CS225015B1 - 2-alkylthio-6 benzoylaminobenzotiazoly - Google Patents

Abstract

The purpose of the invention is the preparation of previously unknown 2-alkylthio-6-benzoylaminobenzothiazoles of the general formula where R represents ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, n-amyl, isoamyl, occlopentyl or 2-hydroxyethyl. The preparation is carried out by dissolving 6-benzoylamino-2-benzothiazolinethione in a potassium hydroxide solution and alkylating the potassium salt of 6-benzoylamino-2-mercaptobenzothiazole thus obtained with alkyl halides. The prepared compounds are antimycobacterially active against typical and atypical tuberculous mycobacteria and have low acute toxicity. Particularly significant is the activity against Myoobacterium tuberoulosis INH-R and Myoobacterium avium. The compounds according to the invention can be used as an active ingredient of antimycobacterial preparations and as intermediates for further syntheses.

Description

The purpose of the invention is the preparation of previously unknown 2-alkylthio-6-benzoylaminobenzothiazoles of the general formula

where R is ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, n-amyl, isoamyl, cyclopentyl or 2-hydroxyethyl.

The preparation is carried out by dissolving 6-benzoylamino-2-benzothiazolinethione in a potassium hydroxide solution and alkylating the thus obtained potassium salt of 6-benzoylamino-2-mercaptobenzothiazole with alkyl halides.

The prepared compounds are antimycobacterially active against typical and atypical tuberculous mycobacteria and have low acute toxicity. Particularly significant is the activity against Mycobacterium tuberoulosis INH-R and Mycobacterium avium. The compounds according to the invention can be used as an active ingredient of antimycobacterial preparations and as intermediates for further syntheses.

Prior to the invention are 1-alkylthio-b-beijisoylnimlnobenzotinsolve.

6-benzoylamino-2-sec.butylthiobenzothiazole is effective against typical and atypical tuberculous mycobacteria (Sidóová E. and Odlerová Ž., Czechoslovak AO 207 299 /1980/).

We have now found that 1 further, previously unknown 2-alkylthio-6-benzoylaminobenzothiazoles of the general formula

where R represents ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, n-amyl, isoamyl, cyclopentyl or 2-hydroxyethyl, are antimycobacterially active against typical and atypical tuberculous mycobacteria.

At the same time, a method of preparing the above compounds based on 6-benzoylamino-2-benzothiazolinethione was discovered, which is characterized in that by dissolving it in a potassium hydroxide solution, the potassium salt of 6-benzoylamino-2-mercaptobenzothiazole is prepared and this is allowed to react with an alkyl halide.

The following examples illustrate, but do not limit, the preparation and properties of the compounds of the invention.

Example

Preparation of 6-benzoylamino-2-ethylthiobenzothiazole

To 6-benzoylamino-2-benzothiazolinthione (8.8 g, 0.03 mol) was added ethyl alcohol (75 ml), a solution of potassium hydroxide (2.0 g, 0.036 mol) in water (25 ml) and ethyl iodide (5.6 g, 0.036 mol). The reaction mixture was refluxed for 5 minutes. After cooling the mixture to 5 °C, 6-benzoylamino-2-ethylthiobenzothiazole with a mp of 144-146.5 °C precipitated from the solution in an amount of 8.9 g (94.5%).

The sample was recrystallized from a 5:1 mixture of ethyl alcohol and water using activated charcoal to give a white crystalline product with a melting point of 145.5-146.5 °C.

For C ₎₆ H ₁₄ N ₂ OS ₂ (314.43) calculated: C 61.12 H 4.49 N 8.91 S 20.39 found %: 60.92 4.51 8.86 20.35

Example 2

Preparation of 6-benzoylamino-2-n-propylthiobenzothiazole

The preparation was carried out according to Example 1 using n-propyl iodide (6.1 g, 0.036 mol) with the difference that the reaction mixture was decolorized with activated carbon before cooling. The yield was 70.1%.

The sample was recrystallized from a 4:1 mixture of ethyl alcohol and water using activated charcoal.

M.p.: 130 to 132°C.

_{For C17H16N2OS2} ( _328.46 ) calculated: _{C62.17H4.91N8.53S19.52} found: 62.174.848.5319.55

Example 3

Preparation of 6-benzoylamino-2-isopropylthiobenzothiazole

The preparation was carried out according to Example 2 using isopropyl bromide (4.4 g, 0.036 mol) with a 50.0% yield.

The sample did not require further cleaning after rinsing with ethyl alcohol.

M.p.: 154 to 156°C.

For _C17H16N2OS2 (328.46) calculated: C _62.17 H 4.91 _N 8.53 S 19.52 found «: 61.97 4.98 8.54 _19.29

Example 4

Preparation of 2-allylthio-6-benzoylaminobenzothiazole

The preparation was carried out as in Example 1 using allyl bromide (4.4 g, 0.036 mol) except that the reflux time was 10 minutes and the reaction mixture was decolorized with activated carbon before cooling. The yield was 65.1%.

The sample did not require further cleaning after rinsing with ethyl alcohol.

M.p.: 134 to 136°C.

For _C17H14N2OS2 ( _{326.44 )} calculated: C62.55H4.32N8.58S19.64 found: _{62.304.258.5619.60}

Example 5

Preparation of 6-benzoylamino-2-n-butylthiobenzothiazole

The preparation was carried out according to example 1 using n-butyl iodide (6.6 g, 0.036 mol) with a 90.8% yield.

The sample did not require further cleaning after rinsing with ethyl alcohol.

M.p.: 139 to 140°C.

For C ₁₈ H ₁₈ N ₂ 0S ₂ (342.48) calculated: C 63.13 H 5.30 N 8.18 S 18.72 found 62.81 5.27 8.02 18.65

Example 6

Preparation of 6-benzoylamino-2-isobutylthiobenzothiazole

The preparation was carried out according to Example 4 using isobutyl iodide (6.6 g, 0.036 mol) with a 71.6% yield.

The sample was recrystallized from a 6:1 mixture of ethyl alcohol and water using activated charcoal.

M.p.: 151.5 to 153°C.

For C. _n H _in N _o 0S, (342.48) calculated: C 63.13 H 5.30 «8.18 S 18.72 ^{18182 2} found %: 63.22 5.34 8.16 18.62

Example 7

Preparation of 2-n-amylthio-6-benzoylaminobenzothiazole

The preparation was carried out according to Example 1 using n-amyl iodide (7.2 g, 0.036 mol) and a reflux time of 15 minutes with 89.3% yield.

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225015 ⁴ '

The sample was recrystallized from benzene using activated charcoal.

M.P.: 151 to 153 °C.

For C ₁₉ H ₂₀ N ₂ OS ₂ (356.51) calculated: 0.64.01 H 5.65 N 7.86 S 17.99 found «: 64.23 5.69 7.90 17.80

Example 8 w

Preparation of 6-benzoylamino-2-isoamylthiobenzothiazole

The preparation was carried out according to Example 1 using isoamyl iodide (7.2 g, 0.036 mol) and a reaction time of 45 minutes with 85.0% yield.

The sample did not require further cleaning after rinsing with ethyl alcohol.

M.p.: 134 to 136°C.

For C ₁₉ H ₂₀ N ₂ OS ₂ (356.51) calculated: 0 64.01 H 5.65 íí 7.86 S 17.99 found %·. 63.73 5.42 7.58 17.88

Example 9

Preparation of 6-benzoylamino-2-cyclopentylthiobenzothiazole

The preparation was carried out according to Example 1 using cyclopentyl iodide (7.1 g, 0.036 mol) with the difference that the reaction mixture was decolorized with activated carbon before cooling. The yield was 53.3%.

The sample was recrystallized from an 8:1 mixture of ethyl alcohol and water using activated charcoal.

M.p.: 165 to 166.5°C.

For C^gNgOSg (354.49) calculated: 0 64.38 H5.12 N 7.90 S 18.09 found %: 64.25 5.13 7.90 18.12

Example

Preparation of 6-benzoylamino-2-(2-hydroxyethyl)thiobenzothiazole

The preparation was carried out according to Example 1 using ethylene chlorohydrin (2.9 g,

0.036 mol) and using a 30 minute reaction time. Before cooling, the reaction mixture was decolorized with activated carbon and diluted with water to double volume. The yield was 82.8%.

The sample was recrystallized from an 8:1 mixture of ethyl alcohol and water using activated charcoal.

M.p.: 163 to 165°C.

For C ₁₆ H _{) 4} N ₂ O ₂ S ₂ (330.43) calculated: C 58.16 H 4.27 N 8.48 S 19.41 detected %: 58.44 4.29 8.41 19.40 Example 11 Antimycobacterial activity of compounds under Ta invention compared to with the effectiveness of Izoni-

azide(INH).

Minimum inhibitory concentration (MIC) of the compounds of the invention compared to the MIC of Isoniazid (INH), given: a) in mol/1.10^, b) in µg/ml.

Compound according to the example Mycobacterium (M.) ^H 37 ^R v tuberculosis INH-R M. bird M. kansas and b and b and b and b 1 33 103.6 11 34.5 >33 >103.6 >33 >103.6 2 33 108.2 11 36.0 >33 >108.2 >33 >’08.2 3 3.7 12.1 3.7 12.1 1.2 3.9 3.7 12.1 4 33 107.5 11 35.8 >33 >107.5 3.7 12.0 5 >33 >112.9 33 Ί2.9 >33 >112.9 >33 >112.9 6 3.7 12.6 3.7 12.6 3.7 12.6 3.7 12.6 7 33 >117.8 33 117.8 >33 >117.8 >33 >117.8 8 >33 >117.8 3.7 13.2 >33 >117.8 >33 >117.8 9 >33 115.8 3.7 13.0 3.7 13.0 3.7 13.0 10 1.2 3.9 ’,2 3.9 1.2 3.9 1.2 3.9 INH 0.4 0.5 33 45.2 11 15.0 ’,2 1.6

Antimycobacterial activity against tuberculous mycobacteria was monitored in liquid and semi-synthetic Šulová medium. The strains used for testing were Myeobacterium (M.) tuberculosis (collection VÚPL, Bratislava), M. tuberculosis INH-R and M. avium (collection KHS Brno) and M. kansasii PKG 8 (collection Dr. Runyon, Salt Lake City, USA).

By weighing according to molecular weight, molar solutions of the substances in dimethyl sulfoxide were prepared and added to p5d in a constant solvent volume of 1% in the following concentrations: 0.4.10' ⁵ , 1.2.10 ^-5 , 3.7.10 ^- 11.10”^ and 33.10”^ mol/1. Isonicotinic hydrazide (Isoniazid, INH; Jenapharm, GDR) was tested under the same experimental conditions.

Example 12

Maximum Tolerated Dose (MTD) of the compounds according to the invention compared to the MTD found for Isoniazid

The maximum tolerated dose, which provides information on acute toxicity, was determined in white ICR mice weighing 20 g by single administration of the substance by esophageal gavage according to the method described by Wagner (Wagner, W.H., Advan. Tubercul. Res., Vol. 9, 104-177. Karger, Basel, 1958.). The DTM of the compounds according to examples 3, 6 and 10 and the DTM of Isoniazid were determined.

The DTM of the compounds mentioned for the invention was 250 mg/kg, while the DTM of Isoniazid was 125 mg/kg.

It is significant that some compounds according to the invention are several times more effective against M. tuberculosis INH-R and M. avium than Isoniazid and are also highly effective against M. tuberculosis ^H 37 ^R V ^{and M} · kansasii, but at the same time their DTM is twice as high as the DTM of Isoniazid, i.e. compared to Isoniazid they have only half the acute toxicity.

The compounds of the invention can be used as an active ingredient in antimycobacterial preparations or as intermediates for further synthesis.

Claims (2)

225015 Compound 1od of Example Mvcobacterium (M.) H37Rv tuberculosis INH-R M. avium M. kansasii abababab 1 33 103,6 11 34,5> 33> 103,6> 33> 103,6 2 33 108,2 11 36,0> 33> 108,2> 33> '08, 2 3 3,7 12,1 3,7 12,1 1,2 3,9 3,7 12,1 4 33 107,5 11 35,8 > 33> 107,5 3,7 12,0 5> 33> 112,9 33 Ί2.9> 33> 112,9> 33> 112,9 6 3,7 12,6 3,7 12,6 3, 7 12.6 3.7 12.6 7 33> 117.8 33 117.8> 33> 117.8> 33> 117.8 8> 33> 117.8 3.7 13.2> 33> 117, 8> 33> 117,8 9> 33 115,8 3,7 13,0 3,7 13,0 3,7 13,0 10 1,2 3,9 ', 2 3,9 1,2 3,9 1,2 3,9 INH 0,4 0,5 33 45,2 11 15,0 ', 2 1,6 Antimycobacterial activity against tuberculous mycobacteria has been observed in liquid semisynthesis of pulae Sula. For testing, Myeobacterium (M.) tuberculosis Η ^ γΚ ^ (VÚPL collection, Bratislava), M. tuberculosis INH-R and M. avium (collection of KHS Brno) and M. kansasii PKG 8 (Dr. Runyon, Salt Lake City, USA). Molecular weight weights were prepared in dimethyl sulphoxide and added to p5d in a 1% constant volume solvent at the following concentrations: 0.4.10 "5, 1.2.10-5, 3.7.10-11.10" ^ and 33.10 µmol / l. Isonicotin hydrazide (Izoniazid, INH; Jenapharm, NDR) was tested under the same experimental conditions. EXAMPLE 12 Dosis Tolerance Maximum (DTM) of the Compounds of the Invention Compared to DTM Detected for Izoniazid Dosis Tolerata maxima, which provides information on acute toxicity, was determined on a white ICR mouse weighing 20 g with a single dose of the oesophageal probe. The method described by Wagner (Wagner, WH, Advan. Tubercul. Res., Vol. 9, 104-177. Karger, Basel, 1958). The DTM compounds of Examples 3, 6 and 10 and DTM of Isoniazid were determined. The DTMs of the compounds p: a1 of the invention were 250 mg / kg, while the DTM of Isoniazid was 125 mg / kg. Significantly, some of the compounds of the invention, by their potency against M. tuberculosis INH-R and M. avium, are several times higher than Isoniazid and yet are highly effective against M. tuberculosis H37RV and M · kansasii, while their DTM is twice as potent. higher than the DTM of Isoniazid, thus having only half the acute toxicity compared to Isoniazid. The compounds of the invention may be used as an active ingredient of antimycobacterial preparations or as intermediates for saline synthesis. OBJECT OF THE INVENTION 1. 2-alkylthio-6-benzoylaminobenzothiazoles of the general formula Wherein R is ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, n-amyl, isoamyl, cyclo-parityl or 2-hydroxymethyl. 2. A process for the preparation of compounds according to claim 1, characterized in that a potassium β-6-benzoylamino-2-mercaptobenzothiazole is reacted with an alkyl halide of formula (SX) wherein X is chloro, bromo or iodo and R is as defined in (1), ethyl alcohol-water 3: 1 at boiling for 5 to 45 moderate.