BENZO[C]QUINOLIZINE DERIVATIVES, THEIR PREPARATION AND USE AS 5.ALPHA.-REDUCTASES INHIBITORS

DERIVES DE LA BENZO[C]QUINOLIZINE, LEUR PREPARATION ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE 5.ALPHA.-REDUCTASES

English Abstract

The present invention refers to benzo[c]quinolizine
derivatives of general formula (I), their pharmaceutically
acceptable salts or esters, processes for their preparation
and pharmaceutical compositions containing them.

French Abstract

Cette invention a trait à des dérivés de la benzo[c]quinolizine répondant à la formule générale (I), à leurs sels ou esters accep tables du point de vue pharmaceutique, à leurs méthodes de préparation ainsi qu'à des compositions pharmaceutiques les contenant.

Claims

-14-
CLAIMS:

1. Benzo[c]-quinolizine compounds of formula (I)
Image
wherein:
R1, R2, R3, R4, R5, same or different, are chosen in the group consisting of:
H,
C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane, norbornane, camphane,
adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole,
pyrrolidine, piperidine, halogen, CN, azide, NRR', C1-8alkylamino,
phenylamino, naphthylamino, C1-8alkyloxy, phenyloxy, naphthyloxy, COOR,
CONRR' wherein R and R', same or different, are chosen in the group
consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclo-octane, norbornane, camphane,
adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole,
pyrrolidine, piperidine, phenylC1-8alkyl, naphthylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, phenyl,
naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine,
piperidine;
X is chosen in the group consisting of: O, C(=O)R, COOR, NO2, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: single bond, C1-8alkyl, C2-8alkenyl,



-15-
C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-
heptane, cyclooctane, norbornane, camphane, adamantane, CO, CONR, NR,
wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-
8alkinyl,
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,
cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C1-8alkoxy,
C1-8alkoxy-C1-8alkyl, phenylC1-8alkyl, naphthylC1-8alkyl, phenyl, naphthyl,
phenyloxy, naphthyloxy, phenylamino, naphthylamino, C1-8alkylcarbonyl,
phenylcarbonyl, naphthylcarbonyl, halogen, CN, NRR', C1-8alkylamino,
pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine,
wherein
the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane, norbornane, camphane,
adamantane, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole,
pyrrolidine, piperidine can be substituted by halogen, OR, phenyl, NRR', CN,
COOR, CONRR', C1-8alkyl (wherein R and R' are as above defined);
n is an integer comprised between 1 and 4;
the symbol Image means that the corresponding bonds a, b, c, d e, f, and g can
be single or double bonds; and their pharmaceutically acceptable salts or
esters;
with the proviso that when b or f are a double bond then the group R5 is
absent; and with the proviso that the following compounds are excluded from
the claim: 4-carbonitril-2,3-dihydro-(1H)-benzo[c]quinolizin-3-one, 3,4-
dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one,
Image


-16-
Image
2. Benzo[c]quinolizine compounds of formula (I) according to claim 1
wherein:
R5 = H, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine,
piperidine;
X=O;
Q=single bond, CO, CONR, NR (wherein R is as defined in claim 1);
W=H, F, Cl, Br, Me, t-butyl, C1-8alkoxy, 2,5-dimethylhexyl, trifluoromethyl,
2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl,
phenyl-C1-8alkyl, C1-8alkylcarbonyl, phenylcarbonyl;
n=1 and 2;
R1, R2, R3, R4, R6 =H, Me, CN, phenyl, COOR, CONRR' (wherein R and R' are
as defined in claim 1).


-17-
3. Benzo[c]quinolizine compounds according to claims 1 or 2 of formula
1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl (11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl (11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,4,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
5,6-dihydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-
one;
8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one
(cis) and (trans);
8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one
(cis) and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-
one (cis) and (trans).
4. Process for the preparation of compounds according to any one of
claims 1 to 3 wherein:
the amide-group of a compound of formula (2)



-18-
Image
is protected with a protecting group Z to give the compound (3)
Image
the above said compound (3) is reduced to compound (4)
Image



-19-
and compound (4) is reacted with a silylether (6)
Image
prepared "in situ" by resting a vinyl-ketone (5)
Image
(wherein R1, R2, R6 are as defined in claim 1) with a silylating agent,
and are finally hydrolized to give the final compound of formula (I)
wherein X = 0.
5. Process according to claim 4 wherein a double bond is introduced in
position a or b of formula (I) by reaction of dichlorodicyanoquinone (DDQ)
with the corresponding silylenolethers or by oxidation with quicksilver
(mercury) acetate of the saturated compound obtained according to claim 4
and the possible transformation of the group X is performed via the
corresponding enoltriflates and following carbonylation in the presence of
palladium diacetate, triphenylphosphine and suitable nucleophilic reagent.


-20-
6. Compound of formula (4)
Image
wherein W, Q, n, R3, R4, R5 are as defined in claim 1 and Z is a carboxy or
thiocarboxy ester protecting group for the amide-group with the proviso that
when R3 = R4 = R5 = (WQ)n = H then Z is not a -COO-lower alkyl group or a
-CSO-lower alkyl group.
7. Pharmaceutical composition wherein the active principle is a compound
of formula (I)
Image
wherein:
R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of:
H,
C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane, norbornane, camphane,
adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole,
triazole, pyrrolidine, piperidine, halogen, CN, azide, NRR', C1-8alkylamino,
phenylamino, naphthylamino, C1-8alkyloxy, phenyloxy, naphthyloxy, COOR,



-21-
CONRR' wherein R and R', same or different, are chosen in the group
consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane, norbornane, camphane,
adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole,
pyrrolidine, piperidine, phenylC1-8alkyl, naphthylC1-8alkyl;
R5 is chosen in the group consisting of: H, C1-8alkyl, COOR, CN, phenyl,
naphthyl, pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine,
piperidine;
X is chosen in the group consisting of: 0, C(=O)R, COOR, NO2, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: single bond, C1-8alkyl, C2-8alkenyl,
C2-8alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclo-
heptane, cyclooctane, norbornane, camphane, adamantine, CO, CONR, NR,
wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-
8alkinyl,
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,
cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C1-8alkoxy,
C1-8alkoxy-C1-8alkyl, phenylC1-8alkyl, naphthylC1-8alkyl, phenyl, naphthyl,
phenyloxy, naphthyloxy, phenylamino, naphthylamino, C1-8alkylcarbonyl,
phenylcarbonyl, naphthylcarbonyl, halogen, CN, NRR', C1-8alkylamino,
pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine,
wherein
the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane, cyclooctane, norbornane, camphane,
adamantine, phenyl, naphthyl, pyridine, imidazole, pyrrole, indole, triazole,
pyrrolidine, piperidine can be substituted by halogen, OR, phenyl, NRR', CN,
COOK, CONRR', C1-8alkyl (wherein R and R' are as above defined);
n is an integer comprised between 1 and 4;
the symbol Image means that the corresponding bonds a, b, c, d e, f, and g can
be single or double bonds; with the proviso that when b or f are a double
bond then the group R5 is absent;
their pharmaceutically acceptable salts or esters or mixtures thereof in


-22-
combination with the suitable pharmaceutical acceptable excipients.
8. Pharmaceutical composition according to claim 7 for use in the
inhibition of the 5alphaR-I and/or 5alphaR-II iso-enzymes.
9. Pharmaceutical composition according to claims 7 and 8 in the form
suitable for topical use.
10. Use of a pharmaceutical composition according to claim 7 for the
treatment of acne, baldness, prostatic cancer and prostatic hypertrophy in
men and hirsutism in women.

Description

CA 102245758 2005-O1-07
Benzo[c]quinoiizine derivatives, their preparation and use as 5a-
reductases inhibitors.
Field of the invention
The present invention refers to benzo[c]quinolizine derivatives of
general formula (I)
R' ~~-SnW)n
i: ~,~ (I)
~' a
g a b .1 ~f ~ ,.
''d T ! T
z Rs
wherein:
R1, R2, R3, R4, R6, same or different, are chosen in the group
consisting of: H, C1_$alkyl. C2_$alkenyl, CZ_8alkiny7., cycloalkyl,
aryl, heterocycle, halogen, CN, azide. NRR', C1_$alkylamino,
arylamino, C1_$alkyloxy, aryloxy, C00R, GONRR' wherein R and R', same
or different, are chosen in the group consisting of: H, C1_8alkyl,
cycloalkyl, aryl, heterocycle, arylCl_8alkyl;
R5 is chosen in the group consisting of: H, C1_8alkyl, C00R. CN, aryl.
heterocycle;
X is chosen in the group consisting of: 0, C(=0)R, COOR, N02, CONR'R
wherein R and R' are as above defined;
Q is chosen in the group consisting of: Single bond. C1_8alkyl, C~_
$alkenyl. CZ_$alkinyl, cycloalkyl, C0, CONK, NR, wherein R is as above
defined;
W is chosen in the group consisting of: H. CI_aalkyl. CZ_$alkenyl. C2_
8alkinyl, cycloalkyl, trifluoromethyl, C1_8alkoxy. C1_8alkoxy-C1_

CA 02245758 2005-O1-07
- 2 -
8alkyl, arylCl-8alkyl, aryl, aryloxy, arylamino, C1-8alkylcarbonyl,
arylcarbonyl, halogen, CN, NRR', C1-8alkylamino, heterocycle wherein
the groups alkyl, alkenyl, alkinyl, cycloalkyl, aryl, heterocycle, can
be substitued;
n is an integer comprised between 1 and 4;
the symbol - - means that the corresponding bonds a, b, c, d e, f,
and g can be S111g12 or double bonds;
with the proviso that when b or f are a double bond then the group R5
is absent; and with the groviso that the following two compounds are
excluded: 4-carbonitril-2,3-dihydro-(1H)-benzo[c)quinolizin-3-one and
3,4-dihydro-1-phenyl-4aH-benzo[c]quinolizin-3-one;
their pharmaceutically acceptable salts or esters, their process for
preparation and their use as inhibitors of steroid 5alpha-reductases
(hereinafter indicated as 5alpha-reductases).
The invention refers also to compounds of formula (4)
(4)
wherein W, Q, n, R3, R4, R5 are as above defined and Z is a protecting
group for the amide-group with the proviso that when R3 = R4 = RS -
(wQ)n = H than Z is not a group ethoxycarbonyl.
State of the art
The enzyme known as steroid 5alpha-reductase is a system formed by
two iso-enzymes (type I and type II or SalphaR-I and 5alphaR-II
respectively)) which converts testosterone into dihydrotestosterone,

CA 02245758 1998-08-07
-
- , t . '.
,_ - . .
- 2a -
the most powerful androgen circulating in the body.
The type I iso-enzyme (5alphaR-I) is mainly present in liver and skin
while the type II iso-enzyme (5alphaR-II) is mainly present in the
prostate tissue and in the male sexual organs and its activity is
essential in the fetal developping process for the differentiation of
the external sexual organs.
The production of dihydrotestosterone is associated with some
pathologies which are widely diffused as for example benign prostate
hypertrophy, prostate cancer, baldness and acne in men and hirsutism
in women. More particularly iso-enzyme I plays a role in the
pathologies regarding the skin while iso-enzyme-II is involved in
Alv~~igCD j~~


CA 02245758 1998-08-07
W O 97129107 PCT/EF~97100552
- 3 -
prostate pathologies.
._ . _ In the recent years a lot of international searchers have tried to
isolate new compounds capable of inhibiting the 5a-reductase enzyme in
order to treat the above said pathologies, especially, if possible,
acting selectively on only one of the two iso-enzymes.
Inhibitors of 5a-reductase, and also of the iso-enzymes 5aR-I and 5aR-
II were already described, for example finasteride used with success
in the treatment of benign prostate hypertrophy [see for example
J.Med.Chem. 36, x+313-15 (19g3), J.Med.Chem. 3'7, 3871-'74 (1994)]. It is
ZO therefore evident the importance of developing new compounds capable
of inhibiting the action of the 5a-reductase enzyme and in particular
capable of acting selectively on 5oR-I iso-enzyme which, as said, is
responsible, of widely diffused pathologies having an high impact as
baldness in men and hirsutism in women.
Detailed description of the invention
The present invention refers to new compounds capable of inhibiting
the 5a-reductase enzyme, either selectively in respect of 5aR-I and
5aR-II or on both the iso-enzymes, useful for the treatment of the
pathologies mediated by the enzyme.
The-products according to the invention have general formula (I)
(I)
RZ ~'3


CA 02245758 2005-05-19
- 4 -
wherein the substituents R1, R2, R3, R4, R5, R6, X, Q, W, n and the
symbol ----- are as above defined.
According to the present invention with group C1_8alkyl. C2_8alkenyl
and C2_8alkinyl are indicated linear or branched alkyl radicals as for
example: methyl, ethyl, propyl, isopropyl, butyl, pentyl,_ hexyl,,
heptyl, octyl, ethylene, propene, butene, isobutene, acetylene,
propine , butine etC.
''v~ith cycloalkyl are indicated: cyclopropane, cyclobutane.
~~yclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane,
camphane, adamantane.
With aryl are indicated: phenyl and tlaphthyl.
Heterocycle means in particular: saturated or aromatic heterocycles
containing one or more N atoms, more particularly: piridine,
i.midazole, pyrrole. indole, triazoles, pyrrolidine, piperidine,
~falogen means: fluorine, chlorine, bromine, iodine.
T'he substituents of the above said group W are preferably: halogen,
OR, phenyl. NRR', CN, COOR. CONRR', C1_8alkyl (wherein R and R' are as
above defined).
In particular, according to the present invention compounds of formula
(I) are preferred wherein:
R5 = H, heterocycle
X = 0
Q = single bond. C0, CONR. NR (wherein R is as above defined)
W - H, F, C1, Br, Me, t-butyl, C1_$alkoxy, 2,5-dimethylhexyl,
t:~ifluoromethyl. 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl. 4-
f:Luoro-phenyl, phenyl, phenyl-C1_8alkyl, Cl-$alkylcarbonyl,
phenylcarbonyl .


CA 02245758 1998-08-07
WO 97129107 PCT/EP'97/00552
n = 1 and 2
' Rl. R2, R3, R4, R6 = H, Me, CN, phenyl, COOR, CONRR' (wherein R and R'
are as above defined).
Among the pharmaceutically acceptable esters and salts according to
the present invention the following can be mentioned: hydrochloride,
sulphate, citrate, formiate, phosphate.
Preferred compounds according to the present invention are:
1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,4,4a,5,6 hexahydro-1-methyl-(11H)-benzo[c]quinolizine-3-one;
1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
1-methyl-1,2,5,6 tetrahydro-(12H)-benzo[c]quinolizine-3-one;
4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
5,6-dihydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-chloro-1-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one;
8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and
(trans);
t
8-chloro-4-methyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one;
4,8-dimethyl-4.4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis)


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WO 97/29107 PCT/EP97100552
- 6 -
and (trans);
8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one
(cis) and (trans).
The compounds according to the present invention can be prepared for
example starting from compounds of formula 2
R4
R3
(WQ~n ~ ( 2 )
N' '_O
6
H
(2}
wherein R3, R~, W, Q and n are as above defined, following the
reaction Scheme reported hereinafter.
The compounds 2 are commercialy available or can be prepared according
to known techniques.
As it can be seen from the Scheme the preparation of the compounds
according to the invention involves the protection of the amide-group
in compound 2 by the protecting group Z, for example tert-
butoxycarbonyl (t-Boc), to give compound 3; compound 3 is reduced to
compound 4, for example (when R5 is H) with sodium borohydride in
ethanol (pH 3), which is reacted with a silylether 6, produced "in
situ" starting from vinyl-ketones 5 (wherein R1, R2 and R6 are as
above defined) with a silylating agent as
trimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and
thereafter hydrolized, for example in sodium hydrogencarbonate, to
give the compounds of formula ( I ) wherein X - 0 . The possible
introduction of the double bonds and the transformation of the group X


CA 02245758 1998-08-07
WO 97!29107 PCT/EF97/00552
_ 7 _
in one of the other groups mentioned above can be easily performed
according to known techniques starting from the corresponding compound
of formula (I) obtained as indicated. For example the introduction of
the double bonds in position a or b, can be performed by reaction of
dichlorodicyanoquinone (DDQ) with the corresponding silylenolethers or
by oxidation with mercuric acetate of the saturated corresponding
compound obtained as described above. The transformation of group X
can be performed via the corresponding enoltriflates and their
carbonylation in the presence of palladium diacetate,
triphenylphosphine and the suitable nucleophilic reagent (alcohol,
amine, nitro-group).
Example 1
Preparation of N-(t-butoxycarbonyl)-3,4-dihydroguinolin-2(1H) one
[compound 3 wherein (QW)n = H, R3 = R4 = H]
5 g (34 mmoles) of 3,4-dihydroquinolin-2(1H)-one [compound 2 wherein
(QW)2 - H, R3 - R4 - H] and 111 ml of CH2C12 are charged, under
nitrogen, in a 250 ml round bottom flask, equipped with magnetic
stirrer.
To the above said mixture 4.7 ml (34 mmoles) of triethylamine
(distilled on KOH), 8.9 g (40.8 mmoles) of di-butyl dicarbonate and 1
g (8.2 mmoles) of 4-dimethylaminopyridine are added. The mixture is
stirred under reflux for 5 h, then for one night at room temperature
and thereafter the solvent is removed and 200 ml of water are added.
The aqueous phase is extracted with diethylether and the organic phase
is neutralized with an aqueous solution of KHS04 (1 M). The organic
phase is washed with a saturated solution of NaCl and dried on Na2S04.
After filtration and removal of the solvent 8.23 g of the desired

CA 02245758 2005-O1-07
product are obtained (white crystals). M.p.: 68 - 69°C. Yield: 98%.
Example 2
Preparation of N-(t-butox carbonyl)-2-ethox -1 2 3 4-
tetrahydroquinoline [compound 4 wherein (QW)n = H, R3 = R4 = R5 = H].
4.35 g (17.6 mmoles) of the compound obtained from example 1 and 136
ml of absolute ethanol are charged in a 500 ml .round bottom flask
equipped with magnetic stirrer.
The solution is cooled at -25°C and 2.66 g (70.4.mmoles} of NaBH4
(subdivided in 6 portions) are added to the mixture in 1 h. After 4 h
ZO a solution of HCl 2N in absolute ethanol is added to the mixture, up
to pH 3, and the mixture is stirred at 0°C for 1,5 h. 100 ml of water
are added, the aqueous phase is extracted with methylene chloride, the
organic phase is washed with a saturated solution of NaHC03 and a
saturated solution of NaCl and the mixture is dried on _Na2S04. After
filtration the solvent is removed and 4,74 g of the expected product
are obtained (dense yellow liquid); yield g6%.
Operating as above said other compounds 4 wherein the substituents can
not be reduced by NaBH4 are obtained; if substituents which could be
reduced by NaBH~ are present these must be previously protected.
Example 3
Preparation of 1.2.4.~a.5,6-hexahvdro-(11H)-benzo~cl4uinolizin-3-one
[compound of formula (I) wherein X = 0; (QW)n = H; R1 = R2 = R3 = R4 =
R5 = R6 = H; a.b,c.e,f,g = Single bond]
70 ul (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1
- RZ = R6 = H] and 2 ml of anhydrous CH2C12 are charged, at 0°C under
argon in a two-necked round bottom flask equipped with magnetic
stirrer and dropping funnel.

CA 02245758 1998-08-07
WO 97129107 PCT/EP97/00552
- 9 -
1'70 ul (1.22 mmoles) of triethylamine (distilled on KOH)
and 209 ul


(1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf)
(drop


by drop) are added to the mixture. In this conditions 2-


' (trimethylsilyloxy}-1,3-butadiene [compound 6 wherein R1
= R2 = R6 =


H] is formed "in situ". The mixture is stirred for 45 minutes
and


thereafter a solution of 100 mg (0.36 mmoles} of the product
from


Example 2 in 2 mI of anhydrous CH2Ci2 is added therein, drop
by drop,


together with 69ul (0.36 mmoles) of TMSOTf. The mixture is
brought to


room temperature and after 30 minutes 4 ml of a saturated
solution of


NaHC03 are added and the mixture is stirred vigorously for
36 h.


4 ml of water are added to the mixture and the aqueous phase
is


extracted with methylene chloride, the organic phase is washed
with a


saturated solution of NaHC03, water, a saturated solution
of NaCl and


is dried on Na2S04. After filtration the solvent is removed
and 5g mg


of crude product are obtained. The product is purified by
flash


chromatography on silica gel column (FCC) eluting with methylene


chloride and triethylamine 10. 18 mg of the wanted product
are


obtained (crystals). M.p.: 53 - 54C. Yield 25%.


Using various vinyl-ketones 5, or using directly the various


silylenolethers 6 (when available), it is possible to prepare
the


corresponding derivatives of formula (I).


In particular when I-methoxy-3-(trimethylsilyloxy)-1-3-butadiene


(compound 6 wherein R1 - MeO, R2 = H, R6 = H) was used, 4,4a,5,6-


- tetrahydro-(11H)-benzo[c]quinolizin-3-one (compound I wherein
X = 0,


(QW)n = H, R1 = R2 = R3 = R4 = R5 = R6 = H, a = double bond;
b,c,e,f,g


- single bond] was directly obtained according to the synthesis


described in the following Example 4.



CA 02245758 2005-O1-07
- 10 -
Example 4
Preparation of 4,4a,5,6-tetrahydro-(lIH)-benzo[c]quinolizin-3-one
[compound I wherein X = 0. (QWjn = H; R1 = R2 = R3 = R4 = R5 = R6 = H;
a = double bond; b.c.e,f,g = single bond].
To a stirred solution of compound 4 [ (QW)n = H. R3 = R4 = H] (4 g.
14.42 mmolj of the example 3, in 75 ml of anhydrous CH2C12 under argon
at -10°C is added, dropwise in 7 min, 28.84 ml of a 1M solution of
TiCl4 in CH2C12 maintaining the temperature heloca -5°C.~Then 1-
methoxy-3-(trimethylsilyloxyj-1-3-butadiene. (compound 6. R1 = MeO, R2
= H. R6 = H) (3.29 ml, 17.3 mmol) is added by syringe at 0°C, and the
reaction was left aside at room temperature for 1 h. The reaction
mixture is added, cautiously, with 100 ml of NaHC03 satured solution,
and then stirred for 30 min. The organic layer is separated, washed
with water, filtered on Celite and dried over Na2S04. After removal of
the solvent the crude product is purified by flash column
chromatography (eluant light-petroleum ether/ethyl acetate 1:4)
affording 0.72 g (25~ yield) of the expected product (white crystals.
m.p.: 135-137°C).
Example 5
a)- Preparation of 4-methyl-4.4a.5,6-tetrahydro-(11H)-
benzo~clquinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; RI = R3 = R4 = R5 = R6 = H; RZ = Me; a = double bond;
b.c.e,f,g - single bonds], 4 methyl-1.2,5.6-tetrahydro-(11H)-
benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me; b = double bond; a.c,e.f,g
- single bonds] and 4-methyl-5.6-dihydro-(11H)-benzo[c]quinolizine-3-
one [compound of formula (Ij wherein X = 0; (QW)2 = H; R1 = R3 = R4 =

CA 02245758 1998-08-07
WD 97129107 PCTlEF97lOD552
- 11 -
R6 = H; R2 = Me; a,b = double bonds; c.e,f,g = single bonds
.


._ . _ 1 g (4.64 mmol) of 4-methyl-1,2,4,4a,5,6-hexahydro-(11H)-


benzo[c]quinolizine-3-one [compound of formula (I)
whe
i
X


,
re
n
- 0;


(QW)n = H; R1 = R3 = R4 = R5 = R6 = H; R2 = Me; a,b,c,e,f,g
= single


bonds, obtained according to example 3 by reaction of compound
4


(wherein - -
(QW)n H~ R3 R4 - R
- H) of exam
l
2


5
p
e
and


ethylvinylketone (compound 5 wherein R
= R
= H; R
= M
)
d 12


1
6
2
e
an
0 ml


of 5% solution (v/v) of glacial acetic acid in water are
charged under


nitrogen in a two-necked round bottom flask, equipped with
magnetic


stirrer, refrigerator and dropping funnel. Under vigorous
stirring,


727 g (18-56 mmol) of tetrasodic salt EDTA and 5.92 g (18.56
mmol) of


(CH3C02)2Hg are added and the reaction mixture is heated
at 90C for


2h. After cooling at room temperature the reaction mixture
is added


with 120 ml of water and extracted with methylene chloride
(4x70 ml).


The separated organic phase is washed with a satured solution
of


NaHC03, with a satured solution of NaCl then dried over Na2S04.
After


removal of the solvent the crude product is purified by flash


chromatography on silica gel by elution with ethylacetate/light


petroleum ether 2:1 affording:


83- mg (10%) (gummy solid) of cis-4-methyl-4,4a,5,6-tetrahydro-(11H)-


benzo[c]quinolizine-3-one [compound of formula (I) wherein
X - 0;


(QW)n = H; R1 - R3 = R4 = R5 = R6 = H; R2 = Me; a = double
bond;


b,c,e,f,g = single bonds]


350 mg (40%) (crystals, m.p.. 148-150C) of 4 methyl-2,2,5,6-


tetrahydro-(11H)-benzo[c]quinolizine-3-one [compound of formula
(I)


wherein X = 0; (QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me;
b = double


bond; a,c,e,f,g = single bonds] and




CA 02245758 1998-08-07
WO 97/29107 PCT/EP97/00552
- 12 -
107 mg (12%) (gummy solid) of 4-methyl-5,6-dihydro-(11H)-
_ benzo[c]quinolizine-3-one [compound of formula (I) wherein X - 0;
(QW)n = H; R1 = R3 = R4 = R6 = H; R2 = Me; a,b=double bonds; c,e,f,g =
single bonds].
Activity Test
The inhibition potency of the prepared compounds in respect of the
iso-enzymes 1 and 2 of 5a-reductase was determined using tissue
samples (for example prostate human tissue) or human cellular systems
(for example DU 145 cells) expressing iso-enzymes 2 and 1
respectively.
The samples are incubated in the presence of testosterone labelled
with tritium and thereafter the quantity of labelled
dihydrotestosterone formed in the absence and in the presence of the
inhibitor is measured.
The compounds showed high inhibiting power of 5a-reductase enzyme (in
particular of iso-enzyme 1) with an inhibition higher than 50% at the
concentration of 10 - 100 nM.
For the therapeuticaladministration the compounds according to the
invention are prepared in the form of pharmaceutical compositions
containing the active principle and the organic or inorganic
excipients suitable for the oral, parenteral or topic administration
of the compositions. The pharmaceutical compositions can thererfore be
in the solid form (dragees, suppositories, creams, ointments), liquid
form (solutions, suspensions, emulsions) and can possibly contain the
stabilizers, conservatives, humectants, emulsifier, buffers or salts
used for equilibrating the osmotic pressure which are commonly used in '
the art.


CA 02245758 1998-08-07
W O 97/29107 PCTIEP97100552
- 13 -
Generally the administration of the compounds is performed according
._ . _ to the modalities and quantities observed for the known agents used
' for the same purposes and taking into consideration the age and
conditions of the patients.
~, .. , . . E ".; ~ r, (' ~~,'t,~

Representative Drawing