Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
7~
Our Canadian Patent Application Serial ~o~ 353,1~1 relates to new
hydroxyamino eburnane derivatives of the general :Eormula I,
R OOC,~,
NH R2
OH
wherein R and R eaeh stand for a Cl 6 alkyl group, as well as to acid addition
salts and optically active isomers of these eompounds. This application is
divided out of Application Serial No. 353,1~1.
The new compounds of formula I are useful as peripheral vasodilating
agents and as intermediates in the preparation of other compounds giving valu-
able therapeutic effects, for example vincamine and apovincamine. If a salt
of a compound of formula I is being used as a final pxoduct, clearly the salt
must be pharmaceutically acceptable.
The new compounds are pr~pared according to the invention by reacting
a compound of formula VII, or a salt thereof.
~ N ~ VII
HOOC
\ CH - CH
R OOC
wherein R and R are as defined above, with a ni.trosating agent in an acidic
medium and, if required, converting the product in-to an acid addition salt or
converting a salt into the free base or resolving the produc-t into op-tically
active isomers.
The compound of formula VII can be obtained by -treating a compound of
,. ~
~ .~ - 2 --
i. ,;~,
;formula Va or Vb, or a salt thereof
H ~ Va
. R OOC ~
R OOC R
' [~ N ~
¦ ~ Vb
C - CEI,~ ~
fH2
CEI
R OOC / COOR
. wherein R and R are as defined above, with alkall.
~, The compound of formula Va or Vb can be obtained by subjecting to
;~ catalytic hydrogerlation a compound of formula IVa or IVb, or a free base
thereof,
~ ~ N X
; N ~ IVa
" CE~ CH2 2
- 3 -
71~
N ~ N X
1 H / 1 IVb
Rlooc~ f 2
1 2
i R oC COOR
wherein R and R are as defined above and X is an acid resldue.
The compound of formula IVa or IVb can be obtained by reacting a
hexahydroindoloquinolisinium compound of formula II
~ ~ N X II
J
.
R
wherein R and X are as defined above, with a methylenemalonic acid diester of
formula III
' ~ COOR
i CH =C 1 III
'~ 2 \ C
wherein R is as defined above. The reaction between the compound of formula
II and the met}-ylenemalonic acid ester of formula III is optionally carried out in the presence of a basic catalyst.
If desired, the compounds of the general formulae IVa and IVb obtained
as intermediates in the syn-thesis are converted into the free base, the com-
pounds of the general formulae Va, Vb, VII and I are converted into their salts
i - 4 -
i
9~J~
and/or resolved, and the subsequent reaction steps are performed optionally
with the appropriate optically active isomers.
The compounds of formulae IVa, IVb, Va, Vb and VII are novel and com-
pounds of formulae IVa, IVb, Va and Vb display biological activity. This appli-cation is directed to these compoundsj i.e. to indoloquinolisines of formula
VIII, and sal~s thereof
~/\J l\N ~~ N VI I I
R300C H
,C - C}12~.-
R OOC I R2
wherein A stands for hydrogen or a C-N bond and when A is C-N bond then the
nitrogen atom bears a positive charge balanced by a negatively charged acid
residue ~ , Y s-tands for hydrogen or a group of the general formula
-CH2CH~COORl)2, Rl and R2 both stand for Cl 6 alkyl groups, R3 is the same as
Rl or, when Y and A both s~and forhydrogen, R3 can also stand for hydrogen.
The indoloquinolisines of formula VIII and their salts can be prepared
by a process which comprises:
~ a) for preparing a combound in which A is a C-N bond, reacting a com-
pound of formula II
~3\ N ' 1~ ~ ~ ~ ( 11
H
R2
wherein R2 and X are as defined above, wi~h a methylenemalonic acid diester of
formula III / COOR
CH2= C 1 III
2 0 COOR
- 4a -
7~
wherein Rl is as defined above, to ob~ain a compound of formula IVa
R OOC ~ ~ ~
or of formula IVb ~ ~ ~ N~ IVb
R OOC ~ CH / ~
RlOOC ~ I R2
ICH2
R OOC ~r tCOOR1
whare R1, R2~ and X are as defined above;
(b) if a compound wherein A stands for a hydrogen atom is required,
subjecting a compound of formula IVa Dr IVb obtained by process ~a) to ca~alytic
hydrogenation to obtain a compound of formula Va
N ~ { ~ Va
R OOC
R OOC R
or o:E formula Vb
- 4b -
~9
N
R OOC ~ Vb
C - CH 2 R2
CH
/ \
wherein R and R are as defined above;
(c) if a compound wherein R , Y and A are hydrogen is required,
treating a compound of formula Va or Vb obtained by process (b) with alkali, -toobtain a compound of formula VII
~ N ~
HOOC H ¦ ~ VI I
CH - CH
I~ OOC
wherein R and R are as defined above; and, if required, converting the com-
pound of formula VII into a salt thereof.
In the compounds oE the invention R and R may represent e.g. a
:lO methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl,
isopentyl,
f ~ 4 C
5~71~
n-hexyl or isohexyl group.
The new ccmpo~7nds of the general formula (I) are vr~ ;7hlP intermedi-
ates of the synthesis of cc~pounds with P~ellPnt phr7~nr7~putical effects. Thus
e.g. when a cc~,pound of the general f~r~71a (I) is treated with a dilute aqueous
acid, a mixture of the corresponding vin~r~mini~ acid ester and apovin~amin;c
acid ester is formed. These compounds can be separated from each other by frac-
tional cryst~Al1;~;7t;~n, and, if desired, converted into other esters. Thus thecom~ounds of the general formula (I) can he converted either lnto v;ncr~m;nP~ a
substance of valuable phr~rmr~r~ltical effects, or into apov;n~Aminic acid ethylester (CavlntonR), a substance even more efective than vlncAm;np~ or both pharn~
aceutically active com~ounds can be prepared sLmultaneously from the approrr;
compound of the general f~rn~1A (I).
Moreover, the compounds of the ~PnPrAl formula ~I) c~lso possess valu-
able phArmA~logical effects, in particular they increase the blood flow of ~he
limbs.
The compo~md~s of the ~n~rAl formula (II) utilized a~s starting sub-
stances in the process of the invention, wherein R2 is a Cl 6 aIkyl group and X
stands for an acid residue, can be preE~red as described in J. Am. Chem. Soc.
~7, 1580-1589.
me reac~ants o~ the general Eormula (III) can be prepared as des-
cribed in J. OrgO Chem. 4! 493 (1~39) e.g. ~y reacting a n~ n;c acid ester with
parafor~A1rl~hyde.
The reaction of the compounds of the general for~ll~P (II) and (III)
is perfonned in an inert orgam c solven-t. As inert organic solvent e.g. a hydro-
carbon, a hA1Og~n~ted
-- 5 --
hydrocarbon, an alcohol, acetonitrile and the li]ce can be applied. ~lalogenated
hydrocarbons, SUC]I as dichlorometha7le and chloroEorm, and C1 6 aliphatic
alcohols, such as tert.-butanol, proved to be particularly preferred. The reac-
tion is performed optionally in the presence of a basic catalyst, such as an
aliphatic or cyclic organic amine ~e.g. diethylamine, triethylamine, piperidine
or pyridine). Catalytic amounts of an alkali metal alcoholate, such as potas-
sium tert.-butoxide, can also be applied for the same purpose. The reaction is
performed preferably at room temperature. Depending on the temperature, the
reaction time varies from some hours to some days.
The relative amounts of the compounds of the general formulae (IVa)
and (IVb) formed in this step depend on the amount of the reactant of the
general formula (III) applied. When the reactant o:E the general formula (III)
is applied in a large excess, a compound of the general formula (IVc),
[3`\ J~ X
C - CH ~ (IVc)
R OOC /1 2 R
CH
1 2 ~COOR
C - Cl-l - Cl-l
l / \ 12 ~COOR
R OOC COOR
~herein R , R2 and X are as defined above, also forms in srnaller amount beside
the compounds of the general formulae (IVa) and (IVb). In practice it is, ho~-
ever, not recommended to apply the reactant of the general formula (III) in too
large excess.
~7~
The intermediates of the general formulae ~IVa), (IVb) and (IVc) are
new, and also possess biological activities. The compounds of the general
formulae (IVa), ~IVb) and (IVc) can be converted into the free bases in a man-
ner known per se~ by treating the salts with an alkali The scope of the inven-
tion also extends to the preparation of the free bases. Although the next step
of the synthesis can also be performed with the free bases, it is preferred to
apply the acid addition salts of the general formulae (IVa) and/or (IVb) as
starting substances in the catalytic hydrogenation.
In the next step of the synthesis the compounds of the general
formulae (IVa) and/or (IVb) are subjected to catalytic hydrogenation. Metals
capable of hydrogen transfer, such as palladium, platinum, nickel, iron, copper~
cobalt, chromium, zinc, molybdenum or tungsten, furthermore oxides and sulfides
thereof can equally be used as hydrogenating catalysts. Supported catalysts
may also be applied in the hydrogenation step; of the supports e.g. carbon (pri-
marily activated carbon), silicon dioxide, alkaline earth metal sulfates and
alkaline earth metal carbonates are to be mentioned. Most frequently palladium-
on-activated carbon or Raney-nickel is applied as catalyst, but the catalyst
should always be selected on the basis of the nature of the substance to be
hydrogenated and the reaction conditions. Catalytic hydrogenation is performed
in an inert solvent in which the starting substance is well soluble, such as
water, Cl 6 aliphatic alcohols, Ialogenated Cl 6 aliphatic hydrocarbons, ethyl
acctate, dioxane, glacial acetic acid or mixtures thereof. If platinum oxide
is applied as catalyst, hydrogenation is performed preferably in a neutral or
slightly acidic mediuTn, whereas if Raney-nickel is utilized, it is pre:Eerred to
conduct the reaction in a neutral medium. Depending on the nature of the star-t-
ing substance and other reaction parameters (time and pressure), the tempera-
ture of the reaction may vary over a wide range. Catalytic hydrogenation is
performed preferably at room temperature and under atmospheric pressure until
the uptake of the calculated amount of hydrogen.
When a single compound of the general formula (IVa) or (IVb) is
hydrogenated, a single compound of the general formula (Va) or (Vb) is obtained,
whereas when a mixture of the compounds of the general formulae (IVa) and (IVb)
is hydrogenated, the respective mixture of the compounds of the general
formulae (Va) and (Vb) is formed. If the mixture subjected to hydrogenation
also contains a compound of the general formula (IVc), one also obtains the
corresponding reduced substance of the general formula (Vc),
l3\N J~,
R OOC ~ (Vc)
CH
1 2 ~COOR
C - CH - CH
/ \\ 12 `'COOR
R OOC COOR
wherein Rl and R are as defined above, in the reaction product beside the com-
pounds o:E the general formulae (Va) and ~Vb).
The intermediates of the gencral formulae (Va), ~Vb) and (Vc) are new
alld biologically active. If desired, these compounds can be converted into
their acid addition salts utilizing e.g. the acids listed below in connection
with the preparation of the salts of the end-products, or, if desired, the
racemic compoullds can be resolved in a manner known per se. The scope of -the
invention embraces both the acid addition salts and the optically active iso-
mers of the compounds having the general formulae (Va), ~Vb) and ~Vc).
When neutralizing the mother liquor obtained in the catalytic hydro-
genation, and subjecting it to preparative layer chromatography, a compound of
the general formula ~VI),
~ N ~" -J ~VI)
R OOC ~ -2
R OOC ~ 2 R
wherein R and R are as defined above~ can also be isolated in a rather small
amount. The compound of the general formula (VI) is a structural isomer of the
compound of the general formula ~Va); in the compounds of the general formula
~Va) the hydrogen is attached in position ~ to the 12b carbon atom and thus it
is in cis position related to substituent R , whereas in the compounds of the
general formula (VI) the hydrogen is attached in position ~ to the 12b carbon
atom and thus its relative position to substituent R is trans. This also
proves unambiguously that when subjecting a compound o~ the general formula
~IVa) or ~IVb) to catalytic hydrogenation, a stereoselective reduction takes
place, and the respective cis compound oE the general formula (Va) or (Vb) is
obt~ined .
In the next step o~ the synthesis the compounds of the general
formulae (Va) and/or (Vb) are treated with an alkali. For this purpose an
inorganic base, preferably an alkali metal hydroxide, such as potassium or
sodium hydroxide, can be applied. The reaction is performed in an inert
- ~o~
organic solvenl or in a mixture of such solvents. As organic solvent it is pre-
ferred to apply an alcohol corresponding to group RlO- of the starting sub-
stance. The reaction can be performed at any temperature between room tempera-
ture and the boiling point of the reaction mixture. Depending on the tempera-
ture applied, the reaction proceeds within 10 minutes and 1.5 hours.
Any of the compounds of the general formulae (Va), (Vb) and (Vc) and
any mixtures thereof yield the same hemiester of the general formula (VII) upon
treatment with an alkali. When a compound of the general formula ~Vb~ is
applied as starting substance, it first transforms into the corresponding com-
pound of the general formula (Va) upon the effect of the alkali. The reactioncan be monitored by thin layer chromatography, and, if desired, it can be inter-
rupted at an appropriate stage to separate the compound of the general formula
(Va) from the mixture. The resulting compound of the general formula (Va) is
identical to that obtained by hydrogenating a compound of the general formula
(IVa) or a mixture of the compounds of the general formulae (IVa) and (IVb).
The compounds of the general formula (VII) are new and biologically
active. If desired, these compounds can be converted into their acid addition
salts, or the racemic compounds can be resolved according to known techniques.
The scope of the invention also embraces the salts and optical]y active isomers
oE the compounds having the general formula (VII).
In the last step o:E the synthesis accord:ing to the invention a com-
pound oE the general formula (VII) is subjected to llitrozation in acidic medium.
Tllis reaction can be performed e.g. with an alkali nitrite, such as potassium
or sodium nitrite, in glacial acetic acid. Alternatively, the compound of the
general formula (VII) can be nitrosated with a Cl 6 alkylni-trite, preferably
tert.-butylnitrite or amylnitrite, in an inert organic solvent, preferably in a
halogenated Cl 6 aliphatic hydrocarbon (such as dlchloromethane), in the pre-
55~7~3
sence of an acid dissolved in some drops of a Cl 6 aliphatic alcohol, prefer-
ably in the presence of ethanolic hydrochloric acid.
The four-step synthesis according to the invention can also be per-
formed in a single series oE operations, without isolating, crystallizing and
identifying the intermediates formed.
The reaction mixtures obtained in any step of the process according
to thc invention can be processed in a manner known per se, depending on the
naturc of the starting substances, end-products, solvents, etc. If the product
scparates from the mixture at the end of the reaction, it can be isolated by
t`iltration. If the product remains in solution, the reaction may be filtered
in order -to remove the solid by-products eventually formed, and then the fil-
trate can be evaporated in vacuo, or the product can be precipitated from the
filtrate by an appropriate solvent. The bases can also be isolated in the form
of their acid addition salts so that an appropriate acid or a solution thereof
is added to the solution containing the base. Dissolved compounds can also be
isolated from their solutions by preparative thin layer chromatography.
The processing of the reaction mixtures obtained in the intermediate
steps of the synthesis generally yields the intermediates in crystalline form.
If the resulting substance is an amorphous powder or an oil, it can be crystal-
~0 lized generally easily in common solvents selected in accordance with the solu-
bility of the intermediate in question.
If desired, any of the intermediates or the end product can be sub-
jected to further purification, such as recrystallization, etc.
The compounds of the general formula (I) can be converted into their
pharmaceutically acceptable acid addition salts by reacting them with the appro-
priate acids.
O-f the acids used for salt formation e.g. the following are to be men-
- 12 - ~ '7~
tioned: mineral acids, such as hydrohalic acids ~e.g. hydrochloric acid, hydro-
bromic acid), sulfuric acid, phosphoric acid, nitric acid, perchloric acid, etc.;
organic carboxylic acids, such as :Eormic acid, acetic acid7 propionic acid,
glycolic acid, maleic acid~ hydroxymaleic acid, fumaric acid, salicylic acid,
lactic acid, cinnamic acid, benzoic acid, phenylace~ic acid, p-aminobenzoic
acid, p-hydroxybenzoic acid, p-aminosalicylic acid, etc.; alkylsulfonic acids,
such as methanesulfonic acid, ethanesulfonic acid, etc.; cycloaliphatic sul-
fonic acids, such as cyclohexylsulfonic acid; arylsulfonic acids, such as
p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, etc.; amino
acids, such as aspartic acid, glutamic acid, etc.
The new compolmds of the general formula (I) possess vasodilatating
effects, and act primarily on the cirulation of the limbs.
The pharmacological tests were perEormed on dogs anaesthetizcd with
chloralose urethane. The test substance was administered in~ravenously as an
aqueous solution in a dosage of 1 mg/kg body weight, and the arterial blood
pressure, pulse rate and arterial blood flow were measured. The latter measure-
ment was performed on the arteria femoralis and on the arteria carotis interna.
The resistance of these vessel systems was calculated from the values obtained
by the formula
. blood pressur~
vascular reslstance =
blood flow ln the vessel examined
The results are listed in Tables 1 and 2. The abbreviations have -the
Eollowing meanings:
MABP = medium arterial blood pressure
PR = pulse rate
CBF = blood flow in the carotis interna
CVR = carotis vascular resistance
FBF = blood flow in the arteria femoralis
FVR = femoral vascular resistance
f~
13 -
Circulation influencing effects of 1 mg/kg of (+)-cis-14-methoxycarbonyl-14-
hydroxyamino-eburnane (3~H,16~Et), prepared according to Example 9 (average -
standard error)
Time (min.)~` 0 1 3 5 20
~ABP mm Hg 132 _ 9.3118 - 7-9 124 -+ 6.2126 -+ 6-8 132 + 7.8
% -10.2 - 5.8 - ~.1 0
PR min 149 ~]0.9161 ~15.8158 _15.5156 ~17.7148 +13.9
% + 7.7 -~ 5.7 + 4.1 - 0.9
CBF ml.min 49 _13.061 -20.2 55 _17.655 _16.049 +13.0
% +20.5 ~ 8.9 -~ 9 0 0
CVR
mm Hg.min.ml3.1+ 0.62.4+ 0.5 2.8-~ 0.62.8+ 0.63.1+ 0.6
% -25 -12 -11 + 1.3
FBF ml.min72 +18.8117 +29.1 81 +25.177 22.270 +17.9
% +71 -~ 9.5 + 5.8 - 3.4
I~VR
mm l-lg.min.ml 2.3+ 0.7 1.2+ 0.22.0+ 0.62.1+ 0.7 2.5-~ 0.8
% -~5 -13 - 7.8 + 3.9
Determined before treatment (0) and 1, 3, 5 and 20 minutes after the treatment
. ~,
7~
-- 1'1 --
Table 2
~laximum percentage e:Efects of (_)-cis-14-methoxycarbony]-14-hydroxyamino-
eburnane (3~11,16~Et) in the individual tests
Number of the dog used
T e s t Average -
247 256 259 263 standard error
h~BP - 11 -150 - 5 -10.2+ 2.3
PR 0 + 9 +14 + 8 -t 7.7_ 3.0
CB~ + 38 +25 +14 + 5 +20.5_ 7.3
CVR - 34 -32-22 -13 -25 _ 5.5
FBF ~116 ~57 +67 +44 +71 +15.9
FVR - 58 -43-46 -32 -44.7+ 5.3
~Statistically significant average (P<0.05)
The data of the tables demonstrate that the compound, when adminis-
tered in an intravenous dosage of 1 mg/kg body weight, provokes a temporary and
slight decrease in blood pressure and increases the pulse rate. The main
efcct of the compound resides in the increase of the blood 1OW in the two ves-
sel systems investigated. This effect is particularly significant on thQ limb
vessels (71 %), which is a consequence of an about 45% dilatation in the ves-
sels concerned. Simultaneously, a dilatation of 25% can be observed on the
carotis vessel sys-tem, which results in a 20% increase in the blood flow.
Tlle new compounds of the general ormula (I) and pharmaceutically
acceptable acid addition salts thereof can be converted into pharmaceutical com-
positions by admixing them with non-toxic, inert, solid or liquid carriers and/
or auxiliary agents commonly applied in the preparation of compositions for
enteral or parenteral administration. As carrier e.g. water, gelatine,
. ~
7l~
- 15 -
lactose, starch, pectill, magnesiuTn stearate, stearic acid, talc, vegetable oils
~such as peanut oil, olive oil), etc. can be applied.
The pharmaceutical compositions can be presen-ted in conventional
forms, such as in the form of solid (e.g. round or edged tablets, coated
tablets, capsules, pills, suppositories, etc.) or liquid preparations (e.g.
oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine cap-
sules, injectable oily or aqueous solutions or suspensions, etc.). The amount
of the solid carrier may vary within ~ide limits; a dosage unit may contain pre-ferably about 25 to lO00 mg of a solid carrier. If desired, conventional pharm-
aceutical additives, such as preservatives, stabilizing agents, wetting agents,
emulsifying agents, salts for adjusting the osmotic pressure, buffers, flavour-
ing agellts, odourants, etc. can also be added to the pharmaceutical composi-
tions. Beside the new compounds of -the general formula (I), the pharmaceutical
compositions may also contain other known and therapeutically active agents.
The pharmaceutical compositions are presented preferably in the form
of unit dosages, and they are prepared according to conventional methods, such
as by sieving, blending, granulating and pressing or dissolving the active
agents and other ingredients. If necessary, the compositions can be subjected
to other pharmacotechnological operations, such as sterilization, etc.
The invention is elucidated in detail by the aid of the following non-
limiting Examples.
Example 1
~ -Ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12b~-
octahydro indolo[2~3-a]quinolisine and (~ -ethyl-1~-(2',2',4',4'-tetraethoxy-
carbonyl-butyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine
A solution of 8.0 ml (8.4 g, 48.8 mmoles) of methylenemalonic acid
diethyl ester in 10 ml of dichloromethane is added to a stirred suspension of
- 16 -
10.00 g (28.4 mmoles~ of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quino-
lisin-5-ium-perchlorate in 60 ml of dichloromethane and 3.6 ml (2.60 g, 25.7
mmo]es) of triethylamine. The reaction mixture is allowed to stand for 2 days
at room temperature.
The solvent is evaporated in vacuo, and the residual orange red oil
is triturated thrice with 30 ml o:E ether, each, and thrice with 30 Ml of petro-
leum ether, each.
18 g of a mixture oE l-ethyl-1-(2',2'-diethoxycarbonylethyl)-1,2,3,4,
6,7-hexahydro-12H-indolo~2,3-a]quinolisin-5-ium perchlorate and 1-ethyl-1-(2',
2',4',4'-tetraethoxycarbonyl-butyl~-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-
quinolisin-5-ium perchlorate are obtained as an oily substance. This mixture
is utilized directly, i.e. without puriEication, in the next step of the syn-
thesis.
rR (K~r): 3260 (indole N~l), 1735, 1715 (C0), 1615 and 1520 (C=N) cm 1.
The oily mixture (18 g) obtained as described above is dissolved in a
mixture of 200 ml of ethanol and 50 ml of dichloromethane, and the mixture is
hydrogenated in the presence of 8 g of a pre-hydrogenated 10% palladium-on-car-
boll catalyst. After the uptake of -the required amount of hydrogen the catalyst
is Eiltered off and washed thrice with 3 ml of ethanol, each, and then thrice
with 30 ml oE dichlorome-thane, each. The ~iltrate and the wash are combined,
evaporated to dryness in vacuo, and the residue is crystallized :Erom 50 ml of
etllallol. The separated substance is Eiltered off, washed wi-th e-thanol and
dried .
9.0 g of (+)-1~-ethyl-1~-(2',2',~ '-tetraethoxycarbonyl-butyl)-1,2,
3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine perchlora-te are obtained,
which corresponds to a yield of 45.3% calculated for 1-ethyl-l,2,3,4,6,7-hexa-
hydro-12H-indolo[2,3-a]quinolisin-5-ium perchlorate.
- 17
The product melts at 216-218C after crystallization from ethanol.
Analysis:
calculated for C33H46N208 HC104 (mol.wt.: 699-18)
C: 56.68 %, Il: 6.63 %, N: 4.01 %
found: C: 57.00 %, H: 6.55 %, N: 4.10 %
(+)-la-Ethyl-1~-(2',2'~',4'-tetraethoxycarbonyl-butyl)-1,273,4,6,7,
12,12b~-octahydro-indolo[2,3-a]quinolisine hydrochloride melts at 211-212C
(from ethanol).
Mass spectrum (m/e, %): 426 (M -172; 6), ~25 (3), 411 (0.3), 397 (0.3),
381 (2), 353 (1), 267 (100), 253 (3~, 237 (5), 197 (8), 185 (6), 1~ (6), 170
(10), 169 (10), 156 (6), 1~4 (5), 127 (10), 99 (10).
(~)-l~-Ethyl-1~-(2',2',4',4'-tetraethoxycarbonyl-butyl)-1,2,3,4,6,7,
12,12b~-octahydro-indolo[2,3-a]quinolisine base can be prepared by dissolving
either the hydrochloride or the perchlorate in dichloromethane, shaking the
solution with an 5% aqueous sodium carbonate solution, separating the organic
phase, drying it over anhydrous magnesium sulEate, filtering, and evaporating
I-l-NMR (CDC13, ~): 7.86 (lH, indole NH), ~.30-3.85 (8H, m, OCH2),
1.~5-1.0 (1511, m, Cl-12-CI13) ppm.
Ethanol is distilled off from the ethanolic mother liquor obtained
after the removal oE (~ -e-thyl-1~-(2',2',4',4'-tetraethoxycarbonyl-bu-tyl)-
1,2,3,~,6,7,12512b~-octahydro-indolo[2,3-a3quinolisine perchlorate, the residue
is dissolved in 30 ml of dichloromethane, and the solution is shaken with 20 ml
o-E a 5~ aqueous sodium carbonate solution. The organic phase is separated,
dried over anhydrous magnesium sulfa-te, filtered, and the filtrate is evapor-
ated to dryness in vacuo. The residue is dissolved in 10 ml of ethanol, and
the solution is acidified to pl-l 5 with ethanolic hydrochloric acid. The hydro-
7~3
- 18 -
chloride is precipitated from the solution with 10 ml of ether, the solid is
filtered of-E, washed with ether and dried.
4.0 g of (+)-1~-ethyl-1~-(2',2'-diethoxycarbonylethyl)-lJ2,3,4,6,7,12-
12b~-octahydro-indolo[2,3-a]quinolisine hydrochloride are obtained, which cor-
responds to a yield of 30.4% calculated for 1-ethyl-1,2,3,4,6,7-hexahydro-12H-
indolo[2,3-a]quinolisin-5-ium perchlorate.
The product melts at 202-204C (from ether).
IR (K~r): 3300 (indole N~l), 1720 (CO) cm
Mass spectrum (m/e, %): 426 (M , 15), 425 (12), 411 (1), 397 (1), 381
(8), 365 (0.5), 353 (2), 307 (0.6), 267 (100), 253 (2), 237 (~), 197 (12), 185
(8), 184 (7), 170 (10), 169 (12), 156 (5), 145 (0.6), 144 (5), 143 (3), 127 (1),
124 (3).
~ -Ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12b~-
octahydro-indolo[2,3-a]quinolisine base is prepared by dissolving the hydro-
chloride in dichloromethane, shaking the solution with a 5% aqueous sodium
carbonate solution, separating the organic phase, drying it over anhydrous
magnesium sulfate, filtering, and evaporating the filtrate to dryness.
I-l-NMR (CDC13, ~): 7.82 (lH, indole NH), 7.2-6.85 (4H, m, aromatic
protons), 3.90 (4H, q, J=7.3 cps, O-CH2), 1.2-0.8 (9H, m, -CH3) ppm.
(+)-1~-Ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12b~-
octahydro-indolo[2,3-a]quinolisine base, obtained as described above, is sub-
jected to preparative layer chromatography on a KG-60 PF254+366 grade silica
gel plate, applying a 14:3 mixture of benzene and methanol as solvent and ace-
tone as eluting agent. ~fter evaporating the eluate and crys-tallizing the
residue from ethanol, a substance of higher Rf value is isolated.
In this way 0.25 g of (+)-1~-ethyl-1~-(2',2'-diethoxycarbonylethyl)-
1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine are ob-tained, which cor-
5~7~
- 19 -
responds to a yield of 2% calculated for l-ethyl~lJ2,3,4,6,7-hexahydro-12H-
indolo[2,3-a]quinolisin-5-ium perchlorate.
M.p.: 127-128 C (from ethanol).
IR (KBr): 3280 (indole NH) 7 1730, 1705 (C0) cm 1.
Mass spectrum (m/e, %~: 426 (M , 13), 425 (7.1), 411 (0.8), 397 (0.8),
381 ~4.2), 366 (0.9), 353 (1.8), 337 (0.8), 335 (0.5), 307 (0.6), 267 (100).
Example 2
(+)-I~-Ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12jl2b~-
octahydro-indolo~2,3-a]quinolisine and (~ ethyl-1~-(2',2',4',4'-tetraethoxy-
carbonyl-butyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine
A solution of 3.03 ml (3.12 g, 18.4 mmoles) of methylenemalonic acid
diethyl ester in 5 ml of dichloromethane is added to a stirred suspension of
5.00 g (14.2 mmoles) of 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quino-
lisin-5-ium perchlorate in 30 ml of dichloromethane and 0.080 g (0.715 mmoles)
of potassium tert.-butoxide. The reaction mixture is allowed to stand at room
temperature for one day.
Thereafter the solvent is evaporated in ~acuo, and the orange-red
oily residue is triturated thrice with 5 ml of petroleum ether, each.
9 g of a mixture of l-ethyl-1-(2',2'-diethoxycarbonylethyl)-1,2,3,4,
6,7-hexahydro-12~1-indolo[2,3-a]quinoLisin-5-ium perchlorate and 1-ethyl-1-(2',
2',~',4'-tetraethoxycarbonyl-butyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-
quillolisin-5-ium perchlorate are obtained as an oily substance. This mixture
:is applied directly, i.e. without purification, in the next step of the syn-
thesis.
IR (KBr): 3260 (indole NH), 1735, 1715 (C0)~ 1615, 1520 ~C=N) cm l.
The oily residue (9 g) obtained as described above is dissolved in a
mixture of 10 ml of ethanol and 25 ml of dichloromethane, and the solution is
7~
- ~o -
hydrogenated in the presence of 6 g of a pre-hydrogena-ted 10% palladium-on-
carbon catalyst. ~fter the uptake of the required amount of hydrogen the
catalyst is filtered off and washed thrice with 3 ml of ethanol, each, and then
thrice with 10 ml of dichloromethane, eacll. The filtrate and the wash are com-
bined, evaporated to dryness in vacuo, and tlle residue is crystallized from
30 ml of ethanol. The separated substance is filtered off, washed with ethanol,
and dried.
8.0 g of a mixture of (+)-lc~-ethyl-1~-(2',2',4',4'-tetraethoxy-
carbonyl-butyl)-1,2,3,4,6,7,12,12bc~-octahydro-indolo[2~3-a]cluinolisine per-
chlorate and (+)-lc~-ethyl-1~-(2~,2~-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12bc
octahydro-indolo[2,3-a~cluinolisine perchlorate are obtained; m.p.: 181-185C.
This salt mixture can be used in the next step of the synthesis
directly in the ethanol-dichloromethane solution obtained after filtering off
the catalyst.
In order to determine the composition of the perchlorate salt mixture
0.8 g of the mixture are dissolved in 6 ml of dichloromethane, the solution is
shaken ~.~ith 4 ml of a 5% aqueous sodium carbonate solution, the organic phase
is separated, driecl over anhydrous magnesium sulfate, filtered, and the
filtrate is evaporated to clryness in vacuo. The residue is subjected to pre-
parative layer chromatography (adsorbent: aluminium oxide Typ-T; solvent: 3:1
mixture of dichlorollletllane and benzene; eluting agent: 20:1 mixture of dichloro-
metllane and methallol).
The substance with hig}ler Rf value is dissolved in 1.2 ml of ethanol,
ancl-tlle solution is aciclified to pl-l 5 wi-th ethanolic hydrochloric acid. The
hydrocllloride is precipitated with 1.2 ml of ether, filtered off "~ashed ~ith
ether and dried.
0.46 g of (:~)-lc~-ethyl-1~-(2',2'-diethoxycarbonyletllyl)-1,2,3,4,6,7,
12,12b~-octahydro-indolo[2,3-a]quinolisine hydrochloride are obtained, which
corresponds to a yield of 70.5%. M.p.: 202-204C (from ethanol and ether).
The substance with lower Rf value is converted into the perchlorate
with 70% aqueous perchloric acid solution, and the salt is crystallized -from
ethanol.
0.26 g of (+)-1~-ethyl-1~-(2',2',4',4'--tetraetlloxycarbonyl-butyl)-
1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine perchlorate are obtained,
which corresponds to a yield of 26%. M.p.: 216-218C (from ethanol).
Example 3
(~ -Ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12b~-
octahydro-indolo~2,3-a]quinolisine
600 mg (1 mmole) of (+)-1~-ethyl-1~-(2',2',4',4'-tetraethoxycarbonyl-
butyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine, prepared as des-
cribed in Example 1 or 2, are dissolved in 8 ml of ethanol, and a solution of
120 mg of potassium hydroxide in 1 ml of water and 1 ml of ethanol is added.
As indicated by thin layer chromatography using aluminium oxide (Typ-T) as
adsorbent and a 3:1 mixture of dichloromethane and benzene as solvent, the reac-
tion proceeds at room temperature within 20 minutes. In this system the Rf
value of (+)-l~-ethyl-1~-(2',2'-diethoxycarbonylethyl)~1,2,3,4,6,7,12,12b~-
octahydro-indolo[2,3-a]quinolisine is higher than that of (~ ethyl-1~-(2'9
2',4',~'-tetraethoxycarbonyl-butyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]-
uillolisine. I`he reaction mixture is neutralized to pH 6 with acetic acid, and
the solvent is distilled off in vacuo. The residue is dissolved in 3 ml of
ter, the solution is rendered alkaline (pH = 9) with an 5% aqueous sodium
carbonate solution, and then extracted thrice with 5 ml of dichloromethane,
each. The organic solutions are combined, dried over anhydrous magnesium sul-
fate, filtered, and the solvent is evaporated in vacuo. The oily residue is
~,
- 22 -
dissolved in 3 ml of ethanol, ethanolic hydrochloric acid is added to the solu-
tion, and the hydrochloride thus formed is crystallized with ether.
0.25 g of (-L)-l~-ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,
12,12b~-octahydro-indolo[2,3-a]quinolisine hydrochloride are obtained, which
corresponds to a yield of 53%. M.p.: 2Ul-204C (from ether).
IR (KBr): 3300 (indole NH), 1720 (C0) cm
Example 4
Ethyl-lB-(2'-carboxy-21-ethoxycarbonylethyl)-1,2,3,4,6,7,12,
12b~-octahydro-indolo[Z,3-a]quinolisine
~ solution of 0.067 g (1.2 mmoles) of potassium hydroxide in 0.3 ml
of water and 0.9 ml of ethanol is added to a solution of 0.46 g (1.08 mmoles)
of (~)-la-ethyl-1~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12b~-octallydro-indolo[2,3-a~quinolisine, prepared as described in Example 1 or 2, in 3 ml of
ethanol. The reaction mixture is boiled on a steam bath for 1.5 hours. There-
af~er the solvent is evaporated in vacuo, the oily residue is dissolved in 3 ml
of water, and the aqueous solution is extracted twice with 2 ml of ether, each.
The aqueous phase is neutralized to pH 6 with acetic acid. The separated white~
crystalline subst~nce is filtered off, washed with 5 ml of water, and dried.
0.32 g of (+)-1~-ethyl-1~-(2'-carboxy-2'-ethoxycarbonylethyl)-1,2,314,
6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine are obtained, which corresponds
to a yield of 74%. M.p.: 113-115 C (from water).
When subjected to thin layer chromatography on KG-G silica gel plate,
utilizing a mixture of 15 ml of benzene, 5 ml of methanol and 2 drops of concen-trated aqueous ammonia as solvent, the Rf value of l~-ethyl-1~-(2',2'-diethoxy-
carbonylethyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine is higher
than that of (+)-l~-ethyl-1~-(2'-carboxy-2'-ethoxycarbonylethyl)-1,2,3,4,6,7,12,
12bc~-octahydro-indolo[2,3-a]quinolisille.
- 23 ~ 5~
IR ~KBr): 3360 (indole NH), 1715 (C0), 1600 (COO ) cm
Mass spectrum (m/e, %): 354 (M -44; 53), 353 (58), 339 (8), 325 (0.3),
30~ (12), 281 (2), 267 (100), ... 44 (1000).
Example 5
(+)-l~-Ethyl-1~-(2'-carboxy-2'-ethoxycarbonylethyl)-1,2,3,4,6,7,12,
12b~-octahydro-indolo[2,3-a]quinolisine
A solution of 0.092 g (l.G4 mmoles) of potassium hydroxide in 0.3 ml
of water and 0.9 ml of ethanol is added to a solution o-E 0.428 g (0.715 mmoles)of (+)-l~-ethyl-13-~2',2',4',4'-tetraethoxycarbonyl-butyl)-1,2,3,4,6,7,12,12b~-
octahydro-indolo[2,3-a~quinolisine, prepared as described in Example 1 or 2, in
3 ml of ethanol. The reaction mixture is boiled on a steam bath ~or 0.75 hours.
Thereafter the solvent is evaporated in vacuo3 the oily residue is dissolved in
3 ml of water, and the resulting solution is washed twice with 2 ml of ether,
each~ The aqueous solution is neutralized to pH 6 with ace-tic acid, the separ-
a~ed white, crystalline substance is filtered off, washed with 5 ml of water,
and dried.
0.24 g of (+)-la-ethyl-1~-~2'-carboxy-2'-ethoxycarbonyl-ethyl)-1,2,3,
4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine are obtained, which corres-
ponds to a yield of 74%. M.p.: 112-114C.
Example 6
(+)-1~-Ethyl-1~-(2'-carboxy-2'-ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,
].2b~-octahydro-indolo[2,3-a]quinolisine
The filtrate obtained in Example 2 after removing the catalyst from
the reaction mixture, which is an ethanoldichloromethane solution of (+)-1~-
ethyl-l~-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12,12bu-octahydro-indolo-
[2,3-a]quinolisine perchlorate and (~ -ethyl-1~-(2',2',4',4'-tetraethoxy-
carbonyl-butyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine per-
`~'i
- 24 - ~ 7~
chlorate and contains the two salts i.n a weight ratio of about 3:1, is applied
as starting substance.
The solvent is evaporated in vacuo, and the oily salt mixture ob-
tained as residue is dissolved in 50 ml of dichloromethane. 30 ml of a 5%
aqueous sodium carbonate solution are added, the mixture is shaken, the organic
phase is separated, dried over anhydrous magnesium sulfate, filtered, and the
filtrate is evaporated to dryness in vacuo. 1.54 g of the oily residue, which
is a mixture of 2.34 mmoles of the diethoxy base and 0.90 mmoles of the tetra-
ethoxy base, are dissolved in 16 ml of ethanol, and a solu~ion of 0.24 g (4.28
mmoles) of potassium hydroxide in 2 ml of water is added. The reaction mixture
is boiled for 1 to 1.5 hours on a steam bath. Thereafter the solvent is evapor-
ated in vacuo, the residue is dissolved in 10 ml of water, and this alkaline
solution is extracted thrice with 10 ml of ether, each. The organic extracts
are combined, dried over anhydrous magnesium sulfate, filtered, and the
filtrate is evaporated. 0.4 g of an oily substance is obtained as a residue,
which consists mainly of the starting compound mixture. The pH of the aqueous
phase is adjusted to 6 with acetic acid, and the separated organic substance is
extracted four times with 15 ml of dichloromethane, each. The organic extracts
are combined, dried over anhydrous magnesium sulfate, filtered, and the
filtrate is evaporated in vacuo. The oily residue is triturated with 10 ml of
ether, the separated substance is filtered off, washed with 5 ml of ether, and
dried.
0.76 g of ~ -ethyl-1~-(2'-carboxy-2'-ethoxycarbonylethyl)-1,2,3,4,
6,7,12,12b~-octahydro-indoloL2,3-a~quinolisine are obtained, which corresponds
to a yield o:E 59%. M.p.: 10~-111C (under decomposition).
25 -
Example 7
(~)-Cis-14-ethoxycarbonyl-14-hydroxyamino-eburnane (3al-1,16~Et)
A solution of 0.39 g ~5.65 mmoles) of sodium nitrite in 5 ml of liater
is added to a solution of 0.75 g (1.885 mmoles) of ~+)-1~-ethyl-1~-(2'-carboxy-
2'-ethoxycarbonylethyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine,
prepared as described in Example 6, in 15 ml of glacial acetic acid. The reac-
tion proceeds at room temperature within one hour. The reaction mixture is
rendered alkaline (pH = 11) with a 30% aqueous sodium hydroxide solution under
very intense ice cooling, and the separated organic substance is extracted four
times with 40 ml of dichlorome~hane, each. The dichloromethane extracts are
combined, washed with 10 ml of water, dried over anhydrous magnesium sulfate,
filtered, and the filtrate is evaporated in vacuo. The 0.60 g of solid ob-
tained as a residue are triturated with 5 ml of dichloromethane, the separated
substance is filtered off, washed with 3 ml of dichloromethane, and dried.
0.52 g of (+)-cis-14-ethoxycarbonyl-14-hydroxyamino-eburnane ~3~H,
16~Et~ are obtained, which corresponds to a yield of 72%. M.p.: 156-158C
(from dichloromethane).
When subjected to thin layer chromatography on a silica gel KG-C plate
using a 14:3 mixture of benzene and methanol, the Rf value of (+)-cis-14-ethoxy-carbonyl-14-hydroxyamino-eburnane (3~1-1,16~Et) is higher than that of the start-
ing (~ -ethyl~ 2'-carboxy-2'-ethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b~-
octahydro-illdolo[2,3-a]quinolisine.
The title compound did not show melting point depression in admixture
wi-th (+~-cis-14-ethoxycarbonyl-14-hydroxyamino-eburnane (3~}-1,16~Et) preparçd as
described in the Hungarian patent application No. RI-634, and was identical
with the latter compound with respect to all of the physical and chemical char-
acteristics.
.~
43
- 26 -
IR (KBr): 3400 (NH, O}l), 1700 (CO~ cm 1.
I-l-NMR (CDC13, c~): 8.3 (l}I, N~I), 4.0 (211, q, J=7.3 cps, COOCII2CH3~,
1.18 (3H, t, J=7.3 cps, COOCH2CH3) ppm.
~(ass spectrum ~m/e, %): 383 (M, 98), 382 (59), 366 (100), 354 (10),
338 (7.7), 310 (31), 292 ~29), 278 (8.5), 267 ~40), 253 (92), 237 ~15), 211 (1~).
Example 8
(-)-3aS,16~S-14-Ethoxycarbonyl-14-hydroxyamino-eburnane
(+)-Cis-14-ethoxycarbonyl-14-hydroxyamino-eburnane (3rxl-I,16c~Et) is re-
solved with diben~oyl-l)-tartaric acid to obtain the title compound. M.p.: 169-
171C (from dichloromethane); ~C~]D20 = -56.1 (c - 1.05, in climethyl formamide).
Example 9
Cis-14-methoxycarl~onyl-14-IIydroxyamino-eburnane (3cl11,16~Et)
One proceeds as described in Examples 2, 6 and 7 with the difference
that -the 8 ml of methyleneIlIalonic acid diethyl ester is replaced by an equiva-
lent amount of methylenemalonic acid dimethyl ester.
The title compound melts at 179C (from methanol).
IR (KBr): 3420 (Nll, OH), 1710 (CO2CH3) cm
Il-NMR (CDC13, ~): 8.05 (lI-I, Nl-l), 7.6-7.0 (4H, m, aromatic protons),
3.5 (311, s, CO2CH3), 1.1 (3H, t, CH2C~3) ppm-
Mass spectrum: m/e 70 eV, M = 369.
Analysis:
calculated :for C21H27N3O3 (mol.wt.: 369-14):
C: 68.27 %, II: 7.36 %, N: 11.3S %
fOUIlcl: C: 6S.5S %, II: 7.29 %~ N: 11.2S %
Example lû
(~)-Cis-14-ethoxycarbonyl-14-hydroxyamino-eburnane (3c~I,lGc~Et)
8.00 g of a mixture of (+)-lc~-ethyl-lB-(2',2'-dietIIoxycarbonyl-ethyl)-
- 27 -
1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]quinolisine and (~ ethyl-1~-(2',
2',4',4'-tetraethoxycarbonyl-butyl)-1,2,3,4,6,7,12,12b~-octahydro-indolo[2,3-a]
quinolisinc perchlorates, prepared as described in Example 2, are dissolved in
80 ml of dichloromethane. The solution is shaken with 40 ml of a 5% aqueous
sodium carbonate solution, the organic phase is separated, dried over anhydrous
magnesium sulfate, filtered, and the filtrate is evaporated to dryness in vacuo.
The oily residue is dissolved in 80 ml of ethanol, a solution of 1.00 g of
potassium hydroxide in 4 ml of water is added, and the reaction mixture is
allowed to stand at room temperature for 3.5 hours.
Thereafter the solvent is evaporated in vacuo, the oily residue is
dissolved in 16 ml of water, and the solution is extracted twice with 8 ml of
benzene, each.
32 ml of glacial acetic acid are added to the aqueous phase, the mix-
ture is cooled in an ice ba-th, and a solution of 2.00 g of sodium nitrite in
4 ml of water is added dropwise within lO minutes. The mixture is allowed to
stand at room temperature for one hour, thereafter the pH of the mixture is ad-
justed to 9 with a 30% aqueous sodium hydroxide solution under intense cooling
with ice. The resulting mixture is extracted thrice with 50 ml of ethyl
acetate, each. The organic phases are combined, washed with 20 ml of water,
dried over anhydrous magnesium sulfate, filtered, and the filtrate is evapor-
ated in vacuo, to obtain 4.00 g of a solid residue.
This solid residue is recrystallized from 20 ml o~ dichloromethane to
obtain 3.44 g of the title compound, which is identical with that obtained
according to Example 7. This corresponds to a yield of 65% calcula~ed for the
5.00 g of the perchlorate mixture used as starting substance.
