2-Alkoxy-N-(1-Azabicyclo[2.2.2]oct-3-Yl)benzamides and Thiobenzamides

1. Field of Invention.

The present invention relates to certain novel N-(3-quinuclidinyl)benzamides and thiobenzamides; namely, the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides which exhibit gastrokinetic and anti-emetic properties in warm blooded animals with minimal neuropharmacological side effects. The invention is also concerned with methods of and compositions for increasing gastric emptying and alleviating emesis, particularly emesis due to administration of platinum anticancer drugs such as cisplatin.

2. Information Disclosure Statement.

Quinuclidine analogs of sulpiride were prepared and studied by Mikhlina, E. E. et al as reported in Khim-Farmatsevt, Zh. 10. No. 11, 56-60 (1976); C.A. 86 : 155489r exemplified by the compound: 5-aminosulfonyl-N-[1-azabicyclo [2.2.2]oct-3-yl)-2-methoxybenzamide. This compound and others in the series were reported by the authors not to have antiemetic activity. The above named compound was reported in USSR Pat. No. SU-414-261 to have neuroleptic activity. In comparison, the compounds of the present invention show strong gastrokinetic and antiemetic activity without neuroleptic activity {blockade of d-amphetamine lethality in mice).

Syntheses of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamide and N-[1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. et al in Khim-Farmatsevt. Zh. 7, 20-24 (1974); C.A. 79, 146358a and the latter in Khim. Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); C.A. 65: 2220b. These compounds were reported to exhibit hypotensive, narcotic and ganglionic stimulation and blocking activities, properties not seen in the compounds of the present invention.

Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamid e was reported in Ger. Offen. No. 2,548,968; C.A. 87, 68001c and in equivalently related U.S. Pat. No. 4,093,734 from 4-amino-3-chloro-5-trifluoromethyl benzoic acid chloride and 3-aminoquinuclidine. The compound is in a class among pyrrolidinyl and piperidinyl benzamides which are said to be useful as anxiolytics, anticonvulsives, antiemetics and antiulcerogenics. None of the compounds have orthoalkoxy substitution on benzamide as do the compounds of the present invention.

It is widely recognized that substituted benzamides are a class of drugs known to be effective in psychiatry and gastroenterology (Sulpiride and other Benzamides; International Workshop on Sulpiride and other benzamides, Florence, Feb. 17-18 (1978), Raven Press]. However, the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides of this invention exhibit effects only on gastrointestinal motility and do not show neuropharmacological activity. This is in marked contrast to the compounds described in the prior art which show a range of pharmacological activities that include both neuropharmacological and gastrointestinal effects.

The novel 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamides and thiobenzamides of this invention have the formula: ##STR2## wherein X is oxygen or sulfur, R.sub.1 is loweralkyl and R.sub.2 is selected from the group consisting of hydrogen, halo, 4,5-benzo, alkoxy or Am wherein Am is selected from amino, methylamino or dimethylamino, and n is 1 or 2, and the pharmaceutically acceptable acid addition salts thereof.

In the further definition of symbols in the formulas hereof and where they appear elsewhere throughout this specification and the claims, the terms have the following significance.

The term "loweralkyl" as used herein includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, heptyl, and octyl radicals and the like. The term "loweralkyl" has the formula--0--loweralkyl.

The terms "halo" or "halogen" when referred to herein include fluorine, chlorine, bromine and iodine unless otherwise stated.

"Pharmaceutically acceptable acid addition salts" include the acid addition salts, hydrates, alcoholates and salts of the compounds of Formula which are physiologically compatible in warm blooded animals. The acid addition salts may be formed by either strong or weak acids. Representative of strong acids are hydrochloric, sulfuric and phosphoric acids. Representative of weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, cyclohexamic and the like.

Protected amino groups used in synthesis are acetylamino or benzoylamino radicals and the like on the benzamide moiety mentioned hereinbelow in synthetic methods.

The gastric emptying activity was determined by the method of Droppleman, D., Gregory, R., and Alphin, R., J. Pharmacological Methods 4(3) 227-30 (1980) wherein the rate of emptying of a test meal in rats compared to controls was observed. Indicative of the activity of two preferred compounds of Examples 1 and 3 are the results obtained by intraperitoneal administration of 1.0 mg/kg which significantly increased gastric emptying (as determined by the Student t-test) 60 minutes after feeding the test meal by 49% and 61% respectively.

Anti-emetic properties are exhibited in the compounds when tested by the procedure of Chen and Enxor, J. Pharmac. Exp. Ther. 98, 245-250 (1950) and Leonard, A. et al., J. Pharmac. Exp. Ther. 154, 339-345 (1966).

Anti-emetic properties in the control of emesis due to administration of platinum anti-cancer drugs were determined by a modification of the method described by Gylys, J. A., in Res. Commun. Chem. Pathol. Pharmacol. 23, No. 1, January 1979, pp 61-68 as follows: cisplatin (cis-diamminedichloro-platinum) is administered at a dose of 3 mg/kg intravenously to non-fasted dogs (both sexes). Ninety minutes after cis-platinum administration, the test drug in saline at a dose volume of 2 ml/kg is administered intravenously. A control group of dogs are given the cisplatin followed by saline at 90 min without test drug. The dogs are observed continuously for a period of 5 hr counting the number of emetic episodes compared to emetic episodes observed for the controls. Utilizing this procedure, the two compounds of Examples 1 and 3, preferred for control of emesis due to cisplatin administered in a single dose of 1 mg/kg gave 68% and 94% reduction in the number of emetic episodes respectively.

It is therefore a primary object to provide novel 2-alkoxy-N-[1-azabicyclo[2.2.2]oct-3-yl-benzamides and thiobenzamides.

A further object is to provide 2-alkoxy-N-(1-azabicyclo [2.2.2]oct-3-yl-benzamides and thiobenzamides having antiemetic and gastric-emptying enhancement properties.

A still further object is to provide means for controlling violent emetic episodes due to administration of platinum anticancer drugs.

An additional object is to provide novel compositions useful as anti-emetics generally and specifically in combination with platinum anticancer drugs and compositions for controlling gastric emptying.

The benzamido compounds of Formula I are prepared by reacting a suitably activated benzoic acid derivative with 3-aminoquinuclidine to form the corresponding benzamide under a variety of conditions. Two general methods, A and B, are illustrated in the following equations:

Method A, using an Acid Chloride ##STR3## R.sub.1, R.sub.2 and n are as defined under Formula I except R.sub.2 cannot be unprotected amino.

(a) Suitable solvents are chloroform and diethyl ether.

Method A is illustrated by Examples 5, 6, 7 and 9.

Method B, using 1,1'-Carbonyldiimidazole ##STR4## R.sub.1, R.sub.2 and n are as defined under Formula I. (a) e.g., tetrahydrofuran.

Method B is illustrated in Examples 1, 3 and 8.

Compounds wherein R.sub.2 is primary amino may also be prepared from a compound prepared by Methods A or B, wherein R.sub.2 is nitro by catalytic reduction of the nitro compound.

Alternatively, compounds wherein R.sub.2 is amino may be prepared by procedures of Method A utilizing a starting benzoyl halide wherein the amino group has been protected, or they may be prepared from compounds prepared in Methods A or B wherein R.sub.2 is nitro and reducing the nitro radical to an amino radical.

Preferably, the compounds wherein R.sub.2 is amino or methylamino are prepared by Method B.

The free base of any compound of Formula I from its acid addition salt may be regenerated by usual procedures of partitioning between dilute aqueous base and a suitable solvent, separating the solvent layer, drying and evaporating.

The preparation of the thiobenzamido compounds of Formula II may be accomplished by mixing and reacting a benzamido compound of Formula I with a mixture of phosphorus pentasulfide (P.sub.2 S.sub.5) and potassium sulfide (K.sub.2 S) or by mixing and reacting 3-aminoquinuclidine with an appropriately substituted benzaldehyde and sulfur. The reaction sequences are illustrated by the following: ##STR5## In these methods, compounds wherein R.sub.2 is nitro may be reduced to compounds wherein R.sub.2 is amino.

A preferred group of compounds encompassed by Formula I have the formula: ##STR6## wherein Am is amino (i.e., --NH.sub.2) or methylamino. The compounds are highly potent as gastric emptiers and as anti-emetics in conjunction with cisplatin cancer treatment, being more potent than metoclopramide and devoid of undesirable neuroleptic side effects even at much higher doses than required for their gastric emptying and anti-emetic effects. As will be recognized from the above description, these compounds (Ic) are preferably prepared by Method B.

The following examples are provided merely by way of illustrating the methods of preparation and compounds and are not to be construed as being limiting in nature.

In a closed system equipped with an oil bubbler, 30 ml of tetrahydrofuran was added to a mixture of 4-amino-5-chloro-2-methoxybenzoic acid, 2.02 g, (0.010 mole, and 1,1'carbonyldiimidazole, 1.62 g (0.010 mole) with stirring. When evolution of carbon dioxide ceased, nitrogen was bubbled through the reaction mixture for 1 hr. A solution of 3-aminoquinuclidine, 1.26 g, (0.010 mole) in 10 ml tetrahydrofuran was added dropwise to the stirred reaction mixture and stirring at room temperature continued for 3 hrs. TLC analysis (3% conc. ammonium hydroxide solution in methanol) showed some product formation. The mixture was heated at reflux temperature for 18 hours and then concentraded to an oil. TLC analysis showed the presence of the product, imidazole, and 3-aminocuinuclidine. The oil was dissolved in methylene chloride (75 ml) and washed twice with 50 ml portions of aqueous sodium bicarbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated to yield 2.0 g (67%) of a glassy amorphous solid, the free base of the title compound.

In another reaction on a 0.020 mole scale, 5.18 g (83.8%) of the product as the free base was obtained.

The products were combined, dissolved in methanol (20 ml) and the solution and treated with a solution of fumaric acid (2.73 g) in methanol (50 ml). Absolute ether was added to precipitate the salt which was collected by filtration and recrystallized from methanol-water (200:20) with isopropyl ether added to the point of incipient cloudiness. The recrystallized salt (5.38 g) melted at 223.degree.-225.degree. C.

Analysis: Calculated for C.sub.19 H.sub.24 N.sub.3 O.sub.5 Cl: C,53.59; H,5.68; N,9.89. Found: C,53.35; H,5.72; N,9.95.

To an isopropyl alcohol solution of the free base of the title compound such as was obtained by the procedure of Example 1 is added an equal molar amount of 37% (conc.) hydrochloric acid. The crude salt is separated by filtration and recrystallized from acetone-water to give the title compound, m.p. 158.degree.-160.degree. C.

To a mixture of 1,'-carbonyldiimidazole, 1.23 g (0.00756 mole) and 5-chloro-2-methoxy-4-methylaminobenzoic acid, 1.63 g (0.00756 mole) was added 50 ml of tetrahydrofuran. Nitrogen was bubbled into the solution for 30 minutes to remove any carbon dioxide that was present. To the solution was added 3-aminoquinuclidine, 0.95 g, (0.00756 mole) in one portion, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to an oil which was shown to be 1:1 mixture of the free base of the product and imidazole. The mixture was dissolved in 20 ml methanol and treated with a solution containing 0.47 g fumaric acid in 20 ml of hot methanol. Upon cooling, 1.52 g of white solid formed. Recrystallization from water-methanol gave 0.84 g of the product as a white solid; m.p. 237.degree.-238.degree. C.

Analysis: Calculated for C.sub.20 H.sub.26 N.sub.3 O.sub.6 Cl: C,54.61; H,5.96; N,9.55. Found: C,54.61; H,5.98; N,9.51.

To an isopropyl alcohol solution of the free base of the title compound, such as was obtained by the procedure of Example 3, is added an equal molar amount of 37% (conc.) hydrochloric acid. The crude salt is separated by filtration and recrystallized from ethanol-water to give the title compound, m.p. 225.degree.-258.degree. C.

In a closed system equipped with an oil bubbler, a solution of 2-methoxybenzoyl chloride, 2.76 g (0.0016 mole) in 50 ml absolute ether was added dropwise over 10 min to a stirred solution of 3-aminoquinuclidine, 1.81 g (0.0144 mole) in 100 ml absolute ether. After the addition was completed, the mixture was stirred at room temperature for an additional 2 hrs. The solid hydrochloride salt was collected by filtration under nitrogen. The salt (3.83 g) was dissolved in sodium bicarbonate solution and extracted twice with 25 ml portions of methylene chloride. The extract was dried over magnesium sulfate and concentrated to yield 1.25 g clear oil (33.3%). TLC analysis (3% conc. ammonium hydroxide in methanol) showed the free base to be pure. A solution of 1.17 g of the free base in 5 ml methanol was treated with a solution of 0.52 g fumaric acid in 10 ml methanol. Isopropyl ether was added to give approximately 100 ml of solution from which the fumarate salt precipitated. The salt was collected under nitrogen and dried in a vacuum oven at 60.degree. C. overnight. NMR and elemental analyses showed that the product was a hemihydrate. Analysis: Calculated for C.sub.19 H.sub.25 N.sub.2 O.sub.6.5 : C,59.21; H,6.54; N,7.27. Found: C,59.18; H,6.30. n,7.25.

A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole). anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211.degree.-212.degree. C. The NMR analysis was satisfactory.

Analysis: Calculated for C.sub.16 H.sub.23 N.sub.2 O.sub.3 Cl: C,58.80; H,7.09; N,8.57. Found: C,58.38; H,7.13; N,8.44.

In a closed system equipped with an oil bubbler, a solution of 2,4-dimethoxybenzoyl chloride, 13.08 g, (0.0652 mole) in 200 ml absolute ether was added dropwise over 30 minutes to a stirred solution of 3-aminoquinuclidine, 7.80 g, (0.0619 mole) in 200 ml absolute ether. The mixture was stirred overnight, and the solid hydrochloride salt of the product was filtered under nitrogen. The material was dried in a vacuum oven at 40.degree. C. to give 18.70 g (92%). A 2.94 g (0.009 mole) portion of the hydrochloride salt in 20 ml methanol was treated with a solution of sodium methoxide prepared from 0.23 g (0.010 mole) sodium metal and 10 ml methanol. After standing a few minutes, the mixture was filtered and the filtrate concentrated on a rotary evaporator, and the residue was triturated with 75 ml methylene chloride. After filtering to remove some insuluble solids, the filtrate was concentrated to yield 2.53 g of the free base of the title compound (97% recovery from the hydrochloride salt). The free base was dissolved in 100 ml acetone and concentrated sulfuric acid (0.483 ml) added dropwise with stirring. The solid that formed was collected under nitrogen to give 2.76 g of the salt which recrystallized from methanol-isopropyl ether and dried in a vacuum oven at 60.degree. C. for 2 hrs and then overnight at 78.degree. C.; m.p. 223.degree.-225.degree. C.

Analysis: Calculated for C.sub.16 H.sub.24 N.sub.2 O.sub.7 S: C,49.47; N,7.23. Found: C,49.41; H,6.30; N,7.25.

In a closed system equipped with an oil bubbler, tetrahydrofuran, 100 ml, was added to a mixture of 2,4-dimethoxybenzoic acid, 3.64 g (0.020 mole) and 1,1'carbonyldimidazole, 3.24 g (0.020 mole). No evolution of carbon dioxide was observed and after stirring for 3 hrs, TLC (ethyl acetate) and mass spectral analysis showed that the starting material had reacted to form (2,4-dimethoxybenzoyl) imidazole and imidazole. A solution of 3-aminoquinuclidine, 2.52 g (0.020 mole) in 10 ml tetrahydrofuran was added to the mixture, and the solution was heated to reflux temperature for 1 hr and then allowed to stand overnight at room temperature. A solution of fumaric acid, 2.32 g (0.020 mole) in 50 ml methanol was added to the reaction mixture. Tetrahydrofuran was added until the solution became slightly turbid. The solution was chilled in a refrigerator. The solid which precipitated from solution was collected by filtration and found to be a fumarate salt of 3-aminoquinuclidine. The filtrate was concentrated to an oil and triturated with tetrahydrofuran. The solid precipitate which formed on standing was filtered and shown by TLC (3% concentrated ammonium hydroxide in methanol) to be the desired product plus traces of imidazole and 3-aminoquinuclidine. Recrystallization from methanol-iropropyl ether gave 5.41 g white crystalline solid (67% yield calculated as the monofumarate). NMR and elemental analysis showed the salt to contain less than one equivalent of fumaric acid. The salt was dissolved in boiling methanol (50 ml) and treated with an additional 0.77 g (0.0066 mole) fumaric acid in 10 ml hot methanol. Isopropyl ether was added until the hot solution became turbid. The solid obtained on cooling was collected, recrystallized from methanol-isopropyl ether and dried in a vacuum oven at 78.degree. C. overnight. NMR and elemental analysis showed the salt to be a 1.5 fumarate, m.p. 192.degree.-192.5.degree. C.

Analysis: Calculated for C.sub.22 H.sub.28 N.sub.2 O.sub.9 : C,56.89; H,6.08; ,6.03. Found: C,56.81; H,6.13; N,6.04.

To a solution of 3.82 g (0.0192 mole) of 3-amino quinuclidine dihydrochloride in about 25 ml of carbon dioxide-free water was added 8 g (0.025 mole) of barium hydroxide octahydrate. The mixture was warmed for 5 minutes and then dried to a powder on a rotary evaporator. While protecting from contamination with carbon dioxide in the atmosphere, the powder was extracted in sequence with hot benzene and a 1:1 mixture of benzene-methylene chloride solution. The combined extracts were dried over magnesium sulfate and the mixture filtered. To the filtrate with agitation was added dropwise a solution of 3.4 g (0.0171 mole) of 2-propoxybenzoyl chloride in 50 ml of methylene chloride. The mixture was warmed on a steam bath to evaporate about 75% of the methylene chloride. Ligroin (60-110) was added and the mixture solidified. The solid was recrystallized from anhydrous ethyl alcohol to give 3.9 g (62.0%), m.p. 210.degree.-211.degree. C.

Analysis: Calculated for C.sub.17 H.sub.25 N.sub.2 O.sub.2 Cl: C,62.86; H,7.75; N,8.62. Found: C,62.62; H,7.59; N,8.54.

A solution of 1.69 g (0.00768 mole) of 3-methoxy-2-naphthoic acid chloride in 15 ml of methylene chloride was added dropwise to a stirred solution of 0.97 g (0.00768 mole) of 3-aminoquinuclidine in 25 ml of methylene chloride in a closed system equipped with an oil bubbler. The reaction mixture was stirred overnight at ambient temperature, and then concentrated to give an off-white glassy solid. Two recrystallizations from methanol-isopropyl ether gave 1.95 g (73.4%) of the product as an off-white solid which was vacuum dried at ambient temperature, m.p. 248.degree.-252.degree. C. Analysis: Calculated for C.sub.19 H.sub.23 N.sub.2 O.sub.2 Cl: H,6.68; N,8.08. Found: C,65.40; H,6.72; N,8.01.

One half mole of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide fumarate is partitioned between dilute sodium hydroxide and 400 ml of benzene. The benzene solution is dried with sodium sulfate and distilled to a volume of 250 ml. To this is added a finely-ground mixture of 9 g of phosphorous pentasulfide and 9 g of potassium sulfide. The mixture is refluxed for 4 hr. and an additional 9 g of phosphorous pentasulfide is added and reflux continued for 2 hr. The benzene is decanted off. The solid is dissolved in a suitable solvent and reacted with fumaric acid to give the title compound.

Pharmaceutical Methods and Compositions

Generally, the method of controlling emesis and gastric emptying in accordance with this invention comprises administering internally to warm blooded animals including human beings certain 2-alkoxy-N-[1-azabicyclo[2 2.2]oct-3-yl)benzamides and thiobenzamides of Formula I, preferably Formula Ic, or a non-toxic organic or inorganic acid addition salt thereof in a wide variety of pharmaceutical forms well known in the art, preferably with a non-toxic pharmaceutical carrier such as is described below in an amount to control emesis and/or facilitate gastric emptying. The active agent is administered orally, subcutaneously, intravenously or intramuscularly or parenterally and, if necessary, in repeated doses until satisfactory response is obtained. The daily dosage is from about 5 to about 300 mg of active medication, advantageously from about 5 mg to 50 mg. Co-administration of the compounds of Formula I and the platinum drug is within the purview of the method of this invention.

In the particular method of controlling emesis due to administration of platinum drugs in cancer treatment, it may at times be desirable to administer a mixture comprised of compounds of Formula I. preferably Ic, and the platinum drug to the animal, including humans, the daily dosage being within the range cited above.

The pharmaceutical compositions for general use as antiemetics and gastric emptyiers of this invention comprise at least one of the compounds of Formula I, preferably Formula Ic above, as active ingredients in an amount to provide effective antiemetic or gastric emptying action. The compositions contain 0.05 to 100 mg active medicament per unit dose. Preferably, the compositions contain from about 5 mg to 100 mg of medicament, advantageously from about 5 mg to about 50 mg per unit dose. The compounds are thus presented in a therapeutic composition suitable for oral, parenteral, subcutaneous, intramuscular, intraperitoneal or intravenous administration. Thus, for example, compositions for oral administration can take the form of elixirs, capsules, tablets or coated tablets containing carriers conveniently used in the pharmaceutical art. Exemplary of solid carriers including tableting and capsulating excipients are lactose, sucrose, potato and maize starches, talc, gelatin, agar, pectin or acacia, stearic and silicic acids, magnesium stearate, terra alba and polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient can be comprised of a sterile parenterally acceptable liquid; e.g., water or arachis oil contained in ampoules.

The pharmaceutical compositions for use in conjunction with administration of platinum drugs in cancer treatment will be formulated to contain from about 0.1 mg/kg to about 3.0 mg/kg body weight, preferably 1.0 mg/kg body weight or less. As stated above, co-formulation of platinum anti-cancer drug and compounds of Formula I are within the scope of this invention and it is only necessary that the active ingredient of Formula I constitute an effective amount.

In all of the above, it is only necessary that a suitable effective dosage will be consistent with the dosage form employed. The exact individual dosages, as well as daily dosages, will of course be determined according to standard medical principles under the direction of a physician or veterinarian. Generally, the pharmacology tests on rats in comparison to metoclopramide suggests that much less of the active agent selected from a compound of Formula Ic would be required for a given antiemetic effect or gastric emptying effect than would be required for metaclopramide and dosages can thereby be estimated to some extent.

The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art without departing from the spirit of the invention, and it is therefore understood that the invention is to be limited only by the scope of the appended claims.