1H-2,1,3-benzothiadiazine-2,2-dioxide compounds or derivatives thereof

A pharmaceutical compound having the formula: ##STR1## in which n is 1 or 2, m is 1 or 2, p is 1 to 6, q is 0 or 1 to 3, PA1 R.sup.1 and R.sup.2 are each hydrogen or C.sub.1-4 alkyl, PA1 R.sup.3, R.sup.4 and R.sup.5 are each hydrogen, C.sub.1-4 alkyl, optionally substituted phenyl or optionally substituted phenyl-C.sub.1-4 alkyl, or R.sup.3 and R.sup.4 together form an alkylene link of formula --(CH.sub.2).sub.3 -- or --(CH.sub.2).sub.4 --, or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a C.sub.3-6 cycloalkyl group, PA1 R.sup.6 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, nitro or amino, PA1 the dotted line represents an optional double bond, and PA1 the fluorine atom is attached at the 6 or 7-position; and salts and esters thereof.

This application claims the benefit of United Kingdom Application Nos. 
9717832.1 filed Aug. 22, 1997 and 9815388.5 filed Jul. 15, 1998. 
This invention relates to novel compounds with pharmaceutical properties. 
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 EP-A 0433149. 
The compounds of the invention are of the following formula: 
##STR2## 
in which n is 1 or 2, m is 1 or 2, p is 1 to 6, q is 0 or 1 to 3, 
R.sup.1 and R.sup.2 are each hydrogen or C.sub.1-4 alkyl, 
R.sup.3, R.sup.4 and R.sup.5 are each hydrogen, C.sub.1-4 alkyl, optionally 
substituted phenyl or optionally substituted phenyl-C.sub.1-4 alkyl, or 
R.sup.3 and R.sup.4 together form an alkylene link of formula 
--(CH.sub.2).sub.3 -- or --(CH.sub.2).sub.4 --, or R.sup.4 and R.sup.5 
together with the carbon atom to which they are attached form a C.sub.3-6 
cycloalkyl group, 
R.sup.6 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, carboxy, hydroxy, cyano, 
halo, trifluoromethyl, nitro or amino, 
the dotted line represents an optional double bond, and 
the fluorine atom is attached at the 6 or 7-position; 
and salts and esters thereof. 
The compounds of the invention and their pharmaceutically acceptable salts 
and esters are indicated for use in the treatment of disorders of the 
central nervous system. 
A C.sub.1-4 alkyl group can be methyl, ethyl or propyl and can be branched 
or unbranched and includes isopropyl and tert. butyl. A C.sub.1-4 alkoxy 
group is one such C.sub.1-4 alkyl group attached through oxygen to the 
ring. An optionally substituted phenyl-C.sub.1-4 alkyl group is an 
optionally substituted phenyl attached through one such C.sub.1-4 alkyl 
group, and is preferably optionally substituted phenyl-(CH.sub.2).sub.x -- 
where x is 1 or 2, and most preferably optionally substituted benzyl. A 
halo substituent is preferably fluoro, chloro or bromo. 
An optionally substituted phenyl group is optionally substituted with one 
or more, preferably one to three, substitutents selected from, for example 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, carboxy, hydroxy, cyano, halo, 
trifluoromethyl, nitro and amino. 
Preferably R.sup.3 and R.sup.4 are each hydrogen, C.sub.4 alkyl, optionally 
substituted phenyl or optionally substituted phenyl-C.sub.1-4 alkyl, and 
R.sup.5 is hydrogen. 
It will be appreciated that when p is more than one, the recurring unit is 
not necessarily the same, and when q is 2 or 3 the values of R.sup.6 need 
not be the same. 
A preferred group of compounds is one of formula (I) above, in which the 
dotted line represents a double bond, n is 2 and m is 1, R.sup.1 and 
R.sup.2 are both hydrogen, p is 2, R.sup.3 is C.sub.1-4 alkyl, R.sup.4 and 
R.sup.5 are hydrogen and q is 0 or 1. 
Preferred compounds are those which exhibit one or more of the following 
features: 
(i) the fluorine substituent is in the 6-position 
(ii) the dotted line represents a double bond 
(iii) n is 2 and m is 1 
(iv) R.sup.1 and R.sup.2 are both hydrogen 
(v) p is 2 
(vi) R.sup.3 is C.sub.1-4 alkyl, especially isopropyl 
(vii) R.sup.4 and R.sup.5 are hydrogen 
(viii) q is 0 or 1, and preferably 0 
(ix) R.sup.6 is C.sub.1-4 alkoxy, hydroxy, halo or amino, and especially 
amino(--NH.sub.2). 
A particularly preferred group of compounds is of the formula: 
##STR3## 
in which R.sup.3 is C.sub.1-4 alkyl and especially isopropyl, 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, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, 
citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 
2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic 
acid. 
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. 
It will be appreciated that when a phenyl substituent is acidic such as, 
for example, a carboxy group, the opportunity exists for esters. These can 
be aliphatic or aromatic, being preferably alkyl esters derived from 
C.sub.1-4 alkanols, especially methyl and ethyl esters. An example of an 
ester substituent is --COOR' where R' is C.sub.1-4 alkyl. 
Some of the compounds of the invention contain one or more asymmetric 
carbon atoms which gives rise to isomers. 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: 
##STR4## 
with a compound of the formula: 
##STR5## 
where the substituents have the values given above, and X is a leaving 
group such as, for example, a halo atom, or a mesylate or tosylate. The 
coupling can also be effected by reacting the compound of formula (III) 
with an aldehyde equivalent of the compound of formula (IV). Such 
aldehydes can be prepared from the appropriate terminal alkene by 
oxidation employing, for example, ozone or osmium tetroxide, followed by 
reductive amination using, for example, sodium cyanoborohydride, borane in 
pyridine or triacetoxy borohydride, and the compound of formula (III). 
The reaction is preferably carried out in a polar solvent such as, for 
example, acetonitrile or water, at a temperature of from 50.degree. C. to 
150.degree. C., and in the presence of sodium iodide and a base such as, 
for example, sodium carbonate. 
The intermediate compounds of formula (III) are known in the art, whereas 
compounds of formula (IV) are novel. The latter can be prepared by 
reacting the appropriate alkane derivative of formula: 
##STR6## 
where X is a leaving group, and Y is halo, preferably bromo, with a 
compound of formula: 
##STR7## 
Preferred alkane reactants are dihalo-alkanes, 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.degree. C. to 100.degree. 
C., for instance room temperature. 
Some of the intermediate compounds of formula (VI) are known in the 
literature, and they can readily be prepared by a variety of routes, the 
principal route being a trioxan catalysed reaction between the appropriate 
sulphamoyl compound prepared from an aniline and sulphamoyl chloride, and 
an alkyl sulphonic acid as, for example: 
##STR8## 
Other aldehydes or ketones can be used in the reaction instead of trioxan 
to produce compounds in which R.sup.4 is other than hydrogen. 
An alternative synthesis of compounds of formula (VI) is by reductive 
animation and cyclisation, starting from a nitro aldehyde as, for example: 
##STR9## 
The last step can be carried out by reaction of H.sub.2 NSO.sub.2 NH.sub.2 
in pyridine or diglyme. Instead of starting with the nitro aldehyde, it is 
possible to substitute a ketone, such as ortho-nitro acetophenone, which 
allows the synthesis of compounds of formula (I) in which R.sup.4 is other 
than hydrogen. 
As indicated above, the compounds of formula (I) can be produced by 
reacting a compound of formula (III) with an appropriate aldehyde 
intermediate. The latter can be prepared by oxidation of the corresponding 
alkene prepared, for example, in the following manner (this route is 
especially useful for preparing compounds where R.sup.3, R.sup.4 or 
R.sup.5 is other than hydrogen). 
##STR10## 
As mentioned above, the compounds of the invention and their 
pharmaceutically acceptable salts have useful central nervous system 
activity. The compounds are 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 .sup.3 H! ketanserine. In this test, the 
compounds of the invention in the following Examples had a Ki of less than 
15 nM. The compounds of the invention are also active serotonin reuptake 
inhibitors as measured by their displacement of .sup.3 H! paroxetine at 
the reuptake site, Neuropharmacology Vol. 32 No. 8, 1993, pages 737-743. 
Because of their 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, Alzheimer's and 
sleep disorders. 
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 20 mg/kg per day, for example in the treatment 
of adult humans, dosages of from 0.5 to 100 mg per day may be used. 
The compounds of the invention will normally be administered orally or by 
injection and, for this 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. 
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 0.5 to 100 mg, more usually 1 to 100 mg, of the 
active ingredient.

The following Preparations and Examples illustrate routes to the synthesis 
of the compounds of the invention. 
PREATION 1 
6-Fluoroindole 
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 hours, cooled, allowed to stand 
for 16 hours, poured into ice-water (2000 ml), stirred for 15 minutes and 
the resultant precipitate isolated by filtration, washed with water (500 
ml), dried to give a red solid. 
6-Fluoroindole 
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 (1400 ml) and the mixture hydrogenated at 
80 psi for 3.5 hours. The suspension was then filtered through a celite 
pad, which was washed through with toluene (2.times.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. 
PREATION 2 
7-Fluoroindole 
2 Fluoronitrobenzene (20.0 g, 0.142 mol) was dissolved in dry 
tetrahydrofuran (400 ml) and cooled to -50.degree. C. Vinylmagnesium 
chloride (288 ml, 15% wt/vol) was added at -45.degree. C. and stirred at 
this temperature for one hour. Poured onto saturated ammonium chloride 
(600 ml). Separated and aqueous extracted with diethyl ether (2.times.200 
ml). Dried (MgSO4), filtered and concentrated in vacuo to yield a dark oil 
which was purified by column chromatography on silica using toluene as 
mobile phase. Fractions concentrated to yield a crystalline solid. 
7-Fluoroindole(alternative preparation) 
To a stirred solution of boron trichloride in dichloromethane (1.0 M, 3.650 
1, 3.65 mol) at -10.degree. C. under nitrogen was added 2-fluoroaniline 
(387 g, 3.48 mol) and the temperature rose to 18.degree. C. The mixture 
was stirred for 45 minutes before chloroacetonitrile (300 g, 3.97 mol) 
followed by aluminium chloride (500 g, 3.75 mol). 1,2-Dichloroethane 
(5.71) was added the mixture heated and the dichloromethane distilled from 
the reaction vessel. The dichloroethane solution was then heated at 
78-80.degree. C. for 18 hours. The reaction mixture was then cooled to 
2.degree. C. and hydrochloric acid (2.5 M, 450 ml) was added slowly with a 
resultant exotherm. More hydrochloric acid (2.5 M, 5.550 1) was added and 
then the mixture was warmed to reflux for 10 minutes then cooled. The 
dichloroethane layer was separated and the aqueous layer extracted with 
dichloromethane (1 l) combined with the dichloroethane, washed with brine 
(2 l), dried (MgSO4), filtered and the solvent evaporated in vacuo to give 
a solid 321.7 g. This solid was dissolved in a mixture of dioxan (10 l) 
and water (1 l) and treated under nitrogen with sodium borohydride (73.0 
g, 1.93 mol) then heated under reflux for 1 hour. More sodium borohydride 
(12 g) was added and the mixture heated for a further 3 hours, cooled to 
45.degree. C. and the solvent removed in vacuo. The residue was 
partitioned between dichloromethane (2000 ml) and water (2000 ml). The 
organic layer was separated, dried (MgSO4), filtered and evaporated in 
vacuo to give an oil which was further purified by filtering through 
silica. 
PREATION 3 
4-(6-Fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine 
Powdered potassium hydroxide (144.4 g) was added carefully to a 
mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and 
4-piperidone monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml). The 
mixture was then heated under reflux under nitrogen for 18 hours and then 
more potassium hydroxide (40 g) was added and the reaction mixture heated 
under reflux for a further 4 hours. The reaction mixture was allowed to 
cool to room temperature and poured onto ice-water (3000 ml) and stirred 
for 1 hour and the precipitated solid isolated by filtration and dried at 
50.degree. C. in vacuo to give a solid. 
PREATION 4 
4-(6-Fluoroindol-3-yl)piperidine 
A mixture of platinum oxide (1.0 g) in ethanol (37.5 ml) and glacial acetic 
acid (12.5 ml) was treated under nitrogen with 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (20 g, 92.6 mmol) in 
ethanol (187.5 ml) and glacial acetic acid (62.5 ml). The nitrogen was 
evacuated and hydrogen was admitted. The reaction mixture was then 
hydrogenated at 60 psi until the reaction was complete by tlc. The 
catalyst was removed by filtration and the solvent evaporated in vacuo to 
give a yellow solid which was dried at 60.degree. C. in vacuo. 
Similarly prepared was 4-(7-fluoroindol-3-yl)-piperidine from 
4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine. 
PREATION 5 
3,4-Dihydro-3-(1-methylethyl)-1H-2,1.3-benzothiadiazine-2,2-dioxide 
1) 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 12-17%). The mixture was cooled to 0.degree. C. using an 
external cardice (solid CO2)/acetone bath. Then isopropyl isocyanate (25 
g, 0.294 mol) was added dropwise to the mixture, stirred under nitrogen, 
keeping the temperature below 30.degree. C. during the addition. The 
stirred suspension was then heated under reflux for 30 minutes, 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.times.100 ml) and then dried 
in an air stream at room temperature to give a pale yellow crystalline 
solid, isopropyl sulfamic acid. 
2) A 500 ml 3-necked round bottom flask equipped with a water condenser, 
thermometer and magnetic stirrer bar was charged with isopropylsulfamic 
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 hour, 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.degree. C.) to give a 
clear, colourless liquid, isopropyl sulfamoyl chloride. 
3) A 100 ml 3-necked round bottom flask equipped with a magnetic stirrer 
bar, thermometer and pressure equalising dropping funnel was charged with 
aniline (36.7 g, 0.39 mol, 2.2 mol equivalent) and toluene (500 ml). The 
solution was cooled to 5.degree. C. and then isopropylsulfamoyl chloride 
(28.2 g, 0.179 mol) was added dropwise. The mixture was allowed to warm up 
to room temperature and stirred overnight. The solvent was removed in 
vacuo and the residue suspended in water (500 ml) and extracted with ethyl 
acetate (2.times.250 ml). The bulked extracts were washed with water and 
then dried over magnesium sulfate. Filtration was followed by evaporation 
to dryness in vacuo to give a cream coloured solid as product, 
N-phenyl-N'-(1-methylethyl)sulfamide. 
4) A 500 ml 3-necked round bottom flask equipped with a thermometer, 
magnetic stirrer bar and pressure equalising dropping funnel was charged 
with N-phenyl-N'-(1-methylethyl)sulfamide (18.64 g, 86.8 mmol), 
dichloromethane (166 ml) and methane sulfonic acid (105 ml). The stirred 
mixture was cooled to 5.degree. C. using an external ice-bath. Then a 
solution of trioxane (2.58 g, 28.7 mmol) in dichloromethane (83 ml) was 
added rapidly (exotherm to 17.degree. C.) and the reaction mixture was 
cooled back to 5.degree. C. The reaction mixture was poured onto ice/water 
and the organic layer separated. This organic layer was washed with water 
(3.times.100 ml) and then dried over magnesium sulfate. Filtration was 
followed by evaporation to dryness in vacuo to give a brown oil as 
product, 3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de. (See also J.O.C. 44, 1979, pp 2032-34.) 
Similarly prepared: 
3,4-Dihydro-6-methoxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de from 4-methoxy aniline and isopropylsulfamoyl chloride. 
Ethyl 
3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-6-carbox 
ylate from ethyl 4-aminobenzoate and isopropylsulfamoyl chloride. 
3,4-Dihydro-6-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxid 
e from 4-fluoroaniline and ispropylsulfamoyl chloride. 
3,4-Dihydro-3-(1-methylethyl)-6-trifluoromethyl-1H-2,1,3-benzothiadiazine-2 
,2-dioxide from 4-trifluoromethylaniline and isopropylsulfamoyl chloride. 
3,4-Dihydro-3-methyl-1H-2,1,3-benzothiadiazine-2,2-dioxide from aniline and 
methanesulfamoyl chloride (prepared according to the method of Weiss G et 
al, Justus Liebigs Ann Chem 40 (1969)). 
3,4-Dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
(alternative preparation) 
To a 500 ml 3-necked round bottom flask equipped with overhead mechanical 
stirrer, thermometer and nitrogen bubbler was charged 2-nitrobenzaldehyde 
(200 g, 1.32 mol) in methanol (1300 ml), to which was added isopropylamine 
(78.0 g, 113 ml, 1.32 mol) in one portion with stirring under nitrogen. 
The reaction mixture was then stirred for 100 minutes (followed reaction 
by GC), then added to a 4 litre stainless steel Parr hydrogenator, 
containing a suspension of 5% palladium on charcoal (13.24 g, 6% cat. 
loading) in methanol (500 ml) and the suspension hydrogenated under 
hydrogen at 60 psi for 3 hours. The suspension was filtered through a pad 
of celite, the pad washed with methanol (500 ml) and the combined filtrate 
evaporated under reduced pressure to leave a yellow oil, 
2-amino-N-(1-methylethyl)-benzylamine. 
To a 500 ml 3-necked round bottom flask equipped with reflux condenser, 
thermometer, magnetic stirrer bar and nitrogen bubbler was charged 
2-amino-N-(1-methylethyl)-benzylamine (148.0 g, 0.907 mol), sulfamide 
(87.9 g, 0.907 mol) and pyridine (975 ml) and the stirred solution heated 
at reflux for 5 hours under nitrogen (reaction followed by GC and HPLC). 
The reaction mixture allowed to cool, then pyridine removed under reduced 
pressure. The residue was dissolved in 5N hydrochloric acid (1000 ml) and 
ethyl acetate (1000 ml) and the acidic layer was extracted with further 
ethyl acetate (5.times.1000 ml). The combined organic layer was washed 
with 5N hydrochloric acid (250 ml), then extracted with 2N sodium 
hydroxide (3.times.1000 ml), the combined aqueous layer washed with 
diethyl ether (2.times.500 ml). Ice was then added to the aqueous layer, 
followed by addition of 5N hydrochloric acid with cooling and stirring of 
the suspension to pH 1. The oily suspension was stirred at room 
temperature overnight, the solid filtered and dried at room temperature 
under vacuum to leave an off-white solid, 
3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 
Similarly prepared were, 
3,4-Dihydro-3-(but-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide from 
n-butylamine and 2-nitrobenzaldehyde. 
3,4-Dihydro-3-(1-methylpropyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide from 
(1-methylpropyl)amine and 2-nitrobenzaldehyde. 
3,4-Dihydro-3-ethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide from ethylamine 
and 2 nitrobenzaldehyde. 
3,4-Dihydro-3-prop-1-yl-1H-2,1,3-benzothiadiazine-2,2-dioxide from 
n-propylamine and 2-nitrobenzaldehyde. 
3,4-Dihydro-3-(2-methylprop-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
prepared from 2-nitrobenzaldehyde and 2-methylprop-1-ylamine. 
3,4-Dihydro-3-(1,1-dimethylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
prepared from 2-nitrobenzaldehyde and 1,1-dimethylethylamine. 
4-Methyl-1H-2,1,3-benzothiadiazine-2,2-dioxide prepared from 
2-aminoacetopheneone and sulfamide. 
PREATION 6 
1-(2-Chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2 
,2-dioxide 
3,4-Dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (16.725 
g, 74.1 mmol) was dissolved in DMF (400 ml) and then treated with sodium 
hydride (3.26 g, 60% oil dispersion, 81.5 mmol, 1.1 equivalent). The 
mixture was stirred at room temperature and under nitrogen for 45 minutes. 
1-Bromo-2-chloroethane (7.4 ml, 12.75 g, 88.9 mmol, 1.2 equivalent) was 
added in one portion to the stirred mixture, and stirred overnight at room 
temperature. The solvent was removed in vacuo and the residue suspended in 
water and extracted into ethyl acetate (3.times.150 ml). The bulk extracts 
were washed with water (3.times.100 ml) and brine, then dried over 
magnesium sulfate. Filtration was followed by evaporation to dryness in 
vacuo and the residue (approximately 22 g) chromatographed on silica using 
dichloromethane as eluent. 
This gave a white solid 
1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine 
-2,2-dioxide!. 
Similarly prepared were: 
3,4-Dihydro-1-(3-chloroprop-1-yl)-3-(1-methylethyl)-1H-2,1,3-benzothiadiazi 
ne-2,2-dioxide using 1 bromo-3-chloropropane. 
3,4-Dihydro-1-(4-chlorobut-1-yl)-3-(1-methylethyl)-1H-2,1,3-benzothiadiazin 
e-2,2-dioxide using 1 bromo-4-chlorobutane. 
EXAMPLE 1 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-(1-methylethyl)- 1H-2,1,3-benzothiadiazine-2,2-dioxide 
A mixture of 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (8.68 g, 
40.2 mmol, 1.05 equivalent), 
1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine- 
2,2-dioxide (11.05 g, 38.3 mmol), anhydrous sodium carbonate (20.297 g, 
0.192 mol, 5 equivalents) and de-ionised water (200 ml) was stirred 
(mechanical stirring) and warmed under reflux for 20 hours. After cooling 
to room temperature, the mixture was extracted with chloroform 
(3.times.150 ml). The bulked extracts were washed with water and then 
dried over magnesium sulfate. Filtration was followed by evaporation to 
dryness in vacuo to yield an orange solid (approximately 18 g). This 
material was purified further by chromatography on silica first using 
dichloromethane to remove some residual chloroethylated starting material 
and then eluting with ethyl acetate to remove final product. This yielded 
an orange solid which was triturated with a mixture of 
dichloromethane/diethyl ether. This gave a yellow solid after filtration, 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
80-82.degree. C. 
The free base was dissolved in methanol, phosphoric acid added and the 
precipitate filtered to yield the phosphate salt, m.p. 166-168.degree. C. 
Similarly prepared: 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-methyl-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p.175-177.degree. C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-(methylpropyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p.147-148.degree. C. 
3-n-Butyl-3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyr 
idyl!-1-ethyl}-1H-2,1,3-benzothiadiazine-2,2-dioxide. MS M+H=483!. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-(2-methylprop-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. MS 
M+H=483!. 
3,4-Dihydro-3-(1,1-dimethylethyl)-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetr 
ahydro-1-pyridyl!-1-ethyl}-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
145.8-146.4.degree. C. 
3,4-Dihydro-6-fluoro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyri 
dyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
93-96.degree. C. 
Ethyl 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide-6-carboxylate 
, m.p. 198-205.3.degree. C. 
3,4-Dihydro-1-{4-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-bu 
tyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
129.5-130.6.degree. C. 
3,4-Dihydro-1-{3-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-pr 
opyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
129.5-130.6.degree. C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-ethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p.142.6-143.3.degree. 
C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-propyl-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p.208-210.degree. C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1-piperidinyl!-1-ethyl}-3-(1-methy 
lethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. MS M+H!.sup.+ =471. 
3,4-Dihydro-1-{2-4-(7-fluoroindol-3-yl)-1-piperidinyl!-1-ethyl}-3-(1-methy 
lethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. MS M+H!.sup.+ =471. 
3,4-Dihydro-1-{2-4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, MS 
M+H!.sup.+ =469. 
EXAMPLE 2 
3,4-Dihydro-2,2-dioxo-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyr 
idyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-6-carboxylic 
acid. 
Prepared from ethyl 
3,4-dihydro-2,2-dioxo-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-py 
ridyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-6-carboxylate 
by lithium hydroxide hydrolysis in aqueous tetrahydrofuran, m.p. 
192.8-194.4.degree. C. 
EXAMPLE 3 
6-Amino-3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyrid 
yl!-1-ethyl)-3-(1-(methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 
1-(2-Chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-nitro-1H-2,1,3-benzothiad 
iazine-2,2-dioxide(1.67 g, 0.005 mol) prepared from 
3,4-dihydro-3-(1-methylethyl)-6-nitro-1H-2,1,3-benzothiadiazine-2,2-dioxid 
e (prepared from 4-nitroaniline and isopropyl sulfamoyl chloride by methods 
described above was dissolved in absolute ethanol (50 ml) and hydrogenated 
at 60 psi in the presence of 5% palladium on charcoal (0.2 g). After 1 
hour and no further hydrogen uptake, the catalyst was filtered, washed 
with ethanol and the solution evaporated to dryness giving 
6-amino-1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothia 
diazine-2,2-dioxide. 
Potassium carbonate (0.75 g, 0.0052 mol) was dissolved in water (10 ml) and 
to this was added 
6-amino-1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothia 
diazine-2,2-dioxide (1.34 g, 0.0044 mol) and 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (1.03 g, 0.0048 mol). 
This suspension was heated with rapid stirring under nitrogen for 24 
hours. After cooling, the product was extracted with chloroform 
(3.times.50 ml) and the fractions dried over magnesium sulfate. After 
filtering and removing the solvent, a solid was obtained (1.76 g) which 
was chromatographed on flash silica eluting with 5% 
methanol-dichloromethane. The product, 
6-amino-3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyri 
dyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide was 
triturated with ether and dried in vacuo, m.p. 154.5-155.5.degree. C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl)-6-methoxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a 
yellow amorphous solid, m.p. 142-145.degree. C. 
EXAMPLE 4 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-6-hydroxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-6-methoxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(1.0 
g, 2 mmol) was dissolved in dry dichloromethane (20 ml) and cooled to 
0.degree. C. Boron tribromide (2.2 ml, 1.0 M solution in dichloromethane) 
was added and stirred at ambient temperature for 16 hours. The solution 
was cooled to 0.degree. C. and boron tribromide (3.2 ml) added. After 
pouring onto ice-water, the product was extracted with ethyl acetate 
(2.times.150 ml), extracts dried, filtered and the solvent removed to give 
a pale yellow solid (1.0 g) Column chromatography using flash silica 
eluting with 5% methanol/dichloromethane gave 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-6-hydroxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as 
a yellow solid, m.p. 80-82.degree. C. 
EXAMPLE 5 
3,4-Dihydro-8-fluoro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyri 
dyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
1) A 3-necked round bottom flask equipped with a magnetic stirrer bar was 
charged with 2-fluoroaniline(2 g, 18 mmol) and Et.sub.3 N (3 ml, 21.6 
mmol) in toluene (20 ml) and is treated at 0.degree. C., under argon 
atmosphere, with isopropylsulfamoyl chloride (3.17 g, 19.8 mmol) and the 
temperature maintained below 15.degree. C. After the addition, the 
reaction was allowed to warm to room temperature and maintained during 24 
hours. Then the solvent was evaporated at vacuo and the residue was 
dissolved in EtOAc. The organic phase was washed with water, dried over 
Na.sub.2 SO.sub.4, filtered and evaporated to dryness yielding 3.9 g of an 
oil, N-(2fluorophenyl-N'-(1-methylethyl) sulfamide, which was used without 
further purification. This oil and methanesulfonic acid (34 ml, 525 mmol) 
were dissolved in dry dichloromethane (80 ml) and the solution was treated 
at 0.degree. C., under argon atmosphere, with a solution of trioxane (0.86 
g, 9.6 mmol) in CH.sub.2 Cl.sub.2 (20 ml). After 15 minutes, the mixture 
was poured onto a mixture ice-water. The aqueous phase was extracted three 
times with CH.sub.2 Cl.sub.2. The organic phase is dried over Na.sub.2 
SO.sub.4, filtered and evaporated to dryness. The crude product was 
purified by flash chromatography using as eluent CH.sub.2 Cl.sub.2 /hexane 
(2:1) to give 
3,4-dihydro-8-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de. 
2) A 3-necked round bottom flask equipped with a water condenser, 
thermometer and magnetic stirrer bar was charged with a mixture of 
3,4-dihydro-8-fluoro-3-(1-methylethyl)-1H-benzothiadiazine-2,2-dioxide (1 
g, 6.8 mmol) and NaH (400 mg, 17 mmol) was added at 0.degree. C., under 
argon atmosphere, in DMF (20 ml). After 1 hour, there was added 
1-bromo-2-chloroethane (1.4 ml, 17 mmol) and then the reaction was stirred 
at room temperature overnight. The reaction was quenched with a saturated 
solution of NH.sub.4 Cl and poured into water. The aqueous phase was 
extracted with CH.sub.2 Cl.sub.2, dried over Na.sub.2 SO.sub.4 and 
evaporated to dryness yielding an oil, 
1-(2-chloroethyl)-3,4-dihydro-8-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothi 
adiazine-2,2-dioxide which was used without further purification. 
Similarly prepared were: 
1-(2-Chloroethyl)-3,4-dihydro-3-(1-methylethyl)-8-trifluoromethyl-1H-2,1,3- 
benzothiadiazine-2,2-dioxide from 2-trifluoromethylaniline and 
isopropylsulfamoyl chloride. 
1-(2-Chloroethyl)-3,4-dihydro-8-methyl-3-(1-methylethyl)-1H-2,1,3-benzothia 
diazine-2,2-dioxide from o-toluidine and isopropylsulfamoyl chloride. 
8-Chloro-1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothia 
diazine-2,2-dioxide from 2-chloroaniline and isopropylsulfamoyl chloride. 
EXAMPLE 6 
3,4-Dihydro-8-fluoro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyri 
dyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
A suspension of 
1-(2-chloroethyl)-3,4-dihydro-8-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothi 
adiazine-2,2-dioxide (1.35 g), 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (31.45 g, 6.7 mmol) and 
Na.sub.2 CO.sub.3 (3.6 g, 34.6 mmol) in water (8 ml) was heated at 
100.degree. C. under argon atmosphere for 30 hours. After cooling to room 
temperature the product was extracted with dichloromethane. The organic 
phase was dried over Na.sub.2 SO.sub.4 and evaporated to dryness. The 
crude mixture was purified by flash chromatography using as eluent 
CH.sub.2 Cl.sub.2 /MeOH (97:3) yielding 
3,4-dihydro-8-fluoro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyr 
idyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a 
pale brown solid. 
1H-NMR (CDCl3, 200 Mz), d: 8.37 (broad s, 1H), 7.74 (dd,), 7.13-6.84 (m, 
6H), 6.10 (broad s, 1H), 4.43 (s, 2H), 4.26 (m, 1H), 3.73 (t,2H), 3.25 
(broad s, 2H), 2.97 (t, 2H), 2.76 (t, 2H), 2.49 (broad s, 2H), 1.25 
(d,6H). 
Similarly prepared were; 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-8-methyl-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
199-201.degree. C. 
3,4-Dihydro-8-chloro-1-(2-4-(6-fluoroindol-3-yl)1,2,5,6-tetrahydro-1-pyrid 
yl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
hydrochloride MS M+H!.sup.+ =503.1 (seen as free base), 
EXAMPLE 7 
Ethyl 
3,4-dihydro-2,2-dioxo-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-py 
ridyl!-1-ethyl}-1-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate 
Ethyl 
3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzot 
hiadiazine-8-carboxylate (1.1 g)(prepared from ethyl 
3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carbox 
ylate and (prop-2-en-1-yl) bromide) was dissolved in dichloromethane (80 
ml) and cooled to -75.degree. C. Ozone was passed through the solution 
until the solution became blue. At which time, dimethyl sulfide (5 ml) was 
added and the solution allowed to come to room temperature over 1 hour. 
The solution was washed with water to remove the DMSO present, dried over 
anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a 
solid, ethyl 
3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiad 
iazine-8-carboxylate. This was dissolved in dichloroethane (50 ml) 
containing glacial acetic acid(5 drops) together with 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.8 g, 1.1 equiv.). 
Sodium triacetoxy borohydride (0.8 g, 1.1 equiv.) was added and the 
solution stirred overnight at room temperature. After washing with 2N 
sodium hydroxide (30 ml) and brine, the solution was dried, filtered and 
evacuated in vacuo to yield an off-white solid. Column chromatography 
eluting with ethyl acetate/hexane to ethyl acetate gave the required 
product, ethyl 
3,4-dihydro-2,2-dioxo-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-py 
ridyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate, 
m.p. 95-97.degree. C. 
EXAMPLE 8 
7-fluoro 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-1 
-ethyl}-1-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
1) To a solution of 4-fluoro-2-nitrotoluene (5 g, 32 mmol) in DMF (32 ml) 
was added dimethylformamide dimethyl acetal (5.56 ml, 42 mmol) and the 
mixture warmed at 140.degree. C. for 18 hours in Argon atmosphere. Then 
the solution was allowed to reach room temperature and diethyl ether (100 
ml) and water (100 ml) was added. The organic layer was washed with water 
(2.times.100 ml) and brine (1.times.100 ml), dried (MgSO.sub.4) and 
solvent concentrated at reduced pressure, affording 
N,N-dimethyl-2-(4-fluoro-2-nitrophenyl)ethenylamine as a red solid. No 
further purification was necessary. 
2) N,N-Dimethyl-2-(4-fluoro-2-nitrophenyl)ethenylamine (6.72 g, 32 mmol) 
and NaIO.sub.4 (20.53 g, 96 mmol) were stirred in 50% aqueous THF (160 ml) 
at room temperature for 1.5 hours. The mixture was filtered in a celite 
pad and eluted with EtOAc. The organic layer was washed with NaHCO.sub.3 
(saturated solution, 3.times.100 ml), dried over Na.sub.2 SO.sub.4 and 
concentrated in vacuo. The residue was purified by flash chromatography 
(50% CH.sub.2 Cl.sub.2 /hexane) affording 4-fluoro-2-nitro benzaldehyde as 
an orange oil. 
3) To a solution of 4-fluoro-2-nitro benzaldehyde (3.76 g, 25 mmol) in dry 
MeOH (120 ml), was added isopropyl amine (2.1 ml, 25 mmol) and the mixture 
stirred for 2 hours at room temperature in Argon atmosphere. Then it was 
then transferred into a Parr bottle containing 5% Pd on charcoal (246 mg) 
under Argon and hydrogenated at 30 psi for 18 hours. The suspension was 
filtered over a celite pad, washed with MeOH and evaporated at reduced 
pressure to afford (2-amino-4-fluorophenyl)-N-(1-methylethyl)-methylamine 
as a yellow oil. 
4) (2-Amino-4-fluorophenyl)-N-(1-methylethyl)-methylamine (1.47 g, 7.3 
mmol) and sulfamide (703 mg, 7.3 mmol) were suspended in 8 ml of dry 
pyridine and the mixture stirred at 115.degree. C. for 18 hours in Argon 
atmosphere. After cooling at room temperature the solvent was removed in 
vacuo and the residue dissolved in EtOAc (50 ml) and washed with 5N HCl 
(2.times.50 ml). Solvents were removed to afford 
3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de as a pale yellow solid. 
5) A solution of 
3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de(1.48 g, 6.07 mmol) in dry DMF (15 ml) was added via a cannula to a flask 
containing sodium hydride (175 mg, 7.28 mmol) and DMF (2 ml) in Argon 
atmosphere, and stirred for 2 hours at room temperature when 
1-bromo-2-chloroethane (7.28 mmol, 605 .mu.l) was added dropwise. The 
mixture was stirred overnight at room temperature and water (75 ml) added. 
The product was extracted with EtOAc (3.times.50 ml) and the combined 
organic extracts were washed with water (1.times.100 ml) and then brine 
(1.times.100 ml), dried over sodium sulphate and solvent evaporated at 
reduced pressure. The residue was purified by flash chromatography on 
silica gel (EtOAc:Hexanes 1:4) affording pure 
1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothi 
adiazine-2,2-dioxide. 
6) To a 25 ml two-necked flask equipped with a reflux condenser and in 
Argon atmosphere, were added 
1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothi 
adiazine-2,2-dioxide(678 mg, 2.2 mmol), 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (523 mg, 242 mmol), 
anhydrous K.sub.2 CO.sub.3 (1.09 g, 11 mmol) and 10 ml of deionised water. 
The mixture was vigorously stirred under Argon for 64 hours at 100.degree. 
C., allowed to reach room temperature and extracted with EtOAc (3.times.25 
ml). The combined organic extracts were dried (Na.sub.2 SO.sub.4) and 
solvent removed at reduced pressure. The residue was purified by flash 
chromatography on silica gel (EtOAc:hexane 1:3) affording 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-3-(1-methylethyl)-7-fluoro-1H-2,1,3-benzothiadiazine-2,2-dioxide as a 
pale yellow solid, m.p. 103-105.degree.. 
.sup.1 H NMR (200 MHz, CDCl.sub.3) .delta. 8.20 (br s, 1H), 7.79 (dd, 1H), 
7.14 (d, 1H), 7.06 (t, 1H), 7.02 (d, 1H), 6.98 (s, 1H), 6.90 (dt, 1H), 
6.78-6.65 (m, 2H), 6.16 (m, 2H), 4.58 (s, 2H), 4.19 (7x, 1H), 3.99 (dt, 
2H), 3.33 (dd, 2H), 2.85 (dt, 2H), 2.62 (m, 2H), 1.12 (d, 6H). 
Similarly prepared were: 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-(1-methylethyl)-7-trifluoromethyl-1H-2,1,3-benzothiadiazine-2,2-diox 
ide, m.p. 101-103.degree. C. 
1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-ethyl}-7-metho 
xy-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p. 88-900.degree. C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-5-methyl-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
hydrochloride MS M+H!=483.1 seen as free base 
5-Chloro-3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyri 
dyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
hydrochloride MS M+H!.sup.+ =503.1 seen as free base. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-5-methoxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p. 72-74.degree. C. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-5-hydroxy-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p. 186-188.degree. C. 
3,4-Dihydro-5-fluoro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyri 
dyl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
107-109.degree. C. 
5-Bromo-3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyrid 
yl!-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 
99-101.degree. C. 
EXAMPLE 9 
1-{2-4-(6-Fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-ethyl)-3-(1-me 
thylethyl)-5-fluoro-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide 
1) To a solution of 4-fluoro-2-nitrotoluene (3 g, 17.96 mmol) in DMF (25 
ml) was added (MeO).sub.2 CHNMe.sub.2 (3.12 ml, 23.35 mmol) and the 
mixture warmed at 140.degree. C. for 4 hours in argon atmosphere. Then the 
solution was allowed to reach room temperature and diethyl ether (100 ml) 
and water (100 ml) was added. The organic layer was washed with water 
(2.times.100 ml) and brine (1.times.100 ml), dried (MgSO.sub.4) and 
solvent concentrated at reduced pressure, affording an oil which was 
treated with NaIO.sub.4 (11.5 g, 53.6 mmol). The mixture was stirred in 
50% aqueous THF (100 ml) at room temperature for 24 hours. The mixture was 
filtered in a celite pad and eluted with EtOAc. The organic layer was 
washed with NaHCO.sub.3 (saturated solution, 3.times.100 ml), dried over 
Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by 
flash chromatography (50% CH.sub.2 Cl.sub.2 /Hexane) affording 
2-nitro-6-fluorobenzaldehyde as a brown solid. 
2) To a solution of 2-nitro-6-fluorobenzaldehyde(1.21 g, 7.16 mmol) in dry 
methanol (15 ml), was added isopropyl amine (1 ml, 11.4 mmol) and the 
mixture stirred for 24 hours at room temperature in argon atmosphere. Then 
NaBH.sub.4 (0.3 g, 7.9 mmol) was added and the reaction mixture was 
stirred for 36 hours. The suspension was neutralized by addition of HCl 
5N, then was extracted with diethyl ether (1.times.100 ml) and dried over 
MgSO.sub.4 and evaporated at reduced pressure to afford 
N-(1-methylethyl)-(2-nitro-6-fluorophenyl)methylamine as a brown oil. 
3) A suspension of N-(1-methylethyl)-(2-nitro-6-fluorophenyl)methylamine 
(0.4 g, 1.89 mmol), tin chloride dihydrate (1.75 g) in water (8 ml) was 
added HCl 12N (2 ml). The mixture was refluxed for 4 hours. Then, the 
reaction mixture was allowed to reach room temperature and was neutralized 
by addition of NaOH 2N and extracted with diethyl ether (1.times.100 ml), 
dried over MgSO.sub.4 and evaporated under reduced pressure to afford 
N-(1-methylethyl)-(2-amino-6-fluorophenyl)methylamine. 
4) N-(1-methylethyl)-(2-amino-6-fluorophenyl)methylamine (0.3 g, 1.6 mmol) 
and sulphamide (5.08 g, 2.5 mmol) were suspended in 7 ml of dry pyridine 
and the mixture stirred at 115.degree. C. for 24 hours in argon 
atmosphere. After cooling at room temperature the solvent was removed in 
vacuo and the residue dissolved in EtOAc (50 ml) and washed with 5N HCl 
(2.times.50 ml). Solvents removal afforded 
5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de as a pale yellow solid. 
5) A solution of 
5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxi 
de (0.22 g, 0.9 mmol) in dry DMF (15 ml) was added via cannula to a flask 
containing NaH (25 mg, 0.99 mmol) and DMF (7 ml) in argon atmosphere, and 
stirred for 2 hours at room temperature. 1-Bromo-2-chloroethane (0.19 ml, 
2.25 mmol,) was then added dropwise and the mixture stirred at room 
temperature for 4 days. Then, the mixture was extracted with EtOAc 
(3.times.50 ml). The combined organic extracts were washed with water 
(1.times.100 ml) and then brine (1.times.100 ml), dried over Na.sub.2 
SO.sub.4 and solvent evaporated under reduced pressure. The residue was 
purified by flash chromatography on silica gel (EtOAc:Hexane 1:4) 
affording pure 
1-(2-chloroethyl)-5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothi 
adiazine-2,2-dioxide. 
1. To a 25 ml two-necked flask equipped with a reflux condenser and in 
argon atmosphere, were added 
1-(2-chloroethyl)-5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothi 
adiazine-2,2-dioxide(620 mg, 2.4 mmol), 
6-fluoro-3-tetrahydropyridinylindole (0.79 g, 3.6 mmol), anhydrous K.sub.2 
CO.sub.3 (1.98 g, 12 mmol) and 10 ml of deionised water. The mixture was 
vigorously stirred under argon for 24 hours at 100.degree. C., allowed to 
reach room temperature and extracted with EtOAc (3.times.25 ml). The 
combined organic extracts were dried (Na.sub.2 SO.sub.4) and solvent 
removed at reduced pressure. The residue was purified by flash 
chromatography on silica gel (EtOAc:Hexane 1:3) affording 
1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-ethyl}-3-(1-m 
ethylethyl)-5-fluoro-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide as a 
pale yellow solid, m.p. 107-109.degree. C. 
EXAMPLE 10 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-1-(1,3H)-2,1,3-benzothiadiazine-2,2-dioxide 
Anthranilonitrile was taken up in freshly distilled tetrahydrofuran and 
cooled to -.sub.78 .degree. C. under nitrogen in a dry ice/acetone bath. 
Lithium diisopropyl amide (56.2 ml, 0.1142 mol, 2M solution in THF) was 
added and the mixture stirred for 10 minutes before (prop-2-en-1-yl) 
bromide (12.4 g, 0.1022 mol) was added dropwise. The mixture was stirred 
for a further 1 hour with cooling and then allowed to warm to room 
temperature, after which time aqueous ammonium chloride was added. The 
mixture was concentrated under reduced pressure, taken up in ethyl 
acetate, washed with aqueous ammonium chloride solution(3.times.100 ml), 
dried over anhydrous magnesium sulfate, filtered and concentrated under 
reduced pressure. The resulting oil was purified by chromatography on 
silica gel, eluent hexane/ethyl acetate (increasing % of ethyl acetate), 
to give N-(prop-2-en-1-yl) anthranilonitrile as a yellow oil. 
Lithium aluminium hydride (5.0 g) was stirred in ether, under nitrogen at 
0.degree. C. N-(prop-2-en-1-yl) anthranilonitrile (13.2 g, 0.083 mol) was 
added dropwise and the mixture refluxed for 2 hours. Ethyl acetate was 
added and the mixture was washed with 2 molar NaOH(3.times.100 ml), the 
organics dried over anhydrous magnesium sulfate, filtered through celite 
and concentrated under reduced pressure to give an orange oil, N 
(prop-2-en-1-yl)-2-(ethanamine) aniline. 
N-(prop-2-en-1-yl)-2-(ethanamine) aniline (14.2 g, 86 mmol) in pyridine (20 
ml) was added dropwise to sulfamide(8.3 g) in pyridine (60 ml) at reflux. 
The reaction mixture was stirred at reflux under nitrogen for 2.5 hours, 
after which time 2N hydrochloric acid was added. The mixture was extracted 
with dichloromethane (3.times.100 ml),the organics collected and dried 
over anhydrous magnesium sulfate, filtered and concentrated under reduced 
pressure. Column chromatography on silica gel, (eluent ethyl 
acetate/hexane) gave 
3,4-dihydro-1-(prop-2-en-1-yl)-(1,3H)-2,1,3-benzothiadiazine-2,2-dioxide 
as a solid. 
To a 250 ml round bottomed flask containing dioxan(120 ml) and water(20 ml) 
was added 
3,4-dihydro-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (2.1 
g, 9.1 mmol). A crystal of osmium tetroxide was added whereupon the 
solution turned black. Sodium periodate (3.54 g, 2.2 equivalents) in water 
(30 ml) was warmed to ensure dissolution and then added, causing the 
solution to turn a cloudy brown over 5 minutes. The reaction mixture was 
left overnight and filtered through celite. The product was extracted with 
ethyl acetate and the organics washed with water. The product was finally 
obtained as an oil by filtering through a flash silica pad eluting with 
4:1 petrol ether/ethyl acetate. 
To a dry 100 ml round bottomed flask containing powdered molecular sieves 
4A (1.5 g) was added 
3,4-dihydro-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.8 g, 
3.54 mmol) in methanol (30 ml)and 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.76 g) dissolved in 
methanol (10 ml). Borane-pyridine (1 ml) was added after 1 hour and the 
solution stirred overnight. 5 MHCl (10 ml) was added followed by 50% 
sodium hydroxide solution(5 ml) and water(5 ml). Solution was filtered 
through celite and ethyl acetate(3.times.50 ml) added. The organics were 
collected, washed with water, dried, filtered and the solvent removed in 
vacuo. Column chromatography through flash silica eluting with ethyl 
acetate/hexane gave product, 
3,4-dihydro-(1-(2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1- 
ethyl}-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 183-185.degree. C. 
EXAMPLE 11 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-1- 
ethyl}-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide 
2-Aminoacetophenone(5.6 g, 41.5 mmol)and sulfamide (4 g, 41.5 mm) were 
added to diglyme (70 ml, dried over 4A molecular sieves) and the solution 
heated under nitrogen at 150.degree. C. After 1 hour a solid forms but 
heating was continued for 2 hours in total. After cooling, ether was added 
followed by 2N sodium hydroxide which dissolved the solid formed. The 
aqueous phase was collected, diluted with ethanol and (prop-2-en-1-yl) 
bromide (8 ml) added, stirring being continued overnight. After 
concentration under vacuo the residue was partitioned between water and 
ethyl acetate. The organic phase was collected, dried, over magnesium 
sulfate, filtered and the solvent evaporated under reduced pressure to 
yield a yellow oil, 
3,4-dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-diox 
ide. 
3,4-Dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-diox 
ide(2.4 g, 10 mmol) was dissolved in dry tetrahydrofuran (40 ml) under 
nitrogen and the solution cooled to -78.degree. C. in an acetone/dry ice 
bath. Methyl magnesium bromide (5 ml, 3M solution in ether) was added at 
this temperature and kept for 30 minutes when it was allowed to come to 
room temperature. After stirring for 2 hours, water was added and the 
solution concentrated. Partitioning between ethyl acetate and dilute 
HCl(aq) and collection of the organic extracts followed by drying, 
filtering and removal of solvent gave a product showing 75% conversion to 
product. Column chromatography eluting with ethyl acetate/hexane gave 
product, 
3,4-dihydro-4,4-dimethyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2- 
dioxide. This compound (1.85 g, 7.3 mmol) was dissolved in 
N-methylpyrrolidine (30 ml) under nitrogen and sodium hydride (350 mg) was 
added at room temperature resulting in a vigorous effervescence. After the 
gas evolution had subsided (30 minutes), methyl iodide (300 mg) was added 
and the solution stirred overnight. The reaction was poured onto water and 
extracted with ethyl acetate(3.times.50 ml). Organic phase was washed with 
water (2.times.100 ml), dried, filtered and vacced to an oil, 
3,4-dihydro-1-(prop-2-en-1-yl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2 
,2-dioxide. 
3,4-Dihydro-1-(prop-2-en-1-yl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2, 
2-dioxide (2.17 g) was taken up in dioxan (60 ml)/water (20 ml) and osmium 
tetroxide added (one crystal). 
Reaction stirred at room temperature and sodium periodate (3.2 g) in water 
(25 ml) added. After stirring overnight, the reaction was filtered and 
concentrated. The residue dissolved in ethyl acetate/water, extracted, 
organics washed with water, dried, filtered and the solvent removed to 
yield an oil, 
3,4-dihydro-1-(2-oxoethyl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-d 
ioxide. 
Using conditions described above, reacting 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine with 
3,4-dihydro-1-(2-oxoethyl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-d 
ioxide gave 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide as a white 
solid, m.p. 193-6.degree. C. 
and similarly, 
4-(6-Fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine with 
3,4-dihydro-4,4-dimethyl-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2-diox 
ide was obtained 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-4,4-dimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide as a white solid, 
m.p. 158-160.degree. C. as its hydrochloride salt. 
EXAMPLE 12 
3,4-Dihydro-1-{2-4-(6-Fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-1- 
ethyl}-1-3,4-dimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide 
This compound was synthesised from 
4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide 
(prepared in the above example) as follows: 
4-Methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(2 g) was 
dissolved in ethanol(50 ml) and treated with sodium borohydride (350 mg) 
at room temperature. After 15 minutes, the solvent was removed in vacuo 
and water added(200 ml). The product was extracted with 
chloroform(3.times.100 ml), dried, filtered and evaporated in vacuo to 
give a solid. This was dissolved in dry dimethylformamide (35 ml) and 
treated with sodium hydride (350 mg) at room temperature for 30 minutes 
followed by methyl iodide(600 .mu.l). The reaction was stirred at room 
temperature for 1 hour, poured into water(250 ml), extracted with ether 
(3.times.75 ml), dried, filtered and the solvent removed to give 
3,4-dihydro-3,4-dimethyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2- 
dioxide. This product was dissolved in dioxan (25 ml) and treated with 
osmium tetroxide (2 crystals) and sodium periodate(3.6 g) in water(25 ml) 
and stirred at room temperature overnight. Water was added(100 ml) and the 
product extracted with ether(3.times.100 ml), dried, filtered and the 
solvent removed to give an oil. This was dissolved in methanol(50 ml) and 
treated with 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridine (1.2 g) 
at room temperature overnight in the presence of acetic acid(1 ml) and 3A 
molecular sieves(2 g). Sodium cyanoborohydride(1 g) was then added and the 
reaction stirred for 4 hours. A further quantity of acetic acid (1 ml) and 
sodium cyanoborohydride(1 g) were added and stirred at room temperature 
for 18 hours. Saturated sodium bicarbonate (250 ml) was added and the 
mixture extracted with ethyl acetate (3.times.100 ml). After drying, 
filtering and removal of solvent, flash chromatography on the residue 
eluting with chloroform/ethyl acetate to ethyl acetate gave product, 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-3,4-dimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p.105-108.degree. C. 
EXAMPLE 13 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-4-(2-methylethyl)- -1H-2,1,3-benzothiadiazine-2,2-dioxide 
Sulfamoyl chloride was prepared in situ by cautiously adding to a solution 
of chlorosulfonyl isocyanate (7.05 g, 0.05 mol) in acetonitrile (50 ml) 
cooled to 0-5.degree. C., water (0.9 ml) in acetonitrile (5 ml) keeping 
the temperature below 10.degree. C., whilst stirring for 1 hour. A 
solution of 1-(prop-2-en-1-yl) aniline (6.65 g, 0.05 mol) and 
triethylamine (5.05 g, 0.05 mol) was stirred at 0-5.degree. C. and the 
sulfamoyl chloride prepared above was added slowly keeping the temperature 
below 10.degree. C., stirring overnight. The reaction was poured into 
ice-water(100 ml) and the product, 1-phenyl-1-(prop-2-en-1-yl) sulfamide 
was collected by filtration. This was treated with 2-methylpropionaldehyde 
and methane sulfonic acid as described previously to give 
3,4-dihydro-4-(2-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine 
-2,2-dioxide. This compound was converted to 
3,4-dihydro-4-(2-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2 
-dioxide by methods discussed previously. 
3,4-Dihydro-1-(2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-4-(2-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide m.p. 
196-198.degree. C. was prepared from 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridine and 
3,4-dihydro-4-(2-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2 
-dioxide using previously described methods. 
Similarly prepared was 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-4-spirocyclopentyl-1H-2,1,3-benzothiadiazine-2,2-dioxide m.p. 
151-153.degree. C. from 1-phenyl-1-(prop-2-en-1-yl) sulfamide and 
cyclopentanone as starting materials. 
3,4-Dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-et 
hyl}-3-methyl-4-(2-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 
This compound can be prepared by previously mentioned methodology from 
4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridine and 
3,4-dihydro-3-methyl-4-(2-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadi 
azine-2,2-dioxide (prepared from 
3,4-dihydro-4-(2-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine 
-2,2-dioxide mentioned previously and methyl iodide, with sodium hydride as 
base) to give 
3,4-dihydro-1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-e 
thyl}-3-methyl-4-(2-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p.180-182.degree. C. 
EXAMPLE 14 
1{2-4-(6-Fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-ethyl}-1-3,4,5, 
6,7,7a-hexahydro-1H-pyridor2,1-d1-2,1,3-benzothiadiazine-2,2-dioxide 
2-(2' -Nitrophenyl)pyridine(3 g) was dissolved in acetic acid(30 ml) and 
hydrogenated at 70 psi over platinum oxide. After 1 hour, the product was 
filtered and the reaction concentrated, taken up in ethyl acetate (100 ml) 
and washed with 1N sodium hydroxide. After drying, filtering and removal 
of solvent a dark oil(2.5 g) was obtained. This was dissolved in 
pyridine(60 ml) with sulfamide (1.5 g, 15 mmol) and heated at reflux under 
nitrogen for 6 hours. After concentrating, it was partitioned between 
ether and 2N sodium hydroxide. To the aqueous phase was added an excess of 
1-(prop-2-en-1-yl) bromide and DMF(20 ml)and the reaction warmed to 
50.degree. C. for 3 days. The reaction was concentrated and the residue 
taken up in ethyl acetate, washed with water(2.times.100 ml) and 2N 
hydrochloric acid(30 ml). The solvent was dried, filtered and evaporated 
to give, after suction filtration through flash silica eluting with 
hexane-ethyl acetate (1:4), an orange oil, 
1-(prop-2-en-1-yl)-3,4,5,6,7,7a-hexahydro-1H-pyrido2,1-d!-2,1,3-benzothia 
diazine-2,2-dioxide. This was transformed with previously discussed 
methodology to give 
1-{2-4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl!-1-ethyl}-3,4,5, 
6,7,7a-hexahydro-1H-pyrido2,1-d!-2,1,3-benzothiadiazine-2,2-dioxide, 
m.p.135-137.7.degree. C. as its hydrochloride salt. 
EXAMPLE 15 
3.4-Dihydro-1-{2-3-(6-fluoroindol-3-yl)-pyrrolidinyl!-1-ethyl}-1-3-(1-meth 
ylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 
6-Fluoroindole(10.03 g, 74.29 mmol) and maleimide(21.62 g, 222.9 mmol) were 
added to a stirred solution of acetic acid under nitrogen and heated at 
reflux for 144 hours. The solution was then evaporated in vacuo, dissolved 
in ethyl acetate and washed with saturated sodium bicarbonate solution. 
The aqueous layer was re-extracted with ethyl acetate(2.times.150 ml) and 
the organics dried, filtered and evaporated in vacuo. Column 
chromatography eluting with petroleum ether and ether/petroleum ether gave 
the product as a yellow solid. 
To a stirred solution of the 3-(6-fluoroindol-3-yl) pyrrolidinedione in dry 
tetrahydrofuran (150 ml) was added lithium aluminium hydride (8.58 g, 
214.5 mmol) as a solid portionwise. After refluxing under nitrogen 
overnight, the reaction was cooled and hydrated sodium sulfate added. 
After the effervescence had subsided, water (1 ml) was added and the 
reaction filtered, the residue washed with methanol and then concentrated 
in vacuo to afford a brown solid, 3-{6-fluoro-indol-3-yl}-pyrrolidine. 
Column chromatography eluting with dichloromethane to 
dichloromethane:methanol:ammonia (9:1.5:0.1) gave an orange solid. 
3-{6-Fluoro-indol-3-yl}-pyrrolidine (500 mg, 2.45 mmol), potassium 
carbonate (1.04 g, 9.8 mmol), and 
1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine- 
2,2-dioxide (708 mg, 2.45 mmol) were refluxed in water (15 ml) under 
nitrogen overnight. The solid was dissolved in ethyl acetate(2.times.100 
ml) and washed with brine, dried, filtered and evaporated in vacuo to 
afford a brown oil. Column chromatography eluting with ethyl acetate gave 
a yellow solid, 
3,4-dihydro-1-{2-3-(6-fluoroindol-3-yl)-pyrrolidinyl!-1-ethyl}-3-(1-methy 
lethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p.50.8-54.4.degree. C. 
The following Examples illustrate typical formulations containing the 
compound of the invention. 
EXAMPLE 16 
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 10% 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. 
EXAMPLE 17 
Capsules each containing 20 mg of medicament are made as follows: 
______________________________________ 
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.