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Publication numberUS3304307 A
Publication typeGrant
Publication dateFeb 14, 1967
Filing dateSep 12, 1963
Priority dateSep 12, 1963
Publication numberUS 3304307 A, US 3304307A, US-A-3304307, US3304307 A, US3304307A
InventorsMizzoni Renat Herbert
Original AssigneeCiba Geigy Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Dibenzocycloalkadienes
US 3304307 A
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Description  (OCR text may contain errors)

United States Patent 3,304,307 DIBENZOCYCLOALKADIENES Renat Herbert Mizzoni, Long Valley, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 12, 1963, Ser. No. 308,332 10 Claims. (Cl. 260-2943) The present invention has for its object dibenzocycloalkadiene compounds, in which the cycloalkadiene portion has from five to seven ring members, and one of its carbon atoms, connecting together the two benzo portions, is substituted by an amino-lower alkyl radical, in which amino is separated from the ring carbon atom by at least two carbon atoms, and by bydroxymethyl or acyloxymethyl, in which acyl is the radical of an organic carboxylic acid, or the salts of such compounds, as well as N-oxides of the compounds having N-oxide-forming amino groups, the salts of N-oxides of the compounds having N-oxide-forming amino groups, or quaternary ammonium derivatives of compounds having quaternary ammonium derivative-forming amino groups.

These compounds are represented by the compounds of the following formula P Phz in which each of the groups of Ph and Ph is a 1,2- phenylene (or o-phenylene) radical, the group A is a direct bond between the two groups Ph and Ph2, lower alkylene separating the groups Ph and Ph by at most two carbon atoms, or lower alkenylene separating the groups Ph and Ph by two carbon atoms, Am is an amino group, the group of the formula (C,,H is lower alkylene separating Am from the ring carbon atom by at least two carbon atoms, and R is hydrogen or the acyl radical of an organic carboxylic acid, or the salts of such compounds, as well as N-oxides of the compounds having N-oxide-forming amino groups, the salts of N- oxides of the compounds having N-oxide-forming amino groups, or quaternary ammonium derivatives of compounds having quaternary ammonium derivative-forming amino groups. Also included within the scope of this invention is the procedure for the manufacture of the above compounds.

The benzo portions of the compounds of this invention, represented in the above formula by the 1,2-phenylene radicals P11 and Phg, are unsubstituted or substituted by one or more than one of the same or of different substituents which may be attached to any of the positions available for substitution. Such substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and the like, etherified hydroxyl, especially lower alkoxy, e.g. methoxy, et-hoxy, n-propyloxy, isopropyloxy and the like, as well as lower alkenyloxy, e.g. allyloxy and the like, lower alkylenedioxy, e.g. rnethylenedioxy, 1,1-ethylenedioxy and the like, or any other etherified hydroxyl group, esterified hydroxyl, particularly halogeno (representing hydroxyl esterified by a hydrohalic acid), e.g. fiuoro, chloro, bromo and the like, or halogenolower alkyl, e.g. trifiuoromethyl (a pseudohalogeno group) and the like. Representative 1,2-phenylene groups Ph and Ph in the above formula are above all 1,2-phenylene, (lower alkyl)-1,2-phenylene, (etherified hydroxy)-l,2-phenylene, particularly (lower alkoxy)-1,2-

phenylene, as well as (lower alkenyloxy)-l,2-phenylene or (lower alkylenedioxy)1,2-phenylene, (esterified hydroxy)-1,2-phenylene, particularly (halogeno)-1,2-phenylene or (halogeno-lower alkyl)-1,2-pheny1ene, such as (trifluoromethyl) -1,2-phenylene.

As mentioned above, the cycloalkadiene portion has from five to seven ring members, one of which connects together the two benzo portions. In case the cycloalkadiene portion has more than five ring members, the additional carbon atoms form a lower alkylene or a lower alkenylene radical between the two benzo portions. In the above formula, the radical A is, therefore, a direct bond between the groups Ph and Ph It may also stand for lower alkylene having preferably from one to three carbon atoms, which separates the groups Ph, and Ph by at most two carbon atoms, and stands for methylene, 1,1-ethy1ene, 1,2-ethylene, 1,1-propylene, 1,2-propylene and the like, or for lower alkenylene having preferably from two to three carbon atoms, which separates the groups Ph and Ph by at most two carbon atoms and is represented by 1,2-ethenylene or 1-methyl-1,2-ethenylene.

An amino group, represented in the above formula by Am, is an N-unsubstituted amino group, an N-monosubstituted amino group or an N,N-disubstituted amino group.

An N-monosubstituted amino group is, for example, N-aliphatic substituted amino, particularly N-lower alkylamino, e.g. N-methyl-amino, N-ethyl-amino and the like, N-cycloaliphatic substituted amino, such as N-cycloalkylamino, in which cycloalkyl has from three to eight, preferably from five to six, ring carbon atoms, e.g. N-cyclopropylamino, N-cyclopentlyamino, N-cyclohexylamino, N-cycloheptylamino and the like, N-cycloaliphatic-aliphatic-substituted amino, such as N-cycloalkyl-lower alkyl-amino, in which cycloalkyl has from three to eight, preferably from five to six, ring carbon atoms, e.g. N- cyclopropylmethylamino, N-cyclopentylmethylamino, N- cyclohexylmethylamino, N-( 2-cyc1ohexylethyl)-amino and the like, N-aromatic substituted amino, such as N-phenylamino and the like, N-aromatic aliphatic substituted amino, such as N-phenyl-lower alkyl-amino, e.g. N-benzylamino, N-(2-phenylethyl)-amino and the like, or any other suitable N-monosubstituted amino group.

An N-monosubstit'uted amino group is also N-acylamino, in which acyl is the radical of an organic carboxylic acid having from one to twelve carbon atoms; such acids are aliphatic acids, particularly lower alkanoic acids, e.g. acetic, propionic, butyric, isobutyric acid and the like, as well as carbocyclic aryl carboxylic acids, such as monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic, 4 methyl-benzoic, 3,4-dimethoxy-benzoic, 4- chloro-benzoic acid and the like, or heterocyclic aryl carboxylic acids, for example, mono'cyclic azacyclic aryl carboxylic acids, e.g. nicotinic, isonicotinic acid and the like, or any other suitable organic carboxylic acid.

An N,N-disubstituted amino group is, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N- ethyl-N-methylamino, N,N-diethylamino, N,N-di-n-propylamino and the like, as well as N-cycloalkyl-N-lower alkyl-amino, in which cycloalkyl has from three to eight, preferably from live to six, ring carbon atoms, e.g. N- cyclopentyl-N-methyl-amino, N-cyclohexyl-N-ethylamino and the like, N-lower alkyl-N-phenyl-lower alkyl-amino, e.g. N-benzyl-N-methyl-a-mino, N-methyl-N-(Z-phenylethyl)-amino and the like, or any other N,N-disubstituted amino group, such as, for example, N-hydroxy-lower alkyl-N-lower alkyl-amino, in which hydroxy is separated from amino by at least two carbon atoms, e.g. N-ethyl- N-(2-hydroxyethyl)-amino and the like, or N,N-di-hydroxy-lower alkyl-amino, in which hydroxy is separated from amino by at least two carbon atoms, e.g. N,N-di-(2- hydroxyethyl)-amino and the like. An N,N-disubstituted amino group may also be rep-resented by N,N-alkylene-imino, in which alkylene has from four to eight carbon atoms, e.g. l-pyrrolidino, l-piperidino, 2-methyl-1- piperidino, l-hexamethyleneimino, l-heptamethylene-imino and the like, N,N-oxalkylene-imino, in which alkylene has preferably four carbon atoms and the oxa-oxygen is separated from the imino group by two carbon atoms, e.g. 4-morpholino and the like, N,N-thia-alkylene-imino, in which alkylene has preferably four carbon atoms and the thiasulfur is separated from the imino group by two carbon atoms, e.g. 4-thiamorpholino and the like, or N,N- aza-al-kylene-imino, in which alkylene has from four to six carbon atoms, and in which the aza-nitrogen atom is separated from the imino group by at least two carbon atoms and may be substituted, for example, by lower alkyl, hydroxy-lower alkyl, acyl, carbo-loWer al koxy and the like, such as, for example, l-piperazino, 4-lower alkyl-piperazino, e.g. 4-methyl-l-piperazino and the like, 4-hydroxy-lower alkyl-piperazino, e.g. 4-(2-hydroxyethyl)-1-piperazino and the like, 4-acyl-piperazino, e.g. 4-acetyl-1-piperazino, 4-carbethoxy-l-piperazino and the like, as Well as any other 1-N,N(N-lower alkyl-azaalkylene)-imino group, e.g. 1-N,N-(3-aza-3-methyl hexamethylene)-imino, 1-N,N-(4-aza -,4-methyl-heptamethylene)-imino and the like.

An N,N-dis-ubstituted amino group may also be an N-substituted N-acyl-amino group, in which acyl is the acyl radical of an organic carboxylic acid, such as one of those previously mentioned, and the second substituent attached to the nitrogen atom is one of the aliphatic, cyc'loaliphatic, cycloaliphatic-aliphatic, carbocyclic aryl, or carbocyclic aryl-aliphatic radicals previously mentioned as substituting N-mono-substituted amino groups. N-substituted N-acyl-amino groups are, for example, N-lower alkanoyl-N-lower alkyl-am-ino, e.g. N-acetyl-N-methylamino and the like, or any other suitable N-su bstituted N-acyl-amino group.

The lower alkylene radical connecting the amino group with the ring carbon atom, represented in the above for.- mula by the group of the formula -(C,,H is lower alkylene, having from two to seven, preferably from two to four, carbon atoms separating the amino group, for example, the group Am, from the ring carbon atom by at least two, preferably by two to four, carbon atoms. It represents above all 1,2-ethylene, 1-methy1-1,2-ethylene, 2-methyl-1,2-ethylene, 1,3-propylene, 1-methyl-1,'3- propylene, 1,4-butylene and the like, as Well as 1,5- pentylene, 1,6-hexylene, 1,7-heptylene and the like.

The other substituent attached to the ring carbon atom connecting the two benzo radicals is preferably hydroxymethyl or an acyloxymethyl group, in which acyl is the radical of an organic carboxylic acid. The group R in the above formula representing primarily hydrogen, is also the acyl radical of an organic carboxylic acid having from one to twelve carbon atoms. Such acids are, for example, aliphatic carboxylic acids, such as alkanoic, particularly lower al kanoic, acids, e.g. formic, acetic, propionic, butyric, pivalic, heptanoic acid and the like, cycloalkane carboxylic acids, in which cycyloalkane has from three to eight, preferably from five to seven, ring carbon atoms, e.g. cyclopentane carboxylic acid, cyclohexane carboxylic acid and the like, or cycloalkyl-lower alkanoic acids, in which cycloalkyl has from three to eight, preferably from five to seven, ring carbon atoms, e,g. 3-cyclo-pentyl-propionic, cyclohexylacetic acid and the like, substituted alkanoic acids, such as, for example, halogeno-lower alkanoic acids, e.g. chloroacetic, dichloroacetic, trifluoroacetic, trichloroacetic acid and the like, or lower al-koxy-lower alkanoic acids, e.g. methoxyacetic acid and the like, carbocyclic aryl carboxylic acids, especially monocyclic carbocyclic aryl carboxylic acids, e.g. benzoic, 4-methyl-benzoic, 4-methoxy-benzoic, 3,4,5-trimethoxy benzoic, 4-O-ethoxy-carbonyl-syringic, 3,-4-dichloro-benzoic, 3-nitro-benzoic, 3-N,N-dimethylamino-benzoic acid and the like, or bicyclic aryl carboxylic acids, e.g. l-naphthoic, 2-naphthoic acid and the like,

carbocyclic aryl-aliphatic carboxylic acids, such as monocyclic carbocyclic aryl-lower alkanoic acids, e.g. phenylacetic, diphenylacetic, 3-phenyl-propionic, 4-methoxyphenyl-acetic acid and the like, or monocyclic carbocyclic aryl-lower alkenoic acids, e.g. cinnamic, 4-chloro-cinnamic, 3,4,5-trimethoxy-benzoic acid and the like, heterocyclic aryl carboxylic acids, such as monocyclic heterocyclic aryl carboxylic acids, e.g. nicotinic, isoniotinic, 2- furoic, Z-thienoic acid and the like, or heterocyclic arylaliphatic carboxylic acids, such as monocyclic heterocyclic aryl-lower alkanoic acids, e.g. 2-pyridyl-acetic, 2- thienyl-acetic acid and the like.

Salts of the compounds of this invention are acid addition salts thereof, for example, pharmaceutically acceptable, nontoxic acid addition salts, such as those with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or organic acids, such as organic carboxylic acids, e.g. formic, acetic, propionic, pivalic, glycolic, lactic, succinic, methyl-succinic, maleic, malic, tartaric, citric, benzoic, dihydro-cinnamic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z phenoxybenzoic, 2- acetoxybenzoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, ethane, 1,2-dicarboxylic, Z-hydroxyethane sulfonic, p-toluene sulfonic, naphthalene 2-sulfonic acid and the like. Other acid addition salts may be useful as intermediates, for example, in the purification of the free compounds or in the manufacture of other salts, or serve for identification and characterization purposes. Addition salts prepared primarily for the latter are amongst others those with acidic organic nitro compounds, e.g. picric, pierclonic, flavianic acid and the like, or metal complex acids, e.g. .phosphctungstic, phosphomolybdic, chloroplatinic, Reinecke acid and'the like.

Also included within the scope of the present invention are the N-oxides, the salts of N-oxides and the quaternary ammonium derivatives of the compounds having amino groups capable of forming such derivatives, particularly those with N,N-disu-bstituted amino groups. Salts of N- oxides are the acid addition salts, for example, the pharmaceutically acceptable, non-toxic acid addition salts, of such N-oxides with the above-mentioned acids, whereas quaternary ammonium derivatives are primarily the lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, or phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like, quaternary ammonium halides, e.g. chloride, bromide, iodide and the like, quaternary ammonium sulfates, quaternary ammonium lower alkane sulfonates, e.g. methane sulfonate, ethane sulfonate and the like, quaternary ammonium lower hydroxy-alkane sulfonates, e.g. methyl Z-hydroxy-ethane sulfonate and the like, or quaternary ammonium monocyclic carbocyclic aryl sulfonates, e.g. p-toluene sulfonate and the like, as well as the corresponding quaternary ammonium hydroxides, and the salts of such hydroxides with acids other than hydrohalic, sulfuric or organic sulfonic acids, particularly with the organic carboxylic acids mentioned hereinabove.

The compounds of this invention may be obtained in the form of racemates, the resolution of which will be discussed hereinbelow.

The compounds of this invention have diuretic and natriuretic agents to relieve excessive water and salt retention. Contrary to known diuretic and saliuretic agents, the compounds of this invention do not raise the excretion of potassium; it even appears, that they cause a slight retention of potassium.

Especially useful as diuretic and natiuretic agents are, the compounds of the formula in which each of the groups R and R represents hydrogen, lower alkyl, lower alkoxy or halogeno, Am is amino, N-lower alkylamino, N-lower alkanoyl-amino, N,N-dilower alkyl-amino, N,N-alkylene-amino, in which alkylene has from four to seven carbon atoms, 4-morpholino, or 4-lower alkyl-l-piperazino, the group of the formula is lower alkylene having from two to four carbon atoms and separating the group Am from the ring carbon atom by two to four carbon atoms, and R is hydrogen or lower alkanoyl, or acid addition salts, for example, pharmaceutically acceptable, non-toxic addition salts thereof.

The compounds of the present invention are prepared according to known methods. I prefer to prepare them by converting in a dibenzocycloalkadiene compound, in which the cycloalkadiene portion has from five to seven ring members, and one of its carbon atoms, connecting together the two benzo portions, is substituted by an amino-lower alkyl radical, in which amino is separated from the ring carbon atom by at least two carbon atoms, and by a substituent capable of being converted into hydroxymethyl, particularly in a compound of the formula in which Ph Ph A, Am and the group of the formula (C H have the previously-given meaning, and R is a group capable of being converted into a hydroxymethyl group, the group capable of being converted into hydroxymethyl, i.e. the group R into hydroxymethyl, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting in a resulting compound the hydroxymethyl group into an acyloxymethyl group, in which acyl is the radical of an organic carboxylic acid, and/or, if desired, converting in a resulting compound an acyloxymethyl group into hydroxymethyl, and/or, if desired, converting in a resulting compound an amino group into another amino group, and/or, if desired, converting a resulting compound into a salt thereof, and/or, if desired, converting a resulting compound, having an amino group capable of forming an N-oxide group or a quaternary ammonium group, into an N-oxide or a quaternary ammonium compound, and/or, if desired, converting a resulting N-oxide into a salt there of, and/ or, if desired, converting a resulting quaternary ammonium compound into another quaternary ammonium compound, and/or, if desired, separating a resulting mixture of isomers into the single isomers.

A group capable of being converted into a hydroxymethyl group, such as the group R in the above formula, is a carboxyl group or a functionally converted carboxyl group, more especially a nitrogen-free functionally converted carboxyl group, particularly an esterified carboxyl group, such as a carbo-lower alkoxy group, e.g. carbomethoxy, carboethoxy and the like, as well as a halogenocarbonyl group, e.g. chloro-carbonyl and the like, group, or an anhydride grouping formed by the carboxyl group with a lower alkanoic acid, e.g. acetic, propionic acid and the like. The carboxyl group, and the functionally converted carboxyl group are converted into the desired bydroxymethyl group by reduction.

Especially useful as reducing agents are complex hydride reducing reagents, such as light metal aluminum hydrides, for example, alkali metal aluminum hydrides, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, alkaline earth metal aluminum hydrides, e.g. magnesium aluminum hydride and the like, as well as aluminum hydride or any other suitable complex aluminum hydride reagent, such as di-lower alkyl aluminum hydride, e.g. dibutyl aluminum hydride and the like, or light metal borohydrides, such as alkali metal borohydrides, e.g. lithium borohydride, sodium borohydride, potassium borohydride and the like, or alkaline earth metal borohydrides, e.g. calcium borohydride and the like, or any other suitable complex hydride reducing reagent. These reagents are used in the presence of a diluent, the selection of which depends on the solubility of the starting material and the reactivity of the reducing agent; suitable diluents are, for example, diethyl ether, tetrahydrofuran, ethanol and the like. If necessary, the reaction is carried out at an elevated temperature, and/or in the presence of an activator, e.g. aluminum chloride and the like.

The above conversion, particularly of an esterified carboxyl group, such as a carbo-lower alkoxy group, into hydroxymethyl is also carried out by treating the starting material with catalytically activated hydrogen, using heavy metal catalysts, such as copper catalysts, particularly copper chromium oxide and the like, nickel catalysts and the like; if necessary, the reaction is carried out at an elevated temperature and/or in a closed vessel under pressure.

An esterified carboxyl group, such as carbo-lower alkoxy, representing the group R in the starting material, is also converted into hydroxymethyl by treatment of the starting material with nascent hydrogen generated, for example, by reacting an alkali metal, particularly sodium, with a lower alkanol, e.g. methanol, ethanol, isopropanol, n-butanol and the like. If necessary, the reaction mixture is carried out while cooling or at an elevated temperature.

The starting materials used in the above reaction are known or may be prepared according to known methods. For example, a dibenzocycloalkadiene compound, in which the cycloalkadiene portion has from five to seven ring members, and one of the carbon atoms, connecting together the two benzo portions, is substituted by a substituent capable of being converted into hydroxymethyl, such as a compound of the formula 1'1. in which Ph Ph A and R have the previously-given meaning, may be converted into an alkali metal, e.g. sodium, potassium and the like, salt thereof (for example, by treatment with an alkali metal hydride, an alkali metal amide, an alkali metal lower alkanolate and the like, in the presence of an appropriate solvent or solvent mixture) and is then treated wtih a reactive esteri-fied hydroxy-lower alkyl-amine, in which the amino group and the hydroxyl group are separated by at least two carbon atoms, such as a compound of the formula X (C H )Am, in which Am and the group of the formula (C H have the previously-given meaning, and X is a reactive esterified hydroxyl group, particularly halogeno, e.g. chloro, bromo and the like, or organic sulfonyloxy, e.g. p-methylphenylsulfonyloxy and the like, and is separated from the group Am by at least two carbon atoms; the above reaction is preferably carried out in the presence of a diluent and at an elevated temperature.

An amino-lower alkyl group, in which the carbon atom adjacent to the amino group is unsubstituted, may also be introduced by treating a salt of the above intermediate with a reactive esterified hydroxy-lower alkane carboxylic acid amide, in which the nitrogen of the arnido group is separated from the reactive esterified hydroxyl group (such as halogeno, e.g. chloro, bromo and the like) by at least two carbon atoms, and in which the nitrogen of the arnido group is unsubstituted, N-monosubstituted or N,N-disubstituted, and converting in a resulting compound having an amido group, such group into an aminomethyl group, for example, by treatment with a suitable hydride reducing reagent, e.g. lithium aluminum hydride and the like, according to known methods.

An amino-lower alkyl group in which both the amino group and the carbon atom adjacent to the amino group,

' are unsubstituted, may also be introduced by reacting the above intermediate with a lower alkeno-nitrile, in which the double bond of the alkeno portion is activated by the cyano group, or reacting a salt of the above intermediate with a reactive esterified hydroxy-lower alkanonitrile, and converting in a resulting nitrile compound the cyano group into methylenearnino according to known methods, for example, by treatment with a hydride reducing reagent, e.g. lithium aluminum hydride and the like.

Compounds of this invention, in which the carbon atom adjacent to the amino group of the amino-lower alkyl substituent is unsubstituted, may also be prepared by con vetting in a dibenzocycloalkadiene compound, in which the cycloalkadiene portion has from five to seven ring members, and one of the carbon atoms, connecting together the two benzo portions, is substituted by hydroxymethyl or acyloxymethyl, in which acyl is the radical of an organic carboxylic acid, and a substituent capable of being converted into an amino-lower alkyl group, in which amino is separated from the ring carbon atom by at least two carbon atoms, and the carbon atom adjacent to the amino group of the amino-lower alkyl substituent is unsubstituted, particularly in a compound of the formula in which Ph Pl'lg, A and R have the previously-given meaning, the group of the formula (C H is lower alkylene, and Arn is a group capable of being converted into an aminomethyl group, in which the methyl portion is unsubstituted, the group capable of being converted into amino-lower alkyl into the latter, particularly a group Arn into the aminomethyl group, in which methyl is unsubstituted, and, if desired, carrying out the optional steps.

A group Arn capable of being converted into the aminornethyl group is a functionally converted, nitrogcncontaining carboxyl group, such as a carbamyl group, in which the nitrogen atom is unsubstituted, N-monosubstituted or N,N-dis'ubstituted, a cyano group or any other equivalent group. The desired conversion of such group is carried out according to known methods, such as those mentioned above, for example, by treatment of the starting material with a suitable complex hydride reducing reagent, especially one of the previously described light metal aluminum hydrides, e.g. lithium aluminum hydride and the like, which, if necessary, may be used in the presence of an activator, such as aluminum chloride and the like. Cyano groups may also be converted into aminomethyl groups by reacting the nitrile starting material with catalytically activated hydrogen, using a heavy metal catalyst, such as nickel catalyst and the like, or with nascent hydrogen, as generated, for example, by the action of an alkali metal on a lower alkanol.

The starting materials used in the above reaction are prepared according to known methods. For example, in the previously described intermediates having a carbamyllower alkyl or a cyano-lower alkyl group, and a substituent capable of being converted into hydroxymethyl or an acyloxymethyl group, the substituent is converted into the latter, for example, by treatment with a light metal borohydride reagent, e.g. sodium borohydride and the like, or hydrogen activated by a copper chromium oxide catalyst, or any other suitable method.

The above modifications may be combined for the preparation of those compounds of this invention, in which the carbon atom adjacent to the amino group is unsubstituted; this may be achieved by simultaneously converting in a dibenzocycloalkadiene compound, in which the cycloalkadiene portion has from five to seven ring members, and one of the carbon atoms, connecting to-- gether the two benzo portions, is substituted by a substituent capable of being converted into an amino-lower alkyl group, in which amino is separated from the ring carbon atom by at least two carbon atoms, and the carbon atom adjacent to the amino group of the amino-lower alkyl substituent is unsubstituted, and by a substituent capable of being converted into hydroxymethyl, particularly in a compound of the formula Phi Phg

in which Ph P112, A, R Am and the group of the formula (C H2n 2) have the previously-given meaning, the groups capable of being converted into an aminolower alkyl group or hydroxymethyl, respectively, into the latter, particularly the groups R, and Arn into hydroxymethyl and aminoethyl, respectively, and, if desired, carrying out the optional steps.

The above reaction is carried out according to known methods, for example, by treatment with a suitable complex hydride reducing reagent, especially one of the previously-described light metal aluminum hydrides, e.g. lithium aluminum hydride and the like, if necessary in the presence of an activator, such as aluminum chloride and the like, or by treatment with nascent hydrogen as generated by an alkali metal and a lower alkanol.

The starting materials used in the above procedure are prepared as previously shown.

Conversion of the hydroxymethyl group in a resulting compound into an acyloxymethyl group, in which acyl is the acyl radical of an organic carboxylic acid is carried out according to known esterification methods. For example, the hydroxyl compound is treated with the reactive functional derivative of an organic carboxylic acid, such as an organic carboxylic acid halide, particularly chloride, for example, the acid chloride of lower alkanoic acid, e.g. acetyl chloride, propionyl chloride and the like, as well as the anhydride of such an organic carboxylic acid, particularly the anhydride of a lower alkanoic acid, e.g. acetic acid anhydride, propionic acid anhydride and the like. The esterification reaction with such reagents may be performed in the absence or in the presence of an esterification reagent, for example, a suitable base, e.g. N,N,N-trimethylamine, N,N,N-triethylamine and the like, or more especially pyridine, collidine or any other equivalent organic base. Acid anhydrides may also be used in the presence of an acid, for example, sulfuric, perchloric acid and the like, which is preferably used in catalytic amounts. If desired, a liquid organic base used as an esterification reagent may also serve as a diluent, or, if necessary, the reaction mixture may be diluted with an inert solvent. The esterification reaction may be performed while cooling, at room temperature or at an elevated temperature; if necessary, the atmosphere of an inert gas, e.g. nitrogen, may be required.

Other esterification reagents are ketenes, for example, ketene itself, methyl-ketene or other substituted ketenes; these ketenes furnish an acetyl, a propionyl radical or other substituted acetyl radicals. The reaction with a ketene is performed in an inert solvent, such as an aromatic hydrocarbon, e.g. toluene and the like.

In a resulting compound, an acyloxymethyl group may be converted into hydroxymethyl according to known hydrolysis methods, for example, by treatment with a base,

e.g. sodium hydroxide, potassium hydroxide and the like.v

In a resulting compound an amino group may be con verted into another amino group. For example, an N- unsubstituted and N-monosubstituted may be converted into an N-acyl-amino or an N-substituted N-acyl-amino group according to known procedures, for example, by

treatment with a suitable acylation reagent, particularly an organic acid halide, e.g. chloride and the like, such as one of the previously-described reagents, if desired, in the presence of an additional basic reagent, which may also serve as a diluent, or an additional solvent, and, if necessary, while cooling or heating, and in the atmosphere of an inert gas, e.g. nitrogen.

In a resulting compound having an N-acylamino or an N-substituted N-acyl-amino group, the carbonyl portion of the acyl group may be converted into methylene according to the previously-described procedure, particularly by treating the compound having such group with a suitable aluminum hydride, e.g. lithium aluminum hydride and the like.

Furthermore, an N-unsubstituted amino group or an N-monosubstituted amino group may b econverted into an N-monosubstituted amino group and an N,N-disubstituted amino group, respectively, according to known methods, for example, by a so-called alkylation procedure, using a reactive esterified alcohol reagent, such as an aliphatic halide compound, or by procedures suitable for the manufacture of compounds having specifically substituted amino groups, such as formation of a Schitf-base compound by treatment with an aldehyde and reduction of the double bond, for example, with a borohydride reagent, e.g. sodium borohydride and the like, methylation with formic acid-formaldehyde, or any other similar procedures available for the substitution of an N-unsubstituted amino group or an N-monosubstituted amino group.

A resulting salt may be converted into the free compound, for example, by treatment with an alkaline reagent, such as a metal hydroxide, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia, or any other suitable alkaline reagent, as well as, for example, a hydroxyl ion exchange preparation.

A free compound may be converted into its acid addition salts by reacting it with one of the previously-mentioned acids. The salt-forming reaction may be carried out, for example, by treating a solution of the free compound in a solvent or solvent mixture with the acid or a solution thereof and isolating the desired salt. The latter may also be obtained by treating the free compound with a suitable anion exchange preparation. The monoor poly-salts may be obtained in the form of their hydrates or may contain solvent of crystallization.

N-oxides of the compounds of the present invention having an N-oxide forming amino group, may be prepared, for example, by treating the compound or a salt thereof with an N-oxidizing reagent in the presence of an inert solvent or solvent mixture. Such reagents are, for example, ozone, hydrogen peroxide, inorganic peracids, e.g. persulfuric acid and the like, organic persulfonic acids, e.g. p-toluene persulfonic acid and the like, or primarily organic percarboxylic acids, e.g. peracetic acid, perbenzoic acid, monoperphthalic acid and the like. The N-oxides may be isolated in the form of the free compounds or the acid addition salts thereof; N-oxide free bases may be converted into their acid addition salts or the salts may be converted into the free N-oxide compounds, according to the previously-described procedures.

The quaternary ammonium derivatives of a compound of this invention having a quaternary ammonium derivative-forming amino group, may be obtained, for example, by reacting the compound with a lower alkyl halide, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide, iodide and the like, a lower alkyl lower alkane sulfonate, e.g. methyl or ethyl methane or ethane sulfonate and the like, a lower alkane hydroxy-lower alkane sulfonate, e.g. methyl 2-hydroxy-ethane sulfonate, ethyl 2-hydroxy-ethane sulfonate and the like, or lower alkyl carbocyclic aryl sulfonate, e.g. methyl p-toluene sulfonate and the like, as

well as phenyl-lower alkyl halides, e.g. benZyl or Z-phenylethyl chloride, bromide or iodide and the like. The quaternizing reaction may be performed in the absence or presence of a solvent, while cooling, at room temperature or at an elevated temperature, at atmospheric pressure or in a closed vessel under pressure, and, if desired, in the atmosphere of an inert gas, e.g. nitrogen.

Resulting quaternary ammonium compounds may be converted into other quaternary ammonium compounds, such as the corresponding quaternary ammonium hydroxides; the latter are obtained by reacting a quaternary ammonium halide with silver oxide or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchange preparation, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be obtained quaternary ammonium salts by reacting a hydroxide with an acid, for example, one of those used for the preparation of acid addition salts. A quaternary ammonium compound may also be converted directly into another quaternary ammounium salt without the formation of an intermediate quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or with hydrochloric acid in anhydrous methanol to yield the quaternary ammonium chloride. The conversion of one quaternary ammonium compound into another may also be carried out with the help of an anion exchange preparation.

Compounds of the present invention may be obtained in the form of racemates. They may be resolved into the optically active forms, the levo-rotatory l-form and the dextrorotary d-form, according to known resolution procedures, for example, by treating a solution of the free basic racemate in a suitable solvent or solvent mixture with one of the optically active forms of an acid having an asymmetric carbon atom, or a solution thereof and separating the resulting salts on the basis of their differing solubilities. Especially useful as optically active forms of salt-forming acids, having an asymmetric carbon atom are the d-tartaric acid (L-tartaric acid) and the l-tartaric acid (D-tartaric acid); the optically active forms of di-benzoyl tartaric, di-p-toluyl-tartaric, malic, mandelic, IO-camphor sulfonic acid, quinic acid and the like, may also be used. A free and optically active compound is obtained from a resulting salt according to the methods outlined hereinbefore, and an optically active compound may be converted into an acid addition salt, as well as into N-oxide, .a salt of an N-oxide or a quaternary ammonium compound as previously described.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out. It also includes any new intermediates, which may be formed in one of the procedures outlined hereinbefore.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A solution of 7.3 g. of ethyl 9-(2-cyanoethyl)-fiuorene 9-carboxylate in ml. of tetrahydrofuran is added dropwise to a solution of 3.7 g. of lithium aluminum hydride in ml. of tetrahydrofuran While stirring; during the addition the temperature rises slightly. Stirring at room temperature is maintained for eighteen hours, whereupon the reaction mixture is decomposed by adding in the following order 11.1 ml. of ethyl acetate, 3.7 ml. of water, 7.4 ml. of a 15 percent aqueous solution of sodium hydroxide and 11.1 ml. of water in fifteen minute intervals. The solid material is filtered off, the solvent is evaporated which is recrystallized from isopropanol, and melts at 125 as the hemihydrate; yield: 5.0 g.

The starting material used in the above procedure is prepared as follows: To a solution of 28.7 g. of ethyl fiuorene 9-carboxylate in 50 g. of pyridine added 65.0 g. of acrylonitrile while stirring. To this solution is then added dropwise 10.1 ml. of a 50 percent aqueous sodium hydroxide solution while stirring; the temperature of the reaction mixture rises slightly during the addition. After standing overnight at room temperature, the reaction mixture is poured into about 500 ml. of water, and is acidified with hydrochloric acid while cooling. The organic material is extracted with methylene chloride; the dried organic solution is evaporated under reduced pressure, and the residue is distilled. The desired ethyl 9-(2-cyanoethyl)- fluorene 9-carboxylate is collected between 198 and 240! 0.15 mm.; yield: 24.0 g.

Example 2 A solution of 22.4 g. of ethyl 9-(3-N,N-dimethylaminopropyD-fiuorene 9-carboxylate in 100 ml. of tetrahydrofuran is added dropwise to a solution of 4.6 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran While stirring. The reaction mixture is agitated for an additional eighteen hours at room temperature and is then decomposed by adding in the following order 13.8 ml. of ethyl acetate, 4.6 ml. of water, 9.2 ml. of a 15 percent aqueous solution of sodium hydroxide and 13.8 ml. of water. The solid material is filtered off and the filtrate is evaporated under reduced pressure. The oily residue is dissolved in anhydrous diethyl ether, and the solution is gassed with dry hydrogen chloride. A white hygroscopic precipitate is formed which is repeatedly dissolved in isopropanol and precipitated with diethyl ether to yield the desired 9-(3 N,N dimethylaminopropyl) 9 hydroxymethyl-fluorene hydrochloride of the formula and then recrystallized from ethyl methyl ketone, M.P. 194-195"; yield: 9.5 g.

The starting material is prepared as follows: To 4.6 g. of a 53 percent mineral oil suspension of sodium hydride in 50 ml. of toluene is added dropwise while refluxing, a solution of 23.8 g. of ethyl fluorene 9-carboxylate in 75 ml. of toluene. The reaction mixture is refluxed while stirring for two hours and is then treated dropwise (over a period of ten minutes) with a solution of 13.3 g. of 3-N,N-dimethylaminopropyl chloride in 50 ml. of toluene, while stirring. Refluxing is continued for 2 /2 hours, cooled and filtered. The filtrate is evaporated to dryness to'yield the oily ethyl 9-(3-N,N-dimethylaminopropyl)- :fluorene 9-carboxylate, which is distilled and collected at 138142/0.025 mm.; yield: 22.4 g.

Example 3 A solution of 20.7 g. of ethyl 9-[2-(1-piperidino)- et-hyl]-fiuorene 9-carboxylate in 100 ml. of tetrahydro furan is added to a stirred solution of 4.0 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at room temperature for an additional twenty-one hours and is then decomposed by adding in the following order and in intervals of fifteen minutes, 12 ml. of ethyl acetate, 4 ml. of water, 8 ml. of a fifteen percent aqueous solution of sodium hydroxide and 12 ml. of water. The solid material is filtered off, the filtrate is concentrated under reduced pressure and the oily residue, containing the 9-hydroxymethyl-9-[2- (1-piperidino)-ethyl]-fluorine, is dissolved in 300 ml. of anhydrous diethyl ether and gassed with dry hydrogen chloride. The white precipitate is filtered off and dried under reduced pressure to yield the 9-hydroxymethyl-9- [2-( l-piperidino)-ethyl]-fluorene hydrochloride of the formula o out-ore no-orn carom-N CHTHCI CH2-CH2 which melts at 272-273 after recrystallization from anhydrous ethanol; yield: 9.3 g.

A solution of the 9-hydroxymethyl-9-[2-(1-piperidino)- ethyl] -fluorene, when treated with picric acid, yields the 9-hydroxymethyl-9- [2 (1 piperidino) ethyl] fluorene picrate.

The starting material used in the above reaction is prepared as follows: To a refluxing mixture of 4.6 g. of a 53 percent suspension of sodium hydride in mineral oil in 50 ml. of toluene is added 23.8 g. of ethyl fiuorene 9-carboxylate in 50 ml. of toluene; the addition is completed after thirty minutes, and refluxing with stirring is continued for 2 /2 hours, after which a solution of 16.2 g. of 1-(2-chloroethyl)-piperidine in 75 ml. of toluene is added. Refluxing is continued for an additional two hours; the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The ethyl 9-[2-(1-piperidino)- ethyl]-fluorene 9-carboxylate obtained as an oil, is purified by distillation and is collected at 160-162/0.025 mm.; yield: 20.7 g.

Example 4 A solution of 7.3 g. of 9-hydroxymethyl-9-[2-(1-piperidino)-ethyl]-fiuorene hydrochloride in water is treated with an aqueous sodium hydroxide solution, and the 9- hydroxymethyl-9-[2-(l-piperidino)-ethyl]-fluorene is extracted with methylene chloride and obtained by evapois recrystallized from isopropanol, M.P. 234235; yield: 1.6 g.

Example 5 A solution of 26.9 g. of ethyl 9-(2-N,N-dimethylam inoethy-l)-fluorene carboxylate in ml. of tetrahydrofuran is added dropwise to a stirred solution of 7.0 g. of lithium aluminum hydride in ml. of tetrahydrofuran. After stirring for eighteen hours, the reaction mixture is decomposed by adding in the following order 21 ml. of ethyl acetate, 7 ml. of water, 14 ml. of a 15 percent aqueous sodium hydroxide solution and 21 ml. of water. The solid material is filtered oil, and the filtrate is concentrated under reduced pressure to yield the 9-(2-N,N-dimethylamino-ethyl)-9-hydroxymethyl-fluorene of the formula which slowly crystallizes and is dissolved in a mixture of methylene chloride and diethyl ether. The solution is gassed with dry hydrogen chloride. The white precipitate is recrystallized from a mixture of isopropanol and ethanol to yield 9-(2-N,N-dimethylaminoethyl)-9-hydroxymethylfluorene hydrochloride, which melts at 224-225 yield: 17.0 g. Y

The starting material is prepared according to the procedure described in Example 2, i.e. by reacting the sodium salt of 23.8 g. of ethyl fluorene 9-carboxylate with 13.0 g. of 2-N,N-dimethylaminoethyl chloride; the resulting ethyl 9-(2-N,N-dimethylaminoethyl)-fluorene 9-carboxylate is collected at l22132/0.01 mm.; yield: 26.9 g.

Other compounds, such as, for example, 9-(3-aminopropyl) 9 hydroxymethyl 1 methyl fluorene, 9 (2- N,N diet-hylamino 2 methyl ethyl) 9 hydroxymethyl 2 methoxy fluorene, 9 (3 aminopropyl)- 2,7 dichloro 9 hydroxymethyl fluorene, 9 (3- aminopropyl) 9 hydroxymethyl 2 t-rifluoromethylfluorene, 9 hydroxymethyl 9 [2 (4 morpholino)- ethyl] fluorene, 9 (4 aminobutyl) 9 hydroxymethyl fluorene, 9 (3 aminopropyl) 9 hydroxymethyl- 9,10 dihydro anthracene, 9 (2 N,N dimethylamino ethyl) 9 hydroxymethyl 9,10 dihydro anthracene, 9 (2 aminoethyl) 9 hydroxy methyl 1'0 methyl- 9,10 dihydro anthracene, 2 chloro 9 hydroxymethyl 9 [2 (4 methyl 1 piperazino) ethyl] 9,10- dihydro anthracene, 5 (3 aminopropyl) 5 hydroxymethyl 10,11 dihydro dibenzo[a,d]cycloheptadiene, 5 (3 aminopropyl) 5 hydroxymethyl dibenzo[a,d] cycloheptatriene and the like, are prepared according to the previously described procedure by reducing in methyl 9 (2 cyanoethyl) 1 methyl fluorene 9 carboxylate, ethyl 9 (2 N,N diethylamino 2 methyl ethyl) 2- methoxy-fluorene 9-carboxylate, ethyl 9-(2-cyanoethyl)- 2,7-dichloro-fluorene 9-carboxylate, ethyl 9-(2-cyanoethyl)-2-trifluoromethyl-fluorene 9-carboxylate, methyl 9-[2- (4-morpholino)-ethyl]-fluorene 9-carboxylate, ethyl 9-(3- cyanopropyl)-fluorene 9-carboxylate, ethyl 9-(2-cyanoethyl)-9,10-dihydro-anthracene 9-carboxylate, ethyl 9-(2-N, N dimethylaminoethyl) 9,10 dihydro anthracene 9- carboxylate, methyl 9-cyanomethyl-10-methyl-9,10-dihydro-anthracene 9-carboxylate, ethyl 2-chloro-9-[2-(4- methyl 1 piperazino) ethyl] 9,10 dihydro anthracene 9-carboxylate, ethyl 5-(2-cyan0ethyl)-l0,1l-dihydrodibenzo[a,d]cycloheptadiene S-carboxylate, ethyl 5-(2- cyanoet-hyl) dibenzo[a,d]cycloheptatriene S-carboxylate and the like, theesterified carboxyl group to hydroxymethyl and, if necessary, the cyano group to amino methyl according to the process described in the previous examples, particularly by treatment with lithium aluminum hydride.

The above starting materials are known or may be prepared according to known methods. For example, a dibenzocycloalkadiene compound, in which the cycloalkadiene portion has from five to seven ring members, and one of its carbon atoms connects the two benzo portions, such as l-methyl-fiuorene, 2-methoxy-fiuorene, 2,7- dichloro-fluorene, 2-trifluoromethyl-fluorene, 9,10-dihydroanthracene, l0-met-hyl-9,IO-dihydroanthracene, 2-chloro 9,10 dihydroranthracene, 10,11 dihydro-dibenzo [a,d]cycloheptadiene, dibenzo[a,d,]cycloheptatriene and the like, may be converted into its alkali metal salt (for example, by adding a solution of the dibenzocycloalkadiene compound in an inert solvent, e.g. diethyl ether and the like, to an alkali metal in liquid ammonia, or to an organic hydrocarbon alkali metal compound, such as a phenyl or a naphthyl alkali metal compound, in an inert solvent, e.g. tetrahydrofuran and the like, or by reacting one of the above dibenzocycloalkadiene compounds, in which the cycloalkadiene portion has from five to seven ring members and one of its carbon atoms connecting the two benzo portions, is substituted by halogeno, in an inert solvent, e.g. tetrahydrofuran and the like, with an alkali metal), and reacting the latter with solid carbon dioxide to form a dibenzocycloalkadiene compound in which the cycloalkadiene portion has from five to seven ring members and one of its carbon atoms connecting the two benzo portions, is substituted by a carboxyl group. The latter may also be obtained by reacting one of the above dibenzocycloalkadiene compounds, in which the cycloalkadiene portion has from five to seven ring members and one of its carbon atoms connecting the two benzo portions, is substituted by halogeno with silver cyanide and converting in a resulting nitrile compound the cyano group into carboxyl by hydrolysis with aqueous sulfuric acid. The resulting carboxylic acid compound is then esterified with an alcohol, such as a lower alkanol, in the presence of an acid. The resulting ester is converted into an alkali metal salt thereof (for example, by treatment with an alkali metal hydride, an alkali metal amide and the like) and reacted with a reactive esterified amino-lower alkanol, carbamyl-lower alkanol or cyano-lower alkanol, or the free ester compound is reacted with -a lower alkeno-nit rile, in which the double bond is activated by the cyano group, in the presence of a base, e.g. pyridine and the like. If necessary, a carbamyl group or a cyano group in a resulting compound is then converted into an aminomethyl group by reduction, for example, with lithium aluminum hydride.

Compounds having an N-oxide-forming amino group may be converted into their N-oxides according to known methods; for example, a solution of 9-[2-(1-piperidino)- ethyl] 9 hydroxymethyl fluorene in methanol, when treated with hydrogen peroxide, yields the 9-[2-(l-piperidino) ethyl] 9 hydroxymethyl fluorene N oxide, which is converted into its acid addition salts, for example, the picrate by treatment of a solution of the free N-oxide in ethanol with picric acid.

The 9 [2 (1 piperidino) ethyl] 9 hydroxymethyl-fluorene methiodide is obtained by treating a solution of the 9 [2 (1 piperidino) ethyl] 9' hydroxymethylfluorene in ethanol with an excess of methyl iodide.

Example 6 The new compounds of this invent-ion are useful in the form of compositions for enteral, e.g. oral, or parenteral use, which contain the new compounds in admixture with a pharmaceutically acceptable, organic or inorganic, solid or liquid carrier. These compositions consist essentially of a pharmacologically elfective amount of a dibenzocycloalkadiene compound, in which the cycloalkadiene portion has from five to seven ring members and one of its carbon atoms connecting together the two benzo portions, is substituted by an amino-lower alkyl group, in which amino is separated from the ring carbon atom by at least two carbon atoms, and by a member selected from the group consisting of hydroxymethyl and acyloxymethyl, in which acyl is the radical of an organic carboxylic acid, a salt thereof, an N-oxide of said compound having an N- oxide-forming amino group, a salt of an N-oxide of said compound having an N-oxide-forming amino group, and a quaternary ammonium derivative of said compound having a quaternary ammonium derivative-forming amino group as the pharmacologically active ingredient together with a pharmaceutically acceptable carrier; per dosage unit, the pharmaceutical compositions of this invention contain from about five percent to about eighty percent of the pharmacologically active ingredient. Carrier mateing, wetting, emulsifying, coloring, flavoring agents and the like, salts for varying the osmotic pressure, butters, etc. They may also contain, in combination, other pharmacologically useful substances.

For example, capsules, each containing 0.250 g. of 9-(3- aminopropyl)-9-hydroxymethyl fiuorene hydrochloride, are prepared as follows (for 10,000 capsules):

Ingredients: G.

9- 3-aminopropyl -9-hydr0xymethylfluorene hydrochloride 2,500.0

Lactose, U.S.P. 1,000.0

The lactose is placed in a suitable mixer together with 1000.0 g. of 9-(3-aminopropyl)-9-hydroxymethyl-fiuorene hydrochloride. After thoroughly mixing, the balance of the 9-(3-aminopropyl)-9-hydroxymethyl-fluorene hydrochloride has been added, and mixing is continued until the powders are homogeneously distributed. Portions of 0.350 g. of the resulting mixture are then filled into No. 1 gelatine capsules.

Example 7 A solution of 10.0 g. of ethyl 9-cyanomethyl-fluorene 9-carboxylate in 75 ml. of tetrahydrofuran is added to a solution of 6.0 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at room temperature for eighteen hours and is then treated in the following order wth 18 ml. of ethyl acetate, 6 ml. of water, 12 ml. of a 15 percent aqueous solution of sodium hydroxide and 18 ml. of water. The mixture is filtered, the solid material is Washed with methylene chloride, and the combined filtrates are concentrated under reduced pressure. The viscous residue is extracted three times with hot diethyl ether, and the combined extracts are gassed with dry hydrogen chloride. The amorphous hygroscopic 9-(Z-aminoethyl)-9-hydroxymethyl fiuorene hydrochloride of the formula HO-Ofiz oHroHrNHtr-lol is crystallized by boiling it with ethyl methyl ketone and recrystallized from a mixture of isopropanol and ethyl methyl ketone, M.P. 168-470".

The starting material used in the above procedure is prepared as follows: A solution of 12.0 g. of ethyl fiuorene 9-carboxylate in 50 ml. of dry toluene is added to a refluxing mixture of 2.2 g. of a 53 percent suspension of sodium hydride in mineral oil, in 50 ml. of toluene while stirring. After refluxing for three hours, the reaction mixture is treated with a solution of 4.5 g. of chloroacetonitrile in 25 ml. of toluene, which is added over a period of thirty minutes. Refluxing and stirring is continued for three hours; the reaction mixture is then cooled, filtered and evaporated under reduced pressure to yield the ethyl 9- cyanomethyl-fiuorene-9-carboxylate, which is distilled and collected at 146174/0.05 mm.; yield: 10.0 g.

What is claimed is:

1. A member selected from the group consisting of a compound of the formula A P41 P r R-0Gg (onHzn)Am in which each of the groups Ph and Ph is a member selected from the group consisting of 1,2-phenylene, (lower alkyl)-l,2-phenylene, (lower alkoxy)-l,2-phenylene, (lower alkenyl-oxy)1,2-phenylene, (lower alky-lenedioxy)-1,2-phenylene, A is a member selected from the group consisting of a direct bond between the two groups Ph and P11 lower alkylene separating the groups Ph and Ph by at most two carbon atoms, and lower alkylene separating the groups Ph, and Ph by two carbon atoms, Am is a member selected from the group consisting of amino, lower alkylamin-o, cycloalkylamino and cycloalkyl-lower alkylamino with 3 to 8 ring-carbon atoms, phenylamino, phenyl-loiwer al kylamino, lower alkanoylamino, m-onocyclic carbocyc'lic or azacyclic aroylamino, dilower alkylamino, N-cycloalkyl-N-lower alkylamino with 3 to 8 ring-carbon atoms, N-lower alkyl-N-phenyl-lower alkylamino, N-hydroxy-lower alkyl-N-lower alkylamino and di-hydroxy-lower alkylamino in which hydroxy is separated from the nitrogen atom by at least 2 carbon atoms, alkylenei-mino with 4 to 8 carbon atoms, oxaalkyleneimino, thiaalkyleneimin-o, azaalkyleneimino, N-l ower alkyl-azaalkyleneimino, N-hydroxy-lower alkyl-azaalkyleneimino, N-lower alkanoyl-azaalkyleneimino and N- carbo-l-ower alkoxy-azaalkyleneimino in which the heteroatom is separated from imino by at least 2 carbon atoms and N-lower alkanyl-N-lower alkylamino,

( n zn) is lower alkylene separating Am from the ring carbon atom by at least two carbon atoms, and R is a member selected from the group consisting of hydrogen, lower alkanoyl, cyeloalky l-carbonyl and cycloa'lkyl-lower alkan-oyl with 3 to 8 ring-carbon atoms, hal-ogeno-lower alkanoyl, lower alkoxy-lower alkanoyl, monocyolic carbocyclic or heterocyclic aroyl and aryl-lower al kanoyl, a salt thereof, an N-oxide of a compound having an N-oxide-forming amino group, a salt of an N-oxide of a compound having an N-oxide-forming amino group, and a quaternary ammonium derivative of a compound having a quaternary ammonium derivative-forming amino group.

2. A member selected from the group consisting of the compound having the formula in which each of the groups R and R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halogeno, Am is a member selected from the group consisting of amino, N-lower alkyl-amino, N-lower alkanoyl-amino, N,N-di-lower alkyl-amino, N,N- alkylene-imino, in which alkylene has from four to seven carbon atoms, 4-morpholino and 4-lower alkyl-l-piperazino, the group of the formula (C H is lower alkylene having from two to four carbon atoms and separating the group Am from the ring carbon atom' by two to four carbon atoms, and R is a member selected from the group consisting of hydrogen and lower alkanoyl, and an acid addition salt thereof.

3. 9-(3-aminopropyl) -9ahydroxymethyl-fluorene.

4. An acid addition salt of 9-(3-a-minopropyl)-9-hydroxymethyl-fluorene.

5. 9 (3 ami-nopropyl) 9 hydroxymet-hyl fluorene hydrochloride.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2551316 *Feb 20, 1948May 1, 1951Searle & Co9-aminoalkyl 9-alkanoyl 9, 10 dihydroanthracenes
US3177209 *Sep 7, 1961Apr 6, 1965Kefalas AsDihydroanthracene compounds
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4792551 *Jul 15, 1983Dec 20, 1988Syntex (U.S.A.) Inc.9-anthryloxyaminoalkanes and related compounds as anti-inflammatory and analgetic agents
US5538986 *Dec 6, 1993Jul 23, 1996Schering CorporationTricyclic derivatives, compositions and methods of use
US5760246 *Dec 17, 1996Jun 2, 1998Biller; Scott A.Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
US6472414May 18, 1999Oct 29, 2002Bristol-Myers Squibb CompanyConformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
WO1995015939A1 *Dec 5, 1994Jun 15, 1995Schering CorpTricyclic derivatives, pharmaceutical compositions containing them