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WO2016013947A1 - New analogs of 1,2,4-triazoles and a process for preparing analogs of 1,2,4-triazoles - Google Patents

New analogs of 1,2,4-triazoles and a process for preparing analogs of 1,2,4-triazoles Download PDF

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WO2016013947A1
WO2016013947A1 PCT/PL2015/000115 PL2015000115W WO2016013947A1 WO 2016013947 A1 WO2016013947 A1 WO 2016013947A1 PL 2015000115 W PL2015000115 W PL 2015000115W WO 2016013947 A1 WO2016013947 A1 WO 2016013947A1
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dihydroxyphenyl
triazolo
chloro
precipitate
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Andrzej Niewiadomy
M. Monika KARPIŃSKA
Joanna Wietrzyk
Joanna MATYISAK
Mariusz GAGÓS
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Instytut Immunologii i Terapii Doswiadczalnej PAN
Instytut Przemyslu Organicznego
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • the present invention relates to novel analogs of 1 ,2,4-triazoles and a process for preparing analogs of 1,2,4-triazoles, in particular analogs having medicinal properties.
  • analogs of 1,2,4-triazoles fused to 6-membered carbocyclic and heterocyclic rings exhibit different biological activity.
  • the compounds based on l,2,4-triazolo[3,4-a]phthalazine are primarily known as antagonists of GABA receptors (mainly a3 and a5 subunits) and as the ligands having a high affinity for the receptors of calcium channel gates. They are characterized by, among others, anticonvulsant activity.
  • GABA receptors mainly a3 and a5 subunits
  • anticonvulsant activity In the review of literature derivatives of l,2,4-triazolo[4,3- 6]pyridazine are also indicated as the agonists of GABA receptors.
  • these compounds are characterized by anticonvulsant and antiviral activity, as well as cytostatic properties.
  • derivatives of l ,2,4-triazolo[4,3-ct]pyrimidine act as antagonists of adenosine receptors. Many of them exhibit also antitumour activity. This type of activity is assigned to sulfonamide, hydrazine and pyrazole derivatives. Other derivatives have anti-inflammatory, analgesic and antibacterial properties.
  • Fused system of l ,2,4-triazolo[4,3-b]pyridazine is typically obtained in the cyclization reaction of 3 -hydrazine, 3-hydrazide or 3-hydrazone derivatives using appropriate agents closing linear systems and appropriate reaction media.
  • Pyridazine Derivatives and Related Compounds, Part 8 Synthesis of Different Heterocycles from 3-Hydrazinopyridazine; Collins I., Castro J.L., Street L.J., Tetrahedron Lett. 2000, 41, 781-784.
  • Fused system of l,2,4-triazolo[4,3-0]pyrimidine is most often obtained in analogous cyclization processes using suitable 2-hydrazine (hydrazone) derivatives.
  • Condensation of l,2-dihydro-2-thiooxopyrimidin-4( H > )ones with hydrazonyl chlorides also leads to the described compounds, as known from the publication Hassaneen H.M., Abdelhadi H.A., Abdallah T.A., Tetrahedron 2001, 57, 10133-10138. Novel synthesis of l,2,4-triazolo[4,3-a]pyrimidin-5-one derivatives.
  • None of the described synthetic methods includes the preparation of fused triazole derivatives with 2,4-dihydroxyphenyl substituent at position 3 of the fused system or a modified form thereof.
  • the present invention relates to new analogs of 1 ,2,4-triazoles of the general formula I:
  • R 2 H, Me-, Et-, Pr-, iPr-, C1-, HO-, MeO-, EtO-
  • R 3 H, HO-, Me-, MeO-
  • R' H, CI, Br, F 3 C-
  • a process for preparing compounds of a group of 3-aryl-substituted 1,2,4- triazoles is based on a reaction of heteroarylhydrazines with a number of modified thioaryloylating agents E.
  • the consecutive processes running "on pot" are a terminal thiohydrazide transformation, equilibrium regiospecific anular rearrangement and thione/thiol isomerization, conditioning endocyclization by eliminating H 2 S.
  • Linear thiohydrazide moieties of intermediary compounds substituted to heterocyclic systems can be treated as ambident acids (or anions), which release readily leaving SH " ions deprotonating nitrogen atoms.
  • the rate and yield of the reaction also determines the appropriate substitution of thiocarbonyl system of electrophilic reagents.
  • R H, Me, Et, Pr, iPr, CI, OH, MeO, EtO
  • substance E can be in the form of:
  • S3MTB bis[(2,4-dihydroxy-3-methylphenyl)methanethione] sulfoxide
  • S 5 MTB bis [(2,4-dihydroxy- 5 -methylpheny l)methanothione] sulfoxide
  • SETB bis[(5-ethyl-2,4-dihydroxyphenyl)methanothione] sulfoxide
  • SC 1TB bis[(5-chloro-2,4-dihydroxyphenyl)methanothione] sulfoxide
  • S3TTB bis[(2,3,4-trihydroxyphenyl)methanothione] sulfoxide.
  • Transitional isomerizing linear forms may be considered a part of a rigid, sufficiently coplanar system and they have no possibility of free rotation across a multiple bond, which facilitates the processes of endocyclization. Isomerization rearrangements cause changes in the electronic structure, dipole moment and the shape of the equipotential surface.
  • the condition is a suitable location of NHNH 2 moiety, allowing for a directional protonation/deprotonation of nitrogen atoms and stabilization by forming geometrically favored rings.
  • the ring was provided with the groups of a variable electron characteristic (polarity), taking into consideration a greater opportunity of approximating the molecule to hydrogen binding sites or location in hydrophobic spaces, given the function of benzenediol (benzenetriol) in interaction with molecular targets.
  • This direction of -R changes includes also or above all the impact of substitution on the course of subsequent intermediary reactions, as well the properties of the final product.
  • 2,3,4- and 2,4,6-trihydroxylphenyl analogs were obtained. It was interesting, because these directions of substitution affect both the nature of electronic and steric interactions in every area of hydrogen bonds and changes in particle energy.
  • Example 1 6-chloro-3-(2,4-dihydroxyphenyl)-l,2,4-triazolo[4,3- bjpyridazine
  • Formula VII 0.0017 moles of 3-chloro-6-hydrazinopyridazine and 0.0017 moles of bis[(2,3,4- trihydroxyphenyl)methanothione] sulfoxide S3TTB were transferred into 8.5 ml of methanol and heated at reflux temperature for 3 h. Hot reaction mixture was filtered through a Buchner funnel. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated and the resultant precipitate II was recrystallized from methanol/water (2:3) solvent system (4 ml). The compound of Formula VII was obtained.
  • Example 8 Formula X, 3-(5-ethyl-2,4-dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4- triazolof 4, 3-a Jpyrimidine
  • 3-chloro-6-hydrazinopyridazine used in the examples above was purchased according to Aldrich catalog, Cat. No. 632619, while N-[4-(trifluoromethyl)pyrimidin- 2- yl]hydrazine (2-hydrazino-4-(trifluoromethyl)pyrimidine) was purchased according to Fluorochem catalog, Cat. No. 017278.
  • test compounds at a concentration of 1 mg/ml were prepared ex tempore for each experiment dissolving 1 mg of the preparation in 100 ⁇ DMSO + 900 ⁇ of culture medium. The solvent for further dilutions was culture medium. The compounds were tested at concentrations of 100, 10, 1, 0.1 ⁇ g/ml. Cisplatin at concentrations of 100, 10, 1, 0.1 ⁇ g/ml and DMSO at concentrations corresponding to its concentration in the samples of the compounds: 1, 0.1, 0.01 and 0.001% were applied as a control. In each experiment samples containing specified concentrations of the preparation were applied in triplicate. The experiments were performed in triplicate.

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Abstract

The present invention relates to new analogs of 1,2,4-triazoles of the general formula (I) with different type of substitution of 2,4-dihydroxyphenyl system. The analogs have antiproliferative properties. Furthermore, a process for the preparation of new analogs was disclosed.

Description

New analogs of 1 ,2,4-triazoles and a process for preparing analogs of 1,2,4-triazoles
The present invention relates to novel analogs of 1 ,2,4-triazoles and a process for preparing analogs of 1,2,4-triazoles, in particular analogs having medicinal properties.
Depending on their structure, analogs of 1,2,4-triazoles fused to 6-membered carbocyclic and heterocyclic rings exhibit different biological activity. The compounds based on l,2,4-triazolo[3,4-a]phthalazine are primarily known as antagonists of GABA receptors (mainly a3 and a5 subunits) and as the ligands having a high affinity for the receptors of calcium channel gates. They are characterized by, among others, anticonvulsant activity. In the review of literature derivatives of l,2,4-triazolo[4,3- 6]pyridazine are also indicated as the agonists of GABA receptors. Furthermore, these compounds are characterized by anticonvulsant and antiviral activity, as well as cytostatic properties. In contrary, derivatives of l ,2,4-triazolo[4,3-ct]pyrimidine act as antagonists of adenosine receptors. Many of them exhibit also antitumour activity. This type of activity is assigned to sulfonamide, hydrazine and pyrazole derivatives. Other derivatives have anti-inflammatory, analgesic and antibacterial properties.
Fused system of l ,2,4-triazolo[4,3-b]pyridazine is typically obtained in the cyclization reaction of 3 -hydrazine, 3-hydrazide or 3-hydrazone derivatives using appropriate agents closing linear systems and appropriate reaction media. The descriptions known from publications including: Deeb A., Hassaneen M., Kotb M., Heteroatom Chemistry, 2005, 16, 278-284. Pyridazine Derivatives and Related Compounds, Part 8: Synthesis of Different Heterocycles from 3-Hydrazinopyridazine; Collins I., Castro J.L., Street L.J., Tetrahedron Lett. 2000, 41, 781-784. Rapid analogue synthesis of trisubstituted triazolo[4,3-6]pyridazines; Skoumbourdis A.P., LeClair C.A., Stefan E., Tuijanski A.G., Maguire W., Titus S.A., Huang R., Auld D.S., Inglese J., Austin C:P., Michnick S.W., Xia M., Thomas C.J. Bioorg. Med Chem. Lett. 2009, 19, 3686-3692. Exploration and optimization of substituted triazolothiadiazines and triazolopyridazines as PDE4 inhibitors, in particular cases allow for the preparation of a limited range of modification of the basic system.
Fused system of l,2,4-triazolo[4,3-0]pyrimidine is most often obtained in analogous cyclization processes using suitable 2-hydrazine (hydrazone) derivatives. Condensation of l,2-dihydro-2-thiooxopyrimidin-4( H>)ones with hydrazonyl chlorides also leads to the described compounds, as known from the publication Hassaneen H.M., Abdelhadi H.A., Abdallah T.A., Tetrahedron 2001, 57, 10133-10138. Novel synthesis of l,2,4-triazolo[4,3-a]pyrimidin-5-one derivatives. In turn, a non-standard reaction for preparing l ,2,4-triazolo[4,3-d]pyrimidine was presented by Dandia A., Singh R., Singh D., Kapil A., Letters in Organic Chemistry, 2009, 6, 100-105. Facile Regioselective Green Synthesis of Triazolo [4,3 -a] Pyrimidines in Aqueous Medium, wherein the multiple condensation of 2-amino-l,3,4-triazole, the active methyl group of ethyl cyanoacetate and 4-chlorobenzaldehyde (carbonyl group) leads to the described systems.
None of the described synthetic methods includes the preparation of fused triazole derivatives with 2,4-dihydroxyphenyl substituent at position 3 of the fused system or a modified form thereof.
The present invention relates to new analogs of 1 ,2,4-triazoles of the general formula I:
Figure imgf000003_0001
General formula I
with different type of substitution of 2,4-dihydroxyphenyl system, wherein:
R,=.H, HO-, Me-, MeO-
R2 = H, Me-, Et-, Pr-, iPr-, C1-, HO-, MeO-, EtO-
R3 = H, HO-, Me-, MeO-
R' = H, CI, Br, F3C-
X = N, Y=CH in the first embodiment
while in the second embodiment X = CH, Y=N.
Because of their antiproliferative properties, among numerous possible analogs of 1 ,2,4-triazoles, the most important compounds include, among others:
• 6-chloro-3-(2,4-dihydroxyphenyl)-l,2,4-triazolo[4,3-6]pyridazine,
• 6-chloro-3-(2,4-dihydroxyphenyl-3-methylphenyl)-l ,2,4-triazolo[4,3- &]pyridazine,
• 6-chloro-3-(5-ethyl-2,4-dihydroxyphenyl)- 1 ,2,4-triazolo[4,3-Z>]pyridazine,
• 6-chloro-3-(5-chloro-2,4-dihydroxyphenyl)-l,2,4-triazolo[4,3- ']pyridazine,
• 6-chloro-3-(2,3,4-trihydroxyphenyl)-l,2,4-triazolo[4,3-¾]pyridazine,
• 3-(2,4-dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4-triazolo[4,3- ctjpyrimidine, • 3-(2,4-dihydroxy-3-methylphenyl)-7-(trifluoromethyl)-l,2,4-triazolo[4,3- et]pyrimidine,
• 3-(5-ethyl-2,4-dihydroxyphenyl)-7-(trifluoromethyl)- 1 ,2,4-triazolo[4,3- ot]pyrimidine,
• 3-(5-chloro-2,4-dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4-triazolo[4,3- tt]pyrimidine.
A process for preparing compounds of a group of 3-aryl-substituted 1,2,4- triazoles is based on a reaction of heteroarylhydrazines with a number of modified thioaryloylating agents E. The consecutive processes running "on pot" are a terminal thiohydrazide transformation, equilibrium regiospecific anular rearrangement and thione/thiol isomerization, conditioning endocyclization by eliminating H2S.
Linear thiohydrazide moieties of intermediary compounds substituted to heterocyclic systems can be treated as ambident acids (or anions), which release readily leaving SH" ions deprotonating nitrogen atoms. At appropriate basicity and stereoaccessibility of nitrogen atoms of the heterocyclic system, the rate and yield of the reaction also determines the appropriate substitution of thiocarbonyl system of electrophilic reagents.
The fundamental of the process for preparation of analogs of 1,2,4-triazoles of the general formula I, wherein substrates are introduced into the solution, and then the product is isolated consists in that heteroarylhydrazine is reacted in monohydric alcohol with the addition of pyridine with the substance E of the general formula II:
Figure imgf000004_0001
General formula II
wherein: R = H, Me, Et, Pr, iPr, CI, OH, MeO, EtO
and subsequently the resultant mixture is separated into filtrate I and precipitate I, which is then concentrated, while the resultant precipitate II is crystallized from an aqueous solution of a monohydric alcohol. Preferably, a monohydric alcohol is methanol or ethanol. In case when the final compound precipitates from the solution during the course of the reaction, precipitate I is combined with precipitate II, and subsequently their mixture is subjected to crystallization. Particularly useful among heteroarylhydrazines are 3-chloro-6-hydrazinopyridazine or 2-hydrazino-4- (trifluoromethyl)pyrimidine. Depending on the location and type of R substituent, substance E can be in the form of:
STB: bis[(2,4-dihydroxyphenyl)methanethione] sulfoxide
S3MTB: bis[(2,4-dihydroxy-3-methylphenyl)methanethione] sulfoxide S 5 MTB : bis [(2,4-dihydroxy- 5 -methylpheny l)methanothione] sulfoxide SETB: bis[(5-ethyl-2,4-dihydroxyphenyl)methanothione] sulfoxide
SC 1TB: bis[(5-chloro-2,4-dihydroxyphenyl)methanothione] sulfoxide
S3TTB: bis[(2,3,4-trihydroxyphenyl)methanothione] sulfoxide.
The synthesis is done according to the Scheme:
Figure imgf000005_0001
Scheme
Transitional isomerizing linear forms may be considered a part of a rigid, sufficiently coplanar system and they have no possibility of free rotation across a multiple bond, which facilitates the processes of endocyclization. Isomerization rearrangements cause changes in the electronic structure, dipole moment and the shape of the equipotential surface. In the case of multicentric basicity of nucleophilic reagents, the condition is a suitable location of NHNH2 moiety, allowing for a directional protonation/deprotonation of nitrogen atoms and stabilization by forming geometrically favored rings.
In search for the correct directions of phenolic substituent modification, the ring was provided with the groups of a variable electron characteristic (polarity), taking into consideration a greater opportunity of approximating the molecule to hydrogen binding sites or location in hydrophobic spaces, given the function of benzenediol (benzenetriol) in interaction with molecular targets. This direction of -R changes includes also or above all the impact of substitution on the course of subsequent intermediary reactions, as well the properties of the final product. Within these series also corresponding 2,3,4- and 2,4,6-trihydroxylphenyl analogs were obtained. It was interesting, because these directions of substitution affect both the nature of electronic and steric interactions in every area of hydrogen bonds and changes in particle energy.
The invention is further illustrated by the following examples.
Example 1 - Formula III, 6-chloro-3-(2,4-dihydroxyphenyl)-l,2,4-triazolo[4,3- bjpyridazine
Figure imgf000006_0001
Formula III
0.007 moles of 3-chloro-6-hydrazinopyridazine and 0.007 moles of bis[(2,4- dihydroxyphenyl)methanethione] sulfoxide (STB) were transferred into 35 ml of EtOH and heated at reflux temperature for 3 h. Hot reaction mixture was filtered through a Biichner funnel. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated to dryness, 32 ml of the MeOH/water solvent system (1 : 1) was added and it was stored for 24 h. Precipitate II was filtered and recrystallized from 20 ml of the MeOH/water (2:3) solvent system. The compound of Formula III was obtained.
Yield 68%, melting point 201-203°C. For the formula: CUH7C1N402, M=262.65 calculated C, 50.30; H, 2.69; N, 21.33; obtained: C, 50.22; H, 2.68; N, 21.29.
IR (KBr, cn 1): 3090 (OH + CAR-H), 1627 (C=N), 1564 (C=C), 1539 (C=C), 1473, 1416, 1304, 1233, 1185 (C-OH), 1133, 1086, 1013, 973, 844, 810, 779, 745, 704; Ή NMR (500 MHz, DMSO-i¾, 3, ppm): 1 1.20 (s, 1H, C2 -OH), 9.95 (s, 1H, C4 -OH), 8.52 (d, J=9.8 Hz, 1H, C8-H), 8.13 (d, J=8.2 Hz, 1H, C6>-H), 7,54 (d, J= 9.7 Hz, 1H, C7-H), 8.0 (dd, J=7.8 and 2.4 Hz, 1H, C5 -H), 6.51 (d, J=2.5 Hz, 1H, C3<-H); MS (EI, m/z): 262 (MQ+, 21), 227 (10), 205 (5), 199 (18), 171 (8), 121 (9), 168 (85), 108 (2), 79 (4), 52 (4), 39 (5).
Example 2 - Formula IV, 6-chloro-3-(2,4-dihydroxyphenyl-3-methylphenyl)-l,2,4- triazolof 4, 3-b]pyridazine
Figure imgf000007_0001
Formula IV
0.0017 moles of 3-chloro-6-hydrazinopyridazine and 0.0017 moles of S3MTB were transferred into 8.5 ml of methanol and heated at reflux temperature for 2.5 h. Hot reaction mixture was filtered through a Biichner funnel. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated and the resultant precipitate II was recrystallized from methanol/water (2:3) solvent system (4 ml). The compound of Formula IV was obtained.
Yield 73%, melting point 151-152°C. For the formula: C12H9C1N402, M=276.68 calculated C, 52.09; H, 3.28; N, 20.25; obtained: C, 51.94; H, 3.30; N, 20.18.
IR (KBr, cm-1): 3434, 3099 (OH), 3043 (CAR-H), 2924 (CH), 1621 (C=N), 1533 (C=C), 1459, 1386, 1323, 1267, 1235, 1206, 1168 (C-OH), 1134, 1085, 1054, 951, 894, 855, 814, 795, 778, 758, 742, 707, 628; Ή NMR (500 MHz, CDC13, δ, ppm): 1 1.62 (s, 1H, C2>-OH), 9.99 (s, 1H, C4 -OH), 8.55 (d, J=9.7 Hz, 1H, C8 -H), 8.24 (d, J=8.5 Hz, 1H, C6>-H), 7.58 (d, J=9.7 Hz, 1H, C7>-H), 6.62 (d, J= 8.7 Hz, 1H, C5>-H), 2.10 (s, 3H, CH3); MS (EI, m/z): 276 (M+, 53), 241 (100), 213 (3), 138 (3), 94 (8), 64 (5), 39 (5).
Example 3 - Formula V, 6-chloro-3-(5-ethyl-2,4-dihydroxyphenyl)-l,2,4-triazolo[4,3- b Jpyridazine
Figure imgf000007_0002
Formula V
0.0017 moles of 3-chloro-6-hydrazinopyridazine and 0.0017 moles of SEBT were transferred into 8.5 ml of methanol and heated at reflux temperature for 3 h. Hot reaction mixture was filtered through a Biichner funnel. Filtrate I was concentrated and the resultant precipitate II was recrystallized from methanol/water (3: 1) solvent system (5 ml). The compound of Formula V was obtained.
Yield 71%, melting point 141-143°C. For the formula: Ci3HnClN402, M=290.71 calculated C, 53.71 ; H, 3.81 ; N, 19.27; obtained: C, 53.84; H, 3.80; N, 19.36. IR (KBr, cm"1): 2965 (OH, CAR-H), 2924 (CH), 1617 (C=N), 1559 (C=C), 1439, 1407, 1274,1245, 1141 , 1089, 1039, 1013, 972, 930, 903, 846, 802, 766, 744; Ή NMR (500 MHz, CDC13, S, ppm): 9.95 (s, 1H, C4-OH), 8.51 (d, J=9.7 Hz, 1H, C8-H), 7.79 (s, 1H, C6-H), 7.54 (d, J=9.7, 1H, C7-H), 6.56 (s, 1H, C3-H), 2.54 (m, 2H, CH2CH3), 1.16 (t, 3H, CH2CH3); MS (EI, m/z): 290 (M+, 32), 277 (33), 275 (100), 78 (4), 69 (5), 64 (4).
Example 4 - Formula VI, 6-chloro-3-(5-chloro-2,4-dihydroxyphenyl)-l,2,4- triazolo[4, 3-b Jpyridazine
Figure imgf000008_0001
Formula VI
0.0017 moles of 3-chloro-6-hydrazinopyridazine and 0.0017 moles of SCITB were transferred into 8.5 ml of methanol and heated at reflux temperature for 3 h. Reaction mixture was stored for 24 h at room temperature and then it was filtered through a Buchner funnel. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated and the resultant precipitate II was recrystallized from methanol/water (2:3) solvent system. The compound of Formula VI was obtained.
Yield 69%, melting point 167-168°C. For the formula: Ci3H6Cl2N402, M=297.10 calculated C, 44.47; H, 2.04; N, 18.86; obtained: C, 44.38; H, 2.03; N, 18.92.
IR (KBr, cm"1): 3419 (OH), 3086 (CAR-H), 2922 (C-H), 161 1 (C=N), 1562 (C=C), 1539 (C=C), 1493, 1478, 1410, 1337, 1298, 1261, 1234, 1 183 (C-OH), 1158, 1095, 1057, 1018, 991, 944, 898, 837, 783, 757, 739; Ή NMR (500 MHz, DMSO-<¾, δ, ppm): 1 1.82 (s, 1H, C2 -OH), 10.87 (s, 1H, C4<-OH), 8.54 (d, J=9.7 Hz, 1H, C8-H), 7.94 (s, 1H, C6- H), 7.57 (d, J=9,7 Hz, 1H, C7-H), 6.56 (s, 1H, C3>-H); MS (EI, m/z, B): 297 (M+, 2), 296 (100), 262 (13), 233 (12), 205 (6), 170 (12), 158 (6), 142 (10), 134 (5), 99 (7), 79 (5), 69 (7), 51 (5), 38 (15), 36 (44).
Example 5 - Formula VII, 6-chloro-3-(2,3,4-trihydroxyphenyl)-l,2,4-triazolo[4,3- bjpyridazine
Figure imgf000008_0002
Formula VII 0.0017 moles of 3-chloro-6-hydrazinopyridazine and 0.0017 moles of bis[(2,3,4- trihydroxyphenyl)methanothione] sulfoxide S3TTB were transferred into 8.5 ml of methanol and heated at reflux temperature for 3 h. Hot reaction mixture was filtered through a Buchner funnel. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated and the resultant precipitate II was recrystallized from methanol/water (2:3) solvent system (4 ml). The compound of Formula VII was obtained.
Yield 63%, melting point 172-172°C. For the formula: CUH7N402C1, M=278.66 calculated C, 47.41 ; H, 2.53; N, 20.1 1 ; obtained: C, 47.50; H, 2.50; N, 20.16.
IR (KBr, cm-'): 3397 (OH), 3228 (OH), 1630 (C=N), 1508 (C=C), 1479, 1420, 1328, 1297, 1231, 1174 (C-OH), 1083, 1010, 980, 897, 801, 720; Ή NMR (500 MHz, CDC13, 3, ppm): 1 1.81 (s, 1H, C -OH), 10.32 (s, 1H, C4-OH), 8.85 (s, 1H, C3 --H), 8.54 (d, J=9.7 Hz, 1H, C8-H), 7.87 (d, J=9.7 Hz, 1H, C7-H), 6.65 (d, J=7.3 Hz, 1H, C6 -H), 6.52 (d, J=7.3 Hz, 1H, C5'-H); MS (EI, m/z): 278 (M0+, 21), 276 (14), 258 (7), 244 (17), 215 (12), 200 (51), 168 (85), 158 (10), 152 (39), 128 (13), 112 (25), 95 (13), 79 (32), 72 (15), 69 (30), 45 (24), 39 (36), 36 (49).
Example 6 - Formula VIII, 3-(2,4-dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4- triazolof 4, 3 -a Jpyrimidine
Figure imgf000009_0001
Formula VIII
0.0014 moles of 2-hydrazino-(4-trifluoromethyl)pyrimidine and 0.0014 moles of STB were transferred into 7 ml of methanol and heated at reflux temperature for 3 h. Reaction mixture was stored for 24 h at room temperature and then it was filtered through a Buchner funnel. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated and 12 ml of methanol/water (1 : 1) solvent system. Isolated precipitate II was recrystallized from 6 ml of methanol. The compound of Formula VIII was obtained.
Yield 66%, melting point 185-186°C. For the formula: Ci2H7F3N402, M=296.19 calculated C, 48.66; H, 2.38; N, 18.91 ; obtained: C, 48.54; H, 2.37; N, 18.86.
IR (KBr, cm-1): 3201 , 31 17 (OH), 1630 (C=N), 1587 (C=C), 1555 (C=C), 1528, 1455, 1432, 1402, 1375, 1337, 1302, 1274, 1201 (C-OH), 1 159, 1087, 1005, 978, 969, 866, 819, 784, 776, 761, 716, 686, 653, 640. Ή NMR (500 MHz, DMSO-<¾, δ): 10.94 (s, 1H, C2 -OH), 10.13 (s, 1H, C4-OH), 9.75 (d, J=6.9 Hz, 1H, C6-H), 7.97 (d, J=8.6 Hz, 1H, C6'-H), 7.89 (d, J=6.9 Hz, 1H, C5-H), 6.50 (d, J=8.6 and 2.3 Hz, 1H, C5-H), 6.42 (d, J=2.3 Hz, 1H, C3-H); MS (EI, m/z): 296 (M+), 278, 340, 227, 166, 121, 109, 80, 52, 40.
Example 7 - Formula IX, 3-(2,4-dihydroxy-3-methylphenyl)-7-(trifluoromethyl)-l,2,4- triazolo[ 4, 3 -a Jpyrimidine
Figure imgf000010_0001
OH Formula IX
0.0014 moles of 2-hydrazino-4-(trifluoromethyl)pyrimidine and 0.0014 moles of S3MTB were transferred into 7 ml of methanol and heated at reflux temperature for 3 h. Hot reaction mixture was filtered through a Biichner funnel. Precipitate I and filtrate I were obtained. Filtrate I was concentrated and the resultant precipitate II was combined with precipitate I, filtered and recrystallized from 4 ml of methanol/ water (3: 1) solvent system. The compound of Formula IX was obtained.
Yield 82%, melting point 280-281°C. For the formula: Ci3H9F3N402, M=310.23 calculated C, 50.33; H, 2.92; N, 18.06; obtained: C, 50.41 ; H, 2.92; N, 18.02.
IR (KBr, cm-'): 3176 (OH), 2927 (C-H), 1617 (C=N), 1553 (C=C), 1436, 1402, 1382, 1341, 1294, 1 1592 (C-OH), 1 154, 1 101, 1074, 1014, 966, 910, 877, 859, 821, 798, 784, 770, 728, 715; 1H NMR (500 MHz, DMSO-t& S, ppm): 1 1.23 (s, 1H, C2-OH), 10.02 (s, 1H, C4-OH), 9.75 (d, J=6.9 Hz, 1H, C6-H), 7.89 (d, J=6.9 Hz, 1H, C5-H), 7.84 (d, J=8.6 Hz, 1H, C6"H), 6.57 (d, J=8.6 Hz, 1H, C6-H), 2.08 (s, 3H, CH3); MS 10 (EI, m/z, B): 310 (M+, 100), 296 (6), 281 (10), 265 (4), 253 (4), 223 (3), 164 (16), 148 (1 1), 1 19 (4), 94 (4), 65 (4), 39 (4).
Example 8 - Formula X, 3-(5-ethyl-2,4-dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4- triazolof 4, 3-a Jpyrimidine
0.0014 moles of 2-hydrazino-4-(trifluoromethyl)pyrimidine and 0.0014 moles of bis[(5- ethyl-2,4-dihydroxyphenyl)methanothione] sulfoxide (SETB) were transferred into 7 ml of methanol and heated at reflux temperature (3 h). Reaction mixture was stored for 24 h at room temperature and then it was filtered. Precipitate I and filtrate I were obtained, wherein precipitate I was discarded. Filtrate I was concentrated to dryness, 5 ml of the diethyl ether was added, mixed, and it was stored (1 h) at room temperature. After filtering, the resultant precipitate was recrystallized from 5 ml of methanol/water (3:2) solvent system.
Yield 76%, melting point 196°C. For the formula: C4H1 1F3N4O2, M=324.26 calculated C, 51.86; H, 3.42; N, 17.82; obtained: C, 51.78; H, 3.44; N, 17.21.
IR (KBr, cm-1): 3245 (OH), 3057 (CAR-H), 2948 (C-H), 1623 (C=N), 1592 (C=N), 1507 (C=C), 1492, 1451, 1370, 1328, 1275, 1247, 1218 (C-OH), 1 186, 1 144, 1039, 1008, 922, 835, 791, 763, 730; Ή NMR (500 MHz, DMSO-^, δ, ppm): 10.76 (s, 1H, C2'-OH), 10.1 1 (s, 1H, C4-OH), 9.76 (d, J=6.9 Hz, 1H, C6-H), 7.90 (d, J=6.7 Hz, 1H, C5-H), 7.84 (s, 1H, C6-H), 6.40 (s, 1H, C3-H), 2.55 (q, 2H, CHZC¾), 1.17 (s, 3H, CH2CHj); MS (EI, m/z, B): 324 (M0+, 38), 309 (M°+-CH3, 100), 212 (15), 181 (24), 164 (8), 165 (16), 149 (6), 121 (3), 68 (8), 65 (5), 39 (4).
Example 9 - Formula XI, 3-(5-chloro-2,4-dihydroxyphenyl)-7-((rifl oromethyl)-l,2,4- triazolof 4, 3 -a Jpyrimidine
Figure imgf000011_0001
Formula XI
0.0014 moles of 2-hydrazino-4-(trifluoromethyl)pyrimidine and 0.0014 moles of SC1TB were transferred into 7 ml of methanol and heated for 3 h at reflux temperature. Reaction mixture was stored for 24 h at room temperature and then it was filtered through a Buchner funnel. Precipitate I and filtrate I were obtained. Filtrate I was concentrated and the resultant precipitate II was combined with precipitate I. The mixture of precipitates was recrystallized from methanol/water (1 : 1) solvent system (6 ml). The compound of Formula XI was obtained.
Yield 68%, melting point 188-189°C. For the formula: Ci2H6ClF3N402, M=330.65 calculated C, 43.59; H, 1.83; N, 16.94; obtained: C, 43.66; H, 1.82; N, 17.00.
IR (KBr, cm"1): 3260 (OH), 3072 (CAR-H), 2954 (C-H), 2849 (C-H), 1606 (C=N), 1583 (C=C), 1484, 1445, 1364, 1335, 1304, 1273, 1252, 1224, 1 192 (C-OH), 1 159, 1 142, 1050, 1000, 909, 829, 789, 758, 724; Ή NMR (500 MHz, DMSO-d6, δ, ppm): 10.94 (s, 1H, Cr-OH), 10.47 (s, 1H, C4 -OH), 8.79 (d, J=4.9 Hz, 1H, C6-H), 8.14 (s, 1H, C6 -H), 7.28 (d, J=4.9 Hz, 1H, C5-H), 6.65 (s, 1H, C5 -H); MS (EI, m/z, B): 331 (M++l, 67), 330 (M+, 2), 261 (3), 189(34), 187(100), 178 (4), 164 (5), 131 (6), 94 (4), 69(6).
3-chloro-6-hydrazinopyridazine used in the examples above was purchased according to Aldrich catalog, Cat. No. 632619, while N-[4-(trifluoromethyl)pyrimidin- 2- yl]hydrazine (2-hydrazino-4-(trifluoromethyl)pyrimidine) was purchased according to Fluorochem catalog, Cat. No. 017278.
Comparative example
The obtained compounds were examined for their antitumour activity. To this end tests of antiproliferative activity against such human cancer cells as: bladder cancer HCV 29T, lung cancer A549, breast cancer T47D and colon adenocarcinoma SW707 were performed. The results of the experiments in the form of ID50 (the dose inducing a 50% inhibition of proliferation of the tumour cell population), determined for each compound are summarized in Table 1. An accepted activity criterion for novel compounds in in vitro screening tests is the ID50 level not higher than 4 μg/ml [Geran RI et al. Cancer Chemotherapy Reports, 3, 2 (part3):59-61, 1972].
SRB Cytotoxicity Assay
The tests were performed using the SRB cytotoxicity assay, which measures the inhibition of target cell proliferation in 72-hour in vitro culture. [Skehan et al. J. Natl. Cancer Inst, 82: 1107-1 1 12, 1990].
Stock solutions of the test compounds at a concentration of 1 mg/ml were prepared ex tempore for each experiment dissolving 1 mg of the preparation in 100 μΐ DMSO + 900 μΐ of culture medium. The solvent for further dilutions was culture medium. The compounds were tested at concentrations of 100, 10, 1, 0.1 μg/ml. Cisplatin at concentrations of 100, 10, 1, 0.1 μg/ml and DMSO at concentrations corresponding to its concentration in the samples of the compounds: 1, 0.1, 0.01 and 0.001% were applied as a control. In each experiment samples containing specified concentrations of the preparation were applied in triplicate. The experiments were performed in triplicate.
Cell lines
In the experiments cell lines from the cell line bank of the Institute of Immunology and Experimental Therapy of Polish Academy of Sciences in Wroclaw were used. The cells were cultures in RPMI + opti-MEM (1 : 1) medium supplemented with 5% FBS, 2 mM of glutamine, 1 mM of sodium pyruvate and 0.8 mg/1 of insulin in the case of the T47D line. All media contained antibiotics: 100 mg/ml of streptomycin and lOO U/ml of penicillin. The cells were cultured in humidified atmosphere of 5% C02 at 37°C.
The study was performed in the Institute of Immunology and Experimental Therapy of Polish Academy of Sciences in Wroclaw.
Table 1. Antiproliferative activity of the compounds
Figure imgf000013_0001

Claims

1. New analogs of 1 ,2,4-triazoles of the general formula I:
with different type of substitution of 2,4-dihydroxyphenyl system, wherein:
R,= H, HO-, Me-, MeO-
R2 = H, Me-, Et-, Pr-, iPr-, C1-, HO-, MeO-, EtO-
R3 = H, HO-, Me-, MeO-
R' = H, CI, Br, F3C-
X = N, Y=CH or X = CH, Y=N.
2. The analog according to claim 1, characterized in that it is 6-chloro-3-(2,4- dihydroxyphenyl)-l,2,4-triazolo[4,3-£]pyridazine.
3. The analog according to claim 1, characterized in that it is 6-chloro-3-(2,4- dihydroxyphenyl-3-methylphenyl)-l,2,4-triazolo[4,3-6]pyridazine.
4. The analog according to claim 1, characterized in that it is 6-chloro-3-(5-ethyl-2,4- dihydroxyphenyl)- 1 ,2,4-triazolo[4,3-£]pyridazine.
5. The analog according to claim 1, characterized in that it is 6-chloro-3-(5-chloro- 2,4-dihydroxyphenyl)-l,2,4-triazolo[4,3-&]pyridazine.
6. The analog according to claim 1, characterized in that it is 6-chloro-3-(2,3,4- trihydroxyphenyl)-l,2,4-triazolo[4,3- »]pyridazine.
7. The analog according to claim 1, characterized in that it is 3-(2,4- dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4-triazolo[4,3-ot]pyrimidine.
8. The analog according to claim 1, characterized in that it is 3-(2,4-dihydroxy-3- methylphenyl)-7-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrimidine.
9. The analog according to claim 1, characterized in that it is 3-(5-ethyl-2,4- dihydroxyphenyl)-7-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrimidine.
10. The analog according to claim 1, characterized in that it is 3-(5-chloro-2,4- dihydroxyphenyl)-7-(trifluoromethyl)-l ,2,4-triazolo[4,3- ]pyrimidine.
1 1. Process for preparation of analogs of 1,2,4-triazoles of the general formula I,
Figure imgf000015_0001
wherein substrates are introduced into the solution, and then the product is isolated, characterized in that heteroarylhydrazine is reacted in monohydric alcohol with the addition of pyridine with the substance the general formula II:
Figure imgf000015_0002
wherein: R - H, Me, Et, Pr, iPr, CI, OH, MeO, EtO
and subsequently the resultant mixture is separated into filtrate I and precipitate I, which is then concentrated, while the resultant precipitate II is crystallized from an aqueous solution of a monohydric alcohol.
12. Process according to claim 1 1, characterized in that precipitate I is combined with precipitate II.
13. Process according to claim 1 1, characterized in that heteroarylhydrazine is 3- chloro-6-hydrazinopyridazine.
14. Process according to claim 1 1, characterized in that heteroarylhydrazine is 2- hydrazino-4-(trifluoromethyl)pyrimidine.
15. Process according to claim 1 1, characterized in that the substance of general formula II is bis[(2,4-dihydroxyphenyl)methanethione] sulfoxide.
16. Process according to claim 1 1 , characterized in that the substance of general formula II is bis[(5-ethyl-2,4-dihydroxyphenyl)methanothione] sulfoxide.
17. Process according to claim 1 1, characterized in that the substance of general formula II is bis[(2,4-dihydroxy-3-methylphenyl)methanethione] sulfoxide.
18. Process according to claim 1 1, characterized in that the substance of general formula II is bis[(5-chloro-2,4-dihydroxyphenyl)methanothione] sulfoxide.
19. Process according to claim 11, characterized in that the substance of general formula II is bis[(2,3,4-trihydroxyphenyl)methanothione] sulfoxide.
20. Process according to claim 1 1, characterized in that the substance of formula II is bis[(2,4-dihydroxy-5-methylphenyl)methanothione] sulfoxide.
21. Process according to claim 1 1, characterized in that a monohydric alcohol is ethanol or methanol.
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Citations (2)

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COLLINS L; CASTRO J.L.; STREET L.J., TETRAHEDRON LETT., vol. 41, 2000, pages 781 - 784
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