AU7657991A - Spiro(benzofurancycloalkane)carboxamides as 5ht3 antagonists - Google Patents

Description

SPIRO[BENZOFURANCYCLOALKANE]- CARBOXAMIDES AS 5HTg ANTAGONISTS

Background of the Invention

This application is a continuation-in-part application of U.S. Serial No. 07/512,709 filed April 23, 1990.

Field of the Invention

This invention is directed to novel compounds and their valuable use as pharmaceutical agents as 5HT3 antagonists having unique central nervous system, anti-emetic and gastric prokinetic activity void of any significant D2 receptor binding properties. This invention also describes novel processes necessary for their preparation.

Spiro[benzofurancycloalkane]carboxamide substituted compounds which exhibit 5HT3 antagonists properties including CNS, anti-emetic and * gastric prokinetic activity which are void of any significant D2 receptor binding affinity. This invention also relates to pharmaceutical compositions and methods for the treatment of gastroinstestinal and mental disorders using said compounds. This invention also describes novel processes for their preparation.

5-Hydroxytryptamine, abbreviated "5HT", is commonly known as serotonin. Serotonin is found throughout the body including the gastrointestinal tract, platelets, spleen and brain, and appears to be involved in a great number of physiological processes such as a neurotransmitter at certain neurones in the brain, and is implicated in a number of central nervous system (CNS) disorders. Additionally, serotonin appears to act as a local hormone in the periphery: it is released in the gastrointestinal tract, where it increases small intestinal motility, inhibits stomach and colon motility, and stimulates stomach acid production. Serotonin is most likely involved in normal intestinal peristalsis.

The various physiological activities exerted by serotonin are related to the variety of different receptors found on the surface membrane of cells in different body tissue. The first classification of serotonin receptors included two pharmacologically distinct receptors discovered in the guinea pig ileum. The "D" receptor mediates smooth muscle contraction and the "M" receptor involves the depolarization of cholinergic nerves and release of acetylcholine. Three different groups of serotonin receptors have been identified and the following assignment of receptors has been proposed: D-receptors are 5HT2-receptors; M-receptors are termed 5HT3-receρtors; and all other receptor, which are clearly not 5HT2 or 5HT3, should be referred to as 5HT-|-like.

5HT3-receptors have been located in non-neurological tissue, brain tissue, and a numbr of peripheral tissues related to different responses. It has been reported that 5HT3-receptors are located on peripheral neurones where they are related to serotonin's (excitatory) depolarizing action. The following subtypes of 5HT3 receptor activity have been reported: 5HT3B subtype involving postganglionic sympathetic and parasympathetic neurones, leading to depolarization and release of noradrenaline and acetylcholine, respectively; 5HT3C subtype involving on enteric neurones, where serotonin may modulate the level of acetylcholine; and 5HT3A subtype involving on sensory nerves such as those involved in the stimulation of heart nerve endings to produce a reflex bradycardia, and also in the perception of pain.

Highly selective 5HT3-antagonists have been shown to be very effective at controlling and preventing emesis (vomiting) induced by chemotherapy and radiotherapy in cancer patients. The anti-emetic effects of 5HT3-antagonists in animals exposed to cancer chemotherapy or radiation are similar to those seen following abdominal vagotomy. The antagonist compounds are believed to act by blocking 5HT3-receptors situated on the cell membranes of the tissue forming the vagal afferent input to the emetic coordinating areas on the brain stem.

Serotonin is also believed to be involved in the disorder known as migraine headache. Serotonin released locally within the blood vessels of the head is believed to interact with elements, of the perivascular neural plexus of which the afferent, substance P-containing fibers of the trigeminal system are believed relevant to the condition. By activating specific sites on sensory neuronal terminals, serotonin is believed to generate pain directly and also indirectly by enhancing the nociceptive effects of other inflammatory mediators, for example bradykinin. A further consequence of stimulating the afferent neurones would be the local release of substance P and possibly other sensory mediators, either directly or through an axon reflex mechanism, than providing a further contribution to the vascular changes and pain of migraine. Serotonin is known to cause pain when applied to the exposed blister base or after an intradermal injection; and it also greatly enhances the pain response to bradykinin. In both cases, the pain message is believe to involve specific 5HT3 receptor on the primary afferent neurones.

5HT3-antagonists are also reported to exert potential antipsychotic effects, and are believed to be involved in anxiety. Although not understood well, the effect is believed to be related to the indirect blocking of serotonin 5HT3-mediated modulation of dopamine activity.

Many workers are investigating various compounds having 5HT3- antagonist activity.

Reported Developments

The development of 5HT3 agents originated from work carried out with metoclopramide (Beecham's Maxolon, A.H. Robins' Reglan), which is marketed for use in the treatment of nausea and vomiting at high doses. Metochlopramide is a dopamine antagonist with weak 5HT3-antagonist activity, which becomes more prominent at higher doses. It is reported that the 5HT3 activity and not the dopamine antagonism is primarily responsible for its anti-emetic properties. Other workers are investigating this compound in connection with the pain and vomiting accompanying migraine.

Merrell Dow's compound MDL-72222 is reported to be effective as an acute therapy for migraine, but toxicity problems have reportedly ended work on this compound. Currently four compounds A.H. Robins' Zacopride, Beecham's BRL-43694, Glaxo's GR-38032F and Sandoz' ICS-205-930 are in clinical trials for use in chemotherapy-induced nausea and vomiting. GR- 38032F is also in clinical trials for the treatment of anxiety and schizophrenia. Zacopride is reported to be in clinical trials for anxiety, while ICS-205-930 is reported useful in the treatment of carcinoid syndrome.

Compounds reported as gastroprokinetic agents include Beecham's BRL-24924, which is a serotonin-active agent for use in gut motility disorders such as gastric paresis, reflux esophagitis, and is known to also have 5HT3- antagonist activity.

Metoclopramide, Zacopride, Cisapride and BRL-24924 are characterized by a carboxamide moiety situated para to the amino group of 2- chloro-4-methoxy aniline. BRL-43694, ICS-205930, GR-38032F and GR- 65630 are characterized by a carbonyl group in either the 3-position of indole or N-benzoate, while Zacopride, BRL-24924, BRL-43694, ICS-205930 have also bridged azabicyclic groups in the form of a carboxamide or carboxylic ester.

Dibenzofurancarboxamides and 2-carboxamide-substituted benzoxepines are reported to have 5HT3-antagonist and gastroprokinetic activity in copending Application Serial Nos. 277,582; 277,611 and 412,768; and U.S. Patents Nos. 4,857,517; 4,859,683 and 4,863,921 ; all of which are assigned to the same assignee as the present application.

Summary of the Invention

This invention relates to spiro[benzofuran-2(3H),1'-cycloalkane]- carboxamides having 5HT3-antagonist, gastric prokinetic, and anti-emetic activity and lack D2 receptor binding activity, and to therapeutic compositions comprising said compounds. Preferred compounds of this invention are described by general Formula I below.

Formula I

wherein

R-j is hydrogen, alkyl, halo, amino, acetylamino, dialkylamino or carbamyl;

R2 is hydrogen, alkyl, halo, trifluoromethyl, sulfamyl, mono- and di- alkylsulfamyl, alkyl-sulfonyl, alkoxy, hydroxy, nitro, cyano, carboxy, carbalkoxy or carbamyl;

R3 is hydrogen or alkyl; R is 1 -azabicyclo[2.2.2]oct-3-yl, 1 -azabicyclo- [2.2.2]oct-4-yl, 1-azabicyclo[3.3.1]non-4-yl, 9-methyl-9-azabicyclo[3.3.1]non- 3-yl, 9-methyl-7-oxa-9-azabicyclo[3.3.1]non-3-yl or l-(p-fluorophenoxypropyl)- 3-methoxypiperidin-4-yl;

n is 1 , 2, 3 or 4; and pharmaceutically acceptable salts thereof.

This invention relates also to pharmaceutical compositions including an effective therapeutic amount of the aforementioned spiro[benzofurancyclo- alkane]carboxamide compounds of Formula I and therapeutic methods for the treatment of a patient suffering from gastrointestinal disorders and/or psychochemical imbalances in the brain by administering said pharmaceutical composition.

Detailed Description

As employed above and throughout the disclosure, the following, unless otherwise indicated, shall be understood: "Alkyl" means a saturated aliphatic hydrocarbon which may be either straight- or branched-chained containing from about 1 to about 6 carbon atoms.

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbon atoms.

o

II

"Carbamyl" means a group of the formula ~"^C"~^NH2.

"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.

"Acyl" means an organic radical derived from an organic acid, a carboxylic acid, by the removal of its acid hydroxyl group. Preferred acyl groups are benzoyi and lower alkyl carboxylic acids groups such as acetyl and propionyl.

The following numbering system is used to describe the compounds of this invention:

The chemical nomenclature for the R groups defined above are presented below.

& N 3-quinuclidine;

4-quinuclidine;

(9-methylazabicyclo[3.3.1]nonane);

7-(3-oxo-9-methylazabicyclo[3.3.1]nonane); and

4-[3-methoxy-1 -(-[4-fluorophenoxy]- propyl)piperidine].

Certain of the compounds of the present invention may exist in enolic or tutomeric forms, and all of these forms are considered to be included within the cope of this invention.

The compounds of this invention may be useful in the form of the free base, in the form of salts and as a hydrate. All forms are within the scope of the invention. Acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitiated by side effectts ascribable to the anions. Although pharmaceutically aceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, maleic acid, citrix acid, lactic acid, tartaric acid, malonic acid, methansefulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene- sulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, methane- sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl- sulfamate and quinate, respectively.

The acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

Preferred compounds of this invention include those of Formula I wherein R-j, R2, R3 and n are as described above and R is 1-azabicyclo- [2.2.2]oct-3-yl, 1 -azabicyclo[2.2.2]oct-4-yl and 1-azabicyclo[3.3.1]non-4-yl.

More preferred compounds of this invention include those of Formula I wherein R is as described for the preferred compounds, R-j is hydrogen, amino, loweralkylamino or dilower-alkylamino; R2 is hydrogen or halo; and R3 is hydrogen.

Most preferred compounds of this invention include those of Formula I wherein R is as described for the preferred compounds; R-j is hydrogen or amino; R2 is hydrogen or halo; R3 is hydrogen; and n is 2 or 3, while n is 3 is even further preferred.

The present compounds may be prepared by the following general procedure:

Condensation of a substituted spiro[benzofuran-2(3H),1 '-cycloalkane]-7- carboxylic acid, acid halides or ester with an amine of the formula R-NH2 results in the corresponding carboxamide.

In general this reaction may be accomplished by adding ethyl chloroformate to a solution of the acid in the presence of triethylamine at reduced temperatures, such as 0°C, followed by addition of the amine of formula R-NH2. The reaction may also be accomplished by combining the acid and amine in the presence of a dehydrating catalyst, such as a carbodiimide in an appropriate solvent.

The starting materials, that is, the substituted spiro[benzofuran-2(3H),1 ^*- cycloalkane]-7-carboxylic acids, acid halides and esters are also novel. These may be prepared from the corresponding substituted spiro[benzofuran- 2(3H),1'-cycloalkanes] by a carbonation procedure as shown in the following reaction:

Formation of the acid halides and esters may be carried out in the usual way.

If the desired substituent or substituents (i.e. R-| and/or R2) are such as to interfere with the carbonation reaction such as in the cases where the desired substituent is amino or alkylamino, the substituent or substituents may be protected with standard blocking groups, known in the art, followed by deprotection by standard procedures at a point subsequent to the carbonation. Where the desired substituent is an amino group, this may be converted to the phthalimido group by heating with phthalic anhydride. Following the carbonation, the amino group may be regenerated by hydrazinolysis. This sequence is shown in the following reaction scheme:

When the desired substituent is alkylamino, protection may be accomplished by acetylation, with subsequent deprotection by alkaline hydrolysis as shown in the following scheme: acetic anhydride or acetylchloride/Et₃N

where R4 is an alkyl group.

As an alternative to carbonation of the appropriately substituted spiro[benzofuran-2(3H),1'-cycloalkane], or a protected derivative thereof, the desired substitution may be introduced subsequent to the carbonation and/or condensation with the amine, R-NH2.

When the desired substitution is halo, such as bromo or chloro, the carboxylic acid, acid halide or an ester thereof may be halogenated using N- bromosuccinimide or N-chloro-succinimide in dimethylformamide. If the ester is used, this may be converted to the carboxylic acid by alkaline hydrolysis. These reactions are shown in the following scheme:

where X is bromo or chloro When the desired substitution at the 5-position is sufamyl or mono- or di- alkylsulfamyl, the sulfonyl chloride may be prepared from the ester using chlorosulfonic acid, followed by formation of the sulfonamide using ammonia or an alkyl amine.

where R' is hydrogen or alkyl.

Further, if the desired substitution at the 5-position is alkylsulfonyl, this may be introduced using the alkylsulfonyl chloride in the presence of a catalyst such as aluminum chloride.

where R4 is loweralkyl.

Depending on the chemistry involved, other desired end products having various R2 substituents can be prepared at any appropriate stage of the synthesis by using suitable reactions in order to convert one group to another, Thus, for example, when R2 is chloro, bromo or iodo, this may be reacted with cuprous cyanide in quinoline at about 150°C to produce those compounds where R2 is cyano. This in turn may be converted to the acids, esters or amides.

The halo group may also be reacted with trifluoromethyl-iodide and copper powder at about 150°C in DMF to obtain those compounds where R2 is CF3. Halo may also be reacted with cuprous methanesulfinate in quinoline at 150°C to obtain the methylsulfonyl substituent.

The R2 position of the spiro[benzofuran]ester may be nitrated in the customary manner using HNO3 and H2S04 at room temperature.

The spiro[benzofuran-2(3H),1'-cycloalkane] derivatives can be prepared according to the following scheme:

Thus, the appropriately substituted salicylaldehyde derivative is treated with chloromethylmethyl ether in the presence of 18-crown-6 in an appropriate solvent such as acetonitrile to form the methoxymethoxybenzaldehyde derivative. The benzylidene cycloalkane derivative is formed using a Wittig reaction wherein the methoxymethoxy benzaldehyde derivative is reacted with a cycloalkyltri-phenylphosphonium halide in the presence of methyllithium. The resulting methoxymethoxybenzylidene cycloalkane is deprotected (i.e. the methoxymethyl group removed) by treatment with aqueous acetic acid. The cyclization to form the desired spiro[benzofuran-2(3H),1 '-cycloalkane] is then accomplished using trifluoroacetic acid.

As mentioned above, the substituents Ri and R2 can be present on the starting salicylaldehyde or may be introduced onto the molecule during a subsequent step. The salicylaldehyde may also be substituted with groups which may subsequently be converted to the desired substituents.

Therefore, it is also desirous that when substitution on the final spiro[benzofuran-2(3H),1'-cycloalkane]-7-carboxamide is 4-amino, an appropriate starting material may be 6-nitro-salicylaldehyde.

6-nitrosalicylaldehyde is converted to 4-nitro[benzofuran-2(3H),1'- cycloalkane] as described above and the nitro group is reduced under catalytic hydrogenation conditions to give the 4-amino derivative which is subsequently converted to the final product through the sequence described earlier.

The amino group may also be converted to mono- and di-alkylamino groups at this point by treatment with lower alkyl halides or sulfates.

The amino group may also be diazotized to the diazonium flouride which is then thermally decomposed to the flourine derivative compound. The amine may also be diazotized and heated in an aqueous medium to form the alcohol or heated in an alcohol to form the alkoxy compound. Chlorosulfonation of the amine group may form the corresponding sulfamyl or mono- and di-alkylsulfamyl groups.

The starting materials necessary for preparation of the compounds of the present invention are available commercially, or are available through standard chemical procedures known in the art.

Certain compounds of the present invention have one or more asymmetric carbon atoms present in the amine portion of the carboxamide. It is also possible to have an asymmetric center when R3 is alkyl. Thus, a given compound may exist as two or more stereoisomers. When it is desired to prepare a pure stereoisomer of a compound of the present invention, this may be accomplished by using, as the starting amine, a stereochemically pure amine. As an alternative, the final spiro[benzofuran-2(3H),1'-cycloalkane]- carboxamide derivative, if prepared as a mixture of stereoisomers, may be resolved (i.e. the stereoisomers separated and purified) by standard procedures known in the art. 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 results in forms that are separable by fractional crystallization, distillation or chromatography.

It is convenient to carry out condensation of the intermediate carboxylic acids mentioned above with the amines of the formula H2N-Z using stereospecific materials of each reactant. Accordingly, the acid may be resolved into its stereoisomers prior to condensation with resolved amine.

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 gastro-esophageal 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, esophageal reflux, peptic ulcer and emesis. The compounds of this invention exhibit 5HT3 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 compounds are selective in that they have little or no dopaminergic antagonist activity.

Various tests in animals can be carried out to show the ability of the compounds of this invention to exhibit pharmacological responses 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 5HT3 receptors and their D2 dopamine receptor binding properties.

It has been found that the compounds of this invention, when tested in the above variety of situations, show a marked activity.

One such test is the "Rat Gastric Emptying: Amberlite Bead Method". This test is carried out as follows:

The study is designed to assess the effects of a test agent on gastric emptying of a solid meal in the rat. The procedure is a modification of those used in L.E. Borella and W. Lippmann (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 intragastrically. 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 determined for each treatment group. The percent change from control is calculated as follows:

Mean Control Group - Mean Test Agent Group _{x 10}o Mean Control Group

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 ability of the compounds of this invention as anti-emetic agents the following test for "Cisplatin-lnduced 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.

Cisplatin is administered (i.v.) 30 minutes after the first dosing with the

0.9% saline. Cisplatin, 10 mg/kg is administered in a dose volume of 2.0 ml/kg.

The time of cisplatin administration is taken as 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.

An 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, Euroo. 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-1 dopamine (non-cyclase linked) receptor agent with K^*ι values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 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 K2 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 striatum) is used as the receptor source because it contains the highest density of dopamine receptors in the brain and periphery.

Procedure

Male Charles-River rats weighing 250-300g 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 polytron homogenizer. The homogenate is centrifuged at 40,000g (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.

Specific 3H-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 MgS04, 2 mM EDTA»2Na, 120 mM NaCI, 0.1% ascorbic acid, 0.4 nM 3H-spiroperidol and test compound or assay buffer. When catecholamines 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 spectrophotometry using a quench curve. Proteins are determined by the method of Bradford, M. Anal. Biochem. 72, 248 (1976) using Bio-Rad's Coomassie 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 (260-290g) 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 cannuia in the left carotid artery and connected to a heparin/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 5HT and measurements are made of the fall in heart rate. In each rate, consistent responses are first established with the minimum dose of 5HT that evokes a clear fall in heart rate. Injections of 5HT 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 5HT. The effect of the compound on the 5HT-evoked bradycardia is calculated as a percent of the bradycardia evoked by 5HT before injection of compound.

In separate experiments to measure the duration of 5HT antagonism caused by the compounds of this invention, a single dose of compound is injected 5 minutes before 5HT, and the effects of 7 repeated challenges with 5HT are then monitored. The effects of the compound on the efferent vagal limb of the Bezold-Jarisch reflex are checked by electrically stimulating the peripheral 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 strains with a maximally effective voltage (20 V at 10 Hz). Pulse frequency may vary from 5-30 Hz and frequency response curves are constructed before and 10 minutes after i.v. injection of a single dose of compound.

The results of the 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 motility 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 administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelially including transdermal, opthalmic, 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 may 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 ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations 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 preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of 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 gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch potato starch, lyginic 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 coating 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 using 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 pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations.

The active compound may also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. 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 preservative 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 preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms 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, 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 preparation of sterile injectable solutions, the preferred methods of preparation are vacuum 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 pharmaceutical 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 this invention may be prepared by the following representative examples.

Example 1

N-[1-azabicyclo[2.2.2]oct-3-yl]-5-chlorospiro- [benzofuran-2(3H).1'-cvclohexane]-7-carboxamide

A. 2-Methoxymethoxybenzaldehvde .125g of salicylaldehyde is dissolved in 1250 ml of anhydrous acetonitrile and the solution cooled in an ice bath. 115g of potassium-t- butoxide is added and the mixture stirred for 15 minutes. 28g of 18-crown-6 is added and this stirred for 30 minutes. 115 ml of chloromethylmethyl ether is then added over a period of 5 minutes and the mixture stirred in the ice bath for 5 minutes, then at ambient temperatures for 1.5 hours. The mixture is filtered and the clear filtrate evaporated in vacuo. The oil residue is dissolved in 1 L of ether and this solution washed with water, 5% sodium hydroxide solution, water, brine then dried over sodium sulfate. This was filtered and evaporated in vacuo to 153g of 2-methoxy-methoxybenzaldehyde which is used, without further treatment for the next step.

B. 2-Methoxymethoxybenzylidene cvclohexane

130g of cyclohexyltriphenylphosphonium bromide is suspended in 1.3L of anhydrous tetrahydrofuran and cooled to 5°C in an ice bath. 218 ml of 1.4 M methyllithium in ether is added over a period of 10 minutes. The mixture is stirred for 10 minutes and 50.8g of 2-methoxymethoxy-benzaldehyde in 100 ml of tetrahydrofuran is added over 10 minutes. The mixture is stirred at ice bath temperature for 5 minutes, then at room temperature for 1.5 hours. 200 ml of water is added, the mixture stirred for 15 minutes, then evaporated in vacuo. The residue is taken up in 500 ml water/1 L ether. This is filtered, the layers separated and the aqueous extracted with ether. The combined ether solution is washed with water, brine, dried over sodium sulfate, then filtered and evaporated in vacuo to give the crude product which is purified by flash chromatography in petroleum ether/methylene chloride (1 :1) to give 2-methoxymethoxybenzylidene cyclohexane.

C. 2-Hydroxybenzylidene cvclohexane

34.2g of 2-methoxymethoxybenzylidene cyclohexane is suspended in 1.5L of 2 Normal acetic acid in water and this stirred at reflux for 44 hours. The mixture is extracted with ether and the ether solution washed with water, 10% aqueous sodium bicarbonate solution, water, brine, then dried over sodium sulfate. The ether solution is filtered, and evaporated in vacuo to give

2-hydroxybenzylidene cyclohexane which is used, without further treatment, for the next step.

D. Spirofbenzofuran-2(3HV1 '-cvclohexane] 24.9g of 2-hydroxybenzylidene cyclohexane is dissolved in 250 ml of trifluoroacetic acid and the solution stirred at room temperature for 1.5 hours. The solution is evaporated in vacuo and the residue dissolved in 250 ml of ether. The ether solution is washed with water, saturated sodium bicarbonate solution, water, brine and dried over sodium sulfate. This is filtered, evaporated to a crude product which is purified by flash chromatography in hexane/methylene chloride (2:1) to give 19.6g spiro[benzofuran-2(3H),1'- cyclohexane]. E. Spiro[benzofuran-2(3H).1 '-cvclohexane]-7-carboxylic acid

37.3 ml of 2.5M n-butyl lithium in hexane is added to 150 ml of hexane and 14.1 ml of tetramethylethylenediamine is added over a period of 1 minute. The mixture is stirred at room temperature for 30 minutes and 13.5g of spiro[benzofuran-2(3H),1 '-cyclohexane] in 20 ml of hexane is added over 1 minute and the solution heated at reflux for 5.5 hours. The mixture is cooled in an ice bath and dry carbon dioxide gas is bubbled in for 45 minutes. The mixture is diluted with 150 ml of ether and 200 ml of water, then acidified with 6N hydrochloric acid. The layers are separated and the aqueous layer extracted with ether. The combined organic solution is washed with water, then extracted with 2 x 250 ml of 5% sodium hydroxide solution. With cooling, the basic solution is acidified with 6N HCI and the resulting oil extracted into ether. The ether solution is washed with water, brine, dried over sodium sulfate, then evaporated in vacuo to give the crude product which is purified by crystallization from ethyl acetate to give spiro[benzofuran-2(3H),1'- cyclohexane]-7-carboxylic acid.

F. Methyl spirofbenzofuran-2t'3HV1 '-cvclohexanel-7-carboxylate To a solution of 2.86g of spiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxylic acid in 200 ml of ether is added a solution of approximately 3g of diazomethane in 200 ml of ether in large portions over a period of 5 minutes. The solution is stirred at room temperature for 2.5 hours. 6 ml of glacial acetic acid is carefully added and the mixture stirred for 5 minutes. The solution is washed with 200 ml of saturated sodium bicarbonate solution, water, brine, and dried over sodium sulfate. The solution is filtered, evaporated to give 2.96g of methyl spiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxylate. This is used without further treatment, for the next step.

G. Methyl-5-chlorospirofbenzofuran-2(3H).1'-cvclohexane1-7-carboxylate 2.59g of methyl spiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxylate and 2.11g of freshly recrystallized N-chloro-succinimide are dissolved together in 13 ml of dimethyl-formamide and the solution stirred at room temperature for four days. The solution is diluted with 40 ml of water and extracted with 2 x 50 ml of ether. The ether solution is washed with 3 x 50 ml of water, brine, dried over sodium sulfate. The solution is filtered and evaporated to a white solid, methyl-5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxylate. H. 4-Chlorospirofbenzofuran-2f3HU'-cvclohexane]-7-carboxylic acid

2.66g methyl-5-chlorospiro[benzofuran-2(3H),1 '-cyclohexane]-7- carboxylate is refluxed in a mixture of 100 ml methanol and 25 ml 10% (w/w) aqueous sodium hydroxide for 2 hours. The reaction mixture is evaporated jn vacuo to remove most of the methanol, then diluted with 100 ml of ether and 100 ml of 5% hydrochloric acid. The layers are separated and the aqueous layer extracted with ether. The combined ether solution is washed with water, brine, and dried over sodium sulfate. This solution is filtered and evaporated in vacuo to give 2.40g of 5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxylic acid.

I. N- 1-azabicvclor2.2.21oct-3-vn-5-chlorospiro-fbenzofuran-2f3Hl1'- cvclohexane -7-carboxamide 0.50g 5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxylic acid is dissolved in 2.5 ml of chloroform and 0.39g of triethylamine. The solution is cooled in an ice bath, 0.22 ml of ethyl chloroformate is added over a period of 5 minutes and the solution is stirred at 0°C for 1.5 hours. 2.5 ml of chloroform is added followed by a solution of 1.86g 3-aminoquinuclidine hydrochloride in 6 ml of 50% (w/w) aqueous potassium carbonate solution and 3 ml of water which had been cooled to 0°C. This mixture is stirred at 0°C for 30 minutes, then at room temperature for 18 hours. The mixture is partitioned between 50 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer is washed with water, brine, dried over sodium sulfate, filtered and evaporated to the crude product which is crystallized from ethyl acetate to give N-[1-azabicyclo[2.2.2]- oct-3-yl]-5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide; m.p. 160-162°C.

Example 2 When the amines of Table I below are substituted for 3-amino- quinuclidine in Example 11, then the corresponding compounds of Table II are prepared. Table 1

a. 4-amino-1-azabicyclo[2.2.2]octane

b. 4-amino-1-azabicyclo[3.3.1]nonane ^NH*7 ^Λ— N-

3-amino-9-methyl-9-azabicyclo[3.3.1]nonane

d. 3-amino-7-oxa-9-methyl-9-azabicyclo[3.3.1]no nane

e. 1 -(p-fluorophenoxypropyl)-3-methoxy-4-aminopiperidine

Table II

a. N-[1 -azabicyclo[2.2.2]oct-4-yl]-5-chlorospiro[benzofuran-2(3H),1 '- cyclohexane]-7-carboxamide

b. N-[1-azabicyclo[3.3.1]non-4-yl]-5-chlorospiro[benzofuran-2(3H),1'- cyclohexane]-7-carboxamide

c. N-[9-methyl-9-azabicyclo[3.3.1]non-3-yl]-5-chlorospiro[benzofuran- 2(3H),1'-cyclohexane]-7-carboxamide

d. N-[7-oxa-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-5-chlorospiro- [benzofuran-2(3H),1'-cyclohexane]-7-carboxamide e. N-[1-(p-fluorophenoxypropyl)-3-methoxy-piperidin-4-yl]-5-chlorospiro- [benzof uran-2(3H), 1 '-cyclohexane]-7-carboxamide

Example 3

N-[1-azabicyclo[2.2.2]oct-3(S)-yl]-5-chlorospiro- fbenzofuran-2(3H).1'-cvclohexane]-7-carboxamide

N-[1-azabicyclo[2.2.2]oct-3(R)-yl]-5-chlorospiro- fbenzofuran-2f3H).1'-cvclohexane]-7-carboxamide

- When (S-)-3-aminoquinuclidine is substituted for 3-aminoquinuclidine in Example 11, then N-[1-azabicycIo[2.2.2]oct-3(S)-yl]-5-chlorospiro[benzofuran- 2(3H),1'-cyclohexane]-7-carboxamide (m.p. 143-146°C) is obtained.

In a similar manner when (R+)-3-aminoquinuclidine is used the product obtained is N-[1 -azabicyclo[2.2.2]oct-3(R)-yl]-5-chlorospiro[benzofuran- 2(3H),1'-cyclohexane-7-carboxamide (m.p. 149-155°C).

Example 4 When the triphenylphosphonium derivatives of Table III below are substituted for cyclohexyltriphenylphosphonium bromide in Example 1 B, then the corresponding compounds of Table IV are prepared.

Table III

a. Cyclobutyltriphenylphosphonium bromide b. Cyclopentyltriphenylphosphonium bromide c. Cycloheptyltriphenylphosphonium bromide d. 3-Methylcyclohexyltriphenylphosphonium bromide

Table IV

a. 2-Methoxymethoxybenzylidenecyclobutane b. 2-Methoxymethoxybenzylidenecyclopentane c. 2-Methoxymethoxybenzylidenecycloheptane d. 2-Methoxymethoxybenzylidene-3'-methylcyclohexane Example 5 When the compounds of Table IV, above are substituted for 2-methoxymethoxybenzylidene cyclohexane in Example 1C, and the corresponding products treated sequentially as in Examples 1 D through 11, then the corresponding compounds of Table V are prepared.

Table V

a. N-[1 -azabicyclo[2.2.2]oct-3-yl]-5-chlorospiro[benzofuran-2(3H),1 '- cyclobutane]-7-carboxamide

b. N-[1 -azabicyclo[2.2.2]oct-3-yl]-5-chlorospiro[benzofuran-2(3H),1 '- cyclopentane]-7-carboxamide

c. N-[1-azabicyclo[2.2.2]oct-3-yl]-5-chlorospiro[benzofuran-2(3H),1'- cycloheptane]-7-carboxamide

d. N-[1 -azabicyclo[2.2.2]oct-3-yl]-5-chlorospiro[benzof uran-2(3H, 1 '3'- methylcycloheptane]-7-carboxamide

Example 6

4-Amino-N-[1-azabicyclo[2.2.2]oct-3-yl]- spirofbenzofuran-2(3H .1'-cvclohexane^'|-7-carboxamide

A. 2-methoxymethoxy-6-nitrobenzaldehvde

When 6-nitrosalicylaldehyde is substituted for salicylaldehyde in Example 1A, then 2-methoxymethoxy-6-nitrobenzaldehyde is prepared.

B. (2-Methoxymethoxy-6-nitrobenzylidenetovclohexane When 2-methoxymethoxy-6-nitrobenzaldehyde is substituted for

2-methoxymethoxybenzaldehyde in Example 1 B, then (2-methoxymethoxy-6- nitrobenzylidene)cyclohexane is prepared.

C. (2-hvdroxy-6-nitrobenzylidenetovclohexane When (2-methoxymethoxy-6-nitrobenzylidene)cyclohexane is substituted for 2-methoxymethoxybenzylidenecyclohexane in Example 1 C, then (2-hydroxy-6-nitrobenzylidene)cyclohexane is prepared. D. 4-Nitrospiro[benzof uran-2(3HΪ.1 '-cvclohexane!

When (2-hydroxy-6-nitrobenzylidene)cyclohexane is substituted for 2-hydroxybenzylidenecyclohexane in Example 1 D, then 4-nitrospiro- [benzofuran-2(3H),1 '-cyclohexane] is prepared.

E. 4-Aminospiro[^'benzofuran-2(3H 1 '-cvclohexane]

0.50g of 4-nitrospiro[benzofuran-2(3H),1'-cyclohexane] is dissolved in 10 ml of ethyl acetate and 0.25g of platinum oxide is added. The mixture is shaken under 45 psi of hydrogen for 24 hours, filtered, evaporated in vacuo and the crude product purified by flash chromatography to give 4-aminospiro- [benzofuran-2(3H), 1 '-cyclohexane].

F. 4-Phthalimidospirofbenzofuran-2(3H 1 '-cvclohexane] 2.02g of 4-amiπospiro[benzofuran-2(3H),1 '-cyclohexane] and 1.48g of phthalic anhydride are heated together at 160°C for 3 hours, cooled and the resulting solid crystallized from ethanol to give 4-phthalimido[benzofuran- 2(3H), 1 '-cyclohexane].

G. 4-Phthalimidospirofbenzofuran-2(3H^.1'-cvclohexane]-7-carboxylic acid When 4-phthalimidospiro[benzofuran-2(3H),1 '-cyclohexane] is substituted for spiro[benzofuran-2(3H),1'-cyclohexane] in Example 1E, then 4-phthalimidospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxylic acid is obtained.

H. 4-aminospiro|^"benzofuran-2(3H).1 '-cvclohexane]-7-carboxylic acid 2.00g of 4-phthaiimidosρiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxylic acid and 0.60 ml of 98% hydrazine are heated together at reflux in 40 ml of absolute ethanol for 4 hours. The reaction mixture is allowed to cool, filtered and the filtrate evaporated in vacuo. The residue is stirred with 5% sodium hydroxide solution, filtered, and the filtrate adjusted to pH 7 with 1 N hydrochloric acid, and the product extracted into methylene chloride which is washed, dried and evaporated. The crude product is purified by flash chromatography to give 4-aminospiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxylic acid. I. 4-Amino-N-[1-azabicvclof2.2.21oct-3-vHspiro-rbenzofuran-2f3H).1'- cvclohexane]-7-carboxamide

To a solution of 1.43g of 4-aminospiro[benzofuran-2(3H),1'- cyclohexane]-7-carboxylic acid in 8 ml of piridine at 0°C is added 1.4g of N,N'- dicyclohexylcarbodiimide in one portion. The mixture is stirred at 0°C for 1 hour and then 1.23g of 3-aminoquinuclidine dihydrochloride is added. The mixture is then allowed to warm and stirred at room temperature overnight. 8 ml of 1 N sodium hydroxide solution is added, the mixture stirred for 30 minutes, then filtered. The [residue or filtrate] is taken up in methylene chloride, washed with water, dried over magnesium sulfate and concentrated to dryness to give 4-amino-N-[1-azabicyclo[2.2.2]oct-3-yl]spiro[benzofuran-2(3H),1'- cyclohexane]-7-carboxamide.

Example 7 4-Amino-N-[1-azabicyclo[2.2.2]oct-3-yI]-5- chlorospirorbenzofuran-2f3HV1'-cvclohexane]-7-carboxamide

A. 5-Chloro-4-phthalimidospirorbenzofuran-2f3H .1'-cvclohexane]-7- carboxvlic acid When 4-phthalimidospiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxylic acid is substituted for methyl-5-chlorospiro[benzofuran-2(3H),1'- cyclohexane]-7-carboxylate in Example 1G, then 5-chloro-4-phthalimidospiro- [benzofuran-2(3H),1'-cyclohexane]-7-carboxylic acid is prepared.

B. 4-Amino-N-[1-azabicvclof2.2.2]oct-3-yl]-5-chlorospirofbenzofuran-

2(3HΪ.1'-cvclohexane1-7-carboxamide

When 5-chloro-4-phthalimidospiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxylic acid is substituted for 4-phthal-imidospiro[benzofuran-2(3H),1'- cyclohexane]-7-carboxylic acid in Example 6H, and the corresponding product treated as in Example 61, then 4-amino-N-[1-azabicyclo[2.2.2]oct-3-yl]-5- chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide is obtained. Example 8

N-[1-Azabicyclo[2.2.2]oct-3-yl]-5-bromospiro-

[benzofuran-2(3H 1'-cvclohexane]-7-carboxamide

When N-bromosuccinimide is substituted for N-chlorosuccinimide in Example 1G, and the corresponding product treated as in Examples 1H and 11, then N-[1 -azabicyclo[2.2.2]oct-3-yl]-5-bromospiro[benzofuran-2(3H),1 '-cyclo- hexane]-7-carboxamide is prepared.

Claims (19)

WE CLAIM:

1. A compound of the formula

wherein

Rl is hydrogen, alkyl, halo, amino, acetylamino, alkylamino, dialkylamino or carbamyl;

R2 is hydrogen, alkyl, halo, triflouromethyl, sulfamyl, mono- and di- alkylsulfamyl, alkylsulfonyl, alkoxy, hydroxy, nitro, cyano, carboxy, carbalkoxy or carbamyl;

R3 is hydrogen or alkyl;

R is 1 -azabicyclo[2.2.2]oct-3-yl, 1 -azabicyclo-[2.2.2]oct-4-yl, 1-azabi- cyclo[3.3.1 ]non-4-y I, 9-methyl-9-azabicyclo[3.3.1 ]non-3-yl, 9-methyl-7-oxa-9- azabicyclo[3.3.1]non-3-yl or 1-(p-fluorophenoxypropyl)-3-methoxypiperidin- 4-yl; and

n is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R is 1-azabicyclo[2.2.2]oct- 3-yl, 1 -azabicyclo[2.2.2]oct-4-yl or 1-azabicyclo[3.3.1]non-4-yl.

3. A compound according to claim 1 wherein R2 is hydrogen or halo.

4. A compound according to claim 2 wherein R-j is hydrogen, amino, loweralkylamiho or di-loweralkylamino;

R2 is hydrogen or halo; and

R3 is hydrogen.

5. A compound according to claim 4 wherein n is 2.

6. A compound according to claim 4 wherein n is 3.

7. A compound according to claim 6 wherein

R^*l is hydrogen or amino; and

R2 is hydrogen or halo.

8. A compound according to claim 7 which is N-[1 -azabicyclo[2.2.2]oct-3- yl]spiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide.

9. A compound according to claim 7 which is 4-amino-N-[1 -azabicyclo- [2.2.2]oct-3-yl]spiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide.

10. A compound according to claim 7 which is N-[1-azabicyclo[2.2.2]oct-3- yl]-5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide.

11. A compound according to claim 7 which is N-[-azabicyclo[2.2.2]oct-3(S)- yl]-5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide.

12. A compound according to claim 7 which is N-[-azabicyclo[2.2.2]oct-3(R)- yl]-5-chlorospiro[benzofuran-2(3H),1 '-cyclohexane]-7-carboxamide.

13. A compound according to claim 7 which is N-[1-azabicyclo[2.2.2]oct-3- yl]-5-bromospiro[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide.

14. A compound according to claim 1 which is 4-amino-N-[1 -azabicyclo- [2.2.2]oct-3-yl]-5-bromospiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxamide.

15. A compound according to claim 7 which is 4-amino-N-[1 -azabicyclo- [2.2.2]oct-3-yl]-5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7- carboxamide.

16. A compound according to claim 5 which is 4-amino-N-[1 -azabicyclo- [2.2.2]oct-3-yl]-5-chlorospiro[benzofuran-2(3H),1'-cyclopentane]-7- carboxamide.

17. A method for the treatment of a patient suffering from gastric prokinetic disorders comprising administering thereto a gastric prokinetic effective amount of a compound of the formula according to claim 1.

18. A method for the treatment of a patient suffering from emesis comprising administering thereto an emeticly effective amount of a compound of the formula according to claim 1.

19. A pharmaceutical composition including an effective 5HT3-antagonist amount os a compound according to claim 1 in admixture with a pharmaceutical carrier.