FI91154C - Analogous Process for Preparing Therapeutically Usable Ester Derivatives of Hexahydro-8-Hydroxy-2,6-Methano-2H-Quinolizin-3 (4H) -one - Google Patents

Description

i 91154

The present invention relates to an analogous process for the preparation of therapeutically useful hexahydro-8-hydroxy esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one. For the preparation of ester derivatives of 6-methano-2H-quinolizin-3 (4H) -one of formula 10 V - and 15 wherein Rx is ^ R10,

Ori -

20 * N

R 9 wherein R 1 is hydrogen or C 1-6 alkyl and R 10 is hydrogen or C 1-6 alkyl; and the wavy line indicates that the configuration of the oxygen substituent 25 in the ring may be endo or exo; as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts.

Examples of the aforementioned C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl and butyl.

When the wavy line in the general structural formula is converted to a straight line, this indicates that the configuration of the compounds is endo. By such endo-compounds, myOs can be meant in the form trans. Similarly, exo compounds can be referred to as the cis form.

·: 35 Hydrates of any of the foregoing ·; are given as equivalents with the compounds themselves and include compounds in which the carbonyl (i.e., the group S = O in the ring) is present in the form (= OH) 2.

Preferred group S compounds are those in which the ester is attached to the polycyclic ring in the endo configuration.

The aforementioned pharmaceutically acceptable acid addition salts may be non-toxic salts formed with suitable acids such as inorganic acids, for example hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid; or with organic acids such as organic carboxylic acids, for example acetic, propionic, glycolic, maleic, hydroxymalein, malic, tartaric, lemon, salicylic, 2-acetyloxybenzoic, nicotinic or with isocotinic acid; or with organic sulfonic acids, for example methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalenesulfonic acid. Quaternary ammonium salts are formed with alkyl halides such as methyl chloride, methyl bromide, methyl iodide or ethyl bromide; or with sulfate esters such as methyl 4-toluenesulfonate or methyl 2-naphthalenesulfonate.

The following are specific examples of compounds useful in the present invention: endo-hexahydro-8- (1-methyl-3-indazolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one, endo- hexahydro-8- (3-indazolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one.

The analogous process according to the invention for the preparation of the ester derivatives of hexahydro-8-hydroxy-2,6-methano-2H-quinolithin-3 (4H) one and their salts described above is characterized in that the alcohol of formula

II

91154 3 wherein the wavy line represents the same as above, or a reactive derivative thereof is reacted with an acid of the formula

5 RiCOOH

wherein Rx is as defined above, or with its reactive equivalent.

Reactive equivalent of an acid means 10 corresponding acid chlorides or bromides; or the corresponding Gly-oxylyl chloride or bromide; or a carboxylic acid imidazole obtained by the reaction of a suitable acid halide with N, N-carbonyldiimidazole; or any similar acid derivative which would produce a simple carboxylic acid ester upon reaction with an alcohol or a reactive alcohol derivative. More specifically, when -OH in an alcohol is equatorial (exo), it can be reacted with the appropriate carboxylic acid imidazole obtained from the reaction of an acid halide and N, N-carbonyl-20-diimidazole. Alternatively, the acid can be converted to the acid chloride by standard procedures (e.g., thionyl chloride) and then reacted with an alcohol or an alkali metal salt of the alcohol, such as a lithium salt, obtained from the reaction of lithium hydride and alcohol in tetrahydrofuran.

When the OH group in the starting alcohol is axial (endo), it can be converted to the corresponding ester by reaction with a suitable acid chloride or bromide so that the reaction is carried out in an equivalent amount of a suitable tertiary base such as 4-dimethylaminopyridine. in a solvent such as xylene. In this case, however, prolonged heating (24 to 28 hours) in a lamp room of 140 ° C or higher is not required, so that the procedure would not be suitable for use with acid halides which are not • · · · «« 4 stable. in the circumstances mentioned. Tate was advised to use an alternative procedure for the preparation of such compounds. In this procedure, a suitable acid chloride or bromide or glyoxyllyl chloride or 5-bromide in a nitroparaffin solvent is reacted with a solution of an alcohol superacid salt and an equivalent amount of the heavy metal salt of the same superacid. Glyoxylyl chloride can be used in said process because it is easily decarbonylated under the conditions used. The reaction itself can be carried out for about 1 to 24 hours at temperatures ranging from -80 ° C to ambient temperatures (about 23 ° C). Examples of suitable superacids where M = H are MBF 4, MAsF 6, MSbF 6 / MPF 6. MTaF6 or MNbF6, with examples of suitable ras-15 casmetals (M) being silver and thallium Examples of nitroparaffin solvents are nitromethane, nitroethane, 1-nitropropane and 2-nitropropane.

In fact, when the group R: contains a secondary amino group, it is usually protected from the benzyl group during the excess reaction. The product is deprotected by conventional procedures, for example by hydrogenation with hydrogen and a palladium catalyst.

The alcohol used as a reactant in the process described above can be obtained from known alkyl 25 (O) -4-cyclopentene-1-carboxylates in a multi-step process. In particular, the double bond in said cyclopentene is oxidized to 1,2-diol using N-methylmorpholine N-oxide in the presence of an osmium tetroxide catalyst. The diol is then decomposed into the corresponding dialdehyde using sodium metaperiodate. Robinson-Schttpf cyclization of the dialdehyde with a lower alkylglycine ester and acetonecarboxylic acid, preferably at pH 4, gives the following type of pseudopelletierine derivative: 91154

O

II

EtOCCH2 \

OF

EtOC-

O

10

The ketone group is reduced to the alcohol using sodium borohydride and the product is reacted with dihydropyran to protect the -OH group with tetrahydropyranyl ether. Dieckmann cyclization of Dlesterl using a strong base (e.g. potassium t-butoxide) followed by acid hydrolysis in aqueous solution and decarboxylation gives the desired alcohol. The alcohols common to Jaije can exist in two conformations: axial and equatorial.

The main product obtained from the above reaction is an axial alcohol and can be separated from the equatorial isomer by crystallization from a camphor sulfonate or tetrafluoroborate salt.

The compounds of the invention are useful in the treatment of pain, especially migraine, vascular and cluster obstruction and trigeminal neuralgia. They are also useful in the treatment of nausea and in the treatment of vomiting caused by chemotherapeutic agents due to the treatment of sybva.

In the past, acute migraine attacks have been treated with 30 peripheral vasoconstrictors (airway nervous system contractors), such as ergotamine, which can be administered with caffeine, and dihydroergotamine; antipyretic-Silia analgesics (analgesic antipyretic) such as acetosalicylic acid or p-acetylaminophenol and / or 35 antiemetics such as cyclizine, metoclopramide and 6-thyletherazine. It has also been reported (J.B. Hughes, Med. J. Aust. 2, No. 17, 580 (1977)) that relief of incipient migraine can be initiated by a slow intramuscular injection of metaoclopramide (10 mg).

5 It is believed that 5-hydroxytryptamine (5-HT) is a naturally occurring Alne that is most likely to be labeled in the pathophysiology of migraine. After ingestion, 5-HT and its metabolite, 5-hydroxyindole-acetic acid, are excreted in the urine at the onset of most seizures. Llsaksl plasma and verlhlutalelden 5-HT levels fall rapidly at the beginning of the seizure and split into low slksl for a period of time as the scarlet fever continues. Llsdksl migraene attacks have been clearly associated with certain individuals during the trompocytopenia season. It has been suggested that compounds that block 5-HT activity would be useful in the symptomatic treatment of migraine (JR Fozard, Congress of the International Paansarky 1980, reported in Advances in Neurology, Vol 33., Raven Press, New York, 1982).

Known anti-migraine drugs, methysergidil, propranolol, amitriptyline, and chloropromazine have very different pharmacological functions, but all are 5-HT-D receptor antagonists at doses used clinically for the prevention of migraine. Metoclopramide is a potential 5-HT-M receptor antagonist! and it has been suggested (J.R. Fozard supra) that M-receptor blockade, which occurs in afferent sensory nerves, allows for symptomatic relief in an achilles migraine attack.

The 5-HT receptor antagonist activity of (-) - cocaine and some related compounds, including pseudotropyl benzoate (i.e., benzoyl-pseudotropin) and 3,5-dichlorobenzoyltropine, has been described (JR Fozard et al., Eur. J. Pharmacol ., 59, (1979) 195-210; JR 35 Fozard, Naunyn-Schmiedeberg's Arch Pharmacol., 326, 91154 7 (1984), 36-44). The pA2 values reported for metoclopramide, pseudotropyl benzoate, and (-) - cocaine, and benzoyltropine are 7.2, 7.0, 7.7, and 7.2, respectively, while the pA2 value is defined as 5 For 3,5-dichlorobenzoyltropine, the same procedure is 9.3 (JR Fozard et al., Eur. J. Pharmacol., 49, (1978) 109-112; JR Fozard Naunyn-Schmiedeberg's Arch Pharmacol., 326 (1984)). 36 - 44). In a double-blind clinical trial, 3,5-dichlorobenzoylropropin was shown to be effective in 10 cases of acylic migraine seizures (C.

Loisy et al., Cephalalgia, 5, (1985) 79-82). An additional set of tropine esters in which pA2 values for 5-HT-M receptor blockade are deficient at 7.7 and 13.6 are described in Rlchardson et al. tolmesta, Nature, 316, (1985) 26 - 15 131.

The compounds of the present invention block 5-hydroxytryptamine (5-HT) M receptors in afferent neurons, some of which act as analgesics for pain. As in the case of over-the-counter, blockade of the M-re-20 receptor appears to be a mechanism by which the shoulder blades are relieved. Accordingly, the compounds in question are useful in the manufacture of a mgreen when used in a manner that is effective in blocking the m-receptor.

In addition, compounds that block 5-HT-M receptors, including metoclopramide, 3,5-dichlorobenzoyltropine, and (3-α-tropanyl) -1H-indole-3-carboxylic acid ester, are very effective in preventing nausea and vomiting caused by chemical chemotherapeutic agents in a non-model experiment (WD Miner et al., Brit. J.

Pharmacol., 88, (1986) 374P; W. D. Miner and G.J. Sanger, Brit. J. Pharmacol., 88, (1986) 497-499; B. Costall et al., Neuropharmacology, 25, (1986) 959-961). Vomiting from cytotoxic drugs is believed to involve a 5-HT-M receptor mechanism (W.D. Miner and G.J.

8

Sanger, Brit. J. Pharmacol., 88, (1986) 497-499). Based on this, the agents in question are useful in the treatment of vomiting caused by cytotoxic drugs when used to adequately block said M-5 receptors.

The activity of the compounds against 5-HT can be assessed by determining their pA2 values in an isolated canine heart as described in J.R. Fozard et al., Eur. J. Pharmacol., 59, 195-210 (1979). In the described method, the molar concentration of antagonist that reduces the effect of double the 5-HT EDSO on the effect of EDSO obtained in the absence of the antagonist is determined. The pA2 value is the negative logarithm of said molar concentrations. In general, the higher the pA2 value, the more effective the substance. When tested in this way, the pA2 values of the substances in question are generally in the range of 8-10.

The activity of these compounds against 5-HT can be determined by measuring in vivo the effect of the compound on the Von 20 Bezold-Jarisch reflex induced by intravenous injection of 5-HT in rats (see Paintal AS, Physiol. Rev., 53, 159 227 (1973), JR Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, (1984) 36-44).

The transient slowing of the heart is due to the increased activity of the 25 afferent circulatory nerve (vagus) due to the stimulation of afferent nerve targets inside and outside the heart.

The compounds in question appear to be highly selective in their activity against the 5-HT-M receptor. Their potency against other 5-HT receptors and other spasmogens, especially carbachol, phenylephrine, histamine and calcium, is known to be at least 3 orders of magnitude lower than against 5-HT-M receptors. Accordingly, their use in the treatment of migraine and vomiting due to cytotoxic drugs should not be associated with any side effects.

91154 9

The subject compounds can be administered in a variety of ways to achieve the desired effect. The compounds may be administered alone or in the form of pharmaceutical preparations to a patient to be treated orally or parenterally, for example, subcutaneously or intravenously. They can be given by myds inhalation or Pera needles. The amount of agent to be administered will vary and may be any amount effective in relieving migraine or effective amount of vomiting caused by cytotoxic drugs. Depending on the patient and the route of administration, the amount of substance to be administered may vary over a wide range, ranging from about 0.01 to 10 mg / kg, usually 0.03 to 3.0 mg / kg, of the patient's body weight per dose. Unit doses of these substances may contain, for example, about 0.5 to 100 mg, usually 1 to 50 mg and preferably 30 mg of the substance, and may be administered, for example, one to four times a day.

The term "unit dosage form" is used herein to mean a single or multiple dosage form containing the active ingredient in admixture or otherwise in association with a solvent or carrier, said amount being such that one or more of the previously defined unitary dosages will normally be required. In the case of multiple dosage forms, such as liquids or divided tablets, said aforementioned unit is one part, such as 5 ml (teaspoonful) of liquid volume or half or a quarter of the tablet obtained, of a multiple dosage form.

Specific formulations of the subject compounds are prepared in ways well known per se in the pharmaceutical art and generally contain one or more of the active compounds of the invention in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent therefor. The active ingredient 35 is usually mixed with a carrier or dissolved in a solvent or contained in or encapsulated in a capsule, sachet, cachet, other packaging of paper, and the carrier solvent may be a solid, semi-solid, or liquid material. as a solvent, excipient or excipient for the active ingredient Suitable carriers or solvents are well known per se, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, for a description of the preparation of such formulations.

Such formulations may be applied to enteral or parenteral administration and may be administered to a patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like.

The compounds of the invention can be used in the treatment of migraine with other antimigraine drugs having different modes of action. These drugs include prophylactic drugs such as barbiturates, diazepam, chloropromazine, amitriptyline, propranolol, methysergide, pitsotifen, cypro-20 rheptadine, dihydroergotamine, and clonidine, and drugs that are controlled by kSytin astringents, for example ergotamine and dihydroergotamine, analgesics / anti-inflammatory agents, for example aspirin, paracetamol and indomethacin, or anti-nausea drugs, for example, cyclicin, metoclopramide and thiethylperazine (see JF Fozard, J. Pharm. Pharm. , 297-321 (1975); JR Saper, J. Amer. Med. Assoc., 239, 480-484 (1978); JR Fozard supra). By way of example, the compounds of the invention would be useful in combination with 300 to 1200 mg of aspirin or 2 to 6 mg of methysergide administered individually.

The following examples are provided to illustrate the compounds used in the present invention, but should not be construed as limiting it in any way.

91154 11

Example 1

To a stirred solution of 160 g of diethyl malonate in 1.5 liters of dimethylformamide at 0 ° C under nitrogen was added 30 g of lithium hydride. When the evolution of hydrogen ceased (2 hours), 143 g of cls-1,4-dichloro- After 72 hours, the mixture was diluted with a mixture of ether and hexane (1: 4) and poured into water. gave diethyl 3-cyclopentene-1,1-dicarboxylate, bp 70-80 ° C / 0.1 mm, containing a small amount of diethyl 2-vinylcyclopropane-1,1-dicarboxylate.

The crude cyclopentene diester (148.5 g) obtained in Y113 was added to a solution of 118 g of potassium hydroxide in 1333 ml of 80% ethanol, and the stirred solution was heated at 60-70 ° C above. The ethanol was evaporated and treated with a solution of concentrated sulfuric acid (107 ml) in water (274 ml). Extraction of the acid mixture with ether-ether (3 x 400 ml) followed by evaporation of the dried ether extracts gave J33nn0s divalent acid which was decarboxylated to the monobasic acid in a 13mmitt3m31-13 dle oil bath at 170-180 ° C for one hour. J33n-25 nOil oil was distilled to give crude 3-cyclopenten-1-carboxylic acid, b.p. 68-73 ° C (1 mm), slightly with V-vinyl-V-butyrolactone. A solution of 98 g of potassium carbonate in 300 ml of water was added and the mixture was extracted with ether to remove V-vinyl-T-butyrolactone. Acidification of the solution and extraction with ether gave pure 3-cyclopentene-1-carboxylic acid.

Example 2

A mixture of 52 g of 3-cyclopentene-1-carboxylic acid and excess thionyl chloride was stirred at room temperature for one hour. The excess thionyl chloride was evaporated and the residue was distilled to give 3-cyclopentene-1-carbonyl chloride, b.p. 52 - 58 "C.

The acid chloride obtained above was slowly added to a cold stirred solution of 32 g of pyridine 150 in 5 ml of ethanol. The mixture was stirred for a further hour, the ethanol was evaporated and the residue was treated with water and ether. The ether layer was separated, washed several times with ve-Del and dried. Evaporation of the ether continued to give ethyl 3-cyclopentene-1-carboxylate, b.p. 62.5 -10 66 ° C / 14 mm.

Example 3

A solution of 84.6 g of N-methylmorpholine N-oxide, 1 g of osmium tetroxide, 230 ml of water and 115 ml of acetone was stirred at room temperature for 30 minutes. A solution of 80 g of ethyl 3-cyclopentene-1-carboxylate in 115 ml of acetone was added to the stirred mixture very slowly over 8 hours. The stirred mixture was heated at 50 ° C for 2 hours to quench the reaction (confirmed by TLC using ethyl 20 acetate / hexane 70/30). Sodium bisulfite (10 g) was added, stirring was continued for another 15 minutes, and the mixture was filtered through Celite. The pH of the filtrate was adjusted to 7 with 12 N sulfuric acid (37 ml), the acetone was evaporated, the pH of the solution was adjusted to two with 12 N sulfuric acid (13 ml) and the solution was extracted with ethyl acetate (4 x 250 ml). Evaporation of the dried ethyl acetate solution gave 4-ethoxycarbonyl-1,2-cyclopentanediol.

Example 4

A solution of 85.4 g of sodium periodate 500 in 30 ml of water was slowly added to a stirred solution of 69 g of 4-ethoxycarbonyl-1,2-cyclopentanediol in 690 ml of tetrahydrofuran. The reaction was exothermic and cooling was negligible. After 2 hours, the sodium iodate was filtered off and the solution was concentrated at room temperature to remove most of the tetrahydrofuran. The aqueous solution distributed to Jaije contained the desired β-ethoxycarbonyl-liglutaraldehyde and was used directly in the next reaction.

To a stirred suspension of 400 g of potassium hydrogen phthalate in 800 ml of water was added successively a solution of 80 g of acetonedicarboxylic acid in 1,200 ml of water, a solution of 80 g of glycine ethyl ester hydrochloride in 400 ml of water, and finally a solution of 10 β-ethoxycarbonylglutaraldehyde obtained in excess. The mixture was stirred for 20 hours at room temperature during which time carbon dioxide evolved. The mixture was basified by the addition of excess aqueous potassium carbonate and extracted with ethyl acetate several times. Evaporation of the dried ethyl acetate extracts gave a syrup consisting mainly of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-one.

Example 5

Sodium borohydride was added in small portions to a stirred solution of 87.6 g of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-one in 750 ml of ethanol. The mixture was stirred overnight at room temperature, the ethanol was evaporated and the mixture was treated with 200 ml of water. Hydrochloric acid (2M) was added until the mixture was acidic and this solution was basified with additional saturated potassium carbonate solution. Extraction with ethyl acetate and evaporation of the dried extracts gave a syrup consisting mainly of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-30 ol. The syrup can be purified by column chromatography using silica and eluting with hexane-ethyl acetate (30:70).

Example 6

A solution of 26.1 g of crude 7-ethoxycarbonyl-9-35 (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-ol in 250 ml of methylene chloride was treated with one equivalent of methanesulfonic acid (8.42 g). . The methylene chloride solution was concentrated to 35 mL, 9.5 mL of dihydropyran and one drop of methanesulfonic acid 11-5 were added, and the solution was stirred for 3 hours at room temperature. The solution was poured into saturated sodium potassium carbonate solution and the product was separated by extraction with ethyl acetate.

Evaporation of the dried ethyl acetate extracts gave silrapla which contained predominantly 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-ol tetrahydropyranyl ether. It can be purified by column chromatography using silica and eluting with hexane-ethyl acetate (20:80), Rf 0.7.

15 Example 7

A solution of 34 g of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-ol tetrahydropyranyl ether in 800 ml of anhydrous toluene was treated with 19 g of potassium tert-butoxide and stirred. the mixture was warmed at 100 ° C for two hours. Hydrogen formic acid (7.85 g) was added to the cooled mixture, potassium formate was filtered off and the toluene solution was evaporated to give silrapla. Silrappla was treated with 300 ml of 5 N hydrochloric acid and the stirred solution was refluxed. The cooled mixture was clarified by extraction with methylene chloride and the aqueous acid solution was evaporated to dryness. The residue was dissolved in a small amount of water and the solution was treated with a large excess of saturated potassium carbonate solution. Extraction of the residue with ethyl acetate and evaporation of the dried ethyl acetate solution afforded endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one as an oil which crystallized on standing. The female was converted to its camphorsulfonate salt, m.p. 178 ° C, using one equivalent of camphorsulfonic acid in ethanol.

Il 91154 15

Example 8

A stirred mixture of 1-methyl-3-indazolylcarboxylic acid (0.31 g), thionyl chloride (2 ml) and chloroform (10 ml) was refluxed for 2 hours and the solvent 5 was evaporated to give 1-methyl-3- indatsolyylikarbonyylikloridia.

A stirred solution of 395 mg of aqueous silver tetrafluoroborate in anhydrous nitroethane (10 mL) was treated with a solution of endo-hexahydro-10-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one tetrafluoroborate (475 mg) in anhydrous nitroethane (10 ml) at -78 ° C. A solution of 1-methyl-3-indazolylcarbonyl chloride (340 mg) in anhydrous nitroethane (5 ml) was added slowly over one hour and the reaction mixture was then allowed to warm to room temperature over 10 hours.

The mixture was poured into saturated aqueous potassium carbonate solution (30 ml). The resulting mixture was filtered and the separated solid was washed with ethyl acetate. The filtrate was then extracted twice with ethyl acetate (2 x 20 ml) and the solvent was evaporated from the combined ethyl acetate fractions. A solution of the ethyl acetate (20 ml) was washed with water (3 x 15 ml) and dried over magnesium sulphate, and the solvent was evaporated to give the residue. This material was purified by preparative silica plate chromatography using ethanol / ethyl acetate (30:70) as eluent. The desired product compound, endo-hexahydro-8- (1-methyl-3-indazolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one, formed vybhyk-30 with an Rf of 0.35 and isolated by extraction with ethanol / ethyl acetate (50:50).

Example 9

A mixture of 1.84 g of quinolinecarboxylic acid, 25 ml of methylene chloride and trifluoroacetic anhydride was stirred at room temperature for 5 minutes and then cooled to 0 ° C. A mixture of 1.92 g of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4) -one, 1.2 g of trifluoroacetic acid, 25 ml of methylene chloride and 20 ml of tetrahydrofuran was added hltaastl and mixture 5 was stirred at room temperature for 20 hours. The solid obtained was burned by filtration and the filtrate was basified with additional potassium carbonate. The resulting basic solution was extracted with ethyl acetate, and the ethyl acetate extract was dried and filtered. The solvent 10 was then evaporated to a residue which was treated with ether and ethereal hydrogen chloride to give endo-hexahydro-8- (4-quinolinylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one hydrochloride. melting at about 302 ° C to a fraction of the recrystallization from ethanol.

II

Claims (2)

91154 17 An analogous process for the preparation of therapeutically useful hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -5-one ester derivatives of formula 10 wherein Rr is “Οτι - tø I *« 9 Wherein R 9 is hydrogen or C 1-4 alkyl and R 10 is hydrogen or C 1-4 alkyl; and the wavy line indicates that the configuration of the oxygen substituent in the ring may be endo or exo; and pharmaceutically acceptable acid addition and quaternary anunonium salts thereof, characterized in that an alcohol of the formula wherein the wavy line is as defined above or a reactive derivative thereof is reacted with an acid of the formula wherein RjCOOH 18 is as defined above, or with its reactive equivalents. Process according to Claim 1, characterized in that endo-hexahydro-5 8- (1-methyl-3-indazolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one is prepared. II 91154 19