CA1109469A - Benzofuran derivatives, process for their preparation and their therapeutic applications - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE.

This invention relates to compounds having the general formula :

in which is selected from :

a radical 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 in which R"1 and R"2 are C1-6 alkyl;

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

Description

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.

( ) 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%).

(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%.

(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 (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%.

(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%. -; 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%.

(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~.

) 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%.

.

(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~

(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%.

(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~.

(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~.

(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%.

. .
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%.

.
~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%.

.

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%.

. . .
(I) Rl = H; R2 = CH2COoc H
2-(2-Ethoxycarbonyl-ethvlamino)-4=(2-benzofuryl)~ -1-~L~

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~

- 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.
.~

~: '

3 ~ ! 3 j 5 i 1 5 , ~ , . . . . . . . .
5 ~ 5 } j j I ,i j , ~ , , , o , , I
j 5 1+5 i I i i i ''Z
~, , , I
I ~ I I I I ~ I I I
H r~ 5 5 ~ i 5 o o I ~ I o 1 5 ~ I o I ~o ~ + ! ~ ¦ j I I + j I-m ~5 a) I ~ 5 ~ 5 1 ~
~"! 3~5 ~ 5 i , i ~ 5 ! ~ 3 ~ 5 ~ i o I
~ I I ~ I b I I ,.~, I -, I .~
E~ ~ I + } I + I ++ I ~i + I + I+

5 1 ,5 ,~
~, 5 + I I + 5 5 + I + I
i ! ! I ! 5 5 5 ~Z 5 ~ o I

Claims (7)

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) in which is selected from :

a radical 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 in which R"1 and R"2 are C1-6 alkyl;
a radical in which n is selected from 4,5 and 6;
the radical ; and the radical , or of their pharmacologically acceptable acid addition salts, comprising :
a) reacting an acrylate having the formula :

(III) with nitromethane, in the presence of a strong base, to give a nitro ester having the formula :

(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 :

(V) c) reacting the resulting pyrrolidin-2-one with triethyloxonium tetrafluoborate within an inert solvent, to give an 2-ethoxy-pyrroline having the formula :

(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) in which is selected from :

a radical 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 in which R"1 and R"2 are C1-6 alkyl;
a radical in which n is selected from 4, 5 and 6;
the radical ; and the radical , 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.