Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-01-06
2001-10-30
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S101000, C548S427000, C514S287000, C514S290000, C514S411000
Reexamination Certificate
active
06310208
ABSTRACT:
BACKGROUND OF THE INVENTION
Serotonin is a vasoconstrictor and neurotransmitter present in the brain, intestinal tissue and blood platelets. Regulation of the binding of serotonin can provide a method of treatment and prevention of a variety of illnesses including central nervous disorders, personality disorders, nervous system damage, cardiovascular disorders and gastrointestinal disorders. The compounds of this invention bind to serotonin receptors and are suitable for treatment of many therapeutic indications including those listed above.
SUMMARY OF THE INVENTION
The present invention relates to tricyclic compounds. In particular, it relates to benzo[e]isoindoles and benzo[h]isoquinolines of the general formula
wherein
R
1
-R
4
each independently signify hydrogen, halogen, hydroxy, lower alkyl, lower-alkoxy or phenyl or R
2
and R
3
together represent —O—CH
2
—O—;
R
5
signifies hydrogen, lower-alkyl or benzyl; and
n signifies 0 or 1 as well as pharmaceutically acceptable acid addition salts of the compounds of formula I, with the exception of racemic 2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one.
The compounds of formula I are novel with the exception of rac. 2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one (DE 19 26 022). The compounds described in this Offenlegungsschrift have antiphologistic properties for use against inflammations as well as oedemas following contusions, distortions or fractures.
Since the compounds in accordance with the invention can bind to serotonin receptors (5HT
2
), they are especially suitable for the treatment or prevention of central nervous disorders such as depressions, bipolar disorders, anxiety states, sleep and sexual disorders, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or pain of a different kind, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks, mental organic disorders, mental disorders in childhood, aggressivity, age-related memory disorders and behavioral disorders, addiction, obesity, bulimia etc., nervous system damage caused by trauma, stroke, neurodegenerative diseases etc.; cardiovascular disorders such as hypertension, thrombosis, stroke etc; and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
Objects of the present invention include: compounds of formula I and pharmaceutically acceptable acid addition salts thereof, their racemic mixtures and the corresponding enantiomers thereof and as pharmaceutically active substances; the manufacture of these compounds and salts; medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof; the production of such medicaments; and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of illnesses and disorders of the aforementioned kind, and, respectively, for the production of corresponding medicaments. Only the named known compound itself is excluded from the objects of the present invention as previously defined.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions of the general terms are used in the present specification and apply irrespective of whether the terms appear alone or in combination.
As used herein, the term “lower” denotes residues with a maximum of 7, preferably up to 4, carbon atoms.
The term “alkyl” denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl or t-butyl.
The term “alkoxy” denotes an alkyl group bonded via an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy.
The term “halogen” can signify Cl, Br, F or I.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
Those compounds in which R
4
signifies hydrogen, R
5
signifies methyl and n signifies 1 are preferred, and particularly preferred are compounds wherein further, R
1
signifies hydrogen, hydroxy, halogen or methyl, R
2
signifies hydrogen or ethyl and R
3
signifies hydrogen, methyl or methoxy.
Some particularly preferred representatives of the class of substances defined by general formula I above are:
rac-trans-8-Ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
rac-cis-7-methoxy-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
rac-cis-2,9-dimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo [h]isoquinolin-6-one;
rac-cis-7-chloro-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
rac-cis-7-fluoro-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
rac-cis-2,7,9-trimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
(+)-trans-8-ethyl-7-hydroxy-9-methoxy-2-methyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
(+)-cis-2,7-dimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one;
(+)-cis-2,7,9-trimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one and
(+)-cis-2-methyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one.
Compounds of general formula I as well as their pharmaceutically acceptable acid addition salts can be manufactured in accordance with the invention in manners set forth below:
a) cyclizing a compound of the general formula (II)
wherein R
6
signifies lower-alkyl, to a compound of the general formula (IA)
or
b) cyclizing a compound of the general formula (III)
to a compound of the general formula (IB)
or
c) alkylating or benzylating a compound of general formula I in which R
5
signifies hydrogen, or
d) desalkylating a compound of general formula I in which R
5
signifies alkyl or benzyl, or
e) in a compound of general formula I in which at least one of R
1
-R
4
signifies an alkoxy group, converting this/these into (a) hydroxy group(s), and
f) if desired, converting the compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) the cyclization of a correspondingly substituted acetic acid ester of general formula II can be effected with polyphosphoric acid at a reaction temperature of about 120° C. Toluene is especially suitable as the solvent. Another cyclization method comprises the reaction of a corresponding ester with phosphorus oxychloride in the presence of a strong base.
The cyclization of a compound of formulas III to compounds of formulas IB (see Scheme 2) in accordance with variant b) is effected analogously to variant a). A mixture of polyphosphoric acid and toluene is reacted with a corresponding acetic acid ester for several hours at about 120° C. and the product is subsequently purified according to known methods.
In accordance with process variant c) the alkylation or benzylation at the N atom of the ring nitrogen is effected with an alkyl or benzyl halide, preferably methyl bromide, ethyl bromide, propyl bromide or benzyl bromide. Conveniently, a compound of general formula I in which R
5
signifies hydrogen is reacted with an aforementioned alkyl or benzyl halide in the presence of an alkaline salt, for example K
2
CO
3
, in anhydrous DMF at about 125° C.
The desalkylation at the N atom of the ring nitrogen is effected in accordance with process variant d) by treating a compound of general formula I in which R
5
signifies alkyl in anhydrous chloroform and at room temperature with a cyanogen halide, preferably cyanogen bromide, subsequently heating under reflux and, after concentration under reduced pressure, again boiling under reflux with hydrochloric acid for several hours. Another possibility comprises treatment of a corresponding compound with 2,2,2-trichloroethyl c
Bos Michael
Stadler Heinz
Wichmann Jurgen
Dawson Arthur D.
Epstein William H.
Hoffmann-La Roche Inc.
Huang Evelyn Mei
Johnston George W.
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