WO2016203488A1 - Preparation of novel deferasirox analogues for antimalarial activity - Google Patents

Preparation of novel deferasirox analogues for antimalarial activity Download PDF

Info

Publication number
WO2016203488A1
WO2016203488A1 PCT/IN2015/000343 IN2015000343W WO2016203488A1 WO 2016203488 A1 WO2016203488 A1 WO 2016203488A1 IN 2015000343 W IN2015000343 W IN 2015000343W WO 2016203488 A1 WO2016203488 A1 WO 2016203488A1
Authority
WO
WIPO (PCT)
Prior art keywords
arc
substituted
hydroxyphenyl
triazol
bis
Prior art date
Application number
PCT/IN2015/000343
Other languages
French (fr)
Inventor
Freddy H. HAVALDAR
Bhushan Vasant DABHOLKAR
Ganesh Baban MULE
Original Assignee
Havaldar Freddy H
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Havaldar Freddy H filed Critical Havaldar Freddy H
Publication of WO2016203488A1 publication Critical patent/WO2016203488A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the field of present invention provides a method for synthesis of a series of N- substituted 3,5-diphenyl-l,2,4-triazole derivatives having general structure (I),
  • Iron is an essential element for the growth of all living organisms. This metal is used in catalysis of DNA synthesis and for a variety of enzymes concerned in electron transport and energy metabolism. The antimalarial action of iron chelators is dictated by three factors:
  • Iron(III)-binding capacity chelator ingress into parasitized erythrocytes and chelator egress from parasites after treatment.
  • Various iron chelators were accessed to improve drug lipophilicity leading to increased access of drug to intracellular parasites and to faster speed of action. Deferoxamine does indeed penetrate the infected red cell and its antimalarial activity is dependent on this.
  • an effective antimalarial iron chelator would have the ability to cross lipid membranes well, have a high affinity for iron, selectively bind iron as compared to other trace metals and selectively bind iron (III) rather than iron(II).
  • the hydrophilic/hydrophobic balance or relative lipophilicity of a compound is an important factor in the movement of an agent across a lipid- containing membrane to enter a cell and in determining its usefulness.
  • the oral iron chelator deferiprone has mostly been tested in vivo in symptomatic and asymptomatic malaria (Mabeza et al., 1999; Smith and Meremikwu, 2003) while deferoxamine has also been tested in vivo in conjunction with standard antimalarial regimen (Gordeuk et al., 1992; Thuma et al., 1998).
  • the antimalarial activity of deferasirox, another oral iron chelator has only been evaluated once in vitro and was found to be at least as good as that of deferoxamine (Goudeau et al., 2001 ).
  • deferasirox 4-[(3,5-Bis-(2-hydroxyphenyl)-l ,2,4)triazol- l-yl]-benzoic acid (deferasirox) is a tridentate orally active iron chelator being developed as a new pharmacological agent for the chronic treatment of patients with iron overload. Two deferasirox molecules are necessary to fully complex the six coordination sites of an iron atom.
  • U.S. Patent No 6,465,504 discloses synthesis of substituted 3,5-diphenyl-l , 2,4- triazoles and their use as pharmaceutical metal chelators.
  • 3,5-Diphenyl-l ,2,4-triazoles have been known for a long time and their use is described for herbicides, e.g. in EP 185,401 , as angiotensin II receptor antagonists in EP 480,659, or very generally as intermediates and starting compounds for fine chemicals, e.g. in JP 06345728. It has now been found that certain substituted 3,5-diphenyl- l ,2,4-triazoles have valuable pharmacological properties when used in the treatment of malaria.
  • the object of the invention is to provide a method for synthesis of a series of N- substituted 3.5-bis(2-hydroxyphen ⁇ )- l H- 1 ,2,4-triazol- 1 -yl derivatives.
  • the invention provides a method for synthesis of a series of N-substituted 3,5-bis(2-hydroxyphenyl)- l H- l ,2,4-triazol- l -yl derivatives :
  • the method involves salicyclic acid (1) was coupled with salicylamide (2) to give 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3).
  • 4-Substituted ani lines (4a-d) were converted to their corresponding hydrazines via diazotization and simultaneous reduction with stannous chloride to afford 4-substituted phenyl hydrazines (5a-d).
  • the method for synthesis of 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3) involves coupling of salicyclic acid (1) and salicylamide (2) in presence of thionyl chloride in an aromatic hydrocarbon solvent which results in the formation of 2-(2-hydroxyphenyl)-4H- 1 ,3-benzoxazin-4-one (3).
  • Aromatic hydrocarbon is selected from m-xylene, p-xylene, o-xylene, toluene, dimethoxyethane, benzene.
  • Salicylic acid (1) and salicylamide (2) were coupled in presence of thiony l chloride in solvent xylene. After the completion of reaction, excess of xy lene was distilled out. Methanol was added, precipitated solid was filtered and washed with methanol and dried to obtain solid at 55°C to 60°C under vacuum tray drier which gave 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3). The reaction monitoring and purity of compound (3) was confirmed by normal phase thin layer chromatography TLC method using a mobile phase chloroform: methanol (9.8 : 0.2) and detected using uv fluorescence at maxima ⁇ ma 254.
  • the 4-substituted phenyl hydrazines (5a-d) were prepared as : Substituted anilines (4a-d) were diazotized by concentrated HCl and aqueous NaN0 2 solution and the resulting mixture was reduced using mixture of 8 ⁇ 2 ⁇ 2 ⁇ 2 0 and concentrated HCl. The solid was filtered and dried resulting in a w hite powder, 4-substituted phenyl hydrazines (5a-d).
  • the schematic representation of the reaction scheme is as fol lows.
  • n-propionic acid was heated to boiling temperature of the reaction mixture and kept at this temperature ( 132°C) for 2 hours. After completion of the reaction, 57 mL of ethyl acetate was added to the suspension after cool ing and the suspension was further stirred for 30 minutes. The resulting crystal l ine product was filtered, washed with 30 ml of ethyl acetate on the filter and dried to a constant weight.
  • a white crystal line product obtained was N-substituted 3,5- bis(2-hydroxyphenyl)- 1 H- 1 ,2,4-triazol- 1 -y 1 (6a-d).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to processes for the preparation of novel deferasirox analogues for antimalarial activity. The present invention further provides process for synthesis of novel deferasirox analogues.

Description

Preparation of novel deferasirox analogues for antimalarial activity;
The field of invention:
The field of present invention provides a method for synthesis of a series of N- substituted 3,5-diphenyl-l,2,4-triazole derivatives having general structure (I),
Figure imgf000002_0001
(I) wherein R = hydrogen, alkyl, sulfonamide, amine or nitro. Prior art and background of invention:
It has now been found that certain substituted 3,5-diphenyl- l ,2,4-triazoles have valuable pharmacological properties when used in the treatment of disorders which cause an excess of metal in the human or animal body or are caused by it.
It is also known that anion chelation therapy has been considered as a possible treatment for various infectious diseases including malaria. Iron is an essential element for the growth of all living organisms. This metal is used in catalysis of DNA synthesis and for a variety of enzymes concerned in electron transport and energy metabolism. The antimalarial action of iron chelators is dictated by three factors:
Iron(III)-binding capacity, chelator ingress into parasitized erythrocytes and chelator egress from parasites after treatment. Various iron chelators were accessed to improve drug lipophilicity leading to increased access of drug to intracellular parasites and to faster speed of action. Deferoxamine does indeed penetrate the infected red cell and its antimalarial activity is dependent on this. One would predict that an effective antimalarial iron chelator would have the ability to cross lipid membranes well, have a high affinity for iron, selectively bind iron as compared to other trace metals and selectively bind iron (III) rather than iron(II). The hydrophilic/hydrophobic balance or relative lipophilicity of a compound is an important factor in the movement of an agent across a lipid- containing membrane to enter a cell and in determining its usefulness. The oral iron chelator deferiprone has mostly been tested in vivo in symptomatic and asymptomatic malaria (Mabeza et al., 1999; Smith and Meremikwu, 2003) while deferoxamine has also been tested in vivo in conjunction with standard antimalarial regimen (Gordeuk et al., 1992; Thuma et al., 1998). The antimalarial activity of deferasirox, another oral iron chelator, has only been evaluated once in vitro and was found to be at least as good as that of deferoxamine (Goudeau et al., 2001 ).
4-[(3,5-Bis-(2-hydroxyphenyl)-l ,2,4)triazol- l-yl]-benzoic acid (deferasirox) is a tridentate orally active iron chelator being developed as a new pharmacological agent for the chronic treatment of patients with iron overload. Two deferasirox molecules are necessary to fully complex the six coordination sites of an iron atom.
U.S. Patent No 6,465,504 discloses synthesis of substituted 3,5-diphenyl-l , 2,4- triazoles and their use as pharmaceutical metal chelators.
3,5-Diphenyl-l ,2,4-triazoles have been known for a long time and their use is described for herbicides, e.g. in EP 185,401 , as angiotensin II receptor antagonists in EP 480,659, or very generally as intermediates and starting compounds for fine chemicals, e.g. in JP 06345728. It has now been found that certain substituted 3,5-diphenyl- l ,2,4-triazoles have valuable pharmacological properties when used in the treatment of malaria.
Efforts have been devoted to the modification and optimization of the existing structure of deferasirox antimalarial agents which relied on the empirical development of a structure-activity relationship (SAR), On the other hand, it is also an increasing prevalence of one such strategy that has been pursued in recent years to develop new antimalarial agents with novel chemical structures which could have modes of action rather than analogs of the existing ones.
Description of drawings and figures:
Figure 1 : IR spectrum of compound 6a.
Figure 2 : Ή NMR spectrum of compound 6a.
Figure 3 : L,C NMR spectrum of compound 6a.
Figure 4 : Mass spectrum of compound 6a.
Figure 5 : IR spectrum of compound 6b.
Figure 6 : Ή NMR spectrum of compound 6b.
Figure 7 : 13C NMR spectrum of compound 6b.
Figure 8 : Mass spectrum of compound 6b.
Figure 9 : IR spectrum of compound 6c.
Figure 10 : Ή NMR spectrum of compound 6c.
Figure 1 1 : bC NMR spectrum of compound 6c.
Figure 12 : Mass spectrum of compound 6c.
Figure 13 : IR spectrum of compound 6d.
Figure 14 : Ή NMR spectrum of compound 6d.
Figure 1 5 : C NMR spectrum of compound 6d.
Figure 16 : Mass spectrum of compound 6d. Object of the invention:
The object of the invention is to provide a method for synthesis of a series of N- substituted 3.5-bis(2-hydroxyphen\ )- l H- 1 ,2,4-triazol- 1 -yl derivatives.
Summary of the invention:
In one of the aspect, the invention provides a method for synthesis of a series of N-substituted 3,5-bis(2-hydroxyphenyl)- l H- l ,2,4-triazol- l -yl derivatives :
The method involves salicyclic acid (1) was coupled with salicylamide (2) to give 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3).
4-Substituted ani lines (4a-d) were converted to their corresponding hydrazines via diazotization and simultaneous reduction with stannous chloride to afford 4-substituted phenyl hydrazines (5a-d).
4-Substituted phenyl hydrazine (5a-d) were condensed w ith compound (3) to afford N-substituted 3,5-bis(2-hydroxyphenyl)- l H- 1 .2,4-triazol- l -yls (6a-d).
In the other aspect of invention it is provided that antimicrobial activity of N- substituted 3,5-bis(2-hydroxyphenyl)- l H- l ,2,4-triazol- l -yls (6a-d) have been tested in vitro for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella typhosa bacteria by agar well diffusion method. Detailed description of the invention:
The method for synthesis of 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3) involves coupling of salicyclic acid (1) and salicylamide (2) in presence of thionyl chloride in an aromatic hydrocarbon solvent which results in the formation of 2-(2-hydroxyphenyl)-4H- 1 ,3-benzoxazin-4-one (3).
Aromatic hydrocarbon is selected from m-xylene, p-xylene, o-xylene, toluene, dimethoxyethane, benzene.
In one of the most preferred aspect of invention it is provided that the process for the synthesis of 2-(2-hydroxyphenyl)-4H-' l ,3-benzoxazin-4-one (3) is carried as :
Salicylic acid (1) and salicylamide (2) were coupled in presence of thiony l chloride in solvent xylene. After the completion of reaction, excess of xy lene was distilled out. Methanol was added, precipitated solid was filtered and washed with methanol and dried to obtain solid at 55°C to 60°C under vacuum tray drier which gave 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3). The reaction monitoring and purity of compound (3) was confirmed by normal phase thin layer chromatography TLC method using a mobile phase chloroform: methanol (9.8 : 0.2) and detected using uv fluorescence at maxima λ ma 254. The mass spectrum of the compound (3) in ESI mode showed the peak molecular ion m/z [M+H] at 240.0. The structure of 2-(2-hydroxypheny l)-4H- l ,3-benzoxazin-4-one (3) was confirmed by mass spectrum.
In one of the preferred aspect of invention it is prov ided that the 4-substituted phenyl hydrazines (5a-d) were prepared as : Substituted anilines (4a-d) were diazotized by concentrated HCl and aqueous NaN02 solution and the resulting mixture was reduced using mixture of 8ηΟ2· 2Η20 and concentrated HCl. The solid was filtered and dried resulting in a w hite powder, 4-substituted phenyl hydrazines (5a-d).
In the most preferred aspect of the invention it is provided that preparation of N- substituted 3,5-bis(2-hydroxyphenyl)- 1 H- 1 ,2,4-triazol- 1 -y Is (6a-d).
A suspension 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3), 4-substituted phenyl hydrazines (5a-d) and n-propionic acid was heated to the boiling temperature. After completion of the reaction, ethyl acetate was added to the suspension. The resulting crystalline product was filtered. A white crystalline product obtained was N-substituted 3,5-bis(2-hydroxyphen> )- l H- l ,2,4-triazol- l -yls (6a-d).
The schematic representation of the reaction scheme is as fol lows.
Figure imgf000008_0001
(1) 2) (3)
Figure imgf000008_0002
(6a-d) a) R=H
b) R=SO2.NH2
c) R=4-CH2.NH.S02CH3
d) R=CH2.l,2,4-triazole
Examples:
1. Preparation of 2-(2-hydroxyphenyl)-4H-l ,3-benzoxazin-4-one (3)
Xylene ( 1 50 mL) and salicylic acid ( 1 ) ( 1 00 g, 0.072 mol) were added to a 500 mL, 4 necked round-bottom flask equipped with a mechanical stirrer and thermocouple. Thionyl chloride (87 g, 0.036 mol)) was added at 10°C to 15°C. After addition of thionyl chloride, the reaction mass was stirred at 10°C to 1 5°C for 30 minutes. The reaction mass was further heated at 35°C-40°C for 1 hr.
A solution of salicylamide (2) ( 100 g, 0.072 mol) in 200 mL of xylene was added to the reaction mass at 25°C to 30°C . After addition, the reaction mass was gradually heated at 80°C to 120°C and stirred for 2 hrs. After completion of reaction, excess of xylene was removed under vaccum. Methanol 200 mL was added to the reaction mass at 70°C to 80°C and stirred for 1 hour. The reaction mass was cooled gradually at 25°C to 30°C. The solid was filtered and washed with methanol and dried at 55°C to 60°C under vacuum tray drier to yield 165 g 2-(2-hydroxyphenyl)-4H- l ,3-benzoxazin-4-one (3). Yield 95%, m.p. 239°C . LCMS: m/z = 240.22 (M+H) calcd. for C H9N30: 239.2.
2. 4-Substituted-phenyl hydrazines (5a-d)
Substituted anilines (4a-d) (0.04 mol), 30.0 mL water and 30.0 mL concentrated HC1 were added to a round-bottom glass flask equipped with a magnetic stirrer and cooled in an ice bath. 25.0 mL 20% Aqueous NaN02 solution was added maintaining the temperature 0°C to 10°C and the resulting mixture was stirred for 0.5 hour. A mixture of SnCl2 ' 2H20 (20.0 g, 0. 105 mol) and concentrated HC1 (40 mL) w as then added to the reaction mass maintaining the temperature 0° to 10°C followed by stirring in the ice-bath to obtain substituted phenyl hydrazines (5a-d).
3. N-substituted 3,5-bis (2-hydroxyphenyl)-l H-l,2,4-triazol-l-yls (6a-d)
A suspension of (0.04 mol) 2-(2-hydroxyphenyl) benz[l,3]oxazin-4-one (3), (0.0524 mol) 4-substituted phenyl hydrazines (5a-d) and 57.0 mL of
n-propionic acid was heated to boiling temperature of the reaction mixture and kept at this temperature ( 132°C) for 2 hours. After completion of the reaction, 57 mL of ethyl acetate was added to the suspension after cool ing and the suspension was further stirred for 30 minutes. The resulting crystal l ine product was filtered, washed with 30 ml of ethyl acetate on the filter and dried to a constant weight. A white crystal line product obtained was N-substituted 3,5- bis(2-hydroxyphenyl)- 1 H- 1 ,2,4-triazol- 1 -y 1 (6a-d).
- I
4-[3,5-Bis(2-hydroxyphenyl)-l H-l ,2,4-triazol-l-yl]benzene (6a) : IR, v. cm :
3332.4 (C=N str.), 3066.3 (O-H, aromatic), 2930.3 (C-H str.), 2594.9 (N=N str.), 1660, 1609, 1591 (C=C, aromatic), 1 557.2.1497 (triazinc ring str. ), 835- 827 (C-C aromatic str.); Ή NMR (CDC13), δ ppm : 6.90-7.09 (m, 4H, Ar-H).
7.37-7.49 (m, 8H, Ar-H), 8.04-8.06 (dd, 1 H, Ar-H), 10.08 (br. s, 2 -OH); ''c NMR ((CDClj), δ ppm : 1 13 ,41 (ArC), 1 13.77 (ArC). 1 16.20 (ArC), 1 16.99 (ArC), 1 19.16 (ArC), 1 19.63 (ArC), 123,82 (ArC), 126.98 (ArC), 128.85 (ArC), 129.22 (ArC), 130.97 (ArC), 131 .55 (ArC), 131 .48 (ArC), 137.51 (ArC-N), 1 5 1.46 (C=N)S 1 55.63 (ArC-OH), 1 56.33 (C=N), 1 58.62 (ArC-OH); LCMS : m/z = 330. 1 (M+ l ); calcd. for Ο23Η27αΝ4Ο : 329.5; Anal. Calc. for C23H27C IN4O : C, 72.94; H, 4.59; N, 12.76. Found : C, 72.80; H, 4.34; N. 12.73. 4-[3,5-Bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl]benzenesulfonamide
(6b) : IR, v, cm"' : 3329.5 (ON str.), 3152.1 (O-H str.), 1609.3, 1560.1 (C=C aromatic), 1498.4, 1479.1 (triazine ring str.), 1342.2, 1167.9 (-SO2NH2 str.), 899.6, 833.1 (C-C aromatic); Ή NMR (CDC13), δ ppm : 6.89-7.05 (m, 4H, Ar- H), 7.50 (br. s, S02NH2), 7.37 -7.89 (m, 8H, Ar-H), 8,04-8.06 (dd, 1H, Ar-H).
10.39 (br. s, 2H, -NH2), 10.74 (br. s, 2 -OH); NMR (CDCI3), δ ppm : 113.45 (ArC), 113.62 (ArC), 114.18 (ArC), 116.31 (ArC), 117.17 (ArC), 119.52 (ArC), 123.93 (ArC), 126.89 (ArC), 127.01 (ArC), 131.20 (ArC), 131.67 (ArC), 132.72 (ArC). 136.23 (ArC), 140.21 (ArC). 143.90 (ArC-SO2.NH2), 148.32 (ArC-N), 152.14 (C=N), 155.36 (ArC-OH), 156.42 (C=N), 159.76 (ArC-OH); LCMS : m/z = 409.8 (M+l); calcd. for C23H26ClN3O : 408.9; Anal. Calc. for C23H26CIN3O: C, 60.54; H, 4.62; N, 12.84. Found : C, 60.44; H, 4.55; N, 12.69.
4-[3,5-Bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yljbenzylmethane
sulfonamide (6c): IR, v, cm'' : 3321.8 (C=N str.), 3076.9.1 (O-H str.), 1615.1, 1561.1, 1537.0 (C=C aromatic), 1514.8, 1484.0 (triazine ring str.), 1302.5, 1129.1 (-SO2str.), 899.6, 855.1 (C-C aromatic); Ή NMR (CDCI3), δ ppm : 2.52 (s, 3H, SO2CH3), 4.38 (s, 2H, -N.CH2), 6.87-7.04 (m, 4H. Ar-H), 7.36-7.48
(m, 7H, Ar-H), 8.04-8.05 (d, 1H, Ar-H), 10.12 (br. s, 2 -OH); '"C NMR (CDC13), 6 ppm : 29.10 (C-N), 55.48 (C-SO2), 113.53 (ArC), 113.86 (ArC), 116.37 (ArC), 117.16 (ArC), 119.33 (ArC), 119.81 (ArC), 123.92 (ArC), 127.14 (ArC), 131.16 (ArC), 131.38 (ArC), 131.76 (ArC), 132.68 (ArC), 137.31 (ArC- N), 151.69 (C=N), 155.76 (ArC-OH), 156.47 (ArC-OH), 158.37 (C=N); LCMS: m/z - 436.48 (M+l); calcd. for C24H29ClN4O : 437.1; Anai. Calc. for C24H29CIN4O : C, 58.81; H, 3.95; N, 15.67. Found : C, 58.65; H, 3.88; N, 15.33. 2,4-[3,5-Bis(2- ydroxyphenyl)-lH-l,2,4-triazol-l-yl-{4-(lH-l,2,4-triazol-l- yl)}]benz l (6d) : IR, v, cm'' : 3387.4 (O-H str.), 3132.2 (C=N str.), 2026.8 (C-NH str.), 1696.1, 1644.0, 1614.1 (C=C aromatic), 1516.7, 1492.6 (triazine ring str.), 855.1, 828.3 (C-C aromatic); Ή NMR (CDC13), δ ppm : 5.43 (s, 2H, CH2), 6.87-8.21 (m, 12H, Ar-H), 8.80- 8.84 (d, IH, Ar-H), 9.03 (s, IH. Ar-H),
10.12 (br. s, 2 -OH); '"C NMR (CDC13), δ ppm : 29.10 (C-N), 51.93 (CH2), 113.67 (ArC), 114.34 (ArC), 116.20 (ArC), 117.06 (ArC), 119.27 (ArC), 119.70 (ArC), 123.95 (ArC), 126.77 (ArC), 128.84 (ArC), 131.02 (ArC), 131.45 (ArC), 132.41 (ArC), 136.11 (ArC-N), 137.44, 151.76 (C=N), 155.49 (ArC-OH), 156.33 (ArC-OH), 159.41 (C=N); LCMS : m/z = 436.48 (M+l); calcd. for C24H29ClNi)O : 437.1; Anal. Calc. for C24H29CIN4O : C, 58.81; H, 3.95; N, 15.67. Found: C, 58.65; H, 3.88; N, 15.33.

Claims

Claims:
1. N-substituted 3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl derivatives having general formula (I) :
Figure imgf000013_0001
Formula (I) wherein R is H or S02NH2, CH2-NHS02-CH3 or CH2-l,2,4-triazole
2. A method for synthesis of N-substituted 3,5-bis(2-hydroxyphenyl)-lH- 1,2,4-triazol-l-yl derivatives having general formula (I) comprising :
(a) Diazotised 4-substituted aniline (4) was converted to hydrazine and simultaneous reduction with stannous chloride to afford 4- substituted phenyl hydrazine (5).
(b) Condensation of 4-substituted phenyl hydrazine (5) with 2-(2- hydroxyphenyl)-4H-l,3-benzoxazin-4-one (3) in presence of acid to form N-substituted 3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l- yi (I).
3. A method for synthesis of N-substituted 3,5-bis(2-hydroxyphenyl)-lH- 1,2,
4-triazol-l-yl derivatives according to claim 2 wherein acid for condensation of 4-substituted phenyl hydrazine w ith
Figure imgf000013_0002
4H-l,3-benzoxazin-4-one(3) is n-propionic acid. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptabl carrier of formula 1 .
5 , The compound or the pharmaceutical composition for use in treating conditions, disorders or diseases that can be prevented and/or treated by iron chelation therapy.
6. Pharmaceutical composition according to claim 5 wherein dosage forms are tablet, capsule etc.
PCT/IN2015/000343 2015-06-16 2015-09-01 Preparation of novel deferasirox analogues for antimalarial activity WO2016203488A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2303/MUM/2015 2015-06-16
IN2303MU2015 2015-06-16

Publications (1)

Publication Number Publication Date
WO2016203488A1 true WO2016203488A1 (en) 2016-12-22

Family

ID=57546634

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2015/000343 WO2016203488A1 (en) 2015-06-16 2015-09-01 Preparation of novel deferasirox analogues for antimalarial activity

Country Status (1)

Country Link
WO (1) WO2016203488A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573266A (en) * 2017-09-19 2018-01-12 黑龙江鑫创生物科技开发有限公司 A kind of synthetic method of 4-hydrazinobenzene-1-sulfonamide hydrochloride
CN110862384A (en) * 2019-09-29 2020-03-06 广东工业大学 A kind of indole fluorescent probe and its preparation method and application
CN115057827A (en) * 2022-07-20 2022-09-16 河南大学 Deferasirox derivatives, their synthetic methods, and their application in the preparation of iron-overloaded hepatocellular carcinoma diagnostic and therapeutic drugs
CN115353492A (en) * 2022-08-26 2022-11-18 浙江野风药业股份有限公司 Method for continuously synthesizing 1- (4-hydrazinophenyl) methyl-1, 2,4-triazole

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465504B1 (en) * 1996-06-25 2002-10-15 Novartis Ag Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465504B1 (en) * 1996-06-25 2002-10-15 Novartis Ag Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STEFAN STEINHAUSER ET AL.: "Complex Formation of ICL670 and Related Ligands with FeIII and FeII", EUR. J. INORG. CHEM., no. 21, 2004, pages 4177 - 4192, XP002484059 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573266A (en) * 2017-09-19 2018-01-12 黑龙江鑫创生物科技开发有限公司 A kind of synthetic method of 4-hydrazinobenzene-1-sulfonamide hydrochloride
CN110862384A (en) * 2019-09-29 2020-03-06 广东工业大学 A kind of indole fluorescent probe and its preparation method and application
CN110862384B (en) * 2019-09-29 2022-12-30 广东工业大学 Indole fluorescent probe and preparation method and application thereof
CN115057827A (en) * 2022-07-20 2022-09-16 河南大学 Deferasirox derivatives, their synthetic methods, and their application in the preparation of iron-overloaded hepatocellular carcinoma diagnostic and therapeutic drugs
CN115057827B (en) * 2022-07-20 2023-06-30 河南大学 Deferasirox derivative, synthesis method thereof and application thereof in preparation of iron overload hepatocellular carcinoma diagnosis and treatment drugs
CN115353492A (en) * 2022-08-26 2022-11-18 浙江野风药业股份有限公司 Method for continuously synthesizing 1- (4-hydrazinophenyl) methyl-1, 2,4-triazole

Similar Documents

Publication Publication Date Title
Bayrak et al. Synthesis of some new 1, 2, 4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activities
CN101824002B (en) Water soluble triazole compound and synthesis method thereof
Ünver et al. New thiophene-1, 2, 4-triazole-5 (3)-ones: Highly bioactive thiosemicarbazides, structures of Schiff bases and triazole–thiols
JP7579253B2 (en) Thyroid hormone receptor beta agonist compounds
Hussain et al. Synthesis and antimicrobial activities of 1, 2, 4‐Triazole and 1, 3, 4‐Thiadiazole derivatives of 5‐Amino‐2‐Hydroxybenzoic acid
Kaushik et al. Convenient synthesis, antimalarial and antimicrobial potential of thioethereal 1, 4-disubstituted 1, 2, 3-triazoles with ester functionality
HU211474A9 (en) Azole compounds, their production and use
Gupta et al. Synthesis of some 4-amino-5-(substituted-phenyl)-4H-[1, 2, 4] triazole-3-thiol derivatives and antifungal activity
WO2016203488A1 (en) Preparation of novel deferasirox analogues for antimalarial activity
MALANI et al. A brief review article: Various synthesis and therapeutic importance of 1, 2, 4-triazole and its derivatives.
HU187399B (en) Process for preparing imidazolyl-propanol derivatives
Al-Khuzaie et al. Synthesis, characterization and evaluation antimicrobial activity of some new substituted 2-mercapto-3-phenyl-4 (3H)-quinazolinone
CA2322195C (en) Novel diphenyl-substituted 5-ring-heterocycles, method for producing them and their use as medicaments
Venkatagiri et al. Synthesis, Characterization, and Antimicrobial Activity of a Series of 2-(5-Phenyl-1, 3, 4-oxadiazol-2-yl)-N-[(1-aryl-1 H-1, 2, 3-triazol-4-yl) methyl] anilines Using Click Chemistry
RU2402550C1 (en) 2-[(1z)-1-(3,5-diphenyl-1,3,4-thiadiazol-2(3h)-ylidene)methyl]-3,5-diphenyl-1,3,4-thiadiazol-3-ium chloride and synthesis method thereof
Özdemir Synthesis of novel fluoroquinolone-triazole hybrid compounds as antimicrobial agents
Bai et al. Synthesis and antibacterial activity evaluation of aminoguanidine or dihydrotriazine derivatives
AU740324B2 (en) New triazoles as therapeutic agents for fungal infections
SK34994A3 (en) Method of preparation of 1,3-bis(1,2,4-triazole-1-yl)- propane-2-ol derivatives
AU2014222276A1 (en) 1-substituted, 4-(substituted phenoxymethyl)-1,2,3-triazole compounds with antifungal properties and methods for preparation thereof
CA2956464C (en) Bisamidinium-based inhibitors for the treatment of myotonic dystrophy
Aly et al. Synthesis, Reactions, and Biological Applications of 1, 2, 4-triazoles: A Review
Akram Synthesis and Biological Activities of Some New Heterocycles Containing Nitrogen and Sulphu
DK164362B (en) TRIAZOLD DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE
RU2757808C1 (en) 2-alkylthio-5-(1h-1,2,4,-triazole-1-ilmethyl)-1,3,4-thiadiazoles, method for production thereof and fungicidal compositions based thereon

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15895524

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15895524

Country of ref document: EP

Kind code of ref document: A1