Riluzole series. synthesis and in vivo 'antiglutamate' activity of 6- substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines

Article abstract of DOI:10.1021/jm980202u

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2- benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo 'antiglutamate' activity were the 6-OCF₃ (riluzole), 6-OCF₂CF₃, 6-CF₃, and 6-CF₂CF₃ substituted derivatives with ED₅₀ values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a β-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2- methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED₅₀ = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.

Full text of DOI:10.1021/jm980202u

2828
J . Med. Chem. 1999, 42, 2828-2843
Rilu zole Ser ies. Syn th esis a n d in Vivo “An tiglu ta m a te” Activity of
6-Su bstitu ted -2-ben zoth ia zola m in es a n d 3-Su bstitu ted -2-im in o-ben zoth ia zolin es
Patrick J imonet,* Franc¸ois Audiau, Michel Barreau, J ean-Charles Blanchard, Alain Boireau, Yvette Bour,
Marie-Annick Cole´no, Adam Doble, Gilles Doerflinger, Claudine Do Huu, Marie-He´le`ne Donat,
J ean Marie Duchesne, Pierre Ganil, Claude Gue´re´my, Eliane Honore´, Bernard J ust, Roselyne Kerphirique,
Sylvie Gontier, Philippe Hubert, Pierre M. Laduron, J oseph Le Blevec, Mireille Meunier, J ean-Marie Miquet,
Conception Nemecek, Martine Pasquet, Odile Piot, J eremy Pratt, J ean Rataud, Michel Reibaud,
J ean-Marie Stutzmann, and Serge Mignani
Rhoˆne-Poulenc S.A., Rhoˆne-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 13 quai J ules Guesde,
B.P. 14, F 94403 Vitry-sur-Seine Cedex, France
Received April 1, 1998
Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotrans-
mission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted
derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing
alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent
anticonvulsant activity against administration of glutamic acid in rats. The most active
compounds displaying in vivo “antiglutamate” activity were the 6-OCF3 (riluzole), 6-OCF2CF3,
6-CF3, and 6-CF2CF3 substituted derivatives with ED50 values between 2.5 and 3.2 mg/kg i.p.
Among the second series of variously substituted benzothiazolines, compounds as active as
riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a
â-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their correspond-
ing sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and
2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED50 ) 1.0
and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the
best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.
In tr od u ction
croiontophoretically applied excitatory amino acids in
motoneurons of the facial nucleus.6 Thus riluzole seems
to interfere with glutamatergic transmission at both the
pre- and postsynaptic level. However, riluzole did not
act as a competitive antagonist at NMDA type recep-
tors,7 and it had negligible activity on 3-(2-carboxy-
piperazin-4-yl)propyl-1-phosphonic acid binding, a se-
lective NMDA antagonist.8 Furthermore, it did not
interact, at least at submillimolar concentrations, with
kainate (KA) and quisqualate (QUIS) sensitive subtypes
of excitatory amino acid receptor.9 Finally it has also
been demonstrated that riluzole is a highly specific
blocker of inactivated Na channels,10 which in turn
inhibit glutamate release.
In the 1950s, a number of 2-benzothiazolamines were
intensively studied as central muscle relaxants. The
major work concerned with this field is that of Domino
1
et al. Since then medicinal chemists have not taken
an active interest in this chemical family. Biologists’
attention was drawn to this series when the pharma-
cological profile of riluzole was discovered. Riluzole (1,
6-(trifluoromethoxy)-2-benzothiazolamine, PK 26124,
RP 54274, Rilutek) was found to interfere with glutamate
neurotransmission in biochemical, electrophysiological,
and behavioral experiments.
In pharmacological experiments, riluzole possessed
anticonvulsant properties in different models including
maximal electroshock in mice, convulsions induced by
glutamic acid decarboxylase inhibitors in mice and rats,
sound-induced convulsions in DBA/2 mice, and photo-
sensitive epilepsy in baboons. However, unlike benzo-
diazepines, valproic acid, or barbiturates, riluzole was
ineffective against seizures induced by pentylenetetra-
zole, bicuculline, or picrotoxin11 and did not induce
phencyclidine-like behavioral activity in pigeons, rats,
or monkeys.12 Riluzole has been shown to have interest-
ing neuroprotective effects in vitro, protecting primary
cultures of rat cortical neurones against anoxic stress13
and against an excitotoxic factor present in cerebrospi-
nal fluid from ALS patients.14 Furthermore, rat moto-
neurons were protected by riluzole from the excitotoxic
effects of glutamic acid uptake inhibitors.15 These stud-
In biochemical models riluzole antagonized the re-
lease of acetylcholine induced by N-methyl-D-aspartate
(NMDA) in vitro and blocked the increase in cyclic
guanosine monophosphate levels in the cerebellar cortex
induced by glutamate in vitro and in vivo.2 Riluzole was
also found to be a potent antagonist of glutamate-
stimulated release of D-aspartate in rodent cerebellar
cells,3,4 and it decreased the glutamate-induced release
of dopamine (DA) in the “push-pull” model in the cat
striatum.5
In addition, electrophysiological studies have shown
riluzole to be active against responses evoked by mi-
* To whom correspondence should be addressed.
10.1021/jm980202u CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2829
Ta ble 1. Physical Properties and “Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines
protection against glutamic
acid evoked convulsions
ED50, mg/kg i.p.v
no.
R
method
formulaa
mp,°C
119s
cryst. solvent
EtOH-H2O
ClogP34
1
2
3
4
5
6
7
8
OCF3
A
Ew
A
E
A
B
C8H5F3N2OS
C7H6N2S
C7H5FN2S
C7H5ClN2S
C7H5BrN2S
C7H5IN2S
3.41
2.00
2.15
2.72
3.2
>10
>10
>10
>10
>10
>10
>10
>10
10
>10
>10
>10
5
>10
>10
>10
7
H
F
Cl
Br
184b
209c
EtOH
e
I
214e
208f
207g
243h
acetone
MeCN
d
NH2
CN
C7H7N3S
C8H5N3S
A
A
E
9
CO2Et
NO2
SO2Me
OMe
O-t-C4H9
SiMe3
C6H11
Ph
C10H10N2O2S
C7H5N3O2S
C8H8N2O2S2
C8H8N2OS
C11H14N2OS
C10H14N2SSi
C13H16N2S
13H10N2S
C8H8N2S
C9H10N2S
10H12N2S
10H12N2S
11H14N2S
11H14N2S
12H16N2S
12H16N2S
C12H16N2S
13H18N2S
14H20N2S
EtOH-H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
B
B
A
D
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
224i
147j
183
140
217k
248l
137m
115n
119o
125p
114q
146
122
134
196
121
109
186
249
155r
118t
134
147
161
156
191
122u
PrOH
EtOH-H2O
CHCl3-hexane
d
MeCN
CHCl3-EtOAc-EtOH
d
cyclohexane
cyclohexane
cyclohexane
EtOAc-cyclohexane
cyclohexane
cyclohexane
d
4.58
C
Me
Et
n-Pr
i-Pr
n-Bu
t-Bu
2.50
3.03
3.56
3.43
4.09
3.83
4.62
C
C
C
C
C
C
6
>10
4
4
n-Pen
t-Pen
CH2CMe3
n-Hex
n-Hep
CH2CF3
COCF3
SCF3
OCHF2
OCH2CF3
OCH2C2F5
OCF2CHF2
OC2F5
C2F5
7.5
>10
>10
7
d
4.36
5.14
5.67
C
C
cyclohexane
cyclohexane
d
EtOAc
i-Pr2O/cyclohexane
toluene
>10
C9H7F3N2S
8
C9H5F3N2OS
C8H5F3N2S2
C8H6F2N2OS
C9H7F3N2OSr
C10H7F5N2OS
C9H6F4N2OS
C9H5F5N2OS
C9H5F5N2S,HCl
C8H5F5F3S
>10
8
4.03
2.74
6.50
31
7.5
6.5
7.5
8.5
2.5
2.5
2.5
2.2
32
33
34
35
36
37
d
toluene
toluene
cyclohexane
EtOH-acetone
cyclohexane
4.16
5.15
3.26
2.96
CF3
(() MK-801
a
b
Microanalysis results on new compounds were within (0.4% of theoretical values unless otherwise indicated. Lit.39 mp 182 °C.
c Lit.40 mp 210 °C. Purified on a silica gel column and triturated in 40/60 petroleum ether. e Lit.41 mp 217 °C. f Lit.42 mp 207 °C. Lit.19
d
g
mp 198 °C. Lit.43 mp 242 °C. Lit.44 mp 224-6 °C. Lit.43 mp 147 °C. Lit.52 mp 219-21 °C. Lit.45 mp 227-8 °C. Lit.19 mp 136 °C.
h
i
j
k
l
m
Lit.41 mp 116 °C. o Lit.46 mp not indicated. Lit.47 mp 123-6 °C. Lit.48 mp not indicated. Lit.49 mp 153-4 °C. Lit.50 mp 117-9 °C.
n
t
p
q
r
s
Lit.51 mp 116 °C. N: calcd, 11.29; found, 10.8. v The variability in the glutamic acid-induced convulsion test is between 15 and 25%.
u
w
Method E: commercially available product (Aldrich).
Sch em e 1
ies suggest that riluzole may have neuroprotective
effects in whole animals, and this has indeed been
demonstrated in animal models of cerebral ischemia.16,17
Clinical studies have also demonstrated that riluzole
slows disease progression in amyotrophic lateral scle-
rosis.18
In this paper, we describe the synthesis of many close
analogues of riluzole, thus showing the crucial impor-
tance of the 6-substituent of these benzothiazoles, and
the preparation of 3-substituted derivatives of riluzole
and their in vivo “antiglutamate” activity. All the
compounds were evaluated, together with reference
drugs, for their ability to protect against seizures
induced by intracerebroventricular administration of
glutamic acid in rats.
classical synthetic route19 used for the preparation of
most of them: 1, 3, 5, 8, 9, 13, 15-37. One-pot reaction
of the appropriate aniline with thiocyanogen generated
from bromine and alkaline thiocyanate in acetic acid
medium led to formation of the desired products in good
to moderate yields (method A). The starting anilines
have been described in the literature, except 4-(2,2,2-
trifluoroethyl)aniline which was prepared by reduction
of the corresponding nitro compound. Another classical
way20 previously used for the preparation of 2-ben-
zothiazolamines is cyclization of phenylthioureas with
bromine in chloroform (Scheme 2, method B): com-
pounds 6, 11, and 12 were thus prepared.
Ch em istr y
6-Su bstitu ted -2-ben zoth ia zola m in es. 2-Benzothi-
azolamines 1-37 bearing various substituents in the
6-position are listed in Table 1. Scheme 1 shows the

2830 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
J imonet et al.
Ta ble 2. Physical Properties and “Antiglutamate” Activity of Trifluoromethoxy-2-benzothiazolamines
protection against glutamic
acid-evoked convulsions
ED50, mg/kg i.p.c
OCF3
position
no
method
formulaa
mp,°C
cryst. solvent
1
38
39
40
6
4
5
7
A
B
B
C
C8H5F3N2OS
C8H5F3N2OS
C8H5F3N2OS,HCl
C8H5F3N2OS
119
132
158
108
EtOH-H2O
3.2
>10
CCl4
d
e
>10
b
>10
a
b
Microanalysis results were within (0.4% of theoretical values unless otherwise indicated. Determined for C, H, N. c The variability
in the glutamic acid-induced convulsion test is between 15 and 25%. Washed with acetone. e Purified on a silica gel column.
d
Sch em e 2
Sch em e 3
Ta ble 3.
3-Substituted-2-imino-6-trifluoromethoxy-benzothiazolines
protection against glutamic
acid-evoked convulsions
no
R
method
ED50, mg/kg i.p.a
1
H (riluzole)
3.2
5.0
5.0
4.5
10
7.0
4.0
3.5
>10
>10
>10
>10
7.0
41 methyl
42 ethyl
43 n-propyl
44 n-butyl
45 allyl
46 propargyl
47 CH2CN
F
F
F
F
F
F
F
F
F
F
48 CH2Ph
49 (CH2)2Ph
50 CH2CO2Me
51 CH2CO2H
52 CH2CONH2
53 CH2CONEt2
54 (CH2)2SO2NH2
55 (CH2)2SO2NHMe
56 (CH2)2SO2NMe2
57 (CH2)2SO3H
58 (CH2)2OH
F
F
I
I
I
9.0
6.0
4.0
Compounds 2, 4, and 10 are commercially available
and 7 was obtained through reduction of the corre-
sponding nitro compound 10. Positional isomers of
riluzole were synthesized as outlined in Scheme 2
according to method B and are listed in Table 2. Two
isomers, 38 and 39, with the trifluoromethoxy group at
the 4- or 5-position were obtained from the correspond-
ing ortho or meta thioureas. Cyclization of this last
thiourea did not give the 7-trifluoromethoxylated isomer
40; it only gave the 5-trifluoromethoxylated isomer 39.
Synthesis of 40 was achieved via a five-step procedure
(Scheme 2, method C): Nitration of 2-trifluoromethoxy-
acetanilide with nitronium tetrafluoroborate afforded a
mixture of mononitrated products which, after separa-
tion and hydrolysis, yielded the 2-nitroaniline isomer;
this compound was treated with amyl nitrite and iodine
to give the corresponding 2-iodonitro derivative. After
reduction, the resulting 2-iodoaniline was finally cy-
>10
>10
8.0
I
F
a
The variability in the glutamic acid-induced convulsion test
is between 15 and 25%.
shown in Scheme 3 (method D). The bromo compound
5 was treated with n-butyllithium and chlorotrimeth-
ylsilane to give after hydrolyses the desired product, 14,
in a low but not optimized yield.
3-Su b st it u t ed -2-im in o-b en zot h ia zolin es. Com-
pounds listed in Tables 3-6 were synthesized by the
routes outlined in Scheme 4. Alkylation of 6-trifluo-
romethoxy-2-benzothiazolamine 1 occurred exclusively
on the endocyclic nitrogen, at the 3-position.
22
The
reaction was carried out very easily by mixing 1 and
the alkylating agent R-X in an alcohol, methylethyl
ketone, or dimethylformamide and refluxing the mix-
ture for several hours (method F). In many experiments,
salts of the expected products precipitated. The simplic-
21
clized into 40 by using thiourea and Ni(Et3P)4 gener-
ated in situ from bis(triethylphosphine)nickel(II) chlo-
ride and sodium cyanoborohydride as a reducing agent.
The trimethylsilyl derivative, 14, was prepared as

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2831
Sch em e 4a
a
Reagents: (a) RX, EtOH or MEK or DMF, reflux; (b) Br(CH2)nOH, EtOH, reflux; (c) TosCl, pyridine, 0 °C-rt, (d) CF3CO2Et, Et3N,
EtOH, rt; (e) R1R2NH2, NaHCO3, DMF, 80 °C or R′SNa, DMF; (f) aqueous K2CO3, MeOH, rt; (g) Br(CH2)2OH, 160 °C; (h) TosCl, Et3N,
CH2Cl2, 0 °C-rt; (i) R1R2NH, NaHCO3, DMF, 80 °C; (j) HCl, aqueous AcOH, reflux; (k) Br2, KSCN, AcOH, rt; (l) CH2dCHSO2F, DMF, rt;
(m) R1R2NH, acetone, reflux or AcOH, reflux; (n) aqueous HCl or HBr, reflux; (o) VOC-Cl, DBU, CH2Cl2, rt, then aqueous HCl, MeOH,
reflux; (p) 1 equiv mCPBA, EtOH, -35 °C (m ) 1) or 2 equiv mCPBA, CH2Cl2, rt (m ) 2).
Ta ble 4. Sulfur-Containing 3-Substituted Benzothiazolines
when the required alkylating agents R-X were not
commercially available, alternative methods were used.
According to method G, riluzole reacted with an
appropriate hydroxyalkyl bromide to give 58 or 96.24
When treated by p-toluenesulfonyl chloride, the alcohol
58 did not give the corresponding tosylate since, pre-
dictably, intramolecular nucleophilic attack of the imino
protection against glutamic
acid-evoked convulsions
ED50, mg/kg i.p.a
group occurred, leading to the tricyclic derivative 97.
This cyclization also occurred spontaneously with acetyl,
trityl, or t-Boc-imino protected compounds.25 To over-
come this difficulty, imine nitrogen nucleophilicity was
decreased by imine acylation with an electron-with-
drawing group such as trifluoroacetyl (compounds 98
and 99); thus the tosylates 100 and 101 were isolated
with a good yield and reacted with appropriate thiolate
R′SNa or amines RlR2NH to give the expected com-
pounds 69, 80, and 81. However, yields were still low
(10-30%), except for 69 (83%).
Method H avoided cyclization side reactions by react-
ing 2-bromoethanol with 4-trifluoromethoxy aniline.26
The resulting compound 102 was tosylated to give the
ditosylate 103, which was then condensed with an
appropriate amine RlR2NH to give 104-107 after acid
hydrolyses. Ring closure to the benzothiazoline deriva-
tives 76-79 was effected by thiocyanogen generated in
situ from bromine and potassium thiocyanate in acetic
acid medium.27 Overall yield remained low due to the
nonoptimized thiazole ring formation step.
S(O)m-R
no.
R
m
n
method
F
59
60
61
62
63
64
65
66
67
68
69
70
71
Me
Me
Me
Et
0
1
0
0
0
1
2
0
0
1
0
1
2
1
1
2
2
2
2
2
2
2
2
3
3
3
3.0
2.3
1.0
2.2
2.4
1.1
1.8
2.0
4.5
4.2
4.2
2.3
5.0
F
F
F
Pr
Me
Me
H
Ph
Ph
Me
Me
Me
F
G
a
The variability in the glutamic acid-induced convulsion test
is between 15 and 25%.
ity of this reaction and the availability of many potential
alkylating reagents allowed a rapid synthesis of a large
number of compounds: 41-50, 52, 53, 58, 59, 61-63,
67, 73-75. Yields were moderate or low, except for
molecules containing a thioether group on the side
chain, due to â-halosulfide reagent activation via an
electrophilic episulfonium.23 In some cases, especially
Sulfonamides 54, 55, 56 and sulfonic acid 57 were
synthesized according to method I. Michael addition of

2832 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
Ta ble 5. Nitrogen-Containing 3-Substituted Benzothiazolines
J imonet et al.
a
The variability in the glutamic acid-induced convulsion test is between 15 and 25%.
Ta ble 6. Simultaneous Modifications in Positions 3 and 6
of their benzothiazoline precursors 50 (R ) CH2CO2-
Me) and 110 (R ) (CH2)2StBu), respectively. Vinylchlo-
roformate (VOC-Cl) monodemethylation of the dimeth-
29
ylamino derivative 73 (R ) (CH2)2N(CH3)2 gave 72.
Sulfoxides (compounds 60, 64, 68, and 70) and sulfones
(compounds 65 and 71) were prepared from their
respective parent thioethers by oxidation with m-
chloroperbenzoic acid (mCPBA). Use of 1 equiv of
mCPBA in ethanol at -35 °C afforded sulfoxides,
whereas 2 equiv of mCPBA in dichloromethane at room
temperature gave sulfones.
protection against glutamic
acid-evoked convulsions
ED50, mg/kg i.p.a
no.
R
Z
82
73
83
84
85
86
87
88
89
NMe2
NMe2
NMe2
S(O)Et
S(O)Et
S(O)Et
S(O)Et
S(O)2Et
S(O)2Et
H
>10
2.3
>10
>10
>10
1.2
OCF3
t-Bu
t-Bu
n-Bu
OCF3
CF3
C2F5
OC2F5
The 6-substituted analogues of the most active ben-
zothiazolines bearing amino- and sulfur-containing side
chains are listed in Table 6; they were obtained follow-
ing the same synthetic pathway (method F) as the
trifluoromethoxylated compounds, a pathway starting
from the corresponding benzothiazoles. The importance
of the imino group of the thioether-containing com-
pounds 61 and 62 was demonstrated by the synthesis
of imino-modified benzothiazolines (Table 7, Schemes
5 and 6). Imino alkylated benzothiazolines 90 and 91
were obtained by direct alkylation of the N-2-alkylated
benzothiazoles 113 and 114 with chloroethyl-methyl-
(or ethyl)-sulfide (Scheme 5). Acetylation of 61 provided
94. Reaction of the tricyclic key intermediate 116 with
hydroxylamine and methoxylamine led, after alkylation
of the free thiol, to oximes 92 and 93, respectively,
whereas ring opening with sodium methoxide gave
directly the 2-benzothiazolone 95 (Scheme 6).30 The
1.7
2.1
2.6
a
The variability in the glutamic acid-induced convulsion test
is between 15 and 25%.
4-trifluoromethoxyaniline to ethenesulfonyl fluoride
easily gave 108,28 which was converted into either the
expected benzothiazoline sulfonamides by reaction with
appropriate amines or the sulfonic acid by hydrolysis
in aqueous acetic acid, followed by the usual thiazole
ring closure.
Compounds 51 (R ) CH2CO2H) and 66 (R ) (CH2)2-
SH) could not be obtained directly from riluzole by
reaction with the functionalized reagent; they were thus
prepared in a two-step process after acidic hydrolyses

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2833
Ta ble 7. Simultaneous Modifications in Positions 2 and 3
OCH3), 13 (R ) O-t-C4H9), 16 (R ) C6H5), and 29 (R )
COCF3) displayed very weak activity (ED50 g 10 mg/kg
i.p.). Thus electronic factors seem to be relatively
unimportant, since substitution with electron-donating
groups as well as electron-withdrawing groups at the
6-position did not increase the activity of the parent
compound 2. Additional evidence for this trend comes
from comparison of the activity for the 6-trifluo-
romethoxy derivative 1 with the 6-chloro derivative 4
(ED50 ) 3.2 mg/kg i.p. vs ED50 > 10 mg/kg i.p.,
respectively). It is known that the trifluoromethoxy
group deactivates the benzene ring by inductive electron
withdrawal and donates electrons by resonance exactly
as does chlorine.32 Replacement of chlorine by such a
“pseudohalogen” in compounds of medicinal interest has
frequently resulted in active compounds; for example
the 7-chloro substituent in diazepam was replaced by a
trifluoromethoxy group with retention of activity.33 Thus
it appears that riluzole’s in vivo activity depends es-
sentially on nonelectronic factors such as lipophilicity.
protection against glutamic
acid-evoked convulsions
no.
R
X
ED50, mg/kg i.p.a
62
90
91
92
93
94
95
SMe
SEt
SMe
SEt
SEt
SMe
SMe
NH
NMe
NEt
NOMe
NOH
NCOMe
O
2.2
3.7
8.5
>10
>10
>10
>10
a
The variability in the glutamic acid-induced convulsion test
is between 15 and 25%.
Sch em e 5a
Examination of the structure of the most potent
compounds in the series gave support to this hypoth-
esis: all the significantly active compounds fell into two
sets: (1) compounds bearing a rather large alkyl sub-
stituent and (2) compounds bearing a polyfluoroalkyl
or a polyfluoroalkoxy substituent. (1) On varying the
size of the alkyl moiety it appeared that there was an
optimal size for activity. Among the linear alkyl sub-
stituted derivatives (compounds 17-19, 21, 23, 26, 27),
the most potent is 21 (R ) C4H9). Lengthening or
shortening the chain decreased the potency (C4H9
C3H7 ∼ C2H5 > CH3 and C4H9 > C5H11 ∼ C6H13
>
>
C7H15). Changing the butyl group (compound 21) to a
tert-butyl group (compound 22) or a trimethylsilyl group
(compound 14) did not affect the activity; on the other
hand, decreasing the size of branched substituents
(compound 20, R ) isopropyl) or increasing the size
(compounds 24, R ) t-C5H11, 25, R ) CH2-t-C4H9) led
to compounds with weak activity (ED50 > 10 mg/kg i.p.).
(2) Compounds closely related to riluzole 1, 6-pentafluo-
roethoxy-2-benzothiazolamine 35 and perfluoroalkyl
derivatives 36 and 37 displayed strong “antiglutamate”
activities with ED50 values of 2.5 mg/kg i.p. Replacement
of one or more fluorine atoms by hydrogens always
decreased the activity (28 (R ) CH2CF3) < 36 (R )
C2F5); 31 (R ) OCHF2) < 1 (R ) OCF3); 34 (R ) OCF2-
CHF2) < 35 (R ) OC2F5)). All these results are consis-
tent with lipophilicity of the substituent at the 6-posi-
tion as a major contributing factor for “antiglutamate”
activity. Calculated ClogP34 of compounds listed in Table
1 showed that values around 4.0 are the most favorable
in the alkyl series, whereas a wider range is observed
in the fluorinated series: 2.96 (compound 37)-5.15
(compound 35). Thus, in this latter series no clear-cut
correlation can be made between ClogP and biological
activity since in vivo testing involves not only drug-
receptor interactions but also additional parameters
such as bioavailability, metabolism, and brain penetra-
tion. In addition, the trifluoromethoxy group position
on the aromatic ring was of crucial importance, since
all positional isomers of riluzole (compounds 38-40)
have ED50 values of >10 mg/kg i.p. (Table 2).
a
Reagents: (a) NH2NH2, (b) SOCl2, (c) aqueous RNH2, (d)
Cl(CH2)2SR′, MEK, reflux.
same reaction performed with sodium methyl sulfide did
not lead to 2-benzothiazolethione, but unexpectedly
stopped at a stable tricyclic benzothiazole derivative 119
(inactive in our tests), which contains a rarely observed
four-heteroatom-substituted carbon atom.
Resu lts a n d Discu ssion
Compounds 1-95 were evaluated for their ability to
protect against seizures induced by intracerebroven-
tricular administration of glutamic acid in rats31 (see
Experimental Section). The in vivo “antiglutamate”
activity of the studied compounds is listed in Tables
1-7. In this test, the noncompetitive NMDA receptor
antagonist dizocilpine ((()MK-801, see Table 1) was
found to be active with an ED50 of 2.2 mg/kg i.p.
(administered 10 min before challenge).
6-Su bstitu ted -2-ben zoth ia zola m in es. In this test,
riluzole 1 had an ED50 of 3.2 mg/kg i.p., whereas the
unsubstituted 2-benzothiazolamine 2 was much less
active. Many 6-substituted-2-benzothiazolamines such
as compounds 7 (R ) NH2), 8 (R ) CN), 9 (R )
CO2C2H5), 10 (R ) NO2), 11 (R ) SO2CH3), 12 (R )
From the in vivo data obtained in this study we can
only speculate that the moiety in the 6-position in

2834 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
J imonet et al.
Sch em e 6a
a
Reagents: (a) thiourea, 1 N H2SO4, 60 °C; (b) 1,2-dibromoethane, DMF; (c) NH2OR, 1 N NaOH, refulx; (d) EtONa, EtOH, EtBr, rt;
(e) MeONa, MeOH, reflux; (f) MeSNa, EtOH, rt.
riluzole or in its active analogues is an essential
anchorage point allowing lipophilic interactions at a
binding site, but influence of other parameters such as
bioavailability and/or other mechanisms of action cannot
be ruled out. Study of this series of compounds in
relevant in vitro tests would be required to corroborate
this hypothesis and thereby to allow quantitative struc-
ture-activity relationship (QSAR) analysis of substitu-
ent effects. QSAR analysis of a set of substituted
benzothiazoles has already been done using sodium flux
measurements in rat cortical membranes as an in vitro
test.35 Our conclusions are similar to those reached by
Hays et al.: need for a small liphophilic substituent and
emphasis on other probable mechanisms of action
limiting QSAR interpretation and responsible for in vivo
effects.
3-Su bstitu ted -2-im in o-ben zoth ia zolin es. In con-
trast with the 2-methylamino-6-trifluoromethoxy-ben-
zothiazole 113 which was inactive at 10 mg/kg i.p. (data
not shown), the 3-methyl derivative 41 displayed a good
anticonvulsant activity (ED50 ) 5 mg/kg i.p.). This
encouraging result prompted us to study systematically
the substituent influence at the 3-position (Table 3).
Replacement of the methyl group by another aliphatic
chain such as an ethyl, propyl, allyl, or propargyl group
(compounds 42, 43, 45, and 46, respectively) did not
substantially affect the activity, whereas introduction
of larger alkyl substituents (e.g., butyl, compound 44)
or aromatic substituents (compounds 48 and 49) re-
duced the potency dramatically. At this stage, we
prepared some functionalized benzothiazolines: ester
(50), amides (52 and 53), sulfonamides (54-56), car-
boxylic acid (51), sulfonic acid (57), and alcohol (58) did
not display more potency than riluzole, and no clear-
cut correlation between structure and activity can be
deduced.
A significantly enhanced “antiglutamate” activity was
obtained by introduction of nitrogen- or sulfur-contain-
ing 3-substituents. Concerning the sulfur-containing
series, results showed that the methylthioethyl deriva-
tive 61 was one of the most potent benzothiazolines with
an ED50 of 1 mg/kg i.p. (Table 4). Surprisingly, the
corresponding sulfoxide 64 and sulfone 65 were as active
as their parent thioether. This might suggest that the
active molecule in vivo is in fact a common metabolite.36
Lengthening or shortening the alkyl chain by one carbon
atom (compounds 59, 60, and 69-71), as well as the
replacement of the methylthio group by a thiol or larger
and/or aromatic substituents (compounds 62, 63, 67,
and 68), resulted in a loss of anticonvulsant effect;
however, all compounds diplayed a reasonable level of
activity (ED50 e 5 mg/kg i.p.). Looking at the amino-
containing series, in contrast to the monomethylated
compound 72, the dimethylaminoethyl-substituted ben-
zothiazoline 73 and the cyclic analogue 74 demonstrated
good anticonvulsant potency with an ED50 value of
about 2 mg/kg i.p. (Table 5). Homologation of 73 to the
aminopropyl derivative 75 resulted in a reduced protec-
tive effect, thus indicating the â-position of the amino
group to be preferable. Replacement in 73 of the

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2835
Ta ble 8. Neuroprotective Activities of Selected
Benzothiazolines
broventricular administration of glutamic acid in rats.
Two sets of products were shown to be active in this
model: compounds bearing a large but not too large
alkyl substituent, and compounds bearing a polyfluo-
roalkyl or a polyfluoroalkoxy substituent. These biologi-
cal data suggest that the 6-substituted-2-benzothiazol-
amine series possesses excitatory amino acid antagonist
activity. This may endow members of this series with
interesting anticonvulsive and neuroprotective proper-
ties. Indeed, riluzole, a lead in this series, has been
shown to be neuroprotective in curative treatment in
animal models of focal and global ischaemia17 and had
been selected for clinical trials in amyotrophic lateral
sclerosis where it showed efficacy in slowing disease
progression.
As a second step, 3-substituted-2-imino-benzothiazo-
lines were evaluated in the same test. It was shown that
a wide variety of modifications in the 3-position of
riluzole were possible. Of all the analogues, compounds
as active as riluzole or up to 3 times more potent were
found among benzothiazolines bearing heteroatoms in
the â-position of the alkyl substituent; the dialkylamino-
ethyl- and unchanged or oxidized alkylthioethyl-ben-
zothiazolines are strong “antiglutamate” compounds in
vivo, twice as active as the noncompetitive NMDA
antagonist dizocilpine. The most potent glutamic acid
antagonists in vivo protected mice against mortality
induced by hypobaric hypoxia, a simple pharmacological
test capable of predicting neuroprotective potential for
these compounds. Anti-ischemic activities of RP 66055
(3-{2-[1-(4-fluorophenyl-piperazinyl)]ethyl}-2-imino-6-
trifluoromethoxybenzothiazoline), a fluorinated deriva-
tive of the benzothiazoline 80, were recently reported.38
ED50 (mg/kg i.p.)
no.
Glua
H.H.b
61
64
65
73
74
78
79
80
81
1.0
1.1
1.8
2.3
2.0
3.0
2.2
3.5
10.0
3.2
14.0
5.5
2.5-10
4.0
<5
2.5-10
2.5-10
5.5
>10
riluzole
4.0
a
Protection against glutamic acid-evoked convulsions in rats.
b
The variability in this test is between 15 and 25%. Protective
effect against mortality induced by hypobaric hypoxia in mice. The
variability in this test is 20%.
dimethylamino group by a group containing an aromatic
moiety such as N-methyl-N-benzylamino group (76) or
N-methyl-N-phenethylamino group (77) gave com-
pounds with reduced potency. Unexpectedly however,
the 4-phenyl-piperidinyl derivative 78 as well as the
4-phenyl-1,2,3,6-tetrahydropyridyl and 4-phenyl-piper-
azinyl analogues (compounds 79 and 80, respectively)
displayed a high level of activity in the same range
(ED50 ) 2-3 mg/kg i.p.). In this series, as for the
aminated aliphatic one, lengthening of the alkyl chain
(compound 81) decreased “antiglutamate” activity.
To study simultaneous modifications at the 3- and
6-positions, the 6-trifluoromethoxy groups of three of the
most active benzothiazolines were replaced by other
substituents which had been shown previously to be the
most efficient in the benzothiazole series, i.e., polyfluo-
roalkoxy, polyfluoroalkyl, and alkyl groups (Table 6).
Surprisingly, from these three series of derivatives, only
the 6-polyfluoroalkyl- (compounds 87 and 88) and
6-polyfluoroalkoxy- (compounds 73, 86, and 89) substi-
tuted compounds displayed high and comparable poten-
cies, suggesting that the presence of an electron-
withdrawing group containing fluorine atoms is of
crucial importance.
Furthermore, the importance of the 2-imino group in
the thioalkyl series was illustrated by the slight (com-
pound 90) or more dramatic (compound 91) decrease of
activity observed with the 2-N-alkylated-iminoben-
zothiazolines. A decrease was also seen with the 2-N-
hydroxylated and 2-N-acylated derivatives (compounds
92-94), as well as with the keto analogue 95 (Table 7).
Neu r op r otective Activities of Selected Com -
p ou n d s. Some of the most active and representative
benzothiazolines have been evaluated for their protec-
tive effects against mortality induced by hypobaric
hypoxia.37 As shown in Table 8, all compounds studied
display high protective activities following i.p. admin-
istration. Activities in the hypobaric hypoxia model are
very similar to that of riluzole, except for the thioether
61 which, surprisingly, is about 3 times less effective.
ED50 values for the other compounds range between 2.5
and 10 mg/kg, thus showing the potential neuroprotec-
tive activity of riluzole derivatives.
Exp er im en ta l Section
Melting points were determined on a Ko¨fler apparatus and
1
are uncorrected. H NMR spectra were recorded on a Bruker
WP 200 (200 MHz), a Bruker WM 250 (250 MHz), or a Bruker
AM 400 (400 MHz). IR spectra were taken on a FT-IR Nicolet
60 SX-R, a Perkin-Elmer 580 B, or a Perkin-Elmer 983 G.
Mass spectra were recorded on a Finnigan 3300 spectrometer
(EI at 70 eV) or on a Nermag R10-10B (DCl, NH3). NMR data
are reported in ppm downfield relative to external TMS (0
ppm) as standard. Elemental analyses are indicated by the
symbol of the elements, and the results were within ( 0.4%
(for C, H, Br, Cl, F, N, S) of the theoretical values unless
otherwise noted. Medium-pressure chromatographic separa-
tions were performed on silica gel (0.04-0.063 mm supplied
by Merck). All organic solutions were dried over magnesium
sulfate. Yields are not optimized. Compounds 1, 3, 5-9, 11,
12, 15-21, 30, and 37 were prepared according to literature
procedures.19,39-52
Meth od A. 6-P en tyl-2-ben zoth ia zola m in e (23). 4-Pen-
tylaniline (4.9 g; 0.03 mol), AcOH (45 mL), and potassium
thiocyanate (11.6 g; 0.12 mol) were stirred at 19 °C for 10 min,
and then a solution of bromine (1.5 mL; 0.03 mol) in AcOH
(20 mL) was added over 20 min; during the addition, the
temperature rose to 35 °C. The reaction mixture was stirred
for 21 h at room temperature, then poured into cold water (600
mL), made alkaline with 28% aqueous NH4OH (∼90 mL), and
extracted with EtOAc (250 + 150 mL). The organic phase was
washed with water (150 mL), dried, filtered, and evaporated.
A crude yellow product was obtained which was chromato-
graphed on silica gel (500 g) eluted with 5:5 cyclohexane-
EtOAc and crystallized from cyclohexane (55 mL) to yield 23
as white pearly crystals (4.3 g; 71%): mp 122 °C; NMR (DMSO,
200 MHz) δ 0.82 (t, 3H, CH3), 1.36 (m, 4H, 2 CH2), 1.55 (quint,
2H, CH2), 2.55 (t, 2H, CH2Ar), 6.97 (dd, 1H, H5), 7.22 (d, 1H,
H4), 7.32 (bs, 2H, NH2), 7.92 (d, 1H, H7); IR (KBr) 820, 865,
Con clu sion s
A series of 6-substituted-2-benzothiazolamines was
first evaluated against seizures induced by intracere-

2836 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
J imonet et al.
1055, 1105, 1285, 1300, 1465, 1530, 1560, 1625, 2850, 2865,
2920, 2950, 3100, 3275, 3430 cm-1; MS m/z 220 (M+), 163 (M+
- (CH2)3CH3). Anal. (C12Hl6N2S) C, H, N, S.
1H, H4), 7.75 (mf + d, 3H, NH2, H7); IR (KBr) 800, 865, 1175,
1215, 1250, 1485, 1550, 1600, 1610, 1650, 3050, 3150, 3280,
3400 cm-1; MS m/z 234 (M+), 207 (M+ - HCN), 165 (M+
CF3). Anal. (C8H5F3N2OS‚HCl) C, H, Cl, N, S.
-
Fourteen other new compounds were synthesized according
to method A: 13 (28%), Anal. (C11H14N2OS) C, H, N, S; 22
(68%), Anal. (C11H14N2S) C, H, N, S; 24 (65%), Anal. (C12H16N2S)
C, H, N, S; 25 (54%), Anal. (C22H16N2S) C, H, N, S; 26 (41%),
Anal. (C13H18N2S) C, H, N, S; 27 (65%), Anal. (C14H20N2S) C,
H, N, S; 28 (29%), Anal. (C9H7F3N2S) C, H, F, N, S; 29 (11%),
Anal. (C9H5F3N2OS) C, H, F, N, S; 31 (52%), Anal. (C8H6F2N2-
OS) C, H, F, N, S; 32 (43%), Anal. (C9H7F3N2OS) C, H; 33
(39%), Anal. (C10H7F5N2OS) C, H, F, N, S; 34 (50%), Anal.
(C9H6F4N2OS) C, H, F, N, S; 35 (55%), Anal. (C9H5F5N2OS) C,
H, F, N, S. Base 36 was converted to the hydrochloride and
crystallized as noted in Table 1: 36 (18%), Anal. (C9H6F3NS‚
HCl) C, H, Cl, F, N.
4-(2,2,2-Tr iflu or oeth yl)a n ilin e. The starting material for
24 was prepared as follows: To a stirred solution of 4-(2,2,2-
trifluoroethyl)nitrobenzene53 (3.8 g; 0.0185 mol) in EtOH (20
mL) was added 5% Pd/C (0.17 g), and then a solution of
hydrazine hydrate (1.8 mL; 0.036 mol) in EtOH (10 mL) was
added dropwise over 20 min; during the addition the reaction
temperature rose to 44 °C. After addition, the mixture was
refluxed for 15 min and cooled to room temperature. The
catalyst was filtered off, and the filtrate was concentrated, then
diluted with water, and extracted with EtOAc (200 mL). The
organic phase was dried and the solvent evaporated under
reduced pressure to yield a yellow oil (2.7 g; 83%) which was
purified by chromatography on silica gel. Elution with 7:3
cyclohexane-EtOAc gave 4-(2,2,2-trifluoroethyl)aniline as an
oil (2.3 g; 71%): NMR (CDCl3, 200 MHz) δ 3.25 (q, J ) 10 Hz,
2 H, CH2CF3), 3.60 (mf, 2H, NH2), 6.66 (dd, 2H, H3, H5), 7.10
(bd, 2H, H2, H6); MS m/z 175 (M+), 106 (M+ - CF3).
Meth od C. 7-(Tr iflu or om eth oxy)-2-ben zoth ia zola m in e
(40). Step 1. 2-Nitr o-6-(tr iflu or om eth oxy)a ceta n ilid e. Ni-
tronium tetrafluoroborate (20 g; 0.15 mol) was added in small
portions over 40 min to a stirred solution of 2-(trifluo-
romethoxy) acetanilide53 (21.9 g; 0.1 mol) in CH3CN (200 mL)
cooled at -30 °C. The reaction mixture was allowed to stand
at -5 °C for 30 min and was poured into cold water. The solid
thus obtained was filtered off, washed with water, and then
crystallized in toluene (200 mL) to give 2-nitro-6-(trifluo-
romethoxy)acetanilide (3.6 g). The filtrate was concentrated
under reduced pressure and chromatographed on alumina (700
g) containing water (3% w/w), eluting with toluene then CH2-
Cl2 to afford another crop (1.5 g). Total yield was 19%: mp
160 °C; NMR (CDCl3, 200 MHz) δ 2.25 (s, 3H, COCH3), 7.41
(t, J ) 9 Hz, 1H, H4), 7.6 (d, J ) 9 Hz, 1H, H5), 7.88 (mf, 1H,
NH), 7.95 (dd, 1H, H3); IR (KBr) 675, 695, 735, 815, 805, 1080,
1175, 1210, 1260-1275, 1365, 1450, 1475, 1510, 1450, 1595,
1610, 1675, 3270 cm-1; MS m/z 264 (M+), 221 (M+ - COCH3).
Step 2. 2-Nitr o-6-(tr iflu or om eth oxy)a n ilin e. A mixture
of 2-nitro-6-(trifluoromethoxy) acetanilide (12.5 g; 0.0473 mol),
EtOH (125 mL), and concentrated HCl (125 mL) was refluxed
for 3.5 h, then concentrated under reduced pressure, poured
onto ice-water (800 mL), made alkaline with 28% aqueous
NH4OH (95 mL), and extracted with EtOAc (4 × 250 mL). The
organic layer was dried and evaporated to yield 2-nitro-6-
(trifluoromethoxy)aniline as a yellow oil (9.9 g; 94%): NMR
(CDCl3, 200 MHz) δ 6.35 (mf, 2H, NH2), 6.72 (dd, 1H, H4),
7.42 (bdd, 1H, H3), 8.10 (dd, 1H, H5); IR (CC14) 730, 1080,
1185, 1220, 1250, 1365, 1460, 1530, 1580, 1630, 3400, 3525
cm-1; MS m/z 222 (M+), 192 (M+ - NO), 153 (M+ - CF3).
Step 3. 2-Iod o-3-(tr iflu or om eth oxy)n itr oben zen e. Io-
dine (65.8 g; 0.26 mol) followed by isoamylnitrite (10 mL; 0.075
mol) was added to a stirred solution of 2-nitro-6-(trifluo-
romethoxy)aniline (11 g; 0.05 mol) in CHCl3 (200 mL). The
reaction mixture was refluxed for 4 h and allowed to stand at
room temperature overnight. The liquid phase was taken off
and concentrated to give a purple oil (18 g) which was
chromatographed on silica gel (700 g), eluting with 8:2 cyclo-
hexane-EtOAc. 2-Iodo-3-(trifluoromethoxy)nitrobenzene was
thus obtained as a red oil (6.7 g; 40%) suitable for use in the
following step.
Step 4. 2-lod o-3-(tr iflu or om eth oxy)a n ilin e. A mixture
of 2-iodo-3-(trifluoromethoxy)-nitrobenzene (7 g; 0.021 mol),
EtOH (65 mL), H2O (65 mL), Fe (powder) (9.5 g), and
concentrated HCl (2.2 mL) was refluxed for 4.5 h. The cooled
mixture was poured into ice-water (500 mL), made alkaline
with 28% aqueous NH4OH (10 mL), and extracted with EtOAc
(5 × 200 mL). The organic phase was dried, evaporated, and
chromatographed on silica gel (400 g), eluting with 8:2 cyclo-
hexane-AcOEt to give 2-iodo-3-(trifluoromethoxy)aniline as
a light brown oil (4.1 g; 64%): NMR (DMSO, 300 MHz) δ 6.55
(d, J ) 9 Hz, 1H, H4), 6.74 (dd, 1H, H6), 7.15 (t, J ) 9 Hz, 1H,
H5); IR (CCl4) 715, 1025, 1080, 1170, 1215, 1265, 1460, 1470,
1570, 1615, 3070, 3375, 3475 cm-1; MS m/z 303 (M+), 175 (M+
- HI).
Meth od B. 4-(Tr iflu or om eth oxy)-2-ben zoth ia zola m in e
(38). Step 1. N-[2-(Tr iflu or om eth oxy)p h en yl]th iou r ea . A
stirred solution of 2-(trifluoromethoxy)aniline54 (17.7 g; 0.1
mol), ammonium thiocyanate (8 g; 0.105 mol), sodium hydro-
gen sulfite (0.7 g), and 20% hydrochloric acid (18.2 mL) was
heated at 90 °C for 14 h. The cooled mixture was filtered,
washed with water to neutrality, triturated with isopropyl
ether, filtered, and dried to give the desired product as a white
solid (16 g; 68%): mp 157 °C; NMR (CDCl3, 200 MHz) δ 6.25
(mf, 2H, NH2), 7.30-7.60 (rnt, 5H, Ar), 7.87 (mf, 1H, NH); IR
(KBr) 725, 775, 1065, 1155, 1175, 1220, 1265, 1310, 1450, 1490,
1520, 1590, 1615, 1625, 3030, 3075, 3150, 3250, 3425 cm-1
;
MS m/z 236 (M+), 219 (M+ - NH3), 151 (M+ - OCF3). Anal.
(C8H7F3N2OS) C, H, F, N, S.
In a similar way, starting from 3-(trifluoromethoxy)aniline
(4 g; 0.024 mol), N-[3-(trifluoromethoxy)phenyl]thiourea was
obtained as a white solid (1.7 g; 30%): mp 86 °C; MS m/z 236
(M+), 203 (M+ - SH).
Step 2. 4-(Tr iflu or om eth oxy)-2-ben zoth iazolam in e (38).
To a stirred suspension of N-[2-(trifluoromethoxy)phenyl]-
thiourea (16 g; 0.068 mol) in CHCl3 (130 mL) was added
dropwise a solution of bromine (7 mL; 0. 136 mol) in CHCl3
(15 mL). The reaction mixture was refluxed for 2.5 h and
allowed to stand at room temperature overnight. The mixture
was evaporated to dryness in vacuo, and the orange residue
was treated with diluted NH4OH and extracted with CH2Cl2
(2 × l50 mL), dried, filtered, and evaporated. A yellowish solid
(14 g) was obtained which was crystallized twice from CCl4 to
yield 38 as white crystals (6.5 g; 41%): mp 132 °C; NMR
(CDCl3, 200 MHz) δ 7.08 (t, J ) 9 Hz, 1H, H6), 7.17 (mf, 2H,
NH2), 7.21 (mt, 1H, H5), 7.5 (dd, 1H, H7); IR (KBr) 710, 785,
1055, 1175, 1250, 1285, 1430, 1470, 1540, 1575, 1605, 1640,
1645, 3100, 3250, 3295, 3495 cm-1; MS m/z 234 (M+), 214 (M+
- HF), 165 (M+ - CF3). Anal. (C8H5F3N2OS) C, H, F, N, S.
By the same method, starting from N-[3-(trifluoromethoxy)-
phenyl]thiourea (12.8 g; 0.054 mol), 5-(trifluoromethoxy)-2-
benzothiazolamine (3 g) was obtained after chromatography
on silica gel, eluting with 8:1:1 toluene-MeOH-diethylamine.
The base was converted to the hydrochloride and washed with
acetone to give 39 (3.2 g; 22%): mp 158 °C; NMR (base)
(DMSO, 200 MHz) δ 7.00 (bd, J ) 8.0 Hz, 1H, H6), 7.27 (mf,
Step 5. 7-(Tr iflu or om eth oxy)-2-ben zoth iazolam in e (40).
A mixture of 2-iodo-3-(trifluoromethoxy)aniline (3.7 g; 0.012
mol), DMF (120 mL), thiourea (3.7 g), bis(triethylphosphine)-
NiII (1.8 g), and sodium cyanoborohydride (1.5 g) was heated
at 85 °C with stirring for 16 h. Additional bis(triethylphos-
phine)NiII (1 g) and NaBH3CN (0.7 g) were added, and heating
was kept at 85 °C for 6 h. The reaction mixture was poured
into water (600 mL) and extracted with EtOAc (5 × l00 mL).
The organic layer was dried, evaporated, and chromatographed
on silica gel (600 g), eluting with 2:1 cyclohexane-EtOAc to
yield 40 (0.4 g; 14%). After a second chromatography (the same
eluting mixture), an analytical sample melted at 108 °C: NMR
(CDCl3, 200 MHz) δ 5.35 (mf, 2H, NH2), 7.05 (bd, 1H, H6),
7.33 (t, 1H, H5), 7.60 (dd, 1H, H4). IR (KBr) 710, 775, 1060,
1110, 1120, 1160, 1220, 1260, 1290, 1435, 1480, 1530, 1550,

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2837
1570, 1610, 1630, 3120, 3280, 3360 cm-1; MS m/z (234 M+),
207 (M+ - HCN), 165 (M+ - CF3). Anal. (C8H5F3N2OS) C, H,
N, S.
3-Allyl-2-im in o-6-tr iflu or om eth oxy-ben zoth iazolin e Hy-
d r obr om id e (45): mp 225 °C; 1H NMR δ (200 MHz, DMSO-
d6) 5.0 (d, 2H, J ) 4.5 Hz, NCH2), 5.22 and 5.29 (d, J ) 16 Hz,
and d, J ) 10 Hz, NCH2CHdCH2), 5.95 (m, 1H, NCH2CHd
CH2), 7.59 (bd, 1H, 5-H), 7.76 (d, 1H, J ) 9 Hz, 4-H), 8.22 (bs,
1H, 7-H), 10.0-11.0 (m, 2H, dNH‚HBr); MS m/e 274 (M+), 259
(80). Anal. (C11H9F3N2OS‚HBr) C, H, Br, F, N, S.
2-Im in o-3-(2-p r op yn yl)-6-tr iflu or om eth oxy-ben zoth ia -
zolin e Hyd r obr om id e (46): mp 210 °C (sublimes); 1H NMR
δ (200 MHz, DMSO-d6) 3.69 (bs, 1H, NCH2CtCH), 5.32 (bs,
2H, NCH2CtCH), 7.63 (bs, 1H, 5-H), 7.87 (d, 1H, J ) 9 Hz,
4-H), 8.27 (bs, 1H, 7-H), 10.4-11.1 (m, 2H, dNH‚HBr); MS
m/e 272 (M+), 271 (85). Anal. (C11H7F3N2OS‚HBr) C, H, Br, F,
N, S.
3-(2-Cyan oeth yl)-2-im in o-6-tr iflu or om eth oxy-ben zoth i-
a zolin e Oxa la te (47): mp 180 °C; 1H NMR δ (200 MHz,
DMSO-d6) 3.00 (t, 2H, J ) 7 Hz, CH2CN), 4.42 (t, 2H, J ) 7
Hz, NCH2), 5.00-5.80 (bb, 3H, dNH‚(COOH)2), 7.42 (bd, 1H,
J ) 8 Hz, 5-H), 7.63 (d, J ) 8 Hz, 1H, 4-H), 7.87 (bs, 1H, 7-H);
MS m/e 286 (M - 1+), 233 (100); (CI+) 288 (M + 1+). Anal.
(C11H8F3N3OSC2H2O4) C, H, F, N, S.
3-Be n zyl-2-im in o-6-t r iflu or om e t h oxy-b e n zot h ia zo-
lin e Hyd r obr om id e (48): mp 200 °C (sublimes); 1H NMR δ
(200 MHz, DMSO-d6) 5.65 (m, 2H, NCH2), 7.25-7.50 (m, 5H,
ArH), 7.55 (bd, 1H, 5-H), 7.68 (d, 1H, J ) 9 Hz, 4-H), 8.25 (bs,
1H, 7-H), 10.3-11.0 (m, 2H, dNH‚HBr); MS m/e 324 (M+), 91
(100). Anal. (C15H11F3N2OS‚HBr‚H2O) C, H, Br, F, N, S.
2-Im in o-3-p h en eth yl-6-tr iflu or om eth oxy-ben zoth ia zo-
lin e Hyd r obr om id e (49): mp 210 °C (sublimes); 1H NMR δ
(250 MHz, DMSO-d6) 3.03 (t, 2H, J ) 7.5 Hz, NCH2CH2Ar),
4.57 (t, 2H, J ) 7.5 Hz, NCH2CH2Ar), 7.15-7.4 (m, 5H, ArH),
7.5 (bd, 1H, 5-H), 7.71 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, IH, 7-H),
10.2-10.7 (m, 2H, dNH‚HBr); MS m/e 338 (M+), 234 (100).
Anal. (C16H13F3N2OS‚HBr) C, H, Br, F, N, S.
Meth od D. 6-(Tr im eth ylsilyl)-2-ben zoth iazolam in e (14).
A 1.6 M solution of n-BuLi in hexane (46 mL) was added with
stirring under Ar to a -70 °C cooled solution of 5 (6.8 g; 0.03
mol) in dry THF (100 mL), followed by a solution of chloro-
trimethylsilane (9.3 mL; 0.04 mol) in dry THF (10 mL) at 0
°C. After the temperature was allowed to rise to 20 °C, the
reaction mixture was refluxed for 1.5 h and then cooled to -10
°C before additional n-BuLi solution (19 mL) was added. The
temperature was allowed to rise to 0 °C, and to the light red
solution thus obtained was added a solution of chlorotrimeth-
ylsilane (4.7 mL; 0.037 mol) in dry THF (10 mL). During the
addition, the temperature rose to 17 °C, and then the reaction
mixture was refluxed for 4.5 h. The cooled mixture was poured
into water (100 mL), alkalized with 28% aqueous NH4OH, and
extracted with CH2Cl2 (4 × 200 mL). The lower layer was
dried, filtered, and evaporated in vacuo. The orange oil (10.1
g) thus obtained was chromatographed twice on silica gel using
a 6:4 mixture of EtOAc-cyclohexane to yield a white solid (0.55
g). This material was triturated with 40/65 petroleum ether,
filtered, and dried to yield 14 (0.45 g; 7%): mp 140 °C; NMR
(DMSO, 200 MHz) δ 0.25 (mf, 9H, (CH3) 3Si), 7.34 (s, 2H, H4,
H5), 7.53 (mf, 2H, NH2), 7.78 (s, 1H, H7); IR (KBr) 840, 900,
1050, 1105, 1150, 1245, 1260, 1300, 1380, 1445, 1455, 1520,
1545, 1585, 1632, 2895, 2950, 3090, 3280, 3425 cm-1; MS m/z
222 (M+), 207 (M+ - CH3). Anal. (C10H14N2SSi) C, H, N, S.
Gen er a l P r oced u r es for 3-N-Alk yla tion of 6-Su bsti-
tu ted -2-ben zoth ia zola m in e (Meth od s F -I). Meth od F .
3-(2-Meth ylth io-eth yl)-2-im in o-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r och lor id e (61). A stirred suspension of
6-trifluoromethoxy-2-benzothiazolamine 1 (10 g, 0.0427 mol)
and 2-methylthioethyl chloride (5 mL, 0.050 mol) in 20 mL of
methyl ethyl ketone (MEK) was heated under reflux for 24 h.
After cooling to room temperature, the resulting precipitate
was filtered and washed twice with 20 mL of MEK to give 61
2-Im in o-3-m eth oxycar bon ylm eth yl-6-tr iflu or om eth oxy-
1
ben zoth ia zolin e Hyd r obr om id e (50): mp 246 °C dec; H
NMR δ (200 MHz, DMSO-d6) 3.77 (s, 3H, CO2CH3), 5.37 (s,
2H, NCH2CO2), 7.6 (bd, 1H, 5-H), 7.84 (d, 1H, J ) 9 Hz, 4-H),
8.24 (bs, 1H, 7-H), 10.2-11.2 (m, 2H, dNH‚HBr); MS m/e 306
(M+), 247 (100), 220 (95). Anal. (C11H9F3N2O3S‚HBr) C, H, Br,
F, N, S.
1
(11.5 g, 78%) as a colorless solid: mp 208 °C; H NMR δ (200
MHz, DMSO-d6) 2.17 (s, 3H, SCH3), 2.9 (t, 2H, J ) 7 Hz,
CH2S), 4.6 (t, 2H, J ) 7 Hz, NCH2), 7.58 (bd, 1H, 5-H), 7.8 (d,
1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 10.0-1 1.7 (m, 2H,
dNH‚HCl); MS m/e 308 (M+), 234 (100). Anal. (C11H11F3N2-
OS2‚HCl) C, H, Cl, F, N, S.
3-Am in oca r bon ylm eth yl-2-im in o-6-tr iflu or om eth oxy-
ben zoth ia zolin e (52): mp 228 °C; 1H NMR δ (200 MHz,
DMSO-d6) 4.53 (bb, 2H, NCH2CO), 6.96 (d, 1H, J ) 8.5 Hz,
4-H), 7.20 (bd, 1H, J ) 8.5 Hz, 5-H), 7.25 and 7.65 (two bb,
1H each, CONH2), 7.60 (bs, 1H, 7-H), 8.45 (bb, 1H, dNH); MS
m/e 291 (M+), 220 (100). Anal. (C10H8F3N3O2S) C, H, F, N, S.
3-Die t h yla m in oc a r b on ylm e t h yl-2-im in o-6-t r iflu o-
r om eth oxy-ben zoth ia zolin e Hyd r och lor id e (53): mp 223
°C; 1H NMR δ (250 MHz, DMSO-d6) 1.05 and 1.32 (t, 1H each,
J ) 7 Hz, CON(CH2CH3)2, 3.31 and 3.49 (q, 2H each, J ) 7
Hz, CON(CH2CH3)2), 5.55 (s, 2H, NCH2CO), 7.57 (bd, 1H, 5-H),
7.62 (d, 1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 10.6-11.6 (m,
2H, dNH‚HCl); MS m/e 347 (M+), 113 (100). Anal. (C14H16F3N3-
O2S‚lHCl) C, H, Cl, F: calcd, 14.85; found, 14.30; N, S.
3-Meth ylth iom eth yl-2-im in o-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r och lor id e (59): mp 170 °C (sublimes); 1H
NMR δ (200 MHz, DMSO-d6) 2.2 (s, 3H, SCH3), 5.76 (s, 2H,
NCH2S), 7.6 (bd, 1H, 5-H), 7.91 (d, 1H, J ) 9 Hz, 4-H), 8.2
(bs, 1H, 7-H), 10.85-11.4 (m, 2H, dNH‚HCl); MS m/e 294 (M+),
247 (100). Anal. (C10H9F3N2OS2‚HCl) C, H, Cl, F, N, S.
3-(2-Eth ylth io-eth yl)-2-im in o-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r och lor id e (62): mp 160 °C (sublimes); 1H
NMR δ (200 MHz, DMSO-d6) 1.12 (t, 3H, J ) 7.5 Hz,
SCH2CH3), 2.65 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.93 (t, 2H, J
) 7 Hz, CH2S), 4.61 (t, 2H, J ) 7 Hz, NCH2), 7.58 (bd, 1H,
5-H), 7.8 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, 1H, 7-H), 10.2-11.4
(m, 2H, dNH‚HCl); MS m/e 322 (M+), 234 (100). Anal.
(C12H13F3N2OS2‚HCl) C, H, Cl, F, N, S.
Compounds 41-50, 52, 53, 59, 62, 63, 67, 73-75 were
prepared from 1 in the same way as 61 using the appropriate
alkylating reagents. Compounds 82 and 83 were prepared from
22 and 2, respectively.
2-Im in o-3-m e t h yl-6-t r iflu or om e t h oxy-b e n zot h ia zo-
lin e (41): mp 60-62 °C; 1H NMR δ (200 MHz, DMSO-d6) 3.41
(s, 3H, NCH3), 7.2 (d, 1H, J ) 9 Hz, 4-H), 7.31 (bd, 1H, 5-H),
7.7 (bs, 1H, 7-H); MS m/e 248 (M+), 220 (100). Anal. (C9H7F3N2-
OS) C, H, F: calcd, 22.96; found, 22.08; N, S.
3-E t h yl-2-im in o-6-t r iflu or om et h oxy-b en zot h ia zolin e
Hyd r och lor id e (42): mp 234 °C; 1H NMR δ (200 MHz,
DMSO-d6) 0.8 (t, 3H, J ) 7 Hz, NCH2CH3), 4.42 (q, 2H, J ) 7
Hz, NCH2CH3), 7.6(bd, 1H, 5-H), 7.85 (d, 1H, J ) 9 Hz, 4-H),
8.2 (bs, 1H, 7-H), 11.3-12.7 (m, 2H, NH‚HCl); MS m/e 262
(M+), 234 (80),165 (100). Anal. (C10H9F3N2OS‚HCl) C, H, Cl,
F, N, S.
2-Im in o-3-p r op yl-6-t r iflu or om e t h oxy-b e n zot h ia zo-
1
lin e Hyd r och lor id e (43): mp 231 °C dec; H NMR (base) δ
(200 MHz, DMSO-d6) 0.91 (t, 3H, J ) 7.5 Hz, NCH2CH2CH3),
1.62 (m, 2H, NCH2CH2CH3), 3.86 (t, 2H, J ) 7.5 Hz, NCH2-
CH2CH3), 7.1 (d, 1H, J ) 9 Hz, 4-H), 7.2 (bd, 1H, 5-H), 7.58
(bs, 1H, 7-H), 8.4 (bs, 1H, NH); MS m/e 276 (M+), 234 (100),
165 (80). Anal. (C11H11F3N2OS‚HCl) C, H, Cl, N, S.
3-Bu t yl-2-im in o-6-t r iflu or om et h oxy-b en zot h ia zolin e
Hyd r obr om id e (44): mp 243 °C; 1H NMR δ (200 MHz,
DMSO-d6) 0.9 (t, 3H, J ) 7.5 Hz, NCH2CH2CH2CH3), 1.38 (m,
2H, NCH2CH2CH2CH3), 1.63 (m, 2H, NCH2CH2CH2CH3), 4.29
(t, 2H, J ) 7.5 Hz, NCH2CH2CH2CH3), 7.6 (bd, 1H, 5-H), 7.86
(d, 1H, J ) 9 Hz, 4-H), 8.21 (bs, 1H, 7-H), 10.0-10.8 (m, 2H,
dNH‚HBr); MS m/e 290 (M+), 234 (100), 165 (85). Anal.
(C12H13F3N2OS‚HBr) C, H, Br, F, N, S.
2-Im in o-3-(2-pr opylth io-eth yl)-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r och lor id e (63): mp 187 °C; 1H NMR δ
(200 MHz, DMSO-d6) 0.87 (t, 3H, J ) 7.5 Hz, SCH2CH2CH3),
1.47 (m, 2H, SCH2CH2CH3), 2.56 (t, 2H, J ) 7 Hz, SCH2CH2-
CH3), 2.91 (bt, 2H, J ) 7 Hz, NCH2CH2S), 4.56 (t, 2H, J ) 7

2838 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
J imonet et al.
Hz, NCH2CH2S), 7.6 (bd, 1H, 5-H), 7.8 (d, IH, J ) 9 Hz, 4-H),
8.16 (bs, 1H, 7-H), 10.5-11.5 (m, 2H, dNH‚HCl); MS m/e 336
(M+), 234 (100). Anal. (C13H15F3N2OS2-HCl) C, H, Cl, F, N,
S.
2-Im in o-3-(2-ph en ylth io-eth yl)-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r och lor id e (67): mp 174 °C; 1H NMR δ
(200 MHz, DMSO-d6) 3.5 (t, 2H, J ) 6.5 Hz, NCH2CH2S), 4.65
(t, 2H, J ) 6.5 Hz, NCH2CH2S), 7.15 (m, 5H, ArH), 7.49 (bd,
1H, 5-H), 7.6 (d, 1H, J ) 9 Hz, 4-H), 8.02 (bs, 1H, 7-H), 10.5-
11.5 (m, 2H, dNH‚HCl); MS m/e 371 (M+), 234 (90), 136 (100).
Anal. (C16H13F3N2OS2‚HCl) C, H, Cl, F, N, S.
3-(2-Dim eth ylam in o-eth yl)-2-im in o-6-tr iflu or om eth oxy-
ben zoth ia zolin e Dih yd r och lor id e (73): mp 200 °C (sub-
limes); 1H NMR δ (200 MHz, DMSO-d6) 2.92 (s, 6H, N(CH3)2),
3.5 (t, 2H, J ) 6 Hz, NCH2CH2NMe2), 4.85 (t, 2H, J ) 6 Hz,
NCH2CH2NMe2), 7.51 (bd, 1H, 5-H), 8.18 (d, 1H, J ) 9 Hz,
4-H), 8.2 (bs, 1H, 7-H), 10.7-11.7 (m, 3H, dNH‚HCl and NR3‚
HCl); MS m/e (CI+) 306 (M + 1+). Anal. (C12H14F3N3OS‚2HCl)
C: calcd, 38.11; found, 38.70; H, Cl, F, N, S.
2-Im in o-3-(2-piper idin o-eth yl)-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Dih yd r och lor id e (74): mp 200 °C (sublimes);
1H NMR δ (200 MHz, DMSO-d6) 1.3-2.0 (m, 6H, H-piperidine),
3.15 and 3.47 (m, 2H and 4H, N(piperidine)-CH2), 4.88 (t, 2H,
J ) 6.5 Hz, NCH2CH2N(piperidine, 7.6 (bd, 1H, 5-H), 8.07 (bs,
1H, 7-H), 8.24 (d, 1H, J ) 9 Hz, 4-H), 10.5-11.5 (m, 3H, d
NH‚HCl and NR3‚HCl); MS m/e 346 (M+), 111 (70), 98 (100);
Anal. (C15H18F3N3OS‚2HCl) C, H, Cl, F, N, S.
melt at 220 °C (mp of tosylate of 97). 100: 1H NMR δ (200
MHz, DMSO-d6) 2.37 (s, 3H, ArCH3), 4.57 (t, 1H, J ) 5 Hz,
CH2OTos), 4.80 (t, 1H, J ) 5 Hz, NCH2, 7.16 and 7.32 (2d, 2H
each, J ) 8 Hz, ArH), 7.68 (bd, 1H, J ) 8.5 Hz, 5-H), 7.98 (d,
1H, J ) 8.5 Hz, 4-H), 8.25 (bs, 1H, 7-H); MS m/e 528 (M+), 91
(100).
To a stirred solution of 100 (6.9 g, 13 mmol) in 100 mL of
dimethylfonnamide were added NaHCO3 (1.1 g, 13 mmol) and
N-phenylpiperazine (2.4 g, 14 mmol). The mixture was heated
to 80 °C overnight. After cooling, the reaction mixture was
concentrated to dryness in vacuo, and water was added to the
yellow residue. Extraction of the organic phase with ethyl
acetate gave the pure trifluoroacetylated precursor of 80 after
purification by flash chromatography using 80:20 EtOAc/
cyclohexane as eluent (2.4 g, 36%): mp 88 °C; 1H NMR δ (400
MHz, DMSO-d6) 3.00-4.00 (m, 10H, N(piperazine)-CH2), 5.00
(m, 2H, NCH2CH2N(piperazine)), 6.90 (t, 1H, J ) 7.5 Hz, 4′-
ArH), 7.00 (d, 2H, J ) 7.5 Hz, 2′-ArH), 7.33 (t, 2H, J ) 7.5
Hz, 3′-ArH), 7.74 (bd, 1H, J ) 8.5 Hz, 5-H), 8.22 (d, 1H, J )
8.5 Hz, 4-H), 8.30 (bs, 1H, 7-H), 11.00 (bs, 1H, NR3‚HCl); MS
m/e 518 (M+), 132 (100).
A solution of the protected compound prepared above (1.06
g, 1.9 mmol) in a mixture of saturated aqueous K2CO3 (12 mL)
and methanol (50 mL) was stirred at room temperature for 5
h. Methanol was then removed under reduced pressure and
the organic phase extracted with EtOAc. EtOAc was evapo-
rated and the crude product transformed into HCl salt to give
80 (0.78 g, 89%): mp 230 °C; 1H NMR δ (400 MHz, DMSO-d6)
3.0-3.5 (m, 10H, N(piperazine)-CH2), 4.67 (m, 2H, NCH2-
CH2N(piperazine)), 6.83 (t, 1H, J ) 7.5 Hz, ArH), 6.99 (d, 2H,
J ) 7.5 Hz, ArH), 7.25 (t, 2H, J ) 7.5 Hz, ArH), 7.56 (bd, 1H,
5-H), 7.96 (d, 1H, J ) 9 Hz, 4-H), 8.1 (bs, 1H, 7-H), 10.0-11.5
(m, 2H, dNH‚HCl); MS m/e 422 (M+), 188 (95), 132 (100);
(FAB+) 423 (M + 1+); Anal. (C20H21F3N4OS‚1HCl) C, H, Cl, F,
N, S.
3-(3-D im e t h y la m in o -p r o p y l)-2-im in o -6-t r iflu o r o -
m eth oxy-ben zoth ia zolin e Oxa la te (75): mp 218 °C; 1H
NMR δ (200 MHz, DMSO-d6) 2.05 (m, 2H, NCH2CH2CH2-
NMe2), 2.76 (s, 6H, N(CH3)2), 3.14 (t, 2H, J ) 6 Hz, CH2NMe2),
4.12 (t, 2H, J ) 6 Hz, NCH2CH2CH2NMe2), 7.38 (bd, 1H, 5-H),
7.48 (d, 1H, J ) 9 Hz, 4-H), 7.81 (bs, 1H, 7-H); MS m/e 319
(M+), 248 (100); Anal. (C13H16F3N3OS‚1.6C2H2O4) C, H, F:
calcd, 12.54; found, 11.90; N, S.
3-(2-Dim eth yla m in oeth yl)-2-im in o-ben zoth ia zolin e Di-
Compounds 69 and 81 were prepared from 96 following an
analogous synthetic pathway.
1
h yd r och lor id e (82): mp 200 °C (sublimes); H NMR δ (200
MHz, DMSO-d6) 2.90 (s, 6H, N(CH3)2), 3.50 (CH2NMe2, this
signal is overlapped by DOH signal of (CD3)2SO), 4.82 (bt, 2H,
J ) 7.5 Hz, NCH2), 7.42 and 7.58 (2t, 1H each, J ) 8 Hz, 5-H
and 6-H), 8.00 and 8.05 (2d, 1H each, J ) 8 Hz, 4-H and 7-H),
10.50-11.60 (very bb, 3H, dNH‚HCl and NR3‚HCl); MS m/e
221 (M+), 71 (100). Anal. (C11H15N3S‚2.0HCl) C, H, Cl, N, S.
6-ter t-Bu tyl-3-(2-dim eth ylam in oeth yl)-2-im in o-ben zoth i-
a zolin e Dih yd r och lor id e (83): mp 200 °C (sublimes); 1H
NMR δ (200 MHz, DMSO-d6) 1.32 (s, 9H, C(CH3)3), 2.92 (s,
6H, N(CH3)2), 3.50 (bb, 2H, NCH2CH2NMe2), 4.87 (bb, 2H,
NCH2CH2NMe2), 7.60 (bd, 1H, J ) 8.5 Hz, 5-H), 8.05 (bd, 1H,
J ) 8 Hz, 4-H), 8.10 (bs, 1H, 7-H), 11.25 (bb, 2H, dNH‚HCl);
MS m/e 277 (M+), 71 (100). Anal. (C15H23N3S‚2.0HCl) C: calcd,
51.42; found, 50.7; H, Cl, N, S.
3-(3-Met h ylt h io-p r op yl)-2-im in o-6-t r iflu or om et h oxy-
ben zoth ia zolin e Hyd r och lor id e (69): mp 181 °C; 1H NMR
δ (400 MHz, DMSO-d6) 1.98 (m, 2H, NCH2CH2CH2SMe), 2.06
(s, 3H, SCH3), 2-64 (t, 2H, J ) 7 Hz, NCH2CH2CH2SMe), 4.42
(t, 2H, J ) 7 Hz, NCH2CH2CH2SMe), 7.6 (bd, 1H, 5-H), 7.83
(d, 1H, J ) 9 Hz, 4-H), 8.17 (bs, 1H, 7-H), 10.5-11.2 (m, 2H,
dNH‚HCl); MS m/e 321 (M+), 248 (100), 220 (90). Anal.
(C12H13F3N2OS2‚HCl) C, H, Cl, F, N.
2-Im in o-3-(3-(4-p h en yl-1-p ip er a zin yl)p r op yl)-6-tr iflu o-
r om eth oxy-ben zoth ia zolin e Dih yd r och lor id e (81): mp
260 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.25 (m, 2H,
NCH2CH2CH2N(piperazine)), 3.1-3.95 (m, 10H, N(piperazine)-
CH2, 4.52 (t, 2H, J ) 7 Hz, NCH2CH2CH2N(piperazine)), 6.88
(t, 1H, J ) 7.5 Hz, ArH), 7.01 (d, 2H, J ) 7.5 Hz, ArH), 7.28
(t, 2H, J ) 7.5 Hz, ArH), 7.63 (bd, 1H, 5-H), 7.99 (d, 1H, J )
9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 10.8-11.3 (m, 3H, dNH‚HCl
and NR3‚HCl); MS m/e 304 (70), 248 (80), 201 (65), 173 (100),
132 (95), 106 (90); (CI+) 437 (M + 1+); Anal. (C21H23F3N4OS‚
2HCl) C: calcd, 49.51; found, 48.7; H, Cl, F, N, S.
Meth od G. 2-Im in o-3-[2-(4-ph en yl-1-piper azin yl)-eth yl]-
6-tr iflu or om eth oxy-ben zoth ia zolin e Hyd r och lor id e (80).
Ethyl trifluoroacetate (17 g, 0.12 mol) was added slowly to a
stirred suspension of 3-(2-hydroxy-ethyl)-2-imino-6-trifluo-
romethoxy-benzothiazoline 5824 (27.8 g, 0.1 mol) and triethyl-
amine (1 6 mL, 0.11 mol) in 200 mL of absolute ethanol at
room temperature. The reaction mixture was stirred overnight
at room temperature. The solvent was then removed, and the
solid residue dissolved in boiling ethanol/water (1:1); the
solution was cooled, and the white precipitate was collected
and washed with the same solvent to provide the trifluoro-
3-(3-Hyd r oxyp r op yl)-2-im in o-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r obr om id e (96). Compound 96 was pre-
pared from 6-trifluoromethoxy-2-benzothiazolamine, following
1
method F: mp 181 °C; H NMR δ (200 MHz, DMSO-d6) 1.90
(m, 2H, NCH2CH2CH2OH), 3.50 (t, J ) 6 Hz, 2H, NCH2-
CH2CH2OH), 4.35 (t, 2H, J ) 6 Hz, N-CH2CH2CH2OH), 7.60
(bd, 1H, J ) 8 Hz, 5-H), 7.82 (bd, 1H, J ) 8 Hz, 4-H), 8.22 (bs,
1H, 7-H), 10.0-10.3 (bb, 2H, dNH‚HBr); Anal. (C11H11F3N2O2S‚
HBr) C, H, Br, F, N, S.
1
acetylated compound 59 (32 g, 85%): mp 141 °C; H NMR δ
(200 MHz, DMSO-d6) 3.85 (bq, 2H, J ) 5 Hz, NCH2CH2OH),
4.60 (bt, 2H, J ) 5 Hz, NCH2CH2OH), 5.00 (bt, 1H, NCH2-
CH2OH), 7.66 (bd, 1H, J ) 8.5 Hz, 4-H), 8.03 (d, 1H, J ) 8.5
Hz, 4-H), 8.25 (bs, 1H, 7-H); MS m/e 374 (M+), 45 (100).
The imino-protected alcohol 98 (53 g, 0.14 mol) was added
slowly to an ice-cooled solution of p-toluenesulfonyl chloride
in 120 mL of dry pyridine. The reaction mixture was stirred
overnight at room temperature. The solution was then poured
onto ice and acidified to pH 4 with concentrated HCl. The
resulting solid was collected and washed several times with
water to give 100 (68 g, 90%), mp 145 °C, then solidified to
Meth od H. 3-[2-(4-p h en yl-1-p ip er id in yl)-eth yl]-6-tr i-
flu or om eth oxy-2-im in o-ben zoth ia zolin e (39). 4-Trifluo-
romethoxy-aniline (88.5 g, 0.5 mol) and 2-bromo-ethanol (31.2
g, 0.25 mol) were heated at 160 °C for 1.5 h. After cooling, the
mixture was suspended in 200 mL of CH2Cl2, and the resulting
solid was collected to provide the hydrobromide of the starting
material (44.1 g). The filtrate was evaporated in vacuo to give
74 g of an oily residue which was purified by flash chroma-

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2839
tography (EtOAc/cyclohexane 40:60) to give the alcohol 102
(26.8 g, 49%) as a yellow oil.
Met h od I. 3-[2-(Am in osu lfon yl)et h yl]-2-im in o-6-t r i-
flu or om eth oxy-ben zoth ia zolin e Hyd r och lor id e (54). A
solution of ethenesulfonyl fluoride28 (11.9 g, 0.108 mol) in DMF
(10 mL) was added dropwise to a solution of 4-trifluo-
romethoxy-aniline (19.14 g, 0.108 mol) in 20 mL of DMF. The
mixture was stirred at room temperature for 2 h, and the
solution was poured into water (300 mL). The mixture was
extracted with Et2O (3 × 100 mL), and the combined extracts
were washed with water (2 × 100 mL) and then dried (MgSO4)
and evaporated to lead to the sulfonyl fluoride 108 as an
orange oil (25.8 g, 75%): 1H NMR δ (400 MHz, CDCl3) 3.57
(m, 2H, CH2SO2F), 3.77 (t, 2H, J ) 6.5 Hz, NCH2), 4.05 (very
bb, 1H, NH), 6.56 (d, 2H, J ) 8.5 Hz, 3,5-ArH), 7.08 (d, 2H, J
) 8.5 Hz, 2,6-ArH).
This sulfonyl fluoride (8.6 g, 0.03 mol) was dissolved in
acetone (20 mL) and added dropwise to a refluxing mixture of
8 N NH4OH solution (30 mL, 8 molar equiv) and acetone (30
mL). After 1 h at the same temperature, the acetone was
removed in vacuo and the mixture extracted with EtOAc (2 ×
50 mL). The combined extracts were dried (MgSO4), filtered,
and concentrated under vacuum. The residue obtained was
purified by flash chromatography on silica gel, using 50%
EtOAc/cyclohexane as eluent, to give the sulfonamide 109 (R
) NH2) as a colorless oil (5.45 g, 64%): 1H NMR δ (200 MHz,
CDCl3) 3.37 (t, 2H, J ) 6.5 Hz, CH2SO2NH2), 3.63 (bm, 2H,
NCH2), 4.39 (bb, 1H, NH), 5.16 (bb, 2H, SO2NH2), 6.58 (d, 2H,
J ) 8.5 Hz, 3,5-ArH), 7.05 (bd, 2H, J ) 8.5 Hz, 2,6-ArH).
This sulfonamide (4.12 g, 0.0144 mol) was dissolved in acetic
acid (20 mL) at room temperature. KSCN (5.6 g, 0.0577 mol)
was added all at once, and then a solution of bromine (2.3 g,
0.0144 mol) in acetic acid (10 mL) was added dropwise (15
min). The reaction mixture was stirred overnight at room
temperature, then diluted with water (30 mL), and treated
with 30% NaOH. The orange precipitate was filtered and then
washed with methanol. The methanolic solution was concen-
trated to dryness and the solid residue solubilized in EtOH/
Et2O and treated with HCl in Et2O (3.6 mL of 4.2 N solution)
to give the expected sulfonamide 54 as a colorless solid (2.9 g,
53%): mp 225 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6)
3.61 (bt, 2H, J ) 6 Hz, CH2SO2NH2), 4.81 (bt, 2H, J ) 6 Hz,
NCH2), 7.39 (bb, 2H, NH2), 7.63 (bd, 1H, J ) 8.5 Hz, 5-H),
7.81 (d, 1H, J ) 8.5 Hz, 4-H), 8.21 (bs, 1H, 7-H), 11.00 (2bb,
2H, dNH‚HCl); MS m/e 341 (M+), 234 (100). Anal. (C10H10F3-
N3O3S2.HCl) C: calcd, 31.79; found, 31.30; H, Cl, F, N, S.
Compounds 55 and 56 were prepared from 108 as described
for 54, using the appropriate amine.
To an ice-cooled and stirred solution of the alcohol 102 (20.9
g, 0.095 mol) and Et3N (26.7 mL, 0.19 mol) in 200 mL of CH2-
Cl2 was added dropwise p-toluenesulfonyl chloride (36.2 g, 0.19
mol). The mixture was stirred for 1.5 h at 0 °C and then
allowed to reach ambient temperature. After dilution with 200
mL of CH2Cl2, the organic phase was washed with water, dried
(MgSO4), and evaporated to give 48.4 g of an oily residue which
was crystallized in absolute ethanol. This gave the ditosylate
103 (27.6 g, 55%) as a white solid, mp 88 °C.
A stirred solution of the ditosylate 103 (7.2 g, 13.6 mmol),
NaHCO3 (2.4 g, 28.6 inmol), and 4-phenylpiperidine (4.85 g,
28.6 mmol) in 50 mL of DMF was heated at 80 °C overnight
(ca. 18 h). The solvent was evaporated in vacuo and the residue
washed twice with water. The crude product was added to a
solution of concentrated HCl (30 mL), acetic acid (30 mL), and
water (20 mL), and the mixture was heated at 110 °C for 3 h.
After cooling, the reaction mixture was poured into 100 mL of
water and treated by aqueous K2CO3. The resulting solid was
collected and recrystallized in 2-propanol to give 106 (6.2 g,
85%) as the p-toluenesulfonate salt, mp 176 °C.
To a suspension of the substituted aniline 106 (2.96 g, 8.12
mmol), obtained by treatment of the p-toluenesulfonate salt
with 1 N NaOH, and KSCN (3.17 g, 32.5 mmol) in acetic acid
(15 mL), a solution of bromine (1.29 g, 8.12 mmol) in acetic
acid (15 mL) was added dropwise. The reaction was allowed
to continue overnight at room temperature. The mixture was
poured into 100 mL of water, neutralized by 30% NaOH
solution, and then extracted twice with EtOAc (200 mL). The
extracts were dried and concentrated in vacuo to give 3.0 g of
crude product. The dark oily residue was purified by flash
chromatography using EtOAc as eluent to afford 78 (2.06 g,
60%) transformed into diHCl salt in Et2O: mp 220 °C
(sublimes); 1H NMR δ (200 MHz, DMSO-d6) 1.95-2.25(m, 4H,
piperidine-CH2), 2.9 (m, 1H, piperidine-CH), 3.27 (m, 2H,
piperidine-axial NCH2), 3.55 (bt, 2H, J ) 7 Hz, NCH2CH2-
piperidine), 3.68 (bd, 2H, J ) 12.5 Hz, piperidine-equatorial
NCH2), 4.91 (bt, 2H, J ) 7 Hz, NCH2CH2piperidine), 7.15-
7.4 (m, 5H, ArH), 7.55 (bd, 1H, 5-H), 8.1 (bs, 1H, 7-H), 8.2(d,
1H, J ) 9 Hz, 4-H), 11.35 (m, 2H, dNH‚HCl); MS m/e 421
(M+), 187 (100), 174 (80). Anal.(C21H22F3N3OS‚2HCl) C, H, Cl,
F, N, S.
Compounds 76, 77, and 79 were prepared following an
analogous synthetic pathway.
3-[2-(N-b en zyl-N-m et h yl-a m in o)et h yl]-2-im in o-6-t r i-
flu or om eth oxy-ben zoth ia zolin e Hyd r och lor id e (76): mp
2-Im in o-3-[2-(m eth yla m in osu lfon yl)eth yl]-6-tr iflu or o-
m eth oxy-ben zoth ia zolin e Hyd r och lor id e (55): mp 242 °C;
1H NMR δ (400 MHz, DMSO-d6) 2.64 (d, 3H, J ) 5 Hz, SO2-
NHCH3), 3.62 (t, 2H, J ) 6.5 Hz, CH2SO2, 4.74 (t, 2H, J ) 6.5
Hz, NCH2), 7.53 (q, 1H, J ) 5 HZ, SO2NHCH3), 7.63 (bd, 1H,
J ) 8.5 Hz, 5-H), 7.75 (d, 1H, J ) 8.5 Hz, 4-H), 8.17 (bs, 1H,
7-H); MS m/e 355 (M+), 234 (100). Anal. (C11H12F3N3O3S2‚HCl)
C, H, Cl, F, N, S.
1
180 °C; H NMR δ (200 MHz, DMSO-d6) 2.55 (s, 3H, NCH3),
3.05 (m, 2H, CH2N(Me)benzyl), 3.96 (bs, 2H, NCH2Ph), 4.63
(m, 2H, NCH2CH2N(Me)benzyl), 7.27 (m, 5H, ArH), 6.8-7.5
(m, 2H, dNH‚HCl), 7.44 (bd, 1H, 5-H), 7.74 (d, 1H, J ) 9 Hz,
4-H), 8.07 (bs, 1H, 7-H); MS m/e (CI+) 382 (M + 1+). Anal.
(C18H18F3N3OS‚1HCl) C: calcd, 51.74; found, 51.0; H, Cl, F,
N, S.
3-[2-(Dim eth yla m in osu lfon yl)eth yl]-2-im in o-6-tr iflu o-
r om eth oxy-ben zoth ia zolin e (56): mp 140 °C; 1H NMR δ
(200 MHz, DMSO-d6) 2.81 (s, 6H, SO2N(CH3)2), 3.43 (t, 2H, J
) 7 Hz, CH2SO2NMe2), 4.28 (t, 2H, J ) 7 Hz, NCH2), 7. 11 (d,
1H, J ) 8.5 Hz, 4-H), 7.27 (bd, 1H, J ) 8.5 Hz, 5-H), 7.61 (bs,
1H, 7-H), 8.61 (s, 1H, dNH); MS m/e 369 (M+), 234 (100). Anal.
(C12H14F3N3O3S2) C, H, F, N, S.
2-(2-Im in o-6-t r iflu or om e t h oxy-3-b e n zot h ia zolin yl)-
eth a n esu lfon ic Acid (57), The sulfonyl fluoride 108 (7.0 g,
0.024 mol) was dissolved in glacial acetic acid (30 mL) and
heated under reflux for 40 h. After the mixture cooled, the
colorless needles were filtered, washed with water, and dried
to give the expected sulfonic acid 109 (R ) OH) (2.0 g, 29%):
mp 220 °C; 1H NMR δ (400 MHz, DMSO-d6) 2.85 (t, 2H, CH2-
SO3), 3.50 (t, 2H, CH2N), 7.3 (d, 2H, J ) 8 Hz, ArH), 7.4 (d,
2H, J ) 8 Hz, ArH), 9.3 (bs, NH + SO3H + H2O); MS m/e 285
(M+), 190 (100).
2-Im in o-3-[2-(N-m et h yl-N-p h en et h yl-a m in o)et h yl]-6-
tr iflu or om eth oxy-ben zoth ia zolin e Dih yd r och lor id e (77):
mp 216 °C; H NMR δ (200 MHz, DMSO-d6) 3.02 (s, 3H, N +
CH3), 3.0-3.55 (m, 4H, N + (Me)CH2CH2Ph), 3.61 (t, 2H, J )
6 Hz, NCH2CH2N + (Me) (CH2)2Ph), 4.94 (t, 2H, J ) 6 Hz,
NCH2CH2N + (Me)CH2CH2Ph), 7.34 (m, 5H, ArH), 7.2-7.5
(m, 1H, NR3‚HCl), 7.64 (bd, 1H, 5-H), 8.2 (bs, 1H, 7-H), 8.23
(d, 1H, J ) 9 Hz, 4-H), 10.9-11.9 (m, 2H, dNH‚HCl); MS m/e
(CI+) 396 (M + 1+). Anal. (C199H20F3N3OS‚2HCl) C, H, Cl, F,
N, S.
1
2-Im in o-3-[2-(4-p h en yl-1,2,3,6-t et r a h yd r o-1-p yr id yl)-
eth yl]-6-tr iflu or om eth oxy-ben zoth ia zolin e Dih yd r och lo-
1
r id e (79): mp 256 °C; H NMR δ (300 MHz, DMSO-d6) 2.9
(m, 2H, 3-pyridyl-CH2), 3.65 (m, 4H, NCH2CH2N + pyridyl and
2-pyridyl-CH2), 4.12 (m, 2H, 6-pyridyl-CH2), 4.95 (t, 2H, NCH2-
CH2N + pyridyl), 6.27 (bs, 1H, CH2CH‚C(Ph), 7.3-7.6 (m, 5H,
ArH), 7.0-7.9 (m, 1H, NR3‚HCl), 7.6 (bd, 1H, 5-H), 8.19 (bs,
1H, 7-H), 8.25 (d, 1H, J ) 9 Hz, 4-H), 10.9-11.9 (m, 2H, d
NH‚HCl); MS m/e 419 (M+), 185 (100). Anal. (C21H20F3N3OS‚
2HCl) C, H, Cl, F, N, S.
This sulfonic acid (1.8 g, 0.0063 mol) was dissolved in glacial
acetic acid (20 mL). KSCN (2.46 g, 0.025 mol) was added all
at once to this solution, followed by a dropwise addition of a

2840 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
J imonet et al.
solution of bromine (1.0 g, 0.0063 mol) in acetic acid (10 mL).
The mixture was then stirred overnight at room temperature,
then diluted with water (30 mL) and treated with 30% NaOH.
After acidification with 1 N HCl, the precipitate was filtered,
washed with water, and dried. Recrystallization in methanol
gave the expected benzothiazoline sulfonic acid 57 as a yellow
powder (1.05 g, 49%): mp >260 °C; 1H NMR δ (200 MHz,
DMSO-d6) 2.97 (bt, 2H, J ) 6 Hz, NCH2CH2SO3H), 4.51 (bt,
2H, J ) 6 Hz, NCH2CH2SO3H), 7.61 (bd, 1H, J ) 8.5 Hz, 5-H),
7.80 (d, 1H, J ) 8.5 Hz, 4-H), 8.11 (bs, 1H, 7-H), 10.20 (bb,
2H, dNH‚HCl); MS m/e (CI+) 360 (M + NH4+), 343 (M + 1+).
Anal. (C10H9F3N2O4S2) C: calcd, 35.09; found, 34.5; H, F, N,
S.
(2-Im in o-6-t r iflu or om et h oxy-3-b en zot h ia zolin yl)a ce-
tic Acid (51). A stirred solution of 2-imino-3-methoxycarbo-
nylmethyl-6-trifluoromethoxy-benzothiazoline 50 (10.19 g,
0.026 mol) in 6 N HCl (40 mL) was heated to reflux for 20 h.
The reaction mixture was cooled to room temperature and the
precipitate filtered and washed with water. Treatment of this
solid with 1 N NaOH (60 mL), followed by recrystallization in
water (25 mL), yielded the sodium salt of the expected
compound 51 as a colorless solid (3.12 g, 28%): mp >260 °C;
1H NMR δ (200 MHz, DMSO-d6) 4.30 (bs, 2H, NCH2CO2Na),
6.83 (dd, 1H, J ) 8.5 Hz, J ′) 2 Hz, 4-H), 7.18 (bd, 1H, J ) 8.5
Hz, 5-H), 7.54 (bs, 1H, 7-H); MS m/e 234 (M - CH2CO2Na +
1+), 219 (100). Anal. (C10H6F3N2NaO3S) C, H, F, N, S.
NCH2CH2S(O)Me), 7.59 (bd, 1H, 5-H), 7.8 (d, 1H, J ) 9 Hz,
4-H), 8.13 (bs, 1H, 7H); MS m/e 324 (M+), 259 (100), 234 (95);
Anal. (C11H11F3N2O2S2-1.0HCl‚0.79H2O) C, H, Cl, F, N, S:
calcd, 17.77; found, 17.2.
Compounds 60, 68, 70, and 84-87 could be obtained from
the corresponding thioether following the same synthetic
pathway.
(R S )-2-Im in o-3-m e t h ylsu lfin ylm e t h yl)-6-t r iflu or o-
m eth oxy-2-ben zoth ia zolin e Hyd r och lor id e (60): mp 150
1
°C (sublimes); H NMR δ (200 MHz, DMSO-d6), 2.93 (s, 3H,
S(O)CH3), 5.9 (m, 2H, NCH2S(O)Me), 7.63 (bd, 1H, 5-H), 7.98
(d, 1H, J ) 9 Hz, 4-H), 8.18 (bs, 1H, 7-H), 11.35 (m, 2H, d
NH‚HCl); MS m/e 310 (M+), 247 (80); Anal. (C10H9F3N2O2S2‚
1.0HCl) C, H, Cl, F, N, S.
(R S )-2-Im in o-3-(2-p h e n ylsu lfin yle t h yl)-6-t r iflu or o-
m eth oxy-2-ben zoth ia zolin e Hyd r och lor id e (68): mp 210
1
°C; H NMR δ (200 MHz, DMSO-d6), 3.30 and 3.57 (two dt,
1H each, J ) 14 and 7.5 Hz, CH2S(O)Ph), 4.7 (t, 2H, J ) 7.5
Hz, NCH2CH2S(O)Ph), 7.4-7.8 (m, 7H, ArH, 4-H and 5-H),
8.12 (bs, 1H, 7-H), 10.5-11.5 (m, 2H, dNH‚HCl); MS m/e 386
(M+), 261 (100); Anal. (C16H13F3N2O2S2‚1.0HCl‚0.48H2O) C, H,
Cl, F, N, S.
(RS)-2-Im in o-3-(3-m et h ylsu lfin ylp r op yl)-6-t r iflu or o-
m et h oxy-2-b en zot h ia zolin e (70): mp 114 °C; 1H NMR δ
(200 MHz, CDCl3), 2.27 (m, 2H, NCH2CH2CH2S(O)Me), 2.6 (s,
3H, S(O)CH3), 2.83 (m, 2H, CH2S (O)Me), 4.07 and 4.20 (two
dt, 1H each, J ) 11 and 6 Hz, NCH2CH2CH2S(O)Me), 6.92 (d,
1H, J ) 9 Hz, 4-H), 7.11 (bd, 1H, 5-H), 7.17 (bs, 1H, 7-H); MS
m/e 338 (M+), 234 (90), 220 (100); Anal. (C12H13F3N2O2S2) C,
H, F, N, S.
2-Im in o-3-(2-m er ca p toeth yl)-6-tr iflu or om eth oxy-ben -
zoth ia zolin e Hyd r obr om id e (66). The intermediate 2-imino-
3-(2-tert-butylthioethyl)-6-trifluoromethoxy-benzothiazoline 110
(prepared following method F) was converted to 66 by a
method similar to that described for 51 (using 48% HBr
(RS)-2-Im in o-3-(2-eth ylsu lfin yleth yl)-6-tert-bu tyl-2-ben -
zoth ia zolin e (84). The corresponding thioether was obtained
by reacting the 6-tert-butyl-2-benzothiazolamine 22 with
2-chloroethyl-ethyl-sulfide, following method F: mp 100 °C;
1H NMR δ (200 MHz, DMSO-d6), 1.20 (t, 3H, J ) 6.5 Hz,
SCH2CH3), 1.30 (s, 9H, C(CH3)3), 2.60-3.30 (m, 4H, CH2-
SOCH2CH3), 4.25 (t, 2H, J ) 7 Hz, NCH2CH2SOEt), 7.05 (d,
1H, J ) 8.5 Hz, 4-H), 7.27 (dd, 1H, J ) 8.5 Hz, J ′) 1 Hz, 5-H),
7.50 (d, 1H, J ) 1 Hz, 7-H), 8.18 (bb, 1H, dNH); MS m/e 311
(M + 1+), 231 (100). Anal. (C12H13F3N2O2S2) C, H, F, N, S.
(RS)-2-Im in o-3-(2-eth ylsu lfin yleth yl)-6-n-bu tyl-2-ben -
zoth ia zolin e Hyd r och lor id e (86). The corresponding thio-
ether was obtained by reacting the 6-n-butyl-2-benzothiazol-
amine 21 with 2-chloroethyl-ethyl-sulfide, following method
F: mp 174 °C; 1H NMR δ (200 MHz, DMSO-d6), 0.90 (t, 3H, J
) 7 Hz, butyl-CH3), 1.20 (t, 3H, J ) 7.5 Hz, SCH2CH3), 1.32
(m, 2H, butyl-CH2CH3), 1.58 (m, 2H, butyl-CH2CH2CH3), 2.68
(t, 2H, J ) 7 Hz, butyl-CH2CH2CH2CH3), 2.70-3.05 (m, 2H,
SOCH2CH3), 3.15 and 3.35 (two dt, 1H each, J ) 14 and 6.5
Hz, NCH2CH2SOEt), 4.75 (t, 2H, J ) 6.5 Hz, NCH2CH2SOEt),
7.40 (bd, 1H, J ) 8.5 Hz, 5-H), 7.60 (d, 1H, J ) 8.5 Hz, 4-H),
7.82 (bs, 1H, 7-H), 10.88 (bb, 2H, dNH‚HCl); MS m/e 310 (M+),
231 (100). Anal. (C15H22N2OS2‚1.0HCl) C, H, Cl, N, O, S.
(R S )-2-I m in o -3-(2-e t h y ls u lfin y le t h y l)-6-t r iflu o r o -
m eth oxy-2-ben zoth iazolin e Hydr och lor ide (86). The start-
ing thioether was obtained by reacting 6-trifluoromethoxy-2-
benzothiazolamine with 2-chloroethyl-ethyl-sulfide, following
method F: mp 174 °C; 1H NMR δ (200 MHz, DMSO-d6), 1.20
(t, 3H, J ) 7.5 Hz, SCH2CH3), 2.60-3.05 (m, 2H, SOCH2CH3),
3.15 and 3.35 (two dt, 2H, J ) 14 and 6.5 Hz, NCH2CH2SOEt),
4.80 (t, 2H, J ) 6.5 Hz, NCH2CH2SOEt), 7.62 (bd, 1H, J ) 8.5
Hz, 5-H), 7.80 (d, 1H, J ) 8.5 Hz, 4-H), 8.20 (bs, 1H, 7-H),
10.5-11.80 (two very bb, 2H, dNH‚HCl); MS m/e 338 (M+),
234 (100). Anal. (C12H13F3N2O2S2‚1.0HCl‚0.8H2O) C, H, Cl, F,
N, S.
1
instead of 6 N HCl): yield 0.85 g (53%); mp 180 °C; H NMR
δ (300 MHz, DMSO-d6) 2.85 (dd, 2H, J ) 8 Hz, J ′ ) 7 Hz,
NCH2CH2SH), 3.07 (t, 1H, J ) 8 Hz, NCH2CH2SH), 4.45(t,
2H, J ) 7 Hz, NCH2CH2SH), 7.60 (bd, 1H, J ) 8.5 Hz, 5-H),
7.96 (d, 1H, J ) 8.5 Hz, 4-H), 8.20(bs, 1H, 7-H), 10.45 (bb, 2H,
dNH‚HBr); MS m/e 294 (M+), 234 (100). Anal. (C10H9F3N2-
OS2‚HBr) C, H, Br, F, N, S.
2-Im in o-3-(2-m et h yla m in oet h yl)-6-t r iflu or om et h oxy-
ben zoth ia zolin e Dih yd r och lor id e (72). To a stirred solu-
tion of 2-imino-3-(2-dimethylaminoethyl)-6-trifluoromethoxy-
benzothiazoline 73 (2.7 g, 0.0088 mol) and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) (1.35 g, 0.0088 mol) in CH2Cl2 at
room temperature was added dropwise vinyl chloroformate
(2.17 g, 0.020 mol), and the reaction mixture was allowed to
stand overnight at the same temperature. The precipitate was
then filtered and washed with CH2Cl2, and the filtrate was
concentrated to dryness. The residue was purified by rapid
filtration on silica gel leading to a yellow oil of the intermediate
dicarbamate (1.1 g, 29%).
After refluxing this compound with 37% HCl (2 mL) in
methanol (10 mL) for 24 h, the reaction mixture was concen-
trated to dryness and the residue recrystallized in ethanol to
give the dihydrochloride of the expected compound 72 as
1
colorless crystals (0.31 g, 33%): mp 152 °C; H NMR δ (300
MHz, DMSO-d6), 2.62 (s, 3H, NCH3), 3.4 (t, 2H, J ) 5 Hz,
NCH2CH2NHMe), 4.78 (t, 2H, J ) 5 Hz, NCH2CH2NHMe), 7.6
(bd, 1H, 5-H), 8.08 (d, 1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H),
9.49 (m, 2H, NHR2‚HCl), 10.7-11.7 (m, 2H, dNH‚HCl); MS
m/e (CI+) 292 (M + 1+). Anal. (C11H12F3N3OS‚2HCl) C, H, Cl,
F, N, S.
(R S )-2-Im in o-3-(2-m e t h ylsu lfin yle t h yl)-6-t r iflu or o-
m eth oxy-2-ben zoth ia zolin e (64): m-Chloroperbenzoic acid
(60.5 g, 0.263 mol) was added progressively to a stirred solution
of 3-(2-methylthioethyl)-6-trifluoromethoxy-2-benzothiazolimine
61 (81.3 g, 0.263 mol) in 900 mL of absolute ethanol at -35
°C. The reaction mixture was stirred for 30 min after the
addition was completed and then poured into 3 L of Et2O. To
this cold stirred solution, 65 mL of a 4 N Et2O‚HCl solution
was added dropwise. The resulting white precipitate was
filtered and purified by acid-base treatment to give 64 as
hydrochloride (72.5 g, 70%): mp 186 °C; 1H NMR δ (200 MHz,
DMSO-d6), 2.67 (s, 3H, S(O)CH3), 3.19 and 3.38 (two dt, 1H
each, J ) 14 and 6.5 Hz, CH2S(O)Me), 4.76 (t, 2H, J ) 6.5 Hz,
(RS)-2-Im in o-3-(2-eth ylsu lfin yleth yl)-6-tr iflu or om eth yl-
2-ben zoth ia zolin e Hyd r och lor id e (87). The starting thio-
ether was obtained by reacting the 6-trifluoromethyl-2-
benzothiazolamine 37 with 2-chloroethyl-ethyl-sulfide, following
method F: mp 150 °C; 1H NMR δ (200 MHz, DMSO-d6), 1.17
(t, 3H, J ) 7.5 Hz, SCH2CH3), 2.65-3.00 (m, 2H, SOCH2CH3),
3.15 and 3.35 (two dt, 2H, J ) 14 and 6.5 Hz, NCH2CH2SOEt),
4.82 (t, 2H, J ) 6.5 Hz, NCH2CH2SOEt), 7.94 (limit AB, 2H,
J ) 8.5 Hz, 4-H and 5-H), 8.50 (bs, 1H, 7-H), 11.20 (very bb,

Riluzole Series
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2841
2H, dNH‚HCl); MS m/e 322 (M+), 218 (100). Anal. (C12H13F3N2-
OS2‚1.0HCl) C, H, Cl, F, N, S.
(b) This compound (7.05 g, 0.0284 mol) and 2-chloroethyl-
ethyl-sulfide were dissolved in 2-butanone and heated under
reflux for 48 h. The reaction mixture was then cooled to room
temperature, and the precipitate was collected by filtration,
washed with the same solvent, and recrystallized from 2-pro-
panol to give 90 as a colorless powder (5.33 g, 50.3%): mp 150
2-Im in o-3-(2-m eth ylsu lfon yleth yl)-6-tr iflu or om eth oxy-
ben zoth ia zolin e Hyd r och lor id e (65). m-Chloroperbenzoic
acid (26.9 g, 0.117 mol) was added to a stirred solution of
2-imino-3-(2-methylthioethyl)-6-trifluoromethoxy-benzothiazo-
line 61 (17.8 g, 0.0577 mol) in 400 mL of CH2Cl2 at room
temperature. The reaction was allowed to continue overnight
at room temperature, and then the mixture was poured into
200 mL of Et2O. The hydrochloride was precipitated by
addition of 4 N Et2O‚HCl and the resulting solid recrystallized
in water to give 65 (17.4 g, 80%): mp >260 °C; 1H NMR δ
(200 MHz, DMSO-d6), 3.21 (s, 3H, SO2CH3), 3.75 (t, 2H, J )
6.5 Hz, NCH2CH2SO2Me), 4.83 (t, 2H, J ) 6.5 Hz, NCH2CH2-
SO2Me), 7.65 (bd, 1H, 5-H), 7.76 (d, 1H, J ) 9 Hz, 4-H), 8.2
(bs, 1H, 7-H), 10.5-11.5 (m, 2H, dNH‚HCl); MS m/e 340 (M+),
234 (100), 165 (30); Anal. (C11H11F3N2O3S2‚1.0HCl) C, H, Cl,
F, N, S.
1
°C (sublimes); H NMR δ (250 MHz, DMSO-d6) 1.14 (t, 3H, J
) 7.5 Hz, SCH2CH3), 2.65 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.93
(t, 2H, J ) 7 Hz, NCH2CH2SEt), 3.14 (s, 3H, dNCH3), 4.67 (t,
2H, J ) 7 Hz, NCH2CH2SEt), 7.63 (bd, 1H, J ) 8.5 Hz, 5-H),
7.82 (d, 1H, J ) 8.5 Hz, 4-H), 8.28 (bs, 1H, 7-H), 9.00-11.50
(very bb, 1H, dNMe‚HCl); MS m/e 336 (M+), 248 (100). Anal.
(C13H15F3N2OS2‚l.0HCl) C, H, Cl, F, N, S.
2-Eth ylim in o-3-(2-m eth ylth ioeth yl)-6-tr iflu or om eth oxy-
ben zoth ia zolin e Hyd r och lor id e (91). Compound 91 was
preprared in the same way as described for 90 using ethyl-
amine in the first step to obtain the 2-(ethylamino)-benzothia-
zole 114 and 2-chloroethyl-methyl-sulfide in the second step:
1
mp 208 °C (sublimes); H NMR δ (200 MHz, DMSO-d6) 1.35
Compounds 71, 88, and 89, starting from the corresponding
thioether 69, 120, and 121, respectively, were prepared
following the same synthetic pathway.
(t, 3H, J ) 7.5 Hz, dNCH2CH3), 2.18 (s, 3H, SCH3), 2.90 (t,
2H, J ) 7 Hz, NCH2CH2SMe), 3.55 (q, 2H, J ) 7.5 Hz, dNCH2-
CH3), 4.75 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 7.60 (bd, 1H, J )
8.5 Hz, 5-H), 7.83 (d, 1H, J ) 8.5 Hz, 4-H), 8.28 (bs, 1H, 7-H),
11.65 (bb, 1H, dNEt‚HCl); MS m/e 336 (M+), 262 (100). Anal.
(C13H15F3N2OS2‚1.0HCl) C, H, Cl, F, N, S.
2-Im in o-3-(3-m eth ylsu lfon ylpr opyl)-6-tr iflu or om eth oxy-
1
ben zoth ia zolin e Oxa la te (71): mp 180 °C; H NMR δ (200
MHz, DMSO-d6), 2.1 (m, 2H, NCH2CH2CH2SO2Me), 3.0 (s, 3H,
SO2CH3), 3.28 (m, 2H, NCH2CH2CH2SO2Me), 4.21 (t, 2H, J )
7 Hz, NCH2CH2CH2SO2Me), 7.46 (bd, 1H, 5-H), 7.56 (d, 1H, J
) 9 Hz, 4-H), 7.9 (bs, 1H, 7-H); MS m/e 354 (M+), 275 (100),
248 (60), 234 (100),165 (40); Anal. (C12H13F3N2O3S2, C2H2O4)
C, H, F, N, S.
3-(2-E t h y lt h io e t h y l)-2-m e t h o x y im in o -6-t r iflu o r o -
m eth oxy-ben zoth ia zolin e (92): (a) To a solution of thiourea
(12 g, 0.157 mol) in 1 N sulfuric acid (200 mL) was added the
2-chloro derivative 112 (25.4 g, 0.1 mol), and the yellow
suspension was heated to 60 °C. After 25 h the mixture was
cooled to room temperature, and the precipitate was collected
by filtration, washed with water and petroleum ether, and
dried to give the thiol 115 as a colorless solid (22.7 g, 90.3%):
mp 228 °C; 1H NMR δ (250 MHz, DMSO-d6) 7.35 and 7.42
(limit AB, 1H each, J ) 8.5 Hz, 4-H and 5-H, respectively),
7.87 (bs, 1H, 7-H), 13.5-14.3 (very bb, 1H, NdC-SH); MS m/e
251 (M+), 69 (100).
3-(2-E t h ylsu lfon ylet h yl)-2-im in o-6-p en t a flu or oet h yl-
ben zoth ia zolin e (88): mp 125 °C; 1H NMR δ (400 MHz,
CDCl3), 1.40 (t, 3H, J ) 7 Hz, SO2CH2CH3), 3.03 (q, 2H, J )
7 Hz, SO2CH2CH3), 3.45 (t, 2H, J ) 7.5 Hz, NCH2CH2SO2Et),
4.43 (t, 2H, J ) 7.5 Hz, NCH2CH2SO2Et), 7.15 (d, 1H, J ) 8
Hz, 4-H), 7.46 (s, 1H, 7-H), 7.48 (d, 1H, J ) 8 Hz, 5-H); MS
m/e 388 (M+), 199 (100). Anal. (C13H13F5N2O2S2) C, H, F, N, S.
The starting 3-(2-ethylthioethyl)-2-imino-6-pentafluoroethyl-
benzothiazoline (120) was prepared following method F start-
ing from the 6-pentafluoroethyl-2-benzothiazolamine 36: mp
< 50 °C; 1H NMR δ (400 MHz, CDCl3) 1.30 (t, 3H, J ) 7.5 Hz,
SCH2CH3), 2.65 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.90 (dd, 2H,
J ) 7 Hz, NCH2CH2S), 4.17 (dd, 2H, J ) 7 Hz, NCH2CH2S),
7.00 (d, 1H, J ) 8 Hz, 4-H), 7.20 (bb, 1H, dNH), 7.46 (bd + s,
2H, 5-H + 7-H).
3-(2-Eth ylsu lfon yleth yl)-2-im in o-6-p en ta flu or oeth oxy-
ben zoth ia zolin e Hyd r och lor id e (89): mp 230 °C; 1H NMR
δ (200 MHz, DMSO-d6), 1.24 (t, 3H, J ) 7.5 Hz, SO2CH2CH3),
3.30 (q, 2H, J ) 7.5 Hz, SO2CH2CH3), 3.72 (t, 2H, J ) 7 Hz,
NCH2CH2SO2Et), 4.78 (t, 2H, J ) 7 Hz, NCH2CH2SO2Et), 7.62
(bd, 1H, J ) 8.5 Hz, 5-H), 7.74 (d, 1H, J ) 8.5 Hz, 4-H), 8.16
(bs, 1H, 7-H), 11.90 (very bb, 2H, dNH‚HCl); MS m/e 404 (M+),
165 (100). Anal. (C13H13F5N2O3S2‚1.0HCl) C, H, Cl, F, N, S.
The starting 3-(2-ethylthioethyl)-2-imino-6-pentafluoro-
ethoxy-benzothiazoline hydrochloride (121) was prepared fol-
lowing method F starting from the 6-pentafluoroethoxy-2-
benzothiazolamine 35: mp 115 °C; 1H NMR δ (200 MHz,
DMSO-d6) 1.14 (t, J ) 7.5 Hz, 3H, SCH2CH3), 2.64 (q, J ) 7.5
Hz, 2H, SCH2CH3), 2.94 (bt, J ) 7 Hz, 2H, NCH2CH2S), 4.58
(bt, J ) 7 Hz, 2H, NCH2CH2S), 7.57 (bd, 9 Hz, 1H, 5-H), 7.83
(d, J ) 9 Hz, 1H, 4-H), 8.17 (bs, 1H, 7-H), 1 1.0 (bb, 2H, dNH2
+ Cl-).
(b) This thiol (22.4 g, 0.089 mol) was dissolved in DMF (90
mL) and added to a stirred and hot (100 °C) solution of 1,2-
dibromoethane (163 g, 0.86 mol) in DMF (90 mL). After 19 h
at the same temperature the mixture was cooled to 0 °C, and
the white precipitate was collected and recrystallized from a
95% aqueous solution of EtOH (450 mL) to give the tricyclic
thiazolium salt 116 (18.37 g, 57.6%): mp >260 °C; 1H NMR δ
(200 MHz, DMSO-d6) 4.28 (t, 2H, J ) 7.5 Hz, dN+CH2CH2S),
5.02 (t, 2H, J ) 7.5 Hz, dN+CH2CH2S), 7.83 and 8.18 (two bd,
1H each, J ) 8.5 Hz, 4-H and 5-H), 8.50 (bs, 1H, 7-H); MS m/e
356 (M - 1+), 278 (100). Anal. (C10H7BrF3NOS2‚0.5H2O) C,
H, Br, F, N, S.
(c) This salt (3.6 g, 0.01 mol) was added to an aqueous
solution (5 mL) of methoxylamine hydrochloride (2.5 g, 0.03
mol). This mixture was treated with 1 N NaOH (10 mL),
heated under reflux for 20 min, and then cooled, filtered, and
concentrated. The residue was added to water and extracted
with Et2O (2 × 100 mL). The combined organic extracts were
washed with water, dried (MgSO4), and evaporated to give the
thiol oxime 117 as a colorless solid (1.23 g, 37.9%): mp 70 °C;
1H NMR δ (200 MHz, DMSO-d6), 2.66 (t, 1H, J ) 8 Hz, SH),
2.80 (dd, 2H, J ) 8 and 7 Hz, NCH2CH2SH), 3.80 (s, 3H, d
NOCH3), 4.03 (t, 2H, J ) 7 Hz, NCH2CH2SH), 7.28 and 7.35
(limit AB, 2H, J ) 8.5 Hz, 5-H and 4-H, respectively), 7.72
(bs, 1H, 7-H); MS m/e 324 (M+), 233 (100).
3-(2-Eth ylth ioeth yl)-2-m eth ylim in o-6-tr iflu or om eth oxy-
ben zoth ia zolin e Hyd r och lor id e (90). (a) 2-Chloro-6-tri-
fluoromethoxy-benzothiazole55 (22.05 g, 0.087 mol) and a 40%
aqueous solution of methylamine were shaken at 110 °C in a
sealed pressure flask. After 24 h the mixture was poured into
distilled water (300 mL), and the precipitate was collected by
filtration, washed with water, and dried to give 2-methyl-
amino-6-trifluoromethoxy-benzothiazole 113 as a white solid
(19.52 g, 90.4%): mp 168 °C; 1H NMR δ (200 MHz, DMSO-d6)
2.96 (dt, 3H, NHCH3), 7.20 (dd, 1H, J ) 9 and 2 Hz, 5-H),
7.45 (d, 1H, J ) 9 Hz, 4-H), 7.80 (m, 1H, 7-H), 8.1 (bq, 0.7H,
J ) 5 Hz, NHMe); Anal. (C9H7F3N2OS) C, H, F, N, S.
(d) To a solution of 117 (1.15 g, 0.0035 mol) in EtOH (5 mL)
under an atmosphere of nitrogen was added sodium ethylate
(prepared from 0.081 g of Na in 5 mL of EtOH) followed by
ethyl bromide (0.77 g, 0.0071 mol). The resulting mixture was
stirred at room temperature overnight then evaporated to
dryness under vacuum, and the solid residue was washed with
water and recrystallized from EtOH to give 92 as a colorless
solid (0.56 g, 45.5%): mp 68 °C; 1H NMR δ (200 MHz, DMSO-
d6) 1.20 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.60 (q, 2H, J ) 7.5
Hz, SCH2CH3), 2.85 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 3.78 (s,
3H, dNOCH3), 4.02 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 7.25 (limit

2842 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15
J imonet et al.
AB, 2H, 5-H and 4-H), 7.72 (bs, 1H, 7-H); MS m/e 352 (M+),
89 (100). Anal. (C13H15F3N2O2S2) C, H, F, N, S.
the survival time for each mouse was measured. With this
material and protocol, two groups of six mice can be observed
simultaneously. Under these conditions, the mean survival
time for control mice was 230.4 ( 4.0 s. Each compound to be
tested was given to six mice per dose (2.5 mL/100 g body
weight) by intraperitoneal route (i.p.) 30 min before the
challenge. In this test, riluzole (1) displayed an ED50 of 4.0 (
0.8 mg/kg (20% variability). The same variability was observed
with the other compounds evaluated, unless otherwise stated
in Table 8 for compounds 65, 78, and 79.
3-(2-E t h y lt h io e t h y l)-2-h y d r o x y im in o -6-t r iflu o r o -
m eth oxy-ben zoth ia zolin e (93). Compound 93 was prepared,
as described above for 92, using hydroxylamine: mp 136 °C;
1H NMR δ (200 MHz, DMSO-d6) 1.22 (t, 3H, J ) 7.5 Hz,
SCH2CH3), 2.62 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.85 (t, 2H, J
) 7 Hz, NCH2CH2SEt), 4.05 (t, 2H, J ) 7 Hz, NCH2CH2SH),
7.22 (limit AB, 2H, J ) 8.5 Hz, 5-H and 4-H), 7.70 (bs, 1H,
7-H); MS m/e 338 (M+), 89 (100). Anal. (C12H13F3N2O2S2) C,
H, F, N, S.
2-Ac e t y lim in o -3-(2-m e t h y lt h io e t h y l)-6-t r iflu o r o -
m eth oxy-ben zoth ia zolin e (94). Acetyl chloride (0.46 g,
0.0058 mol) was added dropwise to a stirred solution of 61 (1.34
g, 0.0039 mol) and triethylamine (0.79 g, 0.0078 mol) in
acetone (15 mL), and the mixture was left at room temperature
overnight. Water was then added, and the white precipitate
was collected by filtration and recrystalized from refluxing
methanol to give 94: mp 110 °C; 1H NMR δ (200 MHz, CDCl
3) 2.25 (s, 3H, SCH3), 2.35 (s, 3H, dNCOCH3), 2.95 (t, 2H, J )
7.5 Hz, NCH2CH2SMe), 4.55 (t, 2H, J ) 7.5 Hz, NCH2CH2-
SMe), 7.32 (AB, 2H, 5-H and 4-H), 7.55 (bs, 1H, 7-H); MS m/e
350 (M+), 234 (100). Anal. (C13H13F3N2O2S2) C, H, F, N, S.
The authors thank C. Pauchet for some biological data, M.
Vuilhorgne, Mrs. Foucault, and co-workers for structural data
and elemental analyses, and C. Luttmann for ClogP calcula-
tions.
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zolon e (95). The tricyclic thiazolium 116 (4.35 g, 0.012 mol)
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vacuum. The residue was purified by flash chromatography
on silica gel eluting with 20% EtOAc in cyclohexane to give
95 as a yellow oil (1.13 g, 30.2%): 1H NMR δ (200 MHz,
DMSO-d6) 2.13 (s, 3H, SCH3), 2.84 (t, 2H, J ) 6.5 Hz,
NCH2CH2SMe), 4.15 (t, 2H, J ) 6.5 Hz, NCH2CH2SMe), 7.40
(bd, 1H, J ) 8.5 Hz, 5-H), 7.55 (d, IH, J ) 8.5 Hz, 4-H), 7.89
(bs, 1H, 7-H); MS m/e 309 (M+), 74 (100). Anal. (C11H10F3-
NO2S2) C, H, F, N, S.
2,3-Dih ydr o-9a -m eth ylth io-7-tr iflu or om eth oxy-th iazolo-
[2,3-b]ben zoth ia zole (119). The tricyclic thiazolium 116 (4.35
g, 0.012 mol) was added to a stirred ethanolic solution (45 mL)
of sodium methanethiolate (0.9 g, 0.012 mol). After 0.5 h at
room temperature, the precipitate was removed and the
filtrate evaporated to dryness. Recrystallization from ethanol
gave 119 as a colorless solid (1.8 g, 46.1%): mp 86 °C; 1H NMR
δ (200 MHz, DMSO-d6) 2.20 (s, 3H, SCH3), 2.90 and 3.20 (two
m, 1H each, NCH2CH2S), 3.60 and 4.61 (two m, 1H each,
NCH2CH2S), 7.13 (limit AB, 2H, J ) 8.5 Hz, 5-H and 4-H,
respectively), 7.43 (bs, 1H, 7-H); MS m/e 325 (M+), 278 (100).
Anal. (C11H10F3NOS3) C, H, F, N, S.
Glu ta m ic Acid -In d u ced Seizu r es.31 Groups of seven male
Sprague-Dawley rats per dose weighing 200 ( 20 g were used.
Drugs were injected i.p. at at least 3 concentrations (normally
1, 3, and 10 mg/kg) plus vehicle alone 30 min prior to
intracerebroventricular (icv) administration of 10 µL/rat of a
12.5 µmol/kg solution of L-glutamic acid in saline according to
a free hand technique. After this treatment, the rats were
observed for 30 min; L-glutamic acid alone provoked seizures
immediately after injection: animals ran wildly, jumped
violently, and exhibited clonic seizures. ED50 for studied
compounds was defined as the dose of drug (mg/kg) which
totally protected 50% of the rats from clonic convulsions. In
this test, riluzole (1) displayed an ED50 of 3.2 ( 0.6 mg/kg (19%
variability). A similar variability was observed with the other
evaluated compounds. The majority of compounds were tested
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