NZ228853A - Esters of hexahydro-8-hydroxy-2,6-methano-2h- quinolizin-3(4h)-one derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £28853 No.: Date: wo PI Priority Date(s): .. kv.

Complete Specification Class: ^rfrfT).

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Publication Date: .

P.O. Journal, No: , ...Agtf,.

NEW ZEALAND PATENTS ACT, 1953 22 88 5 COMPLETE SPECIFICATION ESTERS OF HEXAHYDRD-8-HYDROXy-2,6-M3THANO-2H-QUINOLIZIN -3 (4H) -ONE AND RELATED COMPOUNDS 11 We, Marrell Dow Pharmaceuticals Inc., a corporation organised tinder the laws of the State of Delaware, USA, having an office at 2110 East Galbraith Road, Cincinnati, Ohio 45215, USA hereby declare the invention for which J&/ we pray that a patent may be granted to coec/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) 22 88 53 ESTERS OP HEXAHYDRO-8-HYDROXY-2,6-METHANO-2H-QOINOLI2IN-3 (4H)-ONE AMD RELATED COMPOUNDS The present invention is directed to esters of hexa-hydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one and hexahydro-8-hydroxy-2,6-methano-2H-quinolizines with certain aromatic and heterocyclic carboxylic acids.

More particularly, the present invention is directed to compounds of the formula: wherein A is =H2, =0, = (H) {OH) or =N-OH; B is =H2, = (H) (CH3) f =(H) (CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentamethylene or —CH2CH2—O—CH2CH2—; Ri is wherein R9 is hydrogen, C1-4 alkyl or phenyl(C1-2 alkyl); Rio is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and B or Rg C-35466A -lq V m 22 88 53 the pharmaceutically acceptable acid addition and quaternary ammonium salts o£ the aforesaid compounds.

Examples of the Ci_4 alkyl groups referred to above are ^ 5 methyl, ethyl, propyl, isopropyl and butyl. Examples of the C1-4 alkoxy groups are methoxy, ethoxy and propoxy, with butoxy being an additional example when the alkoxy is Ci_4. The halogens referred to above can be fluorine, chlorine or bromine. When the wavy line in the general structural f oris 10 mula is changed to a solid line, this indicates that the configuration of the compounds is endo. Such endo-compounds can also be referred to as trans. Similarly, exo-compounds can also be referred to as cis. Any hydrates of the present compounds are considered as equivalent to the compounds 15 themselves and this would include compounds in which the carbonyl (i.e., A is =0) exists as (=OH)2^ A preferred group of compounds are those wherein the ester is attached to the polycyclic ring in the endo-20 configuration. A further preferred group are those having the endo-configuration wherein A is =0 and =(0H)2» In a still further preferred group, B is additionally =H2.

The pharmaceutically acceptable acid addition salts ^ 25 referred to above can be non-toxic salts with suitable acids such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; or with organic acids such as organic carboxylic acids, for example, acetic, propionic, glycolic, maleic, hydroxymaleic, J 30 malic, tartaric, citric, salicylic, 2-acetyloxybenzoic, nicotinic or isonicotinic; or organic sulfonic acids, for example methanesulfonic, ethanesulfonic, 2-hydroxyethane-sulfonic, 4-toluenesulfonic or 2-naphthalenesulfonic. Quaternary ammonium salts are formed with alkyl halides such 35 as methyl chloride, methyl bromide, methyl iodide or ethyl bromide; or with sulfate esters such as methyl 4-toluene-sulfonate or methyl 2-naphthalenesulfonate.

C-35466A # 22 8 8 5 J Some specific examples of compounds encompassed by the present invention are the following: endo-Hexahydro-8-(l-methyl-3-indazolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one 5 endo-Hexahydro-8-(3-indazolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.

The compounds of the present invention can be prepared by reacting an alcohol or a reactive derivatives thereof, /Q\ 10 said alcohol having the formula wherein A' is =0 or =H2, with a reactive equivalent of an acid of the formula: RiCOOH wherein Ri is defined as above. By a reactive equivalent of 20 the acid is meant the corresponding acid chloride or bromide or the corresponding glyoxylyl chloride or bromide or the carboxylic acid imidazole obtained by the reaction of the appropriate acid halide with N,N-carbonyldiimidazole; or any similar acid derivative which would yield the simple carbox-<^w' 25 ylic acid ester on reaction with an alcohol or with a reactive derivative of an alcohol. More specifically, where the -OH in the alcohol is "equatorial (exo), then it can be reacted with the appropriate carboxylic acid imidazole obtained by the reaction of the acid halide with N,N-carbonyldiimida-30 zole. Alternatively, the acid can be converted to the acid chloride by standard procedures (e.g., thionyl chloride) and then reacted with the alcohol or an alkali metal salt of the alcohol such as the lithium salt obtained by the reaction of lithium hydride with the alcohol in tetrahydrofuran.

When the -OH group in the starting alcohol is axial (endo), it can also be converted to the corresponding ester by reaction with the appropriate acid chloride or bromide C-35466A * 22 88 53 with the reaction being carried out in the presence of an equivalent of a suitable tertiary base such as 4-dimethyl-aminopyridine in a high boiling inert solvent such as xylene. In this case, however, long heating (24-84 hours) 5 at a temperature at or above 140°C is necessary so that the procedure would not be suitable for use with acid halides that are not stable under the indicated conditions. Thus, it was necessary to use an alternative procedure for the preparation of such compounds. In this procedure, an appro-fr>, 10 priate acid chloride or bromide or a glyoxylyl chloride or bromide, in a nitroparaffin solvent, is reacted with a solution of a super acid salt of the alcohol and an equivalent amount of a heavy metal salt of the same super acid. The glyoxylyl chloride can be used in the process as indi-15 cated because it decarbonylates readily under the conditions used. The reaction itself can be carried out over a period of 1-24 hours at temperatures ranging from -80°C to ambient temperatures (about 23°C). Examples of suitable super acids with M = H are MBF4, MAsFg, MSbF6, MPFg, MTaFe or MNbF6 with 20 examples of suitable heavy metals (M) being silver and thallium. Examples of nitroparaffin solvents are nitromethane, nitroethane, 1-nitropropane and 2-nitropropane.

Actually, where the group Ri contains a primary or t > secondary amino group, it is usually protected during the above reaction, with a benzyl group being commonly used to protect a secondary amine and a benzyloxycarbonyl group being used to protect a primary amine. In either case, the protecting group in the product is removed by conventional 30 procedures, for example by hydrogenation with hydrogen and a palladium catalyst.

Various procedures can be used to convert those compounds wherein A is =0 and whose preparation is described 35 below, to other different bridged derivatives of the present invention by standard methods. Thus, the ketone group in the polycyclic system can be reduced to the corresponding C-35466A 22 8 8 § 3 alcohol using an alkali metal (sodium or potassium) boro-hydride in a lower alkanol such as methanol or ethanol.

The ketone group can also be reduced completely to a methylene group by a two step procedure. In the first step, the ketone is reacted with ethylene dithiol or trimethylene dithiol in the presence of a strong acid such as hydrochloric acid or BF3 to give the corresponding dithioketal. The reaction is carried out in a suitable polar solvent such as nitromethane or acetic acid. The dithioketal is then reduced with hydrazine in the presence of Raney nickel in a / lower alkanol solvent such a 2-propanol at elevated temperatures (60-100°C). Actually this same procedure can be used to reduce the original starting alcohol, hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one, to 8-hydroxy-2,6-methanooctahydro-2H-quinolizine which can itself be reacted with acid derivatives as described earlier to give the corresponding esters.

Compounds containing other B-groups (i.e. aminomethyl, methylene or methyl groups) can be obtained from products in which A is =0 and =B is H2 by a Mannich reaction using formaldehyde and a secondary amine such as dimethylamine, diethylamine, piperidine or pyrrolidine. This reaction gives the corresponding aminomethyl compound and, when B is dimethylaminomethyl, the amino moiety is eliminated on heating at 90-110°C in an inert solvent such as toluene to give the corresponding methylene compound (B is =CH2). This exocyclic methylene compound can be isolated by standard methods and transformed into a methyl group by hydrogena-tion, for example, by using hydrogen and platinum oxide.

To obtain those compounds in which A is hydroxyimino (=N-OH), the ketone referred to above can be reacted with hydroxylamine hydrochloride by standard procedures.

The alcohol used as a reactant in the above procedure can be obtained from known alkyl (Ci_4) 3-cyclopentene-l- C-35466A 22 8853 carboxylates by a multi-step procedure. Specifically, the double bond in the indicated cyclopentene is oxidized to a 1,2-diol using N-methylmorpholine N-oxide in the presence of osmium tetroxide catalyst. The diol is then cleaved to the corresponding dialdehyde using sodium metaperiodate. A Robinson-Schopf cyclization of the dialdehyde with a lower alkyl glycine ester and acetone-dicarboxylic acid, preferably at pH 4, gives a pseudopelletierine derivative of the following type: The ketone group is reduced to an alcohol using sodium boro-20 hydride and the product is reacted with dihydropyran to protect the -OH group as a tetrahydropyranyl ether. Dieckmann cyclization of the diester using a strong base (e.g. potassium t-butoxide) followed by aqueous acid hydrolysis and decarboxylation gives the desired alcohol. The resulting ' 25 alcohols can exist in two conformations - axial and equatorial. The main product obtained by the above procedure is the axial alcohol and it can be separated from the equatorial isomer by crystallization of the camphorsulfonate or tetrafluoroborate salt.

O 30 The present compounds are useful for the treatment of pain, especially migraine, vascular and cluster headaches and trigeminal neuralgia. They are also useful in the treatment of nausea and vomiting arising from treatment with 35 cancer chemotherapeutic agents.

In the past, acute attacks of migraine have been treated with a peripheral vasoconstrictor, such as ergotamine, which C-35466A 228853 may be co-administered with caffeine, and dihydroergotamine; an antipyretic analgesic, such as acetylsalicylic acid or p-acetylaminophenol; and/or an antiemetic such as cyclizine, metoclopramide and thiethylperazine. It has also been ^ 5 reported (J. B. Hughes, Med. J. Aust. 2, No. 17, 580 (1977)) that immediate relief of an acute migraine attack can be obtained by slow intravenous injection of metoclopramide (10 mg). ,0\ 10 believed that 5-hydroxytryptamine (5-HT) is the . v naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and it metabolite 5-hydroxyindoleacetic acid are excreted in the urine during most attacks. Further, plasma and platelet 15 5-HT concentrations fall rapidly at the onset of an attack and remain low while the headache persists. Moreover, attacks of migraine have been clearly associated with periods of thrombocytopaenia in certain patients. It has been proposed that compounds which block the activity of 5-HT would 20 be of use in the symptomatic treatment of migraine (J. R. Fozard, International Headache Congress 1980, reported in Advances in Neurology, Vol 33., Raven Press, New York, 1982). ^ 25 The known migraine prophylactic drugs, methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but all are 5-HT D-receptor antagonists at the doses used clinically for the prophylaxis of migraine. Metoclopramide is a potent 5-HT M-v__/' 30 receptor antagonist and it has been proposed (J. R. Fozard supra) that a blockade of the M-receptor present on afferent sensory neurones affords symptomatic relief in an acute migraine attack.

The potency as 5-HT receptor antagonists of (-) cocaine and some related compounds, including pseudotropyl benzoate (i.e., benzoylpseudotropine) and 3,5-dichlorobenzoyltropine has been reported (J. R. Fozard et al., Eur. J. Pharmacol., C-35466A vv.',,.vr o -U.A '~\ J 22 88 5 59, (1979) 195-210; J. R. Fozard, Naunyn-Schmiedeberq's Arch Pharmacol., 326, (1984), 36-44). The pA2 values reported for metoclopramide, pseudotropyl benzoate, nor (-) cocaine and benzoyltropine are 7.2, 7.0, 7.7, and 7.2 respectively 5 whilst the pA2 value determined for 3,5-dichlorobenzoyltro-pine by the same procedure is 9.3 (J. R. Fozard et al., Eur. J. Pharmacol., 49, (1978) 109-112; J. R. Fozard, Naunyn-Schmiedeberq' s Arch Pharmacol., 326, (1984), 36-44). In a double-blind clinical trial, 3,5-dichlorobenzoyltropine 10 proved an effective treatment for the acute migraine attack (C. Loisy et al., Cephalalgia, 5, (1985) 79-82). A further series of tropine esters, with pA2 values for blockade of the 5-HT M-receptors between 7.7 and 13.6 have been described by Richardson et al., Nature, 316, (1985) 26-131.

The compounds of the present invention block the M-receptors for 5-hydroxytryptamine (5-HT) on afferent sensory neurones, certain of which subserve the transmission of pain. As explained above, the blocking of such 20 M-receptors appears to be a mechanism whereby the symptoms of migraine can be relieved. Accordingly, the present compounds are useful in the treatment of migraine when administered in amounts sufficient to effectively block the said M-receptors.

In addition, compounds blocking 5-HT M-receptors, including metoclopramide, 3,5-dichlorobenzoyltropine and (3a-tropanyl)-lH-indole-3-carboxylic acid ester, are highly effective in preventing the nausea and vomiting induced by 30 cancer chemotherapeutic agents in an animal experimental model (W. D. 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). It is believed that cytotoxic drug-induced 35 vomiting involves a 5-HT M-receptor mechanism (W. D. Miner and G. J. Sanger, Brit J. Pharmacol., 88, (1986) 497-499). Accordingly, the present compounds are useful in the treatment of cytotoxic drug-induced vomiting when administered in C-35466A II 3 amounts sufficient to effectively block the said v 22 8 8 5 M-receptors.

The activity of the compounds against 5-HT can be n 5 assessed by determining their pA2 values in the isolated rabbit heart as described by J.R. Fozard et al., Eur. J. Pharmacol., 59, 195-210 (1979). In the method described, the molar concentration of antagonist which reduces the effects of twice the ED50 of 5-HT to that of the ED50 in the absence of antagonist is determined. The pA2 value is the w negative logarithm of said molar concentrations. In general terms, the higher the pA2 value the more potent is the compound. When tested in this way, the present compounds show pA2's generally in the range of about 8 to 10.

The activity of these compounds against 5-HT can be assessed in vivo by measurement of the effect of the compound on the Von Bezold-Jarisch Reflex induced by 5~HT injected intravenously into the rat (see Paintal A.S., Physiol. Rev., 53, 159-227 (1973); J.R. Fozard, Naunyn-Schmiedeberq ' s Arch. Pharmacol., 326, (1984) 36-44). The transient cardiac slowing arises from an increased afferent vagus activity arising from stimulation by 5-HT of sensory afferent fibers in and around the heart. 1 ) The present compounds appear to be highly selective in their action against the 5-HT M-receptor. Their potency against other 5-HT receptors and other spasmogens, in parti-^ cular carbachol, phenylephrine, histamine and calcium, is w 30 known to be at least three orders lower that against 5-HT M-receptors. Accordingly, their use in the treatment of migraine or cytotoxic drug-induced vomiting should be without any side effects.

The present compounds can be administered in various manners to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or paren- C-35466A * 22 8 8 5 3 terally, for example, subcutaneously or intravenously. They can also be administered by inhalation or by suppository. The amount of compound administered will vary and can be any effective migraine-relieving amount or amount effective in 5 cytotoxic drug vomiting. Depending upon the patient and the r mode of administration, the quantity of compound adminis tered may vary over a wide range to provide from about 0.01 mg/kg to about 10 mg/kg, usually 0.03 to 3.0 mg/kg, of body weight of the patient per dose. Unit doses of these com-^ 10 pounds can contain, for example, from about 0.5 mg to 100 mg, usually 1 to 50 mg and preferably 3 to 30 mg, of the compound and may be administered, for example, from 1 to 4 times daily.

The term "unit dosage form" is used herein to mean a single or multiple dose form containing a quantity of the active ingredient in admixture with or otherwise in association with the diluent or carrier, said quantity being such that one or more predetermined units are normally required 20 for a single therapeutic administration. In the case of multiple dose forms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 ml (teaspoon) quantity of a liquid or a half or quarter of a ^ scored tablet, of the multiple dose form. ^ 25 Specific formulations of the present invention are prepared in a manner well known per se in the pharmaceutical art and usually comprise one or more active compounds of the invention in admixture or otherwise in association with a 30 pharmaceutically acceptable carrier or diluent therefor.

The active ingredient will usually be mixed with a carrier, or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or diluent may be solid, semisolid or liquid material 35 which serves as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are well known per se. See Remington's Pharmaceutical Sciences, Mack C-35466A £'■ f> 22 88 5 Publishing Company, Easton, Pennsylvania, for a description of the preparation of such formulations.

The formulations of the invention may be adapted for 5 enteral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like.

The compounds of the present invention can be used in fTs 10 migraine therapy in combination with other antimigraine drugs having different modes of action. Such drugs include those used prophylactically, such as barbiturates, diazepam, chlorpromazine, amitriptyline, propranolol, methysergide, pizotifen, cyproheptadine, dihydroergotamine, and clonidine, 15 and those used in the acute attack, such as vasoconstrictor agents, e.g., ergotaiaine and dihydroergotamine, analgesic/ anti-inflammatory agents, e.g., aspirin, paracetamol and indomethacin, or antinauseants, e.g., cyclizine, metoclopramide, and thiethylperazine (see J. P. Fozard, J. Pharm. 20 Pharmaco., 27, 297-321 (1975); J. R. Saper, J. Amer. Med. Assoc., 239, 480-484 (1978); J. R. Fozard, supra). As an example, compounds of the present invention would be beneficial in combination with aspirin 300-1200 mg or methysergide 2-6 mg given daily.

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

O 30 EXAMPLE 1 To a stirred solution of 160 g of diethyl malonate in 1.5 1 of dry dimethylformamide at 0°C under nitrogen was slowly added 30 g of lithium hydride. After the evolution of hydrogen ceased (2 hours) 143 g of cis-1,4-dichloro-2-35 butene was slowly added and the mixture allowed to come to room temperature. After 72 hours, the mixture was diluted with a mixture of ether and hexane (1:4) and poured into water. The organic layer was washed with water and brine C-35466A 22 88 53 o before drying over magnesium sulfate. Distillation gave diethyl 3-cyclopentene-l,l-dicarboxylate, bp 70-80°C/0.1 mm, containing a small amount (-10%) of diethyl 2-vinylcyclo-propane-1,1-dicarboxylate.

The impure cyclopentene diester (148.5 g) obtained above was added to a solution of 118 g of potassium hydroxide in 1333 ml of 80% ethanol and the stirred solution warmed at 60-70°C overnight. The ethanol was evaporated and the /Os 10 residue treated with an ice cold solution of concentrated sulphuric acid (107 ml) in water (274 ml). Extraction of the acid mixture with ether (3 x 400 ml) followed by evaporation of the dried ether extracts gave a residue of the diacid which was decarboxylated to the monoacid by heating 15 in an oil bath at 170-180°C for 1 hour. The residual oil was distilled to give crude 3-cyclopentene-l-carboxylic acid, bp 68-73°C (1 mm) containing some y~vinyl~Y"butyro-lactone. A solution of 98 g of potassium carbonate in 300 ml of water was added and the mixture extracted with ether 20 to remove the Y~vinyl~Y~butyrolactone. Acidification of the aqueous solution and extraction with ether afforded pure 3-cyclopentene-l-carboxylic acid.

EXAMPLE 2 y 25 A mixture of 52 g of 3-cyclopentene-l-carboxylic acid and excess thionyl chloride was stirred at room temperature for 1 hour. The excess thionyl chloride was evaporated and the residue distilled to give 3-cyclopentene-l-carbonyl chloride, bp 52-58°C. vJ 30 The acid chloride obtained above was slowly added to an ice cooled stirred solution of 32 g of pyridine in 150 ml of ethanol. The mixture was stirred for a further hour, the ethanol evaporated and the residue treated with water and 35 ether. The ether layer was separated, washed several times with water and dried. Evaporation of the ether left a residue of ethyl 3-cyclopentene-l-carboxylate, bp 62.5-66°C/14 mm.

C-35466A 22 8853 EXAMPLE 3 A solution containing 84.6 g of N-methylmorpholine N-oxide, 1 g of osmium tetroxide, 230 ml of water and 115 ml 5 of acetone was allowed to stir for 30 minutes at room temperature. To this stirred mixture was added, very slowly over at least 8 hours, a solution of 80 g of ethyl 3-cyclo-pentene-l-carboxylate in 115 ml of acetone. The stirred mixture was heated at 50°C for 2 hours to complete the reac-10 tion (verified by TLC examination using ethyl acetate/hexane 70/30). Sodium bisulfite (~10 g) was added, the stirring continued for a further 15 minutes, and the mixture filtered through Celite. The pH of the filtrate was adjusted to 7 by the addition of 12 N sulfuric acid (37 ml), the acetone 15 evaporated, the pH of the residual solution adjusted to 2 with 12 N sulfuric acid (13 ml) and the solution extracted with ethyl acetate (4 x 250 ml). Evaporation of the dried ethyl acetate solution gave 4-ethoxycarbonyl-l,2-cyclo-pentanediol.

EXAMPLE 4 A solution of 85.4 g of sodium periodate in 500 ml of water was slowly added to a stirred solution of 69 g of 4-ethoxycarbonyl-l,2-cyclopentanediol in 690 ml of tetrahy-25 drofuran. The reaction was exothermic and cooling was necessary. After two hours a precipitate of sodium iodate was filtered off and the solution concentrated at room temperature to remove most of the tetrahydrofuran. The resulting aqueous solution contained the desired JB-ethoxycarbonyl-30 glutaraldehyde and was used directly in the next reaction.

To a stirred suspension of 400 g of pot.assium hydrogen phthalate in 800 ml of water was added, in sequence, a solution of 80 g of acetonedicarboxylic acid in 1200 ml of 35 water, a solution of 80 g of glycine ethyl ester hydrochloride in 400 ml of water, and finally the solution of ]3-ethoxycarbonylglutaraldehyde obtained above. The mixture was stirred for 20 hours at room temperature during which C-35466A # 22 88 53 time carbon dioxide evolved. The mixture was basified by the addition of an excess of aqueous potassium carbonate and extracted with ethyl acetate several times. Evaporation of the dried ethyl acetate extracts gave a syrup consisting ,s~*\ 5 mainly of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9- azabicyclo-[3.3.1]nonan-3-one.

EXAMPLE 5 Sodium borohydride (17 g) was added in small portions to /p> 10 a stirred solution of 87.6 g of 7-ethoxycarbonyl-9-(ethoxy-^ carbonylmethyl)-9-azabicyclo[3.3.l]nonan-3-one in 750 ml of ethanol. The mixture was stirred overnight at room temperature, the ethanol evaporated and the residue treated with 200 ml of water. Hydrochloric acid (2 M) was added until 15 the mixture was acid and this acid solution was immediately basified by the addition of saturated potassium carbonate solution. Extraction with ethyl acetate and evaporation of the dried extract gave a syrup which consisted mainly of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3.3.1]-20 nonan-3-ol. The syrup can be purified by column chromatography using silica and elution with hexane-ethyl acetate (30:70).

EXAMPLE 6 A solution of 26.1 g of the crude 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl)-9-azabicyclo[3.3.l]nonan-3-ol in 250 ml of methylene chloride was treated with one equivalent of methanesulfonic acid (8.42 g). The methylene chloride solu-tion was concentrated to about 35 ml, 9.5 ml of dihydropyran O' 30 was added together with one drop of methanesulfonic acid, and the mixture stirred for 3 hours at room temperature. The mixture was then poured into saturated potassium carbonate solution and the product separated by extraction with ethyl acetate.

Evaporation of the dried ethyl acetate extracts gave a syrup consisting mainly of the tetrahydropyranyl ether of 7-ethoxycarbonyl-9-{ethoxycarbonylmethyl)-9-azabicyclo[3.3.1]- C-35466A 22 8 8 53 nonan-3-ol. It can be purified by column chromatography using silica and elution with hexane-ethyl acetate (20:80), Rf 0.7.

EXAMPLE 7 A solution of 34 g of the tetrahydropyranyl ether of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3.3.1]-nonan-3-ol in 800 ml of anhydrous toluene was treated with 19 g of potassium tert-butoxide and the stirred mixture 10 heated at 100°C for 2 hours. Anhydrous formic acid (7.85 g) was added to the cooled mixture, the potassium formate was filtered off, and the toluene solution evaporated to give a syrup. The syrup was treated with 300 ml of 5 N hydrochloric acid and the stirred solution refluxed overnight. The 15 cooled mixture was clarified by an extraction with methylene chloride and the aqueous acid solution evaporated to dryness. The residue was dissolved in a little water and the solution treated with a large excess of saturated potassium carbonate solution. Extraction of the resulting mixture 20 with ethyl acetate and evaporation of the dried ethyl acetate solution gave endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one as an oil which crystallized on standing. The base was converted to its camphorsulfonate salt, m.p. 178°C, using one equivalent of camphor sulfonic v"~/ 25 acid in ethanol.

EXAMPLE 8 A stirred mixture of l-methyl-3-indazolylcarboxylic acid (0.31 g), thionyl chloride (2 ml) and chloroform (10 ml) was ' 30 refluxed for 2 hours and the solvent was evaporated to give a residue of l-methyl-3-indazolylcarbonyl chloride.

A stirred solution of 395 mg of anhydrous silver tetra-fluoroborate in anhydrous nitroethane (10 ml) was treated 35 with a solution of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one tetrafluoroborate (475 mg) in anhydrous nitroethane (10 ml) at -78°C. A solution of l-methyl-3-indazolylcarbonyl chloride (340 mg) in anhydrous nitroethane C-35466A

Claims (12)

22 88 5 3 (5 ml) was slowly added during one hour and the reaction mixture was then allowed to warm to room temperature overnight. The mixture was poured into a saturated aqueous solution of potassium carbonate (30 ml). The mixture 5 obtained 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 residue in ethyl acetate (20 ml) was washed with 10 water (3 x 15 ml) and dried over magnesium sulfate, and the solvent was evaporated to give a residual material. This material was purified by silica preparative plate chromatography using a mixture of ethanol/ethyl acetate (30:70) as eluant. The desired product compound, endo-hexahydro-8-(1-15 methyl-3-indazolylcarbonyloxy)-2,6-methano-2H-quinolizin- 3(4H)-one, formed a band with an Rf 0.35 and was isolated by extraction with ethanol/ethyl acetate (50:50). EXAMPLE 9 .20 A mixture of 1.84 g of 4-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 ^ 25 acid, 25 ml of methylene chloride and 20 ml of tetrahydro-furan was slowly added and the mixture stirred at room temperature for 20 hours. The solid present was removed by filtration and the filtrate was basified by the addition of ^ aqueous potassium carbonate. The resulting basic solution W 30 was extracted with ethyl acetate and the ethyl acetate extract was dried and filtered. The solvent was then evaporated to give residual material which was treated with ether and ethereal hydrogen chloride to give endo-hexahydro-8-(4-quinolinylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one 35 hydrochloride melting at about 302°C (dec) after recrystal-lization from ethanol. C-35466A -16- 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 22 8853 WHAT CLAIM IS; wTTflT rg

1. A compound of the formula: B VA N "TN O-C-RI wherein A is =H2, =0, =(H)(0H) or =N-0H; B is =H2, = (H) (CH3) , =(H) (CH2NR3R4) or =CH2 wherein R3 and R4 are C2_4 alkyl or are combined to give tetramethylene, pentamethylene or —CH2CH2-0-CH2CH2—; Ri is wherein R9 is hydrogen, Ci_4 alkyl or phenyl(C1-2 alkyl); Rio is hydrogen, halogen, Ci_4 alkyl, Ci_4 alkoxy, hydroxy, cyano or -CONH2; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds.

2. A compound according to Claim 1 which has the formula: or C-35466A -17- 22 8853 B :-Ri wherein A is =H2, =0, =(H)(0H) or =N-0H; B is =H2, = (H) (CS3) , =(H) (CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentamethylene or -CH2CH2-0-CH2CH2-; Rx is wherein Rg is hydrogen, C1-4 alkyl or phenyl(Ci-2 alkyl); and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds.

3. A compound according to Claim 1 which has the formula: wherein Rg is hydrogen, C1-4 alkyl or phenyl(Ci-2 alkyl); and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds. wherein A is =H2, =0, =(H)(0H) or =N-0H; Ri is Rg C-35466A -18- 228853

4. A Compound according to Claim 1 which has the formula: wherein Rg is hydrogen, C1-4 alkyl or phenyl(Ci_2 alkyl); and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds.

5. A compound according to Claim 1 which is endo-hexa-hydro-8-(l-methyl-3-indazolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.

6. A process for preparing a compound of the formula: wherein Ri is Rg wherein A wherein Rg is hydrogen, C1-4 alkyl or phenyl(Ci_2 alkyl); Rio is hydrogen, halogen, Ci_4 alkyl, C1-4 alkoxy, hydroxy, cyano or C-35466A -19- 228853 -CONH2; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds which comprise reacting an alcohol or a reactive derivative thereof, said alcohol having the formula: wherein A' is defined as above, with a reactive equivalent of an acid of the formula RlCOOH wherein Ri is defined as above.

7. A process according to Claim 6 for preparing a compound of the formula: wherein A' is =H2 or =0; Ri is Rio or wherein Rg is hydrogen, Ci_4 alkyl or phenyl(Ci-2 alkyl); Rio is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid C-35466A -20- •. "W. 228853 addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula: with an acid of the formula RiCOOH wherein A1, Ri and the wavy line are defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corresponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for.a period up to 24 hours.

8. A compound as claimed in any one of claims 1-5 substantially as hereinbefore described with reference to any example thereof.

9. A process as claimed in claim 6 or claim 7 when performed substantially as hereinbefore described with reference to any example thereof.

10. A compound of claim 1 when prepared by a process as claimed in any one of claims 6, 7 and 9.

11. A pharmaceutical composition useful for the treatment of pain, migraine, vascular and cluster headaches, trigeminal neuralgia, and the treatment of nausea and vomiting arising from treatment with cancer chemotherapeutic agents comprising an effective amount of a compound as claimed in any one of claims 1-5, 8 and 10, or a pharmaceutically acceptable acid addition and quaternary ammonium salt thereof, in combination with pharmaceutically acceptable carrier. m 22 88 53

12. A pharmaceutical composition as claimed in claim 11 substantially as hereinbefore described with reference to any example thereof. 'U- ,:.D THIS ^f-^DAYOF 19 A. J. PARK & SON PER AGENTS THE APPLICANTS - 22 -