NL8302297A - EHOMEBURANE DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

N / 31,514-Kp / Pf / vdM v * - 1 - E-Homoeburnane derivatives, process for their preparation, as well as pharmaceutical compositions containing these compounds.

The present invention relates to novel E-homoeburnane derivatives, to a process for their preparation and to pharmaceutical compositions containing these compounds as the active ingredient. More particularly, the invention relates to novel racemic or optically active E-homo-burnan derivatives of the formula 1 of the formula sheet wherein R and R independently represent an alkyl group having 1-6 carbon atoms, as well as acid addition salts thereof.

In accordance with a further aspect of the present invention there is provided a process for the preparation of racemic or optically active E-homoeburnane derivatives of formula 1, which process comprises carrying out a racemic or optically active octahydroindolo, 2,3-a / quinoline derivative with formula 2 of the formula sheet, wherein A is hydrogen or a -CH 2 -CH (CO 1 R 1) 2 - or -CH 2 -C (CO 2 R 1) 2 -CH 2 -CH (CO 2 R 1) 2 group, wherein R 1 and R are as defined above , R 3 is identical to R 1 or, if A represents hydrogen, R 3 may also represent hydrogen, or an acid addition salt thereof of a cyclization reaction, if desired, the splitting into enantiomers of the compounds of formula 1 obtained and / or conversion of the racemic or optically active compounds of formula 1 in acid addition salts thereof.

The compounds of formula 1 are pharmaceutically active, for example, some compounds from this group, especially those from the cis series, exhibit antidepressant activity, while others, especially the trans series compounds, are potent antihypoxial agents .

According to a further aspect of the invention, pharmaceutical compositions are provided which, as active ingredient, contain at least one racemically or optically active E-homo-burnan derivative of the formula 1 or a pharmaceutically acceptable acid addition salt thereof, in mixture with inert solid or liquid pharmaceutical carriers and / or 8302297 * - 2 - additives.

The term "alkyl group of 1-6 carbon atoms" as used herein refers to straight or branched chain aliphatic hydrocarbon groups of 1-6 carbon 5 atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, n- butyl, sec.-butyl, tert-butyl, n-pentyl, isopenyl, n-hexyl or isohexyl groups, etc.

If desired, the compounds of formula 1 can be converted into their acid addition salts. Suitable acids for this purpose include inorganic acids, such as hydrogen halides, for example hydrogen chloride, hydrogen bromide; sulfuric, phosphoric, nitric, perhaloic acids, for example, perchloric acid, etc; organic carboxylic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymalinic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, p-amino ~ benzoic acid, parahydric acid , paramino salicylic acid, etc .; alkyl sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, etc .; Cycloaliphatic acids, for example cyclohexylsulfonic acid; aryl sulfonic acids, for example p-toluenesulfonic acid, naphthyl sulfonic acid, sulfanilic acid, etc .; amino acids, such as aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutaric acid, etc.

The starting materials of the formula II can be prepared in the manner described in Belgian patent 883,576 by electrophilic alkalization of the corresponding hexahydroindolo [2,3-a] quinolizinium salts with a methylene malonic dialkyl ester and subsequent hydrogenation. if desired, and further partial hydrolysis.

The cyclization of the compounds of formula 2, wherein A represents a hydrogen atom or a CH2-CH (CO2R1) 2 - or -CH2-C (CO2R1) 2 -CH2-CH (CO2R1) 2 group, R3 has the same meaning when R 2 and R 3 and R 3 are as defined above, can be performed with sufficiently strong bases, for example, alkali metal hydrides, such as sodium hydride, potassium hydride, etc., alkali metal alcoholates, such as potassium or sodium ethylate, preferably potassium tert-butylate in aprotic organic 8302297 * «» - 3 - solvents, such as xylene, toluene and preferably benzene. The cyclization is preferably performed at the boiling temperature of the reaction mixture. The reaction is completed in a very short period of time, generally in 10-40 min, preferably even in 15-30 min.

The cyclization of the compounds of the general formula II, wherein A and R represent a hydrogen-1 2 atom, R and R have the meanings already given, is carried out with a dehydrating agent, preferably phosphorus-oxychloride or phosphorus pentoxide, at preferably in an organic solvent that is inert under the reaction conditions, such as aromatic hydrocarbons, preferably benzene or chlorinated hydrocarbons, preferably chloroform or carbon tetrachloride.

When the compounds of formula II are used in the form of their acid addition salts, for example hydrohalides, perchlorates, etc., it is preferable to release the basic compounds from their salts prior to cyclization. The liberation of the bases can be carried out, for example, with a dilute aqueous solution of an inorganic base, such as an alkali metal carbonate, for example sodium carbonate, potassium carbonate, an alkali metal hydroxide, for example sodium hydroxide, potassium hydroxide, etc., in a water immiscible inert organic solvent, such as halogenated hydrocarbons, for example dichloromethane, chloroform, etc .:

Using the process of the invention, both cis and trans compounds of the formula 1 can be prepared from the corresponding cis and trans compounds of the formula 2.

Racemic and optically active compounds of the formula I can also be prepared using the method according to the invention. Racemic end products of the formula I are obtained from racemic compounds, which, if desired, can be cleaved into their enantiomers by customary methods. Optically active end products can be obtained directly from optically active starting compounds.

8302297 * '- 4 -

The racemic or optically active compounds of formula 1 can be converted into their acid addition salts with an organic or inorganic acid.

The salts are generally prepared in a 5-inert organic solvent, for example in an aliphatic alcohol of 1-6 carbon atoms, by dissolving the racemic or optically active compounds of formula 1 in this solvent, adding the corresponding acid to the solution until the pH becomes slightly acidic / pH ca. 6 / and 10 subsequent separation of the resulting acid addition salt from the reaction mixture by preferably precipitating with a water-immiscible organic solvent, such as that jigl

If desired, the racemic or optically active compounds of the formula 1 or the acid addition salts thereof can be subjected to further purification, for example by recrystallization. The solvents to be used for recrystallization are selected in connection with the solubility and crystallizability of the compounds to be recrystallized.

The antihypoxial activity of some compounds within the scope of the invention, in particular of 3S, 17a-trans derivatives, was tested by the survival time of mice under oxygen deficiency conditions at normal atmospheric pressure.

The test was performed as follows

Five male mice were placed in a 3 liter glass cylinder through which a mixture of 96% nitrogen and 4% oxygen was passed. The elapsed time between placing the mice in the cylinder and the death of the animals was measured. Animals that lived at least twice as long as the average survival time of the untreated animals are considered to be protected. The animals are treated in groups of ten, while an intraperitoneal dose of 50 mg / kg body weight was administered at a time 30 min prior to placing the animals in the glass cylinder.

The results are shown in the following table.

8302297 - 5 -

Table

Survival Time Protection

Compound - _ mean, min * * (+) - trans-14-oxo-15-ethoxycarbonyl-E-homoeburnane (3 8.17a) 8.3 + 1.1 + 32 20

Control 6.3 ^ 1.45 - 0

Vincamine 7.1 + 1.30 +13 0 15

In particular, of the compounds of formula 1, the 38,17a-cis compounds are potent antidepressants.

The active ingredients of formula 1 or far-2q maceutically acceptable acid addition salts thereof can be converted into pharmaceutical compositions for parenteral or enteral administration by mixing them with solid and / or liquid carriers and / or further additives commonly used in the preparation of pharmaceutical together-25 statements. As the carrier, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils, for example peanut oil, olive oil, etc. can be used.

The compositions can be finished in the form of solid, eg, tablets, cough pills, dragees, capsules, such as hard gelatin capsules, suppositories, etc., or liquid, eg, oily or aqueous solutions, suspenses, emulsions, syrups, soft gelatin capsules, injectable oily or aqueous solutions such as suspenses, etc. medicaments. The amount of solid carrier can vary within wide limits, but preferably it is between 25 mg and 1 g. The pharmaceutical compositions optionally also contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers, flavors, fragrances, etc. Optionally, other pharmaceutically active compounds are also present in the compositions.

The pharmaceutical compositions are preferably manufactured in dosage units suitable for the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which include, for example, sieving, mixing, granulating, pressing or dissolving the ingredients. The compositions obtained can also be subjected to subsequent operations which are customary in the pharmaceutical industry, such as, for example, sterilization.

Further details of the present invention will be gleaned from the accompanying examples, which, however, in no way limit the scope of the present invention.

Example I.

20 (+) - cis-14-Oxo-15-ethoxycarbohyl-E-homoburane (3a, 17a).

From 800 mg (1.90 mmol) (+) - ethyl -13 - (2 ', 2'-diethoxycarbonylethyl) -1,2,3,4,5,7,12b α-octahydroindole / 2, 3-a / quinolizine hydrochloride, which was prepared according to Belgian Patent No. 883,576, the base was liberated in 25 ml of dichloromethane using 10 ml of a 10% aqueous sodium carbonate solution. After separation, the extraction was repeated with 5 ml of dichloromethane. The organic phases were combined, dried over solid anhydrous magnesium sulfate, filtered and the solvent was removed from the filtrate by vacuum distillation.

The oily residue was dissolved in 15 ml of absolute benzene, after which 258 mg (2.3 mmol) of potassium tert-butylate was added to the solution and the reaction mixture was heated under reflux for 20 min under nitrogen atmosphere.

After cooling, the reaction mixture was neutralized with ice cooling to a pH of 6 using acetic acid, and the solvent was then removed by vacuum distillation. The evaporation residue was dissolved in 20 ml of dichloromethane and the solution was shaken with 10 ml of a 5% aqueous sodium carbonate solution to adjust the pH to 9. After separation, the extraction was repeated with another 5 ml portion of dichloromethane and the organic phase was separated. The combined organic phases were dried over solid anhydrous magnesium sulfate, filtered and the solvent was removed from the filtrate by distillation in vacuo.

960 mg of an oily product was obtained, which was recrystallized on it from 1.5 ml of methanol.

Finally, 480 mg of the desired compound were obtained in a yield of 66.5%.

Melting point 143-144 ° C (ethanol).

IR spectrum (KBr): 1738 (ester), 1690 (lactam) cm 1 ^ '

Mass spectrum (m / e,%): 380 (M +, 100), 379 (35), 363 (20), 352 (17), 351 (26), 335 (12), 323 (9.1), 307 ( 55), 252 (35), 237 (17). ^ H-NMR spectrum (CDCl ^ cT) ï 8.52-7.35 (4H, m, aromatic), 4.31 (2H, q, J = 7.2 Hz, 0CH2), 4.08 (1H , m, 3-H), 3.75 (1H, d, J = 11 Hz, 15-H), 1.34 (3H, t, J = 7.6 Hz, 0CH2CH3) 0.91 (3H, t, J = 8.1 Hz, CH 2 CH 3).

Example II.

(+) - trans-14-0xo-15-ethoxycarbonyl-E-homoburan (3α, ΐ7α).

In 10 ml of absolute benzene, 400 mg (0.94 mmol) (+) -1 ct-ethyl-ltf- (2 ', 2'-diethoxycarbonyl-ethyl) -1,2,3,4,6,7, 12,12b B-octahydroindolo / 2,3-aquinololizine, which was obtained as a by-product in example I of the Belgian patent no. 883,576, on which 125 mg of 30 (1.11 mmol) potassium tert-butylate was added to the solution was added. The reaction mixture was refluxed under nitrogen atmosphere for 20 min.

The pH of the reaction mixture was adjusted to 6 using acetic acid with ice cooling. The solvent was evaporated in vacuo, the residue was dissolved in 10 ml of dichloromethane and the solution was shaken with a 5% aqueous sodium carbonate solution to adjust the pH to 9. The extraction was repeated with a further portion of 8302297 * -8-5 ml of dichloromethane and the combined organic phases were dried over solid anhydrous magnesium sulfate, filtered and the solvent was removed from the filtrate by vacuum distillation. 300 mg of an oily product was obtained, which was recrystallized therefrom from 2 ml of ethanol.

Finally, 260 mg of the desired compound were obtained in a yield of 73.0%.

Melting point 173-175 ° C (ethanol).

10 IR spectrum (KBr) s 2750-2700 (Bohlmann), 1735 (ester), 1680 (lactam) cm-1 »

Mass spectrum (m / e,%): 380 (M +, 100), 379 (38), 363 (14), 352 (11), 351 (16), 335 (11), 323 (5.5), 307 ( 34) ... * ^ H-NMR spectrum (CDClg * 5) s 8.56-7.24 (4H, m, aromatic protons), 4.32 (2H, q, J = 7.6 Hz, 0CH2), 4.08 (1H, dd, J1 = 13.6 Hz, J2 = 2.7 Hz, 15-H), 3.41 (1H, s, 3-H), 1.35 (3H, t , J = 7.6 Hz, 0CH2CH3), 0.74 (3H, t, J = 6 Hz, CH2CH3).

Example III.

(+) - cis-14-Oxo-15-ethoxycarbony1-E-homoburnane 20 (3a, 17a).

From 634.5 mg and 698.0 mg (1 mmol) (+) - 1 -a ethyl-13- (2 ', 2', 4 ', 4'-tetraethoxycarbonylbutyl) -1,2,3,4,6 , 7, 12,12b α-octahydroindolo / 2,3-a7quinolizine hydrochloride d © resp. hydrogen perchlorate was released corresponding base using 10 ml of a 10% aqueous sodium carbonate solution in 25 ml of dichloromethane. The organic phases were combined, dried over solid anhydrous magnesium sulfate, filtered and the solvent was evaporated from the filtrate in vacuo.

The residual oil was dissolved in 15 ml of absolute benzene, to which 145 mg (1.3 mmol) of potassium tert-butylate was added to the solution and the reaction mixture was heated to reflux for half an hour under nitrogen temperature. The reaction mixture was cooled and its pH adjusted to 6 using acetic acid. The solvent was distilled off under vacuum, then the residue was dissolved in 10 ml of dichloromethane, the solution was made alkaline with 10 ml of 5% aqueous sodium carbonate solution to a pH of 9 and extracted with an additional 8302297% on it. 9 - 5 ml portion of aqueous dichloromethane. The organic phases were combined, dried over solid anhydrous magnesium sulfate, filtered and the organic solvent was removed from the filtrate by vacuum distillation. The residual oily product was crystallized from 1 ml of ethanol.

307 mg of the desired compound are obtained in 80.8% yield,

Melting point 143-144 ° C (ethanol).

Example IV.

(+) - cis-14-Oxo-15-ethoxycarbonyl-E-homoburnane (3a, 17a).

The procedure described in Example III was followed starting from 870 mg (1 mmol) (+) - 1a-ethyl-1 (S-15- (2 ', 2', 4 ', 4', 6 ', 6'-hexaethoxycarbonylhexyl -1,2,3,4,6,7,12, -12b-octahydrorndolo / 2,3-aquinololine hydrogen perchlorate prepared according to Belgian Patent No. 883.

576.

264 mg of the desired compound are obtained in a yield of 69.5%. Melting point was 142-143 ° C (ethanol).

Example V.

(3.) -cis-1 4-Oxo-15-ethoxycarbonyl-E-homo-eburnane- (3β <, 17 «<) hydrochloride.

In a mixture of 3 ml of dichloroethane and 2 ml of ethanol, 200 mg of (+) -cis-14-0xo-15-ethoxycarbonyl-E-homoeburnan (3a, 17a) was dissolved and the pH of the solution was adjusted to 2 using hydrogen chloride in ethanol. The reaction mixture was evaporated to dryness and the evaporation residue was crystallized from 1.5 ml of ethanol. 165 mg of the desired compound are obtained in a yield of 75.2%.

Melting point: 2Q4-207 ° C (toluene).

Example VI.

(+) - cis-14-Oxo-15-ethoxycarbonyl-E-homoburnane 35 (3a, 17a).

In 2 ml of absolute benzene, 300 mg (+) - 1 "-ethyl-1 & - (2'-carboxy-2'-ethoxycarbonylethyl) -1,2,3,4,6,7,12, -12ba-octahydroindolo- / 2,3-a / quinolizine prepared according to example V and example VI of Belgian patent 8302297-10 - no. 883,576, suspended in 2 ml absolute benzene and 2 ml phosphorus oxychloride was added to the suspension under ice-cooling. The reaction mixture was then refluxed with stirring for 8-9 h.

The reaction mixture was then cooled and evaporated to dryness under vacuum. The residue was triturated under 2 ml of ice water, the pH was adjusted to 9 using a 10% aqueous sodium carbonate solution and the organic extracted with 3 portions of 2 ml of dichloromethane. The combined organic phases were dried over solid anhydrous magnesium sulfate, filtered and the solvent was removed from the filtrate by vacuum distillation. 225 mg of an oily product were obtained, which was then recrystallized from 0.5 ml of ethanol.

156 mg (+) -cis-14-Oxo-15-ethoxy-carbonyl-E-homoeburnane (3a> 17a) were obtained. Yield 54.3%.

Melting point 142-144 ° C (ethanol).

IR spectrum (KBr): 1725 (ester CO), 1680 (lactam CO) cm "1, 20 8302297

Claims (11)

1. Racemically or optically active E-homoburnane. . 1 2 derivative of the formula 1 of the formula sheet, wherein R and R independently represent an alkyl group having 1-6 carbon atoms, and acid addition salts thereof. Pharmaceutical composition, characterized in that it contains as active ingredient at least one racemic or optically active compound of formula 1, as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof in admixture with inert solid or liquid pharmaceutical carriers and / or additives. Pharmaceutical composition according to claim 2, characterized in that it has a form suitable for parenteral or enteral administration. Pharmaceutical composition according to claim 2 or 3, characterized in that it is in the form of a dosage unit. 5. Process for the preparation of racemic or optically active E-homoburner derivatives of the formula I 12 of the formula sheet, where R and R independently represent an alkyl group of 1-6 carbon atoms, as well as acid addition salts thereof, which process comprises carrying out a racemic or optically active octahydroindolo / 2,3-a7quinoline derivative of the formula 2, wherein A is hydrogen or a -C ^ -CH / CC ^ R ^ or -Cl ^ -C (CO ^^ -) ^ 25 is "CH -, - CH (C0" R ^} - group, where R1 and R ^ are as defined above. 3Z... 1.,. R equals R or, if A stands for hydrogen, R may also represent hydrogen atoms, or an acid addition salt thereof, of a cyclization reaction, optionally splitting into enantiomers the compounds of formula 1 obtained and / or converting the racemic or optically active compounds of formula 1 into acid addition salts thereof. 6. Process according to claim 5, characterized in that octahydroindolo / 2,3-a / quinolizine derivatives of formula 2, wherein A is hydrogen or a -CH2-CH (CO2R ^) or -CH2-CH (CO2R ^) 2-CH 2 ~ CH 2 CO 2 R "^ 2 ~ group is R 3, and R 2 and R as defined in claim 5 are cyclized with a strong base. 8302297 .v - * tf - 12 - 7. Process according to claim 6, characterized in that an alkali metal hydride or an alkali metal alcoholate is used as a strong base. A process according to claim 5, characterized in that an octahydroindolo [2,3,3-a] quinolizine derivative 3 "i of formula 2 wherein A and R represent hydrogen and R and 2 R have the same meaning as defined in claim 5, undergo a cyclization reaction with phosphorus oxychloride. 9. Process according to any one of claims 5-8, 10, characterized in that the cyclization reaction is carried out in an inert organic aprotic non-polar solvent. Process according to claim 9, characterized in that an aromatic hydrocarbon is used as an inert organic aprotic non-polar solvent. 11. A process for the preparation of pharmaceutical compositions, characterized in that at least one racemic or optically active compound of formula 1, as defined in claim 5, or a pharmaceutically acceptable acid addition salt thereof is mixed with inert solid or liquid pharmaceutical carriers and / or additives. 8302297> N / 3-1.514-Kp / Pf / cs Belongs to O.A. in the name of Richter Gedeon Vegyëszeti Gydr R.I in Budapest / Hungary. 'Οζϊ'Φ'ΐ kVr H 2 r1 ° 2C \ H ^ kJ R302CXI R2 8302297