Functionalized tyrosine kinase inhibitors modified with precious metal electrophiles and methods associated therewith

Patent metadata

Field	Value
Publication number	US-10047057-B2
Application number	US-201515126443-A
Country	US
Kind code	B2
Filing date	Mar 15, 2015
Priority date	Mar 15, 2014
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

Newly synthesized thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylamino chain. One compound tested acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitinib in NCI-H1975 (with IC50 values of 1.7 and 30 μM, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.

First claim

We claim:

1. A compound, pharmaceutically acceptable salt, or solvate of Formula I or Ia:

wherein X is halide, OH − , H 2 O, —OC(O)R 9 , —P((—CH 2 )qCH 3 ) 3 , nitrate, sulfate or a carbene of structure

wherein q is 0, 1, 2, or 3;
X 1 and X 2 are independently halo, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkynyl, nitro, amino, —NHC(O)(R 10 ), —NHC(O)O(R 10 ), —C(O)NHR 10 , or —OC(O)NHR 10 ;
M is Au or Pt and if M is Au, R 1 and R 2 are not present;
R 1 and R 2 are amino, ammonia or pyridine groups or together with the platinum atom to which they are attached, R 1 and R 2 form the ring —NH 2 —(CH 2 ) v —NH 2 — wherein v is 1, 2, 3, or 4 or R 1 and R 2 together can be any of the following groups a-h;

wherein A is H, —CH 3 , —OCH 3 , CF 3 or NO 2 ;
R 3 is —N(R 26 )— or S; wherein R 26 is hydrogen or C 1 -C 6 alkyl;
R 4 is hydrogen, C 1-6 alkyl, or CH 2 —R 12 ;
E is —(CH 2 ) q —;
R 5 is a direct bond, —NH— or C 1 -C 6 alkylene;
or R 5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
R 7 is hydrogen, methyl, —CH(R 17 )(R 18 ), —C(O)O—R 18 , or —OC(O)—R 18 ; wherein
R 17 is hydrogen or C 1-6 alkyl;
R 18 is hydrogen, C 1-6 alkyl, —CH(R 19 )(R 20 ), phenyl, naphthyl, C 3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R 19 is hydrogen or C 1-6 alkyl;
R 20 is hydrogen, C 1-6 alkyl;
R 8 is —NR 13 —, —C(O) NR 13 —, —NR 13 C(O)—, —O—, —S—, —OC(O)—, and —C(O)O—
R 13 is —H or —C 1-6 alkyl;
R 9 is hydrogen, C 1-6 alkyl, phenyl, naphthyl, C 3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R 11 and R 12 are independently hydrogen, hydroxyl, C 1-6 alkyl, —OCH 3 , —CF 3 , NO 2 ;
R 24 and R 25 are independently hydrogen or C 1-4 alkyl;
and
Z is independently one or more halide or nitro, or one or more counterions sufficient to balance the charge of the compound.

2. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein X 1 is F or Cl and X 2 is F or Cl.

3. The compound, pharmaceutically acceptable salt, or solvate of claim 1 , wherein X 2 is F and X 1 is Cl.

4. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein M is Au and X is —P(—CH 2 —CH 3 ) 3 .

5. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein R 3 is —NH or S.

6. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein R 5 and R 7 together are ethyl or —NHCH 3 .

7. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein R 4 is H or CH 3 .

8. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein R 13 is H or CH 3 .

9. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein R 9 is ethyl.

10. The compound, pharmaceutically acceptable salt, or solvate of claim 1 wherein X 1 is C 1 and X 2 is F, wherein R 3 is —NH or S, wherein R 5 and R 7 together are ethyl or —NHCH 3 , wherein E is methylene, wherein R 4 is H or CH 3 , wherein R 13 is H or CH 3 , and wherein R 9 is ethyl.

11. A pharmaceutical composition comprising compound, pharmaceutically acceptable salt, or solvate of Formula I or Formula Ia:

wherein X is halide, OH, H 2 O, —OC(O)R 9 , —P((—CH 2 )qCH 3 ) 3 , nitrate, sulfate or a carbene of structure

wherein q is 0, 1, 2, or 3;
X 1 and X 2 are independently halo, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkynyl, nitro, amino, —NHC(O)(R 10 ), —NHC(O)O(R 10 ), —C(O)NHR 10 , or —OC(O)NHR 10 ;
M is Au or Pt and if M is Au, R 1 and R 2 are not present;
R 1 and R 2 are amino, ammonia or pyridine groups or together with the platinum atom to which they are attached, R 1 and R 2 form the ring —NH 2 —(CH 2 ) v —NH 2 — wherein v is 1, 2, 3, or 4 or R 1 and R 2 together can be any of the following groups a-h;

wherein A is H, —CH 3 , —OCH 3 , CF 3 or NO 2 ;
R 3 is —N(R 26 )— or S; wherein R 26 is hydrogen or C 1 -C 6 alkyl;
R 4 is hydrogen, C 1-6 alkyl, or CH 2 —R 12 ;
E is —(CH 2 ) q —;
R 5 is a direct bond, —NH— or C 1 -C 6 alkylene;
or R 5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
R 7 is hydrogen, methyl, —CH(R 17 )(R 18 ), —C(O)O—R 18 , or —OC(O)—R 18 ; wherein
R 17 is hydrogen or C 1-6 alkyl;
R 18 is hydrogen, C 1-6 alkyl, —CH(R 19 )(R 20 ), phenyl, naphthyl, C 3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R 19 is hydrogen or C 1-6 alkyl;
R 20 is hydrogen, C 1-6 alkyl;
R 8 is —NR 13 —, —C(O) NR 13 —, —NR 13 C(O)—, —O—, —S—, —OC(O)—, and —C(O)O—
R 13 is —H or —C 1-6 alkyl;
R 9 is hydrogen, C 1-6 alkyl, phenyl, naphthyl, C 3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R 11 and R 12 are independently hydrogen, hydroxyl, C 1-6 alkyl, —OCH 3 , —CF 3 , NO 2 ;
R 24 and R 25 are independently hydrogen or C 1-4 alkyl;
and
Z is independently one or more halide or nitro, or one or more counterions sufficient to balance the charge of the compound and one or more pharmaceutically acceptable diluents, excipients, or carriers.

12. The composition of claim 11 , wherein X 1 is F or C 1 and X 2 is F or Cl.

13. The composition of claim 11 , wherein X 2 is F and X 1 is Cl.

14. The composition of claim 11 , wherein M is Au and X is —P(—CH 2 —CH 3 ) 3 .

15. The composition of claim 11 , wherein R 3 is —NH or S.

16. The composition of claim 11 , wherein R 5 and R 7 together are ethyl or —NHCH 3 .

17. The composition of claim 11 , wherein R 4 is H or CH 3 and wherein R 13 is H or CH 3 .

18. The composition of claim 11 , wherein R 9 is ethyl.

19. A method of treating cancer comprising administering to an individual in need thereof a compound, a pharmaceutically acceptable salt, or a solvate of Formula I or Formula Ia:

wherein X is halide, OH, H 2 O, —OC(O)R 9 , —P((—CH 2 )qCH 3 ) 3 , nitrate, sulfate or a carbene of structure

wherein q is 0, 1, 2, or 3;
X 1 and X 2 are independently halo, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkynyl, nitro, amino, —NHC(O)(R 10 ), —NHC(O)O(R 10 ), —C(O)NHR 10 , or —OC(O)NHR 10 ;
M is Au or Pt and

Assignees

• Univ Wake Forest

Inventors

• Bierbach Ulrich
• Yang Mu
• Pickard Amanda J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07F1/005

  without C-Metal linkages · CPC title

• C07D239/94 Primary

  Nitrogen atoms · CPC title

• C07F15/0093

  without a metal-carbon linkage · CPC title