Hydroxymethylimidazodiazepines and their esters

Details Hydroxymethylimidazodiazepines and their esters Hydroxymethylimidazodiazepines and their esters

1997-09-04

2001-01-16

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S562000

Reexamination Certificate

active

06174881

ABSTRACT:

The present invention is concerned with hydroxymethylimidazodiazepines and their esters of the general formula
wherein A and the two carbon atoms denoted by &agr; and &bgr; together signify one of the residues
R
1
signifies hydrogen or lower-alkanoyl;
R
2
signifies phenyl, o-halophenyl or 2-pyridyl;
R
3
signifies hydrogen, lower-alkyl, methylaminomethyl, allylaminomethyl or diethylaminomethyl;
R
4
signifies halogen, CF
3
or nitro;
R
5
signifies hydrogen or halogen,
as well as pharmaceutical acceptable salts thereof.
These compounds and salts are novel and have valuable pharmacodynamic properties. They are therefore suitable for therapeutic purposes, especially for anxiolytic and/or anticonvulsant and/or muscle relaxant and/or sedative-hypnotic purposes. A particular advantage of the novel compounds of general formula I is the good water solubility of their salts as well as a short duration of action for the uses referred to above.
Objects of the present invention are the mentioned compounds of formula I and salts thereof per se and as therapeutically active substances, their manufacture and their use for therapeutic purposes and, respectively, for the production of corresponding medicaments as well as medicaments containing a compound of formula I or a salt thereof and the production of such medicaments.
The term “lower” denotes residues or compounds with a maximum of 7, preferably a maximum of 4, carbon atoms. The term “alkyl” denotes straight-chain or branched saturated hydrocarbon residues, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec.-butyl, iso-butyl and tert.-butyl. The term “alkenyl” denotes straight-chain or branched hydrocarbon residues which contain a C—C double bond, such as allyl, but-2-enyl, 3-methyl-but-2-enyl and the like. The term “halogen” embraces fluorine, chlorine, bromine and iodine. The term “amino” denotes residues such as NH
2
, NH-lower-alkyl, N-di-loweralkyl, NH-lower-alkenyl, morpholino, piperidino, pyrrolidin-1-yl, methylpiperiazin-1-yl and the like. The term “alkanoyl” denotes residues such as acetyl, propionyl and the like.
When A in formula I signifies a residue of formula A
1
, there are preferred those compounds in which R
1
signifies hydrogen, R
2
signifies o-fluoro- or o-Cl-phenyl, R
3
signifies hydrogen or allylaminomethyl and R
4
iodine or chlorine.
The following compounds are examples of these:
8-Chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a]benzodiazepine-2methanol;
1-allylaminomethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol;
8-chloro-6-(2-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol;
8-iodo-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol.
When A in formula I signifies a residue of formula A
2
, there are preferred those compounds in which R
1
signifies hydrogen or carbonylmethyl, R
2
signifies o-fluorophenyl, R
3
signifies hydrogen and R
5
signifies chlorine.
The following compounds are examples of these:
2-Chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f][1,4]diazepine-8-methanol;
methyl[2-chloro-4-(2-fluorophenyl)-8,9-dihydro-6H-imidazo[1,2-a]thieno[3,2-f]diazepin-8-yl]acetate.
The compounds of general formula I mentioned earlier and their pharmaceutically acceptable acid addition salts can be manufactured in accordance with the invention by
a) converting compounds of the general formulae
with a basic reagent into compounds of the general formula
 wherein A, R
2
and R
3
have the above significance, or
b) converting compounds of general formula Ia or IIa into compounds of the general formula
 wherein A, R
2
and R
3
have the above significance and R
6
signifies lower-alkanoyl, or
c) hydrolyzing compounds of general formula Ib to compounds of general formula Ia, or
d) reducing compounds of the general formula
 wherein A, R
2
and R
3
have the above significance and R
5
signifies lower-alkyl, to compounds of the general formula
or
e) cleaving off the protecting group from a compound of the general formula
 wherein A and R
2
and R
3
have the above significance and R
4
signifies a protecting group, or
f) cyclizing compounds of the general formula
 wherein A and R
2
have the above significance and R
5
signifies lower-alkyl, in an acidic medium to compounds of general formula I in which R
3
signifies hydrogen, and
g) if desired, converting a compound of general formula I into a pharmaceutically usable acid addition salt.
Compounds of general formula Ia can be manufactured according to process variant a) by treating compounds of formulae IIa with a basic reagent. This is conveniently carried out as follows: a compound of formula IIa is stirred under a protective gas atmosphere for several hours in an alkali hydroxide solution, preferably in sodium hydroxide, or treated with sodium hydrogen carbonate and subsequently worked up according to known methods.
Compounds of general formula Ib are obtained in accordance with process variant b) starting from compounds of formula Ia by reacting these compounds conveniently with acetic anhydride or the like in the presence of strong acid, for example perchloric acid, or starting from a compound of formula IIa by reacting this with sodium acetate or the like. These methods will be familiar to any person skilled in the art.
The compounds of general formula Ib are hydrolyzed to compounds of general formula Ia according to process variant c). This is conveniently effected with a methanolic sodium methanolate solution.
Compounds of formula Ia are obtained in accordance with process variant d). This is effected by reducing a compound of general formula III with a suitable reducing agent, for example with a lithium aluminum hydride solution. This is conveniently carried out as follows: the reducing agent is dissolved in a suitable organic solvent, for example tetrahydrofuran, cooled to about −70 to −80° C. and treated with a solution of a compound of general formula III. After a reaction period of about 1 hour the mixture is warmed slowly to 0° C. and subsequently worked up according to usual methods.
Compounds of general formula la are obtained in accordance with process variant e). Suitable protecting groups and methods for their cleavage will be familiar to any person skilled in the art, although, of course, only those protecting groups can be used which can be cleaved off by methods under the conditions of which other structural elements in the compounds are not concomitantly effected. Compounds of general formula I in which R
1
signifies hydrogen and R
3
signifies aminomethyl and R
2
has the significance set forth above can be conveniently manufactured by converting a compound of general formula IVb which carries a protecting group into compounds of general formula Ia in one process step by treating the reactive compounds of formula IVb with a corresponding amine and by simultaneously cleaving off the protecting group by working in the acidic range. The following are especially preferred amines: diethylamine, morpholine, methylamine, allylamine and the like.
The compounds of formula I are converted into pharmaceutically acceptable acid addition salts in accordance with process variant g). Salts with both inorganic acids and organic acids come into consideration. Examples of such salts are the hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like. These salts can be manufactured according to methods which are known per se and which will be familiar to any person skilled in the art.
The starting products of formulae Ia, III, IVb and V above can be prepared in accordance with Scheme 1 or 2 hereinafter.
In Schemes 1 and 2 A and R
2
have the significance set forth above, R
5
signifies lower-alkyl and R
6
signifies halogen.
The compounds of general formulae IX and XIV have a central significance for the manufacture o

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