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Medicinal uses of hydrazones

a technology of hydrazone and hydrazone, which is applied in the field of medicinal uses of hydrazone, can solve the problems of lack of oxygen supply, tissue damage, health problems affecting hundreds of millions of people, etc., and achieve the effects of increasing the transcription of hif-1 target genes, and increasing the biological activity of hif-1

Inactive Publication Date: 2004-03-18
ALMSTEAD JI IN KIM +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds effectively increase vascularization and EPO production, providing therapeutic benefits for conditions like anemia, ischemic heart disease, peripheral vascular disease, and wound healing, while also offering neuroprotection and improving cerebral and coronary circulation.

Problems solved by technology

Ischemic cardiac disease and peripheral vascular disease are major health problems affecting hundreds of millions of people worldwide.
Ischemia results when there is a lack of oxygen supply.
Tissue damage can result from hypoxia, that is, when oxygen supply in tissue is insufficient to meet metabolic demands.
In particular, several small molecules have been described which mimic the hypoxic induction of VEGF by activating HIF-1.alpha.. However, many of these molecules, such as cobaltous chloride or deferoxamine cannot be considered candidate drug-like molecules because of unfavorable pharmacokinetic characteristics.
Still other molecules, such as mersalyl, cannot be considered because of their reactivity.
However, in adults other organs such as the liver and brain produce small but significant amounts of EPO.
However, its extensive use could be limited by high production costs and lack of oral bioavailability.

Method used

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  • Medicinal uses of hydrazones
  • Medicinal uses of hydrazones
  • Medicinal uses of hydrazones

Examples

Experimental program
Comparison scheme
Effect test

examples 1-32

[0112] The following chart shows the structure of compounds made according to the procedures described in Examples 1-32.

1TABLE I 9 Example R1 R3 R2 / R4 R5 R6 Z (bond) EC.sub.50.sup.1 1 2-pyridyl H Nil H 2-pyridyl Double 1.6 2 2-pyridyl CH.sub.2 Nil H 2-pyridyl Double 0.65 3 2-pyridyl H Nil CH.sub.3 2-pyridyl Double 0.75 4 2-pyridyl H H / H H 2-pyridyl Single 5.7 5 2-pyridyl CH.sub.3 Nil CH.sub.3 2-pyridyl Double 26.2 6 2-pyridyl H Nil H 2-benzothiazole Double 1.5 7 2-pyridyl H Nil H 2-quinoline Double 3.15 8 2-pyridyl H Nil H 2-(5,7-bis- Double 1.57 trifluoromethyl- [1,8]-naphthyridyl) 9 2-pyridyl H Nil H 3-chloro-6-Double 6.7 pyridazine 10 2-pyridyl H Nil H 3-chloro-6-Double 1.56 trifluoromethyl-2- pyridyl 11 2-pyridyl CH.sub.3 Nil H 3-chloro-6- Double 15 trifluoromethyl-2- pyridyl 12 2-pyridyl H Nil CH.sub.3 4,6-dimethyl-2- Double 4.78 pyrimidine 13 2-pyridyl H Nil CH.sub.3 4-trifluoromethyl- Double 4.3 phenyl 14 2-pyridyl H Nil H 9H-1,3,4,9- Double 2.3 Tetraaza-2-fluorene 15 2-pyrid...

example 1

[0114] N-Pyridin-2-yl-N'-2-ylmethylene-hydrazine (1c): 10

[0115] To a solution of 2-pyridinecarboxaldehyde 1a (10 mmol, 1 equiv.) in ethanol (20 mL) is added 2-hydrazinopyridine 1b (10 mmol, 1 equiv.) to form a 0.5 M solution. The mixture is heated at reflux (60.degree. C.) for 6 hours or until the TLC (66% ethyl acetate / hexanes) shows disappearance of starting material. Upon forming or cooling, the desired product N-pyridin-2-yl-N'-2-ylmethylene-hydrazine 1c, precipitates and is filtered and washed with diethylether. The pale yellow solid is dried under vacuum for 15 hours. Generally, only the first crop is collected, characterized and tested.

[0116] Utililizing substantially the method of Example 1 and appropriate hydrazine, aldehyde, or ketone, the following subject compounds of Examples 2-108 are obtained. Modifications are described below.

example 2

[0117] N-Pyridin-2-yl-N'-(1-pyridin-2-yl-ethylidene)hydrazine: 11

[0118] In a procedure analogous to Example 1, 2-acetylpyridine is combined with 2-hydrazinopyridine to form N-Pyridin-2-yl-N'-(1-pyridin-2-yl-ethyli-dene)hydrazine. N-Pyridin-2-yl-N'-(1-pyridin-2-yl-ethylidene)hydrazine is precipitated out of ethanol with water. The solid is filtered and dried to afford the product as a dihydrate.

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Abstract

Compounds having a structure according to Formula (I): are effective in a method of increasing erythroproietin and vascularization of tissue in a subject in need thereof.

Description

[0001] This application is a Divisional of application Ser. No. 10 / 134,890, filed Apr. 29, 2002, which claims priority under Title 35, United States Code 119(e) from Provisional Application Serial No. 60 / 288,765, filed May 4, 2001.[0002] This invention is directed to compounds that are useful in methods of treating hypoxia related disorders. The invention is also directed to pharmaceutical compositions comprising the compounds.[0003] Ischemic cardiac disease and peripheral vascular disease are major health problems affecting hundreds of millions of people worldwide. Ischemia results when there is a lack of oxygen supply. It is estimated that about half of the deaths that occur in the United States each year alone are caused by ischemic heart disease. This invention relates, in part, to methods for the treatment of such diseases and pharmaceutical compositions in the treatment thereof.[0004] Oxygen is essential for an organism's survival, given its role in essential metabolic process...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/135A61K31/15A61K31/44A61K31/47A61K31/4745A61K31/50A61K31/53A61P9/00A61P13/12A61P25/00A61P43/00
CPCA61K31/135A61K31/15A61K31/44A61K31/53A61K31/4745A61K31/50A61K31/47A61P13/12A61P25/00A61P43/00A61P9/00
Inventor ALMSTEAD, JI-IN KIMIZZO, NICHOLAS JOHNJONES, DAVID ROBERTKAWAMOTO, RICHARD MASARU
Owner ALMSTEAD JI IN KIM
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