United States Patent (19) 11 Patent Number: 4,713,391 Chiang et al. 45 Date of Patent: Dec. 15, 1987

54 AZABICYLOALKANEPHENYL Sonntag, Chem. Revs., 52, (1953), 312-399. SUBSTITUTED ALKANE CARBOXYLATES, Primary Examiner-Donald G. Daus THER PREPARATION AND USE AS Assistant Examiner-William A. Teoli, Jr. ANTICHOLINERGICAGENTS Attorney, Agent, or Firm-Francis A. Cooch; Werten F. 75 Inventors: Peter K. Chiang, Bethesda; Michelle W. Bellamy M. Richard, Silver Spring; Felipe N. Padilla, Wheaton, all of Md.; Frank 57 ABSTRACT I. Carroll, Durham; Philip Abraham, This invention relates to novel compositions, their prep Cary, both of N.C. aration and the use thereof as agents in (73) Assignees: The United States of America as the treatment or prophylaxis of or represented by the Secretary of the nerve gas poisoning in animals. These compositions and Army, Washington, D.C.; Research pharmaceutical preparations containing them in their Triangle Institute, Research free base form and acid addition salts thereof are repre Triangle, N.C. sented by the formula

(21) Appl. No.: 855,857 R 22 Filed: Apr. 17, 1986 N 51) Int. Cl." ...... C07D 209/02; H61K 31/40 52 U.S.C...... 514/412; 548/452 CH2 58 Field of Search ...... 548/452; 514/412 O R2 (56) References Cited O-C-C U.S. PATENT DOCUMENTS Rl 4,499,099 2/1985 Watts ...... 548/452 X 4,533,498 8/1985 Blaney et al...... 548/452 X wherein R represents lower alkyl groups containing 1 OTHER PUBLICATIONS to 7 carbon atoms; R represents hydrogen, phenyl, Furstoss et al., Chem. Abstracts, 72, (1970), entry cyclohexyl, and cyclopentyl; and R2 represents lower 111268Z. alkyl groups containing 1 to 7 carbon atoms, hydroxy House, Modern Synthetic Reactions, W. A. Benjamin, methyl, and hydroxyl. Inc., N.Y., (1965), pp. 54-55. Kaplan, J. Am. Chem. Soc., 88, (1966), 4970-4971. 11 Claims, 2 Drawing Figures U.S. Patent Dec. 15, 1987 Sheet 1 of 2 4,713,391

2 AZAPROPHEN O H OO S O 7 8 9 O t -LOG (M) 2 PA2= 10.4 as 80 - CD K=3.9x IO"M C2 or 60 H Ll d O up 40 SS 2O

O-8 O-7 O-6 IO-5 (M) FIG. U.S. Patent Dec. 15, 1987 Sheet 2 of 2 4,713,391

S s CN --

C g o O O H

O O O O O OO O V CN

O AMYLASE RELEASE (% CONTROL) 4,713,391 1. 2 antimuscarinic agents than , benactyzine, and AZABICYTLOALKANEPHENYL SUBSTITUTED aprophen are potentially good candidates for therapeu ALKANE CARBOXYLATES, THEIR tically useful . PREPARATION AND USE AS ANTICHOLNERGICAGENTS PHARMACOLOGICAL INFORMATION The nature of muscarinic receptors has been studied BACKGROUND OF THE INVENTION mainly by investigating the chemical and physical char 1. Field of the Invention acteristics of the drugs with which they interact. The This invention relates to the preparation and use of formation of a -receptor complex involves interac azabicycloalkane phenyl substituted alkane carboxyl O tions of several different types between groups in the ates, including pharmacologically useful compositions drug molecule and in the receptor. The power of a drug thereof, as anticholinergic agents. to become attached to a receptor has been termed its 2. Prior Disclosure affinity while its ability to induce or antagonize a stimu Nerve gas poisons function by irreversibly inhibiting lus has been called either intrinsic activity or efficacy. acetylcholinesterase (AChE). This leads to a build up of 15 excess acetylcholine resulting in overstimulation of The activities of muscarinic drugs and their antago both the peripheral and central nervous system. A sin nists may be assayed on isolated pieces of gut (usually gle acute dose of a nerve gas can lead to death with the guinea-pig ileum or rabbit duodenum) suspended in a primary cause of death being respiratory failure. suitable oxygenated medium. Agonists produce con The organophosphate nerve agents GD (soman), GB 20 tractions of such preparations which are blocked by (sarin) and VX are extremely potent pre-treatment with anticholinergic drugs. Several meth inhibitors (anticholesterases). Like other organophos ods normally used for determining the activity of antag phate poisons, they owe their biological activity to onists are based upon that described by Schild in Brit. J. phosphylation of serine hydroxyl at the active site of the Phrmacol, Vol. 2, page 189 (1947), and the antagonistic enzyme acetylcholinesterase, thereby deactivating it in 25 activity is usually expressed as a pA2 value, i.e. the an essentially irreversible manner. As a consequence of negative logarithm of the molar concentration of the this deactivation, the neurotransmitter acetylcholine antagonist which reduces the effect of a double dose of accumulates at sites, producing an effect the agonist to that of a single one. Alternatively, pa2 roughly equivalent to continuous stimulation of cholin can be defined as representing the negative logarithm of ergic fibers throughout the central and peripheral ner 30 KB, which is the affinity of a drug to bind a receptor. It vous systems. is obvious that this assay does not measure precisely and Standard therapy for organophosphate nerve agent selectively only one type of pharmacological activity. poisoning is based on the concurrent administration of an anticholinergic agent to antagonize the effects of the However, when used with an understanding of its scope accumulated acetylcholine and a cholinesterase reac 35 and limitations, it does provide valuable information in tivator to dephosphylate the inhibited enzyme. The the development of anticholinergic drugs and their standard anticholinergic agent used in therapy is atro structure-activity relationship. Additionally, another pine sulfate. Pyridinium oximes such as 2-(hydrox method to assay the activity of agonists or antagonists yimino)methyl-1-methylpyridinium halide (2-PAM) for the muscarinic receptors is their effect on the release are the most studied cholinesterase reactivators. Vari 40 of a-amylase from isolated pancreatic acini cells as ous other drugs have been examined as adjuncts to this described in American J. Physiol, Volume 235, pages therapy in order to control the convulsions which are a 743-747, (1978); and J. Physiol, Volume 270, pages side-effect of the poisoning, to assist in countering respi 439-454, (1977). A prototype agonist, such as carba ratory failure, or because of their antimuscarinic prop chol, stimulates the release of a-amylase by acting on erties. Specific examples are benactyzine, and aprophen. 45 the muscarinic receptors of pancreatic acini cells. The Atropine is known to antagonize the muscarinic effects potency of an antagonist on the muscarinic receptors is of acetylcholine and is the best-known of the so-called measured by its ability to inhibit the release of a-amy antimuscarinic agents. The usefulness of atropine has lase stimulated by . Like the ileum assay, it is stimulated the study of other antimuscarinic agents as a reliable assay for the potencies of muscarinic anticho potential treatment drugs for anticholinesterase poison SO linergic agents. ling. Since the ionic nature of many cholinesterase reac BRIEF DESCRIPTION OF THE DRAWINGS tivators limits their efficacy to the peripheral nervous FIG. 1 illustrates the inhibition of the acetylcholine system, the anticholinergic drugs are the primary induced contraction of guinea pig ileum by azaprophen. source of protection for the central nervous system. 55 The practical usefulness of the anticholinergic drugs is FIG. 2 illustrates the inhibition of the release of ot limited by their central nervous system activities and amylase from pancreatic acini cells induced by 10M their toxicities. carbachol by azaprophen. There is a need for new effective anticholinergic SUMMARY OF THE INVENTION agents for the pre-treatment (prophylaxis) against and treatment of organophosphate nerve agent poisoning. This invention relates to novel azabicycloalkane Like atropine, such agents must exhibit a higher affinity phenyl substituted alkane carboxylate compositions, than acetylcholine for the receptor sites. In addition, their preparation and the use thereof as anticholinergic neutral molecules with some degree of lipid solubility agents in the treatment or prophylaxis of nerve gas are preferred because of their ability to penetrate the 65 poisoning in animals. These compositions and pharma bloodbrain barrier and protect the central nervous sys cologically useful preparations containing them in their tem. Benactyzine and aprophen are two examples of free base form and acid addition salts thereof are repre such compounds. Compounds which are more effective sented by the formula 4,713,391 4. representing the corresponding salts and free com R pounds, respectively. The compositions of this invention are water soluble N and can be administered to the animal systemically (i.e. CH2 orally or parenterally) either prior to and/or after it has been exposed to organophosphate poisoning. These compositions are obtained by a method which is in itself O novel, which comprises the steps of I (a) reducing a compound having the formula: 10 R wherein R represents lower alkyl groups containing 1 N to 7 carbon atoms; R represents hydrogen, phenyl, CH2 cyclohexyl, and cyclopentyl; and R2 represents lower 15 alkyl groups containing 1 to 7 carbon atoms, hydroxy methyl, and hydroxyl. These compositions are referred O to by applicants as azabicycloalkane phenyl substituted alkane carboxylates which especially includes azapro with LiALH4 to form the corresponding derivative phen and related compounds. 20 DETAILED DESCRIPTION OF THE R INVENTION N Practical utility has been established for compositions CH2 and pharmaceutical preparations containing them in 25 their free base form and acid addition salts thereof are represented by the formula OH (b) reacting the hydroxyl derivative formed in step R 30 (a) with a compound having the formula N

CH2

35 O R2 O II O-C-C This novel method for the preparation azabicycloalkane Rl-(O) phenyl substituted alkane carboxylates is illustrated in the following chemical reaction sequence for the prepair where R represents lower alkyl groups containing 1 to ration of azaprophen: 7 carbon atoms; R represents hydrogen, phenyl, cyclo hexyl, and cylopentyl; and R2 represents lower alkyl groups containing 1 to 7 carbon atoms, hydroxymethyl, and hydroxyl. The lower alkyl groups include methyl, 45 ethyl, n-propyl, isopropyl, n-butyl, tertiary-butyl, n a Ge. penty, isopentyl or hepty, especially methyl, as well as Sa ethyl and propyl. So Salts of compounds of the present invention are acid CH3 CH3 H 50 addition salts, especially pharmaceutically useful non OH toxic acid addition salts, such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulphuric, or phosphoric acid, or with organic acids, such as organic carboxylic acids, for example, acetic, propionic, glycollic, malonic, succinic, maleic, hydrox 55 ymaleic, methylmaleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, embonic, nico HC O tinic or isonicotinic, or organic sulfonic acids, for exam CH3 H ple, methanesufonic, ethanesulfonic, 2-hydroxy-ethane 60 sulfonic, ethane-1,2-disulfonic, benzenesulfonic, p-tol o---CH uene-sulfonic, naphthalene-2-sulfonic, or cyclohexane O sulfamic acid, as well as ascorbic acid. In view of the close relationship between the new 65 compounds in their free form and in the form of their (a) LiAlH4 salts, the free compounds or their salts are in this con (b) (C6H5)(CH3)C(O)Cl. text and whenever appropriate, to be understood as also 4,713,391 5 6 is much greater than compounds presently in use. Aza MATERIALS AND METHODS prophen is a novel anticholinergic drug useful for treat Applicants have prepared several compounds as po ment or prevention of nerve gas poisoning. It should tential and assayed them for antimusca also be useful for treatment of poisoning by organo rinic activity. The chemical structural relationship be phosphorus insecticides, in ophthalmology to produce a tween azaprophen (6-methyl-6-azabicyclo[3.2.1- dilatation of the pupil (mydriasis), as bronchial dilators, octane-3a-ol. 2,2-diphenylproprionate) and other anti and before operations to inhibit bronchial secretions and cholinergic agents depicted in the structures below: to block the vagus nerve. The treatment of various conditions like colic where contractions of smooth mus H CH 3 10 cle cause intense pain, and the treatment of Parkinson's Ne/ disease and motion sickness are other potential uses of N this drug. CH2 METHODS 15 Guinea Pig Ileum Assay C-CH3 The ability of azaprophen to block the acetylcholine induced contraction of the guinea pig ileum was assayed according to the method of M. C. Pankaskie, et al., J. Medicinal Chemistry Vol. 28 pages 1117, (1985); R. K. 20 Gordon and P. K. Chiang, J. Pharmacology and Experi Azaprophen mental Therapeutics, Vol. 236, pages 85-89 (1986); and "Pharmacological Experiments on Isolated Prepara tions', Department of Pharmacology, University of Edinburg, pages 58-87, 1970. Distal ileum was obtained H-e 25 from male albino guinea pigs (200-500 grams). A seg CH3 ment of distal ileum about 20 cm in length was excised 5 cm above the ileo-caecal junction and immediately placed in oxygenated Krebs-Ringer solution containing o--h 118 mM NaCl, 4.7 mM KCI, 25 mM NaHCO3, 0.93 O CH2OH 30 mM KH2PO4, 2.5 mM CaCl2, 1.2 mM MgCl2, and 11 Atropine Sulfate mM glucose. Segments 2.5 cm in length were suspended in a 10 ml organ bath, which was aerated with 5% CO2 CH3 and 95% O2, and maintained at 37 C. Isometric con e Ce tractions were recorded by a transducer (Harvard Ap 35 paratus, Natick, MA) at 1 gram tension. The concentra tion response curve for acetylcholine (ACh) was ob (Or tained using a series of ACh doses of increasing concen 2-PAM Chloride tration; the maximal contractile response was desig nated 100%. The antimuscarinic activity of azaprophen (ability to block the ACh-induced contraction) was expressed as the KB or pA2 values, which were calcu C OH lated using computer programs for the Schild plot as described by R. J. Tallarida, et al., in Manual of Phar 45 macological Calculations With Computer Programs, pages 29-31, (1981). O O -ochscHNCHCH), a-Amylase Release from Pancreatic Acini Cells Pancreatic acini cells were prepared from a male Benactyzine Sprague Dawley rat (150 grams) according to a modifi 50 cation of the procedures of S. R. Peikin, et al., American Journal Physiology, Vol. 235, pages 743 to 747 (1978) which is described by R. K. Gordon and P. K. Chiang, J. Pharmacology and Experimental Therapeutics, Vol. O CH3 236, pages 85 to 89, (1986). Dispersed pancreatic acini 55 cells were prepared by three successive incubations with collagenase (0.8 mg/ml, Sigma Co.) and resus O O -o-CHCHNCH-CH), pended in 16 ml of Dulbecco's minimum essential me dium containing 0.2% albumin, 0.01% trypsin inhibitor, Aprophen and 0.09% theophylline, aerated with 100% O2, and diluted 1:5 before use. Viability test by trypan blue As indicated by the results in the Table below, azapro exclusion was greater than 99%. Dispersed acini were phen showed much greater anticholinergic activity in incubated with varied doses of azaprophen and the guinea-pig ileum antimuscarinic assay than atropine, 1X 10.5M carbachol in 0.5 ml of incubation medium. benactyzine, and aprophen. o-Amylase secreted from the acini was determined as It is well established that activity in the guinea-pig 65 described by J. D. Gardner, et al., in "Regulation of ileum antinuscarinic assay correlates with in vivo anti Amylase Release From Dispersed Pancreatic Acinar cholinergic activity. All presently used drugs show Cells', J. Physiol, Vol. 270, pages 439-454, (1977) using high activity in this screen. The activity of azaprophen the Phadebas kit (Pharmacia) diluted 1:2. The Iso, the 4,713,391 7 8 concentration of azaprophen required for 50% inhibi pionic acid (4.64 g, 0.019 mol) and thionyl chloride. tion was calculated by a computer program ALLFIT, After stirring overnight at 25 C., the precipitate was as described by P. J. Munson, et al., in "Computer Mod separated by filtration and washed with dry THF. The eling of Several Ligands Binding to Multiple Recep residue obtained on evaporation of the solvents from tors', Endocrinology, Vol. 105, pages 1377-1381, (1979). the filtrate was dissolved in CH2Cl2 (50 mL) and washed with 5% NaHCO3 solution and saturated so RESULTS dium chloride solution, and dried (Na2SO4). The resi FIG. 1 shows the inhibition of the ACh-induced con due on evaporation was chromatographed on silica gei traction of guinea pig ileum by azaprophen. The pa2 is (200 g) using CHCl3:MeOH:NH4OH (80:18:2) as eluant 10.4 (KB=3.9x10-11M), which is 50 to 2350 times 10 to give 4.51 g (66%) of pure free base as a waxy solid. more potent than aprophen, benactyzine, atropine, 1H NMR (CDCl3)61.96 (s, 3, CH3), 2.11 (s, 3, NCH3), QNB and adiphenine as setforth in the Table. FIG. 2 5.22 (t, 1, >CHO-), 7.12-7.38 (aromatics). shows the inhibition of the carbachol-induced release of The hydrogen chloride salt was prepared by treating -amylase from pancreatic acini cells. The ISO is the above free base with a solution of 3% HCl in dry 6.8x10-11M, which is 30 to 5,000 times lower than 15 MeOH. Recrystallization of the solid obtained from aprophen, benactyzine and QNB, and 10 times better EtOAc/ET2O gave 3.60 g (48%) of azaprophen: mp than atropine. A comparison of the particular potencies 187-191 C. 1H NMR (CDCl3)61.97 (s, 3, CH3), 2.12 of azaprophen with other known antimuscarinic agents (d, 3, NCH3), 2.47 (d, 2, NCH2), 5.35 (m, 1, CHO), is summarized in the Table. 7.12-7.63 (ArH). EXAMPLE Anal. Calcd for C23H27NO2.HCl: C, 71.58; H, 7.31; This working example setforth below illustrates the N, 3.63. Found: C, 71.64; H, 7.32; N, 3.62. preparation of a representative composition, but in no 6-Methyl-6-azabicyclo3.2.1]octane-3a-ol Benzilate way limits the scope of this invention. Fumarate 6-Methyl-6-azabicyclo3.2.1]octane-3-a-ol 25 To a stirred solution of 423 mg (3 mmol) of 6-methyl 2,2-diphenylpropionate Hydrochloride (Azaprophen) 6-azabicyclo3.2.1]octane-3-ols in 30 mL acetone was Azaprophen and the benzilate ester of 6-methyl-6- added 417 mg (1.5 mmol) benziloyl imidazole (prepared azabicyclo3.2.1]octane-3-a-ol were synthesized from from benzylic acid and carbonyl diimidazole). After 6-methyl-3-oxo-6-azabicyclo 3.2.1 octane as shown in 30 stirring overnight at 25 C, the residue obtained on ... the previously mentioned "Chemical Reaction Se evaporation was placed on a silica gel (100 g) column quence For Preparing Azaprophen'. The ketone was and eluted with a solvent mixture of CHCl3:MeOH:N- reduced to a mixture of isomeric alcohols with H4OH (80:18:2) to give 200 mg (38%) of free base. aluminum hydride. The mixture was treated A solution of the free base in MeOH (1 mL) was with 2,2-diphenylpropionyl chloride or benziloyl imid 35 treated with fumaric acid (33 mg) in 1 mL of MeOH, azole to give a mixture of esters. The desired products diluted with and cooled. The fumarate salt crys were obtained as a waxy solid which were purified as tals were separated by filtration, washed with ether, and salts and were characterized by elemental and spectral dried to give 153 mg (35%) of product: mp 204-205 C. analysis. 1H NMR (CDCl3)62.61 (s, 3, NCH3), 3.45 (s, 3, CH3OH), 5.22 (t, 1, d. CHO-), 6.58 (s, 1, -CH= EXPERIMENTAL CH-), 7.15-7.58 (aromatics). 6-Methyl-6-azabicyclo3.2.1]octane-3-ols Anal. Calcd for C22H25NO3.HOOCCH=CH To a suspension of 10.0 g of LiAlH4 in 500 mL dis COOH, CH3OH: C, 68.01; H, 7.08; N, 3.17. Found: C, tilled THF was added a solution of 6-methoxy-3-oxo-6- 68.06; H, 7.10; N, 3.15. azabicylos.2.1]octane (11.6 g., 0.083 mol) in 150 mL. 45 THF dropwise, and the resulting mixture was heated to UTILITY reflux for 2 hours. The excess of LiAlH4 was destroyed Compositions of this invention represented by a com by careful addition of a 20% solution of sodium potas pound such as azaprophen and pharmaceutical compo sium tartrate, and the mixture was extracted with sitions thereof have been found to exhibit extremely CH2Cl2. The CH2Cl2 solution was washed with a satu 50 potent antimuscarinic activity. rated solution of NaCl, dried (Na2SO4), and evaporated As previously disclosed herein, applicants have deter to give 10.0 g (85%) of 6-methyl-6-azabicyclo[3.2.1]oc mined, for example, that azaprophen is 10 to 5,000 times tane-3-ols. NMR (CDCl3)62.40 (d, 2, NCH2), 2.42 (s, 3, more potent as an antinuscarinic agent than other com NCH3), 4.1 (m, 1, HC-OH). pounds known to be used for this purpose. Additionally, The hydrogen chloride salt was prepared by adding a 55 utilities for these compositions include (1) antidotes for 3% solution of HCl (gas) in dry methanol to a solution organophosphate poisoning, (2) coronary insufficiency, of alcohol (250mg) in MeOH. The analyical sample was (3) cerebral vasospasms; (4) endarteritis, (5) spastic coli recrystallized from MeOH/Et2O to give 108 mg of pure tis, (6) renal and hepatic colic, (7) peptic ulcer, (8) cho product: mp 246-247 C. (dec). lecystitis, (9) dysmenorrhea, and (10) exytocic agents. Anal. Calcd from C8H15NO.HCl: C, 54.08; H, 9.08; These compositions may be used as medicaments, for N, 7.88. Found: C, 53.94; H, 9.09; N, 7.80. example, in the form of pharmaceutical preparations, which contain such compounds together with pharma 6-Methyl-6-azabicyclo[3.2.1]octane-3a-ol ceutically acceptable, organic or inorganic, solid or 2,2-Diphenylpropionate Hydrochloride (Azaprophen) liquid excipients which are suitable for systemic, for To a stirred solution of 5.5 g (0.039 mol) of isomeric 65 example, oral, or parenteral administration. Moreover, 6-methyl-6-azabicyclo3.2.1]octane-3-ols in dry THF at these preparations may, be in the solid form, for exam 0-5C. was added dropwise a solution of 2,2-diphenyl ple, as tablets, dragees or capsules, or in liquid form, for propionyl chloride prepared from 2,2-diphenylpro example, as solutions, suspensions or emulsions. They 4,713,391 9 10

may contain auxiliary substances, such as preservatives, R stabilizers, wetting agents or emulsifiers, salts for con N trolling the osmotic pressure, buffers, dye stuffs or fla- 5 CH2 voring substances. The pharmaceutical preparations, O R2 II which may be formulated by methods which are them Omc-C selves known, may also contain other therapeutically 10 R1 valuable substances. wherein R represents lower alkyl groups having 1 to 7 carbon atoms; R represents hydrogen, phenyl, cyclo TABLE hexyl, and cyclopentyl; and R2 represents lower alkyl Antimuscarinic Activity of Azaprophen and Standard 15 groups having 1 to 7 carbons, hydroxymethyl, and hy droxyl; and pharmaceutically acceptable acid addition Anticholinergic Compounds salts thereof. Guinea pig Pancreatic acini 2. The compound of claim 1 wherein R is selected from the group consisting of methyl, ethyl and propyl. ileum contraction a-amylase release 20 3. The compound of claim 2 wherein R and R2 are Compound pA2 Value KB (M) I50 (M) methyl and R is phenyl. 4. The compound of claim 2 wherein R and R2 are Azaprophen 10.4 - 0.4 3.9 x 10. 6.8 x 101 - 2.4 ethyl and R is phenyl. 5. The compound of claim 2 wherein R is methyl and Aprophen 8.5 - 0.1 3.1 x 10-9 1.1 x 108 - 0.2 25 R2 is ethyl and R1 is phenyl. Adiphenine 7.1 - 0.3 9.2 x 10-8 3.5 x 10-7 - 0.3 6. The compound of claim 2 wherein R is ethyl and Benactyzine 8.2 + 0.8 6.5 x 10-9 3.0 x 108 - 0.5 R2 is methyl and R1 is phenyl. 7. A method for the treatment or prophylaxis of Atropine 8.7 - 0.1 2.0 x 10-9 5.9 x 10-10-5.7 nerve gas poisoning comprising administering, to an QNB 8.7 - 0.9 2.0 x 10-9 2.1 x 10-8- 06 30 animal, an anticholinergic amount of a compound of claim 1. 8. The method of claim 7 wherein the administration The symbols pa2 represent the antagonistic activity is effected prior to poisoning. 9. The method of claim 7 wherein the administration and the symbols QNB represent quinuclidinyl benzyl-35 is effected subsequent to poisoning. ate. 10. The method of claim 7 wherein R and R2 are selected from the group consisting of methyl, ethyl and We claim: propyl. 11. The method of claim 10 wherein R and R2 are 1. An azabicycloalkane phenyl substituted alkane 40 methyl. carboxylate compound having the formula k k k it

45

50

55

65