Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof

a technology of co and compound, applied in the direction of iron organic compound, drug composition, biocide, etc., can solve the problems of small but important percentage of patients with adverse reactions, small increase in the number of hemorrhagic strokes, and substantial morbidity and mortality

Inactive Publication Date: 2006-07-06
ALFAMA INVESTIGACAO E DESENVOLVIMENTO DE PRODUTOSFARMACEUTICOS LDA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interactions of NSAIDs with such target depends on the structure and dose of the compound, and may have beneficial or adverse consequences.
NSAIDs are generally well tolerated; however, adverse reactions do occur in a small but important percentage of patients.
Because of the very extensive use of NSAIDs this results in substantial morbidity and mortality.
Long term administration of aspirin also leads to a small increase in the number of hemorrhagic strokes.
These studies have revealed several potential disadvantages of cyclooxygenase inhibitors in general, and of selective COX-2 inhibitors in particular.
Neurol 144, 339), they do not provide the prophylactic benefits of aspirin in vascular disease, which is largely, if not exclusively based on the reduction of COX-1 mediated thromboxane A2 synthesis in platelets.
Therefore, it is difficult to predict the long term effects of compounds, which exhibit sustained NO release.

Method used

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  • Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof
  • Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof
  • Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of the Sugar Derivatized Cyclopentadiene Ligand 1

[0108] To a solution of CpNa (2.2 g, 24.3 mmol) in DMF (8 ml) was added a solution of the protected sugar (3.7 g, 8.1 mmol) in DMF (20 ml) at −30 ° C. The reaction mixture was stirred at low temperature for 15 min and then was allowed to warm up to room temperature and stirred for a further 2 h. Destilled water (40 ml) was added to the mixture to destroy the excess of CpNa. The mixture was extracted with dichloromethane (2×100 ml) and the organic layer was dried with Na2SO4 and DMF was evaporated under vacuum. The residue was purified by columm chromatography on silica (AcOEt / n-hexane 1:8) to give the tittle compound 1 as a yellow oil. Yield g (75%). Since several isomers are present, the compound was best characterized and stabilized by transformation into its T1+ salt by action of TIOC2H5 or the Na+ salt by action of NaH. The ionic derivative of cyclopentadiene 1 as the T1+ salt, hereby abbreviated as CpsTI, was easily ...

example 2

Preparation of Compound 2

[0111] To a solution of Mo(CO)3(NCMe)3 (0.4 g, 1.14 mmol) in toluene (20 ml) was added a solution of CpsH (0.4 g, 1.14 mmol) in toluene (20 ml) at room temperature. The reaction mixture was stirred for 2 h and the orange solution was filtered through Celite. The filtrate was concentrated to dryness and the residue was dissolved in dichloromethane (50 ml). Solid CHI3 (0.37 g, mmol) was added to the dichloromethane solution and the colour immediately turned to a deep red. The reaction mixture was stirred for a further 30 min to ensure completion of the reaction and the solvent was removed under vacuum. The title compound 3 was isolated as a red solid. Yield (68%). Anal. Calc. for C22H31MoO7Sil: C, 40.13; H, 4.75. Found: C, 39.84; H, 4.45. Selected IR (KBr, cm−1): 2039, 1963,1884, vs, v(CO);

example 3

Preparation of Compound 3

[0112] Solid MnBr(CO)5 (0.14 g, 0.54 mmol) was added as a solid to a stirred solution of CPsTI (0.3 g, 0.54 mmol) in THF (40 ml) at room temperature. The reaction mixture was stirred for 16 h and the solvent was removed under vacuum. The residue was extracted in dichloromethane to yield the title compound 2 as a waxy yellow solid. Yield g (73%). Anal. Calc. for C22H31MnO7Si: C, 53.98; H, 6.32. Found: C, 53.51; H, 6.15. Selected IR (KBr, cm−1): 2019,1928, vs, v(CO).

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Abstract

Several classes of in vivo carbon monoxide-releasing compounds are useful for the treatment and / or prevention of diseases, such as chronic inflammatory, e.g., rheumatoid arthritis, and of diseases with a strong inflammatory component, such as atherosclerosis, stroke, coronary disease, and Alzheimers disease. The in vivo carbon monoxide-releasing compounds can be attached to known drug vectors and / or known anti-inflammatory drugs, such as aspirin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional application of U.S. application Ser. No. 10 / 356,738, filed Feb. 3, 2003, which is based on and claims the benefit of U.S. Provisional Application No. 60 / 353,233, filed Feb. 4, 2002. The entire disclosure of these applications are relied upon and incorporated by reference herein.BACKGROUND OF THE INVENTION [0002] The history of analgesic and anti-inflammatory medicines started with the use of decocted salicylate-containing plants by ancient Greek and Roman physicians. Willow bark was already used 300 BC for treating fever and pain. Sodium salicylate was introduced in 1875 as an antipyretic. At Bayer in Germany the less corrosive acetylsalicylic acid was synthesized and introduced into medicine in 1899 under the name of aspirin. [0003] The impressive anti-inflammatory, analgesic and antipyretic effects of aspirin prompted researchers to develop a large number of related compounds most of which are organic ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/185A61K31/19A61K31/00A61K45/00A61K31/18A61K31/192A61K31/28A61K31/555A61K31/60A61K31/603A61K31/616A61K31/695A61K31/7048A61K31/7135A61K33/00A61K33/14A61K33/32A61K45/06A61K47/48A61P9/00A61P9/10A61P11/06A61P25/28A61P29/00C07F11/00C07F13/00C07F15/02C07F17/00
CPCA61K31/00A61K31/28A61K31/555A61K31/60A61K31/603A61K31/616A61K31/695A61K31/7048A61K31/7135A61K33/00A61K33/14A61K33/32A61K45/06A61K47/48015C07F11/005C07F13/005C07F15/02C07F17/00A61K2300/00Y10S514/825Y10S514/929Y10S514/826Y10S514/887Y10S514/894Y10S514/903Y10S514/886Y10S514/824Y10S514/879Y10S514/959Y10S514/964Y10S514/921Y10S514/958Y10S514/95A61K47/52A61P11/06A61P19/02A61P25/28A61P29/00A61P9/00A61P9/10
Inventor HAAS, WERNERROMAO, CARLOSROYO, BEATRIZFERNANDES, ANA C.GONCALVES, ISABEL
Owner ALFAMA INVESTIGACAO E DESENVOLVIMENTO DE PRODUTOSFARMACEUTICOS LDA
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