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.

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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.

…………………………….

 

 

………………………………….

 

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%).

 

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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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Sep 052014
 

Some derivatives ) are known as being intermediates in the preparation of anti-tumor medicaments such as vinblastine, vincristine and vinorelbine.

R=CH3, vinblastine

R=CHO, vincristine

n=2, anhydrovinblastine

n=1, vinorelbine

The remarkable anti-tumor properties of these complex natural molecules, extracted from the Madagascar periwinkle, Carantheus roseus, are known and they are already used in anti-cancer treatment. Vinblastine and vincristine are “spindle poisons” which oppose the formation of the mitotic spindle during cellular division, thus preventing cellular proliferation.

Vincristine and vinblastine are active agents in the treatment of leukemia, lymphosarcoma and solid tumors. Vinblastine is also used in the treatment of Hodgkin’s disease.

Vinorelbine is currently used in the treatment of the most widespread form of cancer of the lungs, that is lung cancer of non-small cells. It is also used in the treatment of metastasic cancers of the breast.

The methods currently used for preparing vinblastine and vincristine involve extraction of these molecules from plants. The plants have to be crushed and dried before these substances can be extracted. The extraction process is long and costly, given that the extract obtained is very complex, containing at least 200 different alkaloids. The yields are also very low; 5 to 10 g of vinoblastine are obtained per ton of dried plant material, and 0.5 to 1 g of vincristine per ton of dried plant material.

Many research groups have thus tried to achieve synthesis of these molecules by using more efficient procedures which enable better yields and which make use of derivatives with interesting anti-tumor properties but which are endowed with lower levels of toxicity.

 

just an animation

The patent FI 882 755, filed by the HUATAN-MAKI Oy Company, relates to the formation of vinblastine and vincristine by irradiation of catharanthine and of vindoline with UV radiation in an acidic aqueous solution, under an atmosphere of oxygen or an inert gas. The yields obtained in these reactions are extremely low.

Furthermore, other processes are known which make use of anhydrovinblastine which is an intermediate in the synthesis of vinblastine, vincristine and also of vinorelbine.

Anhydrovinblastine is thus a key chemical intermediate which enables access to all alkaloids of the vinblastine type. This intermediate is synthesised by coupling catharanthine and vindoline.

The latter two alkaloids are also extracted from the Madagascar periwinkle but, in contrast to vincristine and vinblastine, they represent the main constituents of the extract obtained. In fact, 400 g of catharanthine per ton of dried plant material and 800 g of vindoline per ton of dried plant material are obtained.

The preparation of anhydrovinblastine by coupling catharanthine and vindoline is therefore a favoured route for synthesising this intermediate product.

There are several methods for preparing anhydrovinblastine from catharanthine and vindoline.

The patent FR 2 296 418 filed by ANVAR describes a process during the course of which the N-oxide of catharanthine is coupled to vindoline in the presence of trifluoroacetic anhydride.

When this process is performed at ambient temperature only the inactive 16′-R epimer of anhydrovinblastine is obtained. The naturally occurring active 16′-S epimer is obtained as the major product when this reaction is performed at a temperature which is at least 50° C. lower and under an inert gas. Nevertheless, even at low temperature, 10% of the 16′-R epimer of anhydrovinblastine is still produced.

 

 

This process has several disadvantages. The operating conditions are extremely restrictive due to the use of anhydrous solvents, the low temperature and the atmosphere of inert gas. The product obtained has to be subjected to a purification procedure due to the presence of 10% of the 16′-R epimer of anhydrovinblastine. The yield of isolated anhydrovinblastine is low, of the order of 35%.

A second process, suggested by VUKOVIC et al. in the review “Tetrahedron” (1998, volume 44, pages 325-331) describes a coupling reaction between catharanthine and vindoline initiated by ferric ions. Catharanthine is also oxidised in this reaction. The yield of anhydrovinblastine is of the order of 69% when the reaction is performed under an atmosphere of inert gas. However, this process has the major disadvantage that it leads to many secondary products. These are impurities resulting from further oxidation of the dimeric alkaloids formed, whatever the chosen operating conditions. This makes the purification stage difficult and delicate.

An improved process was suggested in the patent U.S. Pat. No. 5,037,977 and this increases the yield of anhydrovinblastine to 89%. However, this improvement is described only for very small amounts of reagents and its extension to the industrial scale seems to be difficult. In any case, these processes based on ferric ions lead in all cases to many secondary products due to the fact that these ions are responsible for parasitic reactions.

A third process described by GUNIC et al. in “Journal of the Chemical Society Chemical Communications” (1993), volume 19, pages 1496-1497, and by Tabakovic et al. in “Journal of Organic Chemistry” (1997), volume 62, pages 947-953, describes a coupling reaction between catharanthine and vindoline as a result of anodic oxidation of catharanthine. However, this process also suffers from disadvantages which, on the one hand, are due to the requirement for an inert atmosphere and, on the other hand, are connected with the nature of the electrochemical process itself, involving wear of the electrodes, difficulty in controlling the reproducibility and the cost of electrolytes. And, as in all the preceding methods, the anhydrovinblastine is contaminated with about 10% of the 16′-R epimer of anhydrovinblastine.

http://www.google.com/patents/US6365735

EXAMPLE 11 Preparation of 21′α-Cyanoanhydrovinblastine

0.537 mmol of catharanthine hydrochloride (200 mg), 0.537 mmol of vindoline (245 mg) and 0.054 mmol of dimethyl viologen (14 mg) and 0.028 mmol of triphenylpyrilium hydrogen sulfate (11 mg) are added to 50 ml of 0.1 N sulfuric acid. The entire mixture is irradiated with light of wavelength λ>400 nm in a Pyrex irradiation flask, under an atmosphere of oxygen. The reaction is terminated after 2 h 30 min of irradiation.

The aqueous phase is then saturated with lithium tetrafluoroborate and then extracted with dichloromethane. A solution of 15 ml of dichloromethane containing 100 μl (1.34 mmol, 2 eq.) of trimethylsilyl cyanide, TMSCN, is then added to the reaction medium. The organic phase is washed with a solution of 0.1 M sodium carbonate, dried and evaporated under reduced pressure at 20° C.

 

 

 

The only product in the residue (403 mg, 0.509 mmol, 95%) is recrystallised from absolute isopropanol. 340 mg of white crystals of 21′α-cyanoanhydrovinblastine (0.430 mmol; yield: 80%) are recovered.

C47H55N5O8

M.pt. 212° C. (iPrOH) IR film 3450, 2950, 2220, 1740, 1610 cm−1; MS M/z (relative intensity) 818 (MH+, 3), 122 (100), 108 (21);

NMR 1H (500 MHz, CDCl3) 9.78 (s, 1H, OH), 8.04 (s, 1H, Na′H), 7.51 (1H, H-9′), 7.16 (1H, H-11′), 7.13 (1H, H-12′), 7.12 (1H, H-10′), 6.63 (s, 1H, H-9), 6.13 (s, 1H, H-12), 5.85 (m, 1H, H-14), 5.47 (s, 1H, Hα-17), 5.54 (m, 1H, H-15′), 5.30 (m 1H, H-15), 4.18 (1H, H62-2), 3.60 (s, 3H, C16′—COOCH3), 3.38 (1H, H62-3), 3.35 (1H, Hβ-3′), 3.31 (1H, Hβ-5), 3.25 (1H, Hβ-6′), 3.24 (m, 1H, Hβ-5′), 3.15 (1H, Hβ-17′), 3.14 (m, 1H, Hα-5′), 3.12 (1H, Hα-6′), 2.82 (1H, Hα-3), 2.72 (s, 3H, NaCH3), 2.66 (s, 1H, Hα-21), 2.62 (1H, Hα-3′), 2.46 (1H, Hα-5), 2.40 (1H, Hα-17′), 2.20 (1H, Hβ-5), 2.11 (s, 3H, CH3—COO), 2.11 (1H, H-19′), 2.03 (1H, H-19′), 1.80 (1H, Hα-6), 1.80 (1H, H-19), 1.35 (1H, H-19), 1.21 (m, 1H, H-14′), 1.04 (3H, H-18′), 0.81 (3H, H-18).

NMR 13C (125 MHz, CDCl3) 174.69 (C16′COOCH3), 171.74 (C16COOCH3), 171.03130.01 (C15), 129.34 (C8′), 129.16 (C15′), 124.63 (C14), 123.48 (C9), 123.24 (C8), 122.49 (C11′), 121.00 (C10), 119.21 (C10′), 119.21 (CN), 118.35 (C9′), 115.65 (C7′), 110.64 (C11—OCH3), 55.40 (C16′), 53.30 (C7), 52.46 (C16′—COOCH3), 52.30 (C16—COOCH3), 52.26 (C5′), 50.50 (C5), 50.41 (C5), 44.86 (C6), 44.48 (C3′), 42.76 (C20), 38.32 (Na—CH3), 34.00 (C17′), 33.28 (C14′), 30.92 (C19), 28.63 (C8′), 25.92 (C19′), 21.19 (CH3—COO), 11.86 (C18′), 8.50 (C18).

Patent Citations
Cited Patent Filing date Publication date Applicant Title
US4737586 Apr 29, 1986 Apr 12, 1988 Agence Nationale De Valorisation De La Recherche Process for the preparation of bis-indolic compounds
US5037977 Aug 8, 1989 Aug 6, 1991 Mitsui Petrochemical Industries Ltd. Reacting catharanthine with vindoline in presence of ferric ions, inactivating iron with ligand, reducing
DE3801450A1 Jan 20, 1988 Aug 18, 1988 Univ British Columbia Verfahren fuer die synthese von vinblastin und vincristin
DE3826412A1 Aug 3, 1988 Feb 16, 1989 Univ British Columbia Verfahren fuer die synthese von vinblastin und vincristin
WO1989012056A1 Jun 9, 1989 Dec 14, 1989 Huhtamaeki Oy Process for the preparation of dimeric catharanthus alkaloids
Non-Patent Citations
Reference
1 E. Gunic et al., “Electrochemical Synthesis of Anhydrovinblastine“, J. Chem. Soc., Chem. Commun., 1993, pp. 1496-1497.
2 I. Tabakovic et al., “Anodic Fragmentation of Catharanthine and Coupling with Vindoline. Formation of Anhydrovinblastine“, J. Org. Chem., 1997, vol. 62, pp 947-953.
3 J. Vucovik et al., “Production of 3′,4′-anhydrovinblastine: a Unique Chemical Synthesis“, Pergamon Journals Ltd., 1988, vol. 44, pp. 325-331.
4 Richard J. Sundberg et al.; “Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates” Tetrahedron., vol. 48, No. 2,-Jan. 10, 1992; pp. 277-296, XP002083507 Oxford GB-the whole document.
5 Richard J. Sundberg et al.; “Oxidative fragmentation of catharanthine by dichlorodicyanoquinone“; Journal of Organic Chemistry,-Mar. 1, 1991; pp. 1689-1692, XP002083508 Easton US -the whole document.
6 Richard J. Sundberg et al.; “Photoactivated C16-C21 fragmentation of catharanthine” Tetrahedron Letters, vol. 32, No. 26, Jun. 24, 1992, pp. 3035-3038 XP002083509 Oxford GB-the whole document.
7 Richard J. Sundberg et al.; “Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates” Tetrahedron., vol. 48, No. 2,—Jan. 10, 1992; pp. 277-296, XP002083507 Oxford GB—the whole document.
8 Richard J. Sundberg et al.; “Oxidative fragmentation of catharanthine by dichlorodicyanoquinone“; Journal of Organic Chemistry,—Mar. 1, 1991; pp. 1689-1692, XP002083508 Easton US —the whole document.
9 Richard J. Sundberg et al.; “Photoactivated C16-C21 fragmentation of catharanthine” Tetrahedron Letters, vol. 32, No. 26, Jun. 24, 1992, pp. 3035-3038 XP002083509 Oxford GB—the whole document.
Citing Patent Filing date Publication date Applicant Title
US7235564 * Dec 3, 2004 Jun 26, 2007 Amr Technology, Inc. 11′-substituted; potent inhibitors of cellular mitosis and proliferation
US7238704 * Dec 3, 2004 Jul 3, 2007 Amr Technology, Inc. For use as inhibitors of cellular mitosis and proliferation
US7745619 Oct 31, 2007 Jun 29, 2010 Albany Molecular Research, Inc. alkaloids; anticarcinogenic, antiproliferative agent; inhibitor of cellular mitosis and cell proliferation; binding to tubulin leads to cell cycle arrest in M phase and subsequently to apoptosis; antiallergen, antiinflammatory, antidiabetic, autoimmune diseases; asthma, arthritis, Alzheimer’ disease
US7842802 Dec 10, 2008 Nov 30, 2010 Albany Molecular Research, Inc. Vinorelbine derivatives
US8048872 Apr 29, 2008 Nov 1, 2011 Stat of Oregon Acting by and Through The Oregon State Board of Higher Education on Behalf of the University of Oregon Treatment of hyperproliferative diseases with vinca alkaloid N-oxide and analogs
US8053428 Apr 6, 2007 Nov 8, 2011 Albany Molecular Research, Inc. Vinorelbine derivatives
WO2005055939A2 * Dec 3, 2004 Jun 23, 2005 Amr Technology Inc Vinca derivatives

 

 

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A MESSAGE FROM MICHAEL A. LUTHER, SENIOR VICE PRESIDENT DISCOVERY AND DEVELOPMENT
Dear Anthony,As a company with a deep history of discovery innovation, Albany Molecular Research Inc. (AMRI) continues to explore scientific solutions that provide our customers with enhanced flexibility and access to state-of-the-art science and technologies. As part of our aim to provide you with high-value services in the area of biology and pharmacology, today we announced new platforms that enhance our discovery biology offerings.One of our new platforms comprises IND-enabling support services, which are aimed at supporting the successful initiation and completion of customer Investigational New Drug (IND) programs. As part of this offering we now provide in vitro DMPK studies, related to drug-drug interactions and metabolism, which are routinely included in IND submissions. Our Drug Metabolism and Pharmacokinetics (DMPK) group provides in vitro DMPK and bioanalytical/PK services as part of our Drug Discovery and Development Solutions (DDS) business. These services span all stages of drug discovery including exploratory, hit-to-lead, lead optimization and candidate selection, as well as the pre-clinical IND-enabling stage.

More recently, we have expanded into the protein market with an initial focus on protein expression and purification. As part of a public-private pharmaceutical research and development initiative in Buffalo, N.Y., our current and ongoing activities encompass the production of purified recombinant proteins as reagents and tools for biological assays and sterile, pyrogen-free materials for proof-of-concept, non-human in vivo studies. We are very excited to be able to offer these expanded biology services as we continue to seek innovative ways to provide relevant drug discovery services and expertise to academia and the global Bio-Pharmaceutical industry from early discovery to candidate selection and beyond.

Our goal is to leverage our deep expertise to provide you with high quality and innovative scientific solutions that drive your pipeline and portfolio. As always, if you have questions about any of the services we can provide, please contact us to request a quote so we can discuss your needs.

Sincerely,

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Abstract Image

Lifitegrast, SAR 1118

SAR-1118-023

CAS 1025967-78-5

L-​Phenylalanine, N-​[[2-​(6-​benzofuranylcarbonyl​)​-​5,​7-​dichloro-​1,​2,​3,​4-​tetrahydro-​6-​isoquinolinyl]​carbonyl]​-​3-​(methylsulfonyl)​-

INNOVATOR

SAR1118 is a white to off-white solid crystallized from methylethylketone. m.p. 154.4oC;
[α]D25=-5.0o(c =1% (w/w) inMeOH); solubility 90 μg/mL in water at 25oC(parent);
FT-IR(KBr): νmax3427, 3302, 3030, 2923, 1727, 1659, 1294, 1140, 826, 764 cm-1;
ESI-MS:m/z615.1[M+1]+, 637.0 [M+Na]+;
1H NMR (300 MHz,d6-DMSO): δ 12.90 (bs, 1H), 9.05 (d,J=6.0Hz,1H), 8.13 (d,J= 1.9 Hz,1H), 7.73 (m, 4H), 7.57 (m, 1H), 7.41 (bs, 1H), 7.05 (d,J= 1.9 Hz,1H),4.78 (bm, 3H),
3.63 (bm, 3H), 3.30 (m, 1H), 3.16 (s, 3H), 3.02 (m, 1H), 2.77 (m, 2H) ppm;
13CNMR (75.5 MHz,d6-DMSO): δ 172.1, 169.6, 163.6, 153.7, 147.8, 140.6, 125.7, 106.9, 53.1,
43.6, 36.4, 26.0 ppm;
Elemental analysis: calcd. for C29H24Cl2N2O7S: C 56.6%, H 3.9%, N 4.6%,S 5.2%, Cl 11.5%; found C 55.1%, H 4.0%, N 4.4%, S 5.2%, Cl 11.2%

SAR 1118 ophthalmic solution from SARcode Bioscience (Brisbane, Calif.) is a first-in-class molecule that inhibits T-cell inflammation by blocking the binding of two key cellular surface proteins (LFA-1 and ICAM-1) that mediate the chronic inflammatory cascade, so it may be able to reduce the inflammation associated with dry-eye disease.

In September, the company initiated enrollment in a Phase III study (OPUS-1). This study will assess the safety and efficacy of SAR 1118 for the treatment of dry-eye disease. Approximately 588 patients will be randomized to receive SAR 1118 5.0% ophthalmic solution or placebo twice daily for 12 weeks. The primary outcome measures include inferior corneal fluorescein staining, vision-related function subscale of the Ocular Surface Disease Index, and safety and tolerability. The company plans to complete the study in the first half of 2012.
The Phase II trial was a randomized, placebo-controlled, multicen-ter trial that included 230 patients with dry eye. In this study, SAR 1118 demonstrated dose-dependent significant improvements in inferior corneal staining over 12 weeks. A statistically significant increase in tear production and improvement in vision-related functions were seen as early as two weeks after initiation of treatment. SAR 1118 was well-tolerated, and no serious ocular adverse events were reported.
Has been found to be an effective inhibitor of Lymphocyte Function- Associated Antigen- 1 (LFA- 1) interactions with the family of Intercellular Adhesion Molecules (ICAM), and has desirable pharmacokinetic properties, including rapid systemic clearance

A growing body of evidence points to a role for inflammation mediated by lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 in the pathogenesis of diabetic macular oedema. This phase 1b clinical trial assessed the safety, tolerability, and pharmacokinetics of topically administered SAR 1118, a novel LFA-1 antagonist, in human subjects

Topical SAR 1118 was safe and well tolerated, and dose-dependent levels of drug were detected in aqueous. However, vitreous levels were below the threshold of detection with the concentrations tested. Further investigation of this medication for posterior segment applications would require intravitreal delivery or chemical modification of the drug.

In a Phase 2 dry eye trial, subjects receiving SAR 1118 demonstrated a reduction in corneal staining, increased tear production, and improved visual-related function as compared to placebo. These data were part of the scientific program of the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting held in Fort Lauderdale, Florida. SAR 1118 is a first-in-class topically administered small molecule integrin antagonist that inhibits T-cell mediated inflammation, a key component of dry eye disease.

In the randomized, placebo-controlled, multi-center trial, which included 230 subjects with dry eye disease, SAR 1118 demonstrated dose-dependent significant improvements (p<0.05) in inferior corneal staining over 12 weeks. As early as two weeks, a statistically significant(p<0.05) increase in tear production and improvement in visual-related functions (ability to read, drive at night, use a computer, and watch television) were observed, demonstrating early onset of action. Visual-related function was assessed using the Ocular Surface Disease Index (OSDI), a validated instrument designed to measure the severity of dry eye disease and the impact on vision-related function and quality of life. SAR 1118 was safe and well-tolerated with no serious ocular adverse events reported. Most ocular adverse events were transient and related to initial instillation.

“We are encouraged by the clinical effects of SAR 1118 in improving both signs and symptoms of dry eye, which supports the broad anti-inflammatory mechanism of this novel molecule,” commented Charles Semba, MD, Chief Medical Officer of SARcode Corporation. “We are excited to begin Phase 3 development in the later part of 2011, and have discussed appropriate and acceptable endpoints with the regulatory bodies to facilitate a smooth path towards approval.”

“It is well known that dry eye disease can have a deleterious effect on visual function, daily activities, workplace productivity, and quality of life. The potential to impact a patient’s quality of life in as early as 2 weeks could be a major advance in the current dry eye treatment model,” said Quinton Oswald, Chief Executive Officer of SARcode Corporation. “We hope to achieve similar results in our Phase 3 program.”

About Dry Eye Syndrome

Dry eye syndrome is a prevalent and often chronic condition estimated to affect approximately 20 million people in the US. It is among the most common diseases treated by ophthalmologists throughout the world, and has been shown to have a significant impact upon quality of life. Dry eye varies in severity and etiology, and symptoms most commonly manifest as discomfort, visual disturbances, and tear film instability due to decreased quality or quantity of tears. A major contributing factor towards the development of dry eye is inflammation caused by T-cell infiltration, proliferation and inflammatory cytokine production that can lead to reduction in tear film quality and ocular surface damage.

About SAR 1118 – SAR 1118 is a potent novel small molecule lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; alphaLbeta2) antagonist under investigation for a broad range of ocular inflammatory conditions including dry eye and diabetic macular edema. LFA-1 is member of the integrin family of adhesion receptors found on the surface of all leukocytes and represents a therapeutic target central to a number of inflammatory stimuli. SAR 1118 has demonstrated potency in blocking LFA-1 binding to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54), thereby inhibiting cell adhesion, cytokine production, and cellular proliferation in in vitro models.

About SARcode Corporation – SARcode Corporation, founded in 2006, is a venture-backed ophthalmic biopharmaceutical company based in Brisbane, CA. SARcode’s lead development program is a novel class of lymphocyte function-associated antigen-1 (LFA-1) antagonists for the treatment T-cell mediated inflammatory diseases. Institutional investors include Alta Partners and Clarus Venture Partners. For more information, visit www.sarcode.com

……………………….for a scheme see     http://newdrugapprovals.org/2014/09/04/lifitegrast-sar-1118-effective-inhibitor-of-lfa-1-interactions-with-icam-1/

http://www.google.com.mx/patents/WO2005044817A1?cl=en

EXAMPLE 14 [0305] This example describes the synthesis of

Figure imgf000097_0002

[0306] which was prepared according to Scheme 9 and the procedure below.

[0307] SCHEME 9

Figure imgf000097_0003

[0308] a) To a solution of 3-carboxylbenzenesulfonyl chloride (3.54 g, 16 mmol) in ethyl acetate (50 mL) at 0 °C was added concentrated ammonia (2.5 mL). The reaction was neutralized with HCl in dioance (20 mL), diluted with ethyl acetate (100 mL), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate yielded the title compound, which was used without purification. [0309] b) Crude compound 14.1 was dissolved in THF (50 mL), to it was added borane (1.0 M in THF, 50 L) over 20 minute period. After the reaction was stirred at room temperature for 15 hours, the reaction was diluted with brine (20 mL) and water (10 mL), extracted with ethyl acetate (100 mL). The organic extract was dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate yielded the title compound, which was used without further purification. [0310] c) To crude compound 14.2 solution in DCM (100 mL) was added activated 4A molecular sieve powder (8 g), pyridinium dichromate (7.55 g, 20 mmol). After the reaction was stirred at room temperature for 2 hours, the reaction mixture was filtered through silica gel (50 g), rinsed with ethyl acetate. The residue after concentration of the filtrate was purified by silca gel column with 30-50% ethyl acetate in hexane to give compound 14.3 (477mg, 16%, 3 steps). ESI-MS (m/z): (M+H4″) 186. [0311] d) Compound 14.4 was made according to Example 8e except that compound 14.3 was used instead of compound 8.7. MS (ESI4) m/z: 260 (M+H4″). [0312] e) Compound 14 was made according to Example 3g except that compound 14.4 was used instead of compound 3.4. 1H NMR (400 MHz, CD3OD) δ 7.89 (s, 1 H), 7.80 (s, 1 H), 7.75 (m, 2 H), 7.64 (s, 1 H), 7.57(d, 1 H), 7.34 (d, 2 H), 6.93 9s, 1 H), 5.00 (m, 1 H), 3.99 (m, 1 H), 3.73 (m, 1 H), 3.40 (dd, 1 H), 3.12 (dd, 1 H), 2.89 (m, 2 H) ppm; ESI-MS (m/z) 616 (M+H4″). [0313] EXAMPLE 15 [0314] This example describes the synthesis of

Figure imgf000098_0001

which was prepared according to Scheme 10 and the procedure below. [0315] SCHEME 10 rr–λ I BuLi, THF m-CPBA

Figure imgf000099_0001

s ) 2. DMF CH2CI2

Figure imgf000099_0002

15.1 15.2

Figure imgf000099_0003

[0316] a) To a solution of 0.2 mol of furan in 200 mL of dry THF was added 0.2 mol of «-BuLi (1.6 M in hexanes) at -78 °C, the resulting solution was stirred at room temperature for 4 hours. Subsequently, the mixture was cooled to -78 °C and treated with 0.21 mol of dimethyl disulfide, and the mixture was stirred at room temperature overnight, followed by adding 10 mL of saturated aqueous NH C1. The mixture was concentrated at room temperature, and the residue was diluted with 200 mL of saturated aqueous NH4C1 and extracted with ether. The extract was then washed with brine and dried with anhydrous Na2SO . The solvent was removed, and the residue was distilled to collect, the fraction at 135-140 °C/760 mmHg to give compound 15.1 in 55% yield. 1H NMR (400 MHz, CD3C1): δ 7.50 (s, IH), 6.45 (m, IH), 6.39 (s, IH), 2.42 (s, 3H) ppm. [0317] b) To a solution of 0.1 mol of compound 15.1 in 100 mL of dry THF was added 0.1 mol of n- uLi (1.6 M in hexanes) at -78 °C, the resulting solution was stirred at room temperature for 4 hours. Subsequently, the mixture was cooled to -78 °C and treated with 0.12 mol of dry DMF, and the mixture was stirred at room temperature overnight. The reaction was quenched by adding 10 mL of saturated aqueous NH4C1, and the mixture was concentrated. The residue was diluted with 100 mL of brine and extracted with EtOAC. The extract was washed with brine and dried with anhydrous Na2SO4. The solvent was removed and the residue was purified to give the title compound in 65% yield. 1H NMR (400 MHz, CD3C1): δ 9.52 (s, IH), 7.24 (d, J= 3.4 Hz, IH), 6.42 (d, J= 3.4Hz, IH), 2.60 (s, 3H) ppm; ESI-MS (m/z) (M+H4) 143.1. [0318] c) A mixture of 50 mmol of compound 15.2 and 120 mmol of -CPBA in 100 mL of CH2C12 was stirred at room temperature overnight. The mixture was diluted with 150 mL of CH2C12, and the mixture was washed with saturated aqueous NaHCO3 for several times. The solution was then dried with anhydrous Na2SO4 and concentrated. The residue was purified to give compound 15.3 in 70% yield. 1H NMR (400 MHz, CD3C1): δ 9.83 (s, IH), 7.33 (m, 2H), 3.27 (s, 3H) ppm; ESI-MS (m/z): (M+H4″) 175.0.

[0319] d) Compound 15.4 was made according to Example 8e except that compound 15.3 was used instead of 8.7. ESI-MS (m/z): (M+H4″) 248.1. [0320] e) Compound 15 was made according to Example except that compound 15.4 was used instead of 3.4. 1H NMR (400 MHz, CD3OD): δ 7.92 (s, IH), 7.76 (m, IH), 7.67 (s, IH), 7.34 (m, IH), 7.13 (s, IH), 6.69 (s, IH), 6.49 (s, IH), 5.11 (m, IH), 4.73 and 4.88 (m, 2H), 3.76 and 4.02 (m, 2H), 3.46 (m, IH), 3.30 (m, IH), 3.17 (s, 3H), 2.94 (m, 2H) ppm; ESI-MS (m/z): (M+H4) 605.05. [0321]

…………………………………….

US 20110092707

http://www.google.com/patents/US20110092707

Formula I:

Figure US20110092707A1-20110421-C00002

has been found to be an effective inhibitor of Lymphocyte Function-Associated Antigen-1 (LFA-1) interactions with the family of Intercellular Adhesion Molecules (ICAM), and has desirable pharmacokinetic properties, including rapid systemic clearance. Improved forms, including crystalline forms, and their uses in treatment of disorders mediated by the interaction of LFA-1 and ICAM are described herein. Novel polymorphs of the compound of Formula I which may afford improved purity, stability, bioavailability and other like characteristics for use in pharmaceutical formulations and methods of use thereof are useful in treating disease.

Methods of Manufacture of the Compound of Formula I

In one embodiment, the compound of Formula I was synthesized as in the following Schemes 1-7. Alternate steps were used in the process as described below. The variants of this overall route yield superior yields, cost of goods and superior chiral purity compared to previously described methods. The final product of this synthesis yields crystalline Form A directly.

Figure US20110092707A1-20110421-C00009

A first alternative protecting strategy produces compound 5, a trityl protected species as shown in Scheme 1. The synthesis begins by reductively aminating 3, 5, dichlorobenzaldehyde, compound 1, with 1-chloro-2-aminoethane and sodium cyanoborohydride in 35% yield. Cyclization of compound 2 using aluminum chloride catalysis and ammonium chloride at 185° C. provided compound 3 in 91% yield. Protection of the free amine of compound 3 as the trityl protected species afforded compound 4 in 89% yield. A carboxylic acid functionality was introduced by treatment of compound 4 with n-butyllithium (nBuLi) and Tetramethylethylenediamine (TMEDA), with subsequent introduction of carbon dioxide, to produce compound 5 in 75% yield.

Figure US20110092707A1-20110421-C00010

Bromophenylalanine was used as the starting material for the right hand portion of the final molecule as shown in Scheme 2. t-Butylcarbamate (Boc) protection of the amino group was accomplished, using sodium bicarbonate (3 equivalents), t-butyl dicarbonate (Boc2O, 1.1 equivalent) in dioxane and water, to obtain compound 7 in 98% yield. A methyl sulfone functionality was introduced by treating the bromo compound 7 with copper iodide (0.4 equivalents), cesium carbonate (0.5 equivalents), L-proline (0.8 equivalents), and the sodium salt of methanesulfinic acid (3.9 equivalents) in dimethylsulfoxide (DMSO) at 95-100° C. for a total of 9 hours, with two further additions of copper iodide (0.2 equivalents) and L-proline (0.4 equivalents) during that period. Compound 8 was isolated in 96% yield. The carboxylic acid of compound 8 was converted to the benzyl ester, compound 9, in 99% yield, using benzyl alcohol (1.1 equivalent), dimethylaminopyridine (DMAP, 0.1 equivalent) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC, 1.0 equivalent). The amino group of compound 9 is deprotected by adding a 4N solution of HCl in dioxane to compound 9 at 0° C. in methylene chloride. The HCl salt of the free amino species, compound 10 was isolated in 94% yield.

Figure US20110092707A1-20110421-C00011

Compound 5 was treated with triethylamine (TEA, 5 equivalents) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1.25 equivalents) for 10 minutes in dimethylformamide (DMF), and then compound 10 was added to the solution. After stirring at room temperature for 18 hours, the product, compound 11 was isolated in 70% yield. Removal of the trityl protecting group was accomplished by treating compound 1, with HCl in dioxane (4N, excess) at room temperature for 2 hours, diethyl ether added, and the solid product, compound 12, was isolated by filtration in 95% yield.

Figure US20110092707A1-20110421-C00012

The benzofuranyl carbonyl moiety of the compound of Formula I was prepared using two alternative schemes, Scheme 4 and Scheme 4″. In one embodiment, the benzofuranyl carbonyl moiety was prepared by protecting the hydroxyl group of compound 13 by reacting with tert-butyldimethylsilyl chloride (1.0 equivalents) and triethylamine (TEA, 1.1 equivalents) in acetone, to give compound 14 in 79% yield. A solution of compound 14 in methanol was then treated with sodium borohydride (1.0 equivalent) at room temperature overnight. The reaction was quenched with an addition of acetone, stirred at room temperature for a further 2.5 hours, aqueous HCl (4N) was added with the temperature controlled to below 28C, tetrahydrofuran (THF) was added, and the solution stirred overnight under argon and in the absence of light. The product, compound 15, was isolated quantitatively by extraction into methylene chloride, concentrated at low heat, and used without further purification. The triflate ester, compound 16, was produced in 69% yield from compound 15 by reacting it with N-phenyl-bis(trifluoromethanesulfonimide) (1.0 equivalent) in methylene chloride for 72 hours. Compound 16 in a mixture of DMF, methanol, and triethylamine, was added to a prepared solution of palladium acetate, diphenyl, DMF and methanol in an autoclave. Carbon monoxide was charged into the autoclave to a pressure of 8 bar, and the reaction mixture was heated at 70° C. for 6 hours. After workup, compound 17 was isolated in 91% yield. Lithium hydroxide (4 equivalents) in methanol and water was used to hydrolyze the ester and permit the isolation of compound 18 in 97% yield.

Figure US20110092707A1-20110421-C00013

In one embodiment, the benzofuranyl carbonyl moiety of the compound of Formula I was prepared according to Scheme 4″. By way of an Arbuzov reaction, diethyl 2-(1,3-dioxolan-2-yl)ethylphosphonate, compound 1″, was prepared from 2-(2-bromoethyl)-1,3-dioxolane by the addition of triethyl phosphate. After removal of ethyl bromide through distillation at 210° C. the crude reaction mixture was cooled and then by way of vacuum distillation, compound 1″ was collected as a colorless oil in 94% yield.

In the next step, n-butyllithium (2.15 equivalents) in hexane was cooled to −70° C. and diisopropylamine (2.25 equivalents) was added while keeping the temperature below −60° C. Compound 1″ (1 equivalent) dissolved in tetrahydrofuran (THF) was added over 30 min at −70° C. After 10 min, diethyl carbonate (1.05 equivalents) dissolved in THF was added over 30 min keeping the reaction temperature below −60° C. After stirring for one hour at −60° C., the reaction was allowed to warm to 15° C. and furan-2-carbaldehyde (1.3 equivalents) dissolved in THF was added. After stirring for 20 hrs at room temperature, the reaction was rotary evaporated to dryness to yield ethyl 2-(1,3-dioxolan2-yl)methyl-3-(furan-2-yl)acrylate, compound 5″. Crude compound 5″ was used directly in the next reaction.

The crude compound 5″ (1 equivalent) was dissolved in ethanol and added to a mixture of water and phosphoric acid (85%, 15 equivalents) over 30 min while keeping the temperature below 50° C. After stirring for 20 hrs at room temperature, another 200 ml of phosphoric acid (85%) was added and the mixture was heated to 50° C. for an additional two hrs. After removal of ethanol by rotary evaporation, the material was extracted with toluene, washed with water, dried with sodium sulfate, treated with charcoal, filtered and dried down to an oil. This oil was distilled to afford ethyl benzofuran-6-carboxylate, compound 6″, (bp 111-114.5° C.) which crystallized on standing. Compound 6″ was recovered at 57% yield based on compound 1″.

Compound 6″ (875 mmol) was dissolved in methanol and tetrahydrofuran (THF). Sodium hydroxide (4 M, 3 equivalents) was added and the reaction was stirred overnight. After concentration via rotary evaporation, the aqueous solution was extracted with methyl tert-butyl ether (MTBE), acidified to pH 2 with the addition of hydrochloric acid (HCl) and cooled resulting in fine crystals of benzofuran-6-carboxylic acid, i.e., compound 18. Compound 18 was isolated, washed with water and dried to a final yield of 97% yield.

Figure US20110092707A1-20110421-C00014

The benzofuran carboxylic acid 18 was treated with oxalyl chloride (1.2 equivalents) and a catalytic amount of DMF, stirring for 5.5 hours until a clear solution was obtained. The solvent was removed under reduced pressure and the acid chloride of compound 18 was stored under argon until use, on the next day. The acid chloride, in methylene chloride was added slowly to a methylene chloride solution of the compound of Formula I and diisopropylethylamine (DIPEA) which was cooled to 0-5° C. The reaction was not permitted to rise above 5° C., and after completion of addition, was stirred at 5° C. for a further 0.5 hour. Upon aqueous workup and extraction with methylene chloride, the product, compound 19, was isolated in quantitative yield.

Taking the compound of Formula I directly as the crude reaction product after transfer hydrogenolysis, and reconcentrating down from a solution in methylene chloride, the amorphous form of the compound of Formula I was obtained in 97% purity.

Figure US20110092707A1-20110421-C00015

An alternative protection strategy in this synthetic approach is illustrated in Scheme 6.

…………………….

WO 2014018748

http://www.google.com/patents/WO2014018748A1?cl=en

[0040] Methods of Manufacture of the Compound of Formula I

Figure imgf000009_0001

[0041] In one embodiment, the compound of Formula I is synthesized as in the following Schemes 1-7. The final product of this synthesis yields the compound of Formula I as an amorphous solid or as a crystalline form such as Forms A-E, or a pharmaceutically acceptable salt, either directly or indirectly. Variants of this overall route may provide superior yields, cost of goods, and/or superior chiral purity.

[0042] Protecting groups for amino and carboxy groups are known in the art. For example, see Greene, Protective Groups in Organic Synthesis, Wiley Interscience, 1981, and subsequent editions.

[0043] In various embodiments in the subsequent schemes, HATU is used as a reagent in amide- bond forming reactions. Alternatively, HATU is not used. In various embodiments, at least one amide-bond forming reaction is performed with thionyl chloride as a reagent in place of HATU. In various embodiments, all amide-bond forming reactions are performed with thionyl chloride as a reagent to form acid chlorides.

[0044] Scheme 1

Figure imgf000011_0001

[0045] A first alternative protecting strategy produces compound 5′, a protected species as shown in Scheme 1. The synthesis begins by reductively aminating 3, 5, dichlorobenzaldehyde, compound . Cyclization of compound 2′ provides compound 3′. Protection of the free amine of compound 3′ as a protected species provides compound 4′. A carboxylic acid functionality is introduced by treatment of compound 4′ with introduction of carbon dioxide, to produce compound 5′. In various embodiments, the protecting group of compound 4′ is a benzofuranyl carbonyl moiety derived from compound 18′.

[0046] In various embodiments, upon scaleup to multikilogram and larger scale reactions, treatment of compound 4′ with strong base (such as n-butyllithium (nBuLi) to generate a lithio species, or lithium diisopropyl amide (LDA) to generate the lithio species) is performed in flow mode rather than batchwise reaction due to instability of lithio species except at cold temperatures. Flow rates and residence times may be adjusted to maximize yield.

[0047] Scheme IB

Figure imgf000012_0001
Figure imgf000012_0002

5′ 4″”

[0048] In various embodiments, 6-hydroxy-l, 2,3, 4-tetrahydro-isoquino line (Compound 3″) is used as a starting material for Compound 5′. The starting material is chlorinated (x2) for example, with N-chlorosuccinimide. In various embodiments, the chlorination is performed in the presence of a sulfonic acid. In various embodiments, the sulfonic acid is selected from p- toluenesulfonic acid and methanesulfonic acid. Following protection of the amino group, the hydroxy group is functionalized, for example, as the triflate ester, which is carbonylated to yield the amino-protected methyl ester. Hydrolysis of the methyl ester yields the amino protected carboxylic acid.

[0049] Scheme 2

Figure imgf000012_0003

[0050] In various embodiments, bromophenyl alanine is used as the starting material for a portion of the final molecule as shown in Scheme 2. The starting material is protected with an amino protecting group to allow for introduction of a methyl sulfone functionality in compound 8′. Protecting groups are rearranged by introduction of an orthogonal protecting group for the carboxylic moiety, followed by deprotection of the amino group to provide compound 10′. In various embodiments, expensive or exotic bases are replaced with carbonate base such as potassium carbonate or calcium carbonate as a reagent.

[0051] Scheme 2A

Figure imgf000013_0001

10

[0052] In various embodiments, 3-methylsulfonylbenzaldehyde is converted into the 3- methylsulfonylphenylalanine derivative and functionalized to yield compound 10 as shown above.

[0053] Scheme 3

Figure imgf000014_0001

12′

[0054] Compounds 5′ and 10′ are joined through amide bond formation followed by deprotection of the remaining amino group in the presence of the carboxylic protecting group to yield compound 12′ or a salt thereof, such as the HCL salt.

[0055] Scheme 3

Figure imgf000014_0002

[0056] As an alternative to Scheme 3, compound 10″ is coupled with compound 5′ to yield the bromo compound 12″”, with subsequent introduction of a methyl sulfone functionality in place of bromine at a later step to produce compound 19′. Alternatively, instead of a bromine, compound 10″ includes X, where X is any halide (CI, I, Br, F) or a leaving group such as OTs, OTf, or the like.

[0057] Scheme 4

Figure imgf000015_0001

[0058] The benzofuranyl carbonyl moiety of the compound of Formula I can be prepared using various alternative schemes. In one embodiment, the benzofuranyl carbonyl moiety is prepared by protecting the hydroxyl group of compound 13′, reducing the carbonyl of compound 13′ to yield the benzofuranyl moiety, followed by carboxylation to yield compound 18′.

[0059] Scheme 4A

[0060] In one embodiment, compound 18′ is prepared from 6-hydroxybenzofuran via the triflate ester and the 6-carboxy methyl ester as intermediates, as shown in Example 4A.

[0061] Schem

Figure imgf000015_0002

[0062] The benzofuran carboxylic acid 18′ is coupled with compound 12′ (or a salt thereof) by amide bond formation to yield protected compound 19′, as shown in Scheme 5. Amide bond formation is known in the art

[0063] Schem

Figure imgf000016_0001

[0064] As an alternative to Schemes 3-5, compounds 18′ and 5″ may be coupled through amide bond formation followed by deprotection of the remaining carboxylic group to form compound 12″. Amide bond formation between compound 12″ and 10′ yields compound 19′ with a protected carboxylic group.

[0065] Scheme 5B

Figure imgf000017_0001

[0066] As an alternative to Schemes 1-5, compounds 12″ and 10″ may be coupled through amide bond formation followed by introduction of a methyl sulfone functionality in place of the bromine in converting compound 19″ to compound 19′ (similar to Scheme 2). Alternatively, instead of a bromine, compound 10″ includes X, where X is any halide (CI, I, Br, F) or a leaving group such as OTs, OTf, or the like. Compound 12″ can also be made using the following scheme:

Figure imgf000018_0001

[0067] Scheme 6

Figure imgf000018_0002

[0068] Final deprotection of compound 19′ to yield the compound of Formula I or a salt thereof is accomplished in a variety of ways. In various embodiments, the resulting compound of Formula I is provided in higher optical purity and/or higher overall purity and/or higher overall yield.

EXAMPLES

[00111] Example 1

Figure imgf000029_0001

Scheme El

[00112] Reductively aminating 3,5-dichlorobenzaldehyde, compound 1, with l-chloro-2- aminoethane and sodium cyanoborohydride provided 35% yield of compound 2. Cyclization of compound 2 using aluminum chloride catalysis and ammoniun chloride at 185°C provided compound 3 in 91% yield. Protection of the free amine of compound 3 as the trityl protected species afforded compound 4 in 89%> yield. A carboxylic acid functionality was introduced by treatment of compound 4 with n-butyllithium (nBuLi) and tetramethylethylenediamine (TMEDA), with subsequent introduction of carbon dioxide, to produce trityl protected compound 5 in 75% yield.

[00113] Example 1 A

Figure imgf000030_0001

2″

Figure imgf000030_0002

Scheme El A

[00114] To a glass reactor was charged 3,5-dichlorobenzaldehyde. Absolute ethanol was added to the batch slowly (this addition is mildly exothermic) and agitation started. 2,2- Diethoxyethyl amine (1.03 equiv) was slowly added to the batch, keeping the batch temperature at 20-78 °C. The batch was then heated to 76-78 °C for 2 h. GC-MS analysis indicated reaction completion (starting material < 1%). The batch was cooled to ambient temperature for work-up. The batch was concentrated in vacuo to a residue and azeotroped with heptanes (x2). The residue was cooled and held at 0-5 °C for 12 h to form a suspension. The solids were collected by filtration and the cake was washed with cold (0-5 °C) heptanes, and dried under hot nitrogen (45-50 °C) to afford Compound 2′ as a white solid (94% yield).

[00115] To a glass reactor was charged concentrated 95-98%) sulfuric acid (25.9 equiv).

The batch was heated to 120-125 °C and a solution of Compound 2′ in CH2CI2 was added slowly over 1 h, keeping the batch temperature between 120-125 °C. The batch was then stirred at 120— 125 °C for 6 h. The batch was cooled to < 50 °C. To a glass reactor was charged DI water and the batch temperature was adjusted to 0-5 °C. The reaction mixture was slowly transferred, keeping the batch temperature between 0-50 °C. DI water was used to aid the transfer. To the batch was added Dicalite 4200. The batch was filtered through a pad of Dicalite 4200. To the filtrate was added 50% aqueous sodium hydroxide solution slowly over 3 h, keeping the batch temperature between 0-50 °C to adjust the pH to 12. The resulting suspension was stirred at 45- 50 °C for 2 h and the solids were collected by filtration. The filter cake was slurried in DI water at 30-35 °C for 1 h. The batch was filtered. The cake was washed with heptanes and dried in vacuum oven at 45-50 °C for 22 h to give crude compound 2″ as a tan solid (75% yield), which was further purified by recrystallization.

[00116] To a reactor was added platinum dioxide (0.012 equiv), Compound 2″, and

MeOH (10 vol) and the suspension was stirred at room temperature under argon for 10 minutes. The reaction mixture was inerted with argon three times and then stirred under 125 psi of hydrogen at room temperature for 25 hours. HPLC analysis indicated complete reaction with less than 1% of the starting material remaining. After standing, the supernatant was decanted from the solids (catalyst) by vacuum. To the solids was added methanol and the slurry was mixed under nitrogen. The solids were allowed to settle on the bottom over several hours. The supernatant was decanted from the solids by vacuum. The combined supernatants were filtered through Celite under a blanket of nitrogen and the filter pad was washed with MeOH (x2). The combined filtrate and washes were concentrated to dryness. The residue was slurried in MTBE. The mixture was treated with 3 M HC1 while maintaining the temperature <40 °C resulting in the formation of a heavy precipitate. The mixture was stirred at 35-40 °C for 60 to 90 minutes. The batch was cooled to 0-5 °C, stirred for 60 to 90 minutes and then filtered. The filter cake was washed with cold DI water (x2) followed by a displacement wash with MTBE (x2). The filter cake was dried under reduced pressure to afford Compound 3 Hydrochloride Salt (86% yield). The hydrogenation catalyst can be recovered and re-used.

[00117] Compound 3 and trityl chloride were added to the reaction flask. DCM (10 vol) was added to the reactor and agitation was started to form slurry. The reaction mixture was cooled to 10-15 °C. N,N-Diisopropylethylamine (2.5 equiv) was slowly added to the reaction mixture, maintaining the temperature at 15-25 °C during the addition. Once addition was complete, the batch was stirred at 15 to 25 °C for a minimum of 60 minutes. The reaction was assayed by HPLC by diluting a sample with acetonitrile and then injecting it on the HPLC. The first assay after 30 minutes indicated that the reaction was complete with <1% of starting material observed by HPLC analysis. The reaction mixture was diluted with DI water (5 vol). The reaction mixture was stirred for 5 minutes after which it was transferred into a separation funnel and the phases were allowed to separate. The DCM layer was washed with DI water (5 vol) by stirring for 5 minutes and then allowing the phases to separate. The DCM layer was washed with brine (5 vol) by stirring for 5 minutes and then allowing the phases to separate. The DCM layer was dried over magnesium sulfate, filtered and the filter cake was washed with DCM (x2). The combined filtrate and washes were concentrated to a residue that was azeotroped with EtOAc (x2). The residue was suspended in EtOAc and stirred for 1 hour in a 40 °C water bath. The resulting slurry was cooled to 0-5 °C for 1 hour and then filtered. The filter cake was washed twice with EtOAc and then dried under reduced pressure to afford Compound 4.

[00118] Exam le IB

Figure imgf000032_0001

21 4″

[00119] To 1, 2,3, 4-tetrahydro-6-hydroxy-isoqino line in acetonitrile was added p- toluenesulfonic acid and N-chlorosuccinimide. The suspension was cooled to ambient temperature, and the product isolated by filtration for a yield of approximately 61% with purity greater than 95%. The isolated TsOH salt was recrystallized until purity was greater than 99.7%. To one equivalent of the TsOH salt suspended in methanol was added 2M sodium carbonate (0.55 eq.) and 1.2 eq. of Boc anhydride. The suspension was stirred at room temperature overnight. The reaction was monitored by HPLC. Upon completion, the mixture was cooled to below 10 °C, water was added, and the Boc-protected dichloro compound was isolated by filtraton. The product was washed and dried at 40 °C for a yield of 95% and purity of >97%. The Boc-protected dichloro compound was suspended in dichloromethane (10 volumes) and pyridine (5 volumes) was added. The mixture was cooled to below 2 °C, and triflic anhydride (1.25 eq) was added. The mixture was stirred at 0-2 °C for 10 minutes, and then poured into 10 volumes of 6%) aqueous sodium hydrogen carbonate solution. After washing with dichloromethane, the organic phases were combined and dried over magnesium sulphate. Following purification, the product (Compound 4′) was obtained in 90% yield and >98% purity. Compound 4′ was dissolved in dimethylformamide and methanol at room temperature. Diisopropylamine (4 eq) was added. Under CO atmosphere, l,3-bis(diphenylphosphino)propane (0.1 eq) and palladium acetate (0.1 eq) was added. The reaction was heated to refiux, and monitored by HPLC. Upon near completion, the mixture was cooled to ambient temperature. Workup with water, ethyl aceate, and brine yielded Compound 4″, which was used without further purification. Compound 4″ was dissolved in methanol and 2.4 M sodium hydroxide (10 volumes each) and refiuxed. The mixture was cooled to ambient temperature, and toluene was added. Following aqueous workup, the pH was adjusted to 2.3 with 3M hydrochloric acid, and crude product was isolated by filtration in 53% yield with greater than 80% purity.

[00120] Exam le 2

Figure imgf000033_0001

Scheme E2

[00121] t-Butylcarbamate (Boc) protection of the amino group of bromophenyl alanine was accomplished, using sodium bicarbonate (3 equivalents), t-butyl dicarbonate (Boc20, 1.1 equivalent) in dioxane and water, to obtain compound 7 in 98% yield. A methyl sulfone functionality was introduced by treating the bromo compound 7 with copper iodide (0.4 equivalents), cesium carbonate (0.5 equivalents), L-proline (0.8 equivalents), and the sodium salt of methanesulfinic acid (3.9 equivalents) in dimethylsulfoxide (DMSO) at 95-100°C for a total of 9 hours, with two further additions of copper iodide (0.2 equivalents) and L-proline (0.4 equivalents) during that period. Compound 8 was isolated in 96%> yield. The carboxylic acid of compound 8 was converted to the benzyl ester, compound 9, in 99% yield, using benzyl alcohol (1.1 equivalent), dimethylaminopyridine (DMAP, 0.1 equivalent) and N-(3- dimethylaminopropyl)-N-ethylcarbodiimide (EDC, 1.0 equivalent). The amino group of compound 9 is deprotected by adding a 4N solution of HC1 in dioxane to compound 9 at 0°C in methylene chloride. The HCl salt of the free amino species, compound 10 was isolated in 94% yield.

[00122] Example 2 A

[00123] Example 2 was repeated with potassium carbonate in place of cesium carbonate.

[00124] Example 2B

[00125] Boc-protected bromophenylalanine (Compound 7) (100g) was dissolved in

DMSO (400 mL) with stirring and degassing with argon. Sodium methane sulfmate (98g), copper iodide (28.7g), potassium carbonate (40 g) and L-proline (26.75g) were added at 28-30 °C. Reaction was heated to about 87 °C for about 17-19 hours. Reaction was cooled and quenched with crushed ice, stirred for 30-40 minutes, and the pH was adjusted from about 12 to about 3-4 with citric acid (350 g). Quenched reaction mixture was filtered, extracted with dichloromethane x3, washed with ammonium chloride solution, washed with sodium bisulphite solution, and washed with brine. Crude product in dichloromethane was concentrated in vacuo until moisture content was below about 0.5%, and used in next step without further isolation. Crude compound 8 in dichloromethane was charged with benzyl alcohol and DMPA with stirring under nitrogen. Reaction cooled to 0-5 °C. EDC-HCL (1.03 equiv) added with stirring for 30 minutes. Upon completion of reaction by TLC and HPLC, the reaction was quenched with sodium bicarbonate solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with citric acid solution, and combined organic layers were washed with brine solution. Dichloromethane was removed at 45- 50 °C, and the concentrate was used for next step without further isolation. The amino group of compound 9 was deprotected by adding a 4N solution of HCl in dioxane to compound 9 at 10- 15°C in methylene chloride. The HCl salt of the free amino species, compound 10 was isolated by filtration from diethyl ether. Isolation of compound 10 was performed through recrystallization using a dimethylformamide/dichloromethane solvent system.

[00126] Example 3

Figure imgf000035_0001

Scheme E3

[00127] Compound 5 was treated with triethylamine (TEA, 5 equivalents) and 2-(7-Aza- lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 1.25 equivalents) for 10 minutes in dimethylformamide (DMF), and then compound 10 was added to the solution. After stirring at room temperature for 18 hours, the product, compound 11 was isolated in 70% yield. Removal of the trityl protecting group was accomplished by treating compound 11, with HC1 in dioxane (4 N, excess) at room temperature for 2 hours, diethyl ether added, and the solid product, compound 12, was isolated by filtration in 95% yield. The compound 12 exists in both amorphous and crystalline form and can be isolated in either form.

[00128] Example 3 A

[00129] Compound 5 was dissolved in isopropyl acetate and cooled to 20 to 25 °C.

Thionyl chloride was added, with cooling to 10 to 15 °C, and N-methylmorpholine was added slowly. The reaction was monitored by HPLC. Compound 10, water, and isopropyl acetate were stirred at 15 to 20°C until a solution was achieved. N-methylmorpholine was added followed by addition of the Compound 5 reaction mixture (acid chloride of Compound 5). The reaction was monitored by HPLC. Upon completion, the biphasic layers were allowed to settle, and the aqueous layer was removed. The upper organic layer was extracted with water, and the remaining organic layer was distilled under vacuum. Dioxane and IpAc were added with further distillation. Once dry, 4N anhydrous HC1 in dioxane was added. The mixture was stirred at 20 to 25°C for 12 hours, and checked for complete deprotection by HPLC. Once complete, the thick slurry was filtered, washed with IP Ac and dried under vacuum at 45 to 55°C. Yield of Compound 12 was 88%.

[00130] Example 4

[00131] The benzofuranyl carbonyl moiety of the compound of Formula I was prepared using various schemes, (Schemes E4, E4A, and E4B).

Figure imgf000036_0001

15

Phenyl-bis-triflate

Figure imgf000036_0002

18 ‘

Scheme E4

[00132] The benzofuranyl carbonyl moiety was prepared by protecting the hydroxyl group of compound 13 by reacting with tert-butyldimethylsilyl chloride (1.0 equivalents) and triethylamine (TEA, 1.1 equivalents) in acetone, to give compound 14 in 79% yield. A solution of compound 14 in methanol was then treated with sodium borohydride (1.0 equivalent) at room temperature overnight. The reaction was quenched with an addition of acetone, stirred at room temperature for a further 2.5 hours, aqueous HCl (4N) was added with the temperature controlled to below 28 °C, tetrahydrofuran (THF) was added, and the solution stirred overnight under argon and in the absence of light. The product, compound 15, was isolated quantitatively by extraction into methylene chloride, concentrated at low heat, and used without further purification. The triflate ester, compound 16, was produced in 69% yield from compound 15 by reacting it with N- phenyl-bis(trifluoromethanesulfonimide) (1.0 equivalent) in methylene chloride for 72 hours. Compound 16 in a mixture of DMF, methanol, and triethylamine, was added to a prepared solution of palladium acetate, l,3-Bis(diphenylphosphino)propane (dppp), DMF and methanol in an autoclave. Carbon monoxide was charged into the autoclave to a pressure of 8 bar, and the reaction mixture was heated at 70 °C for 6 hours. After workup, compound 17 was isolated in 91% yield. Lithium hydroxide (4 equivalents) in methanol and water was used to hydro lyze the ester and permit the isolation of compound 18′ in 97% yield.

[00133] Example 4A

[00134] Example 4 was repeated with triflic anhydride and sodium hydroxide as reagents for the ester hydrolysis.

[00135] Compound 15 (6-Hydroxybenzofuran) was stirred in dichloromethane and diisopropylethylamine. Triflic anhydride (1.2 eq.) was added, keeping the temperature below 20C. The reaction was monitored by HPLC. The reaction was quenched with methanol, solvent was removed with vacuum, and the crude residue of Compound 16 was used without further purification. Compound 16 as crude residue was dissolved in 4 volumes of dimethylformamide and 2 volumes methanol. To the solution was added 0.02 eq. of palladium acetate, 0.02 eq. of dppp, and CO under pressure. The reaction was monitored by HPLC. Following workup, Compound 17 was isolated as a crude oily residue without further purification. The residue of compound 17 was dissolved in methanol (5 volumes) and 1 volume of sodium hydroxide (27.65%) was added. The mixture was heated to 40C until full conversion of HPLC. The mixture was cooled to ambient temperature and 3 volumes of water were added. The pH was adjusted to about 2 with 3M hydrochloric acid. The suspension was filtered, washed with water, and dried to give Compound 18′ in about 75% overall yield with purity >99.5%.

[00136] Example 4B

Figure imgf000037_0001

Scheme E4B [00137] Diethyl 2-(l,3-dioxolan-2-yl)ethylphosphonate, compound 1″, was prepared from

2-(2-bromoethyl)-l,3-dioxolane by the addition of triethyl phosphate. After removal of ethyl bromide through distillation at 210°C the crude reaction mixture was cooled and then by way of vacuum distillation, compound 1″ was collected as a colorless oil in 94% yield.

[00138] In the next step, n-butyllithium (2.15 equivalents) in hexane was cooled to -70 °C and diisopropylamine (2.25 equivalents) was added while keeping the temperature below -60 °C. Compound 1″ (1 equivalent) dissolved in tetrahydrofuran (THF) was added over 30 min at -70 °C. After 10 min, diethyl carbonate (1.05 equivalents) dissolved in THF was added over 30 min keeping the reaction temperature below -60 °C. After stirring for one hour at -60 °C, the reaction was allowed to warm to 15 °C and furan-2-carbaldehyde (1.3 equivalents) dissolved in THF was added. After stirring for 20 hrs at room temperature, the reaction was rotary evaporated to dryness to yield ethyl 2-((l,3-dioxolan2-yl)methyl-3-(furan-2-yl)acrylate, which was used directly in the next reaction.

[00139] The crude compound (1 equivalent) was dissolved in ethanol and added to a mixture of water and phosphoric acid (85%>, 15 equivalents) over 30 min while keeping the temperature below 50°C. After stirring for 20 hrs at room temperature, another 200 ml of phosphoric acid (85%>) was added and the mixture was heated to 50 °C for an additional two hrs.

After removal of ethanol by rotary evaporation, the material was extacted with toluene, washed with water, dried with sodium sulfate, treated with charcoal, filtered and dried down to an oil. This oil was distilled to afford ethyl benzofuran-6-carboxylate, compound 6″, (bp 111-114.5°C) which crystallized on standing. Compound 6″ was recovered at 57%> yield based on compound

1″.

[00140] Compound 6″ (875 mmol) was dissolved in methanol and tetrahydrofuran (THF).

Sodium hydroxide (4 M, 3 equivalents) was added and the reaction was stirred overnight. After concentration via rotary evaporation, the aqueous solution was extracted with methyl tert-butyl ether (MTBE), acidified to pH 2 with the addition of hydrochloric acid (HC1) and cooled resulting in fine crystals of benzofuran-6-carboxylic acid, i.e., compound 18′. Compound 18′ was isolated, washed with water and dried to a final yield of 97%> yield.

[00141] Example 5

Figure imgf000039_0001

10% Pd/C, HCOOH/NEt3

MeOH/THF 5:1

Figure imgf000039_0002

Form A of Formula I

Scheme E5

[00142] The benzofuran carboxylic acid 18′ was treated with oxalyl chloride (1.2 equivalents) and a catalytic amount of DMF, stirring for 5.5 hours until a clear solution was obtained. The solvent was removed under reduced pressure and the acid chloride of compound 18′ was stored under argon until use, on the next day. The acid chloride, in methylene chloride was added slowly to a methylene chloride solution of the compound of Formula 12 and diisopropylethylamine (DIPEA) which was cooled to 0-5 °C. The reaction was not permitted to rise above 5°C, and after completion of addition, was stirred at 5°C for a further 0.5 hour. Upon aqueous workup and extraction with methylene chloride, the product, compound 19, was isolated in quantitative yield.

[00143] The benzyl ester of compound 19 was removed by transfer hydrogenolysis using

10% palladium on carbon, using formic acid and triethylamine in a 5: 1 mixture of methanol:THF, to produce the compound of Formula I in 95% yield.

[00144] A final step of slurrying in methyl ethylketone (MEK) produced Form A of the compound of Formula I. The product was washed with water to remove residual MEK. Alternatively, the product of the hydrogenolysis step was slurried in acetonitrile to yield Form A of the compound of Formula I.

[00145] Taking the compound of Formula I directly as the crude reaction product after transfer hydrogenolysis, and reconcentrating down from a solution in methylene chloride, the amorphous form of the compound of Formula I was obtained in 97% purity.

[00146] Example 6

[00147] An alternative protection strategy was performed in Scheme E6.

Figure imgf000040_0001

Scheme E6

[00148] Boc-protection was used for the ring nitrogen in the intermediates 21 and 22.

Compound 5 was deprotected with HC1 in dioxane to produce compound 23 in better than 97%> yield. Boc-protection was introduced, using di-tert-butyl dicarbonate (1.1 equivalent), and compound 21 was obtained in better than 95% yield. Compound 10 was coupled with compound 21 to obtain compound 22, using HATU and triethylamine in DMF. The product, compound 22, was obtained in quantitative yield, and greater than 90% purity. Deprotection with HC1 yielded the compound of Formula 12 in 97.4% yield.

[00149] Transfer hydrogeno lysis of compound 19 produced the compound of Formula I with optical purity of 98.5% (S) enantiomer compared to 79-94.5% (S) enantiomer optical purity obtained by hydrolysis of the corresponding methyl ester.

……………………………..

ACS Med. Chem. Lett., 2012, 3 (3), pp 203–206
DOI: 10.1021/ml2002482
Abstract Image

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

http://pubs.acs.org/doi/suppl/10.1021/ml2002482/suppl_file/ml2002482_si_001.pdf

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US8592450 Feb 16, 2012 Nov 26, 2013 Sarcode Bioscience Inc. Compositions and methods for treatment of eye disorders
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