DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments 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 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

Boldenone Undecylenate

Uncategorized Comments Off

May 032016

Boldenone Undecylenate

cas 13103-34-9,

C₃₀ H₄₄ O_{3, 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:

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

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:

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:

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

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

drugs Comments Off

May 032016

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.
http://www.sciencedirect.com/science/article/pii/S0378517312010125

doi:10.1016/j.ijpharm.2012.11.005

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

Elpamotide

PEPTIDES, Phase 3 drug, Uncategorized Comments Off

May 032016

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

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)

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

https://www.google.com/patents/US8574586

PATENT

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

CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)N)NC(=O)CNC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCCNC(=N)N)N

ASP 3026

Uncategorized Comments Off

May 022016

ASP3026

ASP3026;

CAS 1097917-15-1; ASP-3026; ASP 3026; UNII-HP4L6MXF10;

N2-[2-Methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-1,3,5-triazine-2,4-diamine;

2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine

(N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel selective inhibitor of the fusion protein EML4-ALK.

¹H NMR (CDCl₃, 400 MHz) (ppm) = 1.31 (d, 6H, J = 6.8 Hz), 1.58–1.80 (m, 4H), 1.90–2.04 (m, 2H), 2.16–2.84 (m, 12H), 3.18–3.32 (m, 1H), 3.66–3.76 (m, 2H), 3.88 (s, 3H), 6.48–6.60 (m, 2H), 7.18–7.26 (m, 1H), 7.50–7.72 (m, 2H), 7.86–7.92 (dd, 1H, J = 1.2 Hz, J = 7.6 Hz), 8.06–8.16 (m, 1H), 8.28–8.48 (m, 1H), 8.48–8.62 (m, 1H), 9.28 (s, 1H).

Molecular Formula:	C₂₉H₄₀N₈O₃S
Molecular Weight:	580.7447 g/mol

ASP3026 is a novel and selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. Significant tumor penetration was observed. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts.

ASP-3026 was studied in P1 clinical trials at Astellas Pharma for the oral treatment of advanced solid tumors and advanced B-cell lymphoma. In 2014 the product was discontinued by Astellas due to strategic reasons

JP 2012153674

WO 2012102393

WO 2011145548

WO 2009008371

PATENT

WO2012102393

The compound of the formula (1) has an excellent EML4-ALK fusion protein and inhibitory activity of the kinase of the mutant EGFR protein, we are already reported to be useful as an active ingredient of a pharmaceutical composition for cancer treatment (Patent Document 1). Further, it is the compound of formula (1) there are five polymorphs shown as A01 ~ A05 type, among others A04 type crystal is in finding reported that the most stable type crystals (Japanese Patent Document 2).
[Formula 1] 　a compound of formula (1) described in Patent Document 1 production method of (Patent Document 1 of Example 23), referring to Production Examples and Examples described in this document, the reaction formula (I) It is shown in. That is, 2,4-dichloro-1,3,5-triazine (hereinafter, may be referred to as “compound of formula (15)”.), 2- (isopropylsulfonyl) aniline (hereinafter, “the formula (8) sometimes referred to compound “.) using, by reacting according to the method described in production example 7 of this document, to give compounds of formula (14) to (production example 22 of Patent Document 1), then , the resulting compound of formula (14), a known method (e.g., International Publication No. 2005/016894 pamphlet reference) was prepared by 2-methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] aniline (hereinafter, may be referred to as “formula (13) compounds of.”) is used to react according to the method described in example 1 of the document, and the target it is a method for producing a compound of formula (1) to.

[Formula 2]

Patent Document 1: International Publication No. 2009/008371 pamphlet
Patent Document 2: WO 2011/145548 pamphlet

Example 1
The first step 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (R ¹ and R ² Synthesis of methyl Any compound of formula (10))
　4,4 – N and dimethoxy piperidine monohydrochloride (35.9 g), N-dimethylformamide and (75 mL) were mixed, and the mixed solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (57.5 mL) was added It was. It was separately prepared here 5-fluoro-2-nitroanisole (30.0 g) and N, N-dimethylformamide (30 mL) was stirred for 5 hours at room temperature. Water (120 mL) was added at room temperature to the reaction mixture, after stirring for 4 hours, the precipitated crystals were collected by filtration. The resulting crystals N, N-dimethylformamide and a mixed solution of water (1: 1) (60mL) , water (60 mL), was further washed sequentially with water (60 mL), and dried under reduced pressure at 40 ° C. to give 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (49.9 g, 96.1% yield) as crystals.
D2: 1.72-1.80 (4H, m) , 3.14 (6H, s), 3.44-3.50 (4H, m), 3.91 (3H, m), 6.52 (1H, d, J = 2.4Hz), 6.60 (1H, dd, J = 2.4,9.2Hz), 7.88 (1H, D, J = 9.2Hz)
ESI Tasu: 297

The second step 4- (R (4,4-dimethoxy-1-yl) -2-methoxyaniline ¹ and R ² is methyl none has the formula (Compound 6)) Synthesis of

　4,4-dimethoxy – 1- (3-methoxy-4-nitrophenyl) piperidine and (45.0 g) in tetrahydrofuran and a (225 mL) were mixed, 5% palladium carbon (about 50% wet product, 4.5 g) to this mixed solution was added at room temperature, under a hydrogen atmosphere (2.4821×10 ⁵ Pa), and the mixture was stirred for 5 hours and a half at room temperature. Then filtered off and palladium-carbon, washed with tetrahydrofuran (90mL), was concentrated under reduced pressure filtrate until total volume of about 90mL obtain a slurry. After the slurry was stirred for 1 hour at 40 ° C., n- heptane (135 mL) was added and after stirring for 1 hour at 40 ° C., cooled to 0 ° C., was added n- heptane (405 mL), precipitated crystals It was collected by filtration.The obtained crystals were washed with a mixed solution of tetrahydrofuran (9 mL) and n- heptane (54 mL), and dried in vacuo at 40 ℃, 4- (4,4- dimethoxy-1-yl) -2-methoxy to give aniline (37.9g, 93.7% yield) as crystals.
D2: 1.72-1.80 (4H, m) , 2.90-2.97 (4H, m), 3.11 (6H, s), 3.73 (3H, m), 4.21 (1H, br), 6.30 (1H, d, J = 2.4 , 8.4Hz), 6.46_6.56 (2H, M)
ESI Tasu: 267

The third step 4,6-dichloro-N- [2-(propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (Lv is Cl any, compounds of formula (7) synthesis of)

　cyanuric chloride (25.0 g), sodium bicarbonate (13.7 g), were mixed 2- (isopropylsulfonyl) aniline (29.7 g) and acetone (200 mL), and stirred at room temperature for 25 hours. After adding water (200 mL) at room temperature the reaction mixture was stirred for 19 hours, the precipitated crystals were collected by filtration. The resulting crystals acetone and a mixed solution of water (1: 1) was washed with (100 mL), and dried in vacuo at 40 ° C., 4,6-dichloro-N- [2-(propane-2-sulfonyl) to give phenyl] -1,3,5-triazin-2-amine (45.1g, 95.8% yield) as crystals.
D1: 1.32 (6H, d, J = 6.8Hz), 3.22 (1H, sept, J = 6.8Hz), 7.37 (1H, m), 7.74 (1H, m), 7.93 (1H, m), 8.44 (1H , M), 10.02 (1H, Br)
ESI-: 345, 347

Fourth step 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxy-phenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , (a Lv is Cl, R 5- triazine-2,4-diamine ¹and R ² none is methyl, the formula (compound 5)) synthesis of
4,6-dichloro-N- [2-( propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (40.0 g) was mixed with tetrahydrofuran (400 mL), to this mixed solution 4- (4,4-dimethoxy-piperidin-1 yl) -2-methoxyaniline (32.2 g) and N, N- diisopropylethylamine (16.38g) was stirred for 4 hours at room temperature.Thereafter, isopropyl acetate (40 mL), then extracted by adding a mixed solution of potassium carbonate (2.0 g) and water (40 mL). The obtained organic layer was concentrated under reduced pressure until the total volume of about 200 mL, as a seed crystal, 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- inoculated with [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (4 mg), to give a slurry and stirred for about 15 minutes. The slurry n- heptane (200 mL) was added and filtered off cooled to 18 hours with stirring to precipitate crystals to 0 ° C.. The resulting crystals were washed with a mixed solution of tetrahydrofuran (40 mL) and n- heptane (40 mL), and dried in vacuo at 40 ° C., 6- Chloro -N- [4- (4,4- dimethoxy-piperidine – 1-yl) -2-methoxyphenyl] -N ‘- [2- (the propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (61.4 g, 92.4% yield) It was obtained as a crystal.
D1: 1.30 (6H, d, J = 6.8Hz), 1.88-1.92 (4H, m), 3.18-3.26 (1H, m), 3.23 (3H, s), 3.87 (1H, br), 6.53 (2H, br), 7.21-7.23 (1H, m ), 7.62 (1H, br), 7.88 (1H, d, J = 7.9Hz), 8.05 (1H, br), 8.48 (1H, br), 9.41 (1H, br )
ESI-: 575,577

The fourth alternative process (e.g. without using a seed crystal) 6-Chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane 2-sulfonyl) phenyl] (a Lv is Cl, R-1,3,5-triazine-2,4-diamine ¹ and R ² none is methyl, the formula (5) synthesis of compound of)
4 , and mixed 6-dichloro -N- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (23.0 g) in tetrahydrofuran (230 mL), to this mixed solution 4- (4,4-dimethoxy-1-yl) -2-methoxyaniline (18.5 g) and N, N- diisopropylethylamine (12.7 mL) was stirred for 2 hours at room temperature. Thereafter, isopropyl acetate (57.5 mL), then extracted by adding potassium carbonate (5.75 g) and a mixed solution of water (115 mL). The resulting organic layer was concentrated under reduced pressure. The resulting residue is added and stirred in tetrahydrofuran (50mL) to obtain a slurry. After stirring for 1 hour at the slurry was added tetrahydrofuran (75 mL) and n- heptane (75mL) 40 ℃, cooled to 0 ° C., and stirred for a further 18 hours.Thereafter, n- heptane (50 mL) was added, and the precipitated crystals were collected by filtration. The resulting crystals tetrahydrofuran and n- heptane mixed solution (5: 7) After washing with (24 mL), and dried in vacuo at 40 ° C., 6- chloro-N- [4- (4,4-dimethoxy piperidin-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (30.6g, 80.0% yield ) was obtained as a crystal.

The fifth step and the sixth step (continuous process) 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino ) phenyl] piperidin-4-one synthesis of compound) (formula (3)
6-chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [ 2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (60.0 g), tetrahydrofuran (540 mL) and 10% palladium carbon (about 50% wet product, 10.7 g) and mixed, N to the mixture, added to N- diisopropylethylamine (16.11g) and 2-propanol (60 mL), under a hydrogen atmosphere (2.4131X10 ^{5 of 5} Pa), and stirred for 7 hours at 40 ° C.. Filtration of the palladium-carbon, and washed with tetrahydrofuran (120 mL), the resulting filtrate activated carbon (12.0 g) was added to, and stirred at room temperature overnight. Then filtered off and the activated carbon, and washed with tetrahydrofuran (120mL), N- [4- ( 4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane – to obtain a solution containing 2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine. To this solution was added a mixed solution of 35% hydrochloric acid (21.7 g) and water (120 mL), and stirred for 21 hours at room temperature. To the reaction mixture, it was added a mixed solution of potassium carbonate (35.9 g) and water (120 mL), and extracted. Activated carbon (12.0 g) was added to the obtained organic layer was stirred for 16 h, filtered, washed with activated carbon in tetrahydrofuran (120 mL). The filtrate obtained total amount was concentrated under reduced pressure to approximately 120 mL. After addition of acetone (180 mL) to the resulting mixture, as a seed crystal, 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5 after stirring for 1 hour and inoculated triazin-2-yl} amino) phenyl] piperidin-4-one crystals (60 mg), water (480 mL) was stirred for 20 hours was added, and the precipitated crystals were collected by filtration . The obtained crystals were washed with a mixed solution of acetone (36 mL) and water (96 mL), and dried in vacuo at 40 ℃, 1- [3- methoxy-4 – ({4- [2- (propane -2 – was obtained sulfonyl) anilino] -1,3,5-triazine-2-yl} amino) phenyl] piperidine-4-one (45.8g, 88.7% yield (yield in a continuous two steps)) as crystals .
D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Fifth Step N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine 2,4-diamine (R ¹ and R ² is methyl any formula (4) of compound) synthesis of
6-chloro-N- [4- (4,4-dimethoxy-1-yl) – 2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (5.0 g), tetrahydrofuran (45 mL), 2-propanol (5mL ), 10% palladium-carbon (about 50% wet product, 1.0 g) were mixed, added N, N- diisopropylethylamine (1.81 mL) to this mixed solution, under a hydrogen atmosphere (2.4821X10 ^{5 of 5} Pa), 40 ° C. in and the mixture was stirred for 5 hours and a half. Filtration of the palladium-carbon was washed with tetrahydrofuran (10 mL), and extraction was performed with 10% brine (20 mL). The resulting organic layer was concentrated under reduced pressure. Acetone to the concentrated residue (10 mL), was added diisopropyl ether (40 mL), it was collected by filtration stirred precipitated crystals 30 minutes. The obtained crystals were washed with diisopropyl ether (20 mL), and dried in vacuo at 40 ℃, N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl]-N’- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (4.31 g, 91.6% yield) as crystals.
D2,343K: 1.17 (6H, d, J = 6.8Hz), 1.80 (4H, dd, J = 5.5,5.7Hz), 3.15 (6H, s), 3.21 (4H, dd, J = 5.5,5.7Hz) , 3.77 (3H, s), 6.50 (1H, dd, J = 2.5,8.7Hz), 6.62 (1H, d, J = 2.5Hz), 7.25-7.28 (1H, m), 7.34 (1H, d, J 8.7 Hz =), 7.58 (1H, br), 7.77-7.79 (1H, yd), 8.28 (1H, s), 8.49 (1H, br), 8.63 (1H, br), 9.25 (1H, br)
ESI +: 543

Sixth Step 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (equation (3) a compound of) synthesis of
N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (4.0 g), and tetrahydrofuran (36 mL) and 2-propanol (4 mL) solution of 35% hydrochloric acid containing (1.44 g) a mixture of water (4 mL) was added on, and the mixture was stirred for 17 hours at room temperature. To the reaction mixture, it was added a mixed solution of potassium carbonate (2.4 g) and water (4 mL), and extracted.The resulting organic layer was concentrated under reduced pressure. After stirring for 30 minutes by addition of acetone (12 mL) and water (4 mL) to the concentrated residue, add water (28 mL) was stirred for 1 hour, the precipitated crystals were collected by filtration. The obtained crystals were washed with a mixed solution of acetone (8 mL) and tetrahydrofuran (3 mL), and dried in vacuo at 40 ℃, 1- [3- methoxy-4 – ({4- [2- (propane -2 – give sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (3.42g, 99.2% yield) as crystals.
D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Seventh Step N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (formula (1) compounds) synthesis
of 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1 , 3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (20.0 g), methyl piperazine (8.07 g), were mixed in toluene (200 mL) and acetic acid (9.0 mL), 1 hour at room temperature It stirred. To this mixture solution was added sodium triacetoxyborohydride (17.06 g), and stirred at room temperature for 20 hours. To the reaction mixture, water (60 mL) and methanol (20 mL) was added, extraction to give an organic layer and an aqueous layer 1. This organic layer, water (20 mL) and re-extracted to give a water layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (200 mL). Methanol (220 mL) to the resulting aqueous layer, a mixed solution of sodium hydroxide (9.68 g) and water (48 mL) was added, as a seed crystal, N-{2-methoxy-4- [4- (4-methylpiperazin- 1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystal of diamine (2.0mg) inoculated, after stirring at room temperature for 1.5 hours, add water (220 mL), further stirred for 2 hours at room temperature, the precipitated crystals were collected by filtration. The resulting crystals were washed with a mixed solution of methanol (40mL) and water (40mL), and then dried under reduced pressure at 50 ℃, N- {2- methoxy-4- [4- (4-methyl-piperazine -1 – yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (20.15g, 86.1% yield) It was obtained as A06-form crystals.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

Alternatively 1 (Example not using seed crystals) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N seventh step ‘- [ 2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (compound of formula (1))

　1- [3-methoxy-4 – ({4- [2 – (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (5.0 g), methyl piperazine (2.02 g), toluene (50 mL) and acetic acid (1.5 mL) were mixed and stirred at room temperature for 1 hour. To this mixture solution was added sodium triacetoxyborohydride (4.72 g), and stirred at room temperature for 18 hours. To the reaction mixture, water (15 mL) and methanol (5 mL) was added, extraction to give an organic layer and an aqueous layer 1. This organic layer, water (5 mL) and re-extracted to give a water layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (50 mL). The resulting aqueous layer methanol (55 mL), a mixed solution was added sodium hydroxide (2.0 g) and water (10 mL), was stirred for 62 hours at room temperature, add water (55 mL), at room temperature for a further 2 hours stirring, the formed crystals were separated by filtration. The obtained crystals were washed with a mixed solution of methanol (5 mL) and water (5 mL), and dried in vacuo at 40 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin–1 – yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (4.56g, 78.0% yield) It was obtained as A06-form crystals.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581
alternative seventh step 2 (example using reducing catalyst) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane -2 – sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine synthesis of compounds of formula (1)
1- [3-methoxy-4 – ({4- [2- (propan-2 sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (5.0 g), tetrahydrofuran (30 mL), methylpiperazine (1.81 g) and 10% palladium carbon (about 50 % wet product, were mixed 0.8 g), under a hydrogen atmosphere (2.4821X10 ^{5 of 5}Pa), and stirred for 7 hours at 40 ° C.. Filtration of the palladium-carbon, and washed with tetrahydrofuran (10 mL), the resulting filtrate was concentrated under reduced pressure. To the concentrated residue 2-butanone (9 mL) was added, followed by stirring at 60 ° C. 30 minutes, cooled slowly, at 30 ° C. n-heptane (9 mL) was added, and stirred for 19 hours at room temperature, the precipitated crystals were collected by filtration did.The resulting crystals of 2-butanone and (1 mL) was washed with a mixture of n- heptane (1 mL), and dried in vacuo at 40 ℃, N- {2- methoxy-4- [4- (4-methyl piperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (3.09 g, yield: 88.0%) was obtained.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

　N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , 5-triazine-2,4-diamine by recrystallization purification steps (formula (1 compound of))
(the a method) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (8.80 g), 2-butanone (211 mL) after mixing and confirmation of dissolution and stirring at 65 ° C. 30 minutes for clarifying filtration. After filtrate was total volume concentrated normal pressure to approximately 70 mL, and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (0.9 mg), and stirred for about 10 minutes to obtain a slurry. After stirring for 3 hours at 70 ° C., cooled to 5 ℃ at a rate of 20 ° C. / h and stirred for 17 hours, the precipitated crystals were collected by filtration. The resulting crystals were washed with 2-butanone were cooled with ice water (35.2 mL), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (7.88 g, 89.5% yield, purity 99.4%) was obtained as a A04 type crystal (A04 type ratio 98.9%).

(B method): N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl ] -1,3,5-triazine-2,4-diamine (8.80g), was mixed activated carbon (0.88 g) and 2-butanone (211 mL), after stirring for 1 hour at 75 ° C., was subjected to activated carbon filtration .The filtrate activated carbon (0.88g) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. The filtrate activated carbon (0.88g) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. After filtrate was total volume concentrated normal pressure to approximately 70 mL, and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (0.9 mg), and stirred for about 10 minutes to obtain a slurry. After stirring for 3 hours at 70 ° C., cooled to 5 ℃ at a rate of 20 ° C. / h and stirred for 16 hours, the precipitated crystals were collected by filtration. The resulting crystals were washed with 2-butanone were cooled with ice water (35.2 mL), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (6.60 g, 75.0% yield, purity 99.3%) was obtained as A04 type crystal (A04 type ratio 100%).

Example 2
The first step 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (R ¹ and R ² is methyl Any formula (Compound 10)) Synthesis of
4,4 – dimethoxy piperidine monohydrochloride (69.9kg) and N, N-dimethylformamide (125.7kg) was mixed, to this mixed solution 1,8-diazabicyclo [5.4.0] undec-7-ene and (117.3kg) N It was added N- dimethylformamide (17.0kg). N of separately prepared here 5-fluoro-2-nitroanisole (60.0kg), the N- dimethylformamide (57.0kg) was added at room temperature, N, N- dimethylformamide (29.0 kg) solution was added 5 hours It stirred. At room temperature with a seed crystal of 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (about 6 g) was added to the reaction mixture was stirred at room temperature for 14 hours. Water (240 kg) was added at room temperature to the reaction mixture, after stirring for 22 hours, the precipitated crystals were collected by filtration. The obtained crystals N, washed with a mixed solution of N- dimethylformamide (56.9kg) and water (60kg), washed twice with water (120 kg), and dried in vacuo at 50 ° C., 4, 4 – to give dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (99.7kg, 96.0% yield) as crystals.

D2: 1.72-1.80 (4H, m) , 3.14 (6H, s), 3.44-3.50 (4H, m), 3.91 (3H, m), 6.52 (1H, d, J = 2.4Hz), 6.60 (1H, dd, J = 2.4,9.2Hz), 7.88 (1H, D, J = 9.2Hz)
ESI Tasu: 297

The second step 4- (R (4,4-dimethoxy-1-yl) -2-methoxyaniline ¹ and R ² is methyl none has the formula (Compound 6)) Synthesis of
4,4-dimethoxy – 1- (3-methoxy-4-nitrophenyl) piperidine (99.0kg), 5% palladium carbon (about 50% wet product, 10.5 kg), were mixed at room temperature in tetrahydrofuran (440 kg), under a hydrogen atmosphere (200 ~ 300 kPa ), and stirred at room temperature for 3 hours. Then filtered off and palladium-carbon, tetrahydrofuran and washed with (180.5Kg), the filtrate was concentrated under reduced pressure until the total volume of about 220L, as a seed crystal 4- (4,4-dimethoxy-1-yl) – crystals of 2-methoxyaniline was inoculated (approximately 10g). To the resulting slurry n- heptane (205.4kg) was added at 40 ° C., after stirring for 1 h, was stirred and cooled to 0 ° C. 16 hours. To this slurry was added n- heptane (613.5kg), After stirring for 2 hours, the crystals were collected by filtration. The obtained crystals were washed with a mixed solution of tetrahydrofuran (17.8 kg) and n- heptane (81.5kg), and dried in vacuo at 50 ℃, 4- (4,4- dimethoxy-1-yl) -2 – give methoxyaniline (84.1kg, 94.5% yield) as crystals.

D2: 1.72-1.80 (4H, m) , 2.90-2.97 (4H, m), 3.11 (6H, s), 3.73 (3H, m), 4.21 (1H, br), 6.30 (1H, d, J = 2.4 , 8.4Hz), 6.46_6.56 (2H, M)
ESI Tasu: 267

The third step 4,6-dichloro-N- [2-(propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (Lv is Cl any, compounds of formula (7) synthesis of)

　cyanuric acid chloride (40.0kg) and acetone (249.2kg) was mixed at a 17 ℃. Sodium hydrogen carbonate in the mixed solution (21.9 kg), 2-a (isopropylsulfonyl) aniline (47.5Kg) was added, and stirred at room temperature for 23 hours. After adding to the reaction mixture water (320 kg) at room temperature, and stirred for 3.5 hours, the precipitated crystals were collected by filtration. After washing the obtained crystals with a mixed solution of acetone (63.0kg) and water (80 kg), and dried in vacuo at 50 ° C., 4,6-dichloro -N- [2- (propane-2-sulfonyl) phenyl ] -1,3,5-triazin-2-amine (71.6kg, 95.1% yield) was obtained as crystals.

D1: 1.32 (6H, d, J = 6.8Hz), 3.22 (1H, sept, J = 6.8Hz), 7.37 (1H, m), 7.74 (1H, m), 7.93 (1H, m), 8.44 (1H , M), 10.02 (1H, Br)
ESI-: 345, 347

Fourth step 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxy-phenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , (a Lv is Cl, R 5- triazine-2,4-diamine ¹and R ² none is methyl, the formula (compound 5)) synthesis of
4,6-dichloro-N- [2-( propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (70.9 kg) in tetrahydrofuran (611.1kg) was mixed at room temperature, to this mixed solution 4- (4,4-dimethoxy-piperidine 1-yl) -2-methoxyaniline (57.1kg), N, N- diisopropylethylamine (29.1 kg) was stirred for 4 hours at room temperature. Thereafter, isopropyl acetate (61.0kg), then extracted by adding potassium carbonate (3.6 kg) and a mixed solution of water (71 kg).The resulting organic layer total amount was concentrated under reduced pressure at an external temperature of about 40 ° C. to approximately 360 L, as a seed crystal, 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2 – methoxyphenyl] -N ‘- [2- was inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (approximately 7 g) to give a slurry. To this slurry of 2-propanol (111.0kg), n- heptane (243.1kg) was added and after cooling for 2 hours at room temperature, was collected by filtration stirred precipitated crystals were cooled to 0 ℃ 18 hours. The resulting crystals tetrahydrofuran (74.9kg), 2- propanol (44.6kg), was washed with a mixed solution of n- heptane (97.6kg), and then dried under reduced pressure at 50 ℃, 6- chloro -N- [ 4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine It was obtained (108.9kg, 92.4% yield) as crystals.

D1: 1.30 (6H, d, J = 6.8Hz), 1.88-1.92 (4H, m), 3.18-3.26 (1H, m), 3.23 (3H, s), 3.87 (1H, br), 6.53 (2H, br), 7.21-7.23 (1H, m ), 7.62 (1H, br), 7.88 (1H, d, J = 7.9Hz), 8.05 (1H, br), 8.48 (1H, br), 9.41 (1H, br )
ESI -: 575,577
fifth step and the sixth step (continuous process) 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazine – 2-yl} amino) phenyl] piperidin-4-one synthesis of compound) (formula (3)
6-chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (108.2kg), tetrahydrofuran (866.0kg), 10% palladium carbon (about 50% wet goods, 23.3 kg) were mixed, N to this mixed solution was added to N- diisopropylethylamine (28.9 kg) and 2-propanol (85.5kg), under a hydrogen atmosphere (100 ~ 300kPa), 4 hours at 40 ° C. did. Filtration of the palladium-carbon was washed with tetrahydrofuran (193.3kg), N- [4- ( 4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane -2 – to obtain a solution containing a sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine. To this solution was added 35% hydrochloric acid (39.1 kg) of mixed solution of water (217kg), and stirred for 15 hours at room temperature. To the reaction mixture, added potassium carbonate (64.8kg) and a mixed solution of water (217kg), and extracted. Activated carbon (10.8 kg) was added to the obtained organic layer and stirred for 17 hours at room temperature, filtered and washed activated carbon with tetrahydrofuran (96.0kg). The resulting filtrate was concentrated under reduced pressure until the total volume of about 380L at 40 ° C.. After the resultant mixture was added acetone (257.1Kg), as a seed crystal, 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] 1,3,5 – after stirring for 1 hour was inoculated triazin-2-yl} amino) phenyl] piperidin-4-one crystals (approximately 11g), the addition of water (865Kg) was stirred for 15 hours, the precipitated crystals were collected by filtration did. The obtained crystals were washed with a mixed solution of acetone (50.9kg) and Tsunemizu (173 kg), and dried in vacuo at 50 ℃, 1- [3- methoxy-4 – ({4- [2- (propane 2-sulfonyl) anilino] -1,3,5-triazine-2-yl} amino) phenyl] piperidine-4-one (82.9kg, 89.0% yield (yield in a continuous two steps)) as crystals Obtained.

D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Seventh Step N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (formula (1) compounds) synthesis
of 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1 , 3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (60.1kg), methylpiperazine (24.2kg), was mixed with toluene (500 kg) and acetic acid (28.4kg), 1 hour at room temperature It stirred. To this mixture solution was added sodium triacetoxyborohydride (51.4kg), and stirred at room temperature for 17 hours. To the reaction mixture, methanol (47.5kg) and water (180.1kg) was added, extraction to give an organic layer and an aqueous layer 1. The organic layer was re-extracted by adding water (60.0kg), to obtain an aqueous layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (523.4kg). The resulting aqueous layer methanol (522.3kg), a mixed solution of 48% sodium hydroxide (60.6kg) and water (112.7kg) was added, as a seed crystal N- {2- methoxy-4- [4- (4 – methyl-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystal of diamine (about 6 g) were inoculated, after stirring at room temperature for 2 hours, added water (660.2kg), further stirred for 3.5 hours at room temperature, the precipitated crystals were collected by filtration. The obtained crystals were washed with a mixed solution of methanol (104.4kg) and water (132.0kg), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin- 1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (54.2kg, yield: 77.1 %) was obtained as A06-form crystals.

D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

　N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , purification step by recrystallization 5-triazine-2,4-diamine (compound of formula (1))
N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (54.3kg), activated charcoal (5.4 kg), 2-butanone (1046.1 kg) were mixed, stirred for 1 hour at 75 ° C., was subjected to active carbon filtration. The filtrate activated carbon (5.4kg) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. The filtrate activated carbon (5.4kg) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. After filtrate was total volume approximately until 430L normal pressure concentrated and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- inoculated with [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (approximately 5 g), after stirring for 3 hours, It was cooled to 5 ℃ at a rate of 20 ℃ / h, and the precipitated crystals were collected by filtration. After washing with the resulting crystals were cooled in 5 of 5 ° C. 2-butanone (220L), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (42.6kg, 78.5% yield, purity 99.5%) was obtained as A04-form crystals (A04 type ratio 100%).

Ken Jones, president and chief executive officer, Astellas Pharma Europe

Paper

Organic Process Research & Development (2015), 19(12), 1966-1972

Strategy for Controlling Polymorphism of Di(Arylamino) Aryl Compound ASP3026 and Monitoring Solution Structures via Raman Spectroscopy

Kazuhiro Takeguchi^*^†^§, Kazuyoshi Obitsu^†, Shun Hirasawa^†, Ryoki Orii^†, Shigeru Ieda^‡, Minoru Okada^†, andHiroshi Takiyama^§

^† Technology Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001,Japan

^‡ Astellas Pharma Tech Co., Ltd., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan

^§ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Org. Process Res. Dev., 2015, 19 (12), pp 1966–1972

DOI: 10.1021/acs.oprd.5b00208

Publication Date (Web): October 23, 2015

*E-mail:kazuhiro.takeguchi@astellas.com. Tel.: +81-293-23-5459. Fax: +81-293-23-5993.

Abstract

ASP3026(N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date, and the most stable polymorph (A04) was selected for designing solid formulations. The influence of crystallization process parameters on nucleation of A03 and A04 was clarified for process development. A04 was obtained at relatively high temperatures and A03 at relatively low temperatures, regardless of the superaturation ratio. A03 and A04 were therefore able to be selectively obtained via temperature control, possibly due to temperature-dependent variations in the concentrations of conformers in solution. The relationship between polymorphs and solution structures before nucleation was investigated using in situ Raman spectroscopy. The relationship with the intensity ratios of nine Raman bands of both polymorphs and ASP3026 solution structures was investigated in detail. Our findings suggest that the solution structure shifted from a structure similar to that of A04 to one similar to that of A03 with decreasing temperature.

Chairman of Astellas Pharma Inc. Mr. Masafumi Nogimori is conferred with Netherlands Honor – ‘Officer in the Order of Oranje-Nassau’

PAPER

Effect of Temperature and Solvent of Solvent-Mediated Polymorph Transformation on ASP3026 Polymorphs and Scale-up

Kazuhiro Takeguchi^*^†^§, Kazuyoshi Obitsu^†, Shun Hirasawa^†, Ryoki Orii^†, Shigeru Ieda^‡, Minoru Okada^†, andHiroshi Takiyama^§

^† Technology Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001,Japan

^‡ Astellas Pharma Tech Co., Ltd., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan

^§ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00068

Publication Date (Web): April 28, 2016

*Telephone: +81-293-23-5459. Fax: +81-293-23-5993; e-mail:kazuhiro.takeguchi@astellas.com.

Abstract

ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date. Process development was conducted for large-scale pilot plant manufacturing, and obtaining the desired polymorph A04 was key after a synthetic route of ASP3026 was selected for scale-up. The effects of temperature and solvent species on induction time of polymorph transformation were investigated using in situ Raman spectroscopy, and selective transformation conditions of A02 to A03 and A04 were examined in detail. A04 was obtained at high temperatures using highly polar non-hydrogen-bond-donating solvents, while A03 was obtained at low temperatures using low-polarity or hydrogen-bond-donating solvents. Further, the desired polymorph A04 was successfully obtained in high purity in first stage scale-up manufacturing. Given these findings, this method of solvent-mediated polymorph transformation may aid in process development for obtaining desired polymorphs.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00068

REFERENCES

1: Awad MM, Shaw AT. ALK Inhibitors in Non-Small Cell Lung Cancer: Crizotinib and Beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39. PubMed PMID: 25322323.

2: George SK, Vishwamitra D, Manshouri R, Shi P, Amin HM. The ALK inhibitor ASP3026 eradicates NPM-ALK⁺ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model. Oncotarget. 2014 Jul 30;5(14):5750-63. PubMed PMID: 25026277; PubMed Central PMCID: PMC4170597.

3: Mori M, Ueno Y, Konagai S, Fushiki H, Shimada I, Kondoh Y, Saito R, Mori K, Shindou N, Soga T, Sakagami H, Furutani T, Doihara H, Kudoh M, Kuromitsu S. The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice. Mol Cancer Ther. 2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395. Epub 2014 Jan 13. PubMed PMID: 24419060.

Patent ID	Date	Patent Title
US2015150850	2015-06-04	TREATING CANCER WITH HSP90 INHIBITORY COMPOUNDS
US8906885	2014-12-09	Treating cancer with HSP90 inhibitory compounds
US2013338358	2013-12-19	METHOD FOR PRODUCING DI(ARYLAMINO)ARYL COMPOUND AND SYNTHETIC INTERMEDIATE THEREFOR
US2013096100	2013-04-18	DI(ARYLAMINO)ARYL COMPOUND
US2013059855	2013-03-07	CRYSTAL OF DI(ARYLAMINO)ARYL COMPOUND
US2010099658	2010-04-22	DI(ARYLAMINO)ARYL COMPOUND

////ASP3026, EML4-ALK, ASP 3026, ASTELLAS

CC(C)S(=O)(=O)C1=CC=CC=C1NC2=NC=NC(=N2)NC3=C(C=C(C=C3)N4CCC(CC4)N5CCN(CC5)C)OC

Cebranopadol hemicitrate, セブラノパドール

Uncategorized Comments Off

May 022016

Cebranopadol hemicitrate, GRT-6005

Grünenthal GmbH innovator

SYNTHESIS COMING WATCH OUT………. Glitter Glitter Glitter Glitter

A mu-opioid agonist for treatment of neuropathic pain and pain due to osteoarthritis.

CAS No.863513-92-2(Cebranopadol Hemicitrate)

CAS 863513-91-1(FREE FORM)

Spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-, trans

MF C₂₄ H₂₇ F N₂ O, MW, 378.48

Spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-, (1α,4β)-

Cebranopadol (GRT-6005) is a novel opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states.^[1]^[2]^[3] As of November 2014, it is in phase III clinical trials. Cebranopadol is unique in its mechanism of action as an opioid, binding to and activating all four of the opioid receptors; it acts as afull agonist of the nociceptin receptor (K_i = 0.9 nM; EC₅₀ = 13.0; IA = 89%), μ-opioid receptor (K_i = 0.7 nM; EC₅₀ = 1.2; IA = 104%), and δ-opioid receptor (K_i = 18 nM; EC₅₀ = 110; IA = 105%), and as a partial agonist of the κ-opioid receptor (K_i = 2.6 nM; EC₅₀ = 17; IA = 67%).^[1] The ED50 values of 0.5-5.6 µg/kg when introduced IV & 25.1 µg/kg after oral administration.^[4]

Cebranopadol shows highly potent and effective antinociceptive and antihypertensive effects in a variety of different animal modelsof pain.^[1] Notably, it has also been found to be more potent in models of chronic neuropathic pain than acute nociceptive paincompared to selective μ-opioid receptor agonists.^[1] Relative to morphine, tolerance to the analgesic effects of cebranopadol has been found to be delayed (26 days versus 11 days for complete tolerance).^[1] In addition, unlike morphine, cebranopadol has not been found to affect motor coordination or reduce respiration in animals at doses in or over the dosage range for analgesia.^[1] As such, it may have improved and prolonged efficaciousness and greater tolerability in comparison to currently available opioid analgesics.^[1]

As an agonist of the κ-opioid receptor, cebranopadol may have the capacity to produce psychotomimetic effects and other adverse reactions at sufficiently high doses, a property which could potentially limit its practical clinical dosage range.^[5]

Cebranopadol (trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [K_i (nM)/EC₅₀(nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat 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. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol’s duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). 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.

Almost 20 years ago, a new member of the opioid receptor family and its endogenous agonist were described (Meunier et al., 1995; Reinscheid et al., 1995). Because of its partial homology to the opioid receptors [mu-opioid peptide (MOP) receptor, delta-opioid peptide (DOP) receptor, kappa-opioid peptide (KOP) receptor] and its insensitivity to the prototypical opioid agonist and antagonist ligands morphine and naloxone, this receptor was initially termed opioid receptor-like receptor, ORL1. Subsequently, it was renamed the nociceptin/orphanin FQ peptide (NOP) receptor after its endogenous ligand nociceptin, and it is now considered to be a non-opioid member of the opioid receptor family (Cox et al., 2009). At a cellular level, the actions of the NOP receptor are broadly similar to those of the opioid receptors (Chiou et al., 2007; Lambert, 2008). Although NOP receptors are clearly expressed at all levels of the pain pathways, it is thought that NOP and MOP receptors are not colocalized in the same neurons and may, thus, have independent actions in at least partly distinct neuronal networks (Monteillet-Agius et al., 1998).

The role of the NOP receptor in pain and analgesia has remained unclear for some time owing to inconsistent findings in early reports using nociceptin to activate the receptor. Being a peptide, nociceptin was administered locally into the central nervous system (CNS) where it produced both pronociceptive and antinociceptive effects when administered supraspinally (Meunier et al., 1995; Calo and Guerrini, 2013). Remarkably, when administered into the spinal cord of rodents and nonhuman primates, nociceptin consistently produced antinociceptive effects (Ko et al., 2009; Sukhtankar and Ko, 2013). Subsequent studies of systemic administration of nonpeptide NOP receptor agonists revealed that such compounds were effective analgesics in animal pain models. Although evidence for antinociceptive and antihyperalgesic effects in rodents is limited and inconsistent (Jenck et al., 2000; Reiss et al., 2008), Ko et al. (2009) demonstrated impressive antinociceptive and antiallodynic potency and efficacy using the NOP receptor agonist Ro64-6198 in Rhesus monkeys. Potency and efficacy were comparable with those of alfentanil but with a complete absence of alfentanil-associated side effects such as itching/scratching and respiratory depression and no evidence of reinforcing effects (Ko et al., 2009; Podlesnik et al., 2011).

Currently, strong MOP receptor agonists are the most effective drugs for the treatment of moderate to severe acute and chronic pain. However, although these drugs provide potent analgesia, they also carry the risk of severe side effects such as respiratory depression, nausea, vomiting, and constipation, and their use may lead to physical dependence and tolerance (Zöllner and Stein, 2007). In addition, opioids are considered to have limited efficacy in treating chronic nociceptive and neuopathic pain owing to a reduction in the already low therapeutic index (Rosenblum et al., 2008; Labianca et al., 2012). For these reasons, there is an unmet medical need for potent and well-tolerated analgesics for the treatment of moderate to severe chronic nociceptive and neuropathic pain.

As NOP and opioid receptor agonists modulate pain and nociception via distinct yet related targets, combining both mechanisms may constitute an interesting and novel approach for the development of innovative analgesics. Notably, a supra-additive interaction between intrathecal morphine and intrathecal nociceptin has been described in rodents (Courteix et al., 2004), as well as an enhancement of the antinociceptive effect of systemic morphine by systemic administration of Ro64-6198 (Reiss et al., 2008). Furthermore, a synergistic effect of concurrent NOP and MOP receptor activation without significant side effects has been demonstrated in nonhuman primates after systemic administration (Cremeans et al., 2012). At the same time, activation of NOP receptors has been proposed to counteract supraspinal opioid activity; in animal studies, NOP receptor agonists do not generate typical opioid-like side effects and may even ameliorate opioid-related side effects when administered concurrently with an opioid agonist (Ko et al., 2009; Rutten et al., 2010; Toll, 2013). Thus, a combination of NOP and opioid receptor activation may be particularly suited to provide potent analgesia with reduced opioid-like side effects.

To explore the potential benefits of NOP and opioid receptor coactivation, novel compounds acting as agonists on both NOP and opioid receptors have been designed (Molinari et al., 2013; Zaveri et al., 2013). This article describes the preclinical pharmacology of cebranopadol, a potent NOP and opioid receptor agonist derived from a novel chemical series of spiro[cyclohexane-dihydropyrano[3,4-b]indol]-amines (S. Schunk, K. Linz, C. Hinze, S. Frormann, S. Oberbörsch, B. Sundermann, S. Zemolka, W. Englberger, T. Germann, T. Christoph, B.Y. Kögel, W. Schröder, S. Harlfinger, D. Saunders, A. Kless, H. Schick, and H. Sonnenschein, submitted manuscript) that was developed by Grünenthal (Aachen, Germany) and is currently in clinical development for the treatment of severe chronic pain……..http://jpet.aspetjournals.org/content/349/3/535.full

WO 2013170968

WO 2013170966

WO 2013170971

WO 2013170972

WO 2013170970

WO 2013170969

WO 2013170967

WO 2004043967

US 20130150590

PAPER

ACS Medicinal Chemistry Letters (2014), 5(8), 857-862.

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

^†Departments of Medicinal Chemistry, ^‡Preclinical Drug Safety, ^§Molecular Pharmacology, ^∥Pain Pharmacology,^⊥Pharmacokinetics, and ^#Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH, D-52099 Aachen, Germany

^○ ASCA GmbH Angewandte Synthesechemie Adlershof, Magnusstr. 11, 12489 Berlin, Germany

ACS Med. Chem. Lett., 2014, 5 (8), pp 857–862

DOI: 10.1021/ml500117c

Publication Date (Web): June 24, 2014

*(S.S.) E-mail: stefan.schunk@grunenthal.com.

Abstract

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.

http://pubs.acs.org/doi/abs/10.1021/ml500117c?source=chemport&journalCode=amclct

MP 258-282 DEG CENT

October the family Grünenthal GmbH celebrated its longtime employee in Aachen-Eilendorf. Proud 680 years of service …

PATENT

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

PATENT

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

PATENT

http://www.google.com/patents/WO2008040481A1?cl=en

see A4

PATENT

http://www.google.com/patents/US20130231381

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.

……………………

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

synthesis…………http://pubs.acs.org/doi/suppl/10.1021/ml500117c/suppl_file/ml500117c_si_001.pdf

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)

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).

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);

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]+

PATENTS

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

References

Linz K, Christoph T, Tzschentke TM; et al. (June 2014). “Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist”. J. Pharmacol. Exp. Ther. 349 (3): 535–48. doi:10.1124/jpet.114.213694.PMID 24713140.
Schunk S, Linz K, Hinze C; et al. (August 2014). “Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol”. ACS Med Chem Lett 5 (8): 857–62.doi:10.1021/ml500117c. PMID 25147603.
Lambert DG, Bird MF, Rowbotham DJ (September 2014). “Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist”. Br J Anaesth114: 364–6. doi:10.1093/bja/aeu332. PMID 25248647.
Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. Journal of Pharmacol Exp Ther. 2014 Jun;349(3):535-48. doi: 10.1124/jpet.114.213694
Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). “Psychotomimesis mediated by kappa opiate receptors”. Science 233 (4765): 774–6. doi:10.1126/science.3016896.PMID 3016896.
Expert Opinion on Investigational Drugs (2015), 24(6), 837-844
Journal of Pharmacology and Experimental Therapeutics (2014), 349(3), 535-548,
External links
- About Cebranopadol – Oceanic Program
- Cebranopadol Search Results – ClinicalTrials.gov

Cebranopadol
Systematic (IUPAC) name

(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
Pharmacokinetic data
Biological half-life	~4.5 hours
Identifiers
CAS Number	863513-91-1
ATC code	None
PubChem	CID 11848225
ChemSpider	29398942
Chemical data
Formula	C₂₄H₂₇FN₂O
Molar mass	378.482 g/mol

////Cebranopadol hemicitrate, GRT-6005, Cebranopadol, セブラノパドール

CN([C@]1(CC[C@]2(OCCc3c2[nH]c4c3cc(cc4)F)CC1)c5ccccc5)C

SQ 109, Pyrrole Hybrid Derivatives, Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Uncategorized Comments Off

May 012016

Abstract Image

Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity towardMycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.

Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N′-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Sanjib Bhakta^†, Nicolò Scalacci^‡^⊥, Arundhati Maitra^†, Alistair K. Brown^#^‡, Saiprasad Dasugari^‡, Dimitrios Evangelopoulos^§, Timothy D. McHugh^§, Parisa N. Mortazavi^†, Alexander Twist^‡, Elena Petricci^∥, Fabrizio Manetti^*^∥, and Daniele Castagnolo^*^⊥^‡

^† Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, U.K.

^‡ Department of Applied Sciences, Northumbria University Newcastle, Ellison Place, NE1 8ST, Newcastle upon Tyne,U.K.

^§ Centre for Clinical Microbiology, University College London, London, NW3 2PF U.K.

^∥ Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy

^⊥ Institute of Pharmaceutical Science, King’s College London, 150 Stamford Street, London SE1 9NH, U.K.

^# School of Medicine, Pharmacy and Health, Durham University, Queen’s Campus, Stockton-on-Tees, TS17 6BH, U.K.

J. Med. Chem., 2016, 59 (6), pp 2780–2793

DOI: 10.1021/acs.jmedchem.6b00031

Publication Date (Web): February 23, 2016

*FB: e-mail, fabrizio.manetti@unisi.it; tel, +390577234256., *D.C.: e-mail, daniele.castagnolo@kcl.ac.uk; tel, +44(0)2078484506.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00031

SQ109 is a drug undergoing development for treatment of tuberculosis.^[1]^[2]

Background

On October 16, 2007, it was given the status of Orphan drug by the U.S. Food and Drug Administration (FDA) for use against drug-susceptible and drug-resistant TB bacteria.^[3]

SQ109 completed three phase I studies in the U.S. and one Phase II efficacy studies in tuberculosis patients in Africa. SQ109 showed activity against both drug susceptible and Multi-drug-resistant tuberculosis bacteria, including Extensively drug-resistant tuberculosis strains. In preclinical studies SQ109 enhanced the activity of anti-tubercular drugs isoniazid and rifampin and reduced by >30% the time required to cure mice of experimental TB.

SQ109 is being developed by OOO Infectex in Russia and by Sequella Inc internationally. In July 2012, Infectex received notification from the Russian Ministry of Health for approval to begin the pivotal clinical trial associated with a drug registration submission, and can proceed with the clinical development of SQ109 for treatment of tuberculosis in the Russian Federation.^[4]

References

Jia, L.; Tomaszewski, J. E.; Hanrahan, C.; Coward, L.; Noker, P.; Gorman, G.; Nikonenko, B.; Protopopova, M. (2009). “Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug”. British Journal of Pharmacology 144 (1): 80–87. doi:10.1038/sj.bjp.0705984. PMC 1575972. PMID 15644871.
Meng, Q.; Luo, H.; Liu, Y.; Li, W.; Zhang, W.; Yao, Q. (2009). “Synthesis and evaluation of carbamate prodrugs of SQ109 as antituberculosis agents”. Bioorganic & Medicinal Chemistry Letters 19 (10): 2808–10. doi:10.1016/j.bmcl.2009.03.091. PMID 19362471.
“New FDA Orphan Drugs: AVI-4658, SQ109, ATIR”. Medscape Medical News. 11 November 2007.

“PRESS RELEASE Maxwell Biotech Venture Fund`s Portfolio Company, Infectex, Receives Russian Regulator`s Approval to Conduct Pivotal Clinical Trial for Sequella’s Antibiotic, SQ109, for Tuberculosis”. Reuters. 26 July 2012.

SQ109
Names

IUPAC name N-Adamantan-2-yl-N’-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine
Identifiers
IUPHAR/BPS	7997
Jmol 3D model	Interactive image
PubChem	5274428
SMILES [show]
Properties
Chemical formula	C₂₂H₃₈N₂
Molar mass	330.56 g·mol⁻¹

SQ109; SQ-109; SQ 109; UNII-9AU7XUV31A; CHEMBL561057; N’-(2-adamantyl)-N-[(2E)-3,7-dimethylocta-2,6-dienyl]ethane-1,2-diamine; More…
Molecular Formula:	C₂₂H₃₈N₂
Molecular Weight:	330.55052 g/mol

SQ109 is an orally active, small molecule antibiotic for treatment of pulmonary TB. Currently in Phase I clinical trials, SQ109 could replace one or more drugs in the current first-line TB drug regimen, simplify therapy, and shorten the TB treatment regimen.

Patent ID	Date	Patent Title
US2014045791	2014-02-13	COMBINATION THERAPY TO TREAT MYCOBACTERIUM DISEASES
US8202910	2012-06-19	Compositions and methods for treatment of infectious disease
US2011118307	2011-05-19	Compositions and methods for the treatment of infectious diseases
US7842729	2010-11-30	Anti tubercular drug: compositions and methods
US2009281054	2009-11-12	COMPOSITIONS AND METHODS COMPRISING CAPURAMYCIN ANALOGUES
US7456222	2008-11-25	Anti tubercular drug: compositions and methods
US6951961	2005-10-04	Methods of use and compositions for the diagnosis and treatment of infectious disease
US2004033986	2004-02-19	Anti tubercular drug: compositions and methods
US2004019117	2004-01-29	Anti tubercular drug: compostions and methods

///////SQ109, bm 212

ImmunoPET Imaging of Insulin-Like Growth Factor 1 Receptor in a Subcutaneous Mouse Model of Pancreatic Cancer

Uncategorized Comments Off

Apr 302016

The role of insulin-like growth factor-1 receptor (IGF-1R) in cancer tumorigenesis was established decades ago, yet there are limited studies evaluating the imaging and therapeutic properties of anti-IGF-1R antibodies. Noninvasive imaging of IGF-1R may allow for optimized patient stratification and monitoring of therapeutic response in patients. Herein, this study reports the development of a Zirconium-89 (⁸⁹Zr)-labeled anti-IGF-1R antibody (⁸⁹Zr-Df-1A2G11) for PET imaging of pancreatic cancer. Successful chelation and radiolabeling of the antibody resulted in a highly stable construct that could be used for imaging IGF-1R expressing tumors in vivo. Western blot and flow cytometry studies showed that MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines expressed high, moderate, and low levels of IGF-1R, respectively. These three pancreatic cancer cell lines were subcutaneously implanted into mice. By employing the PET imaging technique, the tumor accumulation of ⁸⁹Zr-Df-1A2G11 was found to be dependent on the level of IGF-1R expression. Tumor accumulation of ⁸⁹Zr-Df-1A2G11 was 8.24 ± 0.51, 5.80 ± 0.54, and 4.30 ± 0.42 percentage of the injected dose (%ID/g) in MIA PaCa-2, BxPC-3, and AsPC-1-derived tumor models at 120 h postinjection, respectively (n = 4). Biodistribution studies and ex vivo immunohistochemistry confirmed these findings. In addition, ⁸⁹Zr-labeled nonspecific human IgG (⁸⁹Zr-Df-IgG) displayed minimal uptake in IGF-1R positive MIA PaCa-2 tumor xenografts (3.63 ± 0.95%ID/g at 120 h postinjection; n = 4), demonstrating that ⁸⁹Zr-Df-1A2G11 accumulation was highly specific. This study provides initial evidence that our ⁸⁹Zr-labeled IGF-1R-targeted antibody may be employed for imaging a wide range of malignancies. Antibodies may be tracked in vivo for several days to weeks with ⁸⁹Zr, which may enhance image contrast due to decreased background signal. In addition, the principles outlined in this study can be employed for identifying patients that may benefit from anti-IGF-1R therapy.

ImmunoPET Imaging of Insulin-Like Growth Factor 1 Receptor in a Subcutaneous Mouse Model of Pancreatic Cancer

^†Department of Medical Physics, ^‡Department of Radiology, and ^⊥Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin 53705, United States

^§ Department of Molecular Medicine and Biopharmaceutical Sciences, Department of Nuclear Medicine, Seoul National University, Seoul 110-744, Korea

^∥ NeoClone Biotechnologies International, Madison, Wisconsin 53713, United States

Mol. Pharmaceutics, Article ASAP

DOI: 10.1021/acs.molpharmaceut.6b00132

Publication Date (Web): April 07, 2016

*Department of Radiology, University of Wisconsin, Room 7137, 1111 Highland Ave, Madison, WI 53705-2275. E-mail: wcai@uwhealth.org. Phone: 608-262-1749. Fax: 608-265-0614.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

http://pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.6b00132

//////////

Keywords:

Positron emission tomography (PET), Zirconium-89 (⁸⁹Zr), Insulin-like growth factor-1 receptor (IGF-1R), Molecular imaging,

VX-? , an Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication from Vertex

PRECLINICAL, Uncategorized Comments Off

Apr 302016

VX-?

An Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication from Vertex

SYNTHESIS COMING……..

CAS 1259498-06-0

MF C₂₃ H₂₇ F₂ N₇ O, MW, 455.50

1-Piperidinecarboxamide, N-[(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-pyrimidinyl]amino]cyclohexyl]-

N-[(1R,3S)-3-[[5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide

N-[(1R,3S)-3-[[5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide , (1R,3S)-cis-diaminocyclohexane.

Specific Rotation

[α]²¹_D = −165.7° (c = 1 in MeOH).

¹H NMR (300 MHz, d₆-DMSO) δ 12.23 (s, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.34–8.18 (m, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 6.33 (d, J= 7.6 Hz, 1H), 4.24–4.00 (m, 1H), 3.75–3.57 (m, 1H), 3.57–3.42 (m, 4H), 3.28–3.09 (m, 4H), 2.15 (d, J = 11.4 Hz, 1H), 2.01 (d, J = 11.2 Hz, 1H), 1.83 (d, J = 9.7 Hz, 2H), 1.60–1.07 (m, 4H).¹⁹F NMR (282.4 MHz, d₆-DMSO) −138.10, −158.25 ppm.

HRMS (ESI) [M + H]⁺ calculated for C₂₂H₂₆F₂N₇O₂ 458.2111, found 458.2110.

Influenza spreads around the world in seasonal epidemics, resulting in the deaths of hundreds of thousands annually – millions in pandemic years. For example, three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing influenza virus to humans from other animal species.

Influenza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within about 6 feet) infected persons. Transmission might also occur through direct contact or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune systems might be infectious for 10 or more days after onset of symptoms. [00103] Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus and Thogoto virus.

The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are: HlNl (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2 , H7N3 and H10N7. [00105] The Influenza virus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

The Influenza virus C genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children. [00107] Influenza A, B and C viruses are very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NSl, NS2(NEP), PA, PBl, PB1-F2 and PB2.

HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins have been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1. [00109] Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.

Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral medications. Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people that have asthma, diabetes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific influenza strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective. [00111] Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.

Also, because of the absence of RNA proofreading enzymes, the RNA- dependent RNA polymerase of influenza vRNA makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant — antigenic drift. The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.

PAPER

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00063

Development of a Scalable Synthesis of an Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication

Jianglin Liang^*, John E. Cochran, Warren A. Dorsch, Ioana Davies, and Michael P. Clark

Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00063

Publication Date (Web): April 08, 2016

A scalable, asymmetric route for the synthesis of the influenza virus replication inhibitor 2 is presented. The key steps include an enzymatic desymmetrization of cis-1,3-cyclohexanediester in 99% yield and 96% ee, S_NAr displacement of a methanesulfinylpyrimidine, and a Curtius rearrangement to form a morpholinyl urea. This high-yielding route allowed us to rapidly synthesize hundreds of grams of 2 in 99% purity to support in vivo studies.

About Influenza

Often called “the flu,” seasonal influenza is caused by influenza viruses, which infect the respiratory tract.¹ The flu can result in seasonal epidemics² and can produce severe disease and high mortality in certain populations, such as the elderly.³ Each year, on average 5 to 20 percent of the U.S. population gets the flu⁴ resulting in more than 200,000 flu-related hospitalizations and 36,000 deaths.⁵The overall national economic burden of influenza-attributable illness for adults is $83.3 billion.⁵ Direct medical costs for influenza in adults totaled $8.7 billion including $4.5 billion for adult hospitalizations resulting from influenza-attributable illness.⁵ The treatment of the flu consists of antiviral medications that have been shown in clinical studies to shorten the disease and reduce the severity of symptoms if taken within two days of infection.⁶ There is a significant need for new medicines targeting flu that provide a wider treatment window, greater efficacy and faster onset of action.

About Vertex

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canada and Australia. For four years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences. For additional information and the latest updates from the company, please visit www.vrtx.com.

Vertex’s press releases are available at www.vrtx.com.

SYNTHESIS COMING

WO-2010148197

http://www.google.co.in/patents/WO2010148197A1?cl=en

General Scheme 44 SIMILAR TO A POINT BUT NOT SAME

(a) Pd(PPh₃)₄ sodium carbonate, DME/water, reflux (b) meta-chloroperbenzoic acid, dichloromethane, rt. (c) 20a, tetrahydrofuran, 5O°C (d) trifluoroacetic acid, dichloromethane, rt.

SIMILAR NOT SAME

(e) morpholιne-4-carbonyl chloride, dimethylformamide, rt (f) sodium methoxide, methanol, rt.

Formation of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-lΗ- pyrrolo[2,3-b]pyridine (44b)

2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol) , 5-fluoro-1-(p- tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na₂Cθ3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh₃ )₄ (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (60OmL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50 °C to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H- pyrrolo[2,3-b]pyridine as a white solid.

¹H NMR (300 MHz, OMSO-d6) δ 8.70 – 8.58 (m, 2H), 8.54 – 8.41 (m, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.45 (d, J= 8.2 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

Formation of 5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1- tosyl-1H-pyrrolo[2,3-b]pyridine (44c)

5-fluoro-3 – [5 -fluoro-4-(methylthio)pyrimidin-2-yl] – 1 -tosyl- 1 H-pyrrolo [2,3 – b]pyridine, 44b, (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) and treated portionwise with m-CPBA (27.5 g, 122.6 mmol) while keeping the temperature below 20 °C. After addition was complete, the reaction was stirred at room temperature for 2 hours, then treated with another portion of m-CPBA (1.9 g) and stirred for another hour. The reaction mixture was washed with 12% aqueuous K₂CO3 (2 x 1.0 L) and the organic layer was dried on Na₂SO₄ and concentrated in vacuo to provide 50 g of 5-fluoro-3-[5-fluoro-4- (methylsulfinyl)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid.

¹H NMR (300 MHz, DMSO-rf<5) δ 9.11 (d, J= 1.5 Hz, 1H), 8.69 (s, 1H), 8.65 (dd, J = 9.0, 2.9 Hz, 1H), 8.52 (dd, J= 2.8, 1.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).

[001057] Formation of tert-butyl N-[(IR, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p- tolylsulfonyl)pyrrolo [2,3-b] pyridin-3-yl]pyrimidin-4-yl] amino] cyclohexyl] carbamate (44d)

5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine, 44c, (5.9 g, 10.5 mmol) and tert-butyl N-[(IR, 35^*)-3-aminocyclohexyl]carbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50 °C for 6 hours, then cooled to room temperature. C₆ lite was added and the solvent was removed under reduced pressure. The C₆ lite-supported residue was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7 g of tert-butyl N-[(IR, 3S)- 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4- yl]amino]cyclohexyl]carbamate.

¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1H), 8.46 – 8.41 (m, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.06 (d, J= 3.2 Hz, 1H), 7.27 (d, J= 8.4 Hz, 2H), 4.91 (d, J = 8.0 Hz, 1H), 4.41 (s, 1H), 4.29 – 4.01 (m, 1H), 3.64 (s, 1H), 2.47 (d, J= 11.5 Hz, 1H), 2.36 (s, 3H), 2.24 (d, J = 13.1 Hz, 1H), 2.08 (d, J= 10.9 Hz, 1H), 1.91 (d, J= 13.8 Hz, 1H), 1.43 (s, 9H), 1.30 – 1.03 (m, 4H).

Formation of (IS, SΛHVHS-fluoro^-β-fluoro-1-Cp- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine (44e) tert-Butyl N-[(IR, 3S>3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate, 44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). After 5 minutes, the volatiles were evaporated under reduced pressure, and the resulting residue was treated with IN NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3 x 30 mL) and vacuum dried to provide 2.7 g of (IS, 3R)-Nl -[5-fluoro-2-[5- fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-l,3-diamine as a white solid.

¹H NMR (300 MHz, MeOD) d 8.56 (dd, J = 8.0, 3.9 Hz, 2H), 8.35 – 8.26 (m, 1H), 8.12 (dd, J= 10.3, 6.1 Hz, 3H), 7.43 (d, J= 8.4 Hz, 2H), 4.36 – 4.21 (m, 1H), 3.28 – 3.13 (m, 1H), 2.48 (d, J= 12.3 Hz, 1H), 2.46 (s, 3H), 2.25 – 1.97 (m, J= 17.3, 10.6, 4.1 Hz, 4H), 1.76 – 1.28 (m, 3H).

Formation of N-[(IR, 3S>3-[[5-fluoro-2-[5-fluoro-1-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] morpholine- 4-carboxamide (44f)

(15, 3R)-M-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3- yl]pyrimidin-4-yl]cyclohexane- 1,3 -diamine, 44e, (2.3 g, 4.6 mmol) was dissolved in DMF (5OmL) and treated with morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6 mL, 32.3 mmol). After one hour, the resulting solution was diluted with water (400 mL) and stirred for an additional two hours. The resulting precipitate was collected by filtration, washed with water (3 x 50 mL) and dried to provide the crude product. This material was purified by flash chromatography on a 4Og column using EtOAc/DCM 20- 100%, to provide 2.0 g of N-[(1R, 35)-3-[[5-fluoro-2-[5-fluoro-1-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4- carboxamide as a white solid.

¹H NMR (300 MHz, DMSO-Λ5) δ 8.53 – 8.43 (m, J = 11.9, 2.7 Hz, 3H), 8.22 (d, J = 3.9 Hz, 1H), 8.07 (d, J= 8.4 Hz, 2H), 7.44 (d, J= 8.3 Hz, 2H), 6.32 (d, J= 7.5 Hz, 1H), 4.05 (s, J= 19.4 Hz, 1H), 3.62 (s, 1H), 3.58 – 3.45 (m, 4H), 3.27 – 3.18 (m, 4H), 2.36 (s, 3H), 2.12 (d, J= 11.7 Hz, 1H), 1.99 (d, J= 9.5 Hz, 1H), 1.83 (d, J= 10.3 Hz, 2H), 1.53 – 1.11 (m, J = 32.3, 22.8, 10.9 Hz, 4H).

ormation of N-[(IR, 3S>3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-yl] amino] cyclohexyl]morpholine-4-carboxamide (706)

N- [( IR, 35)-3 – [ [5 -fluoro-2- [5 -fluoro- 1 -(p-tolylsulfonyl)pyrrolo [2,3 -b]pyridin-3 – yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide, 44f, (2.0 g, 3.2 mmol) was suspended in methanol (50 mL) and treated with 25% sodium methoxide in methanol (19.9 mL, 92.3 mmol) . After stirring for 1 hour, the solvent was evaporated under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was collected, dried on Νa₂SO₄ and concentrated to provide the crude product as a yellow solid. This material was purified by silica gel chromatography on a 4Og column, using DCM/MeOH 1-6%. The purified fractions were treated with 2N HCl in ether and concentrated to provide 1.5 g of N-[(1R, 35)-3-[[5-fluoro-2-(5-fluoro-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-morpholine-4-carboxamide as a white solid.

HCI D DCM

44e

Formation of (IS, S^-M-^-fluoro-S-CS-fluoro-1H-pyrrolo^S-^pyridin- 3-yl)phenyl)cyclohexane-1,3-diamine (44e)

To a solution of tert-butyl (IR, 35)-3-(2-fluoro-5-(5-fluoro-1-tosyl-lH-pyrrolo-[2,3- &]pyridin-3-yl)phenylamino)cyclohexylcarbamate, 44d, (0.65 g, 1.09 mmol) in methylene chloride (22 mL) was added hydrogen chloride (2.71 mL of 4M solution in 1,4-dioxane, 10.86 mmol). The reaction was heated to 50 °C and stirred for 6 hours. The mixture was cooled to room temperature and concentrated in vacuo, producing a yellow solid. The crude residue was purified via silica gel chromatography (25-50% Ethyl Acetate/hexanes gradient). Desired fractions were combined and concentrated in vacuo to produce 350 mg of 44e as a yellow powder.

General Scheme 67 SIMILAR TO A POINT BUT NOT SAME

(a) Pd/C (wet, Degussa), hydrogen, EtOH (b) 2,4-dichloro-5-fluoropyrimidine, ¹Pr₂NEt, THF, reflux (c) LiOH, THF/water, 5O°C

SIMILAR BUT NOT SAME

(d) DPPA, Et₃N, THF, 85 °C (e) 5-fluoro-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1- tosyl-l//-pyrrolo[2,3-i]pyridine, XPhos, Pd₂(dba)₃, K₃PO₄, 2-methylTHF, water, 125 °C (f)

Formation (IR, 35)-ethyl 3-aminocyclohexanecarboxylate (67b)

To a solution of (IR, 35)-ethyl 3-(benzyloxycarbonylamino)cyclohexane-carboxylate, 18b, (14.0 g, 45.9 mmol) in ethanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol). The mixture was evacuated and then stirred under atmosphere of nitrogen at room temperature overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated in vacuo to provide an oil that was used without further purification.

Formation (IR, SS^-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane- carboxylate (67c)

To a solution of (IR, 3«S)-ethyl S-aminocyclohexanecarboxylate, 67b, (5.1 g, 24.1 mmol) and 2,4-dichloro-5,-fluoropyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) was added diisopropylethylamine (9.6 mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to provide 6.7 g of (IR, 35^*)-ethyl 3-(2- chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate as a white solid: LCMS RT = 3.1 (M+H) 302.2.

Formation (IR, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (67d)

To a solution of (IR, 35^*)-ethyl 3-(2-chloro-5-fluoropyrimidin-4- ylamino)cyclohexane-carboxylate, 67c, (20.0 g, 66.3 mmol) in THF (150 mL) was added added a solution of LiOH hydrate (8.3 g, 198.8 mmol) in 100ml water. The reaction mixture was stirred at 50 °C overnight, To the reaction mixture was added HCl (16.6 mL of 12 M solution, 198.8 mmol) and EtOAc. The organic phase was washed with brine and dried over MgSO₄ and the solvent was removed under reduced pressure to afford 17.5 g of product that was used without further purification: ¹H NMR (300 MHz, CDC13) δ 7.91 (d, J = 2.7 Hz, 2H), 5.24 (d, J = 7.3 Hz, 2H), 4.19 – 4.03 (m, 3H), 3.84 – 3.68 (m, 3H), 2.59 (ddd, J= 11.5, 8.2, 3.6 Hz, 2H), 2.38 (d, J = 12.4 Hz, 2H), 2.08 (d, J = 9.6 Hz, 6H), 1.99 – 1.76 (m, 5H), 1.63 – 1.34 (m, 6H), 1.32 – 1.15 (m, 4H).

Formation N-((1R, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)- pyrrolidine-1-carboxamide (67e)

A solution of (IR, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane- carboxylic acid, 67d, (8.2 g, 30.0 mmol), (azido(phenoxy)phosphoryl)oxybenzene (9.7 mL, 45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) in THF (200 mL) was degassed under nitrogen for 15 minutes. The reaction mixture was heated at 85 °C for 30 minutes until LC/MS indicated complete consumption of carboxylic acid, 67d. To the reaction mixture was added pyrrolidine (7.5 mL, 90.0 mmol) and the reaction was heated at 85 °C for an additional 15 min. The mixture was diluted into brine and extracted with EtOAc. The organic phase was separated, dried over MgSO₄. The product was isolated (6.25 g) by filtration after partial removal of solvent in vacuo: ¹H NMR (300 MHz, CDC13) δ 7.87 (d, J = 2.8 Hz, 2H), 5.04 (d, J = 8.1 Hz, 2H), 4.09 (ddd, J = 26.9, 13.4, 5.6 Hz, 4H), 3.91 – 3.71 (m, 2H), 3.32 (t, J= 6.5 Hz, 7H), 2.45 (d, J= 11.5 Hz, 2H), 2.08 (dd, J= 22.1, 12.0 Hz, 4H), 1.96- 1.82 (m, 9H), 1.54 (dd, J= 18.6, 8.5 Hz, 2H), 1.22 – 1.01 (m, 6H).

Formation N-((IR, 3S>3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridm-3- yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (67f)

A solution of N-((1R, 3«S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)- pyrrolidine-1-carboxamide, 67e, (6.8 g, 20.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (12.5 g, 30.0 mmol) and K₃PO₄ (17.0 g, 80.0 mmol) in 2-methyl TΗF (180 mL) and water (20 mL) was degassed under nitrogen for 30 min. To the mixture was added dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd₂(dba)₃ (0.5 g, 0.5 mmol). The reaction mixture was heated in a pressure bottle at 125 °C for 2.5 hr. The reaction mixture was filtered through celite, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8%MeOΗ/CΗ₂Cl₂) to afford 11.5 g of the desired product: ¹H ΝMR (300 MHz, CDC13) δ 8.54 (s, 1H), 8.49 (dd, J= 9.0, 2.8 Hz, 1H), 8.32 (d, J= 2.1 Hz, 1H), 8.13 (d, J= 8.3 Hz, 2H), 8.07 (d, J= 3.2 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 4.98 (d, J = 6.3 Hz, 1H), 4.37 – 4.16 (m, 1H), 4.08 (d, J = 7.3 Hz, 1H), 3.99 – 3.80 (m, 1H), 3.33 (t, J= 6.5 Hz, 4H), 2.52 (d, J= 11.6 Hz, 1H), 2.39 (s, 3H), 2.29 (d, J= 11.3 Hz, 1H), 2.12 (d, J= 11.1 Hz, 1H), 1.99 – 1.81 (m, 5H), 1.70 – 1.55 (m, 1H), 1.22 – 1.08 (m, 2H).

Formation N-((IR, 3S>3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)- pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (895)

A solution of N-((1R, 35)-3-(5-fluoro-2-(5-fluoro-1-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide, 67f, (11.5 g, 19.3 mmol) in TΗF (150 mL) was added sodium methoxide (4.173 g, 19.31 mmol). After stirring the reaction mixture for 2 minutes, the mixture was poured into an aqueous saturated solution of NaHCO₃. The organic phase was washed with brine, dried over MgSO₄ and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (10%MeOH/CH₂Cl₂) to afford 6.5g of the desired product. The product was converted to an HCl salt by dissolving in MeOH (100 mL) and adding 2.4 mL of 12M HCl solution at room temperature. The solution was stirred at for lhour and the HCl salt precipitated out and filtered to provide 7.05g of the HCl salt: ¹H NMR (300 MHz, DMSO) δ 9.36 (s, 2H), 9.05 (d, J= 3.0 Hz, 2H), 8.49 (d, J= 5.6 Hz, 2H), 8.41 (dd, J= 2.6, 1.4 Hz, 2H), 8.31 (d, J= 9.5 Hz, 2H), 5.92 (s, 3H), 4.24 (s, 3H), 3.64 (s, 2H), 3.18 (t, J= 6.6 Hz, 7H), 2.07 (dt, J = 22.7, 11.5 Hz, 4H), 1.87 (t, J = 12.6 Hz, 4H), 1.77 (dd, J = 8.0, 5.3 Hz, 7H), 1.65 – 1.13 (m, 8H).

PATENT

US-20120171245-A1 / 2012-07-05

INHIBITORS OF INFLUENZA VIRUSES REPLICATION

Charifson, Paul S. [US] ET AL

/////////VX-? , an Azaindolyl-Pyrimidine Inhibitor, Influenza Virus Replication, Vertex, preclinical, 1259498-06-0

O=C(NC1CCC[C@@H](C1)Nc2nc(ncc2F)\C\4=C\N=C3\N\C=C(\F)/C=C3/4)N5CCCCC5

Cymipristone

china, NDA, Uncategorized Comments Off

Apr 292016

ChemSpider 2D Image | Cymipristone | C34H43NO2

Cymipristone

(8S,11R,13S,14S,17S)-11-{4-[Cyclohexyl(méthyl)amino]phényl}-17-hydroxy-13-méthyl-17-(1-propyn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrén-3-one

Estra-4,9-dien-3-one, 11-[4-(cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)-, (11β,17β)-

11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one

Estra-4,9-dien-3-one, 11-[4-(cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-, (11β,17β)- (9CI)
(11β,17β)-11-[4-(Cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)estra-4,9-dien-3-one
Saimisitong

Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,

A progesterone receptor antagonist potentially for termination of intrauterine pregnancy.

CAS No.329971-40-6

Molecular FormulaC₃₄H₄₃NO₂
Average mass497.711 Da
Steroid Compounds, a Method for Preparation thereof, Pharmaceutical Compositions Containing the Same and Use thereof

This invention relates to steroid compounds and pharmaceutical acceptable salts thereof, a method for preparation thereof, pharmaceutical compositions containing the same as active component, and their use in the preparation of medicines for treating diseases associated with progestogen dependence and for fertility control, abortion or contraception and for anticancer use.
Mifepristone (11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in French Patent No. 2,497,807 to Rousell-Uclaf, published May 31, 1983. It is the first progesterone receptor antagonist put into clinical application and is a new type of anti-progestin. It binds to progesterone receptor and glucocorticoid receptor, having an affinity with progesterone receptor in rabbit endometrium five-fold higher than that of progesterone and thereby having strong anti-progesterone effect. It causes degeneration of pregnant villus tissue and decidual tissue, endogenous prostaglandin (PG) release, luteinizing hormone decrease, corpus luteum dissolution, and necrosis of embryo sac whose development depends on corpus luteum, leading to abortion. Therefore, it can be used as a non-surgical medicine for stopping early pregnancy. It can also be used, inter alia, in contraception and as an antineoplastic. (The Antiprogestin Steroid Ru486 and Human Fertility Control, 1985, New York: Plenum Press) .
Onapristone (11β-[4-(N,N-diemthylamino)phenyl]-17α-hydroxy-17β-(3-hydroxypropyl)-13α-4,9-estradiene-3-one), is a steroid compound which is disclosed in German Patent No. 3,321,826 to Schering AG, published Dec. 20, 1984. It has a strong antiprogestin activity and can be used in abortion (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), anticancer (Breast Cancer Research and Treatment, 1989, 14:275-288), etc. It was reported that onapristone had toxicity to human liver (European Journal of Cancer, 1999, 35(2):214-218).
Lilopristone (11β-[4-(N,N-dimethylamino) phenyl]-17α-[3-hydroxy-1(Z)-propenyl]-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3,347,126 to Schering AG, published July 11, 1985. It has a strong antiprogestin activity and can be used in abortion, contraception (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), etc. It was reported that the clinical effect of lilopristone in stopping early pregnancy was only equivalent to that of mifepristone (Human Reproduction, 1994, 9(1):57-63).
ZK112993 (11β-(4-acetylphenyl)-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is as steroid compound which is disclosed in German Patent No. 3,504,421 to Schering AG, published Aug. 7, 1986. It has a potent antiprogestin activity and can be used in, inter alia, anticancer (Anticancer Res., 1990, 10:683-688).
In European Patent No. 321,010 to Akzo NV, The Netherland published June 21, 1989 are disclosed “11-arylsteroid compounds” having a strong antiprogestin activity.

PATENT

WO 2001018026

http://www.google.com/patents/EP1219632A1?cl=en

The preparation method of the present invention includes the following single- or multi-step procedures:

1. Method for the preparation of 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (IV) which includes the following steps:

(1) Preparation of Grignard reagent (III)

4-bromo-N-methyl-N-cyclohexylaniline (II) is reacted with magnesium in tetrahydrofuran (THF) to obtain Grignard reagent of formula (III).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (III) prepared in step (1) are brought to an additive reaction to obtain compound of formula (V).

(3) Hydrolytic reaction

The compound of formula (V) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of form (VI).

2. Method for preparation of 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI) which includes the following steps:

(1) Preparation of Grignard reagent of formula (IX)

4-bromo-N-cyclohexylaniline (VII) is first protected by trimethylchlorosilane, then reacted with magnesium in THF to obtain Grignard reagent of formula (IX).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (IX) prepared in step (1) are brought to an additive reaction to obtain compound of formula (X).

(3) Hydrolytic reaction

The compound of formula (X) prepared in step (2) is subjects to a hydrolytic reaction to obtain compound of formula (XI).

Example 2:

9g 4-bromo-N-cyclohexylaniline (VII) (CA registration number [113388-04-8], see Synthetic Communications, 1986, 16(13): 1641-1645 for its preparation) was placed into a four-necked flask and 15 ml (1.5 mol/L) n-BuLi solution in n-hexane. The mixture was stirred for 30 min at room temperature. Then 8 g trimethylsilyl chloride (Me₃SiCl) was added and the mixture was stirred for 1 hour. Solvent and excessive Me₃SiCl was evaporated under reduced pressure to yield 4-bromo-(N-cyclohexyl-N-trimethylsilylaniline) (VIII) which was formulated into a solution with 7.5 ml anhydrous tetrahydrofuran for further use.
1.3 g magnesium was placed into a four-necked flask and a small amount of the above solution was added dropwise and slowly at 40°C. After completion of addition, the temperature was kept for 1 hour to yield a solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenylmagnesium bromide (IX) in tetrahydrofuran for further use.

(2) Preparation of 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cylohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

5g 3,3-ethylenedioxy-5,10-epoxy-17α-(1-propinyl)-17β-hydroxy-9(11)-estrene (IV) was placed into a four-necked flask and 10 ml anhydrous tetrahydrofuran and a catalytic amount of cuprous chloride (Cu2Cl2) added. Then solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenyl magnesium bromide (IX) in tetrahydrofuran was added dropwise and slowly while controlling the temperature below 5°C. After completion of addition, the mixture was allowed to react for 2 hours at room temperature and to stand overnight. Saturated ammonium chloride aqueous solution was added and the tetrahydrofuran layer separated which was washed with saturated ammonium chloride solution. The solution in tetrahydrofuran was washed with saturated saline and dried over anhydrous sodium sulfate. Evaporation of tetrahydrofuran under reduced pressure yielded a residual which was chromatographed on silica gel column using cyclohexane: acetone (5:1) as developing agent to yield 3 g 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

IR (KBr) cm^-1: 3420 (C₅, C₁₇-OH), 1610, 1510 (benzene backbone), 840, 808 (ArH).
¹H NMR (CDCl₃) δ ppm: 0.52(3H, S, C₁₃-CH₃), 2.72(3H, S, N-CH₃), 3.92(4H, m, -O-CH₂CH₂-O-), 4.24(1H, m, C₁₁-H), 6.65-7.00 (4H, ArH).

(3) Preparation of 11β- [4- (N-cyclohexylamino)phenyl] -17α- (1-propinyl) -17β-hydroxy-4,9-estradiene-3-one (XI).

1.5g 3,3-ethylenedioxy-5,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene (X) and 0.75 g para-toluenesulfonic acid (PTS) were dissolved in 15 ml 90 % ethanol (v/v). The mixture was stirred for 2 hours while controlling the temperature at 40°C-50°C. After completion of the reaction, the reactant was poured into diluted sodium hydroxide aqueous solution, extracted with dichloroethane, washed with water to neutrality, and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography on silica gel column using cyclohexane: ethyl acetate (5:1) as developing agent yielded 0.9 g 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI).

IR (KBr) cm^-1: 3400 (C₁₇-OH), 1658 (unsaturated ketone), 1613, 1514 (benzene backbone), 865, 810 (ArH).
¹H NMR (CDCl₃) δ ppm: 0.50 (3H, S, C₁₃-CH₃), 1.76 (3H, S, C≡C-CH₃), 4.32(1H, S, C₁₁-H), 5.75(1H, S, C₄-H), 6.9-7.10 (4H, ArH).

PATENT

WO 2006063526

PATENT

WO 2007009397

Example 1

Race meters mifepristone synthetic routes:

Epoxy adduct match rice mifepristone

(N- hexylamino methylcyclohexyl) phenyl magnesium bromide (1) 4-

In the four-necked flask, 1.4 g of magnesium into pieces (Mg) and 10 ml of anhydrous tetrahydrofuran (THF), no iodine or add a little change, at about 50 ° C, a solution of 10.86 g of 4-bromo-methyl -N- cyclohexyl aniline (dissolved in 24 ml of anhydrous tetrahydrofuran) dropwise Bi, incubation was continued for 1 hour with stirring to give 4- (N- methyl-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran solution (to be used in the next step an addition reaction ).

(2) 3,3-ethylenedioxy -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propyl block-yl) -9 (10) – Preparation of estra-ene (adduct) of

In the four-necked flask, into 5 g of 3,3-ethylenedioxy-5,10-epoxy -17 α – (1- propynyl) – 17 (3 – hydroxy – 9 (11) – estra-ene (epoxy), 29.1 ml anhydrous tetrahydrofuran (THF) and 0.1 g cuprous chloride (of Cu ₂ of Cl ₂ ), a solution of 4- (N- methyl -N-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran

Nan solution, temperature control 5. C, the drop was completed, the incubation was continued for 5 hours, the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, points to the water layer, the organic layer was washed with saturated ammonium chloride solution, the aqueous layer extracted with ethyl acetate number times, the organic layers combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, a silica gel column, eluent cyclohexane: acetone = (5: 1) to give 3,3-ethylene dioxo -5 α, 17 β – dihydroxy -11 β – [4- (- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – female steroidal women (adduct) solid 6 grams.

IR. ‘KBi cm- ^ SlS OI ^ ^ -OH lS jSlS benzene backbone), 819 (aromatic hydrogen). NMR Ή: (CDC1 ₃ ) ppm by [delta]: 0.47 (3H, the S, the C _IR CH ₃ ), 1.88 (3H, the S, the C ≡ the C-CH ₃ ), 2.72 (3H, the S, the N-CH ₃ ), 6.65- 7.03 (4H, ArH) _O

(3) 11 β – [4- (N- methyl -N- cyclohexylamino) phenyl] -17 α – (1- propynyl) -17 β – hydroxy-estra-4,9-diene – Preparation of 3-one (match rice mifepristone) of

‘2.5 g of p-toluenesulfonic acid (PTS) and 5 grams of 3,3-ethylenedioxythiophene -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – estra-ene (adduct) was dissolved in 50 ml of ethanol 90% (V / V), and at 5 ° C – 40 ° C the reaction was stirred 3 hours, the reaction solution was poured into dilute aqueous sodium hydroxide solution, the precipitated solid was suction filtered, washed with water until neutral, the filter cake was dissolved in 50 ml of ethyl acetate, then with saturated aqueous sodium chloride solution to the water layer was evaporated part of the solvent, the precipitated solid was suction filtered, and dried to give a pale yellow solid 11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one (match rice mifepristone) 3 grams.

^ Cm & lt IRCKB ¹ : 3447 (the C _{. 17} -OH), among 1655 (unsaturated ketone), 1607,1513 (benzene backbone), 865,819 (aromatic hydrogen).

NMR ¾: (CDC1 ₃ ) ppm by [delta]: 0.56 (3H, the S ₅ the C ₁₃ -CH ₃ ), 1.89 (3H, the S ₅ -C ≡ the C-the CH3), 2.74 (3H, the S, the N-the CH3), 4.34 ( lH, the S, the C _N -H), 5.75 (lH, the S, the C ₄ -H), 6.68-6.99 (4H, ArH).

PATENT

CN 102107007

PATENT

CN 102106805

PAPER

Journal of Chromatography B

Volume 878, Issues 7–8, 1 March 2010, Pages 719–723

Determination of cymipristone in human plasma by liquid chromatography–electrospray ionization-tandem mass spectrometry

doi:10.1016/j.jchromb.2010.01.027

Abstract

A rapid, specific and sensitive liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for determination of cymipristone in human plasma. Mifepristone was used as the internal standard (IS). Plasma samples were deproteinized using methanol. The compounds were separated on a ZORBAX SB C₁₈ column (50 mm × 2.1 mm i.d., dp 1.8 μm) with gradient elution at a flow-rate of 0.3 ml/min. The mobile phase consisted of 10 mM ammonium acetate and acetonitrile. The detection was performed on a triple-quadruple tandem mass spectrometer by selective reaction monitoring (SRM) mode via electrospray ionization. Target ions were monitored at [M+H]⁺m/z 498 → 416 and 430 → 372 in positive electrospray ionization (ESI) mode for cymipristone and IS, respectively. Linearity was established for the range of concentrations 0.5–100 ng/ml with a coefficient correlation (r) of 0.9996. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.5 ng/ml. The validated method was successfully applied to study the pharmacokinetics of cymipristone in healthy Chinese female subjects.

CHEMICAL ABSTRACTS, vol. 115, no. 25, 23 December 1991 (1991-12-23) Columbus, Ohio, US; abstract no. 270851g, X. ZHAO ET AL.: “Synthesis and terminating early pregnancy effect of mifepristone derivatives” page 117; XP002219009 & ZHONGGUO YAOKE DAXUE XUEBAO, vol. 22, no. 3, 1991, pages 133-136,

//////////Cymipristone, Saimisitong, Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,

Claude Shannon's 100th birthday

энкломифен Enclomiphene citrate إينكلوميفان

NDA Comments Off

Apr 292016

Enclomiphene citrate

An estrogen receptor (ER) antagonist potentially for treatment of hypogonadotropic hypogonadism.

ICI-46476; RMI-16289

CAS No.15690-57-0(free)

7599-79-3(Enclomiphene citrate)

Molecular Weight	598.08
Formula	C26H28ClNO▪C6H8O7

Ethanamine, 2-[4-[(1E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)

Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl-, (E)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate (1:1), (E)-
(E)-Clomiphene citrate
Androxal
Clomiphene B citrate

Enclomid
Enclomiphene citrate
trans-Clomiphene citrate

Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene). These two isomers have been found to contribute to the mixed estrogenic and anti-estrogenic properties of clomifene.

Enclomifene

Zuclomifene

PATENT

WO 2015138340

EXAMPLE 1

Preparation of trans-clomiphene citrate from

1- {4- [2-(Oiethylamino)ethoxy| phenylj-1 ,2-diphenylethanol

Dehydration

[0023] l-{4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) dissolved in ethanol containing an excess of hydrogen chloride was refluxed 3 hours at 50 °C. The solvent and excess hydrogen chloride were removed under vacuum and the residue was dissolved in dichloromethane. 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanaminium hydrogen chloride (7) was obtained.

Chlorination

The hydrochloride salt (7) solution obtained above was treated with 1.05 equivalents of N-chlorosuccinimide and stirred at room temperature for about 20 hours. Completion of the reaction was confirmed by HPLC. The hydrochloride salt was converted to the free base by addition of saturated aqueous bicarbonate solution. The mixture was stirred at room temperature for 30 minutes after which the phases were separated and the organic phase was evaporated in vacuo. 2-{4-[2-chloro-l,2- diphenylvinyl]phenoxy}-N,N-diethylethanamine (clomiphene -1.8:1 E:Z mixture) (8) was obtained.

Separation of clomiphene isomers

Clomiphene (8) obtained above is dissolved in methanol and racemic binaphthyl- phosphoric acid (BPA) is added under stirring. When the precipitate begins separating from the solution, stirring is stopped and the mixture is allowed to settle at room temperature for 2 hours. The precipitate is filtered, washed with methanol and ether and dried. Trans-clomiphene-BPA salt (3) is obtained.

The enclomiphene-BPA salt (3) obtained above is extracted with ethyl acetate and NH₃ solution. To the organic solution washed with water and dried, citric acid dissolved in ethanol is added. The solution is allowed to settle for about one hour at room temperature; the precipitate is then filtered and dried under vacuum. The obtained precipitate, trans-clomiphene citrate (1) is dissolved in 2-butanone for storage.

EXAMPLE 2

Synthesis of Clomiphene Using a Single Solvent

Step 1 – Dehydration of l-i4-r2-(Diethylamino)ethoxy1phenyl|-l,2- diphenylefhanol to form 2-{4-[(Z)-l,2-diphenylvinyllphenoxy}-N,N-diethylethanaminium hydrogen sulfate (7) [0030] The synthesis route described in Example 1 utilized HC1 for the dehydration step and utilized ethanol at 50 °C as the solvent. Sulfuric acid was investigated as an alternative to HC1 for the dehydration step (as described in Example 1) in part due to the more favorable corrosion profile of sulfuric acid. Dichloromethane (methylene chloride) was investigated as an alternative solvent for the dehydration step as this would render removal of the ethanol solvent prior to the chlorination step unnecessary.

A 100 mL 3-neck round bottom flask, fitted with a temperature probe and a stir bar, was charged with l- {4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) (6.60 g, 16.9 mmol) and 66 mL (lxlO³ mmol) of methylene chloride to give a yellow solution which was cooled in an ice bath to 0 °C. Concentrated sulfuric acid (H₂S0₄, 0.96 mL, 18.1 mmol) was added at a rate such that the internal temperature did not exceed 5 °C. Upon completion of the addition, the mixture was allowed to stir one hour at ambient temperature. Completion of the reaction was confirmed by high performance liquid chromatography (HPLC). The reaction resulted in 7.96 grams of 2- (4-[(Z)- 1 ,2- diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7), a yield of 100%. Thus, sulfuric acid was demonstrated to be a suitable acid for the dehydration step.

[0042] Using these HPLC conditions, starting material has a retention time of 3.30 min and product has a retention time of 4.05 min.

It was determined that removal of water produced by the dehydration reaction was important before performing the chlorination step. When ethanol is used as the solvent for this reaction, as in Example 1, the water is removed azeotropically upon removal of the ethanol. Several methods of drying the dichloromethane solution were attempted. Drying with MgS0₄ had a deleterious effect on the subsequent chlorination step, rendering the chlorination process very messy with a number of new impurities observed following HPLC analysis which were determined to be the corresponding chlorohydrins. On the other hand, a wash with brine was sufficient to remove enough water and had no deleterious effect on the chlorination step. Accordingly, the solution was stirred vigorously with brine (66 ml) for 30 minutes and then the phases were separated prior to chlorination step.

Step 2- Synthesis of 2-|4-r2-chloro-L2-diphenylvinyl1phenoxyl-N,N- diethylethanamine 8

The solution of 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7.94 grams) in methylene chloride obtained in step 1 is stirred at room temperature and treated with N-chlorosuccinimide (2.37 g, 17.7 mmol, 1.05 equivalents) in a single portion and left to stir at room temperature for 12 hours. The yellow solution became orange and then went back to yellow. After 12 hours, a sample was removed, concentrated and assayed by HPLC to confirm the extent of reaction. HPLC analysis revealed that the reaction had proceeded but not to completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred at room temperature for an additional 4 hours. The reaction was again assayed by HPLC which revealed that the reaction was near completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred for an additional 12 hours at room temperature. The reaction was again assayed by HPLC and an additional 0.058 equivalents of N-chlorosuccinimide (131 mg, 0.98 mmol) was added and the solution stirred for an additional 4 hours. HPLC indicated that the reaction was complete at that point. The reaction was carefully quenched by slow addition of 66 mL (600 mmol) of saturated aqueous sodium bicarbonate solution and the quenched mixture was stirred for 30 minutes at room temperature – the reaction mixture pH should be about 8-9 after addition of saturated aqueous sodium bicarbonate solution. The reaction yielded 6.86 grams of 2-{4-[2-chloro-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanamine (8). The phases were separated and the organic phase was evaporated in vacuo. The resulting light brown oil was transferred to a tared amber bottle using a small volume of dichloromethane.

[0055] Using these HPLC conditions, the retention time of product is 15 minutes.

Chromatographic Separation of Clomiphene Isomers

Clomiphene (mixture of isomers) in free base form obtained by steps 1 and 2 is loaded onto a chromatographic column (e.g. batch high pressure chromatography or moving bed chromatography) using the same solvent as used in steps 1 and 2 (here DCM) in order to separate the cis- and trans-clomiphene isomers. Trans-clomiphene is preferably eluted using a solvent suitable for recrystallization.

PATENT

Indian (1978), IN 143841

http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19780211&CC=IN&NR=143841B&KC=B

PAPER

Separation of E- and Z-isomers of clomiphene citrate by high-performance liquid chromatography using methenamine as mobile phase modifier
Journal of Chromatography (1984), 298, (1), 172-4.

http://www.sciencedirect.com/science/article/pii/S0021967301927074

PATENT

http://www.google.com/patents/CN103351304A?cl=en

SYTHESIS

Patent
US2914562https://www.google.co.in/patents/US2914562

PATENT

US2914529

http://www.google.co.in/patents/US2914529

PAPER

J. Med. Chem.1967, 10, 84–86.

http://pubs.acs.org/doi/pdf/10.1021/jm00313a017

J. Org. Chem.1983, 48, 2782-2784.

http://pubs.acs.org/doi/pdf/10.1021/jo00164a036

PAPER

Chem Commun (London) 2015, 51(44): 9133

Chem. Commun., 2015, 51, 9133-9136
DOI: 10.1039/C5CC01968K

A transition-metal-free, ambient-pressure, and general methodology for carbonylative Suzuki coupling has been developed.

Graphical abstract: Transition-metal-free, ambient-pressure carbonylative cross-coupling reactions of aryl halides with potassium aryltrifluoroborates

CN103351304A *	Jul 1, 2013	Oct 16, 2013	暨明医药科技（苏州）有限公司	Synthesis method of clomiphene
US2914563 *	Aug 6, 1957	Nov 24, 1959	Wm S Merrell Co	Therapeutic composition
US3848030 *	Mar 10, 1972	Nov 12, 1974	Richardson Merrell Spa	Optical isomers of binaphthyl-phosphoric acids
US5681863 *	Dec 5, 1994	Oct 28, 1997	Merrell Pharmaceuticals Inc.	Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors

Reference
1	*	RAO ET AL.: “Synthesis of carbon-14 labeled clomiphene.“, JOUMAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 22, no. 3, 1985, pages 245 – 255, XP055180053, Retrieved from the Internet <URL:http://onlinelibrary. wiley .com/doi/10.1002/jlcr.2580220306/abstract> [retrieved on 20150504]

//////////энкломифен, Enclomiphene citrate, إينكلوميفان , ICI-46476, RMI-16289, nda filed,