4,5,6,7-Tetrahydro-thieno[3,2-c]-pyridine derivatives and process for their preparation

Abstract

This invention relates to 4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine derivatives, having the formula: ##STR1## in which R.sub.1 is hydrogen or alkyl having 1-6 carbon atoms; R.sub.2 is hydrogen, an alkyl group having 1-6 carbon atoms or a phenyl or benzyl radical; R.sub.3 represents an alkyl group having 1-6 carbon atoms or a benzyl radical, and their pharmaceutically acceptable acid addition salts.Said derivatives have an anti-inflammatory and antalgic activity.

Description

This invention relates to new thieno[3,2-c]pyridine derivatives, and to a process for their preparation.

Said compounds may also be used as intermediate derivatives in the synthesis of a large number of derivatives used in both the chemical and pharmaceutical industries.

The new compounds of this invention have the following general formula: ##STR2## in which R.sub.1 represents hydrogen or a lower alkyl group; R.sub.2 represents hydrogen, a lower alkyl group or a phenyl or benzyl radical; R.sub.3 represents a lower alkyl radical or a benzyl radical.

In the above formula (I) the lower alkyl and alkoxy groups contain 1-6 carbon atoms.

The invention includes also within its scope the acid addition salts of the derivatives of the formula (I) with pharmaceutically acceptable inorganic or organic acids.

The invention relates also to a process for the preparation of compounds of the formula (I) as defined above, comprising condensing a derivative of the formula: ##STR3## in which R.sub.1, R.sub.2 and R.sub.3 have the above-defined meanings, with formaldehyde, to give an imine having the formula: ##STR4## which is then cyclized to the derivative of the formula (I).

The condensation with formaldehyde may be effected in aqueous medium or within an organic solvent, such as benzene, for example. Cyclization of the imine may be effected either by action, in aqueous medium, of an organic acid (e.g., acetic acid) or an inorganic acid (e.g., hydrochloric or sulfuric acid), or by action, in anhydrous medium, and within an organic solvent such as ether, benzene or dimethylformamide, of hydrochloric acid.

The starting compounds of the general formula (II) may be obtained according to the following reaction scheme (W. H. HERZ & L. TSAI, J. Am. Chem. Soc., 1955, 77, 3529): ##STR5##

The acid addition salts of the compounds of the formula (I) may be obtained by conventional methods which will be apparent to those skilled in the art.

The following non-limiting Examples are given to illustrate the preparation of the compounds of this invention.

EXAMPLE 1

7-Methoxy-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine

(Derivative n.sup.o 1)

2-(2-Thienyl)-2-methoxy-ethylamine (157 g; 1 mole) is added over 2 minutes, with stirring, to a 37% aqueous formaldehyde solution (94.3 g; 1.1 mole). The temperature rises to 60.degree. C and is maintained at this value during 90 minutes. After cooling, the reaction mixture is extracted with benzene. The organic extracts, after drying over sodium sulfate and concentration in vacuo, give the crude formimine (169 g).

To this material is added over 30 minutes, with stirring and while maintaining the temperature at 20.degree.-30.degree. C, 300 ml of a 6.6N solution of hydrogen chloride in dimethylformamide. The reaction medium is then left aside 90 minutes at room temperature. The resulting precipitate is filtered off, washed with acetone and dried, to give the hydrochloride (124 g), m.p. 180.degree. C (Kofler block) (Yield: 60%).

______________________________________Analysis: for C.sub.8 H.sub.12 ClNOS C H N______________________________________Calculated %: 46.71 5.88 6.81Found %: 46.50 6.50 6.95______________________________________

The compounds of following Examples 2-10 are obtained according to the same procedure.

EXAMPLE 2______________________________________7-Ethoxy-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.2) HydrochlorideAnalysis: for C.sub.9 H.sub.14 ClNOS C H N______________________________________Calculated %: 49.19 6.42 6.38Found %: 48.90 6.08 6.61______________________________________ EXAMPLE 3______________________________________7-Isobutoxy-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.3) FumarateAnalysis: for C.sub.15 H.sub.21 NO.sub.5 S C H N______________________________________Calculated %: 55.03 6.47 4.28Found %: 55.19 6.62 4.06______________________________________ EXAMPLE 4______________________________________7-Benzyloxy-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.4) HydrochlorideAnalysis: for C.sub.14 H.sub.16 ClNOS C H N______________________________________Calculated %: 59.66 5.72 4.97Found %: 59.81 5.61 5.05______________________________________ EXAMPLE 5______________________________________7-Methoxy-7-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.5) HydrochlorideAnalysis: for C.sub.9 H.sub.14 ClNOS C H N______________________________________Calculated %: 49.19 6.42 6.38Found %: 49.49 6.37 6.38______________________________________ EXAMPLE 6______________________________________7-Ethoxy-7-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.6) MaleateAnalysis: for C.sub.14 H.sub.19 NO.sub.5 S C H N______________________________________Calculated %: 53.66 6.11 4.47Found %: 53.47 6.08 4.63______________________________________ EXAMPLE 7______________________________________7-Methoxy-6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.7) HydrochlorideAnalysis: for C.sub.9 H.sub.14 ClNOS C H N______________________________________Calculated %: 49.19 6.42 6.38Found %: 48.95 6.23 6.51______________________________________ EXAMPLE 8______________________________________7-Ethoxy-6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.8) HydrochlorideAnalysis: for C.sub.10 H.sub.16 ClNOS C H N______________________________________Calculated %: 51.38 6.90 5.99Found %: 51.12 6.99 6.21______________________________________ EXAMPLE 9______________________________________6,7-Dimethyl-7-methoxy-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.9) FumarateAnalysis: for C.sub.14 H.sub.19 NO.sub.5 S C H N______________________________________Calculated %: 53.66 6.11 4.47Found %: 53.39 6.43 4.22______________________________________ EXAMPLE 10______________________________________7-Methoxy-6-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine(Derivative n.degree.10) HydrochlorideAnalysis: for C.sub.14 H.sub.16 ClNOS C H N______________________________________Calculated %: 59.66 5.72 4.97Found %: 59.87 5.69 5.19______________________________________

The results of toxicological and pharmacological tests reported below demonstrate the useful, particularly anti-inflammatory and antalgic, activities of the derivatives of this invention.

Thus, this invention relates also to a therapeutic composition having in particular an anti-inflammatory and antalgic activity, comprising, as active ingredient, a derivative of the formula (I) or a therapeutically acceptable acid addition salt thereof, together with a therapeutically administrable carrier.

TOXICOLOGICAL INVESTIGATION

Said investigation demonstrated the low toxicity and the good tolerance of the derivatives of this invention. For indicative purposes, the LD.sub.50 /24hrs/kg of the animal, determined in Swiss mice by the intravenous route, by the method according to MILLER and TAINTER is 262 mg for derivative 1, 145 mg for derivative 2, 180 mg for derivative 3, 95 mg for derivative 4, 138 mg for derivative 5, 224 mg for derivative 6, 210 mg for derivative 7, 129 mg for derivative 8, 175 mg for derivative 9 and 195 mg for derivative 10.

PHARMACOLOGICAL INVESTIGATION

1. Anti-inflammatory Action

a. Localized carrageenin-induced edema method.

0.1 ml of a 1% carrageenin solution is injected at time 0 in the metatarsal flexor muscles of the right hind limb of rats. The animals of the treated group are administered orally, additionally, 100 mg/kg of the test derivative, respectively 1 hour prior to and then simultaneously with the phlogogenic agent, and then 1 hour and 2.5 hours thereafter. The determinations effected with a ROCH micrometer at times 0, 1 hour, 2 hrs, 3 hrs and 5 hrs after carrageenin administration make it possible to determine, as a function of time, the percent anti-inflammatory activity. The results obtained are tabulated in following Table I:

TABLE I______________________________________ Percent anti-inflammatory activityDerivative after 1 hour after 2 hours after 5 hours______________________________________1 35 41 502 36 44 523 39 48 584 42 50 605 39 49 576 40 49 617 36 48 628 38 53 619 44 52 6210 37 50 56______________________________________ b. Ovalbumin-induced systemic edema method

Rats are administered a simultaneous intraperitoneal injection of 1 ml ovalbumin and 0.5 ml of a 1% Evans Blue solution. The animals of the treated group are additionally administered orally 100 mg/kg of the test derivative, one hour prior to ovalbumin administration and then simultaneously with said ovalbumin administration. The intensity of the phenomenon thus induced is rated according to a scale from 1 to 5, according to the progress of the inflammatory syndrome. The measurements are effected after 2 hours and after 3 hours. Thus are determined the mean intensity of the edema and the percent decrease of the edema reaction with respect to the control group. Said percentages are given in following Table II:

TABLE II______________________________________ Percent decreaseDerivative after 2 hrs after 3 hrs______________________________________1 51 602 48 593 51 634 53 645 49 606 44 587 47 588 44 569 50 6310 48 57______________________________________

2. Antalgic Action

a. Mechanical stimulation method according to Haffner (Deutsch. Wish. 1959, 55, 731-733)

This method comprises placing a pressure forceps at the base of the tail of a mouse and recording the number of bites self-inflicted by the animal in its endeavour to remove the forceps. The decrease of the number of bites prior to and subsequently to oral administration of the test compound at a dosage of 100 mg/kg provides a measure of the antalgic activity of the derivatives of this invention. The mean percent antalgia thus determined as a function of time is given in following Table III.

TABLE III______________________________________mean percent antalgiaDerivative after 30 min. after 1 hr after 2 hrs after 3 hrs______________________________________1 75 63 59 512 71 66 62 593 68 60 55 484 75 69 66 575 67 61 55 466 66 60 55 487 70 65 61 538 71 65 59 509 68 63 56 4910 73 66 60 53______________________________________ b. Acetic acid method, according to Koster, Anderson and Beer (Fed. Proced. 18., 1959, 412, 1, 626)

Intraperitoneal injection of a dilute acetic acid solution induces, in mice, characteristic writhing movements which are repeated due to the effect of pain.

Administration of derivatives of the formula (I) to the animals of the treated group, at an oral dosage of 100 mg/kg, 30 minutes prior to intraperitoneal injection of acetic acid, shows that, with respect to the untreated reference group, the number of writhing movements is markedly decreased within the next thirty minutes.

The percent antalgia thus determined is, with all the derivatives tested, greater than 60%.

The toxicological and pharmacological investigations reported above show that the compounds of this invention are endowed with a good tolerance and possess substantial anti-inflammatory and antalgic activities.

For oral administration, the composition of this invention may be formulated as tablets, coated tablets, capsules, drops and syrups. It may also be formulated for rectal administration, as suppositories and, for parenteral administration, as injectable solutions.

Each unit dose contains advantageously from 0.030 g to 0.300 g active ingredient, the administrable dosages varying within a range from 0.030 g to 0.900 g active ingredient per 24 hours.

Non-limiting Examples of pharmaceutical formulations of the composition of this invention are given below.

EXAMPLE 11______________________________________ Coated tablets______________________________________ Derivative n.degree.1 0.100 g Talc 0.010 gCORE Wheat starch 0.025 g Magnesium stearate 0.010 g Talc 0.010 g Potato starch 0.015 g Gum arabic 0.005 g Gelatin 0.002 gCOATING Tartrazine traces White wax 0.001 g Carnauba wax 0.001 g Sugar, sufficient to make 1 coated tablet______________________________________ EXAMPLE 2______________________________________ Tablets______________________________________Derivative N.degree.4 0.100 gTalc 0.005 gStarch 0.025 gMagnesium stearate 0.005 gCellulose 0.010 gPolyvinyl pyrrolidone 0.010 g______________________________________ EXAMPLE 13______________________________________ Capsules______________________________________Derivative n.degree.5 0.150 gMagnesium stearate 0.010 gTalc 0.010 gStearic acid 0.005 g______________________________________ EXAMPLE 14______________________________________ Drops______________________________________Derivative n.degree.7 2.00 gFlavoured excipient, to make 30 ml______________________________________ EXAMPLE 15______________________________________ Injectable solution______________________________________Derivative n.degree.10 0.150 gIsotonic solution 5 ml______________________________________

Endowed with a very good tolerance, particularly from the digestive standpoint, the composition of this invention possesses anti-inflammatory and antalgic properties which make it usefully administrable for therapeutic purposes, both for short treatment periods and for extended treatment periods.

Claims

1. A compound selected from the group consisting of 4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine derivatives having the formula: ##STR6## in which R.sub.1 is selected from the group consisting of hydrogen and the alkyl radicals having 1-6 carbon atoms; R.sub.2 is selected from the group consisting of hydrogen, an alkyl group having 1-6 carbon atoms, the phenyl radical, and the benzyl radical; R.sub.3 is selected from the group consisting of an alkyl group having 1-6 carbon atoms, and the benzyl radical; and the pharmaceutically acceptable acid addition salts of said derivatives.

2. Process for the preparation of a compound selected from the group consisting of 4,5,6,7-tetrahydro-thieno[3,2-c]-pyridine derivatives having the formula: ##STR7## in which R.sub.1 is selected from the group consisting of hydrogen and the alkyl radicals having 1-6 carbon atoms; R.sub.2 is selected from the group consisting of hydrogen, an alkyl group having 1-6 carbon atoms, the phenyl radical, and the benzyl radical; R.sub.3 is selected from the group consisting of an alkyl group having 1-6 carbon atoms, and the benzyl radical; and the pharmaceutically acceptable acid addition salts of said derivatives, comprising condensing a derivative of the formula: ##STR8## in which R.sub.1, R.sub.2 and R.sub.3 have the above-defined meanings, with formaldehyde, to give an imine of the formula: ##STR9## and subsequently cyclizing said imine (III) to the derivative of the formula (I).

3. Process as claimed in claim 2, wherein the condensation with formaldehyde is effected in aqueous medium.

4. Process as claimed in claim 2, wherein the condensation with formaldehyde is effected within an organic solvent.

5. Process as claimed in claim 2, wherein the cyclization of the imine is effected by action of an acid in aqueous medium.

6. Process as claimed in claim 2, wherein the cyclization of the imine is effected by action of hydrochloric acid in anhydrous medium, within an organic solvent.