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Isradipine

March 9, 2015 1:01 pm / Leave a comment

Isradipine

CAS Registry Number: 75695-93-1

CAS Name: 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester

Additional Names: isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate; 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-isopropyloxycarbonylpyridine-5-carboxylic acid methyl ester; isrodipine

Manufacturers’ Codes: PN-200-110

Trademarks: Clivoten (Lifepharma); DynaCirc (Novartis); Esradin (Sigma-Tau); Lomir (Novartis); Prescal (Novartis)

Molecular Formula: C19H21N3O5

Molecular Weight: 371.39

Percent Composition: C 61.45%, H 5.70%, N 11.31%, O 21.54%

Properties: mp 168-170°.

Melting point: mp 168-170°

Derivative Type: S(+)-Form

Manufacturers’ Codes: PN-205-033

Properties: Crystals from ether + hexane, mp 142°. [a]D20 +6.7° (c = 1.5 in ethanol).

Melting point: mp 142°

Optical Rotation: [a]D20 +6.7° (c = 1.5 in ethanol)

Derivative Type: R(-)-Form

Manufacturers’ Codes: PN-205-034

Properties: Crystals from ether + hexane, mp 140°. [a]D20 -6.7° (c = 1.67 in ethanol).

Melting point: mp 140°

Optical Rotation: [a]D20 -6.7° (c = 1.67 in ethanol)

Keywords: Antianginal; Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

Isradipine (tradenames DynaCirc, Prescal) is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack. More recent research in animal models suggests that isradipine may have potential uses for treating Parkinson’s disease Chan et al. 2007.

Isradipine is given as either a 2.5mg or 5mg capsule. ^[1]

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

Isradipine is a drug used to lower blood pressure but recently it was found by a team from Nortwestern University, that this molecule can also slow the progression of Parkinson’s disease, and restore the dopamine neurons (In animals tests). Isradipine is a calcium channel blocker of the 1,4-dihydropyridine class with a benzoxadiazole moiety in position 4.
The synthesis of the 1,4-dihydropyridine ring is quite classic, the first step consists in a Knoevenagel reaction of methyl acetoacetate on the benzoxadiazole 4-carboxaldehyde using piperidine and acetic acid as catalyst and diisopropylether as solvent in a 61% yield (this is the first time I see a Knoevenagel reaction in an ether!!!???? DCM, Toluene OK, but maybe I am wrong). The second step of this synthesis is the condensation of the acrylate obtained with the isopropyl aminocrotonate in ethanol to give the desire 1,4-dihydropyridine Isradipine in 67% yield after recrystallisation.

(WO/2005/005437) An improved Process for the Manufacture of Isradipine (Shasun Chemical & Drugs Limited)

http://www.google.com.ar/patents/WO2005005437A1?cl=en

Isradipine is 4-(4-Benzofi–razanyl)-l,4-d–hydro-2,6-dimethyl-3,5- pyiicϊ-nedicarboxylic acid med yl 1-methylethyl ester having die chemical structure of formula (I).

( I ) Isradipine is therapeutically indicated for treating cardiovascular diseases.

The cardiovascular diseases include angina, pectoris, hypertension and congestive heart failure. It is also used to treat high blood pressure. Isradipine was disclosed in the German specification DE 2949491 and US patent Nos. 4466972 and 4567271. DE 2949491 describes the general procedure to prepare 1,4-dihydropyridine derivatives. US 4466972, GBQ2103203A, LU 0088342A9, EP 0000150A1, EP 0000150B1, AU 0538515B2 and od er related patents describe the general mediod for d e preparation of Benzoxadiazoles and dieir derivatives of general formula (EL). These references in its entirety is hereby incorporated by reference into this application.

( II ) Where in Ri is -CH₃ and -R₂ is — CH(CH₃)2 it refers to Isradipine of formula ( I ). When Ri and R₂ are not identical the general procedures described in diese patent specifications produces a mixture of isomers of formula ( II ). These procedures for the preparation of Isradipine is characteristic of formation of the ^‘ isomeric impurities, 1) 4-(4-Benzoi-urazanyl)-l,4-α^ydro-2,6-climedιyl-3,5- pyridinedicarboxylic acid di-methyl ester of formula ( III ) and 2) 4-(4- Benzofurazanyl)-l,4-α^ydro-2,6-d–methyl-3,5-pyrid–nedicarboxylic acid di-1- med ylethyl ester of formula ( IV) along with Isradipine. The US patent 4466972 describes the preparation of compounds of general formula (II) by refluxing 2, 1, 3-benzoxadiazole-4-carboxaldehyde, keto ester and concentrated ammonia or a β-amino ester in presence of ethanol, followed by evaporation and purification by chromatography.

( HI )H

( I V ) Tl ese symmetrical ester isomers ( III ) and ( IN ) are difficult to separate from the Isradipine and the separation is effected only by a chromatographic purifications. The drawback witii the procedures described in these patents is that it is very difficult to produce die product in commercial quantities as it involves d e purification of the product by chromatographic separations. A single step process for the preparation of Isradipine was described in CH 661270. This procedure involves first reacting 2,l,3-benzoxadiazole-4- carboxaldehyde with isopropyl acetoacetate in the presence of catalytic quantities of acetic acid and piperidine in refluxing toluene, and further reacting it widi mediyl-β-aminocrotonate. The Isradipine formed in d e reaction mixture was dien- separated by toluene distillation followed by cyclohexane treatment. The crude product obtained was dien crystallised from etiianol to get Isradipine. When we have repeated this process in our laboratory we got the Isradipine with substantially higher amount of symmetrical ester isomers ( III ) and ( IV ) are present in d e product. Removal of these symmetrical ester isomers is very difficult even after several repurifications from ethanol.

Stap 2

Example 4

Preparation of Isradipine using crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester Dissolved the crude 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester ^‘ obtained in example – 1 (25 g, 0.10 mol) in absolute edianol (375 ml) and added in to the solution isopropyl-β-aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28 °C for 7 hr. Removed sample from d e reaction mixture and analysed die sample by qualitative HPLC. Distilled ethanol from the reaction mixture- under vacuum at 50°C. Dissolved d e residue in ethyl acetate (235 ml) and washed twice widi water (90 ml). Dried the organic layer over sodium sulphate and distillation under vacuum at 50 °C. Dissolved the concentrate in ethanol (65 ml) at 70°C and slowly cooled to 5°C to get die product crystallised. Filtered the product and washed with pre cooled ethanol (25 ml). Recrystauised the product from ethanol (60 ml) and dried at 70°C under vacuum to obtain Isradipine (yield = 20 g, purity = 98.2% and Impurity III = 0.64%, Impurity IV = 0.51% by HPLQ

Example 5 Preparation of Isradipine using purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester Dissolved 2-acetyl-3-benzo–urazan-4-yl-acrylic acid methyl ester (25 g, 0.10 mol) in absolute ethanol (375 ml) and added in to the solution isopropyl-β- aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28 °C for 5 hr. Removed sample from the reaction mixture and analysed the sample by qualitative HPLC. Distilled ethanol from the reaction mixture under vacuum at 50°C. Dissolved the residue in ethyl acetate (235 ml) and washed twice wid w?ater (90 ml). Dried die organic layer over sodium sulphate and distillation under vacuum at 50 °C. Dissolved the concentrate in ethanol (65 ml) at 70°C and slowly cooled to 5°C to get the product crystallised. Filtered the product. and washed with pre cooled ethanol (25 ml). Recrystallised the product from edianol (60 ml) and dried at 70°C under vacuum to obtain 25 g Isradipine (yield = 67%, purity 99.5%, Impurity III = 0.20%, and Impurity IV = 0.12% by HPLC)

Example 6 Preparation of Isradipine using purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester Dissolved the purified 2-acetyl-3-benzofurazan-4-yl-acrylic acid mediyl ester, obtained in example — 3 (25 g, 0.10 mol) in absolute ethanol (375 ml) and added in to the solution isopropyl-β-aminocrotonate (13.15 ml, 0.09 mol). Stirred the reaction mixture under nitrogen atmosphere at 25-28 °C for 5 hr. Removed sample from the reaction mixture and analysed the sample by qualitative HPLC. Distilled ethanol from die reaction mixture under vacuum at 50°C. Dissolved die residue in ethyl acetate (235 ml) and washed twice with water (90 ml). Dried the organic layer over sodium sulphate and distillation under vacuum at 50 °C. Dissolved the concentrate in ethanol (65 ml) at 70°C and slowly cooled to 5°C to get the product crystallised. Filtered the product and washed with pre cooled ethanol (25 ml) and dried at 70°C under vacuum to obtain 30g Isradipine (purity = 99.4%, Impurity III = 0.22%, and Impurity IV = 0.11% by HPLC). Throughout this application, various publications are referenced.

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

Side effects

Common side effects include: ^[2]

Dizziness
Warmth, redness, or tingly feeling under your skin
Headache
Weakness, tired feeling
Nausea, vomiting, diarrhea, upset stomach
Skin rash or itching

Serious side effects include: ^[2]

Lightheadedness or fainting
Shortness of breath, especially from minimal physical activity
Swelling in the hands and feet
Rapid and/or heavy heartbeat
Chest pain

If you experience one or more of these serious side effects, contact your health care provider immediately.

Significant drug interactions

There are other interactions beyond those listed below. Make sure to speak with a Pharmacist or Doctor if you have any concerns.

Three major interactions are listed below.

1. It is advised that those using Isradipine not take Anzemet (Dolasetron), as both agents can cause a dose-dependent PR intervaland QRS complex prolongation. ^[3]

2. Onmel/Sporanox (Itraconazole) exhibits a negative inotropic effect on the heart and thus could spur an additive effect when used concomitantly with Isradipine. Onmel/Sporanox also inhibits an important cytochrome liver enzyme (CYP 450 3A4) which is needed to metabolize Isradipine and other Calcium Channel Blockers. This will increase plasma levels of Isradipine and could cause an unintentional overdose of the medication. Caution is advised when administering both agents together. ^[4]

3. Zanaflex (Tizanidine) demonstrates anti-hypertensive effects and should be avoided in patients taking Isradipine due to the possibility of synergism between both medications. ^[5]

4. The anti-biotic Rifadin (Rifampin) lowered plasma concentrations of Isradipine to below detectable limits. ^[1]

5. Tagamet (Cimetidine) increased Isradipine mean peak plasma levels. A downward dose adjustment may be necessary with this particular instance of polypharmacy. ^[1]

6. Severe hypotension was reported with Duragesic (Fentanyl) anesthesia when it was combined with other Calcium Channel Blockers. Even though Isradipine, another Calcium Channel Blocker, has not been used in conjunction with Fentanyl anesthesia in any studies, caution is advised. ^[1]

Note: There was no significant interaction between Isradipine and Warfarin (Coumadin), Isradipine and Microzide Hydrochlorothiazide, Isradipine and Lanoxin (Digoxin), and Isradipine and Nitrostat (Nitroglycerin).

Overdose

Symptoms of an Isradipine overdose include: ^[1]

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

…………………

US 4466972

http://www.google.com.na/patents/US4466972

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

………………………………….

http://www.google.com.ar/patents/CN101768153B?cl=en

isradipine is a class Benzofurazan dihydropyridine class of compounds, the synthesis is more complex, especially in the purified material is particularly difficult.

US Patent US4466972 and PCT application W02005 / 00437 respectively disclose two synthetic isradipine

Methods. However, the product prepared by conventional methods contain a certain amount of a formula homologues impurity, the impurity is structured as follows:

wherein, R1, R2 simultaneously or separately as methyl, ethyl and isopropyl. The homologue of the impurities with isradipine extremely difficult to separate, resulting in ineffective purification isradipine.

In addition, conventional processes for preparing key intermediates involved in 4-methyl benzofurazan. However, the preparation method of the key intermediates is still unsatisfactory. For example, the Chinese Patent 200 510 125 267 (Publication No. CN1847233A) in

Discloses an intermediate 4-methyl benzofurazan preparation methods, the preparation process is as follows:

It is clear that the above method steps long, dangerous operation, poor control, and cause a lot of pollution.

Accordingly, there is an urgent need to develop new, efficient and simple isradipine important intermediates for preparing 4-methyl benzofurazan method.

[0019]

[0020] (b) in an inert solvent, such that 4-methyl benzofurazan oxide reduction to form 4-methyl benzofurazan, i.e. a compound of formula 3;

[0021]

[0028]

[0029] to form isradipine.

Example 7 β – amino crotonic acid isopropyl ester (Compound 8)

The isopropyl acetoacetate (72.0g, 0 5mol.), Ammonium acetate (57. 8g, 0 75mol.) And tert-butanol / ethanol (1: 1,600ml) were mixed in IOOOml flask, 300 mesh sieve (50g), heated to reflux, TLC plate monitor. After the reaction is substantially completed, cooled to room temperature, filtered and the filtrate was concentrated until no liquid was distilled off, the residual liquid was distilled under reduced pressure, to collect 110-120 ° C fraction (degree of vacuum of 0. IMPa) to give compound 8 (66. Og). Y = 92. 4%.

1H-WR (CDCl3):…… 5 02-4 95 (1H, m), 4 48 (1H, s), 1 88 (3H, d), 1 23-1 21 (6H , d)

Example 8 isradipine (Isradipine)

In the protection teams, three-necked flask Compound 6 (3.0g, 20mmol), i3- amino crotonic acid isopropyl ester (Compound 8) (2. 7g, 16. 6mmol), methyl acetoacetate (3. 50g, 30mol), Ac2O (2. 05g, 20mmol), conc. H2SO4 (0. 4g, 4mmol) and tert-butanol / ethanol (1: 1,65ml) mixing the liquid phase monitoring, when the remainder is less than 3 Compound 6 When the 7% to terminate the reaction. The reaction was concentrated, the residue was dissolved CH2Cl2 (55ml), washed with water (45ml X Magic, dried, concentrated, drain pump, to give 6. 7g end yellow foam-like solid. Ethanol QOml) dissolved by heating, stirring crystallization (overnight) to give a pale yellow powder isradipine (4. 3g) (HPLC purity> 99.8%, impurity content homologues thereof are less than 0.1), yield 66.8%.

1H-WR (CDCl3):…… 7 62-7 60 (lH, m), 7 31-7 26 (2H, m), 5 46 (lH, s), 4 92-4 . 86 (1H, m), 3. 57 (3H, s), 2. 32-2. 30 (6H, m), 1. 21-1. 19 (3H, d), 0. 95-0. 94 (3H, d)

Comparative Example 1

isradipine (Isradipine) prepared by the United States Patent US4466972:

In the protection teams, three-necked flask Compound 6 (3.0g, 20mmol), i3- amino crotonic acid isopropyl ester (Compound 8) (2. 7g, 16. 6mmol), methyl acetoacetate (3. 50g, 30mol), Ac2O (2. 05g, 20mmol), conc. H2SO4 (0. 4g, 4mmol) and ethanol (65ml) were mixed and stirred, the liquid phase monitoring, when the compound 6 is less than 3.7% remaining, the reaction is stopped. The reaction was concentrated, the residue was dissolved CH2Cl2 (55ml), washed with water (45ml X Magic, dried, concentrated, drain pump, to give 6. 3g end yellow foam-like solid. Ethanol OOml) was dissolved by heating, stirring crystallization (overnight) to give a pale yellow powder isradipine (4. Ig) (HPLC purity: 99.0%, impurity content was homologues greater than 0.3%), a yield of 63.7%.

Compared with Comparative Example 1 (homolog impurity content was greater than 0.3%), was the content of impurities isradipine homologs prepared in Example 1-8 is less than 0.1% by the embodiment of the present invention.

The 10 cases of isradipine

Example 8 was repeated, except that, with t-butanol / ethanol (1: 2,70ml) or t-butanol / ethanol O: 1, 70ml) replaces t-butanol / ethanol (1: 1,65ml) 0

The results showed that isradipine yield of about 62%, the test substance impurity content of less than 0.1% homologous.

External links

MedlinePlus DrugInfo medmaster-a693048
DDB 30003
Drug offers hope for Parkinson’s – BBC News, 11 June 2007.
[1] – Commentary of Chan et al. publication
[2] – ArsTechnica – Why neurons die in Parkinson’s patients

…………

CN1847233A21 Nov 200518 Oct 2006圣玛精细化工有限责任公司Method for preparing 4-formoxylbenzofuran

US446697219 Mar 198221 Aug 1984Sandoz Ltd.Hypotensive, antiischemic, antispasmodic agents

WO2005005437A115 Jul 200420 Jan 2005Radhakrishnan Selvar MullaiyurAn improved process for the manufacture of isradipine.

References: Dihydropyridine calcium channel blocker. Prepn: P. Neumann, DE 2949491; idem, US 4466972 (1980, 1984 both to Sandoz). Prepn of enantiomers: A. Vogel, DE 3320616 (1983 to Sandoz), C.A. 101, 7162s (1984). Comparative study of in vitro effects on human and canine cerebral arteries: E. Müller-Schweinitzer, P. Neumann, J. Cereb. Blood Flow Metab.3, 354 (1983). Effect on a-adrenoceptor mediated vasoconstriction in rats: K. Jie et al., Arch. Int. Pharmacodyn. 278, 72 (1985). Pharmacokinetics: F. L. S. Tee, J. M. Jaffe, Eur. J. Clin. Pharmacol. 32, 361 (1987). Clinical evaluation in angina and coronary artery disease: C. E. Handler, E. Sowton, ibid. 27, 415 (1984); in hypertension: E. B. Nelson et al., Clin. Pharmacol. Ther. 40, 694 (1986). Comparison of hemodynamic effects of enantiomers: R. P. Hof et al., J. Cardiovasc. Pharmacol. 8, 221 (1986). Series of articles on pharmacology and clinical use: Am. J. Med. 86, 1-146 (1989).

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

Isradipine
Systematic (IUPAC) name

3-methyl 5-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Trade names	DynaCirc
AHFS/Drugs.com	monograph
MedlinePlus	a693048
Pregnancy category	C
Legal status	UK: POM US: ℞-only
Routes	Oral
Pharmacokinetic data
Bioavailability	15-24%
Protein binding	95%
Metabolism	100% Hepatic
Half-life	8 hours
Excretion	70% Renal, 30% Fecal
Identifiers
CAS number	75695-93-1
ATC code	C08CA03
PubChem	CID 3784
DrugBank	DB00270
ChemSpider	3652
UNII	YO1UK1S598
KEGG	D00349
ChEMBL	CHEMBL1648
Chemical data
Formula	C₁₉H₂₁N₃O₅
Molecular mass	371.387 g/mol

…….

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en.wikipedia.org/wiki/Alappuzha

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CILNIDIPINE 西尼地平

March 9, 2015 5:59 am / Leave a comment

Cilnidipine

西尼地平

CAS 132203-70-4

(E) – (±) 1 ,4 a dihydro-2 ,6 – dimethyl-4 – (3 – nitrophenyl) -3,5 – pyridinedicarboxylic acid, 2 – methoxy- ethyl butylester 3 – phenyl – 2 – propenyl ester FRC-8653 Cinalong
More FRC 8653 1,4-Dihydro-2 ,6-dimethyl-4-(3-nitrophenyl) 3 ,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
Molecular formula:C ₂₇ H ₂₈ N ₂ O ₇
Molecular Weight:492.52

CAS Name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester

Additional Names: (±)-(E)-cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate

Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Manufacturers’ Codes: FRC-8653

Trademarks: Atelec (Morishita); Cinalong (Fujirebio); Siscard (Boehringer, Ing.)

Percent Composition: C 65.84%, H 5.73%, N 5.69%, O 22.74%

Properties: Crystals from methanol, mp 115.5-116.6°. LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally;³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada).

Melting point: mp 115.5-116.6°

Toxicity data: LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally; ³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada)

Ajinomoto (INNOVATOR)

NMR………http://file.selleckchem.com/downloads/nmr/S129301-Cilnidipine-NMR-Selleck.pdf

HPLC……..http://file.selleckchem.com/downloads/hplc/S129301-Cilnidipine-HPLC-Selleck.pdf

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

Cilnidipine (INN) is a calcium channel blocker. It is sold as Atelec in Japan, asCilaheart, Cilacar in India, and under various other trade names in East Asian countries.

Cilnidipine is a dual blocker of L-type voltage-gated calcium channels in vascular smooth muscle and N-type calcium channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood.

Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. in india j b chemicals & pharmaceuticals ltd and ncube pharmaceutical develope a market of cilnidipine.

Hypertension is one of the most common cardiovascular disease states, which is defined as a blood pressure greater than or equal to 140/90 mm Hg. Recently, patients with adult disease such as hypertension have rapidly increased. Particularly, since damages due to hypertension may cause acute heart disease or myocardial infarction, etc., there is continued demand for the development of more effective antihypertensive agent.

Meanwhile, antihypertensive agents developed so far can be classified into Angiotensin II Receptor Blocker (ARB), Angiotensin-Converting Enzyme Inhibitor (ACEI) or Calcium Chanel Blocker (CCB) according to the mechanism of actions. Particularly, ARB or CCB drugs manifest more excellent blood pressure lowering effect, and thus they are more frequently used.

However, these drugs have a limit in blood pressure lowering effects, and if each of these drugs is administered in an amount greater than or equal to a specific amount, various side-effects may be caused. Therefore, there have been many attempts in recent years to obtain more excellent blood pressure lowering effect by combination therapy or combined preparation which combines or mixes two or more drugs.

Particularly, since side-effect due to each drug is directly related to the amount or dose of a single drug, there have been active attempts to combine or mix two or more drugs thereby obtaining more excellent blood pressure lowering effect through synergism of the two or more drugs while reducing the amount or dose of each single drug.

For example, US 20040198789 discloses a pharmaceutical composition for lowering blood pressure combining lercanidipine, one of CCB, and valsartan, irbesartan or olmesartan, one of ARB, etc. In addition, a combined preparation composition which combines or mixes various blood pressure lowering drugs or combination therapy thereof has been disclosed.

cilnidipine Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. Cilnidipine has similar blood pressure lowering efficacy as compared to amlodipine. One of the distinct property of cilnidipine from amlodipine is that it does not cause reflex tachycardia.

In recent years, cardiovascular disease has become common, the incidence increased year by year, about a patient of hypertension in China. 3-1. 500 million, complications caused by hypertension gradually increased, and more and more young patients with hypertension technology. In recent years, antihypertensive drugs also have great development, the main first-line diuretic drug decompression 3 – blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, ar blockers and vascular angiotensin II (Ang II) receptor antagonist.

In the anti-hypertensive drugs, calcium antagonists are following a – blockers after another rapidly developing cardiovascular drugs, has been widely used in clinical hypertension, angina and other diseases, in cardiovascular drugs in the world, ranked first.

Cilnidipine for the long duration of the calcium channel blockers, direct relaxation of vascular smooth muscle, dilation of peripheral arteries, the peripheral resistance decreased, with lower blood pressure, heart rate without causing a reflex effect.

Cilnidipine is a dihydropyridine CCB as well as an antihypertensive. Cilnidipinehas L- and N-calcium channel blocking actions. Though many of the dihydropyridine CCBs may cause an increase in heart rate while being effective for lowering blood pressure, it has been confirmed that cilnidipine does not increase the heart rate and has a stable hypotensive effect. (Takahiro Shiokoshi, “Medical Consultation & New Remedies” vol. 41, No. 6, p. 475-481)

http://www.mcyy.com.cn/e-product2.asp
Löhn M, Muzzulini U, Essin K, et al. (May 2002). “Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C”. J. Hypertens.20 (5): 885–93. PMID 12011649.

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

Cilnidipine (CAS NO.: 132203-70-4), with its systematic name of (+-)-(E)-Cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate, could be produced through many synthetic methods.

Following is one of the synthesis routes: By cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 °C.

………………..

http://www.google.com/patents/EP0161877A2?cl=en

AN EXAMPLE

Example 1

3.51 g (10 mM) of 2-(3-nitrobenzylidene) acetoacetic acid cinnamyl ester were mixed with 1.38 g (12 mM) of 3-aminocrotonic acid methyl ester, and heated at 120°C for 3 hours. The reaction mixture was separated by silica gel column chromatography, and 3.00 g of cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (trans) were obtained (yield 67%). This derivative was recrystallized once from methanol.
Elemental Analysis; ^C₂₅^H₂₄^N₂⁰₆
- Calcd. (%) C: 66.95, H: 5.39, N: 6.25
- Found (%) C: 67.03, H: 5.31, N: 6.20

(trans)

- m.p.; 143.5-144.5°C
- IR (cm^-1); v_NH 3370, ν_CO 1700, ν_NO2 1530, 1350
- NMR δ_CDCl3; 2.34(s,6H), 3.60(s,3H), 4.69(d,2H), 5.13(s,lH), 6.14(tt,lH), 6.55(d,lH), 7.1-8.1(m,9H)

(cis)

- m.p.; 136-137°C
- IR (cm^-1); v_NH 3360, ν_CO 1700, 1650, ν_NO2 1530, 1350
- NMR δ_CDCl3; 2.30(s,6H), 3,60(s,3H), 4.80(d,lH), 5.10(s,1H), 5.77(tt,lH), 6.56(d,1H), 6.64(bs,1H), 7.1-8.1(m,9H)

EXAMPLE 13

Example 13 Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Elemental Analysis; C₂₇H₂₈N₂O₇
- Calcd. (%) C: 65.84, H: 5.73, N: 5.69
- Found (%) C: 65.88, H: 5.70, N: 5.66
- m.p.; 115.5-116.5°C
- IR (cm^-1); v_NH 3380, ν_CO 1710, 1680, ν_NO2 1530, 1350
- NMR δ_CDCl3; 2.34(s,6H), 3.25(s,3H), 3.50(t,2H), 4.15(t,2H), 4.68(d,2H), 5.15(s,lH), 5.9-6.9(m,3H), 7.1-8.2(m,9H)

Cilnidipine pk_prod_list.xml_prod_list_card_pr?p_tsearch=A&p_id=131335

cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 C.

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

NMR

CARBOHYDRATE POLYMERS 90 PG 1719-1724 , YR2012

Numerous peaks were found in the spectrum of cilnidipine: 2.3555 (3H, s, CH3), 2.3886(3H, s, CH3), 3.2843(CD3OD), 3.3292(3H, s, OCH3), 3.5255–3.5623(2H, m, CH3OCH2CH2 ), 4.1224–4.1597(2H, m, CH3OCH2CH2 ), 4.6695–4.7293(2H, m, CH2 CH CH ), 4.8844(D2O), 5.1576(1H, s, CH), 6.2609(1H, dt, CH2 CH CH ), 6.5518(1H, d, CH2 CH CH ), 7.2488–7.3657(6H, m, ArH), 7.7002(1H, dd, ArH), 7.9805(1H, dd, ArH), 8.1548(1H, s, ArH)

References:

Dihydropyridine calcium channel blocker. Prepn: T. Kutsuma et al., EP 161877; eidem, US 4672068(1985, 1987 both to Fujirebio).

Pharmacology: K. Ikeda et al., Oyo Yakuri 44, 433 (1992).

Mechanism of action study: M. Hosonoet al., J. Pharmacobio-Dyn. 15, 547 (1992).

LC-MS determn in plasma: K. Hatada et al., J. Chromatogr. 583, 116 (1992). Clinical study: M. Ishii, Jpn. Pharmacol. Ther. 21, 59 (1993).

Acute toxicity study: S. Wada et al., Yakuri to Chiryo 20, Suppl. 7, S1683 (1992), C.A. 118, 32711 (1992).

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

U.S Patent No. 4,572,909 discloses amlodipine;

U.S Patent No. 4,446,325 discloses aranidipine;

U.S Patent No. 4,772,596 discloses azelnidipine;

U.S Patent No. 4,220,649 discloses barnidipine;

U.S Patent No. 4,448,964 discloses benidipine;

U.S Patent No. 5,856,346 discloses clevidipine;

U.S Patent No. 4,466,972 discloses isradipine;

U.S Patent No. 4,885,284 discloses efonidipine; and

U.S Patent No. 4,264,61 1 discloses felodipine.
read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

Planar chemical structures of these calcium blockers of formula (I) are shown below.
Amlodipine is 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in USP 4,572,909, Japanese patent publication No. Sho 58-167569 and the like.
Aranidipine is 3-(2-oxopropoxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,446,325 and the like.
Azelnidipine is 2-amino-3-(1-diphenylmethyl-3-azetidinyloxycarbonyl)-5-isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,772,596, Japanese patent publication No. Sho 63-253082 and the like.
Barnidipine is 3-(1-benzyl-3-pyrrolidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,220,649, Japanese patent publication No. Sho 55-301 and the like.
Benidipine is 3-(1-benzyl-3-piperidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine and is described in the specifications of U.S. Patent No. 4,501,748, Japanese patent publication No. Sho 59-70667 and the like.
Cilnidipine is 2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-3-(3-phenyl-2-propenyloxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,672,068, Japanese patent publication No. Sho 60-233058 and the like.
Efonidipine is 3-[2-(N-benzyl-N-phenylamino)ethoxycarbonyl]-2,6-dimethyl-5-(5,5-dimethyl-1,3,2-dioxa-2-phosphonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,885,284, Japanese patent publication No. Sho 60-69089 and the like.
Elgodipine is 2,6-dimethyl-5-isopropoxycarbonyl-4-(2,3-methylenedioxyphenyl)-3-[2-[N-methyl-N-(4-fluorophenylmethyl)amino]ethoxycarbonyl]-1,4-dihydropyridine disclosed in USP 4,952,592, Japanese patent publication No. Hei 1-294675 and the like.
Felodipine is 3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridine disclosed in USP 4,264,611, Japanese patent publication No. Sho 55-9083 and the like.
Falnidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-3-(2-tetrahydrofurylmethoxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,656,181, Japanese patent publication (kohyo) No. Sho 60-500255 and the like.
Lemildipine is 2-carbamoyloxymethyl-4-(2,3-dichlorophenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in Japanese patent publication No. Sho 59-152373 and the like.
Manidipine is 2,6-dimethyl-3-[2-(4-diphenylmethyl-1-piperazinyl)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,892,875, Japanese patent publication No. Sho 58-201765 and the like.
Nicardipine is 2,6-dimethyl-3-[2-(N-benzyl-N-methylamino)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,985,758, Japanese patent publication No. Sho 49-108082 and the like.
Nifedipine is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,485,847 and the like.
Nilvadipine is 2-cyano-5-isopropoxycarbonyl-3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,338,322, Japanese patent publication No. Sho 52-5777 and the like.
Nisoldipine is 2,6-dimethyl-3-isobutoxycarbonyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,154,839, Japanese patent publication No. Sho 52-59161 and the like.
Nitrendipine is 3-ethoxycarbonyl-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,799,934, Japanese patent publication (after examination) No. Sho 55-27054 and the like.
Pranidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-(3-phenyl-2-propen-1 -yloxycarbonyl)-1,4-dihydropyridine disclosed in USP 5,034,395, Japanese patent publication No. Sho 60-120861 and the like.

read more on dipine series………http://organicsynthesisinternational.blogspot.in/p/dipine-series.html

MAHABALIPURAM, INDIA

Mahabalipuram – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Mahabalipuram

Mahabalipuram, also known as Mamallapuram is a town in Kancheepuram district in the Indian state of Tamil Nadu. It is around 60 km south from the city of …‎Shore Temple – ‎Seven Pagodas – ‎Pancha Rathas – ‎

Map of mahabalipuram .

Krishna’s Butter Ball in Mahabalipuram, India. The surface below the rock is …

http://www.weather-forecast.com/locations/Mamallapuram

Come to Mahabalipuram (also known as Mammallapuram), an enchanting beach that is located on the east coast of India.
Moonraikers Restaurant, Mamallapuram

Hotel Mamalla Bhavan – Mahabalipuram Chennai – Food, drink and entertainment

A carving at the Varaha Temple, Mahabalipuram

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Saroglitazar magnesium….New patent WO 2015029066 Cadila Healthcare Ltd

March 9, 2015 3:57 am / 2 Comments on Saroglitazar magnesium….New patent WO 2015029066 Cadila Healthcare Ltd

SAROGLITAZAR

WO 2015029066

Dwivedi, Shri Prakash Dhar; Singh, Ramesh Chandra; Patel, Vikas; Desai, Amar Rajendra

Cadila Healthcare Ltd

Polymorphic form of pyrrole derivative and intermediate thereof

The present invention relates to Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivs. thereof. The present invention also provides an amorphous form of saroglitazar free acid and processes of prepn. thereof. The present invention also provides pharmaceutical compn. comprising an amorphous form saroglitazar magnesium.

Amorphous forms of saroglitazar free acid and its salt form are claimed. Also claims the process for the synthesis the same compound. Useful for treating obesity, hyperlipidemia and hypercholesteremia. Picks up from WO2015011730, claiming the stable composition comprising saroglitazar magnesium or its derivatives. Zydus-Cadila has developed and launched saroglitazar for treating diabetic dyslipidemia and hypertriglyceridemia.

In September 2013, saroglitazar was launched for treating dyslipidemia and hypertriglyceridemia.

As of March 2015, Zydus-Cadila is developing saroglitazar for treating nonalcoholic steatohepatitis and type II diabetes (both in phase III clainical trials).

Pyrrole derivative of present invention is chemically 2-ethoxy-3-(4-(2-(2-methyl- 5-(4-(methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)ph’enyl)propanoate, which may be optically active or racemic and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The INN name for pyrrole derivative is Saroglitazar® which is magnesium salt of pyrrole compound o f saroglitazar,

the process comprising: 5WO 2015/029066 PCT/IN2014/000551 (a) dissolving saroglitazar magnesium of Formula (I) in one or more organic solvents to obtain a solution, (b) adding the solution in one or more o f anti-solvent at temperature from about -80°C to about 150°C to obtain saroglitazar magnesium o f Formula (I); and (c) obtaining the amorphous saroglitazar magnesium by removal of anti-solvent.

Example-1: Preparation of saroglitazar magnesium (Ί) In a 5 Liter three necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 2-ethoxy-3-(4-hydroxy-phenyl)- propionic acid ethyl ester (A) (100.0 g) and cyclohexane (1300.0 ml) were charged and reaction mixture was heated to 45° to 55°C. Potassium carbonate (58.0 g) was added and stirred for 30 min. methanesulfonic acid 2-[2-methyl-5-(4-methyIsulfanyl-phenyl)-pyrroll-yl]-ethyl ester (A l) (150.24 g) and THF (200.0 ml) were added and heated to 75°C to 85°C for 36 hour. The reaction mixture was cooled to 25° to 35°C and water (1000.0 ml) was added and stirred for 15 min. The separated aqueous layer was treated with cyclohexane (200.0 ml) and stirred for 15 min. The organic layers were combined and washed with caustic solution (600.0 ml). The separated organic layer was washed with water (600.0 ml) and characoalized with (5.0 g) charcoal and stirred for 30 min and filtered. The filtrate was distilled to remove cyclohexane and the residue was collected (residue-A). The residue-A as obtained was treated with ethanol (400.0 ml) and stirred for 15 min. Sodium hydroxide 20.14 g solution in water (200.0 ml) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with water (1800.0 ml) and stirred for 15 min. The separated aqueous layer was washed with n-butyl acetate. The separated aqueous layer was added magnesium acetate tetrahydrate solution (90.0 g) in water (100.0 ml) and stirred for I hour. The aqueous layer was extracted with methylene dichloride (200 ml). The separated organic layer was washed with sodium chloride solution and charcoalized. The charcoalized solution was filtered and filtrate was distilled to remove methylene dichloride completely. The residue was diluted with methylene dichloride (1000 ml) and stirred for 30 min. The organic solution was added into n-heptane (1500 mL) and stirred for 3 hours. The product was filtered and washed with n-heptane and dried in vacuum tray dryer at 25°C to 30°C for 3 hours. The product was sieved through 0.5 mm sieve and milled through jet-milled. The product was further dried in vacuum tray drier at 40°C to 50°C for 6 hours followed by drying at 55°C to 65°C for 40 hours to obtain substantially amorphous saroglitazar magnesium (I). The compound is characterized by x-ray power diffraction (FIG.I).

……………………………………………………………………….

WO/2015/011730

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015011730

The present invention relates to the stable pharmaceutical composition of a suitable hypolipidemic agent. Preferably, the present invention discloses novel formulations of the compound of formula (I), or pharmaceutically acceptable salts of compounds of formula (I). More particularly the present invention relates to the stable pharmaceutical composition of compounds of formula (I) comprising compounds of formula (I) or its pharmaceutically acceptable salts, wherein the pH of the formulation is maintained above 7. formula (I)

The compounds of formula (I) are new synthetic compounds having hypolipidemic activity. The compounds of formula (I) are used primarily for triglyceride lowering, with concomitant beneficial effect on glucose lowering and cholesterol lowering.

The structural formula of compounds of formula (I) is shown below.

wherein ‘R’ is selected from hydroxy, hydroxyalkyl, acyl, alkoxy, alkylthio, thioalkyl, aryloxy, arylthio and M⁺ represents suitable metal cations such as Na⁺, K⁺, Ca⁺², Mg⁺² and the like. Preferably, R is selected from alkylthio or thioalkyl groups; most preferably R represents -SCH₃.The Mg⁺² salt is preferred. The compounds of formula (I) are generally insoluble in water, but freely soluble in dimethyl sulfoxide, dichloromethane & slightly soluble in methanol and IPA.

…………………………………………….

see also my full fledged article on its synthesis

https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

see also my full fledged article on its synthesis

https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

see also my full fledged article on its synthesis

https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

see also my full fledged article on its synthesis

https://newdrugapprovals.org/2013/06/07/cadila-banks-on-diabetes-druglipaglynsaroglitazar/

FDA publishes List of Guidances planned for 2015

March 9, 2015 3:29 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

At the beginning of each year the FDA always publishes a list of the guidances it plans to publish during that year. It has done so again in 2015. The document is relatively comprehensive, containing five pages. Find out more about the Guidances the FDA plans on publishing in 2015.

http://www.gmp-compliance.org/enews_4660_FDA-publishes-List-of-Guidances-planned-for-2015_9293,9266,Z-QAMPP_n.html

At the beginning of each year the FDA always publishes a list of the guidances it plans to publish during that year. It has done so again in 2015. The document is relatively comprehensive, containing five pages. The list is subdivided into different categories. It contains for example also guidances planned in connection with the topics Clinical Pharmacology or Clinical/Statistical.

CGMP is a category of its own for which “only” three new guidances are planned for 2015:

A questions & answers (Q&A) paper on the topic data integrity
CGMP rules for outsourced facilities (pharmacy compounding)
Rules for the…

View original post 190 more words

FDA approves first biosimilar product Zarxio

March 7, 2015 3:49 am / Leave a comment

FDA approves first biosimilar product Zarxio

03/06/2015 08:56 AM EST

The U.S. Food and Drug Administration today approved Zarxio (filgrastim-sndz), the first biosimilar product approved in the U.S.

read my old post

https://newdrugapprovals.org/2015/01/14/sandozs-zarzio-filgrastim-would-be-the-first-biosimilar-drug-available-in-the-us/

March 6, 2015

The U.S. Food and Drug Administration today approved Zarxio (filgrastim-sndz), the first biosimilar product approved in the United States.

Biological products are generally derived from a living organism. They can come from many sources, including humans, animals, microorganisms or yeast.

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product, known as a reference product. The biosimilar also must show it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

Sandoz, Inc.’s Zarxio is biosimilar to Amgen Inc.’s Neupogen (filgrastim), which was originally licensed in 1991. Zarxio is approved for the same indications as Neupogen, and can be prescribed by a health care professional for:

patients with cancer receiving myelosuppressive chemotherapy;
patients with acute myeloid leukemia receiving induction or consolidation chemotherapy;
patients with cancer undergoing bone marrow transplantation;
patients undergoing autologous peripheral blood progenitor cell collection and therapy; and
patients with severe chronic neutropenia.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, M.D. “Patients and the health care community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy and quality standards.”

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the Affordable Care Act that President Obama signed into law in March 2010. The BPCI Act created an abbreviated licensure pathway for biological products shown to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product, called the “reference product.” This abbreviated licensure pathway under section 351(k) of the Public Health Service Act permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product, and enables a biosimilar biological product to be licensed based on less than a full complement of product-specific preclinical and clinical data.

A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.

The FDA’s approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen. Zarxio has been approved as biosimilar, not as an interchangeable product. Under the BPCI Act, a biological product that that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

The most common expected side effects of Zarxio are aching in the bones or muscles and redness, swelling or itching at injection site. Serious side effects may include spleen rupture; serious allergic reactions that may cause rash, shortness of breath, wheezing and/or swelling around the mouth and eyes; fast pulse and sweating; and acute respiratory distress syndrome, a lung disease that can cause shortness of breath, difficulty breathing or increase the rate of breathing.

For this approval, the FDA has designated a placeholder nonproprietary name for this product as “filgrastim-sndz.” The provision of a placeholder nonproprietary name for this product should not be viewed as reflective of the agency’s decision on a comprehensive naming policy for biosimilar and other biological products. While the FDA has not yet issued draft guidance on how current and future biological products marketed in the United States should be named, the agency intends to do so in the near future.

Sandoz, a Novartis company, is based in Princeton, New Jersey. Neupogen is marketed by Amgen, based in Thousand Oaks, California.

FDA approves new antifungal drug Cresemba, Θειικό ισαβουκοναζόνιο, Isavuconazonium Sulphate

March 7, 2015 3:44 am / Leave a comment

Isavuconazonium sulfate

Изавуконазониев сулфат

CAS 946075-13-4

Molecular Formula:	C₃₅H₃₆F₂N₈O₉S₂
Molecular Weight:	814.837 g/mol

BAL-8557-002, BAL 8557

[2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate;hydrogen sulfate

Image result for Isavuconazonium sulfate

1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47.

Isavuconazonium is a second-generation triazole antifungal approved on March 6, 2015 by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis, marketed by Astellas under the brand Cresemba. It is the prodrug form of isavuconazole, the active moiety, and it is available in oral and parenteral formulations. Due to low solubility in waterof isavuconazole on its own, the isovuconazonium formulation is favorable as it has high solubility in water and allows for intravenous administration. This formulation also avoids the use of a cyclodextrin vehicle for solubilization required for intravenous administration of other antifungals such as voriconazole and posaconazole, eliminating concerns of nephrotoxicity associated with cyclodextrin. Isovuconazonium has excellent oral bioavailability, predictable pharmacokinetics, and a good safety profile, making it a reasonable alternative to its few other competitors on the market.

FDA approves new antifungal drug Cresemba

03/06/2015 02:10 PM EST

The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.

.syn……https://newdrugapprovals.org/2013/10/02/isavuconazole-basilea-reports-positive-results-from-study/

March 6, 2015

Release

Aspergillosis is a fungal infection caused by Aspergillus species, and mucormycosis is caused by the Mucorales fungi. These infections occur most often in people with weakened immune systems.

Cresemba belongs to a class of drugs called azole antifungal agents, which target the cell wall of a fungus. Cresemba is available in oral and intravenous formulations.

“Today’s approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Cresemba is the sixth approved antibacterial or antifungal drug product designated as a Qualified Infectious Disease Product (QIDP). This designation is given to antibacterial or antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act.

As part of its QIDP designation, Cresemba was given priority review, which provides an expedited review of the drug’s application. The QIDP designation also qualifies Cresemba for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act. As these types of fungal infections are rare, the FDA also granted Cresemba orphan drug designations for invasive aspergillosis and invasive mucormycosis.

The approval of Cresemba to treat invasive aspergillosis was based on a clinical trial involving 516 participants randomly assigned to receive either Cresemba or voriconazole, another drug approved to treat invasive aspergillosis. Cresemba’s approval to treat invasive mucormycosis was based on a single-arm clinical trial involving 37 participants treated with Cresemba and compared with the natural disease progression associated with untreated mucormycosis. Both studies showed Cresemba was safe and effective in treating these serious fungal infections.

The most common side effects associated with Cresemba include nausea, vomiting, diarrhea, headache, abnormal liver blood tests, low potassium levels in the blood (hypokalemia), constipation, shortness of breath (dyspnea), coughing and tissue swelling (peripheral edema). Cresemba may also cause serious side effects including liver problems, infusion reactions and severe allergic and skin reactions.

Cresemba is marketed by Astellas Pharma US, Inc., based in Northbrook, Illinois.

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The active substance is isavuconazonium sulfate, a highly water soluble pro-drug of the active triazole isavuconazole. The chemical name of the active substance isavuconazonium sulfate is 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47. The active substance has the following structure:

The structure of the active substance has been confirmed by elemental analysis, mass spectrometry, UV, IR, 1H-, 13C- and 19F-NMR spectrometry, and single crystal X-ray analysis, all of which support the chemical structure. It appears as a white, amorphous, hygroscopic powder. It is very soluble in water and over the pH range 1-7. It is also very soluble in methanol and sparingly soluble in ethanol. Two pKa values have been found and calculated to be 2.0 and 7.3. Its logPoct/wat calculated by software is 1.31. Isavuconazonium sulfate has three chiral centres. The stereochemistry of the active substance is introduced by one of the starting materials which is controlled by appropriate specification. The two centres, C7 and C8 in the isavuconazole moiety and in an intermediate of the active substance, have R configuration. The third chiral centre, C29, is not located on isavuconazole moiety and has both the R and S configurations. The nondefined stereo centre at C29 has been found in all batches produced so far to be racemic. Erosion of stereochemical purity has not been observed in the current process. The active substance is a mixture of two epimers of C29. An enantiomer of drug substance was identified as C7 (S), C8 (S) and C29 (R/S) structure. The control of the stereochemistry of isavuconazonium sulfate is performed by chiral HPLC on the active substance and its two precursors. Subsequent intermediates are also controlled by relevant specification in the corresponding steps. Two crystal forms have been observed by recrystallisation studies. However the manufacturing process as described yields amorphous form only.

Two different salt forms of isavuconazonuium (chloride and sulfate) were identified during development. The sulfate salt was selected for further development. A polymorph screening study was also performed. None of the investigated salts could be obtained in crystalline Form………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002734/WC500196130.pdf

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Isavuconazonium (Cresemba ) is a water-soluble prodrug of the triazole antifungal isavuconazole (BAL4815), a 14-a-demethylase inhibitor, under development byBasilea Pharmaceutica International Ltd and Astellas Pharma Inc. Isavuconazonium, in both its intravenous and oral formulations, was approved for the treatment of invasive aspergillosis and invasive mucormycosis (formerly termed zygomycosis) in the US in March 2015. Isavuconazonium is under regulatory review in the EU for invasive aspergillosis and mucormycosis. It is also under phase III development worldwide for the treatment of invasive candidiasis and candidaemia. This article summarizes the milestones in the development of isavuconazonium leading to the first approval for invasive spergillosis and mucormycosis.

Introduction

The availability of both an intravenous (IV) and an oral formulation of isavuconazonium (Cresemba ), as a result of its water solubility, rapid hydrolysis to the active entity isavuconazole and very high oral bioavailability, provides maximum flexibility to clinicians for treating seriously ill patients with invasive fungal infections [1]. Both the IV and oral formulations have been approved by the US Food and Drug Administration (FDA) to treat adults with invasive aspergillosis and invasive mucormycosis [2]. The recommended dosages of each formulation are identical, consisting of loading doses of 372 mg (equivalent to 200 mg of isavuconazole) every eight hours for six doses, followed by maintenance therapy with 372 mg administered once daily [3]. The Qualified Infectious Disease Product (QIDP) designation of the drug with priority review status by the FDA isavuconazonium in the US provided and a five year extension of market exclusivity from launch. Owing to the rarity of the approved infections,

isavuconazonium was also granted orphan drug designation by the FDA for these indications [2]. It has also been granted orphan drug and QIDP designation in the US for the treatment of invasive candidiasis [4]. In July 2014, Basilea Pharmaceutica International Ltd submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for isavuconazonium in the treatment of invasive aspergillosis and invasive mucormycosis, indications for which the EMA has granted isavuconazonium orphan designation [5, 6]. Isavuconazonium is under phase III development in many countries worldwide for the treatment of invasive candidiasis and candidaemia.

1.1 Company agreements

In 2010, Basilea Pharmaceutica International Ltd (a spinoff from Roche, founded in 2000) entered into a licence agreement with Astellas Pharma Inc in which the latter would co-develop and co-promote isavuconazonium worldwide, including an option for Japan. In return for milestone payments, Astellas Pharma was granted an exclusive right to commercialize isavuconazonium, while Basilea Pharmaceutica retained an option to co-promote the drug in the US, Canada, major European countries and China [7]. The companies amended their agreement in 2014, making Astellas Pharma responsible for all regulatory filings, commercialization and manufacturing of isavuconazonium in the US and Canada. Basilea Pharmaceutica waived its right to co-promote the product in the US and Canada, in order to assume all rights in the rest of the world [8]. However, Astellas Pharma remains as sponsor of the multinational, phase III ACTIVE trial in patients with invasive candidiasis.

2 Scientific Summary

Isavuconazonium (as the sulphate; BAL 8557) is a prodrug that is rapidly hydrolyzed by esterases (mainly butylcholinesterase) in plasma into the active moiety isavuconazole

(BAL 4815) and an inactive cleavage product (BAL 8728).

References

1. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013;6:163–74.

2. US Food and Drug Administration. FDA approves new antifungal drug Cresemba. 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm. Accessed 12 Mar 2015.

3. US Food and Drug Administration. Cresemba (isavuconazonium sulfate): US prescribing information. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf. Accessed 18 Mar 2015.

4. Astellas Pharma US Inc. FDA grants Astellas Qualified Infectious Disease Product designation for isavuconazole for the treatment of invasive candidiasis (media release). 2014. http://newsroom astellas.us/2014-07-16-FDA-Grants-Astellas-Qualified-Infectious-Disease-Product-Designation-for-Isavuconazole-for-the-Treatmentof-Invasive-Candidiasis.

5. European Medicines Agency. Public summary of opinion on orphan designation: isavuconazonium sulfate for the treatment of invasive aspergillosis. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/07/WC500169890.pdf. Accessed 18 Mar 2015.

European Medicines Agency. Public summary of opinion on orphan designation: isavuconazonium sulfate for the treatment of mucormycosis. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/07/WC500169714.pdf. Accessed 18 Mar 2015.

7. Basilea Pharmaceutica. Basilea announces global partnership with Astellas for its antifungal isavuconazole (media release).2010. http://www.basilea.com/News-and-Media/Basilea-announcesglobal-partnership-with-Astellas-for-its-antifungal-isavuconazole/343.

8. Basilea Pharmaceutica. Basilea swaps its isavuconazole North American co-promote rights for full isavuconazole rights outside of North America (media release). 2014. http://www.basilea.com/News-and-Media/Basilea-swaps-its-isavuconazole-North-Americanco-promote-rights-for-full-isavuconazole-rights-outside-

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Image result for Isavuconazonium sulfate

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http://www.jpharmsci.org/article/S0022-3549(15)00035-0/pdf

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http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000ChemR.pdf

FDA Orange Book Patents

US 6812238

US 7459561

FDA Orange Book Patents: 1 of 2
Patent	7459561
Expiration	Oct 31, 2020
Applicant	ASTELLAS
Drug Application	N207500 (Prescription Drug: CRESEMBA. Ingredients: ISAVUCONAZONIUM SULFATE)

from FDA Orange Book

FDA Orange Book Patents: 2 of 2
Patent	6812238
Expiration	Oct 31, 2020
Applicant	ASTELLAS
Drug Application	N207500 (Prescription Drug: CRESEMBA. Ingredients: ISAVUCONAZONIUM SULFATE)

FREE FORM

Isavuconazonium; Isavuconazonium ion; Cresemba; BAL-8557; 742049-41-8;

[2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate

Molecular Formula:	C₃₅H₃₅F₂N₈O₅S⁺
Molecular Weight:	717.773 g/mol

Patent IDDatePatent TitleUS20102494262010-09-30STABILIZED PHARMACEUTICAL COMPOSITIONUS74595612008-12-02N-substituted carbamoyloxyalkyl-azolium derivativesUS71898582007-03-13N-phenyl substituted carbamoyloxyalkyl-azolium derivativesUS71511822006-12-19Intermediates for N-substituted carbamoyloxyalkyl-azolium derivativesUS68122382004-11-02N-substituted carbamoyloxyalkyl-azolium derivatives

REF

http://www.drugbank.ca/drugs/DB06636

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CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=[N+](C=N3)C(C)OC(=O)N(C)C4=C(C=CC=N4)COC(=O)CNC)(C5=C(C=CC(=C5)F)F)O.OS(=O)(=O)[O-]

FDA expands approved use of Opdivo to treat lung cancer

March 5, 2015 9:29 am / Leave a comment

FDA expands approved use of Opdivo to treat lung cancer

03/04/2015 01:28 PM EST

The U.S. Food and Drug Administration today expanded the approved use of Opdivo (nivolumab) to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

March 4, 2015

Release

Lung cancer is the leading cause of cancer death in the United States, with an estimated 224,210 new diagnoses and 159,260 deaths in 2014. The most common type of lung cancer, NSCLC affects seven out of eight lung cancer patients, occurring when cancer forms in the cells of the lung.

Opdivo works by inhibiting the cellular pathway known as PD-1 protein on cells that blocks the body’s immune system from attacking cancerous cells. Opdivo is intended for patients who have previously been treated with platinum-based chemotherapy.

“The FDA worked proactively with the company to facilitate the early submission and review of this important clinical trial when results first became available in late December 2014,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide patients and health care providers knowledge of the survival advantage associated with Opdivo and will help guide patient care and future lung cancer trials.”

Opdivo’s efficacy to treat squamous NSCLC was established in a randomized trial of 272 participants, of whom 135 received Opdivo and 137 received docetaxel. The trial was designed to measure the amount of time participants lived after starting treatment (overall survival). On average, participants who received Opdivo lived 3.2 months longer than those participants who received docetaxel.

The safety and efficacy of Opdivo to treat squamous NSCLC was supported by a single-arm trial of 117 participants who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed 15 percent of participants experienced ORR, of whom 59 percent had response durations of six months or longer.

The most common side effects of Opdivo are fatigue, shortness of breath, musculoskeletal pain, decreased appetite, cough, nausea and constipation. The most serious side effects are severe immune-mediated side effects involving healthy organs, including the lung, colon, liver, kidneys and hormone-producing glands.

Opdivo for squamous NSCLC was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness in the treatment of a serious condition. Opdivo is being approved more than three months ahead of the prescription drug user fee goal date of June 22, 2015, the date when the agency was scheduled to complete its review of the application.

The FDA previously approved Opdivo to treat patients with unresectable (cannot be removed by surgery) or metastatic melanoma who no longer respond to other drugs.

Opdivo is marketed by Princeton, New Jersey-based Bristol-Myers Squibb.

see

https://newdrugapprovals.org/2014/07/08/japan-approves-worlds-first-pd-1-drug-nivolumab/

SHIRDI, MAHARASHTRA, INDIA

Shirdi – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Shirdi

pronunciation (help·info) (Marathi: शिर्डी) is a town and falls under the jurisdiction of municipal council popularly known as Shirdi Nagar Panchayat, located …

Map of shirdi maharashtra .

Shraddha Inn,Shirdi

SHIRDI PRASADALAYA BOJAN

Solar Kitchen Feeds Many at Shirdi, India Shrine

Rajdhani Restaurant: Rajdhani at Shirdi

The well equipped kitchen provides food two times a day, daily. Around 27, 000 of people are distributed food at cheap rate. The food comprises of dal,

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GIVINOSTAT

March 5, 2015 3:45 am / 4 Comments on GIVINOSTAT

GIVINOSTAT, ITF2357, UNII-5P60F84FBH, ITF-2357, Gavinostat,

[6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate,

diethyl-[6-(4-hydroxycarbamoyl-phenylcarbamoyloxymethyl)-naphthalen-2-yl-methyl]-amine

4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]benzohydroxamic acid

CAS 497833-27-9 FREE BASE

199657-29-9 HCL SALT

Molecular Formula: C₂₄H₂₇N₃O₄

Molecular Weight: 421.48888 g/mol

PHASE 2 Italfarmaco (INNOVATOR)

Italfarmaco S.P.A.

DESCRIBED IN U.S. Pat. No. 6,034,096 or in U.S. Pat. No. 7,329,689.

GIVINOSTAT

Givinostat (INN^[1]) or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.^[2] It is a hydroxamate used in the form of its hydrochloride.

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas),^[3] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis^[4] and polycythaemia vera.^[5]

In 2010, orphan drug designation was assigned in the E.U. for the treatment of systemic-onset juvenile idiopathic arthritis and for the treatment of polycythemia vera. In 2013, this designation was assigned by the FDA for the treatment of Duchenne’s muscular dystrophy and for the treatment of Becker’s muscular dystrophy.

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.^[6]^[7]

Givinostat hydrochloride, an orally active, synthetic inhibitor of histone deacetylase, is being evaluated in several early clinical studies at Italfarmaco, including studies for the treatment of myeloproliferative diseases, polycythemia vera, Duchenne’s muscular dystrophy and periodic fever syndrome. The company was also conducting clinical trials for the treatment of Crohn’s disease and chronic lymphocytic leukemia; however, the trials were terminated.

No recent development has been reported for research into the treatment of juvenile rheumatoid arthritis, for the treatment of multiple myeloma and for the treatment of Hodgkin’s lymphoma.

Muscular dystrophies (MDs) include a heterogeneous group of genetic diseases invariably leading to muscle degeneration and impaired function. Mutation of nearly 30 genes gives rise to various forms of muscular dystrophy, which differ in age of onset, severity, and muscle groups affected (Dalkilic I, Kunkel LM. (2003) Muscular dystrophies: genes to pathogenesis. Curr. Opin. Genet. Dev. 13:231-238). The most common MD is the Duchenne muscular dystrophy (DMD), a severe recessive X-linked disease which affects one in 3,500 males, characterized by rapid progression of muscle degeneration, eventually leading to loss of ambulation and death within the second decade of life.

Attempts to replace or correct the mutated gene, by means of gene or cell therapy, might result in a definitive solution for muscular dystrophy, but this is not easy to achieve. Alternative strategies that prevent or delay muscle degeneration, reduce inflammation or promote muscle metabolism or regeneration might all benefit patients and, in the. future, synergize with gene or cell therapy. Steroids that reduce inflammation are currently the only therapeutic tool used in the majority of DMD patients (Cossu G, Sampaolesi M . (2007) New therapies for Duchenne muscular dystrophy: challenges, prospects and clinical trials. TRENDS Mol . Med. 13:520-526).

Diethyl- [ 6- ( 4-hydroxycarbamoyl-phenyl-carbamoyloxy- methyl ) -naphthalen-2-yl-methyl ] -ammonium chloride , which is described in WO 97/43251 (anhydrous form) and in WO 2004/065355 (monohydrate crystal form), herein both incorporated by reference, is an anti-inflammatory agent which is able to inhibit the synthesis of the majority of pro-inflammatory cytokines whilst sparing anti-inflammatory ones. Diethyl- [ 6- ( 4-hydroxycarbamoyl-phenyl-carbamoyloxy- methyl ) -naphthalen-2-yl-methyl ] -ammonium chloride is also known as ITF2357.

The monohydrate crystal form of diethyl- [ 6- ( 4- hydroxycarbamoyl-phenyl-carbamoyloxy-methy1 ) – naphthalen-2-yl-methyl ] -ammonium chloride is known as Givinostat .

Givinostat is being evaluated in several clinical studies, including studies for the treatment of myeloproliferative diseases, polycythemia vera, periodic fever syndrome, Crohn’s disease and systemic- onset juvenile idiopathic arthritis. Orphan drug designation was assigned in the E.U. for the treatment of systemic-onset juvenile idiopathic arthritis and for the treatment of polycythemia vera.

Givinostat has been recently found to act also as a Histone Deacetylase inhibitor (WO 2011/048514).

Histone deacetylases ( HDAC ) are a family of enzymes capable of removing the acetyl group bound to the lysine residues in the N-terminal portion of histones or in other proteins.

HDACs can be subdivided into four classes, on the basis of structural homologies. Class I HDACs (HDAC 1, 2, 3 and 8) are similar to the RPD3 yeast protein and are located in the cell nucleus. Class II HDACs (HDAC 4, 5, 6, 7, 9 and 10) are similar to the HDA1 yeast protein and are located both in the nucleus and in the cytoplasm. Class III HDACs are a structurally distinct form of NAD-dependent enzymes correlated with the SIR2 yeast protein. Class IV (HDAC 11) consists at the moment of a single enzyme having particular structural characteristics. The HDACs of classes I, II and IV are zinc enzymes and can be inhibited by various classes of molecule: hydroxamic acid derivatives, cyclic tetrapeptides , short-chain fatty acids, aminobenzamides , derivatives of electrophilic ketones, and the like. Class III HDACs are not inhibited by hydroxamic acids, and their inhibitors have structural characteristics different from those of the other classes .

The expression “histone deacetylase inhibitor” in relation to the present invention is to be understood as meaning any molecule of natural, recombinant or synthetic origin capable of inhibiting the activity of at least one of the enzymes classified as histone deacetylases of class I, class II or class IV.

Although HDAC inhibitors, as a class, are considered to be potentially useful as anti-tumor agents, it is worth to note that, till now, only two of them (Vorinostat and Romidepsin) have been approved as drugs for the cure of a single tumor form (Cutaneous T-cell lymphoma ) .

It is evident that the pharmaceutical properties of each HDAC inhibitor may be different and depend on the specific profile of inhibitory potency, relative to the diverse iso-enzymes as well as on the particular pharmacokinetic behaviour and tissue distribution.

Some HDAC inhibitors have been claimed to be potentially useful, in combination with other agents, for the treatment of DMD (WO 2003/033678, WO 2004/050076, Consalvi S. et al. Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases. (2011) Mol. Med. 17 : 457-465 ) .

The potential therapeutic use of HDAC inhibitors in DMD may however be hampered by the possible harmful effects of these relatively toxic agents, especially when used for long-term therapies in paediatric patients .

Givinostat, as anti-inflammatory agent, has been already used in a phase II study in children with Systemic Onset Juvenile Idiopathic Arthritis; Givinostat administered at 1.5 mg/kg/day for twelve weeks achieved ACR Pedi 30, 50 and 70 improvement of approximately 70% (Vojinovic J, Nemanja D. (2011) HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. Mol. Med 17:397-403) showing only a limited number of mild or moderate but short lasting, adverse effects.

To date more than 500 patients (including 29 children) have been treated with Givinostat. Repeated dose toxicity studies were carried out in dogs, rats and monkeys. Oral daily doses of the drug were administered up to nine consecutive months. The drug was well tolerated with no overt toxicity at high doses. The “no adverse effect levels” (NOAEL) ranged from 10 to 25 mg/kg/day depending on the animal species and the duration of treatment.

In juvenile animals Givinostat at 60 mg/kg/day did not affect the behavioural and physical development and reproductive performance of pups.

No genotoxic effect was detected for Givinostat in the mouse lymphoma assay and the chromosomal aberration assay in vitro and in the micronucleus test and UDS test in vivo.

Patent	Submitted	Granted
Monohydrate hydrochloride of the 4-hydroxycarbamoyl-phenyl)-carbamic acid (6-diethylaminomethyl-naphtalen-2-yl) ester [US7329689]	2005-11-03	2008-02-12

Adverse effects

In clinical trials of givinostat as a salvage therapy for advanced Hodgkin’s lymphoma, the most common adverse reactions were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia (decreased platelet counts, seen in one third of patients), and mild leukopenia (a decrease in white blood cell levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment.^[8]

Mechanism of action

Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6.^[7]

It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera.^[9]^[10] In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease.^[5]

………………….

PATENT

https://www.google.com/patents/WO2004065355A1?cl=en

Hydrochloride of (6-diethylaminomethyl-naphthalen-2-yl)- methyl ester of (4-hydroxycarbamoylphenyl)-carbamic acid (II)

has been described in US patent 6,034,096 as a derivative of hydroxamic acid having anti-inflammatory and immunosuppressive activity, probably owing to the ability thereof to inhibit the production of pro-inflammatory cyto ines. This compound is obtained according to

Example 12 of the above-mentioned patent as an anhydrous, amorphous, hygroscopic, deliquescent solid which is difficult to handle.

crystalline form of monohydrous hydrochloride of

(6-diethylaminomethyl-naphthalen-2-yl)-methyl ester of

(4~hydroxycarbamoylphenyl)-carbamic acid (I).

This form is particularly advantageous from the industrial perspective because it is stable and simpler to handle than the anhydrous and amorphous form described above.

………………

PATENT

http://www.google.co.in/patents/US7329689

Hydrochloride of (6-diethylaminomethyl-naphthalen-2-yl)-methyl ester of (4-hydroxycarbamoylphenyl)-carbamic acid (II)

has been described in U.S. Pat. No. 6,034,096 as a derivative of hydroxamic acid having anti-inflammatory and immunosuppressive activity, probably owing to the ability thereof to inhibit the production of pro-inflammatory cytokines. This compound is obtained according to Example 12 of the above-mentioned patent as an anhydrous, amorphous, hygroscopic, deliquescent solid which is difficult to handle.

The 4-(6-diethylaminomethyl-naphthalen-2-ylmethoxycarbonylamino)-benzoic acid can be prepared as described in Example 12, point C, of U.S. Pat. No. 6,034,096.

The acid (1.22 kg, 3 moles) was suspended in THF (19 l) and the mixture was agitated under nitrogen over night at ambient temperature. The mixture was then cooled to 0° C. and thionyl chloride (0.657 l, 9 moles) was added slowly, still under nitrogen, with the temperature being maintained below 10° C. The reaction mixture was heated under reflux for 60 minutes, DMF (26 ml) was added and the mixture was further heated under reflux for 60 minutes.

The solvent was evaporated under vacuum, toluene was added to the residue and was then evaporated. This operation was repeated twice, then the residue was suspended in THF (11.5 l) and the mixture was cooled to 0° C.

The mixture was then poured into a cold solution of hydroxylamine (50% aq., 1.6 l, 264 moles) in 5.7 l of water. The mixture was then cooled to ambient temperature and agitated for 30 minutes. 6M HCl was added until pH 2 was reached and the mixture was partially evaporated under vacuum in order to eliminate most of the THF. The solid was filtered, washed repeatedly with water and dissolved in a solution of sodium bicarbonate (2.5%, 12.2 l). The solution was extracted with 18.6 l of a mixture of THF and ethyl acetate (2:1 v/v). 37% HCl (130 ml) were added to the organic layer in order to precipitate the monohydrate of the (6-diethylaminomethyl-naphthalen-2-yl)-methyl ester hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid. If necessary, this operation can be repeated several times to remove any residues of the original acid.

Finally, the solid was dried under vacuum (approximately 30 mbar, 50° C.), producing 0.85 kg (60%) of compound (I).

HPLC purity: 99.5%; water content (Karl Fischer method): 3.8%; (argentometric) assay: 99.8%.


Elemental analysis
C %	H %	Cl %	N %

Calculated for	60.56	6.35	7.45	8.83
C₂₄H₃₀ClN₃O₅
Found	61.06	6.48	7.48	8.90

…..

PATENT

http://www.google.co.in/patents/US20120302633

The hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphtalenyl) ester, also known as ITF 2357 and having the International Non Proprietary Name (INN) of Givinostat® is an organic compound with immunosuppressive and anti-inflammatory activity,

…………………..

http://www.google.com/patents/US6034096

EXAMPLE 12

4-[6-(Diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]-benzohydroxamic acid hydrochloride

A. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (22.2 g, 115 mmol) was added to a solution of 2,6-naphthalenedicarboxylic acid (25 g, 115 mmol) and hydroxybenzotriazole (15.6 g, 115 mmol) in dimethylformamide (1800 ml) and the mixture was stirred at room temperature for 2 hours. Diethyl amine (34.3 ml, 345 mmol) was added and the solution was stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the crude was treated with 1N HCl (500 ml) and ethyl acetate (500 ml), insoluble compounds were filtered off and the phases were separated. The organic phase was extracted with 5% sodium carbonate (3×200 ml) and the combined aqueous solutions were acidified with concentrated HCl and extracted with ethyl acetate (3×200 ml). The organic solution was then washed with 1N HCl (6×100 ml), dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure yielding 18.5 g (Yield 60%) of pure 6-(diethylaminocarbonyl)-2-naphthalenecarboxylic acid; m.p.=122-124° C.

¹ H-NMR d 8.67 (s, 1H), 8.25-8.00 (m, 4H), 7.56 (d, 1H), 3.60-3.20 (m, 4H), 1.30-1.00 (m, 6H).

B. A solution of 6-(diethylaminocarbonyl)-2- naphthalenecarboxylic acid (18 g, 66 mmol) in THF (200 ml) was slowly added to a refluxing suspension of lithium aluminium hydride (7.5 g, 199 mmol) in THF (500 ml). The mixture was refluxed for an hour, then cooled at room temperature and treated with a mixture of THF (25 ml) and water (3.5 ml), with 20% sodium hydroxide (8.5 ml) and finally with water (33 ml). The white solid was filtered off and the solvent was removed under reduced pressure. Crude was dissolved in diethyl ether (200 ml) and extracted with 1N HCl (3×100 ml). The aqueous solution was treated with 32% sodium hydroxide and extracted with diethyl ether (3×100 ml). The organic solution was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure yielding 12.7 g (79% yield) of pure 6-(diethylaminomethyl)-2-naphthalenemethanol as thick oil.

¹ H-NMR d 7.90-7.74 (m, 4H), 7.49 (m, 2H), 5.32 (t, 1H, exchange with D₂ O), 4.68 (d, 2H), 3.69 (s, 2H), 2.52 (q, 4H), 1.01 (t, 6H).

C. A solution of 6-(diethylaminomethyl)-2-naphthalene-methanol (12.5 g, 51 mmol) and N,N’-disuccinimidyl carbonate (13.2 g, 51 mmol) in acetonitrile (250 ml) was stirred at room temperature for 3 hours, then the solvent was removed and the crude was dissolved in THF (110 ml). This solution was added to a solution of 4-amino benzoic acid (7.1 g, 51 mmol) and sodium carbonate (5.5 g, 51 mmol) in water (200 ml) and THF (100 ml). The mixture was stirred overnight at room temperature, then THF was removed under reduced pressure and the solution was treated with 1N HCl (102 ml, 102 mmol). The precipitate was filtered, dried under reduced pressure, tritured in diethyl ether and filtered yielding 13.2 g (yield 64%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]-benzoic acid; m.p.=201-205° C. (dec.)

¹ H-NMR d 10.26 (s, 1H), 8.13 (s, 1H), 8.05-7.75 (m, 6H), 7.63 (m, 3H), 5.40 (s, 2H), 4.32 (s, 2H), 2.98 (q, 4H), 1.24 (t, 6H).

D. A solution of 4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]benzoic acid (13.1 g, 32 mmol) and thionyl chloride (7 ml, 96 mmol) in chloroform (300 ml) was refluxed for 4 hours, then the solvent and thionyl chloride were evaporated. Crude was dissolved in chloroform (100 ml) and evaporated to dryness three times. Crude was added as solid to a solution of hydroxylamine hydrochloride (2.7 g, 39 mmol) and sodium bicarbonate (5.4 g, 64 mmol) and 1N sodium hydroxide (39 ml, 39 mmol) in water (150 ml) and THF (50 ml). The mixture was stirred overnight at room temperature, then THF was removed under reduced pressure and the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. Crude was dissolved in THF and treated with a 1.5 N etheric solution of HCl. The solid product was filtered and dried yielding 6 g (yield 41%) of pure 4-[6-(diethylaminomethyl)naphth-2-ylmethyloxycarbamoyl]benzohydroxamic acid hydrochloride as white solid; m.p.=162-165° C., (dec.)

¹ H-NMR d 11.24 (s, 1H, exchange with D₂ O), 10.88 (s, 1H, exchange with D₂ O), 10.16 (s, 1H), 8.98 (bs, 1H, exchange with D₂ O), 8.21 (s, 1H), 8.10-7.97 (m, 3H), 7.89 (d, 1H), 7.80-7.55 (m, 5H), 5.39 (s, 2H), 4.48 (d, 2H), 3.09 (m, 4H), 1.30 (t, 6H).

http://www.molbase.com/

Some nmr predictions

CAS NO. 497833-27-9, [6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate H-NMR spectral analysis

[6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate NMR spectra analysis, Chemical CAS NO. 497833-27-9 NMR spectral analysis, [6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate H-NMR spectrum

13 C NMR PREDICTIONS

COSY NMR…..http://www.nmrdb.org/

HMBC /HSQC

NMR spectra of reference

· 1H NMR prediction

· 13C NMR prediction

· COSY prediction

· HSQC/HMBC prediction

· All predictions

References

World Health Organization (2010). “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63”. WHO Drug Information 24 (1): 58–9.
2
National Cancer Institute (2010). “Gavinostat”. NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.
3
“Search results for ITF2357”. ClinicalTrials.gov.
4
Committee for Orphan Medicinal Products (23 February 2010). “Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis”. European Medicines Agency. Retrieved 2010-09-15.
5
Committee for Orphan Medicinal Products (3 March 2010). “Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera”. European Medicines Agency.
6
WO patent application 1997/043251, “Compounds with anti-inflammatory and immunosuppressive activities”, published 1997-11-20, assigned to Italfarmaco S.p.A.
7
Leoni F, Fossati G. (2005). “The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo”. Molecular Medicine 11: 1. doi:10.2119/2006-00005.Dinarello. PMID 16557334.
8
Tan J, Cang S, Ma Y, Petrillo RL, Liu D (2010). “Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents”. Journal of Hematology & Oncology 3: 5. doi:10.1186/1756-8722-3-5. PMID 20132536. Review.
9
Vannucchi AM, Guglielmelli P, Pieri L, Antonioli E, Bosi A (2009). “Treatment options for essential thrombocythemia and polycythemia vera.” Expert Review of Hematology 2 (1): 41–55. doi:10.1586/17474086.2.1.41. Review.

Guerini V, Barbui V, Spinelli O, et al. (April 2008). “The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F)”. Leukemia 22 (4): 740–7. doi:10.1038/sj.leu.2405049. PMID 18079739.

US6034096	12 May 1997	7 Mar 2000	Italfarmaco S.P.A.	Compounds with anti-inflammatory and immunosuppressive activities

WO1997043251A1	May 12, 1997	Nov 20, 1997	Italfarmaco Spa	Compounds with anti-inflammatory and immunosuppressive activities
WO2004063146A1	Jan 7, 2004	Jul 29, 2004	Italfarmaco Spa	Hydroxamic acid derivatives having anti-inflammatory action
WO2004065355A1	Jan 8, 2004	Aug 5, 2004	Italfarmaco Spa	Monohydrate hydrochloride of the 4-hydroxycarbamoyl-phenyl)-carbamic acid (6-diethylaminomethyl-naphtalen-2-yl) ester
WO2006003068A2	Jun 7, 2005	Jan 12, 2006	Italfarmaco Spa	Alpha-amino acid derivatives with antiinflammatory activity
WO2008097654A1	Feb 8, 2008	Aug 14, 2008	Nancie M Archin	Methods of using saha for treating hiv infection

Citing Patent	Filing date	Publication date	Applicant	Title
US8518988 *	3 Dec 2010	27 Aug 2013	Chemi Spa	Polymorph of the hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphthalenyl) ester
US20120302633 *	3 Dec 2010	29 Nov 2012	Chemi Spa	Novel polymorph of the hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphthalenyl) ester
WO2011092556A1	3 Dec 2010	4 Aug 2011	Chemi Spa	Novel polymorph of the hydrochloride of the (4-hydroxycarbamoyl-phenyl)-carbamic acid (6-dimethylamino methyl-2-naphtalenyl) ester

Givinostat

Systematic (IUPAC) name
{6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
Clinical data
Pregnancy category	—
Legal status	Investigational Orphan status in EU for sJIA
Routes	Oral
Identifiers
CAS number	497833-27-9
ATC code	None
PubChem	CID 9804992
ChemSpider	7980752
UNII	5P60F84FBH
Chemical data
Formula	C₂₄H₂₇N₃O₄
Molecular mass	421.489 g/mol

Italfarmaco S.p.A.

Stato	Italia
Tipo	Società per azioni
Fondazione	1938 a Milano
Fondata da	Gastone De Santis
Sede principale	Milano
Filiali	Spagna – Portogallo Grecia – Russia Cile – Brasile Turchia
Persone chiave	Francesco De Santis, [Presidente Holding]
Settore	sanità
Prodotti	Farmaci
Fatturato	>500 milioni di Euro (gruppo) (2011)
Dipendenti	>1900 (gruppo) (2011)
Sito web	www.italfarmaco.com

FAVIPIRAVIR, ファビピラビル

March 4, 2015 2:22 pm / 1 Comment on FAVIPIRAVIR, ファビピラビル

FAVIPIRAVIR

Toyama (Originator)

RNA-Directed RNA Polymerase (NS5B) Inhibitors

Chemical Formula:		C₅H₄FN₃O₂
CAS #:		259793-96-9
Molecular Weight:		157.1
		ANTI-INFLUENZA COMPOUND
clinical trials		http://clinicaltrials.gov/search/intervention=Favipiravir
Chemical Name:		6-fluoro-3-hydroxy-2-pyrazinecarboxamide

Synonyms:		T-705, T705, Favipiravir

ChemSpider 2D Image | favipiravir | C5H4FN3O2

Molecular FormulaC₅H₄FN₃O₂
Average mass157.103 Da

259793-96-9 [RN]

2-Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo-

6-Fluoro-3-hydroxypyrazine-2-carboxamide

6-Fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide

8916

Avigan

ファビピラビル
Favipiravir

6-Fluoro-3-hydroxypyrazine-2-carboxamide

C₅H₄FN₃O₂ : 157.1
[259793-96-9]

https://www.pmda.go.jp/files/000210319.pdf

The drug substance is a white to light yellow powder. It is sparingly soluble in acetonitrile and in methanol, and slightly soluble in water and in ethanol (99.5). It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.1. The drug substance is not hygroscopic at 25°C/51% to 93%RH. The melting point is 187°C to 193°C, and the dissociation constant (pKa) is 5.1 due to the hydroxyl group of favipiravir. Measurement results on the partition ratio of favipiravir in water/octanol at 25°C indicate that favipiravir tends to be distributed in the 1-octanol phase at pH 2 to 4 and in the water phase at pH 5 to 13.

Any batch manufactured by the current manufacturing process is in Form A. The stability study does not show any change in crystal form over time; and a change from Form A to Form B is unlikely.

Experimental Properties

PROPERTY	VALUE	SOURCE
melting point (°C)	187℃ to 193℃	https://www.pmda.go.jp/files/000210319.pdf
water solubility	slightly soluble in water	https://www.pmda.go.jp/files/000210319.pdf
pKa	5.1	https://www.pmda.go.jp/files/000210319.pdf

T-705 is an RNA-directed RNA polymerase (NS5B) inhibitor which has been filed for approval in Japan for the oral treatment of influenza A (including avian and H1N1 infections) and for the treatment of influenza B infection.

The compound is a unique viral RNA polymerase inhibitor, acting on viral genetic copying to prevent its reproduction, discovered by Toyama Chemical. In 2005, Utah State University carried out various studies under its contract with the National Institute of Allergy and Infectious Diseases (NIAID) and demonstrated that T-705 has exceptionally potent activity in mouse infection models of H5N1 avian influenza.

T-705 (Favipiravir) is an antiviral pyrazinecarboxamide-based, inhibitor of of the influenza virus with an EC90 of 1.3 to 7.7 uM (influenza A, H5N1). EC90 ranges for other influenza A subtypes are 0.19-1.3 uM, 0.063-1.9 uM, and 0.5-3.1 uM for H1N1, H2N2, and H3N2, respectively. T-705 also exhibits activity against type B and C viruses, with EC90s of 0.25-0.57 uM and 0.19-0.36 uM, respectively. (1) Additionally, T-705 has broad activity against arenavirus, bunyavirus, foot-and-mouth disease virus, and West Nile virus with EC50s ranging from 5 to 300 uM.

Studies show that T-705 ribofuranosyl triphosphate is the active form of T-705 and acts like purines or purine nucleosides in cells and does not inhibit DNA synthesis

In 2012, MediVector was awarded a contract from the U.S. Department of Defense’s (DOD) Joint Project Manager Transformational Medical Technologies (JPM-TMT) to further develop T-705 (favipiravir), a broad-spectrum therapeutic against multiple influenza viruses.

Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.

Favipiravir, also known as T-705, Avigan, or favilavir is an antiviral drug being developed by Toyama Chemical (Fujifilm group) of Japan with activity against many RNA viruses. Like certain other experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative. In experiments conducted in animals Favipiravir has shown activity against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.^[1]Activity against enteroviruses^[2] and Rift Valley fever virus has also been demonstrated.^[3] Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608.^[4] The agent has also shown some efficacy against rabies,^[5] and has been used experimentally in some humans infected with the virus.^[6]

In February 2020 Favipiravir was being studied in China for experimental treatment of the emergent COVID-19 (novel coronavirus)disease.^[7]^[8] On March 17 Chinese officials suggested the drug had been effective in treating COVID in Wuhan and Shenzhen.^[9]^[10]

Discovered by Toyama Chemical Co., Ltd. in Japan, favipiravir is a modified pyrazine analog that was initially approved for therapeutic use in resistant cases of influenza.^7,9 The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes.^7,12,13

Not only does favipiravir inhibit replication of influenza A and B, but the drug shows promise in the treatment of influenza strains that are resistant to neuramidase inhibitors, as well as avian influenza.^9,19 Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.^10,14,15

Mechanism of action

The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.^[11] Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype.^[12] Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations.^[13]^[14] Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process.^[15] Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them.^[1] In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics.^[16] However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.^[17]

Approval status

In 2014, Japan approved Favipiravir for treating viral strains unresponsive to current antivirals.^[18]

In March 2015, the US Food and Drug Administration completed a Phase III clinical trial studying the safety and efficacy of Favipiravir in the treatment of influenza.^[19]

Ebola virus trials

Some research has been done suggesting that in mouse models Favipiravir may have efficacy against Ebola. Its efficacy against Ebola in humans is unproven.^[20]^[21]^[22] During the 2014 West Africa Ebola virus outbreak, it was reported that a French nurse who contracted Ebola while volunteering for MSF in Liberia recovered after receiving a course of favipiravir.^[23] A clinical trial investigating the use of favipiravir against Ebola virus disease was started in Guéckédou, Guinea, during December 2014.^[24] Preliminary results showed a decrease in mortality rate in patients with low-to-moderate levels of Ebola virus in the blood, but no effect on patients with high levels of the virus, a group at a higher risk of death.^[25] The trial design has been criticised by Scott Hammer and others for using only historical controls.^[26] The results of this clinical trial were presented in February 2016 at the annual Conference on Retroviruses and Opportunistic Infections (CROI) by Daouda Sissoko^[27] and published on March 1, 2016 in PLOS Medicine.^[28]

SARS-CoV-2 virus disease

In March 2020, Chinese officials suggested Favipiravir may be effective in treating COVID-19.^[29]

SYN

https://link.springer.com/article/10.1007/s11696-018-0654-9

Image result for FAVIPIRAVIR SYNTHESIS

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1315 kb)

Ref

https://pdfs.semanticscholar.org/be8e/cb882b99204983d2f60077c7ab8b53f4d62c.pdf

Drug Discoveries & Therapeutics. 2014; 8(3):117-120.

As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA viruses in vitro and in vivo. A four-step synthesis of the compound is described in this article, amidation, nitrification, reduction and fluorination with an overall yield of about 8%. In addition, we reported the crystal structure of the title compound. The molecule is almost planar and the intramolecular O−H•••O hydrogen bond makes a 6-member ring. In the crystal, molecules are packing governed by both hydrogen bonds and stacking interactions.

2.2.1. Preparation of 3-hydroxypyrazine-2-carboxamide To a suspension of 3-hydroxypyrazine-2-carboxylic acid (1.4 g, 10 mmol) in 150 mL MeOH, SOCl2 was added dropwise at 40°C with magnetic stirring for 6 h resulting in a bright yellow solution. The reaction was then concentrated to dryness. The residue was dissolved in 50 mL 25% aqueous ammonia and stirred overnight to get a suspension. The precipitate was collected and dried. The solid yellow-brown crude product was recrystallization with 50 mL water to get the product as pale yellow crystals (1.1 g, 78%). mp = 263-265°C. 1 H-NMR (300 MHz, DMSO): δ 13.34 (brs, 1H, OH), 8.69 (s, 1H, pyrazine H), 7.93-8.11 (m, 3H, pyrazine H, CONH2). HRMS (ESI): m/z [M + H]+ calcd for C5H6N3O2 + : 140.0460; found: 140.0457.

2.2.2. Preparation of 3-hydroxy-6-nitropyrazine-2- carboxamide In the solution of 3-hydroxypyrazine-2-carboxamide (1.0 g, 7 mmol) in 6 mL concentrate sulfuric acid under ice-cooling, potassium nitrate (1.4 g, 14 mmol) was added. After stirring at 40°C for 4 h, the reaction mixture was poured into 60 mL water. The product was collected by fi ltration as yellow solid (0.62 g, 48%). mp = 250-252°C. 1 H-NMR (600 MHz, DMSO): δ 12.00- 15.00 (br, 1H, OH), 8.97 (s, 1H, pyrazine H), 8.32 (s, 1H, CONH2), 8.06 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 163.12, 156.49, 142.47, 138.20, 133.81. HRMS (ESI): m/z [M + H]+ calcd for C5H5N4O4 + : 185.0311; found: 185.0304.

2.2.3. Preparation of 6-amino-3-hydroxypyrazine-2- carboxamide 3-Hydroxy-6-nitropyrazine-2-carboxamide (0.6 g, 3.3 mmol) and a catalytic amount of raney nickel were suspended in MeOH, then hydrazine hydrate was added dropwise. The resulting solution was refl uxed 2 h, cooled, filtered with diatomite, and then MeOH is evaporated in vacuo to get the crude product as dark brown solid without further purification (0.4 g, 77%). HRMS (ESI): m/z [M + H]+ calcd for C5H7N4O2 + : 155.0569; found:155.0509.

2.2.4. Preparation of 6-fluoro-3-hydroxypyrazine-2- carboxamide To a solution of 6-amino-3-hydroxypyrazine-2- carboxamide (0.4 g, 2.6 mmol) in 3 mL 70% HFpyridine aqueous at -20°C under nitrogen atmosphere, sodium nitrate (0.35 g, 5.2 mmol) was added. After stirring 20 min, the solution was warmed to room temperature for another one hour. Then 20 mL ethyl acetate/water (1:1) were added, after separation of the upper layer, the aqueous phase is extracted with four 20 mL portions of ethyl acetate. The combined extracts are dried with anhydrous magnesium sulfate and concentrated to dryness to get crude product as oil. The crude product was purified by chromatography column as white solid (0.12 g, 30%). mp = 178-180°C. 1 H-NMR (600 MHz, DMSO): δ 12.34 (brs, 1H, OH), 8.31 (d, 1H, pyrazine H, J = 8.0 Hz), 7.44 (s, 1H, CONH2), 5.92 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 168.66, 159.69, 153.98, 150.76, 135.68. HRMS (ESI): m/z [M + H]+ calcd for C5H5FN3O2 + : 158.0366; found: 158.0360.

SEE

Chemical Papers (2019), 73(5), 1043-1051.

PAPER

Medicinal chemistry (Shariqah (United Arab Emirates)) (2018), 14(6), 595-603

http://www.eurekaselect.com/158990/article

PATENT

CN 107641106

PAPER

Chemical Papers (2017), 71(11), 2153-2158.

https://link.springer.com/article/10.1007%2Fs11696-017-0208-6

Image result for A practical and step-economic route to Favipiravir

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 514 kb)

References

Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D. F.; Barnard, D. L.; Gowen, B. B.; Julander, J. G.; Morrey, J. D. (2009). “T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections”. Antiviral Research 82 (3): 95–102. doi:10.1016/j.antiviral.2009.02.198. PMID 19428599. edit
WO 2000010569
WO 2008099874
WO 201009504
WO 2010104170
WO 2012063931

Process route

hydrolysis
CLIP
Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence.
For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used

CLIP

Synthesis of Favipiravir
ZHANG Tao1, KONG Lingjin1, LI Zongtao1,YUAN Hongyu1, XU Wenfang2*
(1. Shandong Qidu PharmaceuticalCo., Ltd., Linzi 255400; 2. School of Pharmacy, Shandong University, Jinan250012)
ABSTRACT: Favipiravir was synthesized from3-amino-2-pyrazinecarboxylic acid by esterification, bromination with NBS,diazotization and amination to give 6-bromo-3-hydroxypyrazine-2-carboxamide,which was subjected to chlorination with POCl3, fluorination with KF, andhydrolysis with an overall yield of about 22％.

PATENT
US6787544

Figure US06787544-20040907-C00005

subs G₁

G₂

G₃

G₄

R²

compd 32 N

C—CF₃

…………………
EP2192117
Figure US20100286394A1-20101111-C00001
Example 1-1

To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35° C., and the solution was stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the solution was stirred at 20 to 30° C. for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10° C., and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly yellowish white solid product.
¹H-NMR (DMSO-d₆) δ values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m), 1.67-1.81 (4H, m), 1.91-2.07 (4H, m), 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad)
Example 1-2
4.11 ml of acetic acid was added at 5 to 15° C. to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5° C., and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product.
Examples 2 to 5
The compounds shown in Table 1 were obtained in the same way as in Example 1-1.

TABLE 1



Example No.	Organic amine	Example No.	Organic amine

2	Dipropylamine	4	Dibenzylamine
3	Dibutylamine	5	N-benzylmethylamine

Dipropylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
¹H-NMR (DMSO-d₆) 6 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz)
Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
¹H-NMR (DMSO-d₆) 6 values: 0.36 (6H, t, J=7.3 Hz), 0.81 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m), 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz)
Dibenzylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
¹H-NMR (DMSO-d₆) δ values: 4.17 (4H, s), 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz)
N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
¹H-NMR (DMSO-d₆) δ values: 2.57 (3H, s), 4.14 (2H, s), 7.37-7.53 (5H, m), 8.02-8.08 (1H, m)
Preparation Example 1

300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.
¹H-NMR (DMSO-d₆) δ values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)

CLIP
jan 2014

Investigational flu treatment drug has broad-spectrum potential to fight multiple viruses
First patient enrolled in the North American Phase 3 clinical trials for investigational flu treatment drug

BioDefense Therapeutics (BD Tx)—a Joint Product Management office within the U.S. Department of Defense (DoD)—announced the first patient enrolled in the North American Phase 3 clinical trials for favipiravir (T-705a). The drug is an investigational flu treatment candidate with broad-spectrum potential being developed by BD Tx through a contract with Boston-based MediVector, Inc.

Favipiravir is a novel, antiviral compound that works differently than anti-flu drugs currently on the market. The novelty lies in the drug’s selective disruption of the viralRNA replication and transcription process within the infected cell to stop the infection cycle.

“Favipiravir has proven safe and well tolerated in previous studies,” said LTC Eric G. Midboe, Joint Product Manager for BD Tx. “This first patient signifies the start of an important phase in favipiravir’s path to U.S. Food and Drug Administration (FDA) approval for flu and lays the groundwork for future testing against other viruses of interest to the DoD.”

In providing therapeutic solutions to counter traditional, emerging, and engineered biological threats, BD Tx chose favipiravir not only because of its potential effectiveness against flu viruses, but also because of its demonstrated broad-spectrum potential against multiple viruses. In addition to testing favipiravir in the ongoing influenzaprogram, BD Tx is testing the drug’s efficacy against the Ebola virus and other viruses considered threats to service members. In laboratory testing, favipiravir was found to be effective against a wide variety of RNA viruses in infected cells and animals.

“FDA-approved, broad-spectrum therapeutics offer the fastest way to respond to dangerous and potentially lethal viruses,” said Dr. Tyler Bennett, Assistant Product Manager for BD Tx.

MediVector is overseeing the clinical trials required by the FDA to obtain drug licensure. The process requires safety data from at least 1,500 patients treated for flu at the dose and duration proposed for marketing of the drug. Currently, 150 trial sites are planned throughout the U.S.

SOURCE BioDefense Therapeutics

Efficient synthesis of 3H,3’H-spiro[benzofuran-2,1′-isobenzofuran]-3,3′-dione as novel skeletons specifically for influenza virus type B inhibition.

Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.
Eur J Med Chem. 2013 Apr;62:534-44. doi: 10.1016/j.ejmech.2013.01.015. Epub 2013 Jan 29.

US3631036 *	Nov 4, 1969	Dec 28, 1971	American Home Prod	5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds
US3745161 *	Apr 20, 1970	Jul 10, 1973	Merck & Co Inc	Phenyl-hydroxy-pyrazine carboxylic acids and derivatives
US4404203 *	May 14, 1981	Sep 13, 1983	Warner-Lambert Company	Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents
US4545810 *	Mar 25, 1983	Oct 8, 1985	Sds Biotech Corporation	Herbicidal and plant growth regulant diphenylpyridazinones
US4565814 *	Jan 18, 1984	Jan 21, 1986	Sanofi	Pyridazine derivatives having a psychotropic action and compositions
US4661145 *	Sep 20, 1984	Apr 28, 1987	Rohm And Haas Company	Plant growth regulating 1-aryl-1,4-dihydro-4-oxo(thio)-pyridazines
US5420130	May 16, 1994	May 30, 1995	Synthelabo	2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics
US5459142 *	Aug 23, 1993	Oct 17, 1995	Otsuka Pharmaceutical Co., Ltd.	Pyrazinyl and piperazinyl substituted pyrazine compounds
US5597823	Jun 5, 1995	Jan 28, 1997	Abbott Laboratories	Tricyclic substituted hexahydrobenz [e]isoindole alpha-1 adrenergic antagonists
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EP0023358A1 *	Jul 28, 1980	Feb 4, 1981	Rohm And Haas Company	Process for the preparation of pyridazine derivatives
GB1198688A				Title not available
HU9401512A				Title not available
JPH09216883A *				Title not available
JPS5620576A				Title not available

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^ Koons C (7 August 2014). “Ebola Drug From Japan May Emerge Among Key Candidates”. Bloomberg.com.
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^ Hayden, Frederick. “Influenza virus polymerase inhibitors in clinical development”. Current Opinion in Infectious Diseases. doi:10.1097/QCO.0000000000000532.
^ “Phase 3 Efficacy and Safety Study of Favipiravir for Treatment of Uncomplicated Influenza in Adults – T705US316”. FDA. Retrieved 17 March 2020.
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Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]
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World Health Organization: Influenza (Avian and other zoonotic) [Link]

Favipiravir
Names

IUPAC name 5-Fluoro-2-hydroxypyrazine-3-carboxamide
Other names T-705; Avigan; favilavir
Identifiers
CAS Number	259793-96-9
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL221722
ChemSpider	431002
PubChem CID	492405
UNII	EW5GL2X7E0
CompTox Dashboard (EPA)	DTXSID60948878
InChI [show]
SMILES [show]
Properties
Chemical formula	C₅H₄FN₃O₂
Molar mass	157.104 g·mol⁻¹
Pharmacology
ATC code	J05AX27 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////

ANTHONY MELVIN CRASTO

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PALINAVIR

March 4, 2015 7:28 am / Leave a comment

PALINAVIR, BILA-2011-BS

UNII-632S1WU9Z2, 154612-39-2, n-[(1s)-1-[[(1s,2r)-1-benzyl-3-[(2s,4r)-2-(tert-butylcarbamoyl)-4-(4-pyridylmethoxy)piperidino]-2-hydroxypropyl]carbamoyl]-2-methylpropyl]quinaldamide,

N-[(2S)-1-[[(2S,3R)-4-[(2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-4-ylmethoxy)piperidin-1-yl]-3-hydroxy-1-phenylbutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]quinoline-2-carboxamide

Molecular Formula:C₄₁H₅₂N₆O₅

Molecular Weight:708.88878 g/mol

Patent	Submitted	Granted
Substituted pipecolinic acid derivatives as HIV protease inhibitors [US5614533]	1997-03-25
Substituted pipecolinic acid derivatives as HIV protease inhibitors. [EP0560268]	1993-09-15	1995-01-04

……………………….

PATENT

http://www.google.com/patents/WO2013105118A1?cl=en

Scheme 5: Synthesis of Palinavir (6):

The organic solvent mentioned according to the invention is selected from the group consisting of organic solvents, wherein the organic solvents are polar aprotic such as DCM, THF, Ethyl acetate, acetone, DMF, acetonitrile, DMSO ; polar protic solvents such as lower alcohol particularly (C1-C6) alkyl alcohol, water, acetic acid ; non-polar solvents such as hexane, benzene, toluene, chloroform, pet. ether, 1,4-dioxane, heptane either alone or mixtures thereof . Additionally the purification or separation of crude product can be accomplished by known techniques viz. extraction, column chromatography in a suitable organic solvent with the aid of instruments such as TLC, HPLC, GC, mass spectroscopy, or distillation, crystallization, derivatization.

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………………………….

J Org Chem 1997,62(11),3440

The reaction of tert-butoxycarbonyl-L-phenylalanine (I) with isobutyl chloroformate in THF gives the expected mixed anhydride which is treated with diazomethane and HCl yielding the corresponding chloromethyl ketone (II). The reduction of (II) with NaBH4 in THF affords the (S)-chlorohydrin (IV), which is treated with KOH in ethanol to obtain the chiral epoxide (V)(1,2). Ring opening of (V) with (?(cis)-N-tert-butyl-4-(4-pyridylmethoxy)piperidine-2-carboxamide (VI) by a treatment with LiCl in refluxing ethanol gives a mixture of diastereomers that is separated by chromatography giving the pure isomer (VII). The reaction of (VII) with tert-butoxycarbonyl-L-valine (VIII) by treatment first with trifluoroacetic acid (TFA), and condesation by means of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and NMM (N-methylmorpholine) affords the expected condensation product (IX). Finally, this compound is condensed with quinoline-2-carboxylic acid (X) by means of BOP and NMM as before. 2) The piperidine (VI) has been obtained by condensation of (?(cis)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (XI) with 4-(chloromethyl)pyridine (XII) by means of NaH in DMS, followed by hydrolysis with HCl.

Palinavir can also be obtained as follows: The controlled oxidation of 2(S)-(dibenzylamino)-3-phenyl-1-propanol (XIII) with pyridine-SO3 complex in DMSO gives the corresponding aldehyde (XIV), which is condensed with bromochloromethane (XV) by means of Li in THF followed by hydrolysis with HCl yielding regioselectively the 1-chloro-2-butanol (XVI). The debenzylation of (XVI) by hydrogenation over Pd/C affords the free amine (XVII), which is treated with tert-butoxycarbonyl anhydride/triethylamine and dehydrochlorinated with KOH in methanol to give the desired chiral epoxide (V).

The chiral piperidine (2S,4R)(VI) has been obtained as follows: The cyclization of 3-buten-1-ol (XXII) with (S)-1-phenylethylamine (XXIII) and glyoxylic acid (XXIV) by means of tosyl chloride in THF gives a mixture of the (2S,4R) and (2R,4S) lactones (XXV), which is resolved by fractional crystallyzation of their salts with the chiral camphorsulfonic acid (XXVI), followed by elimination of the acid with ammonia to afford (2S,4R)(XXVII). The reaction of lactone (XXVII) with isopropylmagnesium chloride and tert-butylamine in THF gives (2S,4R)-N-tert-butyl-4-hydroxy-1-(1(S)-phenylethyl)piperidine-2-carboxamide (XXVIII), which is debenzylated by hydrogenation and protected with tert-butoxycarbonyl anhydride yielding (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (2S,4R)(XI), which is finally condensed with 4-(chloromethyl)pyridine (XII) as before to obtain the chiral piperidine (2S,4R)(VI), already reported.

The condendsation of epoxide (V) with (2S,4R)(VI) by means of basic alumina in THF, followed by elimination of the protecting group with HCl and NaOH yields directly the condensation product (XVIII) as a pure diastereomer and with a free amino group. Finally, this compound is condensed with N-(2-quinolylcarbonyl)-L-valine (XIX) through its activation compound with isobutyl chloroformate (the 4(S)-isopropyl-2-(2-quinolyl)oxazol-5(4H)-one (XX)). The N-acyl-L-valine (XIX) has been obtained by acylation of L-valine (XXI) with quinoline-2-carboxylic acid (X) through its acyl chloride obtained with SOCl2.

………………………..

Palinavir is an inhibitor with five chiral centers. It contains the amino acid valine and pipecolinin acid. The previous way to create this drug faced three major obstacles. First, the reaction from 2 to 3 used diazomethane. Therefore, is is difficult, if not impossible, to produce large quantities. Secondly, the steps included in going from 4 to 5 gave way to racemers which is very inefficient. Finally, chromatography is needed at two separate times.

Four issues were addresses in route to product 1. First, because of the number of chiral centers, stereochemical control was a concern. high chemical yields were a second concern. Also, multi step procedures were advantageous to cut down on purification steps. Finally, the synthesis tried to restrict the use of hazardous reagents. The following retrosynthesis reaction was conceived and three target molecules were identified as seen in figure 1.

Molecule 3 uses a diaseteroselective addition of in situ (chloromethyl)lithium to N,N-dibenzylphenylalaninol and is derived from a four step process.

Recrystallization of 13 is required. Molecule 14 was not reached because it posed a problem later in the reaction. The N-benzyl protection group could not be removed to react with 9.

8 is a derivative of naturally occurring pipocolic acid, 16, named 3-buten-1-ol. Selective crystallization of diastereomeric salts can lead to 17a, but a more efficient way is by having a 60:40 mixture of lactones 17a,b. This leads to 18a,b using a Brodroux process. Crystallization of 18a,b lead to a poor overall yield. Instead, 18a,b undergoes salt crystallization with (-)-camphorsulfonic acid. Finally, 18a underwent hydrolysis and then addition of di-tert butyl dicarbonate leads to 8.

8 was then transformed to 5 in a three step process.

8 was added to NaOH and alkylated with 4-picolyl chloride. The protecting group was lost with the addition of acid.

Derivation of 9 was started by a simple substitution of 19, quinoline-2-carboxylic acid, to 20, an acid chloride, with the help of thionyl chloride. Acylation of amino acid L-valine to 20 was accomplished by a biphasic system.

In the original synthesis of palinavir, a 2:1 mixture of 3 to 5 was needed to produce only ~35% of 6 and flash chromatography was needed. On a large scale without chromatography, 6 was produced with a 85% yield, but 21 was also produced. To keep the production of 21 to a minimum, the reaction was performed in a solution that was degassed. This insured that the pyridine ring would not react in the presence of air. With this precaution, only 1-2% of the yield was 21. A washing of the solution with 1 M KH2PO4 removed and left over 5. Deprotection was achieved with the addition of concentrated HCl and followed by adding NaOH. The product of 10 was a “viscous syrup”. 22 was 1-1.5% of the product and was not removed before the addition of 9 to form 80-85% palinavir.

Coupling of 10 and 9 is the final step in the synthesis , although there are still some purification steps left.

Two recrystallizations were required for the final 99.6% purity.

………………………..

J. Org. Chem., 1997, 62 (11), pp 3440–3448

DOI: 10.1021/jo9702655

http://pubs.acs.org/doi/abs/10.1021/jo9702655

Palinavir is a potent peptidomimetic-based HIV protease inhibitor. We have developed a highly convergent and stereoselective synthesis which is amenable to the preparation of multikilogram quantities of this compound. The synthetic sequence proceeds in 24 distinct chemical steps (with several integrated, multistep operations) from commercially available starting materials. No chromatographies are required throughout the process, and the final product is purified by crystallization of its dihydrochloride salt to >99% homogeneity.

crude palinavir (1) as a thick brown oil (yield not determined). HPLC analysis (Supelcosil LZ-ABZ, 10−50% 1% TFA in MeCN/1% TFA in 25 min, 1 mL/min flow rate): 1, t_R 17.80 min (84.1%); 24, t_R 18.47 min (2.0%); 25, t_R 19.97 min (1.45%).

palinavir dihydrochloride (1750 g, 51% yield) containing 0.25% w/w isopropanol (by ¹H NMR):

mp 175−185 °C.

[α]²⁵_D −13.0° (c 1, MeOH). [α]²⁵_Hg365 +44.9° (c 1, MeOH).

IR (KBr) ν 3700−2300, 1660, 1555, 1520 cm^-1.

¹H NMR (DMSO-d₆) δ 10.00 (broad s, 1H), 8.88 (d, J = 6.3 Hz, 2H), 8.61 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 8.51 (d, J = 9.6 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 6.0 Hz, 2H), 7.89 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.2 Hz, 2H), 7.08 (t, J = 7.5 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 4.86 (AB quartet, 2H), 4.37 (broad t, J = 7.8 Hz, 1H), 4.21 (d, J = 11.4 Hz, 1H), 4.11 (broad m, 1H), 3.96 (broad m, 1H), 3.80−3.65 (m, 2H), 3.26 (t, J = 7.4 Hz, 1H), 3.15−3.01 (m, 2H), 2.94 (broad d, J = 12.0 Hz, 1H), 2.62 (dd, J = 13.6, 10.6 Hz, 1H), 2.56 ((broad d, J = 12.0 Hz, 1H), 2.20−2.05 (m, 2H), 1.86 (m, 1H), 1.69 (q, J = 11.7 Hz, 1H), 1.31 (s, 9H), 0.81 (d, J = 6.3 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H).

¹³C NMR (DMSO-d₆) δ 170.4, 166.4, 163.3, 158.3, 149.5, 145.9, 141.9, 138.6, 138.2, 130.7, 129.3, 129.1, 129.0, 128.3, 128.2, 128.0, 125.9, 124.1, 118.6, 72.3, 68.8, 67.2, 64.8, 58.0, 57.8, 54.4, 51.3, 51.1, 35.4, 34.1, 31.1, 28.2, 19.5, 17.9.

FAB-MS m/z 709 (MH⁺ of free base). Anal. Calcd for C₄₁H₅₄Cl₂N₆O₅ (corrected for 8% water content as determined by Karl Fisher analysis and 0.25% w/w isopropanol as determined by ¹H NMR): C, 58.31; H, 7.29; N, 9.93. Found: C, 57.76; H, 7.25; N, 9.89. Titration of HCl content using NaOH: 2.09 ± 0.03 mol HCl. HPLC homogeneity (Supelcosil LC-ABZ, 10−50% 1% TFA in MeCN/1% TFA in 25 min, 1 mL/min flow rate): palinavir dihydrochloride, t_R 18.24 min (99.51%); 25 t_R 20.39 min (0.33%). HPLC homogeneity (Nova-Pak C₈, 20−80% MeCN/50 mM NaH₂PO₄ in 25 min, 1 mL/min flow rate): palinavir dihydrochloride, t_R 15.52 min (99.67%); 25 t_R 13.52 min (0.33%).

PURE palinavir (1) as a white amorphous powder (1902 g, 84% yield):

mp 100−107 °C. [α]²⁵_D −11.5° (c 1, MeOH).

IR (KBr) ν 3700−3100, 1660, 1520, 1495 cm^-1.

¹H NMR (CDCl₃) δ 8.54 (d, J = 5.7 Hz, 2H), 8.48 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H, part of AB), 8.22 (d, J = 8.3 Hz, 1H, part of AB), 8.13 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 5.4 Hz, 2H), 7.13 (d, J = 7.3 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.57 (s, 1H), 4.61 (d, J = 13.4 Hz, 1H, part of AB), 4.51 (d, J = 13.4 Hz, 1H, part of AB), 4.32 (dd, J = 8.6, 6.4 Hz, 1H), 4.22 (m, 1H), 3.97 (m, 1), 3.47−3.33 (m, 2H), 2.94 (dd, J = 14.3, 4.1 Hz, 1H), 2.89 (d, J= 8.6 Hz, 1H), 2.79−2.72 (m, 1H), 2.77 (dd, J = 14.3, 10.8 Hz, 1H), 2.43 (dd, J = 13.4, 8.3 Hz, 1H), 2.40−2.25 (m, 3H), 1.95 (broad d, J = 12.4 Hz, 1H), 1.65 (q J = 11.8 Hz, 2H), 1.32 (s, 9H), 0.95 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H).

¹³C NMR (CDCl₃) δ 171.6, 171.2, 165.0, 149.8, 148.8, 147.9, 146.5, 137.6, 137.5, 130.3, 129.9, 129.5, 129.4, 129.0, 128.8, 128.5, 128.2, 127.7, 126.4, 121.7, 118.8, 75.0, 71.9, 68.1, 66.7, 59.4, 56.9, 54.6, 50.9, 50.2, 34.8, 33.3, 29.8, 29.7, 28.7, 19.6, 17.5.

FAB-MS m/z 709 (MH⁺). Anal. Calcd for C₄₁H₅₂N₆O₅(corrected for 0.7% water content as determined by Karl Fisher analysis): C, 68.98; H, 7.42; N, 11.77. Found: C, 68.71; H, 7.47; N, 11.71. HPLC homogeneity (Supelcosil LC-ABZ, 10−50% 1% TFA in MeCN/1% TFA in 25 min, 1 mL/min flow rate): palinavir (1), t_R 17.83 min (99.59%); 25 t_R20.00 min (0.41%). HPLC homogeneity (Nova-Pak C₈, 10−80% MeCN/50 mM NaH₂PO₄ in 25 min, 1 mL/min flow rate): palinavir (1), t_R 17.37 min (99.51%); 25 t_R 15.87 min (0.49%).

Reference
1	*	ARUN K. GHOSH ET AL: “The Development of Cyclic Sulfolanes as Novel and High-Affinity P2 Ligands for HIV-1 Protease Inhibitors“, JOURNAL OF MEDICINAL CHEMISTRY, vol. 37, no. 8, 1 April 1994 (1994-04-01), pages 1177-1188, XP055057710, ISSN: 0022-2623, DOI: 10.1021/jm00034a016
2	*	KAY BRICKMANN ET AL: “Synthesis of Conformationally Restricted Mimetics of [gamma]-Turns and Incorporation into Desmopressin, an Analogue of the Peptide Hormone Vasopressin“, CHEMISTRY – A EUROPEAN JOURNAL, vol. 5, no. 8, 2 August 1999 (1999-08-02), pages 2241-2253, XP055057517, ISSN: 0947-6539, DOI: 10.1002/(SICI)1521-3765(19990802)5:8<2241: :AID-CHEM2241>3.0.CO;2-L
3	*	KIRAN I N C ET AL: “A concise enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol via Co-catalyzed HKR of anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane“, TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 52, no. 3, 19 January 2011 (2011-01-19), pages 438-440, XP027558447, ISSN: 0040-4039 [retrieved on 2010-12-14]
4	*	M. TOKUNAGA: “Asymmetric Catalysis with Water: Efficient Kinetic Resolution of Terminal Epoxides by Means of Catalytic Hydrolysis“, SCIENCE, vol. 277, no. 5328, 15 August 1997 (1997-08-15), pages 936-938, XP055057541, ISSN: 0036-8075, DOI: 10.1126/science.277.5328.936
5	*	PARKES K E B ET AL: “STUDIES TOWARD THE LARGE-SCALE SYNTHESIS OF THE HIV PROTEINASE INHIBITOR RO 31-8959“, JOURNAL OF ORGANIC CHEMISTRY, ACS, US, vol. 59, no. 13/16, 1 January 1994 (1994-01-01), pages 3656-3664, XP002011975, ISSN: 0022-3263, DOI: 10.1021/JO00092A026
6	*	R. SANTHOSH REDDY ET AL: “Co(iii)(salen)-catalyzed HKR of two stereocentered alkoxy- and azido epoxides: a concise enantioselective synthesis of (S,S)-reboxetine and (+)-epi-cytoxazone“, CHEMICAL COMMUNICATIONS, vol. 46, no. 27, 1 January 2010 (2010-01-01), page 5012, XP055057537, ISSN: 1359-7345, DOI: 10.1039/c0cc00650e
7	*	SHINJI NAGUMO ET AL: “Intramolecular Friedel-Crafts type reaction of vinyloxiranes linked to an ester group“, TETRAHEDRON, vol. 65, no. 47, 1 November 2009 (2009-11-01), pages 9884-9896, XP055057655, ISSN: 0040-4020, DOI: 10.1016/j.tet.2009.09.037
8	*	SUNITA K. GADAKH ET AL: “Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2-phenylethyl)oxirane“, TETRAHEDRON: ASYMMETRY, vol. 23, no. 11-12, 1 June 2012 (2012-06-01), pages 898-903, XP055057475, ISSN: 0957-4166, DOI: 10.1016/j.tetasy.2012.06.003 Want to know everything on vir series click http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html AND http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

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