ANTITHROMBOTIC THERAPEUTIC COMPOSITIONS

COMPOSES THERAPEUTIQUES POUR PREVENIR LES THROMBOSES

English Abstract

ANTITHROMBOTIC THERAPEUTIC COMPOSITIONS
ABSTRACT OF THE DISCLOSURE
This invention relates to therapeutic compositions
comprising, as active ingredients, a combination of a pyridine
derivative having an anti-blood-platelet-aggregation activity
with a derivative having beta-blocking properties, which
exhibit synergistic anti-thrombotic activity.

Claims

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:
l. A therapeutic composition comprising in combination as
active ingredients, a pyridine derivative having anti-blood-
platelet-aggregation activity and a derivative having beta-
blocking properties, said combination of active ingredients
having synergistic anti-thrombotic activity;
said pyridine derivative being selected from compounds
having the formula:
<IMG>
(I)
in which:
X represents oxygen or sulfur;
R represents a phenyl or benzoyl group which may carry
one or more substituents selected from halogen atoms and the
straight- or branched-chain lower alkyl groups, the straight-
or branched-chain lower alkoxy groups, the nitro, amino,
sulfonylamino, carboxy, lower alkoxycarbonyl, cyano, phenyl,
hydroxy(lower)alkyl, methylene-dioxy and ethylene-dioxy
groups; an alpha-naphthyl group or a thienyl group;
R1 represents a hydrogen or halogen atom or a hydroxy
group, a straight- or branched-chain lower alkyl group, a
straight- or branched-chain lower alkoxy group, or a phenyl
group;
R' represents a lower alkyl group; and
n is an integer from 1 to 15;
and the symbols R1 may have different meanings in each radical
CHR1 when n is greater than 1;
19

said beta-blocking derivatives being selected from
compounds having the formulas:
<IMG> (II)
and
<IMG> (III)
in which:
R2 is a mono- or polycyclic, carbo- or heterocyclic
radical having at least one ring of aromatic character, and
which is attached to the oxygen atom by a ring carbon atom;
R3 is hydrogen or the acyl radical of an organic
carboxylic acid; and
R4 is a substituted or unsubstituted aliphatic,
cycloaliphatic or araliphatic hydrocarbon radical; and

R5 is hydrogen or a lower alkyl radical;and
the pharmaceutically acceptable inorganic or organic acid
addition salts thereof.
2. The therapeutic composition of claim 1 wherein:
R2 is attached to the oxygen atom by a carbon atom of
an aromatic ring.
3. The therapeutic composition of claim 2 wherein R2 is a
carbocyclic radical selected from the group consisting of
phenyl and partially saturated bicyclic or polycyclic radicals.
4. The therapeutic composition of claim 3 wherein R2 is
selected from the group consisting of the naphthyl, indanyl,
and fluorene radicals.
5. The therapeutic composition of claim 1 wherein R2 is a
heterocyclic radical containing one or more nitrogen, oxygen or
sulfur atoms.
6. The therapeutic composition of claim 5 wherein R2 is a
partially saturated monocyclic or bicyclic heterocyclic radical.
7. The therapeutic composition of claim 6 wherein R2 is
selected from the group consisting of the pyridyl, pyrimidyl,
indolyl and quinolyl radicals.
8. The therapeutic composition of claim 1 wherein R2 is
substituted with a substituted or unsubstituted aliphatic or
cycloaliphatic hydrocarbon radical, an esterified or etherified
hydroxy or mercapto group, or an acyl, carboxy, nitro,
substituted or unsubstituted amino group, or an oxo group.
21

9. The therapeutic composition of claim 1 wherein R3 is a
lower alkanoyl.
10. The therapeutic composition of claim 9 wherein R3 is
benzoyl.
11. The therapeutic composition of claim 1 wherein R4 is
straight- or branch-chained lower alkyl, cycloalkyl or lower
phenyl alkyl groups.
12. The therapeutic composition of claim 1 wherein the
pyridine derivative of formula I is selected from the group
consisting of:
5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine,
(ticlopidine);
5-(3,4,5-trimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-hydroxy-2-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c}
pyridine;
5-p-chlorobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-p-chlorobenzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(3,5-dimethoxy-benzyl)3-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(3,4,5-trimethoxy-benzyl)-4,5,6,7-tetrahydro-furo[3,2-c]
pyridine;
5-(3-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-methyl-benzyl)-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(4-methyl-benzyl)-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(2-fluoro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-dichloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
22

5-(2-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-phenyl-ethyl)-4,5,6,7-tetrahydro-furo[3,2 c]pyridine;
5-(1-methyl-2-hydroxy-2-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(4-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2,6-dichloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(2-nitro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-p-hydroxyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-p-methoxyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-p-chloroyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-hydroxy-2-o-methoxyphenyl-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-hydroxy-2-m-methoxyphenyl-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(3-o-chloroyphenyl-3-hydroxy-propyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-hydroxy-3-p-nitrophenyl-propyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(3-hydroxy-3-phenyl-propyl)-4,5,6,7-tetrahydro-thieno[3,2.-c]
pyridine;
5-(2-benzoyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-o-bromobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
23

5-p-nitrobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-p-fluoroyphenyl-2-hydroxy ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2,5 dimethoxy-2-phenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine;
5-(2,3,4-trimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-benzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-dimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(3-(4-fluoro-benzoyl)-propyl]-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-o-methoxycarbonylbenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-o-carboxybenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-o-methoxycarbonylbenzyl-6-methyl-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(?-naphthyl-methyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-[(5-chloro-2-thienyl)methyl]-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[2-hydroxy-2-(2-thienyl)-ethyl]-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-o-cyanobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-methylenedioxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[2-(4-bis-phenyl)-2-hydroxy-ethyl]-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-o-hydroxy-methylbenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
24

5-benzhydryl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(l-o-chlorophyenyl-butyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(1-o-chlorophyenyl-pentyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(l-o-chlorophyenyl-propyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(l-o-chlorobenzyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c}
pyridine;
5-(l-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
13. The therapeutic composition of claim 1 wherein the
pyridine derivative is 5-(2-chloro benzyl-4,5,6,7-tetrahydro-
thieno [3,2-C] pyridine (ticlopidine) hydrochloride.
14. The therapeutic composition of claim 1 wherein the beta-
blocking derivative of formual II is selected from the group
consisting of:
l-isopropylamino-3-[(1)-naphthyloxy]-2-propanol (propranolol):
(?)l-isopropylamino-3-[4-(2-methoxy-ethyl)-phenoxy]-2-propanol
(metoprolol);
2-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl] acetamide
(atenolol);
3'-acetyl-4'-(2-hydroxy-3-isopropylamino-propoxy)-butyranilide
(acebutolol);
1-(4-indolyl-oxy)-3(isopropylamino)-2-propanol (Pindolol):
(-)-l-tert-butylamino)-3-[3-(4-morpholino-1,2,5-thiadiazol-3-yl)
oxy]-2-propanol (timolol);
l-(tert-butylamino)-3-(2-chloro-5-methyl-phenoxy)-2 propanol
(bupranolol);
(?)-5-[3-tert-butylamino)-2-hydroxy-propoxy]3,4-dihydro-2H-
naphthalenone (bunolol);

1-(2'-allyl-phenoxy)-3-isopropylamino-2-propanol (alprenolol):
and 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol
(oxprenolol).
15. The therapeutic composition of claim 1 wherein the beta-
blocking derivative of formula III is selected from the group
consisting of:
2-isopropylamino-1-(1-naphthyl)-ethanol;
2-tert-butylamino-1-(2,5 dimethoxy-phznyl)-ethanol;
1-(3,4-dichlorophenyl)-2-isopropylamino-ethanol;
2-isopropylamino-1-(4-nitro-phenyl)-propanol;
2-isapropylamino-1-(methylsulfonylaminophenyl)-ethanol;
1-(4-carbamoyl-3-hydroxyphenyl)-2-tert-butylamino-ethanol;
and 2-tert-butylamino 1-(1,2,3,4-tetrahydro-5-naphthyl)-ethanol.
16. The therapeutic composition of claim 1 wherein the
pyridine derivative having anti-blood-platelet-aggregation
activity is ticlopidine hydrochloride and the beta-blocking
derivative is selected from the group consisting of propranolol,
acebutolol, metoprolol, and antenolol.
17. A therapeutic composition in unit dosage form comprising
a therapeutically administrable carrier and as active
ingredients, a pyridine derivative having anti-blood-platelet-
aggregation activity and a derivative having beta-blocking
properties, said combination of active ingredients having
synergistic anti-thrombotic activity;
26

in which:
R2 is a mono- or polycyclic, carbo- or heterocyclic
radical having at least one ring of aromatic character, and
which is attached to the oxygen atom by a ring carbon atom;
R3 is hydrogen or the acyl radical of an organic
carboxylic acid; and
R4 is a substituted or unsubstituted aliphatic,
cycloaliphatic or araliphatic hydrocarbon radical; and
R5 is hydrogen or a lower alkyl radical; and the
pharmaceutically acceptable inorganic or organic acid addition
salts thereof.
28

said pyridine derivative being selected from compounds
having the formula:
<IMG> (I)
in which:
X represents oxygen or sulfur;
R represents a phenyl or benzoyl group which may carry
one or more substituents selected from halogen atoms and the
straight- or branched-chain lower alkyl groups, the straight-
or branched-chain lower alkoxy groups, the nitro, amino,
sulfonylamino, carboxy, lower alkoxycarbonyl, cyano, phenyl,
hydroxy(lower)alkyl, methylene-dioxy and ethylene-dioxy
groups; an alpha-naphthyl group or a thienyl group;
R1 represents a hydrogen or halogen atom or a hydroxy
group, a straight- or branched-chain lower alkyl group, a
straight- or branched-chain lower alkoxy group, or a phenyl
group;
R' represents a lower alkyl group; and
n is an integer from l to 15;
and the symbols R1 may have different meanings in each radical
CHR1 when n is greater than 1;
said beta-blocking derivatives being selected from
compounds having the formulas:
<IMG> (II)
and
<IMG> (III)
27

18. The therapeutic dosage unit of claim 16 containing about
0.05 to about 0.2 g of said pyridine derivative and about 0.01
to about 0.15 g of said beta-blocking derivative.
19. The therapeutic dosage unit of claim 17 wherein the
pyridine derivative of formula I is selected from the group
consisting of:
5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine,
(ticlopidine);
5-(3,4,5-trimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-hydroxy-2-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-p-chlorobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-p-chlorobenzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(3,5-dimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(3,4,5-trimethoxy-benzyl)-4,5,6,7-tetrahydro furo[3,2-c]
pyridine;
5-(3-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-methyl-benzyl)-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(4-methyl-benzyl)-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(2-fluoro benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-dichloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(2-phenyl-ethyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine;
5-(2-phenyl-ethyl)-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(1-methyl-2-hydroxy-2-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine,
29

5-(3-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(4-methyl-benzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine;
5-(4-fluoro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2,6-dichloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(2-nitro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(4-hydroxy-benzyl) 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine,
5-(2-p-hydroxyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-p-methoxyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-p-chloroyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-hydroxy-2-o-methoxyphenyl-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-hydroxy-2-m-methoxyphenyl-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(3-o-chloroyphenyl-3-hydroxy-propyl) -4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(1-phenyl-ethyl3-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-hydroxy-3-p-nitrophenyl-propyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(3-hydroxy-3-phenyl-propyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(2-benzoyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-o-bromobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-p-nitrobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-p-fluoroyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;

5-(2,5-dimethoxy-2-phenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine;
5-(2,3,4-trimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-benzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-dimethoxy-benzyl?-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[3-(4-fluoro-benzoyl)-propyl]-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-o-methoxycarbonylbenzyl-4,596,7-tetrahydro-thieno[3,2-c]
pyridine;
5-o-carboxybenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-o-methoxycarbonylbenzyl-6-m2thyl-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(?-naphthyl-methyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-[(5-chloro-2-thienyl)methyl] 4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[2-hydroxy-2-(2-thienyl)-ethyl]-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-o-cyanobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-methylenedioxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[2-(4-bis-phenyl)-2-hydroxy-ethyl]-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-o-hydroxy-methylbenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-benzhydryl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(l-o-chlorophyenyl-butyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(1-o-chlorophyenyl-pentyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
31

5-(l-o-chlorophyenyl-propyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyrldine;
5-(1-o-chlorobenzyl-ethyl)-4,5,6,7 tetrahydro-thieno[3,2-c]
pyridine;
5-(1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
20. The theraoeutic dosage unit of claim 17 wherein the
pyridine derivative is 5-(2-chloro-benzyl-4,5,6,7-tetrahydro-
thieno [3,2-C] pyridine (ticlopidine) hydrochloride.
21. The therapeutic dosage unit of claim 17 wherein the beta-
blocking derivative of formual II is selected from the group
consisting of:
l-isopropylamino-3-[(1)-naphthyloxy]-2-propanol (propranolol);
(?)l-isopropylamino-3-[4-(2-methoxy-ethyl)-phenoxy)-2-propanol
(metoprolol);
2-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]acetamide
(atenolol);
3'-acetyl-4l-(2-hydroxy-3-isopropylamino-propoxy)-butyranilide
(acebutolol);
1-(4-indolyl-oxy)-3(isopropylamino)-2-propanol (Pindolol):
1-(tert-butylamino)-3-[3-(4-morpholino-1,2,5-thiadiazol-3-yl)
oxy]-2-propanol (timolol);
l-(tert-butylamino)-3-(2-chloro-5-methyl-phenoxy)-2-propanol
(bupranolol);
(?)-5-[3-tert-butylamino)-2-hydroxy-propoxy]3,4-dihydro-2H-
naphthalenone (bunolol);
1-(2l-allyl-phenoxy)-3-isopropylamino-2-propanol (alprenolol);
and 1-(2-allyloxy-phenoxy)-3 isopropylamino-2-propanol
(oxprenolol).
32

22. The therapeutic dosage unit of claim 17 wherein the beta-
blocking derivative of formula III is selected from the group
consisting of:
2-isopropylamino-1-(1-naphthyl)-ethanol;
2-tert-butylamino-1-(2,5-dlmethoxy-phenyl)-ethanol;
1-(3,4-dichlorophenyl)-2-isopropylamino-ethanol;
2-isopropylamino-1-(4-nitro-phenyl)-propanol;
2-isopropylamino-1-(methylsulfonylaminophenyl)-ethanol;
1-(4-carbamoyl-3-hydroxyphenyl)-2-tert-butylamino-ethanol;
and 2-tert-butylamino-1-(1,2,3,4-tetrahydro-5-naphthyl)-ethanol.
23. The therapeutic dosage unit of claim 17 wherein the
pyridine derivative having anti-blood-platelet-aggregation
activity is ticlopidine hydrochloride and the beta-blocking
derivative is selected from the group consisting of propranolol,
acebutolol, metoprolol, and antenolol.
24. The therapeutic dosage unit of claim 23 containing about
0.05 to about 0.2 g of ticlopidine hydrochloride and about 0.01
to about 0.15 g of one of said beta-blocking derivatives.
33

Description

7~
NTITHROMBOTIC_ THERAPEUTIC COMPOSITIONS
This invention relates to therapeutic compositions having
an antithrombotic activity comprising, as active ingredients, a
combination of a derivative having anti-blood-platelet-
aggregating propert;es and of a derivative having beta-receptor
block;ng properties.
The derivative having anti-blood-platelet-aggregat.ing
properties is selected from the pyridine compounds having the
formula
~R' - - ..
~ _(CHRl)n~R (I)
in which: .
X represents oxygen or sulfur;
R represents a phenyl or benzoyl group which may carry one
or more substituents selected from halogen atoms and the
straight- or branched-chain lower alkyl.groups, the straight-
or branched-chain lower alkoxy groups, the nitro~ amino,
sul~onylamino, carboxy, lower alkoxycarbonyl, cyano, phenyl,
hydroxy(lower)alkyl~ methylene-dioxy and ethylene-dioxy groups;
an alpha-naph~hyl group or a thienyl group;
.

7~5~
Rl represents a hydrogen or halogen atom or a hydroxy
group, a straight- or branched-chain lower alkyl group, a
straight- or branched-chain lower alkoxy group, or a phenyl
graup;
R' repesents a lower alkyl group; and
n is an integer from 1 to 15;
and the symbols Rl may have different meanings in each
radical CHRl when n is greater than l;
and the pharmaceutically acceptable acid addition salts and
quaternary ammonium derivatives of said compoundsO
The terms "lower alkyl group" and lower alkoxy group" are
intended to mean groups having 1-6 carbon atoms and particularly
1-4 carbon atoms.
Non-limiting Examples of derivatives of the formula ~I)
useful in the therapeutic composition o~ this invention include:
5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,7-c]pyridine,
(ticlopidine);
5-(3,4,5-trimethoxy-benzyl)-4,5,6,7~tetrahydro-thieno[3,2-c]
pyridine;
5-(LI-methoxy-benzyl)-4,5~6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-hydroxy-2-phenyl-ethyl)-4,596,7-tetrahydro-thieno~3,2-c]
pyridine;
5-p-chlorobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-p-chlorobenzyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine;
5-(3,5-dimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c]
pyridine;
5-(3,4,5-trimethoxy-benzyl)-4,5,6,7-tetrahydro-furo[3,2-c]
pyridine;
5-(3-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[312-c]pyridine;
(2~

5-(3-methyl-benzyl)-4,5,657-tetrahydro-furo[3,2-c]pyridine;
5-(4-methyl-benzyl)-4,5,6,7-tetrahydro-furo[3,2 c]pyridine;
5-(2-fluoro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-dichloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(2-phenyl-ethyl)-4,596,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-phenyl-ethyl)-4, 5t 6,7-tetrahydro-furo[3,2-c~pyridine;
5-(1-methyl-2-hydroxy 2-phenyl-ethyl)-495,6,7 tetrahydro~thieno
[3,2-c~pyridine;
5-~2-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridirle;
5-(3-methyl-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(4-methyl-ben~yl)-4,5,6,7-tetrahydro-thieno[3,~-c]pyridineg
5-~4-~luoro-benzyl)-4,5,6,7--tetrahydro-thieno[3,2-c]pyrid.ine;
5-(2,6-dichloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-t2-nitro-benzyl)-4,5,6,7-tetrahydrn-thieno[3,2-c]pyridine;
5-(4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thienoC3,2-c~pyridine;
5-(2-p-hydroxyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahyd:ro-thieno
[3,2-c]pyridine;
5-(2-p-methoxyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-p-chloroyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2-hydroxy-2-o-methoxyphenyl-ethyl)-4,5,6,7-tetrahydro-thieno
t},2-c]pyridine;
5-(2-hydroxy-2-m-methoxyphenyl-ethyl)-4,5,6,7-tetrahydro-thieno
t3,2-c]pyridine;
5-(3-o-chloroyphenyl-3-hydroxy-propyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
(3)

5-(3-hydroxy-3~p-nitrophenyl-propyl) 4,5,6,7-te-trahydro-thieno
[3,2-c]pyridine;
5-(3-hydroxy-3-phenyl-propyl)-4,5,6,7-tetrahydro-thieno[312-c]
pyridine;
5-(2-benzoyl-ethyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-o-bromobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-p-nitrobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-t3-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-p-fluoroyphenyl-2-hydroxy-ethyl)-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-(2,5-dimethoxy-2-phenyl-2-hydroxy-ethyl)-4,556,7-tetrahydro-
thieno[3,2-c]pyridine;
5-(2,3,4-trimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c}
pyridine;
5-benzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(2-methoxy-benzyl) 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-(3,4-dimethoxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[3-(4-fluoro-ben~oyl)-propyl]-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-o-methoxycarbonylbenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-o-carboxybenzyl-4,5,6,7-tetrahydro thieno[3,2-c]pyridine;
5-o-meth~xycarbonylbenzyl-6-methyl-4,5,6,7-tetrahydro-thieno
~3,2-c]pyridine;
5-(~-naphthyl-methyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
5-[(5-chloro-2-thienyl)methyl]-4,5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-[2-hydroxy-2-(2-thienyl)-ethyl]-4,5,6,7-tetrahydro-thieno
[3,2-c]pyridine;
5-o-cyanobenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine;
(4)

f~
5-(3,4~methylenedioxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2~c]
pyridine;
5-[2-~4-bis-phenyl)-2-hydroxy-ethyl] 4,5,6,7-tetrahydro-thieno
[392-c]pyridine;
5-o-hydroxy-methylbenzyl-4,5,6,7-tetrahydro-thieno[3,2-c~
pyridine;
5-ben~hydryl-4,5,6,7-tetrahydro-thieno[3,2-c~pyridine;
5-(1-o-chlorophyenyl-butyl)-4,5~6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(1-o-chlorophyenyl-pentyl)-4,516,7-tetrahydro-thieno~3,2-c~
pyridine;
5-~1-o chlorophyenyl-propyl)-4 J 5,6,7-tetrahydro-thieno[3,2-c]
pyridine;
5-(1-o-chlorobenzyl-ethyl)_4,5,6,7-tetrahydro--thieno[3,~-c]
pyridine;
5-(1-phenyl-ethyl~ 4,5,6,7-tetrahydro-thieno[3,2-c]pyridirle;
The derivatives having beta-blocking properties are selected
from the following compounds of the formulas (II) and (~I13 and
their pharmaceutically acceptable inorganic or organic acid
addition salts.
A first family of compounds of this type is that
represented by the formula (II)
R2-0-CH2-~H-CH2-NH R4 (II)
R3
in which:
R2 represents a mono- or polycyclic, carbo- or hetero-
cylcic radical having at least one ring of aromatic character,
and which is attached to the oxygen atom by a ring carbon atom,
preferably of the aromatic ring;
(5)

5~
R~ is hydrogen OI' the acyl radical of an organic
carboxylic acid; and
R4 represents a substituted or unsubstituted aliphatic,
cyclo-aliphatic or araliphatic hydrocarbon radicàl;
and derivatiYes thereof, including the pharmaceutically
acceptable inorganic or organic acid addition salts thereo~.
The carbocyclic radicals R~ are typically phenyl
radicals, and also optionally partly saturated bicyclic (e.g.
naphthyl, indanyl) or polycyclic (e.g., ~luorene) radicals.
The heterocyclic radicals R2 may contain one or more
nitrogen, oxygen or sulfur atoms. They are optionally partly
saturated monocyclic ~pyridyl, pyrimidyl) or bicyclic (indolyl,
quinolyl) radicals.
Said radicals R2 may be substituted with at least an
optionally substituted aliphatic or cycloaliphatic hydrocarbon
radical, an optionally esterified or etheri~ied hydroxy or
mercapto group, or an acyl, carboxy, nitro, optionally
substituted amino, or oxo group.
The acyl radicals R3 are typically the corresponding
radicals of the organic carboxylic acids, particularly lower
alkanoyl or benzoyl.
The aliphatic hydrocarbon radicals R4 are typically
straight- or branched-chain lower alkyl groups; the cyclo-
aliphatic radicals are typically cycloalkyl groupsl and the
araliphatic radicals are typically lower phenylalkyl groups.
(6)

~ ~ ~7 ~5~
Non-limiting Examples of compounds of the formula (II)
useful in the therapeutic composition of this invention are
given below:
l-isopropylamino-3-[(1)-naphthyloxy~-2-propanol (propranolol):
(~)l-isopropylamino-3-[4-(2-methoxy-ethyl)-phenoxy]-2-propanol
(metoprolol);
2-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl] acetamide
(atenolol);
3'-acetyl-4'~(2-hydroxy-3-isopropylamino-propoxy)-butyranilide
(acebutolol);
1-(4-indolyl-oxy)-3(isopropylamino)-2-propanol (pindolol);
(-)-l-tert-butyla~ino)-3~[3-(4 morpholino-1,2?5-thiadiazol-3-yl)
oxy]-2-propanol (timolol);
l-(tert-butylamino)-3-(2-ohloro-5-methyl-phenoxy)-2-propano.l
(bupranolol);
(~)-5-[3-tert-butylamino)-2-hydroxy-propoxy]3,4-dihydro-2tl-
naphthalenone (bunolol);
1-(2'-allyl-phenoxy)-3-isopropylamino-2-propanol (alprenolol):
and 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol
(oxprenolol).
The second family of the cornpounds having beta-blocking
properties is that represented by.the formula ~III)
û - R3 ~5
R2- ~H - H - NH - R~ (III)
in which R2, R3, and R4 have the meanings given for the
formula (II) and R5 is hydrogen or a lower alkyl radical9 and
their pharmaceutically acceptable inorganic or organic acid
addition salts.
(7)

The compounds of the Formula (III) useful in the
therapeutic composition of this invention include particularly:
2-isopropylamino~ naphthyl)-ethanol;
2-tert-butylamino-1-(2,5-dimethoxy-phenyl~-ethanol;
1-(3,4-dichlorophenyl)-2-isopropylamino-ethanol;
2-isopropylamino-1-(4-nitro-phenyl)-propanol;
2-isopropylamino-1-(methylsulfonylaminophenyl)-ethanol;
l-t4-carbamoyl-3-hydroxyphenyl)~2-tert-butylamino-ethanol; and
2-tert-butylamino-1-(1,2,3,4-tetrahydro-5-naphthyl~-ethanolO.
The combinations of active ingredients employed in the
therapeutic compositions of this invention exhibit a
synergistic effect which will be evidenced by means of the
following illustrative, Example which gives the result~ oF a
toxicological and pharmacological investigation effected wi-th
compositions of this invention comprising, as the compound
having anti-blood-platelet-aggregating properties, ticlopidine
hydrochloride having the formula: '
C ~ ~ ~HCl
t8)

7~
and, as compouncls having beta-blocking properties:
(a) propranolol having the formula:
~ CH3
O-CH2-,,CH-CH2-N~I-CH
~H CH
(b) acebutolol having the formul~:
~H CO C 2 2 3
_CO-CH3 ~ CH3
-CH2- I H-CH2-NH-C~,
(c) metoprolol having the formula:
~3C Hz - ICH-CHz-NH - C~c H
CH CH O CH
and (d) atenolol having the formula:
~CH2-CO-NH2
~3 CH3
1-CH2- ~CH-CH2-NH- C~
(g) - -

5~
I. ~OXICOLOGICAL INVESTIGArION
__
This investigation included determinations of:
1. Acute toxicity of ticlopidine hydrochloride7 (LD50
rat/kg: p.o. 1938 mg; i.p. 291 mg; LD50 mice/kg p.o. 777 m9;
i.p. 532 mg), of propranolol; (LD50/kg : p.o. 35 mg in the
male and 45 mg in the female), of metoprolol (LD50 rat/kg:
p.o. 4070 mg; i.v. 70.1 mg; LD50 mice/kg: p.o. 2380 mg; i.v.
74.6 mg), of acebutolol and o~ atenolol (LD5n rat/kg: p.o.
3000 mg; i.v. ~ 50-60 mg; LD50 mice/kg: p.o. ~ 2000 mg, i.v.
100 mg) and of the combinations thereof of this invention.
2. Chronic and delayed toxicity.
3. Local and systemic tolerance.
It was found that the compositions of this inventionJ on
administration by gastric intubation~ are perfectly tolerated,
under the condition of the experiment without inducing any
local or systemic reactionO
The toxicities of the compositions of this invention are
the same as that of their components and, this respect~ no
potentation phenomenon was found to occur.
II. PHARMACOLOGICAL INVESTIGATION
This investigatisn concerned myocardial necrosis induced
in animals under severe stress conditions which may be
reproduced by infusion o~ adrenalin.
~ 10)

Mongrel dogs o~ either sex, weighing about 10 kg, were
distributed into 15 groups of 5 animals each: except ~or one
group of untreated dogs (controls, Group 1), the other groups
were orally administered a test material, twice a day, for l~
days, repsectively:
Group 2: 50 mgJkg ticlopidine hydrochloride
_~: 100 mg/kg ticlopidine hydrochloride
50 mg~kg ticlopidine hydrochloride
~ 5 mg/kg propranolol
Group 5 100 mg/kg ticlopidine hydrochloride
+10 mg/kg propranolol
Group 6: 50 mg~kg ticlopidine hydrochloride
~25 mg/kg acebutolol
Group 7: 100 mg/kg ticlopidine hydrochloride
+50 mg/kg acebutolol
50 mg/kg ticlopidine hydrochloride
~10 mg/kg metoprolol
Group 9 lûO mg/kg ticlopidine hydrochloride -.-
+20 mg/kg metoprolol
Group 10: 50 mg/kg ticlopidine hydrochloride
~ 5 mg/kg atenolol
Group 11: 100 mg/kg ticlopidine hydrochloride
~10 mg~kg atenolol
Group 12: 10 mg/kg propranolol
Gr~ 13: S0 mg/kg acebutolol
Group_14: 20 mg/kg metoprolol
Group 15: 10 mg/kg atenolol
(11)

Eighteen hours after the last treatment the dogs were anesthe-
tized with phenobarbltal (25 mg/kg, i.v.~; a catheter was placed
in the femoral artery, the blood pressure was recorded via a
STAHAM P 23 GD sensor and the ECG was recorded (Dl and D2)
with a RACIA polygraph. The adrenalin was inFused by the
cephalic route at a dosage of 4 ~L g~kg/mn at a rate of 2 ml/mn
for 4 hours.
Arterial blood samples were taken before and after the end
of the infusion, to effect the blood-platelet counts.
The animals were freed ~rom the catheters and were allowed
to wake up. The animals which survived 7 days later were sacri-
ficed and autopsied; the hearts were cut out and examined macro-
scopically prior to taking samples for histological examination.
Any macroscopic anomalies are rated according to the ~ollowing
code (~able I) which was established arbitrarily and which takes
into account the extent of the damages (p. 13).
~12)

7~g
o~,l
o
.~1 ,_1 ~ ~ r~l ~ ~ ~ ~ ~
E h .
tll E C.)
U~:C ~
... , ... ,.. o~
U
h ~n
o N N N N N N N N N
E E-~-l
O ~) O
. U15::Q .
.... ...................... ..................
.,~
O h
h O ~ t~ ~r~r~ r~ r~
E E~l
~ q) o
;~: C Q
...... ,........ ~
.~
LL~ ~
C~ h ~ ~ ~ ~ ~ ~ ~ ~ ~ ~_
I_ h F a)
h
:. : ...............................................
~.C.) ,.
h h u~
E
1~ r .
..............................................
a)~ a~ a~, ~ ~
~ ~ ~ u ~ ~ c~ a
+) E C) ~ 1 o~1) ~1 h ~--1 o ~1 h ~1
:~ E ~ ~ C) ~1 h ~) ~.) ~1
O. ~ :~ ~ C ~1 h +~ C ~1 h
o ~1 c a) h ~ C a) ~ ~
> ~ > ~ ~a a) > ~ t~
U ~ S ~ S +~ S ~ S
x f~ n
LL a~ 1 ~ ~ ~ r~
C~ J ~ J ~ J ~: J
~ .
f~ tn .
> ~l ~
h
O X `
W V

5~
The following results were obtained:
Blood-platelet count
.
The blood-platelet count e~fected immediately prior to
and after adrenalin infusion shows a 32.4% decrease in the
controls (Group 1). In contrast, in the treated anirnals, the
count tends to increase, with the exception, however~ of those
which were administered only beta-blocking compounds:
Group 2: + 14.0% ~ + 15.5%
Group 3: + 13.2% Group 11:+ 18.2%
Group 4: ~ 18.0% ~ 20.0%
+ 20.0% Gro~p 13:- 24.1%
+ 17.0% ~ 17.4%
Group 7: + 19.5% ~ 27.6%
Group 8: + 15.1%
Grou~ 9: + 16.~%
Survival Time:
,
The number of animals that survived on the 7th day after
adrenalin per~usion is reported below:
Group 1: 2~5 Grou~ :4/5
Group 2: 3/5 Group 11:5J5
Group 3: 4/5 ~ : 2/5
Gro_e_~: 4/5 Group 13:2/5
Group 5 5/5 Group 14:2/5
Group 6: 4/5 Group 15:2/5
Group 7- 5/5
Group 8: 4/5
Group 9- 5/5
(14)

Macroscopic Lesions:
It is found that the treated animals reach necrosis
scores (calculated according to the above Table) of a markedly
lesser magnitude than the controls; the necrosis scores of the
animals administered only beta-blocking compounds are
substantially identical with those of the controls:
_rou~ 1:18.0 Group 10: 2.6
Group 2: 6~8 Group 1]: 1.0
Group 3: 4.8 Groue 12:15.4
Group 4: 2.8 Group 13:19.6
Group_5 2 2 Group_14:16.1
.
Groue~ .7 Group 15: 13.4
Group 7:~.4
Groue 8:3 0
.
Grou~ 9: 1.8
It may be concluded, frorn the set of results obtained, that in-
travenous perfusion of adrenalin induces in the controls serious
disorders which are essentially shown by a drop of the number
of blood-platelets and by a myocardial involvement o~ necrotic
type. In contrast, pretreatment with ticlopidine hydrochloride
provides significant protection against myocardia necrosis,
improves the survival time and increases the number of blood-
platelets. Said results are enhanced when ticlopidine
hydrochloride is combined with a beta-blocking material, both
products thus functioning according to a synergistic e~fect. It
should be noted that the beta-blocking materials, when adminis-
tered individually, have no effect on the blood-platelet count
which is found to decrease, on the survival time which is iden-
tical with that of the controls, and on the macroscopic lesions
which are substantially identical with those of the controls.
(15)

~ 7~3
The pharmacological investigation reported above shows
the usefulness of the combination of a compound having
anti-blood-platelet-aggregating properties with a- compound
having beta-blocking properties, said combinations exhibiting
valuable antithrombotic properties.
In view of this antithrombotic activityl the combination
of this invention may be advan~ageously used in human and
veterinary medicine.
The active lngredients are generally used together with a
therapeutically administrable carrier. Thus, the cornposition
of this invention may advantageously be formulated as tablets,
coated tablets or capsules for oral administration, and as sup-
positories for rectal administration. Generally, each un;t dose
will contain 0.05-0.200 g of anti-blood-platelet-aggregating
material. and Ø010-O.lS0 g of beta~blocking material.. The
daily dosage regimen may vary from 0.05 g to 1 9 for the
anti-blood-platelet-aggregating material and from 0.010 9 to
0.600 9 for the beta-blockiny material.
Non-limiting Examples of pharmaceutical formulations of
the compositions of this invention are given below:
1. Tablets
Ticlopidine hydrochloride . . . . . . 0.200 g
Propranolol . . . . . . . . . . . . . 0.030 g
Excipients: starch, lactose, stearic acid, talc,
sufficient to make one 0.400 g tablet.
(16)

2 Coated Tablets
.
Ticlopidine hydrochloride O . . . . 0.150 g
Acebutolol . . . . . . . . . . . . . 0.150 9
Excipients: corn starch, dicalcium phosphate, shellac,
gelatin, granulated sugar1 talc, titanium dioxide,
carnauba wax, sufficient to make one 0.650 g coated
tablet.
3 Capsules
.
Ticlopidine hydrochloride . . . . . . 0.180 9
Propranolol . . . . . . O . . . . . . 0.025 9
Excipient5: stearic acid,`talc, suffic;ent to make one
capsule.
4~ Capsules
Ticlopidine hydrochloride . . . . . . 0.150 9
~cebutolol . . . . ~ . . . . . . . . 0.150 g
Excipients: talc, stearic acid, sufficient to make
- . .
one capsule.
5. Capsules
Ticlopidine hydrochloride . . . . . . 0.200 9
Metoprolol . O . . . . . . . . . . . 0.150 9
Excipients: talc, lactose, sufficient to make one
capsule.
.
6. Capsules
Ticlopidine hydrochloride . . . . . . 0~180 9
Atenolol . . . . . . . . . . . . . . 0.025 g
Excipients: talc, stearic acid, sufficient to make one
capsule.
tl7)

~7~
In view of their antithrombotic properties, the
compositions of this invention reduce the risk of accidents in
patients suffering from thrombo-embolic diseases.
Therefore, the compositions are applicable for preventîve
or curative purposes 9 in accidents related to a thrombotic
process, particularly ~hen the latter involves the
blood-platelets in their devel~opment; the compositions of this
invention are particularly use~ul in patients in which-there is
a risk of development or of relapse of a coronary or cerebral
ischemic acc;dent or of any vascular ischemic episode.
(18)