CA1051899A - Vincamine compounds - Google Patents

Abstract

VINCAMINE COMPOUNDS

Abstract of the Disclosure This invention provides new compounds of formula I, I

wherein R1 is bromine, fluorine, chlorine, hydroxyl, lower, alkyl or lower alkoxy, with the proviso that when R1 is in the 11 or 12 position, R1 is other than methoxy, and pharmaceutically acceptable acid addition salts thereof. These compounds are useful as vigilance-increasing agents.

Description

~18~
VINCAMrNE COMPOU~S

The present invention relates to ne~ hetero-cyclic compounds.
In accordance with the invention there areprovided new compounds of formula I, ~3~N
HO~, ,' CH300C ~

wherein Rl is bromine, fluorine, chlorlne, hydroxyl, lower alkyl or lower alkoxy, with the proviso that when Rl is in the 11 or 12 position, Rl is other than methoxy.
Also provided by the invention are pharmaeeutically aeeeptable aeid addition salts of said compounds.
Lower alkyl or alkoxy refers to 1 to 4 carbon atoms. I j Further, in aceordanee with the invention l ¦
a eompound of formula I as described above may be obtained ~y a process comprising a) eyelising a compound of formula II, 1 ~ ~ II

C~300C(R

lOO-4110 9~

wherein Rl is bromine, fluorinel chlorlne, hyd:roxyl, lower alkyl or lower alkoxy, and R2 is lower alkyl, in the presence of acid, or b~ treating a compound of formula III, ~ \ N ~ III
C1~300CJ~

wherein Rl is as defined above, at a tempera-ture below OC with a hydrogen halide, and subsequently hydrolyzing the resulting reaction product, or c) brominating vincamine to produce a compound of formula I', 3 22 ~ ~

Where necessary or desired, the resulting compound is converted into a pharmaceutically acceptable acid addition salt thereof.

~ ~ -2-- ~5~

Process variant a) may, for example, be effected using a hydrogen h~lide solution, e.g. hydrochloric acid in methanol, aqueous hydrogen iodide or hydrogen bromide in glacial acetic acid. A temperature be~ween 0 and 80C, preferably a temperature between 10 and 60C, may be used.
Reaction step b) may be effected as follows:-The compound of formula III may be allowed to react at a temperature below 0C~ preferably at a temperature from -150C to 20C, with a preferably completely dry and pre-ferably halogen-free hydrogen halide.
Hydrogen bromide is preferred as the hydroqen halide, although hydrogen chloride or hydrogen iodide may also be used.
The reaction solution may be subsequently evaporated to dryness, the residue may then be suspended, at a temperature below 0C, preferably at a temperature from -150C to -20C, in a suitable solvent which does not freeze at the reaction temperature, e.g. acetone or tetrahydrofuran. A suitable water-containing mi~ture which does not freeze at the reactiontemperature, and comprising a solvent such as acetone or tetrahydro'uran, an organic or inorganic base, e.g.
pyridine, sodium hydrogen carbonate or an alkali hydroxide, and water, preferably at a volume ratio of 70:20:10, may subsequently be added. The mixture is conveniently allowed to warm up to room temperature.

, . . .
'i -3 , .. ...

- ~ ~ 100-4110 Process variant c) mav be effected in conven-tional manner for the introduction of bromine into the aromatic nucleus of such compounds. A catalyst such as iron (III) chloride or iron (I~I) bromide, boron tribro-mide, zinc (II) chloride, aluminium chloride or iodine may be used. The reaction may, for example, be effected by suspending optically active or racemic vincamine in an inert solvent, e.g. chloroform, chlorobenzene, methylene chloride.
Suitable temperatures are from -20 to +20C.
Bromine is preferably added in a solution of one of the above inert solvents to vincamine in a similar solution.
A compound of formula II used as starting material in process variant a) may be obtained by reducing a compound of formula XI, 1 r / ~ XI

CH300c(R2o)C=C~l .

wherein Rl is as defined above, and R2 is lower alkyl.

- 5 - 100~4110 ~5~1399 The reduction may be effected either cata-lytically or in the presence of an organometallic com-pound. The catalytic reduction is preferably effected in an inert solvent, e.g. methanol or ethanol, with the addition of a weak base, e.g. potassium acetate or diethylamine. The reaction is preferably effected at room temperature and normal pressure. Of the usual hydrogenation catalysts the preferred ones are palladium catalysts, especially on carriers. When the hydrogen lo take up is complete, the reaction mixture is worked up, e.g. in such a manner that the catalyst is filtered off, the resulting enol ether of formula II, wherein Rl and R2 are as defined above, -- _ is 1solated from the filtrate in known manner, purified and, if desired, any mixture of Z- and E-isomers is separated chromatographically.
The reduction may alternatively be effected with or~anometallic compounds, preferably lithium alu~lnium hydride. The reduction is preferably effected in an inert solvent, preferably cyclic or open chain ethers, e.g. tetrahydrofuran, dioxane, diethyl ether, diglyme or dibutyl ether. The reduction is preferably effected at a temperature between about 0 and 80C.
The decomposition of the reaction complex is subsequently effected in kno~ manner, and the resulting enol ethers of formula II, wherein Rl and R2 are as defined above, are isolated from the reaction mixture and purified.

39~

A compound of formula XI may be obtained by subjecting a compound of formula X, t ; x CH300C(R20)C-C~ ' wherein Rl is as defined above, and R2 is lower alkyl, to a Bischler-Napieralski ring closure.

The reaction may conveniently be effected by dissolving the compound of formula X in phosphorus oxychloride or polyphosphoric acid or a mixture of both, and boiling conveniently in an atmosphere of nitrogen or other inert gas.
Alternatively the ring closure may be effected by dissolving the compound of formula X in a mixture of phosphorus oxychloride and polyphosphoric acid and an inert solvent such as toluene, chlorobenzene or chloxoform, and heating preferably at a te~.perature from 60 to 120C.

~ 7 100-4110 8~3 The resulting immonium salt of formula XI
may be isolated, from the reaction mixture in known manner. The salt of formula XI may be converted into the perchl.orate salt form by precipi.tation with 10%
aqueous sodium perchlorate from a methanolic solution, or by distribution of the immonium salt of formula XI
between 10 % sodium perchlorate/ethanol and methylene chloride.

A compound of formula X may be obtained by condensing a compound of formula IX, ~l /OR2 (C~ )2 ~-Ci~ IX
COOC~

wherein R2 is lower alkyl with a compound of formula VIII, 1 ~ VIII
}I ~
01~ ~

wherein Rl is as defined above.

~0~

The reaction may, for example, be effected in a inert organic solvent, e.g. 1,2-dimethoxyethane, tetra-hydrofuran, dioxane, diethy:L ether or dimethyl formamide.
The reaction is preferably effected in the presence cf a strongly basic condensation agent, e.g.
an alkali metal amide such as sodium amide, an-alkali metal hydride such as sodium hydride, or an alkali metal alcoholate such as potassium tert.butylate or sodium methylate. The reaction may conveniently be effected at room temperature.
The resulting mixture contains the Z and E
isomer forms of the compound of formula X ~7hich may be isolated as such from the reaction mixture in kno~n manner, e.g. chromatoqraphicallyr or further separated into Z and E isomer forms in kno~m manner.

The compound of formula VIII may be obtained by treating a compound of formula VII, ~l ~ VII

(C2~50)2C~

wherein Rl is as defined above, with acid, e.g. aqueous acetic acid, e.g~ under reflux.

1~5~899 A compound of formula VII may be obtained by fusing a compound of formula VI, Rl.- ~ ~ N
~~~ C ~ VI
( C ?.~ 1 5 ) ~ ' ~

wherein Rl is as defined above, with imidaæole.
S A compound of formula VI may be produced by reacting (S)-ethy.l-[3~
toluenesulphonyloxy)prop-l-yl]malonaldehydic acid ethyl ester diethyl acetal of formula IV

~ COOC2H5 ~
(C~ 50)2C ~ 0~ \\0 IV

with a tryptamine derivative of formula V, I~J CH2-~H2-N~12 v wherein Rl is as defined above.

1(~51899 Compounds of formula III used as starting materials in process variant b) may be obtained from the reaction described in process variant a).
A compound of formula I may be obtained in racemic form using racemic starting materials. Alterna-tively a compound of formula I may be obtained in indi-vidual optical isomer form, substantially free from its optical antipode, in conventional manner. For example diastereoisomeric salt frac~ional crystallization may be usedl either of the compound of formula I or starting materials therefor.
Insofar as the preparation of any particular starting material is not particularly described, these compounds may be prepared in conventional manner, or by analogous processes to the processes described herein, or by analogous processes to known processes.
Similarly separation of isomers may be effected in conventional manner.
The free base forms of the compounds of formula I
may be con~erted into acid addition salt forms in the usual manner and vice versa. A suitable acid is hydro-bromic acid.

- 11 - 100-411~

~0~8~g In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.
The optical rotation values refer to measure-ments with chloroform as solvent in all the optically active compounds.

- 12 ~ 100-4110 ~)S1899 EX~MPLE 1: ~3S,14S,16S)-10-fluoro-vincamine and (3S,16S)-10-fluoro-apovincamine ~process variant a)]
10 cc of 33 % hydrogen bromide in acetic acid are added ~o 3.86 g of a mixture of the ~ and E
isomers of 3-[(lS,12bS)-l-ethyl-9-fluoro-1,2,3,4,6,7,12, 12b-octahydro-indolo[2,3-a~quinolizin-1-yl]-2-methoxy-propenoic acid methyl ester, and the mixture is stirred in an atmosphere of nitrogen for half an hour in a bath of 60. Subsequent concentrating by evaporation yields a foam. This is dried at 50/20 mm and pulverized. The residue is dissolved in 20 cc of methylene chloride, added dropwise to 20 cc of 2 ~ arnmonia stirred at 0, the water phase is separated, again extracted with 10 cc of methylene chloride, the 1st and then the 2nd organic phase are washed with 20 cc of the same wash water~ are combined, dried with 3 g of sodium sulphate and concen-trated by evaporation at 30/20 mm. The resulting bro~m foam is chromatographed on 100 g of silica gel 0.05 ~
20 0.20 mmtapplied with methylene chloride/methanol (99 1) on a long thin column, in 100 cc fractions of the same solvent mixture. Fractions 8 to 13 contain the main quantity, fractions 14 to 30 smaller quantities of (3S,16S)-10-fluoro-apovincamine, crystallizable from methanol. The following fractions 31 to 36 are eluted ~D51~9~
with methylene chloride/methanol (98 : 2) and contain (3S,l~S,16S)-10-fluoro-vincamine~

(3S,14S,16S)-10 fluoro-vincamine:

M.P.218 ( dec.) ; ta~D = ~ 4,1 ~1 ~, CHC13).

~I~IR spectrum (C~C13, 100 me ~ -O,B9 (T,7 c.p.s./H3C(21)/3 H) 1,17 ~ 3~ (M /14 H) among them at2,10 + 2,20 (~B,15c.p.s./H2C(15)) 3,80 (S /lI3COOC(22)/3 H) 3,88 (S /~C(3) /1 ~) 4,62 (S /I~OC~l~) /1 H jexchangeable) 6,66 - 7,20 (~`I /IIC(9,1~.,12)/3 ~) (3S,16S)-JO-fluoro-apovincamineo ~ P 17~ o; ~20 _ + 155 (1 %, CHC13).

NM~ spectrum (CDC13, 100 megacycles per second):

1,01 ~T,7 c.p.s./H3C(21)/ 3 H) 1,22 ~ 3'~3 (M / 72 H) among them ~ 1,91 (Q,7 c.p.s./H2C(20)) 3,93 (S /H3COOC(22~/3 H) 4,11 (S /HC(3) /1 ~) 6,1q (S /~C(15) /1 ~
6,70 - 7,27 (M /HC(g,11,12)/3 ~I) - 14 ~ 100-4~10 ~gl S189~
The 3-~(lS,12bS)-l-ethyl-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-indolo~2,3-a~quinolizin-1-yll-2-methoxy-propenoic acid methyl ester, used as starting material, is produced as follows:
a) tS)--3-ethyl-3-diethoxymethyl-1-~2-(5-fluoro-indol-3-yl)-ethyl~-2~ eridone 100 millimols of crud~ (S)-ethyl-[3~
toluenesulphonyloxy)-prop-l-yl.~-malonaldehydic acid ethyl ester dieLhylacetal are dissolved in 50 cc of dimethyl sulphoxide at a bath temperature of 30, a solution of 17.82 g of 5-fluoro-tryptamine in 50 cc of dimethyl sulphoxide is slowly added while stirring, and stirring is effected at 30 for 16 hours~ 200 cc of a

2 ~ sodium carbonate solution and 100 cc of toluene are subsequently added dropwise at 23 while stirring. The resulting mixture is filtered and washed with 50 cc of toluene. The water phase of the filtrate is separated, extraction is effected with 50 cc of toluene and both toluene phases are successively washed with 200 cc of the same mixture water/ethanol (80 . 20). The combined toluene phases are stirred with 20 g of sodium sulphate, filtration and evaporation at 40/20 mm are effected, whereby crude (S)-2-ethyl-2-diethoxymethyl-5-~2-(5-fluoro-indol-3-yl)ethylamino¦-pentanoic acid ethyl ester results as yellow, clear oil. The so obtained product may be - 15 ~ ~ ~ Sl 8~ g 100-4110 used without further purification for the reaction with imidazole~
This crude material is mixed with 100 g of imidazole. The mixture is melted at 100 and left at 130 in an atmosphere of nitrogen for 20 hours. After cooling the reaction solution to 100, the melted material is poured into 80 cc of toluene having a temperature of 100. The solution which is cooled while stirring begins to form crystals at ~5, and at 0 is a mash whlch can still be stirred. 300 cc of 6 ~ hydrochloric acid are added dropwise to this mash at 0 with stirring and strong cooling. The water phase is separated in the cold, exLraction is effected with 50 cc of toluene, and both toluene phases are washed with 100 cc of the same aqueous 2 ~ ammonia solution. After concentrating the combined toluene phases by evaporation at 40/20 mm, a yellowish oil is obtained, ~hich is chromato~raphed on 50 parts of silica gel with methylene chloxide/methanol (98 : 2) in fractions of 25 parts. The combined residues of fractions 8 to 10 yield white crystals after crystalli-zation from ethyl acetate~hexane (20 : 80) at 0, M.P. 101; [~2D= + 6.7 (1 %, CHC13), of the title compound (a) 1~5~899 b) (S)-3-ethyl-3-formyl-1-~2-(5-fluoro-indol-3-yl)-.________ ________ _____.____________________ ___ ethyl~-2-~ieeridone 39.05 g of (S)-3-ethyl-3-diethoxymethyl-1-[2-(5-fluoro-indol-3-ylj-ethyl]-2-piperidone are mixed with 80 cc of 99 % acetic acid and 20 cc of water. The mixture is heated to the boil for half an hour in an at-- mosphere of nitrogen. After cooling, the solvent is re-moved by evaporation; the oily residue is subsequently taken up twice in 50 cc amounts of toluene and again concentrated by evaporation in order to remove most of the water and acetic acid. After crystallization from ethyl acetate/hexane (1 : 2) at 0, brownish crystals are obtained. M.P. 116, [a~ D= -31.5 (1 %, CHC13).

~) 3- ~S)-3-ethyl-1-[2-(5-fluoro-indol-3-yl)-ethyl]-2-__ ______________________________________________ oxo-3-pi~eridyl~-2-methoxy-~o~enoic acid methyl ester _ _ _ _ _

3.185 g of dimethylphosphonomethoxyacetic acid methyl ester are added dropwise at room temperature to a suspension of 360 mg of sodium hydride in 10 cc of absolute tetrahydrofuran in the absence of moisture.
After stirring at room temperature for 30 minutes, a solution of 3.164 g of (S)-3-ethyl-3-formyl-~-~2-(5-fluoro-indol-3-yl)-ethyl]-2-piperidone in 10 cc of ab-solute tetrahydrofuran is added dropwise to the reaction solution. The reaction mixture is subsequently stirred - 17 - ~S~9 100-4110 at room temperature for a further 2 hours, is poured on ice and ex~racted with methylene chloride. The organic phases are dried and concen~ration is effected. A
yellowish oil is obtained, consisting of a mixture of the ~ and E isomers of 3-~(S)-3-ethyl~ 2-(5-fluoro-indol-3-yl)-ethyl]-2-oxo-3-piperidyl~--2-methoxy-propenoic acid methyl ester.

d) (S)-l-cthyl-9-fluoro-1-(2-methoxy-2-methoxycar~on vinyl)-2,3,a,5,7,12-hexahydro-lH-lndo~o[2,3-al-~uinol~zin-5-ium perchlorate

4.025 g of a mixture of E/~ isomers of 3-S(S)-3-ethyl-1-[2-(5-fluoro-indol-3-yl)-ethyl]-2-oxo-3-piperidyll,-2-methoxy-propenoic acid methyl ester are dissolved in 5 cc of phosphorus o~ychloride, and the solu-tion is boiled in an atmosphere of nitrogen for 3 hours.The solution is subsequently evaporated at 60 and 20 mm, and suhsequently at 60 for 15 minutes in a high vacuum.
After taking up in 10 cc of chloroform, evaporation is repeated in analogous manner, whereby the crude iminium chloride is o~tained as yellow-brown foam. 20 g of silica gel 0.05 - 0.20 mm are applied on a colurnn with methylene chloride, the crude iminium chloride is dissolved in methylene chloride at 30 and placed on the column. Washing is then effected with methylene chloride until shortly before the appearance of the clearly ~5~99 - 18 - 100-~110 visible, dark brown zone on the column outlet (100 -200 cc). Elution is subsequently effected with 120 cc of methylene chloride/methanol (90 : 10) and this eluate is concentrated by evaporation at 30/20 mm until a foam is o~ained.
50 cc of 10 % sodium perchlorate are added to water at 0, and the solution of the above foam in 5 cc of methanol is added dropwise while stirring.
The light yellow precipitate is filtered at 0, is washed twice with 20 cc amounts of water and suction-dried. Water is removed by distillation from the residue at 20 mm and a bath temperature of 30 until a solution results. This is added dropwise at 0 to 50 cc of sodium perchlorate (10 %), the precipitate is filtered in the cold, is washed 6 times with 20 cc amounts of water having a temperature of 0 and is suction-dried.
Drying is subsequently effected, whereby the title com-pound is obtained in the form of an E and Z isomer mix-ture.

e) 3-[(lS,12bS)-l-ethyl-9-fluoro-1,2,3,4,6,7,12,12b-_________________________________________________ octahydro-indolo r 2~3-a~quinolizin-1-yl~-2-methoxy-____________________ __ _________________________ ~ropenoic acid methyl ester _______________ _______ The E and Z isomer mixture of (S)-l-ethyl-9-fluoro-1-(2-methoxy-2-methoxycarbonylvinyl)-105~89~
100-411~

2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a~quinolizin-5-ium perchlorate is dissolved at 30 in 10 cc of methylene chloride/ethanol (80 : 20), and the solution is added to a prehydrogenated mixture of 982 mg of potassium acetate, 2 g of 10 % Pd on charcoal and 8 cc of ethanol, as well as 2 cc of water.The mixture is then hydrogenated at room temperature and normal pressure,while stirriny, until 8 millimols of hydrogen have been taken up and hydrogen consumption practically stops. After filtering through "Hyflo", and washing with 20 cc of methylene chloride/
ethanol (80 : 20), the filtrate is concentrated by eva-poration at 30/20 mm, the residue is disso7ved in 20 cc of methylene chloride, mixed at 0 with 20 cc of 2 N
ammonia and divided. The organic phase i5 separated, extracted with 10 cc of methylene chloride, the 1st - and 2nd methylene chloride phases ~ washed with 20 cc of the same water, combined and dried with sodium sulphate.
The reaction mixture is concentrated by evaporation at 30/20 mm, pulverize~, and dried in a high vacuum, whereby a mixture of the Z and E isomers of 3-~(lS,12bS)-l-ethyl-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-indolot2,3-a~- 1 quinolizin-l-yll-2-methoxy-propenoic acid methyl ester is obtained in crude form as yellow-brown residue.

* Trademark for a brand of diatomaceous earth, used as a filtering agent.

~,,~ -19-~S1~9 100-4110 EXA~PL~ 2- (3S,14S,16S~-10-fluoro-vincamine [process variant b)]
1 cc of absolutely dry and bromine-free hydrogen bromide is condensed with 354.4 mg of (3S,16S) 10-fluoro-apovincamine at -78. ~fter stirring at -78 for 15 minutes the resulting solution is evapor-ated to dryness at -78 and a pressure of 20 mm, the reaction vessel is filled with dry nitrogen, and evacuation and filling with nitrogen are repeated twice.
The residue is first suspended at -78 in

5 cc of acetone having a temperature of ~78, 1.5 cc of 10 N potassium hydroxide are subsequently added at -40 while stirring vigorously, the resulting mash is stirred at -40 for 1 hour and is neutralized with 1 g of solid carbon dioxide while stirring. The reaction mixture is subsequently divided ~etween 20 cc of methylene chloride and 7 cc of 2 N ammonia, the aqueous phase is extracted with 10 cc of methylene chloride and both methylene chloride phases are successively washed with 5 cc of the same wash water, dried with sodium sulphate and concentrated by evaporation.
The residue is (3S,14S,16S)-10-fluoro-vincamine with small amounts of (3S,16S)-10-fluoro-apovincamine and (3S,14R,165)-10-fluoro-14-epivincamine as by-products. Crystallization ~rom toluene yields (3S,14S,16S)-10-fluoro-vincamine, having the characteristics indicated in Example 1.

21 10518~ 100-4110 (3R,14R,16P~)-10-fluoro-vincamine, having the same characteristics as (3S,14S,16S)-10-fluoro-vincamine, but an inverse direction of rotation, is obtained in analogous manner, using (3R,16R)-10-fluoro-apovincamine as starting material.
Racemic 10-fluoro~vincamine is obtained in analogous manner, using racemic 10-fluoro-apovincar~ine as starting material; M.P. 230 (decomp.).

EXAMPLE 3. (3S,l S)-10-methoxy-apovincamine, (3S,16S)-10-hydroxv-a~ovincamine, (3S,14S,16S)-10-methoY.y-vincamine, and (3S,14S,16S)-10-hydrox~y-vinca}r,ine [process variant a)]
10 cc of 33 g6 hydrogen bromide in acetic acid are added to 3.985 g of a mixture of the Z and E
isomers of 3- ~(lS,12bS)-l-ethyl-9-methoxy-1,2,3,4,6,7,12,12~
octahyd.ro-indolo[2,.3-a]quinolizin-1-yl]-2-methoxypropenoic acid m~ethyl ester, and stirring is effected in an atmosphere of nitrogen for half an hour in a bath of 60~
Subsequent concentrating by evaporation gives a foam.
This is d~ried at 50/20 mm and pulverized. The residue is dissol.ved in 20 cc of methylene chloride, is added drop~"ise to 20 cc of 2 N ammonia stirred at 0, the water phase is separated, extracted ~,rith 10 cc of methylene chloride, the 1st and then the 2nd organic phase are washed with 20 cc of the same wash water, are - 22 - ~51~ 100-4110 combined, dried with 3 g of sodium sulphate and concent-rated by evaporation at 30/20 mm. The resulting brown foam is chromatographed on 100 g of silica gel 0.05-0.20 mm, applied with methylene chloride/methanol (96:~ on a long, thin column, in 100 cc fractions with methylene chloride containing ~-10 ~ of methanol.
The products are eluted in the following sequence: with methylene chloride/methanol (96:4) (3S,16S)-10-r.ethoxy-apovincamine, then (3S,14S,16S)-10-methoxy-vincamine; with methylene chloride/methanol (90:10) (3S,16S)-10-hydroxy-apovincamine, then (3S,14S,16S)-lO~hydroxv-vincarine. (3S,16S~10 methoxy-apovincam1ne may be crystallized as hydrobromide from isopropyl alcohol, (3S,16S)-10-hydroxy-apovincamine as base from toluene.

- 23 ~ 99 100-4110 (3S,16S)-10 _ethoxv-apovincamine M.P~(hydrobromide) = 235 ~ dec. ~ ]D ((ob 25) CEICl ) IR spectrum (CDC13, ~00 :megacycles per second):

1,02 ~T, 7c.p.s/~13C(21) / 3 H) 1,20 - 3,~4 (~`I / 12 ~) among them at l,g2 (~, 7 c.p.s./ H2C(20) ~5 (S / ~3~--0-C(10) / 3 ~l) 3993 (S / H3Cooc(22~ /3 ~I ) 4,13 ~S / ~IC(3) / 1 ~)

6,10 (S / ~IC(~-5) / 1 H) 6,7~ (Q, 9 + 3 cps./~C(ll) 1 ~I ) 6,91 (D, 3c.p.s.~HC(9) /1 1~)

7,13 (D, gc~p~s~Hc(l2) / 1 1~) _3S,16S)-]0-hydroxy apovincamine ~20 _ ~ 121 (0,25 ~J ~ C ~ iCl 3 ) ~R spectrum (CDC13, 100 megacycles per second):
1,00 (T, 7c.ps./~T3C(213 / 3 I~) 1,23 - 3,51 (J;i . /12 ~I) among them at 1,92 (Q, 7c.p.s./H2C(20) 3,92 (S / ~13~00ct22) / 3 H) 4,16 ~S / ~C(3) / 1 }'~
ap. 6 ~br. S / ~IO-C(10), exchangeable / 1 H) 6~07 (S / ~1~(15) / 1 }~) 6,68 ( Q~ g ~ 2C-P S~ .C(ll) / 1 ~) 6,83 (D, 2c.p.s/HC(9) ~ 1 H) 7.7 (]~I 9c.p.s/HC(12) / 1 }I) - 24 - ~05~99 1~0-4110 (3S,14S,16S) ~0- methoxy-vincamine M P 160 ;~a~ 20 = ~ 16,2 (0,3 ~, C~C13~, N.~ s~ectrum (C~Cl.~, 100 megacycles per second):
19 (T, 7c-ps-/X3C(21) / 3 }I) 1,~2 - 3,~3 (M /1 among them at 2,09 ~ 2,20 (AB, 14 c.p.s.~2C(15) 3,80 ~- 3,~2 (2 S / H3C-0 C(10) ~ H3COO(~) / 6 H) 3,~8 (S / ~C(3) / 1 ~I) 4,60 (S 1HO-C(14), exchangeable / 1 ~) 6,72 (~, 9 ~ 3 c.p.s./~C(ll) / 1 H) 6,~G - 7,20 (~I / ITC(9) -~ IIC(12) / 2 ~J) (3S,14S,l~S)-10- hydroxy-vincamlne M.P. (hydrogen fumarate)= 207 (dec.) ~J2)0 ( base) = -~ 25,1 (0,25 ~, CHC13).
N~,~ spectrum (C~C13, 100 megacycles per second):
0,~9 (T, 7 c.p.s;/H3C(2i) / 3 ~I) 1,14 - 3,51 (~ 14 H) among them at 2,11 ~ 2,21 (AB~l4c~p~s~/H2c(l5) 3,82 (S /~3COOC(2~) / 3 ~I) 3,9S ~s /~c(3) / 1 ~1) ap~ 4,7 (br. S /HO~C(10) + ~iO-C(14), exchangeable / 2 H~
6,64 (Q, 9 + 3 c-p.s./HC(ll) / 1 ~) 6,77 - 7,03 (M / ~C(9) ~ HC(12) / 2 H) - 25 - ~ 9 ~ 100-4110 The 3-[~lS,12bS)-1-ethyl-9-methoxy-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizin-l-yl]-2-methoxypropenoic acld methyl ester, used as startlng material, is produced as follows:

a) 1S~-3-ethyl-3-formyl-1-[2-(5~me'hoxy-indol-3-yl)-ethy ll_ 2_~ r ldone 100 millimols of crude (S)-ethyl-[3-(p-toluylsulphonyloxy)-prop~l-yl]-malonaldehydic acid ethyl ester diethyl acetal are dissolved in 50 cc of dimethylsulphoxide at a bath temperature of 30, a solution of 19.02 g of 5-methoxy-tryptamine in 50 cc of dimethylsulpho~ide is slowly added while stirring, and stirring is effected at 30 for 16 hours. 200 cc of a 2 N sodium carbonate solution and 100 cc of toluene are subsequently added dropwi.se at 23 ~hile styrring.
The resulti.ng mixture is filtered and washed with 50 cc of toluene. The water phase of the filtxate is separated, eY.traction is effected with 50 cc of toluene, and both toluene phases are successively washed with 200 cc o~
the same mixture water/ethanol (80:20). The combined toluene phases are stirred with 20 g of sodium sulphate, filtered and concentrated byevaporation at 40/20 mm, whereby crude (S)-2-ethyl-2-diethoxymethyl-5-[2-(5-methoxy-indol-3-yl)-ethylamino]-pentanoic acid ethyl ester ls obtained as brown oil. The so obtained product may he used without further purification for the reaction in imidazol.

- - 26 ~ 5~ ~9 9 103-4110 This crude ma~erial is mixed with 100 g of imidazol. The mixture is melted at 100 and left at 130 for 20 hours in an atmosphere of nitrogen. After cooling the reaction solution to 100, the melted material is poured into 80 cc of toluene having a temperature of 100.
The solution cooled with stirring begins to form crystals at 45, and at 0 is a mash which can still be stirred. 300 cc of 6 N hydrochloric acid are added dropwise at 0 to this rnash while s~irring. The water phase is separated in the cold, extrac~ion is effected with 50 cc of toluene, and both toluene phases are washed with 100 cc of the same aqueous 2 N ammonia solution. The combined toluene phases yield a brown oil [diethoxyacetal of the title compound a)] after concen~ra-ting at 40/20 mm. This oil is mixed with 80 cc o~ 99 acetic acid and 20 cc of water. ~he mixture is heated to the boil for half an hour in an atmosphere of nitrogen.
After cooling the solvent is evaporated; the oily residue is su~sequently taken up twice in 50 cc amounts ol toluene and again concentrated ~yevaporation~, in order to remove most of the water and acetic acid.
A rough chromatography on 10 parts of silica gel 0.05-0.20 mm with methylene chloride : ~ethanol - 98:2 in fractions, corresponding to 5 parts, yields in fractions 5-12 a yellow oil, which may be crystallized from ethyl acetate : hexane = 3:7 at 0. White crystals of (S)-3-ethyl-3-formyl-1-[2-(5-methoxy-indol-3-yl)-ethyl]-2-piperidone are obtained.

lOS~B99 - 27 - 100~4110 M.P. 108; [a]D = -24.3 l~ 1 %, CHC13).
b) 3- ~S)-3-ethyl-1-[2-(5 methoxy-indol-3-yl)-ethyl~-2-oxo-3-~i~eridyl}-2-methoxy-~ro~enoic acid ~ethyl ester _ _ _ _ _ _ _ _ _ _ _ 3.185 g of dimethylphosphonomethoxyacetic acid methyl ester are added dropwise at room temperature to a suspension of 360 mg of sodium hydride in 10 cc of absolute tetrahydrofuran in the absence of moisture.
~fter stirring at room temperature for 30 minutes, a solution of 3.284 g of (S)-3-ethyl-3-formyl-N-[2-(5-methoxy-indol-3-yl)-ethyl]-2-piperidone in 10 cc of absolute tetrahydrofuran is added drop~7ise at room temp-erature to the reaction solution ~7hile stirring for 30 minutes. The reaction mixture is subsequent,ly stirred at room temperature for a further 2 hours, poured on ice and extracted with methylene chloride. The organic phases are dried and concentrated. A yellowish oil, con-sisting of a mixture of the Z and E isomers of 3-~(S)-3-ethyl-1-[2-(5-methoxy-indol-3-yl)ethvl]~2-oxo-3-pipe~idyl~-2-methoxy-propenoic acid methyl ester, is obtained.
c) ~S)-l-ethyl-9-methoxy-1-(2-methoxy-2-methoxy-carbon~lv_nyl)_213,4l6~7Ll__hexahvdro-lH-indolo[2 3-a]auinoli2in-5-ium ~erchlorate ________1____________________._ __________ 4.145 g of a mixture of the Z and E isomers of 3-{(S)-3-ethyl-1-[2-(5-methoxy-indol-3-yl)-ethyl]-2-oxo 3-piperidyl}-2-methoxy-propenoic acid methyl ester are treated in a manner analogous to that described in - 28 - 105~89~ 100-4110 Example 1 d), whereby a mixture of isomers of the above title compound is obtained.

d) 3- [ (1SL12bS) -1-ethY1~9-m-e-t-h-OXY-1L-13L41617~12112b octahydro-indolo~213-al~uinolizin-l-yl~-2-meth _____ _____ ______ ____ ____________ _____________ pro~enoic acld ~e.hyl ester The E and Z isomer mixture of (S)-l-ethyl-9-methoxy-1-(2-methoxv-2-methoxycarbonylvinyl)-2,3,4,6,7,12-hexahydro-lH-indolo[2,3-a]quinolizin-5-ium perchlorate is treated in a manner analogous to that described in Example 1 e), whereby a mixture of the Z and E isomers of 3-[(lS,12bS)-l-ethyl-9-methoxy-1,2,3,4,7,12,12b-octahydro-indolo[2,3-a]quinolizin-1-yl]-2-methoxy-propenoic acid methyl ester is obtained.

EXAMPLE 4: (3S,14S,16~)-10-methoxy-v_ncamine ~process variant b)]
1 cc of absolutely dry and bromine-free hydrogen bromide is cor.densed with 447.4 m~ of (3S,16S)-10-methoxy-apovincamine hydrobromide at -78.
After stirring at -78 for 15 minutes, the resulting solution is evaporated to dryness at -78 and a pressure of 20 mm, the reaction vessel is filled with dry nitrogen, and evacuation and filling with nitrogen are repeated twiceO
The residue is first suspended at -78 in 5 cc of acetone having a temperature of -78, 1.5 cc of ~ 10 N potassium hydroxide are subsequently added at -40 - 29 - ~S~9 loo- 4110 while s~irring vigorously, the resulting mash is stirred at -40 for 1 hour and is neutralized with 1 g of solid carbon dioxide while stirring. The reaction mixture is subsequently divided between 20 cc of methylene chloride and 7 cc of 2 N ammonia, the water phase is extracted with 10 cc of methylene chloride, and both methylene chloride phases are successively ~ashed ~7ith 5 cc of the same wash water, are dried ~lith sodium sulphate and concentrated by evaporation.
The residue is (3S,l~S,16S)-10-methoxy-vincamine with small amounts of (3S,16S)-10-methoxy-apovincamine and (3S,14R,16S)-10-methoxy~ -epivincamine as by-products. Crystallization from lsopropyl alcohol yields (3S,14S,16S)-10-methoxy-vincamine wilh the same data as indicated in Example 3.
(3R,14R,16P~)-10-methoxy-vincamine, having the same characteristics as (3S,14S,16S)-10-methoxy-vincamine, but an inverse direction of rotation, is obtained in analogous manner, using (3P~,16R)-10-methoxy-apovincamine as starting material.
- Racemic 10-methoxy-vincamine is obtained in analogous manner, using racemic 10-methoxy-apovincamine as starting material; M.P. 230 (decomp.).

_ 30 _ ~5~ oo-~llo EXAMPLE 5: (3S,14S,16S)-]0-hydroxy-vlncamine [process variant b)]
1 cc of absolutely dry and bromine-free hydroc3en bromide is condensed with 357.4 mg of (3S,16S)-10-hydroxy-apovincamine at -78. After ~ stirrin~ at -73 for 15 minutes, the resulting solution is evaporated to dryness at -78 and a pressure of 20 ~m, the reaction vessel is filled with dry nitro~en, and evacuation and filling with nitro~en are repeated lo twice.
The residue is first suspended at -78~ in 5 cc of acetone having a temperature of -78, i.5 cc of 10 N potassium hydroxide are subsequently added at -~0 - while stirring vigorously, the resulting mash is stirred at -40 for 1 hour and is neutralized with 1 g of solid carbon dioxide while stirring. The reaction mixture is subsequently divided bet~leen 20 cc of methylene chloride and 7 cc of 2 N ammonia, the water phase is extracted ~ith 10 cc of methylene chloride, and both methylene chloride phases are successively washed with 5 cc of the same wash water, dried with sodium sulphate and concentrated by evaporation.
The residue is (3S,14S,16S)-10-hy~roxy-vincamine ~lith small amounts of (3S,16S)-10-hydroY~y-apovincamine and (3S,14R,16S)-10-hydroxy-14-epivincamine as by~products. Crystallization from isopropyl alcohol in the presence of fumaric acid yields crystals of - 31 - ~ g ~ 100-4110 (3S,14S,16S~-10-hydroxy-vincamine hydrogen fumarate isopropyl alcohol having the data indicated in Example 3.
(3R,14R,16R)-10-hydro~y-vincamine, having the same characteristics as (3S,14S,16S)-10-hydroxy-vincamine, but an inverse direction of rotation, is obtained in analocJous manner, using (3R,16R)-10-hydroxy-apovincamine as starting material.
Racemic 10-hydroxy-vincamine is obtained in analogous manner, using racemic 10-hydroxy-apovincar,ine as starting material; M.P. 230 (decomp.).

EXA~P1E 6: (3S,14S,16S)-ll-bromo-vincamine [process variant c)]
14.19 g of (3S,14S,16S)-vincamine and 10.81 g of iron trichloride hexahydrate are suspended at 0 in 80 cc of chloroform, and 44 cc of a 1 molar solution of bromine in chloroform are added dropwise thereto while stirring. After further stirring at 0 for half an hour 120 cc of 2 N ammonia are added, the rusty brown precip-itate is filtered off, the two phases of the filtrate are - separated, the water phase is extracted with 40 cc of methylene chloride, the organic phases are washed with water, combined, dried with sodium sulphate and concentrated by evaporation.
The residue is taken up in 80 cc of isopropyl -~ alcohol, ~rhereby spontaneous crystallization occurs.

- 32 - ~05~ 100-4110 These crude crystals of (3S,14S,16S~ bromo-vincamine are isolated at 0.
Pure ~3S,14S,16S)-ll-bromo-vincamine ls obtained by chromatography of the crude crystals on silica gel with methylene chloride : methanol = 98:2 as solvent, and subsequent crystallization from isopropyl alcohol.
M.P. 214 (dec. ~; [~20 - ~ 8,7 (1 ~, C~C13j.

N~iR spectrum (CDC13, 100 megacycles per second).
0,86 (~, 7c.p.s./ H3~(21) / 3 ~) 3,49 (~ / 14 ~I) among them at ap.2,07 ~ 2,16 (AB, 15 C.pos./H2C(15) 3,80 (ap. S / E~3COGC(22) ~ ~IC(3) / 4 ~I) 4,63 (S ! liO-C(14), exchangeable / 1 H) 7,04 ~ 7,48 (M / HC(9 * 10 ~ 12) / 3 ~) Racemic ll-bromo-vincamine is obtained in analogous manner, using racemic vincamine as starting material; M.P. 230 (decomp.).

- EX~VIPLE 7: (3S,14S,16S)-9-fluoro-vincamine [process variant b)]
1 cc of absolutely dry and bromine-free hydrogen bromide is condensed w th 354.4 mg of (3S,16S)-9~fluoro-apovincamine at -78. After stirriny at -78 ~or 15 minutes, the resulting solution is evaporated to dryness at -78 and 20 mm and is dried for 16 hours under these conditions.

- 33 ~ ~ 8~9 100-4110 ~he residue is first suspended at -78 in 5 cc of acetone having a temperature of -78, 1.5 cc of 10 N aqueous potassium hydroxide are then added at -40 while stirring vigorously, the resul~ing mash is fur~her stirred at -40 for 1 hour, is neutralized with 1 g of solid carbon dioxide while stirring, is di~ided bet~een 20 cc of methylene chloride and 7 cc of 2 N ammonia, the aqueous phase is extracted with 10 cc of methylene chloride, the organic phases are washed with water, dried with sodium sulphate and concentrated by evaporation.
The residue is (3S,l~S,16S)-9-fluoro-vincamine with small amounts of (3S,16S)-9-fluoro-apovincamine and (3S,14R,16S)-9-fluoro-14-epivincar.ine as by-products. Crystallization from toluene yields (3S,14S,16S)-9-fluoro-vincamine.
~.p 210 (dec. ); [a]D = -~ 6,0 ~ (1 %, C~IC13).

NMP~ sp~ctrum (CDC13, 100 megacycles per second)~

0,88 (T, 7 C-p-S~ 3C(21) / 3 ~) 1,18 - 3,50 (M j 14 H) among them at ap.2,03 + 2,17 (AB, 13 c-p-S~/H2C(i.5) 3 at 3,23 (EI2C(6) 3,79 (S / H3COOC(22) / 3 H) 3,86 (S / HC(3) / 1 H) 4,64 (S / HO-C(14) exchangeable / 1 H) 6,57 - 7,20 (M / HC(10 + 11 ~ 12) / 3 H) ~ 34 ~ 105~99 loo-~llo (3R,14R,16R)-9--fluoro-vincamine, having ~he same characteristics as (3S,14S,16S)-9-fluoro-v~ncamine, but an inverse direction of rot~tion, is obtained in analogous manner, using (3R,16R)-9-fluoro-apovincamine as starting material.
.

EX~MPLE 8: (3S, lAS ,16S)-ll-chloro-vincamine __ __ [process variant a)]
(3S,l~S,16S)-ll-chloro-vinca~ine is obtained in a manner analogous to that described in 10 E~ample 1 by reacting a mixture of the Z znd E isomers of 3-[(lS,12bS)-l-eth~l-10-chloro-1,2,3,~,6~7,12,12b-octahydro-indolo~2,3-a]quinolizin-l-yl]-2-methoxy-propenoic acid methyl ester with hydrogen bromide in acetic acid.
M.P. 222 (dec .); []D = + 1,7 (0,1 %, CMC13).

pectrum (C~C13, 100 megacycles per second):
0,87 (T, 7c-p-s-/ ~13C(21) / 3 H) 1,08 -- 3,46 (~' / 14 H) among them at2,07 ~ ,17 (~B,14c.~s.JH2C(15) 3,78 ~S ! H3COOC(22) ) and 3,82 (shoulder / HC(3) /together 4 H);
~,55 (broad / HO-C(14), exchangeable / 1 H) 6,94 - 7,40 (M / HC(9 ~ 10 -~ 12) / 3 H) ~ 35 ~ 100-4110 1C~51~399 EXAMPLE 9: (3S,14S,16S)-9-hvdrox~-vinca~ine ~process variant a)~
(3S,14S,16S)-9-hydro~y-vincamine is obtained in a manner analogous to that described in Example 1 by reac~ing a mixture of the Z and E isomers of 3-~(lS,12bS)-l-ethyl-8-hydro~y-1,2,3,4,6,7,12,12b-octahydro-indolo~2,3-a)quinolizin-1-yll-2-methoxy-propenoic acid methyl ester with hydrogen bromide in acetic acid o M.P. 220 (decomp.) from methylene chloride;
[~3D = ~13,5 (1 %, C~IC13).
NMR s~ectrum (CD3SOCD3, 100 megacycles per second):
0,~3 (T, I C-p-s- / EI3C(2~) / 3 I-l) 1,02 - 3,40 ~M /1~ H) among them at 2,13 + 2,21 (AB, 15c.p.s. /~2C(15) at 3,10 (S / H2C(6) 3,67 (S / H3COOC~2) / 3 H) ~,71 ('; ~ C(3) / 1 H) 5,6~ t~ /1/2 CH~C12 / 1 ~I) 20. 6,3~ (I), 7 c.p.s. / HC(10) / 1 H) ~'~5~ (D, 8 c.p.s./ HC(12) / ] H) f),~0 (S / H0-C(14), exchangeable / 1 H) G,7~ (ap. T, 8 ~ 7 c.p.s~HC(ll) / 1 H) 9,06 (S / Ho-C(9). exchangeable / 1 H) - 36 ~ ~05~899 100-4110 EXAMlPlE 10: (3S,l~S,16S)-l: methyl-vincamine [process varia~t a)]
(3S,14S,16S)-12-Methyl-vincamine is obtained in a manner analogous to that described in Example 1 by reactin~ a mixture of the Z and E isomers of 3-[~lS,12bS)~l-ethyl~ methyl-1,2,3,4,6,7,12,12b-octahydro-indolo~2,3-a3quinolizin-1-yl]-2-methoxypropenoic acid methyl ester with hydrogen bromide in acetic acid.
M.P. 224 (dec.) ; [a]D -- ~ 7,6 (1 ~, CHC13).

N~R spectrum (CDCl , 90 megacycles per second):
__ 3 0,89 (T, 7c.p.s. / H3C(21~ / 3 ~i) 1,13 - 3,43 (~1 ~ 17 H) among them at2~0o + 2,19 ~AB,14~p.S~/ H2C(]5) . at 2,47 (S / C~3C(12) 3,81 (S / H3COOC(22) / 3 H) 3,86 (S / ~C(3) / 1 ~1) 3,99 (S / HO C(l~), exchan~ea~le ~ 1 H) 6,82 - 7,4~ (M / ~3C(9 + ~0 + 11) / 3 h) ~S~99 100-4110 The compounds of formula I exhibit pharmacolo-gical activity. In particular the compounds exhibit vigi-lance-increasing ana psychostimulation activity, as indi-cated in standard tests, for example in mice by an in-crease in excitability and by a decrease in sleep and in-crease in wakefulness in rats according to the electron-cephalogram.
The compounds are therefore further indicated for use as vigilance-increasing agents. For this use an indicated daily dose is from about 1 to about 500 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 250 mg, or in sustained release form.
The (3S,14S, 16S) compounds are the preferred compounds.
The Example 1 compound is particularly interes-ting.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also pro-vides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tabletO

- 38 100~4110 ~5~l9~

The 14--epi forms of the compounds of formula I
are useful intermediates for the preparation of pharma-cologically active compounds.

Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of a compound of formula I, I

wherein R1 is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, with the proviso that when R1 is in the 11 or 12 position, R1 is other than methoxy, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) cyclising a compound of formula II, II

wherein R1 is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, and R2 is lower alkyl, in the presence of acid, or b) treating a compound of formula III, III

wherein R1 is as defined above, at a temperature below 0°C with a hydrogen halide, and subsequently hydrolyzing the resulting reaction product, or c) brominating vincamine to produce a compound of formula I', I' and where necessary converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.

2. A compound of formula I, I

wherein R1 is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, with the proviso that when R1 is in the 11 or 12 position, R1 is other than methoxy, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to Claim 1, or by an obvious chemical equivalent thereof.

3. A process according to Claim 1 for the production of (3S,14S,16S)-11-bromo-vincamine or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting (3S,14S,16S)vincamine with bromine in an inert solvent, and where necessary converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.

4. (3S,14S,16S)-11-bromo-vincamine or a pharmaceutically acceptable acid addition salt thereof whenever produced by a process according to Claim 3 or an obvious chemical equivalent thereof.