CA1215061A - 17-18-dehydro-apovincaminol and process therefor - Google Patents

Abstract

ABSTRACT OF DISCLOSURE

The invention relates to a process for preparing a compound of formula (II) (II) or an acid addition salt thereof which comprises reducing a compound of formula (III) (III) with a selective reducing agent, and where required, forming an acid addition salt of the compound of formula (II) so obtained, and to compounds of formula II. The compounds of formula II are useful as intermediates in the preparation of 17, 18-dehydro-apovincaminol-3',4',5'-trimethoxy-benzoate of formula(I)

Description

The present invention relates to a process for preparing a new intermediate compound of formula II, as de-fined herein after and acid addition salts thereof, and to the compound and salts themselves.
This application is divided out of cop ending parent application serial no. 395,934 filed on February 10, 1982.
According to one aspect of the present invention there is provided a process for preparing a compound of formula (II) 1 o I
(II) /

or an acid addition salt thereof which comprises reducing a compound of E~rmula (III) (III) , with a selective reducing agent, and where required, forming an acid addition salt of the compound of formula (II) so obtained.
According to another aspect of the present invent lion there is provided a compound of formula II above or an acid addition salt thereof.
The invention of the above mentioned parent apt placation relates -to a new polycyclic compound containing a double bond in the D-ring, i.e. the new 17,18-dehydro-apovin-caminol-3'4'5'-trimethoxy-benzoate of the formula (I) UP

Luke 3 \ OH / (I) SHEA

SHEA

and pharmaceutically acceptable acid addition salts there-of. According to another aspect of the invention of the parent application there is provided a method for preparing 17,18-dehydro-apovincaminol-3',4',5'-trimethoxy-beenzoate and pharmaceutically acceptable acid addition salts thereof.
Still another aspect of the invention of the parent application is a pharmaceutical composition which comprises as active in-gradient a pharmaceutically effective amount of the compound of formula /1/ or a pharmaceutically acceptable acid addition salt thereof with at least one pharmaceutically inert carrier or delineate and optionally further pharmaceutically active sub-stances.
The new 17,18-dehydro-apovincaminol-3',4',5'-trimethoxy-benzoate of formula /1/ is prepared starting from 17,18-dehydro-vincamine of formula lea No No Ho lea or 17,18-dehydro-epivincamine of formula (Ivy) SCHICK

2 5 Ivy or a mixture of the compounds of formulae/lVa/ and lob The starting compounds of Eormulae/lVa/ and lob are crown in -the art. It was first suggested by Wenkert J. Am. Chum. Sock ~7/7/l 1580/1965/ 7 that aspidosperma alkaloids can be converted into vincamine alkaloids. As a typical example the transformation vincadifformine vincamone-~ vincamine was discussed.
The hypothesis was proved by Kuthey et at.
/ J. Am. Chum. Sock 93/1/, 255/~971./ 7 and was extended the transformation tabersonine-~ 17,18-dehydro-vincamine.
A synthesis based on the latter conversion is disclosed in the Belgian Patent Specification No. 818.144.
The known starting compounds have a vascotropin activity. The compound of formula I can be prepared by treating compound(s) of formula lea and/or lob with a suitable dehydrating agent, reducing the obtained compound of formula iota/

with a selective reducing agent, preferably a complex metal hydrides and then reacting the resulting compound of formula I I

IT I

IT

obtained with 3,~,5-trimethoxy-benzoic acid or a don-votive thereof capable of acylation and if desired, convert tying the compound of formula (I) obtained into an acid addition salt thereof.
The new compound of formula (I) and pharmacy-tidally acceptable acid addition salts thereof inhibit the phosphodiesterase enzyme activity and are particularly suitable for treating skin diseases accompanied by pathos logical cell proliferation. The compounds have also trophy-lactic effect.
Skin diseases accompanied by a pathological pro-liberation of epidermis are relatively frequent and involve several per cent of population. Diseases of this kind include benign and malignant diseases, such as psoriasis Utopias dermatitis, primary contact dermatitis, allergic contact dermatitis,baso- and spinocellulary carcinoma, ichthyosis, premalignus hyper]ceratosis, light induced courtesies, acne and seborrheic dermatitis. Certain diseases are characteristic for human beings while others may be observed in animals as well.

Since a part of the skin diseases accompanied by a pathological cell proliferation does not occur on animals, e.g. psoriasis, the anti-psoriatic activity of the compounds can only be demonstrated in tests indirectly.

I

- Voyeurs et at. / Arch. Durham 104, 359-365 /1971/ 7 established that the pathol~ca proliferation is accompanied by the decrease ox the level of cyclic adenozine monophosphato camp As it Is well known, c-AMP Is produced by adony1 colas and Is decomposed my p~ospllodi-esters. Voyeurs successfully Influenced psoriasis by agents stimulating the activity of adenyl Seychelles / erg. norepinephrTne/ or Inhlbltlng the ~ctlvtty of phosphodlsst0rase ego. papaverine/.
When planning our model experiments we set out from the assumption that the Inverse of Viruses statement Is also true, I.e. If a compound Inhlplts the activity of phosphodiesterase, this Indirectly renders it probable that said compound is suitable for treating psoriasis or other skin diseases accompanied by a pato~lo~loal cell proll~eratlon. This assumption has been verified, the compound Chilean In vlfro 3 phosphodlesterase Inhibitor activity proved effective In Nikko treatment of psoriasis The model experiments were performed by means of phosphodlesteras0 Isolated from animal tissues / rat brain, cattle brain, cattle heart/, The enzyme was Isolated by the technique ox J. Schroeder and HO Rlch0nberg / Bloc hem. phase. Act 302~ 50 !~973~ 7 whereupon thy phosphodlesterase isolated was purified according to the method of JUG. IIardman and EYE. Sutherland [J. Blot. Comma, 3704 (1965)] and the activity of the purified enzyme was measured by a radio isotopic method developed by G. Pooh, in the presence of an excess amount of c-AMP tricium-labeled /10.1 moles of a c-AMP substrate containing 2,59 K By of camp/, in an incubator. The measurement was first carried out without the inhibitory substance and then in the presence of 17,18-dehydro-apivincamin-ol-3',4',5'-trimethoxy-benzoate as an inhibitor agent, after an incubation time of 20 minutes NO Arch. Pharmacol. 268, 272 /
1971/]. From the test compound a 1 mole stock solution was prepared with aqueous hydrochloric acid solution and different amounts of the stock solution were added to the enzyme proper-ales corresponding to 5 x 10 6, 1 x 10 5 and 5 x 10 5 mole/lit.
of the test compound. A solution of papaverine used as refer-once compound is added to the enzyme propriety in an analogous manner.
The activity of the solutions containing 17,18-dehydro-apovincaminol-3',~',5'-trimethoxy-beenzoate and papaverine was expressed in per cents of -the control enzyme solution without any inhibitory substance, 100 %/. The results obtained on an enzyme isolated from rat brain are as follows:

Test compound The effect of a enzyme inhibitor/ 5 x 10 6 1 x 10 5 5 x 10 5 mole/lit. concentration of the test compound on enzyme activity in % of the control _ _ _ 17 t 18-dehydro-apovincaminol-

3',4',5'-trimethoxy-benzoate.HC1 84.7 40.7 38.6 papaverine.HCl 91.2 89.7 60.5 The tests on an enzyme isolated from cattle brain and cattle hear-t, rest. were carried out in an analogous way. On the basis of the results obtained the enzyme activity was platted against the logarithm of -the concentration of enzyme inhibitor Melissa/ and from the curve inhibitor concern-traction, which resulted in a 50 % decrease of enzyme activity was read off /¦50/. The results obtained are shown in the following table:
¦50 (moles) on phosphodiester-Test compound aye isolated from cattle cattle rat brain heart brain _ _ _ _ _ . . . _ 17,18-dehydro-apovinca-minol-3',4',5'-trimethoxy--benzoate.HCl 15 3 10 _ _ Papaverine.HCl 90 5070 . . . _ . _ . _ The results set forth in the above table clearly show that the new compound of formula I on an enzyme isolated from cattle brain was 6-times, on an enzyme isolated from cattle heart 18-times and on an enzyme isolated from rat brain 7-times more so effective than papaverine used as reference substance.
The first clinical tests were carried out with preparations for topical use, e.g. ointments, creams, solutions, tinctures, pastes, aerosols, etc. containing the new compound of formula X as an active ingredient. More par-titularly, creams containing owe owe OWE 0.25/, and OKAY, rest. owe 17, 18-dehydro-apovincaminol-3',~',5'-trimethoxy-benzoate were employed.
Clinical tests were performed on patients suffering from psoriasis. During the tests the patients have not no-ceiled any systemic, e.g. immunosuppressive, cytostatic or ~lucocorticoid treatment for their basic disease.
Groups of 5 were examined by the so-called plaque method. One side of symmetrical slain lesions was treated by a crime containing the active ingredient in the desired concentration, while on the other side placebo was applied.
The remaining psoriatic sites on the skin were subjected to other topical treatments for example with ointments contain-in flumethasone pivalate and salicylic acid, as active ingredient, which are widely used for the treatment of psoriasis.
The tests were started with creams having a higher active ingredient concentration and then further patients were treated with preparations containing the smallest effective active ingredient concentration. The skin was treated 2 to 3-times a day until the symptoms disappeared or were consider-ably improved /1 to 6 weeks/.
The efficiency was evaluated upon observing three symptoms: inflammation, infiltration and desquamation (peeling). The intensity of the symptoms was qualified by scores between 0 and 3. The total number of scores served as a measure of the reduction of symptoms. The results were evaluated by methods of mathematical statistics. Turing the treatment undesirable side effects have never been observed.
The results are shown in the following table.
0 = no symptom, 1 = moderate symptom, 2 = strong symptoms 3 = very strong symptoms.
Evaluations were made before the treatment /1/, after a one-week treatment /11/ and after a two-week treatment /111/. The results set forth in the hollowing table are the average number of scores total number of scores/number of patient/ for creams containing owe of active ingredient.

Average number of scores Active ingredient Infiltration Inflammation Desquamation I II III I II It I I IT

__ _ _ _ ___ dodder--apovincaminol-3 '4 '5 2,6 I 0,6 2,8 2,2 1,6 2,0 0.8 0,2 -trimethoxy--bonniest The test unambiguously proved that the compositions can successfully be used for treating psoriasis. No side effects effects were observed.
According to an aspect of the invention of the parent application there is provided a process for preparing new17,18-dehydro-apovincaminoe-3',4',5'-trimethoxy-beenzoate of the formula I/

SHEA\

SHEA

and pharmaceutically acceptable acid addition salts thereof by at) treating compound(s) of the formula (Ivy) , N (Ivy) Eye SHUCKS
and/or (Ivy) (Ivy) Eye with a suitable dehydrating agent, reducing the resulting compound of formula (III) 1 (III) SCHICK C~2~-15 so obtained with a selective reducing agent, preferably a complex metal Hyde ride and then reacting the compound of formula (II) (II) EYE C c-2~-~5 obtained with 3,4,5-trimethoxy-ber~.oic acid or a derivative thereof capable of acylation and if desired, converting the compo~lrld of the formula (I) obtain nod into a pharmaceutically acceptable acid addition salt thereof; or a) reacting the compound of formula (III~ with a selective reducing agent, preferably a complex metal hydrides and reacting the new compound of formula (II) obtained with 3,4,5-trimethoxy-benzoic acid or a derivative thereof capable of acylation and if desired, converting the compound of form-via (I) obtained into a pharmaceutically acceptable acid addition salt there-oil or a) reacting the compound of formula (II) with 3,4,5-trimethoxy~benzoic acid or a derivative thereof cap-able of acylation and if desired, converting the compound of formula (I) obtained into a pharmaceutically acceptable acid addition salt thereof.
According to another aspect of the invention of the parent application there are provided pharmaceutical compositions having a phosphodiesterase inhibiting activity, in particular for treating and prophylaxis of skin diseases accompanied by a pathological cell proliferation which come prose as active ingredient a pharmaceutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable acid addition salt thereof with a-t least one pharmaceutically inert carrier or delineate and optionally further, pharmaceutically active substances Lo .. . . .

The new compound of formula (I) is prepared from the known compound(s) of formula (lea) and/or (lob) which are treated with a dehydrating agent. As a dehydrating agent for example sulfuric acid, Lewis acid, formic acid, a mixture of formic acid and a lower aliphatic carboxylic acid halide acetic android or _-toluene-sulfonic acid may be employed. The reaction is preferably carried out in the presence of an organic solvent, preferably a chlorinated hydrocarbon. The compound of formula (III) obtained as a result of this reaction does not contain a center of asymmetry in the position any more.
The compound of formula (III) obtained is then reacted with a selective reducing agent, preferably a come pled metal hydrides For this purpose for example sodium dihydro-bis(2-methoxyethoxy)-aluminate (Renal), lithium-aluminum hydrides etc. can be used. The reaction is per-formed in the presence of an organic solvent, preferably Bunsen or a homologue thereof or an ether.
The reduction results in the compound of formula (11), which is then reacted with 3,~,5-trimethoxy-benzoic acid or a derivative thereof capable of acylat:ion.

Acylatlon Is accomplished In the presence of an organic solvent, preferably Bunsen or a hQmologue thereof, chlorinated hydrocarbons or al1phatle kittens or pyrldlneO If the reaction Is carried out with a 3,4,5-trlmethoxy-benzoyl halide, an cold binding agent Is added to the reaction mixture In an amount equivalent to the halogenlc cold formed in the reaction or In a slight excess. As an cold binding agent for example alkali metal carbonates, alkali metal hydrocarbonates or organic basic amld0s, such us pyrldlne can be employed, If the reaction Is carried out with 3,4,5-tr1methoxy-benzolc cold, a catalytic amount of an cold, preferably hydra-chlorlc acid or sulfuric acid or a carboxyl activator and/or a dehydrating agent Is added to the reaction mixture. As a carboxyl activator for example halo~enated phenols preferably pentachlorophenol, as a dehydrating agent for example NUN ~d1cyclohexyl-carbodilmlde may be employed. The acylatlon Is carried out at a temperature between -20 C and the boiling temperature of the reaction mlxt~rs, preferably ZOO C and 60 C.
The product Is Isolated from the reaction mixture generally by extraction and/or evaporation.
If desired, the product obtained may be con-vented Into an cold addition salt -thereof. Pro-furred representatives of the Inor~anlc cold addition salts are e.g. chlorohydrate, sulfate and pros-plate salts. The preferred organic acid addition salts include the hydrogentartarate, succinate, citrate and ascorbate salts. The salts are prepared by adding an alp Cole, ethereal or acetone solution of the acid component to the product of formula (I). The preparation of salts is carried out at a pi between 3 and 6.
The pharmaceutical compositions contain 0.1 to 8.0 OWE by weight, preferably 0.2 to owe by weight of active ingredient The compositions optionally contain also further pharmaceutically active ingredient, e.g.
antibiotics, cytostatic agent, prostaglandins, ditranol, salicyclic acid, tar, antiinflammatory agents, immune-suppressive agents, glucocorticoids and in case of parent tonal administration focal anesthetics. us a glucocor-tweaked preferably triamcinolon astound is employed. The compositions preferably are finished as formulations suitable for topical, local application, ago. creams, ointments, solutions, joyless, aerosols, aerosol foams, plasters, etc.
The active ingredient preferably is incorporated into a cream, easy to wash down.
Creams are prepared by dissolving the active ingredient in an alcoholic solvent, preferably propylene or dipropylene glycol or a mixture ~2~5~

thereof with water and subsequently admixing the solution obtained with a well smear able skin compatible fatty phase.
The fatty phase may contain Seattle, stroll, cetostearyl alcohol, paraffin oil, glycerine menstruate, etc.
The creams may further contain emulsifying agents, preferably polypoxyethylene-sorbitane moonlit or menstruate and preserving agents, e.g. various benzoic acid derivatives, preferably _-hydroxy-benzoic acid methyl ester.
The creams optionally contain 0.25 to 2.0 % by weight of active ingredient, 45 to 50 % by weight of glycol, 23 to 27 % by weight of paraffin oil, 11 to 15 % by weight of stroll alcohol and further additive(s) up to 100 %.
The active ingredient may be formulated also as an ointment which cannot be washed down with water. In this case the active ingredient is directly incorporated into the fatty phase.
Solutions may be prepared for example with 20 to 40 % by weight of propylene glycol or dipropylene glycol, 40 to 55 % by weight of a 96 % ethanol and distilled water up to 100 %.
Aerosol formulations are prepared by adding a solution of the active ingredient in propylene glycol a teat, preferably isopropyl myristate and a suitable propellant, preferably freon.

I

on aerosol foam ma for example be prepared by adding an alcoholic solution of the active ingredient to a mixture of 0.5 to owe by weight of cetostearyl alcohol, 1 to OWE by weight of bouncily alcohol, 15 to owe by weight of polyoxy-ethylene-sorbitane moonlit or moo-Stewart and 25 to 30% by weight of water followed by the addition of freon.
For parenteral administration preferably inject lion solutions suitable for subcutaneous or intricateness administration are prepared. For this purpose a salt of the active ingredient is dissolved in a owe aqueous sodium chloride solution and the pi of the solution is adjust ted to 5.
The present invention and that of the cop ending parent application is further illustrated by the following examples which are not intended to limit the scope of the inventions in any way Example_ 17,18-Dehydro-apovincamine _ 13.4 g(38 moles) of a 1:1 mixture of a 1:1 mixture of 17, 18-dehydro-vincamine and dodder 14-epivincamine is dissolved in 200 ml. of dry chloroform.
To the solution 20 g. of dry formic acid and 11,3 g. of actively chloride are added and the reaction mixture is allowed to stand for 2 hours. The mixture is then diluted I

with 200 ml. of chloroform whereupon It Is shaken with 550 my Ice-cooled I N aqueous sodium hydroxide solution and subsequently 100 ml. of water The organic phase Is dried on sodium sulfate, filtered and the filtrate is evaporated to dryness. 11.9 9. (35.6 moles) of the title compound are obtained, molting at 110 to 112 C
after recrystalllzat10n from ethanol.
20 _ ~143 (ant, chloroform) Formula C21H2202N2 (molecular weight 334) The same procedure us tolJowed and the end product Is obtained practically with the same yield If pure dodder vincamine or the 14-oplmer thereof is employed as a starting compound.
Example 2 17tl8-Dehydro-a~ovlncaminol A solution of 5.5 I (16~5 moles) of Lowe--dehydro-apovîncamine In 200 ml. of absolute dlethyl ether are added to 5 9. of llthl~luminlum hydrlde In 300 ml. of absolute dlethyl ether dripless, whereupon the reaction mixture Is Bud for one and a half hour. The excess of the reducing avert is then decomposed with water carefully, the mixture Is shaken with water, the ethereal phase is dried on sodium sulfate, filtered and the filtrate is evaporated. The evaporation residue is recrystallized from 25 ml.

L Eye _ I g _ of ethanol to yield 4.8 9. (95 I) of the title compound, melting at 156 to 166 C.
Clue - 26 (c 1, chloroform) Formula C20H220N2 (molecular wright 306) Example 3 _ eye Incaminol-3'~4',5'-~rimethoxy-bonniest ---To a solution of 10 9. (32.7 moles) of 17,18-dehydro-apovlncamlnol in 200 ml. of absolute Bunsen 12 ml. of absolute pyrldlne and 11.2 9. (48 moles) of 3,4,5-trlmethoxy-benzoyl chloride are added The reaction mixture Is kept at 40 C
for one and a half hour, and Is then diluted with 200 ml. of Bunsen. The reaction mixture Is shaken with 120 ml. of Ice-cooled, I N aqueous sodium hydroxide solution and subsequently with 50 ml. of water, the organic phase Is dried on sodium sulfate, flittered and the filtrate Is declared by passing through a column filled with alumina. By evaporation of the declared solution 13.2 9. (By I) of the title compound are obtained, molting at 138 to 140 C after rGcrystalllzatlon from ethanol.
2D0 = ~31.5 (Cal, chloroform) Formula Cowan ( Example 4 17,18-Dehydro-apovincaminol-3',4',5'-trimethoxy-beenzoate hydrogentartarate . .
The product of Example 3 is dissolved in ethanol and a solution ox D-tartaric acid is added until the precipi-station of salt is complete.
The title compound is obtained, melting at 110 to 112 C (decomp.).
34H38OllN2 (molecular weight 650):
calculated: N 4.3 %;
found: N 4.24 %.
u-v- spectrum Max 209, 251, 304, 315 no.

Example _ The preparation of creams 17,18-dehydro-apovincaminol-3',4',5'-trimethoxy-benæoate 2 g.
propylene glycol So g.
paraffin oil 26 g.
polyethylene glycol 400 5 g.
stroll alcohol 15 g.
glycerol menstruate 2 g.
The active ingredient is dissolved in propylene glycol on a water bath the temperature of which does not exceed 50C. The other components are heated up to melt, whereupon are cooled to 40 to 45 C under stirring. To the melt the solution of active ingredient is added under stirring and the cream obtained is stirred until it is cooled ,,-, "

down.
Creams containing 0,25 I, 0.5, 1.0 and 1.5 of active Ingredient con be prepared In an analogous way.

17,18-dehydro-apovlncamlnol-3',4',5'-trlmethoxy-benzoate 1.0 g.
trlamclnolon acetonlde 0.1 9.
propylene glycol 50.9 JO
paraf~lne oil 26.0 9.
polyethylene glycol 400 5.0 9.
stroll alcohol 15.0 9.
glycerol menstruate 2.0 9.
The procedure described on Example 5 Is lot lowed except that two active Ingredients are dissolved In propylene glycol.
~!~ `
17,18-aehydro-apovlnceminol-3',4',5'-trlmefhoxy bonniest 0.25 trlamclnolon acetonlde Owe %
propylene glycol / 30.0 96 % ethanol ad 100.0 A tincture Is prepared by mixing the Ingredients fisted above.

I

Example S . .
17,18-dehydro-apovlncamlnol-3',4',5'-trlm0thoxy bonniest 0.25 kestrel alcohol 1.0 %
bouncily alcohol 2,0 %
polyoxyethylene sorbltane menstruate 15.0 %
96 % ethanol 30.0 %
logon 20.0 distilled water ad 100,0 An aerosol foam Is prepared using the above Ingredients.

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of formula (II) (II) or an acid addition salt thereof which comprises reducing a compound of formula (III) (III) with a complex metal hydride as a selective reducing agent, and where required, forming an acid addition salt of the compound of formula (II) so obtained.

2. A process according to claim 1, wherein the selective reducing agent is an aluminum complex.

3. A process according to claim 1, wherein the selective reducing agent is lithium-aluminium hydride.

4. A process according to claim 1, wherein the reaction is effected in an organic solvent.

5. A compound of formula II as defined in claim 1 or an acid addition salt thereof whenever prepared by a process according to claim 1, 2 or 3, or by an obvious chemical equivalent thereof.

6. A compound of formula II as defined in claim 1, or an acid addition salt thereof whenever prepared by a process according to claim 4, or by an obvious chemical equivalent thereof.

7. A process for preparing 17, 18-dehydro-apovin-caminol which comprises reducing 17,18-dehydro-apovincamine with lithium-aluminium hydride.

8. The compound 17,18-dehydro-apovincaminol whenever prepared by a process according to claim 7 or by an obvious chemical equivalent thereof.