CH628612A5 - Process for the preparation of novel benzo-(b)-bicyclo-(3,3,1)-nonenes - Google Patents

Description

The invention relates to a process for the preparation of new benzo- (b) -bicyclo- [3,3, l] -nenenes of the general formula I.

[I]

in which

R 1 and R 2 each represent a hydrogen atom, a lower alkyl or alkenyl group or an optionally substituted aryl-lower alkyl group or R! the formyl group and R 2 are hydrogen or a lower alkyl group, or R 1 and R 2 together with the nitrogen atom form a heterocyclic 5- or 6-membered ring,

R3 is a free, etherified or esterified hydroxy group,

and

X and Y each represent a hydrogen or halogen atom, a hydroxy group, alkyl (l-óC) -, alkoxy (l-óC) -, nitro, trifluoromethyl or acyloxy group, and their salts, which is characterized in that that a compound of formula II

in which X and Y have the meaning given above, with formamide, N-lower-alkyl-formamide, N, N-di-lower-alkyl-formamide or ammonia or an amine of the general formula III

R '

1

NH.

[III]

50

R '

[II]

in which R'i and R'2 have the meaning given for Rj and R2, with the exception of the formyl group, or a salt of this compound in the presence of a reducing agent and, if appropriate, converted into the corresponding salt with an acid.

The compounds of the general formula I have valuable full biological activities, especially anorectic (appetite-suppressing) activity. In addition, the toxicity of the compounds is very low.

The compounds of formula II can be prepared in a conventional manner, starting from an optionally substituted (X and / or Y) / 3-tetralone. The tetraion in question, which is commercially available or can be easily prepared in the usual manner from commercially available tetraions, is e.g. treated with pyrrolidine and gives the corresponding

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4th

2- (Pyrrolidino) enamine. The enamine can be converted to the corresponding 4-hydroxy-benzo- (b) -bicyclo- [3,3, l -] - nonen-11-one with acro-linine at low temperature. Alternatively, the tetraion in question can be reacted directly with acro-linene at elevated temperature in the presence of a tertiary amine, such as trimethylamine, to directly obtain the corresponding 4-hydroxy-benzo (b) bicyclo [3,3, l] nonene To result in -11-one. The 4 hydroxy group of this compound can then optionally be etherified or esterified. The condensation of 2-tetralonenamine with acrolein can preferably be carried out at temperatures from -60 ° C to +25 ° C in a variety of solvents. However, the best conditions are low temperatures of -50 to -45 ° C for the addition of acrolein, after which the temperature is allowed to rise to room temperature in a controlled manner within up to three hours.

The alternative direct condensation of the optionally substituted (X and / or Y) / 3-tetraion with acrolein can preferably be carried out at temperatures between +30 and +120 ° C in a variety of solvents, but preferably at the boiling point of the solvent used in the presence a tertiary alkylamine such as triethylamine or trimethylamine.

A very suitable reducing agent for the reaction according to the invention is formic acid or a formic acid derivative, such as a salt of formic acid, and the amine of the formula III. In the latter case, the separate addition of amine III is even superfluous. This reaction can be carried out at elevated temperature, preferably in the range of 80 to 150 ° C and most conveniently at the boiling point of the reaction mixture.

Other reducing agents suitable for this reaction are metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium trimethoxyborohydride and / or 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 , Pt02, Pd / C, etc. Some reducing agents can split off the ether or ester group, which is optionally present in the 4-position, at the same time, giving compounds with a hydroxy group in the 4-position, for example at LiAlH4.

After the reaction according to the invention for the preparation of the compounds I, further reactions can be carried out to convert a compound of the formula I into a salt or nitrogen oxide or to convert a compound of the formula I into another compound of the formula I.

It is thus possible to convert a substituent present on the phenyl nucleus into another substituent which falls under the definition of X and / or Y. For example, a methoxy group can be converted to a hydroxyl group, e.g. by treatment with molten pyridine hydrochloride in the absence of a solvent or by hydrolysis with HBr; a hydroxy group can be converted to an alkoxy group, a halogen atom or an acyloxy group in the usual manner.

The amines (Rj and / or R2 = hydrogen) according to the invention which are unsubstituted or monosubstituted on the nitrogen atom can be (ar) alkylated in a customary manner, e.g. by reacting the compound with an (ar) alkyl halide or by acylating the compound with subsequent reduction of the carbonyl group.

To introduce methyl groups on the nitrogen atom, the known method according to Eschweiler-Clarke (reaction with formaldehyde + formic acid) or the reaction with formaldehyde or halogen formate esters and subsequent reduction with e.g. Sodium cyanoborohydride are preferably used.

An N-acyl derivative can preferably be obtained by acylating a compound I in which at least one of the groups Rj and / or R2 is a hydrogen atom in a conventional manner using an anhydride or acid halide.

Such acylations of 4-alcohol derivatives I (R3 = OH) lead to the simultaneous esterification of the 4-hydroxy group.

If an N-formyl derivative is obtained directly, the amine in question can be hydrolyzed, e.g. using potassium or sodium hydroxide to obtain the primary amine I. Such hydrolysis can lead to simultaneous hydrolysis of the 4-ester group into a 4-alcohol group. For example, the reductive amination, in which the ketone II is reacted with formamide in the presence of formic acid (Leuckart-Wallach reaction), results in the first case in the N-formyl derivative I, which can be hydrolyzed to the primary amine I or to the corresponding one N-methyl compound I can be reduced.

An O-acyl derivative (R3 = acyloxy) in which the primary or secondary amine group remains unchanged can be prepared by treating the amine I in which R3 = OH with an acylating agent such as an acid halide or anhydride in the presence of a strong one Acid such as trifluoroacetic acid or perchloric acid.

All of these additional conversions are known standard procedures. Insofar as special reagents for these additional conversions have been mentioned, it goes without saying that these reagents can be replaced by other reagents known in organic chemistry which have a similar effect to those indicated.

The preparation of the ketone II used as the starting compound for the synthesis according to the invention of a compound of the formula I results in a mixture consisting of two enantiomers of the formula II in which the 4-alcohol or ester group is in the exo position and two enantiomers of the 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 further used as such and then optionally broken down optically after conversion into the racemic compound I or it can first be split up and then converted into an optically active end product of the formula I.

The replacement of the oxo group in the 11-position of ketone II by an amino group introduces a further center of asymmetry and leads to a mixture of two diastereomers I in which the amino group is in the syn or anti position, based on the benzene ring. These individual diastereomeric forms can be isolated from the mixture in a conventional manner, e.g. by column chromatography, preparative thin layer chromatography and / or fractional crystallization.

The preparation of the diastereomers and enantiomers of the compounds of formula I and their mixtures also fall under the invention.

The new compounds of formula I can be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt, depending on the conditions under which the reaction is carried out. The pharmaceutically suitable salts can also be obtained by treating the free base I with an organic or inorganic acid such as HCl, HBr, HJ, H2S04, H3P04, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid etc.

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The expression “alkyl group” as used to define X, Y, R! and R2 is applied to formula I means a saturated, branched or unbranched hydrocarbon chain with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclopropyl-methyl, isopropyl, , Isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl or hexyl group. The same applies to the alkyl groups in the term "alkoxy group" as used to define X and Y.

The term "alkenyl group" as used to define R [and R2 in Formula I means an unsaturated branched or unbranched hydrocarbon group having 2 to 6 carbon atoms, such as vinyl, allyl and 3-methylbut-2- enyl group.

“Halogen atom” is preferably a chlorine or bromine atom.

An “aralkyl group”, as given for the definition of R, and R2, is to be understood as an alkyl group with 1 to 6 carbon atoms which is substituted by at least one aromatic group; preferably a phenylalkyl group in which the alkyl group has 1 to 4 carbon atoms and the phenyl group can be substituted by 1 or more halogen atoms, lower alkyl groups or lower alkoxy groups (1 to 4C), such as a benzyl, phenylethyl, phenylpropyl , Phenylbutyl, 1-methyl-1-phenyl-ethyl, o-, m- or p-anisyl-, o-, m- or p-chlorobenzyl-, veratryl-, o-, m- or p-methyl- phenethyl or o-, m- or p-hydroxy-phenethyl group.

An “acyl group” as given for the definition of R 1 and R 2 means a group which is derived from an aliphatic, aliphatic or aromatic carboxylic acid. The aliphatic carboxylic acids include acids with 1 to 18 carbon atoms including those with a carbocyclic ring and especially those with 1 to 8 carbon atoms such as acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, hexanoic acid, heptanoic acid, trimethyl acetic acid, cyclopentanoic or cyclohexane carboxylic acid . The araliphatic or aromatic carboxylic acids include unsubstituted and substituted araliphatic or aromatic carboxylic acids with 1 to 18 carbon atoms, especially the optionally substituted phenylcarboxylic acids and optionally substituted phenylalkylcarboxylic acids in which the alkyl group contains 1 to 4 carbon atoms and can be saturated or unsaturated such as benzoic acid, o- , m- or p-toluic acid, o- or p-chlorobenzoic acid, p-methoxy-benzoic acid, phenylacetic acid, phenylpropionic acid, cinnamic acid, phenylbutyric acid, p-methylphenylacetic acid, p-nitrobenzoic acid, etc.

The acyl group in the terms "acyloxy group" and "esterified hydroxy group" in the definitions of X, Y and R3 has a similar meaning.

The etherified hydroxy group mentioned for the definition of R3 is an aliphatic (1 to 6C) ether group, a cy-cloaliphatic (5 to IOC) ether group, an aromatic ether group, preferably a phenyl ether, an araliphatic ether group, preferably a phenylalkyl ether, or a terocyclic ether group like a tetrahydropyranyl ether. The phenyl group in the phenyl or phenylalkyl ethers can be substituted by Ci to C4 alkyl groups, Ci to C4 alkoxy groups, halogen atoms and / or nitro groups.

The heterocyclic 5- or 6-membered rings, as mentioned in the definition of Rj and R2 (together with the nitrogen atom), are derived from 5- or 6-membered cyclic amines of the formula III such as pyrrole, pyrrolidine, pyrroline , Piperidine, piperazine, imidazole or morpholine.

The nitrogen oxides of the compounds according to the invention are prepared by oxidizing a compound of the formula I with H202 or a peracid.

20th

The compounds obtained according to the invention and their pharmaceutically suitable salts have, as mentioned, valuable appetite-inhibiting properties. Long-term oral administration of compounds of the formula I 5 did not lead to habituation to the anorectic effect. The compounds of formula I, especially the 11-syn isomers I, also show moderate anti-inflammatory activity. In addition, the entire pharmacological profile of the new compounds shows an antide-io pressive activity.

The compounds obtained according to the invention can be administered orally, parenterally or locally (the latter essentially for anti-inflammatory purposes) in a daily dose of 0.005 to 50 mg, preferably 0.01 to 10 mg / kg of body weight.

In a mixture with suitable auxiliaries, the compounds of the formula I can be pressed into solid dosage units, such as pills, tablets and dragées, or filled into capsules.

With the aid of suitable liquids, the compounds of the formula I can also be prepared as injection preparations in the form of solutions, suspensions or emulsions.

25 For topical or topical administration, the compounds can also be incorporated into a cream or ointment.

Preferred compounds are those of the formula I in which Rj and R2 each represent a hydrogen atom or a methyl group and / or the benzene nucleus is substituted by one or two halogen atoms and / or R3 is a hydrogen atom, a lower aliphatic acyl group (1 to 8C ) or a lower aliphatic acyl group, such as a benzoyl group.

Starting compounds The preparation of 4-exo and 4-endo-hydroxy- as well as 4-exo and 4-endo-benzyloxy-8-chloro-benzo (b) -bicyclo [3,3, l] -nonen-ll-one is used described, starting from 6-chloro-2-tetralone. Another 40 starting compounds of formula II are prepared in a similar manner.

A. 6-Chloro-2-tetralone-pyrrolidine amine A solution of 6-chloro-2-tetralone (260 g) in benzene (1.5 L) and pyrrolidine (208 ml) was made under nitrogen for 2.5 hours using a Dean - and heavy water separator heated to reflux to separate the water. The reaction mixture was evaporated to dryness under reduced pressure, vented with nitrogen gas at the end of the distillation. The residue was triturated with hexane. 6-Chloro-2-tetralone-pyrrole

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din-enamine (276 g; 82%) mp 121-122 ° C.

B. 8-chloro-4-hydroxy-benzo (b) bicyclo [3,3, l] nonen-l 1-one B 1. 6-chloro-2-tetralone-pyrrolidine amine (390 g) was in individual portions within 10 minutes with stirring to 55 a solution of acrolein (214 ml) in methylene dichloride (3.0 l), which was cooled to -50 to -55 ° C, added. The reaction mixture was stirred at -50 to -55 ° C for 30 minutes and the temperature was then raised to +5 ° C over 3 hours. Water (420 ml) was added and then 4N hydrochloric acid (400 ml) and the resulting 2-phase mixture were stirred at room temperature for 2 hours and left to stand overnight. The layers were separated and the aqueous layer extracted with methylene dichloride. The methylene dichloride extracts were washed with 1N hydrochloric acid and aqueous brine, dried and evaporated to dryness. A mixture (about 60:40) of 8-chloro-4-exo and 8-chloro-4-endo-hydroxy-benzo (b) bicyclo [3,3, l] nonen-11-one was obtained as an oil ( 371).

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

The crude ketol mixture (810 g) was dissolved in toluene, filtered through aluminum oxide and the eluate evaporated. A mixture (about 60:40) of 8-chloro-4-exo and 8-chloro-4-endo-hydroxy-benzo (b) bicyclo [3,3, l] nonen-l 1-one was obtained as an oil (792 g).

C. 4-exo and 4-endo-benzoyloxy-8-chloro-benzo (b) bicyclo-

[3,3,1] -nonen-11 -one A solution of 8-chloro-4-exo and 8-chloro-4-endo-hydroxy-benzo (b) bicyclo [3,3, l] nonen III-one (52 g) in pyridine (104 ml) was cooled to 2 ° C. with stirring and benzoyl chloride (30.5 ml) was added dropwise, the temperature being kept below 10 ° C. Stirring was continued at 5 to 10 ° C for 3.5 hours, then water was added to the cooled mixture with stirring to precipitate the product, which was dissolved in methylene dichloride, with 2N hydrochloric acid and water to pH 7 washed, dried and evaporated. A mixture of 4-exo and 4-endo-benzoyl-oxy-8-chloro-benzo (b) bicyclo [3,3, l] nonen-ll-one (62 g) was obtained (about 60:40).

A solution of the product in methylene dichloride was filtered through an aluminum oxide column, concentrated and the residue was recrystallized from methylene dichloride cyclohexane. Pure 4-exo-benzoyloxy-8-chloro-benzo (b) bicyclo [3,3, l] nonen-ll-one (26 g), mp. 184 to 186 ° C., was obtained. The mother liquor was chromatographed on aluminum oxide, a further amount (7.5 g) of pure 4-exo-benzoyloxy-8-chloro-benzo (b) bicyclo [3,3, l] nonen-ll-one and pure 4- endo-benzoyloxy-8-chloro-benzo (b) bicyclo [3,3, l] no-

nen-ll-one (18.5 g), mp 120 to 122 ° C.

example 1

4-exo-benzoyloxy-8-chloro-ll-anti-formamido-benzo

(b) bicyclo [3,3,1] nonen A suspension of 4-exo-benzoyloxy-8-chloro-benzo (b) bicyclo [3,3, l] nonen-ll-one (33.5) in a mixture of Formamide (134 ml) and formic acid (67 ml) were heated to boiling for 2.5 hours. After the mixture was cooled, water was added and the solid was filtered off, washed with water and dried (32.5 g). The product was recrystallized from methylene dichloride / methanol. You got

4-exo-benzoyloxy-8-chloro-ll-anti-formamido-benzo (b) bicyclo-clo-

[3,3, l] nonen as prisms (28.5 g), mp. 224 to 226 ° C.

Example 2

4-endo-benzoyloxy-8-chloro-ll-formamido-benzo (b) -

bicyclo [3,3, l] nonen A suspension of 4-endo-benzoyloxy-8-chloro-benzo (b) -bicyclo [3,3, l] no-nen-11-one

(18.5 g) in a mixture of formamide (74 ml) and formic acid (37 ml) was heated under reflux with stirring for 2.5 hours. After the mixture had cooled, water was added and the gummy substance was dissolved in methylene dichloride, washed to neutrality and chromatographed on silica gel. 4-Endo-benzoyloxy-8-chloro-11 -anti-formamido-ben-zo (b) bicyclo [3,3, l] nonen was obtained

(7 g) as prisms, mp. 150 to 152 ° C and 4-endo-benzoyloxy-8-chloro-1 l-synformamido-benzo (b) bicy-clo [3,3, l] nonen as an almost colorless gum ( 3.5 g).

5

Example 3

4-Acetoxy- or 4-Benzoyloxy-ll-formamido-substituted benzo (b) -bicyclo [3,3, l] nonen Starting from the desired 4-acyloxybenzo (b) bicy-io clo [3,3, l] nonen -ll-one compound which was not substituted or substituted on the benzene ring, the following compounds were prepared as described in Examples 1 and 2:

4-exo-acetoxy-8-methoxy-l-anti-formamido-benzo (b) bicyclo-i5 [3,3, l] nonen,

Mp 172-173 ° C;

4-exo-benzoyloxy-8-bromo-ll-anti-formamido-benzo (b) bicy-

clo [3,3, l] nonen,

Mp 229 to 230 ° C; 20 4-endo-benzoyloxy-8-bromo-II-anti-formamido-benzo (b) bi-cyclo [3,3, l] nonen, (oil); 4-exo-benzoyloxy-8,9-dichloro-ll-anti-formamido-benzo (b)

bicyclo [3,3, l] nonen,

Mp 242 to 243 ° C;

25 4-endo-p. Nitrobenzoyloxy-9-chloro-l 1-anti-formamido-benzo- (b) bicyclo [3,3, l] nonen,

Mp 142-149 ° C;

4-endo-p.Nitrobenzoyloxy-9-chloro-11-syn-formamido-benzo- (b) bicyclo [3,3, l] nonen,

30 mp 197-200 ° C; 4-exo-acetoxy-ll-anti-formamido-benzo (b) bicyclo [3,3,1]

nuns,

Mp 121-122 ° C;

4-exo-acetoxy-1 l-syn-formamido-benzo (b) bicyclo [3,3,1] 35 nonen,

Mp 182-184 ° C;

4-exo-acetoxy-8-chloro-9-CF3-ll-anti-formamido-benzo (b) -bicyclo [3,3, l] nonen.

40 Example 4

4-exo-hydroxy-8-chloro-1 l-anti-amino-benzo (b) -bicyclo [3,3,1] nonen-HCl A suspension of 4-exo-benzoyloxy-8-chloro-ll-anti- formamido-benzo (b) bicy-45 clo [3,3, l] nonen

(8 g) in ethanol (80 ml) and 10 M potassium hydroxide solution (14 ml) was refluxed for 4 hours to give a solution. After cooling, aqueous saline was added to precipitate the amine, which was filtered off, washed with so water and dried. 4-Exo-hydroxy-8-chloro-11-anti-amino-benzo (b) bicyclo [3, -3, l] nonen were obtained as prisms (5 g). The amine (4.3 g) was dissolved in ethanol / toluene and converted to the hydrochloride by adding a solution of hydrogen chloride 55 gas in ether. Recrystallization from isopropanol gave pure 4-exo-hydroxy-8-chloro-11-anti-amino-benzo (b) bicyclo [3, -

3, 1] nonene hydrochloride (4.1 g) mp 183-194 ° C (dec.).

60 The following were produced in the same way:

4-exo-hydroxy-8-methoxy-ll-anti-amino-benzo (b) bicyclo-

[3,3,1] nonene HCl; 4-exo-hydroxy-8-bromo-11-anti-amino-benzo (b) bicyclo-] 3, -3, 1] nonen-HCl;

65 4-endo-hydroxy-8-bromo-1 l-anti-amino-benzo (b) bicyclo [3, -3, l] nonen-HCl;

4-exo-hydroxy-8,9-dichloro-11-anti-amino-benzo (b) bicyclo [3,3, l] nonen-HCl;

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4-endo-hydroxy-8,9-dichloro-1 l-anti-amino-benzo (b) bicyclo-

[3,3, l] nonen-HCl; 4-endo-hydroxy-8,9-dichloro-ll-syn-amino-benzo (b) bicyclo-

[3,3, l) nonene HCl;

4-exo-hydroxy-11-anti-amino-benzo (b) bicyclo [3,3,1] nonene-HCl;

4-exo-hydroxy-8-methyl-1 l-anti-amino-benzo (b) bicyclo-

[3,3, l] nonen-HCl;

4-exo-hydroxy-8-chloro-9-CF3-1 l-anti-amino-benzo (b) bi-

cycloj 3.3, 1] nonen-HCl; 4-exo-hydroxy-8-nitro-ll-anti-amino-benzo (b) bicyclo [3, 3, l] nonen-HCl.

Example 5

4-Hydroxy-8-chloro-ll-methylamino-benzo (b) -bicyclo [3,3, l] nonen-HCl A solution of 4-exo-benzoyloxy-8-chloro-ll-anti-formamido-benzo (b )bi-

Cyclo [3,3,1] nonen (7.25 g) in dry tetrahydrofuran (110 ml) was added dropwise with stirring to a suspension of lithium aluminum hydride (2.0 g) in dry tetrahydrofuran (40 ml) and the mixture was added for 5 hours Reflux heated. After adding water, the inorganic solids were filtered off. The filtrate was concentrated, toluene was added and the solution was evaporated in vacuo. This gave 4-exo-hydroxy-8-chlorine-II-anti-methylamino-benzo (b) bicyclic

clo [3,3, l] nonen (6.5 h) as gum, which was dissolved in methylene dichloride and converted into the hydrochloride by adding a saturated solution of hydrogen chloride gas in ether. Recrystallization from methylene dichloride / ether acetate gave pure

4-exo-hydroxy-8-chloro-l l-anti-methylaminobenzo (b) bicy-

clo [3,3, ionone hydrochloride as prisms (4.2 g) mp> 190 ° C (dec.).

In the same way, 4-endo-hydroxy-8-chloro-ll-anti-methylamino-benzo (b) bi-

cyclo [3,3, l] nonene hydrochloride,

Mp 262-268 ° C and

4-endo-hydroxy-8-chloro-11-syn-methyl-amino-benzo (b) bi-

cyclo [3,3, l] nonene hydrochloride prepared starting from the corresponding 4-endo-aceto-xy or benzoyloxy-11-formamidö compounds.

Example 6

4-Hydroxy-1 l-methylamino-substituted-benzo (b) -bicyclo [3,3,1] nonen Starting from the desired 4-acetoxy- or 4-benzoyloxy-1 l-formamido-benzo (b) bicyclo [3,3, l] nonen, which was not substituted on the phenyl ring or was substituted by 9-chloro, 8-methoxy, 8-hydroxy, 8-methyl, 8,9-dichloro or 8-chloro-9-nitro the following 11-methylamino compounds prepared in the manner described in Example 4. 4-exo-hydroxy-ll-anti-methylamino-benzo (b) bicyclo [3,3, ionons;

4-endo-hydroxy-11-anti-methylamino-benzo (b) bicyclo [3, 3, 1] nonen;

4-exo-hydroxy-8-methoxy-1 l-anti-methylamino-benzo (b) bi-

cyclo [3,3, l] nonen;

4-endo-hydroxy-8-methoxy-11 -anti-methylamino-benzo (b) bi-

cyclo [3,3, l] nonen;

4-endo-hydroxy-8-methoxy-1 l-syn-methylamino-benzo (b) bi-

cyclo [3,3, l] nonen;

4 (endo), 8-dihydroxy-l l-anti-methylamino-benzo (b) bicyclo- [3,3, l] nonen;

4-cxo-hydroxy-8-methyl-11-anti-methylamino-benzo (b) bi-cyclof3,3, 1 ions;

4-exo-hydroxy-8,9-dichloro-1 l-anti-methylamino-benzo (b) -

bicyclo [3,3,1] nonen;

4-exo-hydroxy-9-chloro-1 l-anti-methylamino-benzo (b) bicy-

clo [3.3, 1 ions; 4-exo-hydroxy-8-chloro-9-nitro-11-anti-methylamino-benzo (b) bicyclo [3,3,1] nonen.

Example 7

8-bromo-4-exo-hydroxy-11-anti-methylamino-benzo (b) bicyclo [3,3, l] nonen-HCl A mixture of 4-exo-benzoyloxy-8-bromo-benzo (b) bicyclo [3,3, l] no-nen-11-one

(6 g) and N-methylformamide (18 ml) in formic acid (9 ml) was heated under reflux for three hours. The reaction mixture was cooled to room temperature, diluted with water and treated with 2N sodium hydroxide solution to obtain a yellow rubbery substance which was extracted with methylene dichloride. The methylene dichloride extracts were washed with water, dried and evaporated to a brown, gummy substance (5.97 g). The gum (5.97 g) was dissolved in ethanol (120 ml) and 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 dichloride. The methylene dichloride 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 dichloride and converted to the hydrochloride by the addition of a solution of hydrogen chloride gas in ether. Recrystallization from methylene chloride and methanol ether gave pure 4-exo-hydroxy-8-bromo-II-anti-methylaminobenzo (b) bicyclo-

[3,3,1-ion hydrochloride as colorless crystals (1.30 g) mp 264 to 270 ° C.

Example 8

4-exo-acetoxy-8-chloro-ll-anti-methylamino-benzo (b) -

bicyclo [3,3,1] nonen-HCl A solution of 4-exo-hydroxy-8-chloro-ll-anti-methylamino-benzo (b) bi-

Cyclo [3,3,1] nonen (4 g) in a mixture of perchloric acid (6 ml), acetic anhydride (10 ml) and glacial acetic acid (20 ml) was left to stand for one hour. The solution was poured into ice water, solid potassium carbonate added until the solution was alkaline, and the product extracted into methylene dichloride, washed to neutrality, dried and evaporated to dryness. You got

4-exo-acetoxy-8-chloro-ll-anti-methylamino-benzo (b) bicy-

clo [3,3, l] nonen (4.7 g) as gum. The product was dissolved in methylene dichloride and filtered through alumina washed with acid. The eluate was concentrated and a saturated solution of hydrogen chloride gas in ether was added to precipitate the hydrochloride (3.65 g). Recrystallization from methanol-ethyl acetate gave

4-exo-acetoxy-8-chloro-ll-anti-methylamino-benzo (b) bicy-

clo [3,3, ionone hydrochloride as prisms (3.1 g) mp 256 ° C.

Similarly, the following compounds were made;

4-exo-acetoxy-8-chloro-11 -anti-amino-benzo (b) bicyclo-

[3.3, 1] nonene-HCl, mp- 256 ° C;

4-endo-acetoxy-8-chloro-1 l-anti-amino-benzo (b) bicyclo-

[3.3, 1] nonen-HCl, mp 259-263 ° C; 4-exo-acetoxy-8,9-dichloro-11-anti-methylamino-benzo (b) -bicyclo [3,3, l] nonen-HCl, mp. 247 to 253 ° C

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Example 9

4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo- (b) bicyclo [3,3, l] nonen-HCl benzoyl chloride (2.3 ml) was added to a solution of 4-exo-hydroxy- 8-chloro-1 l-anti-amino-benzo (b) bicyclo- [3,3, l] nonen

(4.8 g) in trifluoroacetic acid (20 ml) was added dropwise 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 extracted into ethyl acetate. The extract was washed with 2M NaOH and water to pH 7, then dried and evaporated to give a gum (5 g). Recrystallization from ether gave 4-exo-benzoyloxy-8-chloro-ll-anti-amino-benzo (b) bicyclo-

[3.3, 1] nonen (3.2 g).

Treatment of the crystalline product in methylene dichloride with a saturated solution of hydrogen chloride gas in ether gave

4-exo-benzoyloxy-8-chloro-ll-anti-amino-benzo (b) bicyclo

[3,3, l] nonen-HCl,

Mp 213-220 ° C.

Example 10

By treating the 4-hydroxy-1-amino and 11-methylamino compounds with the corresponding acyl halides, the following compounds were prepared similarly to Example 9:

4-exo-benzoyloxy-8-chloro-1 l-anti-methylamino-benzo (b) bi-

cyclo [3,3,1] nonene-HCl; 4-exo- (2,2-dimethylpropionyloxy) -8-chloro-ll-anti-amino-

benzo (b) bicyclo [3,3,1] nonene HCl; 4-endo-benzoyloxy-8-methoxy-11-syn-methylamino-ben-zo (b) bicyclo [3,3, l] nonen-HCl;

4-exo-benzoyloxy-8-bromo-II-anti-amino-benzo (b) bicyclo- [3,3, l] nonen-HCl.

Example 11

4-exo-hydroxy-8,9-dichloro-ll-anti-dimethylamino-benzo (b) bicyclo [3,3,1] nonene-HCl A solution of 4-exo-hydroxy-8,9-dichloro ll-anti-amino-benzo (b) bicyclo- [3,3, l] nonen

(16.6 g) in a mixture of formic acid (16.6 ml) and formalin (15.5 ml) was heated under reflux for two hours, diluted with water and an excess of potassium bicarbonate solution added and extracted with methylene dichloride. The extract was washed neutral with water, dried and evaporated and the residue was recrystallized from ether. You got

4-exo-hydroxy-8,9-dichloro-ll-anti-dimethylamino-benzo (b)

bicyclo [3.3, 1] nonen (16.2 g), mp 133-135 ° C. The product was dissolved in methylene chloride and treated with a solution of hydrogen chloride in ether to give the hydrochloride, mp 248-273 ° C.

The same compound was obtained by heating a mixture of

4-exo-benzoyloxy-8,9-dichloro-benzo (b) bicyclo [3,3, l] nonen-11-one with dimethylformamide in formic acid under reflux in a similar manner to that described in Example 7.

Example 12

4-Hydroxy-11-dimethylamino-benzo (b) bicyclo- [3,3, l] nonen Starting from the desired 4-hydroxy-11-amino-benzo (b) bicyc! O [3,3,1 jnonen,

which was unsubstituted on the phenyl ring or substituted by 8,9-dichloro, 8-methoxy, 8-hydroxy, 9-chlorine, 8-chlorine or 8,10-dichloro, the following 11-dimethylamino compounds were substituted for those described above Prepared in this way: 4-exo-hydroxy-11 -anti-dimethylamino-benzo (b) bicyclo-

[3,3, l] nonen-HCl;

4-exo-hydroxy-8-methoxy-1 l-anti-dimethylamino-benzo (b) -

bicyclo [3,3,1] nonene-HCl;

4-endo-hydroxy-8,9-dichloro-11 -anti-dimethylamino-benzo-

(b) bicyclo [3,3,1] nonene HCl; 4-endo-hydroxy-8,9-dichloro-11-syn-dimethylamino-benzo

(b) bicyclo [3,3,1] nonene HCl;

4 (exo), 8-dihydroxy-1 l-anti-dimethylamino-benzo (b) bi-

cyclo- [3,3, l] nonen-HCl,

4-exo-hydroxy-8-chloro-1 l-anti-dimethylamino-benzo (b) -

bicyclo [3,3, ionene HCl; 4-endo-hydroxy-8-chloro-ll-anti-dimethylamino-benzo (b) -

bicyclo [3,3,1] nonene HCl;

4-endo-hydroxy-8-chloro-1 l-syn-dimethylamino-benzo (b) -

bicyclo [3,3,1] nonene-HCl; 4-exo-hydroxy-9-chloro-ll-anti-dimethylamino-benzo (b) -

bicyclo [3,3,1] nonene-HCl;

4-exo-hydroxy-8,10-dichloro-1 1-syn-dimethylamino-benzo- (b) bicyclo [3,3, 1] nonene-HCl.

Example 13

4-exo-acetoxy-8,9-dichloro-ll-anti-dimethylamino-benzo (b) bicyclo [3,3, l] nonen-HCl acetylation of 4-exo-hydroxy-8,9-dichloro-ll-anti -dimethylamino-benzo-

(b) bicyclo [3,3,1] nonen (4.0 g) with acetic anhydride (8 ml) and pyridine (8 ml) at room temperature

4-exo-acetoxy-8,9-dichloro-ll-anti-dimethylamino-benzo

(b) bicyclo [3.3, 1] nonen (4.4 g, mp 122.5 to 124 ° C.

This substance was dissolved in methylene chloride and treated with a solution of hydrogen chloride in ether, the hydrochloride being formed, mp. 234 to 279 ° C.,

The following compounds were acylated in a similar manner.

4-endo-acetoxy-8,9-dichloro-ll-anti-dimethylamino-benzo

(b) bicyclo [3,3,1] nonene-HCl; 4-exo-phenylacetoxy-8,9-dichloro-ll-anti-dimethylamino-

benzo (b) bicyclo [3,3,1] nonene-HCl; 4-exo-benzoyloxy-8,9-dichloro-l 1-anti-dimethylamino-ben-

zo (b) bicyclo [3,3,1] nonene-HCl; 4-exo-heptanoyloxy-8,9-dichloro-ll-anti-dimethylamino-

benzo (b) bicyclof 3,3,1] nonene-HCl; 4-exo- (2,2-dimethylpropionyloxy) -8,9-dichloro-ll-anti-dimethylamino-benzo (b) bicyclo [3,3, l] nonen-HCl.

Example 14

Esters of 4-hydroxy-1-dimethylamino-benzo (b) -bicyclo [3,3, 1] nonene derivatives Starting from the desired 4-hydroxy-1-dimethylamino-benzo (b) bicyclo [3,3, l] nonen, which was not substituted on the phenyl ring or was substituted by 8-methoxy, 8-bromo, 8-chloro or 8-methyl, the following esters of 4-hydroxy-11-dimethylamino compounds were prepared in the manner described above :

4-exo-acetoxy-ll-anti-dimethylamino-benzo (b) bicyclo-

[3,3, l] nonen-HCl;

4-exo-benzoyloxy-l l-anti-dimethylamino-benzo (b) bicyclo-

[3,3, l] nonen-HCl; 4-exo- (2,2-dimethylpropionyloxy) -11-anti-dimethylamino-benzo (b) bicyclo [3,3,1] nonene-HCl;

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4-exo- (l-phenylpropionyloxy) -l 1-anti-dimethylamino-ben-

zo (b) bicyclo [3,3,1] nonene HCl;

4-exo-cinnamoyloxy-11 -anti-dimethylamino-benzo (b) bicy-

clo [3,3,1] nonen-HCl;

4-exo-decanoyloxy-11 -anti-dimethylamino-benzo (b) bicy-

clo [3,3, l] nonen-HCl;

4-exo-acetoxy-8-bromo-1 l-anti-dimethylamino-benzo (b) bi-

cyclo [3,3,1] nonene-HCl;

4-endo benzoyloxy-8-chloro-l 1-syn-dimethylamino-benzo

(b) bicyclo [3,3,1] nonene HCl; 4-exo- (2,2-dimethylpropionyloxy) -8-chloro-ll-anti-dime-

thylamino-benzo (b) bicyclo [3,3,1] nonen-HCl; 4-endo-benzoyloxy-8-chloro-1 1-anti-dimethylamino-benzo

(b) bicyclo [3,3,1 | nonen-HCl;

4-exo-acetoxy-8-chloro-11 -anti-dimethylamino-benzo (b) bi-

cyclo- [3,3, l] nonene-HCl 4-exo-benzoyloxy-8-chloro-ll-anti-dimethylamino-benzo- (b) bicyclo [3,3, l] nonene-HCl.

Example 15

4-exo-acetoxy-ll-anti-acetamido-benzo (b) -bicyclo [3,3,1 jnones 4-exo-hydroxy-ll-anti-amino-benzo (b) bicyclo [3, 3, l] nonen

(20 g) was suspended in acetic anhydride (40 ml) and the mixture was stirred at room temperature for one hour and then poured into water. The solid was collected and dried. You got

4-exo-acetoxy-ll-anti-acetamido-benzo (b) bicyclo [3,3,1] nonen

(12.6 g), mp 213-214 ° C.

In the same way were made with phenylpropionyl chloride:

4-exo-phenylpropionyloxy-ll-anti-phenylpropionylamido

benzo (b) bicyclo [3,3, l] nonen, 4-exo-propionyloxy-ll-anti-propionylamido-benzo (b) bicyclo [3,3, l] nonen.

A suspension of 4-exo-benzoyloxy-8-chloro-l 1 -anti-amino-benzo (b) bicyclo- [3,3, l] nonen in acetic anhydride gave 4-exo-benzoyloxy- with stirring in the manner described above. 8-chlorine-ll-anti-acetami-do-benzo (b) bicyclo [3,3, l] nonen.

A mixture of 4-exo-benzoyloxy-8-chloro-1 l-anti-amino-benzo (b) bicyclo-

[3,3, l] nonen and benzoyl chloride in toluene with stirring gave 4-exo-benzoyloxy-8-chloro-ll-anti-benzoyl-amido-benzo (b) -bicyclo [3,3, l] nonen.

Example 16

4-exo-hydroxy-1 l-anti-ethylamino-benzo (b) -bicyclo [3,3, l] nonen-HCl A hot suspension of. Was added to a suspension of LiAlH4 (3.3 g) in dry tetrahydrofuran 4-exo-acetoxy-11 -anti-acetamido-benzo (b) bicyclo- [3,3,1 ions

(12.5 g) in a mixture of tetrahydrofuran and dioxane (300 ml) was added and the mixture was heated under reflux for two hours. The excess lithium aluminum hydride was destroyed by adding 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 resulting solid was recrystallized from methane ether. 4-exo-hydroxy-1 l-anti-ethylamino-benzo (b) bicyclo-

[3,3,1 ion hydrochloride (12 g), mp> 265 ° C.

The following were prepared in the same way: 4-exo-hydroxy-11-anti-phenylpropylamino-benzo (b) bicyclo-

[3,3, l] nonen-HCl;

4-exo-hydroxy-11-anti-propylamino-benzo (b) bicyclo- [3,3, l] nonen;

4-exo-hydroxy-8-chloro-11 -anti-ethylamino-benzo (b) bicy-

clo [3,3,1 jnonen; 4-exo-hydroxy-8-chloro-ll-anti-cyclopropylmethylamino-

benzo (b) bicyclo [3,3, l] nonen; 4-exo-hydroxy-8-chloro-ll-anti-p-hydroxyphenethylamino-benzo (b) bicyclo [3,3, l] nonen.

Example 17

4-exo-hydroxy-11 -anti-N-methyl-N- (3-methyl-but-2-enyl) amino-benzo (b) bicyclo [3,3,1 jonen hydrochloride To a suspension of 4- exo-hydroxy-ll-anti-methylamino-benzo (b) bicyclo- [3,3, l] nonen

(5.5 g) and potassium bicarbonate (5.0 g) in dimethylformamide (10 ml) and methylene chloride (1 ml) were stirred with a solution of l-bromo-3-methyl-but-2-ene (5.5 ml ) in dimethylformamide (10 ml) while keeping the mixture at room temperature. The reaction mixture was stirred for a further 15 minutes and then poured into water and the product extracted with methylene dichloride. The extract was washed with water, dried and evaporated to give an oil which was chromatographed on alumina. Elution with benzene gave an oil (5 g) which was dissolved in ether and treated with a saturated solution of hydrogen chloride in ether. The resulting solid was recrystallized from methanol ether. 4-exo-Hydroxy-ll-anti-N-methyl-N- (3-methyl-but-2-enyl) -amino-benzo (b) bicyclo [3,3, l] nonene hydrochloride ( 3.1 g), mp 258 to 259 ° C.

Example 18

In an analogous manner to that described in Example 1, various benzo (b) bicyclo [3,3,1] nonene derivatives were prepared by reacting

4-exo-benzoyloxy-8-chloro-benzo (b) bicyclo [3,3, l] no-nen-ll-one with the desired amine of formula III in the presence of formic acid or the amine salt of formic acid in a suitable inert solvent solved or not solved. This is how:

4-exo-benzoyl-8-chloro-11 -anti-morpholino-benzo (b) bicy-

clo [3,3, l] nonen; 4-exo-benzoyl-8-chloro-ll-anti-piperidino-benzo (b) bi-cyclo [3,3, l] nonen.

Example 19

In the manner described in Example 1, the following compounds were prepared by refluxing the corresponding starting ketones in a mixture of formic acid and formamide or dimethylformamide. 4-exo-p. Nitrobenzoyloxy-9-chloro-11-anti-formamido-benzo

(b) bicyclo [3,3, l] nonene-HCl,

Mp 269 to 272 ° C;

4-exo-p. Nitrobenzoyloxy-8-nitro-9-chloro-l 1-anti-formami-

do-benzo (b) bicyclo [3,3, l] nonen-HCl,

Mp 276-279 ° C (dec.);

4-exo-p. Nitrobenzoyloxy-9-chloro-10-nitro-ll-anti-forma-

mido-benzo (b) bicyclo [3,3, l] nonen-HCl,

Mp 253-262 ° C (dec.);

4-endo-p. Nitrobenzoyloxy-8-nitro-9-chloro-11-anti-forma-

mido-benzo (b) bicyclo [3,3,1 ionic HCl,

Mp 229-231 ° C;

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4-endo-hydroxy-8-chloro-9-nitro-11 -anti-formamido-benzo-

(b) bicyclo [3,3, l] nonene HCl,

Mp 248 ° C;

4-exo-methoxy-8-chloro-11 -anti-dimethylamino-benzo (b) -bicyclo [3,3, l] nonen (01);

4-exo-hydroxy-8-t.butyl-l l-anti-dimethylamino-benzo (b) -

bicyclo [3,3,1] nonen (01);

4-exo-decanoyloxy-8-chloro-l 1-anti-dimethylamino-benzo- (b) bicyclo [3,3, l] nonen-HCl.

Claims (10)

628 612 2nd PATENT CLAIMS 1. Process for the preparation of new benzo (b) bicyclo [3,3,1] nonenes of the general formula I [I] in which R, and R2 each represent a hydrogen atom, a lower alkyl or alkenyl group or an optionally substituted aryl-lower alkyl group or Ri represents the formyl group and R2 represents hydrogen or a lower alkyl group, or Ri and R2 together with the nitrogen atom represent a heterocyclic 5- or 6-link ring, R3 is a free, etherified or esterified hydroxy group, 20 and X and Y each represent a hydrogen or halogen atom, a hydroxy group, alkyl (1-6C), alkoxy (1-6C), nitro, trifluoromethyl or acyloxy group, and their salts, characterized in that to connect the For-25 mei II [II] in which X and Y have the meaning given above, with formamide, N-lower alkyl-formamide, N, N-di-lower-alkylformamide or ammonia or an amine of the general formula III • R * ^ 1 N NH ' t [III] R ' in which R '] and R'2 have the meaning given for Rj and R2, with the exception of the formyl group, or a salt of this compound in the presence of a reducing agent and, if appropriate, converted into the corresponding salt with an acid. 2. The method according to claim 1, characterized in that a compound of the formula I obtained, in which Ra and / or R2 is a hydrogen atom, is alkylated or aralkylated and optionally converted into a salt. 3. The method according to claim 1 or 2, for the preparation of compounds of the formula (Shark) 3rd 628 612 in which Rj, R2 and R3 have the meaning given above and Hai is a chlorine or bromine atom and n is 1 or 2. 4. The method according to claim 1, characterized in that a compound of the formula I obtained, in which X and / or Y is a methoxy group, is hydrolyzed to the corresponding compound, in which X and / or Y is a hydroxyl group and optionally in a Converts salt. 5. The method according to any one of the preceding claims, characterized in that the compound obtained is separated into the individual diastereo isomers and / or enantiomers. 6. A process for the preparation of a compound of the formula I in which Rj and R2 are hydrogen atoms, characterized in that a compound of the formula I in which Rj is a formyl group and R2 is a hydrogen atom is prepared by the process according to claim 1 and this hydrolyzed and optionally converted into a salt. 7. A process for the preparation of a compound of the formula I in which Rt is the methyl group and R2 is hydrogen or a lower alkyl group, characterized in that a compound of the formula I is prepared by the process according to claim 1 in which R is a formyl group and R2 is hydrogen or a lower alkyl group, and this is reduced and optionally converted into a salt. 8. A process for the preparation of a compound of formula I in which R3 is an esterified hydroxy group 5 characterized in that a compound of the formula I is prepared by the process according to claim 1, in which R3 is a hydroxyl group, and then this group is acylated. 9. A process for the preparation of a compound of the formula io I in which one of the groups Rj and R2 is an acyl group, characterized in that a compound of the formula I is prepared by the process according to claim 1, in which one or both of the groups Rt and R2 is a hydrogen atom, and this is acylated and optionally converted into a salt. 10. A process for the preparation of nitrogen oxides of the compound of the formula I, characterized in that a compound of the formula I is prepared by the process according to claim 1 and this is mixed with H202 or a 20 acid converts.