Sep 212014
 

 

GA-1

 

 

Continuous flow chemistry: a discovery tool for new chemical reactivity patterns

Jan Hartwig,a   Jan B. Metternich,b   Nikzad Nikbin,b  Andreas Kirschninga and   Steven V. Ley*b  

*Corresponding authors
aInstitut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany
bInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, UK
Org. Biomol. Chem., 2014,12, 3611-3615

DOI: 10.1039/C4OB00662C

Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.

 

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Sep 162014
 

 

 

An automated flow-based synthesis of imatinib: the API of gleevec 

M.D. Hopkin, I.R. Baxendale, S.V. Ley, J.C.S. Chem. Commun.2010, 46, 2450-2452.

http://pubs.rsc.org/en/Content/ArticleLanding/2010/CC/c001550d#!divAbstract

A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation.

An in-linesolvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.

Graphical abstract: A flow-based synthesis of Imatinib: the API of Gleevec

 

see supp info

http://www.rsc.org/suppdata/cc/c0/c001550d/c001550d.pdf

 

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Sep 152014
 
20140911lnp2-Figure2

INSULIN LITE
Researchers identified a protein (sphere representation) that binds to and activates the insulin receptor (ribbon structure), though it’s less potent at turning on the receptor than insulin itself.
Credit: J. Agric. Food Chem

Bitter Fruit Bears Protein That Can Act Like Insulin

Diabetes: Researchers discover a protein in bitter melon that binds to and activates the insulin receptor, offering a potential path to new diabetes treatments
Practitioners of traditional medicine have long turned to a knobby green fruit known as bitter melon (Momordica charantia) to treat ailments such as diabetes. Researchers dug into the melon and discovered a protein that binds to and activates the insulin receptor, improving glucose metabolism in diabetic mice (J. Agric. Food Chem. 2014, DOI: 10.1021/jf5002099). The protein may be a starting point for the development of novel therapies for diabetes, the scientists say.
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20140911lnp2-bittermelon

THERAPEUTIC FRUIT?
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Sep 142014
 

The flow synthesis of heterocycles for natural products and medicinal chemistry applications

http://link.springer.com/article/10.1007%2Fs11030-010-9282-1

M. Baumann, I.R. Baxendale, S.V. Ley, Mol. Div. 2011, 15, 613-630.

This article represents an overview of recent research from the Innovative Technology Centre in the field of flow chemistry which was presented at the FROST2 meeting in Budapest in October 2009. After a short introduction of this rapidly expanding field, we discuss some of our results with a main focus on the synthesis of heterocyclic compounds which we use in various natural product and medicinal chemistry programmes.

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Sep 142014
 

 

Untitled-1

 

Synthesis of (-)-hennoxazole A: integrating batch and flow chemistry methods

A. Fernández, Z.G. Levine, M. Baumann, S. Sulzer-Mossé, C. Sparr, S. Schläger, A. Metzger, I.R. Baxendale, S.V. Ley,Synlett, 2013, 24, 514-518.

A new total synthesis of (–)-hennoxazole A is reported. The synthetic approach is based on the preparation of three similarly sized fragments resulting in a fast and convergent assembly of the natural product. The three key reactions of the synthesis include a highly stereoselective 1,5-anti aldol coupling, a gold-catalyzed alkoxycyclization reaction, and a stereocontrolled diene cross-meta­thesis. The synthesis involves integrated batch and flow chemistry methods leading to the natural product in 16 steps longest linear ­sequence and 2.8% overall yield.

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https://www.thieme-connect.de/DOI/DOI?10.1055/s-0032-1318109

 

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Sep 142014
 

 

op-2013-001548_0014

 

 

Continuous flow-processing of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow synthesis of (E/Z)-tamoxifen

P.R.D. Murray, D.L. Browne, J.C. Pastre, C. Butters, D. Guthrie, S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1192-1208.

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

 

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http://pubs.acs.org/doi/abs/10.1021/op4001548

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Sep 102014
 

Paricalcitol3Dan.gif

thumbnail image: New Route to Paricalcitol

Synthesis offers potential routes to analogues of vitamin-D-based drug

Paricalcitol, an A-ring-modified 19-nor analogue of 1α,25-dihydroxyvitamin D2, is currently used for the treatment and prevention of secondary hyperparathyroidism associated with chronic renal failure.

Read more

http://www.chemistryviews.org/details/ezine/6508291/New_Route_to_Paricalcitol.html

 

Paricalcitol.svg

Zemplar; 131918-61-1; 19-Nor-1alpha,25-dihydroxyvitamin D2; Compound 49510; Paracalcin; Zemplar (TN); 19-Nor-1,25-(OH)2D2; CHEBI:7931
Molecular Formula: C27H44O3   Molecular Weight: 416.63646
Abbott (Originator), Tetrionics (Bulk Supplier)
launched 1998
(1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5S)-6-hydroxy-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol
For treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4

Paricalcitol (chemically it is 19-nor-1,25-(OH)2-vitamin D2. Marketed by Abbott Laboratories under the trade name Zemplar) is a drugused for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated withchronic renal failure. It is an analog of 1,25-dihydroxyergocalciferol, the active form of vitamin D2 (Ergocalciferol).

Paricalcitol is a synthetic vitamin D analog. Paricalcitol has been used to reduce parathyroid hormone levels. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.

Chemical structure for paricalcitol

Medical uses

Its primary use in medicine is in the treatment of secondary hyperparathyroidism associated with chronic kidney disease.[2] In three placebo-controlled studies, chronic renal failure patients treated with paricalcitol achieved a mean parathyroid hormone (PTH) reduction of 30% in six weeks. Additionally there was no difference in incidence of hypercalcemia or hyperphosphatemia when compared to placebo.[3] A double-blind randomised study with 263 dialysis patients showed a significant advantage over calcitriol (also known as activated vitamin D3; a similar molecule to 1,25-dihydroxyergocalciferol, adding a methyl group on C24 and lacking a double-bond in the C22 position). After 18 weeks, all patients in the paricalcitol group had reached the target parathormone level of 100 to 300 pg/ml, versus none in the calcitriol group.[4] Combination therapy with paricalcitol and trandolapril has been found to reduce fibrosis inobstructive uropathy.[5] Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in 227 patients with chronic kidney disease.[6]

Patents

Country Patent Number Approved Expires (estimated)
United States 6136799 1998-10-08 2018-10-08
United States 5246925 1995-04-17 2012-04-17

Mechanism of action

3D structure of paricalcitol

Like 1,25-dihydroxyergocalciferol, paricalcitol acts as an agonist for the vitamin D receptor and thus lowers the bloodparathyroid hormone level.[1]

Pharmacokinetics

Within two hours after administering paricalcitol intravenous doses ranging from 0.04 to 0.24 µg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with multiple dosing.[9]

 

vitamin D is a fat-soluble vitamin. It is found in food, but also can be formed in the body after exposure to ultraviolet rays. Vitamin D is known to exist in several chemical forms, each with a different activity. Some forms are relatively inactive in the body, and have limited ability to function as a vitamin. The liver and kidney help convert vitamin D to its active hormone form. The major biologic function of vitamin D is to maintain normal blood levels of calcium and phosphorus. Vitamin D aids in the absorption of calcium, helping to form and maintain healthy bones.

The 19-nor vitamin D analogue, Paricalcitol (I), is characterized by the following formula:

Figure US20070149489A1-20070628-C00001

 

In the synthesis of vitamin D analogues, a few approaches to obtain a desired active compound have been outlined previously. One of the methods is the Wittig-Homer attachment of a 19-nor A-ring phosphine oxide to a key intermediate bicyclic-ketone of the Windaus-Grundmann type, to obtain the desired Paricalcitol, as is shown for example in U.S. Pat. Nos. 5,281,731 and 5,086,191 of DeLuca.

The synthesis of Paricalcitol requires many synthetic steps which produce undesired by-products. Therefore, the final product may be contaminated not only with a by-product derived from the last synthetic step of the process but also with compounds that were formed in previous steps. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.

U.S. Pat. Nos. 5,281,731 and 5,086,191 of DeLuca disclose a purification process of Paricalcitol by using a HPLC preparative method.

As the unwanted products have almost the same structure as the final product, it may difficult to get a sufficiently pure drug substance, vitamin D analogue, using this route to purify the drug substance. Moreover, the high polarity of Paricalcitol makes it very difficult to purify by HPLC and to recover the solid product. Furthermore, HPLC preparative methods are generally not applicable for use on industrial scale. There remains a need in the art to provide a method of preparing the vitamin D analogue Paricalcitol in a sufficiently pure form which is applicable for use on an industrial scale.

 

Paricalcitol (chemical name: 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(Z),22(E)-triene; Synonyms: 19-nor-1,25-dihydroxyvitamin D2, Paracalcin) is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Paricalcitol inhibits the secretion of parathyroids hormone (PTH) through binding to the vitamin D receptor (D. M. Robinson, L. J. Scott, Drugs, 2005, 65 (4), 559-576) and it is indicated for the prevention and treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD).

Paricalcitol is marketed under the name Zemplar®, which is available as a sterile, clear, colorless, aqueous solution for intravenous injection (each mL contains 2 microgram (2 μg) or 5 μg paricalcitol as active ingredient) or as soft gelatin capsules for oral administration containing 1 μg, 2 μg or 4 μg paricalcitol.

The molecular formula of paricalcitol is C27H44O3 which corresponds to a molecular weight of 416.65. It is a white, crystalline powder and has the following structural formula:

 

 

Historically, nor-vitamin D compounds were described in 1990 as a new class of vitamin D analogs wherein the exocyclic methylene group C(19) in ring A has been removed and replaced by two hydrogen atoms (see e.g. WO 90/10620). So far, two different routes have been discovered for the synthesis of such 19-nor-vitamin analogs which specifically may be used for the preparation of paricalcitol.

The first synthesis of paricalcitol is disclosed in WO 90/10620 (additional patents from patent family: EP patent no. 0 387 077, U.S. Pat. No. 5,237,110, U.S. Pat. No. 5,342,975, U.S. Pat. No. 5,587,497, U.S. Pat. No. 5,710,294 and U.S. Pat. No. 5,880,113) and generally described in Drugs of the Future, 1998, 23, 602-606.

Example 3 of WO 90/10620 provides the preparation of 1α,25-dihydroxy-19-nor-vitamin D2 (Scheme 1) by using experimental conditions analogous to the preparation of 1α,25-dihydroxy-19-nor-vitamin D3. According to this description the starting material 25-hydroxyvitamin D2 is first converted to 1α,25-dihydroxy-3,5-cyclovitamin D2 (a2) using the procedures published by DeLuca et al. in U.S. Pat. No. 4,195,027 and Paaren et al. published in J. Org. Chem., 1980, 45, 3252. Acetylation of compound a2 followed by dihydroxylation of the exocyclic methylene group using osmium tetroxide in pyridine gives the 10,19-dihydroxy compound a4 which is converted with sodium metaperiodate (diol cleavage) to the 10-oxo-intermediate a5. Reduction of the 10-oxo group in a5 is carried out by treatment with sodium borohydride in a mixture of ethanol and water giving the corresponding 10-hydroxy derivative a6. Mesylation of the 10-hydroxy group in a6 (→a7) followed by reduction with lithium aluminium hydride in THF gives the 10-deoxy intermediate a8 wherein the 1-OAcyl group was simultaneously cleaved during the reduction step. Solvolysis (cycloreversion) of a8 by treatment with hot (55° C.) acetic acid results in the formation of two monoacetates (a9 and a10) which are separated and purified by using HPLC. Finally both monoacetates are saponified with aqueous potassium hydroxide in methanol yielding paricalcitol which is purified by HPLC.

The preparation of paricalcitol according to the method provided in WO 90/10620 has several drawbacks:

    • (1) the starting material 25-hydroxyvitamin D2 is one of the major metabolites of vitamin D2 and not readily available in larger amounts. Additional efforts have to be made in order to synthesize the starting material in sufficient amounts resulting in a protractive and unattractive total synthesis of paricalcitol. Examples for the preparation of 25-hydroxyvitamin D2 are described e.g. in U.S. Pat. No. 4,448,721; WO 91/12240; Tetrahedron Letters, 1984, 25, 3347-3350; J. Org. Chem., 1984, 49, 2148-2151 and J. Org. Chem., 1986, 51, 1264-1269;
    • (2) the use of highly toxic osmium tetroxide which requires special precaution for its handling;
    • (3) use of HPLC for separation of isomers and purification of the final compound. As teached in WO 2007/011951 paricalcitol is difficult to purify by HPLC and as a preparative method HPLC is generally not applicable for use on industrial scale;
    • (4) the yields for the preparation of paricalcitol are not described in WO 90/10620. Generally, the provided yields for the preparation of the analogue compound 1α,25-dihydroxy-19-nor-vitamin D3 are very low especially for the corresponding steps 7 to 11 (yield starting from 1α,25-dihydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D3 1-acetate which is the vitamin D3 analogue to a5 in Scheme1: step 7: 63.4%, steps 8-10: 10.7%, step 11: 51.7%; overall yield starting with step 7: 3.5%).

 

 

Another strategy for synthesizing 19-nor vitamin D compounds is disclosed in EP 0 516 410 (and corresponding U.S. Pat. No. 5,281,731, U.S. Pat. No. 5,391,755, U.S. Pat. No. 5,486,636, U.S. Pat. No. 5,581,006, U.S. Pat. No. 5,597,932 and U.S. Pat. No. 5,616,759). The concept is based on condensing of a ring-A unit, as represented by structure b1 (Scheme 2), with a bicyclic ketone of the Windaus-Grundmann type, structure b2, to obtain 19-nor-vitamin D compound (b3).

 

 

Specific methods for synthesizing compounds of formula b1 are shown in Schemes 3, 4 and 5. According to Scheme 3, the route starts with the commercially available (1R,3R,4R,5R)(−)quinic acid (b4). Esterification of b4 with methanol followed by protection of the l- and 3-hydroxygroup using tert.-butyldimethylsilyl chloride (TBDMSCl) gives compound b5. Reduction of the ethyl ester in b5 yields b6 which is subjected to a diol cleavage giving compound b7. The 4-hydroxy group is protected as trimethylsilylether resulting in the formation of b8 which is further converted in a Peterson reaction with ethyl (trimethylsilyl)acetate before being deprotected with dilute acetic acid in tetrahydrofurane (THF). The resulting compound b9 is treated with 1,1-thiocarbonyldiimidazole to obtain b10. Subsequent reaction with tributyltin hydride in the presence of a radical initiator (AIBN) gives b11. Compound b11 is then reduced with DIBAH to the allylalcohol b12 which is then reacted with NCS and dimethyl sulfide giving the allylchloride b13. Finally the ring A synthon b14 is prepared by treatment of the allychloride b13 with lithium diphenylphosphide followed by oxidation with hydrogen peroxide.

In an alternative method for synthesizing the ring A unit (Scheme 3), the intermediate b5 can be also subjected to radical deoxygenation using analogues conditions as previously described, resulting in the formation of b16. Reduction of the ester (→b17), followed by diol cleavage (→b18) and Peterson reaction gives intermediate b11 which can be further processed to b14 as outlined in Scheme 3.

Another modification for the preparation is shown in Scheme 5. As described, b7 can be also subjected to the radical deoxygenation yielding intermediate b18 which can be further processed to b14 as depicted in Schemes 3 and 4.

 

 

 

 

 

 

In EP 0 516 411 (and its counterpart, U.S. Pat. No. 5,086,191) is disclosed the preparation of intermediates useful for the synthesis of 19-nor vitamin D compounds (Scheme 6). The key step is the condensation of compounds c1 which can be prepared in an analogous manner as previously described for e.g. b14 (Scheme 3) with compounds c2, resulting in compounds of formula c3.

 

 

EP 0 516 411 discloses that Grignard coupling of hydroxy-protected 3-hydroxy-3-methylbutylmagnesium bromide with compound c5 (Scheme 7) can give hydroxy-protected 1α,25-dihydroxy-19-nor vitamin D3 or coupling of the corresponding 22-aldehyde c3 (X1=X2=TBDMS, R1=—CHO) with 2,3-dimethylbutyl phenylsulphone can give after desulfonylation, 1α-hydroxy-19-norvitamin d2 in hydroxy-protected form.

 

 

An additional method for preparation of 1α-hydroxy-19-nor-vitamin D compounds is provided in EP 0 582 481 (and corresponding U.S. Pat. No. 5,430,196, U.S. Pat. No. 5,488,183, U.S. Pat. No. 5,525,745, U.S. Pat. No. 5,599,958, U.S. Pat. No. 5,616,744 and U.S. Pat. No. 5,856,536) (Scheme 8). Similar to the strategy as described above and shown in schemes 3 to 7, the basis for preparing 1α-hydroxy-19-nor-vitamin D compounds is an independent synthesis of ring A synthon and ring C/D synthon which are finally coupled resulting in vitamin analogs.

Thus the synthesis of 1α-hydroxy-19-nor-vitamin D compounds comprises the coupling of either the ketone d1 with the acetylenic derivatives d2 or ketone d4 with acetylenic derivatives d3, yielding compounds of formula d5. Partial reduction of the triple bond giving d6 followed by reduction using low-valent titanium reducing agents results in the formation of 7,8-cis and 7,8-trans-double bond isomers (d7). Compounds of formula d7 can be also obtained directly from d5 by reaction of d5 with a metal hydride/titanium reducing agent. The isomeric mixture of compounds of formula d7 may be separated by chromatography to obtain separately the 7,8-trans-isomer. The 7,8-cis-isomer of structure d7 can be isomerized to yield the corresponding 7,8-trans-isomer. Finally any protecting groups, if present, can be then removed to obtain 1α-hydroxy-19-nor-vitamin D compounds.

 

 

The main disadvantage of the strategies as shown in Schemes 3 to 8 is the fact that ring A as well as ring C/D of the vitamin D derivative has to be separately synthesized before coupling them to compounds like 1α-hydroxy-nor-vitamin D or a protected precursor thereof. According to literature procedure, the ring fragment C/D can be prepared from vitamin D2 by ozonolysis (see e.g. J. C. Hanekamp et al., Tetrahedron, 1992, 48, 9283-9294) from which the ring A is cleaved (and disposed). This fragment has then to be separately synthesized e.g. by using other sources or starting materials like quinic acid in up to 10 steps or more. Therefore such strategies for the total synthesis of 1α-hydroxy-nor-vitamin D compounds become protractive and unattractive for large scale and according to the procedures provided in these patents, the final compounds are obtained only in amounts of <10 mg and in most cases even <1 mg.

Paricalcitol is an active Vitamin D Analog. Paricalcitol is used for the treatment and prevention of secondary hyperparathyroidism associated with chronic kidney disease.

It has been shown to reduce parathyroid hormone levels by inhibiting its synthesis and secretion.

…………………………….

 

 

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The 25-hydroxyvitamin D2 (I) is converted into the cyclovitamin D2 acetate (II) according to known methods. The dihydroxylation of the methylene group of (II) with OsO4 in pyridine gives vicinal diol (III), which is oxidized with NaIO4 yielding the ketonic cyclovitamin (IV). The reduction of the ketonic group of (IV) with NaBH4 in ethanol/water affords the corresponding hydroxy derivative (V), which is treated with mesyl chloride and triethylamine to give the mesylate (VI). The reduction of (VI) with LiAlH4 in THF yields the 19-nor-cyclovitamin D (VII), which is treated with hot acetic acid to afford both monoacetates (VIII) and (IX), separated by HPLC. Finally, both monoacetates (VIII) and (IX) are hydrolyzed with KOH in methanol.

…………………………

EXAMPLEShttp://www.google.com/patents/US20070149489

 

HPLC method:
Column: Hypersyl Gold (250 × 4.6 5 μm)
Mobile phase: (A) water (95%)
(B) acetonitrile (5%)
Gradient: From 0 to 10 min (A) isocraticaly
From 10 to 30 min (B) increases from 0 to 55%
From 30 to 40 min (A) isocraticaly
From 30 to 40 min (B) increases from 55 to 100%
Detection: 252 nm
Flow: 2 mL/min
Detection limit: 0.02%

 

Example 1 Crystallization of Paricalcitol from Acetone

500 mg of Paricalcitol were dissolved in 75 ml of acetone in a sonicator at 28° C. over a period of 15 minutes. The clear solution was filtered through glass wool into another flask, and the solution was then concentrated by evaporation, until the volume was 57.5 ml acetone (control by weight). The solution was cooled to −18° C., and the temperature was maintained at −18° C. for 20 hours. The crystals were filtered and washed with 20 ml of cold (−18° C.) acetone, then dried at high vacuum in an oven at 28° C. for 22 hours to obtain a yield of 390 mg (purity of 98.54%).

 

………………………………………………………….

http://www.google.com/patents/US20110184199

 

FIG. 3 is a flow chart showing a detailed example for the synthesis of paricalcitol according to route A1.

FIG. 4 is a flow chart showing the general synthesis of paricalcitol according to route A1.

FIG. 5 is a flow chart showing a detailed example for the synthesis of paricalcitol according to route B1.

FIG. 6 is a flow chart showing the general synthesis of paricalcitol according to route B1.

FIG. 7 is a flow chart showing the general synthesis of paricalcitol using Julia olefination for installation of the side chain according to route B2.

FIG. 8 is a flow chart showing a detailed example for the synthesis of paricalcitol according to route C1.

FIG. 9 is a flow chart showing the general synthesis of paricalcitol according to route C1.

FIG. 10 is a flow chart showing the general synthesis of paricalcitol using Julia olefination for installation of the side chain according to route C2.

 

Example B11Process Step 12Deprotection of IM-A10b(I) and IM-A10b(II) to Paricalcitol

 

 

A mixture consisting of IM-A10b(I) and IM-A10b(II) (41 mg, HPLC purity 54.8%) was dissolved in 1M TBAF in THF (1.5 mL) at temperature 20-25° C. and stirred for 2 h. Then, the reaction mixture was diluted with MeOH (1.5 mL) and 2M aqueous NaOH (0.3 mL) was added. The mixture was stirred for another 2 h and monitored by TLC. Then AcOEt (20 mL) and saturated aqueous NaHCO3 solution (20 mL) were added and the phases separated. The organic phase was washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The product was purified by column chromatography on silica gel (15 g), with mobile phase cyclohexane/AcOEt (100:0 to 92:8).

Yield 11 mg (81%).

In an additional purification, the product (Paricalcitol, 11 mg) was dissolved in acetone (1 mL) at 35-40° C. The solution was filtered and then cooled to −18° C. to initiate crystallization. The obtained slurry was stirred for 15 min at room temperature (20-25° C.) and again cooled to −18° C. for 3.5 h. The solid material was filtered off, washed with cold (−18° C.) acetone (0.25 mL) and dried in vacuo (6 mbar, 40° C.).

Yield of paricalcitol: 4 mg (36%, HPLC purity 98.3%)

 

Example C7Process Step 12Hydrolysis of IM-A11a to Paricalcitol

 

 

To a solution of IM-A11a(I) and IM-A11a(II) (5.24 g, HPLC-purity 94.2%) in EtOH (80 mL) was added at room temperature (20-25° C.) 2M aqueous NaOH solution (8 mL). The reaction mixture was stirred for 1 h 20 min (TLC monitoring), then EtOAc (8 mL) was added and the mixture was concentrated under reduced pressure to a volume of 40 mL whereupon the crystallization started. Water (50 mL) was added to the suspension and after stirring for 75 min at room temperature the solid was isolated by filtration (pH of the mother liquor measured 8-9). The wet product was slurried in EtOH/H2O (24 g, 1:1) at room temperature, filtered, washed with EtOH/H2O (5 mL, 1:1) and dried (40° C., 10 mbar).

Yield of paricalcitol: 4.26 g (89.5%, HPLC-purity 97.7%).

 

…………………………………………………..

 

US5854390 * Feb 6, 1996 Dec 29, 1998 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Chromatographic purification of vancomycin hydrochloride by use of preparative HPLC
US6448421 * Jun 16, 1997 Sep 10, 2002 Chugai Seiyaku Kabushiki Kaisha Purifying a crude product derivative through a reverse phase chromatography and then crystallizing from an organic solvent; oxy gonane and indene, cyclohexyl derivatives
US20070149489 * Jul 18, 2006 Jun 28, 2007 Anchel Schwartz Preparation of paricalcitol
US7795459 * Apr 28, 2009 Sep 14, 2010 Alphora Research Inc. Paricalcitol purification
US20110137058 * Feb 15, 2011 Jun 9, 2011 Formosa Laboratories, Inc. Preparation of paricalcitol
DE102009013609A1 Mar 17, 2009 Nov 5, 2009 Formosa Laboratories, Inc. Herstellung von Paricalcitol

References

  1.  “Zemplar (paricalcitol) dosing, indications, interactions, adverse effects, and more”Medscape Reference. WebMD. Retrieved 26 January 2014.
  2.  Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3edit
  3.  “Zemplar: Drug Information”
  4.  Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2005/2006 (in German).
  5.  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.2009.346PMID 19759524.
  6.  Thadhani, R; Appelbaum, E; Pritchett, Y; Chang, Y; Wenger, J; Tamez, H; Bhan, I; Agarwal, R et al. (2012). “Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease – The PRIMO Randomized Controlled Trial”. JAMA 307 (7): 674–684. doi:10.1001/jama.2012.120PMID 22337679.
  7.  “PARICALCITOL capsule, liquid filled [Teva Pharmaceuticals USA Inc]“ (PDF). DailyMed. Teva Pharmaceuticals USA Inc. September 2013. Retrieved 26 January 2014.
  8.  “Zemplar Soft Capsules 1 mcg – Summary of Product Characteristics”electronic Medicines Compendium. AbbVie Limited. 15 April 2013. Retrieved 26 January 2014.
  9.  Rxlist: Zemplar
  10. Anchel Schwartz, Alexei Ploutno, Koby Wolfman, “Preparation of paricalcitol.” U.S. Patent US20070149489, issued June 28, 2007.US20070149489 
Systematic (IUPAC) name
(1R,3R,7E,17β)-17-[(1R,2E,4S)-5-hydroxy-1,4,5-trimethylhex-2-en-1-yl]-9,10-secoestra-5,7-diene-1,3-diol
Clinical data
Trade names Zemplar
AHFS/Drugs.com monograph
MedlinePlus a682335
Pregnancy cat.
Legal status
Routes Oral, Intravenous
Pharmacokinetic data
Bioavailability 72%[1]
Protein binding 99.8%[1]
Metabolism Hepatic[1]
Half-life 14-20 hours[1]
Excretion Faeces (74%), urine (16%)[1]
Identifiers
CAS number 131918-61-1 Yes
ATC code H05BX02
PubChem CID 5281104
IUPHAR ligand 2791
DrugBank DB00910
ChemSpider 4444552 Yes
UNII 6702D36OG5 Yes
 
ChEMBL CHEMBL1200622 Yes
Synonyms (1R,3S)-5-[2-[(1R,3aR,7aS)-1-[(2R,5S)-6-hydroxy-5,6-dimethyl-3E-hepten-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-cyclohexane-1,3-diol
Chemical data
Formula C27H44O3 
Mol. mass 416.636 g/mol

more………….

 

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Sep 092014
 

20140813lnp1-dirhodium

ACS Meeting News: New class of inorganic reagents may provide less toxic and more versatile alternatives to popular platinum-based drug

More than half of all cancer patients receive a platinum-based drug such as cisplatin as part of their chemotherapy. But the compounds have dangerous side effects and many tumors develop resistance to the drugs, prompting chemists to seek out less toxic and more selective alternatives.

In one of the latest examples, Amanda David, a graduate student in chemistry professor Kim R. Dunbar’s group at Texas A&M University, described a family of promising dirhodium complexes during a symposium on bioinorganic chemistry sponsored by the Division of Inorganic Chemistry at the American Chemical Society meeting in San Francisco this week.

The Texas A&M team developed the dirhodium complexes with Claudia Turro at Ohio State University. In cell culture experiments, the compounds exhibited lower toxicities and were as effective or better than cisplatin against lung cancer cells

read at

http://cen.acs.org/articles/92/web/2014/08/Rhodium-Expands-Collection-Metal-Based.html

 

(J. Am. Chem. Soc. 2014, DOI: 10.1021/ja503774m).http://pubs.acs.org/doi/full/10.1021/ja503774m

Abstract Image

The new dirhodium compound [Rh2(μ-O2CCH3)21-O2CCH3)(phenbodipy)(H2O)3][O2CCH3] (1), which incorporates a bodipy fluorescent tag, was prepared and studied by confocal fluorescence microscopy in human lung adenocarcinoma (A549) cells. It was determined that 1 localizes mainly in lysosomes and mitochondria with no apparent nuclear localization in the 1–100 μM range. These results support the conclusion that cellular organelles rather than the nucleus can be targeted by modification of the ligands bound to the Rh24+ core. This is the first study of a fluorophore-labeled metal–metal bonded compound, work that opens up new venues for the study of intracellular distribution of dinuclear transition metal anticancer complexes.

Syn of cisplatin

File:Cisplatin-stereo.svg

The synthesis of cisplatin is a classic in inorganic chemistry. Starting from potassium tetrachloroplatinate(II), K2[PtCl4], the first NH3 ligand is added to any of the four equivalent positions, but the second NH3 could be added cis or trans to the bound amine ligand. Because Cl has a larger trans effect than NH3, the second amine preferentially substitutes trans to a chloride ligand, and therefore cis to the original amine. The trans effect of the halides follows the order I->Br->Cl-, therefore the synthesis is conducted using [PtI4]2− to ensure high yield and purity of the cis isomer, followed by conversion of the PtI2(NH3)2 into PtCl2(NH3)2, as first described by Dhara.[2][3]

Synthesis of cisplatin

2 Dhara SC (1970). Indian Journal of Chemistry 8: 193–134.

3 Alderden RA, Hall MD, Hambley TW (2006). “The Discovery and Development of Cisplatin”. J. Chem. Ed. 83 (5): 728–724. doi:10.1021/ed083p728.

Keywords: anticancer drug, photodynamic therapy, rhodium complex

 

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Sep 052014
 

September 4, 2014

FDA Release

The U.S. Food and Drug Administration today granted accelerated approval to Keytruda (pembrolizumab) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.

Melanoma, which accounts for approximately 5 percent of all new cancers in the United States, occurs when cancer cells form in skin cells that make the pigment responsible for color in the skin. According to the National Cancer Institute, an estimated 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.

Keytruda is the first approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells. Keytruda is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.

“Keytruda is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Many of these treatments have different mechanisms of action and bring new options to patients with melanoma.”

The five prior FDA approvals for melanoma include: ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

The FDA granted Keytruda breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation. Priority review is granted to drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases.

The FDA action was taken under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. An improvement in survival or disease-related symptoms has not yet been established.

Keytruda’s efficacy was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with Keytruda, either at the recommended dose of 2 milligrams per kilogram (mg/kg) or at a higher dose of 10 mg/kg. In the half of the participants who received Keytruda at the recommended dose of 2 mg/kg, approximately 24 percent had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumor shrink at the 10 mg/kg dose.

Keytruda’s safety was established in the trial population of 411 participants with advanced melanoma. The most common side effects of Keytruda were fatigue, cough, nausea, itchy skin (pruritus), rash, decreased appetite, constipation, joint pain (arthralgia) and diarrhea. Keytruda also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands and liver, occurred uncommonly.

Keytruda is marketed by Merck & Co., based in Whitehouse Station, New Jersey.

 

 

 

Pembrolizumab, LambrolizumabMK-3475

STRUCTURAL FORMULA
Heavy chain
QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG 50
INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD 100
YRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200
YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT 250
LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300
RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350
LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400
DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447
Light chain
EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50′
LIYLASYLES GVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL 100′
TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150′
QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200′
THQGLSSPVT KSFNRGEC 218′
Disulfide bridges
22-96 22”-96” 23′-92′ 23”’-92”’ 134-218′ 134”-218”’ 138′-198′ 138”’-198”’
147-203 147”-203” 226-226” 229-229” 261-321 261”-321” 367-425 367”-425”
Glycosylation sites (N)
Asn-297 Asn-297”
lambrolizumab, or MK-3475

1374853-91-4

C6504H10004N1716O2036S46 (peptide)
MOL. MASS 146.3 kDa (peptide)

Pembrolizumab, Lambrolizumab (also known as MK-3475) is a drug in development by Merck that targets the PD-1 receptor. The drug is intended for use in treating metastatic melanoma.

http://www.ama-assn.org/resources/doc/usan/lambrolizumab.pdf  structureof lambrolizumab, or MK-3475

https://download.ama-assn.org/resources/doc/usan/x-pub/pembrolizumab.pdf  

Statement on a Nonproprietary Name Adopted by the USAN Council. November 27, 2013.

see above link for change in name

may 2, 2013,

An experimental drug from Merck that unleashes the body’s immune system significantly shrank tumors in 38 percent of patients with advanced melanoma, putting the company squarely in the race to bring to market one of what many experts view as the most promising class of drugs in years.

The drugs are attracting attention here at the annual meeting of the American Society of Clinical Oncology, even though they are still in the early stage of testing. Data from drugs developed by Bristol-Myers Squibb and by Roche had already been released.

The drugs work by disabling a brake that prevents the immune system from attacking cancer cells. The brake is a protein on immune system cells called programmed death 1 receptor, or PD-1.

Merck’s study, which was presented here Sunday and also published in the New England Journal of Medicine, involved 135 patients. While tumors shrank in 38 percent of the patients over all, the rate was 52 percent for patients who got the highest dose of the drug, which is called lambrolizumab, or MK-3475.

But that is what is disclosed tonight, as to pembrolizumab, or MK-3475. Wow. With over $44 billion in 2013 worldwide revenue, that disclosure implies (to seasoned SEC lawyers) that spending on this one drug (or, biologic, to be more technical about it — but remember 40 years ago, Merck had no protein chain biologics research & development programs in its pipe — only chemical drug compounds). . . is material, to that number. Normally that would, in turn, mean that the spending is approaching 5 per cent of revenue. So — Merck may be spending $2.2 billion over the next 12 rolling months, on MK-3475. That’s one BIGhairy science bet, given that Whitehouse Station likely already had over $2 billion invested in the program, at year end 2013.

About Pembrolizumab
Pembrolizumab (MK-3475) is an investigational selective, humanized monoclonal anti-PD-1 antibody designed to block the interaction of PD-1 on T-cells with its ligands, PD-L1 and PD-L2, to reactivate anti-tumor immunity. Pembrolizumab exerts dual ligand blockade of PD-1 pathway.
Today, pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials across 30 different tumor types, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide, including new Phase 3 studies in head and neck and other cancers. For information about Merck’s oncology clinical studies, please click here.
The Biologics License Application (BLA) for pembrolizumab is under priority review with the U.S. Food and Drug Administration (FDA) for the proposed indication for the treatment of patients with advanced melanoma previously-treated with ipilimumab; the PDUFA date is October 28, 2014. Pembrolizumab has been granted FDA’s Breakthrough Therapy designation for advanced melanoma. If approved by the FDA, pembrolizumab has the potential to be the first PD-1 immune checkpoint modulator approved in this class. The company plans to file a Marketing Authorization Application in Europe for pembrolizumab for advanced melanoma in 2014.
About Head and Neck Cancer
Head and neck cancers are a related group of cancers that involve the oral cavity, pharynx and larynx. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer (epithelium) of the head and neck (called the). The leading risk factors for head and neck cancer include tobacco and alcohol use. Infection with certain types of HPV, also called human papillomaviruses, is a risk factor for some types of head and neck cancer, specifically cancer of the oropharynx, which is the middle part of the throat including the soft palate, the base of the tongue, and the tonsils. Each year there are approximately 400,000 cases of cancer of the oral cavity and pharynx, with 160,000 cancers of the larynx, resulting in approximately 300,000 deaths.


About Merck Oncology: A Focus on Immuno-Oncology
At Merck Oncology, our goal is to translate breakthrough science into biomedical innovations to help people with cancer worldwide. Harnessing immune mechanisms to fight cancer is the priority focus of our oncology research and development program. The Company is advancing a pipeline of immunotherapy candidates and combination regimens. Cancer is one of the world’s most urgent unmet medical needs. Helping to empower people to fight cancer is our passion. For information about Merck’s commitment to Oncology visit the Oncology Information Center at http://www.mercknewsroom.com/oncology-infocenter.


About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

 

Hamid, O; Robert, C; Daud, A; Hodi, F. S.; Hwu, W. J.; Kefford, R; Wolchok, J. D.; Hersey, P; Joseph, R. W.; Weber, J. S.; Dronca, R; Gangadhar, T. C.; Patnaik, A; Zarour, H; Joshua, A. M.; Gergich, K; Elassaiss-Schaap, J; Algazi, A; Mateus, C; Boasberg, P; Tumeh, P. C.; Chmielowski, B; Ebbinghaus, S. W.; Li, X. N.; Kang, S. P.; Ribas, A (2013). “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma”. New England Journal of Medicine 369 (2): 134–44. doi:10.1056/NEJMoa1305133PMID 23724846

key words
FDA,  approved,  Keytruda,  advanced melanoma, PD-1 blocking drug, pembrolizumab, LambrolizumabMK-3475, Monoclonal antibody

 

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Sep 052014
 

Acebutolol

Acebutolol
N-(3-Acetyl-4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl)butanamide
3′-acetyl-4′-(2-hydroxy-3-(isopropylamino)propoxy)butyranilide
(±)-acebutolol
Acetobutolol; Sectral; Prent; Neptal; Acebutololum; Acebutololo; (+-)-Acebutolol; dl-Acebutolol; Acebrutololum

Molecular Formula: C18H28N2O4   Molecular Weight: 336.42592
CAS Registry Number: 37517-30-9
CAS Name: N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl]butanamide
Additional Names: 3¢-acetyl-4¢-[2-hydroxy-3-(isopropylamino)propoxy]butyranilide; 1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane; 5¢-butyramido-2¢-(2-hydroxy-3-isopropylaminopropoxy)acetophenone
Percent Composition: C 64.26%, H 8.39%, N 8.33%, O 19.02%
Melting point: mp 119-123°
Derivative Type: Hydrochloride
CAS Registry Number: 34381-68-5
Manufacturers’ Codes: M & B 17803A; IL-17803A
Trademarks: Acecor (SPA); Acetanol (RPR); Neptal (Procter & Gamble); Prent (Bayer); Sectral (RPR)
Molecular Formula: C18H28N2O4.HCl
Molecular Weight: 372.89
Percent Composition: C 57.98%, H 7.84%, N 7.51%, O 17.16%, Cl 9.51%
Properties: Crystals from anhydr methanol-anhydr diethyl ether, mp 141-143°. Freely sol in water. Soly at room temperature (mg/ml): water 200; ethanol 70.
Melting point: mp 141-143°
Therap-Cat: Antihypertensive; antianginal; antiarrhythmic (class II).
Acebutolol (trade names SectralPrent) is a beta blocker for the treatment of hypertension and arrhythmias.
A cardioselective beta-adrenergic antagonist with little effect on the bronchial receptors. The drug has stabilizing and quinidine-like effects on cardiac rhythm as well as weak inherent sympathomimetic action.

Brief background information

Salt ATC Formula MM CAS
- C07AB04
C07BB04
18 H 28 N 2 O 4 336.43 g / mol 37517-30-9
(R) be the bases C07AB04
C07BB04
18 H 28 N 2 O 4 336.43 g / mol 68107-81-3
(S) be the bases C07AB04
C07BB04
18 H 28 N 2 O 4 336.43 g / mol 68107-82-4
(RS) -monogidrohlorid C07AB04
C07BB04
18 H 28 N 2 O 4 · HCl 372.89 g / mol 34381-68-5
Acebutolol
Acebutolol structure.svg
Acebutolol ball-and-stick.png
Systematic (IUPAC) name
(RS)-N-{3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}butanamide
Clinical data
Trade names Sectral
AHFS/Drugs.com monograph
MedlinePlus a687003
Licence data US FDA:link
Pregnancy cat. (AU) B (US)
Legal status ℞ Prescription only
Routes oral, iv
Pharmacokinetic data
Bioavailability 40% (range 35 to 50%)
Metabolism Hepatic
Half-life 3-4 hours (parent drug)
8-13 hours (active metabolite)
Excretion Renal: 30%
Biliary: 60%
Identifiers
CAS number 37517-30-9 Yes
ATC code C07AB04
PubChem CID 1978
DrugBank DB01193
ChemSpider 1901 Yes
UNII 67P356D8GH Yes
KEGG D02338 Yes
ChEBI CHEBI:2379 Yes
ChEMBL CHEMBL642 Yes
Chemical data
Formula C18H28N2O4 
Mol. mass 336.426 g/mol
Physical data
Melt. point 121 °C (250 °F)

Application

  • antagonist of β-adrenergic
  • β-blocker

Classes of substances

  • Acetophenones
    • 1-aryloxy-3-amino-2-propanol
      • Butyric acid anilides

       

Synthesis pathway

Chemical structure for Acebutolol

File:Acebutolol synthesis 01.svg

Synthesis a)


Trade Names

Country Trade name Manufacturer
Germany Printemps Bayer
Sali-Printemps - “-
Tredalat - “-
France Sektral Sanofi-Aventis
United Kingdom Sekadreks Aventis
Sektral Aventis
Italy Atsekor SPA
AlOl SIT
Printemps Bayropharm
Sektral Rhône-Poulenc Rorer
Japan Atsetanol Sanofi-Aventis
Chugai
Sektral Organon
USA - “- Wyeth-Ayerst
Ukraine No No

Formulations

  • ampoule 25 mg;
  • Capsules 100 mg, 200 mg;
  • Tablets of 200 mg, 400 mg, 500 mg (as hydrochloride)

Pharmacology

Acebutolol is a cardioselective beta blocker with ISA (intrinsic sympathomimetic activity; see article on pindolol). It is therefore more suitable than non cardioselective beta blockers, if a patient with asthma or chronic obstructive pulmonary disease (COPD) needs treatment with a beta blocker. (For these reasons, it may be a beta-blocker of choice in inclusion in Polypill strategies). In doses lower than 800mg daily its constricting effects on the bronchial system and smooth muscle vessels are only 10% to 30% of those observed under propranolol treatment, but there is experimental evidence that the cardioselective properties diminish at doses of 800mg/day or more.

The drug has lipophilic properties, and therefore crosses the blood–brain barrier. Acebutolol has no negative impact on serum lipids (cholesterol and triglycerides). No HDL decrease has been observed. In this regard, it is unlike many other beta blockers which have this unfavourable property.

The drug works in hypertensive patients with high, normal, or low renin plasma concentrations, although acebutolol may be more efficient in patients with high or normal renin plasma concentrations. In clinically relevant concentrations, a membrane-stabilizing effect does not appear to play an important role.

Pharmacokinetics

Acebutolol is well absorbed from the GI tract, but undergoes substantial first-pass-metabolization, leading to a bioavailability of only 35% to 50%. Peak plasma levels of acebutolol are reached within 2 to 2.5 hours after oral dosing. Peak levels of the main active metabolite, diacetolol, are reached after 4 hours. Acebutolol has a half-life of 3 to 4 hours, and diacetolol a half-life of 8 to 13 hours.

Acebutolol undergoes extensive hepatic metabolization resulting in the desbutyl amine acetolol which is readily converted into diacetolol. Diacetolol is as active as acebutolol (equipotency) and appears to have the same pharmacologic profile. Geriatric patients tend to have higher peak plasma levels of both acebutolol and diacetolol and a slightly prolonged excretion. Excretion is substantially prolonged in patients with renal impairment, and so a dose reduction may be needed. Liver cirrhosis does not seem to alter the pharmacokinetic profile of the parent drug and metabolite.

Indications

Contraindications

  • Stable or Unstable Angina (due to its partial agonist or ISA activity)

Contraindications and Precautions

Further information: Propranolol

Acebutolol may not be suitable in patients with Asthma bronchiale or COPD due to its bronchoconstricting (β2 antagonistic) effects.

Side effects

Further information: Propranolol

The development of anti-nuclear antibodies (ANA) has been found in 10 to 30% of patients under treatment with acebutolol. A systemic disease with arthralgic pain and myalgias has been observed in 1%. A lupus erythematosus-like syndrome with skin rash and multiforme organ involvement is even less frequent. The incidence of both ANA and symptomatic disease under acebutolol is higher than under Propranolol. Female patients are more likely to develop these symptoms than male patients. Some few cases of hepatotoxicity with increased liver enzymes (ALTAST) have been seen. Altogether, 5 to 6% of all patients treated have to discontinue acebutolol due to intolerable side effects. When possible, the treatment should be discontinued gradually in order to avoid a withdrawal syndrome with increased frequency of angina and even precipitation of myocardial infarction.

Dosage

The daily dose is 200mg – 1,200mg in a single dose or in 2 divided doses as dictated by the severity of the condition to be treated. Treatment should be initiated with low doses, and the dose should be increased cautiously according to the response of the patient. Acebutolol is particularly suitable for antihypertensive combination treatment with diuretics, if acebutolol alone proves insufficient. In some countries injectable forms for i.v.-injection with 25mg acebutolol exist, but these are only for cases of emergency under strict clinical monitoring. The initial dose is 12.5 to 25mg, but additional doses may be increased to 75 to 100mg, if needed. If further treatment is required, it should be oral.

 

Sectral (acebutolol HCl) structural formula illustration

Sectral (acebutolol HCl) is a selective, hydrophilic beta-adrenoreceptor blocking agent with mild intrinsic sympathomimetic activity for use in treating patients with hypertension and ventricular arrhythmias. It is marketed incapsule form for oral administration. Sectral (acebutolol) capsules are provided in two dosage strengths which contain 200 or 400 mg of acebutolol as the hydrochloride salt. The inactive ingredients present are D&C Red 22, FD&C Blue 1, FD&C Yellow 6, gelatin, povidone, starch, stearic acid, and titanium dioxide. The 200 mg dosage strength also contains D&C Red 28 and the 400 mg dosage strength also contains FD&C Red 40. Acebutolol HCl has the following structural formula:

View Enlarged Table
Acebutolol HCl is a white or slightly off-white powder freely soluble in water, and less soluble in alcohol. Chemically it is defined as the hydrochloride salt of (±)N-[3-Acetyl-4-[2- hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] butanamide.

 

 

External links

US3857952
EXAMPLE 5 5-Butyramido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone (3.36 g.; prepared as described in Example (4) was dissolved in anhydrous methanol (50 ml.), and anhydrous diethyl ether (200 ml.) added. A saturated solution of anhydrous hydrogen chloride in anhydrous diethyl ether (25 ml.) was added dropwise with stirring. An oil was precipitated, which crystallized on further stirring. The solid was filtered off and recrystallized from a mixture of anhydrous methanol and anhydrous diethyl ether to give 5-butyramido-2′-(2- hydroxy-3-isopropyl’amino-propoxy)acetophenone hydrochloride (2.5 g.), m.p. l4ll43C.

EXAMPLE 4 Crude 5-butyramido-2′-(2,3-epoxypropoxy)acetophenone (16 g), isopropylamine (20 g.) and ethanol (100 ml.) were heated together under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and theresidual oil was dissolved in N hydrochloric acid. The acid solution was extracted with ethyl acetate, theethyl acetate layers being discarded. The acidic solution was brought to pH 11 with 2N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extracts were concentrated under reduced pressure to give an oil which was crystallised from a mixture of ethanol and diethyl ether to give 5′-butyramido-2- (2-hydroxy-3-isopropylaminopropoxy)acetophenone (3 g.), m.p. 119l23C.

Similarly prepared was cyclohexylamino-2-hydroxypropoxy)acetophenone, m.p. 112113C.

Crude 5-butyramido-2-(2,3-epoxypropoxy)acetophenone used as startingmaterial was prepared as follows:

p-Butyramidophenol (58 g.; prepared according to Fierz-David and Kuster, loc.cit.), acetyl chloride (25.4 g.) and benzene (500 ml.) were heated together under reflux until a solution formed (12 hours). This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene.

The combined benzene extracts were dried and evaporated to dryness under reduced pressure to give pbutyramidophenyl acetate (38 g.) as an off-white solid, mp. 102-l03C. A mixture of p-butyramidophenyl acetate (38 g.), aluminium chloride (80 g.) and 1,l,2,2-tetrachloroethane (250 ml.) was heated at 140C. for 3 hours. The reaction mixture was cooled and treated with iced water. The tetrachloroethane layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were extracted with 2N aqueous sodium hydroxide and the alkaline solution was acidified to pH 5 with concentrated hydrochloric acid. The acidified solution was extracted with chloroform and the chloroform extract was dried and concentrated under reduced pressure to give 5′-butyramido-2-hydroxyacetophenone 15.6 g.), m.p. 114l17C. A solution of 5-butyramido-2′- hydroxyacetophenone (15.6 g.) in ethanol (100 ml.) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g.) and ethanol (100 ml.). The resulting solution’was evaporated to dryness under reduced pressure and dimethylformamide (100 ml.) was added to the solid’residue. Ap-

proximately ml. of dimethylformamide was removed by distillation under reduced pressure. Epichlorohydrin ml.) was added and the solution was heated at 100C. for 4 hours. The solution was concentrated under reduced pressure to give a residual oil which was treated with water to’give a solid. The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressure to give crude 5-butyramido- 2-(2,3-epoxypropoxy)acetophenone (16 g.), m.p. 1101 16C.

The crude compound may be purified by recrystallisation from ethyl acetate, after, treatment with decolourizing charcoal, to give pure 5′-butyramido-2′-(2,3- epoxypropoxy)acetophenone, m.p. 136138C.

Links

  • GB 1247384 (May & Baker; appl. 22.12.1967).
  • DAS 1,815,808 (May & Baker; appl. 19.12.1968; GB -prior. 22.12.1967, 5/14/1968, 2.8.1968).
  • US 3,726,919 (May & Baker; 10/4/1973; GB -prior. 22.12.1967, 05.14.1968, 2.8.1968).
  • US 3,857,952 (May & Baker; 31.12.1974; GB -prior. 22.12.1967, 14.05.1968, 2.8.1968).
Literature References:
Cardioselective b-adrenergic blocker. Prepn: K. R. H. Wooldridge, B. Basil, ZA 6808345eidem, US3857952 (1969, 1974 both to May & Baker).
Pharmacology: Cuthbert, Owusu-Ankomah, Br. J. Pharmacol. 43, 639 (1971); Basil et al., ibid. 48, 198 (1973); Lewis et al., Br. Heart J. 35, 743 (1973).
HPLC determn in plasma and urine: M. Piquette-Miller et al., J. Chromatogr. 526, 129 (1990).
Crystal structure: A. Carpy et al., Acta Crystallogr. B35, 185 (1979).
Review of pharmacology and therapeutic efficacy: B. N. Singh et al., Drugs 29, 531-569 (1985); G. DeBono et al., Am. Heart J. 109, 1211-1223 (1985).
Comprehensive description: R. T. Foster, R. A. Carr, Anal. Profiles Drug Subs. 19, 1-26 (1990).
Keywords: Adrenergic Blocker,  Antianginal,  Antiarrhythmic, Antihypertensive, Aryloxypropanolamine Derivatives, Acebutolol, β-adrenergic receptor

 

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