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BARDOXOLONE METHYL

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Bardoxolone methyl.svgImage result for Bardoxolone MethylImage result for Bardoxolone Methyl2D chemical structure of 218600-53-4

BARDOXOLONE METHYL

  • Molecular FormulaC32H43NO4
  • Average mass505.688 Da

Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate

methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate

2-Cyano-3,12-dioxoolean-1,9(11)-dien-28-oic acid methyl ester
(6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-carboxylic acid methyl ester

BARD
CDDO-Me
Methyl-CDDO
NSC-713200
RTA-402
TP-155C

218600-53-4  CAS

218600-44-3 (free acid)

(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-methyl 11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carboxylate
(4aS,6aR,6bS,8aR,12aS,14bS)-Methyl 11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-4a-carboxylate
2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid, methyl ester
2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester
606-850-4 [EINECS]
Methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate [ACD/IUPAC Name]
Oleana-1,9(11)-dien-28-oic acid, 2-cyano-3,12-dioxo-, methyl ester
Innovator – Reata Pharmaceuticals in collaboration with Abbott

Treatment of pulmonary arterial hypertension (PAH), diabetic nephropathies and hereditary nephritis, Phase 3

str1

Compounds were synthesized as below:

Figure imgf000017_0001

Scheme 1

Figure imgf000017_0002

Scheme 2

a: HCO2Et/MeONa/THF,b: PhSeCl/AcOEt; 30%H202/THF,c: NH2OH-HCI EtOH/H2O, d: MeONa/MeOH/Et2O,e: KOH/MeOH,f: Jones,g:HCO2Et/MeONa/PhH,h: Lil/DMF Compound 10 was prepared by formylation of OA (Compound 9) (Simonsen and Ross, 1957) with ethyl formate in the presence of sodium methoxide in THF (Clinton et al., 1961). Compound 7 was obtained by introduction of a double bond at C-l of Compound 10 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30%) hydrogen peroxide (Sharpless et al, 1973). Compound 11 was synthesized from Compound 10 by addition of hydroxylamine in aqueous ethanol; cleavage of Compound 11 with sodium methoxide gave Compound 12 (Johnson and Shelberg, 1945). Compound 14 was prepared from Compound 13 (Picard et al, 1939) by alkali hydrolysis followed by Jones oxidation. Compound 15 was prepared by formylation of Compound 14 with ethyl formate in the presence of sodium methoxide in benzene. Compound 16 was synthesized from Compound 15 by addition of hydroxylamine. Cleavage of 16 with sodium methoxide gave Compound 17. Compound 6 (CDDO) was prepared by introduction of a double bond at C-l of Compound 17 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30% hydrogen peroxide, followed by halogenolysis with lithium iodide in DMF (Dean, P.D.G., 1965).

A synthetic triterpenoid compound with potential antineoplastic and anti-inflammatory activities. Bardoxolone blocks the synthesis of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2), two enzymes involved in inflammation and carcinogenesis. This agent also inhibits the interleukin-1 (IL-1)-induced expression of the pro-inflammatory proteins matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13) and the expression of Bcl-3; Bcl-3 is an IL-1-responsive gene that preferentially contributes to MMP-1 gene expression. /Bardoxolone/ (NCI Thesaurus)

Bardoxolone methyl (also known as “RTA 402” and “CDDO-methyl ester”) is an orally-available first-in-class synthetic triterpenoid. It is an inducer of the Nrf2 pathway, which can suppress oxidative stress and inflammation, and is undergoing clinical development for the treatment of advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients.

Bardoxolone methyl was previously being investigated by Reata Pharmaceuticals, Inc. in partnership with Abbott Laboratories and Kyowa Hakko Kirin, as an experimental therapy for advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients. Reata, in consultation with the BEACON Steering Committee, has decided to terminate the Phase 3 BEACON trial of bardoxolone methyl in patients with stage 4 chronic kidney disease and type 2 diabetes. This decision was made based upon a recommendation of the Independent Data Monitoring Committee (IDMC) to stop the trial “for safety concerns due to excess serious adverse events and mortality in the bardoxolone methyl arm.” [1][2][3][4]

RTA-402 is a triterpenoid anti-inflammatory agent in phase II trials at Reata Pharmaceuticals for the treatment of pulmonary arterial hypertension.

This company and M.D. Anderson Cancer Center had been evaluating clinically the product for the treatment of lymphoma. Reata had been evaluating the compound in combination with gemcitabine in patients with unresectable pancreatic cancer and melanoma. Preclinical studies were also being conducted by Reata for the treatment of inflammatory bowel disease (IBD) and autoimmune disease. Reata Pharmaceuticals and Kyowa Hakko Kirin had been conducting phase II clinical studies for the treatment of diabetic nephropathy. Reata and Abbott also had been conducting phase III clinical trials for delaying progression to end-stage renal disease in patients with chronic kidney disease and type 2 diabetes; however, in 2012 these trials were discontinued due to serious adverse events and mortality. Phase II clinical trials for this indication were discontinued by Kyowa Hakko Kirin in Japan. The compound had been in early clinical studies for the treatment of multiple myeloma; however, no recent development has been reported for this indication. Phase I clinical trials for the treatment of solid tumors have been completed.

RTA-402 has demonstrated a wide variety of potentially therapeutic mechanisms, including inhibition of inducible nitric oxide synthase and cyclooxygenase expression, stimulation of expression of cytoprotective enzymes such as NAD(P)H quinine oxidoreductase and hemeoxygenase-1, and reduction in pSTAT3 levels. In cancer patients, the drug candidate exploits fundamental physiological differences between cancerous and non-cancerous cells by modulating oxidative stress response pathways. Due to this mechanism, RTA-402 is toxic to cancer cells, but induces protective antioxidant and anti-inflammatory responses in normal cells. In previous studies, the compound was shown to inhibit growth and cause regression of cancerous tumors as a single agent and, in combination with radiation and chemotherapy, to suppress radiation and chemotherapy-induced toxicities in normal tissues and cause minimal toxicity in non-human primates when dosed orally at very high doses for 28 consecutive days.

An analog of RTA-401, RTA-402 is a compound found in medicinal plants with a greater potency than the natural product.

RTA-401 was originally developed at Dartmouth College and M.D. Anderson Cancer Center. In November 2004, Reata completed a license agreement with these organizations, and was granted exclusive worldwide rights to this new class of anticancer compounds. In 2008, orphan drug designation was assigned by the FDA for the treatment of pancreatic cancer. In 2010, the compound was licensed to Kyowa Hakko Kirin by Reata Pharmaceuticals in China, Japan, Korea, Thailand and Southeast Asian countries for the treatment of chronic kidney disease. Abbott acquired rights to develop and commercialize the drug outside US, excluding certain Asian markets.

Phase 1

Bardoxolone methyl was first advanced into the clinic to assess its anticancer properties. In two Phase 1 trials that included 81 oncology patients, bardoxolone methyl reduced serum creatinine levels, with a corresponding improvement in estimated glomerular filtration rate (eGFR). Improvements were more pronounced in a subset of patients with established CKD and were maintained over time in patients who continued on bardoxolone methyl therapy for 5 months. Based on these observed effects and the well-described role of oxidative stress and inflammation in CKD, especially in type 2 diabetes, it was hypothesized that bardoxolone methyl could improve renal function in CKD patients with type 2 diabetes.[5]

Phase 2

A multi-center, double-blind, placebo-controlled Phase 2b clinical trial (BEAM) conducted in the US studied 227 patients with moderate to severe CKD (eGFR 20 – 45 ml/min/1.73m²) and type 2 diabetes. The primary endpoint was change in estimated GFR following 24 weeks of treatment. Following 24 weeks, patients treated with bardoxolone methyl experienced a mean increase in estimated GFR of over 10 ml/min/1.73m², compared with no change in the placebo group. Approximately three-quarters of bardoxolone methyl treated patients experienced an improvement in eGFR of 10 percent or more, including one-quarter who saw a significant improvement of 50% or more compared to less than 2% of patients on placebo. Adverse events were generally manageable and mild to moderate in severity. The most frequently reported adverse event in the bardoxolone methyl group was muscle spasm. Final data was published in The New England Journal of Medicine.

Concerns have been raised whether there is a true improvement in kidney function because of the significant weight loss of the patients in the active-treatment-group that ranged from 7.7-10.1 kg (7-10% of the initial body weight) and whether this weight loss in patients receiving bardoxolone included muscle wasting with a commensurate decrease in the serum creatinine level. In that case the decrease in creatinine would not necessarily be a true improvement in kidney function.[6][7][8][9][10]

Phase 3

A multinational, double-blind, placebo-controlled Phase 3 outcomes study (BEACON) was started in June 2011, testing bardoxolone methyl’s impact on progression to ESRD or cardiovascular death in 1600 patients with Stage 4 CKD (eGFR 15 – 30 ml/min/1.73m²) and type 2 diabetes. This phase 3 trail was halted in October 2012 because of adverse effects (namely a higher cardiovascular mortality in the treatment arm).[11]

Mechanism of action

Bardoxolone methyl is an inducer of the KEAP1Nrf2 pathway.

PAPER

http://modernsteroid.blogspot.com/2012/04/synthetic-oleane-triterpenoids-as.html

Image result for BARDOXOLONE METHYL SYNTHESIS

The synthetic oleane triterpenoid 6 (bardoxolone methyl) is currently in late-stage clinical trials as an orally bioavailable treatment of chronic kidney disease (CKD) in patients with type 2 diabetes. The compound is semi-synthetically derived from oleanolic acid (see Scheme above for the conversion of 1 into 6), which is produced by the fruit and leaves of the olive tree. Oleanolic acid itself is known to possess modest anti-inflammatory activity. However, when chemists at Dartmouth College installed a highly electrophilic enone system within the triterpenoid A-ring framework, in vitro potency increased by about 6 orders of magnitude relative to 1, as determined by an ‘iNOS’ assay. This assay quantitates inhibition of induction of ‘inducible nitric oxide synthase’ (iNOS), an enzyme that produces NO from arginine in macrophages and is recognized as playing a key role in inflammation. 
          The clinically relevant molecular target of 6 that is thought to mediate its therapeutic effects is the Kelch-like ECH-associated protein 1 or KEAP1, a repressor of another cytoplasmic protein, Nrf2. The oleane triterpenoids bind to KEAP1 and, in doing so, block the ubiquitination of Nrf2, which is a master regulator of the antioxidant and anti-inflammatory response. The ubiquitination of Nrf2 typically leads to sequestration and proteolysis of Nrf2, thereby preventing an aberrant anti-inflammatory response. Alternatively, Nrf2 activation results in nuclear translocation and subsequent induction of Nrf2 target genes that promote cellular control of oxidative or inflammatory stress. Hence, because Nrf2 activation leads to an antioxidant and anti-inflammatory response, and KEAP1 represses Nrf2 activation, KEAP1 is considered a promising drug target for a number of disease states including chronic kidney disease.
          A biotin-conjugated derivative of 6 (7) has been developed by the Dartmouth team in order to facilitate affinity chromatographic purification of target proteins. The detailed results of this effort have not been reported but it has been disclosed that “this compound can selectively bind to many different proteins in the cell with high affinity.” It remains to be seen (pending the Phase 3 results expected in 2013) if this is a therapeutically beneficial quality of the clinical candidate (6). Structurally simplified tricyclic derivatives based on 6 have also been designed and evaluated as anti-inflammatory and cytoprotective agents. Compounds such as 8 are highly potent suppressors of induction of iNOS and are potent inducers of other cytoprotective enzymes. Given that the eastern substructure of 8 is enantiomeric relative to 6, it is clear that the presence of one or more reactive cyano enone systems is more important for biological potency than the intact triterpenoid carbon skeleton. Usually, the three-dimensional shape of a terpenoid framework, governed by ring-fusion stereochemistry, steric constraints and the pattern of oxygenation of a given molecule, is critical to the specificity of protein binding interactions that occur in a biological system. It will be interesting to see the pharmacokinetic properties and off-target binding profile of a relatively ‘small molecule’ such as 8, which bears two extremely reactive functional groups within its core structure. The authors note that Michael adducts between various thiol nucleophiles and 6 or 8 are not isolable due to reversibility of the conjugate addition. Perhaps this type of reactivity pattern is critical to the safety and bioavailability of these drug candidates to target proteins.
PAPER
Image result for BARDOXOLONE METHYL SYNTHESIS

 

 

https://pubs.acs.org/doi/suppl/10.1021/ol400399x/suppl_file/ol400399x_si_001.pdf

str2

1. To a stirred solution of oleanolic acid (22.8 grams, 0.05 mol, 1.0 equiv) in dimethyl formamide (200 mL) was
added powdered K2CO3 (20.7 grams, 0.15 mol, 3.0 equiv) slowly upon stirring, and the reaction mixture was allowed to
cool to 0 o
C. To the stirred suspension was added iodomethane (3.4 mL, 0.055 mol, 1.1 equiv) slowly, and after the
completion of addition, the reaction was allowed to warm to room temperature overnight. After the completion of the
reaction, dimethyl formamide was removed by distillation. The resulting solid mixture was dissolved in methylene
chloride (1 L) and washed with water (4 x 100 mL) and brine (1 x 100 mL). The organics was dried over Na2SO4 and the
solvent was removed to give the crude product 8 as a white solid, which was used directly for the next step without
further purifications.
2. To a stirred suspension of ester 8 (11.8 grams, 0.025 mol, 1.0 equiv) obtained above in anhydrous dimethyl
sulfoxide (250 mL) was added iodoxybenzoic acid (21.0 grams, 0.075 mol, 3.0 equiv) and fluorobenzene (5 mL). The
resulting suspension was heated to 85 o
C under nitrogen for 24 hours. After the completion of the reaction, it was
quenched with 20% aqueous sodium thiosulfate (200 mL). The resulting mixture was extracted with methylene chloride
(4 x 150 mL), the combined organic extracts were washed with saturated NaHCO3 (100 mL) and brine (100 mL), and
dried over Na2SO4. The solvent was removed to give the crude product 14 as yellowish solid, which was used directly for
the next step without further purifications.
3. To a stirred solution of 14 (9.32 grams, 0.02 mol, 1.0 equiv) in methylene chloride (100 mL) was slowly added mchloroperbenzoic
acid (6.4 grams, ~70% purity, 0.026 mol, 1.3 equiv) at 0 o
C. After the completion of addition, the
reaction was allowed to warm to room temperature and kept stirring for 24 hours. After the completion of the reaction,
the reaction mixture was diluted with methylene chloride (300 mL), and the resulting mixture was washed with 20%
aqueous sodium thiosulfate (3 x 100 mL), 10% potassium carbonate (2 x 100 mL), and brine (100 mL). The organics were
dried over Na2SO4 and the solvent was removed to give crude mixture of 15 and 16 as yellowish solid, which was used
directly for the next step without purifications.
4. To the resulting solution of 15 and 16 obtained above in acetic acid (50 mL) was added dropwise hydrobromic
acid (1.0 mL, 0.009 mol, 0.44 equiv) at room temperature. The reaction mixture was then heated to 35 o
C, and bromine
(5.8 mL, 0.05 mol, 2.4 equiv) was thus added dropwise. The resulting reaction mixture was kept stirring for another 24 h.
After completion of the reaction, the acid was removed under vacuum. And the residue was then quenched with 20%
aqueous sodium thiosulfate (100 mL), and extracted with methylene chloride (4 x 100 mL). The combined organic
extracts were washed with saturated sodium bicarbonate (2 x 50 mL), brine (1 x 50 mL), and dried over Na2SO4. The
solvent was removed to give crude bromo enone 17 as yellowish to yellow solid, which can be used directly for the next
step without further purification or subjected to flash column chromatography to give pure bromo enone 17 as a
yellowish solid.
5. To a stirred solution of bromo enone 17 (5.8 grams, 10.0 mmol, 1.0 equiv) in anhydrous dimethyl formamide (80
mL) was added copper (I) cyanide (1.0 grams, 11.0 mmol, 1.1 equiv) and potassium iodide (328 mg, 2.0 mmol, 0.20
equiv), and the resulting reaction mixture was heated to 120 o
C for 24 h. After the completion of reaction, it was cooled
to room temperature, quenched with water (200 mL), and diluted with ethyl acetate (500 mL). The organic phase was
washed with saturated NaHCO3 (2 x 80 mL), brine (80 mL), and dried over Na2SO4. Removal of solvent and flash column
chromatography over silica gel using hexanes:EtOAc (2:1) to give bardoxolone methyl (1) as a yellowish solid.

 

str3

After the completion of the reaction, it was cooled to room temperature and
quenched with 20% aqueous sodium thiosulfate (20 mL). It was extracted with methylene chloride (3 x 20 mL), the
combined organic extracts were washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL), and dried over Na2SO4.
Removal of solvent and flash column chromatography over silica gel using hexanes:EtOAc (4:1 & 2:1) to give iodo enone
18 (509 mg, 84%) as a yellowish solid. 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 6.00 (s, 1H), 3.70 (s, 3H), 3.04 (dd, 1H, J1 =
10.0 Hz, J2 = 3.7 Hz), 2.92 (d, 1H, J = 4.6 Hz), 1.63-1.94 (m, 9H), 1.46-1.62 (m, 3H), 1.43 (s, 3H), 1.18-1.36 (m, 3H), 1.30 (s,
3H), 1.23 (s, 3H), 1.17 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H), 0.90 (s, 3H); 13C NMR (500 MHz, CDCl3) δ 199.6, 196.9, 178.4,
170.3, 163.5, 124.1, 102.3, 52.1, 49.9, 48.4, 47.4, 46.4, 45.9, 45.4, 42.3, 36.0, 34.7, 33.5, 33.0, 32.1, 31.7, 30.9, 28.3, 28.2,
27.3, 24.8, 23.3, 22.9, 22.4, 21.9, 18.8; FT-IR (solution, CDCl3, cm-1): 2952, 2869, 2253, 1717, 1659, 1469, 1386, 907, 732,
651, 623, 443; HRMS-ESI (calcd. for C31H44IO4 [M+H]+
) 607.2284, found 607.2280.

 

CLIP

 

 

Figure 1 Chemical structures of oleanolic acid, CDDO, CDDO-Me, CDDO-Ma, CCDO-ea, and CDDO-im. Abbreviations: CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; CDDO-Me, CDDO methyl ester; CDDO-Ma, CDDO methyl amide; CDDO-ea, CDDO ethyl amide; CDDO-im, CDDO imidazolide.

Figure 1 Chemical structures of oleanolic acid, CDDO, CDDO-Me, CDDO-Ma, CCDO-ea, and CDDO-im. Abbreviations: CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; CDDO-Me, CDDO methyl ester; CDDO-Ma, CDDO methyl amide; CDDO-ea, CDDO ethyl amide; CDDO-im, CDDO imidazolide.

PATENT

WO1999065478A1

In a preferred embodiment, such compounds include derivatives of ursolic acid and oleanoic acid. In a particularly preferred embodiment, derivatives of OA, e.g., 2-cyano-3,12-dioxoolean-l,9-dien-28oic acid (CDDO):

Figure imgf000014_0002

have been found to be effective in suppression of human breast cancer cell growth, and highly potent in many vitro assay systems such as: suppression of nitric oxide and prostaglandin production in macrophages, inhibition of growth of human breast cancer cells, suppression of nitric oxide formation in rat prostate cells, and suppression of prostaglandin formation in human colon fibroblasts, as detailed in the Figures.

Compounds were synthesized as below:

Figure imgf000017_0001

Scheme 1

Figure imgf000017_0002

Scheme 2

a: HCO2Et/MeONa/THF,b: PhSeCl/AcOEt; 30%H202/THF,c: NH2OH-HCI EtOH/H2O, d: MeONa/MeOH/Et2O,e: KOH/MeOH,f: Jones,g:HCO2Et/MeONa/PhH,h: Lil/DMF Compound 10 was prepared by formylation of OA (Compound 9) (Simonsen and Ross, 1957) with ethyl formate in the presence of sodium methoxide in THF (Clinton et al., 1961). Compound 7 was obtained by introduction of a double bond at C-l of Compound 10 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30%) hydrogen peroxide (Sharpless et al, 1973). Compound 11 was synthesized from Compound 10 by addition of hydroxylamine in aqueous ethanol; cleavage of Compound 11 with sodium methoxide gave Compound 12 (Johnson and Shelberg, 1945). Compound 14 was prepared from Compound 13 (Picard et al, 1939) by alkali hydrolysis followed by Jones oxidation. Compound 15 was prepared by formylation of Compound 14 with ethyl formate in the presence of sodium methoxide in benzene. Compound 16 was synthesized from Compound 15 by addition of hydroxylamine. Cleavage of 16 with sodium methoxide gave Compound 17. Compound 6 (CDDO) was prepared by introduction of a double bond at C-l of Compound 17 with phenylselenenyl chloride in ethyl acetate and sequential addition of 30% hydrogen peroxide, followed by halogenolysis with lithium iodide in DMF (Dean, P.D.G., 1965).

PATENT

WO2009/146216 A2,

Figure imgf000075_0001

Compounds 401, 402, 404, 402-04, 402-35 and 402-56 can be prepared according to the methods taught by Honda et al. (1998), Honda et al. (2000b), Honda et al. (2002), Yates et al. (2007), and U.S. Patent 6,974,801, which are all incorporated herein by reference. The synthesis of the other compounds are disclosed in the following applications, each of which is incorporated herein by reference: U.S. Application Nos. 61/046,332, 61/046,342, 61/046,363, 61/046,366, 61/111,333, 61/111,269, and 61/111,294. The synthesis of the other compounds are also disclosed in the following separate applications filed concurrently herewith, each of which is incorporated herein by reference in their entireties: U.S. Patent Application by Eric Anderson, Xin Jiang, Xiaofeng Liu; Melean Visnick, entitled “Antioxidant Inflammation Modulators: Oleanolic Acid Derivatives With Saturation in the C- Ring,” filed April 20, 2009; U.S. Patent Application by Eric Anderson, Xin Jiang and Melean Visnick, entitled “Antioxidant Inflammation Modulators: Oleanolic Acid Derivatives with Amino and Other Modifications At C-17,” filed April 20, 2009; U.S. Patent Application by Xin Jiang, Xioafeng Liu, Jack Greiner, Stephen S. Szucs, Melean Visnick entitled, “Antioxidant Inflammation Modulators: C-17 Homologated Oleanolic Acid Derivatives,” filed April 20, 2009.

PAPER

Chemical Communications, 2011 ,  vol. 47,   33  p. 9495 – 9497

http://pubs.rsc.org/en/Content/ArticleLanding/2011/CC/c1cc11633a#!divAbstract

http://www.rsc.org/suppdata/cc/c1/c1cc11633a/c1cc11633a.pdf NMR GIVEN

Graphical abstract: DDQ-promoted dehydrogenation from natural rigid polycyclic acids or flexible alkyl acids to generate lactones by a radical ion mechanism

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO)
A mixture of 1 (0.25 g, 0.51 mmol) and DDQ (0.12 g, 0.51 mmol) in anhydrous benzene (20 mL) was
refluxed for 15 min. After filtration, the filtrate was evaporated in vacuo to give a residue, which was
subjected to flash column chromatography (petroleum ether/EtOAc) to give CDDO as an amorphous
solid (0.23 g, 91%). The title compound was known as CAS 218600-44-3

m.p. 180-182 °C;
ESI-MS: 490 [M-H]-, 492 [M+H]+;

1H NMR (300M Hz, CDCl3, 25 °C, TMS): δ 8.05 (1H, s), 5.99 (1H, s), 3.03-2.98 (2H, m), 1.55,1.38,
1.34, 1.22, 1.00, 0.91, 0.85 (each 3H,s ,CH3) ppm.

PAPER

SYNTHESIS

Journal of Medicinal Chemistry, 2000 ,  vol. 43,   22  p. 4233 – 4246

http://pubs.acs.org/doi/full/10.1021/jm0002230

Abstract Image

BARDOXOLONE METHYL…………Methyl 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (25). A mixture of 64 (1.51 g, 2.97 mmol) and DDQ (98%) (0.77 g, 3.32 mmol) in dry benzene (80 mL) was heated under reflux for 30 min. After insoluble matter was removed by filtration, the filtrate was evaporated in vacuo to give a solid. The solid was subjected to flash column chromatography [benzene−acetone (10:1)] to give 25 as an amorphous solid (1.38 g, 92%):  [α]23D +33° (c 0.68, CHCl3). UV (EtOH) λmax (log ε):  244 (4.07) nm. IR (KBr):  2950, 2872, 2233, 1722, 1690, 1665 cm-1. 1H NMR (CDCl3):  δ 8.04 (1H, s), 5.96 (1H, s), 3.68 (3H, s), 3.02 (1H, ddd, J = 3.4, 4.9, 13.4 Hz), 2.92 (1H, d, J = 4.9 Hz), 1.47, 1.31, 1.24, 1.15, 0.99, 0.98, 0.88 (each 3H, s). 13C NMR (CDCl3):  δ 199.0, 196.8, 178.3, 168.6, 165.9, 124.2, 114.7, 114.6, 52.1, 49.8, 47.8, 47.3, 45.9, 45.2, 42.7, 42.2, 35.9, 34.6, 33.4, 32.9, 31.8, 31.6, 30.8, 28.1, 27.1, 26.8, 24.7, 23.2, 22.7, 21.8, 21.7, 18.4. EIMS (70 eV) m/z:  505 [M]+(100), 490 (81), 430 (42), 315 (47), 269 (40). HREIMS Calcd for C32H43O4N: 505.3192. Found:  505.3187. Anal. (Table 1).
FREE ACID
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic Acid (26). A mixture of 25 (612 mg, 1.21 mmol) and LiI (3.0 g) in dry DMF (10 mL) was heated under reflux for 4 h. To the mixture were added water and 5% aqueous HCl solution. The mixture was extracted with EtOAc (three times). The extract was washed with water (three times) and saturated aqueous NaCl solution (three times), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give an amorphous solid. The solid was subjected to flash column chromatography [hexanes−EtOAc (1:1) followed by CH2Cl2−MeOH (15:1)] to give crude 26 (530 mg). The crude product was purified by recrystallization from benzene to give crystals. To remove benzene completely, the crystals were dissolved in CH2Cl2 (20 mL) and the solvent was evaporated in vacuo to give benzene-free26 as an amorphous solid (405 mg, 68%):  [α]22D +33 ° (c 0.28, CHCl3). UV (EtOH) λmax (log ε):  240 (4.21) nm. IR (KBr):  2950, 2867, 2235, 1692, 1665 cm-1. 1H NMR (CDCl3):  δ 8.05 (1H, s), 6.00 (1H, s), 3.06−2.98 (2H, m), 1.48, 1.34, 1.25, 1.16, 1.02, 1.00, 0.90 (each 3H, s). 13C NMR (CDCl3):  δ 199.0, 196.8, 183.7, 168.8, 165.9, 124.2, 114.7, 114.5, 49.8, 47.8, 47.1, 45.9, 45.2, 42.7, 42.3, 35.8, 34.5, 33.3, 33.0, 31.8, 31.5, 30.8, 28.1, 27.1, 26.8, 24.8, 23.2, 22.6, 21.72, 21.71, 18.4. EIMS (70 eV) m/z:  491 [M]+ (100), 476 (62), 445 (29), 430 (27), 269 (94). HREIMS Calcd for C31H41O4N:  491.3036. Found:  491.3020. Anal. (Table 1).
PAPER

Bioorganic and Medicinal Chemistry Letters, 1998 ,  vol. 8,   19  p. 2711 – 2714

http://www.sciencedirect.com/science/article/pii/S0960894X9800479X

Full-size image (3 K)

PAPER

Bioorganic and Medicinal Chemistry Letters, 2005 ,  vol. 15,  # 9  p. 2215 – 2219

http://www.sciencedirect.com/science/article/pii/S0960894X05003306

Full-size image (5 K)

PATENT

WO2002047611A2

Method of synthesis of CDDO. CDDO may be synthesized by the scheme outlined below.

 

Figure imgf000016_0001

Methyl-CDDO. Methyl-CDDO (CDDO-Me), the C-28 methyl ester of CDDO, also exerts strong antiproliferative and apoptotic effects on leukemic cell lines and in primary AML samples in vitro as well as induces monocytic differentiation of leukemic cell lines and some primary AMLs. Thus, CDDO-Me provides chemotherapy for the treatment of leukemias. The present invention demonstrates that this effect is profoundly increased by combination of CDDO-Me with other chemotherapeutic agents. These include retinoids such as ATRA, 9-cis retinoic acid, , LG100268, LGD1069 (Targretin, bexarotene), fenretinide [N-(4- hydroxyphenyl)retinamide, 4-HPR], CD437 and other RXR and RAR-specific ligands. This combination also increases ara-C cytotoxicity, further reduces AML colony formation, inhibits ERK phosphorylation and promotes Bcl-2 dephosphorylation, and inhibits in vitro angiogenesis. The ability of CDDO-Me in combination with retinoids to induce differentiation in leukemic cells in vitro show that these compounds may have similar in vivo effects. The anti-angiogenic properties of CDDO-Me further increase its potent anti-leukemia activity in combination with retinoids. Furthermore, CDDO-Me was found to be more potent at lower concentrations than CDDO.

Method of synthesis of CDDO-Me.

CDDO-Me may be synthesized by the scheme outlined below.

Figure imgf000017_0001

The present invention provides combinations of CDDO-compounds and chemotherapeutic agents that are useful as treatments for cancers and hematological malignancies. In one embodiment, the chemotherapeutics are retinoids. As CDDO- compounds are PPARγ ligands and PPARγ is known to be altered in many types of cancers, the inventors contemplate, that ligation of PPARγ in combination with retinoids such as, RXR-specific ligands, provides a mechanistic basis for maximal increase in transcriptional activity of the target genes that control apoptosis and differentiation. The CDDO-compounds and retinoids in combination demonstrate an increased ability to induce differentiation, induce cytotoxicity, induce apoptosis, induce cell killing, reduce colony formation and inhibit the growth of several types of leukemic cells.

 

 

PAPER

Org Lett. 2013 Apr 5;15(7):1622-5. doi: 10.1021/ol400399x. Epub 2013 Mar 26.

Efficient and scalable synthesis of bardoxolone methyl (cddo-methyl ester).

Bardoxolone methyl (2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid methyl ester; CDDO-Me) (1), a synthetic oleanane triterpenoid with highly potent anti-inflammatory activity (levels below 1 nM), has completed a successful phase I clinical trial for the treatment of cancer and a successful phase II trial for the treatment of chronic kidney disease in type 2 diabetes patients. Our synthesis of bardoxolone methyl (1) proceeds in ∼50% overall yield in five steps from oleanolic acid (2), requires only one to two chromatographic purifications, and can provide gram quantities of 1.

Abstract Image

References

  1.  “Bardoxolone methyl – Oral, Once Daily AIM for Renal/Cardiovascular/Metabolic Diseases”Reata PharmaceuticalsArchived from the original on 15 July 2011. Retrieved June 2, 2011.
  2.  “Abbott and Reata Pharmaceuticals Announce Agreement to Develop and Commercialize Bardoxolone Methyl for Chronic Kidney Disease Outside the U.S.” (Press release). Reata Pharmaceuticals. September 23, 2010. Retrieved June 2, 2011.
  3.  “Reata Pharmaceuticals Licenses Chronic Kidney Disease Drug Bardoxolone Methyl to Kyowa Hakko Kirin”(Press release). Reata Pharmaceuticals. January 7, 2010. Retrieved June 2, 2011.
  4. “Company Statement: Termination of Beacon Trial”.Reata Pharmaceuticals. Retrieved October 18, 2012.
  5. Pergola, P. E.; Krauth, M.; Huff, J. W.; Ferguson, D. A.; Ruiz, S.; Meyer, C. J.; Warnock, D. G. (2011). “Effect of Bardoxolone Methyl on Kidney Function in Patients with T2D and Stage 3b–4 CKD”. American Journal of Nephrology 33 (5): 469–476. doi:10.1159/000327599PMID 21508635.
  6. Pergola, P. E.; Raskin, P.; Toto, R. D.; Meyer, C. J.; Huff, J. W.; Grossman, E. B.; Krauth, M.; Ruiz, S.; Audhya, P.; Christ-Schmidt, H.; Wittes, J.; Warnock, D. G.; Beam Study, I. (2011). “Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes” (pdf). New England Journal of Medicine 365 (4): 327–336.doi:10.1056/NEJMoa1105351PMID 21699484edit
  7.  van Laecke, S.; Vanholder, R. (2011). “Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes”New England Journal of Medicine 365 (18): 1745, author reply 1746–1747.doi:10.1056/NEJMc1110239PMID 22047578.
  8. Rogacev, K. S.; Bittenbring, J. T.; Fliser, D. (2011).“Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes”New England Journal of Medicine 365 (18): 1745–1746, author reply 1746–1747.doi:10.1056/NEJMc1110239PMID 22047579.
  9. Upadhyay, A.; Sarnak, M. J.; Levey, A. S. (2011).“Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes”New England Journal of Medicine 365 (18): 1746, author reply 1746–1747.doi:10.1056/NEJMc1110239PMID 22047580.
  10.  McMahon, G. M.; Forman, J. P. (2011). “Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes”New England Journal of Medicine 365 (18): 1746, author reply 1746–1747.doi:10.1056/NEJMc1110239PMID 22047581.
  11.  ClinicalTrials.gov NCT01351675 Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON)
  12. Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages
    Bioorg Med Chem Lett 1998, 8(19): 2711
  13. Novel synthetic oleanate triterpenoids: A series of highly active inhibitors of nitric production in mouse macrophages
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  24. Anderson, Amy C.; Browning, R. Greg; Couch, Robin D.; Gribble, Gordon W.; Honda, Tadashi; Wright, Dennis L.; Sporn, Michael B.
    Bioorganic and Medicinal Chemistry Letters, 2005 ,  vol. 15,  9  p. 2215 – 2219
  25. Journal of Medicinal Chemistry, 2004 ,  vol. 47,  20  p. 4923 – 4932
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Citing Patent Filing date Publication date Applicant Title
US8440854 * Jan 23, 2012 May 14, 2013 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino acid and other modifications at C-17
US8513436 Dec 19, 2011 Aug 20, 2013 Reata Pharmaceuticals, Inc. Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
WO2002047611A2 * Nov 28, 2001 Jun 20, 2002 Univ Texas Cddo-compounds and combination therapies thereof
WO2008064132A2 * Nov 16, 2007 May 29, 2008 Dartmouth College Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth
WO2009118441A1 * Feb 12, 2009 Oct 1, 2009 Consejo Superior De Investigaciones Cientifícas Use of pentacyclic triterpene for the preparation of a pharmaceutical compound intended for the treatment of multiple sclerosis
WO2013083659A1 Dec 5, 2012 Jun 13, 2013 Cambridge Enterprise Limited Combination treatment comprising ho – 1 inhibitor and immunotherapeutic agent
US7176237 Jan 15, 2003 Feb 13, 2007 The Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
US7435755 Nov 28, 2001 Oct 14, 2008 The Trustees Of Dartmouth College CDDO-compounds and combination therapies thereof
US7678830 Feb 7, 2007 Mar 16, 2010 Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
US7714012 Nov 16, 2007 May 11, 2010 Trustees Of Dartmouth University Synthesis and biological activities of new tricyclic-bis-enones (TBEs)
US7795305 Oct 10, 2008 Sep 14, 2010 Board Of Regents, The University Of Texas System CDDO-compounds and combination therapies thereof
US7863327 May 3, 2005 Jan 4, 2011 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US7915402 Apr 20, 2009 Mar 29, 2011 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring
US7943778 Apr 20, 2009 May 17, 2011 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: C-17 homologated oleanolic acid derivatives
US8034955 Oct 29, 2007 Oct 11, 2011 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US8067394 May 10, 2010 Nov 29, 2011 Trustees Of Dartmouth College Synthesis and biological activities of new tricyclic-bis-enones (TBEs)
US8067465 Mar 11, 2010 Nov 29, 2011 The Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
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US8124656 Feb 23, 2011 Feb 28, 2012 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring
US8124799 Apr 20, 2009 Feb 28, 2012 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
US8129429 Jan 12, 2009 Mar 6, 2012 Reata Pharmaceuticals, Inc. Synthetic triterpenoids and methods of use in the treatment of disease
US8258329 Apr 20, 2009 Sep 4, 2012 Reata Pharmaceuticals, Inc. Dehydroandrosterone analogs including an anti-inflammatory pharmacore and methods of use
US8299046 Nov 16, 2007 Oct 30, 2012 Trustees Of Dartmouth College Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth
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US8586775 Aug 24, 2011 Nov 19, 2013 Trustees Of Dartmouth College Therapeutic compounds and methods of use

 

Tadashi Honda
Professor Honda received his B.S. degree in Chemistry in 1974, his M.S. degree in Organic Chemistry in 1976, and his Ph.D. in Organic Chemistry in 1979 from the University of Tokyo. In 1979, he joined the Department of Drug Discovery Chemistry at Suntory Institute for Biomedical Research in Japan and worked there as a drug synthetic chemist (finally senior researcher) for 13 years. In 1991, he joined the Central Pharmaceutical Research Institute at Japan Tobacco Inc. and worked as a chief senior researcher for 3 years. In 1995, he joined Dr. Gribble’s laboratory at Dartmouth College as a research associate. In 1998, he joined the research faculty of Dartmouth College. In 2005, he was promoted to Research Associate Professor.

http://www.dartmouth.edu/~chem/faculty/th.html

Dr. Honda and his collaborators have further explored new structures based on CDDO and different five-ringed triterpenoids.

During the course of these investigations, Dr. Honda has designed three-ringed compounds with similar enone functionalities in rings A and C to those of CDDO, but having a much simpler structure than five-ringed triterpenoids. He and his collaborators have found that they are also a novel class of potent anti-inflammatory, cytoprotective, growth suppressive, and pro-apoptotic compounds. Amongst such three-ringed compounds, TBE-31 with the C-8a ethynyl group is much more potent than CDDO in various bioassays in vitro and in vivo. Thus, further investigation (design, synthesis, biological evaluation, etc.) of new TBE-31 analogues is currently being performed in order to discover analogues having different and/or better features than TBE-31, for example, higher potency and lower toxicity, better bioavailability and different distributions in organs, high water-solubility and so on.

figure2

Mechanism studies suggest that CDDO regulates various molecules regarding inflammation, differentiation, apoptosis, and proliferation by reversible Michael addition between the cyano enone functionality of CDDO and the sulfhydryl groups of cysteine moieties on these molecules. Based on this fact and the structure of TBE-31, Dr. Honda has designed single-ringed compounds, which represent the ideal simple structure. The synthesis of these new compounds is currently in progress.

figure3

Bardoxolone methyl
Bardoxolone methyl.svg
Clinical data
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
ECHA InfoCard 100.132.153 Edit this at Wikidata
Chemical and physical data
Formula C32H43NO4
Molar mass 505.69 g/mol
3D model (JSmol)

///////////////Bardoxolone Methyl, CDDO-Me; CDDO methyl ester; 218600-53-4; Bardoxolone (methyl); RTA 402 CDDO-Me, CDDO methyl ester, 218600-53-4, Bardoxolone (methyl), RTA 402 , PHASE 3,NSC 713200

CC1(CCC2(CCC3(C(C2C1)C(=O)C=C4C3(CCC5C4(C=C(C(=O)C5(C)C)C#N)C)C)C)C(=O)OC)C

 

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1 Comment

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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