Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PIPERIDYINDOLES AS SEROTONIN RECEPTOR LIGANDS
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 V~IO 98/31686.
The compounds of the invention have the following
formula:
R4 R5
(CH2)m~ ~
N X Y
R~ l
(CRS R2)n
~6
R$ ~
R3
in which R1 and R2 are each hydrogen or C1_6 alkyl,
R~
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R3 is -SR10, -SOR10, -S02R10, -COR10, -CH20H or
-CONHR11, where R10 is Cl_6 alkyl and R11 is hydrogen or
C1_6 alkyl,
R4, R5, R6 and R~ are each hydrogen or C1_6 alkyl,
provided that at least one of R'~, R5, R6 and R~ is C1_~
alkyl,
R8 and R9 are each hydrogen, halo, C1_6 alkyl or cyano,
n is 0 or 1 and m is 2 or 3 ,
00
X is C=O or ~S\ , and
O
Riz
Y is X-Rl2 or \C wherein R12 and R'-3 are each
'Rls
hydrogen, C1_6 alkyl, cyclopropyl or cyclopropyl-Cl_6
alkyl;
and salts thereof.
The compounds of the invention and their
pharmaceutically acceptable salts are indicated for use
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in the treatment of disorders of the central nervous
system.
Accordingly, the present invention also provides the ue
of a compound of the present invention in the
preparation of a medicament for the treatment of a
disorder of the central nervous system.
In the above formula (I), a halo atom is preferably
chloro, bromo or fluoro, and is especially fluoro. A
C1_6 alkyl group can be methyl, ethyl, propyl, butyl or
pentyl or hexyl, 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) R8 and R9 are each hydrogen or halo;
(ii) R8 and R9 are each hydrogen or fluoro;
(iii) R8 is fluoro and R~ is hydrogen;
(iv) R8 is fluoro in the 6-position, and R9 is
hydrogen;
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~0
(v) X is /S~ ;
O
\ Ria
(vi ) Y is ~C~R13 wherein R'-a and R'-3 are both Cl_6 alkyl ;
(vii) Y is ~ -Rsa where R12 is C1_6 alkyl, especially isopropyl;
(viii)n is 1 and R1 and R2 are both hydrogen;
(ix) R3 is at the 6-position or the 7-position,
preferably at the 6-position;
(x) R3 is -SOR10, -S02R10 or -COR10;
(xi) R10 is methyl or ethyl, and especially methyl;
(xii) R3 is -SOCH3 or -S02CH3, at the 6-position or
the 7-position, preferably at the 6-position;
(xiii) the point of attachment of the piperidine group
is at the 3-position. on the indole moiety;
(xiv) R4 is C1-6 alkyl.
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A preferred group of compounds is of the following
formula:
R4 p'II ~R~2
S-N
NON CH2
4
Rs ~s ~ ~ a z s s
R9 'N ~ w
H
R3
5
in which
R8 and R9 are each hydrogen or halo, preferably fluoro,
R3 is at the 6- or 7- position and is -SORl~, -S02R1~ or
-CORD , where RZ~ is C1_6 alkyl,
R4 is Cl_6 alkyl, and
R1~ is C1_6 alkyl; and salts thereof.
A further preferred group of compounds is of the
following formula
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R12
4
R ~W[S R1s
~~N
R$
w
R3
in which
R8 and R9 are each hydrogen or halo, preferably fluoro,
R3 is in the 6- or 7-position and is -SOR10, -S02R10 or
-COR1~, where R10 is C1_6 alkyl,
R4 is Cl_6 alkyl, and
R1~ and R13 are each hydrogen or C1_~ alkyl; and salts
thereof .
A further preferred group of compounds is of the
following formula:
R~ m
H
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R12
R4
C R13
~~N
R$
w
R3
in which
R8 and R9 are each hydrogen or halo, preferably fluoro,
R3 is in the 6- or 7-position and is -SOR10, -S02R10 or
-COR10, where R10 is C1-6 alkyl,
R4 is Cl_6 alkyl, and
R12 and R13 are each hydrogen or C1-6 alkyl; and salts
thereof .
A further preferred group of compounds is of the
following formula:
~a iv
H
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_ g _
R1z
R4
C R13
J
R$
R3
in which
R8 and R9 are each hydrogen or halo, preferably fluoro,
R3 is in the 6- or 7-position and is -SOR10, -S02R10 or
-COR10, where R10 is C1_6 alkyl,
R'1 is C1_6 alkyl, and
R12 and R13 are each hydrogen or C1-~ alkyl; and salts
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, malefic,
R~ iv
H
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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 (R3 is -SOR10) 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 .
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The invention also includes a process for producing a
compound of formula (I) above, which comprises reacting
a compound of the formula:
R4 R5
R~
R$
~6
with a compound of the formula
X-Y
(CH2 )m_~ N (CR~R2)n
Rs
(IV)
where n and m, and the substituents, have the values
given above, and (i) Z is -CH2V~1, where V~1 is a leaving
group such as, for example, a halo atom or a mesylate or
tosylate, or (ii) 2 is -CHO.
R9 H
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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 (III) .
The intermediate compounds of formula (III) can be made
by reacting an indole with the appropriate piperidinone.
Compounds of formula (VI) can be prepared by reacting an
ethane derivative of the formula V-(CH2)m-W (V),
where V is halo, preferably bromo, with a compound of
formula:
X-Y
H N (C R~ R2)n
Ra
(VI)
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Preferred ethane derivatives of formula (V) 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 (IV) can be prepared
from the appropriate alkene by oxidation employing, for
example, ozone or osmium tetroxide.
Alternatively, compounds of formula (VI) can be prepared
by a synthetic route, such as the following:
R~z O
R~z
HOOC R~3I \ R3 _~ R~ ~ \
R3
O H / /
O N
H
R~z Riz Riz
R~ I \ R~ \ R~ \
R3 I Rs E I Rs
O N / O H /
O N /
C~ OH
or by the following route:
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\ N02 \ N02 \ N
3 ~ Rs ~ R ~SO2
F ~ NH ~ N
OMe OMe
OMe OMe
\ N. \ N.
SO2 ~ R3 S02
N ~ N
H OMe
O OMe
The intermediate compounds of formula (VI) 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 (VI) having the following
structure:
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O
\~S~ N / R~ 2
i
HN
Ra
(VIII)
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:
trioxan + R3 '~ l NH- R~z + CH3S03H
N~S02
H
Alternatively, compounds of formula ('VII) can be
synthesised by reaction of sulfamide with an amino
ben~ylamine 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:
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O
R3 ~ COOH R3 ~ ~z N-R
~N-R ~ 12
H -~ R~ H
/ NOz ~ NOz ~ NOz
R ~ H- R1z R \ N/R~z
/ NHz / N~SOz
H
A further alternative route to compounds of
formula (VII) involves the use of an appropriate
N-sulfamoyloxazolidinone of formula:
O
R~2 ~-O
\ N- S02 N
H
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
NH2
R3
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and the resulting sulfonyl urea reacted with trioxan, as
described above, to give the compound of formula (VII).
An alternative route to the compounds of the invention
in which in formula (I) X is:
~S O
~ ~~O
consists of an analogous, reverse, condensation of the
two principal components of the molecule as, for
example, by reacting a compound of the formula:
R4 R5
R$
(VIII)
OOH
R~
with a compound of formula (VII) 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
K~ H
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compounds of formula (VIII) are novel and are included
as part of the present invention.
It will be appreciated that in preparing compounds of
formula (I) in which R3 is -SOR10 or -S02R10, the
appropriate intermediates as, for example, those of
formula (VII), can be prepared by oxidation of the -SR10
substituted compound, by the use of metachloro
perbenzoic acid or Oxone~ or sodium perborate or osmium
tetroxide/sodium periodate.
As mentioned above, the compounds of the invention and
their pharmaceutically acceptable salts have useful
central nervous system activity. They have been shown
to increase release of tritiated-5HT from guinea pig
cortical slices in a test with the following procedure.
Cortical slices from the brains of male guinea pigs were
incubated with 50 nM [3H]-5-HT for 30 minutes at 37°C.
The slices were washed in basal buffer containing 1 ~M
paroxetine and then transferred to baskets. The baskets
were used to transfer the tissue between the washing and
release buffers, all of which contained 1 ~.M paroxetine.
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In order to obtain a stable baseline release, the slices
were incubated for 11 minutes in buffer and then
transferred for 4 minutes to a second tube containing
buffer. Following incubation they were again
transferred, for a further 4 minutes, to a buffer in
which NaCl had been substituted, on an equimolar basis,
to give a KCl concentration of 30 mM (release sample).
The tritium in the tissue samples and in the buffers
from the three incubation periods was estimated by
liquid scintillation spectroscopy. Test compound was
present throughout the three incubation periods. The
compounds of the invention enhanced release of 5-HT.
Compounds of the invention have been demonstrated to be
active at the serotonin 1B and 1D receptors. Their
activity may be demonstrated in tests as described in
Pullar, I. A. et al, European Journal of Pharmacology,
407, 39-46.
Compounds of the invention have also been demonstrated
to be active at the serotonin, 5-HT2A, receptor. Their
binding activity has been demonstrated in a test
described by Nelson, D. L. et al, J. Pharmacol. Exp.
Ther., 265, 1272-1279, in which the affinity of the
compound for the human 2A receptor is measured by its
ability to displace the ligand [3H]-ketanserin.
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Compounds of the invention are also active serotonin
reuptake inhibitors as measured by their displacement of
[3H]-paroxetine at the reuptake site, Neuropharmacology
Vol. 32 No. 8, 1993, pages 737-743.
Because of their ability to enhance 5-HT release as well
as selective affinity for 5-HT receptors, the compounds
of the present invention are indicated for use in
treating a variety of conditions such as depression,
obesity, bulimia, alcoholism, pain, hypertension,
ageing, memory loss, sexual dysfunction, anxiety,
schizophrenia, gastrointestinal disorders, headache,
cardiovascular disorders, smoking cessation, drug
addiction, emesis, epilepsy, Alzheimer's and sleep
disorders. Compounds of the present invention may be
particularly useful in the treatment of depression.
Compounds of the invention may also be useful for the
treatment of obsessive compulsive disorder.
The present invention also provides a method of treating
a warm blooded mammal including a human suffering from
or susceptible to a disorder of the central nervous
system, which comprises administering to said human an
effective amount of a compound of the present invention,
or a pharmaceutically acceptable salt thereof.
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The present invention further provides a method of
inhibiting the 5-HT2A receptor which comprises
administering to a warm blooded mammal including a human
in need of such treatment a therapeutically effective
amount of a 5-HT2A antagonist of formula I.
The present invention also provides a method of
inhibiting the reuptake of serotonin, which comprises
administering to a warm blooded mammal including a human
in need of such treatment a therapeutically effective
amount of a serotonin reuptake inhibitor of formula I.
The compounds of the invention are effective over a wide
dosage range, the actual dose administered being
dependent on such factors as the particular compound
being used, the condition being treated and the type and
size of mammal being treated. However, the dosage
required will normally fall within the range of 0.01 to
mg/kg per day, for example in the treatment of adult
20 humans, dosages of from 0.1 to 100 mg per day may be
used, preferably from 2 to 20 mg per day as, for
example, for the preferred compounds of formula (II) and
(III) .
The compounds of the invention will normally be
administered orally or by injection and, for this
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purpose, the compounds will usually be utilised in the
form of a pharmaceutical composition. Such compositions
are prepared in a manner well known in the
pharmaceutical art and comprise at least one active
compound.
Accordingly the invention includes a pharmaceutical
composition comprising as active ingredient a compound
of formula (I) or a pharmaceutically acceptable salt or
ester thereof, associated with a pharmaceutically
acceptable excipient. In making the compositions of the
invention, the active ingredient will usually be mixed
with a carrier, or diluted by a carrier, or enclosed
within a carrier which may be in the form of a capsule,
sachet, paper or other container. The excipient may be
a solid, semi-solid or liquid material which acts as a
vehicle, excipient or medium for the active ingredient.
Some examples of suitable excipients are lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum
acacia, calcium phosphate, alginates, tragacanth,
gelatin syrup, methyl cellulose, methyl- and propyl-
hydroxybenzoate, talc, magnesium stearate or oil. The
compositions of the invention may, if desired, be
formulated so as to provide quick, sustained or delayed
release of the active ingredient after administration to
the patient.
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Depending on the route of administration, the foregoing
compositions may be formulated as tablets, capsules or
suspensions for oral use and injection solutions or
suspensions for parenteral use or as suppositories.
Preferably the compositions are formulated in a dosage
unit form, each dosage containing from 0.1 to 100 mg,
more usually 2 to 20 mg, of the active ingredient.
The following Preparations and Examples illustrate
routes to the synthesis of the compounds of the
invention.
EXAMPLES
1-Dimethylamino-2-(4-fluoro-2-nitro)phenylethene
A mixture of 4-fluoro-2-nitrotoluene (50 g,
0.32 mol), dimethylformamide dimethylacetal
(76.77 g) and dimethylformamide (910 ml) were
heated under reflux under nitrogen with stirring
for 7 hr, cooled, allowed to stand for 16 hr,
poured into ice-water (2 1), stirred for 15 mins
and the resultant precipitate isolated by
filtration, washed with water (500 ml), dried to
give a red solid. (Org. Synth. (1985), 63, 214-25)
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6-Fluoro-1H-indole
A 40 litre Cook hydrogenator was charged under a
nitrogen atmosphere with 10% palladium on charcoal
(9 g) suspended in toluene (400 ml). To this
suspension was added 1-dimethylamino-2-(4-fluoro-2-
nitro) phenylethene (137.2 g, 0.653 mol) in toluene
(1.4 1) and the mixture hydrogenated at 80 psi for
3.5 hr. The suspension was then filtered through a
Celite pad, which was washed through with toluene
(2 x 200 ml) and the filtrate and washings
evaporated under reduced pressure to give a brown
oil which crystallised on standing to a yellow
brown solid 93.65 g. This solid was dissolved in
ethyl acetate-hexane (7:3) and filtered through a
pad of flash silica. The required fractions were
collected and evaporated under reduced pressure to
give a pale brown solid. (Org. Synth. (1985), 63,
214-25)
Similarly prepared were:
6,7-Difluoro-1H-indole
8 (1H NMR, CDC13, ppm) . 6.50 (1H, m) , 6. 90 (1H, m) ,
7.30 (2H, m) , 8 .4 (1H, br) .
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6-Fluoro-7-methyl-1H-indole (J.Med.Chem., 1976
19(3) 391-5)
S (1H NMR, CDC13, ppm) . 2.4 (3H, s) , 6.50 (1H, ) ,
6.90 (1H, t) , 7.20 (1H, m) , 7.4 (1H, m) , .0 (1H,
s) .
6-Fluoro-3-(6-methyl-1,2,3,6-tetrahydro-4-
pyridinyl)-1H-indole and 6-fluoro-3-(2-methyl-
1,2,3,6-tetrahydro-4-pyridinyl)-lH-indole
Powdered potassium hydroxide (4.01 g, 71.5 mmol) is
dissolved in a mixture of methanol (70 ml) and
water (1 ml), and stirred until no solid remains.
6-Fluoro indole (l.lOg, 8.73 mmol) and 2-
methylpiperidone trifluoroacetiC acid salt (4.188,
18.4 mol) [2-methyl 4-piperidones can be
synthesised by known methods in the literature ,
for example Mistryukov, E. A.; Aronova, N. I.
Izv. Akad. Nauk SSSR, Ser. Khim. (1966), (12),
2171-6. ] are added as single portions, and the
mixture is heated to reflux under a nitrogen
atmosphere for four hours, before being allowed to
cool to 50°C. Water (70 ml) is then added in a
dropwise manner over 20 mins, and. the mixture is
then stirred for a further 1 hour, during which
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time the temperature falls to r.t. The yellow
precipitate that forms is collected by vacuum
filtration, rinsed with a small amount of cold
water, then dried in vacuo at 60°C for,l6 hours.
This affords 1 . 60g, (79.7 0) of the title compound
in a ratio of 2:1 for the regioisomers.
1H NMR (CDC13) , 8 (ppm) ; 1.22-1 .34 (2x d, 3H) ,
2.12-2.60 (m, 2.5 H), 2.92-3.8 (m, 2.5H), 3.68
(br.s 1H), 6.10 (s, 0.33H), 6.22 (s, 0.67H), 6.82-
6 . 98 (t, 1H) , 7.00-7.10 (d, 1H) , 7 .14 (s, 1H) , 7 .74
(m, 1H), 8.34 (br.s, 1H); MS, reqd. 230.1; obs.
231.1.(M+1 ; FIAPOS); 229.1 (M-1 ; FIANEG)
Similarly prepared were
6,7-Difluoro-3-(6-methyl-1,2,3,6-tetrahydro-4-
pyridix~.yl)-1H-indole) and 6,7-difluoro-3-(2-methyl-
1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole
1H NMR (CD30D) , (ppm) ; 1.40 (m, 3H) , 2.32-2.84 (m, 2H) ,
3.06-3.32 (m, 1H), 3.34-3.58 (m, 1H), 3.64-3.88 (m, 1H),
6.22 (s, 0.28H), 6.40 (s,,0.72H), 7.04-7.20 (m, 1H),
7.50 (s, 1H), 7.70-7.78 (s, 1H); MS, reqd. 248.1; obs.
249.1 (M+1 ; FIAPOS); 247.1 (M-1 ; FIANEG).
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6-Fluoro-7-methyl-3-(6-methyl-1,2,3,6-tetrahydro-4-
pyridinyl)-1H-indole) and 6,7-difluoro-3-(2-methyl-
1,2,3,6-tetrahydro-4-pyridinyl)-1H-indo1e
iH NMR ( (CD3) 2S0) , 8 (ppm) ; 1 . 30-1 .44 (m, 3H) , 2 .20-2 .40
(m, 1H), 2.54 (s, 3H), 3.04-3.86 (m, 4H), 6.14-6.24 (m,
1H) , 6. 98-7. 10 (m, 1H) , 7.52-7.72 (s, 1H) , 7. 72-7.82 (m,
1H) .
tert-Butyl 4-(6-fluoro-1H-indol-3-yl)-6-methyl-3,6-
dihydro-1(2H)-pyridinecarboxylate and tert-butyl 4-(6-
fluoro-1H-indol-3-yl)-2-methyl-3,6-dihydro-1(2H)-
pyridinecarboxylate
Di-tert butyl dicarbonate (5.908, 0.027 mol) is
dissolved in THF at 0°C, and a mixture 6-fluoro-3-(6-
methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole and 6-
fluoro-3-(2-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-
indole (5.178, 0.022 mol) is added portionwise over 5
minutes. The mixture is stirred at this temperature for
1 hour, then for 3 hours at room temperature, before 100
ml aqueous sodium bicarbonate (sat. solution) is added.
This mixture is extracted with ethyl acetate (3 x 100
ml), then the combined organic layers are dried over
MgS04, before the solvent is removed in vacuo. The
residual pale yellow oil is passed through a silica pad,
eluted with dichloromethane, then 10o methanol, 90%
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dichloromethane, to give 7.368, 1000 of the desired
product after removal of the solvent. The ratio of
regioisomers is 2:1.
1H NMR (CDC13) , ~ (ppm) ; 1.18 (d, 3H) , 1.50 (s, 9H) ,
2.20-2.30 (br. d, 1H), 2.76-2.90 (br. d, 1H), 3.72-3.82
(br. d, 1H), 4.30-4.54 (br d, 1H), 4.64 (m, 1H), 6.10
(br. s, 1H) , 6. 90 (t, 1H) , 7. 06 (d, 1H) , 7.12 (s, 1H) ,
7.74 (m, 1H), 8.54 (m, 1H); MS, reqd. 330.1; obs. 331.1
(M+1 ; FIAPOS); 329.1 (M-1 ; FIANEG)
Similarly prepared were
tert-Butyl 4-(6,7-difluoro-1H-indol-3-yl)-6-methyl-3,6-
dihydro-1(2H)-pyridinecarboxylate and tert-butyl 4-(6,7-
difluoro-1H-indol-3-yl)-2-methyl-3,6-dihydro-1(2H)-
pyridinecarboxylate
1H NMR (CDC13), (ppm); 1.20-1.28 (m, 3H), 1.44 (s, 9H),
1.84-2.10 (m, 1H), 2.12-2.58 (m, 1H), 2.60-3.16 (m, 1H),
3.62-3.84 (m, 1H), 4.22-4.82 (m, 1H), 6.08 (br. s, 1H),
6.88-7.00 (m, 1H), 7.00-7.12 (m, 1H), 7.38-7.60 (m, 1H);
MS, reqd. 348.1; obs. 347.1 (M-1 ; FIANEG).
tert-Butyl 4-(6-fluoro-7-methyl-1H-indol-3-yl)-6-methyl-
3,6-dihydro-1(2H)-pyridinecarboxylate and tert-butyl 4-
(6-fluoro-7-methyl-1H-indol-3-yl)-2-methyl-3,6-dihydro-
1(2H)-pyridinecarboxylate
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1H NMR (CDC13) , 8 (ppm) ; 1.18-1.32 (m, 3H) , 1.50 (s, 9H) ,
2.20-2.70 (m, 4H), 2.78-3.14 (m, 1H), 3.60-3.86 (m, 1H),
4.04-4.72 (m, 2H), 6.02-6.12 (m, 1H), 6.82-6.94 (m, 1H),
7.10-7.12 (m, lH) , 7.54-7.62 (m, 1H) , 7.96 (br. s, 1H) .
tert-Butyl 4-(6-fluoro-1H-indol-3-yl)-(2S,4R)-2-methyl-
1-piperidinecarboxylate and tert-butyl 4-(6-fluoro-1H-
indol-3-yl)-(2R,4S)-2-methyl-1-piperidinecarboxylate
A mixture of of tert-butyl 4-(6-fluoro-1H-indol-3-yl)-6-
methyl-3,6-dihydro-1(2H)-pyridine Carboxylate and tert-
butyl 4-(6-fluoro-1H-indol-3-yl)-2-methyl-3,6-dihydro-
1(2H)-pyridine Carboxylate (2.06g, 6.24 mmol) is
dissolved in dry ethanol (40 ml), along with a
suspension of 10o palladium on carbon (0.50 g). This
mixture is agitated under 70 psi pressure of hydrogen
gas for 16 hours, before the catalyst is removed by
filtration through a celite plug. The solvent is removed
in vacuo, and the residue purified by column
chromatography, using 25o ethyl acetate, 75% hexane as
the eluent. After removal of the solvent, this affords
1.218, 58 o yield of tert-butyl 4-(6-fluoro-1H-indol-3-
yl)-2-methyl-1-piperidinecarboxylate as a mixture of Cis
and trans products. This mixture is subjected to
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preparative HPLC, firstly using an achiral column
(Kromasil KR60-5SIL column, eluted with 89% hexane, 9%
dichloromethane, 2% ethanol and 0.1o dimethylamine) to
separate the trans and cis isomers (retention times =
11.6 and 12.2 min), then using a chiral stationary phase
column (Chiralcel-OJ column, eluted with 60o hexane, 40%
ethanol and 0.2% dmea) to resolve the two traps
enantiomers (retention times = 9.1 and 10.5 min). 1H NMR
(CDC13) , 8 (ppm) ; 1.28 (d, 3H) , 1.50 (s, 9H) , 1.82-2 . 06
(m, 3H), 2.88-3.22 (m, 3H), 4.00-4.20 (br. m, 1H), 4.50-
4.66 (br. m, 1H) , 6.88 (t, 1H) , 6.92 (s, 1H) , 7.04 (d,
1H), 7.52 (m, 1H), 8.20 (br. s, 1H); MS, reqd. 332; obs.
331.1 (M-l; FIANEG).
Similarly prepared were
tert-Butyl 4-(6,7-difluoro-7.H-indol-3-yl)- (2S,4R)-2-
methyl-1-piperidinecarbo,xylate and tert-butyl 4-(6,7-
difluoro-1H-indol-3-yl)- (2R,4S)-2-methyl-1-
piperidinecarboxylate
1H NMR (CDC13) , (ppm) ; 1. 16-1 . 34 (m, 3H) , 1 . 52 (s, 9H) ,
1.60-1.92 (m, 2H), 1.94-2.36 (m, 2H), 2.96-3.38 (m, 2H),
3.80-4.32, (m, 1H), 4.36-4.74 (m, 1H), 6.82-7.00 (m,
2H), 7.18-7.30 (m, 1H); MS, reqd. 250.1; obs. 251.1 (M+l
; FIAPOS); 249.1 (M-1 ; FIANEG).
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tert-Butyl 4-(6-fluoro-7-methyl-1H-indol-3-yl)- (2S,4R)-
2-methyl-1-piperidinecarboxylate and tert-butyl 4-(6-
fluoro-7-methyl-lH-indol-3-yl)- (2R,4S)-2-methyl-1-
piperidinecarboxylate
1H NMR (CDC13) , 8 (ppm) ; 1 .24-1.32 (m, 3H) , 1 .48 (s, 9H) ,
1.56-1.70 (m, 1H), 1.78-1.96 (m, 2H), 1.98-2.10 (m, 1H),
2.38 (s, 3H), 2.96-3.24 (m, 2H), 4.08 (br. s, 1H), 4.52
(br. s, 1H) , 6.82-6. 96 (m, 2H) , 7.34-7.40 (m, 1H) , 7. 82
(br. s, 1H) .
6-Fluoro-3-[(2S,4R)-2-methylpiperidin-4-yl]-1H-indole and 6-
fluoro-3-[(2R,4S)-2-methylpiperidin-4-yl]-1H-indole
tert-Butyl (2S,4R)-4-(6-fluoro-IH-indol-3-yl)-2-methyl-
1-piperidinecarboxylate (1.21 g, 3.64 mmol) is dissolved
in trifluoroacetic acid (50 ml) and dichloromethane
(50m1) and the mixture stirred at room temperature under
nitrogen for 1 hour. The reaction is then quenched by
the cautious addition of saturated aqueous sodium
bicarbonate (500 mI), and the mixture extracted with
ethyl acetate (2 x 250 ml). The organic layers are
combined, dried over MgS04, then the solvent is removed
in vacuo. This affords the desired product as a clear
oil (0.848, 1000 yield). 1H NMR (CD30D), 8 (ppm); 1.06
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(d, 3H), 1.60-1.70 (m, 1H),1.72-1.98 (m, 3H), 2.72-2.90
(m, 2H), 2.92-3.12 (m, 1H),3.14-3.24 (m, 2H), 6.6 (t,
1H),6.9 (d, 1H), 6.94 (d, 1H), 7.34 (d.d,1H); MS,
reqd. 232.1; obs. 233.1 (M+1 ; FIAPOS); 231.1 (M-1 ;
FIANEG) .
Similarly prepared were
6-Fluoro-7-methyl-3-[(2S,4R)-2-methylpiperidin-4-yl]-1H-
indole and 6-fluoro-7-methyl-3-[(2R.4S)-2-
methylpiperidin-4-yl]-1H-indole
1H NMR ( {CD3) 2S0) , 8 (ppm) ; 1 . 02-1 . 10 (m, 3H) , 1 . 50-1 . 92
{m, 4H), 2.34 (s, 3H), 2.66-2.88 (m, 2H), 2.94-3.08 (m,
1H), 3.18-3.28 {m, 1H), 6.70-6.84 (m, 1H), 7.08 (s, 1H),
7.24-7.36 (m, 1H).
6,7-D,ifluoro-3-[(2S,4R)-2-methylpiperidin-4-yl]-1H-
indole and 6,7-difluoro-3-[(2R,4S)-2-methylpiperidin-4-
yl]-1H-indole (as a mixture)
The synthesis of the above compound was carried out in
the same manner as that use to synthesise the 6-fluoro
analogue. No HPLC was carried out, and instead, column
chromatography (silica gel, eluted with 98%
dichloromethane, 2% methanol and 0.2% aqueous ammonia)
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afforded the trans isomers as a racemic mixture.lH NMR
(CDC13) , $ (ppm) ; 1. 18 (d, 3H) , 1 .60-1 . 92 (m, 2H) , 1. 96-
2.12 (d, 2H), 2.34 (br.s, 2H), 2.78-3.12 (m, 2H), 3.14-
3.28 (m, 1H), 3.32-3.46 (m, 1H), 6.80-7.06 (m, 2H),
7.18-7.30 (m, 1H); MS, reqd. 250.1; obs. 251.1 (M+1 ';
FIAPOS) ; 249.1 (M-1 ; FIANEG) .
(1-MethylethyZ)sulfamic acid
A 250 ml 3-necked round bottom flask equipped with a
magnetic stirrer bar, pressure equalising dropping
funnel, thermometer and nitrogen gas bleed was charged
with nitromethane (75 ml) and fuming sulfuric acid
(30 g, i.e. oleum 12-170). The mixture was cooled to
0°C. using an external cardice (solid C02)/acetone bath.
Then isopropyl isocyanate (25 g, 0.294 mol) was added
dropwise to the mixture, stirred under nitrogen, keeping
the temperature below 30°C. during the addition. The
stirred suspension was then heated under reflux for
mins, then allowed to cool to room temperature and
stirred overnight. Diethyl ether (100 ml) was added to
the mixture, which was then filtered. The filter pad
was washed with more ether (3 x 100 ml) and then dried
25 in an air stream at room temperature to give a pale
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yellow crystalline solid, (1-methyl ethyl)sulfamic acid.
(JOC 1976 41 (25) 4028-9)
(1-Methylethyl)sulfamoyl chloride
A 500 ml 3-necked round bottom flask equipped with
a water condenser, thermometer and magnetic stirrer
bar was charged with (1-methyl ethyl)sulfamic acid
(34.8 g, 0.25 mol), phosphorus pentachloride
(52.06 g, 0.25 mol) and toluene (400 ml). The
mixture was warmed under reflux for 1 hr, then
cooled back down to room temperature. The solvent
was removed in vacuo to give a pale brown oil which
was then purified by distillation under reduced
pressure (approximately 15 mm Hg and 110°C.) to
give a clear, colourless liquid, (1-methyl
ethyl)sulfamoyl chloride (JOC 1976 41 (25) 4028-9)
N- (4-Methylthiopher~.yl) -2, 2-dimethylmalox~.amic
acid
Thionyl chloride (8.15 g, 5 ml, 0.069 mol) was
added to a stirred solution of 2,2-
dimethylmalonic acid (7.26 g, 0.055 mol) in
dry THF (55 ml). The mixture was heated under
reflux for 3 hr. The reaction mixture was
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cooled to room temperature and 4-
methylthioaniline (15.3 g, 0.11 mol) in THF
(30 ml) was then added dropwise over 30 mins
to the solution. The mixture was stirred at
room temperature for 2 hr. The reaction
mixture was then concentrated in vacuo and
then treated with hydrochloric acid (2N, 100
ml). The product was extracted with ethyl
acetate (2 x 100 ml). The organic extracts
were combined, then washed with water (100 ml)
and saturated sodium hydrogen carbonate
solution (5 x 80 ml). The organic layer was
then acidified with hydrochloric acid (5N, 250
ml) and the resultant white crystalline
precipitate was collected by filtration to
afford N-(4-methylthiophenyl)-2,2-
dimethylmalonamic acid. mp 130-132°C.
N-(4-Methylthiophenyl)-N'-(1-methylethyl)sulfamide
(1-Methylethyl)sulfamoyl chloride (6.63 g, 0.034
mol) was added dropwise to a solution of 4-
(methylthio) aniline (4.48 g, 0.032 mol) and
triethylamine (4.87 ml, 0.035 mol) in dry
dichloromethane (100 ml) at 0°C. under a nitrogen
atmosphere. After addition, the resultant mixture
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was allowed to warm to room temperature and was
stirred for 6 hr. The reaction mixture was further
extracted with dichloromethane and the organic
extracts washed with water (2 x 50 ml), dried
(MgS04) and concentrated in vacuo to yield N-(4-
methylthiophenyl)-N'-(1-methylethyl)sulfamide as a
white solid. ~ (1H NMR, DMSO, ppm) . 0.8 (6H, d),
2.3 (3H, s), 3.2 (1H, m), 3.35 (1H, s), 6.9-7.1
(4H, m) , 9.5 (1H, s) . M.P. 65-68°C.
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1H-
2,1,3-benzothiadiazine-2,2-dioxide
N-(4-Methylthiophenyl)-N'-(1-methylethyl)sulfamide
(4.35 g, 0.016 mol) was dissolved in dry
dichloromethane (150 ml) and methanesulphonic acid
(18.87 ml, 0.303 mol). The solution was cooled at
0°C. before the addition of trioxan (0.480 g, 0.005
mol) in dichloromethane (15 ml). After stirring at
0°C. for 1 hr, the reaction mixture was poured onto
ice-water (250 ml), the layers separated, dried
(MgS04) and concentrated in vacuo to yield 3,4-
dihydro-6-(ethylsulfonyl)-3-(l-methylethyl)-1H-
2,1,3-benzothiadiazine-2,2-dioxide as a white
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solid. S (1H NMR, DMSO, ppm) . 0.9 (6H, d) , 2.3
(3H, s) , 3 . 9 (1H, m) , 4.5 (2H, s) , 6.6 (1H, d) , 7. 0
(2H, m) , 10. 1 (1H, s)
3,4-Dihydro-3-(1-methylethyl)-6-(methylsulfonyl)-
1H-2,Z,3-benzothiadiazine-2,2-dioxide
A solution of OXONE~ (potassium peroxymonosulfate)
(5.65 g, 0.0092 mol) in water was added to a
solution of 3,4-dihydro-3-(1-methylethyl)-6-
(methylthio)-1H-2,1,3-benzothiadiazine-2,2-dioxide
(1 g, 0.0037 mol) in acetone/water (25 m1/2.5 ml)
stirring at room temperature. After 30 mins, water
(25 ml) and ethyl acetate (50 ml) were added to
the mixture. The two layers were separated and the
organic layer was then dried (MgS04) and
concentrated in vacuo to afford 3,4-dihydro-3-(1-
methylethyl)-6-(methylsulfonyl)-1H-2,1,3-
benzothiadiazine-2,2-dioxide as a pale yellow
solid. 8 (1H NMR, CDC13, 300MHz, ppm) . 1 . 0 (3H, d) ,
2 . 9 (3H, s) , 4 . 1 (1H, m) , 4. 6 (2H, s) , 6.8 (1H, d) ,
7.6 (2H, m) , 9. 9 (1H, s) .
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3,3-Dimethyl-6-methylthio-2,4-(1H,3H)-
quinolinedione
Phosphorus pentoxide (4.49 g, 0.032 mol) was added
to a stirred solution of N-(4-methylthiophenyl)-
2,2-dimethylmalonamic acid (5.0 g, 0.020 mol) in
methanesulfonic acid (35 ml). The reaction mixture
was warmed to 70°C. and stirred for 90 mins. The
product mixture was then cooled to room temperature
and poured over ice. The product was extracted
with ethyl acetate (2 x 200 ml). The organic
extracts were combined, washed with water (200 ml),
saturated sodium hydrogen carbonate solution (200
ml) , dried (MgS04) and concentrated imracuo to give
3,3-dimethyl-6-methylthio-2,4(1H,3H)-quinolinedione
as a yellow solid. Mp 152°C.
3,4-Dihydro-3,3-dimethyl-6-methylthio-2(1H)-
quinolinone
Triethylsilane (34.75 ml, 49.1 g, 0.042 mol) was
added dropwise to a stirred solution of 3,3-
dimethyl-6-methylthio-2,4(1H,3H)-quinolinedione
(12.79 g, 0.054 mol) in trifluoroacetic acid (520
ml) under nitrogen at 60°C. The reaction was then
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allowed to cool slowly to room temperature and was
stirred for 16 hr. The solvent was then evaporated
in vacuo to afford a yellow residue. The residue
was then poured into saturated potassium carbonate
solution (200 ml). The product was extracted with
ethyl acetate (3 x 150 ml). The organic extracts
were combined, washed with water (200 ml), dried
and concentrated in vacuo to afford 3,4-dihydro-
3,3-dimethyl-6-methylthio-2(1H)-quinolinone as a
yellow solid. Mp 154°C.
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1-(prop-
2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1H-
2,1,3-benzothiadiazine-2,2-dioxide (10 g, 0.0367
mol) was added to a suspension of sodium hydride
(1.61g, 60% dispersion) in dry dimethylformamide
(200 ml) at room temperature under a nitrogen
atmosphere. The pale grey suspension was stirred
for ten mins, and then allyl bromide (3.49 ml,
0.0404 mol) was added in one portion. The reaction
mixture was stirred at 80°C. for 3 hr. The mixture
was then concentrated in vacuo to yield a brown
residue. The residue was dissolved in ethyl
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acetate (50 ml) and washed with water (2 x 50 ml).
The organic layer was then dried (MgS04) and
concentrated in vacuo to afford 3,4-dihydro-3-(1-
methylethyl)-6-methylthio-1-(prop-2-en-1-yl)-1H-
2,1,3-benzothiadiazine-2,2-dioxide. 8 (1H NMR, DMSO,
ppm) . 1 . 1 (6H, d) , 2.5 (3H, s) , 4 . 1 (1H, m) , 4.5
(2H, d) , 4.7 (2H, s) , 5.3 (1H, dd) , 5.4 (1H, dd) ,
6. 0 (1H, m) , 7.0 (1H, d) , 7.3 (2H, m) .
Similarly prepared was
3,3-Dimethyl-5-methanesulphonyl-1-(prop-2-en-1-yl)-
1,3 dihydro-2H-indol-2-one
from 3,3-dimethyl-5-methanesulphonyl-1,3 dihydro-
2H-indol-2-one [Lit. Ref. EP 0780388]
8 (1H NMR, CDC13, ppm) ; 1.45 (6H, s) , 3 . 05 (3H, s) ,
4 . 35 (2H, d) , 5.25-5.3 (2H, m) , 5. 75-5. 9 (1H, m) ,
6. 9 (1H, d) , 7. 75 (1H, s) , 7. 85 (1H, m)
25
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(3,4-Dihydro-2,2-dioxido-3-(1-methylethyl)-6-
methylsulfonyl-1H-2,1,3-benzothiadiazin-1-yl]
ethanal.
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1-(prop-
2-en-1-yl)-1H-2,2,3-benzothiadiazine-2,2-dioxide
(10 g, 0.032 mol) was dissolved in dioxan (100 ml)
and water (20 ml). Osmium tetroxide (2 crystals)
was added to the solution and the mixture was
stirred for five mins at room temperature, before
the addition of sodium periodate (34.288, 0.160
mol) dissolved in water (25 ml). After stirring at
ambient temperature for 14 hr, the reaction mixture
was filtered through celite. The filtrate was then
concentrated in vacuo to yield an oil. The oil was
dissolved in ethyl acetate (100 ml) and washed with
water (2 x 50 ml). The organic layer was then
dried and concentrated in vacuo to afford [3,4-
dihydro-2,2-dioxide-3-(1-methylethyl)-6-
methylsulfonyl-1H-2,1,3-benzothiadiazin-1-
yl]ethanal as'a yellow solid. 8 (1H NMR, DMSO, ppm)
2.1 (6H, d) , 3 .2 (3H, s) , 4. 0 (1H, m) , 4.8 (2H,
s) , 4 . 9 (2H, s) , 7. 0 (1H, d) , 7.7 (1H, dd) , 7.8
(1H, d) , 9.6 (1H, s) .
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Similarly prepared was
3,3-Dimethyl-5-methanesulphonyl-2,3 dihydro-2H-
indol-1-yl-2-one ethanal
from 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1-
(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-
dioxide
8 (1H NMR, CDC13, ppm) ; 1.45 (6H, s) , 3.05 (3H, s) ,
4 .9 (2H, s) , 6.9 (1H, d) , 7.7 (1H, s) , 7.9 (1H, m) ,
9.6 (1H, s) .
1-(2-Chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-
methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide.
To a 250 ml 3 necked flask equipped thermometer,
pressure equalised dropping funnel, nitrogen
bubbler and magnetic stirrer bar was added 600
sodium hydride (1.77 g, 1.062 g, 0.04425 mol,)
hexane washed, to dry DMF (75 ml). To this stirred
suspension was added dropwise a solution of 3,4-
dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-
benzothiadiazine-2,2-dioxide (10.0 g, 0.0368mo1) in
dry DMF (75 ml) (slight exotherm). The suspension
was stirred under nitrogen for 2 hr until hydrogen
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evolution ceased. 1-Bromo-2-chloroethane (6.33 g,
3.77 ml, 0.04425 mol) was added dropwise and the
reaction mixture allowed to stir at room
temperature under nitrogen overnight. The reaction
mixture was poured onto ice-water (800 ml) with
stirring for 1 hr, filtered and washed with water
(200 ml) to leave a white solid which was dried in
vacuo at 50°C. to give a solid. Mp 74-75°C.
5-Methylthio-2-nitrobenzoic acid.
5-Chloro-2-nitrobenzoic acid (25.2 g, 0.125 mol)
was stirred in water. To this was added sufficient
sodium hydroxide solution (2M, 42 ml, 0.084 mol) to
dissolve the acid completely. A solution of sodium
sulfide nonahydrate (33.0 g, 0.1375 mol) in water
(75 ml) was added and the solution was stirred at
60 °C for 2.5 hr. This resultant red solution was
added to a solution of sodium hydroxide (500 10 ml,
0.125 mol) in water (15 ml) , dimethyl sulfate (24
ml, 0.25 mol) was added and the solution heated
under reflux for 1 hour. The solution was cooled
and acidified with hydrochloric acid (5M, 32 ml,
0.16 mol). The precipitated yellow solid was
filtered off, washed with water, dried at 60°C.
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under vacuum, mp 173°C. (lit. J. Heterocyclic
Chemistry 1981 18 117). Mp 175-178°C.)
Methyl 4-methylthio-2-nitro benzoate
To a suspension of 4-methylthio-2-nitro benzoic acid
(10g;0.047mo1) [ Lit. Ref. DE 2421541] in dry
dimethylformamide (300mL) was added potassium carbonate
(8.43g; 0.061mo1) and iodomethane (6.41mL; 0.103mo1) and
the solution stirred at room temperature for 24hrs. The
reaction was poured into water and extracted with ether
(3x500mL). The combined organic extracts were washed
with water, dried over anhydrous magnesium sulphate,
filtered and the solvent removed under vaccuo to yield a
yellow solid. This was dried at 50°C under vaccuum.
(10.4g; 97.50)
1H NMR (CDC13) , & (ppm) ; 2.5 (s, 3H) , 3 .85 (s, 3H) , 7.25-
7.3 (m, 2H), 7.85 (d, 1H)
Methyl 2-amino-4-methylthio benzoate
Methyl 4-methylthio-2-nitro benzoate (10.4g; 0.046mo1)
was dissolved in ethanol and Raney nickel added as an
aqueous suspension. The solution was hydrogenated at
60psi on a Parr hydrogenator for 6 hrs. The catalyst
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was filtered off through celite, washed with ethanol to
give the product which was used directly in the next
step. ( 8.9g; 98%)
1H NMR (CDC13) , 8 (ppm) ; 2 .4 (s, 3H) , 3.9 (s, 3H) , 5. 75
(br s, 2H) , 6.6 (d, 1H) , 7.3 (dd, 1H) , 7.9 (d, 1H)
Methyl 2-methylsulphonylamino-4-methylthio benzoate
To a stirred solution of methyl 2-amino-4-methylthio
benzoate (11.53g; 0.0585mo1) in dry pyridine (60mL) was
added slowly over a 5 minute period methane sulphonyl
r
chloride (4.98mL; 0.0643mo1). An exotherm was produced
taking the internal temperature to 35°C. After stirring
overnight at room temperature, the pyridine was removed
under vaccuo and water (150mL) was added. Concentrated
hydrodrochloric acid was added to pH2 and the product
was extracted with ethyl acetate (3x100mL). The organic
extracts were washed with water (2x100mL), 2N HCl
(2x100mL) and water (2x100mL). After drying with
anhydrous magnesium sulphate, filtering and removing the
solvent, the product was isolated as a red oil which
solidified on standing. (15.68; 97%)
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1H NMR (CDC13) , 8 (ppm) ; 2 .5 (s, 3H) , 3 .05 (s, 3H) , 3 .95
(s, 3H), 7.47 (dd, 1H), 7.7 (d, 1H), 7.95 (d, 1H), 10.25
(s, 1H)
Methyl 2-(N-(prop-2-en-1-yl)-N-methylsulphonyl)amino-4-
methylthio benzoate
To a solution of methyl 2-methylsulphonylamino-4-
methylthio benzoate (6.9g; 0.025mo1) in dry
dimethylformamide (120mL) was added anhydrous potassium
carbonate (34.4g;0.25mo1) and tetrabutylammonium bromide
( 0.81g; 2.51mmo1). Allyl bromide (20 equivalents) was
added in one portion and the solution was stirred
overnight at room temperature. The reaction was poured
into water and the product extracted with ethyl acetate.
The organic extracts were washed with water, dried over
anhydrous magnesium sulphate, filtered and he solvent
removed to give an oil. Column chromatography eluting
with 20%-50% ethyl acetate- hexane gave a clear oil
(7.2g; 92%) .
1H NMR (CDC13) , 8 (ppm) ; 2 .5 (s, 3H) , 3 .05 (s, 3H) , 3 .9
(s, 3H) , 4.65 (d, 2H) , 5.25-5.4 (m, 2H) , 5.8-6. 0 (m,
1H), 7.26 (d, 1H), 7.35 (m, 1H), 7.75 (d, 1H)
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6-Methylthio-1-(prop-2-en-1-yl) -1H-2,1-benzothiazine-4-
(3H)-one 2,2-dioxide
To a solution of sodium hydride (1.32g; 0.0552m of 50 0
dispersion in paraffin oil) in dry dimethylformamide
(60mL) was slowly added under nitrogen at OoC a solution
of methyl 2-(N-(prop-2-en-1-yl)-N-methylsulphonyl)amino-
4-methylthio benzoate (7.2g;0.023mo1) in dry
dimethylformamide (15m1). After stirring overnight at
room temperature the reaction was poured into ice water
and the product extracted with ethyl acetate, washed
repeatedly with water and dried over magnesium sulphate.
After filtering and removal of the solvent, the oil was
chromatographed on silica eluting with. 20o ethyl acetate
to give the product, 4.2g; 65%)
1H NMR (CDC13) , 8 (ppm) ; 2 .53 (s, 3H) , 4.3 (s, 2H) , 4.55
(m, 2H), 5.3-5.47 (m, 2H), 5.85-6.0 (m, 1H), 7.25 (d,
1H), 7.5 (dd, 1H), 7.95 (d, 1H)
3,3-Dimethyl-6-methylthio-1-prop-2-en-1-yl -1H-2,1-
benzothiazine-4-(3H)-one 2,2-dioxide
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1-(Prop-2-en-1-yl)-6-methylthio-benzothiazine-4-one 2,2-
dioxide (2.078; 0.0067mo1) was dissolved in dry
dimethylformamide (50mL) and potassium carbonate (2.038;
0.0147mo1) added followed by iodomethane (1.25mL;
0.02mo1). The reaction was stirred overnight at room
temperature and water was added. The product was
extracted with ethyl acetate and, after washing with
water and drying over magnesium sulphate the product was
isolated as a solid (2.0g; 890)
1H NMR (CDC13) , 8 (ppm) ; 1. 65 (s, 6H) , 2 .5 (s, 3H) , 4 . 55
(d, 2H), 5.3-5.5 (m, 2H), 5.9-6.1 (m, 1H), 7.05 (d, 1H),
7.45 (dd, 1H) , 8 . 0 (d, 1H)
3,3-Dimethyl-6-methylthio-1-(prop-2-en-1-yl) -1H-2,1-
benzothiazine 2,2-dioxide
1-(Prop-2-en-1-yl)-3,3-dimethyl-6-methylthio-1H-2,1-
benzothiazine-4-(3H)-one 2,2-dioxide (2g; 0.006mo1) was
dissolved in methanol (40mL) and sodium borohydride
(0.458; 0.012mo1) was added in one portion. After the
initial effervescence, the reaction was left stirring
overnight. The solvent was removed under vaccuo, water
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added and the product extracted with chloroform. After
washing the organic extracts with water, drying over
magnesium sulphate and filtering, the product was
isolated as a white solid (1.8g; 90%) of 3,4-dihydro-
3,3-dimethyl-6-methylthio-1-(prop-2-en-1-yl) -1H-2,1-
benzothiazin-4-of 2,2-dioxide, used immediately in the
next step.
1H NMR (CDC13) , 8 (ppm) ; 1 .4 (s, 3H) , 1 .6 (s, 3H) , 2 .5
(s, 3H), 3.35 (dd, 1H), 4.25-4.55 (m, 2H), 4.6-4.7 (dd,
1H), 5.3-5.5 (m, 1H), 6.9 (d, 1H), 7.22 (dd, 1H), 7.4
(d, 1H)
3,4-Dihydro-1-(prop-2-en-1-yl) -3,3-dimethyl-6-
methylthio-1H-2,1-benzothiazin-4-of 2,2-dioxide (1.8g;
0.0053m) was dissolved in trifluoroacetic acid (30mL)
and triethylsilane (lSmL) was added in one portion.
After stirring for 4hrs, the reaction was reduced to an
oil under vaccuo and after the addition of saturated
sodium bicarbonate, the product extracted with
dichloromethane, dried, filtered and isolated as a
colourless solid.(1.6g; 93%)
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iH NMR (CDC13) , ~ (ppm) ; 2.45 (s, 6H) , 2.4 (s, 3H) , 4.4
(d, 2H), 5.25-5.5 (m, 2H), 5.9-6.03 (m, 1H), 6.85 (d,
1H), 7.05 (d, 1H), 7.15 (dd, 1H)
3,4-Dihydro-3,3-dimethyl-I-(prop-2-en-1-yI)-6-
sulphonylmethyl-1H-2,1-benzothiazine 2,2-dioxide
3,4-Dihydro-3,3-dimethyl-6-methylthio-1-(prop-2-en-1-yl)
-1H-2,1-benzothiazine 2,2-dioxide (1.6g;0.00539mo1) was
dissolved in acetone (50mL) and oxone (7.298;
0.01185mo1) in water (20mL) was added. The solution
went opaque and was stirred for 30min at room
temperature. The acetone was removed on the rotary and,
water and ethyl acetate were added. The product was
extracted with ethyl acetate (2x100mL) and the organic
extracts washed with water (2x100mL). After drying,
filtering and removal of solvent, a solid was isolated
(1.2g; 68%)
1H NMR (CDC13) , 8 (ppm) ; 1.5 (s, 6H) , 3.05 (s, 3H) , 3.35
(d, 2H), 4.57 (m, 2H), 5.35-5.55 (m, 2H), 5.87-6.0 (m,
1H), 7.05 (d, 1H), 7.68 (dd, 1H), 7.75 (dd, 1H)
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[3,4-Dihydro-3,3-dimethyl-6-sulphonylmethyl-1H-2,1-
benzothiazin-1-yl 2,2-dioxide] ethanal
To 3,4-dihydro-3,3-dimethyl-1-(prop-2-en-l-yl)-6-
sulphonylmethyl-1H-2,1-benzothiazine 2,2-dioxide (1.2g;
0.00365mo1) dissolved in tetrahydrofuran (100m1) was
added sodium periodate (1.56g; 0.0073mo1) dissolved in
water (20m1) with warming . A crystal of osmium
tetroxide was added and the solution stirred at room
temperature overnight. Water was added and the product
was extracted with ethyl acetate (3x100m1). The organic
extracts were collected, washed with. water, dried over
anhydrous magnesium sulphate, filtered and the solvent
removed in vaccuo to give a gum. (1.0g; 830)
1H NMR (CDC13) , 8 (ppm) ; 1.53 (s, 6H) , 3.05 (s, 3H) , 3.38
(d, 2H), 4.73 (s, 2H), 6.7 (dd, 1H), 7.7-7.8 (m, 2H),
9.75 (s, 1H)
1-(2-Chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-
methysulfonyl-1H-2,1,3-benzothiadiazine-2,2-
dioxide.
A 500 mL 3 necked flask equipped thermometer,
pressure equalised dropping funnel, nitrogen
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bubbler and magnetic stirrer bar was charged with
1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-
methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide
(10.0 g, 0.0299 mol) and chloroform (200 ml). To
this solution was added in one portion m-
chloroperbenzoic acid (20.6 g , ~4 equivalents,
nominal purity 56-86 %), this resulted in an
exotherm which raised the temperature from 20°C. to
50°C. This solution was then stirred for 15 mins,
water (100 ml) was added then 2M sodium hydroxide
(100 ml). The organic layer was separated, washed
again with 2M sodium hydroxide (100 ml), then water
(100 ml) dried (MgS04), filtered and the filtrate
evaporated under reduced pressure to leave a white-
cream foam, which was dried at 45°C. in vacuo to
yield the product.
8 (1H NMR, CDC13, ppm) . 7.8 (1H, d) , 7.7 (1H, s) ,
7.1 (1H, d) , 4.7 (2H, s) , 4.2 (1H, m) , 4.2 (2H, t) ,
3 . 0 (3H, s) , 1.1 (6H, d) .
1-(2-Chloroethyl)-3,4-dihydro-3,3-dimethyl-6-
methylsulfonyl-2 (1H) -quix~.olinone.
(Prepared from 1-(2-chloroethyl)-3,4-dihydro-3,3-
dimethyl-6-methylthio-2(1H)-quinolinone.
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S (1H NMR, CDC13, ppm) . 7.8 (1H, dd) , 7.7 (1H,
d) , 7.1 (1H, d) , 4.2 (2H, t) , 3 . 6 (2H, t) , 3.0 (3H,
s) , 2 . 8 (2H, s) , 1 .l (6H, s) .
3,3-Dimethyl-1-~2-[(2R,4s)- 4-(6-fluoro-1H-indol-3-yl)-
2-methylpiperidinyl] ethyl-6- (methylsulfonyl) -3,4-
dihydro-1H-2,1-benzothiazine 2,2-dioxide
To a stirred solution of 6-fluoro-3-[(2R,4S)-2-
methylpiperidin-4-yl]-1H-indole (0.718; 0.0033mo1) and
[3,3-d.imethyl-6-sulphonylmethyl-1H-2,1-benzothiazin-1-yl
2,2-dioxide] ethanal in dry tetrachloroethane (70m1) was
added glacial acetic acid (6 drops). The solution was
stirred for l0mins at room temperature and sodium
triacetoxyborohydride (0.768; 0.0036mo1) was added in
one portion and the solution stirred rapidly at room
temperature overnight. The reaction was poured into
water and the product extracted with dichloromethane.
The organic extracts were washed with water(2x100m1) and
dried over anhydrous magnesium sulphate. After
filtration, the solvent was removed in vaccuo to give a
yellow oil. Flash chromatography on silica eluting with
75%-90% ethyl acetate-hexane mixtures gave product as a
yellow solid. (1.0g; 62.5%)
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1H NMR (CDC13) , S (ppm) ; 1.5 (s, 6H) , 2 .6 (m, 2H) , 2 . 85
(m, 4H), 3.05 (s, 3H), 3.3 (m, 4H), 4.1 (m, 2H), 6.15
(s, 1H) , 6.9 (dt, 1H) , 7.05 (dd, 1H) , 7.15 (d, 1H)
7.25 (d, 1H) , 7.7 (d, 1H) , 7.8 (m, 2H) , 8.2 (s, 1H)
Similarly prepared were
3,3-Dimethyl-1-~2-[(2S,4R)-4-(6-fluoro-1H-indol-3-yl)-2-
methylpiperidinyl]ethyl-6-(methylsulfonyl)-3,4-dihydro-
1H-2,1-benzothiazine 2,2-dioxide
from 6-fluoro-3-[(2S,4R)-2-methylpiperidin-4-yl]-1H-
indole
3,3-Dimethyl-1-~2-[(2S,4R)-4-(6-fluoro-7-methyl-1H-
indol-3-yl)-2-methylpiperidinyl]ethyl-5-
methylsulphonyl-1,3-dihydro-2H-indol-2-one
from 6-fluoro-3-[(2S,4R)-2-methylpiperidin-4-yl]-1H-
indole
1H NMR ( (CD3) DSO) , S (ppm) ; 1 . 02-1 . 10 (m, 3H) , 1 .45 (6H,
s), 1.50-1.92 (m, 4H), 2.34 (s, 3H), 2.66-2.88 (m, 2H),
2.94-3.08 (m, 1H), 3.05 (3H, s), 3.05-3.3 (m, 3H), 4.05
4.15 (m, 2H), 6.70-7.1 (m, 3H), 7.24-7.36 (m, 1H), 7.65
( 1H,, s ) , 7 . 8 ( 1H, m)
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3,3-Dimethyl-1-~2-[(2R,4S)-4-(6-fluoro-7-methyl-1H-
indol-3-yl)-2-methylpiperidinyl]ethyl-5-
methylsulphonyl-1,3-dihydro-2H-indol-2-one
from 6-fluoro-3-[(2R,4S)-2-methylpiperidin-4-yl]-1H-
indole
1-~2-[(2R,4S)-4-(6-Fluoro-1H-indol-3-yl)-2-
methylpiperidinyl]ethyl-3-isopropyl-6-(methylsulfonyl)-
3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide and 1-
~2-[(2S,4R)-4-(6-Fluoro-1H-indol-3-yl)-2-
methylpiperidinyl]ethyl-3-isopropyl-6-(methylsulfonyl)-
3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide
A racemiC mixture of 6-fluoro-3-[(2S,4R)-2-
methylpiperidin-4-yl]-1H-indole and 6-fluoro-3-[(2R,4S)-
2-methylpiperidin-4-yl]-1H-indole (0.34g, 1.46 mmol), 1-
(2-Chloroethyl)-3-isopropyl-6-(methylsulfonyl)-3,4-
dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.64g,
1.74 mmol), sodium iodide (0.26g, 1.75 mmol) and sodium
carbonate (0.90g, 8.49 mmol) are suspended in a mixture
of water (50 ml) and acetonitrile (5 ml), and stirred
at reflux under nitrogen for 72 hours. The mixture is
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then cooled to room temperature, water is added (100
ml), and the off white gum that has formed is extracted
with ethyl acetate (2 x 100 ml). The combined organic
layers are combined, dried over magnesium sulfate, and
the solvent evaporated under reduced pressure. Column
chromatography, using hexane (60%) and ethyl acetate
(400) as the eluent affords 0.458 of the desired product
(54.80 yield) as mixture of traps enantiomers. The
enantiomers are subjected to chiral stationary phase
HPLC (Chiralpak-AD column, eluted with 60% hexane, 400
isopropanol and 0.2o dmea, F/R: 1.0 ml/min) to resolve
the two traps enantiomers (retention times = 9.9 and
10.7 min) . 1H NMR (CDC13) , 8 (ppm) ; 1.02-1.22 (m, 9H) ,
1.68-2.12 (m, 4H), 2.70-2.92 (m, 4H), 3.0 (s, 3H), 3.06-
3.26 (m, 2H), 3.94-4.04 (m, 2H), 4.14-4.24 (m, 1H), 5.68
(br. s, 2H), 6.82-6.92 (t, 1H), 6.94 (s, 1H), 7.00-7.08
(d, 1H), 7.50-7.60 (m, 1H), 7.72 (br. s, 1H), 7.80-7.90
(d, 2H), 8.12-8.26 (br. s, 1H). MS, reqd. 562.2; obs.
563.2 (M+1 ; FIAPOS); 561.2 (M-1 ; FIANEG).
1-~2-[(2R,4S)-4-(6,7-Difluoro-lH-indol-3-yl)-2-
methylpiperidinyl]ethyl-3-isopropyl-6-(methylsulfonyl)-
3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide and 1-
~2-C(2S,4R)-4-(6,7-difluoro-1H-indol-3-yl)-2-
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methylpiperidinyl]ethyl-3-isopropyl-6-(methylsulfonyl)-
3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide
A racemic mixture of 6,7-difluoro-3-[(2S,4R)-2-
methylpiperidinyl]-1H-indole and 6,7-difluoro-3-
[(2R,4S)-2-methylpiperidin-4-yl]-1H-indole (0.73g, 2.92
mmol), 1-(2-chloroethyl)-3-isopropyl-6-(methylsulfonyl)-
3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide
(1.28g, 3.49 mmol), sodium iodide (0.52g, 3.48 mmol) and
sodium carbonate (1.80g, 17.0 mmol) are suspended in a
mixture of water (70 ml) and acetonitrile (7 ml), and
stirred at reflux under nitrogen for 24 hours. The
mixture is then cooled to room temperature, water is
added (100 ml), and the off white gum that has formed is
extracted with ethyl acetate (2 x 100 ml). The combined
organic layers are combined, dried over magnesium
sulfate, and the solvent evaporated under reduced
pressure. Column chromatography, using hexane (50%) and
ethyl acetate (500) as the eluent affords 0.428 of the
desired product (20.8% yield) as mixture of traps
enantiomers. The enantiomers are subjected to chiral
stationary phase HPLC (Chiralpak AD eluted with 600
Ethanol, 40o Heptane and 0.2% dmea, F/R: 1.0 ml/min) to
resolve the two traps enantiomers (retention times =
14 . 7 and 16.4 min) . 1H NMR (CDC13) , b (ppm) ; 1 . 02-1. 18
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(m, 3H), 1.36-1.52 (d, 6H), 1.86-2.00 (m, 1H), 2.00-2.10
(d, 1H), 2.12-2.20 (d, 1H), 2.34-2.44 (m, 1H), 2.50-2.62
(m, 1H), 2.70 (s, 1H), 3.06-3.14 (m, 3H), 3.18-3.30 (m,
2H), 3.32-3.50 (m, 1H), 3.90-3.98 (s, 1H), 4.10-4.12 (m,
1H), 4.54-4.78 (m, 4H), 6.92-7.00 (m, 1H), 7.12 (s, 1H),
7.30-7.36 (m, 1H), 7.70 (s, 1H), 7.92-7.98 (m, 1H), 8.56
(s, 1H); MS, reqd. 580.2; obs. 581.2 (M+1 ; FIAPOS).
Similarly prepared were
1-~2- [ (2R, 4S) -4- (6-Fluoro-1H-indol-3-yl) -2-
methylpiperidinyl]ethyl-3,3-dimethyl-6-
(methylsulfonyl)-3,4-dihydro-2(1H)-quinolinone and 1-~2-
[(2S,4R)-4-(6-Fluoro-1H-indol-3-yl)-2-
methylpiperidinyl]ethyl-3,3-dimethyl-6-
(methylsulfonyl)-3,4-dihydro-2(1H)-quinolinone
1H NMR ( (CD3) (ppm) ; 1 . 08-1.20 (m, 3H) 1 .56-2 . 00
2S0) , ,
(m, 4H) , 2.56 (s, 6H) , 2. 66-2. 82 (m, 2H) (s, 2H) ,
, 2 . 94
3.06-3.18 (m, 2H), 3.28 (s, 3H), 4.00-4.22 (m, 2H),
6.84-6.92 (t, 1H), 7.08-7.18 (m, 2H), 7.46-7.6 0 (m, 2H),
7.82-7.92 (m, 2H); MS, reqd. 511.3; obs. 512.3 (M+l ;
FIAPOS) .
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1-~2-[(2R,4S)-4-(6,7-Difluoro-1H-indol-3-yl)-2-
methylpiperidinyl]ethyl-3,3-dimethyl-6-
(methylsulfonyl)-3,4-dihydro-2(1H)-quinolinone
from 4- (6, 7-difluoro-1H-indol-3-yl) - (2R, 45') -2-
methylpiperidine.
1H NMR (CDC13) , 8 (ppm) ; 1.05-1.20 (m, 3H) , 1.6-2.00 (m,
4H), 2.55 (s, 6H), 2.58-2.80 (m, 2H), 2.94 (s, 2H),
3.06-3.18 (m, 2H), 3.3 (s, 3H), 4.00-4.20 (m, 2H), 6.80-
7.06 (m, 2H), 7.1-7.3 (m, 2H), 7.6-7.8 (m, 2H)
1-~2-[(2S,4R)-4-(6,7-Difluoro-1H-indol-3-yl)-2-
methylpiperidinyl]ethyl-3,3-dimethyl-6-
(methylsulfonyl)-3,4-dihydro-2(1H)-quinolinone
from 4-(6,7-difluoro-1H-indol-3-yl)-(2S,4R)-2-
methylpiperidine.
The following Examples illustrate formulations
comprising an active ingredient according to the
invention.
wTnrtr~r ~ ~
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Tablets each containing 10 mg of active ingredient are
made up as follows:
Active ingredient 10 mg
Starch 160 mg
Microcrystalline cellulose 100 mg
Polyvinylpyrrolidone (as loo solution in water) 13 mg
Sodium carboxymethyl starch 14 mg
Magnesium stearate 3 mg
Total 300 mg
The active ingredient, starch and cellulose are mixed
thoroughly. The solution of polyvinylpyrrolidone is
mixed with the resultant powders and passed through a
sieve. The granules so produced are dried and re-passed
through a sieve. The sodium carboxymethyl starch and
magnesium stearate are then added to the granules which,
after mixing, are compressed on a tablet machine to
yield tablets each weighing 300 mg.
Capsules each containing 20 mg of active ingredient are
made as follows:
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Active ingredient 20 mg
Dried starch 178 mg
Magnesium stearate 2 mg
Total 200 mg
The active ingredient, starch and magnesium stearate are
passed through a sieve and filled into hard gelatine
capsules in 200 mg quantities.
EXAMPLE 4
Capsules each containing 20 mg of medicament are made as
follows:
Active ingredient 20 mg
Lactose 171 mg
Sodium lauryl sulphate 2 mg
Sodium starch glycollate 6 mg
Magnesium stearate 1 mg
200 mg
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The active ingredient, lactose, sodium lauryl sulphate
and sodium starch glycollate are mixed thoroughly. The
blend is mixed with the magnesium stearate and filled
into hard gelatine capsules in 200 mg quantities.
Tablets each containing 20 mg and medicaments are made
as follows:
Active ingredient 20 mg
Lactose 103 mg
Microcrystalline cellulose 150 mg
HydroxypropylmethylCellulose 15 mg
Sodium starch glycollate 9 mg
Magnesium stearate 3 mg
300 mg
The active ingredient, lactose, microcrystalline
cellulose, sodium starch glycollate and
hydroxypropylmethylCellulose are passed through a sieve
and blended together. Water is added to the blended
powders to form a damp mass. The damp mass is passed
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through a coarse screen, dried, then re-screened. The
dried granules are mixed with the magnesium stearate and
compressed into tablets of 300 mg weight.
