DE2210799A1 - Hexahydro-oxa or aza benzocyclononones - with cns anti-inflammatory and hypertensive activity - Google Patents

Abstract

Hexahydro-benzocyclononenes of formula (I): (where X is O and R' and R2 are different; R' being OH and R2 being 1-6C alkoxy; 7-9C aralkoxy; amino carrying a 1-6 C alkyl, 3-6C cycloalkyl or 7-9C aralkyl residue; or hydrazino opt. substd. by aryl, or R' and R2 are identical, and are amino groups carrying a 1-6C alkyl, 3-6C cycloalkyl or 7-9C aralkyl residue; amino groups derived from a 5- to 7-membered secondary cyclic amine; or hydrazino opt. subst. by aryl; or X is imino and R' and R2 are each OH). (I) have anticonvulsant, sedative, analgesic or anti-inflammatory activity. (I; X= O, R'=R2=pyrrolidino) also has hypertensive activity.

Description

5.9: 7, iI-Dimethano-8-hetero-iiH-5.6.7.8.9.iO-hexahydrobenzo-cyclononenes The invention relates to new 5,9: 7,11-Dimethano-8-hetero-11H-5.6.7.8 .9.10-hexahydro-benzo-cyclononenes of the formula I. in which X is oxygen and R1 and R2 are different, where R1 is hydroxyl and R2 is an alkoxy radical with 1 to 6 carbon atoms, an aralkoxy radical with 7 to 9 carbon atoms, an amino group which is a straight-chain or branched alkyl radical with 1 to 6 carbon atoms, carries a cycloalkyl radical with 3 to 6 carbon atoms in the ring or an aralkyl radical with 7 to 9 carbon atoms, or a hydrazino radical optionally substituted by aryl, or R1 and R2 are the same and each stand for an amino group which carries the substituents mentioned or is from one secondary cyclic amine with 5 to 7 ring members, or a hydrazino radical optionally substituted by aryl, or X denotes an imino radical and R1 and R2 each represent a hydroxyl group.

The formula given are examples of alkoxy radicals with 1 to 6 carbon atoms methoxy, ethoxy, propoxy or butoxy.

As aralkoxy radical with 7 to 9 carbon atoms come in particular a benzyl or phenylethyl radical into consideration.

Amino groups with a straight-chain or branched alkyl, Aralkyl or cycloalkyl radical are derived from primary amines, such as methylamine, ethylamine, n-propyl- and iso-propylamine, n-butyl-, iso-butyl- and sec-butylamine, benzylamine, Phenylethylamine, cyclopropylamine, cyclobutylamine, cyclpentylamine, cyclohexylamine.

Preferred hydrazino radicals are derived from unsubstituted hydrazine themselves and as arylhydrazines of optionally substituted phenylhydrazines.

For the compounds with secondary cyclic amines for R1 and R2 Pyrrolidino, piperidino and morpholino radicals are appropriate.

As examples of 7-hydroxy-9-alkoxy, 7-hydroxy-9-aralkoxy, and on the N-substituted 7-hydroxy-9-amino- and substituted 7, 9-diamino-8-oxahexahydro-benzo-cyclononenes of the formula I the following compounds may be mentioned: 7-hydroxy-9-methoxy-, 7-hydroxy-9-n-propoxy-, 7-hydroxy-9-n-butoxy, 7-hydroxy-9-iso-butoxy, 7-hydroxy-9-benzyloxy, 7-hydroxy-9-phenylethyloxy, 7-hydroxy-9-methylamino, 7-hydroxy-9-ethylamino, 7-hydroxy-9-n-propylamino, 7-hydroxy-9-isopropylamino, 7-hydroxy-9-n-butylamino, 7-hydroxy-9-isobutylamino, 7-hydroxy-9-benzylamino, 7-hydroxy-9-phenethylamino, 7-hydroxy-9-hydrazino, 7-hydroxy-9-phenylhydrazino, 7, 9-diphenylhydrazino, 7,9-diethylamino, 7,9-di-n-butylamino, 7,9-diisobutylamino, 7,9-dicyclohexylamino and 7,9-dipiperidino-5,9: 7,11-dimethano-8-oxa-11H-5,6,7,8,9,10-hexahydro-benzocyclonones.

The 7-hydroxy-9-alkoxy derivatives are preferred compounds highlighted, in particular 7-hydroxy-9-ethoxy-5,9: 7,11-dimethano-8-oxa-11H-5o678b9,10-hexahydrobenaxyclonone and the derivatives substituted by nitrogen in the 7- and 9-positions, in particular 7,9-dipyrrolidino, 7,9-dimorpholino and 7,9-dihydrazino-8-oxa compounds and the 7, 9-dihydroxy-8-aza compound.

The compounds according to the invention are obtained by using the diketone of the formula II with alcohols with 1 to 6 carbon atoms, araliphatic alcohols with 7 to 9 carbon atoms, primary amines which have a straight-chain or branched alkyl radical with up to 6 carbon atoms, a cycloalkyl radical with 3 to 6 carbon atoms in the ring or an aralkyl radical with 7 to 9 carbon atoms, or with secondary cyclic amines having 5 to 7 ring members or with optionally phenyl-substituted hydrazines or with ammonia in a solvent at higher temperatures, optionally in the presence of a catalyst.

When implementing the initial diet alcohol is a basic one Catalyst very useful. Secondary and tertiary such as dimethylamine, diethylamine, piperidine, trimethylamine and triethylamine or alkali alcoholates, in particular lithium, sodium or potassium alcoholate, of the alcohol in question can be used advantageously. The reaction can take place in one of the reaction conditions inert solvent such as benzene or toluene, or in an excess of the relevant Alcohol can be carried out as a solvent at the same time. In general, the reaction by heating to elevated temperatures, wa from 50 to 100 ° C, preferably accelerated to 60 to 80 ° C and completed the reaction at elevated temperature.

When reacting the starting diketone with primary amines, hydrazines or arylhydrazines, preferably at temperatures from 50 to 90,000, are compounds where R¹ is hydroxyl.

For example, hydrocarbons, such as benzene or toluene, halogenated hydrocarbons such as chloroform or carbon tetrachloride, or lower alcohols such as methanol, ethanol or propanols, or excess Amine can be used as a solvent, With ammonia as a reaction partner of the initial diketone in alcoholic solutions containing ammonia can be reached under the conditions described for the 7,9-dihydroxy-8-aza compound.

To represent the symmetrically substituted compounds in which the substituents R¹ and R² are the same, the starting diketone is usually under otherwise the same conditions with primary or secondary amines, hydrazines or Arylhydrazines at temperatures above 100 ° C, expediently between 100 and 180 Or, optionally implemented in a pressure vessel. The implementation can in the presence of a acidic catalyst, such as benzenesulfonic acid or p-toluenesulfonic acid or the hydrochloride of the amine in question, take place, the catalyst reducing the reaction temperature contributes. The reaction usually takes place at the boiling point under normal pressure of the reaction mixture or under increased pressure, for example by heating in a closed vessel. Secondary acyclic amines as well as hydrazine and aryl hydrazines often convert at temperatures below 100 ° C., for example at temperatures from boiling chloroform or from boiling benzene.

In a further embodiment for the preparation of compounds in which X = 0 and R1 and R² are the same and have the meaning mentioned, a compound of the formula III is used under the conditions described instead of the starting diketone of the formula II in which R3 is a hydroxyl, alkoxyl or alkylamino radical, used as the starting product.

Examples are: 7,9-dihydroxy-, 7-hydroxy-9-methylamino-, 7-hydroxy-9-ethylamino-, 7-hydroxy-9-methoxy- and 7-hydroxy-9-ethoxy-5,9: 7,11-dimethano-8 @@ - 11H-5,6,7,8, 9,10-hexahydrobenzocyolonones.

The production of the starting diketone is for example in Tetrahedron Bettes 1969, 2355. The starting diketone is obtained by recrystallization from water the 7,9-dihydroxy-8-oxa compound available.

The compounds of this invention show in animal studies, for example on dogs and cats, valuable pharmacological properties. They prefer to take action on the central nervous system, chemo-convulsions or electrically-induced convulsions can occur weaken or prevent or have a sedative, analgesic or anti-inflammatory effect. Particularly noteworthy is also one for the dipyrrolidino-8-oxa compound Hypertensive effect on anesthetized animal.

The pharmaceutical processing of the compounds according to the invention the usual application forms, such as solutions, emulsions, tablets, coated tablets or forms of depot in a known manner using the auxiliary, Carriers, disintegrants, binders, coatings or lubricants, flavorings, sweeteners, Means to achieve a depot effect or solubilizers happen.

Example 1 In a suspension of 10 g of starting diketone in 100 ml Ethanol is passed in for 3 hours at 60 ° C. dimethylamine as a basic catalyst and the reaction mixture is then concentrated to 1/3 of the initial volume. the Crystals which have precipitated out are filtered off with suction and recrystallized from benzene. You get 10.3 g of a compound with a melting point of 195 to 196 00, in which X = O, R1 = OH and R2 = C2.

Example 2 In a mixture of 8 g of starting diketone and 5.0 g of β-phenylethanol and 160 ml absol. Benzene is passed in dimethylamine for 3 hours at 60.degree. The reaction mixture is then concentrated to half and the crude crystals recrystallized from benzene. 8.15 g of a compound with a melting point are obtained 122 to 124 ° C, in which X = O, R1 = OH and R² = OCH2CH2-C6H5.

Example 3 2 g of starting diketone are suspended in 25 ml of ethanol.

This suspension is gassed with methylamine at 60 ° C. for 3 hours. Afterward the reaction mixture is evaporated and the residue is recrystallized from benzene. 1.2 g of a compound with a melting point of 128 to 129 oC (decomposition) are obtained, where X = O, R1 = OH and R2 = NHCH3.

Example 4 A mixture of 3 g starting diketone, 1.5 g benzylamine and 50 ml of benzene is refluxed for 3 hours. The one when it cools down Crystals precipitating out give 3.7 g of a compound on recrystallization from benzene from melting point 137 to 138 00, in which X = O, R1 = OH and R2 = NHCH2C6H5.

Example 5 A solution of 11.3 g of the starting diketone and 12.8 g β-Phenylethylamine in 300 ml of benzene is heated to reflux temperature for 3 hours. The crude product which precipitates out when the reaction mixture is concentrated becomes benzene recrystallized. The yield is 11.5 g of a compound having a melting point 108 to 110 ° C in which X = O, R1 = OH and R2 = NHCH2CH2C6H5.

Example 6 A solution of 7 g of starting diketone and 3.3 g of phenylhydrazine in 50 ml of ethanol is heated to reflux temperature for 2 hours. Crystallize on cooling 9.7 g of a compound with a melting point of 156 to 157 oC (from ethanol), in which X = Is 0, R = OH and R2 = NHNHC6H5.

Example 7 10 g of starting diketone are saturated with ammonia in 125 ml Ethanol stirred for 3 hours at 60 to 65 0. The deposited precipitate is sucked off. 8.7 g of a compound with a melting point of 175 to 176 ° C (decomposition) are obtained, where X = NH, R¹ and R² are each OH. The hydrochloride melts at 190-192 00.

Example 8 A mixture of 10 g starting diketone, 15 g pyrrolidine and 300 ml of chloroform is boiled for 4 hours on a water separator. From the evaporation Remaining crude product (melting point 144 to 147 ° C.) is obtained by recrystallization Sation from petroleum ether 6.2 g bucket advertising binding with a melting point of 154 to 155 oC (decomposition) in which X = 0, R1 and R2 each denote the pyrrolidino radical.

Example 9 8 g of starting diketone and 80 ml of morpholine are placed in a pressure vessel Heated to 140 0 for 6 hours. After cooling, the precipitated product becomes filtered off and recrystallized from ethanol. 4.2 g of a compound are obtained from melting point 197 to 200 ° C (replacement), in which X = O and R1 and R2, respectively mean the morpholino radical.

Example 10 Following the same procedure as described in Example 9, 10.2 g of a compound are obtained from 15 g of starting diketone and / 100 ml of isobutylamine from melting point 111 to 112 ° C (from petroleum ether), in which X = 0 and R1 and R², respectively mean the isobutylamine radical.

Example 11 N h the same procedure as described in Example 9, 9.7 g of a compound are obtained from 10 g of starting diketone and 100 ml of cyclohexyl amine from melting point 123 to 124 oC (from ethyl acetate), in which X = 0 and R1 and R² respectively mean the cyclohexylamino radical.

Example 12 A mixture of 5 g of starting diketone, 11.5 g of hydrazine hydrate and 125 ml of benzene is refluxed for 3 hours. When cooling down 5.6 g of a compound with a melting point of 148 ° C. (decomposition) precipitate, in which X = O and and R2 each represent the hydrazino radical Example 13 2 g a 7-hydroxy-9-N-methylamino-8-oxa compound corresponding to formula III and 2,3 g of pyrrolidine are heated to reflux temperature in 100 ml of chloroform for 4 hours.

The reaction mixture is evaporated and the residue from ethyl acetate recrystallized. The yield is 1.1 g of a compound with a melting point of 154 OC (decomposition), in which X = O and R1 and R2 each represent the pyrrolidino radical.

Example 14 Corresponding to 2 g of a 7,9-dihydroxy-8-oxa compound of the formula III and 3 g of pyrrolidine are refluxed in 150 ml of chloroform for 4 hours heated. The resin remaining when the reaction mixture is evaporated becomes out Recrystallized ethyl acetate with the addition of activated charcoal. The yield is 1.2 g of a compound with a melting point of 154 ° C. (decomposition), in which X T 0, and R1 and R2 in each case denote the pyrrolidino radical.

Claims (7)

K> claims 1. 5,9: 7,11-Dimethano-8-hetero-11H-5.6.7.8.9.10-hexahydrobenzocyclononenes of the formula in which X is oxygen and R and R2 are different, where R1 is hydroxyl and R2 is an alkoxy radical having 1 to 6 carbon atoms, an aralkoxy radical having 7 to 9 carbon atoms, an amino group which is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms Cycloalkyl radical with 3 to 6 carbon atoms in the ring or an aralkyl radical with 7 to 9 carbon atoms, or a hydrazino radical optionally substituted by aryl, or R and R are the same and each represent an amino group which carries the substituents described or is derived from a secondary cyclic amine having 5 to 7 ring members, or a hydrazine radical optionally substituted by aryl, or X is an imino radical and R1 and 2 each represent a hydroxyl group. 2. 5,9: 7,11-dimethano-8-oxa-11H-5,6,7,8,9,10-hexahydro-benzocyclonones according to claim 1, in which R1 and R2 each represent the pyrrolidino radical. 3. 5,9: 7,11-dimethano-8-oxa-11H-5,6,7,8,9, iO-hexahydro-benzocyclonones according to claim 1, in which R1 and R2 each represent the morpholino radical. 4. 5,7: 9,11-dimethano-8-oxa-11H-5,6,7,8,9,10-hexahydro-benzocyclonones according to claim 1, in which R1 and R2 each represent a hydrazino radical. 5. Pharmaceutical preparations containing as active ingredient one of the compounds specified in claims 1 to 4. 6. Process for the preparation of the compounds given in claim 1, characterized in that the diketone of the formula with alcohols, amines or hydrazines in a solvent at higher temperatures, if appropriate in the presence of a catalyst. 7. A process for the preparation of the 1 2 compounds indicated in claim 1, in which X 3 0 and R and R are each identical and have the meanings mentioned, characterized in that a compound of the formula in which R is hydroxy, alkoxy or alkylamino, is reacted with primary or secondary amines or hydrazines at elevated temperatures.