Lifitegrast, SAR 1118….effective inhibitor of LFA-1 interactions with ICAM-1

phase 2, Uncategorized Comments Off

Sep 042014

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%

pnmr mass 13c nmr………see http://newdrugapprovals.org/2014/09/04/lifitegrast-sar-1118-effective-inhibitor-of-lfa-1-interactions-with-icam-1/

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

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

[0307] SCHEME 9

[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+H^4″) 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+H^4″). [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+H^4″). [0313] EXAMPLE 15 [0314] This example describes the synthesis of

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

^{s )} 2. DMF CH₂CI₂

15.1 15.2

[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+H^4″) 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+H^4″) 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:

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.

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.

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.

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.

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.

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.

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.

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

[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

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

[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

[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

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

[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

[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

[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

[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

[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:

[0067] Scheme 6

[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

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

2″

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

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

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

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).

Phenyl-bis-triflate

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

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

10% Pd/C, HCOOH/NEt₃

MeOH/THF 5:1

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.

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

http://pubs.acs.org/doi/full/10.1021/ml2002482

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

Cited Patent	Filing date	Publication date	Applicant	Title
US8084047 *	Jul 23, 2009	Dec 27, 2011	Sarcode Bioscience Inc.	Compositions and methods for treatment of eye disorders

Citing Patent	Filing date	Publication date	Applicant	Title
US8367701	Nov 4, 2011	Feb 5, 2013	Sarcode Bioscience Inc.	Crystalline pharmaceutical and methods of preparation and use thereof
US8592450	Feb 16, 2012	Nov 26, 2013	Sarcode Bioscience Inc.	Compositions and methods for treatment of eye disorders
US8758776	Jan 21, 2011	Jun 24, 2014	Sarcode Bioscience Inc.	Compositions and methods for treatment
US8771715	Jan 21, 2011	Jul 8, 2014	Sarcode Bioscience Inc.	Compositions and methods for treatment
WO2012121659A1 *	Mar 8, 2012	Sep 13, 2012	Kat2Biz Ab C/O Interpares Konsult Ab	Reduction of c-0 bonds by catalytic transfer hydrogenolysis
WO2014018748A1 *	Jul 25, 2013	Jan 30, 2014	Sarcode Bioscience Inc.	Lfa-1 inhibitor and polymorph thereof

Keywords:

LFA-1/ICAM-1 antagonist; tetrahydroisoquinoline derivative; SAR 1118; ophthalmic solution; dry eye

Drug development, approval, manufacturing, and post-marketing…..Japan’s journey of a pharmaceutical product

drugs, japan, Uncategorized Comments Off

Sep 042014

Drug development, approval, manufacturing, and post-marketing

Development of a new drug involves a complicated process that requires a lot of time and enormous amounts of funding. In order to create one drug, you would need to evaluate approximately 700,000 candidates¹⁾. Of them, just one reaches the patients. Here, we will share how a new drug begins its journey, from the research and development of candidate compounds, to a product, to the patients, and how we are involved with drugs once the physician prescribes a drug to patients. We will explain what pharmaceutical companies call “the lifecycle of a drug.”
¹⁾from Japan Pharmaceutical Manufacturers Association DATABOOK 2013

The journey of a pharmaceutical product

1. Basic research

Conduct a research to discover new drug candidate substances and components and create new compounds. Most requires 2 to 3 years. This process also functions as an opportunity to research the yet-to-be-defined mechanisms of diseases, where the basic research conducted may not directly lead to a new drug. Discovering a seed for a new drug is like looking for a piece diamond on the bottom of the deep ocean, where these highly uncertain basic research and drug development research could become the base in identifying several million candidate elements. After this process, a screening method to narrow down potential substances will be developed, and several of the candidate substances move on to the next process.
There are two types of research, collaborative research and sponsored research, where pharmaceutical companies and others provide funding support.
The research is conducted after an official contract is exchanged with universities and others.
Collaborative research：(Joint research expenses in the JPMA Transparency Guideline)

Research institutions such as universities and investigators of pharmaceutical companies and others conduct a research cooperatively.

Sponsored research：(Research commissioning expenses in the JPMA Transparency Guideline)

Sponsors such as pharmaceutical companies entrust research institutions such as universities to conduct the research, where accomplishments are reported to the sponsors.
The journey of a pharmaceutical product

2. Development

1) Non-clinical trial
- CMC: Quality
  CMC stands for Chemistry, Manufacturing and Control. Design and research for manufacturing procedures, specifications and stability tests are carried out.
- A process to investigate the efficacy and safety of candidate drug compounds. An animal testing is conducted for pharmacokinetics, pharmacological and toxicity tests. The next trials are conducted based on data obtained from this first process. This process takes about 3 to 5 years.
- The trial is required to be conducted based on GLP for non-clinical trial regarding safety of pharmaceutical products.
2) Clinical trial
- The clinical trial is conducted by pharmaceutical companies and others based on the Pharmaceutical Affairs Law, in order to have a new drug approved or to apply for a new indication for an existing drug. Other than clinical trials conducted by pharmaceutical companies with an objective of approval application, there are trials called investigator-led clinical trials which are conducted by physicians and medical institutions for the purpose of the approval application.
- The trial process investigates the efficacy and safety of the candidate compound on humans. The clinical trial is conducted mainly in 3 steps, Phase I, Phase II and Phase III. This process takes approximately 3 to 10 years. It is required to conduct the trials based on the GCP.
  
  Phase I trial (human pharmacology study) :
  
  Confirms mainly the compound’s safety among healthy people
  
  Phase II trial (exploratory study) :
  
  Confirms the drug’s administration method and administration amount among a small number of patients
  
  Phase III trial (confirmatory trial) :
  
  Confirms the drug’s efficacy and safety among numerous patients

The journey of a pharmaceutical product

3. NDA and regulatory approval application

The enormous amount of data gathered on candidate compounds so far is compiled into an approval application document and submitted to the regulatory authority in each country/region. In Japan, it is submitted to the Ministry of Health, Labour and Welfare (MHLW). The Pharmaceuticals and Medical Devices Agency (PMDA) will conduct a strict review from a scientific standpoint, and once the efficacy and safety of the candidate compound is confirmed, it will obtain approval by the MHLW as a new drug to be manufactured and distributed.
The PMDA website provides a detailed explanation on the complicated and wide-ranging process from application to approval.

Image result for meiji shrine

The journey of a pharmaceutical product

4. Production, Quality, Information Provision & Product Distribution

1) Manufacturing of newly approved drugs and the quality control process.

In every process of the drug development, from manufacturing to shipping and transportation after shipments, there are strict standards in place, ranging from those defined by the Pharmaceutical Affairs Law, those that require approval from regulatory agencies, and unique standards set within companies.
- Approval and inspection of manufacturing site: Under the Pharmaceutical Affairs Law, a GMP compatibility investigation is required for a new drug to be approved. This is an investigation that also confirms that the manufacturing site has the building, facility and administrative system to constantly manufacture the product which has been guaranteed its efficacy, safety and homogeneity.
  GMP investigation is conducted regularly as well as unscheduled, in addition to the investigation conducted at the time of approval.
- The manufacturing process begins from the measuring of raw materials: (Chugai Pharmaceutical “Manufacturing of active pharmaceutical ingredient/solid drug factory”)
- Decision on shipment: Some products, such as vaccines and blood products, require a national test per lot and may take time for it to be shipped out.
  National test process for vaccines
2) Product distribution and provision of information
- In order to provide new products to hospitals and pharmacies, marketing personnel of pharmaceutical companies develop a supply and distribution plan and work with both internal and external parties to distribute the product. Further, pharmaceutical companies, through their Medical Representatives (MR), work to provide, gather and communicate information and at times disseminate their pharmaceutical products in order to promote the appropriate use of its products.
  Source: MR Education and & Accreditation Center of Japan website
- Information is provided via methods such as scientific seminars, where information is not limited just to its own products but also medical and pharmaceutical papers of disease areas related to the product. Pharmaceutical companies hold briefing sessions together with medical academic conferences, medical institutions and physicians to ensure that scientifically-grounded treatments are promoted. It also provides information to support the physicians’ lifelong learning.
- The works of pharmaceutical companies are not limited to distributing products and providing information to healthcare practitioners, but it also provides information on the disease and about treatments. In order to guarantee the credibility and neutrality of the information, physicians specializing in the field provide support in the manner of writing articles, supervising contents, and participating as lecturers at educational seminars and lectures for general citizens.
- Examples of information provision on the disease and treatments
- The JPMA codes and guidelines
  - Japan Pharmaceutical Manufacturers Association(JPMA) Promotional Code
  - Japan Pharmaceutical Manufacturers Association(JPMA) Transparency Guideline

Image result for golden pavilion kyoto

The journey of a pharmaceutical product

5. Post manufacturing and distribution

Conduct surveys and trials on appropriate use, in order to confirm the new drug’s efficacy and safety in a regular and a daily medical setting that cannot be obtained from a clinical trial conducted for the drug’s approval. For example, through post-manufacturing and distribution clinical trials and post-manufacturing and distribution surveys, collect information on adverse reaction and the drug quality, and communicate assessment and analysis results to medical facilities.
Making changes to items listed in the application material submitted to obtain marketing approval, requires companies to submit an approval application for partial approval and obtain an approval per the Pharmaceutical Affairs Law.
The reporting system of adverse reactions and infectious diseases based on the Pharmaceutical Affairs Law, is for pharmaceutical companies and healthcare practitioners such as physicians and pharmacists to report the MHLW. The objective for this is to appropriately collect adverse reaction, infectious diseases and default information of pharmaceutical products and others in approved medical facilities such as hospitals, and promptly conduct safety measures.
Pharmaceutical companies, in order to promote academic research and provide aid for the research, supports research institutions such as universities, hospitals and medical academic conferences. As an academic research aid, it provides scholarship donations to universities and others. For example, in order to promote case reports that communicate product usage experience by expert physicians for products that have been in the market for 3 to 5 years since post-manufacturing and distribution, pharmaceutical companies will bring together a seminar through donations to the medical academic conferences and co-host seminars with academic conferences. Through such activities, it will promote the products’ safety and appropriate usage post-manufacturing and distribution.
There are also clinical research and clinical trials that are led by physicians and medical facilities conducted after a product’s post-manufacturing. Some physician-led clinical trials do not have an objective to apply for approval, but rather are conducted by physicians and researchers in order to provide the best treatment to patients and promote evidence-based medicine.

……………………………………………………………………………….

The various steps in this process are usually conducted by pharmaceutical companies alone. However, at times accomplishments are made through a cooperative effort with universities and medical institutions. In order for cooperative research with universities and medical institutions to steadily progress, and for new drugs to be created as a result, companies sometimes contribute by providing funding to the research. The types of funding provided are presented in the table below. Also, for certain items an example is illustrated and explained in each process within the “product lifecycle,” and is hyperlinked to the cost items of each member companies’ disclosure target within the JPMA‘s “Transparency guideline for the relationship between corporate activities and medical facilities and others.”
The progress of each process within the “product lifecycle” is managed by adhering to various laws and self-regulations. We will explain the process of drug development that at times is considered complicated, to the manufacturing and distribution of new drugs, and related laws and regulations to adhere to. The following table shows one part of the product lifecycle chart.
Product lifecycle and requirements overview

Terminology: Product lifecycle and related laws

news image

PAL：Pharmaceutical Affairs Law
A Law regulating matters related to the manufacturing, distribution, standards and screening, handling and advertising regulation and others for healthcare products, quasi-drugs, cosmetics and medical devices in Japan. (Law No. 145, Aug. 10, 1960).
GLP：Good Laboratory Practice
A standard for conducting non-clinical studies on the safety of drugs. It is a standard regarding animal studies in non-clinical studies, particularly regulated for toxicity studies.
CMC：Chemistry, Manufacturing and Control
Information regarding Chemistry, Manufacturing and Control. It refers to the integrated concept of researches for drug substance process, drug development, and quality assessment, as well as works related to those researches. The pharmaceutical companies’ CMC includes a wide range of work from non-clinical studies, clinical studies to regulatory approval applications.
GCP：Good Clinical Practice
A standards regarding the implementation of clinical trial for pharmaceutical products.
ICH：International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
A project that brings together regulatory authorities in Europe, Japan and the United States. The purpose is to make recommendations on ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration.
GMP：Good Manufacturing Practice
A ministry ordinance related to standards for the manufacturing management and quality management of pharmaceutical products and quasi-drugs. It refers to the standard for the manufacturing management and quality management at manufacturing facilities of pharmaceutical products and others.
PV：Pharmacovigilance
Activities related to the safety monitoring of pharmaceutical products. It refers to the careful monitoring and continuous surveillance of the safety of an approved product during its life on the market.
GQP：Good Quality Practice
A standard on the quality management of pharmaceutical products and others.
GDP：Good Distribution Practice
A standard on pharmaceutical product distribution.
GPSP：Good Post-marketing Study Practice
A standard on the implementation of the pharmaceutical products’ post-marketing surveillance and study.
GVP：Good Vigilance Practice
A standard on the safety management of pharmaceutical products and others after manufacturing and distribution.

Sources:

Image result for imperial palace tokyo

Japanese researchers develop new 30-minute method to detect Ebola virus

Uncategorized Comments Off

Sep 042014

Researchers from the Nagasaki University in Japan have developed a new method to detect the presence of Ebola virus in 30 minutes.

The new method is claimed to allow doctors to rapidly diagnose the infection.

Professor Jiro Yasuda and team was quoted by AFP as saying that the newly developed process is cheaper than the system, which is currently in use in West Africa where the virus has already claimed around 1,500 lives.

Yasuda said: “The new method is simpler than the current one and can be used in countries where expensive testing equipment is not available.

Japanese researchers develop new 30-minute method to detect Ebola virus

http://www.pharmaceutical-technology.com/news/newsjapanese-researchers-develop-new-30-minute-method-detect-ebola-virus-4360875?WT.mc_id=DN_News
Researchers from the Nagasaki University in Japan have developed a new method to detect the presence of Ebola virus in 30 minutes.

Tokyo (AFP) – Japanese researchers said Tuesday they had developed a new method to detect the presence of the Ebola virus in 30 minutes, with technology that could allow doctors to quickly diagnose infection.

Professor Jiro Yasuda and his team at Nagasaki University say their process is also cheaper than the system currently in use in west Africa where the virus has already killed more than 1,500 people.

“The new method is simpler than the current one and can be used in countries where expensive testing equipment is not available,” Yasuda told AFP by telephone.

“We have yet to receive any questions or requests, but we are pleased to offer the system, which is ready to go,” he said.

Yasuda said the team had developed what he called a “primer”, which amplifies only those genes specific to the Ebola virus found in a blood sample or other bodily fluid.

Using existing techniques, ribonucleic acid (RNA) — biological molecules used in the coding of genes — is extracted from any viruses present in a blood sample.

This is then used to synthesise the viral DNA, which can be mixed with the primers and then heated to 60-65 degrees Celsius (140-149 Fahrenheit).

If Ebola is present, DNA specific to the virus is amplified in 30 minutes due to the action of the primers. The by-products from the process cause the liquid to become cloudy, providing visual confirmation, Yasuda said.

Currently, a method called polymerase chain reaction, or PCR, is widely used to detect the Ebola virus, which requires doctors to heat and cool samples repeatedly and takes up to two hours.

“The new method only needs a small, battery-powered warmer and the entire system costs just tens of thousands of yen (hundreds of dollars), which developing countries should be able to afford,” he added.

The outbreak of the Ebola virus, transmitted through contact with infected bodily fluids, has sparked alarm throughout western Africa and further afield.

JAPAN

Levonadifloxacin arginine salt, WCK 771

Uncategorized Comments Off

Sep 022014

STEREOCENTERS SHOWN

Levonadifloxacin arginine salt, WCK 771

S-(−)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic Acid l-Arginine Salt Tetrahydrate

RN: 306748-89-0

C19-H21-F-N2-O4.C6-H14-N4-O2
MW: 534.5855

L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)

WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate

(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate

L-arginine salt of (S)-nadifloxacin

S-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[ij]qumorizine-2-carboxylic acid L-arginine salt is a broad-spectrum antibiotic, medically grouped together with the fluoroquinolone class of antibiotics, which is disclosed and claimed in U.S. patent 6,514,986 B2 as being isolated in a less crystalline anhydrate form and a more crystalline hydrate form.

U.S. patent 6,664,267 describes a crystalline monohydrate form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt that is disclosed as having advantages over the anhydrate and hydrate forms described in US 6,514,986 B2.

SYNTHESIS

A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232………..http://pubs.acs.org/doi/abs/10.1021/jm050035f

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known “floxacin”. The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(−)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

S-(−)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic Acid l-Arginine Salt Tetrahydrate (Crystalline Form) (21). To a three-necked round-bottom flask fitted on an oil bath and equipped with a mechanical stirrer, a thermometer pocket, and a reflux condenser was charged 1 (100 g, 0.278 mol) followed by acetone (300 mL). Stirring was started and to the stirred suspension was charged powderedl-arginine (48.4 g, 0.278 mol) followed by distilled water (250 mL). The reaction mixture was stirred at a temperature between 50 and 60 °C for 1 h to obtain a clear solution. Activated charcoal (3 g) was added to the solution and the solution was filtered hot. To the filtrate was then added acetone (700 mL) and the reaction mixture was allowed to cool to 30−35 °C. The reaction mixture was stirred for an additional 2 h at this temperature. The crystalline solid was filtered under reduced pressure and the wet cake was washed with acetone (100 mL). The resulting solid was dried under vacuum at 65−70 °C to furnish 21 (137 g, 92% yield):

mp 236−240 °C;

1H NMR (DMSO-d6) δ 1.4 (d, 3H, J = 7.0 Hz), 1.5−2.2 (m, 8H), 2.8−4.2 (m, 16H), 4.8 (m, 1H), 7.8 (d, 1H, J = 13.0 Hz), 8.8 (s, 1H). MS (ES+) m/z 535 (M + H).

Anal. (C25H35FN6O6·4H2O) C, H, N. HPLC assay of free base (theoretical free base content) 67.41%, found 67.16%. Estimated l-arginine by HPLC (theoretical l-arginine content) 32.59%, found 32.14%.

S-(−)-Nadifloxacin is S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid (1). Prodrugs and aqueous soluble salts of 1were synthesized and explored for possible use in parenteral or oral formulations………….De Souza, N. J.; Agarwal, S. K.; Patel, M. V.; Bhawsar, S. B.; Beri, R. K.; Yeole, R. D.; Shetty, N.; Khorakiwala, H. F. Chiral Fluoroquinolone Arginine Salt Form. US patent 6,514,986, 2003.

(b) De Souza, N. J.; Deshpande, P. K.; Shukla, M. C.; Mukarram S. M. J.; Kulkarni, D. G.; Rahman, A.; Yeole, R. D.; Patel, M. V.; Gupte, S. V. Crystalline Fluoroquinolone Arginine Salt Form. US patent 6,664,267, 2003.

………………………………………………………….

CN 102532131,

http://www.google.com/patents/CN102532131A?cl=en

quinolones has now grown to four generations, the first generation to nalidixic acid is represented as the representative of the second generation to PPA, only the Gram-negative bacteria effectively, the third generation is the development of these drugs the peak period, there has been a lot of drugs, and is a broad-spectrum antibiotic, which to norfloxacin, ciprofloxacin and other representatives. The fourth-generation quinolone antibiotics is in the third generation on the basis of a broad spectrum of antibacterial spectrum further expanded to make it available against mycoplasma and chlamydia infections.

[0003] R & D has been relatively popular domestic antibiotics, the most widely used on the market today is the third generation fluoroquinolones. Nadifloxacin developed by the Japanese company Otsuka, belongs to the third-generation quinolone antibacterial drugs, topical treatment of acne and folliculitis. 1993 for the first time in Japan (trade name: Acuatim), 2004 in the German market (trade name: Nadixa), 2005 in China listed (trade name: By Union, ointment).

[0004] nadifloxacin irritation due to its absorption and vascular problems, only made of topical formulations for in vitro Propionibacterium acnes (propionibacterium acnes) caused by acne. Wherein the S-(-) – that is the main role difloxacin isomer, the antibacterial activity of the R-isomer of 64 to 256 times that of racemic 2 times.

[0005] fine that gatifloxacin is S-(-) _ nadifloxacin salt on the basis of the system.Significantly improved solubility nadifloxacin well absorbed by the body, so it retains nadifloxacin broad spectrum antimicrobial, antibacterial activity, especially methicillin-sensitive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus Effective characteristics (Antimicrobial Agents and Chemotherapy, 2004,3188 ~ 31920; J. Med. Chem. 2005 (48), 5232 ~ 5242). Pre-clinical tests prove that the product on the market anti-methicillin-resistant Staphylococcus aureus Antibiotic better compare the efficacy, including vancomycin, trovafloxacin, quinupristin + dalfopristin, linezolid amine.

[0006] fine molecular structure that gatifloxacin following formula:

[0007]

[0008] S-(-) _ nadifloxacin (C19H21FN2O4) with L-arginine salt, the further improve the play a major role in antibacterial s-(-) – nadifloxacin isomer content, and improved oral bioavailability, so that it can develop an oral or injectable preparations.

[0009] the literature (J. Med. Chem. 2005 (48), 5232 ~ 5242) discloses the synthesis of S_ (_) _ Nadifloxacin-L-arginine salt, S-(-) _ that fluoride gatifloxacin and L-arginine salt in the reaction solvent system, which solvent system is mainly methanol – water system, according to the paper reported in S-(-) – Nadifloxacin-L-arginine salt, yields were and related substances are not high enough.

Example 1

[0026] In equipped with oil bath, magnetic stirrer, thermometer, reflux condenser flask at 25 ° C was added (S) – (-) – nadifloxacin (100. 0g, 278mmol), dioxane ring (300ml), and the reaction solution was added dropwise to the L-arginine 4g, 278mmol) in distilled water (250ml) was added. Then heated to 50_60 ° C stirred 1.5 hours, and then adding activated carbon (3. Og) for 5 minutes, filtered hot, and then added dropwise at 55-60 ° C dioxane (700ml), and the natural cooling to 30 -35 ° C for 2 hours crystallization. The solid was collected by filtration and acetone (IOOml) wash. Dried at room temperature M hours. To give a white solid 137g, yield: 92%.

……………………………………

WO 2005023805,

http://www.google.com/patents/WO2005023805A1?cl=en

Example 1

Preparation of the single crystal of S-(- -9-fluoro-6,7-dihvdro-8-(4-hvdroxypiperidin-l-ylV5- methyl-l-oxo-lH,5H-benzo[^“i,ι^‘lquinolizine-2-carboxylic acid L-arginine salt terahvdrate.

S-(-)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt (1.0 g) was dissolved in a mixture of acetone (40 ml) and water (10 ml) by heating the suspension at 70 °C for 15 minutes. The clear solution thus obtained was left for slow evaporation at room temperature in a beaker covered with a perforated aluminum foil. The crystal formation started after 2 days. Finally the single crystal was selected for X-ray crystal analysis from a cluster left after complete evaporation of the solvent. The ORTEP diagrams are described in Figures 1 and 2.

………………………………………………………………

WO 2002009758,

http://www.google.com/patents/WO2002009758A2?cl=en

…………………………………………………

WO 2001085095,

EXAMPLE 1

S-(-)-9-Fluoro-6,7-dihvdro-8-(4-hvdroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo Ti l quinolizine-2-carboxylic acid arginine salt Synthesis of SubstantiaUy CrystaUine product A solution of L-(+)-arginine (48.372 g, 0.278 mole) in distilled water (600 ml) was added dropwise over a period of 30 min to the stirred solution/suspension of finely powdered S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylic acid (100 g, 0.278 mole) in acetone (1250 ml). The obtained clear solution was stirred for 30 min and concentrated on a water bath in vacuum (175 mbar) at 80°C. When product started solidifying, the concentration was carried out in vacuum (50 mbar) at 80°C up to dryness. Hexane (1 liter) was added, the reaction mixture was stirred for 4 hr, the solid thus separated was filtered and dried in vacuum (0.7 mbar) for 12 hrs at 70 °C. Yield 145 g (96.9%), m.p. 238-242 °C, and solubility 6 mg/ml (pH 9.5 buffer solution).

The substantially crystalline S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5- methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid arginine salt prepared according to Example 1 possesses the following properties: a) Crystalline form, with a degree of crystallinity as determined by X-ray powder diffraction and as shown in Fig. 1. , b) A thermogram as determined by Differential scanning calorimetry and as shown in Fig. 3. c) Particle size measured as mean mass diameter (MMD) of 83.92 μm, as determined by laser diffraction technique. d) Density of 0.51 g/cm³ (untapped) and 0.7 g/cm³ (tapped). e) Hygroscopicity of 0% increase of weight upon storage for 14 days up to 22% relative atmospheric humidity as determined gravimetricaUy. f) A content of moisture water of 0.1 % by weight as determined by titration according to Karl Fischer. g) A content of acetone of 0.014 % by weight as determined by gas chromatography

……………………………………………………..

WO 2000068229

http://www.google.com/patents/WO2000068229A2?cl=en

Example 1

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyI-l-oxo-lH,5H-benzo [ij] quinolizine-2-car boxy lie acid anhydrate

Method A

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yI)-5-methyl-l-oxo-lH,5H-benzo [ij] quinoIizine-2-carboxylic acid (3.0 g) obtained according to the process described in literature [K Hashimoto et al., Chem.Pharm.Bull.44, 642-5(1996)] was dissolved in acetonitrile (250 ml) at 85 °C. The resulting clear solution was filtered (to remove if any fibrous material is in suspension). The filtrate was concentrated to 125 ml and left at room temperature for crystallization. The crystals thus separated were filtered and dried in a drying cabinet at 40 °C for 2 hr in vacuum at 50 mm of Hg to obtain constant weight. Yield 2.6 g (86%).

Method B:

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyI-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxyIic acid (2.0 g) obtained according to the process described in literature [K.Hashimoto etal., Chem.Pharm.Bull.44, 642-5(1996)] was dissolved in ethyl alcohol (95 %; 200 ml) at 80 °C. The obtained clear solution was filtered (to remove if any fibrous material is in suspension), concentrated to 100 ml and left for crystallization. The separated solid was Altered and dried in a drying cabinet at 40 °C for 3 hr in vacuum at 50 mm of Hg to obtain constant weight. Yield 1.7 g (85 %).

M.p.258-62 °C, moisture content 0 % (by Karl Fisher method) [CXJ_D ²⁶ -299°, HPLC purity 99.8%

Example 8

S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyI-l-oxo-lH,5H-benzo [ij] quinolizine-2-carboxylic acid, L-arginine salt 0.75 hydrate

L-(+)-Arginine (0.958 g., 5.5 mmoles) was added in portions to a suspension solution of S- (-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo [ij] quinoIizine-2-carboxyIic acid 0.2 hydrate (2.0 g., 5.5 mmole) in methanol (400 ml). The obtained solution was concentrated in vacuum to give the desired product as a yellow solid, which was dried at 50 °C at 50 mm/Hg for 5 hours. Yield 3.0 g. (100%), m.p. 220- 223 °C (dec), m/z 535 (M+H), moisture content 2.3% (by Karl Fisher, required 2.46%), [CIJ_D ²⁵ -144 ° (1% methanol c=l), solubility 93 mg/ml.

……………………………..

Chemical and Pharmaceutical Bulletin
Vol. 44 (1996) No. 4 P 642-645

https://www.jstage.jst.go.jp/article/cpb1958/44/4/44_4_642/_article

A Practical Synthesis of (S)-(-)-Nadifloxacin : Novel Acid-Catalyzed Racemization of Tetrahydroquinaldine Derivative

(S)-(-)-Nadifloxacin [(S)-(-)-9-fluoro-6, 7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H, 5H-benzo[i, j]quinolizine-2-carboxylic acid, (S)-(-)-OPC-7251], an antibacterial agent, was synthesized from (S)-(-)-5, 6-difluoro-2-methyl-1, 2, 3, 4-tetrahydroquinoline (DFTQ), which was prepared by the optical resolution of recemic DFTQ with 2, 3-di-O-benzoxyl-L-tartaric acid. Racemization of the undesired enantiomer [(R)-(+)-DFTQ] was studied in the presence of various acids and the best result was obtained in the case of methanesulfonic acid. The absolute configuration of (-)-nadifloxacin was determined as S by X-ray crystallographic analysis.

https://www.jstage.jst.go.jp/article/cpb1958/44/4/44_4_642/_pdf ………..FREE PDF

Full Text PDF [734K]

31 Aug, 2014,
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.

Ishikawa, H.; Tabusa, F.; Miyamoto, H.; Kano, M.; Ueda, H.; Tamaoka, H.; Nakagawa, K. Studies on antibacterial agents. I. Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acids. Chem. Pharm. Bull. 1989, 37, 2103-2108.

(b) Kurokawa, I.; Akamatsu, H.; Nishigima, S.; Asada, Y.; Kawabata, S. Clinical and Bacteriologic Evaluation of OPC-7251 in Patients with Acne: A Double Blind Group Comparison Study vs Cream Base. J. M. Acad. Dermatol. 1991, 25, 674−81.

(c) Morita, S.; Otsubo, K.; Matsubara, J.; Ohtnai, T.; Uchida, M. An Efficient Synthesis of a Key Intermediate towards (S)-(−)-Nadifloxacin. Tetrahedron: Asymmetry 1995, 6 (1), 245−254.
(7) (a) Patel, M. V.; Gupte, S. V.; Sreenivas, K.; Chugh, Y.; Agarwal, S. K.; De Souza, N. J. S-(−)-Nadifloxacin: Oral Bioavailbility and Bioefficacy in Mouse Model of Staphylococcal Septicemia. Abstract of Papers, 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 2000; American Society for Microbiology: Washington, DC, 2000; Poster F-558.
(8) A preliminary version of this work was described in a poster. Deshpande, P. K.; Desai, V. N.; Bhavsar, S. V.; Chaturvedi, N. C.; Ghalsasi, S. A.; Aher, S.; Yeole, R. D.; Pawar, D.; Shukla, M. C.; Patel, M. V.; Gupte, S. V.; De Souza, N. J.; Khorakiwala, H. F. WCK 771A Chiral Benzoquinolizine-2-carboxylic acid Arginine Salt Active against Vancomycin Intermediate Staphylococcus aureus (VISA). Abstract of Papers, 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 2003;American Society for Microbiology: Washington, DC, 2003; Poster F-430

Some quinolones introduced for clinical use.

KEY Levonadifloxacin arginine salt, WCK 771, QIDP

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL

AMBROXOL

Uncategorized Comments Off

Sep 022014

Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Mucobrox, Mucol, Lasolvan, Mucoangin, Surbronc, Ambolar, and Lysopain. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, which play an important role in the body’s natural defence mechanisms. It stimulates synthesisand release of surfactant by type II pneumocytes. Surfactant acts as an anti-glue factor by reducing the adhesion of mucus to thebronchial wall, in improving its transport and in providing protection against infection and irritating agents.^[1]^[2] Ambroxol is often administered as an active ingredient in cough syrup.

Ambroxol is indicated as “secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply”.^[3]

Ambroxolhydrochloridetablets in Japan

There are many different formulations developed since the first marketing authorisation in 1978. Ambroxol is available as syrup, tablets, pastilles, dry powder sachets, inhalation solution, drops and ampules as well aseffervescent tablets.

Ambroxol also provides pain relief in acute sore throat. Pain in sore throat is the hallmark of acutepharyngitis.^[4] Sore throat is usually caused by a viral infection. The infection is self limited and the patient recovers normally after a few days. What is most bothering for the patient is the continuous pain in the throat maximized when the patient is swallowing. The main goal of treatment is thus to reduce pain. The main property of Ambroxol for treating sore throat is the local anaesthetic effect, described first in the late 1970s,^[5]^[6] but explained and confirmed in more recent work.

Ambroxol is a potent inhibitor of the neuronal Na+ channels.^[7] This property led to the development of alozenge containing 20 mg of ambroxol. Many state-of-the-art clinical studies^[4] have demonstrated the efficacy of Ambroxol in relieving pain in acute sore throat, with a rapid onset of action, with its effect lasting at least three hours. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase. Because of this it may be a useful therapeutic agent for both Gaucher disease and Parkinson’s disease.

Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Lasolvan or Mucoangin. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract which play an important role in the body’s natural defence mechanisms. It stimulates synthesis and release of surfactant by type II pneumocytes. Surfactants acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents.

Brief background information

Salt	ATC	Formula	MM	CAS
–	R02AD05 R05CB06 R07AA03	C ₁₃ H ₁₈ Br ₂ N ₂ O	378.11 g / mol	18683-91-5

Systematic (IUPAC) name

trans-4-(2-Amino-3,5-dibrombenzylamino)-cyclohexanol
Clinical data
AHFS/Drugs.com	International Drug Names

Identifiers

ATC code	R05 CB06
PubChem	CID 2132
ChemSpider	10276826
UNII	200168S0CL
KEGG	D07442
ChEMBL	CHEMBL153479
Chemical data
Formula	C₁₃H₁₈Br₂N₂O
Mol. mass	378.10

Synthesis pathway

Синтез a)

Synthesis

Ambroxol synthesis.^[9]

melting point

233-234.5

Kack, J., Koss, F.W., Schraven, E. and Beisenherz, G.; US. Patent 3,536,713; October 27, 1970; assigned to Boehringer lngelheim G.m.b.H.

Kack, J., Koss, F.W., Schraven, E. and Beisenherz, G.; US. Patent 3,536,713; October 27,
1970; assigned to Boehringer lngelheim G.m.b.H.

Trade Names

Page	Trade name	Manufacturer
Germany	Ambrobeta	betapharm
	AmbroGEKSAL	Hexal
	Mucosal	Boehringer Ingelheim
	various generic drugs
France	Muksol	Leurquin Milan
France	Surbronk	Boehringer Ingelheim
Italy	Ambrotus	Epifarma
	ATUS	Metapharma
	Mukoarikodil	Menarini
	Mucosal	Boehringer Ingelheim, 1982
	Viskomucil	Institute of Organic Chem.
Japan	Mucosal	Teijin
Ukraine	AMBROKSOL	Ltd. “Pilot Plant” HNTSLS “m. Kharkiv, Ukraine
	Ambroxol hydrochloride	CJC BHFZ, m. Kyiv, Ukraine
	AMBROBENE	ratiopharm GmbH, Germany
	LAZOLVAN®	Boehringer Ingelheim International GmbH, Germany
	various generic drugs

Formulations

ampoule 15 mg;
Capsules of 45 mg, 75 mg;
drops 7.5 mg, 30 mg,
dry syrup 1.5%, 3%;
Effervescent tablets 30 mg, 60 mg;
coated tablets 30 mg, 60 mg;
granules 1.5%, 3%;
inhalation solution of 7.5 mg;
inaektsiya 1.000 mg;
solution of 0.3%, 0.75%;
Syrup 0.3%;
Tablets of 15 mg, 30 mg, 60 mg (hydrochloride)

Chemical structure for Ambroxol

Ambroxol hydrochloride; Ambroxol HCl; 23828-92-4; Mucosolvan; Mucoangin; UNII-CC995ZMV90; SBB056993

Molecular Formula: C₁₃H₁₉Br₂ClN₂O Molecular Weight: 414.56376

2-Amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine
4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride(1:1)

References

Sanderson RJ et al. (1976), “Morphological and physical basis for lung surfactant action”, Respir Phys 27 (3): 379–92, doi:10.1016/0034-5687(76)90066-9,PMID 989610
Kido H et al. (Nov 2004), “Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the airway and chemical agents up-regulating their levels may have therapeutic potential.”, Biol Chem 385 (11): 1029–34, doi:10.1515/bc.2004.133, PMID 15576322
Malerba M, Ragnoli B. (August 2008), “Ambroxol in the 21st century: pharmacological and clinical update”, Expert Opin Drug Metab Toxicol. 4 (8): 1119–29,doi:10.1517/17425255.4.8.1119, PMID 18680446
de Mey C. et al. (2008), “Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat”, Arzneimittelforschung 58 (11): 557–68,doi:10.1055/s-0031-1296557, PMID 19137906
Püschmann S, Engelhorn R. (1978), “Pharmakologische Untersuchungen des Bromhexin-Metaboliten Ambroxol (Pharmacological study on the bromhexine-metabolite ambroxol)”, Arzneimittelforschung 28 (5a): 889–98, PMID 581987
Klier KF, Papendick U. (1977), “Die lokalanaesthetische Wirkung von NA-872-haltigen Augentropfen (The local anesthetic effect of NA872-containing eyedrops)”, Med Monatsschr. 31 (12): 575–8, PMID 593223
Weiser T. (2006), “Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels”,Neurosci Lett. 395 (3): 179–84, doi:10.1016/j.neulet.2005.10.058, PMID 16293367
[1] Drugs.com, Ambroxol, accessed 21 January 2014
http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-ambroxol_30.html

DE 1 593 579 (Thomae; appl. 10.5.1966).
DOS 2 218 647 (Thomae; appl. 18.4.1972).
DOS 2 223 193 (Thomae; appl. 12.5.1972).
Keck, J.: Justus Liebigs Ann. Chem. (JLACBF) 707, 107 (1967).

Japan Proposes Influenza Drug To Treat Ebola… Pharmaceuticals: Country says Fujifilm’s favipiravir is available

Uncategorized Comments Off

Sep 012014

The Japanese government said this week that it is prepared to make an influenza drug that is not approved for the treatment of Ebola available to West African countries hard-hit by the deadly virus.

Japan Proposes Influenza Drug To Treat Ebola

http://cen.acs.org/articles/92/i35/Japan-Proposes-Influenza-Drug-Treat.html

Pharmaceuticals: Country says Fujifilm’s favipiravir is available.

KEY

Fujifilm’s, favipiravir, EBOLA

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL

Telmapitant……Tachykinin NK1 Antagonists

Uncategorized Comments Off

Sep 012014

Chemical structure for Telmapitant (USAN)

Telmapitant

TELMAPITANT; Telmapitant (USAN); Telmapitant [USAN]; 552292-58-7; HJ5FE4153B; D10391

(5R,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,3,9-triazaspiro[4.5]decane-2,4-dione

1,3,7-Triazaspiro[4.5]decane-2,4-dione, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, (5R,8S)-

(5R,8S)-8-(((1R)-1-(3,5-Bis(Trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,3,7- triazaspiro(4.5)decane-2,4-dione
1,3,7-Triazaspiro(4.5)decane-2,4-dione,

8-(((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-, (5R,8S)-

Molecular Formula: C₂₄H₂₃F₆N₃O₃

Molecular Weight: 515.448139

cas 552292-58-7

Merck & Co. (innovator)

Treatment of Nausea and Vomiting,

SYNTHESIS

……………………………………….

US7902366

http://www.google.com/patents/US7902366

Example 43a Example 43b

Step 1:

To a suspension of lactol Compound 3 (60 g, 93.0 mmol, 1 equiv.) and Wittig Reagent (93.5 g, 200.0 mmol, 2.15 equiv.) in toluene (800 ml) stirred at −78° C. under N₂, a solution of KHMDS (0.5M in toluene, 558 ml, 280.0 mmol, 3 equiv.) was added dropwise at −78° C. The cooling bath was removed and the yellow mixture was warmed to RT to form a red solution. The mixture was allowed to stir at 23° C. for further 1 h before being quenched with saturated NH₄Cl solution. EtOAc was added and layers were separated. The separated aqueous layer was extracted with EtOAc (2×500 ml). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [5% EtOAc-hexane to 10% EtOAc-hexane] gave alkene Compound 42 as white solid (40.5 g, 68%), Electrospray MS [M+1]⁺ 638.1. Continuous elution gave an impure cyclized product Compound 43.

Step 2:

A suspension of alkene Compound 42 (40.5 g, 64 mmol, 1 equiv.) and PtO₂(1.44 g, 6.4 mmol, 0.1 equiv.) in EtOH (400 ml) were stirred under a H₂balloon at 23° C. for 24 h. Another batch of PtO₂(1.44 g, 6.4 mmol, 0.1 equiv) was added and the mixture was stirred for another 24 h at 23° C. The catalyst was filtered via a pad of Celite. This solution of alkane Compound 44 was used in the next step without further purification.

Step 3:

p-TsOH.H₂O (2.42 g, 13.0 mmol) was added to the ethanolic solution of alkane Compound 44 from above and the solution was heated to reflux for 4 h. The solution was cooled to RT and neutralized with Et₃N. Solvents were removed in vacuum and EtOAc was added. Saturated NaHCO₃solution was added and layers were separated. The separated aqueous layer was extracted with EtOAc (300 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [10% ether-hexane] gave enamide Compound 45 (first batch) as yellow oil. Some intermediate and starting material were recovered as yellow oil by continuous elution with [50% EtOAc-hexane]. The yellow oil was dissolved in toluene and 10 mol % p-TsOH was added. The mixture was heated to reflux for 2 h and cooled to RT. Work up was as above and the combined enamide Compound 45 (25 g, 70%), Electrospray MS [M+1]⁺ 564.1, was obtained as yellow oil.

Step 4:

BH₃.Me₂S (13.6 ml, 133 mmo, 3.02 equiv) was added to a solution of enamide Compound 45 (25 g, 44.0 mmol,1 equiv.) in THF at 23° C. under N₂. The mixture was stirred at 23° C. for 18 h and then cooled over an ice-water bath. A solution of NaOH (500 ml, 2N) was added slowly followed by a solution of H₂0₂(500 ml, 30% aqueous). The mixture was allowed to stir from 0° C. to 23° C. for 18 h. Layers were separated and the separated aqueous layer was extracted with Et₂O (500 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-EtOAc, 3:1 (v/v)] gave alcohol Compound 46 as colorless oil (19 g, 74%), Electrospray MS [M+1]⁺ 582.1.

Step 5:

Oxalyl chloride (5.7 ml, 65.3 mmol, 2 equiv.) was added to a solution of DMSO (9.3 ml, 131.0 mmol, 4 equiv.) in CH₂Cl₂(300 ml) at −78° C. under N₂. The mixture was stirred at −78° C. for 15 min before a solution of alcohol Compound 46 (19 g, 32.7 mmol. 1 equiv.) in CH₂Cl₂(50 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et₃N (32 ml, 228.9 mmol, 7 equiv.) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃solution. Layers were separated and the aqueous was extracted with CH₂Cl₂(300 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-ether, 4:1 (v/v)] gave ketone Compound 47 as colorless oil (15 g, 80%), Electrospray MS [M+1]⁺ 580.1.

Step 6:

EtOH (150 ml) was added to Cbz-ketone Compound 47 (15 g, 25.88 mmol, 1 equiv.), followed by NH₄(CO₃)₂(9.95 g, 103.5 mmol, 4 equiv.) and a solution of KCN (3.4 g, 51.77 mmol, 2 equiv.). The resulting mixture was heated at 58° C. under N₂for 72 h. TLC (1:1 EtOAc:hexane) revealed complete consumption of the starting material. The reaction mixture was cooled to RT and poured into sat. aq. NaHCO₃(200 ml) and extracted with EtOAc (3×200 ml). The combined organic layers were dried over MgSO₄and concentrated in vacuo to afford crude Cbz-hydantoin Compound 48 (16.5 g, 98%), Electrospray MS [M+1]⁺650.1. The crude material was used in the next reaction without further purification.

Step 7:

The crude Cbz-hydantoin Compound 48 (16.5 g, 25.4 mmol, 1 equiv.) was dissolved in MeOH (220 ml) and 20% Pd(OH)₂—C (3.6 g) was added. The reaction mixture was shaken in a parr shaker under H₂atmosphere at 40 psi for 18 h. TLC (1:1 EtOAc:hexane) revealed complete consumption of the starting material. The reaction mixture was filtered through a pad of celite and the celite was washed with MeOH. The resulting solution was concentrated in vacuo. The crude product was purified by column chromatography on a Biotage (3:2, EtOAc:hex). Two major spots were collected. The less-polar spot corresponds to the isomer Example 43a (3 g, overall 20% over two steps), Electrospray MS [M+1]⁺ 516.1. The more polar spot corresponds to the isomer Example 43b (4.5 g, overall 30% over two steps), Electrospray MS [M+1]⁺ 516.1.

………………………………..

WO 2003051840

http://www.google.com/patents/WO2003051840A1?cl=en

Example 43a Example 43b

Step 1 :

Compound 3

To a suspension of lactol Compound 3 (60g, 93.0mmol, lequiv.) and Wittig Reagent (93. δg, 200.0mmol, 2.1 δequiv.) in toluene (800ml) stirred at -78°C under δ N₂, a solution of KHMDS (O.δM in toluene, δδδml, 280.0mmol, 3equiv.) was added dropwise at -78°C. The cooling bath was removed and the yellow mixture was warmed to RT to form a red solution. The mixture was allowed to stir at 23°C for further 1 h before being quenched with saturated NH CI solution. EtOAc was added and layers were separated. The separated aqueous layer was extracted with EtOAc 0 (2 x δOOml). The combined organic layers were dried (MgSO ) and filtered.

Removal of solvents in vacuum followed by Biotage column chromatography [δ% EtOAc-hexane to 10% EtOAc-hexane] gave alkene Compound 42 as white solid (40. δg, 68%), Electrospray MS [M+1]⁺ 638.1. Continuous elution gave an impure cyclized product Compound 43. δ Step 2:

Compound 42

A suspension of alkene Compound 42 (40. δg, 64mmol, lequiv.) and PtO₂ (1.44g, 6.4mmol, 0.1 equiv.) in EtOH (400ml) were stirred under a H₂ balloon at 23°C for 24 h. Another batch of PtO₂ (1.44g, 6.4mmol, 0.1 equiv) was added and the 0 mixture was stirred for another 24 h at 23°C. The catalyst was filtered via a pad of Celite. This solution of alkane Compound 44 was used in the next step without further purification. Step 3:

Compound 44

p-TsOH.H₂O (2.42g, 13.0mmol) was added to the ethanolic solution of alkane

Compound 44 from above and the solution was heated to reflux for 4 h. The solution was cooled to RT and neutralized with Et₃N. Solvents were removed in vacuum and EtOAc was added. Saturated NaHCO₃ solution was added and layers

5 were separated. The separated aqueous layer was extracted with EtOAc (300ml x

2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [10% ether- hexane] gave enamide Compound 45 (first batch) as yellow oil. Some intermediate and starting material were recovered as yellow oil by continuous elution with 0 [50%EtOAc-hexane]. The yellow oil was dissolved in toluene and 10mol% p-TsOH was added. The mixture was heated to reflux for 2 h and cooled to RT. Work up was as above and the combined enamide Compound 45 (2δg, 70%), Electrospray

MS [M+1]⁺ 664.1 , was obtained as yellow oil.

Step 4:

BH₃.Me₂S (13.6ml, 133mmo, 3.02 equiv) was added to a solution of enamide Compound 45T25g, 44.0mmol, lequiv.) in THF at 23°C under N₂. The mixture was stirred at 23°C for 18 h and then cooled over an ice-water bath. A solution of NaOH (600ml, 2N) was added slowly followed by a solution of H O₂ (600ml, 30% 0 aqueous). The mixture was allowed to stir from 0°C to 23°C for 18 h. Layers were separated and the separated aqueous layer was extracted with Et.₂0 (600ml x 2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-EtOAc, 3:1 (v/v)] gave alcohol Compound 46 as colorless oil (19g, 74%), Electrospray MS [M+1]⁺ δ 582.1. Step 5:

Compound 46

Oxalyl chloride (δ.7ml, 6δ.3mmol, 2equiv.) was added to a solution of DMSO (9.3ml, 131.0mmol, 4equiv.) in CH₂CI₂ (300ml) at -78°C under N₂. The mixture was 0 stirred at -78°C for 1 δ min before a solution of alcohol Compound 46 (19g, 32.7mmol. lequiv.) in CH₂CI₂ (50ml) was added. The mixture was stirred at -78°C for a further 1 h and Et₃N (32ml, 228.9mmol, 7equiv.) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃ solution. Layers were separated and the aqueous was extracted with CH₂CI₂ (300ml x 2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-ether, 4:1 (v/v)] gave ketone Compound 47 as colorless oil (1δg, 80%), Electrospray MS [M+1]⁺ 680.1.

EtOH (150ml) was added to Cbz-ketone Compound 47 (15g, 2δ.88mmol, lequiv.), followed by NH (CO )₂ (9.9δg, 103.5mmol, 4equiv.) and a solution of KCN (3.4g, 61.77mmoI, 2equiv.). The resulting mixture was heated at 68°C under N2 for 72 h. TLC (1 :1 EtOAc:hexane) revealed complete consumption of the starting

1δ material. The reaction mixture was cooled to RT and poured into sat. aq. NaHCO₃ (200 ml) and extracted with EtOAc (3 x 200ml). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to afford crude Cbz-hydantoin Compound 48 (16.δg, 98%), Electrospray MS [M+1]⁺ 650.1. The crude material was used in the next reaction without further purification.

20 Step 7:

The crude Cbz-hydantoin Compound 48 (16.5g, 2δ.4mmol, lequiv.) was dissolved in MeOH (220ml) and 20% Pd(OH)₂-C (3.6g) was added. The reaction mixture was shaken in a parr shaker under H₂ atmosphere at 40 psi for 18 h. TLC (1 :1 EtOAc:hexane) revealed complete consumption of the starting material. The

26 reaction mixture was filtered through a pad of celite and the celite was washed with MeOH. The resulting solution was concentrated in vacuo. The crude product was purified by column chromatography on a Biotage (3:2, EtOAc:hex). Two major spots were collected. The less-polar spot corresponds to the isomer Example 43a (3 g, overall 20% over two steps), Electrospray MS [M+1]⁺ 616.1. The more polar spot

30 corresponds to the isomer Example 43b (4.6 g, overall 30% over two steps), Electrospray MS [M+1]⁺ 616.1.

US2011098468	4-29-2011	NK1 ANTAGONISTS
US7902366	3-9-2011	NK1 antagonists

English translation of Knabe, J., et al., “Racemates and Enantiomers of . . . ,” Pharmazie 52(12):912-919 (1997).
2		English translation of Schult, Karl E., et al., “Hydantoin-Derivate as Potential . . . ,” Eur. J. Med. Chem.-Chimica Therapeutics 13(1):25-31 (1978).
3		English translation of Schult, Karl E., et al., “Hydantoin-Derivate as Potential . . . ,” Eur. J. Med. Chem.—Chimica Therapeutics 13(1):25-31 (1978).
4		Knabe, J., et al., “Racemates and Enantiomers of Basic Substituted 5-Phenylhydantoins . . . ,” Pharmazie 52(12): 912-919 (1997).
5		Oh, Chang-Hyun et al., “Synthesis of New Hydantoin-3-Acetic Acid Derivatives . . . ,” Bull. Korean Chem. Soc. 9(4):231-235 (1988).
6		Shulte, Karl E., et al., “Hydantoin-Derivate als . . . ,” Eur. J. Med. Chem.-Chimica Therapeutica 13(1):25-31 (1978).
7		Shulte, Karl E., et al., “Hydantoin-Derivate als . . . ,” Eur. J. Med. Chem.—Chimica Therapeutica 13(1):25-31 (1978).
8		Wu, X. et al., “Generation of Cyclopenta [c] piperidines and Pyrrolo [3,4-c]piperidines- . . . ,” Tetrahedron 56(34): 6279-6290 (2000).
9	*	Xiujuan Wu et al 2000. , Stereoselective transformation of 2H-1,4-Oxazin-2-ones into 2,(2),5,5-tri- and tetrasubstituted Analogues. . .

US6436928 *	Dec 14, 2000	Aug 20, 2002	Schering Corporation	Selective neurokinin antagonists
US6635639 *	Feb 13, 2002	Oct 21, 2003	Nps Allelix Corp.	Use of N-alkylamino-heterocylic compounds for the treatment of migraine
US7041682 *	Jul 2, 2003	May 9, 2006	Schering Corporation	Antiemetics, antidepressants, anxiolytic agents, antitussive agents
US7122677 *	Nov 12, 2002	Oct 17, 2006	Scherig Corporation	NK1 antagonists
US20060094720 *	Dec 15, 2005	May 4, 2006	Neng-Yang Shih	NK1 antagonists
US20060223804 *	Jun 30, 2005	Oct 5, 2006	Schering Corporation	NK1 antagonists
EP0790248A1	Jan 20, 1997	Aug 20, 1997	Pfizer Limited	3-Aza-piperidone- (tetrahydropyrimidin-2-one) and 3-oxa-piperidone (1,3 oxazin-2-one) derivatives, their preparation and their use as tachykinin/neurokinin antagonists

key

Telmapitant, Merck, Tachykinin NK1 Antagonists

Aldoxorubicin…CytRx is pouring money into R&D of cancer-fighting drugs

Uncategorized Comments Off

Sep 012014

Aldoxorubicin, DOXO-EMCH

N’-[1-[4(S)-(3-Amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyloxy)-2(S),5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacen-2-yl]-2-hydroxyethylidene]-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide

1H-Pyrrole-1-hexanoic acid, 2,5-dihydro-2,5-dioxo-, (2E)-2-[1-[(2S,4S)-4-[(3-amino-2,3,6-trideoxy-α-L-lyxo– hexopyranosyl)oxy]-1,2,3,4,6,11-hexahydro-2,5,12- trihydroxy-7-methoxy-6,11-dioxo-2-naphthacenyl]-2- hydroxyethylidene]hydrazide

CytRx is pouring money into R&D of cancer-fighting drugs see article

Los Angeles Times

s most promising cancer-fighting drug, aldoxorubicin, is “sort of like a guided … Phase 3 clinical trial of a second-line treatment for soft-tissue sarcoma.

Aldoxorubicin-INNO206 structure

Aldoxorubicin

http://www.ama-assn.org/resources/doc/usan/aldoxorubicin.pdf

in phase 3 Cytrx Corporation

(E)-N’-(1-((2S,4S)-4-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)-2-hydroxyethylidene)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride

1H-Pyrrole-1-hexanoic acid, 2,5-dihydro-2,5-dioxo-, (2E)-2-[1-[(2S,4S)-4-[(3-amino-
2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-
7-methoxy-6,11-dioxo-2-naphthacenyl]-2-hydroxyethylidene]hydrazide

N’-[(1E)-1-{(2S,4S)-4-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-2,5,12-
trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl}-2-
hydroxyethylidene]-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide
MOLECULAR FORMULA C37H42N4O13

MOLECULAR WEIGHT 750.7

SPONSOR CytRx Corp.

CODE DESIGNATION

Aldoxorubicin
INNO 206
INNO-206
UNII-C28MV4IM0B

CAS REGISTRY NUMBER 1361644-26-9

CAS: 151038-96-9 (INNO-206); 480998-12-7 (INNO-206 HCl salt), 1361644-26-9

QC data:	View NMR, View HPLC, View MS
Safety Data Sheet (MSDS):	View Material Safety Data Sheet (MSDS)

hydrochloride

CAS: 151038-96-9

Chemical Formula: C37H42N4O13

Exact Mass: 750.27484

Molecular Weight: 750.75

Certificate of Analysis:	View current batch of CoA
QC data:	View NMR, View HPLC, View MS
Safety Data Sheet (MSDS):	View Material Safety Data Sheet (MSDS)

Chemical structure for Aldoxorubicin (USAN)

In vitro protocol:	Clin Cancer Res. 2012 Jul 15;18(14):3856-67
In vivo protocol:	Clin Cancer Res. 2012 Jul 15;18(14):3856-67.Invest New Drugs. 2010 Feb;28(1):14-9.Invest New Drugs. 2012 Aug;30(4):1743-9.Int J Cancer. 2007 Feb 15;120(4):927-34.
Clinical study:	Expert Opin Investig Drugs. 2007 Jun;16(6):855-66.

Aldoxorubicin (INNO-206): Aldoxorubicin, also known as INNO-206, is the 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin (DOXO-EMCH) with antineoplastic activity. Following intravenous administration, doxorubicin prodrug INNO-206 binds selectively to the cysteine-34 position of albumin via its maleimide moiety. Doxorubicin is released from the albumin carrier after cleavage of the acid-sensitive hydrazone linker within the acidic environment of tumors and, once located intracellularly, intercalates DNA, inhibits DNA synthesis, and induces apoptosis. Albumin tends to accumulate in solid tumors as a result of high metabolic turnover, rapid angiogenesis, hyervasculature, and impaired lymphatic drainage. Because of passive accumulation within tumors, this agent may improve the therapeutic effects of doxorubicin while minimizing systemic toxicity.

“Aldoxorubicin has demonstrated effectiveness against a range of tumors in both human and animal studies, thus we are optimistic in regard to a potential treatment for Kaposi’s sarcoma. The current standard-of-care for severe dermatological and systemic KS is liposomal doxorubicin (Doxil®). However, many patients exhibit minimal to no clinical response to this agent, and that drug has significant toxicity and manufacturing issues,” said CytRx President and CEO Steven A. Kriegsman. “In addition to obtaining valuable information related to Kaposi’s sarcoma, this trial represents another opportunity to validate the value and viability of our linker technology platform.” The company expects to announce Phase-2 study results in the second quarter of 2015.

Kaposi’s sarcoma is an orphan indication, meaning that only a small portion of the population has been diagnosed with the disease (fewer than 200,000 individuals in the country), and in turn, little research and drug development is being conducted to treat and cure it. The FDA’s Orphan Drug Act may grant orphan drug designation to a drug such as aldoxorubicin that treats a rare disease like Kaposi’s sarcoma, offering market exclusivity for seven years, fast-track status in some cases, tax credits, and grant monies to accelerate research

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 1/2 to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

INNO-206 is an anthracycline in early clinical trials at CytRx Oncology for the treatment of breast cancer, HIV-related Kaposi’s sarcoma, glioblastoma multiforme, stomach cancer and pancreatic cancer. In 2014, a pivotal global phase 3 clinical trial was initiated as second-line treatment in patients with metastatic, locally advanced or unresectable soft tissue sarcomas. The drug candidate was originally developed at Bristol-Myers Squibb, and was subsequently licensed to KTB Tumorforschungs. In August 2006, Innovive Pharmaceuticals (acquired by CytRx in 2008) licensed the patent rights from KTB for the worldwide development and commercialization of the drug candidate. No recent development has been reported for research that had been ongoing for the treatment of small cell lung cancer (SCLC).

INNO-206 is a doxorubicin prodrug. Specifically, it is the 6-maleimidocaproyl hydrazone of doxorubicin. After administration, the drug candidate rapidly binds endogenous circulating albumin through the acid sensitive EMCH linker. Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including the heart, bone marrow and the gastrointestinal tract. Once inside the acidic environment of the tumor cell, the EMCH linker is cleaved and free doxorubicin is released at the tumor site. Like other anthracyclines, doxorubicin inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells. It also creates iron-mediated free oxygen radicals that damage the DNA and cell membranes. In 2011, orphan drug designation was assigned in the U.S. for the treatment of pancreatic cancer and for the treatment of soft tissue sarcoma.

CytRx Corporation (NASDAQ:CYTR) has announced it has initiated a pivotal global Phase 3 clinical trial to evaluate the efficacy and safety of aldoxorubicin as a second-line treatment for patients with soft tissue sarcoma (STS) under a Special Protocol Assessment with the FDA. Aldoxorubicin combines the chemotherapeutic agent doxorubicin with a novel linker-molecule that binds specifically to albumin in the blood to allow for delivery of higher amounts of doxorubicin (3.5 to 4 times) without several of the major treatment-limiting toxicities seen with administration of doxorubicin alone.

According to a news from Medicalnewstoday.com; CytRx holds the exclusive worldwide rights to INNO-206. The Company has previously announced plans to initiate Phase 2 proof-of-concept clinical trials in patients with pancreatic cancer, gastric cancer and soft tissue sarcomas, upon the completion of optimizing the formulation of INNO-206. Based on the multiple myeloma interim results, the Company is exploring the possibility of rapidly including multiple myeloma in its INNO-206 clinical development plans.

According to CytRx’s website, In preclinical models, INNO-206 was superior to doxorubicin with regard to ability to increase dosing, antitumor efficacy and safety. A Phase I study of INNO-206 that demonstrated safety and objective clinical responses in a variety of tumor types was completed in the beginning of 2006 and presented at the March 2006 Krebskongress meeting in Berlin. In this study, doses were administered at up to 4 times the standard dosing of doxorubicin without an increase in observed side effects over historically seen levels. Objective clinical responses were seen in patients with sarcoma, breast, and lung cancers.

INNO-206 – Mechanism of action:

According to CytRx’s website, the proposed mechanism of action is as the follow steps: (1) after administration, INNO-206 rapidly binds endogenous circulating albumin through the EMCH linker. (2) circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract; (3) once albumin-bound INNO-206 reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker; (4) free doxorubicin is released at the site of the tumor.

INNO-206 – status of clinical trials:

CytRx has announced that, in December 2011, CytRx initiated its international Phase 2b clinical trial to evaluate the preliminary efficacy and safety of INNO-206 as a first-line therapy in patients with soft tissue sarcoma who are ineligible for surgery. The Phase 2b clinical trial will provide the first direct clinical trial comparison of INNO-206 with native doxorubicin, which is dose-limited due to toxicity, as a first-line therapy. (source:http://cytrx.com/inno_206, accessed date: 02/01/2012).

Results of Phase I study:

In a phase I study a starting dose of 20 mg/m2 doxorubicin equivalents was chosen and 41 patients with advanced cancer disease were treated at dose levels of 20–340 mg/m2 doxorubicin equivalents . Treatment with INNO-206 was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects which is a ~3-fold increase over the standard dose for doxorubicin (60 mg/kg). Myelosuppression and mucositis were the predominant adverse effects at dose levels of 260 mg/m2 and became dose-limiting at 340 mg/m2. 30 of 41 patients were assessable for analysis of response. Partial responses were observed in 3 patients (10%, small cell lung cancer, liposacoma and breast carcinoma). 15 patients (50%) showed a stable disease at different dose levels and 12 patients (40%) had evidence of tumor progression. (source: Invest New Drugs (2010) 28:14–19)

phase 2

CytRx Corporation (CYTR), a biopharmaceutical research and development company specializing in oncology, today announced that its oral presentation given by Sant P. Chawla, M.D., F.R.A.C.P., Director of the Sarcoma Oncology Center, titled “Randomized phase 2b trial comparing first-line treatment with aldoxorubicin versus doxorubicin in patients with advanced soft tissue sarcomas,” was featured in The Lancet Oncology in its July 2014 issue (Volume 15, Issue 8) in a review of the major presentations from the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

“We are honored to have been included in The Lancet Oncology’s review of major presentations from ASCO and pleased that these important clinical findings are being recognized by one of the world’s premier oncology journals,” said Steven A. Kriegsman, CytRx President and CEO. “In clinical trials, aldoxorubicin has been shown to be a well-tolerated and efficacious single agent for the treatment of soft tissue sarcoma (STS) that lacks the cardiotoxicity associated with doxorubicin therapy, the current standard of care. We remain on track to report the full overall survival results from this trial prior to year-end 2014.”

The data presented at ASCO 2014 were updated results from CytRx’s ongoing multicenter, randomized, open-label global Phase 2b clinical trial investigating the efficacy and safety of aldoxorubicin compared with doxorubicin as first-line therapy in subjects with metastatic, locally advanced or unresectable STS. The updated trial results demonstrated that aldoxorubicin significantly increases progression-free survival (PFS), PFS at 6 months, overall response rate (ORR) and tumor shrinkage, compared to doxorubicin, the current standard-of-care, as a first-line treatment in patients with STS. The data trended in favor of aldoxorubicin for all of the major subtypes of STS

phase 3

Aldoxorubicin is currently being studied in a pivotal global Phase 3 clinical trial evaluating the efficacy and safety of aldoxorubicin as a second-line treatment for patients with STS under a Special Protocol Assessment with the FDA. CytRx is also conducting two Phase 2 clinical trials evaluating aldoxorubicin in patients with late-stage glioblastoma (GBM) and HIV-related Kaposi’s sarcoma and expects to start a phase 2b study in patients with relapsed small cell lung cancer

PATENTS WO 2000076551, WO 2008138646, WO 2011131314,

…………………….

WO 2014093815

http://www.google.com/patents/WO2014093815A1?cl=en

Anthracyclines are a class of antibiotics derived from certain types of Streptomyces bacteria. Anthracyclines are often used as cancer therapeutics and function in part as nucleic acid intercalating agents and inhibitors of the DNA repair enzyme topoisomerase II, thereby damaging nucleic acids in cancer cells, preventing the cells from replicating. One example of an anthracycline cancer therapeutic is doxorubicin, which is used to treat a variety of cancers including breast cancer, lung cancer, ovarian cancer, lymphoma, and leukemia. The 6-maleimidocaproyl hydrazone of doxorubicin (DOXO-EMCH) was originally synthesized to provide an acid-sensitive linker that could be used to prepare immunoconjugates of doxorubicin and monoclonal antibodies directed against tumor antigens (Willner et al., Bioconjugate Chem 4:521-527 (1993)). In this context, antibody disulfide bonds are reduced with dithiothreitol to form free thiol groups, which in turn react with the maleimide group of DOXO-EMCH to form a stable thioether bond. When administered, the doxorubicin-antibody conjugate is targeted to tumors containing the antigen recognized by the antibody. Following antigen-antibody binding, the conjugate is internalized within the tumor cell and transported to lysosomes. In the acidic lysosomal environment, doxorubicin is released from the conjugate intracellularly by hydrolysis of the acid-sensitive hydrazone linker. Upon release, the doxorubicin reaches the cell nucleus and is able to kill the tumor cell. For additional description of doxorubicin and

DOXO-EMCH see, for example, U.S. Patents 7,387,771 and 7,902,144 and U.S. Patent Application No. 12/619,161, each of which are incorporated in their entirety herein by reference.

[0003] A subsequent use of DOXO-EMCH was developed by reacting the molecule in vitro with the free thiol group (Cys-34) on human serum albumin (HSA) to form a stable thioether conjugate with this circulating protein (Kratz et al, J Med Chem 45:5523-5533 (2002)). Based on these results, it was

hypothesized that intravenously-administered DOXO-EMCH would rapidly conjugate to HSA in vivo and that this macromolecular conjugate would preferentially accumulate in tumors due to an “enhanced permeability and retention” (EPR) intratumor effect (Maeda et al., J Control Release 65:271-284 (2000)).

[0004] Acute and repeat-dose toxicology studies with DOXO-EMCH in mice, rats, and dogs identified no toxicity beyond that associated with doxorubicin, and showed that all three species had significantly higher tolerance for DOXO-EMCH compared to doxorubicin (Kratz et al, Hum Exp Toxicol 26: 19-35 (2007)). Based on the favorable toxicology profile and positive results from animal tumor models, a Phase 1 clinical trial of DOXO-EMCH was conducted in 41 advanced cancer patients (Unger et al, Clin Cancer Res 13:4858-4866 (2007)). This trial found DOXO-EMCH to be safe for clinical use. In some cases, DOXO-EMCH induced tumor regression.

[0005] Due to the sensitivity of the acid-cleavable linker in DOXO-EMCH, it is desirable to have formulations that are stable in long-term storage and during reconstitution (of, e.g., previously lyophilized compositions) and administration. DOXO-EMCH, when present in compositions, diluents and administration fluids used in current formulations, is stable only when kept at low temperatures. The need to maintain DOXO-EMCH at such temperatures presents a major problem in that it forces physicians to administer cold (4°C) DOXO-EMCH compositions to patients. Maintaining DOXO-EMCH at low temperatures complicates its administration in that it requires DOXO-EMCH to be kept at 4°C and diluted at 4°C to prevent degradation that would render it unsuitable for patient use. Further, administration at 4°C can be harmful to patients whose body temperature is significantly higher (37°C).

[0006] Lyophilization has been used to provide a stable formulation for many drugs. However, reconstitution of lyophilized DOXO-EMCH in a liquid that does not maintain stability at room temperature can result in rapid decomposition of DOXO-EMCH. Use of an inappropriate diluent to produce an injectable composition of DOXO-EMCH can lead to decreased stability and/or solubility. This decreased stability manifests itself in the cleavage of the linker between the doxorubicin and EMCH moieties, resulting in degradation of the DOXO-EMCH into two components: doxorubicin and linker-maleimide. Thus, stable,

reconstituted lyophilized solutions of anthracycline-EMCH (e.g., DOXO-EMCH), and injectable compositions containing the same, are required to solve these problems and to provide a suitable administration vehicle that can be used reasonably in treating patients both for clinical trials and commercially.

DOXO-EMCH. The term “DOXO-EMCH,” alone or in combination with any other term, refers to a compound as depicted by the following structure:

DOXO-EMCH is also referred to as (E)-N’-(l-((2S,4S)-4-(4-amino-5-hydroxy-6- methyl-tetrahydro-2H-pyran-2-yloxy-2,5 , 12-trihydroxy-7-methoxy-6, 11- dioxol,2,3,4,6,l l-hexahydrotetracen-2-yl)-2-hydroxyethylidene)-6-(2,5-dioxo-2H- pyrrol- 1 (5H)yl)hexanehydrazide^»HCl.

………………………………

CN 102675385

http://www.google.com/patents/CN102675385A?cl=en

According to literature reports, (eg see David Willner et al, “(6_Maleimidocaproyl) hydrazoneof Doxorubicm-A New Derivative for the Preparation ofImmunoconjugates oiDoxorubicin,” Bioconjugate Chem. 1993,4, 521-527; JK Tota Hill, etc. man, “The method of preparation of thioether compounds noir,” CN1109886A, etc.), adriamycin 13 – bit hydrazone derivative synthesis and the main process are as follows:

[0004]

[0005] First, maleic anhydride and 6 – aminocaproic acid was refluxed in a large number of acid reaction ko ni acid I; agent under the action of the ring after the cyclization maleimidocaproic acid 2 (yield 30-40% ), cyclic acid anhydride mixture is generally ko, trimethyl silyl chloride and tri-amines such ko; maleimido aminocaproic acid tert-butyl ester with hydrazine to condensation to give 2 – (6 – aminocaproic maleimido ) hydrazine carboxylic acid tert-butyl ester 3 (yield 70-85%), the condensing agent is N-methylmorpholine and isobutyl chloroformate; 3 in a large number of trifluoroacetic acid deprotection ko maleimido ko has trifluoroacetic acid hydrazide 4 (yield 70%); the doxorubicin hydrochloride salt with a ko in trifluoroacetic acid catalyzed condensation in methanol solvent to doxorubicin hydrazone product was obtained (yield 80%) .

[0006] The synthetic method the yield is low (in particular, by maleic acid imido step 2), the total yield of not more than 20%, and the solvent consumption is large, adriamycin hydrazone product per Malek consumes about ko acid reaction solvent, 70mL, tetrahydrofuran 300mL, ko trifluoroacetic acid 40mL, and because the 2 – (6 – maleimido hexanoyl)-hydrazine carboxylic acid tert-butyl ester was purified by column chromatography required, but also to consume a large amount of Solvent. This has resulted in synthesis post-processing complex process, complicated operation. And because the end product of the synthesis of doxorubicin hydrazone ko using trifluoroacetic acid, inevitably there will be in the product ko trifluoroacetic acid impurities, not divisible. Based on the high cost of such a route exists, yield and production efficiency is low, Eri Arts route operational complexity and other shortcomings, is obviously not suitable for mass production, it is necessary to carry out improvements or exploring other Eri Arts synthesis methods.

doxorubicin hydrazone derivative,

Wherein n is an integer of 1-15, characterized in that said method comprises the steps of: (1) the maleic acid chloride of the formula H2N-(CH2) n-COOH amino acid I b in the presence of a base prepared by condensation of maleimido group steps I c acid,

(2) maleic acid imido group I c and then with an acylating reagent of tert-butyl carbazate in the presence of a base in the reaction of step I d,

(3) I d deprotection with trifluoroacetic acid, the alkali and removing trifluoroacetic acid to obtain the maleimido group I e hydrazide steps

(4) an imido group of maleic hydrazide I e and doxorubicin hydrochloride catalyzed condensation of hydrogen chloride to obtain a final product hydrazone derivative of doxorubicin,

[0028]

[0049] The butene-ni chloride 15. 2g (0. Imol) was dissolved in 25mL of chloroform was dried by adding anhydrous potassium carbonate 27. 6g (0. 2mol), the gas and gas protection and conditions of 0 ° C was added dropwise 6 – aminocaproic acid 13. 2g (0. ImoI) in chloroform (50mL) solution, add after reaction at room temperature for 3 hours. Washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtered, concentrated under reduced pressure. The residue was recrystallized from alcohol ko maleimido acid (Compound c) 18. 8g, 90% yield, m.p. :85-87 ° C.

[0050] Compound c 10. 5g (50mmol) and thionyl chloride crab 5. 3mL (75mmol) was heated under reflux the mixture I. 5 hours and concentrated under reduced pressure in an argon atmosphere under the conditions of 0 ° C and added dropwise to the hydrazine carboxylic acid tert-butyl ester 6.6g (50mmol) amine with a three ko

10. 8mL (75mmol) in anhydrous ko ether (50mL) solution added after the reaction was continued at room temperature for I. 5 hours. Washed with 5% hydrochloric acid, 5% sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate overnight, filtered with suction to give the compound of d ko ether solution. The solution was cooled to 0 ° C, was added dropwise trifluoroacetic acid ko 7. 4mL (100mmOl), After the addition the reaction was continued for 10 minutes, suction filtered, the filter cake was washed twice with ether, ko and dried in vacuo to give 6 – maleic acid sub-aminocaproic acid hydrazide trifluoro-ko 12. 2g, 72% yield, m.p. 99-102 ° C. IOmL this salt is added to sodium hydroxide (10%) solution, stirred for a while, with ko extracted with ether, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 6 – aminocaproic maleimido hydrazide (compound e) 7. Sg, 70% yield.

[0051] The doxorubicin hydrochloride 0. 58g (Immol) with compound e 0. 45g (2mmol) was dissolved in 150mL of anhydrous methanol, passing about 2mmol of dry hydrogen chloride, under argon, at room temperature protected from light and reaction conditions 24 inches. Concentrated under reduced pressure at room temperature, the solid was washed with about IOOmL ko nitrile, and dried in vacuo doxorubicin 6 – aminocaproic maleimido hydrazone O. 63g, 80% yield. 1H NMR (CD3OD) δ: 7. 94 (bd, 1H), 7. 82 (t, 1H), 7. 55 (d, 1H), 6. 78 (s, 2H), 5. 48 (s, 1H ), 5. 07 (t, 1H), 4 · 59 (d, 1H), 4 · 21 (m, 1Η), 4 · 02 (s, 3H), 3 · 63-3. 30 (m, 5H) , 2 · 55-2. 26 (m, 4H), 2. 19-1. 88 (m, 3Η), I. 69-1. 18 (m, 12Η, I. 26). [0052] Although specific reference to the above embodiments of the present invention will be described, it will be understood that in the appended claims without departing from the invention as defined by the spirit and scope of the skilled person can be variously truncated, substitutions and changes. Accordingly, the present invention encompasses these deletions, substitutions and changes.

………………………………….

US 5622929

http://www.google.co.in/patents/US5622929

http://www.google.co.in/patents/EP0554708A1

Method A:

As noted below, Method A is the preferred method when the Michael Addition Receptor is a maleimido moiety.

[0077]

Alternatively, the Formula (IIa) compound may be prepared by reaction of the drug with a hydrazide to form an intermediate hydrazone drug derivative followed by reaction of this compound with a Michael Addition Receptor containing moiety according to the general process described in Method B:

…………………………………….

http://www.google.co.in/patents/WO2012167255A1?cl=en

Synthesis of DOXO-EMCH

The synthesis of DOXO-EMCH was done initially in accordance with that previously published by Willner and co-workers (Bioconjugate Chem., 4:521-527, 1993). Problems arose in the initial addition of the 6-maleimidocaproylhydrazine to the C-13 ketone of doxorubicin. HPLC results did not give a good yield of product, only 50-60%. Upon further analysis, we determined TFA was not needed to catalyze the reaction, and instead used pyridine. With pyridine, chromatograms from the HPLC showed 90% DOXO-EMCH relative to 10% DOX. The pyridine may have improved the yield by serving as a base to facilitate formation of the hydrazone. Another problem we encountered in the synthesis was purification of the final product. According to Willner’ s method, 5 volumes of acetonitrile (ACN) were to be added to a concentrated methanolic solution of crude DOXO-EMCH to achieve crystallization after 48 h at 4 °C. By this method, only 10-20%) of the desired product precipitated. To obtain a better yield, the crystallization step was done 4 times with 6 volumes of ACN used in each step. A lesser amount of methanol was needed each time, as less product remained in solution. Even with the multiple crystallizations, a final yield of only 59% was obtained. Various other methods for crystallization were explored, including using different solvents and increasing the initial solubility in methanol by heat, but none gave better results. 1.2 Rate of Hydrolysis of DOXO-EMCH at Varying pH

Subsequent pH studies to determine the rate of hydrolysis of the hydrazone were carried out as a benchmark for later hydrolysis experiments with PPD-EMCH. The results of the hydrolysis experiments showed that at lower pH, the hydrolysis reaction proceeded very quickly in the formation of DOX. Moreover, at higher pH the hydrazone proved to be very robust in that its degradation is very slow.

General HPLC instruments and methods

Analytical HPLC methods were performed using a Hewlett-Packard/ Aligent 1050/1100 chromatograph with an auto injector, diode array UV-vis absorption detector. Method 1.1 : Analytical HPLC injections were onto an Aligent Zorbax Eclipse XDB-C18 reversed phase column, 4.6 mm x 150 mm, eluting at 1.0 mL/min. A gradient of acetonitrile/20 mM sodium phosphate buffer (pH 6.9), 80% buffer to 55% at 10 min, 55% to 40% at 12 min, 40% to 80% at 13 min. Retention times: at 480 nm, DOX (9.4 min), DOXO-EMCH (1 1.2 min).

Synthesis of DOXO-EMCH

The synthesis of DOXO-EMCH was accomplished using the procedure reported by Willner et al, with several changes to improve the yield (Willner, D., et al.,

Bioconjugate Chem., 4:521-27, 1993). DOX’HCl (20 mg, 34 μιηοΐ) was dissolved in 6 mL of methanol. Pyridine (12.53 μί) was added to the solution, followed by 35.4 mg

EMCH’TFA. The reaction was stirred at room temperature overnight. By HPLC, the reaction was 90% complete. The solvent was evaporated to dryness by rotary evaporation. A minimal amount of methanol was used to dissolve the solid, and six volumes of acetonitrile at 4 °C were added to the solution. The resulting solution was allowed to sit undisturbed at 4 °C for 48 h for crystallization. The precipitate was collected, and the crystallization method was repeated 4 times. The resulting solids were combined and washed three times with 1 : 10 methanokacetonitrile. The final yield of DOXO-EMCH was 11.59 mg, 58%. HPLC Method 1.1 was used. NMR spectra corresponded to those previously given by Willner (Bioconjugate Chem. 4:521-27. 1993).

…………………………….

http://www.google.co.in/patents/US20070219351

DOXO-EMCH, the structural formula of which is shown below,

…………………………………

SEE

(6-Maleimidocaproyl)hydrazone of doxorubicin – A new derivative for the preparation of immunoconjugates of doxorubicin
Bioconjugate Chem 1993, 4(6): 521

References

1: Kratz F, Azab S, Zeisig R, Fichtner I, Warnecke A. Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model. Int J Pharm. 2013 Jan 30;441(1-2):499-506. doi: 10.1016/j.ijpharm.2012.11.003. Epub 2012 Nov 10. PubMed PMID: 23149257.

2: Walker L, Perkins E, Kratz F, Raucher D. Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative. Int J Pharm. 2012 Oct 15;436(1-2):825-32. doi: 10.1016/j.ijpharm.2012.07.043. Epub 2012 Jul 28. PubMed PMID: 22850291; PubMed Central PMCID: PMC3465682.

3: Kratz F, Warnecke A. Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Control Release. 2012 Dec 10;164(2):221-35. doi: 10.1016/j.jconrel.2012.05.045. Epub 2012 Jun 13. PubMed PMID: 22705248.

4: Sanchez E, Li M, Wang C, Nichols CM, Li J, Chen H, Berenson JR. Anti-myeloma effects of the novel anthracycline derivative INNO-206. Clin Cancer Res. 2012 Jul 15;18(14):3856-67. doi: 10.1158/1078-0432.CCR-11-3130. Epub 2012 May 22. PubMed PMID: 22619306.

5: Kratz F, Elsadek B. Clinical impact of serum proteins on drug delivery. J Control Release. 2012 Jul 20;161(2):429-45. doi: 10.1016/j.jconrel.2011.11.028. Epub 2011 Dec 1. Review. PubMed PMID: 22155554.

6: Elsadek B, Kratz F. Impact of albumin on drug delivery–new applications on the horizon. J Control Release. 2012 Jan 10;157(1):4-28. doi: 10.1016/j.jconrel.2011.09.069. Epub 2011 Sep 16. Review. PubMed PMID: 21959118.

7: Kratz F, Fichtner I, Graeser R. Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model. Invest New Drugs. 2012 Aug;30(4):1743-9. doi: 10.1007/s10637-011-9686-5. Epub 2011 May 18. PubMed PMID: 21590366.

8: Boga C, Fiume L, Baglioni M, Bertucci C, Farina C, Kratz F, Manerba M, Naldi M, Di Stefano G. Characterisation of the conjugate of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin with lactosaminated human albumin by 13C NMR spectroscopy. Eur J Pharm Sci. 2009 Oct 8;38(3):262-9. doi: 10.1016/j.ejps.2009.08.001. Epub 2009 Aug 18. PubMed PMID: 19695327.

9: Graeser R, Esser N, Unger H, Fichtner I, Zhu A, Unger C, Kratz F. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Invest New Drugs. 2010 Feb;28(1):14-9. doi: 10.1007/s10637-008-9208-2. Epub 2009 Jan 8. PubMed PMID: 19148580.

10: Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008 Dec 18;132(3):171-83. doi: 10.1016/j.jconrel.2008.05.010. Epub 2008 May 17. Review. PubMed PMID: 18582981.

11: Unger C, Häring B, Medinger M, Drevs J, Steinbild S, Kratz F, Mross K. Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. Clin Cancer Res. 2007 Aug 15;13(16):4858-66. PubMed PMID: 17699865.

12: Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):108-13. Review. PubMed PMID: 17652814.

13: Kratz F. DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin Investig Drugs. 2007 Jun;16(6):855-66. Review. PubMed PMID: 17501697.

14: Kratz F, Ehling G, Kauffmann HM, Unger C. Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin. Hum Exp Toxicol. 2007 Jan;26(1):19-35. PubMed PMID: 17334177.

15: Lebrecht D, Geist A, Ketelsen UP, Haberstroh J, Setzer B, Kratz F, Walker UA. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007 Feb 15;120(4):927-34. PubMed PMID: 17131338.

16: Di Stefano G, Lanza M, Kratz F, Merina L, Fiume L. A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond: synthesis, characterization and preliminary biological properties of the conjugate. Eur J Pharm Sci. 2004 Dec;23(4-5):393-7. PubMed PMID: 15567293.

EP0169111A1 *	Jun 18, 1985	Jan 22, 1986	Sanofi	Cytotoxic conjugates useful in therapy, and process for obtaining them
EP0269188A2 *	Jun 18, 1985	Jun 1, 1988	Elf Sanofi	Cytotoxic conjugates useful in therapy, and process for obtaining them
EP0306943A2 *	Sep 8, 1988	Mar 15, 1989	Neorx Corporation	Immunconjugates joined by thioether bonds having reduced toxicity and improved selectivity
EP0328147A2 *	Feb 10, 1989	Aug 16, 1989	Bristol-Myers Squibb Company	Anthracycline immunoconjugates having a novel linker and methods for their production
EP0398305A2 *	May 16, 1990	Nov 22, 1990	Bristol-Myers Squibb Company	Anthracycline conjugates having a novel linker and methods for their production
EP0457250A2 *	May 13, 1991	Nov 21, 1991	Bristol-Myers Squibb Company	Novel bifunctional linking compounds, conjugates and methods for their production

KEY words

Aldoxorubicin, CytRx, CANCER, INNO-206, PHASE 3, oncology, Soft Tissue Sarcoma

USFDA grants Qualified Infectious Disease Product status to two Wockhardt drugs

Uncategorized Comments Off

Sep 012014

Levonadifloxacin arginine salt, WCK 771
RN: 306748-89-0

C19-H21-F-N2-O4.C6-H14-N4-O2
MW: 534.5855

L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)

WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate

(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate

L-arginine salt of (S)-nadifloxacin

A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232

CN 102532131, WO 2005023805, WO 2002009758, WO 2001085095, WO 2000068229

WCK 2349

cas 948895-94-1 methane sulfonate

base..706809-20-3

8-[4-(L-Alanyloxy)piperidin-1-yl]-9-fluoro-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid methanesulfonate

WO 2000068229, WO 2002009758, WO 2007102061, WO 2008053295

Shetty, N.M.; Nandanwar, M.B.; Kamalavenkatesh, P.; et al.
WCK 2349: A novel fluoroquinolone (FQ) prodrug-13 week oral (PO) safety profile in cynomolgus monkeys
47th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 17-20, Chicago) 2007, Abst F1-2133a

keywords USFDA, Qualified Infectious Disease Product status, Wockhardt, drugs, WCK 771, WCK 2349, QIDP

^aChemical name: S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate. ^bChemical name: S-(–)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3, 3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate. ^cChemical name: R-(+)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate.

Aripiprazole lauroxil ……….Alkermes submits new drug application

Uncategorized Comments Off

Aug 282014

Aripiprazole

7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]- 3,4-dihydro-2(1H)-quinolinone.

END AUG 2014

The US Food and Drug Administration (FDA) has received a new drug application (NDA) from Ireland-based Alkermes for its aripiprazole lauroxil to treat schizophrenia.

Aripiprazole lauroxil is an injectable atypical antipsychotic with one-month and two-month formulations, developed for the treatment of schizophrenia, which is a chronic, severe and disabling brain disorder.

The company has submitted the application based on positive results from the pivotal phase three study that assessed the efficacy and safety of aripiprazole lauroxil, where the drug demonstrated significant improvements in schizophrenia symptoms when compared to a placebo.

“We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options.”

Alkermes CEO Richard Pops said: “We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options, to help meet the individual needs of patients and their healthcare providers.

“These attributes, together with the robust clinical data observed in the pivotal study, position aripiprazole lauroxil to be a meaningful new entrant in the growing long-acting injectable antipsychotic market, and we look forward to working with the FDA to bring this important new medication to patients and physicians as quickly as possible.”

The study, in which both doses of aripiprazole lauroxil tested, including 441mg and 882mg, reached the primary endpoint with statistically significant and clinically meaningful reductions in positive and negative syndrome scale (PANSS) scores, according to the company.

In addition, it met all secondary endpoints and demonstrated significant improvements in schizophrenia symptoms against the placebo.

ALKS 9070
ALKS 9072
Aripiprazole lauroxil
RDC 3317
RDC-3317
UNII-B786J7A343

Aripiprazole lauroxil [USAN] CAS 1259305-29-7

Systematic (IUPAC) name
7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
Clinical data
Trade names	Abilify
AHFS/Drugs.com	monograph
MedlinePlus	a603012
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B3 (AU) C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral (via tablets, orodispersable tablets, and oral solution); intramuscular (including as a depot)
Pharmacokinetic data
Bioavailability	87%^[1]^[2]^[3]^[4]
Protein binding	>99%^[1]^[2]^[3]^[4]
Metabolism	Hepatic (liver; mostly via CYP3A4 and CYP2D6^[1]^[2]^[3]^[4])
Half-life	75 hours (active metabolite is 94 hours)^[1]^[2]^[3]^[4]
Excretion	Renal (27%; <1% unchanged), Faecal (60%; 18% unchanged)^[1]^[2]^[3]^[4]
Identifiers
CAS number	129722-12-9
ATC code	N05 AX12
PubChem	CID 60795
IUPHAR ligand	34
DrugBank	DB01238
ChemSpider	54790
UNII	82VFR53I78
KEGG	D01164
ChEBI	CHEBI:31236
ChEMBL	CHEMBL1112
Chemical data
Formula	C₂₃H₂₇Cl₂N₃O₂
Mol. mass	448.385

Aripiprazole (/ˌ ɛər ɨ ˈ p ɪ p r ə z oʊ l / AIR-i-PIP-rə-zohl; brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation (or atypical) class of antipsychotics that is primarily used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as an add on to other treatment), tic disorders, and irritability associated with autism.^[5]

It was approved by the U.S. Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;^[6] and to treat irritability in children with autism on 20 November 2009.^[7] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.^[1]

Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

Regulator status

In the United States, the FDA has approved aripiprazole for the treatment of schizophrenia in adults and adolescents (aged 13–17), of manic and mixed episodes associated with Bipolar I (One) Disorder with or without psychotic features in adults, children and adolescents (aged 10–17),^[59] of irritability associated with autism in pediatric patients (aged 6–17),^[60] and of depression when used along with antidepressants in adults.^[61]

Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.^[62]

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.^[63] It has not been FDA-approved for use as monotherapy in unipolar depression.

Patent status

Otsuka’s US patent on aripiprazole expires on October 20, 2014;^[64] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.^[62] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.^[65] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[1][2]

Dosage forms

Abilify 2mg tablets (US)

Intramuscular injection, solution: 9.75 mg/mL (1.3 mL)
Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]

Synthesis

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:^[66]

U.S. Patent No.4, 734, 416 and U.S. Patent No.5,006,528 discloses the Aripiprazole, 7-{4- [4- (2, 3-dichlorophenyl) -1-piperazinyl] butoxy}- 3,4-dihydro-2 (IH) -quinolinone or 7-{4-[4- (2, 3-dichlorophenyl) -1- piperazinyl] butoxy}-3, 4-dihydro carbostyril, is a typical antipsychotic agent useful for the treatment of Schizophrenia, having the formula as given below.

Aripiprazole

U.S. patent No.5,006,528 discloses preparation of Aripiprazole and its pharmaceutically acceptable acid-addition salts. The process for the preparation of acid salts involves reaction of Aripiprazole with a pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; organic acids such as oxalic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, . benzoic acid and the like as per Scheme-1. Scheme- 1

a. K₂CO₃, Water K CH₂CI₂ c. Column chromatographic purification d. n-Hexane – Ethaπol

ARIPIPRAZOLE ACID SALT

The product Aripiprazole _.obtained by the above process has melting point of 139.0° – 139.5°C.

The process involves purification of the intermediate, 7-(4- bromobutoxy) -3, 4-dihydrocarbostyril (III) by silica gel column chromatography to remove impurities formed during the reaction. The process further involves two recrystallizations of Aripiprazole from ethanol to obtain the pure Aripiprazole though compromising on yields by increasing the operational cost of the product. PCT publication WO 03/026659 discloses low hygroscopic forms of

Aripiprazole and the process for their preparation from the Aripiprazole hydrate Form ^SA’ . It further states that the anhydrous

Aripiprazole made by the Japanese patent publication No. 191256/1990, yields the Aripiprazole, which is significantly hygroscopic. As per PCT publication WO 03/026659 anhydrous crystals of Aripiprazole exist as type-I crystals and type-II crystals. Further discloses that the type-I crystals are prepared -by recrsytallization from ethanol solution of

Aripiprazole or by heating Aripiprazole hydrate at 80⁰C and type-II crystals by heating type-I crystals at 130 to 140⁰C for 15 hrs.

PCT application Publication WO 03/026659 discloses process for the Aripiprazole polymorphic form-B by heating the Aripiprazole hydrate

‘A’ at 90 – 125°C for about 3 – 50 hrs. The process for Polymorphic

Form-C is by heating the Aripiprazole anhydrous to a temperature of 140

– 150⁰C. The process for Form-D is recrystallization from toluene; process for Form-E is heating with acetonitrile or by recrystallization from acetonitrile and the process for Form-F is by heating the suspension of anhydrous Aripiprazole in acetone. The polymorphic Form-G is by heating to 170⁰C for at least 2 weeks in a sealed tube, which is a glassy mass.

PCT publication WO 03/026659 further discloses the characterization data X-ray diffraction pattern; IR absorption and DSC of Form B, Form C, Form-D, Form-E, Form-F and Form-G.It further reported the melting point of Aripiprazole anhydrous Form B as 139.7°C-

Research

Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behavior in animal models without significantly affecting other rewarding behaviors (such as food self-administration).^[67] Aripiprazole may be counter-therapeutic as treatment for methamphetamine dependency because it increased methamphetamine’s stimulant and euphoric effects, and increased the baseline level of desire for methamphetamine.^[68]

http://www.google.com/patents/WO2006030446A1?cl=en

Scheme-3

Aripiprazole Acid addition salt

Form-A, B, C , D , E , F Type-I & Type-II Aripiprazole acid salts used for the preparation of polymorphs

…………………………….

patent expiry

………………….patent…..approved….exp

United States	5006528	1994-10-20	2014-10-20
United States	7115587	2005-01-21	2025-01-21

Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amineU.S. Patent 5,006,528

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2 (1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia (U.S. Pat. No. 4,74,416 and U.S. Pat. No. 5,006,528). Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent, than Alzheimer’s disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention can avert costly hospitalization.

Aripiprazole (Aripiprazole) is an atypical antipsychotic, on 15 November 2002 by the U.S. FDA clearance to market, its efficacy is through the dopamine D2 receptor and serotonin 5HT1A receptor partial agonist activity and serotonin 5HT2A receptor antagonism activity mediated common. With its unique mechanism of action and safety assessment, aripiprazole known as third-generation antipsychotic drugs.

[0003] Aripiprazole is a quinolinone derivative, developed by the Japanese company Otsuka Pharmaceutical, the chemical name

Is: 7 – {4 – [4 – (2,3 – dichlorophenyl)-1_ piperazinyl] butoxy} -3,4 – dihydro-quinolone, the following structural formula:

[0004]

[0005] For the preparation of aripiprazole, Japanese OtsukaPharmaceutical’s patent EP 0367141A2, and related patents US4234585, CN89108934 preparation methods described in 5. In addition, the patent CN1450056A, CN1562973A, CN1784385A, CN1680328A, CN1576273A, etc. describe some of these five Preparation

Method is very similar way. These preparation methods are direct or indirect use of 7 – hydroxy -3,4 – dihydro – quinolin-2 – one (HCS) that the key to higher prices of raw materials, and some methods involve harsh reaction conditions, poor selectivity, low yield, but also increases the cost of industrial production of the product.

[0006] Chinese patent CN1304373C preparation method is not described in the 7 – hydroxy-3 ,4 _ dihydro-2_ (1H) – quinoline

Quinolone intermediates for their preparation of the core reaction is as follows:

[0007]

[0008] This reaction is Friedel-Crafts alkylation reaction, there is a harsh reaction conditions, the yield is low, the reaction selectivity is poor, the shortcomings of high emissions, is not conducive to industrial mass production. SUMMARY OF THE INVENTION

[0009] In order to solve the above problems, the present invention provides a simple, high selectivity, high yield, low cost, environmentally friendly, easy to prepare industrialization aripiprazole and intermediates thereof.

[0010] The technical solution of the present invention, the present invention provides in one aspect a process for preparingaripiprazole novel intermediates.

[0011] The present invention, on the other hand provides a method for the preparation of intermediates.

[0012] The present invention provides the use of the other intermediates for preparing aripiprazole two new preparation methods.

[0013] Specifically, the present invention relates to novel intermediates, compounds of formula ⑴:

[0014]

[0015] wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl and other common alkyl groups in any one, and preferably is ethyl.

[0016] Compound of formula ⑴: 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate, is the following prepared by the procedure:

[0017] Step one, the acylation reaction: with 4 – methyl – 3 – nitro-phenol (VIII) and acetic anhydride as the raw material, DMAP as catalyst, to give 4 – methyl – 3 – nitrophenyl acetate ( VII).

[0018] wherein 4 – methyl – 3 – nitro-phenol (VIII), acetic anhydride, DMAP molar ratio is preferably 1: 1.0 to 1.4: 0.05, at room temperature, the reaction time is preferably 0.5 to 3 hours.

[0019] Step two, the bromination reaction: The resulting product, 4 to Step one – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide and benzoyl peroxide as a raw material , carbon tetrachloride solvent reflux, to give 4 – bromomethyl-3 – nitrophenyl acetate (VI).

[0020] wherein 4 – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide, benzoyl peroxide molar ratio is preferably 1: 1 to 1.2: 0.05, reaction time is preferably 4-18 hours.

[0021] Step three, instead of the reaction: in an appropriate solvent, adding an alkaline agent and diethyl malonate was stirred in an ice bath, was added dropwise step two the resulting product, 4 – bromomethyl-3 – nitrophenyl yl acetate (VI) solution after completion of the addition reaction of 1 to 3 hours to obtain a brown liquid product, 2 – (4_ acetoxy-2 – nitrobenzyl) malonate (V).

[0022], wherein the alkali agent is a common organic or inorganic base selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide; the solvent is selected from tetrahydrofuran, methanol, ethanol, butanol, tert-butanol, toluene or N, N-dimethylformamide; 4 – bromomethyl-3 – nitrophenyl acetate (VI), alkaline agent and lipid diethyl molar ratio is preferably 1: 1.0 to 1.8: 1.0 to 1.4.

[0023] Step 4 Hydrolysis decarboxylation: the product obtained in Step Three 2 – (4_ acetoxy-2 – nitro-benzyl)-malonic acid diethyl ester (V) was added concentrated hydrochloric acid and a suitable solvent, heating and stirring reflux, to give a yellow solid product 3 – (4_ hydroxy-2 – nitrophenyl) propionic acid (IV).

[0024] wherein the solvent is selected from water, methanol, ethanol or acetic acid, water soluble solvent, was heated with stirring under reflux time is preferably 3 to 18 hours. [0025] Step five, the esterification reaction: the product obtained in step 4, 3 – (4 – hydroxy-2 – nitrophenyl) propionic acid (IV) was added to an appropriate solvent, the mixture was stirred in an ice bath, was added dropwise thionyl sulfone, after completion of the addition reaction of 1 to 3 hours, to give a pale brown liquid product 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III).

[0026] wherein the solvent is selected from anhydrous methanol, ethanol, propanol, isopropanol, butanol, t-butanol, benzyl alcohol, alcohol and other common solvents.

[0027] Step VI substitution reaction: 1,4 – dibromobutane was added to an appropriate solvent and an alkaline reagent, heated to 50 ~ 100 ° C, the product obtained was added dropwise Step Five 3 – (4_ hydroxy – nitrophenyl) propionate (III) solution, after the addition was complete the reaction was kept 2 to 4 hours to obtain a brown liquid product 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II).

[0028] wherein the solvent is selected from methanol, 95% ethanol, ethanol, acetonitrile and N, N-dimethylformamide, and the like; said alkaline agent is a common organic or inorganic weak base, such as triethylamine, pyridine, potassium carbonate, sodium carbonate, etc..

[0029] Step 7 condensation reaction: the product obtained in Step Six 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II) adding a suitable solvent, (2,3 – dichlorophenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, to obtain

The intermediate product 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl)-piperazin-1 – yl) butoxy)-2 – nitrophenyl) propionate ⑴.

[0030] Among them, 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate (I), (2, 3 – dichloro-phenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, the four molar ratio is preferably 1: 0.9 to 1.0: 2.0 to 2.2: 0.05 to 0.5. The solvent is selected from methanol, ethanol and N, N-dimethylformamide, acetonitrile and the like. Step six of the alkaline reagent and alkaline reagent used in the same, said catalyst is a common low-iodine salts, such as sodium iodide, potassium iodide.

[0031] The present invention provides two other hand, the use of a compound of formula ⑴ preparing aripiprazole new method.

[0032] Method one: ⑴ intermediate compound of formula in an appropriate solvent in the acid or salt or a base in the presence of a reducing agent under the action of restoring ring closure reaction to obtain aripiprazole.

[0033] Method one reductive cyclization of the reducing agent used is iron, zinc, sodium sulfide, stannous chloride, and preferably iron; reaction solvent is selected from water, methanol, ethanol, ethyl acetate or in one or more of the mixed solvent; said acid is a common organic or inorganic acid, preferably acetic acid or hydrochloric acid; said salt is a common inorganic or organic salts selected from chloride, ferrous chloride, , ammonium sulfate, calcium chloride, zinc chloride, sodium chloride, sodium bromide or sodium acetate and the like; common said base is an inorganic base selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate; the reduction ring-closing reaction temperature range of 30 ~ 140 ° C, preferably about 80 ° C; reaction time ranges from about 0.5 to 8 hours, preferably 2 hours.

[0034] Method two: ⑴ intermediate compound of formula in an appropriate solvent in the first catalyst, the reduction reaction, and then carried out in a suitable solvent can be prepared by cyclization of aripiprazole.

[0035] The reduction reaction of the second approach, the reducing agent is hydrogen or a carboxylic acid; the catalyst is selected from molybdenum, molybdenum dioxide or Raney nickel, preferably Raney nickel; the solvent is selected from methanol, ethanol, ethyl acetate or acetic acid, preferably ethanol; said ring-closing reaction of the solvent is selected from N, N-dimethylformamide, trichlorobenzene or xylene; reaction temperature range of 50 ~ 180 ° C, preferably about 70 ~ 150 ° C; reaction time the range of about 1 to 8 hours.

[0036] In summary, the present invention is described for preparing aripiprazole method in 4– methyl – 3 – nitro-phenol (VIII) as a starting material, by acetylation protected hydroxy, radical instead of 4 – bromomethyl-3 – nitrophenyl acetate (VI), the diethyl malonate and a nucleophilic substitution reaction to obtain 2 – (4_ acetoxy-2 – nitrobenzyl ) malonic acid diethyl ester (V), which is decarboxylated by hydrolysis, esterification, to give 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III), the reaction product with dibromobutane an ether compounds, and with (2,3 – dichlorophenyl)-piperazine hydrochloride 1_ condensation, to give 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl) piperazine -1 – yl) butoxy) -2 – nitrophenyl) propionate (I), and then by reductive cyclization step, or first reduced and then ring-closing reaction of aripiprazole. The synthetic route of the present invention is as follows: [0037]

According to Example 1 of Japanese Unexamined Patent Publication No. 191256/1990, anhydrous aripiprazole crystals are manufactured for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting raw anhydrousaripiprazole with ethanol. Also, according to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996), anhydrousaripiprazole crystals are manufactured by heating aripiprazole hydrate at 80° C. However, the anhydrous aripiprazole crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.

The hygroscopicity of these crystals makes them difficult to handle since costly and burdensome measures must be taken in order ensure they are not exposed to moisture during process and formulation. Exposed to moisture, the anhydrous form can take on water and convert to a hydrous form. This presents several disadvantages. First, the hydrous forms of aripiprazole have the disadvantage of being less bioavailable and less dissoluble than the anhydrous forms ofaripiprazole. Second, the variation in the amount of hydrous versus anhydrousaripiprazole drug substance from batch to batch could fail to meet specifications set by drug regulatory agencies. Third, the milling may cause the drug substance, Conventional Anhydrous Aripiprazole, to adhere so manufacturing equipment which may further result in processing delay, increased operator involvement, increased cost, increased maintenance, and lower production yield. Fourth, in addition to problems caused by introduction of moisture during the processing of these hygroscopic crystals, the potential for absorbance of moisture during storage and handling would adversely affect the dissolubility of aripiprazole drug substance. Thus shelf-life of the product could be significantly decreased and/or packaging costs could be significantly increased. It would be highly desirable to discover a form of aripiprazole that possessed low hygroscopicity thereby facilitating pharmaceutical processing and formulation operations required for producing dosage units of an aripiprazole medicinal product having improved shelf-life, suitable dissolubility and suitable bioavailability.

Also, Proceedings of the 4 the Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) state that, anhydrous aripiprazole crystals exist as type-I crystals and type-II crystals; the type-I crystals of anhydrous aripiprazolecan be prepared by recrystallizing from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80° C.; and the type-II crystals of anhydrousaripiprazole can be prepared by heating the type-I crystals of anhydrousaripiprazole at 130 to 140° C. for 15 hours.

By the aforementioned methods, anhydrous aripiprazole type-II crystals having high purity can not be easily prepared in an industrial scale with good repeatability.

Chemical Synthesis of Aripiprazole (active ingredient for Abilify)

Experimental Procedures for the preparation of Aripiprazole (Abilify, aripiprazole)

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps The first step comprises synthesis of 7 -. (4-bromobutoxy) -3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3, 4 -dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield The resulting 7-BBQ is further reacted with 1 -. (2,3 – dichlorophenyl)-piperazine to obtain Aripiprazole.

Preparation of 7 – (4-Bromobutoxy) 3 ,4-dihydro-2 (1H) quinolinon ( 7 – (4-Bromobutoxy) 3 ,4-dihydrocarbostyril; 7-BBQ)

7-Hydroxy-3 ,4-dihydro-2 (1H)-quinolinone (aka 7-Hydroxy-3 ,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40 – 45 ° C for 24 hours Reaction mass was cooled upto room temperature and was filtered off The resulting filtrate was distilled off.. under vacuum. The resultant mass was cooled to 25-30 ° C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The . solid was filtered and dried under vacuum at 55-60 ° C for 20 hours to obtain title compound mp 110.5-111 ° C; 1H NMR (DMSO-d6) ä 1.81 (2H, m,-CH2-), 1.95 (2H , m,-CH2-), 2.41 (2H, t, J) 7 Hz,-CH2CO-), 2.78 (2H, t, J) 7 Hz,-CH2-C-CO-), 3.60 (2H, t, J) 6 Hz,-CH2Br), 3.93 (2H, t, J) 6 Hz, O-CH2-), 6.43 (1H, d, J) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz ), 7.04 (1H, d, J) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.

Yield: 73-75%; Purity: 93-95%

Preparation of Aripiprazole (7 – {4 – [4 – (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One)

7 – (4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30 ° C. To this potassium carbonate (67.2 gm) and l – (2,3 – dichlorophenyl). piperazine hydrochloride (44.9gm) were added under stirring The reaction mixture was refluxed at 80-85 ° C for 8 hours The reaction mass was cooled to room temperature, filtered and the resulting solid was washed. with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80 ° C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to . obtain title compound Yield: 75-80%; Dimer Impurity: <0.1% 1H NMR:. DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar ]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t,-CH2-O-]; 2.97 [4H, bb, 2 ( -CH2-)]; 2.78 [2H, t,-CH2-N2-)]; 2.39 [4H, m, 2 (-CH2-)]; 1.73 [2H, m, – CH2-]; 1.58 [2H, m .,-CH2-] IR: cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588 .

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water

Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85 ° C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30 ° C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 6 hours to obtain title compound.

Yield: 87-89% HPLC Purity: 99.89

Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.

Hydrate A: Below detectable limit (BDL) at limit of detection 1%.

Particle Size Distribution: d ₁₀ = 15.83 m, d ₅₀ = 60.12 m, d ₉₀ = 144.99 m

Preparation of aripiprazole anhydrous Type I using ethanol and water

Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85 ° C for 1-2 hours. The resulting mixture was cooled to 25-30 ° C within 4 hours and . stirred for 3 hours The resulting solid was filtered and dried under suction for 1 hour The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 3 hours to obtain title compound Yield:.. 90% HPLC Purity: 99.9 %

Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.

Hydrate A: Below detectable limit (BDL) at limit of detection 1%.

Particle Size Distribution: d ₁₀ = 22.01 m, d ₅₀ = 105.10 m, d ₉₀ = 232.97 m

For the Process of references Aripiprazole (Abilify, Japanese: Oh, Bldg re phi, Ann reピplastic AKZO have suitable; Chinese: Ann-law who, aripiprazole)

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori, Yasufumi Uwahodo, and Takao Nishi; Novel Antipsychotic Agents with Dopamine autoreceptor Agonist Properties: Synthesis and Pharmacology of 7 – [4 – (4-Phenyl-1- piperazinyl) butoxy] – 3,4-dihydro-2 (1H)-quinolinone Derivatives ; J. Med Chem. 1998, 41, 658-667.

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi; Carbostyril Derivatives , Otsuka Pharmaceutical Co., Ltd.;. U.S. Patent 5006528 ; Issue Date: Apr 9, 1991

BANDO, Takuji, YANO, Katsuhiko, FUKANA, Makoto, AOKI, Satoshi; Method for producing fine particles of aripiprazole anhydride crystals b; OTSUKA PHARMACEUTICAL CO, LTD, WO 2013002420 A1..

Yuanqiu Hui, Chen Hongwen, Qian Wen, firewood rain column, Xu Dan, Yang Zhimin, Tian Zhoushan; method for preparing high purity of aripiprazole; NJCTT Pharmaceutical Co., Ltd.; application number: 201210292382.0; Publication Number: CN102863377A; Publication date: 2013.01.09 After (The invention relates to the field of medicine and chemical industry, in particular to a method for preparing high purity of aripiprazole would join aripiprazole A solvent is heated, filtered, and the filtrate was added to a solvent B, low temperature mixing, filtration, the filter cake is suspended in water, adjusted to alkaline pH of the aqueous solution, filtration, high temperature vacuum dried to obtain a high-purity refined product Aripiprazole This method is simple, high purity, suitable for the industrial the large-scale application)

ZHENG Siji, LIU Xiaoyi, FU Linyong, TAN Bo, ZHOU Min:.. ARIPIPRAZOLE MEDICAMENT FORMULATION AND PREPARATION METHOD THEREFOR / FORMULATION DE MÉDICAMENT ARIPIPRAZOLE ET SON PROCÉDÉ DE PRÉPARATION / a aripiprazole pharmaceutical formulation and preparation method SHANGHAI ZHONGXI. PHARMACEUTICAL January 2013: WO 2013/000391

Zheng Si Ji, Liu Xiaoyi, Fulin Yong, Tan Bo, Zhou Min: A aripiprazole pharmaceutical formulation and preparation method; Shanghai Pharmaceutical Co., Ltd. and Western; Publication date: 2013.01.02: Application Number: CN 201210235157.3; Publication Number: CN102846543A (the invention provides a method for preparing aripiprazole pharmaceutical formulation, comprising the steps of: an acidic solution containing aripiprazole is dissolved in the acidulant, to obtain an acidic solution containing the drug; Thereafter, the resulting drug-containing acidic solution alkalizing agents and materials prepared by wet granulation or suspension to give aripiprazole pharmaceutical formulation; said excipients include antioxidants)

Zheng Si Ji; Tan wave; Fulin Yong; Liu Xiaoyi; Yuanshao Qing; Cao Zhihui; aripiprazole Ⅰ type microcrystalline, aripiprazole solid preparation and preparation methods; application number: 201110180032.0; Publication Number: CN102850268A; Publication Date: 2013.01.02

Cai Fu Bo, Qin Xinrong, Du Xiaochun, Li Ling; kind of aripiprazole improved method of synthesis; Chengdu Nakasone Pharmaceutical Group Co., Ltd.; Application Number: 200910058148.X; Publication Number: CN101781246A; Publication date: 2010.07.21 (the invention provides a method of synthesis of aripiprazole improved method according to the modified method of the present invention, aripiprazole into the etherification reaction and condensation reaction of two-step synthesis, by an etherification reaction in the quinolone compound and at least 6-fold molar equivalents of 1,4 – dihalo-butane reacted with a non-polar solvent ether aripiprazole precipitate, and recovering 1,4 – dihalo-butane recycling; azeotropic condensation reaction of a ketone to be / water mixture as solvent, aripiprazole etherified with a piperazine compound or a salt thereof in the presence of a base under reflux and alkaline metal iodide compound conditions, the amount of water added to the end of the reaction, cooling crystallization, filtration, and dried to give aripiprazole. improved high yield synthesis of high purity, step simple, low cost, suitable for industrial production.)

GUPTA, Vijay Shankar, KUMAR, Pramod, VIR, Dharam; Process for producing aripiprazole in anhydrous type i crystals; JUBILANT LIFE SCIENCES LIMITED; WO 2012131451 A1

SRIVASTAVA JAYANT GUPTA Vijay Shankar;. Improved process for the preparation of 7 (4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole; wo2011030213 A1

No Generic Abilify in the US until April 2015

On May 7, 2012, The US Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. In its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify ®.. The Federal Circuit Affirmed a Decision of the U.S. District Court for the District of New Jersey Holding that the asserted claims ofU.S. Patent No. 5,006,528 Covering aripiprazole, the active Ingredient in Abilify ®, are Valid, THUS Maintaining Patent and Regulatory Protection for Abilify ® in the U.S. until at least April 20, 2015 . The Case is Otsuka Pharma Co.. V. sand Inc.., 2011-1126 and 2011-1127, US Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, US District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole (Abilify for active Ingredient): 7 – {4 – [4 – (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One
CAS Number 129722 -12-9
aripiprazole chemical name 7 – [4 – [4 – (2,3 – dichlorophenyl) -1 – piperazinyl] butoxy] -3,4 – dihydro-2 ( 1H) – quinolinone

Aripiprazole (, Aripiprazole, Abilify) is an atypical antipsychotic medication for the quinoline derivatives, aripiprazole is a dopamine system stabilizer first, positive and schizophrenia negative symptoms have a significant effect. For the treatment of schizophrenia, the development of Otsuka Pharmaceutical Co., Ltd., in November 15, 2002 by the U.S. Food and Drug Administration (FDA) approval in the U.S., domestic aripiprazole has (Booz clear (brisking, manufacturers : Chengdu Nakasone Pharmaceutical), Austrian (Manufacturer: Shanghai Pharmaceutical Co., Ltd. and Western)) have been approved by the listing in China. On sale in the United States where the law by Bristol-Myers Squibb is responsible. An law where the main patent protection in the United States, and more than three-quarters of its sales from the U.S., patent will expire in April 2015.

Aripiprazole synthetic route

7 – hydroxy-3 ,4. Dihydro -2 (1H) – quinolinone as a starting material, 1,4. Dibromobutane ether to give 7 – (4 – Bromo-butoxy) -3,4 – dihydro – 2 (1H) quinolinone, and then with 1 – (2,3 – dichlorophenyl) piperazine acid condensation aripiprazole (7 – [4 – [4 – (2,3 – dichlorophenyl) -1 – piperazinyl] butoxy] -3,4 – dihydro -2 (1H) – quinolinone)

Aripiprazole preparation method

7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone
A reaction flask was added 7 – hydroxy – 3,4 – dihydro -2 (1H) – quinolone 32.6 g (0.2mol), 1,4 – dibromo butane 129.5g (0.6mol), 11.2% KOH solution 250ml (0.5mol) and DMF975ml, was heated to 60 º C for 2h diluted with 1L water, the aqueous layer with ethyl acetate. acetate (300ml × 2) and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover the solvent, the residue was recrystallized from isopropanol, to give 7 – (4 – Bromo-butoxy) – 3,4 – dihydro -2 (1H) – quinolone 38.7g, yield 68%, mp108 ~ 110 º C.

Synthesis of aripiprazole
in the reaction flask was added 7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone, 29.8g (0.1mol), KI25g (0.15mol) 95% Ethanol 596ml, stirred and heated to 60 º C, was added N-2 30min after 3 – dichlorophenyl piperazine 23.1g (0.1mol) and triethylamine 20ml (0.15mol), stirred for 8h at 60 º C the mixture is filtered. crystallization filtrate was cooled, filtered and the filter cake was recrystallized twice from ethanol and dried to obtain aripiprazole 25.6g, yield 57%, mp138.9 ~ 139.6 º C.

References

“Product Information for ABILIFY^TM Aripiprazole Tablets & Orally Disintegrating Tablets”. TGA eBusiness Services. Bristol-Myers Squibb Australia Pty Ltd. 1 November 2012. Retrieved 22 October 2013.
“ABILIFY (aripiprazole) tablet ABILIFY (aripiprazole) solution ABILIFY DISCMELT (aripiprazole) tablet, orally disintegrating ABILIFY (aripiprazole) injection, solution [Otsuka America Pharmaceutical, Inc.]”. DailyMed. Otsuka America Pharmaceutical, Inc. April 2013. Retrieved 22 October 2013.
“Abilify Tablets, Orodispersible Tablets, Oral Solution – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. Otsuka Pharmaceuticals (UK) Ltd. 20 September 2013. Retrieved 22 October 2013.
“ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS”. European Medicines Agency. Otsuka Pharmaceutical Europe Ltd. Retrieved 22 October 2013.
http://www.webmd.com/drugs/drug-64439-Abilify+Oral.aspx?drugid=64439&drugname=Abilify+Oral&source=1
Hitti, Miranda (20 November 2007). “FDA OKs Abilify for Depression”. WebMD. Archived from the original on 5 December 2008. Retrieved 8 December 2008.
Keating, Gina (23 November 2009). “FDA OKs Abilify for child autism irritability”. Reuters. Retrieved 22 September 2010.
“abilify”. The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
Belgamwar RB, El-Sayeh HG (Aug 10, 2011). “Aripiprazole versus placebo for schizophrenia.”. The Cochrane database of systematic reviews (8): CD006622. PMID 21833956.
Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis”. Lancet 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ (2013). “World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects”. World J. Biol. Psychiatry 14 (1): 2–44. doi:10.3109/15622975.2012.739708. PMID 23216388.
El-Sayeh HG, Morganti C (Apr 19, 2006). “Aripiprazole for schizophrenia.”. Cochrane database of systematic reviews (Online) (2): CD004578. doi:10.1002/14651858.CD004578.pub3. PMID 16625607.
Belgamwar RB, El-Sayeh HG (Aug 10, 2011). “Aripiprazole versus placebo for schizophrenia.”. Cochrane database of systematic reviews (Online) (8): CD006622. doi:10.1002/14651858.CD006622.pub2. PMID 21833956.
Bhattacharjee J, El-Sayeh HG (Jan 23, 2008). “Aripiprazole versus typicals for schizophrenia.”. Cochrane database of systematic reviews (Online) (1): CD006617. doi:10.1002/14651858.CD006617.pub2. PMID 18254107.
Khanna P, Komossa K, Rummel-Kluge C, Hunger H, Schwarz S, El-Sayeh HG, Leucht S (Feb 28, 2013). “Aripiprazole versus other atypical antipsychotics for schizophrenia.”. Cochrane database of systematic reviews (Online) 2: CD006569. doi:10.1002/14651858.CD006569.pub4. PMID 23450570.
“Psychosis and schizophrenia in adults: treatment and management | Guidance and guidelines | NICE”. National Institute for Health and Care Excellence.
Barnes TR (2011). “Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology”. J. Psychopharmacol. (Oxford) 25 (5): 567–620. doi:10.1177/0269881110391123. PMID 21292923.
Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ (2013). “World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects”. World J. Biol. Psychiatry 14 (1): 2–44. doi:10.3109/15622975.2012.739708. PMID 23216388.
De Fruyt J, Deschepper E, Audenaert K, Constant E, Floris M, Pitchot W, Sienaert P, Souery D, Claes S (May 2012). “Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis.”. Journal of psychopharmacology (Oxford, England) 26 (5): 603–17. doi:10.1177/0269881111408461. PMID 21940761.
Gitlin M, Frye MA (May 2012). “Maintenance therapies in bipolar disorders.”. Bipolar disorders. 14 Suppl 2: 51–65. doi:10.1111/j.1399-5618.2012.00992.x. PMID 22510036.
de Bartolomeis A, Perugi G (October 2012). “Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance.”. Expert opinion on pharmacotherapy 13 (14): 2027–36. doi:10.1517/14656566.2012.719876. PMID 22946707.
Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S (Dec 8, 2010). “Second-generation antipsychotics for major depressive disorder and dysthymia.”. Cochrane database of systematic reviews (Online) (12): CD008121. doi:10.1002/14651858.CD008121.pub2. PMID 21154393.
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC (Mar 12, 2013). “Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes”. Cochrane database of systematic reviews (Online) 10 (3): CD008121. doi:10.1371/journal.pmed.1001403. PMID 23554581.
Nelson JC, Papakostas GI (2009). “Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials”. Am J Psychiatry 166 (9): 980–91. doi:10.1176/appi.ajp.2009.09030312. PMID 19687129.
Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S (2010). “Second-generation antipsychotics for major depressive disorder and dysthymia”. Cochrane Database Syst Rev (12): CD008121. doi:10.1002/14651858.CD008121.pub2. PMID 21154393.
Ching H, Pringsheim T (May 16, 2012). “Aripiprazole for autism spectrum disorders (ASD).”. Cochrane database of systematic reviews (Online) 5: CD009043. doi:10.1002/14651858.CD009043.pub2. PMID 22592735.
Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
Australian Medicines Handbook 2013 [Internet]. [cited 2013 Sep 30]. Available from: http://www.psa.org.au/shop/amh
Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jun 25]. Greenwood Village, CO: Thomsen Healthcare; 2013.
“Abilify Discmelt, Abilify Maintena (aripiprazole) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 22 October 2013.
Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (September 2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.”. Lancet 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
Abbasian C, Power P (March 2009). “A case of aripiprazole and tardive dyskinesia”. J Psychopharmacol (Oxford) 23 (2): 214–5. doi:10.1177/0269881108089591. PMID 18515468.
Zaidi SH, Faruqui RA (January 2008). “Aripiprazole is associated with early onset of Tardive Dyskinesia like presentation in a patient with ABI and psychosis”. Brain Inj 22 (1): 99–102. doi:10.1080/02699050701822493. PMID 18183513.
Maytal G, Ostacher M, Stern TA (June 2006). “Aripiprazole-related tardive dyskinesia”. CNS Spectr 11 (6): 435–9. PMID 16816781.
http://www.medicines.org.uk/EMC/pdfviewer.aspx?isAttachment=true&documentid=16161
“ABILIFY (aripiprazole) [package insert].”. Otsuka Pharmaceutical Co, Ltd. Retrieved 18 October 2012.
Group, BMJ, ed. (March 2009). “4.2.1”. British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. “Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.”
Moncrieff J (Jul 2006). “Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse”. Acta Psychiatr Scand 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655.
R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 105-106.
“Abilify (Aripiprazole) – Warnings and Precautions”. DrugLib.com. 14 February 2007. Archived from the original on 4 December 2008. Retrieved 8 December 2008.
http://www.drugs.com/cons/abilify-intramuscular.html
http://www.drugs.com/pro/abilify.html
Starrenburg FC, Bogers JP (April 2009). “How can antipsychotics cause diabetes mellitus? Insights based on receptor-binding profiles, humoral factors and transporter proteins”. European Psychiatry 24 (3): 164–170. doi:10.1016/j.eurpsy.2009.01.001. PMID 19285836.
“Abilify (Aripiprazole) – Clinical Pharmacology”. DrugLib.com. 14 February 2007. Retrieved 8 December 2008.
Brunton, Laurence (2011). Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th Edition. China: McGraw-Hill. pp. 406–410. ISBN 978-0-07-162442-8.
“PDSP Ki Database”. National Institute of Mental Health. Retrieved 30 June 2013.
Nguyen CT, Rosen JA, Bota RG (2012). “Aripiprazole partial agonism at 5-HT2C: a comparison of weight gain associated with aripiprazole adjunctive to antidepressants with high versus low serotonergic activities”. Prim Care Companion CNS Disord 14 (5). doi:10.4088/PCC.12m01386. PMC 3583771. PMID 23469329.
Newman-Tancredi A, Heusler P, Martel JC, Ormière AM, Leduc N, Cussac D (2008). “Agonist and antagonist properties of antipsychotics at human dopamine D4.4 receptors: G-protein activation and K+ channel modulation in transfected cells”. Int. J. Neuropsychopharmacol. 11 (3): 293–307. doi:10.1017/S1461145707008061. PMID 17897483.
Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (2005). “Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist”. J. Pharmacol. Exp. Ther. 315 (3): 1278–87. doi:10.1124/jpet.105.092155. PMID 16135699.
Davies MA, Sheffler DJ, Roth BL (2004). “Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology”. CNS Drug Rev 10 (4): 317–36. doi:10.1111/j.1527-3458.2004.tb00030.x. PMID 15592581.
Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB (1999). “Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes”. Neuropsychopharmacology 20 (6): 612–27. doi:10.1016/S0893-133X(98)00099-2. PMID 10327430.
Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (December 2005). “Intrinsic Efficacy of Antipsychotics at Human D₂, D₃, and D₄ Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D₂/D₃ Partial Agonist”. J Pharmacol Exp Ther 315 (3): 1278–87. doi:10.1124/jpet.105.092155. PMID 16135699.
Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA (2002). “The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor”. Eur J Pharmacol 441 (3): 137–140. doi:10.1016/S0014-2999(02)01532-7. PMID 12063084.
Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003). “Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology”. Neuropsychopharmacology 28 (8): 1400–1411. doi:10.1038/sj.npp.1300203. PMID 12784105.
Zhang JY, Kowal DM, Nawoschik SP, Lou Z, Dunlop J (February 2006). “Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms”. Biochem Pharmacol 71 (4): 521–9. doi:10.1016/j.bcp.2005.11.007. PMID 16336943.
Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A (2008). “Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D₂ Receptors by Aripiprazole in Schizophrenia with PET and [¹⁸F]Fallypride”. Neuropsychopharmacology 33 (13): 3111–3125. doi:10.1038/npp.2008.33. PMID 18418366.
Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF (August 2002). “Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [¹¹C]raclopride”. Neuropsychopharmacology 27 (2): 248–59. doi:10.1016/S0893-133X(02)00304-4. PMID 12093598.
“In This Issue”. Am J Psychiatry 165 (8): A46. August 2008. doi:10.1176/appi.ajp.2008.165.8.A46.
“Abilify Receives Approval for Expanded Use in Children, Teens”. Psych Central. Retrieved 2012-07-16.
“Abilify Gets FDA Approval For Autism Irritability”. Furious Seasons. Retrieved 2012-07-16.
“FDA OKs Abilify for Depression : Antipsychotic Drug Approved for Use in Addition to Antidepressants for Treating Depression”. WebMD. Retrieved 2012-07-16.
“Patent and Exclusivity Search Results”. Electronic Orange Book. US Food and Drug Administration. Retrieved 8 December 2008.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021436s21,021713s16,021729s8,021866s8lbl.pdfSection 2.3 pp 7-8
US 5006528, Oshiro, Yasuo; Seiji Sato & Nobuyuki Kurahashi, “Carbostyril derivatives”, published October 20, 1989
“Barr Confirms Filing an Application with a Paragraph IV Certification for ABILIFY(R) Tablets” (Press release). Barr Pharmaceuticals, Inc. 2007-03-20. Retrieved 2008-12-23.
U.S. Patent 5,006,528
Feltenstein MW, Altar CA, See RE (2007). “Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse”. Biol. Psychiatry 61 (5): 582–90. doi:10.1016/j.biopsych.2006.04.010. PMID 16806092.
Roache JD (2013). “Role of the human laboratory in the development of medications for alcohol and drug dependence”. In Johnson BA. Addiction medicine: science and practice. New York: Springer. p. 145. ISBN 978-1461439899.

External links

WO2006079548A1 *	Jan 27, 2006	Aug 3, 2006	Sandoz Ag	Organic compounds
WO2006079549A1	Jan 27, 2006	Aug 3, 2006	Sandoz Ag	Salts of aripiprazole
WO2014060324A1	Oct 11, 2013	Apr 24, 2014	Sanovel Ilac Sanayi Ve Ticaret A.S	Aripiprazole formulations
EP1844036A1 *	Jan 27, 2006	Oct 17, 2007	Sandoz AG	Salts of aripiprazole
EP2093217A1 *	Jan 27, 2006	Aug 26, 2009	Sandoz AG	Polymorph and solvates of aripiprazole
EP2233471A1 *	Feb 6, 2009	Sep 29, 2010	Adamed Sp. z o.o.	A salt of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4.dihydro-2(1h)-quinolinone with 5-sulfosalicylic acid and its preparation process
EP2359816A1	Feb 8, 2011	Aug 24, 2011	Sanovel Ilac Sanayi ve Ticaret A.S.	Aripiprazole formulations
US7504504	Dec 16, 2004	Mar 17, 2009	Teva Pharmaceutical Industries Ltd.	Methods of preparing aripiprazole crystalline forms
US7714129	Sep 29, 2006	May 11, 2010	Teva Pharmaceutical Industries Ltd.	Methods of preparing anhydrous aripiprazole form II
US8008490	Jan 27, 2006	Aug 30, 2011	Sandoz Ag	Polymorphic forms of aripiprazole and method
US8188076	Feb 26, 2010	May 29, 2012	Reviva Pharmaceuticals, Inc.	Compositions, synthesis, and methods of utilizing arylpiperazine derivatives
US8207163	May 27, 2009	Jun 26, 2012	Reviva Pharmaceuticals, Inc.	Compositions, synthesis, and methods of using piperazine based antipsychotic agents
US8247420	May 21, 2008	Aug 21, 2012	Reviva Pharmaceuticals, Inc.	Compositions, synthesis, and methods of using quinolinone based atypical antipsychotic agents
US8431570	May 7, 2012	Apr 30, 2013	Reviva Pharmaceuticals, Inc.	Methods of utilizing arylpiperazine derivatives
US8461154	May 7, 2012	Jun 11, 2013	Reviva Pharmaceuticals, Inc.	Methods of utilizing arylpiperazine derivatives
US8575185	Feb 26, 2010	Nov 5, 2013	Reviva Pharmaceuticals, Inc.	Compositions, synthesis, and methods of utilizing quinazolinedione derivatives