DE3422411A1 - SPIROSUCCINIMIDES, THEIR PRODUCTION AND USE - Google Patents

Description

100-6063

Spirosuccinimides, their manufacture and use

The present invention relates to spirosuccinimides and processes for their preparation. The invention also relates to pharmaceutical compositions containing spirosuccinimides, as well as the use of these spirosuccinimides in the therapeutic treatment.

The invention relates in particular to the compounds of the formula I,

'm

A for

or

N <"stands,

for optionally by 1 to 6 halogen atoms with one atomic number from 9 to 35 substituted alkyl with 1 to 6 carbon atoms, alkenyl or alkynyl with 3 to 6 carbon atoms each, the multiple bond not being to the nitrogen atom is adjacent, cycloalkyl with 3 to 7 carbon atoms,

- 11 - 100-6063

optionally by hydroxy, alkoxy having 1 to 4 carbon atoms or alkanoyl substituted with 2 to 5 carbon atoms cycloalkyl (with 3 to 7 carbon atoms) -alkyl (with 1 or 2 carbon atoms), benzyl, tetrahydro-benzocycloheptenyl or a rest

is where

r is 1, 2 or 3 or 0 if A is Ri-N ^ stands, and

X stands for hydroxy, mercapto, amino, alkoxy with 1 to 4 carbon atoms, phenoxy, benzoxy, alkylthio with 1 to 4 carbon atoms, phenylthio, benzylthio, alkylamino with 1 to 4 carbon atoms, phenylamino, benzylamino, cyano, formyl, optionally with phenyl or alkyl with 1 to 4 carbon atoms mono- or disubstituted carbamoyl, -CO-N ^), sulfamoyl, guanyl, - \ y> optionally substituted by phenyl or alkyl with 1 to 4 carbon atoms, optionally with 1 to 3 halogen atoms

N = /
an atomic number of 9 to 35 or 2-oxo-pyrrolidinyl substituted alkanoyl with 2 to 5 carbon atoms, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N-alkyl (with 1 to 4 carbon atoms) -dihydronicotinoyl, Al.koxycarbonyl with 2 to 5 carbon atoms, Benzoxycarbonyl, alkoxy (with 1 to 4 carbon atoms) -oxalyl, alkanoyloxy with 1 to 4 carbon atoms or benzoyloxy,

R2 stands for hydrogen, optionally with 1 to 6 halogen atoms with an atomic number of 9 to 35 substituted alkyl with 1 to 6 carbon atoms, hydroxyalkyl with

- 12 - 100-6063

1 to 4 carbon atoms, alkoxy (with 1 to 4 carbon atoms) -alkyl (with 1 to 4 carbon atoms), mercaptoalkyl with 1 to 4 carbon atoms, alkylthio (with 1 to 4 carbon atoms atoms) -alkyl (with 1 to 4 carbon atoms), aminoalkyl with 1 to 4 carbon atoms, mono- or dialkyl (each with

1 to 4 carbon atoms) aminoalkyl (with 1 to 4 carbon atoms), Alkenyl or alkynyl with 3 to 6 carbon atoms each, wherein the multiple bond is not adjacent to the nitrogen atom, cycloalkyl with 3 to 7 carbon atoms, Cycloalkyl (with 3 to 7 carbon atoms) -alkyl (with 1 or

2 carbon atoms), phenyl or benzyl,

R3 is hydrogen, an alkyl group with 1 to 4 carbon atoms or a benzyl group optionally substituted by halogen having an atomic number of 9 to 35 or methoxy means,

R4 and R5 independently of one another are hydrogen or an alkyl group with 1 to 4 carbon atoms denotes -Xl and X2 independently of one another denote oxygen or sulfur, and

m and η are independently 1, 2, 3 or 4, where m + η is not more than 6,

where Xi and X2 should not both mean oxygen, if .m and η both stand for 2, A stands for HNCC ° d ^er Rl ^- N- ¹ C, where Rl is alkyl, hydroxypropyl, chloropropyl, allyl, benzyl, ethoxycarbonyl or benzoylalkyl and R2 is hydrogen, alkyl, allyl, phenyl or benzyl,

and their acid addition salts.

- 13 - 100-6063

If in the following reference is made to "compounds of the formula I", then, of course, those compounds are meant which the Formula I correspond, in which the various features A, R ^, R2 etc. have the above meanings, but taking into account the above restrictive measure between the features is.

In an analogous manner, the following is a susceptible restrictive one Measure to be taken into account if it is stated that certain features are defined "as in formula X".

If, on the other hand, reference is made to the "above meaning" of certain features, so this refers to the meanings given for these features without considering any, after restrictive measures indicated with these meanings.

If the compounds of the formula I contain alkyl, alkoxy or alkylthio groups defined above, have these preferably have 1 or 2 carbon atoms and are in particular methyl, methoxy or methylthio. If a substituent stands for halogen as defined above, it preferably represents fluorine or chlorine.

In the compounds of the formula I, Ri denotes, for example, hydrogen, Methyl, halogen-substituted ethyl, cyclopropylmethyl or cyano. R2 means, for example, ethyl. Preferably m and η are 2 and 2 or for 3 and 1.

As preferred compounds of the formula I, the invention relates to those in which

A for HN <, Rl-N < or N <^,

- 14 - 100-6063

Rl for optionally by 1 to 6 halogen atoms with one atomic number from 9 to 35 substituted alkyl with 1 to 4 carbon atoms, cyclopropylmethyl, cycloalkyl with 3 to 7 carbon atoms, cyano, cyanomethyl or formyl,

R2 stands for hydrogen, optionally with 1 to 6 halogen atoms alkyl with 1 to 4 carbon atoms substituted with an atomic number of 9 to 35 or cycloalkyl with 3 to 7 carbon atoms stands,

R3, R4 and R5 each mean hydrogen,

Xl and X2 independently of one another are oxygen or sulfur mean and

m and η each stand for 2,

where, if A is N <^, Ri is not cyano or

Formyl should stand, and Xi and X2 do not both mean oxygen should, if A for HN <C or Ri-NC ^, in which Ri is alkyl or Is chloropropyl, and R2 is hydrogen or alkyl,

and their acid addition salts.

According to the invention one arrives at the compounds of the formula I and their acid addition salts by adding

a) for the preparation of compounds of the formula Ia,

Yes

- 15 - 100-6063

wherein Ri, R2, R3, R4, R5, Xl, X2, m and η have the above meaning own, compounds of formula II,

II

wherein Ri, R2, R3, R4, R5, Xl, X2 » ^{m and n have the} above meaning, oxidizes, or

b) for the preparation of the compounds of the formula Ib, by which those compounds of the formula I are meant in which A is HNt ^ or Ri-NC ^ and Xi and X2 are not both oxygen
mean, compounds of the formula III,

in

wherein Ri ^{1 stands} for Ri or hydrogen and R2, R3, R4, R5, m and η have the above meaning, reacts with a sulfur-containing reagent, or

100-6063

c) for the preparation of the compounds of the formula Ic,

Ic

wherein R2, R3, R4, R5, m and η have the above meaning and R \ ^a for hydrogen, optionally substituted by 1 to 6 halogen atoms with an atomic number of 9 to 35 alkyl with 1 to 6 carbon atoms, alkenyl or alkynyl with 3 to 6 carbon atoms, where the multiple bond is not adjacent to the nitrogen atom, cycloalkyl with 3 to 7 carbon atoms, optionally substituted by hydroxy, alkoxy with 1 to 4 carbon atoms or alkanoyl with 2 to 5 carbon atoms, cycloalkyl (with 3 to 7 carbon atoms) -alkyl ( with 1 or 2 carbon atoms), benzyl or tetrahydrobenzocycloheptenyl, but m and η are not both 2, if Ri ^{a is} hydrogen, alkyl, hydroxypropyl, chloropropyl, allyl or benzyl and R2 is hydrogen, alkyl, allyl, phenyl or benzyl, the reaction product between compounds of formula IV,

IV

- 17 - 100-6063

wherein R ^ a, R3, R4, R5, m and η are as defined in formula Ic are and RI and RII are independently hydroxy, Alkoxy with 1 to 4 carbon atoms or amino, and compounds of the formula V,

R2-NH2 V

wherein R2 has the above meaning, cyclizes, or d) for the preparation of compounds of the formula Id,

Id

wherein Ri, R2, R3, R4, R5> m and η have the above meaning, but m and η do not both stand for 2, if R ^ alkyl, Hydroxypropyl, chloropropyl, allyl, benzyl, ethoxycarbonyl or benzoylalkyl and R2 denotes hydrogen, alkyl, allyl, Denotes phenyl or benzyl, in compounds of the formula VI,

VI

100-6063

wherein R2, R3, R4, R5, m and η are as defined in the formula Id are introduced by Group Ri,

and the compounds of the formula I obtained, if desired, in their acid addition salts transferred.

The oxidation carried out according to process a) can be carried out by methods known for the preparation of N-oxides. as Oxidizing agents can be used, for example, hydrogen peroxide or organic peracids such as chloroperbenzoic acid.

For the reaction according to method b), for example, the sulfur-containing reagent P4S10 or an organic, sulfur-containing reagent is used Reagent, especially a 2,4-dithioxocyclo-di - ^ - phosphathiane, such as the compound of the formula

The reaction can be in an inert solvent, at a Temperature between approx. 50 and 150 ° C can be carried out.

Starting from a certain compound of the formula III, a mixture of three corresponding compounds of the formula Ib is obtained, wherein

a) Xi and X2 both stand for sulfur,

b) Xi stands for sulfur and X2 for oxygen,

c) Xi stands for oxygen and X2 for sulfur.

- 19 - 100-6063

These compounds can be isolated (e.g. chromatographically) and purified by methods known per se.

The cyclization carried out according to process c) takes place through Heating to higher temperatures, for example between 150 and 250 ° C., optionally in one under the reaction conditions inert solvent.

The reaction of the compounds of formula IV with the amine of Formula V can be carried out by methods known per se, preferably in a closed vessel. The subsequent Cyclization is expediently carried out without isolation or Purification of the intermediates carried out.

The introduction of the group R ^ according to method d) can be based on can be carried out in a known manner, for example by reaction with a compound of the formula Ri-Y, wherein Y is the acid radical of a reactive ester, preferably halogen or an organic sulfonic acid radical.

The compounds of the formula I obtained according to the invention can in free form or optionally as acid addition salts. The free bases can be converted into their acid addition salts in a manner known per se, and vice versa. To the Acid addition salt formation can be used, for example, hydrochloric acid, maleic acid, or methanesulfonic acid.

The starting compounds of the formula IV can be prepared by using methods known per se, compounds of the formula VII,

- 20 - 100-6063

where Ri ^a , £ 3 »R4>&5> ^{m and n are as defined in} formula IV and R _x and Ry are independently cyano or lower alkoxycarbonyl, acid hydrolyzed, decarboxylated and, if appropriate, then reacted with alkanols.

The compounds of the formula VII in which R3 is not hydrogen are obtained by adding compounds of the formula VIII,

VIII

where Ri ^a , R4, R5, R _x , Ry, m and η are as defined in formula VII, with Rßl halides (where R3T has the meaning given for R3 with the exception of hydrogen).

For the preparation of the compounds of the formula VIII, for example compounds of the formula IX,

- 21 - 100-6063

in which Ri ^a , R4, R5, R _x , Ry, m and η are as defined in formula VII, react with hydrogen cyanide in a manner known per se.

The compounds of the formula IX can be prepared by adding compounds of the formula X,

wherein R ^ ^a , R4, R5, m and η are as defined in formula VII, with compounds of formula XI,

CH2

where R _x and Ry are defined as in formula VII, converted by methods known per se.

- 22 -

100-6063

Unless the preparation of the starting compounds is described these are known or can be produced by processes known per se or analogously to the processes described here. ·

The starting compounds of formula VI, for example, insofar as they are not are encompassed by 'of the formula I are known. (This applies, for example, to the starting material used in Example 27 below).

In addition to the compounds of formula I are those compounds that correspond to formula I, where A for R ^ '- NC ^ »Rl' for hydrogen, alkyl, hydroxypropyl, chloropropyl, allyl, benzyl, ethoxycarbonyl or benzoylalkyl, R2 for hydrogen, alkyl, allyl, Phenyl or benzyl, m and η both for 2 and Xi and X2 both for Are oxygen, and R3, R4 and R5 have the above meaning, generally known. For many of them are in the literature pharmacological properties described. See, for example, German Patent 1,211,646, in which cholinergic and analgesic effects of the compounds prepared according to this patent is pointed out. For jen'j in which Ri 'stands for hydroxypropyl, chloropropyl or ethoxycarbonyl, on the other hand, is no pharmacological application known yet.

The present invention relates to the use as pharmaceuticals of the compounds corresponding to the formula I in which A, ^R l. ^R 2. R3. ^R 4. R5 »Xl. X2 » ^{m and n have the} above meaning, where Xi and X2 should not both mean oxygen, if m and η both stand for 2, A stands for HNd or Ri-N <C, in which ^R l is alkyl, allyl, benzyl or benzoylalkyl , and R2 is hydrogen, alkyl, allyl, phenyl or benzyl. The invention also relates to a new pharmaceutical use of the compounds corresponding to the formula I wherein A, Rl, R2 ^»R 3. R4, R5, Xl, X2> m and η have the above significance, with

100-6063

Exception from the compound Z- (4,5) decane-1,3-dione, whose use against the Oemenz of Alzheimer's type, e.g. known from the Belgian patent no. 897 058, but only after the priority date of the present one Invention was published.

The invention relates in particular to the use of the compounds corresponding to formula I in which A, Ri, R2, R3, R4. R5, Xi, X2. m and ^{n have the} above meaning, where A does not represent CH3-NC; should stand if R2 is ethyl, R3, R4, R5 are each hydrogen, Xl and X2 are each oxygen and m and η are each 2, for the treatment of senile dementia, Alzheimer's disease, Huntington's chorea, tardive diskinesia and hyperkinesia .

The compounds of the formula I and the o.e. known compounds and their acid addition salts with physiologically acceptable acids, hereinafter referred to as compounds according to the invention have shown interesting pharmacodynamic properties in animal experiments. They can be used as a particular remedy for that above mentioned indications can be used.

The compounds according to the invention have an effect in the observation test at home, with doses of 1 to 300 mg / kg p.o., a prolongation of the wakefulness and increased reactivity external stimuli.

In the sleep-wake cycle in the chronically implanted rat effect with 1 to 100 mg / kg p.o. an increase in REM sleep.

Furthermore, at 1 to 300 mg / kg p.o. the 1 ^ C-deoxyglucose absorption in certain areas of the brain, especially the limbic system (method according to L. Sokoloff, Journal of Cerebral

- 24 - 100-6063

Blood Flow and Metabolism in 1981, I ₁ 7 - 36, HE Savaki et al, Brain Research 1982, 233, 347 and J. McCulloch et al, Journal of Cerebral Blood Flow & Metabolism 1981, 1, 133 -.. 136). With 2-ethyl-8-methyl-2,8-diazaspiro (4,5) decane-1,3-dione-8-oxide, for example, the ED50 in this experiment is 30 mg / kg po

Because of these activities, they can be used for the indications senile dementia, Alzheimer's disease, Huntingtons chorea, tardive diskinesia, hyperkinesia and mania.

For the above-mentioned applications, the dose to be used varies, of course, depending on the substance used, the type of Administration and the desired treatment. In general, however, doses of about Reached 0.5 to 100 mg / kg of body weight; administration can be carried out with one dose daily or, if necessary, in take several partial doses. For larger mammals, the daily dose is in the range from about 1 to 100 mg of the substance, suitable Dosage forms for e.g. oral applications generally contain about 0.3 to 50 mg of active substance in addition to solid or liquid carriers or diluents.

The compounds according to the invention can be used as medicaments alone or in a suitable dosage form with pharmacologically indifferent ones Substances are administered.

Suitable dosage forms for oral use such as tablets, capsules or ampoules containing suspensions generally about 0.5 to 15 mg, in particular 1 to 10 mg, of active substance in addition to solid or liquid carrier substances or diluents.

- 25 - 100-6063

This dosage is also suitable for drip solutions, whereby the Administration can be done 2 to 4 times daily.

Suitable dosage forms for parenteral applications such as a sterile injectable suspensions generally contain approximately 0.1 to 30 mg, in particular 0.3 to 10 mg, of active substance.

Aqueous solutions, e.g. drip solutions for oral administration, contain approximately 0.1 to 5 mg / ml, e.g. 0.5 to 2 mg / ml of a compound according to the invention.

The compounds according to the invention can be administered using known pharmaceutical forms.

Thus, the compounds according to the invention can be compared with conventional pharmaceutically acceptable diluents or carriers and optionally mixed with other auxiliaries and, for example administered orally, rectally or parenterally. They can be taken orally as tablets, dispersible powders, granules, capsules, syrups, Suspensions, solutions and elixirs and parenterally as solutions or suspensions, e.g. as sterile, injectable aqueous Solution. Oral compositions can contain one or more additives, such as sweeteners, flavors, and colors Contain preservatives so that a good-looking and tasty preparation is obtained. Tablets can contain the active ingredient contain mixed with conventional, pharmaceutically acceptable auxiliaries, e.g. inert diluents such as e.g. calcium carbonate, lactose, disintegrants such as starch or alginic acid, binders such as starch, polyvinylpyrrolidone, gelatin, Lubricants such as magnesium stearate, stearic acid and talc. the Tablets can be coated using known methods so that disintegration and absorption in the gastrointestinal tract are delayed and the activity extends over a longer period of time

- 26 - 100-6063

can. Likewise, the active ingredient in the suspensions, syrups and elixirs can be mixed with auxiliaries which are customary for the production of such compositions, for example suspending agents such as methyl cellulose, tragacanth and sodium alginate; Wetting agents such as lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate and preservatives such as ethyl paraphydroxybenzoate, capsules can contain the active ingredient mixed with a solid diluent such as lactose, starch and a lubricant such as magnesium stearate. The injectable compositions are also formulated in a conventional manner. The pharmaceutical compositions contain up to about 90 % of the active ingredient, supplemented by a carrier or additive. Solid dosage forms, such as tablets or capsules, are preferred in terms of manufacture and administration.

Pharmaceutical compositions containing the inventive Containing compounds are also a subject of the invention.

The following pharmaceutical compositions are, according to known methods:

Capsules

Compound according to the invention, e.g.

2-Ethyl-8-cyclopropylmethyl-2,8-diazaspiro (4,5) decane-1,3-dione or 2,8-dimethyl-2,8-diazaspiro (4,5) decane-1,3-dione

lactose

Cornstarch

Silicon dioxide (Aerosil 200) magnesium stearate

230 mg

1 , 5 mg 133 mg 92 , 2 mg 1 , 3 mg 2 mg

- 27 - 100-6063

After the usual processing, the ingredients are filled into capsules.

Ampoules

Compound according to the invention, e.g.

diazaspiro (4,5) decane-l, 3-dione or

2,8-dimethyl-2,8-diazaspiro (4,5) decane

1,3-dione 10 mg

Sodium chloride 8 mg

Water for injectable solutions qu.s. up to 1 ml

The ampoules are filled with 1 ml of solution, sealed and sterilized at 121 ° C. for 15 minutes.

The invention also relates to pharmaceutical compositions which contain the compounds of the formula I and their acid addition salts with physiologically acceptable acids. For their production, those commonly used in pharmacy can be used Aids and carriers are used.

The following examples illustrate the invention. Temperature information are made in degrees Celsius and are uncorrected.

- 28 - 100-6063

Example 1: 2-Ethy1-8-cycl opropyi methyl -2,8-diazaspiro (4,5) decane-1, S-

A solution of 15.6 g of 2-ethyl-8-cyc1opropylmethyl-2,8-diazaspiro (4,5) -decane-1,3-dione (preparation see Example 27) in 100 ml of chloroform is inert at 0-5 ° 37.8 g of m-chloroperbenzoic acid in 300 ml of chloroform were added for 30 minutes. The yellow solution is stirred for a further 20 hours at room temperature, a further 600 ml of chloroform are added and 200 ml of 5 N potash solution are shaken out. The aqueous phase is extracted twice more with chloroform. The organic extracts are washed one after the other with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a brown oil. After chromatography on 10 times the amount of silica gel with methylene chloride / 10 % methanol / 1% ammonia, a yellow oil is obtained which is converted into the crystalline hydrochloride with alcoholic hydrochloric acid solution.

Mp. From ethanol / ether: 179-180 ^e .

The following compounds are established analogously to Example 1:

Example 2: 2-Ethyl-8-methyl-2,8-diazaspi ro (4,5) decane-1, Scions'oxide

M.p. of the hydrochloride: 238-239 ^e .

Example 3: 2- (2-Methoxy'ethyl) -8-meth.yl-2,8-diazaspiro (4,5) decane-1, S-di

M.p. of the hydrochloride: 204-206 °.

- 29 - 100-6063

Example 4:

2-ethyl-8-methyl-2,8-diazaspiro- (4,5) decane-1,3-dithione, 2-ethyl-8-methyl-2,8-diazaspiro- (4,5) -decan-l-thion-3-one, and 2-ethyl-8-methyl-2,8-diazaspiro- (4,5) -decan-l-one-3-thione

8.7 g of 2-ethyl-8-methyl-2,8-diazaspiro- (4,5) decane-1,3-dione and 12.1 g of Lawesson's reagent are refluxed in 100 ml of toluene for 20 hours. After evaporation of the solvent, the residue is taken up in methylene chloride and extracted one after the other with 2N soda and ice water. The organic phase is dried over sodium sulfate, filtered and evaporated. The yellow residue is chromatographed on 100 times the amount of silica gel, methylene chloride, which contains 2 % methanol and 0.2 % ammonia, being used as the eluent. The 3 title compounds are eluted in sequence in a ratio of 2: 1: 1, which crystallize as hydrochlorides. The hydrochlorides have the following melting points:

2-ethyl-8-methyl-2,8-diazaspiro- (4,5) -decane-1,3-dithione hydrochloride: 257 - 260 ".

2-ethyl-8-methyl-2,8-diazaspiro- (4,5) -decan-l-thion-3-one hydrochloride: 307-310 °.

2-Ethyl-8-methyl-2,8-diazaspiro- (4,5) -decan-l-one-3-thione hydrochloride: 214 - 215 \

- 30 -. 100-6063

Example 5: 2-Ethyl-2,7-diazaspiro (4,5) decane-1,3-dione

10.0 g of [S-ethoxycarbonyl-S-piperidyll-acetic acid ethyl ester are im with 20 ml of anhydrous ethylamine for 12 hours Steel autoclave heated to 180 *. The excess is evaporated Amine in a water jet vacuum at 40 ". The residue is chromatographed on 25 times the amount of silica gel, the title compound with methylene chloride, the 5% methanol and 1% Contains ammonia, is eluted. The compound crystallizes as hydrogen maleate, which melts at 177-180 °.

The raw material is produced as follows:

a) 1-ethoxycarbonyl-3-gigeridylidene-malonic acid diethyl ester

The series is added at 0 * to a well-stirred suspension of 3.5 liters of tetrahydrofuran and 135 ml of titanium tetrachloride after 100 g of N-ethoxycarbonyl-piperidin-3-one and 98.6 g of diethyl malonate. 185 ml of pyridine are then added dropwise at the same temperature over 30 minutes. At room temperature the pulpy reaction mixture is now intensively stirred for 20 hours.

For work-up, the solvent is removed on a rotary evaporator, ice water is added to the residue, it turns yellow in ether and first acidic (2 N_HC1) and then extracted with NaHCO3 solution (10%). The ethereal solution is dried with sodium sulfate and decolorized with activated charcoal. After removing the ether, the remaining, orange-brown syrup is purified by high-speed chromatography over silica gel with ether as the eluent.

- 31 - 100-6063

The yellow, viscous oil obtained in this way becomes without further Cleaning used directly for the next stage.

b) l-ethoxycarbon ^ l-S-c ^ ano-S-piperid ^ l-malonic acid diethyl ester

50 g of the product obtained under a) are in 350 ml Dissolved ethanol and added 9.6 g of glacial acetic acid. At room temperature a solution of 15.7 g of sodium cyanide in 95 ml of water is added dropwise over the course of 10 minutes. One stirs 90 minutes after, then mixed with 2 N HCl solution, evaporated on Rotary evaporator and extracted the residue with ether.

After washing until neutral and drying, the ether is distilled off. A yellow oil is obtained which is used in the next stage without further purification.

c) (3-ethoxy /: arbonyJ-3-piperidyl) -acetic acid ethyl ester

50 g of the product obtained under b) are dissolved in 160 ml of ethanol-water (1: 2) and heated to 60 *. so 230 ml of concentrated hydrochloric acid are added dropwise over a period of 45 minutes to. The mixture is then on for 20 hours Boiled under reflux. After hydrolysis and decarboxylation, the mixture is completely evaporated in vacuo at a bath temperature of 60 °. Of the Evaporation residue can be used directly for the next stage or for the purpose of esterification with 650 ml of ethanol Hydrochloric acid solution boiled on the reflux condenser for 5 hours will.

After the reaction has ended, the bath temperature is reduced in vacuo at 60 " completely constricted. For work-up, one takes in

100-6063

Methylene chloride, which contains 5 % methanol, is extracted twice with 2N soda solution, washed neutral, dried over sodium sulfate, filtered and the solvent is removed on a rotary evaporator. An orange oil is obtained which crystallizes as hydrogen tartrate.

112-115 ".

Analogously to Example 5, the following compounds of the formula I are obtained, in which A stands for Ri-N <^ or HNd and X, and Xp both oxygen mean:

E.g. Rl or H R ₂ R3 R ₄ R5 m η Salt* M.p. 6th [> CH ₂ - -CH ₂ -CH ₃ H H H 2 2 hml 163-165 ° 7th CH ₃ - -CH ₂ -CH ₃ H H' H 3 1 ch 273-276 ° 8th CH ₃ - H H H 2 2 hml 171-173 ° 9 CH ₃ - O H H H 2 2 hml 162-163 ° 10 CH ₃ - .CH ₃
- (CH ₂ J ₃ -N
CH ₃ H H H 2 2 dch 284 ° 11th α -CH ₂ -CH ₃ H H H 2 2 hml 206-207 ° 12th [> CH ₂ - -CH ₃ H H H 2 2 hml 187-189 ° 13th CHSC-CH ₂ - -CH ₂ -CH ₃ H H H 2 2 b 102-104 °

100-6063

E.g. Rl or H R2 R3 R ₄ R5 m η Salt* M.p. 14th -CH ₂ -CH ₃ H H H 2 2 ch 268 ° 15th CH ₃ - -CH ₂ -CHf-OCH ₃ H H H 2 2 ms 201-201 ° 16 CH ₃ - -CH ₂ -CH ₂ -OH H H H 2 2 hb 281-282 ° 17th Χ «" -CH ₂ -CH ₃ H H H 2 2 ch 191-193 ° 18th H -CH ₂ -CF ₃ H H H 2 2 ch 217-220 ° 19th CH ₃ -CH ₂ -CF ₃ H H H 2 2 ch 269-272 ° 20th -CH ₂ -CH ₃ -CH ₂ -CF ₃ H H H 2 2 ch 178-181 ° 21 [> CH ₂ - -CH ₂ -CF ₃ H H H 2 2 ch 202-205 ° 22nd CF ₃ -CH ₂ - -CH ₂ -CH ₃ H H H 2 2 ch 191-195 ° 23 C1-CH2-CH2- -CH ₂ -CH ₃ H H H 2 i ch 140-142 ° 24 CH ₃ - CH ₃ - H H H 3 2 hb 199-202 ° 25th H CH ₃ - H H H 3 2 nds 293-295 ° 26th QCH _E. -CH ₂ -CF ₃ H H H 2 2 b 123-126 °

* b = Base ms = Methanesulfonate ch = Hydrochloride hml = Hydrogen maleate dch = Dihydrochloride nds = Naphthalene disulfonate hb = Hydrobromide

100-6063

Example 27: 2-Ethyl-8-cyclopropylmethyl-2,8-di azaspiro (4.5) decane-1,3-dione

A suspension of 23.3 g of 2-ethyl-2,8-diazaspiro (4,5) -decane-1,3-dione, 20.6 g of cyclopropylmethyl bromide, 27.6 g of potassium carbonate and 18.3 g of potassium iodide in 500 ml absolute dimethylformamide is stirred for 2 hours at 80 °. The batch is concentrated completely and the solid residue is partitioned between water and methylene chloride. The aqueous phase is extracted twice more with methylene chloride and the organic extracts are washed in succession with a little water, dried over sodium sulfate and concentrated to an orange oil. After chromatography on the 20-fold amount of silica gel with methylene chloride / 2 % methanol "as eluant, a yellow oil is obtained which crystallizes as hydrogen maleate.

M.p. of the hydrogen maleate of the title compound: 163-165 ^β .

The compounds of Examples 6 to 17, 19 to 24 and 26, as well as the following compounds of the formula I, in which A is R] _- -N ^ or HN, are obtained analogously to Example 27:
both oxygen mean:

stands and X, and X _?

E.g. Rl or H R ₂ R3 R ₄ R5 m η Salt* M.p. CH ₃ 28 ^ N-CO-CH ₂ - -CH2-CH3 H H H 2 2 hml 155-157 " CH3 29 OHC -CH2-CH3 H H H 2 2 η 142-144 " 30th NC- -CH2-CH3 H H H 2 2 η 125-126 °

100-6063

Example 31 32 33

or H NC-CH2-C2H5O-CO-CH2-

N-CH ₂ -CO-

0 OHC

H ₂ N-CO-C ₂ Hs-O-CO

NH-CO-

CH ₃ ,

: n-so ₂ -

CH3

or

CO-

CH ₃

R ₂

-CH ₃

-CH ₂ -CH ₃ -CH2-CH3

-CH ₃

-CH ₂ -CH ₃

-CH ₂ -CH ₃

-CH ₂ -CH ₃

-CH ₃

-CH2-CH3

-CH2-CH3

-CH2-CH3

R ₄

Salt*

ch

M.p.

212-214 '

79-80 °

194-196 '

137-138 °

3-92 °

208-209 °

84-85 °

210-211 '

156-157 °

122-123 °

130-137 °

100-6063

E.g. Rl or H R ₂ R ₃ R4 R5 m η Salt* M.p. 42 ^NH > -CH2-CH3 H H H 2 2 ch 216-217 ' H2N 43 OH-CH2-CH2- -CH2-CH3 H H H 2 2 ch 215-218 ° 44 C1-CH2-C0- -CH2-CH3 H H H 2 2 η 163-166 ° 45 (CH ₃ ) 3C-0-CQ- -CH2-CH3 H H H 2 2 η 101-104 ' 46 CH3-CO -CH2-CH3 H H H 2 2 η 154-157 ' 47 (CH ₃ ) ₃ C-CO- -CH2-CH3 H H H 2 2 η 109-112 ° 48 CH3O-CO- -CH2-CH3 H H H 2 2 η 117-120 ' 49 CH3-S-CH2- -CH2-CH3 H H H 2 2 Ch 168-171 ° 50 Q> - -CH2-CH3 H H H 2 2 b 210-211 °

* b = Base η = Neutral ch = Hydrochloride Hm! = Hydrogen Maieinat

Claims (11)

SANDOZ-PATENT-GMBH Case 100-6063 7850 Lörrach Spirosuccinimides, their production and use Patent claims: 1. A compound of the formula I, NO, Λ — I wherein A stands for HN <% Ri-NC ^ or N \, Rl Rl for optionally substituted by 1 to 6 halogen atoms with an atomic number of 9 to 35 alkyl with 1 to
6 carbon atoms, alkenyl or alkynyl with 3 to 6 carbon atoms each, the multiple bond not being adjacent to the nitrogen atom, cycloalkyl with 3 to - 2 - 100-6063 Carbon atoms, optionally through hydroxy, alkoxy Cycloalkyl substituted with 1 to 4 carbon atoms or alkanoyl (with 3 to Carbon atoms) -a1kyl (with 1 or 2 carbon atoms), Benzyl, tetrahydro-benzocycloheptenyl or a residue - (CH2) r-X is where r is 1, 2 or 3 or also 0, if A is for R] .- N <[ stands, and
X for hydroxy, mercapto, amino, alkoxy with 1 to 4 carbon atoms, phenoxy, benzoxy, alkylthio with 1 to 4 carbon atoms, phenylthio, benzylthio, alkyl amino with 1 to 4 carbon atoms, phenylamino, benzyl ami no, cyano, formyl, optionally through Phenyl or alkyl with 1 to 4 carbon atoms mono- or disubstituted carbamoyl, -C0-N _v _j, optionally substituted by phenyl or alkyl with 1 to 4 carbon atoms, sulfamoyl, guanyl, - \ / »optionally with 1 to 3 halogen atoms with an atomic number of 9 to 35 or 2-oxo-pyrrolidinyl substituted alkanoyl with 2 to 5 carbon atoms, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N-alkyl (with 1 to 4 carbon atoms) -dihydronicotinoyl, alkoxycarbonyl with 2 to 5 carbon atoms, benzoxycarbonyl, alkoxy (with 1 to 4 carbon atoms) -oxalyl, alkanoyloxy with 1 to 4 carbon atoms or benzoyloxy, R2 for hydrogen, optionally with 1 to 6 halogen atoms with an atomic number of 9 to 35 s substituted alkyl with 1 to 6 carbon atoms, hydroxyalkyl with - 3 ■ - '100-6063 1 to 4 carbon atoms, alkoxy (with 1 to 4 carbon atoms) -alkyl (with 1 to 4 carbon atoms), Mercaptoalkyl with 1 to 4 carbon atoms, alkylthio- (with 1 to 4 carbon atoms) -alkyl (with 1 to 4 carbon atoms), aminoalkyl with 1 to 4 carbon atoms, Mono- or dialkyl (each with 1 to 4 carbon atoms) -aminoalkyl (with 1 to 4 carbon atoms), alkenyl or alkynyl with 3 to 6 carbon atoms each, the multiple bond is not adjacent to the nitrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl (with 3 to 7 carbon atoms) -alkyl (with 1 or 2 carbon atoms), Is phenyl or benzyl, R3 is hydrogen, an alkyl group with 1 to 4 carbon atoms or a benzyl group optionally substituted by halogen having an atomic number of 9 to 35 or methoxy means, R4 and R5 independently of one another are hydrogen or an alkyl group having 1 to 4 carbon atoms, Xl and X2 independently of one another are oxygen or sulfur mean, and m and η are independently 1, 2, 3 or 4, ^ - where m + η is not more than 6, where Xi and X2 should not both mean oxygen, if m and η both stand for 2, A for HNtC! or Ri-N <1, where Rl is alkyl, hydroxypropyl, chloropropyl, allyl, benzyl, ethoxycarbonyl or benzoylalkyl and R2 is hydrogen, alkyl, allyl, phenyl or benzyl, and their acid addition salts. - 4 - 100-6063 2. A compound of formula I according to claim 1, wherein 0
A stands for HN <, Rl-N <or N < , Rl for optionally by 1 to 6 halogen atoms nrt one Atomic number from 9 to 35 substituted alkyl with 1 to 4 carbon atoms, cyclopropylmethyl, cycloalkyl with 3 to 7 carbon atoms, cyano, cyanomethyl or formyl stands, R2 for hydrogen, optionally with 1 to 6 halogen atoms with an atomic number of 9 to 35 substituted alkyl with 1 to 4 carbon atoms or cycloalkyl with 3 to 7 carbon atoms, R3, R4 and R5 each mean hydrogen, Xl and X2 independently of one another are oxygen or sulfur mean and m and η each stand for 2, where, if A is / N- ^, Ri is not cyano or Formyl should stand, and Xi and X2 should not both be oxygen should interpret if A stands for HN <or Ri-Nd, in which Is alkyl or chloropropyl, and R2 is hydrogen or Alkyl means and their acid addition salts. 3. 2-Ethyl-8-methy1-2,8-diazaspiro (4,5) decane-1,3-dione-8-oxide and its acid addition salts. 4. The 2-ethyl-8-cyclopropylmethyl-2,8-diazaspiro (4,5) decane-1,3-dione and its acid addition salts. - 5 - 100-6063 5. The 2-ethyl-8- (2,2,2 ~ trifluoroethyl) -2,8-diazaspiro (4,5) -decane-1,3-dione and its acid addition salts. 6. Process for the preparation of the compounds of the formula I and their acid addition salts according to Claim 1, characterized in that that he a) for the preparation of compounds of the formula Ia, wherein Ri, R2, R3, R4, R5, Xl, X2 » ^{m and n are} as defined in claim 1, compounds of the formula II, II wherein Ri, R2, R3, R4, R5, Xi, X2, m and η as in Claim 1 is defined, oxidized, or - 6 - 100-6063 b) for the preparation of the compounds of the formula Ib, by which those compounds of the formula I are meant in which A is HNd or Rl-Nd and Xi and X2 do not both denote oxygen, compounds of the formula III III wherein Ri ^{1 stands} for Ri or hydrogen and R2, R3, R4, R5, m and η are as defined in claim 1, reacts with a sulfur-containing reagent, or c) for the preparation of the compounds of the formula Ic, IC wherein R2, R3 »R4, R5» m and η are as defined in claim 1 are and Ri * for hydrogen, optionally through 1 to 6 halogen atoms with an atomic number of 9 to 35 substituted alkyl with 1 to 6 carbon atoms, alkenyl - 7 - 100-6063 or alkynyl with 3 to 6 carbon atoms each, where the multiple bond is not adjacent to the nitrogen atom, cycloalkyl with 3 to 7 carbon atoms, optionally substituted by hydroxy, alkoxy with 1 to 4 carbon atoms or alkanoyl with 2 to 5 carbon atoms (with 3 to 7 carbon atoms) Carbon atoms) ^ kyl- (with 1 or 2 carbon atoms), benzyl or tetrahydrobenzocycloheptenyl, but m and η are not both 2, if Ri ^{a is} hydrogen, alkyl, hydroxypropyl, chloropropyl, allyl or benzyl and R2 is hydrogen, alkyl, allyl , Phenyl or benzyl is the reaction product between compounds of the formula IV, wherein Ri ^a , R3, R4, R5, m and η are as defined in the formula Ic and Rl and RlI are independently hydroxy, alkoxy with 1 to 4 carbon atoms or amino, and compounds of the formula V, R2-NH2 V wherein R2 has the meaning given in claim 1, cyclized, or - 8 - 100-6063 d) for the preparation of compounds of the formula Id, wherein Ri, R2, R3, R4, R5, m and η are as in claim 1 are defined, but m and η do not both stand for 2, if Ri is alkyl, hydroxypropyl, chloropropyl, allyl, Benzyl, ethoxycarbonyl or benzoylalkyl and R2 Denotes hydrogen, alkyl, allyl, phenyl or benzyl in compounds of the formula VI, VI wherein R2, R3, R4, R5 »m and η are defined as in the formula Id are introduced by Group Ri, and the resulting compounds of the formula I into their acid addition salts convicted. - 9 - 100-6063 7. Compounds of the formula IV according to claim 6, 8. The reaction product between compounds of the formulas IV and V according to claim 6. 9. A pharmaceutical composition containing a compound of the formula I according to claim 1, wherein A, R1, R2, R3, R4, R5, Xi, X2 » ^m and η are as defined in claim 1, where X1 and X2 are not both oxygen should mean, if m and η both stand for 2, A stands for HNC ^ or Ri-N <Z , where Rl signifies alkyl, allyl, benzyl or benzoylalkyl, and R2 signifies hydrogen, alkyl, allyl, phenyl or benzyl, or a Physiologically acceptable acid addition salt of one of these compounds, together with pharmacologically inert substances. 10. A compound of the formula I according to claim 1, wherein A, Ri, R2, R3, R4, R5, Xi, X2 » ^{m ur |} d ^{n are defined as in} claim 1, where Xi and X2 should not both mean oxygen, if m and η both stand for 2, A stands for HN <^ or Ri-NC ^, in which Ri is alkyl, allyl, benzyl or benzoylalkyl , and R2 denotes hydrogen, alkyl, allyl, phenyl or benzyl, or a physiologically acceptable acid addition salt of one of these compounds, for use as a pharmaceutical. 11. A compound of the formula I according to claim 1, wherein A, Ri, R2 »R3>R4> RS» Xl, X2 » ^{m unc} * η are as defined in claim 1, where A should not stand for CH3-N <I. if R2 is ethyl, R3, R4, R5 are each hydrogen, Xi and X2 are each oxygen and m and η are each 2, or a physiologically acceptable acid addition salt of one of these compounds, for the treatment of senile dementia, Alzheimer ¹ see disease, Huntington's chorea , tardive diskinesia, hyperkinesia and mania.