HU191694B - Process for production of new derivatives of amineburnan carbonic acid - Google Patents

Abstract

The invention relates to a process for the preparation of novel, in the 9- or 11-position, an optionally substituted amino group-containing eburnancarboxylic acid derivatives, of their optical active isomers and their salts. The novel compounds correspond to the general formula (I), wherein R is an amino group or a group of the general formula -NH-COR1, wherein R1 z. As hydrogen, a cycloaliphatic hydrocarbon group having 3.8 carbon atoms or an aromatic hydrocarbon group having 6-14 carbon atoms or a group -NH-SO2R2, wherein R2 z. B. is an optionally substituted aliphatic hydrocarbon group having 1-10 carbon atoms, R3 z. B. is hydrogen or an optionally substituted hydrocarbon group having 1-10 carbon atoms. A is a hydroxyl group and B is hydrogen or A and B together form a chemical bond. The compounds of the general formula (I) have valuable pharmacological effects. The compounds are prepared according to the analogy method in a manner known per se. Further meanings of the substituents can be found in claim 1. Formula I

Description

(57) ABSTRACT

The present invention relates to novel amino-eburanecarboxylic acid derivatives of the general formula (I): wherein:

R is 9 or 11 and is substituted with amino or C 1-4 alkyl, C 4-8 cycloalkyl, optionally halogen, nitro, or one or more 14 carbon atoms substituted with an amino group -NH-COR phenyl substituted with alkoxy, thienyl or pyridyl, or a group -NH-SO ₂ -R ¹ wherein

R ² is C 14 alkyl,

R ³ is hydrogen, C 1 -C 14 alkyl or C 1 -C 6 alkyl substituted by 1 hydroxy,

A is a 3-hydroxyl group,

B is hydrogen, or

A and B together represent a valence bond, provided that

R is amino, or an 11-position -NH-COR ¹ group where R is methyl, A is hydroxy and B is hydrogen, R ³ is other than methyl, and when R is amino groups A and B together represent a bond,

R ³ is other than hydrogen and methyl - and their salts

The compounds of formula I possess valuable therapeutic effects, namely vasodilator, antihypoxic, antispasmodic and anticonvulsant effects.

The present invention relates to novel amino-eburnanecarboxylic acid derivatives of the formula I: wherein:

R is 9 or 11 and is amino or one

-NH-COR ¹ wherein R ¹ is phenyl optionally substituted with C 1 -C 4 alkyl, C 4 -C 8 cycloalkyl, optionally substituted with halogen, nitro, or one or more C 14 alkoxy groups, thienyl or pyridyl, or a group -NH-SO ₂ R ^J where R ² is C 14 alkyl,

R ³ is hydrogen, C 14 alkyl substituted with hydroxy, or C 1-6 alkyl,

A is the hydroxyl group at the β-position,

B is hydrogen, or

A and B together represent a valence bond, provided that

R is amino, or an 11-position -NH-COR ¹ group where R * is methyl, A is hydroxy, and B is hydrogen, R ³ is other than methyl, and when R is amino , A and B together represent a bond, R ³ is different from hydrogen and methyl - and acid addition salts thereof by reacting an amino eburnanecarboxylic acid derivative of formula II wherein R ⁴ is methyl when A and B is as defined for Formula I: or hydrogen when A and B are a bond, or its salt, if desired after hydrolysis, first acylated and optionally the resulting compounds of formula I amino-eburnanecarboxylic acid derivatives Wherein R is -NH-COR ¹ or -NH-SO ₂ R ² a needle group wherein R ¹ and R ¹ are as defined above, R ³ is the same as R ⁴ , A and B are as defined in formula I - esterified or, if desired, transesterified, or an amino ebumane carboxylic acid of formula II or a salt thereof, wherein R ⁴ is methyl when A and B are as defined for formula I, or hydrogen when A and B together are a bond, is first esterified or, if desired, transesterified; falling within I amino-eburnane-carboxylic acid derivative compounds - wherein same meanings as in formula R is an amino group, R ^3, A and B I - acylated, and optionally those one amino eburnán- formula carboxylic acid derivatives wherein R and R ^{3 are} and the above, A is hydroxy, B is hydrogen, and if desired, the resulting amino-ebumane carboxylic acid derivatives of formula I, wherein R, R ³ , A, and B are as defined in formula I, to an acid addition salt.

In the above formulas, R ¹ , R ² , R 3 alkyl groups are straight or branched chain groups such as methyl ethyl, η-propyl, i-ptopyl, η-butyl, i-butyl, sec-butyl, tertiary -butyl, η-pentyl, i-phthalyl, n-texyl, i-hexyl, C4-C8 cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

For example, the acid addition salts of the compounds of Formula I may be salts with the acids listed below. Inorganic acids such as hydrogen halides such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, perhalic acids such as perchloric acid and the like. Organic carboxylic acids such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxyimaleic acid, fumaric acid, succinic acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, amino salicylic acid, etc. Alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like. Cycloaliphatic sulfonic acids such as cyclohexylsulfonic acid. Arylsulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfanylic acid and the like. Amino acids such as aspartic acid, glutamic acid, N-acetyl aspartic acid, N-acetylglutaric acid and the like.

The compounds of the formula I in which R is an amino group of 0 or 11 positions, A and B together are a bond, R ³ is a methyl group, the other compounds have a novel and valuable therapeutic effect.

Known compounds are described in French Patent No. 2,342,980. These were prepared by nitrating the apovincamine, separating the resulting mixture of 9- and 11-nitro-apovincamine, separately reducing the 9- and 11-nitro-apovincamine, or treating the corresponding nitro-vincamine with a dehydrating agent, or the corresponding amino vincamine was treated with a dehydrating agent. In contrast, by the process of the present invention, both 9- and 11-amino-apovincaminic amines can be easily obtained by esterification of the corresponding novel amino-apovincaminic acid. The novel amino-apovinc acid is used as starting material by reduction of the corresponding nitro-apovinc acid.

11-Acetamido-vincamine, which is closest to the compounds of general formula I prepared by the process of the present invention, is prepared according to the method described in U.S. Pat. French Patent No. 4,268,198.

C11- (C1-C5) alkyloxycarbonylamino-apovincaminic acid (C1-C5) -alkyl esters that are close to, but substantially different from, the compounds of the invention are disclosed in U.S. Patent No. 2,442,846. French patent specification.

Among the starting materials of the general formula II, in which R ⁴ is a methyl group, the following compounds are disclosed in U.S. Patent No. 2,341,585. and U.S. Patent No. 2,342,980. can be prepared as described in French Patent Specification.

The starting compounds of formula II wherein R ⁴ is hydrogen, A and B are a direct bond may be prepared by reduction of the corresponding nitro compounds.

In the process of the invention, the acylation of the starting materials of formula II and the compounds of formula I wherein R is an amino group are prohibited with organic carboxylic acids, sulfonic acids or functional derivatives thereof such as halides, anhydrides and the like. . performed. Preferred acid halides are, for example, acid chlorides.

If the acylation reaction uses a starting compound of formula II wherein R ^{4 is} hydrogen, A and B together are a bond, it is also possible to carry out the acylation reaction in the reaction mixture itself to produce the starting compound of formula II. For example, if the appropriate nitroapovinc acid is reduced and the catalyst or reducing agent is removed from the mixture after reduction, the acylating agent can be added directly to the reduction reaction mixture without first isolating the appropriate amino apovinc acid from the reaction mixture. In this way, it is possible to prepare the corresponding acylamino-apovincaminic acid derivatives of the general formula 1 in a single step from the corresponding nitro-apovincaminic acid itself. This is of great importance, for example, in a commercially applicable synthesis.

In the case where a carboxylic acid is used as the acylating agent, a sulfonic acid is used, the reaction may conveniently be carried out in the presence of a condensing agent in an inert organic aprotic dipolar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like. The condensing agent is, for example, a carbodiimide-type compound such as dicyclohexylcarbodiimide, carboxyldiimidazole and the like. can be used. The reaction is conveniently carried out at 0 ° C to 40 ° C, preferably at room temperature.

When an acid anhydride is used as the acylating agent, the reaction is carried out in an organic solvent such as an apolar aprotic solvent such as an optionally halogenated aliphatic or aromatic hydrocarbon such as benzene, chloroform, dichloromethane, etc., but optionally in a polar protic solvent. suitably in a C 1-6 aliphatic alcohol such as methanol or in an excess of anhydride. The reaction temperature may be varied within a wide range, for example from 0 ° C to 150 ° C, but preferably at about 20 ° C.

In the case of acylation with an acid halide, preferably an acid chloride, the reaction is carried out in an inert organic solvent such as aliphatic ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, optionally substituted with aliphatic hydrogen or aromatic. hydrocarbons such as chloroform, benzene, organic bases such as pyridine and the like. we can do it. The reaction preferably uses an acid scavenger such as an inorganic base such as an alkali metal carbonate such as potassium carbonate, sodium carbonate, an alkali metal hydride such as sodium hydride etc. or an organic tertiary base such as triethylamine. , pyridine, etc. The organic bases used, such as pyridine, may in some cases serve as both a solvent and an acid scavenger. The reaction temperature may vary within wide limits, but may conveniently be conducted at a temperature of 0 ° C to 100 ° C. In the case where the starting material is not an ester but an acid, i.e. R ⁴ is hydrogen, due to the acidic nature of the component to be acylated, the acylation is carried out such that the acylating agent and the acylating agent, preferably an acid halide or anhydride, which at the same time is a water miscible organic solvent such as low-carbon aliphatic alcohols, acetone, and the like. and also contains a base, we react. In this case, the reaction may be carried out at a temperature of from about Cr to -100 ° C, preferably about room temperature, preferably from a calculated amount of a base such as an inorganic base such as an alkali metal hydroxide such as potassium or sodium hydroxide, an alkali metal carbonate, Thus, in the presence of potassium or sodium carbonate.

The starting compounds of formula 11 wherein R * is hydrogen and those of formula I wherein R ³ is hydrogenated may be carried out directly or indirectly.

The direct esterification may conveniently be carried out by reacting the corresponding carboxylic acid derivative II or I with an excess of an alcohol R ³ -OH, wherein R ³ is as defined above, except for the exclusion of moisture. and preferably in the presence of a catalyst. The catalyst is a strong organic or inorganic acid such as hydrochloric acid, preferably in the form of a gas, or sulfuric acid, p-toluenesulfonic acid and the like. and a water scavenger such as a suitably selected molecular sieve.

For example, the indirect esterification can be carried out first from the corresponding carboxylic acid derivatives II and I with a base such as an alkali metal hydroxide such as lithium, potassium, sodium hydroxide or an alkali metal carbonate such as sodium or potassium carbonate or ammonium hydroxide, optionally in the reaction mixture, to form a salt and reacting the appropriately separated metal or ammonium salt, or the salt formed in the reaction mixture itself, with a compound of the formula R ³ -Y wherein R ³ is as defined above with the exception of hydrogen and Y is an acid residue. In the case where in the formula R ³ -Y Y is an acid residue such as a halide such as chloride, bromide, iodide or sulfate, the reaction is conveniently carried out in an organic aprotic dipolar solvent such as acetonitrile, dimethylformamide and the like. this may be accomplished by suspending the metal or ammonium salt of the carboxylic acid derivative of formula II or I in the solvent and adding a small amount of the corresponding halide to the suspension. The reaction temperature may range from 50 to 120 ° C. The reaction solvent may also be a mixture of the aforementioned solvent and water, but may be carried out in the presence of a conveniently selected phase-transfer catalyst. Such catalysts include, for example, the corresponding tetraalkylammonium halides.

The hydrolysis of compounds of formula I wherein R is as defined above, A is hydroxy-31, B is hydrogen, and R ³ is C 1-6 alkyl optionally substituted with hydroxy is preferably carried out in an alkaline medium. It is a solvent

5 to 50% water-miscible organic solvent such as aliphatic alcohols such as methanol, ethanol, aliphatic ketones such as acetone and the like. alkamazhatunk. For example, alkaline conditions are provided by excess alkali metal hydroxide, such as sodium or potassium hydroxide. The reaction temperature may range from 20 ° C to 120 ° C.

Compounds of formula I wherein R and R ³ are as defined above, A is a hydroxyl group and B is a dehydration of the hydrogen atom by any of the azeotropic distillation processes generally used and used for the dehydration of vincamine alkaloids, preferably in the presence of p-toluenesulfonic acid water removal. In a preferred embodiment of the process, the compounds of formula I are refluxed in an inert solvent such as aromatic hydrocarbons such as benzene, toluene, etc., while ensuring, for example, the use of a water separator, the water is constantly drained.

The compounds of formula I obtained by the process of the present invention may also be converted, if desired, into an acid addition salt with any of the aforementioned acids.

The acid addition salt formation may be carried out in an inert organic solvent, such as a C 1-6 aliphatic alcohol, by dissolving the racemic or optically active compound of formula I in the above solvent, and then adding the appropriate acid or until the pH of the mixture becomes slightly acidic (about pH 5-6). The precipitated acid addition salt may then be isolated from the reaction mixture by any suitable means, such as filtration.

The compounds of formula I obtained by the process of the invention or their acid addition salts may, if desired, undergo further purification, such as recrystallization. The range of solvents suitable for recrystallization is determined by the solubility and crystallization properties of the material to be crystallized.

The compounds of formula I prepared by the process of the present invention, and their pharmaceutically acceptable acid addition salts, possess valuable therapeutic effects, namely vasodilator, antispasmodic, antihypoxic and anticonvulsant activity.

The dilation effect was investigated in dogs anesthetized with a chloralose-phthobarbital mixture. Limb blood flow was measured on the femoral artery, and cerebral blood flow was measured by measuring the flow of the carotid artery. Electromagnetic flowmeters were used to measure blood flow. Substances were administered intravenously at a dose of 1 mg / kg body weight to six dogs and the percent changes in the measured parameters were evaluated. The reference substance is the (+) - apovincaminic acid ethyl ester commonly used as a cerebral vasodilator in medicine.

The antispasmodic activity of the compounds was determined in isolated guinea pig intestine by the classical technique [Magnus, R., Pflügers Arch. 102, 123 (1904)]. Papaverine used as a spasmolytic agent in medicine was used as a reference substance.

One study of the antihypoxic effect was in normobaric hypoxia in alert mice. 5 male mice were placed in a 3L glass cylinder, which was flushed with a gas mixture containing 96% nitrogen and 4% oxygen. The time from insertion to death was measured for a maximum of 15 minutes. Animals that were still alive at twice the average death time of untreated animals were considered protected. The substances were administered to 10-10 animals intraperitoneally at a dose of 50 mg / kg body weight 30 minutes prior to insertion into the glass cylinder.

The antihypoxic effect was investigated in the following two ways.

Asphyxial anoxia (Caillard C. et al., Life Sci. 16, 1607 (1975)).

The animals were treated after 16 hours of fasting with p. p. and then placed in 100 ml well-sealed vials 1 hour after treatment, the time from closure to last respiratory movement was recorded as survival time. Animals that were 30% longer than the mean survival time of the control group were considered protected.

Hypobaricus hypoxia [Baumel J. et al., Proc. Soe. Biol. N. Y. 132,629 (1969)].

for 1 hour, the animals were orally treated with the substances and placed in a desiccator for 1 hour after treatment. In the desiccator, the pressure was reduced to 170 mmHg in 20 seconds, and from this time until the last respiratory movement, survival time was recorded. Animals that were 100% longer than the mean survival time of the control group were considered protected. ED50 (50% effective dose) was calculated by probit analysis from% of protected animals.

The anticonvulsant activity was investigated as follows.

Maximum Electrock (Mouse) [Swinyard, E. A. et al., J. Pharmacol. exp. Ther. 106: 319 (1959)].

The animals were weighed 22-24 g, shock was applied via a corneal electrode (20 mA, 0.2 sec, HSE shock tip 207). Foods that do not have tonic extensions of the hind limbs as a result of treatment are considered protected.

Metrazole cramp (mouse) [Everett, G.M. and Richards, R.K .: J. Pharmacol. Exp. Ther., 81, 402 (1944)].

The animals were pretreated with 125 mg / kg pentylene tetrazole sub-cutaneously. Persistent clonic spasticity and tonic extensor spasm after treatment were recorded.

Strichnine spasm [Kerley, T. L. et al., J. Pharmacol. Exp. Ther. 132: 360 (1961)].

2.5 mg / kg i. p. strychnine nitrate induced tonic extensor cramps. Animals considered to have a tonic extensor cramp and to survive are treated as protected.

Neurotoxic side effects were determined as follows.

Muscle Coordination (Rotarod) [H. Kwibara et al., Japan J. Pharmacol. 27, 117 (1977)].

After pre-training, animals were selected that were able to rest for 120 sec on a 12 mm / min horizontal horizontal bar. Muscle coordination effects are defined as animals falling off the rotator bar within the time limit.

Muscle Relaxation (Traction),

Male mice (18-22 g) are suspended from the forefoot on a horizontal wire (diameter 5 mm). Animals that did not pull their hind legs to the forefoot within 5 seconds after treatment were classified as reduced muscle tone.

From the above studies, it can be seen that the substitution in ring 'A' has a very beneficial effect on the biological activity. This is primarily manifested by selective increase in blood flow. Some of the compounds specifically increase cerebral blood flow and have little or no effect on limb blood circulation, while others mainly increase limb circulation without cerebral activity. More active cerebral vasodilators than the reference chemical of similar chemical structure are used, in particular, at position 11 substituted compounds, while substitution at position 9 unexpectedly tends to significantly enhance the peripheral vasodilator effect. Of the various substitution possibilities, the benzoylantino group in particular appears to be significant, showing a potent cerebral vasodilation at position 11 and a predominantly limb vasodilation at position 9.

In addition to their circulatory effects, the compounds also have a direct anti-spasmodic (smooth muscle) anticonvulsant property that achieves or exceeds the activity of the reference papaverine.

The compounds have the potential to prolong survival time in lethal cerebral hypoxia, which may be of particular therapeutic benefit in cerebral blood and oxygen supply disorders.

The compounds have outstanding anticonvulsant activity. The substances are more potent than the reference hydantoin derivative mephenytoin - the compounds exhibit no neurotoxic side effects of 10 times the effective anticonvulsant dose, while the reference substance exhibits 3-6 times the anticonvulsant dose with a better margin than the reference substance.

The anticonvulsant antihypoxic activity of the compounds, in combination with the cerebral blood flow enhancer, provides a particularly advantageous therapeutic utility in conditions in which the cerebral oxygen supply is temporarily or permanently impaired.

The active ingredient of the formula I is formulated in pharmaceutical formulations in admixture with non-toxic inert, solid or liquid carriers and / or excipients for parenteral or enteral administration. Suitable carriers include, for example, water, 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 standard pharmaceutical compositions, for example solid (round or square tablets, dragees, capsules, such as hard gelatin capsules, pills, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, in the form of a capsule, injectable oily or aqueous solution or suspension, etc.). The amount of solid carrier can vary widely, 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, salts for adjusting the osmotic pressure, buffering agents, flavoring agents, perfumes and the like. may also be included. The compositions may also optionally contain other pharmaceutically acceptable compounds of known value without exhibiting synergistic effects. Preferably, the composition is formulated in dosage units appropriate to the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which include, for example, sifting, mixing, granulating, and pressing or dissolving the ingredients in the appropriate compositions. The compositions may be subjected to other conventional pharmaceutical operations (e.g., sterilization).

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

Example 1

11-Benzoylamino apovincaminic

3.37 g (0.01 mol) of (+) - 11-aminopovinic acid are dissolved in 100 ml of aq. Sodium hydroxide solution. Benzoyl chloride (1.7 mL, 0.015 mol) was added to the solution with stirring at room temperature. After stirring for two hours, the same amount of benzoyl chloride was added and the mixture was stirred for another two hours. The mixture was then neutralized with 10% aqueous hydrochloric acid, and the precipitated crystals were filtered and washed with 50 ml of water at 50-60 ° C, then with 50 ml of cold water and dried.

3.30 g of the title compound are obtained. Yield: 75%. Melting point: 244-248 ° C.

Elemental analysis for C ₂₇ H ₂₇ N ₃ O ₃ (MW 441.52) calculated: C 73.45, H 6.16, N 9.52, Found C 73 62% H = 5.82%, N = 9.48%.

1 H-NMR (DMSO-d ₆ ) δ: Et: 0.94t (3), H-3. 4.10s (1), H-15: 6.00s (1), NH: 7.95s (1), Ar-H: 7.3-7.6 m (6), H _n . . 7.09-8.05m (2), COOH: 10.10s (1), skeletal proton 1.10-3.4m.

Example 2 (2-Thiophenecarbonylamido) -apovincamic acid

3.37 g (0.01 mol) of (+) - 11-aminopovinic acid are dissolved in 100 ml of aq. Sodium hydroxide solution. Thiophene-2-carboxylic acid chloride (3 mL, 0.03 mol) was added with stirring at room temperature. After stirring for half an hour, the pH of the mixture was adjusted to neutral by adding 10% aqueous hydrochloric acid. The precipitated crystals were filtered off, washed with water (3 x 40 mL) and dried to give the title compound (3.26 g). Yield: 73%. Melting point: 246-248 ° C.

Analysis (MW 4467.5) _2J C ₂ H ₅ N ₃ O ₃ S Calc'd: calculated: C 67.10%, H 5.63%, N 9.39% Found: C = 67.35, H = 6.00%, N = 9.40%.

Example 3

-Amino-apovincaminic acid ethyl ester

a) Ethyl 11-nitro-apovincaminobutyl ester (3.95 g, 0.01 mol) in ethanol (50 ml) and concentrated hydrochloric acid (10 ml) was stirred at 100 ° C for one hour in the presence of tin powder (6 g). The resulting solution was evaporated to dryness in vacuo and the residue was basified to pH 10 with aqueous sodium hydroxide (100 mL). The precipitated product is filtered off, washed three times with 40 ml of 1% aqueous sodium hydroxide solution and three times with 40 ml of water, and dried.

2.80 g of the title compound are obtained. Yield: 77%. Melting point: 86-88 ° C.

1 H NMR Spectrum (CDCl ₃ ) δ: Et: 1.00t (3), 1.90q (2), EtO: 1.40t (3), 4.40q (2), NH ₂ : 3.23 ( 2), H-3, 4.10s (1), H-15: 6.07s (1), skeletal protons: 1.5-3.2m.

b) 3.83 g (0.01 mol) of 11-aminocyclamic acid ethyl ester in the presence of 7.0 g of para-toluenesulfonic acid in 150 ml of benzene are refluxed for 8 hours. The mixture was cooled to room temperature, water (100 mL) was added and the mixture was basified to pH 8 with concentrated aqueous ammonium hydroxide. The aqueous phase was separated, the benzene layer was extracted with water (3 x 100 mL), dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness in vacuo. The residue was triturated with ether to give crystals, which were filtered, washed with ether and dried to give 3.0 g of the title compound. Yield: 82%. Melting point: 83-88 ° C.

Example 4

- (methylsulfonyl) amino -apovinkaminsav ethyl ester monohydrochloride

1.62 g (0.0044 mole) of 11-amino-apovincaminic acid ethyl ester are dissolved in 10 ml of anhydrous pyridine and a solution of 0.6 ml (0.008 mole) of mesyl chloride in 10 ml of chloroform is added under ice-water cooling. The mixture was stirred at 0 ° C for three hours and then evaporated to dryness in vacuo. To the residue were added ethyl acetate (50 mL), saturated aqueous sodium bicarbonate (25 mL), and water (50 mL). The two phases were separated and the ethyl acetate layer was washed with water (2 x 30 mL), dried and evaporated to dryness in vacuo. The residue was the title compound (1.87 g, 96%), which was dissolved in acetone (15 mL) and acidified to pH 3 with ethanolic hydrochloric acid. Addition of 45 ml of diisopropyl ether gives crystals which are filtered, washed with ether and dried.

1.56 g of the title compound are obtained. Yield: 74%. Melting point: 230-234 ° C.

Elemental analysis for C ₂₃ H ₂₉ N ₃ O ₄ S. H, 6.29; N, 8.75. Found: C, 57.53; H, 6.29;

S, 6.67; Cl, 7.38; Found: C, 57.42; H, 6.87; N, 8.56.

S = 6.43%, Cl = 7.40%.

Example 5

Amino vincaminic acid ethyl ester

11-Amino-vincamine (7.4 g, 0.02 mol) in ethanol (500 ml) was refluxed for 2 hours in the presence of 0.5 g of potassium tert-butylate. The mixture was evaporated to dryness in vacuo, the residue was triturated with water (200 mL) and ethanol (40 mL), the resulting crystals were filtered, washed with water (100 mL) and ethanol (20 mL), and dried.

5.43 g of the title compound are obtained. Yield: 71%, m.p. 184-186 ° C.

1 H-NMR (CDCl 3) δ: Et: 0.85t (3), CH ₂ : overlap: H _? 15, 2.08d (l), 2.16d (l) (J ' _am · 14Hz), NH,: 3.80TH ₂ -O: 4.25q (2), H-3, 3.8 $ sft ), H-9, 7.30d (l), H-10, 6.60dd (l), H-12: 6.41d (l).

Example 6

9-Amino-apovincaminic acid ethyl ester monohydrochloride

a) Starting from 3.83 g (0.01 mol) of ethyl 9-aminocortamic acid as described in Example 3

The base of the title compound (2.84 g, 78%) was dissolved in acetone (20 ml) and the solution acidified to pH 3 with hydrochloric acid ethanol. After addition of 20 ml of isopropyl ether, crystals were obtained which were filtered, washed with ether and dried.

2.7 g of the title compound are obtained. Yield: 69%. Melting point: 218-222 ° C.

Elemental analysis results for C ₂₂ H ₂₇ N ₃ O ₃ . H, 6.71; N, 10.44. Found: C, 65.68; H, 6.71;

Cl, 8.83; Found: C, 65.86; H, 6.90; N, 10.28.

Cl = 8.78%.

(b) 3.37 g (0.01 mol) of (-) - 9-amino-apovincamic acid in 100 ml of anhydrous ethanol are saturated with dry hydrochloric acid gas in the presence of 3 g of molecular sieve (Aldrich 20,859-e) and bubbled for 3 hours. reflux. The solution was evaporated to dryness and ethyl acetate (20 mL) was added to the residue. Crystals are obtained which are filtered, washed with ethyl acetate and dried.

3.13 g of the title compound are obtained. Yield: 86%. Melting point: 218-222 ° C.

Example 7

9- (methylsulfonyl) amino -apovinkaminsav ethyl ester monohydrochloride

1.20 g (0.0027 mole) of ethyl 9-amino-apovincamic acid monohydrochloride are dissolved in 15 ml of anhydrous pyridine and 0.37 ml (0.005 mole) of mesyl chloride are added under ice-cooling at 0 ° C. After stirring for two hours at 0-5 ° C, the mixture was evaporated to dryness in vacuo, the residue was dissolved in chloroform (50 ml) and the solution was extracted with saturated aqueous sodium carbonate solution (25 ml) and water (3 x 30 ml). The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 1.09 g (91%) of an oily substance as the base. This was dissolved in 40 ml of acetone and the solution acidified to pH 4 with hydrochloric acid ethanol to give crystals, which were filtered, washed with ether and dried.

1.13 g of the title compound are obtained. Yield: 86%. Mp 189) 192 ° C.

Elemental analysis for C ₂₃ H ₂₉ N ₃ O ₄ · 1S · HCl (MW 480.11): Calculated: C 57.53, H 6.29, N 8.75.

S, 6.67; O, 7.38; Found: C, 57.70; H, 6.80; N, 8.72.

S = 6.40%, Cl = 7.51%.

Example 8

9-Amino-vincaminic acid ethyl ester

Starting from 7.4 g (0.01 mol) of 9-amino-vincamine and proceeding as in Example 5.

5.82 g of the title compound are obtained. Production; 76%. Melting point: 232-234 ° C.

Example 9

- (4-nitro-benzoylamino) -apovinkamin

11-Amino-apovincamine (1.3 g, 0.0037 mol) was dissolved in anhydrous pyridine (10 ml) and para-nitrobenzoyl chloride (1.3 g, 0.007 mol) was added at room temperature and stirred for 1 hour at room temperature. Then, 100 ml of ice water and 150 ml of ethyl acetate were added, the mixture was basified to pH 8 with aqueous sodium hydroxide solution, the ethyl acetate layer was separated, washed four times with 25 ml of water, dried over anhydrous sodium sulfate, filtered and the filtrate evaporate to dryness. The residue was triturated with 100 mL of ether to give crystals, which were filtered, washed with ether and dried to give 1.68 g of the title compound.

Yield: 91%. Melting point: 206-208 ° C.

¹ H NMR (CDCl 3: δ: Et: 1.02t (3), CH ₃ O, 3.9s (3), H-3, 4.025 (1), H-15: 6.28s (1) , NH: 8.58s (1), ArH 7.32-8.08m (7), skeletal protons, 1.4-3.26.

Example 10

- (2-Bromo-benzoylamino) -apovinkamin monohydrogen chloride

11-Amino-apovincamine (3.51 g, 0.01 mol) was dissolved in 40 ml of anhydrous benzene in the presence of 2 ml of triethylamine. A solution of 5.12 g (0.023 mol) of o-bromobenzoyl chloride in 10 ml of benzene is added with stirring at room temperature. After stirring at room temperature for 4 hours, the mixture was evaporated to dryness in vacuo, the residue was dissolved in water (100 ml) and ethyl acetate (50 ml) and basified to pH 8 with concentrated aqueous ammonium hydroxide. The ethyl acetate layer was separated and the aqueous portion was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layer was washed with water (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was an amorphous material, 4.16 g (78%) of the title compound as the base.

¹ H-NMR Spectrum (CDCl ₃ ) δ: Et: 1.1t (3), 1.90q (2), H-3, 4.14s (1), CH ₃ O: 4.00s (3), H -15, 6, 19s (1), ArH + NH: 7.05-7.90m (8), skeletal protons: 0.8-3.4m (10),

The base obtained above is dissolved in 50 ml of acetone and the solution is acidified to pH 3 with ethanolic hydrochloric acid. Addition of ether gives crystals which are filtered, washed with ether and dried.

3.93 g of the title compound are obtained. Yield: 69%. M.p. 208-212 ° C.

Example 11

- (2-Fluoro-benzoylamino) -vinkamin

Dissolve 2.1 g (0.015 mol) of o-fluorobenzoic acid in 100 ml of anhydrous dimethylformamide and stir at 0 ° C with 4.0 g (0.02 mol) of dicyclohexylcarbodiimide and stir for 10 minutes. 7 g (0.01 mol) of 11-amio-vincamine are added. Stirred allowed to stand overnight at 0 ^° C and room temperature for one hour. The precipitated dicyclohexylurea was filtered off and the filtrate was evaporated to dryness in vacuo.

The residue was dissolved in 400 ml of ethyl acetate and the solution was placed in a refrigerator overnight. The remaining crystallized dicyclohexylurea was filtered again. The ethyl acetate filtrate was extracted four times with 50 ml of aqueous hydrochloric acid solution, twice with 50 ml of water, then three times with 50 ml of saturated aqueous sodium bicarbonate solution and again with twice 50 ml of water. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate (50 mL) and petroleum ether (250 mL). For cooling, crystals are obtained, which are filtered, washed with petroleum ether, and dried. 3.8 g of the title compound are obtained. Yield: 78%. Mp 202-205 ° C.

¹ H NMR Spectrum (CDCl ₃ ) δ: Et: 0.90t (3), CH ₃ O: 3.90s (3), OH: 4.7s (1), Ar-H: 7.05-8, 70 m (7), skeleton protons: 1.00-3.4 m (12).

Example 12

- (3,4,5-trimethoxy-benzoylamino) -vinkamin

To a solution of 11-amino-vincamine (1.85 g, 0.005 mol) in dry pyridine (75 ml) was added 3,4,5-trimethoxybenzoyl chloride (2.3 g, 0.01 mol) at room temperature with stirring. The mixture is stirred at room temperature for two hours and then evaporated to dryness in vacuo. The residue was dissolved in a mixture of ethyl acetate (50 mL) and water (50 mL), basified to pH 8 with concentrated aqueous ammonium hydroxide. The two phases were separated and the ethyl acetate layer was washed with water (3 x 25 mL), dried and evaporated to dryness. The residue was dissolved in methanol (25 mL) and diisopropyl ether (100 mL) was added. The next day it is placed in a refrigerator, the precipitated crystals are filtered off, washed with diisopropyl ether and dried.

2.13 g of the title compound are obtained. Yield: 76%. 154-158 ° C.

Example 13

Pivaloyl-amino-vincamine

11-Amino-vincamine (0.74 g, 0.002 mol) was dissolved in 30 ml of anhydrous pyridine and 0.5 ml (0.004 mol) of pivaloyl chloride was added with stirring at 0 ° C. After stirring at this temperature for 2 hours, water (20 mL) was added and the mixture was basified to pH 8 with concentrated aqueous ammonium hydroxide. The precipitated crystals are filtered off, washed with water and dried.

0.71 g of the title compound is obtained. Melting point: 140-144 ° C.

1 H NMR (CDCl ₃ ) δ: Et: 0.88t (3), CH ₃ : 1.30s (9), CH ₃ O: 3.87s (1), H-3, 3.90s (1) , OH: 4.20s (1), Ar-H + NH: 6.97-7.65m (4), skeletal protons: L, 45-3.5m.

Example 14

9-Benzoylamino-vincamine

A suspension of 5.52 g (0.015 mol) of 9-aminocyclamine, 150 ml of anhydrous benzene and 5 ml of anhydrous pyridine was stirred at room temperature.

A solution of 3.5 ml (0.03 mol) of benzoyl chloride in 20 ml of benzene was added. After stirring for three hours at room temperature, water (60 mL) and concentrated ammonium hydroxide solution (pH 8) were added. The benzene layer was separated, washed with water (5 x 20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was taken up in 50 ml of diisopropyl-71

trituration with ether gives crystals which are filtered and washed with ether.

4.92 g of the title compound are obtained. Yield: 69%. Mp 152-156 ° C.

¹ H NMR (CDCl ₂ ) δ: Et: 0.90t (3), 1.65q (2), CH ₃ O: 3.855 (3), H-3; 3.885 (1), OH: 4.75 s (1), NH: 8.465 (1), Ar-H. From 6.8 to 8, Orn (8).

Example 15

9-Acetamido-vincamine

9-Amino-vincamine (6.6 g, 0.018 mol) was dissolved in methanol (600 mL) and acetic anhydride (66 mL) was added at 0 ° C and stirred at 0 ° C for half an hour. 800 g of ice water and 120 g of potassium carbonate are then added with stirring. The methanol was removed by distillation in vacuo, and the remaining aqueous portion was extracted with dichloromethane (5 x 100 mL). The combined dichloromethane layer was washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness. To the residue is added 50 ml of ether, crystals are obtained which are filtered off with suction, dried over ether.

5.92 g of the title compound are obtained. Yield: 80%, m.p. 144-147 ° C.

Example 16 1- (2-Thiophenecarbonylamino) vincanine

A solution of 11.9 g (0.054 mol) of 11-aminocyclanin in 100 ml of pyridine was added dropwise to a stirred solution of thiophene-2-carboxylic acid chloride (7.2 ml, 0.067 mol) in benzene (20 ml) at 20 ° C. After stirring at this temperature for two hours, 50 ml of saturated aqueous sodium bicarbonate solution, 50 ml of water and 200 ml of ethyl acetate were added. After extraction, the layers were separated, the ethyl acetate layer was washed with water (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. To the residue was added 200 ml of ether to give crystals, which were filtered, washed four times with 50 ml of ether and dried.

18.4 g of the title compound are obtained. Yield: 71%. Melting point: 229-231 ° C.

Example 17 1- (2-Thiopheneacetylamino) vincamine 0.3 g (0.0022 mol) of thiophene-2-acetic acid are dissolved in 10 ml of anhydrous dimethylformamide and 0.45 g of dicyclohexylcarbodiimide are added. The solution was stirred at room temperature for 15 minutes and then 0.74 g (0.002 mol) of 11-aminocyclamine was added. The mixture was stirred at room temperature for 24 hours and then placed in the refrigerator the next day. The crystallized dicyclohexylurea was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate (30 mL) and extracted with saturated aqueous sodium bicarbonate solution (10 mL) and water (3 x 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. To the residue is added 20 ml of ether, the crystals are filtered off, washed with ether and dried.

0.51 g of the title compound is obtained. Yield: 52%. M.p. 153-155 ° C.

1 H NMR (CDCl ₃ ) δ: δ: 0.90t (3), 1.7q (2), CH ₃ O: 3.88s (3), CH ₂ CO: 3.94s (2), H -3, 4.00s (1), OH: 4.70 (1) Ar-H: 6.80-7.65m (6), CNH: 7.48 (0.

Example 18

9-Acetamido apovincamin

9-Acetamido-vincamine (5.6 g, 0.014 mol) was added in a solution of water (6.8 g, p-toluenesulfonic acid) in benzene (300 mL) using a water separator and reflux for 4 hours. The mixture was cooled, water (200 mL) was added, basified to pH 8 with concentrated aqueous ammonium hydroxide solution and extracted. The benzene layer was washed with water (4 x 100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 50 mL of ethyl acetate while hot, cooled, and the crystals were filtered and washed with ethyl acetate.

5.0 g of the title compound are obtained. Yield: 91%. Melting point; 138-140 ° C.

1 H-NMR (CDCl ₃ ) δ: Et. 0.99 (3), CH ₃ CO: 2,16s (3), CH ₃ O: 3,80s (3), H-3, 4, O5s (l) 15,6,18s H (I) Ar-h: 7.0-7.65m (3).

Example 19 1- (3,4,5-Trimethoxybenzoylamino) -apovincamine

11- (3,4,5-Trimethoxybenzoylamino) -aminamine (1.3 g, 0.0023 mol) and p-toluenesulfonic acid (1.0 g) in benzene (50 ml) were heated to reflux for 2 hours using a water separator and a reflux condenser. . After cooling, water (20 mL) was added and the mixture was basified to pH 8 with concentrated aqueous ammonium hydroxide solution and extracted. The benzene layer was washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in hot acetone (3 mL), petroleum ether (15 mL) was added, cooled, the precipitated crystals were filtered off, washed with ether and dried.

1.03 g of the title compound are obtained. Yield: 83%. Melting point: 150-152 ° C.

¹ H NMR (CDCl ₃ ) δ: Et: 1.00t (3), CH ₃ OCO. 3,98s (3), CH ₃ O: 3,90s (9), H-3, 4,01s (l) H-15, 6,28s (I), Ar-H, 7, l-7, 8m (5), NHCO: 8.30s (1),

Example 20

11-pivaloylamino apovincamin

11-Pivaloylaminovincamine (0.68 g, 0.0015 mole) in the presence of 0.70 g of anhydrous p-toluenesulfonic acid in 20 ml of benzene was heated under reflux for 3 hours. The mixture was cooled, water (20 mL) was added, basified to pH 8 with concentrated aqueous ammonium hydroxide solution and extracted. The benzene phase was washed with water (4 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 25 ml of spinning hexane by adding a few drops of acetone. On cooling, crystals were obtained, which were filtered, washed with hexane and dried to give 0.44 g of the title compound. Yield: 68%. Melting point: 110-114 ° C.

1 H NMR Spectrum (CDCl ₃ ) δ: Et: 0.97t (3), 1. 92q (2), CH ₃ , 35s (9), CH ₃ O, 3.93s (1), H 3. 4.07s (1), Ar-H ₊ NH: 7.0-7.68m (4).

Example 21

11-Acetamido apovincamin

11-Acetamido-vincamine (18.1 g, 0.044 mol) in benzene (900 ml) was heated to reflux for 5 hours in the presence of 22 g of p-toluenesulfonic acid using a water separator and reflux condenser. The mixture was cooled and water (400 mL) was added, then basified to pH 8 with concentrated aqueous ammonium hydroxide solution and extracted. The benzene layer was washed three times with 300 ml of water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was washed with 50 ml of diisopropyl ether and dried.

14.35 g of the title compound are obtained. Yield: 83%. 136-140 ° C.

¹ H NMR Spectrum: (CDCl ₃ ) δ: Et: 0.98t (3), 1.83q (2), CH ₃ CO: 2.08s (3), CH ₃ O: 3.90s (3), H-3, 4.05s (1), H-15, 6.06s (1), ArH ♦ NH: 6.97 -7.58m (4).

Example 22

9- (Benzoylamino) ethyl -vinkaminsav

9-Benzoylamino-vincamine (1.89 g, 0.004 mol) in anhydrous ethanol (30 ml) was refluxed for one hour in the presence of 0.1 g of potassium tert-butylate. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate (50 mL) and extracted with water (3 x 15 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue is triturated with ether to give crystals which are filtered off, washed with ether and dried.

1.32 g of the title compound are obtained. Yield: 68%. 135-137 ° C. = ♦ 44.82 (c = 1, dichloromethane).

Example 23

9- (Benzoylamino) -apovinkaminsav-etiIész.tcr

Ethyl 9- (benzoylamino) -aminobutyric acid ethyl ester (1.22 g, 0.0025 mol) in the presence of p-toluenesulfonic acid (1.3 g) in benzene (50 ml) was heated to reflux using a water separator. After 2 hours, the mixture was cooled, water (50 mL) was added and basified to pH 8 with concentrated aqueous ammonium hydroxide solution and extracted. The benzene phase was washed with water (4 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness in vacuo. The residue was triturated with 10 mL of hexane to give crystals which were filtered, washed with hexane and dried.

0.93 g of the title compound is obtained. Yield: 79%. Melting point: 112-116 ° C.

[α] D = +186.96 (c = 1, dichloromethane).

1 HNMR (CDCl ₃ ) δ: Et: 1.00t (3), 1.90q (2), EtO: 1.39 / 3), 4.30q (2), H-3.0, 4.0s (1H). ), H-15, 6.17s (1), Ar-H: 7.0-7.98m (8), NH: 7.30s (1).

Example 24

Acetamido-apovinkaminsav- (2-hydroxyethyl) ester

11-Acetamido-apovincamine (2.13 g, 0.0054 mol) in ethylene glycol (70 ml) was stirred at 120 ° C for 1.5 hours in the presence of 0.1 g of potassium tert-butylate. The excess ethylene glycol is then removed by distillation in vacuo. The residue was dissolved in ethyl acetate (50 mL) and extracted with water (3 x 20 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness in vacuo. The residue was triturated with ether (30 mL), and the resulting crystals were collected by suction, washed with ether and dried to give the title compound (1.47 g). Yield: 64%. Melting point: 146-150 ° C.

1 H NMR Spectrum (CDCl ₃ ) δ: Et: 0.98t (3), 1.82q (2), CH 3 CO: 2.16 s (3), H-3 and CH ₂ OCO: 3.85 m (3) , 0CH ₂ 4.52 (2), H-15, Ar-H, 6.04: 6.7-7.8 m (3), NH: 7,36s (l)

Example 25

- (Nicotinoylamino) -Apovincamine *

11-Amino-apovincamine (4.0 g, 0.011 mol) was dissolved in pyridine (80 ml) and nicotinic acid chloride (11.3 g) in dry benzene (100 ml) was added with stirring at room temperature. The mixture was stirred at room temperature for 8 hours and allowed to stand at room temperature the following day. The mixture was evaporated to dryness in vacuo and the residue was dissolved in water (100 mL) and basified to pH 8 with concentrated aqueous ammonium hydroxide. The precipitated material is filtered off, washed with water and dried.

4.00 g of the title compound are obtained.

Yield: 807 '. M.p. 148-152 ° C.

¹ H NMR Spectrum (CDCl 3 δ: Et: 1.00 (3),

1,90q (2), CII ₃ O: 3,90s (l) H-15: 6,06s (I), Ar NH ♦: 7,2-8,93Ín (8).

[.alpha.] D @ 20 = 17.00 (c = 1, dichloromethane).

Example 26

- (2-f'h] ine-benzoyl-amino) -apovinkamin

I- (2-Fluorobenzoylamino) vincamine (9.5 g, 0.019 mole) was heated to reflux for 2 hours with 20 g of p-toluenesulfonic acid in 500 ml of benzene using a water separator and reflux condenser. The mixture was cooled, water (200 mL) was added, basified to pH 8 with concentrated aqueous ammonium hydroxide and extracted. The benzene portion was washed with water (4 x 100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness in vacuo. The residue was crystallized from 300 ml of diisopropyl ether.

7.14 g of the title compound are obtained.

Yield: 86%. Mp 102-105 ° C. lac = -2.40 (c = 1, dichloromethane).

1 H NMR Spectrum (CDCl ₃ ) δ: Et: 1.02t (3), 1.95q (2), CH ₃ O: 4.01s (1), H-3, 4.30s (t), H-. 15: 6.18s (1), ArH: 6.95-8.00m (6), H-12: 7.92d (1), 7.14dd and 8.22dd (1), NH: 8.45 and 8.62s (l), skeleton protons: 1.00-3.4m (10).

Example 27

- (2-Thiophenecarbonylamino) -apovincamine (a) 15.1 g (0.031 mol) of 1,1- (2-thiophenecarbonylamino) -vincamine in 400 ml of benzene with 17 g of p-toluenesulfonic acid water separating cap and reflux using a condenser for two hours. After cooling, water (100 mL) was added and the mixture was basified to pH 8 with concentrated aqueous ammonium hydroxide. After extraction, the benzene portion was washed with water (5 x 50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was crystallized from diisopropyl ether (100 mL).

14.0 g of the title compound are obtained. Yield: 96%. 138-140 ° C.

¹ H NMR (CDCl ₃ ) δ: Et: 1.02 (3),

CTkO: 3.98s (3), H-3: 4.038 (1), H-15, 6.10s (1), ArH: 7.0-7.74ni (6), NH: 8.05s (1). .

(b) Dissolve 6.7 g (0.015 mol) of l- (2-thiophenecarbonylamino) -apovincamic acid in 20 ml of acetone and 15 ml of aqueous sodium hydroxide solution and stir at room temperature with 1.5 ml of stirring solution. dimethyl sulfate was added. After stirring for one and a half hours, 0.5 ml of concentrated aqueous ammonium hydroxide solution was added to the mixture and the mixture was concentrated to half volume in vacuo. The precipitate was filtered off, washed with water (2 x 10 mL) and dried. 6.5 g of the title compound are obtained. Yield: 95%. The physical constants are the same as the product of process (a).

Example 28

- (benzoylamino) -apovinkamin

4.4 g (0.01 mol) of 11-benzoylamino-apovincamic acid in 100 ml of anhydrous methanol are saturated with dry hydrochloric acid gas in the presence of 1 molar molar cellulose (Aldrich 20,859-2) and refluxed for 5 hours with continuous bubbling of gas. bring to a boil. The solution was then evaporated to dryness and basified to pH 8 with a concentrated aqueous ammonium hydroxide solution (100 mL) in ethyl acetate (50 mL). The ethyl acetate layer was separated and washed with water (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness in vacuo. The residue was crystallized from 40 ml of a 1: 1 mixture of diisopropyl ether and hexane.

3.9 g of the title compound are obtained. Yield: 86%. Melting point: 129-132 ° C.

1 H NMR Spectrum (CDCl ₃ ) δ: Et: 1.00t (3), CH ₃ O: 4.00s (3), H 3, 4.10s (1), H-15, 6.125 (1), ArH + NH: 7.08-8.15 ni (9).

Example 29

II-Benzoylamino-apovincaminic acid (2-hydroxyethyl) ester

A mixture of 11-benzoylamino-apovincamine (0.45 g, 0.001 mol) in ethylene glycol (10 ml) and potassium tert-butylate (0.01 g) was heated at 120 ° C for two hours. The mixture was evaporated to dryness in vacuo and the residue was dissolved in water (25 mL) and extracted with ethyl acetate (2 x 30 mL). The ethyl acetate layer was washed with water (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness in vacuo. The residue was crystallized from 8 ml of diisopropyl ether to give 0.38 g of the title compound.

Yield: 78%. 136-138 ° C.

¹ H NMR (CDCl ₃ ) δ: Et: 0.98t (3), H-3, 3.68s (1), CH ₂ OCO: 4.55m (2), HO-CH 3, 80m (-), H-15, 6.03s (1), ArH: 6.98-7.96m (8), NH: 832.

Example 30

- (benzoylamino) -apovinkaminsav- (2-methylpropyl) ester monohydrochloride

11-Benzoylamino-apovincamine (0.8 g, 0.0018 mol) in anhydrous isobutanol (20 mL) in the presence of potassium tert-butylate (0.01 g) was refluxed for two hours and then evaporated to dryness in vacuo. The residue was dissolved in dichloroethane (40 mL) and extracted with water (4 x 5 mL). The dichloroethane phase is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness. The residue weighed 0.83 g (93%) and was the base form of the title compound, which was acidified to pH 3 with hydrochloric ethanol in ether (15 ml). The precipitated crystals were collected, washed with food and dried to give 0.69 g of the title compound.

Yield: 72%. Melting point: 185-186 ° C.

Elemental analysis for C _3s H ₃ N ₃ O ₃ HCl Calc'd (M.W. 534.07) basis:

Calculated: C = 69.71%, H = 6.79%, Ν = 7.86%,

Cl, 6.63%. Found: C, 59.86%, H, 7.00%, Ν = 7.84%,

Cl, 6.70%.

Example 31

11-Amino-vincaminic

11-Amino-vincamine (2.5 g, 0.007 mol) was dissolved in ethanol (100 ml) and a solution of potassium hydroxide (2.5 g) in water (20 ml) was added. The mixture was refluxed for half an hour and then acidified to pH 7 with 10% aqueous hydrochloric acid, cooled to room temperature. The precipitated crystals are filtered off, washed twice with 10 ml of cold 50% ethanol and dried.

2.0 g of the title compound are obtained. Yield: 83%. Mp 255-256 ° C. [α] 25 D = 32.4 (c = 1, pyridine).

Example 32

- (2-Fluoro-benzoylamino) -vinkaminsav

1-Q-Fluorobenzylaminoquinamine (0.30 g, 0.0006 mol) was stirred in ethanol (5 ml) and 10% aqueous potassium hydroxide (3 ml) at 35 ° C for half an hour. The mixture was then acidified to pH 7 with 10% aqueous hydrochloric acid. The precipitated crystals are collected, washed three times with 5 ml of water and dried.

0.25 g of the title compound is obtained. Yield: 85%. Melting point: 247-249 ° C.

Ja] _D = 18 18.6 (c -1, pyridine).

Example 33

-Benzoylamino apovincaminic

11-Nitro-apovincamic acid (3.67 g, 0.001 mol) was dissolved in a mixture of ethanol (5 ml) and aqueous sodium hydroxide solution (10 ml). To the solution was added 0.04 g of 10% palladium on carbon and stirred at room temperature under a hydrogen atmosphere. When 0.03 moles (720 ml) of hydrogen gas were reacted, the catalyst was removed by filtration and washed three times with 2 ml of 50% aqueous ethanol. After filtration and washing of the catalyst, a solution of 3 ml of benzoyl chloride in 30 ml of acetone is added dropwise at room temperature. The pH of the reaction mixture is maintained between 7-8 by adding n aqueous sodium hydroxide solution as needed. After stirring at room temperature for two hours, the precipitate crystals were collected, washed with water and dried to pH 7.

3.88 g of the title compound are obtained. Yield: 88%. The physical constants of the material prepared as described above are the same as in Example 1.

Example 34

- (cyclohexanecarbonyl-amino) -vinkamín

A solution of 11-amino-vincamine (1.85 g, 0.005 mol) in anhydrous pyridine (80 mL)

A solution of 1.46 g (0.01 mol) of cyclohexanecarboxylic acid chloride in 20 ml of anhydrous benzene was added with stirring over 1 hour, and the mixture was stirred at room temperature for 2 hours. After evaporation to dryness in vacuo, the residue was dissolved in a mixture of ethyl acetate (50 mL) and water (50 mL), basified to pH 8 with concentrated aqueous ammonium hydroxide. The two phases were separated and the ethyl acetate layer was washed with water (3 x 25 mL), dried and evaporated to 1/3. The residue was left in the refrigerator the next day, the precipitated crystals were filtered and washed with cold ethyl acetate and dried. 1.67 g of the title compound are obtained. Yield: 70%. Melting point: 170 to 174 ^° F.

Example 35

- (3-Bromo-propionylamino) -apovincamine 2.0 g (0.0055 mol) of 11-amino-apovinamine are dissolved in ml of anhydrous pyridine, and 1.71 g (0.01 mol) of 3-bromine are added under ice-cooling and stirring. propionyl chloride in 30 ml of anhydrous benzene over one hour. The mixture was stirred at room temperature for two hours and then concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (50 mL) and water (50 mL), basified to pH 8 with concentrated aqueous ammonium hydroxide solution and separated. The ethyl acetate portion was dried and evaporated to dryness. The residue was dissolved in methanol (10 mL) and precipitated with ether. The precipitate was filtered off, washed with ether and dried. 1.5 g of the title compound are obtained. Yield 62%. Melting point: 175-180 ° C.

Example 36

- (Cyclohexylcarbonylamino) -apovincamine 4.79 g (0.01 mol) of 11- (cyclohexylcarbonylamino) vincamine (Example 34) in benzene (220 ml) in the presence of 5.5 g of p-toluenesulfonic acid boil using a water separator and reflux for 6 hours. The mixture was cooled and water (200 mL) was added. It is basified to pH 8 with concentrated aqueous ammonium hydride and extracted. The benzene phase was washed with water (4 x 100 mL), dried over anhydrous sodium sulfate and the filtrate was evaporated in vacuo. The residue was triturated with ether to give crystals, which were filtered and washed with food to give 4.0 g of the title compound. Production:

87%. Melting point: 1350-135 ° C.

PATENT CLAIMS

Claims (3)

A process for the preparation of a novel amino-eburnanecarboxylic acid derivative of the Formula I wherein R is 9 or 11 and an amino group or a -NH-COR ¹ wherein R ¹ is C ¹ -C 8 alkyl optionally substituted with halo, C 4 -C 8 cycloalkyl, phenyl optionally substituted with halo, nitro or one or more C 14 alkoxy, thienyl - either a pyridyl group or a group of formula NH-SO ₂ -R ₂ where R ³ is a C 14 alkyl group, R * is hydrogen, C 14 alkyl substituted with hydroxy or C 1-6 alkyl, A is the hydroxyl group at the β-position, B is hydrogen, or A and B together represent a valence bond, provided that R is amino or an 11-position -NH-COR ¹ wherein R ¹ is methyl, A is hydroxy and B is hydrogen, R ³ is other than methyl, and when R is amino, A and B together are a bond. ³ is other than hydrogen and methyl - and acid addition salts thereof, characterized in that an amino-eburanecarboxylic acid derivative of the formula II in which R ⁴ is a methyl group when A and B are as defined in formula I - or a hydrogen atom when A and B are a bond - or, if desired after its hydrolysis, a first acylation thereof and optionally a compound of the resulting amino-eburnanecarboxylic acid derivatives of the formula I in which R is a -NH-COR ¹ or a group of the formula -NH-SO ₂ R ² wherein R ¹ and R ¹ are phen ie, R ³ is the same as R ⁴ , A and B are as defined for formula I, if desired optionally transesterified, or an amino eburnanecarboxylic acid derivative of formula II wherein R ⁴ is methyl when A and B are as defined for formula I or hydrogen when A and B together are a valence bond - or its salt is first esterified or optionally transesterified and optionally into the resulting amino-eburnanecarboxylic acid derivatives of formula I rain compounds - where R is amino, R ^3, A and B are equal to 1 in formula defined above - is acylated, if desired, those falling within the I amino-eburnane-carboxylic acid derivative compounds and, wherein R and R ³ is as defined above, A is a hydroxyl group, B is a symbol is hydrogen, dehydrating and optionally converting the resulting amino-ebumane carboxylic acid derivatives of the formula I wherein R, R ³ , A and B are as defined in the formula I, into an acid addition salt. 2. The process of claim 1, wherein the dehydration is carried out in the presence of a carbodiimide-type dehydrating agent, 3. A process for the preparation of a pharmaceutical composition comprising the novel amino ebumane carboxylic acid derivative of the formula I as claimed in claim 1, wherein: R is 9 or 11 and is amino or one -NH-COR * wherein R 1 is C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl optionally substituted by halogen, phenyl optionally substituted by halogen, nitro or one or more C 14 alkoxy, thienyl or pyridyl, or a group -NH-SO ₂ R ₂ where R ¹ is C 14 alkyl, -111 191,694 R ³ is hydrogen, C 1-4 alkyl substituted with hydroxy, or C 1-6 alkyl, A is the hydroxyl group at the β-position, B is hydrogen, or A and B together represent a bond, when R is amino, or an 11-position -NH-CORj group where R ¹ is methyl, A is hydroxy and B is hydrogen, R ³ is other than methyl, and when R is amino, A and B together represent a bond, R ³ is other than hydrogen and methyl - or pharmaceutically acceptable acid addition salts thereof as an active ingredient in admixture with pharmaceutically acceptable carriers and / or excipients and converted. 1 drawing Published by: National Office for Inventions Responsible publisher: Zoltán Himer o.v. CODE -12191,694 International Classification 07 D461 / 00