Ono Pharmaceutical Co has become the first company in the world to get an approval for a PD-1 checkpoint inhibitor, as regulators in Japan gave the green light to nivolumab, developed with Bristol-Myers Squibb, as a treatment for melanoma.
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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai)
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36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google,
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Japan First to Approve Alectinib アレクチニブ 塩酸塩 (AF 802) for ALK+ NSCLC
Alectinib (AF802, CH5424802, RG7853, RO5424802)
CAS 1256580-46-7 FREE
1256589-74-8 (Alectinib Hydrochloride)
9-Ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile
| Formula: | C30H34N4O2 |
| M.Wt: | 482.62 |
Mechanism of Action:ALK inhibitor
Indication:Non-small cell lung cancer (NSCLC)
Current Status:Phase II (US,EU,UK), NDA(Japan)
Company:中外製薬株式会社 (Chugai), Roche
Japan First to Approve Alectinib for ALK+ NSCLC
Roche announced that the Japanese Ministry of Health, Labor and Welfare (MHLW) has approved alectinib for the treatment of people living with non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase fusion gene-positive (ALK+). The approval was based on results from a Japanese Phase 1/2 clinical study (AF-001JP) for people whose tumors were advanced, recurrent or could not be removed completely through surgery (unresectable).
| Company | Chugai Pharmaceutical Co. Ltd. |
| Description | Anaplastic lymphoma kinase (ALK) inhibitor |
| Molecular Target | Anaplastic lymphoma kinase (ALK) |
| Mechanism of Action | Anaplastic lymphoma kinase (Ki-1) (ALK) inhibitor |
| Therapeutic Modality | Small molecule |
| Latest Stage of Development | Registration |
| Standard Indication | Non-small cell lung cancer (NSCLC) |
| Indication Details | Treat advanced ALK-positive non-small cell lung cancer (NSCLC); Treat non-small cell lung cancer (NSCLC); Treat unresectable progressive or recurrent ALK-positive non-small cell lung cancer (NSCLC) |
| Regulatory Designation |
U.S. – Breakthrough Therapy (Treat advanced ALK-positive non-small cell lung cancer (NSCLC)); |
| Partner |
Alectinib (also known as CH5424802,RO5424802), a second generation oral inhibitor of anaplastic lymphoma kinase (ALK), is being developed by Chugai and Roche for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) that has progressed on Xalkori (Crizotinib).
Alectinib was discovered by Chugai Pharmaceutical Co. Ltd. Chugai became a subsidiary of Roche in 2002 and the Swiss group currently owns 59.9 percent of the company.
On October 8, 2013, Chugai Pharmaceutical announced that it has filed a new drug application to Japan’s Ministry of Health, Labour and Welfare (MHLW) for alectinib hydrochloride for the treatment of ALK fusion gene positive non-small cell lung cancer (NSCLC).
IT is a potent and selective ALK inhibitor with IC50 of 1.9 nM.Alterations in the anaplastic lymphoma kinase (ALK) gene have been implicated in human cancers. Among these findings, the fusion gene comprising EML4 and ALK has been identified in non-small cell lung cancer (NSCLC) and fusion of ALK to NPM1 has been observed in anaplastic large cell lymphoma (ALCL). The possibility of targeting ALK in human cancer was advanced with the launch of crizotinib for NSCLC in the U.S. in 2011. The development of resistance to crizotinib in tumors, however, has led to the need for second-generation ALK inhibitors. One of these, alectinib hydrochloride, has been found to be an orally active, potent and highly selective ALK inhibitor with activity in ALK-driven tumor models. Alectinib has shown preclinical activity against cancers with ALK gene alterations, including NSCLC cells expressing the EML4-ALK fusion and ALCL cells expressing the NPM-ALK fusion. Alectinib was well tolerated and active in a phase I/II study conducted in Japan in patients with ALK-rearranged advanced NSCLC and in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib has been submitted for approval in Japan for the treatment of ALK fusion gene-positive NSCLC and is in phase I/II development for ALK-rearranged NSCLC in the U.S.
……………..
………………….
WO2012023597
http://www.google.fm/patents/WO2012023597A1?cl=en
(Preparation 30)
Compound F6-20
9 – ethyl-6, 6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3 – carbonitrile
Under the same conditions as the synthesis of the compound B3-13-1, and the title compound was synthesized from compound F5-49.
1 H-NMR (400MHz, DMSO-D 6) δ: 12.70 (1H, s), 8.32 (1H, d, J = 7.9 Hz), 8.04 (1H, s), 8.00 (1H, s), 7.61 (1H , d, J = 8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m), 3.27-3.18 (2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H, m ), 1.96-1.87 (2H, m), 1.76 (6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J = 7.3 Hz)
LCMS: m / z 483 [M + H] +
HPLC retention time: 1.98 minutes (analysis conditions U)
Hydrochloride 9 of compound F6-20 – ethyl-6, 6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b I was dissolved at 60 ℃ in a mixture of 10 volumes of methyl ethyl ketone, 3 volumes of water and acetic acid volume 4-carbonitrile -] carbazol-3. I was dropped hydrochloric acid (2N) 1 volume of solution. After stirring for 30 minutes at 60 ℃, and the precipitated solid was filtered and added dropwise to 25 volume ethanol, 9 – Dry ethyl -6,6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) I got a one-carbonitrile hydrochloride – 11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3. Ethyl-6, 6 – 9 – obtained dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3 – I was pulverized with a jet mill carbonitrile monohydrochloride.
1 H-NMR (400MHz, DMSO-D 6) δ: 12.78 (1H, s), 10.57 (1H, br.s), 8.30 (1H, J = 8.4 Hz), 8.05 (1H, s), 7.99 (1H , s), 7.59 (1H, d, J = 7.9 Hz), 7.36 (1H, s) ,4.02-3 .99 (2H, m) ,3.84-3 .78 (2H, m) ,3.51-3 .48 (2H, m), 3.15-3.13 (1H, s) ,2.83-2 .73 (2H, s) ,2.71-2 .67 (2H, s) ,2.23-2 .20 (2H, m) ,1.94-1 .83 (2H, m), 1.75 (6H, s ), 1.27 (3H, t, J = 7.5 Hz)
FABMS: m / z 483 [M + H] +
I was dissolved at 90 ℃ to 33 volume dimethylacetamide F6-20 F6-20 mesylate. Was added to 168 volumes mesylate solution (2 N) 1.2 volume, ethyl acetate solution was stirred for 4 hours. The filtered crystals were precipitated, and dried to obtain a F6-20 one mesylate. I was milled in a jet mill F6-20 one mesylate salt was obtained.
……………………
Journal of Medicinal Chemistry, 54(18), 6286-6294; 2011
http://pubs.acs.org/doi/abs/10.1021/jm200652u
| WO2002043704A1 * | 30 Nov 2001 | 6 Jun 2002 | Yasuki Kato | Composition improved in solubility or oral absorbability |
| WO2008051547A1 * | 23 Oct 2007 | 2 May 2008 | Cephalon Inc | Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors |
| WO2009073620A2 * | 1 Dec 2008 | 11 Jun 2009 | Newlink Genetics | Ido inhibitors |
| WO2010143664A1 * | 9 Jun 2010 | 16 Dec 2010 | Chugai Seiyaku Kabushiki Kaisha | Tetracyclic compound |
| JP2008280352A | Title not available | |||
| JP2009100783A | Title not available | |||
| JPH0892090A * | Title not available |
|
References |
1: Ignatius Ou SH, Azada M, Hsiang DJ, Herman JM, Kain TS, Siwak-Tapp C, Casey C, He J, Ali SM, Klempner SJ, Miller VA. Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol. 2014 Apr;9(4):549-53. doi: 10.1097/JTO.0000000000000094. PubMed PMID: 24736079.
2: Gouji T, Takashi S, Mitsuhiro T, Yukito I. Crizotinib can overcome acquired resistance to CH5424802: is amplification of the MET gene a key factor? J Thorac Oncol. 2014 Mar;9(3):e27-8. doi: 10.1097/JTO.0000000000000113. PubMed PMID: 24518097.
3: Latif M, Saeed A, Kim SH. Journey of the ALK-inhibitor CH5424802 to phase II clinical trial. Arch Pharm Res. 2013 Sep;36(9):1051-4. doi: 10.1007/s12272-013-0157-8. Epub 2013 May 23. Review. PubMed PMID: 23700294.
4: Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013 Jun;14(7):590-8. doi: 10.1016/S1470-2045(13)70142-6. Epub 2013 Apr 30. PubMed PMID: 23639470.
5: Kinoshita K, Asoh K, Furuichi N, Ito T, Kawada H, Hara S, Ohwada J, Miyagi T, Kobayashi T, Takanashi K, Tsukaguchi T, Sakamoto H, Tsukuda T, Oikawa N. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. doi: 10.1016/j.bmc.2011.12.021. Epub 2011 Dec 22. PubMed PMID: 22225917.
6: Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90. doi: 10.1016/j.ccr.2011.04.004. PubMed PMID: 21575866.
Gadgeel S, Ou SH, Chiappori A, et al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. Abstract O16.06. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.
Ou SH, Gadgeel S, Chiappori AA, et al: Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Abstract O16.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.
Kinoshita, Kazuhiro et al,Preparation of tetracyclic compounds such as 11-oxo-5,6-dihydrobenzo[b]carbazole-3-carbonitrile derivatives as anaplastic lymphoma kinase (ALK) inhibitors,Jpn. Kokai Tokkyo Koho, 2012126711, 05 Jul 2012
Furumoto, Kentaro et al, Composition containing tetracyclic compound and dissolution aid (４環性化合物を含む組成物), PCT Int. Appl., WO2012023597, 23 Feb 2012, Also published as CA2808210A1, CN103052386A, EP2606886A1, EP2606886A4, US20130143877
Kinoshita, Kazutomo et al,Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802), Bioorganic & Medicinal Chemistry, 20(3), 1271-1280; 2012
Kinoshita, Kazutomo et al,9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors, Journal of Medicinal Chemistry, 54(18), 6286-6294; 2011
Kinoshita, Kazuhiro et al, Preparation of tetracyclic compounds such as 11-oxo-5,6-dihydrobenzo[b]carbazole-3-carbonitrile derivatives as anaplastic lymphoma kinase (ALK) inhibitors,Jpn. Tokkyo Koho, 4588121, 24 Nov 2010
Japan approves world’s first PD-1 drug, nivolumab
http://www.pharmatimes.com/Article/14-07-07/Japan_approves_world_s_first_PD-1_drug_nivolumab.aspx
old article cut paste
NIVOLUMAB
Anti-PD-1;BMS-936558; ONO-4538
PRONUNCIATION nye vol’ ue mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL DESCRIPTION
A fully human IgG4 antibody blocking the programmed cell death-1 receptor (Medarex/Ono Pharmaceuticals/Bristol-Myers Squibb)
MOLECULAR FORMULA C6362H9862N1712O1995S42
MOLECULAR WEIGHT 143.6 kDa
SPONSOR Bristol-Myers Squibb
CODE DESIGNATION MDX-1106, BMS-936558
CAS REGISTRY NUMBER 946414-94-4
Bristol-Myers Squibb announced promising results from an expanded phase 1 dose-ranging study of its lung cancer drug nivolumab
Nivolumab (nye vol’ ue mab) is a fully human IgG4 monoclonal antibody designed for the treatment of cancer. Nivolumab was developed by Bristol-Myers Squibb and is also known as BMS-936558 and MDX1106.[1] Nivolumab acts as an immunomodulator by blocking ligand activation of the Programmed cell death 1 receptor.
A Phase 1 clinical trial [2] tested nivolumab at doses ranging from 0.1 to 10.0 mg per kilogram of body weight, every 2 weeks. Response was assessed after each 8-week treatment cycle, and were evaluable for 236 of 296 patients. Study authors concluded that:”Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.”[3]
Phase III clinical trials of nivolumab are recruiting in the US and EU.[4]
- Statement On A Nonproprietary Name Adopted By The USAN Council – Nivolumab, American Medical Association.
- A Phase 1b Study of MDX-1106 in Subjects With Advanced or Recurrent Malignancies (MDX1106-03), NIH.
- Topalian SL, et al. (June 2012). “Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer”. New England Journal of Medicine 366. doi:10.1056/NEJMoa1200690. Lay summary – New York Times.
- Nivolumab at ClinicalTrials.gov, A service of the U.S. National Institutes of Health.
The PD-1 blocking antibody nivolumab continues to demonstrate sustained clinical activity in previously treated patients with advanced non-small cell lung cancer (NSCLC), according to updated long-term survival data from a phase I trial.
Survival rates at one year with nivolumab were 42% and reached 24% at two years, according to the median 20.3-month follow up. Additionally, the objective response rate (ORR) with nivolumab, defined as complete or partial responses by standard RECIST criteria, was 17% for patients with NSCLC. Results from the updated analysis will be presented during the 2013 World Conference on Lung Cancer on October 29.
“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” David R. Spigel, MD, the program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the authors of the updated analysis, said in a statement.
“With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging phase I results that support further investigation in larger scale trials.”
In the phase I trial, 306 patients received intravenous nivolumab at 0.1–10 mg/kg every-other-week for ≤12 cycles (4 doses/8 week cycle). In all, the trial enrolled patients with NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and prostate cancer.
The long-term follow up focused specifically on the 129 patients with NSCLC. In this subgroup, patients treated with nivolumab showed encouraging clinical activity. The participants had a median age of 65 years and good performance status scores, and more than half had received three or more prior therapies. Across all doses of nivolumab, the median overall survival was 9.9 months, based on Kaplan-Meier estimates.
In a previous update of the full trial results presented at the 2013 ASCO Annual Meeting, drug-related adverse events of all grades occurred in 72% of patients and grade 3/4 events occurred in 15%. Grade 3/4 pneumonitis related to treatment with nivolumab emerged early in the trial, resulting in 3 deaths. As a result, a treatment algorithm for early detection and management was developed to prevent this serious side effect.
Nivolumab is a fully human monoclonal antibody that blocks the PD-1 receptor from binding to both of its known ligands, PD-L1 and PD-L2. This mechanism, along with early data, suggested an associated between PD-L1 expression and response to treatment.
In separate analysis presented at the 2013 World Conference on Lung Cancer, the association of tumor PD-L1 expression and clinical activity in patients with NSCLC treated with nivolumab was further explored. Of the 129 patients with NSCLC treated with nivolumab in the phase I trial, 63 with NSCLC were tested for PD-L1 expression by immunohistochemistry (29 squamous; 34 non-squamous).
Rheumatoid arthritis & Ginger
As ageing populations grow, diseases such as Rheumatoid arthritis are becoming more prevelant. With advancing years this disease can lead to massive bone destruction with inflammation and pain. The researchers (Al-Nahain et al) in this recent paper study and review ginger (Zingiber official). This spice has traditionally been used for treatment of Rheumatoid arthritis in many countries like India where Ayurvedic doctore have been using it for many hundreds of years.
This review attempts to list the constituents and mechanisms of action.
The study concludes that phytochemicals from Ginger can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from diseases like Rheumatoid arthritis inhibiting bone destruction.
PARP Inhibitor.. Veliparib (ABT-888) 维利帕尼
Veliparib
2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide
CAS number: 912444-00-9 (Veliparib),
912445-05-7 (Veliparib dihydrochloride)
Mechanism of Action:poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor
Indiction:cancer treatment
Development Status:Phase III
Drug Company: AbbVie
PARP Inhibitor Veliparib (ABT-888)
Also known as: ABT-888, 912444-00-9, ABT 888, carboxamide, CHEBI:62880, 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT888, Veliparib
Molecular Formula: C13H16N4O Molecular Weight: 244.29234
| Systematic (IUPAC) name | |
|---|---|
| 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide | |
| Clinical data | |
| Legal status | experimental |
| Identifiers | |
| ATC code | None |
| PubChem | CID 11960529 |
| DrugBank | DB07232 |
| ChemSpider | 10134775 |
| UNII | 01O4K0631N  |
| ChEMBL | CHEMBL506871 |
| Chemical data | |
| Formula | C13H16N4O |
| Mol. mass | 244.29 g/mol |
|
2-10-2012
|
PARP1 TARGETED THERAPY
|
|
|
4-17-2009
|
2-{(R)-2-METHYLPYRROLIDIN-2-YL)-1H-BENZIMIDAZOLE-4-CARBOXAMIDE CRYSTALLINE FORM 1
|
Veliparib (ABT-888)[1] is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC.
It inhibits both PARP1 and PARP2.[2][3]
AbbVie’s Veliparib (ABT-888,), an inhibitor of poly ADP-ribose polymerase 1 and 2 (PARP 1 and PARP 2), is being investigated in multiple tumor types, including 3 phase III studies, all initiated this year, in neoadjuvant treatment of triple-negative breast cancer (clinical trial number:NCT02032277), non-small cell lung cancer (NSCLC, clinical trial number:NCT02106546) and HER2-negative, BRCA1 and/or BRCA2-positive breast cancer (clinical trial number:NCT02163694).
AbbVie, which was spun off from Abbott Laboratories in early 2013, is currently looking to buy Irish drug maker Shire for $46 billion. The proposed deal follows Pfizer’s failed $120 billion attempt to buy AstraZeneca. Humira, AbbVie’s rheumatoid arthritis drug and the world’s top-selling drug last year, accounts for 60% of company revenue and is going off-patent in at the end of 2016. The threat of growing competition for Humira may be a major motivation for AbbVie.
Clinical trials
Numerous phase I clinical trials are in progress.[4]
A phase I/II clinical trial for use with/out doxorubicin (for Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma) started in 2008 and is due to complete in 2010.[5] Results (inc MTD) with topotecan.[6]
A phase II clinical trial for metastatic melanoma has started recruiting.[7] Due to end Dec 2011.
A phase II clinical trial for metastatic breast cancer has started recruiting.[8] Due to end Nov 2011.
A phase II clinical trial for add-on to Radiation Therapy for Patients with Brain Metastases from Non-Small Cell Lung Cancer.
It was included in the I-SPY2 breast cancer trial,[9] and there are encouraging data from that study [10]
A phase I clinical trial for prostate cancer in men who carry the BRCA mutation is underway and is now recruiting (as of May 2013).[11]
……………….
http://www.google.com/patents/US20060229289
EXAMPLE 1
2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide EXAMPLE 1A 1-benzyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate
A solution of 1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate (15.0 g, 57 mmol) and iodomethane (7.11 ml, 114 mmol) in THF (100 mL) was treated with NaN(TMS)2 (1.0 M solution in THF, 114 mL, 114 mmol) at −75° C. under nitrogen. The temperature of the cooling bath was then slowly raised to −20° C. within 1 h and the mixture was stirred at the same temperature for another 3 h. After quenching with water, the mixture was acidified with 2 N HCl (˜100 mL) and was partitioned between water (400 mL) and EtOAc (400 mL). The organic phase was washed with brine and concentrated. The residue was purified by flash column chromatography (silica gel, EtOAc/hexane) to give Example 1A (15.15 g, Yield: 96%). MS (DCI/NH3) m/z 278 (M+H)+.
EXAMPLE 1B
1-[(benzyloxy)carbonyl]-2-methylpyrrolidine-2-carboxylic acid
A solution of Example 1A (15.15 g, 54.63 mmol) in a mixture of THF (100 mL) and water (50 mL) was treated with LiOH.H2O (4.58 g, 109.26 mmol) in water (50 mL). Methanol was added until a transparent solution formed (60 mL). This solution was heated at 60° C. for overnight and the organic solvents were removed under vacuum. The residual aqueous solution was acidified with 2 N HCl to pH 2 and was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to give Example 1B as a white solid (13.72 g, 95.4% yield). MS (DCI/NH3) m/z 264 (M+H)+.
EXAMPLE 1C
benzyl 2-({[2-amino-3-(aminocarbonyl)phenyl]amino}carbonyl)-2-methylpyrrolidine-1-carboxylate
A solution of Example 1B (13.7 g, 52 mmol) in a mixture of pyridine (60 mL) and DMF (60 mL) was treated with 1,1′-carbonyldiimidazole (9.27 g, 57.2 mmol) at 45° C. for 2 h. 2,3-Diamino-benzamide dihydrochloride (11.66 g, 52 mmol), which was synthesized as described in previous patent application WO0026192, was added and the mixture was stirred at rt overnight. After concentration under vacuum, the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1C (16.26 g). Extraction of the aqueous phase with ethyl acetate followed by concentration, filtration and water-EtOAc wash, provided additional 1.03 g of Example 1C. Combined yield: 84%. MS (APCI) m/z 397 (M+H)+.
EXAMPLE 1D
benzyl 2-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]-2-methylpyrrolidine-1-carboxylate
A suspension of Example 1C (17.28 g, 43.6 mmol) in acetic acid (180 mL) was heated under reflux for 2 h. After cooling, the solution was concentrated and the residual oil was partitioned between ethyl acetate and sodium bicarbonate aqueous solution. The organic phase was washed with water and concentrated. The residue was purified by flash column chromatography (silica gel, 3-15% CH3OH in 2:1 EtOAc/hexane) to provide Example 1D (16.42 g, Yield: 99%).
MS (APCI) m/z 379 (M+H)+.
EXAMPLE 1E 2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide
A solution of Example 1D (15.0 g, 40 mmol) in methanol (250 ml) was treated with 10% Pd/C (2.8 g) under 60 psi of hydrogen for overnight. Solid material was filtered off and the filtrate was concentrated. The residual solid was recrystallized in methanol to give 7.768 g of Example 1E as free base. The bis-HCl salt was prepared by dissolving the free base in warm methanol and treating with 2 equivalents of HCl in ether (10.09 g). MS (APCI) m/z 245 (M+H)+; 1H NMR (500 MHz, D2O): δ 1.92 (s, 3 H), 2.00-2.09 (m, 1 H), 2.21-2.29 (m, 1 H), 2.35-2.41 (m, 1 H), 2.52-2.57 (m, 1 H), 3.54-3.65 (m, 2 H), 7.31 (t, J=7.93 Hz, 1 H), 7.68 (dd, J=8.24, 0.92 Hz, 1 H), 7.72 (dd, J=7.63, 0.92 Hz, 1 H); Anal. Calcd for C13H16N4O.2 HCl: C, 49.22; H, 5.72N, 17.66. Found: C, 49.30; H, 5.60; N, 17.39.
EXAMPLE 3 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide EXAMPLE 3A benzyl(2R)-2-[4-(aminocarbonyl)-1H-benzimidazol-2-yl]-2-methylpyrrolidine-1-carboxylate
Example 1D (1.05 g, 2.8 mmol) was resolved on chiral HPLC (Chiralcel OD, 80/10/10 hexane/EtOH/MeOH). The faster eluting peak was collected and concentrated to provide Example 3A (99.4% e.e., 500 mg). MS (APCI) m/z 379 (M+H)+.
EXAMPLE 3B 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide
A solution of Example 3A (500 mg, 1.32 mmol) in methanol (10 ml) was treated with 10% Pd/C (150 mg) under hydrogen for overnight (balloon). Solid material was filtered off and the filtrate was concentrated. The residual solid was further purified by HPLC (Zorbax C-18, CH3CN/H2O/0.1%TFA) and was converted to bis-HCl salt to provide Example 4 as white solid (254 mg). Co-crystallization of the free base with 1 equivalent of L-tartaric acid in methanol gave a single crystal that was suitable for X-ray study. The X-ray structure with L-tartaric acid was assigned the R-configuration. MS (APCI) m/z 245 (M+H)+; 1H NMR (500 MHz, D2O): δ 2.00 (s, 3 H), 2.10-2.19 (m, 1 H), 2.30-2.39 (m, 1 H), 2.45-2.51 (m, 1 H), 2.61-2.66 (m, 1 H), 3.64-3.73 (m, 2 H), 7.40 (t, J=7.95 Hz, 1 H), 7.77 (d, J=8.11 Hz, 1 H), 7.80 (d, J=7.49 Hz, 1 H); Anal. Calcd for C13H16N4O.2 HCl: C, 49.22; H, 5.72; N, 17.66. Found: C, 49.10; H, 5.52; N, 17.61.
……………….
WO2009049111
http://www.google.com/patents/WO2009049111A1?cl=en
EXAMPLE 1 Preparation of ABT-888 Crystalline Form 1 A mixture of ABT-888 dihydrochloride (10 g) was stirred in saturated potassium bicarbonate (50 mL) and n-butanol (50 mL) until the ABT-888 dihydrochloride completely dissolved. The aqueous layer was extracted with a second portion of n-butanol then discarded. The extracts were combined, washed with 15% sodium chloride solution (50 mL) and concentrated. The concentrate was chase distilled three times with heptane (50 mL),dissolved in refluxing 2-propanol (45 mL) and filtered hot. The filtrate was cooled to ambient temperature with stirring over 18 hours, cooled to 0-50C, stirred for 1 hour, and filtered. The filtrant was washed with 2-propanol and dried in a vacuum oven at 45-500C with a slight nitrogen purge.
EXAMPLE 2
Preparation of ABT-888 Crystalline Form 2
A mixture of ABT-888 in methanol, in which the ABT-888 was completely dissolved, was concentrated at about 35 0C, and the concentrate was dried to a constant weight.
EXAMPLE 3 Preparation of ABT-888 Crystalline Form 1
15 16
Step 1 : 2-(2-methyl-2-pyrrolidino)-benzimidazole-4-carboxamide 2 HCl (15) is dissolved in water (3.5 kg / kg 15) at 20 + 5 0C. Dissolution of 15 in water results in a solution of pH 0 – 1.
Step 2: The reaction is run at 20 – 25 0C. One equivalent of sodium hydroxide is added, raising the pH to 2 – 3 with only a mild exotherm (100C observed with rapid addition of 1.0 equiv.). This generates a solution that remains clear for several days even when seeded with free base crystals. 3N NaOH (1.0 equiv., 1.25 kg / kg 15) is charged and the solution polish filtered into the crystallizer/ reactor.
Step 3: 5% Na2CO3 (1.5 equiv., 10.08 kg / kg 15) is then filtered into the crystallizer over 2 hours. Nucleation occurs after approximately l/6th of the Na2CO3 solution is added (-0.25 equiv.)
Step 4: The slurry is mixed for NLT 15 min before sampling (typically 1 to 4 hours (2.5 mg/mL product in the supernatant)). The slurry is filtered at 200C and washed with 6 portions of water (1.0 kg / kg 15 each). Each wash was applied to the top of the cake and then pressured through. No mixing of the wetcake was done.
Step 5 : The solids are then dried. Drying was performed at 500C keeping the Cogeim under vacuum while applying a slight nitrogen bleed. The agitator blade was left in the cake to improve heat transfer to the cake. It was rotated and lifted out of the cake once per hour of drying to speed the drying process while minimizing potential crystal attrition that occurs with continuous agitator use. In one embodiment of Step 1, the volume of water for dissolution of the Dihydrochloride (15) is about 1.3 g water/g 15. In another embodiment of Step 1,, the volume of water for dissolution is about 1.3 g to about 4 g water/g 15. In another embodiment of Step 1, the volume of water for dissolution is 1.3 g to 3.5 g water/g 15. In another embodiment of Step 1, the volume of water for dissolution is 3.5 g water/g 15.
……………………
J. Med. Chem., 2009, 52 (2), pp 514–523
DOI: 10.1021/jm801171j
(2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide
excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a Ki of 5 nM and in a C41 whole cell assay with an EC50 of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.
References
- “ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models” May 2007
- http://www.cancer.gov/drugdictionary/?CdrID=496464
- “ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models”, 2007
- http://clinicaltrialsfeeds.org/clinical-trials/results/term=Drug:+ABT-888
- “ABT-888 and Cyclophosphamide With Versus Without Doxorubicin in Treating Patients With Metastatic or Unresectable Solid Tumors or Non-Hodgkin Lymphoma”
- Phase I Study of ABT-888, a PARP Inhibitor, in Combination with Topotecan Hydrochloride in Adults with Refractory Solid Tumors and Lymphomas.. July 2011. doi:10.1158/0008-5472.CAN-11-1227.
- “A Study Evaluating Efficacy of ABT-888 in Combination With Temozolomide in Metastatic Melanoma”
- “ABT-888 and Temozolomide for Metastatic Breast Cancer”
- “Breast cancer study aims to speed drugs, cooperation”, March 2010
- http://www.centerwatch.com/news-online/article/5737/new-presurgery-combination-therapy-for-triple-negative-breast-cancer
- “Veliparib in Treating Patients With Malignant Solid Tumors That Did Not Respond to Previous Therapy. Clinical Trial NCT00892736”
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4-1-2013
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Design, synthesis and biological evaluation of novel imidazo[4,5-c]pyridinecarboxamide derivatives as PARP-1 inhibitors.
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Bioorganic & medicinal chemistry letters
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8-15-2013
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Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.
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Bioorganic & medicinal chemistry letters
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8-1-2013
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Identification of potent Yes1 kinase inhibitors using a library screening approach.
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Bioorganic & medicinal chemistry letters
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5-1-2010
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A rapid and sensitive method for determination of veliparib (ABT-888), in human plasma, bone marrow cells and supernatant by using LC/MS/MS.
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Journal of pharmaceutical and biomedical analysis
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1-22-2009
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Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer.
|
Journal of medicinal chemistry
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External links
http://kdwn.com/2013/12/16/new-drug-study-method-show-breast-cancer-promise/
| US8013168 | Oct 10, 2008 | Sep 6, 2011 | Abbott Laboratories | Veliparib crystal structure; an anticancer PARP inhibitor |
| US8372987 | Oct 10, 2008 | Feb 12, 2013 | Abbvie Inc. | Title compound is Veliparib, a Poly(ADP-ribose) polymerase i.e. PARP inhibitor; anticancer agent |
| US20060229289 * | Apr 11, 2006 | Oct 12, 2006 | Gui-Dong Zhu | 2-(2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, aka veliparib, for example; poly(ADP-ribose)polymerase inhibitors; antiinflammatory, antitumor agents; Parkinson’s disease |
Penning, Thomas D. et al. Discovery of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the Treatment of Cancer. Journal of Medicinal Chemistry, 52(2), 514-523; 2009
Zhu, Guidong. 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide crystalline form 2 compositions and preparation for treating cancer. PCT Int. Appl. (2009), WO2009049109 A1 20090416
Kolaczkowski, Lawrence . 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide (ABT-888) crystalline form I and its pharmaceutical composition for cancer treatment. PCT Int. Appl. (2009), WO2009049111 A1 20090416.
Zhu, Gui-Dong; Gong, Jianchun; Gandhi, Virajkumar B.; Penning, Thomas D.; Giranda, Vincent L. Preparation of 1H-benzimidazole-4-carboxamides as poly(ADP-ribose)polymerase (PARP) inhibitors. U.S. Pat. Appl. Publ. (2006), US20060229289 A1 20061012.
Your Own Saliva Better For Wound Healing Than Yunnan Baiyao Alone
There are a few herbal formulas within Chinese Medicine that are worth their weight in gold. Yin qiao and/or Gan Mao Ling for colds/flus, Bao Ji Wan for food poisioning/acute digestive disturbances, and Yunnan Baiyao for acute bleeding, among others… In our clinic many of our patients, particularly those prone to getting cuts and scrapes such as construction workers, landscapers, etc. are aware of Yunnan Baiyao. We usually tell them to first rinse the wound if possible, then pour some of the Yunnan Baiyao powder on the wound and then rub in some saliva, then cover lightly. The bleeding stops quickly and the wound heals easily time and time again. Yunnan Baiyao is a top level Chinese military secret, originally developed for healing gun shot wounds in battle, and there is only one manufacturer.
Researchers from the Department of Pathology within the College of Medicine at Xi’an Jiaotong University in…
View original post 186 more words
‘Master switch’ for myelination in human brain stem cells is identified
Scientists at the University at Buffalo have identified the single transcription factor or “master switch” that initiates the critical myelination process in the brain. The research will be published online in Proceedings of the National Academy of Sciences (PNAS) on June 30.
The identification of this factor, SOX10, in human brain cells, brings researchers closer to the goal of treating multiple sclerosis (MS) by transplanting into patients the brain cells that make myelin.
“Now that we have identified SOX10 as an initiator of myelination, we can work on developing a viral or pharmaceutical approach to inducing it in MS patients,” says Fraser Sim, PhD, senior author on the paper and assistant professor in the UB Department of Pharmacology and Toxicology in the School of Medicine and Biomedical Sciences.
“If we could create a small molecule drug that would switch on SOX10, that would be therapeutically important,” he adds.
View original post 514 more words
Eating flavonoids protects men against Parkinson’s disease
07 Apr 2012
Men who eat flavonoid-rich foods such as berries, tea, apples and red wine significantly reduce their risk of developing Parkinson’s disease, according to new research by Harvard University and the University of East Anglia (UEA).
Published today in the journal Neurology ®, the findings add to the growing body of evidence that regular consumption of some flavonoids can have a marked effect on human health. Recent studies have shown that these compounds can offer protection against a wide range of diseases including heart disease, hypertension, some cancers and dementia.
This latest study is the first study in humans to show that flavonoids can protect neurons against diseases of the brain such as Parkinson’s.
Around 130,000 men and women took part in the research. More than 800 had developed Parkinson’s disease within 20 years of follow-up. After a detailed analysis of their diets and adjusting for age and…
View original post 472 more words
Japan scientists find ageing cure – for flowers
Japanese scientists say they have found a way to slow down the ageing process in flowers by up to a half, meaning bouquets could remain fresh for much longer.
Researchers at the National Agriculture and Food Research Organisation in Tsukuba, east of Tokyo, said they had found the gene believed to be responsible for the short shelf-life of flowers in one Japanese variety of morning glory.
“Morning glory” is the popular name for a hundreds of species of flowering plants whose short-lived blooms usually unfold early in the day and are gone by nightfall.
By suppressing the gene—named “EPHEMERAL1″—the lifespan of each flower was almost doubled, said Kenichi Shibuya, one of the lead researchers in a study carried out jointly with Kagoshima University in southern Japan.
“Unmodified flowers started withering 13 hours after they opened, but flowers that had been genetically modified stayed open for 24 hours,” he said.
This…
View original post 166 more words
Edible flowers may inhibit chronic diseases
A new study in the Journal of Food Science, published by the Institute of Food Technologists (IFT), found that common edible flowers in China are rich in phenolics and have excellent antioxidant capacity.
Edible flowers, which have been used in the culinary arts in China for centuries, are receiving renewed interest. Flowers can be used as an essential ingredient in a recipe, provide seasoning to a dish, or simply be used as a garnish. Some of these flowers contain phenolics that have been correlated with anti-inflammatory activity and a reduced risk of cardiovascular disease and certain cancers.
The findings of this study show that common edible flowers have the potential to be used as an additive in food to prevent chronic disease, help health promotion and prevent food oxidization. However, the antioxidant mechanisms, the anti-tumor, anti-inflammation and anti-aging activity of the edible flower extracts should be further studied to…
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Cebranopadol GRT 6005 セブラノパドール a Potent Analgesic NOP and Opioid Receptor Agonist
Cebranopadol
(GRT-6005; GRT 6005; GRT6005)
CAS: 863513-91-1
(1r,4r)-6′-Fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine
Spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-
- C24H27FN2O
- Average mass: 378.482391 Da
Grünenthal GmbH innovator
Cebranopadol(GRT-6005) is a novel first in class compounds with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor.
Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several experimental model models of acute and chronic pain (tail–flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5–5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side–effect profile.
GRT-6005 is a centrally active analgesic in phase II clinical development for the oral treatment of neuropathic pain in patients with painful diabetic polyneuropathy and for the treatment of pain due to osteoarthritis of the knee. It is being developed by Grüenenthal and Forest. No recent development has been reported for research into the treatment of moderate to severe pain following bunionectomy. In 2010, GRT-6005 was licensed to Forest and Grünenthal in Canada and the U.S. for the treatment of moderate to severe chronic pain.
Description: IC50 Value: N/A Cebranopadol and GRT 6006 are novel first-in-class compounds with unique pharmacological and pharmacokinetic profiles that may enhance their effect in certain pain conditions. The unique mode of action of these compounds builds on the ORL-1 receptor and, supported by the established mu opioid receptor, is particularly suitable for the treatment of moderate to severe chronic pain [1]. in vitro: N/A in vivo: N/A Clinical trial: Cebranopadol has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with further Phase II studies planned prior to initiation of Phase III studies.
Neuropathic pain
Neuropathic pain is caused when peripheral nerves are damaged by mechanical, metabolic or inflammatory way. The pain occurring images are mainly due to the occurrence of spontaneous pain, hyperalgesia and allodynia (pain is already triggered by non-noxious stimuli) in. As a result, the lesions to increased expression of Na + channels and thus to spontaneous activity in the damaged axons and their Nachbaraxonen (England et al., Neurology, 1996, 47, 272-276).The excitability of the neurons is increased and they react to incoming stimuli with an increased discharge frequency. This results in an increased sensitivity to pain, which contributes to the development of hyperalgesia and spontaneous pain (Baron, Clin J Pain 2000;. 16 (2 Suppl), 12-20). The causes and manifestations, and therefore the treatment needs of neuropathischerm pain are varied. They arise as a result of injury or disease of the brain, spinal cord or peripheral nerves.Causes may be operations, such as phantom pain after amputation, stroke, multiple sclerosis, spinal cord injury, alcohol or drug abuse or other toxins, cancers but also
Metabolic diseases such as diabetes, gout, kidney failure or liver cirrhosis, or infectious diseases such as mononucleosis, ehrlichiosis, typhoid, diphtheria, HIV, syphilis or Lyme disease. The pain experience is very different signs and symptoms that can change over time in number and intensity. Paradoxically, patients with neuropathic pain outline a slowdown or failure of acute pain perception and the simultaneous increase of neuropathic pain. The typical symptoms of neuropathic pain as tingling, burning, shooting or described, or radiating electrifying. Pharmacological basis for treatment of neuropathic pain include tricyclic antidepressants and anticonvulsants, which are used as monotherapy or in combination with opioids. These drugs usually provide only a certain pain relief during a pain-free but is often not achieved. The often-adjusting side effects are dose increases while the drug to achieve adequate pain relief often in the way. In fact, a higher dosage of a μ-opioid is often required as the treatment of acute pain, thereby reducing the side effects get even more important for satisfactory treatment of neuropathic pain. By the occurrence of typical μ-opioid tolerance development and the concomitant need for dose escalation of this problem is exacerbated. In summary it can be stated that neuropathic pain is difficult to treat and today is alleviated by high doses of μ-opioids only partially (Saudi Pharm J. 2002, 10 (3), 73-85). There is therefore an urgent need for medicines for the treatment of chronic pain, the dose should not be increased until the occurrence of intolerable side effects to ensure a satisfactory pain treatment.
……………
http://www.google.com/patents/US7547707
Example 24 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Non-polar diastereoisomer
4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×60 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The solid contained in the suspension was filtered off with suction and dried. 955 mg of the more non-polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole were obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hot ethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2 mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 h. The solid formed was filtered off with suction. 640 mg of the hemicitrate were obtained as a white solid (m.p. 258-282° C.).
Example 25 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Polar diastereoisomer
4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1 mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture was stirred at RT for 16 h. For working up, the mixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC (3×20 ml). The combined organic phases were dried with sodium sulfate and evaporated. The residue (364 mg of white solid) was suspended in hot ethanol (20 ml), and a similarly hot solution of citric acid (185 mg, 0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolved completely and no longer precipitated out even on cooling to approx. 5° C. Ethanol was removed on a rotary evaporator and the hemicitrate of the more polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained in this way in a yield of 548 mg as a white solid (m.p. 148-155° C.).
| 24 |
 |
hemicitrate | more non-polar diastereomer |
| 25 |
 |
hemicitrate | more polar diastereomer |
………………..
WO 2013113690
(1 r,4r)-6′-fluoro-N,N- dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1 ,1 ‘-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):
http://www.google.com/patents/WO2013113690A1?cl=en
…………………
see A4
…………………………
One particular drug that is of great interest for use in treating cancer pain (and other acute, visceral, neuropathic and chronic pain pain disorders) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine. This drug is depicted below as the compound of formula (I).
The solid forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine that are known so far are not satisfactory in every respect and there is a demand for advantageous solid forms
A) Synthesis of Crystalline Form A100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by FT Raman, TG-FTIR and PXRD.
……………………
In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.
Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol
http://pubs.acs.org/doi/full/10.1021/ml500117c
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/ml500117c
6′-Fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)
hemicitrate were obtained as a white solid (mp 258-282 °C).1H-NMR (300 MHz; DMSO-d6): 1.75-1.87 (m, 4 H); 2.14 (s, 6 H); 2.27 (t, 2 H); 2.61-
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).
13C-NMR (75.47 MHz; DMSO-d6): 22.1; 27.6; 30.2 (2 C); 38.0 (2 C); 43.1; 58.8 (2 C,
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);
112.0 (3JC,F = 10 Hz); 126.5; 126.6; 126.7 (2 C); 127.4 (2 C); 132.4; 138.7; 141.5;
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+
…………………………..
| US20120034297 * | Aug 4, 2011 | Feb 9, 2012 | Gruenenthal Gmbh | Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine |
| US20130012563 * | Jul 6, 2012 | Jan 10, 2013 | Gruenenthal Gmbh | Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine |
| WO2004043967A1 | Nov 5, 2003 | May 27, 2004 | Otto Aulenbacher | Spirocyclic cyclohexane derivatives |
| WO2008040481A1 | Sep 26, 2007 | Apr 10, 2008 | Gruenenthal Gmbh | MIXED ORL 1/μ AGONISTS FOR TREATING PAIN |
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CORAL – Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer
Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.Average amount of daily rescue medication at the end of the maintenance period.
UK Clinical Trials Gateway, 07 October 2013
-
CORAL XT – Open-label Extension Trial of the CORAL Trial
An Open-label, Multi-site Trial to Describe the Safety and Tolerability of Oral Cebranopadol Administered for 26 Weeks in Subjects With Cancer-related Pain Who Have Completed Treatment in the KF6005/07 Trial.Absolute…
UK Clinical Trials Gateway, 12 December 2013
| WO2004043967A1 * | Nov 5, 2003 | May 27, 2004 | Otto Aulenbacher | Spirocyclic cyclohexane derivatives |
| WO2005066183A1 * | Dec 21, 2004 | Jul 21, 2005 | Gruenenthal Gmbh | Spirocyclic cyclohexane derivatives with affinity for the orl1-receptor |
| US20050153998 * | Aug 19, 2004 | Jul 14, 2005 | Fumitaka Ito | Tetrahydroisoquinoline or isochroman compounds |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| US7799931 * | Feb 17, 2009 | Sep 21, 2010 | Gruenenthal Gmbh | Spirocyclic cyclohexane compounds |
| US7951948 * | Apr 19, 2010 | May 31, 2011 | Gruenenthal Gmbh | Spirocyclic cyclohexane compounds |
| US7960404 | Aug 21, 2009 | Jun 14, 2011 | Gruenenthal Gmbh | Spirocyclic cyclohexane compounds |
| US8034936 | Nov 4, 2010 | Oct 11, 2011 | Gruenenthal Gmbh | Spirocyclic cyclohexane compounds useful to treat substance dependency |
| US8053576 | Feb 17, 2009 | Nov 8, 2011 | Gruenenthal Gmbh | Treating conditions associated with the nociceptin/ORL1 receptor system, e.g. pain, drug withdrawal, anxiety, muscle relaxants, anxiolytic agents; e.g. 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluorene |
| US8288406 | Sep 22, 2010 | Oct 16, 2012 | Gruenenthal Gmbh | Hydroxymethylcyclohexylamines |
| US8288430 | Mar 25, 2009 | Oct 16, 2012 | Grunenthal Gmbh | Spiro(5.5)undecane derivatives |
| US8293758 * | Mar 25, 2009 | Oct 23, 2012 | Grunenthal Gmbh | Substituted spirocyclic cyclohexane derivatives |
| US8357705 | Mar 25, 2009 | Jan 22, 2013 | Gruenenthal Gmbh | Substituted cyclohexyldiamines |
| US8404740 | Aug 21, 2009 | Mar 26, 2013 | Gruenenthal Gmbh | Spirocyclic cyclohexane compounds |
| US8614245 * | Jan 8, 2013 | Dec 24, 2013 | Gruenenthal Gmbh | Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine |
| US8618156 * | Jul 6, 2012 | Dec 31, 2013 | Gruenenthal Gmbh | Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine |
| US20130012563 * | Jul 6, 2012 | Jan 10, 2013 | Gruenenthal Gmbh | Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine |
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DR ANTHONY MELVIN CRASTO Ph.D
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GLENMARK SCIENTIST , INDIA
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