Indian Patents
Title of Invention

POLYCYCLIC COMPOUNDS AS POTENT ALPHA2-ADRENOCEPTOR ANTAGONISTS
Abstract The invention provides a compound of formula I, wherein X, Z, R1 to R10, R15, R16, m, n, r and t are as defined in claim 1, or a pharmaceutically acceptable salt or ester thereof, useful as an alpha-2 antagonist. The compounds of formula I can be used for the treatment of diseases or conditions where antagonists of alpha-2 adrenoceptors are indicated to be effective. (FIG. - Nil)
Full Text POLYCYCLIC COMPOUNDS AS POTENT ALPHA2-ADRENOCEPTOR
ANTAGONISTS
FIELD OF THE INVENTION
The present invention relates to pharmacologically active arylquinolizine
derivatives and related compounds and to their pharmaceutically acceptable salts and
esters thereof, as well as to pharmaceutical compositions containing them and to
their use as alpha2 antagonists.
BACKGROUND OF THE INVENTION
Some compounds exhibiting alpha adrenergic activity are well known in the
art. It is also generally known and accepted in the art that those compounds may be
used for the treatment of a wide variety of diseases and conditions of the peripheric
system and the central nervous system (CNS).
The alpha adrenergic receptors can be divided on a pharmacological basis
into alphal- and alpha2-adrenoceptors, which can both be further divided into
subtypes. Three genetically encoded subtypes, namely alpha2A-, alpha2B- and
alpha2C-adrenoceptors, have been discovered in human. Accordingly, ajpha2-
adrenoceptors in humans have been subdivided into three pharmacological subtypes
known as alpha2A-, alpha2B- and alpha2C-adrenoceptors. A fourth,
pharmacologically defined subtype, alpha2D, is known in rodents and in some other
mammals, and it corresponds to the genetically defined alpha2A-adrenoceptors.
The alpha2-adrenoceptor subtypes have distinct tissue distributions and
functional roles. For instance, while alpha2A-adrenoceptors are widely expressed in
various tissues, alpha2C-adrenoceptors are concentrated in the CNS, and they appear
to play a role in the modulation of specific CNS-mediated behavioural and
physiological responses.
Compounds that are non-specific to any of the above-mentioned alpha2
subtypes, and compounds that are specific to certain alpha2 subtypes, are already
known. For example, atipamezole is a non-specific alpha2 antagonist. Atipamezole
has been described in, for example, EP-A-183 492 (cf. p. 13, compound XV) and
Haapalinna, A. et al., Naunyn-Schmiedeberg"s Arch. Pharmacol. 356 (1997) 570-
582. U.S. Patent No. 5,902,807 describes compounds that are selective antagonists
for the alpha2C subtype and may be used in the treatment of mental illness, e.g.
mental disturbance induced by stress. Such compounds include, for example, MK-
912 and BAM-1303. Furthermore, WO-A-99 28300 discloses substituted imidazole
derivatives having agonist-like activity for alpha2B- or 2B/2C-adrenoceptors. In
addition, WO 01/64645 relates to derivatives of quinoline useful as alpha2
antagonists, as well as to selective alpha2C antagonist agents. The disclosures of all
documents cited above in this paragraph are incorporated by reference herein.
Several arylquinolizine derivatives and related compounds have been
described in the literature, some of which possess valuable pharmaceutical effects.
For example, U.S.patents No. 4,806,545 and 4,044,012describe 1,1-disubstituted
indolo[2,3-a]quinolizidines useful as vasodilators and antihypoxic agents. Further,
substituted arylquinolizine derivatives, described for example in U.S. Patent No.
4,686,226 possessing alpha2-adrenoceptor antagonistic activity are useful for
example as antidepressant, antihypertensive, or antidiabetic agents or platelet
aggregation inhibitors. In addition, U.S. Patent No. 3,492,303 relates to indolo[2,3-
a]quinolizidines useful as central nervous system depressants. Molecular modelling
of targets for synthesis of alphalA and alpha2 selective ligands is discussed in
Griffith, R. et al., J. Comput.-AidedMol. Design 13 (1999) 69-78.
SUMMARY OF THE INVENTION
An object of the present invention is to provide further antagonists of alpha2-
adrenoceptors that can be used for the treatment of diseases or conditions of the
peripheric or central nervous system where alpha2-antagonists are indicated to be
useful. Accordingly, an object of the present invention is to provide further
compounds to be used as alpha2 antagonist agents in the treatment of mammals,
including humans and animals.
The invention also provides compounds useful as selective alpha2C
antagonist agents for the treatment of various disorders or conditions of the central
i nervous system where alpha2C antagonists are indicated to be useful.
ACCOMPANYING
o BRIEF DESCRIPTION OF THE DRAWINGS
Figures la and b show the results from two separate locomotor activity tests
where the locomotor activity of mice was tested after injections of vehicle or
amphetamine (amph) (4 micromol/kg). The mice were pre-treated (20 min before
amphetamine) either with vehicle, the subtype non-selective alpha2-antagonist
atipamezole (1 micromol/kg) or the alpha2C-antagonists, compound K (3
micromol/kg)(Fig a) or compound L (3 micromol/kg)(Fig b). * p and *** p Figure 2 shows alpha2-agonist-induced sedation (measured as locomotor
inhibition) in mice. The non-selective alpha2-antagonist atipamezole (Ati)
antagonised the sedative effects of the alpha2-subtype non-selective agonist,
dexmedetomidine (Dex; 50 nmol/kg s.c), while the alpha2C-selective antagonists
did not have significant effects, (veh = vehicle). (***p vehicle)
Figure 3 shows the effect of the alpha2C-selective antagonists compound K
(3 micromol/kg) and compound L (3 micromol/kg), the non-selective antagonist
atipamezole (10 micromol/kg) and the reference antidepressants desipramine (10
micromol/kg) and fluoxetine (10 micromol/kg) in the forced swimming test in rats.
AH compounds, except atipamezole, increased activity (***p vehicle).
Figures 4a and 4b show the effect of compounds K and L on the startle reflex
and its prepulse inhibition in rats. (Veh = vehicle). Asterisks as in Figure 1;
comparisons were performed between PCP (phencyclidine) + vehicle and PCP +
compounds K and L.

Figures 5a and 5b show the effect of the non-selective antagonist atipamezole
(ati) on the startle reflex and its prepulse inhibition in rats in the prescence of
phencyclidine (PCP); (veh = vehicle). Asterisks as in Figure 1, compared to the
vehicle + PCP -group.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention covers the use of compounds of
formula I,
wherein,
X is CR2R2", O, S or NR2;
Z is -CHR8-(CH2)n- or a single bond;
R1 is hydroxy, (C1-C6)alkyl, (C1-C6koxy, halogen, halo(C1-C6)alkyl, (C1-
C6)alkoxy-CO-, CN, NO2, NH2, mono- or di(C1-C6)alkylamino or carboxyl;
R2 and R2" are independently H, hydroxy or (C1-C6)alkyl or R2 and R2" form,
together with the carbon ring atoms to which they are attached, a carbonyl group;
R3 is H, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy(C1-C6)alkyI, (C1-
C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C3-
C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, aryloxy,
aryl(C1-C6)alkoxy, aryloxy(C1-C6)alkyI, aryl(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-
C6)alkyl, NH2, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino,mono- or di(C1-
C6)alkylamino(C1-C6)alkyl, (C1-C6)alkyl-CO-, (C1-C6)alkyl-CO-O-, (C1-C6)alkyl-
CO-O-(C1-C6)alkyl, (C1-C6)alkoxy-CO-, (C1-C6)alkoxy-CO-(C1-C6)alkyl, (C1-
C6)alkoxy-CO-(C1-C6)alkoxy(C1-C6)alkyl, carbarnoyl, mono- or di(C1-
C6)alkylcarbamoyl, carboxyl or (C1-C6)alkyl-S-(C1-C6)alkyl, wherein the said (C3-
C7)cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each
independently being hydroxy, (C1-C6)alkyl, halogen, (C1-C6)alkoxy, NH2, CN or
NO2, or one of R3 or R4 and R6 together form a bond between the ring atoms to
which they are attached;
R4 is H, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy or (C1-
C6)alkoxy(C1 -C6)alkyl;
R5 is H, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-
C6)alkoxy(C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycIoalkyI(C1-C6)alkyl, aryl,
aryl(C1-C6)alkyl, aryloxy, aryl(C1-C6)alkoxy, aryloxy(C1-C6)alkyl, aryl(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkyl-CO-O-, (C1-C6)alkyl-CO-O-
(C1-C6)alkyl, (C1-C6)alkoxy-CO-(C1-C6)alkoxy(C1-C6)alkyl, carbamoyl, mono- or
di(C1-C6)alkylcarbamoyl, carboxyl or (C1-C6)alkyl-S-(C1-C6)alkyl, wherein the said
(C3-C7)cycloalkyl or aryl is unsubstituted or substituted with I or 2 substituents each
independently being hydroxy, (C1-C6)alkyl, halogen, (C1-C6)alkoxy, NH2, CN or
NO2, or R4 and R5 form, together with the carbon ring atoms to which they are
attached, a condensed five to seven membered saturated carbocyclic ring substituted
with 1 to 3 substituent(s) R9 each independently being hydroxy, (C1-C6)alkyI,
halogen, NH2, NO2, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl,
amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino, mono- or di(C1-
C6)alkylamino(C1 -C6)alkyl, (C1-C6)alkoxyI (C1-C6)alkoxy(C1-C6)alkyl, carboxyl,
(C1-C6)alkyl-CO-, (C1-C6)alkyl-CO-O-, (C,-C6)alkoxy-CO-, (C1-C6)alkoxy-CO-(C1-
C6)alkyl, carbamoyl mono- or di(C1-C6)alkylcarbamoyl or oxo;
R6 is H, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl
or R6 forms a bond between the ring atom to which it is attached and the ring atom to
which R7 is attached;
R7 is H, hydroxy, (Cl-C6)alkyl, hydroxy(C1-C6)aIkyl, (C1-C6)alkoxy or (C1-
C6)alkoxy(C1 -C6)alkyl;
R8 is H,hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy or (C1-
C6)alkoxy(C1-C6)alkyl or, only when n is 0, R7 and R8 form, together with the carbon
ring atoms to which they are attached, a condensed five to seven membered saturated
carbocyclic ring unsubstituted or substituted with 1 to 3 substituent(s) R10 each
independently being hydroxy, (C1-C6)alkyl, halogen, NH2, NO2, (C3-C7)cycloalkyl,
hydroxy(C1-C6)alkyl, halo(C1-C6)alkyI, amino(C1-C6)alkyl, mono- ordi(C1-

C6)alkylamino, mono- ordi(C1-C6)alkylamino(C1-C6)alkyi, (C1-C6)alkoxy, (C1-
C6)alkoxy(C1-C6)alkyl, carboxyl, (C1-C6)alkyl-CO-, (C1-C6)alkyl-CO-O-, (C1-
C6)alkoxy-CO-, (C1-C6)alkoxy-CO-(C1-C6)aIkyl, carbamoyl, mono- or di(C1-
C6)alkylcarbamoyl or oxo;
i R15 is H, (C1-C6)aikyl, (C2-C6)alkenyl, hydroxyC1-C6alkyl, (C1
C6)alkoxy(C1-C6)aJkyI, hydroxy(C1-C6)alkoxy(C1-C6)aIkyl, halo(C1-C6)alkyl,
amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)aIkyI-CO-,
(C1-C6)alkyl-CO-0-(C1-C6)alkyl,(C1-C6)alkoxy-CO-,(C1-C6)aIkoxy-CO-(C1-
C6)alkyl, (C1-C6)alkoxy-CO-(C1-C6)alkoxy(C1-C6)alkyl, carbamoyl, mono- or di(C1-
C6)alkylcarfaamoyl or carboxyi;
R16 is H or (C1-C6)alkyl;
R7 and R8 are attached to the carbon ring atoms, which are adjacent;
m is 0 to 2; and
n is 0 or 1,
or a pharmaceutically acceptable saJt or ester thereof, with the proviso, that
the compound is not 1,2,3,4,5,10b-hexahydro-10-thia-3a-aza-cyclopenta[a]fluorine,
for the manufacture of a medicament for the treatment of diseases or conditions
where alpha2 antagonists are indicated to be effective.
In a possible subgroup of the compounds of formula IX is NR2.
In another possible subgroup of the compounds of formula I m is 0, n is 0, R2
is H, R3 is H, hydroxy, (C,-C6)alkyl, hydroxy(C,-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, (C3-C7)cycloaIkyKhalft(C1-C6)alkyl, (C1-C6)alkyl-CO-, (C1-C6)alkyl-CO-
O-(C1-C6)alkyl, (C1-C6)alkoxy-CO- or (C1-C6)alkoxy-CO-(C1-C6)alkyl, R4 isH,
hydroxy, (C1-C6)alkyl or hydroxy(C1-C6)alkyl, R5 is H, hydroxy, (C1-C6)alkyl or (C1-
C6)alkoxy, R is H or (C1-C6)alkyl and R7 is H, (C1-C6)alkyl or hydroxy(C1-C6)alkyl.
In another possible subgroup of the compounds of formula IR3 is H or (C1-
C6)alkyl and R4 is hydroxy or hydroxy(C1-C6)aIkyl.
In another possible subgroup of the compounds of formula IR4 and R5 form,
together with the carbon ring atoms to which they are attached, a condensed six
membered saturated carbocyclic ring.
In another possible subgroup of the compounds of formula IR4 and R6
together form a bond between the ring atoms to which they are attached or R6 forms
a bond between the ring atom to which it is attached and the ring atom to which R7 is
attached.
In a further possible subgroup of the compounds of formula I the compound
is 1 a-ethyl-1,2,3,4,6,7,12,12bp-octahydro-indolo[2,3-a]quinolizin-1 -ol, (1 b-ethyl-
1,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizin-1 -yl)-methanol, 1 a-Methyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin- l-ol, (1a-Methyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-al]quinolizin-l-yl)-methanol or
3,4,4ab,5,6,7,8,13,13bb, 13ca-decahydro-2H-6a, 13-diaza-indeno[ 1,2-c]phenanthren-
1-one.
In another possible subgroup of the compounds of formula IX is CR2R2".
In a further possible subgroup of the compounds of formula IX is S.
In yet another possible subgroup of the compounds of formula IX is O.
When X is O, one possible subgroup of the compounds of formula I includes
R5 and R6 as defined in the description of the use of the compounds of formula I
above.
Another possible subgroup of the compounds of formula I when X is O is
where R5 is H, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-
C6)alkoxy(C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl,
aryl(C1-C6)alkyl, aryloxy, aryl(C1-C6)alkoxy, aryloxy(C1-C6)alkyl, aryl(C1
C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkyl-CO-O-, (C1-C6)alkyl-CO-O-
(C1-C6)alkyl, (C1-C6)alkoxy-CO-(C1-C6)alkoxy(Cl-C6)alkyl, carbamoyl, mono- or
di(C1-C6)alkylcarbamoyl, carboxyl or (C1-C6)alkyl-S-(C1-C6)alkyl and R6 is H,
hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy or (Ci-C6)alkoxy(Ci-C6)alkyl.
Another embodiment of the invention provides new compounds of formula
IA:
wherein,
X is CR2R2", O or S;
Z is -CHR8-(CH2)n- or a single bond;
R1 is hydroxy, (Ci-C6)alkyl, (C1-C6)alkoxy, halogen, halo(Ci-C6)alkyl, (C1
C6)alkoxy-CO-, CN, NO2, NH2, mono- or di(Ci-C6)alkylamino or carboxyl;
R2 and R2" are independently H, hydroxy or (Ci-C6.)alkyl or R2 and R2" form,
together with the carbon ring atoms to which they are attached, a carbonyl group;
R3 is.hydroxy, (Ci-C6)alky(C2-.C6)alkenyl, hydroxy(C1-C6)alky], (Ci-
C6)alkoxy, (C1-C6)alkoxy(C1-C6)a3ky], hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C3-
C7)cycloalkyl, (C3-C7)cycloalkyl(Ci-C6)alkyl, aryl, aryl(C1-G6)alkyl, aryloxy,
aryl(C1-C6)alkoxy, aryloxy(Ci-C6)alkyl, aryl(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-
C6)alkyl, NH2, amino(C1-C6)alkyl, mono- or di(Ci-C6)alkylamino,mono- or di(Ci-
C6)alkylammo(C1-C6)alkyl, (C1-C6)alkyl-CO-, (C1-C6)-O-, (C1-C6)alkyl-
" CO-O-(C1-C6)alkyl,(Cl-C6)alkoxy-CO-,(Ci-C6)a1koxy-CO-(C1-C6)alkyl, (C1-
C6)alkoxy-CO-(Ci-C6)alkoxy(C1-C6)aikyl, carbamoyl, mono- or di(Ci-
C6)alkylcarbamoyl, carboxyl or (C1-C6)alkyl-S-(Ci-C6)alkyl, wherein the said (C3-
C7)cycloalkyl or ary] is unsubstituted or substituted with 1 or 2 substituents each
independently being hydroxy, (Ci-C6)alkyl, halogen, (Ci-C6)alkoxy, NH2, CNor
NO2, or one of R3 or R4 and R6 together form a bond between the ring atoms to
which they are attached;
R4.is hydroxy, (C1-C6)alkyl, hydroxy(Ci-.C6)alkyl, (C1-C6)alkoxy or (Ci-
C6)alkoxy(C1-C6)alkyl;
R5 is H;
R6 is H or R6 forms a bond between the ring atom to which it is attached and
... the ring atom.to which R7is attached;
R7 is H, hydroxy, (C1-C6)aIkyl, hydroxy(C1-C6)a]kyl, (Ci-C6)alkoxy or (C1-
C6)aIkoxy(Ci-C6)aIkyI;
R8 is H,hydToxy, (Ci-C6)liyl. hydroxy(C1-C6)alkyI, (C1-C6)alkoxy or (C1
C6)alkoxy(C1 -C6)alkyl;
R15 is H, (Ci-C6)alkyl, (C1-C6)alkenyl, hydroxy(Ci-C6)alkyl, (C1
C6)alkoxy(Ci-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyi halo(C1-C6)alkyl,
amino(Ci-C6)alkyl, mono- or.di(C1-C6)alkylmino(Ci-C6)alkyl, (C1-C6)alkyl-CO-,
(C1-C6)aIkyl-CO-O-(Ci-C6)aIkyl, (Ci-C6)alkoxy-CO-, (C1-C6)alkoxy"CO-(C1
C6)alkyl, (Cl-C6)aIkoxy-CO-(C1-C6)alkoxy(C1-C6)aIkyl, carbamoyl, mono- or di(C1-
C6)alkylcarbamoyl or carboxyl;
R16isHor(Ci-C6)alkyl;
R7 andR8 are attached to the carbon ring atoms, which, are adjacent;
m is 0 to 2; and
n is 0 or 1,
or a pharmaceutically acceptable salt or ester thereof.
wherein the compound is 1 a-Methyl-1,3,4,5,6,1 1b-hexahydro-2H-l l-oxa-4a-
aza-benzo[a]fluoren-l-ol, (la-Methyl-1,3,4,5,6,1 lbp-hexahydro-2H-1 1-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol, (-)-(1a-Methyl-l,3,4,5,6,l 1bb-hexahydro-2H-l 1-
oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol, (+)-(la-Methyl-l,3,4,5,6,11bb-
hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol, 1a-Isopropyl-
1,3,4,5,6,1 1b-Hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-ol, 1a-Ethyl-
1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-o1, (1a-Ethyl-
1,3,4,5,6,11 bb-hexahydro-2H-11 -oxa-4a-aza-benzo[a]fluoren-l -yl)-methanol, 1 -
Methyl-1a,3,4,6,1 lbP-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene, (1-
Hydroxymethyl-1,3,4,5,6,11 b-hexahydro-2H-11 -oxa-4a-aza-benzo[a]fluoren-1 -yl]-
methanol, 1 -Methoxymethyl-1 a-methyl-1,3,4,5,6,11 bb-hexahydro-2H-l 1 -oxa-4a-
aza-benzo[a]fluorene, (-)-l-Methoxymethyl-1a-methyl-1,3,4,5,6,1 lbb-hexahydro-
2H-1 l-oxa-4a-aza-benzo[a]fluorene, (+)-1 -Methoxymethyl-1a-methyl-
1,3,4,5,6,11bb-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene, 1a-Methyl-
1,3,4,5,6,1 1ba-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene-l-carboxylic acid
ethyl ester, 1 -Ethoxymethyl-1a-methyl-1,3,4,5,6,11 bb-hexahydro-2H-11 -oxa-4a-
aza-benzo[a]fluorene, (1a-Methyl-1,3,4,5,6,1 1ba-hexahydro-2H-ll-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol, (-)-(1a-Methyl-l,3,4,5,6,11ba-hexahydro-2H-l 1-
oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol, (+)-(1a-Methyl-1,3,4,5,6,1 1ba-
hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol, 1a-Ethyl-
1,3,4,5,6,1 lba-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene-l-carboxylic methyl
ester, 1 -Methoxymethyl-1 a-methyl-1,3,4,5,6,11 ba-hexahydro-2H-11 -oxa-4a-aza-
benzo[a]fluorene, (-)-l-Methoxymethyl-la-methyl-l,3,4,5,6,11ba-hexahydro-2H-
1 l-oxa-4a-aza-benzo[a]fluorene, (+)-l-Methoxymethyl-1a-methyl-1,3,4,5,6,1 1ba-
hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene, (1a-Ethyl-1,3,4,5,6,1 1ba-
hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene-l-yl)-methanol, acetic acid 1a-
Methyl- 1,3,4,5,6,11 bb-hexahydro-2H-11 -oxa-4a-aza-benzo[a]fluoren- 1-ylmethyl
ester or (1a-Methyl-1,2,3,4,6,7,12,12ba-octahydroindeno[2,1-a]quinolizin-l -yl)-
methanol.
Another embodiment of the invention provides new compounds of formula
wherein,
X is NR2;
R2 is (Ci-C6)alkyl;
Z, R1, R3-R10, R15, R16, m and n are as defined in claim 1,
or a pharmaceutically acceptable salt and ester thereof, with the provisos, that
a) when m is 0 or R1 is methoxy and R4 is H or ethyl, then R3 is not
methoxy-CO;
b) the compound is not 12-Methyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-
a]quinolizine; 1 -Ethyl-12-methyl-l ,2,3,4,6,7,12,12b-octahydro-
indolo[2,3 -a]quinolizine; 2,3-Diethyl-12-methyl-1,2,3,4,6,7,12,12b-
octahydro-indolo[2,3-a]quinolizine; 12-Methyl-1,2,3,4,6,7,12,12b-
octahydro-indolo[2,3-a]quinolizin-1 -ol; 2-(l -Ethyl-12-methyl-
l,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizin-l-yl)-ethanol; 11-
Methyl-2,3,5,6,11,1 1b-hexahydro-lH-indolizino[8,7-b]indole; (11-
Methyl-2,3,5,6,11,1 1b-hexahydro-1H-indoli2ino[8,7-b]indol-l-yl)-
methanol; (1,1 l-Diethyl-2,3,5,6,11,11b-hexahydro-lH-indolizino[8,7-
b]indol-l-yl)-methanol or 3-(l-ethyl-12-methyl-l,2,3,4,6,7,12,12b-
octahydro-indolo[2,3-a]quinolizin-l-yl)-propionic acid methyl ester; for
example
wherein R3 is hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl or (Ci-
C6)alkoxy(Ci-C6)alkyl and R4 is H, (Ci-C6)alkyl or hydroxy(C1-C6)alkyl; or

wherein the compound is 1a-Ethyl-12-methyl-1,2,3,4,6,7,12bb-octahydro-
indolo[2,3-a]quinolizin-l-oln or 1a-Ethyl-12-ethyl-l,2,3,4,6,7,12bb-octahydro-
indolo[2,3-a]quinolizin-l -o1.
Another embodiment of the invention provides new compounds of formula
wherein,
X is NR2;
R2 is H;
Z is -CHR8-(CH2)n- or a single bond;
n is 0;
R1, R3, R6-R8, R15, R16 and m are as defined in claim 1;
r is 1 to 3;
or a pharmaceutically acceptable salt and ester thereof, with the provisos, that
the compound is not 10-memyl-5,7,7a,8,9,10,11,11a,11b,12-decahydro-6H-6a,12-
diaza-indeno[1,2-a]fluorene; 3-hydroxy-l ,2,3,4,4a,5,6,7,8,13,13b,l3c-dodecahydro-
6a,13-diaza-indeno[l,2-c]phenanthrene-4-carboxylic acid methyl ester; methyl-3-
ethyl-l,2,3a,4,6,7,12b,12c-octahydro-3H,12H-indolo[2,3-g]cyclopent[a]indolizine-2-
carboxylate; methyl-1,2,3a,4,6,7,12b, 12c-octahydro-3H, 12H-indolo[2,3-
g]cyclopent[a]indolizine-2-carboxylateor 12c-ethyl-l,3a,4,6,7,12b,12c-octahydro-
cyclopent[l,2]indolizino[8,7-6]indol-3(2H)-one; for example
wherein r is 1 and R3 is H, hydroxy, (Ci-C6)alkyl or hydroxy(Ci-C6)alkyl; or
12
wherein the compound is 3,4,4ab,5,6,7,8,13,13bb,13ca-decahydro-2H-6a,13-
diaza-indeno[ 1,2-c]phenanthren-1 -one, 1,2,3,4,5,6,7,8,13,13b-decahydro-6a, 13-
diaza-indeno[l,2-c]phenanthrene, acetic acid 1a,2,3,4,4ap,5,6,7,8,13,13bp,13ca-
dodecahydro-6a,13-diaza-indeno[l,2-c]phenanthren-l-yl ester or acetic acid
1b,2,3,4,4ap,5,6,7,8,13,13bb, 13ca-dodecahydro-6a, 13-diaza-indeno[l,2-
c]phenanthren-l-yl ester.
Another embodiment of the invention provides new compounds of formula
ID:
wherein,
X is NR2;
R2 is H;
Z is -CH-(CH2)n-;
n is 0;
R1, R3-R1o R15, R16 and m are as defined in claim 1;
t is 0 to 3;
or a pharmaceutically acceptable salt and ester thereof, with the provisos, that
the compound is not 1,2,3,4,4a,5,6,11,11b,12,13,13a-dodecahydro-4b,l 1-diaza-
indeno[2,1 -a]phenanthrene; 1,2,3,4,4a,5,6,11,11 b, 12-decahydro-4b, 11 -diaza-
indeno[2,1 -a]phenanthrene; 9-methoxy-1,2,3,4,4a,5,6,11,11 b, 12-decahydro-4b, 11-
diaza-indeno[2,l-a]phenanthrene or l-hydroxy-l,2,3,4,4a,5,6,l l,11b,12,13,13a-
dodecahydro-4b,11-diaza-indeno[2,l-a]phenanthrene-2-carboxylic acid methyl ester.
Another embodiment of the invention provides new compounds of formula
wherein,
X is NR2;
R2 is H;
Z, R1, R3-R10, R15, R16 and m are as defined in claim 1;
n is 1,
or a pharmaceutically acceptable salt and ester thereof, with the proviso, that
the compound is not 2,3,4,5,7,8,13,13b-octahydro-2,3-diethyl- 1H-
azepino[1",2":l,2]pyrido[3,4-b]indole; acetic acid 2,3,4,5,7,8,13,13b-octahydro-lH-
azepinof 1 ",2": 1,2]pyrido[3,4-b]indol-2-ylmethyl ester; 2,3,4,5,7,8,13,13b-octahydro-
lH-azepino[l\2\l,2]pyrido[3,4-b]indole-2-[(phenylmethoxy)methyI]or
2,3,4,5,7,8,13,13b-octahydro-lH-azepino[l",2": 1,2]pyrido[3,4-b]indole-4-ethyl-2-
[(phenylmethoxy)methyl]; for example
wherein the compound is 2,3,4,5,7,8,13,13b-Octahydro-1H-
azepino[ 1 ",2": 1,2]pyrido[3,4-b]indole.
Another embodiment of the invention provides new compounds which are
2b-Methoxy-1,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizine, 2a-methoxy-
1,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizine, 1a-Ethyl-2a-methyl-
1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-l-ol, 1a-Isopropyl-
1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-l-ol, (-)-1a-isopropyi-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinoIizin-l-ol, (+)-1a-isopropyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin- l-ol, 1b-Isopropyl-
1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizine, (1 a-Isopropyl-
1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-l-yl)-methanol, (1a-n-
Propyl-1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-l -yl)-methanol, 2-
(1a,2,3,4,6,7,12,12bb-Octahydro-indolo[2,3-a]quinolizin-1 -yl)-butan-2-ol, 1 -
(1,2ot,3,4,6,7,12,12ba-Octahydro-indolo[2,3-a]quinolizin-2-yl)-propan-l -ol, 2-
(1 a,2,3,4,6,7,12,12bb-Octahydro-indolo[2,3-a]quinolizin-1 -yl)-propan-2-ol, 1 -s-
Butyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1 -ol, 1-Cyclohexyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin- 1 -ol, 9-Fluoro-1a-isopropyl-
1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-l-ol, (la-Methyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1 -yl)-methanol, (-)-(1a-
Methyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1 -yl)-methanol, (+)-
(1a-Methyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1 -yl)-methanol,
(1a-Ethyl-1,4,6,7,12,12bb-hexahydroindolo[2,3-a]quinolizin-l-yl)-methanol, 3b,4a-
Dimethyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizine,
(l,2a,3,4,6,7,12,12ba-Octahydroindolo[2,3-a]quinolizin-2-yl)-propan-2-ol,
(1,2a,3,4,6,7,12,12bb-Octahydroindolo[2,3-a]quinolizin-2-yl)-propan-2-ol, (2a-
Ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizin-2-yl)-methanol, (2a-
Ethyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-2-yl)-methanol, (1 -
otEthyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1 -ylmethoxy)-acetic
acid ethyl ester, l-(2a-ethyl-l,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizin-
2-yI)-ethanone, 1-(2a-ethyl-1,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizin-
2-yI)-ethanol, 2-(2a-ethyl-l,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizin-2-
yl)-propan-2-oI, 2-(3-ethyl-1,2a,3a,4,6,7,12,12ba-octahydro-indolo[2,3-
a]quinolizin-2-yl)-propan-2-ol, (3-ethyl-2-methyl-1a,2b,3b,4,6,7,12,12bb-
octahydro-indolo[2,3-a]quinolizin-1 -yl)-methanol, 3-ethyl-l ,2-dimethyl-
la,2b,3b,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizine, 1,2-dimethyl-
1,2,3,4,6,7,12., 12bb-octahydro-indolo[2,3-a]quinolizin-1b-ol, (1 -ethyl-2-methyl-
1b,2p,3P,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizin-3-yl)-methanol, 1-b-
Hydroxymethyl-l-methyl-l,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizine-
6b-carboxylic acid methyl ester, 5,6,7,7ab,8,9,10,l 1,1 lab,l lba-Decahydro-12-oxa-
6a-aza-indeno[ 1,2-a]fluorene, 2,3,4,4ap,5,6,7,8,13bb, 13cb-Decahydro-lH-13-oxa-
6a-aza-indeno[ 1,2-c]phenanthrene, 2,3,4,4ab,5,6,7,8,13ba, 13cb-Decahydro- 1H-13-
oxa-6a-aza-indeno[ 1,2-c]phenanthrene, 2,3,4,4ap,5,6,7,8,13,13bb-decahydro- 1H-
6a, 13-diaza-indeno[ 1,2-c]phenantbxen-13cb-ol, (-)-2,3,4,4ab,5,6,7,8,13,13bb-
decahydro-1 H-6a, 13-diaza-indeno[ 1,2-c]phenanthren-13cb-ol, (+)-
2,3,4,4ab,5,6,7,8,13,13bb-decahydro-1H-6a, 13-diaza-indeno[ 1,2-c]phenanthren-
13cb-ol, (2,3,4,4ab,5,6,7,8,13,13bb-Decahydro-1 H-6a, 13-diaza-indeno[l ,2-
c]phenanthrenyl)-I3cb-methanol or 5,6,7,7a,l 1,1 lb,12-Decahydro-6a,12-diaza-
indeno[l,2-a]fluoren-11a-ol.
The terms employed herein have the following meanings:
The term "halo" or "halogen", as employed herein as such or as part of
another group, refers to chlorine, bromine, fluorine or iodine.
The term "carboxyl", as employed herein, refers to a -COOH group.
The term "oxo", as employed herein, refers to an =O group.
The term "(Ci-C6)alkyl", as employed herein as such or as part of another
group, refers to a straight or branched carbon chain having 1 to 6 carbon atoms.
Representative examples of (Ci-C6)alkyl include, but are not limited to, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, .sec-butyl, tert-butyl, n-pentyl, isopentyl,
neopentyl, n-hexyl, and the like.
The term "(C2-C6)alkenyl", as employed herein as such or as part of another
group, refers to a straight or branched chain radical having 2 to 6 carbon atoms, and
containing (a) double bond(s).
The term "(C3-C7)cycloalkyl", as employed herein as such or as part of
another group, refers to a saturated cyclic hydrocarbon group containing 3 to 7
carbons. Representative examples of cycloalkyl include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "(C3-C7)cycIoalkyl(C1-C6)alkyI", as employed herein refers to a (C3-
C7)cycloalkyl group, as defined herein, appended to the parent molecular moiety
through a (C1-C6)alkyl group, as defined herein.
The term "aryl", as employed herein as such or as part of another group,
refers to a monocyclic or bicyclic aromatic group containing 6 to 12 carbon atoms.
Representative examples of aryl include, but are not limited to, phenyl, naphthyl, and
the like.
The term "aryl(Ci-C6)alkyl", as employed herein as such or as part of another
group, refers to an aryl group, as defined herein, appended to the parent molecular
moiety through an (C1-C6)alkyl group, as defined herein.
The term "aryloxy", as employed herein as such or as part of another group,
refers to an aryl group, as defined herein, appended to the parent molecular moiety
through an -O- group.
The term "aryl(C1-C6)alkoxy", as employed herein as such or as part of
another group, refers to an aryl group, as defined herein, appended to the parent
molecular moiety through an (Ci-C6)alkoxy group, as defined herein.
The term "aryloxy(Ci-C6)alkyl, as employed herein, refers to an aryloxy
group, as defined herein, appended to the parent molecular moiety through an (Ci-
C6)alkyl group, as defined herein.
The term "aryl(Ci-C6)alkoxy(Ci-C6)alkyl, as employed herein, refers to an
aryl(C1-C6)alkoxy group, as defined herein, appended to the parent molecular moiety
through an (Ci-C6)alkyl group, as defined herein.
The term "hydroxy", as employed herein as such or as part of another group,
refers to an -OH group.
The term "hydroxy(C1-C6)alkyl", as employed herein as such or as part of
another group, refers to at least one hydroxy group, as defined herein, appended to
the parent molecular moiety through a (C1-C6)alkyl group, as defined herein.
Representative examples of hydroxy(C1-C6)alkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl,
1 -methyl- 1-hydroxyethyl, 1-methyl-1-hydroxypropyl, and the like.
The term "halo(Ci-C6)alkyl", as employed herein, refers to one or more
halogen, as defined herein, appended to the parent molecular moiety through a (Ci-
C6)alkyl group, as defined herein. Representative examples of halo(C1-C6)alkyI
include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-
chloroethyl, 3-bromopropyl, and the like.
The term "amino", as employed herein as such or as part of another group,
refers to a -NH2 group.
The term "amino(Ci-C6)alkyl", as employed herein, refers to an amino group,
as defined herein, appended to the parent molecular moiety through a (Ci-C6)alkyl
group, as defined herein. Representative examples of amino(Ci-C6)alkyl include, but
are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 2-
aminopropyl, 4-aminobutyl, 1-methyl-1-aminoethyl, and the like.
The term "mono- or di(Ci-C6)alkylamino", as employed herein as such or as
part of another group, refers to one or two (Ci-C6)alkyl group(s), as defined herein,
appended to the parent molecular moiety through an amino group, as defined herein.
Representative examples of mono- or di(Ci-C6)alkylamino include, but are not
limited to methylamino, ethylamino, propylamino, butylamino, dimethylamino,
diethylamino, N-ethyl-N"-methylamino, and the like.
The term "mono- or di(Ci-C6)alkylamino(Ci-C6)alkyl", as employed herein,
refers to a mono- or di(C1-C6)alkylamino group, as defined herein, appended to the
parent molecular moiety through a (Ci-C6)alkyl group, as defined herein.
Representative examples of mono- or di(Ci-C6)alkylamino(C|-C6)alkyl include, but
are not limited to, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N-
methylaminoethyl, N-methylaminopropyl, N-ethyl-N-methylaminomethyl, and the
like.
The term "(Ci-C6)alkoxy", as employed herein as such or as part of another
group, refers to a (Ci-C6)alkyl, as defined herein, appended to the parent molecular
moiety through an -O- group. Representative examples of (Ci-C6)alkoxy include, but
are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy,sec-butoxy, tert-
butoxy, and the like.
The term "(Ci-C6)alkoxy(Ci-C6)alkyl", as employed herein as such or as part
of another group, refers to at least one (Ci-C6)alkoxy group, as defined herein,
appended to the parent molecular moiety through an (C1-C6)alkyl group, as defined
herein. Representative examples of (C1-C6)alkoxy(Ci-C6)alkyl include, but are not
limited to methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3,3-
dimethoxypropyl, 2,4-dimethoxybutyl and the like.
The term "hydroxy(C1-C6)alkoxy", as employed herein as such or as part of
another group, refers to a hydroxy group, as defined herein, appended to the parent
molecular moiety through an (Ci-C6)alkoxy group, as defined herein.
The term "hydroxy(Ci-C6)alkoxy(C|-C6)alkyl, as employed herein, refers to a
hydroxy(C1-C6)alkoxy group, as defined herein, appended to the parent molecular
moiety through an (C1-C6)alkyl group, as defined herein.
The term "carbamoyl", as employed herein as such or as part of another
group, refers to a -CONH2 group.
The term "mono- or di(Ci-C6)-alkylcarbamoyr", as employed herein, refers to
one or two (C1-C6)alkyl group(s), as defined herein, appended to the parent
molecular moiety through a -HNCO- or -NCO- group. Representative examples of
mono- or di(Ci-C6)-aIkylcarbamoyl include, but are not limited to N-
methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl and the like.
The compounds of formula I and IA, IB, IC, ID and IE, as well as the
pharmaceutically acceptable salts and esters thereof, are referred to below as the
compounds of the invention, unless otherwise indicated.
The invention includes within its scope all the possible stereoisomers of the
compounds, including geometric isomers, e.g. Z and E isomers (cis and trans
isomers), and optical isomers, e.g. diastereomers and enantiomers. Furthemore, the
invention includes in its scope both the individual isomers and any mixtures thereof,
e.g. racemic mixtures. The individual isomers may be obtained using the
corresponding isomeric forms of the starting material or they may be separated after
the preparation of the end compound according to conventional separation methods.
For the separation of optical isomers, e.g. enantiomers, from the mixture thereof the
conventional resolution methods, e.g. fractional crystallisation, may be used.
Pharmaceutically acceptable salts, e.g. acid addition salts with both organic
and inorganic acids are well known in the field of Pharmaceuticals. Non-limiting
examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates,
sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and
ascorbates. Pharmaceutically acceptable esters, when applicable, may be prepared by
known methods using pharmaceutically acceptable acids that are conventional in the
field of Pharmaceuticals and that retain the pharmacological properties of the free
form. Non-limiting examples of those esters include esters of aliphatic or aromatic
alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl
esters.
The compounds of the invention can be prepared analogously or according to
the methods known in the literature using suitable starting materials. The starting
materials of formulae II, HI and IV are commercially available or can be prepared via
a variety of known synthetic routes known in the literature.
For example, the starting materials used are arylalkylamines of formula (II)
wherein R1 is as defined above and X is NH, O, CH2 or S.
When X is O, the amines of formula (II) can be prepared, for example,
according to the process disclosed in the U.S. Patent Specification No. 4,710,504.
When X is CH2, the compounds of formula (II) can be prepared as described in J.
Med. Chem. 10 (1967) 856-859. When X is S, the compounds of formula (II) can be
prepared by decarboxylation of the corresponding 3-(thianaphten-3-yl)-L-alanine.
Other starting materials used are compounds of formula (III)
wherein R3 is as defined above and R11 is OH or halogen.
Furthermore, the starting materials used are compounds of formula (IV)
wherein R3-R7 and Z are as defined above and Y is O or NH. Compounds of
formula (IV) can be prepared according to the methods described in Tetrahedron 33
(1977) 1803-1808. Analogously, the corresponding acid chlorides can be used
instead of lactones (Y=O). When R3 and R5 form a ring, compounds of formula (IV)
are obtained by the partial reduction of their corresponding anhydrides.
In general, the compounds of formula (I), wherein X is NH, O or S, can be
prepared e.g. analogously or according to the following reaction scheme 1 :
Scheme 1
wherein R1, R3-R7 and Z are as defined above.
According to the reaction route of scheme I, alkylation of amines (II) with
compounds of formula (III) gives amides (V) which are converted into enamines
(VII) via beta carbolines (V) by Bischler-Napieralski reaction followed by ring D
formation by allowing compounds of formula (VI) to react with 1,3-dihaloalkanes
under basic conditions as described in Gazz. Chim. Jtal. Ill (1981) 257-267. In the
last step, compounds of formula (I) are obtained
1) by oxidation of enamines (VQ) using potassium iodide, iodide and air or
2) by reaction of enamines (VII) with formaldehyde in presence of H?nig
base at 60°C.
Another route for preparing compounds of formula (I), wherein X is NR2, O,
CH2 or S, is illustrated in scheme 2
Scheme 2
wherein X is NR2, O, CH2 or S, R1-R7 and Z are as defined above.
In scheme 2 arylalkylamines of formula (II), wherein X is NH, O, CH2, or S,
are reacted with compounds of formula (IV), or the corresponding acid chloride, to
give amides (VIII) as described in Tetrahedron 33 (1977) 1803-1808. The Bischler-
Napieralski cyclization of the intermediates (VIII) leads to enamines (IX) which are
converted into compounds of formula (I).
The compounds of formula (I), wherein X is NH, can be alkylated with
alkylhalides in the presence of a suitable base at room temperature (Heterocycles 27
(1988) 1179-1190) according to following scheme 3:
wherein R1-R7 and Z are as defined above.
A further method for preparing compounds of formula (I) is illustrated in
scheme 4:
Scheme 4
wherein R2 is BOC and R1, R5 and R6 are as defined above.
In scheme 4 pyridine is alkylated with tryptophyl bromides (X) to give
pyridinium salts (XI) whose partial reduction gives compounds of formula (XII).
Protection of compounds of formula (XII) using di-t-butyl dicarbonate under basic
conditions gives compounds of formula (XIII). The Polonovski-Potier reaction of the
obtained intermediates and their cyclisation using MeOH/HCl yield the compounds
of formula (I).
A further process for the preparation of compounds of formula (I), wherein X
is O, S or NH, R1 and R3-R8 are as defined above, is shown in the following scheme
5:
Scheme 5
In scheme 5 oxidative cyclization of derivative (XIV) with mercuric acetate
according to the method described in Heterocycles 32 (1991) 489-497 gives enamine
(XV). This intermediate can be oxidized or treated with formaldehyde as in scheme 1
or reduced with sodium borohydride to give compounds of formula (I).
A further method for preparing compounds of formula (I), wherein R6 and R7
form a bond, is illustrated in scheme 6:
wherein X is NH and R3 is lower alkyl.
Applying the method described in J. Org. Chem. 52 (1987) 353-356, the
hetero-Diels-Alder reaction of 3,4-dihydro-b-carboline (XVI) with diene ester
(XVII), prepared by the Wittig reaction as described in Can. J. Chem. 65 (1987) 670-
682, gives compounds of formula (XVHI), which are then reduced to alcohols of
formula (I).
A further method for preparing compounds of formula (I) is illustrated in
scheme 7.
Scheme 7
wherein X, R1, R3, R7 and z are as defined above. R12 can be H or OCH3 and
R13 can be an alkyl or aryl group.
In scheme 7, compounds of formula (XIX), when R12 is H, are prepared as
described in J. Chem. Soc, Chem. Commun. (1995) 2317-2318, and compounds of
formula (XDC), when R12 is OCH3, are prepared as described in J. Chem. Soc. (C)
(1971) 736-743. Compounds of formula (XIX) are reacted with Grignard reagents to
give compounds of formula (I). When R12 in formula (XIX) is H, the other R13 group
in formula (I) is also H.
A new method to prepare certain compounds of formula (I) is shown in
scheme 8.
Scheme 8
It is obvious to a skilled person that, in the above reactions, any starting
material or intermediate can be protected, if necessary, in manner well known in the
chemical field. Any protected functionality is subsequently deprotected in a usual
manner.
It should be noted that the above described synthetic routes are meant to
illustrate the preparation of the compounds of the invention and the preparation is by
no means limited thereto, i.e. other synthetic methods which are within the general
knowledge of a skilled person are also possible.
The compounds of the invention may be converted, if desired, into their
pharmaceutically acceptable salt or ester form using methods well known in the art.
The present invention will be explained in more detail by the following
examples. The examples are meant only for illustrating purposes and do not limit the
scope of the invention defined in claims.
EXAMPLE 1
l-PropyI-4,9-dihydro-3H-b-carboline
8.00 g (50.0 mmol) of tryptamine was dissolved in 150 ml of ethyl acetate
and 4.80 ml (52.0 mmol) of n-butyric acid was slowly added. After standing for 4 h
at 0°C, the reaction mixture was filtered to give 12.30 g (49.5 mmol) of tryptamine
butyrate, which was melted. The melt was heated at 200°C and kept for 30 min at
that temperature. Water formed was removed using a Dean-Stark apparatus. The
melt after cooling was mixed with 120 ml of toluene, 23.5 ml (257.7 mmol) of
freshly distilled phosphorus oxychloride was added and the reaction mixture was
refluxed for 4 h. The solution was evaporated in vacuum and the dark oil was mixed
with 20% solution of acetic acid (3 x 50 ml). The solid was filtered off and the
aqueous solution was made alkaline with 25% ammonium hydroxide under cooling
and extracted with dichloromethane (3 x 50 ml). The combined organic phases were
dried over sodium sulfate, the drying agent was filtered off and the filtrate was
evaporated to give the title compound, which was purified by column
chromatography (silica gel, dichloromethane/methanol, 95:5).
NMR: 1.00 (t, 3H), 1.75 (m, 2H), 2.66 (t, 2H), 2.87 (t, 2H), 3.90 (t, 2H),
7.00-7.62 (m, 4H), 8.94 (br s, 1H).
MS: 212 (28%), 211 (12%), 197 (25%), 184 (100%), 169 (13%).
EXAMPLE 2
l-Isobutyl-4,9-dihydro-3H-b-carboline
The procedure of example 1 was repeated, except that isovaleric acid was
used instead of n-butyric acid.
NMR: 0.98 (d, 6H), 2.16 (m, 1H), 2.54 (d, 2H), 2.86 (t, 2H), 3.89 (t, 2H),
7.00-7.62 (m, 4H), 8.60 (br s, 1H).
MS: 226 (16%), 211 (18%), 184 (100%), 169 (13%).
EXAMPLE 3
l-Butyl-4,9-dihydro-3H-b-carboline
The procedure of example 1 was repeated, except that n-valeric acid was used
instead of n-butyric acid.
NMR: 1.00 (t, 3H), 7.00-7.62 (m, 4H), 8.64 (br s, 1H).
MS: 226 (18%), 211 (18%), 184 (100%), 169 (14%).
EXAMPLE 4
l-(2-MethyI-butyl)-4,9-dihydro-3H-b-carboline
The procedure of example 1 was repeated, except that 3-methylvaleric acid
was used instead of n-butyric acid.
NMR: 0.84 (t, 3H), 0.87 (d, 3H), 7.05-7.60 (m, 4H), 12.2 (br s, 1H).
MS: 240 (9%), 225 (10%), 211 (10%), 185 (13%), 184 (100%), 183 (14%),
155 (24%).
EXAMPLE 5
l-Cyclohexylmethyl-4,9-dihydro-3H-b-carboIine
The procedure of example 1 was repeated, except that cyclohexylacetic acid
was used instead of n-butyric acid.
NMR: 1.0-1.9 (m, 11H), 2.56 (d, 2H), 2.85 (m, 2H), 3.88 (m, 2H), 7.14-7.63
(m, 4H), 8.55 (br s, 1H).
MS: 266 (8%), 185 (15%), 184 (100%), 183 (12%), 155 (17%).
EXAMPLE 6
1b-Isopropy 1-1,2,3,4,6,7,12,12b b-octahydroindoIo[2,3-a]quinolizine
2.56 g (11.5 mmol) of 4,9-Dihydro-1-isobutyl-3-H-pyrido[3,4-b]indole
(example 2), 2 ml of N-ethyldiisopropylamine, and 1.35 ml (13.8 mmol) of 1-bromo-
3-chloropropane were dissolved in 50 ml of acetonitrile. The mixture was refluxed
under argon for 8 h. After evaporation of the solvent, 20 ml of methanol and 1.3 g
(34.5 mmol) of sodium borohydride were added. The reaction mixture was stirred for
1 h at room temperature and 20 ml of water was then added. The reaction mixture
was extracted with dichloromethane (3 x 50 ml). The combined organic phases were
dried over sodium sulfate, the drying agent was filtered off and the filtrate was
evaporated to give the title compound, which was purified by column
chromatography (silica gel, dichloromethane/methanol, 95:5).
NMR: 1.02 (br s, 6H), 7.11 (t, 1H), 7.18 (t, 1H), 7.35 (d, 1H), 7.48 (d, 1H),
7.85 (brs, 1H).
MS: 267 (100%), 253 (20%), 197 (35%), 170 (30%), 169 (30%).
EXAMPLE 7
2-(1a,23,4,6,7,12,12bb-Octahydroindolo[2,3-a]quinolizin-l-yI)-butan-2-
ol
To a solution of 190 mg (0.7 mmol) of l-(12,3,4,6,7,12,12b-octahydro-
indolo[2,3-a]quinolizin-l-yl)-ethanone (Tetrahedron Lett. 30 (1989) 719-722) in 5
ml of dichloromethane at -60° C was added 0.11 ml (0.8 mmol) of ethylmagnesium
bromide (1.0 M). The reaction mixture was stirred 30 min at that temperature and 2 h
at room temperature. Water (10 ml) was then added and the reaction mixture was
extracted with dichloromethane (3 x 50 ml). The combined organic phases were
dried over sodium sulfate, the drying agent was filtered off and the filtrate was
evaporated to give the title compound, which was purified by column
chromatography (silica gel, dichloromethane/methanol, 95:5).
NMR: 0.97 (t, 3H), 1.30 (s, 3H), 4.69 (br s, 1H), 7.00-7.50 (m, 4H), 8.36 (br
s,lH).
MS: 297 (100%), 281 (30%), 269 (35%), 225 (28%), 197 (45%), 170 (35%),
169 (34%).
EXAMPLE 8
2-(1a,2,3,4,6,7,12,12bb-Octahydroindolo[2,3,-a]quinolizm-l-y)-propan-2-
ol
The procedure of example 7 was repeated, except that methylmagnesium
bromide (excess) was used instead of ethylmagnesium bromide.
NMR: 1.37 (s, 3H), 1.42 (s, 3H), 4.73 (br s, 1H), 7.00-7.50 (m, 4H), 8.18 (br
s, 1H).
MS: 283 (100%), 267 (42%), 225 (33%), 197 (60%), 170 (50%), 169 (50%).
EXAMPLE 9
1a-lsopropyl-1,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-l-ol
(Compound A)
5.13 g (23.0 mmol) of 4,9-Dihydro-l-isobutyl-3-H-pyrido[3,4-b]indole, 4 ml
of N-ethyldiisopropylamine, and 2.7 ml (27.6 mmol) of l-bromo-3-chloropropane
were dissolved in 100 ml of acetonitrile. The mixture was refluxed under argon for 8
h. The dark solution was concentrated to an oil, which was treated with 20% sodium
hydroxide. After 10 min stirring, the solution was extracted with dichloromethane (3
x 50 ml). The combined organic phases were dried over sodium sulfate, the drying
agent was filtered off and the filtrate was evaporated to give the corresponding
enamine, which was dissolved in 100 ml of acetonitrile. 7.0 g (27.6 mmol) of iodine
and 4.6 g (27.6 mmol) of potassium iodide were added. The reaction mixture was
stirred in the dark under air for 3 h. After evaporation of the solvent, 50 ml of
methanol and, with cooling, 2.6 g (69 mmol) of sodium borohydride were added.
The reaction mixture was stirred for 1 h at room temperature and 20 ml of water was
then added. The reaction mixture was extracted with dichloromethane (3 x 50 ml).
The combined organic phases were dried over sodium sulfate, the drying agent was
filtered off and the filtrate was evaporated to give the title compound, which was
purified by column chromatography (silica gel, dichloromethane/methanol, 95:5).
NMR: 0.47 (d, 3H), 0.90 (d, 3H), 3.48 (br s, 1H), 7.00-7.50 (m, 4H), 8.92 (br
s,lH).
MS: 284 (14%), 239 (13%), 171 (100%), 170 (16%), 169 (33%).
EXAMPLE 10
la-Ethyl-2a-methyl-l,23,4,6,7,12,12bb-octahydro-indolo[2,3-
a]quinolizin-l-ol (Compound B)
The procedure of example 9 was repeated, except that 4,9-dihydro-l-propyl-
3-H-pyrido[3,4-b]indoIe was used instead of 4,9-dihydro-l-isobutyl-3-H-pyrido[3,4-
6]indole and 1,3-dibromobutane was used instead of l-bromo-3-chloropropane.
NMR: 0.69 (t, 3H), 1.00 (d, 3H), 3.20 (br s, 1H), 7.00-7.60 (m, 4H), 9.04 (br
s, 1H).
MS: 284 (5%), 267 (15%), 225 (100%), 210 (15%), 195 (15%), 182 (72%),
171 (41%), 170 (22%), 169 (32%).
EXAMPLE 11
9-Fluoro-la-isopropyI-1,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-
a]quinolizin-l-ol
The procedure of example 9 was repeated, except that 6-fluoro-l-isobutyl-
4,9-dihydro-3H-pyrido[3,4-b]indole (prepared from 5-fluorotryptamine as described
in example 2) was used instead 4,9-dihydro-l-isobutyl-3H-pyrido[3,4-b]indole.
NMR: 0.45 (d, 3H), 0.89 (d, 3H), 3.32 (s, 1H), 6.8-7.25 (m, 3H), 8.94 (br s,
1H).
MS: 302 (26%), 203 (13%), 189 (100%), 161 (26%).
EXAMPLE 12
l-s-Butyl-l,2,3,4,6,7,12,12bb-octahydro-indolo[23-a]quinolizin-l-ol
(mixture of isomers) (Compound C)
The procedure of example 9 was repeated, except that l-(2-methylbutyl)-4,9-
dihydro-3H-pyrido[3,4-b]indole was used instead of 4,9-dihydro-l-isobutyl-3H-
pyrido[3,4-b]indole.
NMR: 0.48 (d, 3H, major isomer), 0.69 (t, 3H, minor isomer), 0.82 (t, 3H,
major isomer), 0.92 (d, 3H, minor isomer), 3.30 (s, 1H), 7.0-7.5 (m, 4H), 8.88 (br s,
1H, minor isomer), 8.93 (br s, 1H, major isomer).
MS: 298 (23%), 172 (24%), 171 (100%), 170 (15%), 169 (23%), 143 (29%).
EXAMPLE 13
l-CycIohexyI-l,2,3,4,6,7,12,12bb-octahydro-indoIo[2,3-a]quinolizin-l-ol
The procedure of example 9 was repeated, except that 1-cyclohexylmethyl-
4,9-dihydro-3H-pyrido[3,4-b]indole was used instead 4,9-dihydro-l-isobutyl-3H-
pyrido[3,4-b]indole.
NMR: 3.35 (br s, 1H), 7.02-7.55 (m, 4H), 8.98 (br s, 1H).
MS: 324 (21%), 172 (12%), 171 (100%), 170 (10%), 169 (15%), 143 (22%).
EXAMPLE 14
(la-Isopropyl-l,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-l-
yl)-methanol
The procedure of example 9 was repeated, except that instead of oxidation
using iodine and potassium iodide, the enamine obtained was treated with 40 %
aqueous formaldehyde and the reaction mixture was heated to reflux for 3 h and the
solvent was evaporated. The residue was diluted with ethyl acetate and washed with
brine. The organic phase was dried over sodium sulfate, the drying agent was filtered
off and the filtrate was evaporated to give the title compound, which was purified by
column chromatography (silica gel, dichloromethane/methanol, 98:2).
NMR 0.58 (br s, 3H), 0.82 (d, 3H), 3.07 (br s, 1H), 3.62 (d, 1H), 4.13 (d,
1H), 7.00-7.50 (m, 4H), 9.41 (br s, 1H).
MS: 298 (100%), 297 (55%), 281 (60%), 170 (75%), 169 (52%).
EXAMPLE 15
(1a-n-propyl-1,2,3,4,6,7,12,12bb-octahydroindoIo[2,3-a]qumoIizin-1-yl)-
methanol
The procedure of example 14 was repeated, except that 4,9-dihydro-l-butyl-
3-H-pyrido[3,4-b]indole was used instead of 4,9-dihydro-l-isobutyl-3-H-pyrido[3,4-
b] indole.
NMR: 0.81 (t, 3H), 3.34 (br s, 1H), 3.65 (d, 1H), 3.82 (d, 1H), 7.00-7.50 (m,
4H), 10.07 (brs, 1H).
MS: 298 (100%), 297 (65%), 281 (67%), 170 (75%), 169 (52%).
EXAMPLE 16
(la-MethyI-l,2,3,4,6,7,12,12bb-octahydroindoIo[2,3-a]quinoIizin-l-yI)-
methanol
The procedure of example 14 was repeated, except that l-ethyl-4,9-dihydro-
3H-pyrido[3,4-b]indole was used instead 4,9-dihydro-l-isobutyl-3H-pyrido[3,4-
b]indole.
NMR: 0.91 (s, 3H), 3.37 (br s, 1H), 3.70 (d, 1H), 3.76 (d, 1H), 7.0-7.6 (m,
4H), 9.78 (br s, 1H).
MS: 270 (97%), 269 (100%), 253 (53%), 197 (48%), 170 (68%), 169 (62%).
EXAMPLE 17
(la-EthyI-l,4,6,7,12,12bP-hexahydroindolo[23-a]quinolizin-l-yl)-
methanol
A mixture of 0.34 g (2.0 mmol) of 3,4-dihydro-b-carboline and 0.39 g (2.5
mmol) of ethyl 2-ethylpenta-2,4-dienoate in 5 ml of chlorobenzene was refluxed for
16 h. The solvent was evaporated and the residue was subjected to column
chromatography (silica gel, dichloromethane/methanol, 99:1) to give the ester
intermediate. This product was reduced in the usual manner with lithium aluminum
hydride in dry tetrahydrofuran to afford the title compound.
NMR: 0.82 (t, 3H), 3.69 (d, 1H), 3.70 (br s, 1H), 3.90 (d, 1H), 5.42 (ddd,
1H), 5.97 (ddd, 1H), 7.0-7.5 (m, 4H), 10.02 (br s, 1H).
MS: 282 (31%), 171 (14%), 170 (100%), 169 (52%).
EXAMPLE 18
2b-Methoxy-1,2,3,4,6,7,12,12ba-octahydro-indollo[2,3-a]quinolizine
and
2a-Methoxy-l,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizine
(Compound D)
1.16 g (14.7 mmol) of pyridine and 3.0 g (13.4 mmol) of tryptophyl bromide
were dissolved in 15 ml of dry diethyl ether. The reaction mixture was heated with
stirring at 60°C until complete evaporation of the solvent. The mixture was then
heated at 100°C for 2 h to give the corresponding pyridinium bromide salt. This was
dissolved in 100 ml of methanol and 1.52 g (40.1 mmol) of sodium borohydride was
added in portions with cooling. The reaction mixture was stirred at room temperature
for 4 h, followed by addition of 20 ml of water. The reaction mixture was extracted
with dichloromethane (3 x 30 ml). The combined organic phases were dried over
sodium sulfate, the drying agent was filtered off and the filtrate was evaporated. The
residue was dissolved in 100 ml of dry dichloromethane and 2.91 g (13.3 mmol) of
di-t-butyl dicarbonate and 0.149 g (1.2 mmol) of 4-(dimethylamino)pyridine were
added. The reaction mixture was stirred for 2 h at room temperature under argon.
The solvent was evaporated and the residue purified by column chromatography
(silica gel, dichloromethane/rnethanol, 98:2). The obtained viscous oil was dissolved
in 40 ml of dichloromethane and 2.54 g (13.3 mmol) of mCPBA was added. The
solution was stirred for 2 h at 0°C, after which the solvent was evaporated and the
crude product was purified by column chromatography (silica gel,
dichloromethane/methanol, 98:2) to yield the Boc Nb-oxide.
To a stirred solution of 0.59 g (1.7 mmol) of Boc Nb-oxide in 15 ml of
dichloromethane at 0°C was slowly added 3.0 ml of trifluoroacetic anhydride. The
cooling bath was removed and stirring was continued for 2 h at rt, after which the
solvent was evaporated. Methanol saturated with hydrogen chloride gas (20 ml) was
added and the mixture was refluxed for 2 h. Alkaline work-up and purification by
column chromatography (silica gel, dichloromethane/methanol, 98:2) yielded two
ethers.
2b-Methoxy-l,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizine:
NMR: 1.54 (ddd, 1H), 3.24 (dd, 1H), 3.38 (dddd, 1H), 3.43 (s, 3H), 7.00-7.50
(m,4H),7.77(brs, 1H).
MS: 256 (100%), 255 (86%), 255 (59%), 197 (35%), 169 (30%).
2a-Methoxy-l,2,3,4,6,7,12,12ba-octahydro-indolo[2,3-a]quinolizine:
NMR:: 3.41 (s, 3H), 3.67 (br s, 1H), 3.68 (br d, 1H), 7.00-7.50 (m, 4H), 7.72
(br s, 1H).
MS: 256 (100%), 255 (75%), 255 (70%), 223 (45%), 197 (40%), 170 (45%),
169 (65%).
EXAMPLE 19
l-(l,2a,3,4,6,7,12,12ba-Octahydroindolo[2,3-a](quinolizin-2-yl)-propan-
l-ol
To a solution of 0.086 g (0.3 mmol) of l,2,3,4,6,7,12,12b-octahydro-
indolo[2,3-a]quinolizine-2-carbaldehyde (J. Chem. Soc. Chem. Commun. 22 (1995)
2317-2318) in 2 ml of dichloromethane at-60°C was added 0.22 ml (1.7 mmol) of
1M ethylmagnesium bromide. The reaction mixture was stirred for 4 h under argon.
Work-up with aqueous sodium hydroxide, followed by extraction with
dichloromethane, and purification by column chromatography (silica gel,
dichloromethane/methanol, 98:2) gave the title compound.
NMR: 1.02 (t, 3H), 1.93 (br d, 1H), 2.30 (br d, 1H), 6.80-7.40 (m, 4H).
MS: 284 (95%), 283 (100%), 225 (80%), 169 (36%).
EXAMPLE 20
(l,2a,3,4,6,7,12,12ba-Octahydromdolo[2,3-a]quinolizin-2-yl)-propan-2-
ol
To a solution of 88 mg (0.31 mmol) of l,2a,3,4,6,7,12,12ba-
octahydroindolo[2,3-a]-quinolizine-2-carboxylic acid methyl ester in 3 ml of dry
tetrahydrofuran was added dropwise 1 ml (3.0 mmol) of a solution of
methylmagnesium chloride (3 M in tetrahydrofuran). The resulting solution was then
refluxed for 90 min. The mixture was then worked-up as in example 7 to give the
crude alcohol, which was purified by column chromatography (silica gel,
dichloromethane/methanol, 95:5) to give the title compound.
NMR:: 1.20 (s, 3H), 1.25 (s, 3H), 3.28 (br d, 1H), 7.0-7.5 (m, 4H).
MS: 284 (86%), 283 (65%), 225 (100%).
EXAMPLE 21
(1,2a,3,4,6,7,12,12bb-Octahydroindolo[2,3-a]quinolizin-2-yl)-propan-2-
ol
As in example 20, 64 mg (0.23 mmol) of 1,2a,3,4,6,7,12,12bb-
octahydroindolo[2,3-a]-quinolizine-2-carboxylic acid methyl ester in 3 ml of dry
tetrahydrofuran and 0.7 ml (2.1 mmol) of a solution of methylmagnesium chloride (3
M in tetrahydrofuran) were refluxed for 90 min. Work-up as above gave, after
column chromatography (silica gel, dichloromethane/methanol, 90:10), the title
compound.
NMR: 1.17 (s, 3H), 1.18 (s, 3H), 4.57 (br s, 1H), 7.0-7.5 (m, 4H), 8.65 (br s,
1H).
MS: 284 (58%), 283 (53%), 225 (100%).
EXAMPLE 22
(2a-Ethyl-l,2,3,4,6,7,12,12ba-octahydroindoIo[23-a]quinolizin-2-yl)-
methanol
To a stirred solution of 0.36 g (3.6 mmol) of diisopropylamine in 4 ml of dry
tetrahydrofuran at -50°C was added 2.0 ml (3.6 mmol) of n-butyllithium (1.8 M in
hexanes). The mixture was allowed to warm up to -30°C (15 min), after which it was
cooled to -70°C. At this temperature, 0.64 g (3.6 mmol) of
hexamethylphosphoramide was added. Stirring was continued for 30 min at this
temperature, after which 0.42 g (1.48 mmol) of methyl l-[2-(3-indolyl)ethyI]-1,2,5,6-
tetrahydropyridine-4-carboxylate in 7 ml of tetrahydrofuran was added. After stirring
for 20 min at -70°C, the mixture was allowed to warm up to -40°C (15 min). At this
temperature, 0.3 g (3.6 mmol) of ethyl iodide was added and stirring was continued
for 1 h. The cooling bath was then removed and, after additional 15 min, the mixture
was quenched with 5% ammonia. The aqueous layer was extracted with
dichloromethane (3 x 20 ml) and the combined organic layers were washed with
water. Drying over sodium sulfate, filtration and evaporation of the solvent gave the
crude enamine, which was dissolved in 50 ml of methanol saturated with hydrogen
chloride and the resulting solution was stirred for 16 h at room temperature. The
solvent was evaporated and the residue was treated with aqueous sodium hydrogen
carbonate. After normal extraction procedures (dichloromethane), the solvent was
evaporated to give the crude product, which was subjected to column
chromatography (silica gel, dichloromethane/methanol, 98:2) to afford the
intermediate ester, 2a-ethyl-l,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizine-
2-carboxylic acid methyl ester. This compound was then treated with lithium
aluminum hydride in dry tetrahydrofuran in the usual manner to give, after column
chromatography (silica gel, dichloromethane/methanol, 95:5), the title alcohol.
NMR: 0.90 (t, 3H), 3.29 (d, 1H), 3.43 (d, 1H), 3.52 (br d, 1H), 7.0-7.5 (m,
4H).
MS: 284 (100%), 283 (98%), 253 (33%), 197 (37%), 170 (33%), 169 (40%),
156 (34%).
EXAMPLE 23
(2a-Ethyl-l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinoIizin-2-yl)-
methanol
A solution of 51 mg (0.16 mmol) of the ester intermediate obtained in
example 22 (2a-ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizine-2-
carboxylic acid methyl ester) in 4 ml of trifluoroacetic acid was refluxed under argon
for 16 h. The acid was evaporated and the residue treated with aqueous sodium
hydrogen carbonate. After normal extraction procedures (dichloromethane) a crude
mixture (20:80) of the two diastereomers, 2a-ethyl-1,2,3,4,6,7,12,12ba-
octahydroindolo[2,3-a]quinolizine-2-carboxylic acid methyl ester and 2a-ethyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizine-2-carboxylic acid methyl
ester, was obtained. The latter isomer was separated by column chromatography
(silica gel, dichloromethane/methanol, 99:1) and it was them reduced in the usual way
with lithium aluminum hydride in dry tetrahydrofuran. Purification as above then
gave the title alcohol.
NMR: 0.87 (t, 3H), 3.51 (d, 1H), 3.78 (d, 1H), 7.0-7.5 (m, 4H).
MS: 284 (95%), 283 (100%), 253 (30%), 197 (30%), 170 (17%), 169 (23%),
156 (19%).
EXAMPLE 24
l-(2a-EthyI-l,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizin-2-yl)-
ethanone and
2-(2a-Ethyl-l,2,3,4,6,7,12,12ba-octahydroindoIo[2,3-a]quinolizin-2-yl)-
propan-2-ol
As in example 20,230 mg (0.74 mmol) of the ester intermediate obtained in
example 22 (2a-ethyl-l,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizine-2-
carboxylic acid methyl ester) in dry tetrahydrofuran (9 ml) and 3.7 ml (11.1 mmol)
of methylmagnesium chloride (3M in tetrahydrofuran) were refluxed overnight.
Usual work-up gave, after column chromatography (silica gel,
dichloromethane/methanol, 98:2 - 95:5), a 5:1 mixture of two compounds.
l-(2a-Ethyl-l,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizin-2-yl)-
ethanone:
NMR: 0.82 (t, 3H), 2.14 (s, 3H), 3.44 (br d, 1H), 7.05-7.50 (m, 4H), 8.05 (br
s, 1H).
MS: 296 (83%), 295 (62%), 253 (100%), 184 (95%).
2-(2a-Ethyl-1,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizin-2-y1)-
propan-2-ol:
NMR: 1.05 (t, 3H), 1.24 (s, 6H), 3.42 (br d, 1H), 7.05-7.50 (m, 4H), 7.88 (br
s,lH).
MS: 312 (48%), 311 (37%), 253 (100%).
EXAMPLE 25
l-(2a-EthyI-lv2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinoIizin-2-yl)-
ethanol
The ketone obtained in the above reaction was reduced with sodium
borohydride in methanol in the usual manner to give the title alcohol as an
inseparable mixture of diastereomers.
NMR: 0.95 (t, 3H, minor), 1.18 (t, 3H, major), 3.61 (q, 1H, minor), 3.67 (q,
1H, major).
MS: 298 (100%), 297 (64%), 253 (87%).
EXAMPLE 26
2,3,4,7,8,13,13b-Octahydro-lH-azepino[1",2":1,2]pyrido[3,4-b]indole
(Compound E)
To a solution of 0.20 g (1.2 mmol) of tryptamine in 5.0 ml of xylene was
added 0.14 g (1.2 mmol) of e-caprolactam. The mixture was refluxed for 7 h. After
evaporation of the solvent, the residue was dissolved in 5.0 ml of toluene, 0.65 ml of
freshly distilled phosphorus oxychloride was added and the reaction mixture was
refluxed for 9 h. The solution was evaporated in vacuum and the residue was mixed
with a 20% solution of acetic acid (3 x 10 ml). The solid was filtered off and the
aqueous solution was made alkaline (pH 11) with 25% ammonium hydroxide under
cooling and extracted with dichloromethane (3 x 20 ml). To the combined organic
layers was added 6.0 ml of 4 M sodium hydroxide and this mixture was refluxed for
1 h. The organic phase was dried over sodium sulfate, the drying agent was filtered
off and the filtrate was concentrated to give an oil, which was dissolved in 30 ml of
methanol. To the cold solution was added 0.2 g (5.6 mmol) of sodium borohydride.
The mixture was stirred at room temperature for 1 h. Water was slowly added and
the reaction mixture was extracted with dichloromethane (3 x 20 ml). The combined
organic phases were dried over sodium sulfate, the drying agent was filtered off and
the solvent evaporated to give the title compound, which was purified by column
chromatography (silica gel, dichloromethane/methanol, 95:5).
NMR: 4.03 (br d, 1H), 7.11-7.46 (m, 4H), 8.05 (br s, 1H).
MS: 240 (52%), 239 (100%), 198 (10%), 170 (24%).
EXAMPLE 27
la-Ethyl-12-methyl-l,2,3,4,6,7,12bb-octahydroindoIo[2,3-a]quinolizin-l-
ol
To a solution of 0.05 g (0.1 mmoles) of la-ethyl-lb-hydroxy-
l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizine and 0.05 g (0.9 mmoles) of
KOH in 1.0 ml of acetone was added 0.02 ml (0.3 mmoles) of iodomethane. The
reaction mixture was stirred at rt for 1 h. Water was slowly added and the reaction
mixture was extracted with dichloromethane (3 x 20 ml). The combined organic
phases were dried over sodium sulfate, the drying agent was filtered off and the
filtrate was evaporated to give the title compound, which was purified by column
chromatography (silica gel, dichloromethane/methanol, 95:5).
NMR: 0.71 (t, 3H), 1.01 (m, 2H), 3.59 (br s, 1H), 3.72 (s, 3H), 7.00-7.50 (m,
4H).
MS: 284 (21%), 283 (100%), 185 (60%), 170 (10%).
EXAMPLE 28
la-Ethyl-12-ethyl-l,3,4,6,7,12bb-octahydro-indolo[2,3-a]quinoIizin-l-ol
The procedure of example 27 was repeated, except that iodoethane was used
instead of iodomethane.
NMR: 0.71 (t, 3H), 1.00 (m, 2H), 1.07 (t, 3H), 3.60 (s, 1H), 4.20 (m, 1H),
4.64 (m, 1H), 7.00-7.50 (m, 4H).
MS: 298 (29%), 297 (19%), 199 (100%), 171 (33%).
EXAMPLE 29
la-MethyI-1,3,4,5,6,11b-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-l-
ol
To a solution of 0.48 g (3.0 mmol) of 2-(3-benzo[b]furanyl)ethylamine in 5.0
ml of xylene was added 0.34 g (3.0 mmol) of a-methyl-d-valerolactone. The mixture
was refluxed for 7.5 h. After evaporation of the solvent the residue was dissolved in
6.0 ml of toluene, 0.72 ml of freshly distilled phosphorus oxychloride was added and
the reaction mixture was refluxed for 11 h. The solution was evaporated in vacuum
and the obtained oil was mixed with a 20% solution of acetic acid (3 x 20 ml). The
solid was filtered off and the aqueous solution was made alkaline (pH 11) with 25%
ammonium hydroxide under cooling and extracted with dichloromethane (3 x 20
ml). To the combined organic phases was added 12.5 ml of 4 M sodium hydroxide
and this mixture was refluxed for 1 h. The organic phase was dried over sodium
sulf ate, the drying agent was filtered off and the filtrate was concentrated to give the
corresponding enamine, which was oxidised as described in example 9.
NMR: 1.18 (s, 3H), 3.25 (br d, 1H), 7.10-7.50 (m, 4H).
MS: 257 (25%), 242 (10%), 172 (100%).
EXAMPLE 30
(la-Methyl-1,3,4,5,6,11bb-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol
The procedure of example 29 was repeated, except that to the formed
enamine, 40 % aqueous formaldehyde was slowly added. The reaction mixture was
refluxed for 3.5 h and the solvent was evaporated. The residue was diluted with ethyl
acetate and washed with brine. The organic phase was dried over sodium sulfate, the
drying agent was filtered off and the filtrate was evaporated to give the title
compound, which was purified by column chromatography (silica gel,
(dichloromethane/methanol, 98:2).
NMR: 0.89 (s, 3H), 3.40 (br s, 1H), 3.62 (d, 1H), 4.29 (d, 1H), 7.10-7.50 (m,
4H).
MS: 271 (69%), 270 (100%), 198 (45%), 171 (52%), 170 (60%).
EXAMPLE 31
la-Isopropyl-l,3,4,5,6,11b-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluoren-l-ol
The procedure of example 9 was repeated, except that 2-(3-
benzo[b]furanyl)ethylamine was used instead of tryptamine.
NMR: 1.00 (m, 6H), 7.25 (m, 2H), 7.44 (m, 2H),
MS: 285 (23%), 242 (10%), 198 (10%), 186 (23%), 172 (100%).
EXAMPLE 32
la-EthyI-l,3,4,5,6,11bb-hexahydro-2H-ll-oxa-4a-aza-benzo[a]fluoren-l-
ol
The procedure of example 29 was repeated, except that a-ethyl-d-
valerolactone was used instead of a-methyl-d-valerolactone.
NMR: 0.73 (t, 3H), 3.22 (br s, 1H), 7.00-7.30 (m, 2H), 7.40-7.55 (m, 2H).
MS: 271 (15%), 186 (18%), 173 (11%), 172 (100%), 170 (28%).
EXAMPLE 33
(la-Ethyl-l,3,4,5,6,11bb-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-
l-yl)-methanol
The procedure of example 30 was repeated, except that a-ethyl-d-valerolacto-
ne was used instead of a-methyl-d-valerolactone.
NMR: 0.62 (t, 3H), 3.48 (br s, 1H), 3.52 (d, 1H), 4.06 (d, 1H), 7.00-7.30 (m,
2H), 7.40-7.55 (m, 2H).
MS: 285 (56%), 284 (100%), 268 (19%), 198 (36%), 172 (20%), 171 (44%),
170 (54%).
EXAMPLE 34
5,6,7,7a,11,11b,12-Decahydro-6a,12-diaza-indeno[1,2-a]fluoren-11a-ol
The procedure of example 29 was repeated, except that instead of 2-(3-
benzo[b]furanyl)ethylamine and a-methyl-d-valerolactone, tryptamine and
hexahydroisobenzofuran-1-one were used.
NMR: 4.45 (br d, 1H), 7.00-7.60 (m, 4H), 9.11 (br s, 1H).
MS: 296 (8%), 143 (100%), 130 (81%).
EXAMPLE 35
l,2,3,4,4a,5,6,7,8,13-Decahydro-6a,13-diaza-iudeno[l,2-c]phenanthrene
To a solution of 0.356 g (1.26 mmol) of N-[2-(3-indolyl)ethyl)]decahydroiso-
quinoline in 20 ml of ethanol was added a solution of 1.6 g of mercuric acetate and
1.88 g of ethylenediaminetetra-acetic acid disodium salt dihydrate in 40 ml of water
and the resulting mixture was refluxed for 3 h. The cooled mixture was made basic
with dilute ammoniumhydroxide (pH 11) and then extracted with dichloromethane
(3 x 30 ml). The combined organic layers were dried over sodium sulfate, filtered
and the solvent evaporated to give the crude enamine (mixture of regioisomers),
which was directly used in the next step (see example 36). The pure enamine could
be obtained by column chromatography (silica gel, dichloromethane/methanol/
triethylamine, 98:1:1).
EXAMPLE 36
23,4,4ab,5,6,7,8,13,13bb-Decahydro-lH-6a,13-diaza-indeno[l,2-
c]phenanthren-13cb-ol (Compound F)
As in example 9,0.42 g (1.51 mmol) of the crude enamine from example 35
was treated with 0.21 g of potassium iodide and 0.32 g of iodine in 30 ml of
acetonitrile. After reduction with 0.29 g of sodium borohydride in 30 ml of
methanol, the crude product was purified by column chromatography (silica,
dichloromethane/methanol, 99:1) to afford the pure alcohol.
NMR: 3.18 (br s, 1H), 7.0-7.55 (m, 4H), 9.18 (br s, 1H).
MS: 296 (25%), 295 (10%), 185 (15%), 171 (100%).
EXAMPLE 37
(2,3,4,4ab,6,7,8,1313bb-Decahydro-1H-6a13-diaza-indeno[l,2-
c]phenanthrenyl)-13c(3-methanol
A solution of 150 mg (1.51 mmol) of the above pure enamine (from example
35), 2 ml of 36% aqueous formaldehyde and 0.2 ml N-ethyldiisopropylamine in 10
ml of acetonitrile was refluxed for 3 h. After work-up the crude product was purified
by column chromatography (silica gel, dichloromethane/methanol, 98:2) to afford the
pure alcohol.
NMR: 3.29 (br s, 1H), 3.98 (d, 1H), 4.17 (d, 1H), 7.0-7.5 (m, 4H), 10.05 (br
s, 1H).
MS: 310 (88%), 309 (100%), 293 (34%), 197 (67%), 184 (35%), 170 (90%),
169 (77%).
EXAMPLE 38
3b,4a-Dimethyl-l,2y3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizine
To a solution of 0.422 g (1.65 mmol) of N-[2"-(3"-indoryl)ethyl)]-2,3-
dimethylpiperidine in 25 ml of ethanol was added 2.1 g of mercuric acetate and 2.46
g of ethylenediaminetetraacetic acid disodium salt dihydrate in 50 ml of water and
the resulting mixture was refluxed for 3 h. The cooled mixture was made basic with
dilute ammoniumhydroxide and then extracted with dichloromethane. Drying over
sodium sulfate, filtration and evaporation of the solvent gave the crude enamine,
which was dissolved in 30 ml methanol and cooled with an ice bath. A few drops of
acetic acid were added followed by 0.322 g of sodium borohydride in portions. After
stirring for 1.5 h, the mixture was worked up in the usual manner to give the crude
product, which was purified by column chromatography (silica gel,
dichloromethane/methanol (98.5:1.5).
NMR: 0.89 (d, 3H), 0.96 (d, 3H), 3.76 (br d, 1H), 7.0-7.5 (m, 4H), 7.71 (br s,
1H).
MS: 254 (95%), 253 (100%), 239 (30%), 170 (31%), 169 (36%).
EXAMPLE 39
(1a-Ethyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]qumolizin-l-
ylmethoxy)-acetic acid ethyl ester
A solution of 0.02 g (0.07 mmol) of (lb-ethyl-l,2,3,4,6,7,12,12ba-octahydro-
indolo[2,3-a]quinolizm-l-yl)-methanol (Gazz. Chim. Ital. 111 (1981) 257-267) in
N,N-dimethylformamide-toluene (1 ml, 1:1) was added to 6.8 mg (0.28 mmol) of
sodium hydride, previously washed with heptane. The reaction mixture was stirred at
rt for 1 h and then ethyl bromoacetate (0.009 ml, 0.084 mmol) in toluene (1 ml) was
added dropwise. The stirring was continued for 3 h at rt. Water was slowly added
and the reaction mixture was extracted with dichloromethane (3 x 20 ml). The
combined organic phases were dried over sodium sulfate, the drying agent was
filtered off and the filtrate was evaporated to give the title compound, which was
purified by column chromatography (silica gel, dichloromethane/ methanol, 5:5).
NMR: 0.61 (t, 3H), 1.28 (t,3H), 3.49 (s, 1H), 4.25 (d, 1H), 4.30 (q, 2H), 4.55
(d, 1H), 6.93 (t, 1H), 7.03 (t, 1H), 7.35 (d, 1H), 7.38 (d, 1H), 10.64(s, 1H).
MS: 370 (40%), 369 (30%), 283 (12%), 267 (100%), 197 (12%), 170 (12%),
169 (16%)
EXAMPLE 40
5,6,7,7ab,8,9,10,11,11ab,11ba-Decahydro-12-oxa-6a-aza-indeno[l,2-
a]fluorene
To a solution of 0.70 g (0.43 mmol) of 2-(3-benzo[b]furanyl)ethylamine in 30
ml of chlorobenzene was added 0.13 g (0.87 mmol) of cis-1,2-
cyclohexanedicarboxylic anhydride. The mixture was irradiated in a microwave oven
(1000 W, T=130°C) for 30 min. Chlorobenzene was replaced by ethanol (5 ml) and
82.7 mg (2.18 mmol) of sodium borohydride was added. The mixture was stirred at
rt for 18 h, after which water was added and the product was isolated in the usual
manner. Trifluoroacetic acid (0.12 ml, 1.53 mmol) in dichloromethane (10 ml) was
added and the reaction mixture was stirred for 2 h at rt. Alkaline work-up (4 M
sodium hydroxide), gave the amide intermediate, which was dissolved in diethyl
ether (15 ml), 0.1 g (2.63 mmol) of lithium aluminum hydride was added and the
reaction mixture was refluxed for 1.5 h. Water was slowly added under cooling.
After normal extraction procedures, the crude product was purified by column
chromatography (silica gel, dichloromethane/methanol, 90:10).
NMR: 1.77 (m, 2H), 2.07 (m, 1H), 2.29 (m, 1H), 2.48 (m, 1H), 3.04 (m, 1H),
3.20 (m, 1H), 4.13 (s, 1H), 7.18-7.50 (m, 4H).
MS: 267 (46%), 266 (100%), 185 (52%), 170 (12%).
EXAMPLE 41
l-Methyl-1a,3,4,6,11bb-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene
(Compound G)
The procedure of example 26 was repeated, except that a-methyl-d-
valerolactone and 2-(3-benzo[b]furanyl)ethylamine were used instead of e-
caprolactam and tryptamine, respectively.
NMR: 0.88 (d, 3H), 3.34 (br s, 1H), 7.19-7.43 (m, 4H).
MS: 241 (40%), 240 (50%), 226 (100%), 198 (10%), 170 (68%), 170 (24%).
EXAMPLE 42
(l-Hydroxymethyl-l,3,4,5,6,11b-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluoren-l-yl]-methanol
The procedure of example 41 was repeated, except that d-valerolactone was
used instead of a-methyl-d-valerolactone, and the obtained enamine was treated with
formaldehyde as in example 14.
NMR: 3.30 (d, 1H), 3.76 (d, 1H), 3.79 (d, 1H), 3.82 (s, 1H), 4.31 (d, 1H),
7.18-7.50 (m,4H).
MS: 287 (56%), 286 (60%), 270 (40%), 256 (100%), 198 (34%), 172 (26%),
170 (54%).
EXAMPLE 43
l-MethoxymethyI-la-methyl-13)4,5,6,11bb-hexahydro-2H-11-oxa-4a-
aza-benzo[a]fluorene
A solution of 173.1 mg (0.64 mmol) of the alcohol described in example 30
in 5 ml of tetrahydrofuran was added to 153.0 mg (6.38 mmol) of sodium hydride,
previously washed with heptane. The reaction mixture was stirred at 35°C for 1 h
followed by dropwise addition of a solution of 0.04 ml (0.64 mmol) of iodomethane
in tetrahydrofuran (5 ml). The stirring was continued for lh. Water was slowly added
and the reaction mixture was extracted with dichloromethane (3 x 20 ml). The
combined organic phases were dried over sodium sulfate, the drying agent was
filtered off and the filtrate was evaporated to give the title compound, which was
purified by column chromatography (silica gel, dichloromethane/methanol, 90:10).
NMR: 0.74 (s, 3H), 3.29 (s, 3H), 3.36 (d, 1H), 3.89 (d, 1H), 7.20-7.52 (m,
4H).
MS: 285 (80%), 284 (100%), 270 (20%), 254 (98%), 198 (35%), 171 (82%),
170 (70%).
EXAMPLE 44
2,3,4,4ab,5,6,7,8,13bb,13cb-Decahydro-lH-13-oxa-6a-aza-indeno[1,2-
c]phenanthreneand 2,3,4,4ab,5,6,7,8,13ba,13cb-decahydro-lH-13-oxa-6a-aza-
mdeno[l,2-c]phenanthrene
The procedure of example 41 was repeated, except that cis-octahydro-
isochromen-1-one was used instead of a-methyl-d-valerolactone. The two isomers
were separated by column chromatography (silica gel, ethyl acetate/heptane, 70:30).
2,3,4,4ab,5,6,7,8,13bb,13cb-Decahydro- 1H-13-oxa-6a-aza-indeno[l ,2-
c]phenanthrene:
NMR: 3.28 (s, 1H), 7.17-7.53 (m, 4H).
MS: 281 (40%), 280 (100%), 238 (15%), 198 (12%), 170 (24%).
2,3,4,4ab,5,6,7,8,13ba,13cb-decahydro-lH-13-oxa-6a-aza-indeno[l,2-
c]phenanthrene:
NMR: 2.75 (d, 1H), 7.15-7.43 (m, 4H).
MS: 281 (38%), 280 (100%), 198 (16%), 170 (30%).
EXAMPLE 45
la-Methyl-1,3,4,5,6,11ba-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluorene-1-carboxylic acid ethyl ester
To a mixture of 0.375 g (2.33 mmol) of 2-(3-benzo[b]furanyl)ethylamine and
triethylamine (0.97 ml, 7.0 mmol) in dichloromethane (3 ml) was added 0.56 g (2.33
mmol) 5-chloro-2-ethoxycarbonyl-2-methylvaleroyl chloride (prepared according to
the process described for the corresponding 2-ethyl derivative in J. Org. Chem. 45
(1980) 32-34) in dichloromethane (4 ml). After stirring at rt for 45 min, water was
added and the mixture was extracted with dichloromethane. Drying over sodium
sulfate, filtration of the drying agent and evaporation of the solvent gave the crude
amide, which was purified by column chromatography (ethyl acetate/heptane, 1:1).
The pure amide (0.3 g, 0.82 mmol) was dissolved in toluene (3 ml) and 0.38 ml (4.1
mmol) of phosphorus oxychloride was added. The mixture was refluxed for 2 h, after
which it was evaporated to dryness. The residue was dissolved methanol (3 ml) and
57 mg (1.5 mmol) of sodium borohydride was added in portions. After stirring at rt
for 1 h, water was added and the mixture was extracted with ethyl acetate. Drying
over sodium sulfate, followed by filtration and evaporation gave the crude ester
which was purified by column chromatography (silica gel, ethyl acetate/heptane,
1:1).
NMR: 0.65 (t, 3H), 1.55 (s, 3H), 3.30 (br s, 1H), 7.16-7.50 (m, 4H).
MS: 313 (70%), 312 (100%), 284 (22%), 240 (32%), 198 (80%), 171 (35%),
170 (95%).
EXAMPLE 46
l-Ethoxymethyl-1a-methyI-1a,4,5,6,11bb-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluorene
The procedure of example 43 was repeated, except that iodoethane was used
instead of iodomethane.
NMR: 0.74 (s, 3H), 1.17 (t, 3H), 3.37 (s, 1H), 3.38 (d, 1H), 3.54 (q, 2H), 3.96
(d, 1H), 7.10-7.60 (m,4H).
MS: 299 (70%), 298 (92%), 270 (40%), 254 (100%), 198 (34%), 171 (86%),
170 (72%).
EXAMPLE 47
(1a-Methyl-l,3,4,5,6,11ba-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol
To a suspension of 0.31 g (8.23 mmol) of lithium aluminum hydride in dry
tetrahydrofuran (10 ml), was added 0.86 g (2.74 mmol) of the ester described in
example 45 in dry tetrahydrofuran (10 ml). The reaction mixture was refluxed for 1
h. Water was slowly added and the reaction mixture was extracted with ethyl acetate
(3 x 20 ml). The combined organic phases were dried over sodium sulfate, filtered
and the filtrate was evaporated to give the desired product, which was purified by
column chromatography (silica gel, ethyl acetate/heptane, 50:50).
NMR: 1.30 (s, 3H), 2.98 (br s, 1H), 3.21 (d, 1H), 3.69 (d, 1H), 4.33 (s, 1H),
7.15-7.55 (m,4H).
MS: 271 (52%), 270 (100%), 198 (34%), 172 (20%), 171 (44%), 170 (66%).
EXAMPLE 48
(la-Methyl-1,2,3,4,6,7,12,12ba-octahydroindeno[2,l-a]quinolizin-l-yl)-
methanol
The procedures described in examples 45 and 47 were repeated, except that
2-(3H-inden-l-yl)-ethylamine was used instead of 2-(3-benzo[b]furanyl)ethylamine.
NMR: 0.82 (s, 3H), 3.07 (br s, 1H), 3.23 (d, 1H), 3.39 (d, 1H), 3.52 (d, 1H),
3.70 (d, 1H), 7.05-7.35 (m, 4H).
MS: 269 (43%), 268 (100%), 252 (29%), 196 (36%), 168 (40%).
EXAMPLE 49
la-Ethyl-l,3,4,5,6,11ba-hexahydro-2H-11-oxa-4a-a2a-benzo[a]fluorene-
1-carboxylic methyl ester
The procedure of example 45 was repeated, except that 5-chloro-2-
ethoxycarbonyl-2-ethylvaleroyl chloride was used instead of 5-chloro-2-
ethoxycarbonyl-2-methylvaleroyl chloride.
NMR: 0.90 (t, 3H), 6.90-7.58 (m, 4H).
MS: 327 (72%), 326 (100%), 312 (20%), 298 (20%), 254 (30%), 198 (54%),
172 (60%), 170 (90%).
EXAMPLE 50
l-Methoxymethyl-1a-methyl-1a,3,4,,5,6,11ba-hexahydro-2H-ll-oxa-4a-
aza-benzo[a]fluorene
The procedure of example 43 was repeated, except that the alcohol described
in example 47 was used as the starting compound.
NMR: 1.44 (s, 3H), 2.99 (d, 1H), 3.15 (br s, 1H), 3.22 (s, 3H), 3.70 (d, 1H),
7.18-7.50 (m,4H).
MS: 285 (84%), 284 (100%), 270 (14%), 254 (92%), 198 (34%), 171 (74%),
170 (50%).
EXAMPLE 51
(la-Ethyl-l,3,4,5,6,11ba-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene-
l-yl)-methanol
The procedure of example 47 was repeated, except that the ester described in
example 49 was used as the starting compound.
NMR: 1.00 (t, 3H), 2.93 (m, 2H), 3.29 (s, 1H), 7.15-7.60 (m, 4H).
MS: 286 (90%), 285 (68%), 284 (100%), 268 (16%), 198 (22%), 171 (22%),
170 (36%).
EXAMPLE 52
l-b-Hydroxymethyl-l-methyl-1,2,3,4,6,7,12,12bb-octahyclro-indolo [2,3-
a]quinoIizine-6b-carboxylie acid methyl ester
The procedure of the preparation of (1b-ethyl-l,2,3,4,6,7,12,12ba-octahydro-
indolo[2,3-a]quinolizin-l-yl)-methanol (Gazz. Chim. Ital. 111 (1981) 257-267) was
repeated, except that L-tryptophan methyl ester was used instead of tryptamine.
NMR: 0.74 (s, 3H), 3.39 (s, 3H), 3.46 (d, 1H), 3.97 (d, 1H), 4.38 (br s, 1H),
7.00-7.50 (m, 4H), 8.90 (br s, 1H).
MS: 328 (26%), 327 (100%), 299 (38%), 268 (32%), 170 (10%), 169 (24%).
EXAMPLE 53
Resolution of la-isopropyl-l^r3,4,6,7,12,12bP-octahydroindolo[2,3-
a] quinolizin-l-ol
A solution of 0.3 g (1.1 mmol) of (±)-la-isopropyl-l,2,3,4,6,7,12,12bfl-
octahydroindolo[2,3-a]quinolizin-l-ol and 0.16 g (1.1 mmol) of L-tartaric acid in 15
ml of acetone was refluxed for 30 min. On standing at room temperature overnight
there was deposited of 200 mg of a solid. After two recrystallizations from methanol
the collected L-tartrate salt was partitioned between dichloromethane and 10%
sodium hydroxide solution, dried over sodium sulfate and evaporated to yield 116.6
mg of (-)-la-isopropyl-l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-l-ol
with [a]D= -64.5° (c, 0.011 in CHC13). The other enantiomer (+)-la-isopropyl-
l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-l-ol [a]D= +64.5°(c,0.011 in
CHCI3) was isolated from the mother liquor in the same manner.
EXAMPLE 54
Resolution of (la-methyl-1,3,4,5,6,11bb-hexabydro-2H-ll-oxa-4a-aza-
benzo[a]fiuoren-l-yl)-methanol
The procedure of example 53 was repeated, except that (+)-diacetyl-L-tartaric
anhydride and isopropanol were used instead of L-tartaric acid and acetone. Optical
purities of the separated enantiomers were confirmed by chiral HPLC (column:
DAICEL CHEMICAL INDUSTRIES, LTD CHIRACEL OJ, dimension 0.46 cm *
25 cm, flow: 0.5 ml/min, mobile phase: n-hexane (Merck Uvasol for
Spectroscopy)/isopropanol (Rathburn, HPLC-grade) (100:20), UV detection at 272
nm, retention times: 8.8 min [(+)-(la-methyl-l,3,4,5,6,11bb-hexahydro-2H-11-oxa-
4a-aza-benzo[a]fluoren-l-yl)-methanol] and 11.1 min [(-)-(la-methyl-
1,3,4,5,6,1 lbb-hexahydro-2H-1 l-oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol].
EXAMPLE 55
Resolution of (la-methyI-l,3,4,5,6,11ba-hexahydro-2H-11-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol
The procedure of example 53 was repeated, except that (-)-di-p-toluoyl-L-
tartaric acid monohydrate and ethyl acetate were used instead of L-tartaric acid and
acetone. Optical purities of the separated enantiomers were confirmed by chiral
HPLC (column: DAICEL CHEMICAL INDUSTRIES, LTD CH3RACEL OJ,
dimension 0.46 cm * 25 cm, flow: 0.8 ml/min, mobile phase: n-hexane (Merck
Uvasol for Spectroscopy)/isopropanol (Rathburn, HPLC-grade) (180:20), UV
detection at 254 nm, retention times: 7.8 min [(+)-(la-methyl-l,3,4,5,6,11ba-
hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol] and 12.6 min [(-)-
(la-methyl-l,3,4,5,6,11ba-hexahydro-2H-ll-oxa-4a-aza-benzo[a]fluoren-l-yl)-
methanol].
EXAMPLE 56
Enantiomers of l-methoxymethyl-1a-methyl-l,3,4,5,6,11b3-bexahydro-
2H-ll-oxa-4a-aza-benzo[a]fluorene
The procedure of example 43 was repeated, except that pure enantiomers,
(+)-(la-methyl-l,3,4,5,6,llbb-hexahydro-2H-ll-oxa-4a-aza-benzo[a]fluoren-l-yl)-
methanol and (-)-(la-methyl-1,3,4,5,6,1 lbb-hexahydro-2H-ll-oxa-4a-aza-
benzo[a]fiuoren-l-yl)-methanol, respectively, from example 54 were used instead of
the alcohol described in example 30. Optical purities of the products were confirmed
by chiral HPLC (column: ROCKLAND TECHNOLOGIES, INS ULTRON ES-
OVM, dimension 4.6 cm * 15 cm, flow: 0.8 ml/min, mobile phase: 0.04 M KH2PO4
(pH 4.6)/acetonitrile (Merck Lichrosolv Isocratic grade for liquid chromatography)
(90:10), retention times 3.8 min [(-)-1 -methoxymethyl-la-methyl-1,3,4,5,6,1 lbb-
hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene] and 5.8 min [(+)-l-methoxymethyl-
la-methyl-1,3,4,5,6,1 lbb-hexahydro-2H-1 l-oxa-4a-aza-benzo[a]fluorene].
EXAMPLE 57
Enantiomers of l-methoxymethyl-la-mettayl-l,3,4,5,6,11ba-hexahydro-
2H-11-oxa-4a-aza-benzo[a] fluorene
The procedure of example 43 was repeated, except that pure enantiomers,
(+)-(1a-methyl-1,3,4,5,6,1 1ba-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-
methanol and (-)-(1a-methyl-1,3,4,5,6,1 1ba-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol, respectively, from example 55 were used instead of
the alcohol described in example 30. Optical purities of the products were confirmed
by chiral HPLC (column: DAICEL CHEMICAL INDUSTRIES, LTD CHIRACEL
OJ, dimension 0.46 cm * 25 cm, flow: 0.8 ml/min, mobile phase: n-hexane (Merck
Uvasol for Spectroscopy), retention times 5.6 min [(+)-l-methoxymethyl-la-methyl-
1,3,4,5,6,11ba-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluorene] and 6.3 min [(-)-l-
methoxymethyI-1a-methyl-1,3,4,5,6,1 1ba-hexahydro-2H-l l-oxa-4a-aza-
benzo[a] fluorene].
The following known compounds can be prepared analogously or according
to the methods known in the literature.
1a-Methyl-l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-l-oI
(Compound H): The procedure of example 6 was repeated, except that l-ethyl-4,9-
dihydro-3H-pyrido[3,4-b]indole (J. Chem. Soc, Perkin Trans I (1977) 2109-2115)
was used instead of 1-isobutyl-4,9-dihydro-3H-pyrido[3,4-b]indole.
2b-Methyl-1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-2-ol and
2a-methyl-l,23,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizin-2-ol are
prepared following the procedures described in J. Org. Chem. 56 (1991) 2701-2712
and Chem. Ber. 106 (1973) 3106-3118. l,2,3,4,6,7,12,12bb-Octahydroindolo[2,3-
a]quinolizin-1a-ol and 1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-alquinolizin-1b-
ol are prepared according to the procedure described in Chem. Pharm. Bull. 34
(1986) 3713-3721. l,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine is
prepared according to the method described in J.Chem. Soc, Chem. Comm., (1972)
461. l,4,6,7,12,12b-Hexahydroindolo[2,3-a]quinolizme (Compound I) is prepared
according to the method described in Tetrahedron 45 (1989) 3975-3992.
3,4,6,7,12,12b-HexahydroindoIo[2,3-a]quinolizine and 1-ethyl- 3,4,6,7,12,12b-
hexahydroindolo[2,3-a]quinolizine are prepared according to the method described
in Bull. Soc. Chim. Fr. 7-8 (1976) 1222. 1a-Ethyl-1,2,3,4,6,7,12,12bb-
octahydroindolo[2,3-a]quinolizine and 1b-ethyl-l,2,3,4,6,7,12,12bb-
octahydroindolo[2,3-a]quinolizine (Compound J) are prepared according to the
method described in Tetrahedron 45 (1989) 7615-7630. 1a-Ethyl-
l,23,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1-ol (Compound K) and
(1b-ethyl-l,2,3,4,6,7,12,12ba-octahydroindolo[2,3-a]quinolizin-1-yl)-methanol
(Compound L) are prepared according to the method described in Gazz. Chim. Ital.
111 (1981) 257-267. (1b-Ethyl-l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-
a]quinolizin-l-yl)-methanol (Compound M) is prepared according to the method
described in Indian J. Chem., Sect. B 22 (1983) 531. 3-Ethyl-2-methyl-
1,4,6,7,12,12b-hexabydro-indolo[2,3-a]quinolizine (Compound N) and 3a-ethyl-
2a-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine are prepared
according to the method described in Tetrahedron 46 (1990) 2633-2650.
2,3,5,6,7,11,11b-Hexahydro-lH-indoIizino[8,7-b]indoIe is prepared according to
the method described in J. Org. Cheni. 53 (1988)4236. (1b,2,3,4,6,7,12,12ba-
Octahydroindolo[2,3-a]quinolizin-l-yl)-methanol (Compound O) is prepared by
reduction of the corresponding ester which synthesis is described in Tetrahedron 52
(1996)9925. l-(1a,2,3,4,6,7,12,12bb-Octahydroindolo[2,3-a]quinolizin-l-yl)-
ethanol (Compound P) is prepared by reduction of its corresponding ketone which
synthesis is described in Tetrahedron Lett. 30 (1989) 719. 1b-Propyl-
l,2,3,4,6,7,12,12bb-octahydro-indolo[2,3-a]quinolizine is prepared according to
the method described in J. Org. Chem. 34 (1969) 330. 1a-Ethyl-1b-methyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizine is prepared according to the
method described in J. Chem. Res. (S) (1995) 382. 2b-Tert-butyl-
1,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizineand 2b-tert-butyl-
1,2,3,4,6,7,12,12ba-octabydro-indolo[2,3-a]quinolizine (Compound Q) are
prepared according to the method described in Tetrahedron 45 (1989) 3975. 2-tert-
Butyl-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizineand2-tert-butyl-
3,4,6,7,12,12b-hexahydro-indolo[2,3-a]quinolizine are prepared according to the
method described in Tetrahedron 47 (1991) 2879-2894. (-)-1a-Ethyl-
l,2,3,4,6,7,12,12bb-octahydroindoIo[2,3-a]quinoIizin-1-ol and(+)-1a-ethyl-
l,2,3,4,6,7,12,12bb-octahydroindolo[2,3-a]quinolizin-1-ol are obtained by
resolution of their racemic mixture (Compound K).
As already mentioned hereinbefore, the compounds of the present invention
show interesting pharmacological properties, namely they exhibit affinity for alpha2
adrenoceptors. The said pharmacological activity of the compounds of the invention
is demostrated with the pharmacological tests presented below.
EXPERIMENT I: Radioligand binding to alpha2-adrenoceptors
Examples of the alpha2-adrenoceptor binding affinities of the compounds
including in the present invention are shown in the Table 1. Many of these
compounds are high-affinity ligands for all the alpha2-receptors, but some of them
display selectivity for the alpha2C-subtype.
Table 1. Calculated Ki values Scorn radioligand binding assays
using cells expressing human alpha2-adrenoceptor subtypes
"Compound Binding affinity (Ki; nM)
a!pha2A alpha2B alpha2C
A 480 330 61
B 130 160 25
G 710 580 87
D 29 81 17
E 30 110 26
F 514 not measured 70
G 96 not measured 22
H 280 45 23
I 150 460 85
J 210 520 75
K 359 245 31
L 85 20 18
M 440 470 110
N 130 1110 46
O 380 270 110
P 290 410 90
Q 27 40 6,4
EXPERIMENT II: In vitro antagonism on the alpha2-adrenoceptors
The functional activities of two compounds (K and L) displaying alpha2C-
selectivity in binding experiments were determined as the abilities of the compounds
to inhibit the epinephrine-stimulated binding of 35S-GTPyS to G proteins (Jasper,
J.R. et al., Biochem. Pharmacol. 55(7) (1998) 1035-44) in membranes of CHO cells
stably transfected with the human alpha2-adrenoceptor subtypes. The antagonist
potencies of compound K and compound L are presented in the Table 2. The results
show that these compounds are selective antagonists for the alpha2C-subtypes.
In vivo effects of alpha2C-selective compounds
It is currently not well-known in the art what effects in vivo could be
attributed to a selective alpha2C-antagonism. Based on available knowledge and our
previous experience, we have selected two different behavioral models, namely d-
amphetamine -stimulated locomotor activity model and the forced swimming test, in
order to demonstrate specific alpha2C-antagonistic effects in the CNS of mice and
rats in vivo. The selection of these methods is essentially based on published
hypotheses on theoretical effects of alpha2C-antagonists; in the lack of suitable
ligands, these hypotheses were based on studies employing mice with genetically
altered alpha2C-adrenoceptor expression (Scheinin, M. et al., Life Sci 68(19-20)
(2001) 2277-85).
EXPERIMENT HI: D-amphetamine stimulated locomotor activity test
Genetically modified mice having non-functional alpha2C-adrenoceptors
(alpha2C-"knockout"; alpha 2C-KO) are more sensitive to the locomotor-enhancing
effects of the psychostimulant d-amphetamine and, on the other-hand, over-
expression of the alpha2C-adrenoceptor in mice (alpha2C-OE) leads to an opposite
effect, i.e. to attenuation of the stimulant effect (Scheinin, M. et al., Life Sci 68(19-
20) (2001) 2277-85). Thus, it could be hypothesized that alpha2C-antagonist would
potentiate the locomotor effects of d-amphetamine.
The above assumption was tested by administering groups of mice (n= 10-
12/dose group) amphetamine (4 micromol/kg s.c.) either alone or together with the
alpha2C-antagonists (3 micromol/kg s.c.) of this invention or with the alpha2-
subtype non-selective potent alpha2-antagonist (1 micromol/kg s.c.) (Haapalinna, A.
et al., Naunyn-Schmiedeberg"s Arch. Pharmacol 356 (1997) 570-582), and by
subsequently measuring the locomotor activity of mice with an automated infrared
photobeam system designed for activity studies (PAS CageRack, SanDiego
Instruments, San Diego, CA., USA). As expected, both of the tested alpha2C-
selective antagonists increased the activity of mice (Figure la+b), as was expected
for alpha2C-antagonist. The subtype non-selective alpha2-antagonist also potentiated
the d-amphetamine effect. The tested compounds did not affect the baseline
locomotor activity of mice (at doses between 0.1 — 10 mg/kg s.c).
EXPERIMENT IV: Antagonism of alpha2-agonist -induced sedation
One of the prominent effects of non-selective alpha2-agonists in rodents is
their ability to cause profound sedation. This effect, measured as locomotor
inhibition by the alpha2-agonist dexmedetomidine was not modified in mice with
genetically altered alpha2C-expression (Scheinin, M. et al., Life Sci 68(19-20) (2001)
2277-85). On the other hand, alpha2-agonist did not have sedative effect in mice
with genetically disrupted alpha2A-adrenoceptor (Hunter, J.C. et al., British Journal
of Pharmacology 122(7) (1997) 1339-44). Therefore, since the sedative effect of
alpha2-agonists is generally attributed to the alpha2A-adrenoceptor, it is expected
that alpha2C-antagonists would not modulate significantly the alpha2-agonist-
induced sedation. This assumption was tested in experiment, where
dexmedetomidine was administered to mice pre-treated with the alpha2C-antagonists
compound K or compound L, or the subtype non-selective antagonist atipamezole
(Haapalinna, A. et al., Naunyn-Schmiedeberg"s Arch. Pharmacol. 356 (1997) 570-
582). As expected, the alpha2C-antagonists did not have clear effects, whereas
atipamezole effectively antagonised the effect of dexmedetomidine. This result
demonstrates the lack of alpha2 A-antagonism of the alpha2C-selecti ve compounds
of the present invention (Figure 2).
EXPERIMENT V: Forced swimming test
Forced swimming test (FST, i.e. Porsolt"s test) is generally used in the
pharmacological screening of new antidepressants. In this test, antidepressants
increase the animals" activity compared to non-treated controls. Alpha2C-KO mice
appeared to be more active, and alpha2C-OE mice were less active in FST (U.S.
Patent No. 5,902,807 and Scheinin, M. et al., Life Sci 68(19-20) (2001) 2277-85).
Therefore, it was tested, whether a selective alfa2C-antagonist would have
antidepressant-like activity (e.g. activity-increasing property) in the FST. The figure
3 shows how both of the alpha2C-compounds increased activity in this test as was
expected based on studies on transgenic mice (Scheinin, M. et al., Life Sci 68(19-20)
(2001) 2277-85) and as reported with recently developed alpha2C-antagonist (WO
01/64645). Also the positive control substances desipramine and fluoxetine
(clinically effective antidepressant agents) were active. The subtype non-selective
alpha2-antagonist atipamezole did not possess antidepressant-like effect, as expected
(WO 01/64645).
EXPERIMENT VI: Prepulse inhibition of the startle reflex
Prepulse-inhibition (PPI) of a startle response refers to the reduction in the
startle response caused by a low intensity non-startling stimulus (the prepulse) which
is presented shortly before the startle stimulus. PPI can be used as an operational
measure of sensorimotor gating and appears to be present in all mammals, including
rats and humans (Swerdlow, N.R. et al., The archives of general psychiatry 51
(1994) 139-154). Normally functioning PPI can be disrupted by psychostimulants,
such as d-amphetamine or phencyclidine (PCP), and reversed by clinically effective
antipsychotics.
In a previous study, alpha2C-KO mutation was associated with weakened PPI
whereas alpha2C-OE demonstrated increased PPI. In other words, the genetically
altered alpha2C-expression in mice was associated with changes in PPI in a way
suggesting that an alpha2C-antagonist would decrease PPI (Scheinin, M. et al., Life
Sci 68(19-20) (2001) 2277-85). This hypothesis was tested with compounds K and L
alone and against PCP -disruption of the PPL
Groups of rats (n -10/group) were administered the alpha2C-antagonists 20
min before, and PCP or vehicle 10 min before measurement of the acoustic startle
reactivity and PPI in a test system designed for startle studies (SR-LAB, San Diego
Instruments, CA, USA). It was found that the alpha2C-antagonists were able to
attenuate the PPI disruption caused by PCP (Figure 3). This was unexpected and
opposite to the hypothesis based on transgenic studies. The non-selective alpha2-
antagonist atipamezole produced different effects than was observed with the
selective alpha2C-antagonists: atipamezole did not enhance PPI, but it increased the
startle reflex per se (i.e. startle without prepulses)(Figure 4).
In conclusion, the results presented in this chapter show that those antagonists
which are classified as alpha2C-selective according to in vitro experiments, appeared
to function as alpha2C-selective antagonists also in vivo in a manner that was
predicted based on the available knowledge on alpha2C-antagonism. However, the
finding that the alpha2C-antagonists did not decrease PPI, as predicted, but on the
contrary, increased PPI, could be considered unexpected and this adds the novelty
value of the now proposed usefulness of the compounds of the present invention.
The compounds according to the invention may be used to treat any disease or
condition wherein alpha-2 antagonists are indicated to be effective. The compounds
can also be used to reverse effects induced by alpha-2 agonists. Accordingly, the
compounds of the invention may be useful in the treatment of various disorders of
the central nervous system (CNS), i.e. different neurological, psychiatric and
cognition disorders (such as depression, anxiety disorders, post traumatic stress
disorder, schizophrenia, Parkinson"s disease and other movement disorders).
Furthermore, they may be used in the treatment of various peripheral disorders, e.g.
diabetes, orthostatic hypotension, lipolytic disorders (such as obesity), Raynaud"s
disease or both male and female sexual dysfunctions.
The selective alpha-2C antagonists of the present invention may be used for
the treatment of various disorders or conditions of CNS-system where alpha-2C
antagonists are indicated to be beneficial, for example, to alleviate the symptoms of
various mental disorders propagated by stress, Parkinson"s disease, depression,
negative symptoms of schizophrenia, attention deficit hyperactivity disorder, post-
traumatic stress-disorder, and anxiety disorders.
In addition, due to the novel and previously unpublished findings of the
effects of the present alpha2C-antagonists on the PCP -disrupted PPI, the alpha2C-
selective compounds can also be used to treat disorders and conditions associated
with sensorimotor gating deficits, particularly disorders and conditions wherein the
sensorimotor gating deficits results in sensory flooding and cognitive fragmentation
causing dysfunction in attention and perception. Such disorders and conditions
I include, but are not limited to, schizophrenia, obsessive compulsive disorder,
Tourette"s syndrome, blepharospasm and other focal dystonias, temporal lobe
epilepsy with psychosis, drug-induced psychosis (for example, psychosis caused by
chronic use of dopaminergic agents) (Braff, D.L. et al., Psychopharmacology (Berl)
156(2-3) (2001) 234-258), Huntingdon"s disease, Parkinson"s disease, disorders
caused by fluctuation of the levels of sex hormones (such as premenstrual
syndrome), and panic disorder.
Further, the symptoms which are usually associated with above-mentioned
disorders or conditions include, but are not limited to, hallucination, delusion,
parathymia, agitation, psychotic cognitive impairment (including deficits in thinking
and speech), social withdrawal and withdrawal symptoms (including delirium)
associated with cessation of cigarette smoking or alcohol or drug abuse. These
symptoms may also be seen in animals in exceptional circumstances, for example,
during withdrawal from masters or during transportation.
Due to their selectivity of action, the alpha-2C antagonists of the invention
have less or no undesirable side-effects attributed to non-selective alpha2-
antagonism, such as increases in blood pressure, heart rate, salival secretions,
gastrointestinal secretion, anxiety, and startle reactivity per se (RufFolo, R.RJ. et al.,
Annu Rev Pharmacol Toxicol 32 (1993) 243-279).
The compound of the invention can be administered for example enterally,
topically or parenterally by means of any pharmaceutical formulation useful for said
administration, and containing at least one active compound of formula I in
pharmaceutically acceptable and effective amounts together with pharmaceutically
acceptable diluents, carriers, and/or excipients known in the art. The manufacture of
such pharmaceutical formulations is well known in the art.
The therapeutic dose to be given to a patient in need of treatment will vary
depending on the compound being administered, the species, age and the sex of the
subject being treated, the particular condition being treated, as well as the route and
method of administration, and are easily determined by person skilled in the art.
Accordingly, the typical dosage for oral administration is from 5 mg/kg to 100 mg/kg
per day and that for parenteral administration from 0.5 mg/kg to 10 mg/kg for an
adult mammal.
The present invention further provides a compound of the invention or an
ester or salt thereof for use as alpha-2 antagonist. Furthermore, a method for the
treatment of diseases or conditions where alpha-2 antagonists, e.g. alpha-2C
antagonists, are indicated to be useful, e.g. a method for the treatment of diseases or
conditions of the central nervous system, is provided. In such a method a
therapeutical ly effective amount of a compound of the invention is administered to a
subject in need of such treatment. The use of the compounds of the invention for the
manufacture of a medicament to be used for the above indications is also provided.
Those skilled in the art will appreciate that the embodiments described in this
application could be modified without departing from the broad inventive concept.
Those skilled in the art also understand that the invention is not limited to the
particular disclosed embodiments, but is intended to also cover modifications to the
embodiments that are within the spirit and scope of the invention.
wherein,
X is CR2R2", 0 or S;
Z is -CHR8-(CH2)n- or a single bond;
R1 is hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halo(Ci-C6)alkyl, (C1-
C6)alkoxy-CO-, CN, NO2, NH2, mono- or di(Ci-C6)alkylamino or carboxyl;
R2 and R2" are independently H, hydroxy or (Ci-C6)alkyl or R2 and R2" form,
together with the carbon ring atoms to which they are attached, a carbonyl group;
R3 is hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy(C1-C6)alkyl, (C1
C6)alkoxy, (C1-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl, (C3-
C7)cycloalkyl, (C3-C7)cycloaikyl(Ci-C6)alkyl, aryl, aryl(Ci-C6)alkyl, aryloxy,
aryl(Ci-C6)alkoxy, aryloxy(Ci-C6)alkyl, aryl(Ci-C6)alkoxy(Ci-C6)alkyl, halo(d-
C6)alkyl, NH2, amino(Ci-C6)alkyl, mono- or di(Ci-C6)alkylamino,mono- or di(C1-
C6)alkylamino(Ci-C6)alkyl, (Ci-C6)alkyl-CO-, (Ci-C6)alkyl-CO-O-, (C1-C6)alkyl-
CO-O-(C1-C6)alkyl, (Ci-C6)alkoxy-CO-, (C1-C6)alkoxy-CO-(C1-C6)alkyl, (C1-
C6)alkoxy-CO-(C1-C6)alkoxy(C1-C6)alkyl, carbamoyl, mono- or di(Ci-
C6)alkylcarbamoyl, carboxyl or (Ci-C6)alkyl-S-(Ci-C6)alkyl, wherein the said (C3-
C7)cycloalkyl or aryl is unsubstituted or substituted with 1 or 2 substituents each
independently being hydroxy, (C1-C6)alkyl, halogen, (Ci-C6)alkoxy, NH2, CN or
NO2, or one of R3 or R4 and R6 together form a bond between the ring atoms to
which they are attached;
R4 is hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6)alkoxy or (C1
C6)alkoxy(Ci-C6)alkyl;
1. A compound of formula IA
R5 is H;
R6 is H or R6 forms a bond between the ring atom to which it is attached and
the ring atom to which R7 is attached;
R7 is H, hydroxy; (Ci-C6)alkyl, hydroxy(C1-C6)alkyl, (Ci-C6)alkoxy or (Ci-
C6)alkoxy(C1-C6)alkyl;
R8 is H,hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy or (C1
C6)alkoxy(Ci-C6)alkyl;
R15 is H, (Ci-C6)alkyl, (C2-C6)alkenyl, hydroxy(Ci-C6)alkyl, (C1-
C6)alkoxy(Ci-C6)alkyl,hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl,halo(Ci-C6)alkyl,
amino(Ci-C6)alkyl, mono- or di(Ci-C6)alkylammo(Ci-C6)alkyl, (Ci-C6)alkyl-CO-,
(C1-C6)alkyl-CO-O-(C1-C6)alkyl,(C1-C6)alkoxy-CO-,(Ci-C6)alkoxy-CO-(Ci-
C6)alkyl, (Ci-C6)alkoxy-CO-(Ci-C6)alkoxy(Ci-C6)alkyl, carbamoyl, mono- or di(Ci-
C6)alkylcarbamoyl or carboxyl;
R16 is H or(Ci-C6)alkyl;
R7 and R8 are attached to the carbon ring atoms, which are adjacent;
m is 0 to 2; and
n is O or l,
or a pharmaceutically acceptable salt or ester thereof.
2. A compound as claimed in claim 1, wherein X is CR2R2".
3. A compound as claimed in claim 1, wherein X is O. (
4. A compound as claimed in claim 1, wherein X is S.
5. A compound as claimed in any one of claims 1 to 4, wherein R3 is hydroxy,
(Ci-C6)alkyl, hydroxy(C1-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy-CO-
or (Ci-C6)alkyl-CO-O-(Ci-C6)alkyl and R4 is (C1-C6)alkyl or hydroxy(Ci-C6)alkyl.
6. A compound as claimed in any one of claims 1 to 5, wherein R3 is hydroxy,
hydroxy(C1-C6)alkyl or (Ci-C6)alkoxy(Ci-C6)alkyl and R4 is (C1-C6)alkyl.
7. A compound as claimed in claim 1, wherein the compound is la-Methyl-
1,3,4,5,6,1 lb-hexahydro-2H-11-oxa-4a-aza-benzo[a]fluoren-l-ol, (1a-Methyl-
1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol, (-)-
(1 a-Methyl-1,3,4,5,6, llbp-hexahydro-2H-ll-oxa-4a-aza-benzo[a]fluoren-l-yl)-
methanol, (+)-(1a-Methyl-1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol, 1a-Isopropyl-1,3,4,5,6,1 lb-Hexahydro-2H-l 1-oxa-
4a-aza-benzo[a]fluoren-l-ol, la-Ethyl-1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluoren-l-ol, (1a-Ethyl-1,3,4,5,6,1 lbp-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol, (l-Hydroxymethyl-1,3,4,5,6,1 lb-hexahydro-2H-l 1-
ox a-4a-aza-benzo[a] fluoren-1 -yl]-methanol, 1 -Methoxymethyl-1a-methyl-
1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene, (-)-l-
Methoxymethyl-la-methyl-1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluorene, (+)-1 -Methoxymethyl-la-methyl-1,3,4,5,6,1 lbb-hexahydro-2H-
1 l-oxa-4a-aza-benzo[a]fluorene, la-Methyl-1,3,4,5,6,1 lba-hexahydro-2H-l 1-oxa-
4a-aza-benzo[a]fluorene-l-carboxylic acid ethyl ester, 1-Ethoxymethyl-la-methyl-
1,3,4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene, (la-Methyl-
1,3,4,5,6,1 lba-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-methanol, (-)-
(1a-Methyl-1,3,4,5,6,1 lba-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluoren-l-yl)-
methanol, (+)-(la-Methyl-l,3,4,5,6,l lba-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluoren-l-yl)-methanol, la-Ethyl-1,3,4,5,6,1 lba-hexahydro-2H-11-oxa-4a-
aza-benzo[a]iluorene-l-carboxylic methyl ester, 1-Methoxymethyl-la-methyl-
1,3,4,5,6,1 lba-hexahydro-2H-l l-oxa-4a-aza-benzo[a]fluorene, (-)-l-
Methoxymethyl-1a-methyl-1,3,4,5,6,1 lba-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluorene, (+)-l-Methoxymethyl-la-methyl-l,3,4,5,6,11ba-hexahydro-2H-
1 l-oxa-4a-aza-benzo[a]fluorene, (la-Ethyl-1,3,4,5,6,1lba-hexahydro-2H-l1-oxa-
4a-aza-benzo[a]fluorene-l-yl)-methanol, acetic acid la-Methyl-l ,3,4,5,6,1 lbb-
hexahydro-2H-l l-ox
a-4a-aza-benzo[a]fluoren-l-ylmethyl ester or (la-Methyl-
1,2,3,4,6,7,12,12ba-octahydroindeno[2,l-a]quinolizin-l-yl)-methanol.
8. A compound as claimed in any one of claims 1, 3, 5, 6 or 7, wherein the
compound is [(-)-(la-methyl-1,3.4,5,6,1 lbb-hexahydro-2H-l l-oxa-4a-aza-
benzo[a]fluoren-l -yl)-methanol].
9. A compound as claimed in any one of claims 1, 3, 5, 6 or 7, wherein the
compound is [(-)-l-methoxymethyl-la-methyl-l,3,4,5,6,1 lbb-hexahydro-2H-l
oxa-4a-aza-benzo[a]fiuorene].
10. A pharmaceutical composition comprising at least one compound as claimed
in any one of claims 1 to 9 and a pharmaceutically acceptable diluent, carrier and/or
excipient.
11. A compound as claimed in any one of claims 1 to 9 for use as a medicament.
The invention provides a compound
of formula I, wherein X, Z, R1 to R10, R15, R16, m, n,
r and t are as defined in claim 1, or a pharmaceutically
acceptable salt or ester thereof, useful as an alpha-2
antagonist. The compounds of formula I can be used for
the treatment of diseases or conditions where antagonists
of alpha-2 adrenoceptors are indicated to be effective.

Documents:

1548-kolnp-2004-granted-abstract.pdf

1548-kolnp-2004-granted-assignment.pdf

1548-kolnp-2004-granted-claims.pdf

1548-kolnp-2004-granted-correspondence.pdf

1548-kolnp-2004-granted-description (complete).pdf

1548-kolnp-2004-granted-drawings.pdf

1548-kolnp-2004-granted-form 1.pdf

1548-kolnp-2004-granted-form 13.pdf

1548-kolnp-2004-granted-form 18.pdf

1548-kolnp-2004-granted-form 3.pdf

1548-kolnp-2004-granted-form 5.pdf

1548-kolnp-2004-granted-gpa.pdf

1548-kolnp-2004-granted-letter patent.pdf

1548-kolnp-2004-granted-reply to examination report.pdf

1548-kolnp-2004-granted-specification.pdf


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Patent Number 217438
Indian Patent Application Number 01548/KOLNP/2004
PG Journal Number 13/2008
Publication Date 28-Mar-2008
Grant Date 26-Mar-2008
Date of Filing 13-Oct-2004
Name of Patentee ORION CORPORATION
Applicant Address ORIONINTIE 1, FIN-02200ESPOO FINLAND
Inventors:
# Inventor's Name Inventor's Address
1 DIN BELLE DAVID LOUHENTIE 13A5, FIN-02130 ESPOO FINLAND
2 JOKELA REIJA PALKKATILNKATU 8C 27, FIN-00240 JELSINKI, FINLAND
3 TOLVANEN ARTO TONTUNMAENTIE 25B, FIN-02200 TURKU FINLAND
4 HAAPALINNA ANTTI MARKULANJTIE 8A FIN 20360 TURKU FINLAND
5 KARJALAINEN ARTO ALBERGANESPLANADI 11A 13, FIN 02600 ESPOO FINLAN
6 SALLINEN JUKKA PUUTARHAKATU 24C 32, FIN 20100, TURKU FINLAND
7 RATILAINEN JARI LIKSENJOPENTIE 54 FIN 80910 KULHO FINLAND
PCT International Classification Number C07D455/00
PCT International Application Number PCT/FI03/00255
PCT International Filing date 2003-04-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/369, 347 2002-04-02 Finland
2 20020642 2002-04-03 Finland