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WO1991016888A1 - Spiro[benzofurancycloalcane] carboxamides en tant qu'antagonistes de 5ht¿3? - Google Patents

Spiro[benzofurancycloalcane] carboxamides en tant qu'antagonistes de 5ht¿3? Download PDF

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Publication number
WO1991016888A1
WO1991016888A1 PCT/US1991/002419 US9102419W WO9116888A1 WO 1991016888 A1 WO1991016888 A1 WO 1991016888A1 US 9102419 W US9102419 W US 9102419W WO 9116888 A1 WO9116888 A1 WO 9116888A1
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WIPO (PCT)
Prior art keywords
azabicyclo
benzofuran
oct
cyclohexane
compound according
Prior art date
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PCT/US1991/002419
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English (en)
Inventor
Raymond D. Youssefyeh
Henry F. Campbell
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Rhone Poulenc Rorer International Holdings Inc
Rorer International Holdings Inc
Original Assignee
Rhone Poulenc Rorer International Holdings Inc
Rorer International Holdings Inc
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Priority to JP91507661A priority Critical patent/JPH05506222A/ja
Publication of WO1991016888A1 publication Critical patent/WO1991016888A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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 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.
  • D-receptors are 5HT2-receptors
  • M-receptors are termed 5HT3-rece ⁇ tors
  • all other receptor which are clearly not 5HT2 or 5HT3, should be referred to as 5HT-
  • 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.
  • 5HT3 receptor activity 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid
  • 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, cycl
  • 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:
  • 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.
  • the desired substituent or substituents 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.
  • the desired substituent is an amino group
  • this may be converted to the phthalimido group by heating with phthalic anhydride.
  • the amino group may be regenerated by hydrazinolysis. This sequence is shown in the following reaction scheme:
  • R4 is an alkyl group.
  • the desired substitution may be introduced subsequent to the carbonation and/or condensation with the amine, R-NH2.
  • 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.
  • the sulfonyl chloride may be prepared from the ester using chlorosulfonic acid, followed by formation of the sulfonamide using ammonia or an alkyl amine.
  • R' is hydrogen or alkyl
  • 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.
  • R4 is loweralkyl
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • Statistical significance may be determined using a t-test for independent samples with a probability of 0.05 or less considered to be significant.
  • 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.
  • 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
  • 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 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 * ⁇ 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.
  • Tissue can be stored indefinitely at -70°C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint,
  • 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.
  • sucrose as a sweetening agent
  • methyl and propylparabens as preservatives
  • a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.

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Abstract

On décrit certains spiro[benzofuranne-2(3H),1'-cycloalcane]carboxamides et leur utilisation en tant qu'antagonistes de 5HT3 agissant dans le système nerveux central et présentant une activité antivomitive et procinétique gastrique exceptionnelle dépourvue de toute propriété de liaison des récepteurs D2. On décrit également de nouveaux procédés de préparation desdites substances.
PCT/US1991/002419 1990-04-23 1991-04-09 Spiro[benzofurancycloalcane] carboxamides en tant qu'antagonistes de 5ht¿3? Ceased WO1991016888A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4931454A (en) * 1987-09-24 1990-06-05 Merck Patent Gesellschaft Mit Beschrankter Haftung Azachroman derivatives with effects on the cardiovascular system

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4931454A (en) * 1987-09-24 1990-06-05 Merck Patent Gesellschaft Mit Beschrankter Haftung Azachroman derivatives with effects on the cardiovascular system

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors

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CA2081011A1 (fr) 1991-10-24
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