JPS6154776B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides biologically active general formulas [] [In the formula, R ₁ and R ₂ are hydrogen, alkyl having 1 to 4 carbon atoms, acetyl, formyl, or 3-methyl-2-butenyl, and R ₃ is hydroxy, alkyl having 1 to 4 carbon atoms.
is alkanoyloxy, benzoyloxy or nitrobenzoyloxy, and X and Y are hydrogen,
halogen, methyl, methoxy or nitro group] A novel benzo(b)bicyclo[3.3.
1] Concerning nonene and salts suitable for its preparations.

The compounds of the general formula (hereinafter referred to as compounds of the present invention) have effective biological effects, particularly appetite suppressing (decreasing) effects. Furthermore, the toxicity of the compounds of the present invention is extremely low.

The compounds of the present invention can be prepared by conventional methods described in the literature for preparing homologous compounds.

Very suitable starting materials for the synthesis of the compounds of the invention are compounds of the general formula [ ].

[In the formula, X, Y and R ₃ have the same meanings as above]
or Y) can be produced from β-tetralone by a conventional method. That is, the corresponding 2-
(pyrrolidino)enamine, which is then reacted with acrolein at low temperature to produce the corresponding 4-hydroxy-benzo(b)bicyclo[3.
3.1] Nonen-11-one is obtained. Alternatively, the tetralone can be directly reacted with acrolein in the presence of a tertiary amine such as trimethylamine at high temperature to produce the corresponding 4-hydroxy-benzo(b)bicyclo[3.3.1]nonen-11-one. It's okay. The 4-hydroxy group of this compound may then optionally be etherified or esterified.

The condensation reaction between 2-tetralone enamine and acrolein can occur in various solvents at suitable temperatures of -60 to +25°C, but preferably at low temperatures of -50 to -45°C during the addition of acrolein. The temperature may be increased gradually over a period of 3 hours to reach ambient temperature. Also, substituted or unsubstituted (X
and/or Y) direct condensation reaction between β-tetralone and acrolein in various solvents from +30 to +120
It may be carried out at a suitable temperature of °C, but preferably
The reaction is carried out in the presence of a tertiary alkylamine such as triethylamine or trimethylamine below the boiling point of the solvent used.

The most preferred and direct method is to use a compound of the formula as a starting material and subject it to reductive amination to produce the compound of the present invention.

According to this method, the ketone of the formula is converted into formamide, N-alkylformamide or N.N-dialkylformamide, or the general formula [] It is reacted with an amine represented by the formula [wherein R ₁ ' and R ₂ ' have the same meanings as R ₁ and R ₂ but exclude the acyl group].
The preferred reducing agent for this reaction is formic acid or a formic acid derivative such as a salt of formic acid with an amine of formula. In the latter case, there is no need to add the amine of formula separately. The reaction is carried out at a high temperature, preferably between 80 and 150 °C.
℃, most preferably at the boiling point of the reaction mixture.

Other suitable reducing agents in the above reaction are metal hydrides and alkali metals, preferably sodium, such as lithium aluminum hydride, sodium borohydride, sodium trimethoxyborohydride and diisobutyl aluminum hydride;・
It is used in an alcohol such as ethanol or isopropanol or in hydrogen in the presence of a suitable catalyst such as nickel, Pt, PtO ₂ , Pd/C, etc.
Using certain reducing agents such as LiAlH ₄
A compound having a hydroxyl group at the 4-position can be produced while removing an ether group or an ester group that may be present at the 4-position.

Furthermore, the compound of the present invention has the general formula [] [In the formula, X, Y and R ₃ are as defined above, and R ₄ is hydrogen, hydroxy, alkoxy, alkyl (1-
4C) or a substituted or unsubstituted aralkyl group] by reducing the imino moiety of the compound.

The compound of the formula is prepared by reacting the primary amine or hydroxylamine or hydroxylamine-alkyl ether of the formula (R ₁ ′=H) with the ketone of the formula under alkaline conditions using a conventional method for producing imines or oximes. It can be manufactured by

Reduction of the imine of formula occurs under mild reaction conditions using standard methods for reducing imino moieties. For example, the reduction can be carried out using metal hydrides, especially aluminum or boron, such as lithium aluminum hydride, dissolved or suspended in a suitable liquid such as ether, in the presence of a suitable catalyst such as Raney-nickel, _Pt or PtO2. Complex metal hydrides derived from or alkali metals in suitable liquids such as ethers, benzene or alcohols may be carried out by hydrogenation methods using sodium amalgams or zinc dust, preferably sodium or, for example, sodium hydroxide. Depending on the type of reducing agent used, this reaction cleaves the 4-ether or 4-ester group to form the corresponding 4
-Alcohol may be formed.

As the third method for producing the compound of the present invention, the formula [] A method using a hydroxyl compound of the formula [wherein X and Y are as defined above and R ₅ is an etherified or esterified hydroxy group] as a starting material may be mentioned.

Compounds of formula V are produced by reduction of ketones of the corresponding formula under mild conditions such that the R ₅ groups present are not removed. Sodium borohydride is suitable as the reducing agent.

A hydroxyl compound of formula can be converted to the corresponding amine in a variety of ways. For example, the hydroxyl group can be replaced with a suitable alkyl- or arylsulfonyloxy group (relay group) such as a mesyloxy group,
After conversion to a tosyloxy group, p-bromophenylsulfonyloxy group, p-chlorophenylsulfonyloxy group, p-nitrophenylsulfonyloxy group, etc., it may be reacted with an amine of the formula. Also, instead of converting the hydroxyl group to an alkyl- or arylsulfonyloxy group as described above,
The hydroxyl group may be halogenated, for example with _PCl5 , _PBr3 , _SOCl2, etc., and then converted to the compound of the desired formula by reaction with an amine of the formula.

Methods for converting hydroxyl groups to amino groups are known and described in various literature.

The aforementioned main reaction for preparing a compound of the invention of formula may be followed by an addition reaction to convert the compound of formula into its salt, or a compound of the invention may be converted to another compound of the invention. Good too.

One substituent present in the phenyl nucleus is replaced by
Alternatively, it is also possible to change to another substituent defined for Y. For example, treatment with molten pyridine.HCl or hydrolysis with HBr in the absence of a solvent,
Methoxy groups can be converted to hydroxyl groups. Hydroxyl groups may be converted to alkoxy groups or halogens using conventional methods.

The amine compounds of the present invention in which the nitrogen atom is unsubstituted or monosubstituted (R ₁ and/or R ₂ are hydrogen) may be alkylated by known methods. For example, the compound may be reacted with an alkyl halide, or the compound may be acylated and then the carbonyl group may be reduced.

Preferred methods for introducing a methyl group into a nitrogen atom include the known Eyler-Clarke method (reaction with formaldehyde + formic acid) and a method in which the reaction with formaldehyde or a haloformic acid ester is followed by reduction with, for example, sodium cyanoborohydride. can be mentioned.

A preferred method for producing the N-acyl derivative of the compound of the present invention is to acylate a compound of the formula in which at least either group R ₁ or R ₂ is hydrogen by a known method using an acid anhydride or an acid halide. can be mentioned.

A 4-alcohol derivative of a compound of formula (wherein
When R ₃ =OH) is acylated as described above, the 4-hydroxy group will also be esterified.

If the N-formyl derivative is produced directly by any of the reactions described above, the amide may be hydrolyzed, for example with potassium or sodium hydroxide, to produce the primary amine of formula. When hydrolyzed as described above, the 4-ester group is also hydrolyzed to produce 4-alcohol. for example,
The first step of reductive amination in which the ketone of the formula is reacted with formamide in the presence of formic acid (Leukart-Waratzha reaction) produces the N-formyl derivative of the formula, which is hydrolyzed to form the primary amine of the formula. N of the corresponding formula to be prepared or reduced
- Methyl compounds may be produced.

As a method for producing O-acyl derivatives (R ₃ = acyloxy) of the compounds of the present invention in which the primary or secondary amine groups are not involved in the reaction, an amine of the formula in which R ₃ =OH is reacted with trifluoroacetic acid or perchloric acid. Examples include a method of treatment with an acylating agent such as an acid halide or an acid anhydride in the presence of a strong acid such as an acid.

Any of these additional transformations may be carried out following the main reaction described above according to standard methods known to those skilled in the art. Although specific reagents are illustrated in the above additional transformations, it is of course possible to use other reagents known to have similar effects to the illustrated specific reagents.

The ketone of the formula used as a starting material when synthesizing the compound of the formula in the present invention is 4-
It is produced as a mixture of two enantiomers of the formula in which the alcohol or ester group is in the exo position and two enantiomers of the formula in which the 4-alcohol or ester group is in the endo position, but the exo-
Enantiomers and endo-enantiomers may be separated by crystallization or chromatography.
Each racemic mixture of the formula obtained as described above may be treated as it is to convert it into a racemic compound of the formula and then optionally resolved, or it may be subjected to a post-resolution treatment to produce the optically active target product of the formula. good.

Substitution of the oxo group at position 11 of the ketone of formula with an amino group or reduction of the imine of formula induces another asymmetric center to produce a mixture of two diastereomers of formula. The amino group of this diastereomer is present in the syn- or anti-position relative to the benzene ring. Each diastereomer may be isolated from the mixture by known methods such as column chromatography, preparative thin layer chromatography and/or fractional crystallization.

Diastereomers, enantiomers and mixtures thereof of the formula are also included within the scope of the invention.

Depending on the reaction conditions, novel compounds of formula may be isolated from the reaction mixture in the form of salts suitable for formulation. The free base of the formula can be combined with an organic or inorganic acid, e.g.
HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ , acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid,
Salts suitable for drug use may be prepared by treatment with succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid, etc.

“Alkyl” in the definition of R ₁ and R ₂ in the general formula
The term refers to branched or straight chain saturated hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, cyclopropyl, cyclopropylmethyl, isopropyl, isobutyl, and t-
means butyl.

"Halogen" preferably means chlorine or bromine.

The novel compounds of the invention and their salts suitable for formulation have an effective appetite-suppressing effect. Oral administration of the compound over a long period of time does not result in tolerance to the appetite suppressing effect. Furthermore, compounds of the formula, particularly the 11-syn isomer of the formula, also have mild anti-inflammatory effects. Furthermore, the overall pharmacological action of the compounds of the present invention exhibits antidepressant effects.

The compounds of the invention may be administered orally, parenterally and topically (where topical administration is intended to be anti-inflammatory in nature). The daily dose per kg body weight is 0.005-50 mg, preferably 0.01-10 mg.

A compound of the formula can be mixed with suitable excipients and compressed to form solid unit dosage forms such as pills, tablets and coated tablets, or formed into capsules.

The compounds of the formula may be administered as injectable solutions, suspensions, or emulsions using suitable liquids.

For topical application, the compound of the formula is formulated into a cream or ointment.

Preferred compounds of the invention are those in which R ₁ and R ₂ are hydrogen or methyl and/or the benzene nucleus is 1
The compound is substituted with 1 or 2 halogens and/or has a formula in which R ₃ represents hydroxy, lower (1-4C) alkanoyloxy, or benzoyloxy.

Starting Materials 6-chloro-2-tetralone to 4-exo- and 4-endo-hydroxy and 4-exo- and 4-endo-benzyloxy-8-chloro-benzo(b) bicyclo[3.3.1]nonene- The method for producing 11-one is as follows. Other starting materials of the formula can be prepared in a similar manner.

A 6-chloro-2-tetralonepyrrolidine enamine A solution of 6-chloro-2-tetralone (260g) in benzene (1.5l) and pyrrolidine (208ml) were refluxed for 2.5 hours under nitrogen, and subjected to Dean and Stark water separation. A vessel was used to collect the produced water. The reaction mixture was evaporated to dryness under reduced pressure, and nitrogen was bubbled through at the end of the distillation. The residue was triturated with hexane to give a 6-
Chloro-2-tetralone pyrrolidine enamine (276 g; 82%) was obtained.

B 8-Chloro-4-hydroxy-benzo(b)bicyclo[3.3.1]nonen-11-one (1) Acrolein (214ml) in methylene dichloride (3.0l) cooled (-50 to -55℃) stirred To the solution was added 6-chloro-2-tetralone pyrrolidine enamine (390 g) in portions over 10 minutes. The reaction mixture was incubated at −50 to −55 °C for 30
Stirred for a minute and then increased the temperature to +5°C over 3 hours. Water (420ml), 5N hydrochloric acid (400ml)
were added sequentially, and the resulting two-layer mixture was stirred at room temperature for 2 hours and left overnight. Separate the layers;
The aqueous layer was extracted with methylene dichloride. The methylene dichloride extract was washed with 1N hydrochloric acid, brine, dried and evaporated to dryness to give 8-chloro-4-exo- and 8-chloro-4-endo-
Hydroxy-benzo(b)bicyclo [3.3.
1] Oily mixture with nonen-11-one (approx.
60:40) (371 g) was obtained.

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

The crude ketol mixture (810 g) was dissolved in toluene, filtered through alumina, and the eluate was evaporated to give 8-chloro-4-exo- and 8-chloro-4-endo-hydroxy-benzo(b)bicyclo[ 3.3.1] An oily mixture of nonen-11-one (approximately 60:40) (792 g) was obtained.

C 4-exo- and 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.
3.1] Nonen-11-one 8-chloro-4-exo- and 8-chloro-
A stirred solution of 4-endo-hydroxy-benzo(b)bicyclo[3.3.1]nonen-11-one (52 g) in pyridine (104 ml) was cooled to 2°C, maintaining the temperature below 10°C. While stirring, benzoyl chloride (30.5 ml) was added dropwise. Temperature 5°~10
Stirring was continued for 3.5 hours at °C. Water was added to the cooled stirring mixture to precipitate the product. The product was dissolved in methylene dichloride, washed with 2N hydrochloric acid, water to pH 7, dried and evaporated to give 4-exo- and 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3・
3.1] Mixture of nonen-11-one (approximately 60:
40) (62g) was obtained.

A solution of the product in methylene dichloride was filtered through an alumina column, concentrated, and the residue was crystallized from methylene dichloride-cyclohexane to determine the melting point.
Purified 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo [3.3.1] at 184-186℃
Nonen-11-one (26 g) was obtained. The mother liquor was further subjected to alumina chromatography to obtain purified 4-exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonen-11-one (7.5 g).
and purified 4-endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.
3.1] nonen-11-one (18.5 g) was obtained.

Example 1 4-exo-benzoyloxy-8-chloro-
11-Anti-formamide-benzo(b)bicyclo[3.3.1]nonene 4-Exo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonene in a mixture of formamide (134 ml) and formic acid (67 ml) 3.3.1] Nonen-
A suspension of 11-one (33.5 g) was boiled under reflux for 2.5 hours. After cooling the mixture, water was added and the solid was separated, washed with water and dried (32.5g). The product was crystallized from methylene dichloride/methanol to form columnar crystals of 4-exo-benzoyloxy-8-chloro-
11-Anti-formamide-benzo(b)bicyclo[3.3.1]nonene (28.5 g) was obtained.

Example 2 4-endo-benzoyloxy-8-chloro-
11-Formamide-benzo(b)bicyclo[3.
3.1] Nonene 4-Endo-benzoyloxy-8-chloro-benzo(b)bicyclo[3.3.1]nonene-11 in a mixture of formamide (74 ml) and formic acid (37 ml)
A stirred suspension of -one (18.5 g) was heated under reflux for 2.5 hours. After the mixture has cooled, water is added, the gum is dissolved in methylene dichloride, washed until neutral and chromatographed on silica gel to give columnar crystals of 4-endo-benzoyloxy-8 with a melting point of 150-152°C. -Chloro-11-anti-formamide-benzo(b)bicyclo[3.3.
1] Nonene (7 g) and almost colorless gum-like 4-endo-benzoyloxy-8-chloro-11-syn-
Formamide-benzo(b)bicyclo [3.3.1]
Nonene (3.5g) was obtained.

Example 3 4-acetoxy- or 4-benzoyloxy-
11-Formamide-substituted benzo(b)bicyclo[3.3.1]nonene Same as in Examples 1 and 2 from the desired 4-acyloxy-benzo(b)bicyclo[3.3.1]nonen-11-one compound. The following 11-formamide compound was produced.

4-exo-acetoxy-8-methoxy-11-
Anti-formamide-benzo(b)bicyclo[3.
3.1] Nonene, melting point 172-173°C; 4-exo-benzoyloxy-8-bromo-
11-Anti-formamide-benzo(b)bicyclo[3.3.1]nonene, melting point 229-230°C; 4-exo-benzoyloxy-8,9-dichloro-11-anti-formamide-benzo(b)bicyclo [3.3.1] Nonene, melting point 242-243°C; 4-endo-p-nitrobenzoyloxy-9
-Chloro-11-anti-formamide-benzo(b)
Bicyclo[3.3.1]nonene, melting point 142-149
°C; 4-endo-p-nitrobenzoyloxy-9
-chloro-11-syn-formamide-benzo(b)bicyclo[3.3.1]nonene, melting point 197-200°C; 4-exo-acetoxy-11-anti-formamide-benzo(b)bicyclo[3.3・1] Nonene, melting point 121-122℃; 4-exo-acetoxy-11-syn-formamide-benzo(b)bicyclo[3.3.1]nonene,
Melting point 182-184°C: Example 4 4-Exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.
1] Nonene HCl 4-exo-benzoyloxy-8-chloro-
11-Anti-formamide-benzo(b)bicyclo[3.3.1]nonene (8 g) was dissolved in ethanol (80
ml) in 10M potassium hydroxide solution (14 ml) was heated under reflux for 4 hours to form a solution. After cooling, add brine to precipitate the amine,
Separate the precipitated amine, wash with water, dry and
Columnar crystalline 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (5 g) was obtained. Dissolve the amine (4.3 g) in ethanol/toluene,
An ethereal solution of hydrogen chloride gas was added to convert it to the hydrochloride salt. Purified 4-exo-hydroxy-8-chloro-11-anti-amino-benzo crystallized from isopropanol, melting point 182-194°C (decomposed).
(b) Bicyclo[3.3.1]nonene hydrochloride (4.1
g) was obtained.

The following compounds were produced in the same manner.

4-Endo-hydroxy-8-bromo-11-anti-amino-benzo(b)bicyclo[3.3.1]
Nonene HCl; 4-exo-hydroxy-8,9-dichloro-
11-Anti-amino-benzo(b)bicyclo[3.
3.1] Nonene HCl; 4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1] Nonene.
HCl: Example 5 4-Hydroxy-8-chloro-11-methylamino-benzo(b)bicyclo[3.3.1]nonene.
HCl 4-exo-benzoyloxy-8-chloro-
A solution of 11-anti-formamide-benzo(b)bicyclo[3.3.1]nonene (7.25 g) in anhydrous tetrahydrofuran (110 ml) was stirred and suspended in anhydrous tetrahydrofuran (40 ml) with lithium aluminum hydride (2.0 g). and added dropwise to the suspension. After stirring the mixture under reflux for 5 hours, water was added,
Solid minerals were separated.

Concentrate the liquid, add toluene and evaporate the solution in vacuo to give a gum of 4-exo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.1] Nonene (6.5g) was obtained. This was dissolved in methylene dichloride and converted to the hydrochloride by adding a saturated ether solution of hydrogen chloride gas. Purified 4-exo-hydroxy-8-chloro-11 crystallized from methylene dichloride/ethyl acetate in the form of columnar crystals with a melting point >190°C (decomposition).
-Anti-methylamino-benzo(b)bicyclo[3.3.1]nonene hydrochloride (4.2 g) was obtained.

Similarly, from a suitable 4-endo-acetoxy-11-formamide compound, 4
-Endo-hydroxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.3.
1] Nonene hydrochloride was produced.

Example 6 4-Hydroxy-11-methylamino-substituted-benzo(b)bicyclo[3.3.1]nonene 9-chloro, 8-methyl, 8.9-dichloro or 8-chloro-9-nitro group, respectively 4-acetoxy- or 4-benzoyloxy-11 optionally with
-Formamide-benzo(b)bicyclo [3.3.
1] From nonene, the following 11 was prepared in the same manner as in Example 5.
- A methylamino compound was produced.

4-Exo-hydroxy-11-anti-methylamino-benzo(b) bicyclo[3.3.1]nonene.HCl; 4-exo-hydroxy-8-methyl-11-anti-methylamino-benzo(b) Bicyclo [3・
3.1] Nonene HCl; 4-exo-hydroxy-8,9-dichloro-
11-Anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.HCl; 4-exo-hydroxy-9-chloro-11-anti-methylamino-benzo(b)bicyclo[3.
3.1] Nonene HCl; 4-exo-hydroxy-8-chloro-9-nitro-11-anti-methylamino-benzo(b)bicyclo[3.3.1] Nonene HCl: Example 7 8- Bromo-4-exo-hydroxy-11-anti-methylamino-benzo(b)bicyclo[3.
3.1] Nonene HCl formic acid (9 ml) and 4-exo-benzoyloxy-8-bromo-benzo(b)bicyclo [3.3.1]
A mixture of nonen-11-one (6g) and N-methyl-formamide (18ml) was boiled under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with water and treated with 2N sodium hydroxide solution to give a yellow gum. Extract this with methylene dichloride,
The methylene dichloride extract was washed with water, dried and evaporated to give a brown gum (5.97g). Dissolve gum (5.97g) in ethanol (120ml) and add 10N
Heated under reflux with potassium hydroxide solution (12ml) for 27 hours. The reaction mixture was cooled to room temperature, diluted with brine, and extracted with methylene dichloride. The methylene dichloride extract was washed with water, dried,
Evaporation in vacuo gave the crude amine (4.23g) as an orange gum. This was dissolved in methylene dichloride, and an ether solution of hydrogen chloride gas was added to convert it to the hydrochloride. Crystallized from methylene chloride and methanol-ether, melting point 264-270
Purified 4-exo-hydroxy- as colorless crystals at °C.
8-Bromo-11-anti-methylamino-benzo
(b) Bicyclo[3.3.1]nonene hydrochloride (1.30
g) was obtained.

Example 8 4-Exo-acetoxy-8-chloro-11-anti-methylamino-benzo(b)bicyclo[3.
3.1] Nonene HCl 4-exo-hydroxy-
8-chloro-11-anti-methylamino-benzo
(b) A solution containing bicyclo[3.3.1]nonene (4 g) was allowed to stand for 1 hour. The solution was taken up in ice water and solid potassium carbonate was added until alkaline. Extract the product with methylene dichloride,
Washed until neutral, dried and evaporated to dryness to give a gummy 4-exo-acetoxy-8-chloro-
11-Anti-methylamino-benzo(b)bicyclo[3.3.1]nonene (4.7 g) was obtained. The product was dissolved in methylene dichloride and passed through acid washed alumina. Concentrating the eluate and adding a saturated ether solution of hydrogen chloride gas gives the hydrochloride (3.65
g) was precipitated. This was crystallized from methanol-ethyl acetate to form columnar crystals with a melting point of 256°C.
exo-acetoxy-8-chloro-11-anti-
Methylamino-benzo(b)bicyclo [3.3.1]
Nonene hydrochloride (3.1g) was obtained.

The following compounds were produced in the same manner.

4-Exo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo [3.3.1]
Nonene HCl, melting point 256℃; 4-endo-acetoxy-8-chloro-11-anti-amino-benzo(b)bicyclo [3.3.1]
Nonene HCl, melting point 259-263℃; 4-exo-acetoxy-8,9-dichloro-
11-Anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.HCl, melting point 247-253°C: Example 9 4-exo-benzoyloxy-8-chloro-
11-Anti-amino-benzo(b)bicyclo[3.
3.1] Nonene HCl 4-exo-hydroxy-8-chloro-11-anti-amino-benzo(b)bicyclo [3.3.1]
Benzoyl chloride (2.3 ml) was added dropwise to a solution of nonene (4.8 g) in trifluoroacetic acid (20 ml). The mixture was stirred at room temperature for 7 hours and poured onto ice. Solid sodium carbonate was added until alkaline and the product was extracted with ethyl acetate. 2M extract
Washed with NaOH, then water until pH 7, dried and evaporated to give a gum (5.0 g).
Crystallization from ether gives 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (3.2 g)
I got it.

The crystalline product in methylene dichloride is treated with a saturated ethereal solution of hydrogen chloride gas to give a melting point of 213
4-Exo-benzoyloxy-8- at ~220°C
Chloro-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene.HCl was obtained.

Example 10 In the same manner as in Example 9, 4-hydroxy-11-
The following compounds were prepared by treatment of amino- and 11-methyl-amino compounds with appropriate acyl halides.

4-exo-benzoyloxy-8-chloro-
11-Anti-methylamino-benzo(b)bicyclo[3.3.1]nonene.HCl; 4-exo-(2.2-dimethylpropionyloxy)-8-chloro-11-anti-amino-benzo(b) ) Bicyclo[3.3.1]nonene.HCl: Example 11 4-Exo-hydroxy-8.9-dichloro-
11-Anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl 4-Exo-hydroxy-8.9-dichloro- in a mixture of formic acid (16.6 ml) and formalin (15.5 ml). A solution of 11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (16.6 g) was boiled under reflux for 2 hours, diluted with water and excess potassium bicarbonate solution. , extracted with methylene dichloride. The extract was washed with water until neutral, dried and evaporated, and the residue was crystallized from ether to give 4-exo-hydroxy-8,9-dichloro-11-anti-, m.p. 133.5-135°C. Dimethylamino-benzo(b)bicyclo[3.3.1]nonene (16.2 g) was obtained. The product was dissolved in methylene chloride and treated with an ethereal solution of hydrogen chloride to determine the melting point.
The hydrochloride salt was obtained at 248-273°C.

In the same manner as in Example 7, dimethylformamide and 4-exo-benzoyloxy-8.
9-dichloro-benzo(b)bicyclo[3.3.1]
The compound was also obtained by refluxing the mixture with nonen-11-one.

Example 12 4-Hydroxy-11-dimethylamino-benzo
(b) Bicyclo[3.3.1]nonene Each of the desired (substituted or unsubstituted) 4-Hydroxy-11-amino-benzo(b)bicyclo[3.
3.1] The following 11-dimethylamino compound was produced from nonene in the same manner as in the above example.

4-Exo-hydroxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl; 4-exo-hydroxy-8-methoxy-11-
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-exo-hydroxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.
3.1] Nonene HCl; 4-exo-hydroxy-9-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.
3.1] Nonene HCl; 4-exo-hydroxy-8,10-dichloro-
11-Syn-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl: Example 13 4-Exo-acetoxy-8.9-dichloro-
11-Anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl 4-exo-hydroxy-8.9-dichloro-
11-Anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene (4.0 g) was dissolved in acetic anhydride (8
ml) and pyridine (8 ml) at room temperature to give 4-exo-acetoxy-8,9-dichloro-11-anti-dimethylamino-benzo(b)bicyclo[3,3・1] Nonene (4.4 g) was obtained. This was dissolved in methylene chloride and treated with an ethereal solution of hydrogen chloride to reach the melting point.
The hydrochloride salt was obtained at 234-279°C.

Example 14 4-Hydroxy-11-dimethylamino-benzo
(b) Bicyclo [3.3.1] Esters of nonene derivatives Desired 4-hydroxy-11-dimethylamino-benzo (b) Bicyclo [3.3.1] optionally containing an 8-bromo or 8-chloro group The following ester of 4-hydroxy-11-dimethylamino compound was produced from nonene in the same manner as described above.

4-Exo-acetoxy-11-anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl; 4-exo-benzoyloxy-11-anti-
Dimethylamino-benzo(b)bicyclo [3.3.
1] Nonene HCl; 4-exo-(2,2-dimethylpropionyloxy)-11-anti-dimethylamino-benzo
(b) Bicyclo[3.3.1]nonene.HCl; 4-exo-acetoxy-8-bromo-11-anti-dimethylamino-benzo(b) Bicyclo[3.
3.1] Nonene HCl; 4-endo-benzoyloxy-8-chloro-
11-Syn-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl; 4-exo-(2.2-dimethylpropionyloxy)-8-chloro-11-anti-dimethylamino-benzo( b) Bicyclo [3.3.1] Nonen
HCl; 4-endo-benzoyloxy-8-chloro-
11-Anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl; 4-exo-acetoxy-8-chloro-11-anti-dimethylamino-benzo(b)bicyclo[3.
3.1] Nonene HCl; 4-exo-benzoyloxy-8-chloro-
11-Anti-dimethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl: Example 15 4-Exo-acetoxy-11-anti-acetamido-benzo(b)bicyclo[3.3.1] Nonene 4-Exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1]nonene (20
g) was suspended in acetic anhydride (40ml) and the mixture was stirred at room temperature for 1 hour and then poured into water. collect the solids,
Drying gave 4-exo-acetoxy-11-anti-acetamido-benzo(b)bicyclo[3.3.1]nonene (12.6 g) with a melting point of 213-214°C.

In the same manner as above, 4-exo-benzoyloxy-8-chloro-11-anti-amino-benzo
(b) From a suspension of bicyclo[3.3.1]nonene in acetic anhydride with stirring, 4-exo-benzoyloxy-8-chloro-11-anti-acetamido-benzo(b)bicyclo[ 3.3.1] Obtained Nonen.

Example 16 4-Exo-hydroxy-11-anti-ethylamino-benzo(b)bicyclo[3.3.1]nonene.HCl LiAlH ₄ (3.3 g) in anhydrous tetrahydrofuran
A suspension of 4-exo-
Acetoxy-11-anti-acetamido-benzo
(b) A hot suspension of bicyclo[3.3.1]nonene (12.5 g) was added, and the mixture was refluxed for 2 hours. Water is added to decompose excess lithium aluminum hydride and the mixture is filtered;
The liquid was evaporated to dryness. The residue was dissolved in ether and treated with a saturated ethereal solution of hydrogen chloride, and the resulting solid was recrystallized from methane-ether to give 4-exo-hydroxy-11-anti-ethylamino-benzo having a melting point >265°C. (b) Bicyclo [3・
3.1] Nonene hydrochloride (12 g) was obtained.

Example 17 4-Exo-hydroxy-11-anti-N-methyl-N-(3-methyl-2-butenyl)-amino-benzo(b)bicyclo[3.3.1]nonene hydrochloride Dimethylformamide (10 ml) ) and methylene chloride (1 ml) to 4-exo-hydroxy-11-
Anti-methylamino-benzo(b)bicyclo[3.
3.1] Add 1-bromo-3-methyl-2-butene (5.5 ml) and dimethylformamide (10 ml) to a stirred suspension of nonene (5.5 g) and potassium hydrogen carbonate (5.0 g). The solution was added dropwise keeping the mixture at room temperature. The reaction mixture was stirred for an additional 15 minutes and poured into water. The product was extracted with methylene dichloride. The extract was washed with water, dried and
Evaporation gave an extract. The oil was chromatographed on alumina, eluting with benzene to give an oil (5 g). This was dissolved in ether and treated with a saturated ethereal solution of hydrogen chloride. The resulting solid is recrystallized from methanol-ether to determine its melting point.
4-Exo-hydroxy-11-anti-N-methyl-N-(3-methyl-2-butenyl)-amino-benzo(b)bicyclo[3.3.1] at 258-259°C
Nonene hydrochloride (3.1g) was obtained.

Example 18 Various 4-hydroxy-benzo(b)bicyclo[3.3.1]nonene-11-oxime derivatives were reduced with sodium in isopropanol.
The corresponding primary amine was obtained. 4-(Endo or Exo)-benzoyloxy-benzo(b)bicyclo[3.3.
1] Oxime was obtained by reacting a nonen-11-one derivative with hydroxylamine/HCl. The following compounds were produced by this method.

4-exo-hydroxy-8-methoxy-11-
Anti-amino-benzo(b)bicyclo [3.3.
1] Nonene HCl, melting point 256-258°C; 4-exo-hydroxy-8,9-dichloro-
11-Anti-amino-benzo(b)bicyclo[3.
3.1] Nonene HCl, melting point 286-300℃; 4-exo-hydroxy-11-anti-amino-benzo(b)bicyclo[3.3.1] Nonene.
HCl, sublimation >265°C: Example 19 The following compounds were prepared analogously to Example 1 by refluxing the appropriate starting ketone in a mixture of formic acid and formamide or dimethylformamide.

4-exo-p-nitrobenzoyloxy-9
-Chloro-11-anti-formamide-benzo(b)
Bicyclo [3.3.1] Nonene HCl, melting point 269
~272°C; 4-exo-p.nitrobenzoyloxy-8
-Nitro-9-chloro-11-anti-formamide-benzo(b)bicyclo[3.3.1]nonene.
HCl, mp 276-279°C (decomposed); 4-exo-p-nitrobenzoyloxy-9
-Chloro-10-nitro-11-anti-formamide-benzo(b)bicyclo[3.3.1]nonene.
HCl, mp 253-262°C (decomposition); 4-endo-p-nitrobenzoyloxy-8
-Nitro-9-chloro-11-anti-formamide-benzo(b)bicyclo[3.3.1]nonene.
HCl, melting point 229-231°C; 4-exo-hydroxy-8-chloro-9-nitro-11-anti-formamide-benzo(b)bicyclo[3.3.1]nonene.HCl, melting point 248°C:

Claims (1)

[Claims] 1 formula [In the formula, R ₁ and R ₂ are hydrogen, alkyl having 1 to 4 carbon atoms, acetyl, formyl, or 3-methyl-2-butenyl, and R ₃ is hydroxy, alkyl having 1 to 4 carbon atoms.
is alkanoyloxy, benzoyloxy or nitrobenzoyloxy, and X and Y are hydrogen,
halogen, methyl, methoxy or nitro group] or a salt thereof suitable for formulation.