Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~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-
100-4110
- ~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.
- 6 - 100-4110
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.
- 8 - 100-4110
~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.
- 9 - 100-4110
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.
- 10 - 100-4110
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
- 13 - 100-4110
~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
- 16 - 100-4110
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.
