Novel compounds for treatment of cancer and disorders associated with angiogenesis function
AssigneeUniversity of Southern California
InventorsNouri Neamati, Antonio Garofalo
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Abstract
Novel compounds for treatment of cancer and disorders associated with angiogenesis function. Also disclosed are a method of preparing the compounds, pharmaceutical compositions and packaged products containing the compounds, a method of using these molecules to treat cancer (e.g., leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, breast cancer, renal cancer, and prostate cancer) and disorders associated with angiogenesis function (e.g., age-related macular degeneration, macular dystrophy, and diabetes), a method of monitoring the treatment, a method of profiling gene expression, and a method of modulating gene expression.
Claims26
A compound of Formula I,
- wherein
- X═C, N, or O;
- Z=O or S;
- R=alkyl, halogen, acetyl, O-alkyl, or N-alykl;
- R′=alkyl, halogen, acetyl, O-alkyl, or N-alykl;
- and
- Y=alkyl, heterocyclic aromatic, aliphatic, sugar, or lipid.
A compound of Formula II,
- wherein
- R is H, alkyl, or halogen;
- R′ is H, alkyl, or halogen;
- X is CH or N;
- and
- Y comprises a homocyclic or heterocyclic ring, wherein Y is 3-, 5-, or 6-pyrazinyl or 3-, 4-, 5-, or 6-pyridinyl when R is H, R′ is H, X is CH, and Y is pyrazinyl or pyridinyl.
A compound of Formula V,
- wherein
- X═C, N, or O;
- Z=O or S;
- R=alkyl, halogen, acetyl, O-alkyl, or N-alykl;
- and
- Y=alkyl, heterocyclic aromatic, aliphatic, sugar, or lipid.
A compound of Formula VI,
- wherein
- X═C, N, or O;
- Z=O or S;
- R=alkyl, halogen, acetyl, O-alkyl, or N-alykl;
- and
- Y=alkyl, heterocyclic aromatic, aliphatic, sugar, or lipid.
A compound of Formula VII,
A method of preparing a compound, comprising:
- contacting hydrazine monohydrate with a compound (13a, 13b, 13c, or 13d) of Formula VII
- wherein
- R is H, R′ is H, and X is CH (13a);
- R is Me, R′ is Me, and X is CH (13b);
- R is F, R′ is H, and X is CH (13c);
- or
- R is H, R′ is H, and X is N (13d),
- to form a compound (14a, 14b, 14c, or 14d, respectively) of Formula IX,
- wherein
- R is H, R′ is H, and X is CH (14a);
- R is Me, R′ is Me, and X is CH (14b);
- R is F, R′ is H, and X is CH (14c);
- or
- R is H, R′ is H, and X is N (14d);
- and
- contacting 14a with pyrrole-2-carboxylic acid chloride to form SC141,
- contacting 14a with nicotinoyl chloride hydrochloride to form SC142,
- contacting 14b, 14c, and 14d with 2-pyrazinecarboxylic acid in the presence of 2,2′-dipyrildisulphide and triphenylphosphine to form SC143, SC144, and SC148, respectively,
- contacting 14a with N—BOC-thiazolidine-4-carboxylic acid in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)/4-(dimethylamino)pyridine (DMAP) and then trifluoroacetic acid (TFA)/anisole to form SC153,
- contacting 14a with N—BOC-β-alanine in the presence of EDC/DMAP and then TFA/anisole to form SC154,
- contacting 14a with 2-indolecarboxylic acid, 5-indolecarboxylic acid, 6-indolecarboxylic acid, and 3-indolecarboxylic acid in the presence of EDC/DMAP to form SC155, SC156, SC157, and SC158, respectively,
- contacting 14a with Boc-3-amino-3-(2-chlorophenyl)propionic acid, Boc-3-amino-3-(4-chlorophenyl)propionic acid, Boc-3-amino-3-(4-fluorophenyl)propionic acid, Boc-3-amino-3-(4-cyanophenyl)propionic acid, Boc-3-amino-3-(4-methoxyphenyl)propionic acid, and Boc-3-amino-3-(4-trifluoromethylphenyl)propionic acid in the presence of EDC/DMAP followed by TFA and anisole to form SC160, SC161, SC162, SC163, SC164, and SC165, respectively,
- contacting 14a with 15a-g in the presence of EDC/DMAP followed by TFA and anisole to form SC166, SC167, SC168, SC169, SC170, SC171, and SC172, respectively,
- contacting 14a with 2-quinoxalinecarboxylic acid, dichloromethane, triphenylphosphine, and 2,2′-dipyridyl disulfide to form SC173, and contacting 14a with pyrrolo[1,2-α]quinoxaline-4-carboxylic acid, dichloromethane, triphenylphosphine, and 2,2′-dipyridyl disulfide to form SC174.
A method of preparing a compound, comprising contacting hydrazine monohydrate with a compound of formula X
- to form SC147.
A method of preparing a compound, comprising contacting 9-hydrazino-9H-pyrrolo[1,2-α]indole and pyridine with nicotinoyl chloride hydrochloride and pyrazine-2-carbonyl chloride, respectively, to form SC175 and SC176.
A method of treating a subject, comprising:
- identifying a subject suffering from or at risk for developing non-small cell lung cancer, CNS cancer, ovarian cancer, breast cancer, renal cancer, prostate cancer, age-related macular degeneration, macular dystrophy, or diabetes;
- and
- administering to the subject an effective amount of a compound of formula XI or XII,
- wherein Ar comprises an aromatic ring and Het comprises a heterocyclic ring.
A method of treating a subject, comprising:
- identifying a subject suffering from or at risk for developing cancer or a disorder associated angiogenesis function;
- and
- administering to the subject an effective amount of a compound of Formula II,
- wherein
- R is H, alkyl, or halogen;
- R′ is H, alkyl, or halogen;
- X is CH or N;
- and
- Y comprises a homocyclic or heterocyclic ring.
Dependencies are inferred from the claim text.