HYDROXYLAMINES AND DERIVATIVES AS ANTI-ANGIOGENIC AGENTS
The present disclosure provides compounds that include hydroxylamines and ester derivatives thereof and methods for using the same for the treatment of angiogenesis and related diseases.
1 . A method of inhibiting angiogenesis in a patient, comprising:
administering to the patient a hydroxylamine compound or an ester derivative thereof, wherein the ester derivative comprises formula I, in a therapeutically sufficient amount to inhibit the angiogenesis;
wherein formula I is:
wherein R 1 and R 2 are, independently, H or C 1 to C 3 alkyl;
R 3 and R 4 are, independently, C 1 to C 3 alkyl;
R 5 is H, OH, or C 1 to C 6 alkyl;
R 6 is or C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R 7 is C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
wherein R 1 and R 2 , taken together, or R 3 and R 4 , taken together, or both are cycloalkyl;
wherein R 6 and R 7 , or R 5 , R 6 and R 7 , taken together, form a carbocycle or heterocycle comprising a 3 to 7 membered ring.
2 . The method of claim 1 , wherein the hydroxylamine compound is:
3 . The method of claim 1 , wherein the hydroxylamine compound is:
4 . The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are a C 1 -C 3 alkyl.
5 . The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are ethyl.
6 . The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are methyl.
7 . The method of claim 6 wherein:
R 5 is H or methyl;
R 6 is methyl substituted with benzyloxy or C 1 -C 6 alkoxy; and
R 7 is methyl.
8 . The method of claim 6 wherein:
R 5 is H or methyl; and
R 6 and R 7 , taken together, is a cyclopropyl group.
9 . The method of claim 6 wherein:
R 5 , R 6 and R 7 , taken together, is a furanyl group.
10 . The method of claim 6 wherein:
R 5 is H; and
R 6 and R 7 , taken together, is a tetrahydrofuranyl group.
11 . The method of claim 6 wherein:
R 5 is H; and
R 6 and R 7 , taken together, is a cyclopropyl group.
12 . The method of claim 1 , wherein the patient is a mammal.
13 . The method of claim 1 , wherein the patient is a human.
14 . The method of claim 1 , further comprising administering one or both of an antioxidant or a reducing agent.
15 . The method of claim 1 , further comprising administering an anti-neoplastic agent.
16 . The method of claim 1 , further comprising administering an additional anti-angiogenic agent.
17 . The method of claim 16 , wherein the anti-angiogenic agent is an anti-oxidant, VEGF antagonist, bFGF antagonist, NOS antagonist, or a combination thereof.
18 . A method of treating a patient having a disease state that involves angiogenesis, comprising:
administering to the patient a hydroxylamine compound or a derivative thereof having formula I in a therapeutically sufficient amount to inhibit pathological angiogenesis;
wherein formula I is:
wherein R 1 and R 2 are, independently, H or C 1 to C 3 alkyl;
R 3 and R 4 are, independently, C 1 to C 3 alkyl;
R 5 is H, OH, or C 1 to C 6 alkyl;
R 6 is or C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R 7 is C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
wherein R 1 and R 2 , taken together, or R 3 and R 4 , taken together, or both are cycloalkyl;
wherein R 6 and R 7 , or R 5 , R 6 and R 7 , taken together, form a carbocycle or heterocycle comprising a 3 to 7 membered ring.
19 . The method of claim 18 , wherein the hydroxylamine compound is:
20 . The method of claim 18 , wherein the hydroxylamine compound is:
21 . The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are a C 1 -C 3 alkyl.
22 . The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are ethyl.
23 . The method of claim 1 wherein R 1 , R 2 , R 3 , and R 4 are methyl.
24 . The method of claim 23 wherein:
R 5 is H or methyl;
R 6 is methyl substituted with benzyloxy or C 1 -C 6 alkoxy; and
R 7 is methyl.
25 . The method of claim 23 wherein:
R 5 is H or methyl; and
R 6 and R 7 , taken together, is a cyclopropyl group.
26 . The method of claim 23 wherein:
R 5 , R 6 and R 7 , taken together, is a furanyl group.
27 . The method of claim 23 wherein:
R 5 is H; and
R 6 and R 7 , taken together, is a tetrahydrofuranyl group.
28 . The method of claim 23 wherein:
R 5 is H; and
R 6 and R 7 , taken together, is a cyclopropyl group.
29 . The method of claim 18 , wherein the patient is a mammal.
30 . The method of claim 18 , wherein the patient is a human.
31 . The method of claim 18 , wherein the disease state is characterized by neoplasm.
32 . The method of claim 31 , wherein the disease state is a cancer.
33 . The method of claim 32 , wherein the disease state is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, acoustic neuroma, neurofibroma, trachoma, or pyogenic granulomas.
34 . The method of claim 18 , further comprising administering an antioxidant or a reducing agent.
35 . The method of claim 31 , further comprising administering an anti-neoplastic agent.
36 . The method of claim 18 , further comprising administering an additional anti-angiogenic agent.
37 . The method of claim 36 , wherein the additional anti-angiogenic agent is an anti-oxidant, VEGF antagonist, bFGF antagonist, NOS antagonist, or a combination thereof.