FI105917B - Process for the preparation of a therapeutically active 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid octahydro-3-hydroxy-2,6-methano-2H-quinolizin-8-yl ester - Google Patents

Description

1 105917

The present invention relates to 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid octahydro-3-hydroxy-2,6-methano-2H-quinolizin-8-yl ester. Preparation of -2,3-Dihydro-2,2-dimethylbenzofuran-7-carboxylic acid octahydro-3-hydroxy-2,6-methano-2H-quinolizin-8-yl ester, a novel 5-HT 3 receptor antagonist . The compound is useful in the treatment of conditions responsive to 5-HT 3 receptor antagonism such as radiation and chemotherapy nausea and vomiting, in the treatment of migraine pain, in the treatment of consciousness disorders such as Alzheimer's disease, in the treatment of endogenous psychosis, hallucinations that occur in patients with schizophrenia and mania when treating irritable or inflammatory bowel disease or in combating drug / drug abuse:

More particularly, the present invention relates to a process for the therapeutically active 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid octahydro-3-hydroxy-2,6-methano-2H-quinozilin-8. -yl ester of formula (I)

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O-C C 30 30 h h hcLLLLL J J J 105 105 105917 and its tautomers, stereoisomers and geometric isomers, and mixtures thereof, and pharmaceutically acceptable salts thereof.

The wavy line used here that binds the ester 5 moiety to the 8-position of the octahydro-2,6-methano-2H-quinolizine moiety of the oxygen atom (sometimes also referred to as the methano-bonded quinolizinyl moiety) indicates that the bond may be endo- in an exo- (cis-) configuration. The preferred configuration is endo. The preparation of such geometric isomers may be accomplished by the methods, techniques and techniques of U.S. Patent 4,906,755, which is incorporated herein by reference. Chirality occurs at the 3-position of the methano-bonded kindinyl moiety, which represents the d- or 1-isomers and their racemate mixtures. If desired, the cleavage of said racemates can be accomplished by standard techniques and techniques well known in the art. The (+) - enantiomer is preferred.

The above pharmaceutically acceptable acid-addition salts may be non-toxic salts formed with suitable acids, such as salts with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid; or organic acids such as organic carboxylic acids such as acetic, propionic, glycolic, maleic, maleic, tartaric, citric, salicylic, 2-acetyloxybenzoic, nicotinic, or with isonicotinic acid; or with organic sulfonic acids, such as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalenesulfonic acid.

The compound of formula (I) is prepared according to the invention by reacting an oxo derivative of formula (II) 35, 105917 ° -115 ° C with a suitable reducing agent at about room temperature until the alcohol of formula I is formed and, if desired, forming a pharmaceutically acceptable salt thereof.

The preparation of the compounds of the present invention may further be illustrated by the following example.

Example 5-Chloro-2,3-dihydro-2,2-dimethyl-benzofuran-7- • carboxylic acid trans-octahydro-3-hydroxy-2,6-methano-2H-20-quinolizin-8-yl ester

Step A: Using Triphosgene 5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid trans-octahydro-3-oxo-2,6-methano-2H-quinolin-8-yl ester 25 containing triethylamine (1.79 g), 4-dimethylaminopyridine (1.09 g) and 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid (3.8 g) in dichloro methane (75 mL) was added slowly to a stirred solution of triphosgene (5.28 g) in dichloromethane 30 (100 mL) at 0 ° C and nitrogen was continuously added. After the addition was complete, the mixture was stirred at room temperature overnight under a nitrogen atmosphere, filtered and evaporated.

A suspension of the residue in anhydrous toluene-35 was heated at reflux, together with 4 105917 a stirred suspension of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one (3.25) g), overnight. The cooled solution was filtered, the toluene washed with aqueous potassium carbonate, dried over magnesium sulfate and evaporated to give a residue (4.8 g) containing the title compound. It was then purified by partitioning between ethyl acetate (200 mL) and 1N methanesulfonic acid (40 mL). By basifying the separated methanesulfonic acid solution with a saturated aqueous solution of potassium carbonate 10, a crystalline solid was obtained which was further purified by crystallization, e.g. from aqueous methanol or silica gel chromatography to give a pure sample of the title compound.

Step A '(Alternative to Step A): Using trichloromethyl-15 chloroformate, 5-chloro-2,3-dihydro-2,2-dimethylbenzouran-7-carboxylic acid trans-octahydro-3-oxo-2,6-methanoic acid. 2H-Quinolizin-8-yl ester: A solution of trichloromethyl chloroformate 20 (1.76 g, 1.08 mL) in dichloromethane (10 mL) was added to a stirred solution of 5-chloro-2,3-dihydro-2 , 2-dimethylbenzofuran-7-carboxylic acid (2 g) and triethylamine (1.4 ml) in dichloromethane (30 ml) at 0 ° C. The mixture was stirred overnight at room temperature, washed with ice-cold saturated aqueous ammonium chloride solution, dried over magnesium sulfate and evaporated to give an oil (2.2 g). A stirred mixture of an oil (2.2 g), hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one (1.6 g) and toluene (30 mL) was heated at reflux overnight. The cooled mixture was washed with a saturated aqueous potassium carbonate solution and then four times with water to remove any unreacted hexahydroquinolizine ion. Evaporation of the dried toluene solution (MgSO 4) gave a solid residue which was recrystallized from ethyl acetate / hexane to give the title compound (0.35 g).

Step B: 5-Chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-5 carboxylic acid trans-octahydro-3-hydroxy-2,6-methano-2H-quinolizin-8-yl ester

Sodium borohydride (1.52 g) was added slowly to a stirred solution of 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid-trans-ox-10 tachydro-3-oxo-2,6-methano -2H-quinolizin-8-yl ester (3.9 g) in ethanol (75 ml) at room temperature and the mixture was stirred at room temperature overnight. The ethanol was evaporated, the residue was dissolved in a mixture of water (20 ml) and 2N hydrochloric acid (20 ml), and the acid solution was made almost immediately basic by the addition of excess saturated aqueous potassium carbonate. Extraction with a mixture of tetrahydrofuran-ethyl acetate (1: 1) and evaporation of the dried extract gave the title compound, m.p. 192-193 ° C.

* k 20 Conversion to the methanesulfonate salt was accomplished by adding one equivalent of an alcoholic solution of methanesulfonic acid and evaporating the solvent.

The racemic mixture can be resolved into its separate enantiomers by basic methods.

The compounds of formula (I) block M-receptors, otherwise known as 5-HT3 receptors, on 5-hydroxytryptamine (5HT) afferent sensory neurons. The activity of the compounds of formula (I) against 5-HT3 receptors can be assessed by determining their pA2 values in isolated rabbit heart ~ J.R. Fozard et al., Eur. J. Pharmacol. 59.

195-210 (1979). The in vivo 5HT3 receptor antagonist effect can be evaluated by measuring the effect of the compound on the Von Bezold-Jarisch reflex induced by 5HT injected intravenously into 105917 rats (see Paintal AS, Physiol. Rev. 53, 159- 227 (1973); JR Fozard, Naunyn-Schmiedeberg's Arch. Phamacol., 22 £, 36-44 (1984).

Using the above standard methods, as well as other standard methods known to illustrate the effect of 5-HT 3 receptor antagonist on the aforementioned end use applications, as well as comparing other 5-HT 3 receptor antagonists known to be useful for such purposes, compounds of Formula 10 (I) in many different treatments.

In general, compounds of formula (I) are useful in the treatment of conditions responsive to 5-HT 3 receptor antagonism. Examples of conditions responsive to 5-HT 3 receptor antagonism are well known to those skilled in the art. Some examples of these conditions include the treatment of anxiety, psychosis, glaucoma, and stimulation of bowel activity (U.S. Patent No. 5 011 846), PA-f panic disorder and / or agoraphobia or obsessive "April 20 miellehäiriöiden (Patent No. EP 422 154) ; treatment of autism or other childhood disorders associated with mental retardation (Patent No. EP-450,757); the treatment of disorders of consciousness such as Alzheimer's disease (U.S. Patent Application Serial No. 806,987); Producing an orexiogenic effect (U.S. Patent Application Serial No. 742,951); serotonin-induced nasal disorders, hay fever, or impaired approach-oriented behavior in stress situations or increased insomnia (Patent No. GB-2,193,633); alleviation or prevention of withdrawal syndrome due to drug or drug addiction and / or withdrawal of drug or drug addiction (Patent Nos. EP 279,114 and GB-2,206,788); treatment of pulmonary embolism (patent No. GB-2,213,265), treatment of cough and / or bronchoconstriction 35 (patent EP-340,270); treatment of nausea, low heart rate 7 105917 and / or low blood pressure related to myocardial imbalance (Patent No. WO91 / 09593); treatment of urinary incontinence (Patent No. EP-467,365); and combination therapy with ACE inhibitors (Patent No. 5, EP-477 625 and EP-477 624), 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (Patent No. EP -433,043); a histamine H 2 receptor antagonist (EP 275 669). All of the foregoing is incorporated herein by reference.

Preferred uses of the compounds of formula (I) are in the treatment of nausea and vomiting, in particular in the treatment of nausea and vomiting caused by radiation and chemotherapy in patients treated for cancer, the treatment of pain associated with migraine and nerve pain, disorders of conscious behavior, - and learning disorders as well as treatment of selective attention disorders, endogenous psychosis associated with the hallucinations, and manifesting themselves • "nee patients suffering from schizophrenia and manias- 20 of, treatment of irritable or inflammatory bowel care, and in addition, they are useful as drugs / drug abuse.

Dosages for patients are about 0.01 to 10 mg / kg body weight, and 0.01 to 1 mg / kg body weight are preferred for parenteral administration, 0.25 to 1 mg / kg body weight for oral administration. . Of course, the dosage required to treat the above conditions will depend on factors such as the severity and condition of the particular disease, the age and condition of the patients, and other normal factors that the attending physician will consider.

The term "patient" refers to warm-blooded animals such as rats, mice, dogs, cats, guinea pigs, and humans. The term "treating" refers to preventing or ameliorating a patient's disease or condition.

The compounds of formula (I) may be administered in various ways to achieve the desired effect. For oral administration, the compounds may be formulated in solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, powders, suspensions or emulsions. The solid unit dosage forms may be in the form of conventional gelatine-type capsules containing, for example, surfactants, lubricants, and inert excipients such as lactose, sucrose and corn starch, or they may be in the form of controlled release preparations. In another embodiment, the compounds of formula (I) may be tabletted with known tablet bases such as lactose, sucrose and corn starch together with binders such as acacia, corn starch or gelatin, disintegrating agents such as potato starch or alginic acid, 20 with magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or aqueous pharmaceutically acceptable solvent which may contain suspending agents, sweetening agents, flavoring agents, and preservatives known in the art of pharmacy.

For parenteral administration, the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered either as a solution or as a suspension. Examples of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol or animal, vegetable or synthetic oils. The pharmaceutical carrier may also contain preservatives, buffers, etc. known in the pharmaceutical art. The compounds of formula (I) may also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote dermal absorption such as ethanol or dimethylsulfoxide (DMSO), with or without other excipients. . Preferably, topical administration is effected using a patch having a reservoir and a porous membrane or some sort of solid matrix.

Some suitable transdermal drug delivery devices are described in U.S. Patent Nos. 3,742,951, 3,797,494, 3,996,934 and 4,031,894, which are incorporated herein by reference. These devices typically comprise a backing film defining one of its side surfaces, and an active agent-permeable adhesive layer defining the other 15 side surfaces, and at least one container containing the active agent between the side surfaces. Alternatively, the active ingredient may be in a plurality of micro-capsules distributed throughout the permeable adhesive layer. Either way impressive

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20 agents are continuously released from the container or microcapsules through a membrane-permeable adhesive layer in contact with the recipient's skin or mucosa. If the active ingredient is absorbed through the skin, the recipient will receive a controlled and predetermined stream of 25 active ingredients. In the case of microcapsules, the encapsulating material may also act as a film.

In another device for transdermal delivery of compounds of formula (I), the pharmaceutically active compound is contained in a matrix from which it is released at a desired rate, constant and controlled rate. The compound is released by passing the matrix through diffusion or microporous flow. Release regulates speed. Such a non-membrane system is described in U.S. Patent No. 3,921,636, which is incorporated herein by reference. At least two modes of release are possible in these systems. Release by diffusion occurs when the matrix is non-porous. The pharmaceutically active compound dissolves and diffuses through the matrix itself. Release via microporous flow occurs as the pharmaceutically active compound is transported through the liquid phase in the pores of the matrix.

Specific formulations are prepared in a manner known per se in pharmaceutical technology, and will usually comprise one or more active compounds of formula (I), in admixture or otherwise with a pharmaceutically acceptable carrier or diluent. The active ingredient is usually admixed with the carrier or diluted with a diluent, or enclosed or encapsulated in a capsule, sachet, starch capsule, paper or other container. The carrier or diluent may be a solid, semi-solid or liquid substance which acts as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are known per se. See descriptions of Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, herein incorporated by reference, for the preparation of such formulations.

Claims (1)

11 105917 Claim 'Method for the therapeutically active 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid ox-5 tachydro-3-hydroxy-2,6-methano-2H-quinozilin-8-yl ester for the preparation of formula (I) aoY ^ P ^ 10 o 10 h3c -JL Hjc - | -L ^ JLci 15 and its tautomers, stereoisomers and geometric isomers, and mixtures thereof, and pharmaceutically acceptable salts thereof, characterized in that an 'oxo derivative of formula (II) ·' is introduced. with a suitable reducing agent at about room temperature until the alcohol of formula I is formed and, if desired, forming a pharmaceutically acceptable salt thereof. 12 105917 Forms of 5-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7- carboxyl-5-cyano-octahydro-3-hydroxy-2,6-methano-2H-quinosilin-8-yl ester med formel (I) B HO ^ q 10 (I) H3c-Cl15 and tautomer, stereoisomer and geometric isomer dharav och blandningar av dessa samt pharmaceutiskt godtag-bara salter därav, tannat av att et oxoderivat med medel (II) 20 ° γ * <3CiX4 (ii) CH3 I ^ ci ° '''τΓΊ 25 (J-cci omsätts med ett warming) reduceringsmedel v id ca rumstem-peratur tulles en alcohol med formeln I harildats, och om 30 öskas, b b, ettaceut ett b b ett ett ett ett ett ett ett farm farm farm farm farm farm farm farm farm farm farm farm farm farm farmttttt t god godttttttttt.