US2010144720A1PendingUtilityA1
Inhibitors of human tumor-expressed ccxckr2
Est. expiryDec 20, 2022(expired)· nominal 20-yr term from priority
A61P 35/00C07C 235/50C07D 401/06C07D 207/06C07D 207/08C07D 207/12C07D 207/09C07D 207/14C07D 401/04C07D 211/42C07D 211/14A61P 35/04C07D 295/13C07D 241/04C07D 207/16C07D 405/14C07D 405/12C07D 405/04C07D 405/06C07D 211/56C07D 241/42C07C 235/48A61P 43/00C07D 407/12
60
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Claims
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
exact text as granted — not AI-modified1 . A modulator of the structure (I), or a salt thereof:
where m is an integer from 1 to 5;
each Y is independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —OH, —OR′, —C(O)R′, —CO 2 R′, —O(CO)R′, —C(O)NR′R″, —OC(O)NR′R″, —SR′, —SOR′, —SO 2 R′, —SO 2 NR′R″, —NR′R″, —NR′C(O)R″, —NR′C(O) 2 R′, —NR′SO 2 R″, —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;
where each R′, R″ and R′″ are independently hydrogen, halogen, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl;
n is 0, 1, 2 or 3;
Z is —CHR 1 R 2 —, —OR 1 , or —NR 1 R 2 ;
R 1 and R 2 are each independently substituted or unsubstituted alkyl or hydrogen, or Z in combination with R 1 and R 2 form a substituted or unsubstituted 5- to 8-membered ring comprising at least one nitrogen and 0 to 3 additional heteroatoms;
R 6 is alkyl, hydrogen, or halogen; and
R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —OH, —OR′, —C(O)R′, —CO 2 R′, —O(CO)R′, —C(O)NR′R″, —OC(O)NR′R″, —SR′, —SOR′, —SO 2 R′, —SO 2 NR′R″, —NR′R″, —NR′C(O)R″, —NR′C(O) 2 R″, —NR′SO 2 R″, —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, or where any two of R 3 , R 4 or R 5 together with the atoms which they substituted form a substituted or unsubstituted 3- to 10-membered heterocycyl.
2 . The modulator of claim 1 , where R 6 is hydrogen.
3 . The modulator of claim 1 , where R 6 is substituted or unsubstituted C 1-8 alkyl.
4 . The modulator of claim 1 , where R 6 is halogen.
5 . The modulator of claim 1 , where R 3 , R 4 , and R 5 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 R 3 , R 4 , and R 5 are each independently selected from the group consisting of —OR′ and hydrogen.
7 . The modulator of claim 1 , where R 3 , R 4 , and R 5 are each —OR′, where R′ is substituted C 1-8 alkyl.
8 . The modulator of claim 1 , where R 4 and R 5 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 CHR 1 R 2 and where R 1 and R 2 together with Z form C 3-10 cycloalkyl with 0 to 3 substituents selected from the group consisting of halogen, —CN, —NO 2 , —OH, —OR′, —C(O)R′, —CO 2 R′, —O(CO)R′, —C(O)NR′R″, —OC(O)NR′R″, —SR′, —SOR′, —SO 2 R′, —SO 2 NR′R″, —NR′R″, —NR′C(O)R″, —NR′C(O) 2 R″, —NR′SO 2 R″, —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 R 1 and R 2 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 —CHR 1 R 2 .
12 . The modulator of claim 1 , where Z is —NR 1 R 2 .
13 . The modulator of claim 1 , where Z in combination with R 1 and R 2 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:
where R 7 is selected from the group consisting of hydrogen, —C(O)R′, —CO 2 R′, —C(O)NR′R″, —SO 2 R′, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 1-8 alkoxyl, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-10 cycloalkyl, unsubstituted or substituted C 6-10 aryl, C6-10 aryloxy unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl.
20 . The modulator of claim 1 , where R 7 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′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′S(O) 2 R″, —CN, oxo (═O or —O—) or —NO 2 , where R′, R″ and R′″ each independently hydrogen, halogen, unsubstituted C 1-8 alkyl, 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, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′S(O 2 R″ and —N 3 , where R′, R″ and R′″ each independently hydrogen, halogen, unsubstituted C 1-8 alkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-8 alkenyl, unsubstituted C 2-8 alkynyl, 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, —NO 2 , —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 NR′R″, —NR′S(O) 2 R″ and —N 3 , 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.
27 . A modulator having the structure (II):
where n=0-4
where each Y is independently hydrogen or halogen;
R 3 , R 4 , and R 5 are each independently R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, halogen, and —OR′;
or any two of R 3 , R 4 , and R 5 , together with the atoms which they substituted, form unsubstituted or substituted 3- to 10-membered heterocyclyl; and
R 7 is selected from the group consisting of hydrogen, —C(O)R′, —CO 2 R′, —C(O)NR′R″, —SO 2 R′, unsubstituted or substituted C 1-8 alkyl (optionally C1-8 alkoxyalkyloxy, CH2CH2OCH2CH 2 OMe)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.
28 . The modulator of claim 27 , where R 7 is C 1-8 alkoxyalkyloxy.
29 . The modulator of claim 27 , where n is 1.
30 . A modulator comprising one of the following formulae:
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31 . A pharmaceutical composition comprising the modulator of claim 1 and a pharmaceutically acceptable carrier.
32 . A pharmaceutical composition comprising the modulator of claim 27 and a pharmaceutically acceptable carrier.
33 . A pharmaceutical composition comprising the modulator of any one of claims 28 - 30 and a pharmaceutically acceptable carrier.
34 . A pharmaceutical composition comprising a compound of the formulae:
and a pharmaceutically acceptable carrier.
35 . A method of inhibiting the binding of chemokines I-TAC and/or SDF-1 to a CCXCKR2 receptor, comprising contacting the composition of any one of claims 32 - 34 with a cell that expresses the CCXCKR2 receptor for a time sufficient to inhibit the binding of the chemokines to the CCXCKR2 receptor.
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.
37 . A method of treating cancer, comprising administering a therapeutically effective amount of the composition of any one of claims 32 - 34 to a cancer patient for a time sufficient to treat the cancer.
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.Join the waitlist — get patent alerts
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