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

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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

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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

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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

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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

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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.

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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

6,7-methylenedioxy-4-phenylcoumarin

SYNTHESIS, Uncategorized Comments Off

Aug 262014

6,7-methylenedioxy-4-phenylcoumarin

8-Phenyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one

6H-1,3-Dioxolo[4,5-g][1]benzopyran-6-one, 8-phenyl-

Molecular Formula: C₁₆H₁₀O₄

Molecular Weight: 266.2482

Coumarins are naturally occurring molecules that are found in plants that have numerous uses in the medical field because of its biological activity. The wide varieties of its uses include antibiotics, anticoagulants, and sometimes even used in the perfume industry.

SYNTHESIS

Synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2 catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in trifluoroacetic acid at room temperature (15-20 degrees C) under atmospheric conditions.

STEP 1

phenyl acetylene is the starting material

Ethyl Phenylpropiolate:

Phenylacetylene (500 mg, 4.896 mmol, 1 equivalent) was added to a round bottom flask and flushed with nitrogen. A septum and balloon of nitrogen was then attached and 3-4mL of THF was added by syringe. The flask was cool to -78^oC in a dry ice and acetone bath. Next, n-butyllithium (2.36 mL, 1.2 equivalent) was added to the solution and allowed to warm to 0^oC for 1 hour. The solution was cooled to -78^oC again for 15 minutes, and then ethyl chloroformate (0.702 mL, 7.344 mmol, 1.5 equivalent) was added dropwise by syringe and allowed to warm again to 0^oC. The reaction mixture was then quenched by adding 10mL of saturated aqueous NaHCO₃ and allowed to stir for 15 minutes. The resulting substance Ethyl Phenylpropiolate was a yellowish-orange liquid.

¹H NMR (200 MHz, CDCl₃) δ 7.60-7.26 (m, 5H),

4.38 (m, 2H), -O CH2 CH3

1.44 (m, 3H); -O CH2 CH3

IR (neat, NaCl)

3551.4, 3399.9, 3958.2, 2934.4, 2872.2, 2236.4, 2211.6, 1744.0, 1709.5 cm^-1

The conversion of phenylacetylene to ethyl phenylpropiolate was made apparent by the comparison of IR spectras. The phenylacetylene reference IR spectra found on the Spectral Database of Organic Compounds shows a strong peak at about 3300 that the IR of the intermediate lacks. Also the intermediate’s IR contains strong peaks at 3000 and 2230 which are both absent from the starting material’s IR spectrum. Both of these changes indicate a successful conversion of phenylacetylene to the intermediate ethyl phenylpropiolate.

STEP 2

This specific reaction will result in a ring closure and addition of the ethyl phenylpropiolate aided by the palladium acetate catalyst. The palladium catalyst allows for the addition of an ester to a phenol resulting in a ring closure and product coumarin derivative.

6,7-methylenedioxy-4-phenylcoumarin:

Sesamol (0.075g, 0.5167mmol, 0.9 equivalent) and ethyl phenylpropiolate (102mg, 0.57405 mmol,1 equivalent) and Palladium acetate (Pd(OAc)₂)(0.00394g, 3mol%) were added to a 1 dram vial and cooled to 0^oC in an ice water bath. Trifluoroacetic acid (0.5mL) was added to the vial, then the vial was capped and the reaction allowed to proceed overnight. The resulting solid was a brown, sticky, crystalline (0.387 mmol, 67 %yield).

¹H NMR (300 MHz, CDCl₃)

δ 7.55-7.38 (m, 5H),

6.90 (s, 1H),

6.83 (s, 1H),

6.24 (s, 1H),

6.05 (s, 2H); CH2 SANDWICHED BETWEEN 2 OXYGEN ATOMS

IR (DCM, NaCl)

3553.8, 3401.9, 2958.2, 2872.2, 2236.3, 2211.4, 1744.4, 1717.4 cm^-1

References

Industry slams FDA draft guidance on biosimilarity

Uncategorized Comments Off

Aug 262014

BIO, PhRMA and Genentech all take particular issue with the FDA’s four possible outcomes for the analytical comparison of a proposed biosimilar product with its reference product

Industry slams FDA draft guidance on biosimilarity

By Zachary Brennan+, 15-Aug-2014

Industry groups BIO and PhRMA, as well as biotech company Genentech, are taking issue with US FDA draft guidance that is designed to help companies design and use clinical pharmacology studies to help prove that a developing biosimilar is similar to its reference product.

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http://www.biopharma-reporter.com/Markets-Regulations/Industry-slams-FDA-draft-guidance-on-biosimilarity

http://www.biopharma-reporter.com/Markets-Regulations/Industry-slams-FDA-draft-guidance-on-biosimilarity?nocount