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The FDA today granted “breakthrough therapy” designation to ofatumumab for treatment of patients with chronic lymphocytic leukemia.

The designation applies to use of ofatumumab (Arzerra, GlaxoSmithKline) in combination with chlorambucil in patients with untreated CLL who unsuitable for fludarabine-based therapy.

Ofatumumab is a human monoclonal antibody that targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops.

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MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

September 15, 2013 1:40 am / 4 Comments on MACITENTAN , 马昔腾坦 , ماسيتانتان , Мацитентан , マシテンタン

MACITENTAN

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide,

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N’-propylsulfamide

CAS NO 441798-33-0

ACT-064992, Opsumit,UNII-Z9K9Y9WMVL
Mechanism of Action: Endothelin receptor antagonist (ERA)
Date of Approval: October 18, 2013(US)
Indication: Pulmonary Hypertension (PAH)
Company: Actelion Pharmaceuticals Ltd
PCT patent application: WO2002053557

FDA N204410, MACITENTANTABLET; ORAL10MG, OPSUMIT, ACTELION PHARMS LTD

Macitentan is achiral

Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

Mp 135–136 °C;………….J. Med. Chem., 2012, 55 (17), pp 7849–7861, DOI: 10.1021/jm3009103/CN 104447572

R_f (silica gel, heptane:ethyl acetate 1:1) 0.44.

LC-MS: t_R = 0.79 min, [M + H]⁺ = 588.86 (major isotope).

HR-LC-MS: t_R = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.

¹H NMR (CDCl₃): δ 8.51 (s, 2 H), 8.49 (s, 1 H), 7.58–7.63 (m, 2 H), 7.16–7.21 (m, 2 H), 6.88 (s, 1 H), 5.61 (t, J = 6.2 Hz, 1 H), 4.72–4.76 (m, 2 H), 4.62–4.66 (m, 2 H), 2.99 (q, J = 6.8 Hz, 2 H), 1.61 (h, J = 7.3 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H)……………..J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

¹³C NMR (CDCl₃): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3…………….J. Med. Chem., 2012, 55 (17), pp 7849–7861,DOI: 10.1021/jm3009103

Macitentan (Opsumit® )is a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process. Macitentan has a number of potentially key beneficial characteristics – i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding and tissue penetration properties. A clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions.

Macitentan (ACT-064992) is a tissue-targeting dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Macitentan inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage. Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. A Phase III clinical trial of macitentan was successfully completed in 2012.

Macitentan is an investigational drug being studied for the treatment of pulmonary arterial hypertension. It acts as a dualendothelin receptor antagonist and is being developed by Actelion.^[1] A Phase III clinical trial was successfully completed in 2012.^[2]

on 22 October 2012 – Actelion (SIX: ATLN) announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension

Actelion’s experimental lung drug macitentan prolonged overall survival by more than a third according to detailed study data, which the company hopes will convince investors it has a viable follow-up product to secure its commercial future.

Europe’s largest standalone biotech company wants the drug, which treats pulmonary arterial hypertension — a disease that causes high blood pressure in the arteries of the lungs — to replace blockbuster Tracleer.

Tracleer currently makes up 87 percent of sales but loses patent protection in 2015 and has also seen its market share eroded by Gilead’s Letairis.

Pharmacokinetics

Macitentan has an active metabolite, ACT-132577, which is an oxidative depropylation product. Both macitentan and ACT-132577 are mainly excreted in form of hydrolysis products via urine (about 2/3 of all metabolites) and faeces (1/3).^[3]

Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, whilerifampicin decreases the area under the curve (AUC) of the drug’s blood plasma concentration by 79%, and ketoconazoleapproximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.^[4]

SYNTHESIS

The synthesis begins with the reaction of chlorosulfonyl isocyanate (1) (dissolved in dichloromethane at 0 ° C) with one equivalent of tert-butanol. This produces a by BOC protected Aminosulfonylchlorid (2). With one equivalent of n-propylamine (dissolved in 3 eq. Of triethylamine, dichloromethane, at 0 ° C, RT 16 h) is produced by a hydrochloric acid elimination BOC-protected sulfamide (3). This is dissolved in 5 M HCl and dioxane (4-8 h), the BOC protecting group is cleaved. The sulfamide formed (4) is potassium tert-butoxide-(dissolved in MeOH, 3h) is converted to the potassium salt (5). Tert-butoxide potassium acts as a very strong base for deprotonation. This sulfamide potassium salt reacts with the nucleophilic substituents on the heteroaromatic Dichlorpyrimidinderivat (6) (dissolved in dimethyl sulfoxide, at room temperature, RT 42-72 h) under KCl-cleavage to a Monochlorpyrimidin intermediate (7). By treatment with ethylene glycol (dissolved in dimethyl ether, potassium-tert-butoxide,), the ethylene glycol side chain is generated (8). With 2-chloro-5-bromo-pyrimidine (dissolved in tetrahydrofuran, close, at 60-75 ° C) is formed under elimination of HCl in an S _N 1 reaction Macitentan (9)…………Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 .

Synthesis of Macitentan

…………………………………………….

SYNTHESIS

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………………………….

SYNTHESIS

(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MACITENTAN.

………………………

http://www.google.com/patents/WO2014155304A1?cl=en

LC-MS (Agilent MS detector G1956B with Agilent 1200 Binary Pump and DAD).

Parameters of the LC-MS method:

Injection volume: 2 |jL

Column: Kinetex C18, 2.6 μιη, 2.1 x 50 mm

Column flow rate: 1 mL/min

Eluents: Eluent A: water + 0.08% TFA

Eluent B: MeCN + 0.012% TFA

Gradient: 2.0 min 95% B

2.8 min 95% B

3.0 min 5% B

Temperature: 40°C Detector wavelength 210 nm

Preparation B: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]- 4-pyrimidinyl] -N’-propylsulfamide (macitentan):

N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane- 1-sulfamide (200 g; 0.46 mol; see Example 2 or 3) and 5-bromo-2-chloropyrimidine (117 g; 0.60 mol; 1.3 eq) were dissolved in toluene (3 L) and DMF (400 mL). The reaction mixture was warmed up to 50°C and toluene (approx. 400 mL) was distilled our under reduced pressure. The mixture was cooled to 0 °C and tBuOK (156 g, 3 eq, 1.38 mol) was added portionwise. It was stirred at 20 °C for 1 h. Water (1 L) was added and the pH of the solution was adjusted to 3-5 using 33% aq. HC1. The mixture was heated to 50°C and the layers were separated. The org. phase was treated with charcoal at 50°C and filtered over Celite. The filter cake was rinsed with toluene. At 50°C, water (1 L) was added to the org. layer. The layers were separated. The org. layer was concentrated under reduced pressure to a total volume of 1 L and cooled to 0°C. The solid obtained was filtered off. It was rinsed with toluene and MeOH. The crude material was suspended in EA (1 L) and heated to 50°C. 300 mL of EA were distilled out and MeOH (400 mL) was added. The suspension was cooled down to 0°C. The solid was filtered off, rinsed with MeOH and dried under reduced pressure to afford the title compound as a white solid (225 g; 83% yield).

……………………

PAPER

http://pubs.acs.org/doi/abs/10.1021/jm3009103

J. Med. Chem., 2012, 55 (17), pp 7849–7861

DOI: 10.1021/jm3009103

Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ET_A with significant affinity for the ET_B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (17)

………………………….. to give 17 (11.99 g, 88%) as a white powder;

mp 135–136 °C; R_f (silica gel, heptane:ethyl acetate 1:1) 0.44.

LC-MS: t_R = 0.79 min, [M + H]⁺ = 588.86 (major isotope).

HR-LC-MS: t_R = 1.96 min; (m + H)/z = 586.9711, found = 586.9714.

¹³C NMR (CDCl₃): δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156.4, 159.7, 163.5, 166.3.

……………

WO 2015004265 click

Example 3 : N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)pr opane- 1- sulfamide (reaction in and work-up with MIBK):

EG (124 mL, 3.7 mol, 6.0 eq.) was added to a warm (40-50°C) suspension of the compound of Preparation A (150 g, 0.37 mol) in MIBK (600 mL). Solid KOtBu (114 g, 1.11 mol, 3.0 eq.) was added portionwise so that IT < 60°C. The mixture was stirred for

2- 3 h at 100-105°C. After completion of the reaction (LC-MS control), it was cooled to 50 °C. A 40%) aq. solution of citric acid monohydrate (300 mL) was added until pH 4 was reached. The layers were separated. The org. phase was washed with water (450 mL) and the layers were separated. Water (450 mL) was added and the mixture was warmed to 50°C. It was stirred at 50°C for 5 min. The layers were separated. The org. phase was concentrated under vacuum at 50°C until 200 mL of MIBK were removed. Hept (800 mL) was added dropwise at 70-75°C until turbidity was observed. The mixture was seeded with an analytically pure sample of N-(5-(4-bromophenyl)-6-(2 hydroxy ethoxy)pyrimidin-4-yl)propane-l-sulfamide and stirred at 60-65°C for 30 min. It was allowed to cool to 5°C within 5 h. It was filtered off, rinsed with a cold MIBK/Hept mixture (300 mL, 1 : 1) and dried under vacuum at 50°C to yield the title compound as a white solid (121 g; 76% yield).

The product had NMR data equivalent to those reported in Bolli et al, J. Med. Chem. (2012), 55, 7849-7861. [M+H]⁺ = 430 and 432. LC-MS: t_R = 1.46 min; purity: 98.4% a/a. Residual ethylene glycol (GC-FID): 530 ppm.

…….

CN 104447572 click

(l) Martin H. Bolli et al. Reported the synthesis of Marcy cefotetan follows:

[0008] The method W 5- (4- desert phenyl) -4,6-dichloro-chewing clever as a starting material, N- propyl amine Lai ugly bell in DMS0 as a reaction solvent, an alcohol bell as t a base under substitution reaction conditions, the reaction temperature needs of 24-7 to give

The intermediate compound 15, compound 15 in hexylene glycol dimethyl off as the reaction solvent, a tertiary alcohol under conditions with a strong base clock as hexanediol substitution reaction, l〇 (TC Reaction of 18-2 to give compound 17, Compound 17 was then reacted with 5-chloro-chewing desert -2 clever substitution reaction at tetraammine Qiao Nan as a reaction solvent, ammoniated axis as the alkali conditions, the reaction to give the final product of Marcy cefotetan The route every step the higher the yield, the experimental use of N- propyl amine Lai ugly bell hygroscopic, unstable and a long time before the two-step reaction, the reaction at the second step requires l〇 (TC high temperature 18-2 technology is not suitable for industrial production.

[0009] International Patent W02002 / 053557 discloses some preparation methods and other Massey cefotetan column derivative method at each step of the preparation of the reaction times are longer, some reactions up to 4 days, and the resulting intermediate are purified by column chromatography method is not suitable for industrial production.

A method for preparing Marcy cefotetan, comprising the steps of: (1) the compound of formula II with N- cyclopropyl sulfonamide compound of formula III 5- (4- bromophenyl) -4, 6- dichloropyrimidine substitution reaction is converted to the formula IV:

Compound (2) in the presence of a strong base of formula IV with a compound of formula V glycol substitution reaction to give a compound of formula VI:

Compound (3) a strong base of formula VI in the presence of a substitution reaction conditions to give a compound of formula I with a compound of formula W occurs:

, The resulting compound of formula I as Marcy cefotetan.

[00 pairs (3) N- [5- (4- desert) -6-mouth – [(5-desert -2- chew clever-yl) oxy] hexyl oxy] -4-chewing clever yl] -N ‘- Lai ugly propyl amine (Formula I) Synthesis

[0036] Weigh 20gN-5- (4- desert) -6- (2-2- light hexyl group -) 4- chew clever group -N ‘- Lai ugly propyl amine, 200ml dried DMS0 added to 1L H jar, add 20g of alcohol t-clock was added in portions, then add 17. 7g5- desert – dichloro chew clever, 30-4 (TC reduction reaction, the reaction and the reaction solution. a 10% sample skillfully acid to adjust PH value 3 to 4, the reaction mixture was added to 1000ml water, olive mix, suction. suction Massey cefotetan get wet crude product 42g, 450ml of methanol was added at room temperature and then beating 20min, filtration and dried 45C to give white solid was dried under vacuum to give 23.2 Marcy cefotetan yield;.. 85%

[0037] The compound (Formula I) relating to the physical and chemical properties, spectroscopic data are as follows:

[0038] branded point; 135-136 ° C; we NMR (300MHz, DMS0) 5 (egg m):… 9 8 (s, lH), 8 7 (s, 2H), 8 5 (s, l H,) 7. 5 (s, 2H), 7. 2 (s, IH), 7. 1 (s, 2H,) 4. 7 (s, 2H), 4. 6 (s, 2H,) 2. 8 (s, 2H,), 1. 5 (m, 2H,), 0. 81 (m, 3H), MS Qiaoqiao m / z 589 ([M + Tin +).

…………

see

WO 2002053557

http://www.google.com/patents/WO2002053557A1?cl=en

………..

NMR spectroscopy

Assignment of the signals mentioned in the text of the H-NMR spectrum of the drug Macitentan

¹ H-NMR

Solvent: CDCl ₃

δ 8.51 (s, 2H, CH) ¹¹ , 8.49 (s, 1 H, CH) ¹⁰ , 7.58 to 7.63 (m, 2H, CH) ⁹ , 7.16 to 7.21 ( m, 2H, CH) ⁸ , 6.88 (s, 1H, NH) ⁷ , 5.61 (t, J = 6.2 Hz, 1H, NH) ⁶ , 4.72 to 4.76 (m, 2H , CH ₂ ) ⁵ , 4.62 to 4.66 (m, 2H, CH ₂ ) ⁴ , 2.99 (q, J = 6.8 Hz, 2H, CH ₂ ) ³ , 1.61 (h, J = 7.3 Hz, 2H, CH₂ ) ² , 0.97 (t, J = 7.4 Hz, 3H, CH ₃ ) ¹ . ^{[Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 .]}

……………………………………………………………………………………

Gatfield, John; Grandjean, Celia Mueller; Bur, Daniel; Bolli, Martin H.; Nayler, Oliver (2014): Proton assignment in macitentan as used in NMR interpretation.Figure_9.tif. PLOS ONE. 10.1371/journal.pone.0107809.g009.

¹³ C-NMR

Solvent: CDCl ₃

δ 11.6, 22.7, 46.1, 65.3, 65.9, 104.8, 112.4, 123.7, 128.0, 131.7, 133.0, 155.7, 156 , 4, 159.7, 163.5, 166.3. ^{[ Journal of Medicinal Chemistry 55, 2012 S. 7849-7861, doi : 10.1021 / jm3009103 . ]}

NMR PREDICT BY ME

1H NMR PREDICT

13C NMR PREDICT BY ME

COSY PREDICT BY ME, WORLDDRUGTRACKER ON A WHEELCHOPPER SCALING NEW HEIGHTS

REFERENCES

Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist”. Journal of Medicinal Chemistry 55 (17): 7849–7861. doi:10.1021/jm3009103. PMID 22862294.
“Macitentan”. Actelion. Retrieved 22 August 2012.
Bruderer, S.; Hopfgartner, G. R.; Seiberling, M.; Wank, J.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2012). “Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans”. Xenobiotica 42 (9): 901–910.doi:10.3109/00498254.2012.664665. PMID 22458347.
Bruderer, S.; Äänismaa, P. I.; Homery, M. C.; Häusler, S.; Landskroner, K.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2011).“Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist”. The AAPS Journal 14 (1): 68–78. doi:10.1208/s12248-011-9316-3. PMC 3282010. PMID 22189899.
Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist“. Journal of Medicinal Chemistry, 2012, 55 (17): 7849–7861
Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Novel sulfamides and their use as endothelin receptor antagonists, WO2002053557 A1, CA2431675A1, CA2431675C, CN1524079A, CN100432070C, DE60118782D1, DE60118782T2, EP1345920A1, EP1345920B1, EP1693372A1, US7094781, US7285549, US20040077670, US20060178365,
Martin Bolli, Christoph Boss, Martine Clozel, Walter Fischli, Thomas Weller, Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases, WO2006051502
Martine Clozel, Therapeutic compositions containing macitentan,WO2010018549 A2, CA2731370A1, CN102099026A, CN102099026B, EP2315587A2, US20110136818(WO2006/051502A2, JMC2012, 7849). Chlorosulfonyl isocyanate ( 1 ) reaction with tert-butyl alcohol 2 , which is then reacted with n-propylamine 3 . 3 de-boc protected through the acid after reaction with potassium t-butoxide 4 . Another compound 5 with NaH after acidic protons off with dimethyl carbonate ( 6 ) to obtain 7 . 7 and formamidine hydrochloride ( 8 ) to ring chlorinated later POCl3 9 . 9 and 4 SNAr reaction occurs 10 . 10under basic conditions with ethylene glycol SNAr reaction occurs again in alkaline conditions with11 SNAr reaction occurs MAXI cefotetan.

External links

Actelion home page

Actelion Ltd

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion’s first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium – the single layer of cells separating every blood vessel from the blood stream. Actelion’s over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).

Macitentan
Systematic (IUPAC) name

N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide
Clinical data
Trade names	Opsumit
Pregnancy category	US: X (Contraindicated)
Legal status	US: ℞-only FDA approved drug
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hydrolysis, oxidation (CYP3A4)
Excretion	2/3 urine, 1/3 faeces
Identifiers
CAS Registry Number	441798-33-0
ATC code	C02KX04
PubChem	CID: 16004692
ChemSpider	13134960
ChEBI	CHEBI:76607
Synonyms	ACT-064992
Chemical data
Formula	C₁₉H₂₀Br₂N₆O₄S
Molecular mass	588.273 g/mol

Patent	Submitted	Granted
Sulfamides and their use as endothelin receptor antagonists [US7094781]	2004-04-22	2006-08-22
Sulfamides and their use as endothelin receptor antagonists [US7285549]	2006-08-10	2007-10-23
Stable Pharmaceutical Compositions Comprising a Pyrimidine – Sulfamide [US2008233188]	2008-09-25
Combination Comprising Paclitaxel for Treating Ovarian Cancer [US2010311774]	2010-12-09
Stable pharmaceutical compositions comprising a pyrimidine-sulfamide [US2010004274]	2010-01-07
SULFONYLUREA MODULATORS OF ENDOTHELIN RECEPTOR [US2011082151]	2011-04-07
ENDOTHELIN RECEPTOR ANTAGONISTS FOR EARLY STAGE IDIOPATHIC PULMONARY FIBROSIS [US2010022568]	2007-04-12	2010-01-28
THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2011136818]	2011-06-09
Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor [US2009318459]	2009-12-24

Patent and Exclusivity

Patent Data

Appl No	Prod No	Patent No	Patent Expiration	Drug Substance Claim	Drug Product Claim	Patent Use Code
N204410	001	US7094781	Oct 12, 2022	Y	Y
N204410	001	US8268847	Apr 18, 2029			U – 1446
N204410	001	US8367685	Oct 4, 2028		Y	U – 1445

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N204410	001	ODE	Oct 18, 2020
N204410	001	NCE	Oct 18, 2018

U1446 METHOD OF TREATING PULMONARY HYPERTENSION COMPRISING ADMINISTERING MACITENTAN IN COMBINATION WITH A COMPOUND HAVING PHOSPHODIESTERASE-5 INHIBITORY PROPERTIES

U1445 METHOD OF TREATING PULMONARY ARTERIAL HYPERTENSION BY ADMINISTERING A PHARMACEUTICAL COMPOSITION COMPRISING MACITENTAN AND A POLYSORBATE, WHERIN THE POLYSORBATE REPRESENTS 0.1 TO 1% OF THE WEIGHT OF SAID PHARMACEUTICAL COMPOSITION

OPSUMIT (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide. It has a molecular formula of C₁₉H₂₀Br₂N₆O₄S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula:

OPSUMIT® (macitentan) Structural Formula Illustration

Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive.

OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum.

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Collagen clue reveals new drug target for untreatable form of lung cancer

September 14, 2013 11:23 am / Leave a comment

Syn-Org-Chemist

Collagen clue reveals new drug target for untreatable form of lung cancer.

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BENAZEPRIL HYDROCHLORIDE SYNTHESIS AND REVIEW

September 14, 2013 4:00 am / 5 Comments on BENAZEPRIL HYDROCHLORIDE SYNTHESIS AND REVIEW

BENAZEPRIL HYDROCHLORIDE, CAS NO 86541-74-4

Benazepril, brand name Lotensin (Novartis), is a medication used to treat high blood pressure (hypertension), congestive heart failure, and chronic renal failure. Upon cleavage of its ester group by the liver, benazepril is converted into its active form benazeprilat, a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.

Dosage forms

Benazepril is available as oral tablets, in 5-, 10-, 20-, and 40-mg doses.

Benazepril is also available in combination with hydrochlorothiazide, under the trade name Lotensin HCT, and with amlodipine(trade name Lotrel).

Side effects

Most commonly, headaches and cough can occur with its use. Anaphylaxis, angioedema and hyperkalemia, the elevation of potassium levels, can also occur.

Benazepril may cause harm to the fetus during pregnancy.

According to coverage of the study on WebMD:

“

ACE inhibitors can pose a potential threat to kidneys as well. The key question was whether damaged kidneys would worsen if patients took ACE inhibitors. In a nutshell, concerns centered on blood levels of potassium andcreatinine, waste products that are excreted by the kidneys. Testing creatinine levels in the blood is used as a way to monitor kidney function (…) kidney problems worsened more slowly in those taking Lotensin. Overall, there were no major differences in side effects between patients taking Lotensin or the placebo.^[2]

”

This study marks the first indication that benazepril, and perhaps other ACE inhibitors, may actually be beneficial in the treatment of hypertension in patients with kidney disease.

The Benazepril hydrochloride, with the CAS registry number 86541-74-4, is also known as (3S)-3-(((1S)-1-Carboxy-3-phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid, 3-ethyl ester, monohydrochloride; Benazepril HCl; Cibacen; Cibacen CHF; Labopol. It belongs to the product categories of Intermediates & Fine Chemicals; Pharmaceuticals; Amines; Aromatics; Heterocycles. This chemical’s molecular formula is C₂₄H₂₉ClN₂O₅ and molecular weight is 460.96. What’s more, its IUPAC name 2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid hydrochloride. In addition, Benazepril hydrochloride (CAS 86541-74-4) is crystalline solid which is soluble in DMSO. It is used in high blood pressure and congestive heart failure. When you are using this chemical, you should not breathe dust and avoid contact with skin and eyes.

Veterinary use

Under the brand names Fortekor (Novartis) and VetACE (Jurox Animal Health), benazepril hydrochloride is used to treat congestive heart failure in dogs and chronic renal failure in dogs and cats.

^ Hou F, Zhang X, Zhang G, Xie D, Chen P, Zhang W, Jiang J, Liang M, Wang G, Liu Z, Geng R (2006). “Efficacy and safety of benazepril for advanced chronic renal insufficiency”. N Engl J Med 354 (2): 131–40. doi:10.1056/NEJMoa053107. PMID 16407508.
^ ^a ^b Hitti, Miranda; Chang, Louise (January 11, 2006). “Drug May Treat Advanced Kidney Disease”. WebMD. Retrieved 2006-09-07.

Prescribing Information for Lotensin

	Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin
	1-Carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one monohydrochloride; 3(S)-[1(S)-Ethoxycarbonyl-3-phenylpropylamino]-2-oxo-2,3,4,5-tetrahydro-1-benzazepine-1-acetic acid monohydrochloride
【CAS】	86541-74-4, 86541-75-5 (free base)
MF	C24-H28-N2-O5.Cl-H
MW	460.9551rot–[Alpha] 20 D -141.0 °. (C = 0.9, ethanol)
	Cardiovascular Drugs, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors
	Launched-1990
	Novartis (Originator), Pierre Fabre (Licensee), Andrx (Generic), Eon Labs (Generic), KV Pharmaceutical (Generic), Mylan (Generic)

Above Preparation of Benazepril hydrochloride (CAS 86541-74-4): The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.

ABOVE SCHEME-EP 1891014 B1

BACKGROUND

Benazepril (CAS REGISTRY No. 86541-75-5) first disclosed inUS 4,410,520 is one of the well-known ACE inhibitors and is used for the treatment of hypertension.
Chemically, Benazepril, is (3S)-1-(carboxymethyl-[[(1(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one.
Benazepril is administered orally in the form of hydrochloride salt (CAS REGISTRY No. 86541-74-4) represented by formula (I).
The preparation of benazepril disclosed in US 4,410,520 , J. Med. Chem. 1985, 28, 1511-1516, and Helvetica Chimica Acta (1988) 71, 337-342, as given in scheme 1, involves reductive amination of ethyl 2-oxo-4-phenyl butyrate (IV) with sodium salt of (3S)-3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1 H-benzazepin-2-one (III).
In example 12 of US 4,410,520 , the crude benazepril (II) obtained in a diastereomeric ratio of SS: SR=70:30 was dissolved in dichloromethane and treated with HCl gas to obtain benazepril hydrochloride. The benazepril hydrochloride of formula (I) obtained as a foam was crystallized from methyl ethyl ketone to obtain in a SS: SR=95:5 diastereomeric ratio. Benazepril hydrochloride was further purified by recrystallization from a mixture of 3-pentanone/methanol (10:1), melting point: 188-190 °C.
Alternatively, in example 27 of US 4,410,520 , benazepril hydrochloride was purified by refluxing in chloroform, filtering, and washing first with chloroform and then with diethyl ether. The melting point of benazepril hydrochloride obtained as per this example is 184-186 °C.
An alternative process disclosed in US 4,785,089 involves nucleophilic substitution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepine-2-one (V), using the chiral substrate ethyl (2R)-2-(4-nitrobenzenesulfonyl)-4-phenyl butyrate (VI) in presence of N-methylmorpholine (scheme 2). The benazepril t-butyl ester (IIa) obtained in a diastereomeric ratio of SS: SR=96:4 was hydrolyzed to benazepril (II) and converted to hydrochloride salt by treating with HCl gas in ethyl acetate. The crystalline suspension of benazepril hydrochloride in ethyl acetate was diluted with acetone and filtered to obtain in a diastereomeric ratio of SS: SR=99.1:0.9. Further purification by refluxing in ethyl acetate afforded benazepril hydrochloride in a diastereomeric ratio of SS: SR=99.7:0.3, melting point of 181 °C.
The above documents do not disclose the crystalline form of benazepril hydrochloride obtained by following the purification processes disclosed in the examples.
The Merck Index., 12^th edition reports benazepril hydrochloride crystals obtained from 3-pentanone+methanol (10:1), melting point 188-190 °C
The crystallization methods taught in the prior art does not consistently produce a constant diastereomeric composition of SS:SR diastereomer. This is evident from the variation in the melting points of the benazepril hydrochloride reported in three different working examples, which varies between 181 to 190°C.
The variation in diastereomeric composition of a pharmaceutical substance is not desirable as it would affect its efficacy. Hence there is a need for a crystallization process that consistently produce a constant diastereomeric composition of SS diastereomer in greater than 99.8%.
Coming to the crystalline form, it is well known in the art that the solid form of a pharmaceutical substance affect the dissolution rate, solubility and bioavailability. The solid form may be controlled by process employed for the manufacture of the pharmaceutical substance. In particular the process of purification of the solid substance by crystallization is used to control the solid form (Organic Process Research & Development, 2003, 7, 958-1027).
It has been found that the crystalline form of benazepril hydrochloride obtained from processes of prior art documents is designated as crystalline Form A as evident from the following documents.
In a monograph published by Al-badar et al in Profiles of Drug Substances, Excipients, and Related Methodology, Vol. 31, 2004, p117-161; benazepril hydrochloride prepared by the process disclosed in US 4,410,520 , and J. Med. Chem. 1985, 28, 1511-1516, has been characterized by powder X-ray diffraction pattern having 2θ peaks at 6.6, 9.9, 11.9, 13.7, 14.0, 14.9, 15.3, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 22.2, 25.2, 25.5, 26.4, 26.6, 27.1, 27.9, 29.8, 30.4, 31.0, 32.6, 33.3, 33.8, 34.4, 35.5, 38.2, 39.9, 43.9, 48.9.
The major peaks are at 6.6, 9.9, 11.9, 13.7, 14.9, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 25.2, 25.5, 26.4, 26.6, 27.9, 31.0, and 32.6.
WO 2004/013105 A1 also discloses that by following the processes of the prior art mentioned above, crystalline benazepril hydrochloride is isolated in a form designated as Form A having a powder X-ray diffraction pattern with 2θ values at 6.7, 10.1, 12.0, 13.8, 15.1, 16.4, 17.4, 19.0, 19.6, 20.2, 20.9, 21.0, 25.3, 25.5, 26.4, 26.6, 27.6, 28.0, 31.0, 32.7.
WO 2004/013105 A1 discloses that benazepril hydrochloride Form A may be prepared from a concentrated solution of the benazepril hydrochloride in a solvent selected from C₁-C₁₀ alcohol, N,N-dimethylformamide, N-methylpyrrolidone by adding an anti-solvent selected from C₄-C₁₂ alkane or C₁-C₁₀ acetate, preferably, hexane or ethyl acetate.
WO 2004/013105 A1 in Example 5 describes a process of making crystalline form A of benazepril hydrochloride by passing HCl gas into a solution of benazepril free base in diethyl ether and filtering the resulting suspension.
Similarly, in Example 6, the benazepril hydrochloride was dissolved in water free ethanol and the resulting solution was added to heptane at 20° C to obtain the crystalline Form A.
Further, WO 2004/013105 A1 , mentions a list of solvents and anti-solvents that can be used to make benazepril hydrochloride crystalline Form A. However, there is no enabling disclosure and the document is silent on the diastereomeric purity of the crystalline form A obtainable by the process disclosed.
The processes of crystallization and/or recrystallization disclosed in the prior art do not consistently produce benazepril hydrochloride with constant diasteromeric content as evident from the variation in the melting point of the crystalline benazepril hydrochloride obtained from crystallization from various solvents.

SYNTHETIC SCHEMES

	Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use
	Watthey, J.W.H. (Novartis AG)
	EP 0072352; GB 2103614; JP 8338260

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.


	Process for the preparation of benazepril
	Kumar, Y.; De, S.; Thaper, R.K.; Kumar, D.S.M. (Ranbaxy Laboratories Ltd.)
	WO 0276375

The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.


	CGS-14824 A
	Casta馿r, J.; Serradell, M.N.
	Drugs Fut 1984,9(5),317

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.


	Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A)
	Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.
	J Label Compd Radiopharm 1987,24(10),1177-84

A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.

US 6548665 B2– above

see translated vesrsion————-First, 2,3,4,5 – tetrahydro-1H-[1] azepin-2 phenyl – one (2) Preparation of
the dry reaction flask, add α- tetralone 20g (0.137mol), stacked acid 7.36g (0.171mol) and chloroform 140ml, was stirred at 40 ℃ in 1h concentrated sulfuric acid was slowly added dropwise 36ml, acid layer was separated and poured into 900ml water to give a creamy solid. Recrystallization with hot water to give white crystals (2) 15.5g (70%), mp141 ℃. (Acidic filtrate and after a small amount of product can be obtained.)
Second, 3,3 – dichloro-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (3) of the prepared
in a dry reaction flask, (2) 48.3g (0.3mol) and xylene solution of 1300ml, phosphorus pentachloride 188g (0.9mol), stirred and gradually heated to at 0.5h 90 ℃, (Caution! When phosphorus pentachloride dissolved hydrogen chloride gas had severe.) 90 ℃ the reaction was continued for 0.5h, filtered to remove a small amount of suspended solids, solvent recovery under reduced pressure, to the residue was added saturated sodium bicarbonate solution, 100ml, stirred until a solid precipitate complete, filtered and the cake washed with ethanol (100ml × 2), diethyl ether (50ml) and dried to give (3) 69.0g (90%), mp185 ~ 187 ℃.
III.3 – chloro-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (4) Preparation of
the reaction flask (3) 10g (0.087mol), Sodium acetate 77g (0.11mol), acetic acid 460ml and 5% Pd-C 0.86g, under atmospheric pressure at room temperature to a hydrogen-absorbing up total of 950ml (about 0.5h). Filtration, recycling the catalyst recovered solvent, the residue was dried under reduced pressure, and then added 900ml of 10% sodium bicarbonate solution and dichloromethane 300ml, stirring, standing, the organic layer was separated and the aqueous layer extracted with dichloromethane (300ml × 3) extracted organic layers were combined, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure. Diethyl ether was added to the cured 350ml, and mashed, filtered and dried to give (4) 8.19g (95%), mp163 ~ 167 ℃.
4 (3) – azido-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (5) Preparation of
the dry reaction flask (4) 15.9g ( 0.08mol), sodium azide 6.4g (0.10mol) and 320ml solution of dimethyl sulfate, the reaction was stirred at 80 ℃ 3h, cooled to room temperature, poured into ice-water (1L) to precipitate a pale yellow solid , filtered and dried under reduced pressure at 75 ℃ to give (5) 14.7g (90%), mp142 ~ 145 ℃.
V.3 – azido-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (6) Preparation of
the dry reaction flask, (5) 3.0g (0.015mol), tetrabutylammonium bromide, 0.5g (0.0015 mol), powdered potassium hydroxide 1.1g (0.016mol) and 30ml of tetrahydrofuran solution of ethyl bromoacetate was added 1.9ml ( 0.016mol), stirred rapidly at room temperature for 1.5h (nitrogen). Water was added: dichloromethane (50:100 ml), stirred, allowed to stand, the organic layer separated. Washed with water, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure to give a pale yellow oil (6) 4.1g (96%) (can be used directly in the next step).
VI.3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (7) Preparation of
the dry reaction flask, (6 ) 20.0g (0.070mol), ethanol 100ml, 10% Pd-C 1.0g stirring, at room temperature, 303.9kPa hydrogenated under a hydrogen pressure 1.5h, intermittent deflated to remove the generated nitrogen gas, after the reaction was collected by filtration Pd / C, recovery of solvents under reduced pressure to give a yellow oil, add ether l00ml, mashed, filtered and dried to give a white solid (7) 17.0g (93%) mp101 ~ 102 ℃.
Seven, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (8) Preparation of
the reaction flask, adding (7) 25.1g (0.096mol), L – tartaric acid 14.4g (0.096mol) and hot ethanol 200ml, stirring to dissolve, cooled at room temperature overnight, filtered and dried under reduced pressure to give a white powder 30.7g, with ethanol Recrystallization twice (each 200ml), to give (8) tartaric acid salt of 13.6g (34%), mp168 ~ 169 ℃, with 10% ammonium hydroxide, to give a white solid (8) 8.0g (95%) mp104 ~ 106 ℃.
Eight, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (9) Preparation of
the reaction flask, (8) 4.0g (0.056mol) and 150ml of methanol solution of sodium hydroxide 2.1g (0.056moI) and a solution of 5ml of water, stirred at room temperature for 2h, the solvent recovered under reduced pressure, the residue was dried and diethyl ether was added 100ml, trace broken, filtered, and dried to give (9) 12.9g (89%) (used directly in the next step).
IX benazepril (1) Synthesis of
the reaction flask (9) 12.9g (0.050mol), 2 – oxo-4 – phenylbutyrate 31.0g (0.15mol), acetic acid and 100ml methanol 75ml, the reaction was stirred at room temperature for 1h (nitrogen). Of sodium borohydride cyanide was slowly added dropwise 3.8g (0.062mol) and 30ml of methanol solution of (4h was completed within), stirred overnight, heat. Concentrated hydrochloric acid 10ml, 1h stirring at room temperature, the solvent was recovered under reduced pressure, water was added to the residue and diethyl ether 400ml l00ml, dissolved with concentrated ammonium hydroxide and the pH adjusted to 9.3, the organic layer was separated and the aqueous layer acidified with concentrated hydrochloric to pH 4.3, extracted with ethyl acetate (100ml × 3) extracted organic layers were combined, dried over anhydrous magnesium sulfate, the solvent recovered under reduced pressure, to the residue was added methylene chloride (150ml) to dissolve. And pass into dry hydrogen chloride after 5min recovered solvent under reduced pressure, to the residue was added hot ethyl ketone 100ml, stirring to dissolve, cooled and precipitated solid was filtered to give crude product (1). A 3 – amyl ketone / methanol (volume ratio 10:1) (110ml) was recrystallized (1) 5.8 g, mp 188 ~ 190 ℃, [alpha] _D²⁰ -141.0 (C = 0.9, C ₂ H ₅ OH )
[Spectral Data] (free base) ^[2]
MS: m / Z (%) 424 (M ⁺ , 2), 351 (100), 190 (22), 91 (65)
] [other synthetic routes
described in the reference literature.

[References]
[1] Briggs LH et al. J Chem Soc, 1937, 456
[2] Watthey WH et al. J Med Clmm, 1985, 28:1511
[3] EP 1986, 206933 (CA, 1987, 107: 77434e)
[4] EP 1983, 72352 (CA, 1983, 99:53621 d)
[5] package insert: Lotensin
[6] property protection case I: Lotensin
[7] property protection case II: Lotensin
[8] Drug Monograph information: BENAZEPRIL

more info

Benazepril M.p. 148.5°.

Proprietary names. Briem; Cibace; Cibacen; Cibacene; Labopal; Lotensin; Tensanil; Zinandril.

C₂₄H₂₈N₂O₅,HCl=461.0

CAS—86541–74–4

A white to off–white crystalline powder. It is soluble in water, ethanol and methanol.

Partition Coefficient.

Log P(octanol/water), 3.50.

Gas Chromatography.

System GP—RI 3030 (benazepril-ME); RI 2985 (M (benazeprilate)-ME3).

Column: 3% OV-101 on Gaschrom Q, 80–100 mesh (Ciba-Geigy), pyrex glass (1.5 m × 2 mm i.d.). Column and injector port temperature: 275°. Carrier gas: helium, flow rate 30 mL/min. MS detection (EI, SIM). Retention times: benazepril (methyl ester derivative) 2.55 min; benazeprilat (derivative) 2.3 min. [G. Kaiser et al.,J. Chromatogr.,1987, 419, 123–133].

High Performance Liquid Chromatography.

System HAA—retention time 17.0 min.

Column: C₁₈ (RP-BDS, 5 μm packing, 250 × 3 mm i.d.). Mobile phase: sodium dihydrogen phosphate (0.025 M, pH 4.8):acetonitrile (55:45). 0.4 mL/min flow rate. UV detection (λ=250 nm). Retention time: benazepril hydrochloride, 4.95 min. [I. E. Panderi and M. Parissi-Polou,J. Pharm. Biomed. Anal.,1999, 21, 1017–1024].

Column: Hypersil ODS (5 μm, 250 × 4.5 mm). Mobile phase: sodium heptanesulfonate (20 mM, pH 2.5):acetonitrile (5% THF) (52:48 v/v), 1.0 mL/min flow rate. UV detection (λ=215 nm). Retention time: 15 min. [D. Bonazzi et al.,J. Pharm. Biomed. Anal.,1997, 16, 431–438].

Ultraviolet Spectrum.

Aqueous acid (0.2 M NH₂SO₄)—237 nm; basic—241 nm; aqueous acid (0.1 M hydrochloric acid)—237.2 nm (hydrochloride salt).

Reference(s):
Clarke’s Analysis of Drugs and Poisons
Watthey, J.W.H. et al.: J. Med. Chem. (JMCMAR) 28, 1511 (1985).
US 4 410 520 (Ciba-Geigy; 18.10.1983; prior. 11.8.1981, 9.11.1981, 19.7.1982).
EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA-prior. 11.8.1981, 9.11.1981).

A significant number of new specialty medications are on track to be approved in 2013, and some will provide increased competition in certain therapy classes.

September 14, 2013 1:21 am / 2 Comments on A significant number of new specialty medications are on track to be approved in 2013, and some will provide increased competition in certain therapy classes.

read all at

http://www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2013/July_August-2013/Near-Term-Specialty-Pipeline-Highlights-July_August_2013

………

Aimee Tharaldson, PharmD, is a senior clinical consultant in the emerging therapeutics department at Express Scripts. She is responsible for monitoring and analyzing the specialty pharmaceutical pipeline. The emerging therapeutics department produces several proprietary reports on the pipeline for use by Express Scripts’ employees and clients. It is also responsible for the safety program that alerts patients, physicians, and clients to important information regarding serious drug safety alerts and market withdrawals. She contributes to Express Scripts’ Drug Trend Report and plays a key role in developing and maintaining Express Scripts’ specialty drug list. She received her doctor of pharmacy degree from the University of Minnesota, College of Pharmacy, and completed a pharmacy practice residency at the Minneapolis VA Medical Center. –

See more at: http://www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2013/July_August-2013/Near-Term-Specialty-Pipeline-Highlights-July_August_2013#sthash.3n823rAw.dpuf

Sanofi to withdraw the lixisenatide New Drug Application (NDA) in the U.S., The company plans to resubmit the NDA in 2015, after completion of the ELIXA CV study.

September 13, 2013 3:09 am / 2 Comments on Sanofi to withdraw the lixisenatide New Drug Application (NDA) in the U.S., The company plans to resubmit the NDA in 2015, after completion of the ELIXA CV study.

lixisenatide

Sanofi Provides Update on Lixisenatide New Drug Application in U.S.

Paris, France – September 12, 2013 – Sanofi (EURONEXT: SAN and NYSE: SNY) announced today its decision to withdraw the lixisenatide New Drug Application (NDA) in the U.S., which included early interim results from the ongoing ELIXA cardiovascular (CV) outcomes study. The company plans to resubmit the NDA in 2015, after completion of the ELIXA CV study.

The decision to withdraw the lixisenatide application follows discussions with the U.S. Food and Drug Administration (FDA) regarding its proposed process for the review of interim data. Sanofi believes that potential public disclosure of early interim data, even with safeguards, could potentially compromise the integrity of the ongoing ELIXA study. Sanofi’s decision is not related to safety issues or deficiencies in the NDA………………………read all at

http://www.pharmalive.com/sanofi-pulls-diabetes-drug-nda

FDA Study: Some Imported Spices Contaminated With Salmonella

September 13, 2013 1:09 am / Leave a comment

Atasteofcreole's Blog

http://www.foodsafetynews.com/2013/09/salmonella-is-prevalent-in-our-spices/

Donna Pierce was a 69-year-old grandmother who loved to laugh and thought that laughter would add years to her life.

Unfortunately, Pierce was one of 87 people who contracted Salmonella Rissen between 2008 and 2009, and she subsequently died from the infection after spending the last month of her life in the hospital.

An investigation into the source of the outbreak pinpointed Salmonella-contaminated white pepper that had been processed by U.F. Union facility in Union City, CA, and originally imported from Vietnam.

This outbreak, along with two other large-scale outbreaks related to Salmonella-contaminated spices between 2007 and 2010, prompted FDA to begin a major investigation into spice safety.

Since imported spices account for more than 80 percent of the U.S. supply, they were an important part of FDA’s investigation and, in a study released in June, the agency found that nearly seven percent of imported spices were…

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Blood pressure drug tends to slow coronary disease

September 12, 2013 10:40 am / Leave a comment

Syn-Org-Chemist

Blood pressure drug tends to slow coronary disease.

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FDA Approves Botox Cosmetic to Improve the Appearance of Crow’s Feet Lines

September 12, 2013 4:09 am / 1 Comment on FDA Approves Botox Cosmetic to Improve the Appearance of Crow’s Feet Lines

WEDNESDAY, September 11, 2013 — The U.S. Food and Drug Administration today approved a new use for Botox Cosmetic (onabotulinumtoxinA) for the temporary improvement in the appearance of moderate to severe lateral canthal lines, known as crow’s feet, in adults. Botox Cosmetic is the only FDA approved drug treatment option for lateral canthal lines.

The FDA approved Botox Cosmetic in 2002 for the temporary improvement of glabellar lines (wrinkles between the eyebrows, known as frown lines), in adults. Botox Cosmetic works by keeping muscles from tightening so wrinkles are less prominent

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http://www.drugs.com/newdrugs/fda-approves-botox-cosmetic-improve-appearance-crow-s-feet-lines-3893.html

BOTOX Cosmetic (onabotulinum toxin A) For Injection, is a sterile, vacuum-dried purifiedbotulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinumtype A grown in a medium containing casein hydrolysate, glucose, and yeast extract, intended for intramuscular use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying.

The primary release procedure for BOTOX Cosmetic uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan’s products BOTOX and BOTOX Cosmetic. One Unit of BOTOX Cosmetic corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice. Due to specific details of this assay such as the vehicle, dilution scheme and laboratory protocols, Units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. The specific activity of BOTOX Cosmetic is approximately 20 Units/nanogram of neurotoxin protein complex.

Each vial of BOTOX Cosmetic contains either 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride; or 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

Since the approval of BOTOX^® Cosmetic by the U.S. Food and Drug Administration in 2002, Allergan has virtually changed the face of medical aesthetics. Men and women between the ages of 18 to 65 now have the ability to choose science-based, non-invasive medical aesthetic solutions, including BOTOX^® Cosmetic and the JUVÉDERM^® family of dermal fillers, to achieve their own results. Over the last seven years, there have been nearly 11.8 million BOTOX^® Cosmetic treatments recorded in the United States.¹ More importantly, its 97 percent satisfaction rating (survey of 117 patients)²^,³ is just one indication of the trust consumers have placed in Allergan.

BOTOX^® Cosmetic is a simple, non-surgical procedure for temporarily reducing the appearance of moderate to severe glabellar lines – the vertical frown lines between the eyebrows that look like an “11” – in adult women and men aged 18 to 65. BOTOX^® Cosmetic reduces the activity of the muscles that cause the “11s” to form by blocking nerve impulses that trigger wrinkle-causing muscle contractions, creating an improved appearance between the brows. Results can last up to four months and may vary with each patient. Ask your doctor if BOTOX^® Cosmetic is right for you.

Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma

September 12, 2013 4:01 am / Leave a comment

CAL 101, IDELALISIB

SEPT 2013

Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma

FOSTER CITY, Calif.–(BUSINESS WIRE)–Sep. 11, 2013– Gilead Sciences, Inc. today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of idelalisib, an investigational, targeted, oral inhibitor of PI3K delta, for the treatment of indolent non-Hodgkin’s lymphoma (iNHL). The data submitted in this NDA support the use of idelalisib for patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy.

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http://www.drugs.com/newdrugs/fda-approves-botox-cosmetic-improve-appearance-crow-s-feet-lines-3893.html

………………………………………….

January 2013 updated

Idelalisib ….US FDA Accepts NDA for Gilead’s Idelalisib for the Treatment of Refractory Indolent Non-Hodgkin’s Lymphoma

JANUARY 14, 2014 8:35 AM / LEAVE A COMMENT

Idelalisib

An antineoplastic agent and p110delta inhibitor

(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

Icos (Originator)

CAL-101
GS-1101
Idelalisib
UNII-YG57I8T5M0

M.Wt: 415.43
Formula: C22H18FN7O

CAS No.: 870281-82-6
CAL-101 Solubility: DMSO ≥80mg/mL Water <1.2mg/mL Ethanol ≥33mg/mL

5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone

idelalisib

Idelalisib (codenamed GS-1101 or CAL-101) is a drug under investigation for the treatment of chronic lymphocytic leukaemia. It is in Phase III clinical trials testing drug combinations with rituximab and/or bendamustine as of 2013. The substance acts as aphosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase.[1][2]

GDC-0032 is a potent, next-generation beta isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with IC 50 of 0.29 nM/0.12 nM/0.97nM,> 10 fold over Selective PI3K [beta].

GS-1101 is a novel, orally available small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) develop by Gilead and is waiting for registration in U.S. for the treatment of patients with indolent non-Hodgkin’s lymphoma that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy and for the treatment of chronic lymphocytic leukemia. The compound is also in phase III clinical evaluation for the treatment of elderly patients with previously untreated small lymphocytic lymphoma (SLL) and acute myeloid leukemia. Clinical trials had been under way for the treatment of inflammation and allergic rhinitis; however, no recent development has been reported. Preclinical studies have shown that GS-1101 has desirable pharmaceutical properties. The compound was originally developed by Calistoga Pharmaceuticals, acquired by Gilead on April 1, 2011.

clinical trials, click link

http://clinicaltrials.gov/search/intervention=CAL-101%20OR%20GS-1101%20OR%20Idelalisib

FOSTER CITY, Calif.–(BUSINESS WIRE)–Jan. 13, 2014– Gilead Sciences, Inc. (Nasdaq: GILD) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the company’s New Drug Application (NDA) for idelalisib, a targeted, oral inhibitor of PI3K delta, for the treatment of refractory indolent non-Hodgkin’s lymphoma (iNHL). FDA has granted a standard review for the iNHL NDA and has set a target review date under the Prescription Drug User Fee Act (PDUFA) of September 11, 2014.

The NDA for iNHL, submitted on September 11, 2013, was supported by a single arm Phase 2 study (Study 101-09) evaluating idelalisib in patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy. Following Gilead’s NDA submission for iNHL, FDA granted idelalisib a Breakthrough Therapy designation for relapsed chronic lymphocytic leukemia (CLL). The FDA grants Breakthrough Therapy designation to drug candidates that may offer major advances in treatment over existing options. Gilead submitted an NDA for idelalisib for the treatment of CLL on December 6, 2013.

About Idelalisib

Idelalisib is an investigational, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta. PI3K delta signaling is critical for the activation, proliferation, survival and trafficking of B lymphocytes and is hyperactive in many B-cell malignancies. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.

Gilead’s clinical development program for idelalisib in iNHL includes Study 101-09 in highly refractory patients and two Phase 3 studies of idelalisib in previously treated patients. The development program in CLL includes three Phase 3 studies of idelalisib in previously treated patients. Combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, also is being evaluated in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid malignancies.

Additional information about clinical studies of idelalisib and Gilead’s other investigational cancer agents can be found at http://www.clinicaltrials.gov. Idelalisib and GS-9973 are investigational products and their safety and efficacy have not been established.

About Indolent Non-Hodgkin’s Lymphoma

Indolent non-Hodgkin’s lymphoma refers to a group of largely incurable slow-growing lymphomas that run a relapsing course after therapy and can lead ultimately to life-threatening complications such as serious infections and marrow failure. Most iNHL patients are diagnosed at an advanced stage of disease, and median survival from time of initial diagnosis for patients with the most common form of iNHL, follicular lymphoma, is 8 to 10 years. The outlook for refractory iNHL patients is significantly poorer.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

The delta form of PI3K is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies, inflammation, autoimmune diseases and allergies. By specifically inhibiting only PI3K delta, a therapeutic effect is exerted without inhibiting PI3K signalling that is critical to the normal function of healthy cells. Extensive studies have shown that inhibition of other PI3K forms can cause significant toxicities, particularly with respect to glucose metabolism, which is essential for normal cell activity.

In 2011, orphan drug designation was assigned to GS-1101 in the U.S. for the treatment of CLL. In 2013, several orphan drug designations were assigned to the compound in the E.U. and U.S.: for the treatment of follicular lymphoma, for the treatment of mucosa-associated lymphoid tissue lymphoma (MALT), for the treatment of nodal marginal zone lymphoma, for the treatment of splenic marginal zone lymphoma, and for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma. Orphan drug designation was also assigned in the U.S. for the treatment of lymphoplasmacytic lymphoma with or without Walenstom’s macroglobulinemia and, in the E.U., for the treatment of Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).

Later in 2013, some of these orphan drug designations were withdrawn in the E.U.; for the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma, for the treatment of extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), for the treatment of of nodal marginal-zone lymphoma and for the treatment of splenic marginal-zone lymphoma. In 2013, the FDA granted a breakthrough therapy designation for the treatment of chronic lymphocytic leukemia.

H. Spreitzer (13 May 2013). “Neue Wirkstoffe – Ibrutinib und Idelalisib”. Österreichische Apothekerzeitung (in German) (10/2013): 34.
Wu, M.; Akinleye, A.; Zhu, X. (2013). “Novel agents for chronic lymphocytic leukemia”.Journal of Hematology & Oncology 6: 36. doi:10.1186/1756-8722-6-36.PMC 3659027. PMID 23680477.

idelalisib

CAL-101 is an Oral Delta Isoform-Selective PI3 Kinase Inhibitor.

CAL-101 (GS 1101) is a potent PI3K p110δ inhibitor with an IC50 of 65 nM. PI3K-delta inhibitor CAL-101 inhibits the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), preventing the activation of the PI3K signaling pathway and thus inhibiting tumor cell proliferation, motility, and survival. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. The targeted inhibition of PI3K-delta is designed to preserve PI3K signaling in normal, non-neoplastic cells. [3][4]

Reference:

[3] Blood 2011, 117, 591-594.

[4] Blood, 2010, 116, 2078-2088.

5. WO 2005113556

6. WO 2005113554

7. WO 2010057048

8. WO 2011156759

9. WO 2012125510

10. WO 2013134288

11. US 2013274198

12. J Med Chem. 2013 Mar 14;56(5):1922-39. doi: 10.1021/jm301522m

http://pubs.acs.org/doi/abs/10.1021/jm301522m

US8207153	6-27-2012	QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
US2012015964	1-20-2012	QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
US2011306622	12-16-2011	METHODS OF TREATING HEMATOLOGICAL DISORDERS WITH QUINAZOLINONE COMPOUNDS IN SELECTED SUBJECTS
US7932260	4-27-2011	Quinazolinones as Inhibitors of Human Phosphatidylinositol 3-Kinase Delta
US2011044942	2-25-2011	METHODS OF TREATMENT FOR SOLID TUMORS
US2010256167	10-8-2010	QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
US2010202963	8-13-2010	THERAPIES FOR HEMATOLOGIC MALIGNANCIES

WO2005113556A1 *	12 May 2005	1 Dec 2005	Icos Corp	Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2005117889A1 *	12 Nov 2004	15 Dec 2005	Didier Bouscary	Methods for treating and/or preventing aberrant proliferation of hematopoietic
WO2005120511A1 *	4 Jun 2005	22 Dec 2005	Joel S Hayflick	Methods for treating mast cell disorders
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US20060106038 *	25 May 2005	18 May 2006	Icos Corporation	Methods for treating and/or preventing aberrant proliferation of hematopoietic cells

……………………….

synthesis

WO2005113556A1

The synthesis of a compound in accordance with formula I is first exemplified using steps A-E below, which provide a synthetic procedure for compound 107, the structure of which is shown below.

(107) is idelalisib

……………….

Synthesis of 2-fluoro-6-nitro-N-phenyl-benzamide (108)

Step A: A solution of 2-fluoro-6- nitrobenzoic acid (100 g, 0.54 mol) and dimethylformamide (5 mL) in dichloromethane (600 mL) was treated dropwise with oxalyl chloride (2 M in dichloromethane, 410 mL, 0.8 mol, 1.5 eq) over 30 min. After stirring 2 h at room temperature, the reaction was concentrated to an orange syrup with some solids present. The syrup was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline (49 mL, 0.54 mol, 1 eq) and sodium bicarbonate (90 g, 1.08 mol, 2 eq) in a mixture of dioxane (250 mL) and water (250 mL) at 6 0C. The temperature reached 27°C at the end of the addition. After 30 min, the reaction mixture was treated with water (1.2 L). The precipitate was collected by vacuum filtration, washed with water (300 mL) , air dried in the funnel, and dried in vacuo at 50°C for 24 h to afford an off-white solid product (139 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, IH), 8.12 (d, J = 7.7 Hz, IH), 7.91-7.77 (m, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.15 > (t, J = 7.4 Hz, IH), ESI-MS m/z 261 (MH+). The reaction described above and compound 108 are shown below.

………………………..

Synthesis of(S) – [1- (2-fluoro-6-nitro-benzoyl) -phenyl-aminocarbonyl] – propyl-carbamic acid tert-butyl ester (109)

Step B: A suspension of compound 108 (0.5 mol) and dimethylformamide (5 mL) in thionyl chloride (256 mL, 2.5 mol, 5 eq) was stirred at 85°C for 5 hours. The reaction mixture was concentrated in vacuo to a brown syrup. The syrup was dissolved in dichloromethane (200 mL) and was slowly added to a solution of N-BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and triethylamine (77 mL, 0.55 mol, 1.1 eq) in dichloromethane (600 mL) at 10 0C. After stirring at room temperature for 3 h, salts were removed by filtration, and the solution was washed with 100 mL of water, saturated sodium bicarbonate, water, 5% citric acid, and saturated sodium chloride. The organic phase was dried with magnesium sulfate and concentrated to a red syrup. The syrup was dissolved in dichloromethane (450 mL) and purified by flash chromatography on a silica gel plug (15 x 22 cm, 4 L dry silica) eluted with hexanes/ethyl acetate (10%, 8 L; 15%, 8 L; 20%, 8 L; 25%, 4 L) to yield the compound 109 as an off-white solid (147 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J = 8.0 Hz, IH), 7.84 (t, J = 8.6 Hz, IH), 7.78- 7.67 (m, IH), 7.65-7.49 (m, 3H), 7.40-7.28 ( m, 2H), 7.19 (d, J = 7.5 Hz, IH), 4.05 (broad s, IH), 1.75- 1.30 (m, 2H), 1.34 (s, 9H), 0.93 (broad s, 3H). ESI- MS m/z 446.3 (MH+) . The reaction described above and compound 109 are shown below.

…………………….

Synthesis of(S) – [1- (5-fluoro-4-oxo-3-phenyl-3 , 4-dihydro-quinazolin-2- yl) -propyl] -carbamic acid tert-butyl ester (110)

Step C: A solution of compound 109 (125 mmol, 1 eq) in acetic acid (500 mL) was treated with zinc dust (48.4 g, 740 mmol, 6 eq) added in 3 portions, and the reaction mixture was allowed to cool to below 35°C between additions. After stirring for 2 h at ambient temperature, solids were filtered off by vacuum filtration and washed with acetic acid (50 mL) . The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL) , washed with water (300 mL) , and the water layer was extracted with EtOAc (300 mL) . The combined organic layers were washed with water (200 mL) , sat’d sodium bicarbonate (2 x 200 mL) , sat’d NaCl (100 mL) , dried with MgSO4, and concentrated to a syrup. The syrup was dissolved in toluene (200 mL) and purified by flash chromatography on a silica gel plug (13 x 15 cm, 2 L dry silica) eluted with hexanes/ethyl acetate (10%, 4 L; 15%, 4 L; 17.5%, 8 L; 25%, 4 L) to yield compound 110 as an off-white foamy solid (33.6 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (td, J = 8.2, 5.7 Hz, IH), 7.64-7.48 (m, 5H), 7.39 (broad d, J = 7.6 Hz, IH), 7.30 (dd, J = 8.3 Hz, IH), 7.23 (d, J = 7.6 Hz, IH), 4.02-3.90 (m, IH), 1.76-1.66 (m, IH), 1.62-1.46 (m, IH), 1.33 (s, 9H), 0.63 (t, J= 7.3 Hz, 3H). ESI-MS m/z 398.3 (MH+). The reaction described above and compound 110 are shown below.

…………..

Syn of (S) -2- (1-amino-propyl) -5-fluoro-3-phenyl-3H-quinazolin-4- one (111)

Step D: A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL) . The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greated than 10) . The aqueous layer was extracted with additional dichloromethane (100 raL) , and the combined organic layers were washed with water (50 mli) and brine (50 mL) . After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%) . 1H NMR (300 MHz,

CDCl3) δ 7.73-7.65 (m, IH), 7.62-7.49 (m, 4H), 7.32- 7.22 (m, 2H), 7.13-7.06 (m, IH), 3.42 (dd, J= 7.5, 5.2 Hz, IH), 1.87-1.70 (m, IH), 1.58-1.43 (m, IH), 0.80 (t, J = 7.4 Hz, 3H) . ESI-MS m/z 298.2 (MH+) . The reaction described above and compound 111 are shown below.

………………

syn of (S) -5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -propyl] – 3H-quinazolin-4-one (107)

Step E: A suspension of compound 111(65.6 mmol, 1 eq) , 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq) , and DIEA (24.3 mL, 140 mmol, 2 eq) in tert- butanol (40 mL) was stirred for 24 h at 800C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the obtained solid crude product was dissolved in MeOH (600 mL) , concentrated onto silica gel (300 mL dry) , and purified by flash chromatography (7.5 x 36 cm, eluted with 10 L of 4% MeOH/CH2Cl2) to yield a solid product. The solid product was then dissolved in EtOH (250 mL) and concentrated in vacuo to compound 107 idelalisib as a light yellow solid (7.2 g, 50%).

1H NMR (300 MHz, 80 0C, DMSO-d5) δ 12.66 (broad s, IH), 8.11 (s, IH), 8.02 (broad s, IH), 7.81-7.73 (m, IH),7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, IH), 2.02-1.73 (m, 2H), 0.79 (t, J= 7.3 Hz, 3H).

ESI-MS m/z 416.2 (MH+).

C, H, N elemental analysis (C22Hi8N7OF-EtOH- 0.4 H2O).

Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6 x 250 mm Chiralpak ODH column, 20 °C, 85:15 hexanes : EtOH, 1 rnL/min, sample loaded at a concentration of 1 mg/mL in EtOH) . The reaction described above and compound 107 idelalisib are shown below.

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Gatfield, John; Grandjean, Celia Mueller; Bur, Daniel; Bolli, Martin H.; Nayler, Oliver (2014): Proton assignment in macitentan as used in NMR interpretation.Figure_9.tif. PLOS ONE. 10.1371/journal.pone.0107809.g009.

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About Idelalisib

About Indolent Non-Hodgkin’s Lymphoma

About Gilead Sciences

CAL-101 is an Oral Delta Isoform-Selective PI3 Kinase Inhibitor.

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