DERIVES DU BENZOFURANNE, PROCEDE DE FABRICATION ET APPLICATIONS THERAPEUTIQUES

BENZOFURAN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE.
This invention relates to compounds having the
general formula :
<IMG>
in which <IMG> is selected from :
a radical <IMG> in which R'1 is hydrogen
and R'2 is selected from hydrogen; C1-6 alkyl: C2-6 alkenyl;
C2-6 alkynyl; phenyl; phenyl C1-6 alkyl; mono-, di- and tri-
methoxyphenyl C1-6 alkyl; C1-6 alkoxy; benzyloxy; di-
C1-6 alkylamino-C1-6 alkyl; C1-6 hydroxyalkyl; C1-6 alkyl-
oxycarbonyl-C1-6 alkyl;
a radical <IMG> in which R"1 and R"2 are
C1-6 alkyl;

a radical <IMG> in which n is selected from 4, 5
and 6;
the radical <IMG> ; and
the radical <IMG>,
and their pharmacologically acceptable inorganic and
organic acid addition salts.
Said compounds are therapeutically useful for
the treatment of dysrhythmia.

Revendications

- 14 -
Having now described our invention what We
claim as new and desire to secure by Letters Patent is:
1. Process for the preparation of compounds
of the formula :
(I)
<IMG>
in which <IMG> is selected from :
a radical <IMG> in which R'1 is
hydrogen and R'2 is selected from hydrogen; C1-6 alkyl;
C2-6 alkenyl; C2-6 alkynyl; phenyl; phenyl C1-6 alkyl;
mono-, di- and tri-methoxyphenyl C1-6 alkyl; C1-6 alkoxy;
benzyloxy; di- C1-6 alkylamino-C1-6 alkyl; C1-6 hydroxy-
alkyl; C1-6 alkyloxycarbonyl-C1-6 alkyl;
a radical <IMG> in which R"1 and R"2 are
C1-6 alkyl;
a radical <IMG> in which n is selected
from 4,5 and 6;
the radical <IMG> ; and

- 15 -
the radical <IMG> ,
or of their pharmacologically acceptable acid
addition salts, comprising :
a) reacting an acrylate having the formula :
<IMG> (III)
with nitromethane, in the presence of a strong base,
to give a nitro ester having the formula :
<IMG>
(IV)
b) reducing the resulting nitro ester,
by hydrogenation in the presence of a catalyst, to give
an amino-ester which is cyclized by heating to a
pyrrolidin-2-one having the formula :
<IMG> (V)
c) reacting the resulting pyrrolidin-2-one
with triethyloxonium tetrafluoborate within an inert
solvent, to give an 2-ethoxy-pyrroline having the
formula :

- 16 -
<IMG> (VI)
d) reacting the resulting 2-ethoxy-pyrroline
with an amine having the formula HNR1R2 in which R1 and
R2 are as defined above, to give a compound of the
formula (I), and
e) optionally converting the resulting compound
to a salt.
2. Process as claimed in claim 1, wherein,
to prepare the compound of the formula (III), 2-formyl-
benzofuran is reacted with carbethoxymethylidene-triphenyl-
phosphoran under Wittig reaction conditions.
3. Process as claimed in claim 1, comprising
reacting a compound having the formula VI with an amine
having the formula HNR1R2 in which R1 and R2 are C1-6
alkyl groups.
4. Process as claimed in claim 1, comprising
reacting a compound having the formula VI with
dimethylamine.
5. Compounds having the formula :
(I)
<IMG>

- 17 -
in which <IMG> is selected from :
a radical <IMG> in which R'1 is hydrogen and
R'2 is selected from hydrogen; C1-6 alkyl; C2-6 alkenyl;
C2-6 alkynyl; phenyl; phenyl C1-6 alkyl; mono-, di- and tri-
methoxyphenyl C1-6 alkyl; C1-6 alkoxy; benzyloxy; di-
C1-6 alkylamino-C1-6 alkyl; C1-6 hydroxyalkyl; C1-6 alkyl-
oxycarbonyl-C1-6 alkyl;
a radical <IMG> in which R"1 and R"2 are C1-6 alkyl;
a radical <IMG> in which n is selected from 4, 5
and 6;
the radical <IMG> ; and
the radical <IMG> ,
and their pharmacologically acceptable acid addition
salts when prepared by a process as claimed in claim
1 or an obvious chemical equivalent thereof.
6. 2-Di-(C1-6 alkyl)amino-4-(2-benzofuryl)-
.DELTA. -1-pyrrolines and their pharmacologically acceptable
acid addition salts, when prepared by a process as
claimed in claim 3 or an obvious chemical equivalent
thereof.
7. 2-Dimethylamino-4-(2-benzofuryl)-.DELTA.-1-
pyrroline and its pharmacologically acceptable acid
addition salts when prepared by a process as claimed
in claim 4 or an obvious chemical equivalent thereof.

Description

-- 1 --
DESCRIPTION
T I T L ~ :
" NEW BENZOFURAN D~RI~TIV~S, PROCESS FOR THEIR PREPARATION
AND THEIR TEIERAPEUTIC APPLICATIONS "
This invention relates to new benzofuran derivatives,
to a process for their preparation and to their therapeutic
applications.
This invention relates to compounds having -the general
formula :
l (I)
N N
: \ R2
in which - N / Q 15 selected from : a radical - N
~ O
R2 R~2
in which R'1 is hydrogen and R'2is selected from hydrogen;
Cl_6 alkyl; C2_6 alkenyl; C2_6 alkynyl; phenyl; phenyl Cl 6
alkyl; mono-, di- and tri-methoxyphenyl Cl 6 alkyl; Cl 6
alkoxy; benzyloxy; di- Cl 6 alkylamino-Cl 6 alkyl; Cl_6 hy~x~y-
alkyl; Cl 6 alkyloxycarbonyl-Cl_6 alkyl;
R"
a radical - N in which R"l and R"2 are Cl_6 alkyl;
R"
~_~ 2
a radical - N ~C~2)n in which _ is selected from 4,5
__~ and 6;
the radical - N O; and
the radical - N~_~N-CH3,
and their pharmacologically acceptable inorganic and organic
acid addition salts.
25 The salts may typically be those formed with hydrochloric,
: sulfuric, phosphoric, methane-sulfonic, malelic, succinic,
pa~oic, acetic, fumaric, lactic, aspartic and citric acids.
~h
' q~

~ 4f~ ~
The compounds of the formula (I) may be prepared
according to the follo~ing scheme :
+(C H ) P~OC2H ~ =CH
CHO __6 5 3 5 ~ ~X~ 2 5
(II) (III)
+CH3N02 ~ ~ ~
+ base ~ O CH-CH2COOC2H5 +cat~ ~ ~ O ~
(IV) CH2N2 (V) ~NH ~ o
H~4 O (C2H5)3 ~ +H~
(Vl~ N OC2H5 (I)
The first reaction comprises reacting 2-formylbenzo-
furan (Bull. Soc. Chim. France 1962, p.l875) with carb-
ethoxy-methylidene-triphenyl-phosphoran, under the usual
conditions for the conventional Wittig reaction, within
an inert solvent such as benzene or toluene.
This reaction provides ethyl 3-(2-benzofuryl)acrylate
(III) which has already been disclosed by Foo Pan and
Tsan Ching Wang (J. Chinese Chem. Soc. 1961, series II,
' 8, 374-9).
The resulting acrylate (III) is then reacted with
nitromethane (generally used as solvent for the reaction)
in the presence of a strong base such as Triton B(+) (benzyl-
trimethyla~monium hydroxide) or of a metal alkoxide suchas sodium ethoxide or methoxide, to give the nitro ester
(IV). The reaction may also be effected in another
solvent such as dimethylformamide.
The nitro ester (IV) is reduced by hydrogenation,at
ordinary pressure in the presence of a catalyst such as
Raney nickel within a solvent such as ethanol : the inter-
__________________________________________________________
(+) trade mark.

3 --mediately formed amino-ester is cyclized by heating to
pyrrolidin-2-one (V).
Pyrrolidinone (V) is treated with triethyloxonium
tetrafluoroborate within an inert solvent such as methyl-
ene chloride and converted to 2-ethoxy-pyrroline (VI).
The latter is reacted with an amine HNRlR2 within a
solvent such as ethanol, to give 2-amino-pyrroline (I),
which, if desired, is then converted to a salt according
to the usual procedures. In the case of volatile amines,
these may be used as the hydrochlorides, to give directly
the hydrochlorides of 2-amino-pyrrolines (I).
The following non-limiting Examples are given to
illustrate the present invention.
EXAMPLE 1
( ) 1 R2 H
a) Ethyl 3-(2-benzofuryl)acrylate (III)
A mixture of 35 g (0.24 mole) 2-formyl-benzofuran (II)
and 83.5 g (0.24 mole) carbethoxymethylidene-triphenyl-
phosphoran in 300 ml benzene is refluxed under a nitrogen
atmosphere for 7 hours. After evaporation to dryness,
under reduced pressure, the residue is triturated with
ether, suction filtered, and recrystallized from isopro-
pyl ether.
M.p. (inst.) = 78C. Yield : 100%.
- 25 The resulting product may contain some triphenylphos-
phine oxide formed in the course of the reaction. It may
be stripped therefrom by distillation (B~p~o 2 = 126C or
B~p~o 5 = 140C (YieId = 80%).
b) Ethvl 4-~itro-3-(2-benzofuryl)butyrate (IV)
51.8 g (0.24 mole) of derivative (III) obtained in
a) above, 61 g (1 mole) nitromethane and 10 ml Triton B
(4~% solution in methanol) are heated to 70-90C for 16-24
hours. After cooling and slow acidification with normal
hydrochloric acid, the nitro ester is extracted with
ether, washed with water, dried over anhydrous sodium

sulfa~e. Evaporation of the ether leaves an oily nitro-
ester residue which is purified by flash distillation.
B-P-o l = 150C or B.P.o 6 = 178C.
The head fractlons containing unreacted ester (III)
may be recycled to another operation (Average yield for
3 successive operations : 69%).
c) 4-(2-Benzofuryl)py_r_lidin-2-one (V)
Ester (IV) (81.5 g; 0.297 mole) obtained in b) is dis-
solved in 500 ml ethanol and hydrogenated at ordinary
pressure at 55C, in the presence of 10 g Raney Nickel.
The hydrogen required for the reaction (14.8 1) is taken
up within 7 hours. After filtration of the catalyst and
evaporation of the ethanol, the oily residue is heated
at 100C under the vacuum of a water pump, for 2 hours.
On trituration with isopropyl ether, the product crystal-
lizes. M.P. (inst.) = 142C. Weight : 47.9 g (80%).
d) 2-Ethoxy-4-(2-benzofur~ -l-pyrroline (VI).
8 g (0.04 mole) 4-(2-benzofuryl)pyrrolidin-2-one (V)
and 12 g (0.06 mole) triethyloxonium tetrafluoroborate
are dissolved in 80 ml methylene chloride and stirred for
a period of time of one week at ordinary temperature. The
mixture is then hydrolyzed by addition of 15 g potassium
hydroxide dissolved in 30 ml water. The insoluble is fil-
tered off and the organic phase is washed with water,
dried over sodium sulfate, and distilled. B.P.o 3 = 128-
130C. Weight : 5.9 g (64%).
e) 2-Amino-4-(~2-benzofuryl) ~-l-pyrroline hydrochloride
The 5.9 g (0.025 mole) of derivative (VI) obtained in
the preceding reaction are dissolved in 50 ml ethanol,
30 with 1.36 g (0.025 mole) ammonium chloride. The desired
hydrochloride of the amino derivative crystallizes on
~ooling. It is~suction filtered and dried in vacuo.
.p. ~inst.) = 253C. Weight : 4 g (42%).
EXAMPLE 2
(I) Rl = H; R = CH
.
,

`g
2-Methylamino-4-(2-benzofuryl)~ -l-pyrroline hydrochloride
The above compound is obtained in the same manner as the
derivative (I) of Example 1, by action of methylamine
hydrochloride on 2-ethoxy-4-(2-benæofuryl)~ -1-pyrroline
(VI), within boiling ethanol. The solution is then evapo-
- rated to dryness and the resiclue is taken up into hot
ethanol. After addition oE ethyl acetate and stirring
for 24 hours at ordinary temperature, the precipitate
is suc~ion filtered and dried. M.p. (inst.)= 151C.
Yield : 45%.
EXAMPLE 3
(I) Rl = H; R2 = iC3H7
2-Isopropylamino-4-(2-benzofuryl) ~-l-pyrroline hydrochloride
The above compound is obtained in the same manner as
the derivative (I) of Example 1, by action of isopropyl-
amine hydrochloride on derivative (VI) within boiling
ethanol. After evaporation of the solvent, the residue is
taken up into hot isopropanol : the desired hydrochloride
crystallizes on addition of isopropyl ether followed by cooling.
- 20 M.p. (inst.) = 186C. Yield : 66%.
. EXAMPLE 4
; (I) Rl = R2 = CH3
2-Dimethylamino-4--(2-benzofuryl) ~ -l-pyrroline
hydrochloride
The above compound is obtained in the same manner as
the derivative (I) of Example 1, by action of dimethyl-
~ amine hydrochloride on 2-ethoxy-4-(2-benzofuryl)~ -1-
-~ pyrroline (VI) within hot ethanol. After evaporation to
dryness and taking up with isopropanol, the hydrochloride
crystallizes on addition of ether.
M.p. (inst.) = 154C. Yield : 84%.
:'
~j, ' .

,}~ 9
EXAMPLE 5
(I) Rl = R2 C2 5
2-Diethylamino-4--(2-benzofuryl ? ~ -1 -pyrroline fumarate
The hydrochloride is obtained by the procedure of
the preceding Examples, by action of diethylamine
hydrochloride on derivative (VI), within boiling ethanol
(20 hrs). After evaporation of the solven-t, the
residue is taken up into chloroform, after which the
solution is washed with N sodium hydroxide and then with
water. The oily residue remaining after evaporation
of the chloroform is distilled under reduced pressure.
B~p~o 1 = 162-168C.
The resulting base is dissolved in propanol,with the
stoichiometric amount of fumaric acid, in the hot. The
fumarate -crystallizes on cooling.
M.p. (inst.) = 154C. Yield : 35%.
EXAMPLE 6
(I) Rl = H; R2 = C H
2-Anilino-4-(2-benzofuryl)~ -1-pyrroline hydrochloride
The base is prepared by action of excess aniline on
derivative (VI), within refluxing ethanol (48 hrs).
After evaporation under reduced pressure, the residue
is taken up into ethyl acetate, within which the base
crystallizes on stirring.
The above base is converted to the hydrochloride by
addition of a solution of anhydrous HCl in ethanol to a
solution of the base in isopropanol, in the hot. The
hydrochloride crystallizes on cooling.
- M.p. (inst.) = 203C. Yield : 58%. -
- 30 EXAMPLE 7
; R2 CH2CH2C6H5
2-Phenethy~_mino-4-(2-benzofuryl) ~-l-pyrroline
hydrochloride
The base is obtained as that of the derivative of
Example 6j from phenethylamine within ethanol, and is
-:

g~
then converted to the hydrochloride. M.p. (inst) =
121C. Yield : 62%.
EXAMPLE 8
(I) Rl - R2 (CH2)4
2-Pyrrolidino~4-(2-benzofuryl) ~-1-pyrroline
hydrochloride
The above compound is obtained in the same manner as
the derivative (I) of Example 1, by action of pyrrolidine
hydrochloride on derivative (VI), within hot ethanol.
After evaporation of the solvent and re-dissolution in
hot isopropanol, the hydrochloride crystallizes on
addition of isopropyl ether and cooling.
M.p. (inst.) = 260C. Yield : 84~.
EXAMPLE 9
) 1 R2 -(CH2)2 ~ ~ (CH2)2 ~
2-Morpholino-4-(2-benzofuryl) ~-1-pyrroline hydrochloride
The above compound is obtained in the same manner
as the derivative (I) of Example 1, by action of
morpholine hydrochloride on derivative (VI) within hot
ethanol, followed by recrystallization from isopropanol.
M.p. (inst.) = 195C. Yield : 81%.
EXAMPLE 10
.
CH3
(I) Rl - R2 = -(CH2)2-N-(CH2)2-
2-(4-Methyl-piperazino)-4-_(2-benzofuryl) a -1-pyrroline
methanesulfonate
The above compound is obtained in the same manner as
the derivative (I) of Example 1, hy action of N-methyl-
piperazine on derivative (VI) within ethanol, in the hot.
After evaporation under reduced pressure, the residue is
triturated with petroleum ether, suction filtered and
dried. M.p. (inst.) = 124.5C. Yield = 58%.
The base is converted to the methanesulfonate by
addition of a slight deficiency of methanesulfonic acid,
within ethyl acetate, and stirring for 3 hrs. The insolu-
ble salt is suction filtered and dried. M.p. 146C.Yield : 79.5%.
'~

L~
EXAMPLE 11
(I) Rl = H; R2 = CH2CH2N(CH3)2
2-(2-Dimethylamino-ethyl)-4-(2-benzoEury~ pyrroline
dihydrochloride
The above compound is obtained in the same manner as
the derivative of Example 6, by action of 2-dimethylamino
ethylamine on derivative (VI), in the hot, within ethanol,
followed by conversion of the base -to the dihydrochloride,
within isopropanol. The dihydrochloride crystallizes on
cooling. M.p. (inst.): 240C. Yield : 52%.
EXAMPLE 12
(I) R = H; R2 = OC2H2C6H5
2-Benzyloxyamino-4~(2-benzofuryl) ~ pyrroline
hydrochloride
- 15 The above compound is obtained in the same manner as
the derivative (I) of Example 1, by action of benzyloxy-
amine hydrochloride on derivative (VI) within ethanol, in
the hot. After evaporation of the solvent and re-dissolution
in hot isopropanol, the hydrochloride crystallizes on
addition of isopropyl ether and cooling.
M.p. (inst.) = 183C. Yield : 39~.
EXAMPLE 13
(I) Rl = H; R2 = OCH3
2-Methoxyamino-4-(2-benzofuryl) ~-l-pyrroline
hydrochloride
The above compound is obtained in the same manner as
the derivative (I) of Example 1, by action of 0-methyl-
hydroxylamine hydrochloride on derivative (VI) within
hot ethanol. M.p. (inst.) = 184C (with dec.).Yield = 67~.
EXAMPLE 14
(I) Rl = H; R2 = CH2CH=CH2
2-Allylamino-4-(2-benzofuryl) ~-l-pyrroline hydrochloride
The above compound is obtained in the same manner as
the derivative (I) of Example 6, by action of allylamine
on compound (VI), within hot ethanol. After evaporation

L~.r~
to dryness, the residue is converted to the hydrochloride
by addition of a solution of MCl in anhydrous ether.
M.p. = 160C. Yield : 98%.
EXAMPLE 15
. .
1 i 2 CH2C _ CH
2-Proparqvlamino-4-(2-benzofuryl) ~-l-p~rroline
hydrochloride
The above compound is obtained in the same manner as
the derivative (I) o~ Example 1, by action of propargyl-
amine hydrochloride on compound (VI), wi-thin hot ethanol.
After evaporation of the solvent, the residue is recrys-
tallized from isopropanol. M.p. = 196C. Yield : 75%.
EXAMPLE 16
.
~OCH3
(I) Rl = H; R2 = CH2CH2 ~ OCH3
2-(3!4-Dime ~ enethylamino)-4-(2-benzofury~
pyrroline hydrochloride
:
The above compound is obtained in the same manner as
the derivative (I) of Example 1, by action of 2-(3,4-
dimethoxy-phenyl)ethylamine hydrochloride on compound
(VI) within hot ethanol. After evaporation of the solvent,
the residue is recrystallized from isopropanol.
M.P. = 180C. Yield : 76%.
EXAMPLE 17
.
R2 CH2CH20H
2-(2-~ydroxy-ethylamino)-4-(2-benzofuryl)-~ -l-pyrroline
hydrochloride
The above compound is obtained in the same manner as
the derivative (I) of Example,6, by action of ethanola-
mine on compound (VI) within hot ethanol. The base isola-
ted after evaporation of the ethanol (M.p.=130C.Yield :69~) is converted to the hydrochloride with a solu-
tion of HCl in anhydrous ether. M.p. = 171C. Yield : 82%.
EXAMPLE 18
. . .
(I) Rl = H; R2 = CH2COoc H
2-(2-Ethoxycarbonyl-ethvlamino)-4=(2-benzofuryl)~ -1-

~L~
-- 10 --
pyrroline hydrochloride
-
The above compound is obtained in the Came manner as
the derivative (I) of Example l, by action of ethyl 2-
amino-acetate hydrochioride on compound (VI), within hot
ethanol. M.p. = 168C. Yield : 69~.
The compounds of the formula (I) exhibit useful
pharmacological properties, particularly in the cardio-
vascular field : increase of the arterial rate o~ flow
and antidysrhythmic action. Their toxicity appears only
at dosages greatly in excess of the pharmacologically
active dosages, which permits their therapeutic use as
drugs for the treatment of dysrhythmias and the improve-
ment of blood circulation.
Results of toxicological and pharmacological in-
vestigations which demonstrate said properties arereported below.
a) Acute toxicity in mice
Each compound was administered orally, intra-
peritoneally, or intravenously as a single dose. The
behavior of the animals and the death rate were observed
for several hours after the treatment, and then daily
for at least one week. The results obtained are given in
Table I below.
T A B L E
Example}L35o, p-o- ¦L~50, i-p-¦LD50'
I ______~____________~____ ----------~------ ~~~~ --1--------------~ --~~~~~-- I :
I 1 ! 115 mg/kg 1 58 mg/kg 1 46 mg/kg IVa~ilation
I ______ ___ _ __ I_______------~------------ --------t----------------------------~
j 2~ 200 mg/kg¦ 58 mg/kg ¦ I agitation -
l ~ I I co~n~sions
I t I t t
i 3 ! 200 mg/kgl 58 mg/kg I j convulsions
~ ! 4 1 240 mg/kgl ! 38 5mg/kgj convulsions
t
1 5 i 180 mg/kgl 58 mg/kg ! j central stimulation!
L _ L _ _
~,ri'

T A s L E [ (continued)
------------ --------- -- r--------------
Example _______ _ ___ LD50' i p 50~ ~ Remarks
6 110 mg/kg 58 mg/kg ~Iyperesthesia
_______. ._____________ ____________ _____________ ______ ___________
________ ~200 mg/kg 98 mg/kg ____________ Convulsions
8 200 mg/kg 76 mg/kg Agitation-oon-
________ _____________ _____________ ____________ vulsions
9 >200 mg/kg 142 mg/kg Convulsions-
_______ _____________ ____________ ____________ cyanosis
>200 mg/kg 142 mg/kg Agitations-con-
_______ ____________ ____________ ____________ vulsions
b) Actions on the central nervous system
The central effects of the various compounds were
investigated in mice by means of a set of tests :
- traction test;
- interaction with the hypnotic effect of barbiturates;
- oxotremorine test;
- reserpine test (ptosis).
The above set of tests failed to evidence a
significant effect on the central nervous system.
c) Cardiovas ular effects
The cardiovascular effects of each compound were
investigated in anesthetized dogs.
A potent arterial dilator effect was evidenced with
a number of compounds.
d) Anti-dysrhythmic effects
The anti-dysrhythmic activity of the compounds of the
formula (I) was evaluated according to the following
pharmacological tests :
- maximum stimulation heart rate (FMS)
The FMS, as determined in vivo in rabbits by cardiac
stimulation by means of a stimulation probe placed in the
left auricular cavity, provides an overall determination
of the duration of the refractory period of the conducti-
ve routes and of the fibres of the myocardium.
~'

L-a~
- 12 -
- dysrhythmia on central stimulation in rabbits : electric
stimulation of the posterior hypothalamus induces an
intense activation of the sympathetic system and of the
dysrhythmias;
- aconitine induced dysrhythmias in rats : -this agent has
a deeply perturbating effect on the ionic permeability
of the membranes;
-ouabaine induced dysrhythmias in guinea-pigs : at toxic
dosages, ouabaine affects transmembrane ionic exchanges;
on the other hand, it induces a concomitant sympathetic
activation;
- anoxia induced dysrhythmias in rats, after pre-
treatment with a subliminal dosage of aconitine (combi-
nation of the effects of a sympathetic stimulation with
those due to perturbations of ionic conductions);
- method according to Harris, in dogs: coronary ligation
and dysrhythmias induced by localized ischemia.
-~ The results obtained are tabulated in Table II. This
Table provides evidence of the potent anti-arhythmic
activity of the compounds of the formula (I).
The compounds of the formula (I) are of high thera-
peutic value in the treatment of a variety of circulatory
or cardiac diseases (circulatory insufficiency; vascular
obturation; angina pectoris; dysrhythmia, and the like).
The compounds are administrable to humans by the oral
or rectal route, as bases or salts (formulated as tablets,
capsules, drops or suppositories) or by the parenteral
route, as aqueous solutions of water-soluble salts or
within another excipient insuring delayed resorption.
The various formulations may contain lO-1000 mg
active ingredient per unit dosage for administration by
the oral and rectal routes, and 5-500 mg active ingredient
for the other routes of administration.
The daily dosage regimen may vary from lO mg to 3 g,
depending on the route of administration and the
therapeutic applications contemplated.
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