Therapeutic agent for treating tumors

Patent metadata

Field	Value
Publication number	US-10280183-B2
Application number	US-201515127083-A
Country	US
Kind code	B2
Filing date	Mar 18, 2015
Priority date	Mar 18, 2014
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

The present disclosure relates to a therapeutic agent of the formula:

Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X-T-W][NH—(CH 2 —CH—O) t (CH 2 ) s -NH—V]  Formula I
or a pharmaceutically acceptable salt thereof, useful for treating tumors, including cancers. Where the compound of Formula I also contains a radionuclide or an imaging agent or both, the compound of formula I is a theranostic agent useful for treating and diagnosing tumors, including cancers.

First claim

What is claimed is:

1. A compound of the formula:
Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X-T-W][NH—(CH 2 —CH—O) t (CH 2 ) s -NH—V]  Formula I

or a pharmaceutically acceptable salt thereof,
wherein,
Z is a hydroxy containing cytotoxic agent wherein the hydroxyl group thereon is replaced by O;
Φ is a phenyl ring;
R and R′ are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m and n and p are independently 1, 2, or 3,
Y is a triazine;
r is 1, 2, or 3;
X is a triazole, to which is optionally fused a cycloalkyl ring containing 5, 6, 7, 8, 9, or 10 carbon ring atoms;
T is O—(CH 2 )a-C(═O)— or (CH 2 —CH 2 —O)o-(CH 2 )f;
a is 1, 2, or 3;
W is Q b -U d or halide or NH—C(═S)—NH—U or NH—C(═O)—(CH 2 ) p1 [(CR1R2) m1 S—S-Φ-(CH 2 ) n1 ] i -C(═O)-A;
b and d are independently 0 or 1, wherein b and d cannot both be 0;
Q is a radionuclide;
U is an imaging agent for detection by PET or SPECT imaging;
o is 1, 2, 3, 4, 5, or 6;
i is 0 or 1;
f is 0, 1, 2, or 3;
R1 and R2 are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m 1 and n 1 and p 1 are independently 1, 2, or 3;
s is 1-6;
t is 1, 2, 3, 4, 5, or 6;
A is a hydroxy containing cytotoxic agent or O-Φ and
V is biotin or folic acid wherein the COOH moiety forms an amide bond with the NH group.

2. The compound according to claim 1 , wherein the compound has the formula:
Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X—(CH 2 —CH 2 —O) o -(CH 2 ) f -W][NH—(CH 2 —CH—O) t (CH 2 ) s -NH—V]   Formula II

or a pharmaceutically acceptable salt thereof,
wherein,
Z is a hydroxyl containing cytotoxic agent wherein the hydroxyl group therein is replaced by O;
Φ is a phenyl ring;
R and R′ are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m and n and p are independently 1, 2, or 3,
Y is a triazine;
r is 1, 2, or 3;
X is a triazole;
o is 1, 2, 3, 4, 5, or 6;
f is 1, 2, or 3;
W is a radionuclide or NH—C(═S)—NH—U;
U is an imaging agent for detection by PET or SPECT imaging;
s is 1-6;
t is 1, 2, 3, 4, 5, or 6; and
V is biotin or folic acid wherein the COOH moiety forms an amide bond with the NH group.

3. The compound of claim 1 wherein the compound has the formula:
Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X-T-W][NH—(CH 2 —CH—O) t (CH 2 ) s -NH—V]   Formula III

or a pharmaceutically acceptable salt thereof,
wherein,
Z is a is a hydroxyl containing cytotoxic agent wherein the hydroxyl group therein is replaced by O;
Φ is a phenyl ring;
R and R′ are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m and n and p are independently 1, 2, or 3,
Y is a triazine;
r is 1, 2, or 3;
X is a triazole, to which is optionally fused a cycloalkyl ring containing 5, 6, 7, 8, 9, or 10 carbon ring atoms;
T is O—(CH 2 )a-C(═O)—;
a is 1, 2, or 3;
W is Q b -U d ;
Q is a radionuclide;
U is an imaging agent for detection by PET or SPECT imaging;
b and d are independently 0 or 1, wherein b and d cannot both be 0;
s is 1-6;
t is 1, 2, 3, 4, 5, or 6; and
V is biotin or folic acid wherein the COOH moiety forms an amide bond with the NH group.

4. The compound according to claim 1 wherein the compound has the formula:
Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X—(CH 2 —CH 2 —O) o -(CH 2 ) f -W′][NH—(CH 2 —CH—O) t (CH 2 ) s -NH—V]   Formula IV

or pharmaceutically acceptable salt,
wherein W′ is a non-radioactive halogen.

5. The compound according to claim 4 wherein W′ is fluorine.

6. The compound according to claim 1 wherein the compound has the formula:
Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X-T-W][NH—(CH 2 —CH—O) t (CH 2 ) s -NH—V]  Formula VI

or a pharmaceutically acceptable salt thereof,
wherein,
Z is a hydroxy containing cytotoxic agent wherein the hydroxyl group thereon is replaced by O;
Φ is a phenyl ring;
R and R′ are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m and n and p are independently 1, 2, or 3,
Y is a triazine;
r is 1, 2, or 3;
X is a triazole, to which is optionally fused a cycloalkyl ring containing 5, 6, 7, 8, 9, or 10 carbon ring atoms;
T is O—(CH 2 )a-C(═O)—, (CH 2 —CH 2 —O)o-(CH 2 )f;
a is 1, 2, or 3;
W is or NH—C(═O)—(CH 2 ) p1 (CR1R2) m1 S—S-Φ-[(CH 2 ) n1 —C(═O)-A];
R1 and R2 are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m 1 and n 1 and p 1 are independently 1, 2, or 3;
s is 1-6;
t is 1, 2, 3, 4, 5, or 6;
A is a hydroxy containing cytotoxic agent and
V is biotin or folic acid wherein the COOH moiety forms an amide bond with the NH group.

7. The compound according to claim 1 having the formula:
Z—C(═O)—(CH 2 ) n -Φ-S—S—(CRR′) m -(CH 2 ) p -C(═O)—NH—(CH 2 ) q -NH—Y[NH—(CH 2 ) r -X-T-W][NH—(CH 2 —CH 2 —O) t (CH 2 ) s -NH—V]  Formula VII

or a pharmaceutically acceptable salt thereof,
wherein,
Z is a hydroxy containing cytotoxic agent wherein the hydroxyl group thereon is replaced by O or O-Φ;
Φ is a phenyl ring;
R and R′ are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m and n and p are independently 1, 2, or 3,
Y is a triazine;
r is 1, 2, or 3;
X is a triazole, to which is optionally fused a cycloalkyl ring containing 5, 6, 7, 8, 9, or 10 carbon ring atoms;
T is (CH 2 —CH 2 —O)o-(CH 2 )f;
a is 1, 2, or 3;
W is —NH—C(═O)—(CH 2 ) p1 [(CR1R2) m1 S—S-Φ-(CH n ) n1 ] i —C(═O)-A;
o is 1, 2, 3, 4, 5, or 6;
i is 0 or 1;
f is 0, 1, 2, or 3;
R1 and R2 are independently hydrogen or alkyl group containing 1 or 2 or 3 carbon atoms;
m 1 and n 1 and p 1 are independently 1, 2, or 3;
s is 1-6;
t is 1, 2, 3, 4, 5, or 6;
A is a hydroxy containing cytotoxic agent or O- Φ and
V is biotin or folic acid wherein the COOH moiety forms an amide bond with the NH group.

8. The compound according to claim 1 wherein both A and Z are hydroxy containing cytotoxic agents.

9. The compound according to claim 1 wherein V is biotin.

10. The compound according claim 1 wherein Z is a taxoid of formula 3.

11. The compound according to claim 1 , wherein the compound selected from the following compounds:

12. A pharmaceutical composition comprised of a therapeutically effective amount of a compound according to claim 1 and a pharmaceutical carrier therefor.

13. A method of treating cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , wherein said cancer is selected from the group consisting of breast, ovarian, leukemia, and lung cancer.

14. A method of diagnosing a tumor in a subject comprising administering to the subject in need thereof a diagnostically effective amount of the theranostic agent claim 1 .

15. The method according to claim 14 wherein Z is a taxoid of formula 3.

16. The method according to claim 14 wherein V is biotin.

17. The method according to claim 14 wherein the compound is a compound selected from the following compounds:

Assignees

• Univ New York State Res Found

Inventors

• Ojima Iwao
• Vineberg Jacob
• Wang Tao

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D251/18

  with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines · CPC title

• C07D251/54

  Three nitrogen atoms · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title