Note: Descriptions are shown in the official language in which they were submitted.
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4-?'MINOALKOXY-1,3-DIHYDROBENZOIMIDAZOL-2-THIONES DERIVATIVES, THEIR
PREPARATION AND
THEIR USE AS DOPAMINE AUTORECEPTOR (D2) AGONISTS
FIELD OF THE INVENTION
This invention relates to a novel series of compounds having potency at the
s dopamine D2 receptor which are illustrated by the following Formula I:
Y
HEN \ O~)n
b'N ~ N-R3
S R1 R2
I
I o BACKGROUND OF INVENTION
Efforts to induce antipsychotic activity with dopamine autoreceptor agonists
have
been successful (Dorsini et al., Adv. Biochem. Psychopharmacol., 16) 645-648,
1977;
Tamminga et al., Science, 200, 567-568, 1975; and Tamminga et al.) Psychiatry,
398-
15 402, 1986). A method for determining intrinsic activity at the dopamine DZ
receptor was
recently reported (I,ahti et al., Mol. Pharm., 42, 432-438, 1993) Intrinsic
activity is
predicted using the ratio of the "low-affinity agonist" (LowAg) state of the
receptor and the
"high-affinity agonist" (HighAg) state of the receptor, i.e. LowAg/HighAg.
These ratios
correlate with the agonist, partial agonist, and antagonist activities of a
given compound,
2o which activities characterize a compounds ability to elicit an
antipsychotic effect.
In accordance with this invention, there is provided a group of compounds
which
are useful antipsychotic agents essentially free from extrapyramidal side
effects (EPS). The
compounds of this invention are dopamine agonists with various degrees of
intrinsic
activity some of which are selective autoreceptor agonists, and therefore
partial agonist (i.e.
2s activate only autoreceptors versus postsynaptic D2 dopamine receptors). As
such, they
provide functional modulation of the dopamine systems of the brain without the
excessive
blockade of the postsynaptic dopamine receptors which have been observed to be
responsible for the serious side effects frequently exhibited by agents found
otherwise
clinically effective for the treatment of schizophrenia. Activation of the
dopamine
so autoreceptors results in reduced neuronal firing a well as inhibition of
dopamine synthesis
and release and therefore provide a means of controlling hyperactivity of the
dopaminergic
systems. The compounds of this invention were also found to have high
intrinsic activity
and therefore they can behave as the natural neurotransmitter, i.e., as full
agonists. As
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such, they are useful in the treatment of diseases having abnormal
concentrations of
dopamine and could be used as dopamine surrogates possibly in the treatment of
Parkinson's disease.
A literature search indicated a series of benzimidazole-2-ones have been
prepared as
s described in German Patent 2700193. In particular, CGP-12177 (Ciba Geigy,
shown
below) was found to be a (3-adrenergic receptor antagonist [J. Biol. Chem.,
258, 3496
3502, 1983].
HN 0 ~ ~t-Bu
~- NH OH
O
t o CGP-12177
BRIEF DESCRIPTION OF THE INVENTION
is The compounds of this invention are 4-aminoethoxy-1,3-dihydro-benzoimidazol-
2-thrones which are illustrated by Formula I
Y
I ~
HEN \ 0 '\)n
a...N ~ N-R3
S R~ R2
I
wherein:
Rl is hydrogen or Cl-C6 allcyl;
R2 is hydrogen or Ct-C6 alkyl;
R3 is selected from hydrogen, straight-chain and
2s branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl or
-CH~mAr where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each
optionally substituted by one or two substituents selected independently
from C,-C6 allryl, halogen, C,-C6 allcoxide and irifluoromethyl;
or NR2R3 is 1, 2, 3, 4-tetrahydroquinolin-1-yl or l, 2, 3, 4-
3o tetrahydroisoquinolin-2-yl;
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m iS 1-5;
nislor2;
Y is halogen, C,-C6 alkyl, and C,-C6 alkoxy;
. and the pharmaceutically acceptable salts thereof.
s Pharmaceutically acceptable acid addition salts have the utility of the free
base.
Such salts are prepared by methods well known to the art are formed with both
inorganic or
arganic acids including but not limited to fumaric, malefic, benzoic,
ascorbic) pamoic,
succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,
oxalic,
propionic, tartaric, salicyclic, citric) gluconic, lactic, malic, mandelic,
cinnamic, citraconic,
i o aspartic, stearic, palinitic, itaconic, glycolic, p-aminobenzoic,
glutamic, benzene-sulfonic,
hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric
acids.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I are generally prepared by the overall sequence
1 s indicated in the following Schemes I-III. Scheme I depicts the synthesis
of invention
compounds where one of R1 or R2 is hydrogen.
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Scheme I
R2
OH O/~CI
~, JN
/ NH2 / NH2 O~n ~R~
'-'~ ~ ( ---~- / NH2 ~~uoroacetic
N02 N02 ~ ~ anhydride
'N02
~ (n = 1 or 2)
O CF3 O CFs
O~N~R~ H2NNH2 O~N~R~ ThioCDI
/ ~ NH2 10% Pd/C / NH2 THF
or
N02 Raney Nickel ~ NH
ethanol
4
O CF3
~~ ~ H
O~N~R1 O~N~R~
Hn
/ N MeOH/H20 / N
HCl salt
2. HCl
N N
H
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Scheme II outlines the synthesis of an inventon compound where neither of R 1
and
R2 are hydrogen.
Scheme II
O~nN ~ Q~N /
/ NHZ H2~H2 / NH2 1. ThioCDI
NO 10% Pd/C ~ NH 2. HCl
ethanol 2
2i
o~N /
H
N
S HC1 salt
N
H
s
Scheme III illustrates a route for obtaining a chlorinated intermediate which
is used
in the synthesis of a chlorinated invention compound.
Scheme III
O ~CI ~_ ~C1
('fin
n
/ NH2 NCS~ NH2
CH3CN
NO2 N02
to ~ Z
The following synthetic procedures for intermediates and invention products
are
included for illustrative purposes only and are should not be construed as
limiting to this
i s disclosure. Those skilled in the art of organic synthesis may be aware of
other preparative
tncthods for preparing the intermediates and invention compounds. The reagents
and
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starting materials used are either commercially available or can be prepared
according to
standard literature procedures.
Intermediate la (n = 1)
2-(2-Chloroethoxy)-6-vitro-phenylamine
Method 1.
To a solution of 2-amino-3-nitrophenol (5.0 g) 32.4 mmol), triphenylphosphine
( 12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7 mmol) in tetrahydrofuran
( 120 mL)
at 0 - 5° C was added over 30 min a solution of diethyl
azodicarboxylate (8.5 g, 48.7
mmol) in tetrahydrofuran (75 mL). The mixture was warmed to 23° C and
stirred for 18
hr. The solvent was removed under vacuum to give a dark brown oil.
Purification by
chromatography (1.3 kg silica gel, 30% hexane - ethyl acetate) afforded 3.1 g
(44.2%) of
is an orange solid, mp 71-73 °C; MS (+)PBEI mle 216/218 (M+).
Elemental analysis for C8H9C1N203:
Calc'd: C, 44.36; H, 4.19; N) 12.93
Found: C, 44.45; H, 4.02; N, 12.97
Method 2.
A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-
dichloroethane
(260.0 g, 2.65 mol)) potassium carbonate (35.0 g) 0.252 mol) and 2-butanone
(750 mL)
was refluxed for 24 hr. The mixture was cooled, filtered and the solids were
washed with
2s ethyl acetate. The filtrate was concentrated to an oily residue that was
dissolved in ethyl
acetate (500 mL). The organic layer was washed with 1 N sodium hydroxide (250
mL),
water (500 mL), and brine (2X 500 mL), dried over anhydrous magnesium sulfate.
Concentration of the filtered solution and trituration of the residue with
hexane afforded
37.8 g (84.6%) of product as an orange solid, mp 71-73 °C; MS (+)PBEI
mle 216/218
(M+).
Intermediate 1 b (n=2)
2-(3-Bromo-propoxy)-6-vitro-phenylamine
Following the procedure of method 2 above and substituting 1,3-dibromopropane
for 1,2-dichloroethane, the title compound is obtained as a yellow solid,
(78.7%) mp 88_89
°C; MS EI mle 274/276 (M+).
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Elemental analysis for C9H11BrN203:
Calc'd: C, 39.29; H, 4.03; N, 10.18
Found: C, 39.71; H, 3.91; N, 10.27
Intermediate 2a
2-(2-Benzylamino-ethoxy)-6-vitro-phenylamine
to
A mixture of 2-(2-chloroethoxy)-6-vitro-phenylamine (3.0 g, 13.8 mmol) and
benzylamine (9.0 g, 84.0 mmol) was heated at 100--110° C for 6 hr. The
excess
benzylamine was removed by distillation under vacuum (70 - 75° C / 0.1
mm) . The
residue was poured into 1 N sodium hydroxide (300 mL) and extracted with ethyl
acetate
is (2X, 300 mL). The combined organic layer was washed with water (2X, 300 mL)
and
brine (300 mL). The ethyl acetate layer was dried over anhydrous magnesium
sulfate,
filtered, and the solvent removed under vacuum to give S.1 g of crude red oil.
Purification
by chromatography (500 g silica gel, ethyl acetate : 2 M NH3 in methanol, 20 :
1 ) afforded
3.54 g (89.3%) of a red semi-solid, mp 33-60 °C; MS EI mle 287 (M+).
Elemental analysis for C15H17N303:
Calc'd: C, 62.71; H, 5.96; N, 14.62
Found: C, 62.64; H, 6.04; N, 14.23
2s Using this general procedure and utilizing 2-(2-chloroethoxy)-6-vitro-
phenylamine
or 2-(3-bromo-propoxy)-6-vitro-phenylamine or 4-chloro-2-(2-chloro-ethoxy)-6-
nitro-
phenylamine and benzylamine, 4-methyl-benzylamine, 1-naphthalene-methylamine)
4-tert-
butyl-benzylamine, thiophene-2-methyl-amine, 4-chloro-benzylamine, thiophene-3-
methyl-
amine or 1,2,3,4-tetrahydroisoquinoline afforded:
?~ 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-vitro-phenylamine as a yellow
solid (89 %), mp 55-57 °C; EI mle 301 (M+).
Elemental analysis for C16H19N343:
. 3s Calc'd: C, 62.71; H) 5.96; N, 14.62
Found: C, 62.64; H, 6.04; N) 14.23
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2c 2-(3-Benzylamino-propoxy)-6-vitro-phenylamine as a viscous orange oil
(85.5 %); MS EI m/e 301 (M+).
Elemental analysis for C16H19N303:
s Calc'd: C, 63.77; H, 6.36; N, 13.94
Found: C, 63.66; H, 6.28; N, 13.89
_2~ 2-f 2-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-6-vitro-phenylamine
as a yellow solid (76.3 %), mp 66-67 °C; MS EI mle 337 (M+).
to
Elemental analysis for C19H19N3~3:
Calc'd: C, 67.64; H, 5.68; N, 12.45
Found: C, 67.20; H, 5.66; N, 12.26
15 2e 2-[2-(4-tert-Butylbenzylamino)-ethoxy]-6-vitro-phenylamine
as an orange viscous oil (83.3 %); MS EI mle 343 (M') which analyzed as the
quarter
hydrate.
Elemental analysis for C19H25N303 ' 0.25 H20:
2o Calc'd: C, 65.59; H, 7.39; N, 12.07
Found: C, 65.89; H, 7.20; N, 11.94
2f 2-[2-(4-Chloro-benzylamino)-ethoxy]-6-vitro-phenylamine as an orange
solid (87.8 %), mp 61-62 °C; MS EI mle 322/324 (M+) which analyzed as
the quarter
2s hydrate.
Elemental analysis for C15H16N3~3' 0.25 H20:
Calc'd: C, 55.22; H, 5.10; N, 12.88
3o Found: C, 55.27; H, 4.96; N, 12.88
2-(2-Benzylamino-ethoxy)-4-chloro-6-vitro-phenylamine as a orange-
brown colored solid (54.0 %), mp 87-88 °C; MS EI mle 321/323 (M+).
3s Elemental analysis for C1gH16C1N303:
Calc'd: C, 55.99; H, 5.01; N, 13.06
Found: C, 55.85; H, 4.90; N, 13.13
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~h_ 4-Chloro-2-vitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-
phenylamine as a yellow solid (44.0 %), mp 74-75 °C; MS EI mle 327/329
(M+)
s Elemental analysis for C13H14C1N302S:
. Calc'd: C, 47.67; H, 4.33; N) 12.75
Found: C, 47.54; H, 4.11; N, 13.06
2i 4-Chloro~2-vitro-6-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-
lo phenylamine as a yellow solid (33.3 %), mp 77-78 °C; MS EI mle
327/329 (M~).
Elemental analysis for C13H14C1N302S:
Calc'd: C, 47.67; H, 4.33; N, 12.75
Found: C, 47.54; H, 4.18; N, 12.80
is
2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-vitro-phenylamine
as a yellow solid (87.1 %), mp 95-97 °C; MS EI mle 313 (M').
Elemental analysis for C17H19N3p2:
2o Calc'd: C, 65.16; H, 6.11; N, 13.41
Found: C, 64.87; H, 6.11; N, 13.40
Intermediate 3a
N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide
To a solution of 2-(2-benzylamino-ethoxy)-6-vitro-phenylamine (2z, 0.5 g, 1.74
mmol) and triethylamine (0.32 mL, 3.48 mmol) in anhydrous methylene chloride (
10 mL)
3o at 23° C was added trifluoroacetic anhydride (0.32 mL, 2.26 mmol).
After 2 hr the reaction
was diluted with ether and washed with saturated sodium bicarbonate (3 x 80
mL) and the
organic layer dried over anhydrous magnesium sulfate. Filtration and
evaporation of the
solvent gave 0.55 g (81.7%) of yellow solid, mp 134-135 °C; MS EI mle
383 (M+).
3s Elemental analysis for C17H16F3N304:
Calc'd: C, 53.27; H, 4.21; N, 10.96
Found: C, 53.09; H, 4.35; N, 10.93.
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This general procedure utilizing 2-[2-(4-methyl-benzylamino)-ethoxy]-6-nitro-
phenylamine, 2-(3-benzylamino-propoxy}-6-nitro-phenylamine, 2- { 2-
[(naphthalen-1-
yhnethyl)-amino)-ethoxy }-6-nitro-phenylamine, 2-[2-(4-tent-butylbenzylamino}-
ethoxy]-6-
s nitro-phenyl-amine, 2-[2-(4-chloro-benzylamino)-ethoxy]-6-nitro-phenylamine,
2-(2-
benzylamino-ethoxy)-4-chloro-6-nitro-phenylamine, 4-chloro-2-nitro-6-{2-
[(thiophen-2-
ylmethyl)-amino]-ethoxy ) -phenylamine, 4-chloro-2-nitro-6- { 2-[(thiophen-3-
ylmethyl)-
amino]-ethoxy}-phenylamine afforded:
to ~ N-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl
benzyl) acetamide as a yellow solid (79 %), mp 172-173 °C; MS EI mle
397 (M").
Elemental analysis for C18H18F3N304:
Calc'd: C, 54.41; H, 4.57; N, 10.58
is Found: C, 54.34; H, 4.33; N, 10.53
3c N-(3-(2-Amino-3-nitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-
acetamide as a yellow solid (67.8 %)) mp 92-93 °C; MS EI mle 397 (M+).
2o Elemental analysis for C18H18F3N304:
Calc'd: C, 54.41; H, 4.57; N, 10.58
Found: C, 54.30; H, 4.50; N, 10.50
3~ N-[2-(2-Amino-3-nitro-phenoxy)-ethyl)-2,2,2-trifluoro-N-
25 naphthalen-1-ylmethyl-acetamide as a yellow-orange colored solid (75.3 %),
mp
133-135 °C; MS EI mle 433 (M'').
Elemental analysis for C21H18F3N304:
Calc'd: C, 58.20; H, 4.19; N, 9.70
3o Found: C, 58.28; H, 4.07; N, 9.48
N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-
2,2,2-trifluoro-acetamide as a yellow solid (82.0 %), mp 80-82 °C; MS
EI mle 439
(M').
Elemental analysis for C21H24F3N3~4:
Calc'd: C, 57.40; H, 5.51; N, 9.56
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Found: C, 57.09; H, 5.31; N, 9.40
~f N-[2-(2-Amino-3-vitro-phenoxy)-ethyl]-N-(4-chloro-benzyl)-2,2,2-
trifluoro~acetamide as a yellow solid (84.0 %), mp 138-139 °C; MS
(+)FAB mle
s 418/420 (M+H) +.
Elemental analysis for C17H15C1F3N304:
Calc'd: C, 48.88; H) 3.62; N, 10.06
Found: C, 48.66; H, 3.47; N, 9.82
m
~,g N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-N-benzyl-2,2,2-
trifluoro-acetamide as a yellow solid (67.9 %), mp 106-108 °C; MS
(+)FAB mle
418/420 (M+H)'".
is Elemental analysis for C17H15C1F3N304:
Calc'd: C, 48.88; H, 3.62; N, 10.06
Found: C, 48.96; H) 3.50; N, 10.03
~h N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-
2o thiophen-2-ylmethyl-acetamide as a yellow solid (59.6 %)) mp 97-98
°C; MS EI mle
423/425 (M+).
Elemental analysis for C15H13C1F3N304S:
Calc'd: C, 42.51; H, 3.09; N, 9.92
2s Found: C, 42.37; H) 2.97; N, 9.84
N-[2-(2-Amino-5-chloro-3-vitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-
thiophen-3-yimethyl-acetamideas a yellow solid (80.0 %), mp 149-150 °C;
MS EI
mle 423/425 (M'").
Elemental analysis for C15H13CIF3N304S:
Calc'd: C, 42.51; H, 3.09; N, 9.92
Found: C, 42.02; H, 2.95; N, 9.78
3s
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Intermediate 4a
N-Benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide
s To a mixture of N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-
trifluoro-
acetamide 3La, 2.4 g, 6.26 mmol) and 10 % palladium on carbon (0.40 g) in
ethanol (200
mL) at 50 -55 °C was added a solution of hydrazine hydrate (2.0 g) in
ethanol (25 mL).
The reaction was allowed to stir for 18 hr at 23 °C, then the catalyst
filtered through solka
floc and the solvent removed under vacuum to afford 1.96 g (88.9 %) of an
amber-colored
oil. Crystallization from ethyl acetate-hexane gave a white solid, mp 118 -119
°C; MS
(+)FAB m!e 354 (M+H+).
Elemental analysis for C17H18F3N302:
Calc'd: C, 56.58; H, 4.72; N, 12.38
is Found: C, 57.49; H, 5.10; N, 11.86
This general procedure utilizing N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-
trifluoro-N-
(4-methyl-benzyl) acetamide, N-[3-(2-amino-3-nitro-phenoxy)-propyl]-N-benzyl-
2,2,2-
trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-
naphthalen-
1-ylinethyl-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-tert-butyl-
benzyl)-
2,2,2-trifluoro-acetamide, N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-chloro-
benzyl)-
2,2,2-trifluoro-acetamide, N-[2-(2-amino-5-chloro-3-nitro-phenoxy)-ethyl]-N-
benzyl-
2,2,2-trifluoro-acetamide, N-[2-(2-amino-S-chloro-3-nitro-phenoxy)-ethyl]-
2,2,2-
trifluoro-N-thiophen-2-ylmethyl-acetamide, and N-[2-(2-amino-5-chloro-3-nitro-
phenoxy)-
2s ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide afforded:
N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-
benzyl)-acetamide as a white solid (85.0 %), mp 94-96 °C; MS EI mle 367
(M'").
so Elemental analysis for C18H2pF3N302:
Calc'd: C, 58.85; H, 5.49; N, 11.44
Found: C, 58.91; H) 5.32; N, 11.45
4c N-Benzyl-N-[3-(2,3-diamino-phenoxy)-propyl]-2,2,2-trifluoro-
3s acetamide as a white solid (86.5 %), mp 56-58 °C; MS EI mle 367
(M+).
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Elemental analysis for C18H2pF3N302:
Calc'd: C, 58.85; H, 5.49; N, 11.44
Found: C, 59.00; H, 5.42; N, 11.48
s
~ N-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-triffuoro-N-naphthalen-1-
ylmethyl-acetamide as a viscous yellow oil (63.0 %); MS (+)FAB mle 404 (M+H+).
Elemental analysis for C21H20F3N302:
io Calc'd: C, 62.53; H, 5.00; N, 10.42
Found: C, 62.45; H, 4.98; N, 10.20
4~ N-(4-tert-Butyl-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-
trifluoro-acetamide as a viscous brown oil (72.7 %); MS EI mle 409 (M+).
is
4f N-(4-Chloro-benzyl)-N-[2-(2,3-diamino-phenoxy).ethyl]-2,2,2-
trifluoro-acetamide as a brown oil (80.9 %); MS EI mle 387/389 (M+).
Elemental analysis for C17H17C1F3N302:
2o Calc'd: C, 52.65; H, 4.42; N, 10.84
Found: C, 52.47; H) 4.51; N, 10.60
N-Benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-
trifluoro-acetamide as a viscous brown oil {76.2 %); MS EI mle 387/389 (M+).
2s
Elemental analysis for C17H17C1F3N302:
Calc'd: C, 52.65; H, 4.42; N, 10.84
Found: C, 52.47; H, 4.39; N, 10.90
4_~ N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-triftuoro-N-
thiophen-2-ylmethyl-acetamide as a viscous brown oil (71.4 %); MS EI m/e
393/395 (M+).
Elemental analysis for C15H15C1F3N302S:
3s Calc'd: C, 45.75; H, 3.84; N, 10.67
Found: C, 45.58; H, 3.93; N, 10.64
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4i N-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-
thiophen-3-ylmethyl-acetamide as a viscous brown oil (75.0 %); MS EI mle
393/395 (M+).
s Elemental analysis for C15H15C1F3N302S:
Calc'd: C, 45.75; H, 3.84; N, 10.67
Found: C, 45.39; H, 3.84; N, 10.56
to Intermediate 5a
N-Benzyl-2,2,2-trifluoro-N-[2-(2-thioxo-2,3-dihydro-1H-benzoimidazol-4
yloxy)-ethyl]-acetamide
is A mixture of N-benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-
acetamide (0.57 g, 1.61 mmol) and 1,1'-thiocarbonyldiimidazole (0.49 g, 3.05
mmol) in
anhydrous tetrahydrofuran (30 mL) was stirred at 23 °C for 2 hr. The
reaction was poured
into water and extracted with ethyl acetate (2 x I50 mL). The organic layer
dried over
anhydrous magnesium sulfate) filtered, and the solvent removed under vacuum.
2o Purification by chromatography (160 g silica gel) ethyl acetate) afforded
0.54 g (85.2 %) of
a yellowish -colored solid. Crystallization from ethyl acetate-hexane gave a
white solid,
mp 158-160 °C; MS (+)FAB mle 395 (M+H)'".
Elemental analysis for C18H16F3N302S:
2s Calc'd: C, 54.52; H, 3.74; N, 10.56
Found: C, 54.68; H, 4.08; N, 10.63
This general procedure utilizing N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-
trifluoro-N-(4-methyl-benzyl)-acetamide, N-benzyl-N-[3-(2,3-diamino-phenoxy)-
propyl]-
30 2,2,2-trifluoro-acetamide, N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-
trifluoro-N=
naphthalen-1-ylmethyl-acetamide, N-(4-tert-butyl-benzyl-N-[2-(2,3-diamino-
phenoxy)-
ethyl]-2,2,2-trifluoro-acetamide, N-(4-chloro-benzyl)-N-[2-(2,3-diamino-
phenoxy)-ethyl]-
2,2,2-trifluoro-acetamide, N-benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-
2,2,2-
trifluoro-acetamide, N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-
trifluoro-N-
3s thiophen-2-ylmethyl-acetamide and N-[2-(2,3-diamino-5-chloro-phenoxy)-
ethyl]-2,2,2-
trifluoro-N-thiophen-3-ylmethyl-acetamide afforded:
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,5~ 2,2,2-Trifluoro-N-(4-methyl-benzyl)-N-[2-(2-thioxo-2,3-dihydro-
1H-benzoimidazol-4-yloxy)-ethyl]-acetamide as an off white solid (90.9 %), mp
195-196 °C; MS EI mle 409 (M+).
s Elemental analysis for C19H18F3N302S:
. Calc'd: C, 55.47; H, 4.43; N, 10.26
Found: C, 55.40; H, 4.24; N) 10.05
5~ N-Benzyl-2,2,2-triftuoro-N-[3-(2-thioxo-2,3-dihydro-1H-
lo benzoimidazol-4-yloxy)-propyl]-acetamide as a yellow foam (99.0 %); MS EI
m/e
409 (M+) which analyzed for a three-quarter hydrate.
Elemental analysis for C19H18F3N302S ~ 0.75 H20:
Calc'd: C, 53.96; H, 4.65; N, 10.40
15 Found: C) 54.05; H, 4.49; N, 10.09
2,2,2-Trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-thioxo-2,3-
dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (95.0 %),
mp 102-103 °C; MS EI mle 445 (M+).
Elemental analysis for C22H18F3N303S:
Calc'd: C, 58.73; H, 4.14; N, 9.34
Found: C, 58.84; H) 4.02; N, 9.17
2s ,fig N-(4-tert-Butyl-benzyi)-2,2,2-trifluoro-N-[2~(2-thioxo-2,3-dihydro-
1H-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (86.4 %), mp 199-
200 °C; MS EI mle 451 (M+).
Elemental analysis for C22H24F3N302S:
3o Calc'd: C, 58.52; H, 5.36; N, 9.31
Found: C, 58.46; H, 5.36; N, 9.25
,5~ N-(4-Chloro-benzyl)-2,2,2-trifluoro-N-[2-(2-thioxo-2,3-dihydro-
1H-benzoimidazol-4-yloxy)-ethyl]-acetamide as a white solid (72.0 9~), mp 194-
ss 196 °C; MS EI mle 429/431 (M+).
Elemental analysis for C18H15C1F3N303S:
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Calc'd: C, 50.30; H, 3.52; N) 9.78
Found: C, 50.50; H, 3.54; N, 9.51
N-Benzyl-N-[2-(6-chloro-2-thioxo-2,3-dihydro-1H-benzoimidazol-4-
s yloxy)-ethyl]-2,2,2-trifluoro-acetamide as a white solid (93.8 %), mp 201-
202 °C.
Elemental analysis for C18H15C1F3N302S:
Calc'd: C, 50.30; H, 3.52; N, 9.78
Found: C, 50.00; H, 3.40; N, 9.67
to
N-[2-(6-Chloro-2-thioxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-
ethyl]- 2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide as a white solid (68.2
%), mp 183-184 °C; MS EI mle 435/437 (M+).
is Elemental analysis for C16H13C~3N3C2S2:
Calc'd: C, 44.09; H, 3.01; N, 9.64
Found: C, 43.76; H, 2.78; N, 9.53
N-[2-(6-C hloro-2-th ioxo-2,3-dihyd ro-1H-benzoimidazol-4-yloxy)-
2o ethyl]- 2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide as a white solid
(64.9
%), mp 179-180 °C; MS EI mle 435/437 (M+).
Elemental analysis for C16H13C1F3N303S:
Calc'd: C, 44.09; H, 3.01; N) 9.64
2s Found: C, 44.11; H, 2.80; N) 9.47
Intermediate 6
30 3-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine
The general procedure used in intermediate 4 using 2-[2-(3,4-dihydro-1H-
isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2j~ afforded 3-[2-(3,4-dihydro-
1H-
isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine as a solid (95 %), mp 76-77
°C. This
ss material was characterized as the dihydrochloride~0.4 H20 salt); MS EI mle
283 (M'').
Elemental analysis for C17H21N30 ~ 2 HCl ~ 0.4 H20:
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Calc'd: C, 56.17; H, 6.60; N) 11.56
Found: C, 56.15; H, 6.68; N) 11.25
s Intermediate 7
4-Chloro-2-(2-chloro-ethoxy)-6-vitro-phenylamine
A solution of 2-(2-chloro-ethoxy)-6-vitro-phenylamine (_l~, 30.0 g, 0.14 mol),
N-
1 o chlorosuccinamide and acetonitrile ( 1.3 L) was refluxed for 4 hr. The
mixture was
concentrated under vacuum and the residue was diluted with ethyl acetate (500
mL). The
organic layer was washed with water (2X, 250 mL) and brine (250 mL), dried
over
anhydrous magnesium sulfate) filtered, and the solvent removed under vacuum to
give an
orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5 g
(95.3 %) as
is orange solid, mp 109-110 °C; MS EI mle 250/252/254 (M'').
Elemental analysis for C8H8C12N2O3:
Calc'd: C, 38.27; H, 3.21; N) 11.16
Found: C, 38.15; H, 3.10; N, 10.96
Example 1
4-(2-Benzylamino-ethoxy)-1,3-dihydro~benzoimidazol-2-thione
2s A suspension of potassium carbonate (0.90 g, 6.50 mmol) and N-benzyl-2,2,2-
trifluoro-N-[2-(2-thioxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-
acetamide (0.367
g, 0.928 mmol) in methanol-water (30 mL:2 mL) was heated to reflux for 2 hr
then the
solvent was evaporated and the residue dissolved in ethyl acetate (100 mL) and
extracted
with water (80 mL). The organic layer was drib over anhydrous magnesium
sulfate,
3o filtered) and the solvent removed under vacuum to give the crude base.
Purification by
chromatography (70 g silica gel, ethyl acetate : 2N NH3 in methanol, 20 : 1 )
afforded 0.27
g (97.2%) of a white solid. Crystallization from methanol gave white needles,
mp 147-149
°C; MS mle FAB 300 (M+H+) containing methanol.
3s Elemental analysis for C16H17N30S ~ 0.75 CH40
Calc'd: C, 62.20; H, 6.23; N, 12.99
Found: C, 62.10; H, 6.07; N, 13.26
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To a solution of 4-(2-benzylamino-ethoxy)-1,3-dihydro-benzoimidazole-2-thione
(0.195 g, 0.65 mmol) in methanol (40 mL) was added an excess of 1 N hydrogen
chloride
in ether to afford 0.155 g (67.4 %) of the hydrochloride salt monohydrate of
the title
s compound as white solid, mp 253-255 °C; MS mle (+)FAB 300 (M+H+).
Elemental analysis for C16H17N30S ~ HCl ~ H20:
Calc'd: C, 54.31; H, 5.70; N, 11.87
Found: C, 54.62; H, 5.48; N, 12.00
to
Example 2
4-[2-(4-Methyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazole-2-thione
is
The general procedure used in example 1 and utilizing 2,2,2-trifluoro-N-(4-
methyl-
benzyl)-N-[2-(2-thioxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl)-acetamide
(Sb)
afforded:
20 4-[2-(Methyl-benzylamino)-ethoxy)]-1,3-dihydro-benzoimidazole-2-thione
as a white solid quarter hydrate (97.2 ~'o), mp 154-156 °C; MS mle EI
313 (M+).
Elemental analysis for C17H19N30S ~ 0.25 H20:
Calc'd: C, 64.23; H, 6.18; N, 13.22
2s Found: C, 64.37; H, 5.93; N, 13.07.
Addition of excess 1N hydrogen chloride in ether gave 4-[2-(4-Methyl-
benzylamino)-ethoxy]-1,3-dihydro-benzoimidazole-2-thione ~ HCI ~ hydrate as a
white
solid (71.1 %), mp > 250 °C; MS mle (+)FAB 314 (M+H)+.
Elemental analysis for C17H19N30S ~ HC1 ~ H20
Calc'd: C, 55.50; H, 6.03; N, 11.42
Found: C, 55.81; H, 5.79; N, 11.33
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Example 3
4-(2-Benzylamino-propoxy)-1,3-dihydro-benzoimidazole-2~thione
s The general procedure used in example 1 and utilizing N-benzyl-2,2,2-
trifluoro-N
[3-(2-thioxo-2,3-dihydro- 1 H-benzoimidazole-4-yloxy)-propyl]-acetamide (Sc)
afforded:
4-(2-Benzylamino-propoxy)-1,3-dihydro-benzoimidazole-2-thione
as a white solid (64.4 %), mp 203-204 °C; MS mle EI 313 (M+).
to
Elemental analysis for C17H19N30S ~ 0.25 H20:
Calc'd: C, 64.23; H, b.18; N) 13.22
Found: C, 64.10; H, 5.08; N, 12.84
i s Addition of excess 1 N hydrogen chloride in ether gave the hydrochloride
salt
quarter hydrate of 4-(2-Benzylamino-propoxy)-1,3-dihydro-benzoimidazole-2-
thione as a
white solid (92.5 %), mp 243-244 °C; MS mle EI 313 (M)+.
Elemental analysis for C17H19N30S ~ HCl ~ 0.25 H20
2o Calc'd: C, 57.62; H, 5.83; N, 11.86
Found: C, 57.58; H, 5.71; N, 11.72
Example 4
2s 4- f 2-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-1,3-dihydro-
benzoimidazole-2-thione
The general procedure used in example 1 and utilizing 2,2,2-trifluoro-N-
naphthalen-1-ylmethyl-N-[2-(2-thioxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-
ethyl]-
3o acetamide (Sd) affonied:
4- { 2-[(Naphthalen-1-ylmethyl)-amino]-ethoxy } -1,3-dihydro-benzoimidazole-2-
thione ~ 0.5 ethyl acetate as a white solid (66.6 % ), mp 191-193 °C;
MS m/e EI 349
(M+).
Elemental analysis for C2pH 19N30S ~ 0.5 C4Hg02:
Calc'd: C, 67.15; H) 5.89; N) 10.68
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Found: C, 66.97; H, 5.75; N, 10.76
Addition of excess 1 N hydrogen chloride in ether to the above product gave
the
three quarters hydrated hydrochloride salt of the title as a white solid (90.0
%), mp 240
s 242 °C; MS mle EI 349 (M)+.
Elemental analysis for C2pH19N30S ~ HCl ~ 0.75 H20
Calc'd: C, 60.14; H, 5.43; N, 10.52
Found: C, 60.42; H, 5.48; N, 10.09
Example 5
4-[2-(4-tert-Butyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazole-2-
is thione
The general procedure used in example 1 and utilizing N-(4-tert-butyl-benzyl)-
2,2,2-trifluoro-N-[2-(2-thioxo-2,3-dihydro- 1 H-benzoimidazol-4-yloxy)-ethyl]-
acetamide
(Se) afforded:
4-[2-(4-tert-Butyl-benzyiamino)-ethoxy]-1,3-dihydro-benzoimidazole-2-thione as
a
white solid (79.3 %), mp 125-127 °C; MS mle EI 355 (M+).
Elemental analysis for C2pH25N3OS:
2s Calc'd: C, 67.57; H, 7.09; N, 11.82
Found: C, 67.02; H, 7.00; N, 11.67
Treatment of the above free base with excess 1 N hydrogen chloride in ether
gave
the one-quarter hydrate of the hydrochloride salt of the title compound as a
white solid
(90.0 %), mp >250 °C; MS mle EI 355 (M)+.
Elemental analysis for C2pH25N30S ~ HCl ~ 0.25 H20:
Calc'd: C, 60.59; H, 6.74; N, 10.60
Found: C, 60.50; H, 5.68; N, 10.44
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Example 6
4-[2-(4-Chloro-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazole-2-thione
s The general procedure used in example 1 and utilizing N-(4-Chloro-benzyl)-
2,2,2-
trifluoro-N-[2-(2-thioxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-
acetamide (Sf)
afforded:
4-[2-(4-Chloro-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazole-2-thione
to as a white solid (85.9 %), mp 160-162 °C; MS mle (+)FAB 334/336
(M+H+).
Elemental analysis for C16II16C1N30S:
Calc'd: C, 57.57; H, 4.83; N, 12.59
Found: C, 57.17; H, 4.64; N, 12.35
is
Treatment with excess 1N hydrogen chloride in ether gave the hydrochloride
salt of
the title compound as a white solid (90.0 %), mp 204-205 °C; MS mle EI
333/335 (M)+.
Elemental analysis for C16H16N30S ~ HCI:
2o Calc'd: C) 51.90; H, 4.63; N, 11.35
Found: C, 51.86; H, 4.46; N, 11.22
Example 7
2s
4-(2-Benzylamino-ethoxy)-6-chloro-1,3-dihydro-benzoimidazole-2-thione
The general procedure used in example 1 and utilizing N-benzyl-N-[2-(6-chloro-
2
thioxo-2,3-dihydro-IH-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-acetamide
(Sg)
3o afforded:
4-(2-Benzylamino-ethoxy)-6-chloro- I,3-dihydro-benzoimidazole-2-thione as a
white solid (88.2 %)) mp 234-237° C; MS mle EI 333/335 (M+).
3s Elemental analysis for C16H16C1N30S ~ 0.4 H20:
Calc'd: C) 56.35; H, 4.97; N) 12.32
Found: C, 56.43; H) 4.76; N, 12.26
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Reaction of the above prepared compound with excess 1N hydrogen chloride in
ether gave 4-(2-Benzylamino-ethoxy)-6-chloro-1,3-dihydro-benzoimidazole-2-
thione~HCl
as a white solid (95.0 %), mp >250 °C; MS mle EI 333/335 (M+).
s
Elemental analysis for C1(H16C1N30S ~ HCI:
Calc'd: C, 51.90; H, 4.63; N, 11.35
Found: C, 51.79; H, 4.62; N, 11.20
to
Example 8
6-Chloro-4-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-1,3-dihydro
benzoimidazole-2-thione
is
The general procedure used in example 1 and utilizing N-[2-(6-chloro-2-thioxo-
2,3-dihydro- 1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-
ylmethyl-
acetamide (Sh) afforded:
20 6-Chloro-4- { 2-[ (thiophen-2-ylmethyl)-amino]-ethoxy } -1, 3-dihydro-
benzoimidazole-2-thione ~ hemihydrate as a white solid (92.0 %), mp 183-184
°C; MS mle
EI 339/341 (M+).
Elemental analysis for C1qH14CIN30S3 ~ 0.5 H20:
2s Calc'd: C, 48.20; H, 4.33; N, 12.04
Found: C, 48.30; H, 3.99; N, 11.91
The hydrochloride salt of the title compound was prepared as a white solid
(90.0 %), mp >250 °C; MS mle (+)FAB 340 (M+H)+.
Elemental analysis for C 14H 14C1N30S3 ~ HCI:
Calc'd: C, 44.68; H, 4.02; N, 11.17
Found: C, 44.28; H, 3.87; N, 10.83
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Example 9
6-Chloro-4-{2-[(thiophen-3-ylmethyl)-amino]~ethoxy}-1,3-dihydro
benzoimidazole-2-thione
s The general procedure used in example 1 and utilizing N-[2-{6-chloro-2-
thioxo-
2,3-dihydro- 1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-
ylmethyl-
acetamide (Si) afforded:
6-Chloro-4- { 2-[(thiophen-3-ylmethyl)-amino]-ethoxy } - I, 3-dihydro-
lo benzoimidazole-2-thione as a white solid (77.0 %), mp 197-198 °C; MS
mle (+)FAB
340/342 {M+H+).
Elemental analysis for C14H14C1N30S3:
Calc'd: C, 49.48; H) 4.15; N, 12.36
is Found: C, 49.27; H, 4.14; N, 12.30
The hydrochloride salt of the title compound was prepared as a white solid
(90.0 %), mp >250 °C; MS mle (+)FAB 340 (M+H)+.
2o Elemental analysis for C14H14C1N30S3 ~ HCI:
Calc'd: C, 44.68; H, 4.02; N, l I.17
Found: C, 44.28; H, 3.87; N) 10.83
2s Example 10
4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-1,3-dihydro
benzoimidazole-2-thione
3o Following the general procedure used in example 1 and utilizing 2-[2-(3,4-
dihydro-
1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2j) afforded the title
compound as a
yellow solid (60.0 %), mp 249-250 °C; MS mle EI 325 (M+).
Ele~ntal analysis for C18H19N30S:
' 3s Calc'd: C, 66.43; H) 5.88; N, 12.91
Found: C, 66.07; H, 5.92; N, 12.85
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The hydrochloride salt of the title compound was prepared as a light yellow
solid
(90.0 %), mp 213-214 °C; MS mle EI 325 (M)+.
Elemental analysis for C16H16C1N30S ~ HCI:
s Calc'd: C, 59.74; H, 5.57; N, 11.61
Found: C) 59.12; H, 5.52; N, 11.50
PHARMACOLOGY
The compounds of this invention are dopamine autoreceptor agonists, that is,
they
t o serve to modulate the synthesis and release of the neurotransmitter
dopamine. They are
thus useful for treatment of disorders of the dopaminergic system, such as
schizophrenia,
Parkinson's disease and Tourette's syndrome. Such agents are partial agonists
at the
postsynaptic dopamine D2 receptor and are thereby useful in the treatment of
alcohol and
drug addiction.
is
Affinity for the dopamine autoreceptor was established by a modification of
the
standard experimental test procedure of Seemen and Schaus, European Journal of
Pharmacology 203: 105-109, 1991, wherein homogenized rat striatal brain tissue
is
incubated with 3H-quinpirole (Quin.) and various concentrations of test
compound, filtered
2o and washed and counted in a Betaplate scintillation counter.
High affinity for the dopamine D-2 receptor was established by the standard
experimental test procedure of Fields, et al., Brain Res., 1~, 578 ( 1977) and
Yamamura et
al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y. (1978) wherein
25 homogenized limbic brain tissue is incubated with 3H-spiroperidol (Spiper.)
and various
concentrations of test compound, filtered and washed and shaken with
Hydrofluor
scintillation cocktail (National Diagnostics) and counted in a Packard 460 CD
scintillation
counter.
The results of the tests with compounds representative of this invention are
given in
so the following table.
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Example IC50 (nM) ICSp (nM)
D2 Quin. D2 Spiper
1 0.36 33.35 92.6
2 0.42 37.7 89.8
3 14.9 1191 79.9
4 0.43 36.9 85.8
0.82 6.87 8.4
6 0.21 88.0 409.3
7 0.39 57.0 139.0
8 0.37 88.0 237.8
9 0.18 85.0 472.2
2.67 234.0 87.6
Hence, the compounds of this invention effect the synthesis of the
neurotransmitter
s dopamine and thus are useful in the treatment of dopaminergic disorders such
as
schizophrenia, Parkinson's disease, Tourette's Syndrome) alcohol addiction,
cocaine
addiction, and addiction to analagous drugs.
Applicable solid carriers for pharmaceutical compositions containing the
1 o compounds of this invention can include one or more substances which may
also act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers,
glidants, compression
aids) binders or tablet-disintergrating agents or an encapsulating material.
In powders, the
carrier is a finely divided solid which is in admixture with the finely
divided active
ingredient. In tablets, the active ingredient is mixed with a Garner having
the necessary
1 s compression properties in suitable proportions and compacted in the shape
and size
desired. The powders and tablets preferably contain up to 99% of the active
ingredient.
Suitable solid carriers include, for example, calcium phosphate, magnesium
stearate, talc,
sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium
carboxymethyl
cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions)
syrups
and elixirs. The active ingredient of this invention can be dissolved or
suspended in a
pharmaceutically acceptable liquid carrier such as water, an organic solvent,
a mixture of
both or pharmaceutically acceptable oils or fat. The liquid carrier can
contain other suitable
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pharmaceutical additives such as solubilizers, emulsifiers, buffers,
preservatives,
sweeteners, flavoring agents, suspending agents, thickening agents, colors,
viscosity
regulators, stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and
parenteral administration include water (particularly containing additives as
above e.g.
s cellulose derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols
(including monohydric alcohols and polyhydric alcohols e.g. glycols) and their
derivatives,
and oils (e.g. fractionated coconut oil and arachis oil). For parenteral
administration the
carrier can also be an oily ester such as ethyl oleate and isopropyl
myristate. Sterile liquid
carriers are used in sterile liquid form compositions for parenteral
administration.
to
Liquid pharmaceutical compositions which are sterile solutions or suspensions
can
be utilized by, for example, intramuscular, intraperitoneal or subcutaneous
injection.
Sterile solutions can also be administered intravenously. Oral administration
may be either
liquid or solid composition forni.
is
Preferably the pharmaceutical composition is in unit dosage form) e.g. as
tablets or
capsules. In such form, the composition is sub-divided in unit dose containing
appropriate
quantities of the active ingredient; the unit dosage fom~s can be packaged
compositions, for
example packeted powders, vials, ampoules) prefilled syringes or sachets
containing
20 liquids. The unit dosage form can be, for example, a capsule or tablet
itself, or it can be the
appropriate number of any such compositions in package form.
The dosage to be used in the treatment of a specific psychosis must be
subjectively
determined by the attending physician. The variables involved include the
specific
2s psychosis and the size, age and response pattern of the patient.
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