U.S. patent number 3,878,205 [Application Number 05/272,088] was granted by the patent office on 1975-04-15 for diazepine derivatives.
This patent grant is currently assigned to Ciba-Geigy Corporation. Invention is credited to Andre Gagneux, Roland Heckendorn, Rene Meier.
United States Patent |
3,878,205 |
Gagneux , et al. |
April 15, 1975 |
DIAZEPINE DERIVATIVES
Abstract
Compounds of the class of
2-(aminomethyl)-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepines,
their 5-oxides and the pharmaceutically acceptable acid addition
salts of said compounds and their 5-oxides have valuable
pharmacological properties, in particular anticonvulsant
effectiveness, and are active ingredients for therapeutic
preparations. Specific embodiments are
2-[(dimethylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benz
odiazepine,
2-[(methylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzod
iazepine,
2-[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine,
2-[(methylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine and
2-[(methylamino)-methyl]-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine.
Inventors: |
Gagneux; Andre (Basel,
CH), Heckendorn; Roland (Arlesheim, CH),
Meier; Rene (Buus, CH) |
Assignee: |
Ciba-Geigy Corporation
(Ardsley, NY)
|
Family
ID: |
4367854 |
Appl.
No.: |
05/272,088 |
Filed: |
July 14, 1972 |
Foreign Application Priority Data
|
|
|
|
|
Jul 23, 1971 [CH] |
|
|
10885/71 |
|
Current U.S.
Class: |
540/558; 534/750;
534/558; 544/132; 548/265.8 |
Current CPC
Class: |
C07D
249/10 (20130101); C07D 487/04 (20130101) |
Current International
Class: |
C07D
249/00 (20060101); C07D 249/10 (20060101); C07D
487/00 (20060101); C07D 487/04 (20060101); C07d
057/02 (); C07d 099/02 () |
Field of
Search: |
;260/38R,293.59,268TR,247.5R |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3703525 |
November 1972 |
Tawada et al. |
|
Primary Examiner: Rollins; Alton D.
Attorney, Agent or Firm: Kolodny; Joseph G. Maitner; John J.
Groeger; Theodore O.
Claims
What we claim is:
1. A diazepine derivative of the formula I ##SPC11##
wherein
R.sub.1 represents a hydrogen atom or an alkyl group having from 1
to 3 carbon atoms,
R.sub.2 and R.sub.3, independently of each other, represent a
hydrogen atom, an alkyl or hydroxyalkyl group having from 1 to 6
carbon atoms, or an aralkyl group having from 7 to 9 carbon atoms,
whereby, when R.sub.2 and R.sub.3 simultaneously represent alkyl
groups as aforesaid, these alkyl groups may optionally be bound
together in the .beta.- or .gamma.-position either directly or via
an oxygen atom or imino group, or alkylimino or hydroxyalkylimino
group having at most 4 carbon atoms, and
wherein each of the rings A and B, independently of the other; is
unsubstituted or substituted by one chlorine atom, fluorine atom,
bromine atom, trifluoromethyl group, nitro group, alkyl group, or
alkoxy group having from 1 to 6 carbon atoms, its 5-oxide and the
pharmaceutically acceptable acid addition salts of said diazepine
derivative or of its 5-oxide.
2. A compound according to claim 1 having the formula I, wherein
R.sub.1, R.sub.2 and R.sub.3 have the meanings given in claim 1,
and wherein each of the rings A and B, independently of the other,
is unsubstituted or substituted as indicated in claim 1, and the
pharmaceutically acceptable acid addition salts thereof.
3. A compound according to claim 1 having the formula I, wherein
R.sub.1 is hydrogen, R.sub.2 and R.sub.3 have the meanings given in
claim 1, and wherein each of the rings A and B, independently of
the other, is unsubstituted or substituted by one fluorine atom,
chlorine atom, bromine atom, trifluoromethyl group or nitro group,
and the pharmaceutically acceptable acid addition salts
thereof.
4. A compound according to claim 1 having the formula Ia
##SPC12##
wherein
R.sub.2 and R.sub.3 have the meanings given in claim 1 and
R.sub.4 and R.sub.5, independently of each other, represent a
hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl or
nitro group or an alkyl or alkoxy group having from 1 to 6 carbon
atoms,
its 5-oxide and the pharmaceutically acceptable acid addition salts
of said compound of the formula Ia or of its 5-oxide
5. A compound having the formula Ia given in claim 4, wherein
R.sub.2 and R.sub.3 have the meanings given in claim 1,
R.sub.4 represents a fluorine, chlorine or bromine atom or a nitro
or trifluoromethyl group, and
R.sub.5 represents a hydrogen, fluorine, chlorine or bromine atom
or a trifluoromethyl group.
6. A compound having the formula Ia given in claim 4, wherein
R.sub.2 and R.sub.3, independently of each other, represent a
hydrogen atom or an alkyl group having from 1 to 6 carbon
atoms,
R.sub.4 represents a fluorine, chlorine, or bromine atom or a nitro
or trifluoromethyl group, and
R.sub.5 represents a hydrogen, fluorine, chlorine or bromine atom
or a trifluoromethyl group,
and the pharmaceutically acceptable acid addition salts
thereof.
7. A compound having the formula Ia given in claim 4, wherein
R.sub.2 and R.sub.3, independently of each other, represent a
hydrogen atom or an alkyl group having from 1 to 6 carbon
atoms,
R.sub.4 represents a chlorine atom in the 8-position and
R.sub.5 represents hydrogen or a fluorine or chlorine atom in the
ortho-position,
and the pharmaceutically acceptable acid addition salts
thereof.
8. A compound having the formula Ia given in claim 4, wherein
R.sub.2 and R.sub.3, independently of each other, represent a
hydrogen atom or the methyl group,
R.sub.4 represents a chlorine atom in the 8-position and
R.sub.5 represents hydrogen or a fluorine or chlorine atom in the
ortho-position,
and the pharmaceutically acceptable acid addition salts
thereof.
9. A compound according to claim 1 which is
2-[(dimethylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benz
odiazepine.
10. A compound according to claim 1 which is
2-(aminomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a]
[1,4]benzodiazepine.
11. A compound according to claim 1 which is
2-[(methylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzod
iazepine.
12. A compound according to claim 1 which is
2-(piperidinomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiaze
pine.
13. A compound according to claim 1 which is
2-[(1-pyrrolidinyl)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]ben
zodiazepine.
14. A compound according to claim 1 which is
2-(morpholinomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiaze
pine.
15. A compound according to claim 1 which is
2-[(4-methyl-1-piperazinyl)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a]
[1,4]benzodiazepine.
16. A compound according to claim 1 which is
2-[(methylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine and its hydrochloride.
17. A compound according to claim 1 which is
2-[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine.
18. A compound according to claim 1 which is
2-(aminomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo
diazepine.
19. A compound according to claim 1 which is
2-[(methylamino)-methyl]-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine and its (2:1)-fumarate.
20. A compound of the formula IV ##SPC13##
wherein
R.sub.3.sup.a represents a lower alkanoyl group, the cyano group, a
lower alkoxycarbonyl group, the phenoxycarbonyl, benzyloxycarbonyl,
chlorocarbonyl or benzoyl group,
R.sub.1 and R.sub.2 have the meanings given in claim 1 and wherein
each of the rings A and B, independently of the other, is
unsubstituted or substituted as indicated in claim 1, and its
5-oxide.
Description
DETAILED DESCRIPTION
The present invention relates to new diazepine derivatives, to
processes for their production, to therapeutic preparations
containing the new compounds, and to the use thereof.
The compounds according to the invention correspond to the general
formula I ##SPC1##
wherein
R.sub.1 represents hydrogen, or an alkyl group having from 1 to 3
carbon atoms,
R.sub.2 and R.sub.3, independently of each other, represent a
hydrogen atom, an alkyl or hydroxyalkyl group having from 1 to 6
carbon atoms, or an aralkyl group having from 7 to 9 carbon atoms,
whereby, when R.sub.2 and R.sub.3 simultaneously represent alkyl
groups as aforesaid, these alkyl groups may optionally be bound
together in the .beta.- or .gamma.-position either directly or via
an oxygen atom or imino group, or alkylimino or hydroxyalkylimino
group having at most 4 carbon atoms, and wherein each of the rings
A and B, independently of the other, is unsubstituted or
substituted by one or more chlorine atoms, fluorine atoms, bromine
atoms, trifluoromethyl groups, nitro groups and/or alkyl and/or
alkoxy groups having from 1 to 6 carbon atoms.
The invention also relates to the 5-oxides of the compounds of the
general formula I, and to the addition salts of the compounds of
the general formula I and of their 5-oxides with inorganic and
organic acids.
In the compounds of the general formula I, R.sub.1 is, as alkyl
group, e.g. the methyl, ethyl or propyl group. Suitable alkyl
groups as substituents of the rings A and B each having 1 to 6
carbon atoms are, e.g. the methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert.butyl, pentyl, isopentyl, neopentyl, tert.pentyl or
hexyl group; and suitable alkoxy groups having 1 to 6 carbon atoms
are, e.g. the methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, pentyloxy, isopentyloxy or hexyloxy group. Preferably,
however, substituents of the rings A and B are fluorine, chlorine
or bromine atoms, trifluoromethyl groups and/or nitro groups. As
alkyl groups having 1 to 6 carbon atoms, R.sub.2 and R.sub.3 are,
e.g. ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl
or hexyl groups, and preferably methyl groups; as hydroxyalkyl
groups having at most 6 carbon atoms, R.sub.2 and R.sub.3 are, e.g.
2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl,
2-hydroxy-1-methyl-propyl, 2-hydroxypentyl, 2-hydroxyhexyl and, in
particular, 2-hydroxyethyl groups; and as phenylalkyl groups having
at most 9 carbon atoms, R.sub.2 and R.sub.3 are, e.g.. benzyl,
phenethyl, .alpha., o-, m- or p-methylbenzyl, 3-phenylpropyl or
.alpha.-methylphenethyl groups.
Alkyl groups R.sub.2 and R.sub.3 bound together in the .beta.- or
.gamma.-position in the above defined manner form, together with
the adjacent nitrogen atom, e.g. the 1-pyrrolidinyl, piperidino,
hexahydro-1H-azepin-1-yl, morpholino, 1-piperazinyl or
hexahydro-1H-1,4-diazepin-1-yl group. The two last-mentioned groups
can be substituted in the 4-position, i.e. in the imino group, e.g.
by a methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or 3-hydroxybutyl
group, whilst all aforementioned rings on carbon atoms can,
moreover, be substituted by ethyl, propyl or, in particular, methyl
groups.
A preferred class of diazepine derivatives are those, wherein
R.sub.1 is hydrogen and wherein the rings A and B are unsubstituted
or substituted by a single substituent defined under formula I.
These diazepine derivatives correspond to the general formula Ia
##SPC2##
wherein
R.sub.2 and R.sub.3 have the meanings given under formula I,
and
R.sub.4 and R.sub.5, independently of each other, represent a
hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl or
nitro group or an alkyl or alkoxy group having from 1 to 6 carbon
atoms.
The radical R.sub.4 is preferably in the 8-position and is, in
particular, one of the mentioned halogen atoms, especially
chlorine, also the nitro group or the trifluoromethyl group. The
radical R.sub.5 is preferably hydrogen or a fluorine, chlorine or
bromine atom or the trifluoromethyl group in any desired position,
particularly, however, it is hydrogen or is a fluorine or chlorine
atom in the o-position.
The compounds of the general formula I, their 5-oxides and the
addition salts of the compounds of the general formula I and of
their 5-oxides with inorganic and organic acids possess valuable
pharmacological properties. They have, in particular, an
anticonvulsive action, such as can be shown, for example, on the
mouse in the pentetrazoleconvulsion test after administration of
oral doses of from ca. 0.4 mg/kg, as well as in the strychnine
convulsion test and in the electroshock test. The following are of
special importance:
2-[(dimethylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benz
odiazepine,
2-[(methylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo
[1,5-a][1,4]benzodiazepine,
2-[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4] benzodiazepine,
2-[(methylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine and
2-[(methylamino)-methyl]-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine, and their pharmaceutically acceptable acid
addition salts. Compared with their anticonvulsive action, the
sedative action of the new compounds is less pronounced. By virtue
of the mentioned properties and others, which can be determined by
selected standard tests [cp. W. Theobald and H. A. Kunz,
Arzneimittelforsch. 13, 122 (1963), and also W. Theobald et al.,
Arzneimittelforsch. 17, 561 (1967)], the compounds of the general
formula I, their 5-oxides, and the corresponding pharmaceutically
acceptable addition salts with inorganic and organic acids
constitute active substances for tranquilisers and anticonvulsants
which can be administered, for example, for the treatment of
conditions of stress and agitation with no, or with only
negligible, effect on vigility; as well as for the treatment of
epilepsy.
The compounds of the general formula I, their 5-oxides and the
corresponding acid addition salts are produced according to the
invention by the reaction of a reactive ester of a compound of the
general formula II ##SPC3##
wherein R.sub.1 has the meaning given under formula I, and the
rings A and B can be substituted as defined there, or of the
5-oxide of such a compound, with a compound of the general formula
III ##SPC4##
wherein R.sub.2 and R.sub.3 have the meaning given under formula I,
or with an alkali metal derivative of such a compound; and,
optionally, the conversion of the obtained reaction product into an
addition salt with an inorganic or organic acid.
Suitable reactive esters of hydroxy compounds of the general
formula II are, e.g. sulphonic acid esters such as the
methanesulphonic acid esters, the o- and p- toluenesulphonic acid
esters, the o- or p-nitrobenzenesulphonic acid esters, or the o- or
p-chlorobenzenesulphonic acid esters. Further suitable reactive
esters of compounds of the general formula II are their hydrohalic
acid esters, especially chlorides or bromides, as well as the
iodides produced in situ from them. An excess of the basic compound
to be reacted of the general formula III can serve as reaction
medium, and simultaneously as acid-binding agent. It is also
possible to use as the reaction medium, in addition to, or in place
of, the excess compound, an inert organic solvent, e.g. a lower
alkanol such as methanol, ethanol, propanol, isopropanol or
butanol, a ketone such as acetone or methyl ethyl ketone, also,
e.g. dioxane, tetrahydrofuran, dimethylformamide or
dimethylsulphoxide, whereby, optionally, the compound of the
general formula III may be also used in excess as an aqueous
solution; or, alternatively, it is possible to use, instead of this
excess, or in addition to it, another acid-binding agent, e.g. a
tertiary organic base such as ethyl-diisopropylamine or collidine,
or an inorganic basic substance such as, e.g. potassium
carbonate.
If, instead of the compound of the general formula III, an alkali
metal derivative of such a compound is used as reaction component,
e.g. a sodium, lithium or potassium derivative, then it is
preferable to use hydrocarbons such as benzene, toluene or xylene,
ethereal liquids such as 1,2-dimethoxyethane, tetrahydrofuran or
dioxane, or acid amides such as dimethylformamide or
hexamethylphosphoric acid triamide, or sulphoxides such as
dimethylsulphoxide, as solvents. The formation of the alkali metal
derivatives of the compounds of formula III, with the exception of
ammonia, is preferably effected in situ, e.g. by addition of at
least the equimolar amount of alkali metal hydride such as sodium
hydride, alkali metal amide such as sodium or lithium amide, or of
an alkali-metal-organic compound such as phenyl- or butyllithium.
The reaction temperatures are preferably between 0.degree. and
120.degree.C, or the boiling temperature of the employed reaction
medium. The preparation of the compounds of the general formula II
and their reactive esters is described below.
A second process for the production of compounds of the general
formula I wherein R.sub.2 and R.sub.3 are hydrogen atoms, whilst
R.sub.1 has the meaning given under formula I, and the rings A and
B can be substituted as defined there, and of their 5-oxides and
the corresponding acid addition salts, comprises the reduction of a
compound of the general formula IV ##SPC5##
wherein R.sub.1 has the meaning given under formula I, and the
rings A and B can be substituted as defined there, or of the
5-oxide of such a compound; and, optionally, the conversion of the
obtained reaction product into an addition salt with an inorganic
or organic acid.
The reduction of the azides of the general formula IV, the
preparation of which is described below, can be carried out both by
chemical methods and by catalytic hydrogenation, e.g. in the
presence of palladium charcoal catalysts, platinum oxide or Raney
nickel, in an organic solvent such as dioxane, ethanol, methanol or
tetrahydrofuran, at room temperature and under normal pressure. A
suitable chemical method is, in particular, the reduction with
tin(II)-chloride in lower alkanolic-aqueous, especially
ethanolic-aqueous, alkali solution, particularly sodium hydroxide
solution, at temperatures of between ca. 0.degree. and the boiling
temperature of the reaction mixture, preferably between ca.
0.degree. and room temperature.
A third process for the production of compounds of the general
formula I of which the radical R.sub.3 is hydrogen, or in which the
lower alkyl groups R.sub.2 and R.sub.3 are bound in the .beta.- or
.gamma.-position by an imino group, whilst R.sub.1 has the meaning
given under formula I, and the rings A and B can be substituted as
defined there, as well as of 5-oxides of such compounds and the
corresponding acid addition salts, comprises the hydrolysis of a
compound of the general formula V ##SPC6##
wherein
R.sub.3.sup. a represents an acyl radical, or a lower alkyl group
bound to a lower alkyl group R.sub.2 in the .beta.- or
.gamma.-position by an acylimino group,
R.sub.1 and R.sub.2 have the meanings given under formula I, and
the rings A and B can be substituted as defined there, or of the
5-oxide of such a compound; and, optionally, the conversion of the
obtained reaction product into an addition salt with an inorganic
or organic acid.
In the starting materials of the general formula V, the preparation
of which is subsequently described, R.sub.3.sup.a or the acyl
radical of the imino group is, in particular, a lower alkanoyl
group such as the acetyl or formyl group, the cyano group, a lower
alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl or
tert.butoxycarbonyl group, a phenoxycarbonyl or benzyloxycarbonyl
group, also a corresponding thiocarbonyl group, or the acyl radical
of another monofunctional derivative of carbonic acid such as, e.g.
the chlorocarbonyl group, or an arenecarbonyl group such as the
benzoyl group.
Hydrolysis can be performed with the aid of an alkali metal
hydroxide, e.g. potassium or sodium hydroxide, at a temperature of
ca. 50.degree. to 120.degree.C, e.g. in a higher boiling organic
solvent containing hydroxyl groups, such as, e.g. ethylene glycol
or diethylene glycol, or in a lower monoalkyl ether of such a
glycol, or in a lower alkanol such as methanol or ethanol.
Furthermore, hydrolysis can also be carried out in an acid medium,
e.g. with hydrogen bromide or hydrogen chloride in acetic acid, or
with alkanolic hydrochloric acid, at a temperature of ca.
50.degree. to 120.degree.C or at the boiling temperature of the
reaction mixture.
The compounds of the general formula II, on which the reactive
esters required as starting materials for the first process are
based, are obtained, for example, starting with compounds of the
general formula VI ##SPC7##
wherein the rings A and B can be substituted as defined under
formula I. Such compounds are described in the literature, e.g.
2-amino-5-chlorobenzophenone [cp. F. D. Chattaway, J.Chem.Soc. 85,
344 (1904)], or 2-amino-2',5-dichlorobenzophenone ]cp. L. H.
Sternbach et al., J. Org. Chem. 26, 4488 (1961)]. The compounds of
the general formula VI are diazotised, and the obtained diazonium
salts subsequently coupled with (2-chloroalkaneamido)-malonic acid
diethyl esters of which the alkaneamido group contains 2 to 5
carbon atoms, especially with (2-chloroacetamido)-malonic acid
diethyl ester ]cp. Ajay Kumar Bose, J. Indian Chem. Soc. 31,
108-110 (1954)], to give the corresponding
(2-chloroalkaneamido)-(2-benzoylphenylazo)-malonic acid diethyl
esters, particularly
(2-chloroacetamido)-(2-benzoyl-phenylazo)-malonic acid diethyl
esters. The coupling products are then converted, by treatment with
at least the double-molar amount, preferably the three- to fourfold
amount, of sodium hydroxide and subsequent neutralisation, into the
compounds of the general formula VII ##SPC8##
wherein R.sub.1 has the meaning given under formula I, and the
rings A and B can be substituted as defined there. These compounds
are reacted, optionally after pretreatment with potassium iodide,
with aqueous ammonia or with hexamethylenetetramine, with the
chlorine atom being thus replaced by the amino group, and
simultaneously, with elimination of water, ring closure occurring
to give carboxylic acids of the general formula IX ##SPC9##
wherein R.sub.1 has the meaning given under formula I, and the
rings A and B can be substituted as defined there. It is also
possible, however, to firstly react the compounds of the general
formula VII with sodium azide, in the presence of potassium iodide,
to compounds of the general formula VIII ##SPC10##
wherein R.sub.1 has the meaning given under formula I, and the
rings A and B can be substituted as defined there; and to then
cyclise these compounds with triphenylphosphine, with evolution of
nitrogen, to compounds of the general formula IX.
The carboxylic acids of the general formula IX are converted in a
manner known per se, e.g. with ethanol or methanol containing
hydrogen chloride, into their ethyl or methyl esters; and these
reduced with lithium aluminium hydride, in an ethereal solvent such
as tetrahydrofuran and at temperatures of around 0.degree.C, to
compounds of the general formula II. The ethyl esters of the
carboxylic acids of the general formula IX required for the
reducation can also be obtained by the treatment of the
aforementioned coupling products with at most the double-molar
amount of sodium hydroxide under mild reaction conditions, i.e. at
room temperature and with neutralisation before processing; and the
subsequent reaction of the ethyl esters of carboxylic acids of the
general formula VII obtained as the main product, in a manner
analogous to that for the free acids, with hexamethylenetetramine
in absolute ethanol.
The compounds of the general formula II obtained by reduction are
converted in a manner known per se, e.g. by reaction with a
sulphonic acid chloride such as methanesulphonic acid chloride or
p-toluenesulphonic acid chloride, in an inert organic solvent such
as methylene chloride, in the presence of an organic base such as
triethylamine or ethyl-diisopropylamine, or by reaction with
thionyl chloride or phosphorus tribromide and, optionally,
subsequently with potassium iodide, into suitable reactive
esters.
The compounds of the general formula IV serving as starting
materials for the second process are produced by the reaction of
reactive esters of compounds of the general formula II, e.g.
methanesulphonic acid esters, with alkali metal azides such as
sodium azide, in inert organic or organic-aqueous solvents, such
as, e.g. aqueous acetone.
The starting materials of the general formula V used in the third
process, in which R.sub.3.sup. a is an acyl group, are obtained,
for example, analogously to the first-mentioned process by
employing, instead of an alkali metal compound of a starting
material of the general formula III, e.g. an alkali metal compound
of a formamide, acetamide or cyanamide substituted in the amide
group by R.sub.2, or of a carbamic acid-lower alkyl ester, -phenyl
ester or -benzyl ester substituted on the nitrogen atom by
R.sub.2.
The compounds of the general formula I obtained by the processes
according to the invention, and also the 5-oxides of these
compounds, are optionally converted, in the usual manner, into
their addition salts with inorganic and organic acids. For example,
the acid desired as salt component is added to a solution of a
compound of the general formula I in an organic solvent. Organic
solvents in which the formed salt is difficultly soluble are
preferably chosen for the reaction, so that the salt can be
separated by filtration. Such solvents are, e.g. methanol, ether,
acetone, methyl ethyl ketone, acetone/ether, acetone/ethanol,
methanol/ether or ethanol/ether.
It is possible to use as pharmaceutical active substances, instead
of free bases, pharmaceutically acceptable acid addition salts,
i.e. salts with such acids of which the anions are not toxic in the
case of the dosage amounts in question. Moreover, it is of
advantage if the salts to be used as pharmaceutical active
substances crystallise well and are not, or only slightly,
hygroscopic. The following may be used, for example, for salt
formation with compounds of the general formula I: hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, ethanesulphonic acid,
2-hydroxyethanesulphonic acid, acetic acid, lactic acid, succinic
acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric
acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic
acid and embonic acid.
The new active substances are administered orally, rectally or
parenterally. The dosage amount depends on the mode of
administration, on the species, on the age and on the individual
condition. The daily doses of the free bases, of their 5-oxides, or
of pharmaceutically acceptable salts of the free bases vary between
0.02 mg/kg and 2 mg/kg for warm-blooded animals. Suitable dosage
units, such as dragees, tablets, suppositories or ampoules,
preferably contain 0.5-25 mg of an active substance according to
the invention.
Dosage units for oral administration contain as active substance
preferably between 1-50 percent of a compound of the general
formula I, or of a pharmaceutically acceptable salt thereof. The
dosage units are prepared by the combination of the active
substance with, e.g. solid pulverulent carriers such as lactose,
saccharose, sorbitol, mannitol; starches such as potato starch,
maize starch or amylopectin, also laminaria powder or citrus pulp
powder; cellulose derivatives or gelatine, optionally with the
addition of lubricants such as magnesium or calcium stearate or
polyethylene glycols, to form tablets or dragee cores. The dragee
cores are coated, for example, with concentrated sugar solutions
which may also contain, e.g. gum arabic, talcum and/or titanium
dioxide; or with a lacquer dissolved in readily volatile organic
solvents or solvent mixtures. Dyestuffs can be added to these
coatings in order to facilitate, for example, identification of the
various doses of active substance.
Other suitable oral dosage units are hard gelatine capsules, as
well as soft closed capsules made from gelatine and a softener,
such as glycerin. The hard capsules contain the active substance
preferably as a granulate, in admixture, for example, with fillers
such as maize starch, and/or lubricants such as talcum or magnesium
stearate, and optionally stabilisers such as sodium metabisulphite
(Na.sub.2 S.sub.2 O.sub.5) or ascorbic acid. In soft capsules, the
active substance is preferably dissolved or suspended in suitable
liquids such as polyethylene glycols, to which likewise stabilisers
may be added.
Suitable dosage units for rectal administration are, e.g.
suppositories consisting of a combination of an active substance
and a suppository foundation substance. The following, for example,
are suitable as base substances: natural or synthetic
triglycerides, paraffin hydrocarbons, polyethylene glycols or
higher alkanols. Hard gelatine capsules consisting of a combination
of the active substance and a foundation substance are likewise
suitable. Suitable foundation substances are, e.g. liquid
triglycerides, polyethylene glycols or paraffin hydrocarbons.
Ampoules for parenteral administration, particularly for
intramuscular administration, preferably contain a water-soluble
salt of an active substance in a concentration of preferably 0.1 -
2 percent, optionally together with suitable stabilisers and buffer
substances, in aqueous solution.
The following specifications further illustrate the production of
tablets, dragees, capsules, suppositories and ampoules:
a. An amount of 50 g of
2-[(dimethylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benz
odiazepine is mixed with 175.80 g of lactose and 169.70 g of potato
starch; the mixture is moistened with an alcoholic solution of 10 g
of stearic acid, and then granulated through a sieve. After the
granulate has dried, the following ingredients are mixed in: 160 g
of potato starch, 200 g of talcum, 2.50 g of magnesium stearate and
32 g of colloidal silicon dioxide; the mixture is subsequently
pressed to obtain 10,000 tablets each weighing 80 mg and each
containing 5 mg of active substance; the tablets may optionally be
provided with grooves to render possible a more precise adjustment
of the dosage amount. It is also possible to use, as active
substance, the same amount of
2-(piperidinomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiaze
pine.
b. A granulate is produced from 50 g of
2-[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo
[1,5-a][1,4]benzodiazepine, 175.90 g of lactose and the alcoholic
solution of 10 g of stearic acid; after drying, the granulate is
mixed with 56.60 g of colloidal silicon dioxide, 165 g of talcum,
20 g of potato starch and 2.50 g of magnesium stearate; and the
mixture finally pressed to obtain 10,000 dragee cores. These are
then coated with a concentrated syrup made from 502.28 g of
crystallised saccharose, 6 g of shellac, 10 g of gum arabic, 0.22 g
of dyestuff and 1.5 g of titanium dioxide; the coated dragees are
finally dried. The obtained dragees each weigh 100 mg and each
contain 5 mg of active substance.
c. To produce 1000 capsules each containing 2 mg of active
substance, an amount of 2 g of
2-[(methylamino)-methyl]-6-(o-fluorophenyl-8-chloro-4H-s-triazolo[1,5-a][1
,4]benzodiazepine hydrochloride is mixed with 256 g of lactose; the
mixture is uniformly moistened with an aqueous solution of 2 g of
gelatine, and then granulated through a suitable sieve (e.g. sieve
III according to Ph.Helv. V). The granulate is mixed with 10.0 g of
dried maize starch and 15.0 g of talcum, and the mixture evenly
filled into 1000 hard gelatine capsules, size 1. It is also
possible to use, as active substance, the same amount of
2-[(methylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine-fumarate-(1:2).
d. A suppository mixture is prepared from 1.0 g of
2-[(dimethylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benz
odiazepine and 169.0 g of adeps solidus; from the prepared mixture
are then poured 100 suppositories each containing 10 mg of active
substance.
e. A solution of 2.0 g of
2-[(methylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzod
iazepinehydrochloride in one litre of water is filled into 1000
ampoules, and these then sterilised. An ampoule contains a 0.2
percent solution of 2 mg of active substance.
The following examples further illustrate the production of the new
compounds of the general formula I and of intermediates not
hitherto described; these examples, however, do not in any way
limit the scope of the invention. Temperatures are expressed in
degrees Centigrade.
EXAMPLE 1
a. An amount of 8.05 (0.02 mole) of methanesulphonic acid ester of
6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
is dissolved in 80 ml of dimethylsulphoxide; the solution is then
added dropwise at 5.degree.-10.degree., with stirring, to a mixture
of 10 g (0.09 mole) of 40.5 percent aqueous dimethylamine solution
and 20 ml of dimethylsulphoxide. The reaction mixture is then
allowed to warm up to room temperature, and is stirred for a
further hour at 20.degree.-25.degree.. It is thereupon poured on
0.5 litre of ice-cold water, and extraction carried out twice with
250 ml of benzene each time. The combined benzene extracts are
washed five times with 100 ml of water each time; they are dried
over sodium sulphate and concentrated in vacuo. The residue is
dissolved in chloroform, and the solution chromatographed through a
column containing 120 g of basic aluminium oxide. After elution
with chloroform, concentration of the eluate by evaporation, and
recrystallisation of the residue from cyclohexane,
2-[(dimethylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benz
odiazepine, M.P. 133.degree.-135.degree., is obtained.
The methanesulphonic acid ester required as starting material is
produced as follows:
b. A solution of 58.0 g (0.25 mole) of 2-amino-5-chlorobenzophenone
[cp. F. D. Chattaway, J.Chem.Soc. 85, 344 (1904)] in 310 ml of
glacial acetic acid/conc. hydrochloric acid (4:1) is diazotised at
room temperature, whilst stirring is maintained, with 50 ml (0.25
mole) of aqueous sodium nitrite solution. An amount of 150 g of ice
is added to the obtained diazonium salt solution, followed by the
rapid addition dropwise of a solution of 52.4 g (0.208 mole) of
(2-chloroacetamido)-malonic acid diethyl ester [cp. Ajay Kumar
Bose, J.Indian Chem.Soc. 31, 108-110 (1954)] in 600 ml of acetone.
An addition is subsequently made dropwise at 5.degree.-10.degree.,
in the course of 20 minutes, of a solution of 276.0 g (2 moles) of
potassium carbonate in 500 ml of water; stirring is continued for
one hour, and benzene and saturated sodium chloride solution are
then added. The benzene solution is separated, washed with
saturated sodium chloride solution, dried over sodium sulphate, and
concentrated by evaporation to obtain 121 g of crude
(2-benzoyl-4-chlorophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester. This crude product is dissolved in 1.5 litres of
dioxane; an amount of 36 g (0.9 mole) of sodium hydroxide dissolved
in 2 litres of water is then added, the mixture stirred for 30
minutes, and the dioxane evaporated off in vacuo. The residue is
diluted with 500 ml of water, and 20 g of active charcoal added;
the mixture is well stirred and then filtered through purified
diatomaceous earth. An addition is made to the filtrate, with
thorough stirring, of 2N hydrochloric acid until an acid reaction
to a congo-red indicator is obtained; the precipitated carboxylic
acid is filtered off under suction, washed with water and then
recrystallised from hot methanol. The obtained crystals, containing
an equimolar amount of methanol, of
1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxyl
ic acid sinter at 137.degree.-138.degree. and melt, with
decomposition, at 169.degree.-171.degree..
c. An amount of 33.2 g (0.200 mole) of potassium iodide is
dissolved in 85 ml of water, and the obtained solution diluted with
850 ml of dioxane; an addition is made at 25.degree., with
stirring, of 71.5 g (0.175 mole) of the compound produced according
to b), and the solution heated for 1 hour at 45.degree.-50.degree..
An amount of 0.5 litre of concentrated aqueous ammonia solution is
thereupon added; the mixture is heated for 2 hours at
45.degree.-50.degree., and concentrated in vacuo. The residue is
dissolved in 2 litres of water, and an addition then made of 2N
hydrochloric acid until the solution shows an acid reaction to a
congo-red indicator. The free carboxylic acid precipitates; it is
filtered off under suction, washed with water until neutral,
subsequently washed with methanol, and dried in vacuo at
120.degree.-130.degree.. The obtained
6-phenyl-8-chloro-4-H-s-triazolo[1,5-a][1,4]benzodiazepine
-2-carboxylic acid decomposes at 170.degree..
This carboxylic acid can also be produced according to d) from the
chloromethyl compound obtained by procedure b):
d. An amount of 0.408 g (0.001 mole) of the chloromethyl compound
obtained according to b), containing an equimolar amount of
methanol, and 0.320 g (0.003 mole) of hexamethylenetetramine is
dissolved in 20 ml of ethanol, and the solution refluxed for 12
hours. The solution is then concentrated at 40.degree. in vacuo,
and the residue dissolved in 20 ml of 0.05N sodium hydroxide
solution; 2N hydrochloric acid is then added until the solution
shows an acid reaction to a congo-red indicator, and the
precipitated crude product processed as under c). The obtained
6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid melts at 170.degree..
e. An amount of 6.77 g (0.020 mole) of
6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid [produced according to c) or d)] is suspended in 250 ml of
abs. ethanol. Whilst stirring and refluxing are maintained, the
solution is saturated with hydrogen chloride gas. The obtained
clear solution is refluxed for a further 10 hours, and afterwards
concentrated at 40.degree. in vacuo. The residue is dissolved in
100 ml of ice-cold 5% sodium bicarbonate solution and 100 ml of
methylene chloride; the organic phase is separataed, washed with
water, dried over sodium sulphate, and concentrated at 40.degree.
in vacuo. The crude viscous residue is refluxed with 100 ml of
ether for one hour, during which process crystallisation occurs.
After cooling to 0.degree., the crystals are filtered off under
suction and washed with ether to obtain
6-phenyl-8-chloro-4-H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester, M.P. 137.degree.-138.degree..
f. An amount of 11.0 g (0.030 mole) of
6-phenyl-8-chloro-4H-s-triazolo-[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester dissolved in 110 ml of abs. tetrachlorofuran is
added dropwise in the course of 1 hour, with ice cooling, to a
suspension of 2.3 g (0.06 mole) of lithium aluminium hydride in 150
ml of abs. tetrahydrofuran. The mixture is stirred for a further 30
minutes at 0.degree.-5.degree., and 11.5 ml of 1N sodium hydroxide
solution then added dropwise. The inorganic salts are filtered off;
the filtrate is then concentrated in vacuo, the residue dissolved
in 200 ml of chloroform, the solution washed with 1N sodium
hydroxide solution and then with water. After drying over sodium
sulphate, the chloroform solution is concentrated in vacuo, and the
residue crystallised from isopropanol. After drying, the obtained
6-phenyl-8-chloro-4H-s-triazolo
[1,5-a][1,4]benzodiazepine-2-methanol melts at
185.degree.--186.degree..
g. An amount of 16.25 g (0.05 mole) of the alcohol obtained
according to f) and 7.6 g (0.075 mole) of triethylamine is
dissolved in 200 ml of abs. methylene chloride. An addition is then
made dropwise at 3.degree.-10.degree., with ice cooling and
stirring, of 8.6 g (0.075 mole) of methanesulphochloride dissolved
in 50 ml of abs. methylene chloride. After completion of the
dropwise addition, the reaction mixture is heated to 20.degree.,
and stirred for a further 30 minutes. It is then cooled to
5.degree., and 100 ml of ice-water added. The methylene chloride
phase is separated, and washed three times with 100 ml of ice-water
each time; it is then dried with sodium sulphate and concentrated
at 30.degree. in vacuo.
The methanesulphonic acid ester of
6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
is obtained as a dark-yellow, non-crystallising oil, and is further
reacted without purification.
EXAMPLE 2
The methanesulphonic acid ester prepared according to Example 1 g)
from 4.9 g (0.015 mole) of
6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
and 2.58 g (0.023 mole) of methanesulphonic acid chloride is
dissolved in 50 ml of methanol; the solution is then added dropwise
to 100 ml of boiling methanol, which is continuously saturated by
the introduction of ammonia gas. Refluxing is carried out for 4
hours with the further introduction of ammonia gas, and the
reaction mixture then concentrated in vacuo to dryness. Sodium
hydroxide solution (0.1N) is added to the residue and extraction
performed with benzene. The benzene extract is washed once with
water, and afterwards repeatedly extracted with 0.1N acetic acid.
The acid extracts are combined, rendered alkaline with conc.
ammonia, and extracted with benzene. The combined benzene extracts
are washed with water and with saturated sodium chloride solution,
dried over sodium sulphate, and concentrated to dryness.
The residue of 1.7 g is dissolved in ether/ethanol/triethylamine
(3:5:2), and the solution chromatographed on a column of 170 g of
silica gel. The employed eluting agent is
ether/ethanol/triethylamine (3:5:2). The fractions containing the
desired reaction product are combined, and concentrated in vacuo to
dryness. Amorphous
2-(aminomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine
is obtained, which liquifies at 69.degree.-75.degree..
EXAMPLE 3
A solution of 6.05 g (0.015 mole) of crude methanesulphonic acid
ester of 6-phenyl-8-chloro-4H-s-triazolo
[1,5-a][1,4]benzodiazepine-2-methanol [produced according to
Example 1 g)] in 50 ml of dimethylsulphoxide is slowly added
dropwise at 15-17.degree. to a solution of 2.55 g (0.03 mole) of
piperidine in 30 ml of dimethylsulphoxide; stirring is then carried
out for a further 3 hours at room temperature. The reaction mixture
is poured on ice-water, and extracted three times with ether. The
organic phase is washed twice with water, and once with saturated
sodium chloride solution; it is then dried over sodium sulphate and
concentrated in vacuo to dryness. The residue is dissolved in
benzene/methylene chloride (1:1), and the solution chromatographed
on a column containing 100 g of basic aluminium oxide, elution
being performed with the same solvent mixture. The fractions
containing the desired reaction product are combined, and
concentrated in vacuo. Amorphous
2-(piperidinomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a]
[1,4]benzodiazepine is obtained, which liquifies at
55.degree.-64.degree..
The following are obtained analogously from 6.05 g (0.015 mole) of
the same methanesulphonic acid ester:
with 5.4 g (0.077 mole) of pyrrolidine:- amorphous
2-[(1-pyrrolidinyl)-methyl]-6-phenyl-8-chloro-4H-s-triazolo
[1,5-a][1,4]benzodiazepine, which liquifies at
53.degree.-63.degree.;
with 2.61 g (0.030 mole) of morpholine:-
2-(morpholinomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiaze
pine, M.P. 111.degree.-113.degree. after crystallisation from
ether;
with 3.05 g (0.030 mole) of 1-methylpiperazine:-
2-[(4-methyl-1-piperazinyl)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[1,5-a]
[1,4]benzodiazepine, M.P. 162.degree.-163.degree. after
crystallisation from ether;
with 2.4 g (0.080 mole) of methylamine:- amorphous
2-[(methylamino)-methyl]-6-phenyl-8-chloro-4H-s-triazolo
[1,5-a][1,4]benzodiazepine, which liquifies at
56.degree.-67.degree..
EXAMPLE 4
Starting with 2.4 g (0.080 mole) of methylamine and 6.32 g (0.015
mole) of crude methanesulphonic acid ester of
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]
benzodiazepine-2-methanol there is obtained, analogously to the
procedure described in Example 3,
2-[(methylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine. An addition is made to this compound in 330 ml
of ethyl acetate of ethereal hydrogen chloride solution until a
sample, to which water has been added, shows a pH-value of ca. 2.
After prolonged cooling, the precipitated crystals are filtered
off, and recrystallised twice from ethanol. The hydrochloride
obtained after drying contains the double-molar amount of crystal
water, and melts at 247.degree.-249.degree..
There is obtained in an analogous manner, starting with 2.4 g (0.08
mole) of methylamine and 6.57 g (0.015 mole) of crude
methanesulphonic acid ester of
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine
-2-methanol,
2-[(methylamino)-methyl]-6-(chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,
4]benzodiazepine. This is dissolved in 130 ml of ethanol, and a
saturated ethanolic fumaric acid solution added until the pH-value
of a sample to which water has been added is ca. 6. After cooling,
the precipitated crystals are filtered off and recrystallised once
from methanol. After drying, the obtained
2-[(methylamino)-methyl]-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][
1,4]benzodiazepine-fumarate-(2:1) melts at
199.degree.-201.degree..
The following 2-[(methylamino)-methyl]-compounds are obtained
likewise analogously to Example 3, by the reaction in each case of
2.4 g (0.080 mole) of methylamine with the given amounts
(corresponding always to 0.015 mole) of the methanesulphonic acid
esters (called in short esters) of the stated alcohols:
from 6.05 g of the ester of
6-(o-chlorophenyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol:-
2-[(methylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[1,5-a][1,4]benzo
diazepine;
from 7.07 g of the ester of
6-(.alpha.,.alpha.,.alpha.-trifluoro-o-tolyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine-2-methanol:-
2-[(methylamino)-methyl]-6-(.alpha.,.alpha.,.alpha.-trifluoro-o-tolyl)-8-c
hloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine;
from 5.80 g of the ester of
6-phenyl-8-fluoro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol:-
2-[(methylamino)-methyl]-6-phenyl-8-fluoro-4H-s-triazolo[1,5-a][1,4]benzod
iazepine;
from 6.71 g of the ester of
6-phenyl-8-bromo-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol:-
2-[(methylamino)-methyl]-6-phenyl-8-bromo-4H-s-triazolo[1,5-a][1,4]benzodi
azepine;
from 6.55 g of the ester of
6-phenyl-8-(trifluoromethyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-met
hanol:-
2-[(methylamino)-methyl]-6-phenyl-8-(trifluoromethyl)-4H-s-triazolo[1,5-a]
[1,4]benzodiazepine;
from 6.20 g of the ester of
6-phenyl-8-nitro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol:-
2-[(methylamino)-methyl]-6-phenyl-8-nitro-4H-s-triazolo[1,5-a][1,4]benzodi
azepine.
The methanesulphonic acid esters required as starting materials are
produced as follows:
b. The following are obtained analogously to Example 1 b)
with the use of 62.5 g (0.25 mole) of
2-amino-5-chloro-2'-fluorobenzophenone:-
[2-(o-fluorobenzoyl)-4-chlorophenylazo]-(2-chloroacetamido)-malonic
acid diethyl ester;
with the use of 66.5 g (0.25 mole) of
2-amino-2',5-dichlorobenzophenone:-
[2-(o-chlorobenzoyl)-4-chlorophenylazo]-(2-chloroacetamido)-malonic
acid diethyl ester;
with the use of 58.0 g (0.25 mole) of
2-amino-2'-chlorobenzophenone:-
[o-(o-chlorobenzoyl)-phenylazo]-(2-chloroacetamido)-malonic acid
diethyl ester;
with the use of 75.0 g (0.25 mole) of
2-amino-5-chloro-2'-(trifluoromethyl)-benzophenone:-
[2-(.alpha.,.alpha.,.alpha.-trifluoro-o-toluoyl)-4-chlorophenylazo]-(2-chl
oroacetamido)-malonic acid diethyl ester;
with the use of 53.8 g (0.25 mole) of
2-amino-5-fluorobenzophenone:-
(2-benzoyl-4-fluorophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester;
with the use of 69.9 g (0.25 mole) of 2-amino-5-bromobenzophenone:-
(2-benzoyl-4-bromophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester;
with the use of 66.2 g (0.25 mole) of
2-amino-5-(trifluoromethyl)-benzophenone:-
(2-benzoyl-.alpha.,.alpha.,.alpha.-trifluoro-p-toylazo)-(2-chloroacetamido
)-malonic acid diethyl ester;
with the use of 60.8 g (0.25 mole) of 2-amino-5-nitrobenzophenone:-
(2-benzoyl-4-nitrophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester.
c. A solution of 8.0 g (0.20 mole) of sodium hydroxide in 400 ml of
water is added dropwise, in the course of 2 hours, to a solution of
51.2 g (0.10 mole) of
[2-(o-fluorobenzoyl)-4-chlorophenylazo]-(2-chloroacetamido)-malonic
acid diethyl ester in 600 ml of dioxane. The temperature of the
reaction mixture rises during this time from 20.degree. initially
to a maximum of 30.degree., and the pH-value is finally 8.5 to 9.0.
The mixture is stirred at room temperature for a further 45
minutes; it is thereupon neutralised by the addition of glacial
acetic acid, and concentrated in vacuo. Ice and 5 percent sodium
bicarbonate solution are added to the residue; and the mixture then
extracted twice with ether. The aqueous phase is retained for
further processing. The organic phases are combined, washed with
ice-cold 5 percent sodium bicarbonate solution and water, dried
over sodium sulphate, and concentrated in vacuo. The residue is
recrystallised from isopropanol. After drying, the
1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-
3-carboxylic acid ethyl ester, obtained as the main product, melts
at 97.degree.-98.degree. .
The above aqueous sodium bicarbonate solutions (the original ones
and the washing-solutions) are combined; 10 percent hydrochloric
acid is added until an acid reaction to a congo-red indicator is
obtained, and the solution extracted three times with methylene
chloride. The combined organic extracts are washed with water and
with saturated sodium chloride solution, dried over sodium
sulphate, and concentrated in vacuo. Crude amorphous
1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-
3-carboxylic acid is thus obtained as secondary product. This crude
acid can be used direct for cyclisation analogously to Example 1 c)
or 1 d).
The following are obtained analogously:
with the use of 52.9 g (0.10 mole) of
[2-(o-chlorobenzoyl)-4-chlorophenylazo]-(2-chloroacetamido)-malonic
acid diethyl ester:
1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-
3-carboxylic acid ethyl ester and the corresponding acid, M.P.
170.degree.-175.degree.;
with the use of 49.4 g (0.10 mole) of
[o-(o-chlorobenzoyl)-phenylazo]-(2-chloroacetamido)-malonic acid
diethyl ester:-
1-[o-(o-chlorobenzoyl)-phenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carbox
ylic acid ethyl ester and the corresponding acid;
with the use of 56.2 g (0.10 mole) of
[2-(.alpha.,.alpha.,.alpha.-trifluoro-o-toluoyl)-4-chlorophenylazo]-(2-chl
oroacetamido)-malonic acid diethyl ester:-
1-[2-(.alpha.,.alpha.,.alpha.-trifluoro-o-toluoyl)-4-chlorophenyl]-5-(chlo
romethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl ester and the
corresponding acid;
with the use of 47.8 g (0.10 mole) of
(2-benzoyl-4-fluorophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester:-
1-(2-benzoyl-4-fluorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxyl
ic acid ethyl ester and the corresponding acid;
with the use of 53.8 g (0.10 mole) of
(2-benzoyl-4-bromophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester:-
1-(2-benzoyl-4-bromophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxyli
c acid ethyl ester and the corresponding acid;
with the use of 52.8 g (0.10 mole) of
(2-benzoyl-.alpha.,.alpha.,.alpha.-trifluoro-p-tolylazo)-(2-chloroacetamid
o)-malonic acid diethyl ester:-
1-(2-benzoyl-.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-5-(chloromethyl)-1
H-1,2,4-triazole-3-carboxylic acid ethyl ester and the
corresponding acid;
with the use of 50.4 g (0.10 mole) of
(2-benzoyl-4-nitrophenylazo)-(2-chloroacetamido)-malonic acid
diethyl ester:-
1-(2-benzoyl-4-nitrophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxyli
c acid ethyl ester and the corresponding acid;
d. A solution of 16.88 g (0.04 mole) of
1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-
3-carboxylic acid ethyl ester and 11.2 g (0.08 mole) of
hexamethylentetramine in 250 ml of abs. ethanol is refluxed for 6
hours. The solution is then concentrated at 40.degree. in vacuo; an
amount of 800 ml of ice-water is then added to the residue, and
extraction performed twice with methylene chloride. The organic
phase is washed twice with ice-cold 1N hydrochloric acid and three
times with water; it is then dried over sodium sulphate and
concentrated in vacuo. The residue is recrystallised from
isopropanol. After drying, the obtained
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carb
oxylic acid ethyl ester melts at 177.degree.-179.degree..
The following are obtained analogously:
from 17.54 g (0.04 mole) of
1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-
3-carboxylic acid ethyl ester:-
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carb
oxylic acid ethyl ester;
from 16.16 g (0.04 mole) of
1-[o-(o-chlorobenzoyl)-phenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carbox
ylic acid ethyl ester:-
6-(o-chlorophenyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester;
from 18.88 g (0.04 mole) of
1-[2-(.alpha.,.alpha.,.alpha.-trifluoro-o-toluoyl)-4-chlorophenyl]-5-(chlo
romethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl ester:-
6-(.alpha.,.alpha.,.alpha.-trifluoro-o-tolyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine-2-carboxylic acid ethyl ester;
from 15.50 g (0.04 mole) of
1-(2-benzoyl-4-fluorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxyl
ic acid ethyl ester:-
6-phenyl-8-fluoro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester;
from 17.94 g (0.04 mole) of
1-(2-benzoyl-4-bromophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxyli
c acid ethyl ester:-
6-phenyl-8-bromo-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester;
from 17.50 g (0.04 mole) of
1-(2-benzoyl-.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-5-(chloromethyl)-1
H-1,2,4-triazole-3-carboxylic acid ethyl ester:-
6-phenyl-8-(trifluoromethyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-car
boxylic acid ethyl ester;
from 16.58 g (0.04 mole) of
1-(2-benzoyl-4nitrophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic
acid ethyl ester:-
6-phenyl-8-nitro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester.
e. and f. The following are obtained analogously to Examples 1 f)
and g):
from 11.54 g (0.03 mole) of
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carb
oxylic acid ethyl ester:-
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol, M.P. 138.degree.-145.degree. (from isopropanol) and its
methanesulphonic acid ester (crude product);
from 12.04 g (0.03 mole) of
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carb
oxylic acid ethyl ester:-
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol and its methanesulphonic acid ester;
from 11.0 g (0.03 mole) of
6-(o-chlorophenyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester:-
6-(o-chlorophenyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
and its methanesulphonic acid ester;
from 13.04 g (0.03 mole) of
6-(.alpha.,.alpha.,.alpha.-trifluoro-o-tolyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine-2-carboxylic acid ethyl ester:-
6-(.alpha.,.alpha.,.alpha.-trifluoro-o-tolyl)-8-chloro-4H-s-triazolo[1,5-]
[1,4]benzodiazepine-2-methanol and its methanesulphonic acid
ester;
from 10.50 g (0.03 mole) of
6-phenyl-8-fluoro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester:-
6-phenyl-8-fluoro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
and its methanesulphonic acid ester;
from 12.33 g (0.03 mole) of
6-phenyl-8-bromo-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester:-
6-phenyl-8-bromo-4H-s-triazolo[1,5-][1,4]benzodiazepine-2-methanol
and its methanesulphonic acid ester;
from 12.0 g (0.03 mole) of
6-phenyl-8-(trifluoromethyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-car
boxylic acid ethyl ester:-
6-phenyl-8-(trifluoromethyl)-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-met
hanol and its methanesulphonic acid ester;
from 11.31 g (0.03 mole) of
6-phenyl-8-nitro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic
acid ethyl ester:-
6-phenyl-8-nitro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
and its methanesulphonic acid ester.
EXAMPLE 5
The following are obtained analogously to Example 1:
with the use of 8.41 g of methanesulphonic acid ester of
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol:-
2-[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine, which, after recrystallisation from
ether/petroleum ether, melts at 114.degree.-116.degree.; and
with the use of 8.74 g of methanesulphonic acid ester of
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol:-
2-[(dimethylamino)-methyl]-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a
][1,4]benzodiazepine.
EXAMPLE 6
The following are obtained, analogously to Example 3, by the
reaction of 2.55 g (0.03 mole) of piperidine:
with 6.32 g (0.015 mole) of crude methanesulphonic acid ester of
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol:-
2-(piperidinomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]
benzodiazepine; and
with 6.57 g (0.015 mole) of crude methanesulphonic acid ester of
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol:-
2-(piperidinomethyl)-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]
benzodiazepine.
EXAMPLE 7
a. A solution of 1.69 g (0.0075 mole) of tin(II)-chloridedihydrate
in 24 ml of 2N sodium hydroxide solution is slowly added dropwise
at 0.degree.-5.degree. to a solution of 1.75 g (0.005 mole) of
2-(azidomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine
in 175 ml of 95 percent aqueous ethanol. The reaction mixture
immediately becomes cloudy. After completion of the dropwise
addition, the reaction mixture is stirred for a further 30 minutes
at 5.degree.-10.degree.; it is then neutralised with 2N
hydrochloric acid, and concentrated in vacuo to dryness. Ice and 2N
sodium hydroxide solution are added to the residue, and extraction
performed with a mixture of ether/methylene chloride (5:1). The
organic phases are extracted with cold 1N hydrochloric acid. The
acid extracts are combined and 5N sodium hydroxide solution added
until a pH-value of 10 is obtained; extraction is then carried out
with ether. The combined ether extracts are washed with water and
with saturated sodium chloride solution, dried over sodium
sulphate, and concentrated by evaporation to dryness. Amorphous
2-(aminomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine
is obtained, which liquifies at 69.degree.-75.degree..
a'. The following are obtained in an analogous manner:
starting with 1.84 g (0.005 mole) of
2-(azidomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo
diazepine:-
2-(aminomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo
diazepine; and
starting with 1.92 g (0.005 mole) of
2-(azidomethyl)-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo
diazepine:-
2-aminomethyl)-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzod
iazepine.
b. The (azidomethyl)-compounds required as starting materials are
produced as follows:
The crude methanesulphonic acid ester produced, according to
Example 1 g), from 3.25 g (0.01 mole) of
6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-methanol
and 1.71 g (0.015 mole) of methanesulphonic acid chloride is
dissolved in 50 ml of acetone, and a solution of 3.25 g (0.15 mole)
of sodium azide in 25 ml of water added. The reaction mixture is
stirred for 1 hour at 30.degree., and thereupon concentrated in
vacuo. The obtained crude azidomethyl-compound is dissolved in
benzene, and washed once with cold 5 percent sodium bicarbonate
solution and twice with water. The organic solution is dried over
sodium sulphate, and concentrated in vacuo. The residue is
dissolved in benzene, and the solution chromatographed on a column
of 30 g of silica gel, elution being performed with benzene. The
fractions is which the desired reaction product is dissolved are
combined, and concentrated in vacuo.
2-(Azidomethyl)-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]
benzodiazepine is obtained as yellow oil, which can be further
reacted direct.
b'.
2-(Azidomethyl)-6-(o-fluoro)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazep
ine and
2-(azidomethyl)-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzo
diazepine are obtained analogously with the use of the
corresponding crude methanesulphonic acid esters prepared,
analogously to Example 1 g), with 1.71 of g (0.015 mole) of
methanesulphochloride from
3.43 g (0.01 mole) of
6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol, and
3.59 g (0.01 mole) of
6-(o-chlorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-meth
anol, respectively.
* * * * *