Friday, 6 December 2013
AstraZeneca today announced that the European Commission (EC) has granted Marketing Authorisation to FluenzTM Tetra. Fluenz Tetra is a nasally administered four-strain live attenuated influenza vaccine for the prevention of influenza in children and adolescents from 24 months up to 18 years of age. The EC approval makes Fluenz Tetra the first and only intra-nasal four-strain influenza vaccine available in Europe.http://www.pharmalive.com/ec-approves-fluenz-tetra
TRANDOLAPRIL
(2S,3aR,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
87679-37-6 CAS NO
Indications. hypertention
Abbott..(opten , godrik, mavik), HOECHST MARION ROUSSEL..Odrik,
RU-44570, Preran,
Aventis Pharma (Originator), Nippon Roussel (Originator), Abbott (Licensee), Chugai (Licensee)
Launched-1993
Trandolapril is a non-sulhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to its biologically active diacid form, trandolaprilat, in the liver. Trandolaprilat inhibits ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Trandolapril may be used to treat mild to moderate hypertension, to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction, as an adjunct treatment for congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.
Trandolapril is an ACE inhibitor used to treat high blood pressure, it may also be used to treat other conditions. It is marketed by Abbott Laboratories with the brand name Mavik.
Tarka is the brand name of an oral antihypertensive medication that combines a slow release formulation of verapamil hydrochloride, acalcium channel blocker, and an immediate release formulation of trandolapril, an ACE inhibtor. The patent, held by Abbott Laboratories, expires on February 24, 2015.
This combination medication contains angiotensin-converting enzyme (ACE) inhibitor and calcium channel blocker, prescribed for high blood pressure.
Trandolapril is a prodrug that is deesterified to trandolaprilat. It is believed to exert its antihypertensive effect through the renin-angiotensin-aldosterone system. Trandolapril has a half life of about 6 hours, and trandolaprilat has a half life of about 10. Trandolaprilat has about 8 times the activity of its parent drug. Approximately 1/3 of Trandolapril and its metabolites are excreted in the urine, and about 2/3 of trandolapril and its metabolites are excreted in the feces. Serum protein binding of trandolapril is about 80%.
Trandolapril is a drug that is used to lower blood pressure. Blood pressure is dependent on the degree of constriction (narrowing) of the arteries and veins. The narrower the arteries and veins, the higher the blood pressure. Angiotensin Il is a chemical substance made in the body that causes the muscles in the walls of arteries and veins to contract, narrowing the arteries and veins and thereby elevating blood pressure. Angiotensin Il is formed by an enzyme called angiotensin converting enzyme (ACE). Trandolapril is an inhibitor of ACE and blocks the formation of angiotensin Il thereby lowering blood pressure. The drop in blood pressure also means that the heart does not have to work as hard because the pressure it must pump blood against is less. The efficiency of a failing heart improves, and the output of blood from the heart increases. Thus, ACE inhibitors such as trandolapril are useful in treating heart failure.
Trandolapril‘s ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity.
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synthesis
(3aR,7aS)-octahydroindole-2(S)-carboxylic acid (I) goes through the process of esterification with benzyl alcohol (II) in the presence of SOCl2 to produce the corresponding benzyl ester (III), and the yielding compound is then condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (IV) in the presence of 1-hydroxybenzotriazole, N-ethylmorpholine and dicyclohexylcarbodiimide (DCC) in DMF to afford the benzyl ester (V) of the desired product. Lastly, the compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.
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Trandolapril along with other related compounds was first disclosed in US4933361. The process for the synthesis of trandolapril was described in US4933361 and WO9633984.
US4933361 describes a process for the synthesis of trandolapril wherein the racemic benzyl ester of octahydro indole-2-carboxylic acid is reacted with N-[1-(S)-ethoxy carbonyl- 3- phenyl propyl]-L-alanine (ECPPA), to get racemic benzyl trandolapril, which is purified using column chromatography to get the 2S isomer of benzyl trandolapril, which is further debenzylated with Pd on carbon to get trandolapril as a foamy solid. This process has certain disadvantages, for example the product is obtained in very low yield. Purification is done using column chromatography, which is not suitable for industrial scale up.
WO9633984 discloses a process in which N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-L- alanine is activated with N-chlorosulfinyl imidazole, to get (N-[I-(S) N-[1-(S)-ethoxy carbonyl-3-phenyl propylj-L-alanyl-N-sulfonyl anhydride and which is further reacted with silyl-protected 2S,3aR,7aS octahydro indole 2-carboxyIic acid to obtain trandolapril. The main disadvantages of this process are that the silyl-protected intermediates are very sensitive to moisture, the process requires anhydrous conditions to be maintained and the solvent used has to be completely dried. It is very difficult to maintain such conditions on an industrial scale, and failing to do so leads to low yield of product.
The processes for preparing N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine N- carboxyanhydride which is used in the process of the present invention are well known and are disclosed in JP57175152A, US4496541 , EP215335, US5359086 and EP1197490B1. Trans octahydro-IH-indole-2-carboxylic acid and its esters are the key intermediates in the synthesis of trandolapril. When synthesized, trans octahydro-1 H-indole-2-carboxylic acid is a mixture of four isomers, as shown below.
From the processes known in the prior art, trans octahydro-1 H-indole-2-carboxylic acid is converted to its ester and the ester is then either reacted directly with N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine (ECPPA) and then the isomers are separated by column chromatography, or alternatively the ester is reacted with ECPPA followed by 0 deprotection. Trans octahydro-1 H-indole-2-carboxylic acid is always used in its protected form. No attempts have been made to resolve free trans octahydro-1 H-indole-2-carboxylic acid to convert it to the desired isomer (isomer D, above). Furthermore, none of the prior art processes is stereoselective, so resolution of the required isomer is required following condensation.
EP0088341 and US4490386 describe a method for the resolution of N-benzoyl (2RS,3aR,7aS) octahydro-1 H-indole-2-carboxylic acid using α-phenyl ethyl amine.
US6559318 and EP1140826 describe a process for the synthesis of (2S,3aR,7aS) 0 octahydro-1 H-indole-2-carboxylic acid using enzymatic resolution of its nitrile intermediate. Enzymatic resolution involves many steps and also requires column chromatography for purification making the process uneconomical industrially.
WO8601803 describes the preparation of (2S,3aR,7aS) octahydro-1 H-indole-2-carboxylic 5 acid ethyl ester and benzyl ester using 10-D-camphor sulphonic acid.
WO2004065368 describes the synthesis of (2S,3aR,7aS) octahydro-1 H-indole-2- carboxylic acid benzyl ester by resolution using 10-D-camphor sulphonic acid to prepare trandolapril. This process gives poor yields because the product has to be first resolved and then the ester is deprotected leading to further loss in yield, making the process low yielding and expensive.
W 02005/051909 describes a process for the preparation of trandolapril, i.e. (N-[I-(S)- carbethoxy-3-phenylpropyl}-S-alanyl-2S,3aR,7aS-octahydroindol-2-carboxyIic acid} as well as its pharmaceutical acceptable salts, using a racemic mixture of trans octahydroindole-2- carboxylic acid with the N-carboxyanhydride of {N-[1-(S)-ethoxycarbonyl-3-phenylpropyl}- S-alanyl (NCA) in a molar ratio of 1 :1 to 1.6:1 in a mixture of water and water-miscible solvent to obtain a mixture of diastereomers of trandolapril. The diastereomers are converted to salts which upon repeated crystallization from acetone and water, and reaction with a base gives pure trandolapril. Thus, the condensation reaction in the presence of water and a water-miscible solvent is not stereoselective.
The processes for preparing N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-l_-alanine N- carboxyanhydride starting from N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine (ECPPA) are well known and are disclosed in JP57175152A, US4496541 , EP215335, US5359086 and EP1197490B1
The angiotensin-converting enzyme (ACE) inhibitor trandolapril is commonly prescribed as a cardiovascular drug for the control and management of mild to severe hypertension Chigh blood pressure) and may be used alone or in combination with diuretics or other antihypertensive agents. Administration of trandolapril is typically oral at a level of around 0.5-4 mg once a 15 day and may also be used in the management of conditions such as heart failure and left ventricular dysfunction following myocardial infarction.
Trandolapril itself is a prodrug, being converted to the acid form “trandolaprilat” in vivo. It is, however, • generally desirable to prepare and administer the ester form.. The structures of trandolapril and trandolaprilat ‘ are shown below.
Trandolapril Trandolaprilat
Various methods for the synthesis of trandolapril and related compounds have been proposed but each of these suffers from drawbacks . Frequently the syntheses require the use of dangerous reagents, which make industrial scale preparation hazardous and difficult and/or involve multiple steps resulting in a long and complex synthesis . One of the most important steps in the synthesis is the formation of the trans-fused octahydroindole ring, which is often difficult to separate from the cis-fused equivalent.
A number of the known synthetic routes to trandolapril proceed via the key intermediate (2S, 3aR,7aS) -octahydro,-lH-indole-2-carboxylic acid. This contains the key trans-fused octahydroindole ring and the correct stereochemistry for the carboxylic acid group at the 2-position. Frequently, these methods require the separation of the cis- and trans-fused rings and, in many cases, resolution of the carboxylate group at the 2 -position is necessary. Where production of the trans-fused ring junction has been possible without generating significant quantities of the cis-product, the syntheses have been long and/or required dangerous reagents such as mercury compounds.
(2S, 3aR, 7aS)-octahydro-lH-indole-2-carboxylic acid
US-A-4691022 gives a synthesis of the above intermediate compound in relatively few steps but requires the trans-octahydroindole as the starting material. The result is also a mixture of the 2-α and 2-β compounds.
EP-A-084164/US-A-4, 933,361 provides an apparently effective method for the synthesis of the cis-fused intermediate beginning with the high-pressure hydrogenation of indole at 100 atmospheres of hydrogen and a platinum catalyst. This document also provides two methods for forming the trans-fused octahydroindole ring, but neither is indicated as being efficient. The first method provides the stereochemistry for the 2 -position from substituted alanine, reacting this with activated cyclohexanone and cyclising the product to give a hexahydroindole . Unfortunately, the reduction of this hexahydroindole to the octahydro- compound produces both cis- and trans-fused product in unknown yield. The second method is to introduce the trans-ring via trans-octahydro-lH-quinolin-2 -one, but no indication of yield in the key step is given and complex series of halogenation, partial re-hydrogenation and re-arrangement are required to reach the desired intermediate .
WO 00/40555 / US 6559318 relies on enzymic resolution of a 2- (2 ‘ , 2 ‘ -methoxyethyl) cyclohexamine with Novozyme7 over 25 hours to provide the N-acetylated (1R, 2S) enantiomer which must then be separated by column chromatography from the. unreacted (IS, 2R) enantiomer. Neither the enzymic resolution nor the chromatography steps are well suited to industrial scale preparations. There are also around ten steps required to reach the desired compound.
The synthetic route to the above octahydroindole intermediate proposed by Henning et al . (Tett. Lett. 24(1983), 5343-5346) quickly and elegantly introduces a 1,2-trans configuration around a cyclohexane ring, but requires the use of mercuric nitrate. The use of mercury compounds is obviously undesirable in the preparation of pharmaceuticals. A further synthesis is provided by Brion et al . (Tett. Lett. 33 (1992) 4889-4892) but it is unclear whether they in fact prepare 5% or 95% of the desired product with 2S stereochemistry. In any case, the method requires eleven steps including an initial pig liver esterase digestion to provide the product in stereochemically pure form but in a 95:5 mixture of isomers at position 2. This method is thus complex and ill suited to industrial scale preparation.
ROUTE A – Separation of enantiomers by the formation of diastereomeric salts with a chiral resolving agent HA* (such as 0, O’ -dibenzoyl-L-tartaric acid), coupling with N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine (ECPPA) derivative and finally deprotecting the carboxylic acid moiety Rλ (such as by hydrogenating a benzyl ester, where Rx = Bn) .
ROUTE B.- Direct reaction of 7A with ECPPA derivative that leads to the formation of diastereoisomers, deprotecting the carboxylic acid moiety and finally separation of diastereoisomers by conventional methods.
1) deprotection >■ trandolapril 2) separation of diastereoisomers
ROUTE C- Treatment of 7A in basic medium and deprotection that leads to the racemic mixture of octahydroindole acid followed by the reaction with ECPPA derivative. This will result in a diastereomeric mixture that can be separated by conventional methods.
COOEtCH,
,1 ) basic medium QC &° ‘ – trandolapril 2) deprotection
2) separation of
racemic diastereoisomers 7A 6C
Route D. Separation of isomers of 6C by conventional methods (i.e. formation of a diastereomeric salt) and coupling with ECCPA derivative.
trandolapril
Route E
This route is an inversion of the steps of route B Firstly the isomers are separated and then the protecting group is removed. 1) separation of diastereoisomers trandolapπl
racemic 2) deprotection
Route F. – The compound 8A is treated to remove the protecting grqup and coupled with an ECPPA derivative,
1) deprotection
2) base treatment
racemic 7A 8A
X activating group
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http://www.google.com/patents/US20060079698
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INTERMEDIATE
(2S,3aR,7aS)-perhydroindole-2-carboxylic acid (42 g).
IR (Nujol, cm-1): 2923, 2854, 1600, 1458, 1377, 1319. 1H-NMR (D2O): δ 1.1-2.5 (m, 8H), 1.65(m,1H), 1.96-2.37 (m,2H), 2.91(td, 1H),4.46(d, 1H). Mass (m/z): 168.3(M-H).
http://www.faqs.org/patents/app/20110065930
(2S,3aR,7aS)-Octahydro-1H-indole-2-carboxylic acid hydrochloride
yield as a white solid.
1H NMR (D2O, 400 MHz): δ 4.42 (dd, 1H, J=11.1, 2.7 Hz), 2.93, (dt, 1H, J=11.8, 3.6 Hz), 2.36 (ddd, 1H, J=12.9, 6.7, 2.7 Hz), 2.31-2.16 (m, 1H), 2.11-2.01 (m, 2H), 1.92-1.90 (m, 1H), 1.79-1.75 (m, 1H), 1.68-1.53 (m, 2H), 1.34-1.13 (m, 3H);
LC-MS (m/z): 170.1 (M+H).sup.+. The isolated product (5) correlates to the material prepared according to U.S. Pat. No. 487,932 and Tetrahedron Lett., 1992, 33, 4889.
CAS No: 144540-75-0
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REF
Tan, X; He, W; Liu, Y (2009). “Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy”. Kidney international 76 (12): 1248–57. doi:10.1038/ki.2009.346. PMID 19759524.
Urbach, H., Henning, R., Teetz, V., Geiger, R., Becker, R. and Gaul, H. (Hoechst A.G.) Bicyclic amino acid derivatives.DE 3151690, EP 084164, EP 170775.JP 1989301659; JP 1989301695
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The ESI mass spectrum of the drug trandolapril displayed a molecular ion peak [M+H] + at 431.1 amu. The tandem mass spectra (MS2) showed the fragment ions at m/z 234.2, 170.2, 160.3, 134.2, 130.3, 117.2, 102.3 and 91
The IR spectrum of new impurity showed the following absorption bands 3277cm-1 (NH stretch), 2941cm-1 (aliphatic CH stretch), 1734 and 1653cm-1 (C=O) stretch and 1192cm-1 (C-O stretch)
1H NMR
13 C NMR
TRP = TRANDOLAPRIL COMPARED WITH 2 IMPURITIES
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TRANDOLAPRIL SPECTRAL DATA
http://www.google.com.br/patents/US20060079698
IR (KBr, cm-1): 3444, 3280, 2973, 2942, 2881, 1735, 1654, 1456, 1367, 1193, 1024, 699.
The 1H-NMR (CDCl3): δ 7.2 (s, 5H), 4.4(m,4H), 4.2 (q,2H), 3.6-1.3 (m, 18H), 1.28(d+t,6H). CI Mass (m/z): 429.6(M-H).
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United States Patent Application 20080171885
http://www.freepatentsonline.com/y2008/0171885.html
M.P.: 122-124° C.,
IR (KBr): 3278.7, 2942.2, 1735.2, 1654.3, 1456.7, 1433.7, 1366.5, 1192.8, 1101.5, 1063.8 and 1023.8 cm−1 (FIG. 1).
1H NMR (CD3OD, δ ppm): 7.33 (s, 5H), 4.34 (m, 3H), 3.86 (q, 2H), 3.28-1.46 (m, 17H) and 1.39 (d+t, 6H),
Mass (m/z, amu): 453.5 (M+Na) and 431.7 (M+H)+ molecular ion.
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MORE INFO FOR READERS
trandolapril
Reaction of cyclohexene with acetonitrile and mercuric acetate followed by ligand exchange with sodium chloride gives the crystalline acetamidomercury chloride in 98% yield. Reaction of the product of formula XIIIa with α-chloro acrylonitrile followed by reaction with NaBH4 and ethanol gives the product of formula XIIIb, which is cyclized with sodium in DMF to get a mixture of Xlllc and XIIId in the ratio of 18.5 : 1. On hydrolysis, IIIa is obtained selectively.
In this method, cyclohexylamine derivative of formula-XXIX is resolved to produce enantiomerically pure product of formula XXX, which is converted to octahydroindole-2-carbonitrile of formula XXVIII a. The product of formula XXVIII a on hydrolysis yields the octahydroindole-2-carboxylic of formula III a.
254750-02-2 cas no
emricasan
PF 03491390, IDN 6556
pfizer
Prevention of fibrosis and inflammation in chronic liver disease
The compound had been studied in phase II clinical trials for the treatment of liver transplant rejection and hepatitis B
(3S)-3-[[(2S)-2-[[2-[(2-tert-butylphenyl)amino]-2-oxoacetyl]amino]propanoyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, C26 H27 F4 N3 O7, 569.5
http://www.ama-assn.org/resources/doc/usan/emricasan.pdf
Conatus’s liver drug emricasan gets FDA orphan drug status
US-based biotechnology firm Conatus Pharmaceuticals has received orphan drug designation from the US Food and Drug Administration (FDA) for its drug candidate emricasan to treat liver transplant recipients with re-established fibrosis to delay the progression to cirrhosis and end-stage liver disease.http://www.pharmaceutical-technology.com/news/newsconatuss-chronic-liver-disease-treatment-emricasan-gets-fda-orphan-drug-status-4139697?WT.mc_id=DN_News
Emricasan, also known as IDN 6556 and PF 03491390, is a first-in-class caspase inhibitor in clinical trials for the treatment of liver diseases. IDN-6556 has marked efficacy in models of liver disease after oral administration and thus, is an excellent candidate for the treatment of liver diseases characterized by excessive apoptosis. IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation.
WO 2002057298
WO 2000001666
Interleukin 1 (“IL-1”) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J.H. et al.. Immunology Today, 7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. Mosely, B.S. et al.. Proc. Nat. Acad. Sci.. 84:4572-4576 (1987); Lonnemann, G. et al. Eur. J. Immunol., 19:1531-1536 (1989).
IL-lβ is synthesized as a biologically inactive precursor, proIL-lβ. ProIL-lβ is cleaved by a cysteine protease called interleukin-lβ converting enzyme (“ICE”) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P.R. et al., J. Biol. Chem., 265:14526-14528 (1992); A.D. Howard et al, J. Immunol., 147:2964-2969 (1991).
ICE is a cysteine protease localized primarily in monocytes. In addition to promoting the pro -inflammatory and immunoregulatory properties of IL-lβ, ICE, and particularly its homologues, also appear to be involved in the regulation of cell death or apoptosis. Yuan, J. et al„ Cell, 75:641-652 (1993); Miura, M. et al. Cell, 75:653-660 (1993); Nett-Giordalisi, M.A. et al, J. Cell Biochem., 17B:117 (1993). In particular, ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer’s and Parkinson’s disease. Marx, J. and M. Baringa, Science, 259:760-762 (1993); Gagliardini, N et al„ Science, 263:826-828 (1994).
Thus, disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as the myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Such inhibitors are also useful for the repopulation of hematopoietic cells following chemo- and radiation therapy and for prolonging organ viability for use in transplantation.
ICE/ced-3 inhibitors represent a class of compounds useful for the control of the above-listed disease states. Peptide and peptidyl inhibitors of ICE have been described. However, such inhibitors have been typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J.J. and D.W. Norbeck, in Drug Discovery Technologies, C.R. Clark and W.H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. These undesirable properties have hampered their development into effective drugs.
Accordingly, the need exists for compounds that can effectively inhibit the action of the ICE/ced-3 family of proteases, for use as agents for preventing unwanted apoptosis, and for treating chronic and acute forms of IL-1 mediated diseases such as inflammatory, autoimmune or neurodegenerative diseases. The present invention satisfies this need and provides further related advantages.
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References |
1: McCall M, Toso C, Emamaullee J, Pawlick R, Edgar R, Davis J, Maciver A, Kin T, Arch R, Shapiro AM. The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice. Surgery. 2011 Jul;150(1):48-55. doi: 10.1016/j.surg.2011.02.023. Epub 2011 May 18. PubMed PMID: 21596412.
2: Pockros PJ, Schiff ER, Shiffman ML, McHutchison JG, Gish RG, Afdhal NH, Makhviladze M, Huyghe M, Hecht D, Oltersdorf T, Shapiro DA. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):324-9. PubMed PMID: 17654603.
3: Hoglen NC, Anselmo DM, Katori M, Kaldas M, Shen XD, Valentino KL, Lassman C, Busuttil RW, Kupiec-Weglinski JW, Farmer DG. A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia. Liver Transpl. 2007 Mar;13(3):361-6. PubMed PMID: 17318854.
4: Baskin-Bey ES, Washburn K, Feng S, Oltersdorf T, Shapiro D, Huyghe M, Burgart L, Garrity-Park M, van Vilsteren FG, Oliver LK, Rosen CB, Gores GJ. Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury. Am J Transplant. 2007 Jan;7(1):218-25. PubMed PMID: 17227570.
5: Poordad FF. IDN-6556 Idun Pharmaceuticals Inc. Curr Opin Investig Drugs. 2004 Nov;5(11):1198-204. Review. PubMed PMID: 15573871.
6: Hoglen NC, Chen LS, Fisher CD, Hirakawa BP, Groessl T, Contreras PC. Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-te trafluoro-phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor. J Pharmacol Exp Ther. 2004 May;309(2):634-40. Epub 2004 Jan 23. PubMed PMID: 14742742.
7: Valentino KL, Gutierrez M, Sanchez R, Winship MJ, Shapiro DA. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int J Clin Pharmacol Ther. 2003 Oct;41(10):441-9. PubMed PMID: 14703949.
8: Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther. 2004 Mar;308(3):1191-6. Epub 2003 Nov 14. PubMed PMID: 14617689.
9: Natori S, Higuchi H, Contreras P, Gores GJ. The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury. Liver Transpl. 2003 Mar;9(3):278-84. PubMed PMID: 12619025.
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http://www.google.com/patents/WO2002057298A2
EXAMPLE 126
(3 S)-3 – [N-(N’-(2-TERT-BUTYLPHENYL)OXAMYL) ALANINYL] AMINO-5-(2′,3′,5′,6′-TETRAFLUOROPHENOXY)-4-OXOPENTANOIC ACID
Part A: [(N-Benzyloxycarbonyl Alaninyl]Aspartic Acid, β-tert-Butyl Ester
To a suspension of aspartic acid β-tert-butyl ester (3.784 g, 20 mmol) in dimethylformamide (150 mL) at room temperture under nitrogen was added bis(trimethylsilyl)-trifluoroacetamide (10.6 mL, 40 mmol). After stirring at room temperature for 30 min, the resulting clear solution was treated with (N- benzyloxycarbonyl)alanine N-hydroxysuccinimide ester (6.406 g, 20 mmol). After stirring at room temperature for an additional 48 hrs, the mixture was treated with water (20 mL), stirred for 15 min and then partitioned between EtO Ac/water. The organic phase was washed with water, 5% KHSO and saturated NaCl solutions, dried over anhydrous Na2SO and evaporated to a dryness. The residue was dissolved in Et2O and extracted with saturated NaHCO3. The aqueous extract was acidified (pH 2.0) with concentrated HCl and extracted with EtOAc. The EtOAc extract was washed with saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to a give the title compound (6.463 g, 82%) as a white foam. TLC(EtOAc-hexane-AcOH; 70:30:2) Rf = 0.50.
Part B: (3S,4RS -3-rAlaninynAmino-5-(2′.3′.5′.6′-TetrafluorophenoxyV4- Hydroxypentanoic Acid tert-Butyl Ester
Starting with [(N-benzyloxycarbonyl)alanmyl]aspartic acid, β-tert-butyl ester and following the methods described in Example 28, Parts B through E gave the title compound as a colorless, viscous oil. TLC(EtOAc-hexane; 1:1) Rf = 0.06.
Part C: (3 S,4RS -3-[ -(Η’-f2-tert-Butylρhenyl)Oxamyl) AlaninyllAmino-5- (2′,3′,5′,6′-Tetrafluorophenoxy)-4-Hvdroxypentanoic Acid tert-Butyl
Ester
To a solution of N-(2-tert-butylphenyl)oxamic acid (0.041 g, 0.19 mmol, prepared from 2-tert-butylaniline by the method described in Example 1, Part A) in
CH C1 (6.0 mL) at 0°C under nitrogen was added hydroxybenzofriazole hydrate (0.030 g) followed by l-ethyl-3 -(3 ‘,3 ‘-dimethyl- l’-aminopropyl)- carbodiimide hydrochloride
(0.050 g, 0.26 mmol). After stirring at 0°C for 10 min, the mixture was treated with
(3S,4RS)-3-(alaninyl)amino-5-(2′,3′,5′,6′-tetrafluorophenoxy)-4-hydroxypentanoic acid tert-butyl ester (0.079 g, 0.19 mmol) and N-methylmorpholine (22 μL, 0.20 mmol).
After stirring at room temperature for 16 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO , saturated
NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to give the crude title compound (0.090 g, 77%) as a viscous oil. TLC(EtOAc-hexane;
1:1) Rf= 0.70.
Part D: r3S -3-rN-rN’-(2-tert-Butylphenyl Oxamyl)AlaninyllAmino-5- (2′,3′,5′.6′-Tetrafluorophenoxy)-4-Oxopentanoic Acid tert-Butyl Ester
To a solution of (3S,4RS)-3-[N-(N’-(2-tert-butylphenyl)oxamyl)alaninyl] amino-5-(2′,3′,5′36′-tetrafluorophenoxy)-4-hydroxypentanoic acid tert-butyl ester (0.0.092 g, ca 0.15 mmol) in CH2C1 (6.5 mL) at room temperature under nitrogen was added iodobenzene diacetate (0.188 g, 0.58 mmol) followed by a catalytic amount of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO, 0.0046 g, 0.03 mmol). After stirring at room temperature for 16 hrs, the mixture was partitioned between EtOAc- water. The organic phase was washed with saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na SO4 and evaporated to a dryness. The residue (0.096 g) was purified by preparative layer chromatography on silica gel eluting with EtOAc- hexane (3:7) to give the title compound (0.071 g, 77%) as a colorless glass. TLC(EtOAc-hexane; 2:3) Rf = 0.60.
Part E: (3S)-3-rN-(N’-r2-tert-Butylphenyl Oxamyl Alaninyl]Amino-5- (2′ ,3 ‘ , 5 ‘ ,6′ -Tetrafluorophenoxy)-4-Oxopentanoic Acid
To a solution of (3S)-3-[N-(N’-(2-tert- butylphenyl)oxamyl)alaninyl]amino-5-(2′,3′,5′,6′-tetrafluorophenoxy)-4-oxopentanoic acid, tert-butyl ester (0.071 g, 0.11 mmol) in CH2C12(2.5 mL)-anisole(0.05 mL) at room temperature under nitrogen was added trifluoroacetic acid (1.5 mL). The resulting clear solution was stirred at room temperature for 1 hr, evaporated to dryness and chased with toluene-CH2Cl2 (1:1). The residue (0.061 g) was purified by preparative layer chromatography on silica gel eluting with MeOH-CH2Cl2 (1:9) to give the title compound (0.044 g, 69%) as a colorless glass. MS(ES) for C26H27F4N3O7 (MW 569.51): positive 570(M+H); negative 568(M-H).
PRANLUKAST
Antiasthmatic.
| Launched – 1995 japan150821-03-7, C27 H23 N5 O4 . H2O, 499.5179 |
103177-37-3 anhydrous, 103180-28-5 (monosodium salt)
Ono-1078
Ono-RS-411
RS-411
SB-205312
Ono-1070 (monosodium salt)
N-[4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide hemihydrate
Ono (Originator)Schering-Plough (Licensee)
……….
J Med Chem 1988, 31(1): 84,
WO 2010002075,
Synth Commun 1997, 27(6): 1065,
WO 1994012492
Leukotriene antagonist.
Prepn: M. Toda et al., EP 173516; eidem, US 4780469 (1986, 1988 both to Ono);
H. Nakai et al., J. Med. Chem. 31, 84 (1988).
Pharmacology: T. Obata et al., Adv. Prostaglandin Thromboxane Leukotriene Res. 15, 229 (1985); idem et al., ibid. 17, 540 (1987).
Clinical evaluations in asthma: Y. Taniguchi et al., J. Allergy Clin. Immunol. 92, 507 (1993); H. Yamamoto et al. Am. J. Respir. Crit. Care Med. 150, 254 (1994).
AU 8546462; EP 0173516; JP 8650977; US 4780469; US 4939141
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. It antagonizes or reduces bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.‘s Singulair (montelukast). It is widely used in Japan.
Medications of this class, which go under a variety of names according to whether one looks at the American, British or European system of nomenclature, have as their primary function the antagonism of bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.
Medications of this group are normally used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists. There are several similar medications in the group; all appear to be equally effective.
Toda synthetic complete with 3 – nitro-2 – hydroxyphenyl ko one for raw materials, ni ko with oxalic ester Claisen condensation occurs, and then heated to reflux for cyclization to construct benzo pyran ring; dehydrated by an amide synthesized ring cyano group, the cyano compound and then with sodium azide tetrazole synthesis. The nitro group on the compound in 5% Pd / C catalyzed hydrogenation of amino acid reacted with the compound Pranlukast held. This method directly using 4 – (4 – phenyl-butoxy)-benzoic acid reaction. Synthetic route is as follows:
[0006]
[0007]
[0008] ② Robert Graham and routes are routes to I-bromo-butane as a raw material, were used as a palladium catalyst, ligand compound formylation carbonylation reactions and condensation of potassium tert-butoxide, closed dehydration under acidic conditions benzopyran ring method. Synthetic route is as follows:
[0009] Robert routes:
[0010]
[0011] Graham route:
[0012]
[0013] The two synthetic routes are not disclosed in the I-Bromo butane feedstock pathway.
[0014] ③ Masayohi 2_ cyano synthetic route to a benzopyran derivative and hydrogen sulfide gas in the base-catalyzed addition reaction of 2 – thiocarbamoylbenzothiazol and pyran derivatives, and then were reacted with anhydrous hydrazine group hydrazone, with sodium nitrite under acidic conditions nitrosation reaction occurs tetrazole ring. Synthetic route is as follows:
[0015]
[0016] The materials used are not mentioned route synthesis method, it is only reflected in the improvement of the synthesis of the tetrazole ring.
[0017] ④ Giles, Hideki and Hayler are tetrazole substituent on the increase, making it easier condensation reaction, but the synthesis of substituted on the nitrogen with tetrazole difficult, and ultimately elimination reaction of lithium used tetrahydro aluminum and other hazardous reagents, is not easy to Eri industrialization. Reaction scheme is as follows:
[0018]
[0019] ⑤ Lee NK with 4_ (4_ Phenylbutoxy) benzonitrile and 2_ hydroxy _3_ iodobenzene ko 1H_4_ thiazolyl ketone and ester ko _5_ acid, concentrated sulfuric acid catalyzed cyclization iodide copper and potassium phosphate removal under the action of hydrogen iodide get Pranlukast held. Reaction scheme is as follows:
[0021] does not mention the route starting 4 – (4 – phenyl-butoxy)-benzonitrile synthesis method, while two – hydroxy – 3 – Synthesis of iodobenzene ko difficult one.
The synthesis method comprises the following steps: a. 4 – Synthesis of chlorobutanol THF was added concentrated hydrochloric acid, feeding the mass ratio of I: I. 389 ~ 5. 556,45-80 ° C was stirred for 5-18h, cooled, extracted with methylene chloride, removal of the solvent, distillation under reduced pressure to give 4 – chlorobutanol; b. 4 – phenyl butanol take benzene, aluminum chloride mixture ,0-25 ° C solution of 4 – chlorobutanol, reaction 5 -10h then poured into ice-water, a liquid, in addition to homogeneous solution U, distillation under reduced pressure, and the resulting colorless transparent liquid that is, 4 – phenyl butanol; c. I-bromo-4 – phenyl butane synthesis of 4 – phenyl butanol 40% hydrobromic acid mixture, feeding the mass ratio of I: 2. 857 ~ 11. 428, heat refluxing, cooling, liquid separation, the organic solvent divided by distillation under reduced pressure to give I-bromo-4 – phenyl butane; d. Synthesis of methyl p-hydroxybenzoate take-hydroxybenzoic acid and methanol, concentrated sulfuric acid and refluxed for 5-20h spin methanol, poured into cold water to precipitate a white solid which was filtered and dried to give the hydroxy benzoate; e. 4 – (4 – phenyl-butoxy)-benzoic acid methyl ester _ take I-bromo-4 – phenyl butane, DMF, toluene, methyl p-hydroxybenzoate and potassium carbonate, a reflux 5 ~ 20h, cooling water, extracted with toluene, light yellow liquid rotary evaporation, recrystallization, and the resulting white solid, that is, 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester; f. 4 – (4 – phenyl-butoxy yl) – benzoic acid taken 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester, 15% NaOH solution was refluxed for I ~ 5h, cooled, acidified, filtered and dried to give 4 – (4 – phenylbutyrate oxy) – benzoic acid; g. sprinkle bromophenyl acetic acid ester molar ratio Preparation of I: I ~ I. 5: O. I ~ I of bromophenol, acetic anhydride, pyridine feeding, reflux 3 ~ 10h, distilled pyridine, acetic acid and excess acetic anhydride distilled under reduced pressure to give the acetic acid esters bromophenol; h. 5 – bromo-2 – Preparation of light taken acetophenone molar ratio of I: I ~ 5: I of acetic acid bromophenol esters, aluminum chloride, tetrachlorethylene for feeding, reflux O. 5 ~ 5. 5h, cooled, the reaction solution was poured into 5% hydrochloric acid and extracted with methylene chloride, the solvent evaporated under reduced pressure, to obtain a gray crystalline 5 – bromo-2 – Light acetophenone; i. 5 – bromo-3 – nitro-2 – Preparation of light acetophenone take 5 – bromo-2 – Light acetophenone, carbon tetrachloride, 50 ~ 90 ° C is added dropwise nitric acid, reflux I ~ 4h, cooled, filtered, and the resulting yellow solid which is 5 – bromo-3 – nitro-2 – hydroxyacetophenone; j. 3 – amino-2 – Light benzene ethanone Preparation of 5 – bromo-3 – nitro-2 – hydroxyacetophenone, 5% Pd / C, methylene chloride, methanol, concentrated hydrochloric acid, water, hydrogenation; the end of the reaction mixture was filtered, the filtrate was The solvent was removed, neutralized with sodium bicarbonate, and the resulting yellow solid ginger i.e., 3 – amino-2 – hydroxyacetophenone; k. 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 _ light base Preparation of acetophenone 4 – (4 – phenyl-butoxy)-benzoic acid, toluene, DMF, 45 ~ 105 ° C was added dropwise SOCl2, 30min the reaction liquid droplets to the 3 – amino-2 – hydroxyphenyl toluene solution of ethyl ketone, the reaction 3 ~ 10h, cooled, neutralized with dilute hydrochloric acid, extracted with toluene, rotary evaporation, and the resulting pale yellow crystals is 3 – [4 – (4_ phenylbutoxy) benzamido] 2_-hydroxyacetophenone; I. 2 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol synthetic sodium, THF, 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – hydroxyacetophenone, diethyl oxalate 4 ~ IOh After stirring the reaction was poured into dilute hydrochloric acid to precipitate the yellow solid which was filtered, and the resulting product, i.e. 2 – [4 – (4_ phenylbutoxy) benzamido] _6_ [1,3 – dioxo-3 – ethoxy propyl intended yl] phenyl discretion ·; m. 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran take 2 – [4 – (4 – phenyl-butoxy yl) benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol, THF, force mouth heat, the addition of concentrated hydrochloric acid, refluxed for 8 ~ 15h, cooled, filtered, and the resulting white solid, that is, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran; η. 4 – oxo-8 – [ 4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran synthesis take four – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – ethoxycarbonyl-4Η-benzopyran was dissolved in DMF, and leads to dry ammonia gas, the reaction solution changed from yellow to red, the reaction solution was poured into cold water, adjusted to acidic, and filtered to give the product 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran; P. 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4Η-benzopyran take DMF, S0C12, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoic amido] _2_ aminocarbonyl-4H-benzopyran, O ~ 15 ° C under stirring for 2 ~ IOh poured into cold water, filtered, and the resulting white solid that is, 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4H-benzopyran; q. Synthesis of pranlukast take four – oxo-8 – [4 – (4 – phenyl-butoxy) benzoyl amino]-2_ cyano-4H-benzopyran, ammonium chloride, sodium azide, DMF, heating I ~ 8h then poured into ice-water, dilute hydrochloric acid, filtered, and the resulting white solid that the final product Pranlukast.
The reaction of ethyl 8-nitro-4-oxo-1-benzopyran-2-carboxylate (I) with ammonia in methanol gives the corresponding amide (II), which is dehydrated with POCl3 yielding 2-cyano-8-nitro-1-benzopyran-4-one (III). The cyclization of (III) with sodium azide by means of pyridinium chloride in hot DMF affords 8-nitro-2-(tetrazol-5-yl)-1-benzopyran-4-one (IV), which is hydrogenated with H2 over Pd/C in methanol – HCl giving 8-amino-2-(tetrazol-5-yl)-1-benzopyran-4-one (V). Finally, this compound is condensed with 4-(4-phenylbutoxy)benzoic acid (VI) by means of oxalyl chloride in dichloromethane-pyridine
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GW Pharmaceuticals obtains Swiss approval for Sativex
GW Pharmaceuticals has received full marketing authorisation from the Swiss authorities for its prescription medicine Sativex to treat moderate to severe spasticity in multiple sclerosis (MS) patients who have not responded to other medications.
Nabiximols (USAN,trade name Sativex) is a patented cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis (MS) patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.Nabiximols is distinct from all other pharmaceutically produced cannabinoids currently available because it is a mixture of compounds derived fromCannabis plants, rather than a mono-molecular synthetic product. The drug is a pharmaceutical product standardised in composition, formulation, and dose, although it is still effectively a tincture of the cannabis plant. Its principal active cannabinoid components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). The product is formulated as an oromucosal spray which is administered by spraying into the mouth. Each spray delivers a near 1:1 ratio of CBD to THC, with a fixed dose of 2.7 mg THC and 2.5 mg CBD. Nabiximols is also being developed in Phase III trials as a potential treatment to alleviate pain due to cancer. It has also been researched in various models of peripheral and central neuropathic pain.
In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GW’s cannabis-based medicinal extract product, to be marketed under the brand name Sativex. “Bayer has obtained exclusive rights to market Sativex in the UK. In addition, Bayer has the option for a limited period of time to negotiate the marketing rights in other countries in European Union and selected other countries around the world.”
In April 2011, GW licensed to Novartis the rights to commercialise nabiximols in Asia (excluding China and Japan), Africa and the Middle East (excluding Israel)
Of the two preliminary Phase III studies investigating the treatment of MS patients, one showed a reduction of spasticity of 1.2 points on the 0–10 points rating scale (versus 0.6 points under placebo), the other showed a reduction of 1.0 versus 0.8 points. Only the first study reached statistical significance. The Phase III approval study consisted of a run-in phase where the response of individuals to the drug was determined. The responders (42% of patients) showed a significant effect in the second, placebo controlled, phase of the trial.[10] A 2009 meta-analysis of six studies found large variations of effectiveness, with a trend towards a reduction of spasticity
Sativex® has now been launched in 11 countries (including the UK, Spain, Italy and Germany) with approvals in an additional 11 countries
