HU204051B - Process for producing nexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3-(4h)-one derivatives - Google Patents

Description

The present invention relates to a process for preparing esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizine with heterocyclic carboxylic acids.

More particularly, the present invention relates to compounds of formula (I) and pharmaceutically acceptable acid addition and quaternary ammonium salts thereof; in this formula

R 1 is a group of formula b or a group of formula wherein R 1 is C 1 -C 4 alkyl, the wavy line indicating that the oxygen substituent configuration on the ring may be endo or exo Examples of the above-mentioned C 1 -C 4 alkyl groups are methyl, ethyl, propyl, isopropyl and butyl If you change the waveguide in the general formula to 15 lines, the configuration of the compounds is endo. Such endo-compounds may also be referred to as trans. Similarly, exo-compounds may be referred to as cis.

A preferred group of compounds is where the ester is attached at the endo position to the polycyclic ring.

The pharmaceutically acceptable acid addition salts mentioned above with the appropriate acids, such as inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid; organic acids such as organic carboxylic acids such as acetic, propionic, glycolic, maleic, hydroxy-maleic, malic, tartaric, citric, salicylic, 2-acetyloxybenzoic, nicotinic or isonicotinic acids; non-toxic salts formed with organic sulfonic acids such as methanesulfone, ethanesulfone, 2-hydroxyethanesulfone, 4-toluenesulfonic acid or 2-naphthalenesulfonic acid. The quaternary ammonium salts are formed with alkyl halides such as methyl chloride, methyl bromide, methyl iodide or ethyl bromide; or sulfate esters, such as methyl 4-toluenesulfonic acid methyl or 2-naphthalenesulfonic acid methyl ester.

Some specific examples of compounds within the scope of the invention include:

endo-hexahydro-8- (1-methyl-3-indazolylcarbonyl-40-oxy) -2,6-methyl-2H-quinolizin-3 (4H) -one, endo-hexahydro-8- (3-indazolyl) carbonyl-oxy) -2,6-methano-2H-quinolizine-3 (4H) -one.

The compounds of the present invention are prepared by reacting an alcohol of formula (Π) or a reactive derivative thereof with a reactive compound equivalent to an acid of formula (IH); wherein R 1 is as defined above and, if desired, converting the resulting compound of formula I into a salt.

The acid equivalent reactive compound is understood to mean the corresponding acid chloride or bromide 50, or the corresponding glyoxyl chloride or bromide, or carboxylic acid imidazole, obtained by reaction of a suitable acid halide with N, N-carbonyldiimidazole; or any similar acid derivative which, when reacted with an alcohol or a reactive derivative of an alcohol, forms a simple carboxylic acid ester. Specifically, if the -OH group in the alcohol is equatorial (exo), it can be reacted with the corresponding carboxylic acid imidazole, which is treated with the acid halide and

It is obtained by the reaction of Ν, Ν-carbomyldiimidazole. Alternatively, the acid may be converted to the acid chloride by conventional means (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 reacting the lithium hydride with the alcohol in tetrahydrofuran.

When the -OH group in the parent alcohol is axial (endo), it can also be converted to the corresponding ester by reaction with a suitable acid chloride or bromide; the reaction is carried out in the presence of a suitable tertiary base such as 4-dimethylaminopyridine in a high boiling inert solvent such as xylene. However, in this case, prolonged reflux (24-84 hours) at a temperature of 140 ° C or higher is required, and the process would not be suitable for use with acid halides which are unstable under the conditions described. In this process, a suitable acid chloride or bromide or glyoxyl chloride or bromide in a nitroparaffin solvent is reacted with a solution consisting of the super-acid salt of the alcohol and an equal amount of the heavy metal salt of the same super-acid. Glyoxyl chloride can be used in the process as described because it is rapidly decarbonylated under the conditions used. The reaction itself is carried out over a period of 1 to 24 hours at a temperature ranging from -80 ° C to room temperature (about 23 ° C). Examples of the corresponding super-acids wherein MH: MBF ₄ , MAsFA, MSbFe, MPFe, MTaFe or MNbFe, the corresponding heavy metal (M) is silver or thallium. Examples of the nitroparaffin solvent are nitromethane, nitroethane, 1-nitropropane and 2-nitropropane.

The compounds of the invention are useful in the treatment of pain, in particular in the treatment of migraine, vascular and clot headaches, and trigeminal neuralgia. They can also be used to reduce nausea and nausea resulting from treatment with anti-cancer chemotherapeutic agents.

For the treatment of acute migraine cramps, peripheral vasoconstrictors such as ergotamine and dihydroergotamine, fever and analgesics such as acetylsalicylic acid or p-acetylaminophenol, previously administered with caffeine, have been used; and / or an anti-emetic agent such as cyclizine, metoclopramide and thiethylperazine. J. B. Hughes (Med. J. Aust, 2, No. 17, 580/1977) reports that acute migraine cramps can be immediately resolved (10 mg) by slow intravenous injection of metoclopramide.

It is believed that 5-hydroxytryptamine (5-HT) is a naturally occurring substance that is likely to play a major role in the pathophysiology of migraine. During most seizures, higher amounts of 5-HT and its metabolite, 5-hydroxyindole acetic acid, are excreted in the urine. Furthermore, plasma and platelet 5-HT levels drop rapidly at the onset of a seizure and remain low during the duration of the headache. In addition, migraine cramps can be clearly associated with thrombopenic periods in some patients. Some have suggested that 5-HT camel should be used in the symptomatic treatment of migraine2

HU 204,051 Β ailment blocking compounds would be useful (J. R. Fozard, International Conference on Headache 1980, Report in Advances in Neurology, Vol. 33, Raven Press, New York, 1982).

The known migraine prophylactic drugs, methysergide, propranolol, amitriptyline and chlorpromazine, have very different therapeutic activities, but all 5-HT D-receptor antagonists are used at the doses clinically used to prevent migraine. Metoclopramide is a potent 5-HT M-receptor antagonist and has been found (J. R. Fozard, supra) to block M-receptor present on afferent sensory neurons in the symptomatic relief of acute migraine cramps.

(-) Cocaine and some related compounds, including pseudotropyl benzoate (i.e., benzoyl pseudotropin) and 3,5-dichlorobenzoyl tropine, have been reported to antagonize the 5-HT receptor [J. R. Fozard et al., Eur. J. Pharmacol., 59, 195-210 (1979); J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol. 326: 36-44 (1984)]. The pA2 values for metoclopramide, pseudotropyl benzoate, nor (-) cocaine and benzoyl tropine were 7.2, 7, 7, 7, 7 and 7,2, respectively, whereas for the same procedure 3,5-dichlorobenzoyl- pA2 for tropine was 9.3 [J. R. Fozard et al., Eur. J. Pharmacol., 49, 109-112 (1978); J. R. Fozard, Naunyn-Schmidedeberg's Arch Pharmacol. 326: 36-44 (1984)]. In a double blind clinical trial, 3,5-dichlorobenzoyl tropine treatment was effective in acute migraine cramps [C. Loisy et al., Cephalalgia 5: 79-82 (1985)]. Other tropine esters for blocking 5-HT M receptors with pA2 values of 7.7 to 13.6 are described by Richardson et al., Natur. 316: 26-131 (1985).

The compounds of the present invention block the 5-hydroxytryptamine (5-HT) M-receptor on afferent sensory neurons, some of which promote the transmission of pain. As noted above, blocking such M-receptors appears to be a mechanism by which the symptoms of migraine can be alleviated. Accordingly, the compounds of the present invention are useful in the treatment of migraine in an amount effective to block said M-receptors.

In addition, 5-HT M-receptor blocking compounds, including metoclopramide, 3,5-dichlorobenzoyltropine and (3-alpha-tropanyl) -1H-indole-3-carboxylic acid ester, have been shown to be very effective in producing antitumor chemotherapeutic agents. in the prevention of nausea and nausea [W. D. Miner et al., Brit. J. Pharmacol., 88: 374P (1986); W.D. Miner and G.J. Sanger, Brit. J. Pharmacol. 88: 497-499 (1986); B. Costall et al., Neuropharmacology, 25, 959-961 (1986)]. D. Miner and G. J. Sanger, Brit. J. Pharmacol., 88, 497-499 (1986)]. Accordingly, the compounds of the present invention are useful in the treatment of nausea induced by cytotoxic drugs by blocking said M-receptors in an effective amount.

The anti-5-HT activity of the compounds can be determined by determining their pA2 value on an isolated salivary gland as described by J. R. Fozard et al., Eur. J. Pharmacol., 1979, 59, 195-210. In the method described, the molar concentration of the antagonist which reduces the effect of 5-HT double ED 50 to the extent that no antagonist is present is determined. The pA2 value is the negative logarithm of said molar concentrations. Generally, the higher the pA2 value, the more potent the compound will be. In this assay, the compounds of the present invention typically have a pA2 of about. Moves between 8-10.

The anti-5-HT activity of these compounds can also be determined in vivo by measuring the effect of the compound on the Von Bezold-Jarisch reflex induced by 5-HT intravenously injected into rats. Paintal A. S Physiol. Rev., 53, 159-227 (1973); J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol. 326: 36-44 (1984)]. The cause of transient cardiac deceleration is increased afferent planetary nerve activity caused by stimulation of the sensory nerves entering the heart and around the heart by 5-HT.

The compounds of the invention appear to be highly selective for the 5-HT M receptor. They are known to have at least three orders of magnitude lower potency against other 5-HT receptors and other spasmogens, particularly carbachol, phenylephrine, histamine and calcium, than 5-HT M receptors. Thus, their use in the treatment of nausea caused by migraine or cytotoxic drug is without side effects.

The compounds of the invention may be administered in various ways to achieve the desired effect. They can be administered to the patients to be treated either neat or in the form of pharmaceutical compositions, either orally or parenterally, for example subcutaneously or intravenously. They may be administered by inhalation or as a suppository. The amount of compound administered is variable and may be any amount effective against migraine relieving or cytotoxic nausea. Depending on the patient and the route of administration, the amount of compound administered may be varied over a wide range, from about one to about one dose. 0.01 mg / kg to 10 mg / kg, usually 0.033.0 mg / kg, based on the patient's weight. A unit dose of the compounds may contain, for example, 0.5 to 100 mg, usually 150 mg, and preferably 3 to 30 mg, of the compound and may be administered, for example, 1 to 4 times daily.

"Unit dosage form" as used herein means a single or multiple unit dosage form containing the active ingredient in admixture with a diluent or carrier, or in other association. Usually one or more predetermined units are required for a medical application. In the case of multiple dose units, such as liquids or scored tablets, the predetermined unit is a fraction, such as 5 ml (teaspoon) of liquid or half or quarter of a tablet.

Specific embodiments of the present invention are prepared in a manner known in the pharmaceutical art.

HU 204051 Β

They will usually contain one or more active compounds of the invention in association with a pharmaceutically acceptable carrier or diluent or other association. The active ingredient is usually mixed with a carrier, or diluted with a diluent, or encapsulated in a sachet, wafer, paper or other container. The carrier or diluent may be a solid, semi-solid, or liquid material that serves as a vehicle, diluent, or medium for the active ingredient. Suitable carriers or diluents are known per se. A description of the production of such embodiments is provided by Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

Embodiments of the present invention may be administered enterally and paxenterally, and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions, or the like.

The compounds of the invention may be used in the treatment of migraine in combination with other anti-migraine drugs of various modes of action. The latter include those used for prophylaxis, for example barbiturate, diazepam, chlorpromazine, amitriptyline, propranolol, methysergide, pizotifen, cyproheptadine, dihydroergotamine, clonidine; drugs for acute seizures such as vasoconstrictors such as ergotamine and dihydroergotamine; analgesic / anti-inflammatory agents such as aspirin, paracetamol and indomethacin; anti-nausea agents such as cyclizine, metoclopramide and thiethylperazine [see, e.g. I. F. Fozard, /. Pharm. Pharmacol., 27, 297-321 (1975); J. R. Saper, J. Amer. Med. Assoc., 239, 480-484 (1978); J. R. Fozard, supra]. By way of example, the compounds of the invention are very beneficial in combination with 300-1200 mg of aspirin or 2-6 mg of methysergide administered daily.

The invention is illustrated by the following examples, which, however, are by no means limiting.

Example 1

160 g of the malonic acid diethyl ester are dissolved in 1.5 l of dry dimethylformamide at 0 ° C under a nitrogen atmosphere. Lithium hydride (30 g) was added slowly with stirring. After the evolution of hydrogen had ceased (2 hours), 143 g of cis-1,4-dichloro-2-butene were added slowly and the mixture was brought to room temperature. After 72 hours, the mixture was diluted with 1: 4 EtOAc and poured into water. The organic layer was washed with water and saturated NaCl solution and dried over magnesium sulfate. Concentration gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester, m.p. 70-80 ° C / 13.3 Pa which is a small amount of ~ 10%) of 2-vinylcyclopropane-1,1-dicarboxylic acid. containing diethyl ester.

The resultant 148.5 g of crude cyclopentene diester is added to a solution of 118 g of potassium hydroxide in 1333 ml of 80% ethanol, and the stirred solution is kept at 60-70 ° C for the next day. The ethanol was distilled off and the residue was 107 ml cc. ice-cold solution of sulfuric acid in 274 ml of water. After extraction of the acidic mixture with ether (3 x 400 mL) and evaporation of the dried ether extracts, diacid remains which is decarboxylated to monosawa by heating in an oil bath at 170-180 ° C for 1 hour. The residual oil was distilled off. The crude 3-cyclopentene-1-carboxylic acid is obtained, m.p. 98 g of potassium carbonate dissolved in 300 ml of water are added and the mixture is extracted with ether to remove gamma-vinyl-gamma-butyrolactone. Acidification of the aqueous solution with 10 and extraction with ether gave pure 3-cyclopentene-1-carboxylic acid.

Example 2 A mixture of 3-cyclopentene-1-carboxylic acid (g) and higher amounts of thionyl chloride was stirred at room temperature for 1 hour. The excess thionyl chloride was distilled off and the residue was evaporated. 3-Cydopentene-1-carbonyl chloride is obtained, m.p. 52-58 ° C.

The acid chloride obtained above is slowly added with stirring to an ice-cold solution containing 32 g of pyridine in 150 ml of ethanol. The mixture was stirred for an additional hour, the ethanol was distilled off, and the residue was treated with water and ether. The ether layer was separated, washed several times with water, and dried. Distillation of the ether gave 3-cyclopentene-1-carboxylic acid ethyl ester, m.p. 62.5-66 ° C / 1862 Pa.

Example 3

A solution of 84.6 g of N-methylmorpholine N-oxide, 1 g of osmium tetrooxide, 230 ml of water and 115 ml of acetone is stirred for 30 minutes at room temperature. To the stirred mixture was added very slowly, at least 8 hours, 80 g of 3-cyclopentene-1-carboxylic acid ethyl ester in 115 ml of acetone. The stirred mixture was kept at 50 ° C for 2 35 h until the reaction was complete (TLC by 70:30 ethyl acetate / hexane). Sodium bisulfite (10 g) was added, stirring was continued for another 15 minutes, and the mixture was filtered through Celite. The filtrate was adjusted to pH 7 with 37 mL of 12 N sulfuric acid, the acetone was distilled off, and the residue was adjusted to pH 2 with 13 mL of 12 N sulfuric acid. 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

Sodium periodate (85.4 g) was dissolved in water (500 ml) and 4-ethoxycarbonyl-1,2-cyclopen50 (69 g) in tetrahydrofuran (690 ml) was added slowly with stirring. The reaction is exothermic and requires cooling. After 2 hours, the sodium iodate precipitate was filtered off and the solution was concentrated at room temperature to remove most of the tetrahydrofuran. The resulting aqueous solution contains the desired beta-ethoxycarbonylglutaraldehyde 55 and can be used directly in the next reaction.

A suspension is prepared using 400 g of potassium hydrogen phthalate and 800 ml of water. While stirring, 80 g of acetic acid 60 g dissolved in 1200 ml of water and 80 g of glycine 4 dissolved in 400 ml of water are added successively.

EN 204051 Β ethyl ester hydrochloride and finally beta-ethoxycarbonyl glutaraldehyde obtained as above. The mixture is stirred for 20 hours at room temperature, during which time carbon dioxide is formed. The mixture was made basic by the addition of a larger quantity of aqueous potassium carbonate solution and extracted several times with ethyl acetate. Concentration of the dried ethyl acetate extracts gives a syrup consisting mainly of 7-ethoxycarbonyl-9-ethoxycarbonylmethyl-9-azabicyclo [3.3.1] nonan-3-one.

Example 5

Dissolve 87.6 g of 7-ethoxycarbonyl-9-ethoxycarbonylmethyl-9-azabicyclo [3.3.1] nonan-3-one in 750 ml of ethanol, stirring a small amount of 17 g of sodium boron. hydride is added. The mixture was stirred at room temperature for the next day, ethanol was distilled off, and 200 ml of water were added to the residue. Hydrochloric acid (2 M) was added until the mixture became acidic. This acidic solution was made immediately basic by addition of saturated potassium carbonate solution. Extraction with ethyl acetate and evaporation of the dried extract give a syrup, which is mainly 7-ethoxycarbonyl-9-ethoxycarbonylmethyl-9-azabicyclo [3.3. l] consists of nonan-3-ol. The syrup was purified by column chromatography on silica gel eluting with 30:70 hexane: ethyl acetate.

Example 6

26.1 g of crude 7-ethoxycarbonyl-9-ethoxycarbonylmethyl-9-azabicyclo [3.3.1] nonan-3-ol are dissolved in 250 ml of methylene chloride. To the solution (8.42 g) was added one equivalent of methanesulfonic acid. The methylene chloride solution was diluted with ca. Concentrate to 35 mL, add 9.5 mL of dihydropyran with 1 drop of methanesulfonic acid, and stir at room temperature for 3 hours. The mixture was then poured into saturated potassium carbonate solution and the product was isolated by extraction with ethyl acetate.

Concentration of the dried ethyl acetate extracts gives a syrup consisting mainly of 7-ethoxycarbonyl-9-ethoxycarbonylmethyl-9-azabicyclo [3.3.1] nonane-3-ol-tetrahydropyranyl ether. The product was purified by silica gel column chromatography eluting with 20:80 hexane: ethyl acetate, Rf 0.7.

Example 7 7-Ethoxycarbonyl-9-ethoxycarbonylmethyl-9-azabicyclo [3.3.1] nonane-3-ol tetrahydropyranyl ether (800 g) was dissolved in dry toluene (800 ml) and potassium (19 g) was added. tert-butylate, the stirred mixture was heated at 100 ° C for 2 hours. To the cooled mixture was added dry formic acid (7.85 g), the potassium formate was filtered off and the toluene solution was evaporated to give a syrup. To the syrup was added 300 ml of 5N hydrochloric acid, and the stirred solution was refluxed for the next day. The cooled mixture was clarified by extraction with methylene chloride and the aqueous acidic solution was evaporated to dryness. The residue was dissolved in a little water and a large amount of saturated potassium carbonate solution was added. The resulting mixture was extracted with ethyl acetate to give, after evaporation of the dried ethyl acetate solution, an endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one as an oil which crystallized on standing. The base is converted to its camphorsulfonate salt with an equivalent of a solution of camphorsulfonic acid in ethanol, m.p.

Example 8

A stirred mixture of 0.31 g of 1-methyl-3-indazolylcarboxylic acid, 2 ml of thionyl chloride and 10 ml of chloroform was refluxed for 2 hours. The residue after distilling off the solvent was 1-methyl-3-indazolylcarbonyl chloride.

Dissolve 395 mg of dry silver tetrafluoroborate in dry ml of nitroethane and add 475 mg of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizine in 10 ml of dry nitroethane with stirring at -78 ° C. (4H) -one tetrafluoroborate. 340 mg of 1-methyl-3-indazolylcarbonyl chloride (5 mL) in dry nitroethane (5 mL) was added slowly overnight and the reaction mixture was kept at room temperature overnight. The mixture was then poured into 30 mL of saturated potassium carbonate solution. The resulting mixture was filtered and the separated solid was washed with ethyl acetate. The filtrate was extracted twice with ethyl acetate (2 x 20 mL) and the solvent was distilled off from the combined ethyl acetate fractions. The residue was dissolved in ethyl acetate (20 mL), washed with water (3 x 15 mL), dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by chromatography on a silica gel preparative plate using 30:70 ethanol: ethyl acetate as eluent. The resulting endo-hexahydro-8- (1-methyl-3-indazolylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one, (Rf 0.35) 50:50 ethanol: ethyl The residue was isolated by extraction with acetate (2.62 g, 84%).

Example 9

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 (4H) -one, 1.2 g of trifluoroacetic acid, 25 ml of methylene chloride and 20 ml of tetrahydrofuran is added slowly. This mixture was stirred at room temperature for 20 hours. The solid was removed by filtration, and the filtrate was made basic with aqueous potassium carbonate. The resulting alkaline solution was extracted with ethyl acetate, and the ethyl acetate extract was dried and filtered. After distilling off the solvent, the residue was treated with ether and ethereal hydrogen chloride. After recrystallization from ethanol, ca. 302 'C op. (Dec.) Endo-hexahydro-8 (4-quinolinylcarbonyloxy) -2,6-methano-2H-quinolizin-3 (4H) -one hydrochloride.

Claims (2)

PATENT CLAIMS A process for the preparation of a compound of formula (I), a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt thereof; in this formula HU 204051 Β R 1 is a group of formula b or a group of the general formula wherein R 9 is C 1 -C 4 alkyl, the wavy line indicating that the oxygen substituent configuration on the ring may be endo or exo; characterized in that the alcohol (es) or a reactive derivative thereof is reacted with a reactive derivative of an acid of the formula (III), wherein R 1 is as defined above and optionally the resulting compound (Γ) is a quaternary ammonium salt or and converting it into a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that the acid chloride derivative of formula (ΙΠ) is used as starting material.