FI64573C - FRAMEWORK FOR THERAPEUTIC USE OF THERAPEUTIC EQUIPMENT (B) BICYCLONES - Google Patents

Description

μ'ν ^^ ΤΓΙ r_, ANNOUNCEMENT c Ar n-i

Ma [e] (1) UTLÄGGNINGSSKRIFT 64 57 3 (45) Patent c.:J: clat (51) Kv.ik. ^ nt.a.3 C 07 e 87A58, 103/365 FINLAND — FINLAND (21) Patent application - PatantanaBknlng 7 6ll89 (22) Hakemlsptlvi - Ansöknlnfadaj 28.04.76 ^^^ (23) Starting point — Glltlghaudag 28.04.76 (41) Has become public - BllvK offuntlig ^ 0.10.76

Patent * and registry holders .... _ ...

_ · (44) Date of dispatch and date of issue. -

Patent- och registerstyreiser v 'Aiuftkui utltgd och utUkriftun publlcured -jl .08.83 (32) (33) (31) Requested privilege —Begird prloritet 29.04.75

England-England (GB) 17846 (71) Akzo NV, IJssellaan 82, Amhem, Holland-Holland (NL) (72) Colin Leslie Hewett, Glasgow, Scotland, David Samuel Savage, Glasgow, Scotland, James Redpath, Bishopbriggs, Scotland, Thomas Sleigh, Wishaw, Scotland, Duncan Robertson Rae, Lanark, Scotland, United Kingdom-Stor-British (GB) (74) Oy Kolster Ab (54) Process for the preparation of therapeutically useful benzo (b) bicyclonone derivatives - Förfarande för framställning av therapeutically useful benzo (b) bicyclonic acid

The present invention relates to a process for the preparation of therapeutically useful benzo (b) bicyclo / 3.3.Inonene derivatives of the formula

Rr x. \ \ / v RA ... /

Xr2- '

Y

wherein and R 2 are hydrogen atoms, alkyl groups having 1 to 6 carbon atoms, alkenyl groups having 2 to 6 carbon atoms, alkanoyl groups having 1 to 4 carbon atoms or benzoyl groups, or R 1 and R 2 together with the nitrogen atom form a morpholino or pyrrolidino group, is hydroxy or an acyloxy group derived from an aliphatic 64573 carboxylic acid having 1 to 10 carbon atoms or a phenyl or phenyl C 1-4 aliphatic carboxylic acid in which the phenyl group may be substituted with a nitro group, X and Y are hydrogen atoms, hydroxy groups, halogen atoms, 1 to 6 carbon atoms alkyl groups, 1 to 6 carbon atoms or alkoxy groups, and pharmaceutically acceptable acid addition salts thereof.

FI patent publication 53 967 discloses benzobicyclononene derivatives which, however, differ in structure and biological activity from the compounds of the formula I.

The compounds of general formula I have a valuable biological effect, in particular an anorectic effect. In addition, the toxicity of the compounds is very low.

The process according to the invention is characterized in that a) the compound of formula II y \ M 'o vj-'

Y

wherein X, Y and are as defined above are reacted with formamide, N- (C 1-6 alkyl) formamide, N, N- (C 1-8 dialkyl) formamide or an amine of formula III R 1 '

HN 'III

/ V 'wherein R 1' and R 21 are the same as R 1 and R 2 except for the alkanoyl group, in the presence of a reducing agent, or b) a compound of formula IV "X-

X R,> \ V

\ - 3 \ - NOH IV

- 1 Γ r-

Y

wherein R 1, X and Y are as defined above, is reduced, after which 3 64573 1) the compound obtained according to process variant a) or b), wherein R 1 or R 2 is a formyl group, is optionally hydrolyzed or reduced, and / or 2) the compound in which R 1 is a hydroxy group and / or R 1 and R 2 are hydrogen atoms is optionally acylated, and / or 3) the compound thus obtained in which R 1 and R 2 are hydrogen atoms is optionally alkylated by a direct alkylation method or acylated first and then by reduction of the acyl moiety , and / or 4) optionally converting the compound thus obtained into a pharmaceutically acceptable salt, whereby the compound obtained can be decomposed into separate diastereomers and / or optical antipodes either before or after these further reactions.

The compounds of the formula II used in process variant a) can be prepared conventionally from optionally substituted (X and / or Y) β-tetralones. The tetralone in question, which is commercially available or can be prepared in a conventional manner from commercially available tetralones, is treated with pyrrolidine to give the corresponding 2- (pyrrolidino) enamine. The enamine is then converted with acrolein at low temperature to the corresponding 4-hydroxy-benzo (b) bicyclo [3.3.1] nonen-11-one. Alternatively, the tetralone in question can be reacted directly with acrolein at elevated temperature in the presence of a tertiary amine such as trimethylamine to give the corresponding 4-hydroxy-Benzo (b) bicyclo [3.3.1] nonen-11-one directly. The 4-hydroxy group of this compound can be etherified or esterified if desired. The condensation of 2-tetralalamine with acrolein can be performed at -60 to + 25 ° C in a solvent, preferably at -50 to -45 ° C, allowing the temperature to rise in a controlled manner to ambient temperature over about 3 hours upon addition of acrolein.

Alternatively, if desired, direct condensation of substituted (X and / or Y) -β-tetralone with acrolein, the reaction may be carried out at + 30 to + 120 ° C in a solvent, preferably at the boiling point of the solvent used in the presence of a tertiary alkylamine such as triethylamine or trimethylamine.

Starting from a compound of formula II, the amines or amides of formula I according to the invention can be prepared most conveniently and directly by reductive amination.

4,64573

In process variant a) the starting ketone II is reacted with formamide, N-alkylformamide or N, N-dialkylformamide or an amine of the general formula III above, in the presence of a suitable reducing agent. A suitable reducing agent for use in this reaction is formic acid or a formic acid derivative such as a formic acid salt or an amine of formula III. In the latter case, separate addition of amine III is not necessary. This reaction can be carried out at an elevated temperature, preferably 80 to 150 ° C, most preferably at the boiling point of the reaction mixture.

Other suitable reducing agents for use in this reaction include metal hydrides such as lithium aluminum hydride, sodium borohydride, sodium trimethoxyborohydride and diisobutylaluminum hydride; an alkali metal, preferably sodium, in an alcohol such as ethanol or isopropanol or hydrogen in the presence of a suitable catalyst such as Raney nickel, Pt, PtCl 2 or a Pd / C catalyst such as LiAlH 2. Some reducing agents may remove any ether or ester group at the 4-position to give a compound having a hydroxy group at the 4-azerase.

In process variant b), the imino group of the compound of general formula IV described above is reduced.

Compounds of formula IV may be prepared by reacting a ketone of formula II with a primary amine of formula III (R 1 = H) or hydroxylamine or hydroxylamine alkyl ether under time conditions by a conventional method used in the preparation of imines and oximes.

The reduction of imine IV of formula IV is carried out under mild reaction conditions. The reduction can be carried out, for example, by hydrogenation in the presence of a suitable catalyst such as Raney nickel, Pt or PtCl 2; in the presence of a metal hydride, especially a metal hydride of complexes derived from aluminum or boron, such as lithium aluminum hydride, in a suitable liquid medium, such as ether; with an alkali metal, for example sodium, in a suitable liquid such as ether, benzene or alcohol; or by means of sodium amalgam or zinc dust, for example in sodium hydroxide. The reaction may be accompanied by the simultaneous removal of the 4-ether or 4-ester to give the corresponding 4-alcohol.

The above primary reactions for the preparation of the compounds (I) of the invention may be followed by further reactions for the conversion of a compound of formula I into a salt or another compound of the invention.

The amines of the invention (R 1 and / or R 2 are hydrogen) can be alkylated in a conventional manner, for example by reaction with an alkyl halide or by acylation of the compound and then reduction of the carbonyl group.

The methyl group can be attached to the nitrogen atom by the well-known Eschweiler-Clarke method (reaction with formaldehyde + formic acid) or by reaction with formaldehyde or halogen formic acid ester and subsequent reduction with, for example, sodium cyanoborohydride.

The N-acyl derivative of the compounds of the invention can be obtained preferably by acylation with an acid anhydride or an acid halide of a compound I in which at least one of R 1 and R 2 is hydrogen.

When the 4-alcohol derivative I (where = OH) is acylated, esterification of the 4-hydroxy group occurs simultaneously.

If the N-formyl derivative is obtained directly from the above-mentioned primary reaction, the amine in question can be hydrolyzed using, for example, potassium or sodium hydroxide to obtain the primary amine I. Such hydrolysis can cause the 4-ester group to be hydrolyzed simultaneously to the 4-alcohol.

The O-acyl derivative of the compound of the invention (R 1 = acyloxy) can be prepared without reacting the primary or secondary amine group by treating amine I where R 1 = OH with an acylating agent such as an acid halide or acid anhydride in the presence of a strong acid such as trifluoroacetic acid or perchloric acid. /

The preparation of starting ketones II gives a mixture of two enan / thiomers consisting of two enantiomers of formula II in which the 4-alcohol or ester group is in the exo position and two enantiomers of formula II in which the 4-alcohol or ester group is in the endo position. The exo enantiomers can be separated from the endo enantiomers by crystallization or chromatography. Each of the racemic mixtures II thus obtained can be treated as such and then, if desired, after conversion to the racemic compound I, or they can be divided first, and then treated into an optically active end product.

Substitution of the oxo group at position 11 of the ketone with an amino group at position 11 or reduction of the imine IV results in the formation of a second center of asymmetry, with the amino group present at the syn or anti position relative to the benzene ring. The individual diastereomeric forms may be isolated from the mixture in a conventional manner, for example, by column chromatography, preparative thin layer chromatography and / or fractional crystallization.

Diastereomers, enantiomers and mixtures thereof of formula I and their preparation are also within the scope of this invention.

The novel compounds of formula I may be isolated from the reaction mixture as a pharmaceutically acceptable salt depending on the conditions under which the reaction is carried out. Pharmaceutically acceptable salts can also be obtained by treating the free base I with an organic or inorganic acid, examples of which are HCl, HBr, HJ, H 2 SO 4, H 2 PO 4, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, etc.

The term "alkyl" as used in connection with the general formula I in defining X, Y, and R 2 means a saturated, straight or branched hydrocarbon radical having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, isopropyl, iso-butyl, tert-butyl , n-pentyl, isopentyl or hexyl. The same applies to the alkyl group in the term "alkoxy" when defining X and Y.

The term "alkenyl" in the definition of the groups of general formula I and R 2 means an unsaturated, straight or branched hydrocarbon group having 2 to 6 carbon atoms, such as vinyl, allyl and 3-methylbut-2-enyl. ^

The term "halogen" means primarily chlorine and bromine.

The term "alkanoyl" in the definition of R 1 and R 2 means a group derived from an aliphatic carboxylic acid. Aliphatic carboxylic acids include acids having 1 to 10 carbon atoms, 7,64573 especially 1 to 8 carbon atoms, such as acetic acid, propionic acid, heptanoic acid, trimethylacetic acid, butyric acid, iso-butyric acid, valeric acid and hexanoic acid. The phenyl or phenyl aliphatic carboxylic acid may be a nitro-substituted carboxylic acid having 1 to 4 carbon atoms in the alkyl group, such as benzoic acid, o-, m- or p-toluic acid, phenylacetic acid, phenylpropionic acid, cinnamic acid, cinnamic acid, phenylacetic acid, phenyl -nitro-benzoic acid, etc.

The acyl group in the term "acyloxy" or "esterified hydroxy group" as used in the definitions of X, Y and R 1 has the same meaning.

The novel compounds of the invention and their pharmaceutically acceptable salts are valuable anorexic agents. Even long-term use of these compounds does not diminish their effect.

The compounds of the invention may be administered orally or parenterally at daily doses of 0.005 to 50 mg, preferably 0.01 to 10 mg, per kilogram of body weight.

For topical administration, the compounds may be formulated as an ointment.

Preferred compounds of the invention are those compounds of the formula I in which and 1 * 2 represent hydrogen or methyl and / or the benzo ring is substituted by one or two halogens and / or R 1 represents hydrogen, a lower aliphatic acyl group (1-8C) or a lower araliphatic acyl group, such as benzoyl.

The following is the preparation of 4-exo- and 4-endo-hydroxy- and 4-exo-and 4-endobenzyloxy-8-chloro-benzo (b) bicyclo [3.3.1] nonen-11-one from 6-chloro-2 tetralone. Other starting materials of formula II are prepared in a similar manner.

A. 6-Chloro-2-tetralone-pyrrolidine-enamine

A solution of 6-chloro-2-tetralone (260 g) in benzene (1.5 L) and pyrrolidine (208 mL) was heated to reflux under nitrogen for 2.5 hours using a Dean-Stark water separator. The reaction mixture was evaporated to dryness under reduced pressure with aeration of nitrogen at the end of the distillation. The residue was triturated with hexane to give 6-chloro-2-tetralone-pyrrolidine-enamine (276 g, 82%), m.p. 121-122 ° C.

8 64573 B. 8-Chloro-4-hydroxy-benzo (b) /3.3.l/none-11-one B.l. 6-Chloro-2-tetralone-pyrrolidine-enamine (390 g) was added portionwise over 10 minutes to a stirred solution of acrolein in methylene chloride (3.0 L) cooled to -50-55 ° C. The reaction mixture was stirred for 30 minutes at -50 to 55 ° C and then allowed to warm to + 5 ° C over 3 hours. Water (420 ml) was added, followed by 5N hydrochloric acid (400 ml), and the resulting biphasic mixture was stirred at room temperature for 2 hours. The mixture was allowed to stand overnight, the layers were separated and the aqueous phase was extracted with methylene chloride. The methylene dichloride extracts were washed with 1N hydrochloric acid, aqueous brine, dried and evaporated to dryness to give a mixture (about 60:40) containing 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy-benzo (b) bicyclo / 3.3.1 / nonen-11-one as an oil (371 g).

B.2. Acrolein (389 ml) was added under a stirred nitrogen atmosphere to a solution of 6-chloro-2-tetralone (738 g) in tetrahydrofuran (738 g) and triethylamine (738 ml), and the mixture was heated under reflux for 2.5 hours. The solvents were distilled off in vacuo and the triethylamine was finally removed by azeotropic distillation with toluene (2.75 L) portionwise (250 mL).

The crude ketol mixture (810 g) was dissolved in toluene, filtered through a pad of alumina and the eluate evaporated to give a mixture (ca. 60:40) containing 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy. benzo (b) bicyclo / X. 3.17-nonen-11-one (18.5 g), m.p. 120-122 ° C. '

Example 1 4-Exo-benzoyloxy-8-chloro-11-anti-formamido-benzo (b) bicyclo [3.3.1] none

A suspension containing 4-exo-benzoyloxy-8-chloro-benzo (b) -bicyclo [J. 3.1 N-non-11-one (33.5 g) in a mixture of formamide (134 ml) and formic acid (67 ml) was heated under reflux for 2.5 hours. After cooling, water was added and the solid was filtered off, washed with water and dried (32.5 g).

The product was crystallized from methylene dichloride / methanol to give 4-exo-benzoyl-8-chloro-11-anti-formamido-benzo (b) bicyclo [3.3.1] / as prisms (28.5 g) m.p. 224-226 ° C.

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Example 2 4-Endo-benzoyloxy-8-chloro-11-formamido-benzo (b) bicyclo [3.3.1] nonene

A stirred suspension of 4-endo-benzoyloxy-8-chloro-benzo (b) bicyclo [3.3.1] ion-11-one (18.5 g) in a mixture of formamide (74 ml) and formic acid (37 ml) heated to reflux for 2.5 hours. After cooling, water was added and the gum was dissolved in methylene chloride, washed neutral and chromatographed on silica gel to give 4-endo-benzoyloxy-8-chloro-11-anti-formamido-benzo (b) bicyclo [3.3.1] -none (7 g). ) prismoina, sp. 150-152 ° C, and 4-endo-benzoyloxy-8-chloro-11-syn-formamido-benzo (b) bicyclo (3.3.Γ) as an almost colorless gum (3.5 g).

Example 3 4-Acetoxy- or 4-benzoyloxy-11-formamido-substituted-benzo (b) bicyclo / 3.3.77ηοηβη Starting from the desired 4-acyloxy-benzo (b) bicyclo / 3.3.Enon-11-one compound, substituted or substituted on the benzo ring, the following 11-formamido compounds were prepared as described in Examples 1 and 2: 4-exo-acetoxy-8-methoxy-11-anti-formamido-benzo (b) bicyclo / 3.3.17 nonen, m.p. 172-173 ° C, 4-exo-benzoyloxy-8-bromo-11-anti-formamido-benzo (b) bicyclo / 3.3./none, m.p. 229-230 ° C, 4-exo-benzoyloxy-8,9-dichloro-11-anti-formamido-benzo (b) bicyclo / X. 3.JL / nonen, mp · 24 2-243 ° C, 4-endo-p-nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo (b) bicyclo [3.3. 142-149 ° C, 4-endo-p-nitrobenzoyloxy-9-chloro-11-syn-formamido-benzo (b) bicyclo / 3.3 .mu.l / nonen, m.p. 197-200 ° C, 4-exo-acetoxy-11-anti-formamido-benzo (b) bicyclo / 3.3.1 / nonen, m.p. 121-122 ° C, 4-exo-acetoxy-11-syn-formamido-benzo (b) bicyclo / 3.3.1 / nonen, m.p. 182-184 ° C.

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Example 4 4-Exo-hydroxy-8-chloro-11-anti-amino-benzo (b) bicyclo [3.3.1] none.HCl

A suspension of 4-exo-benzoyloxy-8-chloro-11-anti-formamido-benzo (b) bicyclo [3.3.1] ethanol (8 g) in ethanol (80 ml) and 10M potassium hydroxide solution (14 ml) was heated under reflux for 4 hours. , during which time dissolution occurred. After cooling, aqueous sodium chloride solution was added to precipitate the amine, which was filtered off, washed with water and dried to give 4-exo-hydroxy-8-chloro-11-anti-aminobenzo (b) bicyclo / 3.3.1 / one prism (5 g). The amine (4.3 g) was dissolved in ethanol / toluene and converted to the hydrochloride by the addition of a solution of hydrogen chloride gas in ether. Crystallization from isopropanol gave pure 4-exo-hydroxy-8-chloro-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene-j hydrochloride (4.1 g), m.p. 182-194 ° C (decomposes).

In a similar manner, the following was prepared: 4-exo-hydroxy-8-methoxy-11-anti-amino-benzo (b) bicyclo [3.3.1] none.HCl, 14-endo-hydroxy-8-chloro-11-anti- amino-benzo (b) bicyclo / 3.3.17nonen. HCl, m.p. 320-330 ° C; 4-endo-hydroxy-8-bromo-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene, in HCl, m.p. 255 ° C (dec.), I-4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene, HCl, m.p. 286-300 ° C, • 4-exo-hydroxy-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene, HCl, m.p. 265 ° C (sub.).

I Example 5 f 4-Hydroxy-8-chloro-11-methylamino-benzo (b) bicyclo [3.3.1] nonene.HCl j To a solution containing 4-exo-benzoyloxy-8-chloro-11-anti-formamido -benzo (b) bicyclo / 3.3 .mu.l (7.25 g) in dry tetrahydrofuran (100 ml) was added dropwise with stirring. a suspension of aluminum hydride (2.0 g) in dry tetrahydrofuran (40 ml), and the mixture was stirred under reflux for 5 k hours. After addition of water, the inorganic solids were filtered off. The filtrate was concentrated, toluene was added and the solution was evaporated in vacuo to give 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo (b) bicyclo [3.i.1] nonene (6.5 g) as a gum. as a substance which was dissolved in methylene chloride and converted into the hydrochloride by adding a saturated solution of hydrogen chloride gas in ether. Crystallization from methylene chloride / ethyl acetate gave pure 4-exo-hydroxy-8-chloro-11-anti-methylaminobenzo (b) bicyclo [3.3. 1N nonene hydrochloride as prism, (4.2 g), mp 1790 ° C (dec).

In a similar manner, 4-endo-hydroxy-8-chloro-11-anti-methylamino-benzo (b) bicyclo [3.3.1] nonene hydrochloride, m.p. 262-268 ° C, and 4-endo-hydroxy-8-chloro-11-syn-methylamino-benzo (b) isocyclo [3.3.1] nonene hydrochloride from the appropriate 4-endo-acetoxy- or benzoyloxy-11- formarnido compounds. Example 6 4-Hydroxy-11-methylamino-substituted-benzo (b) bicyclo / 3.3.1 / none Starting from the desired 4-acetoxy- or 4-benzoyloxy-11-formamido-benzo (b) bicyclo / 3.3.1 / unsubstituted or substituted on the phenyl ring by 9-chloro, 8-methoxy, 8-hydroxy, 8-methyl, 8,9-dichloro or 8-chloro-9-nitro, the following 11 -methylamino compounds as shown in Example 5: 4-exo-hydroxy-11-anti-methylamino-benzo (b) bicyclo / 3.3. Ion nonen, HCl salt m.p. 265-268 ° C, 4-exo-hydroxy-8-methyl-11-anti-methylamino-benzo (b) bicyclo / 3.3.1 / one, HCl salt m.p. 230 ° C (dec.).

4-exo-hydroxy-8,9-dichloro-11-anti-methylamino-benzo (b) bicyclo / 3.3.1 / one, HCl salt m.p. 272-278 ° C, 4-exo-hydroxy-9-chloro-11-anti-methylamino-benzo (b) bicyclo / 3.3.1 / one, HCl salt m.p. 245 ° C (subl.).

4-exo-hydroxy-8-chloro-9-nitro-II anti-methylamino-benzo (b) bicyclo / 3. 3.l7nonen, KCl salt m.p. 250-270 ° C (dec.), 4-exo-hydroxy-8-nitro-9-chloro-11-anti-methylamino-benzo (b) bicyclo [3. 3.1 / nonen, HCl, m.p. 252-258 ° C, (dec.).

Example 7 8-Bromo-4-exo-hydroxy-11-anti-methylamino-benzo (b) bicyclo [3. 3 ._i / nonen-HCl

A mixture of 4-exo-benzoyloxy-8-bromo-benzo (b) bicyclo [3.3.1] nonen-11-one (6 g) and N-methylformamide (18 ml) in formic acid (9 ml) was heated to reflux for 3 hours. hours.

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The reaction mixture was cooled to room temperature, diluted with water and treated with 2N sodium hydroxide solution to give a yellow gum which was extracted with methylene chloride. The methylene dichloride extracts were washed with water, dried and evaporated to a brown gum (5.97 g). The gum (5.97 g) was dissolved in ethanol (120 ml) and the solution was refluxed with 10N potassium hydroxide solution (12 ml) for 27 hours. The reaction mixture was cooled to room temperature, diluted with brine and extracted with methylene chloride. The methylene chloride extracts were washed with water, dried and evaporated in vacuo to give the crude amine as an orange gum (4.23 g) which was dissolved in methylene chloride and converted to the hydrochloride by the addition of a solution of hydrogen chloride gas in ether. Crystallization from methylene chloride and methanol / ether gave pure 4-exo-hydroxy-8-bromo-11-anti-methylamino-benzo (b) bicyclo / 3.3 .mu.l / nonene hydrochloride as a colorless crystal (1.30 g), m.p. . 264-270 ° C.

Example 8 4-Exo-acetoxy-8-chloro-11-anti-methylamino-benzo (b) bicyclo / T. 3.1 / nonen-HCl

A solution of perchloric acid (6 ml), acetic anhydride (10 ml) and glacial acetic acid (20 ml) in the mixture, allowed to stand for 1 hour. The solution was poured into ice water, made alkaline by the addition of solid potassium carbonate, and the product was extracted with methylene chloride, washed neutral, dried and evaporated to dryness to give 4-exo-acetoxy-8-chloro-11-anti-methylamino-benzo (b) bicyclo / 3.3.l / nonen (4.7 g) cumin. The product was dissolved in methylene chloride and filtered through acid-washed alumina. The eluate was concentrated and a saturated solution of hydrogen chloride gas in ether was added to precipitate the hydrochloride (3.65 g) which, on crystallization from methanol / ethyl acetate, gave 4-exo-acetoxy-8-chloro-11-anti-methylamine-benzo (b) bicyclo. /3.3.l/nonen-hydrochloride as prisms (3.1 g) m.p. 256 ° C.

In a similar manner the following compounds are prepared: 4-exo-acetoxy-8-chloro-11-anti-amino-benzo (b) bicyclo / 3.3.1 / nonene. HCl, m.p. 256 ° C, 4-endo-acetoxy-8-chloro-11-anti-amino-benzo (b) bicyclo / 3.3.1 / nonen-HCl, m.p. 259-263 ° C, 13 6 4 5 7 3 4-Exo-acetoxy-8,9-dichloro-11-anti-methylamino-benzo (b) bicyclo [3. 3.1 / nonen-HCl, m.p. 247-253 ° C, 4-exo-acetoxy-8-t, butyl-11-anti-methylamino-benzo (b) bicyclo [3. 3. 1. / no nen, HCl, m.p. 249 ° C (dec.).

Example 9 4-Exo-benzoyloxy-8-chloro-11-anti-amino-benzo (b) bicyclo [T.3.J] nonen-HCl

Benzoyl chloride (2.3 mL) was added dropwise to 4-exo-hydrophilic acid. roxy-8-chloro-11-anti-amino-benzo (b) bicyclo / 3. 3. L / none (4.8 g) in a solution of trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 7 hours and then poured onto ice. Solid sodium carbonate was added until the mixture was alkaline and; the product was extracted with ethyl acetate. The extract was washed with 2M NaOH solution and water to pH 7, then dried and evaporated to give a gum (5.0 g). Crystallization from ether gave 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene (3.2 g).

Treatment of the crystalline product in methylene chloride with a saturated solution of hydrogen chloride gas in ether gave 4-exo-benzoyloxy-8-chloro-11-anti-aminobenzo (b) bicyclo / 3.3.1 / nonen-HCl, m.p. 213-220 ° C.

Example 10 Treatment of 4-hydroxy-11-amino and 11-methylamino-compounds with a suitable acyl halide gives the following compounds using the procedure described in Example 9, 4-exo-benzoyloxy-8-chloro-11-anti-methylamino-benzo (b) bicyclo / 3 .3.l / nonen-HCl, m.p. 252-254 ° C, 4-exo- (2,2-dimethylpropionyloxy) -8-chloro-11-anti-amino-benzo (b) bicyclo / 3.3.17-one-HCl, m.p. 268-272 ° C.

Example 11 4-Exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonen-HCl

A solution of 4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo (b) bicyclo / 3.3.1 / one (16.6 g) formic acid (16.6 ml) and formalin (15 , 5 ml), refluxed for 2 hours, diluted with water and excess potassium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed neutral with water, dried and evaporated, and the residue was crystallized from ethyl ether to give 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo / 3.3.Γ / nonen. (16.2 g) m.p. 133.5-135 ° C. The product was dissolved in methylene dichloride and the solution was treated with a solution of hydrogen chloride gas in ether to give the hydrochloride, m.p. 248-273 ° C;

The same compound is obtained by refluxing 4-exo-benzoyloxy-8,9-dichloro-benzo (b) bicyclo [3.3.1] nonen-11-one and dimethylformamide in formic acid as described in Example 7.

Example 12 4-Hydroxy-11-dimethylamino-benzo (b) bicyclo / 3.3.1 / none Starting from the desired 4-hydroxy-11-amino-benzo (b) bicyclo / 3.3.1 / nonone, unsubstituted or substituted on the phenyl ring 8 , 9-dichloro, 8-methoxy, 8-hydroxy, 9-chloro, 8-chloro and 8,10-dichloro, respectively, the following 11-dimethylamino compounds are prepared as described above.

4-exo-hydroxy-11-anti-dimethylamino-benzo (b) bicyclo / 3.3.1 / nonen-HCl, m.p. 280 ° C (subl.), 4-exo-hydroxy-8-methoxy-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] non-HCl, m.p. 216 ° C (subl.), 4-endo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo / J. 3.1 / nonen-HCl, m.p. 265 ° C (dec.),? 4 (exo), 8-dihydroxy-11-anti-dimethylamino-benzo (b) bicyclo [3 ". 3.1 / nonen-HCl, m.p. 285 ° C (dec.) , 4-exo-hydroxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] none-HCl, mp 252-273 ° C (dec.), 4-exo-hydroxy-8.10 -dichloro-11-syn-dimethylamino-benzo (b) bicyclo [3.3.1] nonen-HCl, mp 255 ° C (subl.), 4-exo-9-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] non-HCl, mp 232 ° C (dec.), 4-exo-hydroxy-8-nitro-9-chloro-11-anti-dimethylamino-benzo (b) bicyclo /3.3.r/_nonen, HCl, mp 261-270 ° C.

Example 13 4-Exo-acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] -none-HCl

Acetylation of 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo / 3.3.1 / nonene (4.0 g) with acetic anhydride 15 64573 (8 ml) and pyridine {8 ml ) at room temperature gives 4-exo-acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo / 3. 3.1 .mu.l / nonen (4.4 g), m.p. 122.5 to 124 ° C. This is dissolved in methylene chloride and treated with a solution of hydrogen chloride in ether to give the hydrochloride, m.p. 234-279 ° C.

Example 14 4-Hydroxy-11-dimethylamino-benzo (b) bicyclo [J ". 3. Esters of 1 / noneene derivatives Starting from the desired 4-hydroxy-11-dimethylamino-benzo (b) bicyclo [3.3.1] nonene, unsubstituted or substituted on the phenyl ring by 8-methoxy, 8-chloro, 8-bromo and 8-methyl, respectively, the following compounds are prepared as described above: 4-Exo-acetoxy-11-anti-dimethylamino-benzo (b) bicyclo / T 3.1 / nonen-HCl, mp 260 ° C (subl.), 4-exo-benzoyloxy-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonen-HCl, mp 248-253 ° C (dec.), 4-exo- (2,2-dimethylpropionyloxy) -11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonen-HCl, mp 228 ° C (subl.) , 4-exo- (1-phenylpropionyloxy) -11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonene-HCl, mp 260-263 ° C, 4-exo-cinnamoyloxy-11-anti-dimethylamino -benzo (b) bicyclo [3.3.1] none-HCl, m.p. 265 ° C (dec.), 4-exo-decanoyloxy-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] none-HCl , mp 217-225 ° C, 4-endo-bentosyl ioxy-8-chloro-11-syn-dimethylamino-benzo (b) bicyclo [3. 3.1 / nonen-HCl, m.p. 252 ° C (dec.), 4-exo-acetoxy-8-bromo-11-anti-dimethylamino-benzo (b) bicyclo / 3.3.1 / one-HCl, m.p. 264-266 ° C, 4-exo- (2,2-dimethylpropionyloxy) -8-chloro-11-antidimethylamino-benzo (b) bicyclo [3.3.1] nonen-HCl, m.p. 178-183 ° C, 4-endo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3 ". 3,1 / nonen-HCl, m.p. 286-289 ° C, 4-exo -acetoxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] none-HCl, mp 294-296 ° C, 4-exo-benzoyloxy-8-chloro-11-anti-dimethylamino -benzo (b) bicyclo [3.3.1] nonene-HCl, mp 258-265 ° C, 4-exo-benzoyloxy-8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo / 3.3 .1 / nonen, HCl, mp 224-229 ° C, 16,64573 4-exo- (2,2-dimethylpropionyloxy) -8,9-dichloro-11-anti-dimethylamino-benzo (b) bicyclo / 3.3 .1 / nonen, HCl, mp 193-200 ° C (dec.), 4-exo-acetoxy-8-t, butyl-11-anti-dimethylamino-benzo (b) bicyclo [3.3.3] nonen , HCl, mp 221 ° C (dec.), 4-exo-benzoyloxy-8-t, butyl-11-arti-dimethylamino-benzo (b) bicyclo [3.1.3] nonene, HCl, mp 235 ° C (dec.), 4-exo-decanoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonene, HCl, mp 249-251 ° C.

Example 15 4-Exo-acetoxy-II-anti-acetamido-benzo (b) bicyclo / 3.3.177 nonene 4-Exo-hydroxy-11-anti-amino-benzo (b) bicyclo / 3.3.1 / nonene (20 g ) was suspended in acetic anhydride (40 ml), and the mixture was stirred at room temperature for 1 hour and then poured into water. The solid was collected and dried to give 4-exo-acetoxy-11-anti-acetamido-benzo (b) bicyclo / 3.3.1 / nonene (12.6 g) m.p. 213-214 ° C.

A stirred suspension of 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo (b) bicyclo [3.3.1] acetic anhydride gives 4-exo-benzoyloxy-8-chloro-acetic anhydride when treated as described above. II-anti-acetamido-benzo (b) bicyclo / T.3.1 / nonen, m.p. 224-227 ° C.

A mixed mixture of 4-exo-benzoyloxy-8-chloro-η-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene and benzoyl chloride in toluene gives 4-exo-benzoyloxy-8-chloro-11. -anti-benzoylamido-benzo (b) bicyclo [3.3.1] nonene, m.p. 220-222 ° C.

Example 16 4-Exo-hydroxy-11-anti-ethylamino-benzo (b) bicyclo / T.3.1 / nonen-HCl

To a suspension of lithium aluminum hydride (3.3 g) in dry tetrahydrofuran was added a hot suspension of 4-exo-acetoxy-11-anti-acetamido-benzo (b) bicyclo / 3.3.1 / none (12.5 g) in tetra- in a mixture of hydrofuran and dioxane (300 ml) and the mixture was refluxed for 2 hours. Excess lithium aluminum hydride was discarded by the addition of water, the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ether, treated with a saturated solution of hydrogen chloride in ether, and the solid formed was recrystallized from methane-ether to give 4-17,64573 exo-hydroxy-11-anti-ethylamino-benzo (b) bicyclo [3.3.1] nonen hydrochloride. (12 g) mp ~ / 265 ° C.

Example 17 4-Exo-hydroxy-11-anti-methyl-N- (3-methyl-but-2-enyl) -amino-benzo (b) bicyclo [3.3.1] nonene hydrochloride To a suspension containing 4-exo-hydroxy-II hydroxy-II anti-methyl-amino-benzo (b) bicyclo / 3.3. Γ / nonen (5.5 g) and potassium carbonate (5.0 g) in dimethylformamide (10 ml) and methylene chloride (1 ml) were added dropwise with stirring 1-bromo-3-methyl-but-2-ene (5.5 ml). ) in dimethylformamide (10 ml) keeping the mixture at room temperature. The reaction mixture was further stirred and then poured into water. The product was extracted with methylene dichloride. The extract was washed with water, dried and evaporated to an oil which was chromatographed on alumina. Elution with benzene gave an oily substance (5 g) which was dissolved in ether and treated with a saturated solution of hydrogen chloride in ether. The solid formed was recrystallized from methanol / ether to give 4-exo-hydroxy-11-anti-N-methyl-N- (3-methyl-but-2-enyl) -amino-benzo (b) bicyclo [3.3. -7none hydrochloride (3.2 g), m.p. 258-259 ° C;

Example 18

As described in Example 1, various benzo (b) bicyclo / 3 'were prepared. 3 .1 / Nonene derivatives by reacting 4-exo-benzoyl-8-chlorobenzo (b) bicyclo [b] 17,7-one-11-one with a preferred amine of formula III in the presence of formic acid or with an amine salt of formic acid dissolved or dissolved in a suitable inert solution. In this way were prepared: 4-exo-benzoyl-8-chloro-11-anti-morpholino-benzo (b) bicyclo / 3.3.1 / one, HCl salt m.p. 283-290 ° C, 4-exo-benzoyl-8-chloro-11-anti-pyrrolidino-benzo (b) bicyclo [3.3.1] nonene, HCl salt m.p. 260 ° C (dec.).

Example 19

The various 4-hydroxy-benzo (b) bicyclo [X.3.1] nonen-11-oxime derivatives were reduced with sodium in isopropanol to give the corresponding primary amines I. The oximes were obtained from 4- (endo- or exo) -benzoyloxy- reactions of benzo (b) bicyclo / 3.3.1 / nonen-11-one derivatives hydroxylamine. With HCl in sodium hydroxide and ethanol. The following compounds were prepared: 4-exo-hydroxy-8-methoxy-11-anti-amino-benzo (b) bicyclo / 3 '. 3.1 / 18 64573 nonen-HCl, m.p. 256-258 ° C, 4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo (b) bicyclo [3.3.1] nonene-HCl, m.p. 286-300 ° C, 4-exo-hydroxy-11-anti-amino-benzo (b) bicyclo [3.3.1] nonen-HCl, subl. 265 ° C.

Example 20

As described in Example 1, the following compounds were prepared by refluxing the corresponding starting ketone in a mixture of formic acid and formamide or dimethylformamide, respectively: 4-exo-p-nitrobenzosyloxy-9-chloro-11-anti-formamido-benzo (b) bicyclo / 3.3.17-one-HCl, m.p. . 269-272 ° C, 4-exo-p-nitrobenzoyloxy-8-nitro-9-chloro-anti-formamido-benzo (b) bicyclo [3.3.1] nonen-HCl, m.p. 276-279 ° C (decomposes), 4-exo-p-nitrobenzoyloxy-9-chloro-10-nitro-11-anti-formamido-benzo (b) bicyclo [3.3.1] nonen-HCl, m.p. 253-262 ° C (decomposes), 4-endo-p-nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamido-benzo (b) bicyclo / 3.3 .mu.l / nonen-HCl, m.p. 229-231 ° C, 4-exo-hydroxy-8-chloro-9-nitro-11-anti-formamido-benzo (b) /3.3.1 / one-HCl, m.p. 248 ° C, 4-exo-hydroxy-8-t-butyl-11-anti-dimethylamino-benzo (b) bicyclo [3. 3.Jänönen (oil), m.p. 230 ° C (dec.), 4-exo-decanoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3. 3. l / nonen-HCl, m.p. 249-251 ° C.

Example 21 (-) - 4-Exo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonene hydrochloride

A suspension of 64.0 g of the racemic compound was treated with a solution of 15.0 g of sodium bicarbonate in 800 ml of water. The mixture was extracted with methylene chloride, washed with water, dried and evaporated to dryness to leave 58.2 g of the free base which was crystallized from methanol. This gave 55.0 g of the free amine, m.p. 109-110 ° C.

A solution of 47.0 g of this racemic amine in 1000 ml of ethanol was treated with a solution of 23.5 g of abenzoyltartaric acid ([.alpha.] D @. = 110 DEG C.) in 100 ml of ethanol. The solution was cooled to give 26.6 g of crystals (the mother liquor was used for the next experiment), which was suspended in 250 ml of methylene chloride. This suspension was added to a solution of 11.0 g of sodium bicarbonate in 250 ml of water. The organic layer was separated, washed with water, dried and evaporated in vacuo to give 16.2 g of (-) - 4-exo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo / 3.3. , λ max = 2.63 °.

To a solution of 16.0 g of (-) - 4-exo-bentosyl-8-chloro-11-anti-dimethylamino-benzo (b) bicyclononene in 250 ml of ether was added 40 ml of a saturated solution of hydrogen chloride in ether. The precipitate was filtered off, washed with ether and crystallized from methanol to give 14.1 g of (-) - 4-exo-benzoyl-8-chloro-11-anti-dimethylamino-benzo (b) bicyclononene hydrochloride, m.p. 278-278.5 ° C (E) * = -7.2 °.

(+) - 4-Exo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo [3.3.1] nonene hydrochloride A suspension of 40.0 g of the mother liquor obtained in the previous experiment in 330 ml of methylene chloride. , was added to a solution of 7.5 g of sodium carbonate in 330 ml of water. The mixture was stirred until clear (about 15 minutes). The organic layer was separated, washed with water, dried and concentrated to dryness to give 32.2 g of the free base, which was dissolved in 900 ml of hot ethanol. To this solution was added a solution of 19.0 g of dibenzoyltartaric acid (+0-7D = + 115 °) in 100 ml of hot ethanol. The mixture was cooled to give 30.3 g of crystals which were suspended in 250 ml of methylene chloride and added to a solution of 11.0 g of sodium carbonate in 250 ml of water. The mixture was stirred for 15 minutes, the organic layer separated, washed with water, dried and evaporated in vacuo to give 16.5 g of (+) - 4-exo-benzoyloxy-8-chlorocri-11-anti-dimethylamino-benzo (b) bicyclo / 3.3 .1 / noneene as oil, i ° \ J + 2.84 °.

The hydrochloride salt was obtained by adding 40 ml of a solution of hydrochloric acid in ether to a solution of 18.2 g of (+) - 4-exo-benzoyloxy-8-chloro-11-antidimethylamino-benzo (b) bicyclo / 3.3.1 / noneene in 330 ml: in ether. The crystals were filtered off, washed with ether and recrystallized from methanol to give 10.9 g of (+) - 4-exo-benzoyloxy-8-chloro-11-anti-dimethylamino-benzo (b) bicyclo / T.3. J./nonen-hydrochloride, m.p. 277.5-27 8.5 ° C, M / d = + 6.7 °.

Claims (1)

A process for the preparation of therapeutically useful benzo (b) bicyclo [3.3.1] nonene derivatives of the formula x / f '\ R3' V- / *. I Λ · ·; r- \> ~ NL j .., / XR2 · '/' Y wherein R1 and I? 2 are hydrogen atoms, alkyl groups having 1 to 6 carbon atoms, alkenyl groups having 2 to 6 carbon atoms, 1-4 carbon-containing alkanoyl groups or benzoyl groups, or and R 2 together with the nitrogen atom form a morpholino or pyrrolidino group, R 1 is a hydroxy or acyloxy group derived from an aliphatic carboxylic acid having 1 to 10 carbon atoms or a phenyl or phenyl-C of an aliphatic carboxylic acid in which the phenyl group may be substituted by a nitro group, X and Y are hydrogen atoms, hydroxy groups, halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms or nitro groups, and pharmaceutically acceptable acid addition salts thereof, that a) the compound of formula II, wherein X, Y and denote a sauna as above, is reacted with formamide. With N- (C 1-6 alkyl) formamide, N, N- (C 1-8 alkylalkyl) formamide or an amine of formula III HNX) III / R 2 '21 64573 wherein R 1' and R 2 'are the same as R 1 and R 2 except for the alkanoyl group, in the presence of a reducing agent, or b) a compound of formula IV X * 3 - \ n - NOH IV 1 / Y wherein, X and Y are as defined above, is reduced, followed by 1. a compound obtained according to process variant a) or b), wherein R 1 or R 2? is a formyl group, optionally hydrolysed or reduced, and / or 2. a compound thus obtained in which R1 and R2 are hydrogen atoms, optionally acylated, and / or 3. a compound thus obtained in which R1 and R2 are hydrogen atoms , optionally alkylated by a direct alkylation method or by acylation first and then by reduction of the acyl moiety, and / or 4. the compound thus obtained is optionally converted into a pharmaceutically acceptable salt, whereby the compound obtained can be decomposed into separate diastereomers and / or optical antipodes either before or after these further reactions. . 64573 22 For the preparation of a therapeutic agent with benzene (b) bicyclo / 3.3 ._l / nonenders ined formeln X \ \ Rl ~ '\ r3 \) \ / I 1' 'r2 Y color R ^ och R2 är väteatomer, alkylgrupper med 1 -6 cholatomers, alkenyl groups with 2-6 cholatomers, alkanoyl groups or benzoyl groups with 1-4 cholaters, or R1 and R2 are equivalents with a quaternary morpholino- or pyrrolidino group, a hydroxy- or an acyloxy group, which is enriched carboxyls with 1-10 cholatomers or phenyl or phenyl-C 1-4 aliphatic carboxyls, color phenyl groups can be substituted with nitro groups, X and Y are a hydrogen atom, hydroxyl group, halogen atom, alkyl group with 1-6 cholatomers, alkoxy group with 1-6 color atom or nitrogen group, and a pharmaceutical form of a compound solution, having the same composition as in II):> - "" 0 / Y color X, Y and R ^ betyder region som ovan, omsätts med formamide, N- (C 1-8 alkyl) formamide, N, N- (C 1-8 alkyl) yes) formamide or amine with formula III R '/ HN 1 XV ·' '