DIBENZOFURANCARBOXAMIDES

Abstract: This invention is directed to certain dibenzofurancarboxamides and their use as 5HT3 antagonists having unique CNS, anti-emetic and gastric prokinetic activity void of any significant D2 receptor binding properties. This invention also describes novel processes necessary for their preparation.

Description: DIBENZOFURΛNCΛ BOXΛMIDES Field of the Invention This invention is directed to certain specific novel chemical compounds and their valuable use as pharmaceutical agents as 5HT 3 antagpniεts having unique CNS, anti-emetic an gastric prokinetic activity void of any significant D 2 receptor binding properties . This invention also describes novel processes necessary for their preparation, separation and purification. Summary of t-.hp. invention This invention relates to the compounds described by general Formula I and to therapeutic compositions comprising as active ingredient a compound of Formula I : FORMULA! where R x is hydrogen, araino or alkylamino, halo? R 2 is hydrogen, halo, εulfamyl, alkylεulfarπyl or alk lsulfonyl; R' is hydrogen or alkyl or together with a vicinal R' group may form 'double bond; and R is . ~<Ξ> and pharraaceutically acceptable salts thereof . The following nomenclature is used in the description of this invention. which refers to saturated, partially saturated and unsaturated compounds described herein. Preferred compounds of this invention include those compounds of Formulae II, III and IV. where R t and R 2 are as described above and R is Preferred compounds include those of Formulae II, III and IV where l is amino or loweralkyla ino and R2 is hydrogen; R l is hydrogen and R2 is halo, or Rl is amino and R 2 is halo. The more preferred compounds include those of Formula II and especially where halo is chloro or bromo and loweralkyl is methyl. The most preferred compounds include those compounds of Formula II where R is TS ) I • ' n< i ts εtereoiεomers, enantiomers, diastereoisomers and racemic mixtures. The present compounds may be prepared by the following general procedure. Condensation of a substituted dibenzofuran-4-carboxylic acid or a 6 ,7 , 8 ,9-tetrahydrodibenzofuran-4-carboxylic acid or a 5a, 6,7 , 8 , 9 ,9a-hexahydrodibenzofuran-4-carboxylic acid or their acid halides or esters with an amine of the formula H2N-R results in the corresponding carboxamide. In general this reaction may be carried out at decreased temperatures, such as 0°C by adding ethyl chlorofor ate to a reaction mixture of the acid in chloroform in the presence of triethyla ine. This is then reacted with the amine of the formula H 2 N- to obtain the desired product. Condensation may also be carried out in the presence of a dehydrating catalyst such as a carbodiimide in a solvent at normal temperatures. The most preferred compounds may be prepared by reacting the Ri and R2 substituted 5a,6,7,8,9,9a-hexahydrodibenzo- furan-4-carboxylic acids, acid halides or esters with 3-aminoquinuclidine to obtain Ri and R2 substituted 5a,6,7,- 8 ,9 ,9a-hexahydrodibenzofuran-4-[N-(1-azabicyclo[2.2.2.]octan- 3-yl) ]carboxamides. This reaction may take place with optically pure starting materials such as the acid or amine which have a specific configuration to obtain the desired εtereospecific amide. Further, the amide may be formed as above and then separated by known techniques into the desired stereoisomers. Preparation and separation will be described in more detail later in this application. The starting materials, that is the substituted dibenzo- furan-4-carboxylic acids, 6,7,8,9-tetrahydrodibenzofuran-4- carboxylic acids and the 5a,6,7,8,9,9a-hexahydrodibenzofuran 4-carboxylic acids are also novel. They may be prepared by the following reaction schemes: Salicylic acid is first esterified and then the phenol(2) is treated with 3-bromocyclohexene under basic conditions in a polar medium to obtain the phenyl cyclohexenyl ether(3) . Claisen rearrangement at high temperature results in the methyl 3-(3'-cyclohexene)εalicy- late(4). Ring closure using trifluoroacetic acid results in the formation of the 5a,6,7,8,9,9a-hexahydrodibenzofuran ring(5).. This may then be hydrolyzed to the acid(6) with aqueous base. When the 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxyl- ate(5) is oxidized with DDQ, dichlorodicyanobenzoquinone, the resultant double bond of the furan ring is formed to obtain 6,7,8,9-tetrahydrodibenzofuran-4-carboxylate(7) . Excess DDQ can result in the dibenzofuran-4-carboxylate produσt(β) . Dehydrogenation of 6,7,8,9-tetrahydrodibenzofuran-4-car- boxy].ate(7) with palladium on carbon catalyst at raised temperatures (230-240°C) results in the dibenzofuran-4-car- oxylate(B) . Deesterification of the esters 7 and 8 may be carried out with aqueous base, as above. r- . I. Oo.> When R 2 substitution is desired the above reactions may be carried out starting with the proper 5-substituted salicylic acid. Thus the following reaction sequences may take place as above. When R2 substitution is halo the above reaction sequence may be carried out starting with 5-halo salicyclic acid. In the case where is εulfamyl it is best that this group be protected initially with an acetyl group on the like and then deacetylated. When i is an amine function this also should be protected with an acetyl group or the like and then deacetylated after the dibenzofuran ring system has been formed. Treatment of a 4-amino or 4-alkylamino salicylic acid with MeOH/HCl followed by acetylation with acetyl chloride in pyridine in the usual manner results in the 4-acetylamino or 4-acetylalkylaminosalicylateε(14) . De ethylation of the alcohol and ester is then carried out using boron tribromide in a non polar solvent to obtain the 4-acetylamino or 4-acetylalkylaminosaliσylic acids(15). Esterifiσation .is accomplished with diazomethane as before and the resultant ester is used in a similar manner as above to obtain the desired 1-amino or alkylamino dibenzofuran-4-carboxylic acid compounds(18, 21, and 24) 24 where R is H or alkyl In a similar manner, when R x and R 2 are both substituted with groups other than hydrogen the following reaction sequences are possible to obtain compounds 27, 30 and 33. 33 When it is desired to have R f substitution of lower alkyl then a suitable starting material should be used. Thus for example if the final product desired is l-amino-2-chloro-8-methyl-5a,6,7,8,9,9a- hexahydrodibenzofuran-4-carboxylic acid(34) then 3-bromo-5-methylcyclohexene should be used as reagent in place of 3-bromocyclohexene. Following the above sequence of steps the final product would be In a similar manner other compounds having R' substitution may be prepared. When the 4-carboxylic acids 6, 9 and 10 are treated with N-chlorosuccinimide or N-bromo- succinimide in a polar medium (DMF) at room temperature, the resulting halogenated products 11, 12 and 13 are formed. 12 where X is cloro or bromo . -15- Halogenation may also be carried out en the 1-acetylamino compounds of the esters 16, 19 and 22. Halogenation occurs in the 2-position. When these halogenated products are treated with base as, above, hydrolysis gives the desired l-amino-2-halo-4- carboxylic acids 27, 30 and 33 of this invention. Certain compounds of this invention have at least one asymmetric carbon atom such aε the 5a,6,7,8,9,9a-hexahydro- dibenzofuran compounds or those compounds wherein at least one R' is other than hydrogen or still those compounds where the R group contains an asymmetric carbon atom. Further, certain compounds of this invention may exist in their cis or trans configuration with respect to the dihydrofuran ring. As a result, those compounds of Formula I may be obtained either as racemic mixtures, diastereoiεomeric mixtures or aε individual enantiomers. When two or three asymmetric centers are present the product may exist as mixtures of two or four diastereomers. Of course it is understood that certain other compounds within the scope of this invention could have a number of εtereocenterε. In general, a compound with x stereocenters can have a maximum of 2 X stereoisomers. Therefore, a compound having three such centers gives rise to a maximum of eight stereoisomers, while one having four produces sixteen, etc. The product may be synthesized as a mixture of the isomers and then the desired iεomer separated by conventional techniques such aε chromatography or fractional crystallization from which each diaεtereomer may be resolved. On the other hand, εyntheεis may be carried out by known stereospecific proceεses using the desired form of the intermediate which would result in obtaining the desired stereospecificity. In the case where R contains an asymmetric carbon atom it is convenient to carry out condensation of 5a,6,7,8,9,9a- hexahydrodibenzofuran-4-carboxylic acid with 3-amino-l-azabi- cyclo[2.2.2.]octane or the like using the optically pure materials. Thus, the hexahydrodibenzofuran-4-carboxylic acid is resolved prior to condensation with resolved 3-aminoquinu- clidine. As a reεult, one can obtain the desired εtereospecific compound. For example, resolution of 3-aminoquinuclidine resultε in S(-)3-aminoquinuclidine and R(+)3-aminoquinucli¬ dine. When S(-)3-aminoquinuclidine is reacted as above with the S,S configuration of 2-chloro-cis-5a,6,7,8,9,9a-hexahy- drodibenzofuran-4-carboxylic acid then the product obtained is 4-[N-(l-azabicyclo[2.2.2.]octan-3(S)-yl) ]-2-chloro-cis- 5aS,6,7,8,9,9aS-hexahydrodibenzofurancarboxamide. In a similar manner the remaining various stereospecific compounds may be prepared by reacting S(-)3-aminoquinuclidine or R(+)3-aminoquinuclidine with the cis S,S or cis R,R configuration or the trans R,S or trans S,R configuration of 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid, acid halide or ester. The remaining compounds of Formula I may so be prepared. More specifically, and to illustrate the scope of this invention, one of the most preferred compounds of this invention, i.e., 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzo- furan-4-[N-(l-azabicyclo[2.2.2.]octan-3-yl) ]carboxamide, has three asymmetric centers. These are at the 5a and 9a positions of the furan ring and at the 3 position of the quinuclidine moiety. Condensation of racemic 2-chloro-5a f - 6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid and racemic 3-aminoquinulidine as above resultε in the εtereoiεomeric mixture of 4-[N-(l-azabicyclo[2.2.2.]octan- 3-yl) ]-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofurancarbox- amideε. Such a mixture can exist as a single entity having its own chemical, physical and pharmacological properties and lies within the scope of the present invention. This mixture consists of eight individual stereoisomers having unique absolute configurationε. Each of theεe εtereoiεo ers also has its own chemical, physical and pharmacological properties and lies within the scope of this invention. The stereoiεo eric mixture can be divided into ciε and trans configurations having their own specific properties and are also within the scope of this invention. The cis configuration has four cis stereoisomers consisting of two racemates and two diastereoisomeric mixtures. The same is true of the trans configuration. The cis and trans racemates and diastereoisomeric mixtures can also be considered to be separate entities becauεe of their unique chemical, phyεical and pharmacological properties and are further included within the scope of this invention. The following chart illustrates these various compounds and is illustrated to be representative of the compounds of this invention. -19- IS B Compounds a through h are individual stereoisomers. Together they form a stereoiεo eric mixture which we call A. Compounds a through d are individual ciε εtereoisomers and together form a cis stereoisomeric mixture which we call B. Compounds a and b together and c and d together are cis racemates which we call D and E. Compounds a and c and b and d are individual cis diastereomers and together form cis diaεtereo eric mixtures called F and G. Compounds e through h show the corresponding trans products H, J, and L. The resolution of the compounds of this invention and their starting materials may be carried out by known procedures. Incorporation by reference is hereby made to the four volume compendium Optical Resolution Procedures for Chemical Compounds: Optical Resolution Information Center, Manhattan College, Riverdale, New York. Such procedures are useful in the practice of thiε invention. A further useful reference is Enantiomers, Racemates and Resolutions: Jean Jacques, Andre Collet and Samuel H. Wilen; John Wiley & Sons, Inc., New York, 1981. Basically, the resolution of the compounds is based on the differences in the physical properties of diastereomers. Conversion of the racemates into a mixture of diastereomers by attachment of an enantiomerically pure moiety resultε in forms that are separable by fractional crystallization, distillation or chro otography. One example of such resolution involves the separation of 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carbox¬ ylic acid into itε enantiomerε using α-methylbenzylamine as the resolving agent. Further if racemic 3-aminoquinuclidine is converted to a benza ide derivative it can also be separated into its enantiomers using chiral HPLC. The benzamidε is hydrolyzed to the amine. The desired resultant resolved products may then be coupled as desired to obtain the amide. The compounds of this invention may be readily converted to their non-toxic acid addition salts by customary methods in the art. The non-toxic salts of this invention are those salts the acid component of which is pharmacologically acceptable in the intended dosages, including those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and from organic acids such as methane εulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, maleic acid, oxalic acid, εucciήic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, abietic acid, etc. We have found that the compounds of this invention have gastric prokinetic and anti-emetic properties and lack D2 receptor binding activity. As such they possess therapeutic value in the treatment of upper bowel motility and gastroesophageal reflux disorders. Further, the compounds of this invention may be useful in the treatment of disorders related to impaired gastrointestinal motility such as retarded gastric emptying, dyspepsia, flatulence, aosophageal reflux, peptic ulcer and e eεiε. The compounds of this invention exhibit 5-HT3 antagonism and are considered to be useful in the treatment of psychotic disorders such as schizophrenia and anxiety and in the prophylaxis treatment of migraine and cluster headaches. We have further found that these co punds are selective in that they have little or no dopa inergic antagonist activity. Various tests in animals can be carried out to show the ability of the compounds of this invention to exhibit pharmacological responεeε that can be correlated with activity in humans. These tests involve such factors as the effect of the compounds of Formula I on gastric motility, emesis, selective antagonism of 5-HT 3 receptors and their D 2 dopamine receptor binding properties. It has been found that the compounds of this invention when tested in the above variety of situation show a marked activity. One such test is the "Rat Gastric Emptying: Amberlite Bead Method". This test is carried out as follows: The test is designed to asεess the effects of a test agent on.gastric emptying of amberlite beads in the rat. The procedure is a modification of those used in L.E. Borella an W. Lippman (1980) Digestion 20: 26-49. Procedure Amberlite© beads are placed in a phenol red solution and allowed to soak for several hours. Phenol red serves as an indicator, changing the beads from yellow to purple as their environment becomes more basic. After soaking, the beads are rinsed with 0.1 NaOH to make them purple and then washed with deionized water to wash away the NaOH. The beads are filtered several times through 1.18 and 1.4 mm sieves to obtain beads with diameters in between these sizes. This is done using..large quantities .of deionized water. The beads are stored in saline until ready to use. Male Sprague-Dawley rats are fasted 24 hours prior to the study with water ad libitum. Rats are randomly divided in treatment groups with an N of 6 or 7. Test agents are prepared in 0.5% methylcellulose and administered to the rats orally in a 10 ml/kg dose volume. Control rats receive 0.5% methylcellulose, 10 ml/kg p.o. One hour after dosing, rats are given 60 Amberlite© beads intra- gastrically. The beads are delivered via a 3 inch piece of PE 205 tubing attached to a 16 gauge tubing adapter and syringe. A small piece of PE 50 tubing is placed inside the tubing adapter to prevent the beads from being pulled back into the syringe. The beads are flushed into each rat's stomach with 1 ml saline. Rats are sacrificed 30 minutes after receiving the beads and their stomachs are removed. The number of beads remaining in each stomach is counted after rinsing the beads with NaOH. The number of beads remaining in each stomach is subtracted from 60 to obtain the number of beads emptied. The mean number of beads ± S.E.M. is deter¬ mined for each treatment group. The percent change from control is calculated as follows: Mean Control Group - Mean Test Agent Group Mean Control Group x lϋ0 Statistical significance may be determined using a t-test for independent samples with a probability of 0.05 or less considered to be significant. In order to demonstrate the ablity of the compounds of this invention as anti-emetic agents *the following test for "Cisplatin-Induced Emesis in the Ferret" may be used. This test is a modified version of a paper reported by A. P. Florezyk, J. E. Schurig and W. T. Brodner in Cancer Treatment Reports: Vol. 66, No. 1. January 1982. Cisplatin had been shown to cause emesis in the dog and cat. Florezyk, et al. have used the ferret to demonstrate the same effects. Procedure Male castrated. Fitch ferrets, weighing between 1.0 and 1.5 kg have an indwelling catheter placed in the jugular vein. After a 2-3 day recovery period, the experimental procedure is begun. 30 minutes prior to administration of cisplatin, ferrets are dosed with the compound in 0.9% saline (i.v.) at a dose volume of 2.0 ml/kg. 45 minutes after administration of cisplatin, ferrets are again dosed with the 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg. Cisplatin is administered (i.v.) 30 minutes after the first dosing with the 0.9% saline. Cisplatin, lb mg/kg is administered in a dose volume of 2.0 ml/kg. The time of cisplatin administration is taken aε time zero. Ferrets are observed for the duration of the experiment (4 hours). The elapsed time to the first emetic episode is noted and recorded, as are the total number of periods of emesis. A n emetic (vomiting) episode is characterized by agitated behavior, such as pacing around the cage and rapid to and fro movements. Concurrent with this behavior are several retching movements in a row, followed by a single, large, retch which may or may not expulse gastric contents. Immediately following the single large retch, the ferret relaxes. Single coughs or retches are not counted as vomiting episodes. D-2 Dopamine Receptor Binding Assay The D-2 dopamine receptor binding assay has been developed with slight modifications using the method of Ian Cresse, Robert Schneider and Solomon H. Snyder, Europ. J. Pharmacol. 46: 377-381(1977). Spiroperidol is a butyrophenone neuroleptic whose affinity for dopamine receptors in brain tissue is greater than that of any other known drug. It is a highly specific D-l dopamine (non-cyclase linked) receptor agent with K, values of 0.1-0.5 for D-2 inhibition and 300 nM for D-l inhibition. Sodium ions are important regulators of dopamine receptors. The affinity of the D-2 receptor is markedly enhanced by the presence of millimolar concentrations of sodium chloride. The Kd in the absence and presence of 120 mM sodium chloride is 1.2 and 0.086 nM respectively. Sodium chloride (120 mM) is included in all assays as a standard condition. The caudate nucleus (corpus striaturft) is used as the receptor source because it contains the highest density of dopamine receptors in the brain and periphery. Procedure Male Charles-River rates weighing 250-300 g are decapitated and their brains removed, cooled on ice, and caudate dissected immediately and frozen on dry ice. Tissue can be stored indefinitely at -70°C. For ' assay caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25°C) using the poly ron homo- genizer. The homogenate is centrifuged at 40,000 g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet is resuspended in fresh buffer and centrifuged again. The final pellet is resuspended in 150 volumes of assay buffer. 3 Specific H-spiroperidol binding is assayed in a total 2 ml reaction volume consisting of 500 μl of caudate homogenate, 50 mM tris buffer (pH 7.4 at 35°C), 5 mM MgSO., 2 mM EDTA«2NA, 120 mM NaCl, 0.1% 4 ascorbic acid, o.4 nM H-spiroperidol and test compound or assay buffer. When catecholaraines are included in the assay, 10 μM pargyline should be included in the reaction mixture to inhibit monoamine oxidase. Samples are incubated at 37°C for 30 minutes followed by addition of 5 ml ice cold 50 mM TRIS (pH 7.7 at 25°C) and filtration through GF/B glass fiber filters on a Brandel Receptor Binding Filtration apparatus. Filters are washed twice with an additional 5 ml of tris buffer each. Assay groups are performed in triplicate and 1 μM d(+) butaclamol is used to determine nonspecific binding. Filters are placed in vials containing 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpm determined by liquid scintillation spectrophoto etry using a quench curve. Proteins are determined by the method of Bradford, M. Anal. Biochem 72, 248(1976) using Bio- Rad's coo assie blue G-250 dye reagent. Bovine gamma globulin supplied by BIO-RAD is used as the protein standard. Bezold-Jarisch effect in anaesthetized rats Male rats 260-290 g are anaesthetized with urethane 1.25 g/kg~ i.p., and the trachea cannulated. The jugular vein is cannulated for intravenous (i.v.) injection of drugs. Blood pressure is recorded from a cannula in the left carotid artery and connected to a haparin/saline- filled pressure transducer. Continuous heart rate measurements are taken from the blood pressure recordings. The Bezold-Jarisch effect is evoked by rapid, bolus i.v. injections of 5-HT and measurements are made of the fall in heart rate. In each rate, consistent responses are first established with the minimum dose of 5-HT that evokes a clear fall in heart rate. Injections of 5-HT are given every 12 minutes and a dose-response curve for the test compound is established by injecting increasing doses of compound 5 minutes before each injection of 5-HT. The effect, of the compound on the 5-HT-evoked brady- cardia is calculated as a percent of the bradycairdia evoked by 5-HT before injection of compound. In separate experiments to measure the duration of 5-HT antagonism caused by the compounds of this invention, a single dose of compound is injected 5 minutes before 5-HT, and the effects of 7 repeated challenges with 5-HT are then monitored. The effects of the compound on the efferent vagal limb of the Bezold-Jarisch reflex are checked by electrically stimulating the. eripheral end of a cut vagus nerve. Unipolar electrical stimulation is applied every 5 minutes via a pair of silver electrodes, using 1 ms rectangular pulses in 5 s trains with a maximally- effective voltage (20 V at 10 Hz). Pulse frequency may vary from 5-30 Hz and frequency-respnse curves are constructed before and 10 minutes after i.v. injection of a single dose of compound. The resultε of these above tests indicate that the compounds for this invention exhibit a valuable balance between the peripheral and central action of the nervous system and may be useful in the treatment of disorders related to impaired gastro-intestinal motilitv such as gastric emptying, dyspepsia, flatulence, esophogeal reflux and peptic ulcer and in the treatment of disorders of the central nervous system such as psychosis. The compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally. Parenteral administr¬ ation in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, trans- epthelially including transdermal, op halmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic. The active compound may..be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or>it may be compressed into tablets, .or it τπay be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipient and used in the form of ingeεtibel tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preprations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 6% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparationε according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg cf active compound. The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelating; excipients such as dicalcium phosphate; a disinte¬ grating agent such as corn starch, potato starch, lginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharma¬ ceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release pre¬ parations and formulations. The active compound may also be administered parenterally or intraperiotoneally. Solutions of the active compound as a free base cr pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactanc such as hydroxypropyl- cellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures • thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a pre¬ servative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous prepara¬ tion of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy εyringability.existε. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganiεms such as bacteria and fungi. The carrier can be a solvent or dispersion-medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimersal, and ' the like. In many cases. SUBSTITUTESHEET it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged, absorption of the injectable compositions of agent delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, .dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the pre¬ paration of sterile injectable solutions, the preferred methods of preparation are vaccum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof. The therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharma¬ ceutical practice. The physician will determine the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment and will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small • dosages by small increments until the optimum effect under the circumstances is reached. The therapeutic dosage will generally be from 0.1 to 20 mg or from about 0.01 mg to about 50 mg/kg of body weight per day and higher although it may be administered in several different dosage units from once to several times a day. Higher dosages are required for oral administration. The compounds of the present invention may be prepared by the following representative examples . EXAMPLE 1 METHYL 5-CHLOROSALICYLATE To a cold solution of 100 ml methanol is slowly added 100 ml thionyl chloride followed by 30 g of 5-chlorosalicylic acid. This is then refluxed overnight, the solvent removed and the residue dissolved in ether. The ether is washed with a sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated to dryness to obtain methyl 5-chlorosalicylate which is used directly in the next step. EXAMPLE 2 METHYL 2-(CYCLOHEXEN-3-YLOXY)-5-CHLOROBENZO TE A mixture of 18.6 g of methyl 5-chloro¬ salicylate, 28 g of K~C0 3 and 20 g of 3-bromo- cyclohexene in 200 ml of DMF is stirred at 90°C overnight. The mixture is then poured into water, extracted with ethyl acetate, washed with wciter, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step. EXAMPLE 3 METHYL 3-(3-CYCLOHEXENYL)-5-CHLOROSALICYLATE Methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzonate (4.5 g) is heated to 210°C for 3 hours. The residue is dissolved in hexane and purified by flash chromatography using first hexanes as eluent and then 5% ethyl acetate/hexane to give pure methyl 3-(3-cyclo hexenyl)5-chlorosalicylate. This is used directly in the next step. EXAMPLE 4 METHYL 2-CHLORO-5a,6,7,8,9,9a-HEXAHYDRODIBENZOFURAN- -CARBOXYLATE A mixture of 2.2 g of methyl 3-(3-cyclohexenyl)-5- chlorosalicylate and 5 ml of trifluoroacetic acid are stirred at room temperature overnight. The acid is removed under vacuo and the residue diluted with ether, washed with sodium bicarbonate solution, then water and dried over magnesium sulfate and evaporated to dryness to give -an oily product. Purification by flash chromatography using hexane as eluent gives first unreacted starting material and then methyl 2- chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxy¬ late. This is used directly in the next step without further purification. EXAMPLE 5 2-CHLORO-5a,6,7,8,9.9a-HEXAHYDRODIBENZOFURAN-4- CARBOXYLIC ACID A mixture of 1.6 g of methyl 2-chlαro-5a,6,7, 8,9,9a-hexahydrodibenzofuran-4-carboxylate in 10 ml of methanol and 20 ml of IN sodium hydroxide is stirred at 50°C for 6 hours. This is cooled, the methanol is removed under vacuo, diluted with 30 ml water and filtered. The aqueous solution is acidified with acetic acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to give crystalline product which is used directly in the next step. EXAMPLE 6 2-CHLORO-5a,6,7,8.9.9a-HEXAHYDRODIBENZOFURAN-4-(N-l- AZABICYCLO[2.2.2. ]OCT-3-YL)CARBOXAMIDE To a cold solution of 1.3 g of 2-chloro-5a,6,- 7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 ml of chloroform is added 0.8 g of triethylamine at room temperature. To this is added 0.7 g of ethylchloroformate in 10 ml of chloroform and stirring continued for 1-1/2 hours. This is added in one portion to a mixture of 15 g K-CO- in 25 ml water containing 5 g of 3-aminoquinuclidine dihydr - chloride. Stirring is continued overnight. The reaction mixture is diluted with 100 ml chloroform and the organic layer separated, washed twice with water, dried over magnesium sulfate and evaporated to dryness to give 1.2 g of oily product. The latter is purified by flash chromatography using 10% methanol/chloroform which results in pure 2-chloro- 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-( -1-azabicylo- [2.2.2. ]oct-3-yl)carboxylate. Calculated: C 64.95; H 7.08; N 7.57 Found: C 64.24; H 6.72; K 7.02 EXAMPLE 7 When 5-chlorosaiicylic acid is replaced in Example 1 with salicylic acid, 5-bromosalicylic acid or 5-methylsulfonylsalicylic acid then the products prepared following the procedures of Examples 1-6 are 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-l-aza- bicylot2.2.2.]oct-3-yl)carboxamide; 2-bromo-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-(N-l-azabicyclo[2.2.2.]- oct-3-yl)carboxamide; and 2-methylsulfonyl-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo[2.2.2.]- oct-3-yl)carboxamide. EXAMPLE 8 METHYL 2-METHOXY-4-AMINO-5-CHLOROBENZOATE To a solution of 50g of 2-methoxy-4-amino-5- chlorobenzoic acid in 500 ml of methanol is added HCl gas until all the material dissolves. Stirring is continued overnight, the solvent removed, ether added, filtered, dried over magnesium sulfate and evaporated to dryness to obtain methyl 2-methoxy-4- amino-5-chlorobenzoate which is used directly in the next step. EXAMPLE 9 METHYL 2-METHOXY- -ACETYLAMINO-5-CHLOROBENZOATE A mixture of 21 g of methyl 2-methoxy-4-amino-5- chlorobenzoate is stirred in 12 ml acetic anhydride and 100 ml acetic acid at 100 c c for 24 hours. The reaction mixture is filtered, diluted with water, filtered and evaporated to dryness to obtain methyl 2-methoxy-4-acetylamino-5-chlorobenzoate which is used directly in the next step. EXAMPLE 10 4-ACETYLAMINO-5-CHLOROSALICYLIC ACID To a mixture of 16 g of methyl 2-methoxy-4- acetylamino-5-chlcrobenzoate in 130 ml of methylene chloride is slowly added 100 ml of a methylene chloride solution of borontribromide (250 g BBr- per liter) and stirring continued for 24 hours. IN sodium hydroxide solution is then added until all material is dissolved. The two layers are separated and the aqueous layer is acidified with IN hydro¬ chloric acid, filtered, washed with water and evaporated to dryness to give 4-acetylamino-5-chloro- salicylic acid which is used directly in the next step. EX AMPLE 11 METHYL 4- CETY MINO-5-CHLOROS LICYL TE To a mixture of 5 g of potassium hydroxide, 8 ml water and 25 ml ethanol at 0°C (with no stirring) is slowly added a solution of 22 g Diazald in 200 ml ether. The combination of diazomethane in ether which is distilled over is cooled in an ice cold flask until the distillation is complete. To this solution is added 13 g of 4-acetylamino-5- chlorosalicylic acid in 150 ml THF. After 1/2 hour the excess diazomethane is decomposed by acetic acid and the mixture filtered to obtain crude methyl 4- acetylamino-5-chlorosalicylate. The filtrate is concentrated to obtain further product which is combined and used directly in the next step. EXAMPLE 12 METHYL 2-(CYCLOHEXEN-3-YLOXY)-4-ACETYLAMINO-5- CHLOROBENZOATE A mixture of 2.5 g methyl 4-acetylamino-5- chlorosalicylate, 2 g of 3-brσmocyclohexene, 2 g 2 C0 3 and 30 ml DMF are combined and heated at 110°C overnight. The reaction mixture is then poured into water, filtered, dried and then extracted into ether. The ether solution is treated with charcoal, filtered and evaporated to dryness to obtain methyl 2-(cyclo- hexen-3-yloxy)-4-acetylamino-5-chlorobenz.oate. This is then purified by recrystallization from ether/ hexane. (M.P. 100-102°C) EXAMPLE 13 METHYL 3-f3-CYCLOHEXENYLi-4-ACETYLAMINO-5-CHLOROSALICYLATE A mixture of 0.6 g of methyl 2-(cyclohexen-3-yloxy)-4- acetylamino-5-chlorobenzoate and 0.5 ml diethylamiline is placed under house vacuum and heated to 220 β C for 2 hours. This reaction mixture is then diluted with 40% ethyl acetate/hexane and purified by dry column chromatography us the same solvent system as eluent. Three fractions are separated: 1. diethylaniline; 2. starting benzoate compound; and 3. methyl 3-(3-cyclohexenyl)-4-acetylamino-5 chloroεalicylate. The latter iε used directly in the next step. EXAMPLE 14 METHYL l-ACETYLAMINO-2-CHLORO-5a.6,7.8.9.9a-HEXA- HYDRODIBENZOFURAN-4-CARBOXYLATE A mixture of 1.2 g of methyl 3-(3-cyclohexenyl)-4- acetylamino-5-chlorosalicylate and 5 ml trifluoroacetic aci are stirred at room temperature overnight. The acid is removed under vacuum and the residue diluted with ether, washed with sodium bicarbonate, then water, dried and evaporated to dryness to give crude methyl l-acetylamino-2- chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate. Thiε product iε purified by flash chro atograph using 10% ethyl acetate/hexane to give pure product. EXAMPLE 15 l-AMINO-2-CHLOR0-5a.6.7,8,9.9a-HEXAHYDRODIBENZOFURAN-4- CARBOXYLIC ACID To a solution of 0.3 g of sodium in 15 ml methanol is added 0.6 g of methyl l-acetylamino-2-chloro-5a,6,7,8,9,9a- hexahydrodibenzofuran-4-carboxylate. stirring is continued at 60 β C for two dayε. This iε then diluted with 5 ml IN sodium hydroxide and stirring continued at .60"C overnight. The methanol is removed in vacuum, diluted with water, filtered, acidified with acetic acid, filtered, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain l-amino-2-chloro- 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. This is purified by crystallization from ethyl acetate/ether. EXAMPLE 16 l-AMIN0-CHL0R0-5a.6.7.8.9.9a-HEXAHYDRODIBENZOFURAN-4- (N-l- AZABICYCLOf2.2.2.10CT-3-YL)CARBOXAMIDE To a cold solution of 0.3 g l-amino-2-chloro-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 ml chloroform is added 0.3 g of triethylamine and then 0.2 g ethylchloroformate in 10 ml chloroform. Stirring is continued for 2 hours. This is then added to a cold mixture of 3 g 3-amino-guinuclidine dihydrochloride in 20 ml water containing 7.5 g K 2 C0 3 . Stirring is continued overnight. The reaction mixture is then diluted with chloroform, the two layers separated and the chloro¬ form layer washed twice with water, dried over magnesium sulfate, filtered and evaporated to dryness to give l-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodi- ■ benzofuran-4- ( N-l-azabicyclo[2.2.2.]oct-3-yl)carboxamide as an oily product. Calculated: C 62.41; H 7.07; N 10.91 Found: C 62.84; H 7.00; N 10.63 EXAMPLE 17 When 2-methoxy-4-amino-5-chlorobenzoic acid is replaced in Example 8 with 2-methoxy-4-aminobenzoic acid; 2-methoxy-4-methylamino-5-chlorobenzoic acid; 2-methoxy-5-sulfamylbenzoic acid; or 2-methoxy-5- methylsulfamyl benzoic acid then the products pre¬ pared following the procedures of Examples 8-16 are l-amino-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N- 1-azabicylo[2.2.2.]oct-3-yl)carboxamide; 1-methy - amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (N-1-azabicyclo[2.2.2.]oc -3-yl)carboxamide; 2-sulfamyl-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (N-l-azabicyclo[2.2.2. ]oct-3-yl)carboxamide; or 2-methylεulfamyl-5a ,6,7,8,9,9a-hexahydrodibenzofuran- 4-(N-1-azabicyclo[2.2.2.]oct-3-yl)carboxamide. EXAMPLE 18 When 3-aminoquinuclidine dihydrochloride in Examples 6, 7 ,16 and 17 is replaced by the amines of Table I below, then the corresponding representa¬ tive carboxamides of Table II below are prepared. TABLE I 4-a ino-l-azabicyclo[ 3.3.1. ]nonane ■ " "• Φ 3-aminoguinuclidine which is 3-amino-l- azabicyclo[2.2.2. ]octane 4-amino-l-azabicyclo[ 2.2.2. ]octane <£> 3-amino-9-methyl-9-azabicylco[ 3.3.1. ] nonane 3-amino-7-oxo-9-methyl-9-azabicylo[ 3.3.1. ] onane l-(p-fluoroρhenoxypropyl)-3-methoxy-4-amino« piperidine TABLE II 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (1-azabicyclo[3.3.1.]non-4-yl)carboxamide 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (1-azabicyclo[2.2.2.]oct-4-yl)carboxamide 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (9-methyl-9-azabicyclo[3.3.1.]non-3-yl)carboxamide 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- (7-oxo-9-methyl-9-azabicylo[3.3.1. ]non-3-yl)carbox¬ amide 2-chloro-5a,6,7,8,9,9 -hexahydrodibenzofuran-4- (1-(p-fluorophenoxypropy1)-3-methoxy piperidin-4-y1)- carboxamide l-amino-2-chloro-5a,6,7 ,8,9,9a-hexahydrodibenzo- furan-4-(1-azabicyclo[3.3.1.]non-4-yl)carboxamide l-amino-2-chloro-5a,6,7,8,9,9a-hexahydrpdibenzo- furan-4-(1-azabicyclo[2.2.2.]oct-4-yl)carboxamide l-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzo- furan-4-(9-methyl-9-azabicyclo[3.3.1. ]non-3-yl)- carboxamide l-amino-2-chloro-5a ,6,7,8,9,9a-hexahydrodibenzo- furan-4-(7-oxo-9-methyl-9-azabicylo[3.3.1. ]non-3-yl)- carboxamide l-amino-2-chloro-5a,6,7,8,9 ,9a-hexahydrodibenzo- furan-4-(l-(p-fluorophenoxypropyl)-3-methoxy piperidin-4-yl)carboxamide EXAMPLE 19 When 3-bromocyclohexene of Examples 2 and 12 is replaced by 3-bromo-4-methylcyclohexene 3-bromo-5-methylcyclohexene 3-bromo-6-methylcyclohexene then the corresponding products are prepared follow¬ ing Examples 2-18. EXAMPLE 20 METHYL 1-ACETYLAMIN0-2-CHL0R0-6 .7 .8 , 9-TETRAHYDRODI- BENZOFURAN- 4 -CARBOXYLATE A mixture of 1 g methyl l-acetylamino-2-chloro- 5a , 6 , 7 , 8 , 9 , 9 a-hexahydrodibenzofuran- 4 -carboxylate and 1 g of dichlorodicyanoquinone in 15 ml of benzene is stirred and heated at 80 °C in a sealed tube for 8 hours . The cooled reaction mixture is then diluted with benzene , filtered and evaporated to dryness . Purification by recrystallization from ethyl acetate/hexane gives pure methyl l-acetylamino-2- chloro-6 , 7 , 8 , 9-tetrahydrodibenzof uran-4-carboxylate . EXAMPLE 21 METHYL l^ACETYLAMINO-2-CHLORODIBENZOFURAN-4- CARBOXYLATE A mixture of 1 g methyl l-acetylamino-2-chloro- 6,7,8,9-tetrahydrodibenzofuran-4-carboxylate and 0.5 g of 5% palladium-charcoal is heated under nitrogen at 230°C for 5 hours. The cooled residue is extracted with toluene and the solvent evaporated to dryneεs. The residue is crystallized from ethyl acetate/hexane to give methyl l-acetylamino-2-chloro- dibenzofuran-4-carboxylate. EXAMPLE 22 1-AMINO-2-CHLORO-6,7,8,9-TETRAHYDRODIBENZOFURAN-4- CARBOXYLIC ACID 1-AMINO-2-CHLORODIBENZOFUR&N-4-CARBOXYLIC ACID When the procedure of Example 15 is followed however methyl l-acetylamino-2-chloro-5a,6,7,8,9,9a- hexahydrodibenzofuran-4-carboxylate is replaced by methyl l-acetylamino-2-chloro-6,7,8,9-tetrahydro- dibenzofuran-4-carboxylate or methyl 1-acetylamino- 2-chlorodibenzofuran-4-carboxylate then the captioned products are prepared. EXAMPLES 23 1-AMINO-2-CHLORO-6,7,8,9-TETRAHYDRODIBENZOFURAN- -(N-l-AZABICYCLO[2.2.2. ]OCT-3-YL)CARBOXAMIDE l-AMINO-2-CHLORODIBENZOFURAN-4-(N-l-AZABICYCLO- [2.2.2.]OCT-3-YL)CARBOXAMIDE When the procedure of Example 16 iε followed however, l-amino-2-chloror5a,6,7,8 ,9 ,9a-hexahydrodi- benzofuran-4-carboxylic acid is replaced by 1-amino- 2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylic acid or l-amino-2-chlorodibenzofuran-4-carboxylic acid then the captioned products are prepared. EXAMPLE 24 METHYL 2-CHLORO-CIS-5a,6,7,8,9,9a-HEXAHYDRODIBENZO- FURAN-4-CARBOXYLATE METHYL 2-CHLORO-TRANS-5a,6,7,8,9,9a-HEXAHYDRODIBENZO- FURAN-4-CARBOXYLATE A mixture of 9 g of methyl 3-(3-cyclohexenyl)-5- chlorosalicylate and 20 ml trifluoroacetic acid is heated at 70°C overnight. The cooled reaction mixture is diluted with hexanes, washed three times with water, dried and evaporated to drynesε. The residue is purified with flash chromatography using 10% ethyl acetate/hexane to give four fractions first fraction 2.2 g of material (mixture of at least two materials) second fraction 2.2 g cis iεomer third fraction 1.6 g mixture of cis and trans isomers fourth fraction 1 g trans isomer EXAMPLE 25 2-CHLORO-CIS-5a,6,7,8,9,9a-HEXAHYDRODIBENZOFURAN-4- CARBOXYLIC ACID A mixture of 2 g methyl 2-chloro-cis-5a,6,7,8, 9,9a-hexahydrodibenzofuran-4-carboxylate in 30 ml IN sodium hydroxide and 5 ml dioxane iε stirred at 60°C for 5 hours. This is then diluted with water, filtered, acidified with acetic acid, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness to obtain an oily product which crystallizes on standing. This is recrystallyzed to obtain 2-rchloro-cis.-5a,6,7,8,9,9a-hexahydrodibenzo- furan-4-carboxylic acid. (M.P. 132-4°C.) EXAMPLE 26 Following the procedure of Example 25 but using the trans isomer in place of this cis, the corres¬ ponding 2-chlor-trans-5a,6,7,8,9,9a-hexahydro- dibenzofuran-4-carboxylic acid is prepared. EXAMPLES 27 -CHL0R0-CIS-5a , 6,7,8,9, 9a-HEXAHYDRODIBENZOFURAN-4- (N-l-AZABICYCLO[ 2.2.2. ] OCT- 3 -YL) CARBOXAMIDE 2-CHLORO-TRANS-5a, 6 ,7 , 8,9, 9a-HEXAHYDRODIBENZOFURAN- 4- (N-l-AZABICYCLO[ 2.2.2. ]OCT-3-YL ) CARBOXAMIDE Following the procedures of Examples 6 and 16 b-iut substituting the cis and trans isomers of Examples 25 and 26, then the above captioned products are pepared. EXAMPLE 28 l-CHL0R0-5a,6,7,8,9,9a-HEXAHYPRODIBENZOFURAN- 4-(N-l-AZABICYCLO[2.2.2. ]OCT-3-YL)CARBOXAMIDE Following the procedures of Examples 1-6 but substituting 4-chlorosalicylic acid in Example 1 for 5-chlorosalicylic acid, then the above captioned carboxamide is prepared. EXAMPLE 29 R-N-fα-METHYLBENZYL,-3-OUINUCLIDINIMINE To 401 g of 3-quinuclidinone hydrogen chloride in 300 ml of methanol iε added a solution of 198 g of 50% sodium hydroxide in 300 ml of methanol. The reaction mixture iε stirred for 30 minutes at 40°C, and to this is added 200 ml of isopropyl alcohol and the mixture filtered. The filtrate is evaporated to dryness, the solids formed are dissolved in 300 ml of toluene, filtered and again evaporated to dryness. To this residue is added 1100 ml of toluene, 280 g of R(+)α-methylbenzylamine and 2.8 g of p-toluene εulfonic acid. This is heated to reflux with stirring and the water removed by Dean Stark trap. After 40 ml of water is collected, the toluene is removed to obtain crude product as an amber oil. This is used directly in the next step. EXAMPLE 30 R-N-fα-METHYLBENZYL- S 3-AMINOQUINUCLIDINE The oil from Example 29 in 1600 ml of methanol is cooled in an ice bath and 120 g of KBH4 is added in small portions with stirring while keeping the temperature between 10-20°C. After addition is complete the temperature is allowed to rise. Most of the solvent is removed and the mixture is filtered, slurried in acetone twice and filtered. The original filtrate and acetone washes are combined and evaporated to one-half the original volume, filtered through a bed of celite and evaporated to dryness. The dark amber oil iε filtered through a bed of celite to obtain a clear amber oil. Thiε iε dissolved in 200 ml of 2-propanol and a solution of 500 ml isopropanol and 559 g of concentrated HCl added in small portions. The temperature is held between 25-50°C with an ice bath. After addition, the reaction mixture is cooled to 20°C and another 700 ml of isopropanol added. The εolid which forms is filtered, washed with cold isopropanol and dried at 45°C in a vaccuum dessicator to obtain R-N(α-methylbenzyl)-S-3-aminoquinuclidinedihydro- chloride. A second crop is obtained by adding 400 ml of acetone to the isopropanol filtrate which is filtered off and dried. This product was used directly in the next step. (M.P. 284°C) EXAMPLE 31 Sf-_ 3-AMINOOUINUCLIDINE To the product from the preceding step (50.2 g) in 500 ml of 4% HCl solution is added 12.3g Pd (II) chloride and hydrogenated overnight. The reaction mixture is filtered, washed with ethanol and evaporated to dryness to obtain a light yellow oil which crystallizes with triturating with 1:1 ethanol:isopropanol. This is recrystallized from ethanol to obtain pure S(-)-3-aminoquinuclidine aε the dihydrochloride. (M.P. > 285°C) • EXAMPLE 32 Rf-- )-3-AMINOOUINUCLIDINE When the procedureε of Examples 29-31 are followed but using S(-)-α-methylbenzylamine in Example 29 in place of R(+) α-methylbenzylamine results in R(+)-3-aminoquinuclidine. EXAMPLE 33 Following the procedures of Examples 29-32 the various amines of this invention may be resolved. EXAMPLE 34 2-CHL0R0-CIS-5aS.6.7.8.9.9aS-HEXAHYDR0DIBENZ0FURAN-4- CARBQXYLIC ACID To a stirred suspension of 48.1 g of S nitrosolve in 150 ml H2O iε added 20.5 g of 5% NaOH εolution. Material becomes cloudy and yellow oil separates. The mixture is extracted with 2 x 100 ml methylene chloride, the latter is then dried with Na S04, filtered, washed and evaporated to dryness. To this is then added 650 ml methanol followed by 60 g of 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid. All the solid dissolves in a short time to obtain complete εolution followed by reprecipitation. The mixture iε then heated to reflux at which time no solid is present. This is then allowed to cool and stand at room temperature. The off white crystalline solid which separates after several hours iε filtered, washed with 50 ml of methanol and dried. The resolved acid salt (88.1 g) is treated with 250 ml of 1 N HCl. The resultant suspension is extracted with methylene chloride (250 ml) which is washed with 1 N HCl (250 ml) . The aqueous iε again extracted with methylene chloride (100 ml) . The combined methylene chloride iε dried over N 2S04, filtered and evaporated to dryneεs to obtain reεolved ciε acid (-) as a white solid. The cis acid iε recryεtallized from acetonitrile to obtain 2-chloro-ciε- 5aS,6,7,8,9,9aS-hexahydrodibenzofuran-4-carboxylic acid. (M.P. 150-154°C) EX MPLE 35 ?.-CHL0R0-CIS-5a . 6 .7 .8 .9 .9aR-HEXAHYDR0DIBENZ0FtraAN-4- CARBOXYLIC ACID Following the procedure of Example 34 and using R nitrosolve in place of S nitroεolve results in the above product. EXAMPT.T. -.fi When the procedures of Examples 34 and 35 are followed but using 2-chloro-trans-5a,6,7,8,9,9a-hexahydrodibenzofuran- 4-carboxylic acid from Example 26 then the corresponding 2-chloro-trans-5aS,6,7,8,9,9aR-hexahydrodibenzofuran-4- carboxylic acid and 2-chloro-trans-5aR,6,7,8,9,9aS-hexahydro- dibenzofuran-4-carboxylic acid are prepared. EXAMPLE 37 2-CHL0R0-CIS-5aS.6.7.8.9.9aS-HRYAHYDR0DIBENZ0FURAN-4-TN-f1- AZ BICYCLOT2.2.2.10CTAN-3 iS )-YT.)CARBOXAMIDE A εolution of 50.19 g of 2-chloro-cis-5aS,6,7,8,9,9aS- hexahydrodibenzofuran-4-carboxylic acid in 50 ml of chloroform is heated to 35°C. To this is added 47 g of thionyl chloride keeping the temperature between 38 and 42°C. This is allowed to stir for two hours at 42°C. The solvent iε removed under vacuum. To a εolution under nitrogen atmosphere of 42 g 50% NaOH in 80 ml of methanol is added to a slurry Of 51 g S 3-amino¬ quinuclidine dihydrochloride in 130 ml of 95% EtOH and mixed for 15 minutes at 40°C. This is filtered and evaporated to dryneεε in vacuo to obtain the S-3-aminoquinuclidine aε the free base. The acid chloride prepared above dissolved in 100 ml toluene is added drop wise to the S-3-aminoquinuclidine in toluene keeping everything under nitrogen. The temperature of the reaction mixture is held at about 20-25°C during the addition. After addition the mixture is heated to 40°c and 200 ml toluene added. The reaction is allowed to stand at room temperature overnight after which time 1 N methanolic NaOH is added until basic. This is then washed with 3 x 500 ml water to a pH 7, dried over magnesium sulfate and evaporated to dryness at 5 mm vacuum and 70°C to obtain 2-chloro-cis-5aS,6,7,8,9,9aS-hexahydrodibenzofuran-4-[N-(1- azabicyclo[2.2.2.]octan-3(S)-yl)carboxamide. (M.P. 256°C) EXAMPLE 38 The various compounds of this invention can be prepared as above using the desired starting aterialε. The followin iε representative of the compounds prepared by this invention: 2-chloro-tranε-5 ,6,7,8,9,9a-hexahydrodibenzofuran-4- [N-(1-azabicyclo[2.2.2.]octan-3-yl) ]carboxamide ; 2-chloro-cis_-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- [N-(l-azabicyclo[2.2.2.]octan-3-yl) ]carboxamide; 2-chloro-cis-5aS,6,7,8,9,9aS-hexahydrodibenzofuran-4- [N-(1-azabicyclo[2.2.2.]octan-3-yl) ]carboxamide; 2-chloro-ciε-5aR,6,7,8,9,9aR-hexahydrodibenzofuran-4- [N-(1-azabicyclo[2.2.2.]octan-3-yl) ]carboxamide; 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- [N-(1-azabicyclo[2.2.2.]octan-3(R)-yl)]carboxamide; 2-chloro-trans-5aS,6,7,8,9,9 R-hexahydrodibenzofuran-4- [N-(1-azabicyclo[2.2.2.]octan-3-yl)]carboxamide; 2-chloro-trans-5aR,6,7,8,9,9aS-hexahydrodibenzofuran-4 ■ [N-(1-azabicyclo[2.2.2.]octan-3-yl) ]carboxamide; 2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4- [N-(l-azabicyclo[2.2.2.]octan-3(S)-yl)]carboxamide; and 2-chloro-cis-5 ,6,7,8,9,9aS-hexahydrodibenzofuran-4- [N-(1-azabicyclo[2.2.2.]octan-3(S)-yl)]carboxamide.

Claims: WE CLAIM: 1. A compound of the formula where R- t is hydrogen, amino or alkylamino, halo; R 2 is hydrogen, halo, sulfamyl, alkylsulfamyl or alkylsulfonyl; R' is hydrogen or alkyl or together with a vicinal R' group may form a double bond; and R is ~© and pharmaceutically acceptable salts thereof . -50- 2. A compound according to claim 1 which is 3. A compound according to claim 1 which is 4. A compound according to claim 1 which is 5. A compound according to claim 2 where R is 6. A compound according to claim 5 where R j and R. are hydrogen. 7. A compound according to claim 5 where R. is amino or loweralkylamino and R 2 is hydrogen. 8. A compound according to claim 5 where Ri is hydrogen and R2 is halo. 9. A compound according to claim 5 where Ri is amino and R2 is halo. 10. A compound of claim 1 which is in the cis configuration. 11. A compound of claim 1 which iε in the trans configuration. 12. A compound according to claim 7 which iε l-amino-5a,6,- 7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo- [2.2.2.]oct-3-yl)carboxamide. 13. a compound according to claim 8 which is 2-chloro-5a,6,- 7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo- [2.2.2.]oct-3-yl)carboxamide. 14. A compound according to claim 9 which is l-amino-2- chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-l-aza- bicyclo[2.2.2.]oct-3-yl)carboxamide. 15. A compound according to claim 8 which iε 2-chloro-cis- 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo- [2.2.2.]oct-3-yl)carboxamide. 16. A compound according to claim 15 which is 2-chloro-cis- 5aS,6,7,8,9,9aS-hexahydrodibenzofuran-4-(N-1-azabicyclo [2.2.2.]oct-3S-yl)carboxamide. 17. A compound according to claim 15 which is 2-chloro-ciε- 5aS,6,7,8,9,9aS-hexahydrodibenzofuran-4-(N-1-azabicyclo [2.2.2.]oct-3R-yl)carboxamide. 18. A compound according to claim 15 which iε 2-chloro-cis- 5aR,6,7,8,9,9aR-hexahydrodibenzofuran-4-(N-1-azabicyclo- [2.2.2.]oct-3S-yl)carboxamide. 19. A compound according to claim 15 which iε 2-chloro-cis- 5aR,6,7,8,9,9aR-hexahydrodibenzofuran-4-(N-1-azabicyclo- [2.2.2.]oct-3R-yl)carboxamide. 20. A compound according to claim 8 which iε 2-chloro-tranε- 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicyclo- [2.2.2.]oct-3-yl)carboxamide. 21. A method for the treatment of gastric disorders in humans and mammals comprising administering thereto an effective amount of a compound of the formula according to claim 1. 22. A method for the treatment of emesis in humans and mammals comprising administering thereto an effective amount of a compound of the formula according to claim 1. 23. A pharmaceutical composition wherein the active ingredient is a compound according to claim 1 in admixture with a pharmaceutical carrier. 24. Λ compound of the formula where i is hydrogen, amino or alkylamino, halo; R2 i hydrogen, halo, suflamyl; alkylsulfamyl or alkylεulfonyl; R' is hydrogen or alkyl or together.with a vicinal R' group may form a double bond; and R3 is hydroxy, halo, alkoxy or aralkoxy; provided that R', i and R2 are not all hydrogen at the same time. 25. Λ compound according to claim 24 which iε in the_cis configuration. 26. Λ compound according to claim 24 which is in the trans configuration.

Inventors: AIREY JOHN EDWARD, CAMPBELL HENRY F, KLEIN SCOTT IRA, KUHLA DONALD E, POWERS MATTHEW RAY, YOUSSEFYEH RAYMOND D, AIREY, JOHN, EDWARD, CAMPBELL, HENRY, F., KLEIN, SCOTT, IRA, KUHLA, DONALD, E., POWERS, MATTHEW, RAY, YOUSSEFYEH, RAYMOND, D.
Applicants: RORER INT OVERSEAS, RORER INTERNATIONAL (OVERSEAS) INC.
Application year: 1989
Main classification: C07D307
IPC codes: C07D307, C07D405, C07D451, C07D453, C07D471, C07D498