DE1919082A1 - Aminoalkyl spirocycloalkanes - Google Patents

Description

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND) Case SU 512/1 + 2 / E

Germany "■

Aminoalkyl spirocyloalkanes.

The present invention relates to the preparation of new 1-aminoalkyl-benzcycloalkane - ^ - spirocycloaliphatic Compounds of the general formula

alkp-Am

(D,

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where Ph is a 1,2-phenylene radical, aik stands for lower alkylene, which participates in the ring formation with 1 to 3 carbon atoms, B stands for lower alkylene or lower alkenylene, which participates in the ring formation with 4 to 6 carbon atoms, alkg stands for lower alkylene , Am denotes an amino group and R denotes hydrogen or hydroxy, their 1-dehydro derivatives (in which alk _{p is} alkylidene). » Ayl derivatives, N-oxides and quaternary ammonium compounds.

The 1,2-phenylene radical Ph is unsubstituted or substituted by one or more identical or different substituents. Substituents are first Line lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -Butyl * free, etherified or esterified hydroxy, such as lower alkoxy, e.g. methoxy, ethoxy., n- or i-propoxy or -butoxy, lower alkanoyloxy, e.g. acetoxy or propionyloxy, or halogen, e.g. fluorine, chlorine or bromine trifluoromethyl, Nitro or "amino, especially di-lower alkyl

. -φ

amino, ζ, bi dimethylamino or diethylamino.

In connection with the radicals or compounds mentioned above or below, the term "lower" defines those having a maximum of 7, preferably _3, carbon atoms.

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The remainder Ph stands in particular for 1,2-phenylene, (Lower alkyl) -l, 2-phenylene, (hydroxy) -1,2-phenylene, mono- or di- (lower alkoxy) -1,2-phenylene, (lower alkanoyloxy) -1,2-phenylene, (Halogen) -1,2-phenylene, or (trifluoromethyl) -1, 2-phenylene.

The lower alkylene radical is alk, in the first place Methylene, 1,2-ethylene or 1,3-propylene, but also 1,1-ethylene, 1,1-, 1,2- or 2,2-propylene, 2-methyl-1,3-propylene, 1,1-, 1,2-, 1,3-, 2,2- or 2,3-butylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- , 2,4- or 3,3-pentylene, 1,3- or 2,3-hexylene or 3 * 5 ~ heptylene.

The lower alkylene or lower alkenylene radical B is preferably 1,4-butylene, 1,5-pentylene or 1,5-pent 2-enylene, but also 1,4-pentylene, 1,4-, 1,5-, 2,5- or 1,6-hexylene, 1,4-, 1,5-, 1,6-, 2,5- or 2,6-heptylene; 1,4-but-2-enylene, 1,4-pent-2-enylene, 1,6-hex-3-enylene or 2,6-hept-3-enylene. . '·

The _{lower alkylene radical alk p} - stands primarily for 1,2-ethylene, 1,2- or 1,3-propylene, but also for 2-methyl-1,3-propylene, 1,2-, 1,3-, 1,4- or 2,3-butylene,. 1,5- or 2,4-pentylene, 1,3-, 1,4- or 1,6-hexylene or 3,5-heptylene.

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The amino group Am is a primary, secondary or preferably a tertiary amino group such as amino, mono- ■ or di-lower alkylamino, e.g. methylamino, ethylamino, n- or i-propylamino or n-butylamino; Dimethylamine, • N-methyl-N-ethylamino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino; free or esterified hydroxy-lower alkylamino, N- (hydroxy-lower alkyl) -N-lower alkylamino or di- (hydroxy-lower alkyl) -amino, in which the hydroxy group from the amino nitrogen atom through at least 2 carbon atoms are separated, e.g. 2-hydroxy-ethylamino, 3-hydroxy-propylamino, N- (2-hydroxy-ethyl) -N-methylamino or di (2-hydroxyethyl) amino; monocyclic cycloalkylamino, Cycloalkyl-lower alkylamino, N-cycloalkyl-N-lower alkylamino or N-cycloalkyl-lower alkyl-N-lower alkylamino, in which cycloalkyl are preferably 3 to 7 carbon atoms has, e.g. cyclopropylamino, cyclopentylamino, cyclohexylamino, Cyclopropylmethylamino, 2-Cyclopentylethylamirio, N-Cyclopentyl-N-methylamino, N-Cyclohexyl-N-methylamino, N-cyclohexyl-N-ethylamino, N-cyclopentyl-methyl-N-ethylamino or N- (2-cyclopentyl-ethyl) -N-methylamino, Aralkylamino or N-lower alkyl-N-aralkylamino, in which

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the aryl, for example phenyl radical, is unsubstituted or substituted like an abovementioned radical Ph, for example benzylamino, 2-phenylethylamino, N-methyl-N-benzylamino, N-ethyl-N-benzylamino or N-ethyl-N- (I. - or 2-phenylethyl) - "amino; lower alkylenamino or free or esterified hydroxy-alkylenamino, e.g. ethyleneimino, pyrrolidino, 2-methylpyrrolidino, piperidino, 2- or 4-methyl-piperidino, 3- or 4-hydroxypiperidino, 3- Hydroxymethyl-piperidino, 1,6- or 2,5-hexamethyleneamino, 1,7- or 2,6-heptamethyleneamino, lower mono-oxaalkylenamino or lower monothiaalkylenamino, for example morpholine, 3-methylrmorpholino or thiomorpholino, monoaza-lower alkylenamino, N -Lower alkyl-monoaza-lower alkylenamino, N- (Hydroxyniederalkyl) ü monoaza-lower alkylenaminOi in which the hydroxyl group is free or esterified, e.g. piperazines, N -. (Methyl, ethyl, n-propyl, i-propyl, 2-hydroxyethyl or 3- Hydroxypropyl) piperazino, N- (methyl., 2-hydroxyethyl or n-propyl) -3 ~ aza-1,5- or -3-a ^z a-l6-hexylenamine o, or N-methyl-4-aza-1,7- or -2,6-heptylenamino. The amino group Am can also be connected to alkp in such a way that alkp-Am together, for example, aza-eyoloalkyl, aza-cycloalkyl-lower alkyl, N-N-leathereralkylazacycloalkyl or N-lower alkyl-azacycloalkyl-lower alkyl, e.g. 2- * or 3-pyrrQlidyl, 1- Methyl or 1-ethyl-3 ~

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pyrrolidyl, 3- or 4-piperidyl or 3- or 4-piperidylmethyl, ! -Methyl- or 1-ethyl-3- or -4-piperidyl or 1-methyl- or 1-ethyl-3- or -4-piperidylmethyl. In the Corresponding compounds of the formula I are the heteroatoms in saturated groups, e.g. those present in the radical Am Heteroatoms separated by at least 2 carbon atoms.

Are acyl derivatives of the present invention

"preferably those of primary or secondary amines or of hydroxyalkyl compounds. The acyl group is preferably lower alkanoyl such as acetyl, propionyl, butyryl or pivalyl, but also lower alkenoyl, such as acryloyl or methacryloylß monocyclic aryl-lower alkanoyl or "Alkenoyl" such as bes & soyl., Phenylacetyl or cinnamoyl. the quaternary compounds of the present invention Preferably lower alkyl or aralkyl, e.g., phenyl lower alkyl, quaternaries Links. These acyl, alkyl or aralkyl radicals are unsubstituted or, in particular substituted in the aromatic part, like a radical Ph.

Dehydration of compounds of the formula I in which R is hydroxy gives the corresponding 1-dehydro derivatives of the present invention. In this ver

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bonds, the double bond can only be bonded to the first carbon atom of alkp, which becomes an alkylidene radical.

The compounds of the present invention show valuable pharmacological properties. First and foremost, they show analgesic effects. These can be detected in animal experiments, preferably on mammals, for example rats, mice or rabbits. The proof of effectiveness is carried out as follows: A heat beam is directed onto the tail of male rats and the duration of the irradiation is measured. The end point of this time interval is the moment at which the animal pulls its tail away from the radiation area. The heat stimulus is never applied for more than 10 seconds. Ten mice are usually used for each test. The time value is determined twice for each animal prior to medication. The compounds according to the invention are then administered orally or subcutaneously, in the form of aqueous solutions or suspensions, for example in a dose range between approximately 1 and 200 mg / kg / day, preferably between 10 and 100 mg / kg / day. After 15, 30 and / or 60 minutes, two time values are determined in the treated animals. For the

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Determination of the presence of analgesic effects will .the average of the control values is calculated and three standard deviation values are added. After 'Medication of the animals obtained time values, which over this sum show an analgesic effect. -, In another test system, holes are made by

approximately 1 mm in diameter into the pulp of incisors anesthetized rabbits. The following day, * electrodes are inserted into these holes and a circuit is made switched on. At a voltage of about 6 volts, the non-anesthetized animals begin to lick. This Volt value is the control value of the animals. Afterwards, the compounds of the invention are as indicated above and administered in approximately the same dose ranges ♦ After approximately 15 minutes, the electrodes are again under Voltage is set and the volt value at which the animal »to starts licking, for sure. If the volt value is above 6 and up to 14 volts, there is an analgesic effect.

Connections of the. Formula I, in which Ph 1,2-phenylene, (lower alkyl) -1,2-phenylene, (hydroxy) -1,2-phenylene, mono- or di- (lower alkoxy) -1,2-phenylene, (lower alkanoyloxy) -1,2-phenylene, (halogen) -1,2-phenylene or (trifluoromethyl) -1,2-phenylene 'means, alk _{x means}

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Is lower alkylene, which is involved in the ring formation with 1 to 3 carbon atoms, B is lower alkylene or alkenylene, which is involved in the ring formation with 4 to 6 carbon atoms, alkp is lower alkylene, R is hydrogen or hydroxy, and Am is amino, Mono- or di-lower alkylamino, hydroxy-lower alkylamino, N- (hydroxy-lower alkyl) -N-lower alkylamino, monocyclic cycloalkylamino, cycloalkyl-lower alkylamino, N-cycloalkyl-N-lower alkylamino or N-cycloalkyl-lower alkyl-N-lower alkylamino, in which the cycloalkyl radicals are 3 to J contain ring members, R _Q -lower alkylamino or N-lower alkyl-NR -lower alkylamino, lower alkylenamino, hydroxy-lower alkylenamino, mono-oxa-, mono-thia- or mono-aza-lower alkylenamino, N-lower alkyl-monoaza-lower alkylenamino, K-hydroxy -lower alkyl-monoaza-lower alkylenamino, or alk "-am together" monocyclic lower aza-cycloalkyl, aza-cyoloalkyl-lower alkyl, N-lower alkyl-aza-cycloalkyl or N-lower al Mean kylaza-cycloalkyl-lower alkyl, in which the heteroatoms of the saturated portions are separated from each other by at least 2 carbon atoms and the rings have 5 or 6 ring members, the lower alkanoyl, lower alkenoyl, R-lower alkanoyl or R-lower alkeno! derivatives of the primary or

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secondary amines or hydroxyalkyl compounds, their _{lower alkyl or R Q} lower alkyl quaternary compounds, N-oxides or their 1-dehydrο derivatives, in which R is phenyl, (lower alkyl) phenyl, (hydroxy) phenyl, mono- or di - (lower alkoxy) phenyl, (lower alkanoyloxy) phenyl, (halogen) phenyl or (trifluoromethyl) phenyl means.

Particularly valuable are compounds of the formula I, where Ph is 1,2-phenylene, (lower alkyl) -l, 2-phenylene, (HydroxyJ-l ^ a-phenylene, mono- or di- (lower alkoxy) -1,2-phenylene, (Halogen) -1,2-phenylene or (trifluoromethyl) -1,2-phenylene, alk, methylene, 1,2-ethylene or 1,3-propylene means B for 1,4-butylene, 1,5-ethylene or 1,5-pent-2-enylene R is hydrogen or hydroxy * alkg is 1,2-ethylsn, 1,2- or 1,3-propylene, and Am Di-nlederaikjrlamino, lower alkylenamino, monooxa- * i Monothia- or Monoaza-lower alkylenamino, M-Niederalkylraonoaza-lower alkylenamino, or N- (hydroxy-lower alkyl or lower alkanoyloxy-lower alkyl) -monoaza-lower alkylenamino means, or alk ^ -Am together for M-lower alkyl-

aza-qycloalkyl or H-lower alkyl-aza-cycloalkyl-ni alkyl, in vjelchen the heteroatoms are separated by at least 2 carbon atoms, and their 1-dehydro-derivatives but also compounds of the formula I and their functional derivatives mentioned, in which all symbols the in

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- li -

this paragraph have the meaning given, but Ph also stands for (lower alkanoyloxy) -1,2-phenylene, and B also means 1,6-hexylene.

The compounds of the general formula II are particularly valuable

(II),

wherein R denotes hydrogen or hydroxy, each of the symbols R _n , R ₀ and R, denotes hydrogen or one or two of the same denotes lower alkoxy, or one "denotes hydroxy, lower alkanoyloxy or halogen and the other hydrogen denotes ¹ n, A denotes Di-lower alkylamino-lower * alkyl, 1-lower alkyl-piperidyl or 1-lower alkylpiperidyl-lower alkyl, B is 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,5-pent-2-enylene, and m stands for the number 1, 2 or 3, and their 1-dehydro derivatives.

Particularly important are compounds of the general formula II in which R is hydrogen or hydroxy

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each of the symbols R ₁ , R ₂ and R, is hydrogen or one or two of the same are methoxy or one is hydroxy, acetoxy or chlorine and the other is hydrogen, A is 3-di ^m sthylamino-propyl, 3- Diethylamino-propyl, 1-methyl- or 1-ethyl-3- or. -4-pjperidyl, or 1-methyl- or 1-ethyl-3- or -4-piperidylmethyl, B ₁ 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,5 Pent-2-enylene and m stands for the number 1, 2 or 3, and its 1-dehydrο derivatives, in particular l- (3-dimethylamino-propylidene) -6-methoxy-l, 2,3,4- tetrahydro-naphthalene-2-spirocyclopentane, which, for example, at a subcutaneous dose of approximately 50 mg / kg / day in the mouse tail test, or at an oral dose of approximately 150 mg / kg / day in the rabbit tooth pulp test, has analgesic effects. demonstrate.

. The new compounds are prepared according to methods known per se, e.g. by being

1) in a 1-X-benzcycloalkane-2-spiroallphatic Compound of the general formula

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in which X is a substituent which can be converted into the group alkp-Am means this converted into the aminoalkyl group defined above, or

2) a l-oxo-benzcycloalkane - ^ - spiroaliphatic Compound of the general formula

with a tertiary aminoalkyl metal compound and hydrolyzed the adduct obtained, and if 1-dehydrο derivatives are desired to have a 1-hydroxy compound obtained in it 1-Dehydrο derivative converted, and, if desired, a obtained Converts connection into another connection according to the invention.

In a starting material shown under 1) the substituent X is e.g. a) a group containing a metal, e.g. an alkali metal, such as lithium, or halogen magnesium, or b) a reactive, esterified hydroxyalkyl group or a phosphonium alkyl group, e.g. βίϊΐθ

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(Halogen, sulfonyloxy or triarylphosphonium halide) alkyl group, like one (chlorine, bromine, methanesulfonyloxy * Ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or triphenylphosphonium chloride) alkyl group, or c) one (nitro, oximino, imino, cyano, carbamoyl, isocyanato or esterified carboxyamino, e.g. carbalkoxyamino) -alkyl-, -alkenyl, -alkanoyl or -hydroxyalkyl group, an amino-alkenyl, amino-alkanoyl or amino-hydroxyalkyl group, a nitrile or preferably carbaiaoyl group, e.g. COAm, in which Am has the meaning given above.

A starting material in which X has the meaning given under a) is combined with a reactive, Esterified or salified aminoalkanol or an unsubstituted or N-substituted Aetfayleriimin implemented.

Starting materials which have a group named under b) as substituent X are invalid with compounds of the general formula H-Am or their alkali metal or acyl, e.g. phthaloyl derivatives j

implemented. . *

Contains a starting material as Substifcuemten X a group named under c), it is converted into a process product by reduction and / or hydrolysis.

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In process variant 1 b), the condensation of the reactive derivative of the alcohol starting material with ammonia or amines _in order to neutralize the acids formed is preferably carried out in the presence of an excess of these basic reagents. in the presence of other condensing agents, for example inorganic or organic bases * such as alkali metal carbonates or bicarbonates or tertiary nitrogen bases such as tri-lower alkylamines, N, N-dimethylaniline or pyridine.

The reduction of nitro compounds, nitriles, Amides, isocyanates, urethanes or alkanoyl compounds is, according to process variant Ic), preferably with simple or complex light metal hydrides, e.g. borohydride or alkali metal aluminum hydrides or borohydrides, such as lithium aluminum hydride or sodium borohydride. In this reduction, the nitrile and Carr bamoyl groups in aminomethyl groups, the isocyanato or esterified carboxyamino groups and in methylamino groups and the alkanoyl groups in alkyl or α-hydroxyalkyl groups convicted. The mentioned oximes, ship's see

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Bases (namely the imino-alkyl or amino-hydroxyalkyl compounds) or the U) -amino-α-hydroxy-alkyl mentioned Reduction products of alkanoyl compounds, but also the nitro compounds and amino-alkenyl compounds are preferably used with nascent hydrogen, which electrolytically or by the action of metals on acids or alcohols, e.g. zinc or iron on mineral acids or alkanoic acids are generated, reduced. Also catalytically activated hydrogen, e.g. hydrogen in the presence of nickel, palladium or platinum catalysts can be used. Isocyanates and urethanes can also e.g. with aqueous mineral acids or alkalis, hydrolyzed or lysed. ■

The metal compound mentioned in process variant 2) is preferably a Grignard compound, such as a halogen-magnesium, preferably chlorine-magnesium

'' Compound, but also an alkali metal, e.g. lithium compound. Such a starting material is reacted with the oxo compound under customary conditions, wherein one, after hydrolysis with water or an aqueous acid or ammonium salt solution, compounds of the formula I, in which R is hydroxy or, under dehydrating conditions, namely in strongly acidic media, their 1-dehydrο derivatives, receives.

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The obtained compounds of the present invention can be converted into one another by methods known per se. For example, in received 1-hydroxy or 1-dehydro derivatives or in compounds, in which the radical B contains a double bond, the hydroxyl group and / or double bond, e.g. with catalytic activated hydrogen, can be eliminated reductively. A hydroxy group R can also be obtained by dehydration, e.g. by pyrolysis or with dehydrating agents, e.g. acids, their halides or anhydrides, such as sulfuric acid, acetyl chloride or acetic anhydride, be eliminated. This gives 1-dehydro derivatives.

Compounds in which Am is a primary or ■ means secondary amino group, can with reactive esters of corresponding alcohols, with lower alkylene oxides, e.g. ethylene oxide, or with aldehydes or ketones and reducing agents, e.g. formic acid, their functional derivatives or nascent hydrogen, implemented, and thereby converted into secondary or tertiary amines or quaternary compounds. Received primary or secondary amines can also, for example, with a reactive functional derivative of a corresponding Acid, such as its halides or an

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- Io -

hydrides, be acylated. An acyl derivative obtained can be cleaved, for example, with acidic or alkaline hydrolyzers, or phthaloy. " ¹ compounds with hydrazine, or reduced with simple or complex light metal hydrides.

Obtained tertiary amines can be converted into their N-oxides, e.g. by treatment with oxidizing agents such as hydrogen peroxide or peracids, e.g. with aliphatic or aromatic percarboxylic acids. It can further into the aromatic content of the process products, e.g. due to the action of nitric acid-sulfuric acid or by pyrolysis of nitrates, preferably in acidic media, e.g. trifluoroacetic acid, nitro groups introduced or existing nitro groups, e.g. with nascent hydrogen, reduced.

Hydroxyl compounds obtained according to the process, e.g. those of the formula I in which the radical Ph or Am contains a hydroxyl group can be esterified and / or to be etherified. Acid halides are used for this or anhydrides, including thianyl halides or phosphorus halides or oxyhalides, also given below subsequent reaction with lower alkanols or alkali metal alcoholates.

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Quaternary compounds obtained can be converted into tertiary Amines are transferred. For example, the benzyl radical in benzyl quaternary compounds can be hydrogenated split off.

Depending on the process conditions and starting materials the end product is obtained in free form or in the form of its acid addition salts, which is also included in the invention. For example, basic, neutral, acidic or mixed salts, optionally also hemi-, mono-, Sesqui- or polyhydrates thereof. The acid addition salts the new compounds can be converted into the free compound in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers. On the other hand the free base obtained can form salts with organic or inorganic acids. For the production of acid addition salts In particular, therapeutically useful acids are used, e.g. mineral acids such as hydrohalic acids, Sulfuric acid, phosphoric acids, or nitric acid Perchloric acid; aliphatic ^, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, vinegar, propionic, amber, glycol, milk, apple, Wine, lemon, aseorbin, maleic, hydroxymalein or

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Pyruvic acid; Phenylacetic, benzoic, ρ-amino-benzoic, 'anthranil-, p-hydroxy-benzoic, salicylic or p-amino-salicylic acid, emboxylic acid, nicotinic acid, methanesulphonic, ethane, sulphonic, hydroxyethanesulphonic, ethylene sulphonic acid ; Halobenzenesulphonic, toluenesulphonic, naphthalenesulphonic acids or sulphanilic acid or cyclohexylsulphamic acid; Methionine, ψ tryptophan, lysine or arginine.

These or other salts of the new compound, such as the picrates, can also be used to purify the obtained Free compounds are used by converting the free compound into salts, separating them and from the salts in turn clears the free connection. ·

. As a result of the close relationship between the new compound in free form and in the form of its acid addition salts are in the preceding and subsequently under the free connection in a meaningful and appropriate manner, if applicable to understand the corresponding acid addition salts.

The invention also relates to those embodiments of the process according to which one obtainable as an intermediate product at any stage of the process Connection goes out and the missing process steps are carried out, or in which the starting materials under the Forms reaction conditions or in which the reaction

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components optionally used in the form of their salts. For example, the above-mentioned amines or alcohols can be used in the form of their alkali metal salts, e.g. sodium or Potassium salts, can be used.

In the method of the present invention

those starting materials are preferably used which correspond to the compounds described at the beginning as being particularly valuable to lead.

The starting materials are known or, if new, can be prepared by methods known per se will. For example, the starting material used in process variant 1 a) is obtained by reducing one in the process 2) 1-oxo compound with sodium borohydride, conversion of the 1-hydroxy compound obtained, e.g. Reaction with thionyl or phosphorus halides, into one of their reactive esters, and reaction of the 1-halogen compound with magnesium, or with alkali metals or their alloys.

The starting point mentioned under 1 b) or Ic) substance is analogous to process variant 2), e.g. as follows Manufactured: By implementing an aliphatic

m ΨΒ ^ Ψ / 1 IBB

Metal offer & rigna ^ verWnäyng, -like formula Me-alkp-O-GI ^ -Cg H ₁ - only the Qxoveriaindüng of process variant 2)> one obtains an adduct whose hydrolysis and hydrogenation (around the Behzyl group and i if also the 1- Hydroxy group to ellmimiefren) dabe speaking 1 -hydroxyalkyl compound liel ^ rfc. ΊΜ preserved the compounds can be modified, the 1-hydroxyalkyl group by methods known per se. For example, it can be esterified with strong mineral acids or sulfonic acids to form reactive esters. One uses, for example, thionyl halides or phosphorus halides or oxyhalides or sulfonic acid halides, such as hiö ^ nyl chloride, phosphorus tribromide or pentabromide or phosphorus oxychloride, p-toluenesulfonic acid chloride or ^ -bromobenzenesulfonic acid chloride. The halogenated alkyl compounds obtained can then be reacted with phosphines, for example triphenyl phosphine.

The previously mentioned l-Hydroxyali ^ l-Ve ^ bdinauBg «n can also, e.g. with hydrogen peroxide or sulfur all salts or oxides, e.g. alkali metal chromates or permanganates ^ chromium (III) or copper (Hl-Mercury- (H) -, ftangan- (3CV) - or silver oxides, in acidic or alkaline media, are oxidized. Uie

The acids obtained can then be converted into acid halides, for example with the acid derivatives mentioned above, and these be reacted further with amines. Aldehydes obtained can be converted into oximes or Schiff's bases. The 1-haloalkyl compounds can also be used with alkali metal cyanides or silver nitrite are reacted, 1-cyano- or 1-nitro-alkyl starting materials being obtained. Valuable starting materials in which X stands for pormyl can be carried out starting from the ketones mentioned under 2) Reaction with dimethylsulfonium methylide or dimethyloxysulfonium methylide (obtained from the corresponding trimethylsulfonium salts) and rearrangement of the obtained Spiro-oxiranes (epoxies) by treatment with Lewis acids, e.g. ρ-toluenesulfonic acid or boron trifluoride. to the corresponding Aldehydes. The mentioned aidehydes can either be reduced or oxidized, being 1-hydroxymethyl or 1-carboxy compounds receives. These can be further converted as described above, while the aldehydes after reaction with nitro, methane or potassium cyanide, the corresponding l · (2-nitroäthenyl) compounds or deliver cyanohydrins. Finally can isocyanate and urethane starting materials starting from the acid halides and sodium azide and sodium azide already mentioned Degradation of the acid azide obtained according to Curtius, i.e. by

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■ - 24 -

Pyrolysis can be obtained in the presence or absence of an alcohol, e.g., lower alkanol.

The starting material used in process variant 2) »can be used according to the in Compt. Rend. 159 » Ρ · 1805 '(1954), J. Org. Chem. 2J_, p. 3844 (1962) Bull. Soc. Chim .. Prance 1957 * Ρ · 346 and I966, p. Methods described in 1963 can be obtained.

Starting materials or end products, which are mixtures of isomers, can be prepared by methods known per se, e.g. separated into the individual isomers by fractional distillation, crystallization and / or chromatography. Racemic products can also be converted into the optical antipodes, for example by separating their diastereoisomeric salts, e.g. be 'separated' by fractional crystallization of the d- or ß-tartrates.

The new compounds can be used as medicinal products, e.g. in the form of pharmaceutical preparations, which these compounds together with pharmaceutical, organic or inorganic, solid or liquid carriers, which are suitable for enteral, e.g. oral, or parenteral administration. For the formation of the same such substances come into question, which with the new

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bonds do not react, such as water, gelatin, sugar, e.g. lactose, glucose or cane sugar, starch, stearic acid, or their salts, e.g. magnesium stearate or calcium stearate, talc, vegetable fats or oils, gum, alginic acid / benzyl alcohol, polyalkylene glycols or others known excipients. The pharmaceutical preparations can be in the form of tablets, coated tablets or capsules or in liquid ** form as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, coloring agents or flavorings, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The pharmaceutical preparations are produced according to methods known per se and contain approximately 0.1 "to 75%> in particular 1 to 50 % active ingredient.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified. ^

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Example 1 . ■ '.

To a mixture of 2.3 g of magnesium turnings, 20 ml of tetrahydrofuran and 1 ml of ethyl bromide (starter) are added dropwise, with stirring, the solution of 11.4 g of 3-dimethylaminopropyl chloride in 20 ml of tetrahydrofuran, the mixture being kept under nitrogen holds, too. The reaction mixture is refluxed for 45 minutes, cooled in an ice bath and a solution of 10 g of 1-oxo-1,2,3,4-tetrahydro-naphthalene-2-spiroeyelohexane in 20 ml of tetrahydrofuran is added dropwise, with stirring The mixture is stirred for a further 3 hours at room temperature, left to stand overnight, the solution of magnesium residues is decanted and evaporated in vacuo The residue is taken up in 150 ml of benzene and 75 ml of mass are added dropwise, with stirring and cooling in an ice bath The mixture is heated and the above solution is decanted from the gel-like residue. The residue is triturated with warm benzene, filtered and washed with 150 ml of warm benzene. The combined organic solutions are washed with water, dried, filtered and evaporated in vacuo The residue is recrystallized from hexane, giving l-hydroxy-l- (3-dimethylaiaino-propyl) -l, 2,3,4-tetrahydro-naphthalene-2-spyrocyclohexane de r formula

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soft at 9O-92 ⁰ melts.

The product is dissolved in 100 ml of ethyl acetate, the solution is acidified with hydrochloric acid in ethyl acetate, the precipitate obtained is filtered off and extracted from isopropanol recrystallized, ftan receives the corresponding hydrochloride which melts at 214 (decomposition).

The starting material is prepared as follows: A solution of 29.8 g of 1-oxo-1,2,3, is slowly added to a suspension of 57j2 g of potassium tert-butoxide in 500 ml of benzene, while cooling and stirring under nitrogen. 4-tetrahydro naphthalene in ¹ IOO ml of benzene was added. The mixture is then, within 45 minutes, mixed with a solution of 46.9 S 1,5-dibromopentane in 50 ml of benzene, slowly warmed and then refluxed for 5 hours. The reaction mixture is left at room temperature overnight and poured onto 350 g of crushed ice and 80 ml of concentrated hydrochloric acid. The organic layer is separated and the aqueous solution is extracted with diethyl ether. The combined organic solutions are washed with 5% aqueous sodium carbonate and water, dried, filtered and evaporated in vacuo. The residue

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is distilled and the boiling at 122-128 ° / 0.3 mm Hg Group collected. 1-Oxo-1,2,3,4-tetrahydronaphthalene-2-spirocyclohexane is obtained.

Example 2;

A solution of 10 g of 1-oxo- 1,2,3, K -tetrahydro-riaphthalin-2-spirocyclohexane in 20 ml of tetrahydrofuran is added dropwise, with stirring and cooling, to a Grignard reagent, which is composed of 1.71 g of magnesium, 0.5 ml of ethyl bromide, 9 * ^ S 1-methyl-4-chloro-piperidine and 50 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 4 hours, left to stand overnight and evaporated in vacuo. The residue is taken up in benzene and a solution of 25 ml of glacial acetic acid in 25 ml of water is added dropwise, while cooling. The organic layer is separated and washed with water. The combined aqueous solutions are mixed with 5 g of ammonium chloride and made basic with aqueous ammonia. The mixture is extracted with diethyl ether, the extract is washed with water, dried, filtered and evaporated in vacuo. The residue is recrystallized from aqueous methanol. The 1-hydroxy-1 - (1 -methyl-k -piperidyl) -1, 2, 3, 4-th trahydro-naphthalene-2-spiroeyclohexane of the formula is obtained

909845/1755

HO

which melts at 137-138 ^0.

3 g of this product are dissolved in 50 ml of ethyl acetate and 10 ml of isopropanol and acidify the solution with hydrogen chloride in ethyl acetate. The precipitate obtained is filtered off and washed with ethyl acetate. The corresponding hydrochloride is obtained which at 225 ° (decomposition) melts.

Example 5:

A solution of 10 g of 1-oxo-1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane in 20 ml of tetrahydrofuran is added dropwise, with cooling and stirring, to a Grignard reagent, which consists of 1.71 g of magnesium, 10.3 S 1-methyl-3-chloromethyl-piperidine, 0.5 ml of ethyl bromide and 50 ml of tetrahydrofuran is made, added. The mixture is further stirred for 5 hours at room temperature, overnight left to stand, then evaporated in vacuo: the residue is taken up in benzene and treated with a solution of 25 ml of ice

9098457 175 5

INSPBCTEO

vinegar in 25 ml of water drop by drop, while stirring and cooling> offset. The organic layer is separated with water washed, the aqueous solutions are combined and made basic with aqueous ammonia. The mixture is extracted with diethyl ether and the extract is washed with water , dried, filtered and evaporated. The residue is recrystallized from aqueous methanol, a solid fraction A and the mother liquor B being obtained. Man takes 2.4 g of the solid material A in 75 ml of hot ethyl acetate and adds isopropanol until it dissolves. The solution is then acidified with hydrogen chloride in ethyl acetate, the precipitate obtained is filtered off and washed with ethyl acetate-isopropanol washed. The higher-melting racemate (caused by 2 asymmetric carbon atoms) is obtained 1-Hydroxy-1 - (1-methyl -3-piperidylmethyl) -1, 2,3, - ^ - tetrahydro naphthalene ^ -spirocyclohexane hydrochloride the formula

* HCl,

which flashes at 288 (decomposition).

909845/1755

The mother liquor B is evaporated in vacuo, the. The residue was taken up in 50 ml of ethyl acetate, the solution acidified with hydrogen chloride in ethyl acetate, the resulting precipitate filtered off, with 100 ml of boiling chloroform triturated and recrystallized from ethyl acetate-isopropanol. The lower-melting racemate of the above compound is obtained, which melts at 220-221 ° (decomposition).

Example 4;

The following compounds are prepared according to the methods described in the preceding examples:

I) 1-Hydroxy-1- (3-dimethylamino-propyl) -5-methoxy-1,2,3 * 4-tetrahydro-naphthalene-2-spirocyclohexane hydrochloride, F. (Decomposition);

II) 1-Hydroxy-1- (3-dimethylamino-propyl) -6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane, Ρ. 93 ~ 95 }

III) 1-Hydroxy-1- (3-dimethylamino-propyl) -6,7-dimetnoxyli2,3 # 4-tetrahydro-naphthalene-2-spirocyolohexane, P. II6-II7 ⁰ ;

IV) l-Hydroxy-l ~ (3-dimethylaminopropyl) -5-chloro-l, 2,3, 4-tetrahydro-naphthalene-2-spirocyclohexane hydrochloride;

V) 1-Hydroxyrl- (3-dimethylamino-propyl) -7-chloro-1,2,3 * 4-tetrahydro-naphthalene-2-spirocyclohexane hydrochloride; the mixture of compounds IV) and V) at 201-205 ° melts /

909845/1755

- ■. - 32 -

VI) l-Hydroxy-l-13-dimethylamino-propyl) -l, 2,3,4-tetrahydro-naphthalene ^ -spirocyclopentane hydrochloride, P. 193 ^and

VII) 1 -hydroxy rl - (3-dimethylamlno-propyl) -ownethoxy-1,2, 3,4-tetrahydro-naphthalene-2-spirocyclopentane, F. 76-78 *

The starting materials are prepared as follows: A solution of 36 S l-0xo-6-methoxy is added to a suspension of 57.2 g of potassium tert-butoxide in 500 ml of benzene within 30 minutes, while cooling and stirring under nitrogen -1,2,3,4-tetrahydro-naphthalene in 150 ml of benzene was added. A solution of 46.9 S 1,5-dibromopentane in 100 ml of benzene is added to the reaction mixture over the course of 45 minutes. The mixture is allowed to slowly warm to room temperature, refluxed for 5 hours and left to stand at room temperature overnight. The mixture is then poured onto 350 g of crushed ice and 80 nil concentrated hydrochloric acid, the organic layer is separated off and the aqueous solution is extracted with dietary ether. The combined organic solutions are washed with 5% aqueous sodium carbonate and water, dried, filtered and evaporated in vacuo. The residue is distilled and the fraction boiling at 160-163 ° / 0.3 mm Hg is collected. The l-oxo-o-methoxy-l ^^^ - tetrahydro-naphthalene-2-spirocyclohexane, which, after recrystallization from methanol, melts at 70-71.5 °.

909845/1755 Λ

- 33 - 1 91S082

The following starting materials are in analog Way, starting from equivalent amounts of corresponding Intermediate products manufactured:

a) l-Oxo-5-methoxy-1,2,3, ^ - tetrahydro-naphthalene ^ -spirocyclohexane, boiling point 138 ⁰ -151 ° / 0 * ² mm Hg.

'b) l-Oxo-l ^^^ - tetrahydro-naphthalene - ^ - spirocyclopentane, Boiling point 99-103 ° / 0.2 mm HgJ

c) l-Oxo-6-methoxy-1,2,3i ^ - ^tetra hydrο-naphthalene-2-spirocyclopentane, boiling point 144-146 ^o / 0.3 mm Hg;

d) l-Oxo ^^ - dihydro-indene ^ -spirocycldhexane, boiling point 110-112 ° / 0 ^ 3 mm Hg, P. 53-56 °.

Another starting material is prepared as follows: A solution of 86 g of butyralactone and 1000 g of chlorobenzene is mixed with 500 g of anhydrous aluminum chloride in portions within 2 hours under nitrogen and the mixture is heated to 95 ° for 20 hours. After cooling, it is poured onto 2500 g of ice and ² K) O ml of concentrated hydrochloric acid. The organic layer is separated and the aqueous solution is extracted with toluene. The combined organic solutions are washed with water, 200 ml of a 20% aqueous potassium hydroxide solution and again with water, dried, filtered and evaporated in vacuo. The residue is distilled and the fraction boiling at 115 ° / 0.3 mm Hg is collected. According to vapor phase chromatography, the product consists of 46- ^ 8 ^ 5-chlorine-, 16-22 #

909845/1755

6-chloro » - and 16-2M% 7-chloro-1-oxo-1,2,3,4-tetrahydro-naphthalene. You leave the product for several days "? / Stand at room temperature, whereby crystals separate out. These are filtered off and washed with a filtered penfcan. A mixture is obtained which consists of 56,4 ^ 5-chloro- and 43.6% 7-chloro-1-oxo-1,2,3,4-tetrahydro-naphthalene (fraction A>. The piltrate allowed to stand for about one week, thereby forming a further precipitation This is filtered off and washed with chilled pentane is ^obtained:.. a mixture consisting of 6o, 9 # 5-chloro, 6-chloro ~ $ 2.9 and 33 »1% 7-chloro-1-oxo-1,2,3,4-te trahydro-naphthalene (fraction B) consists. The solution of fraction A in pentane is thin-layer chromatographed on aluminum oxide The band yields the 5-chloro-1-oxo-1,2,3 * ^ - tetrahydro-naphthalene, which melts at 65.5-67 ° C. The eluate of the slower moving bane gives the 7-glildr- \ l-oxo -1,2,3,4-tetrahydro-naphthalene, which melts at 98-99.5 ° »

Fraction B is as shown above, first with " Potassium tert-butoxide and the potassium compound obtained reacted with 1,5-dibromopentane, whereby one

e) the mixture of 5-chloro and 7-chloro-1-oxo-1, 2 _> 3, 4-tetrahydro-naphthalene-2-spiro-cyclohexane, which is used in. 13O-14O ^Q / O * 2 rnm Hg boils / maintains.

909845/1755

Example 5 t

A mixture of 7 g of 1-hydroxy-1- (3-dimethylamino-propyl) -6-methoxy-1,2,3, ^ - tetrahydro-naphthalene-2-spirocyclopentane (M.p. 76-78 °), 30 ml of chloroform and 5 ml of acetyl chloride is refluxed for 70 minutes and a vacuum

steamed. The residue is taken up in water, the solution is made basic with 2N aqueous sodium hydroxide solution made and extracted with diethyl ether. The extract is washed with water, dried, filtered and in vacuo evaporated. The residue is taken up in ethyl acetate, the solution is acidified with hydrogen chloride in ethyl acetate, the precipitate obtained is filtered off and recrystallized from acetone. The 1- (3-dimethylamino-propylidene) -6-methoxy-1,2,3, ^ - tetrahydro-naphthalene-2-spirocyelopentane hydrochloride is obtained the formula

GH-CH ₂ -GH ₂ -N (CH ₃ ) ₂ * HCl

which melts at 164-165.

909845/1755

Example 6 -fr

A solution of 5 g of l-oxo-6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane in 60 ml of tetrahydrofuran is added dropwise, with cooling and stirring, to a Grignard reagent, which is obtained from 1 , 6 g of magnesium, 8 g of 3-dimethylaminopropyl chloride, 0.5 ml of ethyl bromide and 50 ml of tetrahydrofuran is added and stirring is continued for 3 hours at room temperature. The reaction mixture is left to stand overnight, with cooling and stirring first 75 ml of water and then 50 ml of hot benzene. The organic solution is decanted and hot benzene 3 ~ ^m al was added. The combined organic solutions are washed with water, dried, filtered and attenuates. The residue is recrystallized from chloroform-hexane The 1- (3-dimethylaminopropylidene) -6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane of the formula is obtained

CH-CH ₂ -CH ₂

₂ CH ₂

which melts at 174 - 175 °.

909845/1755

The product is taken up in hot ethyl acetate, and the solution with hydrogen chloride in ethyl acetate, under ' Cool and stir, acidified. The precipitate obtained is filtered off and washed with ethyl acetate. You get the corresponding hydrochloride which at I72 - 174 melts.

Example 7:

A hot solution of 2 g of 1-hydroxy "-! - (3-dimethylamino-propyl) -β-methoxy- 1,2, J>, 4-th trahydro-naphthalene-2-spirocyclopentane (P. 76-78 °) in a minimal amount of ethyl acetate is slowly acidified by adding dropwise hydrogen chloride in ethyl acetate, while stirring. The precipitate obtained after cooling is filtered off and recrystallized from acetone to give 1- (3-dimethylamino-propylidene) -o-methoxy-1 ^^ j ^ -tetrahydro-naphthaiin ^ -spirocyclopentane hydrochloride »The product is identical to that of Example 5.

Example 8 i

The following connections are made according to the in the methods described in Examples 5 to 7 prepared: a) 1- (3-Dimethylamino-propylidene) -Ii2,3j4-tetrahydronaphthalene-2-spirocyclohexane hydrochloride P. I90 - °

909845/1755

1S19082

■ - 38 -

b) 1 - (3-Dimethylamine) propylidene) -6-methoxy-1, 2, 3 * 4-tetrahydro-naphthalene ^ -spirocyclohexane hydrochloride,

p. 189-190 °;

c) l- (3-dimethylamino-propylidene) -6 _{J 7-dimethoxy-l:} 2, _J 3, 4-tetrahydro-naphthalene-S-spirQcyclohexan-hydrochloride 164-167 ° F. and -

d) 1- (3-Dimethylamino-propylidene) -2 _i , 3-dihydro-indene-2 «spirocyGlohexan-hydroGhloridj P. 211-212 °.

Example 9?

A mixture of 6 ^ 2 g l- (3-Dimeti ^ laniino-propyliden) -6-methoxy-1,2 _t y _a ^ -tetrahydro-naphthalene ^ -spiro cyclohexane, 1 g platinum oxide and 100 ml ethanol is made at room temperature until the uptake of 550 wl Wasserstorf hydrogenated "the mixture is filtered, the ^ Pil joined evaporated in vacuo, the residue taken up in diethyl ether., the solution was washed with water, dried filtered, evaporated. The residue is desfe ^ -liert and the practice boiling at 162- \ 6k / 0.3 mm Hg collected. The 1- (3-dimethylamino-propyl) -6-methoxy-1, 2, 5, $ -tetrahydronaphthalene -2-spirocyclohexane of the formula is obtained.

9O084S / T7 55

ORIGINAL INSPECTED

The product is dissolved in anhydrous diethyl ether and the solution with hydrogen chloride in ethyl acetate. neutralized. The precipitate obtained is filtered off and washed with dietary ether. You get the corresponding Hydrochloride which melts at 137-141 °.

Example 10;

A solution of 1 g of 1- (N, N-dimethylcarbamoyl-ethyl) 6-methoxy-1,2,3, ^ - tetrahydro-naphthalene - ^ - spirocyclohexane in 5 ml of dietary ether is added dropwise, with stirring, to a mixture of 0 , 5 g of lithium aluminum hydride and 25 ml of anhydrous dietary ether were added and the reaction mixture was stirred at room temperature overnight. 1.5 ml of ethyl acetate, 0.5 ml of water, 1 ml of a 5 # strength aqueous sodium hydroxide solution and 1.5 ml of water are then added. The precipitate obtained is filtered off, washed with dietary ether, the piltrate is dried and evaporated. The residue is dissolved in a minimal amount of dietary ether, the solution is neutralized with hydrogen chloride in ethyl acetate, and the resulting precipitate is filtered off and washed with ether. 1- (3-Dimethylamino-propyl) -6-methoxy-1,2,3,4-tetrahydro-naphthalene-spirocyclohexane hydrochloride, which ^{melts at 136-139 0} , is obtained. The product is identical to that of Example 9.

909845/1755

- 4ο -

The starting material is prepared as follows: A solution of 11 g of l-oxo-6-methoxy-1,2,3, ^ - tetrahydro-naphthalene -2-spiroeyclohexane in 20 ml of tetrahydrofuran becomes a Grignard reagent, which is composed of 1 , 7 β magnesium, 50 ml tetrahydrofuran and 11.9 S 2-benzyloxy-ethyl chloride is prepared, added dropwise, with stirring and cooling. The reaction mixture is stirred for 5 hours at room temperature, allowed to stand overnight, then cooled again in an ice bath, treated dropwise with 30 ^m l of water, then treated with a mixture of 15 ml of concentrated hydrochloric acid and 75 ml of water and finally ml with 100 diethyl ether, the The organic layer is separated off, the aqueous solution is extracted with diethyl ether, the organic solutions are combined, washed with water, dried, filtered and evaporated. 10 g of the residue are taken up in a minimal amount of hot glacial acetic acid, 3.5 g of 10 # are added Palladium carbon is added and the mixture is hydrogenated at about 25-70 ° and 3.4 atmospheres until the theoretical amount of hydrogen has been absorbed. The reaction mixture is filtered, the filtrate is evaporated in vacuo, the residue is taken up in diethyl ether, the solution is washed with 10 aqueous potassium carbonate solution, dried, filtered and evaporated. 1- (2-Hydroxyethyl) -6-methoxy-1,2,3,4-tetrahydronaphthalene-2-spirocyclohexane is obtained.

90 9845/175 5

To a mixture of 13.7 g of the latter Product, 50 ml of benzene and 4 g of pyridine are added to the solution of 9 g of thionyl chloride in while cooling and stirring Add 10 ml of benzene. The mixture is refluxed until the evolution of sulfur dioxide ceases, then cooled with water and an aqueous solution of potassium carbonate washed, dried, filtered and evaporated. The 1- (2-chloro-ethyl) -6-methoxy-1,2,3j is obtained ty-tetrahydro-naphthalene ^ -spirocyclohexane.

13 g of this product are added in portions to a solution of 4 g of potassium cyanide in 4 ml of water and 16 ml of ethanol at 80 ° with stirring. The reaction mixture is refluxed for 5 hours and evaporated in vacuo. The residue is taken up in water, the mixture is extracted with ethyl acetate, the extract is washed with water, dried, filtered and evaporated in vacuo. To yield the l- (2-cyano-ethyl) _-6-r methoxy l, 2,3,4-tetrahydro-naphthalen-2-spirocyclohexane.

A mixture of 11 g of this product, 12 ml of water, 12 g of sodium hydroxide and 40 ml of ethylene glycol is 4 hours boiled under reflux and then poured in 200 ml of water pour. The resulting solution is treated with concentrated hydrogen chloride acidified and extracted with diethyl ether. The extract is washed with water, dried and filtered and evaporated. The residue is dissolved in 10 # aqueous

909845/1755

Potassium carbonate solution added, the mixture with diethyl ether washed and acidified with hydrochloric acid. It is extracted again with diethyl ether, the extract is dried, filtered and evaporated. 1- (2-Carboxy-ethyl) -6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane is obtained.

A mixture of 5 * 5 g of the latter product, 25 ml of benzene and 2.5 ml of thionyl chloride is refluxed for one hour and evaporated in vacuo. Benzene is added to the residue and this is evaporated. The residue is dissolved in 25 ml of benzene and the solution added dropwise, with stirring, is added to a mixture of 3 S ^ä dimethylamine in 25 ml of benzene, keeping the temperature below 20 °. The mixture is stirred overnight at room temperature and the resulting precipitate is filtered off. The piltrate is evaporated in vacuo, the residue is taken up in diethyl ether, the solution is washed with water, 2N aqueous hydrochloric acid, 2N aqueous sodium hydroxide and water, dried, filtered and evaporated. The 1- (N, N-dimethylcarbamoyl-ethyl) -6-methpxyl * 2,3, ^ - tetrahydro-naphthalene-2-spirocyclohexane is obtained, which is used without further purification.

The above-mentioned chloro-ethyl compound can also with an excess of di-n-butylamine, pyrrolidine, morpholine or 1-methyl-piperazine are reacted, whereby the

909845/1755

1- (2-di-n-butylamino, pyrrolidino, morpholino or N-methyl-pirerazino-ethyl) -6-methoxy-1,2,3, ^ - tetrahydro-naphthalene -2 -spirocyclohexane is obtained.

The above-mentioned cyano compound can also be reduced like the above-mentioned dimethylamide compound, being the 1- (3-aminopropyl) -6-methoxy-1,2,3,4-tetrahydronaphthalene-2-spirocyclohexane receives.

Example 11 ι

Production of 10,000 tablets each containing 100 mg of the active substance:
Components:

l-Hydroxy-1- (3-dimethylaminopropyl) -1,2, ^ * ^ ~ t; etrahydronaphthalene-2-spirocyclohexane hydrochloride 1000 g

Milk sugar 2535 g

Cornstarch. 125 g

Polyethylene glycol 6000 150 g

Talc powder ', 150 g

Magnesium stearate. 40 g

purified water

All powders are sieved with a sieve with a mesh size of 0.6 mm. The active ingredient, the "milk sugar, the The talc, the magnesium stearate and half the amount of the starch are then mixed in a suitable mixer. The rest the corn starch is suspended in 65 ml of water and the sus-

909845/1755

pension to a boiling solution of polyethylene glycol 'in 2βΟ ml. water added. The paste obtained becomes too

added to the powder mixture, and optionally with addition. would give another amount of water, granulated. The granules

is dried overnight at 35 °, through a sieve with 1.2

mm mesh size and formed into tablets (10.3 mm diameter " knife), which have a breaking groove, pressed.

Example 12:

Production of 10 ¹ 000 tablets, each containing 50 mg of the active substance: components;

l- (3-dimethylamino-propylidene) - 500 g

6-methoxy-1 / 2,3,4-tetrahydronaphthalene-2-spirocyclopentane hydrochloride «.

Milk sugar I706 g

Corn starch 9O g

Polyethylene Glycol 6000.90 g

Talc powder, 90 g -

Magnesium stearate 24 g

purified water . q.s.

90984S / 1755 ^:

Procedure: Same as in Example 11, with the difference that the starch is suspended in 45 ml of water and the ethylene glycol is taken up in 180 ml of water. The granulate is compressed into tablets of ¹ J _f l mm in diameter.

Example 13:

. A Grignard reagent, which consists of 2.11 g of magnesium, 0.5 ml of ethyl bromide and 10.6 g of ^ -dimethylamino-propyl chloride is prepared in 40 ml of tetrahydrofuran, is added dropwise, within 20 minutes, with cooling, with a solution of 9 ^ 9 S l-Oxo-l ^^^ - tetrahydro-naphthalene ^ -spirocycloheptane added in 20 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours, over · ' Left overnight by decanting the unchanged Separated magnesium, evaporated under reduced pressure and the residue taken up in 150 ml of benzene. The solution is added dropwise, with stirring and cooling in an ice bath, with 75 ml of water and the mixture on the steam-a heated bath. The organic layer is separated off by decanting and the gel-like residue is extracted three times with 75 ml of hot benzene while stirring. The residue is finally filtered, and with 150 ml of hot benzene

909S4S / 1755

ORfGlNAL INSPECTED

washed. The combined organic solutions are washed with water, dried and evaporated. The residue is taken up in 75 rol of ethyl acetate and the solution with Strongly acidified hydrogen chloride in ethyl acetate. The precipitate obtained is filtered off and washed with ethyl acetate and recrystallized from isopropanol. The l-hydroxy-1- (3-dimethyamino-propyl) -1,2,3 * ^ - tetrahydronaphthalene-2-spirocycloheptane hydrochloride is obtained the formula

which melts at 218 (with decomposition).

1-Hydroxy-1- (3-dimethylamino-propyl) -6-methoxy-1,2,3i ^ -tetrahydro-naphthalene-2-spirocycloheptane is produced in an analogous manner. It dehydrates in strongly acidic Medium, whereby the l- (3-dimethylamino-propyl ± den) -6-metftöxy-Ij 2.3. » 4th trahydro-naphthalene-2-spirocycloheptane hydrochloride the formula

9 © 984S / 115S

-NC CH) ₂ • HCl

CTT f \

which after recrystallization from acetone at I88-189 melts, receives.

Example 14:

A Grignard reagent, which is composed of 1, ^ 9 6

Magnesium, 0.5 ml of ethyl bromide, 7 * ^ 6 g of 3-dimethylamino-propyl chloride and 40 ml of tetrahydrofuran is produced drop by drop, with stirring and cooling, with a solution of 7 g of l-oxo - ^ - benzocyeloheptane - ^ - spirocyclohexane in 20 ml Tetrahydrofuran added. The reaction mixture is left to stand overnight, the solution is decanted and evaporated under reduced pressure. The residue is taken up in benzene and the solution is added dropwise, with stirring Cool, add 60 ml of water and warm the mixture in hot water. The organic solution is decanted, the Triturated residue with warm benzene and the combined

909845/1755

organic solutions washed with water, dried, filtered and evaporated. The residue is in 200 ml Acetate added and the solution with hydrochloric acid acidified in ethyl acetate. The precipitate obtained is filtered off and recrystallized from isopropanol. Man receives the 1-hydroxy-1- (3: £ imethylamino-propyl) -benzocycloheptane-2-spirocyclohexane hydrochloride the formula

HO

which melts at 258 (with decomposition).

Example 15:

A Grignard reagent, which consists of 2.22 g of magnesium, 0.5 ml of ethyl bromide and 11.1 g of 3-dimethylaminopropyl chloride is prepared in 40 ml of tetrahydrofuran, is added dropwise, with stirring and cooling, with a solution of 9.7 g of 1-oxo

909845/1755

1019082

l * 2,3 * ^ - tetrahydro-naphthalene-2-spirocycio-3-hexe.n In 20 ml of tetrahydrofuran are added. The mixture is 5 hours stirred at room temperature and then left to stand overnight. The above solution is decanted under reduced pressure Evaporated pressure, the residue taken up in 100 ml of benzene and the solution dropwise, with stirring and Cool, mixed with 50 ml of water. The mixture is on heated the steam bath, the organic layer separated and the residue triturated three times with 75 ml of hot benzene and finally washed with 100 ml of benzene. The combined solutions are washed with water, dried, filtered, evaporated and the residue recrystallized from hexane. The l-hydroxy-1- (3-dimethylamino-propyl) -1,2,3,4-tetrahydro-naphthalene ^ -spirocyclo ^ -hexene is obtained the formula

which melts at 93 ~ 95 °. The corresponding Hydrochlorld melts at 203 - 205 ° (with decomposition).,

Example. l6 i; ', - L ^ ■

A solution of 4 g of l-hydroxy-l- (3-dimethylaminopropyl) -1,2,3 * ^ -tetrahydro-naphthalene - ^ - spirocyclo ^ -hexene in 50 ml of chloroform and 3 * 35 ml of aeetyl chloride is refluxed for 70 minutes heated and then evaporated under reduced * pressure. The residue is taken up in water, made strongly acidic ^r the solution with concentrated hydrochloric acid and washed with ether. The aqueous solution -; is "basified ■, extracted with ether, wash the extract with water ge ^, dried and evaporated. The residue is iri ■■" with 6N aqueous sodium hydroxide solution was added '■' Essigester, the solution acidified with hydrogen chloride in Essigester, the precipitate obtained äiöfiltri-drt ^'and washed with Essigester. The 1- (3-dimethyiamino-propylidene) -1,2,3 * ^ -i 3-hexen-hydrochloride of the formula is obtained

.HGl

INSPECTEO

which melts at 197 (with decomposition).

Example 17:

A mixture of 42 gl, 6-dihydroxy-l- (3-dimethylaminopropyl) -l, 2,3, ¹ t-tetrahydro-naphthalene-2-spirocyclohexane, 250 ml of chloroform and 38 ml acetyl chloride is heated on a steam bath for 70 minutes and evaporated under reduced pressure. The residue is taken up in water, the solution is washed with ether and the aqueous layer is made basic with 2N aqueous sodium hydroxide solution. This is extracted three times with ether, the extract is washed with water, dried and evaporated. The residue is taken up in ethyl acetate, the solution is acidified with hydrogen chloride in ethyl acetate, the precipitate obtained is filtered off and recrystallized from isopropanol. One obtains the 1- (3-dimethylamino-propylidene) -6-acetoxy-1,2,3 * ^ * "tetrahydro-naphthalene-2-spirocyclohexane hydrochloride of the formula

Cff-CH ₂ -CH ₂ - ^ (CH ₅ ) ₂ .HOl

CH ₃ -CO

909845/1755

Which melts at 188-189 ^0. .

Example l8:

A Grignard reagent, which is composed of magnesium 1.71 S, 10 S * 3 1-Methyl-3-chloromethyl-piperidine, 0.5 ml of ethyl bromide and 50 · ml of tetrahydrofuran is prepared, is reacted with a w solution of 11.6 g l-0xo-6-methoxy-1,2,3, ^ - tetrahydro-naphthalene-2-spirocyclopentane in 20 ml of tetrahydrofuran, with stirring and cooling, added dropwise and then stirred at room temperature for 5 hours. The reaction mixture is left to stand overnight, then evaporated under reduced pressure, the residue is taken up in benzene and a solution of 25 ml of glacial acetic acid in 25 ml of v / water is added dropwise with stirring and cooling. The organic solution is separated, washed with water, the aqueous solutions are combined and made basic with aqueous ammonia. The mixture is extracted with ether, the extract is washed with water, dried, filtered and evaporated. The residue is in 100 ml. Acetate was taken up, the solution was acidified with hydrogen chloride in ethyl acetate and the resulting precipitate was filtered off. This is triturated several times with warm acetone. The 1-hydroxy-l- (l-methyl-3-piperidyl-methyl) -

909845/1755

6-methoxy-1,2,3 * ^ - tetrahydro-naphthalene-2-spirocyclopentane hydrochloride the formula

Hi

. HCl,

which melts at 219 ° (with decomposition).

The acetone solution is evaporated under reduced pressure, the residue is combined with that of the ethyl acetate piltrate and taken up in water. The solution is washed with ether, made basic with 2N aqueous sodium hydroxide solution and extracted with ether. The extract is washed with water, dried and evaporated under reduced pressure. 9 * 8 g of the residue are taken up in 25 ml of ethyl acetate, the solution is combined with the solution of 3 * 5 S maleic acid in 25 ml of warm isopropanol and the mixture is left over Stand in the refrigerator at night. The resulting precipitate is separated off, triturated with ether, washed with a cold mixture of ethyl acetate-isopropanol (3 ^; l), dried and recrystallized from 100 ml of ethyl acetate. The l- (l-methyl-3-piperidyl ~

909845/175 5

methylidene) -6-niethoxy-1,2,3j4-tetrahydro-naphthalene-2 spirocyclopentane maleate of the formula

CH COOH

CH COOH

which melts at 144-146.

Example 19 -i

A Grignard reagent, which is prepared from 12.7 g of magnesium and 63.5 g of 3- ^D i ^met hylamino-propyl chloride ⁱⁿ 400 ml of tetrahydrofuran, with stirring and cooling, with a solution of 4Q g of 1-Oxo-6- hydroxy-1,2,3 * 4-tetrahydronaphthalene-2-spirocyclohexane in 20O ml of tetrahydrofuran was added dropwise and the mixture was then stirred for a further 5 hours at room temperature. The reaction mixture is left to stand overnight, first 200 ml of water and then 200 ml of benzene are added while cooling. The organic solution is decanted

909845/1755

ORIGINAL INSPECTED

and the residue is triturated three more times with benzene. the combined organic solutions are washed with water, dried, filtered and under reduced pressure evaporated. The residue is taken up in a minimal amount of isopropanol and the solution with the approximately the same volume of hexane is added. 1,6-Dihydroxy-1- (3-dimethylamino-propyi) -1,2,3 * ^ - tetrahydro-naphthalene-2-spirocyclohexane is obtained the formula

which melts at 108-115 °. Under these mild conditions (if you don't have hot benzene and no acidic chloroform used and evaporated under reduced pressure) the dehydration shown in Examples 6, 13 and 18 occurs not a.

Example 20 s

By a solution of 3.5 g of l- (3-dimethylamino-

propylidene) -6-methoxy-1,2,3,4-tetrahydro-naphthaliri-2-

909845/1755

■ spirocyclopentän in 35 ml of ethanol is at room temperature, with stirring, passed through methyl bromide for 20 minutes and then left the mixture to stand for 2.5 days. It will evaporated under reduced pressure, the residue extracted with ether and recrystallized from isopropanol. Man receives the l- (3-trimethylammonium-propylidene) -6-methoxy-l, 2, 3,4-tetrahydro-naphthalene-2-spirocyclopentane bromide of the formula

, CH-CH ₂ -GH ₂

ι. O

which melts at 223-224.

Example 21:

A solution of 3 g of 1- (2-nitro-ethenyl) -l, 2,3,4-tetrahydro-naphthalene-2-spirocyclopentane in 15 ml of tetrahydrofuran is added dropwise to a mixture of 0.7 g of lithium aluminum hydride added in 17 ml of ether with stirring. The reaction

909 845/175 5

The mixture is then refluxed for 6 hours, cooled, treated with 0.7 ml of water, 1.4 ml of a 12% aqueous sodium hydroxide solution and 2.1 ml of water, in this order. It is filtered and the filtrate is washed with water The solution is acidified with hydrogen chloride in ethyl acetate, the precipitate obtained is filtered off and recrystallized from acetone , giving 1- (2-aminoethyl) -1,2,3,4-1e trahydrο -naphthalene-2-spirocyclopentane hydrochloride of the formula

H ₂ -CH ₂ -NH ₂ . HCl

sS \

which in the IR spectrum, among other things, shows bands at 750, 1250, 1600 and 2500 cm ¹ .

The starting material is prepared as follows: A mixture of 2.4 g of sodium hydride and 80 ml Dimethyl sulfoxide is reduced to 75% under nitrogen Hydrogen evolution ceases, warmed up. The reaction mixture is then cooled to room temperature with 80 ml

90984S / 1755

Diluted tetrahydrofuran and quickly combined with a solution of 20.4 g of trimethylsulfonium iodide in 80 ml of dimethylsulfoxide, with stirring at -5 to 10 °. At the same temperature, a solution of 20 g of l-oxo-l, 2,3, ⁱ f-tetrahydro-naphthalene-2-spirocyclopentane in 20 ml of tetrahydrofuran is then added over the course of 10 minutes while stirring. After a further 15 minutes, the mixture is stirred at room temperature for 45 minutes. It is then poured into 8θΟ · ml of water, extracted with ether, the extract washed with water, dried and evaporated under reduced pressure. 1 ₅ 2,3,4-tetrahydro-naphthalene-1-spirooxirone-2-spirocyclopentane is obtained.

10.7 g of this epoxide are added to an azeotropically dried solution of 2 g of p-toluenesulfonic acid in 200 ml of benzene and reflux the mixture for 16 hours. It is allowed to cool, washed with an aqueous solution of potassium carbonate and water, dried, filtered and it evaporates under reduced pressure. You get the 1,2,3 * ^ ' Tetrahydro-naphthalene-2-spirocyclopentane-1-carboxaldehyde.

A mixture of 5.3 g of 1,2,3,4-tetrahydro-naphthalene-2-spirocyclopentane-1-carboxaldehyde, 1.6 g nitromethane and 30 "1-1 methanol is, with stirring and cooling in an ice bath, dropwise with 4.6 ml of a 5 normal aqueous sodium hydroxide solution offset. The mixture is at 3 hours

909845/1755

Stirred 20-25, then strongly acidic with 6 normal hydrogen chloride while cooling and diluted with water. The precipitate obtained is filtered off and washed with water. The 1- (2-nitro-ethenyl) -l _J 2 _J 3 * ^ ~ tetrahydro-naphthalene-2-spiroeyclopentane is obtained.

Example 22:

Starting from equivalent amounts of corresponding starting materials, according to Example 3, 1-hydroxy-I- (I-methyl-3-piperidylmethyl) -1,2,3 * 4-tetrahydro-naphthalene-2-spirocyclopentane hydrochloride, F. 214 ° (with decomposition) and according to Example 9 the 1- (3-dimethylamino-propyl) -3-methoxy-1,2,3 * 4-tetrahydro-naphthalene-2-spirocyclopentane hydrochloride, P. 174-176 °.

Example 23:

A mixture of 14.6 g of magnesium and 50 ml of tetrahydrofuran is first with 40 ml of a solution which consists of 73 g of 3-dimethylaminomethyl-propyl chloride in 100 ml of tetrahydrofuran is made, offset. The remainder of this solution is added dropwise to the reaction mixture. This is stirred cooled and finally refluxed for 45 minutes cooked. Then a solution of 70 g of l-oxo-6-methoxy-

9098AS / 1755

i * 2,3 * ^ - tetrahydro-naphthalene-2-spirocyclopentane in 100 ml of tetrahydrofuran, while stirring and cooling in an ice bath, was added dropwise over 50 minutes. The mixture is stirred at room temperature for 4 hours, left to stand overnight, separated from the unchanged magnesium by decantation and evaporated under reduced pressure. The residue is taken up in a minimal amount of benzene, stirred and cooled in an ice bath, and 150 ml of water are added dropwise. The mixture is then heated on the steam bath, the hot solution is separated from a gel by decanting and filtered. The residue is washed with 150 ml of hot benzene, the piltrate is washed with water, dried, filtered and evaporated and the residue is recrystallized from hexane. To yield the l-hydroxy-l- (3-dimethylamino-propyl) -6-methoxy-l _J, 2,3j> ⁱ '--tetrahydro-naphthalene - ^ - spirocyclopentane, which melts at 76-78 ^0th The product is identical to the compound described in Example 4. '

The raw material is produced as follows?

A mixture of 171 g of potassium tert-butoxide and 750 ml of benzene is stirred with a solution of I07, g l-0xo-6-methoxy-l, 2,3,4-tetrahydro-naphthalene in 350 ml Benzene within 15 minutes * while stirring, added «

909845/1755

The mixture is diluted with 150 ml of benzene for 5 minutes at 15 stirred, and then within 35 minutes with a Solution of 13I g of Ii4-di-bromobutane in 100 ml of benzene, under Stirring and cooling in an ice bath are added. The mixture is slowly heated, diluted with 450 ml of benzene, taking 6 hours Boiled reflux, stirred for a further 2 hours and left to stand overnight. The reaction mixture is poured onto ice and 240 ml ' Poured concentrated hydrochloric acid, the organic layer separated and the aqueous solution with 250 ml of ether extracted. The combined organic solutions are mixed with water, 100 ml of a 5% aqueous sodium carbonate solution and water, dried, filtered and under reduced Pressure evaporated. The residue is distilled and the fraction boiling at 137-140 ° / 0.2 mm Hg is collected. 1-Qxo-6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclopentane is obtained. The product is identical to the compound described in Example 4.

Example 24:

A mixture of 60 g of 1-hydroxy-1- (3-dimethylaminepropyl) -6-methoxy-1,2,3i4-tetrahydro-naphthalene-2-spirocyclopentane, 4l ml of acetyl chloride and 300 ml of chloroform is used

909845/1755

refluxed on the steam bath for 80 minutes and evaporated under reduced pressure. The residue is taken up in water, the mixture with. 2 normal aqueous sodium hydroxide solution made basic and extracted with ether. The extract is washed with water / water, dried, filtered and evaporated under reduced pressure. The residue is taken up in a minimal amount Essigester, strongly the solution acidified with hydrogen chloride in Essigester "the resulting precipitate filtered, washed with Essigester and recrystallized from approximately 600 ml of acetone. The 1- (3-dimethylamino-propylidene) -6-methoxy-l ₅ 2j, 3, ^ -tetrahydro-naphthalene ^ -spirocyclopentane hydrochloride is obtained, which melts at 164-166. The product is identical to that of Example 5.

909845/1755

Claims (2)

Patent claims: 1. . 1-Aminoalkyl-benzcycloalkane ^ -spirocycloaliphatic Compounds of the general formula I (D, where, Ph denotes a 1,2-phenylene radical, alk, denotes lower alkylene, which participates in the ring formation with 1 to 3 carbon atoms, B denotes lower alkylene or lower alkenylene, which participates in the ring formation with k to 6 carbon atoms, alk " stands for lower alkylene, Am stands for an amino group and R stands for hydrogen or hydroxy, their 1-dehydrο derivatives, acyl derivatives, N-oxides and quaternary ammonium compounds. 2. Compounds of the formula (I) shown in claim 1, wherein Ph is 1,2-phenylene, (lower alkyl) -1,2-phenylene, (hydroxy) -1,2-phenylene mono- or di- (lower alkoxy) 1 , 2-phenylene, (lower alkanoyloxy) -1,2-phenylene, (halogen) -1,2-phenylene or (trifluoromethyl) -I ₃ 2-phenylene, 90 98 45/1755 Methylene, 1,2-ethylerr or 1,3-propylene denotes, B denotes
1,4-butylene, 1,5-pentylene, 1,6-hexylene or!, S ^ ent-S
R is hydrogen or hydroxy, aiko is 1,2-ethylene, 1,2- or 1,3-propylene, and Am is di-lower alkylamino, lower alkylenamino, monooxa-, monothia- or monoaaa-lower alkyleneamino, N-lower alkyl -monoaza-lower alkylenamino, N- (hydroxy-lower alkyl) -monoaza-lower alkylenamino or N- (lower alkanoyloxy-lower alkyl) -monoaza-nialkylenamino means, or alkp-Am together for N-lower alkyl-azacycloalkyl or N-lower alkyl-azacycloalkyl- stand lower alkyl in which the heteroatoms are separated by at least 2 carbon atoms, and their 1-dehydrο derivatives. 3 Compounds of the general formula II (II), 909845/1755 where R is hydrogen or hydroxy, each of the symbols R ₁ , Rp and R, is hydrogen or one or two of the same are lower alkoxy, or one is hydroxy, lower alkanoyloxy or halogen and the other are hydrogen, A is di-lower alkylamino-lower alkyl, 1 -Lower-alkyl-piperidyl or 1-lower-alkylpiperidyl-lower-alkyl, B, 1,4-butylene, 1,5-pentylene, '1,6-hexylene or 1,5-pent-2-enylene, and m for the number 1 , 2 or 3, and their 1-dehydro derivatives. 4. Compounds of the formula II shown in claim 3, wherein R is hydrogen or hydroxy, each of the symbols R ,, R _p and R- is hydrogen or one or two of them are methoxy or one is hydroxy, acetoxy or chlorine and the other are hydrogen, A for 3-dimethylamine-propyl, 3-diethylaminopropyl, 1-methyl- or 1-ethyl-3- or -4-piperidyl, or 1-methyl- or 1-ethyl-3- or -4- piperidylmethyl, B, 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,5-pent-2-enylene and m for the number 1, 2 or 3, and their 1-dehydrο Derivatives. 5 · l-Hydroxy-1- (3-dimethylamino-propyl) -l, 2,3,4-tetrahydro-naphthalene-2-spirocyclohexane. 9 0 984 5/17 5 5 6. 1-Hydroxy-1- (1-methyl-4-piperidyl) -1, 2,3,4-tetrahydro-naphthalene-2-spiroeyelohexane. 7. 1-Hydroxy-1- (1-methyl-3-piperidylniethyl) -1, 2-3,4-tetrahydro-naphthalene-2-spirocyclohexane. 8. l-Hydroxy-l- (3-dimethylamino-propyl) -5-methoxy · l, 2,3 * ^ - tetrahydro-naphthalene-2-spirocyelohexane. 9 · 1-Hydroxy-1- (3-dimethylamino-propyl) -6-methoxylj2,3,4-tetrahydro-naphthalene-2-spirocyelohexane. 10. 1-Hydroxy-1- (3-dimethylamino-propyl) -6,7-dlmethoxy-1 _J 2 _J 3i ^ -tetrahydro-naphthalene-2-spiroeyelohexane. 11. l-Hydroxy-l- (3-dimethylamino-propyl) -5-chloro-1 * 2,3,4-tetrahydro-naphthalene-2-spirocyclohc ^ an. • · 12.l-hydroxy-l- (3-dimethylamino-propyl) -7-chloro-1 * 2, 3 * ^ -tetrahydro-naphthalene ^ -spiroeyclohexane. 13. 1-Hydroxy-1- (3-dimethylamino-propyl) -1 _a 2,3,4-tetrahydro-naphthalene-2-spiroeyclopentane. 909845/1755 14.l-Hydroxy-1- (3-dimethylamino-propyl) -6-methoxy-1 # 2,3, ^ -tetrahydro-naphthalene ^ -spirocyclopentane. 15. 1- (3-Dimethylamino-propylidene) -6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclopentane. 16. 1- (3-Dimethylamino-propylidene) -6-hydroxy-1,2, 3,4-tetrahydro-naphthalene-2-spirocyclohexane. 3.7. 1- (3-Dimethylamino-propylidene) -1,2,3,4-tetrahydro-naphthalene-2-spiroeyclohexane. 18. 1- (3-Dimethylamino-propylidene) -6-methoxy-1,2> 3,4-t e trahydro-naphthalene ^ -spirocyclohexane. 19. 1- (3-Dimethylamino-propylidene) -6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalene-2-spirocyclohexane. 20. 1- (3-Dimethylamino-propylidene) -2,3-dihydro-indene-2-spirocyclohexane. 909845/1755 21. 1 - (3 -DIME methylamino propyl) -6 -me thoxy -1,2, 3 $ 4 - tetrahydro-naphthalene ^ -spirocyclohexane. ' 22. l-Hydroxy-l- (3-dimethylamino-propyl) -l, 2,5 * ^ - tetrahydro-iiaphthalene-2-spirocycloheptane. 23 · l-hydroxy-l- (3-dimethylamino-propyl) -o ^ - 1 * 2,3 # ^ - tetrahydro-naphthalene-2-spirocycloheptane. 24. l- (3-dirnethylamino-propylidene) -6-methoxy-1,2, 3 # 4-tetrahydro-naphthalene-2-spirocycloheptane. 25 * 1-Hydroxy-1- (3-dimethylamino-propyl) -benzo- suberane ^ -spirocyclohexane. 9-0 9845/1755 2β. l-Hydroxy-l- (3-dimethylamino-propyl) -1,2,3 * ² ^ - tetrahydro-naphthalene) -2-spirocyclo-3-hexene. 27. 1- (3-Dimethylamino-propylidene) -1,2,3,4-tetrahydro-naphthalene-2-splrocyclo-3-hexene. 28. l- (3-Dimethylamino-propyliden ') - 6-acetoxy-1,2, 3, ^ -tetrahydro-naphthalene ^ -spirocyclohexane. 29. l-Hydroxy-1- (l-methyl-3-piperldylmethyl) -6-methoxy-1 * 2,3i ^ -tetrahydro-naphthalene-2-spirocyclopentane. 30. l- (l-methyl-3-piperidylmethylidene) -6-raethoxy-1,2, 3,4-tetrahydro-naphthalene-2-spirocyclopentane. 31. l, 6-dihydroxy-l- (3-dimethylamino-propyl) -l, 2, 3ί ^ -tetrahydro-naphthalene-2-spirocyclohexane. 22. l- (2-Amino-ethyl) -l, 2,3,4-tetrahydro-naphthalene-2-spirocyclopentane. 55., 1 -hydroxy -1 - (1-methyl -3 -piperidyl methyl) -1.2, 3,4-tetrahydro-naphthalene-2-spirocyclopentane. tO98A8 / 1755 '- 70 - ■ 34.1 - (3-Dimethylaniino-propy 1) -3-methoxy-1, 2, 3 * ty-tetrahydro-naphthalene - ^ - spirocyciopentane. 35 · 1- (3-Trimethylammonium-propylidene) -6-methoxy-Ii2,3i4-tetrahydro-naphthalene-2-spirocyclopentane bromide. 36. The claims mentioned in claims 1 to 34 ~ bindings in free form. yj. The compounds mentioned in claims 1 to 3 ^ in the form of their salts. 38. The compounds mentioned in claims 1 to 3 ^ in the form of their therapeutically useful salts. 39 · Pharmaceutical preparations containing compounds of the type shown in claims 1 to 36 and J> 8 together with a pharmaceutical carrier material. 9098-5 / 1755 4o. Process for the preparation of new 1-aminoalkyl -benzcycloalkane-S-spirocycloaliphatic compounds the general formula (D, where Ph is a 1,2-phenylene radical, alk, for Nlederalkylen stands which participates in the ring formation with 1 to 3 carbon atoms, B lower alkylene or lower alkenylene means which has 4 to 6 carbon atoms involved in ring formation, alkp stands for lower alkylene, Am stands for an amino group, and R stands for hydrogen or hydroxy, its 1-dehydro derivatives, acyl derivatives, N-oxides and quaternary ammonium compounds, characterized in that one l) in a l-X-Benzcycloalkane-S-spiroaliphatic Compound of the general formula 90 3845/1755 in which 'X is a substituent which can be converted into the group alkp-Am means this converted into the aminoalkyl group defined above, or 2) a l-oxo-benzcycloalkane ^ -spiroaliphatic Compound of the general formula reacted with a tertiary aminoalkyl metal compound and hydrolyzed the adduct obtained, and if 1-dehydro-derivatives are desired, a 1-hydroxy compound obtained converted into its 1-dehydrο derivative, and, if desired, converting a compound obtained into another compound according to the invention, or converting a compound obtained into 909845/1755 19 ^ 082 their salts * acy, derivatives, N-oxides or quaternary compounds converted, and / or, if desired, a preserved salt converted into the free compound, and / or, if desired, a mixture of isomers obtained into the separate isolations * ORIGINAL INSPECTED Jt. -I: