US2013274263A1PendingUtilityA1
Tubulin inhibitors
Assignee: YM BIOSCIENCES AUSTRALIA PTYPriority: Dec 3, 2003Filed: Mar 12, 2013Published: Oct 17, 2013
Est. expiryDec 3, 2023(expired)· nominal 20-yr term from priority
Inventors:Christopher J. BurnsAndrew Frederick WilksMichael Francis HarteHarrison SikanyikaEmmanuelle Fantino
A61P 39/00A61P 9/00A61P 9/10A61P 43/00A61P 37/08A61P 37/00A61P 37/02A61P 37/06A61P 9/14A61P 31/12A61P 29/00A61P 35/00A61P 31/00A61P 19/02A61P 17/04C07D 213/74C07D 253/07C07D 401/12C07D 239/42C07D 403/12C07D 401/14C07D 241/20Y02A50/30A61K 31/4965
58
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Claims
Abstract
Compounds of general formula (I), (II), (III) and (V) are described for use in modulating microtubule polymerisation and in the treatment of associated disease states. Use of compounds (I), (III) and (V) in the treatment of kinase-associated disease states is also described. Further described are novel compounds of formula (II), (III) and (V).
Claims
exact text as granted — not AI-modified1 . A method of modulating microtubule polymerisation in a subject, said method comprising administering a therapeutically effective amount of at least one compound of formula (I)
or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein:
R 1 is H or C 1-4 alkyl;
Q is a bond or C 1-4 alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , CN, aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 4 R 5 , Oaryl, Ohetaryl, CO 2 R 4 , CONR 4 R 5 , nitro, NR 4 R 5 , C 1-4 alkylNR 4 R 5 , NR 6 C 1-4 alkylNR 4 R 5 , NR 4 COR 5 , NR 6 CONR 4 R 5 and NR 4 SO 2 R 5 ;
R 4 and R 5 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR';
R 6 is selected from H and C 1-4 alkyl;
R 7 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl and C 1-4 alkyl hetaryl;
R 2 is 0-2 substituents independently selected from halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, C 1-4 alkylNR 8 R 9 , OC 1-4 alkylNR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , NR 10 CONR 8 R 9 and NR 8 SO 2 R 9 ;
R 8 and R 9 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 11 ;
R 10 is selected from H, C 1-4 alkyl, aryl and hetaryl;
R 11 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl and C 1-4 alkyl hetaryl;
Y is halogen, OH, NR 12 R 13 , NR 14 COR 12 , NR 14 CONR 12 R 13 or NR 14 SO 2 R 13 ;
R 12 and R 13 are each independently H, CH 2 F, CHF 2 , CF 3 , CN, C 1-4 alkyl optionally substituted with OH, OC 1-4 alkyl, NR 15 R 16, cycloalkyl, cyclohetalkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S and NR 14 ;
R 14 , R 15 and R 16 are each independently selected from H and C 1-4 alkyl;
n=0-4;
W is selected from H, C 1-4 alkyl and C 2-6 alkenyl; where C 1-3 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl or NR 15 R 16 ;
R 15 , and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR 17 ;
R 17 is selected from H and C 1-4 alkyl.
2 . A method according to claim 1 wherein the compound of formula (I) is selected from the group consisting of:
or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof.
3 . A method according to claim 1 , wherein said subject is treated for a hyperproliferation-related disorder or disease state.
4 . A method according to claim 3 , wherein the hyperproliferation-related disorder or disease state is selected from the group consisting of cancer, infectious diseases, vascular restenosis and inflammatory diseases.
5 . A compound of formula (II)
or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
R 1 is H or C 1-4 alkyl;
Q is a bond, or C 1-4 alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , CN, aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 4 R 5 , Oaryl, Ohetaryl, CO 2 R 4 , CONR 4 R 5 , nitro, NR 4 R 5 , C 1-4 alkylNR 4 R 5 , NR 6 C 1-4 alkylNR 4 R 5 , NR 4 COR 5 , NR 6 CONR 4 R 5 and NR 4 SO 2 R 5 ;
R 4 and R 5 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 7 ;
R 6 is selected from H and C 1-4 alkyl;
R 7 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl and C 1-4 alkyl hetaryl;
R 2 is 0-2 substituents independently selected from C 1-4 alkyl and OC 1-4 alkyl;
Y is CH 2 OH, OC 1-4 alkylOH, OC 1-4 alkylR 12 , OC 1-4 alkylNR 12 NR 13 , C(O)R 12 , CH 2 R 12 , COOR 12 , CONR 12 R 13 , OCONR 12 R 13 , CH 2 NR 12 R 13 , NHCOR 12 or NHCONR 12 R 13 ;
R 12 and R 13 are each independently H, C 1-2 alkyl, (CH 2 ) 3 NEt 2 , (CH 2 ) 2 NMe 2 (CH 2 ) 5 NH 2 , (CH 2 ) 2 OH,
W is selected from H, C 1-4 alkyl and C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl or NR 15 R 16 ;
R 15 , and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
R 17 is selected from H and C 1-4 alkyl;
wherein when Y is CH 2 R 12 then R 12 is not H or C 1-2 alkyl.
6 . A compound according to claim 5 selected from the group consisting of:
or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof.
7 . A compound of formula (III)
or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
X 1 , X 2 , X 3 , X 4 are selected from the following:
(i) X 1 and X 4 are N and X 2 and X 3 are C independently substituted with Y;
(ii) X 1 and X 3 are N and X 2 and X 4 are C independently substituted with Y;
(iii) X 2 and X 4 are N and X 1 and X 3 are C independently substituted with Y;
(iv) X 1 is N and X 2 , X 3 , and X 4 are C independently substituted with Y;
(v) X 3 is N and X 1 , X 2 and X 4 are C independently substituted with Y;
(vi) X 4 is N and X 1 , X 2 , and X 3 are C independently substituted with Y;
(vii) X 2 is N and X 1 , X 3 , and X 4 are C independently substituted with Y; and
(viii) X 1 , X 2 , and X 3 are N and X 4 is C substituted with Y;
R 1 is H, C 1-6 alkyl, C 1-6 alkylNR 5 R 6 , C 1-6 alkylNR 5 COR 6 , C 1-6 alkylNR 5 SO 2 R 6 , C 1-6 alkylCO 2 R 5 or C 1-6 alkylCONR 5 R 6 , where R 5 and R 6 are each independently H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, C 1-2 alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 7 ;
R 7 is selected from H and C 1-4 alkyl;
R 2 is selected from C 1-6 alkylOH, OC 2-6 alkylOH, C 1-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 1-6 alkylNR 8 COR 9 , OC 2-6 alkylNR 8 COR 9 , C 1-6 alkylhetaryl, OC 2-6 alkylhetaryl, OCONR 8 R 9 , NR 8 COOR 9 , NR 10 CONR 8 R 9 , CONR 8 R 9 and NR 8 COR 12 ;
R 8 and R 9 are each independently H, C 1-4 alkylNR 11 R 13 , hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 14 ;
R 12 K is C 2-4 alkyl, C 1-4 alkylNR 11 R 13 , hetaryl or cyclohetalkyl;
R 11 and R 13 are each independently H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 14 ;
R 14 is selected from H and C 1-4 alkyl;
R 10 is H or C 1-4 alkyl;
R 3 and R 4 are each independently H, halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CF 3 or OCF 3 ;
Q is a bond, or C 1-4 alkyl;
W is selected from H, C 1-4 alkyl and C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl or NR
R 15 and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 17 ;
R 17 is selected from H and C 1-4 alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 ,C 1-4 alkyl NR 18 R 19 , NR 20 C 1-4 l alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 and NR 18 SO 2 R 19 ;
R 18 and R 19 are each independently H, C 1-4 alkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 21 ;
R 21 is selected from H and C 1-4 alkyl;
R 20 is selected from H and C 1-4 alkyl;
Y is selected from H, OH and NR 22 R 23 ;
R 22 , R 23 are each independently H or C 1-4 alkyl.
8 . A compound according to claim 7 , wherein
R 1 is H, C 1-6 alkyl or C 1-6 alkylNR 5 R 6 , where R 5 and R 6 are each independently H, C 1-4 alkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 7 ; Q is CH; W is selected from C 1-4 alkyl and C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl or NR 15 R 16 ; R 15 and R 16 are each independently H, C 1-4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 17 ; A is aryl or hetaryl optionally substituted with 0-2 substituents independently chosen from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 , C 1-4 alkylNR 18 R 19 , NR 20 C 1-4 alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 and NR 18 SO 2 R 19 ; Y is selected from H, C 1-4 alkyl and NR 22 R 23 .
9 . A compound according to claim 7 wherein the compound is selected from the group consisting of:
or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof.
10 . A compound of formula (V)
or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
(i) X 1 and X 4 are N and X 2 and X 3 are C independently substituted with Y;
(ii) X 2 and X 4 are N and X 1 and X 3 are C independently substituted with Y;
(iii) X 1 is N and X 2 , X 3 , and X 4 are C independently substituted with Y;
(iv) X 3 is N and X 1 , X 2 , and X 4 are C independently substituted with Y;
(v) X 4 is N and X 1 , X 2 , and X 3 are C independently substituted with Y;
(vi) X 2 is N and X 1 , X 3 , and X 4 are C independently substituted with Y; and
(vii) X 1 , X 2 and X 3 are N and X 4 is C substituted with Y;
R 1 is H, C 1-6 alkyl, C 1-6 alkylNR 5 R 6 , C 1-6 alkylNR 5 COR 6 , C 1-6 alkylNR 5 SO 2 R 6 , C 1-6 alkylCO 2 R 5 or C 1-6 alkylCONR 5 R 6 , where R 5 and R 6 are each independently H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, C 1-4 alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 7 ;
R 7 is selected from H and C 1-4 alkyl;
R 2 is selected from OH, OC 1-6 alkyl, C 1-6 alkylOH, OC 2-6 alkylOH, C 1-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 1-6 alkylNR 8 COR 9 , OC 2-6 alkylNR 8 COR 9 , C 1-6 alkylhetaryl, OC 2-6 alkylhetaryl, OCONR 8 R 9 , NR 8 COOR 9 , NR 10 CONR 8 R 9 , CONR 8 R 9 and NR 8 COR 12 ;
R 8 and R 9 are each independently H, C 1-4 alkyl, C 1-4 alkylNR 11 R 13 , hetaryl or cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 14 ;
R 12 is C 2-4 alkyl, C 1-4 alkylNR 11 R 13 , hetaryl or cyclohetalkyl;
R 11 and R 13 are each independently H or C 1-4 alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 14 ;
R 14 is selected from H and C 1-4 alkyl;
R 10 is H or C 1-4 alkyl;
R 3 and R 4 are each independently H, halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CF 3 or OCF 3 ;
Q is a bond or C 1-4 alkyl;
W is selected from H, C 1-4 alkyl and C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl or NR 15 R 16 ;
R 15 and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl or hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 17 ;
R 17 is selected from H and C 1-4 alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 , C 1-4 alkylNR 18 R 19 , NR 20 C 1-4 alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 and NR 18 SO 2 R 19 ;
R 18 and R 19 are each independently H, C 1-4 alkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl or C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR 21 ;
R 21 is selected from H and C 1-4 alkyl;
R 2 ° is selected from H and C 1-4 alkyl;
Y is selected from H, C 1-4 alkyl, OH and NR 22 R 23 ;
R 22 , R 23 are each independently H or C 1-4 alkyl.
11 . A compound according to claim 10 selected from the group consisting of:
or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof.
12 . A compound of the formula:
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
13 . A composition comprising a carrier and at least one compound according to claim 7 .
14 . A method to treat a hyperproliferation-related disorder or disease state in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7 .
15 . A method according to claim 14 , wherein the hyperproliferation-related disorder or disease state is treatable by the modulation of microtubule polymerisation.
16 . A method according to claim 14 , wherein the hyperproliferation-related disorder or disease state is selected from the group consisting of cancer, infectious diseases, vascular restenosis or inflammatory diseases.
17 . A method to treat a protein-kinase related disorder or disease state in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7 .
18 . A method according to claim 17 , wherein the protein-kinase related disorder to disease state is selected from the group consisting of atopy, cell mediated hypersensitivity, rheumatic diseases, other autoimmune diseases and viral diseases.
19 . A method to treat diseases and conditions associated with inflammation and infection in a subject, said method comprising administering a therapeutically effective amount of at least one compound according to claim 7 .Cited by (0)
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