Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
WO2004005289A2 (en) * | 2002-07-02 | 2004-01-15 | Health Research, Inc. | Efficient synthesis of pyropheophorbide a and its derivatives |
USRE38994E1 (en) | 1988-07-20 | 2006-02-28 | Health Research, Inc. | Pyropheophorbides conjugates and their use in photodynamic therapy |
USRE39094E1 (en) | 1988-07-20 | 2006-05-09 | Health Research, Inc. | Pyropheophorbides and their use in photodynamic therapy |
US7078014B2 (en) | 1999-12-23 | 2006-07-18 | Health Research, Inc. | Method for using chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
US7166719B2 (en) * | 2002-06-27 | 2007-01-23 | Health Research, Inc. | Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy |
US7897140B2 (en) | 1999-12-23 | 2011-03-01 | Health Research, Inc. | Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents |
US8133473B2 (en) | 1999-12-23 | 2012-03-13 | Health Research, Inc. | Chlorin and bacteriochlorin-based difunctional aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1131100B1 (en) * | 1999-01-15 | 2003-03-12 | Light Sciences Corporation | Therapeutic compositions for metabolic bone disorders or bone metastases comprising a photosensitizer and a bisphosphonate |
US20030114434A1 (en) * | 1999-08-31 | 2003-06-19 | James Chen | Extended duration light activated cancer therapy |
CA2395567A1 (en) * | 2000-01-12 | 2001-07-19 | Light Sciences Corporation | Novel treatment for eye disease |
US7057100B2 (en) * | 2003-06-26 | 2006-06-06 | The J.C. Robinson Seed Co. | Inbred corn line W23129 |
WO2008008215A2 (en) * | 2006-07-10 | 2008-01-17 | Health Research, Inc. | Method for enhancing pdt efficacy using a tyrosine kinase inhibitor |
US20110070153A1 (en) * | 2008-08-13 | 2011-03-24 | Searete, Llc, A Limited Liability Corporation Of The State Of Delaware | Artificial cells |
WO2017151836A1 (en) | 2016-03-04 | 2017-09-08 | East Carolina University | J-series prostaglandin-ethanolamides as novel therapeutics for skin and/or oral disorders |
US10919904B2 (en) | 2016-08-17 | 2021-02-16 | North Carolina State University | Northern-southern route to synthesis of bacteriochlorins |
WO2018102252A1 (en) | 2016-11-30 | 2018-06-07 | North Carolina State University | Methods for making bacteriochlorin macrocycles comprising an annulated isocyclic ring and related compounds |
WO2019046556A1 (en) | 2017-09-01 | 2019-03-07 | East Carolina University | Compounds, compositions, kits, and methods for activating immune cells and/or an immune system response |
US20220249707A1 (en) | 2019-05-20 | 2022-08-11 | Nirvana Sciences Inc. | Narrow emission dyes, compositions comprising same, and methods for making and using same |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5591847A (en) * | 1994-05-23 | 1997-01-07 | Health Research, Inc. | Long wavelength absorbing photosensitizers related to purpurin-18, bacteriopurpurin-18 and related compounds with imide linkages |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002962A (en) * | 1988-07-20 | 1991-03-26 | Health Research, Inc. | Photosensitizing agents |
US5770730A (en) * | 1996-03-08 | 1998-06-23 | Health Research, Inc. | Synthesis of carbodimide analogs of chlorins and bacteriochlorins and their use for diagnosis and treatment of cancer |
-
1998
- 1998-06-22 US US09/102,394 patent/US5952366A/en not_active Expired - Fee Related
-
1999
- 1999-03-05 WO PCT/US1999/004924 patent/WO1999067249A1/en not_active Application Discontinuation
- 1999-03-05 JP JP2000555901A patent/JP2002518502A/en active Pending
- 1999-03-05 CA CA002335514A patent/CA2335514C/en not_active Expired - Fee Related
- 1999-03-05 EP EP99909878A patent/EP1090006A4/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5591847A (en) * | 1994-05-23 | 1997-01-07 | Health Research, Inc. | Long wavelength absorbing photosensitizers related to purpurin-18, bacteriopurpurin-18 and related compounds with imide linkages |
Non-Patent Citations (1)
Title |
---|
See also references of EP1090006A4 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE38994E1 (en) | 1988-07-20 | 2006-02-28 | Health Research, Inc. | Pyropheophorbides conjugates and their use in photodynamic therapy |
USRE39094E1 (en) | 1988-07-20 | 2006-05-09 | Health Research, Inc. | Pyropheophorbides and their use in photodynamic therapy |
US8133473B2 (en) | 1999-12-23 | 2012-03-13 | Health Research, Inc. | Chlorin and bacteriochlorin-based difunctional aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
US6534040B2 (en) | 1999-12-23 | 2003-03-18 | Health Research, Inc. | Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
US7897140B2 (en) | 1999-12-23 | 2011-03-01 | Health Research, Inc. | Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents |
US7078014B2 (en) | 1999-12-23 | 2006-07-18 | Health Research, Inc. | Method for using chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals |
US6624187B1 (en) | 2000-06-12 | 2003-09-23 | Health Research, Inc. | Long wave length absorbing bacteriochlorin alkyl ether analogs |
JP2002020389A (en) * | 2000-06-12 | 2002-01-23 | Health Res Inc | Long wavelength absorption bacteriochlorin alkyl ether analogue |
US6849607B2 (en) | 2001-05-09 | 2005-02-01 | Health Research, Inc. | Galectin recognized photosensitizers for photodynamic therapy |
EP1256586A1 (en) * | 2001-05-09 | 2002-11-13 | Health Research, Inc. | Galectin recognized photosensitizers for photodynamic therapy |
US7166719B2 (en) * | 2002-06-27 | 2007-01-23 | Health Research, Inc. | Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy |
USRE43274E1 (en) * | 2002-06-27 | 2012-03-27 | Health Research, Inc. | Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy |
WO2004005289A3 (en) * | 2002-07-02 | 2004-04-15 | Health Research Inc | Efficient synthesis of pyropheophorbide a and its derivatives |
WO2004005289A2 (en) * | 2002-07-02 | 2004-01-15 | Health Research, Inc. | Efficient synthesis of pyropheophorbide a and its derivatives |
Also Published As
Publication number | Publication date |
---|---|
EP1090006A1 (en) | 2001-04-11 |
CA2335514A1 (en) | 1999-12-29 |
US5952366A (en) | 1999-09-14 |
CA2335514C (en) | 2008-01-15 |
JP2002518502A (en) | 2002-06-25 |
EP1090006A4 (en) | 2002-11-13 |
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