US2005043244A1PendingUtilityA1
Water-soluble SHPs as novel alkylating agents
Est. expiryJun 13, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61P 35/00A61P 35/02A61P 25/00C07C 311/55A61P 17/00A61P 1/16A61P 1/18A61P 1/04A61P 13/12A61P 13/10A61P 15/00A61K 38/16A61K 38/04A61P 11/00A61P 13/08C07F 9/12
51
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Claims
Abstract
The present invention relates to compounds according to the structure (I): Where R is —CH 3 or —CH 2 CH 2 Cl; R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl; R 2 or R 4 is OP0 3 H 2 , N0 2 , OCO(Glu-OH), NHCO(Glu-OH), NHR 7 and unassigned groups of R 2 , R 3 , R 4 , R 5 and R 6 are, independently, H, F, Cl, Br, I, OH, OP0 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SFs, NH 2 , NHR 7 , N(CH 3 ) 2 , OPO 3 H 2 , or a C1-C7 alkyl group with the proviso that when any two of unassigned groups of R 2 , R 3 , R 4 , R 5 or R 6 are other than H, the other two of unassigned groups of R 2 , R 3 , R 4 , R 5 or R 6 are H. R 7 is H or polyglutamyl as described. Phosphoric acid and glutamic acid can be a free acid or pharmaceutically acceptable salt thereof.
Claims
exact text as granted — not AI-modified1 - 22 . (cancelled)
23 . A pharmaceutical composition comprising an effective amount for treating non-tumorous cancer of a compound or its pharmaceutically acceptable salt according to the structure:
Where R is —CH 3 or —CH 2 CH 2 Cl; R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl;
one of R 2 or R 4 , but not both, is selected from OPO 3 H 2 , NO 2 , OCO(Glu), NHCO(Glu) and NHR 7 and the other of R 2 or R 4 which is unassigned, and R 3 , R 5 and R 6 , are, independently selected from H, F, Cl, Br, I, OH, OPO 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SF 5 , NHR 8 , N(R 9 ) 2 and C 1 -C 7 alkyl, with the proviso that at least two of R 2 , R 3 , R 4 , R 5 and R 6 are H; R 7 is H, glutamyl or a polyglutamic acid polypeptide residue (—COCH(NHR 7 a)CH 2 CH 2 CO 2 H where R 7 a is glutamyl or a polyglutamic acid polypeptide residue having from 1 to 50 peptide linkages; R 8 is H or C 1 -C 7 alkyl;
and R 9 is CH 3 or CH 2 CH 3 ; optionally, in combination with a pharmaceutically acceptable additive, carrier, or excipient.
24 . The composition according to claim 23 wherein R is —CH 2 CH 2 Cl.
25 . The composition according to claim 23 wherein said R′ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or substituted hexyl.
26 . The composition according to claim 25 wherein R′ is methyl.
27 . The composition according to claim 23 wherein R 2 is OPO 3 H 2 or its pharmaceutically acceptable salt.
28 . The composition according to claim 23 wherein R 4 is F, Cl or OCH 3 when R 3 , R 5 and R 6 are each H.
29 . The composition according to claim 23 wherein R 5 is F, Cl, OCH 3 or OCF 3 when R 3 , R 4 and R 6 are each H.
30 . The composition according to claim 23 two of R 3 , R 4 , R 5 or R 6 are independently F or Cl.
31 . The composition according to claim 30 wherein R 4 and R 5 are independently F or Cl.
32 . The composition according to claim 30 wherein R 5 and R 6 are independently F or Cl.
33 . The composition according to claim 31 wherein R 4 and R 5 are Cl.
34 . The composition according to claim 32 wherein R 5 and R 6 are Cl.
35 . The composition according to claim 23 wherein R 5 is OPO 3 H 2 or its pharmaceutically acceptable salt.
36 . The composition according to claim 23 wherein R 2 is NO 2 when R 3 , R 4 and R 6 are each H.
37 . The composition according to claim 23 wherein R 4 is NO 2 and R 2 , R 3 and R 6 are each H.
38 . The composition according to claim 23 wherein R 4 is OCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.
39 . The composition according to claim 38 wherein Glu is in the form of a pharmaceutically acceptable salt.
40 . The composition according to claim 23 wherein R 4 is NHCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.
41 . The composition according to claim 40 for wherein Glu is in the form of a pharmaceutically acceptable salt.
42 . The composition according to claim 23 wherein R 4 is NHR 7 and R 2 , R 3 , R 5 and R 6 are each H.
43 . The composition according to claim 42 for wherein R 7 is α-glutamyl or a pharmaceutically acceptable salt thereof.
44 . The composition according to claim 43 wherein R 7 is H, α-glutamyl or a pharmaceutically acceptable salt thereof or a polyglutamic acid polypeptide residue or a pharmaceutically acceptable salt thereof.
45 . A method of treating non-tumorous cancer in a patient in need of therapy comprising administering to said patient an effective amount of a compound or its pharmaceutically acceptable salt according to the structure:
Where R is —CH 3 or —CH 2 CH 2 Cl; R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl;
one of R 2 or R 4 , but not both, is selected from OPO 3 H 2 , NO 2 , OCO(Glu), NHCO(Glu) and NHR 7 and the other of R 2 or R 4 which is unassigned, and R 3 , R 5 and R 6 , are, independently selected from H, F, Cl, Br, I, OH, OPO 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SF 5 , NHR 8 , N(R 9 ) 2 and C 1 -C 7 alkyl, with the proviso that at least two of R 2 , R 3 , R 4 , R 5 and R 6 are H; R 7 is H, glutamyl or a polyglutamic acid polypeptide residue —COCH(NHR 7 a)CH 2 CH 2 CO 2 H where R 7 a is glutamyl or a polyglutamic acid polypeptide residue having from 1 to 50 peptide linkages; R 8 is H or C 1 -C 7 alkyl;
and R 9 is CH 3 or CH 2 CH 3 ; optionally, in combination with a pharmaceutically acceptable additive, carrier, or excipient.
46 . The method according to claim 45 wherein R is —CH 2 CH 2 Cl.
47 . The method according to claim 45 wherein said R′ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or substituted hexyl.
48 . The method according to claim 47 wherein R′—CH 3 .
49 . The method according to claim 45 wherein R 2 is OPO 3 H 2 or a pharmaceutically acceptable salt thereof.
50 . The method according to claim 45 wherein R 4 is F, Cl or OCH 3 and R 3 , R 5 and R 6 are each H.
51 . The method according to claim 45 wherein R 5 is F, Cl, OCH 3 or OCF 3 and R 3 , R 4 and R 6 are each H.
52 . The method according to claim 45 wherein two of R 3 , R 4 , R 5 or R 6 are independently F or Cl.
53 . The method according to claim 52 wherein R 4 and R 5 are independently F or Cl.
54 . The method according to claim 52 wherein R 5 and R 6 are independently F or Cl.
55 . The method according to claim 53 wherein R 4 and R 5 are Cl.
56 . The method according to claim 54 wherein R 5 and R 6 are Cl.
57 . The method according to claim 45 wherein R 5 is OPO 3 H 2 or a pharmaceutically acceptable salt thereof.
58 . The method according to claim 45 wherein R 2 is NO 2 and R 3 , R 4 and R 6 are each H.
59 . The method according to claim 45 wherein R 4 is NO 2 and R 2 , R 3 and R 6 are each H.
60 . The method according to claim 45 wherein R 4 is OCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.
61 . The method according to claim 60 wherein Glu is in the form of a pharmaceutically acceptable salt.
62 . The method according to claim 45 wherein R 4 is NHCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.
63 . The method according to claim 62 wherein Glu is in the form of a pharmaceutically acceptable salt.
64 . The method according to claim 45 wherein R 4 is NHR 7 and R 2 , R 3 , R 5 and R 6 are each H.
65 . The method according to claim 64 wherein R 7 is a α-glutamyl or a pharmaceutically acceptable salt thereof.
66 . The method according to claim 64 wherein R 7 is H, a α-glutamyl or a pharmaceutically acceptable salt thereof or a polyglutamic acid polypeptide residue or a pharmaceutically acceptable salt thereof.
67 . The method according to claim 45 wherein said cancer is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, or hairy cell leukemia.
68 . (Cancelled)
69 . A method of treating a drug-resistant non-tumorous cancer in a patient in need thereof, said method comprising administering to said patient an effective amount of a composition according to claims 23 or 24 .
70 . A method of treating non-tumorous cancer in a patient in need thereof said method comprising administering to said patient an effective amount of a composition according to claims 23 or 24 in combination with at least one additional anti-cancer agent.
71 . A method of treating non-tumorous cancer in a patient in need thereof said method comprising administering to said patient an effective amount of a composition according to claims 23 or 24 in combination with at least one additional anti-cancer agent selected from the group consisting of antimetabolites, Ara C, etoposide, doxorubicin, taxol, hydroxyurea, vincristine, cytoxan, mitomycin C, adriamycin, topotecan, campothecin, irinotecan, gemcitabine, and cis-platin.
72 . A pharmaceutical composition according to any of claims 23 - 44 in combination with at least one additional anti-cancer agent.
73 . A pharmaceutical composition according to claims 23 or 24 in combination with at least one additional anti-cancer agent selected from the group consisting of antimetabolites, Ara C, etoposide, doxorubicin, taxol, hydroxyurea, vincristine, cytoxan, mitomycin C, adriamycin, topotecan, campothecin, irinotecan, gemcitabine, campothecin and cis-platin.Join the waitlist — get patent alerts
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