CA1066274A - Substituted 6-aryl-4h-s-triazolo- (3,4c)-thieno- (2,3e) -1,4-diazepine and processes for production thereof - Google Patents
Substituted 6-aryl-4h-s-triazolo- (3,4c)-thieno- (2,3e) -1,4-diazepine and processes for production thereofInfo
- Publication number
- CA1066274A CA1066274A CA220,982A CA220982A CA1066274A CA 1066274 A CA1066274 A CA 1066274A CA 220982 A CA220982 A CA 220982A CA 1066274 A CA1066274 A CA 1066274A
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- Canada
- Prior art keywords
- formula
- thieno
- diazepine
- bromo
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of the formula wherein R1 is hydrogen, fluorine, chlorine, bromine, nitro or trifluoromethyl;
and R2 is hydrogen, alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms; and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as tranquilizers, muscle-relaxants and anticonvulsants.
Compounds of the formula wherein R1 is hydrogen, fluorine, chlorine, bromine, nitro or trifluoromethyl;
and R2 is hydrogen, alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms; and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as tranquilizers, muscle-relaxants and anticonvulsants.
Description
1(~ 4 This invention relates to novel 6-phenyl-8-bromo-4H-s-triazolo-[3,4c]-thieno-[2,3e~-1,4-diazepines and non-toxic acid addition salts thereof, as well as to methods of preparing these compounds.
More particularly, the present application relates to a novel class of compounds represented by the formula . .
.. ~ R2 ~ 2 3N
B ~ ~
~ 1 wherein Rl is hydrogen, fluorine, chlorine, bromine, nitro or trifluoromethyl;
and R2 is hydrogen, alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 ~o 4 carbon atoms; and non-toxic, pharmacologically acceptable acid addition salts thereof.
` In accordance with the invention, the compounds embraced by formula (I) above are prepared by the following methods:
(a) by reacting a compound of the formula X
N
Br ~ ~ > (II) ~ Rl wherein Rl has the meaning previously defined, and X is SH-, NH2-, lower alkoxy, lower alkylmercapto- or halogen, with a compound of the formula : R2 -CO-N~I-NH2 (III) ' ' ' . ' '~ "' . :'': , ' ' ' . ' :
:
: , . ,. , . . .. ' : ~,:
.. , ' ~ ~
~ . . . ~ , .. . .
... . .
~(~616~7~
: wherein R2 has the meaning previously defined; or (b) by reacting a compo~md of the formula :. NH-NH2 Br ~S ~
: I ¦ > (IV) .~'' T==~N
, '; ~R~
wherein Rl has the meaningprevicusly defined, with an acid of the formula : R2 ~ COOH (V) wherein R2 has the meaning defined above, or with a functional derivative of this acid; or ~ -(c) by cyclizing a compound of the formula :
~,NH.NH.COR
Br ~ ~ ~ N ~ (VI) ~ ' :,' ,' '.
~ 1 ~
`~ 10 or :
NH.N=C \ 2 Br ~ N ~ NH2 (VII) ~ N
.'; ~ ~ 1 where Rl and R2 have the previously defined meanings;
', L~- 2 -. .
, :- : -,, !,~;~.', ; . , ' ' ' ' ' ' ' ' ' ' ' ' ': , : ' :- ' ' ' ' ' ' ' ' ' ~ ' ~ ' ' ' 662~7~
and where required, converting any product of formula (I) thus produced into a non-toxic, pharmacologically acceptable acid addition salt thereof.
The reaction described under method (a) may be carried out at temper-atures between 100 and 250~C without a solvent as well as with a solvent, such as methanol, ethanol, dioxane, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures of any two or more of these, and in the presence or absence of an acid catalyst, such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or tolu-ene-sulfonic acid; it is allowed to proceed to the end product without the ne-cessity for isolating the intermediate product of formula (VI) which forms undermilder reaction conditions (for instance, at room temperature).
The reaction described under method (b) proceeds with the free acid of the formula (V) or with a suitable functional derivative of this acid.
Examples of suitable functional derivatives of the acid of the formula (V) are an orthoester of the formula R2-C(OR')3; an iminoether of the formula R2-C(=NH)-OR; an amidine of the formula R2-C-(=NH)-NH2; an amide of the formula R2-CONH2;
a thioamide of the formula R2-CSNH2; an ester of the formula R2-COOR" (for example, a methyl, ethyl or nitrophenyl ester); an acid anhydride of the formula (R2-CO)20; or an acid halide of the formula R2-COHal; in these formulae R2 has the meaning previously defined, R' is lower alkyl, and R" is aliphatic, arali-phatic or aromatic hydrocarbyl. The iminoethers and amidines are used in the form of their salts formed with mineral acids, e.g. as their chlorohydrates, as conventional.
The reaction conditions may be chosen pursuant to the particular acid derivative which is used. Generally, the reaction may be carried out with-out a solvent or with a solvent, (such as in methanol, ethanol, chloroform, ; tetrahydrofuran, benzene, toluene or mixtures of any two or more of these), with-out or in the presence of an acid catalyst, such as hydrochloric acid, sulfuric -- acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzene-:,' ~ ~ ~ _ 3 _ :". .,~ - ~. , ' '" ''., . ' "'." '.'''' '.'. ':
, . , . , . , . . ::, , : . ,, , ~ . . . .
,',','. ,'' ' ' "' ' ' "',,' .:" ' '' ' ' ' '' .,, "' "' ,'' ' '' ,'. . , ~.' . ' ' ' ~': ' ' '' ':
: ., . , , : . , .,' , ' . , '':: ,' ,:
:'': , ',. ' ~, , . , : ,: ' : :
6Z~7~
, sulfonic acid or toluenesulfonic acid. The presence of a base,such as 2-methyl-- imidazole, as catalyst is useful as well. The reaction temperature lies between 0 and 300C, preferably 20 to 180C.
The reaction desc;ibed under method (c) proceeds under generally similar conditions to those described for method (a), although slightly higher temperatures, e.g. 150 to 250C may be required in the case of the cyclization of a compound of formula (VII). Compounds of formula ~VI) may be prepared as described above under the description of suitable reaction conditions for reac- ' tion (a) or as described below under Variant V of reaction (b). Compounds of formula (VII) may be prepared as described below under Variant III of reaction (b).
The following further describe the particular variants of method (b).
Variant I
.
In this case the functional derivative of the acid of the formula (V) is an orthoester of the formula R2-C(OR')3 where R2 and R' have the meanings defined above. Usually, the reaction proceeds in the presence of an excess of the orthoester which serves simultaneously as the solvent medium, at temperatures -between 90 and 100C; or one of the aforementioned solvents, optionally in the presence of one of the aforementioned catalysts, at temperatures between room temperature and the reflux temperature of the reaction mixture.
Variant II
In this case the functional derivative of the acid of the formula (V) is an iminoether of the formula R2~C(=NH)-OR', where R2 and R' have the pre-viously defined meanings. It is advantageous to perform the reaction in one of the previously mentioned solvents at a temperature between room temperature and the reflux temperature of the reaction mixture.
Variant III
In this case the functional derivative of acid of the formula (V) is an amidine of the formula R2-C(=NH)-NH2, where R2 has the meaning previously de-fined. It is advantageous to perform the reaction in the presence of a basic . , , ~,j ," ~
. . . . . .
- ~ , .
. ~ ' - ' . ' ,. ' , :
, . ,, ~ " , -- ,. ' , . . - "' ', ~'',,. ",.'., ' ','," ' ' ". ' ~6'~74 catalyst, such as 2-methylimidazole? at elevated temperatures, for example be-tween 150 and 250C. In case the reaction temperature is lower, for example, if the reaction is carried out at room temperature, an intermediate product of the formula (VII) is first formed. This intermediate product may, if desired, be isolated.
Variant IV
In this case the functional derivative of the acid of the formula (V) is an amide or thioamide of the formula R2-CONH2 or R2-CSNH2, where R2 has the meaning defined above. The reaction may be performed with or without a solvent, and without or with catalyst, at temperatures between 0 and 300C.
Variant V
, Here, the functional derivative of the acid of the formula (V) is an ester of the formula R2-COOR", an anhydride of the formula (R2C0)20, or an acid halide of the formula R2-COHal, where R2 and R: have the previously defined mean-ings. The intermediate product of the formula (VI) is first formed, which is then cyclized as indicated under method (a).
' The end products of the formula (I) form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrohalic acid, sulfuric acid, phos-phoric acid, nitric acid, cyclohexylsulfaminic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methane- or toluene-;; sulfonic acid, or the like.
The starting compounds of the formulae (III) and (V) are describedin the literature, and the preparation of the compounds of the formulae (VI) and - (VII) is described above.
; The hydrazine derivatives of the formula (IV) may be prepared by re-acting a compound of the formula (II) with hydrazine. This reaction may be performed in one of the above-mentioned solvents and, if desired, in the presence of one of the previously mentioned acid catalysts, advantageously at a temper-. ~ .
~ ; _ 5 _ ,,.,,,, . ~ , . .
:,,, . ,. : . . . : :. ' ,: . ' ' .. : : . . , -: , . . ,. . , ,,, ,, ~ , . .:
... , . ,,, . , . , . ~ ~ ,:
' ',,'-: ' :' ' ' ' ' ' ; ' , ' :: ~, : : '' . .
' ~066~79~
ature between room temperature and the reflux temperature of the reaction mix-ture.
The compounds of the formula (II), which may be reacted either di-rectly with the compounds of the formula (III) to form compounds of the formula (I), or else may be reacted with hydrazine to form compounds of the formula (IV), are prepared starting from known (see German Offenlegungsschrift No. 2,217,157) compounds of the formula H O
,~S ~ N ~
> (VIII) N
~ 1 :
wherein Rl has the previously defined meaning,by brominating them in conventional manner, and reacting the resulting compounds of the formula H
S ~ ~ (IX) N
wherein Rl has the previously defined meanings, in a solvent, such as pyridine, dimethylformamide or tetrahydrofuran or mixtures thereof. The reaction temper-ature may lie between room temperature and the reflux temperature of the reaction mixture. In this manner the compounds of the formula (II) wherein X is -SH are obtained. They exist in tautomeric equilibrium with the corresponding thiono compounds as follows:
, . ~ .
.. . . . .. . .
. ~ ,, ,, ,, ' ' . ' ' ,. ' ' '~
,, ,; ~ . ' ,' ' , "' ' ,, , . ' ~ ,'"' ' . ' ' ~.~6~74 "; ' -~ , S SH
B~ ~ Br ~ ~ .N ~
~ Rl ~ (llb) wherein Rl has the previously defined meaning. These compounds may, after they have been converted into the corresponding salts by reaction with a metallizing agent, such as sodium methylate or sodium amide in a solvent, be reacted without previous isola~ion with alkylating agents, such as methyl iodide or another lower alkyl iodide to form those compounds of the formula (II) wherein X is lower alkyl-thio.
Compounds of the formulae (VIII) and (IX) may be obtained pursuant to
More particularly, the present application relates to a novel class of compounds represented by the formula . .
.. ~ R2 ~ 2 3N
B ~ ~
~ 1 wherein Rl is hydrogen, fluorine, chlorine, bromine, nitro or trifluoromethyl;
and R2 is hydrogen, alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 ~o 4 carbon atoms; and non-toxic, pharmacologically acceptable acid addition salts thereof.
` In accordance with the invention, the compounds embraced by formula (I) above are prepared by the following methods:
(a) by reacting a compound of the formula X
N
Br ~ ~ > (II) ~ Rl wherein Rl has the meaning previously defined, and X is SH-, NH2-, lower alkoxy, lower alkylmercapto- or halogen, with a compound of the formula : R2 -CO-N~I-NH2 (III) ' ' ' . ' '~ "' . :'': , ' ' ' . ' :
:
: , . ,. , . . .. ' : ~,:
.. , ' ~ ~
~ . . . ~ , .. . .
... . .
~(~616~7~
: wherein R2 has the meaning previously defined; or (b) by reacting a compo~md of the formula :. NH-NH2 Br ~S ~
: I ¦ > (IV) .~'' T==~N
, '; ~R~
wherein Rl has the meaningprevicusly defined, with an acid of the formula : R2 ~ COOH (V) wherein R2 has the meaning defined above, or with a functional derivative of this acid; or ~ -(c) by cyclizing a compound of the formula :
~,NH.NH.COR
Br ~ ~ ~ N ~ (VI) ~ ' :,' ,' '.
~ 1 ~
`~ 10 or :
NH.N=C \ 2 Br ~ N ~ NH2 (VII) ~ N
.'; ~ ~ 1 where Rl and R2 have the previously defined meanings;
', L~- 2 -. .
, :- : -,, !,~;~.', ; . , ' ' ' ' ' ' ' ' ' ' ' ' ': , : ' :- ' ' ' ' ' ' ' ' ' ~ ' ~ ' ' ' 662~7~
and where required, converting any product of formula (I) thus produced into a non-toxic, pharmacologically acceptable acid addition salt thereof.
The reaction described under method (a) may be carried out at temper-atures between 100 and 250~C without a solvent as well as with a solvent, such as methanol, ethanol, dioxane, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures of any two or more of these, and in the presence or absence of an acid catalyst, such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or tolu-ene-sulfonic acid; it is allowed to proceed to the end product without the ne-cessity for isolating the intermediate product of formula (VI) which forms undermilder reaction conditions (for instance, at room temperature).
The reaction described under method (b) proceeds with the free acid of the formula (V) or with a suitable functional derivative of this acid.
Examples of suitable functional derivatives of the acid of the formula (V) are an orthoester of the formula R2-C(OR')3; an iminoether of the formula R2-C(=NH)-OR; an amidine of the formula R2-C-(=NH)-NH2; an amide of the formula R2-CONH2;
a thioamide of the formula R2-CSNH2; an ester of the formula R2-COOR" (for example, a methyl, ethyl or nitrophenyl ester); an acid anhydride of the formula (R2-CO)20; or an acid halide of the formula R2-COHal; in these formulae R2 has the meaning previously defined, R' is lower alkyl, and R" is aliphatic, arali-phatic or aromatic hydrocarbyl. The iminoethers and amidines are used in the form of their salts formed with mineral acids, e.g. as their chlorohydrates, as conventional.
The reaction conditions may be chosen pursuant to the particular acid derivative which is used. Generally, the reaction may be carried out with-out a solvent or with a solvent, (such as in methanol, ethanol, chloroform, ; tetrahydrofuran, benzene, toluene or mixtures of any two or more of these), with-out or in the presence of an acid catalyst, such as hydrochloric acid, sulfuric -- acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzene-:,' ~ ~ ~ _ 3 _ :". .,~ - ~. , ' '" ''., . ' "'." '.'''' '.'. ':
, . , . , . , . . ::, , : . ,, , ~ . . . .
,',','. ,'' ' ' "' ' ' "',,' .:" ' '' ' ' ' '' .,, "' "' ,'' ' '' ,'. . , ~.' . ' ' ' ~': ' ' '' ':
: ., . , , : . , .,' , ' . , '':: ,' ,:
:'': , ',. ' ~, , . , : ,: ' : :
6Z~7~
, sulfonic acid or toluenesulfonic acid. The presence of a base,such as 2-methyl-- imidazole, as catalyst is useful as well. The reaction temperature lies between 0 and 300C, preferably 20 to 180C.
The reaction desc;ibed under method (c) proceeds under generally similar conditions to those described for method (a), although slightly higher temperatures, e.g. 150 to 250C may be required in the case of the cyclization of a compound of formula (VII). Compounds of formula ~VI) may be prepared as described above under the description of suitable reaction conditions for reac- ' tion (a) or as described below under Variant V of reaction (b). Compounds of formula (VII) may be prepared as described below under Variant III of reaction (b).
The following further describe the particular variants of method (b).
Variant I
.
In this case the functional derivative of the acid of the formula (V) is an orthoester of the formula R2-C(OR')3 where R2 and R' have the meanings defined above. Usually, the reaction proceeds in the presence of an excess of the orthoester which serves simultaneously as the solvent medium, at temperatures -between 90 and 100C; or one of the aforementioned solvents, optionally in the presence of one of the aforementioned catalysts, at temperatures between room temperature and the reflux temperature of the reaction mixture.
Variant II
In this case the functional derivative of the acid of the formula (V) is an iminoether of the formula R2~C(=NH)-OR', where R2 and R' have the pre-viously defined meanings. It is advantageous to perform the reaction in one of the previously mentioned solvents at a temperature between room temperature and the reflux temperature of the reaction mixture.
Variant III
In this case the functional derivative of acid of the formula (V) is an amidine of the formula R2-C(=NH)-NH2, where R2 has the meaning previously de-fined. It is advantageous to perform the reaction in the presence of a basic . , , ~,j ," ~
. . . . . .
- ~ , .
. ~ ' - ' . ' ,. ' , :
, . ,, ~ " , -- ,. ' , . . - "' ', ~'',,. ",.'., ' ','," ' ' ". ' ~6'~74 catalyst, such as 2-methylimidazole? at elevated temperatures, for example be-tween 150 and 250C. In case the reaction temperature is lower, for example, if the reaction is carried out at room temperature, an intermediate product of the formula (VII) is first formed. This intermediate product may, if desired, be isolated.
Variant IV
In this case the functional derivative of the acid of the formula (V) is an amide or thioamide of the formula R2-CONH2 or R2-CSNH2, where R2 has the meaning defined above. The reaction may be performed with or without a solvent, and without or with catalyst, at temperatures between 0 and 300C.
Variant V
, Here, the functional derivative of the acid of the formula (V) is an ester of the formula R2-COOR", an anhydride of the formula (R2C0)20, or an acid halide of the formula R2-COHal, where R2 and R: have the previously defined mean-ings. The intermediate product of the formula (VI) is first formed, which is then cyclized as indicated under method (a).
' The end products of the formula (I) form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrohalic acid, sulfuric acid, phos-phoric acid, nitric acid, cyclohexylsulfaminic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methane- or toluene-;; sulfonic acid, or the like.
The starting compounds of the formulae (III) and (V) are describedin the literature, and the preparation of the compounds of the formulae (VI) and - (VII) is described above.
; The hydrazine derivatives of the formula (IV) may be prepared by re-acting a compound of the formula (II) with hydrazine. This reaction may be performed in one of the above-mentioned solvents and, if desired, in the presence of one of the previously mentioned acid catalysts, advantageously at a temper-. ~ .
~ ; _ 5 _ ,,.,,,, . ~ , . .
:,,, . ,. : . . . : :. ' ,: . ' ' .. : : . . , -: , . . ,. . , ,,, ,, ~ , . .:
... , . ,,, . , . , . ~ ~ ,:
' ',,'-: ' :' ' ' ' ' ' ; ' , ' :: ~, : : '' . .
' ~066~79~
ature between room temperature and the reflux temperature of the reaction mix-ture.
The compounds of the formula (II), which may be reacted either di-rectly with the compounds of the formula (III) to form compounds of the formula (I), or else may be reacted with hydrazine to form compounds of the formula (IV), are prepared starting from known (see German Offenlegungsschrift No. 2,217,157) compounds of the formula H O
,~S ~ N ~
> (VIII) N
~ 1 :
wherein Rl has the previously defined meaning,by brominating them in conventional manner, and reacting the resulting compounds of the formula H
S ~ ~ (IX) N
wherein Rl has the previously defined meanings, in a solvent, such as pyridine, dimethylformamide or tetrahydrofuran or mixtures thereof. The reaction temper-ature may lie between room temperature and the reflux temperature of the reaction mixture. In this manner the compounds of the formula (II) wherein X is -SH are obtained. They exist in tautomeric equilibrium with the corresponding thiono compounds as follows:
, . ~ .
.. . . . .. . .
. ~ ,, ,, ,, ' ' . ' ' ,. ' ' '~
,, ,; ~ . ' ,' ' , "' ' ,, , . ' ~ ,'"' ' . ' ' ~.~6~74 "; ' -~ , S SH
B~ ~ Br ~ ~ .N ~
~ Rl ~ (llb) wherein Rl has the previously defined meaning. These compounds may, after they have been converted into the corresponding salts by reaction with a metallizing agent, such as sodium methylate or sodium amide in a solvent, be reacted without previous isola~ion with alkylating agents, such as methyl iodide or another lower alkyl iodide to form those compounds of the formula (II) wherein X is lower alkyl-thio.
Compounds of the formulae (VIII) and (IX) may be obtained pursuant to
2, /07, 3S~
the methods of German Offenlegungsschrift Nos.-2,10G,3~ and 2,144,105, namely, -` 10 by sub~ecting compounds of the formula .; .
Br ~ NH-COCH2NH2 .`'`' C10 (X) , .
wherein Rl has the previously defined meaning. to intramolecular condensation.
; An especially advantageous variant of this reaction consists of effecting the .~. , .
cyclization by boiling in toluene in a vessel provided with a water trap, using silicagel as the dehydrating agent. In this matter significantly higher yields and purer products are obtained.
Compounds of the formula (II), wherein X is lower alkoxy, may be ob-tained by reacting known aminoketones of the formula , ., ~. ~ .
~ 1 - 7 -, . : : .. : . , ' : ' . ' '.:, .' ' ' ' , , :., . . ,: : ' ' :. .:; ' :, : .
:,, ~':' . ' ' , . ' ' ., . : , .
~06627~
Br ~ ~ 2 .
CO (XI) wherein Rl has the previously defined meaning, with a haloorthoacetate of the formula , :. (R 0)3C-CH2Hal (XII) . wherein R' has the previously defined meaning and Hal is chlorine, bromine or iodine, to form a compound of the formula / OR
N=C\
Br~ CH~Hal (XIII) CO
~ 1 wherein R, Rl and Hal have the previous defined meanings. In those instances ..
where Hal is chlorine, it is advantageous first to exchange the aliphatically bonded chlorine atom in the compound of the formula (XIII) for iodine by means of the Finkelstein Reaction, for example, by reacting it with sodium iodide in : .
acetone. Then, the iodo-substituted compound thus obtained is reacted with ammonia in dioxane or tetrahydrofuran. In this manner, an intermediate amino -. .
compound of the formula OR
. N=C
Br ~ N / CH2 (XIV) : f . ~Rl ,. . .
~ 8 -. ' ' - , ' , , . , . . , . . ', ! ' : . ~ ' ~ . ' .. . .
., ' . ~ ' . . : . . ' . , : .
, .' ' . : ' , . . .
., , . - . . . , ... . . . . . .
, ~ 6~'74 wherein R, Rl and R2 have the previously defined meanings, is formed which, however, cyclizes spontaneously into a compound of the formula ~ OR
; Br ~ ~ C > ~IIc) ., ~Rl ; wherein R and Rl have the previously defined meanings.
Compounds of the formula (II~, wherein X is amino, may be prepared by reacting compounds of the formula ~IX), which were obtained by halogenation of compounds of the formula ~VIII), with ammonia. The reaction is advantage-ously performed in a solvent, such as tetrahydrofuran, and in the presence of a Lewis acid, such as titanium chloride, for example.
These compounds also exist in tautomeric equilibrium as follows: -.~ H .
:: , NH2 ~ ,~NH :. :
Br ~ ~ S
~ (II~) ~ ~lle) : wherein Rl has ~he previously defined meaning. .
~ The following examples 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. .
: 8-Bromo-6-~o-chloro-phenyl)-1-methyl-41!-s-triazolo-[3,4c]-thieno .
g : . ,. . - , ~ . -,, , . . . . ... .. . :, .
.. : .. . ,. ~ ,, : , :
, ,.- . , . : . . .
.. . . .
.
6,'~74 ~2,3e]-1,4-diazepine (a) 11.5 gm of 7~bromo~5-(o-chloro-phenyl)-3H-~2,3e]-thieno-1,4-diazepin-2-one (see German Offenlegungsschrift 2,221,623), i.e. a compound of the formula (IX), were heated at 55-60C with lOO cc of absolute pyridine and 6.5 gm of phosphorus pentasulfide for 4 hours while stirring. The mixture was allowed to cool and was then poured into 100 cc of saturated ice-cold NaCl-solu-tion. The precipitate was collected by suction filtration, washed with water, dissolved in 100 cc of methylene chloride, the solution was dried and evaporated, and the residue was treated with a little methylene chloride. After suction ~ 10 filtration, 6 gm of brown crystalline 7-bromo-5-(o-chloro-phenyl)-3H-[2,3e]-- thieno-1,4-diazepine-2-thione, a compound of the formula (IIa), m.p. 214C (de-; comp.) were obtained.
(b) 6.0 gm of this compound were suspended in 100 cc of tetrahydro-furan, and the suspension was stirred at room temperature with 1.2 gm of hydra-zine hydrate for 20 minutes. After evaporation to about 10 cc, 20 cc of ether : were added, and the crystals were collected by suction filtration. Yield: 5.2 gm of 7-bromo-5-(o-chloro-phenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine, m.p. ~ 300C (decomp.), a compound of the formula (IV).
tc) 5.2 gm of this compound were suspended in 50 cc of triethyl orthoacetate, and the suspension was heated to 80C. After about 30 minutes a ~ clear solution was first formed from which later colorless crystals separated 1 out. The mixture was allowed to cool, and~:the crystals were collected by suc-tion filtration and washed with ether. Yield: 5 gm of the compound, m.p. 211-, 213C, of the formula . N ~
H3C ~ N
Br~S ~1' ~S
: ~ N
~ Cl ",~ .1 -- 10 --:' . . . :
,'.''' ,' . ' ' ',...... ' :
' .'' ' ' ~1~66Z74 8-Bromo-6-(o-chloro-phenyl?-l~hydroxyethyl-4H-s-triaiolo-~3~4c]
.
thieno-[2,3el-1,4-diazepine 4.8 gm of 7-bromo-5-(o-chloro-phenyl)-3H-[2,3e]-thieno-1,4-diaze-pine-2-thione [see Example l~a)] were heated together with 3.4 gm of 3-hydroxy-propionic acid hydrazide in 100 cc of n-butanol in an N2-atmosphere until the mixture boiled, and then it was refluxed :Eor 5 hours, whereupon it was partially evaporated, and the compound named in the heading was caused to crystallize out -; by addition of isopropyl ether. The product, m.p. 224-226C, was obtained with a yield of 60% of theory.
The starting compounds of formula (IX) were obtained as follows:
~a) Similar to the example described in German Offenlegungsschrift 2,221,623, 0.03 mol of a compound of the formula (VIII) were dissolved or sus-pended in 60 cc of chloroform and, after addition of 6 cc of pyridine, admixed with 4.7 gm of bromine, in the course of 5 minutes. Stirring was continued for 45 minutes at 25-30C, whereupon the compound of the formula (X) separated out, -` mostly as a yellow precipitate, which was collected by suction filtration and ~ ;
washed with ether. 10 to 12 gm of the con~pound of the formula(IX3 were obtained.
It may be used for thionization as the crude product.
(b) 17 gm of the 2-bromoacetylamino-3-[aryl]-thiophene thus ob-tained were dissolved in 200 to 250 cc of chloroform and admixed at room temper-ature with 20 cc of pyridine, followed by addition of 5 cc of bromine. After 2 hours' stirring, the mixture was shaken several times with water~ the chloroformphase was dried with MgSO4 and evaporated, and the residue stirred with isoether.
Yield: 10 to 15 gm of a 2-bromoacetylamino-3[aryl]-4-bromothiophene.
10 gm of this compound were dissolved in 400 cc of ethylacetate, and over a period of 2 hours gaseous ammonia was introduced into the solution atroom temperature. The precipitated ammonium chloride was separated by suction filtration, the filtrate was evaporated in vacuo, and 7 to 8 gm of an amino-., ~ .
. i~ - 11-"~ ~ ,,. -:: '' . - , ' '' : , . '' ' . '. ~
,:, . . . ., . . ,,, . . , ' ~ ., ., . :' :, . ' '.' :, . ' , ' ,' . '' .,, : : ,:
,74 acylamino compound of the ormula ~X) was obtained.
7 gm of this compound were boiled in 80 cc of toluene and 25 gm of silicagel in a vessel equipped with a water trap for 1 hour. The mixture was cooled to 50-60C, and 50 cc of methanol were added. After suction filtration and washing, 3 to 4 gm of the desired compound of the formula (IX) were obtainedfrom the filtrate.
The preparation of the starting compounds of the formula (II) is illustrated by the following:
0.2 mol of 2-amino-5-bromo-3-(o-chloro-ben~oyl)-thiophene, a com-pound of the formula (XI), was boiled while stirring, with 78.4 gm (0.4 mol) of -: orthoethyl-chloro-acetate (see formula XII) in one liter of benzene for 8 hours;
after about 4 hours of boiling 0.01 ml of trifluoro-acetic acid was added. The solvent was then evaporated, and the unreacted orthoester was removed by high-vacuum distillation.
The raw product thus obtained was stirred in 1.5 liters of acetone with 16 to 20 gm of sodium iodide for 6 hours at room temperature. The mixture was then evaporated, and the residue was taken up in methylene chloride. The methylene chloride solution was extracted with ice water several times and driedwith magnesium sulfate.
The residue (the corresponding crude product of the formula XIII) was taken up in 150 cc of absolute dioxane, and ammonia gas was introduced over a period of 1 to 2 hours at room temperature. Then, the solvent was removed in vacuo, the residue was taken up in methylene chloride, and the solution was washed with ice water, dried with magnesium sulfate and evaporated. The remain-ing oil was identified to be the desired compound and may be reacted, as described above, analogous to the thio compound, into the hydra~ino derivative.
Using the above-described methods, the following additional compounds of the formula (I) were prepared:
'''' ' .
! ~ ~
''' .' ~ . ' ~ ' ,, ' . ~
: '~ ' , ' ' . ' , ' :
' ' : ' ,~ ' . ' ' , . . ~
~LiC) 6 6 1i~7 ~IL
~ Example ~1 R2 M~P. C
., ; 3 Br CH3 205 - 206 6 Cl H 216 - 218 Cl iC3H7 203 - 205 The compounds of this invention, that is, those embraced by formula i (I) above and their non-toxic, pharmacologically acceptable acid addition salts, -- have useful pharmacodynamic properties. ~ore particularly, they exhibit anxiety-; 10 relieving, tension-relieving, muscle-relaxing and very effective anticonvulsive activities in warm-bl~oded animalsj such as mice and rats. They also increase the food-intake in mammals. The compound of this invention, moreover, are char-- acterized by extraordinarily low toxicity.
In the so-called pentetrazole-antagonism test for anticonvulsive activity the compounds of the present invention have been found to be far super-ior to the thieno-1,4-diazepines disclosed in German Offenlegungsschrift 2,155,403 and 2,221,623; and while the compounds of this invention exhibit an activity picture similar to that of the 8-alkyl-6-aryl-thieno-[2,3e]-4H-s-tri-` azolo-[3,4c]-1,4-diazepines disclosed in German Offenlegungsschrift 2,229,845, the former's intensity of activity is more than ten times tha~ of the latter's.
-- Particularly effective are those compounds of the formula (I) where-in Rl is chlorine or bromine, and R2 is methyl, and their non-toxic acid addi-tion salts. The following are specific examples of such particularly effective compounds: 8-bromo-6-o-chloro-phenyl-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine ~Rl=Cl, R2=CH3); and 8-bromo-6-o-bromo-phenyl-1-methyl-4H-; s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine (Rl=Br, R2=CH3).
i ~ l - 13 -.: . ,. : . . . :. . ., . .. : .
':' ' ' ' ,, ', ' ' ' ' '' ''' '. " ~ ,' .' : ~ '.'' ' ~C~6~274 For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally, parenterally or rectally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceuti-cal carrier and one effective dosage unit of the active ingredient, such as tab-lets, 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 0.016 to 0.42 mgm/kg body weight ~oral). The daily dose rate is 0.083 to 2.5 mgm/kg body weight.
The following examples illustrate a few pharmaceutical dosage unit ` compositions comprising a compound of the present invention as an active ingre-dient and represent the best modes contemplated of putting the invention into ~
practical use. The parts are parts by weight unless otherwise specified.
Tablets The tablet composition is compounded from the following ingredients:
8-Bromo-6-(o-chloro-phenyl)-1-methyl-4H-s-triazolo-L~,4~]-thieno-[2,3e]-1,4-diazepine 0.5 parts Lactose 50.0 "
Corn starch 43.5 "
Soluble starch 4.0 "
. Magnesium stearate 1.0 "
Total100.0 parts Preparation:
The triazolo-thieno-diazepine compound and the magnesium stearate are admixed with each other, the mixture is moistened with an aqueous solution of the soluble starch, the moist mass is granulated through a 1 mm-mesh screen, ,: , j ~ - 14 -.....
. .
:' .
, , , .
~66~74 the granulate is dried and again passed through the screen, and the dry granulate is intimately admixed with the lactose and the corn starch. The resulting com-position is compressed into 100 mgm-tablets, each of which contains 0.5 mgm of the triazolo-thieno-diazepine compound and is an oral dosage unit composition with effective anxiolytic, tension-relie~ing, muscle-relaxing and anticonvulsive action.
Coated pills The pill core composition is compounded from the following ingre-dients:
8-Bromo-6-(o-bromo-phenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine 1.0 parts Lactose 2~.5 "
Corn starch 19.0 "
Gelatin 1.0 "
Magnesium stearate 0.5 "
Total 50.0 parts Preparation:
~ 20 The triazolo-thieno-diazepine compound, the lactose and the corn i; starch are intimately admixed with each other, the mixture is granulated through a 1 mm-mesh screen with the aid of an aqueous 10% solution of the gelatin, the granulate is dried and again passed through the screen, and the dry granulate is admixed with the magnesium stearate. The resulting composition is compressed into 50 mgm-pill cores which are subsequently coated with a thin shell consist-ing essentially of a mixture of sugar, titanium dioxide, talcum and gum arabic, . and finally polished with beeswax. Each coated pill contains 1 mgm of the tri-; azolo-thieno-diazepine compound and is an oral dosage unit composition with ef-fective anxiolytic, tension-relieving, muscle-relaxing and anticonvulsive action.
: :.
.' '~l .. ~ ~ - 15 -. . .
, .
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.. . .. . .. . . . .
~OG5iZ7~
Suppositories The suppository composition is compounded from the following ingre-dients:
8-Bromo-6-(o-chloro-phenyl)-1-hydroxy-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine 5.0 parts Suppository base (e.g. cocoa butter)1695.0 "
1700.0 parts Preparation:
The suppository base is melted and cooled to 40C, the finely pul-verized triazolo-thieno-diazepine compound is stirred into the suppository base with the aid of an immersion homogenizer, and 1700 mgm-portions of the resultingmixture at 35C are poured into cooled suppository molds and allowed to harden therein. Each suppository contains 5 mgm of the thiazolo-thieno-diazepine com-pound and is a rectal dosage unit composition with effective anxiolytic, tension-relieving, muscle-relaxing and anticonvulsive action.
; Analogous results are obtained when any one of the other triazolo-benzodiazepinones embraced by formula (I) or a non-toxic, pharmacologically ac-ceptable acid addition salt thereof was substituted for the particular triazolo-. ..
thieno-diazepine in Examples 8 through 10. Likewise, the amount of active in-; gredient in these illustrative 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 embodi-ments, and that various changes and modifications may be made without departing - from the spirit of the invention or the scope of the appended claims.
. ~ i - 16 -.~ " ~. _ ,~ ,. . ~
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the methods of German Offenlegungsschrift Nos.-2,10G,3~ and 2,144,105, namely, -` 10 by sub~ecting compounds of the formula .; .
Br ~ NH-COCH2NH2 .`'`' C10 (X) , .
wherein Rl has the previously defined meaning. to intramolecular condensation.
; An especially advantageous variant of this reaction consists of effecting the .~. , .
cyclization by boiling in toluene in a vessel provided with a water trap, using silicagel as the dehydrating agent. In this matter significantly higher yields and purer products are obtained.
Compounds of the formula (II), wherein X is lower alkoxy, may be ob-tained by reacting known aminoketones of the formula , ., ~. ~ .
~ 1 - 7 -, . : : .. : . , ' : ' . ' '.:, .' ' ' ' , , :., . . ,: : ' ' :. .:; ' :, : .
:,, ~':' . ' ' , . ' ' ., . : , .
~06627~
Br ~ ~ 2 .
CO (XI) wherein Rl has the previously defined meaning, with a haloorthoacetate of the formula , :. (R 0)3C-CH2Hal (XII) . wherein R' has the previously defined meaning and Hal is chlorine, bromine or iodine, to form a compound of the formula / OR
N=C\
Br~ CH~Hal (XIII) CO
~ 1 wherein R, Rl and Hal have the previous defined meanings. In those instances ..
where Hal is chlorine, it is advantageous first to exchange the aliphatically bonded chlorine atom in the compound of the formula (XIII) for iodine by means of the Finkelstein Reaction, for example, by reacting it with sodium iodide in : .
acetone. Then, the iodo-substituted compound thus obtained is reacted with ammonia in dioxane or tetrahydrofuran. In this manner, an intermediate amino -. .
compound of the formula OR
. N=C
Br ~ N / CH2 (XIV) : f . ~Rl ,. . .
~ 8 -. ' ' - , ' , , . , . . , . . ', ! ' : . ~ ' ~ . ' .. . .
., ' . ~ ' . . : . . ' . , : .
, .' ' . : ' , . . .
., , . - . . . , ... . . . . . .
, ~ 6~'74 wherein R, Rl and R2 have the previously defined meanings, is formed which, however, cyclizes spontaneously into a compound of the formula ~ OR
; Br ~ ~ C > ~IIc) ., ~Rl ; wherein R and Rl have the previously defined meanings.
Compounds of the formula (II~, wherein X is amino, may be prepared by reacting compounds of the formula ~IX), which were obtained by halogenation of compounds of the formula ~VIII), with ammonia. The reaction is advantage-ously performed in a solvent, such as tetrahydrofuran, and in the presence of a Lewis acid, such as titanium chloride, for example.
These compounds also exist in tautomeric equilibrium as follows: -.~ H .
:: , NH2 ~ ,~NH :. :
Br ~ ~ S
~ (II~) ~ ~lle) : wherein Rl has ~he previously defined meaning. .
~ The following examples 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. .
: 8-Bromo-6-~o-chloro-phenyl)-1-methyl-41!-s-triazolo-[3,4c]-thieno .
g : . ,. . - , ~ . -,, , . . . . ... .. . :, .
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, ,.- . , . : . . .
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.
6,'~74 ~2,3e]-1,4-diazepine (a) 11.5 gm of 7~bromo~5-(o-chloro-phenyl)-3H-~2,3e]-thieno-1,4-diazepin-2-one (see German Offenlegungsschrift 2,221,623), i.e. a compound of the formula (IX), were heated at 55-60C with lOO cc of absolute pyridine and 6.5 gm of phosphorus pentasulfide for 4 hours while stirring. The mixture was allowed to cool and was then poured into 100 cc of saturated ice-cold NaCl-solu-tion. The precipitate was collected by suction filtration, washed with water, dissolved in 100 cc of methylene chloride, the solution was dried and evaporated, and the residue was treated with a little methylene chloride. After suction ~ 10 filtration, 6 gm of brown crystalline 7-bromo-5-(o-chloro-phenyl)-3H-[2,3e]-- thieno-1,4-diazepine-2-thione, a compound of the formula (IIa), m.p. 214C (de-; comp.) were obtained.
(b) 6.0 gm of this compound were suspended in 100 cc of tetrahydro-furan, and the suspension was stirred at room temperature with 1.2 gm of hydra-zine hydrate for 20 minutes. After evaporation to about 10 cc, 20 cc of ether : were added, and the crystals were collected by suction filtration. Yield: 5.2 gm of 7-bromo-5-(o-chloro-phenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine, m.p. ~ 300C (decomp.), a compound of the formula (IV).
tc) 5.2 gm of this compound were suspended in 50 cc of triethyl orthoacetate, and the suspension was heated to 80C. After about 30 minutes a ~ clear solution was first formed from which later colorless crystals separated 1 out. The mixture was allowed to cool, and~:the crystals were collected by suc-tion filtration and washed with ether. Yield: 5 gm of the compound, m.p. 211-, 213C, of the formula . N ~
H3C ~ N
Br~S ~1' ~S
: ~ N
~ Cl ",~ .1 -- 10 --:' . . . :
,'.''' ,' . ' ' ',...... ' :
' .'' ' ' ~1~66Z74 8-Bromo-6-(o-chloro-phenyl?-l~hydroxyethyl-4H-s-triaiolo-~3~4c]
.
thieno-[2,3el-1,4-diazepine 4.8 gm of 7-bromo-5-(o-chloro-phenyl)-3H-[2,3e]-thieno-1,4-diaze-pine-2-thione [see Example l~a)] were heated together with 3.4 gm of 3-hydroxy-propionic acid hydrazide in 100 cc of n-butanol in an N2-atmosphere until the mixture boiled, and then it was refluxed :Eor 5 hours, whereupon it was partially evaporated, and the compound named in the heading was caused to crystallize out -; by addition of isopropyl ether. The product, m.p. 224-226C, was obtained with a yield of 60% of theory.
The starting compounds of formula (IX) were obtained as follows:
~a) Similar to the example described in German Offenlegungsschrift 2,221,623, 0.03 mol of a compound of the formula (VIII) were dissolved or sus-pended in 60 cc of chloroform and, after addition of 6 cc of pyridine, admixed with 4.7 gm of bromine, in the course of 5 minutes. Stirring was continued for 45 minutes at 25-30C, whereupon the compound of the formula (X) separated out, -` mostly as a yellow precipitate, which was collected by suction filtration and ~ ;
washed with ether. 10 to 12 gm of the con~pound of the formula(IX3 were obtained.
It may be used for thionization as the crude product.
(b) 17 gm of the 2-bromoacetylamino-3-[aryl]-thiophene thus ob-tained were dissolved in 200 to 250 cc of chloroform and admixed at room temper-ature with 20 cc of pyridine, followed by addition of 5 cc of bromine. After 2 hours' stirring, the mixture was shaken several times with water~ the chloroformphase was dried with MgSO4 and evaporated, and the residue stirred with isoether.
Yield: 10 to 15 gm of a 2-bromoacetylamino-3[aryl]-4-bromothiophene.
10 gm of this compound were dissolved in 400 cc of ethylacetate, and over a period of 2 hours gaseous ammonia was introduced into the solution atroom temperature. The precipitated ammonium chloride was separated by suction filtration, the filtrate was evaporated in vacuo, and 7 to 8 gm of an amino-., ~ .
. i~ - 11-"~ ~ ,,. -:: '' . - , ' '' : , . '' ' . '. ~
,:, . . . ., . . ,,, . . , ' ~ ., ., . :' :, . ' '.' :, . ' , ' ,' . '' .,, : : ,:
,74 acylamino compound of the ormula ~X) was obtained.
7 gm of this compound were boiled in 80 cc of toluene and 25 gm of silicagel in a vessel equipped with a water trap for 1 hour. The mixture was cooled to 50-60C, and 50 cc of methanol were added. After suction filtration and washing, 3 to 4 gm of the desired compound of the formula (IX) were obtainedfrom the filtrate.
The preparation of the starting compounds of the formula (II) is illustrated by the following:
0.2 mol of 2-amino-5-bromo-3-(o-chloro-ben~oyl)-thiophene, a com-pound of the formula (XI), was boiled while stirring, with 78.4 gm (0.4 mol) of -: orthoethyl-chloro-acetate (see formula XII) in one liter of benzene for 8 hours;
after about 4 hours of boiling 0.01 ml of trifluoro-acetic acid was added. The solvent was then evaporated, and the unreacted orthoester was removed by high-vacuum distillation.
The raw product thus obtained was stirred in 1.5 liters of acetone with 16 to 20 gm of sodium iodide for 6 hours at room temperature. The mixture was then evaporated, and the residue was taken up in methylene chloride. The methylene chloride solution was extracted with ice water several times and driedwith magnesium sulfate.
The residue (the corresponding crude product of the formula XIII) was taken up in 150 cc of absolute dioxane, and ammonia gas was introduced over a period of 1 to 2 hours at room temperature. Then, the solvent was removed in vacuo, the residue was taken up in methylene chloride, and the solution was washed with ice water, dried with magnesium sulfate and evaporated. The remain-ing oil was identified to be the desired compound and may be reacted, as described above, analogous to the thio compound, into the hydra~ino derivative.
Using the above-described methods, the following additional compounds of the formula (I) were prepared:
'''' ' .
! ~ ~
''' .' ~ . ' ~ ' ,, ' . ~
: '~ ' , ' ' . ' , ' :
' ' : ' ,~ ' . ' ' , . . ~
~LiC) 6 6 1i~7 ~IL
~ Example ~1 R2 M~P. C
., ; 3 Br CH3 205 - 206 6 Cl H 216 - 218 Cl iC3H7 203 - 205 The compounds of this invention, that is, those embraced by formula i (I) above and their non-toxic, pharmacologically acceptable acid addition salts, -- have useful pharmacodynamic properties. ~ore particularly, they exhibit anxiety-; 10 relieving, tension-relieving, muscle-relaxing and very effective anticonvulsive activities in warm-bl~oded animalsj such as mice and rats. They also increase the food-intake in mammals. The compound of this invention, moreover, are char-- acterized by extraordinarily low toxicity.
In the so-called pentetrazole-antagonism test for anticonvulsive activity the compounds of the present invention have been found to be far super-ior to the thieno-1,4-diazepines disclosed in German Offenlegungsschrift 2,155,403 and 2,221,623; and while the compounds of this invention exhibit an activity picture similar to that of the 8-alkyl-6-aryl-thieno-[2,3e]-4H-s-tri-` azolo-[3,4c]-1,4-diazepines disclosed in German Offenlegungsschrift 2,229,845, the former's intensity of activity is more than ten times tha~ of the latter's.
-- Particularly effective are those compounds of the formula (I) where-in Rl is chlorine or bromine, and R2 is methyl, and their non-toxic acid addi-tion salts. The following are specific examples of such particularly effective compounds: 8-bromo-6-o-chloro-phenyl-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine ~Rl=Cl, R2=CH3); and 8-bromo-6-o-bromo-phenyl-1-methyl-4H-; s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine (Rl=Br, R2=CH3).
i ~ l - 13 -.: . ,. : . . . :. . ., . .. : .
':' ' ' ' ,, ', ' ' ' ' '' ''' '. " ~ ,' .' : ~ '.'' ' ~C~6~274 For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally, parenterally or rectally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceuti-cal carrier and one effective dosage unit of the active ingredient, such as tab-lets, 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 0.016 to 0.42 mgm/kg body weight ~oral). The daily dose rate is 0.083 to 2.5 mgm/kg body weight.
The following examples illustrate a few pharmaceutical dosage unit ` compositions comprising a compound of the present invention as an active ingre-dient and represent the best modes contemplated of putting the invention into ~
practical use. The parts are parts by weight unless otherwise specified.
Tablets The tablet composition is compounded from the following ingredients:
8-Bromo-6-(o-chloro-phenyl)-1-methyl-4H-s-triazolo-L~,4~]-thieno-[2,3e]-1,4-diazepine 0.5 parts Lactose 50.0 "
Corn starch 43.5 "
Soluble starch 4.0 "
. Magnesium stearate 1.0 "
Total100.0 parts Preparation:
The triazolo-thieno-diazepine compound and the magnesium stearate are admixed with each other, the mixture is moistened with an aqueous solution of the soluble starch, the moist mass is granulated through a 1 mm-mesh screen, ,: , j ~ - 14 -.....
. .
:' .
, , , .
~66~74 the granulate is dried and again passed through the screen, and the dry granulate is intimately admixed with the lactose and the corn starch. The resulting com-position is compressed into 100 mgm-tablets, each of which contains 0.5 mgm of the triazolo-thieno-diazepine compound and is an oral dosage unit composition with effective anxiolytic, tension-relie~ing, muscle-relaxing and anticonvulsive action.
Coated pills The pill core composition is compounded from the following ingre-dients:
8-Bromo-6-(o-bromo-phenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine 1.0 parts Lactose 2~.5 "
Corn starch 19.0 "
Gelatin 1.0 "
Magnesium stearate 0.5 "
Total 50.0 parts Preparation:
~ 20 The triazolo-thieno-diazepine compound, the lactose and the corn i; starch are intimately admixed with each other, the mixture is granulated through a 1 mm-mesh screen with the aid of an aqueous 10% solution of the gelatin, the granulate is dried and again passed through the screen, and the dry granulate is admixed with the magnesium stearate. The resulting composition is compressed into 50 mgm-pill cores which are subsequently coated with a thin shell consist-ing essentially of a mixture of sugar, titanium dioxide, talcum and gum arabic, . and finally polished with beeswax. Each coated pill contains 1 mgm of the tri-; azolo-thieno-diazepine compound and is an oral dosage unit composition with ef-fective anxiolytic, tension-relieving, muscle-relaxing and anticonvulsive action.
: :.
.' '~l .. ~ ~ - 15 -. . .
, .
:. , , ~ . . ...
. ~. . . .
, , . - : -.: : . ~, , . .: . ..
.' . ' '- : -. ., , .. : . ...
.. . .. . .. . . . .
~OG5iZ7~
Suppositories The suppository composition is compounded from the following ingre-dients:
8-Bromo-6-(o-chloro-phenyl)-1-hydroxy-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine 5.0 parts Suppository base (e.g. cocoa butter)1695.0 "
1700.0 parts Preparation:
The suppository base is melted and cooled to 40C, the finely pul-verized triazolo-thieno-diazepine compound is stirred into the suppository base with the aid of an immersion homogenizer, and 1700 mgm-portions of the resultingmixture at 35C are poured into cooled suppository molds and allowed to harden therein. Each suppository contains 5 mgm of the thiazolo-thieno-diazepine com-pound and is a rectal dosage unit composition with effective anxiolytic, tension-relieving, muscle-relaxing and anticonvulsive action.
; Analogous results are obtained when any one of the other triazolo-benzodiazepinones embraced by formula (I) or a non-toxic, pharmacologically ac-ceptable acid addition salt thereof was substituted for the particular triazolo-. ..
thieno-diazepine in Examples 8 through 10. Likewise, the amount of active in-; gredient in these illustrative 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 embodi-ments, and that various changes and modifications may be made without departing - from the spirit of the invention or the scope of the appended claims.
. ~ i - 16 -.~ " ~. _ ,~ ,. . ~
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Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula (I) wherein R1 is hydrogen, fluorine, chlorine, bromine, nitro or trifluoro-methyl; and R2 is hydrogen, alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms;
or a non-toxic, pharmacologically acceptable acid addition salt thereof, which comprises (a) reacting a compound of the formula (II) wherein R1 has the meaning previously defined and X is SH-, NH2-, lower alkoxy, lower alkylmercapto- or halogen, with a compound of the formula R2-CO-NH-NH (III) wherein R2 has the meaning previously defined; or (b) by reacting a compound of the formula (IV) wherein R1 has the meaning previously defined, with an acid of the formula R2-COOH (V) wherein R2 has the meaning defined above, or with a functional derivative of this acid; or (c) cyclizing a compound of the formula (VI) or (VII) wherein R1 and R2 have the previously defined meanings;
and where required, converting any product of formula (I) thus produced, into a non-toxic, pharmacologically acceptable acid addition salt thereof.
or a non-toxic, pharmacologically acceptable acid addition salt thereof, which comprises (a) reacting a compound of the formula (II) wherein R1 has the meaning previously defined and X is SH-, NH2-, lower alkoxy, lower alkylmercapto- or halogen, with a compound of the formula R2-CO-NH-NH (III) wherein R2 has the meaning previously defined; or (b) by reacting a compound of the formula (IV) wherein R1 has the meaning previously defined, with an acid of the formula R2-COOH (V) wherein R2 has the meaning defined above, or with a functional derivative of this acid; or (c) cyclizing a compound of the formula (VI) or (VII) wherein R1 and R2 have the previously defined meanings;
and where required, converting any product of formula (I) thus produced, into a non-toxic, pharmacologically acceptable acid addition salt thereof.
2. Compounds of the general formula (I) defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1, wherein in the starting materials R1 is chlorine or bromine, and R2 is methyl.
4. A process according to claim 1, wherein in the starting materials R1 is chlorine, and R2 is methyl.
5. A process for the preparation of 8-bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine which comprises cyclizing 7-bromo-5-(o-chlorophenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine with triethyl orthoacetate.
6. A process according to claim 1, wherein in the starting materials R1 is bromine, and R2 is methyl.
7. A process for the preparation of 8-bromo-6-(o-bromophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine which comprises cyclizing 7-bromo-5-(o-bromophenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine with triethyl orthoacetate.
8. A process for the preparation of 8-bromo-6-(o-bromophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine which comprises cyclizing 7-bromo-5-(o-bromophenyl)-3H-[2,3e]-thieno-1,4-diazepine-2-thione with acetic acid hydrazide.
9. A process according to claim 1, wherein in the starting materials R1 is fluorine, and R2 is methyl.
10. A process for the preparation of 8-bromo-6-(o-fluorophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine which comprises cyclizing 7-bromo-5-(o-fluorophenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine with tri-ethyl orthoacetate.
11. A process for the preparation of 8-bromo-6-(o-fluorophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine which comprises cyclizing 7-bromo-5-(o-fluorophenyl)-2-hydrazino-3H-[2,3e]-thieno-1,4-diazepine with acetic acid hydrazide.
12. A process according to claim 1, wherein in the starting materials R1 is chlorine, and R2 is hydroxyethyl.
13. A process for the preparation of 8-bromo-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine which comprises cyclizing 7-bromo-5-(o-chlorophenyl)-3H-[2,3e]- thieno-1,4-diazepine-2-thione with 3-hydroxypropionic acid hydrazide.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2410030A DE2410030C3 (en) | 1974-03-02 | 1974-03-02 | 8-Bromo-6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepines, processes for their preparation and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1066274A true CA1066274A (en) | 1979-11-13 |
Family
ID=5908899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA220,982A Expired CA1066274A (en) | 1974-03-02 | 1975-02-28 | Substituted 6-aryl-4h-s-triazolo- (3,4c)-thieno- (2,3e) -1,4-diazepine and processes for production thereof |
Country Status (9)
| Country | Link |
|---|---|
| CA (1) | CA1066274A (en) |
| DE (1) | DE2410030C3 (en) |
| GB (1) | GB1490269A (en) |
| HK (1) | HK45981A (en) |
| IL (1) | IL46730A (en) |
| IT (1) | IT8047553A0 (en) |
| MY (1) | MY8100030A (en) |
| NZ (1) | NZ176793A (en) |
| ZA (1) | ZA751246B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001122785A (en) * | 1999-10-22 | 2001-05-08 | Nippon Boehringer Ingelheim Co Ltd | Tablet containing brotizolam |
-
1974
- 1974-03-02 DE DE2410030A patent/DE2410030C3/en not_active Expired
-
1975
- 1975-02-28 ZA ZA751246A patent/ZA751246B/en unknown
- 1975-02-28 NZ NZ176793A patent/NZ176793A/en unknown
- 1975-02-28 CA CA220,982A patent/CA1066274A/en not_active Expired
- 1975-02-28 IL IL46730A patent/IL46730A/en unknown
- 1975-03-03 GB GB8756/75A patent/GB1490269A/en not_active Expired
-
1980
- 1980-01-09 IT IT8047553A patent/IT8047553A0/en unknown
-
1981
- 1981-09-10 HK HK459/81A patent/HK45981A/en unknown
- 1981-12-30 MY MY30/81A patent/MY8100030A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HK45981A (en) | 1981-09-18 |
| DE2410030C3 (en) | 1982-11-11 |
| IL46730A (en) | 1981-06-29 |
| ZA751246B (en) | 1977-09-28 |
| DE2410030B2 (en) | 1976-05-06 |
| DE2410030A1 (en) | 1975-10-02 |
| IT8047553A0 (en) | 1980-01-09 |
| AU7864875A (en) | 1976-09-02 |
| MY8100030A (en) | 1981-12-31 |
| GB1490269A (en) | 1977-10-26 |
| NZ176793A (en) | 1978-04-03 |
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