DE2204735A1 - - Google Patents

Description

CATENTANWKLTE DR. E. WIEGAND-DIPUNG. W. NIEMANN 2204735

DR. M. KÖHLER DIPL-ING. C GERNHARDT

MÖNCHEN HAMBURG TELEPHONE: 555 476 8000 MÖNCHEN 15, TELEGRAMS: CARPATENT. NUSSBAUMSTRASSE

February 1, 1972 W 41 002/72

Yoshitomi Pharmaceutica Industries, Ltd., Osaka (Japan)

2-Araino-3-pyridylcarbonyl-thiophene derivatives

The invention relates to new and therapeutically valuable 2-amino-3-pyridylcarbonyl-thiophene derivatives the general formula:

12 3

wherein R, R and R each represent a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, for example a methyl,

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12th

Ethyl, propyl, butyl or isobutyl group or R and R together represent the group - (CH ₂ ), -,
as well as the pharmaceutically acceptable acid addition salts thereof.

The compounds of the general formula I can be prepared by one of the following processes (i) and (ii):

R H denotes, by reacting a compound of the general (i) In the case of the compounds of the general formula I in which

3
RH means

my formula

R ¹ c «0

R - CH ₀

with a compound of the formula

—-I— Il

CH ₀ CO

I ² ^ N ^ III

CN

with sulfur.

The reaction (i) is usually carried out in a solvent, for example methanol, ethanol, 2-propanol, benzene, toluene, Xylene, dimethylformamide, dioxane, tetrahydrofuran or a mixture thereof, preferably in the presence of an organic one Amines, such as cyclohexylamine, diethylamine, morpholine, piperidine or triethylamine, at a temperature of room temperature to reflux temperature about 1 to about 24 hours long carried out.

20 9 8 3 Λ / 1 21 8

(ii) In the case of the compounds of the general formula I in which R is an alkyl group having 1 to 4 carbon atoms in ~ by a compound of the general formula

ix

-N (IT) Z

IV

in the Z is a reactive acid residue, for example one Lower alkanoyl radical, e.g. an acetyl or propionyl radical, an arylsulphonyl radical, e.g. a phenylsulphonyl or p-tolylsulphonyl radical, or an alkylsulfonyl radical, e.g. a methylsulfonyl radical, is hydrolyzed.

The reaction (ii) is usually in a solvent, for example Water, methanol, ethanol, 2-propanol, butanol, acetone, benzene, dioxane, tetrahydrofuran, dimethylformamide or one Mixture of these in the presence of an alkaline compound (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, Potassium carbonate) or an acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid) at a temperature of room temperature to reflux temperature about 1 to about 24 hours long carried out. The starting compounds of the formula IV can are prepared by reacting a compound obtainable by process (i) with a functional derivative (e.g. the acid chloride, the acid anhydride) of an acid of the formula Z-OH and subsequent reaction of the resulting compound of the general formula

2 0 9 8 3 A / 1 2 1 8

in the form of an alkali metal salt with a compound of the general formula

R ³ -Hal VI

where Hai represents a halogen atom (e.g. a chlorine or bromine atom).

The reaction for the preparation of the starting compounds of the formula IV is usually in one of the above solvents at a Temperature from room temperature to reflux temperature about Carried out for 1 to about 24 hours.

The compounds of the formula I can be prepared in the customary manner by treatment with various inorganic and organic Acids, for example hydrochloric acid, hydrobromic acid, Nitric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, succinic acid, oxalic acid and tartaric acid, in the corresponding Acid addition salts are transferred. The connections of the Formula I and its pharmaceutically acceptable acid addition salts have excellent pharmacological effects, e.g. analgesic and anti-inflammatory effects as evidenced by the following tests.

(1) Analgesic effect

A test solution containing the test compound was administered to a group of six male dd-strain mice each weighing about 20 g according to the method of Hendershot et al ("J. Pharmacol.Exptl. Therap.", 125, 237 (1957)) administered orally and one hour later, 0.2 ml of a 0.02% o-phenyl-p-benzoquinone solution was injected intraperitoneally per 20 g of body weight. Then 30 minutes was the frequency of doing this

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induced stretching symptoms and compared with those of a comparison group, from which the inhibition percentage • (therapeutic effect) was calculated. _{The ED, - n} , ie the dose causing a 50% inhibition, was obtained from the dose-effect correlation curve.

(2) Anti-inflammatory effect

According to the method of Winter et al ("Proc.Soc.Exptl.Biol.Med.", 111 , 544 (1962)), a group of five male Donryu strain rats weighing 130 g each were given the test compound containing test solution administered orally. One hour later, 0.05 ml of a 1% carrageenin solution was injected subcutaneously as a phlogogenic substance into the hind paw. Two hours after the administration of the phlogogenic substance, the thickness would ... ..'-. ;; of the paw was measured to determine the percentage increase from the pre-administration condition. The ratio of the ·. Thickness increments between a control group and a test group were calculated as the percentage of inhibition, and the ED ₅₀ , that is, the dose causing 50% inhibition, was obtained from the dose-effect correlation curve.

Results

ED ₅₀ mg / kg Anti-inflammatory
effect link Analgesic effect 50 A. 50 50 B. 50 80 C. 25th 50 D. 25th 70 E. 50

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Compounds A to E in the table above were as follows:

A: 2-Amino-3-nicotinoyl-5-ethylthiophene

B: 2-Amino-3- (2-pyridylcarbonyl) -5-ethylthiophene dimaleate

C: 2-Amino-3-nicotinoyl-5-metb.ylthioph.en

Di 2-methylamino-3- (2-pyridylcarbonyl) -5-ethylthiophene

E: 2-Amino-3- (2-pyridylcarbonyl) -5-methylthiophenedimaleate.

With regard to the various tests including the tests mentioned above, the compounds of the invention can be used in the Formula I and its pharmaceutically acceptable acid addition salts safe as an analgesic anti-inflammatory agent for treatment of various symptoms of inflammation (reddening j Swelling, warming, pain), trauma, postoperative pain and the like in the form of a pharmaceutical preparation with a suitable and conventional carrier or adjuvant which is orally administrable is to be used without endangering the patient. The pharmaceutical preparations can take any conventional form, for example in the form of tablets, capsules, or powder.

Formulation example

50 mg tablets can be made from the following compositions will:

Compound I 50 mg

Lactose. 97 mg

Strength 20 mg

Microcrystalline cellulose 30 mg

Methyl cellulose 1 mg

Magnesium stearate 2 mg

200 mg

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10% powders can be made from the following compositions:

Compound I 10%

Lactose 79%

Strength 10%

Methyl cellulose 1%

100%

The daily dose of Compound I or a salt thereof for adult humans is usually within the range of about 150 to 300 mg for a single or multiple dose, however it may vary depending on the age and / or symptoms of the patient can be varied.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

example 1

A solution of 12 g of butyraldehyde in 9 ml of ethanol was added dropwise over a period of 30 minutes with stirring at 45 to 46 ° C. to a mixture of 25 g of nicotinoyl acetonitrile, 5.5 g of sulfur, 26 ml of dimethylformamide and 14 ml of triethylamine. The resulting mixture was stirred for one hour at 45 to 46 ° C. and then for a further hour at room temperature. 300 ml of ice water was added to the reaction mixture. The crystalline crude product thus formed was collected by filtration and recrystallized from ethanol to give 2-amino-3-nicotinoyl-5-äthylthiophen in the form of pale yellow crystals in 70% yield, mp 150-151 ⁰ C.

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Example 2

To a suspension of 11.2 g of 2- (N-Methy! Acetamido) -3-nicotinoyl-5-ethylthiophene in 20 ml of ethanol, a solution of 1.6 g of sodium hydroxide in 20 ml of water was added and the resulting mixture was refluxed for one hour. Then the mixture was poured into ice water, the aqueous mixture was mixed with Ethyl acetate was extracted, the extract was washed with water and dried over sodium sulfate, and the solvent was distilled off. The crystalline crude product obtained in this way was recrystallized from hexane and 7.6 g of 2-methylamino-3-nicotinoyl-5-ethylthiophene were obtained in the form of pale yellow crystals, mp 70 to 71 ° C.

The starting compound 2- (N-methylacetamido) -3-nicotinoyl-5-ethylthiophene was made in the following way:

To 10 g of 2-amino-3-nicotinoyl-5-ethylthiophene was added 25 ml of acetic anhydride and the solution was refluxed for 10 minutes. Then the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, the solution was washed with water and dried, and the solvent was distilled off. The resulting oil was treated with maleic acid in acetone to give a crude crystalline product which was collected by filtration and recrystallized from a mixture of ethanol and ethyl acetate (1: 2) to give 11.3 g of 2-acetamido-3-nicotinoyl -5-ethylthiophene maleate in the form of pale yellow crystals. This product was gradually brown at 240 ° C and decomposed at 266 ⁰ C. The maleate thus obtained was precipitated by adding 200 ml of water, neutralized with sodium bicarbonate, extracting with three 200 ml

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Portions of ethyl acetate, drying over sodium sulfate and distilling off of the solvent converted into the free base. The 2-acetamido-3-nicotinoyl-5-ethylthiophene remaining in the form of the free base was used for the next implementation.

To a solution of 4 g of 2-acetamido-3-nicotinoyl-5-ethylthiophene in 30 ml of diethylformamide, 0.9 g of sodium hydride (in 50% mineral oil) was added and the resulting mixture became 20 minutes stirred at 50 ° C. for a long time. After cooling, there was 3.8 g of methyl iodide was added and the whole mixture was stirred for 1.5 hours at room temperature. Then 300 ml of ice water were added and the aqueous mixture was added to two 200 ml portions of ethyl acetate extracted. The organic extract layer was washed with water washed and washed with two 30 ml portions of 5% hydrochloric acid extracted again. The acid extract was washed with ethyl acetate and made alkaline with sodium carbonate, the alkaline Solution was extracted with two 200 ml portions of ethyl acetate, with Washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The oily product obtained was purified by column chromatography using silica gel having a particle size of 0.21-0.044 mm (70-325 mesh) and purified from chloroform as eluant. The chlorine ormeluate (12 ml) was concentrated under reduced pressure. The oily residue was treated with oxalic acid in ethyl acetate and a crystalline crude product was obtained Filter and collect from an ethyl acetate / acetone (lsi) mixture Was recrystallized to form 2- (N-Methy! acetamido) -3-nicotinoyl-5-ethylthiophenoxalate in the form of pale yellow crystals, F. 155 to 157 C. The oxalate obtained was by adding · 200 ml of water converted into the free base, with sodium hydrogen

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- ίο -

carbonate neutralized, with three 200 ml portions · ethyl acetate extracted, dried over sodium sulfate and the solvent was distilled off. That which remains in the form of the free base 2- (N-Methylacetamido) -3 ~ nicotinoyl-5-ethylthiophene was used for the next reaction, namely as the starting compound in Example 2, used.

Example 3

Following the same procedure as in Example 2, but using of 2- (N-methyl-p-toluenesulfonamido) -3- (2-pyridylcarbonyl) -5-ethylthiophene (its oxalate: m.p. 104-105 ° C, pale pink crystals) as the starting compound, obtained by reacting 2-amino-3- (2-pyridylcarbonyl) -5-ethylthiophene with p-toluenesulfonyl chloride in Pyridine and subsequent reaction of the 2- (p-toluenesulfonamido) -3- (2-pyridylcarbonyl) -5-ethylthiophene obtained (F. 107 to 109 C, orange crystals) had been prepared with methyl iodide, instead of 2- (N-methylacetamido) -3-nicotinoyl-5-ethylthiophene, 2-methylamino-3- (2-pyridylcarbonyl) -5-ethylthiophene was obtained in the form pale yellow crystals obtained, mp 84 to 85 ° C.

Using the procedure outlined in the example above, but using equivalent amounts of the appropriate starting materials are used, the following connections can also be made:

(1) 2-Amino-3- (2-pyridylcarbonyl) -4,5-dimethylthiophene, pale yellow Crystals, mp 122-123 ° C;

(2) 2-Amino-3- (2-pyridylcarbony1) -4 ₃ 5 _f 6,7 »te trahydro-1-benzthiophene, pale yellow crystals, mp 242 ° C (decomposition);

(3) 2-Amino-3-isonicotinoyl-5-ethylthiophene _? pale yellow crystals, m.p. 216 to 217 ⁰ G;

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(4) 2-Amino-3- (2 ~ pyridylcarbonyl) -5-ethylthiophene hydrochloride, pale brown crystals, mp 219-220 ° C (decomposition); -dimaleate, pale brown crystals, F. 113 - 114 Cj

(5) 2-AmInO-S-HiCOtInOyI ^, 5-dimethylthiophene, pale yellow crystals, M.p. 185 to 186 ° C (decomposition);

(6) 2-Amino-3-nicotinoyl-5-methylthiophene, pale yellow crystals,

F. 144 to 145 ° C and

(7) 2-Amino-3- (2-pyridylcarbonyl) -5-methylthiophene-dimaleate _> brown crystals, m.p. 116-117 ° C.

Although the present invention is based on specific Embodiments and examples explained is for it will be clear to those skilled in the art that this can be changed and modified in many ways without thereby affecting the scope of the present invention Invention is abandoned.

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Claims (1)

- 12 claims 2-Amino-3-pyridylcarbonyl-thiophene derivatives, characterized by the general formula R ¹ T .- CO 12 3
wherein R, R and R each represent a hydrogen atom or a 1 alkyl group with 1 to 4 carbon atoms or R and R together represent the group - (CH ₂ ), -, and their pharmaceutically acceptable acid addition salts. 2. 2-Amino-3-nicotinoyl-5-ethylthiophene. 3. 2-Amino-3- (2-pyridylcarbony1) -4,5-dimethylthiophene. 4. 2-Amino-3- (2-pyridylcarbonyl) -4,5,6,7-tetrahydro-1-benzthiophene, 5. 2-methylamino-3-nicotinoyl-5-ethylthiophene. 6. 2-methylamino-3- (2-pyridylcarbonyl) -5-ethylthiophene. 7. 2-Amino-3-isonicotinoyl-5-ethylthiophene .. 8. 2-Amino-3- (2-pyridylcarbonyl) -5-ethylthiophene. 9. 2-Amino-3-nicotinoy1-4,5-dimethylthiophene. 209834/1218 -ΒΙΟ. 2-amino-3-nicotinoyl-5-methylthiophene. 11. 2-Amino-3- (2-pyridylcarbonyl) -5-methylthiophene. 12. Pharmaceutical preparation, characterized in that it contains at least one compound according to one of the claims as active ingredient 1 to 11 and a pharmaceutically acceptable diluent (carrier). 209834/1218