DE1928704A1 - New 2,4-diones and processes for their preparation - Google Patents

Description

VATINTANWIkLTI

DR. E. WIEGAND DIPPING. W, NIEMANN DR. M. KÖHLER DIPL-ING. C. GERNHARDT

MÖNCHEN HAMBURG TELEPHONE, 55547 «8000 MÖNCHEN 15, TELEGITAMME, KARPATENT NUSSBAUMSTRASSE 10

~ June 6, 1969

W. 14 302/69 - Ko / b ".

Dainippon Pharmaceutical Co. Ltd. Osaka, Japan

New 2,4-diones and processes for their preparation

The invention relates to 1-0xa-3,8-diazaspiro / 4,! Ä / -decane-2,4-dione, which are new chemical compounds and as psychotropic agents with extremely low toxicity are effective, as well as a process for the preparation of these compounds,

In particular, the invention relates to 1-0xa-3,8-diazaspiro / 2j., 5 / -decane-2,4-diones according to the general formula

CO-N-R2

wherein R _{1 is} hydrogen atoms, benzyl groups and groups corresponding to the formula

where R ¹ halogen atoms, hydroxyl groups or benzoyl groups, which may optionally be substituted by a halogen atom, preferably chlorine or fluorine, groups

9 09850/176 6

speaking of the formula

where R "hydrogen atoms, halogen atoms, CF ,, lower alkoxy groups, preferably lower alkoxy groups with C ₁ to C., nitro groups, cyano groups, alkylthio groups with W 1 to 4 carbon atoms, alkyl groups with 1 to 4 carbon atoms, dialkylaminosulfonyl groups, the alkyl part of which has 1 to 4 carbon atoms contains, or represent acetyl groups, groups corresponding to the formula

or groups according to the formula

and η is a positive integer of 2 or 3 and R « Hydrogen atoms, alkyl groups with 1 to 4 carbon atoms, optionally represented by a hydroxyl radical may be substituted, phenyl groups, which are optionally substituted by a halogen atom, preferably chlorine may be, or benzyl groups, their salts and a process for producing the same.

To date, chlorpromazine compounds are known to be useful psychotropic agents, the typical catfish

909850/1766

by a compound of the formula

are reproduced (US Pat. No. 2,64-5,640) * The compounds according to the invention are through the following basic structure according to the formula (I) marked:

CO-N-

0-CO

and are new connections that are completely different are of the known compounds listed above in terms of basic structure.

The compounds having the above basic structure corresponding to the formula (I), with the exception of those in which R _{1 is} a hydrogen atom and Rp is a hydroxylalkyl group having 1 to 4 carbon atoms, can be prepared by a process in which a 1-substituted β 4-cyano -4-piperidlnol of the formula

OH

wherein R ¹ .. has the same meaning as R ₁ except hydrogen, with an isocyanate of the formula

R ' ₂ NC0 (III)

909850/176

wherein R'p is alkyl groups with 1 to 4 carbon atoms, a phenyl group, benzyl groups, benzoyl groups or optionally substituted by halogen atoms Alkanoyl groups, the alkyl part of which contains 1 to 4 carbon atoms, is preferably reacted in a non-polar solvent, and the obtained Intermediate product of the formula

NCONHR'2
I!

CN-E ¹ 2

; ι

o-co

O
; ι

wherein R ¹ . and R'p have the meaning given above, is hydrolyzed.

According to the invention it is preferred that the reaction between the compound of the formula (IV) and the compound of the formula (III) is carried out in a non-polar solvent such as benzene, xylene or toluene. Plan allows this reaction to proceed at room temperature, but if desired the reaction can also be carried out with heating. In general, reaction temperatures can be used from 15 to 5O ⁰ C in the range from O to 15O ⁰ C, preferably. The reaction time is not critical in the context of the invention, but the reaction is usually carried out for more than 5 hours and a reaction time of, for example, 3 to 15 hours is sufficient.

It is also preferred to carry out the reaction in the presence of a catalytic amount of a tertiary amine, for example triethylamine, trimethylamine or pyridine, in particular a trialkylamine to perform.

909850/1766

There is no specific restriction on the molar ratio of the reactants, however, it is generally preferred to use the isocyanate of formula (III) in an amount greater than To use 2 moles per mole of the compound of the formula (IV). It is particularly preferred 'the isocyanate of the formula (III) in an amount of 2 to 3 moles per mole of the compound of formula (IV) to be used.

The compound of the formula (II) is formed through the above reaction. The compound of the formula (II) thus formed is hydrolyzed and the desired compound of the following formula (I ¹ ), "

, s, CO-NR '2

R »l-H Λ Ι

V f oC

in which R · .. and R ' _{2 have} the meanings given above.

The hydrolysis of the compound of the formula (II) can be carried out by heating the compound of the formula (II) in the presence a mineral acid, for example dilute hydrochloric acid. or dilute sulfuric acid and, if desired an alcohol such as methanol or ethanol. Preferably the heating is carried out under reflux.

After the hydrolysis, the system is cooled and the desired compound of the formula (I ¹ ) is obtained in the form of a salt of the mineral acid used for the hydrolysis, for example as a hydroxide or sulfate, by separating off and collecting the resulting precipitate in the customary manner.

909850/1766

1926704

The 'thus obtained compound of the formula (I ¹ ) can, if necessary, using methanol,
Ethanol, Dioxari or a mixed solvent thereof can be further cleaned with water.

In the context of the invention, if an acyl isocyanate, in which R «is a benzoyl or alkanoyl radical,
the alkyl part of which contains 1 to 4 carbon atoms means, specifically used as a reactant of the formula (III), a deacylation reaction during
applied to the hydrolysis stage and compounds of
Formula (I ¹ ), wherein R'p in the formula (I ¹ ) represents a hydrogen atom.

The steps indicated above for the preparation of compounds of formula (I ') according to the invention
are summarized below: "-

R'l

-CX

CN

OH

(IV)

(m)

(II)

NC0HHR »2

o-CO

Hydrolysis • *

C-N-R «2

I 0-CO

(I ¹ ) "

909850/1766

wherein R ^ and R ' _{2 have} the meaning given above.

Furthermore, according to the invention, compounds of the formula (I) in which R- is a benzyl group, on the one hand to a compound in which R is a hydrogen atom, and then furthermore to a compound of the formula (I) in which R _{1 is} a represents another remainder within the meaning of R.

Furthermore, according to the invention, compounds of the formula (I) in which R "represents a hydrogen atom, to compounds of the formula (I) in which R "is a benzyl group or an alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group can, represent, be transferred ""

Therefore it should be pointed out that within the scope of the invention the process according to the invention, comprising the two steps listed above, namely the step of reacting a compound of the formula (IV) and a compound of the formula (III) and the step of hydrolysis of the intermediate product of the formula (II) obtained, also includes embodiments, wherein the compound of the formula (I ¹ ) obtained is further converted to other compounds of the formula (I) in which R ₁ and / or R ^ groups other than them in the originally formed compound of the formula (I) were present, are to be converted. Such embodiments are described below.

A. Conversion of a compound of formula (I) wherein

R _{1 represents} a benzyl group to a compound in which R _{1 represents} a hydrogen atom:

909850/176 6 .. ,,. .

BATH ORIGINAL

This conversion can be carried out by introducing hydrocarbon gas in the reaction system "in an organic solvent that is opposite to the compound to be reduced is inert, for example an alcohol, dioxane or acetic acid, preferably in a practically anhydrous Solvent, in the presence of a metallic reduction catalyst, for example a palladium-carbon catalyst, a platinum catalyst or a nickel catalyst can be carried out. The other

The amount of catalyst used is not particularly critical, but the catalyst is generally used in an amount of about 1 to 5% of the initial reactants. The reaction can be carried out under atmospheric pressure, or elevated pressure and either at room temperature or at elevated temperature. From an operational point of view, it is preferred to carry out the reaction in a solvent such as acetic acid or glacial acetic acid under atmospheric pressure at elevated temperature, preferably in the range from room temperature to In the case of acetic acid, the reaction can be carried out favorably at temperatures of about 40 to 90 ^° C. Reaction (A) is carried out

"listed below:

CO-NR ₂ catalyst

—CO, hydrogen reduction

>' Ο— CO

wherein R _{2 has} the meaning given above,

90 9 8 50 / 17.6 6,;. ,

B. R ₁ 'can be a different radical. _{R 1.} according to the following. Implementation (B) are transferred:,

QCO-NR "2 ^ I ~~? 0-CO. Condensation

OCO-NR "2 , I, (B) 0-0

in which X is a halogen atom, preferably chlorine or bromine, and R ¹ .. has the meaning given above and R " _{2 has} the same meaning as Rg", with the exception of hydrogen.

Reaction (B) can conveniently be carried out by heating in an organic solvent such as benzene, xylene, toluene, acetone and dimethylformamide. The reaction can be carried out at a temperature above 10 ^° C., preferably in the range from 50 to 150 ^° C. The reaction can be carried out under atmospheric pressure, but can also, if desired, be carried out under increased pressure. There is no particular limitation on the reaction time, but generally the reaction is carried out for 1 to 20 hours.

When performing the above implementation, it is preferred to be an acceptor for hydrogen halide, for example Use sodium carbonate, potassium carbonate or triethylamine. In this case, the implementation proceeds even smoother when a catalytic amount of potassium

909850/1766

iodide or sodium iodide, added to the reaction system will.

In the above reaction, the molar ratio of the reactants can be changed as desired, but it is preferred that the compound of the formula (I) wherein R _{1 represents} a hydrogen atom '"· in an equimolar amount in the case of using an acceptor for hydrogen halide, or in an amount of more than 2 moles per mole of R ¹ ^ X in the case of not using an acceptor for hydrogen halide. It is also possible to use the compounds of the formula (I) in which R _{1 is} a hydrogen atom in such excess amounts as 2 to 3 moles per mole of R ¹ ..X to be used and the compound of the formula (i), in which R ₁ denotes a hydrogen atom, to be used as an acceptor for hydrogen halide and as a solvent.

C. R ₁ can be converted to a different radical R ₁ according to the following reaction (C):

I - \ CO-NR "2 ^

R ₅ H + X (CH ₂ Jn-N. XI "'^ condensation ^ -' 0 -— CO

QC0-NR »2 ' ~ \ : ι -— · < ^c > o-co

wherein X represents a halogen atom, R " _{2 has} the meaning given above for formula (B) and R ^ a radical corresponding to the formulas

909850/1766

wherein R "has the meaning given above or

and η is a positive integer of 2 or 3.

The reaction (C) is carried out by heating the reaction participants in a solvent such as benzene, xylene ,, toluene, ether, tetrahydrofuran, dioxane, dimethylformamide or liquid ammonia in the presence of a condensing agent. The reaction temperature is -3O .upper? C, preferably in the range from -30 to 150 ⁰ C. In general, this reaction is carried out for 1 to 24 hours. The molar ratio of the reactants is generally approximately equimolar. Sodium hydride, sodium amide, butyllithite or phenyllithium may be mentioned as preferred .Kpndensantsmittel. The, amount of said condensing agent is in the range of _v, 1 to 2 MPI, .bezogen on reactants.

The compounds of those listed above formula

X (CH ₂ ) n r H X

^ - / 0—

CO-NR "2 I CO

909850/1

which are used in the implementation (O) can = "· -. from a compound of the formula (I) in which R- is a hydrogen atom, according to the following reaction getting produced

X (CH ₂ ) n X «+ HN XI

) —CO

_ / —Λ Q0-KR »2
X (CH ₂ ) nN ^ _) (I.

condensation

in which X and X 'each denote hydrogen atoms and preferably X denotes chlorine and X ¹ · bromine, η denotes an integer of 2 or 3 and R " _{a has} the meaning given above with regard to formula (B).

D. The radical R ₁ can be converted to a different radical R ₁ according to the following reaction (D): ...

QCO-NR " 2 \ \ . .Τ ^ ~ -rr *, 0-CO condensation

GO-N-R "2

j —s. ου-. R ₄ COO (CH ₂ Jn-N. X

^Λ λ ■ f Qi _- ,

_Deca rboxylierun _g

Q- CO-NR "2 ' - ■ - - ■■■ ■■' ■ - ■■■■ ; I (D) 0 — CO
where R "2 and η have the meaning given for formula (B) and R. a group corresponding to the * formula

, R "

' N

909850/1766

wherein R "tile, has the meaning given above, means .. _(..

The compounds of the formula listed above

/ -Ν CO-NR ₂ '^; HQ (CH ₂ ) _n -N Xl

^ - 'o - co

which are used in the reaction (D) can be prepared from a compound of the formula (I) in which R _{1 is} a hydrogen atom by the above-mentioned process (B).

The reaction (D) is carried out by adding -R.COC1

QCO-NR ₂ ;
0— (

ο — co

the elimination of hydrogen chloride in a solvent and then the reaction product obtained is heated in the presence or absence of a solvent under reduced pressure, thereby causing decarboxylation is achieved.

Preferred solvents which can be used in the above elimination of hydrogen chloride are inert organic solvents such as methyl ethyl ketone, isopropyl acetone, toluene and xylene are listed. As preferred, at Solvents which can be used in the above decarboxylation are 1,3-dimethyloxybenzene and tetralin.

The elimination of hydrogen chloride is carried out with heating to about 50 to 150 ^° C. for about 5 to 24 hours.

909850/1766

The decarboxylation is preferably carried out under reduced pressure, in particular under greatly reduced pressure. For example, the decarboxylation is carried out under a pressure below 5 mm Hg, generally in the range from 0.1 to 1 mm Hg. In this case, it is preferred to carry out the reaction at elevated temperatures. For example, it is convenient to allow the reaction to proceed at a temperature in the range 170-230 ⁰ C. When this decarboxylation is carried out in the presence of a metallic copper powder at an elevated temperature under reduced pressure, the reaction proceeds particularly smoothly.

E. The remainder R ₁ can be different. R _{1 can be converted} according to the following reaction (E) (Mannich reaction):

Y - // \\ - C0CHj + (HCHD) m

ι -ν CO-NI
\ '0-CO

,,, Ν C0-N-R2

Y - (/ \> C0 (CH2) 2-N Λ I

\ = J \ —Ό—

o — co

wherein Y is a halogen or hydrogen atom, (HCHO) _m formaldehyde or paraformaldehyde and R _{2 has} the meaning given above for formula (I).

909850/1766

The reaction (E) between an acetophenone, in which the phenyl radical can be substituted by a halogen atom, for example p-Chlö.r.aceto-phe.non, Porm-f: ald ^ hyd- or paraformaldehyde and a compound the ■ formula Cl), in which R ^ is a hydrogen atom, can preferably ■ in the presence of hydrochloric acid in one; inert organic .IjösAingsmittel: such as alcohols such as ethanol. or propanol, can be carried out. Generally ⁰ C under atmospheric pressure for * 3 is executed up to 10 · .Stunden the reaction at 50 to too.

Falla- the compound of the formula (.1) in the form of a. Hydro chip rid, s is used, it is not necessary, _salt: acid use in the above reaction.

F «.; As. stated above, "it is possible within the scope of the invention, -, a ^ compound of the formula (I), in which R _{2 is} a hydrogen atom, to another compound of the formula (I), in which R _{2 is} an alkyl group , which can be substituted by a hydroxyl radical, or a benzyl group:, de.ute-t, to lead. This conversion can be carried out according to the following reaction (F); *

ilkyüermittel

^:: R 'χ-Ν

5.0 ^ 17

«16 -

wherein R ^1,. and R _"2 '' have .. ^■:; ■ -: ■. 'Bedeutungen- the above ■■ - * ^ ->." - ^"-"; - '■ "- ■ -

The reaction is carried out by using a compound of the formula (I) in which RJ is a hydrogen atom, Reacts with known alkylating agents. * As the? · ' like alkylating agents are alkyl halides, "like methyl" ' iodide, ethyl; iodide, propyl bromide, benzyl bromide and hy * droxyäthylbromid, as well as dialkyl sulfate, like'Dimethyl «· sulfate and diethyl sulfate listed, if an alkyl

If halide is used, the reaction is carried out in a solvent such as methyl cellosolve in the presence of, for example, potassium hydroxide. If a dialkyl sulfate is used, the reaction is carried out in a solvent, such as acetone, in the presence of, for example, potassium carbonate.

According to the invention, the desired compounds . of the formula .-. (I) in free: form by treating the pre- * - ' standing compounds of formula (I) in the form of a salt with a weak base, such as aqueous ammonia, sodium bicarbonate, Potassium carbonate or sodium carbonate, with cooling, the use of aqueous ammonia being preferred * ■ - = ■ "■ - '-'" ■■■■■. /.; The base can be converted into a non-toxic acid addition

"Salt together with an inorganic or organic acid, for example hydrochloric acid, phosphoric acid, sulfuric acid, citric acid, maleic acid or .tartaric acid ^ transferred". The salt exchange reaction of a salt of the desired compound of the formula (I) can also be carried out with a salt of another acid. Furthermore, it is possible, if desired, to use a quaternary ammonium salt of the compound '$ & £ Formula (X); ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ M business projections by known agents, for example quaternary ammonium salts of methyl chloride, ethyl chloride or phenyl chloride

909 8 50 /. 1.7 6 6.,, _: . ,

can be used.

The 1-oxa-3,8-diazaspiro / 4,5 ./-decane-2,4-diones according to the invention and their non-toxic salts pharmacologically and neuro / therapeutically valuable properties to cure psychosis and are valuable psychotropic agents. .

Typical examples of compounds according to the invention are as follows:. · ■ - ;.

Formula and name

No

I / ν CO-N-CH ₃

CH ₂ CH ₂ CH ₂ -NXI

^N- · 0-co

Melting point

( ⁰ C)
(XHydroChloride)

* 25Θ - 259 ° c.

3-I ^ thyl-8-C3-pheno thiazinyl (10) propylD-l-oxa-3,8-diazaspiroC4 »53decane-2,4-dione ·

N-

D ¹ C0-N-CH3

{' Ο— (

Ο — CO

142-143 c. * 262 - 263. ⁰ C. (decomposition)

3-methyl-8- C3- «J2-chloi> pheno thiazinyl (10)} propyl} -l "-oxa-3» 8-diazaspiro C4 »5 decane-2,4-dione :,

9 09850/1 76 6

1928704 Melting point formula and name ( ⁰ C)

'( ^X hydrochloride)

CH ₂ CH ₂ CH ₂ -NV

0-CO

150 - I5l ^u c.

♦ 253-255 ⁰ C.

decomposition

3-henyl-8- C3- j2-chlorophenothiazinyl (10)} - propyl> l-oxa-3 * f 8-diazaapiroC4 »5Ud
2,4-dione ·.

Cl

CH ₂ CH ₂ CH ₂ -N

0-CO

• .155 °° ·

('Decomposition)

3-Benzyl-8- C 3- ^ 2-chloropheno thiazinyl (10) y propyl] -l-oxa-3,8-diazaspiroC4,5D decane-2,4-dione

cm

! CH ₂ CH ₂ CH ₂ -]

CO-N-CH ₂ CH ₂ CHj 'Ό-CO

♦ 198 - 200 C.

3Py-S-C3- ^ 2-chloro r ^t pheno thiazinyl (10) J-propylD-l-oxa-3t8-diazaspiroC4 »53 decane-2,4-dione ^{; K}

I / y CO-N-CH2CH2OH

CH 2 CH ₂ CH 2 N V |

^> —'O — co

* 270 - 272 C.

3- (2-Ifydroxyethyl) -8-C3- ^ 2-chlorephenothiazinyl (10)} propylD-1-oxa-3 »8-diazaspiio C415decane-2,4-Ui ^

909850/1766

-,., 43 19 28 7 OA

Formula and Name *

GCÖ.

CF ₃
'CH2CH2CH2-N

-N-CH ₃

- ,. (- ■ ν. ---- ■ 0 — CO

. Melting point _u ' ^: ( ^x HyäroehlqriQ)

- * 259 .- 241 ⁰ C.
(Decomposition.)

J-Methyl-ö-CJ - ^ - trifluoro-jmethylphenothiazinyl (10) ^ pixipylJ-l-oxa-3 »e-äiazaepirp C45H2" 4äin \ "" *

O- ^! CO-N-CH ₃

! tI 0—

GO

* 231-232 c.

₃ -Me thy 1-Θ- C 3- {2- methoxypheno thi a zinyl (10) f propyl D-oxa-3 »O-di C3

decane-2,4-dione <. . '\

QCO-N-CH ₃ O -— CO ¹ '/ "' * 255 - 257 C.
(Decomposition)

34aethyl0C34 ° » ¹ lyd, dazepinyl (5)} propyl3-l-oxa-3» 8-diazaspiro C4,53decane-2i4-dione-; ^; '■ "" ^{: i} -;

t, «. CO-N-CH ₃

CH ₂ CH ₂ CH ₂ -NXI

■ CW ^ O — GO, -

. * 218 - 219 C.

; (Decomposition)

■ 1V- "·"'■' ^v ■ "- ■ '''' - ^ * ¹

9 O 9 8 5 O / 1 7 6 ξ .,.,

Formula and name

OCO -NV>; ι ^ = * 'η .An

0-CO

3-3? Henyl-8- C3- (p-fluoro * benzoyl) prppyl D-1-oxa-3 »8-diazaspiroC4,5 ^ clecan-2,4-dione.

Melting point

( ^x Hydrochloria)

180 - 182 ^U C. * 2Θ7 ■ - 29O ⁰ C. - (decomposition)

ft "

/ \ / —S. -CO-N-γ

? - (/>) - C0-CH2CH2CH2-N YI \ = * 272 - 275 C .. (decomposition)

ρ-8- C3- (p-fluoro-benzoyl) propyl3-l-oxa-3 »8-diazaepiro C4» 5Ddeoan-2,4-dione-.

-N ^/ Y CO-N-CH2 - </ \ 0-CO

* 250 - 251 c. (Decomposition)

3 "Benzyl-8-C 3- (p-fluoro-benzoyl) propylO-l-oxa-3,8-diazaspiro (4> 5) decane-2,4-dione *

j <CO-

N f 0—

CO-N-CH3

| 0-CO

3-methyl-8-C3- (P-fluoro-benzoyl) propylD-l-oxa-3 _t 8-diazaspiroC4> 5-decane-2 _f 4-dione '

COCH2CH2CH2-N

f ν CO-N-CH2CH2CH3

N ^

3-n-propyl-8-C3- (p-fluoivbenzoyl) propyl>l-oxa-3'f θ-diazaspiro C4,5) decane-2,4-dione / * 274 - 275 C (decomposition)

♦ 235-237 c.

(Decomposition)

909850/17 6 6

Formpl and Warne

1928704 melting point

( ⁰ C)
( ^x hydrochloride)

, - <CO-N -N \>'0—

CO * over JOO ⁰ C.

3-i »henyl-8-C2- (p-chlorobenzoyl) ethyl3-l-oxa-3 _f 8-diazaspiroC4i5-mecane-2,4-dione

/ -— ν / -ν CO-N-CH2CH2CH3

Cl - (/ \ VCOCH2CH2-N Y i X = J \ - / ο-α

0 — CO *, 214 - 215 ° C. "(Decomposition)

3-n-Propyl-e-C2- (p-chloro * benzoyl) ethylD-l-oxa-3,8-diazaspiroC4> 5Dclecan-2 _f 4- <üon

j y / V CO-NH

ci - {/ \ VcocH2CH2-N X 1

0 — CO * 225 ⁰ C.

(Decomposition)

8-pC.hloivbenzoyl ethyl-l-oxa-3 \ 8 » diazaspiroC4» 53decane-2,4-dione: '

/ ^ CO-n // \

CH ₂ -N) <1 \ = l

0-CO

C4i

-J, 8-diazaspiro 184 - 186 ° C. * 292 - 293 ⁰ C. (decomposition)

^ r-yCO-N- ^ /> CH2-N VIV = ü \ = ZJ N f 0 - CO

180 - lere *

3-p-chloro * phenyl-8-berizyl-l-oxa-3 »8-diazaspiroC4» 5decane-2,4-dione

90 98 50/1766

Formula and name

—Co

3,8-D.ibenzyl-1-oxa-3,8-diazaapiroC4,5! J decane-2,4-dione.

_r CO-N-CHj 0-CO

3-Methyl-8-benzyl-1-oxa-3,8-diazaspiroC4,5-decane-2,4-dione:

Melting point :-

( ⁰ C) ( ^x HydrochIoria)

113 - 115 C. ♦ 246 - 248 ⁰ C. (decomposition)

* 266 - 268 ⁰ C. (decomposition)

_/ -Ν / -ν CO-U

U ^N > CH ₂ -N Χ I

CO-N-CH2CH2CH3

\ I 0-co 101-103 c.

3-n-Bropyl-8-benzyl-1-oxa-3 »8» diaza8piroC4 »53decane-2,4-dione _{

v / v CO-

TVy ₀ H ₂ -NX / ^Z V-Zn-

-N-CH ₂ CHj

b-co 103-105 c.

3-Ethyl-8-benzyl-1-oxa-3,8-diazaspiroC4,5) decane-2,4-dione.

CO-N-CH ₂ CH ₂ OH -CO 127 - 128 C.

3- (2-Hydroxyethyl) -8-benzyl-1-oxa-3,8-diazaepiroC4i5Ddecane-2,4-dione

/> / —V co- ¹⁰¹

(/ \ y <! H2-N V I

N'b-CO

8-Benzyl-i-oxa-3,8-diazaspiro C4,5-decane-2,4-dione;

185-187 C.

* 291-293 ° C (Decomposition)

909850/1766

! ■,

No-.

Formula and name

OCO-N-CH ₃ [ I 0- (

0-00

5-ifethyl-8- (3-hydroxypropyl) -1-oxa-3,8-diazaspiroC4i53deoan-2 | 4-dione- ·;

Melting point ( ⁰ C)

( ^x hydrochloride)

130-131 ° C. * .250 - 252 ⁰ C, (decomposition

QCO-N-CH ₃ '-ίο-ο

0-CO 83-84 ° C.

3-methyl-8- (3-chloro ^ propyl) -1-oxa-3 »8-diazaspiroC4i5) decane-2,4-dione ¹

/ - \. CO-N-CH ₃ HN. XI ³

0-00

113 -

3-iiethyl-1-oxa-3 | 8-diaza8piro C4,5i3decane-2,4-dione.v

o — co

3-phenyl-l-oxa-3 »8-diazaapi.ro C4,5) decane-2,4-dione ^ 15Θ - 159 ⁰ C.

DC0-N- ^ ~~ ^ 0-co

168-169 ° C

^3-p-i Ghlor- phenyl-l-oxa-3> 8-diazaspiroC4 »5) decane-2,4-dione '

-N-CH ₂ CH ₂ CH ₃

0-CO

* 155 - 157 ° C (decomposition

3-n * Propyl-1-oxa-3, e-diazaepiro C415) decane-2,4-dione ^x

909850/1766

Name and formula

OCO-N f I 0-C

0 — CO melting point ( ⁰ C)

^ Hydrochloric!)

* 202 - 204 C,

3-Benzyl-1-oxa-5> 8-diazaBpiro C4 »5-decane-2,4-dione;

/ ν CO-

HN Y
N Ό—

CO-N-CH2CH2OH

I CO ♦ 206 - 207 ⁰ C.

-l-oxa-3,8-diazaspiroC4 "53decein-2,4-dione"

ι —ν co-:

N f 0—

-N-CH2CH3 0-CO 75-76 ⁰ C.

* 133 - 135 ⁰ C.

3 - '& hyl-l-oxa-3 »8-diazaepiro C415-decane-2,4-dione. '

909850/1766

The compounds of the invention are valuable psychotropic agents with very low toxicity.

For example, with regard to compound 2 of the above compounds, experiments on pharmacologically active; - " did and toxicity carried out. The test procedures and! Results are listed below:

Test procedure:

Male dd mice and male Wistar rats were subjected to experiments to determine the activities and toxicities of the compound.

1. Cataleptic activity

The experiments were carried out according to the following procedures:

Mouse e:

The compound was administered intraperitoneally to a group of 5 mice and the cataleptic condition determined in the mice after 30 minutes, 60 minutes, 120 minutes, 180 minutes and 24 hours and, based on the The point where the peak effect was reached became the dose-response curve established for the connection and the ED, -Q value according to the Litchfield-Wilcoxon method calculated.

• rats:

The compound was given intraperitoneally to one group administered by 5 rats. Then every rat was forcibly forced to assume such an unnatural position that either the left or right fore legs rose at a height of about δ cm. If in this state the rat this Held position for a prescribed period of time (3 3ec) without any movement, it was determined that.3 Catalepsy was present in the rat. The Ratio of Rats

909850/1766

"in which catalepsy was present, for the total group of 5 rats, was given as a percentage and the value of the cataleptic activity was calculated by specifying the observed catalepsy of 50 <f ° as EDc _0.

2. Muscle relaxation activity

The tests were carried out according to the following procedures:

Mice;

After intraperitoneally administering the compound to W a group of 5 mice, these mice were separated, placed in cylindrical wire cages 21 cm in diameter and 60 cm in length, and rotated at a speed of 2 revolutions per minute in a state where the Wire cage inclined 60 ° to the horizontal. Based on the number of mice that failed to hold the wire cage and fell downward over the course of 2 minutes, the ED ^ Q value for each compound was calculated according to standard methods.

Rats :

After intraperitoneally administering the compound to a group of 5 rats, these rats were separated . made to hold on to a vertical sieve and the number of rats that were held on holding the vertical sieve failed, was determined every 30 minutes for 6 hours, and based on the point where the peak effect was reached, the dose-claim curve was regarding of the connection and the EDcQ values accordingly calculated using the Lichfield-Wilcoxon method.

3. Barbiturate potency-learning activity

The experiments were carried out according to the following procedures executed?

909850/1766

The compound was administered intraperitoneally to a group of 5 mice. Thirty minutes later, a non-anesthetic dose (40 mg / kg) of methylhexabital-Na was administered intraperitoneally to each mouse. The length of time between the disappearance of the righting reflex and its recovery was determined and the length of this time compared to the administration of methylhexabital-Na alone was examined. The dosage of the compound required to add 60 minutes to the time on an average of 5 mice was reported as the EDg ₀ (minutes) value of the compound.

4. Prevention of metharaphetamine-induced locomotor activity

The compound was administered to 5 mice and 10 minutes later, methamphetamine was intraperitoneally administered to each mouse at a dose of 5 mg / kg. they were at the same time placed in a photocell cage, which was interrupted by light in a prescribed path. The frequency of light interruption by the mice was determined electrically registered during a course of 10 minutes after 15 minutes from the administration of methamphetamine and the registration frequency with the fall of mice compared to those given methamphetamine alone. The degree of lowering of the frequency was used as a benchmark the prevention ($) specified and the EDcQ value was on based on a prevention of 50 #.

5. Acute lethal toxicity

In the acute toxicity test, each group was tested by 5 mice weighing 1.8 to .20 g and 5 rats im Weight from 180 to 250 g of a suspension of the compound in 1 # gum arabic solution administered intraperitoneally or orally and observed for 7 days.

90 9 8 50/1 7.6 ß.

Test results :

The results of the above experiments are in Tables I, II and III listed. For comparison are also results of the same tests carried out with the above listed known compound (chlorpromazine) were carried out, which for valuable pharmacological activity is known, also listed in the table.

Examined
link

MT-300

Cataleptic activity
(mg / kg)

17, Ό

Ghlorpromaζin- 41.0 hydrochloride

Table I mouse e

Muscle-

relaxing

active

activity

(mg / kg)

7 100 68.0

Barbiturate potentiating activity (mg / kg)

54.5 43.0

Preventing the. ac ö i vitat induced by methamphetamine (mg / kg)

2.6 17.0

Table II

Investigated
link

MT-300 ^±}

Chlorpromazine hydrochloride

Rats

Cataleptic Activity (mg / kg)

21.2 15.0

Muscle relaxation activity (mg / kg)

> 100

12.0

909850/1766

BATH ORIGINAL

Table III
toxicity

Examined Ver
binding Mice
(ID ₅₀ mg / kg) (Ip) ' Rats
(ID ₅₀ mg / kg) (po) X1000 (po) MT-3OO ⁺ ) 2000 94 > 2000 Chlorpromazine
hydrochloride 135 207-455

+) ■ MT-300: 3-methyl-8 - ^ "" 3- {2-chlorophenothiozinyl (10)} - propyl7 "-1-oxa-3,8-diazaspiro / ~ 4,5_7decari-2,4-dione -Hydrochloride

The clinical dosage of the compounds according to the invention depends on the disease syndromes, body weight,
Age and administration method depends, however
generally in the range from 5 to 300 mg per day, preferably in the range from 50 to 150 mg per day.

The compounds of the invention can be administered by dissolving in salt form under sterile conditions in water or in a physiologically acceptable
aqueous medium, such as saline, and can be stored in ampoules for injection. Furthermore, they can be used in unit dosage forms as tablets or capsules for oral administration or, if desired, in combination with suitable auxiliaries, such as
Calcium carbonate, starch, lactose, talc, magnesium stearate,
Carboxymethyl cellulose or gum acasia can be used. Furthermore, the compounds according to the invention can be processed into solutions or oil-water emulsions in aqueous alcohols, glycols or oil for oral administration in the same way as conventional medicinal substances.

9 09 850/1766

An example of preparations made using the compounds according to the invention is the following:

3-Methy 1-8- / 3- {2-chlorophenothiazinyl (10)} - propyl7-1-oxa-3,8-diazaspiro / 4,5_7decan-

2,4-dione hydrochloride 25 g

Lactose 45 g

Starch 9.5 g

Microcrystalline cellulose 20 g

fc magnesium stearate 0.5 g

The above materials were mixed, granulated and processed into tablets according to conventional procedures, so that 1000 tablets each weighing 100 mg 'were obtained.

Some embodiments for making the connections according to the invention are hereinafter as an example ' Ie given.

example 1

Preparation of 8-Benzy1-3-pheny1-1-oxa-3,8-diazaspiro / "4,5_ / decane-2,4-dione a formula

8.6 g of 1-benzyl-4-cyano-4-piperidinol, 9 »52 g of phenyl isocyanate and 1 ml of triethylamine were dissolved in 40 ml of anhydrous benzene. The reaction was carried out at room temperature for 5 hours with stirring. The precipitated crystals were filtered off and recrystallized from benzene and 11 g of 8-Benzy1-3-pheny1-4-phenylcarbamoylimino-1-oxa-3- _t 8-diazaspiro / 4,57decan-2-one in the form

909850/1766

obtained from colorless needles with a melting point of 200 to 202 ^° C.

11 g of the compound thus obtained were dissolved in a mixture of 30 ml of concentrated hydrochloric acid and 70 ml of ethanol and heated under reflux in a water bath for 2 hours. After cooling, the precipitated crystals were filtered off and recrystallized from glacial acetic acid and 7.8 g of the hydrochloride of the desired product were obtained as white crystals with a melting point of 291 to 292 ^° C. (decomposition). This hydrochloride was dissolved in water and the solution made alkaline with ammonia. The precipitated crystals were filtered off and recrystallized from ethanol to give the desired product in the form of färblosen needles having a melting point of 184-186 ⁰ C.

Example 2

Preparation of 3,8-dibenzyl-1-oxa-3,8-diazaspiro- / 4,57deean-2,4-dione hydrochloride the formula

/ v

Y
0-00

, ν / v C02 ^ V A ^ -CH ₂ -NY i \ = / - HCl.

= Y N '0—

In 100 ml of anhydrous benzene, 21.6 g of 1-benzyl-4-cyano-4-piperidinol, 26.6 g of benzyl isocyanate and 2 ml of triethylamine dissolved and the reaction for 3 hours Room temperature; carried out with stirring. The benzene was removed by distillation under reduced pressure. the Removal of the 1-benzyl-4-piperidone (boiling point 147 to 151 s: at 7 mm Hg) contained in the residue,

9098 50/1766

further distillation under reduced pressure gave 14.6 g of 3,8-dibenzyl-4-benzylcarbamoylimino-1-oxa-3,8-diazaspiro / 4,5_7decan-2-one as a gummy residue. This compound was dissolved in a mixture of 20 ml of concentrated hydrochloric acid and 50 ml of ethanol and refluxed for 1 hour, and the precipitated crystals were filtered off. Recrystallization of the separated crystals from methanol gave 8.5 g of the desired product in the form of colorless needles with a melting point of 246 to 248 ^° C. (decomposition).

Example 3

Preparation of 8-benzyl-3-methyl-1-oxa-3,8-diazaspiro £ 4,5_ / decane-2,4-dione hydrochloride the formula

- CO-N-CHj * ·

CH2-N χ I 'HCl.

^N - 'o - co

21.6 g of 1-benzyl-4-cyano-4-piperidinol, 11.4 g of methyl isocyanate and 1 ml of triethylamine were dissolved in 100 ml of anhydrous benzene and the reaction was carried out at room temperature with stirring for 2 hours. The benzene was distilled off under reduced pressure, and then the 1-benzyl-4-piperidone (boiling point 142-146 ⁰ C under 4 mm Hg) removed by further distillation under reduced pressure. 6 g of 8-benzyl-3-methyl-4-methylcarbamoylimino-1-oxa-3,8-diazaspirö / 4,57deean-2-one were obtained as a gummy residue. This compound was dissolved in a mixture of 15 ml of concentrated hydrochloric acid and 30 ml of ethanol and heated under reflux in a water bath for 1 hour. After cooling, the freshly precipitated crystals were filtered off and recrystallized from methanol, giving 4.3 g of the desired product

BATH ORIGINAL

9098 50/1766

in the form of colorless needles with a melting point of up to 268 ^° C. (decomposition).

Example 4

By carrying out the reaction and treatment in the same manner as in Example 1, 8-benzyl-3-p-chlorophenyl-1-oxa-3,8-diazaspiro / 4,5 / decane-2,4-dione (melting point 180-181 ⁰ C) of the following formula

example 5

By carrying out the reaction and treatment in the same manner as in Example 3, 8-benzyl-3-n-propyl-1-oxa-3,8-diazaspiro / ~ 4.57 * decane-2,4-dione hydrochloride was obtained obtain. This compound was made alkaline with ammonia and recrystallized from ethanol and the 8-benzyl-3-n-propyl-1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione (melting point 101 to 103 ⁰ C) the formula obtained

QCO-N-CH2CH2CH3 O-CO

- - "" Example 6

Production of 8-benzyl-1-oxa-3,8-diazaspiro / ~ 4,5 / -decane-2,4-dione the formula

., - _v "/ - \ co-ii-H ■; -;""-·"'.

^ N) -CH ₂ -NVI

X = / ^ - '0-co

9098 50/1766

a) To a solution of 23.7 g of 1-benzyl-4-cyano-4-piperidinol in 100 ml of dry benzene, an excess of acetyl isocyanate in petroleum ether solution and a catalytic amount of triethylamine were added with stirring at room temperature. The reaction system was left over Stand overnight at room temperature and then the precipitated crystals were filtered off. Concentrated hydrochloric acid was added to a solution of the crystals obtained in ethanol and the mixture was heated under reflux for a few minutes g of the hydrochloride of the desired product with a melting point of 291 to 293 ^° C. were obtained.

This hydrochloride was then treated with ammonia and 20 g of the desired product with a melting point of 185 to 187 ^° C. were obtained.

b) 63.8 g of benzoyl isocyanate were added to a solution of 46.5 g of 1-benzyl-4-eyano-4-piperidinol at room temperature with stirring added in 300 ml of dry benzene and then added a catalytic amount of triethylamine. The system was allowed to stand at room temperature overnight, and then the precipitated crystals were separated by filtration away. Crystals obtained in Me were hydrolyzed in the same manner as in a) using hydrochloric acid, and 52 g of the hydrochloride of the desired product obtain.

Example 7

Preparation of 3-phenyl-1-oxa-3,8-diazaspiro / 4,5_7-decane-2,4-dione the formula

909850/1766

60 oil glacial acetic acid "8.1 g eoxa-3,8-diazaspiro / 4, 5_ / decan-2 ^ 4-dione and Ig of a 10 ^v;. A-strength palladium-carbon is added, the reduction was" at elevated Temperature of 50 to 80 ⁽ 'above atmospheric pressure. After a reduction for 1 de the theoretical amount of EU gas was absorbed. After cooling, the palladium-carbon catalyst was filtered off and the glacial acetic acid used as solvent was distilled off under reduced pressure. The remaining crystals were dissolved in water and the solution made alkaline with ammonia The precipitated crystals were filtered off and recrystallized from ethanol, 5.1 g of the desired product being obtained in the form of colorless needles with a melting point of 158 to 159 ^° C .

Example 8 - -

The reactions and treatments were carried out in the same manner as in Example 7 using the dione obtained in Example 5, the 3-p-chlorophenyi-1-oxa-3,8-diazaspiro / 4,5jü.etan-Z , 4 -dione hydrochloride with a melting point of 168 to 169 ⁰ C of the following formula was obtained "■ '

9 0 9 8 5 0/1766 BAD ORIGINAL

Example 9

Preparation of 3-methyl-1-oxa-3,8-diazaspiro / ~ 4,5 _ / - decane-2,4-dione the formula

GO-N-CH3
O-CO.

HN X
>'0—

To 80 ml of glacial acetic acid, 9.3 g of 8-benzyl-3-methyl-i-

fc oxa-3,8-diazaspiro / 4, 57decan-2,4-dione and 1 g of 10 $ strength palladium-carbon is added and the reduction carried out at an elevated temperature of 50 to 80 ⁰ C under atmospheric pressure. After a reduction of 1 hour, the theoretical amount of Hp gas had been absorbed. Compartment cooling, the catalyst was filtered and-the glacial acetic acid used as the solvent under reduced pressure abdestilli3r- _u. The obtained crystals were dissolved in water and the solution was made alkaline with ammonia. The precipitated crystals were recrystallized from benzene and 6.5 g of the desired product were obtained in the form of colorless needles with a melting point of 113 to 114 ^° C.

Example 10

Preparation of 3-n-propyl-1-oxa-3,8-diazaspiro / 4 »5 / -decane-2,4-dione hydrochloride the formula

OCO-N- ^ Sj 0-iCO

BATH ORIGINAL

909 8 5Ö / "17.6 6 ■: ..- ■

19287G4

- 57 -

To 100 ml of ethanol 12 g of e-benzyl - ^ - n-propyl-i-oxa-3 ', 8-diazaspiroZT4,57decan-2,4-dione and 1 g of a 10% palladium carbon were added and the reduction carried out at an elevated temperature of 50 to 80 ⁰ C under atmospheric pressure. After a reduction of 2 hours, the theoretical amount of Hg-G-as was absorbed. After cooling, the palladium-carbon catalyst was filtered off and the ethanol used as the solvent was distilled off under reduced pressure. The remaining oily substance was dissolved in ether and alcoholic hydrochloric acid was added to the solution. The precipitated crystals were recrystallized from a mixture of ethanol and ether and 8 g of the desired product were obtained in the form of colorless, step-like crystals with a melting point of 155 to 157 ^° C. (decomposition).

Example 11

Preparation of 3-benzyl-1-oxa-3,8-diazaspiro / ~ 4> 5_7-d'ecane-2,4-dione hydrochloride the formula

• HCl. 0-00

To 80 ml of glacial acetic acid was added 8 g of 3,8-dibenzyl-1-oxa-3,8-diazaspiro / 4,5j ^r decane-2,4-dione, and 1 g of 10 $ sodium palladium-carbon was added and the reduction in carried out the elevated temperature of 50 to 80 ⁰ C under atmospheric pressure. After a reduction of 2 hours, the theoretical amount of H ₂ -GaS was absorbed. After cooling, the palladium-carbon catalyst was filtered off and the glacial acetic acid used as a solvent was distilled off under reduced pressure. The arrears

909850/1766

The crystals held were dissolved in water and the solution made alkaline with ammonia. The deposited oily matter was extracted with chloroform, washed with water and dried with sodium sulfate, whereupon the chloroform was removed by distillation and 5.8 of an oily Substance were obtained. This oily substance was dissolved in ether and alcoholic hydrochloric acid was added. the

precipitated crystals were crystallized from methanol

siert and 5.0 g of the desired product in the form of faro- W- free needles with a melting point of 202 to 204 ^C C (decomposition).

Example 12

Preparation of 3-methyl-8- (3-hydroxypropyl) -1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione the formula

, ν CO-N-CH ₅

H0CH2CH2CH2-N χ ι

>' 0-CX) ·

3.68 g of 3-methyl-1-oxa-3,8-diazaspiro / ~ 4,57-decane-2,4-dione and 1.80 g of 3-chloro-1-propanol were dissolved in 80 ml of isopropyl acetone, whereupon 2, 1 g of anhydrous potassium carbonate Ψ and 3.0 g of sodium iodide were added. The system was heated under reflux for 20 hours with stirring, then filtered, and the solvent was removed from the filtrate by distillation. The residue was washed with ether and recrystallized from isopropyl alcohol, v / obei 3.2 g of the desired product in the form of colorless needles having a melting point of 1-30 to 131 ⁰ C were obtained.

Example 13

Preparation of 3-methyl-8- (3-chloropropyl) -1-oxa-di- ■ azaspiro / l-, 57decane-2,4-dione of the formula

909850/1766 BAD QH.G.NAL

■ - 39 -

f CO-N-CH5

ClCHaGH ₂ CH ₂ -NV Γ U ^ o-CO

To a solution of 2.75 g of I-methyl-i-oxa-!), 8-diazaspiro / 4,57decane-2,4-dione and 2.35 g of i-bromo-3-chloropropane in 60 ml .Methyl ethyl ketone were 1.05 g of anhydrous Ka-. lium carbonate added. The system was heated under reflux for 12 hours with stirring, then filtered and the solvent was removed from the piltrate by distillation. The residue was mixed with ether and the part which was difficult to dissolve in ether was removed. The ether layer was washed with a small amount of water and dried with magnesium sulfate. After the solvent was concentrated, the system was left to cool. The precipitated crystals were recrystallized from ether and 2.7 g of the desired product were obtained in the form of colorless prisms with a melting point of 85 to 84 ¹¹ C.

Example 14 ,

Preparation of 5-phenyl-8- _/ 0- (p-fluorobenzyl) propyl / -1 -oxa-r-3,8-diazaspiro / 4, 5_7ae.can-2, .4-dione hydrochloride of the formula ■ · ■ . > ^_";: ■.

ι —y co-Ni ' \) -NXI \ = /. ^ ~ A-CO

In 25 ml of anhydrous xylene, 2 g of 3- (p-rFiuor- "benzoylO-propyl chloride, 2.5 g of J-phenyl-t-oxa-Jje-.diazaspiro / 4 -, _ 57, de.can-2., 4r4. ^{Ian un <i 1} -. » ¹ B triethylamine and the solution under reflux in an oil bath for 5 hours

BATH ORIGINAL

heated. After cooling, the precipitated triethylamine hydrochloride was filtered off and the xylene layer was shaken with concentrated hydrochloric acid. The hydrochloric acid layer ... was made alkaline with ammonia, and the precipitated gummy material was extracted with ethyl acetate, washed with water and dried with magnesium sulfate, followed by distillation under reduced pressure. The remaining gummy substance was dissolved in ethanol and alcoholic hydrochloric acid was added to the solution. The precipitated crystals were recrystallized from methanol and 1.8 g of the desired product were obtained in the form of colorless needles with a melting point of 287 to 290 ^° C. (decomposition).

Example 15 '-

The reaction and treatments were carried out in the same manner as in Example 14 using a dione having a p-chlorophenyl substituent at the 3-position while using 3-p-chlorophenyl 1-8- / 3- (pl ^ or "r; enzyl) propyl / -1-oxa-3> 8-diazaspiro / 4,57deean-2, 4-dione hydrochloride having a melting point of 272 to 275 ⁰ C (decomposition obtained in accordance) of the formula

f —V CO- V

0-p-CO

COCH ₂ CSI ₂ CH ₂ -NV \\ = ^λ --- ^/ 0-p-

BATH ORIQINAL

9098SQ - / '1 760. - -

Example 16

Production of 3-benzyl-8- / 3- (p-fluorobenzoyl) propyl7-1-oxa-3,8-diazaspiro / 4, 57decane-2,4-dione hydrochloride of the formula

. . / yC0-N-CH2- ^ 7

F - // \ VCOCH2CH2CH2-N V I ^ = ^ «HC1.

1.6 g of 3- (p-fluorobenzoylpropyl) chloride, 2.1 g of 3-benzy1-1-oxa-3,8-diazaspiro /4,57d.ecane-2,4-dione and 0 Dissolved 9 g of triethylamine and the solution under reflux in an oil bath for 5 hours, followed by the same procedures as in the example. In this case, 1.6 g of the desired product in Porm colorless needles having a melting point 250-251 ⁰ C (decomposition) after recrystallization from methanol obtained.

Example 17

Preparation of 3-Methy1-8- / 3- (p-fluorobenzoyl) propy XJ- 1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione hydrochloride of the formula -

QCO-N-CH5 L I «HCi.

In 20 ml of anhydrous xylene, 1.8 g of 3- (p-3? Luobenzoylpropyl) chloride, 1.65 g of 3-methyl-1-oxa-3,8-diazaspiro / 4,57-decane-2,4-dione and dissolved 1 g of triethylamine and heated the solution under reflux for 6 hours. After this The precipitated triethylamine hydrochloride was cooled down

90 98S0 / 17S6 - BADORIUfNAl ₄

filtered and the xylene layer shaken with concentrated hydrochloric acid. The hydrochloric acid layer was concentrated under reduced pressure. The obtained crystals were recrystallized from methanol and 1.4 g of the desired product
in the form of colorless needles with a melting point of 274
to 275 ⁰ C (decomposition).

Example 18

Preparation of 3-n-Propy1-8- / 3- (p-fluorobenzoyl) propyl / -P 1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione hydrochloride der
formula

f -, CO-N-CH2CH2CH3 Λ - / N / θ-CO

2 g of 3- (p-fluorobenzoylpropyl) chloride, 2.1 g of 3-n-propyl-1-oxa-3,8-diazaspiro- / 4,5j7decane-2,4-dione and 1, Dissolved 1 g of trimethylamine and heated the solution under reflux in an oil bath for 7 hours. After cooling, the same procedures as in Example 17 were followed. 1.9 g of the desired product were obtained in the form of colorless needles with a melting point
obtained from 235 to 237 ⁰ C (decomposition).

Example 19

Preparation of 3-phenyl-8- / 3- ^ 2-chlorophenothiazinyl- (10) J propy 1 / -1 -oxa-3,8-diazaspiro / 4,5_7decane-2,4-dione hydrochloride the formula

CH ₂ CH ₂ CH ₂ -NXI ^ ' .HCI

> * 0-00

909850/17 66

In 20 ml of the 3-free xylene there were 3.1 g of 3- / 2-chloro-ph en o thiazinyl (10) _7 * - '1 - ^ chloropropane, 2.5 g of 3-pheny1-1-oxa - Dissolved 3,8-diazaspiro / 4,5_ / decane-2,4-dione and 1.1 g of triethylamine and heated the solution under reflux in an oil bath for 8 hours. After: cooling, the precipitated triethylamine hydrochloride was filtered off and the xylene layer was shaken mix of concentrated hydrochloric acid. The hydrochloric acid layer was made alkaline and the precipitate was washed with water and dissolved in ether. Then alcoholic hydrochloric acid was added to the ethereal solution. The precipitated crystals were recrystallized from methanol. 2.0 g of colorless small needles with a melting point of 255 to 255 ⁰ C (decomposition) were obtained.

Example 20

Preparation of 3-'Kethy 1-8- / 3- (2-chlorphehothiazinyl- (10) jpropyl / -1 oxa-3,8-dlazaspiro / 4, ^57decari-2., 4-dione hydrochloride '- chloride the formula '- ■' - ^:

Cl

/ Tv CO-N-CH ₅ . CH2CH2CH2-N X-. I. "HCl.

(a) A solution of 3.1 g of 3-Z2 "^# chlorophenothiaziny: - (10) 7-1-chloropropane, 1.9 g of 3-methyl-t-oxa-3.8 ^r -diazaspiro-Z4.57 <3.ecane-2,4-'dione and '1.1 g of triethylamine in 20 ml of v / water-free xylene were heated under reflux in an oil bath for 8 hours, then cooled with ice and 30 ml of a 10% Hydrochloric acid was added, and the obtained crystals were filtered off, washed with water, and then discharged

BATH ORIGINAL

9850/1 / 7.6 6 , _y . _{; r}

19287Q4

. • Ie-ui;. \ Iiol recrystallized with 1.8 g of the desired. Product in the form of colorless small needles with a melting point of 262 to 263 ^° C. (decomposition) were obtained, (b) 3.1 g of 3 - / "2-chlorophenothiazinyl (10) 7-T-chloropropane, 1.84 g of 3 -Kethyl-1-oxa-3,8-diazaspiro £ 4.57 <iecan-2,4-dione, 1.5 g of potassium carbonate and 0.5 g of potassium iodide were refluxed in 50 ml of ethyl ethyl ketone for 8 hours . When the reaction had ended, the insoluble material was filtered off and the piltrate was concentrated. The received rucks -... '.

Was dissolved in 1G ml of ethanol and an excess of ^ r.erter hydrochloric acid was added to the solution and crystals were precipitated. The precipitated crystals were washed with water and with ethanol and then umkristaliisiert from methanol to give 3.5 g of the desired product having a melting point von'262 to 263 ⁰ C (decomposition) were obtained.

Then the product obtained was treated with ammonia treated and the base obtained: melting point 142 to 143 ° C ·

Example 21

The following compounds were obtained in the same way in Example 20:

3-Kethyl-8/3-phenothiazinyi (10) prppyl7 "-1 oxa-3,8-di £ .zaspiro / ~ 4,57 de can-2,4-dione hydrochloride (melting point 258-259 ⁰ C. ) of the formula

I / S.CO-

CH ₂ CH ₂ CH ₂ -NY

^ Ό—

CO-N-CH ₃

0-CO

• HCl,

9098S0 / HÄ6.

BAD ORfGINAL

3-3enzyl-8- / 3- [2-chlorophenothiazinyl (10)} propyl / -1-oxa-3ν8-diazaspiroif4,5 / decane-2,4-dione hydrochloride (decomposes at .155 ¹⁰ C) of the formula

CH2CH2CH2-N Χ i " ^Λ - ^f » Hei, ^ - ^/ 0-co

3-21-PrOPyI-S - / ^ - ^ 2-chlorophenothiazinyl (10) J propyl / -oxa-3,8-diazaspiro / 4,5 / deean-2,4-dione hydrochloride (melting point 198 "to 200 ⁰ C) the formula

OCCl.

QCO-N-CH2CH2CH3 ( I 'HCl,

0-00

3- (2-Hydroxyethyl) -8- / 3- {2-chlorophenothiazinyl (1O) J-propyl / -1-oxa-3,8-diazaspiro / 4,5 / decane-2,4-dione-HydrochlorM (melting point 270 to 272 ⁰ C) of the formula

Cl , - ^ CO-N-CH2CH2OH

CH2CH2CH2-N Y \ «HC1,

\ ^ 0 — CO

3-Methy 1-8- / 3- (2-trifluoromethylphenothiazinyl (1O) J propyl7-1 -oxa-3,8-diazaspiro A * 5_ / decane-2,4-dioii hydrochloride (decomposition "at 239" to 241 ⁰ C) of the formula

t; - ^ C0-N-CH3

CHCHCHK Υ t

0-00

CH2CH2CH2-K Υ t '.HCl. \ - / 0— (

909850/1766

and . ■

3-Kethyl-8- / 3- {2-methoxyphenothiazinyl (1Q) j propyl7 1 -oxa-3,8-diazaspiro / * 4,5 / decane-2,4-dione hydrochloride (melting point 231 to 232 ⁰ C) the formula

I / ν CO-N-CH ₃

CH ₂ CH ₂ CH ₂ -NXI ^N ' 0-CO

Example 22

Production of 3-Pheny1-8- / 2- (p-chlorobenzoyl) ethyl7-1 -oxa-3,8-diazaspiro / ^ ·, 57decane-2,4-dione hydrochloride der Porciel

j . / —Ν CO-N /

Cl - </ ^) - COCH ₂ CH ₂ -NXI ^ = J .HCl. V / \ f o-CO

A solution of 2 g of 2- (p-Chlorb'enzoyläthyl) chloric, 2.5 g of 3-Pheny 1-1-oxa-3,8-diazaspiro / 4,57decan-2,4-diorx 1.1 g of triethylamine in 30 ml of anhydrous xylene was refluxed in an oil bath for 6 hours. After cooling, the precipitated triethylamine hydrochloride ψ was filtered off and the xylene layer shaken with concentrated hydrochloric acid. The precipitated crystals were filtered and recrystallized from methanol · and 3.2 of the desired product in the form of g colorless stair-like crystals having a melting point above 300 ⁰ C. were obtained.

Example 23

In the same way as in Example 22, 3-n-propyl-8- / 2- (p-chlorobenzoyl) ethyl7-1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione hydrochloride was used with a melting point of 214 to

909850/1766 BA & ORIGfNAL

215 ⁰ C (decomposition) obtained according to the formula:

^ '"^;■■"''■' ■ * "''') rtV r— \ CO-N-CH2CH2CH5.

Cl - (/ NVpOCH ₂ CH ₂ -H Xl ..HCl..

V = - /. V- / 0-00

Example 24 "

Preparation of 3-methyl-8- £ 3- {2 ~ chlorophenothiazinyl- (10)} propyl7-1 -oxa-3,8-diazaspiro / 4 »5 / decane-2,4-dione hydrochloride the formula

Cl

QCO-N-CH3 -. [I fHCl. 0 — CO

To a solution of 3.50 g of 2-chlorophenothiazine in 20 μl of dimethylformamide was added 0.5 g of an approximately 50% suspension of sodium hydride in mineral oil. The mixture would be heated under a nitrogen gas stream to 50 to 50 ^V C with stirring for 2 hours and then 3 ', 90 g of 8-chloropropyl-5-methyl-1-oxa-3,8-diazaspiro / 4 ·, 5j decane-2V4 -diön. heated "in 20 ml of dimethylformamide to the above a-eaisch" added ". Then wurde'das mixture to 40 to 50 ⁰ C under Rühreh during 5'Stünden 'and then added 2 ml of anhydrous ethanol. After removing the LösangSEitteis- by / distillation, the residue was 'extracted Diö Ktherschichf wurde'mit ¹ 10 ^ strength.' with ^ether. shaken and then cooled Salssä-'ure the precipitated crystals were filtered and washed with ether and then ~ ^J ^ washed with water ". After recrystallization of the

BATH ORIGINAL

9 0 9 8 ^ € 7Ί.? & €: - ^ - '^ ~

stalle of methanol was added 4.1 g of the desired product as colorless needles having a melting point 262-263 ⁰ C (Zersexzung) was obtained.

Example 25

Preparation of 8 - / ^ £ iO, 11-I) ihydrodibenz / b, f7azepinyl- ( 5)} propyl7-3-methyl-1-oxa-3,8-3,8-diazaspiro / 4,5_7decane-2,4-dione hydrochloride of the formula ■. -. -

Q ¹ CO-N-CH ₅

(I'HCl.

0-00

A mixture of 3.0 g of 3- / 10,11-dihydrodibenz / b> f7 ^aze ~ pynyl (5) _ / - 1-chloropropane, 5.1 g of 3-methy 1-1 -oxa-3,8-diazaspiro / 4,5_7-decane-2,4-dione and 30 ml of absolute xylene were heated under reflux for 14 hours. After cooling, 40 ml of a 10% hydrochloric acid were added and the precipitated crystals were filtered off, washed with water and ether and then recrystallized from methanol, giving 2.0 g of the desired product as a colorless powder with a melting point of 255 to 257 ⁰ C (decomposition) were obtained.

Example 26 . , ..- ".-

Preparation of 8- / 3- {dibenz / b, f / azepinyl (5) J propyl7-3-nethy 1-1 -oxa-3,8-diaza3piro / 4,5_7decane-2,4-dione hydrochloride ier formula

•• Ν-

. ... / - ^ CO-N-CH ₃ CH ₂ CH ₂ CH ₂ -NVI ^v ^ 0-00

BATH ORIGINAL

90 9 8 50/176 6 ........ '

A device made from 3.35 g of 3- / dibenz / b, f / azepinyl (5i / -1-chloropropane, 2.3 g of 3-methyl-1-oxa-3,8-diazaspiro / "4,5 / -decane -2,4-dione, 3.8 g of triethylamine and 30 ml of anhydrous xylene were heated under reflux for 14 hours. After cooling, 40 ml of a 10% hydrochloric acid Zi- βΐΓ; system were added The hydrochloric acid layer was washed with ether, made alkaline with ammonia, extracted with chloroform and washed with water, followed by drying with potassium carbonate and distilling off the solvent. The residue was dissolved in a small amount of benzo and the resulting solution was Column chromatography was subjected to the use of 20 g of silica gel using a 4: 1 mixture of benzene and acetone as the diluent, the eluted liquid was concentrated and the residue was converted into the hydrochloride by using alcoholic hydrochloric acid, whereupon the alcohol was distilled off Back The residue was recrystallized from isopropanol and 2.8 g of the desired product were obtained as a yellow-greenish powder with a melting point of 218 to 219 ^° C. (decomposition).

Example 27

Preparation of 3-methyl-8- / 3- {2-chlorophenothiazinyl- (10) J propyl7-1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione der

Formally - '■

Cl , ν CO-N-CHj

CH2CH2CH2-N \

CO

BA © ORIGINAL

90 98 50/1766

* 50 -

A mixture of 2.1 g of 2-Chlorphenothiazinyl-IO-carboxylic acid chloride and 1.9 g of 8- (3-hydroxypropyl) -3-methyl-1-oxa-3,8-diazaspiro / 4 "5j ^r decan-2 , 4-dione, obtained according to Example 12, was heated in 40 ml of isopropyl acetone under reflux for 20 hours with stirring. The 8- (3-hydroxypropyl) -3-methyl-1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione hydrochloride formed was filtered off and the filtrate was concentrated by distillation. The residue was then extracted with ether, and the ether solution was further extracted with 3,000 hydrochloric acid. Then the aqueous layer was made alkaline with ammonia and extracted with chloroform. The residue was dried with .Natriumsulfat and recrystallized from ethanol, where "., 6 g of 3-methyl-8- (2-chlorophenothiazinyl (.10) carbonyloxy) -propyl7-1-oxa-3,8-diazaspiro / 4,5.7 decane-2,4-dione of the formula

Cl

I / ν CO-N-CHj

COOCH ₂ CH ₂ CH ₂ -NVI>'o- CO

in the form of colorless blames with a melting point of 126.5 to 127 ^° C. were obtained.

1.4 g of the compound obtained were heated at 190 to 200 ⁰ C under reduced pressure of 1.0 g to 1.2 mm Hg in blessing Wart of 0.2 Cu powder. After cooling, the reaction mixture was extracted with chloroform, the copper was filtered off and the solvent was removed from the piltrate by distillation. The residue was dissolved in ether and the

909850/1766

19287OA

Solution resulted the precipitation of crystals which were danr * umkristaliisiert from ethyl acetate to give 0.9 g of the desired product as schwach.gelbe prisms having a melting point of 142 to 143 ⁰ C were obtained.

; - .., example 28 . , _

Preparation "of 8- / 2- (p-chlorobenzoyl) ethyl7-3-propyl-1 -oxa-3,8-d'iazaspiro / "4,57decane-2,4-dione hydrochloride of,

Formula - __. t ^ CO-N-CH ₂ CH ₂ CH ₅

ClH / 7> COCH ₂ CH ₂ -N _v ^ I .HCl.

1.54 g p-chloroacetophenone, 2.4-9 g 3 ^r -nP-ropyl-1-oxa-3, S-diazaspiro / 4,5ydecari-2 _J 4-dione-'hydrochloride and 2,7 ■ -: p-formaldehyde were refluxed for about 10 hours in 50% dilute alcohol. After cooling, the precipitated crystals were filtered off and recrystallized from Mexhanol, with 2.4 g of the desired product being obtained in the form of colorless step-like crystals with a melting point of 214 to 215 ^° G (decomposition).

Example 29

In the same manner as in Example 28, 8- (2- / P-ChIo ^ eIiZOyI) ethyl / -1-bxa-3,8-diazaspiro / ^, 5jdecane-2,4-dione-hydrochloride, melting point 225 ⁰ C (decomposition), and 3-phenyl-8- / 2-p-chlorobenzyl) ethyl 7-1 -oxa-3,8-diazaspiro / 4, ^ 5j ^r decane-2Y4-dione-hydrochloride, melting point above 300 ⁰ C. These. Connections correspond to the following i? Bfmelri "■ -..---. ■ ,,. ..-..-

9 0 9-8-5 »0r / \ 1 ^; 6? 6> = ^ BAO ORIGINAL

QCO-NH
; i .HOI * 'and

ei- ^ ^r ^ COCH ₂ CH ₂ -N ^ X l ^ - '' HCl.

A— / ^ - 'ο-co

■ ■■ .-. Example. 30 , > . - -.-: ■ · - ·

Production of 3-Methy'l-8-berizyl-1 -o'xä-3,8-diazaspi- • o / 4,57decane-2,4-dione of the formula '' '' '"

\ C0-JI-CH3
CH ₂ -N \ I "

-8.9 g ozaspiro / 4,57decane-2,4-dione and 10 g potassium carbonate were suspended in 35 ml acetone and stirred for 2 hours. the .Suspension 5.8 g Dinethylsulfat dropwise over a period of 2, O-.Minuten added, the temperature, below -50 ⁰ C. · -. -Was, whereupon it was stirred for 2 hours. The precipitated inorganic material was filtered off and the filtrate was concentrated. The residue was extracted with hot benzene. xCach distilling off the benzene, the residue recrystallized from ethanol .wurde and thereby 6.12 g of the desired product, melting point 99 to 101 of ⁰ C is obtained.

ORIGINAL BATHROOM

9 0 9 8 5 0 /.1.7 6 6

Example 51

In the same manner as in Example 30 by using diethyl 8-benzyl-3-ethyl-1-oxa-5,8-diazaspiro / 4,5.7decan-2,4-dione, melting point 103 receive ^"0 to 105 C, .

Example 52

Production of 8-spiro ^ "4,5_7decane-2,4-dione the formula

-N-CH2CH2CH3
—CO

15 g of e-Benzyl-i-oxa- ^ jiS-diazaspiro / ^., 5 / decane-2,4-dione and 3.2 g of potassium hydroxide were heated under reflux in methylcellusolve. Then, 8.5 g of n-propyl iodide was added dropwise to the system over 10 minutes, followed by refluxing for 2 hours. After cooling, the precipitated crystals were filtered off and recrystallized from ethanol, 12 g of the desired product in the form of colorless needles with a melting point of 101-103 ^° C. being obtained.

• Example 55

■ In the same way as in Example 32, using hydroxyethyl chloride and benzyl chloride, 8-3enzyl-3- (2-hydroxyethyl) -1-oxa-3,8-diazaspiroQ-, 2,4-dione, melting point 127 to 128 ⁰ C were obtained and 5,8-dibenzyl-1-oxa-5, '8-diazaspiro / V, 5 _r / decane-2,4-dione, melting point 11 5 115- prepared ois ⁰ C satisfying the following formulas entspre ^chen-r: "■ '' ■ - ■ '.' .

BATH

909850/1766 '

CO-N-CH ₂ CHaOH

-00

and

QCO-N-

r ι ο—

o-oo

909850/17 66 ^: "

Claims (9)

Claims 1. 1-Oxa-3,8-diaza8piro / 4,5yclecan-2,4-dione der general formula, as well as their salts: 0-00 wherein R _{1 is} a hydrogen atom, a benzyl group or G groups of the formula. \ /■</'.■-.-■ · '· wherein H ^{1 is} a halogen atom, a hydroxyl group or a 3enzoyl group optionally substituted by a halogen atom, groups corresponding to the formula where R "is a hydrogen atom ,, a -Halogeamtom ,, the CP- ^ ₁ an alkoxy group with 1 to 4 carbon atoms, ei .ie" Titro, cyano, alkyl thio group with -1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, a dialkylanainosulfonyl group, the alkyl part of which contains : ois 4 carbon atoms, or represents an acetyl group, a group corresponding to the formula 9 0 9 8 5 0 / J 7, & ß.,,. . BATHROOM OFIlGlNAL or a group corresponding to the formula and η is a positive integer of 2 or J>. mean,·. - · ■ and R2 represent a hydrogen atom, alkyl groups with -1 to 4 _: - ■■ · carbon atoms which can be substituted by a hydroxyl radical, phenyl groups which can be substituted by a halogen atom, or a benzyl group. ,. . ■. . . · .... 2.. 3-Me thyl-8/3-pheno thiazinyl (.10) propyl / -1 oxa-3,8-dia'zaspirQ / ^., 5j / _-decane-f 4- 2_? Di0n and its salts ... · ■ · 3. 3-methyl-8- / 3-2-chlprphenothiazinyl- (1 ^^ 0) -, propyl / -1-oxa-3,8-diazaspiro- / 4,5 / -decane-2,4-dione and its salts. . .- ..,. ■■:.-......- ■ 4. 3-phenyl-8- _4/3, 2-chlorphenothiazinyl- (10) - propyV- · 1-oxa-3,8-diazaspiro / ^, 5 / d, ECAN-2,4-dione. and. its salts. . ...... ... 5. 3-Benzyl-8- / 3-2-chlorphe_nothiazinyl- (10) -propyl / -1-oxa-3,8-diazaspiro- / 4,5 / -decane-2,4-dlon and, its salts. . . ....... ... ■ -.-. . ·,. 6. 3-n-Propyl-8- / 3-2-chlorophenothiazinyl - (10) ^ propyl _l A «1-oxa-3,8-diazaspiro- / 4,5 / -decane-2,4-clion and its salts. ', -. ... 7. 2- (2-Hydroxyethyl) -8- / 3- "2-ChIOrPhBnOthiazinyl- ■ ( \ o}> propyiy-1-oxa-3,8-diazaspiro / 4,5 / -decane-2,4-dione and its salts. * ........ -, 9098SÖ / 1766 8 .. 3-Metiiyl-8 - ^ - 2-trifluoromettiylpbenotbiazinyl (iO) -propyl7-1-oxa-3,8-diazaspiro / "4,57decane-2,4-dione and its salts. 9. 3-Methyl-8- / 3-2-methoxyph ^ eiiothiazinyl (1O) propyl / -1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione and its salts. 10. 3-Me-t'hy 1-8- / 3-10,11 -dihydrodibenz / b, f / azepinyl- (5) propyl / -1 -oxa-3, 8-diäzäspi: 2 * o ^: / 4 \ 5 / "decan-2," 4-dione and lea sen salts. ■ - ■ '"■' · -" ■ '■' ■ '-'-' ■ '■ - ■ - ^' ~~ - ** ■■■ '"■ 1Ί. 3-MetT ^ l-S ^ -dlbeftz / T3 ^ nzepinylf ^^ (^^ 1-oxa-3, S-dfazaspiro ^, 57decan-2,4-dione and its salts. 12. 3-Phenyl-8- / 5- (p-fluorortienzoyl) propyl7-1 -oxa-3,3-diazaspiro / 4, 5_7decan-2,4-dione and its salts. " 13. 3-p-Ohlorpheny 1-8- / 3- (p-fluoroTdenzoyl) propyl7-'i oxa-3,8-diazasp'irö / ~ 4,57decan-2,4-dione and its salts. 14.'3-Benzy1-8- / 3- (p-fluorobenzoyl) propyi / -1-oxa-3,8-di & za3piro / 4V57 ^ ^ecan "'2,4-dione and its salts. ', 5. 5-Kethy 1-8- / 3- (p-fluorobenzoyl) propyl / -1-oxa-3,8-.iic.>, "£. & Piro / 4,57deoan-2,4-dibn and its salts. '\ 6. 3-n ^; -Propyl-8- / 3- ⁱ (p-fluoro'benzoyl) propyl7-1-oxa-3, ediaza3piro / 4,5_7decan-2,4-dione and its salts. 1 7. 3-Phenyl-8- / 2- (p-chloroT3enzoyl) ethyl7-1 -oxa-3,8-diaza3p-ir6 / 4 ', 5 / decane-2,4-dione and its salts. 18. 3-n-Propyl-8- / 2- (p-chloro) enzoyl) ethyl 7-1-oxa-3,8-diazapiro / 4,57-decane-2,4-dione xöfd-its salts. '. S.- B- / 2- (p-ChlOrtienzoy 1) ^l M %% y3 | 7 ^ 1 ^ - "b ^(x; -3,8-diazaspiro / 4,5y.decan-2,4-dione and its salts. 20. ^ -Phenyl-S-benzyl-i-oxa - ^^ - diazas.pirö ^ Ij ^ decar.-2, / - dion und'de ^: ssen salts. * -.. - ... 21. 3-p-chlorophenyl-8-l3enzy 1-1 -oxa-3,8-diazaspiro / - · ^> cecan-2,4-dione and its salts. 22. 3-Benzyl-8-benzyl-1-oxa-3,8-diazaspiro / 4, 5jäeca.n- 2,4-dione and its salts. 90 9 8 50 / Ί76 & 23 3-i-8 ^v rethyl lDenzyl-1-oxa-3,8-diazaspiro / 4,5. / Decane-2,4-dione and its salts. 24. 3-n, -Propyl-8-benzyl-1-oxa-3,8-diazaspiro / 4,5J decane-2,4-dione and its salts *. ^: ■ \ ^: i> ~ ~. 25. 3-Ethyl-8-'benzyl-1 ^ oxa-3,, 8 * -diazaspiro / "4,5_7decan-2,4-dione and its salts 26. 3- (2-Hydroxyethyl) -8-benzy1-1-oxa-3,8-diazaspiro- / 4,57 <iecan-2,4-dione and its salts. '■' 27. 8-Benzy 1-1-oxa-3,8-dia.zaspiro / 4,5_7decan-2,4-dione and its salts. ^; ' .28 3-Methyl ~ 8- (3-hydroxypropyl) -1-oxa-3,8T-diazas, piro- / 4,57decane-2,4-diQn and its salts »- '..'. . ; - ■ 29. 3-Methyl-8- (3-chloropropyl) -1-oxa-3,8-diazaspiro- / 4,57decane-2,4-dione and its salts. 30. 3-Methyl-1-oxa-3,8-diazaspiro / 4,57decane-2,4-dione and its salts. 31. 3-Phenyl-1-oxa-3,8-diazaspiro / 4,5 / decane-2,4-dione and its salts .. '' 32. 3-p-Chlorophenyl-1-oxa-3,8-diazaspiro / "4,57-decane-2,4-dione and its salts. ■■. 33. 3-n-Propy 1-1-oxa-3,8 * diazaspiro / "4,57decane-2,4-dione and its salts. ''. ; . -;:. · 34. 3-Benzy 1-1 -oxa-3,8-diazaspiro / 4,5_7decan-2,4-dione and its salts. ^; '"- - ■■' - ' · 35. 3- (2-Hydroxyethyl) -1-oxa-3,8-diazaspiro / 4,57deean-2,4-dione and its salts. . ; ; i 36. 3-Ethy1-1-oxa-3,8-diazaspirÖ / 4,5ydecane-2,4-dione and its salts - ... - · ..- ■ -. . _- ■. ., 37. Process for the production of 1-oxa-3,8-diazaspiro- / 4 »57 <3-decane-2,4-dione of the following general formula and its salt 9 0 985071? QCO-NR ¹ ₂ . .-.-. , - ■ ---. ■■■ [ ι ... .......... (γ) ÖÜCO '.--- ■■■ - wherein R ^{1 is} a benzy group or. Groups of the formula. ■■ ^Vl · ■■ '"■' - ^ - " - '' ■ " ■ · '- ■ ^; - ^{1 /: r} R ^i; cdH ₂ ) _n . ^ R " * ^: '""/;'' where -R '- eiß:' iiälogenätomv -eine. Hydroxyl group or a optionally by a hemogen atom. substituted Benzoy! Gruppej groups according to the • - - ■■ · ■ - ■■ ■ Wed "· ^ - ■" = - ;. ■■ ■■ in front of R "a hydrogen atom, a halogen atom, the group oF-v ,, eiiie · 'alkoxy group with.'t -to 4' .carbon atoms, 'a nitro, cyano, alkylthio group -with 1 to 4 carbons- ^ ., _atoms: ■ - an alkyl group, mj-t .1 ibis; contains 4 carbons s-tof fc.toiien, a · Dialicylaminosulfojiylgrjappej / Alky.lteil their pis 1-4- Kohlenstoffato.Ee, OR... represents an acetyl group, a group corresponding to the formula ■ -.... _: or a group corresponding to the formula BATH ORIGINAL or.;. : ί denotes a positive integer of 2 or 3 ", and R ¹ " denotes an alkyl group with 1 to 4 carbon atoms which can be substituted by a hydroxyl radical, or a phenyl group which can be substituted by a halogen atom, or a benzyl group, thereby ge.-cennzeici ^ da3 a 4-cyano-4-piperidinoi substituted in the 1-position of the formula / ν GN R ¹ IN X
>'OH // orin R ¹ .. has the meaning given above, with an isocyanate of the formula wherein R ¹ 2 is as defined above or a benzyl or a Alkanoylisocyanat, lessen alkyl portion contains 1 to 4 carbon atoms, is reacted and the resulting intermediate hydrolyzed v / ill. 38. Process for the preparation of 1-0xa-3,8-diazaspi - ⁰ / ^ · »5_7decan-2,4-diones of the following formula and their salts, QCO-N-R2
; ι ■
0-CO where Rp is ^a hydrogen atom, alkyl groups with 1 to 4. • lohierxFoofxatomen through hydroxyl radicals. be substituted iconneri, phenyl radicals which can be substituted by halogen atoms: or benzyl groups, characterized in that an 8-benzyl-1-oxa-3,8-diazaspiro / 4,57-decane-2, 4-dione of the formula BATH ORIGINAL 90985 0/176 6 • rfοrir_ Rp has the meaning given above ", aurc'n Introducing hydrogen gas into an organic solvent in the presence of a metallic reduction catalyst & <~ - tors is reduced. 39. Process for the preparation of 1 ~ 0xa-3,8-diazasp.-Ro / 4-, 5 / decane-2,4-dione of the following formula and its salts z. OCO-NH "2
0-CO in front of R 'a benzyl group or groups of the formula R '(CH ₂ ) _n . wherein R ^{T is} a halogen atom, a hydroxyl group or a benzoyl group optionally substituted by halogen atoms, 3-groups of the formula by" wherein R "is a hydrogen atom a halogen atom is a group OF ^, an alkoxy group having 1 to 4 carbon atoms, a ITitro group,. a cyano group, an alkylthio group with '. to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, a dialkylaminosulfonyl group, their Alkyl part contains 1 to 4 carbon atoms, or a -U3tyl- BATH 909 8 50/1766 group represent a group of the formula or a group of the formula u.nd η represent a positive integer τοη 2 or 3; and R " _{2 is} an alkyl group having 1 to 4 carbon atoms, ei · .-: iurca can be substituted by a hydroxyl radical, a Phe- -vy! group which can be substituted by a calogen atom", or a benzyl group, characterized in that a compound of the formula wherein Zi denotes a calogen atom and R ¹ .. has the meaning given above, with a 1-oxa-3,8-diazaspiro y 5 / decan-2,4-dione of the formula QCO-
: ι
0— QCO-NR "2
: ι
0-CO wherein R " _{2 has} the meanings given above -u, is condensed. 40. Process for the preparation of 1-0xa-3,8-diazaspiro- / 4-, 5 / decane-2,4-dione of the following formula and their salts OC0-N-Leo BATH ORIGINAL 909850/1766 where λ ~ is a radical of the formula R " : p -. • / or in R "a hydrogen atom, a halogen atom, a group
Oil · ¹ ,, e-Lne alkoxy group having 1 to 4 carbon atoms, one
..itrc-, cyano, or alkylthio group having 1 "-tccen to 4 carbon, an alkyl _b uppe having 1 to 4 carbon atoms, a Jiaikylaainosulfonylgruppe which the alkyl part contains 1 to 4 Kohlenstoffatorne, or represents an acetyl group,
Group of formula or a group of the formula π is a positive integer of 2 or 3 and R " _{2 is} an alkyl group with up to 4 carbon atoms, a phenyl group which can be substituted by halogen atoms, or a benzyl group, characterized by .'- . '·. a compound .. of the formula. . • orin RT has the meaning given above, with
a 1-0xa-3,8-diazaspiroA »5_ / decane-2,4-dione of the formula f yCO-KR "2 ^N Λ) -00 : ;: &,:, γ. »*; - ^{BAD 0} ^ ¹ QINAL 909 8 50/1766 wherein X represents a halogen atom "and R" represents p and η the foregoing hend have given meanings, is condensed. 41. Process for the preparation of 1-0xa-3,8-diazaspi ro / ~ 4,57decane-2,4-diones of the general formula and their Salts · "" " QCO-NR ₂ : ι 0-00 wherein Rp is a hydrogen atom, alkyl groups with 1 "to 4 Carbon atoms which can be substituted by a hydroxyl group, a phenyl group which can be substituted by a halogen atom may be substituted, or a benzyl group and R, a Group of formula COCi .v'orin R "is a hydrogen atom, a halogen atom, a CF group, an alkoxy group with 1 to 4 carbon atoms, an itro group, cyano group, alkylthio group with 1 to 4 carbon atoms, alkyl group with 1 to 4 carbon atoms , · W is a alkylaminosulfonyl group, the alkyl part of which contains 1 to 4 carbon atoms, or represents an acetyl group, and η denotes a positive integer of 2 or 3, characterized in that a compound of the formula R ₄ COCl wherein R- has the meaning given above, with a 1-oxa-3,8-diazaspiro / 4,5. / decane-2,4-dione of the formula QCO-NR "2 ; ι 0-CO BATH ORIGINAL 909850/1766 wherein R "^ and η have the meanings given above, is condensed and then the intermediate product of the formula obtained QC0-N ' \ - 0-C QC0-N-CO wherein R., R ¹ ^ and η have the meanings given above, is decarboxylated by heating. 42. Process for the preparation of 1-oxa-3,8-diazaspi:? O- / 4,5 / decane-2,4-dione the following formula and the salts CO-N-R2 : ι 0 — CO ./orin Y is a hydrogen or halogen atom, R _{2 is} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms which can be substituted by a hydroxyl radical, or a pheny group which can be substituted by a halogen atom, characterized in that that an acetophenone of the formula wherein Y has the meaning given above, formaldehyde or p-formaldehyde and 1- 0xa-3,8-diazaspiro- / 4,5 / decane-2,4-dione the formula / ν CO-NR ₂ HN YI Jf
. N / WCO BADORfQINAL 909850/1766 wherein R _{2 has} the meaning given above, are reacted in the presence of hydrochloric acid in an 'inert organic solvent. 43. Process for the preparation of 1-oxa-3,8-diazaspiro / 4,5 / decane-2,4-dione of the general formula and their salts QCO-N-If ₂ I.
0-CO wherein PJ _{1 is} a benzyl group or groups corresponding to the jOrirel R '(CH ₂ ) _n . v.'orin R ^{1 is} a halogen atom, a hydroxyl group or a benzoyl group optionally substituted by a halogen atom, groups corresponding to the formula • ^ orin R "a hydrogen atom, a halogen atom, the group > -? 3 »an alkoxy group with 1 to 4 carbon atoms, a nitro, cyano, alkylthio group with 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, a dialkylaminosulfonyl group, the alkyl part thereof Contains 1 to 4 carbon atoms, or represents an acetyl group, a group corresponding to the formula BAD ORIQtNAl-909850/17 66 or a group corresponding to the formula -.nd η mean a positive integer of 2 or 3, ληά. R " _{9 is} an alkyl group with 1 to 4 carbon atoms, io can be substituted by a Ky ^ roxylrest, a -hen;. '! group which can be substituted by a halogen atom ". • rann, or mean a benzyl group, characterized in that aa3 a 1-oxa-3,8-diazaspiro / 4,5 / decane-2,4-dione der i'ormel L-N y ι } -MH
R -CO i.it ^ Γ <: \ ·! halides or dialkyl sulfates as alkylating agents 44. Pharmaceutical compositions, characterized by e ^ nen -content as an active ingredient of 1-G:> ;: a-3,8-aiazaspiro / 4,5 / -c.ecane-2,4-dione of the general formula or their salts Q ₁ CO-KR ₂
I.
0-00 vorin? .. a fifth hydrogen atom, a benzyl group or 'rip the formula - '(CH ₂ ) _n _. BAD ORfGINAL 90 9 850/176 6 '1828704 .oi-ir, :. ' a halogen atom, a hydroxyl group or a, e,; o (-o ... ·. Γη Hn by a halo ^ enatom substituted benzoyl, r-jjve, groups corresponding to the formula in K " a hydrogen atom, a halogen atom, the group CP ,,, an alkoxy group having 1 to 4 carbon atoms, a .i "S" xu, cyano, alkylthio group with 1 to 4 carbon atoms, an alkyl group with 1 to 4 carbon atoms, e ..: Dialkylaminosulfony! Group, the alkyl part of which is 1 to 4 carbon :, contains ötoifatome, or represents an acetyl group, ei: ^ G group according to the formula or a 3 group according to the formula ■ nd α is a positive integer of 2 or 3, "nc i-sr, a V. ^r asserstoffatom, alkylene groups having 1 to 4 loi: le: istoffaton; s, the ert by a hydroxyl group substi-.u ^! can be, phenyl groups, which can be substituted by a halogen gate ... or a benzyl group. _r. Combination with physiologically compatible auxiliaries: it ~ elri or adjuvants. 9 09850/1766 ⁰ AD ORfQiNAL