LU85434A1 - SPIROSUCCINIMIDE DERIVATIVES FOR USE AS MEDICINES - Google Patents

Description

w * * I? The subject of the present invention is spirosuccinimides, their preparation and their use in therapy, as active principles of medicaments.

A more particular subject of the present invention is the spirosuccinimides of formula I

10 * 5 R3 2 in which 0 _ A represents H-N <, Ri-N <or 'R1

R1 represents a C1-C5 alkyl group optionally substituted · - · 15 by 1 to 6 halogen atoms having an atomic number of 9 to 35, an alkenyl or C3-C6 alkynyl group in which the multiple bond is not adjacent to the nitrogen atom, a C3-C7 cycloalkyl group, a C1-C2 (cycloalkyl) -alkyl group optionally substituted by a hydroxy group, C1-C4 alkoxy or C2- alkanoyl C5, a benzyl group, a tetrahydrobenzocycloheptenyl group or a residue of formula

- (CH2) r-X

In which r signifies 1, 2 or 3 or also 0 when A represents Rj-N <, and? X represents a hydroxy, mercapto, ami no, (4-C4) alkoxy, phenoxy, benzoxy, C1-C4 alkylthio, phenylthio, benzylthio,, 4 C1-C4 alkylamino, phenylamino, benzylamino, cyano, formyl, carbamoyl optionally monosubstituted or independently di- "substituted by a phenyl or C1-C4 alkyl group, sulfamoyl optionally monosubstituted or independently di-substituted by a phenyl or C1-C4 alkyl group, guanyl, v 2

V K

-¾ ”C2-C5 alkanoyl optionally substituted by 1 to 3 halogen atoms having an atomic number of 9 to 35 or by a 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N- (C1 alkyl group) -C4) dihydronicotinoyl, 5 C2-C5 alkoxycarbonyl, benzoxycarbonyl, (C1-C4 alkoxy) - oxalyl, C1-C4 alkanoyloxy or benzoyloxy, R2 represents hydrogen, a C1-C6 alkyl group optionally substituted by 1 to 6 halogen atoms having an atomic number of 9 to 35, (4-C4 hydroxyalkyl, (C1-C4 alkoxy) -10-C1-C4alkyl, C1-C4 mercaptoalkyl, (C1-C4 alkylthio) C1-C4, amino (C1-C4 alkyl), mono- or independently di- (C1-C4 alkyl)-C1-C4 aminoalkyl, alkenyl or C1-C6 alkynyl in which the multiple bond is not not adjacent to T nitrogen atom, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) - ^ · C1-C2 alkyl, phenyl or benzyl, R3 represents hydrogen, C1-C4 alkyl group " benzyl or benzyl bearing one or more substituents chosen from halogens having an atomic number of 9 to 35 and the methoxy group, R 4 and R 5 each represent, independently of one another, hydrogen or a (4-C 4) alkyl group,

Xl and X2 each represent, independently of one another, oxygen or sulfur, m and n each signify, independently of one another 1, 2, 3 or 25 4, the sum m + n must not be greater than 6,

Xl and X2 should not both signify oxygen when c- m and n each signify 2, A signifies HN C or Ri-N C where Ri signifies an unsubstituted C1-C6 alkyl group, chloropropyl, r, * hydroxypropyl, allyl, benzyl, etoxycarbonyl or benzoylalkyl and R2 means hydrogen, an unsubstituted C1-C6 alkyl group, allyl, phenyl or benzyl, or an acid addition salt of these compounds.

>.

3 - Any alkyl, alkoxy or alkylthio group preferably contains 1 or 2 carbon atoms, and signify in particular ε a methyl, methoxy or methylthio group. The halogen is preferably fluorine or chlorine. When a group has more than 5 substituents, it preferably has a maximum of 3 substituents, unless otherwise indicated.

* R1 represents for example hydrogen, a methyl, halo-ethyl, cyclopropyl-methyl or cyano group. R2 preferably signifies an ethyl group and m and n preferably signify 10 respectively 2 and 2 or 3 and 1.

The preferred compounds of formula I are those in which A is as defined above, R 1 represents a C 4 -C 4 alkyl group optionally substituted by 1 to 6 halogen atoms

Sx · having an atomic number of 9 to 35, cyclopropylmethyl, cycloalkyl T '15 in C3-C7, cyano, cyanomethyl or formyl, R2 represents hydrogen, a C1-C4 alkyl group optionally substituted by 1 to 6 atoms halogen having an atomic number of 9 to 35, or a C3-C7 cycloalkyl group, R3, R4 and R5 each represent hydrogen, Xi and X2 each represent, independently of one another, oxygen or 20 sulfur, and m and n each signify 2, with the conditions that 0 TV / i) when A signifies N R1 does not represent p / \ R1 25 a cyano or formyl group, and

ii) Xi and X2 do not both signify oxygen when A

? means HN <or RiN <where Ri represents an unsubstituted alkyl or chloropropyl group and R2 signifies hydrogen or an unsubstituted alkyl group v 1, or an acid addition salt of these compounds.

The present invention also relates to a process for the preparation of the compounds of formula I or of their acid addition salts, which process comprises: a) for the preparation of the compounds of formula la 5 X1 X 11a)

R,> -S

10 R5 <2

in which Ri to R5, Xi, X2, ni and n are as defined above, the oxidation of a compound of formula II

15 V \ _ 1 κν / νΑ R5 R3 a2 20 in which Rja R5, X] _, X2, m and n are as defined above, or b) for the preparation of the compounds of formula Ib 25 R4 X], - n-r2 "-nC X (Ib):,> McVl / y4 R3 2 * 5 B * * ^ in which R 'represents hydrogen or has the same meaning as Ri as defined above, and R2 to R5 , Xi, X2 »m ^ n are as defined above, X \ and X2 should not both represent oxygen,

5 the substitution of at least one oxo group by a thio group in a compound of formula III

AT

R 4 0 V ^^ X / -N-R2 10 R1, λ X (III) R5 "3? in which R ', R2 a R5, m and n are as defined above, or c) for the preparation of the compounds of formula le 20 X (le) * 3 in which R2 to R5, m and n are such that defined above, 25 and R ^ represents hydrogen, an alkyl group

Cl-C6 optionally substituted with 1 to 6 halogen atoms having an atomic number of 9 to 35, an alkenyl or C3-C6 alkynyl group in which the multiple bond is not adjacent to the nitrogen atom , a C3-C7 cycloalkyl group, (cyclo-; C3-C7 alkyl) C1-C2 alkyl optionally substituted by a hydroxy group, C1-C4 alkoxy or C2-C5 alkanoyl, a benzyl group, or a group tetrahydrobenzocycloheptênyle, •> te »6 m and n should not signify each 2 when Rf signifies hydrogen or an unsubstituted Οχ-Οβ alkyl group, hydroxypropyl, chloropropyl, allyl or benzyl and R £ signifies hydrogen or a group C1-C6 alkyl, allyl, phenyl or benzyl,

cyclization of the product obtained by condensation of a compound of formula IV

10 a r: i (! V) 5 R3 15 in which R *, R3 a R5, m and n are as defined above

for formula le, and R I and R II each signify, independently of one another, groups which can be eliminated, with a compound of formula V

R2-NH2 (V) in which R2 is as defined above for formula le, d) for the preparation of the compounds of formula Id 25 b V (CH2> ™ V ^ - ^ 2:.> £ 4, - 30 7 V * »* £ in which R2 * a R5, m and n are as defined above and R ^> has the same meaning as R] _ as defined above, m and n do not have to mean each 2 when R ^ represents an unsubstituted C1-C6 alkyl, hydroxypropyl, chloropropyl, allyl,

benzyl, ethoxycarbonyl or benzoylalkyl and R2 represents hydrogen, an unsubstituted (4-C6) alkyl, allyl, phenyl or benzyl group, the introduction of the group R b into a compound of formula VI

10> -2> ΛΑ (vi)

15 J

wherein R2a R5, m and n are as defined above for formula Id, and recovery of the compound of formula I or an acid addition salt of this compound.

Process a) can be carried out according to the usual methods for the preparation of N-oxides using, for example, oxidizing agents. Examples of oxidizing agents include hydrogen peroxide or organic peracids such as chloroperbenzoic acid.

Process b) is advantageously carried out using the usual sulfur-containing agents used in analogous reactions, for example P4S10 or a 2,4-dithioxocyclo-di-X5-phos-phathiane, for example the compound of formula 30 s (see formula on next page) * *> 8 5 also designated Lawesson reagent.

The reaction can be carried out in an inert solvent, for example at temperatures between about 50 and 150 ° C.

Mixtures of compounds of formula Ib can be obtained, for example - compounds of formula Ib in which i) Xi and X2 both represent sulfur, ii) Xi represents sulfur and X £ represents oxygen, iii) Χχ represents oxygen and X2 represents sulfur.

? The compounds can be separated according to the usual methods, for example by chromatography.

The process c) can be carried out according to the usual methods for analogous cyclizations. The reaction is advantageously carried out by heating at an elevated temperature, for example at a temperature between about 150 and about 250 ° C, if desired in an inert solvent. If desired, the reaction can be carried out in a closed container, for example in an autoclave. Riet R II can for example represent a hydroxy group, C1-C4 alkoxy or friend no.

Process d) can be carried out according to the usual methods for the preparation of tertiary amines, for example by reaction with a compound of formula R ^ -Y where Y represents a removable group, for example a halogen or the radical of an acid organic sulfonic.

; The compounds of formula I and their acid addition salts can be isolated and purified according to the usual methods. The compounds of formula I can be transformed into their acid addition salts according to the usual methods and vice versa. Acids suitable for the formation of P salts include hydrochloric acid, maleic acid and methanesulfonic acid.

The starting materials of formula IV can for example be prepared by acid hydrolysis of a compound of formula VII

V * w / ·, 1 '10 Rs / \ r3 Ry> in which Ra, R3, R4, R5, m and n are as defined above for formula IV, and Rx and Ry each independently represent l 'from one another, a cyano or lower alkoxycarbonyl group, decarboxylation and optionally reaction with an alkanol or an amine or transformation into another compound of formula IV.

The compounds of formula VII in which R3 has a meaning other than hydrogen, can be obtained by reaction of a compound of formula VIII

. V ^ V "Λ 25 Rl> lCH2) / \ / (HIV) * 5 \ in which, R4, R5, Rx, Ry, m and n are as defined above, with a halide of Ri where Ri has the same meaning as - R3 except hydrogen.

The compounds of formula VIII can for example be> 9 10

s prepared by treating a compound of formula IX

; , Vch2> »\ / r * rî-nC> <,. <*> s y 5 for example by HCN according to the usual methods.

"I

The compounds of formula IX can for example be prepared by reaction of a compound of formula X

10 i r? -NC 0 (χ) ^ ^ (CH2) n / ^ 15 * 5

with a compound of formula XI

20 CH2 (XI) according to the usual methods.

The invention also relates to groups of compounds comprising: a) the compounds of formula Ib as defined above or an acid addition salt of these compounds, rb) the compounds of formula la in which R 1 is such than defined. 5 above and when R 1 is a residue (CH) 2-X> X signifies a hydroxy, alkoxy, phenoxy, formyl, optionally substituted alkanoyl group, benzoyl, cinnamoyl, alkoxycarbonyl, benzoxycarbonyl, alkanoyloxy or benzoyloxy as defined more · * * ei 11 above, and R2 represents hydrogen or an alkyl group "optionally substituted by halogen, alkoxyalkyl," hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl as defined above, 5 or an acid addition salt of these compounds.

When the preparation of the starting materials is not described in the present application, these are known or can * be prepared according to the usual methods.

It has now been found that the compounds of formula I in which A, R1, R2, R3, R4, R5, Xl, X2 "m and n have the meanings given above, A must have a meaning other than CH3-NCT when R2 represents an ethyl group, R3, R4 and R5 represent hydrogen, Χχ and X2 each represent oxygen and m and n each signify 2, hereinafter designated the compounds of the invention ~ 15 have pharmacological properties interesting as shown below.

Among these compounds, the compounds of formula A

20 -N-R2} ^ (CH2) n // - ^ R5 r3 X2 25 in which R3, R4 and R5 have the meanings given above, Xi and X2 each represent oxygen, m and n each mean 2, A represents HN C ° u Rl-N C where Ri signifies an - unsubstituted C1-C6 alkyl group, hydroxypropyl, chloropropyl, ί allyl, benzyl, ethoxycarbonyl or benzoylalkyl and R2 represents hydrogen, a C1-C6 alkyl group unsubstituted, allyl, phenyl or benzyl, are generally known.

The pharmacological properties of some of the compounds of formula A are described in the literature with the exception of,> 12 s compounds of formula A in which R] _ represents a hydroxypropyl, chloropropyl or ethoxycarbonyl group for which no pharmacological activity exists. has been described so far.

The use of the compound of formula A in which A 5 represents CH3N R2 represents an ethyl group, R3, R4 and R5 each represent hydrogen, Xi and X2 each represent oxygen and m and n each mean 2, for the treatment Alzheimer's type dementia is described in Belgian patent 1 no. 897,058 published at a date later than the priority date claimed for the present patent application.

The pharmacological activity of certain other compounds of formula A, for example the cholinergic or analgesic activity, v is described in the German patent ηβ 1,211,646 and by E. Jucker and ~ col!., In Arch. Pharm. (1961), 294, 210-220, and in Helv. Chem.

^ * 15 Acta (1966), 49, 1135-45.

It has now been found that the compounds of the invention and their acid addition salts are useful in the treatment of senile dementia, Alzheimer's disease, Huntington's chorea, late diskinesia, hyperkinesia and mania.

The activity of the compounds of the invention has been demonstrated in particular in the following tests: i) in the observation test in mice, the compounds administered orally at doses of between 1 and 300 mg / kg cause a prolongation of the waking state and an increase in the reactivity to external stimuli, ^ ii) in the test relating to the sleep / waking cycle carried out in i chronically implanted rats, the compounds, administered by i * orally at doses between about 1 and about 30 100 mg / kg, increase the sleep phase AMOR, and 13 ψ * '* 5 iii) in the autoradiographic test with carbon 14 deoxyglucose in rats (according to the method described by L. Solokoff in Journal of Cerebral Blood Flow and Metabolism, 1981, 1_, 7-36, by HE Savaki et al!., in Brain Research 1982, 233, 347 and 5 by 0. McCulloch et al., in Journal of Cerebral Blood Flow and Metabolism 1981, l, 133-136), compounds administered at doses c omissions between about 1 and 300 mg / kg increase the fixation of deoxyglucose to carbon-14 in particular areas of the brain, in particular in the limbic system.

Thanks to these properties, the compounds of the invention are therefore indicated for therapeutic use for the treatment * of senile dementia, Alzheimer's disease, ** Huntington's chorea, late diskinesia, Hyperkinesis and mania.

For their therapeutic use, the compounds of the invention will be administered at a daily dose of between approximately 1 and approximately 100 mg, advantageously in divided doses 2 to 4 times per day in the form of unit doses each containing, for example, approximately 20 0.2 to about 50 mg of active substance, or in a delayed release form.

The compound of Example 2 is the preferred compound. The preferred indications are senile dementia and Alzheimer's disease.

Unit doses suitable for oral administration contain, for example, from about 0.5 to about 15 mg of active substance, for example from 1 to 10 mg. The appropriate doses L for parenteral administration contain, for example, from about 0.2 to about 30 mg of active substance, for example from 0.3 to 10 mg.

The compounds of the invention can be administered in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt. Such salts can be prepared according to the usual methods and have the same order of activity as the free bases.

y - * 9 14 "The invention therefore includes the use of compounds of ^ formula I in which A, Ri, R2, R3, R4, R5, Xl, X2" ni and n have the meanings given above, A must have another meaning than CH3-N C when R2 represents an ethyl group, 5 R3, R4 and R5 represent hydrogen, Χχ and X2 each represent oxygen and m and n each signify 2, and their addition salts pharmaceutically acceptable acids, for the therapeutic treatment of senile dementia, Alzheimer's disease, Huntington's chorea, tardive diskinesia, hyperkinesia and mania.

The invention also includes the compounds of formula I in which A, Rl, R2, R3, R4, R5, Xl, X2> m and n have the meanings given above, Xi and X2 do not have to mean all * = the two oxygen when m and n each signify 2, A signifies 15 HN <or R \ -H <where Ri signifies an unsubstituted C1-C6 alkyl group, allyl, benzyl or benzoylalkyl and R2 signifies hydrogen, a group unsubstituted Οχ-Οβ alkyl, allyl, phenyl or benzyl, and their pharmaceutically acceptable acid addition salts, for use as medicaments, in particular for the therapeutic treatment of senile dementia, Alzheimer's disease , Huntington's chorea, tardive diskinesia, hyperkinesis and mania.

The invention further comprises a medicament containing, as active principle, a compound of formula I in which A 25 Ri, R2, R3, R4, R5, Xi, X2, m and n have the meanings given above, Xi and X2 do not must not signify both> oxygen when m and n each signify 2, A signifies [HN C or Ri-N C where Ri represents an unsubstituted 0χ-0β alkyl group, allyl, benzyl or benzoylalkyl and R2 means hydrogen, unsubstituted C1-C6 alkyl, allyl, phenyl or benzyl, in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt.

For their use in therapy, the compounds are advantageously administered in the form of a pharmaceutical composition comprising the active substance in the form of a free base or 9 B in the form of a pharmaceutically acceptable acid addition salt, in particular combination with a pharmaceutically acceptable vehicle or diluent.

The pharmaceutical compositions can be formulated according to the usual methods and can contain the active substance alone or in combination with a pharmaceutical carrier or diluent. The pharmaceutical compositions for oral administration can be presented, for example, in the form of tablets, dispersible powders, granules, capsules, syrups, suspensions, solutions or elixirs. The liquid forms can contain, for example, from about 0.1 to about 5 mg / ml of active substance, for example from 0.5 to 2 mg / ml. The forms for parenteral administration may, for example, be in the form of solutions or suspensions, for example aqueous sterile injectable solutions. The compositions intended for administration by the rectal route can for example be presented in the form of suppositories.

Pharmaceutical compositions for oral administration may contain excipients such as sweetening agents, flavorings, colors and preservatives to provide a good palatable pharmaceutical preparation. The tablets may contain usual pharmaceutical excipients, such as for example inert diluents, such as calcium carbonate and lactose, dispersing agents 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 according to the usual methods to delay their disintegration and resorption in the gastrointestinal tract and thus prolong their activity.

Suspensions, syrups and elixirs may contain the usual excipients, for example suspending agents such as methylcellulose, gum tragacanth and sodium ginate, wetting agents such as lecithin, polyoxyethylene stearate and polyoxyethylene- * 16 y sorbitan mono-oleate, and preservatives such as ethyl p-hydroxy benzoate. The capsules can contain the active substance mixed for example with a solid diluent such as lactose, starch and a lubricant such as magnesium stearate.

The pharmaceutical compositions can contain up to 90% by weight of active substance. The preferred compositions are in solid form, such as for example tablets or capsules. Representative formulations are as follows: * Capsules 10 Composition Weight

Compound of the invention, for example 2- * ethyl-8-cyclopropylmethyl-2,8-di azaspi ro ^ [4.5] decane-1,3-dione 1 mg 15 Lactose 133.5 mg

Corn starch 92 mg

Silica (e.g. Aerosil 200) 1.2 mg

Magnesium stearate 2.3 mg 230 mg 20 The ingredients are mixed and put in capsules.

Light bulbs

Composition Weight 25 Compound of the invention, for example 2,8-dimethyl-2,8-diazaspiro [4.53decane - = 1,3-dione 10 mg; Sodium chloride 8 mg

Water for solution for injection qs 1 ml 30 The ampoules are filled with 1 ml of the solution, sealed and sterilized at 121 ° C for 15 minutes.

The present invention also relates to a composition

-> pharmaceutical comprising a compound of formula I

in which A, Rj, R2, R3, R4, R5, Χχ, X2, m and n have the meanings given above, 5 Χχ and X2 should not both signify oxygen when m and n each signify 2, A means HN C or Rl-N C where Rl represents an unsubstituted Οχ-Οβ alkyl, allyl, benzyl or benzoylalkyl group and R2 signifies hydrogen, an unsubstituted Cx-Cß 'alkyl group, allyl, phenyl or benzyl or a pharmaceutically acceptable acid addition salt of this compound, in association with a pharmaceutically acceptable carrier or diluent.

The following examples illustrate the present invention * without in any way limiting its scope. In these examples, the temperatures are not corrected and are indicated in degrees Celsius.

- * 15 EXAMPLE 1: 2-ethyl-8-cyclopropylmeth.yl-2,8-diazaspiro [4.53decane- 1,3-dione-8-oxide (process a)

A solution of 15.6 g of 2-ethyl-8-cyclopropylmethyl-2,8-diazaspiro [4.5] decane-1,3-dione (treated for example according to Example 27) in 100 ml of chloroform per 37.8 g of m-chloroperbenzoic acid in 300 ml of chloroform. The yellow solution is stirred for 20 hours at room temperature, treated with 600 ml of chloroform and stirred with 200 ml of a 5N solution of potassium carbonate. The aqueous phase is separated and extracted twice with chloroform. The combined aqueous phases are washed with a saturated aqueous solution of sodium chloride, ~ they are dried over sodium sulfate and concentrated until a brown oil is obtained. After chromatography on ten times the quantity of silica gel using a mixture of ÿ-methylene chloride / 10% methanol / 1% ammonia, a yellow oil is obtained which is converted into the hydrochloride. of the title compound in crystallized form. M = 179-180 ° (C2H5OH / ether).

5 Proceeding in a manner analogous to that described in Example 1, the following compounds are prepared: EXAMPLE 2: 2-ethyl-8-methyl-2 "8-diazaspiro [4.5] decane-lt3-dione-8-oxide F hydrochloride = 238-239 °.

EXAMPLE 3: 2- (2-methoxyeth, yl) -8-methyl-2,8-di azaspiro [4.5] decane- 1,3-dione-8-oxide F of hydrochloride = 204-206 °.

- EXAMPLE 4: 2-ethyl-8-methyl-2,8-di azaspiroC4.5] decane-1,3-di thione, ^ 2-ethyl-8-methyl-2,8-di azaspiro [4.5] decane- l-thione-3- t "15 one and 2-ethyl-8-methyl-2,8-diazaspiro [4.5] decane-l-one-3-thione (method b)

Heated for 20 hours at reflux 8.7 g of 2-ethyl-8-methyl-2,8-diazaspiro [4.5] decane-1,3-dione and 12.1 g of Lawesson reagent (see above) in 100 ml of toluene. After removing the solvent by evaporation, the residue is taken up in methylene chloride, the organic phase is washed with a 2N solution of sodium carbonate and ice water, dried over sodium sulfate, filtered and we concentrate it. The yellow residue is chromatographed on 100 times the amount of silica gel using methylene chloride containing 2% methanol and 0.2% ammonia as eluent. The title compounds are eluted according to the following order in a ratio of 2: 1: 1 and they are characterized as r hydrochlorides: 19. * 2-Ethyl-8-methyl-2,8-diazaspiro hydrochloride [4.5] decane- l, 3-? dithione: F = 257-260 °.

2-Ethyl-8-methyl-2,8-diazaspiro hydrochloride [4.5] decane-1-thione-3-one: mp = 307-310 °.

5 2-Ethyl-8-methyl-2,8-diazaspiro hydrochloride [4.5] decane-1-one-3-thione: mp = 214-215 °.

EXAMPLE 5: 2-ethyl-2,7-diazaspiro [4.5] decane-1,3-dione (process c)

Heated at 180 ° for 12 hours in a steel autoclave 10 g of [3-ethoxycarbonyl-3-piperidyl] -acetic acid ethyl ester and 200 ml of anhydrous ethylamine. The excess amine is removed under the vacuum of the water pump at 40 °. The residue is chromatographed on 25 times the amount of silica gel, using methylene chloride containing 5% methanol and 1% ammonia as eluent. The title compound is crystallized in the form of hydrogen maleate. F = 177-180 °.

The starting product is prepared as follows: a) Diethyl ester of 1-ethoxycarbonyl-3-piperidylidene-malonic acid 20 A well-stirred suspension of 3.5 liters of tetrahydrofuran and 135 ml of titanium tetrachloride add at 0 ° 100 g of N-ethoxycarbonyl-piperidine-3-one and then 98.6 g of diethyl ester as malonic acid. In the course of 30 minutes, 185 ml of pyridine are added dropwise at the same temperature. The reaction mixture is vigorously stirred for 20 hours at room temperature.

The solvent is removed on a rotary evaporator. The residue is treated with ice water, dissolved in ether, and washed first with acid (2N HCl) and then with 10% sodium bicarbonate solution . The ethereal kr 20 * solution is dried over sodium sulfate and treated with activated charcoal.

S The ether is eliminated, which gives a brown-orange syrup which is purified by rapid chromatography on silica gel, using ether as eluent. The resulting yellow oil is used as it is in the next step.

b) Diethyl ester of 1-ethoxycarbonyl-3-cyano-3-pi peri d.yl-mal oni acid

50 g of the product obtained in step a) are dissolved in 350 ml of ethanol and this mixture is treated with 9.6 g of acetic acid. A solution of 15.7 g of sodium cyanide in 95 ml of water is added dropwise at room temperature, the mixture is stirred for 90 minutes, treated with a 2N t HCl solution, and concentrated on a rotary evaporator. The residue is extracted with ether, the organic phase is washed to neutral and dried. The ether is removed, giving a yellow oil which is used as it is for the next step.

c) Ethyl ester of (3-ethoxycarbonyl-3-piperidyl) -acetic acid

50 g of the product obtained in step b) are dissolved in 160 20 ml of ethanol / water (1: 2) and the solution is heated to 60 °. 230 ml of concentrated hydrochloric acid are then added dropwise over 45 minutes and the mixture is boiled for 20 hours at reflux. After hydrolysis and decarboxyation, the mixture is evaporated under vacuum at a bath temperature of 60 ". The residue is used as it is in the following stage or it is esterified with 650 ml of ethanolic hydrochloric acid for 5 hours at reflux. the reaction the solvent is removed at a bath temperature of 60 °.

For the further treatment, the residue is taken up in methylene chloride containing 5% methanol, it is extracted twice with a 2N solution of sodium carbonate, it is washed to neutrality, it is dried over sodium sulfate, it is filtered and evaporated on a rotary evaporator. The title compound c) is obtained in the form of an orange oil. The hydrogen tartrate melts at 112-115 °.

* · * * * 21

Analogously to that described in Example 5, the following compounds are obtained in which A represents H-N <(designated H below) or R] _N <and Xi and X2 both represent oxygen:

5 Ex I R, or H 1 * 2 R3 | R4! Rs | H ηΓ ° 5 ^ I

__I _; _; _ μ _____ seJ___ 6 [> CH2- -CH2-CH3 H | h H 2 2 hml 163-165 * 7 CH3- -CH2-CH3 HHH 3 1 Ch 273-276 * 10 8 CH3 "Ό HHH 2 2 hm1 171 “173 * 9 CH3- OHHH 2 2 hml 162-163 * 1 15 CH3 10 CH3- - (CH2) 3-N ^ HHH 2 2 dch 284 * \ h3 11 Q -CH2-CH3 HHH 2 2 hml 206-207 * 20 days

12 r> -CH2- -CH3 H H H 2 2 hml 187-189 * 13 CH * C-CH2- -CH2-CH3 H H H 2 2 b 102-104 * "22 tf. * Λ

Ex. R1 or H r2 r3 r4 r5 ra n rorme F

5- -------- JLel'_ 14 oo -CH2-CH3 HHH 2 2 Ch 268 * 5 15 CH3- -CH2-CH2-OCH3 HHH 2 2 ms 201-201 * 16 CH3- -CH2-CH2 -OH HHH 2 2 hb 281-282 * * 17 r ^^ CH2- -CH2-CH3 HHH 2 2 ch 191-193 *

10 IXoH

18 H -CH2-CF3 H H H 2 2 ch 217-220 *

NOT

19 CH3 -CH2-CF3 HHH 2 2 ch 269-272 * 15 20 -CH2-CH3 -CH2-CF3 HHH 2 2 Ch 178-181 * 21> CH2- -CH2-CF3 HHH 2 2 ch 202-205 * 2Q 22 CF3-CH2- -CH2-CH3 HHH 2 2 ch 191-195 * 23 CI-CH2-CH2- -CH2-CH3 HHH 2 2 ch 140-142 * 24 CH3- CH3- HHH 3 2 hb 199-202 * 25 25 H CH3- HHH 3 2 nds 293-295 * 26 O- CH2- -CH2-CF3 HHH 22b 123-126 * * b = ms base = methanesulfonate 30 ch = hydrochloride hml = hydrogen maleate dch = dihydrochloride nds = naphthalene-1, 8-di-hb = sulfonate hydrobromide. 5 * »23 EXAMPLE 27: 2-ethyl-8-cycloprop.ylmethyl-2,8-di azaspi ro [4.5üdecane- ~ 1,3-dione (process d) At 80 ° 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 carbonate is stirred for 2 hours potassium and 18.3 g of potassium iodide in 500 ml of dimethylformamide. The mixture is concentrated and the residue is partitioned between water and methylene chloride. The aqueous phase is separated and extracted twice with methylene chloride. The combined organic phases are washed with a little water, dried over sodium sulfate and concentrated until an orange oil is obtained. After chromatography on 20 times the amount of silica gel with methylene chloride containing 2% methanol as eluent, the title compound is obtained in the form of a yellow oil which is converted into hydrogen maleate. F = 163-165 °.

By proceeding in a manner analogous to that described in Example 27, the compounds of Examples 6 to 17, 19 to 24 and 26 are prepared as well as the following compounds of formula I in which A represents R] _- N ^ and Xi and X2 both represent oxygen: 20 -, -----

Ex. R1 Rg R3 R4 R5 min close p _________ S £ l ___ 28 CH- j 'S-CO-CH, - -CH, -CH, HHH 2 2 hml 155-157 ° ch3 ά ά 6 25 29 OHC- -CH2- CH3 HHH 2 2 n 142-144 ° 30 NC- -CH2-CH3 HHH 2 2 n 125-126 ° s 24 ___ ___

Ex. "I r2 r3 r4 r5" i "f ° df F

---------- sel__ 31 NC-CH2- -CH3 HHH 2 2 ch 212-214 * 32 C2H5Q-CO-CH2- -CH2-CH3 HHH 2 2 b 79-80 * 5 '33 [^ N-CH2-C0- -CH2-CH3 HHH 2 2 n 194-196 * 0 34 0HC- -CH3 HHH 2 2 n 137-138 * - 10 ~ 35 Q-CH = CH-CO- -CH2-CH3 HHH 2 2 n 88-92 * 36 H2N-C0- -CH2-CH3 HHH 2 2 n 208-209 * 15 37 C2H5-O-CO- -CH2-CH3 HHH 2 2 n 84-85 * 38 D NH-CO- - CH3 HHH 2 2m 210-211 * CH3 39 ^ N-502- -CH2-CH3 HHH 2 2 n 155-157 * 20 CH3 ^ co- 40 Γ dd -CH2-CH3 HHH 2 2 n 122-123 *, Sr, '25 41 Ijj] -CH2-CH3 HHH 2 2 b 130-137 * ΊΓ 30 CH3 * 25 î * T "' r · ^ -1 ---- 1 - j - TT" i _ ___ | __. 1—1-] - η n. Λ _ form

Ex. Rl R2 R3 R4 R5 m n of F

___________ Sfi] ___

NH

r 42 JC- -CH2-CH3 H H H 2 2 Ch 216-217 * 5 / h2n? 43 HO-CH2-CH2- -CH2-CH3 HHH 2 2 Ch 215-218 * 44 C1-CH2-C0- -CH2-CH3 HHH 2 2 n 163-166 * 10 w 45 (CH3) 3C-O-CO- -CH2-CH3 HHH 2 2 n 101-104 * 46 CH3-CO -CH2-CH3 HHH 2 2 n 154-157 * 15 47 (CH3) 3C-CO- -CH2-CH3 HHH 2 2 n 109-112 * 48 CH3O-CO- -CH2-CH3 HHH 2 2 n 117-120 * 49 CH3-S-CH2- -CH2-CH3 HHH 2 2 ch 168-171 * 20

NOT

50 f V -CH2-CH3 H H H 2 2 n 210-211 * 25 * b = base - n = neutral ch = hydrochloride hml = hydrogen maleate

Claims (16)

26%. _ 1. The spirosuccinimides corresponding to the formula I en "" 5 f "3 * 2 in which O" A represents HN <, Ri-N <or Ri 10 Rl represents a C 1 -C 6 alkyl group optionally substituted by 1 to 6 halogen atoms having an atomic number from 9 to 35, w a C3-C6 alkenyl or alkynyl group in which the multiple bond is not adjacent to the nitrogen atom, a C3-C7 cycloalkyl group, a (C1-C7 cycloalkyl) C1-C2 alkyl group optionally substituted by a hydroxy, C1-C4 alkoxy or C2-C5 alkanoyl group, a benzyl group, a tetrahydrobenzocycloheptenyl group or a residue of formula - (ch2) "—x 20 in which r signifies 1, 2 or 3 or also 0 when A represents Ri-N <, and X represents a hydroxy, mercapto, ami no, C1-C4 alkoxy, phenoxy, benzoxy, alkylthio C1-C4, phenylthio, benzylthio, C1-C4 alkylamino, phenylamino, benzylamino, cyano, formyl, carbamoyl optionally monosubstituted or independently di- ", substituted with a phenyl or C1-C4 alkyl group, optionally monosubstituted sulfamoyl or independently dT-substituted by a phenyl or C1-C4 alkyl group, guanyl, 27 ^, C2-C5 alkanoyl optionally substituted with 1 to 3 halogen atoms having an atomic number of 9 to 35 or by a 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N- (C1-C4 alkyl) dihydronicotinoyl, 5 C2-C5 alkoxycarbonyl, benzoxycarbonyl, (C1-alkoxy) group -C4) - oxalyl, C1-C4 alkanoyloxy or benzoyloxy, R2 represents hydrogen, a C1-C6 alkyl group optionally substituted by 1 to 6 halogen atoms having an atomic number of 9 to 35, C1- hydroxyalkyl C4, (C1-C4 alkoxy) C1-C4 alkyl, C1-C4 mercaptoalkyl, (C1-C4 alkylthio) C1-C4 alkyl, amino (C1-C4 alkyl), mono- or independently di- (C1-C4 alkyl)-C1-C4 aminoalkyl, alkenyl or alkynyl in * C3-C6 in which the multiple bond is not adjacent to the nitrogen atom, cycloa C1-C7 alkyl, (C3-C7 cycloalkyl) - (4-C2, phenyl or benzyl alkyl, R3 represents hydrogen, C1-C4 alkyl, benzyl or benzyl bearing one or more substituents chosen from halogens having an atomic number of 9 to 35 and the methoxy group, 20 R4 and R5 each represent, independently of one another, hydrogen or a (C-C4) alkyl group, Χχ and X2 each represent, independently of one another, oxygen or sulfur , m and n each signify, independently of one another T, 1, 2, 3 or 25 4, the sum m + n must not be greater than 6, Xl and X2 must not both signify oxygen when m and n each signify 2, A signifies HN C or Rj-n <where R1 represents an unsubstituted C1-C6 alkyl group, chloropropyl, hydroxypropyl, allyl, benzyl, etoxycarbonyl or benzoylalkyl and R 2 signifies hydrogen, an unsubstituted C 1 -C 6 alkyl, allyl, phenyl or benzyl group, and the acid addition salts of these compounds. 2. The spirosuccinimides of formula I according to claim 1, characterized in that A represents ^ where R-j has the meaning given to claim 1. 3. The spirosuccinimides of formula I according to claim 1, characterized in that A represents H-N <or R-p-N 'where R] has the meaning given in claim 1, and one of. substituents and X £ signifies sulfur. 4. The spirosuccinimides ae formula I according to claim 10, characterized in that A represents HN C or RjN C where Rj has the meaning given in claim 1, and Xj and X £ ï both mean oxygen . 5 R4 and R5 each represent, independently of one another, hydrogen or a (C-C4) alkyl group, Xl and X2 each represent, independently of one another, oxygen or sulfur , m and n each signify, independently of one another 1, 2, 3 or 10 4, the sum m + n must not be greater than 6, A must have another meaning than CHq-N C when ri R2 represents an ethyl group, R3, R4 and R5 represent hydrogen, S-X] and X? Each represent oxygen and m and n each signify 2, v. And their pharmaceutically acceptable acid addition salts, for the therapeutic treatment of senile dementia, Alzheimer's disease, Huntington's chorea, tardive diskinesia, hyperkinesia and mania. 5 R, - - 15 3 in which R2'a R5, m and n are as defined above for the formula Id, and the recovery of the compounds of formula I in the form of free base or in the form of a salt of addition of acid. 5 R3 '-' 15 in which R ^, R3 a R5, m and n are as defined above for the formula le, and R 1 and RH each signify, independently of one another, groups elimini nabi es 9 with a compound of formula V 20 R2-NH2 (V) in which R2 is as defined above for formula le, d) for the preparation of the compounds of formula Id 25:. ’(Id) 30 3 * '1 v k. 32 in which R? To R5, m and n are as defined above and RJ v, I has the same meaning as Ri as defined above, m and n not having to mean each 2 when R ^ represents an alkyl group unsubstituted C 1 -C 5, hydroxypropyl, chloropropyl, allyl, benzyl, ethoxycarbonyl or benzoylalkyl and R2 represents hydrogen, an unsubstituted (4-C6) alkyl group, allyl, phenyl or benzyl, the introduction of the group R & in a compound of formula VI 10> <-2> ΛΑ (νι) 5 R3 Λ S 30 in which R 'represents hydrogen or has the same meaning as Ri as defined above, and R2a R5, Χχ, X2 »m and n are as defined above, Xi and X2 not both representing oxygen, the substitution of at least one oxo group by a thio group in a compound of formula III -N-R2 10 '' - »C, X (III) ^ v / ys , r5 in which R ', R2 a R5, m and n are as defined above, or c) for the preparation of the compounds of formula le 20 X (IC)) -k0 R3 in which R2 to R5, m and n are as defined above, 25 and R ^ represents hydrogen, a C1-C6 alkyl group optionally substituted by 1 to 6 atoms v d halogen having an atomic number of 9 to 35, a C3-C6 alkenyl or alkynyl group in which v: the multiple bond is not adjacent to the nitrogen atom, a C3-C7 cycloalkyl group, (C3-C7 cycloalkyl) C1-C2 alkyl optionally substituted with hydroxy, C1-C4 alkoxy or C2-C5 alkanoyl, benzyl group, or tet ahydrobenzocycloheptenyl group, 31 * '> ft »m and n should not mean each 2 when R? signifies H 1 hydrogen or an unsubstituted C1-C6 alkyl group, * hydroxypropyl, chloropropyl, allyl or benzyl and R £ signifies hydrogen or a C1-C6 alkyl group, allyl, phenyl or benzyl, cyclization of the product obtained by condensation of a compound of formula IV 5. The spirosuccinimides of formula I according to claim 1, characterized in that A has the meaning given to claim 1, Rj represents a C1-C4 alkyl group optionally substituted by 1 to δ halogen atoms having an atomic number of 9 to 35, cyclopropylmethyl, C3-C7 cycloalkyl, cyano, cyanomethyl or formyl, R2 represents hydrogen, a C1-C4 alkyl group optionally substituted by 1 to 6 halogen atoms having a number atomic from 9 to 35, or a C3-C7 cycloalkyl group, R3, R4 and R5 each represent hydrogen, Xi and X2 each represent, independently of one another, oxygen or sulfur, and m and n each signifies 2, with the conditions that 0 25 IV / i) when A signifies N Ri does not represent "Γ ^ L a cyano or formyl group, and ii) Xi and X2 do not both signify oxygen when A signifies HN £ or R ^ N <where Ri represents an unsubstituted alkyl or chloropropyl group and R2 signifies hydrogen or an unsubstituted alkyl group, and the acid addition salts of these compounds. 6. 2-Ethyl-8- (2,2,2-trifluoroethyl) -2,8-diazaspiro [4.5] decane-1,3-dione, and the acid addition salts of this compound. 7. 2-Ethyl-8-methyl-2,8-diazaspiro [4.5] decane-1,3-dione-8-oxide, and the acid addition salts of this compound. 8. 2-Ethyl-8-cyclopropylmethyl-2,8-diazaspiro [4.5] decane-1,3-dione, and the acid addition salts of this compound. 9. A process for the preparation of the compounds of formula I defined in claim 1, characterized in that it comprises a) for the preparation of the compounds of formula la 10> <CV /> -V,> K5 R 3 2 15 in wherein Ri a R5, Xi, X2 "m and n are as defined in claim 1, the oxidation of a compound of formula II 1 20 a / x (10) —s RS Rj ^ 25 in which Ri'a R5, Xi, X2, m and n are as defined in claim 1, or b) for the preparation of the compounds of formula Ib \ X1 30. V '(CH2) ”\ / ^ 1-N-fi2 R -nC X (Ib> 10. The use of spirosuccinimides of formula IV (CH2 '"' Nv) -H-" 2 3 * 3 Z v- in which! * · A represents HN <, Ri-N <or R1 30 represents an alkyl group in C1-C5 optionally substituted by 1 to 6 halogen atoms having an atomic number from 9 to 35, 33 an alkenyl or C3-C5 alkynyl group in which the ** multiple bond is not adjacent to the atom nitrogen, a C3-C7 cycloalkyl group, a (C1-C7 cycloalkyl) C1-C2 alkyl group optionally substituted by a hydroxy group, C1-C4 alkoxy or C2-C5 alkanoyl, a benzyl group, a tetrahydrobenzocycloheptenyl group or a residue of formula - (CH2) rX 10 in which r signifies 1, 2 or 3 or also 0 when A represents Ri-N <, and X represents a hydroxy, mercapto, amino or alkoxy group at ( 4-C4, phenoxy, benzoxy, C1-C4 alkylthio, phenylthio, benzylthio, alkylamino ((4-C4, phenylamino, benzylamino, cyano, formyl, k - 15 .. carbamoyl optionally monosubstituted or independently di-substituted by a phenyl or C1-C4 alkyl group, sulfamoyl optionally monosubstituted or independently di-substituted by a phenyl or C1-C4 alkyl group, guanyl,, C2-C5 alkanoyl optionally substituted by 1 to 3 20 atoms halogen having an atomic number from 9 to 35 or by a 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N- (C1-C4 alkyl) dihydronicotinoyl, C2-C5 alkoxycarbonyl, benzoxycarbonyl, (alkoxy) group C1-C4) -oxalyl, C1-C4 alkanoyloxy or benzoyloxy, R2 represents hydrogen, a C1-C6 alkyl group optionally substituted by 1 to 6 halogen atoms having an atomic number of ^ 9a 35, C1-C4 hydroxyalkyl, (C1-C4 alkoxy) -alkyl . C1-C4, C1-C4 mercaptoalkyl, (C1-C4 alkylthio) C1-C4 alkyl, amino (C1-C4 alkyl), mono- or independently di-30 (C1-C4 alkyl) -aminoalkyl C1-C4, C3-C5 alkenyl or alkynyl in which the multiple bond is not adjacent to the nitrogen atom, C3-C7 cycloalkyl, (C3-C7 cycloalkyl)-C1-C2 alkyl, phenyl or benzyl, "* * L 34 R3 represents hydrogen, a C1-C4 alkyl group. benzyl or benzyl carrying one or more substituents chosen from halogens having an atomic number of 9 to 35 and the methoxy group, 11. The spirosuccinimides of formula I 20 y — ί- “2 v X (i> Λιαο /) -L * 5 2 <\ in which ° _ ** u ^ 25. represents HN <, Ri ~ N <or t R1 ζ. -, Λ L 35 »V% û Rl represents a C1-C6 alkyl group optionally substituted <by 1 to 6 halogen atoms having an atomic number of 9 to 35, an alkenyl or C3-C5 alkynyl group in which the multiple bond is not adjacent to the nitrogen atom, a C3-C7 cycloalkyl group, a (4-C2 cycloalkyl) group (4-C2 alkyl) optionally substituted by a hydroxy group, C1-alkoxy -C4 or C2-C5 alkanoyl, a benzyl group, a tetrahydrobenzocycloheptenyl group or a residue of formula 10 - (CH2) rX in which r signifies 1, 2 or 3 or also 0 when A represents Rj-N <, and “X represents a hydroxy, mercapto, amino, (4-C4, oxy ^ 15 phenoxy, benzoxy, C1-C4 alkylthio, phenylthio, benzylthio, C4-C4 alkylamino, phenylamino, benzylamino, cyano, formyl, carbamoyl group optionally monosubstituted or independently di-substituted by a phenyl or alkyl group in (4-04, * C0-sulfamoyl optionally monosubstituted or independently di-20 substituted by a phenyl or (4-C4) alkyl, guanyl, C2-C5 alkanoyl group optionally substituted by 1 to 3 halogen atoms having an atomic number of 9 to 35 or by a 2-oxo-pyrrolidinyl, benzoyl group , cinnamoyl, nicotinoyl, dihydronicotinoyl, N- (C1-C4 alkyl) dihydronicotinoyl, C2-C5 alkoxycarbonyl, benzoxycarbonyl, (C1-C4 alkoxy) - oxalyl, C1-C4 alkanoyloxy or benzoyloxy, L R2 represents hydrogen, a C1-C6 alkyl group optionally substituted by 1 to 6 halogen atoms having an atomic number of C 9 to 35, C1-C4 hydroxyalkyl, (C1-C4 alkoxy) -alkyl C1-C4, C1-C4 mercaptoalkyl, (C1-C4 alkylthio) C1-C4 alkyl, amino (C1-C4 alkyl), mono- or independently di- (C1-C4 alkyl) -aminoalkyl C1-C4, C3-C6 alkenyl or alkynyl in which the multiple bond is not adjacent to% i - * at n 36, T nitrogen atom, C3-C7 cycloalkyl, (C3-C7 cycloalkyl) - C1-C2 alkyl, phenyl or benzyl, -7 R3 represents hydrogen, a C1-C4 alkyl, benzyl or benzyl group bearing one or more substituents chosen from the 5 halogens having an atomic number of 9 to 35 and the group methoxy, R4 and R5 each represent, independently of one another, hydrogen or a C1-C4 alkyl group, * Xl and X2 each represent, independently of one another, oxygen or sulfur, m and n each mean, independently of one another 1, 2, 3 or 4, the sum m + n must not be greater than 6, 1 -> - X1 and x2 must not mean you : both oxygen when m and n each signify 2, A sig nifies 15 HN <or Rj-N <where Ri represents an unsubstituted C1-C6 alkyl group, allyl, benzyl or benzoylalkyl and R2 signifies hydrogen, an unsubstituted C1-C6 alkyl group, allyl, phenyl or benzyl, and their pharmaceutically acceptable acid addition salts, for use as medicaments. 2o 12. The spirosuccinimides specific to any one of claims 1 to 8, and their pharmaceutically acceptable acid addition salts, for use as medicaments. 13. A medicament, characterized in that it contains, as active ingredient, a spirosuccinimide as specified in claim 11, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt. "14. A medicament, characterized in that it contains, as active ingredient, a aspirosuccinimide as specified in any one of claims 1 to 8, in the form of the free base or in the form of a salt thereof. 'addition of pharmaceutically acceptable acid. * "** · i S.' 1 37 15. A pharmaceutical composition, characterized in that | 'that it comprises a spirosuccinimide as specified in claim 11, or a pharmaceutically acceptable acid addition salt of this compound, in association with a pharmaceutically acceptable carrier or diluent. 16. Products and processes in substance as above described with reference to the examples cited. * "* J