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|||||||||III USOO55524.07A United States Patent (19) 11) Patent Number: 5,552,407 Wood Et Al |||||||||III USOO55524.07A United States Patent (19) 11) Patent Number: 5,552,407 Wood et al. 45) Date of Patent: Sep. 3, 1996 (54) ANHYDROECGONINE COMPOUNDS AND P. Jacob III et al., “A Pyrolysis Product, Anhydroecgonine THEIR USE ASANTICHOLNERGC Methyl Ester (Methylecgonidine), is in the Urine of Cocaine AGENTS Smokers' J. Anal. Toxicol. 14:353-357 (1990). W. T. Lowry et al., "Identification of Two Novel Cocaine (75) Inventors: Ronald W. Wood, Nyack; Hassan A. Metabolites in Bile by Gas Chromatography and Gas Chro N. El-Fawal, Middletown; John F. matography/Mass Spectrometry in a Case of Acute Intrave Graefe, Greenwood Lake, all of N.Y.; nous Cocaine Overdose' J. Anal. Toxicol. 3:91-95 (1979). Lung C. Chen, Upper Saddle River, Carroll et al., “Probes for the Cocaine Receptor. Potentially N.J.; Jalil Shojaie, Tuxedo, N.Y. Irreversible Ligands for the Dopamine Transporter'J. Med. Chem. 35:1813-1817 (1992). 73) Assignee: New York University Medical Center, Cereda et al., "Synthesis and Biological Evaluation of New New York, N.Y. Antimuscarinic Compounds with Amidine Basic Centers. A Useful Bioisosteric Replacement of Classical Cationic (21) Appl. No.:76,315 Heads' J. Med. Chem. 33:2108-2113 (1990). J. Sharkey et al., "Cocaine Inhibits Muscarinic Cholinergic (22 Filed: Jun. 11, 1993 Receptors in Heart and Brain' J. Pharmacol. Exp. Ther (51 Int. Cl." ......................... A61K 31/44; CO7D 213/20 246:1048-1052 (1988). 52 U.S. C. ............................ 514/291; 546/91; 54.6/132; Meyer et al., “Effects of Benzolytropine and Tropacocaine 54/304 on Several Cholinergic Processes in the Rat Brain' J. 58) Field of Search ..................... 546/132,91; 514/304, Pharmacol. Exp. Ther. 254:584-590 (1988). 514/291 R. F. H. Taylor et al., "Betel-nut chewing and asthma' Lancet 339:1134-1136 (1992). 56) References Cited H. A. N. El-Fawal et al., “The Biventer Cervicis Nerve -Muscle Preparation of Adult Hens: Effects of Phenyl U.S. PATENT DOCUMENTS Saligenin Phosphate Administration” Neurotoxicology 9:625-636 (1988). 4,467,095 8/1984 Treves et al. ........................... 54.6/342 Gross, N. J., “Ipratropium Bromide' New Eng. J. Med. FOREIGN PATENT DOCUMENTS 319:486-494 (1988). M. W. Fischman et al., "A Comparison of the Subjective and 0445731 9/1991 European Pat. Off. ............... 54.6/152 Cardiovascular Effects of Cocaine and Lidocaine in OTHER PUBLICATIONS Humans' Pharmacol. Biochem. Behav. 18:123-127 (1983). Deckers, W., "The chemistry of new derivatives of tropane Chemical Abstracts, vol. 51, No. 21, Abstract 16501e, h, alkaloids and the pharmacokinetics of a new quarternary Nov. 10, 1957. compound' Postgrad. Med. J. 51 (Suppl. 7):76-81 (1975). Chemical Abstracts, vol. 57, No. 3, Abstract 3390g, Aug. 6, 1962, Zirkle et al. Primary Examiner-C. Warren Ivy Chemical Abstracts, vol.53, No. 1, Abstract 1327h, Jan. 10, Assistant Examiner-Zinna N. Davis 1959, Zaugg et al. Attorney, Agent, or Firm-Morrison & Foerster LLP Leete, "Biosynthesis of the Pyrrolidine Rings of Cocaine and Cuscohygrine from 5-CIOrnithine via a Symmetri 57 ABSTRACT cal Intermediate', J. Am. Checm. Soc. 104:1403-1408 Methylecgonidine (MEG; anhydroecgonine methylester), is (1982). produced when cocaine base ("crack') is heated. MEG alone H. S. Orer et al., “Antagonism of Acetylcholine Action in and in combination with cocaine was tested for action on Guinea-Pig Tracheal Smooth Muscle and Epithelium by isolated tracheal rings stimulated to contact with acetylcho Pirenzepine, 4-DAMP and Atropine' Arch. Int. Pharmaco line. At micromolar concentrations, cocaine sensitized tra dyn, 305:45-54 (1990). cheal rings, increasing both the potency and efficacy of T. Inaba, "Cocaine: Pharmacokinetics and biotransformation acetylcholine-induced contraction. Surprisingly, MEG, at in man' Can. J. Physiol. Pharmacol. 67: 1154-1157 (1989). nanomolar concentrations and above, non-competitively and R. W. Foltin et al., “Demonstration of naturalistic methods irreversibly antagonized acetylcholine-induced contraction for cocaine smoking by human volunteers' Drug Alcohol independently of the actions of cocaine. MEG also displayed Depend. 26:145-154 (1990). antihistaminic activity. Therefore, MEG and anticholinergi Davies, H. M. L., "Novel 2-substituted cocaine analogs: cally active derivatives or analogues thereof are useful in the binding properties at dopamine transport sites in rat stria prevention or treatment of a disease or disorder treatable by tum' Eur: J. Pharmacol. 244:93-97 (1993). an antimuscarinic anticholinergic agent, an anti-histaminic J. P. Boni et al., “Pyrolysis of Cocaine Free Base' FASEB.J. agent or a spasmolytic agent, in particular bronchoconstric 205) 1988, abstr. 4891. tion in a number of pulmonary diseases such as asthma. B. R. Martin et al., “Pyrolysis and Volatilization of Cocaine' J. Anal. Toxicol. 13:158-162 (1989). 31 Claims, 6 Drawing Sheets U.S. Patent Sep. 3, 1996 Sheet 1 of 6 5,552,407 U.S. Patent Sep. 3, 1996 Sheet 2 of 6 5,552,407 10/QCIO?{dS/SÅTOHÅd € HELSETÄHLEWN \HO-O-O BININO9OBOHCJAHNV HNHHVOSTIWNºHo C S1SINOSOVO/98/EN/TOHO =Nivooo U.S. Patent Sep. 3, 1996 Sheet 3 of 6 5,552,407 cp 9 2 on 35 p : icts- is - O o co w C C v O O O O O NOISN3L OZTWWON 92 4.NS 9. d y - C NOISNE OEZTWWON U.S. Patent Sep. 3, 1996 Sheet 4 of 6 5,552,407 1.4 - Ach 2x IO-3M 1.2 1.O O.8 O.6 { O.4 O.O -1 a-N -7 -6 -5 -4 LOG COCAINE CONC. (M) F. G. 4A -5 a 9 -6 R -7 S -8 O CD CC 9. -9 - O -7 -6 -5 -4 LOG COCAINE CONC. (M) U.S. Patent Sep. 3, 1996 Sheet 5 of 6 5,552,407 1.4 1.2 A 1.0 O.8 O.6 f f 0.4 A /, y W 0.2 -A 4 -A --0 O.O -10 -9 -8 -7 -6 -5 -4 -3 Acetylcholine F.G. 5 U.S. Patent Sep. 3, 1996 Sheet 6 of 6 5,552,407 -09 -08 -07 -06 -05 -04 -O3 -02 Histamine -o- CONTROLS - meg-7 " meg-9 F.G. 6 5,552.407 1. 2 ANHYDROECGONNE COMPOUNDS AND The role of cholinergic transmission in cocaine abuse was THEIR USE AS ANTICHOLNERGIC studied briefly twenty years ago, and has not been followed AGENTS up to any extent. Cocaine itself has antimuscarinic effects, but only at concentrations higher than those associated with This invention was funded in part by a research grant euphoria. Cocaine bears some structural resemblance to from the National Institute on Drug Abuse, which provides atropine, a prototypical anticholinergic drug, and related to the United States Government certain rights in this compounds. invention. C. DISEASES OF BRONCHOCONSTRICTION AND THEIR TREATMENT BACKGROUND OF THE INVENTION O For a detailed description of anticholinergic agents and Field of the Invention their use in treating various diseases including respiratory diseases, see: Faye, W. P., PRINCIPLES OF MEDICINAL The present invention relates to the discovery of anticho CHEMISTRY, Lea and Fibiger, 1989, pp. 328-348; Gilman, linergic action of cocaine derivatives, in particular methyl A. G. et al., (eds), THE PHARMACOLOGICAL BASIS OF ecgonidine (MEG), and methods of using this compound 15 THERAPEUTICS, 8th Edition, Macmillan Publishing Co., and its anticholinergically active derivatives in the treatment New York, 1990, chapter 8, pp. 150-165, both of which of pulmonary diseases associated with bronchoconstriction. references are hereby incorporated by reference herein). A 2. Description of the Background Art variety of drugs of different classes have found uses in diseases such as asthma and chronic pulmonary disease. A. CRACK COCAINE AND ITS PYROLYSIS 20 These drugs include (1) B-adrenergic agonist bronchodila PRODUCTS tors, (2) the quaternary antimuscarinic n-isopropylatropine that inhibits acetylcholine-induced contraction of the tra "Crack' (cocaine base) is a drug with great abuse poten cheal musculature, (3) the phosphodiesterase inhibitor theo tial that when smoked can lead to a compulsive abuse phylline, (4) mast cell stabilizing agents such as the cro disorder complicated by behavioral and physiological tox 25 moglycates, (5) the antihistamines, and (6) steroids which icity. When a flame is applied to crack, the drug volatilizes reduce inflammatory responses to inhaled substances. See in significant amounts at temperatures only slightly below Gilman et al. (supra). those at which pyrolysis occurs. As the temperature of the drug atmosphere cools the vapors condense, forming drop Current recommended practice for the treatment of lets that deposit in the airways. The first two pyrolysis 30 asthma is to reduce the inflammatory and bronchoconstric products produced on heating are benzoic acid and anhy tive response to allergens while judiciously using bronchodi droecgonine methyl ester (methylecgonidine, MEG) (B. R. lators to provide symptomatic relief. Frequent routine use of Martin et al., J. Anal. Toxicol. 13:158 (1989)). Benzoic acid B-adrenergic agonists by asthmatic patients has been corre is white, and sublimates. MEG is a clear liquid at room lated with increased symptoms, airway hyperresponsiveness temperature. Although yellow and black pyrolysis products 35 and mortality. See: Page, C. E. et al., Am. Rev. Respir: Dis. are commonly seen in drug paraphernalia, MEG predomi 147:S29-32 (1993). nates on a mass basis. The parasympathetic nervous system plays a major role in MEG has been detected in the urine of crack smokers, but regulating bronchomotor tone. Largely owing to the intro not in users of cocaine taken by other routes (P. Jacob III et duction of the quaternary anticholinergic ipratropium bro al., J. Anal. Toxicol. 14:353 (1990)). These authors sug 40 mide (Atrovent(R) (gross, H. J., New Eng. J. Med. gested that MEG might be a cholinergic agonist, based on its 319:486-494 (1988)), anticholinergic therapy of respiratory structural similarity to arecoline and anatoxin A.
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