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Ramosetron (INN),(1-methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl]methanone, 132036-88-5 cas no
| C17H17N3O | |
| 279.33 g/mol |
(1-methyl-1H-indol-3-yl)[(5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl]methanone
YM060
…………………………………………………………………………………..
HYDROCHLORIDE SALT
hyrochloride salt, cas no 132907-72-3
(−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H+]
1H NMR (DMSO-d6, 30° C.): δ ppm (TMS internal standard): 1.82-1.95 (1H, m), 2.12-2.22 (1H, m), 2.66-2.94 (4H, m), 3.63-3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.0 Hz), 8.53 (1H, s), 8.90 (1H, s), 14.42 (1H, br)
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Ramosetron (INN) is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting.[1] Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”.[2] In India it is marketed under the brand name of“IBset”.
It is only licensed for use in Japan and selected Southeast Asian countries. In Japan it is sold under the tradename Iribo (イリボー). [3] Elsewhere it is commonly sold under the tradename Nasea and in India as Nozia (300 mcg/ml Inj. & 100 mcg Tab.) [4]
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1-27-2010
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Process for producing ramosetron or its salt
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11-20-1996
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Intrabuccally dissolving compressed moldings and production process thereof
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3-6-1996
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5-substituted tetrahydrobenzimidazole compounds
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11-15-1995
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Intrabuccally disintegrating preparation and production thereof
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9-7-1994
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Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
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6-24-1994
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NEW USE OF 5-HT3 RECEPTOR ANTAGONISTS
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AU 9048890; EP 0381422; JP 1991223278; US 5344927
| CN1696128A | Nov 2, 2004 | Nov 16, 2005 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
| CN1765896A | Oct 28, 2004 | May 3, 2006 | 北京博尔达生物技术开发有限公司 | Novel preparation method of ramosetron hydrochloride |
| US5496942 * | 14 Feb 1994 | 5 Mar 1996 | Yamanouchi Pharmaceutical Co., Ltd. | 5-substituted tetrahydrobenzimidazole compounds |
| US5677326 * | 30 Sep 1994 | 14 Oct 1997 | Tokyo Tanabe Company Limited | Indoline compound and 5-HT.sub.3 receptor antagonist containing the same as active ingredient |
| US7358270 | 28 Jan 2005 | 15 Apr 2008 | Astellas Pharma Inc. | Treating agent for irritable bowel syndrome |
| US7683090 | 18 Oct 2006 | 23 Mar 2010 | Astellas Pharma Inc. | Treating agent for irritable bowel syndrome |
| US7794748 | 27 Aug 2004 | 14 Sep 2010 | Yamanouchi Pharmaceutical Co., Ltd. | Stable oral solid drug composition |
WO 2010024306
WO 2013005760
WO 2013100701
WO 2011001954
The chemical name of ramosetron is (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole, and it has the structure represented by the formula (II).
It is known that ramosetron or a salt thereof has a potent 5-HT3 receptor antagonism (Patent Reference 1, Non-patent references 1 and 2), and it is on the market as a preventive or therapeutic agent for digestive symptoms (nausea, emesis) caused by administration of an anti-malignant tumor agent (cisplatin or the like). In addition, a possibility has been reported that ramosetron or a salt thereof may be useful as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome (Patent Reference 1), and its clinical trials are now in progress as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome.
As a process for producing ramosetron or a salt thereof, the following production methods are known.
Patent Reference 1 describes a production method shown by the following Production method A, namely a method for producing a tetrahydrobenzimidazole derivative (V) by allowing a heterocyclic compound (III) to react with a carboxylic acid represented by a formula (IV) or its reactive derivative.
(Production Method A)
(In the formula, X2 is a single bond and binds to a carbon atom on the heterocyclic ring represented by Het.)
As an illustrative production method of ramosetron, Patent Reference 1 describes a production method (Production method A-1) in which racemic ramosetron are obtained by using 1-methyl-1H-indole as the compound (III), and N,N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide or N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine, which are acid amides, as the reactive derivative of compound (IV), and allowing them to undergo treatment with phosphorus oxychloride (Vilsmeyer reaction), and then their optical resolution is carried out by fractional crystallization using (+)-dibenzoyltartaric acid.
In addition, the Patent Reference 1 exemplifies an acid halide as one of the reactive derivatives of the compound (IV), and also describes another production method of the compound (V) (Production method A-2) in which the heterocyclic compound (III) is condensed with an acid halide of the compound (IV) by the Friedel-Crafts acylation reaction using a Lewis acid as the catalyst. However, illustrative production example of ramosetron by the Friedel-Crafts acylation reaction is not described therein.
Also, a method similar to the Production example A-1 is described in Non-patent References 1 and 2 as a production method of ramosetron.
In addition, Non-patent Reference 3 describes a method for producing ramosetron labeled with 11C, represented by a Production method B. However, it discloses only the methylation step, and does not disclose a production method of nor-YM060 as the starting material.
(Production Method B)
(In the formula, nor-YM060 means (R)-5-[(1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole which was provided by the present applicant, DMF means dimethylformamide.)
LIU Qing-wen, XU Hao, TIAN Hua, ZHENG Liang-yu, ZHANG Suo-qin
Chemoenzymatic Synthesis of Ramosetron Hydrochloride
2012 Vol. 28 (1): 70-72 [Abstract] ( 1143 ) [HTML 1KB] [PDF 206KB] ( 1052 )
doi:http://www.cjcu.jlu.edu.cn/hxyj/EN/abstract/abstract13356.shtml
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The Vilsmeier-type reaction of 1-methylindole (I) with 5 – (1-pyrrolidinocarbonyl) -4,5,6,7-1 H-tetrahydrobenzimidazole hydrochloride (II) and phosphorous oxychloride in 1,2-dichloroethane gives (-5? -. [(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazol e (III) Optical resolution of (III) with (+)-dibenzoyltartaric acid (DIBTA) in DMF -H2O, followed by exchange of the salt affords YM060.
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Ondansetron: 1,2,3 ,9-Tetrahydro-9-methyl-3-[(2-methyl1-H-imidazole-1-yl)methyl]-4H-carbazol-4-one
Granisetron: Endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide
Tropisetron: Endo-1H-indole-3-carbocylic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester
Dolasetron: 1H-Indole-3 -carboxylic acid (2a, 6a, 8a, 9up)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl Ester
Azasetron: (±)-N-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide
Alosetron: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one
Ramosetron
LY335979, RS-33295-198 (Zosuquidar)
Roche Palo Alto (Originator)
LY335979 (Zosuquidar) is a selective Pgp (P-glycoprotein) inhibitor with a Ki of 59 nM. LY335979 significantly enhanced the survival of mice implanted with Pgp-expressing murine leukemia (P388/ADR) when administered in combination with either daunorubicin, doxorubicin or etoposide.
LY335979 (Zosuquidar)
M.Wt: 636.99
Formula: C32H31F2N3O2.3HCl
Name: Zosuquidar trihydrochloride
Elemental Analysis: C, 60.34; H, 5.38; Cl, 16.70; F, 5.97; N, 6.60; O, 5.02
CAS : 167465-36-3
167354-41-8 (free base)
Roche Bioscience (Originator), Eli Lilly and Company (Licensee).
US5654304, WO1994024107A1, WO2000075121, US6570016
Drug Des Discov 1992, 9(1): 69, Bioorg Med Chem Lett 1995, 5(21): 2473, Drugs Fut 2003, 28(2): 125
Zosuquidar is currently under development. It is now in “Phase 3” of clinical tests in the United States. Its action mechanism consists of the inhibition of P-glycoproteins; other drugs with this mechanism include tariquidar and laniquidar. P-glycoproteins are proteins which convert the energy derived from the hydrolysis of ATP to structural changes in protein molecules, in order to perform coupling, thus discharging medicine from cells. If P-glycoprotein coded with the MDR1 gene manifests itself in cancer cells, it discharges much of the antineoplastic drugs from the cells, making cancer cells medicine tolerant, and rendering antineoplastic drugs ineffective. This protein also manifests itself in normal organs not affected by the cancer (such as the liver, small intestine, and skin cells in blood vessels of the brain), and participates in the transportation of medicine. The compound Zosuquidar inhibits this P-glycoprotein, causing the cancer cells to lose their medicine tolerance, and making antineoplastic drugs effective
Clinicial trials: Clinical report published in 2010 showed that zosuquidar did not improve outcome in older acute myeloid leukemia, in part, because of the presence P-gp independent mechanisms of resistance. (Blood. 2010 Nov 18;116(20):4077-85.)
Zosuquidar is a potent P-glycoprotein inhibitor, which binds with high affinity to P-glycoprotein and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, is a member of the ATP-binding cassette superfamily of transmembrane transporters and prevents the intracellular accumulation of many natural product-derived cytotoxic agents
Zosuquidar
U.S. Patent No. 5,112,817 to Fukazawa et al. discloses certain quinoline derivatives useful as anticancer drug potentiators for the treatment of multidrug resistance. One of the initially promising active agents there-disclosed is MS-073, which has the following structure:
MS-073
U.S. Pat. Nos. 5,643,909 and 5,654,304 disclose a series of 10,11- methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. One such derivative having good activity, oral bioavailability, and stability, is zosuquidar, a compound of formula (2R)-anti-5-
3 – [4-( 10, 11 -difluoromethanodibenzosuber-5-yl)piperazin- 1 -yl]-2-hydroxypropoxy) quinoline.
Zosuquidar
Given the limitations of previous generations of MDR modulators, three preclinical critical success factors were identified and met for zosuquidar: 1) it is a potent inhibitor of P-glycoprotein; 2) it is selective for P-glycoprotein; and 3) no pharmacokinetic interaction with co-administered chemotherapy is observed.
Zosuquidar is extremely potent in vitro (Kj = 59 nM) and is among the most active modulators of P-gp-associated resistance described to date. Zosuquidar has also demonstrated good in vivo activity in preclinical animal studies. In addition, the compound does not appear to be a substrate for P-gp efflux, resulting in a relatively long duration of reversal activity in resistant cells even after the modulator has been withdrawn.
Another significant attribute of zosuquidar as an MDR modulator is the minimal pharmacokinetic (PK) interactions with several oncolytics tested in preclinical models. Such minimal PK interaction permits normal doses of oncolytics to be administered and also a more straightforward interpretation of the clinical results.
Zosuquidar is generally administered in the form of the trihydrochloride salt. Conventional zosuquidar trihydrochloride formulations include those containing zosuquidar (50 mg as free base), glycine (15 mg), and mannitol (200 mg) dissolved in enough water for injection, to yield a free base concentration of 5 mg/mL. The formulation is filled into vials and lyophilized to give a vial containing 50 mg of free base. For such formulations, a 30 mL vial size is necessary to contain 50 mg of thezosuquidar formulation. For a typical >200 mg dose of zosuquidar, multiple 50 mg vials are needed to contain the formulation, greatly increasing manufacturing costs and reducing convenience for the end user {e.g., a pharmacist). Modified Cyclodextrins
Cyclodextrins are cyclic oligomers of glucose; these compounds form inclusion complexes with any drug whose molecule can fit into the lipophile-seeking cavities of the cyclodextrin molecule. See U.S. Pat. No. 4,727,064 for a description of various cyclodextrin derivatives. Cyclodextrins of preferred embodiments can include α-, β-, and χ-cyclodextrins. The α-cyclodextrins include six glucopyranose units, the β- cyclodextrins include seven glucopyranose units, and the χ-cyclodextrins include eight glucopyranose units. The β -cyclodextrins are generally preferred as having a suitable cavity size for zosuquidar. Cyclodextrin can be in any suitable form, including amorphous and crystalline forms, with the amorphous form generally preferred. Cyclodextrins suitable for use in the formulations of preferred embodiments include the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, and maltotrosyl derivatives of β- cyclodextrin, carboxyamidomethyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, and diethylamino-β-cyclodextrin.
Pharmaceutical complexes including various cyclodextrins and cyclodextrin derivatives are disclosed in the following United States patents: U.S. Pat. No. 4,024,223; U.S. Pat. No. 4,228,160; U.S. Pat. No. 4,232,009; U.S. Pat. No. 4,351,846; U.S. Pat. No. 4,352,793; U.S. Pat. No. 4,383,992; U.S. Pat. No. 4,407,795; U.S. Pat. No. 4,424,209; U.S. Pat. No. 4,425,336; U.S. Pat. No. 4,438,106; U.S. Pat. No. 4,474,881; U.S. Pat. No. 4,478,995; U.S. Pat. No. 4,479,944; U.S. Pat. No. 4,479,966; U.S. Pat. No. 4,497,803; U.S. Pat. No. 4,499,085; U.S. Pat. No. 4,524,068; U.S. Pat. No. 4,555,504; U.S. Pat. No. 4,565,807; U.S. Pat. No. 4,575,548; U.S. Pat. No. 4,598,070; U.S. Pat. No. 4,603,123; U.S. Pat. No. 4,608,366; U.S. Pat. No. 4,659,696; U.S. Pat. No. 4,623,641; U.S. Pat No. 4,663,316; U.S. Pat. No. 4,675,395; U.S. Pat. No. 4,728,509; U.S. Pat. No. 4,728,510; and U.S. Pat. No. 4,751,095.
Chemically modified and substituted α-, β-, and χ-cyclodextrins are generally preferred over unmodified α-, β-, and χ-cyclodextrins due to improved toxicity and solubility properties. The degree of substitution of the hydroxy 1 groups of the glucopyranose units of the cyclodextrin ring can affect solubility. In general, a higher average degree of substitution of substituent groups in the cyclodextrin molecule yields a cyclodextrin of higher solubility.
Examples for Pgp inhibitors are cyclosporine A, valpodar, elacridar, tariquidar, zosuquidar, laniquidar, biricodar, S-9788, MS-209, BIBW-22 (BIBW-22-BS) , toremifene, verapamil, dexverapamil , quinine, quinidine, trans- flupentixol, chinchonine and others (J. Roberts, C. Jarry (2003) : J. Med. Chem. 46, 4805 – 4817) . The list of inhibitors of P-glycoprotein is increasing (e.g. Wang et al . (2002) : Bioorg. Med. Chem. Lett. 12, 571 – 574) .
Figure 2: Structures of BIBW-22, MS-209 and S-9788
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7-12-2000
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10,11-methanodibenzosuberane derivatives
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10-17-2007
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Salt and crystalline forms of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline
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9-2-2009
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Salt and crystalline forms of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-YL)piperazin-1-YL]-2-hydroxypropoxy}quinoline
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U.S. Pat. Nos. 5,643,909 and 5,654,304, incorporated herein by reference, disclose a series of 10,11-methanobenzosuberane derivatives useful in enhancing the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride disclosed therein, is currently under development as a pharmaceutical agent.
U.S. pat. No. 5,654,304 (‘304), incorporated by reference herein, discloses a series of 10,11-(optionally substituted)methanodibenzosuberane derivatives useful in enhancing, the efficacy of existing cancer chemotherapeutics and for treating multidrug resistance. (2R)-anti-5-{3-[4-(10,11-Difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinolone trihydrochloride is disclosed in ‘304 and is currently under development as a pharmaceutical agent. WO00/75121 discloses Form I, a crystalline form of (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinolone trihydrochloride.
The art disclosed in U.S. Pat. No. 5,776,939, and U.S. Pat. No. 5,643,909 both incorporated herein by reference, and PCT Patent Applications (Publication numbers WO 94/24107 and 98/22112) teach the use of 1-formylpiperazine to introduce the piperazine group of the compound of formula II
Compound II is a mixture of syn isomer (III)
and anti isomer (IV)
The process as disclosed in U.S. Pat. Nos. 5,643,909 and 5,654,304 (represented by scheme A, below) involves (a) chromatographic separation(s) of the formyl piperazine compound; and (b) deformylation of the formyl piperazine compound to provide compound IV.https://www.google.co.in/patents/US6570016?cl=en
The process of the present invention uses piperazine to react with the (1aα,6α,10bα)-6-halo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptene compound or derivative, instead of formylpiperazine.
The process of the present invention is advantageous because piperazine is readily available in commercial quantities whereas 1-formylpiperazine, which was utilized in the process disclosed in U.S. Pat. No. 5,643,909 is often not readily available in commercial quantities. Additionally piperazine enjoys a significant cost advantage over 1-formylpiperazine.
The use of piperazine instead of 1-formylpiperazine is a significant advancement over the prior art because it obviates the need to deformylate or hydrolyze off the formyl group (step 6, scheme A), thereby providing fewer operational steps. U.S. Pat. No. 5,643,909 teaches the separation of the 1-formylpiperazine compounds by chromatography or repeated crystallization. The present invention obviates the need for chromatographic separations of the formylpiperazine diastereomeric addition compounds (see step 4, scheme A)
EXAMPLES
The following examples and preparations are illustrative only and are not intended to limit the scope of the invention in any way.
Preparation 1 R-1-(5-Quinolinyloxy)-2,3-epoxypropane
A mixture of 5-hydroxyquinoline (5.60 g, 38.6 mmol), R-glycidyl nosylate (10.0 g, 38.6 mmol), powdered potassium carbonate (11.7 g, 84.9 mmol), and N,N-dimethylformamide (100 mL) was stirred at ambient temperature until HPLC analysis (40% acetonitrile/60% of a 0.5% aqueous ammonium acetate solution, 1 mL/min, wavelength=230 nm, Zorbax RX-C8 25 cm×4.6 mm column) indicated complete disappearance of glycidyl nosylate (approximately 6 hours). The reaction mixture was filtered through paper and the filter cake was washed with 200 mL of a 3:1 mixture of MTBE and methylene chloride. The filtrate was washed with 200 mL of water and the aqueous layer was extracted four times with 100 mL of 3:1 MTBE/methylene chloride. The combined organic layers were dried over 30 grams of magnesium sulfate and the dried solution was then stirred with 50 grams of basic alumina for 30 minutes. The alumina was removed by filtration and the filter cake was washed with 200 mL of 3:1 MTBE/methylene chloride. The filtrate was concentrated to a volume of 100 mL, 300 mL of MTBE were added, and the solution was again concentrated to 80 mL. After heating to 50° C., the solution was treated with 160 mL of heptane dropwise over 15 minutes, allowed to cool to 40° C., and seeded, causing the formation of a crystalline precipitate. The mixture was stirred for two hours at ambient temperature and then at 0-5° C. for an additional 2 hours. The crystals were filtered, washed with cold heptane, and dried to provide 5.68 g (73.2%) of (2R)-1-(5-quinolinyloxy)-2,3-epoxypropane as white needles.
mp 79-81° C.;
[α]25 D−36.4° (c 2.1, EtOH);
1H NMR (500 MHz, CDCl3)δ 2.83 (dd, J=4.8, 2.7 Hz, 1H), 2.97 (m, 1H), 3.48 (m, 1H), 4.10 (dd, J=11.0, 6.0 Hz, 1H), 4.43 (dd, J=11.0, 2.7 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 7.38 (dd, J=8.5 Hz, 4.1 Hz, 1H), 7.59 (m, 1H), 7.71 (d, J=8.5 Hz, 1H), 8.61 (m, 1H), 8.90 (m, 1H).
Example 1 (2R)-Anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-qunolin-5-yloxy)-propan-2-ol Trihydrochloride
Preparation of the above compound is exemplified in the following preparative steps.
Step 1 1,1-Difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6 (1H)-one
A solution of sodium chlorodifluoroacetate (350 g) in diglyme (1400 mL) was added dropwise over 4 to 8 hours, preferably over 6 hours, to a solution of 5H-dibenzo[a,d]cyclo-hepten-5-one (25 g) in diglyme (500 mL), with stirring, and under nitrogen, maintaining the reaction temperature at 160°-165° C. The cooled reaction mixture was poured into water (1.8 L) and extracted with ether (1.8 L). The organic phase was washed with water, dried over sodium sulfate (Na2SO4), and evaporated. The residue was recrystallized from ethanol, then from acetone/hexane to give 14 g of 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6(1H)-one.
mp 149.6° C.
Flash chromatography of the combined mother liquors on silica gel, eluting with 20% acetone/hexane, gave an additional 6.5 g of the target compound.
Step 2 (1aα,6β,10bα)-1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol
A solution of 1,1-difluoro-1a,10b-dihydro-dibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one (20.4 g) in tetrahydrofuran/methanol (1:2, 900 mL) was cooled in an ice bath. Sodium borohydride (12 g) was added in portions. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 hours, then poured into water. The product was filtered off, washed with water, and dried to give 20 g of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol (ii).
mp 230.1°-230.6° C.
Step 2A Combined Steps 1 and 2 Procedure (1aα,6β,10bα)-1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol
To a solution of 103.1 g (0.500 mol) of 5H-dibenzo[a,d]cyclohepten-5-one (2) in 515 mL of triethylene glycol dimethyl ether heated to between 180° C. and 210° C. was added over 7 hours, 293.3 g (2.15 mol) of chlorodifluoroacetic acid lithium salt (as a 53% by weight solution in ethylene glycol dimethyl ether). The ethylene glycol dimethyl ether was allowed to distill from the reaction as the salt addition proceeded. The GC analysis of an aliquot indicated that all of the 5H-dibenzo[a,d]cyclohepten-5-one had been consumed. The reaction was cooled to ambient temperature and then combined with 400 mL of ethyl acetate and 75 g of diatomaceous earth. The solids were removed by filtration and washed with 300 mL of ethyl acetate. The washes and filtrate were combined and the ethyl acetate was removed by concentration under vacuum leaving 635 g of dark liquid. The dark liquid was cooled to 18° C. and to this was added, over 15 minutes, 6.62 g (0.175 mol) of sodium borohydride (as a 12% by wt solution in 14 M NaOH). After stirring for 2 h the reaction was quenched by careful addition of 900 mL of a 1:3.5:4.5 solution of conc. HCl-methanol-water. The suspension was stirred for 30 min and the crude product was collected by filtration, washed with 600 mL of 1:1 methanol-water and dried to 126.4 g of dark brown solid. The crude product was slurried in 600 mL of methylene chloride, filtered, washed twice with 150 mL portions of methylene chloride, and dried to 91.6 g (71%) of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol. Gas Chromatography (GC) Conditions; Column: JW Scientific DB-1, Initial Temperature 150° C. for 5 min, 10° C./min ramp, Final temp 250° C. for 5 min. tR: intermediate, 11.5 min; reaction product (alcohol), 11.9 min; starting material, 12.3 minutes.
Step 3 Preparation of (1aα,6α,10b)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa-[c]cycloheptene
A slurry of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol (3.0 g, 11.6 mmol, 1.0 equiv) in heptane (24 mL) was treated with 48% HBr (1.58 mL, 14.0 mmol, 1.2 equiv) and the reaction was heated at reflux with vigorous stirring for 2.5 hr. Solvent was then removed by atmospheric distillation (bp 95-98° C.) until approximately 9 mL of distillate was collected. The reaction was cooled and treated with EtOAc (15 mL), Na2SO4 and activated charcoal. The mixture was stirred at RT for 15 min and filtered through hyflo. The filter cake was washed with 50:50 EtOAc:heptane and the filtrate was concentrated in vacuo to provide the title product as a crystalline solid.
mp 119° C. (3.46 g corr., 93%);
1H NMR (500 MHz CDCl3) δ 7.20-7.41 (8H, m), 5.81 (1H, s), 3.41 (2H, d, J 12.5 Hz);
13CNMR (126 MHz CDCl3) δ 141.3, 141.2, 133.5, 130.1, 129.8, 128.3, 128.2, 112.9, 110.6, 110.5, 108.3, 53.6, 30.2, 30.1, 30.0.
Anal. Calcd. For C16H11BrF2: C, 59.84; H, 3.45. Found: C, 60.13; H, 3.50.
Step 3A Preparation of (1aα,6α,10bα)-6-Bromo-1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene
To a stirred suspension of (1aα,6β,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-ol, (18.4 g, 71.2 mmol) in 151 mL of methylene chloride which had been cooled to 10-17° C. was added phosphorous tribromide (9.6 g, 35.6 mmol) dropwise over 15 minutes. The cooling bath was removed and the reaction was stirred for 2 hours at ambient temperature. Analysis by gas chromatography indicated complete consumption of starting material. Cold water (92 mL) and activated carbon (1.84 g) were added and the resulting mixture was stirred for 30 minutes. The activated carbon was removed by filtration through Hyflo brand filter aid and the two phases were separated. The organic phase was washed with water (184 mL×2), brine (184 ml), dried over magnesium sulfate and concentrated to dryness under vacuum, affording 21.7 g (94.8%) of (1aα,6α,10bα)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene.
1H NMR (CDCl3, 300 MHz) δ 3.36 (s, 1H), 3.40 (s, 1H), 5.77 (s, 1H), 7.16-7.38 (m, 8H).
Steps 4 and 5 (1aα,6α,10bα)-1-(1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl)-piperazine, Hydrobromide Salt
To a solution of 237.5 g (0.739 mol) of (1aα,6α,10bα)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]-cyclopropa[c]cycloheptene in 3.56 L of acetonitrile was added 207.7 g (2.41 mol) of piperazine and the mixture was heated to reflux for 2 hours, at which time analysis by gas chromatography showed complete consumption of (1aα,6α,10bα)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene (iii) and formation of a mixture of syn and anti piperazine compounds (III and IV) in an anti-syn ratio of 55:45. The reaction was cooled to about 7° C. and stirred for 30 minutes at that temperature. The reaction mixture was filtered to remove the precipitated syn-isomer (III) and the filter cake was washed with 250 mL of acetonitrile. The combined filtrate and wash were concentrated under vacuum to 262.4 grams of a foam which was dissolved in 450 mL of acetonitrile with heating. The solution was cooled to about 12° C. in an ice bath and stirred for 1 hour at that temperature. The precipitated syn-piperazine compound of formula (III) was filtered and washed with 125 ml of acetonitrile. The combined filtrate and wash were concentrated under vacuum to 194.1 g and dissolved in 1.19 L of ethyl acetate. The organic solution was washed sequentially with 500 mL portions of 1N sodium hydroxide, water, and saturated sodium chloride. The ethyl acetate solution was dried over sodium sulfate and concentrated to give 137.0 grams of residue which was dissolved in 1.37 L of methylene chloride and seeded with (1aα,6α,10bα)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-yl)-piperazine, hydrobromide salt, followed by the addition of 70.8 grams of 48% aqueous hydrobromic acid. The mixture was stirred for about 45 minutes, causing the anti-isomer to crystallize as its hydrobromide salt. The crystals were filtered, washed with methylene chloride, and dried to provide purified hydrobromide salt of compound (IVa), shown by HPLC to have an anti-syn ratio of 99.3:0.7. Treatment of the isolated hydrobromide salt of compound (IVa) with aqueous sodium hydroxide, extraction into methylene chloride, separation of the aqueous layer and concentration to dryness gave 80.1 grams (33.2% yield based on starting material) of (1aα,6α,10bα)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-yl)-piperazine as the free base. Acidification of a solution of the free base in 800 mL of methylene chloride by addition of 41.2 g of 48% hydrobromic acid as described above afforded 96.4 g of pure hydrobromide salt (title compound) with an anti-syn ratio of 99.8:0.2 (HPLC), mp 282-284° C. 1H NMR (DMSO-d6) δ 2.41 (m, 4H), 3.11 (m, 4H), 3.48 (d, J=12.4 Hz, 2H), 4.13 (s, 1H), 7.2 (m, 8H), 8.65 (bs, 2H). 13C NMR (DMSO-d6) δ 28.0, 42.9, 48.0, 75.1, 108.5, 112.9, 117.3, 127.5, 128.0, 128.6, 129.6, 132.4, 141.3. IR: (KBr) 3019, 2481, 1587, 1497, 1298 cm−1. Anal. Calcd for C20H21BrF2N2: C, 58.98; H, 5.20; N, 6.88. Found: C, 58.75; H, 5.29; N, 7.05.
Step 6 Preparation of (2R)-Anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-quinolin-5-yloxy)propan-2-ol Trihydrochloride
A suspension of (1aα,6α,10bα)-1-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cyclohepten-6-yl)-piperazine, hydrochloride compound of formula IVa (5.41 g, 14.9 mmol) and powdered sodium carbonate (3.16 g, 29.8 mmol) in 54 mL of 3A ethanol was stirred at ambient temperature for 1 hour. R-1-(5-quinolinyloxy)-2,3-epoxypropane (3.00 g, 14.9 mmol) was added in one portion and the reaction mixture was heated to 65° C. for 19 hours. HPLC analysis (Gradient system with solvent A (acetonitrile) and solvent B (0.02M sodium monophosphate buffer containing 0.1% triethylamine adjusted to pH 3.5 with phosphoric acid) as follows: 0-12 min, 30% solvent A/70% solvent B; 12-30 min, linear gradient from 30% to 55% solvent A/70% to 45% solvent B; 30-35 min, 55% solvent A/45% solvent B, 1 mL/min, 1=240 nm, Synchropak SCD-100 25 cm×4.6 mm column) indicated the total consumption of the piperazinyl compound of formula (IV). The mixture was allowed to cool to room temperature, filtered through a plug of silica gel, and eluted with an additional 90 mL of ethanol. The eluent was concentrated to a volume of approximately 60 mL and heated to 65° C. with stirring. A solution of HCl in ethanol (16.1 g at 0.135 g/g of solution, 59.6 mmol) was added dropwise over 10 minutes and the resultant product solution was seeded, causing the trihydrochloride salt to precipitate. The mixture was allowed to cool to ambient temperature and stirred slowly (less than 100 RPM) for 2 hours. The precipitate was filtered, washed with ethanol, and dried in vacuo at 50° C. to give the crude trihydrochloride salt which was further purified by recrystallization from methanol/ethyl acetate to provide 7.45 g (78.4%) of (2R)-anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-quinolin-5-yloxy)-propan-2-ol trihydrochloride.
Step 6a
The syn isomer compound of formula (III) isolated as described supra (combined steps 4 and 5), can be utilized to produce the corresponding syn-5-{3-[4-(10,11-difluoromethano-dibenzosuber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (XII) essentially as shown below for the free base of the anti isomer (IVa)in step 6.
https://www.google.co.in/patents/US6570016?cl=en
………………………………………
http://www.google.it/patents/WO1994024107A1?cl=en
REACTION SCHEME 1
FormuIa 1
Formula 1
Formula 2 Formula 2
Formula 3
Formula 3
Formula 4
Formula I
……………………………………….
http://www.google.com/patents/WO2000075121A3
1HNMR (500 MHz DMSO-d6) δ9.41 (2H, br. s), 7.17-7.31 (8H, m), 4.17 (1H, s), 3.52 (2H, d, J=12.4 Hz), 3.11 (4H, br. s), 2.48-2.51 (4H, m)
13CNMR (126 MHz DMSO-d6) δ142.3, 133.4, 130.5, 129.6, 129.0, 128.4, 115.9, 113.6, 111.3, 76.2, 49.0, 43.6, 29.2, 29.1, 29.0; FD MS: m/e 326 (M+).
Anal. Calcd. For C20H21ClF2N2: C, 66.20; H, 5.83; N, 7.72.
Found: C, 66.08; H, 5.90; N, 7.72.
…………………………………………..
http://www.google.com/patents/US6570016?cl=fr
(2R)-Anti-1-[4-(10,11-difluoromethano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazin-1-yl]-3-qunolin-5-yloxy)-propan-2-ol Trihydrochloride
……………….
Chemical Shift Data and Peak Assignments for the Crystal Forms.
Form II has a solid-state 13C NMR spectrum comprised of isotropic peaks at the following chemical shifts: 29.9, 50.1, 55.3, 62.0, 66.5, 72.0, 75.8, 104.8, 107.5, 108.2, 109.1, 110.2, 112.0, 118.4, 119.5, 120.1, 123.1, 128.7, 131.1, 133.0, 134.8, 136.4, 136.9, 139.9, 140.0, 142.3, 144.5, 146.6, 149.0, 144.2, 153.0 and 153.6 ppm.
Form III has a solid-state 13C NMR spectrum comprised of isotropic peaks at the following chemical shifts: 30.3, 50.4, 59.1, 63.2, 72.8, 77.2, 109.1, 110.2, 112.2, 112.8, 118.7, 119.5, 119.9, 121.0, 122.2, 123.0, 128.9, 130.6, 132.7, 134.0, 136.4, 140.0, 141.0, 141.8, 142.5, 143.3, 146.1, 153.1, 153.8 and 154.7 ppm.
The U.S. Food and Drug Administration said on Friday it has expanded the approved use of the cancer drug Nexavar to include late-stage differentiated thyroid cancer.
Differentiated thyroid cancer is the most common type of thyroid cancer, the FDA said. The National Cancer Institute estimates that 60,220 people in the United States will be diagnosed with it and 1,850 will die from the disease in 2013.
The drug, made by Germany’s Bayer AG and Onyx Pharmaceuticals, is already approved to treat advanced kidney cancer and liver cancer that cannot be surgically removed. Onyx was acquired by Amgen Inc earlier this year.
READ ABOUT SORAFENIB IN MY EARLIER BLOGPOST
https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/
Edoxaban, DU-176b
Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery
for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642 Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825, see s[pecific page 2808 for description ie 14/31 of pdf
WO 2010071121, http://www.google.com/patents/WO2010071121A1
WO 2007032498
N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide
NOV20, 2013
Daiichi Sankyo will file edoxaban on both sides of the Atlantic shortly after the bloodthinner proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation.
The company has presented data on edoxaban, a once-daily oral factor Xa inhibitor, at the American Heart Association meeting in Dallas, from a study involving 21,105 patients across 46 countries. The drug, evaluated in 60mg and 30mg doses, met its primary endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular AF.http://www.pharmatimes.com/Article/13-11-20/Daiichi_Sankyo_anticoagulant_edoxaban_succeeds_in_Phase_III.aspx
Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.[1]
In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.[2]
Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).
Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement[3] (phase III early results compare well to enoxaparin[4]), and for stroke prevention in patients with atrial fibrillation[5][6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.
A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.[7]
Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274
Citation ListPatent Literature
SIMILAR
OTHER SALTS
Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C24H30ClN7O4S · HCl
Molecular Weight: 584.52 g.mol-1
Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:
formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.
Quetiapine, astrazeneca
111974-69-7 cas
US 5,948,437*PED, NDA 022047 Appr may 17 2007 sustained release formulation
NDA 020639 approved 26.9.1997
patent approved expiry
| United States | 5948437 | 1997-11-28 | 2017-11-28 |
| United States | 4879288 | 1994-09-26 | 2011-09-26 |
| Canada | 2251944 | 2007-04-10 | 2017-05-27 |
| United States | 4879288 | 1994-09-26 | 2011-09-26 |
Quetiapine (/kwɨˈtaɪ.əpiːn/ kwi-ty-ə-peen) (branded as Seroquel, Xeroquel, Ketipinor) is a short-acting atypical antipsychotic approved for the treatment of schizophrenia, bipolar disorder, and along with an antidepressant to treat major depressive disorder.
Annual sales are approximately $5.7 billion worldwide, with $2.9 billion in the United States. The U.S. patent, which expiredv in 2011, received a pediatric exclusivity extension which pushed its expiration to March 26, 2012.The patent has already expired in Canada. Quetiapine was developed by AstraZeneca from 1992-1996 as an improvement from first generation antipsychotics. It was first approved by the FDA in 1997. There are now several generic versions of quetiapine, such as Quepin, Syquel and Ketipinor
Seroquel (quetiapine) is a psychotropic medication that is used to treat schizophrenia in adults and children who are at least 13 years old. Seroquel is also used in the treatment of major depression and bipolar disorder. Side effects of Seroquel may include mood or behavior changes, constipation, drowsiness, headache, and trouble sleeping. Older adults with dementia may have a slightly increased risk of death when taking this medication.
Dosing preparations are 25, 50, 100, 200, 300, and 400 mg tablets. Seroquel may interact with a number of other drugs, including, but not limited to, antidepressant medications, antifungal drugs, steroids, cimetidine (Tagamet), thioridazine (Mellaril), and lorazepam (Ativan). During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Seroquel passes into breast milk and may have undesirable effects on a nursing infant.
Quetiapine fumarate is a psychotropic agent belonging to a chemical class of dibenzothiazepine derivatives, designated chemically as 2-[2-(4-dibenzo [b,f] [l,4]thiazepin -1 l-yl-l-piperazinyl)ethoxy]-ethanol fumarate (2: l )(salt). Its molecular formula is C42H5oN604S2*C4H404 having a molecular weight of 883.1 1. The structural formula is:
Quetiapine is marketed as immediate release as well as extended release tablets in United States under the trade name Seroquel® and Seroquel XR® by AstraZeneca.
which is first halogenated with phosphorous oxychloride, then isolated and condensed with 1-(2-hydroxyethoxy) ethyl piperazine to obtainquetiapine. After purification by flash chromatography the yield was 77.7 %. As an alternative to halogenation a process via a thioether in the first step is presented.
U.S. Patent 4,879,288 discloses 1 l-[4-[2-(2-hydroxyethoxy) ethyl] -1 – piperazinyl] dibenzo [b, f] [1 , 4] thiazepine as an antipsychotic drug of dibenzothiazepine class suitable for treatment of various psychotic disorders.
US patent 5,948,437 discloses sustained release formulations of quetiapine using gelling agents such as hydroxypropyl methylcellulose and its derivatives that create a gel structure after contact with water. US patent 4,547,57 1 describes process for the preparation of carboxymethyl ethyl cellulose (CMEC) polymer.
WO 2004012699 discloses modified release dosage forms prepared by using dual – retard— technique comprising micro matrix particles containing quetiapine and hydrophobic release controlling agents, which are coated with hydrophobic release controlling agents.
WO 2005041935 discloses matrix composition comprising quetiapine and a wax material.
WO 2007086079 discloses sustained release compositions of quetiapinecomprising a channelizer and a rate controlling polymer.
WO 2008060228 discloses extended release compositions comprisingquetiapine, hydroxypropyl methyl cellulose and sodium citrate dihydrate.
WO 20091 13051 discloses sustained release compositions containingquetiapine and one or more non-gelling and/or waxy excipients.
WO 2010001413 discloses sustained release dosage forms comprisingquetiapine or its pharmaceutically acceptable salts and one or more non-gellable release controlling polymers.
WO 2010028794 discloses a matrix formulation in the form of a retard tablet comprising quetiapine, at least one matrix-forming, water-insoluble, non-swellable auxiliary agent, and at least one water-soluble binding agent.
The synthesis of quetiapine begins with a dibenzothiazepinone. The lactam is first treated with phosphoryl chloride to produce a dibenzothiazepine. A nucleophilic substitutionis used to introduce the sidechain.U.S. Patent 4,879,288.
Atypical antipsychotic quetiapine (Quetiapine, drugs used its fumarate) for the treatment of schizophrenia (schizophrenia) and dry depressive disorder (bipolar disorder), trade name Seroquel, produced by AstraZeneca. Star molecule drugs, the global sales of about $ 6 billion.
Quetiapine synthesis o-nitro-chlorobenzene ( 1 ) starting a thiophenol occurred and SNAr reaction, hydrogenation of nitro group to an amino group after reaction with phosgene isocyanate 2 , 2 ring closure in hot sulfuric acid to obtain 3 , 3 with phosphorus oxychloride isomerization chlorinated4 , 4 and 5 SNAr reaction occurs fumarate salt formation with quetiapine fumarate.
The route of the compound 4 is not stable enough, then there are improved route. 6 and the reaction of phenyl chloroformate 7
Quetiapine fumarate, Bis [2-(2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl]ethoxy)ethanol] fumarate (IUPAC)2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol-(E)-2-butanedioate (2:1) salt), [ICI 204,636], is a novel dibenzothiazepine antipsychotic developed by Zeneca. It is marketed under the trade name ‘Seroquel’Seroquel. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia.
The initial hope of investigators was that quetiapine would have antipsychotic potential and that it might share some of the properties of clozapine without its toxicity to white blood cells.
The effective dosage range is usually 300-450 mg/day split into two doses. The dose is titrated upwards from 25 mg twice dailybd from day one to 300mg/daya fuller dosage on day 4. Elderly patients or patients with liver problems should be started on lower doses. It is both superior to placebo and, and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and is an effective treatment for in reducing negative symptoms at a dose of 300 mg/day.
Somnolence is the most common adverse event. Abnormalities of the QTqt interval on ECG appear very infrequently and there is no need for a baseline ECG or blood pressure monitoring as used to be the case with ssertindole. There is no need for haematological monitoring as with clozapine. Quetiapine, across the full dosage range, is associated with no greater extrapyramidal symptoms than placeboThere is a reduced potential for extrapyramidal symptoms compared with conventional antipsychotics.
Quetiapine’s general efficacy and side effect profile suggest that, unless there are unforeseen post-marketing complications, quetiapine deserves a major place in the initial and long term management of schizophreniform disorders.
Quetiapine fumarate, Bis [2-(2-[4-(dibenzo[b,f][1,4]thiazepin-11-yl]ethoxy)ethanol] fumarate (IUPAC) 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol-(E)-2-butanedioate (2:1) salt), [ICI 204,636], is a novel dibenzothiazepine antipsychotic developed by Zeneca Pharmaceuticals. It is marketed under the trade name ‘Seroquel’. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia.
With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.
By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),
which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.
Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.
Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”
Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials
http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty
Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million
BAYER PIPELINE AS ON OCT 25 2013
phase 1
| Project | Indication |
|---|---|
| CDK-Inhibitor (BAY 1000394) | Cancer |
| Mesothelin-ADC (BAY 94-9343) | Cancer |
| PSMA Bi TE Antibody (BAY 2010112) | Cancer |
| PI3K-Inhibitor (BAY 1082439) | Cancer |
| FGFR2 Antibody (BAY 1179470) | Cancer |
| HIF-PH (BAY 85-3934) | Anemia |
| Partial Adenosine A1 Agonist(BAY 1067197) | Heart Failure |
| Vasopressin Receptor Antagonist(BAY 86-8050) | Heart Failure |
| sGC Stimulator (BAY 1021189) | Heart Failure |
| S-PRAnt (BAY 1002670) | Symptomatic uterine fibroids |
| BAY 1026153 | Endometriosis |
phase2
| Project | Indication |
|---|---|
| PI3K-Inhibitor (BAY 80-6946) | Cancer |
| Regorafenib | Cancer |
| Refametinib (MEK-Inhibitor) | Cancer |
| Radium-223-Dichloride | Cancer |
| Sorafenib | Additional Indications |
| MR-Antagonist (BAY 94-8862) | Congestive Heart Failure (CHF) |
| MR-Antagonist (BAY 94-8862) | Diabetic Nephopathy |
| Riociguat (sGC Stimulator) | Pulmonary Hypertension |
| Neutrophil Elastase Inhibitor(BAY 85-8501) | Bronchiectasis |
phase 3
| Project | Indication |
|---|---|
| Sorafenib | Breast Cancer |
| Sorafenib | Adjuvant HCC |
| Sorafenib | Adjuvant RCC |
| Regorafenib | HCC 2nd line |
| Rivaroxaban | Major Adverse Cardiac Events |
| Rivaroxaban | CHF and CAD |
| peg rFVIII(BAY 94-9027) | Hemophilia |
| Aflibercept | Myopic choroidal neovascularization (mCNV) |
| Aflibercept | Diabetic Macular Edema (DME) |
| LCS 16 | Contraception |
| Vaginorm | Vulvovaginal atrophy (VVA) |
| Sodium Deoxycholate | Submental fat removal |
| Cipro DPI | Lung infection |
| Tedizolid | Skin and Lung Infections |
| Amikacin Inhale | Gram-negative pneumonia |
Sorafenib tosylate
https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/
TEDIZOLID PHOSPHATE
Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.
“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”
Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”
Cl 223Ra Cl
Xofigo
https://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/
The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.
Finerenone (BAY 94-8862)
The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.
For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.
Molidustat (BAY 85-3934)
In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.
Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.
Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.
Regorafenib, stivarga
Bayer’s Eylea (aflibercept),
https://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/
Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.
In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.
Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.
In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.
In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.
Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf –for cas no
The U.S. Food and Drug Administration (FDA) has issued a positive review for a highly anticipated hepatitis C drug from Gilead Sciences, saying the pill cures more patients in less time than currently available treatments.
The agency posted its review of Gilead’s sofosbuvir online ahead of a meeting Friday where government experts will vote on whether to recommend the drug’s approval.
old article cut paste
Jun. 7, 2013– Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted priority review to the company’s New Drug Application (NDA) for sofosbuvir, a once-daily oral nucleotide analogue inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The FDA grants priority review status to drug candidates that may offer major advances in treatment over existing options. Gilead filed the NDA for sofosbuvir on April 8, 2013, and FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of December 8, 2013.
The data submitted in this NDA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.
Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.
Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.[2]
Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.[3]
Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.
Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[6]
Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.[7][8]
Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir (formerly GS-5885), and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[9]Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.
AS SODIUM SALT
Bottle of rabeprazole 20 mg tablets
| Active Ingredient | Form | Dosage | Drug Type | Application | Product | |
|---|---|---|---|---|---|---|
| RABEPRAZOLE SODIUM | TABLET, DELAYED RELEASE; ORAL | 10MG **Federal Register determination that product was not discontinued or withdrawn for safety or efficacy reasons** | DISCN | 020973 | 001 | |
| RABEPRAZOLE SODIUM | TABLET, DELAYED RELEASE; ORAL | 20MG | RX | 020973 | 002 |
| Patent | Expiration | |
|---|---|---|
| US 5045552*PED | 2013-11-8 | |
| US 5045552 | Pyridine derivatives having anti-ulcerative activity
Pyridine derivatives useful for preventing or treating peptic ulcers, pharmaceutical preparations and methods of treating peptic ulcers are described.
|
2013-5-8(expired) |
Exclusivity is marketing rights granted by the FDA to the EISAI INC.
Pariprazole sodium;Rabeprazole sodium;LY-307640;E-3810;Aciphex;Pariet
Rabeprazole /ˌræ.ˈbɛp.ræ.zɔːl/ is an antiulcer drug in the class of proton pump inhibitors. It was developed by Eisai Co. and is marketed by Janssen-Cilag as the sodium salt under the brand names AcipHex (/ˈæsɨfɛks/, referring to pH) in the US, Pariet in Europe, Brazil, Canada, Japan, Russia and Australia, Acigard, Cyra, Rabium, Esoon,Orporo, Parit, Rabemac, Rabiloz, Razo, Rabifast, Rablet and Rabsiv in India, and Zechin in Pakistan.
Rabeprazole, 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole has the following structural formula
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. So that it can effectively inhibit the secretion of an acid and is therefore effective in the therapy or prevention of human and animal peptic ulcer.
The U.S. Pat. No. 5,045,552 discloses the Rabeprazole and many other substituted benzimidazole-type compounds having anti-ulcer activity. This patent further discloses the process for preparation of Rabeprazole by oxidation of Rabeprazole sulfide using 85% m-chloroperbenzoic acid in a mixture of dichloromethane and diethyl ether followed by work up to get product as oil. The obtained oil is crystallized from a mixture of dichloromethane/ether. Optionally the oily crude is dissolved in aqueous solution of sodium hydroxide. The obtained solution is subjected to azeotropic distillation with ethanol to remove water and adding ether to get crystalline Rabeprazole base.
According to the prior art, Rabeprazole base is crystallized using dichloromethane/ether to obtain crystalline off white product. The HPLC purity is less than or equal to 99% and the isolation procedure involves azeotropic distillation of water, during which the product is exposed to high temperature and leads to certain impurities. Repeated crystallization is needed to remove impurities to get desired quality. Using large volumes of chlorinated solvents in the plant leads to environmental hazardous.
Japanese patent application JP2001039975 teaches that the product obtained by example 33 of U.S. Pat. No. 5,045,552 with a melting range of 140-141° C. corresponds to amorphous rabeprazole sodium
The U.S. Pat. No. 6,919,459 patent also discloses the process for the preparation of Rabeprazole by oxidation of Rabeprazole sulfide using m-Chloroperbenzoic acid (m-CPBA) in a suitable solvent. The reaction mass is subjected to repeated washings at different pH levels and isolate the product from aqueous layer.
Rabeprazole is not stable at acidic conditions and decomposes to form unknown impurities. To remove these impurities repeated crystallizations are required to get desire quality of the final product.
The WO2006/117802 PCT application discloses the process for the preparation of Rabeprazole sodium by oxidation of Rabeprazole sulfide with sodium hypo halite solution in water or a mixture of water and water miscible solvent medium using alkali metal hydroxide and catalyst. The reaction mass is saturated by inorganic saturating agents and the Rabeprazole sodium salt is extracted with water immiscible organic solvent. Organic solvent is distilled and the residue is dissolved in second organic solvent to get clear solution, which is precipitated by adding antisolvent.
The WO2006/120701 PCT application discloses process for manufacture of amorphous Rabeprazole sodium by the reaction of Rabeprazole base with aqueous sodium hydroxide. Ethanol is added to the obtained solution. Solvents are distilled from the solution to get thick mass. Organic solvent is added to the obtained residue to get clear solution, to which antisolvent is added to get amorphous Rabeprazole sodium.
The prior art methods cited above have many disadvantages, these methods involve more number of organic solvents and lack successive extractions and washings of the layers during work up procedure. It leads to many impurities that ultimately affect on purity and yield loss of final product.
The U.S. Pat. No. 6,180,652 and WO 2003101452 PCT application discloses the process for the preparation of amorphous rabeprazole sodium, which is obtained by lyophilization of an aqueous solution of rabeprazole sodium acetone complex and an aqueous NaOH solution of Rabeprazole respectively.
Lyophilization technique is not suitable for production at industrial scale and it needs more time cycle and involves the cost.
We observed that rabeprazole is rapidly degraded in chlorinated solvent like dichloromethane to form unknown impurities, due to impurities while distillation gummy material is formed. It leads to yellowish color in final product, finally it leads to yield loss in final product.
According to prior art methods,
US 6,313,303 discloses the preparation of sulfoxides by oxidizing thio ether with a peroxoborate salt in the presence of an acid anhydride or a metal catalyst; and the preparation of sulfoxides by oxidizing thio ether with an N- halosuccinimide, l,3-dihalo-5,5-dimethyl-hydantoin or dichloroisocyanuric acid salt in the presence of a base.
IN 192030 discloses the purification process of Rabeprazole, in which sulfone enriched Rabeprazole is treated with an amino alcohol e.g. ethanolamine in the presence of an organic solvent, further the reaction mixture washed with water to remove the sulfone impurities. US 7,439,367 (IN218648, 058/MUM/2003, 193/MUM/2003) discloses the preparation of Rabeprazole by oxidizing its corresponding sulfide compound, where aqueous hypohalite solution is used as an oxidizing agent. The said oxidation is carried out at a controlled temperature and pH. During said oxidation the pH of the reaction mixture is maintained in the range of 9 to 12. This process utilizes catalyst such as pyridine, di-isopropyl ethyl amine and N,N-dimethyl amino pyridine.
US 7,060,837 discloses the purification of lansoprazole using ammonia, ammonium hydroxide, diethylamine, triethylamine and methylamine in the presence of solvent. The said patent utilizes acid for the isolation of lanzoprazole in pure form.
US 2008/0161579 (IN190/MUM/2005) discloses a process for the preparation of Rabeprazole sodium comprising oxidation of Rabeprazole sulfide with sodium hypohalite in water or a mixture of water and water miscible solvent using alkali metal hydroxide and catalyst. It also discloses a process for the preparation of Rabeprazole sulfide.
WO 2008/045777 (1856/CHE/2006) discloses the preparation of
Rabeprazole by oxidizing the corresponding sulfide compound using about 0.8 to 1.25 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base where aqueous sodium hypohalite used as an oxidizing agent.
WO 2006/024890 discloses a process for the preparation of Rabeprazole in which the Rabeprazole obtained was treated with the triethylamine in hexane. The use of n-hexane in the final stage is not suitable for manufacturing point of view as it is difficult to remove residual hexane solvent. There are several disadvantages associated with such known processes; all the methods reported in these prior arts leads to the formation of many impurities which ultimately affects the purity of the final product.
US 5,045,552 patent discloses the preparation of Rabeprazole by oxidizing the Rabeprazole sulfide using m-chloroperbenzoic acid as shown in scheme-I. The crude Rabeprazole was dissolved in sodium hydroxide and the resulting solution was azeotropically distilled together with ethanol thrice to remove the water. Finally ether was added to get the crystals of Rabeprazole sodium
WO 03/101452 discloses a method for the preparation of Rabeprazole sodium comprising dissolving Rabeprazole base in aqueous sodium hydroxide and then subjecting to lyophilization.
Souda, S.; Ueda, N.; Miyazawa, S.; Tagami, K.; Nomoto, S.; Okita, M.; Shimomura, N.; Kaneko, T.; Fujimoto, M.; Murakami, M.; Oketani, K.; Fujisaki, H.; Shibata, H.; Wakabayashi, T. (Eisai Co., Ltd.); Pyridine derivs., pharmaceutical compsns. comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same. AU 8781138; EP 0268956; EP 0475456; EP 0654471; EP 0786461; JP 1989006270; JP 1993247035; JP 1995291967; US 5045552; US 5998445 .
Castaner, J.; Prous, J.; E-3810. Drugs Fut 1991, 16, 1, 19.
Sohda, S.; Tagami, K.; Chiku, S.; Synthesis of 14C-labelled sodium pariprazole (E3810). J Label Compd Radiopharm 1993, 33, 9, 849.
Rabeprazole as “CYRA” (Systopic Labs Pvt Ltd), “Elpizole” (Orchid Chemicals & Pharmaceuticals), Elpizole-20 (Orchid Chemicals & Pharmaceuticals), Rablet (Lupin), Acigard (3D), AcipHex, Rabeloc, Pariet, Rabider (Duta Formulations) Rabsiv 20 (Saharsh Biologicals) is supplied in:
HPLC METHOD
Rabeprazole with more impurities, particularly at 2.12 RRT (393 mass), 3.51 RRT (491 mass), 4.47 RRT (457 mass), 4.85 RRT (684 mass) and 4.54 RRT (893 mass). The mass (molecular or formula weight) number of the impurities were identified using LCMS. Particularly, the obtained product contains unknown impurities of higher molecular weight in the range of 0.1-1.0 % at relative retention time (RRT) of 2.12, 3.51, 4.47, 4.85, and 4.54 RRT as measured by high performance liquid chromatography (HPLC) method provided below.
The purity of the product obtained is determined by high performance liquid chromatography method under the conditions mentioned below.
Column: Prontosil Kromabond 100-5-C18 (250 x 4.6 mm), 5μ,
Mobile phase A: 1.36g KH2PO4 to 1 litre water, 0.5ml OfEt3N, Mobile phase B: Methanol: ACN (95:5),
Diluent: Mobile phase A and ACN (70:30),
Flow Rate: 1.0 mL/min,
Detection: UV at 280 nm,
Injection Volume: 20 μL, Run Time: 60 min.
Column oven temperature: 3O0C. Surprisingly the applicant identified a method in which, crude Rabeprazole was treated with diethylamine and optionally addition of TBAB (tetrabutylammmonium bromide) as catalyst, where the impurity level reduced. Though the reported amines like triethyl amine, ethanolamine, and ammonia are effectively used to minimize sulfone impurity, those are failed or unsatisfactory to remove the impurities at 2.12 RRT, 3.51 RRT, 4.47 RRT, 4.85 RRT and 4.54 RRT.
SPECTRAL DATA
EP 1869015 B1 FOR RABEPRAZOLE SODIUM
IR Spectra (KBr, cm-1): 3382, 2927, 1583, 1462, 1384, 1298, 1269, 1190, 1157, 1093, 1018, 745.
H NMR Spectra [200 M Hz, CD3OD] δ (ppm): 8.23 – 8.25 (1H, d, ArH); 7.57 – 7.62 (2H, m, ArH); 7.0 – 7.09 (2H, m, ArH); 6.87 – 6.90 (1H, d, ArH); 4.57 – 4.63 (2H, d, O=S-CH2-Ar); 4.0 – 4.1 (2H, t, -O-CH2-CH2-); 3.49 – 3.55 (2H, t, -CH2-O-CH3); 3.31 (3H, s, -OCH3); 2.1 (3H, s, Ar-CH3); 1.96 – 2.0 (2H, t, -CH2-CH2-CH2-).
MP
As per the process described and exemplified in the U. S. Patent No.
5,045,552, rabeprazole sodium is prepared by oxidizing 2-[[4-(3- methoxyporpoxy)-3-methylpyridine-2-yl]rnethylthio]-1 H-benzimidazole with m- chloroperbenzoic acid to afford the rabeprazole base which is further converted to its sodium salt by using 0.1 N aqueous solution of sodium hydroxide, followed by addition of ethanol. The water is removed by azeotropic distillation and the product is precipitated by using ether as solvent such as diethyl ether, tert-butyl methyl ether. The melting point of the disclosed rabeprazole sodium salt is 140- 1410C. The isolation process described in the U. S. Patent No. 5,045,552 has numerous disadvantages such as large volume of solvents is required for azeotropic removal of water during which the product is exposed to high temperature and leads to certain impurities. Based on these drawbacks the isolation process finds to be unsuitable for preparation of amorphous rabeprazole sodium at commercial scale operations.
Japanese patent application JP 2001039975 indicates that the product obtained by example 33 of the U. S. Patent No. 5,045,552 with a melting point of
140-1410C corresponds to amorphous rabeprazole sodium. In this application, the X-ray powder diffraction pattern of the amorphous rabeprazole sodium is shown.
The PCT patent publication No. WO 03/101452 discloses a method for the preparation of rabeprazole sodium comprising dissolving rabeprazole base in aqueous sodium hydroxide and then subjecting to lyophilization. U.S. Patent No. 6,180,652 B1 (the ‘652 patent) describes acetone complex of rabeprazole sodium, process for its production and characterizes it by powder X-ray diffraction, infra-red spectroscopy and 1H-NMR spectroscopy. The ‘652 patent further reports a process for preparation of amorphous rabeprazole sodium by lyophilizing (freeze-drying) an aqueous solution of rabeprazole sodium acetone complex.
However, lyophilization is a technique, which is not suitable for production at industrial scale because this process presents serious limitations on cost, time, equipment capability and environmental protection.
According to PCT patent publication No. WO 2004/085424A1 , amorphous rabeprazole sodium is obtained by heating the rabeprazole sodium acetone complex at elevated temperature, preferably between 100 and 1100C. It is well known that exposing rabeprazole-type compounds to high temperatures increases the risk of decomposition to form impurities and as such, heat treatment of rabeprazole sodium acetone complex into amorphous rabeprazole sodium is not adequate for the production of a rabeprazole which is suitable for pharmaceutical use.
PCT patent publication No. WO 2007/023393 A2 reports a process for preparation of amorphous rabeprazole sodium, the said process comprises: i) contacting rabeprazole sodium acetone complex with a first solvent system which includes a hydrocarbon solvent or an ether solvent or an alcohol solvent or mixtures thereof; ii) filtering the solid from the solvent system used in step i) or distilling the solvent system used in step i) under reduced or atmospheric pressure, to thereby obtain a residue; iii) contacting the wet solid or the residue of step ii) with a second solvent system which includes a hydrocarbon solvent or an ether solvent; and iv) filtering to obtain a wet solid from the solvent system used in step iii) to obtain a wet solid.
The methods for preparation of amorphous rabeprazole sodium as described in the patents U.S. Patent No. 6,180,652 B1 , PCT patent publication No. WO 2004/085424A1 and PCT patent publication No. WO 2007/023393 A2 involves lengthy process i.e., proceeds via rabeprazole sodium acetone complex intermediate and also the yields obtained in these processes are very low.
U.S. Patent Application No. US2004/0180935A1 teaches a process for production of amorphous rabeprazole sodium by dissolving rabeprazole acid in a mixture of sodium hydroxide and methanol at 25-350C, removing the solvent by evaporation and precipitating the product by adding petroleum ether.
PCT patent publication No. WO 2006/120701 A1 teaches a process for manufacture of amorphous rabeprazole sodium with mean particle diameter between 10 to 55 μm, the said process comprises, addition of rabeprazole to aqueous sodium hydroxide; addition of ethyl alcohol to the solution; distillation of solvents from the solution thus obtained till thick mass is obtained; addition of an organic solvent selected from ethyl acetate, dichloromethane, chloroform, butyl acetate, ethanol, isopropyl alcohol, methanol, tetrahydrofuran, to the residue to obtain a clear solution; addition of this clear solution to an anti-solvent includes diisopropyl ether, diethyl ether, methyl tert-butyl ether, under agitation and isolation of the product.
Since a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk benefits. In such cases, this guideline (ICH guidelines Q3C(R3)) decrees that a concentration of a residual solvent in drug substance should be not more than a specified value, which is toxicologically acceptable. The methods for preparation of amorphous rabeprazole sodium as described in the patents, U.S. Patent Application No. US2004/0180935A1 and PCT patent publication No. WO 2006/120701 A1 suffers with residual solvent problem and thereby commercially not viable. These methods utilize the solvents like diisopropyl ether and petroleum ether as precipitating solvents. These solvents are difficult to remove completely by practical manufacturing techniques. According to the ICH guidelines Q3C(R3), there is no adequate toxicological data for the solvents like diisopropyl ether and petroleum ether on which to base a PDE was found. However, a need still remains for an improved and commercially viable process of preparing pure amorphous rabeprazole sodium that would solve the aforesaid problems associated with processes described in the prior art, which will be suitable for largr-scale preparation, in terms of simplicity, chemical yield and purity of the product, and which would carry out with comparatively smaller volume of solvent
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