PROCESS FOR THE PREPARATION OF IMIDAZO-AND PYRIMIDO-PYRIDOINDOLES

METHODE DE PREPARATION D'IMIDAZO- ET DE PYRIMIDO-PYRIDOINDOLES

English Abstract

ABSTRACT
Imidazo and pyrimido-pyridoindole
derivatives of the general formula:
<IMG>
in which n is 1 or O, Rl is a hydrogen or halogen atom,
or an alkyl, alkoxy or trifluoromathyl radical, R2 is
an alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or benzyl
radical, the phenyl and benzyl raclicals being
unsubstituted or substituted by a halogen atom or an
alkyl or alkoxy radical, R3 is a hydrogen atom or an
alkyl radical and R4 is a hydrogen atom or an alkyl
radical, the alkyl and alkoxy radicals having from 1 to
4 carbon atoms and their pharmaceutically acceptable acid

addition salts, except compounds in which simultaneously
n = 1, Rl, R3 and R4 are hydrogen atoms and R2 is a
methyl radical, are useful in treating convulsions.
They are prepared by reacting a compound of the
general formula:
(II)
<IMG>
wherein R5 is ethyl or mcthyl with an amine R2NH2,
to form an amide wherein -OR5 is replaced by -NHR2
and cyclising thc amide in aqueous formaldehyde.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of imidazo- and
pyrimido-pyridoindole derivatives, in the form of race-
mates or enantiomers, having the general formula (I)
(I)
<IMG>
in which n is 1 or 0, R1 is a hydrogen or halogen atom,
an alkyl, alkoxy or trifluoromethyl radical, R2 is an
alkyl, cycloalkyl, phenyl or benzyl radical, the phenyl
and benzyl radicals being unsubstituted or substituted by
a halogen atom or an alkyl or alkoxy radical, R3 is a
hydrogen atom or an alkyl radical, and R4 is a hydrogen
atom or an alkyl radical, the alkyl and alkoxy radicals
having from 1 to 4 carbon atoms, and their pharmaceutically
acceptable acid addition salts, with the exception of the
compound in which n = 1, R1, R3 and R4 are hydrogen atoms
and R2 is a methyl radical, which process comprises reacting
a compound of the formula (II)
(II)
<IMG>

wherein Rl, R3, R4 and n are as defined above and wherein
R5 represents an ethyl or methyl group with an amine R2NH2,
and cyclising the resulting intermediate of formula (III)
(III)
<IMG>
wherein Rl, R2 R3, R4 and n are as defined above, by
reacting it with aqueous formaldehyde and when a compound
is thereby prepared in which R4 is a hydrogen atom, if
required, N-alkylating it to produce a compound of formula
(I) in which R4 is an alkyl radical, and when required,
converting a free base of formula (I) into a pharmaceutic-
ally acceptable acid addition salt or such a salt into a
free base.
2. A process according to claim 1, wherein the
reaction with the amine is carried out at a temperature of
from ambient to 100°C and the reaction with formaldehyde
at a temperature of from ambient to 70°C.
3. A process according to claim 1, wherein a
reactant of formula II is used in which n is 1.
4. A process according to claim 1, wherein a
reactant is used in which n is 1, R1 is a hydrogen atom,
a chlorine or fluorine atom or a methyl radical, R2 is
a methyl or ethyl radical, R3 is a hydrogen atom or a
methyl radical and R4 is a hydrogen atom or a methyl
radical.
16

5. A process according to claim 1, wherein a
reactant is used in which:
(i) n, R1, R2 and R3 are as defined in claim 1 and
R4 represents an alkyl radical of 1 to 4 carbon atoms;
(ii) n, R2, R3 and R4 are as defined in claim 1 and
Rl represents a trifluoromethyl radical; or
(iii) n, R1, R3 and R4 are as defined in claim 1 and
R2 represents a phenyl radical unsubstituted or substi-
tuted by a halogen atom, alkyl or alkoxy radical.
6. A process according to claim 1, wherein a com-
pound of formula (II) in which n is 1 and an amine R2NH2
are used to prepare a compound of formula:
(Ib)
<IMG>
in which R1, R2, R3 and R4 have any one of the following
combinations of meanings:
<IMG>
17

or a pharmaceutically acceptable acid addition salt
thereof.
7. A process according to claim 1, wherein a
compound of formula (II) in which n is 1 and an amine
R2NH2 are used to prepare a compound of formula:
(Ib)
<IMG>
in which Rl, R2, R3 and R4 have any one of the following
combinations of meanings:
<IMG>
or a pharmaceutically acceptable acid addition salt
thereof.
8. A process according to claim 1, wherein a
compound of formula (II) in which n is 1, R1, R3 and R4 is
each hydrogen is reacted with an amine R2NH2 in which R2 is
<IMG> to prepare a compound of formula:
18

( Ib)
<IMG>
in which R1, R2, R3 and R4 have the above meanings or a
pharmaceutically acceptable acid addition salt thereof.
9. A process according to claim 1, wherein a
compound of formula (II) in which n is O is reacted with
an amine R2NH2 to prepare a compound of formula:
(Ia)
<IMG>
R1, R2, R3 and R4 have any one of the
following combinations of meanings:
<IMG>
19

or a pharmaceutically acceptable acid addition salt
thereof.
10. Imidazo- and pyrimido-pyridoindole
derivatives, in the form of race-mates or enantiomers,
having the general formula (I)
(I)
<IMG>
in which n is 1 or 0, R1 is a hydrogen or halogen atom,
an alkyl, alkoxy or trifluoromethyl radical, R2 is an
alkyl, cycloalkyl, phenyl or benzyl radical, the phenyl
and benzyl radicals being unsubstituted or substituted by
a halogen atom or an alkyl or alkoxy radical, R3 is a
hydrogen atom or an alkyl radical, and R4 is a hydrogen
atom or an alkyl radical, the alkyl and alkoxy radicals
having from 1 to 4 carbon atoms, and their pharmaceutically
acceptable acid addition salts, with the exception of the
compound in which n = 1, R1, R3 and R4 are hydrogen atoms
and R2 is a methyl radical and pharmaceutically acceptable
acid addition salts thereof, whenever prepared by the pro-
cess claimed in claim 1 or an obvious chemical equivalent.
11. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 3, whenever prepared by the process claimed in claim
3 or an obvious chemical equivalent.

12. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 4, whenever prepared by the process claimed in claim
4 or an obvious chemical equivalent.
13. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 5, whenever prepared by the process claimed in claim
5 or an obvious chemical equivalent.
14. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 6, whenever prepared by the process claimed in claim
6 or an obvious chemical equivalent.
15. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 7, whenever prepared by the process claimed in claim
7 or an obvious chemical equivalent.
16. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 8, whenever prepared by the process claimed in claim
8 or an obvious chemical equivalent.
17. Derivatives of formula (I) defined in claim 1
in which n, R1, R2, R3 and R4 have the means given in
claim 9, whenever prepared by the process claimed in claim
9 or an obvious chemical equivalent.
21 .-.

Description

11~9~z
DESCRIPTION
"PROCESS FOR THE PREPARATION OF IMIDAZO- AND
PYRIMIDO-PYRIDOINDOLES"
The present invention relates to the preparation
of pyrimido-pyridoindole derivatives, in the form of
racemates or enantiomers, their addition salts with
pharmaceutically acceptable acids, and their application
in therapy.
The imidazo-and pyrimido-pyridoindole derivatives
have the formula (I)
R - - ~ (I)
R3 1 ~
(H2~C~, N-'R2
o
in which n is 1 or 0, Rl is a hydrogen or halogen atom,
or an alkyl, alkoxy or trifluoromethyl (CF3) radical,
R2 is an alkyl, cycloalkyl, phenyl or benzyl radical,
these last two radicals optionally carrying a halogen
atom or an alkyl or alkoxy radical, R3 is a hydrogen
atom or an alkyl radical and R4 is a hydrogen atom or
an alkyl radical, the alkyl and alkoxy radicals having
from 1 to 4 carbon atoms, with the exception
,

11~9~Z
of the compound in which n = 1, Rl = R3 = R4 = H and
R2 = CH3, but including the pharmaceutically
acceptable acid addition salts of these compounds.
The above derivatives are herein referred
to for bre~ity as."the therapeutic compounds".
They have an asymmetric carbon in the 12b-position
(n=l) or llb-position (n=0) and the above definition
includes them in the form of their racemates and
enantiomers.
A preferred class of the therapeutic
compounds is those in which Rl is a hydrogen atom,
a chlorine or fluorine atom or a methyl radical, R2
is a methyl or ethyl radical, R3 is a hydrogen atom
or a methyl radical and R4 is a hydrogen atom or a
methyl radical~
In another embodiment of the inv~ntion the
therapeutic compounds are those in which
(i) n, Rl, R2 and R3 are as defined for formula (I)
and R4 is an alkyl radical of 1 to 4 carbon atoms;
(ii) n, R2, R3 and R4 are as defined for formula (I)
and Rl :is a trifluoromethyl radical; or
(iii) n, Xl, R3 and R4 are as defined for formula (I)
and R2 is a phenyl radical unsubstituted or substituted
by a halogen atom or an alkyl or alkoxy radical; and
(iv) n, R2, R3 and R4 are as defined for formula (I)
and Rl is an alkoxy radical.

9~
According to the invention, the therapeutic
compounds are prepared from a compound of the
formula (II)
R ~ (II)
l R3 CH2) -C00 (Et or Me)
R4
which is reacted with an amine R2NH2~ in a solvent
such as an alcohol or the amine R2~H2 itself, at a
temperature e.g. from ambient temperature to 100C,
and the resulting intermediate of the formula (III)
(III)
4 R3 (CH2)nCNHR2

112941;~:
-4-
is then cyclised by reaction with aqueous
formaldehyde ! preferably of 30% strength, at a
temperature e.g. from ambient up to 70C. Rl,
R2, R3, R4 and n in the above reactants are
defined as for formula (I).
If R4 is a hydrogen atom in the compound
(I), the latter can then be alkylated,preferably
by an alkyl iodide in a strong base in order to
obtain a derivative (I) in which R4 is an alkyl
radical. The reaction i9 particularly useful to
produce a compound in which R2 is also an alkyl
radical.
The starting compounds (II) in which R3 =
alkyl can be prepared from substituted or
unsubstituted tryptamine in accordance with the
following scheme, Rl and n being as defined above:

_ 5
(Et
CH2CH2 NH2 ~ alk~C~ (C~2)n C ~Me
N hydrochlorid~
H or
base
R~
COO(Et or M~)
This reaction is described in the literature by
J,A. MAÇLAREN, Aust. J. Chem. (1977) 30, 2,045-51.
The starting compounds (II) in which R3 = H and
n = 1 can be prepared from the hydrochloride of substituted
or unsùbstituted tryptamine in accordance with the
following reaction scheme, Rl being as de~ined above:

Rl ~ H2.HCl + EtO-CO-CO-CH2COOEt
J
Rl ~ H.HCl
H ~ OOEt
o / COOEt
Rl ~ EtO~
~NJ~H HC1 gas 1 ~ ~ ~ ~,HCl
CH2cooH H
CH COOEt
(II) 2
The compound (II) in which Rl is H and n is 1 is
described by I..~. GR0VES and G.A. SWAN, ~. Chem. Soc.
(1952) 650.
The starting compounds (II) in which Rl is
different from H are new.
Example of the preparation of a compound (II)
[Rl 9-CH3~ n = 1, R3 = H]
1. 52.62 g (0.25 mol) of 5-methyltryptamine hydro-
chloride are suspended in 250 ml of ethanol and the

lZ
-- 7 --
suspension is heated to the reflux temperature. 57.75 g
of 3-ethoxycarbonyl-1,2-dioxo-1-ethoxypropane are suspen-
ded in 250 ml of ethanol, and 25 ml of concentrated
hydrochloric acid are added dropwise in the course of 10
minutes.The latter suspension is added to the 5-methyl-
trypta~ine suspension kept at the reflux temperature.
The mixture is allowed to cool overnight. The solvent
is removed by evaporation, the residue is dissolved in
400 ml of water and the solution is rendered alkaline with
ammonia, After extraction with ethyl acetate, an oil
is obtained which is chromatographed on a silica column.
After elution with an 8/2 mixture of chloroform and
ethanol, an oil is obtained which solidifies on tritur-
ation with petroleum ether. After recrystallisation
from hexane, the compound obtained
CH ~ H X H
C~l2 COOEt
CO~Et
melts at 102-103C.
2~ 45 ~ of the above compound are heated under reflux
for 20 hours in 450 ml of a 10% strength aqueous solution
of NaOH. Concentrated hydrochloric acid (100 ml) is
added dropwise, in the course of 30 minutes, to the cooled
reaction mixture. The resulting solid is filtered off
and dried over P205.
.. . ..

12
_ ~ _
3. 99.6 g of the crude solid obtained above are
heated under reflux in a mixture of 250 ml of ethanol and
20 ml of concentrated sulphuric acid for 9 hoursO The
mixture is left to stand overnight. The ethanol is
removed by evaporation and the residual solid is rendered
alkaline with ammonia. The basic solution is extracted
with 3 times 300 ml of ethyl acetate. The extract is
evaporated. An oil is obtained which gives a white
solid on trituration with petroleum ether. The solid
is filtered off and dried.
After recrystallisation from hexane, the result-
ing compound (II) melts at 103C.
The following examples illustrate the invention.
The micro-analyses and the IR and NMR spectra
confirm the structure of the compounds.
EXAMPLE 1 2,11b-Dimethyl-2,3,5,6,11,11b-hexahydro-lH-
imidazo[l',5':1,2]pyrido[3,4-b]indol~l-one.
[n=0, Rl=H, R2=CH3, R3=CH3, R4=H]
1. 1-Methylaminocarbonyl-l-methyl-2,3,4,9-tetrahydro-lH-
pyrido[3,4-b]indole.
4.8 g (0.02 mol) of methyl 1-methyl-2,3,4,9-tetra~
hydro-lH-pyrido[3,4-b]indole-1-carboxylate (starting
compound II) are dissolved in 100 ml of ethanol saturated
with methylamine.
The solution is left at ambient temperature for
48 hours, The solvent is removed and the residueis
then taken up in 20 ml of ethanol. The mixture is fil-

tered and the solid is washed with ethanol.
Melting point = 230-231C.
2. 2,11b-Dimethyl-2,3,5,6,11,11b-hexahydro-lH-imidazo-
[1',5':1,2]pyrido[3,4-b]indol-1-one.
12 g (0,05 mol) of the compound obtained a~ove
are placed in 200 ml of ethanol~ 3 g of KOH pellets
and then 25 ml of a 30% strength aqueous solution of for-
maldehyde are added.
The mixture is stirred at 70C for 12 hours.
The precipitate is filtered off and washed with
ethanol. After recrystallisation from propanol, the
compound melts at 252-253C.
EXAMPLE 2 9-Chloro-3-methyl-3,4,6,7,12,12b-hexahydro-
. . _
pyrimido[l',5':1,2]pyrido[3,4-b]indol-2(1H)-
one.
[n=l, Rl=9-Cl, R2=CH3, R3=H, R4=H]
1. N-Methyl-6-chloro-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]-
indole-l-acetamide.
8 g of ethyl 6-chloro-2,3,4,9-tetrahydro-lH-
20 pyrido[3,4-b]indole-1-acetate (starting compound (II))
are dissolved in a mixture of 150 ml of ethanol and 150 ml
of a 33% strength solution of methylamine in ethanol.
The reaction mixture is heated at 200C for 7 hours in an
autoclave. It is left to cool overnight. The solu-
25 tion is evaporated.
The solid, which is recrystallised from ethanol,melts at 228-230C.
,

1~.2C~
_ 10 _
2. 9-Chloro-3-methyl-3,4,6,7,12,12b-hexahydropyrimido-
[1',6':1,2]pyrido[3,4-b]indol-2(1H)-one
1.7 g of the compound obtained above are dissolved
in a mixture of 20 ml of ethanol and 2 ml of a 3~/0 strength
aqueous solution of formaldehyde~at ambient temperature.
The solution is stirred for 30 minutes. The solvent is
removed, the white solid is taken up in cold ethanol and
the mixture is filtered. The product is recrystallised
from ethanol.
Melting point = 257C.
EXAMPLE 3 3,12b-Dimethyl-3,4,6,7,12,12b-hexahydro-
pyrimido[l',6':1,2]pyrido[3,4-b]indol-2(1H)-
one.
[n=l, Rl=H, R2=CH3, R3=CH3, R4=H]
15 1. N-Méthyl-l-methyl-2,3,4,9-tetrahydropyrido[3,4-b]-
indole-l-acetamide.
36.9 g of ethyl 1-methyl-2,3,4,9-tetrahydro-lH-
pyrido[3,4-b]indole-1-carboxylate are introduced into an
autoclave together with 300 ml of a 33% strength solution
of CH3NH2 in ethanol. The mixture is heated at 100C
for 8 hours. The solvent is driven off and the residue
is crystallised from ethanol.
Melting point = 182-183C.
2. 3,12b-Dimethyl-3,4,6,7,12,12b-hexahydropyrimido-
[1',6':1,2]pyrido[3,4-b]indol-2(IH)-one.
20 g of the above compound and 150 ml of ethanol
are introduced into a round-bottomed flask. A 33%

29~12
-- 11--
strength aqueous solution of formaldehyde is added and
the mixture is stirred at ambient temperature for 3 hours.
The solvent is driven off and the residue is dried by
azeotropic distillation with toluene. The residue is
dissolved in 500 ml of chloroform and the solution is
dried over Na2S04. After evaporating the solution, an
oil is obtained. Dry tetrahydrofurane is added and then
driven off. A white solid is obtained which is recry-
stallised from ethyl acetate.
Melting point = 204C.
EXAMPLE 4 3,12,12b-Trimethyl-3,4,6,7,12,12b-hexahydro-
pyrimido[l',6':1,2]pyrido[3,4-b]indol-2(1H)-
one.
[n=l, Rl=H, R2=CH3, R3=CH3, R4=CH3]
'3 g of the compound obtained in Example 2 and
30 ml of dimethylformamide are introduced into,a round-
bottomed flask. 0,53 g of sodium hydride i5 added
and the mixture is stirred at ambient temperature for
2 hours. 0.9 ml of methyl iodide is added and the
mixture is stirred for 1 minute at ambient temperature.
The solvent is driven off and the residue is chromato-
graphed on SiO2. Elution is car~ied out with an 8/2
mixture of CHC13/EtOH. A white solid is obtained
which is recrystallised from CH30CH2CH20CH3.
Melting point = 159-160C.
The compounds of formula ( I ) - which were prepared
by way of examples are shown in the Table below.

1~29~2
~- -12-
The ring-numbering system referred to in
the Table is shown below:
7 6 8 7
8 ~ _ ~ 5 9 ~ ~"~ 6
~7 ~N~ 3 R~ 5 4
R4 3 ~ -R2 R4 1~ ~ -R2
Formula la (= formula I Formula Ib (= formula I
5when n = O) when n = 1)

TABLE
Compounc n Rl R2 ~3 R4 Chtiracter-
no. Meltin~
_ p~nt (~C)¦
1 0 H CH3 CH3 H 252-3
-2 1 H n-C4Hg H H 232
3 1 H ~ H H 233
4 1 HC6H5CH2 H H 204
S 1 9-Cl CH3 H H 257
6 1 9-F CH3 H H 223
7 1 H CH3 H CH3 165-6
8 1 9-CH3 CH3 H H 225
9 1¦ -CH3 CH3 H CH3 136-8
1 H. CH~ CH3 CH3 160
il 1 H CH.l CH3 H 204
12 1 H C2H5 H H 227
13 1 -CH30 CH3 H H 224
14 1 H~ OCEI3 H H ~260
1 9-ClC2H5 H H 256-7
16 1 9-C1` ~ ~ H H 264
17 0 8-F C2E~5 CH3 H 207
18 0 HC2H5 CH3 H ,205 ~ ,
19 0 8-F CEI3 CH3 EI 223
0 8-Cl CH3 CH3 H 248
21 0 8-F ~ CE~.3 H 215
22 0 H ~ C~3 H 214
23 1 9-CF3 C:;3 Ei 230

11~9412
-14-
The therapeutic compounds were subjected to
pharmacological tests in which they showed themselves
to be active as anti-convulsive agents.
The acute toxicity to mice was determined by
intraperitoneal administration. The LD varies from
200 to 2,000 mg/kg.
The anti-convulsive activity was determined
by means of the test for the antagonism towards the
convulsions induced by bicuculline in mice (M. Perez
de la Mora and R. Tapia (1973), Biochem. Pharmacol. 22,
2,635-2,639).
The AD50 of the therapeutic compounds varies
between 30 and 50 mg/kg, administered intraperitoneally.
The above results show that the compounds can
be used for treating epilepsy.
The therapeutic compounds can be presented in
any form which is suitable for oral, parenteral or
endorectal administration, for example in the form of
tablets, dragees, sugar-coated pills, solutions to be
taken orally or injected, and the like, together with
any suitable excipient.
The daily posology can range from 200 to 1,500 mg.
. _ _ ., . .. . .. . , . .... . . _ , ..