Dynamic organ function monitoring agents

a technology of organ function and monitoring agent, applied in the field of new instruments for monitoring organ function, can solve the problems of inability to correlate single value returned several hours after sampling with other important physiologic events, inability to obtain new or repeat data, and inability to accurately predict the effect of organ function, etc., to achieve simple, efficient and effective monitoring of organ function.

Inactive Publication Date: 2005-07-28
MALLINCKRODT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] The novel compositions of the present invention comprise dyes of Formulas 1 to 6 which are hydrophilic and absorb light in the visible and near infrared regions of the electromagnetic spectrum. The ease of modifying the clearance pathways of the dyes after in vivo administration permits their use for physiological monitoring. Thus, blood protein-binding compounds are useful for angiography and organ perfusion analysis, which is particularly useful in organ transplant and critical ill patients. Predominant kidney clearance of the dyes enables their use for dynamic renal function monitoring, and rapid liver uptake of the dyes from blood serves as a useful index for the evaluation of hepatic function.
[0018] The inventive compounds and methods provide simple, efficient, and effective monitoring of organ function. The compound is administered and a sensor, either external or internal, is used to detect absorption and / or emission to determine the rate at which the compound is cleared from the blood. By altering the R groups, the compounds may be rendered more organ specific.

Problems solved by technology

In addition, a single value returned several hours after sampling is difficult to correlate with other important physiologic events such as blood pressure, cardiac output, state of hydration and other specific clinical events (e.g., hemorrhage, bacteremia, ventilator settings and others).
New or repeat data are equally cumbersome to obtain.
Frequently, dosing of medication is adjusted for renal function and thus can be equally as inaccurate, equally delayed, and as difficult to reassess as the values upon which they are based.
However, these markers have several undesirable properties such as the use of radioactivity or ex-vivo handling of blood and urine samples.
The main drawback of high molecular weight polypeptides is that they are immunogenic.
In addition, large polymers with narrow molecular weight distribution are difficult to prepare, especially in large quantities.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of indole disulfonate

(FIG. 1, Compound 5, Y7═SO3−: X7═H: n=1)

[0052] A mixture of 3-methyl-2-butanone (25.2 mL), and p-hydrazinobenzenesulfonic acid (15 g) in acetic acid (45 mL) was heated at 110° C. for 3 hours. After reaction, the mixture was allowed to cool to room temperature and ethyl acetate (100 mL) was added to precipitate the product, which was filtered and washed with ethyl acetate (100 mL). The intermediate compound, 2,3,3-trimethylindolenium-5-sulfonate (FIG. 1, compound 3) was obtained as a pink powder in 80% yield. A portion of compound 3 (9.2 g) in methanol (115 mL) was carefully added to a solution of KOH in isopropanol (100 mL). A yellow potassium salt of the sulfonate was obtained in 85% yield after vacuum-drying for 12 hours. A portion of the 2,3,3-trimethylindolenium-5-sulfonate potassium salt (4 g) and 1,3-propanesultone (2.1 g) was heated in dichlorobenzene (40 mL) at 110° C. for 12 hours. The mixture was allowed to cool to room temperature and the ...

example 2

Synthesis of indole disulfonate

(FIG. 1, Compound 5, Y7═SO3−; X7═H; n=2)

[0054] This compound was prepared by the same procedure described in Example 1, except that 1,4-butanesultone was used in place of 1,3-propanesultone.

example 3

Synthesis of benzoindole disulfonate

(FIG. 2, Compound 8, Y7,Y8═SO3−; X7═H; n=2)

[0055] This compound was prepared by the same procedure described in Example 1, except that hydrazinonaphthalenedisulfonic acid was used in place of hydrazinobenzenesulfonic acid.

[0056] Other compounds prepared by a similar method include polyhydroxyindoles such as:

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Abstract

Highly hydrophilic indole and benzoindole derivatives that absorb and fluoresce in the visible region of light are disclosed. These compounds are useful for physiological and organ function monitoring. Particularly, the molecules of the invention are useful for optical diagnosis of renal and cardiac diseases and for estimation of blood volume in vivo.

Description

CROSS REFERENCE [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 436,759, filed on May 13, 2003, which is a Divisional of U.S. patent application Ser. No. 09 / 687,428, filed on Oct. 13, 2000, now U.S. Pat. No. 6,663,847, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] This invention relates to novel optical probes for use in physiological function monitoring, particularly indole and benzoindole compounds. BACKGROUND OF THE INVENTION [0003] Dynamic monitoring of physiological functions of patients at the bedside is highly desirable in order to minimize the risk of acute renal failure brought about by various clinical, physiological, and pathological conditions (C. A. Rabito, L. S. T. Fang, and A. C. Waltman, Renal function in patients at risk with contrast material-induced acute renal failure: Noninvasive real-time monitoring, Radiology 1993, 186, 851-854; N. L. Tilney, and J. M. Lazarus, Acute renal failure in...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H15/26A61K49/00C07D209/08C07D209/12C07D209/60C07D405/14
CPCC07D209/08C07D405/14C07D209/60C07D209/12
Inventor ACHILEFU, SAMUELJIMENEZ, HERMO N.RAJAGOPALAN, RAGHAVANDORSHOW, RICHARD B.BUGAJ, JOSEPH E.
Owner MALLINCKRODT INC
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