HU201760B - Process for producing 14-spiroheterocyclic-14,15-dihydroeburnamenin derivatives and pharmaceutical compositions comprising same - Google Patents

Abstract

The present invention relates to novel 14-spiro heterocyclic 14,15-dihydro-hexamenine derivatives of formula I wherein R1 is C1-C4 alkyl or aryl substituted with C1-C4 alkoxy. ; Z is O, -NH-O-, or N-R 3, wherein R 3 is hydrogen or C 1-4 alkyl to form their acid and acid addition salts. The compounds of the present invention exhibit antioxidant activity (inhibiting lipid peroxidation). EN 201760 A ■ I scope: 8 pages. 1 drawing, Figure 4 -1-

Description

The present invention relates to novel 14-spiro heterocyclic 14,15-dihydro-eburnamenine derivatives of formula (I) wherein: H1 is C1-C4 alkyl or C1-C4 alkoxy substituted phenyl;

Z is oxygen, -NH-O-, or -NN-R-1, wherein H 3 is hydrogen or C 1 -C 4 alkyl to form acid addition salts thereof by

(a) a 14,15-dihydro-eburnamenine derivative of formula (II) wherein Z is oxygen or -NH-O-, H is C1-C4 alkyl - or an acid addition salt thereof with an organic compound of formula (III) reacting an isocyanate derivative wherein Ki is as defined above and the resulting new 14,15-dihydro-eburnanienine derivative of formula IV wherein R1, R2 and Z are as defined above is isolated without isolation, or

(b) a compound of formula II wherein Z and Rz are as defined above, wherein Z is> N-R3 - where Hs = a 14,15-dihydro-eburnamenine derivative of formula (II) when Hs = H; or an acid addition salt thereof with an organic isocyanate derivative of Formula III, wherein R 1 is as defined above, and the resulting 14,15-dihydro-eburnamenine derivative of Formula IV, wherein R 1, Z is as defined above, and R2 is (C1-C4) -alkyl, optionally after isolation with an alkali metal (C1-C4) alcoholate, and optionally (b), yielding compounds of formula (I) wherein R1 is as defined above and Z = N For R3, R3 is hydrogen, alkylated, and if desired, the resulting compounds of formula (I) wherein R1 and Z are as defined herein. is converted into the specified acid addition salts.

It is known that eburnane backbone compounds such as the natural (+) vincamine, vincanion and their derivatives such as apovincanic acid esters (Cavinton) have very beneficial physiological effects. The main areas of their therapeutic application are vasodilation and improvement of cerebral oxygenation.

It has now been found that the novel spiro-hetorocyclic compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomeric derivatives differ from these known compounds in their substituents at the 14-position of the eburnan backbone, with pharmacologic effects other than the above effects, notably antioxidant they have anti-neuroeytoprotective or anti-asphyxial anoxia activity and are therefore useful as anti-dementia agents.

In the formulas, R 1, R 2 and C 10 alkyl are straight or branched alkyl groups such as methyl, ethyl, n-propyl, i-propyl, η-butyl, sec-butyl and tert-butyl. group. R 1 as an aryl may be, for example, phenyl optionally substituted with 1 to 3 halogens, such as fluorine, chlorine, bromine, or 1 to 3 alkoxy groups, such as ethoxy or nethoxy.

In the compounds of formula (I), the C / D rings may be cis or trans. The hydrogen atoms in the carbon atoms of the compounds and the ethyl group at the carbon atoms in the carbon atoms of 16 may be cis in the case of a cis ring, or trans in the case of a trans ring. The substituent cf or û at position 14 represents the axial or equatorial position of the heteroatom in ring Z attached to ring E relative to ring E. It follows from the above that the compounds of formula (I) may exist in different stereoisomers. It has now been found that under the reaction conditions of the process of the present invention, the stereochemical configuration of the starting compound (II) in the target compounds (I) is retained and the reaction is unaffected.

The 14-spiro-heterocyclic eburnamenine derivatives of formula (I) obtained by the processes of the present invention are novel. So far, compounds of the 14-position eburnane backbone having substituents of this structure have not been prepared. The compounds of formula (I) are pharmaceutically active and can be used as anti-dementia agents. Therefore, the present invention also relates to the preparation of a pharmaceutical composition comprising a compound of formula I or an acid addition salt thereof.

Starting materials bearing Z at the oxygen atom are prepared by treating an octahydroindolo (2,3-a) quinolizine oxime ester derivative with an aqueous sulfuric acid or sulfuric acid salt as described in Hungarian Patent No. 182,380.

Starting materials bearing the Z -NH-O group are prepared from an indoloquinolysinepyruvate oxime ester according to U.S. Patent No. 186,891 by treatment with anhydrous sulfuric acid alcohol.

The starting compounds of formula II wherein Z is = NH are prepared from compounds of the general formula wherein Z is -NH-O- by catalytic hydrogenation as described in Example 4. The catalytic hydrogenation is carried out in a protic solvent, preferably acetic acid, 1-10Ί0 ⁵ torr.

The pharmacological activity of the compounds of the present invention, namely their significant antioxidant (lipid peroxidation inhibition) activity, was demonstrated by the following assays.

HU 201760 A

Examination of the anliooxidant activity was performed on microsomes prepared from rat brain, T..I.Player; Λ.Α. Horton: J.Neuroehem. .17, (2) 122-426 (1981). and rat brain homogenous.uinori, which. J.M.Br.uiighler; J.P.Pregenzer; K.b.Chase; L.A.Duncan; E. J. Jacobsen and J. M. McCail: J. Biol. Chem. 262, (22) 10438-10440 (1987).

NADPH-induced lipid peroxidation in brain microsome:

Male Hannover-Wistar rats (150-250 g) were used to prepare the microsome. After decapitation of rats, whole brains were removed and homogenized in ten volumes of ice-cold 0.25 M sucrose solution. The homogenate was centrifuged at 15,000 g for 10 min at +4 ° C in a 111-8PIN centrifuge, and the supernatant was collected and centrifuged at 78,000 g for 60 min at + 4 ° C in a MSE Superspeed centrifuge. The precipitate was suspended in 0.15 M KCl solution. The microsome thus obtained was frozen in dry ice-acetone and stored at -70 ° C until use.

The composition of the incubation mixture was as follows; 50 mM TRIS-HCl pH: 6.8; 0.2 mM EeCl 2; 1 mM KH2PO4; 0.5 mM ADP; 0.2 mg microsome as well as test compounds. The final incubation volume was 1 ml, the incubation time was 20 minutes, and the incubation temperature was 37 ° C. Lipid peroxidation was induced by the addition of 0.4 mM NAüPH. (Blank samples did not contain NADPH.) The reaction was terminated with 0.375 mL of stop solution of 40% TCA: 5 M HCl = 2: 1. Malondialdehyde formation was determined with thiobarbituric acid. After the reaction was stopped, 1 ml of 1% thiobarbituric acid was added to the samples and the reaction mixture was stirred for approximately 10 minutes. Place in a 100 ° C water bath. The samples were then centrifuged at 2000 g for 10 minutes at + 4 ° C. Color supernatant extinction values were measured at 535 nm on a HITACHI 150-20 spectrophotometer.

Compounds were determined from the concentration-dependence assay by determining the 1C-50 values of the compounds shown in Table I.

ke? induced lipid peroxidation in brain honiogenesis:

hb. Wistar rats (200-300 g) were decapilated and the whole brain homogenized in nine volumes of Krebs-Ringer's buffer: 15 mM 11EPES pH 7.4; 140 mM NaCl; 3.6 mM KCl; 1.5 nM CaCl 2; 0.7 mM MgCl 2; 1.4 nM KIIzl'1 M 1 () mM glucose. The protein content of the solution was then determined and adjusted to 10 µg / ml.

i

The inhibitors were added in a volume of 5 µl to the 200 µl homogenate, and the resulting incubation broth was incubated at 37 ° C for 20 minutes under ice-cooling. Fe 2 '-induced lipid peroxidation was induced by the addition of 5 µl of 8 mM EelNIldz solution. At the end of the incubation period, the reaction was stopped by adding 1 ml of stopping solution (0.8 M HCl, 12.5% TCA) and the samples, 2000 g, for 10 minutes at 4 ° C. Janetzky was centrifuged in a K-70 centrifuge.

To a 0.5 ml portion of the supernatant was added 1 ml of a 1% TBA solution and the samples were placed in a 100 ° C water bath for 20 minutes. The resulting luminous intensity was determined at 535 nm on a HITACHI 150-20 spectrophotometer. Malondialdehyde bis-diethyl acetate was used as a standard.

Table I

Compound sign example number NADPH ind. LP IC-50 (UM) EE 2 * ind.LP 1C-50 (UM) 10 04050 19th 47.5 - 10 06608 20th 6.3 17.8 10 06609 14th 6.3 17.2

From the data in the table it can be seen that each of the compounds prepared according to the various examples has antioxidant (lipid peroxidation) activity.

There are several pathological processes in which highly reactive oxygen free radicals (O2 ') are multiplied. The formation of free radicals leads to oxidation (lipid peroxidation) of unsaturated fatty acids (important constituents of membranes). It is a low specific cell killing process that alters or damages biomolecules. Different levels of function of cells, organs or the entire body can be impaired.

Free radical reactions are likely to play a causal role in the pathogenesis of ischemic injury such as: ischemic bowel disease, myocardial ischemia, haemorrhagic shock, ischemic cerebrovascular dysfunction, renal ischemia.

Because of their lipid peroxidation inhibitory activity, antioxidant compounds provide protection against free-radical damage under ischemic, hypoxic conditions, and therefore antioxidants, such as anti-ischemic, anti-hypoxic compounds, can be used to treat such disorders.

The invention will be described in detail below.

The starting 14,15-dihydro-eburnanienine derivative (11) and the organic isocyanate derivative (111)

The reaction is carried out in a dipolar aprotic solvent such as dimethylformamide or an aprotic solvent such as tetrahydrofuran at a temperature of 60-100 ° C. The reaction time may be from 2 to 16 hours. The reaction is preferably carried out in the form of the base form of the compounds of formula (II), but may also be initiated in the form of an acid addition salt, in which case the base form is liberated in a known manner.

During the reaction, the intermediate of formula (IV) is first formed by ring closure of the 14,15-dihydro-eburnamenine (1). The reaction conditions for the ring closure of the compound of formula (IV) are mainly determined by the substituent Z, but also by the nature of the Ki group of the organic isocyanate. According to process a), when Z = O or -NH-O-, the reaction proceeds preferably at 80-100 ° C for 2-8 hours, without isolation. According to process b), that is, when Z is a 2-N-R 3 group where K 3 = hydrogen, the reaction is conveniently carried out at 60-80 ° C for 5-16 hours.

According to process b), that is, when Z = 0 for N-Ka, Kj is hydrogen, the resulting compound of formula (IV) can be obtained, if desired after isolation or without solvent exchange, by replacing Z with the corresponding group. Conversion to compound (1) (Z = 1> N-R3, R3 = H). The ring closure of the compound of formula IV is then carried out in a protic solvent, preferably an alcohol such as methanol, ethanol, in the presence of an alkali metal C 1 -C 4 alcoholate, at the boiling point of the solvent used, i.e. substantially 60 ° C to 80 ° C. . The total reaction time is thus about 0.5 to 4 hours.

The resulting compounds of formula (I), when R3 is hydrogen for Z = 2N-K.sub.1, may be optionally alkylated to give alkylated derivatives of formula (I) wherein K3 is C1 -C4 alkyl. The alkylation reaction is conveniently carried out in a polar solvent such as chlorinated hydrocarbons, preferably dichloromethane or dichloroethane, a diacyl sulfate such as dimethyl or diethyl sulfate and an alkali metal hydroxide, preferably sodium hydroxide, , for example in the presence of Letrabutylammonium hydroxide.

Prepared according to the methods of the invention. The recovery of the compounds of formula (IV) and (1) can be accomplished by known crystallization from the solvent used.

The novel 14-spiro heterocyclic 14,15-dihydro-eburnamenine derivatives of formula (I) may be converted into acid addition salts, if desired. The acid addition salt formation may be carried out in an inert solvent such as an aliphatic alcohol having 1 to 6 carbon atoms or in a dipolar aprotic solvent such as ether and acetone, by dissolving the compound of formula (I) in the above solvent and then adding the appropriate acid or a solution of the acid in the above solvent until the mixture becomes slightly acidic. The precipitated salt is then removed from the reaction mixture by any suitable means, e.g. by filtration.

The active ingredient of formula (I) may be formulated in pharmaceutical compositions with non-toxic, inert solid or liquid carriers and / or excipients which are suitable for parenteral or enteral administration. Suitable carriers include, for example, urine, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of conventional pharmaceutical compositions, in particular solid forms such as round or square tablets, dragees, capsules such as gelatin capsules, pills, suppositories and the like. in the form of. The amount of solid carrier can vary over a wide range, preferably from about 25 mg to about 1 g. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, and the like. may also be included. They may be prepared by conventional techniques such as sieving, mixing, granulating and pressing the components in the case of solid compositions. The compositions may also be subjected to other conventional pharmaceutical techniques such as sterilization.

The invention will be further illustrated by the following non-limiting examples.

Example 1 (+) - Cis-Spiro- {14,15-dihydro-eburnamenine-14,5 '- (3'-methyloxazolidine-2', 4'-dione) (3cC, 16cC, 14β0) ( 1, Z = 0 (R = methyl) g vincamine, 6 ml of methyl isocyanate and 20 ml of dimethylformamide are stirred for 3 hours at 80 ° C and heated. The reaction was monitored by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was treated with 20 ml of 2% hydrochloric acid, decolorized with charcoal and filtered. The filtrate was adjusted to pH 9 with aqueous ammonium hydroxide solution. The ki-4EN 201760 The 8 precipitates are filtered off, washed with water.

Dried at 0 ° C.

1.47 g of the title clay are obtained.

116-118 ° C (168.5%). J ² n: + 37.8 ° (c = 1, CHCl 3). 5

Example 2 (+) - Cis-Spiro- (14,15-dihydro-eburnamine) -14,5 '- (3'-butyloxazolidine-2', 4'-dione) (3a, 16d). 14j) (1 Z-0) g vincamine, 18 ml butyl isocyanate and 60 ml dimethylformamide are heated at 80 ° C for 4 hours. At the end of the reaction, the solvent was distilled off under reduced pressure, and the residue was heated to boiling in ethanol (20 mL) and heated at 5 ° C for 1 hour. The precipitated crystals were filtered, washed three times with 5 ml of ethanol and dried at 60 ° C. 5.25 g of the title compound are obtained in 76.5% yield.

Melting point: 150-152 ° C.

K ] ^2, d: + 16 ° (c = 1, CHCl3). 25

Example 3 (-) - trans-Spiro- (14,15-dihydro-ebuverminyl) -1,4,5 '- (3'-diethyloxazolidine-2', 4 '-dione).

(3a, Idd, 14a) IP, Z = 0) g of (-) - trans-vincamine, 6 ml of methyl isocyanate and 20 ml of dimethylformamide are heated at 80 ° C for 2 hours. Then, the solvent was distilled off under reduced pressure, the residue was taken up in 5 ml of benzene, the precipitated crystals were filtered off and recrystallized from 5 ml of ethanol. 40

1.35 g of the title compound are obtained.

Production; 64%.

M.p. 208-210 ° C.

[α] ²⁰ d: -26 ° (c = 1, CHCl 3)

Example 4

N -) - cis-14-methoxycarbonyl-14-hydroxyamino-14,15-dihydro-eburnamine (3a ', Ida, 14dN) 50 (11, Z = -NH-O-)

In a solution of 375 ml of methanol and 135 ml of concentrated sulfuric acid at 30 ° C, 50 g of cis-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo [2,3-a] - 55 N-lizine-1-yl-pyrroloic acid methyl ester oxime was dissolved and heated at 60 ° C for 1 hour. After cooling, the reaction mixture was poured into 1500 g of ice water and basified to pH 9 with concentrated aqueous ammonium hydroxide solution and extracted with 350 ml of dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was crystallized from methanol (50 mL). After filtration and drying, 32.7 g (67.4%) of the title compound are obtained.

Melting point: 200-202 ° C (decomposed) [<1 ²⁰ D: -34 ° (c = 1, chloroform)

Example 5 (-) - trans-14-Methoxycarbonyl-14-hydroxyamino-14,15-dihydroeburnamenine (3α;, Idd1 <11, Z = -NH-O-) g (-) - trans-1-ethyl- 1,2,3,4,6,7,12,12bα-octahydroindolo [2,3-a] quinolizine loC-yl-pyrroloic acid methyl ester oxime is dissolved in 90 ml of methanol and 33 ml of concentrated sulfuric acid and stirred for 1 hour. Heat at 60 ° C. After cooling, the reaction mixture was poured into ice water (360 g) and adjusted to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting precipitate was filtered, washed with water, dried at 60 ° C and crystallized from benzene.

7.2 g of the title compound are obtained, 60%. Melting point: 107-108 ° C.

[α] ²⁰ D: -60.6 ° (c = 1, CHCl 3)

EXAMPLE 6 Cis-Spiro (14,16-Dibhydro-n-naphthalene) 14,3 '- (5'-butyl-1,2,5-oxadiazine-4', 6'-dione (3a (, 16a, 14dN)) A mixture of (I, Z = -NH-Ü-) g (-) cis-14-methoxycarbonyl-14-hydroxyamino-14,15-dihydro-eburnamenine, 20 ml of butyl isocyanate and 100 ml of dimethylformamide was heated at 80 ° C for 90 minutes. The solvent was distilled off under reduced pressure, and the residue was crystallized from 30 ml of acetone, filtered and washed twice with 3 ml of acetone each time.

4.8 g of the title compound are obtained, m.p. 238-240 ° C.

Yield: 40%.

[α] _D 20 -14.1 ° (c = 1, CHCl 3)

Example 7

Preparation and separation of a mixture of 4-deoxy-14-amino-vincamine - (3a ', 16a, 14aN) and 14-deoxy-14-anino-epivincannin (3a' _t 16a, 14dN) (II).

g of (-) - cis-14-methoxycarbonyl-14-hydroxy-14,15-dihydro-eburnamenine dissolved in 200 ml of glacial acetic acid and 4.0 g of 10% palladium on carbon catalyst in ⁶ of 10 psig. After the hydrogenation is complete, the mixture is filtered, the solvent is distilled off under reduced pressure, the residue is taken up in 50 ml of dichloromethane and the pH is adjusted to 9 with aqueous ammonium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The dichloromethane solutions are fi

The combined extracts are dried over anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The residual syrup was crystallized from isopropyl alcohol (30 mL). After cooling, filtration and drying, 13.0 g of 14-deoxy-14-aninopinamine is obtained. Concentration of the mother liquor in half gave another crystal (13.2 g), which was a mixture of 14-deoxy-14-amino-vincamine and its epimer. After separation by column chromatography (benzene-methanol = 5: 1), 3.0 g of 14-epi-aminocalcaline and 9.2 g of 14-aminovincamine are obtained.

This gives a total of 22.2 g (58%) of 14-deoxy-14-aminopinamine.

Melting point: 123-125 ° C.

[α] ²⁰ D = -56 ° (c = 1, CHCl 3) and 3.6 g (9.5%) of 14-deoxy-14-aminoepinucamine, m.p. 171-173 ° C.

-12.8 ° (c = 1, CHCl3)

EXAMPLE 8 (-) - trans -14-Deoxy-14-Amino-vincamine (3a), 163, 14oCN) (II) g (-) - trans-14-methoxycarbonyl-14-hydroxyamino, 14,15- Dihydro-eburnamenine was hydrogenated in the presence of 0.5 g of 10% palladium on charcoal at a pressure of 10 DEG C. and the reaction mixture was evaporated after filtration. Dissolve in dichloromethane (30 mL) and adjust the pH to 9 with aqueous ammonia. The dichloromethane solution was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from 15 ml of isopropanol. After filtration, washing with isopropanol and drying, 4.4 g (60%) of the title compound are obtained.

M.p .: 210-212 ° C, [α] D 20 -76.3 ° (c = 1, CHCl 3)

Example 9 cis-14-Deoxy-14-b-cyano-14-n-vincamine (30C, 16cC, 14.3N) (IV) ^{4 * * * * * 10 * * *} g cis-14-Deoxy-14- Amino-vincamine and 8 ml of butyl isocyanate in 20 ml of tetrahydrofuran were heated at reflux for 5 hours. The reaction was monitored by thin layer chromatography. At the end of the reaction, the solvent was removed under reduced pressure and the residue was crystallized from ml of ethanol.

3.9 g (76%) of the title compound are obtained.

Melting point: 198-200 ° C.

[ixj ^zo p: -22.7 ° (c = 1, chloroform)

Example 10 Cis-Spiro- (14,15-dihydro-ebinaminenin) -14,4 '- (1'-butyl-imidazolidine-2', 5-dione) (3

16cC, 140N) (1, Z-NH) g cis-14-deoxy-14-butylcarbanoylamino-14-epivincamine in 80 mL of methanol and. Freshly prepared from 0.3 g metal sodium. Boil in 10 sodium methylate solutions for 1 hour. At the end of the reaction, the solution was evaporated, taken up in 15 ml of 10% animonium chloride solution and extracted with 15 ml of dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, evaporated and the residue was crystallized by treatment with n-hexane.

2.5 g of the title compound are obtained. Melting point: 100-102 ° C.

Yield: 89.6%.

[α] D 25 -8.3 ° (c = 1, CHCl 3)

Example 11 ²⁵ (-) - trans-14-Deoxy-14-butylcarbamoylamino-epivincamine (3cC, 163, 14α'Ν) (IV) g (-) - trans-14-deoxy-14-aminovin30 and 8 ml of butyl isocyanate in 20 ml of tetrahydrofuran was refluxed for 6 hours. The solvent was distilled off under reduced pressure and the residue was crystallized from ethanol (8 ml). 3.47 g of the title compound are obtained in 68.5% yield.

Melting point: 173-175 ° C.

[.alpha.] D @ ²⁰ : -96.7 DEG (c = 1, CHCl3)

Example 12 (-) - Trans-Spiro (14,15-Dihydro-eburnamenine) 14,4 '- (1'-butylimidazolidine-2', 5'-dione) (3a, 163, 14cCN) (I, Z = NH)

(-) - Trans-14-deoxy-14-butylcarbamoylamino-epivincamine (2.4 g) was boiled with 40 ml of 1.5% sodium methylate solution for 30 minutes. After cooling at 0 ° C for 2 hours, the precipitated crystals were filtered off, washed with cold methanol to give 1.80 g of the title compound.

Yield: 78%.

Melting point: 250-253 ° C.

[α] ² D: -64.5 ° (c = 1, CHCl3)

Example 13 (+) - Cis-Spiro- (14,15-Dihydro-eburnamenine) -14,4 '- (1'-butyl-d-methylimidazolidine-2', 5'-dione) (3cC, 16cC) , 143N) (1, Z = NIti,

H1 = methyl)

2 g of (-) - cis-spiro- (14,15-dihydro-eburnamenine) -14,4 '- (1-butyl-imidazolidine-2', 5'-dione) are dissolved in 50 ml of dichloromethane and ml

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Stir with a 40% aqueous solution of 5% sodium hydroxide, 0.5 ml dimethyl sulfate and 0.5 ml tetrabutyl animonium hydroxide for 1 hour. After separation, the dichloromethane solution was washed with water (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from 3 ml of isopropanol.

1.5 g of the expected product are obtained in a yield of 73.5%.

Melting point: 111-113 ° C.

(title 1¾ -11.8 ° (c = 1, CHCl3)

Example 14 (-) - trans-Spiro-14,15-dihydro-eburnamenine) -14,4'-11'-butyl-3'-methyl-imidazolidine-Z ', 5'-dione (3', 163, 14 / N) (I, Z = Mu, Lake = Methyl) g 1 -) - trans-Spiro- (14,15-dihydro-eburnaline) -1,4,4 '- (1'-butylimidazolidine) Starting from 2 ', 5'-dione), the title compound was isolated in the same manner as in Example 13 (1.84 g, 84%).

Mp 155-156 ° C.

[.alpha.] D @ ²⁰ : -76.6 DEG (c = 1, CHCl3).

Example 15 Cis-Spiro- (14,15-dihydro-eburnamenine) -14,4 '- [1' - (4-methoxyphenyl) -imidazolidine-2 ', 5'-dione (3a, 16), 143NJ ( 1, Z = NH, R1 = substituted aryl) g (+) cis-14-deoxy-14-aminocyclamine in 40 ml of tetrahydrofuran was heated to reflux with 1.8 g of n-methoxyphenylisocyanate for 2 hours. Methanol (40 mL) was added and 40 mL of methanol (0.16 g) was added and the mixture was heated to reflux for 30 min.

Yield: 68%.

M.p. 279-280 ° C (O.)] ¾ -13.8 (c-1, DMF)

EXAMPLE 16 Trans-Spiro-yl-4,15-dihydro-eburnamenine) -14,4 '- [1' - (4-methoxyphen]) - imidazolidine-2 ', 5'-dichloro-13,163,14N ) (I, Z = NH, R 1 = substituted aryl) g (-) - trans-14-deoxy-14-aminocyclamine, all following the procedure of Example 15 gives 3.90 g of the title compound.

Yield: 73%

Melting point: 245-251 DEG C. (decomposition) C <x] ²⁰ D: + 64 ° (c = 1, DMF)

Example 17 Trans-Spiro-14,15-Dihydro-eburnamenine) -14,4 '- [1' - (4-methoxyphenyl) -3'-methylimidazolidine-2 ', 5'-diori] ( 3 /, 16ΰ, 14 / N) (1, Z = NH, R 1 = substituted aryl, pto = methyl) g of spirospiro (14,15-dihydro-eburnamenine) -14,4 '- [1' - ( Starting from 4-methoxyphenyl) imidazolidine-2 ', 5'-dione]; Example 1c afforded 1.60 g (76%) of the title compound.

Melting point: 174-176 ° C [α] ² %: + 138.7 ° (c = 1, CHCl 3)

Example 18 Cis-Spiro- (14,15-dihydro-eburnamenine) -14,4 '- [(4-methoxyphenyl) -3'-methylimidazolidine-2', 5'-dione] (3 /, 16 /, 140N) (I, Z = NH, R = substituted aryl, R = methyl) of cis-spiro (14,15-dihydro-eburnamenine) -14.4 ^l - [l '- (4-pyridylmethyl phenyl) imidazolidine-2 ', 5'-dione]; Example 1 gave 1.60 g (76%) of the title compound.

Melting point: 249-251 ° C [C] ^{z n} o: -83.7 ° (c = 1, chloroform)

Example 19 (-) Trans-Spiro (14,15-Dihydro-eburnamenine) -14,4 '- (5'-butyl-1,2,5, -oxadiazine-4', 6'-dione) (3 / , 16 /, 14βΝ) (I, Z = -NH-O-)

In the same manner as in Example 6, 10 g of (-) trans-14-methoxycarbonyl-14-hydroxyamino-14,15-dihydro-eburnamenine were obtained, yielding 2.4 g of the title compound. Mp 224-226 ° C.

Yield: 20% [Al ^z%: -39.7 ° (c = 1, chloroform)

Example 20 (+) Trans-Spiro- (14,15-dihydro-eburnamenine) -14,4 '- (1'-butyl-3'-methyl-imidazolidine -2', 5'-dione (33, 16 ') , 140N) (<1, Z = NH, R3 = = methyl)

In each case, as described in Example 14, 2 g of (+) - trans-spiro (14,15-dihydro-eburon-urine) -14,4 '- (1'-butyl-imidazolidine-2'), Starting with 5'-dione), 1.84 g (84%) of the title compound are obtained.

M.p. 153-154 ° C.

[c <] ^zo d: + 76 ° (c = 1, CHCl3)

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Example 21 + + - trans-Spiro- (14,15-dihydro-eburnanienine) -14,4 '- {1'-butylimidazolidine-2', 5'-d-thio (3),) 6 ° C, 14 / M) (I, Z = NH)

In each of the procedures described in Example 12, starting from 2.4 g of (+) trans-14-deoxy-14-butylcarbamoylaminovincamine, 1.80 g of the zinc compound are obtained. Yield: 78%.

Melting point: 249-250 ° C (m.p. ²⁰ d: + 64 ° (c = 1, CHCl3)

Claims (5)

PATENT CLAIMS Process 1 is a novel process for the preparation of formula (1) 14-spiro heterocyclic 14,15-dihydro-eburnainenin derivatives - wherein 20 Ki is C 1 -C 4 alkyl or phenyl substituted with C 1 -C 4 alkoxy; Z is oxygen, -NH-O- or Ü4-R5, wherein Fb is hydrogen or alkyl having 1 to 4 carbon atoms and is intended to form their acid addition salts, characterized in that a) a 14,15-dihydro-eburnamenine derivative of the general formula (11) - in which Z 30 is an oxygen atom or -NH-O- R 2 is a C 1 -C 4 alkyl group, or an acid addition salt thereof, with an organic isocyanate derivative of formula (III) wherein R 1 is as defined in Scheme 35 to give a new 14,15-dihydroeburnamenine of formula (IV) the derivative wherein R1, R2 and Z are as defined above is heated without isolation; b) for the preparation of a compound of formula (I) wherein Z, wherein R3 is hydrogen, is a compound of formula (II) 14.15-45; -dihydro-eburnamenine-digestate - where Z is as defined above, R 2 is an alkyl group having 1 to 4 carbon atoms, or an acid addition salt thereof with an organic isocyanate derivative of formula (III) wherein R 1 is reacted according to the present invention and the resulting the dihydro-eburnamenine derivative, wherein R 1, R 2 and Z are as defined above, optionally after isolation with an alkali metal C 1 -C 4 alkylate and, if desired, obtaining the compounds of formula (1) wherein R 1 is an and for Z = - N-R 1, R 3 is hydrogen, Alkylation and, if desired, converting the resultant compounds of formula (I) wherein R 1 and Z are as defined herein into the acid addition salts. Process (a) according to claim 1, characterized in that the reaction is carried out in a dipolar-aprotic or aprotic solvent at a temperature of 60-100 ° C, preferably 80-100 ° C. Process (b) according to Claim 1, characterized in that the reaction of the compounds of the formulas (II) and (III) is carried out at a temperature of from 60 to 100 ° C, preferably from 60 to 80 °. The alkali metal C 1 -C 4 alcoholate is treated with sodium methylate in alcohol at a temperature of 60-80 ° C. Process according to claim 1, characterized in that the alkylation is carried out in a polar solvent, preferably a chlorinated hydrocarbon, in the presence of an alkali metal hydroxide and a phase transfer catalyst, with di- (C 1 -C 4) alkyl sulfate. A process for the preparation of a pharmaceutical composition comprising mixing as an active ingredient a compound of formula (I) or an acid addition salt thereof according to claim 1, wherein R 1 and L are as defined in claim 1, with pharmaceutical carriers and / or excipients customary in the pharmaceutical industry. and converting it into a pharmaceutical composition.