CS255889B2 - Process for preparing new racemic and optical active derivatives of 9-and 11-aminoeburnancarboxylic acid - Google Patents

Description

The invention relates to a process for the preparation of novel racemic and optically active derivatives of 9-a

11-aminoeburnanecarboxylic acids of the general formula I wherein

R is an amino or -NH-COR (R) group wherein R (R) is hydrogen, an aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or 5 - or a 6-membered heteroaromatic group containing a sulfur or nitrogen heteroatom, optionally substituted by halogen, nitro or alkoxy (s) of 1 to 4 carbon atoms or denotes an -NH-SO ₂ -R ₂ group, wherein R ₂ represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms 10 carbon atoms or an aromatic hydrocarbon group of 6 to 14 carbon atoms, denotes a hydrogen atom, an aliphatic hydrocarbon group of 1 to 10 carbon atoms, optionally substituted by a hydroxyl group, A denotes a hydroxyl group, V denotes a hydrogen atom or A and V together form a valence bond with the proviso that R ^ is not a methyl group when R is an amino or -NH-COR ^ group at the 11-position where R ^ is methyl, A denotes a hydroxyl group and V denotes a hydrogen atom, and R6 is not a hydrogen atom when V denotes an amino group and A and V together form a valence bond, and salts thereof.

The compounds of the formula I in which R represents a 9- or 11-amino group, A and V together represent a valence bond and R 6 represents a methyl group are known. All other compounds of formula I are novel and have valuable therapeutic properties.

Known compounds of formula (I) are disclosed in French Patent Application No. 2,342,980 and are prepared by nitration of apovincamine, separating the obtained mixture of 9- and 11-nitroapovincanine, separately reducing these isomers or reacting the appropriate nitrovincamine with a dehydrating agent and reducing or reacting the appropriate aminoincamine with a dehydrating agent.

The process according to the invention consists in the acylation optionally after hydrolysis of the racemic or optically active 9- or 11-aminoeburnanecarboxylic acid derivative of the general formula II

(II), or a salt thereof, wherein R 6 represents a methyl group, and when A and V together form a valence bond, may also be a hydrogen atom, then optionally esterifying or optionally transesterifying the compound thus obtained, then optionally dehydrating the racemic or optically active derivative. or 11-aminoeburnanecarboxylic acids of the formula I, in which R and R a are as defined above, A represents a hydroxyl group and V represents a hydrogen atom and optionally transesterification of the compound thus obtained and, optionally, conversion of the racemic or optically active derivative 9- or 11- Aminoeburnanecarboxylic acids of the formula I, in which R, R ^, а and В are as defined above, to the acid addition salt and / or the quaternary salt and / or the resolution of the racemic product thus obtained.

In the above formulas, R R, R ^, R ^

- as an aliphatic hydrocarbon group having 1 to 10 carbon atoms, a straight or branched saturated or unsaturated group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, an isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, vinyl> acrylic, methacrylic and propenyl group, or the like,

as a C3-C8 alicyclic hydrocarbon group, a cycloalkyl group optionally substituted by a C1-C4 alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like;

as an aromatic hydrocarbon group having from 6 to 14 carbon atoms, any monocyclic group, eg a phenyl group, an isolated polycyclic group, eg a diphenyl group, or a condensed polycyclic group, eg a naphthyl group.

Rf as a heteroaromatic group may be any heteroaryl group consisting of 1 or more rings containing 5 or 6 members with 1 or more identical or different heteroatoms such as the (ω) nitrogen and / or oxygen and / or sulfur atom. This group is, for example, pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, imidazolyl, pyrimidinyl, indolyl and quinolyl groups and the like.

Each R 1, R _2, and R 1 group may optionally contain one or more of the following substituents: halogen, amino, C 1 -C 8 alkylamino, C 1 -C 8 dialkylamino in the alkyl moiety, hydroxyl, C 6 -C 14 aryl carbon, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkylthio of 1 to 8 carbon atoms, trifluoromethyl, carboxyl, alkoxycarbonyl of 1 to 8 carbon atoms, thio, sulfinyl, sulfonyl, nitro, keto, aldehydo / formyl / cyano and the above-mentioned heteroaryl groups optionally containing the above-mentioned substituents.

Quaternary salts of the compounds of formula (I) may be, for example, quaternary alkyl halides containing from 1 to 4 carbon atoms in the alkyl radical, such as methyl iodides, methyl bromides, methyl chlorides, ethyl iodides, ethyl bromides, ethyl chlorides and the like; etc.

The acid addition salts of the compounds of formula I may be formed with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, phosphoric and, for example, perchloric acid; on the other hand, the acidic components of these salts may also be organic acids such as formic, acetic, propionic, glycolic, maleic, hydroxymalein, fumaric, succinic, tartaric, ascorbic, citric, malicylic, lactic, cinnamic, benzoic, phenylacetic, p-aminobenzoic, p-hydroxybenzoic, p-aminosalicyl or the like; alkanesulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like; alicyclic sulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid and the like; or amino acids such as aspartic acid _? glutamic, N-acetylasparagic, N-acetylglutaric, and the like.

11-Acetamidovincamine, the preparation of which is disclosed in French Patent Application No. 2,320,302, is a known compound of the most chemically related compound of the formula I prepared using the process of the invention.

(C až-C) alkyl- (C až-C alkyl) alkyl; The term apovincamates refers to apovincaminic acid esters, also called apovincaminates, which are chemically related but essentially different from the compounds of the invention are disclosed in French Patent Application No. 2,442,846.

Starting materials of formula II wherein R ₄ is methyl may be prepared as described in French Patent Applications Nos. 2,341,585 and 2,342,980.

Starting materials of the general formula II, where R ₄ represents a hydrogen atom, while A and V together)

may be prepared by reduction of a suitable nitro compound as described in U.S. Pat. No. 255,890.

In the process according to the invention, the starting materials of the formula II as well as the compounds of the formula I in which R is an amino group can be acylated using any organic carboxylic acid or sulphonic acid or functional derivatives thereof such as halides, anhydrides and the like containing a suitable acidic residue. E.g. can be advantageously used as acyl halides and acyl chlorides.

Alternatively, the starting materials of formula II, wherein R ₄ is a hydrogen atom, while A and V are a valence bond, may be converted in such a way that the acylation is compared with a reaction mixture prepared from a suitable compound of formula II. E.g. the suitable nitroapovincaminic acid is reduced / as described in U.S. Pat. No. 255,890 removes the catalyst or reducing agent, and the acylating agent can be directly added to the reduced mixture without prior isolation of the appropriate aminoapovincaminic acid obtained during the reduction. Thus, it is possible to prepare the acylaminopovincaminic acid derivatives of the formula I from the corresponding nitroapovincaminic acid in a single step, which is of great importance for large-scale synthesis.

Using a carboxylic or sulfonic acid as the acylating agent, the reaction is conveniently carried out in an inert organic polar aprotic solvent such as dimethylformamide, dimethylsulfide, acetonitrile or the like, in the presence of a condensing agent. Compounds of e.g. carbodiimide type such as dicyclohexylcarbodiimide or carbonyldiimidazole can be used for this condensation. This reaction may be carried out at a temperature in the range of 0 to 40 ° C, preferably at room temperature.

When using an acid anhydride as the acylating agent, the reaction may be carried out in an organic solvent such as an apolar aprotic solvent, e.g. an optionally halogenated aliphatic or aromatic hydrocarbon, e.g. benzene, dichloromethane, chloroform and the like; or optionally in a polar protic solvent such as an aliphatic alcohol having 1 to 6 carbon atoms, e.g. ethanol; or in excess acid anhydride. The temperature of this reaction can be varied within a wide range, e.g. 0 to 150 ° C. It is convenient to carry out this reaction at 20 ° C.

In acylation using an acyl halide, preferably acyl chloride, the reaction is carried out in an inert organic solvent, e.g., aliphatic ethers such as diethyl ether, in cyclic ethers such as tetrahydrofuran; in optionally halogenated aliphatic or aromatic hydrocarbons such as chloroform or benzene or in an organic base such as pyridine and the like The reaction is conveniently carried out in the presence of an acid binding agent as an inorganic base such as an alkali metal carbonate such as potassium or sodium carbonate; an alkali metal hydride such as sodium hydride or the like; or an organic tertiary base, e.g. triethylamine, pyridine and the like.

In some cases, the organic base used may also serve as a solvent and acid binding agent. The reaction temperature can be varied within a wide range; the reaction is conveniently carried out at a temperature in the range of 0 to 100 ° C. When the starting material is an acid, i.e. in the formula (II), is hydrogen, the component to be acylated is acidic; the reaction is thus carried out by reacting the acylated substance with an acylating agent, preferably acyl chloride or acid anhydride in an aqueous medium containing a water-miscible organic solvent, e.g., a lower aliphatic alcohol, acetone or the like, and a base. This reaction is carried out at a temperature in the range of 0 to 100 ° C, preferably at room temperature, preferably in the presence of a calculated amount of a base such as an inorganic base such as an alkali metal hydroxide, e.g. potassium or sodium hydroxide or an alkali metal carbonate e.g. potassium or sodium.

The starting materials of formula II wherein R ₄ is hydrogen and compounds of formula I where hydrogen is can be esterified directly or indirectly.

The direct esterification is preferably carried out by reacting the corresponding compound of formula (I) or (II) with an excess of an alcohol of formula ^R 3 ° ^H where it is as defined above, except that it is not hydrogen, preferably in the presence of a catalyst and excluding any moisture. A strong organic or inorganic acid, e.g. hydrogen chloride, preferably in gaseous form, and sulfuric acid or p-toluenesulfonic acid or the like, and a water-binding agent, e.g. a suitably selected molecular sieve, may be used.

Indirect esterification can be carried out, for example, by first converting a suitable carboxylic acid derivative of the formula I or II into a salt, optionally in a reaction mixture using a base, e.g. an alkali metal hydroxide such as lithium, potassium or sodium hydroxide, or carbonate an alkali metal such as sodium or potassium carbonate; or an ammonium hydroxide, whereupon the alkali metal salt or ammonium salt separated in a suitable manner or formed and dissolved in the reaction mixture is reacted with a compound of the formula wherein it is as defined above, except that it is not hydrogen and Y is an acid residue. When Y in the formula R ^-Y represents a halogen such as chlorine, bromine or iodine or sulphate, the reaction may conveniently be carried out in an organic aprotic polar solvent such as acetonitrile, dimethylformamide or the like by adding in portions a small excess of the appropriate halide compound ammonium salts of a carboxylic acid derivative of the formula I or II in a solvent. This reaction can be carried out at a temperature in the range of 50 to 120 ° C. When a mixture containing the above solvent with water is used, the reaction is carried out in the presence of a suitable phase transfer catalyst, e.g. a suitable tetraalkylammonium halide.

Hydrolysis of a compound of formula (I) wherein R is as defined above, A represents a hydroxyl group, V represents a hydrogen atom and R 1 represents an optionally substituted C 1 -C 10 aliphatic hydrocarbon group, C 3 -C 8 alicyclic hydrocarbon group or an aromatic hydrocarbon group C 6 -C 14 carbon atoms are preferably carried out in an alkaline medium. As solvents, organic solvents containing 5 to 50% water can be used, eg aliphatic alcohols such as methanol or ethanol or aliphatic ketones such as acetone and the like. Alkaline conditions are ensured by using, for example, an excess of alkali metal hydroxide such as sodium or potassium hydroxide. The temperature of this reaction may be in the range of 20 to 120 ° C.

The dehydration of the compounds of formula I wherein R and R R is as defined above, A represents a hydroxyl group and V represents a hydrogen atom, can be carried out by any method conventionally used and used in dehydrating a vincamine alkaloid, suitably by cleavage of water in the presence removal by azeotropic distillation. According to a preferred embodiment of the invention, the respective compound of formula I is boiled in an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, toluene, or the like, in the presence of p-toluenesulfonic acid, while water is continuously removed from the system using e.g.

If desired, the compounds of the formula I prepared by the process according to the invention can be converted into quaternary salts. For quaternization, an alkyl halide such as chloride, bromide, iodide or alkyl sulfate is preferably used in a slight excess over the equivalent amount. The reaction is preferably carried out in an anhydrous inert organic solvent such as an aliphatic alcohol having 1 to 6 carbon atoms, e.g. absolute methanol, absolute ethanol and the like; or using a ketone such as acetone or butanone or a nitrile such as acetonitrile as a solvent. The quaternization is preferably carried out at a higher temperature.

Optionally, the compounds of formula I prepared by the process of the invention can be converted to acid addition salts using any of the acids listed above.

The acid addition salts may be formed in any inert organic solvent such as a C 1 -C 6 aliphatic alcohol by dissolving the racemic or optically active compound of formula I in the above solvent and adding the appropriate acid or solution thereof in the above solvent to the solution of the compound of formula Even until the solution is weakly acidic (i.e. to a pH of 5 to 6). Then, the acid addition salt precipitated from the mixture is separated in a suitable manner, e.g. by filtration.

Using a racemic starting compound yields the racemic end product; however, using an optically active starting material, the end product is an optically active compound. The racemic end product can be resolved using any known resolution method. However, cleavage can be carried out at any stage of the process of the invention.

Optionally, the racemic and optically active compounds of the formula I and their acid addition salts obtained by the process according to the invention can be subjected to further purification, for example recrystallization. The use of the solvent for recrystallization depends on the solubility and crystallization characteristics of the solvent.

The racemic and optically active compounds of formula I and their pharmaceutically acceptable acid addition salts and quaternary salts exhibit valuable therapeutic properties, in particular vasodilator, spasmolytic, antihypoxic and anticonvulsant effects.

The vasodilatory effect was studied in dogs anaesthetized with a mixture of chloralose and pentobarbital. Large blood circulation was measured on the femoral artery, while cerebral blood circulation was observed on the internal carotid. Electromagnetic flow meters were used to measure blood circulation. Test substances were administered intravenously to 6 dogs at a dose of 1 mg / kg body weight and the percent changes in the measured parameters were evaluated. The commonly used therapeutic cerebral vasodilator ethyl / + / -ovincamate was used as reference drug.

Circulatory effects /% changes / intravenous dose of 1 mg / kg body weight of anesthetized dogs.

Compound

Carotid flow

Femoral artery flow

Ethyl (+) - apovincamate / reference medicine / + 30 + 15 Ethyl 11-thiophenecarbonylaminoapovincamate + 65 0 Ethyl 11-benzoylaminoapovincamate + 80 0 Methyl 11-acetylaminoapovincamate + 50 0 Isobutyl-11-acetylaminoapovincamate + 60 0 Ethyl 9-methanesulfonylaminoapovincamate 0 + 70 Ethyl 9-acetylaminoapovincamate 0 + 50 Ethyl 9-benzoylamino-camacetate + .35 + 140

The spasmolytic activity of the compounds was determined using the traditional method, i.e., on isolated gut guinea pig fMagnus R. Pfugers Arch. 102, 123 (1904). Papaverine and ethyl / + / apovincamate were used as reference drugs used as therapeutical spamolytic agents.

Inhibition of barium chloride induced guinea pig intestinal contraction

Compound ED ₅₀ ( _y µg / ml) Papaverine (reference medicine) Ethyl - / + / - apovincamate / reference medicine / Methyl-11-benzoylaminoapovincamate Methyl 11- (2-fluorobenzoylamino) -apovincamate 5.4 ’ 2,0 2.5 4.0

In one method, the antihypoxic effect was studied in non-anesthetized mice under hypoxia at normal pressure. Five male mice were placed in a 3 liter glass cylinder, which was filled with a gas mixture of 96% nitrogen and 4% oxygen. From this point until the animals died, the early 15 minute interval was measured as maximum. Animals could be considered protected if they survived twice the length of time compared to the time of death of untreated animals. Test compounds were administered intraperitoneally to 10 animals at a dose of 50 mg / kg body weight 30 minutes before being placed in a glass cylinder.

Antihypoxic effect of intraperitoneal dose of 50 mg / kg body weight of non-anesthetized mice in hypoxia at normal pressure

Compound Survival time average + deviation% min. Protection % Control 6.0 + 1.04 - - ' Ethyl 9-aminoapovincamate 7.3 + 2.31 .22 10

Antihypoxic activity was also investigated using two other methods.

According to the asphyxia anoxia test fCaillard O. et al.Life SCi. 16, 1697 (1975)], the animals were fasted for 16 hours, then treated orally and placed in tightly sealed 100 ml glass containers per hour. Survival time was considered to be the early interval from closure of the vessel to the last breathing. Animals were considered protected if they survived 30% longer than the mean survival time of the control group.

According to the hypoxia test under reduced pressure fBaumel J. et al .: Proc. Soc. Biol. N. Y. 132, 629 (1969)], the animals were fasted for 16 hours, then treated orally and placed in an desiccator in an hour, where the pressure was reduced to 22.66 mPa over 20 seconds. Survival time was recorded from that time until the last breathing. Animals were considered protected if they survived 100% longer than the mean survival time of the control group. ED value ^ g / i.e. the dose that was effective at 50% was calculated from the percentage of animals protected using the analytical method.

Compound Antihypoxic efficacy at asphyxia anoxia ^ED 50 hypoxia for decrease. th. mg / kg po. Mephenytoin (reference medicine) ? 80.0 > 80,0 ‘ Ethyl - / + / - apovincamate / reference medicine / ^ 50.0 > 50.0 Methyl-11- (4-nitrobenzoylamino) - -apovincamate 40.9 42.1 Methyl 11-benzoylaminoapovincamate 25.0 > 50.0

Anticonvulsive efficacy was studied using the following methods.

Using maximum electroshock £ Swinyard E.A. et al .: J. Pharmacol. Exp. Ther. 106, 319 (1959) was given a shock (20 mA, 0.2 seconds) of HSE Shock Device Type 207 / mice weighing 22-24 g using corneal electrodes. Animals were considered to be protected when the tense stretching of their lower limbs by the drug was removed.

Using the metrazole seizure method £ Everett G. M. and Richards R. K .: J. Pharmacol. Exp. Ther., 81, 402 (1944), a subcutaneous dose of 125 mg / kg pentylentetrazole was administered to mice following pretreatment. Continuous clonic seizures and tense elongated seizures stopped by the drug have been reported.

Using strychnine seizure [Kerley T. L. et al. J. Pharmacol. Exp. Ther. 132, 360 (1961)], elicited stretched convulsions were induced by an intraperitoneal dose of 2.5 mg / kg strychnine nitrate. These animals were considered to be protected when strained stretched convulsions were stopped by the drug, leaving the animals alive.

Neurotoxic side effects were observed using the following methods.

Using the Muscle Incoordination Method (Rotating Bar Method). Kwibara et al., Japan J. Pharmacol 27, 117 (1977) J, were selected after pre-training that could remain for 120 seconds on a 20 mm horizontal bar rotating at 12 rpm.

The effect of muscle non-coordination was determined when the animals fell from the rod within this time limit.

To determine the effect of muscle relaxation (traction test), male mice weighing 18 to 22 g were fastened to their upper limbs on a horizontal wire of 5 mm diameter. These animals had hypomyotonia when their lower limbs were not attracted to the upper limbs within 5 seconds by drug action.

Compound

Anticonvalsive efficacy

Neurotic effects

Max. elek- Metra- Strich- Rotating Traction a little bit zolový ninová rod attack attack ^ED 50 mg / kg AFTER. ED ₅₀ mg / kg AFTER

Mephenytoin (reference medicine) 26.3 24.5 0 Methyl-11-benzoylamino- apovincaminate 16.0 15.9 180 mg / kg Yippee ineffective Ethyl-11-benzoylamino- apovincaminate 16.7 9.7 180 mg / kg Yippee ineffective

Based on the above research, it can be concluded that biological activity is very advantageously influenced by substitution in ring A. This is shown primarily in the increase in blood circulation. Cerebral blood circulation is specifically improved and large blood circulation is not or very difficult to be affected by some compounds of formula I, while other compounds of formula I enhance large circulation without cerebral effect. In general, compounds substituted at the 11-position, in particular by the benzoylamino group, have a stronger cerebral vasodilatory effect than the comparative compound of similar chemical structure, while compounds substituted by the same group at the 9-position exhibit mainly peripheral vasodilatory effect.

In addition to circulatory effects, the compounds also exhibit a direct spasmolytic effect on smooth muscles equal to or greater than the effect of papaverine used as a comparative compound.

The compounds of formula I have an extraordinary anticonvulsant effect: they are more effective than mephenytoin used as a reference drug, neurotoxic side effects are not observed even after 10 times the anticonvulsive effective dose, while neurotoxic side effects manifest themselves after 3 to 6 times the anticonvulsively effective dose of the reference medicine. The therapeutic ratio / safety index / reference drug is much narrower.

The anticonvulsive and antihypoxic effects of the compounds of the invention together with their cerebral blood circulation enhancing activity provide particularly advantageous therapeutic use in diseases where the cerebral oxygen supply is temporarily or chronically disrupted.

The compounds of formula (I) may be converted into pharmaceutical formulations by mixing with conventional non-toxic inert solid or liquid carriers and / or excipients which are commonly used in such formulations and are useful for enteral or parenteral administration. As carrier, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc and vegetable oils such as peanut oil or olive oil or the like can be used. The active ingredients may be formulated into conventional pharmaceutical preparations such as in the form of solids (such as rounded or square tablets, dragees, capsules, e.g., hard gelatin capsules, pills, suppositories or the like) or liquid form (such as oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc./. The amount of solid carrier may be in a wide range, preferably in the range of 25 mg to 1 g. The formulations may optionally contain commonly used pharmaceutical ingredients such as preservatives, stabilizers, wetting agents and emulsifiers, as well as salts useful for adjusting osmotic pressure, buffers, and fragrances, etc. In addition, the compositions may optionally contain other known therapeutically valuable compounds. The compositions are preferably formulated in a unit dosage form suitable for the desired mode of administration.

Pharmaceutical preparations are prepared using general methods, including, but not limited to; eg, sieving, mixing, granulating and compressing or dissolving the ingredients to formulate / convert them into suitable formulations. These may be subjected to other operations (e.g. Sterilization / commonly used in the pharmaceutical industry.

The invention will be illustrated in more detail by the following examples without limiting the scope of the invention.

Example 1

Preparation of 11-benzoylaminoapovincamic acid

3.37 g (0.01 mol) of (+) - 11-aminoapovincaminic acid are dissolved in 100 ml of 1N aqueous sodium hydroxide solution, and 1.7 ml (0.015 mol) of benzoyl chloride are added dropwise while stirring at room temperature. The mixture was stirred for 2 hours, then an equal amount of benzoyl chloride was added and the mixture was stirred for a further 2 hours. The pH of the mixture is adjusted to neutral by adding 10% aqueous hydrochloric acid, the precipitated crystals are filtered off, washed with 50 ml of water heated to 50-60 ° C and then with 50 ml of cold water and dried to give 3.30 g (75% yield). the desired compound, mp Mp 244-248 ° C.

Analysis

For ^C 27 ^H 27 ^N 3 ° 3 (molecular weight 441.52):

H, 6.16; N, 9.52. Found:% C, 73.62;% H, 6.82;% N, 9.48.

_1H -NMR spectrum (DMSO-d6, -): Et: 0.94t (3), H-3: 4.10s (1); 11-15: 6,00s / l /, NH: 7.95s / l /,

Ar-H: 7.3-7.6m (6), H _Qrtho . 7.9 to 8.05m (2), COOH: 10.10s (1): skeletal protons: 1.10 to 3.4m.

Example 2

Preparation of 11- (2-thiophenecarbonylamino) -apovincaminic acid ml (0.03 mol) of thiophene-2-carbonyl chloride was added dropwise with stirring at room temperature to a solution of 3.37 g (0.01 mol) of (+) - 11-aminoapovincaminic acid in 100 ml of 1N aqueous sodium hydroxide solution. 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 3 x 40 ml of water and dried to give 3.26 g (73% yield) of the title compound, mp: 246-248 ° C.

Analysis

For ^C 25 ^H 25 ^N 3 ^S 3 ° / ^m ° l ^e k ^by L c and weight ^of 447.5 /:

H, 5.63; N, 9.39. Found:% C, 67.35;% H, 6.00;% N, 9.40.

Example 3

Preparation of ethyl 11-aminoapovincamate

Method a)

A mixture containing 3.95 g (0.01 mol) of ethyl 11-nitroapovincamate in 50 ml of ethanol, 10 ml of concentrated hydrochloric acid and 6 g of tin powder was stirred for 1 hour at 100 ° C and then filtered while hot. The solution thus obtained is evaporated to dryness under reduced pressure, the residue is taken up in 100 ml of water and basified to pH 10 by the addition of 1N aqueous sodium hydroxide solution. The precipitate is filtered off, washed with 3 x 40 ml of 1% aqueous sodium hydroxide solution and x 40 ml water and dried to give 2.80 g (77% yield) of the title compound, m.p. Mp 86-88 ° C.

¹ H-NMR ^{with Pectrum} (CDCl 3, b ¹ ): Et: 1.00t (3), 1.90q (2) (EtO)], 40t (3), 4.40q (2), NH 2: 3.23 (2), H-3: 4.10s (l), H-15: 6.07s (l), skeletal protons: 1.5 to 3.2m.

Method b)

A mixture containing 3.83 g (0.01 mol) of ethyl 11-amineincamate and 7.0 g of p-toluenesulfonic acid in 150 ml of benzene was heated under reflux for 8 hours using a water trap. The mixture was cooled to room temperature, water (100 ml) was added and basified to pH 8 with concentrated aqueous ammonium hydroxide solution. The aqueous phase was separated, the benzene layer was extracted with water (3 x 100 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was triturated with ether, the obtained crystals were filtered, washed with ether and dried to give 3 g (82% yield) of the desired compound.

At .1. ad 4

Preparation of ethyl 11-methanesulfonylaminoapovincamate monohydrochloride

A solution of 0.6 µl L (0.008 mol) methanesulfonyl chloride in 10 ml chloroform was added to a solution of 1.62 g (0.004 4 mol) ethyl 11-aminoapovincamate in 10 ml anhydrous pyridine under cooling with ice water, then stirred for 3 hours at room temperature. 0 ° C and then evaporated to dryness under reduced pressure. The residue is taken up in a mixture of 50 ml of ethyl acetate, 25 ml of a saturated aqueous solution of sodium bicarbonate and 50 ml of water. The layers were separated, the ethyl acetate phase was washed with water (2 x 30 ml), dried and evaporated to dryness under reduced pressure. The residue, which is in the form of the base of the desired substance (1.86 g, 96% yield), is dissolved in 15 ml of acetone and acidified by adding ethanolic hydrogen chloride solution to pH 3. The crystals obtained after the addition of 45 ml of diisopropyl ether are filtered, washed with ether. and dried to give 1.56 g (74% yield) of the monohydrochloride form of the title compound, m.p. Mp 230-234 ° C. ·

Analysis for ^C 23 ^H 29 ^N 3 ° 4 ^S 1 ^HCl (MW 480.11):

Calculated: C 57.53, H 6.29, N 8.75, S 6.67, Cl 7.38; Found: C 57.42, H 6.87, N 8.56, S 6.43, Cl 7.40.

Example 5

Preparation of ethyl 11-amineincamate

A mixture containing 7.4 g (0.02 mol) of 11-amino-vincamine and 0.5 g of potassium tert-butoxide in 500 ml of ethanol is heated at reflux for 2 hours, then evaporated to dryness under reduced pressure. The residue is taken up in a mixture of 200 ml of water and 40 ml of ethanol, the crystals obtained are filtered, washed with a mixture of 100 ml of water and 20 ml of ethanol in 3 portions and dried to give 5.43 g (71% yield) of the title compound. Mp 184-186 ° C.

HNMR ^{P e} ktrum / CDCl ^, ^ / Et: 0.85 t / 3 / CH _2: overlapping H ₂ ~ 15: 2,08d / l /, 2,16d / l / ^{/ J} gem ^{= 14 Hz /} ' ^NH 2 ^{: 3} ' ⁸⁰ ' ^CH 2 ~ ^0: 4 _from 25q / 2 / _from H-3: 3.84s / l / H-9: 7.30d / l /, H-10: 6.60dd (1), H-12; 6.41d (l).

Example 6

Preparation of ethyl 9-amino-apovincamate monohydrochloride

Method a)

Using 3.83 g (0.01 mol) of ethyl 9-amineincamate as described in Example 3 afforded 2.84 g (78% yield) of the desired product as a base which was dissolved in 20 ml of acetone and acidified. by adding ethanolic hydrogen chloride solution to pH 3. The crystals obtained after the addition of 20 ml of diisopropyl ether are filtered, washed with ether and dried to give 2.7 g (69% yield) of the monohydrochloride form of the title compound, m.p. Mp 218-222 ° C.

Analysis for C ₂₂ H ₂₇ N ₃ O ₃ · HCl (MW 401.96):

Calculated: C 65.68, H 6.71, N 10.44, Cl 8.83; Found: C, 65.86; H, 6.90; N, 10.28; Cl, 8.78.

Method b).

A solution containing 3.37 g (0.01 mol) of - [9-amino-apovincaminic acid in 100 ml of anhydrous ethanol is saturated with dry hydrogen chloride gas in the presence of 1 g of molecular sieve (3 M-10, Aldrich 20, 859-2). Then the mixture was refluxed for 3 hours with continuous hydrogen chloride feed. The mixture was evaporated to dryness and 20 ml of ethyl acetate were added to the residue. The obtained crystals were filtered, washed with ethyl acetate and dried to give 3.13 g (86% yield) of the desired compound, m.p. Mp 218-222 ° C.

Example 7,

Preparation of 9-methanesulfonylaminoapovincamate monohydrochloride

0.37 ml (0.005 mol) of methanesulfonyl chloride was added to a solution containing 1.10 g (0.002 7 mol) of ethyl 9-aminoapovincamate monohydrochloride in 15 ml of anhydrous pyridine. The mixture is stirred at 0-5 ° C for 2 hours, then evaporated to dryness under reduced pressure, the residue is dissolved in 50 ml of chloroform and the organic solution is extracted with 25 ml of saturated aqueous sodium carbonate solution and then with 3 x 30 ml of water. The chloroform layer was dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness to give the oily base of the title compound in a yield of 1.09 g (91%). This base is dissolved in 40 ml of acetone and the solution is acidified by adding ethanolic hydrogen chloride solution to pH 4. The crystals obtained after the addition of ether are filtered, washed with ether and dried to give 1.13 g (96% yield) of the monohydrochloride form of the desired product. tt Mp 189-192 ° C.

Analysis for ^C 23 ^H 29 ^N 3 ^O 4 ^S · HCl (MW 480.11).

calculated: 57.53% C, 6.29% H, 8.75% N, 6.67% S, 7.38% Cl found: 57.70% C, 6.80% H, 8.72% N 6.40% S, 7.51% Cl.

Example

Preparation of ethyl 9-amineincamate.

Using 7.4 g (0.02 mol) of 9-amino-amine and the method described in Example 5 gave 5.82 g (76% yield) of the desired product, m.p. Mp 232-234 ° C.

Example 9

Preparation of methyl 11- (4-nitrobenzoylamino) -apovincamate 1.3 g (0.007 mol) of 4-nitrobenzoyl chloride was added to a solution containing 1.3 g (0.003 7 mol) of 11-aminoapovincamine in 10 ml of anhydrous pyridine, then the mixture was stirred 1 hour at room temperature. A solution containing 100 ml of ice water and 150 ml of ethyl acetate was added to the solution, and the mixture was basified by adding 1 N aqueous sodium hydroxide solution to pH 8. The ethyl acetate layer was separated, washed with 4 x 25 ml of water, dried with anhydrous sodium sulfate, filtered and filtrate. evaporate to dryness under reduced pressure. The residue was triturated thoroughly with 100 ml of ether, the obtained crystals were filtered, washed with ether and dried to give 1.68 g (91% yield) of the title compound, m.p. Mp 206-208 ° C.

¹ _H - _NMR spectrum (CDCl ₃ ,?): Et: 1.02t (3), CH ₃ O: 3.98s (3), H-3: 4.02s (1), H-15: 6, 28s / l /,

NH: 8.583 (1), ArH: 7.32 to 8.08m (7), skeletal protons: 1.4 to 3.26.

Example 10

Preparation of methyl 11-7 2-bromobenzoylamino / apovincamate monohydrochloride

3.51 g (0.01 mol) of 11-aminoapovincamine and 2 ml of triethylamine are dissolved in 40 ml of anhydrous benzene. ·

After addition of a solution containing 5.12 g (0.023 mol) of 2-bromobenzoyl chloride in 10 ml of benzene to the above mixture at room temperature with stirring, the solution is stirred at room temperature for 4 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of water and 50 ml of ethyl acetate and basified to pH 8 with concentrated aqueous ammonium hydroxide solution. The ethyl acetate layer was separated, the aqueous phase was extracted with 2 x 5 ml of ethyl acetate and the combined ethyl acetate solution was washed with 3 x 50 ml of water. dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness to give 4.16 g (78% yield) of the desired product base as an amorphous residue.

@ 1 H NMR (CDCl3) .delta.: Et: 1.01t (3), 1.90q (2), H-3: 4.14s (1), CH3: 4.00s (3), H- 15 6,19s / l / H-NMR J ^J

ArH + NH: 7.05 to 7.90 m (8), skeletal protons: 0.8 to 3.4 m (10).

The above base was dissolved in acetone (50 mL) and acidified to pH 3 with ethanolic HCl. The crystals obtained after ether addition were filtered, washed with ether and dried to give 3.93 g (60% yield) of the monohydrochloride form of the title compound, m.p. Mp 208-212 ° C.

Example 11

Preparation of 11- (2-fluorobenzoylamino) -vincamine

2.1 g (0.015 mol) of 2-fluorobenzoic acid are dissolved in 100 ml of anhydrous dimethylformamide, and to this solution at 0 DEG C. is added initially 4.0 g (0.02 mol) of dicyclohexylcarbodiimide and after stirring for 10 minutes 7 g (0.01 mol) of 11-aminincincamine. The mixture was further stirred at 0 ° C for 1 hour and then left to stand overnight at room temperature. The precipitated dicyclohexylurea is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue was dissolved in 400 mL of ethyl acetate and left in the refrigerator overnight. The crystallized dicyclohexylurea is filtered again and the filtrate is extracted 4 times with 50 ml of 1N aqueous hydrochloric acid solution, then with 2 x 50 ml of water and finally with 3 x 50 ml of saturated aqueous sodium bicarbonate solution and 2 x 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 hot mixture containing 50 ml of ethyl acetate and 250 ml of petroleum ether. After cooling, crystals were obtained, which were filtered, washed with petroleum ether and dried to give 3.8 g (78% yield) of the desired product, m.p.

Mp 202-205 ° C.

¹ H-NMR ( ^CDCl 3) ^{: Et:} 0.90t (3), CH ₃ O: 3.90s (3), OH: 4.76s (1), Ar-H: 7.05 to 8.70m / 7 (skeletal protons: 1.00 to 3.4 (12)).

Example 12

Preparation of 11- (3,4,5-trimethoxybenzoylamino) -vincamine

2,3 g (0,01 mol) of 3,4,5-trimethoxybenzoyl chloride is added to a solution containing 1.85 g (0.005 mol) of 11-amino-amine in 75 ml of anhydrous pyridine at room temperature with stirring. The solution was stirred at room temperature for 2 hours, then evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and 50 ml of water and basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8. The layers were separated, the ethyl acetate phase was washed with 3 x 25 ml of water, dried and evaporated to dryness. The residue was dissolved in 25 ml of hot ethanol and, after addition of 100 ml of diisopropyl ether, the solution was left in a refrigerator overnight. The obtained crystals were filtered, washed with diisopropyl ether and dried to give 2.13 g (76% yield) of the title compound, m.p. Mp 154-158 ° C.

Example 13

Preparation of 11-pivaloylamino-amine

0.5 ml (0.004 mol) of pivaloyl chloride is added to a solution containing 0.74 g (0.002 mol) of 11-amino-amine in 30 ml of anhydrous pyridine at 0 ° C with stirring. The mixture is further stirred at the same temperature for 2 hours, then 20 ml of water are added and basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8. The precipitated crystals are filtered, washed with water and dried to give 0.71 g of the desired product from. 78% yield m.p. Mp 140-144 ° C.

'/

1 H-NMR (CDCl ₃ ,?): 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 to 7.65m (4), skeletal protons: 1.45 to 3.5m.

Example 14

Preparation of 9-benzoylamino-amine

A solution containing 3.5 ml (0.03 mol) of benzoyl chloride in 20 ml of benzene was added in portions with stirring to a suspension of 5.52 g (0.015 mol) of 9-amino-amine in 150 ml of anhydrous benzene and 5 ml of anhydrous pyridine. After stirring for an additional 3 hours at room temperature, 60 ml of water are added and the pH is adjusted to 8 by adding concentrated ammonium hydroxide solution. The benzene phase is separated, washed with 5 x 20 ml of water, dried over anhydrous sodium sulfate, filtered and filtrate evaporate to dryness under reduced pressure. The residue is triturated with 50 ml of diisopropyl ether, the crystals obtained are filtered and washed with ether to give 4.92 g (69% yield) of the title compound, m.p. Mp 152-156 ° C.

1 H-NMR (CDCl ₃ ,?): Et: 0.90t (3), 1.65q (2); CH ₃ O: 3.85s (3), H-3: 3.88s (L) ; OH: 4.75s (l), NH: 8.46s (l), Ar-H: 6.8 to 8.0m (8).

Example 15

Preparation of 9-acetoamidovincamine

To a solution of 6.6 g (0.018 mole) of 9-amino-amine in 600 ml of methanol was added dropwise at 0 ° C 66 ml of acetic anhydride, then the solution was further stirred at 0 ° C for 30 minutes. 800 g of ice water and 120 g of potassium carbonate are then added with stirring. Methanol was distilled off under reduced pressure and the remaining aqueous mixture was extracted with 5 x 100 ml dichloromethane. The combined dichloromethane solution was washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. After addition of 50 ml of ether to the residue, the precipitated crystals are filtered, washed with ether and dried. 5.92 g (80% yield) of the desired compound is obtained, m.p. Mp 144-147 ° C.

Example 16

Preparation of 11- (2-thiophenecarbonyl) -aminovincamine

A solution of 7.2 ml (0.067 mol) of thiophene-2-carbonyl chloride in 20 ml of benzene was added dropwise with stirring at 20 ° C to a mixture containing 19.9 g (0.054 mol) of 11-amino-amine in 100 ml of pyridine. The mixture is stirred for an additional 2 hours at the same temperature, then 50 ml of a saturated aqueous sodium bicarbonate solution, 50 ml of water and 200 ml of ethyl acetate are added. After extraction, the phases are separated, the ethyl acetate layer is washed with 2 x 30 ml of water, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure. After addition of 200 ml of ether to the residue, the obtained crystals were filtered, washed with 4 x 50 ml of ether, and dried. 18.4 g (71% yield) of the desired product is obtained, m.p. Mp 229-231 ° C.

Example 17

Preparation of 11- (2-thiovenacetyl) -aminovincamine

0.45 g of dicyclohexylcarbodiimide is added to a solution of 0.3 g (0.002 mol) of thiophene-2-acetic acid in 10 ml of anhydrous dimethylformamide. The solution was stirred at room temperature for 15 minutes. Then, 0.74 g (0.002 mol) of 11-aminincincamine is added. The mixture was stirred at room temperature for 24 hours, then left in a refrigerator overnight. The precipitated dicyclohexylurea is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate and extracted sequentially with 10 ml of saturated aqueous sodium bicarbonate solution and then with 3 x 10 ml of water. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. After addition of 20 ml of ether to the residue, the precipitated crystals were filtered and washed with ether. After drying, 0.51 g (52% yield) of the title compound of m.p. 153-155 ° C.

¹ H-NMR (CDCl ₃ ): Et: 0.90t (3), 1.7q (2), CH ₃ O: 3.88s (3), CH ₂ CO: 3.94s (2), H -3: 4.00s (l), OH: 4.70 (1), Ar-H 6.80 to 7.65m (6), CONH: 7.48 (1)

Example 18 '. χ

Preparation of 9-acetamidoapovincamine

A mixture containing 5.6 g (0.014 mol) of 9-acetamidovincamine and 6.8 g of p-toluenesulfonic acid in 300 ml of benzene was refluxed for 4 hours using a water trap.

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, and filtered. After evaporating the filtrate to dryness under reduced pressure, the residue obtained is dissolved in 50 ml of hot ethyl acetate and, after cooling, the precipitated crystals are filtered and washed with ethyl acetate to give 5.0 g (91% yield) of the desired product, m.p. 138-140 ° C.

¹H-NMR / CDC1 ₃ '/ -. Et: 0.99 t / 3 /, CH ₃ CO: 2.66 s / 3 /, CH ₃ O: 3.80 s / 3 /, H-3: 4.05 s / l /, H-15 6.18 s / l (Ar-H: 7.0-7.65 m / 3).

Example 19

Preparation of 11- (3,4,5-trimethoxybenzoylamino) -apovincamine

Mixture containing 1,3 g (0,002 3 mol) of 11- (3,4,5-trimethoxybenzoylamino) -vincamine and

1.0 g of p-toluenesulfonic acid in 50 ml of benzene was refluxed for 2 hours using a water trap. After cooling, 20 ml of water are added to the mixture and the mixture is basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8. After extraction, the benzene phase is washed 3 times with 20 ml of water, dried over anhydrous sodium sulfate and filtered. After evaporation of the filtrate to dryness under reduced pressure, the residue is dissolved in 3 ml of hot acetone, ml of petroleum ether is added and, after cooling, the precipitated crystals are filtered off and washed with ether. After drying, 1.03 g (83% yield) of the desired product is obtained, m.p. Mp 150-152 ° C.

^{7 7 1} H-NMR ^{with Pectrum} (CDCl ₃ ^,? ): Et: 1.00t (3), CH ₃ CO: 3.98s (3), CH ₃ O: 3.90s (9), H-3 H-15: 6.28 s (1), Ar-H: 7.1-7.8 m (5), NHCO: 8.30 s / l.

Example. 20 May

Preparation of 11-pivaloylaminoapovincamine

A mixture containing 0.66 g (0.001 5 mol) of 11-pivaloylamino-amine and 0.70 g of anhydrous p-toluenesulfonic acid in 20 ml of benzene was heated under reflux for 3 hours using a water trap, then cooled and 20 ml of water were added. The mixture was basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8 and extracted. The benzene phase is washed with 4 x 10 ml of water, dried over anhydrous sodium sulfate and filtered. After evaporation of the filtrate to dryness under reduced pressure, the residue is dissolved in 20 ml of hot hexane containing a few drops of acetone. After cooling, the obtained crystals were filtered, washed with hexane and dried to give 0.44 g (68% yield) of the desired product, m.p. Mp 110-114 ° C.

¹ H-NMR / CDCl 3, d ^r / i Et: 0.97 t / 3 / l, 92q / 2 /, CH3 l, 35/9 /, CH ₃ O: 3,93s / l / H-3 4.07 s (l), Ar-H + nH: 7.0-7.68 m (4).

Example 21

Preparation of 11-acetamidoapovincamine

A mixture containing 18.1 g (0.044 mol) of 11-acetamidovincamine and 22 g of p-toluenesulfonic acid in 900 ml of benzene was refluxed for 5 hours using a water trap, then cooled and 400 ml of water were added. The mixture was basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8. After extraction, the benzene layer was washed with water (3.times.300 ml), dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness under reduced pressure. After washing the residue with 50 ml of diisopropyl ether and drying, 14.35 g (83% yield) of the desired product is obtained, m.p. Mp 136-140 ° C.

^{1 1} H-NMR ^{with Pectrum} (CDCl ₃ , ^CH ₃ ) -. 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 (l), ArH + NH: 6.97 to 7.58m (4).

Example 22

Preparation of ethyl 9-benzoylamino cinnamate

A solution containing 1.89 g (0.004 mol) of 9-benzoylamino-amine and 0.1 g of potassium tert-butoxide in 30 ml of anhydrous ethanol is heated at reflux for 1 hour, then evaporated to dryness. The residue was dissolved in 50 ml of ethyl acetate and extracted with 3 x 15 ml of water. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. After trituration of the residue with ether, the obtained crystals were filtered, washed with ether and dried to give 1.32 g (68% yield) of the title compound, [α] _D = + 44.82 ° (= 1, dichloromethane).

Example 23

Preparation of ethyl 1-9-benzoylaminopovincamate

A mixture containing 1.22 g (0.002 5 mol) of ethyl 9-benzoylamino cinnamate and 1.3 g of p-toluenesulfonic acid in 50 ml of benzene was heated under reflux for 2 hours using a water trap, then cooled. After addition of 50 ml of water, the pH is adjusted to 8 using concentrated aqueous ammonium hydroxide solution. After extraction and separation, the benzene layer is washed with 4 x 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. After trituration of the residue with 10 ml of hexane, the obtained crystals are filtered, washed with hexane and dried to give 0.93 g (97% yield) of the desired product, mp 112-116 ° C, = + 186.96 ° / s = 1, dichloromethane (1 H-NMR ^{with Pect} rum (CDCl ₃ ): Et: 1.00t (3), 1.90q (2), EtO: 1.39 (3), 4.30q (2), H -3: 4.0s / l (H-15: 6.17s / l), Ar-H: 7.0 to 7.98m (8), NH: 7.30s / l.

Example 24

Preparation of 2-hydroxyethyl-11-acetamidoapovincamate

A mixture of 11-acetamidoapovincamine (2.13 g, 0.005 mol) and potassium tert-butoxide (0.1 g) in ethylene glycol (70 ml) was stirred at 120 ° C for 90 minutes, then excess ethylene glycol was removed by distillation under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and extracted with 3 x 20 mL of water. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was triturated with 30 ml of ether and the crystals obtained were washed with ether and dried to give 1.47 g (64% yield) of the title compound, m.p. Mp 146-150 ° C.

l _u ммп spectrum / CDCl ,, ^ / Et: 0.98 t / 3 / l, 82q / 2 / CH _q CO 2,16s / 3 /, H, and CH 3 OCO _about 3.85 / 3), OCH ₂ : 4.52m (2), H-15: 6.04, Ar-H: 6.7 to 7.8m (3), NH: 7.36s (1).

Example 25

Preparation of 11-nicotinoyl-aminoapovincamine

A solution of 11.3 g of nicotinoyl chloride in 100 ml of anhydrous benzene was added dropwise with stirring to 4.0 g (0.011 mol) of 11-aminoapovincamine dissolved in 80 ml of pyridine. The mixture was stirred at room temperature for 8 hours, then set aside overnight. Then the solution was evaporated to dryness under reduced pressure, the residue was dissolved in 100 ml of water and basified to pH 8 with concentrated aqueous ammonium hydroxide solution. The precipitated product was filtered, washed with water and dried to give 4.00 g / 80% yield. the desired compound, mp M.p. 148-152 ° C.

~ + 17.00 ° (s = 1, dichloromethane).

¹ H-NMR ^{with Pectrum} (CDCl ₃ , δ): Et: 1.00t (3), 1.90q (2), CH ₃ O: 3.90s (1), H-15: 6.06s (1) /, ArH + NH:

7.2 to 8.93 m (8).

Example 26

Preparation of 11- (2-fluorobenzoylamino) -apovincamine

A mixture containing 9.5 g (0.019 mol) of 11- (2-fluorobenzoylamino) vincamine and 20 g of p-toluenesulfonic acid in 500 ml of benzene was heated under reflux for 2 hours using a water trap, then cooled. After addition of 200 ml of water, the pH is adjusted to 8 using concentrated aqueous ammonium hydroxide solution. After extraction and separation, the benzene layer is washed with 4 x 100 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Recrystallization of the residue from 300 ml of diisopropyl ether gave 7.14 g (86% yield) of the desired product, m.p. Mp 102-105 ° C, [(* -] D = -2.40 ° (d = 1, dichloromethane)).

χ ¹ H-NMR ^{with Pectrum} (CDCl ₃₎ , t: Et: 1.02t (3), 1.95q (2), CH ₃ O: 4.01s / l /, H-3: 4.30s / l (H-15: 6.18s / l), ArH: 6.95 to 8.00m (6), H-12: 7.92d (l), 7.14dd and 8.22dd (l), NH: 8.45 and 8.62 s (l), skeletal protons: 1.00 to 3.4 m (10).

Example 27

Preparation of 11- (2-thiophenecarbonyl) -aminoapovincamine

Method a)

A mixture containing 15.1 g (0.031 mol) of 11- (2-thiophenecarbonyl) -aminovincamine and 17 g of p-toluenesulfonic acid in 400 ml of benzene was heated under reflux for 2 hours using a water trap, then cooled. After addition of 100 ml of water, the pH is adjusted to 8 using concentrated ammonium hydroxide solution. After extraction, the benzene phase is washed with 5 x 50 ml of water, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure. Recrystallization of the residue from 100 ml of diisopropyl ether gave 14.0 g (96% yield) of the desired product, m.p. 138-140 ° C.

¹ H-NMR ^{with Pectrum} (CDCl ₃ , δ: Et: 1.02 t / 3), CH ₃ O: 3.98s (3), H-3: 4.03s (1), H-15: 6, 10s / l /,

ArH: 7.0 to 7.74m (6), NH: 8.05s / l /

Method b)

1.5 ml of dimethyl sulfate was added to a solution containing 6.7 g (0.015 mol) of l- (2-thiophenecarbonyl) -aminoapovincamic acid in 20 ml of acetone and 15 ml of 1N aqueous sodium hydroxide solution at room temperature with stirring. After stirring for 90 minutes, 0.5 ml of concentrated aqueous ammonium hydroxide solution was added to the mixture, then the mixture was evaporated under reduced pressure to half volume. The precipitated substance was filtered, washed with 2 x 10 ml of water and dried to give

6.5 g (95% yield) of the desired compound, the physical properties of which are the same as the product obtained according to method a). ’

Example 28

Preparation of 11-benzoylaminoapovincamine

A solution of 4.4 g (0.01 mol) of 11-benzoylaminoapovincaminic acid in 100 ml of anhydrous liver is saturated with dry hydrogen chloride gas in the presence of a 3 m @ 2 molecular sieve (Aldrich 20, 859-2), then the mixture is heated for 5 hours under while bubbling hydrogen chloride solution continuously. Then the solution is evaporated to dryness, the residue is taken up in a mixture of 100 ml of ethyl acetate and 50 ml of water and basified to pH 8 by addition of concentrated aqueous ammonium hydroxide solution. After separation, the ethyl acetate layer is washed with 2 x 30 ml of water, dried with anhydrous sodium sulfate, it is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from 40 ml of a 1: 1 mixture of diisopropyl ether and hexane

3.9 g (86% yield) of the title compound, m.p. Mp 129-132 ° C.

^{1 1} H-NMR ^{with Pectrum} (CDCl ₃ ): Et: 1.00t (3), CH ₃ O: 4.00s (3), H-3: 4.10s (1), H-15: 6.12s (l), _to ArH + NH: 7.08 to 8.15m (9)

Example 1 a d 29

Preparation of 2-hydroxyethyl-11-benzylaminoapovincamate

A solution of 0.45 g (0.01 mol) of 11-benzoylaminoapovincamine in 10 ml of ethylene glycol was heated at 120 ° C for 2 hours in the presence of 0.01 g of potassium tert-butoxide, then evaporated to dryness under reduced pressure. The residue was dissolved in 25 mL of water and extracted with 2 x 30 mL of ethyl acetate. The ethyl acetate solution was washed with 2 x 10 mL water, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness under reduced pressure. Recrystallization of the residue from 8 ml of diisopropyl ether gave 0.38 g (78% yield) of the desired product, m.p. Mp 136-138 ° C.

¹ H-NMR ^{ektrum P} / CDC1 ₃ · '/ ·. Et: 0.98t (3), H-3: 3.68s / l /, CH ₂ OCO: 4.55m / 2 /, HO-CH ₂ : 3.80m / 2 /, H-15: 6.03s (1), ArH: 6.98-7.96m (8), NH: 8.32.

Example 30

Preparation of 2-methylpropyl-11-benzoylaminoapovincamate monohydrochloride

A solution containing 0.8 g (0.001 8 mol) of 11-benzoylamino-pancincamine and 0.01 g of potassium tert-butoxide in 20 ml of anhydrous isobutanol was heated at reflux for 2 hours, then evaporated to dryness under reduced pressure. The residue was dissolved in 40 ml of dichloroethane and extracted with 4 x 5 ml of water. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness. The residue (0.83 g, 93% yield) is in the form of the base of the title compound, which is dissolved in 15 ml of ether and acidified by addition of ethanolic hydrogen chloride solution to pH 3. The precipitated crystals are filtered, washed with ether and dried to give 0 69 g (72% yield) of the monohydrochloride form of the title compound, m.p. Mp 185-186 ° C.

Analysis for C ₃₁ H ₃₅ N ₃ O ₃ HCl (MW 534.07) calculated: 69.71% C, 6.79% H, 7.86% N, 6.63% Cl; Found:% C, 69.86;% H, 7.00;% N, 7.84. '

Example 31

Preparation of 11-Amininincaminic Acid

A solution containing 2.5 g of potassium hydroxide in 20 ml of water was added to a solution of 2.5 g (0.007 mol) of 11-amino-amine in 100 ml of ethanol, then the mixture was heated under reflux for 30 minutes. After cooling the solution to room temperature, the pH was adjusted to 7 by adding 10% aqueous hydrochloric acid solution. The precipitated crystals were filtered, washed with 2 x 10 ml cold 50% ethanol, and dried to give 2 g (83% yield) of the desired compound. mp 255-256 DEG C. C ^ -id ^{= +32 '4} ° / с = 1, pyridine /.

Example 32

Preparation of 11- (2-fluorobenzoylamino) -vincaminic acid

A solution containing 0.30 g (0.000 6 mol) of 11- (2-fluorobenzoylamino) -vincamine, 5 ml of ethanol and 3 ml of a 10% aqueous potassium hydroxide solution is stirred at 35 ° C for 30 minutes, then adjusted to pH by adding 10% aqueous hydrochloric acid to 7. The precipitated crystals are filtered, washed with 3 x 5 ml of water and dried to give 0.25 g (85% yield) of the desired compound, m.p. Mp 247-249 ° C] = - + 18.6 ° (α = 1, pyridine).

Example 33 ‘

Preparation of 11-benzoylaminoapovincamic acid

To a solution containing 3.67 g (0.001 mol) of 11-nitroapovincaminic acid, 5 ml of ethanol and 10 ml of 1N aqueous sodium hydroxide solution is added 0.04 g of 10% palladium on carbon catalyst and then stirred at room temperature under hydrogen. atmosphere. After uptake of 0.03 mol (720 ml) of hydrogen gas, the catalyst was removed by filtration and washed with 3 x 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 was added dropwise to the obtained solution at room temperature, while optionally maintaining the pH of the reaction mixture by adding 1 N aqueous sodium hydroxide solution at 7-8. The precipitated crystals were filtered, washed with water and dried to give 3.88 g (88% yield) of the desired compound, whose physical properties were the same as the product prepared in Example 1.

Example 34

Preparation of 11-acyclohexylamine-amine

A solution of 1.46 g (0.01 mol) of cyclohexanecarboxylic acid chloride in 20 ml of anhydrous benzene is added in portions over 1 hour to a solution containing 1.85 g (0.005 mol) of 11-amino-amine in 80 ml of anhydrous pyridine at room temperature. stirring. The solution was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue is taken up in a mixture of 50 ml of ethyl acetate and 50 ml of water and basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8. The phases are separated, the ethyl acetate layer is washed with 3 x 25 ml of water, dried and evaporated to a third volume. The residue was left in a refrigerator overnight, the obtained crystals were filtered, washed with cold ethyl acetate and dried to give 1.67 g (70% yield) of the desired product, m.p. Mp 170-174 ° C.

Example 35.

Preparation of 11- (3'-bromopropionylamino) -apovincamine

A solution containing 1.71 g (0.01 mol) of 3-bromopropionyl chloride in 30 ml of anhydrous benzene was added portionwise over an hour to a solution of 2.0 g (0.005 5 mol) of 11-aminoapovincamine in 50 ml of anhydrous pyridine with stirring and ice cooling. . The mixture was further stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue is taken up in a mixture of 50 ml of ethyl acetate and 50 ml of water and basified by addition of concentrated aqueous ammonium hydroxide solution to pH 8. After separation, the ethyl acetate phase is dried and evaporated to dryness. The residue was dissolved in 10 mL of methanol and precipitated by addition of ether, the product obtained was filtered, washed with ether and dried to give 1.5 g (62% yield) of the title compound, m.p. 176 DEG-180 DEG.

Example 36

Preparation of 11-cyclohexylaminoapovincamine

A mixture containing 4.79 g (0.01 mol) of 11-cyclohexylamino-amine (prepared according to Example 34) and 5.5 g of p-toluenesulfonic acid in 220 ml of benzene was refluxed for 6 hours using a water trap, then cooled and 200 ml of water are added. The pH of the mixture was adjusted to 8 by adding concentrated aqueous ammonium hydroxide solution. After extraction, the benzene phase was washed with water (4 x 100 mL), dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness under reduced pressure. After thoroughly trituration of the residue with ether, the obtained crystals were filtered and washed with ether to give 4.0 g (87% yield) of the title compound, m.p. Mp 130-135 ° C.

Claims (1)

A process for the preparation of novel racemic and optically active derivatives of 9- and 11-aminoeburnan carboxylic acids of the formula I wherein: R represents an amino group or an -NH-COR 6 group where it represents a hydrogen atom, an aliphatic hydrocarbon group having 1 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms or a 5- or 6-membered group a heteroaromatic group containing as the heteroatom sulfur or nitrogen optionally substituted by halogen, nitro or alkoxy or groups having 1 to 4 carbon atoms or represents an -NH-SO ₂ -R ₂ group wherein R ₂ represents an aliphatic hydrocarbon group having 1 to 10 carbon atoms carbon atoms or an aromatic hydrocarbon group of 6 to 14 carbon atoms, Rg denotes a hydrogen atom, an aliphatic hydrocarbon group of 1 to 10 carbon atoms, optionally substituted by a hydroxy group, A denotes a hydroxyl group, V denotes a hydrogen atom or A and V together form a valence bond with the proviso that Rg is not a methyl group when R is an amino or -NH-CORg group at the 11-position where R ₁ is a methyl group, A is a hydroxyl group and V is a hydrogen atom, and Rg is not a hydrogen atom when R is an amino group and A and V together form a valence bond and their salts, characterized in that they acylate them optionally after hydrolysis racemically or optically the active 9- or 11-aminoeburnanecarboxylic acid derivative of the formula II or a salt thereof, wherein R ₄ represents a methyl group and the other substituents are as defined above, together form a valence bond, may also be hydrogen, optionally esterify or optionally transesterify the thus obtained the compound is then optionally dehydrated by a racemic or optically active 9- or 11-aminoeburnanecarboxylic acid derivative of the formula I, wherein R and R význam are as defined above, A is a hydroxyl group and V is a hydrogen atom and optionally transesterified transforms the race so obtained or a optically active 9- or 11-aminoeburnanecarboxylic acid derivative of the formula I, wherein R, R,, А and В are as defined above, to the acid addition salt and / or the quaternary salt and / or the racemic product thus obtained is resolved.