CA1051887A - Triazolo (4,3-d) (1,4) benzodiazepine-3,6-diones - Google Patents

Abstract

Abstract Compounds having the structure or a pharmaceutically acceptable acid-addition salt thereof, wherein R1 is hydrogen, alkyl, phenyl or benzyl; R2 is hydrogen or alkyl; R3 is amino, alkylamino, dialkylamino or

Description

~(~5~387 This invention relates to novel ~ria~olo [4,3-d]-[1,4]benzodiæePine-3~6-diones which are useful as anti-inflammatory agents.
Compounds of the present invention have the structure N _ N
(CH2)n R3 or a pharmaceutically acceptable acid-addition salt thereof, wherein Rl is hydrogen, alkyl, phenyl or benzyl; R2 is hydrogen or alkyl; R3 is amino, alkylamino, dialkylamino or CH2-(CH2)m wherein A is CH-Q, oxygen or N-Q, Q is hydrogen, alkyl or phenyl and m is 0 or 1; R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy or alkylthio; and n is 2, 3 or 4; wherein alkyl is alkyl of 1 to 4 carbon atoms.
This invention also provides a process for the preparation of a compound having the formula 4 ~ N~ 2 N Nl (CH2)n R3 ,~ ~

~C~51~7 or a pharmaceutically acceptable acid-addition salt thereof, wherein Rl is hydrogen, alkyl, phenyl or benzyl; R2 is hydrogen or alkyl, R3 is amino, al]cylamino, dialkylamino or ,~ C~2-(CH2)m wherein A is CH-Q; oxygen or N-Q, Q is hydrogen, alkyl or phenyl and m is 0 or 1; R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, alkyl, alkoxy or alkylthio; and n is 2, 3 or 4; wherein alkyl is alkyl of 1 to 4 carbon atoms which comprises reacting a compound of the formula IRl 4 ~ ~ IV

wherein Rl is alkyl, phenyl or benzyl and R2 and R4 are defined as above with a bzse strong enough to remove the amide proton and form a salt of the formula IRl O

4 ~ ~ R2 V
Il ~0 ~ N

reacting this salt with a compound of the formula R3(CH2)nX

'7 wherein X is chlorine, bromine, iodine, alkylsulfonate or arylsulfonate and R3 and n are cLefined as above to form a compound of Formula I wherein Rl is alkyl, phenyl or benzyl and, if desired, reducing the compound of Formula I wherein R1 is benzyl to form a compound of Formula I
wherein Rl is hydrogen.
The term "alkyl" as used throughout the specification, either by itself or as part of a larger group, refers to both straight and branched chain alkyl groups containiny 1,

2, 3 or 4 carbon atoms.
The term "alkoxy", as used throughout the specification, refers to a group of the formula Y-O-, wherein Y is alkyl as defined above.
The term "halogen", as used throughou~ the specification, refers to fluorine, chlorine, bromine, and iodine.
Exemplary of the heterocyclic moieties contemplated by the formula CH2- (CH2)n -N A

are l-pyrrolidinyl, l-piperidinyl, 3-oxazolidinyl, 4-mor-pholinyl, l-imidazolidinyl, l-piperazinyl, 4-alkyl-1-piperazinyl,

3-alkyl-1-imidazolidinyl, 4-alkyl-1-piperidinyl, and 3-alkyl-l-pyrrolidinyl.
The novel compounds of this invention are produced from compounds having the formula ~Rl ~ ~ O II

i~5~ 37 wherein R5 can be halogen ~preferably bromine or chlorine)~
sulfhydryl, alkoxy, alkylthio, or phenyl-alkyithio and R1 can be alkyl, phenyl, or benzyl. The compounds of forrnula II are known; see for example United States paten~ number 3,414,563 and Swiss Patent 485,742.
Reaction of a benzodiazepine of formula II with an alkyl carbazate having the formula H2N-NHC-OZ, wherein Z
is alkyl, yields a compound having the structure

4 ~ / ~ ~ 2 III

_~--C--OZ
H o wherein Rl is alkyl, phenyl or benzyl. The reaction can be run without a solvent, or in a nonreacting organic solvent, at a temperature of from about 50C to 250C for about 5 minutes to 24 hours, preferably from about 80C to 140C for about 30 minutes to 6 hours. The benzodiazepine of formula II, and the alkyl carbazate are reacted in approximately a 1:1 molar ratio. Heating a compound of formula III at an elevated temperature, e.g., 80C to 200C, preferably 100C to 180C, yields a compound having the structure 4 ~ N ~ R2 IV

N ~
N

~3S~3'7 wherein Rl is alkyl~ phenyl, or benzylO The compounds of formula IV are novel intermediates, and as such, they constitute a part of this inven-tion In order to obtain the triazolobenzodiazepines of formula I, a triazo]obenzodiazepine of formula IV is reacted with a base strong enough to remove the amide proton, e.g., thallous ethoxide, sodium hydride, sodium ethoxide or sodium amide, and form a salt having the s-tructure R4 ~ ~ ~ P~2 V

Il ~=O
M N

The salt of formula V is subsequently reacted with a compound having the formula R3(CH2~nX, wherein X is chlorine, bromine, iodine, alkylsulfonate (e.g., methanesulfonate~ or arylsulfonate (e.g., toluenesulfonate) and R3 and n are defined as above to obtain a compound having the structure IRl ~\ _ N VI
Il ~=G
N ~
(1H2 ~ n_R3 wherein R1 is alkyl, phenyl or benzyl. The reaction of a triazolobenzodiazepine of formula IV with thallous ethoxide is run in a non-reactive polar solvent, e.gO, dimethylformamide, at a temperature of from about 0C to 180C, preferably at

-5-1(~53L~
room temperature to 809C, for a period of about 1 minute to 5 hours, preferably for 10 minutes to 1 hour~ The reaction of a salt of formula V with a compound of the structure R3(CH2)nX
is run at about 50C to 200C for a period of about 30 minutes to 72 hours~ preferably at 80C to 140C for 2 to 24 hours.
Alternatively, the compounds of formula Vl can be pre-pared by first reacting a salt, such as the salt of formula V
with a compound having the formula H0-(CH2)n X VII

wherein X and n are as defined previously, to obtain compounds having the structure R~
R4 ~ ~ R2 N VIII
~1 ~

( CH2 ) n~OH

wherein Rl is alkyl, phenyl or benzyl. The reaction of a salt of formula V with a compound having the formula H0-(CH2)n-X
is run at about 50C to 200C for a period of about 30 minutes to 72 hours, preferably at 80C to 140C for 2 to 24 hours.
The compounds of formula VIII are novel intermediates, and as such, they constitute a part of this invention.
The compounds of formula VI~I can be converted to the corresponding compounds of formula VI using procedures well known in the art. The proton of the hydroxyl group in the compounds of formula VIII is first converted to a leaving ~S~

group, e.g. D by reacting the compolmds with an alkyl (or aryl)sulfonyl halide in the presence of a non-reacting organic baseO The resulting intermediate can then be converted to a compound of formula Vl by reacting it with ammonia, an alkylamine, or a dialkylamine or an amine having the formula CH2(CH2)m A

wherein A and m are defined as above. This reaction can be carried out in an organic solvent, e.g., toluene, at a temperature of from 25C to 200C for 15 minutes to 24 hours, preferably at 80C to 150C for 1 hour to 5 hours.
Reduction of triazolobenzodiazepines of formu]a VI, wherein Rl is benzyl, to yield compounds having the structure IX
~,^~ N----~ O
4 ~ ~ R2 N N

(CH2 ) n~R3 ~5~

can be accomplished by reacting the com~ound with hydrogen under pressure in the presence of a catalyst, e.q., palla-dium or Raney nickel, or by reacting the compound with anhydrous liquid hydrofluoric acid.
Compounds of ~ormula I wherein R2 is hydrogen are preferred.
Compounds of formula I wherein R3 is dialkylamino are preferred.
Compounds of formula I wherein n is 2 or 3 are pre-ferred.
Compounds of formula I wherein R4 is in the 9 or 10-position are preferred, and those wherein R4 is in the 10-position are particularly preferred. Compounds of formula I wherein R4 is halogen or trifluoromethyl are preferred, chlorine being the most preferred halogen.
The triazolobenzodiazepines of formula I form pharma-ceutically acceptable acid-addition salts with inorganic and organic acids. These acid-addition-salts, in addition to having the useful pharmacological activity of the cor-2~ responding free base, frequently provide useful means forisolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such a.s sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate acid.
Illustrative are the hydrohalides, especially the hydro-chloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, tartrate, maleate, fumarate, citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulfon-ate, and the like.
The triazoloben~odiazepines of formula I, and the pharmaceutically acceptable acid-addition salts of the com-pounds, are useful in treating inflammation in mammalian species, e.g., rats, dogs, cats, monkeys, etc. Joint tender-ness and stiffness (in condiditions such as rheumatoid arthritis) are relieved by the above described compounds7 The compounds of this invention are formulated for use as anti-inflammatory agents according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs, or powders, or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. The compounds of this invention may be administered in amounts of 100 mg/70kg/day to 2 g/70kg/day, preferably 100 mg/70kg/day to 1 g/70kg/day.
The following examples are specific embodiments of this invention.

~ 5~ ~7 M~59/74 Example 1 3H s-triaæolo[4,3-d][1,4]henzodiazepine-3,6(5H)-dione, . _ . _ .. . .
hydrochloride (1:1) A. 10-Chloro-2,7-dihydro-7-methyl-3H-s-triazolo[4,3~d]-[1,4]benzodiazepine-3,6(5H)-dione ~ . . . .
5,7-Dichloro-1,3-dihydro-1-methyl-2~ 1,4-benzodia-zepin-2-one (50 g) and ethylcarba~ate (43 g) are refluxed in 2,000 ml of toluene for 4 hours. The toluene is decanted from the insoluble mixture and removed under vacuum, produc-ing a white powder which is freed from the accompanying viscous material by stirring with acetonitrile The white powder is insoluble and is filtered off; the filtrate is saved.
The residue from the original reaction mixture is re-fluxed for 4 hours in dioxane. The solvent is then removed under vacuum leaving a white powder which is stirred with acetonitrlle to remove viscous impurities. This mixture is filtered, the white powder combined with the powder obtained previously (total 45 g) and recrystallized from 50~ methanol-dioxane to yield the title compound, melting point 268-269C.
Both acetonitrile filtrates are combined, stripped and heated at about 100C for 2 days. This process yields another 5.5 g of product.
Anal. Calc'd for CllH9ClN4O2:

C, 49.92; H, 3.42; N, 21.17; Cl, 13.40.
Found: C, 49.85; H, 3.44; N, 21.20; Cl, 13.32.

MT5g/74 ~5~

B. 10-Chloro-2-~2-(dimeth~lamino)l_thyl]-2,7--dihydro-7-methyl-3H-s-triazolo[4,3-d]~ ]benzodiazepine-3,6~5H)-dione, hydrochloride (1:1) 10-Chloro-2,7-dihydro-7-methyl-3H-s-triazolo[4,3-d]-[1,4]benzodiazepine-3,6(5H)-dione t7.92 g) is suspended in 120 ml of tetrahydrofuran. Thallous ethoxide (7.5 g) is added dropwise to the suspension while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes and the mixture is then filtered. The filter cake is washed by stirring as a slurry with ether, and filtered to yield 13.5 g of the thallium sa]t.
2-(Dimethylamino)ethyl chloride (1.5 equivalents) is added to a refluxing suspension of the thallium salt in 600 ml of toluene. After 2 hours of reflux, another equal amount of 2-(dimethylamino)ethyl chloride is added and the refluxing is continued for 5 hours.
The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts.
The infusorial earth is washed by stirring in benzene and filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 x 4.5 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield 7.5 g of product. Recrystallization from ethyl acetate and then from hexane gives a pure product.
A sample (3.5 g) of the product is dissolved in a mixture of methanol and ether (just sufficient methanol to achieve solution), and slightly more than one equivalent of MT59~74 :~CDS~ 7 HCl (ethereal) is added. The precipltate is filtered off and further purified by diss~lving it in hot methanol, followed by reprecipitation with ether, to gi~e 3.6 g of the title compound, which is dried under vacuum at 140C
overnight. The product has a melting point of 284-285.5C.
Anal. Calc'd. for C15HlgC12N5O2:
C, 48.40; H, 5.15; N~ 18.81; Cl; 19.05.
Found: C, 48.14; H, 5.42; N, 18.60; Cl, 18.78.

Example 2 10 10-Chloro-2-[3-(dimeth lamino) ro 1]-2,7-dih dro-7-meth 1-Y P PY . Y
3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H) dione 10-Chloro-2,7-dihydro-7-methyl-3H-s-txiazolo[4,3-d]-[1,4]benzodiazepine-3,6(5H)-dione (2.64 g, prepared as des-cribed in Example lA) is dissolved in 40 ml of dimethyl-formamide at 70C. Thallouc ethoxide (2.49 g) is added dropwise to the solution while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes, the mixture is cooled to 25C, and 200 ml of ether is added.
The resulting precipitate is filtered off and dried at 25C
under vacuum for 4 hours to yield 4.5 g of the thallium salt.
3-(Dimethylamino)propyl chloride (l.S equivalents) is added to a refluxing solution of the thallium salt prepared above in 150 ml of toluene After 3 hours of reflux, an equal amount of 3-(dimethylamino)propyl chloride is added and the refluxing is continued for 5 hours.

The reaction mix-ture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and filtered through fresh infusorial earth. The ~wo solu-tions are combined and passed through a 12 x 3 cm column of magnesium silicate. The column is further eluted wlth about 3 liters of ethyl acetateO After comhining the solutions, the solvents are removed under vacuum to yield 2.6 g of product. Recrystallization from ethyl acetate yields the title compound, which is dried for 2 hours at 100C under vacuum. The title compound has a melting point of 178-179C.

Anal. Calc'd. for C H ClN5O2:

C, 54.95; H, 5.76; M, 20.02; Cl, 10.14~
Found: C, 54.72; H, 6.00; N, 20.02; Cl, 10.06.

Examples 3 - 13 Following the procedure of Example 1, but sub-stituting the compounds indicated in column I below for 5,7-dichloro-1,3~dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, the compounds indicated in column II are obtained.

3LO S~ MT 5 9/7 4 I ~a o ~ ~
I I O I h I ~ O
O ~'C) O ~r O u~

~ O ~ ,rd r-.IJ ~I NI O O a) N O I ~ ~ I ~>
rl ` O ~a O .~ ra ~ ~) N 11) ~-1 O ~) ~ Or~l N I ,~ ~1 1~ ~ a) (~1 a) S~ ^ O (I) ~ tl) O ~I rd ~ ^ i O ~ 1 o N ~
rl E~ N -r~ 1 0 '-- O ~ ~
rd h al O ~ ~ ~ N 'a ~ O N

H ~ ~ ` O^ X I I ~ r ~1 O ~1 ,^/ ~o ~- a3o ~ ~)o I --~ o ~ a ~ u) lw c~
C ~ o ~ ri ~ r-l O E~
~a--rd .CE~ h Q, E~ I ~ h -,1 ,~
d ~) Itd O r---drd ~1 1 ~1 I O ~ ~ r~ N r I I N r-l I 11) r-/ r-l 'd ~ ~ ~, (11 o ~ ~ ~rl ~
I er ~ d.C I -rl~ ~ rl.C r~l ~1 N ,~ rl I o ~ o ~ o ~ o ~a o ~1a~ r~l O ~ Oa) ~ a)(I) ~ ~r a) I I a) r( I ~ a~ ~ N OE~ ~a NE~ O N E~ tN 1~ N
r~ >1 0 I~rl r 1 ~ r~-rl ~ ~ tlJr~ 5 C) r~ Gl O O I I nt .~ N ~~ ~ ) .C~a .C O ~Grd rl r~ ra ~a ~ r~J -r~ O O ~r~
N ~r~ ~ ~ ¦`~ ~ Q O--~r~ Q -,~--rd ~a -r~ ~ rl O ra F ~ 'd ~a rl U') I IJ r~ O I r~ I I O 1-l I ra N I O rd O
0 a) ~ ~ o(~ O N O ~ I ~ N
Q 1~ ~ ~ ~ ra~ I~ ~ r-l 1~ r-l L. r~ rl ~ ¦ Q .C
¦ ~ I I r~l ~ I ~ r~l .C I ~ C) .C I ~ ~ Il ) I r~ G) a3 O r-l O I 11) I a) o I ~ s~ o a N I O
I O I O ra I ~ r-~ I
O N r~l I -1 C~
r~ ~ ~ r~ Q o a) ~, ,~ ~ .,~ ra I ~ ,,, ~ Q ~ F~ 'd Q) ~a ~ r rO r~
S~ I a) ~ r~ I N I ~ ~ ~ ~ Q~
~O ~ 1 1 r l N
r~ r-l N r~l~a r~ rd I O I I r-l N I ~r~
O r~ O N O C ~ r) ra Hr_~ ~ h ~a ri ~ ~ r~ C ~~ ~ O
.I I rd O C a) ru ~ ~ r-l r-l N
~:O _~ ~ N ~ Q
,_1 C C ~ N F~ C :~ o 5O ~1 ~r~ x Q
~-1~~1 ,C a) ~CI Q C ` ra ~I ra IU a) O
,C -~ ) r~ a I E~ ~ ,C
c.) o a) o ~ ~r ~ I ~, O ~) N ~ 1-1 I a) r~l Il') O ~ r~l r~ 1 r~l C r-l O
r-l O ~: O ~1 0 r-l O Q O r-l ~ 1 ~ ,~l r~ h ~N S~ ~ r~ O I
N r-l ~ O I O ,C O ~ O r~ r_l ~U 11) r-l O r~l ~) r-l `r~ ~ Il) O ~ i N C $-1 ,C a) .~ r~l .~ ~ N S-l R Sl (~ O ~ O F V I O ~ ~ Q a) ~ r~ I rl I I I ~ I I I rl I C
~_1 ~ ra ~ 1~ ra oo Q-r~
X

1~51~,~37' I oI I o I o Ct ~-- ~t~ ~ ht-- h --` ~ ~ O ~ ~ ` I ~S ~ o tIt O
O I ~ `3 r~ ` N '~ h rl ~t ~~1 ~t ~ I ~ .C (~t S~ -t ,t Q O
t~J ~ atr-l ~ O.C ~ Cl ~ r t rl 0 --t O t-~~ O ~r t-- S ~ S ~ N tJt >1 '-I OS ''I Oa~ ~ o ~ ` v I ~--O -~t~ O ,1 1 0 rt ~t ,~ O r-- r I
raat N r~ C~ I ~ h ` h t~ I ~t o I r~ ,_ ~ ~ I t r~
t,, ,1 ,_,1 ,1 ~I N ~ I ~
rl ht 5:1~a h ~-- ns ~ _ u~ ¦ ~t t t U~ ~t ~ , t H I I -- ~ h `- >
HI Utl~t trtl~~: I t ~ ~: ~ at ~ t~t N I ~ I ~ I t I ` I t ~ ~ ~) I tlt ~~ xl~I ~ ta) utl~ Ct O O at,~ N
E~I ~ IN (~ I~ I I ~ ~t rl -tN I (~tI I tltO :1~ l at o o ~ o ,~
~l o ~o o ~
OO h -th ~ t ,Irl I ,1 ,1 td ^ -1 Il) 0 c~t ~ Q, o ~U Q~ ~t ~ ~ N
~ ~ al~1 ~ at~ ~Gt r~ ~t ut ~ I
:>1 S N~ .C Nr-t t_ N ~t t '-- ,-t r-- at t -~I ~ ~ at ~ >1 1 ~ ~ l q at o I ~ao I ~ ~ Q,~ -I t I ~t ~ ~r ,t o ~l l- o ~ l o at s l l at X ~ h ~ N I ~ N ~ r-- N ~ a) O ~t o ~ t t- ~ at ,t I ~ ~1.C~
~ ~ at ~>~ l at ~~ o ~ o rt ~ -~
N r_ Q -rl N r~ R --t `-- ~t R '~ h ~ --- at -~ t t t~ ~1 ~ h ~I ~ tlt l I
at ~ ~r o tIt ~ ~r o ~ r o (~t ~ N (~t --' ~) h R .C ` r-t R ~ ` --t ~ S ` ~1 '--.C ~ '-- I `
I t ~t ~ I ~ ~-1 .C I rl '-t L I rl -r~ I O ~:r t- at ~ U tl- at ~ ~t N '~ ~ V ~t ~J ~ ~ r-t c~ ~ at I O
.rt~1 1a) ~: I ^ I
t ~ I O I I ~t ut V I o ~ I ~t X I
I N O ~t I N I O ~
O ~ 1 S O I O .~ t )-t~-l~ ~t h ~ h ~t ~, at >~ o,~ Ut ~ R~ N
5 N rl I ,~ Ct S ~ (~
-1 Nrt al l ~1 ~v a~ ~V ~
q /~ I R t~ OI --I I O I O
v ~ I ~ I ~t ~~t I O N
' ~r~-1 N ` O` N I t ~
I I ~I Nr-l I ~ Ct ~-1 0 ~ ~ R
l_t O I h ~1~I tlt r~ 1 S I
~ 0 ~ ::~Q:>1 Q. rt ~
El~ N ~ ~ ~ N I r-t ~3v^v 11~ at `t~) t-a t'q I
I O I -1 I r~I rl ` I I
o C,'t I ~ I O I ~C I I O
r-l ~t ~ N O N O N O ~t ~r~ ~ ~ h i h ~ S t ::~
N ~ N a) O ,-1 o Ct O .C
.c a) ~ R ~ R -~ ~
a) I s ,~ at ,Q at o Q ~r t t a)~t ~r v I I I ` I S I ` I I
`J ~ ~ ~ Q, u-t ~t ~rt ,~

at ~ ~ o ~ ~t ~t X ~ , t ~ ,-t 30 ~

~L85~

Examples 14 - 16 Following the procedure of Example 2, but sub-stituting the compounds indicated in column I below for 3-~dime~hylamino)propyl chloride, the compounds indicated in column II are obtained.

~5~

r-O
o I
N t~
.q I ! ~ I
O
~I r-~ Q~
I ~ O O rl O
O r~S~ r~ ~ r~
h ~ 0 0 1~ 0 Il) O I~ N ~: r-l N ~
O r~l O ~ 1 0 r~ rl Ql rl -r~
~ O S~
I ~E~ ~ I h ~ I
O
Hr-l r~51 j O U~
HI O aJ>1 1 ) U~ I U~l r~ N ~ ~ rl 5~ ~~
~r1 1~ 0 ~1 ~) ~ ~1 t't ~D
E~:>~r~ r~ rO I
~Q~ h ~d `' ~
,~ 0~ 1 1 ~ I I ~ I
o~ I ^~ ~: a) ~5~ a V~u~l~l O ~ ~

~ I ''O 1-- N O i~ N
t~ ~ IO O-r~ O O
~',~ Or~ H h ~
~'C; O .C~c~ O
0 r1V ~ N U >t N
~ E R~
I I (I)O-rl ~) 0 ~1 a) ~1 t~ Nr~l r~ Q H r~ Q

rc ~
rt O r-t ~ ~J
a~ u r~ ~ Q
r~ r~
O
O Rl H U ~ r-t ~ ~ O
r~
OQ~ O
V O
Q, ,~ o a~
O ~ U~ rO
,r, .C rl r~
O
~ `~ r~
I
~ ~ ~ U

r~
R

~D
~ r~ r~ r~
X

3L~S~ 7 Example 17 10-Chloro-2-[3-(dimethylami~o)propyl]-2,7-dihydro-3H-s-trlazolof4,3-d~[1,4~benzodiazepine-3,6(5H)-dione A. 7-Ben~yl-10-chloro-2,7-dihydro-31l-s-triazolo[4,3-d]-[1,4]benzodiazepine-3,6(5H)-dione l-Benzyl-5,7-dichloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (0.10 mole) and ethyl carbazate (0.]1 mole) are mixed together in 400 ml of dimethylforrnamide for 30 minutes while heating at 130C to yield 7-benzyl-10-chloro-2,7-dihydro-3H-s-triazolo~4,3-d][1,4]benzodiazepine 3,6(SH)-dione.

B 7-Benzyl-10-chloro-2-[3-(dimethylamlno)propyl]-2,7-.

dihydro-3H-s-triazolo[4,3-d][1,4]benzodia~epine-3,6-(SH)-dione 7-Benzyl-10-chloro-2,7-dihydro-3H-s-triazolo[4,3-d]-11,4]benzodiazepine-3,6(5H)-dione (0.02 mole) is dissolved in 100 ml of dimethylformamide at 70C. Thallous ethoxide (0.02 mole) is added to the solution and stirred for 1 hour at room temperature. The solution is diluted wi-th 300 ml of ether, and the precipitated salt i5 filtered off.

3-(Dimethylamino)propyl chlori(1e (1.5 equivalents) is added to a refluxing solution of the thallium salt prepared above in 150 ml of toluene. After 3 hours of reflux, an equal amount of 3-(dimethylamino)propyl chloride is added and the reflu~ing is continued for 14 hours.
The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is ~ashed by stirriny in toluene and filtered throuyh fresh infusorial earth. The two solu-tions are combined and passed through a 12 x 3 cm column of magn~sium silicate. The column is further eluted with about 3 liters oF ethyl aceta-te. After combining the solutions, the solvents are removed under vacuum to yield 7-benzyl-10-chloro-2-[3-(dimethylamino)propyl]-2,7-dihydro-3H-s-triazolo-[4,3-d][1,4]benzodiazepine-3,6(5H)-dione.

C. 10-Chloro-2-[3-(dimethylamino~propyl]-2,7-dihydro~3H-s-triazolo[4,3-d3[1,4]benzodiazepine-3,6(5H)-dione 7-Benzyl-10-chloro-2-[3-(dimethylamino)propyl]-2,7-dihydro-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)-dione (0.01 mole) is hydrogenated at 60C in 300 ml of acetic acid contining 0.3 g of pre~reduced Raney nickel. The initial hydrogen pressure is 60 p.s.i. The reduction is stopped after 0.01 mole of hydrogen is absorbed, the catalyst is filtered off, and the solvent is evaporated. The residue is stirred with water and 10-chloro-2-[3-(dimethylamino)-propyl]-2,7-dihydro-3H-s-triazolo[4,3-d][1~4]benzodiazepine-3,6(5H)-dione is filtered off and dried.

Examples 18 - 20 Following the procedure of Example 17, but sub-stituting the compound indicated in column I below for 1-benzyl-5,7 dichloro-1,3-dihydro-2H-1,4-henzodiazepin-2-one and the compound indicated in column II ~elow for 3-(dimethylamino)propyl chloride, the compound indicated in column III is obtained.

~S~37 I I I
o ~ o o u)lo ~ '' ~'~ ~
N ~ H ~r ~ ~ O ,1 O ~ 4, 1 ~ Q ~ Q) a) o y, ~ I ~ ~ ~ ~ ~ I ~
r~ O
H ~ ~ ~ ~ ¦ O ~ N
H ~ a~
a) E~ O ~ Q a) ~ ~
~; O I ~ r~ o :~ o ~ o ~1 ~ o O ~r I h S N a) Id N
o ~ t o O ~ O ~ -~
I ~a N a) ~ I I O ~ O I U~
>1 ~ N I r~ Ul ¦ N I
~ Q

Q) ~ :>~
h o O
,~ ~ O
^ s~
U O r1 H
H ,~
,~
,~
~ a) ~ c~
,~ o c o ~ o ,~
U ~ ~J h ul ~
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I ~ I
u O ~ o o h N ~, 5, ~ ~ ~ o ~ ~::
,~ O -~1 N -,~ O
~; N ~ ~
2 0 1 ~:: I a) I N
a.~ r~ Q r~ I
` Q
I ~r I ~ I
o ~ o,~ o a) h ~I s~ I ~ N
H O I O ~1 O 1 5 ~ ~ ~ I ~
E~ u I ~ O ~> O
~5 I ~ I ~, I I N
o I x I ~ I I a) U ~ O ,~ Q
N ~ N ,~ ~ N
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Q`-- o 5~ Q I
~ -,1 1 5~ !

co ~ o ~ ,~
30 ~

Example 21 10-Chloro-2,7-dihydro-2-[3-(isopropylamino)pro~yl]-7-me-th 3H-s-triazolo[4,3 d][l,4]benzodia~.epine-3,6(5H)-dione A. 10-Chloro=2,7-dihydro-2-(3 hydroxypropyl)-7-methyl-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)-dione . . _ 10-Chloro-2,7-dihydro-7-methyl-3H-s-triaæolo~4,3-d]-[1,4]benzodiazepine-3,6(5H)-dione (7.92 g, prepared as described in Example lA) is suspended in 120 ml of tetra-hydrofuran. Thallous ethoxide (7.5 g) is added dropwise to the suspension while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes and the mixture is then filtered to yield 13.5 g of the thallium salt.
To a stirring, refluxing suspension of 3 g of -the thallium salt in toluene is added 3 ml of 1-chloro-3-hydroxy-propane. After refluxing for 72 hours, another 3 ml of the chloro alcohol is added and heating is continued for another 24 hours. The solution is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and then filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 x 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solu-tions, the solvents are removed under vacuum to yield 1.3 g of a product. Recrystallization from ethyl acetate, and dry-ing under vacuum for 2 houxs at 100CI gives the title com-pound, melting point 171-172C.

~ 5~ MT 5 9/7 4 Anal. Calc'd. for C14H15ClM~O3:
C, 52.10; ~, ~.68; N, 17.36; Cl, 10.99.
Found: C, 51.88; H, 4.75; N, 17.38; Cl, 11.10.

B. 10-Chloro-2,7-dihydro-7-methyl-2-[3~ toluene-sulfonyloxy)propyl]-3H-s-triazolo~4,3-d]~1,4~-benzodiazepine-3,6(5H)-dione .
10-Chloro-2,7-dihydro-2-(3-hydroxypropyl)-7-methyl~3H-s-txiazolo~4,3-d]ill4~benzodiazepine-3,6(5H)-dione (1.0 mole) and ~-toluenesulfonyl chloride (0.20 mole) are added to 150 ml of pyridine. The reaction mixture is stirred at 5C
for 24 hours. The reac-tion is poured into 700 ml of water and the resulting precipitate is filtered off. The filter cake is washed with fresh water, filtered off and dried at 25C under vacuum for 24 hours to yield the title compound.

C. 10-Chloro-2,7-dihydro-?-[3-(isopropylamino)propyl] 7-methyl-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6-~5H)-dione 10-Chloro-2,7-dihydro-7-methyl-2-[3-(~toluene-sulfonyloxy)propyl]-3H-s-triazolo[4,3-d][1,43benzodiazepine-3,6(5H)-dione (0.05 mole)and isopropylamine (0.1 rnole) are refluxed in 600 ml of toluene for 3 hours. The reaction mixture is cooled to 25C and the resulting precipitate is Eiltered off. The product is extracted from the toluene filtrate into 10% hydrochloric acid. The acid solution is made basic with 10~ sodium bicarbonate and the product is extracted into chloroform. The solvent is removed under vacuum, and the residue is recrystallized from ethanol and ~ 8~7 MT59/7~

dried under vacuum at 40C for 3 hours to give the title compound.

~ 22 1O-Chloro-2,7-dihydro-7-meth~1-2-~2~ piperidinyl)eth 3H-s-triazolo[4,3~d][1,4]benzodiazepine-3,6(5~ dione A. 10-Chloxo-2,7-dlhydro-7-methyl-3H-s-triazolo[4,3-d]-. _ _ _ _ _ [1,4]benzodiazepine-3,6(5H)-dione .
5,7~Dichloro-1,3-dihydro-1-methyl-2H-1,4-benzodia-zepin-2-one (50 g) and ethylcarbaza-te (43 g) are refluxed in 2,000 ml of toluene for 4 hours. The toluene is decanted from the insoluble mixture and removed under vacuum, produc-ing a white powder which is freed from the accompanyingviscous material by stirring with acetonitrile. The white powder is insoluble and is filtered off; the filtrate is saved.
The residue from the original reaction mixture is refluxed for 4 hours in dioxane. The solvent is then re--moved under vacuum leaving a white powder which is stirred with acetonitrile to remove viscous impurities. This mix-ture is filtered, the white powder combined with the powder obtained previously (total 45 g) and recrystallized from 50 methanol-dioxane to yield the title compound, melting point 268-269C.
~ oth acetonitrile filtrates are combined, stripped and heated at about 100C for 2 days. This process yields another 5.5 g of product.

105~8~ MT59/74 B, 10-Chloro-2,7-dihydro-7-meth~1~?-[2~ piperidinyl)-ethyl]-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6-.
~5_)-dione 10-Chloro-2,7-dihydro-7~methyl-3ll-s-triazolo[4,3-d~-[1,4]benzodiazepine-3,6(5H)-dione (7.92 g) is suspended in 120 ml of tetrahydrofuran. Thallous ethoxide (7.5 g~ is added dropwise to the suspension while stirring~ After the thallous ethoxide is added, stirriny is continued for 45 minutes and the mixture is then filtered. The filter cake is washed by stirring as a slurry with ether, and filtered to yield 13.5 g of the thallium salt.
2-(1-Piperidinyl)ethyl chloride (1.5 equivalents) is added to a refluxing suspension of the thallium salt in 600 ml of toluene. After 2 hours of reflux, another equal amount OL
2-(1-piperidinyl)ethyl chloride is added and the refluxing is continued for 5 hours.
The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in benzene and filtered through fresh infusorial earth. The two solu~
tions are combined and passed through a 12 x 4.5 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield the product.

1~ 5~8~7 MT59/74 Example 23 10-Chloro-2,7-dihydro-7-methyl-2-[3-(1-piperidinyl)propyll-3H-.. . .
s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)-dione 10-Chloro-2,7-dihydro-7-methyl-3H~s-triazolo~4,3-d]-[1,4]benzodiazepine-3,6(5H)-dione (2.64 g~ prepared as described in ~xample 22A is dissolved in 40 ml of dimethyl-formamide at 70C. Thallous ethoxide (2.49 g) is added drop-wise to the solution while stirring. After the thallous ethoxide is added, stirring is continued for 45 minutes, the mixture is cooled to 25C, and 200 ml of ether is added. The resulting precipitate is filtered off and dried at 25C under vacuum for 4 hours to yield 4.5 g of the thallium salt.
3-(1-Piperidinyl)propyl chloride (1.5 equivalents) is added to a refluxing solution of the thallium salt prepared above in 150 ml of toluene. After 3 hours of reflux, an equal amount of 3-(1-piperidinyl)propyl chloride is added and the refluxing is continued for 5 hours.
The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and filtered through fresh infusorial earth. The two solu-tions are combined and passed through a 12 x 3 cm column of magnesium silicate~ The column is further eluted with about 3 liters of ethyl acetate. After combining the solutions, the solvents are removed under vacuum to yield the product.

Examples 24-34 Following the procedure of ~xample22, but substitut-ing the compounds indicated in column I below for 5,7-dichloro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, the compounds indicated in column II are o~tained.

I ~ r~i O~i r~ 1 0 r~ i3 rl r_ ~ rd rJ ~) ~ I ~ t\i O I ~ ~J a h I -r~ r~ ~ I ~ Ql Nrl I ~1 i3 Qj r-i O ~ ~ i rr a) J I ~ ) 11) 1 0 ~ ~ N 11~ ~ O ~~ O ri Q) ~ ~ I O
ri >~ N ~i r-i O S t~l ~ I r~ O~ h rd ~ ~r O
i3 S sa I O ri ~ ri ~Dr~; O -11 0 0 ri ~ ri I O ~1 ) I ~ ri O N rr~ Ql h ~ ~ N rc~r\i ~ N i3 0 r~ O N
~ O ~ -ri ~ I I I r\l ri ~¦ ~i ai r-i O ~ r~ rl ¦
O N -ri h ~ ~ I Q; I h ~ ¦~; -ri Q ~ N ~ ¦ ~1 ~i aJ
i h ~ I h r_I 1~ U~ S ~) 1~
-- O Qj I I -- o ~ i ~ ~I r~i ri ~ ri I -rl I ~ QO U~ I~Dh f7 i3 ~ ~ h ~D ~ Ui ¦ ~l~
H ~ ~i I Q~ -1~ 1 ~~: I r~i I ~ ~ I I Q;
i-iI ~i ~ I ~ ¦r ~~ r_ NQ~ ~ ~ ~ O ~--~ I rr~ I r ¦ N
O -ri ~ r-i ~ I ~ r-i 1~j~ r l ¦Q) r~
~i IJ ~ ~ ~ S ~~ ~ S~ rl r_ Ih ~ ~
~ >~ i ri I ~ O¦ r-i ri ~i r~3 r~) ri O r-l O
r-i~ I ~1 Gi ~ ~1-- (1) NO ~ Q~ ~ N
Ori O I ~ ~ ai ~ ~ .C ~S r-l Ql ~ S ~
t_r~ r j r~I ~ Nr.\i r-i Ql- ~) N~ ~ ~-ri ~ N >1 ~ rlJ
I I ~ Q)I~ (I) ~IiI ~tSii-- Ql t~ Ci O Q~
~ r~i O O r~i r~i-ri -~1 ~ O r-i ~ O r-i O 0 1~ ~C ~i r~i t~i ~1 0 r~h ~ O S ~ ~h ~ Oh ~ N -ri~ j3 0 r~
1 r~ N ~ ri r ~ N ~ j~ at\i I N I i_ r-i 10r-i ~ O I~ ri S~r-i S I ~~ ~ ri ~~ .ri ri II I-- ~ r-i i >~ ~U N _~~ r~ Qj ~ Q~r~ a) S rci h ~O I Qi ~ r-i ri ;~;rl i h r_~) -ri I ~ j r_~ h I i-~) O r-i r_ ~ I i I
Ql >1 h ~I Q) ~Qi j3 rr~I Q~ ~I a) Ul j~~ h ~ ~r CL) Q) rr~
R ~ ~ ~D r~ 3 ~ ~ 3 ~ D Q S ~ Q i3 ri ¦ ~ ~ ri r-iO r-i er ~. -ri r-i ~ -rj iC ~ 1 r~i ¦ ri I~ ~i tl~ ¦rr) ~ ~ r.~i ~ ) rr~ rr\ rs~

O r-i O I ()) Q~ O I ~1 S i O
1~ 1 ~ ~i 1-i lN S r~ N I o I i3 O I O ~j I ~ ~ aJ
r i I ~ ~ Q~ S Qi I N I N
4 1 ~i S -ri ~ .ri Q O I (a Qi C; I ri 3 -rl ~v I h ~ ~ I A
~ Q ~) ~ rv Q)r~ Qi I ~r rd ri ~i ~
~ I Q) ri I N I ~ r~) ~ ~ ~ ~ O
ri ~r E' i3 ~i ~1i~ ~ r-i S li) ~ N
I Qj ~-ri I r~i 1 ri N ri r-i r~i N r~i ~r~i N I I ¦ ~i (~ r~ Q) O I I r~i iN I ri I Q
--v ~ I ¦ O ri O N O i~~ ~ I ~) ~j rr~ I
I ~ I i l~i ri ~ h ~
H ~ I ~ ~ U~v Q ~ r-i r-i N r-i O ~ ~1 N ~J Si~1 Qi Q) ~
~; h ,-i S ~ I S N ~ S ~I Ql I
1-- ~ ri Q) ~q- ri ~i rj ~) X Q ~ ~ ¦
--5 r-i ~ Qi v Q S ~ v ri ~i Ql Qi O ¦
r~i S ~) ~i ¦ ¦.1_) r~
OU Q) O ~ r Qi Irfi O r~l O O ~) OI j-; I ~ N ~ h I Qi r-i I O
Ui O N r-i r~i l~ N r~ i O N I I j~ .rj r-i O ~i U I ¦ O r-i O Q o r-l ~ ¦ r~i r~
~ rj ri i i N h ~ h I h ~i ri O I >~
N ,-i i3 0 1 0 CO ~r O ri j3 ~ r~i N ~1 ~ l~i Qi r-i O ~i ~r~i ~ r~i h Q~ O ~ ~ ~ Qi Ql ri N S s~ ~ C~1 ~ r ~ U ~) U E~ v I o ~ r~ Q ~i ~ ai o r-i ~ ~v iri ~ Ui r~) N 1~ i~ ~ 00 ~ r~i ~~ N

3 0 ~ ~
~ ~ N N r.\~ ~ N

1~ 5~ 8~17 MT 5 9/7 4 O
N O I ri O I \ t\l N I
--~ r~ r-l ~ I I I Itl ~
o ~ 1 a) o ~ I s ~ r_ a) r~ - ri ~1 N 11 ) ~ N U~ 1 h u-- ri 1~ ~ Q I O ~ ~) ~ -rl ~ Q~-rl ~D rl tf) rl V I ~D

-rl ¦ ~ tN I ~ I r-l 11 ) ~i ~ ¦ rl ~ 5~ 1--I N O ~
~) Q I O Q~ -- N ~~ r~i a) H~ r_ N I r~l N t~l ri ~1 0 .~ N
HN r~ i 0 ~~ I .C ~) ~
I :>~-r~ ri O ~ N~ al rl ~o ~ ~ ~ a) ~
E~~ ~ O ~ .~: o ~ u~ ¦ ri E~ r-i O
~O il) N .C ~1 N >1 1 ~1`~ >.1 M
r-l r~
O5 ~ r-l ~D rd 1~ a) ri tr) N O ri a) O ~I Q I I Q a I ~r-l ~a .4 ~ r_ I~ r_ r_ I r_ ~ I -ri r_ O rl ~ ~ r~ ~r 1~ r-l ~a O
r~ ~ ~ > 1 0 h ri r-l I .~ r-i N ,~ N~ ~ r-i r~ r~ r~ ~
r_ r-i ~L) O .C ~ r_ N Ql~ rC -~ ~ ~~~ 4-ri I ~
rl I al ~ r-i i 11) ~ r-i r_ ~ H I O
I ~ O I ~ ~ û Q~ O
I r-l ~ riO rl ~r rl I ri r~ J ~r r~
~ ~ r~ i ~ N

_~ l ¦ ~1 N
~ X I
O I I ~ I O ~::
h u~ O -ri O S-rl ~a I h Q~ h S ~ ~ N ~ E~ N
ri O 1 Id S ~ 1 ~i I ri rl rl Ci I rl I N ~i ~a ~ 1: I` ~
I I O I O I O
) N ~) I O N
--1 rl ~ J h ~:
p I ~ aJ r-i I a a) o a) I Q I ~ ~ 4 h N r~l I r-l ri ~ I
2 0 r-l ri ~ ~ ~ Q~ r er r ~ ~ N I r-~) o a) I Q~ ¢i r~ I
::~ I N I ~ ¦ l .rl r-i1-- ~ 1~ N ~--I ~ ~ N
oI a) I I I o I I
C)~ Q O ~ O N o r-~ I h >1 h ~:: h o ~ o a) o Q I - r~ ~ ~ O O ~
r-l N ~Il') r~i NIJ ) r-i 111 r-i O

Q) _i Q

El rl tN t~ d X f~

1~ S~ 8~7 MT59/74 ~ les 35-37 Following the procedure of ~xample 23 but sub-stituting the compounds indicated in column I below for 3~ piperidinyl)propyl chloride, the compounds indicated in column II are obtained.

~L~S~7 o o , ~, , ~ I I
I rl o I ~ o i -- N - ~~ N _ ~ ~1 ^
N - rl ~t~l rl 11-) N N Ir) ;`, 4 `
~ I I ~ J I ~ I I

HO :>~ NO ~ N O ~ N
h ~ rd s~
~:: ~ 0--1 ~ 0 ~
~.C ~ o~ ~ o ~. ~ o _-Irl ~ N-rt,-- N rl Q N
O~v ~1 ~ ~ ~ G
r C: Qr` ~: Q 1` :>~Q
N ~v O ~ ~ O ~ ~ 0 ~1 n ~1 0~ ~ 0~ ~ 0 V O S~ ~O N ~ o N ,_ ~1 ~1 ~v ~ (~
I ~ ~ x I a) ~ ~ I
v ~ Ir) C u O ~ ~ O E '`~ ~
l l ` Ol l ` O l -~ ` O
o ~ ~ ~1 o r~ ~r ~ o I ~r ,1 --~v ~ _~ ~ _,~

~3 ~ ~ ., .~1 -r~ h Ll h O
O O --~1 ~1 ~
.C ~ t) Uv U

O O

H~1 ~1 ~:

~
rr~'J ,~ O
O~J ~I N

N ~
~1 X
O r~
~1 ~') ,-!

~) r~) e P~ Ln ~ r~
~r~

--2g--~35~ 37 Example 38 10-Chloro-2,7-dihydro-2- E 3-(1-piperidinyl)propyl]-3H-s-. _ .
triazolo[4,3-d][1,4]benzodiazepine~3,6(5H)-dione -A. 7-sen~yl 10-chloro-2,7 dihydro-3H-s-triazolo-[4,3-d][1,41benzodiazepine-3,6(5H)-dione ~ ~.
l-Benzyl-5,7-dichloro-1,3~dihydro-2H-1,4-benzodia-zepin-2-one (0.10 mole) and ethyl carbazate (0.11 mole) are mixed together in 400 ml of dimethylformamide for 30 minutes while heating at 130C to yield 7-benzyl-10-chloro-2,7-di-hydro-3H-s-triazolo[4,3-d]~1,4]benzodiazepine~3,6(5H)-dione.

B. 7-Benzyl-10-chloro-2,7-dihydro-2=[3-(1-pi~eridinyl)-propyl]-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6-(5H)-dione 7-Benzyl-10-chloro-2,7-dihydro-3H-s-triazolo[4,3-d3-[1,4]benzodiazepine-3,6(5H)-dione (0.02 mole) is dissolved in 100 ml of dimethylformamide at 70C. Thallous ethoxide (0.02 mole) is added to the solution and stirred for 1 hour at room temperature. The solution is diluted with 300 ml of ether, and the precipitated salt is filtered off.
3-tl-Piperidinyl)propyl chloride (1.5 ec{uivalents) is added to a refluxing solution of the thallium salt pre-pared above in 150 ml of toluene. After 3 hours of reflux, an equal amount of 3-(1-piperidinyl)propyl chloride is added and the refluxing is continued for 14 hours.
The reaction mixture is cooled to room temperature and filtered through infusorial earth to remove the thallium saits. The infusorial earth is washed by stirrinq in toluene and filtered through fresh infusorial earth. The two 59/7~

solutions are combined and passed through a 12 x 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combining the solu-tions, the solvents are removed under vacuum to yield 7-b~nzyl-lO-chloro-2,7-dihydro-2-~3~ piperidlnyl)propyl]~3H-s-tria-zolo[4,3-d][1,4~benzodiazepine-3,6(5H)-dione.

C. 10-Chloro-2,7-dihydro-2-[3-(l-piperidinyl)pro~l]-3H-~-triazolo~4,3-d][1,4]benzodiazepine-3,6(5H)-dione 7-Benzyl-10-chloro-2,7-dihydro-2-[3-(1-piperidinyl)-propyl]-3H-s-triazolol4,3-d][1,4]benzodiazepine-3,6(5H)-dione (0.01 mole) is hydrogenated at 60C in 300 ml of acetic acid containing 0.3 g of pre-reduced Raney nickel. The initial hydrogen pressure is 60 p.s.i. The reduction is stopped after 0.01 mole of hydrogen is absorbed, the catalyst is filtered off, and the solvent is evaporated. The residue is stirred with water and lO-chloro-2,7-dihydro-2-[3-(l-piperidinyl)propyl]-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)-dione is filtered off and driedO

Bxamples 39-41 Following the procedure of Example38 but sub-stituting the compound indicated in column I below for l-benzyl-5,7-dichloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one and the compound indicated in column II below for 3-(l-piperidinyl)propyl chloride, the compound indicated in column III is obtained.

~5~ 7 MT5 ~3/74 I o a N
:~ G I I ~
X ~ Q, O Q I ~ I Xl ~ 5~ ~
.C,-- ~ ~ In ~ ~ N
h a~ A
O E~ ~ ~ ~ N
O ~ ~ O ~ E~ 0 I ~ ,1 ~ ~ ~ I I ~ N
~r O ~ ~a A ~ O a) H~ ~/ I I ~ AQ~ Q
H ~ O ~ r~ Q, N ~ ,_ H
I ~ ~ ~ N I
~~ ~: O ~D U7 1 1 ~ ~ O) ~ a~
E~I ~ ~ ~ I ~ UI~A I ^ ~ ~
:~o a) o~ o ~ I ~ o~ o ,_ N I ~ C I O h :~ ~ A
O~ ~ ~ ~ ~ ~ ~ N
A ,I ~ Q, ,1 1 ,1 4 ,1 ,1 O t~ ¦ N I O--O ' O 1` ~~
~ P~ X ~ A 0 l ~ l ~1 ~1 h a O P~ S~
~1 -1 ~1 ~1 0 H ~ O I ~ I
- H,1 ~a ~ ~ C~
~1 1 ~ I
o ~ ~ ~ ~ ~1 O
~~--I ~ o .
_~ s~ .c o o u I ~ I ~ I ~
I ~ I A I A
~ ~ ~ N N

2 01 a~

o ~ I o o --I ^ ~ ,1 :>1~ ~ N
H0 X 1:: 0 ~ ~ 0 ~ 0-,1 ~ ~ -1 h S
5O.C Q, 0 ~ ~ 0 1 k ~ ~ o ~ r1 a) ~ ~ Q~
Q) N .C ~ N .C
~1U ~ ~ U I a ~i ~ o 0 I ---A I t~ -,1 ~ I I I
I l_ O I r~ O I ~ I
,1 I N ~1 I N ~ I ~
~ O ~: ~ 0 ~ ~ 0 A
N h al N h al N ~ Q, al ~ I 0 ~ I al ~ N
R .C ~ R .C ~r .4 ~ ~
I ,1 ~ I -1 ~ I -,1 A

a)!
~Q ~ o a .~, X

E~ample 42 10-Chloro-2,7-dihydro-7-methyl-2-[3-(1-piperazinyl)pro~yl]-3H-~ .
s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H~-dione A. 10-Chloro-2,7-dihydro-2-(3-hydroxypropyl)-7-methyl-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H~-dione 10-Chloro-2,7-dihydro-7-methyl-3H-s-triazolo[4,3-d]-[1,4]benzodiazepine-3,6(5H3-dione (7.92 g, prepared as described in Example 22A is suspended in 120 ml of tetra-hydrofuran. Thallous ethoxide (7.5 g) is added dropwise to the suspension while stirring. After ~he thallous ethoxide is added, stirring is continued for 45 minutes and themixture is then filtered to yield the thallium salt.
To a stirring, refluxing suspension of 3 g of the thallium salt in toluene is added 3 ml of 1-chloro-3-hydroxy-propane. After refluxing for 72 hours, another 3 ml of the chloro alcohol is added and heating is continued for another 24 hours. The solution is cooled to room temperature and filtered through infusorial earth to remove the thallium salts. The infusorial earth is washed by stirring in toluene and then filtered through fresh infusorial earth. The two solutions are combined and passed through a 12 x 3 cm column of magnesium silicate. The column is further eluted with about 3 liters of ethyl acetate. After combinin~ the solu-tions, the solvents are removed under vacuum to yield the product.

:1~ 53L~3~7 MT 5 9/7 4 O B. 10-Chloro-2,7 dihydro-7-methyl-2-[3-(~-toluene~
.
sulfonyloxy)propyl] 3H-s~triazolo[4,3-d]~1,4]-.
benzodiazepine-3,6(5H)-dione 10-Chloro-2,7-dihydro-2-(3-hydroxypropyl)-7-methyl-3 -s-triazolo[4,3-d][l/43benzodiazepine-3,6[5H~-dione (1.0 mole~ and ~-toluenesulfonyl chloride (0.20 mole) are added to 150 ml of pyridine. The-reaction mixture is stirred at 5C for 24 hours. The reaction is poured into 700 ml of water and the resulting precipitate is filtered off. The filter cake is washed with fresh water, filtered off and dried at 25C under vacuum for 24 hours to yield the title compound.

C. 10-Chloro-2,7-dihydro-7-methyl-2-[3-(1-piperazinyl)-propyl]-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6-(5H)-dione 10-Chloro-2,7-dihydro-7-methyl-2-[3-(~-toluene-sulfonyloxy)propyl~-3H-s-triazolo[4,3-d][1,43benzodia2epine-3,6(5H)-dione (0.05 mole) and piperazine (0.1 mole) are re-fluxed in 600 ml of toluene for 3 hours. The reaction mix-ture is cooled to 25C and the resulting precipitate is fil-tered off. The product is extracted from the toluene fil-trate into 10% hydrochloric acid. The acid solution is made basic with 10% sodium bicarbonate and the product is extracted into chloroform. The solvent is removed under vacuum, and the residue is recrystallized from ethanol and dried under vacuum at 40C for 3 hours to give the title compound.

Claims (17)

The embodiments of the invention in which an exclusive property or privilege is claimed are defines as follows:

1. Process for the preparation of a compound having the formula I

or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is hydrogen or alkyl; R2 is hydrogen; R3 is dialkyl-amino or wherein A is CH-Q or N-Q, Q is hydrogen and m is 0 or 1; R4 is halogen and n is 2, 3 or 4;
wherein alkyl is alkyl of 1 to 4 carbon atoms which comprises reacting a compound of the formula IV

wherein R1 is alkyl or benzyl and R2 and R4 are defined as above with a base strong enough to remove the amide proton and form a salt of the formula V

and thereafter reacting this salt either with a) a compound of the formula R3(CH2)nx wherein x is chlorine, bromine, iodine, alkylsulfonate or arylsulfonate and R3 and n are defined as above to form a compound of Formula I wherein R1 is alkyl or benzyl and, if desired, reducing the compound of Formula I wherein R1 is benzyl to form a compound of Formula I wherein R1 is hydrogen or with b) a compound of the formula wherein X and n are defined as above to form a compound of the formula VIII
wherein R1, R2, R4 and n are defined as above, converting the hydroxyl group of this compound of Formula VIII to an alkyl or aryl sulfonate and reacting the resulting intermediate with a dialkylamine or an amine of the formula wherein A and n are defined as above to form a compound of Formula I and, if desired, reducing the compound of Formula I
wherein R1 is benzyl to form a compound of Formula I wherein R1 is hydrogen.

2. A process according to claim 1 for the preparation of a compound having the formula or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is hydrogen or alkyl; R2 is hydrogen; R3 is dialkyl-amino or wherein A is CH-Q or N-Q, Q is hydrogen and m is 0 or 1; R4 is halogen and n is 2, 3 or 4;
wherein alkyl is alkyl of 1 to 4 carbon atoms which comprises reacting a compound of the formula IV

wherein R1 is alkyl or benzyl and R2 and R4 are defined as above with a base strong enough to remove the amide proton and form a salt of the formula V

and reacting this salt with a compound of the formula R3(CH2)nx wherein x is chlorine, bromine, iodine, alkylsulfonate or arylsulfonate and R3 and n are defined as above to form a compound of Formula I wherein R1 is alkyl or benzyl and, if desired, reducing the compound of Formula I wherein R1 is benzyl to form a compound of Formula I wherein R1 is hydrogen.

3. A process for the preparation of the compounds defined in claim 2 which comprises reacting a salt of the formula V

with a compound of the formula wherein X and n are defined as in claim 2 to form a compound of the formula VIII

wherein R1, R2, R4 and n are defined as in claim 2, converting the hydroxyl group of this compound of Formula VIII to an alkyl or aryl sulfonate and reacting the resulting intermediate with a dialkylamine or an amine of the formula wherein A and n are defined as in claim 2 to form a compound of Formula I and, if desired, reducing the compound of Formula I
wherein R1 is benzyl to form a compound of Formula I wherein is hydrogen.

4. A process in accordance with claim 1 wherein R3 is dialkylamino.

5. A process in according with claim l wherein R3 is

6. A process in accordance with claim l wherein R1 is alkyl or benzyl.

7. A process in accordance with claim l wherein R1 is hydrogen.

8. The process in accordance with claim 1 for preparing a compound having the name 10-chloro-2-[2-(dimethylamino)ethyl]-2,7-dihydro-7-methyl-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6 (5H)dione, hydrochloride.

9. The process in accordance with claim 1 for preparing a compound having the name 10-chloro-2-[3-(dimethylamino)propyl]-2,7-dihydro-7-methyl-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)dione.

10. A compound havinq the formula I

or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is hydrogen or alkyl; R2 is hydrogen; R3 is dialkylamino or wherein A is CH-Q or N-Q, Q is hydrogen and m is 0 or 1; R4 is halogen and n is 2, 3 or 4; wherein alkyl is alkyl of 1 to 4 carbon atoms, whenever prepared according to the process of claim 1.

11. A compound having the formula I

or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is hydrogen or alkyl; R2 is hydrogen; R3 is dialkyl-amino or wherein A is CH-Q or M-Q, Q is hydrogen and m is 0 or 1; R4 is halogen and n is 2, 3 or 4;
wherein alkyl is alkyl of 1 to 4 carbon atoms, whenever prepared according to the process of claim 2 or 3.

12. A compound is accordance with claim 10 wherein R3 is dialkylamino, whenever prepared according to the process of claim 4.

13. A compound in accordance with claim 10 wherein R3 is , whenever prepared according to the process of claim 5.

14. A compound in accordance with claim 10 wherein R1 is alkyl or benzyl, whenever prepared according to the process of claim 6.

15. A compound in accordance with claim 10 wherein R1 is hydrogen, whenever prepared according to the process of claim 7.

16. The compound in accordance with claim 10 having the name 10-chloro-2[2-(dimethylamino)ethyl]-2,7-dihydro-7-methyl-3H-s- triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)dione, hydrochloride, whenever prepared according to the process of claim 8.

17. The compound in accordance with claim 10 having the name 10-chloro-2-[3-(dimethylamino)propyl]-2,7-dihydro-7-methyl-3H-s-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)dione, whenever prepared according to the process of claim 9.