TREA

Reduced and quaternized psoralens as photo-activated therapeutics

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Information

  • Patent Grant
  • 5356929
  • Patent Number
    5,356,929
  • Date Filed
    Friday, April 23, 1993
    31 years ago
  • Date Issued
    Tuesday, October 18, 1994
    29 years ago
Information
Abstract
The invention features phototherapeutic compositions comprising Type 1, Type 2, or Type 3 psoralens and methods of using such compounds for treatment of proliferative diseases of skin, blood and bone marrow.
Description
Claims
  • 1. A photochemotherapeutic compound wherein said compound is a psoralen from the group consisting of
  • (A) a compound having the structure of Formula I ##STR3## wherein R.sub.3 is H, amino, nitro, carboethoxy, halo or alkyl, wherein R.sub.4 is H, methyl or trifluromethyl,
  • wherein R.sub.5 is H or alkoxy,
  • wherein R.sub.4 ' and R.sub.5 ' are alkylamino or halo, and
  • wherein R.sub.8 is H, alkyl, halo, haloakyl or alkoxy,
  • (B) a compound having the structure of Formula II ##STR4## wherein R.sub.3 is H, alkyl or halo, wherein R.sub.4 is H, methyl or trifluoromethyl,
  • wherein R.sub.5 is H or alkoxy,
  • wherein R.sub.4 ' and R.sub.5 ' are alkylammonium, alkyl or halo, and at least one of R.sub.4 ' and R.sub.5 ' is alkylammonium, and
  • wherein R.sub.8 is H, alkyl, halo, haloalkyl or alkoxy, and,
  • (C) a compound having the structure of Formula III ##STR5## wherein R.sub.3 is H, amino, alkyl or halo, wherein R.sub.4 is H, methyl or trifluoromethyl,
  • wherein R.sub.5 is H or alkoxy,
  • wherein R.sub.4 ' and R.sub.5 ' are alkyl, halo or alkylammonium and at least one of R.sub.4 ' and R.sub.5 ' is alkylammonium, and
  • wherein R.sub.8 is alkyl, halo, haloalkyl or alkoxy.
  • 2. A photochemotherapeutic compound of the formula ##STR6## wherein R.sub.3 is H, amino, nitro, carboethoxy, halo or alkyl, wherein R.sub.4 is H, methyl or trifluromethyl,
  • wherein R.sub.5 is H or alkoxy,
  • wherein R.sub.4 ' and R.sub.5 ' are alkylamino or halo, and
  • wherein R.sub.8 is H, alkyl, halo, haloakyl or alkoxy.
  • 3. A compound of claim 2 which is 5-N-phthalimidomethyl-4',5'-dihydro-8-hydroxypsoralen.
  • 4. A compound of claim 2 which is 5-N-phthalimidomethyl-4',5'-dihydro-8-methoxypsoralen.
  • 5. A compound of claim 2 which is 5-amino-4',5'-dihydro-8-methoxypsoralen.
  • 6. A compound of claim 2 which is 4,5',8-trimethyl-4'-aminomethyl-4',5'-dihydropsoralen.
  • 7. A compound of claim 2 which is 4,4',8-trimethyl-5'-aminomethyl-4',5'-dihydropsoralen.
  • 8. A compound of claim 2 which is 3,5-dinitro-4',5'-dihydro-8-methoxypsoralen.
  • 9. A compound of claim 2 which is 5-iodo-4',5'-dihydro-8-methoxypsoralen.
  • 10. A compound of claim 2 which is 3-carboethoxy-4',5'-dihydropsoralen.
  • 11. A compound of claim 2 which is 8-methoxy-3-iodo-4',5'-dihydropsoralen.
  • 12. A compound of claim 2 which is 8-[2-(N,N-dimethylamino)ethoxy]-4',5'-dihydropsoralen HCl salt.
  • 13. A compound of claim 2 which is 4-trifluoromethyl-4',5'-dihydro-4',8-dimethylpsoralen.
  • 14. A compound of claim 2 which is 4-trifluoromethyl-4',5'-dihydro-5',8-dimethylpsoralen.
  • 15. A photochemotherapeutic compound of the formula ##STR7## wherein R.sub.3 is H, alkyl or halo, wherein R.sub.4 is H, methyl or trifluoromethyl,
  • wherein R.sub.5 is H or alkoxy,
  • wherein R.sub.4 ' and R.sub.5 ' are alkylammonium, alkyl or halo, and at least one of R.sub.4 ' and R.sub.5 ' is alkylammonium, and
  • wherein R.sub.8 is H, alkyl, halo, haloalkyl or alkoxy.
  • 16. The compound of claim 15 which is 5'-[(N-pyridinium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 17. The compound of claim 15 which is 4'-bromo-5'-N-[(4-ethylpyridinium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 18. A compound of claim 15 which is 5'-bromo-4'-N-[(4-ethylpyridinium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 19. A compound of claim 15 which is 3,5'-dibromo-4'-N-[(4-ethylpyridinium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 20. A compound of claim 15 which is 5'-[N,N,N-trimethylammonium)methyl]-4,4',8-trimethylpsoralen or salts thereof.
  • 21. A compound of claim 15 which is 5'-[N-(4-ethylpyridinium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 22. A compound of claim 15 which is 5'-[N,N-dimethylammonium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 23. A compound of claim 15 which is 5'-[N,N,N-trimethylammonium)methyl]-4,8-dimethylpsoralen or salts thereof.
  • 24. A photochemotherapeutic compound of the formula ##STR8## wherein R.sub.3 is H, amino, alkyl or halo, wherein R.sub.4 is H, methyl or trifluoromethyl,
  • wherein R.sub.5 is H or alkoxy,
  • wherein R.sub.4 ' and R.sub.5 ' are alkyl, halo or alkylammonium and at least one of R.sub.4 ' and R.sub.5 ' is alkylammonium, and
  • wherein R.sub.8 is alkyl, halo, haloalkyl or alkoxy.
  • 25. A compound of claim 24 which is 5'-[(N,N,N-trimethylammonium)methyl]-4',5'-dihydro-4,8-dimethylpsoralen or salts thereof.
  • 26. A compound of claim 24 which is 5'-[(N-morpholino-N-methylammonium)methyl-4',5'-dihydro-4,8-dimethylpsoralen or salts thereof.
  • 27. A compound of claim 24 which is 4'-bromo-5'-[(N,N,N-trimethylammonium)methyl]-4',5'-dihydro-4,8-dimethylpsoralen or salts thereof.
  • 28. A method of treating a proliferative skin disorder in a human patient comprising administering to said patient either parenterally, orally or topically an effective amount of a compound as recited in claim 1, 2, 15 or 24 and then irradiating said patient with ultraviolet light.
  • 29. A photochemotherapeutic formulation comprising an effective amount of compound as recited in claim 1, 2, 15 or 24 in admixture with suitable carriers, stabilizers or adjuvants.
  • 30. A method of treating a disease of the blood or bone marrow in a human patient comprising the steps of:
  • first, obtaining cells from the blood or bone marrow of said patient;
  • second, introducing in vitro into said cells a compound as recited in claims 1 2, 15 or 24;
  • third, exposing said cells containing said compound to ultraviolet light; and,
  • fourth, returning said cells to the blood or bone marrow of said patient.
  • 31. A method of treating a disease of the blood or bone marrow in a human patient comprising the steps of:
  • first, administering to said patient a compound as recited in claims 1, 2, 15 or 24;
  • second, obtaining cells from the blood or bone marrow of said patient;
  • third, exposing said cells to ultraviolet irradiation; and,
  • fourth, returning said cells to the blood or bone marrow of said patient.
  • 32. A photochemotherapeutic formulation comprising an effective amount of a compound as recited in claim 1, 2, 15 or 24 in admixture with suitable carriers, stabilizers or adjuvants.
BACKGROUND OF THE INVENTION

This application is a continuation-in-part of U.S. patent application Ser. No. 07/633,268, filed Dec. 21, 1990, now U.S. Pat. No. 5,216,176 which is a continuation-in-part of patent application Ser. No. 07/300,869 filed Jan. 23, 1989, now abandoned. This application and the aforementioned parent applications all share common inventorship and assignment. Many proliferative skin diseases (psoriasis, vitiligo, eczema, mycosis fungoides, etc), cancerous conditions (T cell lymphomas), and autoimmune disorders are being treated by the combined utilization of photosensitizing chemicals [applied topically or taken orally] plus ultraviolet light. Terms such as photosensitization, photochemotherapy, photopheresis and PUVA (psoralens ultra violet A radiation) are commonly used to refer to special applications of this method. Clinically useful behavior has been found in such chemical families as heme-derived products, porphyrins, phthalocyanins, and psoralens. The oldest and most established phototherapeutics are the psoralens or linear furocoumarins in which three major commercial pharmaceuticals dominate: 8-methoxypsoralen (methoxsalen or 8-MOP); 4,5',8-trimethylpsoralen (trioxsalen or TMP), and 5-methoxypsoralen (5-MOP) . The widely accepted mechanism of action for psoralens is penetration of the target cell's membrane, intercalation into nuclear DNA, and photo-induced bis 2+2 cycloaddition crosslinking of the double helix. Structural and mechanism studies have shown that the 3,4-double bond and the 4',5'-double bond in psoralen (Formula O below) form cyclobutane adducts with the double bonds in the pyrimidine bases of DNA. This renders the DNA unable to uncoil and serve as a template for new gene expression. Thus, the target cell is rendered non-viable (J. E. Hearst, Chemical Research in Toxicology, 2, 69, 1989; T. F. Anderson and J. J. Vorhees, Ann. Rev. Pharmacol. Toxicol., 10, 177, 1982). The basic structure of psoralen with the ring numbering structure used herein, is as depicted in Formula O below. ##STR1## A severe limitation to the acceptance of psoralen-based photochemotherapy is the understanding that the natural cellular level repair processes of bi-functional DNA-crosslinks are highly error-prone. Errors in cellular repair processes of true crosslinks translate to mutagenic/carcinogenic events and, in the clinical use of psoralens, represent a significant post-treatment risk of cancer induction. It is known in the art that bent, nonlinear furocoumarins (known as angelicins), which are by their structure limited to the photogeneration of only non-crosslinked mono-adducts, are far less mutagenic/carcinogenic (F. Baccichetti et al., U.S. Pat. No. 4,312,883; R. S. Cole, "Repair of DNA Containing Interstrand Crosslinks in E Coli," Proc. Nat. Acad. Sci. USA, 70, 1064, 1973). An alternative mechanism is available by which psoralens manifest phototoxicity to a cell. A 22,000 Da protein present in psoralen-sensitive cells has been found to be a specific binding site for photo-activated psoralens. The binding of psoralens to this receptor followed by UVA light activation prevents the binding of epidermal growth factor (EGF), an important cellular messenger for growth and differentiation. Thus, the therapeutic photobiology of psoralens can be explained by a non-DNA target for their molecular activity (N. D. Heindel, J. Van Dongen, B. S. Sachais, J. H. Phillips, M. A. Gallo, and J. D. Laskin, J. Pharm. Sci., 80, 686, 1991). The invention features new types of psoralen phototherapeutics and phototherapeutic formulations thereof capable of binding to a non-DNA target in mammalian cells. More specifically, psoralens of the present invention are of three types, which respectively inhibit: These compounds, which offer the promise of beneficial photobiology without the risk of forming potentially carcinogenic bis 2+2 cyclobutane crosslinks with DNA, are characterized on the basis of their molecular structure as follows: ##STR2## The term "psoralen", as used herein refers to any compound having the structure depicted in Formula O above, or any derivative of that structure wherein the 4',5'-double bond is suceptible to reduction. The invention also features a method of preparing a quaternary amino psoralen substituted in the furan ring, wherein the method includes a first step of effecting a selective bromine atom substitution upon a furan ring methyl in either 4,4',8-trimethylpsoralen or 4,5',8-trimethylpsoralen by reaction with N-bromosuccinimide and benzoyl peroxide, the method further including a second step of aminating the selectively brominated psoralen from step 1 by reaction with any tertiary amine. A method of treating a proliferative skin disorder in a human patient is also provided by the invention. This method comprises administering to the patient either parenterally, orally, or topically an effective amount of a phototherapeutic compound of the invention, after which the patient is irradiated with UVA. Similarly, the invention features a method of treating a disease of the blood or bone marrow in a human patient comprising obtaining cells from the blood or bone marrow of the patient, introducing in vitro into the cells a phototherapeutic compound of the invention, exposing the cells so treated to ultraviolet light, and returing the treated irradiated cells to the blood or bone marrow to the patient.

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4294822 Kaufman Oct 1981
4312883 Baccichetti et al. Jan 1982
4452811 della Valle Jun 1984
4727517 della Valle et al. Apr 1988
4950770 Heindel et al. Aug 1990
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Continuation in Parts (2)
Number Date Country
Parent 633268 Dec 1990
Parent 300869 Jan 1989