NO142395B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE Witch Hydro-1H AZEPINES - Google Patents

Description

This invention relates to a method for the production of

new hexahydro-1H-azepine derivs.

It has been known for some time that compounds containing an azepine ring have pharmaceutical activity, particularly analgesic activity. A well-known non-adherent pain reliever of this type on the market is e.g. ethyl 1-methyl-4-phenyl-hexahydroazepine-4-carboxylate, which is known as etoheptazine.

We have now found that a new series of hexahydroazepines, which are substituted in either the 3- or 4-position with a lower alkyl group and a phenyl radical substituted in the meta-position with an oxygen-containing substituent such as hydroxy, lower alkoxy, benzyloxy or lower alkanoyloxy , generally exhibit pharmaceutical activity or analgesic antagonism. Some of the compounds show a new and interesting combination of analgesic and analgesic, antagonistic activity. Some of the new compounds can also be used as intermediates in the production of similar compounds.

The new compounds produced by the method according to the invention are hexahydroazepine derivatives with the general formula:

and acid addition salts and quaternary ammonium salts thereof, where R"<*>" is a hydrogen atom, a lower alkyl group, a benzyl group or a lower alkanoyl group, R 2 is a lower alkyl group,

R 3 is a hydrogen atom, a lower alkyl, lower alkenyl,

]a/ere alkynyl or cyclopropylmethyl group, R is a lower alkyl group and the term "lower" means that the radical contains up to 6, preferably up to 4, carbon atoms.

There are two asymmetric carbon atoms in the molecule, and the compound can exist in the form of all the optically active isomers as well as the racemates. If an optically active isomer is desired, a cleavage can be carried out using methods known per se.

Preferred compounds of the above general formula (I) are hexahydro-1H-azepines in which R is methyl, R"<*>" is hydrogen, methyl or acetyl, R 2 is methyl, ethyl, n-propyl, iso-propyl or n-butyl, and R 3 is hydrogen, methyl, ethyl, n-propyl, allyl, 3-methyl-but-2-enyl (ie, commonly called dimethylally), propynyl or cyclopropylmethyl.

The compounds of formula (I) are produced according to the invention in that a compound of formula (II):

where R, R and R are as indicated above, is reduced by a hydride

transfer agent such as lithium aluminum hydride or sodium borohydride.

When the product from the reduction does not contain the desired radicals R 1 and/or R 3, one or both radicals can be converted into another radical R 1 and/or R 3 by methods known per se, such as by reduction, alkylation, formylation, acylation, hydrogenolysis and hydrolysis.

Compounds of the above general formula (I) wherein R"^

is different from lower alkanoyl and R 3 is different from hydrogen can be prepared by "alkylation", as defined below, of a compound of the general formula (I) wherein

3

R is hydrogen.

The term "alkylation" as used here means that a radical R 3 selected from alkyl, alkenyl, alkynyl or cyclopropylmethyl is introduced onto the nitrogen atom in the hexahydroazepxn ring. Many methods for alkylating compounds are known, and the method most suitable to give the desired product can be used, the following methods being generally preferred.

A compound of the general formula (I) in which R"<*>" is different from lower alkanoyl can be reacted with an alkyl halide of the general formula

(where R 3 has the above meaning and Hal is a halogen atom) in the presence of an acid acceptor such as an alkali metal carbonate (e.g. potassium carbonate), preferably in solution in an organic solvent by e.g. 25 - 100°C, preferably 80 - 100°C.

A 1-methyl group can be introduced into a compound of the general formula (I) where R, R and R<2> have the meanings given above, by reductive methylation, e.g. using formaldehyde and hydrogen in the presence of a hydrogenation catalyst.

2 3 The compounds of the general formula (I) where R, R and R

have the meanings given above and R^" is a hydrogen atom,

can be obtained from the corresponding compounds of the general formula (I) where R''" is lower alkyl or benzyl, by cleaving the ether group in a known manner, e.g. by treating the lower alkyl or benzyl ethers with hydrogen bromide or boron tribromide or by subjecting the benzyl ethers to hydrogenolysis. Optionally, the product obtained can then be acylated (eg with acetic anhydride) to give the corresponding compound where R"<*>" is a lower alkanoyl radical.

A compound of the general formula (VII), which can be prepared in a manner known per se, is converted, as will be seen, into an alkali metal derivative thereof (e.g. by reaction with an alkali metal amide) and then reacted with a dihalobutane (eg 1-bromo-4-chlorobutane) to give a compound of general formula (XVII). Cyclization of this compound to the unsaturated compound of the general formula (XVIII)

can be carried out by reaction with a Grignard reagent. Subsequent reduction gives a compound of the general formula (III) where R 3 is hydrogen, i.e. a compound of formula (XIX). If the hexahydroazepine produced by this method is not the desired one, it can optionally be treated in one of the ways described above or in the following to give the desired product.

If it is desired to prepare an acid addition salt, a compound of the general formula (I) can be treated with a pharmaceutically acceptable acid, e.g. hydrochloric acid, sulfuric acid or maleic acid. Likewise, the free base can be prepared by neutralizing an acid addition salt, e.g. with an alkali metal carbonate. A quaternary ammonium salt can be prepared by reacting the free base with an alkyl halide.

The reaction components used in the above-described reactions are either known compounds that are commercially available or can be produced by known methods, or derivatives thereof that can be produced by well-known methods from suitable starting materials by following methods described in the art for the known connections.

A compound of the general formula (I) or an acid addition salt or quaternary ammonium salt thereof can be used together with a pharmaceutically acceptable carrier in a pharmaceutical preparation. The carrier may be solid, liquid or cream-like, and any suitable carrier known in the art may be used. The preparation can be in the form of a tablet, capsule or solution.

The new compounds have valuable pharmacological activity and/or are intermediates for the preparation of similar compounds. In standard pharmacological tests, the new compounds generally show a particular ability to relieve pain and can thus be useful as pain relievers. In addition, some of the compounds have the ability

to counteract narcotic pain relievers.

When pharmacologically assessing the properties of the compounds in

vivo, the compounds are tested on mice by Haffner's tail-clamp method (see F. Haffner, Deutsch. Med. Wschr. 55, 731 (1929) or by the StiaLings-heat method on the tail according to D'Amour-Smith (J. Pharmacol, 72, 74 (1941). The analgesic antagonism can be tested by the method of Casy et al described in J. Pharm. Pharmacol, 20, 769 (1968).

When the new compounds by the test methods described above are administered orally and/or intraperitoneally in a dose of about 10 to about 200 mg/kg, they generally exhibit an analgesic effect.

When the new compounds produced according to the invention are used as painkillers, they can be administered to warm-blooded animals, e.g. mice, rats, rabbits, dogs, cats or monkeys alone or in combination with pharmacologically acceptable carriers, the ratio of which is determined by the solubility and chemical nature of the compounds, the chosen route of administration and standard biological practice. For example they can be administered orally in a form containing such excipients as starch, milk or sugar.

They can also be administered orally in the form of solutions, or they can be injected parenterally. For parenteral administration, they can be used in the form of a sterile solution or suspension containing other solutes, e.g., sufficient saline or glucose to make the solution isotonic.

The dosage of the new compounds will vary according to the form of administration and the particular compound chosen. Furthermore, it will vary with the particular individual being treated. In general, treatment is initiated with a small dose that is essentially

equal to less than the optimal dose for the compound. The dose is then increased in small steps until the optimal effect for the particular case is achieved. In general, the novel compounds are preferably administered at a concentration which generally produces effective results without causing any untoward or harmful side effects.

effects.

The following examples shall serve to further illustrate the invention.

Example 1

3-(m- methoxyphenyl)- 2, 3- dimethylhexahydro- 1H- azepine

(a) 2-(m-Methoxyphenyl)propionitrile (64g) was added

to a stirred suspension of sodium amide (18g) in dry toluene (160ml) at 60°C. After completion of the addition, dry tetrahydrofuran (20 ml) was added and the mixture was stirred at 80°C for 1 hour. This mixture was then added dropwise to a

solution of l-bromo-4-chlorobutane (72 g) in dry toluene (200 ml)

at 5-10°C under nitrogen over a period of 2 hours, the mixture was then warmed to room temperature and stirred overnight. The reaction mixture was poured into water and the toluene layer was separated. The organic layer was washed successively with 2N hydrochloric acid and water. After drying over magnesium sulfate and evaporation of the solvent, 6-chloro-2-(m-methoxyphenyl)-2-methyl-hexane-nitrile was obtained by careful distillation as a colorless oil (43.4 g), b.p. 152 - 154°c at o.8 mm Hg. (Found: C 67.0;

H 7.3; N 5.7. C^H^ClNO requires C 66.8; H 7.2; N 6.0%) .

(b) The chloronitrile from part (a) (3.13 g) in dry toluene

(100 ml) was added to methylmagnesium iodide (0.0285 mol) in ether (20 ml) under a stream of nitrogen. After completion of the addition, the ether was distilled from the reaction mixture until the internal temperature was 90°C, and the mixture was then heated to this temperature for 24 hours. After cooling, the reaction mixture was poured onto a mixture of ice and ammonium chloride, the aqueous layer was separated and extracted with benzene. The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure at 40°C to give a viscous oil. The oil was extracted repeatedly with boiling ether to give a yellow gum from which precipitated pale yellow rhombs of 3-(m-methoxyphenyl)-2,3-dimethyl-

4,5,6,7-tetrahydro-3H-azepine hydroiodide (1.0 g) sm. p. 164 -

168°C, from propan-2-ol. The compound could be recrystallized for analysis from propan-2-ol. (Found: C 50.35; H 6.2; N 3.8.

ci5H2iNO"HI requires c 50'2; H 6<0; N 3.8%) .

(c) The tetrahydroazepine hydroiodide (6.1 g) was added portionwise to a solution of aluminum lithium hydride (1.5 g)

in ether (200 mL) under reflux. After completion of the addition, dry tetrahydrofuran (100 mL) was added and the mixture was heated under reflux for 4 hours.

After cooling to room temperature, the reaction mixture was quenched by the addition of water (1.5 mL) and 2N sodium hydroxide (3 mL). Filtration and evaporation gave an oil which was distilled to give 3.1 g of the title compound as a colorless oil,

b.p. 128 - 230°C at 0.5 mm Hg. (Found: C 77.15; H 9.9; N 5.6. C15H23NO requires c 77'2? H 9<9: N 6.0%) .

The above oil was dissolved in propan-2-ol and treated with

a solution of hydrogen chloride in dry ether to give colorless needles of the hydrochloride, sm. mp 166 - 167°C. (Found: C 66.8; H 8.8;

N 5,<0.><C>15<H>23<N>O.HCL requires C 66.7; H 9.0:, N 5.2%).

Example 2

1.. 2 , 3- Trimethyl- 3-( m- methoxyphenyl) hexahydro- 1H- azepine The azepine from example 1 (c) (3.0 g) in absolute ethanol (100 ml) containing 40% aqueous formaldehyde (2 ml) was hydrogenated at an initial ice pressure of 3.9 kg/cm 2 . After the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off to give the product as an oil (2.21 g), b.p. 104 - 110°C at 0.01 mm Hg.

(Found: C 78.0; H 10.2; N 5.4. C.^H„_N0 requires C 77.9; H 10.2;

lb 25

N 5.7%).

The above oil was converted to the hydrobromide in propan-2-ol with 50% aqueous hydrogen bromide. The product was recrystallized from propan-2-ol and had m.p. 232 - 235°C. (Found: C 58.5; H 8.0;

N 4.2. c16H25NO-HBr requires c 58.4; H 8.0; N 4.3%).

Example 3

3-(m-hydroxyphenyl)-1,2,3-trimethylhexahydro-1H-azepine The azepine from Example 2 (2.1 g) was heated under reflux with 50% hydrogen bromide for 2 hours. On cooling, one got

colorless rhombs of the hydrobromide (2.06 g), sm. p. 234 -

236°C. The product could be obtained as either needles, sm. p. 230 - 231°C, or diamonds, sm. m. 234 - 240°C, clear at 250°C, after recrystallization from methanol. These two crystal forms were shown to be identical by intron formation, infrared spectrum and analysis. (Found: C 57.3; H 7.8; N 4.2. C^H^NO .HBr requires C 57.3; H 8.0; N 4.6%) .

Example 4

3-(m-Hydroxyphenyl)-2,3-dimethylhexahydro-1H-azepine The azepine from Example 1 (c) (4.6 g) was heated under reflux with 50% aqueous hydrogen bromide (10 ml) for 2 hours. The solvent was removed under reduced pressure and the orange-colored oil was evaporated repeatedly with propan-2-ol. The product crystallized from propan-2-ol/ether as a colorless hydrobromide (3.55 g), sm. mp 163 - 165°C. (Found: C 55.9; H 7.4;

N 4.<7.> C 14<H>21<N>O.HBr requires C 5.60; H 7.4; N 4.7%).

Example 5

1-Allyl-2,3-dimethyl-3-(m-hydroxyphenyl)hexahydro-1H-azepine 2,3-Dimethyl-3-(m-hydroxyphenyl)hexahydro-1H-azepine hydrobromide (1.5 g) was heated under reflux with anhydrous potassium carbonate (2.8 g) and l-bromo-2-propane (0.61 g) in propane-

2-on (75 ml) for 16 hours. The reaction mixture was cooled, filtered and evaporated to an oil which was dissolved in propane-2-

etc. and acidified with 50% aqueous hydrogen bromide. Repeated evaporation with small amounts of propan-2-ol removed the last traces of water, and the product was crystallized from propan-2-ol (800 mg), sm. mp 212 - 214°C. (Found: C 60.0; H 7.95; N 4.0. C^H^NO.HBr requires C 59.9; H 7.7; N 4.1%).

Claims (1)

Analogous process for the preparation of therapeutically active hexahydro-1H-azepine compounds of the formula or acid addition salts or quaternary ammonium salts thereof, where R is a hydrogen atom, a lower alkyl group, a benzyl group or a lower alkanoyl group; R 2 is a lower alkyl group; R 3 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a cyclopropylmethyl group; and R is a lower alkyl group, characterized in that a tetrahydro-azepine of the formula (where R, R 1 and R 2 have the meanings given above) is reduced with a hydride transfer agent such as lithium aluminum hydride or sodium borohydride, after which, the compound formed optionally N -demethylated when R 3 is a methyl group, to form a corresponding compound where R is hydrogen, and, optionally, the formed compound is alkylated when R 3 is hydrogen to give a corresponding compound where R is lower alkyl, lower alkenyl, lower alkynyl or cyclopropylmethyl, and optionally the compound formed is hydrolyzed or deforated when R^" is different from hydrogen, to give a corresponding compound where R"*" is hydrogen, and optionally the compound formed is alkylated or acylated when R^" is hydrogen, for to give a corresponding compound where R^ has the meanings given in the preamble except for hydrogen, and optionally a racemate obtained is subjected to cleavage to form an optical act v isomer, and optionally a free base is converted into an acid addition salt or quaternary ammonium salt thereof.