Note: Descriptions are shown in the official language in which they were submitted.
1~ 52~91 M-1049 Foreign
5-(OPTIONALLY SUBSTITUTED PHENYL)-
6H-1,3,4-THIADIAZINE-2-AMINES
SUMMARY OF THE INVENTION
The present invention relates to fluorophenyl com-
pounds which are useful as muscle relaxants and which have
the following general formula
S.~ NH-alkyl
~ ~ ~N
wherein the alkyl group contains 1-7 carbon atoms and is
straight or branched chain. Such compounds show a parti-
~: 10 cularly desirable separation of effects producing a muscle
rel:axant effect at doses which are not sedative.
The present application also relates to a method of
~ : achieving a muscle-relaxing effect in a patient comprises
:~: :administering to a patient in which a muscle relaxing
effect is desired an amount effective to achieve a mus-
~; cle-relaxing efect of a compound of the formula
~: : R
R3~ S ~ N-R
R2 N
: :wherein R i5 H, Cl 7 straight or branched chain alkyl;
:Rl is H, Cl_7 straight or branched chain alkyl, allyl
~or phenyl;
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M-1049 Foreign
R2 is phenyl, phenyl monosubstituted with F, Cl, Cl_4
straight or branched chain alkyl or phenyl disubstituted
in the 2- and 4-positions with Cl or Cl_4 straight or
branched chain alkyl; and
R3 is H or Cl_4 straight or branched chain alkyl,
with the proviso that when R3 is straight or branched
chain alkyl, R2 is unsubstituted phenyl;
or a pharmaceutically acceptable acid addition salt
thereof.
DETAILED DESCRIPTION OF THE INVENTION
Illustrative examples of straight or branched chain
Cl_7 alkyl groups which R and Rl may represent as used
herein include, for example, methyl, ethyl, n-propyl, iso-
propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pen-
tyl, isopentyl, neopentyl, n-hexyl, iso-hexyl, n-heptyl,
iso-heptyl, etc. Illustrative examples of straight or
branched chain Cl_s alkyl and Cl_4 alkyl groups mentioned
in describing the groups Rl and R2-R3, respectively, in-
clude, for example, the corresponding examples mentioned
above.
Pharmaceutically acceptable acid addition salts of
the compounds of Formula I include those of any suitable
inorganic or organic acid. Suitable inorganic acids are,
for example, hydrochloric, hydrobromic, sulfuric or phos-
phoric acid. Suitable organic acids are, for example,carboxylic acids, such as acetic, propionic, glycolic,
lactic, pyruvic, malonic, succinic, fumaric, malic, tar-
taric, citric, ascorbic, maleic, hydroxymaleic, benzoic,
hydroxybenzoic, phenylacetic, cinnamic, salicylic and
2-phenoxybenzoic, or sulfonic acids such as, for example,
methanesulfonic and 2-hydroxyethane sulfonic acid.
Of the compounds of Formula I, those wherein R2 is
substituted phenyl are preferred, especially 4-fluoro-
phenyl, and R3 is H.
Illustrative examples of compounds of this invention
include those wherein R and Rl ~re H, CH3, C2Hs or C3H7,
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~1~2$91 M-1049 Foreign
--3--
especially those wherein one of R and Rl is H. These
include, for example, N-methyl-5-phenyl-6H-1,3,4-thiadia-
zin-2-amine, N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadia-
zin-2-amine, 5-(2,4-dichlorophenyl)-6H-1,3,4-thiadiazin-
s 2-amine, 5-(2,4-dichlorophenyl)-N-methyl-6H-1,3,4-thia-
diazin-2-amine, 5-(2,4-dichlorophenyl)-N-ethyl-6H-1,3,4-
thiadiazin-2-amine, 5-(2,4-dichlorophenyl)-N,N-dimethyl-
6H-1,3,4-thiadiazin-2-amine, 5-(2,4-dichlorophenyl)-N-
phenyl-6H-1,3,4-thiadiazin-2-amine, 5-(2,4-dichlorophe-
nyl)-N-(l-methylethyl)-6H-1,3,4-thiadiazin-2-amine, 5-(2,-
4-dichlorophenyl)-N-propyl-6H-1,3,4-thiadiazin-2-amine, 5-
(2-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine,
N-ethyl-6-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine,
5-(2,4-dichlorophenyl)-N-hexyl-6H-1,3,4-thiadiazin-2-amine
and N-butyl-5-(2,4-dichlorophenyl)-6H-1,3,4-thiadiazin-2-
amine, 5-(2,4-dichlorophenyl)-N-2-propenyl-6H~1,3,4-thia-
diazin-2-amine, 5-(2,4-dichlorophenyl)-N-heptyl-6H-1,3,4-
thiadiazin-2-amine and their acid addition salts.
The compounds of this invention are useful as muscle
relaxants. These compounds can be administered to warm-
blooded animals, mammals, rats, mice, dogs, cats, horses,
pigs, cows, sheep and humans. As used herein, the term
"patient" is intended to mean the animal or mammal being
treated.
The muscle-relaxing activity of the compounds of this
invention may be illustrated by their effectiveness in
standard pharmacological screening tests, e.g., by demon-
strating an antagonism of decerebrate rigidity in rats; by
inhibition of polysynaptic reflexes in the anesthetized
cat; and by the mouse Straub tail test.
The compounds of this invention can be administered
orally or parenterally either alone or in the form of a
pharmaceutical preparation. Pharmaceutical preparations
containing conventional pharmaceutical carriers and as
active ingredients compounds of this invention can be
employed in unit dosage forms such as solids, for example,
tablets, capsules and pills, or liquid solutions, suspen-
sions or emulsions for oral and parenteral administration.
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~i52~91 M-1049 Foreign
The dosage unit administered can be any muscle-relaxing
effective amount. The quantity of compound administered
c:an vary over a wide range to provide from about 10 to
~.00, preferably 10-30, mg/kg of body weight of the patient
per day, to achieve the desired effect. Unit doses can
contain about 5-500 mg of a compound of Formula I and may
be administered, for example, from 1 to 4 times daily.
The compounds of Formula I are prepared by reacting a
phenacyl halide of the formula
0 H
.. .
~2--C-C-x
R3
wherein X is Cl or Br,
with a 4-substituted thiosemicarbazide of the formula
S
H2N-NH-C-N-R
Rl
wherein R, Rl, R2 and R3 are as hereinbefore defined. The
reaction is generally conducted in the presence of a sol-
vent, e.g., a lower alkanol, such as, methanol, ethanol,
isopropanol, n-propanol, n-butanol and the like, pre-
ferably methanol. ~he reaction time may vary from about
15 minutes to about 1 hour, preferably about 30 minutes,
depending upon the reactants, the solvent and the reaction
temperature which may vary from about 60C to about 80C,
preferably about 65C. The product is generally worked-up
by permitting the reaction mixture to cool and then con-
centrating it in vacuo. The resultant residue is recrys-
tallized from an appropriate solvent, e.g., a mixture of a
lower alkanol with, e.g., acetone, butanone or ethyl ace-
tate, e.g., methanol/acetone or methanol/ethyl acetate,
producing the compound of Formula I as its hydrohalide
salt.
Both the phenacyl halide and the 4-substituted thio-
semicarbazide which are employed as starting materials in
the preparation of the compounds of Formula I are either
commercially available or, when unavailable, are very
~1~2991
M-1049 Foreign
readily preparable by standard chemical reactions which
are well-known to those of ordinary skill in the art. For
example, the phenacyl halides may be prepared by halo-
yenating the corresponding methyl (optionally-substi-
tuted)phenyl ketone using a sulfuryl halide, e.g., sul-
furyl chloride, in e.g., acetic acid, to prepare the cor-
responding phenacyl chloride or by reacting the corres-
ponding optionally substituted benzene with a haloacetyl
halide, e.g., chloroacetyl chloride via a Friedel Crafts
reaction using an aluminum trichloride catalyst, e.g., to
prepare the corresponding phenacyl chloride. The 4-sub-
stituted thiosemicarbazides may be prepared by conven-
tionally reacting the appropriate substituted isothio-
cyanate with hydrazine in the presence, e.g., of diethyl
ether.
EXAMPLES
The following examples are illustrative of the inven-
tion.
EXAMPLE 1
N-Methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydrochloride
5.255 g ~.05 mole) of 4-methyl-thiosemicarbazide and
7.73 g (.05 mole) of phenacyl chloride are heated and
stirred at reflux t65C) in 200 ml of methanol for 30
minutes. At this time, the solvent is removed in vacuo.
The residue is dissolved in methanol, warmed and then
diluted with acetone. Thereafter, it is concentrated to
approximately 200 ml. After standing for 2 days, 8.33 g
of N-methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine hydro-
chloride are deposited. m.p. 176-178C.
EXAMPLE 2
N-Ethyl-5-(4-fluorophenyl)-6 -1,3,4-thiadiazin-2-amine
hydrochloride
11.19 g of 4-ethyl-thiosemicarbazide and 17.6 g of
4-fluorophenacyl chloride are heated and stirred under
reflux (65C) in 400 ml of methanol for 30 minutes in a
one liter round bottom flask equipped with a magnetic
stirring bar and a condenser protected by a CaC12 drying
~ iS~g 9 1 M-1049 Foreign
tube. The solution is allowed to cool to room temperature
and is then concentrated to a yellow solid residue. The
residue is recrystallized from methanol/butanone yielding
21.0 g (75.5%) of N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-
thiadiazin-2-amine hydrochloride. m.p. 192-193C. The
fluffy, yellowish white solid is dried under high vacuum
at 65C.
EXAMPLE 3
5-(2,4-Dichlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydro-
chloride
11.17 g (.05 mole) of 2,4-dichlorophenacyl chloride
and 4.36 g (.05 mole) of thiosemicarbazide are stirred and
heated in 2S0 ml of methanol at reflux (65C) for 30 minu-
tes. The resultant suspension is allowed to cool and is
filtered to yield a first crop of 4.S6 g of 5-(2,4-di-
chlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrochloride.
The reaction mixture is then diluted with ethyl acetate
and concentrated on a steam bath further yielding 6.2 g of
the same compound. The two products are added together
and recrystallized from methanol/ethyl acetate. m.p.
170-172C.
EXAMPLE 4
5-(2~4-DichloroPhenyl)-N-methyl-6H-l~3~4-thiadiazin-2
amine monohydrochloride
11.17 g of 2,4-dichlorophenacyl chloride and 5.755 g
of 4-methyl-thiosemicarbazide are reacted in 200 ml of
methanol using the procedure of Example 2. The initial
crystallization is made from methanol/ethyl acetate. The
solid is then recrystallized from methanol/ethyl acetate
and dried at 65C under high vacuum to produce 5-(2,4-di-
chlorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine mono-
hydrochloride. m.p. 195C.
EXAMPLE S
5-(2v4-Dichlorophenyl)-N-ethyl-6H-1,3,4-thiadiazin-2-amine
monohydrochloride
Utilizing the reaction conditions of Example 2, 9.3 g
(.04 mole) of 2,4-dichlorophenacyl chloride and 4.77 g
.04 mole) of 4-ethylthiosemicarbazide are reacted in 200
~5;~:!39~
M-1049 Foreign
ml of methanol to produce 6.5 g of 5-(2,4-dichlorophe-
nyl)-N-ethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride
after recrystallization which, in this case, was from
methanol/ethyl acetate. m.p. 197-198C.
EXAMPLE 6
';-(2,4-Dichlorophen~l)-N,N-dimethyl-6H-1,3,4-thiadiazin-
2-amine monohydrochloride
4.16 g (.035 mole) of 4,4-dimethyl-thiosemicarbazide
and 7.82 g (.035 mole) of 2,4-dichlorophenacyl chloride
are reacted under the conditions of Example 2. After con-
centration, ethyl acetate is added to the residue and fur-
ther concentration is employed. A yellow, needle-like
solid is produced. The solid is dried under high vacuum
at 65C. Subsequently, it is recrystallized from metha-
nol/ethyl acetate and again dried under high vacuum toproduce 5-(2,4-dichlorophenyl)-N,N-dimethyl-6H-1,3,4-thia-
diazin-2-amine monohydrochloride. m.p. 219-222C.
EXAMPLE 7
5-(2,4-Dichlorophenyl)-N-phenyl-6H-1,3,4-thiadiazin-2-
amine monohYdrochloride
4.54 9 (.03 mole) of 4-phenyl-thiosemicarbazide and
6.70 9 (.03 mole) of 2,4-dichlorophenacyl chloride are
reacted in 200 ml of methanol using the conditions of
Example 2. Recrystallization of the solid is from metha-
nol/ethyl acetate, yielding 6.5 g of 5-(2,4-dichloro-
phenyl)- N-phenyl-6H-1,3,4-thiadiazin-2-amine monohydro-
chloride. m.p. 186C. The solid was subsequently dried
under high vacuum at 65C.
EXAMPLE 8
5-(2J4-Dichloro~henyl)-N-(l-methylethYl)-6~-1 L3 ~ 4-thiadia-
zin-2-amine monohydrochloride
3.99 g (.03 mole) of 4-isopropyl-thiosemicarbazide
and 6.70 g l.03 mole) of 2,4-dichlorophenacyl chloride are
reacted in 150 ml of methanol under the conditions of
Example 2. The concentrated product is crystallized and
recrystallized from methanol/ethyl acetate. The product
is dried under high vacuum at 65C and recrystallized
again from methanol/ethyl acetate. It is finally dried
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1152~91 M-1049 Foreign
again at 65C under high vacuum producing 5-(2,4-dichlo-
rophenyl)-N-(l-methylethyl)-6H-1,3,4-thiadiazin-2-amine
monohydrochloride. m.p. 207-208C.
EXAMPLE 9
5-(2,4-Dichlorophenyl)-N-propyl-6H-1,3,4-thiadiazin-2-
amine monohydrochloride
6.70 g ~.03 mole) of 2,4-dichlorophenacyl chloride
and 3.99 g (.03 mole) of 4-n-propyl-thiosemicarbazide are
reacted in 150 ml of methanol under the conditions of
Example 2. The concentrated product is crystallized and
then recrystallized from methanol/ethyl acetate, to pro-
duce 6.4 g of 5-(2,4-dichlorophenyl)-N-propyl-6H-1,3,4-
thiadiazin-2-amine monohydrochloride. m.p. 184-185C.
The product is then dried at 65C under high vacuum.
EXAMPLE 10
5-(2-FluorophenYl)-~-methyl-6H-1,3,4-thiadiazin-2-amine
monohydrochloride
8.62 9 (.05 mole) of 2-fluorophenacyl chloride and
5.22 g of 4-methyl-thiosemicarbazide are reacted in 150 ml
of methanol under the conditions of Example 2. The pro-
duct is recrystallized from methanol/ethyl acetate, yield-
ing 6.7 g of 5-(2-fluorophenyl)-N-methyl-6H~1,3,4-thia-
diazin-2-amine monohydrochloride. m.p. 183-184C.
EXAMPLE 11
5-(2,4-~ichloroPhenYl)-N-hexyl-6H-l~3~4-thiadiazin-2
amine monohydrochloride
3.50 g of n-hexyl-thiosemicarbazide and 4.47 g of
2,4-dichlorophenacyl chloride are reacted under the con-
ditions of Example 2 in 200 ml of methanol. The resultant
solid is recrystallized from methanol/ethyl acetate pro-
ducing 4.5 9 of 5-(2,4-dichlorophenyl)-N-hexyl-6H-1,3,4-
thiadiazin-2-amine monohydrochloride. m.p. 173-174C.
EXAMPLE 12
~-ButYl-s-l2~4-dichlorophe-nyl)-6H-l~3~4-thiadiazin-2
amine monohYdrochloride
4.47 g of 2,4-dichlorophenacyl chloride and 2.66 9 of
4-n-butyl-thiosemicarbazide are reacted under the con-
ditions of Example 2 in 150 ml of methanol. The solid
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M-1049 Foregin
llSZ9~
g
obtained is recrystallized from methanol/ethyl acetate,
producing 3.98 g of N-butyl-5-(2,4-dichlorophenyl)-6H
:L,3,4-thiadiazin-2-amine monohydrochloride. m.p. 180-
182C.
S EXAMPLE 13
S-(2,4-Dichlorophenyl)-N-2-Propenyl-6H-1,3,4-thiadiazin-
2-amine monohydrochloride
3.93 g (.03 mole) of 4-allyl-thiosemicarbazide and
7.00 g (.03 mole) of 2,4-dichlorophenacyl chloride are
reacted in accordance with the conditions of Example 1.
Recrystallization from methanol/methyl acetate produces 8
g of 5-(2,4-dichlorophenyl)-N-2-propenyl-6H-1,3,4-thia-
diazin-2-amine. m.p. 188-189C.
EXAMPLE 14
5-(2,4-Dichlorophenyl)-N-hePtyl-6H-1,3,4-thiadiazin-2-
amine monohydrochloride
3.78 g (.02 mole) of 4-n-heptyl-thiosemicarbazide and
4.67 g (.02 mole) of 2,4-dichlorophenacyl chloride are
reacted analogously to Example 1. After recrystal~lzation
from methanol/methyl acetate, 5.2 g of 5-(2,4-dichloro-
phenyl)-N-heptyl-6H-1,3,4-thiadiazin-2-amine monohydro-
chloride are produced. m.p. 175-177C.
EXAMPLE 15
N-Ethyl-6-methyl-5-Phenyl-6H-l~3~4-thiadiazin-2-amine
hydrobromide
.05 Mole of -methyl-penacyl bromide and .05 mole of
4-ethyl-thiosemicarbazide are reacted using the procedure
of Example 1 to prepare 8.0 g of N-ethyl-6-methyl-5-phe-
nyl-6H-1,3,4-thiadiazin-2-amine hydrobromide. m.p. 174-
-
175C. After recrystallization from methanol/ethyl ace-
tate, the product is dried at 65C under high vacuum.
EXAMPLE 16
5-(4-FluoroPhenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine
hydrochloride
~.63 g of 4-fluorophenacyl chloride and 4.66 g of
4-methyl-thiosemicarbazide are reacted by using the con-
ditions of Example 1. The resultant product is recrystal-
lized from methanol/ethyl acetate yielding 5.6 g of
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1~52991 M-1049 Foreign
--10--
5-(4-fluorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine
hydrochloride. M.p. 139-141C. The product compound is
dried under high vacuum at 65C.
EXAMPLE 17
An illustrative composition for tablets is as fol-
lows:
Per Tablet
ta) 5-(2,4-Dichlorophenyl)-N-methyl- 100.0 mg
6H-1,3,4-thiadiazin-2-amine
monohydrochloride
(b) Wheat starch 15.0 mg
(c) Lactose 33.5 mg
(d) magnesium stearate 1.5 mg
A portion of the wheat starch is used to make a granulated
starch paste which together with the remainder of the
wheat starch and the lactose is granulated, screened and
mixed with the active ingredient (a), and the magnesium
stearate. The mixture is compressed into tablets weighing
150 mg each.
EXAMPLE 18
An illustrative composition for a parenteral injec-
tion is the following wherein the quantities are on a
weight to volume basis.
Amount
(a) 5-(2,4-Dichlorophenyl)-N-methyl- 100.0 mg
6H-1,3,4-thiadiazin-2-amine
monohydrochloride
(b) Sodium chloride q.s.
(c) Water for injection to make 20.0 ml
-
The composition is prepared by dissolving the active in-
gredient (a) and sufficient sodium chloride in water for
injectioh to render the solution isotonic. The composi-
tion may be dispensed in a single ampoule containing 100
mg of the active ingredient for multiple dosage or in 20
ampoules for single dosage.
1~ 5 ~ ~ 1 M-1049 Foreign
EXAMPLE 19
An illustrative composition for hard gelatin capsules
is as follows:
Amount
(a) 5-(2,4-Dichlorophenyl~-N-methyl- 200.0 mg
6H-1,3,4 thiadiazin-2-amine
monohydrochloride
(b) Talc 35.0 mg
-
The composition is prepared by passing the dry powders of
(a) and (b) through a fine mesh screen and mixing them
well. The powder is then filled into No. 0 hard gelatin
capsules at a net fill of 235 mg per capsule.
EXAMPLE 20
An illustrative composition for pills is the fol-
lowing:
-
Per Pill
(a) 5-(2,4-Dichlorophenyl)-N-methyl- 200 mg
6H-1,3,4-thiadiazin-2-amine
monohydrochloride
(b) Corn Starch 130 mg
(c) Liquid glucose 20 ml
The pills are prepared by blending the active ingredient
(a) and the corn starch; then adding the liquid glu~ose
with thorough kneading to form a plastic mass from which
the pills are cut and formed.
EXAMPLE 21
The compounds of the preceding examples each can be
administered to achieve muscle relaxation in a patient in
which a mu5cle-relaxing effect is desired, e.g., in a
patient suffering from a muscle spasm. Muscle relaxation
is inducible in rats by adminlstration o chlordiazepoxide
(Librium) paenterally (i~v.) So also, the compounds of
this invention induce comparable muscle relaxation under
similar conditions. For example, the compound of Example
6 has about 3 times tha potency of chlordiazepoxide while
the compound of Example 10 has about 1/2 the po~ency of
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1~91 M-104~ Foreign
-12-
chlordia7epoxide, under similar conditions of parenteral
administration. It is, therefore, anticipated that the
compound under consideration will be administered to
humans for the same indications and under the same dosage
S conditions (adjusted for differential potency) as those
seen in rats for chlordiazepoxide. For example~ the com-
pound of Example 6 could be administered in doses of 1-50
mg, 2 to 4 times daily, to achieve beneficial effects.
EXAMPLE 22
Compositions similar to those described in Examples
17-20 are prepared except that 5-(4-fluorophenyl)-N-
methyl-6H-1,3,4-thiadiazin-2-amine hydrochloride or N-
ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine hy-
drochloride are used in place of the 5-(2,4-dichloro-
phenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine hydrochlo-
ride.
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