US 5,721,099 A · Complex combinatorial chemical libraries encoded with tags

Abstract

Encoded combinatorial chemistry is provided, where sequential synthetic schemes are recorded using organic molecules, which define choice of reactant, and stage, as the same or different bit of information. Various products can be produced in the multi-stage synthesis, such as oligomers and synthetic non-repetitive organic molecules. Conveniently, nested families of compounds can be employed as identifiers, where number and/or position of a substituent define the choice. Alternatively, detectable functionalities may be employed, such as radioisotopes, fluorescers, halogens, and the like, where presence and ratios of two different groups can be used to define stage or choice. Particularly, pluralities of identifiers may be used to provide a binary or higher code, so as to define a plurality of choices with only a few detachable tags. The particles may be screened for a characteristic of interest, particularly binding affinity, where the products may be detached from the particle or retained on the particle. The reaction history of the particles which are positive for the characteristic can be determined by the release of the tags and analysis to define the reaction history of the particle.

Claims38

Dependent claims

A solid support having bound thereto (i) a compound produced by a single reaction series and (ii) a combination of at least four distinguishable identifiers which differ one from another, each of which is encompassed by the formula:

--F.sup.1 '--F.sup.2 --C--E--C'
wherein C--E--C' is a tag which is capable of analysis, the components of which provide for separation from other tags and allow either for detection or for the addition of a detectable component;
F.sup.1 ' is a functional group that attaches -F.sup.2 --C--E--C' said solid support either directly or through other than the tag component of another identifier;
and
F.sup.2 is a linking component capable of being selectively cleaved to release the tag;
wherein each identifier or combination thereof encodes information as to a particular choice at a particular stage in the reaction series.

3 more elements

F.sup.1 --F.sup.2 --(C--(E--C').sub.a).sub.b
wherein:
F.sup.1 is --CO.sub.2 H, --CH.sub.2 X, --NHR.sup.1, --OH, --CHN.sub.2, --SH, -C(O)CHN.sub.2, S(O).sub.2 CHN, --N.sub.3, --NO.sub.2, --S(O.sub.2)N.sub.3 or --C(O)X;
F.sup.2 is ##STR44## A is --O--, --OC(O)O--, --OC(O)-- or --NHC(O)--;
C is a bond, or
C.sub.1 -C.sub.20 alkylene optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or
--((C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p -- with the proviso that the maximum number of carbon atoms in C+C' is 20;
C' is --H, --F, --Cl, or
C.sub.1 -C.sub.20 alkyl optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or
--(C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p --;
E is C.sub.1 -C.sub.10 alkyl substituted by 1-20 F, Cl or Br, or
Q-aryl, in which aryl is a mono- or bi-cyclic aromatic ring containing up to 10 carbon atoms and up to 2 heteroatoms selected from O, S, and N, which is substituted by 1-7 F, Cl, NO.sub.2, SO.sub.2 R.sup.5 or a substituted phenyl, which is substituted with 1-5 F, Cl, NO.sub.2 or SO.sub.2 R.sup.5, and Q is a bond, O, S, NHR.sup.4, C.dbd.O, --C(O)NR.sup.5, --NR.sup.5 C(O)--, --C(O)O-- or OC(O)--;
E--C' may be --H, --OH or amino;
R.sup.1 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.3 is --C.dbd.O, --C(O)O, --C(O)NR.sup.1, --S, --SO or --SO.sub.2 ;
R.sup.4 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.5 is C.sub.1 -C.sub.6 alkyl;
a is an integer from 1 to 5;
b is an integer from 1 to 3;
m and n are independently integers from 0 to 20;
p is an integer from 1 to 7;
X is a leaving group;
Y is a bond, --O, --S or --NHR.sup.4 ;
Z is a bond,
phenylene, which is optionally substituted by 1-4 F, Cl, Br, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl substituted by 1-13 F or Cl, or C.sub.1 -C.sub.6 alkyloxy substituted by 1-13 F, Cl or Br,
(C(R.sup.4).sub.2).sub.1-20 or (CF.sub.2).sub.1-20,
with the proviso that when Z is a bond one of its adjacent Y's is also a bond;
and
each of said identifiers being bound to said solid support either directly or through other than the tag component of another identifier, wherein each identifier or combination thereof encodes information as to a particular choice at a particular stage in the reaction series.

26 more elements

A library of compounds, each compound in the library being produced by a single reaction series and being bound to an individual solid support, each solid support having bound to it a combination of at least four distinguishable identifiers which differ one from another, each of which prior to binding to the solid support is encompassed by the formula:

F.sup.1 --F.sup.2 --(C--(E--C').sub.a).sub.b
wherein:
F.sup.1 is --CO.sub.2 H, --CH.sub.2 X, --NHR.sup.1, --OH, --CHN.sub.2, --SH, --C(O)CHN.sub.2, S(O).sub.2 CHN.sub.2, --N.sub.3, --NO.sub.2, --S(O.sub.2)N.sub.3 or --C(O)X;
F.sup.2 is ##STR47## A is --O--, --OC(O)O--, --OC(O)-- or --N HC(O)--;
C is a bond, or
C.sub.1 -C.sub.20 alkylene optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or --((C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p -- with the proviso that the maximum number of carbon atoms in C+C' is 20;
C' is --H, --F,--Cl, or
C.sub.1 -C.sub.20 alkyl optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or --((C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p --;
E is C.sub.1 -C.sub.10 alkyl substituted by 1-20 F, Cl or Br, or
Q-aryl, in which aryl is a mono- or bi-cyclic aromatic ring containing up to 10 carbon atoms and up to 2 heteroatoms selected from O, S, and N, which is substituted by 1-7 F, Cl, NO.sub.2, SO.sub.2 R.sup.5 or a substituted phenyl, which is substituted with 1-5 F, Cl, NO.sub.2 or SO.sub.2 R.sup.5, and Q is a bond, O, S, NHR.sup.4, C.dbd.O, --C(O)NR.sup.5, --NR.sup.5 C(O)--, --C(O)O-- or OC(O)--;
E--C' may be --H, --OH or amino;
R.sup.1 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.3 is --C.dbd.O, --C(O)O, --C(O)NR.sup.1, --S, --SO or --SO.sub.2 ;
R.sup.4 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.5 is C.sub.1 -C.sub.6 alkyl;
a is an integer from 1 to 5;
b is an integer from 1 to 3;
m and n are independently integers from 0 to 20;
p is an integer from 1 to 7;
X is a leaving group;
Y is a bond, --O, --S or --NHR.sup.4 ;
Z is a bond,
phenylene, which is optionally substituted by 1-4 F, Cl, Br, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl substituted by 1-13 F or Cl, or C.sub.1 -C.sub.6 alkyloxy substituted by 1-13 F, Cl or Br,
(C(R.sup.4).sub.2).sub.1-20 or (CF.sub.2).sub.1-20,
with the proviso that when Z is a bond one of its adjacent Y's is also a bond;
and
each of said identifiers being bound to said solid support either directly or through other than the tag component of another identifier, wherein each identifier or combination thereof encodes information as to a particular choice at a particular stage in the reaction series for the compound bound to such solid support.

24 more elements

A process for identifying a compound having a characteristic of interest, which comprises:

(a) providing a library of compounds, each compound in the library being produced by a reaction series and being bound to an individual solid support, such solid support also having bound to it a plurality of distinguishable identifiers which differ one from another, each of which identifiers is encompassed by the formula:
F.sup.1 '--F.sup.2 --C--E--C'
wherein C--E--C' is a tag which is capable of analysis, the components of which provide for separation from other tags and allow either for detection or for the addition of a detectable component;
F.sup.1 ' is a functional group that attaches --F.sup.2 --C--E--C' to said solid support either directly or through other than the tag component of another identifier;
and
F.sup.2 is a linking component capable of being selectively cleaved to release the tag;
wherein each identifier or combination thereof encodes information as to a particular choice at a particular stage in the reaction series for the compound bound to such solid support;
(b) either
(i) first screening the library from step (a) in an assay so as to detect the presence of a compound of interest in the library and then separating the compound so detected, still bound to the solid support, from the library, or
(ii) first treating each solid support in the library of step (a) so as to release a portion of the compound from the solid support while retaining each such solid support with the tag component still bound thereto, and then screening each compound so released in an assay so as to detect the presence of a compound of interest;
(c) treating either
(i) the solid support, to which the compound of interest is bound, from step (b)(i) or
(ii) the solid support, from which the compound of interest had been released in step (b)(ii),
so as to cause the tag components of each of the identifiers bound thereto to be released;
(d) analyzing each tag component of step (c) so released;
and
(e) determining the particular choices at the particular stages in the reaction series by which said compound was synthesized, based on the analysis of all such tag components in step (d), so as to thereby identify the compound of interest.

14 more elements

A process for identifying a compound having a characteristic of interest, which comprises:

(a) providing a library of compounds, each compound in the library being produced by a reaction series and being bound to an individual solid support, such solid support also having bound to it a plurality of distinguishable identifiers which differ one from another, each of which identifiers prior to binding to the solid support is encompassed by the formula:
F.sup.1 F.sup.2 --C--(E--C').sub.a).sub.b
wherein:
F.sup.1 is --CO.sub.2 H, --CH.sub.2 X, --NR.sup.1 R.sup.1, C(O)R.sup.1, --OH, --CHN.sub.2, --SH, --C(O)CHN.sub.2, --S(O).sub.2 Cl, --S(O).sub.2 CHN.sub.2, --N.sub.3, --NO.sub.2, --S(O.sub.2)N.sub.3, --OC(O)X, --C(O)X, NCO or NCS;
F.sup.2 is ##STR50## A is --O--, --OC(O)O--, --OC(O)-- or--NHC(O)--;
C is a bond, or
C.sub.1 -C.sub.20 alkylene optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or --((C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p --with the proviso that the maximum number of carbon atoms in C+C' is 20;
C is --H, --F, --Cl, or
C.sub.1 -C.sub.20 alkyl optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or --((C(R.sup.4).sub.2)m--Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p --;
E is C.sub.1 -C.sub.10 alkyl substituted by 1-20 F, Cl or Br, or
Q-aryl, in which aryl is a mono- or bi-cyclic aromatic ring containing up to 10 carbon atoms and up to 2 heteroatoms selected from O, S, and N, which is substituted by 1-7 F, Cl, NO.sub.2, SO.sub.2.sup.R.sup.5 or a substituted phenyl, which is substituted with 1-5 F, Cl , NO.sub.2 or SO.sub.2 R.sup.5, and Q is a bond, O, S, NHR.sup.4, C.dbd.O, --C(O)NR.sup.5, --NR.sup.5 C(O)--, --C(O)O-- or OC(O)--;
E--C' may be --H, --OH or amino;
R.sup.1 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.3 is --C.dbd.O, --C(O)O, --C(O)NR.sup.1, --S, --SO or --SO.sub.2 ;
R.sup.4 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.5 is C.sub.1 -C.sub.6 alkyl;
a is an integer from 1 to 5;
b is an integer from 1 to 3;
m and n are independently integers from 0 to 20;
p is an integer from 1 to 7;
X is a leaving group;
Y is a bond, --), --S or --NHR.sup.4 ;
Z is a bond,
phenylene, which is optionally substituted by 1-4 F, Cl, Br, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl substituted by 1-13 F or Cl, or C.sub.1 -C.sub.6 alkyloxy substituted by 1-13 F, Cl or Br, (C(R.sup.4).sub.2).sub.20 or (CF.sub.2).sub.1-20, with the proviso that when Z is a bond one of its adjacent Y's is also a bond;
and
wherein each identifier or combination thereof encodes information as to a particular choice at a particular stage in the reaction series for the compound bound to such solid support;
(b) either
(i) first screening the library from step (a) in an assay so as to detect the presence of a compound of interest in the library and then separating the compound so detected, still bound to the solid support, from the library, or
(ii) first treating each solid support in the library of step (a) so as to release a portion of the compound from the solid support while retaining each such solid support with the tag component still bound thereto, and then screening each compound so released in an assay so as to detect the presence of a compound of interest;
(c) treating either
(i) the solid support, to which the compound of interest is bound, from step (b)(i) or
(ii) the solid support, from which the compound of interest had been released in step (b)(ii),
so as to cause the tag components of each of the identifiers bound thereto to be released;
(d) analyzing each tag component of step (c) so released;
and
(e) determining the particular choices at the particular stages in the reaction series by which said compound was synthesized, based on the analysis of all such tag components in step (d), so as to thereby identify the compound of interest.

33 more elements

A kit for recording information concerning the history of a reaction series on each of a plurality of individual solid supports, comprising at least four different, separated, distinguishable identifiers which differ one from another, each of which is encompassed by the formula:

F.sup.1 --F.sup.2 --(C--(E--C').sub.a).sub.b
wherein:
F.sup.1 is --CO.sub.2 H, --CH.sub.2 X, --NHR.sup.1, --OH, --CHN.sub.2, --SH, --C(O)CHN.sub.2, S(O).sub.CHN.sub.2, --N.sub.3, --NO.sub.2, --S(O.sub.2)N.sub.3 or --C(O)X;
F.sup.2 is ##STR53## A is --O--, --OC(O)O--, --OC(O)-- or --NHC(O)--;
C is a bond, or
C.sub.1 -C.sub.20 alkylene optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or --(C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p -;
with the proviso that the maximum number of carbon atoms in C +C' is 20;
C' is --H, --F, --Cl, or
C.sub.1 -C.sub.20 alkyl optionally substituted by 1-40 F, Cl, Br, C.sub.1 -C.sub.6 alkoxy, NR.sup.4 R.sup.4, OR.sup.4 or NHR.sup.4, or --(C(R.sup.4).sub.2).sub.m --Y--Z--Y(C(R.sup.4).sub.2).sub.n --Y--Z--Y).sub.p -;
E is C.sub.1 -C.sub.10 alkyl substituted by 1-20 F, Cl or Br, or
Q-aryl, in which aryl is a mono- or bi-cyclic aromatic ring containing up to 10 carbon atoms and up to 2 heteroatoms selected from O, S, and N, which is substituted by 1-7 F, Cl, NO.sub.2, SO.sub.2 R.sup.5 or a substituted phenyl, which is substituted with 1-5 F, Cl, NO.sub.2 or SO.sub.2 R.sup.5, and Q is a bond, O, S, NHR.sup.4, C.dbd.O, --C(O)NR.sup.5, --NR.sup.5 C(O)--, --C(O)O-- or OC(O)--;
E--C' may be --H, --OH or amino;
R.sup.1 is --H or C.sub.1 C.sub.6 alkyl;
R.sup.3 is --C.dbd.O, --C(O)O, --C(O)NR.sup.1, --S, --SO or --SO.sub.2 ;
R.sup.4 is --H or C.sub.1 -C.sub.6 alkyl;
R.sup.5 is C.sub.1 -C.sub.6 alkyl;
a is an integer from 1 to 5;
b is an integer from 1 to 3;
m and n are independently integers from 0 to 20;
p is an integer from 1 to 7;
X is a leaving group;
Y is a bond, --O, --S or --NHR.sup.4 ;
Z is a bond,
phenylene, which is optionally substituted by 1-4 F, Cl, Br, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl substituted by 1-13 F or Cl, or C.sub.1 -C.sub.6 alkyloxy substituted by 1-13 F, Cl or Br, (C(R.sup.4).sub.2).sub.1-20 or (CF.sub.2).sub.1-20, with the proviso that when Z is a bond one of its adjacent Y's is also a bond;
each identifier or combination thereof encodes information as to a particular choice at a particular stage in the reaction series for the compound bound to such solid support.

22 more elements

Dependencies are inferred from the claim text.

Complex combinatorial chemical libraries encoded with tags

Life of this patent

Complex combinatorial chemical libraries encoded with tags

Life of this patent

Abstract

Claims38