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(12) United States Patent (10) Patent No.: US 7,141,611 B2 Gamble Et Al

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(12) United States Patent (10) Patent No.: US 7,141,611 B2 Gamble Et Al US007 141611B2 (12) United States Patent (10) Patent No.: US 7,141,611 B2 Gamble et al. (45) Date of Patent: *Nov. 28, 2006 (54) HIGH MOLECULAR WEIGHT PRIMARY C07C 29/76 (2006.01) ALPHATIC ALCOHOLS OBTANED FROM C07C 29/28 (2006.01) NATURAL PRODUCTS AND USES THEREOF CD7C 29/86 (2006.01) (75) Inventors: William R. Gamble, Longmont, CO (52) U.S. Cl. ...................... 514/724; 514/164:568/840; (US); Zhengjie Liu, Superior, CO 568/913:568/918 (US); David T. Bailey, Boulder, CO (58) Field of Classification Search ................ 514/164, (US); Pedro P. Perez, Hialeah, FL 514/724; 568/840,913, 918 (US); Dean P. Stull, Longmont, CO See application file for complete search history. (US); Steven L. Richheimer, Westminster, CO (US); Rebecca L. (56) References Cited Nichols, Broomfield, CO (US); Rod U.S. PATENT DOCUMENTS Lenoble, Westminster, CO (US) 5,663,156 A * 9/1997 Granja et al. ............... 514, 164 (73) Assignee: Wyeth, Madison, NJ (US) 6,235,795 B1* 5/2001 Hernandez et al. ......... 514,724 (*) Notice: Subject to any disclaimer, the term of this 6,423,697 B1 * 7/2002 Friedman .................... 514, 164 patent is extended or adjusted under 35 6,596,776 B1* 7/2003 Gamble et al. ............. 514,724 U.S.C. 154(b) by 0 days. * cited by examiner This patent is Subject to a terminal dis claimer. Primary Examiner Peter O'Sullivan (74) Attorney, Agent, or Firm Hogan & Hartson, LLP (21) Appl. No.: 10/622,249 (57) ABSTRACT (22) Filed: Jul.18, 2003 This invention provides an isolated mixture of higher (65) Prior Publication Data molecular weight primary aliphatic alcohols having 20, 22. 24, 26, 27, 28, 30, 32 and 34 carbon atoms and having US 2004/OO19119 A1 Jan. 29, 2004 enhanced purity. This invention also provides a process for Related U.S. Application Data obtaining the alcohol mixture by extracting a natural product with organic solvents with or without saponification of the (63) Continuation of application No. 10/133,986, filed on natural product. The alcohol mixture is useful in pharma Apr. 25, 2002, now Pat. No. 6,596.776, which is a ceutical compositions, foodstuffs and dietary Supplements continuation-in-part of application No. 09/949.285, and is effective for lowering total cholesterol and LDL filed on Sep. 7, 2001, now abandoned, which is a cholesterol and increasing HDL-cholesterol levels and continuation-in-part of application No. 09/845,043, therefore is effective in treating hypercholesterolemia. The filed on Apr. 27, 2001, now abandoned, which is a composition may be used to reduce the risk of coronary heart continuation-in-part of application No. 09/337,339, disease, to inhibit the atherosclerotic process (platelet hyper filed on Jun. 21, 1999, now Pat. No. 6,225,354. aggregability, ischemia and thrombosis), and can be used as an anti-inflammatory and anti-thrombotic agent. The com (60) Provisional application No. 60/236,515, filed on Sep. position also possesses neurotrophic properties and is useful 29, 2000. for improving male sexual activity. (51) Int. Cl. A6 IK3I/045 (2006.01) 5 Claims, 6 Drawing Sheets U.S. Patent Nov. 28, 2006 Sheet 6 of 6 US 7,141,611 B2 ?un61-I9 E3 2. E [I] ? ) E 8 eueleW 6ulueS US 7,141,611 B2 1. 2 HGH MOLECULAR WEIGHT PRIMARY ering Blood-Lipid in Beeswax.” Zhongguo Zhong Yao Zhi, ALPHATIC ALCOHOLS OBTANED FROM 21(9):553-4, 576 (1996)); (H. Sho, et al., “Effects of Oki NATURAL PRODUCTS AND USES THEREOF nawa Sugar Cane Wax and Fatty Alcohols on Serum and Liver Lipids in the Rats,” JNutri Vitaminol, 30(6):553–559 CROSS-REFERENCE TO OTHER 5 (1984)); (S. Kato, K. Hamatani, et al., “Octacosanol Effects APPLICATIONS Lipid Metabolism in Rat Fed on a High Fat Diet.” BrJ Nutr, 73(3):433–441 (1995)); and (Kabiry, et al., “Tissue Distri This patent application is a continuation of U.S. patent bution of Octacosanol in Liver and Muscle of Rats After application Ser. No. 10/133,986, filed Apr. 25, 2002, now Serial Administration.” Ann Nutr Metab, 39(5):279-284 U.S. Pat. No. 6,596.776, which is a continuation-in-part of 10 (1995)); and (I. Gouni-Berthold, et al., “Policosanol: Clini U.S. Pat. No. 09/949,285, filed Sep. 7, 2001, now aban cal pharmacology and therapeutic significance of a new doned, which is a continuation-in-part of U.S. patent appli lipid-lowering agent.” Am Heart J. 143:356–365 (2002)). cation Ser. No. 09/845,043, filed Apr. 27, 2001, now aban Many investigational studies based on clinical studies using doned, which is a continuation-in-part of U.S. patent the natural mixtures of straight chain aliphatic alcohols have application Ser. No. 09/337,339, now issued U.S. Pat. No. 15 been published. 6.225,354, filed Jun. 21, 1999. U.S. patent application Ser. A procedure for obtaining a natural mixture of aliphatic No. 10/133,986 also claims benefit of Provisional Applica alcohols from animal and vegetable waxes (a natural tion No. 60/236,515 filed on Sep. 29, 2000. All of the Sourced wax) is also known in the prior art. This prior art above-referenced applications are incorporated herein by procedure is based on the extraction of alcohol mixtures reference. with fluid extractant in the sub- and super-critical states between 20° C. and 100° C. Selective extraction can be BACKGROUND OF THE INVENTION carried out with this procedure, but when this is applied to beeswax it is only possible to obtain between 10% to 15% 1. Field of the Invention of a C-20 to C-34 alcohol mixture. The present invention pertains to a biologically active 25 Another project (S. Inaa, K. Furukama, T. Masui, K. mixture of high purity, high molecular weight straight Honda, J. Ogasawara, and G. Tsubikamoto, “Process for chained primary aliphatic alcohols (referred to herein as Recovering Primary Normal Aliphatic Higher Alcohols' JP aliphatic alcohols) having enhanced purity that is isolated 60–119514 (1996)) proposed a very similar extraction from a naturally occurring source. More particularly the method applied to waxes that is based on fluids (CO, with invention pertains to a mixture of high purity, high molecu 30 lar weight straight chained primary aliphatic alcohols that is ethylene) in Sub- and Super-critical states. obtained from saponified and/or unsaponified starting mate There are several different commercial dietary supple rials by liquid extraction, wherein the resulting aliphatic ments, foods and drugs that aid in the lowering of total blood alcohols in the mixture contain 20 to 34 carbon atoms. cholesterol (lowering lipid, LDL-cholesterol, and total cho 2. Description of the State of Art 35 lesterol levels) which are considered as effective, safe and All kinds of waxes, and more especially beeswax, have well-tolerated but most produce different adverse side always been a matter of interest. This has been the case not effects. Since lipid-lowering therapy must be chronically only because of their industrial applications, but also administered, safety and tolerability are very important for because of their chemical composition. The amount of their definitive acceptance. beeswax in honey ranges between 0.9% to 1.13%, depend 40 It has been described that treatment with some lipid ing on the methods used to separate the wax from the honey. lowering drugs reduces the tendency for platelet hyperag This wax contains esters, hydrocarbons, free fatty acids, free gregation frequently seen in hyperlipidemic patients and alcohols and a long list of minor compounds. experimental data have shown anti-aggregatory effects mediated by these compounds. Nevertheless, only some The natural mixture of aliphatic alcohols obtained from cholesterol-lowering drugs show this property. beeswax has been studied by several authors to learn about 45 its composition and main features. The obtaining of different Atherosclerosis is a variable combination of changes of mixtures of aliphatic alcohols from various waxes has also the intima of the arteries consisting of the focal accumula been reported. (J. A. Lamberton, et al., Australian Journal of tion of lipids, complex carbohydrates, blood and blood Chemistry, 13:261-268 (1959); A. Horn and J. S. Martic, products, fibrous tissue and calcium deposits, frequently also Journal of Science Food and Agriculture, 10:571 (1957); 50 associated with medial changes. Thus, atherosclerosis is Kreger, (1948); Wimbero, (1904); and Mitsui and Col. known as a multifactorial process and includes hyperlipi (1942)). These studies Suggest a method for obtaining ali demia as a risk factor. phatic alcohols based on the homogeneous saponification Among the factors contributing to atherosclerosis devel with alcoholic potassium hydroxide. opment, platelet aggregation has a very important place. The Another method reports an extraction of the natural 55 granule contents released from platelets activate arachidonic aliphatic alcohol mixture through a high efficiency vacuum. acid, which metabolizes into cyclic endoperoxides. These The high vacuum wax distillation for the chemical isolation are mainly transformed into thromboxane A (TXA), a of mixed derivatives and the extraction of the remaining wax strong vasoconstrictor and platelet aggregatory agent. Plate are done using petroleum ether. The solvent is evaporated let aggregation can be elicited by numerous compounds, and the remaining Solids are acetylated for further purifica- 60 such as collagen, ADP, and epinephrine. Thus, different tion through alumina chromatography. Finally, through alka experimental “in vivo..” “ex vivo,” or “in vitro” models that line hydrolysis, aliphatic alcohols are obtained and then test effectiveness of putative antiplatelet drugs commonly recrystallized in ethanol, showing a melting point range test their effect on platelet aggregation induced by these from 62° C. to 82° C. agents. These tests are also used for testing platelet aggre Blood-lipid lowering effects of a natural mixture of 65 gation in healthy Volunteers and in patients with diseases straight chain aliphatic alcohols have been demonstrated by which induce hyperaggregability Such as hypercholester several authors: (F.
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