Drug – bio-affecting and body treating compositions – Dentifrices – Plant extract of undetermined constitution
Reexamination Certificate
2001-09-21
2003-03-04
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Dentifrices
Plant extract of undetermined constitution
C424S049000, C424S195110, C512S005000, C131S275000
Reexamination Certificate
active
06528041
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene of the formula I
from the toxic compound &bgr;-asarone of
Acorus calamus
or from crude calamus oil containing &bgr;-asarone. The present invention also relates to a process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene from toxic compound &bgr;-asarone of
Acorus calamus
or from crude calamus oil containing &bgr;-asarone and useful as a new kind of aroma molecule. The present invention also relates to a process for the preparation of salicylamide based antipsychotic drug from 1-Propyl-2, 4, 5-trimethoxybenzene, and other uses thereof.
BACKGROUND OF THE INVENTION
&bgr;-asarone (cis-2,4,5-trimethoxy-1-propenylbenzene) is found in a number of plants such as
Orthodon calveriei Level
and
Acorus gramineus
(Nguyen, X. D.; Ladinh, M, Vuviet, N.; Luudam, C. and Leclercq, P. A., J. of Essential Oil Research 7(1):111-112 (1995) and Perrett, S. and Whitfield, P. J., Phytotherapy Research 9(6):405-409 (1995)). Among all the plants, the highest percentage of &bgr;-asarone is present in tetraploid and hexaploid varieties of
Acorus calamus
(Rost, L. C. M., Planta Medica 36:350 (1979); Srivastava, M., Saxena, A. and Baby, P., Orient. J. Chem., 13(1): 97-98 (1997); Tang, W. and Eisenbrand, G., Chinese Drugs of Plant Origin, Springer-verlag, New York, 45-46 (1992) and Kaul, M. K., Medicinal Plants of Kashmir & Ladakh, Indus Publishing Company, 92-93 (1997)).
Acorus calamus Linn,
a member of the family of Araceae, commonly known as “sweet flag”, is a perennial plant (Grieve, M., A Modern Herbal, Tiger Books International, London, 726-729 (1998)) that grows in the wild along swamps, brooks, rivers and lakes worldwide. The plant is also cultivated widely in India, Pakistan, Bangladesh, China, Japan, Poland, Hungary, Yugoslavia, Bulgaria, USSR, Holland, USA and several other countries because of its varied medicinal activities and the great demand for its essential oil in the flavour and perfumery industries, in alcoholic beverages and for its antibacterial, antifungal and insecticidal properties (Treben, M. Health Through God's Pharmacy, Wilhelm Ennthaler, Steyer, Austria, 12-14 (1986); Akitar, H.; Virmani, O. P.; Popli, S. P., Misra, L. N., Gupta, M. M., Srivastava, G. N., Abraham, Z. and Singh, A. K., Dictionary of Indian Medicinal Plants, CIMAP, RSM Nagar, Lucknow, 10-11 (1992); Motley, T. J., Economic Botany, 48: 397-412 (1994) and Lawrence, B. M. and Reynolds, R. J., Perfumer & Flavorist 22(2):59-67 (1997)). However, photochemical reports on
Acorus calamus
reveals that the qualitative and quantitative composition of calamus oil and particularly the percentage of asarone is greatly affected by the location, growth stages and the species of
Acorus calamus
. A lot of discrepancy and variability has been noticed in asarone percentage of Asian and American calamus oil. It has been found that the oil of diploid plants (N. American) does not contain the carcinogenic compound &bgr;-asarone at all. The triploid race (E. European) contains limited amount of &bgr;-asarone varying from 3 to 8% and is therefore, usable in terms of both clinical effectiveness and safety (Stahl, E. and Keller, K., Planta Medica 43:128-140 (1981)). However, calamus oil originating from tetraploid or hexaploid varieties distributed extensively in Asian countries like India, Japan, Pakistan and China, contains a very high percentage of &bgr;-asarone varying from 70 to 90% (Waltraud, G. and Schimmer, O., Mutation Research 121:191-194 (1983); Mazza, G., J. of Chromatography 328:179-206 (1985); Nigani, M. C.; Ateeque, A.; Misra, L. N. and Ahmad, A., Indian Perfumer 34: 282-285 (1990) and Bonaccorsi, I.; Cortroneo, A.; Chowdhury, J. U. and Yusuf, M., Essenze Derv. Agrum, 67(4): 392-402 (1997)). The higher percentage of &bgr;-asarone is experimentally proved to be carcinogenic in animals and was found to induce tumours in the duodenal region after oral administration (Taylor, J. M.; Jones, W. I.; Hogan, E. C.; Gross, M. A.; David, D. A. and Cook, E. L., Toxicol. Appl. Pharmacol. 10:405 (1967); Keller, K.; Odenthal, K. P. and Leng, P. E., Planta Medica 1:6-9 (1985) and Riaz, M.; Shadab, Q.; Chaudhary, F. M., Hamdard Medicus 38(2); 50-62 (1995)). In addition, &bgr;-asarone has also shown chromosome damaging effect on human lymphocytes in-vitro after metabolic activation (Abel, G., Planta Medica 53(3): 251-253 (1987)). As a result, the use of this well known medicinal plant which had been in use for many years, is now prohibited in flavour, perfumery and human food (Harborne, J. B. and Baxter, H., Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., Washington D.C., 474 (1993) and McGuffin, M., American Herbal Products Association's Botanical Safety Handbook, CRC Press, Inc., Boca Raton Fla., USA, 231 (1997)).
The oil and extracts of
Acorus calamus
have been reported to have numerous pharmacological activities. Some of the active ingredients found therein are glucosides, sitosterol (Patra, A. and Mitra, A. K., Indian J. Chem., Sec B, 17B:412 (1979), amino acids, acoramone (Patra, A. and Mitra, A. K., J. of Natural Products 44(6):668-669 (1981), flavones, fatty acid, sesquiterpene named calamnonone (Wu, Li.; Xiang, T.; Liu, T., Li, M.; Gao, Z. and Meng, X., Bopuxue Zazhi 15 (3):249-251 (1998) and triterpenoid saponins (Rai, R., Siddiqui, I. R. and Singh, J., Indian J. Chem., Sec B, 37 B(5), 473-476 (1998)) Modern applications of the
Acorus calamus
plant include its use in cleansing of facial skin (Horste, B.; Sarma, I.; Gercikovs, I. and Gordejeva, V., L. V. Patent No. 92-920022, issued May 28, (1992); germination inhibitors (Nawamaki, K. and Kuroyanagi, M., Phytochenistry 43 (6):1175-1182, (1996); in formulation for alcoholic bitters (Sargunas, G.; Daniuniene, G.; Talacka, C.; and Aleksiunas S., L. T. Patent No. 36793, issued Jan. 25, (1996) and for the prevention and improvement of vision disorders (Mihara, T., JP Patent No. 10324636 A2, issued Dec. 8, (1998)).
Acorus calamus
, known as “vaich” in Hindi, has also been credited with many medicinal properties from ancient ties in Ayurvedic system of India (Vohora, S. B.; Shah, S. A. and Dandiya, P. C., J. of Ethnopharmacology 28(1): 53-62 (1990); Rastogi, R. P. and Mehrotra, B. N., Compendium of Indian Medicinal Plants, 1:1, (1990), C. S. I. R., New Delhi and Asolkar, L. V., Kakkar, K. K. and Chakre, O. J., Glossary of Indian Medicinal Plants with Active Principles, Publications & Information Directorate (C. S. I. R), New Delhi, Part-I, 18-20 (1992)). It is known for more than 2000 years in China for treating a number of disorders (Albert, Y. L., Encyclopaedia of Common Natural Ingredient Used in Food, Drugs and Cosmetics, ed, John Wiley & Sons Inc. New York, 111-112 (1996)). However, all the above uses and medicinal potential of
Acorus calamus
have been hampered because of carcinogenic effect of &bgr;-asarone (Opdyke, D. L. J., Food Cosmet. Toxicol., 15: 623, (1997)). &agr;-Asarone is also reported to be fatal in rats (Lopez, M. L.; Hernandez, A.; Chamorro, G. and Mendoza, F. T., Planta Medica 59(20):115-120 (1993) and Chamorro, G., Salazar, M., Salazar, S. and Mendoza, T., Revista-de-Investigation-Clinica 45(6):597-604 (1993)). As a result, countries such as India, Pakistan, Bangladesh, Japan and China where plants of tetraploid and hexaploid origin contain 70 to 90% &bgr;-asarone are most affected by the prohibition on the use of calamus oil.
The levels of &bgr;-asarone can be easily detected by IR-spectroscopy (Stahl, E. and Keller, K, Pharmazie 36(1):53-57 (1981); HPTLC (Narayana, D. B. A.; Raghuvanshi, P; Agarwal, S. and Srinivas, K. S., Indian Drugs 32(6):254-257 (1995); densitometry (Tamas, M.; Oprean, R. and Roman, L., Farmacia (Bucharest) 44 (5-6): 13-21 (1996)); gas chromatography (Baxter, R. M.; Dandiya, P. C.; Kandel, S. I.; Okanya, A. and Walker, G. C., Nature 185:466-467 (1960) and Spilkova, J. T.; Tomasch, J.; Vavra R. and Dusek, J, Ceska Slov. Farm., 45 (3):
Council of Scientific and Industrial Research
Ladas & Parry
Rose Shep K.
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