HU176463B - Process for preparing benzobicyclononene derivatives - Google Patents

Abstract

Novel compounds of the formula I <IMAGE> in which R1 and R2 in each case denote a hydrogen atom, a lower alkyl or lower alkenyl group or an optionally substitued aryl-lower-alkyl group or R1 denotes the formyl group and R2 denotes hydrogen or a lower alkyl group, or R1 and R2 together with the nitrogen atom form a heterocyclic 5- or 6-membered ring, R3 denotes a free, etherified or esterified hydroxyl group and X and Y in each case represent a hydrogen or halogen atom, a hydroxyl group, an alkyl(1-6C), alkoxy(1-6C), nitro, trifluoromethyl or acyloxy group, and the salts thereof, are prepared by reacting a compound of the formula II <IMAGE> in which X and Y have the abovementioned meaning, with formamide or ammonia or with a corresponding amine in the presence of a reducing agent. These compounds, their salts and N-oxides are biologically active.

Description

The present invention relates to a process for the preparation of novel biologically active tricyclic compounds.

The present invention relates in particular to the preparation of novel benzo [b] bicyclo [3.3.1] nonene derivatives of the formula I and their salts. In this formula

R 1 and R _{2 are} hydrogen, C 1-4 alkyl, C 2-5 alkenyl, C 1-4 alkanoyl, or phenyl (C 1-4) alkanoyl, or

Ri and _R2 with the nitrogen atom form a 5- or 6-membered ring optionally containing an oxygen atom as a further heteroatom a heterocyclic ring,

R _{3 is} hydroxyl or C 1-10 aliphatic or phenyl (C 1-4) aliphatic acyl,

X and Y are hydrogen, hydroxy, halogen, C 1-4 alkyl or alkoxy, nitro, or -CF ₃ .

The compounds of the formula I have valuable biological effects, in particular an appetite suppressant. In addition, the toxicity of these compounds is also very low.

The compounds of the present invention may be prepared by conventional methods for the preparation of similar compounds in the literature.

Very suitable starting materials for the synthesis of compounds of formula I are compounds of formula II wherein X, Y and R ₃ are as defined above.

These compounds of formula (II) may be prepared in conventional manner from an optionally substituted (X and / or Y) O-tetralone. Said tetralone, which is commercially available from commercially available tetralones, is treated with pyrrolidine to produce the corresponding 2- (pyrrolidino) enamine. The enamine is then reacted with acrolein to give the corresponding 4-hydroxybenzo [b] bicyclo [3.3.1] nonen-11-one. Alternatively, tetralone is directly reacted with acrolein at elevated temperature in the presence of a tertiary amine such as trimethylamine and thus directly

4-Hydroxybenzo [b] bicyclo [3.3.1] nonen-11-one is prepared. The 4-hydroxy group of this compound can then be esterified. The condensation of 2-tetralenamine with acrolein is preferably carried out at temperatures between -60 ° C and + 25 ° C in a variety of solvents, with a temperature range of -50 ° C to -45 ° C being added to the acrolein, and allow to rise to room temperature over a period of up to 3 hours during inspection.

Alternatively direct condensation of the optionally substituted (X and / or Y) 0-tetralone with acrolein is preferably at a temperature of + 30 ° C to + 120 ° C in various solvents, preferably at the boiling point of the solvent used, a tertiary alkylamine such as triethylamine or trimethylamine. When starting from a compound of formula (II), the amines or amides of formula (I) of the invention are more preferably and directly prepared by reductive amination. ¹⁰

The method is that corresponding to the formula (II) ketone formamide, N-alkilformamiddal or Ν, Ν-dialkilformamiddal or (III) with an amine of formula wherein R and R _'2 are as _R1 and _R2 of 15 except that it cannot be acyl, and is reacted in the presence of a suitable reducing agent.

A very suitable reducing agent for this reduction is formic acid or a formic acid derivative such as formic acid salt and the amine of formula (III). In the latter case, the addition of a separate amine of formula III is unnecessary. This reaction is carried out at an elevated temperature, preferably in the range of from 80 to 150 ° C, and in particular 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 diisobutylaluminium hydride, and an alkali metal, preferably platinum, an alcohol, anhydrous , palladium on carbon and the like. Some reducing agents, such as lithium aluminum hydride 35, are capable of removing the ether or ester moiety that may be present at the 4-position, and at the same time move the hydroxy group to the 4-position.

The compounds of the invention may also be prepared by reacting an imino group of a compound of formula IV wherein X, Y and R ₃ are as defined above and R 4 is hydrogen, hydroxy, C 1-4 alkyl, alkoxy or optionally substituted aralkyl. 45

Compounds of formula (IV) may be prepared by reacting a ketone of formula (II) with a primary amine of formula (R 1 = H) or a hydroxylamine or a hydroxylamine alkyl ether under alkaline conditions to produce imines and oximes in general. according to the methods used.

Reduction of the imine of formula (IV) under mild reaction conditions is carried out according to standard standard methods for reduction of the imino moiety. The reduction may be effected, for example, by hydrogenation in the presence of a suitable catalyst such as Raney nickel, Pt or PtO ₂ , by reduction with a metal hydride, in particular a complex metal hydride derived from aluminum or leather, such as lithium-aluminum hydride, as a liquid, for example, ether. The reduction may be carried out with an alkali metal, preferably sodium, in a suitable liquid such as ether, benzene or alcohol, and may be reduced with sodium amalgam or zinc powder, such as sodium hydroxide. The reaction may simultaneously result in the cleavage of the 4-ether or 4-ester group and the corresponding 4-alcohol is obtained depending on the reducing agent.

In a third method, the compounds of formula (I) are prepared from a compound of formula (V) having a hydroxyl group, wherein X and Y are as defined above, and R ₅ is an etherified or esterified hydroxyl group.

The compounds of general formula (V) is obtained by reduction from the corresponding (II), ketones under mild conditions that do not remove the presence of R _s group. A suitable reducing agent in this regard is sodium borohydride.

The hydroxyl compounds of formula (V) can be converted to the corresponding amines in various ways. For example, the hydroxy group in question may be converted into an alkyl or arylsulfonyloxy group (leaving group) such as mesyloxy, tosyloxy, p-bromophenylsulfonyloxy, ρ-chlorophenylsulfonyloxy, p-nitrophenylsulfonyloxy or the like. followed by reaction with an amine of formula (III).

Instead of converting the hydroxy group to the aforementioned alkyl or arylsulfonyloxy group, the hydroxy group may also be halogenated with, for example, phosphorus pentachloride, pentabromide, thionyl chloride and the like, and the resulting product treated with an amine of formula (III). the desired compounds of formula (I) are obtained.

Conversion of a hydroxyl group to an amino group is well known and described in the manuals.

The above-described primary reactions for the preparation of the compounds of formula I according to the invention may be followed by further reactions to convert the compounds of formula I into their salts or nitric oxides and to convert a compound of the invention into another compound of the invention.

It is also possible to convert a substituent on the phenyl ring to another substituent corresponding to X and / or Y. For example, a methoxy group can be converted to a hydroxyl group by, for example, hydrolysis with molten pyridine hydrochloride without solvent or with hydrobromic acid. A hydroxy group may be converted to an alkoxy group, halogen atom or acyloxy group by conventional means.

Unsubstituted or substituted at the nitrogen of the invention are mono-substituted with (R? And / or R ₂ is hydrogen) amines appropriate (ar) alkylated, for example by reacting the compound of formula (r) · halide, or first acüezzük compound and subsequent reduction of the carbonyl.

The Eschweiler-Clark method (reaction with formaldehyde and formic acid) or the reaction with formaldehyde or halogen formic acid esters followed by reduction with, for example, sodium cyanoborohydride is well known for introducing methyl groups onto the nitrogen atom.

Preferably, an N-acyl derivative of the compounds of the present invention is prepared by acylating an anhydride or an acid halide in a conventional manner to acylate a compound of formula I wherein at least one of R ₁ and R ₂ is hydrogen.

Such acylations, which are carried out on the 4-alcohol derivative (where R ₃ = OH in the formula I) simultaneously lead to the esterification of the 4-hydroxyl group.

In the case where an N-formyl derivative is obtained directly from any of the above primary reactions, the amide may be hydrolyzed, for example, with potassium or sodium hydroxide to give the primary amine of formula (I). Such hydrolysis can simultaneously result in the hydrolysis of the 4-ester group to 4-alcohol. For example, reductive amination, wherein the ketone of formula II is reacted with formamide in the presence of formic acid (Leuckart-Wallach reaction), predominantly yields the N-formyl derivative of formula I, which is then the primary compound of formula I which can be hydrolyzed to an amine or reduced to the N-methyl compound of formula (I).

An O-acyl derivative of the compounds of the invention in which the primary or secondary amine group remains unreacted may be prepared by treating an amine of formula (I) wherein R ₃ = OH with an acylating agent such as an acid halide or anhydride. in the presence of a strong acid such as trifluoroacetic acid or perchloric acid.

All of these additional transformations, which may be carried out after the aforementioned primary reactions, may be carried out by conventional methods well known in the art. When referring to a typical reagent for use in these additional transformations, it is understood that this reagent may be replaced by a reagent well known in the art of organic chemistry, in so far as it has the same activity as the typical reagent described.

The synthesis of ketones of formula (II) used as starting materials for the synthesis of compounds of formula (I) according to the invention yields a mixture of two enantiomers of formula (II) in which the 4-alcohol or ester group is exo and includes two enantiomers of formula (II) wherein the 4-alcohol or ester group is in the end-position. The exo-enantiomers can be separated from the endo-enantiomers by crystallization or chromatography. Each of the racemic mixtures thus obtained, which is a mixture of compounds of formula (II), can be reacted and subsequently resolved upon conversion to a racemic compound of formula (I), or resolved, and subsequently, to an optically active final product of formula (I) converted.

Substitution of the oxo group at the 11-position of the ketone (II) with an amino group or reduction of the imine (IV) creates another asymmetric center in the two diastereomeric mixtures of formula (I) in which the amino group is colored - or is in an anti-position relative to the benzene ring. The individual diastereomeric forms may be selected from the mixture by conventional means, such as column chromatography, preparative thin layer chromatography and / or fractional crystallization.

The preparation of compounds of formula I in the form of diastereomers, enantiomers and mixtures thereof is within the scope of the present invention.

The novel compounds of formula (I) may be isolated from the reaction mixture in the form of pharmaceutically acceptable salts, depending on the reaction conditions used. Pharmaceutically acceptable salts may also be prepared by reacting the free base of formula (I) with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, malonic acid, malonic acid, , ascorbic acid and the like.

The term "alkyl" in the substituents X, Y, R, and R _{2 for} the compounds of formula I is a saturated branched or unbranched C 5 -C 4 hydrocarbon radical such as methyl, ethyl, n-propyl, η-butyl, cyclopropyl, cyclopropylmethyl, isopropyl, isobutyl or tert-butyl. The same meaning applies to the alkyl group in the "alkoxy group" of X and Y.

R and R in the formula (I) according to _two substituents "alkenyl" refers to an unsaturated, branched or unbranched C2-5 hydrocarbon radical such as vinyl, allyl and 3-methylbut-2-enyl group picture5 wearing.

Preferably, "halogen" refers to chlorine or bromine.

The term "acyl" denotes a group derived from R] and _R2 substituents by an aliphatic, araliphatic or aromatic carboxylic acid 0. Aliphatic carboxylic acids have from 1 to 10 carbon atoms, which may form a carbocyclic ring, and in particular from 1 to 8 carbon atoms. Acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, _5-hexanoic acid, heptanoic acid and trimethylacetic. The araliphatic or aromatic carboxylic acids may be unsubstituted or substituted C 1 -C 4 alkyl moieties, which may be optionally substituted phenylcarboxylic acids, I and optionally substituted phenylalkylcarboxylic acids, wherein the alkyl group contains 1 to 4 carbon atoms and may be saturated or unsaturated . Such acids include benzoic acid, ο-, m- or p-toluoylic acid, o- or p-chlorobenzoic acid, p-methoxybenzoic acid, phenylacetic acid, phenylpropionic acid, cinnamic acid, phenylbutyric acid, p-methylphenylacetic acid, p-nitrobenzoic acid and the like.

The term "acyloxy" in the term "acyloxy" or "esterified hydroxy" means the same for X, Y and R ₃ .

! The heterocyclic five- or six-membered rings for the substituents R ₁ and R ₂ (together with the nitrogen atom) may be derived from the 5- or 6-membered cyclic amines of formula (III) such as pyridine, pyrrolidine, pyrroline, piperidine, or morpholine.

Nitric oxides of the compounds of the present invention are prepared by oxidizing the compounds of formula (I) with hydrogen peroxide or peracetic acid.

The novel compounds of the present invention, as well as their pharmaceutically acceptable salts, have, as already mentioned, a valuable appetite suppressant effect. Prolonged oral administration of the compounds of formula (I) does not alter the appetite suppressant effect. The compounds of Formula I, in particular the 11-color isomers of Formula I, also exhibit moderate anti-inflammatory activity. In addition, the general pharmacological profile of the compounds of formula (I) according to the invention is also characterized by an anti-depressant effect.

The compounds of the present invention may be administered orally, parenterally and topically (the latter route of administration being mainly for anti-inflammatory purposes), the daily dosage being in the range of 0.005 to 50 mg, preferably 0.01 to 10 mg per kilogram of body weight.

When mixed with suitable excipients, the compounds of the formula I can be compressed into solid dosage units such as pills, tablets or capsules. 25

When combined with suitable liquids, the compounds of formula (I) may also be formulated as injectables, such as solutions, suspensions, or emulsions.

For topical applications, the compounds may also be formulated in ointments or creams.

Preferred compounds of the invention are those compounds of formula I wherein R 1 and R _{2 are} hydrogen or methyl and / or the benzene ring is substituted with one or two halogen atoms and / or R _{3 is} hydrogen, (C 1 -C 8) lower carbon. an aliphatic acyl group or a lower araliphatic acyl group such as benzoyl.

The preparation of starting materials and compounds 40 according to the invention is illustrated by the following examples.

Starting materials

Preparation of 4-exo and 4-endo-hydroxy and 4-exo and 4-endo-benzyloxy-8-chlorobenzo [b] bicyclo [3.3.1] nonen-11-one 6-chloro-2 starting from -tetralone. Other starting materials of formula II are prepared in a similar manner.

A) 6-Chloro-2-tetralone-pyrrolidin-enamine

A solution of 260 g of 6-chloro-2-tetralone in 1.5 L of benzene and 55 208 ml of pyrrolidine is refluxed under nitrogen for 2.5 hours and the water formed is separated with a Dean and Stark water separator. The reaction mixture was concentrated to dryness under reduced pressure and the apparatus was purged with nitrogen gas at the end of the distillation. The residue was triturated with hexane to give 276 g of 6-chloro-2-tetralone-pyrrolidinamine.

M.p. 121-122 ^e C. 82% yield. 65

B) 8-Chloro-4-hydroxybenzo [b] bicyclo [3.3.1] nonene

-11 C.

B) l. 6-Chloro-2-tetralone-pyrrolidine enamine (390 g) was added portionwise over 10 minutes to a stirred solution of acrolein (214 mL) in methylene chloride (3.0 L) cooled to -50 ° C to -55 ° C. The reaction mixture was stirred for 30 minutes at -50 ° C to -55 ° C, then allowed to rise to + 5 ° C over 3 hours. Then 420 inl of water and 400 ml of 5N hydrochloric acid were added and the resulting biphasic mixture was stirred at room temperature for 2 hours and then allowed to stand overnight. The layers were separated and the aqueous layer was extracted with methylene chloride. The methylene chloride extracts were washed with 1N hydrochloric acid, then with brine, dried and evaporated to dryness. In this way, 8-chloro-4-exo and 8-chloro-4-endo-hydroxybenzo [b] bicyclo [3.3.1] nonen-11-one (371 g) are obtained (approximately 60:40). .

B) 2nd 389 ml of acrolein were added with stirring to a solution of 738 g of 6-chloro-2-tetralone in 738 ml of tetrahydrofuran and 738 ml of triethylamine under nitrogen atmosphere and the mixture was refluxed for 2.5 hours. The solvent was removed in vacuo and the triethylamine was finally recovered by azeotropic distillation with toluene, using a total of 2.75 L of toluene in 250 mL portions.

The resulting crude biaxial mixture (810 g) was dissolved in toluene, filtered through alumina and the eluate evaporated. This gives 792 g of an oily mixture (approximately 60:40) of 8-chloro-4-exo and 8-chloro-4-endo-hydroxybenzo [b] bicyclo [3.3.1] nonen-11-ol. contains.

C) 4-Exo and 4-endo-benzoyloxy-8-chloro-benzo [b] bicyclo [3.3.1] nonen-11-one g of 8-chloro-4-exo and 8-chloro-4-endo-hydroxy A solution of benzo [b] bicyclo [3.3.1] nonen-11-one in 104 ml of pyridine is cooled to 2 ° C with stirring and 30.5 ml of benzoyl chloride is added dropwise while maintaining the temperature below 10 ° C. Stirring was continued at 5-10 ° C for 3.5 hours. Water was added to the cooled mixture with stirring to precipitate the product, which was dissolved in methylene chloride, washed with 2N hydrochloric acid and water to pH 7, then dried and evaporated. 62 g of product are obtained which is a mixture (approximately 60:40) of 4-exo and 4-endo-benzoyloxy-8-chloro-benzo [b] bicyclo [3.3.1] nonen-11-one.

A solution of the product in methylene chloride was passed through an alumina column, the filtrate was concentrated and the residue was recrystallized from methylene chloride-cyclohexane. 26 g of pure 4-exo-benzoyloxy-8-chlorobenzo [b] bicyclo [3.3.1] nonen-11-one are obtained, m.p. 184-186 ° C. The mother liquor was chromatographed on alumina to give 7.5 g of pure 4-exo-benzoyloxy-8-chlorobenzo [b] bicyclo [3.3.1] nonen-11-one and

18.5 g of pure 4-endo-benzoyloxy-8-chlorobenzo [b] bicyclo [3.3.1] nonen-11-one are obtained, m.p. 120-122 ° C.

Example 1

4-Exo-benzoyloxy-8-chloro-11-anti-formamidobenzo [b] bicyclo [3.3.1] nonene

A suspension of 33.5 g of 4-exo-benzoyloxy-8-chlorobenzo [b] bicyclo [3.3.1] nonen-11-one in a mixture of 134 ml of formamide and 67 ml of formic acid is refluxed for 2.5 hours. The mixture was cooled, water was added, and the solid was collected by filtration, washed with water and dried. 32.5 g are obtained. This product was crystallized from methylene chloride / methanol to give 28.5 g of 4-exo-benzoyloxy-8-chloro-11-anti-formamidobenzo [b] bicyclo [3.3.1] nonene as prisms.

Mp 224-226 ° C.

Example 2

4-endo-benzoyloxy-8-chloro-11-formamido-benzo [b] bicyclo [3.3.1] ionone

A suspension of 18.5 g of 4-endo-benzoyloxy-8-chloro-benzo [b] bicyclo [3.3.1] -nonene-11-one in 74 ml of formamide and 37 ml of formic acid is heated under reflux for 2.5 hours. The mixture was cooled, water was added, and the resulting gum was dissolved in methylene chloride, washed with neutral and chromatographed on silica gel. In this way, 7 g

4-endo-benzoyloxy-8-chloro-11-anti-formamido-b-enzo [b] bicyclo [3.3.1] nonene is obtained in the form of prisms, m.p. 150-152 ° C and 3.5 g of 4-endo Benzoyloxy-8-chloro-11-syn-formamidobenzo [b] bicyclo [3.3.1] nonene is obtained in the form of an almost colorless gum.

Example 3

4-Acetoxy or 4-benzoyloxy-11-formamido-substituted-benzo [b] bicyclo [3.3.1] ionone

From the desired 4-acyloxy-benzo [b] bicyclo [3.3.1] nonen-11-one compound, which is unsubstituted or substituted on the benzene ring, the following 11-formamido compounds are prepared from

As described in Examples 2:

4-exo-acetoxy-8-methoxy-11-anti-formamidobenzo [b] bicyclo [3.3.1] non-m.p. 172-173 ° C.

4-exo-benzoyloxy-8-bromo-11-anti-formamidobenzo [b] bicyclo [3.3.1] ionone, m.p. 229-230 ° C, 4-exo-benzoyloxy-8,9-dichloro-11-anti -formamidobenzo [b] bicyclo [3.3.1] m.p. 242-243 ° C,

4-endo-p-nitrobenzoyloxy-9-chloro-11-anti-formamidobenzo [b] bicyclo [3.3.1] ion, m.p. 142-149 ° C.

4-endo-p-nitrobenzoyloxy-9-chloro-11-syn-formamide ^5- benzo [b] bicyclo [3.3.1], m.p. 197-200 ° C,

4-exo-acetoxy-11-anti-formamidobenzo [b] bicyclo [3.3.1] nonene, m.p. 121-122 ° C,

4-exo-acetoxy-11-syn-formamidobenzo [b] bicyclo [3.3.1], m.p. 182-184 ° C,

4-exo-acetoxy-8-chloro-9-CF ₃ -11-anti-formamidobenzo [b] bicyclo [3.3.1] nonene.

Example 4

4-exo-hydroxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] ionene · HCl g 4-exo-benzoyloxy-8-chloro-11-anti-formamidobenzo [b] bicyclo [3.3.1 A suspension of jnone in a mixture of 80 ml of ethanol and 14 ml of 10 M potassium hydroxide was refluxed for 4 hours. During this time, a solution is obtained, which is cooled, and saturated aqueous saline is added to precipitate the amine. The precipitated amine was collected by filtration, washed with water and dried. This gives 5 g of 4-exo-hydroxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene in the form of prisms. 4.3 g of the amine are dissolved in ethanol / toluene and converted to the hydrochloride with ethereal hydrogen chloride and then crystallized from isopropanol. 4.1 g of pure 4-exo-hydroxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene hydrochloride are obtained.

182-194 ° C (dec.).

The following compounds were prepared in a similar manner:

4-exo-hydroxy-8-methoxy-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene · HCl, 4-endo-hydroxy-8-chloro-11-anti-aminobenzo [b] ] bicyclo [3.3.1 jnonene · HCl, m.p. 320-330 ° C,

4-endo-hydroxy-8-bromo-11-anti-amino-benzo [b] bicyclo [3.3.1] -nonene · HCl, m.p. 255 ° C (dec.),

4-exo-hydroxy-8,9-dichloro-11-anti-aminobenzo [b] bicyclo [3.3.1] non-HCl, m.p. 286-300 ° C.

4-exo-hydroxy-11-anti-aminobenzo [b] bicyclo [3.3.1] non-HCl, m.p. 265 ° C (sublimal).

Example 5

4-Hydroxy-8-chloro-11-methylaminobenzo [b] bicyclo [3.3.1] nonene · HCl

A solution of 7.25 g of 4-exo-benzoyloxy-8-chloro-11-anti-formamidobenzo [b] bicyclo [3.3.1] nonene in 110 ml of dry tetrahydrofuran is added dropwise with 2.0 g of lithium aluminum hydroxide 40 ml slurry in dry tetrahydrofuran and the mixture was stirred and refluxed for 5 hours. After addition of water, the inorganic solids were removed by filtration, the filtrate was concentrated, toluene was added and the solution concentrated in vacuo. 5 g of 4-exo-hydroxy-8-chloro-11-anti-methylaminobenzo [b] bicyclo [3.3.1] nonene are thus obtained in the form of a gum which is dissolved in methylene chloride and converted to the hydrochloride with ethereal hydrogen chloride gas. This product was crystallized from methylene chloride / ethyl acetate to give 4.2 g of pure 4-exo-hydroxy-8-chloro-11-anti-methylaminobenzo [b] bicyclo [3.3.1] mononene hydrochloride. form.

M.p.> 190 ° C (dec.). 15

In a similar manner, 4-endo-hydroxy-8-chloro-11-anti-methylaminobenzo [b] bicyclo [3.3.1] nonene hydrochloride was prepared, m.p. 262-268 ° C.

Example 6

4-Hydroxy-11-methylamino-substituted-benzo [b] bicyclo [3.3.1] nonene

Starting from the desired 4-acetoxy or 4-benzoyloxy-11-formaminobenzo (b) bicyclo [3.3.1] nonene which is unsubstituted in the phenyl ring or 9-chloro, 8-methoxy, 8-hydroxy in the phenyl ring Containing 8-methyl, 8,9-dichloro or 8-chloro-9-nitro, the following 11-methylamino compounds were prepared as described in Example 5.

4-exo-hydroxy-11-anti-methylaminobenzo [b] bicyclofl 3.3.1 ionone (hydrochloride m.p. 265-268 ° C), 4-exo-hydroxy-8-methyl-11-anti-methylamino benzo [b] bicyclo [3.3.1] ionone (hydrochloride melting point 230 ° C with decomposition), 4-exo-hydroxy-8,9-dichloro-11-anthymethylaminobenzo [b] bicyclo [3.3.1 jnonene (having a hydrophilic melting point of 272-278 ° C), 4-exo-hydroxy-9-chloro-11-methylmethylamyrobenzo [b] bicyclo [3.3.1] ionone (its hydrochloride melting at 245 ° C and sublimal), 4-exo-hydroxy-8-chloro-9-nitro-11-anti-methylaminobenzo [b] bicyclof 3.3.1-ionone (its hydride is melted at 250-270 ° C with decomposition),

4-exo-hydroxy-8-nitro-9-chloro-11-anti-methylaminobenzo [b] bicyclo [3.3.1] nonene HCl, m.p. 252-258 ° C (dec.).

Example 7

8-Bromo-4-exo-hydroxy-11-anti-methylaminobenzo [b] bicyclo (3.3.1 jnonene · HCl g 4-exo-benzoyloxy-8-bromo-benzo [b] bicyclo [3.3.1] ionone-11) The mixture is cooled to room temperature, diluted with water and treated with 2N sodium hydroxide solution to give a yellow gum which is extracted with dichloromethane. The methylene chloride extracts were washed with water, dried and evaporated to give 5.97 g of a brown gum, which was dissolved in ethanol (120 ml) and refluxed with 10 ml of sodium hydroxide solution (12 ml) for 27 hours. After cooling to room temperature, diluting with saturated brine and extracting with dichloromethane, the methylene chloride extracts were washed with water, dried and evaporated in vacuo to yield 4.23 g of crude orange amine. crystallized from methylene chloride and a mixture of methanol and ether to give 1.30 g of pure 4-exo-hydroxy-8-bromo-11-anti-methyl20-aminobenzo [b] bicyclo [ 3.3.1 Jnonene hydrochloride is obtained in the form of colorless crystals.

264-270 ° C.

Example 8

4-exo-acetoxy-8-chloro-11-anti-methylaminobenzo [b] bicyclo [3.3.1] ionene · HCl g 4-exo-hydroxy-8-chloro-11-anti-methylaminobenzo [b] Bicyclo [3.3.1 jnone was allowed to stand for 1 hour in a mixture of 6 ml of perchloric acid, 10 ml of acetic anhydride and 20 ml of glacial acetic acid. The solution is then poured into ice water, solid potassium carbonate is added until alkaline and the product is extracted with dichloromethane, washed to neutral, dried and evaporated to dryness. This gives 4.7 g of 4-exo-acex toxin-8-chloro-11-antimethylaminobenzo [b] bicyclo [3.3.1] nonene as a gum. The product is dissolved in methylene chloride and the solution is filtered through acid washed alumina. The eluate was concentrated and saturated ethereal hydrogen chloride gas was added to the residue to precipitate 3.65 g of hydrochloride, which was crystallized from methanol-ethyl acetate. 3.1 g of 4-exo-acetoxy-8-chloro-11-anthiomethylaminobenzo [b] bicyclo [3.3.1] mononene hydrochloride are thus obtained in the form of prisms. Mp 256 ° C.

The following compounds were prepared in a similar manner:

4-exo-acetoxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] non-HCl, m.p. 256 ° C,

4-endoacetoxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] non-HCl, m.p. 259-263 ° C,

4-exo-acetoxy-8,9-dichloro-11-enimylaminobenzo [b] bicyclo (3.3.1) nonene · HCl, m.p. 247-253 ° C.

4-exo-acetoxy-8-tert-butyl-11-anti-methylaminobenzo (b) bicyclo [3.3.1] non-HCl, m.p. 249 ° C (dec.).

Example 9 Example 12

4-Exo-benzoyloxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene · HCl

3.3 ml of benzoyl chloride was added dropwise

To a solution of 4.8 g of 4-exo-hydroxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene in 20 ml of trifluoroacetic acid was stirred at room temperature for 7 hours and then poured onto ice . Solid sodium carbonate is then added until alkaline and the product is extracted with ethyl acetate. The extract was washed with 2M sodium hydroxide solution and then with water to pH 7, then dried and evaporated. This gives 5.0 g of a gum which is crystallized from ether to give 3.2 g of 4-exo-benzoyloxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene.

The crystalline product is treated with a saturated ethereal hydrogen chloride gas solution in methylene chloride to give 4-exo-benzoyloxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene-HCl. M.p. 213-220 ° C.

Example 10

When the 4-hydroxy-11-amino and 11-methylamino compounds are treated with the corresponding acyl halide as described in Example 9, the following compounds are prepared:

4-exo-benzoyloxy-8-chloro-11-anti-methylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 252-254 ° C.

4-exo- (2,2-dimethylpropionyloxy) -8-chloro-11'-aminobenzo [b] bicyclo [3.3.1] nonene HCl, m.p. 268-272 ° C.

Example 1

4-exo-hydroxy 8,9-dichloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl

16.6 g of 4-exo-hydroxy-8,9-dichloro-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene 16.6 ml of formic acid and

A solution of 15.5 ml of a mixture of formalin is refluxed for 2 hours, diluted with water, then an excess of potassium bicarbonate solution is added and extracted with dichloromethane. The extract is washed with water to neutral, dried and evaporated. The residue was recrystallized from ether to give 16.2 g of 4-exo-hydroxy-8,9-dichloro-11-antimethylaminobenzo [b] bicyclo [3.3.1] nonene. 133-135 ° C. The product was dissolved in methylene chloride and a saturated ethereal hydrogen chloride solution was added to give the hydrochloride. M.p. 248-273 ° C.

The same compound is obtained when a mixture of 4-exo-benzoyloxy-8,9-dichlorobenzo [b] bicyclo [3.3.1] nonen-11-one and dimethylformamide in formic acid is refluxed as described in Example 7. 65

4-Hydroxy-11-dimethylaminobenzo [b] bicyclof 3.3.1 Jnones

Starting from the desired 4-hydroxy-11-aminobenzo [b] bicyclo [3.3.1] nonene, which is unsubstituted in the phenyl ring or 8,9-dichloro, 8-methoxy, 8-hydroxy in the phenyl ring, Containing 9-chloro or 10 8,10-dichloro, the following 11-dimethylamino compounds were prepared as described above.

4-exo-hydroxy-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 280 ° C (sublimal), 4-exo-hydroxy-8-methoxy-11-anti- -dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 216 ° C (sublimal),

4-endo-hydroxy-8,9-dichloro-11-anti-dimethylamino-20-benzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 265 ° C (dec.),

4-exo-8-dihydroxy-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 285 ° C (dec.),

4-exo-hydroxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 252-273 ° C (dec.),

4-exo-hydroxy-9-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 255 ° C (sublimal), 4-exo-hydroxy-8.10 -dichloro-11-syn-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 232 ° C (dec.).

Example 13

4-Exoacetoxy-8,9-dichloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl

4.0 g of 4-exo-hydroxy-8,9-dichloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene are acetylated with 8 ml of acetic acid in 8 ml of pyridine at room temperature to give 4-exo-acetoxy- 8,9-dichloro-1,1-anti-dimethyl] aminobenzo [b] bicyclo [3.3.1] nonene is obtained in a yield of 4.4 g, m.p. 122.5-124 ° C. This compound was dissolved in methylene chloride and treated with ethereal hydrogen chloride gas to give the hydrochloride. Mp 234-279 ° C.

Example 14

4-Hydroxy-11-dimethylaminobenzo [b] bicyclo [3.3.1] ionone ester derivatives

Starting from the desired 4-hydroxy-11-dimethylaminobenzo [b] bicyclo [3.3.1] nonene compound which is unsubstituted on the phenyl ring or 8-methoxy, 8-bromo, 8-chloro or 8-methyl in the phenyl ring containing a substituent group, the following 4-hydroxy-11-dimethylamino compounds can be prepared as described above:

4-exo-acetoxy-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 260 ° C (sublimal),

4-exo-benzoyloxy-11-anti-dimethylamino-benzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 248-253 ° C (dec.),

4-exo- (2,2-dimethylpropionyloxy) -11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 228 ° C (sublimal),

4-exo- (1-phenylpropionyloxy) -1-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 260-263 ° C.

4-exo-cinnamoyloxy-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 265 ° C (dec.),

4-exo-decanoyloxy-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 217-225 ° C.

4-exo-acetoxy-8-bromo-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 252 ° C (dec.),

4-endo-benzoyloxy-8-chloro-11-syn-dimethylaminobenzo [b] bicyclo [3.3.1] ionone HCl, m.p. 264-266 ° C.

4-exo- (2,2-dimethylpropionyloxy) -8-chloro-1,1-antimethylaminobenzo [b] bicyclo [3.3.1] ionone · HCl, m.p. 178-183 ° C.

4-exo- (1-phenylpropionyloxy) -1-1-anti-dimethylaminobenzo [b] bicyclo [3.3.1] mononene · HCl, m.p. 260-263 ° C.

4-endo-benzoyloxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyldolo [3.3.1] nonene · HCl, m.p. 286-289 ° C.

4-exo-acetoxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene-HCl, m.p. 294-296 ° C.

4-exo-benzoyloxy-8-chloro-11-anthi-dimethylaminobenzo [b] bicyclo [3.3.1] nonene-HCl, m.p. 258-265 ° C.

4-exo-benzoyloxy-8,9-dichloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 224-229 ° C.

4-exo- (2,2-dimethylpropionyloxy) -8,9-dichloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 193-200 ° C (dec.) .

4-exo-acetoxy-8-tert-butyl-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] ionone HCl, m.p. 221 DEG C. (dec.),

4-exo-benzoyloxy-8-tert-butyl-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] ionone · HCl, m.p. 235 ° C (dec.),

4-exo-decanoyloxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene-HCl, m.p. 249-251 ° C.

Example 15

4-Exoacetoxy-11-anti-acetic acid doobenzo [b] bi-cycloph 3.3.1 Jnone g 4-exo-hydroxy-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene It is suspended in 40 ml of acetic anhydride and the mixture is stirred for 1 hour at room temperature and then poured into water. The solid was collected and dried to give 12.6 g of 4-exoacetoxy-11-anti-acetamidobenzo [b] bicyclo [3.3.1] nonene.

M.p. 213-214 ° C.

-exo-benzoyloxy-8-chloro-1,1-anti-aminobenzo [b] bicyclo [3.3.1] monomer suspended in 4-exo-benzoyloxy-8-chloro-11-anti-acetamido- benzo [b] bicyclo [3.3.1 gives Jnonene.

Mp 224-227 ° C.

A mixture of 4-exo-benzoyloxy-8-chloro-11-anti-aminobenzo [b] bicyclo [3.3.1] ionone and benzoyl chloride is stirred in toluene and 4-exo-benzoyloxy-8-chloro-11-anti-benzoylamino benzo [b] bicyclo [3.3.1] lonone is obtained. Melting point: 220-222 ° C.

Example 16

4-Exo-hydroxy-11-anti-ethylaminobenzo [b] bicyclof3.3.1 Jnonene · HCl

To a suspension of 3.3 g of lithium aluminum hydride in dry tetrahydrofuran was added a warm suspension of 12.5 g of 4-exoacetoxy-11-anti-acetamido-benzo [b] bicyclof.3.3.1 Jnonene in tetrahydrofuran and 300 ml of dioxane and reflux for 2 hours. during their yarn. Excess lithium aluminum hydride is decomposed by addition of water, the mixture is filtered and the filtrate is 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. 12 g of 4-exo-hydroxy-11-antiethylamino-benzo [b] bicyclo [3.3.1] -nonene hydrochloride are thus obtained.

Melting point:> 265 ° C.

Example 17

4-Exo-hydroxy-11 -anti-N-methyl-N- (3-methyl-but-2-enyl) -aminobenzo [b] bicyclo [3.3.1] mononene hydrochloride

To a suspension of 5.5 g of 4-exo-hydroxy-11-anti-methylaminobenzo [b] bicyclo [3.3.1] nonene and 5.0 g of potassium bicarbonate in 10 ml of dimethylformamide and 1 ml of methylene chloride are added dropwise with stirring, A solution of 1-bromo-3-methyl-but-2-n-5 ml in 10 ml of dimethylformamide was added while maintaining the mixture at room temperature. The reaction mixture was stirred for an additional 15 minutes and then poured into water and the product was extracted with dichloromethane. The extract was washed with water, dried and evaporated to give an oil which was chromatographed on alumina. Benzene was eluted with 5 g of an oil which was dissolved in ether and treated with saturated ethereal hydrogen chloride. The resulting solid was recrystallized from methanol-ether to give 3.1 g of 4-exo-hydroxy-11-anti-N-methyl-N- (3-methylbut-2-enyl) aminobenzo [b] ] bicyclo [3.3.1] nonene hydrochloride is obtained. Melting point: 258-259 ° C.

4-exo-hydroxy-8-chloro-9-nitro-11-anti-formamidobenzo [b] bicyclo (3.3.1) nonene · HCl, m.p. 248 ° C.

4-exo-hydroxy-8-tert-butyl-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] ionone, m.p. 230 DEG C. (dec.),

4-exo-decanoyloxy-8-chloro-11-anti-dimethylamino-benzo [b] bicyclo [3.3.1] -nonene · HCl, m.p. 249-251 ° C (dec.).

Example 18

In a similar manner to that described in Example 1, various benzo [b] bicyclo [3.3.1] nonene derivatives were prepared by 4-exo-benzoyloxy-8-chlorobenzo [b] bicyclo [3.3.1] nonen-11- is reacted with the desired amine of formula (III) in the presence or absence of formic acid in the presence or absence of a suitable inert solvent.

Thus, the following compounds are prepared:

4-exo-benzoyl-8-chloro-11-anti-morpholinobenzo [b] bicyclo [33.1] mononene (hydrochloride m.p. 283-290 ° C),

4-Exo-benzoyl-8-chloro-11-anti-pyrrolidinobenzo [b] bicyclo [3.3.1] ionone (hydrochloride melting point 260 ° C with decomposition).

Example 19

In the case where 4-hydroxybenzo [b] bicyclo [3.3.1] nonene-11-oxime derivatives are reduced with sodium in isopropanol, the corresponding primary amines of formula (I) are obtained. The oximes are prepared by reacting 4- (endo or exo) benzoyloxy-benzo [b] bicyclo [3.3.1] -one-11-one derivatives with hydroxylamine * HCl in a mixture of sodium hydroxide and ethanol. The following compounds were obtained:

4-exo-hydroxy-8-methoxy-11-anti-aminobenzo [b] bicyclo [3.3.1] anonene · HCl, m.p. 256-258 ° C.

4-exo-hydroxy-8,9-dichloro-11-anti-aminobenzo [b] bicildo [3.3.1] -nonene · HCl, m.p. 286-300 ° C.

4-exo-hydroxy-11-anti-aminobenzo [b] bicyclo [3.3.1] nonene · HCl, sublimation> 265 ° C.

Example 20

The following compounds were prepared as described in 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-formamidobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 269-272 ° C.

4-exo-p-nitrobenzoyloxy-8-nitro-9-chloro-11-anti-formamidobenzo [b] bicyclo [3.3.1] nonene · HCl, m.p. 276-279 ° C (dec.),

4-exo-p-nitrobenzoyloxy-9-chloro-10-nitro-11 • anti-formamidobenzo [b] · bicyclof.3.3.1 Jnonene · HCl, m.p. 253-262 ° C (dec.),

4-endo-p-nitrobefluoyloxy-8-nitro-9-chloro-11-anti-formamidobenzofibrobicyclof 3.3.1 Jnonene · HQ, m.p.

Example 21 (-) - 4-Exo-benzoyloxy-8-chloro-11-anti-dimethylaminobenzo (b) bicyclo [3.3.1] mononene hydrochloride

To a suspension of the racemic compound (64.0 g) was added a solution of sodium bicarbonate (15.0 g) in water (800 ml). The mixture was extracted with methylene chloride, and the extract was washed with water, dried and evaporated to dryness. 58.2 g of the free base are obtained, which is then crystallized from methanol. The resulting free amine (55.0 g) had a melting point of 109-110 ° C.

A solution of 47.0 g of the above racemic amine in 1000 ml of ethanol is added to a solution of 23.5 g of dibenzoyl tartaric acid ([α] _D = - 110 ° C) in 100 ml of ethanol. The solution was cooled to give a crystalline product. This was separated from the mother liquor and used for the next experiment, while 29.6 g of crystalline material was suspended in 250 ml of methylene chloride. The suspension is 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 concentrated in vacuo. 16.2 g of (-) 4-exo-benzoyloxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] amonene are obtained in the form of an oil.

[α] D = -2.63 °.

To a solution of (-) - 4-exo-benzoyl-8-chloro-11-anti-dimethylaminobenzo [b] bicyclonone (16.0 g) in ether (250 ml) was added ether saturated with hydrochloric acid (40 ml). The precipitated solid is filtered off, washed with food and crystallized from methanol. There was thus obtained 14.1 g of (-) - 4-exo-benzoyl-8-chloro-11-anthime-thiaminobenzo [b] bicyclononene hydrochloride, m.p. 278-278.5 ° C.

[?] J = 7.2 °.

(+) - 4-Exo-benzoyloxy-8-chloro-1-anhydridylmethyl-4-enzo [b] bicyclo [3.3.1] mononene hydrochloride

A suspension of 40.0 g of mother liquor from the previous experiment in 330 ml of methylene chloride is added to a solution of 7.5 g of sodium carbonate in 330 ml of water. The mixture is stirred until clear. This is about 15 minutes. The organic layer was separated, washed with water, dried and evaporated to dryness. 32.2 g of the free base are obtained, which is dissolved in 900 ml of hot ethanol. To this solution is added 19.0 g of dibenzoyl tartaric acid (1 <*] ΐ) ⁼ ) in 100 ml of hot ethanol. After cooling, 30.3 g of crystalline material precipitated out of solution. This was collected and suspended in 250 ml of methylene chloride. The suspension is added to a solution of 1.0 g of sodium carbonate in 250 ml of water and stirred for 15 minutes. The organic layer was separated, washed with water, dried and concentrated in vacuo. 16.5 g of (+) - 4-exo-benzoyloxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] · nonene are obtained in the form of an oil.

[α] _D = + 2.84 °.

The hydrochloric acid salt is formed to give 18.2 g of i +) - 4-exo-benzoyloxy-8-chloro-11-anti-dimethylaminobenzo [b] bicyclo [3.3.1] nonene hydrochloride. Melting point: 277.5-278.5 ° C.

[α] _D = + 6.7 °.

Claim:

Claims (1)

Claim: A process for the preparation of benzo [b] bicyclo [3.3.1] nonene derivatives of the formula I and their pharmaceutically acceptable salts and optical isomers, wherein R ₍ and R _{2) are} hydrogen, (C 1 -C 4) -alkyl, (C 2 -C 5) -alkenyl, (C 1 -C 4) -alkanoyl or phenyl (C 1 -C 4) -alkanoyl, or R 1 and R _{2 taken} together with the nitrogen atom to which they are attached represent a five or six membered heterocyclic ring optionally containing an additional heteroatom, R ₃ is hydroxy, C 1-10 aliphatic or phenyl (C 1-4) aliphatic alkanoyloxy, X and Y are hydrogen, hydroxy, halo, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, nitro or -CF ₃ ; a) a compound of formula II wherein R ₃ , X and Y are as defined above, in the presence of a reducing agent, formamide, N-alkylformamide or a N, N-dialkylformamide having a C 1-4 alkyl moiety or a compound of general formula III; with a compound of formula which latter compounds wherein R 'apart _and R₁ is an alkanoyl, and phenyl alkanoyl group at the same R, and R ₂ or represents b) for the preparation of compounds of formula I wherein R ₁ and R _{2 are} hydrogen, a compound of formula IV wherein R 1 is hydroxy or C 1-4 alkoxy, while R ₃ , X and Y are within the scope of the present invention. is reduced, if desired i) a compound obtained according to process variant a), wherein R or R ₂ formyl group, optionally hydrolysed or reduced to the compound is or b) resulting variant, in which R ₃ is a hydroxyl group and / or R or R ₂ hydrogen, optionally acylated, and / or ii) alkylation of the resulting compound wherein R) or R _{2 is} hydrogen, optionally directly or by acylation and subsequent reduction, and / or conversion of the resulting compound into a pharmaceutically acceptable salt, if desired; and, if desired, separating the resulting compound into diastereomeric isomers and / or optical antipodes, before or after the subsequent reactions. 1 sheet with formulas Responsible for publishing: Director of Economic and Legal Publishing 814158 - Zrínyi Printing House, Budapest * International classification: C 07 C 87/45, C 07 D 295/00