Inhibitors of human tumor-expressed CCXCKR2

• US 20040171655A1
• Filed: 12/22/2003
• Published: 09/02/2004
• Est. Priority Date: 12/20/2002
• Status: Active Grant

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Wright, J.J., Schall, Thomas, Melikian, Anita, Burns, Jennifer, McMaster, Brian E.
• Granted Patent: US 7,649,011 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 235/48 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 235/50 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings

Abstract

Pharmaceutical compositions containing organic compounds or salts thereof that serve as modulators for the SDF-1 or I-TAC chemokines are disclosed. The compounds and compositions are useful in the treatment of cancer, especially in the inhibition of cancer proliferation, growth, and metastasis. Methods of interfering with SDF-1 and/or I-TAC binding to the CCXCKR2 receptor and treating cancer using the compounds and pharmaceutical compositions of the present invention are also disclosed.

Claims

1. A modulator of the structure (I), or a salt thereof:

2. The modulator of claim 1, where R⁶ is hydrogen.

3. The modulator of claim 1, where R⁶ is substituted or unsubstituted C_1-8 alkyl.

4. The modulator of claim 1, where R⁶ is halogen.

5. The modulator of claim 1, where R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, —

OR′

, and substituted or unsubstituted C_1-8 alkyl.

6. The modulator of claim 1, where R³, R⁴, and R⁵ are each independently selected from the group consisting of —

OR′ and

hydrogen.

7. The modulator of claim 1, where R³, R⁴, and R⁵ are each —

OR′

, where R′

is substituted C_1-8 alkyl.

8. The modulator of claim 1, where R⁴ and R⁵ together with the atom which they substitute form substituted or unsubstituted 5- to 6-membered heterocyclyl containing 1 to 2 oxygen atoms.

9. The modulator of claim 1, where Z is CHR¹R² and where R¹ and R² together with Z form C_3-10 cycloalkyl with 0 to 3 substituents selected from the group consisting of halogen, —

CN, —

NO₂, —

OH, —

OR′

, —

C(O)R′

, —

CO₂R′

, —

O(CO)R′

, —

C(O)NR′

R″

, —

OC(O)NR′

R″

, —

SR′

, —

SOR′

, —

SO₂R′

, —

SO₂NR′

R″

, —

NR′

R″

, —

NR′

C(O)R″

, —

NR′

C(O)₂R″

, —

NR′

SO₂R″

, —

NR′

(CO)NR″

R′

″

, unsubstituted or substituted C_1-8 alkyl, unsubstituted or substituted C_2-8 alkenyl, unsubstituted or substituted C_2-8 alkynyl, unsubstituted or substituted C_3-8 cycloalkyl, unsubstituted or substituted C_6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl.

10. The modulator of claim 1, where R¹ and R² together with Z form a 3- to 10-membered heterocyclyl with 0 to 3 substituents selected from the group consisting of halogen, —

OR, substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted C_1-8 alkenyl, substituted or unsubstituted C_1-8 alkynyl, substituted or unsubstituted C_6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl.

11. The modulator of claim 1, where Z is —

CHR¹R²—

.

12. The modulator of claim 1, where Z is —

N R¹R²—

.

13. The modulator of claim 1, where Z in combination with R¹ and R² is selected from the group consisting of substituted or unsubstituted morpholinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, and substituted or unsubstituted piperazinyl.

14. The modulator of claim 1, where Z is a substituted or unsubstituted group of the formula:

15. The modulator of claim 1, where Z is a substituted or unsubstituted group of the formula:

16. The modulator of claim 1, where Z is a substituted or unsubstituted group of the formula:

17. The modulator of claim 1, where Z is a substituted or unsubstituted group of the formula:

18. The modulator of claim 1, where Z is a substituted or unsubstituted group of the formula:

19. The modulator of claim 16, where Z is a substituted or unsubstituted group of the formula:

20. The modulator of claim 1, where R⁷ is substituted or unsubstituted C_1-10 alkyl, substituted or unsubstituted C_1-10 alkoxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted C_3-10 cycloalkyl.

21. The modulator of claim 1, where n is 1, 2, or 3.

22. The modulator of claim 1, where m is 1 or 2, and each Y is a halogen.

23. The modulator of claim 1, where m is 0.

24. The modulator of claim 1, where substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl can each independently be substituted 1 to 3 times with halogen, —

OR′

, —

NR′

R″

, —

SR′

, —

SiR′

R″

R″

′

, —

OC(O)R′

, —

C(O)R′

, —

CO₂R′

, —

CONR′

R″

, —

OC(O)NR′

R″

, —

NR″

C(O)R′

, —

NR′

—

C(O)NR″

R″

′

, —

NR″

C(O)₂R′

, —

S(O)R′

, —

S(O)₂R′

, —

S(O)₂NR′

R″

, —

NR′

S(O)₂R″

, —

CN, oxo (═

O or —

O—

) or —

NO₂, where R′

, R″ and

R″

′

each independently hydrogen, halogen, unsubstituted C_1-8alkyl, unsubstituted C_3-6 cycloalkyl, unsubstituted C_2-8 alkenyl, unsubstituted or C_2-8 alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted or substituted heterocyclyl.

25. The modulator of claim 1, where substituted aryl and substituted heteroaryl can each independently be substituted 1 to 3 times with halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, —

OR′

, oxo (═

O or —

O), —

OC(O)R′

, —

NR′

R″

, —

SR′

, —

R′

, —

CN, —

NO₂, —

CO₂R′

, —

CONR′

R″

, —

C(O)R′

, —

OC(O)NR′

R″

, —

NR″

C(O)R′

, —

NR″

C(O)₂R′

, —

NR′

—

C(O)NR″

R″

′

, —

NH—

C(NH₂)═

NH, —

NR′

C(NH₂)═

NH, —

NH—

C(NH₂)═

NR , —

S(O)R′

, —

S(O)₂R′

, —

S(O)₂NR′

R″

, —

NR′

S(O)₂R″ and

—

N₃, where R′

, R″ and

R″

′

each independently hydrogen, halogen, unsubstituted C_1-8 alkyl, unsubstituted C_3-6 cycloalkyl, unsubstituted C_2-8alkenyl, unsubstituted C_2-8alkynyl, unsubstituted or substituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl.

26. The modulator of claim 1, where substituted heterocyclyl can be substituted 1 to 3 times with halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, —

OR′

, oxo (═

O or —

O), —

OC(O)R′

, —

NR′

R″

, —

SR′

, —

R′

, —

CN, —

NO₂, —

OC(O)NR′

R″

, —

NR″

C(O)R′

, —

NR″

C(O)₂R′

, —

NR′

—

C(O)NR″

R″

′

, —

NH—

C(NH₂)═

NH, —

NR′

C(NH₂)═

NH, —

NH—

C(NH₂)═

NR′

, —

S(O)R′

, —

S(O)₂NR′

R″

, —

NR′

S(O)₂R″ and

—

N₃, where R′

, R″ and

R″

′

each independently hydrogen, halogen, unsubstituted C_1-8 alkyl, unsubstituted or C_3-6 cycloalkyl, unsubstituted C_2-8 alkenyl, unsubstituted C_2-8 alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl.

31. A pharmaceutical composition comprising the modulator of claim 1 and a pharmaceutically acceptable carrier.

36. A method of inhibiting the binding of chemokines I-TAC and/or SDF-1 to a CCXCKR2 receptor, comprising contacting the modulator of claim 1 with a cell that expresses the CCXCKR2 receptor for a time sufficient to inhibit the binding of the chemokines to the CCXCKR2 receptor.

38. A method of treating cancer, comprising administering a therapeutically effective amount of the modulator of claim 1 to a cancer patient for a time sufficient to treat the cancer.

27. A modulator having the structure (II):

28. The modulator of claim 27, where R⁷ is C_1-8 alkoxyalkyloxy.

29. The modulator of claim 27, where n is 1.

32. A pharmaceutical composition comprising the modulator of claim 27 and an pharmaceutically acceptable carrier.

30. A modulator comprising one of the following formulae:

33. A pharmaceutical composition comprising the modulator of claim and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising a compound of the formulae:

35. A method of inhibiting the binding of chemokines I-TAC and/or SDF-1 to a CCXCKR2 receptor, comprising contacting the composition of claim 3234 with a cell that expresses the CCXCKR2 receptor for a time sufficient to inhibit the binding of the chemokines to the CCXCKR2 receptor.

37. A method of treating cancer, comprising administering a therapeutically effective amount of the composition of claim 3234 to a cancer patient for a time sufficient to treat the cancer.