Antiallergic (1H-tetrazol-5-yl)tetrazolo[1,5-a]quinolines and derivatives thereof

(1H-Tetrazol-5-yl)tetrazolo[1,5-a]quinolines and related compounds which are useful as antiallergic agents are described herein. The compounds are prepared by the reaction of an appropriate halocyanoquinoline or isoquinoline with ammonium chloride and an azide such as sodium azide in an inert solvent such dimethylformamide.

The present invention relates to a group of compounds containing two 
tetrazole rings with one of the tetrazole rings fused into a tricyclic 
system and the second being a substituent on that ring system. More 
particularly, the present invention relates to compounds having the 
following general formula: 
##STR1## 
wherein Tet is the divalent tetrazolo group of the formula 
##STR2## 
which is attached to the ring system to give either isomeric form; A is 
--CH.dbd. or --N.dbd.; n is 0, 1 or 2; X is H, alkyl or 1-4 C, alkoxy or 
1-4 C, halogen, methylmercapto, methylsulfonyl, or two X's can be combined 
as methylenedioxy; with the proviso that, when X is methylmercapto or 
methylsulfonyl, then n must be 1; and the pharmaceutically acceptable 
salts thereof. 
The substituent with the free valence entering the ring between the 
positions marked as 4 and 5 can only be attached to either of those two 
positions. The X substituent can only be attached at available 7-, 8- 
and/or 9-positions in the left hand ring in the structure shown above. 
Halogen is fluorine, chlorine or bromine. Examples of the alkyl groups are 
methyl, ethyl, propyl and isopropyl; examples of the alkoxy groups are 
methoxy, ethoxy, propoxy, isopropoxy and butoxy. 
Particularly preferred compounds are those having the following general 
formula: 
##STR3## 
wherein (X).sub.n is defined as above; and the pharmaceutically acceptable 
salts thereof. 
Equivalent to the above tetrazoles for the purposes of this invention are 
the pharmaceutically acceptable salts and also the hydrates of the 
compounds and their salts. The term "pharmaceutically acceptable salt" as 
used herein is intended to include non-toxic cationic salts such as the 
alkali metal salts, e.g., sodium and potassium; alkaline earth metal salts 
such as calcium, magnesium or barium; salts with ammonia; and salts with 
organic bases, e.g., amines such as triethylamine, n-propylamine, 
tri-n-butylamine, tromethamine, triethanolamine and N-methylglucamine. 
While the indicated salts can be considered as equivalent to the 
tetrazoles as far as pharmacological effects are concerned, certain of 
these salts have the further advantage of better physical properties. 
Thus, for example, they give solid forms which can be handled much more 
easily than the tetrazole itself. 
The compounds of the present invention are prepared from a halocyanide of 
the formula: 
##STR4## 
wherein --CN is substituted at the 4- or 5-position; (X).sub.n is defined 
as above and Z is --N.dbd.C(Hal)--, wherein Hal is chlorine or bromine, in 
either isomeric form. The halocyanide is heated with ammonium chloride and 
sodium azide in an inert solvent such as dimethylformamide. Although the 
chlorocyanide is preferred in the procedure above, the corresponding 
bromocyanide can also be used. Similarly, sodium azide is the preferred 
azide although other alkali metal azides could also be used. 
Where the starting material above is a 2-chloro-3-cyanoquinoline, this can 
be prepared by starting from an appropriate substituted acetanilide. This 
is heated with phosphoryl chloride and dimethylformamide to give the 
corresponding 2-chloro-3-quinolinecarboxaldehyde. The process involved is 
discussed in detail by meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1, 
1981, 1520. The chloroquinolinecarboxaldehyde is then reacted with 
hydroxylamine hydrochloride, formic acid and sodium formate with heating 
to give the corresponding 3-cyano-2(1H)-quinolinone. This is then heated 
with an excess of phosphoryl chloride to give the desired 
2-chloro-3-cyanoquinoline. 
Alternatively, it is possible to obtain the desired 
2-chloro-3-cyanoquinoline directly from an appropriate acetanilide. The 
acetanilide is heated with dimethylformamide and phosphorus oxychloride 
and, after the initial reaction is complete, hydroxylamine (hydrochloride) 
is added to the reaction mixture and the product indicated earlier is 
isolated. Thus, cyclization to a quinoline takes place and a cyano 
substituted product is obtained. 
While all of the basic reactants are the same, this procedure for preparing 
the cyano compounds differs from that described earlier in that the 
reaction is not carried out stepwise with isolation of some type of 
product after each step of the procedure. With this difference in 
procedures, the actual series of reactants involved in the two procedures 
is not identical. Thus, with acetanilide as the starting material, the 
reaction with dimethylformamide and phosphoryl chloride actually gives, in 
solution, the cyclized quinoline with a 3-iminium [--CH.dbd.N.sup..sym. 
&lt;], substituent. This iminium (salt) can actually be used as such in 
solution without resorting to isolation wherein the iminium is changed to 
the corresponding (quinoline)-3-carboxaldehyde. In the stepwise procedure, 
the carboxaldehyde is reacted with hydroxylamine to give the oxime which 
is then dehydrated to the nitrile but, in the course of this reaction in 
the quinoline procedure under consideration here, the 2-chloro substituent 
is hydrolyzed to a ketone and an additional separate step is needed to get 
back to 2-chloro-substitution. In contrast, in the one-step procedure, the 
iminium salt can be considered as an aldehyde equivalent and it reacts 
directly with hydroxylamine to give the oxime. But, since an excess of 
dehydrating agent is present (phosphoryl chloride), the oxime is 
immediately dehydrated to the nitrile without affecting the 2-chloro atom. 
Although the procedure is described above for an aldehyde equivalent 
(iminium salt), it is possible to carry out the same process on aldehydes 
too. That is, reaction of an aldehyde with phosphorus oxychloride and 
hydroxylamine also gives a nitrile directly. 
The method above can be generalized to provide a process for the general 
conversion of an aldehyde or an aldehyde equivalent (such as an iminium 
salt) to the corresponding nitrile by reaction with hydroxylamine and 
phosphoryl chloride. The process as described herein can be further 
generalized to include the immediately preceding step of the formation of 
an aldehyde or aldehyde equivalent as obtained in the synthesis of the 
iminium intermediates used in the present application or aldehydes as 
obtained from an aromatic compound by a Vilsmeier-type reaction. 
The tetrazoles of the present invention are converted to the corresponding 
pharmaceutically acceptable salts by reacting them with a substantially 
equimolar amount of the appropriate base in an aqueous solution or in a 
suitable organic solvent such as methanol or ethanol. The salts are 
recovered by standard methods such as filtration if they are insoluble in 
the original medium, or, if they are soluble in that medium, the salt is 
precipitated by evaporation of the solvent or by addition of a non-solvent 
for the salt. 
The compounds of the present invention possess antiallergic activity. Thus, 
they are useful in the treatment of conditions in which antigen-antibody 
reactions are responsible for disease and particularly in the treatment of 
allergic diseases such as (but not limited to) extrinsic asthma, hay 
fever, urticaria, eczema or atopic dermatitis and upper respiratory 
conditions such as allergic rhinitis. 
The compounds of the present invention may be administered either as 
individual therapeutic agents or as mixtures with other therapeutic 
agents. They may be administered alone but are generally administered in 
the form of pharmaceutical compositions, i.e., mixtures of the active 
agents with suitable pharmaceutical carriers or diluents. Examples of such 
compositions include tablets, lozenges, capsules, powders, aerosol sprays, 
aqueous or oily suspensions, syrups, elixirs and aqueous solutions for 
injection. The compounds are most preferably administered in oral dosage 
forms. 
The nature of the pharmaceutical composition and the pharmaceutical carrier 
or diluent will, of course, depend on the desired route of administration, 
i.e., orally, parenterally or by inhalation. Oral compositions may be in 
the form of tablets or capsules and may contain conventional excipients 
such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth 
or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, maize-starch, 
calcium phosphate, sorbitol or glycine), lubricants (e.g., magnesium 
stearate, talc, polyethylene glycol or silica), disintegrants (e.g., 
starch) or wetting agents (e.g., sodium lauryl sulfate). Oral liquid 
preparations may be in the form of aqueous or oily suspensions, solutions, 
emulsions, syrups, elixirs, etc., or may be presented as a dry product for 
reconstitution with water or other suitable vehicle before use. Such 
liquid preparations may contain conventional additives such as suspending 
agents, flavoring agents, diluents or emulsifying agents. For parenteral 
administration or inhalation, solutions or suspensions of a compound of 
the present invention with conventional pharmaceutical vehicles may be 
employed, e.g., as an aerosol spray for inhalation, as an aqueous solution 
for intravenous injection or as an oily suspension for intramuscular 
injection. The compounds may also be administered by means of inhalers or 
other devices which permit the active compounds in the form of dry powders 
to come into direct contact with the lungs. Procedures for the preparation 
of compositions as discussed above are described in standard texts, such 
as Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, 
Penna. 
The compounds of the present invention or pharmaceutical compositions 
thereof may be administered to human asthmatic patients in single oral 
doses of approximately 1-1000 mg of active ingredient and multiple oral 
doses totaling up to about 4000 mg/day of active ingredient. When 
administered by inhalation, lower doses are generally given, i.e., on the 
order of about 0.1 of the normal dosage for the particular compound in 
question. These values are illustrative only, however, and the physician 
of course will ultimately determine the dosage most suitable for a 
particular patient on the basis of factors such as age, weight, diagnosis, 
severity of the symptoms and the particular agent to be administered. 
The antiallergic activity of the present compounds is demonstrated by the 
IgE mediated rat Passive Cutaneous Anaphylaxis (PCA) test. This test is 
generally accepted as one of the best animal models for the qualitative 
determination of antiallergic activity. Disodium cromoglycate is active in 
this test when administered i.p. but not orally. The method can be 
described briefly as follows: 
PCA Test Method 
1. Antisera--Various standard methods described in the literature were used 
for the preparation of reaginic antisera to ovalbumin in either Hooded 
Lister or Brown Norway adult rats. 
2. Animals--Adult male Sprague-Dawley or female Wistar Kyoto rats were used 
as antisera recipients in the test. The animals were allowed to acclimate 
for 5-14 days with food and water ad lib. 
3. Sensitization--Recipient rats were passively sensitized by the 
intradermal injection of 100 microliters of two dilutions of antiserum 
(one injection on each side of the back). Sensitization occurred 48-72 
hours prior to antigen challenge. 
4. Administration of Test Compound--Four to six animals were used for each 
test compound/dilution. Compounds were homogenized in an appropriate 
carrier solution, and administered i.p. at 60 mg/kg 5 minutes prior to 
challenge or p.o. at 100 mg/kg 5 to 240 minutes prior to challenge. 
5. Antigen Challenge and Reaction Evaluation--Ovalbumin (0.1-1.0 mg in a 
0.5% solution of Evan's Blue dye) in saline was given to each rat by i.v. 
administration. Thirty minutes later, the resultant PCA reactions were 
measured for average diameter and color intensity from the reflected 
surface of the skin. Test compound activity is expressed as percent 
inhibition based on control reactions. 
When tested by the above procedure, the compounds of the present invention 
were active both i.p. and orally. 
In addition to activity in the PCA test as described above, the compounds 
of the present invention also inhibit the release of histamine in the rat 
Passive Peritoneal Anaphylaxis (PPA) test. This method can be described 
briefly as follows: 
PPA Test Method 
1. Antisera--Reaginic antibody to ovalbumin for this test was prepared in 
adult male B.sub.6 D.sub.2 F.sub.1 mice. 
2. Animals Adult male Sprague Dawley or female Wistar Kyoto rats were used 
as antibody recipients. The animals were allowed to acclimate for 5-14 
days with food and water ad lib. 
3. Sensitization--Recipient rats were sensitized i.p. with 2 ml of an 
appropriate saline dilution of the mouse anti-ovalbumin antiserum 
determined from prior experiments. Sensitization took place 2 hours prior 
to antigen challenge. 
4. Administration of Test Compound--Five to ten animals were used for each 
test compound/dilution. Compounds were homogenized in saline with an 
equivalent of sodium bicarbonate to effect solubilization, if appropriate, 
and administered i.p. at 60 .mu.g, 30 seconds prior to antigen challenge 
or p.o. 5 to 60 minutes prior to antigen challenge. 
5. Antigen Challenge and Assay Evaluation--Two mg of ovalbumin in 5 ml of 
modified Tyrode's Solution was administered by i.p. injection and the 
animals were sacrificed 5 minutes later. Peritoneal shock fluids were 
collected and classified by centrifugation. Protein was removed from the 
samples by perchloric acid precipitation and subsequent centrifugation. 
The samples were then analyzed for histamine content by an automated 
fluorometric assay. Histamine levels of peritoneal shock fluids from 
treatment animals were then compared to those of shock fluids from control 
animals. Drug effect was expressed as percent inhibition of histamine 
release.

The following examples are presented to illustrate the present invention 
but they should not be construed as limiting in any way. 
EXAMPLE 1 
To a mixture of 11880 ml of phosphoryl chloride and 2500 g of acetanilide 
was added, with cooling and stirring in an ice bath, 3380 g of 
dimethylformamide at such a rate that the temperature did not exceed 
60.degree. C. The addition took about 45 minutes, at which time the 
cooling bath was removed and the mixture was heated to 75.degree. C. for 
22 hours. The mixture was then cooled and the excess phosphoryl chloride 
was removed by rotary evaporation. The residual dark brown oil was then 
poured into about 32 liters of water with stirring. Ice was added to the 
aqueous mixture to keep the temperature below 50.degree. C. The dark 
yellow solid which formed was separated by filtration and dried in a 
forced-air oven at 70.degree. C. to give 
2-chloro-3-quinolinecarboxaldehyde melting at about 
145.degree.-147.degree. C. 
EXAMPLE 2 
To the mixture obtained by the addition of 210 g of 
4-(methylthio)acetanilide to 1246 g of phosphoryl chloride there was added 
254 g of dimethylformamide over a period of 30 minutes with stirring. The 
reaction was exothermic and the rate of addition was controlled so that 
the temperature did not exceed 75.degree. C. After the addition was 
complete, the reaction was heated at 75.degree. C. for 2.5 hours. The 
mixture was then quenched in water and the yellow precipitate which formed 
was separated by filtration and dried to give 
2-chloro-6-methylthio-3-quinolinecarboxaldehyde. 
When the above procedure was repeated using 3,4-dimethoxyacetanilide, the 
procedure obtained was 2-chloro-6,7-dimethoxy-3-quinolinecarboxaldehyde. 
EXAMPLE 3 
A mixture was prepared from 6 liters of 97% formic acid, 300 g of 
hydroxylamine hydrochloride, 500 g of sodium formate, and 700 g of 
2-chloro-3-quinolinecarboxaldehyde and this mixture was heated to reflux 
(110.degree. C.). The resulting solution was then maintained at 
110.degree. C. for 18 hours. The solution was then cooled and the solid 
which crystallized was separated by filtration and then successively 
washed twice with water, once with ethanol and once with methylene 
chloride to give 3-cyano-2(1H)-quinolinone. 
EXAMPLE 4 
A mixture was prepared from 15 g of 
2-chloro-6,7-dimethyl-3-quinolinecarboxaldehyde, 5.4 g of hydroxylamine 
hydrochloride, 8.5 g of sodium formate and 155 ml of 97% formic acid and 
this was heated at reflux for 3 hours. Initially, the mixture became a 
heavy yellow paste but a homogeneous brown solution formed later. However, 
by the end of the 3-hour reflux period, the mixture was again 
heterogeneous and it was cooled and poured into 300 ml of water. The solid 
which formed was separated by filtration and dried to give 
3-cyano-6,7-dimethyl-2(1H)-quinolinone melting at about 300.degree. C. The 
indicated product contained 1/4 molecule of water of hydration. 
When the above procedure was repeated using the appropriate starting 
materials, the following compounds were obtained: 
3-Cyano-6,7-dimethoxy-2(1H)-quinolinone (1/4H.sub.2 O) melting at greater 
than 300.degree. C. 
3-Cyano-6-methylthio-2(1H)-quinolinone (1/6 H.sub.2 O) melting at about 
287.degree.-288.degree. C. 
EXAMPLE 5 
To a solution of 10 ml of 30% hydrogen peroxide and 100 ml of acetic acid 
there was added 4.0 g of 3-cyano-6-methylthio-2(1H)-quinolinone and the 
mixture was heated at reflux for 1.5 hours. A homogeneous solution formed 
initially but, during the course of the reaction, a light yellow 
precipitate appeared. The mixture was cooled and the solid was separated 
by filtration to give 3-cyano-6-methylsulfonyl-2(1H)-quinolinone melting 
at greater than 310.degree. C. 
EXAMPLE 6 
A mixture of 50 g of 3-cyano-2(1H)-quinolinone and 250 ml of phosphoryl 
chloride was heated at reflux for 18 hours. Volatile material was 
evaporated from the mixture under reduced pressure and the resulting 
residue was carefully added to water. The solid which formed was separated 
by filtration, washed with water and dried to give crude product. This was 
dissolved in methylene chloride and the resulting solution was treated 
with silica gel and filtered to give a pale yellow solution. Hexane was 
added to the solution which was then placed on a steam bath until 
crystallization occurred. The solid was then separated by filtration to 
give 2-chloro-3-cyanoquinoline. This compound melts at about 
163.degree.-164.degree. C. 
EXAMPLE 7 
A mixture was prepared from 67.5 g of 
3-cyano-6,7-dimethyl-2(1H)-quinolinone and 340 ml of phosphoryl chloride 
and this was heated at reflux for 18 hours. The mixture was cooled, excess 
phosphoryl chloride was removed by vacuum evaporation, and the residue was 
carefully added to water with vigorous stirring. The solid which formed 
was separated by filtration and recrystallized from methylene chloride to 
give 2-chloro-3-cyano-6,7-dimethylquinoline melting at about 
189.degree.-190.degree. C. 
When the above procedure was repeated using the appropriate starting 
materials, the following compounds were obtained: 
2-Chloro-3-cyano-6,7-dimethoxyquinoline. 
2-Chloro-3-cyano-6-(methylthio)quinoline melting at about 
227.degree.-228.degree. C. 
2-Chloro-3-cyano-6-methylsulfonylquinoline melting at about 
233.degree.-235.degree. C. 
EXAMPLE 8 
To a mixture of 118 ml of phosphoryl chloride and 25 g of acetanilide was 
added, with cooling and stirring in an ice bath, 41 g of dimethylformamide 
at such a rate that the temperature did not exceed 75.degree. C. After the 
addition was complete, a heat lamp was applied and the temperature was 
maintained at 75.degree. C. for 20 hours. Heating was then stopped and the 
mixture was allowed to cool for a few minutes and the temperature fell to 
62.degree. C. Hydroxylamine hydrochloride (14 g) was added all at once to 
the stirred mixture. After about 2-3 minutes, a slow exothermic reaction 
started and the mixture began to boil with considerable gas evolution. The 
temperature rose slowly from 62.degree. C. to 77.degree. C. over a period 
of about 15 minutes. By this time, gas evolution had almost stopped. The 
mixture was then allowed to cool to room temperature and a heavy solid 
precipitated. The mixture was then quenched carefully by the addition of 
1000 ml of water with vigorous stirring. The solid was then separated by 
filtration and dissolved in methylene chloride and the methylene chloride 
solution was treated with charcoal filtered, concentrated and cooled. 
Filtration then gave light yellow crystals of 2-chloro-3-cyanoquinoline. 
EXAMPLE 9 
A mixture was prepared from 10 g of 2-chloro-3-quinolinecarboxaldehyde, 5.2 
g of hydroxylamine hydrochloride and 100 ml of phosphoryl chloride and 
heated with a heat lamp. The mixture was heterogeneous until the 
temperature reached 90.degree. C. and there was no noticeable exotherm or 
gas evolution. After heating at reflux for 30 minutes, the mixture was 
cooled for 16 hours. It was then quenched in 700 ml of water. The tan 
solid which formed was separated by filtration and dried to give 7 g of 
crude 2-chloro-3-cyanoquinoline. 
EXAMPLE 10 
To a solution of 10.0 g of 2-bromo-4-cyanoquinoline in 150 ml of 
dimethylformamide was added 5.3 g of ammonium chloride and 6.5 g of sodium 
azide. The heterogeneous mixture was heated at 120.degree. C. for 16 hours 
and then cooled and filtered to remove the solid present. The filtrate was 
poured into 500 ml of water and acidified with concentrated hydrochloric 
acid. A heavy creamy white precipitate formed and this was separated by 
filtration and dried. The solid was then redissolved in aqueous base and 
the alkaline solution was extracted with methylene chloride to remove any 
insoluble material. The aqueous solution was then acidified by the 
addition of hydrochloric acid and the precipitate which formed was 
separated by filtration to give 
5-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline melting at about 
250.degree.-251.degree. C. with decomposition. 
EXAMPLE 11 
A mixture of 7.0 g of 2-chloro-3-cyano-1,8-naphthyridine, 4.4 g of ammonium 
chloride and 5.3 g of sodium azide in 200 ml of dimethylformamide was 
heated at 120.degree. C. for 16 hours. The mixture was then poured into 
600 ml of water and acidified to a pH of 2 by the addition of concentrated 
hydrochloric acid. The precipitate which formed was separated by 
filtration and added to 1500 ml of aqueous 1N sodium hydroxide solution. 
It was necessary to heat the mixture to 45.degree. C. in order to obtain a 
homogeneous solution. The solution was then treated with charcoal and 
filtered through Celite to give a light yellow solution. Acidification of 
this solution gave a pale yellow-white solid which was separated and dried 
to give 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a][1,8]naphthyridine melting at 
about 280.degree.-282.degree. C. with decomposition. 
EXAMPLE 12 
A mixture of 6.6 g of 2-chloro-3-cyanoquinoline, 5.0 g of sodium azide and 
4.2 g of ammonium chloride in 100 ml of dimethylformamide was heated at 
120.degree. C. for 17 hours. The mixture was poured into 500 ml of water 
and then acidified to a pH of 2 with hydrochloric acid. A heavy yellow 
precipitate formed and was separated by filtration. The solid was then 
redissolved in aqueous base, using about 1500-2000 ml of water because of 
the low solubility of the sodium salt. Concentrated hydrochloric acid was 
then added to the clear yellow solution until a pH of 2 was obtained. A 
heavy precipitate formed and this was separated by filtration and dried to 
give 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline melting at about 
280.degree.-282.degree. C. with decomposition. This compound has the 
following structural formula: 
##STR5## 
EXAMPLE 13 
The procedure of the preceding example was repeated using the appropriate 
substituted quinoline but the redissolving and reprecipitation of the 
product was omitted. The following compounds were obtained: 
7,8-Dimethyl-4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline (containing 1/4 
mole of water of hydration) melting at about 284.degree.-286.degree. C. 
with decomposition. 
7.8-Dimethoxy-4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline (containing 1.5 
mole of water of hydration) melting at about 275.degree.-276.degree. C. 
with decomposition. 
7-Methylsulfonyl-4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline melting at 
about 274.degree.-275.degree. C. with decomposition. 
7-Methylthio-4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline melting at about 
269.degree.-271.degree. C. with decomposition. 
7-Chloro-4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline is also obtained in 
the same way, with the starting material obtained by the procedures of 
Examples 4 and 7. 
EXAMPLE 14 
A mixture of 7.0 g of 1-chloro-4-cyanoisoquinoline, 4.3 g of ammonium 
chloride, 5.3 g of sodium azide and 100 ml of dimethylformamide was heated 
at 120.degree. C. for 16 hours. The mixture was poured into 600 ml of 
water and acidified to a pH of 2 with hydrochloric acid. The cream colored 
precipitate which formed was separated by filtration and dried and then 
recrystallized from dimethylsulfoxide to give 
5-(1H-tetrazol-5-yl)tetrazolo[5,1-a[isoquinoline hemihydrate melting at 
about 235.degree.-250.degree. C. decomposition. 
EXAMPLE 15 
A mixture of 128 g of 2-chloro-3-cyanoquinoline, 80 g of ammonium chloride, 
and 97 g of sodium azide in 1800 ml of dimethylformamide was heated at 
110.degree. C. for 15 hours. The mixture was then poured into 4 liters of 
water. The resulting, almost homogeneous, solution was then stirred and 
acidified with concentrated hydrochloric acid to pH 2. The heavy 
precipitate which formed was separated by filtration and, while still wet, 
it was added to 4 liters of water containing 1.1 equivalents (based on 
theoretical yield) of sodium hydroxide. The resulting aqueous mixture was 
then heated to about 50.degree.-60.degree. C. but showed no signs of 
becoming homogenous. The mixture (in 2 portions) was then diluted with 
water to a total volume of 8 liters and heated to 80.degree. C. The 
solutions were treated with charcoal and filtered through Celite to give 
pale yellow filtrates. These were combined and cooled for 16 hours. The 
solid which formed was then separated by filtration to give the sodium 
salt of 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline. 
EXAMPLE 16 
4-(1H-Tetrazol-5-yl)tetrazolo[1,5-a]quinoline (120 g) was dissolved in a 
solution of 22 g of sodium hydroxide and 6 liters of water at 80.degree. 
C. Powdered charcoal was added to the brown solution which was filtered 
hot to give a pale yellow clear filtrate. The solution was allowed to cool 
for 18 hours and the solid which precipitated was separated by filtration 
and dried to give the sodium salt of 
4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline (21/3H.sub.2 O) melting at 
about 315.degree.-317.degree. C. with decomposition. 
EXAMPLE 17 
A mixture of 20 g of 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline, 5.1 g 
of potassium hydroxide and 200 ml of water was heated to 80.degree. C. 
Charcoal was added and the solution was filtered hot. When the filtrate 
was cooled, a solid crystallized from the solution. This was separated by 
filtration to give the potassium salt of 
4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline (1/3H.sub.2 O) melting at 
about 310.degree. C. 
EXAMPLE 18 
4-(1H-Tetrazol-5-yl)tetrazolo[1,5-a]quinoline (20 g) and 7.4 g of calcium 
acetate were added to 1800 ml of water and the mixture was heated to 
90.degree. C. The solids dissolved slowly and solution was obtained after 
2 hours. Charcoal was then added and the solution was filtered hot. The 
precipitate which formed upon cooling was separated by filtration to give 
the calcium salt of 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline (3.5 
H.sub.2 O) as a fluffy pink solid melting at greater 310.degree. C. 
EXAMPLE 19 
A solution was prepared from 20 g of 
4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline, 15 g of tromethamine and 
150 ml of water at 80.degree. C. This was treated with charcoal and 
filtered and the filtrate was cooled. The precipitate which then formed 
was separated by filtration to give the tromethamine salt of 
4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline as a pale yellow crystalline 
powder melting at about 263.degree.-264.degree. C. with decomposition. 
EXAMPLE 20 
4-(1H-Tetrazol-5-yl)tetrazolo[1,5-a]quinoline (20 g) and 14.7 g of 
triethanolamine were added to 150 ml of water and a clear solution was 
obtained upon warming to 50.degree. C. The solution was treated with 
charcoal and filtered hot and the filtrate was diluted with 2-propanol 
until precipitation began. The solution was then cooled to 0.degree. C. 
and the solid which formed was separated by filtration to give the 
triethanolamine salt of 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline as a 
tan powder melting at about 148.degree.-150.degree. C. 
EXAMPLE 21 
A solution was prepared from 800 g of N-methyl-D-glucamine and 5000 ml of 
water and 940 g of 4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline was 
added. The mixture was heated to 50.degree. C. for 1 hour to bring about 
solution of the solids. Powdered charcoal (40 g) was added to the 
homogeneous brown solution and this was filtered to give a clear brown 
solution. To the filtrate was added 15000 ml of ethanol and the mixture 
was allowed to stand overnight. A solid crystallized from the solution in 
the form of fluffy white needles. The solid was collected by filtration, 
washed with ethanol and dried to give the N-methyl-D-glucamine salt of 
4-(1H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline melting at about 
153.degree.-155.degree. C.