Tunable indocyanine dyes for biomedical applications

• US 6,264,920 B1
• Filed: 08/10/2000
• Issued: 07/24/2001
• Est. Priority Date: 01/18/2000
• Status: Expired due to Fees

• Current Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Rajagopalan, Raghavan, Dorshow, Richard B., Achilefu, Samuel, Bugaj, Joseph E.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/637,518
• Time in Patent Office: 348 Days
• Field of Search: 424/1.11, 424/9.1, 424/9.6, 424/1.65, 424/9.61, 252/301.16, 252/301.17, 252/301.19, 252/301.21, 252/301.34, 252/301.35
• US Class Current: 424/9.6
• CPC Class Codes: A61K 41/0033 Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds ultrasound therapy per se A61N7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The sensitivity and specificity of the optical modality can be enhanced by the use of highly absorbing dyes as contrast agents. Novel indocyanine dyes that absorb and emit light in the near infrared region of electromagnetic spectrum are disclosed. These dyes are useful for imaging, diagnosis and therapy of various diseased states. Particularly, the molecules of the invention are useful for optical diagnostic imaging and therapy, in endoscopic applications for the detection of tumors and other abnormalities, for localized therapy, for photoacoustic tumor imaging, detection and therapy, and for sonofluorescence tumor imaging, detection and therapy.

Claims

1. A method for restoring in vivo or in vitro fluorescence by adding one to fifty percent biocompatible organic solvents to the diagnostic or therapeutic compositions of dye molecules wherein said dye molecules are represented by the formula:

wherein a₄ and b₄ are independently from 0 to 5;

W⁴ and X⁴ are independently selected from the group consisting of (C((CH₂)_zzOH)₂, C((CH₂)_zzCO₂H)₂, C((CH₂)_zzNR_ppR_pz)₂; and

zz is from 1 to 5;

R_pp and R_pz are selected from the group consisting of —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂CO₂H, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_j—

CH₂—

CO₂H;

Y⁴ and Z⁴ are independently selected from the group consisting of —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂CO₂H, —

(CH₂)_e—

NH₂, —

CH₂—

(CH₂—

O—

CH₂)_f—

CH₂—

NH₂, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_j—

CH₂—

CO₂H;

A₂ is a single or a double bond;

if A₂ is a single bond, then B₂ is independently selected from the group consisting of —

O—

, —

S—

, —

Se—

, —

P— and

—

NR³⁸ and D₂ is CR⁴²;

if A₂ is a double bond, then B₂ is selected from the group consisting of —

O—

, —

S—

, —

Se—

, —

P— and

—

NR³⁸, C₂ is selected from nitrogen and —

CR⁴¹ and D₂ is —

CR⁴²;

R⁴⁵ to R⁵⁷ are independently selected from the group consisting of hydrogen, C1-C10 alkyl C1-C10 alkoxyl, cyano, nitro, halogen, and —

NR⁴³R⁴⁴;

R R^14, R¹⁵ and R³⁸ to R⁴² are selected from the group consisting of -hydrogen, C1-C10 alkyl, C1-C10 alkoxyl —

CH₂(CH₂—

O—

CH₂)_c—

CH₂—

OH, —

(CH₂)_d—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_e—

CH₂—

CO₂H, —

(CH₂)_f—

NH₂, and —

CH₂—

(CH₂—

O—

CH₂)_g—

CH₂—

NH₂;

c, e, g, h, and i are independently from 1 to 10;

d, f and j are independently from 1 to 100; and

R⁴³ and R⁴⁴ are selected from the group consisting of hydrogen and C1-C10 alkyl.

2. The method of claim 1 wherein said dye molecule is dissolved in a medium comprising one to 50 percent dimethyl sulfoxide (DMSO).

3. The composition of claim 1 wherein a₄ and b₄ are independently from 0 to 3;

A₂ is a single bond;

B₂ is selected from the group consisting of —

O—

, —

S—

, and —

NR³⁸;

C₂ is selected from —

CH₂;

D₂ is CR⁴²;

R⁴⁶ to R⁵⁷ are hydrogens;

W⁴ and X⁴ are independently selected from the group consisting of C((CH₂)_zzOH)₂, C((CH₂) _zzCO₂H)₂, and C((CH₂)_zzNR_ppR_pz)₂;

Y⁴ and Z⁴ are independently selected from the group consisting of —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_j—

CH₂—

CO₂H;

R_pp and R_pz are independently selected from —

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_dCH₂—

CO₂H, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH_2j—

CH₂—

CO₂H;

c, e, g, h, i, and zz are independently from 1 to 5;

d, f and j are independently from 1 to 100; and

R¹⁴ and R¹⁵ are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C alkoxyl, —

CH₂(CH₂—

O—

CH₂)_c—

CH₂—

OH, —

(CH₂)_dCO₂H, —

CH₂—

(CH₂—

O—

CH₂)_e—

CH₂—

CO₂H, —

(CH₂)_f—

NH₂, and —

CH₂—

(CH₂—

O—

CH₂)_g—

CH₂—

NH₂.

4. The composition of claim 1 wherein a₄ and b₄ are 3;

A₂ is a double bond;

B₂ is —

O—

;

C₂ and D₂ are CH;

R⁴⁶ to R⁵⁷ are hydrogens;

W⁴ and X⁴ are independently selected from the group consisting of -C((CH₂)_zzOH)₂, C((CH₂)_zzCO₂H)₂ and C((CH₂)_zzNR_ppR_pz)₂;

Y⁴ and Z⁴ are the same and are selected from the group consisting of —

(CH₂)_cCO₂H, —

CH₂CH₂—

O—

CH₂)_d—

CH₂—

CO₂H and —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H.