US2010144671A1PendingUtilityA1
Compositions and Methods for Cancer Treatment
Assignee: WOMEN AND INFANTS HOSPITAL OFPriority: Mar 4, 2005Filed: Mar 3, 2006Published: Jun 10, 2010
Est. expiryMar 4, 2025(expired)· nominal 20-yr term from priority
A61P 35/02A61K 31/59A61P 35/00
48
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Claims
Abstract
Bromoacetoxycalcidiol (B3CD), which is structurally related to calcidiol, exhibits cytotoxic and apoptotic activity toward cancer cells, including highly aggressive neuroblastoma cells. A series of small molecules designed around the structure of B3CD is expected to have growth inhibitory and apoptogenic activities toward a wide range of malignancies. B3CD shows no apparent toxicity in vivo, indicating potential value as a chemotherapeutic agent which will be particularly useful in treating highly aggressive tumors.
Claims
exact text as granted — not AI-modified1 . A method for inhibiting cancer cell proliferation, comprising administering to said cell an amount of a calcidiol derivative effective to inhibit proliferation of the cancer cell.
2 . The method of claim 1 wherein the cancer cell is selected from the group consisting of colon, breast, lung, prostate, melanoma, renal, ovarian, bladder, pancreatic, hepatocarcinoma, neuroblastoma, glioblastoma, medulloblastoma, skin, squamous cell carcinoma, acute promyelocytic leukemia, myeloblastic and myelomonocytic cells.
3 . The method of claim 1 wherein the cancer cell is a neuroblastoma cell.
4 . The method of claim 3 wherein the neuroblastoma cell is selected from the group consisting of SK-N-SH, SH-SY5Y, SMS-KCN and SMS-KCNR.
5 . The method of claim 1 wherein the cancer cell is a prostate cancer cell.
6 . The method of claim 1 wherein the cancer cell is comprised within a mammal.
7 . The method of claim 6 wherein the mammal is human.
8 . A method of inducing apoptosis in a cancer cell, comprising administering an amount of a calcidiol derivative to a cell effective to induce apoptosis in said cell.
9 . The method of claim 8 , wherein the calcidiol derivative is bromoacetoxycalcidiol (B3CD).
10 . A method for treating neuroblastoma or prostate cancer, comprising administering to a mammal in need thereof, an effective amount of a calcidiol derivative in a pharmaceutically acceptable vehicle.
11 . The method of claim 10 , wherein the calcidiol derivative is bromoacetoxycalcidiol (B3CD) in a pharmaceutically acceptable vehicle.
12 . A method for inhibiting TrkB signaling comprising administering to a mammal exhibiting neuroblastoma or prostate cancer an amount of a calcidiol derivative in a pharmaceutically acceptable vehicle effective to suppress BDNF and inhibit angiogenesis.
13 . The method claim 12 , wherein the calcidiol derivative is bromoacetoxycalcidiol (B3CD) in a pharmaceutically acceptable vehicle effective to suppress BDNF and inhibit angiogenesis.
14 . A method for treating or preventing a disorder associated with uncontrolled cell proliferation, the method comprising administering to a subject in need thereof a composition comprising an effective amount of a calcidiol derivative.
15 . The method of claim 14 , wherein the calcidiol derivative is bromoacetoxycalcidiol (B3CD).
16 . The method according to claim 15 wherein the disorder is selected from the group consisting of neuroblastoma, prostate cancer, lymphoma and leukemias.
17 . The method of claim 15 further comprising administering a second therapeutic agent.
18 . The method of claim 17 wherein the second therapeutic agent is selected from analgesics, anti-inflammatory agents and antibiotics.
19 . The method of claim 1 , wherein the calcidiol derivative is a compound of formula I:
wherein:
A 1 is single or double bond;
A 2 is a single, double or triple bond;
X 1 and X 2 are each independently H 2 or CH 2 , provided X 1 and X 2 are not both ═CH 2 ;
and X 1 can be substituted with CH 2 OR 11
wherein R 11 is C(O)alkyl, C(O)aryl, or C(O)aralkyl;
R 1 is H, OH, or OSi(R 10 ) 3 ;
wherein R 10 is alkyl, aryl, alkenyl, or aralkyl;
R 2 is O(CH 2 ) n R 12 ;
wherein R 12 is halogen, haloalkyl, amino, alkyl amino, thiol, alkyl thio, hydroxyl, alkoxy, or alkenyl;
n is an integer from 1-6;
and any of the CH 2 groups may be replaced by CO;
R 3 and R 4 independently H, C 1 -C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl;
R 5 is H, C 1 -C 4 alkyl, hydroxyalkyl, haloalkyl, or carbonyl;
R 6 and R 7 are each independently alkyl or haloalkyl;
R 8 is H or biotin;
R 9 is H, hydroxyl, or halogen; and
pharmaceutically acceptable esters, salts, solvates, clathrates, stereoisomers, enantiomers prodrugs thereof.
20 . The method of claim 19 , wherein the calcidiol derivative is a compound of formula II
wherein X is F, Cl, Br, I, N 3 , N 2 , NH 2 , CN, S—CH 3 , or —N═C═S;
R is
or a pharmaceutically acceptable salt, solvate, clathrate, stereoismoer, enantiomer or prodrug thereof.
21 . The method of claim 20 , wherein the calcidiol derivative is bromoacetoxycalcidiol (B3CD):
or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomer, enantiomer, or prodrug thereof.
22 . The method of claim 19 , wherein the calcidiol derivative is selected from the group consisting of
Bromoacetoxycalcidiol (B3CD) Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
25-Biotin-Bromoacetoxycalcidiol
6-(2,4-Dinitro-phenylamino)-hexanoic acid 2- (4-(2-bromo-acetoxy)-2-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-cyclohexylidene)-ethyl ester
Bromo-acetic acid 3-hydroxy-5-{2-[1-(5- hydroxy-1,5-dimethyl-hexyl)-7a-methyl- octahydro-inden-4-ylidene]-ethylidene}-4- methylene-cyclohexyl ester
Bromo-acetic acid 3-(tert-butyl-dimethyl- silanyloxy)-5-{2-[1-(5-hydroxy-1,5-dimethyl- hexyl)-7a-methyl-octahydro-inden-4-ylidene]- ethylidene}-4-methylene-cyclohexyl ester
Trifluoro-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
4-Bromo-butyric acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
4-Cyano-butyric acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
Acrylic acid 3-{2-[1-(5-hydroxy-1,5-dimethyl- hexyl)-7a-methyl-octahydro-inden-4-ylidene]- ethylidene}-4-methylene-cyclohexyl ester
6-{4-[2-(5-Bromomethoxymethoxy-2- methylene-cyclohexylidene)-ethylidene]-7a- methyl-octahydro-inden-1-yl}-2-methyl-heptan- 2-ol
6-{4-[2-(5-Aminomethoxymethoxy-2- methylene-cyclohexylidene)-ethylidene]-7a- methyl-octahydro-inden-1-yl}-2-methyl-heptan- 2-ol
6-{4-[2-(5-Bromomethoxy-2-methylene- cyclohexylidene)-ethylidene]-7a-methyl- octahydro-inden-1-yl}-2-methyl-heptan-2-ol
2-Methyl-6-{7a-methyl-4-[2-(2-methylene-5- ethylsulfanylmethoxy-cyclohexylidene)- ethylidene]-octahydro-inden-1-yl}-heptan-2-ol
Bromo-acetic acid 3-(2-{1-[2-(2-hydroxy-2- methyl-propoxy)-1-methyl-ethyl]-7a-methyl- octahydro-inden-4-ylidene}-ethylidene)-4- methylene-cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hex-3-ynyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-4-oxo-hexyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-ethyl-5-hydroxy- 1-methyl-hept-3-ynyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(3,5-dihydroxy-1,5- dimethyl-4-oxo-hexyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hex-3-ynyl)-7a-methyl-3,3a,5,6,7,7a- hexahydro-inden-4-ylidene]-ethylidene}-4- methylene-cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-ethyl-5-hydroxy- 1-methyl-4-oxo-heptyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-(2-{1-[1-(4-hydroxy-4- methyl-3-oxo-pentyl)-cyclopropyl]-7a-methyl- octahydro-inden-4-ylidene}-ethylidene)-4- methylene-cyclohexyl ester
Bromo-acetic acid 4-methylene-3-{2-[7a- methyl-1-(6,6,6-trifluoro-5-hydroxy-1-methyl- 5-trifluoromethyl-hexyl)-octahydro-inden-4- ylidene]-ethylidene}-cyclohexyl ester
3-(4-{2-[5-(2-Bromo-acetoxy)-2-methylene- cyclohexylidene]-ethylidene}-7a-methyl- octahydro-inden-1-yl)-butyric acid
23 . The method of claim 1 further comprising obtaining the calcidiol derivative.
24 . A novel calcidiol derivative of formula I:
wherein:
A 1 is single or double bond;
A 2 is a single, double or triple bond;
X 1 and X 2 are each independently H 2 or CH 2 , provided X 1 and X 2 are not both ═CH 2 ;
and X 1 can be substituted with CH 2 OR 11
wherein R 11 is C(O)alkyl, C(O)aryl, or C(O)aralkyl;
R 1 is H, OH, or OSi(R 10 ) 3 ;
Wherein R 10 is alkyl, aryl, alkenyl, or aralkyl;
R 2 is O(CH 2 ) n R 12 ;
Wherein R 12 is halogen, haloalkyl, amino, alkyl amino, thiol, alkyl thio, hydroxyl, alkoxy, or alkenyl;
n is an integer from 1-6;
and any of the CH 2 groups may be replaced by CO;
R 3 and R 4 independently H, C 1 -C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl;
R 5 is H, C 1 -C 4 alkyl, hydroxyalkyl, haloalkyl, or carbonyl;
R 6 and R 7 are each independently alkyl or haloalkyl;
R 8 is H or biotin;
R 9 is H, hydroxyl, or halogen; and
pharmaceutically acceptable esters, salts, solvates, clathrates, stereoisomers, enantiomers prodrugs thereof.
25 . The novel calcidiol derivative of claim 24 having formula II
wherein X is F, Cl, Br, I, N 3 , N 2 , NH 2 , CN, S—CH 3 , or N═C═S;
R is
or a pharmaceutically acceptable salt, solvate, clathrate, stereoismoer, enantiomer or prodrug thereof.
26 . The novel calcidiol derivative of claim 24 , which is bromoacetoxycalcidiol (B3CD)(bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-4-ylidene]-ethylidene}-4-methylene-cyclohexyl ester):
or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomer, enantiomer, or prodrug thereof.
27 . The novel calcidiol derivative of claim 24 , which is selected from the group consisting of:
Bromoacetoxycalcidiol (B3CD) Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
25-Biotin-Bromoacetoxycalcidiol
6-(2,4-Dinitro-phenylamino)-hexanoic acid 2- (4-(2-bromo-acetoxy)-2-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-cyclohexylidene)-ethyl ester
Bromo-acetic acid 3-hydroxy-5-{2-[1-(5- hydroxy-1,5-dimethyl-hexyl)-7a-methyl- octahydro-inden-4-ylidene]-ethylidene}-4- methylene-cyclohexyl ester
Bromo-acetic acid 3-(tert-butyl-dimethyl- silanyloxy)-5-{2-[1-(5-hydroxy-1,5-dimethyl- hexyl)-7a-methyl-octahydro-inden-4-ylidene]- ethylidene}-4-methylene-cyclohexyl ester
Trifluoro-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
4-Bromo-butyric acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
4-Cyano-butyric acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hexyl)-7a-methyl-octahydro-inden-4- ylidene]-ethylidene}-4-methylene-cyclohexyl ester
Acrylic acid 3-{2-[1-(5-hydroxy-1,5-dimethyl- hexyl)-7a-methyl-octahydro-inden-4-ylidene]- ethylidene}-4-methylene-cyclohexyl ester
6-{4-[2-(5-Bromomethoxymethoxy-2- methylene-cyclohexylidene)-ethylidene]-7a- methyl-octahydro-inden-1-yl}-2-methyl-heptan- 2-ol
6-{4-[2-(5-Aminomethoxymethoxy-2- methylene-cyclohexylidene)-ethylidene]-7a- methyl-octahydro-inden-1-yl}-2-methyl-heptan- 2-ol
6-{4-[2-(5-Bromomethoxy-2-methylene- cyclohexylidene)-ethylidene]-7a-methyl- octahydro-inden-1-yl}-2-methyl-heptan-2-ol
2-Methyl-6-{7a-methyl-4-[2-(2-methylene-5- ethylsulfanylmethoxy-cyclohexylidene)- ethylidene]-octahydro-inden-1-yl}-heptan-2-ol
Bromo-acetic acid 3-(2-{1-[2-(2-hydroxy-2- methyl-propoxy)-1-methyl-ethyl]-7a-methyl- octahydro-inden-4-ylidene}-ethylidene)-4- methylene-cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hex-3-ynyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-4-oxo-hexyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-ethyl-5-hydroxy- 1-methyl-hept-3-ynyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(3,5-dihydroxy-1,5- dimethyl-4-oxo-hexyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-hydroxy-1,5- dimethyl-hex-3-ynyl)-7a-methyl-3,3a,5,6,7,7a- hexahydro-inden-4-ylidene]-ethylidene}-4- methylene-cyclohexyl ester
Bromo-acetic acid 3-{2-[1-(5-ethyl-5-hydroxy- 1-methyl-4-oxo-heptyl)-7a-methyl-octahydro- inden-4-ylidene]-ethylidene}-4-methylene- cyclohexyl ester
Bromo-acetic acid 3-(2-{1-[1-(4-hydroxy-4- methyl-3-oxo-pentyl)-cyclopropyl]-7a-methyl- octahydro-inden-4-ylidene}-ethylidene)-4- methylene-cyclohexyl ester
Bromo-acetic acid 4-methylene-3-{2-[7a- methyl-1-(6,6,6-trifluoro-5-hydroxy-1-methyl- 5-trifluoromethyl-hexyl)-octahydro-inden-4- ylidene]-ethylidene}-cyclohexyl ester
3-(4-{2-[5-(2-Bromo-acetoxy)-2-methylene- cyclohexylidene]-ethylidene}-7a-methyl- octahydro-inden-1-yl)-butyric acid
28 . A pharmaceutical composition comprising the calcidiol derivative of claim 24 and a pharmaceutically acceptable carrier.
29 . The pharmaceutical composition claim 28 further comprising a biologically active agent selected from the group consisting of an immunosuppressant, analgesic and antibiotic.
30 . The pharmaceutical composition of claim 29 , wherein the calcidiol derivative is bromoacetoxycalcidiol (B3CD).
31 . The pharmaceutical composition of claim 28 comprising a tablet, troche or liquid.
32 . The composition of claim 28 comprising an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomer, enantiomer, or prodrug thereof.
33 . A packaged formulation for use in inhibiting cancer cell proliferation comprising the pharmaceutical composition of claim 28 and instructions for use in accordance with the method of claim 1 .Join the waitlist — get patent alerts
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