Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-25
2003-04-29
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S095000, C546S153000, C514S294000
Reexamination Certificate
active
06555549
ABSTRACT:
FIELD OF THE INVENTION
The present invention refers to benzo[c]quinolizine derivatives of general formula (I)
wherein:
R
1
, R
2
, R
3
, R
4
, R
6
, same or different, are chosen in the group consisting of: H, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkinyl, cycloalkyl, aryl, heterocycle, halogen, CN, azide, NRR′, C
1-8
alkylamino, arylamino, C
1-8
alkyloxy, aryloxy, COOR, CONRR′ wherein R and R′, same or different, are chosen in the group consisting of: H, C
1-8
alkyl, cycloalkyl, aryl, heterocycle, arylC
1-8
alkyl;
R
5
is chosen in the group consisting of: H, C
1-8
alkyl, COOR, CN, aryl, heterocycle;
X is chosen in the group consisting of: O, C(═O)R, COOR, NO
2
, CONR'R wherein R and R′ are as above defined;
Q is chosen in the group consisting of: simple bond, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkinyl, cycloalkyl, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkinyl, cycloalkyl, trifluoromethyl, C
1-8
alkoxy, C
1-8
alkoxy-C
1-8
alkyl, arylC
1-8
alkyl, aryl, aryloxy, arylamino, C
1-8
alkylcarbonyl, arylcarbonyl, halogen, CN, NRR′, C
1-8
alkylamino, heterocycle wherein the groups alkyl, alkenyl, alkinyl, cycloalkyl, aryl, heterocycle, can be substituted;
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 simple or double bonds;
with the proviso that when b or f are a double bond then the group R
5
is absent; and with the proviso 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)
wherein W, Q, n, R
3
, R
4
, R
5
are as above defined and Z is a protecting group for the amide-group with the proviso that when R
3
=R
4
=R
5
=(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 5alphaR-I and 5alphaR-II respectively)) which converts testosterone into dihydrotestosterone, 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 prostate pathologies.
In the recent years a lot of international searchers have tried to isolate new compounds capable of inhibiting the 5&agr;-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 5&agr;-reductase, and also of the iso-enzymes 5&agr;R-I and 5&agr;R-II were already described, for example finasteride used with success in the treatment of benign prostate hypertrophy [see for example J.Med.Chem. 36, 4313-15 (1993), J.Med.Chem. 37, 3871-74 (1994)]. It is therefore evident the importance of developing new compounds capable of inhibiting the action of the 5&agr;-reductase enzyme and in particular capable of acting selectively on 5&agr;R-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 5&agr;-reductase enzyme, either selectively in respect of 5&agr;R-I and 5&agr;R-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)
wherein the substituents R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, X, Q, W, n and the symbol
-----
are as above defined.
According to the present invention with group C
1-8
alkyl, C
2-8
alkenyl and C
2-8
alkinyl 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 ecc.
With cycloalkyl are indicated: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane.
With aryl are indicated: phenyl and naphtyl. Heterocycle means in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: piridine, imidazole, pyrrole, indole, triazoles, pyrrolidine, piperidine. Halogen means: fluorine, chlorine, bromine, iodine.
The substituents of the above said group W are preferably: halogen, OR, phenyl, NRR′, CN, COOR, CONRR′, C
1-8
alkyl (wherein R and R′ are as above defined).
In particular, according to the present invention compounds of formula (I) are preferred wherein:
R
5
=H, heterocycle
X═O
Q=simple bond, CO, CONR, NR (wherein R is as above defined) W=H, F, Cl, Br, Me, t-butyl, C
1-8
alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4 -fluoro-phenyl, phenyl, phenyl-C
1-8
alkyl, C
1-8
alkylcarbonyl, phenylcarbonyl.
n=1 and 2
R
1
, R
2
, R
3
, R
4
, R
6
=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-(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,5,6tetrahydro-(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).
The compounds according to the present invention can be prepared for example starting from compounds of formula 2
wherein R
3
, R
4
, 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 b
Guarna Antonio
Serio Mario
Applied Research Systems ARS Holding N.V.
Coppins Janet
Hedman & Costigan ,P.C.
Rotman Alan L.
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