WO2016203488A1

WO2016203488A1 - Preparation of novel deferasirox analogues for antimalarial activity

Info

Publication number: WO2016203488A1
Application number: PCT/IN2015/000343
Authority: WO
Inventors: Freddy H. HAVALDAR; Bhushan Vasant DABHOLKAR; Ganesh Baban MULE
Original assignee: Havaldar Freddy H
Priority date: 2015-06-16
Filing date: 2015-09-01
Publication date: 2016-12-22

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),

(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.

(1) 2) (3)

(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 C₂₄H29ClN_i)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) :

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

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.