JPH05506222A - Spiro[benzofurancycloalkane]carboxamide as a 5HT↓3 antagonist - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] ″ Spiro[benzofurancycloalkanecocarpoki as a 5H’LP antisubstance to sa tsu This is a continuation application.

Concerning their beneficial use as medicaments such as antagonists. In addition, the present invention and all other receptors (these are clearly 5HT).

Sensory nerves that are involved in stimulation of the nerve endings and cause reflex bradycardia, and sensory nerves that are involved in the perception of pain. - 5HT is thought to affect specific 5HT receptors in afferent neurons. serotonin 5F (possibly involved in indirect inhibition of T3-mediated modulation).

Many researchers are investigating various compounds with 5HT antagonist activity.

It has been reported that this is the cause of its anti-emetic properties. Other researchers found that pain This compound is being studied for migraine with nausea and vomiting.

Merrell Dow's compound Sushi-72222 is effective for migraine headaches. BRL-43694 available for acute treatment, Glaxo's GR-38 032F and Sandoz's [C5-205-930 are used for chemotherapy. It is in clinical trials for use in nausea and vomiting induced by vomiting. Also, GR- 38032F is in clinical trials for the treatment of anxiety and schizophrenia.

Zacobride is reported to be in clinical trials for anxiety, while rc s-205-930 is reported to be beneficial in the treatment of carcinoid syndrome .

A compound reported as a gastric prokinetic drug is Beecham's BRL-24924. This includes gastroparesis, for use in motility disorders such as reflux esophagitis. It is a serotonin activator and is also known to have 5HT and antagonist activity. Ru.

Metoclopramide, zafubrid, cisabride and CfBRL-24924 are 2- The carboxyl group located at the distal position relative to the amino group of chloro-4-methoxyaniline Samido moiety Zacobride, BRL-24924, BRL-43694, ICS-20 5930 is also a cross-linked compound in the form of sulfoxamide or carboxylic acid ester. Cultivate an azanicyclic group.

Dibenzofurancarboxamide and 2-carboxamide-substituted penzoxebine are Pending U.S. Patent Application Nos. 2n, 582, 277.611 and 412 ．． 768, as well as U.S. Patent Nos. 4.857.517 and 4.859.683. and No. 4.863.921 (all of which are assigned to the same Tin Acceptance as the present application). It has been reported that 5HT increases antagonist activity and gastric prokinetic activity in There is.

- cycloalkane] carboxamides, as well as therapeutic compositions containing said compounds. do. Preferred compounds of the invention are described by general formula I below.

Formula I (In the formula, R8 is hydrogen, alkyl, halo, amino, acetylamino dialkylamino or carbamil, R2 is hydrogen, alkyl, halo, trifluoromethyl, sulfamyl, mono- and di-alkylsulfamyl, alkyl-sulfonyl, alkoxy, hydroxy, nitro, carboquine, carbalkoxy or carbamyl; R1 is hydrogen or alkyl; R is 1-azabicyclo[2,2,2]-3-octyl, 1-azabicyclo[22 ,2]-4-octyl, 1-azabicyclo[3,3,1]-4-nonyl, 9-meth Chil-9-asabinculo[3,3,1]-3-nonyl, 9-methyl-7-oxa -9-azabicyclo[3,3,1]-3-nonyl or 1-(p-fluorophore noxypropynoly-3-methoxypiperidin-4-yl, n is ], 2.3 or 4), and its pharmaceutically used salts.

The present invention also provides therapeutically beneficial amounts of spiro[benzofurancyclo a pharmaceutical composition comprising a carboxamide compound, and administering the pharmaceutical composition described above. Treatment of patients suffering from gastrointestinal disorders and/or psychochemical imbalances caused by Regarding.

detailed description The following terms used above and throughout this disclosure refer to the following terms unless otherwise specified: It should be understood as follows.

“Alkyl” means a saturated aliphatic hydrocarbon containing from about I to about 6 carbon atoms (which is directly may be chain or branched).

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

"Carbamyl" means a group of the formula -Co-m.

“Alkoxy” refers to an alkyl-oxy group (1 alkyl” as above) means. A lower alkoxy group is preferred. Exemplary groups are methoxy, ethoxy, n -Including propoxy, l-propoxy and n-butoxy.

“Acyl” is an organic acid derived from a carboxylic acid by removal of the acid hydroxyl group means an organic group Preferred acyl groups are benzoyl and acetyl and acyl groups. It is a lower alkyl carboxylic acid group such as ropionyl.

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

The chemical nomenclature of the above R group is expressed as follows.

naan), and acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, cyclohexylsulfamic acid, quinic acid, etc. Corresponding acid addition salt sulfonate, p-)/ is sulfonate, cyclohexylsulfamate , dissolved in alcohol solution or other suitable solvent and evaporated the solution. by isolating the salt by or by reacting the free base with the acid in an organic solvent (in which case the salt can be obtained by direct separation or by concentration of the solution) and R is 1-azabicyclo[2,2,21-3-octyl, l-azabicyclo [2,2,21-4-octyl and l-azabicyclo[3,3,11-4-noni] compound of the formula (1), where R3 is hydrogen or halo, and R3 is hydrogen is hydrogen, and n is 2 or 3 (more preferably n is 3) ) Contains a compound of formula ■.

Compounds of the invention may be prepared by the following general procedures.

Substituted spiro [ben' oligofuran-2 (3M), 1'-cycloalkane-7-ka Corresponds to the condensation of a carboxylic acid, acid halide or ester with an amine of the formula R-NHt Produces carboxamides.

Generally, this reaction involves converting ethyl chloroformate in the presence of triethylamine to 0. to a solution of the acid at a low temperature, such as °C, followed by the addition of the amine of formula R-NH, This can be done by In addition, the reaction is carried out using carbodiimide in an appropriate solvent. et al., the corresponding substituted spiro[benzofuran-2(3H),1'-cycloalkaline It can be produced by carbonation gas saturation operation shown in the reaction below.

Amino groups can be regenerated by treatment with hydrazine. This order is based on the reaction mechanism below. If the desired substituent is alkylamino, protection can be achieved by acetylation. followed by deprotection by alkaline hydrolysis as shown in the mechanism below. and/or the amine R-NH.

carboxylic acids, when the desired substituent is halo such as bromo or chloro; The halide or ester is N-bromosuccinimide in dimethylformamide. Alternatively, it can be halogenated using N-chloro-succinimide. Esther used If used, this can be converted to the carboxylic acid by alkaline hydrolysis. this( (wherein X is bromo or chloro) the desired substituent at position 5 is sulfamyl or is a mono- or dialkylsulfamyl, use chlorosulfonic acid. Sulfonyl chlorides can be prepared from esters using Sulfonamides can be generated using rukylamine.

can be prepared according to the mechanism.

Thus, appropriately substituted salicylaldehyde derivatives such as acetonitrile can be Treatment with chloromethyl methyl ether in the presence of 18-crown-6 in a suitable solvent. to produce methoxymethquine benzaldehyde derivatives. benzyridensi Chloalkane derivatives are produced using the Witzteig reaction; in this case, methoxy Metquin benzaldehyde derivatives are cycloalkylated in the presence of methyllithium Reacted with liphenylphosphonium halide. Obtained methoxymethoxy The benzylidenecycloalkane is deprotected by treatment with aqueous acetic acid (i.e. methoxymethyl group is removed). The desired spiro[benzofuran-2(3 H), 1'-cycloalkane] using trifluoroacetic acid. It is done using

As mentioned above, substituents R7 and R1 may be present in the starting salicylaldehyde ( , and may also be introduced into the molecule during subsequent steps. Also, salicylaldehyde The do may be substituted with a group that can be subsequently converted into the desired substituent.

Therefore, the final spiro[benzofuran-2(3H),1'-chloroalkane]-7 - When the substituent of carpoxamide is 4-amino, a suitable starting material is 6- Also preferred is nitrosalicylaldehyde.

6-Nidrosalicylaldehyde is 4-nitrospiro[benzofuran] as described above. -2(38), I'-cycloalkane], whose nitro group undergoes catalytic hydrogenation. reduction under conditions to give the 4-amino derivative, which was subsequently reduced in the order previously described. converted to the final product.

Also, the amino group can be removed by lower alkyl halide or sulfate at this point. can be converted into mono- and di-alkylamino groups by treatment.

Also, its amino group can be diazotized to diazonium fluoride, which then It is thermally decomposed into fluorine derivative compounds. Additionally, the amine is diazotized in the aqueous medium. can be heated in alcohol to produce alcohol, or heated in alcohol to produce alcohol. can produce cy compounds. The chlorosulfonation of the amine group results in the corresponding sulfamyl group or mono- or dialkylsulfamyl groups.

The starting materials necessary for making tI4 of the compounds of the invention are commercially available or known in the art. It can be obtained by known conventional chemical operations.

Compounds of the invention include one or more undesired molecules present in the amine moiety of the carboxamide. Cultivate chi carbon atoms. In addition, when R1 is alkyl, it may have an asymmetric center. is possible. Thus, a given compound may exist as two or more stereoisomers. obtain. If it is desired to produce pure stereoisomers of the compounds of the invention, , this can be done by using a stereochemically pure amine as the starting amine. I can do it. Alternatively, the final spiro[benzofuran-2(3H), 1°-so [Chloalkane]carboxamide derivatives are prepared as mixtures of stereoisomers. If the stereoisomers are (can be separated and purified). Separation of compounds is based on differences in the physical properties of diastereomers. Ku. Racemic formation into a mixture of diastereomers by the combination of enantiomerically pure moieties The transformation is a form that can be separated by fractional crystallization, distillation or chromatography. occurs.

Using the stereospecific nature of each reactant, the above intermediate carboxylic acid and the formula: )(2 It is convenient to carry out the condensation of the N--Z amine. Therefore, the acid is a split amine may be resolved into its stereoisomers prior to condensation with

The present inventors have demonstrated that the compounds of the present invention have gastric prokinetic and antiemetic properties, and , was found to have no receptor binding activity. As such, they are It has therapeutic value in the treatment of upper intestinal motility disorders and gastroesophageal reflux disorders. Furthermore, the main Light compounds are associated with delayed gastric emptying. emptying), indigestion, flatulence, esophageal reflux, peptic ulcers, and vomiting. It may be beneficial in the treatment of diseases associated with impaired gastrointestinal motility. Compounds of the invention shows 5HTs antagonistic effects and is useful in the treatment of mental disorders such as schizophrenia and anxiety, as well as It is believed to be useful in the prevention of headaches and cluster headaches. Furthermore, the present inventors in that these compounds develop little or no dopaminergic antagonist activity. found to be selective.

Perform various animal studies to demonstrate pharmacological responses that correlate with activity in humans The ability of the compounds of the invention can be demonstrated. These tests include gastric motility, vomiting, HT, selective antagonism of receptors and their D2 dopamine receptor binding with factors such as the effect of the compound of formula (1) on compatibility.

The compounds of the present invention exhibit significant activity when tested in the various situations described above. I found out.

One such test is “Empty the Rat Stomach: Amberlite Bead Method.” (RAT Emptying: Amberlite Baad Method) ” is.

This test is conducted as follows.

The study evaluated the effect of a test drug on gastric emptying of solid food in rats. is designed to. Its operating beam, E, Borel la. Also, Lippmann (1988) Digestion 20: This is an improvement on the procedure used in 26-49.

Masumi Amberlite™ beads are macerated in a phenol red solution for several hours.

Phenol red can be used as an indicator and as their environment becomes more basic. The beads change color from yellow to purple over time. After macerating, the beads were treated with NaO in O, IN. Rinse them with H to make them purple, then wash with deionized water to remove the NaOH. Ru.

Beads 1. l8rttn and 11. These sieves are filtered several times through a sieve of Obtain beads with a diameter between 1 and 2. This is done using large amounts of deionized water. Ru. Store the beads in saline until ready for use.

Male Sprague-Dawley rats were tested prior to the study. Make up 24 hours with water ad libitum. Randomize rats into treatment groups of 6 or 7 N Separate.

The test drug was prepared in 0.5% methylcellulose with a dosage volume of 10ml/kg. Orally administered to rats. Control rats received 0.5% methylcellulose, loml /kg Receive Il and Ol. One hour after dosing, rats received 60 ambers. 8f beads are given intragastrically. Connect beads to 16 gauge tube adapter delivered by a 3-inch piece of PH205 tubing attached to the cylinder and syringe. put out Place a small piece of PH50 tube inside the tube adapter and make sure the beads are Prevents being pulled back into the syringe.

The beads are flooded into the stomach of each rat with 1 ml of saline.

Thirty minutes after receiving the beads, rats are sacrificed and their stomachs removed. Respectively Count the number of beads remaining in the stomach of the patient after rinsing the beads with NaOH. Ru.

Subtract the number of beads remaining in each stomach from 60 to get the number of beads emptied. obtain. The mean number of beads±S, ε0M, is determined for each treatment group. Is it a control? The rate of change (%) is calculated as follows.

Average control group - Heikyo test drug group X 100 average control group Statistical differences in rearing can be determined using t-tests on independent samples, with q greater than or equal to 0.05. It is thought that the lower level of establishment is due to differences in upbringing.

In order to demonstrate the ability of the compounds of the invention as anti-emetic agents, “white weasel thissis” The following test for tatin-induced emesis may be used. This test is for A, P, Flow Florezyk, J. E., Schurig and f1. T, paper reported by Brodner, Cancer T reatment Reports: Volume 66, Issue 1, January 1982 improved method be.

Cisplatin has been shown to cause vomiting in dogs and cats. Floret body Weight 1.0~! , 5k [I's male neutered white weasel is It has an indwelling catheter placed in the jugular vein. After a 2-3 day collection period, the experimental Start making.

Thirty minutes before administration of cisplatin, white ferrets were given a dose volume of 2.0 ml/kg. Dosing (i, v, ) the compound in 0.9% saline.

Cisplatin is administered 30 minutes after the first dose of 0.9% saline.

Cisplatin 10/kg is administered in a dosage volume of 2.0 ml/kg.

The time of cisplatin administration is designated as time 0. The white weasel was kept for the duration of the experiment (4 hours). Stand and observe. Observe the time elapsed until the first vomiting episode and determine the duration of vomiting. Record as total number.

Vomiting episodes are caused by rushing back and forth around the cage and rapid movement back and forth. It is characterized by violent behavior such as movement. At the same time as this behavior, exhale several times in succession. , followed by one loud vomit, even though the contents of the stomach were vomited. Well, you don't have to do that again. Immediately after one big spit, the white weasel Relax. One cough or vomit counts as a vomiting episode. do not have.

D-2 Dopamine receptor binding assay D-2 Dopamine receptor binding assay Sei is Ian Cresse (fan Cresse), Robert Schneider (Robert 5chneidar) and Solomon H. Snyder (Solo monH, 5nyder) method (Europ, J, Pharmacol, 46:377-381 (1977)) with slight improvements. . Spiroperidol is a butyrophenone neuroleptic that reduces dopamine in brain tissue. Its affinity for the receptor is similar to that of other known drugs. It's big. It is 0 for D-2 suppression, 1 value for 1 to 0.5 and for n-1 suppression. Highly specific fl-1 dopamine (non-cyclase) that develops a value of 1 at 300 nM -ase binding) receptor agent.

Sodium ions are important regulators of dopamine receptors. D-2 receipt The affinity of the protein is significantly increased by the presence of millimolar concentrations of sodium chloride. be strengthened. ■ In the absence and presence of 20 mmol of sodium chloride, 2 is 1. 2 and 0,086nl+1. Sodium chloride (120 mmol) is standard included in all assays.

The caudate nucleus (striatum) is used as a receptor source. If possible, it will help the brain and This is because the periphery contains a high density of dopamine receptors.

temporary Male Charles-River weighing 250-300g. ) Decapitate the rats, remove their brains, cool on ice, and immediately dissect the caudate. , freeze on dry ice. Tissues can be stored indefinitely at -70°C.

For the assay, place the caudate in Tris buffer using a Polytron homogenizer. Homogenize with 30 ml (pH 7,7 at 25'C). 40,000 homogenate g (SS-34 rotor TI8.000~+9.0OORPlil)'t'1 Centrifuge for 5 minutes. Resuspend the pellet in fresh buffer and centrifuge again do. Resuspend the final pellet in 150 volumes of assay buffer.

Specific 8H-spiroberidol binding was detected in the caudate homogenate 5oolI11 buffer solution (35°C, 5°C chill, 4) 50 mm IJ mol, Mg 5045 mm Mol, EDTA-2Na 2 mmol, NaC 1120 mmol, Ascorbyl alpha 1%, 'H-spiroperidol 0.4 nM and test compound or assay Measurements are made in a total reaction volume of 2 ml consisting of buffer. Catecholamines are assayed. pargyline IOμ to inhibit monoamine oxidase. M should be included in the reaction mixture. Samples were incubated at 37'C for 30 minutes. tosane, followed by 50 mmol of ice-cold Tris (pH 7.7 at 25°C) 5 ml added Astringent Blundell receptor binding filtration device r-GF/B glass fiber filter filtered through a router. The filters were each washed twice with an additional 5 ml of Tris buffer. Ru. Assay groups were performed in triplicate, and lμM d(+)butaclamol was used to eliminate nonspecific binding. used to measure. The filter is Ecosci Phosphor. nt phosphor) in a vial containing 10 ml and shaken for 30 minutes. The dpm was measured by liquid scintillation spectrophotometry using a quenching curve. determined. The protein is Coomassie Blue from Bio-Rad. -250 dye reagent using the method of Bradford (M , Anal, Biochem, 72.248 (1976)) be done. Urine gamma globulin supplied by Bio-Rad is the protein standard material used as.

Insert. Cannulate the jugular vein for intravenous (i, v, ) infusion of drugs. Insert les. Blood pressure is measured using a pressure transducer filled with heparin/saline Recorded from a cannula in the left apical artery connected to the 0. Continuous heart rate measurement measures blood pressure taken from the record. Betsut Luto Jarish effect is 5HT quick big round i, V, induced by injection and measurements of heart rate reduction are made. At each heart rate, A consistent response was first established at the lowest dose of 5HT that induced a clear decrease in heart rate. be done. Infusions of 5HT are given every 12 minutes ~ straw volume response for test compound The curve injects increasing doses of compound 5 minutes before each injection of 5HT. It is established by The effect of the compound on 5HT-induced bradycardia Calculated as the percentage of bradycardia induced by 5HT before injection of 5HT.

In another experiment to determine the duration of 5HT antagonism produced by compounds of the invention. A single dose of compound was injected 5 minutes before 5HT, then 7 doses of 5HT were administered. The effect of repeated challenge is monitored. centrifugal of bezolto-jalissiko reflux The effects of the compounds of the present invention on the vagal limb show that the distal end of the severed vagus nerve is electrified. It can be investigated by stimulating the air. Unipolar electrical stimulation produces a maximum predynamic voltage (10 Using a rectangular pulse of 1a+s in a strain of 5 at 20V at Hz), a pair of 11! electric Applied every 5 minutes by pole. The pulse frequency can be varied from 5 to 30Hz, and the frequency The response curve is 1. for a single dose of the compound. v, made before and 10 minutes after injection.

The results of the above tests demonstrate that the four compounds of the present invention have both peripheral and central effects on the nervous system. 2 shows a beneficial balance of gastric emptying, indigestion, bloating, esophageal reflux and Treatment of diseases associated with impaired gastrointestinal motility, such as peptic ulcers, as well as psychosis. Shows that it may be beneficial in the treatment of disorders of the central nervous system.

The compounds of the invention may be administered to mammalian hosts in a variety of forms appropriate to the selected route of administration. , for example, orally or parenterally. In this regard, parenteral administration is including administration by the route of administration. Intravenous administration, administration, intramuscular administration, subcutaneous administration, intraocular administration, Intra-encapsulated administration, transepithelial administration including transdermal administration, ocular administration, sublingual administration and buccal administration; topical administration. (local administration to the eyes, skin, bulb, rectum, insufflation method, and nasal inhalation via aerosol) (including) and rectal systemic administration. The active compound can be administered orally, for example, with an inert diluent or an assimilable edible carrier. , or it can be enclosed in hard or soft shell gelatin capsules, and It can be compressed into tablets, or it can be mixed directly with food. For oral administration The active compound is mixed with excipients to form ingestible tablets, sublingual tablets, and troches. Can be used in the form of capsules, elixirs, suspensions, syrups, wafers, etc. Ru. Such compositions and preparations should contain at least 0.1% of active compound. be. The proportions (%) of compositions and formulations may, of course, vary and may range from approximately Conveniently, it is between 2% and about 6%. Activation in such therapeutically beneficial compositions The amount of compound is such that a suitable dosage I is obtained. Preferred compositions of the invention or the formulation is such that an oral dosage unit form contains about 50-300 mg of active compound. It is prepared in

Tablets, troches, pills, capsules, etc. may also contain the following ingredients: Toraga Binders such as gum canthus, gum acacia, corn starch or gelatin Excipients such as dicalcium phosphate: corn starch, potato starch, ligic acid disintegrants such as, lubricants such as magnesium stearate; and sucrose, lactose or sweeteners such as saccharin or peppermint, oil of wintergreen, or cherry. Spices such as spices may be added. If the dosage unit form is a capsule, it is In addition to the physical materials described above, a liquid carrier may also be included. Various other substances may be May be present as a covering or to improve the physical form of the dosage unit. Good too. For example, tablets, pills or capsules may be made with shellac, sugar or both. May be coated. A syrup or elixir contains sucrose as a sweetening agent and a preservative. As methylparaben and propylparaben, dye and cherry or orange Spices, such as spices, may be used to contain the active compound. Of course, in dosage unit form The materials used to make II are pharmaceutically pure and in the amounts used are substantially Should be non-toxic. Additionally, the active compound may be incorporated into sustained release formulations and formulations. You may be

The active compounds may also be administered parenterally or intraperitoneally. free base or Pharmacologically, solutions of active compounds as salts are hydroxypropyl cellulose. They may be prepared in water, suitably mixed with a surfactant such as water. In addition, if the dispersion liquid prepared in rolls, liquid polyethylene glycol, and mixtures thereof and in oil. It can be manufactured. Under normal conditions of storage and use, these preparations prevent the growth of microorganisms. Contains preservatives.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile injectable solutions. Contains sterile powders for the extemporaneous preparation of liquids or dispersions. In all cases, the form is sterile It needs to be fluid enough to allow for easy syringability. Ru. It must be stable under the conditions of manufacture and storage and must be free from bacteria and fungi. It must be preserved against the contaminating action of microorganisms such as The carrier is a solvent or a dispersion medium, such as water, ethanol, polyols (e.g. glycerol, (propylene glycol, liquid polyethylene glycol, etc.), and appropriate mixtures thereof. Contains compounds and vegetable oils. Adequate fluidity is required, for example, when using coatings such as lecithin. for use, maintenance of the required particle size in the case of dispersions, and the use of surfactants. more sustainable. Prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, e.g. Parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. may occur. often contains isotonic agents, e.g. sugars or sodium chloride Obtained with aluminum nostearate and gelatin.

Sterile injectable solutions contain the active compounds in the required amount in combination with various of the other ingredients enumerated above. prepared by mixing in a suitable solvent and, if necessary, subsequently sterile filtration. . Generally, dispersions contain the various sterile active ingredients in a basic dispersion medium and as required above. It is prepared by incorporating the specified ingredients into a sterile vehicle.

For sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freezing. condensation techniques, in which the active ingredients are extracted from a previously sterile-filtered solution. Produces a powder of additional desired ingredients.

The therapeutic compounds of the invention may be used alone or in combination with the pharmaceutical carriers described above. The proportion can be administered depending on the solubility and chemical properties of the compound and the chosen route of administration. and as determined by normal pharmaceutical practice.

The physician determines the dosage of the therapeutic agent of the invention, which is optimal for prophylaxis or treatment. Yes, it varies depending on the mode of administration and the particular compound selected, and it may vary during treatment. varies depending on the particular patient. Generally, doctors start treatment with lower doses and Try to gradually increase it in small increments until you reach the best effect under these circumstances. treatment Dosage is generally 0.1 to 20 or about 0.1 to 20 kg/kg body weight daily. O1■ ~ approx. 5 0■ or more, but it may be administered in several different dosage units in one to several IBI times. It is possible. Higher dosages are required for oral administration.

Compounds of the invention may be prepared according to the representative examples below.

Example I N-[1-azabicycloC2,2,2]-3-octyl]-5-chlorospiro[ benzofuran-2(3H), 1'-cyclohexane]-7-carpoxamide A, 125 g of 2-methoxymethoxybenzaldehyde salicylaldehyde was dissolved in anhydrous acetic acid. Dissolve in 1250 ml of tonitrile and cool the solution in a water bath. potassium t- 115 g of butoxide are added and the mixture is stirred for 15 minutes. 18-Crown -628 g is added and this is stirred for 30 minutes. Then chloromethyl methyl ether 115 ml of water was added over a period of 5 minutes and the mixture was placed in a water bath for 5 minutes. Stir for 1.5 hours and then at ambient temperature for 1.5 hours. Filter the mixture and make clear The filtrate is evaporated under reduced pressure. Dissolve the oil residue in 1 liter of ether and add this solution to water. washed, washed with 5% sodium hydroxide solution, washed with water, washed with saline solution, then washed with Dry with sodium sulfate. This was filtered, evaporated under reduced pressure and 2-methoxymethane Obtained 153 g of toxybenzaldehyde, which was used in the next step without further treatment. do.

8, 2-Methoxymethoxybenzylidene cyclohexane cyclohexyl trif 130 g of phenylphosphonium bromide in 1.3 liters of anhydrous tetrahydrofuran cooled to 5° C. in a water bath. 1.4M methyllithium in ether Add 218 ml over a period of 10 minutes. Stir the mixture for 10 minutes , 2-methoxymethoxy-benzaldehy in 100 ml of tetrahydrofuran Add 50.8 g of chloride over 10 minutes. The mixture was stirred for 5 minutes at water bath temperature and then Stir at room temperature for 1.5 hours. Add 200ml of water and let the mixture stand for 15 minutes Stir and then evaporate under reduced pressure. Dissolve the residue in 500 ml of water/1 liter of ether. absorb it inside. Filter it, separate the layers and extract the aqueous layer with ether. Match The ether solution was washed with water, brine, dried over sodium sulfate, and filtered. , evaporated under reduced pressure to obtain the crude product, which was dissolved in petroleum ether/methylene chloride (1:1 ) was purified by flash chromatography in 2-methoxymethoxyben Zylidenecyclohexane is obtained.

C2-Hydroxybenzylidene cyclohexane 2-methoxymethoxybenzylide 34.2 g of cyclohexane was suspended in 1.5 liters of 2N acetic acid in water. The mixture was stirred at reflux for 44 hours. The mixture was extracted with ether and the ether solution Washed with water, washed with 10% aqueous sodium bicarbonate solution, washed with water, washed with saline solution. , dried with sodium sulfate. The ether solution was filtered and evaporated under reduced pressure to give 2- Hydroxybenzylidenecyclohexane was obtained, which was carried on to the next step without further treatment. used for.

D spiro[benzofuran-2(3H), 1'-cyclohexane]2-hydro Dissolve 24.9g of xybenzylidenecyclohexane in δOml of trifluoroacetic acid. and stir the solution for 1.5 hours at room temperature. The solution was evaporated under reduced pressure and the residue Dissolve in 250 ml of ether. Wash the ethereal solution with water and saturated sodium bicarbonate. Wash with solution, water, brine and dry over sodium sulfate. this Filtration and evaporation gave the crude product, which was dissolved in hexane/methylene chloride (2:I). was purified by flash chromatography to give spiro[benzofuran-2(3 H).

19.6 g of lo-cyclohexane were obtained.

2.5M lobethyllithium in hexane 37.31111 in hexane 150 ml and 14.1 ml of tetramethylethylenediamine over a period of 1 minute. Add. The mixture was stirred at room temperature for 30 minutes, then spritzed in 20 ml of hexane. 13.5g of b[benzofuran-2(3H),1'-cyclohexane] in 1 minute and heat the solution to reflux for 5.5 hours. water the mixture Cool in a bath and sparge with dry carbon dioxide gas for 45 minutes. Ether the mixture Dilute with 50 ml of water and 200 g+1 of water, then acidify with hydrochloric acid. layer Separate and extract the aqueous layer with ether. The combined organic solution was washed with water and then 2X2 Extract with 50 ml of 5% sodium hydroxide solution. Basic solution while cooling is acidified with 6N hydrochloric acid and the resulting oil is extracted with ether. ether solution in water washed with brine, dried over sodium sulfate, and then evaporated under reduced pressure to obtain The product was obtained and purified by crystallization from ethyl acetate to give spiro[benzofuran- 2(3H), 1°-cyclohexane]-7-carboxylic acid is obtained.

Spiro[benzofuran-2(3H), 1'-cyclo in 200 ml of ether A solution of 2.86 g of hexanecho-7-carboxylic acid in 200 ml of ether A solution of 3 g of diazomethane is added in portions over a period of 5 minutes. the The solution is stirred at room temperature for 2.5 hours. Carefully add 6 ml of glacial acetic acid and stir the mixture. Stir for 5 minutes. Wash the solution with 200 ml of saturated sodium bicarbonate solution. , washed with water, washed with brine and dried with sodium sulfate. Filter the solution and Evaporate to methyl spiro [benzofuran-2(3H), 1'-cyclohexane] -7-carpoxyle) 2.96 g are obtained. Do not process this further and proceed to the next step use.

Methyl spiro U benzofuran-2(3H), 1'-cyclohexane]-7-cal 2.59 g of boxylate and freshly recrystallized N-chloro-succinimide 2. 11 g were dissolved together in 13 ml of dimethylformamide and the solution was kept at room temperature for 4 days. Stir for a while.

The solution is diluted with 40 ml of water and extracted with ether 2X501111. Aete Wash the solution with 3X501111 water, brine, and dry with sodium sulfate. Let dry. The solution was filtered and evaporated to give a white solid, methyl-5-chlorospirate. B[benzofuran-2(3H), 1°-cyclohexane-7-carboxylate get the same amount.

H4-chlorospiro [benzofuran-2(3H), 1'-cyclohexane] reduced Evaporate under pressure to obtain 5-chlorospiro[benzofuran-2(3H), 1'-cyclo 2.40 g of hexane]-7-carboxylic acid are obtained.

-Carboxylic acid o, 50g in chloroform 2.5ml and triethylamine 0. Zofuran-2(3H), 1'-cyclohexane]-7-carpo dissolved in 39 g Get xamide.

Melting point 160-162°C0 If so, prepare the corresponding compounds in Table 2.

c, 3-amino-9-methyl-9-azabicyclo[3,3,1]nonane d, 3- Amino-7-oxa-9-methyl-9-azabicyclo[:1 3.1]noe, 1 -(p-fluorophenoxyprobyl)-3-methoxy-4-aminobibe a, N -ε1-Azabicyclo[2,2,2]-4-octyl]-5-chlorospiro[beta] Zofuran-2(3H), 1'-cyclohexane]-7-carpoxamide b, N -[1-Azabicyclo[3,3,1]-4-noninoly5-chlorospiro[ben Zofuran-2(3H), 1'-cyclohexane]-7-carpoxamide c, N- [9-Methyl-9-azabicyclo[3,3,1]-3-nonyl]-5-chloros Pyro[benzofuran-2(3H),1'-cyclohexane]-7-carpoxamide de d, N-[7-oxa-9-methyl-9-azabicyclo[3,3,1]-3- Nonyl]-5-chlorospirobenzofuran-2 (3K), 1'-cyclohebovine ]-7-carpoxamide e, N-[1-(p-fluorophenoquinepropyl)-3-methoquino-piperidi -4-ylco-5-talolospiro[benzofuran-2(3H),1'-cyc] Rohe Beef Sun〕-7-Carpoxamide Cutinory 5-talolospiro [benzofuran-2(3H), 1'-cycloheki Suspiro [benzofuran-2(3H), 1'-cyclohexaneco-7-carpo Xamide (M point 149-155°C) Theal.

Prepare.

Sac and a, cyclobutyltriphenylphosphonium bromide b, cyclopentyltrif phenylphosphonium bromide C, cycloheptyltriphenylphosphonium promide mido d, 3-methylcyclohexyltriphenylphosphonium bromide a, 2- Methoxymethoxybenzylidene cyclobutane b, 2-methoxymethoxybenzylidene Dencyclopentane c 2-methoxymethoxybenzylidenecyclohebutane d 2-methoxybenzylidene-3'-methylcyclohexanehexane ( Using two different products, the corresponding products were treated sequentially as in Example ID~1■. iii, the corresponding products in Table 5.

Table 5 a, N-[1-azabicic O[2,2,2]-3-octyl]-5-'10 Roshiro [benzofuran-2(3H), 1'-cyclobutane]-7-carpoki Samido b, N-El-azabicyclo[2,2,2]-3-octyl-5-k lorospiro[benzofuran-2(3H),1”-cyclopentane]-7-cal Boxamidro[benzofuran-2(3H), 1'3'-methylcyclohebutane co-7-carpoxamide When used, 2-methoxymethoxy-6-nitrobenzaldehyde is used as I! I make Ru.

When used in place of quinmethoxybenzaldehyde, (2-methoxymethoxybenzaldehyde) -6-Nitrobenzylidene) cyclohexane is prepared.

C9(2-hydroxy-6-nitrobenzylidene)cyclohexane(2-methoxy cymethoxy-6-nitrobenzylidene) cyclohexane to the 2-methoxymethane of Example IC. When used in place of oxymethoxybenzylidenecyclohexane, (2-hydro xy-6-nitrobenzylidene) cyclohexane.

D 4-Nitrospiro [benzofuran-2(3H), 1°-cyclohexane] (2-Hydroxy-6-nitrobenzylidene)cyclohexane in Example ID 2 -Hydroxybenzylidene When used in place of cyclohexane, 4-nitros Prepare pyro[benzofuran-2(3H), I'-cyclohexane].

E, 4-aminospiro [benzofuran-2(3H), 1'-cyclohexane] 4-Nitrospiro[benzofuran-2(3H), 1'-cyclohexane 30. Dissolve 50 g in 10 ml of ethyl acetate and add 25 g of platinum oxide. the The mixture was heated under 3.2 kg/cm' (45 psi) of hydrogen for 24 hours; Filter, evaporate under reduced pressure and purify the crude product by flash chromatography. and 4-aminospiro [benzofuran-2(3H), 1°-cyclohexane] get.

4-Aminospiro[benzofuran-2(3H), 1'-cyclohexane 12. 02g and 1.48g of phthalic anhydride were heated together at 160°C for 3 hours, cooled, The resulting solid was crystallized from ethanol to give 4-phthalimidospiro[benzofuran]. -2 (3H).

1゛-cyclohexane] is obtained.

4-2 Talimidospiro[benzofuran-2(3H), l'-cyclohexane Example IE spiro[benzofuran-2(3H),1'-cyclohexane] ] When used in place of 4-phthalimidospiro[benzofuran-2 (3M) , 1'-cyclohexane 1-7-carboxylic acid is obtained.

8, 4-aminospiro[benzofuran-2(3H), l'-cyclohexane ]-7-carboxylic acid 4-phthalimidospiro[benzofuran-2(3H), 1'-cyclohexane Co-7-carboxylic acid 2. OOg and 0.60ml of 98% hydrazine in anhydrous ether Heat together and reflux in 40 ml of alcohol for 4 hours. the reaction mixture Cool, filter and evaporate the filtrate under reduced pressure. The residue was dissolved in 5% sodium hydroxide. The filtrate was adjusted to pH 7 with IN hydrochloric acid and the product was dissolved in chloride solution. Extract with tylene, wash, dry and evaporate. Flash the crude product. 4-Aminospiro[benzofuran-2(3H)] was purified by chromatography. , I'-cyclohexane]-7-carboxylic acid is obtained.

1, 4-amino-N-[1-azabicyclo[2,2,2]-3-octylco spiro[benzofuran-2(3)(),1'-cyclohexane]-7-carpox Samid 4-Aminospiro[benzofuran-2(3I(), In a solution of 1.43 g of 1'-cyclohexane]-7-carboxylic acid, N, N'- Add 1.4 g of dicyclohexylcarbodiimide. The mixture at 0℃ Stir for 1 hour and add 1.23 g of 3-aminoquinuclidine dihydrochloride. . The mixture is then warmed up and stirred at room temperature overnight. Sodium hydroxide solution of IN 8 ml are added and the mixture is stirred for 30 minutes and then filtered. residue or filtration Absorb the liquid in methylene chloride, wash with water, dry over magnesium sulfate, and concentrate to dryness. and 4-amino-N-[1-azabicyclo[2,2,2]-3-octylcose Pyro[benzofuran-2(3H).

1'-Cyclohexane]-7-carpoxamide is obtained.

Example 7 4-amino-N-[1-azabicyclo[2,2,2]-3-octyl]-5-k lorospiro[benzofuran-2(3F(),1'-cyclohexane]-7-cal 4-phthalimidospiro[benzofuran-2(3H), I''-cyclohexane ] (3F(), I'-Cyclohedoxun]-7-carboxylate used in place of 5-chloro-4-phthalimidospiro[benzofuran-2(3H), Prepare l'-cyclohexane]-7-carboxylic acid.

B 4-amino-N-[+-azabicycloC222-3-octyl]-5-k lorospiro[benzofuran-2(3H),1'-chlorohexane]-7-carpo Kissamide 5-chloro-4-phthalimidospiro[benzofuran-2(3F(), 1'- cyclohexane]-7-carboxylic acid in Example 6H. Zofuran-2(3H), used in place of l'-cyclohexyl-7-carboxylic acid 4-amino-N -[l-Azabicyclo[2,2,2]-3-octyl-5-chlorospiro[beta] Obtain nzofuran-2(3H), 1'-cyclohedrin]-7-carpoxamide .

Example 8 N-[1-Azabicyclo[2,2,2]-3-octylcola-promospiro[ Benzofuran-2(3H), I'-cyclohexaneco-7-carpoxamide N- Bromosuccinimide was used in place of N-chlorosuccinimide in Example IC. , when the corresponding products are treated as in Examples IH and II, N-[1- Azabicyclo[2,2,2]-3-octyl]-5-promospiro[benzofura 2(3H), 1'-cyclohexane]-7-carpoxamide is prepared.

Summary book The present invention relates to a species of spiro[benzofuran-2(3H), 1'-cycloalkaline Carboxamides and significant, unique central nervous system activity with no receptor binding , as 5HTI antagonists that foster anti-emetic activity and gastric prokinetic activity. Regarding the use of. The present invention also discloses the new method necessary for making those g4 .

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Claims (19)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 is hydrogen, alkyl, halo, amino, acetylamino, alkylamino, dia rkylamino or carbamyl, R2 is hydrogen, alkyl, halo, triflic Oromethyl, sulfamyl, mono- and di-alkylsulfamyl, alkyls sulfonyl, alkoxy, hydroxy, nitro, cyano, carboxy, carboal koxy or carbamyl, R3 is hydrogen or alkyl, R is 1-azabicyclo[2.2.2]-3-octyl, 1-azabicyclo[2. 2.2]-4-octyl, 1-azabicyclo[3.3.1]-4-nonyl, 9- Methyl-9-azabicyclo[3.3.1]-3-nonyl, 9-methyl-7-oxy Cir-9-azabicyclo[3.3.1]-3-nonyl or 1-(p-fluorophore enoxypropyl)-3-methoxypiperidin-4-yl, and n is 1, 2, 3 or 4) A compound represented by or a pharmaceutically acceptable salt thereof. 2. R is 1-azabicyclo[2.2.2]-3-octyl, 1-azabicyclo[ 2.2.2]-4-octyl or 1-azabicyclo[3.3.1]-4-noni The compound according to claim 1, which is 3. 2. A compound according to claim 1, wherein R2 is hydrogen or halo. 4. R1 is hydrogen, amino, lower alkylamino or di-lower alkylamino the law of nature, R2 is hydrogen or halo, and 3. A compound according to claim 2, wherein R3 is hydrogen. 5. 5. A compound according to claim 4, wherein n is 2. 6. 5. A compound according to claim 4, wherein n is 3. 7. Claims in which R1 is hydrogen or amino and R2 is hydrogen or halo A compound according to item 6. 8. N-[1-azabicyclo[2.2.2]-3-octyl]spiro[benzof Ran-2(3H),1'-cyclohexane]-7-carboxamide A compound according to scope item 7. 9.4-amino-N-[1-azabicyclo[2.2.2]-3-octyl]spi B[benzofuran-2(3H),1'-cyclohexane]-7-carboxamide The compound according to claim 7. 10. N-[1-azabicyclo[2.2.2]-3-octyl]-5-chloros Pyro[benzofuran-2(3H),1'-cyclohexane]-7-carboxami 8. The compound according to claim 7, which is 11. N-[1-azabicyclo[2.2.2]-3(S)-octyl]-5-k lorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carbo 8. The compound according to claim 7, which is a xamide. 12. N-[1-azabicyclo[2.2.2]-3(R)-octyl]-5-k lorospiro[benzofuran-2(3H),1'-cyclohexane]-7-carbo 8. The compound according to claim 7, which is a xamide. 13. N-[1-azabicyclo[2.2.2]-3-octyl]-5-bromos Pyro[benzofuran-2(3H), 1'-cyclohexane]-7-carboxa 8. The compound according to claim 7, which is a mido. 14.4-amino-N-[1-azabicyclo[2.2.2]-3-octyl]- 5-bromospiro[benzofuran-2(3H),1'-cyclohexane]-7- A compound according to claim 1 which is a carboxamide. 15.4-amino-N-[1-azabicyclo[2.2.2]-3-octyl]- 5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7- 8. The compound according to claim 7, which is a carboxamide. 16.4-amino-N-[1-azabicyclo[2.2.2]-3-octyl]- 5-chlorospiro[benzofuran-2(3H),1'-cyclohexane]-7- 6. The compound according to claim 5, which is a carboxamide. 17. Patients suffering from gastric prokinetic disorders should receive a gastric prokinetically effective dose. Claimed scope 1. Gastric prokinetic therapy, characterized in that the compound of the formula according to item 1 is administered. treatment for patients suffering from chronic disorders. 18. A compound of the formula according to claim 1 in an emetic-effective amount in a patient suffering from emesis. A method of treating a patient suffering from vomiting, characterized by administering. 19. An effective 5HT3 antagonistic amount of a compound according to claim 1 is mixed with a pharmaceutical carrier. A pharmaceutical composition comprising: