NOVEL CHEMOTHERAPEUTIC AGENTS AGAINST INFLAMMATION AND CANCER

• US 20100168228A1
• Filed: 10/12/2007
• Published: 07/01/2010
• Est. Priority Date: 10/13/2006
• Status: Abandoned Application

• Current Assignee: Reliance Life Sciences Pvt. Ltd.
• Original Assignee: Reliance Life Sciences Pvt. Ltd.
• Inventors: Gangan, Vijay, Bose, Julie Saha
• Application Number:
  US12/528,785
• Publication Number:
  US 20100168228A1
• Time in Patent Office: Days
• US Class Current: 514/469
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/621 having the hydroxy group in position 2 esterified, e.g. benorylate
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07C 69/734 Ethers
• CPC Class Codes: C07C 69/88 with esterified carboxyl groups
• CPC Class Codes: C07C 69/92 with etherified hydroxyl groups
• CPC Class Codes: C07D 307/86 with an oxygen atom directly attached in position 7

Abstract

Novel compounds, their methods of preparation and use in therapies related to cancer and inflammation are provided. Compounds comprise esters of cinnamic acid, vanillic acid and 4-hydroxy cinnamic acid and derivatives and salts thereof. Compounds with novel benzofuran lignan structure as a potent antimitotic agent and inducer of apoptosis are provided. Formulations and methods for treatment of diseases mediated by NF-kappaB are also provided.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I which is an ester derivative of cinnamic acid:

wherein R is selected from the group consisting of aryl and hetero-aryl, and derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof; and

a pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to 1 wherein R is selected from vannilic acid, ferulic acid, eugenol, salicylic acid and derivatives thereof in the compound of formula I.

3. A compound of formula I selected from the group consisting of:

Methyl 4-{[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}-3-methoxy benzoate (CAMVE;

Compound

     1);

2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl (2E)-3-(3,4 dihydroxy phenyl)acrylate (Compound

     2);

Methyl 2-{[(2E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy}benzoate (Compound

     3);

4-Allyl-2-methoxyphenyl (2E)-3-(3,4-dihydroxyphenyl)acrylate (Compound

     4);

(±

)-2β

-[4-O-(3,4,-dihydroxycinnamyl)-3-methoxyphenyl]-3α

-methyl-7-methoxy-5-[(E)-1-propenyl]-2,3-dihydrobenzofuran (Compound

     5);

Methyl(E)-3-[2β

-{4-O-[3,4-dihydroxycinnamyl)-3-methoxyphenyl}-7-methoxy-3α

-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]propen-2-enate (Compound

     6);

2-Methoxy-4-[(1E)-prop-1-en-1-yl]phenyl (2E)-3-(3,4-dihydroxyphenyl)acrylate (Compound

     7);

4-Formyl-2-methoxyphenyl (2E)-3-(3,4-dihydroxyphenyl)acrylate (Compound

     8); and

derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof.

4. The pharmaceutical composition according to 1 wherein the compound of formula I is selected from any one of compounds 1 through 8.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II which is an ester derivative of vanillic acid:

wherein R is selected from the group consisting of aryl and hetero-aryl, and derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof; and

a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to 4 wherein R is selected from vannilic acid, ferulic acid, eugenol, salicylic acid and derivatives thereof in the compound of formula II.

7. A compound of formula II selected from the group consisting of:

4-(Methoxycarbonyl)phenyl 4-hydroxy-3-methoxybenzoate (Compound

     9);

2-Methoxy-4-(methoxycarbonyl)phenyl 4-hydroxy-3-methoxybenzoate (Compound

     10);

2-Methoxy-4-[(1E)-3-methoxy-3-oxoprop-1en-1yl]phenyl 4hydroxy-3methoxy benzoate (Compound

     11);

Methyl(E)-3-[2β

-{4-O-(3-methoxy-4-hydroxyphenyl carbonyl)-3-methoxyphenyl}-7-methoxy-3α

-methoxycarbonyl-2,3-dihydro-1-benzofuran-5yl]prop-2-enoate (Compound

     12);

4-Allyl-2-methoxyphenyl 4-hydroxy-3-methoxybenzoate (Compound

     13);

2-Methoxy-4-[(1E)-prop-1en-1-yl]phenyl 4-hydroxy-3-methoxybenzoate (Compound

     14);

4-Formyl-2-methoxyphenyl 4-hydroxy-3-methoxybenozoate (Compound

     15);

(±

)-2β

-[4-O-(3-Hydroxy-4-methoxy)-3-methoxyphenyl]-3α

-methyl-7-methoxy-5-[(E)-1-propenyl]-2,3-dihydrobenzofuran (Compound

     16); and

derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof.

8. The pharmaceutical composition according to 4 wherein the compound of formula I is selected from any one of compounds 9 through 16.

9. A process for preparation of an ester derivative of formula I or II, the process comprising the steps of:

esterifying vanillic acid;

protecting all hydroxyl groups in the esterified vanillic acid as methoxymethyl (MOM) ether derivatives;

hydrolysis to generate a corresponding acid;

reacting the corresponding acid with a phenolic compound to generate a corresponding fused ester derivative; and

deprotecting of the hydroxyl groups using methanolic HCl to yield the ester derivative of formula II.

10. A compound obtained by the process of 9.

22. A compound according to any one of formula I, formula II, formula III or any one of compounds 1-29, or a compound according to 10, 16, or 20, wherein the compound modulates NF-kappaB activity or expression.

36. A method of treating a proliferative disease in an individual comprising administering to the individual:

a) a therapeutically effective amount of a composition comprising a compound according to 22, and

b) an effective amount of at least one other chemotherapeutic agent, wherein said chemotherapeutic agent is selected from the group consisting of antimetabolites, platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkloids, proteasome inhibitors, macrolides, and topoisomerase inhibitors.

37. A method of treating a tumor in an individual comprising:

a) a first therapy comprising administering to the individual a therapeutically effective amount of a composition comprising a compound according to 22, and

b) a second therapy comprising chemotherapy, radiation therapy, surgery, or combinations thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I which is an ester derivative of 4-hydroxy cinnamic acid:

wherein R is selected from the group consisting of aryl and hetero-aryl, and derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof; and

a pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to 11 wherein R is selected from vannilic acid, ferulic acid, eugenol, cinnamic acid, salicylic acid and derivatives thereof in the compound of formula III.

13. A compound of formula I selected from the group consisting of:

Methyl 4-{[(2E)-3-(4-hydroxyphenyl)prop-2-enoyl]oxy}-3-methoxybenzoate (Compound

     17);

2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl(2E)-3-(4-hydroxy phenyl)acrylate (Compound

     18);

4-Formyl-2-methoxyphenyl (2E)-3-(4-hydroxyphenyl)acrylate (Compound

     19);

2-Methoxyphenyl (2E)-3-(4-hydroxyphenyl)acrylate (Compound

     20);

4-Allyl-2-methoxyphenyl (2E)-3-(4-hydroxyophenyl)acrylate (Compound

     21);

Methyl [3,4-bis O-(4-hydroxyphenylacryloyl)]phenylacrylate (Compound

     22);

2-Methoxy-4-(1E)-prop-1en-1yl]phenyl (2e)-3-(4-hydroxyphenyl)acrylate (Compound

     23);

Methyl (E)-3-[2β

-{4-O-(4-hydroxycinnamoyl)-3-methoxyphenyl}-7-methoxy-3α

-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl-prop-2-enoate (Compound

     24); and

derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof.

14. The pharmaceutical composition according to 11 wherein the compound of formula I is selected from any one of compounds 17 through 24.

15. A process for preparation of an ester derivative of formula III, the process comprising the steps of:

esterifying 4-hydroxy cinnamic acid;

protecting all hydroxyl groups in the esterified 4-hydroxy cinnamic acid as methoxymethyl (MOM) ether derivatives;

hydrolysis to generate a corresponding acid;

reacting the corresponding acid with a phenolic compound to generate a corresponding fused ester derivative; and

deprotecting of the hydroxyl groups using methanolic HCl to yield the ester derivative of formula III.

16. A compound obtained by the process of 15.

17. A compound having a benzofuran lignan structure selected from the group consisting of:

(±

)-2β

-{4-O-(3-methoxy-4-hydroxy cinnamoyl)-3-methoxyphenyl]-3α

-methyl-7-methoxy-5-[(E)-1-propenyl]-2,3-dihydrobenzofuran (Compound

     25);

2-methoxy-4-(methoxycarbonyl)phenyl 3,4,5-trihydroxybenzoate (Compound

     26);

5-[(E)-2-carboxyvinyl]-2β

-(4-hydroxy-3-methoxyphenyl)-7-methoxy-2,3-dihydro-1-benzofuran-3α

-carboxylic acid (Compound

     27);

5-[(E)-2-carboxyvinyl]-7-hydroxy-2β

-(4-hydroxy-3-methoxy phenyl)-2,3-dihydro-1-benzofuran-3α

-carboxylic acid (Compound

     28);

(±

)-2β

-[4-O-(4-hydroxy cinnamoyl)-3-methoxyphenyl]-3α

-methyl-7-methoxy-5-[(E)-1-propenyl]-2,3-dihydrobenzofuran (Compound

     29), and

derivatives, polymorphs, isomers, prodrugs, geometric isomers, optical isomers, esters, ethers, carbamates, solvates, hydrates, and salts thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from any one of compounds 25 through 29.;

and

a pharmaceutically acceptable excipient.

19. A process for preparation of a compound comprising a benzofuran lignan structure, the process comprising the steps of:

reacting boron tribromide with Methyl (E)-3-[2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]prop-2-enoate in dichloromethane under appropriate conditions;

decomposing the reaction mixture with water;

washing an organic layer therefrom with saturated solution of sodium bicarbonate, water, and brine;

concentrating the organic layer by contacting with anhydrous sodium sulphate to yield a crude mass of a compound comprising a benzofuran lignan structure; and

optionally, purifying the crude mass by radial chromatography with increasing concentrations of ethyl acetate in petroleum ether.

20. A compound obtained by the process of 19.

21. A compound according to any one of 17 and 20 wherein the compound has an apoptotic, antimitotic, antitumor or antiproliferative activity.

23. A pharmaceutical formulation suitable for treating a disease or condition by modulating NF-kappaB activity comprising a therapeutically effective amount of a compound of 22;

and

a pharmaceutically effective excipient.

24. A pharmaceutical formulation comprising an effective amount of a compound of 22 sufficient to cause cell cycle arrest.

25. A pharmaceutical formulation suitable for treating a disease or condition associated with inflammation comprising a therapeutically effective amount of a compound of 22;

and

a pharmaceutically effective excipient.

26. A pharmaceutical formulation suitable for treating cancer comprising:

a therapeutically effective amount of a compound of 22; and

at least one anticancer drug selected from the group consisting of;

Acivicin®

;

Aclarubicin®

;

Acodazole Hydrochloride®

;

Acronine®

;

Adozelesin®

;

Aldesleukin®

;

Altretamine®

;

Ambomycin®

;

Ametantrone Acetate®

;

Aminoglutethimide®

;

Amsacrine®

;

Anastrozole®

;

Anthramycin®

;

Asparaginase®

;

Asperlin®

;

Azacitidine®

;

Azetepa®

;

Azotomycin®

;

Batimastat®

;

Benzodepa®

;

Bicalutamide®

;

Bisantrene Hydrochloride®

;

Bisnafide Dimesylate®

;

Bizelesin®

;

Bleomycin Sulfate®

;

Brequinar Sodium®

;

Bropirimine®

;

Busulfan®

;

Cactinomyde®

;

Calusterone®

;

Caracemide®

;

Carbetimer®

;

Carboplatin®

;

Carmustine®

;

Carubicin Hydrochloride®

;

Carzelesin®

;

Cedefingol®

;

Chlorambucil®

;

Cirolemycin®

;

Cisplatin®

;

Cladribine®

;

Crisnatol Mesylate®

;

Cyclophosphamide®

;

Cytarabine®

;

Dacarbazine®

;

Dactinomycin®

;

Daunorubicin Hydrochloride®

;

Decitabine®

;

Dexormaplatin®

;

Dezaguanine®

;

Dezaguanine Mesylate®

;

Diaziquone®

;

Docetaxel®

;

Doxorubicin®

;

Doxorubicin Hydrochloride®

;

Droloxifene®

;

Droloxifene Citrate®

;

Dromostanolone Propionate®

;

Duazomycin®

;

Edatrexate®

;

Eflornithine Hydrochloride®

;

Elsamitrucin®

;

Enloplatin®

;

Enpromate®

;

Epipropidine®

;

Epirubicin Hydrochloride®

;

Erbulozole®

;

Esorubicin Hydrochloride®

;

Estramustine®

;

Estramustine Phosphate Sodium®

;

Etanidazole®

;

Etoposide®

;

Etoposide Phosphate®

;

Etoprine®

;

Fadrozole Hydrochloride®

;

Fazarabine®

;

Fenretinide®

;

Floxuridine®

;

Fludarabine Phosphate®

;

Fluorouracil®

;

Fluorocitabine®

;

Fosquidone®

;

Fostriecin Sodium®

;

Gemcitabine®

;

Gemcitabine Hydrochloride®

;

Hydroxyurea®

;

Idarubicin Hydrochloride®

;

Ifosfamide®

;

Ilmofosine®

;

Interferon Alfa-2a®

;

Interferon Alfa-2b®

;

Interferon Alfa-n1®

;

Interferon Alfa-n3®

;

Interferon Beta-I a®

;

Interferon Gamma-I b®

;

Iproplatin®

;

Irinotecan Hydrochloride®

;

Lanreotide Acetate®

;

Letrozole®

;

Leuprolide Acetate®

;

Liarozole Hydrochloride®

;

Lometrexol Sodium®

;

Lomustine®

;

Losoxantrone Hydrochloride®

;

Masoprocol®

;

Maytansine®

;

Mechlorethamine Hydrochloride®

;

Megestrol Acetate®

;

Melengestrol Acetate®

;

Meiphalan®

;

Menogaril®

;

Mercaptopurine®

;

Methotrexate®

;

Methotrexate Sodium®

;

Metoprine®

;

Meturedepa®

;

Mitindomide®

;

Mitocarcin®

;

Mitocromin®

;

Mitomalcin®

;

Mitomycin®

;

Mitosper®

;

Mitotane®

;

Mitoxantrone Hydrochloride®

;

Mycophenolic Acid®

;

Nocodazole®

;

Nogalamycin®

;

Ormaplatin®

;

Oxisuran®

;

Paclitaxel®

;

Pegaspargase®

;

Peliomycin®

;

Pentamustine®

;

Peplomycin Sulfate®

;

Perfosfamide®

;

Pipobroman®

;

Piposulfan®

;

Piroxantrone Hydrochloride®

;

Plicamycin®

;

Plomestane®

;

Porfimer Sodium®

;

Porfiromycin®

;

Prednimustine®

;

Procarbazine Hydrochloride®

;

Puromycin®

;

Puromycin Hydrochloride®

;

Pyrazofurin®

;

Riboprine®

;

Rogletimide®

;

Safingol®

;

Safingol Hydrochloride®

;

Semustine®

;

Simtrazene®

;

Sparfosate Sodium®

;

Sparsomycin®

;

Spirogermanium Hydrochloride®

;

Spiromustine®

;

Spiroplatin®

;

Streptonigrin®

;

Streptozocin®

;

Sulofenur®

;

Talisomycin®

;

Taxol®

;

Taxotere®

;

Tecogalan Sodium®

;

Tegafur®

;

Teloxantrone Hydrochloride®

;

Temoporfin®

;

Teniposide®

;

Teroxirone®

;

Testolactone®

;

Thiamiprine®

;

Thioguanine®

;

Thiotepa®

;

Tiazofurin®

;

Tirapazamine®

;

Topotecan Hydrochloride®

;

Toremifene Citrate®

;

Trestolone Acetate®

;

Triciribine Phosphate®

;

Trimetrexate®

;

Trimetrexate Glucuronate®

;

Triptorelin®

;

Tubulozole Hydrochloride®

;

Uracil Mustard®

;

Uredepa®

;

Vapreotide®

;

Verteporfin®

;

Vinblastine Sulfate®

;

Vincristine Sulfate;

Vindesine®

;

Vindesine Sulfate®

;

Vinepidine Sulfate®

;

Vinglycinate Sulfate®

;

Vinleurosine Sulfate®

;

Vinorelbine Tartrate®

;

Vinrosidine Sulfate®

;

Vinzolidine Sulfate®

;

Vorozole®

;

Zeniplatin®

;

Zinostatin®

;

Zorubicin Hydrochloride®

, 20-epi-1,25 dihydroxyvitamin D3;

5-ethynyluracil;

abiraterone;

aclarubicin;

acylfulvene;

adecypenol;

adozelesin;

aldesleukin;

ALL-TK antagonists;

altretamine;

ambamustine;

amidox;

amifostine;

aminol evulinic acid;

amrubicin;

amsacrine;

anagrelide;

anastrozole; and

rographolide;

angiogenesis inhibitors;

antagonist D;

antagonist G;

antarelix;

anti-dorsalizing morphogenetic protein-1;

antiandrogen, prostatic carcinoma;

antiestrogen;

antineoplaston;

antisense oligonucleotides;

aphidicolin glycinate;

apoptosis gene modulators;

apoptosis regulators;

apurinic acid;

ara-CDP-DL-PTBA;

arginine deaminase;

asulacrine;

atamestane;

atrimustine;

axinastatin 1;

axinastatin 2;

axinastatin 3;

azasetron;

azatoxin;

aza osine;

baccatin III derivatives;

balanol;

batimastat;

BCR/ABL antagonists;

benzochlorins;

benzoylstaurosporine;

beta-lactam derivatives;

beta-alethine;

betaclamycin B;

betulinic acid;

bFGF inhibitor;

bicalutamide;

bisantrene;

bisaziridinylspermine;

bisnafide;

bistratene A;

bizelesin;

breflate;

bropirimine;

budotitane;

buthionine sulfoximine;

calcipotriol;

calphostin C;

camptothecin derivatives;

canarypox IL-2;

capecitabine;

carboxamide-amino-triazole;

carboxyamidotriazole;

CaRest M3;

CARN 700;

cartilage derived inhibitor;

carzelesin;

casein kinase inhibitors (ICOS);

castanospermine;

cecropin B;

cetrorelix;

chlorins;

chloroquinoxaline sulfonamide;

cicaprost;

cis-porphyrin;

cladribine;

clomifene analogues;

clotrimazole;

collismycin A;

collismycin B;

combretastatin A4;

combretastatin analogue;

conagenin;

crambescidin 816;

crisnatol;

cryptophycin 8;

cryptophycin A derivatives;

curacin A;

cyclopentanthraquinones;

cycloplatam;

cypemycin;

cytarabine ocfosfate;

cytolytic factor;

cytostatin;

dacliximab;

decitabine;

dehydrodidemnin B;

deslorelin;

dexifosfamide;

dexrazoxane;

dexverapamil;

diaziquone;

didemnin B;

didox;

diethylnorspermine;

dihydro-5-azacytidine;

dihydrotaxol, 9-;

dioxamycin;

diphenyl spiromustine;

docosanol;

dolasetron;

doxifluridine;

droloxifene;

dronabinol;

duocarmycin SA;

ebselen;

ecomustine;

edelfosine;

edrecolomab;

eflomithine;

elemene;

emitefur;

epirubicin;

epristeride;

estramustine analogue;

estrogen agonists;

estrogen antagonists;

etanidazole;

etoposide phosphate;

exemestane;

fadrozole;

fazarabine;

fenretinide;

filgrastim;

finasteride;

flavopiridol;

flezelastine;

fluasterone;

fludarabine;

fluorodaunorunicin hydrochloride;

forfenimex;

formestane;

fostriecin;

fotemustine;

gadolinium texaphyrin;

gallium nitrate;

galocitabine;

ganirelix;

gelatinase inhibitors;

gemcitabine;

glutathione inhibitors;

hepsulfam;

heregulin;

hexamethylene bisacetamide;

hypericin;

ibandronic acid;

idarubicin;

idoxifene;

idramantone;

ilmofosine;

ilomastat;

imidazoacridones;

imiquimod;

immunostimulant peptides;

insulin-like growth factor-I receptor inhibitor;

interferon agonists;

interferons;

interleukins;

iobenguane;

iododoxorubicin;

ipomeanol, 4-;

irinotecan;

iroplact;

irsogladine;

isobengazole;

isohomohalicondrin B;

itasetron;

jasplakinolide;

kahalalide F;

lamellarin-N triacetate;

lanreotide;

leinamycin;

lenograstim;

lentinan sulfate;

leptolstatin;

letrozole;

leukemia inhibiting factor;

leukocyte alpha interferon;

leuprolide+estrogen+progesterone;

leuprorelin;

levamisole;

liarozole;

linear polyamine analogue;

lipophilic disaccharide peptide;

lipophilic platinum compounds;

lissoclinamide 7;

lobaplatin;

lombricine;

lometrexol;

lonidamine;

losoxantrone;

lovastatin;

loxoribine;

lurtotecan;

lutetium texaphyrin;

lysofylline;

lytic peptides;

maitansine;

mannostatin A;

marimastat;

masoprocol;

maspin;

matrilysin inhibitors;

matrix metalloproteinase inhibitors;

menogaril;

merbarone;

meterelin;

methioninase;

metoclopramide;

MIF inhibitor;

mifepristone;

miltefosine;

mirimostim;

mismatched double stranded RNA;

mitoguazone;

mitolactol;

mitomycin analogues;

mitonafide;

mitotoxin fibroblast growth factor-saporin;

mitoxantrone;

mofarotene;

molgramostim;

monoclonal antibody, human chorionic gonadotrophin;

monophosphoryl lipid A+myobacterium cell wall sk;

mopidamol;

multiple drug resistance gene inhibitor;

multiple tumor suppressor 1-based therapy;

mustard anti cancer compound;

mycaperoxide B;

mycobacterial cell wall extract;

myriaporone;

N-acetyldinaline;

N-substituted benzamides;

nafarelin;

nagrestip;

naloxone+pentazocine;

napavin;

naphterpin;

nartograstim;

nedaplatin;

nemorubicin;

neridronic acid;

neutral endopeptidase;

nilutamide;

nisamycin;

nitric oxide modulators;

nitroxide antioxidant;

nitrullyn;

O₆-benzylguanine;

octreotide;

okicenone;

oligonucleotides;

onapristone;

ondansetron;

ondansetron;

oracin;

oral cytokine inducer;

ormaplatin;

osaterone;

oxaliplatin;

oxaunomycin;

paclitaxel analogues;

paclitaxel derivatives;

palauamine;

palmitoylrhizoxin;

pamidronic acid;

panaxytriol;

panomifene;

parabactin;

pazelliptine;

pegaspargase;

peldesine;

pentosan polysulfate sodium;

pentostatin;

pentrozole;

perflubron;

perfosfamide;

perillyl alcohol;

phenazinomycin;

phenylacetate;

phosphatase inhibitors;

picibanil;

pilocarpine hydrochloride;

pirarubicin;

piritrexim;

placetin A;

placetin B;

plasminogen activator inhibitor;

platinum complex;

platinum compounds;

platinum-triamine complex;

porfimer sodium;

porfiromycin;

propyl bis-acridone;

prostaglandin J2;

proteasome inhibitors;

protein A-based immune modulator;

protein kinase C inhibitor;

protein kinase C inhibitors, microalgal;

protein tyrosine phosphatase inhibitors;

purine nucleoside phosphorylase inhibitors;

purpurins;

pyrazoloacridine;

pyridoxylated hemoglobin polyoxyethylene conjugate;

raf antagonists;

raltitrexed;

ramosetron;

ras farnesyl protein transferase inhibitors;

ras inhibitors;

ras-GAP inhibitor;

retelliptine demethylated;

rhenium Re 186 etidronate;

rhizoxin;

ribozymes;

RII retinamide;

rogletimide;

rohitukine;

romurtide;

roquinimex;

rubiginone B1;

ruboxyl;

safingol;

saintopin;

SarCNU;

sarcophytol A;

sargramostim;

Sdi 1 mimetics;

semustine;

senescence derived inhibitor 1;

sense oligonucleotides;

signal transduction inhibitors;

signal transduction modulators;

single chain antigen binding protein;

sizofuran;

sobuzoxane;

sodium borocaptate;

sodium phenylacetate;

solverol;

somatomedin binding protein;

sonermin;

sparfosic acid;

spicamycin D;

spiromustine;

splenopentin;

spongistatin 1;

squalamine;

stem cell inhibitor;

stem-cell division inhibitors;

stipiamide;

stromelysin inhibitors;

sulfinosine;

superactive vasoactive intestinal peptide antagonist;

suradista;

suramin;

swainsonine;

synthetic glycosaminoglycans;

tallimustine;

tamoxifen methiodide;

tauromustine;

tazarotene;

tecogalan sodium;

tegafur;

tellurapyrylium;

telomerase inhibitors;

temoporfin;

temozolomide;

teniposide;

tetrachlorodecaoxide;

tetrazomine;

thaliblastine;

thalidomide;

thiocoraline;

thrombopoietin;

thrombopoietin mimetic;

thymalfasin;

thymopoietin receptor agonist;

thymotrinan;

thyroid stimulating hormone;

tin ethyl etiopurpurin;

tirapazamine;

titanocene dichloride;

topotecan;

topsentin;

toremifene;

totipotent stem cell factor;

translation inhibitors;

tretinoin;

triacetyluridine;

triciribine;

trimetrexate;

triptorelin;

tropisetron;

turosteride;

tyrosine kinase inhibitors;

tyrphostins;

UBC inhibitors;

ubenimex;

urogenital sinus-derived growth inhibitory factor;

urokinase receptor antagonists;

vapreotide;

variolin B;

vector system, erythrocyte gene therapy;

velaresol;

veramine;

verdins;

verteporfin;

vinorelbine;

vinxaltine;

vitaxin;

vorozole;

zanoterone;

zeniplatin;

zilascorb;

zinostatin stimalamer, antimetabolites, platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkloids, proteasome inhibitors, macrolides, and topoisomerase inhibitors.

27. A pharmaceutical formulation according to any one of 23 to 26 further comprising at least one more therapeutically effective compound.

28. A pharmaceutical formulation according to any one of 23 to 27, wherein the formulation is suitable for administration by oral, parenteral, enteral, intraperitoneal, topical, transdermal, ophthalmic, nasally, local, non-oral, aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, or intrathecal route.

29. A sealed vial comprising an unit dosage of a pharmaceutical formulation according to any one of 23 to 27.

30. The sealed vial according to 29 comprising a sub-therapeutic dosage of a pharmaceutical formulation according to any one of 23 to 27 for use in metronomic administration.

31. Use of a compound according to 22 for preparing a medicament for treatment of an NF-kappaB related disease or condition.

32. The use of 31 wherein the disease or condition is cancer or inflammation.

33. The use of 32 wherein the cancer is selected from the group consisting of breast, ovary, testicle, prostate, head, neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach, kidney, liver, pancreas, brain, intestine, heart, adrenal cancer and neoplastic disease.

34. A method for treating an inflammatory disease, the method comprising administering a pharmaceutical composition according to any one of 23 and 27 to a patient in need thereof.

35. A method for treating cancer, the method comprising administering a pharmaceutical composition according to any one of 24 through 27 to a patient in need thereof.

38. The compounds as per formula I, II, III and its compositions and use as per preceding claims substantially described herein exemplified herein substantially in the examples and figures.