Method for inhibiting blood-platelet aggregration with .beta.-naphthoquinone compounds

A method of inhibiting blood-platelet aggregation in warm-blooded animals comprising administering to warm-blooded animals a blood-platelet aggregation inhibiting effective amount of a compound selected from the group consisting of a compound of the formula ##STR1## wherein R is selected from the group consisting of --NH--CO--NH.sub.2, --NH--CO--CH.sub.3, --OH and their non-toxic, pharmaceutically acceptable acid addition salts.

French BSM patent No. 924 M describes the use as medicaments of 
.beta.-naphthoquinone derivatives due to their having hemostatic 
properties and vitamin properties. It is known that blood-platelets 
interact with the coagulation factors and the components of the vascular 
wall to play an essential and favorable role in the maintenance of 
vascular integrity, in hemostasis and, on the other hand an unfavorable 
role, in the initiation of thromboses and in the development of 
atherosclerosis. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide a novel method for inhibiting 
blood-platelet agglomeration in warm-blooded animals, including humans. 
This and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel method of the invention for inhibiting blood-platelet aggregation 
in warm-blooded animals comprises administering to warm-blooded animals a 
blood-platelet aggregation inhibiting effective amount of a compound 
selected from the group consisting of a compound of the formula 
##STR2## 
wherein R is selected from the group consisting of --NH--CO--NH.sub.2, 
--NH--CO--CH.sub.3, --OH and their non-toxic, pharmaceutically acceptable 
acid addition salts. 
Examples of suitable acids for the preparation of the non-toxic, 
pharmaceutically acceptable acid addition salts are inorganic acids such 
as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, 
sulfuric acid and phosphoric acid and organic acids such as propionic 
acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, 
tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, 
alkanesulfonic acids such as methanesulfonic acid and arylsulfonic acids 
such as benzenesulfonic acid. 
Among the preferred compounds of the formula I are those where R is 
--NH--CO--NH.sub.2, those wherein R is --NH--CO--CH.sub.3 and those 
wherein R is --OH. Especially preferred is 
1,2-naphthoquinone-2-semicarbazone. 
The compound may be administered orally, rectally or parentally and may be 
in the form of tablets, dragees, gelules, capsules, suppositories and 
injectable solutions. Examples of suitable pharmaceutical carriers are 
talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, 
aqueous or non-aqueous vehicles, fatty substances of animal or vegetable 
origin, various wetting, dispersing or emulsifying agents, and 
preservatives. 
Due to their remarkable blood-platelet aggregation inhibiting properties, 
the .beta.-naphthoquinones of formula I are useful in the treatment or the 
prevention of arterial thrombotic complications (cerebral vascular injury, 
myocardial infarction) or venous thrombotic complications (phlebitis) and 
any vascular injury connected with atherosclerosis (in particular 
cerebral), in the treatment and the prevention of ischemic injuries, in 
the treatment of blood-platelet disorders. The usual daily dose depending 
on the product, the patient treated and the illness in question can be 
0.01 to 1.3 mg/kg. The compounds of formula I are known and can be 
prepared by the process in French patent No. 2,103,504. 
In the following examples, there are described several preferred 
embodiments to illustrate the invention. However, it is to be understood 
that the invention is not intended to be limited to the specific 
embodiments.

EXAMPLE 1 
Tablets were prepared containing 10 mg of naftazone and sufficient 
excipient of lactose, starch, talc and magnesium stearate for a tablet of 
150 mg. 
EXAMPLE 2 
An injectable solute was prepared containing 5 mg of naftazone and sterile 
aqueous excipient for a value of 2 ml. 
EXAMPLE 3 
8.6 g of naftazone were introduced into 200 ml of acetic anhydride and 
after heating for 10 hours at 140.degree. C., then cooling, filtration is 
carried out. The precipitate was extracted with chloroform, followed by 
evaporation to dryness, taking up in ethanol, passing through activated 
charcoal, filtration and slow crystallization to obtain 5.1 g of product 
of formula I with R=--NH--CO--CH.sub.3 as a yellow ocher micro-crystalline 
powder melting at 137.degree.-138.degree. C. 
PHARMACOLOGICAL STUDY 
I--Inhibition of blood-platelet aggregation 
At present, many compounds are capable of inhibiting the blood-platelet 
functions but only two, aspirin and ticlopidine, have a recognized 
pharmacological activity: inhibition of blood-platelet aggregation. 
Naftazone was compared with ticlopidine and aspirin in a rat and a second 
time, in vitro on rat and human blood-platelets. 
In vitro 
The aggregation of human or rat blood-platelets isolated from their plasma 
and stimulated by ADP or thrombin in the presence of different 
concentrations of naftazone (10.sup.-4 M to 10.sup.-8 M) was importantly 
and significantly reduced. It is approximately on the order of 70 to 20% 
for naftazone concentrations ranging from 10.sup.-4 M to 10.sup.-6 M, 
respectively. 
Ex vivo 
The effect of naftazone compared with aspirin and ticlopidine in a rat, 
after repeated injections of 10 mg/kg/day of each of the products, allowed 
an important and significant inhibition of blood-platelet aggregation 
induced by ADP or thrombin to be demonstrated (table 1). 
______________________________________ 
Plasma rich 
in platelets Washed platelets 
Group (n) Thrombin ADP Thrombin 
ADP 
______________________________________ 
D Naftazone (6) 
32.9 .+-. 7.7.sup.b 
20.6 .+-. 
24.3 .+-. 
20.7 .+-. 
5.6.sup.c,d 
18.8.sup.a,b,c,d 
19.2.sup.a,b,c,d 
______________________________________ 
The results of the aggregation induced by thrombin or ADP are expressed 
(average.+-.S.D.) as a percentage of optical transmission. The numbers of 
the same column modified by the same letter are significantly different 
(p&lt;0.05 at minimum)according to the Newman-Keuls test after analysis of 
the variance. These results show that, under the experimental conditions 
used, naftazone significantly inhibited blood-platelet aggregation induced 
by ADP or thrombin. This inhibition, revealed in vitro on human or rat 
blood-platelets, was confirmed in a rat. Furthermore, this effect was 
equivalent to that revealed with ticlopidine and aspirin under the same 
conditions. 
Various modifications of the method of the invention may be made without 
departing from the spirit or scope thereof and its should be understood 
that the invention is intended to be limited only as defined in the 
appended claims.