U.S. patent application number 11/082598 was filed with the patent office on 2005-07-28 for dynamic organ function monitoring agents.
This patent application is currently assigned to MALLINCKRODT INC.. Invention is credited to Achilefu, Samuel, Bugaj, Joseph E., Dorshow, Richard B., Jimenez, Hermo N., Rajagopalan, Raghavan.
Application Number | 20050163715 11/082598 |
Document ID | / |
Family ID | 24760412 |
Filed Date | 2005-07-28 |
United States Patent
Application |
20050163715 |
Kind Code |
A1 |
Achilefu, Samuel ; et
al. |
July 28, 2005 |
Dynamic organ function monitoring agents
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.
Inventors: |
Achilefu, Samuel; (St.
Louis, MO) ; Jimenez, Hermo N.; (Hazelwood, MO)
; Rajagopalan, Raghavan; (Maryland Heights, MO) ;
Dorshow, Richard B.; (St. Louis, MO) ; Bugaj, Joseph
E.; (St. Charles, MO) |
Correspondence
Address: |
WOOD, HERRON & EVANS, LLP
2700 CAREW TOWER
441 VINE STREET
CINCINNATI
OH
45202
US
|
Assignee: |
MALLINCKRODT INC.
St. Louis
MO
63134
|
Family ID: |
24760412 |
Appl. No.: |
11/082598 |
Filed: |
March 17, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11082598 |
Mar 17, 2005 |
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10436759 |
May 13, 2003 |
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6887854 |
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10436759 |
May 13, 2003 |
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09687428 |
Oct 13, 2000 |
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6663847 |
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Current U.S.
Class: |
424/9.6 |
Current CPC
Class: |
C07D 209/12 20130101;
C07D 209/08 20130101; C07D 209/60 20130101; C07D 405/14
20130101 |
Class at
Publication: |
424/009.6 |
International
Class: |
A61K 049/00 |
Claims
What is claimed is:
1. A method for performing a diagnostic or therapeutic procedure
comprising administering to a mammal an effective amount of the
formula 11wherein R.sub.16, R.sub.17, R.sub.18, R.sub.20, R.sub.21,
R.sub.22 and R.sub.23, Y.sub.3, and Z.sub.3 are independently
selected from the group consisting of --H, C1-C10 alkoxyl, C1-C10
polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl,
saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen,
hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C5-C20
aryl, --SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(C- H.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T- ,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.fNH.sub.2, --CH.sub.2--(CH.sub.2--O-
--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH- .sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(C-
H.sub.2--O--CH.sub.2).sub.k--CH.sub.2--CO.sub.2T; R.sub.15 is
selected from the group consisting of --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH- .sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T; R.sub.19 is
selected from the group consisting of --H, C5-C10 alkoxyl, C5-C10
polyalkoxyalkyl, C7-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl,
saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen,
hydrophilic peptides, arylpolysulfonates, C7-C10 alkyl, C5-C20
aryl, --SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(C- H.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T- ,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.l--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.3 and X.sub.3 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.3 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; a, b, d, f, h,
i, and j independently vary from 1-10; c, e, g, and k independently
vary from 1-100; a.sub.3 and b.sub.3 vary from 0 to 5; R.sub.a,
R.sub.b, R.sub.c, and R.sub.d are defined in the same manner as
Y.sub.3; and T is either H or a negative charge.
2. The method of claim 1 comprising administering an effective
amount of the formula wherein R.sub.16, R.sub.17, R.sub.18,
R.sub.20, R.sub.21, R.sub.22 and R.sub.23, Y.sub.3, and Z.sub.3 are
independently selected from the group consisting of --H, C1-C5
alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20
polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic
peptides, arylpolysulfonates, C1-C5 alkyl, C5-C20 aryl,
--SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--C- H.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e--CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--- CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.s- ub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.-
2).sub.k--CH.sub.2--CO.sub.2T; R.sub.15 is selected from the group
consisting of --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T, and
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T; R.sub.19 is
selected from the group consisting of --H, C5 alkoxyl, C5
polyalkoxyalkyl, C7-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl,
mono- and disaccharides, nitro, hydrophilic peptides,
arylpolysulfonates, C5-C20 aryl, --SO.sub.3T, --CO.sub.2T, --OH,
--(CH.sub.2).sub.aSO.sub.3T, --(CH.sub.2).sub.aOSO.sub.3T,
--(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2--(CH.sub.2--O-- -CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e--CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--- CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.l--CO.s- ub.2T, and
--(CH.sub.2).sub.l--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.-
2).sub.k--CH.sub.2--CO.sub.2T; W.sub.3 and X.sub.3 are selected
from the group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c,
--S--, and --Se; V.sub.3 is a single bond or is selected from the
group consisting of --O--, --S--, --Se--, and --NR.sub.a; a, b, d,
f, h, i, and j independently vary from 1-5; c, e, g, and k
independently vary from 1-50; each a.sub.3 and b.sub.3
independently vary from 0 to 5; R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are defined in the same manner as Y.sub.3; and T is either
H or a negative charge.
3. The method of claim 1 wherein said procedure utilizes light of
wavelength in the region of 350-1300 nm.
4. The method of claim 1 wherein said procedure comprises
monitoring a blood clearance profile by fluorescence using light of
wavelength in the region of 350 to 1300 nm.
5. The method of claim 1 wherein said procedure comprises
monitoring a blood clearance profile by absorption using light of
wavelength in the region of 350 to 1300 nm.
6. The method of claim 1 wherein said procedure is for
physiological function monitoring.
7. The method of claim 6 wherein said procedure is for renal
function monitoring.
8. The method of claim 6 wherein said procedure is for cardiac
function monitoring.
9. The method of claim 6 wherein said procedure is for kidney
function monitoring.
10. The method of claim 6 wherein said procedure is for determining
organ perfusion 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 surgical patients:
Causes, clinical patterns, and care, Surgical Clinics of North
America, 1983, 63, 357-377; B. E. VanZe, W. E. Hoy, and J. R.
Jaenike, Renal injury associated with intravenous pyelography in
non-diabetic and diabetic patients, Annals of Internal Medicine,
1978, 89, 51-54; S. Lundqvist, G. Edbom, S. Groth, U. Stendahl, and
S.-O. Hietala, Iohexol clearance for renal function measurement in
gynecologic cancer patients, Acta Radiologica, 1996, 37, 582-586;
P. Guesry, L. Kaufman, S. Orlof, J. A. Nelson, S. Swann, and M.
Holliday, Measurement of glomerular filtration rate by fluorescent
excitation of non-radioactive meglumine iothalamate, Clinical
Nephrology, 1975, 3,134-138). This monitoring is particularly
important in the case of critically ill or injured patients because
a large percentage of these patients face the risk of multiple
organ failure (MOF), resulting in death (C. C. Baker et al.,
Epidemiology of Trauma Deaths, American Journal of Surgery, 1980,
144-150; R. G. Lobenhofer et al., Treatment Results of Patients
with Multiple Trauma: An Analysis of 3406 Cases Treated Between
1972 and 1991 at a German Level I Trauma Center, Journal of Trauma,
1995, 38, 70-77). MOF is a sequential failure of lung, liver, and
kidneys, and is incited by one or more severe causes such as acute
lung injury (ALI), adult respiratory distress syndrome (ARDS),
hypermetabolism, hypotension, persistent inflammatory focus, or
sepsis syndrome. The common histological features of hypotension
and shock leading to MOF include tissue necrosis, vascular
congestion, interstitial and cellular edema, hemorrhage, and
microthrombi. These changes affect the lung, liver, kidneys,
intestine, adrenal glands, brain, and pancreas, in descending order
of frequency (J. Coalson, Pathology of Sepsis, Septic Shock, and
Multiple Organ Failure. In New Horizons: Multiple Organ Failure, D.
J. Bihari and F. B. Cerra (Eds). Society of Critical Care Medicine,
Fullerton, Calif., 1986, pp. 27-59). The transition from early
stages of trauma to clinical MOF is marked by the extent of liver
and renal failure and a change in mortality risk from about 30% to
about 50% (F. B. Cerra, Multiple Organ Failure Syndrome. In New
Horizons: Multiple Organ Failure, D. J. Bihari and F. B. Cerra
(Eds). Society of Critical Care Medicine, Fullerton, Calif., 1989,
pp.1-24).
[0004] Serum creatinine measured at frequent intervals by clinical
laboratories is currently the most common way of assessing renal
function and following the dynamic changes in renal function which
occur in critically ill patients (P. D. Dollan, E. L. Alpen, and G.
B. Theil, A clinical appraisal of the plasma concentration and
endogenous clearance of creatinine, American Journal of Medicine,
1962, 32, 65-79; J. B. Henry (Ed). Clinical Diagnosis and
Management by Laboratory Methods, 17th Edition, W. B. Saunders,
Philadelphia, Pa., 1984); C. E. Speicher, The right test: A
physician's guide to laboratory medicine, W. B. Saunders,
Philadelphia, Pa., 1989). These values are frequently misleading,
since age, state of hydration, renal perfusion, muscle mass,
dietary intake, and many other clinical and anthropometric
variables affect the value. 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). An
approximation of glomerular filtration rate can be made via a
24-hour urine collection, but this requires 24 hours to collect the
sample, several more hours to analyze the sample, and a meticulous
bedside collection technique. New or repeat data are equally
cumbersome to obtain. Occasionally, changes in serum creatinine
must be further adjusted based on the values for urinary
electrolytes, osmolality, and derived calculations such as the
"renal failure index" or the "fractional excretion of sodium."
These require additional samples of serum collected
contemporaneously with urine samples and, after a delay, precise
calculations. 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. Finally, clinical decisions in the critically ill
population are often as important in their timing as they are in
their accuracy.
[0005] Exogenous markers such as inulin, iohexol, .sup.51Cr-EDTA,
Gd-DTPA, or .sup.99mTc-DTPA have been reported to measure the
glomerular filtration rate (GFR) (P. L. Choyke, H. A. Austin, and
J. A. Frank, Hydrated clearance of gadolinium-DTPA as a measurement
of glomerular filtration rate, Kidney International, 1992, 41,
1595-1598; M. F. Twedle, X. Zhang, M. Fernandez, P. Wedeking, A. D.
Nunn, and H. W. Strauss, A noninvasive method for monitoring renal
status at bedside, Invest. Radiol., 1997, 32, 802-805; N. Lewis, R.
Kerr, and C. Van Buren, Comparative evaluation of urographic
contrast media, inulin, and .sup.99mTc-DTPA clearance methods for
determination of glomerular filtration rate in clinical
transplantation, Transplantation, 1989, 48, 790-796). Other markers
such as .sup.123I and .sup.125I labeled o-iodohippurate or
.sup.99mTc-MAG.sub.3 are used to assess tubular secretion process
(W. N. Tauxe, Tubular Function, in Nuclear Medicine in Clinical
Urology and Nephrology, W. N. Tauxe and E. V. Dubovsky, Editors,
pp. 77-105, Appleton Century Crofts, East Norwalk, 1985; R.
Muller-Suur, and C. Muller-Suur, Glomerular filtration and tubular
secretion of MAG.sub.3 in rat kidney, Journal of Nuclear Medicine,
1989, 30, 1986-1991). However, these markers have several
undesirable properties such as the use of radioactivity or ex-vivo
handling of blood and urine samples. Thus, in order to assess the
status and to follow the progress of renal disease, there is a
considerable interest in developing a simple, safe, accurate, and
continuous method for determining renal function, preferably by
non-radioactive procedures. Other organs and physiological
functions that would benefit from real-time monitoring include the
heart, the liver, and blood perfusion, especially in organ
transplant patients.
[0006] Hydrophilic, anionic substances are generally recognized to
be excreted by the kidneys (F. Roch-Ramel, K. Besseghir, and H.
Murer, Renal excretion and tubular transport of organic anions and
cations, Handbook of Physiology, Section 8, Neurological
Physiology, Vol. II, E. E. Windhager, Editor, pp. 2189-2262, Oxford
University Press, New York, 1992; D. L. Nosco, and J. A.
Beaty-Nosco, Chemistry of technetium radiopharmaceuticals 1:
Chemistry behind the development of technetium-99m compounds to
determine kidney function, Coordination Chemistry Reviews, 1999,
184, 91-123). It is further recognized that drugs bearing sulfonate
residues exhibit improved clearance through the kidneys (J. Baldas,
J. Bonnyman, Preparation, HPLC studies and biological behavior of
techentium-99m and 99mTcN0-radiopharmaceuticals based on quinoline
type ligands, Nucl. Med. Biol., 1999, 19, 491-496; L. Hansen, A.
Taylor, L., L. G. Marzilli, Synthesis of the sulfonate and
phosphonate derivatives of mercaptoacetyltriglycine. X-ray crystal
structure of
Na.sub.2[ReO(mercaptoacetylglycylglycylaminomethane-sulfonate)]3H.sub.2O,
Met.-Based Drugs, 1994, 1, 31-39).
[0007] Assessment of renal function by continuously monitoring the
blood clearance of exogenous optical markers, viz., fluorescein
bioconjugates derived from anionic polypeptides, has been developed
by us and by others (R. B. Dorshow, J. E. Bugaj, B. D. Burleigh, J.
R. Duncan, M. A. Johnson, and W. B. Jones, Noninvasive fluorescence
detection of hepatic and renal function, Journal of Biomedical
Optics, 1998, 3, 340-345; M. Sohtell et al., FITC-Inulin as a
Kidney Tubule Marker in the Rat, Acta. Physiol. Scand., 1983, 119,
313-316, each of which is expressly incorporated herein by
reference). 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. Thus, there is a need in the art to
develop low molecular weight compounds that absorb and/or emit
light that can be used for assessing renal, hepatic, cardiac and
other organ functions.
SUMMARY OF THE INVENTION
[0008] The present invention overcomes these difficulties by
incorporating hydrophilic anionic or polyhydroxy residues in the
form of sulfates, sulfonates, sulfamates and strategically
positioned hydroxyl groups. Thus, the present invention is related
to novel dyes containing multiple hydrophilic moieties and their
use as diagnostic agents for assessing organ function.
[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.
[0010] As illustrated in FIGS. 1-7, these dyes are designed to
inhibit aggregation in solution by preventing intramolecular and
intermolecular induced hydrophobic interactions.
[0011] The present invention relates particularly to the novel
compounds comprising indoles of the general Formula 1 1
[0012] wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7, and
Y.sub.1 are independently selected from the group consisting of
--H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20
polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino,
C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides,
arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, --SO.sub.3T,
--CO.sub.2T, ---OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH- .sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.1 is selected from the group consisting
of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--, and --Se; a, b, d,
f, h, i, and j independently vary from 1-10; c, e, g, and k
independently vary from 1-100; R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are defined in the same manner as Y.sub.1; T is either H or
a negative charge.
[0013] The present invention also relates to the novel compounds
comprising benzoindoles of general Formula 2 2
[0014] wherein R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12,
R.sub.13, R.sub.14, and Y.sub.2 are independently selected from the
group consisting of --H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl,
C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides,
amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic
peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl,
--SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(C- H.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T- ,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.2 is selected from the group consisting
of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--, and --Se; a, b, d,
f, h, i, and j independently vary from 1-10; c, e, g, and k
independently vary from 1-100; R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are defined in the same manner as Y.sub.2; T is either H or
a negative charge.
[0015] The present invention also relates to the novel composition
comprising cyanine dyes of general Formula 3 3
[0016] wherein R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19,
R.sub.20, R.sub.21, R.sub.22, R.sub.23, Y.sub.3, and Z.sub.3 are
independently selected from the group consisting of --H, C1-C10
alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20
polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano,
nitro, halogen, hydrophilic peptides, arylpolysulfonates,
C1-C.sub.10 alkyl, C1-C10 aryl, --SO.sub.3T, --CO.sub.2T, --OH,
--(CH.sub.2).sub.aSO.sub.3T, --(CH.sub.2).sub.aOSO.sub.3T,
--(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH- .sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.3 and X.sub.3 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.3 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; a, b, d, f, h,
i, and j independently vary from 1-10; c, e, g, and k independently
vary from 1-100; a.sub.3 and b.sub.3 vary from 0 to 5; R.sub.a,
R.sub.b, R.sub.c, and R.sub.d are defined in the same manner as
Y.sub.3; T is either H or a negative charge.
[0017] The present invention further relates to the novel
composition comprising cyanine dyes of general Formula 4 4
[0018] wherein R.sub.24, R.sub.25, R.sub.26, R.sub.27, R.sub.28,
R.sub.29, R.sub.30, R.sub.31, R.sub.32, R.sub.33, R.sub.34,
R.sub.35, R.sub.36, Y.sub.4, and Z.sub.4 are independently selected
from the group consisting of --H, C1-C10 alkoxyl, C1-C10
polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl,
saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen,
hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10
aryl, --SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH- .sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.eC- H.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2, --CH.sub.2--(CH.sub.2--O-
--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH- .sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(C-
H.sub.2--O--CH.sub.2).sub.k--CH.sub.2--CO.sub.2T; W.sub.4 and
X.sub.4 are selected from the group consisting of
--CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--, and --Se; V.sub.4 is a
single bond or is selected from the group consisting of --O--,
--S--, --Se--, and --NR.sub.a; a.sub.4 and b.sub.4 vary from 0 to
5; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g,
and k independently vary from 1-100; R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are defined in the same manner as Y.sub.4; T is either H or
a negative charge.
[0019] The present invention also relates to the novel composition
comprising cyanine dyes of general Formula 5 5
[0020] wherein R.sub.37, R.sub.38, R.sub.39, R.sub.40, R.sub.41,
R.sub.42, R.sub.43, R.sub.44, R.sub.45, Y.sub.5, and Z.sub.5 are
independently selected from the group consisting of --H, C1-C10
alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20
polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano,
nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10
alkyl, C1-C10 aryl, --SO.sub.3T, --CO.sub.2T, --OH,
--(CH.sub.2).sub.aSO.sub.3T, --(CH.sub.2).sub.aOSO.sub- .3T,
--(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).s- ub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(C- H.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T- ,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.5 and X.sub.5 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.5 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; D.sub.5 is a
single or a double bond; A.sub.5, B.sub.5 and E.sub.5 may be the
same or different and are selected from the group consisting of
--O--, --S--, --Se--, --P--, --NR.sub.a, --CR.sub.cR.sub.d,
CR.sub.c, alkyl, and --C.dbd.O; A.sub.5, B.sub.5, D.sub.5, and
E.sub.5 may together form a 6 or 7 membered carbocyclic ring or a 6
or 7 membered heterocyclic ring optionally containing one or more
oxygen, nitrogen, or a sulfur atom; a, b, d, f, h, i, and j
independently vary from 1-10; c, e, g, and k independently vary
from 1-100; a.sub.5 and b.sub.5 vary from 0 to 5; R.sub.a, R.sub.b,
R.sub.c, and R.sub.d are defined in the same manner as Y.sub.5; T
is either H or a negative charge.
[0021] The present invention also relates to the novel composition
comprising cyanine dyes of general Formula 6 6
[0022] wherein R.sub.46, R.sub.47, R.sub.48, R.sub.49, R.sub.50,
R.sub.51, R.sub.52, R.sub.53, R.sub.54, R.sub.55, R.sub.56,
R.sub.57 and R.sub.58, Y.sub.6, and Z.sub.6 are independently
selected from the group consisting of --H, C1-C10 alkoxyl, C1-C10
polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl,
saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen,
hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10
aryl, --SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aCONH(CH- .sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aPO.su- b.3HT, --(CH.sub.2).sub.aPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOPO.sub.3HT, --(CH.sub.2).sub.aOPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHPO.sub.3HT,
--(CH.sub.2).sub.aNHPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2)- .sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bPO.sub.3T.sub.- 2,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aCONH(- CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.s- ub.3HT,
--(CH.sub.2).sub.aNHCO(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3HT,
--(CH.sub.2).sub.aNHCSNH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3HT, and
--(CH.sub.2).sub.aOCONH(CH.sub.2).sub.bPO.sub.3T.sub.2,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.6 and X.sub.6 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.6 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; D.sub.6 is a
single or a double bond; A.sub.6, B.sub.6 and E.sub.6 may be the
same or different and are selected from the group consisting of
--O--, --S--, --Se--, --P--, --NR.sub.a, --CR.sub.cR.sub.c,
CR.sub.c, alkyl, and --C.dbd.O; A.sub.6, B.sub.6, D.sub.6, and
E.sub.6 may together form a 6 or 7 membered carbocyclic ring or a 6
or 7 membered heterocyclic ring optionally containing one or more
oxygen, nitrogen, or sulfur atom; a, b, d, f, h, i, and j
independently vary from 1-10; c, e, g, and k independently vary
from 1-100; a.sub.6 and b.sub.6 vary from 0 to 5; R.sub.a, R.sub.b,
R.sub.c, and R.sub.d are defined in the same manner as Y.sub.6; T
is either H or a negative charge.
[0023] The inventive compositions and methods are advantageous
since they provide a real-time, accurate, repeatable measure of
renal excretion rate using exogenous markers under specific yet
changing circumstances. This represents a substantial improvement
over any currently available or widely practiced method, since
currently, no reliable, continuous, repeatable bedside method for
the assessment of specific renal function by optical methods
exists. Moreover, since the inventive method depends solely on the
renal elimination of the exogenous chemical entity, the measurement
is absolute and requires no subjective interpretation based on age,
muscle mass, blood pressure, etc. In fact it represents the nature
of renal function in this particular patient, under these
particular circumstances, at this precise moment in time.
[0024] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1: Reaction pathway for the preparation of indole
derivatives.
[0026] FIG. 2: Reaction pathway for the preparation of benzoindole
derivatives.
[0027] FIG. 3: Reaction pathway for the preparation of
indocarbocyanine derivatives.
[0028] FIG. 4: Reaction pathway for the preparation of
benzoindocarbocyanine derivatives.
[0029] FIG. 5: Reaction pathway for the preparation of robust
indocarbocyanine derivatives.
[0030] FIG. 6: Reaction pathway for the preparation of robust
benzoindocarbocyanine derivatives.
[0031] FIG. 7: Reaction pathway for the preparation of
long-wavelength absorbing indocarbocyanine derivatives.
[0032] FIG. 8a: Absorption spectrum of indoledisulfonate in
water.
[0033] FIG. 8b: Emission spectrum of indoledisulfonate in
water.
[0034] FIG. 9a: Absorption spectrum of
indocarbocyaninetetrasulfonate in water.
[0035] FIG. 9b: Emission spectrum of indocarbocyaninetetrasulfonate
in water.
[0036] FIG. 10a: Absorption spectrum of chloroindocarbocyanine in
acetonitrile.
[0037] FIG. 10b: Emission spectrum of chloroindocarbocyanine in
acetonitrile.
[0038] FIG. 11: Blood clearance profile of
carbocyanine-polyaspartic (10 kDa) acid conjugate in a rat.
[0039] FIG. 12: Blood clearance profile of
carbocyanine-polyaspartic (30 kDa) acid conjugate in a rat.
[0040] FIG. 13: Blood clearance profile of indoledisulfonate in a
rat.
[0041] FIG. 14: Blood clearance profile of
carbocyaninetetrasulfonates in a rat.
DETAILED DESCRIPTION
[0042] In one embodiment of the invention, the dyes of the
invention serve as probes for continuous monitoring of renal
function, especially for critically ill patients and kidney
transplant patients.
[0043] In another aspect of the invention, the dyes of the
invention are useful for dynamic hepatic function monitoring,
especially for critically ill patients and liver transplant
patients.
[0044] In yet another aspect of the invention, the dyes of the
invention are useful for real-time determination of cardiac
function, especially in patients with cardiac diseases.
[0045] In still another aspect of the invention, the dyes of the
invention are useful for monitoring organ perfusion, especially for
critically ill, cancer, and organ transplant patients.
[0046] The novel dyes of the present invention are prepared
according the methods well known in the art, as illustrated in
general in FIGS. 1-7 and described for specific compounds in
Examples 1-11.
[0047] In one embodiment, the novel compositions, also called
tracers, of the present invention have the Formula 1, wherein
R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7, and Y.sub.1 are
independently selected from the group consisting of --H, C1-C5
alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20
polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic
peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl,
--SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--C- H.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e--CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--- CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.s- ub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.-
2).sub.k--CH.sub.2--CO.sub.2T; W.sub.1 is selected from the group
consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--, and
--Se; a, b, d, f, h, l, and j independently vary from 1-5; c, e, g,
and k independently vary from 1-20; R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are defined in the same manner as Y.sub.1; T is a negative
charge.
[0048] In another embodiment, the novel compositions of the present
invention have the general Formula 2, wherein R.sub.8, R.sub.9,
R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, and Y.sub.2 are
independently selected from the group consisting of --H, C1-C5
alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20
polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic
peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl,
--SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.2 is selected from the group consisting
of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--, and --Se; a, b, d,
f, h, l, and j independently vary from 1-5; c, e, g, and k
independently vary from 1-20; R.sub.a, R.sub.b, R.sub.c, and
R.sub.d are defined in the same manner as Y.sub.2; T is a negative
charge.
[0049] In another embodiment, the novel compositions of the present
invention have the general Formula 3, wherein R.sub.15, R.sub.16,
R.sub.17, R.sub.18, R.sub.19, R.sub.20, R.sub.21, R.sub.22,
R.sub.23, Y.sub.3, and Z.sub.3 are independently selected from the
group consisting of --H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl,
C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and
disaccharides, nitro, hydrophilic peptides, arylpolysulfonates,
C1-C5 alkyl, C1-C10 aryl, --SO.sub.3T, --CO.sub.2T, --OH,
--(CH.sub.2).sub.aSO.sub.3T, --(CH.sub.2).sub.aOSO.sub- .3T,
--(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).s- ub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.3 and X.sub.3 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.3 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; a, b, d, f, h,
i, and j independently vary from 1-5; c, e, g, and k independently
vary from 1-50; a.sub.3 and b.sub.3 vary from 0 to 5; R.sub.a,
R.sub.b, R.sub.c, and R.sub.d are defined in the same manner as
Y.sub.3; T is either H or a negative charge.
[0050] In another embodiment, the novel compositions of the present
invention have the general Formula 4, wherein R.sub.24, R.sub.25,
R.sub.26, R.sub.27, R.sub.28, R.sub.29, R.sub.30, R.sub.31,
R.sub.32, R.sub.33, R.sub.34, R.sub.35, R.sub.36, Y.sub.4, and
Z.sub.4 are independently selected from the group consisting of
--H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl,
C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic
peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl,
--SO.sub.3T, --CO.sub.2T, --OH, --(CH.sub.2).sub.aSO.sub.3T,
--(CH.sub.2).sub.aOSO.sub.3T, --(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.4 and X.sub.4 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.4 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; a.sub.4 and
b.sub.4 vary from 0 to 5; a, b, d, f, h, i, and j independently
vary from 1-5; c, e, g, and k independently vary from 1-50;
R.sub.a, R.sub.b, R.sub.c, and R.sub.d are defined in the same
manner as Y.sub.4; T is either H or a negative charge.
[0051] In another embodiment, the novel compositions of the present
invention have the general Formula 5, wherein R.sub.37, R.sub.38,
R.sub.39, R.sub.40, R.sub.41, R.sub.42, R.sub.43, R.sub.44,
R.sub.45, Y.sub.5, and Z.sub.5 are independently selected from the
group consisting of --H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl,
C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and
disaccharides, nitro, hydrophilic peptides, arylpolysulfonates,
C1-C5 alkyl, C1-C10 aryl, --SO.sub.3T, --CO.sub.2T, --OH,
--(CH.sub.2).sub.aSO.sub.3T, --(CH.sub.2).sub.aOSO.sub- .3T,
--(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).s- ub.bSO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--O--H,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.5 and X.sub.5 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.5 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a D.sub.5 is a
single or a double bond; A.sub.5, B.sub.5 and E.sub.5 may be the
same or different and are selected from the group consisting of
--O--, --S--, --NR.sub.a, --CR.sub.cR.sub.d, CR.sub.c, and alkyl;
A.sub.5, B.sub.5, D.sub.5, and E.sub.5 may together form a 6 or 7
membered carbocyclic ring or a 6 or 7 membered heterocyclic ring
optionally containing one or more oxygen, nitrogen, or sulfur atom;
a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k
independently vary from 1-50; a.sub.5 and b.sub.5 vary from 0 to 5;
R.sub.a, R.sub.b, R.sub.c, and R.sub.d are defined in the same
manner as Y.sub.5; T is either H or a negative charge.
[0052] In yet another embodiment, the novel compositions of the
present invention have the general Formula 6, wherein R.sub.46,
R.sub.47, R.sub.48, R.sub.49, R.sub.50, R.sub.51, R.sub.52,
R.sub.53, R.sub.54, R.sub.55, R.sub.56, R.sub.57, R.sub.58,
Y.sub.6, and Z.sub.6 are independently selected from the group
consisting of --H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10
polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides,
nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl,
C1-C10 aryl, --SO.sub.3T, --CO.sub.2T, --OH,
--(CH.sub.2).sub.aSO.sub.3T, --(CH.sub.2).sub.aOSO.sub.3T,
--(CH.sub.2).sub.aNHSO.sub.3T,
--(CH.sub.2).sub.aCO.sub.2(CH.sub.2).sub.b- SO.sub.3T,
--(CH.sub.2).sub.aOCO(CH.sub.2).sub.bSO.sub.3T,
--CH.sub.2(CH.sub.2--O--CH.sub.2).sub.c--CH.sub.2--OH,
--(CH.sub.2).sub.d--CO.sub.2T,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.e-- -CH.sub.2--CO.sub.2T,
--(CH.sub.2).sub.f--NH.sub.2,
--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.g--CH.sub.2--NH.sub.2,
--(CH.sub.2).sub.h--N(R.sub.a)--(CH.sub.2).sub.i--CO.sub.2T, and
--(CH.sub.2).sub.j--N(R.sub.b)--CH.sub.2--(CH.sub.2--O--CH.sub.2).sub.k---
CH.sub.2--CO.sub.2T; W.sub.6 and X.sub.6 are selected from the
group consisting of --CR.sub.cR.sub.d, --O--, --NR.sub.c, --S--,
and --Se; V.sub.6 is a single bond or is selected from the group
consisting of --O--, --S--, --Se--, and --NR.sub.a; D.sub.6 is a
single or a double bond; A.sub.6, B.sub.6 and E.sub.6 may be the
same or different and are selected from the group consisting of
--O--, --S--, --NR.sub.a, --CR.sub.cR.sub.d, CR.sub.c, and alkyl;
A.sub.6, B.sub.6, D.sub.6, and E.sub.6 may together form a 6 or 7
membered carbocyclic ring or a 6 or 7 membered heterocyclic ring
optionally containing one or more oxygen, nitrogen, or sulfur atom;
a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k
independently vary from 1-50; a.sub.5 and b.sub.5 vary from 0 to 5;
R.sub.a, R.sub.b, R.sub.c, and R.sub.d are defined in the same
manner as Y.sub.6; T is either H or a negative charge.
[0053] The dosage of the tracers may vary according to the clinical
procedure contemplated and generally ranges from 1 picomolar to 100
millimolar. The tracers may be administered to the patient by any
suitable method, including intravenous, intraperitoneal, or
subcutaneous injection or infusion, oral administration,
transdermal absorption through the skin, or by inhalation. The
detection of the tracers is achieved by optical fluorescence,
absorbance, or light scattering methods known in the art (Muller et
al. Eds, Medical Optical Tomography, SPIE Volume IS11, 1993, which
is expressly incorporated herein by reference) using invasive or
non-invasive probes such as endoscopes, catheters, ear clips, hand
bands, surface coils, finger probes, and the like. Physiological
function is correlated with the clearance profiles and rates of
these agents from body fluids (R. B. Dorshow et al., Non-Invasive
Fluorescence Detection of Hepatic and Renal Function, Bull. Am.
Phys. Soc. 1997, 42, 681, which is expressly incorporated by
reference herein).
[0054] The organ functions can be assessed either by the
differences in the manner in which the normal and impaired cells
remove the tracer from the bloodstream, by measuring the rate or
accumulation of these tracers in the organs or tissues, or by
obtaining tomographic images of the organs or tissues. Blood pool
clearance may be measured non-invasively from convenient surface
capillaries such as those found in an ear lobe or a finger, for
example, using an ear clip or finger clip sensor, or may be
measured invasively using an endovascular catheter. Accumulation of
the tracer within the cells of interest can be assessed in a
similar fashion. The clearance of the tracer dyes may be determined
by selecting excitation wavelengths and filters for the emitted
photons. The concentration-time curves may be analyzed in real time
by a microprocessor. In order to demonstrate feasibility of the
inventive compounds to monitor organ function, a non-invasive
absorbance or fluorescence detection system to monitor the signal
emanating from the vasculature infused with the compounds is used.
Indole derivatives, such as those of Formulas 1-6, fluoresce at a
wavelength between 350 nm and 1300 nm when excited at the
appropriate wavelength as is known to, or readily determined by,
one skilled in the art.
[0055] In addition to the noninvasive techniques, a modified
pulmonary artery catheter can be used to make the necessary
measurements (R. B. Dorshow, J. E. Bugaj, S. A. Achilefu, R.
Rajagopalan, and A. H. Combs, Monitoring Physiological Function by
Detection of Exogenous Fluorescent Contrast Agents, in Optical
Diagnostics of Biological Fluids IV, A. Priezzhev and T. Asakura,
Editors, Procedings of SPIE 1999, 3599, 2-8, which is expressly
incorporated by reference herein). Currently, pulmonary artery
catheters measure only intravascular pressures, cardiac output and
other derived measures of blood flow. Critically ill patients are
managed using these parameters, but rely on intermittent blood
sampling and testing for assessment of renal function. These
laboratory parameters represent discontinuous data and are
frequently misleading in many patient populations. Yet,
importantly, they are relied upon heavily for patient assessment,
treatment decisions, and drug dosing.
[0056] The modified pulmonary artery catheter incorporates an
optical sensor into the tip of a standard pulmonary artery
catheter. This wavelength specific optical sensor can monitor the
renal function specific elimination of an optically detectable
chemical entity. Thus, by a method analogous to a dye dilution
curve, real-time renal function can be monitored by the
disappearance of the optically detected compound. Modification of a
standard pulmonary artery catheter only requires making the fiber
optic sensor wavelength specific, as is known to one skilled in
this art. Catheters that incorporate fiber optic technology for
measuring mixed venous oxygen saturation currently exist.
[0057] The present invention may be used for rapid bedside
evaluation of renal function and also to monitor the efficiency of
hemodialysis. The invention is further demonstrated by the
following examples. Since many modifications, variations, and
changes in detail may be made to the described embodiments, it is
intended that all matter in the foregoing description and shown in
the accompanying drawings be interpreted as illustrative and not in
a limiting sense.
EXAMPLE 1
Synthesis of indole disulfonate
(FIG. 1, Compound 5, Y.sub.7.dbd.SO.sub.3.sup.-: X.sub.7.dbd.H:
n=1)
[0058] 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.degree. 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-sulfonat- e (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.degree. C. for 12 hours. The mixture
was allowed to cool to room temperature and the resulting
precipitate was filtered and washed with isopropanol. The resulting
pink powder was dried under vacuum to give 97% of the desired
compound.
[0059] Other compounds prepared by a similar method described above
include polyhydroxyl indoles such as 7
EXAMPLE 2
Synthesis of indole disulfonate
(FIG. 1, Compound 5, Y.sub.7.dbd.SO.sub.3.sup.-; X.sub.7.dbd.H;
n=2)
[0060] 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, Y.sub.7,Y.sub.8.dbd.SO.sub.3.sup.-;
X.sub.7.dbd.H; n=2)
[0061] This compound was prepared by the same procedure described
in Example 1, except that hydrazinonaphthalenedisulfonic acid was
used in place of hydrazinobenzenesulfonic acid.
[0062] Other compounds prepared by a similar method include
polyhydroxyindoles such as: 8
EXAMPLE 4
Synthesis of benzoindole disulfonate
(FIG. 2, Compound 8, Y.sub.7,Y.sub.8.dbd.SO.sub.3.sup.-;
X.sub.7.dbd.OH; n4)
[0063] This compound was prepared by the same procedure described
in Example 1, except that 3-hydroxymethyl-4-hydroxyl-2-butanone was
used in place of 3-methyl-2-butanone.
EXAMPLE 5
Synthesis of Bis(ethylcarboxymethyl)indocyanine Dye
[0064] 9
[0065] A mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (9.1 g,
43.58 mmoles) and 3-bromopropanoic acid (10.0 g, 65.37 mmoles) in
1,2-dichlorobenzene (40 mL) was heated at 110.degree. C. for 12
hours. The solution was cooled to room temperature and the red
residue obtained was filtered and washed with acetonitrile: diethyl
ether (1:1) mixture. The solid obtained was dried under vacuum to
give 10 g (64%) of light brown powder. A portion of this solid (6.0
g; 16.56 mmoles), glutaconaldehyde dianil monohydrochloride (2.36
g, 8.28 mmoles) and sodium acetate trihydrate (2.93 g, 21.53
mmoles) in ethanol (150 mL) were refluxed for 90 minutes. After
evaporating the solvent, 40 mL of 2 N aqueous HCl was added to the
residue and the mixture was centrifuged and the supernatant was
decanted. This procedure was repeated until the supernatant became
nearly colorless. About 5 mL of water:acetonitrile (3:2) mixture
was added to the solid residue and lyophilized to obtain 2 g of
dark green flakes. The purity of the compound was established with
.sup.1H-NMR and liquid chromatography/mass spectrometry
(LC/MS).
EXAMPLE 6
Synthesis of Bis(pentylcarboxymethyl)indocyanine Dye
[0066] 10
[0067] A mixture of 2,2,3-trimethyl-[1H]-benz[e]indole (20 g, 95.6
mmoles) and 6-bromohexanoic acid (28.1 g, 144.1 mmoles) in
1,2-dichlorobenzene (250 mL) was heated at 110.degree. C. for 12
hours. The green solution was cooled to room temperature and the
brown solid precipitate formed was collected by filtration. After
washing the solid with 1,2-dichlorobenzene and diethyl ether, the
brown powder obtained (24 g, 64%) was dried under vacuum at room
temperature. A portion of this solid (4.0 g; 9.8 mmoles),
glutaconaldehyde dianil monohydrochloride (1.4 g, 5 mmoles) and
sodium acetate trihydrate (1.8 g, 12.9 mmoles) in ethanol (80 mL)
were refluxed for 1 hour. After evaporating the solvent, 20 mL of a
2 N aqueous HCl was added to the residue and the mixture was
centrifuged and the supernatant was decanted. This procedure was
repeated until the supernatant became nearly colorless. About 5 mL
of water:acetonitrile (3:2) mixture was added to the solid residue
and lyophilized to obtain about 2 g of dark green flakes. The
purity of the compound was established with .sup.1H-NMR, HPLC, and
LC-MS.
EXAMPLE 7
Synthesis of polyhydroxyindole sulfonate
(FIG. 3, Compound 13, Y.sub.7,Y.sub.8.dbd.O.sub.3-; X.sub.7.dbd.OH;
n=2)
[0068] Phosphorus oxychloride (37 ml, 0.4 mole) was added dropwise
with stirring to a cooled (-2.degree. C.) mixture of
dimethylformamide (DMF, 0.5 mole, 40 mL) and dichloromethane (DCM,
40 mL), followed by the addition of acetone (5.8 g, 0.1 mole). The
ice bath was removed and the solution refluxed for 3 hours. After
cooling to room temperature, the product was either partitioned in
water/DCM, separated and dried, or was purified by fractional
distillation. Nuclear magnetic resonance and mass spectral analyses
showed that the desired intermediate, 10, was obtained. Reaction of
the intermediate with 2 equivalents of
2,2,3-trimethyl-[H]-benz[e]indolesulfonate-N-propanoic acid and 2
equivalents of sodium acetate trihydrate in ethanol gave a
blue-green solution after 1.5 hours at reflux. Further
functionalization of the dye with bis(isopropylidene)acetal
protected monosaccharide is effected by the method described in the
literature (J. H. Flanagan, C. V. Owens, S. E. Romero, et al., Near
infrared heavy-atom-modified fluorescent dyes for base-calling in
DNA-sequencing application using temporal discrimination. Anal.
Chem., 1998, 70(13), 2676-2684).
EXAMPLE 8
Synthesis of polyhydroxyindole sulfonate
(FIG. 4, Compound 16, Y.sub.7,Y.sub.8.dbd.SO.sub.3.sup.-;
X.sub.7.dbd.H; n=1)
[0069] Preparation of this compound was readily accomplished by the
same procedure described in Example 6 using
p-hydroxybenzenesulfonic acid in the place of the monosaccharide,
and benzoindole instead of indole derivatives.
EXAMPLE 9
Synthesis of polyhydroxyindole sulfonate
(FIG. 5, Compound 20, Y.sub.7,Y.sub.8.dbd.H; X.sub.7.dbd.OH;
n=1)
[0070] The hydroxyindole compound was readily prepared by a
literature method (P. L. Southwick, J. G. Cairns, L. A. Ernst, and
A. S. Waggoner, One pot Fischer synthesis of
(2,3,3-trimethyl-3-H-indol-5-yl)-acetic acid derivatives as
intermediates for fluorescent biolabels. Org. Prep. Proced. Int.
Briefs, 1988, 20(3), 279-284). Reaction of
p-carboxymethylphenylhydrazine hydrochloride (30 mmol, 1 equiv.)
and 1,1-bis(hydroxymethyl)propanone (45 mmol, 1.5 equiv.) in acetic
acid (50 mL) at room temperature for 30 minutes and at reflux for 1
gave (3,3-dihydroxymethyl2-methyl-3-H-indol-5-yl)-acetic acid as a
solid residue.
[0071] The intermediate
2-chloro-1-formyl-3-hydroxymethylenecyclo-hexane was prepared as
described in the literature (G. A. Reynolds and K. H. Drexhage,
Stable heptamethine pyrylium dyes that absorb in the infrared. J.
Org. Chem., 1977, 42(5), 885-888). Equal volumes (40 mL each) of
dimethylformamide (DMF) and dichloromethane were mixed and the
solution was cooled to -10.degree. C. in acetone-dry ice bath.
Under argon atmosphere, phosphorus oxychloride (40 mL) in
dichloromethane was added dropwise to the cool DMF solution,
followed by the addition of 10 g of cyclohexanone. The resulting
solution was allowed to warm up to room temperature and heated at
reflux for 6 hours. After cooling to room temperature, the mixture
was poured into ice-cold water and stored at 4.degree. C. for 12
hours. A yellow powder was obtained. Condensation of a portion of
this cyclic dialdehyde (1 equivalent) with the indole intermediate
(2 equivalents) was carried out as described in Example 5. Further,
the functionalization of the dye with bis(isopropylidene)acetal
protected monosaccharide was effected by the method described in
the literature (J. H. Flanagan, C. V. Owens, S. E. Romero, et al.,
Near infrared heavy-atom-modified fluorescent dyes for base-calling
in DNA-sequencing application using temporal discrimination. Anal.
Chem., 1998, 70(13), 2676-2684).
EXAMPLE 10
Synthesis of polyhydroxylbenzoindole sulfonate
(FIG. 6, Compound 22, Y.sub.7,Y.sub.8.dbd.H; X.sub.7.dbd.OH;
n=1)
[0072] A similar method described in Example 8 was used to prepare
this compound by replacing the indole with benzoindole
derivatives.
EXAMPLE 11
Synthesis of Rigid heteroatomic indole sulfonate
(FIG. 7, Compound 27, Y.sub.7, Y.sub.8, X.sub.7.dbd.H; n=1)
[0073] Starting with 3-oxo-4-cyclohexenone, this heteroatomic
hydrophilic dye was readily prepared as described in Example 8.
EXAMPLE 12
Minimally Invasive Monitoring of the Blood Clearance Profile of the
Dyes
[0074] A laser of appropriate wavelength for excitation of the dye
chromophore was directed into one end of a fiber optic bundle and
the other end was positioned a few millimeters from the ear of a
rat. A second fiber optic bundle was also positioned near the same
ear to detect the emitted fluorescent light, and the other end was
directed into the optics and electronics for data collection. An
interference filter (IF) in the collection optics train was used to
select emitted fluorescent light of the appropriate wavelength for
the dye chromophore.
[0075] Sprague-Dawley or Fischer 344 rats were anesthetized with
urethane administered via intraperitoneal injection at a dose of
1.35 g/kg body weight. After the animals had achieved the desired
plane of anesthesia, a 21 gauge butterfly with 12" tubing was
placed in the lateral tail vein of each animal and flushed with
heparinized saline. The animals were placed onto a heating pad and
kept warm throughout the entire study. The lobe of the left ear was
affixed to a glass microscope slide to reduce movement and
vibration.
[0076] Incident laser light delivered from the fiber optic was
centered on the affixed ear. Data acquisition was then initiated,
and a background reading of fluorescence was obtained prior to
administration of the test agent.
[0077] The compound was administered to the animal through a bolus
injection in the lateral tail vein. The dose was typically 0.05 to
20 .mu.mole/kg of body weight. The fluorescence signal rapidly
increased to a peak value, then decayed as a function of time as
the conjugate cleared from the bloodstream.
[0078] This procedure was repeated with several dye-epetide
conjugates in normal and tumored rats. Representative profiles are
shown in FIGS. 6-10.
[0079] While the invention has been disclosed by reference to the
details of preferred embodiments of the invention, it is to be
understood that the disclosure is intended in an illustrative
rather than in a limiting sense, as it is contemplated that
modifications will readily occur to those skilled in the art,
within the spirit of the invention and the scope of the appended
claims.
* * * * *