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Патент USA US3075977

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United States Patent 0
Patented Jan. 29, 1963
1
2
3,075,967
BENZOTHIAZINES
for such treatment being adjusted for the activity of the
particular compound employed. In addition, the com
pounds of this invention are useful as tranquilizers and
thus can be administered perorally in the same manner
as ChlordiazepoXide in the treatment of irrational fears,
John Krapcho, New Brunswick, N.J., assignor to Olin
Mathieson Chemical Corporation, New York, N.Y., a
corporation of Virginia
N0 Drawing. Filed June 12, 1961, Ser. No. 116,273
‘
3,075,967
C6
anxiety and tension, the dosage for such treatment being
adjusted for the activity of the particular compound em
14 (Zlaims. (Cl. 260-—239.3)
ployed.
This application is a continuation-in-part of my ap
The compounds of this invention can be prepared by
plication, Serial No. 842,202, ?led September 25, 1959, 1O condensing
a compound of the Formula II:
and now abandoned.
This invention relates to new chemical compounds hav
ing valuable therapeutic properties and processes for the
preparation thereof.
The therapeutically active compounds of this invention 15
GH-R
O-R
are bases of the general Formula I:
s/ \R
(II)
wherein X and R are as hereinbefore de?ned, with an
20 aminoalkyl halide of the formula B—A-Y, wherein B
and A are as hereinbefore de?ned and Y is halide, par
ticularly chloride. This reaction is preferably conduct
ed by heating the reactants in the presence of a basic
condensing agent, such as an alkali metal, an alkali metal
amide (e.g., sodamide), or an alkali metal hydroxide.
(I)
and the acid-addition salts thereof, wherein X is hy
drogen, lower alkyl, lower alkoxy, nitro, halo or tri?uoro
methyl; each R is hydrogen, lower alkyl, an X-substitu’t
ed phenyl lower alkyl, an X-substituted phenyl, furyl,
To form the acid-addition salts, the free base initially
formed is interacted with at least one equivalent of the
desired acid.
To prepare the starting materials (the compounds of
thienyl, pyridyl or piperonyl; A is lower alkylene (pref 30 Formula II) a Z-aminothiophenol of the Formula III:
erably ethylene and propylene); and B is a basic nitro
gen-containing radical of less than twelve carbon atoms.
Among the suitable radicals represented by the symbol
B are: amino; (lower alkyl) amino; di(lower alkyl)amino; 35
(hydroXy-lower alkyl)amino; di(hydroXy-lower alkyl)
—SH
X
NHz
amino; phenyl(lower alkyl)amino; N-(lower alkyl)-phen
(III)
yl (lower alkyl)amino; and saturated 5 to 6 membered
monocyclic heterocyclic radicals of less than twelve car
wherein X is as hereinbefore de?ned, is interacted with
an acrylic acid derivative of the Formula IV:
bon atoms, as exempli?ed by piperidino; (lower alkyl)
piperidino; di(lower alkyl)piperidino; (lower alkoxy)
40
piperidino; 2, 3 or 4-piperidyl; 2, 3 or 4-(N-lower alkyl
piperidyl); pyrrolidino; (lower aklyl)pyrrolidino; di(low
R—C=O—COOH
1'1 Ilt
(1V)
er alkyl)pyrrolidino; (lower alkoxy)pyrrolidino; 2 or 3
wherein R is as hereinbefore de?ned.
pyrrolidyl; 2 or 3-(N-lower alkyl-pyrrolidyl); morpholino;
Suitable reactants III include 2-aminobenzenethiol; 2
amino-(lower alkyl)benzenethio1s, such as 2-aminotolu
(lower alkyl)morpholino; di(lower a1kyl)morpholino;
(lower alkoxy)morpholino; thiamorpholino; (lower
alkyl)thiamorpholino; di(lower alkyl)thiamorpholino;
(lower alkoxy)thiamorpholino; piperazino; (lower alkyl)
piperazino (e.g., N4-methylpiperazino); di(lower alkyl)
piperazino; and (lower alkoXy) piperazino. The terms
“lower alkyl,” “lower alkoxy,” and “lower alkylene,” as
employed herein, include both straight and branched
enethiols, (e.g., Z-amino-p-toluenethiol), 2-amino-ethy1
benzenethiols, 2-amino-n-propylbenzenethiols, 2-amino
isopropylbenz'enethiols, 2-aminobutylbenzenethiols, and 2
aminohexylbenzenethiols; 2-amino-lower alkoxybenzene
thiols, such as Z-amino~methoxybenzenethiols (e.g., 2
amino~p-anisolethiol), Z-amino - ethoxybenzenethiols, 2
amino-n-propoxybenzenethiols, and 2-amino-pentoxybcn
chain radicals of less than eight carbon atoms. The par
ticularly preferred compounds are those wherein X is
hydrogen or chloro, one R is phenyl, A is ethylene or
zenethiols; Z-aminonitrobenzenethiols (e.g., 2-amino-n
nitrobenzenethiol); Z-arnino-halobenzenethiols, such as
propylene and B is di(lower alkyl)amino.
As to the salts, those coming within the purview of
this invention include the acid-addition salts, particular
zenethiol), 2-amino-bromobenzenethiols and Z-amino
ly the non-toxic acid-addition salts. Acids useful for pre 60
paring these acid-addition salts include, inter alia, inor
ganic acids, such as the hydrohalic acids (e.g., hydro—
chloric and hydrobromic acid), sulfuric acid, nitric acid,
Z-amino-chlorobenzenethiols (e.g., 2-amino-4-chloroben
?uorobenzenethiols; and 2-amino-tri?uoromethylbenzene
thiols, such as 2-amino-4-tri?uoromethylbenzenethiol.
Suitable reactants IV include acrylic acid; a-lower
alkenoic acids of more than three carbon atoms (e.g.,
crotonic acid, 2-pentenoic acid, Z-heXenoic acid, 2-octenoic
acid, 3-methylcrotonic acid, Z-methylcrotonic acid, 2-ethyl
boric acid and phosphoric acid, and organic acids such as
acrylic acid, 2,3-dimethylcrotonic acid and 4-methyl-2
which are utilizable in the treatment of Parkinsonism.
and 3-phenyl-4-methyl-Z-pentenoic acid); 3-(substituted
oxalic, tartaric, citric, acetic and succinic acid, theophyl 65 pentenoic acid); 3-phenyl-a-lower alkenoic acids of more
than two carbon atoms (e.g., cinnamic acid, 3-phenyl-i
line and 8-chlorotheophylline.
crotonic acid, 3-phenyl-2-pentenoic acid, 3-phenyl-2-hexe
The compounds of this invention and the acid-addi~
noic acid, Z-methylcinnarnic acid, 2-ethylcinnamic acid
tion salts thereof are therapeutically active compounds
Thus, the compounds of this invention can be adminis 70 phenyl)-a-lower alkenoic acids of more than two carbon
atoms (e.g., m-nitrocinnamic acid, p-methylcinnamic acid,
tered perorally in the same manner as benztropine meth
o,a-dimethylcinnamic acid, p-ethylcinnamic'acid, m,p-di
anesulfonate in the treatment of Parkinsonism, the dosage
methoxycinnamic acid, p-methoxycinnamic acid, 2-ethyl
3,075,967
A
the solvent, there remains about 43 g. of 2,3-dihydro-5~
3
p-ethoxycinnamic acid, p-tri?uoromethylcinnamic acid, p
chlorocinnamic acid, 3-o-tolylcrotonic acid and 3-p-meth
oxyphenyl-Z-pentenoic acid); 3-(phenyl-lower alkyD-or
(dirnethylaminoethyl)-2-phenyl-l,5 - benzothiazepin - 4
one. Part of this material (36.5 g.) is dissolved in 50 ml.
of ethanol and treated with 18.7 ml. of 6 N alcoholic
lower alkenoic acids of more than two carbon atoms (e.g.,
w-phenyl-a-lower alkenoic acids of more than three carbon
hydrogen chloride. Dilution of the resulting solution
gives about 39.5 g. of colorless product; M.P. about 195
205°. Crystallization from 600 ml. of acetonitrile gives
atoms, such as 5-phenyl-2-pentenoic acid 5-phenyl-2-meth
yl-2-pentenoic acid, and 6-phenyl-2-hexenoic acid) and
lower alkyl, lower alkoxy, nitro, halo and tri?uorornethyl
substituted phenyl derivatives thereof; 3-piperonyl-a-lower
alkenoic acids of more than two carbon atoms (e.g., 3
a colorless product; M.P. about 222-224“.
EXAMPLE 2
10
piperonylacrylic acid, 3-piperonyl-2-methyl acrylic acid,
2,3-Dihydro-S-(3-Dimethylaminopropyl)-1 ,S-Benzothia
and 3-piperonylcrotonic acid); 3-(2-furyl)-a-lower alke
zepin-4-One-Hydr0chl0ride, MOno-hydrate
noic acids of more than two carbon atoms [e.g., 3-(2~
To a suspension of 7.8 g. of sodarnide in 200 ml. of
toluene is added a suspension of 33.5 g. of 2,3-dihydro
furyl)acry1ic acid, 3-(2-furyl)-2-ethyl acrylic acid and 3
(2-furyl)crotonic acid]; 3-(2-thienyl)-a-lower alkenoic
15
acids of more than two carbon atoms [e.g., 3-(2-thienyl)
acrylic acid, 3-(2-thienyl)-2-methyl crotonic acid and 3
(2-thienyl)-crotouic acid]; 3-(2-pyridyl)-a-lower alkenoic
acids of more than two carbon atoms [e.g., 3-(2-pyridyl)
acrylic acid, 3-(2-pyridyl)-2-methylacrylic acid and 3-(2
pyridy1)crotonic acid]; 3-(4-pyridyl)-a-lower alkenoic
1,5-benzothiazepin-4-one (J.C.S., 1927, p. 2738) in 300
m1. of toluene. This mixture is re?uxed for one hour,
cooled and treated with 25.5 g. of 3-dimethylaminopropyl
chloride. The mixture is re?uxed for two hours and the
product is isolated as in Example 1 to give about 11.0 g.
20
acids of more than two carbon atoms [e.g., 3—(4-pyridyl)
acrylic acid and 3-(4~pyridyl)crotonic acid]; Z-Phenyl-a
of 2,3-dihydro-5-(3-dimethylaminopropyl)-l,5-benzothia
zepin-4-0ne, B.P. about 164° (0.4 mm.). Part of this
material (10.1 g.) is dissolved in 20 ml. of absolute alco
1101 and treated with an equivalent of hydrogen chloride
in 7 ml. of absolute alcohol. The resulting solution is di
a-phenylacrylic acid, or-phenylcrotonic acid, 2-phenyl-2 25 luted to 400 ml. with anhydrous ether to give an oil.
pentenoic acid, and 2-phenyl-2-hexenoic acid); 2-(sub
Tritration with ether gives a ‘colorless product weighing
stituted phenyl)-a-lower alkenoic acids of more than two
about 11.0 g., M.P. about 101-105“. After crystallization
carbon atoms; Z-(phenyl-lower alkyl)-a-lower alkenoic
from 20 ml. of acetonitrile, the colorless product melts
acids of more than two carbon atoms (e.g., 2-benzylacrylic
at about 106-108".
lower alkenoic acids of more than two carbon atoms (e.g.,
acid and 2-phenethylcrotonic acid); 2-(substituted phenyl
lower a1kyl)-a-lower alkenoic acids of more than two
EXAMPLE 3
carbon atoms; 3,3-diphenylacrylic acid; 2,3-diphenylacrylic
2,3-Dihydro-2-Phenyl-5-(Z-Diethylaminoethyl) -1,5
acid; 2,3,3-triphenylacrylic acid; 2,3-diphenyl-a-lower
Benz0thiazepin-4-One Hydrochloride
alkenoic acids of more than two carbon atoms; 3,3-diphen
Following the procedure used in Example 1 but sub
yl-a-lower alkenoic acids of more than two carbon atoms; 35 stituting an equivalent amount of 2-diethylaminoethyl
2,3,3-triphenyl-a-iower alkenoic acids of more than two
chloride for the Z-dimethylaminoet-hyl chloride, a colorless
product melting at about 179-180° is obtained.
alkenoic acids of more than two carbon atoms; 3,3-di(sub
EXAMPLE 4
stituted phenyl)-a-lower alkenoic acids of more than two
carbon atoms; 2-(substituted phenyl)-3-phenyl-a-lower 40
2,3-Dihydro-2-Phenyl-5- [2- (1 -Pyrrolidinyl) ethyl] -
carbon atoms; 3-(substituted phenyl)-3-phenyl-a-lower
alkenoic acids of more than two carbon atoms; 2,3
di(substituted phenyl)-a-lower alkenoic acids of more
than two carbon atoms; 3-(phenyl-lower alkyl)-2-phenyl
1,5-Berzzothiazepin-4-One Hydrochloride
Following the procedure used in Example 1 but sub
stituting an equivalent amount of 2-(1-pyrrolidinyl)ethyl
a-lower alkenoic acids of more than two carbon atoms;
2-piperonyl-a-lower alkenoic acids of more than two car 45 chloride for Z-dimethylaminoethyl chloride, a colorless
product melting at about 193-195° is obtained.
bon atoms; 2-(2-furyl)-a-lower alkenoic acids of more
than two carbon atoms; 2-(2~thienyl)-a-lower alkenoic
acids of more than two carbon atoms; 2-(2-pyridyl)
a-lower alkenoic acids of more than two carbon atoms;
and 2-(4-pyridyl)-a-lower alkenoic acids of more than 50
two carbon atoms.
The following examples illustrate the invention (all
temperatures being in centigrade):
EXAMPLE 1
2,3-Dihydr0-5-(Z-Dimethylaminoethyl) -2-Phenyl-1,5
Benzothiazepin-4-0ne Hydrochloride
To a stirred suspension of 7.8 g. of sodamide in 500 ml.
of dry toluene is added a suspension of 50.8 g. of 2,3
dihydro-2-phenyl-1,5-benzothiazepin-4-one (J.C.S., 1927,
EXAMPLE 5
2,3-Dihydro-2-Phenyl-5-(3-Dimethylaminopropyl)
1,5-Benzothiazepin-4-One Hydrochloride
Following the procedure used in Example 1 but sub
stituting an equivalent amount of S-dimethylamino
propyl chloride for Z-dimethylaminoethyl chloride, a
colorless product which crystallizes from butanone and
melts at about 127-129“ is obtained.
EXAMPLE 6
2,3-Dihydr0-2-Phenyl-5-[2-(N-Methyl-N-Phenethylami
no) ethyl] -1 ,5 -Benzothiazepin-4-One Hydrochloride
Substitution of an equivalent quantity of 2—(N-methyl
N-phenethylamino)ethy1 chloride for the Z-dimethyl
aminoethyl chloride in Example 1 gives 2,3-dihydro-2
p. 2738) in 500 ml. of toluene. The resulting mixture is
stirred at room temperature for thirty minutes and the
resulting solution treated with a solution of 25.0 g. of 2
phenyl - 5 - [2 - (N - methyl) - N - phenethylamino)
dimethylaminoethyl chloride in 110 ml. of toluene. This
mixture is heated and maintained at 60-65" for a period 65 ethyl] -1,5-benzothiazepin-4-one hydrochloride.
of three hours, cooled and treated with 150 m1. of water.
EXAMPLE 7
The aqueous layer is discarded and the organic phase
added to a cold solution of 25 m1. of concentrated hydro
2,3-Dihydr0-2-Methyl-3-Phenyl-5-(2-Dimethylamino
chloric acid in 300 ml. of water. The mixture is shaken
ethyl) -1,5-Benzothiazepin-4-One Hydrochloride
and the solid which separates is ?ltered and the cooled ?l 70
(a) Preparation of 2,3-dihydro-2-methyl-3-phenyl-1,5
trate treated with a solution of 18 g. of sodium hydroxide
benzothiazin-4-0ne.—A mixture of 26.4 :x-phenylcrotonic
in 50 ml. of water. The liberated base is extracted three
acid (J.A.C.S. 53, 3541 (1931)), and 15.7 g. of 2-amin0
times with 600 ml. portions of ether and the combined
thiophenol is heated in an oil bath at 160-175 ° for one
ether extract washed twice with 100 ml. portions of water
and dried over magnesium sulfate. After evaporation of 75 hour. The mixture is cooled and puri?ed by crystalliza
5
3,075,967
6
tion from isopropyl alcohol and acetonitrile to give a
colorless solid; M.P. about 206—207°.
benz0thiazepin-4-one.-A mixture of .173 g. of p-chloro~
(b) Preparation of 2,3-dihydro-2-methyl-3-phenyl- -(2
cinnamic acid and 119‘ g. of 2-aminobenzenethio1 is
heated in an oil bath for two hours at 180-200“. After
ride.—-19.0 g. of 2,3-dihydro-2-methyl-3-phenyl-1,5-benzo
cooling, the product is puri?ed by crystallization from
dimethylformamide, M.P. about 204-205".
dimethylaminoethyl)1,5-benzothiazepin-4-one hydrochlo
thiazepin-4-one is reacted with 2.7 g. of sodamide and
7.6 g. of Z-dimethylaminoethyl chloride according to the
procedure described in Example 1. This colorless mate
(b) 2,3-dihydro-2-(p-chlorophenyl)~5-(2-dimethylami
noethyl)-J,5-benzothiazepin-4-one hydrochloride.—8.7 g.
of 2,3-dihydro-2-(p-chlorophenyl)-1,5—benzothiazepin-4
rial, obtained after crystallization from absolute alcohol,
one is reacted with 1.25 g. of sodamide and 3.8 g. of 2
melts at about 239—240°.
EXAMPLE 8
10 dimethylaminoethyl chloride according to the procedure
described in Example 1. This material, after puri?ca
tion from acetonitrile, melts at about 205-206°.
EXAMPLE 13
2,3-Dihydro-2-Methyl-5-(Z-Diethylaminoethyl) -
1,5-Benzothiazepin-4-0ne Hydrochloride
35.4 g. of 2,3~dihydro-2-methyl-1,5-benzothiazin-4-one 15 2,3-Dihydro-2-(p-Methylphenyl) -5-(2-Dimethylamino
ethyl ) -J ,5 -Benzothiazepin-4-One Hydrochloride
(J.C.S.,1927, p. 2738) is reacted with 8.7 g. of sodamide
and 31.0 g. of 2-diethylaminoethyl chloride acpording to
(a) Preparation of 2,3-dihydro-Z-(p-methylphenyl)
the procedure described in Example 1 to give about 43.5 g.
1,S-benzothiazepin-4-one.-A mixture of 90 g. of p
of colorless solid; M.P. about 170-173". After crystal
methylcinnamic acid and 70 g. of Z-amiuothiophenol is
lization from 300 ml. ethanol-600 m1. of ethyl ether, the N) 0 heated
in an oil bath. This mixture is puri?ed by crystal
product melts at about 175—l76°.
lization from ldimethylformamide to give a colorless
EXAMPLE 9
solid; M.P. about ZOO-202°.
(b) Preparation of 2,3-dihydro-2-(p-methylphenyl)-5
2,3-Dihydro-2-(3,4-Dimethoxyphenyl) -5-(2-Diethyl
(Z-dimethylaminoethyl) -1,5-benzothiazepin-4-0ne hydro
aminoethyl) -1,5-Benzothiazepin-4-One Hydrochloride
(a) Preparation of 2,3-dihydro-2-(3,4-dimethoxyphen1
chl0ride.—-33.0 g. of 2,3-dihydro-2-(p-methylphenyl)-1,5
(b) Preparation of 2,3-dihydro~2-(3,4-dimethoxyphen
2,3-Dihydro-2-(Z-Furyl)~5-(2~Dimethylaminoethyl)
benzothiazepin-4-one is reacted with 5.0 g. of sodamide
yl)-1,5-benzothiazepin-4-one.—A mixture of 104 g. of
and 16.0 g. of Z-dimethylaminoethyl chloride according
3,4-dimethoxycinnamic acid and 62 g. of 2-aminoben
to the procedure described in Example 1. This material,
zenethiol is heated in an oil bath at 175-185 ° for one
after puri?cation from acetonitrile and ethanol, melts at
30
hour at forty-?ve minutes. After cooling, the residue is
about 213-215".
puri?ed by crystallization from acetonitrile to give a
EXAMPLE 14
colorless product; M.P. about 160-162°.
yl)-5-(2-diethylaminoethyl)-1,5-benzothiazepin-4~one hy-‘
drochloride.—34.5 g. of 2,3-dihydro-2-(3,4-dimethoxy
35
phenyl)-1,5-benzothiazepin-4-one is reacted with 4.3 g.
of sodamide and 15 g. of 2-diethylaminoethyl chloride
according to the procedure described in Example 1. This
product, after crystallization from acetonitrile, melts at
about 179-181“.
EXAMPLE 10
1,5-Benzothiazepin-4-One Hydrochloride
(a) Preparation of 2,3-dihydro-2-(2-furyl)-1,5-benzo
thiazepin-4-o-ne.-A mixture of 42 g. of 2-furanacrylic
acid and 38 g. of 2-aminobenzenethiol is heated in an oil
bath ‘at 170—180° for one hour. After cooling, the product
is puri?ed by crystallization from acetonitrile to give a
colorless product; M.P. about 154—156°.
(b) Preparation of 2,3 - dihydro-Z-(2-furyl)-5-(2-di—
methylaminoethyl)-1,5-benzothiazepin-4-one hydrochlo
2,3-Dihydro-2-(p-Methoxyphenyl) -5- (Z-Dimethylamino
ethyl) —1,5-Benzothiazin-4-One Hydrochloride
(a) Preparation of 2,3-dihydro-2-(p-methoxyphenyl)
ride.—l2 g. of 2,3-dihydro-2-(2-furyl)-l,5-benzothiaze
pin-4-one is reacted with 2.0 g. of sodamide and 6.1 g. of
Z-dimethylaminoethyl chloride according to the procedure
described in Example 1. The colorless product, after
crystallization from butanone and acetonitrile, melts at
1,S-benzothiazepin-4-one.—-A mixture of 64 g. of p-rneth
oxycinnamic acid (Ber. 60, 2112 (1927)), and 45 g. of
2-aminobenzenet-hiol is heated in an oil bath at l95—200°
for one hour and ?fteen minutes. The mixture is cooled
about 196—198°
EXAMPLE l5
and puri?ed by crystallization from 95% alcohol; M.P. 50
about 120-122".
2,3-Dihydr0-2- (3-Pz'peronyl) -5- (Z-Dimethylaminoathyl) -
(b) Preparation of 2,3-dihydro-2-(p-methoxyphenyl)
J ,5 -Benz0thiazepin-4-One Hydrochloride
Following the procedure of steps (a) and (I?) of Ex
ample 14 but substituting an equivalent quantity of 3
piperonylacrylic acid for the Z-furylacrylic acid in step
(a), 2,3 - dihydro-2-(3-piperonyl)-5-dimethylaminoethyl
5-(2-dimethylaminoethyl) - 1,5 - benzothiazepin-4-one hy
drochloride.—47.0 g. of 2,3-dihydro-2—(p~methoxyphen
yl)-1,5-benzothiazepin-4-one is reacted With 6.2 g. of
sodamide and 21 g. of Z-dimethylaminoethyl chloride
according to the procedure described in Example 1. This
1,5-benzothiazepin-4-one hydrochloride is obtained.
material, after crystallization from acetonitrile, melts at
Similarly, by following the procedure of Example 14
about 210—2l2°.
EXAMPLE 11
60 but substituting 2-(4-pyridyl)-acrylic acid, 3-(2-pyridyl)
acrylic acid and 3-(2-thieny1)acrylic acid for the 3-(2
2,3-Dihydro-2-(o-Methoxyphenyl)~5-(2-Dimethylamino
furyl)acrylic acid in step (a), 2,3-dihydro-3-(4-pyridyl)
ethyl) -l,5-Benz0thiazepin-4-0ne Hydrochloride
S-(Z-dimethylarninoethyl) - 1,5 - benzothiazepin-4-one hy
drochloride, 2,3-dihydro-2- ( 2-pyridyl) -5- ( Z-dimethylami
noethyl)-1,5-benzothiazepin-4-one hydrochloride, and 2,3
Following the procedure of steps (a) and (b) of Ex
ample 10 but substituting -o-methoxycinnamic acid for
the p-methoxycinnamic acid in step (a), 2,3-dihydro-2
dihydro - 2 - (Z-thienyl) - 5 - (Z-dimethylaminoethyl)-1,5
benzothiazepin-4-one hydrochloride are obtained, respec
(o-methoxyphenyl)-5-(2-dimethylaminoethyl) - 1,5 - ben
tively.
zothiazepin-4-one is obtained as a colorless solid; M.P.
about 118-120°.
EXAMPLE 12
2,3-Dihydro-2-(p-Chlorophenyl) -5-(2-Dimethylamino
ethyl)-J,5-Benzothiazepin-4-0ne Hydrochloride
(a) Preparation of 2,3-dihydro-2-(p-chlorophenyl) -1,5
EXAMPLE 16
70
2,3-Dihydr0-5-(2—Morpholinoethyl)-2-Phenyl-1,5
Benzothiazepin-4-0ne Hydrochloride
Following the procedure of Example 1 but substituting
an equivalent amount of 2-morpholinoethyl chloride for
the Z-dimethylaminoethyl chloride, 2,3-dihydro-5-(2-mor
3,075,967
r
7
8
What is claimed is;
pholinoethyl) - 2 - phenyl-l,S-benzothiazepin-ll-one hydro
‘
1. A compound selected from the group consisting of
bases of the formula
chloride is obtained.
EXAMPLE 17
2 ,3 -Dihyclr0—5 - (.Z-Piperidinocthyl ) -2-Phenyl
A-B
l
1,5-Bcnzothiazepin-4-One Hydrochloride
Following the procedure of Example 1 but substituting
an equivalent amount of 2~piperidinoethyl chloride for the
Z-dimethylaminoethyl chloride, 2,3~dihydro-5-(2-piper
idinoethyl)-2-phenyl-1,5-benzothiazepin-4-one hydrochlo
10
ride is obtained.
EXAMPLE l8
2,3-Dihydro-5- [3-(4-Methyl-1 -Piperazinyl) Propyl] -
Z-Phenyl-l,5-Benz0rhiazepin-4-One Hydrochloride
and pharmaceutically-acceptable acid addition salts there
of, wherein X is selected from the group consisting of
15 hydrogen, lower alkyl, lower alkoxy, nitro, halo and tri
Following the procedure of Example 1 but substituting
an equivalent amount of l-methyl—4-(3-chloropropyl)
fluoromethyl; each R is selected from the group consisting
piperazine for the Z-dimethylaminoethyl chloride, 2,3-di
alkyl, di_- X - substituted phenyl - lower alkyl, mono - X
of hydrogen, lower alkyl, mono-X-substituted phenyl-lower
substituted phenyl,
hydro-5-[3-(4-methyl-l - piperazinyDpropyl] - 2 - phenyl
l,5-benzothiazepin-4-one hydrochloride is obtained.
and B is selected from the group consisting of amino,
EXAMPLE 19
2,3-D ihydr0-5- (2-Dicthylaminoethyl ) -2~Ethy l—2-Phenyl
1 ,S-Benzothiozepin-4-One Hydrochloride
Following the procedure of Example 9 but substituting
di - X- substituted phenyl, furyl,
thienyl, pyridyl and piperonyl; A is lower alkylene;
(lower alkyl)amino, di(lower alkyl) amino, (hydroxy
lower alkyD-amino, di(hydroxy-lower alkyl) amino, phenyl
25
(lower alkyl)amino, N-(lower alkyl)phenyl(lower alkyl)
amino, piperidyl, (lower aIkyDpiperidyl, di(lower alkyl)
piperidino, (lower alkoxy)piperidino, pyrrolidyl, (lower
alkyl)pyrrolidyl, di(lower alkyDpyrrolidino, (lower
alkoxy)pyrrolidino, morpholino, (lower alkyl) morpho
an equivalent amount of B-ethylcinnamic acid for the
3,4-dimethoxycinnamic acid in step (a), 2,3-dihydro-5-(2
diethylaminoethyl ) -2-ethyl-2-phenyl-l ,5 - benzothiazepin
lino, di(lower alkyDmorpholino, (lower alkoxy)morpho
4-one hydrochloride is obtained.
30 lino, thiamorpholino, (lower alkyl)thiamorpholino, di
(lower alkyl)thiamorpholino, (lower alkoxy)thiamor
EXAMPLE 20
pholino, piperazino, (lower alkyl)piperazino, di(lower
alkyl)piperazino and (lower alkoxy)piperazino.
7-Ch lore-2,3-Dihydro-Z-Pheny l-5-( 2-D iethylamino
ethyl) -] ,5 -Benz0thiozepin-4-0ne Hydrochloride
Following the procedure of Example 9 but substituting
an equivalent amount of cinnamic acid for the 3,4-dimeth
2. A compound of the formula
35
ower alkyl)
oxycinnamic acid and an equivalent amount of Z-arnino- -
(lower alkylene) -N- (lower alkyl)
chlorothiophenol for the Z-aminobenzenethiol in step (a),
7-chloro-2,3-dihydro-2-phenyl-5-(2 - diethylarninoethyl)
O
1,5-benzothiazepin-4-one hydrochloride is obtained.
CH:
'
'
EXAMPLE 21
7-Methyl-2,3-Dihydro-2-Phenyl-5 - (2-D iethy lwmino
ethyl) -1,5-Benz0thiazepin-4-0ne Hydrochloride
Following the procedure of Example 9 but substituting
45
3. A pharmaceutically-acceptable acid-addition salt of
the compound of claim 2.
an equivalent amount of cinnamic acid for the 3,4-dimeth
oxycinnamic acid and an equivalent amount of Z-amino
4-toluenethiol for the 2~aminobenzothiol in step (a),
(lower alkyl)
(llower alkylene) -N- (lower alkyl)
7-methyl - 2,3 - dihydro - 2 - phenyl - 5 - (Z-diethylamino
ethyl)-l,5-benzothiazepin-4-one hydrochloride is obtained.
N
EXAMPLE 22
\
7-Methoxy-2,3-Dihydro-2-Pheny1-5-(Z-Diethylomino
ethyl )1 ,5-Benzolhiazepin-4-One Hydrochloride
55
an equivalent amount of cinnamic acid for the 3,4-dimeth
oxycinnamic acid and an equivalent amount of 2-amino
7-methoxy-2,3-dihydro - 2 - phenyl - 5 - (2 - diethylamino
I
.
0:0
\ C H:
\ /C-?a
Following the procedure of Example 9 but substituting
4-anisolethiol for the 2-aminobenzenethiol in step (a),
.
4. A compound of the formula
S
60
ethyl)-l,5-benzothiazepin-4-one hydrochloride is obtained.
5. A pharmaceutically-acceptable acid-addition salt of
the compound of claim 4.
6. A compound of the formula
EXAMPLE 23
7- ( Tri?oromethyl ) -2,3-Di hydro-2 -Pheny [-5 - (2-D iethyl
aminoethyl ) -1 ,5 -Benzothiazcpin-4-One Hydrochloride
(lower alkyl)
65
Following the procedure of Example 9 but substituting
an equivalent amount of cinnamic acid for the 3,4-dimeth
(liower alkylene) -N- (lower alkyl)
N
\
4-(tri?uoromethyl)-thi0phenol for the Z-aminobenzene 70
thiol in step (a), 7-(tri?uoromethyl)-2,3-dihydro-2
phenyl-S-(Z-diethylaminoethyl) - 1,5 - benzothiazepin - 4
0:0
\
oxycinnamic acid and an equivalent amount of 2-amino
/
CH2
/OH-lower alkyl)
S
one hydrochloride is obtained.
7. A pharmaceutically-acceptable acid-addition salt of
The invention may be variously otherwise embodied
75
the
compound of claim 6.
within the scope of the appended claims.
3,075,967
10
8. A compound of the formula
2,3-dihydro - 2 - phenyl - 5 - (2 - diethylaminoethyl) - 1,5
(lower alkyl)
(lower alkylene) -N- (lower alkyl)
benzothiazepin-ll-one.
15
2,3 - dihydro - 2 - phenyl - 5 - [2,(1 - pyrrolidinyl)ethyl]
/
12. A pharmaceutically-acceptable acid addition salt of
1,5-benzothiazepin-4-one.
13. A pharmaceutically-acceptable acid-addition salt of
\CH/@
2,3 - dihydro - 2 - phenyl - 5 - (3 - dimethylaminopropyl)
1,5-benzothiazepin-4-one.
14. A pharmaceutisally-acceptable acid-addition salt of
2,3 - dihydro - 2 - phenyl - 5 - [2 - (N - methyl ~ N - phen
ethylamino) ethyl] ~ 1 ,5-benzothiazepin-4-one.
9. A pharmaceutically-acoeptable acid-addition salt of
the compound of claim 8.
10. A pharmaceutically-acceptable acid-addition salt of
2,3-dihydro-5-(2 - dimethylaminoethyl) - 2 - phenyl - 1,5
benzothiazepin-4-one.
11. A pharmaceutically-acceptable acid-addition salt of
15
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,852,510
Hoffman et a1 _______ _‘__ Sept. 16, 1958
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