CS213038B1 - Arylthioacetamidoximes - Google Patents

Description

The present invention relates to arylthioacetamidoximes of formula I,

-SCHiC '

NH, (I)

3 wherein each of R and R is hydrogen or mettioxyl, R is hydrogen, methyl, ethyl, chlorine, methoxy, ethoxy, methylthio or ethylthio, or wherein R, R or R, R together are indicates strings

3

-CH = Cl-CH = CH- or - (CHg) 2 -, wherein at least one of R, R, R is different from hydrogen, and salts thereof with pharmaceutically acceptable inorganic or organic acids, preferably hydrochlorides. The compounds of the formula I and their salts show antireserpia activity in mice and are therefore suitable as medicaments for mental depression.

The following are a few typical compounds of Formula 1 for which acute toxicity values in mice (LU-θ in mg / kg by intravenous administration) and doses that significantly antagonize reserpine ptosis in mice (ED in mg / kg) are given. kg by intraperitoneal administration): (4-chlorophenylthio) acetamidoxime (hydrochloride) 125, 25; (2-methoxyphenylthioacetamidoxime (hydrochloride), 125, 25; (3-methoxyphenylthlo) acetamidoxime (hydrochloride), 120, 24; (4-methylthiophenylthio) acetamidoxime hydrochloride), 120, 24; (3,4-dimethoxyphenylthio) acetamidoxime (hydrochloride), 175, 35; (2-naphthylthio) acetamidoxime (hydrochloride), 120, 24

213 038

The compounds of the invention also show antagonist activity against reserpine hypothermia in mice (effective doses of ED in mg / kg, which, when administered intraperitoneally, increase the rectal temperature of mice by 1 ° C compared to the control reserpine group): (3-methoxyphenylthio) acetamidoxime (hydrochloride, 24; (1-naphthylthio) acetamidoxime (hydrochloride), 10. The compounds of the invention also have a moderate central stimulatory effect, which results in a significant increase in the spontaneous motility of the mouse in a known environment; (4-Chlorophenylthio) aceamidoxime (hydrochloride) also exhibits a hypotensive effect (a dose of 25 mg / kg iv reduces the blood pressure of normotensive tays by 20% for at least 10 min), diuretic effect (oral dose of 100 mg / kg increases diuresis in mice by 100% compared to control group) and antitussive effect (oral dose of 125 mg / kg reduces the cough activity of rats induced by aerosol of aqueous citric acid solution to 52% compared to control). Thus, it is apparent that the compounds of the invention have therapeutically useful effects, so that they must be of technical importance.

The compounds of the invention are prepared by the procedures described in the Examples. The starting materials are thiopherols of formula 11,

These thiophenols are generally known and can be obtained either as commercial reagents or by procedures described in the literature (in which case references are given in the examples). These thiophenols are converted by reaction with an equivalent of a solution of sodium methoxide in methanol into sodium salts which are treated with chloroacetonitrile in boiling methanol. (Arylthio) acetonitriles of formula III

SCH ^ CN (III)

3 in which the symbols R to R denote again the same as in formula I,

Most of these intermediates are new; if they have already been described in the literature (albeit by a different methodology), the corresponding reference is again given in the exemplary embodiment. The conversion of the nitriles II to amidoximes I is carried out by reaction with hash of hydroxylamine (liberated from hydroxylamine hydrochloride by reaction with an equivalent of a solution of sodium methoxide in methanol) in boiling methanol. First, amidoxime bases of the formula I are obtained from the reaction mixtures with isolation processes, some of which crystallize well and can be purified and characterized by crystallization. The crude oily bases of formula I or the pure crystalline base of formula I are converted to the corresponding salts by acid neutralization. When using a solution of anhydrous hydrogen chloride in ether or a mixture of ethanol and ether, well-crystalline hydrochlorides are obtained which are soluble in water and are more suitable than the free bases for the preparation of dosage forms and for carrying out animal pharmacological tests.

, 213 038

Further details of the preparation of the compounds according to the invention are given in the examples, where the characteristics of the compounds according to the invention (base and salts) are also given.

Examples

1. (4-Ethoxyphenyl (thio) acetamidoxime)

To a solution of 30.9 g of 4-ethoxythiophenol (M.Protiva et al., CoUect.Czech.Chem.Comrnun. 29. 2161, 1964) in 60 ml of methanol is added a solution of sodium methoxide prepared by dissolving 1.6 g of sodium in 115 ml. of methanol. The solution was stirred at room temperature for 15 min and then 15.1 g of chloroacetonitrile was slowly added dropwise. The mixture was stirred at room temperature for 2 h and then refluxed for 5 h. It is filtered while hot and the filtrate is evaporated under reduced pressure. The residue was dissolved in 35 ml of hot ethanol and crystallized upon cooling. 31.0 g (80%) of new (4-ethoxyphenylthio) acetonitrile of m.p. Mp 67-68 ° C. Recrystallization from ethanol no longer increases.

Treatment of 13.2 hydroxylamine hydrochloride with a solution of sodium methoxide, prepared by dissolving 4.4 g of sodium in 75 ml of methanol, gives a hydroxylamine base solution to which 31.0 g of (4-ethoxyphenylthio) acetonitrile is added and the mixture is refluxed for 5 hours. cooler. It is filtered while hot and the filtrate is evaporated. under reduced pressure. The residue crystallized from a mixture of hexane and ether. Filtration gave 29.5 g (65%) of (4-ethoxy-phenylthio) -acetamidoxime base, m.p.

- 55 ° C. A solution of 29.5 g of this base in 70 ml of ethanol was neutralized by adding a solution of anhydrous hydrogen chloride in ether. On standing, 21.5 g of hydrochloride crystallized. 125-128 [deg.] C. Recrystallization from ethanol / ether gave analytically pure product, m.p. 127-129 [deg.] C.

2. (4-Methylphenylthio) acetamidoxime

Similar to Example 1, 4-methylthiophenol is reacted with chloroacetonitrile in 91% yield of (4-methylphenylthio) acetonitrile, boiling at 168-170 / 4.27 kPa (see also AA 3antilli et al., US Pat. 3,553.198; Chem. Abstr. (£ 5, 5935, 1971). Subsequent reaction with hydroxylamine gave 90% yield of (4-methylphenylthio) acetamidoxime base, melting at 67.5-69.5 ° C (hexane). It gives a hydrochloride crystallizing from a mixture of ethanol and ether and melting at 142-145 ° C.

3. (4-Ethylphenylthio) acetamidoxime

Similar to Example 1, 4-ethylthiophenol (K.Pelz and M. Protiva, Collect.Cechech.Commun. 32, 2161, 1987) is obtained in 56% yield of new (4-ethylphenylthio) acetonitrile, b.p. 138 [deg.] C / 0.13 kPa. Subsequent reaction with hydroxylamine afforded an oily base of (4-ethylphenylthio) acetamidoxime in 90% yield to give the hydrochloride, m.p. 125-128 ° C (ethanol ether).

4. (4-Chlorophenylthio) acetamidoxime

Similar to Example 1, 4-chlorothiophenol was reacted with chloroacetonitrile in 63% yield of (4-chlorophenylthio) acetonitrile melting at 88-89 ° C (see also EAFalco et al., J. Org. Chem. 26, 1143, 1961). Subsequent reaction with hydroxylamine afforded an oily base of (4-chlorophenylthio) acetamidoxime in 77% yield to give the hydrochloride, m.p. 140.5-142 ° C (ethanol-ether).

213 038

5. (2-Methoxyphenylthioacetamidoxime)

Similar to Example 1, the reaction of 2-methoxythiophenol (F.Mauthner. Ser.Deut. Chem. Ges. 39, 1348, 1906) with chloroacetonitrile is obtained in 75% yield of new (2-methoxyphenylthio) acetonitrile, boiling at 132 ° C. -134 ° C / 0.07 kPa. Subsequent reaction with hydroxylamine yielded a crystalline base of (2-methoxyphenylthio) acetamidoxime in 75% yield, melting at 113-115 ° C (benzene). It gives the hydrochloride melting at 120-122 ° C (ethanol-ether).

6. (3-Methoxyphenylthio) acetamidoxime

Similar to Example 1, reaction of 3-methoxythiophenol (F.Mauthner, Ser. Deut. Chem. Ges. 39, 3596, 1906) with chloroacetonitrile is obtained in 48% yield of new (3-methoxyphenylthio) acetonitrile with b.p. 164-168 [deg.] C / 0.31 kPa. Subsequent treatment with hydroxylamine affords an oily base (3-methoxyphenylthiolacetamidoxime) in 40% yield, which affords the hydrochloride melting at 114-116 ° C (ethanol-ether).

7. (4-Methoxyphenylthio) acetamidoxime

8. (4-Methylthiophenyl) acetamidoxime

Similar to Example 1, by reacting 4- (methylthio) thiophenol (J.O. Jílek et al. Collect.Cech.Sommun. 39, 3338, 1974) with chloroacetonitrile in 60% yield, new (4-methylthio phenylthio) acetonitrile with m.p. 62-64 ° C (ethanol). Subsequent reaction with hydroxylamine yielded in 79% yield a crystalline base of (4-methylthiophenylthio) acetoamidoxime, melting at 70-72 ° C (benzene). It provides the hydrochloride with m.p. 143-146 ° C (ethanol-ether).

9. (4-Ethylthiophenylthio) acetamidoxime

Similar to Example 1, 4- (ethylthio) thiophenol (JO Jílek et al. Collect.Czech.Chem.Commun. 39. 3338, 1974) is obtained with chloroacetonitrile new (4-ethylthiophenylthio) acetonitrile (tl 168- 170 DEG C./0.11 kPa) in a yield of 66%. Subsequent reaction with hydroxylamine yields a crystalline base of (4-ethylthiophenylthio) acetamidoxime in 80% yield, m.p. 63-66 ° C (benzene-petroleum ether). It gives the hydrochloride melting at 117-119 ° C (ethanol-ether).

10. (2-Methoxy-4-chlorophenylthio) acetamide oxime

Similar to Example 1, by reacting 2-methoxy-1-chlorothiophenol (JOJílek et al., Collect.Czech.Chem.Commun. 43, 1747, 1978) with 38% yield, new (2-methoxy-4) is obtained. (chlorophenylthio) acetonitrile boiling at 176 ° C / 0.33 kPa. Subsequent reaction with hydroxylamine afforded an oily base of (2-methoxy-4-chlorophenylthio) acetamidoxime in 70% yield to give the hydrochloride, m.p. 152-154 ° C (ethanol-ether).

11. (3-Methoxy-4-chlorophenylthio) acetamidoxime

Similar to Example 1, by reacting 3-methoxy-1-chlorothiophenol (I. Red et al., Collect.Czech.Chem.Commun. 42, 1705, 1977) with chloroacetonitrile in 70% yield, a new (3-methoxy- 4-chlorophenylthio) acetonitrile, boiling at 168 ° C / 0.19 kPa. Subsequent reaction afforded a crystalline base of (3-methoxy-4-chlorophenylthio) acetamidoxime in 60% yield, mp 139-141 ° C (benzene). It gives the hydrochloride melting at 143-145 ° C (ethanol-ether).

12. (3,4-Dimethoxyphenylthie) acetamidoxime

Similar to Example 1, a new (3,4-dimethoxyphenylthia) was obtained by reacting 3,4-di-rethoxythiophenol (K.Fries et al., Justus Liebig Ann.Chem. 468. 172, 1929) in 74% yield. Acetonitrile with mp 101-103 ° C (ethanol). Subsequent reaction with hydroxyl

213,038 amine in 66% yield of crystalline base (3,4 ^r 'imethoxyfenylthio) acetamide oxime, m.p. 142-144 ° C (ethanil). Mp 179-182 ° C (methanol-ether).

13. (1-Naphthyl) acetamidoxime

Similar to Example 1, a new (1-naphthylthio) acetonitrile is obtained in a 70% yield by reacting 1-thionaphthol (F. Taboury, Suli.Soc.Chim.Fr. / 3/29, 761, 1903) in 70% yield. ° C / 0.21 kPa. Subsequent treatment with hydroxylamine affords an oily base of (1-naphthylthio) acetamidoxime in 48% yield, which yields crystalline hydrochloride melting at 139-141 ° C (ethanol-ether).

14. (2-Naphthylthio) acetamidoxime

Similar to Example 1, reaction of 2-thionaphthol (O.Dann and M. Kokorudz, Chem. 3er. 91, 172, 1958) with chloroacetonitrile is obtained in 54% yield of (2-naphthylthio) acetoritrile, melting at 81-84 ° C (see also AASantilli et al., US Pat. 3,553.198; Chem.Abstr. 75, 5935, 1971). Subsequent reaction with hydroxylamine yields a crystalline base of (2-naphthylthio) acetamidoxime in 88% yield, m.p. Mp 93-96 ° C. It gives the hydrochloride melting at 149-152 ° C (ethanol-ether).

15. (5,6,7,8-Tetrahydro-1-naphthylthio) acetamidoxime

Similar to Example 1, it is obtained by reacting 5,6,7,8-tetrahydro-1-thionaphthal (F. Rollpfeiffer et al., Ser.Deut.ChemTGes. 58, 1654, 1925) with chloroacetonitrile in 78% yield. New (5,6,7,8-tetrahydro-1-naphthylthio) acetonitrile 160-162 ° C / 1.33kRa. Subsequent reaction with hydroxylamine affords an oily base of (5,6,7,8-tetrahydro-1-naphthylthio) acetamidoxime in 70% yield, which yields crystalline hydrochloride melting at 148-152 ° C (ethanol-ether).

16. (5,6,7,8-Retrahydro-2-naphthylthio) acetamidoxime

Similar to Example 1, 5,6,7,8-tetrahydro-2-thionaphthol (W. Davies and QNPorter, J. Chem. Soc. 1956, 2609) is obtained by reacting chloroacetonitrile in 70% yield. 6,7,8-tetrahydro-2-naphthylthio) acetonitrile boiling at 173 ° C / 0.19 kPa. Subsequent treatment with hydroxylamine afforded an oily base of (5,6,7,8-tetrahydro-2-naphthylthio) acetamidoxime in 75% yield, which afforded crystalline hydrochloride melting at 139-141 ° C (ethanol-ether).

Claims (1)

SUBJECT OF THE INVENTION Arthioacetamidoxymy of formula I, Wherein each of R and R is hydrogen or methoxy, R is hydrogen, methyl, ethyl, chlorine, methoxy, ethoxy, methylthio, or ethylthio, Or wherein the substituents R, R or R, R together denote the chains -CH = Cl-CH = CH- or 1 2 3 (CHg) 2 -, provided that at least one of the substituents R, R ^J , R is different from hydrogen, and their salts with pharmaceutically acceptable inorganic or organic acids, preferably hydrochlorides.