Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-19
2002-04-16
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S074000, C546S075000
Reexamination Certificate
active
06372756
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel chemical compound useful as an analgesic, anti-inflammatory, and immunosuppressive compound when administered to patients.
BACKGROUND
Sinomenine, which has a molecular formula of C
19
H
23
NO
4
, is a crystalline alkaloid derived from a medicinal plant,
Sinomenium acutum
. Sinomenine has long been used in China and Japan as a drug of Kampo traditional medicine for the treatment of neuralgia and rheumatic diseases, and has also been a popular example of an opiate useful for mass spectrometry studies conducted in the 1960s in the United States and elsewhere.
Sinomenine has been used for the treatment of various diseases and ailments (Wong, K.C., et al.,
History of Chinese Medicine, National Quarantine Service, Shanghi,
2nd ed., pp. 119, (1936)), including pain, inflammation, cough, and autoimmune or chronic inflammatory diseases such as rheumatoid arthritis. Sinomenine exerts moderate analgesic and potent anti-inflammatory (Huo, H. R., et al.,
Study on the Mechanism of Sinomenine on Analgesic and Anti
-
Inflammatory Activities, Xi'an Yike Daxue Xuebao,
10:346-349, (1989)) and immunosuppressive properties (Hojo, H., et al.,
Effect of Sinomenine on Antibody Responses in Mice, J. Immunopharmocol,
7:33-42, (1985); Liu, L., et al.,
Inhibition of Lymphocyte Proliferation by the Anti
-
Arthritic Drug Sinomenine, Int. J. Immunopharmocol,
16:685-691, (1994)). Sinomenine has also been shown to have immunomodulatory properties (Kaever, V. et al.,
Immunomodulatory Properties of the Anti
-
Arthritic Alkaloid Sinomenine
, Abstract: 9th International Congress of Immunology (1995). Further, there is evidence of sinomenine having histamine-releasing properties (Okayama 1976). Additionally, animal studies have shown a protective effect against fulminant hepatitis (Kondo, Y., et al.,
Protection by Sinomenine Against Endotoxin
-
Induced Fulminant Hepatitis in Galactosamine
-
Sensitized Mice, Biochem. Pharmacol.,
48:1050-1052, (1994)) and effectiveness in reversal of cardiac arrythmias (Sun, F., et al.,
The Effect of Sinomenine on Experimental Arrythmia, Xi'an Yike Daxue Xuebao,
11:324-326, (1990)). The efficacy of sinomenine in the therapy of rheumatic arthritis has been confirmed by clinical studies (Key, S. Y., et al.,
Clinical Trials of Sinomenine on the Treatment of Rheumatoid Arthritis, Beijing Yi Xue,
8:183-186, (1986)).
Additionally, the immunosuppressive effects of sinomenine on lymphocytes and macrophages in vitro have previously been examined (Liu, L. et al.,
Inhibition of Lymphocyte Proliferation by the Anti
-
Arthritic Drug Sinomenine, Int. J. Immunopharmac.,
16(8):685-691 (1994)). Lymphocyte proliferation, which likely plays a key role in rheumatic disease (Panayi, G. S.,
The Immunopathogenesis of Rheumatoid Arthritis, Br. J. Rheumat.,
32 (suppl. 1):4-14, (1993)), can be inhibited by sinomenine in a reversible manner without exhibiting direct cytotoxic effects (Hojo, H., et al.,
Effect of Sinomenine on Antibody Responses in Mice, J. Immunopharmacol,
7(1):33-42, (1985); Liu, L. et al.,
Inhibition of Lymphocyte Proliferation by the Anti
-
Arthritic Drug Sinomenine, Int. J. Immunopharmac.,
16(8):685-691 (1994); Liu, L., et al.,
Impairment of Macrophage Eicosanoid and Nitric Oxide Production by an Alkaloid Extracted From Sinomenine Acutum, Arzneim
-
Forschung/Drug Res.,
44:1223-1226, (1994)). The molecular mechanisms underlying its inhibitory effect on T-lymphocyte proliferation are still unclear but the involvement of opioid receptors in T-lymphocyctes is likely (Wybran, J., et al.,
Suggestive Evidence for Receptors for Morphine and Methionine
-
Enkephaline on Normal Blood T
-
Lymphocytes, J. Immunol.,
123:1068-1070, (1979)).
Typically, sinomenine is extracted from the dried plant
Sinomenium acutum
. There is evidence that it has been administered subcutaneously and orally as a decoction of the roots and stems of
Sinomenium acutum
. For a less crude extract, the stems of the dried plant are soaked in 10% azua ammoniae and homogenized. The homogenate is soaked in benzol for one week, then 2% HCl is added to the benzol solution and the entire homogenate is filtered. The extract is then alkalized with ammonium and a phase separation is performed with chloroform. The chloroform layer is selected and filtered again. The product is then dehydrated using anhydrous potassium carbonate and evaporated to dryness. The resulting crystals are further purified by a diethyl ether extraction.
Discovery of other, superior compounds for treatment would be advantageous since sinomenine finds wide use for the treatment of various medical conditions.
SUMMARY OF THE INVENTION
A novel compound, N-demethyl-sinomenine, also known as des-17-methyl-sinomenine, has been discovered and characterized. Thus, one aspect of the invention is a novel chemical compound, N-demethyl-sinomenine, or a pharmaceutically acceptable salt, ester, or hydrate form thereof. Another aspect of the invention is a pharmaceutical composition employing N-demethyl-sinomenine along with a pharmaceutically acceptable carrier. A further aspect of the invention is a method of treating a patient for a disorder by administration of N-demethyl-sinomenine to the patient.
Evidence is provided which indicates that the N-demethyl-sinomenine has an immnosuppressive activity as much as five-fold higher than sinomenine. N-demethyl-sinomenine also has a greater water solubility than sinomenine. Thus, this more potent compound may be administered in lieu of sinomenine, potentially lowering costs and increasing overall effectiveness.
REFERENCES:
Hitotsuyangi, Y., et al., “Syntheses of Antitumor Morphinane alkaloids, Sinococuline and 6-epi-, 7-epi, and 6-epi-7-epi-Sinococuline, from Sinomenine,”J. Org. Chem., 60(14):4549-4558 (1995).
Candinas, D., et al., Immunomodulatory Effects of the Alkaloid Sinomenine in the High Responder ACI-to-Lewis Cardiac Allograft Model,Transplantation, 62(12):1855-1860 (1996).
Chen-ling, Zhu, Clinical Studies of Sinomenium Acutum on 311 Rheumatoid Arthritis Cases,Bulletin of Chinese Medicinal Herbs, 11:41-44 (1979).
Hojo, H., et al., Effect of Sinomenine on Antibody Responses in Mice,J. of Immunopharmac., 7(1):33-42 (1985).
Junbao, L., et al., Pharmacokinetic Parameters and Bioavailability of Sinomenine Hydrochloride, J. Xi'an Med. Univ., 4(1):16-19 (1992).
Kaever, V., et al., Immunomodulatory Properties of the Anti-Arthritic Alkaloid Sinomenine, 9th International Congress of Immunology, Abstract (1995).
Kametani, T., et al., Studies on the Syntheses of Heterocyclic Compounds. Part CCC. Syntheses of Salutaridine, Sinoacutine, and Thebaine. Formal Total Syntheses of Morphine and Sinomenine,J. Chem. Soc., (C)2030-2033 (1969).
Kondo, Y., et al., Protection by Sinomenine Against Endotoxin-Induced Fulminant Hepatitis in Galactosamine-Sensitized Mice,Biochem. Pharma., 48(5): 1050-1052 (1994).
Liu, L., et al., Inhibition of Lymphocyte Proliferation by the Anti-Arthritic Drug Sinomenine,Int. J. Immunopharmac., 16(8):685-691 (1994).
Liu, L., et al., Impairment of Macrophage Eicosanoid and Nitric Oxide Production by an Alkaloid from Sinomenium Acutum, Arzneimittel-Forschung/Drug Research, 44(II), 11:1223-1226 (1994).
Liu, L. et al, Amelioration of Rat Experimental Arthritides by Treatment with the Alkaloid Sinomenine,Int. J. Immunopharmac., 18(10):529-543 (1996).
Nozaka, T., et al., Mutagenicity of Isoquinoline Alkaloids, Especially of the Aporphine Type,Mutation Res., 240:267-279 (1990).
Okuda, T., et al., A Case of Drug Eruption Caused by the Crude Drug Boi® (Sinomenium Stem/Sinomeni Caulis et Rhizoma),J. Derma., 22:795-800 (1995).
Pu-mine, S., et al., Treatment of Rheumatoid Arthritis with Sinomenine on 60 Cases, J. Xien Yi Xue, 10(9):292 (1985).
Shiao-yin, K., et al., Clinical Trials of Sinomenine on the Treatment of Rheumatoid Arthritis,J. Beijing Med., 8(3):186-189 (1986).
Wheeler, D.M.S., et al., Mass Spectral Studies of Alkaloids Related to Morphine,J. Am. Chem. Soc., 89(17):4494-4501 (1967).
Yamasaki, H., Pharmacology of Sinomeni
Christians Uwe
Kaever Volkhard W.
AvMax, Inc.
Cooley & Godward LLP
Rotman Alan L.
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