Inhibitors of human tumor-expressed CCXCKR2

• US 7,649,011 B2
• Filed: 12/22/2003
• Issued: 01/19/2010
• Est. Priority Date: 12/20/2002
• Status: Active Grant

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Burns, Jennifer, McMaster, Brian E., Schall, Thomas, Melikian, Anita, Wright, J. J.
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US10/743,281
• Publication Number:
  US 20040171655A1
• Time in Patent Office: 2,220 Days
• Field of Search: 548/574, 548/491, 548/561, 548/455, 548/517, 548/518, 548/525, 548/527, 548/567, 514/414, 514/418, 514/422, 514/428
• US Class Current: 514/414
• 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 compound of the structure (I), or a salt thereof:

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

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

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

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

OR′ and

hydrogen.

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

OR′

, where R′

is substituted C_1-8 alkyl.

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

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

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

11. The compound 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.

12. The compound of claim 1, where n is 1, 2, or 3.

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

14. The compound of claim 1, where m is 0.

15. The compound 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 are independently selected from the group consisting of hydrogen, halogen, unsubstituted C_1-8 alkyl, unsubstituted C_3-6 cycloalkyl, unsubstituted C_2-8 alkenyl, unsubstituted or C_2-8 alkynyl, and unsubstituted aryl.

16. The compound of claim 1, where substituted aryl 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′

″

are independently selected from the group consisting of hydrogen, halogen, unsubstituted C_1-8 alkyl, unsubstituted C_3-6 cycloalkyl, unsubstituted C_2-8 alkenyl, unsubstituted C_2-8 alkynyl, and unsubstituted or substituted aryl.

17. The compound 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′

″

are independently selected from the group consisting of hydrogen, halogen, unsubstituted C_1-8 alkyl, unsubstituted or C_3-6 cycloalkyl, unsubstituted C_2-8 alkenyl, unsubstituted C_2-8 alkynyl, and unsubstituted aryl.

21. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

18. A compound having the structure (II):

19. The compound of claim 18, where R⁷ is C_1-8 alkoxyalkyloxy.

22. A pharmaceutical composition comprising the compound of claim 18 and a pharmaceutically acceptable carrier.

20. A compound comprising one of the following formulae:

23. A pharmaceutical composition comprising the compound of claim 20 and a pharmaceutically acceptable carrier.