FR2529554A1 - E-HOMO-EBURNANE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME - Google Patents

Abstract

THE INVENTION RELATES TO RACEMIC OR OPTICALLY ACTIVE DERIVATIVES OF E-HOMO-EBURNANE OF FORMULA I (CF DRAWING IN BOPI) OR R AND R ARE INDEPENDENTLY AN ALKYL GROUP WITH 1 TO 6 CARBON ATOMS, AND THEIR SALTS D ADDITION OF ACIDS. APPLICATION: ANTIDEPRESSIVE AND ANTIHYPOXIC AGENTS.

Description

The present invention relates to new

  derived from E-homo-eburnane, to a process for their preparation

  ration and to pharmaceutical compositions containing

  these as an active ingredient More specifically

  Dent, the present invention relates to novel racemic or optically active derivatives of E-homo-eburnane which have the following general formula (I):

/ I /

R 2 C

H in which:

  R 1 and R 2 independently represent a common alkyl group

  carrying 1 to 6 carbon atoms,

  as well as their acid addition salts.

  The present invention also relates to a process for the preparation of racemic or optically active derivatives of E-homo-butane of the general formula

  (I), which method comprises subjecting a racemic derivative

  that or optically active octahydro indolol 2,3-a Jquinoli-

  zine which corresponds to the general formula (II) below

II

  wherein AA is a hydrogen atom or a group -CH 2 -CH (CO 2 R 1) 2 or CH 2 -C (CO 2 R) 2 -CH 2 -CH (CO 2 R) 2, o R and R are as defined above, R 3 is identical to R 1, or, if A represents an atom

  of hydrogen, R 3 can also be a hydrogen atom

gene,

  or an acid addition salt thereof, to a cyclisa-

  tion, to solve, if desired, the compounds of

  mule (I obtained and / or to convert the racemic compounds

  or optically active compounds of formula (I) in their

acid.

  The compounds of formula (I) are pharmaceutically

  actively involved, for example some of their representatives,

  especially those belonging to the cis series, pre-

  feel an anti-depressive activity, while others,

  especially the compounds of the trans series, are of

antihypoxic agents.

  The present invention also relates to

  pharmaceutical compositions which comprise as ingredients

  active ingredient, at least one racemic or optically active derivative of Ehomo-eburnane of general formula (I) or a salt

  addition of pharmaceutically acceptable acid

  that of it, mixed with supports and / or

  inert pharmaceutical additives, solid or liquid.

  By "alkyl group having from 1 to 6 carbon atoms" is meant in the present context straight or branched chain hydrocarbon groups containing from 1 to 6 carbon atoms, for example methyl groups,

  ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert.

  butyl, n-pentyl, isopentyl, n-hexyl or isohexyl.

  If desired, the compounds of formula (I) may

  to be converted into their acid addition salts.

  acids suitable for this purpose include

  such as hydracids, for example hydrochloric acid,

4

  or hydrobromic acid, phosphoric acid, sulfuric acid,

  Furic acid, nitric acid, perhaloic acids as

  perchloric acid, etc., organic carboxylic acids,

  such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, 1 '

  maleic acid, salicylic acid, lactic acid,

  cinnamic acid, benzoic acid, phenylacetic acid, aminobenzoic acid, p-hydroxybenzoic acid,

  p-amino-salicylic acid, etc .; alkylsulfonic acids

  such as methanesulphonic acid, ethane-

  sulfonic, etc .; cycloaliphatic acids, for example

  cyclohexylsulfonic acid; arylsulfonic acids

  such as p-toluenesulphonic acid,

  naphthyl sulfonic acid, sulfanylic acid, etc .; amino

  acids, such as aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetyl-glutaric acid, etc. The starting compounds of formula (II) can be prepared in the manner described in Belgian Pat. No. 883,576, by electrophilic alkylation of the corresponding hexahydroindolol 2,3-a-quinolizinium salts, by

  dialkyl ester of methylene malonic acid and then

  followed, if desired, by partial hydrolysis.

the extra.

  Cyclization of the compounds of formula (II), in which A represents a hydrogen atom or a CH 2 -CH (CO 2 R 1) 2 or -CH 2 -C (CO 2 R 1) 2 -CH 2 group CH (CO 2 R 1) 2 R 3 a

2 2 2 2 1 22

  same meaning that R and R 1 and R 2 are as defined

  above, can be carried out using sufficient bases

  particularly strong, for example alkali metal hydrides

  such as sodium hydride, potassium, etc., al-

  alkali metal coolates, such as sodium ethoxide

  or potassium, and preferably tert-butoxide of

  potassium, in aprotic organic solvents such as

  xylene, toluene and preferably benzene.

  The reaction is preferably carried out at the boiling point of the reaction mixture. The reaction is completed within a very short time, generally within 10 to 40 minutes, and preferably in the space of 15 to 15 minutes.

minutes.

  The cyclization of the compounds of formula (II), in which A and R 3 represent a hydrogen atom and R 1 and R 2 are as defined above, is carried out

  with the aid of a dehydrating agent, preferably oxy-

  chloride or phosphorus pentoxide, preferably in an organic solvent inert under the reaction conditions, such as an aromatic hydrocarbon, preferably

  benzene or a chlorinated hydrocarbon, for example chlorine

  roform or carbon tetrachloride.

  If the compounds of formula (II) are used

  in the form of their acid addition salts, for example

  full of their hydrohalides, perchlorates, etc., it is pre-

  able to release basic compounds from their salts before cyclization The release of bases can be

  for example using an aqueous solution di-

  derived from a mineral base, such as an alkali metal carbonate, for example sodium or potassium carbonate, an alkali metal hydroxide, for example hydroxide hydroxide,

  sodium, potassium, etc. in an inert organic solvent.

  te, immiscible with water, such as a halogenated hydrocarbon, for example dichloromethane, chloroform, etc.

  The process according to the present invention

  to prepare both the cis compounds and the compounds

  trans trans of formula (1) from corresponding cis and trans compounds of formula (II) respectively

  can also be prepared by the process according to

  invention of racemic or optically active compounds

  Formula (1) From the racemic compounds, racemic end products of formula (I) are obtained which, if desired, can be resolved by conventional techniques. Starting from optically active starting compounds, it is possible to obtain directly optically active end products. Racemic or optically active compounds

  of formula (I) can be converted into their

  acid addition, using an organic or mineral acid.

  The salts are usually prepared in a soil

  inert organic compound, for example in an aliphatic alcohol

  with 1 to 6 carbon atoms, by dissolving the racemic or optically active compounds of formula (I) in this solvent, adding the corresponding acid to the solution while the pH becomes slightly acidic (about pH 6) and subsequent separation of the addition salt

  acid obtained from the reaction mixture, preferably

  precipitated by a non-miscible organic solvent

  water, such as diethyl ether.

  If desired, the racemic or optimal compounds

  active ingredients of formula (1), or their addition salts

  of acids, may be subject to further purification.

  for example to recrystallization. The solvents used

  for recrystallization are selected on the basis of the solubility and crystallizability of the

compounds to be recrystallized.

  The antihypoxic activity of certain compounds within the scope of the invention, in particular

  derivatives 3 (, 17 trans, is evaluated by the duration of over-

  life of mice, in normobarometric hypoxia.

  The test is carried out as follows: Five male mice are placed in a 3-liter glass cylinder, in which a mixture of 96% nitrogen and 4% oxygen is passed. The time between the moment is measured. The mice are placed in the cylinders and the one where they die Animals living at least twice as long as the average survival time of the animals

  untreated animals, are considered to be

  The animals are treated in groups of 10, by administering an intraperitoneal dose of 50 mg / kg of body weight, 30 minutes before introducing them.

in the glass cylinder.

  The results are shown in the table below.

BOARD

  Compound Survival Time Protection Average%% (min)

/ I / -Trans-14-oxo-

15-ethoxycarbonyl-

E-homo-eburnane

/ 3, 17 / 8.3-1.1 + 32 20

  Control 6,3-1,45 O Vincamine 7,1-1,30 + 13 0 Among the compounds of formula (I), the compounds

  3 <, 17 o -cis are specific anti-depressants

powerful.

  The active ingredients of formula (I) or their

  acid addition salts acceptable from the phar-

  can be converted into pharmaceutical compositions.

  for parenteral or enteric use, mixing them with

  with solid and / or liquid supports and / or

  very usual additives used in the preparation of pharmaceutical compositions.

  water, gelatin, lactose, starch,

  tine, magnesium stearate, stearic acid, talc,

  vegetable oils, for example peanut oil, from which

  live, etc. The compositions may be formulated into solid formulations, for example tablets,

  lozenges, lozenges, capsules such as

  hard gelatine capsules, suppositories, etc .; or in the form of liquid formulations, for example oily or aqueous solutions, suspensions,

  emulsions, syrups, gelatin capsules,

  aqueous or oily suspensions or solutions

  Injectables The amount of solid support can vary

  within a wide range, but it is

  preferably between about 25 mg and 1 g.

  pharmaceutical positions may also contain

  conventional pharmaceutical additives, such as preservatives, stabilizing agents, wetting agents, emulsifiers, salts capable of adjusting the osmotic pressure, buffers, flavoring agents,

  flavoring agents, etc. Optionally, other

  from the pharmaceutical point of view may also

  be present in the formulations.

  The pharmaceutical compositions are preferably

  manufactured in unit doses, suitable for

  desired mode of administration The pharmaceutical compositions

  may be prepared by conventional techniques,

  which include, for example, sieving, mixing,

  tion, compression or dissolution of the components.

  The compositions obtained may be submitted to other

  operations commonly used in the pharmaceutical industry.

  tick, for example sterilization.

EXAMPLE 1

  Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane / 100% (/) From 800 mg (1.90 mmol) of () -1-ethyl-1-r hydrochloride - (2 ', 2' diethoxycarbonylethyl) -1,2,3,4,6,7,12,

  12b (-octahydroindolo / 2,3-a) quinolizine prepared according to

  Belgian Patent No. 883,576, the base is released in 25

  ml of dichloromethane, using 10 ml of a solution a-

  pig with 10% sodium carbonate After separation,

  the extraction is repeated with 5 ml of dichloromethane.

  The organic phases are combined, dried over sodium

  anhydrous magnesium fate, filtered and the solvent is removed from the filtrate by vacuum distillation. The oily residue is dissolved in 15 ml of absolute benzene and the solution is supplemented with 258 mg

  (2.3 mmol) of potassium tert-butylate and then the

  The reaction mixture is refluxed under an atmosphere of

zote for 20 minutes.

  After cooling with ice, the mixture

  The reaction mixture is neutralized at pH 6 with acetic acid.

  The evaporation residue is dissolved in 20 ml of dichloromethane, the solution is shaken with 10 ml of dichloromethane and the solution is shaken with 10 ml of dichloromethane.

  a 5% aqueous solution of sodium carbonate for

  After separation, the extraction is repeated

  with another 5 ml portion of dichloromethane and

  the organic phase is separated.

  binaries are dried over anhydrous magnesium sulfate solid, filtered and the solvent is removed from the filtrate by

vacuum distillation.

  960 mg of an oily product are thus obtained

  which is then crystallized in 1.5 ml of methanol.

  480 mg of the desired compound are obtained.

Yield: 66.5%.

  Melting point: 143 to 144 ° C (ethanol).

  IR (K Br): 1738 (ester), 1690 cm -1 (lactam).

  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).

  1 H NMR Spectrum (CD C 13, δ) 8.52-7.35 (4H, m, aromatic), 4.31 (2H, q, J = 7.2 Hz, OCH 2), 4.08 (1H, m, 3-H), 3.75 (1H, d, J = 11Hz, 15-H), 1.34 (3H, t, J + 7.6Hz, OCH 2 CH 3) ,

  0.91 (3H, t, J + 8.1 Hz, CH 2 CH 3).

EXAMPLE 2

  (+) - Trans-14-oxo-15-ethoxycarbonyl-E-homo-ébur-

nane (3 o, 17 d,)

  400 mg (0.94 mmol) of (+) - 1? -Ethyl-1 (- (2 ', 2' -

  -diethoxycarbonyl-ethyl) -1,2,3,4,6,7,12,12 b (-octahydroindolol 2,3-a-quinolizine obtained as a by-product in Example 1 of Belgian Patent No. 883 576, are dissolved in 10 ml of absolute benzene, then 125 mg (1.11 mmol) of potassium tert-butoxide is added to the solution. The reaction mixture is heated under reflux in an atmosphere.

nitrogen for 20 minutes.

  The pH of the reaction mixture is adjusted to 6 with acetic acid while the system is cooled.

  The solvent is evaporated under vacuum, the residue

  dissolved in 10 ml of dichloromethane and the solution

  The mixture is shaken with a 5% aqueous solution of carbon dioxide

  sodium nitrate to adjust pH to 9 Extraction is repeated with another 5 ml portion of dichloromethane

  and the combined organic phases are dried over sodium

  anhydrous magnesium fate, filtered and the solvent is removed from the filtrate by vacuum distillation. This gives 300 mg of an oily product, which is then

  recrystallized from 2 ml of ethanol.

  260 mg of the desired compound are thus obtained.

Yield: 73.0% -

  Melting point: 173-175 ° C (ethanol) IR spectrum (K Br): 2750-2700 (Bohlmann), 1735 (ester),

1680 cm -1 (lactam).

  Mass Spectrum (mie,%): 380 (M +, 100), 379 (38), 363 (14),

  352 (11), 351 (16), 335 (11), 323 (5.5), 307 (34)

  NMR spectrum H (CD C 13, -): 8.56-7.24 (4H, m, aromatic protons)

  ticks), 4.32 (2H, q, J = 7.6Hz, OCH 2), 4.08 (1H, dd, J 4 = 13.6Hz Je = 2.7Hz, 15-H) , 3.41 (1H, s, 3-H), 1.35 (3H, t, J = 7.6

  Hz, OCH 2 CH 3), 0.74 (3H, t, J = 6Hz, CH 2 CH 3).

EXAMPLE 3

  (+) - cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnan (3.17 μ) From 634.5 mg and 698.0 mg (1 mmol of hydrochloride and acid perchlorate of (+ ) -1-ethyl-1 r - (2 ', 2', 4 ', 4'-tetraethoxycarbonylbutyl) -1,2,3,4,7,7,12,12b d-octahydroindolol 2,3-a 7 quinolizine respectively, the corresponding base is liberated with 10 ml of a 10% aqueous solution of ca. sodium carbonate in 25 ml of

  dichloromethane The organic phases are combined, separated

  on solid anhydrous magnesium sulphate,

  and the solvent is distilled off from the filtrate

under vacuum.

  The residual oil is dissolved in 15 ml of

  absolute zend, then 145 mg (1.3 mmol) of the tert-bu-

  The reaction mixture is cooled and its pH is adjusted to 6 with acetic acid. vacuum distillation, the residue is dissolved

  in 10 ml of dichloromethane, the solution is alkaline

  10 ml of a 5% aqueous solution of car-

  sodium bicarbonate, until its pH is equal to 9, then extracted with another 5 ml portion of aqueous dichloromethane. The organic phases are combined, dried over

  solid anhydrous magnesium sulphate, filtered and the sol-

  The organic oil is removed from the filtrate by vacuum distillation. The residual oil produced is crystallized in

1 ml of ethanol.

  307 mg of the desired product is obtained.

Yield: 80.8%.

  Melting point: 143 to 144 ° C (ethanol)

EXAMPLE 4

  (+) - Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane

(3.17o).

  The procedure described in Example 3 is repeated starting from 870 mg (1 mmnole) perchlorate.

  (+) - 1 O (-ethyl-1H) - (2 ', 2', 4 ', 4', 6 ', 6'-hexaethoxy)

  carbonylhexyl) -1,2,3,4,6,7,12-12 b-octahydroindolof 2,3-a-7-quinolizine, prepared according to the Belgian patent n

883,576.

  264 mg of the desired product are thus obtained.

Yield: 69.5%.

  Melting point: 142 to 143 ° C (ethanol).

EXAMPLE 5

  (+) - cis-14-oxo-15-ethoxycarbhydrochloride

bonyl-E-homo-eburnane (3 o, 17 Co)

  mg of (+) - cis-14-oxo-15-ethoxycarbonyl-E-

  homo-butane (3%, 17%) are dissolved in a mixture of 3 ml of dichloroethane and 2 ml of ethyl alcohol and

  p H of the solution is adjusted to 2 with hydrochloric acid

  The reaction mixture is evaporated in ethanol

  to dryness and the evaporation residue is crystalline

in 1.5 ml of ethanol.

  165 mg of the desired product is obtained.

* Yield: 75.2%.

  Melting point: 204 to 207 ° C (toluene).

EXAMPLE 6

  (+) - Cis-14-oxo-15-ethoxycarbonyl-E-homo-ébur-

nane (3-X, 17 o 3)

  300 mg of (+) - 1-ethyl-1 - (2'-carboxy-2 '-

  ethoxycarbonylethyl) -1,2,3,4,6,7,12,12 bo-octahydroindolo-

  f 2,3-a? quinolizine prepared according to Example 5 or Example 6 of Belgian Pat. No. 883,576, are suspended in 2 ml of absolute benzene and 2 ml of oxychloride are added.

  phosphorus to the suspension while it is cooled

  by the ice The reaction mixture is then heated

  The mixture is refluxed for 8 to 9 hours with stirring.

  The reaction mixture is cooled and evapo-

  The residue is triturated with 2 ml of ice-cold water, its pH is adjusted to 9 with the aid of

  10% aqueous solution of sodium carbonate and the

  The organic phases are extracted with three 2 ml portions of dichloromethane. The combined organic phases are dried over anhydrous solid magnesium sulphate,

  and the solvent is removed from the filtrate by distillation.

  In a vacuum, 226 mg of an oily product are obtained.

  which is then recrystallized in 0.5 mg of ethanol.

We obtain as follows:

  156 mg of (+) - cis-14-oxo-15-ethoxycarbonyl

E-homo-eburnane (3 o, 17).

Yield: 54.3%.

  Melting point: 142 to 144 ° C (ethanol).

  IR spectrum (K Br): 1725 (CO ester), 1680 (CO lactam).

  As is apparent from the foregoing, the invention is in no way limited to those of its modes of

  implementation which have just been described in an explicit way.

  quotes; it encompasses all the variants that may come to the mind of the technician in the field, without departing from the scope or scope of the present invention.

Claims (11)

claims   1 Racemic or optically active derivatives of E-   homa-éburnan, characterized in that they correspond to the general formula (I) below: N in which:   R 1 and R independently represent a common alkyl group carrying 1 to 6 carbon atoms and their acid addition salts.   2.Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one racemic or optically active derivative of formula (I) according to claim 1, or a pharmaceutically acceptable acid addition salt of pharmaceutical view thereof, in admixture with carriers and / or inert pharmaceutical additives, solid or liquid.   Pharmaceutical compositions according to claim   2, characterized in that they are in a suitable form   parenteral or enteric administration.   Pharmaceutical compositions according to claim   2 or 3, characterized in that they are in the form of his units.   Process for the preparation of racemic or optically active derivatives of E homo-eburnane which have the following general formula (1): "II   wherein R 1 and R 2 are independently an alkyl group   the container of 1 to 6 carbon atoms, and their acid addition salts, which process is characterized by subjecting a racemic or optically active derivative   of octahydroindolo / 2,3-a 7-quinolizine which responds to the   general formula (II) below: / II / wherein A is a hydrogen atom or a group -CH 2 -CH (CO R 1) or -CH 2 -C (CO 2 R) 2 -CH 2 CH (CO 2 RR), o R 1 and 2 22 3 2 2   R are as defined above, R is identical to R 1, or, if A represents a hydrogen atom, R may also   represent a hydrogen atom, or a salt of addition of   of the latter, to a cyclization, in that, if desired, the compounds of formula (I) obtained and / or   the racemic or optically active compounds are converted into   of formula (I) in their acid addition salts.   Process according to Claim 5, characterized in that octahydroindolo / 2,3-a-7-quinolizine derivatives of formula (II), in which A is a hydrogen atom or a -CH 2 -CH (CO) group. 2 R 1) 2 or -CH 2 -CH (CO R 1) 1 -CH -CH 1 3 2 ii 22 (CO 2 R 1) 2, R is identical to R and R and R 2 are as defined in claim 5, are subject to   cyclization using a strong base.   Method according to claim 6, characterized in   an alkali metal hydride or a metal alkoxide   Alkaline tal is used as a strong base.   Process according to Claim 5, characterized in that an octahydroindolol 2,2-a-7-quinolizine derivative of the formula (II), in which A and R 3 represent an atom   of hydrogen and R 1 and R 2 are as defined in the   5, is subject to cyclisation by means of o- phosphorus xychloride.   Process according to any one of the claims   5 to 8, characterized in that the cyclization is carried out   in an aprotic, aprotic, organic, inert solvent.   Process according to claim 9, characterized in that an aromatic hydrocarbon is used as a   apolar solvent, aprotic, inert organic.   Process for the preparation of pharmaceutical compositions   ticks, characterized in that at least one component is   racemic or optically active salt of formula (I) according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, with carriers and / or pharmaceutical additives, inert, solid or liquid.