Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1995-03-15
1999-07-20
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 165, 424 181, 424 59, 514630, 514649, 564340, 564341, 564219, A61K 5104, A61K 742, C07C32100, A01N 3302
Patent
active
059253320
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to compounds which are particularly useful in radioimaging and radiochemotherapy as it particularly relates to the treatment and location of malignant melanomas and other pigmenting disorders. Novel acyl derivatives of phenolic thioether amines and their use in compositions for blocking melanin synthesis in human or animal melanocyte cells are also described. More particularly, the compositions involving the novel derivatives are useful in treating pigmentation problems due to a variety of skin disorders, including skin cancer in the form of melanoma.
BACKGROUND OF THE INVENTION
Phenylthioalkylamines is a broad class of compounds having a variety of uses which include therapeutics. U.S. Pat. Nos. 4,134,996 and 4,183,927 disclose certain phenylthioalkylamine compounds which are useful as platelet aggregation inhibitors. Other phenylthioalkylamine compounds of applicant's published International application WO91/16302 are useful as depigmenting agents in treating a variety of pigmentary diseases. Such diseases are often characterized in the elevated levels of the enzyme tyrosinase in melanocytes; i.e., human and animal cells which synthesize the pigment melanin. There are a variety of pigmentary diseases, such as melasma, melanoma, moles and the like. In particular, moles are susceptible to becoming melanoma after exposure to sunlight which precipitates increased synthesis of tyrosinase.
Usually commercial forms of depigmenting compositions are based on the use of hydroquinone. However, the hydroquinone preparations are very unstable and cause skin irritation. Hydroquinone compositions can also cause permanent whitening of the skin if used for a prolonged period and at a high concentration. As to treatment of melanoma, this is presently attended to by surgical procedures, since any type of known non-surgical treatment of melanoma is unsatisfactory.
Research work has been conducted in the field of phenolic and diphenolic compounds to serve as a basis for chemotherapeutic treatment of melanoma and skin depigmentation. In particular, 4-S-cysteinylphenol (4-S-CP) and 4-S-cysteaminylphenol (4-S-CAP) have been synthesized and evaluated for cytotoxicity to normal epidermal melanocytes to determine their effectiveness as depigmenting agents and antimelanoma agents. Miura et al, "Synthesis of Cysteinylphenol, Cysteaminylphenol, and Related Compounds, and In Vivo Evaluation of Antimelanoma Effect", Arch. Dermatol Res. (1987) 279:219-225, disclose the effect of 4-S-CAP and 4-S-CP in depigmentation of black hair follicles as manifested by loss of functioning melanocytes. It was established that 4-S-CAP was a potent agent in prolonging the lifespan of melanoma-bearing mice and hence exhibited inhibition of melanoma growth. 4-S-CP and the methyl ester of 4-S-CP also exhibited some inhibition of melanoma growth, although not as active as 4-S-CAP.
The same compounds, 4-S-CP and 4-S-CAP, were also investigated for properties of depigmentation of black guinea pig skin by topical application. The results of this work is reported by Ito et al, "Depigmentation of Black Guinea Pig Skin by Topical Application of Cysteaminylphenol, Cysteinylphenol, and Related Compounds", The Journal of Investigative Dermatology, Vol. 88 No. 1, Jan. 1987. Although 4-S-CAP demonstrated depigmenting properties, inflammatory changes of the skin of the guinea pigs was prominent. 4-S-CAP was capable, however, of:
4-S-CP and 4-S-CAP were also investigated for their selective cytotoxicity on follicular melanocytes. This was reported by Ito et al, "Selective Cytotoxicity of 4-S-Cysteaminylphenol on Follicular Melanocyte of the Black Mouse: Rational Basis for its Application to Melanoma Chemotherapy", Cancer Research, Jun. 15, 1987 47:3278-3284. It was reported that 4-S-CAP demonstrated cytotoxicity in the depigmentation of black hair follicles, whereas it had no effect on the albino follicles. Hence 4-S-CAP is actively engaged in the melanin synthesis of the melanocytes.
4-S-CAP, however, has several limita
REFERENCES:
patent: 4134996 (1979-01-01), Dunbar et al.
patent: 4183927 (1980-01-01), Begin et al.
Jimbow et al., "Exploitation of Pigment Biosynthesis Pathway as a Selective Chemotherapeutic Approach for Malignant Melanoma," The Journal of Investigative Dermatology, vol. 100, No. 2, Feb. 1993, pp. 231S-238S.
Synthesis of Cysteinylphenol, Cysteaminylphenol, and Related Compounds, and in Vivo Evaluation of Antimelanoma Effect by S. Miura, T. Ueda, K. Jimbow, S. Ito, K. Fujita -Arch. Dermatol. Res. 279:219-225, 1987.
Depigmentation of Back Guinea Pig Skin by Topical Application of Cysteaminylphenol, Cysteinylphenol, and Related Compounds by Y. Ito, K. Jimbow, S. Ito -J. Invest. Dermatol. 88:77-82, 1987.
Selective Cytotoxicity of 4-S-Cysteaminylphenol on Follicular Melanocytes of the Black Mouse: Rational Basis for Its Application to Melanoma Chemotherapy by Y. Ito, K. Jimbow -Cancer Res. 47:3278-3284, 1987.
Selective Cytotoxicity of N-acetyl-4-S-cysteaminylphenol on Follicular Melanocytes of Black Mince by M. Wong, K. Jimbow -Brit. J. Dermatol. 124:56-61, 1991.
Selective Cytotoxicity of a Phenolic Melanin Precursor, 4-S-Cysteaminylphenol, on in Vitro Melanoma Cells by K. Yamada, K. Jimbow, R. Engelhardt, S. Ito -Biochem Pharmacology 38:2217-2221, 1989. for the Development of an Antimelanoma and Melanomaradioimaging Agent by T. Iwashina, K. Jimbow, L. I. Wiebe -Appl Radiat Isot 45:703-705, 1994.
Reactivity of Orthoquinones Involved in Tyrosinase-Dependent Cytotoxicity: Differences Between Alkylthio-and Alkoxy-Substituents by C.J. Cooksey, K. Jimbow, E.J. Land, P.A. Riley -Melanoma Res. 2:283-293, 1992.
4-S-Cysteaminylphenol and its Analogues as Substrates for Tyrosinase and Monoamine Oxidase by J.M. Pankovich, K. Jimbow, S. Ito -Pigment Cell Res. 3:146-149, 1990.
Experimental Antimelanoma Agents: The Synthesis of 4-S-Cysteaminyl and Excerpta Medica 20:158-159, 1989.
Mechanism of Growth Inhibition of Melanoma Cells by 4-S-Cysteaminylphenol and its Analogues by S. Inoue, S. Ito, K. Wakamatsu, K. Jimbow, K. Fujita -Biochem Pharmacol 39:1077-1083, 1990.
Melanocytoxicity and Antimelanoma Effects of Phenolic Amine Compounds in Mice in Vivo by F. Alena, K. Jimbow, S. Ito -Cancer Research 50.3743-3747 Jun. 15, 1990.
N-Acetyl-4-S-cysteaminylphenol as a New type of Depigmenting Agent for the Melanoderma of Patients with Melasma by K. Jimbow -Arch Dermatol 127:1528-1534, 1991.
Action of Cysteaminylphenols on Human Melanoma Cells in Vivo and in Vitro: 4-S-Cysteaminylphenol Binds Protein Disulphide Isomerase by P.G. Parsons, D. Favier, M. McEwan, H. Takahashi, K. Jimbow, S. Ito -Melanoma Res 1:97-104, 1991.
Selective in Vivo and in Vitro Incorporation and Accumulation of Phenolic Thioether Amine into Malignant Melanoma and Identification of a (58 kD) Binding Glycoprotein By. K. Yamada, K. Jimbow -Melanoma Res 2:225-233, 1992.
Glutathione Plays a Key Role in the Depigmenting and Melanocytotoxic Action of N-Acetyl-4-S-Cysteaminylphenol in Black and Yellow Hair Follicles by F. Alena, W. Dixon, P. Thomas, K. Jimbow -J. Invest Dermatol 104:792-797, 1995.
Selective in Vivo Accumulation of N-Acetyl-4-S-Cysteaminylphenol in B16F10 Murine Melanoma and Enhancement of its in vitro and in vivo Antimelanoma Effect by Combination of Buthionine Sulfoximine by F. Alena, T. Iwashina, A. Gili, K. Jimbow -Cancer Res 54:2661-2666, 1994.
The in Vivo Melanocytotoxicity and Depigmenting Potency of N-2,4-Acetoxphenyl Thioethyl Acetamide in the Skin and Hair by M. Jimbow, H. Murusyk, K. Jimbow -British J. Dermatol (in press), 1995.
The in Vivo Antimelanoma Effect of 4-S-Cysteaminylphenol and its N-Acetyl Derivative by T. Miura, K. Jimbow, S. Ito -Int. J. Cancer 46:931-934, 1990.
Malignant Melanoma: A Life Threatening Skin Cancer Affecting Young People--Its Diagnosis and Management by G.J. Lauzon, K. Jimbow -Am Royal Col Phys Surg 23:105-110, 1990.
Electron Donor and Acceptor Properties of Melanin Pigments in the Skin by K. Reszka, K. Jimbow -In: Oxidative Stress in Dermatology, ed by Fuchs J and
Hartley Michael G.
Hollinden Gary E.
The Governors of the University of Alberta
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