This disclosure describes substituted 3-benzhydrylthiazolo(3,2-a)pyridines which are useful as diuretic agents.

BRIEF SUMMARY OF THE INVENTION 
This invention relates to new organic compounds and, more particularly, is 
concerned with novel substituted 
3-benzhydrylthiazolo[3,2-a][1,3]diazacyclenes which may be represented by 
the following structural formula: 
##STR1## 
wherein R.sub.1 is hydrogen, fluoro, chloro, bromo or alkyl having up to 3 
carbon atoms; R.sub.2 is hydrogen, fluoro, chloro, bromo or alkyl having 
up to 3 carbon atoms; R.sub.3 is hydrogen or alkyl having up to 3 carbon 
atoms; and Q is a divalent moiety of the formulae: 
##STR2## 
as well as the pharmaceutically acceptable acid-addition salts thereof. 
The invention is also concerned with pharmaceutical compositions 
comprising these new compounds as well as methods for inducing diuresis 
employing these new compounds and, further, to methods for their 
preparation. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel free bases of the present invention are obtainable as either 
white to light tan crystalline materials having characteristic melting 
points or as oils having characteristic absorption spectra. The free bases 
are, in general, relatively insoluble in water but soluble in most organic 
solvents such as lower alkanols, benzene, acetone, chloroform, etc. The 
organic bases of this invention form acid-addition salts with a variety of 
pharmacologically acceptable organic and inorganic salt-forming reagents. 
Thus, acid-addition salts, formed by admixture of the organic free base 
with an acid, suitably in a neutral solvent, are formed with such acids as 
sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, 
malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the 
like. For purposes of this invention, the free bases are equivalent to 
their acid-addition salts. The acid-addition salts of the organic bases of 
the present invention are, in general, crystalline solids, relatively 
soluble in water, methanol and ethanol but relatively insoluble in 
non-polar organic solvents such as diethyl ether, benzene, toluene, and 
the like. 
The novel compounds of the present invention may be readily prepared in 
accordance with the following reaction scheme: 
##STR3## 
wherein R.sub.1, R.sub.2, R.sub.3 and Q are as hereinbefore defined. In 
accordance with the above reaction scheme, an appropriately substituted 
1,1-diaryl-2-alkanone (1) is dissolved in glacial acetic acid and treated 
with about one equivalent of bromine at 60.degree.-70.degree. C. whereby 
the corresponding 1,1-diaryl-3-bromo-2-alkanone (2) is obtained. Treatment 
of (2) with tetrahydropyrimidine-2(1H)-thione, 
tetrahydro-5,5-dimethylpyrimidine-2(1H)-thione, 
hexahydro-1,3-dizaepin-2(2H)-thione or hexahydro-1,3-diazocin-2(1H)-thione 
in acetone as solvent at the reflux temperature thereof provides the 
corresponding 3-benzhydrylthiazolo[3,2-a][1,3]-dizacyclan-3-ol (3). 
Heating the diazacyclanol (3) above its decomposition point, usually 
160.degree.-220.degree. C., for from about 5 to about 30 minutes provides 
the dehydrated product (4). Alternatively, the diazacyclanol (3) may be 
boiled in a solvent such as ethanol, butanol or dioxane until dehydration 
has occurred. Addition of an acid such as hydrochloric or hydrobromic 
promotes the reaction. 
In general terms, the process of step one may be carried out in glacial 
acetic acid or an equivalent at 50.degree.-80.degree. C. for 30 minutes to 
4 hours. Suitable solvents for the second step include acetone, 
methylethylketone, chloroform, benzene, toluene and the like and the 
reaction may range from 25.degree.-60.degree. C. for one to 72 hours. 
Procedures for the preparation of the 1,1-diaryl-2-alkanones (1) are well 
known and may be found in such references as: M. J. Hatch and D. J. Cram, 
J.A.C.S. 75, 38 (1953); E. J. Cragoe, Jr., A. M. Pietruszkiewicz and C. M. 
Robb, J. Org. Chem. 23, 971 (1958); E. M. Schultz, U.S. Pat. No. 
2,703,329. It is also possible to prepare the 
1,1-diaryl-3-bromo-2-alkanone derivatives (2) by other methods, for 
example, the Arndt-Eistert synthesis of an acid with diazomethane and 
hydrobromic acid [G. W. Wheland, Advanced Organic Chemistry, John Wiley 
and Sons, Inc., 2nd Edition, p. 462 (1948)] . 
The new compounds of the present invention possess diuretic activity in 
warm-blooded animals as established when tested by the method of P. S. 
Chan and D. Poorvin, Clinical and Experimental Hypertension, 1 (6), 
817-830 (1979), "Sequential Method for Combined Screening Antihypertensive 
and Diuretic Agents in the Same Spontaneously Hypertensive Rat". Basically 
this test uses male, 8 week old, spontaneously hypertensive rats of the 
Okamoto strain weighing about 300 g. One rat is dosed by gavage with the 
test compound at 100 mg./kg. of body weight with 0.9% sodium chloride 
loading at 25 ml./kg. of body weight at zero hour. The test compound is 
suspended in 2% preboiled starch at 50 mg./ml. The rat is placed in a 
metabolism cage and the 0-5 hour urine is collected. The urinary sodium, 
potassium and chloride content are determined by the Technicon 
Autoanalyzer; method N-20 for sodium and potassium and method N-5b for 
chloride. At the end of the fifth hour, the rat is placed in a regular 
animal cage and provided with water ad libitum. A second identical dose of 
the test compound is given by gavage, without sodium chloride loading, at 
the 24th hour. Four hours later, the rat is restrained in a supine 
position with elastic tapes. The femoral area is locally anesthetized by 
subcutaneous infiltration of 2% lidocaine. The iliac artery is isolated 
and punctured with a 26 gauge thin wall needle which is connected to a 
Statham P23Db pressure transducer-Beckman Dynograph recorder system for 
monitoring blood pressure. The blood pressure is recorded for 15 minutes 
or until it is stabilized. Based on the data obtained and using the 
three-stage "sequential probability ratio test", statistical method, the 
criteria for determining if a test compound is considered active are as 
follows: 
Test I: If the mean arterial blood pressure (MABP) is .ltoreq.116 and/or 
the urinary sodium is .gtoreq.1.21 mEq, the compound is active. If the 
MABP is between 117-146 and/or the urinary sodium is between 1.21-0.93, a 
second rat is tested. 
Test II: If the average MABP of the two rats is &lt;122 and/or the average 
urinary sodium of the two rats is &gt;1.16 mEq, the compound is considered 
active. If the MABP is between 123-137 and/or the average urinary sodium 
is between 1.16-1.01, a third rat is tested. 
Test III: If the average MABP of the three rats is .ltoreq.128 and/or the 
average urinary sodium is .gtoreq.1.10, the compound is active. 
The results of this test on representative compounds of the present 
invention appear in Table I. 
TABLE I 
__________________________________________________________________________ 
Urinary Values in mEq/5 hr. 
Compound Vol. (ml.) 
Na.sup.+ 
K.sup.+ 
__________________________________________________________________________ 
3-[o-Fluoro-.alpha.-(p-fluorophenyl)benyl]-6,7-dihydro-5H- 
thiazolo[3,2-a]pyrimidine hydrobromide 
21.5 2.55 
0.59 
3-(p-Methyl-.alpha. -phenylbenzyl)-6,7-dihydro-5H-thiazolo- 
[3,2-a]pyrimidine hydrobromide 
17.5 1.68 
0.63 
3-(p-Fluoro-.alpha. -phenylbenzyl)-6,7-dihydro-5H-thiazolo- 
[3,2-a]pyrimidine hydrobromide 
19.0 2.02 
0.49 
3-[p-Chloro-.alpha. -(p-fluorophenyl)benzyl] -6,7-dihydro-5H- 
thiazolo[3,2-a]pyrimidine hydrobromide 
11.5 1.50 
0.83 
3-[Bis-(p-fluorophenyl)methyl]-6,7-dihydro-5H-thiazolo- 
[3,2-a]pyrimidine hydrobromide 
17.5 2.19 
0.76 
3-(p-Fluoro-.alpha.-phenylbenzyl)-6,7-dihydro-6,6-dimethyl- 
5H-thiazolo[3,2-a]pyrimidine hydrobromide 
14.8 1.50 
0.48 
3-(p-Fluoro-.alpha.-m-tolylbenzyl)-6,7-dihydro-6,6-dimethyl- 
5H-thiazolo[3,2-a]pyrimidine hydrobromide 
15.5 1.75 
0.54 
3-[o-Chloro-.alpha. -(p-fluorophenyl)benzyl]-6,7-dihydro-6,6- 
dimethyl-5H-thiazolo[3,2-a]pyrimidine hydrobromide 
14.3 1.47 
0.55 
3-[p-Chloro-.alpha.-(p-fluorophenyl)benzyl]-6,7-dihydro-6,6- 
dimethyl-5H-thiazolo[3,2-a]pyrimidine hydrobromide 
14.2 1.74 
0.66 
3-[o-Fluoro-.alpha.-(p-fluorophenyl)benzyl]-6,7-dihydro-6,6- 
dimethyl-5H-thiazolo[3,2-a]pyrimidine hydrobromide 
14.0 1.40 
0.55 
3-[m-Fluoro-.alpha. -(p-fluorophenyl)benzyl] -6,7-dihydro-6,6- 
dimethyl-5H-thiazolo[3,2-a]pyrimidine hydrobromide 
16.8 1.73 
0.61 
3-[Bis-(p-fluorophenyl)methyl]-6,7-dihydro-6,6-dimethyl- 
5H-thiazolo[3,2-a]pyrimidine hydrobromide 
17.5 1.73 
0.53 
3-[p-Chloro-.alpha.-(p-fluorophenyl)benzyl] -5,6,7,8-tetra- 
hydrothiazolo[3,2-a][1,3]diazepine hydrobromide 
11.0 1.51 
0.71 
3-(p-Fluoro-.alpha.-phenylbenzyl)-5,6,7,8-tetrahydrothiazolo- 
[3,2-a][1,3]diazepine hydrobromide 
18.5 2.41 
0.91 
3-[o-Chloro-.alpha.-(p-fluorophenyl)benzyl] -5,6,7,8-tetra- 
hydrothiazolo[3,2-a][1,3]diazepine hydrobromide 
19.0 1.92 
0.63 
3-[Bis-(p-fluorophenyl)methyl]-5,6,7,8-tetrahydrothia- 
zolo[3,2-a][1,3]diazepine hydrobromide 
24.3 2.98 
0.72 
__________________________________________________________________________ 
The novel compounds of the present invention have thus been shown to be 
valuable diuretic agents of low toxicity when administered orally. The 
amount of a single dose or of a daily dose will vary but should be such as 
to give a proportionate dosage of from about 5 mg. to about 100 mg. per 
day for a subject of about 70 kg. body weight. The dosage regimen may be 
adjusted to provide the optimum therapeutic response, for example, doses 
of 1.0-25 mg. may be administered on a four times per day regimen, or the 
dose may be proportionately increased as indicated by the exigencies of 
the therapeutic situation. 
The compounds of the present invention may be administered as active 
components of compositions in unit dosage form such as tablets, pills, 
capsules, powders, granules, oral solutions or suspensions and the like. 
For preparing solid compositions such as tablets, the active compound is 
mixed with conventional tableting ingredients such as starch, lactose, 
sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium 
phosphate, gums and functionally similar materials as pharmaceutical 
diluents or carriers. The tablets or pills can be laminated or otherwise 
compounded to provide a dosage form affording the advantage of prolonged 
or delayed action, or predetermined successive action of the enclosed 
medication. For example, the tablet or pill can comprise an inner dosage 
and an outer dosage component, the latter being in the form of an envelop 
over the former. The two components can be separated by an enteric layer 
which serves to resist disintegration in the stomach and permits the inner 
component to pass intact into the duodenum or to be delayed in response. A 
variety of materials can be used for such enteric layers or coatings, such 
materials including a number of polymeric acids or mixtures of polymeric 
acids with such materials as shellac, shellac and and cetyl alcohol, 
cellulose acetate, and the like. A particularly advantageous enteric 
coating comprises a styrene maleic acid copolymer together with known 
materials contributing to the enteric properties of the coating. 
The liquid forms in which the compounds of the present invention may be 
incorporated for administration include aqueous solutions, suitably 
flavored syrups, aqueous or oil suspensions, flavored emulsions with 
edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, 
and the like, as well as elixirs and similar pharmaceutical vehicles. 
Suitable dispersing or suspending agents for aqueous suspensions include 
synthetic and natural gums such as tragacanth, acacia, alginic acid, 
dextran, sodium carboxymethylcellulose, methylcellulose, 
polyvinylpyrrolidone, gelatin and the like. 
The term unit dosage form refers to physically discrete units suitable as 
unitary dosages, each unit containing a predetermined quantity of active 
material calculated to produce the desired therapeutic effect in 
association with the required pharmaceutical diluent, carrier or vehicle. 
The specifications for the unit dosage forms of this invention are 
dictated by and are directly dependent on (a) the unique characteristic of 
the active material and the particular therapeutic effect to be achieved, 
and (b) the limitations inherent in the art of compounding such an active 
material for therapeutic use. 
A preferred embodiment of the present invention may be represented by 
structural formula (I) but wherein R.sub.1 is hydrogen, methyl, fluoro, 
chloro or bromo; R.sub.2 is hydrogen, methyl, fluoro, chloro or bromo; 
R.sub.3 is hydrogen or methyl; and Q is a divalent moiety of the formula: 
##STR4## 
as well as the pharmacologically acceptable acid-addition salts thereof. 
The invention will be described in greater detail in conjunction with the 
following specific examples.