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  Plant extracts and alkaloids having antitussive activityUSPTO Application #: 20050256101Title: Plant extracts and alkaloids having antitussive activity Abstract: The present invention provides plant extracts, isolated alkaloids, synthetic alkaloids and compositions having antitussive activity. In some preferred embodiments, the plant extracts and the isolated alkaloids are from a plant of a genus in the family Stemonaceae. In other preferred embodiments, the plant extracts and the isolated alkaloids are from a plant of the genus Stemona, Croomia, or Stichoneuron. In especially preferred embodiments, the plant extracts and the isolated alkaloids are from the plant Stemona tuberosa. The present invention further provides methods for isolating such plant extracts and alkaloids. In addition, the present invention provides methods for reducing or suppressing coughing by administering plant extracts, alkaloids and compositions having antitussive activity. (end of abstract) Agent: Townsend And Townsend And Crew, LLP - San Francisco, CA, US Inventors: Ge Lin, Hoi Sing Chung, Po Ming Hon, Hui Dong, Paul P.H. But USPTO Applicaton #: 20050256101 - Class: 514214010 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of One Nitrogen And Six Carbons, Polycyclo Ring System Having The Seven-membered Hetero Ring As One Of The Cyclos, Ring Nitrogen Of The Seven-membered Hetero Ring Is Shared By An Additional Cyclo Of The Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20050256101. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] This invention pertains to the field of plant extracts, isolated plant alkaloids, and synthetic alkaloids that have antitussive activity and which are useful as pharmaceutical agents for reducing or suppressing coughing. BACKGROUND OF THE INVENTION [0002] Coughing provides a means for clearing the tracheal and bronchial trees of accumulated secretions and/or foreign bodies. The mechanism of coughing is initiated by an appropriate stimulus which elicits a deep inspiration, followed by closure of the epiglottis and relaxation of the diaphragm. Thereafter, a sharp muscle contraction against the closed epiglottis occurs, thereby, producing increased pressure in the intra-thoracic and intra-airway passages. The positive intra-thoracic pressure causes a narrowing of the trachea due to enfolding of its compliant posterior membrane and opens the epiglottis. When the epiglottis opens, the combination of the large pressure differential between the thoracic cavity and the atmosphere, coupled with the narrowing of the trachea, produces a massively increased rate of air flow through the trachea. The force created by this increased rate of air flow can effect the clearance of expectorate mucus and foreign materials from the airway. [0003] Coughing is caused by a variety of stimuli, including physiological, mechanical, or chemical stimuli. For example, coughing is produced by inflammatory mechanisms, mechanical disorders, and chemical and thermal stimulation. Also for example, inflammatory stimuli can be initiated by edema of the mucosal membranes. The edema, in turn, can be from any etiology, for example, bacterial or viral infection, the common cold, or excessive cigarette smoking. Inflammatory stimuli may also be elicited by irritation from exudative processes such as post-nasal drip and gastric reflux. Such stimuli may arise in the airways, for example as in laryngitis, bronchitis, pneumonia or an abscess in the lungs. [0004] Further, mechanical stimuli, for example the inhalation of particulate matter, can cause coughing. Other mechanical disorders which result in compression of the air passages or increased pressure upon any area of the respiratory system may result in coughing. Such mechanical difficulties may arise from intra-mural or extra-mural etiologies. For example, extra-mural causes of coughing include extra-mural pressure caused by an aortic aneurysm, granulomas, pulmonary neoplasms, mediastinal tumors, and the like. Intra-mural lesions, such as bronchiogenic carcinoma, bronchial adenoma, the presence of foreign bodies or bronchial asthma also result in coughing. Decreased pliancy of the respiratory membranes may also result in chronic coughing, as in the case of patients suffering from cystic fibrosis. [0005] Chemical stimuli, for example the inhalation of irritant gases (e.g., cigarette smoke or chemical fumes) may also elicit coughing. Other chemical entities result in coughing due to their reactive effect upon the respiratory system itself or on the balance and uptake of respiratory gases. Additionally, many chemical agents induce coughing due to their reaction with enzymes involved in the respiratory process. Lastly, thermal stimuli, such as the inhalation of either very hot or cold air, may also result in coughing. [0006] In some disease states, a persistent cough can be the only or primary symptom. For example, patients suffering from bronchial asthma can result in incessant coughing. Moreover, in some medical conditions, for example, asthma, the cough mechanism itself may further aggravate the patient's condition. Asthma is a condition marked by recurrent attacks of paroxysmal dyspnea with wheezing, which is due to spasmodic contraction of the bronchi. The condition is caused by various etiologies. In some cases, asthma is the result of an allergic reaction. A variety of factors including vigorous exercise, chemical or particulate irritation, or even psychological stress can stimulate or provoke coughing. Moreover, the violent contractions of the thoracic cavity which accompany coughing further aggravates already irritated respiratory membranes. A review of the physiology of coughing is presented by Karlsson et al., Pulmonary Pharmacology and Therapeutics (1999) 12.215-238. [0007] A variety of antitussive drugs have been developed for the treatment of coughing, for example, morphine-like compounds and compounds that act on opioid receptors. However, these compounds have adverse side effects. For example, the use of morphine-like compounds are known to result in addiction, respiratory suppression, and inhibitory action of smooth muscle contraction (e.g., resulting in constipation), and psychotomimetics. In particular, codeine is known to be highly addictive and dextromethorphan is known to induce hallucinations, delusions, or other symptoms of a psychosis. Moreover, drugs having strong antitussive activity, for example codeine and dextromethorphan, are known to adversely act on the central nervous system. Further, drugs that act on opioid receptors are known to adversely effect urination (Leander et al. Pharmacol. Exp. Ther., 227:35 (1983). A review of antitussive drugs is presented by Hey et al., Annual Reports in Medicinal Chemistry 35:53-62 (2000) and Bolser, Pulmonary Pharmacology 9:357-364 (1996). [0008] A variety of drugs are available for the treatment of coughing. However, the number of safe and effective antitussive agents devoid of unwanted side effects, for example, sedation and addiction, is limited. In view of the serious adverse side effects of the drugs used to treat coughing, there is a need for antitussive drugs that are free of such side effects and are effective in reducing or suppressing coughing. The present invention fulfills these and other needs. SUMMARY OF THE INVENTION [0009] The present invention provides, inter alia, antitussive compounds that are free of side-effects and are effective in reducing or suppressing coughing. In one aspect, the antitussive compounds are plant extracts or their derivatives such as from the family Stemonaceae. [0010] As such, in one embodiment, the present invention provides a compound having Formula I: 1 [0011] In Formula I, R.sup.1 is selected from a hydrogen and an .alpha.(S)-methyl-.gamma.(S)-butyroylactonyl; R.sup.2 is selected from a .beta.-oriented hydrogen and an .alpha.-oriented hydrogen; R.sup.3 is selected from a .beta.-oriented hydrogen and an a-oriented hydrogen; R.sup.4 is hydroxyl; R.sup.5 is selected from a hydroxymethyl and a carboxyl. In an alternative embodiment, R.sup.4 and R.sup.5 together with the carbons to which they are attached, join to form a substituted .gamma.(S)-butyroylactonyl or substituted furane ring; and R.sup.6 is selected from a .beta.-oriented hydrogen and an a-oriented hydrogen. In another embodiment, R.sup.4 and R.sup.5 together with the carbons to which they are attached, join to form a substituted .gamma.(S)-butyroylactonyl and R.sup.2 and R.sup.6 are both absent and form a pyrrole ring, provided however, that when R.sup.1 is .alpha.(S)-methyl-.gamma.(R)-butyroylactonyl, R.sup.3 is an a-oriented hydrogen. [0012] In another embodiment, the present invention provides a pharmaceutical composition, the composition comprising a compound having Formula I: 2 [0013] R.sup.1 is selected from a hydrogen and an .alpha.(S)-methyl-.gamma- .(S)-butyroylactonyl; R.sup.2 is selected from a .beta.-oriented hydrogen and an a-oriented hydrogen; R.sup.3 is selected from a .beta.-oriented hydrogen and an .alpha.-oriented hydrogen; R.sup.4 is hydroxyl; R.sup.5 is selected from a hydroxymethyl and a carboxyl, or alternatively, R.sup.4 and R.sup.5 together with the carbons to which they are attached, join to form a substituted .gamma.(S)-butyroylactonyl or substituted furane ring; and R.sup.6 is selected from a .beta.-oriented hydrogen and an .alpha.-oriented hydrogen. In another embodiment, R.sup.4 and R.sup.5 together with the carbons to which they are attached, join to form a substituted .gamma.(S)-butyroylactonyl and R.sup.2 and R.sup.6 are both absent and form a pyrrole ring, provided however, that when R.sup.1 is .alpha.(S)-methyl-.gamma.(R)-butyroylactonyl, R.sup.3 is an .alpha.-oriented hydrogen, and a pharmaceutically acceptable carrier. [0014] In another embodiment, the present invention provides a method for reducing coughing in a subject, the method comprising: administering a pharmaceutically effective amount of a compound having Formula I: 3 [0015] wherein: R.sup.1 is selected from a hydrogen and an .alpha.(S)-methyl-.gamma.(S)-butyroylactonyl; R.sup.2 is selected from a .beta.-oriented hydrogen and an .alpha.-oriented hydrogen; R.sup.3 is selected from a .beta.-oriented hydrogen and an .alpha.-oriented hydrogen; R.sup.4 is hydroxyl; R5 is selected from a hydroxymethyl and a carboxyl. In an alternative embodiment, R.sup.4 and R.sup.5 together with the carbons to which they are attached, join to form a substituted .gamma.(S)-butyroylactonyl or substituted furane ring; and R.sup.6 is selected from a .beta.-oriented hydrogen and an .alpha.-oriented hydrogen. In another embodiment, R.sup.4 and R.sup.5 together with the carbons to which they are attached, join to form a substituted .gamma.(S)-butyroylactonyl and R.sup.2 and R.sup.6 are both absent and form a pyrrole ring, provided however, that when R.sup.1 is .alpha.(S)-methyl-.gamma.(R)-butyroylactonyl, R.sup.3 is an .alpha.-oriented hydrogen, thereby reducing coughing in a subject. [0016] In yet another embodiment, the present invention provides a Stemonaceae family plant extract having antitussive activity, wherein the Stemonaceae family plant extract inhibits a cough in a subject. In certain aspects, the genus belonging to the Stemonaceae family is selected from Stemona, Croomia, or Stichoneuron. Preferably, the species of the Stemona or Croomia genus is selected from S. collinsae, S. japonica, S. mairei, S. parviflora, S. sessilifolia, S. tuberosa, C japonica, and C. heterosepala wherein C. represents Croomia. In one preferred embodiment, the Stemona species is Stemona tuberosa. The plant extract can be an aqueous extract or a total alkaloid extract. [0017] In other embodiments, the present invention provides a pharmaceutical composition, comprising: a Stemonaceae family plant extract having antitussive activity, wherein the Stemonaceae family plant extract inhibits a cough in a subject. [0018] In still yet another embodiment, the present invention provides a method for reducing coughing in a subject, comprising: administering a pharmaceutically effective amount of a Stemonaceae family plant extract having antitussive activity, wherein the Stemonaceae family plant extract inhibits a cough in a subject. [0019] In yet another embodiment, the present invention provides a method for preparing a total alkaloid extract having antitussive activity from a Stemonaceae family plant, the method comprising: (a) contacting a Stemonaceae family plant sample with an alcohol to form a liquor; (b) evaporating the alcohol in the liquor to form a syrup; (c) adjusting the syrup to an acid pH to form a supernatant fraction; (d) adjusting the supernatant fraction to a basic pH, and then extracting with an organic solvent to form an organic solution; and (e) evaporating the organic solvent to dryness to form a total alkaloid extract having antitussive activity. [0020] In still yet another embodiment, the present invention further provides a method for preparing four Stemona alkaloids having antitussive activities from a total alkaloid extract as mentioned above, the method further comprising separating, purifying and crystallizing the total alkaloid extract, to form four Stemona alkaloids having antitussive activity. The four Stemona alkaloids can be separated using conventional chromatographic techniques. [0021] In still yet another embodiment, the present invention provides a method for preparing an aqueous extract having antitussive activity from a Stemonaceae family plant, the method comprising: (a) contacting a Stemonaceae family plant sample with an aqueous solvent to form a liquor; and (b) evaporating the liquor to dryness to form an aqueous extract having antitussive activity. Continue reading... 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