IE47795B1 - New thieno(2,3-c)pyridine derivatives and their therapeutic applications - Google Patents

Description

This invention relates to new thieno-pyridine derivatives, and to their application in human and veterinary medicine.

Thieno[3,2-c] pyridine derivatives unsubstituted at 45 position, their therapeutic applications, typically as antiinflammatory agents, and methods for their preparation are already known from U,S. Patent 3,845,055.

This invention relates to thieno[2,3-c] pyridine derivatives having the following formula: in which and R^, which may be the same or different, represent each a hydrogen atom or an alkyl group, and their pharmaceutically acceptable acid addition salts.

The thienof2,3-c]pyridine derivatives according to the 15 present invention are prepared by a process comprising the following -steps : - a) condensing a compound of the following formula (VII) with a sulfonyl chloride having the formula ClSC^Ry in which Rg is a lower alkyl radical or a phenyl radical optionally substituted with a halogen atom or a lower alkyl group, within a two-phase solvent system and in the presence of sodium carbonate; b) oxidizing in a solvent medium the resulting alcohol having the following formula (V,: c) treating the resulting ketone, having the following formula (III)s - 4 17 7 9 5 with a basic agent of the formula RO M+ in which R is a branched or straight-chain aliphatic alkyl radical and M+ is an alkali metal cation, in an alcohol solvent having the formula ROH and at the reflux temperature of the reaction mixture, to give the compound of formula (I), General formula (I) may also be represented under its zwitterion form : The groups and R2 are typically g lower alkyl 10 groups, such as methyl, for example.

The essential step of the preparation process described above comprises treating with a basic agent a derivative having the following formula (III) : in which R^ and have the aforementioned meanings and R3 is a lower alkyl radical, preferably a methyl group, or a phenyl radical optionally substituted with a halogen atom or a lower alkyl group such as a methyl group. The reaction - 5 - + compnses splitting off a sulfimc acid as its R^SC^M salt, under the influence of an alkoxide RO M+, according to the following scheme: This reaction is carried out by refluxing in a branched- or straight-chain C _ aliphatic alcohol ROH, in the L-3 - + presence of its sodium or potassium alkoxide (RO Na or — *f* RO K ), The use of potassium tert.butoxide in tert-butanol is particularly advantageous.

The compound (III) is obtained by oxidation of the corresponding alcohol (IV) : (V) The reaction is effected in acetone, using a solution of chromic anhydride in sulfuric acid as oxidizing agent.

The alcohol (v) is in turn prepared by condensing the corresponding 4,5,6,7-tetrahydro-thienopyridine (VII) with a sulfonyl chloride ClSO2R3· The reaction is effected in a two-phase water-chloroform system, in the presence of sodium or potassium carbonate.

The derivative (V) in which R^ = R2 = H and R^ = ptolyl, has already been mentioned in the literature by J.P. Maffrand + F. Eloy; J, Het. Chem. 1976, 13, 1347.

The starting material (VII) in which R^ = H is described in the above reference, or in Patent Specification No. 44146 - 7 4779S An example of the preparation of derivative (VII) in which = CHj is given in the present disclosure.

Preparation of 4-hydroxy-2-methyl-4,5,6,7-tetrahydro-thieno]2, 3-c] pyridine : (VII); Rx = CH3? R2 = H.

A mixture of 5-methyl-thiophene-2-carboxaldehyde (30 g; 0.237 mole) and aminoacetaldehyde dimethylacetal (27.4 g; 0.261 mole) in benzene (250 ml) is refluxed for 2 hours in a flask provided with a Dean-Stark water separator with overhead condenser. After evaporating to dryness, the residue is dissolved in ethanol (250 ml). Sodium borohydride (13.5 g; 0.355 mole) is added portionwise, and the resulting material is left aside overnight at room temperature. Excess sodium borohydride is destroyed by addition of acetone and the mixture is evaporated to dryness. The residue is taken up into water and extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated to dryness. The resulting residual oil is distilled under reduced pressure; b.p.2 = 127°C; Yield : 90%. The resulting N-(5methyl-2-thienyl)methyl aminoacetaldehyde dimethylacetal is heated at 60°C for 1 hour in 6N hydrochloric acid (250 ml). After evaporating to dryness, the residue is triturated with acetone. The off-white crystals of the desired hydrochloride are recrystallized from acetonitrile; M.p. = 120°C.

Overall yield : 61%.

The following non-limiting Examples illustrate the present invention.

EXAMPLE 1 Preparation of 4-hydroxy-thienor2,3-c] pyridine Derivative N°1 (I) ; R^ = R^ = H. a) Preparation of 4-hydroxy-6-tosyl-4,5,6,7-tetrahydro-thienor2,3-c] pyridine (V) : R^ = Rj = H; R3 = p-tolyl. - 8 To a mixture of 4-hydroxy-4,5,6,7-tetrahydro-thienoΓ2,3-c] pyridine hydrochloride (45 g; 0.234 mole), chloroform (100 ml) and saturated aqueous potassium carbonate solution (150 ml) is added dropwise, at room temperature and under vigorous mechanical stirring, a solution of p-toluenesulfonyl chloride (45 g; 0.234 mole) in chloroform (250 ml) and stirring is continued for a further 4 hours. After decantation, the chloroform phase is washed with water, dried over anhydro us sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (silica; eluent : tolueneethyl acetate 7:3) and recrystallized from isopropanol.

Beige crystals; M.p. = 130°C (isopropanol); Yield : 86%. b) Preparation of 4-oxo-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (III) : = = H; R^ = p-tolyl.

Jones' reagent (28.4 ml; 2.50 M solution of chromic anhydride in 8.35 N sulfuric acid) is added to a solution of 4-hydroxy-6-tosyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (20.3 g; 0.064 mole) prepared as described in a), in acetone (250 ml). Stirring is continued for a further 2 hours at room temperature, after which the precipitated inorganic salts are filtered off, the filtrate is evaporated to dryness and the residue is taken up into methylene chloride. The organic phase is washed with a 5% aqueous sodium bicarbonate solution and then with water, after which it is dried over sodium sulfate and evaporated to dryness. The solid residue is recrystallized from benzene. Translucent white crystals; M.P. = 172°C (benzene); Yield : 98%. c) Preparation of 4-hydroxy-thieno[2,3-c] pyridine (I) R = R2 = H. Derivative N°l.

A solution of 4-oxo-6-tosyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (19.6 g; 0.064 mole; obtained in b) above) and potassium tert-butoxide (28.6 g; 0.255 mole) in tert47795 - 9 butanol (300 ml) is refluxed for 2 hours under a nitrogen atmosphere. Evaporation of the solvent in vacuo leaves a residue which is taken up into 2N hydrochloric acid. The aqueous phase is extracted with ether, made basic by addition of concentrated ammonia, and evaporated to dryness. The residue is extracted four times with boiling ethyl acetate.

The organic extracts are filtered through a silica bed and evaporated to dryness. The solid residue is recrystallized from ethanol-acetonitrile. (Yield : 78%). White crystals? M.p. = 2O6°C (ethanol-cyclohexane).

EXAMPLE 2 Preparation of 4-hydroxy-7-methyl-thieno[2,3-c] pyridine (I) Derivative n°2; R^ = H; R2 = CH^ a) Preparation of 4-hydroxy-7-methyl-6-tosyl-4,5,6,7tetrahydro-thienor2.3-cl pyridine (V) : R^=H; R2 = CH3? R3 = p-tolyl.

This compound is prepared according to the procedure of Example 1 a), from 4-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridine hydrochloride. Off-white crystals; M.p. 120°C (benzene-cyclohexane). Yield : 96%. b) Preparation of 7-methyl-4-oxo-6-tosvl-4,5,6,7tetrahydro-thienor2.3-c1 pyridine (III) : R = H; R2 = CH3? R3 = p-tolyl.

This compound is prepared according to the procedure of Example 1 b) from the tosyl derivative described in a) above. White crystals; M.p. = 164°C (benzene-acetone); Yield s 90%. c) Preparation of 4-hydroxy-7-methyl-thienor2,3-c] pyridine (I) : R^ = H; R2 = CH3· Derivative N°2.

This compound is prepared according to the procedure of Example 1 c), from the tosyl derivative described in b) above. White crystals, M.p. = 22O°C (cyclohexane-ethanol). Yield ϊ 50%. - 10 EXAMPLE 3 Preparation of 4-hydroxy-2-methyl-thienor2,3-c]pyridine (I). Derivative N°3. R^ = CH^,· TS.^ = H, a) Preparation of 4-hydroxy-2-methyl-6-tosyl-4,5,6,75 tetrahydro-thienoT2.3-c] pyridine (V) : R^CH^; R^ = H; R^ = p-tolyl.

This compound is prepared according to the procedure of Example 1 a), from 4-hydroxy-2-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride (previously prepared).

White crystals. M.p. = 132°C (benzene); Yield : 48%. b) Preparation of 2-methyl-4-oxo-6-tosyl-4,5,6,7tetrahydro-thienor2,3-c] pyridine (III) : R^CH^; R2= H; R3 = p-tolyl.

This compound is prepared according to the procedure 15 of Example 1 b), from the tosyl derivative described in a) above. Off-white crystals; M.p. 124°C. Yield : 83%. c) Preparation of 4-hydroxy-2-msthyl-thienor2,3-c]pyridine (I) : = CH3; R2 = H. Derivative N°3.

This compound is prepared according to the procedure 20 of Example 1 c', from the tosyl derivative described in b) above. Greyish crystals? M.p. = 22O°C (ethanol-acetonitrile); Yield : 36%.

EXAMPLE 4 Preparation of 4-hydroxy-thienor2.3-c] pyridine : Derivative 25 n°l.

This example is a modification of the process for the preparation of Derivative N°1 illustrated in Example 1. a) Preparation of 4-hydroxy-6-mesyl-4,5,6,7~tetrahydro-thienof2,3-c]pyridine (V) : R^ = R2 = H; Rg = CE^.

To a mixture of 4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride (50 g; 0.26 mole), chloroform (200 ml) and saturated aqueous potassium carbonate solution 4779 - 11 (100 ml) is added dropwise a solution of methanesulfonyl chloride (30 g; 0.26 mole) in chloroform (50 ml), at room temperature and with vigorous mechanical stirring. Stirring is continued a further 2 hours at room temperature. After decantation, the chloroform phase is washed with dilute hydrochloric acid, then with water, and is dried over anhydrous sodium sulfate. Evaporation of the solvent, in vacuo leaves crystals which are reorystallized from methanol.

Light brown crystals; M.p. = 140°C (methanol); Yield : 76%. b) Preparation of 6-mesyl-4-oxo-4,5,6,7-tetrahydrothienor2,3-c1 pyridine (III) : = R2 = H; R3 = CH3.

This compound is prepared according to the procedure of Example lb), from the methane sulfonyl derivative described in a) above. Beige crystals, M.p. = 120°C (isopropanol15 ethyl acetate); Yield : 70%. c) Preparation of 4-hydroxy-thienor2,3 -c] pyridine (I) R1 = *2 = This compound is prepared according to the procedure of Example lc), from the methanesulfonyl derivative described in b) above (Yield ; 80%).

White crystals; M.p. = 2O6°C (ethanol-cyclohexane).

The results of toxicological and pharmacological tests reported below demonstrate the useful activities of the derivatives of the formula (I), typically their anti25 inflammatory activities.

Thus, this invention includes also within its scope a therapeutic composition having, in particular, antiinflammatory activities, comprising, as active ingredient, an efficient amount of a derivative of the formula (I) and/ or a pharmaceutically acceptable acid addition salt thereof, together with usual carriers and excipients. 7 7 S 5 - 12 I - Toxicological investigation The compounds of this invention benefit from an excellent tolerance and a low toxicity. Thus, the LD^^/24 hrs/kg body weight of animals, determined in mice according to the method of Miller & Tainter, by the oral route, is in excess of 800 mg for all derivatives.

In addition, the tests effected on acute toxicity, chronic toxicity, sub-chronic toxicity and delayed toxicity in various animal species failed to disclose any local or systemic reaction, any perturbation in the regularly effected biological controls, and any anomaly in the microscopic and macroscopic examinations effected in the animals sacrificed and autopsied at the end of the experimentation.

IX - Pharmacological investigation The pharmacological investigation concerned the antiinflammatory activity of the compounds of this invention.

This activity was investigated according to 2 methods : a) Method of localized carrageenin-induced edema An 1% (0.1 ml) carrageenin solution is injected in the metatarsal flexor muscles of the right hind limb of rats at time 0. The animals of the treated group are additionally administered orally 100 mg/kg body weight of the test derivative, respectively 1 hour prior to injection of the phlogogenic agent, simultaneously with said injection, and then 1 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 provide a measure, as a function of time, of the percent anti-inflammatory activity, with respect to the reference group.

The results thus obtained are set forth in following Table I. 4779S - 13 TABLE I Percent anti-inflammatory activity after Derivative N° 1 hr 2 hrs 3 hrs 5 hrs 1 40 45 49 49 2 42 48 52 51 3 45 49 50 52 b) Method of the ovalbumin-induced systemic edema A simultaneous intraperitoneal injection of 1 ml ovalbumin and 0.5 ml of 1% aqueous Evans blue solution is effected in rats. On the other hand, the animals of the treated group are orally administered 100 mg/kg body weight of the test derivative, 1 hour prior to ovalbumin administration and simultaneously therewith. 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. Thus are determined, as a function of time, the mean intensity of the edema and the percent decrease of the edema reaction with respect to the reference group. The percent antiinflammatory activity obtained 2 hrs and 3 hrs after ovalbumin injection is set forth in following Table II : TABLE II Percent anti-inflammatory activity after Derivative N° 2 hrs 3 hrs 1 49 58 2 53 61 3 48 60 The results of said investigations demonstrate low toxicity and the valuable anti-inflammatory properties of the derivatives of this invention, which make them highly useful in human and veterinary medicine. 7 9 5 - 14 The therapeutic composition of this invention maybe formulated, for oral administration, as tablets, coated tablets, capsules, drops and syrups. It may also be formula ted, for rectal administration, as suppositories and, for parenteral administration, as injectable solutions.

Each unit dose contains advantageously Ο.Ο1Ο-Ο.25Ο g active ingredient, the daily dosage regimen varying from 0.010 g to 0.750 g active ingredient, according to the age of the patient and the condition treated.

Non-limiting Examples of therapeutic compositions containing compounds of this invention are given below : 1° - Tablets Derivative N°1 .................... 0.100 g Excipient : wheat starch, lactose, gum arabic, silica, magnesium stearate. 2° - Coated tablets Derivative N°3 .................... 0.075 g Excipient: talc, polyvinyl20 pyrrolidone, magnesium stearate, calcium carbonate, shellac, gum arabic, sugar, titanium oxide, glucose, white wax, resin, carnauba wax, lactose, sucrose, tartrazine yellow, patent blue. 3° - Capsules Derivative N°2 .................... 0.150 g Excipient : talc, corn starch, stearic acid. 4779S - 15 4° - Injectable ampoules Derivative N°1.................... 0.100 g Excipient : isotonic solution, sufficient to make 5 ml. o - Suppositories Derivative N°3 ................... 0.100 g Excipient : semi-synthetic triglycerides.

The good tolerance of the derivatives of this 10 invention, together with their substantial anti-inflammatory activities, are apparent from the above toxicological and pharmacological investigations.

Thus, the therapeutic composition of this invention may profitably be administered to humans in the treatment of any inflammatory conditions, whatever their etiology : chronic inflammatory rheumatism; degenerative rheumatism; ab-articular conditions; inflammatory conditions of the otorhino-laryngologic area; in traumatology; in odontostomatology; in post-operative surgery and in gynecology.

Claims (4)

1. CLAIMS :1. Thieno[2,3-c]pyridine derivatives having the following formula : 5 in which and R^, which may be the same or different, represent each a hydrogen atom or an alkyl group, and their pharmaceutically acceptable acid addition salts.

2. Derivatives as claimed in claim 1, wherein the alkyl group is a C^ θ lower alkyl group. 10

3. Therapeutic composition having, in particular, anti-inflammatory activities, comprising, as active ingredient, an efficient amount of at least one compound as claimed in claim 1, together with pharmaceutically acceptable carriers and excipients. 15

4. Therapeutic composition as claimed in claim 3, in unit dosage form, each unit dose containing 10-250 mg active ingredient.