Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-25
2004-04-20
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06723850
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention refers to a process for the preparation of (1H)-benzo[c]quinolizin-3-ones derivatives of general formula (I) which involves only three steps and the use, as starting products, of commercially available, or easily preparable, compounds. The compounds of formula (I) are useful as inhibitors of 5&agr;-reductases.
FIELD OF THE INVENTION
The present invention refers to a process for the preparation of (1H)-benzo[c]quinolizin-3-ones derivatives of general formula (I)
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
, 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;
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, arylcarboxyl, arylcarboxyamide, 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;
and their pharmaceutically acceptable salts or esters,
starting from commercially available, or easily preparable compounds, and involving only three steps.
STATE OF THE ART
Compounds of general formula (I) as above defined are known 5&agr;-reductases inhibitors useful for the treatment of the pathologies mediated by the enzyme (for example acne, baldness, prostatic cancer and hypertrophy in men and hirsutism in women) (see International Application No PCT/EP97/00552). They are also active as plant growth regulators.
As it is described in the above said patent application, up to now the compounds of formula (I) are produced by a process involving various steps starting from a compound of formula II
According to the process the amide-group of compound II is protected as N-Boc derivative, the obtained compound is reduced, reacted with a silyloxydiene produced “in situ” and hydrolized to obtain a compound of formula III
Finally the introduction of the double bond in position b is performed by reaction with dichlorodicyanoquinone with the corresponding silylenolethers or by oxidation with mercuric acetate.
As it can be seen the above described process involves many steps which i.a. have a negative effect on the final yields of the desired compounds.
In view of the importance of these compounds as 5&agr;-reductase inhibitors, it is evident the interest in making available new processes in order to prepare the desired compounds in a more efficient way.
DETAILED DESCRIPTION OF THE INVENTION
The present invention allows to overcome the above said problems by a synthesis process that involves only three steps and moreover uses, as starting compounds, compounds which can be easily synthesized or are commercially available.
According to the present invention in the compounds of formula (I) group C
1-8
alkyl, C
2-8
alkenyl and C
2-8
alkinyl represent 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.
The term cycloalkyl represents: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane.
The term aryl represents: phenyl and naphtyl.
The term heterocycle represents in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: pyridine, imidazole, pyrrole, indole, triazoles, pyrrolidine, pyperidine.
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, the process according to the present invention allows the preparation of the compounds of formula (I) wherein:
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-(ditrifuoromethyl)phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl-C
1-8
alkyl, C
1-8
alkylcarbonyl, phenylcarbonyl.
n=1 or 2
R
1
, R
2
, R
3
, R
4
, R
5
=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.
Specific compounds prepared according to the process of the invention are:
2,3,5,6-tetrahydro-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-8-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,8-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,4-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-6-methyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-6-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-6,8-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,4,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5,8-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5,8-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,4,5-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1 ,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5,6,8-tetramethyl-(1H)-benzo[c]quinolizin-3-one.
According to the invention the above defined compounds of formula (I) can be prepared starting from compounds of general formula 2 and 3:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, W, Q and n are as above defined.
The compounds 2 and 3 are commercially available or can be prepared according to known techniques.
As it can be seen from the Scheme 1 the preparation of the compounds I according to the invention involves the N-alkylation of
Guarna Antonio
Occhiato Ernesto
Serio Mario
Applied Research Systems ARS Holding N.V.
Hedman & Costigan ,P.C.
Robinson Binta
Rotman Alan L.
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