US2020316214A1PendingUtilityA1
Anti-cancer compounds and conjugates thereof
Est. expiryOct 2, 2035(~9.2 yrs left)· nominal 20-yr term from priority
Inventors:Oliver Booth ViningVenkata Rami Reddy MacherlaAlexander Wayne SchammelIppei UsuiJacob Neal BeverageElizabeth Paige StoutBryan Junn LeeSteven Bruce CohenEduardo Esquenazi
A61K 47/68031C07K 5/0205C07D 277/22C07K 16/2878A61P 35/00C07K 16/30A61K 47/6803
52
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Disclosed herein are compounds, drug-conjugates thereof, methods of preparing drug-conjugates, and uses thereof. Also disclosed are pharmaceutical compositions and methods of treatment. The compounds and drug-conjugates disclosed herein can be used to treat a variety of conditions, diseases and ailments such as bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of Formula IIa, IIb, IIc or IId:
or pharmaceutically acceptable salts or solvates thereof,
wherein:
R 1 is selected from the group consisting of hydrogen, deuterium, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 2 is selected from the group consisting of R D , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 3 is selected from the group consisting of hydrogen, deuterium, and optionally substituted C 1 -C 6 alkyl, an optionally substituted hydroxyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 4 is an optionally substituted C 1 -C 6 alkyl;
R 5 is hydrogen, deuterium or an optionally substituted C 1 -C 6 alkyl;
R 6 is hydrogen, deuterium or an optionally substituted C 1 -C 6 alkyl;
X 1 and X 2 are each independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, halogen, —CN, —N 3 , —COOR B , —NR A R B , —OR B , SR B , —COOH, —NHR A , —OH, and —SH; wherein at least one of X 1 and X 2 in Formula IIa and Formula IId is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, halogen, —CN, —N 3 , —COOR B , —NR A R B , OR B , SR B , —COOH, —NHR A , —OH, and —SH;
R A is selected from the group consisting of hydrogen, deuterium, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R B is selected from the group consisting of R 1A -L 1 -, R 3A -L 1 -, R 4A -L 1 -, Mc-L 1 -, Mal-L 3 -L 1 -, R 1A -Mal-L 3 -L 1 -Val-Cit-PAB—C(O)— or Mal-L 3 -L 1 -Val-Cit-PAB—C(O)—;
R 7 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted heteroaryl, or —C(═O)R C ;
R C is selected from the group consisting of an optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, and hydroxyl; and
R 8 is hydrogen, deuterium, —OR D , or —SR D ;
R D is selected from the group consisting of R 1A -L 1 -, R 3A -L 1 -, R 4A -L 1 -, Mc-L 1 -, Mal-L 3 -L 1 -, R 1A -Mal-L 3 -L 1 -Val-Cit-PAB—C(O)— and Mal-L 3 -L 1 -Val-Cit-PAB—C(O)—;
R 3A is
R 4A is a conjugation moiety;
R 1A is a conjugated targeting moiety;
L 1 is a linker or a bond; and
L 3 is an alkanoyl.
2 . The compound of claim 1 , wherein R D is R 1A -Mc-Val-Cit-PAB—C(O)—, R 1A -Mal-L 3 -Val-Cit-PAB—C(O)—, Mc-Val-Cit-PAB—C(O)— or Mal-L 3 -Val-Cit-PAB—C(O)—.
3 . The compound of claim 1 , wherein R B is R 1A -Mc-Val-Cit-PAB—C(O)—, R 1A -Mal-L 3 -Val-Cit-PAB—C(O)—, R 1A -Mal-L 3 -Val-Cit-PAB—C(O)—, Mc-Val-Cit-PAB—C(O)— or Mal-L 3 -Val-Cit-PAB—C(O)—.
4 . The compound of claim 1 , wherein R 8 is hydrogen, or —OR D .
5 . The compound of claim 1 , wherein X 1 is hydrogen; and X 2 is —OR B , or X 2 is hydrogen; and X 1 is —OR B .
6 . The compound of claim 1 , wherein the targeting moiety binds to one or more tumor-associated antigens or cell surface receptors selected from the group consisting of CD19, CD22, CD30, CD33, CD56, CD70, CD79b, CD74, CD138, HER2, GPNMB, PSMA, SLC44A4, CA6, CA-IX, Mesothelin, CD66e, CEACAM5, and Nectin-4, or the targeting moiety is a protein ligand, a protein scaffold, a peptide, cysteine-engineered antibody, antibody-like protein, monoclonal antibody (mAB), an antibody fragment, surrogate, or variant.
7 . The compound of claim 1 , wherein R 1A comprises a targeting moiety selected from the group consisting of brentuximab, inotuzumab, gemtuzumab, milatuzumab, trastuzumab, glembatumomab, lorvotuzumab, or labestuzumab, or derivatives thereof.
8 . The compound of claim 1 , wherein L 1 is —(CHR 13 )—CH 2 —(CR 14 R 15 )—S—S—(CR 16 R 17 )—(CH 2 ) n (CO) r —; n is 1, 2, 3, 4, or 5; r is 0 or 1; R 13 is hydrogen or SO 3 H; and R 14 , R 15 , R 16 and R 17 are each independently hydrogen or an optionally substituted C 1 -C 6 alkyl.
9 . The compound of claim 1 , wherein L 1 comprises
or a dipeptide selected from the group consisting of -Phe-Lys-, -Val-Ala-, -Val-Lys-; -Ala-Lys-, -Val-Cit-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg-, and -Trp-Cit-.
10 . The compound of claim 1 , wherein R 1A -L 1 - is
where q is 0 to 6; and L is a linker, or
R 1A -L 1 - is
where s is 0 or 1; and t is 0 to 30, or R 1A -L 1 - is
where t is 0 to 30.
11 . The compound of claim 1 , wherein:
R 4A — is
and
R is hydrogen, —C(═O)N(CH 2 CH 3 ) 2 , or —SO 2 N(CH 2 CH 2 ) 2 O.
12 . The compound of claim 1 , wherein R D is
13 . The compound of claim 1 , wherein R B is
14 . The compound of claim 1 , wherein the compound is
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R D is Ab1-Mc-Val-Cit-PAB—C(O)— and Ab1 is an antibody.
15 . A method of treating cancer, comprising administering a compound of claim 1 to a subject in need thereof, wherein the cancer is selected from the group consisting of a carcinoma, a sarcoma, a lymphoma, and a blastoma.
16 . A method of treating cancer, comprising administering a compound of claim 1 to a subject in need thereof, wherein the cancer is selected from the group consisting of uterine sarcoma cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, non-Hodgkin lymphoma, glioblastoma, pancreatic cancer, prostate cancer, and thyroid cancer.
17 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.Join the waitlist — get patent alerts
Track US2020316214A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.