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Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use

a selective inhibitor and cyclooxygenase technology, applied in the field of new drugs, can solve the problems of undesirable side effects, gastrointestinal ulceration and renal toxicity, and the repeated use of nsaids has been associated with adverse effects, so as to improve the cardiovascular profile of cox-2 selective inhibitors, anti-inflammatory properties, and unexpected potential for wound healing

Inactive Publication Date: 2007-07-05
NICOX SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides novel COX-2 selective inhibitors with at least one oxime group or hydrazone group, or a pharmaceutically acceptable salt thereof. These compounds have potent analgesic, antiinflammatory, and wound healing properties, and may also have improved cardiovascular profile. The invention also provides compositions containing these compounds in a pharmaceutically acceptable carrier. The compounds can be nitrosated or nitrosylated, and can optionally contain a nitric oxide donor or stimulate endogenous production of nitric oxide. The methods of the invention can be used to treat and prevent inflammation, pain, fever, gastrointestinal disorders, and renal and respiratory toxicity. The invention also provides methods for reducing the gastrointestinal toxicity of COX-2 selective inhibitors.

Problems solved by technology

The chronic use of NSAIDs has been associated with adverse effects, such as gastrointestinal ulceration and renal toxicity.
The undesirable side effects are also due to the inhibition of prostaglandin in the affected organ.
However, these compounds can result in dyspepsia and can cause gastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).

Method used

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  • Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
  • Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
  • Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

1-(3-(1-(Hydroxyimino)-4-(nitrooxy)butyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene

1a. Methyl (2Z)-2-hydroxy-4-(4-methylthiophenyl)-4-oxobut-2-enoate

[1720] Dimethyloxalate (26 g, 180.7 mmol) was added to a stirred suspension of sodium methoxide (9.75 g, 180.7 mmol) in dry toluene (200 mL) at 0° C. The white suspension was stirred for 15 minutes at 0° C. A solution of 4′-(methylthio)acetophenone (15 g, 90.4 mmol) in dry toluene (150 mL) was then added dropwise over 15 minutes resulting in a yellow suspension which was stirred for 2 hours at room temperature. The thick yellow suspension was transferred to a 2 L flask and stirred vigorously with 10% HCl (250 mL) and EtOAc (200 mL) to dissolve all the solids. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were washed with water (250 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to give thick brown oil. The brown oil was dissol...

example 2

1-(1-Cyclohexyl-1-(3-(hydroxyimino)-4-(nitrooxy)butyl)pyrazol-4-yl)-4-(methylsulfonyl)benzene

2a. Methyl(2Z)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-4-oxobut-2-enoate

[1727] Oxone (4.39 g, 7.1 mmol) in water (14 mL) was added dropwise to a solution of the product of Example 1a (1.5 g, 6.0 mmol) in a mixture of MeOH (30 mL) and CH2Cl2 (2 mL) at 0° C. The resultant suspension was gradually warmed to room temperature over a period of 1 hour. The solid was filtered and the filtrate was diluted with CH2Cl2, washed with saturated NaHCO3, water, dried (Na2SO4) and filtered. The solvent was evaporated to give the title compound (0.8 g, 47%). mass spectrum (API-TIS) m / z 285 (MH+), 302 (MNH4+).

2b. Methyl-1-cyclohexyl-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate.

[1728] The product of Example 2a (7.4 g, 26 mmol) and cyclohexyl hydrazine hydrochloride (4.3 g, 29 mmol) were heated at reflux in MeOH (100 mL for 6 hours. The reaction mixture was cooled to room temperature and a few drops of ...

example 3

1-(3-(2-Aza-2-methoxy-1-(3-(nitrooxy)propyl)vinyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

3a. 1-(3-(2-Aza-2-methoxy-1-(3-(nitrooxy)propyl)vinyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

[1734] NaOH (75.0 mg, 1.88 mmol, 125 μL of 15 N solution) was added dropwise to a suspension of the product of Example 2f (0.27 g, 0.62 mmol) and methoxylamine hydrochloride (129 mg, 1.54 mmol) in ethanol (5 ml) and CH2Cl2 (0.5 mL) and the reaction mixture was stirred at room temperature for 4 hours. The residue, after evaporation of the solvent, was extracted into EtOAc, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative thin layer chromatography eluting with (1:1) EtOAc:Hexane to give the title compound, a mixture of isomers, (0.18 g, 63%) as a white foam. mp 35-40° C. 1H-NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.5 Hz, 0.6H), 8.05 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.4 Hz, 0.6H), 7.57 (d, J=8...

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Abstract

The invention provides novel cyclooxygenase 2 (COX-2) selective inhibitors having at least one oxime group or hydrazone group and novel compositions and kits comprising at least one COX-2 selective inhibitor having at least one oxime group or hydrazone group, optionally nitrosated and / or nitrosylated, and, optionally, at least one nitric oxide donor, and / or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention having at least one oxime group or hydrazone group can be optionally nitrosated and / or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and / or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and / or preventing renal and / or respiratory toxicity; for treating and / or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

Description

RELATED APPLICATIONS [0001] This application is a divisional of U.S. application Ser. No. 10 / 608,333, filed Jun. 30, 2003, now allowed, which claims priority under 35 USC § 119 to U.S. Application No. 60 / 392,044 filed Jun. 28, 2002.FIELD OF THE INVENTION [0002] The invention provides novel cyclooxygenase 2 (COX-2) selective inhibitors having at least one oxime group or hydrazone group and novel compositions and kits comprising at least one COX-2 selective inhibitor having at least one oxime group or hydrazone group, optionally nitrosated and / or nitrosylated, and, optionally, at least one nitric oxide donor, and / or, optionally, at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating and / or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and / or preventing renal and / or respiratory toxicity; for treating and / or preventing other disorders resulting fro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/541A61K31/5377A61K31/496A61K31/655A61K31/55A61K31/454A61K31/4196A61K31/4192A61K31/4164A61K31/415A61K45/00A61P1/00A61P1/04A61P7/00A61P7/02A61P9/00A61P9/10A61P11/00A61P11/02A61P11/06A61P13/00A61P13/02A61P13/12A61P15/00A61P17/00A61P19/02A61P25/00A61P25/02A61P25/28A61P27/02A61P29/00A61P31/00A61P35/00A61P37/08A61P43/00C07D231/12
CPCC07D231/12A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P13/00A61P13/02A61P13/12A61P15/00A61P17/00A61P19/02A61P25/00A61P25/02A61P25/28A61P27/02A61P29/00A61P31/00A61P35/00A61P37/08A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10
Inventor RANATUNGE, RAMANI R.GARVEY, DAVID S.RICHARDSON, STEWART K.
Owner NICOX SA
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