NO140822B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE INDOLOBENZAPINS - Google Patents

Description

- Certain octahydropyridoindolobenzazepines are known from

US Patent No. 3,373,168 and 3,457,271, belonging to

Hoffmann-La Roche, Inc. These compounds can be represented

of the following formula (1):

where R is straight-chain or branched alkyl with 1-7 carbon-

atoms.

According to IUPAC 1957 rules, the same compounds can be represented by formula and designated as 1,2,3,4,4a,8,9,14a-octahydropyrido[4',5':2,3]-indolo[1,7- ab][1]benzazepines. The IUPAC designation and nomenclature will be used in this description.

The compounds of formula (1) are described in the cited US Patent Nos. 3,373,168 and 3,457,271 as having anti-depressant activity and are useful as anti-depressant agents. These compounds are prepared according to the two patents by reduction of the corresponding hexahydro compounds either with sodium in a mixture, of tetrahydrofuran and liquid ammonia or with zinc in hydrochloric acid. The first method is preferred as it gives higher yields.

The compounds produced according to the invention have a different steric configuration at the hydrogen atoms in the 4a and 14a positions from the compounds according to the above-mentioned patents. The indication of this is that the compounds according to the invention have a trans-configuration of the 4a- and 14a-hydrogens and that the compounds according to the above-mentioned patents have a cis-configuration. The compounds according to the invention are prepared either directly or indirectly, by reduction of a 1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab]-benzazepine with borohydride/ tetrahydrofuran complex followed by acidification with hydrochloric acid, which is found to result in trans configuration. The compounds according to the invention are generally CNS depressants, in contrast to the compounds according to the above-mentioned patents, which are antidepressants.

According to the invention, a class of connecting

look at the formula

where the hydrogen atoms in positions 4a and 14a are in trans configuration in relation to each other,

n is 0 or 1,

X is an anion of a pharmaceutically acceptable acid, and R a is benzyl, phenethyl, C 1 -C 4 alkyl, cyclopropyl, C 1 -C 8 cycloalkylmethyl, exo-7-nocarylmethyl, 1-adamantylmethyl or 2-adamantylmethyl•

The analogy method according to the invention is characterized by the fact that a compound of the formula

where 0

a ,<!> 7

R_ is equal to R or a methoxymethyl, or is -C-R

^ 7

where R is phenyl, phenethyl, hydrogen, C^-C^ alkyl, C2_C^ alkenyl, C^-Cy-cycloalkyl, C^-C^ c<y>cloalken-yl, Cr-C, cycloalkadienyl, exo-7- norcaryl, 1-adamantyl or 2-adamantyl,

is reduced by treatment with a borohydride/tetrahydrofuran complex followed by treatment with hydrochloric acid, and that the free base, if desired, is converted into a salt by reaction with a pharmaceutically suitable acid.

Synthesis of the compounds

In the formulas given above, and later in the description, Ra, R<2>, R^, n and x are as previously defined.

Starting materials

1,2,3,4,8,9-hexahydropyrido[4',3<1>:2,3]indolo[1,7-ab][1]=benzazepines of formula II can be prepared, e.g. by the method described in the above-mentioned Hoffmann-La Roche patents, namely by N-nitrosation of iminodibenzyl, reduction of the product to N-aminoiminodibenzyl, condensation with a suitable substituted 4-piperidinone, and cyclization with an acid. Methyl- and ethyl-substituted hexahydropyridoindolobenzazepines are known compounds, several other 3-substituted hexahydropyridoindolobenzazepines are described in US Patent No. 3,764,684, issued October 9, 1973. The compounds

0

2 "7

of formula II where R is -C-R can of course be prepared by conventional acylation of the corresponding compound where Ro is hydrogen, using a suitable acylating agent such as an acyl chloride, alternatively these compounds can be obtained by condensation of N-aminoiminodibenzyl with a suitable l- acyl-4-piperidone.

Reaction ( 1)

The reduction of the hexahydro precursors to the octahydro compounds is best carried out with a four- to five-fold excess of borohydride/tetrahydrofuran complex at a temperature as low as 0° C, or as high as the reflux temperature of tetrahydrofuran. The reducing power of the borohydride/tetrahydrofuran reagent can be further increased by dilution with a higher-boiling ether, e.g. diglyme, which allows the reaction to be carried out at a higher temperature, usually not above 100 - 110° C. The reaction mixture is then acidified with approx. 4-10 molar hydrochloric acid, heated to 100° C, can be cooled and neutralized with caustic soda. The product may then be recovered by any suitable means, including extraction, evaporation followed by extraction, conversion to an addition salt, etc.

The most striking properties of the compounds of formula Ia are their CNS depressant (more specifically sedative sedative) activity, which is totally unexpected from what is disclosed in US Patent Nos. 3,373,168 and 3,457,271. Although it is believed that this activity is associated with the steric configuration of the compounds according to the invention, one does not wish to be bound by this theory. Nevertheless, the proposed structure of the compounds according to the invention is based on the following considerations: (a) Reduction of a hexahydro compound (3) with borohydride in tetrahydrofuran increases the molecular weight by 2, as determined by mass spectroscopy, which means that two hydrogens have been added, (b) ultraviolet spectroscopy shows that the diphenylamine chromophore, formed by rings C and E, and the nitrogen in the 14-position are intact after the reduction, and this means that the aromatic rings C and E are retained, (c) reductive s< The destruction of the Cg-Cg bond, which includes benzylic carbon atoms, is ruled out both by ultraviolet and nuclear magnetic resonance spectroscopy, (d) the only possibility is then saturation of the C4a~^i4a~ double bond, (e) nuclear magnetic resonance spectroscopy of the known octahydro compounds shows that these have a cis configuration.

The formation of octahydroindolobenzazepines by the process according to the invention, where the rings B and C form an indoline group is not only new but also totally unexpected, especially in light of the results a recent investigation of the reaction of indoles with diborane has shown, Monti et al., Tetrahedron 27 , 3331

(1971).

In this description and claims, the compounds according to the invention will be indicated as the trans compounds in order to separate them from the compounds with the configuration described in US Patent No. 3,373,168 and 3,457,271. However, this designation is used with the understanding that if it is finally shown that either this isomer statement is incorrect or a complete isomeric relationship exists, the term "trans" as used here will indicate compounds with a configuration to the compounds specifically described here. The steric configuration of the compounds according to the invention can thus be characterized as identical to that obtained when a C₁-C₂ double bond is reduced with the borohydride/tetrahydrofuran complex, followed by acidification with hydrochloric acid.

Salts

Representative pharmaceutically suitable acids which can be used to prepare acid addition salts according to the invention are the following: hydrochloric acid, hydrobromic acid, sulfuric acid, sulphamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, citric acid, pamoic acid, succinic acid, methanic acid. sulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid and p-toluenesulfonic acid.

Stereoisomers

All compounds of formula I have at least two asym-

4a 14a

tric centers, resulting from the reduction of A' to the trans-condensed system. The invention includes the racemate as well as the individual enantiomers. If the 3-substituent includes a group capable of existing in stereoisomeric forms, all the resulting diastereoisomers are also included.

Examples

Preparation of compounds according to the invention is illustrated by the following examples, where all parts, ratios and percentages are on a weight basis unless otherwise stated.

Example 1

( + )-trans-1,2,3,4,4a,8,9,14a-octahydro-3-methylpyrido-[ 4', 3' :2, 3] indolo[ 1, 7- ab][ ljbenzazepine

A solution of 4.76 g of 1,2,3,4,8,9-hexahydro-3-methyl-pyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine ( which can be prepared according to US Patent No. 3,457,271, column 4, lines 27 - 54) in 50 ml of tetrahydrofuran was added dropwise to a stirred 1N solution of borohydride in tetrahydrofuran (42 ml) under a nitrogen atmosphere. After the addition was complete, the mixture was refluxed under a nitrogen atmosphere for 5 hours, then cooled in ice and quenched with 20 mL of 6N hydrochloric acid. The mixture was distilled, the separated liquid being replaced from time to time by the addition of dioxane. The mixture was again refluxed at 91°C for 1 hour with additional 6N hydrochloric acid, then cooled to 70°C, basified with sodium hydroxide, and evaporated in vacuo. The semi-solid residue was treated with water and chloroform, and the chloroform layer was further worked up to yield 1.50 g of a solid product with a melting point of 128 - 131° C. The mother liquors gave a further amount of the material with a melting point of 129.5 - 130, 5° C. Crystallization from ether raised the melting point to 132 - 134° C, UV spectrum: ^<3>°<**> 279.5 nm (loge 4.13).

Reduction of 1,2,3,4,8,9-hexahydro-3-methylpyrido-[4',3':2,3]indolo[1,7-ab][1]benzazepine with sodium in liquid ammonia gave the known (+)-cis-octahydro compound with melting point 120 - 122° C, X"<01>"<1>^<011> 287 nm (log e 4.08).

The (+)-trans-1,2,3,4,4a,8,9,14a-octahydro-3-methyl-pyrido[41,3':2,3]indolo [1,7ab] [1]benzazepine can also be prepared by following an alternative route involving the reductive split-int of 3-methoxymethylhexahydro compound as shown below.

A. A mixture of 2.74 g (0.01 mol) 1,2,3,4,8,9-hexahydro-pyrido[4<1>,3':2,3]indolo[1,7ab][ 1]benzazepine, prepared as shown in Section A of Example 2, and 75 ml of dry benzene were heated to boiling until complete solution was obtained.

10.5 ml, 0.075 mol triethylamine was added to the hot solution, followed by dropwise addition of 7.0 ml (0.026 mol) chloromethyl methyl ether. The resulting mixture was refluxed for 15 minutes, cooled to room temperature and filtered. The filtrate gave on evaporation 3.05 g of a yellow oil which by infrared spectroscopy was found to contain no free

-NH groups.

B. 3.0 g, 0.01 mol of the product from the previous step

in 50 ml of freshly purified tetrahydrofuran was added dropwise with stirring and under a nitrogen atmosphere to 75 ml of an IM solution of borohydride in tetrahydrofuran. The resulting mixture was refluxed under nitrogen for 26 hours, then allowed to cool in ice water and carefully digested with 50 mL of 5.5N hydrochloric acid. About. 30 ml of the liquid was removed by distillation, and 50 ml of glacial acetic acid was added to redissolve the precipitate formed. The solution was refluxed for 1 hour, cooled to 55-60°C and made alkaline with 50% caustic soda. The product was recovered by extraction with ether, followed by evaporation of the solvent, and column chromatography in benzene solution on basic aluminum oxide I. The pure product melted at 136 - 138° C, and was identical to the material prepared by the first method described in this example.

Example 2

(+)-trans-3-(cyclopropylmethyl)-1,2,3,4,4a,8,9,14a-octahydro-pyrido[ 4', 3' ;2, 3] indolo[ 1, 7ab][ 1 ] benzazepine

A. A mixture of 24.6 g of N-aminoiminodibenzyl(5-amino-10,11-dihydro-5H-dibenz[b,fJazepine and 14.8 g of 4-piperidone hydrochloride in 250 ml of ethanol was heated on a steam bath for 15 minutes and cooled, a solution of 20 g of concentrated sulfuric acid in 250 ml of ethanol was added. The resulting mixture was reheated on a steam bath for a further 40 minutes, the resulting solution was cooled, basified with ammonia and then diluted with 1 liter of water .The impure, semi-solid material that separated was taken up in ether, and the aqueous mother liquors were extracted with further portions of ether. The combined ether extracts were concentrated to 500 ml and treated under a nitrogen atmosphere and with vigorous stirring, with 50 ml of 5N hydrochloric acid. The resulting precipitate was filtered off, washed with ether and 1N hydrochloric acid, and dried in vacuo at 100° C. to give 1,2,3,4,8,9-hexahydropyrido[4',3':2,3 ]indolo[1,7-ab][1]-benzazepine hydrochloride with melting point 309° C, a salt only slightly soluble in water. The salt obtained was dissolved in aqueous acetic acid, made basic with ammonia, the impure product was filtered off and recrystallized from benzene whereby the free 1,2,3,4,8,9-hexa-hydropyrido[4 *,3":2 ,3]indolo[1,7-ab][l]benzazepine was obtained.

B. To a solution of 16.4 g of 1,2,3,4,8,9-hexahydropyrido-[4<1>, 3':2,3]indolo[1,7-ab][1]benzazepine in 500 ml of dichloromethane was added to 7.3 g of cyclopropanecarbonyl chloride, followed by the dropwise addition of 10 ml of triethylamine. A mild exothermic reaction took place, after which stirring of the mixture was continued at room temperature overnight. The mixture was then washed with 1N hydrochloric acid and water and dried over anhydrous sodium carbonate. Evaporation to dryness gave impure 3-(cyclo-propylcarbonyl)-1,2,3,4,8,9-hexahydropyrido[4<1>,3<1>:2,3]indolo-[1,7- ab][1]benzazepine obtained as a glassy product. Recrystallization from ethanol gave the pure product with melting point: 154 - 156° C.

A solution of 8.6 g of the above compound in 120 ml of tetrahydrofuran was added dropwise to a suspension of 2.3 g of lithium aluminum hydride in 180 ml of tetrahydrofuran. After the addition was complete, the mixture was first boiled under autobake for 4 hours and was then allowed to stir at room temperature overnight and was finally cleaved in the usual way. After filtration from the inorganic salts, the filtrate was dried over anhydrous sodium carbonate and evaporated in vacuo, the residue was dissolved in a 1:1 mixture of ethyl acetate-benzene and chromatographed on a 14 x 2.2 cm column of basic alumina, activity I. The eluate was evaporated to dryness, the residual oil was dissolved in absolute alcohol, saturated with ethanolic hydrogen chloride, and again evaporated to dryness. On crystallization of the residue from benzene, 3-(cyclopropylmethyl)-1,2,3,4,8,9-hexahydropyrido-[4',3':2,3]indolo[1,7-ab][ 1]benzazepine (formula II; R 2 = cyclo-propylmethyl) with melting point 267° C.

C. A solution of 9.25 g of the free base of the above-mentioned hexahydro compound in 75 ml of tetrahydrofuran was reduced with 100 ml of a 1M solution of borohydride in tetrahydrofuran according to the procedure of Example 1. The title compound weighed 4.43 g and had a melting point of 152.5 - 155° C, UV-CH OH

spectrum: ^max ^81 11111 (lo9 e 4.10). The hydrochloride salt melted at 273 - 276°C.

Reduction of 3-(cyclopropylmethyl)-1,2,3,4,8,9-hexa-hydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine with sodium in liquid ammonia gave the (+)-cis product which formed a hydrochloride salt with melting point 241 - 243° C, UV spectrum:

X CH 3 OH 285 nm (log e 4.10).

max - '

The above-mentioned two octahydro compounds were found to have different R^ values in a thin-layer chromatography system where chloroform-butanol-28% aqueous ammonia in the volume ratios 95:10:5 was used as solvent.

Example 3

(+)-trans-3-(cyclopropylmethyl)-1,2,3,4,4a,8,9,14a-octahydro-pyrido[41,3*:2,3]indolo[1,7—ab] [1 ]benzazepine (by one-step reduction)

A solution of 100 g of 3-(cyclopropylcarbonyl)-1,2,3,4,8,9-hexahydro<p>yrido[4',3':2,3][indolo[1,7-ab][l ]benz-axepine in 500 ml of tetrahydrofuran was added over approx. 30 minutes to approx. 946 ml of an IM solution of borohydride in tetrahydrofuran. The resulting solution was allowed to stand for 72 hours after which a solution of 50 ml of concentrated hydrochloric acid in 100 ml of water was added and the mixture was distilled until the temperature reached 100° C. The remaining material was cooled and diluted with 200 ml of water and 75 ml of 50% -ig sodium hydroxide. The product was extracted with methylene chloride and was recovered as a crystalline material after treatment with acetone of the methylene chloride distillation residue. Yield: 60.3 g with melting point 146 - 151° C. After recrystallization from methanol-chloroform in the volume ratio 9:1, the melting point was raised to 153 - 155° C.

A sample of the above material was converted to the mesylate salt (methanesulfonate) with a melting point of 227 - 232°C.

Example 4

(+)-trans-3-ethyl-1,2,3,4,4a,8,9,14a-octahydropyrido[4<1>,3<1>:-2, 3] indolo[ 1, 7- ab ][ 1] benzazepine

To a mixture of 9.0 g of N-nitrosoiminodibenzyl,

12.4 g of 1-acetyl-4-piperidone and 13.0 g of zinc dust in 75 ml of absolute ethanol were added dropwise to 24 ml of glacial acetic acid with constant stirring and periodic cooling to keep the reaction temperature at 20 - 25° C. After After 6 hours, unchanged zinc was filtered off and the mother liquor evaporated to near dryness. After extracting the residue with benzene, the extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent was stripped off. The yellow-brown residue was dissolved in 50 ml of ethanol, treated with a solution of 8 ml of concentrated sulfuric acid in 50 ml of ethanol and was heated on a steam bath for approx. 10 minutes. The mixture was poured into cold water, whereby a gum separated, from which the aqueous layer was decanted. After dissolving the gum in ethyl acetate, the solution was washed with saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave a yellow-white solid which on crystallization from acetone gave 3-acetyl-1,2,3,4,8,9-hexa-hydropyrido[4',3':2,3]indolo[1,7- ab][1]benzazepine as a white solid with a melting point of 193 - 196° C.

The above-mentioned 3-acetyl compound was reduced with borohydride in tetrahydrofuran according to the method according to example 3. The title compound was isolated in a 36% yield, as a hydrochloride salt with a melting point of 258 - 260° C (decomposition), UV spectrum: ^a^g <H> 2?6 nm (loge 4.11).

Alternatively, the above compound could be prepared by reduction of the 3-acetyl compound under more drastic conditions, as follows: A hot solution of the 3-acetyl compound (11.53 g, 0.0365 mol) in 300 mL of diglyme was rapidly added dropwise to a mixture of 250 ml of diglyme and 150 ml of 1-molar borohydride in tetrahydrofuran. The stirred mixture was then heated under nitrogen at 100°C for 20 hours. The mixture was cooled to 20°C, cleaved with 75 ml of 10N hydrochloric acid and refluxed at 90°C for 1 hour. It was then cooled to 60° C., made alkaline with 100 ml of 50% caustic soda, concentrated in water, and extracted with chloroform. The chloroform extract gave a 67% yield of the 3-ethyl product.

Example l 5

(+)-trans-1,2,3,4,4a,8,9,14a-octahydro-3-isobutylpyrido-[ 4', 3' :2, 3] indolo[ 1, 7- ab][ 1] benzazepine

1,2,3,4,8,9-hexahydro-3-isobutyrylpyrido[4 * , 3 ' : 2, 3] - indolo[1,7-ab][1]benzazepine with melting point 122 - 124° C was prepared by a reaction of 1,2,3,4,8,9-hexahydropyrido-[4',3':2,3]indolo[1,7-ab][1]benzazepine with isobutyryl chloride. This amide was reduced with borohydride-tetrahydrofuran in diglyme in the same manner as described as the alternative method for reducing the 3-acetyl compound to the 3-ethyl compound in Example 4.

The title compound was isolated as its hydrochloride addition salt, mp 286-289°C (dec).

Example 6

(+)-trans-3-benzyl-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3] indolo[ 1, 7- ab][ 1] benzazepine

Condensation of N-nitrosoiminodibenzyl with 1-benzyl-4-piperidone under the conditions described in Example 4 for condensation with 1-acetyl-4-piperidinone from 3-benzyl-1,2,3,4,8,9-hexahydropyrido [4',3':2,3]indolo[1,7-ab][1]benzase-pine (hydrochloride with melting point 200° C). Reduction of the free base with borohydride-tetrahydrofuran in diglyme under the conditions of the alternative method described in Example 4 for the reduction of the 3-acetyl compound aa an 84% yield of the title compound, which was isolated as its hydrochloride salt, m.p. 210-212°C (fission). The free base was obtained by treating the hydrochloride salt in methanol solution with an anhydrous ammonia. The free base melted-at 146 - 148° C, UV spectrum: ^maxH 2^ 11111 ^oae ^,13).

Example 7

(+)-trans-1,2,3,4,4a,8,9,14a-octahydro-3-(exo-7-norcarylmethyl)-pyrido[ 4', 4' :2, 3] indolo[ 1, 7- ab][ 1] benzazepine

A solution of 7.05 g (0.0178 mol) of 1,2,3,4,8,9-hexahydro-3-[(exo-7-norcaryl)carbonyl]pyrido[4 ' , 4 ' : 2, 3]indolo-[1,7-ab][1]benzazepine, which was prepared from 1,2,3,4,8,9-hexa-hydropyrido[4<1>,3<1>:2,3] indolo[1,7-ab][1]benzazepine and (exo-7-norcaryl)carbonyl chloride, in 100 ml diglyme was added dropwise under a nitrogen atmosphere to a stirred mixture of 100 ml 1M borohydride in tetrahydrofuran and 400 ml diglyme. The mixture was heated to 100° C. for 23 hours and was cooled at approx. 20° C. 75 ml of 10N hydrochloric acid was added, the mixture was refluxed at 100° C for 1 hour, cooled to 60° C and basified with 100 ml of 50% NaOH.

The product was isolated and purified by several extraction and recrystallization steps. Its melting point was 186 - 187°C.

Further representative compounds of formula (1) which can be prepared according to the above-mentioned method are listed below: (1) (+)-trans-3-cyclohexylmethyl-1,2,3,4,4a,8,9,14a -octahydro-pyrido[4<1>,3':2,3]indolo[1,7-ab][1]benzaxepine hydrochloride with melting point 180° C (decomposition), (2) (+)-trans-3-cyclopentylmethyl -1,2,3,4,4a,8,9,14a-octahydro-pyrido[4<1>,3':2,3]indolo[1,7-ab][1]benzazepine hydrochloride with melting point 263° C (cleavage), (3) (+)-trans-3-cyclopropyl-1,2,3,4,4a,8,9,14a-octahydro-pyrido[4',3':2,3]indolo[1 ,7-ab] [l]benzazepine hydrochloride, m.p. 195° C (decomposition), (4) (+)-trans-3-(1-adamantylmethyl)-1,2,3,4,4a,8,9,14a-octa-hydropyrido[4 *,3': 2,3]indolo[1,7-ab] [1]benzazepine hydrochloride, m.p. 195 - 196° C (decomposition), (5) (+)-trans-3-(2-adamantylmethyl)-1,2,3,4,4a,8,9,14a-octa-hydropyrido [4 ' ,3 ' :2,3] indolo [1-, 7-ab] benzazepine hydrochloride, m.p. 169 - 170°C (decomposition. (6) ( + )trans-1,2,3,4,4a,8,9,14a-octahydro-3-phenethylpyrido-[4<1>,3':2,3 ]indolo[l,7-ab][1]benzazepine, m.p. 270°C (dec.).

Pharmacological testing

The compounds produced according to the invention exhibit analgesic activity and sedative-calming effects. The analgesic activity is shown by the phenylquinone twist test (PQW) and the sedative-calming effect is shown as results of the rodent assessment. The procedures used are described in what follows.

Primary rodent assessments

Decreased locomotor activity (L.M.A.)

These signs of reaction are measured subjectively by observing how an animal behaves when it is removed from an observation cage and placed on a table top. Untreated animals will immediately begin actively exploring their surroundings. Animals that have received a depressant compound will show a gradually decreasing receptivity to the new surroundings. The degree of stimulation of the observer necessary to elicit active movement is estimated on a discretionary scale. ThisThis varies from a grade of

-1 where only a slight touch of the animal's body is necessary, to

-4 where the animal is unresponsive or minimally receptive to the application of a pain stimulus (press on the end of the tail). ED5q is the oral dose that induces a clear reduction in locomotor activity (with a grade of at least -1). Groups of 5 mice were given decreasing oral doses at 0.5 log intervals (300, 100, 30 etc), until no behavioral effects were evident. Decreased locomotor activity is indicative of general central nervous system depressive activity.

Ptosis (Pto.)

Results given in: mg/kg po/mouse.

The degree of eyelid closure is used as a measure of central nervous system depression. An animal is removed from its observation cage and allowed to be outside the cage for 30 seconds. After this time, the degree of eyelid closure is estimated on a discretionary scale. Passive ptosis, cvs. closure that can be temporally reversed by touch is generally indicative of sedative activity of a psychotropic compound (active ptosis, i.e. eye closure that remains unchanged by touch is generally a sign of adrenergic blocking activity. It is a relatively rare observed phenomenon). Only passive ptosis was observed for these compounds, for which ED,-q is anqitt.

Catalepsy (Cat.)

Results given in: mg/kg po/mouse).

An animal's ability to remain in an abnormal state is used as another indication of depressive activity on the central nervous system. A test animal is removed from its observation cage and placed so that its hind feet are on the table top and its front feet are resting on the side of the observation cage. If an animal remains in this position for at least 10 seconds, it is considered to show cataleptic behavior.

The analgesic activity of the compounds according to the invention is suitably determined by the phenylquinone twist test as described below:

Phenylquinone twist (P.Q.W.)

Results given in: mg/kg po/mouse.

Groups of at least 10 mice are given phenyl-p-benzoquinone at 2.5 mg/kg intraperitoneally 30 minutes after oral administration of graded doses of the test compound. Two or more dose concentrations are used for each compound. For the assessment, a "twist" is defined as stretching, twisting a hind foot inward, or contraction of the abdomen. The total number of twists for each animal, treated and control animals next to each other, is counted during a 30 minute period. The ED5Q' calculated on the basis of the percentage of animals at each dose concentration that showed 50% or less of the mean number of writhes of the control animals is recorded for each compound subjected to this evaluation test. The PQW test is very often used as an indicator of potential analgesic activity in humans, especially for non-narcotic compounds.

The results obtained for certain compounds according to the invention are listed in the following table, where codeine and chlorpromazine are used as standards for the sake of comparison.

The free amines of formula Ia and some of their pharmaceutically acceptable inorganic or organic acid addition salts are substantially insoluble in water. As CNS depressants, they are best administered orally at a concentration of approx. 0.1 - 10 mg/kg body weight. Certain addition salts of the compounds of formula I are more water soluble and can be administered by sub-cutaneous or intramuscular injection. The dose used in such cases will generally be within the range of 0.02 - 5 mg/kg body weight.

As analgesics, the compounds according to the invention are administered orally at a concentration of 0.1 - 10 mg/kg or parenterally at a dose of approx. 0.05-5 mg/kg body weight.

The compounds produced according to the invention can be formulated into compositions comprising a compound of formula Ia together with a pharmaceutically acceptable carrier. The carrier can be either solid or liquid, and the compositions can be in the form of tablets, liquid-filled capsules, dry-filled capsules, aqueous solutions, non-aqueous solutions, suppositories, syrups, suspensions, etc. The compositions may contain suitable preservatives, coloring and flavoring agents. Some examples of what can be used in the production of the products are gelatin capsules, sugars such as lactose and sucrose, starch, dextran and cellulose derivatives, such as methyl cellulose and cellulose acetate phthalate, gelatin, talc, stearic acid salts, vegetable oils such as peanut oil, sesame oil, olive oil, corn oil and the oil from theobroma, liquid petrolatum, polyethylene glycol, glycerol, sorbitol, propylene glycol, ethanol, agar,

water and isotonic saline.

When preparing the compositions for pharmaceutical use, conventional methods and precautions are used. Compositions intended for parenteral administration must be sterile, and this can be achieved either by using sterile ingredients and carrying out the preparation under aseptic conditions, or by sterilizing the final composition according to the commonly known methods such as autoclaving under appropriate temperature and pressure conditions. Ordinary care should be exercised so that there are no incompatible conditions between the active components and the diluting preservatives or flavoring agents or under the conditions used in the preparation of the compositions.

The compositions can be administered to warm-blooded animals orally, rectally or parenterally. This can be done by swallowing, in the case of liquid or solid preparations, by suppositories, or by injecting liquid preparations intravenously, intramuscularly, intraperitoneally or subcutaneously.

The compounds of the invention are administered to warm-blooded animals to elicit the desired pharmaceutical response. The dosage forms are produced with varying strengths depending on the strength of the compound and the desired effect.

Claims (1)

1. Analogy procedure when preparing a therapy tically active compound of general formula where the hydrogen atoms in positions 4a and 14a are in trans configuration in relation to each other, n is 0 or 1, X is an anion of a pharmaceutically acceptable acid, and Ra is benzyl, phenethyl, C₁-C₂. alkyl, cyclopropyl, C 1 -C 8 cycloalkylmethyl, exo-7-nocarylmethyl, 1-adamantyl methyl or 2-adamantylmethyl, characterized in that a compound of the formula R, is equal to Ra or a methoxymethyl, or is where R 7 is phenyl, phenethyl, hydrogen, C1~C4 alkyl, C2~C4 a^-k^y1' C3-G?-cycloalkyl, C5-C? cycloalkenyl, C5~C7 cycloalkadienyl, exo-7-norcaryl, 1-adamantyl or 2-adamantyl, is reduced by treatment with a borohydride/tetrahydrofuran complex followed by treatment with hydrochloric acid, and that the free base, if desired, is converted into a salt by reaction with a pharmaceutically suitable acid.