Antiallergic triazolo(pyrrolo, thieno or furano)azepines of formula ##STR1## the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein PA0 each of the dotted lines independently represents an optional bond; PA0 -E-G- is a bivalent radical of formula EQU --X--C(R.sup.1).dbd.CH-- (a-1); or EQU --CH.dbd.C(R.sup.2)--X-- (a-2); PA0 X represents O, S or NR.sup.3 ; PA0 R.sup.3 represents hydrogen, C.sub.1-6 alkyl or C.sub.1-4 alkylcarbonyl; PA0 -B.dbd.D- is a bivalent radical of formula EQU --C(R.sup.4).dbd.N-- (b-1); or EQU --N.dbd.C(R.sup.5)-- (b-2); PA0 L represents hydrogen; C.sub.1-6 alkyl; substituted C.sub.1-6 alkyl; C.sub.3-6 alkenyl; C.sub.3-6 alkenyl substituted with aryl; or, PA0 L represents a radical of formula -Alk-Y-Het.sup.1 (c-1), -Alk-NH--CO-Het.sup.2 (c-2) or -Alk-Het.sup.3 (c-3). Compositions comprising said compounds, processes of preparing the same and intermediates in the preparation thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS 
This application is based upon PCT Application Ser. No. PCT/EP 93/03322, 
filed Nov. 25, 1993, which claims priority from European Application Ser. 
No. 92.203.777.5, filed on Dec. 4, 1992. 
The present invention is concerned with novel triazolo(pyrrolo, thieno or 
furano)azepine derivatives having antiallergic activity. 
In EP-A-0,339,978 there are described (benzo- or pyrido)cyclohepta 
heterocyclics which are useful as PAF antagonists, antihistaminics and/or 
anti-inflammatory agents. 
In the J. Med. Chem., 26 (1983), 974-980 there are described some 
1-methyl-4-piperidinylidene-9-substituted pyrrolo[2,1-b][3]benzazepine 
derivatives having neuroleptic properties. 
In WO 92/06981 there are described substituted imidazobenzazepines and 
imidazopyridoazepines having antiallergic and anti-inflammatory activity. 
The compounds of the present invention differ structurally from the cited 
art-known compounds by the fact that the central 7-membered ring 
invariably contains a nitrogen atom of a fused triazole ring, and by their 
favorable antiallergic activity. 
The present invention is concerned with novel triazolo(pyrrolo, thieno or 
furano)azepines of formula 
##STR2## 
the pharmaceutically acceptable addition salts and stereochemically 
isomeric forms thereof, wherein 
each of the dotted lines independently represents an optional bond; 
-E-G- is a bivalent radical of formula 
EQU --X--C(R.sup.1).dbd.CH-- (a-1); or 
EQU --CH.dbd.C(R.sup.2)--X-- (a-2); 
X represents O, S or NR.sup.3 ; 
R.sup.3 represents hydrogen, C.sub.1-6 alkyl or C.sub.1-4 alkylcarbonyl; 
R.sup.1 and R.sup.2 each independently represent hydrogen, C.sub.1-4 alkyl, 
halo, ethenyl substituted with hydroxycarbonyl or C.sub.1-4 
alkyloxycarbonyl, hydroxyC.sub.1-4 alkyl, formyl, hydroxycarbonyl or 
hydroxycarbonylC.sub.1-4 alkyl; 
-B.dbd.D- is a bivalent radical of formula 
EQU --C(R.sup.4).dbd.N-- (b-1); or 
EQU --N.dbd.C(R.sup.5)-- (b-2); 
R.sup.4 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with 
hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted 
with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 
alkyl, formyl or hydroxycarbonyl; 
R.sup.5 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with 
hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted 
with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 
alkyl, formyl, hydroxycarbonyl, phenyl or pyridinyl; 
L represents hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with 
one substituent selected from the group consisting of hydroxy, C.sub.1-4 
alkyloxy, hydroxycarbonyl, C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 
alkloxycarbonylC.sub.1-4 alkyloxy, hydroxycarbonylC.sub.1-4 alkyloxy, 
C.sub.1-4 alkylaminocarbonylamino, C.sub.1-4 alkylaminothiocarbonylamino, 
aryl and aryloxy; C.sub.1-6 alkyl substituted with both hydroxy and 
aryloxy; C.sub.3-6 alkenyl; C.sub.3-6 alkenyl substituted with aryl; 
wherein each aryl is phenyl or phenyl substituted with halo, cyano, 
hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy or aminocarbonyl; or, 
L represents a radical of formula 
EQU -Alk-Y-Het.sup.1 (c-1), 
EQU -Alk-NH--CO-Het.sup.2 (c-2) or 
EQU -Alk-Het.sup.3 (c-3); wherein 
Alk represents C.sub.1-4 alkanediyl; 
Y represents O, S or NH; 
Het.sup.1, Het.sup.2 and Het.sup.3 each represent furanyl, thienyl, 
oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or 
two C.sub.1-4 alkyl substituents; pyrrolyl or pyrazolyl optionally 
substituted with formyl, hydroxyC.sub.1-4 alkyl, hydroxycarbonyl, 
C.sub.1-4 alkyloxycarbonyl or with one or two C.sub.1-4 alkyl 
substituents; thiadiazolyl or oxadiazolyl optionally substituted with 
amino or C.sub.1-4 alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl 
each optionally substituted with C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, 
amino, hydroxy or halo; and 
Het.sup.3 may also represent 4,5-dihydro-5-oxo-1H-tetrazolyl substituted 
with C.sub.1-4 alkyl, 2-oxo-3-oxazolidinyl, 
2,3-dihydro-2-oxo-1H-benzimidazol-1-yl or a radical of formula 
##STR3## 
wherein 
A-Z represents S--CH.dbd.CH, S--CH.sub.2 --CH.sub.2, S--CH.sub.2 --CH.sub.2 
--CH.sub.2, CH.dbd.CH--CH.dbd.CH, or CH.sub.2 --CH.sub.2 --CH.sub.2 
--CH.sub.2. 
As used in the foregoing definitions halo defines fluoro, chloro, bromo and 
iodo; C.sub.1-4 alkyl defines straight and branched chain saturated 
hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, 
methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 
2-methylpropyl and 1,1-dimethylethyl; C.sub.1-6 alkyl defines C.sub.1-4 
alkyl radicals as defined hereinbefore and the higher homologs thereof 
having from 5 to 6 carbon atoms such as, for example, pentyl and hexyl; 
C.sub.3-6 alkenyl defines straight and branched chain hydrocarbon radicals 
containing one double bond and having from 3 to 6 carbon atoms such as, 
for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 
2-pentenyl, 3-pentenyl, 3,3-dimethyl-2-propenyl, hexenyl and the like; 
C.sub.1-4 alkanediyl defines bivalent straight or branched chain 
hydrocarbon radicals containing from 1 to 4 carbon atoms such as, for 
example, methylene, 1,1-ethanediyl, 1,2-ethanediyl, 1,3-propanediyl, 
1,4-butanediyl and the like. 
The term pharmaceutically acceptable addition salt as used hereinbefore 
defines the non-toxic, therapeutically active addition salt forms which 
the compounds of formula (I) may form. The compounds of formula (I) having 
basic properties may be converted into the corresponding therapeutically 
active, non-toxic acid addition salt forms by treating the free base form 
with a suitable amount of an appropriate acid following conventional 
procedures. Examples of appropriate acids are for example, inorganic 
acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and 
the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; 
or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 
2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, 
butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 
2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, 
methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, 
cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the 
like acids. 
The compounds of formula (I) having acidic properties may be converted in a 
similar manner into the corresponding therapeutically active, non-toxic 
base addition salt forms. Examples of such base addition salt forms are, 
for example, the sodium, potassium, calcium salts, and also the salts with 
pharmaceutically acceptable amines such as, for example, ammonia, 
alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, 
e.g. arginine, lysine. The term pharmaceutically acceptable addition salts 
also comprises the solvates which the compounds of formula (I) may form, 
e.g. the hydrates, alcoholates and the like. 
The term stereochemically isomeric forms as used hereinbefore defines the 
possible different isomeric as well as conformational forms which the 
compounds of formula (I) may possess. Unless otherwise mentioned or 
indicated, the chemical designation of compounds denotes the mixture of 
all possible stereochemically and conformationally isomeric forms, said 
mixtures containing all diastereomers, enantiomers and/or conformers of 
the basic molecular structure. All stereochemically isomeric forms of the 
compounds of formula (I) both in pure form or in admixture with each other 
are intended to be embraced within the scope of the present invention. 
Some compounds of the present invention may exist in different tautomeric 
forms and all such tautomeric forms are intended to be included within the 
scope of the present invention. 
An interesting group of compounds of formula (I) comprises those compounds 
of formula (I) wherein R.sup.1, R.sup.2, R.sup.4 and R.sup.5 represent 
hydrogen. 
Another group of interesting compounds of formula (I) are those wherein X 
represents S or NCH.sub.3. 
Further interesting compounds of formula (I) are those wherein L is 
C.sub.1-4 -alkyl. 
The most preferred compounds are: 
5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidininylidene)pyrrolo[3,2- 
d][1,2,4]triazolo[1,5-a]azepine; 
10-(1-methyl-4-piperidinylidene)-10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a]aze 
pine; and 
6,10-dihydro-10-(1-methyl-4-piperidinylidene)-5H-thieno[2,3-d][1,2,4]triazo 
lo[1,5-a]azepine, the stereoisomers and the pharmaceutically acceptable 
acid-addition salts thereof. 
In the following paragraphs there are described different ways of preparing 
the compounds of formula (I). In order to simplify the structural formulae 
of the compounds of formula (I) and the intermediates intervening in their 
preparation, the triazolo(pyrrolo, thieno or furano)azepine moiety will be 
represented by the symbol T hereinafter. 
##STR4## 
The compounds of formula (I) can be prepared by cyclizing an alcohol of 
formula (II) or a ketone of formula (III). 
##STR5## 
Said cyclization reaction is conveniently conducted by treating the 
intermediate of formula (II) or (III) with an appropriate acid, thus 
yielding a reactive intermediate which cyclizes to a compound of formula 
(I). Appropriate acids are, for example, strong acids, in particular 
superacid systems, e.g. methanesulfonic acid, trifluoromethanesulfonic 
acid, trifluoroacetic acid, methanesulfonic acid/boron trifluoride, 
hydrofluoric acid/boron trifluoride, or Lewis acids, e.g. aluminum 
chloride, tin(IV)chloride and the like, trimethylsilyl iodide, 
phosphorylchloride and the like. Obviously, only those compounds of 
formula (I) wherein L is stable under the given reaction conditions can be 
prepared according to the above reaction procedure. In case of superacids 
the reaction is preferably conducted in an excess of said acid; in case of 
a Lewis acid such as, e.g. tin(IV)chloride, the reaction can conveniently 
be conducted in a reaction-inert solvent such as, for example, a 
halogenated hydrocarbon, e.g. dichloromethane, 1,2-dichloroethane and the 
like. 
In the foregoing and following preparations, the reaction mixture is worked 
up following art-known methods and the reaction product is isolated and, 
if necessary, further purified. 
The compounds of formula (I) wherein the central ring of the tricyclic 
moiety does not contain an optional bond may also be prepared by cyclizing 
an intermediate of formula (IV). 
##STR6## 
In formula (IV) and hereinafter W represents an appropriate leaving group 
such as, for example, halo, e.g. chloro, bromo and the like; or a 
sulfonyloxy group such as, for example, methanesulfonyloxy, 
4-methylbenzenesulfonyloxy and the like. Said cyclization reaction can 
conveniently be conducted in a reaction-inert solvent such as, for 
example, an aromatic hydrocarbon, an alkanol, a ketone, an ether, a 
dipolar aprotic solvent, or a mixture of such solvents. The addition of an 
appropriate base such as, for example, an alkali or an earth alkaline 
metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide 
or oxide; or an organic base, may be utilized to pick up the acid which is 
liberated during the course of the reaction. In some instances the 
addition of an iodide salt, preferably an alkali metal iodide, is 
appropriate. Somewhat elevated temperatures and stirring may enhance the 
rate of the reaction. 
Alternatively, the compounds of formula (I) wherein a double bond exists 
between the piperidinyl and the triazolo(pyrrolo, thieno or furano)azepine 
moiety, said compounds being represented by formula (I-a), can be prepared 
by dehydrating an alcohol of formula (V) or (VI). 
##STR7## 
Said dehydration reaction can conveniently be conducted employing 
conventional dehydrating reagents following art-known methodologies. 
Appropriate dehydrating reagents are, for example, acids, e.g. sulfuric 
acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, carboxylic 
acids, e.g. acetic acid, trifluoroacetic acid and mixtures thereof; 
anhydrides, e.g. acetic anhydride, phosphorus pentoxide and the like; 
other suitable reagents, e.g. zinc chloride, thionyl chloride, boron 
trifluoride etherate, phosphoryl chloride pyridine, potassium bisulfate, 
potassium hydroxide or phosphoryl chloride. Optionally, said dehydration 
reaction is conducted in a reaction-inert solvent such as, for example, a 
halogenated hydrocarbon, e.g. dichloromethane. In some instances said 
dehydration reaction may require heating the reaction mixture, more 
particularly up to the reflux temperature. Again, only those compounds of 
formula (I-a) wherein L is stable under the given reaction conditions can 
be prepared according to the above reaction procedure. Particularly 
noteworthy is the fact that the latter reaction when performed on 
intermediate (V) wherein the dotted line does not represent an optional 
bond, in some instances may also yield a compound with a double bond in 
the tricyclic moiety and a single bond bridging the tricyclic moiety and 
the piperidine: 
##STR8## 
The compounds of formula (I) wherein L is C.sub.1-6 alkyl, said compounds 
being represented by the formula (I-b), can be converted into the 
compounds of formula (I) wherein L is hydrogen, said compounds being 
represented by the formula (I-c), in a number of manners. A first method 
involves dealkylating - carbonylating the compounds of formula (I-b) with 
a C.sub.1-4 alkylchloroformate and subsequently hydrolyzing the thus 
obtained compound of formula (VII-a). 
##STR9## 
The reaction with the C.sub.1-4 alkylchloroformate is conveniently 
conducted by stirring and heating the starting material (I-b) with the 
reagent in an appropriate solvent and in the presence of a suitable base. 
Appropriate solvents are, for example, aromatic hydrocarbons, e.g. 
methylbenzene, dimethylbenzene, chlorobenzene; ethers, e.g. 
1,2-dimethoxyethane, and the like solvents. Suitable bases are, for 
example, alkali or earth alkaline metal carbonates, hydrogen carbonates, 
hydroxides, or organic bases such as, N,N-diethylethanamine, 
N-(1-methylethyl)-2-propanamine, and the like. The compounds of formula 
(VII-a) are hydrolyzed in acidic or basic media following conventional 
methods. For example, concentrated acids such as hydrobromic, hydrochloric 
acid or sulfuric acid can be used, or alternatively bases such as alkali 
metal or earth alkaline metal hydroxides, e.g. sodium hydroxide, potassium 
hydroxide and the like, in water, an alkanol or a mixture of water-alkanol 
may be used. Suitable alkanols are methanol, ethanol, 2-propanol and the 
like. In order to enhance the rate of the reaction it is advantageous to 
heat the reaction mixture, in particular up to the reflux temperature. 
The compounds of formula (I-b) may also be converted directly into the 
compounds of formula (I-c) by stirring and heating them with an 
.alpha.-haloC.sub.1-4 alkyl chloroformate in an appropriate solvent such 
as, for example, a halogenated hydrocarbon, e.g. dichloromethane, 
trichloromethane; an aromatic hydrocarbon, e.g. methylbenzene, 
dimethylbenzene; an ether, e.g. 1,2-dimethoxyethane; an alcohol, e.g. 
methanol, ethanol, 2-propanol, optionally in the presence of a base such 
as, for example, an alkali or earth alkaline metal carbonate, hydrogen 
carbonate, hydroxide or an amine, e.g. N,N-diethylethanamine, 
N-(1-methylethyl)-2-propanamine, and the like. 
The compounds of formula (I-c) can also be prepared by debenzylating a 
compound of formula (I-d) by catalytic hydrogenation in the presence of 
hydrogen and an appropriate catalyst in a reaction-inert solvent. 
##STR10## 
A suitable catalyst in the above reaction is, for example, 
platinum-on-charcoal, palladium-on-charcoal, and the like. An appropriate 
reaction-inert solvent for said debenzylation reaction is, for example, an 
alcohol, e.g. methanol, ethanol, 2-propanol, and the like, an ester, e.g. 
ethyl acetate and the like, an acid, e.g. acetic acid and the like. 
The compounds of formula (I) wherein L is other than hydrogen, said 
compounds being represented by formula (I-e) and said L by L.sup.1, can be 
prepared by N-alkylating the compounds of formula (I-c) with a reagent of 
formula L.sup.1 -W (VIII). 
##STR11## 
Said N-alkylation reaction can conveniently be conducted in a 
reaction-inert solvent such as, for example, an aromatic hydrocarbon, an 
alkanol, a ketone, an ether, a dipolar aprotic solvent, a halogenated 
hydrocarbon, or a mixture of such solvents. The addition of an appropriate 
base such as, for example, an alkali or an earth alkaline metal carbonate, 
hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide, or an 
organic base, may be utilized to pick up the acid which is liberated 
during the course of the reaction. In some instances the addition of an 
iodide salt, preferably an alkali metal iodide, is appropriate. Somewhat 
elevated temperatures and stirring may enhance the rate of the reaction. 
Alternatively, said N-alkylation may be carried out by applying art-known 
conditions of phase transfer catalysis reactions. 
The compounds of formula (I) wherein L is C.sub.1-6 alkyl or substituted 
C.sub.1-6 alkyl can also be prepared by reductive N-alkylation of the 
compounds of formula (I-c) following art-known procedures. The compounds 
of formula (I) wherein L is C.sub.1-6 alkyl or substituted C.sub.1-6 alkyl 
can further be prepared by the addition reaction of the compounds of 
formula (I-c) with a suitable alkene following art-known procedures. 
The compounds of formula (I) wherein L is C.sub.1-6 alkyl substituted with 
hydroxy can be prepared by reacting a compound of formula (I-c) with a 
suitable epoxide following art-known procedures. 
The compounds of formula (I) with a double bond in the tricyclic moiety 
and/or a double bond bridging the tricyclic moiety and the piperidine may 
be reacted into compounds of formula (I) with a single bond at either one 
or both of the beforementioned sites following art-known reduction 
procedures. 
The compounds of formula (I) may further be converted into each other 
following art-known functional group transformation procedures. 
For example, the compounds of formula (I) wherein R.sup.1 or R.sup.2 is 
formyl may be prepared by reacting the corresponding compound of formula 
(I) wherein R.sup.1 or R.sup.2 is hydrogen with e.g. N,N-dimethylformamide 
in the presence of a suitable reagent, e.g. phosphoryl chloride. The 
compounds of formula (I) wherein R.sup.1 or R.sup.2 is formyl may be 
further converted in the corresponding hydroxymethyl compounds following 
art-known reduction procedures. 
The compounds of formula (VII-a) intervening in the preparations described 
hereinbefore are novel and have especially been developed for use as 
intermediates in said preparations. Consequently, the present invention 
also relates to novel compounds of formula 
##STR12## 
the addition salts and the stereochemically isomeric forms thereof, 
wherein 
each of the dotted lines independently represents an optional bond; 
-E-G- and -B.dbd.D- are as defined for the compounds of formula (I); and 
Q represents C.sub.1-6 alkyloxycarbonyl, C.sub.1-4 alkylcarbonyl or 
C.sub.1-6 alkyl substituted with halo, cyano, amino, or methylsulfonyloxy. 
Particularly interesting compounds of formula (VII) are those wherein Q 
represents C.sub.1-6 alkyloxycarbonyl, the addition salts and the 
stereochemically isomeric forms thereof. 
In the following paragraphs there are described several methods of 
preparing the starting materials employed in the foregoing preparations. 
The intermediates of formula (II) can be prepared from the corresponding 
ketones of formula (III) by reduction. 
##STR13## 
Said reduction can conveniently be conducted by reacting the starting 
ketone (III) with hydrogen in a solvent such as, for example, an alcohol, 
e.g. methanol, ethanol; an acid, e.g. acetic acid; an ester, e.g. ethyl 
acetate; in the presence of a hydrogenation catalyst, e.g. 
palladium-on-charcoal, platinum-on-charcoal, Raney Nickel. 
In order to enhance the rate of the reaction, the reaction mixture may be 
heated and, if desired, the pressure of the hydrogen gas may be raised. 
Alternatively, the alcohols of formula (II) can also be prepared by 
reducing the ketones (III) with a reducing agent such as, for example, 
lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride and 
the like in a suitable solvent such as, for example, an ether, e.g. 
1,1'-oxybisethane, tetrahydrofuran and the like; an alcohol, e.g. 
methanol, ethanol and the like. 
The ketones of formula (III) wherein L represents hydrogen are prepared by 
hydrolysis of a carbamate of formula (III-a) in acidic or basic media 
following conventional methods as described hereinbefore for the 
preparation of compounds of formula (I-c) from the compounds of formula 
(I-b). 
##STR14## 
The intermediates of formula (III-a) can be prepared by reacting an acid 
halide of formula (IX) with a triazole derivative of formula (X). 
##STR15## 
Said reaction is conveniently conducted by stirring and heating the 
reactants in the presence of a base such as, for example, an amine, e.g. 
N,N-diethylethanamine, N-methylmorpholine and the like, in a suitable 
solvent such as, for example, pyridine, acetonitrile or a mixture thereof. 
The intermediates of formula (III-c) can also be prepared from an ester of 
formula (XI) by reaction with a triazole of formula (X) in the presence of 
a strong base such as, for example, methyl lithium, butyl lithium, sodium 
amide, a dialkyl lithium amide, e.g. diisopropyl lithium amide, or a 
mixture thereof, in a suitable reaction-inert solvent, e.g. 
tetrahydrofuran, hexane, methylbenzene and the like, or a mixture thereof. 
Said reaction is conveniently conducted at low temperatures. For example 
the reagent (X) may be stirred at a temperature between about -80.degree. 
C. to about -40.degree. C., whereupon the strong base is added. 
Subsequently the ester is added and the reaction mixture is allowed to 
warm up gently to room temperature. 
##STR16## 
The intermediates of formula (V) can be prepared by addition of a Grignard 
reagent (XII) to a ketone of formula (XIII) in a reaction-inert solvent, 
e.g. tetrahydrofuran. 
##STR17## 
The tricyclic ketones of formula (XIII) in turn are prepared from 
intermediates of formula (XIV) by oxidation with a suitable oxidizing 
reagent in a reaction-inert solvent. 
##STR18## 
Suitable oxidizing reagents are, for example, manganese dioxide, selenium 
dioxide, ceric ammonium nitrate and the like. Reaction-inert solvents are, 
for example, a halogenated hydrocarbon, e.g. dichloromethane, 
trichloromethane and the like, or a dipolar aprotic solvent, e.g. 
N,N-dimethylformamide, N,N-dimethylacetamide and the like, or a mixture of 
a carboxylic acid and water, e.g. acetic acid and water. 
The compounds of formula (XIV) wherein the dotted lines do not represent an 
optional bond can be prepared from the corresponding compounds of formula 
(XIV) wherein said dotted lines do represent an optional bond, following 
art-known hydrogenation procedures, e.g. by reaction with hydrogen in the 
presence of a hydrogenation catalyst. 
##STR19## 
The intermediates of formula (XIV-a) wherein -B-D- is a radical of formula 
--N.dbd.CH--, said intermediates being represented by (XIV-a-1), can be 
prepared from a benzazepine of formula (XV) by reaction with a reagent of 
formula (XVI) or a derivative thereof in a reaction-inert solvent such as, 
for example, an alcohol, e.g. methanol, ethanol, and the like. 
##STR20## 
The intermediates of formula (XV) can be prepared by reacting an 
intermediate of formula (XVII) with hydrazine or a derivative thereof in a 
reaction-inert solvent such as, for example, an alcohol, e.g. methanol, 
ethanol and the like. 
##STR21## 
The intermediates of formula (XVII) can be prepared by reacting an 
intermediate of formula (XVIII) or a derivative thereof, in an acidic 
medium. In (XVIII) R represents C.sub.1-4 alkyl or both radicals R taken 
together represent C.sub.2-6 alkanediyl, e.g. 1,2-ethanediyl, 
1,3-propanediyl, 2,2-dimethyl-1,3-propanediyl. 
##STR22## 
The above cyclization reaction is conveniently conducted by stirring the 
starting material (XVIII) in a carboxylic acid, such as, for example, 
acetic acid, propanoic acid and the like, optionally in admixture with a 
mineral acid such as, for example, hydrobromic acid, methanesulfonic acid 
and the like. 
The intermediates of formula (XVIII) can be prepared by reacting an 
intermediate of formula (XIX) or a derivative thereof, wherein R' is 
C.sub.1-4 alkyl, with a reagent of formula (XX) in a reaction-inert 
solvent, such as, for example, an ether, e.g. 1,2-dimethoxyethane, 
tetrahydrofuran and the like. 
##STR23## 
Alternatively, the intermediates of formula (XIV-a-1) can be prepared by 
reacting an intermediate of formula (XXI) under hydrogen pressure in the 
presence of a suitable catalyst, e.g. Raney nickel and the like, in a 
reaction-inert solvent, e.g. methanol, ethanol, and the like. 
##STR24## 
The intermediates of formula (XXI) can be prepared by the cyclization of an 
intermediate of formula (XXII) in the presence of an acid, e.g. sulfuric 
acid. 
##STR25## 
The intermediates of formula (XXII) can be prepared by the S-alkylation of 
an intermediate of formula (XXIII) with a reagent of formula R'-W (XXIV) 
in a reaction-inert solvent, e.g. methanol, ethanol, and the like, 
optionally in the presence of a base e.g. sodium methoxide. 
##STR26## 
The intermediates of formula (XXIII) can be prepared by the cyclization of 
an intermediate of formula (XXV) in the presence of a base, e.g. potassium 
hydroxide. 
##STR27## 
The intermediates of formula (XXV) can be prepared by reacting an 
intermediate of formula (XXVI) with hydrazine or a derivative thereof in a 
reaction-inert solvent, e.g. ethanol. The resulting intermediate of 
formula (XXVII) is then further reacted with a reagent of formula (XXVIII) 
in a reaction-inert solvent, e.g. benzene, and the like. 
##STR28## 
The intermediates of formula (XIV) can also be prepared from cyclization of 
an intermediate of formula (XXIX). 
##STR29## 
Said cyclization reaction is conveniently conducted in the presence of a 
Lewis acid, e.g. aluminum chloride, and the like. In some instances it may 
be appropriate to supplement the reaction mixture with a suitable amount 
of sodium chloride. 
The intermediates of formula (V) can also be prepared from the cyclization 
of an intermediate of formula (III) in the presence of an acid in a 
reaction-inert solvent. 
##STR30## 
An appropriate acid in the above reaction is, for example, a Lewis acid, 
e.g. tin(IV)chloride and the like. A suitable reaction-inert solvent is, 
for example, a halogenated hydrocarbon, e.g. dichloromethane, 
1,2-dichloroethane, and the like. 
The intermediates of formula (VI) can be prepared by reaction of a ketone 
of formula (XXX) with an intermediate of formula (XIV) in the presence of 
e.g. lithium diisopropyl amide in a reaction-inert solvent, e.g. 
tetrahydrofuran. 
##STR31## 
The compounds of formula (V), (XIII) and (XIV) intervening in the 
preparations described hereinbefore are novel and have especially been 
developed for use as intermediates in said preparations. Consequently, the 
present invention also relates to novel compounds of formula 
##STR32## 
the addition salt forms thereof and the stereochemically isomeric forms 
thereof, wherein L, -B.dbd.D- and -E-G- are as defined under formula (I). 
The compounds of formula (I) and some of the compounds of formula (VII), 
the pharmaceutically acceptable acid addition salts and the 
stereochemically isomeric forms thereof, possess useful pharmacological 
properties. In particular they are active antiallergic agents, which 
activity can clearly be demonstrated by the test results obtained in a 
number of indicative tests. Antihistaminic activity can be demonstrated in 
`Protection of Rats from Compound 48/80--induced Lethality` test (Arch. 
Int. Pharmacodyn. Ther., 234, 164-176, 1978). The ED.sub.50 -values for 
the compounds 2, 3, 4, 5, 7, 8, 9, 14, 16, 19, 23, 26, 27, 29 and 31 were 
found to be equal or below 0.31 mg/kg. 
An advantageous feature of the compounds of the present invention resides 
in their excellent oral activity; the present compounds when administered 
orally have been found to be practically equipotent with the same being 
administered subcutaneously. 
An interesting feature of the present compounds relates to their fast onset 
of action and the favorable duration of their action. 
In view of their antiallergic properties, the compounds of formula (I), the 
compounds of formula (VII) and their addition salts are very useful in the 
treatment of a broad range of allergic diseases such as, for example, 
allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic 
asthma and the like. 
In view of their useful antiallergic properties the subject compounds may 
be formulated into various pharmaceutical forms for administration 
purposes. To prepare the antiallergic compositions of this invention, an 
effective amount of the particular compound, in base or acid addition salt 
form, as the active ingredient is combined in intimate admixture with a 
pharmaceutically acceptable carrier, which carrier may take a wide variety 
of forms depending on the form of preparation desired for administration. 
These pharmaceutical compositions are desirably in unitary dosage form 
suitable, preferably, for administration orally, rectally, percutaneously, 
or by parenteral injection. For example, in preparing the compositions in 
oral dosage form, any of the usual pharmaceutical media may be employed 
such as, for example, water, glycols, oils, alcohols and the like in the 
case of oral liquid preparations such as suspensions, syrups, elixirs and 
solutions: or solid carriers such as starches, sugars, kaolin, lubricants, 
binders, disintegrating agents and the like in the case of powders, pills, 
capsules and tablets. Because of their ease in administration, tablets and 
capsules represent the most advantageous oral dosage unit form, in which 
case solid pharmaceutical carriers are obviously employed. For parenteral 
compositions, the carrier will usually comprise sterile water, at least in 
large part, though other ingredients, for example to aid solubility, may 
be included. Injectable solutions, for example, may be prepared in which 
the carrier comprises saline solution, glucose solution or a mixture of 
saline and glucose solution. Injectable suspensions may also be prepared 
in which case appropriate liquid carriers, suspending agents and the like 
may be employed. In the compositions suitable for percutaneous 
administration, the carrier optionally comprises a penetration enhancing 
agent and/or a suitable wetting agent, optionally combined with suitable 
additives of any nature in minor proportions, which additives do not 
introduce a significant deleterious effect on the skin. Said additives may 
facilitate the administration to the skin and/or may be helpful for 
preparing the desired compositions. These compositions may be administered 
in various ways, e.g., as a transdermal patch, as a spot-on or as an 
ointment. Addition salts of the subject compounds due to their increased 
water solubility over the corresponding base form, are obviously more 
suitable in the preparation of aqueous compositions. 
It is especially advantageous to formulate the aforementioned 
pharmaceutical compositions in dosage unit form for ease of administration 
and uniformity of dosage. 
Dosage unit form as used in the specification and claims herein refers to 
physically discrete units suitable as unitary dosages, each unit 
containing a predetermined quantity of active ingredient calculated to 
produce the desired therapeutic effect in association with the required 
pharmaceutical carrier. Examples of such dosage unit forms are tablets 
(including scored or coated tablets), capsules, pills, powder packets, 
wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls 
and the like, and segregated multiples thereof. 
The present invention also relates to a method of treating warm-blooded 
animals suffering from said allergic diseases by administering to said 
warm-blooded animals an effective antiallergic amount of a compound of 
formula (I), a compound of formula (VII) or an addition salt form thereof. 
In general it is contemplated that an effective antiallergic amount would 
be from about 0.001 mg/kg to about 20 mg/kg body weight, and more 
preferably from about 0.01 mg/kg to about 5 mg/kg body weight.

The following examples are intended to illustrate and not to limit the 
scope of the present invention in all its aspects. 
EXPERIMENTAL T 
A. PREATION OF THE INTERMEDIATE COMPOUNDS 
EXAMPLE 1 
a) A mixture of 3-thiopheneethanol methanesulfonate (ester) (0.286 mol), 
1,2,4-triazole (0.571 mol) and potassium carbonate (39.47 g) in 
acetonitrile (1100 ml) was refluxed overnight. The mixture was filtered 
off and the filtrate was evaporated. The residue was taken up in water and 
extracted with dichloromethane. The organic layer was dried (MgSO.sub.4), 
filtered off and evaporated. The residue (49.08 g) was purified by column 
chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 
OH/NH.sub.4 OH 99/1/0.1 to 97/3/0.1) (35-70 .mu.m). The pure fractions 
were collected and evaporated, yielding 42.4 g (83%) of 
1-[2-(3-thienyl)ethyl]-1H-1,2,4-triazole (interm. 1). 
In a similar way there were prepared: 
1-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1H-1,2,4-triazole (interm. 2); and 
1-[2-(5-methyl-2-furanyl)ethyl]-1H-1,2,4-triazole (interm. 27). 
b) Butyllithium in hexane (192 ml) was added dropwise at -70.degree. C. 
under nitrogen to a solution of N-(1-methylethyl)-2-propanamine (43.4 ml) 
in tetrahydrofuran (400 ml) and the mixture was stirred for 30 minutes. A 
solution of intermediate (1) (0.236 mol) in tetrahydrofuran (50 ml) was 
added dropwise and the mixture was stirrred at -70.degree. C. for 1 hour. 
Ethyl 1-methyl-4-piperidinecarboxylate (0.284 mol) in tetrahydrofuran (50 
ml) was added and after the addition was completed, the mixture was 
stirred at -70.degree. C. for 1 hour. The mixture was brought slowly to 
room temperature. The mixture was poured into water and extracted with 
1,1'-oxybisethane/dichloromethane. The organic layer was dried 
(MgSO.sub.4) and evaporated. The residue (64.3 g) was purified by column 
chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 
OH/NH.sub.4 OH 96/4/0.1 to 90/10/0.1) (35-70 .mu.m). The pure fractions 
were collected and evaporated, yielding 29.55 g (41% ) of 
(1-methyl-4-piperidinyl)[2-[2-(3-thienyl)ethyl]-2H-1,2,4-triazol-3-yl]meth 
anone (interm. 3); 
In a similar way there were prepared: 
(1-methyl-4-piperidinyl)[1-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1H-1,2,4-tria 
zol-5-yl]methanone (interm. 4); 
[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl][2-[2-(1-methyl-1H-pyrrol-2-yl) 
ethyl]-2H-1,2,4-triazol-3-yl]methanone (interm. 5); 
[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl][2-[2-(3-thienyl)ethyl]-2H-1,2, 
4-triazol-3-yl]methanone (interm. 28); and 
[2-[2-(5-methyl-2-furanyl)ethyl]-2H-1,2,4-triazol-3-yl](1-methyl-4-piperidi 
nyl)methanone (interm. 29). 
c) Tin(IV)chloride (0.394 mol) was added dropwise at room temperature to a 
solution of intermediate (3) (0.0985 mol) in 1,2-dichloroethane (500 ml) 
and the mixture was stirred and heated at 80.degree. C. for 4 hours. The 
mixture was cooled, poured into ice, basified with ammonia and extracted 
with dichloromethane. The organic layer was washed with water, dried 
(MgSO.sub.4), filtered off and evaporated till dryness. The residue was 
purified by column chromatography over silica gel (eluent: CH.sub.2 
Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 92/8/1 then 85/15/1). The pure fractions 
were collected and evaporated, yielding 16.4 g (55%) of product. A sample 
(3.2 g) was dissolved in methanol and the mixture was refluxed for several 
hours in the presence of norit. The mixture was filtered over celite and 
the filtrate was evaporated in vacuo. The residue was crystallized from 
2-propanone/1,1'-oxybisethane, yielding 1.44 g of 
(.+-.)-6,10-dihydro-10-(1-methyl-4-piperidinyl)-5H-thieno[2,3-d][1,2,4]tri 
azolo[1,5-a]azepin-10-ol; mp. 158.3.degree. C. (interm. 6). 
In a similar way there was prepared: 
(.+-.)-6,10-dihydro-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-5H-thie 
no[2,3-d][1,2,4]triazolo[1,5-a]azepin-10-ol (interm. 30). 
EXAMPLE 2 
a) Hydrazine monohydrate (65 ml) was added dropwise to a solution of methyl 
1-methyl-1H-pyrrole-2-acetate (0.326 mol) in ethanol (300 ml) and the 
mixture was refluxed for 4 hours. The mixture was evaporated till dryness. 
The residue was taken up in dichloromethane and an aqueous potassium 
carbonate solution (10%) and extracted with dichloromethane. The organic 
layer was dried (MgSO.sub.4) and evaporated. The residue (48.8 g) was 
taken up in 1,1'-oxybisethane and the precipitate was filtered off, 
yielding 45.3 g (90%) of 1-methyl-1H-pyrrole-2-acetic acid, hydrazine 
(interm. 7). 
b) 2-isothiocyanato-1,1-dimethoxyethane (0.357 mol) was added dropwise to a 
solution of intermediate (7) (0.286 mol) in benzene (500 ml) and the 
mixture was stirred and refluxed for 1 hour. The mixture was cooled to 
0.degree. C. The precipitate was filtered off and dried with 
1,1'-oxybisethane, yielding 78.2 g (91%) of 
2-[[(2,2-dimethoxyethyl)amino]thioxymethyl]-1-methyl-1H-pyrrole-2-acetic 
acid, hydrazide (interm. 8). 
c) A mixture of intermediate (8) (0.26 mol) in potassium hydroxide 2N (524 
ml) was refluxed for 2 hours. The mixture was cooled on an ice bath. 
Ammonium chloride was added and filtered off. The precipitate was washed 
with water and dried in vacuo, yielding 61.72 g (84%) of 
4-(2,2-dimethoxyethyl)-5-[(1-methyl-1H-pyrrol-2-yl)methyl]-4H-1,2,4-triazo 
le-3-thiol (interm. 9). 
d) Iodomethane (15.4 ml) was added to a solution of intermediate (9) (0.193 
mol) in a solution of sodium methoxide in methanol (53.2 ml) and methanol 
(500 ml) and the mixture was stirred at room temperature for 2 hours. The 
mixture was evaporated, the residue was taken up in water and extracted 
with dichloromethane. The organic layer was washed with water, dried 
(MgSO.sub.4) and evaporated. The residue was taken up in 1,1'-oxybisethane 
and the precipitate was filtered off, yielding 56 g (98%) of 
4-(2,2-dimethoxyethyl)-3-[(1-methyl-1H-pyrrol-2-yl)methyl]-5-(methylthio)- 
4H-1,2,4-triazole (interm. 10). 
e) A mixture of intermediate (10) (0.287 mol) in sulfuric acid (500 ml) was 
stirred at 0.degree. C. for 2 hours. The mixture was poured into ice 
water, alkalized with ammonia and extracted with dichloromethane 
(+methanol). The organic layer was dried (MgSO.sub.4) and evaporated. The 
residue (39.67 g) was purified by column chromatography over silica gel 
(eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 98/2/0.1 to 97/3/0.1) 
(35-70 .mu.m). The pure fractions were collected and evaporated, yielding 
25 g (34%) of 
9,10-dihydro-9-methyl-3-(methylthio)pyrrolo[2,3-d]-1,2,4-triazolo[4,3-a]az 
epine (interm. 11). 
f) Intermediate (11) (0.108 mol) was refluxed with Raney nickel catalyst 
(140 g) (washed with methanol) in ethanol (400 ml) for 24 hours. The 
mixture was heated for 24 hours more. The catalyst was filtered off and 
the solvent was evaporated. The residue (15 g) was purified by column 
chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 
OH/NH.sub.4 OH 98/2/0.1). The pure fractions were collected and 
evaporated, yielding 10.6 g (53%) of product. A sample (2 g) was 
recrystallized from methanol/1,1'-oxybisethane, yielding 1.5 g of 
9,10-dihydro-9-methylpyrrolo[2,3-d]-1,2,4-triazolo[4,3-a]azepine; mp. 
177.7.degree. C. (interm. 12). 
EXAMPLE 3 
a) A mixture of O-ethyl 3-thiopheneethanimidate hydrochloride (0.14 mol) in 
1,2-dimethoxyethane (150 ml) was stirred at 15.degree. C. 
2,2-dimethoxyethanamine (0.14 mol) was added portionwise and the mixture 
was stirred overnight. The mixture was evaporated, yielding 
N-(2,2-dimethoxyethyl)-3-thiopheneethanimidamide monohydrochloride 
(interm. 13). 
In a similar way, but in tetrahydrofuran as a solvent, was prepared: 
N-(2,2-dimethoxyethyl)-2-thiopheneethanimidamide monohydrochloride (interm. 
14). 
b) A mixture of intermediate (13) (0.14 mol) in acetic acid (150 ml) was 
stirred under nitrogen. Methanesulfonic acid (27 g) was added portionwise 
and the mixture was stirred overnight. The mixture was poured into ice and 
alkalized with sodium hydroxide. The precipitate was filtered off and the 
water layer was extracted with dichloromethane/methanol and evaporated. 
The precipitate and the residue were put together, yielding 13.8 g (60%) 
of 4H-thieno-[2,3-d]azepin-5-amine (interm. 15). 
In a similar way, but using hydrogen bromide 30% in acetic acid instead of 
methane-sulfonic acid, was prepared: 
8H-thieno[2,3-d]azepin-7-amine (interm. 16). 
c) A mixture of intermediate (15) (0.153 mol) in hydrazine monohydrate 
(31.35 ml) and methanol (780 ml) was stirred at room temperature for 30 
minutes. The mixture was evaporated in vacuo at 40.degree. C. till a 
volume of 200 ml, diluted in water and filtered off, yielding fraction 1. 
The aqueous layer was extracted with dichloromethane. The organic layer 
was washed with water, dried (MgSO.sub.4), filtered off and evaporated, 
yielding fraction 2. The 2 fractions were put together, yielding 19.88 g 
(73%) of 5-hydrazino-4H-thieno[2,3-d]azepine (interm. 17). 
In a similar way there was prepared: 
7-hydrazino-8H-thieno[2,3-d]azepine (interm. 18). 
d) A mixture of intermediate (17) (0.111 mol) and methanimidamide acetate 
(0.166 mol) in ethanol (1200 ml) was refluxed for 2 hours 30 minutes. The 
cooled solution was filtered off and evaporated in vacuo. The residue was 
dissolved in dichloromethane, washed with water, dried (MgSO.sub.4), 
filtered off and evaporated. The residue was crystallized from 
2,2'-oxybispropane, yielding, 15.58 g (74%) of product. A sample was 
purified by column chromatography over silica gel (eluent: CH.sub.2 
Cl.sub.2 /CH.sub.3 OH 97/3). The pure fractions were collected and 
evaporated. The residue was recrystallized from ethyl 
acetate/2,2'-oxybispropane, yielding 1.08 g of 
10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a]azepine; mp. 146.3.degree. C. 
(interm. 19). 
In a similar way there was prepared: 
10H-thieno[2,3-d]-1,2,4-triazolo[4,3-a]azepine; top. 184.1.degree. C. 
(interm. 20). 
e) A mixture of intermediate (19) (0.0835 mol) and manganese dioxide (158 
g) in N,N-dimethylformamide (840 ml) was stirred rapidly and heated at 
40.degree. C. for 48 hours. The mixture was filtered hot over celite, 
washed with hot N,N-dimethylformamide and evaporated in vacuo. The residue 
was taken up in 2-propanone/2,2'-oxybispropane and filtered off. The 
precipitate was washed with 2,2'-oxybispropane and dried, yielding 9.85 g 
(58% ) of 10H-thieno[3,2-d]-1,2,4-triazolo[1,5-a]azepin-10-one (interm. 
21). 
In a similar way there was prepared: 
9-methylpyrrolo[2,3-d]-1,2,4-triazolo[4,3-a]azepin-10(9H)-one (interm. 22). 
In a similar way, but in a mixture of acetic acid and water as a solvent, 
was prepared: 
10H-thieno[2,3-d][1,2,4]triazolo[4,3-a]azepin-10-one (interm. 23). 
f) 1,2-dibromoethane (few drops) was added to a stirring mixture of 
magnesium turnings (0.105 mol) in tetrahydrofuran (5 ml) under nitrogen. 
When the reaction was started, pure 4-chloro-1-methylpiperidine (few 
drops) was added, the remaining 4-chloro-1-methylpiperidine (0.115 mol) in 
tetrahydrofuran (50 ml) was added dropwise to maintain a temperature 
between 40.degree. and 50.degree. C. The mixture was diluted with 
tetrahydrofuran (50 ml) and refluxed for 2 hours. A suspension of 
intermediate (21) (0.049 mol) in tetrahydrofuran (200 ml) was added 
portionwise at 60.degree. C. and the mixture was refluxed for 2 hours. The 
mixture was cooled, decomposed with a ammonium chloride solution and 
extracted with dichloromethane/methanol. The organic layer was dried 
(MgSO.sub.4), filtered off and evaporated. The residue was purified by 
column chromatography over silica gel (eluent 1: CH.sub.2 Cl.sub.2 
/CH.sub.3 OH/NH.sub.4 OH 90/10/1 and eluent 2: CH.sub.2 Cl.sub.2 /CH.sub.3 
OH/NH.sub.4 OH 50/50/1). The pure fractions were collected and evaporated, 
yielding 2.53 g (17% ) of 
10-(1-methyl-4-piperidinyl)-10H-thieno[3,2-d]-1,2,4-triazolo[1,5-a]azepin- 
10-ol (interm. 24). 
In a similar way there were prepared: 
(.+-.)-9,10-dihydro-9-methyl-10-(1-methyl-4-piperidinyl)pyrrolo[2,3-d]-1,2, 
4-triazolo[4,3-a]azepin-10-ol (interm. 25); and 
(.+-.)-10-(1-methyl-4-piperidinyl)-10H-thieno[2,3-d][1,2,4]triazolo[4,3-a]a 
zepin-10-ol (interm. 26). 
B. PREATION OF THE FINAL COMPOUNDS 
EXAMPLE 4 
A mixture of intermediate (25) (0.008 mol) in phosphorus oxychloride (96 
ml) was stirred and refluxed for 2 hours. The mixture was cooled and 
evaporated in vacuo. The residue was taken up in water, basified with 
ammonia, extracted with dichloromethane and washed with water. The organic 
layer was dried (MgSO.sub.4), filtered off and evaporated. The residue (2 
g) was purified by column chromatography over silica gel (eluent: CH.sub.2 
Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 94.5/5/0.5). The pure fractions were 
collected and evaporated. The residue (1.5 g) was recrystallized from 
2-butanone/methanol, yielding 0.8 g (36%) of 
9,10-dihydro-9-methyl-10-(1-methyl-4-piperidinylidene)pyrrolo[2,3-d]-1,2,4 
-triazolo[4,3-a]azepine; mp. 262.0.degree. C. (comp. 1). 
In a similar way there were prepared: 
10-(1 
-methyl-4-piperidinylidene)-10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a]azepine 
; mp. 244.9.degree. C. (comp. 2); 
10-(1-methyl-4-piperidinylidene)-10H-thieno[2,3-d][2,4]triazolo[4,3-a]azepi 
ne; mp. 239.5.degree. C. (comp. 3); 
6,10-dihydro-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinylidene]-5H-thieno 
[2,3-d][1,2,4]triazolo[1,5-a]azepine ethanedioate(2:3) monohydrate; mp. 
158.6.degree. C. (comp. 16); and 
(.+-.)-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-10H-thieno[2,3-d][1, 
2,4]triazolo[1,5-a]azepine; mp. 170.8.degree. C. (comp. 17). 
EXAMPLE 5 
Intermediate (4) (0.116 mol) was added portionwise to methanesulfonic acid 
(210 ml) at 0.degree. C. and the mixture was stirred at 80.degree. C. for 
3 hours. The mixture was poured into ice, basified with sodium hydroxide 
and extracted with dichloromethane. The organic layer was dried 
(MgSO.sub.4) and evaporated till dryness. The residue (28 g) was purified 
by column chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 
/CH.sub.3 OH/NH.sub.4 OH 95/5/0.2) (15 .mu.m). The pure fractions were 
collected and evaporated. The residue (0.87 g) was crystallized from 
1,1'-oxybisethane, yielding 0.67 g (2%) of 
5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidininylidene)pyrrolo[3,2 
-d][1,2,4]triazolo[1,5-a]azepine; mp. 169.1.degree. C. (comp. 4). 
EXAMPLE 6 
Tin(IV)chloride (12.6 ml) was added dropwise at room temperature to a 
solution of intermediate (5) (0.0285 mol) in 1,2-dichloroethane (300 ml) 
and the mixture was stirred and heated at 80.degree. C. for 2 hours. The 
mixture was cooled, poured into ice and basified with ammonia. The mixture 
was filtered over celite and the filtrate was extracted with 
dichloromethane. The organic layer was dried (MgSO.sub.4) and evaporated. 
The residue (11.52 g) was purified by column chromatography over silica 
gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 97/3/0.1 to 
95/5/0.1) (35-70 .mu.m). The pure fractions were collected and evaporated. 
The residue (4.4 g) was recrystallized from 2-butanone and 
2,2'-oxybispropane, yielding 3.19 g (38%) of 
(.+-.)-7,10-dihydro-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-7-meth 
ylpyrrolo[3,2-d]-1,2,4-triazolo[1,5-a]azepine; mp. 140.1.degree. C. (comp. 
5). 
In a similar way there was prepared: 
(.+-.)-8-methyl-10-(1-methyl-4-piperidinyl)-10H-furo[3,2-d][1,2,4]triazolo[ 
1,5-a]azepine; mp. 111.8.degree. C. (comp. 18). 
EXAMPLE 7 
Compound (1) (0.00355 mol) in ethanol (250 ml) was hydrogenated with 
palladium on activated carbon 10% (1 g) as a catalyst for 6 hours at room 
temperature under a 3 bar pressure in a Parr apparatus. After uptake of 
hydrogen (1 eq.), the catalyst was filtered through celite and the 
filtrate was evaporated. The residue (0.9 g) was purified by column 
chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 
OH/NH.sub.4 OH 95/5/0.5) (15-40 .mu.m). The pure fractions were collected 
and evaporated. The residue (0.7 g) was crystallized from 
2-butanone/2,2'-oxybispropane, yielding 0.57 g (70%) of 
5,6,9,10-tetrahydro-9-methyl-10-(1-methyl-4-piperidinylidene)pyrrolo[2,3-d 
]-1,2,4-triazolo[4,3-a]azepine; mp. 214.1.degree. C. (comp. 6); 
In a similar way there were prepared: 
(.+-.)-5,6,7,10-tetrahydro-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]- 
7methylpyrrolo[3,2-d]-1,2,4-triazolo[1,5-a]azepine; 132.1.degree. C. (comp. 
7); and 
(.+-.)-5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidinyl)pyrrolo[3,2- 
d][1,2,4]triazolo[1,5-a]azepine; mp. 142.8.degree. C. (comp. 8). 
EXAMPLE 8 
a) A mixture of intermediate (6) (0.034 mol) in phosphoric acid 98% (80 ml) 
was stirred and heated at 100.degree. C. for 6 hours. The mixture was 
cooled, poured into ice water, basified with ammonia and extracted with 
dichloromethane. The organic layer was dried (MgSO.sub.4) and evaporated. 
The residue (10.61 g) was purified by column chromatography over silica 
gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 95/5/0.1 to 
90/10/0.1 to 75/25/0.2) (35-70 .mu.m). The pure fractions were collected 
and evaporated. Fraction 1 was crystallized from n-pentane, yielding 1.6 g 
(21% ) of 
6,10-dihydro-10-(1-methyl-4-piperidinylidene)-5H-thieno[2,3-d][1,2,4]triaz 
olo[1,5-a]azepine; 141.2.degree. C. (comp. 9). Fraction 2 was treated with 
norit in methanol and crystallized from n-pentane, yielding 1.12 g (12%) 
of (.+-.)-10-(1-methyl-4-piperidinyl)-10H-thieno[2,3-d][1,2,4]triazolo[1,5 
-a]azepine; mp. 136.7.degree. C. (comp. 10). 
b) A mixture of compound (10) (0.00342 mol) and compound (9) (0.00342 mol) 
was hydrogenated in acetic acid (1.65 ml) and ethanol (150 ml) with 
palladium on activated carbon (2 g) as a catalyst at 50.degree. C. 
overnight under a 3 bar pressure in a Parr apparatus. The catalyst was 
filtered through celite and the filtrate was evaporated till dryness. The 
residue was taken up in dichloromethane and washed with potassium 
carbonate 10%. The organic layer was dried (MgSO.sub.4), filtered off and 
evaporated. The residue was purified by column chromatography over silica 
gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 90/10/1) (15-40 
.mu.m). The pure fractions were collected and evaporated. The residue (1.5 
g) was crystallized from 2,2'-oxybispropane, yielding 0.92 g (76%) of 
(.+-.)-6,10-dihydro-10-(1-methyl-4-piperidinyl)-5H-thieno[2,3-d][1,2,4]tri 
azolo[1,5-a]azepine; mp. 123.4.degree. C. (comp. 11). 
EXAMPLE 9 
a) Carbonochloridic acid ethyl ester (14.8 ml) was added dropwise at 
80.degree. C. to a solution of compound (4) (0.0193 mol) in 
N,N-diethylethanamine (5.4 ml) and methylbenzene (500 ml) and the mixture 
was stirred and refluxed for 3 hours. The mixture was cooled, poured into 
water, decanted off and extracted with ethyl acetate. The organic layer 
was washed with water, dried (MgSO.sub.4), filtered off and evaporated. 
The residue (9.34 g) was purified by column chromatography over silica gel 
(eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 97.5/2.5/0.1) (15 
.mu.m). The pure fractions were collected and evaporated. The residue was 
recrystallized from 2-butanone/2,2'-oxybispropane yielding 1.8 g (36%) of 
ethyl 
4-(5,6,7,10-tetrahydro-7-methylpyrrolo[3,2-d][1,2,4]triazolo[1,5-a]azepin- 
10-ylidene)-1-piperidinecarboxylate monohydrate; mp. 104.1.degree. C. 
(comp. 12). 
In a similar way there was prepared: 
ethyl 
4-(5,6-dihydro-10H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepin-10-ylidene)-1 
-piperidinecarboxylate (comp. 13); 
(.+-.)-ethyl 
4-(10H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepin-10-yl)-1-piperidinecarbox 
ylate (comp. 19); and 
ethyl 
10-(10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a]azepin-10-ylidene)-1-piperidine 
carboxylate (comp. 20). 
b) Compound (12) (0.0205 mol) was heated in a solution of potassium 
hydroxide (11.5 g) in 2-propanol (175 ml) and water (175 ml) for 63 hours. 
The mixture was cooled and evaporated. The residue was diluted in water 
(200 ml) and extracted with dichloromethane. The organic layer was dried 
(MgSO.sub.4), filtered off and evaporated. The residue (5.95 g) was 
purified by column chromatography over silica gel (eluent: CH.sub.2 
Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 92/8/0.5 to 80/20/0.5). The pure 
fractions were collected and evaporated, yielding 4.1 g (74%) of product. 
A sample (2 g) was crystallized from 2-butanone/2,2'-oxybispropane, 
yielding 1.8 g of 
5,6,7,10-tetrahydro-7-methyl-10-(4-piperidinylidene)pyrrolo[3,2-d][1,2,4]t 
riazolo[1,5-a]azepine; mp. 183.1.degree. C. (comp. 14). 
In a similar way, but in an acid environment, was prepared: 
6,10-dihydro-10-(4-piperidinylidene)-5H-thieno[2,3-d][1,2,4]triazolo[1,5-a] 
azepine; 198.8.degree. C. (comp. 15); 
(.+-.)-10-(4-piperidinyl)-10H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepine 
hemihydrate; mp. 136.3.degree. C. (comp. 21); and 
10-(4-piperidinylidene)-10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a]azepine 
(comp. 22). 
EXAMPLE 10 
A mixture of compound (14) (0.00471 mol), 1-(2-bromoethyl)-4-methoxybenzene 
(0.007 mol), potassium iodide (0.08 g) and potassium carbonate (1.3 g) in 
4-methyl-2-pentanone (50 ml) was stirred and refluxed overnight. The 
mixture was cooled and evaporated. The residue was taken up in 
dichloromethane. The organic layer was washed with water, dried 
(MgSO.sub.4), filtered off and evaporated. The residue (4 g) was purified 
by column chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 
/CH.sub.3 OH/NH.sub.4 OH 97/3/0.2) (15 .mu.m). The pure fractions were 
collected and evaporated. The residue (1.45 g) was recrystallized from 
ethanol/2,2'-oxybispropane, yielding 1.14 g (55%) 
5,6,7,10-tetrahydro-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinylidene]-7 
-methylpyrrolo[3,2-d][1,2,4]triazolo[1,5-a]azepine; mp. 138.9.degree. C. 
(comp. 23). 
In a similar way there were prepared: 
10-[1-[3-(4-fluorophenoxy)propyl]-4-piperidinylidene]-6,10-dihydro-5H-thien 
o[2,3-d][1,2,4]triazolo[1,5-a]azepine; mp. 131.3.degree. C. (comp. 24); 
(.+-.)-(E)-10-[1-(3-phenyl-2-propenyl)-4-piperidinyl]-10H-thieno[2,3-d][1,2 
,4]triazolo[1,5-a]azepine; mp. 149.0.degree. C. (comp. 25); 
1-ethyl-1,4-dihydro-4-[2-[4-(5,6,7,10-tetrahydro-7-methylpyrrolo[3,2-d][1,2 
,4]triazolo[1,5-a]azepin-10-ylidene)-1-piperidinyl]ethyl]-5H-tetrazol-5-one 
(comp. 26); 
10-[1-(2-ethoxyethyl)-4-piperidinylidene]-6,10-dihydro-5H-thieno[2,3-d][1,2 
,4]triazolo[1,5-a]azepine; mp. 82.5.degree. C. (comp. 27); and 
(.+-.)-2-methyl-3-[2-[4-(10H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepin-10-y 
l)-1piperidinyl]ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 200.1.degree. 
C. (comp. 28). 
EXAMPLE 11 
A mixture of compound (14) (0.0092 mol) and methyl 2-propenoate (0.018 mol) 
in methanol (40 ml) was stirred and refluxed overnight. The mixture was 
evaporated till dryness. The residue (2.7 g) was purified by column 
chromatography over silica gel (eluent: CH.sub.2 Cl.sub.2 /CH.sub.3 
OH/NH.sub.4 OH 96/4/0.2). The pure fractions were collected and 
evaporated. The residue was crystallized from 
2-propanone/2,2'-oxybispropane, yielding 1.3 g (52%) of methyl 
4-(5,6,7,10-tetrahydro-7-methylpyrrolo[3,2-d][1,2,4]triazolo[1,5-a]azepin- 
10-ylidene)-1-piperidinepropanoate; mp. 138.9.degree. C. (comp. 29). 
In a similar way there was prepared: 
methyl 
10-(10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a]azepin-10-ylidene)-1-piperidine 
propanoate; mp. 128.1.degree. C. (comp. 30). 
EXAMPLE 12 
Oxirane (0.017 mol) was bubbled through methanol at 0.degree. C. This 
mixture was added dropwise over a 30 minutes period to a solution of 
compound (15) (0.00844 mol) in methanol at room temperature. The mixture 
was stirred at room temperature for 24 hours. The mixture was evaporated 
and the residue was taken up in dichloromethane. The organic layer was 
washed with water, dried (MgSO.sub.4), filtered off and evaporated. The 
residue was purified by column chromatography over silica gel (eluent: 
CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 95/5/0.5) (15-40 .mu.m). The 
pure fractions were collected and evaporated. The residue (2 g) was 
recrystallized from 2-propanone, yielding 1.15 g (43%) of 
4-(5,6-dihydro-10H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepin-10-ylidene)-1 
-piperidineethanol; mp. 149.8.degree. C. (comp. 31). 
EXAMPLE 13 
a) At 0.degree. C., phosphoryl chloride (0.022 mol) was added dropwise to 
N,N-dimethylformamide (13 ml). This mixture was stirred for 30 minutes. 
Compound (4) (0.0106 mol) was added portionwise at 0.degree. C. Then, the 
temperature was raised to 30.degree. C. and stirring at this temperature 
was continued for 3 hours. The reaction mixture was cooled, poured out 
into ice water and the resulting solution was alkalized with potassium 
carbonate. This mixture was extracted with dichloromethane. The separated 
organic layer was washed with water, dried (MgSO.sub.4), filtered, treated 
with activated charcoal, filtered over diatomaceous earth and the filtrate 
was evaporated. The residue was crystallized from 2,2'-oxybispropane. The 
precipitate was filtered off (2.2 g) and recrystallized from acetonitrile. 
The precipitate was filtered off and dried, yielding 1.3 g (39%) of 
5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidinylidene)pyrrolo[3,2-d 
][1,2,4]triazolo[1,5-a]azepine-8-carboxaldehyde; mp. 204.5.degree. C. 
(comp. 32). 
b) A mixture of compound (32) (0.018 mol) in methanol (190 ml) was cooled 
till 0.degree. C. Sodium borohydride (5.8 g) was added portionwise and the 
mixture was stirred for 1 hour. The mixture was poured into ice and 
extracted with dichloromethane. The organic layer was washed with water, 
dried (MgSO.sub.4), filtered off and evaporated till dryness. The residue 
(5.05 g) was purified by column chromatography over silica gel (eluent: 
CH.sub.2 Cl.sub.2 /CH.sub.3 OH/NH.sub.4 OH 92/8/0.5). The pure fractions 
were collected and evaporated. The product was recrystallized from 
2,2'-oxybispropane, yielding 1.4 g (24%) of 
5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidinylidene)pyrrolo[3,2-d 
][1,2,4]triazolo[1,5-a]azepine-8-methanol hemihydrate; mp. 201.2.degree. C. 
(comp. 33). 
C. COMPOSITION EXAMPLES 
The following formulations exemplify typical pharmaceutical compositions in 
dosage unit form suitable for systemic or topical administration to 
warm-blooded animals in accordance with the present invention. 
"Active ingredient" (A.I.) as used throughout these examples relates to a 
compound of formula (I) or a compound of formula (VII), a pharmaceutically 
acceptable acid addition salt or a stereochemically isomeric form thereof. 
EXAMPLE 14 
Oral Drops 
500 g of the A.I. is dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 
l of the polyethylene glycol at 60.degree..about.80.degree. C. After 
cooling to 30.degree..about.40.degree. C. there are added 35 l of 
polyethylene glycol and the mixture is stirred well. Then there is added a 
solution of 1750 g of sodium saccharin in 2.5 l of purified water and 
while stirring there are added 2.5 l of cocoa flavor and polyethylene 
glycol q.s. to a volume of 50 l, providing an oral drop solution 
comprising 10 mg/ml of the A.I. The resulting solution is filled into 
suitable containers. 
EXAMPLE 15 
Oral Solutions 
9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are 
dissolved in 4 l of boiling purified water. In 3 l of this solution are 
dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g 
of the A.I. The latter solution is combined with the remaining part of the 
former solution and 12 l of 1,2,3-propanetriol and 3 l of sorbitol 70% 
solution are added thereto. 40 g of sodium saccharin are dissolved in 0.5 
l of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. 
The latter solution is combined with the former, water is added q.s. to a 
volume of 20 l providing an oral solution comprising 5 mg of the A.I. per 
teaspoonful (5 ml). The resulting solution is filled in suitable 
containers. 
EXAMPLE 16 
Capsules 
20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 
g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously 
stirred together. The resulting mixture is subsequently filled into 1000 
suitable hardened gelatin capsules, each comprising 20 mg of the A.I. 
EXAMPLE 17 
Film-coated Tablets 
Preparation of Tablet Core 
A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed 
well and thereafter humidified with a solution of 5 g sodium dodecyl 
sulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90.RTM.) in about 200 ml 
of water. The wet powder mixture is sieved, dried and sieved again. Then 
there are added 100 g microcrystalline cellulose (Avicel.RTM.) and 15 g 
hydrogenated vegetable oil (Sterotex.RTM.). The whole is mixed well and 
compressed into tablets, giving 10.000 tablets, each comprising 10 mg of 
the active ingredient. 
Coating 
To a solution of 10 g methyl cellulose (Methocel 60 HG.RTM.) in 75 ml of 
denaturated ethanol there is added a solution of 5 g of ethyl cellulose 
(Ethocel 22 cps.RTM.) in 150 ml of dichloromethane. Then there are added 
75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of 
polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. 
The latter solution is added to the former and then there are added 2.5 g 
of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of 
concentrated colour suspension (OpaSpray K-1-2109.RTM.) and the whole is 
homogenated. The tablet cores are coated with the thus obtained mixture in 
a coating apparatus. 
EXAMPLE 18 
Injectable Solutions 
1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate are 
dissolved in about 0.5 l of boiling water for injection. After cooling to 
about 50.degree. C. there are added while stirring 4 g lactic acid, 0.05 g 
propylene glycol and 4 g of the A.I. The solution is cooled to room 
temperature and supplemented with water for injection q.s. ad 1 l volume, 
giving a solution of 4 mg A.I. per ml. The solution is sterilized by 
filtration (U.S.P. XVII p. 811) and filled in sterile containers. 
EXAMPLE 19 
Suppositories 
3 g A.I. is dissolved in a solution of 3 g 2,3-dihydroxybutanedioic acid in 
25 ml polyethylene glycol 400. 12 g surfactant (SPAN.RTM.) and 
triglycerides (Witepsol 555.RTM.) q.s. ad 300 g are molten together. The 
latter mixture is mixed well with the former solution. The thus obtained 
mixture is poured into moulds at a temperature of 37.degree.-38.degree. C. 
to form 100 suppositories each containing 30 mg of the A.I.