US2017247324A1PendingUtilityA1
Aldehyde capture ligation technology for synthesis of amide bonds
Est. expiryDec 26, 2033(~7.4 yrs left)· nominal 20-yr term from priority
C07K 5/0806C07K 1/1075C07C 231/10C07D 207/16C07K 7/06C07C 231/12C07C 391/02C07K 5/06165C07K 5/06034C07C 319/12C07D 209/20C07K 5/06026C07K 5/1008C07D 233/64C07K 5/06078C07C 2603/10C07K 5/0808C07K 5/06052C07C 245/08
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Claims
Abstract
The present invention relates to ligation agents and their use in making an amide ligation product. Methods of making the ligation agents are also disclosed.
Claims
exact text as granted — not AI-modified1 . A ligation agent of Formula I:
wherein
A is selected from the group consisting of
fluorescent dyes, and cytotoxic small molecule drugs;
X is selected from the group consisting of
represents a point of attachment to —C(O)—Se—X—(CR 4 2 ) m C(O)R 3 ;
represents a point of attachment to —(CR 4 2 ) m C(O)R 3 ;
represents a point of attachment to —Se—C(O)-A;
n is 1-3;
m is 0-3;
each R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, amino acids, peptides, and protecting groups for the protection of an amine;
each R 2 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , —C(O)NR 5 R 6 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, and amino acid side chains;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, and aryl;
each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl;
with the proviso that m is 0-3 when A is (R 1 ) 2 N(C(R 2 ) 2 ) n — and X is
and with the proviso that m is 0-2 when A is (R 1 ) 2 N(C(R 2 ) 2 ) n — and X is
2 . The ligation agent of claim 1 , wherein X is
3 . The ligation agent of claim 2 , wherein the ligation agent is selected from the group consisting of:
wherein R 3 is an aryl or an alkyl;
wherein R 3 is an aryl or an alkyl.
4 . The ligation agent of claim 1 , wherein X is
5 . The ligation agent of claim 4 , wherein the ligation agent is selected from the group consisting of:
wherein R 3 is an aryl or an alkyl.
6 - 15 . (canceled)
16 . A compound of Formula II:
wherein
each X is selected from the group consisting of
each
represents a point of attachment to —Se—Se—X—(CR 4 2 ) m C(O)R 3 ;
each
represents a point of attachment to —(CR 4 2 ) m C(O)R 3 ;
each m is independently 0-3;
each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and aryl;
each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl;
with the proviso that m is 0-3 when X is
and with the proviso that m is 0-2 when X is
17 . The compound of claim 16 , wherein X is
18 . The compound of claim 17 , wherein the compound is selected from the group consisting of:
wherein R 3 is an aryl or an alkyl;
wherein R 3 is an aryl or an alkyl.
19 . The compound of claim 16 , wherein X is
20 . The compound of claim 19 , wherein the compound is selected from the group consisting of:
wherein R 3 is an aryl or an alkyl.
21 . A method of making a ligation agent of Formula I:
wherein
A is selected from the group consisting of
fluorescent dyes, and cytotoxic small molecule drugs;
X is selected from the group consisting of
represents a point of attachment to —C(O)—Se—X—(CR 4 2 ) m C(O)R 3 ;
represents a point of attachment to —(CR 4 2 ) m C(O)R 3 ;
represents a point of attachment to —Se—C(O)-A;
n is 1-3;
m is 0-3;
each R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, amino acids, peptides, and protecting groups for the protection of an amine;
each R 2 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , —C(O)NR 5 R 6 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, and amino acid side chains;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, and aryl;
each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl;
with the proviso that m is 0-3 when A is (R 1 ) 2 N(C(R 2 ) 2 ) n — and X is
and with the proviso that m is 0-2 when A is (R 1 ) 2 N(C(R 2 ) 2 ) n — and X is
said method comprising:
(i) providing a compound of Formula II:
wherein
each X is selected from the group consisting of
each
represents a point of attachment to —Se—Se—X—(CR 4 2 ) m C(O)R 3 ;
each
represents a point of attachment to (CR 4 2 ) m C(O)R 3 ;
each m is independently 0-3; each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and aryl; each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl; with the proviso that m is 0-3 when X is
and
with the proviso that m is 0-2 when X is
(ii) (a) providing a compound of Formula III:
wherein
A is selected from the group consisting of
fluorescent dyes, and cytotoxic small molecule drugs;
represents a point of attachment to —C(O)—OH;
n is 1-3; each R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, amino acids, peptides, and protecting groups for the protection of an amine; and each R 2 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , —C(O)NR 5 R 6 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, and amino acid side chains; each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl; or (ii) (b) providing a compound of Formula III′:
wherein
A is selected from the group consisting of
fluorescent dyes, and cytotoxic small molecule drugs;
Y is selected from the group consisting of O, S, Se, a good leaving group, and Dawson's auxiliary; Y′ is optionally present and, if present, is a C 1 -C 6 alkyl, an ester, or an amide;
represents a point of attachment to
is a solid support;
n is 1-3; each R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, amino acids, peptides, and protecting groups for the protection of an amine; and each R 2 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , —C(O)NR 5 R 6 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, C 1 -C 6 alkoxy, and amino acid side chains; each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy; and R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and aryl; and (iii) reacting the compound of Formula II with the compound of Formula III or the compound of Formula III′ under conditions effective to make a ligation agent of Formula I.
22 . The method of claim 21 , wherein said providing a compound of Formula II comprises:
providing a substituted halogenated benzene aldehyde or substituted halogenated benzene ketone; and reacting the substituted halogenated benzene aldehyde or substituted halogenated benzene ketone with a diselenide in the presence of a cation scavenger under conditions effective to produce a compound of Formula II.
23 . The method of claim 22 , wherein the substituted halogenated benzene aldehyde or substituted halogenated benzene ketone is a compound of Formula IV:
wherein
X is selected from the group consisting of
represents a point of attachment to —X′;
represents a point of attachment to —(CR 4 2 ) m C(O)R 3 ;
X′ is a halogen;
each m is independently 0-3;
each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and aryl; and
each R 4 is independently selected from the group consisting of H, —C(O)R 7 , —C(O)OR 8 , NO 2 , —NR 5 R 6 , halogen, OH, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkoxy.
24 . The method of claim 22 , wherein the diselenide is an alkaline metal diselenide.
25 . The method of claim 22 , wherein the cation scavenger is selected from the group consisting of HMPA, DMPU, DMI, tetraalkyl ureas, and cyclic alkyl ureas.
26 . The method of claim 21 , wherein a compound of Formula III is provided.
27 . The method of claim 21 , wherein a compound of Formula III′ is provided.
28 . The method of claim 27 , wherein the solid support is selected from the group consisting of a Tenta gel, Rink amide resin, Merrifield resin, trityl resin, PAM resin, and Kaiser resin.Join the waitlist — get patent alerts
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