Phenyl xanthene dyes

Patent metadata

Field	Value
Publication number	US-9493656-B2
Application number	US-201514741258-A
Country	US
Kind code	B2
Filing date	Jun 16, 2015
Priority date	May 9, 2003
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Fluorescent phenyl xanthene dyes are described that comprise any fluorescein, rhodamine or rhodol comprising a particular C9 phenyl ring. One or both of the ortho groups on the lower C9 phenyl ring is ortho substituted with a group selected from alkyl, heteroalkyl, alkoxy, halo, haloalkyl, amino, mercapto, alkylthio, cyano, isocyano, cyanato, mercaptocyanato, nitroso, nitro, azido, sulfeno, sulfinyl, and sulfino. In one embodiment, halo and/or hydroxy groups are used. Optimal dyes contain a lower C9 phenyl ring in which both ortho groups are the same and the lower ring exhibits some form a symmetry relative to an imaginary axis running from the phenyl rings point of attachment to the remainder of the xanthene dye through a point para to the point of attachment. The phenyl xanthene dyes may be activated. Furthermore, the phenyl xanthene dyes may be conjugated to one or more substances including other dyes. The phenyl xanthene dyes are useful for a number of purposes, including labels for use in automated DNA sequencing as well the formation of fluorescent “bar codes” for polymeric particles used in the multiplexed analysis of analytes.

First claim

We claim:

1. A lipid soluble fluorescent phenyl xanthene dye having a structure of formula I:

where A is —OH or NR3′R3″;
B is ═O or =N+R6′R6″;
R1 is selected from hydrogen, Rx, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or alternatively, R1 may be taken together with R2 to form part of a benzo, naptho or polycyclic aryleno group which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R2 is selected from hydrogen, Rx, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or alternatively, R2 may be taken together with R1 to form part of a benzo, naptho or polycyclic aryleno group which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R3′, when present, is selected from hydrogen, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R3″, when present, is selected from (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or, alternatively, R3″ may be taken together with R4 to form a 5- or 6-membered ring which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R4 is selected from hydrogen, Rx, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or, alternatively, when A is —NR3′R3″, R4 may be taken together with R3″ to form a 5- or 6-membered ring which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R5 is selected from hydrogen, Rx, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or, alternatively, when B is —NR6′R6″+, R5 may be taken together with R6″ to form a 5- or 6-membered ring which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R6″, when present, is selected from (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or, alternatively R6″ may be taken together with R5 to form a 5- or 6-membered ring which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R6′, when present, is selected from hydrogen, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R7 is selected from hydrogen, Rx, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or, alternatively, R7 may be taken together with R8 to form part of a benzo, naptho or polycyclic aryleno group which is optionally substituted with one or more of the same or different Ra or suitable Rb groups, or alternatively, when B is —NR6′R6″+, R7 may be taken together with R6′ to form a 5- or 6-membered ring optionally substituted with one or more of the same or different Ra or suitable Rb groups;
R8 is selected from hydrogen, Rx, (C1-C20) alkyl or heteroalkyl optionally substituted with one or more of the same or different Rb groups, (C5-C20) aryl or heteroaryl optionally substituted with one or more of the same or different Ra or suitable Rb groups and (C6-C40) arylalkyl or heteroaryl alkyl optionally substituted with one or more of the same or different Ra or suitable Rb groups, or, alternatively, R8 together with R7 may form part of a benzo, naptho or polycyclic aryleno group which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;

R 11 and/or R 15 are selected from alkyl, heteroalkyl, alkoxy, halo, haloalkyl, amino, alkylthio, cyano, isocyano, mercaptocyanato, nitro, and sulfinyl, and R 12 , R 13 , and R 14 are, independently, selected from hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, alkoxy, halo, haloalkyl, amino, alkylthio, cyano, isocyano, cyanato, mercaptocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, carboxyl, and carboxyamide;
R x is selected from —NR c R c , —OR d , —SR d , halo, haloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c and —OC(NH)NR c R c ;
R a is selected from hydrogen, (C1-C8) alkyl or heteroalkyl, (C5-C20) aryl or heteroaryl and (C6-C28) arylalkyl or heteroarylalkyl;
R b is selected from —NR c R c , ═O, —OR d , ═S, —SR d , ═NR d , ═NOR d , halo, haloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS(O) 2 NR c R c , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c and —OC(NH)NR c R c ;
each R c is independently hydrogen or R d , or alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5- to 8-membered saturated or unsaturated ring which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or R d groups;
each R d is independently R a or R a substituted with one or more of the same or different R a or R e groups;
each R e is selected from —NR a R a , ═O, —OR a , ═S, —SR a , ═NR a , ═NOR a , halo, haloalkyl, —CN, —NC, —OCN, —S

Assignees

• Applied Biosystems Llc
• Life Technologies Corp

Inventors

• Lam Joe Y L
• Menchen Steven M
• Zou Ruiming
• Benson Scott C

Classifications

• C09B11/22

  containing OH groups bound to an aryl nucleus {and their ethers and esters} · CPC title

• C09B11/26

  Triarylmethane dyes in which at least one of the aromatic nuclei is heterocyclic {(phthaleins C09B11/24)} · CPC title

• C07D311/82

  Xanthenes · CPC title

• C09B11/06

  Hydroxy derivatives of triarylmethanes in which at least one OH group is bound to an aryl nucleus {and their ethers or esters} · CPC title

• C07D491/14

  Ortho-condensed systems · CPC title