Tunable indocyanine dyes for biomedical applications

• US 6,180,087 B1
• Filed: 01/18/2000
• Issued: 01/30/2001
• 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:
  US09/484,320
• Time in Patent Office: 378 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 548/400, 544/63, 544/224, 544/3, 544/53, 544/54, 544/57, 544/58.1, 544/66, 544/67, 544/68, 544/242
• 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 composition comprising indocyanine dyes of 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 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)_i—

CH₂—

CO₂H;

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

(CH₂)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, —

(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 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 D₂is —

CR⁴²;

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

NR⁴³R⁴⁴, R¹⁴, R¹⁵ and R³⁸ to R⁴² are independently 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 independently selected from the group consisting of hydrogen and C1-C10 alkyl, and a pharmaceutically acceptable carrier or excipient.

2. 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;

R⁴⁵ is selected from the group consisting of a hydrogen, and a halogen atom;

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)_d—

CH₂—

CO₂H, —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H, and —

(CH₂)_i—

N(R¹⁵)—

CH₂—

(CH₂—

O—

CH₂)_j—

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-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.

3. 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)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H and —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H.

16. A method for making the composition of claim 1 comprising conjugating the dyes to peptides or biomolecules by solid phase synthesis.

4. A method for performing a diagnostic or therapeutic procedure which comprises administering to an individual an effective amount of the composition of indocyanine dyes of 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 independently 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—

CH₂—

CO₂H, —

(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 selected from the group consisting of —

O—

, —

S—

, —

Se—

, —

P— and

—

NR³⁸ and C₂ is CR⁴¹ 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 aryl, hydroxyl, C1-C10 alkoxyl, cyano, nitro, halogen, and —

NR⁴³R⁴⁴;

R¹⁴, R¹⁵ and R³⁸ to R⁴² are independently selected from the group consisting of -hydrogen, C1-C10 alkyl, C1-C10 alkoxyl, —

(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 independently selected from the group consisting of hydrogen and C1-C10 alkyl.

5. The method of performing the diagnostic or therapeutic procedure of claim 4 which comprises administering to an individual an effective amount of the composition of indocyanine dyes 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—

, or —

NR³⁸;

C₂ is —

CH₂;

D₂ is CR⁴² R⁴⁵ is selected from the group consisting of a hydrogen, and a halogen atom;

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 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, 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-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.

6. The method of performing the diagnostic or therapeutic procedure of claim 4 which comprises administering to an individual an effective amount of the composition of indocyanine dyes 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)_c—

CO₂H, —

CH₂—

(CH₂—

O—

CH₂)_d—

CH₂—

CO₂H, and —

(CH₂)_g—

N(R¹⁴)—

(CH₂)_h—

CO₂H.

7. The method of claim 4 wherein said procedure utilizes light of wavelength in the region of 350-1300 nm.

8. The method of claim 4 wherein said diagnostic procedure is optical tomography.

9. The method of claim 4 wherein said diagnostic procedure is fluorescence endoscopy.

10. The method of claim 4 further comprising monitoring a blood clearance profile of said dyes by fluorescence, absorbance or light scattering wherein light of wavelength in the region of 350-1300 nm is utilized.

11. The method of claim 4 wherein said procedure further comprises a step of imaging and therapy wherein said imaging and therapy is selected from the group consisting of absorption, light scattering, photoacoustic, and sonofluoresence technique.

12. The method of claim 4 wherein said procedure is for diagnosing atherosclerotic plaques and blood clots.

13. The method of claim 4 wherein said procedure further comprises administering localized therapy.

14. The method of claim 4 wherein said therapeutic procedure comprises photodynamic therapy.

15. The method of claim 4 wherein said therapeutic procedure comprises laser assisted guided surgery (LAGS) for the detection of micrometastases.