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United States Patent (19) 11 Patent Number: 4,713,391 Chiang Et Al

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United States Patent (19) 11 Patent Number: 4,713,391 Chiang Et Al 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 anticholinergic agents in (73) Assignees: The United States of America as the treatment or prophylaxis of organophosphate 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 ACETYLCHOLINE (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 atropine, benactyzine, and AZABICYTLOALKANEPHENYL SUBSTITUTED aprophen are potentially good candidates for therapeu ALKANE CARBOXYLATES, THEIR tically useful drugs. 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 drug-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 cholinesterase 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 cholinergic 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 carbachol. 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
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