Cyanine dyes and synthesis methods thereof

• US 6,114,350 A
• Filed: 04/19/1999
• Issued: 09/05/2000
• Est. Priority Date: 04/19/1999
• Status: Expired due to Term

• Current Assignee: PerkinElmer Life Sciences, Inc.
• Original Assignee: PerkinElmer Life Sciences, Inc.
• Inventors: Buzby, Philip Richard, Bobrow, Mark Norman, Randall, Malcolm Harry, Erickson, Thomas Joseph, Trometer, Joseph David, Miller, Joseph John Jr., Ahern, David George
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US09/294,678
• Time in Patent Office: 505 Days
• Field of Search: 548/165, 548/304.4, 548/152, 548/179, 548/217, 546/181, 544/51, 544/353, 544/105, 514/224.2, 514/230.5, 514/249, 514/311, 514/367, 514/375, 514/394, 514/415
• US Class Current: 514/311
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0052 Small organic molecules oligomers, polymers, dendrimers A61K49/0054
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Abstract

A cyanine dye having the formula ##STR1## wherein R₁ -R₈ are each independently selected from a group consisting of hydrogen, C₁ -C₆ alkyl group, and C₀ -C₄ alkyl group having a hydrophilic substituent thereon. R₁₁ and R₁₂ are chosen to include a free or protected thiol, amine or hydroxyl substituent capable of reacting with a target molecule through a nucleophilic displacement mechanism. The dye is useful in labeling a variety of target molecules. Processes are described for synthesizing suitable heterocyclic and indole derivatives as precursors for the aforementioned cyanine dyes.

Claims

1. A compound of the formula:

##STR9## wherein Y₁ is selected from a group consisting of;

##STR10## wherein R₁, R₂, R₃, and R₄ are each independently selected from a group consisting of hydrogen, C₁ -C₆ alkyl group, a C₀ -C₄ alkyl group having a hydrophilic substituent selected from a group consisting of sulfonyl, carboxyl, hydroxyl, substituted amines and quaternary amines;

wherein R₉, R₉ '"'"', R₁₀ and R₁₀ '"'"' are each independently selected from a group consisting of C₁ -C₃₀ alkyl, and a heteroatom substituted C₁ -C₃₀ alkyl wherein the heteroatom is O, N or S; and

wherein R₁₁ is selected from a group consisting of;

##STR11## wherein R₁₃, R'"'"'₁₃, R"₁₃ and R'"'"'"₃ are each independently C₁ -C₃₀ alkyl, Q is sulfur, nitrogen-hydrogen or oxygen, X is a halogen and Y is a halogen.

2. The compound of claim 1 wherein R₁₃ comprises more than two carbon atoms.

3. The compound of claim 1 wherein at least two adjacent R groups of R₁ -R₄, R₉, R₉ '"'"', R₁₀ and R₁₀ '"'"' are fused to form a ring structure.

4. The compound of claim 1 wherein at least one of R₁ -R₄, is the C₀ -C₄ alkyl group having the hydrophilic substituent.

8. A process for preparing a compound (1) as claimed in claim 1 which comprises:

reacting a nitrogen containing heterocyclic compound of the formula;

##STR14## wherein Y₁ is selected from a group consisting of;

##STR15## wherein R₁, R₂, R₃, and R₄ are each independently selected from a group consisting of hydrogen, C₁ -C₆ alkyl group, a C₀ -C₄ alkyl group having a hydrophilic substituent selected from a group consisting of sulfonyl, carboxyl, hydroxyl, substituted amines and quatenary amines, wherein R₉, R₉ '"'"', R₁₀ and R₁₀ '"'"' are each independently selected from a group consisting of C₁ -C₃₀ alkyl, and a heteroatom substituted C₁ -C₃₀ alkyl wherein the heteroatom is protected O, N or S; and

with XR₁₃ Q moiety of a bifunctional hydrocarbon wherein X is chlorine, bromine or iodine, R₁₃ is C₁ -C₃₀ alkyl and Q is sulfur, nitrogen or oxygen.

9. The process of claim 8 wherein Q is sulfur.

10. The process of claim 8 wherein said bifunctional hydrocarbon is a thiol.

11. The process of claim 8 wherein said bifunctional hydrocarbon is an amine.

12. The process of claim 8 wherein said bifunctional hydrocarbon is an alcohol.

5. A compound of the formula:

##STR12## wherein Y₁ is selected from a group consisting of;

##STR13## wherein R₁, R₂, R₃, and R₄ are each independently selected from a group consisting of;

hydrogen, C₁ -C₆ alkyl group, a C₀ -C₄ alkyl group having a hydrophilic substituent selected from a group consisting of sulfonyl, carboxyl, hydroxyl, substituted amines and quaternary amines;

wherein R₉, R₉ '"'"', R₁₀ and R₁₀ '"'"' are each independently selected from a group consisting of C₁ -C₃₀ alkyl, and a heteroatom substituted C₁ -C₃₀ alkyl wherein the heteroatom is O, N or S;

wherein R₁₁ is selected from a group consisting of R₁₄ SH, R₁₄ NH₂ and R₁₄ OH; and

wherein R₁₄ is selected from a group consisting of;

C₃ -C₃₀ alkyl and C₃ -C₃₀ alkyl having a phenyl, hydroxyl, sulfonyl, or halogen atom or a heteroatom substituted phenyl.

6. The compound of claim 5 wherein at least one of R₁ -R₄, is the C₀ -C₄ alkyl group having the hydrophilic substituent.

7. The compound of claim 5 wherein at least two adjacent R groups of R₁ -R₄, R₉, R₉ '"'"', R₁₀ and R₁₀ '"'"' are fused to form a ring structure.

13. A method of treating a neurotransmitter defect or deficiency disorder by using the compound

of claim 5 wherein Y₁ is ##STR16##

14. The method of claim 13 wherein the compound functions as a mimic of a naturally occurring alkaloid.

15. The method of claim 14 wherein the naturally occurring alkaloid is selected from a group consisting of:

Harmaline, Cinchera, Yohimbine, Rauwolfia and Ergot.