Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-18
2001-12-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S226500, C514S259500, C514S312000, C514S318000, C514S322000, C514S323000, C514S362000, C514S372000, C514S387000, C514S414000, C544S011000, C544S049000, C544S284000, C544S286000, C546S158000, C546S198000, C546S199000, C546S201000, C548S134000, C548S207000, C548S305100, C548S455000
Reexamination Certificate
active
06329366
ABSTRACT:
This invention relates to pharmaceutical compounds and their use in the treatment of disorders of the central nervous system.
It is well known that compounds active at serotonin receptors have potential in the treatment of disorders of the central nervous system and, for example, certain halo-substituted indole compounds having serotonin antagonist properties are disclosed in WO 98/31686.
The compounds of the invention have the following formula:
in which R
1
and R
2
are each hydrogen, halo, cyano or methyl,
the dotted line represents an optional double bond,
where R
4
and R
5
are each hydrogen, C
1-6
alkyl, cyclopropyl or cyclopropyl-C
1-6
alkyl,
n is 0 or 1, and
R
3
is —SR
6
, —SOR
6
, —SO
2
R
6
, —COR
6
, —CH
2
OH or —CONHR
7
, where R
6
is C
1-6
alkyl and R
7
is hydrogen or C
1-6
alkyl;
provided that when one of R
1
and R
2
is hydrogen and the other is fluoro,
R
4
and R
5
are each hydrogen or C
1-6
alkyl,
and n is 0,
then R
3
is not —COR
6
or —CONHR
7
;
and salts thereof.
The compounds of the invention and their pharmaceutically acceptable salts are indicated for use in the treatment of disorders of the central nervous system.
In the above formula (I), a halo atom is preferably chloro, bromo or fluoro, and is especially fluoro. A C
1-6
alkyl group can be methyl, ethyl, propyl, butyl or pentyl, and can be branched or unbranched including isopropyl and tert. butyl.
Preferred compounds are those which have one or more of the following features:
(i) R
1
and R
2
are each hydrogen or halo;
(ii) R
1
and R
2
are each hydrogen or fluoro;
(iii) R
1
is fluoro and R
2
is hydrogen;
(iv) R
1
is fluoro in the 6-position, and R
2
is hydrogen;
(v) the dotted line represents a double bond;
(vi)
(vii)
(viii) R
4
and R
5
are each hydrogen or C
1-6
alkyl;
(ix)
where R
4
is C
1-6
alkyl, especially isopropyl;
(x) n is 1;
(xi) n is 1 and R
3
is at the 6-position;
(xii) R
3
is —SOR
6
, —SO
2
R
6
or —COR
6
;
(xiii) R
6
is methyl or ethyl, and especially methyl;
(xiv) R
3
is —SOCH
3
or —SO
2
CH
3
, at the 6-position.
A preferred group of compounds is of the following formula:
in which R
1
and R
2
are each hydrogen or fluoro, R
3
is at the 6- or 7- position and is —SOR
6
, —SO
2
R
6
or —COR
6
, where R
4
and R
6
are each C
1-6
alkyl, especially methyl or ethyl.
Especially preferred are compounds of formula (II) in which R
1
is fluoro, R
2
is hydrogen, R
3
is at the 6-position, R
4
is C
1-6
alkyl, preferably isopropyl, R
6
is preferably methyl, and preferably the dotted bond represents a double bond.
Especially preferred compounds are of the formula:
where R
3
is —SOCH
3
or —SO
2
CH
3
, or a pharmaceutically acceptable salt thereof.
As indicated above, it is, of course, possible to prepare salts of the compound of the invention and such salts are included in the invention. Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, pyruvic, lactobionic, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, naphthalene-2-sulphonic, bisethanesulphonic acid or methanesulphonic acid. A preferred salt is the tartrate.
In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
Some of the compounds of the invention contain one or more asymmetric carbon atoms which gives rise to isomers. Moreover, compounds which are substituted by a sulphinyl group (R
3
is —SOR
6
) also exist in isomeric forms. These compounds are normally prepared as racemic mixtures and can conveniently be used as such, but individual isomers can be isolated by conventional techniques, if so desired. Such racemic mixtures and individual optical isomers form part of the present invention. It is preferred to use an enantiomerically pure form.
The invention also includes a process for producing a compound of formula (I) above, which comprises reacting a compound of the formula:
with a compound of the formula
where n, R
1
, R
2
, R
3
, X and Y have the values given above, and (i) Z is —CH
2
W, where W is a leaving group such as, for example, a halo atom or a mesylate or tosylate, or (ii) Z is —CHO.
The reaction is preferably carried out in a polar solvent such as, for example, acetonitrile or water, at a temperature of from 50° C. to 150° C., and in the presence of sodium iodide and a base such as, for example, sodium carbonate. When an aldehyde intermediate is employed, the reaction is one of reductive amination using, for example, sodium cyanoborohydride, borane in pyridine or triacetoxy borohydride in the presence of the compound of formula (IV).
The intermediate compounds of formula (IV) are known in the art, whereas compounds of formula (V), and their salts, in which n is 1, are novel. Compounds of formula (V) can be prepared by reacting an ethane derivative of the formula V—CH
2
CH
2
—W (VI), where V is halo, preferably bromo, with a compound of formula:
Preferred ethane derivatives of formula (VI) are dihalo-ethanes, for instance bromo chloroethane, and the reaction is preferably carried out in an organic solvent such as, for example, dimethyl formamide, with a strong base such as sodium hydride, at a temperature of from 0° C. to 100° C., for instance room temperature.
Aldehyde intermediates of formula (V) can be prepared from the appropriate alkene by oxidation employing, for example, ozone or osmium tetroxide.
Alternatively, compounds of formula (V) can be prepared by a synthetic route, such as the following:
or by the following route:
The intermediate compounds of formula (VII) are known in the literature, and they can readily be prepared by a variety of routes as, for example, in the case of compounds of formula (VII) having the following structure:
the principal route of synthesis is by means of a reaction between the appropriate sulfamoyl compound prepared from an aniline and sulfamoyl chloride and trioxan, in the presence of an acid, for example, an alkyl sulfonic acid:
Alternatively, compounds of formula (VIII) can be synthesised by reaction of sulfamide with an amino benzylamine in pyridine or diglyme. The amino benzylamine can be prepared in three steps from the appropriate nitrobenzoic acid via amide formation and a two step reduction as, for example:
A further alternative route to compounds of formula (VIII) involves the use of an appropriate N-sulfamoyloxazolidinone of formula:
which can be readily prepared by reacting chlorosulfonylisocyanate and amine with chloro- or bromo-ethanol. The N-sulfamoyloxazolidinone is then reacted with an aniline of formula
and the resulting sulfonyl urea reacted with trioxan, as described above, to give the compound of formula (VIII).
An alternative route to the compounds of the invention in which in formula (I) X is:
consists of an analogous, reverse, condensation of the two principal components of the molecule as, for example, by reacting a compound of the formula:
with a compound of formula (VIII) above, employing the Mitsunobu reaction. The reaction is carried out in an organic solvent such as tetrahydrofuran or dimethyl formamide, at a temperature of, for example, 0° C. to 5° C. employing a dialkylazodicarboxylate and triphenylphosphine or tributylphosphine. Intermediate compounds of formula (IX) are novel and are included as part of the present invention.
It will be appreciated that in preparing compounds of formula (I) in which R
3
is —SOR
6
or —SO
2
R
6
, the appropriate intermediates as, for example, those of formula (VIII), can be prepared by oxidation of the —SR
6
substituted compound, by the use of
Fairhurst John
Gallagher Peter Thaddeus
Miles Martin Victor
Desai Manisha A.
Eli Lilly and Company Limited
McKenzie Thomas
Shah Mukund J.
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