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Sonidegib/Erismodegib..Novartis Cancer Drug LDE225 Meets Primary E

(2014-02-20 17:50:17)
标签:

erismodegiblde225nov

sonidegib

erismodegib

健康

分类: PHASE3

Sonidegib / Erismodegib

CODE DESIGNATION .. LDE225, NVP-LDE-225

Treatment of medulloblastoma  Phase3 2014 FDA FILING

Treatment of advanced basal cell carcinoma PHASE3 2014 FDA FILING

Treatment of SOLID TUMORS .. PHASE1 2017 FDA FILING

READ Malignant Solid Tumors of Childhood

THERAPEUTIC CLAIM Oncology,  Antineoplastics & Adjunctive Therapies

CHEMICAL NAMES

. 1 [1,1 '-Biphenyl]-3-carboxamide, N-[6 - [(2R, 6S) 2 ,6-dimethyl-4-morpholinyl]-3-pyridinyl] -2 -
methyl-4'- (trifluoromethoxy) -, rel-

. 2 N-{6 - [(2R, 6S) 2 ,6-dimethylmorpholin-4-yl] pyridin-3-yl}-2-methyl-4'-
(TRIFLUOROMETHOXY) BIPHENYL-3-carboxamide

N-[6 - [(2S, 6R) -2,6-dimethylmorpholin-4-yl] pyridin-3-yl]-2-methyl-3-[4 - (trifluoromethoxy) phenyl] benzamide

N-(6 - ((2S, 6R) -2,6-dimethylmorpholino) pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy) biphenyl-3-carboxamide

MOLECULAR FORMULA C26H26F3N3O3

MOLECULAR WEIGHT 485.5

SPONSOR Novartis Pharma AG 

CAS REGISTRY NUMBER 956697-53-3 free form

NOTE ... DIPHOSPHATE SALT IS THE DRUG WITH CAS 1218778-77-8

sonidegib - European Medicines Agency  READ THIS ..

Summary EudraCT Number: 2012-004022-21 Sponsor's Protocol  ...  READ THIS

Novartis announced that the pivotal trial of the investigational oral compound LDE225 (sonidegib) in advanced basal cell carcinoma met its primary endpoint of demonstrating an objective response rate among patients within six months of treatment. Objective response included complete response (clinically significant tumor response with complete absence of disease) and partial response (clinically significant tumor shrinkage).
Basal cell carcinoma is the most common form of skin cancer, accounting for more than 80% of non-melanoma skin cancers, and can be highly disfiguring and life-threatening if it grows. Worldwide incidence of basal cell carcinoma is rising by 10% each year due to factors such as an aging population and increased ultraviolet exposure. Although basal cell carcinoma rarely metastasizes, once it does, it can be associated with significant morbidity.
"For people living with advanced basal cell carcinoma there are currently limited treatment options," said Alessandro Riva, president, Novartis Oncology ad interim and global head, Oncology Development and Medical Affairs. "These results demonstrate the potential for LDE225 to offer a treatment option for this patient population, and we look forward to sharing these data with regulatory authorities worldwide. "
Full study results will be presented at a future scientific meeting.

About the Study

The Phase II, randomized, double-blind BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) study was designed to assess the safety and efficacy of two oral dose levels of LDE225 (200 mg and 800 mg) in patients with locally advanced or metastatic basal cell carcinoma [4], which are subtypes of advanced basal cell carcinoma.

The primary endpoint was the proportion of patients achieving an objective response rate, defined as a confirmed complete response and partial response as their best overall response per modified RECIST criteria, within six months of starting treatment with LDE225. Key secondary endpoints of the study included assessing the duration of tumor responseand the rate of complete response. Other secondary endpoints included progression-free survival, time to tumor response and overall surviva

Date: February 19, 2013
Source: Novartis 
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MORE ABOUT SONIDEGIB

Sonidegib  ( INN ) or  Erismodegib  ( USAN ), Also known as  LDE225  is a  Hedgehog Signalling pathway  inhibitor (via  smoothened  antagonism) as an anticancer agent being Developed by  Novartis . [1] [2]  It has been Investigated as a potential treatment for:

NVP-LDE-225, a product candidate developed by Novartis, is in phase III clinical trials for the treatment of medulloblastoma and basal cell carcinoma. Phase II trials are in progress for the treatment of adult patients with relapsed or refractory or untreated elderly patients with acute leukemia.

Early clinical trials are ongoing for the oral treatment of advanced solid tumors, for the treatment of myelofibrosis in combination with ruxolitinib and for the treatment of small cell lung cancer. A phase II clinical trial for the treatment of basal cell carcinomas in Gorlin's syndrome patients with a cream formulation of NVP-LDE-225 was discontinued in 2011 since the formulation did not demonstrate tumor clearance rate sufficient to support further development.

Dana-Farber Cancer Institute and the Massachusetts General Hospital are conducting phase I clinical trials for the treatment of locally advanced or metastatic pancreatic cancer in combination with chemotherapy. In 2009, orphan drug designation was assigned in the EU for the treatment of Gorlin syndrome.

Demonstrated it has significant efficacy against melanoma  in vitro  and  in vivo . [21]  It Also Demonstrated efficacy in a Mouse Model of pancreatic Cancer. [22]

NVP-LDE225 Diphosphate salt (Erismodegib, Sonidegib) 

Formula Image

Synonym: Erismodegib, Sonidegib
CAS Number :1218778-77-8
. Mol Formula: C 2 6 H 2 6 F 3 N 3 O 3  ∙ 2H 3 PO 4
MW: 681.5
NMR. http://www.chemietek.com/Files/Line2/Chemietek, 20NVP-LDE225% 20% [02],% 20NMR.pdf
HPLC- http://www.chemietek.com/Files/Line3/Chemietek, 20NVP-LDE225% 20% [02],% 20HPLC.pdf

Brief Description:

A potent, selective, and orally bioavailable Smoothened (Hedgehog Signaling Pathway) antagonist, currently in clinical trials. Diphosphate salt offers a much better bioavailability than free base (Ref. a)
a. Pan, S., et al, Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist, ACS Med. Chem. Lett., 2010, 1 (3), pp 130-134.

About LDE225

LDE225 (sonidegib) is an oral, investigational, selective smoothened inhibitor being studied in a variety of cancers. Smoothened (SMO) is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a critical role in stem cell maintenance and tissue repair . LDE225 is currently in clinical development for a variety of diseases including myelofibrosis, leukemia and solid tumors.

Given that LDE225 is an investigational compound, the safety and efficacy profile has not yet been fully established. Access to this investigational compound is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the compound. Given the uncertainty of clinical trials, there is no guarantee that LDE225 will ever be commercially available anywhere in the world.

Possibility (LDE225) is effective in medulloblastoma relapsed or refractory hedgehog pathway inhibitor sonidegib has been revealed. That the anti-tumor effect was observed in some patients and tolerability in 1/2 test phase.

4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, which was held in San Francisco November 21 to 24 in (WFNO-SNO2013), rice Dana-Farber It was announced by Mark Kieran Mr. Children's Hospital Cancer Center.

The research group, announced the final results of the Phase 1 trial that target advanced solid cancer in children of sonidegib. 1 dose increased multi-test phase, was initiated from 372mg/m2 once-daily dosing to target children under the age of 18 more .. than 12 months (233mg/m2 group 11 people, 16 people 372mg/m2 group, 11 people group 425mg/m2, 680mg/m2 group 21 women) who participated 59 people, including medulloblastoma 38 patients 12 median age was (2 - 17).

Creatine phosphokinase elevation of grade 4 only were seen at 372mg/m2 as dose-limiting toxicity only, and became two recommended dose phase and 680mg/m2. Nausea muscle pain creatine kinase rise malaise (22.0%) (15.3%) (15.3%) , (13.6%), vomiting side effects were many, was (13.6%). Hypersensitivity vomiting creatine kinase increased (3.4%) (1.7%) (1.7%), rhabdomyolysis side effects of grade 3/4 was (1.7%). (One group 372mg/m2, 425mg/m2 group one) complete response was obtained in two people, a strong correlation was found between the activation of the hedgehog pathway and effect.

Phase III clinical trials that target medulloblastoma the activated hedgehog pathway currently are underway.

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs:. Innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R & D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 136,000 full-time-equivalent associates and operate in more than 140 countries around the world.

Increased levels of Hedgehog signaling are sufficient to initiate cancer formation and are required for tumor survival.
These cancers include, but are not limited to, prostate cancer ("Hedgehog signalling in prostate regeneration, neoplasia and metastasis", Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy . P A., Nature 2004 Oct 7;. 431 (7009) :707-12;
"Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling", Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, Ruiz i Altaba A., Proc Natl Acad Sci USA 2004 Aug 24;.. 101 (34) :12561-6),
breast cancer ("Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer", Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M., Cancer Res. 2004 Sep. 1; 64 (17) :6071-4),
medulloblastoma ("Medulloblastoma growth inhibition by hedgehog pathway blockade", Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy P A., Science. 2002 . Aug 30; 297 (5586) :1559-61),
basal cell carcinoma ("Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions", Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C ., Porter JA, Rubin LL, Wang F Y., Proc Natl Acad Sci USA 2003 Apr 15;. 100 (8) :4616-21;
"Activating Smoothened mutations in sporadic basal-cell carcinoma", Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage F J., Nature 1998 Jan 1;.. 391 (6662) :90-2),
pancreatic cancer ("Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis", Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo C, Yajnik V ., Antoniu B, McMahon M, Warshaw AL, Hebrok M., Nature 2003 Oct 23;. 425 (6960) :851-6;
"Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours", Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy P A ., Nature 2003 Oct 23;.. 425 (6960) :846-51),
and small-cell lung cancer ("Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer", Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin S B., Nature 2003 Mar 20..; 422 (6929) :313-7).
Links
PATENTS
2 WO 2008154259
3 WO 2010033481
4 WO 2011009852
5 WO 2011062939
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Links
SYNTHESIS
2-Methyl-4'-tr {fluoromethoxy-biphenyl-3-carboxylic acid {6 - (cis-2 ,6-dimethyl-morpholin-4-yl)-pyrid »n-3-yl |-amide:
Figure imgf000003_0001

The following Examples serve to illustrate the invention without limiting the scope thereof, it is understood that the invention is not limited to the embodiments set forth herein, but embraces ali such forms thereof as come within the scope of the disclosure,

Figure imgf000013_0001

Step 1:

To a Solution of 2-Chloro-5-nitro-pyridine 1 (5.58 g, 35.2 mmol) and c/s-2, 6 - dimethylmorpholine (4.05 g, 35.2 mmol) in anhydrous DMF (. 30 mi) was Added K 2 CO. 3  (9.71 g, 70.4 mnrtoL). The Mixture was Heated at 50 º C overnight. After Concentration, the Residue is partitioned Between EtOAc and Water. The EtOAc Layer is dried over anhydrous Na 2 SO 4  and Concentrated to give Crude Product 3 as a yellow solid, after purification by silica gel chromatography, obtained pure product (7.80 g, 93.2%) LC-MS m / z:. 238.2 (M + 1).

Step 2:

The above material 3 (7.3Og. 30.8 mmoL) was hydrogenated in the presence of 10% Pd-C (1.0 g) in MeOH (120 ml) under hydrogen overnight. The suspension was filtered through celite and the filtrate was concentrated to give the crude product 4 (5.92 g) as a dark brown oil which was used directly in the next step without further purification. LC-MS m / z. 208.2 (M +1).

Step 3:

To a solution of 3-bromo-2-methyl benzoic acid (2.71 g, 12.6 mmoL), 6 - ((2S, 6R) -2,6 - dimethylmorpholino) pyridin-3-arnine 4 (2.61 g, 12.6 mmoL), and HATU (4.80 g, 12.6 mmoL) in anhydrous DMF (30 mL) was added diisopropylethylamine (6.58 mL, 37.8 mmoL) dropwise. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL), and then extracted with EtOAc (3 × 120 mL). The organic layer was dried and concentrated to give the crude product. This crude product was then purified by flash column chromatography using 30% EtOAc in hexane as eiuent to give 5 as a white solid (4.23 g, 83.0%) LC-MS m / z:. 404.1 (M +1).

Step 4:

A mixture of 4 - (trif! uoromethoxy) phenylboronic acid (254 mg, 1.24 mmol), 3-bromo-N-[6 - (2,6-dimethyl-morpholin-4-yl)-pyridin-3-ylJ-4 5-methyl-benzamide (250 mg, 0.62 mmol), Pd (PPh 3 ) 4  (36 mg, 0.03 mmol), Na 2 CO. 3  (Aqueous Solution 2.0 M, 1.23 mL, 2.4 mmol) and DME (4.5 mL) in a sealed tube was heated at 130 º C overnight. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and concentrated to give the crude product which was then purified by preparative mass triggered HPLC (C 18  column, etuted with CH 3 CN-H 2 O containing 0.05% TFA) to give N-(6 - ((2S, 6R)-2 ,6 dimethyfmorpholino) pyridin-3-yl)-2-rnethyl - 4'-(trifluoromethoxy) biphenyi-3-carboxamide (183.5 mg, 61.1% yield) LC-MS m / z: 486.2 (M +1)..

The resultant crystalline product (Form A) was converted to the amorphous form by dissolving in 3% w / w aqueous ethanol, and the resultant solution spray dried at about 150 º C.

Form B was prepared by heating the amorphous form in an oven at 110 º C for 2 hours. In a further embodiment, the invention relates to a process step or steps, or an intermediate as described herein.

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PAPER
ChemMedChem,  2013  ., Vol 8, 8 P 1261 -. 1265
Thumbnail image of graphical abstract
Continued optimization provided a novel type of Smoothened (Smo) antagonist based on a pyridazine core. The compound, NVP-LEQ506, currently in phase I clinical trials, combines high intrinsic potency and good pharmacokinetic properties resulting in excellent efficacy in rodent tumor models of medulloblastoma . Activity against a Smo mutant conferring resistance observed in a previous clinical trial with a competitor compound suggests additional therapeutic potential.

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SYNTHESIS

US20120196849 , ENTRY ..... 95
Figure US20120196849A1-20120802-C00097
LC-MS m / z 486.2 (M + 1)
USE SIMILAR METHODOLOGY
EXAMPLESThe present invention is further exemplified, but not limited, by the following example that illustrates the preparation of compounds of Formula I according to the invention.Example 1 4'-cyano-6-methyl-biphenyl-3-carboxylic acid [4 - ( morpholine-4-sulfonyl)-phenyl]-amide

 

Figure US20120196849A1-20120802-C00003

Step 1:. To a solution of 3-iodo-4-methyl-benzoic acid (10.0 g, 38.2 mmol) in methanol (70 ml) is added concentrated sulfuric acid (0.5 ml) The reaction mixture is heated at 70 ° C. for 48 hours, cooled to room temperature and ambient Then Concentrated. After that, ethyl acetate (100 ml) and Aqueous NaHCO (Saturated, 100 ml) Solution are Added to the Residue. The Organic Layer is Separated and Washed again with Aqueous NaHCO (Saturated, 100 ml) Solution. The Organic Layer is Separated, dried over anhydrous Na 2 SO and Concentrated to yield 3-iodo-4-methyl-BENZOIC acid methyl ester 1. Purification It is used without further in the next step .  1 H NMR (400 MHz, DMSO-d 6 ) delta 8.31 (s, 1H), 7.87 (d, 1H, J = 8.4 Hz), 7.48 (d, 1H, J = 8.4 Hz), 3.85 (s, 3H ), 3.35 (s, 3H); LC-MS m / z: 277.0 (M +1).

Step 2: To a round-bottom flask containing 3-iodo-4-methyl-benzoic acid methyl ester (1.38 g, 5.00 mmol), 4-cyanophenylboronic acid (1.10 g, 7.48 mmol), palladium acetate (168 mg, 0.748 mmol ), 2 - (dicyclohexylphosphino) biphenyl (0.526 g, 1.50 mmol) and potassium fluoride (0.870 g, 15.0 mmol) is added anhydrous 1,4-dioxane (15 ml) The flask is purged with argon and sealed The mixture is.. stirred at 130 ° C. for 18 hours, cooled to ambient temperature and then water (20 ml) and ethyl acetate (20 ml) are added. Solid is removed under vacuum filtration. The filtrate is extracted with EtOAc (20 ml × 2) . The Organic layers are combined, Washed with Aqueous HCl (5%, 20 ml) and Saturated NaHCO (20 ml). It is dried over MgSO 4 , and Concentrated. Residue is The Purified by silica gel column Chromatography (EtOAc / Hexane , gradient) to give 4'-cyano-6-methyl-biphenyl-3-carboxylic acid methyl ester 2; LC-MS m / z: 252.1 (M +1).

Step 3: To a Solution of 4'-Cyano-6-methyl-3-carboxylic acid BIPHENYL-methyl ester 2 (2.56 g, 10.3 mmol) in 1,4-dioxane-H 2 O (1:1 Mixture, 20 ml ) is added NaOH (1.22 g, 30.2 mmol)). The reaction is stirred at ambient temperature for 24 hours. To this mixture is added aqueous HCl (1 N, 36 ml) and it is then extracted with ethyl acetate (40 ml × 3). The Organic layers are combined, dried over anhydrous Na 2 SO 4 . The Solver is removed. Obtained The solid is Washed with small Air Amount of acetonitrile and dried to give 4'-Cyano-6-methyl-3-BIPHENYL- carboxylic acid 3:  1 H NMR (DMSO-d 6 ) delta 7.94 (d, 2H, J = 4.0 Hz), 7.84 (dd, 1H, J 1 = 8.4 Hz, J 2 = 1.2 Hz), 7.75 (d, 1H , J = 1.2 Hz), 7.61 (d, 2H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.4 Hz), 2.29 (s, 3 H); LC-MS m / z 238.1 (M +1 ).

Step 4:. To a suspension of 4'-cyano-6-methyl-biphenyl-3-carboxylic acid 3 (40 mg, 0.17 mmol) in anhydrous methylene chloride (5 ml) is added 2 drops of DMF Then oxalyl chloride (32 mg, 22 μl, 0.25 mmol) is added The mixture is stirred at ambient temperature until it turns clear After that, it is concentrated, re-dissolved in anhydrous methylene chloride (3 ml), and added to a solution of 4.. - (morpholine-4-sulfonyl)-phenylamine (61 mg, 0.25 mmol) and triethylamine (34 mg, 47 μl, 0.33 mmol) in methylene chloride (2 ml). The mixture is stirred for 2 hours, concentrated and the residue is purified Preparative by mass triggered HPLC (C 18  column, eluted with CH 3 CN-H 2 O containing 0.05% TFA) to give 4'-Cyano-6-methyl-BIPHENYL-3-carboxylic acid [4 - (morpholine-4-sulfonyl )-phenyl]-AMIDE:  1 H NMR (DMSO-d 6 ) delta 10.64 (s, 1H), 8.07 (d, 2H, J = 8.8 Hz), 7.97 (d, 2H, J = 8.4 Hz), 7.95 ( d, 1H, J = 8.8 Hz), 7.89 (s, 1H), 7.43 (d, 2H, J = 8.4 Hz), 7.67 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz), 3.63 (m, 4H), 2.84 (m, 4H) 2.32 (s, 3H); LC-MS m / z: 462.1 (M +1).

Example 2 4'-cyano-6-methyl-biphenyl-3-carboxylic acid [6 - (2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide

Figure US20120196849A1-20120802-C00004

Step 1: To a Solution of 2-Chloro-5-nitro-pyridine 4 (. 2.38 g, 15 mmol) and cis-2 ,6-dimethylmorpholine (. 1.73 g, 15 mmol) is Added K 2 CO. (4.14 g , 30 mmol.). The Mixture was Heated at 50 ° C. overnight. After Concentration, is the Residue partitioned Between Water and EtOAc. Layer The EtOAc is dried over anhydrous Na 2 SO and Concentrated to give 6 as a Yellow Crude Product . solid The crude product is used directly in next step without further purification LC-MS m / z:. 238.1 (M +1).

Step 2: The above crude material 6 is hydrogenated in the presence of Pd-C (0.2 g) in MeOH (100 mL) under hydrogen over 10 h The suspension is filtered through celite and the filtrate is concentrated to give the crude product 7. as a dark brown oil which is used directly in the next step without further purification LC-MS m / z:. 208.1 (M +1).

Step 3: To a solution of 3-bromo-4-methyl benzoic acid (. 108 mg, 0.5 mmol), 6 - (2,6-Dimethyl-morpholin-4-yl)-pyridin-3-ylamine 7 (104 mg , 0.5 mmol.), amd HATU (190 mg, 0.5 mmol.) in dry DMF (5 mL) is added triethylamine (139 uL, 1.0 mmol.) dropwise. The resulting mixture is stirred at room temperature for 2 h. After concentration , the residue is partitioned between EtOAc and water. The organic layer is dried and concentrated to give the crude product. The final compound is purified by flash column chromatography using 50% EtOAc in hexane as eluent to give 8 as a white solid. LC- MS m / z: 404.1 (M +1).

Step 4: A mixture of 4-cyanophenyl boronic acid (18 mg, 0.12 mmol), 3-bromo-N-[6 - (2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl] -4 8-methyl-benzamide (40 mg, 0.1 mmol), Pd (PPh 3 ) (11 mg, 0.01 mmol), and Na 2 CO. (42 mg, 0.4 mmol) in a combined system of Solvent Toluene (0.2 mL) and water (0.2 mL) and ethanol (0.05 mL) is heated at 140 ° C. under microwave irradiation for 30 min. The reaction mixture is diluted with EtOAc and water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with Brine and Crude Concentrated to give the Product which is triggered mass Purified by Preparative HPLC (C 18  column, eluted with CH 3 CN-H 2 O containing 0.05% TFA) to give 4'-Cyano-6-methyl-3-BIPHENYL -carboxylic acid [6 - (2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide LC-MS m / z: 427.2 (M +1)..

USE THIS COMPD IN ABOPVE AND YOU WILL GET SONIDEGIB

4 - (Trifluoromethoxy) phenylboronic acid

  • CAS Number  139301-27-2 
  • Linear Formula CF 3 OC 6 H 4 B (OH) 2 
  • Molecular Weight 205.93

CONDENSE WITH ... 3-bromo-N-[6 - (2,6-dimethyl-4-yl-MORPHOLIN)-pyridin-3-yl]-4-methyl-benzamideACS Medicinal Chemistry Letters,  2010  , Vol 1, 3 P. 130 - 134

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PAPER
ACS Medicinal Chemistry Letters,  2010  , Vol 1, 3 P 130 -.. 134
Figure
ENTRY 5m

A Mixture of 4 - (TRIFLUOROMETHOXY) phenylboronic acid (254 mg, 1.24 mmol), 3-bromo-N-[6 - (2,6 -
dimethyl-4-yl-MORPHOLIN)-pyridin-3-yl] -4 - E methyl-benzamide (250 mg, 0.62 mmol), Pd (PPh3) 4
(36 mg, 0.03 mmol), Na2CO3 (2.0 M Aqueous Solution, 1.23 mL, 2.4 mmol) and DME (4.5 mL)
was Heated in a Sealed Tube at 1300C overnight. The Reaction Mixture was Diluted with EtOAc
and Water. The Aqueous Layer was Extracted with EtOAc. The combined Organic Layer was
Washed with Brine and Concentrated to give the Crude Product which was Then Purified by
Preparative mass triggered HPLC (C18 column, eluted with CH3CN-H2O containing 0.05% TFA)
to give N-(6 - ((2S, 6R) 2 ,6-dimethylmorpholino) pyridin-3-yl)-2-methyl-4'-
(TRIFLUOROMETHOXY) BIPHENYL-3 -carboxamide (5m, 183.5 mg, 61.1% yield) LC-MS m / z: 486.2 (M +1)..
HRMS (m / z): [M + H] +
calcd for C26H27N3O3F3 486.2005; found 486.1986,
1H- NMR (500 MHz, DMSO-d6): delta (ppm) 10.15 (s, 1H), 8.43 (d, 1H), 7.94 (dd, 1H), 7.52-7.43
(m, 5H), 7.38 (m, 1H) , 7.33 (m, 1H), 6.86 (d, 1H), 4.06 (d, 2H), 3.62 (m, 2H), 2,34 (m, 2H), 2.22
(s, 3H), 1.16 (d, 6H ).

http://pubs.acs.org/doi/suppl/10.1021/ml1000307/suppl_file/ml1000307_si_001.pdf

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Reference

  1.  "LDE225 - PubChem" PubChem National Institutes of Health Retrieved 16 February 2014...
  2.  Pan, S; Wu, X; Jiang, J; Gao, W; Wan, Y; Cheng, D; Han, D; Liu, J; Englund, NP; Wang, Y; Peukert, S; Miller-Moslin, K; Yuan, J; Guo, R; Matsumoto, M; Vattay, A; Jiang, Y; Tsao, J; Sun, F; Pferdekamper, AC; Dodd, S; Tuntland, T; Maniara, W; Kelleher, JF; Yao, Y; Warmuth, M; Williams, J; Dorsch, M (10 June 2010) "Discovery of NVP-LDE225, a Potent and Selective Antagonist Smoothened.".  ACS Medicinal Chemistry Letters  1  (3):. 130-134  DOI : 10.1021 / ml1000307 .
  3.  "A Study to Identify Predictive Biomarker Signatures of Response to LDE225 (Hedgehog Inhibitor) In Patients With Pancreatic Cancer resectable" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  4.  "With Gemcitabine + Nab-paclitaxel LDE-225 (Hedgehog Inhibitor) as Neoadjuvant Therapy for Pancreatic Adenocarcinoma" . ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  5.  "Dose-Escalation, and Safety Study of Gemcitabine in Locally LDE225 and Advanced or Metastatic Pancreatic Cancer Patients" . ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  6.  "A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in surgically resectable Pancreas Cancer" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  7.  "Study in Combination With Docetaxel With LDE225 in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients (EDALINE)" . ClinicalTrials.gov . National Institutes of Health. 13 February 2014.
  8.  "LDE225 in Treating Patients With Stage II-III Estrogen Receptor and HER2-Negative Breast-Cancer" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  9.  "A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Journal of (BOLT)" . ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  10.  "To Evaluate the Safety, Local Tolerability, PK and PD of LDE225 on Sporadic Superficial Basal Cell Carcinomas and Nodular Skin (sBCC)" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  11.  "A Trial to Evaluate the Safety, Local Tolerability, Pharmacokinetics and Pharmacodynamics of Basal Cell Carcinomas LDE225 on Skin in Gorlin Syndrome Patients" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  12.  "Combination of the Hedgehog Inhibitor, LDE225, With Etoposide and Cisplatin in the First-Line Treatment of Patients With Extensive Stage Small Cell Lung Cancer (ES-SCLC)" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  13.  "A Phase III Study of Oral LDE225 Versus (VS) Temozolomide (TMZ) in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  14.  "A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  15.  "Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors" . ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  16.  "Dose Finding and Safety of Oral LDE225 Patients With Advanced Solid Tumors in" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  17.  "LDE225 and Paclitaxel in Solid Tumors" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  18.  "Study of Efficacy and Safety of Adult Patients With Relapsed LDE225 in / Refractory Acute Leukemia" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  19.  "Nilotinib and LDE225 in the Treatment of Chronic Myeloid Leukemia or Accelerated Phase in Patients Who Developed Resistance to Prior Therapy" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  20.  "A Phase Ib / II Dose-Finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF" ClinicalTrials.gov . National Institutes of Health. 13 February 2014. Retrieved 16 February 2014.
  21.  Jalili, A; Mertz, KD; Romanov, J; Wagner, C; Kalthoff, F; Stuetz, A; Pathria, G; Gschaider, M; Stingl, G;. Wagner, SN (30 July 2013)  "NVP-LDE225, a potent and Selective Growth smoothened antagonist Reduces melanoma in vitro and in vivo. "  (PDF).  PloS One  8  (7): e69064.  DOI : 10.1371/journal.pone.0069064 PMC  3728309 . PMID  23,935,925 .
  22.  Fendrich, V; Wiese, D; Waldmann, J; Lauth, M; Heverhagen, AE; Rehm, J;. Bartsch, DK (November 2011) "Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic Mouse Model of Islet cell neoplasms. ".  Annals of Surgery  254  (5): 818-23. DOI : 10.1097/SLA.0b013e318236bc0f PMID  22,042,473 .
  23. ChemMedChem,  2013  ., Vol 8, 8 P 1261 -. 1265
  24. ACS Med. Chem. Lett., 2010, 1 (3), pp 130-134.
  25. MORE REF

sonidegib

. Skin Cancer Foundation "Skin Cancer Facts." Available at: http://www.skincancer.org/skin-cancer-information/skin-cancer-facts  . Accessed on February 14, 2014.

Rubin AI, Chen EH, Ratner D (2005) Current Concepts: Basal-Cell Carcinoma N Engl J Med; 353:2262-9...

ClinicalTrials.gov "A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Journal of (BOLT)" Available at:. http://clinicaltrials.gov/ct2/show/NCT01327053?term =% 22% 22LDE225 + and +% 22BOLT% 22 & rank = 1. Accessed on February 14, 2014.

. National Cancer Institute Dictionary of Cancer Terms "Complete Response." Available at:  http://www.cancer.gov/dictionary?CdrID=45652  Accessed on February 14, 2014..

 . National Cancer Institute Dictionary of Cancer Terms "Partial Response." Available at:  http://www.cancer.gov/dictionary?CdrID=45819  Accessed on February 14, 2014..

Wong CSM, Strange RC, Lear JT (2003) Basal cell carcinoma BMJ;.. 327:794-798.

 Copcu E, Aktas A. Simultaneous Two Organ metastases of the giant basal cell carcinoma of the Skin Semin Surg Oncol Int 2005; 2:1-6 Available at:... http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC544837 /  . Accessed on February 14, 2014.

 Skin Cancer Foundation. "Journal of Basal Cell Treatment Options." Available at http://www.skincancer.org/skin-cancer-information/basal-cell-carcinoma/bcc-treatment-options  . Accessed on February 14, 2014.

Stuetz A, et al LDE225, smoothened a specific inhibitor, for the Topical treatment of nevoid basal cell carcinoma syndrome (Gorlin's syndrome) Melanoma Research 2010; 20:.... E40 Available at: http://journals.lww.com/ melanomaresearch/Fulltext/2010/06001/FC24_LDE225 , _a_specific_smoothened_inhibitor, _for.87.aspx # FC24_LDE225% 2C_a_specific_smoothened_inhibitor% 2C_for.87.aspx? s = 2 & _suid = 139234380607909969110518506816.

Novartis.com. "The Pipeline of Novartis Oncology: LDE225." Available at: http://www.novartisoncology.com/research-innovation/pipeline.jsp  . # Accessed on February 14, 2014.

 Children's Medical Research Center, Children's Memorial Hospital / Northwestern University Feinberg School of Medicine. "The Sonic hedgehog / patched / gli Signal Transduction pathway." Available at  http://www.childrensmrc.org/iannaccone/gli/  . Accessed on February 14 , 2014.

 . Gupta S, Takebe N, LoRusso P. Targeting the Hedgehog pathway in Cancer Ther Adv Med Oncol 2010 July; 2 (4):. 237-250 Available at:. http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3126020 /  . Accessed on February 14, 2014.

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