LU81145A1 - TETRAHYDROALSTONIN DERIVATIVES AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

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The present invention relates to tetrahydroalstonine derivatives, their addition salts with pharmaceutically acceptable acids, their preparation and their therapeutic use.

Tetrahydroalstonine, a product of natural origin, isolable for example from Catharanthus lanceus and Rauwolfia vomitoria, is known.

Its biological activity has been described in the French patent, 1,397,537 and in the Belgian patent 834,585.

• The derivatives of this application correspond to the following formula 3 A.

"I η ß ch * 2 ° ^ in which R. is a hydroxyalkyl, alkyl or alkoxycarbonyl radical or a 1 J 2 hydrogen atom is either a hydroxyl radical or a straight or branched alkoxy radical of 1 to 6 carbon atoms and which may bear, as substituents, halogens, either a cycloalkyl-alkoxy radical or a cycloalkoxy radical, * or an alkoxy radical carrying a piperidino, morpho lino, piperazino or pyrrolidino group, or a dislkylamino-alkoxy radical, or an amino radical, or an alkylamino radical, either a dialkylamino radical, or a cycloalkylamino radical, or an OMs radical (Me = alkali or alkaline earth metal). with the exception of the canposë-. for which R ^ is H and = Ch ^ O.

The alkyl and alkoxy radicals have from 1 to 6 carbon atoms, the cycloalkyl and cycloalkoxy radicals from 3 to 6 carbon atoms.

The addition salts of compounds 1 (1} to pharmaceutically acceptable acids are part of the invention.

According to the invention, the acid I (R ^ H, R2 = OH) is prepared from | tetrahydroalstonine (R ^ H, R ^ CH ^) or THA by saponification, the esters (I) can be obtained according to conventional methods, notably either by direct esterification of the acid, (by reaction between the chloride of acid and alcohol R2H or one of its alkaline salts either by transesterification of tetrahydroalstonine.

; The amides (1} are obtained from the acid (I) (Rj = H, R2 = OH) or one of its functional derivatives by conventional amidification.

''

The compounds (I) carrying a radical H are obtained from compounds (I) in which is H by conventional reactions I - formylation of the compound, I - reaction of the compound with an alkyl halide, i • - reaction of the compound with an alkoxycarbonyl halide.

; The compounds (I) are active in therapy, in the field of the central nervous system, as antianoxics and as psychotropic I in particular as antidepressants.

! | The following examples illustrate the present invention.

l ·.

IR, NMR, UV and mass analyzes and spectra confirmed the structure of the compounds.

: THA = tetrahydroalstonine.

| Example 1 Didëhydro-16,17 methyl-19C ^ oxayohimbane- I carboxylic acid ~ 16 and its hydrochloride.

H, R2 = Oh]

30 g of THA are introduced into an aqueous potassium solution! colic (21 g of KOH, 600 ml of water and 600 ml of ethanol). It is brought to reflux for 2.5 h.

i i Ethanol is removed by distillation under reduced pressure jus <I, obtaining a residue forming about one fifth of the volume in; 3 #

The residue is dissolved in 1 liter of water, the solution is neutralized with 6N hydrochloric acid until pH = 7 and extracted 6 times with 500 ml of chloroform. The chloroform phases obtained by decantation are combined, washed with water and then dried over anhydrous sodium sulfate.

After filtration, the chloroform is removed in a water bath at 40 ° C under reduced pressure.

25 g of the acid (I) are thus collected.

The hydrochloride of the acid is prepared by dissolving the latter in chloroform and passing a stream of chlorine gas in this solution.

F = 225 ° C with decomposition, = -26.6 ° (c = 0.6; EtOH).

Example 2 Isobutyl ester of didâhydro-16,17-methyl 1 -19 ° acid (oxayohimbane-carboxylic-16 and its hydrochloride.

j \ = H, Ε ^ ΟΟΗ, ςΗ ^ J

9 g of the acid of Example 1 are dissolved in 300 ml of anhydrous and alcohol-free chloroform.

2.35 ml of freshly distilled pyridine on potassium hydroxide are added at once.

2.5 ml of oxalyl chloride dissolved in 10 ml of anhydrous chloroform are added.

The reaction mixture is then left for 3 hours with stirring and at room temperature.

30 ml of freshly distilled isobutyl alcohol are added to the acid chloride solution thus formed. Stirring at room temperature is continued for one hour.

300 ml of distilled water are added and the mixture is evaporated almost to dryness.

1000 ml of water are then added to the oily residue, alkalized with a 10% ammonia solution and four kings are extracted with 400 ml of chloroform. The chloroform phases obtained by decantation are combined, washed with water and then dried over anhydrous sodium sulfate. After filtration, the chloroform is removed in a water bath at 40 ° C under reduced pressure.

4 I '! !

The residue obtained is dissolved in 300 ml of chloroform and stirred.

Ited to. 50 ° C in the presence of 2 g of activated vegetable black. After filtration, the mixture is evaporated at. dry and taken up in a minimum of isobutanol e-: an anhydrous solution of hydrochloric ether is added until pH. The crystals formed are wrung out.

6 g of the hydrochloride of the isobutyl ester are thus collected.

! r Ί 25 F = 250 ° C with decomposition, c <= - * 3.8 ° (c = i; CHCl,}.

\ L J D

* 1 · * Example 3 Morpholino-ethyl ester of didehydro-16 acid ,: | methyl-l9c <oxayohiinbane -carboxylic-16 and its chic | .hydrate, dd 1 ^ Εχ = Β, R2 = 0 (CH2) 2- ‘10.56 g of THA are dissolved in 400 ml of anhydrous benzene distilled over calcium chloride.

690 mg of metallic sodium, previously washed in anhydrous benzene, is added while stirring and under argon, the reaction mixture is left to react for ten minutes and; 4.3 g of morpholino-ethanol are added in 15 minutes beforehand! dissolved in 20 ml of anhydrous benzene and brought to reflux for d. ’5:30 am under argon, in the presence of a molecular sieve.

i After removing the excess of "sodium by filtration, 11.11 l of water are added and the mixture is extracted with benzene. Wash with 100 ml of water, dry over evaporation dry sodium sulphate.

y ^, r The product obtained is dissolved in inethanol and then | hydrochloric ether.

f The hydrochloride crystallizes.

j: F = 305 ° C, j 25 = -12.6 ° (c = 0.54; H2O)

I * DJ D

!vs ! \ -— ·

L

y 5

Example 4 Cyclopropylamide of didehydro-16,17-methyl-19o ^ oxayohimbane -carboxylic-16 acid and its hydrochloride.

[RfS 'R2 = N "^ <iJ

10f5gde: Γ'acid of Example 1 is dissolved in 350 ml of chloroform ✓ anhydrous and alcohol-free.

2.8 ml of freshly distilled pyridine "are added all at once to potash and then 3 ml of oxalyl chloride previously dissolved in 12 ml of anhydrous chloroform is added.

The reaction mixture is then left for 3 hours at room temperature while stirring.

To the acid chloride solution thus formed, 20 ml of cyclopropylamine are added over 15 minutes and the stirring is continued for 30 minutes after the end of the addition.

Add 1 liter of water. The organic layer is decanted and the remaining aqueous phase is extracted 3 times with 500 ml of chloroform. The four organic phases are combined, washed with water and then dried over anhydrous sodium sulfate.

After filtration, the chloroform is removed in a water bath at 40 ° C. under reduced pressure.

_ J The residue is dissolved in the minimum amount of methanol (approximately 20 ml) and anhydrous hydrochloric ether is added until pH = 1.

! The precipitate formed is drained and dried.

i

The amide hydrochloride is obtained.

F = 225-22S ° C, Γ, Ί 25 = -59.7 ° (c = l? DMF).

° <. D

", Example 5 Inethyl ester of 1-hydroxymethyl acid didehy- ~ r 'î' i | dro-16,17 méthy1-19 ° ^ cxayohimbane -carboxylic-16.

J: R1 = GH2OH, R2 = OCH3] To 5g of ΤΞΑ dissolved in 50 ml of chloroform, 200 ml of a 30% aqueous solution of formaldehyde was added in the presence of 1 ml 1; acéuic acid.

The mixture is warmed to 50 ° C. while stirring for 2 hours, then the reaction mixture is left at room temperature for approximately 15 h. f 4 I 6 f, 't i | ‘... · - T”. We pour about 300 ni of distilled water on the i! - reaction mixture. Extraction is carried out 4 times with methylene chloride, or: I it is washed with water; dried over sodium sulfate and then evaporated to dryness.

I The mixture is chromatographed on a column of silica gel using pure chloroform, then using a chloroform mixture, I J metranol C99 / 1) ° n eluted 3 g of the desired product.

I J the product is crystallized from a methyl chloride mixture | I t lene / ether after treatment with vegetable black.

I F = 171 ° C, jc ^ J D = -186e (c = l; CHCI3); 1 Example 6 Methyl ester of 1-methoxycarbonyl acid dideh; J ‘dro-16,17 methyl-lS'X oxayohimbane-carboxylic-16.

I J ^ Rj ^ COOCÎ ^, r2 = och3 J

IA 14 g of tetrahydroalstonine dissolved in 120 ml of dimethyl I 5 sulfoxide, 3.84 g of sodium hydride are added while stirring and I under · argon - i 7.52 g of methyl chloroformate are then added to the i help. bulb with bromine, while stirring and cooling to a temperature; The tuff is close to + 5 ° C. The reaction mixture is left under agitation for 1 hour and water is slowly added (approximately 1 liter). ; I Extracted with ether 4 times, washed with water, dried over sodium sulfati: i then evaporated to dryness.

1 I The product crystallizes from a mixture of methylene chloride / i 1 methano 1 (> /, ^ „p | 15 F = 183 ° C, D = -276.8 ° (c = 1.17; CHCl3): f | The compounds of the invention prepared by way of examples are represented in the following table (I).

; i EC1 = hydrochloride.

i> -; .’Ir.

j; |; · J fa 'I.

7

EXAMPLE 7 Ethoxycarbonyl acid 1-didehydro-16,17 methyl-19 θ ("-oxayohimbane-carboxylic-16

^ "Coo c2h5 f r2 = nh c2h5J

7.4 g of ethylamide of didehydro-16,17-methyl-19C> (-oxayohimbane-carboxylic-16 acid) are added using a dropping funnel,

* - in solution in 70 ml of DMF

in a flask containing 2 g of sodium hydride. The operation is carried out under argon while stirring.

Qn allowed to react for 30 minutes and then 4 ml of ethyl chloroformate are added dropwise.

Cool in an ice bath and add water. Extracted 5 times with ether, washed with water, dried over sodium sulfate and evaporated to dryness. The ether extract is dissolved in a mixture of chloroform and ethanol. Concentrate and leave in the cold. The crystallized product is obtained.

F = 240 ° C 20 CX = -240 ° (c = l. CHC1-)

__ J D J

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TABLE I

i Compound R, R-, F Γ, 25; n "1 '2 co 0.

HCl 1 (exl) H OH 225 HCl - 32 7 2 H OC-H ,. 260 ''

C = 0.835 DMF

3 H OCH - CF, H2gg “20.2

2 3 268 C = 1.025 EtOH

- "- CH_ HCl * i o t; 4 (ex2) H OCH Clf 3 J'0 ^ CH3 c = 1 CHC13 ^ HC1 oi e 5 H 0CH2— <J 268

j C = 1.39 EtOH

O Base

| _ 215 '= = 0.96 EtOB

7 H o (CH2) ^ 3Q5 "15'2

N — f C = 1.5 EtOH

! 8 (ex3) H 0 (CH2) 2V \ Ε ^ 5 "12.6 d; ^ '-' c = 0.54 H-, 0 I 9 h NE2 HC1 - 43.9

j ♦ 240 c - 0.305 EtOH

i · .............. —........ · Ι · ΙΙΙΙ— I I., I ·. · .. 1 ..... 1. He !...! · »'· I; / H ECl - 31.5

I 10 H 23Q

i ^ 'r · b- C = 1 r.tOE

:; 2 “5 i 1 —————— H _ T- -

11 H N

220

C, H c = 0.9 EtOH

; HCl - 59.7 12 (ex4) H N -__

1,225-228 c = 1 DMF

9 TABLE I (continued) ------- „j— - i '" ~~ "·

Compound R. R_ F 25 n ° 1 2 (° C) L ° ^ J d HCl - 131.8

13 H N (CH3) 2280 c = 0.92 EtOH

Base - 186 14 (ex5) CH2OH OCH3 171 c = 1 CHC13 ... Base - 171.8 15 (ex6) CH3 OCH3 183 c = 1.06 CHC13

Base - 276.8 16 coo ch3 och3 174 c = 1.17 chci3

Base - 240 17 (ex7) COO C ^ NH C2H5 24Q c = 1 CHC13

Base - 270.2 18 COO C2H5 CHsO 134 c = l CHC13

Base - 235.6 19 C0 ° CH3 NH C2E5 231 c = 1 CHC13

The compounds of the invention have been subjected to various pharmaceutical tests.

10 | The compounds have indeed been subjected to the hypobaric anoxia test | in the mouse and in the test of the action on the duration of sleep induced by sodium 4-hydroxy-butyrate in the curarized rat.

HYPOBARIC ANOXIA

CD1 strain mice are maintained in an oxygen-depleted atmosphere, by creating a partial vacuum (190 mm of mercury corresponding to 5.25% oxygen).

The survival time of the animals is noted. This time is increased by agents capable of promoting tissue oxygenation and in particular of the brain. The test compounds are administered, in several doses, intraperitoneally, 10 minutes before the test.

The percentages of increase in survival time compared to the values obtained in the control animals are calculated. The average active dose (AMD), dose mistletoe increases survival time by 100%! is determined graphically.

! The AMD of the compounds of the invention varies from 10 to 60 mg / kg per route! i.p · / I: ACTION ON THE DURATION OF "SLEEP"

This action was determined by the influence of the compounds on the duration of the "sleep" induced by socium 4-hydroxy-butyrate (GHB) in the rat paralyzed under artificial respiration in which the electrocorticographic activity is recorded by cortical electrodes .

The compounds of the invention reduce the total duration of sleep by 20 to 40% compared to the controls.

The toxicity of the compounds has been determined intraperitoneally; on mice.

! 30 The LD 50 ranges from 300 to 1000 mg / kg.

11 pharmac The pharmacological study of the compounds of the invention shows that they are active in the test of hypobaric anoxia in mice while being only slightly toxic and that they exert a significant awakening action in the test of "sleep" induced by sodium 4-hydroxy- • butyrate.

The compounds of the invention, having both anti-anoxic activity and psychotropic activity, can be used in therapy. canic for the treatment of the disorders of the vigilance, in particular to fight against the behavioral disorders attributable to cerebrovascular damage and to cerebral sclerosis in, „geriatrics, as well as for the treatment of absences due to cranial traumas, and treatment of depressive states.

The invention therefore includes all pharmaceutical compositions containing the compounds and / or their salts as active ingredients, in combination with any excipients suitable for their administration, in particular by oral or parenteral route.

The routes of administration can be the oral and parenteral routes.

The daily dosage can range from 10 to 200 mg. 1 \ 9.

Claims (4)

12: i Ψ (i " 1. Compounds corresponding to formula (I) A u ç i ^ T | î — ίι'Ύ k. ,. JA CH. | 1> · 3 IH "I I R" 2 χ \ in which R, is a hydroxyalkyl, alkyl or alkoxycarbonyl radical or a hydrogen atom 1 "! R2 is either a hydroxyl radical, i · or a straight or branched alkoxy radical of 1 to 6 carbon atoms and which can carry halogen substituents, or a cycloalkyl-alkoxy radical, or a cycloalkoxy radical, or an alkoxy radical carrying a group piperidino, morpholino, pipërazinO; or pyrrolidino, either a dialkylamino-alkoxy radical, 1 or an amino radical, | tj is an alkylamino radical, i is a dialkylamino radical, î or a cycloalkylamino radical, ïi 1! or a radical OMe (Me = alkali or alkaline-earth metal), \ with the exception of the square for which is H and R2 = CH ^ O. I 1 the alkyl and alkoxy radicals having from 1 to 6 carbon atoms, • the cycloalkyl and cycloalkoxy radicals from 3 to 6 carbon atoms, Ή Lj as well as their addition salts with pharmaceutically acceptable acids. 2 ** r-canriYiï f insf ίΛΏ r3 la f cfr \ ninô · Γΐη nKf icnf 1 OQ pcf pv 2 2. Methyl ester of 1-methoxycarbonyl acid 16,17-didehydro-19-methyl 0> (-oxayohimbane-carboxylic-16. J! M j: 3. Process for the preparation of the compounds according to claim I, - 1 process characterized in that the acid (I) H, R £ = OH JH 13 "e (I) is obtained according to conventional methods notammenn rar esterification of l acid or one of its functional derivatives c: by transesterification of tetrahydroalstonine; Iss amides (I) are obtained by amidification of the acid or one of its functional derivatives; the derivatives (I) carrying a substituent in position 1 are obtained, from the corresponding compounds (I) in which 5. is H1 by formylation or by reaction.with an alkyl or alkoxycarbonyl halide. * 4. Medicinal product, characterized in that it contains a compound as specified in claim 1 or revenciration 2. '„' y \ \ \ V \ '; V. v V / »