AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Boldenone Undecylenate

 Uncategorized  Comments Off on Boldenone Undecylenate
May 032016
 

Boldenone Undecylenate

cas 13103-34-9,

C30 H44 O3,   452.67
Androsta-​1,​4-​dien-​3-​one, 17-​[(1-​oxo-​10-​undecenyl)​oxy]​-​, (17β)​-
  • Androsta-1,4-dien-3-one, 17β-hydroxy-, 10-undecenoate (7CI,8CI)
  • (17β)-17-[(1-Oxo-10-undecenyl)oxy]androsta-1,4-dien-3-one
  • 10-Undecenoic acid, ester with 17β-hydroxyandrosta-1,4-dien-3-one (8CI)
  • Ba 29038
  • Ba 9038
  • Boldefarm
  • Boldenone 10-undecenoate
  • Boldenone undecylenate
  • Equipoise
  • Parenabol
  • Vebonol

Boldenone undec-10-enoate; 17b-[(1-Oxo-10-undecenyl)oxy]-androsta-1,4-dien-3-one; 17b-Hydroxyandrosta-1,4-dien-3-one 10-undecenoate

CAS # 13103-34-9, Boldenone undecylenate, Boldenone undec-10-enoate, 17b-[(1-Oxo-10-undecenyl)oxy]-androsta-1,4-dien-3-one, 17b-Hydroxyandrosta-1,4-dien-3-one 10-undecenoate

PATENT

http://www.google.com/patents/CN104327143A?cl=en

Boldenone (17β- hydroxy-1,4-dien-3-one male steroid, CAS: 846-48-0) The structural formula is:

Figure CN104327143AD00031

Boldenone (Boldenone) is a derivative of testosterone, with a strong ability to support enhanced blood vessels, increase muscle, highlighting the blood vessels, increase appetite and other clinical role.

 Domestic remain alcohol fermentation Preparation of 4- androstenedione (4AD) and 1,4-androstenedione (ADD), the company is numerous, very adequate supply of raw materials. Cheap and easily available 4AD and ADD steroid hormone drugs as key intermediates wide range of applications. Boldenone is an existing technology to the two aforementioned materials are prepared, in particular: (1) from 4-androstenedione as starting material Boldenone, synthetic route is as follows: C

Figure CN104327143AD00032

After the above process route of the first reduction step of the reduction reaction of a 4- substrate androstenedione is added in one solvent dissolved in methanol, and then control the temperature dropping reducing a solution of potassium borohydride reduction reaction. According to this operation and the order of addition, the reduction reaction selectivity, impurities, must be introduced in the subsequent selective oxidation processes to ensure product quality; dehydrogenation process uses a chemical method dehydrogenation need to use more expensive as the dehydrogenation reagent DDQ using bio-dehydrogenation there is a long process cycle, easy contamination and other defects. There is a whole process line production process, long period, poor selectivity, multi-product, active manganese dioxide need freshly prepared, high production costs low.

(2) 1,4 androstenedione as a starting material Boldenone. Since ADD structure contains 3-one and two-keto-17-one, although I, 4- diene in the presence of the male left, increasing the structural stability of the three keto group, but still can not avoid the reduction reaction due 3 position ketone group is reduced to generate a 3-hydroxy-products. In order to avoid the reduction process due to 3-hydroxy-keto group is reduced to generate impurities, Chinese patent CN103030677A use of three-one ether of protection and then be prepared to restore technical solutions, synthetic route is as follows:

Figure CN104327143AD00041

Said routing reduction step, a reduction reaction substrate ether solvent such as methanol was added at once dissolved and then put into a reducing agent, sodium borohydride, thanks in advance 3 ether ketone way of protection, in reducing Reaction to avoid the formation of by-products. Compared with the traditional 4-androstenedione route, eliminating the above process dehydrogenation reaction step, but there are still many steps, long period, higher production costs and other issues.

[0005] In recent years, adding different metal ions in the reduction reaction in order to improve the selectivity of the reduction reaction gradually attracted people’s attention. By participating in a metal borohydride multi carbonyl precursor compound remaining reduction reaction was added CeCl3 · 6H20, CoCl2 · 6H20, CdCl2 · (5/2) H20, CuCl, Cufc the like, to selectively reducing a compound of the structure in different positions keto, thereby obtaining reduced product having a different regioselectivity and stereoselectivity. In order to achieve the 1, 4_ androstenedione preparation Boldenone selective reduction objectives, technical personnel respectively potassium borohydride, sodium borohydride, boron and zinc borohydride as a reducing agent in the reduction reaction were added to the different After the metal ion, in accordance with a first reduction reaction substrate 1, 4_ androstenedione is added in one solvent dissolved, adding metal ions, the reducing agent added in the order reduction reaction. According to the above operation and the addition order, no matter how varying the process parameters have not been able to better achieve the selective reduction of 17-keto purposes.

[0006] Preparation Boldenone prior art process route, the reduction reactions using first reduction reaction substrate added in one solvent to dissolve, then add the reducing agent addition sequence and addition manner. Multi-keto-reduction reaction of the compound according to this method, there is a poor selectivity, multi-product of the state. In order to get qualified products often require the introduction of the first steps were selective oxidation or reduction reaction is not required to protect the keto group in the preparation process route, and then turn reduction, deprotection steps. Preparation prior Boldenone increased reaction step, extend the production cycle, improve the generation costs.

Synthetic route of the present invention are as follows:

Figure CN104327143AD00042
Example always 350ml of methanol was added and the reaction vial IOOml water, cooled with stirring to -10 ° C, 4. 5g of sodium borohydride was added. Then added to -KTC~_5 ° C graded crushed through a 20 mesh processed 50gl, 4- androstenedione, androstenedione added 1,4_ time of 20 minutes ~ 30 minutes. Canada finished continue to -KTC~_5 ° C the reaction was stirred 0.5 hours. The reaction mixture was added a pre-cooled to square ° C~5 ° C water, continuing to 0 ° C~5 ° C was stirred for 0.5 hours, suction filtered, and dried to give 49. 7g of crude product. The crude product is then mixed with methanol and ethyl acetate solvent crystallization to give 47. 6g Boldenone, HPLC purity of 98.6%.

References

Analytical Chemistry (Washington, DC, United States) (2011), 83(4), 1243-1251.

///////Boldenone Undecylenate

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Optimization of thermosensitive chitosan hydrogels for the sustained delivery of venlafaxine hydrochloride

 drugs  Comments Off on Optimization of thermosensitive chitosan hydrogels for the sustained delivery of venlafaxine hydrochloride
May 032016
 

 

image

 

 

Optimization of thermosensitive chitosan hydrogels for the sustained delivery of venlafaxine hydrochloride

Original Research Article

Pages 482-490

Ying Peng, Jie Li, Jing Li, Yin Fei, Jiangnan Dong, Weisan Pan

International Journal of Pharmaceutics

Volume 441, Issues 1–2, Pages 1-834 (30 January 2013)

  • Delivery of venlafaxine hydrochloride with thermosensitive chitosan hydrogels system: diffusion controlled release and kinetic gelation mechanism is nucleation and growth.
  • Abstract

    Chitosan/glycerophosphate disodium (GP) thermosensitive hydrogels were prepared for the sustained delivery of venlafaxine hydrochloride (VH) and optimization of this formulation was mainly studied. Release mechanism was investigated by applying various mathematical models to the in vitro release profiles. Overall, drug release from the hydrogels showed best fit in first-order model and drug release mechanism was diffusion-controlled release. Optimization of VH chitosan/GP thermosensitive hydrogels was conducted by using a three-level three-factorial Box–Behnken experimental design to evaluate the effects of considered variables, the strength of the formulation, chitosan concentration and GP amount, on the selected responses: cumulative percentage drug release in 1 h, 24 h and the rate constant. It presented that higher strength and GP concentration resulted in higher initial release and rate constant, which supported the hypothesis that the kinetic gelation mechanism of this system was nucleation and growth. Drug release profiles illustrated that controlled drug delivery could be obtained over 24 h, which confirmed the validity of optimization. In vivo pharmacokinetic study was investigated and it demonstrated that compared with VH solution, chitosan/GP thermosensitive hydrogels had a better sustained delivery of VH.

///////Optimization, thermosensitive chitosan hydrogels, sustained delivery, venlafaxine hydrochloride

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Elpamotide

 PEPTIDES, Phase 3 drug, Uncategorized  Comments Off on Elpamotide
May 032016
 

STR1

STR1

Elpamotide str drawn bt worlddrugtracker

Elpamotide

L-Arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-alpha-aspartylglycyl-L-asparaginyl-L-arginyl-L-isoleucine human soluble (Vascular Endothelial Growth Factor Receptor) VEGFR2-(169-177)-peptide

MF C47 H76 N16 O13
Molecular Weight, 1073.2164
L-​Isoleucine, L-​arginyl-​L-​phenylalanyl-​L-​valyl-​L-​prolyl-​L-​α-​aspartylglycyl-​L-​asparaginyl-​L-​arginyl-
  • 10: PN: WO2008099908 SEQID: 10 claimed protein
  • 14: PN: WO2009028150 SEQID: 1 claimed protein
  • 18: PN: JP2013176368 SEQID: 18 claimed protein
  • 1: PN: WO2009028150 SEQID: 1 claimed protein
  • 2: PN: WO2010027107 TABLE: 1 claimed sequence
  • 6: PN: WO2013133405 SEQID: 6 claimed protein
  • 8: PN: US8574586 SEQID: 8 unclaimed protein
  • 8: PN: WO2004024766 SEQID: 8 claimed sequence
  • 8: PN: WO2010143435 SEQID: 8 claimed protein

Phase III

A neoangiogenesis antagonist potentially for the treatment of pancreatic cancer and biliary cancer.

OTS-102

CAS No.673478-49-4, UNII: S68632MB2G

Company OncoTherapy Science Inc.
Description Angiogenesis inhibitor that incorporates the KDR169 epitope of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1; VEGFR-2)
Molecular Target Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2) (KDR/Flk-1)
Mechanism of Action Angiogenesis inhibitor; Vaccine
Therapeutic Modality Preventive vaccine: Peptide vaccine
  • Originator OncoTherapy Science
  • Class Cancer vaccines; Peptide vaccines
  • Mechanism of Action Cytotoxic T lymphocyte stimulants
  • 16 Jun 2015 No recent reports on development identified – Phase-II/III for Pancreatic cancer (Combination therapy) and Phase-II for Biliary cancer in Japan (SC)
  • 09 Jan 2015 Otsuka Pharmaceutical announces termination of its license agreement with Fuso Pharmaceutical for elpamotide in Japan
  • 01 Feb 2013 OncoTherapy Science and Fuso Pharmaceutical Industries complete a Phase-II trial in unresectable advanced Biliary cancer and recurrent Biliary cancer (combination therapy) in Japan (UMIN000002500)

STR1

Elpamotide str drawn bt worlddrugtracker

Elpamotide , credit kegg

Elpamotide is a neoangiogenesis inhibitor in phase II clinical trials at OncoTherapy Science for the treatment of inoperable advanced or recurrent biliary cancer. Phase III clinical trials was also ongoing at the company for the treatment of pancreas cancer, but recent progress report for this indication are not available at present.

Consisting of VEGF-R2 protein, elpamotide is a neovascular inhibitor with a totally novel mechanism of action. Its antitumor effect is thought to work by inducing strong immunoreaction against new blood vessels which provide blood flow to tumors. The drug candidate only act against blood vessels involved in tumor growth and is associated with few adverse effects.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival

The vaccine candidate was originally developed by OncoTherapy Science. In January 2010, Fuso Pharmaceutical, which was granted the exclusive rights to manufacture and commercialize elpamotide in Japan from OncoTherapy Science, sublicensed the manufacturing and commercialization rights to Otsuka Pharmaceutical. In 2015, the license agreement between Fuso Pharmaceutical and OncoTherapy Science, and the license agreement between Fuso Pharmaceutical and Otsuka Pharmaceutical terminated.

 

 

 

WO 2010143435

US 8574586

WO 2012044577

WO 2010027107

WO 2013133405

WO 2009028150

WO 2008099908

WO 2004024766

 

PATENT

WO2013133405

The injectable formulation containing peptides, because peptides are unstable to heat, it is impossible to carry out terminal sterilization by autoclaving. Therefore, in order to achieve sterilization, sterile filtration step is essential. Sterile filtration step is carried out by passing through the 0.22 .mu.m following membrane filter typically absolute bore is guaranteed. Therefore, in the stage of pre-filtration, it is necessary to prepare a peptide solution in which the peptide is completely dissolved. However, peptides, since the solubility characteristics by its amino acid sequence differs, it is necessary to select an appropriate solvent depending on the solubility characteristics of the peptide. In particular, it is difficult to completely dissolve the highly hydrophobic peptide in a polar solvent, it requires a great deal of effort on the choice of solvent. It is also possible to increase the solubility by changing the pH, or depart from the proper pH range as an injectable formulation, in many cases the peptide may become unstable.

 

 In recent years, not only one type of peptide, the peptide vaccine formulation containing multiple kinds of peptides as an active ingredient has been noted. Such a peptide vaccine formulation is especially considered to be advantageous for the treatment of cancer.

 

 The peptide vaccine formulation for the treatment of cancer, to induce a specific immune response to the cancer cells, containing the T cell epitope peptides of the tumor-specific antigen as an active ingredient (e.g., Patent Document 1). Tumor-specific antigens these T-cell epitope peptide is derived, by exhaustive expression analysis using clinical samples of cancer patients, for each type of cancer, specifically overexpressed in cancer cells, only rarely expressed in normal cells It never is one which has been identified as an antigen (e.g., Patent Document 2). However, even in tumor-specific antigens identified in this way, by a variety of having the cancer cells, in all patients and all cancer cells, not necessarily the same as being highly expressed. That is, there may be a case in which the cancer in different patients can be an antigen that is highly expressed cancer in a patient not so expressed. Further, even in the same patient, in the cellular level, cancer cells are known to be a heterogeneous population of cells (non-patent document 1), another even antigens expressed in certain cancer cells in cancer cells may be the case that do not express. Therefore, in one type of T-cell epitope peptide vaccine formulations containing only, there is a possibility that the patient can not be obtained a sufficient antitumor effect is present. Further, even in patients obtained an anti-tumor effect, the cancer cells can not kill may be present. On the other hand, if the vaccine preparation comprising a plurality of T-cell epitope peptide, it is likely that the cancer cells express any antigen. Therefore, it is possible to obtain an anti-tumor effect in a wider patient, the lower the possibility that cancer cells can not kill exists.

 

 The effect of the vaccine formulation containing multiple types of T-cell epitope peptide as described above, the higher the more kinds of T-cell epitope peptides formulated. However, if try to include an effective amount of a plurality of types of T cell peptide, because the peptide content of the per unit amount is increased, to completely dissolve the entire peptide becomes more difficult. Further, because it would plurality of peptides having different properties coexist, it becomes more difficult to maintain all of the peptide stability.

 

 For example, in European Patent Publication No. 2111867 (Patent Document 3), freeze-dried preparation of the vaccine formulation for the treatment of cancer comprising a plurality of T-cell epitope peptides have been disclosed. This freeze-dried preparation, in the preparation of peptide solution before freeze drying, each peptide depending on its solubility properties, are dissolved in a suitable solvent for each peptide. Furthermore, when mixing the peptide solution prepared in order to prevent the precipitation of the peptide, it is described that mixing the peptide solution in determined order. Thus, to select a suitable solvent for each peptide, possible to consider the order of mixing each peptide solution is laborious as the type of peptide increases.

In order to avoid difficulties in the formulation preparation, as described above, a vaccine formulation comprising one type of T-cell epitope peptides, methods for multiple types administered to the same patient is also contemplated. However, when administering plural kinds of vaccine preparation, it is necessary to vaccination of a plurality of locations of the body, burden on a patient is increased. Also peptide vaccine formulation, the DTH (Delayed Type Hypersensitivity) skin reactions are often caused called reaction after inoculation. Occurrence of skin reactions at a plurality of positions of the body, increases the discomfort of the patient. Therefore, in order to reduce the burden of patients in vaccination is preferably a vaccine formulation comprising a plurality of T-cell epitope peptide. Further, even when the plurality of kinds administering the vaccine formulation comprising a single type of epitope peptides, when manufacturing each peptide formulation is required the task of selecting an appropriate solvent for each peptide.

Patent Document 1: International Publication No. WO 2008/102557
Patent Document 2: International Publication No. 2004/031413 Patent
Patent Document 3: The European Patent Publication No. 2111867
PATENT
PATENT

///////////Elpamotide, Phase III,  A neoangiogenesis antagonist, pancreatic cancer and biliary cancer, OTS-102, OncoTherapy Science Inc, peptide

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