Novel benzothienyl amino (propyl and butyl) ketones

Abstract

Compounds having the formula ##STR1## wherein R.sub.1 and R.sub.2 are alkyl having one to 4 carbon atoms, allyl or ##STR2## is pyrrolidino, piperidino, perhydroazepino or morpholino, RX is an inorganic acid, organic acid or an alkyl bromide or iodide, m is 3 or 4, and n is zero or one. The compounds are prepared by (1) reacting benzothienyl-lithium with ##STR3## followed by hydrolysis, or (2) when the substituent is located at the 2 position of the benzothienyl group, by reacting benzothiophene with ##STR4## followed by reaction with ##STR5## The compounds possess bloodplaque aggregation, spasmolytic, analgesic, anti-inflammatory and coronary, cerebral and peripheral vaso-dilatory properties.

Description

The present invention has at its object novel benzothienyl amino propyl and butyl ketones, a method of preparation thereof and their application in therapeutics.

The compounds of the invention have the general formula: ##STR6## where: R.sub.1 and R.sub.2 designate each an alkyl radical saturated or not having 1 to 4 carbon atoms of form together with the nitrogen atom to which they are bound a heterocyclic radical chosen from the following: pyrrolidino, piperidino, perhydroazepino and morpholino; and

HX represents an acid compound chosen from the following: hydrochloric acid, bromhydric acid, sulphuric acid, phosphoric acid, boric acid; oxalic, maleic, malic, fumaric, citric, embonic, methane sulfonic, acetylsalicylic, nicotinic, parachlorophenoxyacetic or parachlorophenoxyisobutyric acid; methyl bromide, methyl iodide, ethyl bromide, butyl bromide, benzyl bromide; m is worth 3 or 4; and n represents 0 or 1.

The method of the invention comprises the following succession of operations:

reaction of bromobenzothiophene of formula (II) ##STR7## on n.butyl-lithium of formula (III): n.C.sub.4 H.sub.9 --Li (III) to give benzothienyl-lithium of formula (IV) ##STR8## addition of an aminoalkylnitrile of formula (V) ##STR9## where R.sub.1, R.sub.2 and m have the same significance as in formula (I), on the benzothienyl-lithium previously obtained to produce a compound of formula (VI) ##STR10## which is hydrolised to finish up directly with the ketone of formula (I) ##STR11## which may be subjected to a salification by an acid compound of formula HX defined above, which gives salts of formula ##STR12## It is also possible to prepare compounds of formula (I'): ##STR13## where R.sub.1, R.sub.2, HX, m and n have the same significance as above, by the following succession of operations: condensation of a chlorated acid chloride of formula (VII) ##STR14## where m is worth 3 or 4, on benzothiophene of formula (VIII): ##STR15## in the presence of a Lewis acid, from which results the chlorated ketone of formula (IX): ##STR16## followed by a condensation of amine of formula (X) ##STR17## where: R.sub.1 and R.sub.2 have the same value as in formula (I) on said compound of formula (IX) to give the basis of formula (I) ##STR18## which may be subjected to salification by an acid compound of formula HX such as defined above.

The following preparations are given as examples.

EXAMPLE 1: 1-(benzothien-2'-yl)-4-N-morpholino butanone

A solution of n-butyl lithium in 100 ml of anhydrous diethylic ether is prepared at 0.degree. C. from 14 g of lithium and 14 g of n-butyl bromide. A solution of 13 g of 2-bromo benzothiophene in 50 ml of diethylic ether is slowly added with agitation, under nitrogen and at a temperature of -20.degree. C. Agitation continues for two hours. 15 g of 4-N-morpholino butyronitrile is poured in. Agitation is carried out for 16 hours at -20.degree. C. Hydrolysis is carried out by pouring with agitation on to 150 g of piled ice. The ether is decanted and the aqueous phase extracted with ether. The united etherated phases are dried on disodic sulfate and the solvent is evaporated. The residue is recrystallized in cyclohexane.

Thus is obtained, with a yield of 60%, white crystals having a melting point of 61.degree. C.

EXAMPLE 2: 1-(benzothien-2'-yl)-4-N-morpholino butanone hydrochloride

Compound 1 in basic form is transformed into hydrochloride by saturation with a flow of gaseous hydrochloric acid of its solution in ethylic ether.

The resulting product is in the form of white crystals having a melting point of 172.degree. C.

EXAMPLE 3: 1-(benzothien-2'-yl)-4-N,N-diallylamino butanone oxalate

A mixture of 4.6 g of 1-(benzothien-2'-yl)-4-chloro butanone and 1.8 g of diallylamine is heated at reflux for 10 hours. After cooling, 250 ml of water are added to the reaction product, which is alkalysed by addition of soda and extracted with diethylic ether. The ether is dried on disodic sulfate and evaporated. The oily residue is dissolved in the minimum of acetone and heated to reflux for 30 minutes with a solution of 3 equivalents of oxalic acid in acetone. Centrifugation is carried out after cooling and recrystallization in acetonitrile.

Thus are obtained, with a yield of 60%, white crystals having a melting point of 172.degree. C.

The compounds shown in the following tables I and II were prepared in the same way.

TABLE I__________________________________________________________________________ ##STR19## compoundNo. of m ##STR20## HX (.degree.C.)pointMelting solventRecrystallisation (%)Yield__________________________________________________________________________4 3 ##STR21## chlorhydric acid 180 Acetonitrile 705 3 ##STR22## chlorhydric acid 186 Methanol 706 3 ##STR23## citric acid 168 Acetonitrile (1) + methanol 50)7 3 ##STR24## p. chloro- phenoxyiso butyric acid 159 petroleum ether (1) ethylic ether 40)8 4 N(C.sub.3 H.sub.7)2 methyl 142 Acetonitrile 40 iodide__________________________________________________________________________ TABLE II__________________________________________________________________________ ##STR25## poundcom-No. of ##STR26## HX (.degree.C.)pointMelting tion solventRecrystallisa- (%)Yield__________________________________________________________________________ 9 ##STR27## bromhydric acid 138 absolute ethanol 6510 ##STR28## p.chloro- phenoxy- isobutyric acid 180 petroleum ether 6511 ##STR29## bromhydric acid 167 Acetonitrile 6012 ##STR30## bromhydric acid 165 Acetronitrile (1) + methanol (3) 6013 ##STR31## bromhydric acid 178 methanol 7014 ##STR32## bromhydric acid 227 methanol 7015 ##STR33## bromhydric acid 146 Acetonitrile 7516 ##STR34## citric acid 162 Acetonitrile 7517 ##STR35## bromhydric acid 186 Acetonitrile (2) + methanol (1) 65__________________________________________________________________________

The compounds of formula (I) were tested on laboratory animals and showed themselves particularly active as blood-plaque aggregation inhibitors. They also showed an appreciable activity as spasmolytic, analgesic, anti-inflammatory agents and coronary, cerebral and peripheral vaso-dilatators.

1. Acute toxicity

The acute toxicity of the compounds of formula (I) were evaluated orally (esophagean probe) on a mouse deprived of food 18 hours before the beginning of the test. The products were placed in suspension in a solution of dilute carboxymethyl cellulose. Calculation of the 50 lethal dose (LD 50) was effected according to the method of Miller and Tainter (Miller L. C., Tainter M. L., Proc. Soc. Exptl. Biol. Med. 1944, 57, 261-264).

The death rate was checked for seven days following the treatment.

Table III gives the 50% lethal doses (LD 50) in milligrams per kilogram body weight.

TABLE III______________________________________ LD 50No. of compound (mg/kg/p.o.)______________________________________1 1 2002 1 5004 9505 1 3009 >1 20010 1 10011 1 10012 50013 76014 85015 95016 1 20017 1 000______________________________________

2. Activity on blood-plaque aggregration

The blood plaques used for these studies were human blood-plaques introduced into the test in the form of blood-plaque rich plasmas (B.P.R.P.).

These latter were obtained as water-repellent material by slow centrifugation from human blood samples.

The study of blood-plaque aggregation was made by means of an aggregate-meter with continuous agitation and graphic recording according to the conventional method. (PROST R. S., SOUVERAIN C. H., DOUMENC J., Etude de l'agregation plaquettaire a l'aide de l'agregametre de MUSTARD--Coagulation, 1971, 4, 2, 145-151).

The agents employed for inducing aggregation were diphosphoric adenosine acid (D.P.A.), 1-(3',4'-di-hydroxyphenyl)-2-methylamino ethanol (adrenaline) and collagene. All these reactants were prepared from mother solutions diluted in a Michaelis' buffer. Their concentration in the test may vary according to the affinity of the blood-plaques.

An optimum concentration is thus sought by successive tests on the same B.P.R.P.

The inhibitory activity on the aggregation was evaluated by addition of the product under study to the B.P.R.P. before introduction of the aggregating agent.

The concentrations of compounds of formula I(X) in the B.P.R.P. are: C(X)=2.5.times.10.sup.-5 g/ml for aggregation with D.P.A. and adrenaline, and C (X)=2.times.10.sup.-5 g/ml for collagene.

The reference product (R) is 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido[5,4-d]pyramidine (known under the trademark "Dipyridamole") used in the concentration C (R)=5.times.10.sup.-4 g/ml for aggregation with D.P.A. and adrenaline and C (R)=2.times.10.sup.-4 g/ml for aggregation with collagene.

The following table IV indicates the activity of some compounds of formula I: a (X) the activity of the reference product: a (R) and the different values of the ratio: ##EQU1##

In addition, in order to ensure a better comparison between the activity of the compounds of the invention and that of the reference product, Table IV shows the values of the ratio ##EQU2##

We get: LD 50 (R)=2150 mg/kg/p.o.)

TABLE IV__________________________________________________________________________ Inhibitory activity of the blood-plaque aggregation__________________________________________________________________________No. of D.P.A. D.P.A. or ADRENALINE ADRENALINEcompound tested a(X) (%) a(R) (%) ##STR36## ##STR37## a(X) (%) a(R) (%) ##STR38##__________________________________________________________________________1 -- -- -- 8.9 .times. 10.sup.-2 9 91 1 .times. 10.sup.-12 -- -- -- 7.2 .times. 10.sup.-2 15 91 1.65 .times. 10.sup.-13 15 87 1.7 .times. 10.sup.-1 -- -- -- --4 -- -- -- 1.1 .times. 10.sup.-1 78 78 15 8 53 1.5 .times. 10.sup.-1 8.3 .times. 10.sup.-2 84 78 1.16 15 87 1.7 .times. 10.sup.-1 -- -- -- --9 15 79 1.9 .times. 10.sup.-1 <9 .times. 10.sup.-2 86 86 111 10 55 1.8 .times. 10.sup.-1 10.sup.-1 51 88 5.8 .times. 10.sup.-112 29 79 3.6 .times. 10.sup.-1 2.15 .times. 10.sup.-1 80 88 9.1 .times. 10.sup.-113 18 79 2.3 .times. 10.sup.-1 1.4 .times. 10.sup.-1 84 77 1.114 -- -- -- 1.3 .times. 10.sup.-1 42 77 5.5 .times. 10.sup.-115 17 85 2 10.sup.-1 1.15 10.sup.-1 82 86 9.5 .times. 10.sup.-116 47 85 5.5 .times. 10.sup.-1 9 .times. 10.sup.-2 -- -- --__________________________________________________________________________ No. of COLLAGENE compound tested a(X) (%) a(R) (%) ##STR39## ##STR40##__________________________________________________________________________ 1 12 36 3.3 .times. 10.sup.-1 1.8 .times. 10.sup.-1 2 12 36 3.3 .times. 10.sup.-1 1.4 .times. 10.sup.-1 3 13 67 1.95 .times. 10.sup.-1 -- 4 39 88 4.5 .times. 10.sup.-1 2.3 .times. 10.sup.-1 5 12 88 1.4 .times. 10.sup.-1 1.7 .times. 10.sup.-1 6 32 93 3.5 .times. 10.sup.-1 -- 9 16 51 3 .times. 10.sup.-1 1.8 .times. 10.sup.-1 11 12 36 3.3 .times. 10.sup.-1 1.95 .times. 10.sup.-1 12 12 53 2.3 .times. 10.sup.-1 4.3 .times. 10.sup.-1 13 -- -- -- -- 14 -- -- -- -- 15 -- -- -- -- 16 92 36 2.5 1.8 .times. 10.sup.-1__________________________________________________________________________

This table shows that, taking into account the value of the ratio ##EQU3## the inhibitory activity of the blood-plaque aggregation of the compounds of the invention is at least equal to that of the reference product. For certain compounds, such as No. 17, it is even substantially superior.

3. Spasmolytic activity

The spasmolytic activity was studied on a rat's isolated duodenum maintained in a survival medium of an aerated Tyrode solution heated to 38.degree. C. according to the technique of Magnus (Magnus R.-Archivs ges. Physiol., 1905, 180, 1-71).

The contracting agent used was barium chloride, the reference antagonist agent being papaverine hydrochloride (R). The average activity of the compounds of formula I (X) in comparison with that of the reference agent was expressed by calculating the ratio of the 50 efficient doses (ED 50) determined graphically on logarithmic paper: ##EQU4##

For example: a substance having a relative activity expressed by the FIG. 2 presents an activity equal to twice that of papaverine hydrochloride.

The results obtained, given in table V, show that the compounds of the invention have an interesting spasmolytic activity.

TABLE V______________________________________Spasmolytic activityNo. of Spasmolytic activitycompound tested ED 50 (X) (g/ml) ED 50 (R) (g/ml) ##STR41##______________________________________ 3 1.2 .times. 10.sup.-6 2.5 .times. 10.sup.-6 2.08 9 0.5 .times. 10.sup.-6 4.05 .times. 10.sup.-6 8.1010 3.8 .times. 10.sup.-6 4 .times. 10.sup.-6 1.0511 1.05 .times. 10.sup.-6 6.5 .times. 10.sup.-6 6.212 1.35 .times. 10.sup.-6 6.5 .times. 10.sup.-6 4.813 2.25 .times. 10.sup.-6 3.5 .times. 10.sup.-6 1.5515 3 .times. 10.sup.-6 4.75 .times. 10.sup.-6 1.616 1.5 .times. 10.sup.-6 4 .times. 10.sup.-6 2.717 2.15 .times. 10.sup.-6 7.25 .times. 10.sup.-6 3.4.______________________________________

4. Analgesic and anti-inflammatory activity

The intraperitoneal injection of phenylparaquinone (P.P.Q.) in a mouse causes the appearance of a painful syndrome appearing within 5 minutes of the injection and disappearing after about 30 minutes (SIEGMUND E. A., CADMUS A., LU G., J. Pharmacol, Exp. Therap. 1957, 119, 453). This painful syndrome manifests itself in the animal by a series of characteristic crises, more or less close together and fleeting, during which we can note a twisting or stretching of the body, a hollowing of the sides and a stretching of the hind legs.

It is therefore possible to note the number of crises in a given interval of time.

The preventive administration of analgesic or anti-inflammatory substances prevents the appearance of crises or reduces the frequency thereof.

The reference substance (R) used in the tests was the ester of N-(7-chloro-4 quinolyl) anthranilic acid and 2,3-dihydroxy n.propanol (known under the trademark Glafenine).

It was administered orally with a dose of 25 mg/kg.

The compounds of formula I (X) were administered digestively with a dose of 50 mg/kg.

The interval of time (t) which was chosen to evaluate the analgesic activity was between 10 and 15 minutes which is the period of maximum frequency of the crises. This activity was expressed in the following way:

n: number of crises observed in the control mice; n': number of crises observed in mice previously treated with the reference substance (R); n": number of crises observed in mice having received the substance (X).

The percentage activity of R is equal to ##EQU5##

The percentage activity of X is equal to ##EQU6## The activity of X in relation to that of R is estimated by the ratio ##EQU7## For example: a compound X for which ##EQU8## is 0.5 has an activity equal to half that of the reference product.

Table IV following gives the results observed.

In addition, so as to permit a better appreciation of the compounds of the invention table VI shows the values of the ratio:

TABLE VI______________________________________Analgesic and anti-inflammatory activity Analgesic and anti-No. of inflammatory activitycompound tested a(X) a(R) ##STR42## ##STR43##______________________________________ 2 38 75 5 .times. 10.sup.-1 3.3 .times. 10.sup.-2 6 55 77 7 .times. 10.sup.-1 -- 9 47 45 1 <4.2 .times. 10.sup.-211 48 75 6.5 .times. 10.sup.-1 4.5 .times. 10.sup.-212 68 45 1.5 10 .times. 10.sup.-214 39 74 5.3 .times. 10.sup.-1 5.9 .times. 10.sup.-215 51 45 1.13 5.3 .times. 10.sup.-216 44 75 5.9 .times. 10.sup.-1 4.2 .times. 10.sup.-217 55 45 1.2 5 .times. 10.sup.-2______________________________________

This table shows that for a dose administered corresponding to a small fraction of the lethal dose some compounds of formula I have an analgesic and anti-inflammatory activity similar to that of the reference product.

Other compounds have an activity representing approximately 6/10 that of R. This activity must nevertheless be considered interesting since the reference product is a particularly active analgesic.

5. Vaso-dilatatory activity

The vaso-dilatatory activity as regards the smooth musculature of the vessels was demonstrated on the isolated heart of a gumea-pig perfused with a Locke solution maintained at 37.degree. C. after providing the aorta with a cannula.

The coronary flow is recorded, by means of an electronic device fitted with a Fleish totaliser, before and after addition of the substance X under study (concentration: 1.times.10.sup.-5 g/ml), the reference product (R) being 2,6-bis(diethanolamino)4,8-dipiperidinopyrimido[5,4-d]pyrimidine (known under the trademark "Dipyridamole") used at a concentration of 1.times.10.sup.-5 g/ml.

The percentage flow increase P was calculated at the climax of the activity of X or R.

Table VII below gives, as examples, the results observed with some compounds of formula I.

TABLE VII:______________________________________Vaso-dilatatory activityCode No. of compound tested P (X) P (R) ##STR44##______________________________________ 1 28 43 6.5 .times. 10.sup.-110 60 43 1.411 41 53 7.75 .times. 10.sup.-112 33 53 6.25 .times. 10.sup.-115 172 71 2.42______________________________________

This table shows that the vaso-dilatatory activity of the products of the invention ranges from 0.6 to 2.5 times that of the reference product.

These pharmacological results show the interest of the formula I compounds in the treatment of coronary and cardiac insufficiencies, pains of inflammatory and other origins, and spasms.

Formula I compounds can be administered to man and animals orally, rectally or parenterally, particularly associated with the appropriate excipient in each case.

As examples, they may be presented in the form of tablets, pills, gelules, suppositories or injectable solutions.

The daily dosage may, according to the case, range from 50 to 600 mg.

Claims

1. A compound having the formula ##STR45## wherein R.sub.1 and R.sub.2 are alkyls having 1 to 4 carbon atoms or allyl;

HX is selected from the group consisting of hydrochloric acid, bromhydric acid, sulfuric acid, phosphoric acid, boric acid, oxalic acid, maleic acid, malic acid, fumaric acid, citric acid, embonic acid, methanesulfonic acid, acetylsalicylic acid, nicotinic acid, parachlorophenoxyacetic acid, parachlorophenoxyisobutyric acid, methyl bromide, methyl iodide, ethyl bromide, butyl bromide and benzyl bromide;

m is 3 or 4; and

n is 0 or 1.

2. A compound as claimed in claim 1 having the formula ##STR46##

3. A compound as claimed in claim 2 in which R.sub.1 and R.sub.2 are allyl, HX is oxalic acid and n is 1.

4. A compound as claimed in claim 2 in which R.sub.1 and R.sub.2 are methyl, HX is hydrochloric acid and n is 1.

5. A compound as claimed in claim 1 having the formula ##STR47## wherein HX is methyl iodide.

6. A compound as claimed in claim 1 having the formula ##STR48##

7. A compound as claimed in claim 6 in which R.sub.1 and R.sub.2 are ethyl, HX is bromhydric acid or p-chlorophenoxyisobutyric acid, and n is 1.

8. A compound as claimed in claim 6 in which R.sub.1 and R.sub.2 are propyl, HX is bromhydric acid and n is 1.

9. A compound as claimed in claim 6 in which R.sub.1 and R.sub.2 are --CH(CH.sub.3).sub.2, HX is bromhydric acid and n is 1.