U.S. patent number RE28,972 [Application Number 05/637,585] was granted by the patent office on 1976-09-21 for 5-aryl-1h-1,5-benzodiazepine-2,4-diones.
This patent grant is currently assigned to Boehringer Ingelheim GmbH. Invention is credited to Peter Danneberg, Rolf Giesemann, Herbert Merz, Karl-Heinz Weber, Karl Zeile.
United States Patent |
RE28,972 |
Weber , et al. |
September 21, 1976 |
**Please see images for:
( Certificate of Correction ) ** |
5-Aryl-1H-1,5-benzodiazepine-2,4-diones
Abstract
5-Aryl-1H-1,5-benzodiazepine-2,4-diones of a formula selected
from the group consisting of ##SPC1## Wherein ##SPC2## wherein
R.sub.1 is allyl, methylallyl, dimethylallyl, chloroallyl,
cyclohexyl, cycloalkylmethyl, cycloalkenylmethyl of 4 to 7 carbon
atoms, phenyl, tolyl, xylyl, methoxyphenyl, dimethoxyphenyl,
halophenyl, phenylalkyl of 7 to 8 carbon atoms, pyridyl or where A
is straight or branched alkylene of 1 to 4 carbon atoms, and X is
hydroxyl, alkoxy, acyloxy, dialkylamino of 2 to 4 carbon atoms, or
a 5- to 6-membered nitrogen-containing heterocyclic ring linked to
A through a ring nitrogen atom, R.sub.2 is hydrogen or methyl,
R.sub.3 is naphthyl, pyrimidyl, thienyl, pyridyl, methylpyridyl or
halopyridyl, R.sub.4 is hydrogen, methyl, methoxy, trifluoromethyl,
cyano, halogen, lower alkanoyl or (lower alkoxy of 1 to 2 carbon
atoms)-carbonyl, R.sub.5 is hydrogen, methyl, ethyl, methoxy,
trifluoromethyl, cyano, nitro, halogen, lower alkanoyl or lower
alkoxy-carbonyl, R.sub.6 is hydrogen, methyl, ethyl, methoxy or
halogen, R.sub.7 is cyano.[.,.]. .Iadd.or .Iaddend.lower alkanoyl
.[.or lower alkoxycarbonyl.]., R.sub.8 is cyano, nitro, lower
alkanoyl or lower alkoxycarbonyl, R.sub.9 is hydrogen, methyl,
ethyl, methoxy or halogen, and R.sub.10 is hydrogen, methyl,
methoxy, trifluoromethyl or halogen, Useful as psychosedatives and
anticonvulsives in warm-blooded animals.
Inventors: |
Weber; Karl-Heinz
(Gau-Algesheim, DT), Merz; Herbert (Ingelheim am
Rhein, DT), Zeile; Karl (Ingelheim am Rhein,
DT), Giesemann; Rolf (Bingen, DT),
Danneberg; Peter (Ingelheim am Rhein, DT) |
Assignee: |
Boehringer Ingelheim GmbH
(Ingelheim am Rhein, DT)
|
Family
ID: |
27092882 |
Appl.
No.: |
05/637,585 |
Filed: |
December 4, 1975 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
840839 |
Jul 10, 1969 |
03660381 |
May 2, 1972 |
|
|
Current U.S.
Class: |
540/518 |
Current CPC
Class: |
C07D
243/12 (20130101) |
Current International
Class: |
C07D
243/12 (20060101); C07D 243/00 (20060101); C07D
243/12 () |
Field of
Search: |
;260/239.3B |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Rossi et al., "La Chimica e l'Industria," vol. 51, No. 5, (May
1969), pp. 479-485. .
Buchi et al., "Helv. Chim. Acta," vol. 39, pp. 957-965,
(1965)..
|
Primary Examiner: Trousof; Natalie
Assistant Examiner: Bond; Robert T.
Attorney, Agent or Firm: Hammond & Littell
Claims
We claim:
1. A compound of a formula selected from the group consisting of
##SPC32##
wherein
R.sub.1 is alkyl of 1 to 4 carbon atoms, hydroxyethyl,
hydroxypropyl, acetoxyethyl, cyclohexyl, benzyl or phenyl,
R.sub.2 is naphthyl, pyrimidyl, thienyl, pyridyl, methyl-pyridyl or
chloropyridyl,
R.sub.3 is chlorine, bromine, trifluoromethyl or cyano,
R.sub.4 is cyano.[.,.]. .Iadd.or .Iaddend.acetyl .[.or
methoxycarbonyl.].,
R.sub.5 is cyano, nitro, acetyl or methoxycarbonyl, and
R.sub.6 is halogen or trifluoromethyl.
2. A compound of a formula selected from the group consisting of
##SPC33##
and ##SPC34##
wherein
R.sub.1 is straight or branched alkyl of 1 to 3 carbon atoms or
hydroxyalkyl of 2 to 3 carbon atoms,
R.sub.3 is pyridyl,
R.sub.4 is halogen, trifluoromethyl or cyano,
R.sub.5 is hydrogen, trifluoromethyl, nitro, cyano or halogen,
R.sub.8 is cyano or nitro, and
R.sub.10 is halogen or trifluoromethyl.
3. A compound according to claim 1, which is
7-chloro-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
4. A compound according to claim 1, which is
7-cyano-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
5. A compound according to claim 1, which is
5-(2'-acetyl-phenyl)-7-chloro-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-d
ione.
6. A compound according to claim 1, which is
1-methyl-5-(2'-pyridyl)-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4-(3H,5H
)-dione.
7. A compound according to claim 1, which is
1-ethyl-7-chloro-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
8. A compound according to claim 1, which is
7-bromo-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
Description
This invention relates to novel
5-aryl-1H-1,5-benzodiazepine-2,4-diones, as well as to a method of
preparing these compounds.
More particularly, the present invention relates to
5-aryl-1H-1,5-benzodiazepine-2,4-diones of a formula selected from
the group consisting of ##SPC3##
And ##SPC4##
Wherein
R.sub.1 is allyl, methylallyl, dimethylallyl, chloroallyl,
cyclohexyl, cycloalkylmethyl, cycloalkenylmethyl of 4 to 7 carbon
atoms, phenyl, tolyl, xylyl, methoxyphenyl, dimethoxyphenyl,
halophenyl, phenylalkyl of 7 to 8 carbon atoms, pyridyl or
where
A is straight or branched alkylene of 1 to 4 carbon atoms, and
X is hydroxyl, alkoxy, acyloxy, dialkylamino of 2 to 4 carbon
atoms, or a 5- to 6-membered nitrogen-containing heterocyclic ring
linked to A through a ring nitrogen atom,
R.sub.2 is hydrogen or methyl,
R.sub.3 is naphthyl, pyrimidinyl, thienyl, pyridyl, methylpyridyl
or halopyridyl,
R.sub.4 is hydrogen, methyl, methoxy, trifluoromethyl, cyano,
halogen, lower alkanoyl or (lower alkoxy of 1 to 2 carbon
atoms)-carbonyl,
R.sub.5 is hyrogen, methyl, ethyl, methoxy, trifluoromethyl, cyano,
nitro, halogen, lower alkanoyl or lower alkoxy-carbonyl,
R.sub.6 is hydrogen, methyl, ethyl, methoxy or halogen,
R.sub.7 is cyano.[.,.]. .Iadd.or .Iaddend.lower alkanoyl .[.or
lower alkoxycarbonyl.].,
R.sub.8 is cyano, nitro, lower alkanoyl or lower
alkoxycarbonyl,
R.sub.9 is hydrogen, methyl, ethyl, methoxy or halogen, and
R.sub.10 is hydrogen, methyl, methoxy, trifluoromethyl or
halogen.
The compounds according to the present invention may be prepared by
arylation or heteroarylation at the nitrogen atom in 5-position of
a 1H-1,5-benzodiazepine-2,4-dione of the formula ##SPC5##
wherein
R.sub.1 and R.sub.2 have the same meanings as in formulas I, II and
III above,
R.sub.n is R.sub.4, R.sub.7 or R.sub.10, as defined above, and
Y is hydrogen, an alkali metal or acyl, with a compound of the
formula
wherein R.sub.m is R.sub.3, ##SPC6##
as defined above, and
X is halogen.
The arylation is carried out in the presence of copper powder, a
copper-I-salt or a copper-II-salt or a mixture thereof, either by
using the aryl halide of the formula V in excess or in a polar
aprotic solvent, such as dimethylformamide, dimethylsulfoxide or
hexamethylphosphoric acid triamide. If a solvent is used, the aryl
halide is merely added in the calculated quantity. The reaction
temperature depends on the starting materials employed in each case
and lies in general between 90.degree. and 180.degree.C. If a
compound of the formula II wherein Y is hydrogen or acyl is used,
the addition of a suitable organic or inorganic base, such as an
alkali metal carbonate, alkali metal bicarbonate or alkali metal
alcoholate, preferably of an alkali metal acetate, in molar
quantities or in excess is required in order to bind the hydrogen
halide formed by the acrylation reaction. If in a compound of the
formula I the radical R.sub.1 represents a hydroxyalkyl group, the
hydroxyl group may subsequently be converted into an alkoxy group
by treatment with a diazoalkane in the presence of borofluoride
etherate.
If the radical R.sub.1 in a compound of the formula I is
dialkylaminoalkyl, it is possible to introduce a double bond into
the alkyl group by quaternization and splitting off trialkylamine.
Furthermore, in a compound of the formula I wherein R.sub.1 is
alkenyl, the latter may be hydrogenated in known manner.
The 1H-1,5-benzodiazepine-2,4-diones of the formula IV used as
starting materials for the preparation of a compound of the formula
II are also novel. They may, for instance, be obtained by reaction
of a correspondingly substituted 2-nitroaniline with a malonic acid
monoalkylester halide, reduction of the formed 2-nitromalonic acid
alkyl ester anilide, and cyclization of the 2-aminomalonic acid
ethylester anilide according to the following reaction sequence:
##SPC7##
According to the process described above, the following end
products may, for instance, be obtained:
7-chloro-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-1-methyl-5-(1'-naphthyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-1-methyl-5-(2'-thienyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-1-methyl-5-(3'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-5-[5'-chloropyridyl-(2')]-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5
H)-dione,
7-chloro-1-methyl-5-[4'-methyl-pyridyl-(2')]-1H-1,5-benzodiazepine-2,4-(3H,
5H)-dione,
7-chloro-1-methyl-5-(2'-nitrophenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dion
e,
7-chloro-5-(2'-cyanophenyl)-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dion
e,
7-chloro-5-(2'-methoxycarbonyl-phenyl)-1-methyl-1H-1,5-benzodiazepine-2,4-(
3H,5H)-dione,
5-(2'-acetylphenyl)-7-chloro-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dio
ne,
.[.7-methoxycarbonyl-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-di
one,.].
1-methyl-5-(2'-pyridyl)-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4-(3H,5H)
-dione,
7-bromo-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-1-methyl-5-(2'-pyrimidyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-cyano-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
1-ethyl-8-chloro-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
1-ethyl-7-chloro-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
1-ethyl-7-chloro-5-(3'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-1-n-propyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
1-n-butyl-7-chloro-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4(3H,5H)-dione,
7-chloro-1-cyclohexyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dion
e,
7-chloro-1-(.beta.-hydroxyethyl)-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(
3H,5H).[.-benzodiazepine-2,4-(3H,5H).].-dione,
7-chloro-1-dimethylaminoethyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,
5H)-dione,
8-chloro-1-phenyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
8-chloro-1-phenyl-5-thienyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-bromo-5-(2'-cyanophenyl)-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
7-bromo-1-methyl-5-(2'-nitrophenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
1-methyl-5-(2'-nitrophenyl)-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4-(3H
,5H)-dione,
5-(2'-cyanophenyl)-1-methyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4-(3H
,5H)-dione,
5-(2'-cyanophenyl)-7-fluoro-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dion
e,
7-fluoro-1-methyl-5-(2'-nitrophenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dion
e,
7-chloro-1-isopropyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
7-acetyl-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione,
7-chloro-1-dimethylamino-ethyl-5-(2'-nitrophenyl)-1H-1,5-benzodiazepine-2,4
-(3H,5H)-dione,
7-chloro-1-cyclohexyl-5-(2'-nitrophenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-
dione,
1-acetoxyethyl-5-(2'-nitrophenyl)-7-trifluoromethyl-1H-1,5-benzodiazepine-2
,4-(3H,5H)-dione,
1-acetoxyethyl-7-chloro-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-di
one.
The following examples further illustrate the present invention and
will enable others skilled in the art to understand it more
completely. It should be understood, however, that the invention is
not limited solely to the particular examples given below.
EXAMPLE 1
7-chloro-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
A mixture of 225 gm. (1 mol) of
7-chloro-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione, 147 gm.
(1.5 mol) of potassium acetate, 225 gm. (1.6 mol) of
o-bromopyridine, 180 gm. of copper powder and 1300 ml. of
dimethylformamide was heated for 15 hours at 160.degree.C. while
stirring. The mixture was vacuum-filtered while hot over a little
kieselguhr and washed afterwards with 200 ml. of hot
dimethylformamide. Upon cooling, a recrystalline product separated
out of the filtrate. 2 liters of semi-concentrated ammonia were
stirred into the mixture, stirring was continued for 15 minutes, it
was vacuum-filtered, the filter cake was washed with water until
free from copper, and the raw product obtained was recrystallized
from acetonitrile and subsequently from
methylene-chloride-petroleum ether. Yield: 50-55% of theory of the
compound of the formula ##SPC8##
having a melting point of 231.degree.-233.degree.C.
The starting material was obtained as follows: 373 gm. (2 mol) of
2-nitro-4-chloro-N-methylaniline were refluxed with 330 gm. of
malonic acid monoethylester chloride in 1500 ml. of benzene for 2-3
hours. After cooling, washing and evaporation, 590 gm. of
2-nitro-4-chloro-N-methylmalonic acid-monoethylester-anilide were
obtained. 200 gm. of this ester, upon being hydrogenated in
methanol with Raney nickel at 6 atmospheres and 20.degree.C.,
yielded 137 gm. of 2-amino-4-chloro-N-methylmalonic acid
ethylester-anilide, m.p. 114.degree.-117.degree.C. 872.2 gm. of the
aminoester were stirred at room temperature into a solution of 81.5
gm. of sodium in 7.25 liters of ethanol. The sodium salt of
7-chloro-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione
precipitated. It was vacuum filtered off, dissolved in 3 liters of
water, the solution was acidified with concentrated hydrochloric
acid, vacuum filtered, and the filter cake was dried at
100.degree.C. in vacuo. Yield: 596 gm (82.5% of theory), m.p.
215.degree.-217.degree.C.
EXAMPLE 2
1-Methyl-5-(2'-nitrophenyl)-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H
)-dione
26 gm. (0.1 mol) of
1-methyl-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-dione
were heated with 13 gm. of potassium acetate, 1 gm. of anhydrous
copper sulfate and 350 gm. of o-chloro-nitrobenzene for one hour at
150.degree.C. The reaction solution was diluted with methylene
chloride, washed with dilute ammonia, sodium hydroxide solution and
water, the organic phase was dried, and the solvent evaporated in
vacuo. The residue was carefully admixed with petroleum ether,
whereby a precipitate was formed, which was recrystallized from
methylene chloride/isopropylether. Yield: 30 gm. (80% of theory) of
the compound of the formula ##SPC9##
having a melting point of 230.degree.-232.degree.C.
EXAMPLE 3
Using a procedure analogous to that described in Example 1,
1-methyl-5-(1'-naphthyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 209.degree.-211.degree.C., of the formula ##SPC10##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
1-chloro-naphthalene.
EXAMPLE 4
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-thienyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 173.degree.-174.degree.C., of the formula ##SPC11##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-thiophene.
EXAMPLE 5
Using a procedure analogous to that described in Example 1,
1-methyl-5-(3'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 164.degree.-166.degree.C., of the formula ##SPC12##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
m-bromo-pyridine.
EXAMPLE 6
Using a procedure analogous to that described in Example 1,
1-methyl-5-[5'-chloro-pyridyl-(2')]-7-chloro-1,5-benzodiazepine-2,4-(3H,5H
)-dione, m.p. 216.degree.-217.degree.C., of the formula
##SPC13##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
2,5-dichloro-pyridine.
EXAMPLE 7
Using a procedure analogous to that described in Example 1,
1-methyl-5-[4'-methyl-pyridyl-(2')]-7-chloro-1,5-benzodiazepine-2,4-(3H,5H
)-dione, m.p. 225.degree.-227.degree.C., of the formula
##SPC14##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione, and
2-chloro-4-methyl-pyridine.
EXAMPLE 8
Using a procedure analogous to that described in Example 2,
1-methyl-5-(2'-nitro-phenyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione
, m.p. 206.degree.-208.degree.C., of the formula ##SPC15##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-chloro-nitrobenzene.
EXAMPLE 9
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-cyano-pheno)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 209.degree.-210.degree.C., of the formula ##SPC16## was
prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-chloro-cyanobenzene.
EXAMPLE 10
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-methoxycarbonyl-phenyl)-7-chloro-1,5-benzodiazepine-2,4-(3H
,5H)-dione, m.p. 183.degree.-184.degree.C., of the formula
##SPC17##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
methyl-o-chloro-benzoate.
EXAMPLE 11
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-acetyl-phenyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dion
e, m.p. 205.degree.-206.degree.C., of the formula ##SPC18##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-chloro-acetophenone.
EXAMPLE 12
Using a procedure analogous to that described in Example 1,
1-n-propyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 177.degree.-178.degree.C., of the formula ##SPC19##
was prepared from
1-n-propyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
.[.EXAMPLE 13.].
.[.Using a procedure analogous to that described in Example 1,
1-methyl-5-phenyl-7-methoxycarbonyl-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 145.degree.-147.degree.C., of the formula ##SPC20##
was prepared from
1-methyl-7-methoxycarbonyl-1,5-benzodiazepine-2,4-(3H,5H)-dione and
chlorobenzene..].
EXAMPLE .[.14.]. .Iadd.13 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 244.degree.-246.degree.C., was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.15.]. .Iadd.14 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-pyridyl)-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-d
ione, m.p. 164.degree.-168.degree.C., was prepared from
1-methyl-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.16.]. .Iadd.15 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-ethyl-5-(2'-pyridyl)-8-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 194.degree.-196.degree.C., of the formula ##SPC21##
was prepared from
1-ethyl-8-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.17.]. .Iadd.16 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-ethyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 194.degree.-196.degree.C., was prepared from
1-ethyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.18.]. .Iadd.17 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-ethyl-5-(3'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 196.degree.-198.degree.C., was prepared from
1-ethyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
m-bromo-pyridine.
EXAMPLE .[.19.]. .Iadd.18 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-n-butyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 148.degree.-149.degree.C., was prepared from
1-n-butyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.20.]. .Iadd.19 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-phenyl-5-(2'-pyridyl)-8-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 203.degree.-204.degree.C., of the formula ##SPC22##
was prepared from
1-phenyl-8-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.21.]. .Iadd.20 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-pyridyl)-7-bromo-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 197.degree.-198.degree.C., of the formula ##SPC23##
was prepared from
1-methyl-7-bromo-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.22.]. .Iadd.21 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-methyl-5-(2'-pyrimidyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 243.degree.-245.degree.C., of the formula ##SPC24##
was prepared from
1-methyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyrimidine.
EXAMPLE .[.23.]. .Iadd.22 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-cyclohexyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 190.degree.C., of the formula ##SPC25##
was prepared from
1-cyclohexyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.24.]. .Iadd.23 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-isopropyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 165.degree.-167.degree.C., was prepared from
1-isopropyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.25.]. .Iadd.24 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-methyl-5-phenyl-7-acetyl-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 134.degree.-137.degree.C., of the formula ##SPC26##
was prepared from
1-methyl-7-acetyl-1,5-benzodiazepine-2,4-(3H,5H)-dione and
chlorobenzene.
EXAMPLE .[.26.]. .Iadd.25 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-(.beta.-hydroxy-ethyl)-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3
H,5H)-dione, m.p. 176.degree.-178.degree.C., of the formula
##SPC27##
was prepared from
1-(.beta.-hydroxy-ethyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione
and o-bromo-pyridine.
EXAMPLE .[.27.]. .Iadd.26 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-ethyl-5-(2'-pyridyl)-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-di
one, m.p. 153.degree.-155.degree.C., was prepared from
1-ethyl-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.28.]. .Iadd.27 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-benzyl-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 216.degree.-128.degree.C., of the formula ##SPC28##
was prepared from
1-benzyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-bromo-pyridine.
EXAMPLE .[.29.]. .Iadd.28 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-(.beta.-hydroxy-ethyl)-5-(2'-pyridyl)-7-trifluoromethyl-1,5-benzodiazepi
ne-2,4-(3H,5H)-dione, m.p. 149.degree.-151.degree.C., was prepared
from
1-(.beta.-hydroxy-ethyl)-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-
dione and o-bromo-pyridine.
EXAMPLE .[.30.]. .Iadd.29 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-(.beta.-acetoxy-ethyl)-5-(2'-pyridyl)-7-chloro-1,5-benzodiazepine-2,4-(3
H,5H)-dione, m.p. 196.degree.-198.degree.C., of the formula
##SPC29##
was prepared from
1-(.beta.-acetoxy-ethyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione
and o-bromo-pyridine.
EXAMPLE .[.31.]. .Iadd.30 .Iaddend.
Using a procedure analogous to that described in Example 2,
1-(.gamma.-hydroxy-propyl)-5-(o-nitro-phenyl)-7-chloro-1,5-benzodiazepine-
2,4-(3H,5H)-dione, m.p. 162.degree.-163.degree.C., of the formula
##SPC30##
was prepared from
1-(.gamma.-hydroxy-propyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione
and o-chloro-nitrobenzene.
EXAMPLE .[.32.]. .Iadd.31 .Iaddend.
Using a procedure analogous to that described in Example 2,
1-cyclohexyl-5-(o-nitro-phenyl)-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-di
one, m.p. 182.degree.-183.degree.C., was prepared from
1-cyclohexyl-7-chloro-1,5-benzodiazepine-2,4-(3H,5H)-dione and
o-chloro-nitrobenzene.
EXAMPLE .[.33.]. .Iadd.32 .Iaddend.
Using a procedure analogous to that described in Example 1,
1-methyl-5-phenyl-7-cyano-1,5-benzodiazepine-2,4-(3H,5H)-dione,
m.p. 260.degree.-262.degree.C., of the formula ##SPC31##
was prepared from
1-methyl-7-cyano-1,5-benzodiazepine-2,4-(3H,5H)-dione and
chlorobenzene.
The compounds according to the present invention, i.e., those
embraced by formulas I, II and III above, have useful
pharmacodynamic properties. More particularly, the compounds of the
instant invention exhibit very effective psychosedative and
anticonvulsive activities in warm-blooded animals, such as mice,
rats, golden hamsters, cats and dogs, with extremely low
toxicity.
Particularly effective are those compounds of the formulas I, II
and III wherein
R.sub.1 is straight or branched alkyl of 1 to 3 carbon atoms or
hydroxyalkyl of 2 to 3 carbon atoms,
R.sub.2 is hydrogen,
R.sub.3 is pyridyl,
R.sub.4 is halogen, trifluoromethyl or cyano in 7-position,
R.sub.5 is trifluoromethyl, nitro, cyano or halogen in
2-position,
R.sub.6 is hydrogen,
R.sub.7 is cyano in 7-position,
R.sub.8 is cyano or nitro,
R.sub.9 is hydrogen, and
R.sub.10 is halogen or trifluoromethyl in 7-position.
The psychosedative and anticonvulsive activities of the compounds
according to the present invention were ascertained by standard
pharmacological test methods on laboratory animals, namely,
Swinyard et al., J. Pharmacol. Exptl. Therm. Volume 106, page 319
(1952); Janssen et al., Psychopharmacologia Volume 1, page 389
(1960); and Broadhurst et al., J. Genet. Psychol. Volume 95, page
217 (1959).
For pharmaceutical purposes the compounds according to the present
invention are administered to warm-blooded animals perorally or
parenterally as active ingredients in customary dosage unit
compositions, that is, compositions in dosage unit form consisting
essentially of an inert pharmaceutical carrier and one effective
dosage unit of the active ingredient, such as tablets, coated
pills, capsules, wafers, powders, solutions, suspensions,
emulsions, syrups, suppositories and the like. One effective dosage
unit of the compounds according to the present invention is from
0.0083 to 0.84 mgm/kg body weight, preferably 0.0166 to 0.42 mgm/kg
body weight. The daily dose rate is from 0.083 to 2.5 mgm/kg.
Such dosage unit compositions may, in addition to one or more of
the compounds according to the invention, also contain one
effective dosage unit of one or more other pharmacologically active
ingredients, such as spasmolytics or psychopharmaceuticals.
The following examples illustrate a few dosage unit compositions
comprising a compound of the instant invention as an active
ingredient and represent the best mode contemplated of putting the
invention to practical use. The parts are parts by weight unless
otherwise specified.
EXAMPLE .[.34.]. .Iadd.33 .Iaddend.
Coated Pills
The pill core composition was compounded from the following
ingredients:
______________________________________
7-Chloro-1-isopropyl-5-(2'-pyridyl)-
1H-1,5-benzodiazepine-2,4-(3H,5H)- dione 5.0 parts Lactose 28.5
parts Corn starch 15.0 parts Gelatin 1.0 parts Magnesium stearate
0.5 parts Total 50.0 parts
______________________________________
Compounding procedure:
The benzodiazepinedione compound was intimately admixed with the
lactose and the corn starch, the mixture was granulated by
moistening it with an aqueous 10% solution of the gelatin and
forcing the moist mass through a 1 mm-mesh screen, and the
granulate was dried at 40.degree.C. and again passed through the
screen. The resulting dry granulate was admixed with the magnesium
stearate, and the mixture was compressed into 50-mgm pill cores,
which were then coated with a thin shell consisting essentially of
an aqueous suspension of sugar, titanium dioxide, talcum and gum
arabic. The coated pills were finally polished with beeswax. Each
coated pill contained 5.0 mgm of the benzodiazepinedione compound
and, when administered perorally to a warm-blooded animal of about
60 kg body weight in need of such treatment, produced very good
psychosedative and anticonvulsive effects.
Analogous results were obtained when an equal amount of the
following compounds was substituted for benzodiazepinedione
compound in the above pill core composition:
(a)
7-Chloro-1-methyl-5-(2'-nitro-phenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-di
one;
(b)
7-Chloro-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione;
(c)
7-Chloro-1-methyl-5-(2'-cyano-phenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-di
one;
(d)
7-Bromo-1-methyl-5-(2'-pyridyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione;
a nd
(e)
1-Methyl-5-(2'-pyridyl)-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4-(3H,5H
)-dione.
EXAMPLE .[.35.]. .Iadd.34 .Iaddend.
Suppositories:
The suppository composition was compounded from the following
ingredients:
______________________________________
7-Cyano-1-methyl-5-phenyl-1H-1,5- benzodiazepine-2,4-(3H,5H)-dione
5.0 parts Cocoa butter 1695.0 parts Total 1700.0 parts
______________________________________
Compounding procedure:
The finely powdered benzodiazepinedione compound was stirred with
the aid of an immersion homogenizer with the cocoa butter which had
previously been melted and cooled to 40.degree.C. 1700 mgm-portions
of the homogeneous mixture were then poured at 35.degree.C. into
cooled suppository molds. Each suppository contained 5.0 mgm of the
benzodiazepinedione compound and, when administered by the rectal
route to a warm-blooded animal of about 60 kg body weight in need
of such treatment, produced very good psychosedative and
anticonvulsive effects.
Analogous results were obtained when an equal amount of
7-chloro-1-methyl-5-(2'-cyano-phenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-di
one was substituted for the benzodiazepinedione compound in the
above suppository composition.
Analogous results were also obtained when an equal amount of any
one of the other compounds embraced by formulas I, II and III above
was substituted for the particular benzodiazepinedione compounds in
Examples 33 and 34. Likewise, the amount of active ingredient in
these examples may be varied to achieve the dosage unit range set
forth above, and the amounts and nature of the inert pharmaceutical
carrier ingredients may be varied to meet particular
requirements.
While the present invention has been illustrated with the aid of
certain specific embodiments thereof, it will be readily apparent
to others skilled in the art that the invention is not limited to
these particular embodiments, and that various changes and
modifications may be made without departing from the spirit of the
invention.
* * * * *