Intracellular delivery compounds
View Patent ↗Provided are compounds having the Formula I: pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and their use in the intracellular delivery of antibodies.
1. A compound having the Formula I:
wherein,
each Ba is independently selected from adenine (A), guanine (G), cytosine (C), and thymine (T);
X is O or S;
each R 1 is independently selected from hydrogen and (C 1 -C 6 )alkyl substituted with a fluorophore;
q is an integer from 12 to 35;
r is an integer from 1 to 10;
t is an integer from 1 to 10;
L is —CH 2 —R 2 —*;
R 2 is —(C 1 -C 6 )alkyl substituted with 1 or 2 groups selected from —C(═O)NR a , —NR a C(═O)R b , —NR a C(═O)R d , ═NOR e , —NR a , —NR a R b , —OR b , —S(O) k R b , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —S(O) 2 NR a , —C(═O)OR b , —OC(═O)OR b , —OC(═O)R b , —C(═O)NR a R b , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R b , phenyl, —OC(═O)NR a , —NR a C(═O)NR a R b , —NR a C(═O)NR a , —NR a (C═S)NR a R b , —NR a (C═S)NR a , and —C(═O)R b ;
k is 0, 1, or 2;
each R a is independently hydrogen or (C 1 -C 6 )alkyl optionally substituted with R f ;
each R b is independently (C 1 -C 6 )alkyl optionally substituted with R f or —C(═O)R f ;
R d is —[(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl] v C(═O)NH;
R e is —[(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl] p C(═O);
each R f is independently
wherein the wavy bond indicates the point of attachment to the (C 1 -C 6 )alkyl defined by R a , or the (C 1 -C 6 )alkyl or carbonyl each defined by R b ;
R g is (C 1 -C 6 )alkyl or —[(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl] w C(═O)NH;
ring A is
wherein the dashed bonds indicate the points of attachment to the triazolyl of R f , and the wavy bond indicates the point of attachment to the (C 1 -C 6 )alkyl defined by R a , or the (C 1 -C 6 )alkyl or carbonyl each defined by R b ;
p is an integer from 1 to 10;
v is an integer from 1 to 10;
w is an integer from 2 to 12;
* indicates the point of attachment to A T ; and
A T is an antibody.
2. The compound of claim 1 , wherein R 2 is —(C 1 -C 6 )alkyl substituted with —C(═O)NR a , —NR a C(═O)R b , —NR a C(═O)R d , ═NOR e , —NR a , —NR a R b , —OR b , —S(O) k R b , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —S(O) 2 NR a , —C(═O)OR b , —OC(═O)OR b , —OC(═O)R b , —C(═O)NR a R b , —NR a C(═O)R b , —NR a C(═O)OR b , —OC(═O)NR a R b , —OC(═O)NR a , —NR a C(═O)NR a R b , —NR a C(═O)NR a , —NR a (C═S)NR a R b , —NR a (C═S)NR a , or —C(═O)R b .
3. The compound of claim 1 , wherein R 2 is —(C 1 -C 6 )alkyl substituted with —C(═O)NR a , —NR a C(═O)R b , —NR a C(═O)R d , ═NOR e , —NR a , —R a R b , —OR b , —S(O) 2 NR a R b , —S(O) 2 NR a , —C(═O)OR b , —C(═O)NR a R b , —NR a C(═O)R b , —NR a C(═O)OR b , —NR a C(═O)NR a R b , —NR a C(═O)NR a , or —C(═O)R b .
4. The compound of claim 1 , wherein R 2 is —(C 1 -C 6 )alkyl-NR a C(═O)R d , —(C 1 -C 6 )alkyl-NR a C(═O)R b , or —(C 1 -C 6 )alkyl(=NO)R e .
5. The compound of claim 1 , wherein R d is —[(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl] v C(═O)NH.
6. The compound of claim 1 , wherein R e is —[(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl] p C(═O).
7. The compound of claim 1 , wherein R g is —[(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl] v C(═O)NH.
8. The compound of claim 1 , wherein each R a is independently selected from hydrogen and (C 1 -C 6 )alkyl.
9. The compound of claim 1 , wherein R b is (C 1 -C 6 )alkyl substituted with R f or —C(═O)R f .
10. The compound of claim 1 , wherein p is an integer from 1 to 6.
11. The compound of claim 1 , wherein v is an integer from 1 to 6.
12. The compound of claim 1 , wherein w is an integer from 2 to 8.
13. The compound of claim 1 , wherein R f is
14. The compound of claim 1 , wherein ring A is
15. The compound of claim 1 , wherein the fluorophore, if present, is fluorescein.
16. The compound of claim 1 , wherein the compound is of the Formula IIb:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is of the Formula IIIa:
or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1 to 10 , wherein the compound is of the Formula IVa:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein X is S.
20. The compound of claim 1 , wherein r is an integer from 3 to 5.
21. The compound of claim 1 , wherein t is an integer from 2 to 4.
22. The compound of claim 1 , wherein q is an integer from 15 to 25.
23. The compound of claim 1 , wherein the thiophosphate oligonucleotide sequence beginning at the 3′ end is TCCATGAGCTTCCTGATGCT (SEQ ID NO.: 5).
24. The compound of claim 1 , wherein A T is an IgG antibody.
25. The compound of claim 1 , wherein A T is anti-STAT3, panitumumab, CTLA4, or VEGFR2.
26. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof (“TCCATGAGCTTCCTGATGCT” disclosed as SEQ ID NO.: 5).
27. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
28. A method of treating a disease or disorder selected from autoimmune disease, developmental disorder, inflammatory disease, metabolic disorder, cardiovascular disease, liver disease, intestinal disease, infectious disease, endocrine disease, neurological disorder, and cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
29. A process for producing a compound having the Formula I:
wherein,
each Ba is independently selected from adenine (A), guanine (G), cytosine (C), and thymine (T);
X is O or S;
each R 1 is independently selected from hydrogen and (C 1 -C 6 )alkyl substituted with a fluorophore;
q is an integer from 12 to 35;
r is an integer from 1 to 10;
t is an integer from 1 to 10;
L is —CH 2 —R 2 —*;
R 2 is —(C 1 -C 6 )alkyl-NR a C(═O)R b ;
R a is hydrogen or (C 1 -C 6 )alkyl;
R b is (C 1 -C 6 )alkyl substituted with R f or —C(═O)R f ;
R f is
ring A is
wherein the dashed bonds indicate the points of attachment to the triazolyl of R f and the wavy bond indicates the point of attachment to the (C 1 -C 6 )alkyl or carbonyl each defined by R b ; and
R g is (C 1 -C 6 )alkyl or —[(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl] w C(═O)NH;
w is an integer from 2 to 12;
* indicates the point of attachment to A T ; and
A T is an antibody;
the process comprising reacting a compound having the Formula 100:
wherein
X 2 is —CH 2 (C 1 -C 6 )alkyl-NR a C(═O)R b ;
R a is hydrogen or (C 1 -C 6 )alkyl;
R b is (C 1 -C 6 )alkyl substituted with R 40 or —C(═O)R 40 ; and
R 40 is
wherein the wavy line indicates the point of attachment to the (C 1 -C 6 )alkyl or carbonyl defined by R b ;
with a compound having the Formula A T -Y, wherein Y is —R g N 3 .