WO2021186458A1 - 6-oxo-3-phenylpyridazine based cyclooxygenase-2 inhibitors for the treatment of inflammatory diseases - Google Patents
6-oxo-3-phenylpyridazine based cyclooxygenase-2 inhibitors for the treatment of inflammatory diseases Download PDFInfo
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- WO2021186458A1 WO2021186458A1 PCT/IN2021/050041 IN2021050041W WO2021186458A1 WO 2021186458 A1 WO2021186458 A1 WO 2021186458A1 IN 2021050041 W IN2021050041 W IN 2021050041W WO 2021186458 A1 WO2021186458 A1 WO 2021186458A1
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- phenylpyridazin
- thiazol
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- benzylidene
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N0 2 , -CH 3 , and -C 2 H 5 ; Het is selected from the formula II, III, and
- 3 ⁇ 4 is selected from the group consisting of -F, -Cl, - Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
- Emorfazone an analgesic and anti-inflammatory pyridazine derivative
- pyridazine derivatives have emerged as a novel prototype for developing non-ulcerogenic cyclooxygenase-2 (COX-2) inhibitory anti-inflammatory agents (Singh et al, Future Medicinal Chemistry, 2017, 9(1), p. 95-127).
- the generation of the COX-2 is responsible for the development of inflammatory events in a cell, which ultimately leads to the development of inflammatory diseases, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis (Chen et al, Oncotarget, 2017, 9(6), p. 7204-7218; Varela et al, Inflammation, 2018, 41(4), p. 1115-1127).
- inflammatory diseases for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis (Chen et al, Onco
- the COX-2 inhibitors may be used to treat diseases associated with the higher activity of the COX- 2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- diseases associated with the higher activity of the COX- 2 for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- U.S. Patent No. 4,404,203 provides the preparation of critical intermediates, for example, 6-phenyl-4,5-dihydropyridazin-3(2H)-one and 6-phenylpyridazin-3(2H)- one.
- the primary objective of the present invention is to provide novel 6-oxo-3-phenylpyridazine based cyclooxygenase -2 (COX-2) inhibitors of formula I, which can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- COX-2 6-oxo-3-phenylpyridazine based cyclooxygenase -2
- the present inventors have identified novel 6-oxo-3- phenylpyridazine based COX-2 inhibitors of formula I, which can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- diseases associated with the higher activity of the COX-2 for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N0 2 , -CH 3 , and -C 2 H 5 ;
- Het is selected from the formula II, III, and
- Ri is selected from the group consisting of -F, -Cl, - Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
- novel 6-oxo-3- phenylpyridazine based COX-2 inhibitors of formula I which can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- the present invention provides a compound of formula I,
- R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N0 2 , -CH 3 , and -C 2 H 5 ; Het is selected from the formula II, III, and IV,
- R is selected from the group consisting of -F, -Cl, - Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
- the present invention provides a compound of formula V, v
- R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N0 2 , -CH 3 , and -C 2 H 5 ;
- R is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
- the present invention provides a compound of formula VI,
- R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N0 2 , -CH 3 , and -C 2 H 5 ;
- R is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
- the present invention provides a compound of formula VII, [028] wherein, R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N0 2 , -CH 3 , and -C 2 H 5 ; R, is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
- the present invention provides a compound selected from the group of
- the present invention provides a compound selected from the group of [042] 2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazineyl)-5-(2-oxoindolin-3-ylidene)thiazol-4(5H)-one
- the present invention provides a compound selected from the group of [047] 6-Phenyl-2-(4-((2-(4-phenylthiazol-2- yl)hydrazinylidene)methyl)phenyl)pyridazin-3(2H)-one, and [048] 2-(4-((2-(4-(4-Bromophenyl)thiazol-2- yl)hydrazineylidene)methyl)phenyl) -6-phenylpyridazin-3 (2H) -one . [049] In the ninth aspect, the present invention provides a compound selected from the group of [047] 6-Phenyl-2-(4-((2-(4-phenylthiazol-2- yl)hydrazinylidene)methyl)phenyl)pyridazin-3(2H)-one, and [048] 2-(4-((2-(4-(4-Bromophenyl)thiazol-2- yl)hydr
- the present invention provides a compound 5-(4-Methoxybenzylidene)-2-(2-(4-(6-oxo-3- phenylpyridazin-l(6H)-yl)benzylidene)hydra-zineyl)thiazol-4(5H)-one
- novel 6-oxo-3-phenylpyridazine based cyclooxygenase-2 (COX-2) inhibitors of formula I may be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- the compounds of formula V for example, 2-(4-((2-(4-(4- fluorophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)-6-phenylpyridazin- 3(2H)-one; 2-(4-((2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)methyl) phenyl)-6-phenylpyridazin-3(2H)-one; and 2-(4-((2-(4-(4-iodophenyl) thiazol-2-yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3(2H)-one can be prepared by following the example 4 and example 5 by using appropriate substituted phenacyl bromide.
- Example 9 In vitro COX-1 & COX-2 inhibition assay [076] The compounds 4, 5, 7, and 8 were subjected to the COX-1 &
- COX-2 inhibition assay using assay kits of the human COX-1 & COX-2, which was obtained from Cayman Chemicals (560131, Ann Arbor, MI, USA). The kit supplier’s instructions were followed to carry out the COX- 1 & COX-2 inhibition assay. The result is provided in the following Table 1.
- These compounds can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
- diseases associated with the higher activity of the COX-2 for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
Abstract
The present invention provides a compound of formula I, (I) wherein R is selected from the group consisting of -H, -F, -Cl, -Br, -I, -NO2, -CH3, and -C2H5; Het is selected from the formula II, III, and IV, (II) (III) IV) wherein R1 is selected from the group consisting of –F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
Description
[002] TITLE OF INVENTION
[003] 6-Oxo-3-Phenylpyridazine Based Cyclooxygenase-2 Inhibitors for the Treatment of Inflammatory Diseases
[004] Technical field of the invention:
[005] The present invention provides a compound of formula I,
[006] wherein R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N02, -CH3, and -C2H5; Het is selected from the formula II, III, and
[007] wherein ¾ is selected from the group consisting of -F, -Cl, - Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
[008] Background of the invention:
[009] Pyridazine, a famous diazine ring, is part of many
pharmacodynamic agents (Khalil el al, Bioorganic & Medicinal Chemistry, 2014, 22(7), p. 2080-2089; Saeed et al. , Archives ofPharmacal Research, 2012, 35(12), p. 2077-2092; Bingham et al, Journal of Pharmacology & Experimental Therapeutics, 2005, 312(3), p. 1161-1169; Ahmed et al, European Journal of Medicinal Chemistry, 2019, 171, p. 25- 37). Emorfazone (Pentoil), an analgesic and anti-inflammatory pyridazine derivative, is in clinical use in Japan and is claimed to lack gastric side effects (Singh et al, Future Medicinal Chemistry, 2017, 9(1), p. 95- 127). Recently, pyridazine derivatives have emerged as a novel prototype for developing non-ulcerogenic cyclooxygenase-2 (COX-2) inhibitory anti-inflammatory agents (Singh et al, Future Medicinal Chemistry, 2017, 9(1), p. 95-127). The generation of the COX-2 is responsible for the development of inflammatory events in a cell, which ultimately leads to the development of inflammatory diseases, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis (Chen et al, Oncotarget, 2017, 9(6), p. 7204-7218; Varela et al, Inflammation, 2018, 41(4), p. 1115-1127). Accordingly, the COX-2 inhibitors may be used to treat diseases associated with the higher activity of the COX- 2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
[010] U.S. Patent No. 4,404,203 provides the preparation of critical intermediates, for example, 6-phenyl-4,5-dihydropyridazin-3(2H)-one and 6-phenylpyridazin-3(2H)- one.
[Oil] Objective:
[012] The primary objective of the present invention is to provide novel 6-oxo-3-phenylpyridazine based cyclooxygenase -2 (COX-2)
inhibitors of formula I, which can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
[013] Summary of the invention:
[014] The present inventors have identified novel 6-oxo-3- phenylpyridazine based COX-2 inhibitors of formula I, which can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
[015] The present invention provides a compound of formula I,
[016] wherein R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N02, -CH3, and -C2H5; Het is selected from the formula II, III, and
IV,
[017] wherein Ri is selected from the group consisting of -F, -Cl, - Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
[018] Detailed description of the invention: [019] The present inventors have identified novel 6-oxo-3- phenylpyridazine based COX-2 inhibitors of formula I, which can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
[020] In the first aspect, the present invention provides a compound of formula I,
[021] wherein R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N02, -CH3, and -C2H5; Het is selected from the formula II, III, and IV,
[022] wherein R, is selected from the group consisting of -F, -Cl, - Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
[023] In the second aspect, the present invention provides a compound of
formula V,
v
[024] wherein R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N02, -CH3, and -C2H5; R is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy. [025] In the third aspect, the present invention provides a compound of formula VI,
[026] wherein R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N02, -CH3, and -C2H5; R, is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy. [027] In the fourth aspect, the present invention provides a compound of formula VII,
[028] wherein, R is selected from the group consisting of -H, -F, -Cl, - Br, -I, -N02, -CH3, and -C2H5; R, is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
[029] In the fifth aspect, the present invention provides a compound selected from the group of
[030] 6-Phenyl-2-(4-((2-(4-phenylthiazol-2-yl)hydrazinylidene)methyl) phenyl) pyridazin-3(2H)-one
[031] 2-(4-((2-(4-(4-Bromophenyl)thiazol-2- yl)hydrazineylidene)methyl)phenyl)-6- phenylpyridazin-3(2H)-one [032] 2-(4-((2-(4-(4-fluorophenyl)thiazol-2- yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3 (2H)-one [033] 2-(4-((2-(4-(4-chlorophenyl)thiazol-2- yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3 (2H)-one, and [034] 2-(4-((2-(4-(4-iodophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)- 6-phenylpyridazin-3 (2H)-one [035] In the sixth aspect, the present invention provides a compound selected from the group of
[036] 5 -(4-Chlorobenzylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)- yl)benzylidene)- hydra-zinyl)thiazol-4(5H)-one [037] 5 -(4-Methoxybenzylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin - 1(6H)- yl)benzylidene)hydra-zineyl)thiazol-4(5H)-one
[038] 5 -(4-fluorobenzylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
[039] 5-(4-bromobenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one, and [040] 5 -(4-iodobenzylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
[041] In the seventh aspect, the present invention provides a compound selected from the group of [042] 2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazineyl)-5-(2-oxoindolin-3-ylidene)thiazol-4(5H)-one
[043] 5 -(5 -fluoro-2-oxoindolin-3 -ylidene)-2-(2-(4-(6-oxo-3 - phenylpyridazin- 1(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one [044] 5-(5-chloro-2-oxoindolin-3-ylidene)-2-(2-(4-(6-oxo-3- phenylpyridazin- 1(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one, and [045] 5-(5-methyl-2-oxoindolin-3-ylidene)-2-(2-(4-(6-oxo-3- phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
[046] In the eighth aspect, the present invention provides a compound selected from the group of [047] 6-Phenyl-2-(4-((2-(4-phenylthiazol-2- yl)hydrazinylidene)methyl)phenyl)pyridazin-3(2H)-one, and [048] 2-(4-((2-(4-(4-Bromophenyl)thiazol-2- yl)hydrazineylidene)methyl)phenyl) -6-phenylpyridazin-3 (2H) -one . [049] In the ninth aspect, the present invention provides a compound
2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)-yl)benzylidene)hydrazineyl)-5 - (2-oxoindolin-3- ylidene)thiazol-4(5H)-one
[050] In the tenth aspect, the present invention provides a compound 5-(4-Methoxybenzylidene)-2-(2-(4-(6-oxo-3- phenylpyridazin-l(6H)-yl)benzylidene)hydra-zineyl)thiazol-4(5H)-one
[051] The novel 6-oxo-3-phenylpyridazine based cyclooxygenase-2 (COX-2) inhibitors of formula I may be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease,
ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
[052] The method of preparation of some compounds of the present invention has been exemplified in example 4, example 5, example 7, and example 8. The process of preparing 6-phenylpyridazin-3(2H)-one is provided in U.S. Patent No. 4,404,203. The method of preparation of other intermediates is provided in example 1, example 2, and example 6. The COX-2 inhibitory activity of the compounds 4, 5, 7, and 8 is exemplified in example 9.
[053] While the present invention has been described in terms of its specific embodiments and examples, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
[054] EXAMPLES
[055] Example 1: Synthesis of 4-(6-Oxo-3-phenylpyridazin- l(6/7)yl)benzaldehyde (1)
[056] A mixture of 6-phenylpyridazin-3(2H)-one (10 mmoles), p- fluorobenzaldehyde (10 mmoles), anhydrous K2C03 (10 mmoles) in dimethylsulfoxide (40 mL) was heated to 100°C for 5 hours, and
discharged in the crushed ice. The fdtered solid was recrystallized from ethanol m.p: 187-189°C; ½-NMR (500 MHz, DM SO A, d in ppm): 7.14 (d, 1H, Ar-H), 7.43 (brs, 3H, Ar-H), 7.88 (m, 3H, Ar-H), 7.99 (brs,
3H, Ar-H), 8.12 (d, 1H, Ar-H), 10.01 (s, 1H, -CHO); 13C-NMR(125 MHz, DMSO-£¾ d in ppm): 126.50 (2C), 126.59, 128.13, 128.61, 129.45
(2C), 130.26, 131.78, 132.37, 134.41, 135.56, 145.22, 146.55, 154.17, 159.11, 192.85.
[057] Example 2: Synthesis of 2-(4-(6-Oxo-3-phenyl pyridazin-l(6H)-yl)benzylidene)hydrazine-l-carbothioamide (2)
[058] The mixture of compound 1 (10 mmoles), thiosemicarbazide (10 mmoles), and acetic acid (40 mL) was heated to 125°C for 3 hours to acquire a precipitate. The fdtered precipitate was recrystallized from dioxane to get the compound m.p: 235-237°C; ^H-NMR (500 MHz, DMSO- d in ppm): 7.18 (d, 1H, Ar-H), 7.49 (brs, 3H, Ar-H), 7.74 (d, 2H, Ar-H), 7.94 (m, 4H, Ar-H), 8.12 (m, 3H, Ar-H + NH2), 8.25 (s, 1H, azomethine-H), 11.52 (s, 1H, NH); 13C-NMR(125 MHz, DMSO-A, d in ppm): 126.14, 126.54 (2C), 127.89 (2C), 128.57 (2C), 129.43 (2C), 129.65, 129.72, 131.54, 134.61, 142.94, 144.85, 159.08, 160.73, 178.61.
[059] Example 3: Synthesis of 2-(4-(6-Oxo-3-phenylpyridazin-l(6/7)- yl)benzylidene)-N-phenylhydrazine-l-carbothioamide (3)
[060] The mixture of compound 1 (10 mmoles), 2-phenylhydrazine-l- carbothioamide (10 mmoles), and acetic acid (40 mL) was heated to
125°C for 3 hours to acquire a precipitate. The filtered precipitate was recrystallized from dioxane to get the compound m.p: 247-249°C; * H- NMR (500 MHz, DMSO-£/6, d in ppm): 7.15 (d, 2H, Ar-H), 7.37, 7.46, 7.59 (3brs , 7H, Ar-H), 7.75, 7.88 (2brs, 4H, Ar-H), 8.05 (brs, 3 H, Ar-H), 8.23 (s, 1H, azomethine-H), 10.19 & 11.93 (2s, 2H, 2NH); 13C-
NMR(125MHz, DMSO-£/6, d in ppm): 125.91 (2C), 126.11 (2C), 126.37, 126.50, 128.21, 128.58 (2C), 129.42 (2C), 130.12, 131.48, 131.57, 132.33, 134.03, 134.53, 139.44, 142.32, 143.06, 144.90, 154.26, 159.14, 176.55.
[061] Example 4: Synthesis of 6-Phenyl-2-(4-((2-(4-phenylthiazol-2- yl)hydrazinylidene)methyl)phenyl)pyridazin-3(2H)-one (4)
[062] A mixture of compound 2 (10 mmoles), 2-bromo-l-phenylethan-l- one (10 mmoles) and sodium acetate (20 mmoles) in acetic acid (30 mL) was refluxed for 4 hours. The solid produced was collected and purified
from dioxane. m.p. 280-281°C; 1 H-NMR (500 MHz, DM SO- A, d in ppm): 7.04-7.50 (m, 9H, Ar-H + thiazole-H), 7.79-8.11 (m, 9H, Ar-H + azomethine-H), 12.28 (s, 1H, NH); 13C-NMR(125 MHz, DMSO-A, d in ppm): 168.60, 159.07, 144.82, 142.46, 140.67, 135.13, 134.64, 134.44, 132.37, 131.60, 131.52, 130.10, 129.43, 129.08 (2C), 128.02 (2C), 126.79
(2C), 126.55 (2C), 126.34 (2C), 126.0 (2C), 104.33.
[063] Example 5: Synthesis of 2-(4-((2-(4-(4-Bromophenyl)thiazol-2- yl)hydrazineylidene)-methyl)phenyl)-6-phenylpyridazin-3(2H)-one (5)
[064] A mixture of compound 2 (10 mmoles), 2-bromo-l-(4- bromophenyl)ethan-l-one (10 mmoles) and sodium acetate (20 mmoles) in acetic acid (30 mL) was refluxed for 4 hours. The solid produced was collected and purified from dioxane. m.p. 261 -262°C: * H-NMR (500
MHz, DMSO-A, d in ppm): 7.20-8.33 (m, 17H, Ar-H + thiazole-H5
+azomethine-H), 12.31 (s, 1H, NH); 13C-NMR(125 MHz, DMSO-A, d in ppm): 168.78, 159.08, 149.92, 144.83, 142.53, 141.64, 140.87, 134.66, 134.36, 132.02, 131.62, 131.51, 130.11, 129.44, 128.59 (2C), 128.04, 127.91 (2C), 126.84, 126.57 (2C), 126.34, 126.15, 121.03, 105.24.
[065] The compounds of formula V, for example, 2-(4-((2-(4-(4- fluorophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)-6-phenylpyridazin-
3(2H)-one; 2-(4-((2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)methyl) phenyl)-6-phenylpyridazin-3(2H)-one; and 2-(4-((2-(4-(4-iodophenyl) thiazol-2-yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3(2H)-one can be prepared by following the example 4 and example 5 by using appropriate substituted phenacyl bromide.
[066] Example 6: Synthesis of 2-(2-(4-(6-Oxo-3- phenylpyridazin-l(6H)- yl)benzylidene)hydrazineyl)thiazol-4(5H)-one
(6)
[067] A mixture of compound 2 (10 mmoles), ethyl 2-chloroacetate (10 mmoles) and sodium acetate (20 mmoles) in acetic acid (30 mL) was refluxed for 4 hours. The solid produced was collected and purified from dioxane.
ppm): 3.92 (s, 2H, -S-CH2-), 7.20 (d, 2H, Ar-H), 7.48 (q,3H, Ar-H), 7.80 (d, 2H, Ar-H), 7.89 (d, 2H, Ar-H), 8.14 (d, 2H, Ar-H), 8.48 (s, 1H, azomethine-H), 12.12
ppm): 170.43, 159.06, 155.87, 154.58, 144.88, 143.59, 134.57, 134.15, 131.64, 130.14 (2C), 129.43 (2C), 128.25 (2C), 126.56 (2C), 126.34 (2C),
33.54.
[068] Example 7: Synthesis of 5-(4-Methoxy benzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)-yl)benzylidene) hydrazineyl)thiazol-4(5H)-one (7)
[069] A mixture of compound 6 (10 mmoles), and 4- methoxybenzaldehyde (10 mmoles) and piperidine (0.5 mL) in dioxane (30 mL) was refluxed for 3 to 6 hours. The solid produced was collected and purified using dioxane. m.p. > 300°C; ^H-NMR (500MHz, DMSO-£¾ d in ppm): 3.91 (s, 3H, OCH3), 6.94 (d, 2H, Ar-H), 7.24 (d, 2H, Ar- H), 7.50-7.58 (2brs, 5H, Ar-H), 7.80-8.12 (3brs, 6H, Ar-H+ CH-benzylidene), 8.18 (d, 1H, Ar-H), 8.50 (s, 1H, azomethine-H), 11.12 (s, 1H, NH); 13C-NMR(125 MHz, DMSO-ri6, d in ppm): 168.27, 166.11,
165.48, 159.09, 155.46, 155.17, 144.76, 134.65, 131.61 (2C), 130.98 (2C), 130.11 (2C), 129.44 (3C), 129.16 (3C), 127.21 (2C), 126.55 (3C), 126.16 (2C), 55.68. [070] The compounds of formula VI, for example, 5-(4-
Chlorobenzylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)- yl)benzylidene)-hydra-zinyl)thiazol-4(5H)-one ; 5 -(4- fluorobenzybdene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one; 5-(4- bromobenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin- 1(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one; and 5-(4- iodobenzylidene)- 2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)-yl)benzylidene)hydrazinyl) thiazol-4(5H)-one can be prepared by following the example 7 using appropriate substituted benzaldehyde.
[071] Example 8: Synthesis of 2-(2-
(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazineyl)-5-(2- oxoindolin-3-ylidene)thiazol-4(5H)-one (8)
[072] A mixture of 6 (10 mmoles), indoline-2,3-dione (10 mmoles) and piperidine (0.5 mL) was refluxed in dioxane (30 mL) for 2 hours. The solid was filtered hot, washed with ethanol, and purified with dioxane.
ppm): 6.76 (d, 1H,
Ar-H), 6.93 (d, 1H, Ar-H), 7.05 (d, 2H, Ar-H), 7.22 (d, 2H,Ar-H), 7.50 (brs, 3H, Ar-H), 7.87, 7.92 (2brs, 5H, Ar-H), 8.18 (d, 1H, Ar-H), 8.36
(s,lH, azomethine-H), 11.20, 12.51 (2s, 2H, 2NH); 13C-NMR(125 MHz, DMSO-£/6, d in ppm): 175.43, 168.22, 161.15, 159.53, 159.23, 157.51, 155.34, 145.12, 143.60, 134.58, 134.38, 132.33, 132.24, 131.68, 130.29,
129.48 (2C), 129.14 (2C), 128.71 (2C), 126.67 (3C), 126.22 (2C), 122.14, 121.92.
[073] The compounds of formula VII, for example, 5-(5-fluoro-2- oxoindolin-3-ylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)-yl) benzylidene)hydrazinyl)thiazol-4(5H)-one;
[074] 5-(5-chloro-2-oxoindolin-3-ylidene)-2-(2-(4-(6-oxo-3- phenylpyridazin-l(6H)-yl)benzylidene)hydrazinyl)thiazol-4(5H)-one; and 5 -(5 -methyl-2-oxoindolin-3 - ylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- l(6H)-yl)benzybdene)hydrazinyl)thiazol-4(5H)-one can be prepared by
following the example 8 using appropriate substituted isatin.
[075] Example 9: In vitro COX-1 & COX-2 inhibition assay [076] The compounds 4, 5, 7, and 8 were subjected to the COX-1 &
COX-2 inhibition assay using assay kits of the human COX-1 & COX-2, which was obtained from Cayman Chemicals (560131, Ann Arbor, MI, USA). The kit supplier’s instructions were followed to carry out the COX- 1 & COX-2 inhibition assay. The result is provided in the following Table 1.
[077] Table 1: In vitro COX-1 & COX-2 inhibition (N = 3, Mean ± SD)
[078] *All values had p < 0.5 (SPSS software); SI: IC50 for COX-1 in nM / IC 50 for COX-2 in mpi. [079] The in vitro COX-1 & COX-2 inhibition assay results indicate that compounds 4, 5, 7, and 8 have better COX-2 inhibitory activity than celecoxib and indomethacin. These compounds can be used to treat diseases associated with the higher activity of the COX-2, for example, gout, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, ulcerative colitis, depression, epilepsy, irritable bowel diseases, kidney injury, cancer, asthma, hepatitis, pancreatitis, and atherosclerosis.
Claims
1. A compound of formula I,
wherein R is selected from the group consisting of -H, -F, -Cl, -Br, -I, -N02, - CH3, and -C2H5; Het is selected from the formula II, III, and IV,
wherein R, is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
2. A compound of formula V,
v wherein R is selected from the group consisting of -H, -F, -Cl, -Br, -I, -N02, - CH3, and -C2H5; R, is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
3. A compound of formula VI,
wherein R is selected from the group consisting of -H, -F, -Cl, -Br, -I, -N02, - CH3, and -C2H5; R, is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
4. A compound of formula VII,
wherein, R is selected from the group consisting of -H, -F, -Cl, -Br, -I, -N02, - CH3, and -C2H5; R| is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy.
5. A compound selected from the group of 6-Phenyl-2-(4-((2-(4-phenylthiazol-2- yl)hydrazinylidene)methyl)phenyl)pyridazin-3(2H)-one
2-(4-((2-(4-(4-Bromophenyl)thiazol-2-yl)hydrazineylidene)methyl)phenyl)-6- phenylpyridazin-3(2H)-one
2-(4-((2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3(2H)-one
2-(4-((2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3(2H)-one, and
2-(4-((2-(4-(4-iodophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)-6- phenylpyridazin-3 (2H)-one
6. A compound selected from the group of
5-(4-Chlorobenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)- hydra-zinyl)thiazol-4(5H)-one
5-(4-Methoxybenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydra-zineyl)thiazol-4(5H)-one
5-(4-fluorobenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
5-(4-bromobenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one, and
5-(4-iodobenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
7. A compound selected from the group of
2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)-yl)benzylidene)hydrazineyl)-5-(2- oxoindobn-3-ylidene)thiazol-4(5H)-one
5-(5-fluoro-2-oxoindolin-3-ylidene)-2-(2-(-4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
5-(5-chloro-2-oxoindolin-3-ylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin-l(6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one, and
5 -(5 -methyl -2-oxoindolin-3 -ylidene)-2-(2-(4-(6-oxo-3 -phenylpyridazin- 1 (6H)- yl)benzylidene)hydrazinyl)thiazol-4(5H)-one
8. A compound selected from the group consisting of
6-Phenyl-2-(4-((2-(4-phenylthiazol-2- yl)hydrazinylidene)methyl)phenyl)pyridazin-3(2H)-one, and 2-(4-((2-(4-(4-Bromophenyl)thiazol-2-yl)hydrazineylidene)methyl)phenyl)-6- phenylpyridazin-3(2H)-one
9. A compound 2-(2-(4-(6-oxo-3- phenylpyridazin- 1 (6H)-yl)benzylidene)hydrazineyl)-5 -(2-oxoindolin-3 - ylidene)thiazol-4(5H)-one
10. A compound 5-(4-Methoxybenzylidene)-2-(2-(4-(6-oxo-3-phenylpyridazin- l(6H)-yl)benzylidene)hydra-zineyl)thiazol-4(5H)-one
Dr. Amrish Chandra Agent of the applicant IN/PA No: 2959
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998041511A1 (en) * | 1997-03-14 | 1998-09-24 | Merck Frosst Canada & Co. | Pyridazinones as inhibitors of cyclooxygenase-2 |
| US20030013739A1 (en) * | 1998-12-23 | 2003-01-16 | Pharmacia Corporation | Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia |
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2021
- 2021-01-16 WO PCT/IN2021/050041 patent/WO2021186458A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998041511A1 (en) * | 1997-03-14 | 1998-09-24 | Merck Frosst Canada & Co. | Pyridazinones as inhibitors of cyclooxygenase-2 |
| US20030013739A1 (en) * | 1998-12-23 | 2003-01-16 | Pharmacia Corporation | Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia |
Non-Patent Citations (1)
| Title |
|---|
| KHAN ABIDA, DIWAN ANUPAMA, THABET HAMDY K, IMRAN MOHD: "Synthesis of novel N‐substitutedphenyl‐6‐oxo‐3‐phenylpyridazine derivatives as cyclooxygenase‐2 inhibitors", DRUG DEVELOPMENT RESEARCH, vol. 81, no. 5, 1 August 2020 (2020-08-01), US , pages 573 - 584, XP055860216, ISSN: 0272-4391, DOI: 10.1002/ddr.21655 * |
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