LU85996A1 - NOVEL 11-HYDROXYOXAYOHIMBANE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

# »Λ * 5 10 I 'NEW DERIVATIVES OF TYPE 11-HYDROXYOXAYOHIMBANE AND THEIR-, APPLICATION IN THERAPEUTICS.

15

The present invention relates to new pentacyclic derivatives of the * oxayohimbane type hydroxylated in position 11 and their application in therapy. .

The present invention relates to pharmaceutical compositions having as subject derivatives of., 11-hydroxyajmaijcine, optionally in the form of an addition salt with a therapeutically acceptable acid,> corresponding to formula I: 5 9 6 '' 7 / X 5 d 1 * 4 HO HN \

12 I

H. I

. in which /) R1

Il R ^ represents an aminoalkyl group of type - (CH ^ -N ^ where the ί · · * ν - -> * 2 * 1 R 'groups are either hydrogen atoms or alkyl radicals or form together with l nitrogen atom to which they are attached a heterocycle nucleus of the morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl type, and n is 2 or 3.

5

The starting compounds used in the processes of the present invention are the corresponding 11-methoxylated pentacyclic indole derivatives of formula II:

-rvYY

H, CO 11

3 I

H · · γγ.

The compounds of the invention are more particularly advantageously obtained from the tetraphylline of formula II in which 0 R ^ = CH ^ according to two different schemes.

1st diagram.

~ I \

It has in fact been demonstrated that tetraphylline can be easily X-transformed into the esters of formula JJ in which has the meaning mentioned for the formula. 1. (Belgian patents η ° 764 „950 and 780.854).

5 - These esters are then treated with ταη -reactive such as a halide.

boron for the purpose of demethylation at 11 of the methoxy group according to the technique described in Belgian patent n ° 877.573, to give the esters of formula I..

2nd diagram.

0 It has in fact been shown that tetraphylline can be easily transformed into 11-hydroxyajmalicine of formula I in which R1 = CH ^ ”(Belgian patent n ° 877.573). From 11-hydroxyajmaiicin, it is // also possible to obtain, in a conventional manner, the esters of - "” / ',. V ....

Vt, ’3 1 formula 1, either by hydrolysis of Π-hydroxyajmalicine to 11-hydroxyajmalicinic acid and esterification (Belgian patent n ° 764,950), or by transesterification of ll-hydroxyajmalicine (Belgian patent n ° 780,854).

5

Many derivatives having the oxayohimbane skeleton, including tetraphylline and ajmalicine, have been found to be compounds endowed with interesting cardiovascular properties.

The compounds of the invention have also been found to be active: in de. . numerous pharmacological tests and are therefore likely to be used ‘··.;. * · * as an active principle in medicinal products. In particular, the compounds of. . <the invention have been found to be active as a positive inotropic (cardiotonic). *

This test was carried out on dogs anesthetized with Nembutal and 15 instrumented by a probe introduced by the femoral artery into the left ventricle and for which the dp / dt is recorded continuously.

The substances studied are administered by slow intravenous __ injection (60 seconds) into a superficial vein of the paw.

The positive inotropic activity is compared to that obtained in the same Xr i "η n" ψ · experimental conditions for Ouabain at a dose of 40 pg / kg (digital reference). ί. The table ri-desspus shows ·, the results obtained with the reference ouabain ,; compared with the results obtained with the compounds of the invention.

IS

- - ·· - i --’------------- - „y T * 11 1 1 '” * ”- -

Products Dose i.v mg / kg bw / dt (% increase),

OuabaTne 0.04 40 * la 13 75 •) 0 1 b 16 50 le 12 85 1 d .13 45 1 e 9,5 60 1 f 19 55

The compounds of the invention have been found to be of equal or greater activity than the reference compound well known for its good cardiotonic activity.

l Λ W · "~" v * • 1 4 r ^ "" "1 The following examples illustrate the process for preparing compounds of the invention:

EXAMPLE 1 Hydroxy-11 2-dimethylaminoethyl ajmalicinate, (la) 5

A suspension of 9.6 g of 11-hydroxy-ajmalicinic acid and 9.4 g of potassium carbonate in 200 m! of isopropanol is brought to reflux under argon. After ten minutes, 4.3 g of dimethylamine hydrochloride hydrochloride are gradually added. The flow is continued 0 for five hours, the reaction mixture is filtered and evaporated to dryness.

T * The residue is taken up in ie. methylene chloride, washed with ammonia.

then diluted with water. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue 8.9 g (yield: 77%) crystallizes from methanol.

/ 5

Fus: 183 - 185 ° C.

"Ji *" · (chci; c = i), 0 U, V. (MeOH) x (lodge): 227 (4.62); 300 (3.83) lildX - L R. (KBr): 3580, 3500; 3280., 2980 * 2940, 2860, 2840, 2790, 1690 ,. 1630, 1610 cm "1

S

5.M. : M + at 425 (calculated for = 425 NMR (CDCI3) ξ: 7.73 s (NH); 7.58 s (H1?); 4.33 t (COOCHj); * it 2.37 s (NC- H3 ) 2); 1.08 d (3H 18).

AT

i *. ’5 * m 1 Example 2: Hydroxy-11 ethyl 2-diethylamino-ajmalicinate. (Ib) To a solution of 11.8 g of Ν, Ν-diethylethanolamine in 500 ml of dry toluene, 2.3 g of sodium are added. To the mixture obtained, 36.8 g of 11-hydroxyamalicine are added and the mixture is refluxed under an argon atmosphere for six hours. The reaction mixture is then cooled, washed with water until neutral. The toluene phase is then dried over anhydrous sodium sulfate and distilled to dryness under vacuum. The residue 34.2 g (yield: 75%) crystallizes from ethanol.

10

Fus -152 ° C.

i- a n: - 22 ° (CHCL; c = 1) 15 U.V. (MeOH) λ (logs) 227 (4.61); 299 (3.75)

tUdX

I.R. (KBr): 3590, 3280, 2980, 2910, 2845, 1670, 1620, 1615 cm ”1. SM: M + at 453 (calculated for C2g N3 = 453 ~ '...-. Vj; ... ·. »Z: èr> RMN (CDCI3) 6: 7.67 s (NH}; 7.43 s ( H17); 4.23 t (COOC ^); ^ -. 2.53 q (N (CH3) 2); 1.07 t (N-lCHj-C ^^. L> · / - _ ν '50 6 "+ V" I "" "m 'i Example 3: Hydroxy-Π 2-morpholino ethyl ajmalicinate (Ic) To a solution cooled to -5 ° C of 15 g of 2-morpholino ethyl tetraphyllinate in 550 ml of chloroform, a solution of 25 ml of boron tribromide in 280 ml of anhydrous chloroform is added dropwise, without exceeding 0 ° C. The mixture is stirred for 24 hours at -5 ° C. 150 is then added. ml of methanol and the reaction mixture is poured onto an ice-cold ammonia solution After decantation, the aqueous phase is exhausted with chloroform, the combined organic phases are washed with water, dried over calcium chloride, filtered and evaporated, dried under vacuum. The residue 9, S g (yield = 68%) is "crystallized from ethyl acetate.

f! 5 Fus: 163 - 165.?C.

* a D: - 28 ° (CHCÎ ^ c = 1) U.V. (MeOH) X (log ε): 227 (4.60); 299 (3.79)

’O maX

- • j 'V ^ I.R., (KBr): 3520, 3180, 2980, 2920, 2860, 1705, 1635, 1615 cm - S.M.: M + to 467 calculated for Cn H33 Nj 05 "467 5 Ç-M.N. (CDOJ3) is .: 7.45.5 (H17); 7.37 s (NH); 4.30 t (COOCHj); J 1.13 d (3H 18). ' h m im g ^

Im · 1 Example 4; Hydroxy-11 ajmalidnate of pyrrolidino-2 ethyl. (Idl il; - * · ‘" "^ i! This compound can be prepared by any of the methods described! Above.

: 5 '

Fus: 220 - 222 ° C (ethyl acetate) P - a D: - 28 ° (CHCl3; c = 1) 10 U.V, (MeOHU (lodge): 223 (9, 52); 296 (3.77)

HlOX

'1, R. (KBr): 3280, 2980. 2960, 2990, 2920, 2890. 2820, 2760, 1705, 1625 cm "1 1 15 v SM: M + at 951 calculated for C2fi H33 = 951 NMR (CDC13) 6: 7.77 s (NH); 7.96 s (H17); 9.33 t (COOCHj); 1.08 d (3H 18). ** f ';' \ b! - -: I..

! \

V

i '! 9 'û jt * "ί :::' βί, ~ ρίβ 5: Hyciroxy · - '!) A ;, ui.ed, χ de pipérld ·:' L · ;.. Ss' -". U tse {; <> upare jyav ru v qw ·. “. .h n ... v. ·. · ·· Cî "'d 3?‘ - S.

ï: 170 -, 71 ° C (MeOH) e D: - 22 ° (CHCIj? c “1)

Q

(MeOH) λ (^ χ Uocjr): 227 (4.63); 299 (3..81) '. R, (Kß; ·); 3340, 2940. ^, {j, / J33, 2-S29 2 du, I'10, 1 = .35, • 610 cm ^ S. h). : K * at 4C>: for C_7 H, r NLj 0 ^ ~ Φίϋ R..Μ, N. fCDCI ^ l 5: /, 6 / ï; BARE); 7.50 s (K, ..,); 4, “‘> t {COOC / d,}: d * “t, f, i; l - · * ‘J * î x ^ · £?

,; 3A

; * \ S

/ V

/.

/ * 'remple 6 · Kyoroxy-'l 1 ajmaHcina'e de N r; é'hy; y ^ xïrazîno-2 ethyl. }

This t.o.nosé can be prepared. ; i.cte ', 1LH: Cvi ;; p.: e' J s ** ιη ·. '· {!' · V · c-tc 'F’îs: VJ * i - 1 * î5 ° C (ethyl acetate), a f): - 20 ° (CHC! 3; c = i) Ü.V. (f.teOH) λ. , v Cûqü 5: 226. 60); 298 (3.79) ιΠαΧ I.R. -, KEr); 3570, 3320, r; 30, -2G;>), ib ''}, * 515. Hi}; tV? "'ν" <c. \ ΐ "; at * 180 calculated for C ^ y Nj,. 0J {··· JU0 RMN (CDCI3) ¢: 7.77 s (NH) ï 7," 3 s (Hr /); H, 33 m {; OudH?); | * 2.33 s (N-CH-); 7.10 <J (3H 13),

ί O

>

.V

/ 1 ------- 7 /

Claims (5)

1 V 3 - II ... HO 1H v y * t N, - 'i2 I j! 10 lx 0 R J-DOC v '"\ / 15 in! Ηφ / ΎΪ le il. Represents a ρνοαρβ am.ineaikyle of type - * .v where the' R * groups are followed by hydrogen atoms' 0 of the radicals a.Ykyles or form together with nitrogen to which they feel attached a hey nucleus of the 'morpholinyl, piparidinyl, pyrrolidi · / c.tzinylvi type and n is 2 or 1; and the salts of add t.'.> .i Y ..r'Yr therapeutically ac ··. Ey.YY 25 2. Derivative according to, y,. <·>:> \ In 1 cy ?. - "I £; represents lo n Y .ri ·, ... · '.? IYiyle, 1 P 3, Derivative .v - n the claim in which Ei represents In qivr; pe die .hylamino-2-éthy.Y. 4, "i> é ·; l-vê se c. La r..vend \ · .; stolon 1 in léguai. 3 5th represent the ur ge re, - cl ino- :: '* Y'; t” n , 5, Derivative ne: n la r; harmed this. Y ·> ·. i urn; rag i. î-epréser; .s the grc. this' pyr 1Idino-Y t - ’y *; -t '·' the r. vendieatici, * a? u-q ^ ei Y reprY r- - Y group-v. v..pr? .-- ino-Y-éYe- 1 r. fl- '- De ·· v> se'. ru; In \ n- 'uecur.ioe i. donations Y geel * · Y ‘g, - -. . Y. ’'. Y Λΐ ’I - t! y l --i ^ lté 1. - .. -j Ÿt '. Ιΐγ: * y * 1 · · '·' ï 'r'pÔX ^' C i YiV-, nr \\ "'1 I é: Y · Cr.UV ^ .frYYYir': _. · Υ ',' Υ '- * y. ^ v * * \ ^ <k;' \ t ·: »'i. ·, -jr ^ licine 0 .:: - ·. · ·. -; v ··. ·. 0.' - '-vr the s ·· .. «on i. ·:: · λ whatever ·:.: ·, ·. ·'. ·· * ·; icav .0. * 0 prepare; ·;: drug idea :; repe p os J. '; 7i: - /; 0 i 4 *