# US 7,608,244 B2 · Hydrophilic light absorbing compositions for determination of physiological function in critically ill patients

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- Number: US 7,608,244 B2
- Document ID: US7608244B2
- Status: Granted
- Kind: B2
- Application number: 11/778,447
- Filed: 2007-07-16
- Published: 2007-11-22
- Granted: 2009-10-27
- Earliest claimed: 2000-10-16
- Assignees: Mallinckrodt Inc.
- Inventors: Samuel Achilefu; Raghavan Rajagopalan; Richard B. Dorshow; Joseph E. Bugaj; Muthunadar P. Periasamy
- Web page: https://patentgrep.com/patent/US7608244B2

## CPC

- C07D 209/58: [b]- or [c]-condensed
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 49/0021: {the fluorescent group being a small organic molecule}
- A61K 49/0032: {Methine dyes, e.g. cyanine dyes}
- A61P 13/12: of the kidneys
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 209/12: Radicals substituted by oxygen atoms
- C07D 209/60: Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of Formula 2
wherein
W2 is selected from the group consisting of O, Se, NRc, and S;
Y2 is selected from the group consisting of C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, C1-C10 aminoalkyl, hydrophilic peptides, arylpolysulfonates, C1-C10 aryl, —(CH2)aOSO3T, —(CH2)aNHSO3T, —(CH2)aCO2(CH2)bSO3T, —(CH2)aOCO(CH2)bSO3T, —(CH2)aCONH(CH2)bSO3T, —(CH2)aNHCO(CH2)bSO3T, —(CH2)aNHCONH(CH2)bSO3T, —(CH2)aNHCSNH(CH2)bSO3T, —(CH2)aOCONH(CH2)bSO3T, —(CH2)aPO3HT, —(CH2)aPO3T2, —(CH2)aOPO3HT, —(CH2)aOPO3T2, —(CH2)aNHPO3HT, —(CH2)aNHPO3T2, —(CH2)aCO2(CH2)bPO3HT, —(CH2)aCO2(CH2)bPO3T2, —(CH2)aOCO(CH2)bPO3HT, —(CH2)aOCO(CH2)bPO3T2, —(CH2)aCONH(CH2)bPO3HT, —(CH2)aCONH(CH2)bPO3T2, —(CH2)aNHCO(CH2)bPO3HT, —(CH2)aNHCO(CH2)bPO3T2, —(CH2)aNHCONH(CH2)bPO3HT, —(CH2)aNHCONH(CH2)bPO3T2, —(CH2)aNHCSNH(CH2)bPO3HT, —(CH2)aNHCSNH(CH2)bPO3T2, —(CH2)aOCONH(CH2)bPO3HT, —(CH2)aOCONH(CH2)bPO3T2, —CH2(CH2—O—CH2)c—CH2—OH, —(CH2)d—CO2T, —CH2—(CH2—O—CH2)e—CH2—CO2T, —(CH2)f—NH2, —CH2—(CH2—O—CH2)g—CH2—NH2, —(CH2)h—N(Ra)—(CH2)i—CO2T, and —(CH2)j—N(Rb)—CH2—(CH2—O—CH2)k—CH2—CO2T;
R8 is C1-C10 alkyl; —H or C1-C10 aryl
R9, R10, R11, R12, R13 and R14 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, —SO3T, —CO2T, —OH, —(CH2)aSO3T, —(CH2)aOSO3T, —(CH2)aNHSO3T, —(CH2)aCO2(CH2)bSO3T, —(CH2)aOCO(CH2)bSO3T, —(CH2)aCONH(CH2)bSO3T, —(CH2)aNHCO(CH2)bSO3T, —(CH2)aNHCONH(CH2)bSO3T, —(CH2)aNHCSNH(CH2)bSO3T, —(CH2)aOCONH(CH2)bSO3T, —(CH2)aPO3HT, —(CH2)aPO3T2, —(CH2)aOPO3HT, —(CH2)aOPO3T2, —(CH2)aNHPO3HT, —(CH2)aNHPO3T2, —(CH2)aCO2(CH2)bPO3HT, —(CH2)aCO2(CH2)bPO3T2, —(CH2)aOCO(CH2)bPO3HT, —(CH2)aOCO(CH2)bPO3T2, —(CH2)aCONH(CH2)bPO3HT, —(CH2)aCONH(CH2)bPO3T2, —(CH2)aNHCO(CH2)bPO3HT, —(CH2)aNHCO(CH2)bPO3T2, —(CH2)aNHCONH(CH2)bPO3HT, —(CH2)aNHCONH(CH2)bPO3T2, —(CH2)aNHCSNH(CH2)bPO3HT, —(CH2)aNHCSNH(CH2)bPO3T2, —(CH2)aOCONH(CH2)bPO3HT, —(CH2)aOCONH(CH2)bPO3T2, —CH2(CH2—O—CH2)c—CH2—OH, —(CH2)d—CO2T, —CH2—(CH2—O—CH2)e—CH2—CO2T, —(CH2)f—NH2, —CH2—(CH2—O—CH2)g—CH2—NH2, —(CH2)h—N(Ra)—(CH2)i—CO2T, and —(CH2)j—N(Rb)—CH2—(CH2—O—CH2)k—CH2—CO2T;
a, b, d, f, h, i, and j independently vary from 1-10 with the proviso that when a=2 and b=2, Y2 is not —(CH2)aCONH(CH2)bSO3T;
c, e, g, and k independently vary from 1-100;
Ra, Rb, Rc, and Rd are defined in the same manner as Y2; and
T is either H or a negative charge.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R8 is C1 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R9 to R14 is —H or —SO3T.

### Claim 4 (depends on 1)

The compound of claim 1 wherein Y2 is selected from the group consisting of —(CH2)d—CO2T, —(CH2)aNHSO3T, —CH2—(CH2—O—CH2)g—CH2—NH2, and —(CH2)h—N(Ra)—(CH2)i—CO2T.

### Claim 5 (depends on 1)

The compound of claim 1 wherein W2 is S; and Y2 is selected from the group consisting of —(CH2)aNHSO3T, —CH2—(CH2—O—CH2)g—CH2—NH2, and —(CH2)h—N(Ra)—(CH2)i—CO2T.

### Claim 6

A pharmaceutical composition comprising an effective amount of a compound of Formula 2
wherein
W2 is selected from the group consisting of O, Se, NRc, and S;
Y2 is independently selected from the group consisting of C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, C1-C10 aminoalkyl, hydrophilic peptides, arylpolysulfonates, C1-C10 aryl, —(CH2)aOSO3T, —(CH2)aNHSO3T, —(CH2)aCO2(CH2)bSO3T, —(CH2)aOCO(CH2)bSO3T, —(CH2)aCONH(CH2)bSO3T, —(CH2)aNHCO(CH2)bSO3T, —(CH2)aNHCONH(CH2)bSO3T, —(CH2)aNHCSNH(CH2)bSO3T, —(CH2)aOCONH(CH2)bSO3T, —(CH2)aPO3HT, —(CH2)aPO3T2, —(CH2)aOPO3HT, —(CH2)aOPO3T2, —(CH2)aNHPO3HT, —(CH2)aNHPO3T2, —(CH2)aCO2(CH2)bPO3HT, —(CH2)aCO2(CH2)bPO3T2, —(CH2)aOCO(CH2)bPO3HT, —(CH2)aOCO(CH2)bPO3T2, —(CH2)aCONH(CH2)bPO3HT, —(CH2)aCONH(CH2)bPO3T2, —(CH2)aNHCO(CH2)bPO3HT, —(CH2)aNHCO(CH2)bPO3T2, —(CH2)aNHCONH(CH2)bPO3HT, —(CH2)aNHCONH(CH2)bPO3T2, —(CH2)aNHCSNH(CH2)bPO3HT, —(CH2)aNHCSNH(CH2)bPO3T2, —(CH2)aOCONH(CH2)bPO3HT, —(CH2)aOCONH(CH2)bPO3T2, —CH2(CH2—O—CH2)C—CH2—OH, —(CH2)d—CO2T, —CH2—(CH2—O—CH2)e—CH2—CO2T, —(CH2)fNH2, —CH2—(CH2—O—CH2)gCH2NH2, —(CH2)hN(Ra)—(CH2)iCO2T, and —(CH2)j—N(Rb)—CH2—(CH2—O—CH2)k—CH2—CO2T;
R8 is C1-C10 alkyl;
R9, R10, R11, R12, R13 and R14 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, —SO3T, —CO2T, —OH, —(CH2)aSO3T, —(CH2)aOSO3T, —(CH2)aNHSO3T, —(CH2)aCO2(CH2)bSO3T, —(CH2)aOCO(CH2)bSO3T, —(CH2)aCONH(CH2)bSO3T, —(CH2)aNHCO(CH2)bSO3T, —(CH2)aNHCONH(CH2)bSO3T, —(CH2)aNHCSNH(CH2)bSO3T, —(CH2)aOCONH(CH2)bSO3T, —(CH2)aPO3HT, —(CH2)aPO3T2, —(CH2)aOPO3HT, —(CH2)aOPO3T2, —(CH2)aNH PO3HT, —(CH2)aNHPO3T2, —(CH2)aCO2(CH2)bPO3HT, —(CH2)aCO2(CH2)bPO3T2, —(CH2)aOCO(CH2)bPO3HT, —(CH2)aOCO(CH2)bPO3T2, —(CH2)aCONH(CH2)bPO3HT, —(CH2)aCONH(CH2)bPO3T2, —(CH2)aNHCO(CH2)bPO3HT, —(CH2)aNHCO(CH2)bPO3T2, —(CH2)aNHCONH(CH2)bPO3HT, —(CH2)aNHCONH(CH2)bPO3T2, —(CH2)aNHOSNH(CH2)bPO3HT, —(CH2)aNHOSNH(CH2)bPO3T2, —(CH2)aOCONH(CH2)bPO3HT, —(CH2)aOCONH(CH2)bPO3T2, —CH2(CH2—O—CH2)C—CH2—OH, —(CH2)dCO2T, —CH2(CH2—O—CH2)e—CH2—CO2T, —(CH2)f—NH2, —CH2—(CH2—O—CH2)g—CH2NH2,(CH2)h—N(Ra)—(CH2)i—CO2T, and —(CH2)j—N(Rb)—CH2—(CH2—O—CH2)k—CH2—CO2T;
a, b, d, f, h, i, and j independently vary from 1-10 with the proviso that when a=2 and b=2, Y2 is not —(CH2)aCONH(CH2)bSO3T;
c, e, g, and k independently vary from 1-100;
Ra, Rb, Rc, and Rd are defined in the same manner as Y2; and
T is either H or a negative charge.

### Claim 7 (depends on 6)

The composition of claim 6 further comprising a contrast agent.

### Claim 8 (depends on 6)

The composition of claim 6 wherein the compound comprises a radioactive halogen.

### Claim 9 (depends on 6)

The composition of claim 6 wherein at least one R group of the compound is replaced by a polyamino carboxylic acid.

### Claim 10 (depends on 6)

The composition of claim 6 further comprising a radioactive metal ion or a paramagnetic ion.

### Claim 11 (depends on 6)

The composition of claim 6 formulated as at least one of a liposome, a micelle, a microcapsule, or a microparticle.

### Claim 12

A method for performing a diagnostic or therapeutic procedure comprising administering to a mammal an effective amount of a compound of formula 2
wherein
W2 is selected from the group consisting of O, Se, and NRc;
Y2 is independently selected from the group consisting of C1-C10alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20polyhyd roxyalkyl, C5-C20 polyhydroxyaryl, saccharides, C1C10 aminoalkyl, hydrophilic peptides, arylpolysulfonates, C1-C10 aryl, —(CH2)aOSO3T, —(CH2)aNHSO3T, —(CH2)aCO2(CH2)bSO3T, —(CH2)aOCO(CH2)bSO3T, —(CH2)aCONH(CH2)bSO3T, —(CH2)aNHCO(CH2)bSO3T, —(CH2)aNHCONH(CH2)bSO3T, —(CH2)aNHCSNH(CH2)bSO3T, —(CH2)aOCONH(CH2)bSO3T, —(CH2)aPO3HT, —(CH2)aPO3T2, —(CH2)aOPO3HT, —(CH2)aOPO3T2, —(CH2)aNHPO3HT, —(CH2)aNHPO3T2, —(CH2)aCO2(CH2)bPO3HT, —(CH2)aCO2(CH2)bPO3T2, —(CH2)aOCO(CH2)bPO3HT, —(CH2)aOCO(CH2)bPO3T2, —(CH2)aCONH(CH2)bPO3HT, —(CH2)aCONH(CH2)bPO3T2, —(CH2)aNHCO(CH2)bPO3HT, —(CH2)aNHCO(CH2)bPO3T2, —(CH2)aNHCONH(CH2)bPO3HT, —(CH2)aNHCONH(CH2)bPO3T2, —(CH2)aNHCSNH(CH2)bPO3HT, —(CH2)aNHCSNH(CH2)bPO3T2, —(CH2)aOCONH(CH2)bPO3HT, —(CH2)aOCONH(CH2)bPO3T2, —CH2(CH2—O—CH2)C—CH2—OH, —(CH2)d—CO2T, —CH2—(CH2—(CH2—O—CH2)e—CH2CO2T, —(CH2)fNH2,—CH2—(CH2—O—CH2)gCH2NH2,(CH2)h—N(Ra)(CH2)iCO2T, and —(CH2)j—N(Rb)—CH2—(CH2—O—CH2)k—CH2—CO2T;
R8 is C1-C10 alkyl;
R9 R10 R11 R12 R13 and R14 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-C10alkyl, C1-C10 aryl, —SO3T, —CO2T, —OH, —(CH2)aSO3T, —(CH2)aOSO3T, —(CH2)aNHSO3T, —(CH2)aCO2(CH2)bSO3T, —(CH2)aOCO(CH2)bSO3T, —(CH2)aCONH(CH2)bSO3T, —(CH2)aNHCO(CH2)bSO3T, —(CH2)aNHCONH(CH2)bSO3T, —(CH2)aNHCSNH(CH2)bSO3T, —(CH2)aOCONH(CH2)bSO3T, —(CH2)aPO3HT, —(CH2)aPO3T2, —(CH2)aOPO3HT, —(CH2)aOPO3T2, —(CH2)aNHPO3HT, —(CH2)aNHPO3T2, —(CH2)aCO2(CH2)bPO3HT, —(CH2)aCO2(CH2)bPO3T2, —(CH2)aOCO(CH2)bPO3HT, —(CH2)aOCO(CH2)bPO3T2, —(CH2)aCONH(CH2)bPO3HT, —(CH2)aCONH(CH2)bPO3T2, —(CH2)aNHCO(CH2)bPO3HT, —(CH2)aNHCO(CH2)bPO3T2, —(CH2)aNHCONH(CH2)bPO3HT, —(CH2)aNHCONH(CH2)bPO3T2, —(CH2)aNHCSNH(CH2)bPO3HT, —(CH2)aNHCSNH(CH2)bPO3T2, —(CH2)aOCONH(CH2)bPO3HT, —(CH2)aOCONH(CH2)bPO3T2, —CH2(CH2—CH2)2OH, —(CH2)dCO2T, —CH2(CH2—O—CH2)e—CH2—CO2T, —(CH2)1—NH2, —CH2—(CH2—O—CH2)g—CH2—NH2, —(CH2)h—N(Ra)—(CH2)iCO2T, and —(CH2)j—N(Rb)—CH2—(CH2—O—CH2)k—CH2—CO2T;
a, b, d, f, h, i, and j independently vary from 1-10 with the proviso that when a=b 2 and b=2,Y2 is not —(CH2)aCONH(CH2)bSO3T;
c, e, g, and k independently vary from 1-100;
Ra, Rb, Rc, and Rd are defined in the same manner as Y2; and
T is either H or a negative charge, and thereafter performing the diagnostic or therapeutic procedure.

### Claim 13 (depends on 12)

The method of claim 12 further comprising imaging by at least one of optical imaging, nuclear imaging, or magnetic resonance imaging.

### Claim 14 (depends on 12)

The method of claim 12 wherein the compound is administered in a formulation selected from at least one of liposome, micelles, microcapsules, or microparticles.

### Claim 15 (depends on 12)

The method of claim 12 wherein the compound is administered in a formulation selected from at least one of ultra small iron oxide particles, silver particles, or gold particles.

### Claim 16 (depends on 12)

The method of claim 12 further comprising administering a non-optical contrast agent and imaging by at least one of magnetic resonance, ultrasound, x-ray, positron emission tomography, computed tomography, optoacoustic imaging, and single photon emission computed tomography.

### Claim 17 (depends on 12)

The method of claim 12 wherein said procedure is for physiological function monitoring selected from least one of renal function monitoring, cardiac function monitoring, or kidney function monitoring determining organ perfusion in vivo.

### Claim 18 (depends on 12)

The method of claim 12 further comprising optically imaging the mammal.

### Claim 19 (depends on 16)

The method of claim 16 wherein the non-optical contrast agent composition is selected from the group consisting of a magnetic resonance composition, a computed tomography composition, an x-ray composition, a nuclear imaging composition, a positron emission tomography composition, a single photon emission computed tomography composition, an optoacoustic composition, and an ultrasound composition.

### Claim 20 (depends on 16)

The method of claim 16 wherein the compound stabilizes or buffers the non-optical contrast agent.