JPH07504192A - 2,6-methano-2H-quinolidine derivatives as 5-HT3 receptor antagonists - 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] Title of the invention 2,G-methanol 2H-quinolidi as a 5-HT3 receptor antagonist derivatives The present invention describes a novel 5-HT3 receptor antagonist, 5-chloro-2,3-dihydro- 2,2-dimethylbenzofuran-7-carboxylic acid-octahydro-3-hydroxy C-2,6-methano-2H-quinolidin-8-yl ester, process for its preparation, and 5-HT3 receptors, such as the nausea and vomiting induced by radiation therapy and chemotherapy. Treatment of symptoms that respond to antagonism, treatment of pain associated with migraine, treatment of Alzheimer's disease. Treatment of cognitive disorders such as hallucinatory internalization of the type exhibited in patients with schizophrenia and mania Treatment of sexual psychosis, treatment of irritative or inflammatory bowel diseases, or cessation of drug abuse Concerning end-use applications.

More specifically, the invention describes the formula compounds, their tautomers, stereo and geometric isomers and mixtures thereof, and pharmaceuticals. Use only acceptable salts. Oxygen in the ester moiety as used herein The atom is octahydro-2,6-methanol 2H-quinolidine moiety (hereinafter referred to as methano bridge) The wavy line bonding to the bridge quinolidinyl moiety (sometimes called the bridge quinolidinyl moiety) indicates that the bond is Indicates that it is in the indo (trans) or exo (ance) configuration. preferred solid The placement is at the end. The preparation of such geometric isomers is described in U.S. Pat. No. 4,906. , 755, but this can be done by the method and technique of 1p.g. Incorporated herein. Chirality at the 3-position of the methano-bridged quinolidinyl moiety is present, giving rise to the d- or 1-isomer and racemic mixtures thereof. as desired Therefore, the resolution of the racemate described above is carried out by e-semi-procedures and techniques well known in the art. Can be implemented. The (+) enantiomer is preferred.

The pharmaceutically acceptable acids and salts mentioned above are P! Organic acids, e.g. hydrochloric acid, bromide suitable acids such as hydrogen, nitric, sulfuric or phosphoric acids; or organic carboxylic acids, e.g. For example, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, Malic acid, tartaric acid, citric acid, salicylic acid, 2-acetyloquine benzoic acid, nicotine or isonicotinic acid; or organic sulfonic acids, such as methanesulfonic acid , ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 4-toluenosulfone acids, or non-toxic salts with NRIIs such as 2-naphthalenesulfonic acid. I can do it.

The preparation of the compounds of the present invention is shown in the Examples below. Hydro-2,2-dimethylhenzofuran-7゜carboxylic acid trans-oxyhydride Rho-3-hydroxy-2,6-methano-2H-quinolidin-8-yl ester stage Floor A: l = Liphosgene used 5-Chloro-2,3-dihuman 1m-2,2-dimepurhenzofuran 7-carbo 3-oxo-2,6-methano-21(-quinolidi) Triethylamine (1, 798), 4-dimethylaminopyridine (1,098) and 5-chloro-2,3 -Dissolution of dihydro-2,2-dimethylhenzofuran-7-carboxylic acid (3.8 g) The solution was stirred with triphosgene (5.28 g) in dichloromethane (100 ml). Add the solution slowly at 0°C, and continuously blow nitrogen into the mixture. After addition, the mixture was stirred at room temperature under nitrogen overnight, 11! filtered and evaporated.

A suspension of the residue in anhydrous toluene was diluted with hexahydrotohydroxy-2,6-meth A stirred suspension of no-2H-quinolidin-3(4H)-one (3°25 g) and They were allowed to reflux together overnight. Filter the cooled solution and wash the toluene with aqueous potassium carbonate solution. After drying over magnesium sulfate and evaporating, a residue containing the title compound ( 4.8g) was produced. Next, this was mixed with ethyl acetate (200 ml) and IN methanesulfate. M was prepared by distributing the mixture between Hon M (40 il). separated methane When a rubonic acid solution is made basic with a saturated aqueous solution of potassium carbonate, a crystalline solid forms, which Further, for example, crystallization from an aqueous methanol solution or silica gel chromatography Purification by a method yielded a pure sample of the title compound.

Step A' (instead of Step A) Use of nitrichloromethyl chloroformate 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carvone Acid trans-octahydro-3-oxo-2,6-methano・2■-quinolidine- 8-yl ester trichloromethylchlorophore in dichloromethane (fowl) Dissolved α of Noshimate (1.76g, 1.08ml) was added to dichloromethane (30ml). 5-chloro-2,3-dihydro-2,2-dimethylhenzofuran-7 in il) - Carbo; 0 in a mixed solution of M (2g) and triethylamine (1.4ml) Added at °C. Stir the mixture overnight at room temperature and add the salt (a water-cooled saturated aqueous solution of hyammonium). Washed with iα, dried with magnesium sulfate, and evaporated to yield an oil (2.2 g). . The oil (2.2 g), hexahythro-8-hydroxy-2,6-methano-2 )(-quinolidin-3(411)-one (1°6g> and toluene (30il) The stirred mixture was refluxed overnight. The unreacted end of Kisahitoroginori To remove the dione, the n-compound was cooled and washed with a saturated aqueous solution of potassium carbonate. Washed with water 21 times. Evaporating the dry toluene solution (MgSO4) leaves a solid residue. When this is recrystallized from ethyl acetate/.\xane, the title (arsenic compound (o, 3gg) was produced.

Stage PiB: 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-U/I, ;t? ＞　Ft、　l２１２２しにと’zt=l’田二と]-り大””人≦ Industrial methanol 2H-quinolizine 8-yl ester in ethanol (75 il) 5-chloro-2,3-dihydro-2,2-dimethylhenzofuran-7-carvone Acid trans-octahydro-3-oxo-2,6-methano-211-quinolidine -8-yl ester (3,9 g) was added to a stirred solution of sodium borohydride at room temperature. Lium (1.52 g) was added slowly and the mixture was stirred at room temperature overnight. ethanol evaporate and dissolve the residue in a mixture of water (201) and 2N hydrochloric acid (2On+l). and the acidic solution almost immediately by addition of an excess of saturated aqueous potassium carbonate solution. Made basic. Tetrahydrofuran/ethyl acetate (1:I) iHn compound extraction, Evaporation of the dry extract yielded the title compound. Melting point: 192-193°C.

Conversion to the methanesulfonate salt is performed by adding 1 equivalent of an alcoholic solution of methanesulfonic acid to the methanesulfonate salt. It was carried out by addition and solvent evaporation.

Racemic mixtures can be separated into their separate enantiomers by standard techniques .

The compounds of the present invention are effective for 5HT3 receptors on cardiac sensory neurons, known as 5HT3 receptors. Blocks the 1 receptor for hydroxytryptamine (5HT). 5HT3 The activity of the compounds of the present invention towards receptors was determined by J.R. Fozard (J.

R, F'ozard) et al., Eur, J, t"harmacol, vol. 50 + 95 -210 (1979), in isolated rabbit hearts. It can be evaluated by measuring A2M. 5HT3 receptor antagonist activity in vivo was injected intravenously into rats. can be evaluated by measuring the effect of a compound on curative delinquency [Beintal Ai Nis (1'aintal, A, S,), Physiol, Rev, 53, pp. 159-227 (1973); Naunyn-5ch+wiedeberg’s Arch, Pharmac ol, Vol. 326, pp. 36-44 (1984)).

51 (T3 receptor antagonist Use recognized standard procedures for demonstrating activity and for such purposes. Comparison with Ike's 5-1-IT3 receptor antagonist, which is known to be useful. According to the present invention, the compounds can be used for various treatments.

+12, the compounds of the present invention are effective against symptoms that respond to antagonism of the 5-If T3 receptor. Useful in treating. Examples of symptoms that respond to antagonism to 5-11T receptors are , for those skilled in the art, it is around λ〇. Some examples of these conditions are anxiety, psychosis, glaucoma treatment of gastric motility (U.S. Pat. No. 5,011,846), panic disorder thoughts, and/or obsessive phobia or obsessive-compulsive disorder (coIIlp) treatment of ulsive disorders (Patent CP 422,154); Automania that occurs in childhood with metal retarrlation. treatment of other disorders (patent El' 450,757): such as Alzheimer's disease Treatment of Cognitive Disorders (U.S. Patent Application No. 806.987); No. 742.951); serotonin-induced nasal disease, rhinitis , or a decrease in the behavior of trying to approach others under stressful situations (inpair) d approaCh-oriented behavior) or insomnia. Progression (Patent G[l　2,1!73.G3:J); Addiction to drug or substance dependence and/or alleviation or prevention of withdrawal symptoms resulting from suppression of dependence (Patent El” 27! 1.1 and G82.20 (i, 78B); treatment of pulmonary embolism (Patent Gll 2 , 231.205) Treatment of cough and/or bronchoconstriction (Special: 'FEP 340) ．． 270); Treatment of nausea, bradycardia, and/or hypotension associated with myocardial instability (Patent W O91/OD 503): r: f, loss g (J) treatment (1-ki permission EP 4G7.3G5): and ACE inhibition inhibition therapy (patent El'47) 7.625 and U El' 477, G34); 3-[2-(Tumedelamino ) combined with ethylcoat methyl-111-indole-5-methanesulfonamide therapy (patent EP 433,043), and histamine 1 (2-receptor antagonist) (Patent EP 275,669). See above for details Incorporated herein by.

A preferred use of the compounds of the invention is in patients undergoing treatment for specific cancers of group 11j. Treatment of nausea and vomiting induced by radiation therapy, migraine and neuralgia. Treatment of associated pain, memory and 3L cognitive dysfunction of V'2 disorders, and selective treatment of malfunctions, schizophrenia and chronic illness Q], and Thailand that appears in Tomoe soup This includes its usefulness in treating and stopping hallucinatory endogenous psychosis.

19ffffi to the patient is within the range of about 0.01 to about 10mg per kg of body weight 0.01 to Img per kg of body weight is preferred for parenteral administration; 0.251 mg is preferred for intestinal administration. Naturally, it is necessary to treat the above symptoms. The appropriate amount depends on factors such as the degree and stage of the particular disease, the age and condition of the patient, and Varies depending on other factors considered by the diagnostician. Treatment refers to the patient's illness or illness. means to prevent or alleviate symptoms.

m1 "Awn, person J (1, Laso l-, myna, dog, drawing, guinea pig, tau , and heart-blooded animals such as humans.

Compounds of formula (1) can be administered in a variety of ways to achieve the desired effect.

For oral administration, the compounds may be administered in capsules, pills, tablets, or lozenges (Iozer+). ges), melts, powders, suspensions, or emulsions (nights). You can do it. Solid unit a amount Cedar formula includes, for example, surfactants, lubricants, and lactose, rt! sugar , and regular gelatin containing inert fillers such as corn starch These may be in the form of capsules or they may be sustained release formulations.

In another ridge pattern, compound fI71 of formula (1) is combined with lactose, sucrose, and corn starch. together with conventional tablet bases such as arabicum, maize, eta, or gelatin. Bonds such as chlorine, phlegm, and potato starch and alginic acid; Tablets in combination with surfactants like allyic acid or magnesium stearate can be converted into Liquid formulations may contain suspending agents, sweetening agents, flavoring agents, The active ingredient is placed in an aqueous or non-aqueous solvent, which may also contain preservatives and preservatives. Prepared by dissolving min.

For parenteral administration, the compound is dissolved in a physiologically acceptable pharmaceutical carrier, m. '(l or !Q) can be administered.

Examples of suitable confectionery carriers are water, saline solution, degistrose solution, fructose soluble iα, ethanol. or oils of animal, vegetable or synthetic origin. Confectionery carriers are known for this technology. As such, preservatives, buffers, etc. may also be included.

The compounds of the invention may also be administered topically. This preferably promotes transdermal absorption. such as ethanol and dimethyl sulfoxide (DMSO), which are widely Simply dosing with or without other solvents and with or without other shaping. This can be achieved by creating a solution of the compound.

Local administration is accomplished using reservoir and porous membrane or solid-based patches. is preferable.

Some suitable transdermal devices include U.S. Pat. Nos. 3,742,951 and 3,79 7.4! '1.1, No. 3.9913.934, and No. 4,031,894 and are incorporated herein by reference. These devices are generally A backing material on one side and an activator-permeable adhesive layer on the other side. , and at least one reservoir layer containing an active agent sandwiched between the surfaces of the reservoir layer. are doing. Instead, multiple microcapsules distributed throughout the permeable adhesive layer Active agents can be included therein. In either case, the active agent is permeation of the active agent from the capsule through the membrane and into contact with the recipient's skin or mucous membranes. is continuously transported to the adhesive layer. If the active agent is absorbed through the skin, the active agent A controlled, predetermined flow is administered to the recipient. In the case of microcapsules, the cap The cell forming agent can also function as a membrane.

In another device for transdermal administration of compounds according to the invention, the pharmaceutically active compound is from which the compound is delivered at the desired slow, constant, and controlled rate. It will be revealed. The substrate is permeable to release of the compound by diffusion or porous flow. . Release is rate regulated. Such a system, which does not require a membrane, is described in U.S. Pat. No. 921,636, incorporated herein by reference. at least 2111 release is possible in these systems. Diffusional release occurs when the substrate is non-porous. Ru. The pharmaceutically active compound dissolves and diffuses into the substrate itself. microporous Flow-induced release involves transporting the pharmaceutically active compound through the liquid phase in the pores of the substrate. Occurs when

Specific formulations of the invention are made by methods well known in the U-straw technology and are generally pharmaceutically acceptable. one of the inventions mixed with or otherwise associated with the carrier or diluent in which it is introduced. The active compounds listed above are included. The active ingredient is mixed with a carrier or with a diluent. diluted or enclosed in a capsule, sacini, cachet, or other container; or encapsulated. The carrier or diluent can be solid, semisolid, or liquid and Serves as a vehicle, auxiliary, or medium for ingredients. A suitable carrier or diluent is , is well known in this technology. For FA's description of such formulations, please refer to this specification. “Remington Pharmaceutical Science 1” included in the book (Mac Publishing Co., Ltd., pencil version for See Stone).

international search report

Claims (8)

[Claims] 1. formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ compounds, their tautomers, stereo and geometric isomers, and mixtures thereof; and its pharmaceutically acceptable salts. 2. A compound according to claim 1 for use as a pharmaceutically active compound. 3. Treatment of nausea and vomiting, treatment of migraines, treatment of cognitive disorders, schizophrenia and mania. Claims used to treat, treat irritable or inflammatory bowel syndrome, or treat drug abuse A compound according to item 1. 4. a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition. 5. Treatment of nausea and vomiting, treatment of migraines, treatment of cognitive disorders, schizophrenia and mania. Claims used to treat, treat irritable or inflammatory bowel syndrome, or treat drug abuse Item 4. Pharmaceutical composition according to item 4. 6. Treatment of nausea and vomiting, treatment of migraines, treatment of cognitive disorders, schizophrenia and mania. A pharmaceutical composition for the treatment of irritable or inflammatory bowel syndrome, or for the treatment of drug abuse. May be combined, if necessary, with a pharmaceutically acceptable carrier for the preparation of Use of the compound according to claim 1. 7. Treatment of nausea and vomiting, treatment of migraines, treatment of cognitive disorders, schizophrenia and mania. Claim 1 for the treatment of irritable or inflammatory bowel syndrome, or for the treatment of drug abuse. A method of treating a patient in need of such treatment with an effective amount of a compound described above. 8. alcohol ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Oxo derivatives ▲Mathematical formulas, chemical formulas, tables, etc. ▼ react with a suitable reducing agent and, if necessary, form a pharmaceutically acceptable salt. Depending on the situation, there are formulas▲mathematical formulas, chemical formulas, tables, etc.▼ A method for producing a compound with