US 8,642,278 B2Granted

Inhibition of cell proliferation

AssigneeUniversity of South Florida

InventorsSaid M. Sebti, Srikumar Chellappan, Nicholas James Lawrence

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Abstract

The disclosed modulators of Rb:Raf-1 interactions are potent, selective disruptors of Rb:Raf-1 binding, with IC50 values ranging from 80 nM to 500 nM. Further, these compounds are surprisingly effective in inhibiting a wide variety of cancer cells, including osteosarcoma, epithelial lung carcinoma, non-small cell lung carcinoma, three different pancreatic cancer cell lines, two different glioblastoma cell lines, metastatic breast cancer, melanoma, and prostate cancer. Moreover, the disclosed compounds effectively disrupt angiogenesis and significantly inhibited tumors in nude mice derived from human epithelial lung carcinoma tumors. Accordingly, the disclosed compounds, pharmaceutical compositions comprising the compounds, methods of inhibiting cell proliferation, methods of treating subjects with cancer, and methods of preparing the disclosed compounds are provided.

Claims86

Dependent claims

A method of inhibiting proliferation of a cell, comprising contacting the cell with an effective amount of a compound represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is optionally substituted, and zero, one, or two of the ring atoms in Ring A are N;
and
Ring A is fused with zero, one, or two optionally substituted 3-15 membered monocyclic or polycyclic rings selected from the group consisting of aryl, heteroaryl, heterocyclyl, and cycloaliphatic;
Y is an optionally substituted C1-3 alkylene or C1-3 alkenylene;
X2 is optionally substituted ═NH;
X3 is optionally substituted —NH2,
each substitutable carbon is optionally substituted with a carbon substituent independently selected from the group consisting of —F, —Cl, —Br, —I, —CN,—NO2, —Ra, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —C(S)Ra, —OC(S)Ra, —C(S)ORa, —C(O)SRa, —C(S)SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSOaRa, —PO2RaRb, —OPO2RaRb, —PO3RaRb, OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, NRcC(O)N(RaRb), —C(NRc)—N(RaRb), —NRd—C(NRc)—N(RaRb), —NRaN(RaRb), —CRc═CRaRb, —C≡CRa, ═O, ═S, ═CRaRb, ═NRa, ═NORa, and ═NNRa, or two substitutable carbons are linked with C1-3 alkylenedioxy;
each substitutable nitrogen is:
optionally substituted with a nitrogen substituent independently selected from the group consisting of —CN, —NO2, —Ra, —ORa, —C(O)Ra, —C(O)Ra—aryl, —OC(O)Ra, —C(O)ORa, —SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), and oxygen toform an N-oxide;
and
optionally protonated or quaternary substituted to carry a positive charge which is balanced by a pharmaceutically acceptable counterion;
wherein
each Ra—Rd is independently —H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 aralkyl, aryl, heteroaryl, heterocyclyl, or cycloaliphatic, or, —N(RaRb), taken together, is an optionally substituted heterocyclic group;
X2, X3, each nitrogen substitutent, and each carbon substituent is optionally protected with a protecting group;
and
provided the compound is not benzyl N,N′-bis(tert-butoxy carbonyloxy)carbamimidothioate or a salt represented by

14 more elements

A method of modulating Rb:Raf-1 binding in a proliferating cell, comprising contacting the cell with an effective amount of a compound represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is optionally substituted, and zero, one, or two of the ring atoms in Ring A are N;
and
Ring A is fused with zero, one, or two optionally substituted 3-15 membered monocyclic or polycyclic rings selected from the group consisting of aryl, heteroaryl, heterocyclyl, and cycloaliphatic;
Y is an optionally substituted C1-3 alkylene or C1-3 alkenylene;
X2 is optionally substituted ═NH;
X3 is optionally substituted —NH2,
each substitutable carbon is optionally substituted with a carbon substituent independently selected from the group consisting of —F, —Cl, —Br, —I, —CN,—NO2, —Ra, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —C(S)Ra, —OC(S)Ra, —C(S)ORa, —C(O)SRa, —C(S)SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSO3Ra, —PO2RaRb, —OPO2RaRb, —PO3RaRb, —OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), —C(NRc)—N(RaRb), —NRd—C(NRc)—N(RaRb), —NRaN(RaRb), —CRc═CRaRb, —C≡CRa, ═O, ═S, ═CRaRb, ═NRa, ═NORa, and ═NNRa, or two substitutable carbons are linked with C1-3 alkylenedioxy;
each substitutable nitrogen is:
optionally substituted with a nitrogen substituent independently selected from the group consisting of —CN, —NO2, —Ra, —ORa, —C(O)Ra, —C(O)Ra-aryl, —OC(O)Ra, —C(O)ORa, —SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc—C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), and oxygen to form an N-oxide;
and
optionally protonated or quaternary substituted to carry a positive charge which is balanced by a pharmaceutically acceptable counterion;
wherein
each Ra-Rd is independently —H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 aralkyl, aryl, heteroaryl, heterocyclyl, or cycloaliphatic, or, —N(RaRb), taken together, is an optionally substituted heterocyclic group;
X2, X3, each nitrogen substitutent, and each carbon substituent is optionally protected with a protecting group;
and
provided the compound is not benzyl N,N′-bis(tert-butoxy carbonyloxy)carbamimidothioate or a salt represented by

14 more elements

A method of treating or ameliorating a cell proliferation disorder, comprising contacting the proliferating cells in a subject in need of such treatment with an effective amount of a compound represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is optionally substituted, and zero, one, or two of the ring atoms in Ring A are N;
and
Ring A is fused with zero, one, or two optionally substituted 3-15 membered monocyclic or polycyclic rings selected from the group consisting of aryl, heteroaryl, heterocyclyl, and cycloaliphatic;
Y is an optionally substituted C1-3 alkylene or C1-3 alkenylene;
X2 is optionally substituted ═NH;
X3 is optionally substituted —NH2, each substitutable carbon is optionally substituted with a carbon substituent independently selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO2, —Ra, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —C(S)Ra, —OC(S)Ra, —C(S)ORa, —C(O)SRa, —C(S)SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSO3Ra, —PO2RaRb, —OPO2RaRb, —PO3RaRb, —OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), —C(NRc)—N(RaRb), —NRd—C(NRc)—N(RaRb), —NRaN(RaRb), —CRc═CRaRb, —C≡CRa, ═O, ═S, ═CRaRb, ═NRa, ═NORa, and ═NNRa, or two substitutable carbons are linked with C1-3 alkylenedioxy;
each substitutable nitrogen is:
optionally substituted with a nitrogen substituent independently selected from the group consisting of —CN, —NO2, —Ra, —ORa, —C(O)Ra, —C(O)Ra—aryl, —OC(O)Ra, —C(O) ORa, —SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), and oxygen to form an N-oxide;
and
optionally protonated or quaternary substituted to carry a positive charge which is balanced by a pharmaceutically acceptable counterion;
wherein
each Ra-Rd is independently —H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 aralkyl, aryl, heteroaryl, heterocyclyl, or cycloaliphatic, or, —N(RaRb), taken together, is an optionally substituted heterocyclic group;
X2, X3, each nitrogen substituent, and each carbon substituent is optionally protected with a protecting group;
and
provided the compound is not benzyl N,N′-bis(tert-butoxy carbonyloxy)carbamimidothioate or a salt represented by

13 more elements

A method of inhibiting angiogenic tubule formation in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is optionally substituted, and zero, one, or two of the ring atoms in Ring A are N;
and
Ring A is fused with zero, one, or two optionally substituted 3-15 membered monocyclic or polycyclic rings selected from the group consisting of aryl, heteroaryl, heterocyclyl, and cycloaliphatic;
Y is an optionally substituted C1-3 alkylene or C1-3 alkenylene;
X2 is optionally substituted ═NH;
X3 is optionally substituted —NH2,
each substitutable carbon is optionally substituted with a carbon substituent independently selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO2, —Ra, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —C(S)Ra, —OC(S)Ra, —C(S)ORa, —C(O)SRa, —C(S)SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSO3Ra, —PO2RaRb, —OPO2RaRb, —PO3RaRb, —OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), —C(NRc)—N(RaRb), —NRd—C(NRc)—N(RaRb), —NRaN(RaRb), —CRc═CRaRb, —C≡CRa, ═O, ═S, ═CRaRb, ═NRa, ═NORa, and ═NNRa, or two substitutable carbons are linked with C1-3 alkylenedioxy;
each substitutable nitrogen is:
optionally substituted with a nitrogen substituent independently selected from the group consisting of —CN, —NO2, —Ra, —ORa, —C(O)Ra, —C(O)Ra—aryl, —OC(O)Ra, —C(O)ORa, —SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRC(O)Ra, —NRcC(O) ORa, —NRcC(O)N(RaRb), and oxygen to form an N-oxide;
and
optionally protonated or quaternary substituted to carry a positive charge which is balanced by a pharmaceutically acceptable counterion;
wherein
each Ra-Rd is independently —H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 aralkyl, aryl, heteroaryl, heterocyclyl,or cycloaliphatic, or, —N(RaRb), taken together, is an optionally substituted heterocyclic group;
X2, X3, each nitrogen substituent, and each carbon substituent is optionally protected with a protecting group;
and
provided the compound is not benzyl N,N′-bis(tert-butoxy carbonyloxy)carbamimidothioate or a salt represented by

14 more elements

A method of treating or ameliorating a cell proliferation disorder, wherein the cellular proliferation disorder is selected from the group consisting of osteosarcoma, epithelial lung cancer, non-small cell lung cancer, glioblastoma, melanoma, breast cancer and prostate cancer, comprising contacting the proliferating cells in a subject in need of such treatment with an effective amount of a compound represented by structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is optionally substituted, and zero, one, or two of the ring atoms in Ring A are N;
and
Ring A is fused with zero, one, or two optionally substituted 3-15 membered monocyclic or polycyclic rings selected from the group consisting of aryl, heteroaryl, heterocyclyl, and cycloaliphatic;
Y is an optionally substituted C1-3 alkylene or C1-3 alkenylene;
X2 is optionally substituted ═NH;
X3 is optionally substituted —NH2,
each substitutable carbon is optionally substituted with a carbon substituent independently selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO2, —Ra, —ORa, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —C(S)Ra, —OC(S)Ra, —C(S)ORa, —C(O)SRa, —C(S)SRa, —S(O)Ra, —SO2Ra, —SO3Ra, —OSO2Ra, —OSO3Ra, —PO2RaRb , —OPO2RaRb, —PO3RaRb, —OPO3RaRb, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Re, —C(O)NRaSO2Rc , —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRcC(O)ORa, —NRcC(O)N(RaRb), —C(NRc)—N(RaRb), —NRd—C(NRc)—N(Ra Rb), —NRaN(RaRb), —CRc═CRaRb,—C≡CRa, ═O, ═S, ═CRaRb, ═NRa, ═NORa, and ═NNRa, or two substitutable carbons are linked with C1-3 alkylenedioxy;
each substitutable nitrogen is:
optionally substituted with a nitrogen substituent independently selected from the group consisting of —CN, —NO2, —Ra, —ORa, —C(O)Ra, —C(O)Ra-aryl, —OC(O)Ra, —C(O)ORa, —S(O)Ra, —SO2Ra, —SO3Ra, —N(RaRb), —C(O)N(RaRb), —C(O)NRaNRbSO2Rc, —C(O)NRaSO2Rc, —C(O)NRaCN, —SO2N(RaRb), —NRaSO2Rb, —NRcC(O)Ra, —NRc(O)ORa, —NRcC(O)N(RaRb), and oxygen to form an N-oxide;
and
optionally protonated or quaternary substituted to carry a positive charge which is balanced by a pharmaceutically acceptable counterion;
wherein
each Ra-Rd is independently —H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 aralkyl, aryl, heteroaryl, heterocyclyl, or cycloaliphatic, or, —N(RaRb), taken together, is an optionally substituted heterocyclic group;
X2, X3, each nitrogen substituent, and each carbon substituent is optionally protected with a protecting group;
and
provided the compound is not benzyl N,N′-bis(tert-butoxy carbonyloxy)carbamimidothioate or a salt represented by

14 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/562,903Filed 22 Nov 2006 · us provisional application
Priority: 22 Nov 2005
Published: US 2007/0254318 A11 Nov 2007
Granted: 4 Feb 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07C 323/45
Containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton: having at least one of…
C07C 279/06
Having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton: being further substituted by halogen atoms, or by…
C07C 335/32
Isothioureas: having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
C07D 213/53
Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom: nitrogen atoms