Abstract
Full Text
CHEMISTRY
L. F. TREFILOVA and I. Ya. POSTOVSKII
SOME DIPHENYL DERIVATIVES AND THEIR TUBERCULOSTATIC ACTIVITY
(Presented by Academician I. N. Nazarov, January 15, 1957)
It is known that unsubstituted aniline has tuberculostatic action in vitro at a concentration of \(2 \cdot 10^{-4}\) mol/l \((^1)\). Para-substituted anilines—4-aminophenol, 4-methoxyaniline, 4-ethoxyaniline, 4-propoxyaniline—show greater activity: their tuberculostatic action appears at concentrations of \(2 \cdot 10^{-4}\), \(1 \cdot 10^{-5}\), \(1.25 \cdot 10^{-6}\), \(6.25 \cdot 10^{-7}\) mol/l \((^2)\). A significantly more active compound than aniline proved to be 4-aminodiphenyl: it shows tuberculostatic action already at a concentration of \(1.25 \cdot 10^{-7}\) mol/l \((^4)\). Taking these observations into account, Ch. P. Ivanov and I. M. Panaiotov \((^5)\) synthesized 4-hydroxy-4-aminodiphenyl and its alkyl ethers for testing their tuberculostatic activity.
Among derivatives of aromatic amines, azomethines and thiourea derivatives may be of interest as tuberculostatic compounds. The tuberculostatic activity of azomethines had already been studied earlier by Erlenmeyer and co-workers \((^6)\) and by Bäuzer and co-authors \((^7)\). The fungicidal action of certain azomethines is also known \((^8)\). As for thiourea derivatives, they have more than once been the subject of investigations of their antitubercular and fungicidal properties \((^9)\).
In the course of our investigations on the synthesis of compounds with possible antitubercular action, starting from 4-aminodiphenyl and its para-alkoxy derivatives, we obtained a series of new diphenyl derivatives, in particular azomethines (Table 1) and \(N,N'\)-substituted thioureas (Table 2). In addition, azomethines—derivatives of 4-diphenylaldehyde—were obtained.
The azomethines (Table 1) were obtained in almost quantitative yield by heating, in alcoholic solution, equimolecular amounts of 4-aminodiphenyl and its \(n\)-alkoxy derivatives with various aromatic aldehydes (benzaldehydes 1–5, salicylic aldehyde 6–10, vanillin 11–15, para-acetylaminobenzaldehyde 16–20, cinnamic aldehyde 21–25, piperonal 26), and also with furfural 27–31 and 9-formylacridine 32. Azomethines from 4-diphenylaldehyde were synthesized by reaction of this aldehyde with aromatic amines (aniline 33, \(n\)-anisidine 34, sulfanilamide 35, 4-aminodiphenyl 36, and 4-amino-4-methoxydiphenyl 37). The azomethines obtained are yellowish or yellow crystalline substances that crystallize well from alcohol, acetone, and dioxane.
Derivatives of \(N\)-diphenyl-\(N'\)-phenylthiourea (Table 2) were obtained in good yield (80–96%) by heating, in alcoholic solution, equimolecular amounts of 4-aminodiphenyl and its \(n\)-alkoxy derivatives with various mustard oils (allyl mustard oil 1–5, \(n\)-methoxyphenyl mustard oil 6–10, \(n\)-ethoxyphenyl mustard oil 11–15, \(n\)-chlorophenyl mustard oil 16–20). The thioureas obtained are colorless crystalline substances crystallizing from alcohol.
Table 1
| No. | Compound | Substituent (X) | Empirical formula | M.p., °C | N, % found | N, % calc. |
|---|---|---|---|---|---|---|
| 1 | X–C₆H₄–C₆H₄–N=CH–C₆H₅ | H | C₁₉H₁₅N | 147–148¹⁰ | ||
| 2 | X–C₆H₄–C₆H₄–N=CH–C₆H₅ | HO | C₁₉H₁₅ON | 202–203¹¹ | ||
| 3 | X–C₆H₄–C₆H₄–N=CH–C₆H₅ | CH₃O | C₂₀H₁₇ON | 173–174 | 4.99 | 4.88 |
| 4 | X–C₆H₄–C₆H₄–N=CH–C₆H₅ | C₂H₅O | C₂₁H₁₉ON | 146–147 | 4.90 | 4.65 |
| 5 | X–C₆H₄–C₆H₄–N=CH–C₆H₅ | C₄H₉O | C₂₃H₂₃ON | 180–181 | 4.29 | 4.25 |
| 6 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–OH | H | C₁₉H₁₅ON | 140–141 | 5.29 | 5.13 |
| 7 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–OH | HO | C₁₉H₁₅O₂N | 210–212 | 4.85 | 4.84 |
| 8 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–OH | CH₃O | C₂₀H₁₇O₂N | 193–194 | 4.65 | 4.62 |
| 9 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–OH | C₂H₅O | C₂₁H₁₉O₂N | 185–186 | 4.64 | 4.41 |
| 10 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–OH | C₄H₉O | C₂₃H₂₃O₂N | 175–176 | 4.17 | 4.06 |
| 11 | X–C₆H₄–C₆H₄–N=CH–C₆H₃(OH)(OCH₃) | H | C₂₀H₁₇O₂N | 185–186 | 4.82 | 4.62 |
| 12 | X–C₆H₄–C₆H₄–N=CH–C₆H₃(OH)(OCH₃) | HO | C₂₀H₁₇O₃N | 254–255 | 4.64 | 4.39 |
| 13 | X–C₆H₄–C₆H₄–N=CH–C₆H₃(OH)(OCH₃) | CH₃O | C₂₁H₁₉O₃N | 186–187 | 4.41 | 4.20 |
| 14 | X–C₆H₄–C₆H₄–N=CH–C₆H₃(OH)(OCH₃) | C₂H₅O | C₂₂H₂₁O₃N | 182–183 | 4.30 | 4.03 |
| 15 | X–C₆H₄–C₆H₄–N=CH–C₆H₃(OH)(OCH₃) | C₄H₉O | C₂₄H₂₅O₃N | 129–130 | 4.07 | 3.73 |
| 16 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–NHCOCH₃ | H | C₂₁H₁₈ON₂ | 235–236 | 8.55 | 8.91 |
| 17 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–NHCOCH₃ | HO | C₂₁H₁₈O₂N₂ | 244–246 | 8.66 | 8.84 |
| 18 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–NHCOCH₃ | CH₃O | C₂₂H₂₀O₂N₂ | 263–264 | 8.34 | 8.13 |
| 19 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–NHCOCH₃ | C₂H₅O | C₂₃H₂₂O₂N₂ | 273–279 | 8.06 | 7.82 |
| 20 | X–C₆H₄–C₆H₄–N=CH–C₆H₄–NHCOCH₃ | C₄H₉O | C₂₅H₂₆O₂N₂ | 244–245 | 7.44 | 7.25 |
| 21 | X–C₆H₄–C₆H₄–N=CH–CH=CH–C₆H₅ | H | C₂₁H₁₇N | 189–190 | 4.88 | 4.94 |
| 22 | X–C₆H₄–C₆H₄–N=CH–CH=CH–C₆H₅ | HO | C₂₁H₁₇ON | 210–211 | 4.71 | 4.68 |
| 23 | X–C₆H₄–C₆H₄–N=CH–CH=CH–C₆H₅ | CH₃O | C₂₂H₁₉ON | 190–191 | 4.63 | 4.47 |
| 24 | X–C₆H₄–C₆H₄–N=CH–CH=CH–C₆H₅ | C₂H₅O | C₂₃H₂₁ON | 181–182 | 4.54 | 4.28 |
| 25 | X–C₆H₄–C₆H₄–N=CH–CH=CH–C₆H₅ | C₄H₉O | C₂₅H₂₅ON | 175–176 | 4.08 | 3.94 |
| 26 | C₆H₅–C₆H₄–N=CH–benzodioxolyl | — | C₂₀H₁₅O₂N | 144–145 | 4.82 | 4.65 |
| 27 | X–C₆H₄–C₆H₄–N=CH–furyl | H | C₁₃H₁₃ON | 106–107 | 5.70 | 5.66 |
| 28 | X–C₆H₄–C₆H₄–N=CH–furyl | HO | C₁₇H₁₃O₂N | 266–267 | 5.35 | 5.32 |
| 29 | X–C₆H₄–C₆H₄–N=CH–furyl | CH₃O | C₁₈H₁₅O₂N | 126–127 | 5.03 | 5.05 |
| 30 | X–C₆H₄–C₆H₄–N=CH–furyl | C₂H₅O | C₁₉H₁₇O₂N | 157–158 | 4.83 | 4.81 |
| 31 | X–C₆H₄–C₆H₄–N=CH–furyl | C₄H₉O | C₂₁H₂₁O₂N | 165–166 | 4.51 | 4.39 |
| 32 | C₆H₅–C₆H₄–N=CH–[[unclear: fused N-containing aromatic ring]] | — | C₂₆H₁₈N | 205–206 | 7.98 | 7.82 |
| 33 | C₆H₅–C₆H₄–CH=N–C₆H₅ | — | C₁₉H₁₅N | 150–151¹² | ||
| 34 | C₆H₅–C₆H₄–CH=N–C₆H₄–OCH₃ | — | C₂₀H₁₇ON | 181–182 | 5.07 | 4.88 |
| 35 | C₆H₅–C₆H₄–CH=N–C₆H₄–SO₂NH₂ | — | C₁₉H₁₆O₂N₂S | 239–240 | 8.29 | 8.33 |
| 36 | C₆H₅–C₆H₄–CH=N–C₆H₄–C₆H₅ | — | C₂₅H₁₉N | 245–246¹³ | ||
| 37 | C₆H₅–C₆H₄–CH=N–C₆H₄–C₆H₄–OCH₃ | — | C₂₆H₂₁ON | 241–243 | 3.99 | 3.86 |
The melting points and the results of analysis of the azomethines are given in Table 1, and those of the thioureas in Table 2.
Azomethines described in the literature are 1¹⁰, 2¹¹, 33¹², 36¹³ (Table 1), and the thiourea derivatives are 6¹⁴, 11 and 16¹⁵ (Table 2). The remaining compounds presented here were obtained for the first time.
In testing the tuberculostatic action of the azomethines in vitro against the virulent strain K₁ (human type), compounds 1, 6, 11, 13, 32 (Table 1) completely inhibited bacterial growth at drug concentrations from \(1 \cdot 10^{-6}\) to \(1 \cdot 10^{-7}\); the other compounds were less active, or exhibited no tuberculostatic activity at all.
The thiourea derivatives (Table 2) showed no activity at concentrations greater than \(1 \cdot 10^{-4}\). Thus, thiourea derivatives with a diphenyl residue should be assigned to compounds weakly active with respect to the tubercle bacillus in vitro, although the corresponding phenyl compounds are distinguished by high activity.
Table 2
| No. | Compound | Substituent (X) | Empirical formula | m.p., °C | N, % found | N, % calc. |
|---|---|---|---|---|---|---|
| 1 | X–diphenyl–NH–C(=S)–NHCH₂CH=CH₂ | H | C₁₆H₁₆N₂S | 159–160 | 10.57 | 10.44 |
| 2 | X–diphenyl–NH–C(=S)–NHCH₂CH=CH₂ | HO | C₁₆H₁₆ON₂S | 237–238 | 10.01 | 9.85 |
| 3 | X–diphenyl–NH–C(=S)–NHCH₂CH=CH₂ | CH₃O | C₁₇H₁₈ON₂S | 177–178 | 9.20 | 9.39 |
| 4 | X–diphenyl–NH–C(=S)–NHCH₂CH=CH₂ | C₂H₅O | C₁₈H₂₀ON₂S | 169–170 | 8.94 | 8.97 |
| 5 | X–diphenyl–NH–C(=S)–NHCH₂CH=CH₂ | C₄H₉O | C₂₀H₂₄ON₂S | 169–170 | 8.38 | 8.23 |
| 6 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OCH₃ | H | C₂₀H₁₈ON₂S | 193–194^(14) | — | — |
| 7 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OCH₃ | HO | C₂₀H₁₈O₂N₂S | 244–246 | 8.33 | 8.00 |
| 8 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OCH₃ | CH₃O | C₂₁H₂₀O₂N₂S | 206–207 | 8.05 | 7.69 |
| 9 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OCH₃ | C₂H₅O | C₂₂H₂₂O₂N₂S | 209–210 | 7.43 | 7.40 |
| 10 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OCH₃ | C₄H₉O | C₂₄H₂₆O₂N₂S | 202–203 | 7.11 | 6.89 |
| 11 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OC₂H₅ | H | C₂₁H₂₀ON₂S | 197–198^(15) | — | — |
| 12 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OC₂H₅ | HO | C₂₁H₂₀O₂N₂S | 243–245 | 7.79 | 7.69 |
| 13 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OC₂H₅ | CH₃O | C₂₂H₂₂O₂N₂S | 210–212 | 7.50 | 7.40 |
| 14 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OC₂H₅ | C₂H₅O | C₂₃H₂₄O₂N₂S | 211–212 | 7.14 | 7.14 |
| 15 | X–diphenyl–NH–C(=S)–NH–C₆H₄–OC₂H₅ | C₄H₉O | C₂₅H₂₈O₂N₂S | 204–205 | 6.78 | 6.66 |
| 16 | X–diphenyl–NH–C(=S)–NH–C₆H₄–Cl | H | C₁₉H₁₅N₂SCl | 202–203* | 8.39 | 8.27 |
| 17 | X–diphenyl–NH–C(=S)–NH–C₆H₄–Cl | HO | C₁₉H₁₆ON₂SCl | 246–247 | 7.99 | 7.90 |
| 18 | X–diphenyl–NH–C(=S)–NH–C₆H₄–Cl | CH₃O | C₂₀H₁₇ON₂SCl | 215–216 | 7.78 | 7.60 |
| 19 | X–diphenyl–NH–C(=S)–NH–C₆H₄–Cl | C₂H₅O | C₂₁H₁₉ON₂SCl | 216–218 | 7.33 | 7.32 |
| 20 | X–diphenyl–NH–C(=S)–NH–C₆H₄–Cl | C₄H₉O | C₂₂H₂₃ON₂SCl | 205–207 | 6.86 | 6.82 |
* In (15) 195°.
It is interesting that azomethine, obtained from 4-diphenylaldehyde and aniline (33), has absolutely no effect on the growth of tubercle bacilli, whereas the isomeric azomethine, obtained from 4-aminodiphenyl and benzaldehyde (1), possesses high tuberculostatic activity, \(0.2 \cdot 10^{-6}\). Compounds 34, 35, 36, and 37 also proved inactive. This indicates that, in the manifestation of antitubercular action, the essential role is played not so much by the diphenyl residue as by 4-aminodiphenyl.
The toxicity of the most active azomethines 1, 6, 11, and 13 (Table 1) was tested on white mice. The indicated azomethines proved to be considerably less toxic than 4-aminodiphenyl; however, in experiments on mice infected with the virulent strain K₁, they did not show a therapeutic effect.*
The microbiological tests of the compounds described here and the experiments on white mice were carried out by Candidate of Medical Sciences E. I. Chertkova (Sverdlovsk Scientific-Research Tuberculosis Institute).
Experimental Part
1. Preparation of 2-oxy-3-methoxybenzylidene-4-aminodiphenyl (11, Table 1). To a hot solution of 1.69 g (0.01 mole) of 4-aminodiphenyl in 4 ml of alcohol was added a hot solution of 1.52 g (0.01 mole) of vanillin in 4 ml of alcohol. The mixture was heated on a water bath for half an hour. After 10 min the solution becomes orange and small crystals precipitate from it. After cooling, the azomethine was filtered off and dried, m.p. 184–186°. Yield 2.9 g (95.7% of theory). The product was recrystallized from alcohol—yellow needles, m.p. 185–186° (for analysis see Table 1).
2. Preparation of N-4-(4′-methoxydiphenyl)-N′-(ethoxyphenyl)thiourea (13, Table 2). To a hot solution of 0.4 g
* It is evidently of interest to carry out further testing of the physiological action of the azomethines presented here, in particular their carcinogenic properties, if one takes into account that 4-aminodiphenyl shows a clearly carcinogenic action (16). The possibility is not excluded of finding among the azomethines of diphenyl carcinostatic substances as well, especially since one of the azomethines of the fluorene series, related to the carcinogenic derivative of fluorene, showed anticancer action (17).
A solution of 0.36 g (0.002 mole) of p-ethoxyphenyl isocyanate in 3 ml of alcohol was added to 0.46 g (0.002 mole) of 4-methoxy-4-aminodiphenyl in 10 ml of alcohol. The mixture was heated on a water bath for 15 min; the small colorless crystals that precipitated after cooling were filtered off and dried, m.p. 210–212°. Yield 0.7 g (92% of theory). After recrystallization from alcohol, m.p. 211–212° (for analysis see Table 2).
Ural Polytechnic Institute
named after S. M. Kirov
Received
4 I 1957
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