Sep 022014
 
Figure imgf000005_0001
 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
 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
Abstract Image

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,

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]

Figure CN102532131AD00031

[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,

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,
…………………………………………………
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

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) [CXJD 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%), [CIJD 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

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.
Figure
  1.  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. Bull198937, 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. 199125, 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 19956 (1), 245−254.

  2. (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 Papers40th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 2000; American Society for Microbiology:  Washington, DC, 2000; Poster F-558.

  3. (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 Papers43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, ChicagoSeptember 2003;American Society for Microbiology:  Washington, DC, 2003; Poster F-430

 Some quinolones introduced for clinical use.

KEY  Levonadifloxacin arginine salt, WCK 771, QIDP
Share
Sep 022014
 

Ambroxol structural formulae.png

 

 

 

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 syruptabletspastilles, 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
13 H 18 Br 2 N 2 O 378.11 g / mol 18683-91-5

Ambroxol ball-and-stick.png
Systematic (IUPAC) name
trans-4-(2-Amino-3,5-dibrombenzylamino)-cyclohexanol
Clinical data
AHFS/Drugs.com International Drug Names
 
Identifiers
 
ATC code R05CB06
PubChem CID 2132
ChemSpider 10276826 Yes
UNII 200168S0CL Yes
KEGG D07442 Yes
ChEMBL CHEMBL153479 Yes
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
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

References

  1.  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
  2.  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.2004.133PMID 15576322
  3.  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:10.1517/17425255.4.8.1119PMID 18680446
  4.  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-0031-1296557PMID 19137906
  5.  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
  6.  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
  7.  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.2005.10.058PMID 16293367
  8.  [1] Drugs.com, Ambroxol, accessed 21 January 2014
  9.  http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-ambroxol_30.html
  1. DE 1 593 579 (Thomae; appl. 10.5.1966).
  2. DOS 2 218 647 (Thomae; appl. 18.4.1972).
  3. DOS 2 223 193 (Thomae; appl. 12.5.1972).
  4. Keck, J.: Justus Liebigs Ann. Chem. (JLACBF) 707, 107 (1967).

Links

  • GB 1 178 034 (Boehringer Ingelheim; appl. 10.5.1967; D-prior. 10.5.1966).
  • U.S. 3 536 713 (Boehringer Ingelheim; 27.10.1970; appl. 10.5.1967; S-prior. 10.5.1966).
  • 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).
Share
Sep 012014
 

Favipiravir.svg

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

 

Share
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 H2 balloon 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 NaHCO3 solution 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 NaHCO3 solution. 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 N2 for 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 MgSO4 and 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 H2 atmosphere 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.

 

 

4-29-2011
NK1 ANTAGONISTS
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

Share
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:

 

OH

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]

Figure CN102675385AD00041

[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,

Figure CN102675385AC00021

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,

Figure CN102675385AC00022

(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,

Figure CN102675385AC00023

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

Figure CN102675385AC00024

(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,

Figure CN102675385AC00031

[0028]

Figure CN102675385AD00073
Figure CN102675385AD00091

[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

OR

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

Share
Sep 012014
 
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.
Levonadifloxacin arginine salt, WCK 771
RN: 306748-89-0
 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.
Share
Aug 282014
 

Aripiprazole3DanBall.gif

Aripiprazole2D1.svg

 

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 Yes
ATC code N05AX12
PubChem CID 60795
IUPHAR ligand 34
DrugBank DB01238
ChemSpider 54790 Yes
UNII 82VFR53I78 Yes
KEGG D01164 Yes
ChEBI CHEBI:31236 Yes
ChEMBL CHEMBL1112 Yes
Chemical data
Formula C23H27Cl2N3O2 
Mol. mass 448.385

Aripiprazole (/ˌɛərɨˈpɪprəzl/ 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]

Aripiprazole synth.png
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-

File:Aripiprazole synthesis.svg

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 synth.png

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]

Figure CN101538252BD00031

[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]

Figure CN101538252BD00032

[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]

Figure CN101538252BD00041

[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]

Figure CN101538252BD00061

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)

Chemical Synthesis of Abilify-Aripirazole-Atypical Antipsychotics-Otsuka-BMS-aripiprazole - Ann re ピ have suitable plastic AKZO

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

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

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

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

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

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

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

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water
Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85 ° C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30 ° C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 6 hours to obtain title compound.
Yield: 87-89% HPLC Purity: 99.89
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 15.83 m, d 50 = 60.12 m, d 90 = 144.99 m
Preparation of aripiprazole anhydrous Type I using ethanol and water
Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85 ° C for 1-2 hours. The resulting mixture was cooled to 25-30 ° C within 4 hours and . stirred for 3 hours The resulting solid was filtered and dried under suction for 1 hour The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 3 hours to obtain title compound Yield:.. 90% HPLC Purity: 99.9 %
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 22.01 m, d 50 = 105.10 m, d 90 = 232.97 m

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

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

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

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

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

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

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

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

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

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

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

No Generic Abilify in the US until April 2015

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

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

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

Aripiprazole synthetic route

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

Aripiprazole preparation method

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

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

 

References

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

External links

WO2006079548A1 * Jan 27, 2006 Aug 3, 2006 Sandoz Ag Organic compounds
WO2006079549A1 Jan 27, 2006 Aug 3, 2006 Sandoz Ag Salts of aripiprazole
WO2014060324A1 Oct 11, 2013 Apr 24, 2014 Sanovel Ilac Sanayi Ve Ticaret A.S Aripiprazole formulations
EP1844036A1 * Jan 27, 2006 Oct 17, 2007 Sandoz AG Salts of aripiprazole
EP2093217A1 * Jan 27, 2006 Aug 26, 2009 Sandoz AG Polymorph and solvates of aripiprazole
EP2233471A1 * Feb 6, 2009 Sep 29, 2010 Adamed Sp. z o.o. A salt of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4.dihydro-2(1h)-quinolinone with 5-sulfosalicylic acid and its preparation process
EP2359816A1 Feb 8, 2011 Aug 24, 2011 Sanovel Ilac Sanayi ve Ticaret A.S. Aripiprazole formulations
US7504504 Dec 16, 2004 Mar 17, 2009 Teva Pharmaceutical Industries Ltd. Methods of preparing aripiprazole crystalline forms
US7714129 Sep 29, 2006 May 11, 2010 Teva Pharmaceutical Industries Ltd. Methods of preparing anhydrous aripiprazole form II
US8008490 Jan 27, 2006 Aug 30, 2011 Sandoz Ag Polymorphic forms of aripiprazole and method
US8188076 Feb 26, 2010 May 29, 2012 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of utilizing arylpiperazine derivatives
US8207163 May 27, 2009 Jun 26, 2012 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of using piperazine based antipsychotic agents
US8247420 May 21, 2008 Aug 21, 2012 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of using quinolinone based atypical antipsychotic agents
US8431570 May 7, 2012 Apr 30, 2013 Reviva Pharmaceuticals, Inc. Methods of utilizing arylpiperazine derivatives
US8461154 May 7, 2012 Jun 11, 2013 Reviva Pharmaceuticals, Inc. Methods of utilizing arylpiperazine derivatives
US8575185 Feb 26, 2010 Nov 5, 2013 Reviva Pharmaceuticals, Inc. Compositions, synthesis, and methods of utilizing quinazolinedione derivatives
Share
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
scheme-2-coumarin-synthesis
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 -78oC 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 0oC for 1 hour.  The solution was cooled to -78oC 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 0oC.  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.
scheme-1-coumarin-synthesis
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 0oC 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

Kotani, M., Yamamoto, K., Oyamada, J., Fujiwara, Y., Kitamura, T.,Synthesis20049, 1466-1470.

Oyamada, J., Jia, C., Fujiwara, Y., Kitamura, T., 2002Chemistry Letters,20023, 380-381.

Kitamura, T., Yamamoto, K., Kotani, M., Oyamada, J., Jia, C., Fujiwara, Y.,Bulletin of the Chemical Society of Japan200376, 1889-1895

http://www.ncbi.nlm.nih.gov/pubmed/17446885

http://wenku.baidu.com/view/ce68818683d049649b665879.html

Mech

scheme-3-possible-mechanism

 

The insertion of the ethyl phenylpropiolate to the sesamol-palladium intermediate is initially achieved in a cis confirmation.  There is then an internal rearrangement of the palladium and CO2Et ligands to the trans confirmation which then allows for an electrophilic aromatic substitution to close the ring.

 

ETHYL PHENYL PROPIOLATE

Ethyl phenylpropiolateEthyl phenylacetylenecarboxylate~Phenylpropiolic acid ethyl ester

1H NMR

13 C NMR

 

 

MASS

 

 

 

IR

 

RAMAN

 

UNDERSTAND SPECTRA WITH METHYLENE DIOXY GROUP USING  A DIFFERENT EXAMPLE

2635-13-4 Structure4-Bromo-1,2-(methylenedioxy)benzene

1H NMR

13 C NMR

 

IR

 

MASS

 

 

RAMAN

 

 

PRESENTING TO YOU COUMARIN TO UNDERSTAND SPECTRA

COUMARIN

91-64-5 Structure

1H NMR

 

13 C NMR

IR

 

MASS

 

RAMAN

 

 

NOW PHENYL ACETYLENE

536-74-3 Structure

1H NMR

 

 

 

 

13 C NMR

 

MASS

 

IR

AND

 

 

Share
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.

READ AT

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

 

 

Share
Aug 252014
 

JM 3100.svg

Plerixafor

cas 110078-46-1

CXCR4 chemokine antagonist

Stem cell mobilization [CXCR4 receptor antagonist]

A bicyclam derivate, highly potent & selective inhibitor of HIV-1 & HIV-2.

Bone marrow transplantation; Chronic lymphocytic leukemia; Chronic myelocytic leukemia; Myelodysplastic syndrome; Neutropenia; Sickle cell anemia

Plerixafor; Mozobil; AMD3100; 110078-46-1; Amd 3100; bicyclam JM-2987; AMD-3100; UNII-S915P5499N; JM3100
  • JKL 169
  • Mozobil
  • Plerixafor
  • SDZ SID 791
  • UNII-S915P5499N
Molecular Formula: C28H54N8
Molecular Weight: 502.78196
1,​4-​bis((1,​4,​8,​11-​tetraazacyclotetradecan-​1-​yl)methyl)benzene
1,4,8,11-Tetraazacyclotetradecane, 1,1′-(1,4-phenylenebis(methylene))bis-
1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]
1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane
Johnson Matthey (Innovator)
Plerixafor is a hematopoietic stem cell mobilizer. It is used to stimulate the release of stem cells from the bone marrow into the blood in patients with non-Hodgkin lymphoma and multiple myeloma for the purpose of stimulating the immune system. These stem cells are then collected and used in autologous stem cell transplantation to replace blood-forming cells that were destroyed by chemotherapy. Plerixafor has orphan drug status in the United States and European Union; it was approved by the U.S. Food and Drug Administration on December 15, 2008.

Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor. Each single-use vial is filled to deliver 1.2 mL of the sterile solution that contains 24 mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required.

Plerixafor is a hematopoietic stem cell mobilizer with a chemical name l, 1′-[1,4phenylenebis (methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. It has the molecular formula C28H54N8. The molecular weight of plerixafor is 502.79 g/mol. The structural formula is provided in Figure 1.

Figure 1: Structural Formula

 

MOZOBIL (plerixafor) Structural Formula Illustration

 

Plerixafor is a white to off-white crystalline solid. It is hygroscopic. Plerixafor has a typical melting point of 131.5 °C. The partition coefficient of plerixafor between 1octanol and pH 7 aqueous buffer is < 0.1.

Plerixafor (hydrochloride hydrate)

(CAS 155148-31-5)
Formal Name 1,​4-​bis((1,​4,​8,​11-​tetraazacyclotetradecan-​1-​yl)methyl)benzene,​ octahydrochloride
CAS Number 155148-31-5
Molecular Formula C28H54N8 • 8HCl • [XH2O]
Formula Weight 794.5
The α-chemokine receptor, CXCR4, on CD4+ T-cells is used by CXCR4-selective HIV forms as a gateway for T-cell infection. In mammalian cell signaling, CXCR4 activation promotes the homing of hematopoietic stem cells, chemotaxis and quiescence of lymphocytes, and growth and metastasis of certain cancer cell types. Plerixafor (hydrochloride) is a macrocyclic compound that acts as an irreversible antagonist against the binding of CXCR4 with its ligand, SDF-1 (CXCL12). It suppresses infection by HIV with an IC50 value of 1-10 ng/ml with selectivity toward CXCR4-tropic virus. Plerixafor mobilizes hematopoietic stem and progenitor cells for transplant better than the ‘gold standard’, G-CSF alone 4and synergizes with G-CSF. It also increases T-cell trafficking in the blood and spleen as well as the central nervous system. Plerixafor regulates the growth of primary and metastic breast cancer cells7 and inhibits dissemination of ovarian carcinoma cells.
Plerixafor hydrochloride (AMD-3100), a chemokine CXCR4 (SDF-1) antagonist, is launched in the U.S. for the following indications: to enhance mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and to enhance mobilization of hematopoietic stem cells for transplantation in patients with multiple myeloma.
In 2009, the product was approved in EU for these indications.AnorMED filed an orphan drug application for AMD-3100 with the FDA in January 2003 and received approval in July 2003 as immunostimulation for increasing the stem cells available in patients with multiple myeloma and non-Hodgkin’s lymphoma. Orphan drug status was also granted by the EMEA in October 2004 as a treatment to mobilize progenitor cells prior to stem cell transplantation.
In 2011, orphan drug designation was assigned by the FDA for the treatment of AML and by the EMA for the adjunctive treatment to cytotoxic therapy in acute myeloid leukemia.

Plerixafor (rINN and USAN, trade name Mozobil) is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients. The stem cells are subsequently transplanted back to the patient. The drug was developed by AnorMED which was subsequently bought by Genzyme.

 

History

The molecule 1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane], consisting of two cyclam rings linked at the amine nitrogen atoms by a 1,4-xylyl spacer, was first synthesised by Fabbrizzi et al. in 1987 to carry out basic studies on the redox chemistry of dimetallic coordination compounds.[1] Then, it was serendipitously discovered by De Clercq that such a molecule, could have a potential use in the treatment of HIV[2] because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the virus’s main cellular receptor, CD4).[2]Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients.[3]

Indications

Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factor (G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation.[4] The drug is approved for patients with lymphoma and multiple myeloma.[5]

Contraindications

Pregnancy and lactation

Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraception. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.[5]

Adverse effects

Nauseadiarrhea and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient.[5][6]

The European Medicines Agency has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor.[7]

Phase III clinical development in combination with G-CSF (granulocyte colony-stimulating factor) is under way at Genzyme (which acquired the product through its acquisition of AnorMED in late 2006) in a stem cell mobilization regimen in non-Hodgkin’s lymphoma (NHL). The trials are designed to evaluate the potential of plerixafor in combination with G-CSF, to rapidly increase the number of peripheral blood stem cells capable of engraftment, thereby increasing the proportion of patients reaching a peripheral blood stem cell target and, as a result, reducing the number of apheresis sessions required for patients to collect a target number of peripheral blood stem cells. A phase I safety trial had been under way for the treatment of renal cancer, however, no recent development for this indication has been reported. An IND has been filed in the U.S. seeking approval to initiate clinical evaluation of the drug candidate to help repair damaged heart tissue in patients who have suffered heart attacks. Currently, an investigator-sponsored study is ongoing to evaluate plerixafor as a single agent in allogeneic transplant. AMD-3100, in combination with mitoxantrone, etoposide and cytarabine, is also in phase I/II clinical trials at the University of Washington for the treatment of acute myeloid leukemia (AML).

The University has also been conducting early clinical trials for increasing the stem cells available for transplantation in patients with advanced hematological malignancies, however, no recent developments on this trial have been reported. Genzyme has completed a phase I/II clinical study of plerixafor hydrochloride in combination with rituximab for the treatment of chronic lymphocytic leukemia. The former AnorMED had been developing plerixafor for the treatment of rheumatoid arthritis (RA), but no clinical development has been reported as of late. AnorMED was also developing plerixafor for the treatment of HIV, but discontinued the trials in 2001 due to abnormal cardiac activity and lack of efficacy.

By blocking CXCR4, a specific cellular receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. Once in the circulating blood, the stem cells can be collected for use in stem cell transplant. In terms of use for cardiac applications, there is clinical evidence that the presence of stem cells circulating in the bloodstream or directly injected into the hearts of patients who have suffered a heart attack may result in improved cardiac function.

 

Chemical properties

Plerixafor is a macrocyclic compound and a bicyclam derivative.[4] It is a strong base; all eight nitrogen atoms accept protons readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinccopper and nickel, as well as cobalt and rhodium. The biologically active form of plerixafor is its zinc complex.[8]

Synthesis

Chemical structure for JM 3100

Three of the four nitrogen atoms of the macrocycle 1,4,8,11-tetraazacyclotetradecan are protected with tosyl groups. The product is treated with 1,4-dimethoxybenzene or 1,4-bis(brommethyl)benzene and potassium carbonate in acetonitrile. After cleaving of the tosyl groups with hydrobromic acid, plerixafor octahydrobromide is obtained.[9]

SEE   CHINESE JOURNAL OF MEDICINAL CHEMISTRY    2010 20 (6): 511-513   ISSN: 1005-0108   CN: 21-1313/R

DOWNLOAD………http://download.bioon.com.cn/upload/201207/24113552_9395.pdf

http://www.zgyhzz.cn/qikan/epaper/zhaiyao.asp?bsid=14753

( 1 ) BASE FORM
0155g ( 8016% ), m p 129 ~ 131 e 。
1H-NM R
( CDC l3 ) D: 7.28( s, 4H, A r-H ), 3.55 ( br s, 4H,A r-CH2 ), 2.82 ~ 2.52( m, 32H, NCH2, NHCH2 ),
1.86 ~ 1.68 ( m, 8H, CCH2C )。 ESI-M S m /z:
503.55 [M + H]+ 。

………………………………………..

SEE

http://doc.sciencenet.cn/upload/file/2011531154034454.pdf

…………………………………..

 

………………………….

http://www.google.com/patents/US5756728

 

U.S. Pat. No. 5,021,409 is directed to a method of treating retroviral infections comprising administering to a mammal in need of such treatment a therapeutically effective amount of a bicyclic macrocyclic polyamine compound. Although the usefulness of certain alkylene and arylene bridged cyclam dimers is generically embraced by the teachings of the reference, no arylene bridged cyclam dimers are specifically disclosed.

WO 93/12096 discloses the usefulness of certain linked cyclic polyamines in combating HIV and pharmaceutical compositions useful therefor. Among the specifically disclosed compounds is 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11 tetraazacyclotetradecane (and its acid addition salts), which compound is a highly potent inhibitor of several strains of human immune deficiency virus type 1 (HIV-1) and type 2 (HIV-2).

European Patent Appln. 374,929 discloses a process for preparing mono-N-alkylated polyazamacrocycles comprising reacting the unprotected macrocycle with an electrophile in a non-polar, relatively aprotic solvent in the absence of base. Although it is indicated that the monosubstituted macrocycle is formed preferentially, there is no specific disclosure which indicates that linked bicyclams can be synthesized by this process.

U.S. Pat. No. 5,047,527 is directed to a process for preparing a monofunctionalized (e.g., monoalkylated)cyclic tetramine comprising: 1) reacting the unprotected macrocycle with chrominum hexacarbonyl to obtain a triprotected tetraazacyloalkane compound; 2) reacting the free amine group of the triprotected compound prepared in 1) with an organic (e.g., alkyl) halide to obtain a triprotected monofunctionalized (e.g., monoalkylated) tetraazacycloalkane compound; and 3) de-protecting the compound prepared in 2) by simple air oxidation at acid pH to obtain the desired compound. In addition, the reference discloses alternative methods of triprotection employing boron and phosphorous derivatives and the preparation of linked compounds, including the cyclam dimer 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane, by reacting triprotected cyclam prepared as set forth in 1) above with an organic dihalide in a molar ratio of 2:1, and deprotecting the resultant compound to obtain the desired cyclam dimer.

J. Med. Chem., Vol. 38, No. 2, pgs. 366-378 (1995) is directed to the synthesis and anti-HIV activity of a series of novel phenylenebis(methylene)-linked bis-tetraazamacrocyclic analogs, including the known cyclam dimer 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane. The cyclam dimers disclosed in this reference, including the afore-mentioned cyclam dimer, are prepared by: 1) forming the tritosylate of the tetraazamacrocycle; 2) reacting the protected tetraazamacrocycle with an organic dihalide, e.g., dibromo-p-xylene, in acetonitrile in the presence of a base such as potassium carbonate; and 3) de-protecting the bis-tetraazamacrocycle prepared in 2) employing freshly prepared sodium amalgam, concentrated sulfuric acid or an acetic acid/hydrobromic acid mixture to obtain the desired cyclam dimer, or an acid addition salt thereof.

Although the processes disclosed in U.S. Pat. No. 5,047,527 and the J. Med. Chem. reference are suitable to prepare the cyclam dimer 1,1′- 1,4-phenylene bis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane, they involve the use of cyclam as a starting material, a compound which is expensive and not readily available. Accordingly, in view of its potent anti-HIV activity, a number of research endeavors have been undertaken in an attempt to develop a more practical process for preparing 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane.

 

EXAMPLE 1

a) Preparation of the 1,4-phenylenebis-methylene bridged hexatosyl acylic precursor of formula III

To a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 43.5 g (0.25 mol) of N,N’-bis(3-aminopropyl) ethylenediamine and 250 ml of tetrahydrofuran. To the resultant solution is added, over a period of 30 minutes with external cooling to maintain the temperature at 20° C., 113.6 g (0.8 mol) of ethyl trifluoroacetate. The reaction mixture is then stirred at room temperature for 4 hours, after which time 52.25 ml. (0.3 mol) of diisopropylethylamine is added. The resultant reaction mixture is warmed to 60° C. and, over a period of 2 hours, is added a solution of 33.0 g (0.125 mol) of α,α’-dibromoxylene in 500 ml. of tetrahydrofuran. The reaction mixture is then maintained at a temperature of 60° C., with stirring, for an additional 2 hours after which time a solution of 62.0 g. (1.55 mol) of sodium hydroxide in 250 ml. of water is added. The resultant mixture is then stirred vigorously for 2 hours, while the temperature is maintained at 60° C. A solution of 152.5 g. (0.8 mol) of p-toluenesulfonyl-chloride in 250 ml. of tetrahydrofuran is then added, over a period of 30 minutes, while the temperature is maintained at between 20° C. and 30° C. The reaction is then allowed to proceed for another hour at room temperature. To the reaction mixture is then added 1 liter of isopropyl acetate, the layers are separated and the organic layer is concentrated to dryness under vacuum to yield the desired compound as a foamy material.

b) Preparation of the hexatosyl cyclam dimer of formula IV

To a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 114.6 g. (0.10 mol) of the compound prepared in a) above and 2.5 liters of dimethylformamide. After the system is degassed, 22.4 g. (0.56 mol) of NaOH beads, 27.6 g (0.2 mol) of anhydrous potassium carbonate and 5.43 g. (0.016 mol) of t-butylammonium sulfate are added to the solution, and the resultant mixture is heated to 100° C. and maintained at this temperature for 2.5 hours. A solution of 111.0 g (0.3 mol) of ethyleneglycol ditosylate in 1 liter of dimethylformamide is then added, over a period of 2 hours, while the temperature is maintained at 100° C. After cooling the reaction mixture to room temperature, it is poured into 4 liters of water with stirring. The suspension is then filtered and the filter cake is washed with 1 liter of water. The filter cake is then thoroughly mixed with 1 liter of water and 2 liters of ethyl acetate. The solvent is then removed from the ethyl acetate solution and the residue is re-dissolved in 500 ml. of warm acetonitrile. The precipitate that forms on standing is collected by filtration and then dried to yield the desired compound as a white solid.

c) Preparation of 1,1′- 1,4-phenylenebis-(methylene)!-bis-1,4,8,11-tetraazacyclotetradecane

In a 4-necked, round-bottom flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 26.7 g.(0.02 mol) of the compound prepared in b) above, 300 ml. of 48% hydrobromic acid and 1 liter of glacial acetic acid. The resultant mixture is then heated to reflux and maintained at reflux temperature, with stirring, for 42 hours. The reaction mixture is then cooled to between 22° C. and 23° C. over a period of 4 hours, after which time it is stirred for an additional 12 hours. The solids are then collected using suction filtration and added to 400 ml. of deionized water. The resultant solution is then stirred for 25 to 30 minutes at a temperature between 22° C. and 23° C. and filtered using suction filtration. After washing the filter pad with a small amount of deionized water, the solution is cooled to between 10° C. and 15° C. 250 g. of a 50% aqueous solution of sodium hydroxide is then added, over a period of 30 minutes, while the temperature is maintained at between 5° C. and 15° C. The resultant suspension is stirred for 10 to 15 minutes, while the temperature is maintained at between 10° C. and 15° C. The suspension is then warmed to between 22° C. and 23° C. and to the warmed suspension is added 1.5 liters of dichloromethane. The mixture is then stirred for 30 minutes, the layers are separated and the organic layer is slurried with 125 g. of sodium sulfate for 1 hour. The solution is then filtered using suction filtration, and the filtrate is concentrated under reduced pressure (40°-45° C. bath temperature, 70-75 mm Hg) until approximately 1.25 liters of solvent is collected. To the slurry is then added 1.25 liters of acetone, and the filtrate is concentrated under reduced pressure (40°-45° C. bath temperature, 70-75 mm Hg) until approximately 1.25 liters of solvent is collected. The slurry is then cooled to between 22° C. and 23° C. and the solids are collected using suction filtration. The solids are then washed with three 50 ml. portions of acetone and dried in a vacuum oven to obtain the desired compound as a white solid.

EXAMPLE 2

The following is an alternate procedure for the preparation of the 1,4-phenylenebis-methylene bridged hexatosyl acyclic precursor of formula III.

To a 3-necked, round-bottomed flask, equipped with a mechanical stirrer, heating mantle, internal thermometer and addition funnel, is added 3.48 g. (20 mmol) of N,N’-bis-(3-aminopropyl)ethylenediamine and 20 ml. of tetrahydrofuran. To the resultant solution is added, over a period of 20 minutes with external cooling to maintain the temperature at 20° C., 5.2 ml. (42 mmol) of ethyl trifluoroacetate. The reaction mixture is then stirred at room temperature for 1 hour, after which time a solution of 2.64 g. (10 mmol) of α,α’-dibromoxylene in 20 ml. of tetrahydrofuran is added. The resultant reaction mixture is then stirred at room temperature for 4 hours. A solution of 4.8 g. (120 mmol) of sodium hydroxide in 20 ml. of water is then added and the resultant mixture is warmed to 60° C. and maintained at this temperature, with vigorous stirring, for 2 hours. Over a period of 20 minutes, 13.9 g. (73 mmol) of p-toluenesulfonylchloride is then added portionwise, while the temperature is maintained at 20° C. The reaction is then allowed to proceed for another hour at room temperature. To the reaction mixture is then added 100 ml. of isopropyl acetate, the layers are separated and the organic layer is washed with saturated sodium bicarbonate aqueous solution. The solution is then condensed to 40 ml., cooled to 4° C. and kept at that temperature overnight. The resultant suspension is filtered and the solid is washed with 10 ml. of isopropyl acetate. The solvents are then removed from the filtrate to yield the desired compound as a brown gel.

…………………………

see

Synthesis and structure-activity relationships of phenylenebis(methylene)linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker
J Med Chem 1995, 38(2): 366

http://pubs.acs.org/doi/abs/10.1021/jm00002a019

…………………………………………………

see

New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor
J Med Chem 1999, 42(2): 229

http://pubs.acs.org/doi/full/10.1021/jm980358u

……………………………………………………..

CN 102584732

 http://www.google.com/patents/CN102584732B?cl=en

[0003]

Figure CN102584732BD00041

[0004] plerixafor (trade name Mozobil ™) was developed by the U.S. company Genzyme chemokine receptor 4 (CXCR4) antagonist specificity. The drug is a hematopoietic stem (progenitor) cell activator, and can stimulate hematopoietic stem cell proliferation and differentiation into functional blood circulation.

[0005] As the non-Hodgkin’s lymphoma (NHL) and multiple myeloma (Korea) most of the cases and the progress of cases to alleviate the need for autologous peripheral blood stem cell transplantation, and plerixafor joint G-CSF can significantly improve the number of patients with ⑶ 34 + cells, about 60% of the patient’s peripheral blood can ⑶ 34 + cells increased to ensure that the NHL and MM patients with autologous hematopoietic stem cell transplantation success.

[0006] U.S. FDA approval on December 15, 2008 its listing, clinical studies showed that the drug can greatly increase the number of white blood cells of patients and to promote hematopoietic stem cells from bone marrow to the blood flow, and granulocyte colony-stimulating factor (G-CSF ) have a synergistic effect; has been used in multiple myeloma and Hodgkin’s lymphoma patients with stem cell transplantation in clinical trials.

[0007] About plerixafor or synthetic analogs have some at home and abroad reported in the literature, there are J.0rg.Chem.2003, 68,6435-6436; J.Med Chem.1995, 38 (2): 366-378; J.SynthCommun.1998 ,28:2903-2906; Tetrahedron, 1989,45 (1) :219-226; Chinese Journal of Pharmaceuticals 2007,38 (6); World Patent W09634860A1; W09312096A1; U.S. Patent US5047527, US5606053, US5801281, US5064956, Chinese patent CN1466579A.

[0008] J.Med Chem.1995, 38 (2) = 366-378 relates to a preparation method comprises the following steps: a) forming a salt of trimethoxy benzene tetraaza macrocycles; 2) reacting the protected tetrazole hetero macrocycle in acetonitrile under the presence of a base such as potassium carbonate as dibromo-p-xylene is reacted with an organic dihalide; 3) using freshly prepared sodium amalgam, concentrated sulfuric acid or acetic acid / hydrobromic acid mixture deprotected target product.

[0009] US 5047527 relates to preparation of the cyclic four monofunctional amine, the method comprising: a) reacting the unprotected macrocycle of reaction with chromium hexacarbonyl to obtain protection tetraazadecalin three compounds; 2) 3 Protection of the free amino compound with an organic halide to obtain three-protected monofunctional tetraaza naphthenic compounds; 3) simple air oxidation, deprotection to obtain the desired product. [0010] J.Synth Commun.1998 ,28:2903-2906 describes an improved method for synthesizing intermediates Plerixafor, the method using phosphor protection, deprotection to give a smooth 1,1 ‘- [1,4 - phenylene bis (methylene)] _ two _1, 4,8,11 – tetraazacyclododecane fourteen burn.

[0011] US 5606053 relates to a process for preparing dimers 1, I ‘- [1,4 - phenylene bis (methylene)] – two -1,4,8,11 – tetraazacyclododecane-tetradecane method. The preparation of compounds include: 1) the four-amine as the starting material, obtained by acylation of toluene Juan acyclic intermediates and three xylene sulfonate and toluene sulfonate and toluene intermediates; 2) and xylene sulfonate and intermediates trimethylbenzene toluenesulfonic acid intermediates after alkylation separation dibromo xylene, toluene sulfonate and then obtain a non-cyclic dimers of six toluenesulfonic acylated; 3) six isolated bridged acyclic toluenesulfonic acid dimer form is reacted with ethylene glycol ditosylate three equivalents of cyclization; 4) deprotection to obtain the objective product was purified by hydrobromic acid and acetic acid.

[0012] US 5801281 relates to preparation of dimer 1, I ‘- [1,4 _-phenylene bis (methylene)] – two _1, 4,8,11

[0013] – tetraazacyclo tetradecane, comprising: a) reacting the acyclic tetraamine with 3 equivalents of ethyl trifluoroacetate, the reaction; 2) with 0.5 equivalents of the tri-dibromo-p-xylene-protected acyclic alkylation of the amine obtained form four non-cyclic dimers; 3) hydrolysis to remove the six trifluoroacetyl compound group; 4) acylation of the compound toluenesulfonic bridged tetraamine dimer; 5) B Juan xylene glycol ester cyclization; 6) and glacial acetic acid mixed with hydrobromic acid deprotection was the target product.

Under the [0014] US 5064956 discloses a multi-alkylated single-ring nitrogen of the compound prepared, the method involves reacting the unprotected macrocycle in an aprotic, relatively non-polar solvent in presence of alkali electrophilic reagent. Not mentioned in this document similar to the embodiment Seclin dimer synthesis.

[0015] Through the open Plerixafor synthetic route research and meta-analysis of the literature, mainly in the following four synthetic routes:

[0016] Route One, is 1,4,8,11 – tetraazacyclododecane cyclotetradecane as raw material, NI, N4, N8 three protected with 1,4 – bis (halomethyl) benzene-bridged deprotection to obtain the finished product. The following reaction scheme, wherein R is p-toluenesulfonyl group, a methanesulfonyl group, a trifluoroacetyl group, a tert-butoxycarbonyl group and the like:

[0017]

Figure CN102584732BD00061

[0018] Route II is di (2 – aminopropyl) ethylenediamine as raw material, the ring and the reaction with 1,4 – bis (halomethyl) benzene-bridged, and then deprotection Bullock Suffolk.

[0019] Route 3 to 1,4,8,11 – tetraazacyclododecane cyclotetradecane as raw material, under anhydrous, anaerobic conditions, after the ring protection with 1,4 – bis (halomethyl ) benzene bridging, and then deprotection plerixafor. Synthesis scheme below, wherein R is P, Ni, etc.;

Figure CN102584732BD00071

[0021] line four, based on acrylate as starting material, first with ethylene diamine as raw material by Michael addition of the amine solution, then with malonate cyclization 1,4,8,11 – Tetraaza _5, 7,12 – three oxo cyclotetradecane by α, α ‘- dibromo-p-xylene bridging, the final deprotection plerixafor. Reaction Roadmap follows:

[0022]

Figure CN102584732BD00081

[0023] The above synthesis route and the existing methods have the following disadvantages:

[0024] In an intermediate of the synthesis route, the existing technology, the need for column purification of the intermediates, low yield.

[0025] route to protect the stability of the two because of the strong, leading to the final deprotection step difficult, long production cycle, low yield, and finished organic residues can not be achieved within the standard limits.

Higher dry anaerobic demands [0026] Route 3 on, harsh reaction conditions, deprotection is not complete, intermediates need to repeatedly purified, low yield, after repeated recrystallization, finished monohetero difficult to control in 0.1% less.

[0027] Anhydrous ethylene diamine route and need four anhydrous THF, more stringent requirements on the process, and to use dangerous borane dimethyl sulfide, while the second step is only about 35% lower yield. Selectivity of the reaction is not high shortcomings, so do not be the most economical and reasonable synthetic route.

[0028] We prepared by Plerixafor prepared by methods disclosed above may Plerixafor single impurity of 0.1% or less is difficult to achieve, it is difficult to meet the quality requirements of the injection material, the same techniques can not reach the European Quality of ICH guidelines of the relevant technical requirements, low yield, high cost required for each step of the intermediate column to afford a large amount of solvent, time consuming, and the greater the elution solvent toxicity, is not suitable for industrial production.

(I) Preparation of 1,4,8 _ tris (p-toluenesulfonyl) -1,4,8,11 – tetraazacyclododecane-tetradecane: the raw 1,4,8,11 – tetraazacyclododecane cyclotetradecane suspended in methylene chloride, in the role of acid binding agent, at a temperature 10 ~ 30 ° C, p-toluenesulfonyl chloride and 3 ~ 8h, filtered, and the filtrate was collected and concentrated to dryness to obtain a residue; will have The residue of said C ^ C3 alkyl group in a mixed solvent of alcohol and an aprotic solvent, purification, crystallization segment greater than 95% purity of 1,4,8 – tris (p-toluenesulfonyl) _1, 4,8,11 – tetraaza cyclotetradecane;

[0032] (2) Preparation of 1,1 ‘- [1,4 - (phenylene methylene)] – two – [4,8,11 - tris (p-toluenesulfonyl)] -1,4, 8,11 – tetraazacyclododecane-tetradecane: A (I) the resulting 1,4,8 – tris (p-toluenesulfonyl) _1, 4,8,11 – tetraazacyclododecane-tetradecane, α, α two bromo-p-xylene in place of anhydrous acetonitrile, was added acid-binding agent, the reaction was refluxed under nitrogen for 5 to 24 hours; After the reaction was cooled to room temperature, the reaction mixture was then collected by filtration and the filter cake was purified to obtain a mixed solvent I , I, – [1,4 - (phenylene methylene)] – two – [4,8,11 - tris (p-toluenesulfonyl)] _1, 4,8,11 – tetraazacyclododecane ten four alkyl;

[0033] (3) Synthesis Plerixafor: A (2) the resultant I, 1′-[1,4 _ (phenylene methylene)] – two – [4,8,11 - tris (p-toluene sulfonyl)] -1,4,8,11 – tetraazacyclododecane myristic acid solution was added to the mixture, stirred and dissolved, the reaction was warmed to reflux for 10 to 24 hours, cooled, filtered, and filter cake was collected; the filter cake was dissolved in purified water, adjusted with sodium hydroxide solution or potassium hydroxide solution to the PH-12, filtered, and the filtrate was extracted with a halogenated solvent, and the organic layer was dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure P Le Suffolk crude;

[0034] (4) Purification Plerixafor: Plerixafor the crude was dissolved into a solvent and heated to reflux to dissolve, filtered, and the crystallization solvent is added dropwise at 40 ~ 45 ° C crystallization 30min, filtered and the filtrate then cooled to 20 ~ 25 ° C crystallization I hour at O ​​~ 5 ° C crystallization three hours, filtered, and the filter cake was dried Plerixafor.

Plerixafor Preparation: 6 [0075] Implementation

[0076] The starting material 1,4,8,11 – tetraazacyclo tetradecane (5g, 25mmol) was suspended in dichloromethane (50g) was added N, N-diisopropylethylamine (7.5ml) , a solution of p-toluenesulfonyl chloride (10.8g, 56.5mmol) and methylene chloride (50g) in a solution of, at 25 ~ 30 ° C reaction temperature 3h, filtered, and the filtrate was collected and concentrated to dryness and to the residue in methanol (30g), toluene (IOg) was heated to reflux, filtered, and the filtrate was cooled to 40 ° C crystallization 30min, filtered to remove impurities little over protection, and the filtrate was added methyl tert-butyl ether (30g), stirring rapidly cooled to O ~ 5 ° C crystallization 3h, filtered, and dried to give 1,4,8 – tris (p-toluenesulfonyl) -1, 4,8,11 – tetraazacyclododecane-tetradecane (9.6g, 61.9%), purity of 97.2%.

[0077] The 4,8 _ tris (p-toluenesulfonyl) _1, 4,8,11 – tetraazacyclododecane-tetradecane (9g, 13.6mmol) α, α ‘- dibromo-p-xylene (1.81 g, 6.8mmol) in dry acetonitrile was placed (90ml) was added potassium carbonate (15.0g, 108.5mmol), the reaction was refluxed under nitrogen for 5 hours. Cooled to room temperature and filtered to collect the filter cake, was added anhydrous methanol (10ml), ethyl acetate (30ml), dichloromethane (IOml) hot melt, whereby the cooling crystallization, filtration, and dried under reduced pressure to obtain white solid (16. lg, 83%), purity 97.5%.

[0078] The intermediate obtained above (5g, 3.5mmol) was added to glacial acetic acid (25ml) and concentrated hydrochloric acid (25ml) was stirred until dissolved in the mixed solution was heated to reflux for 24 hours, cooled, collected by filtration cake. The filter cake was dissolved in purified water (20ml), adjusting the PH value of the solution with sodium hydroxide to 12, filtered, and the filtrate was extracted with dichloromethane (50mlX3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain sand Bullock Fu crude (1.4g, 79.5%), purity 98.6%.

[0079] The crude Plerixafor (1.4g) is placed in tetrahydrofuran (14g), heated to reflux to dissolve, filtered, and added dropwise n-hexane (42g), and 40 ~ 45 ° C crystallization 30min, filtered little solid, The filtrate was rapidly cooled to 20 ~ 25 ° C crystallization I hour and then at O ​​~ 5 ° C crystallization three hours, filtered, 45 ° C and dried under reduced pressure to obtain the finished Plerixafor (1.2g, 85.7%), purity 99.93 %, the largest single miscellaneous 0.04%.

………………………………….

http://www.google.com/patents/US8420626?cl=en

Figure US08420626-20130416-C00014

wherein, n is 0 or 1, Ts is tosyl radical, P is trifluoroacetyl or p-tosyl radical;
To the NaOH solution of the starting material 7 is dropwise added ether solution of tosyl chloride. The system is stirred over night. A white solid is formed and filtrated. The filter cake is washed with water and ethyl ether, respectively, recrystallized to give a white solid intermediate of formula 8. To the dried acetonitrile solution of the compound of formula 8 is slowly dropwise added dried acetonitrile solution of 1,2-di-p-tosyloxypropane under reflux state, refluxed for 2-4 days, stood until room temperature. A white solid is precipitated and filtrated. The filter cake is washed with water and ethyl acetate, respectively, recrystallized to give a white solid compound of formula 9. The compound of formula 9 is dissolved in 90% concentrated sulfuric acid, allowed to react at 100° C. for 24-48 hours, stood until room temperature. To the reaction solution are dropwise added successively ethanol and ethyl ether. A white solid is precipitated, filtrated, dried, and dissolved in NaOH solution. The aqueous phase is extracted with chloroform. The chloroform phase is combined, concentrated, recrystallized to give a white solid compound of formula 10. To the chloroform solution of the compound of formula 10 and triethylamine is dropwise added chloroform solution of tosyl chloride. The mixture is allowed to react at room temperature over night, concentrated and column separated (eluant: dichloromethane/methanol system) to give a white solid compound of formula 11 (protective group is tosyl); or to the methanol solution of the compound of formula 10 is dropwise added ethyl trifluoroacetate. The mixture is allowed to react at room temperature over night, concentrated and column separated (eluant: ethyl acetate) to give a white solid compound of formula 11 (protective group is trifluoroacetyl);

 

Pharmacokinetics

Following subcutaneous injection, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in extravascular compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoproteins has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidneys, with 70% of the drug being excreted within 24 hours.[5]

Pharmacodynamics

In the form of its zinc complex, plerixafor acts as an antagonist (or perhaps more accurately a partial agonist) of the alpha chemokine receptor CXCR4 and an allosteric agonist ofCXCR7.[10] The CXCR4 alpha-chemokine receptor and one of its ligandsSDF-1, are important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. The in vivo effect of plerixafor with regard to ubiquitin, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells.[11]

Interactions

No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs.[5]

Legal status

Plerixafor has orphan drug status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration for this indication on December 15, 2008.[12] In Europe, the drug was approved after a positive Committee for Medicinal Products for Human Use assessment report on 29 May 2009.[7] The drug was approved for use in Canada by Health Canada on December 8, 2011.[13]

Research

Small molecule cancer therapy

Plerixafor was seen to reduce metastasis in mice in several studies.[14] It has also been shown to reduce recurrence of glioblastoma in a mouse model after radiotherapy. In this model, the cancer surviving radiation are critically depended on bone marrow derived cells for vasculogenesis whose recruitment mediated by SDF-1 CXCR4 interaction is blocked by plerixafor.[15]

Use in generation of other stem cells

Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factor (VEGF) can produce mesenchymal stem cells andendothelial progenitor cells in mice.[16]

Other uses

Blockade of CXCR4 signalling by plerixafor (AMD3100) has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia produced by chronic treatment with morphine, though only animal studies have been conducted as yet.[17]

Plerixafor
JM 3100.svg
JM 3100 3D.png
Systematic (IUPAC) name
1,1′-[1,4-Phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane]
Clinical data
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a609018
Pregnancy cat. (US)
Legal status -only (US)
Routes Subcutaneous injection
Pharmacokinetic data
Protein binding Up to 58%
Metabolism None
Half-life 3–5 hours
Excretion Renal
Identifiers
CAS number 110078-46-1
ATC code L03AX16
PubChem CID 65015
IUPHAR ligand 844
DrugBank DB06809
ChemSpider 58531 Yes
UNII S915P5499N Yes
 
Synonyms JM 3100, AMD3100
Chemical data
Formula C28H54N8 
Mol. mass 502.782 g/mol

http://www.google.com/patents/CN102653536A?cl=en

(Plerixafor), chemical name: 1, I ‘- [I, 4_ phenylene ni (methylene)] – ni -1,4,

8,11 – tetraazacyclo tetradecane, its molecular structure is as follows:

[0004]

Figure CN102653536AD00041

Synthesis of domestic and foreign literature in general, all require 1,4,8,11 – tetraazacyclo-tetradecane for 3 protection (eg of formula I), of the three methods are used to protect the p-toluenesulfonamide chloride, trifluoroacetic acid ko ko cool, tert-butyl carbonate ni. Use of p-toluenesulfonamide-protected deprotection step into strict step because deprotecting reagent (such as hydrobromic acid / glacial acetic acid, concentrated sulfuric acid, etc.) side reactions often occur.The use of trifluoroacetic acid ko ko ester protecting, since the trifluoromethyl group strongly polar ko, resulting fourth-NH unprotected decrease in activity, usually not fully reflect the subsequent reaction, thereby further into ー is introduced after deprotection difficult to remove impurities 1,4,8,11 – tetraazacyclo-tetradecane.

[0006] tert-butyl carbonate ni selective protection of the amino group is widely used (polyamines, amino acids, p printed tidic chains, etc.), but to use it for 1,4,8,11 – tetraazacyclo tetradecane rarely reported, abroad it for 1,4,8,11 – tetraazacyclo tetradecane protection coverage, we use the t-butyl carbonate brother attempted 3 protection, he was surprised to find that in certain conditions, the three protection up to 90% (see Figure I), with high selectivity, significantly higher than the reported domestic Boc protected

Selectivity of the reaction (see table below).

[0007]

Figure CN102653536AD00051

[0008] 2 by three protection product with quite different polarity protection products, flash column chromatography using silica gel column to separate the protector 3 of sufficient purity, and deprotection conditions milder (only hydrochloric acid solution), in a certain extent reduce the incidence of side effects, so capable of synthesizing high purity products.

[0009]

Figure CN102653536AD00052

SUMMARY OF THE INVENTION

Figure CN102653536AD00053

 

Figure CN102653536AD00061

xample I: 3Boc protection 1,4,8,11 _ tetraazacyclo Preparation tetradecane

[0048] 1,4,8,11 taken tetraazacyclo tetradecane _ 10g (0.05mol), and acetone – water (2: l) 50ml, tris ko amine 10. 119g (0. Lmol), ni ko isopropyl amine 3. 225g (0. 025mol), at room temperature was added dropwise tert-butyl carbonate, brother 38. 194g (0. 175mol), dropwise at room temperature after stirring for 24 hours, HPLC monitoring of the reaction. After completion of the reaction 50 ° C under reduced pressure to dryness to give a pale yellow oil, 150g on a silica gel column, and eluted with ko acid esters ko collecting ko ko acid ester liquid evaporated to dryness under reduced pressure to give a white foam 23. 12g, yield of 92.36%. 1HNMR (400MHz, CDCl3, 6 ppm): 1. 74 (2H, q, 5. 5);

I. 96 (2H, q, 6. 5); 2. 66 (2H, t, 5. 5); 2. 82 (2H, t, 5. 5); 3. 33 (4H, m); 3. 34 (2H, m); 3. 37 (2H, m), 3. 43 (4H, m).

[0049] Implementation Example 2: 6Boc protection Bullock Suffolk Preparation

[0050] Take 3Boc protection 1,4,8,11 _ tetraazacyclo tetradecane 20. 03g (0. 04mol), dissolved in anhydrous ko nitrile 400ml, anhydrous potassium carbonate 20g, aa ‘ni chlorine ni toluene 3.5012g (0.02mol), sodium iodide 75mg, at reflux for 24 hours under nitrogen, TLC monitoring of the reaction. After completion of the reaction, cooled to room temperature, filtered, the filter cake was washed with 200ml of ko nitrile, nitrile ko combined solution was evaporated to dryness under reduced pressure to give the protected Bullock 6Boc Suffolk 21. 20g, yield of 96.06%. Alcohol with ko – a mixed solvent of water and recrystallized to give a white solid. [0051] Implementation Example 3: Bullock Suffolk • 8HC1 • 3H20 Preparation of compounds

[0052] Protection Bullock Suffolk take 6Boc 20g, add methanol 200ml, stirring to dissolve, concentrated hydrochloric acid was added dropwise at room temperature, 60ml, was stirred at room temperature after the addition was complete 48 inches, TLC monitoring of the reaction. After completion of the reaction, filtration, the filter cake was dried 50 ° C under reduced pressure to give a white solid 13. 54g, yield of 88.04%.

 

Figure CN102653536AD00071

 

[0053] Implementation Example 4: Preparation of Suffolk Bullock…………Plerixafor BASE

[0054] Take Bullock Suffolk • 8HC1 • 3H20 compound 13. 54g, add water 40ml ultrasound to dissolve after stirring constantly with 50% sodium hydroxide solution to adjust the pH to 12 and filtered, the filter cake 50 ° C minus pressure and dried to give a white solid 7. 24g, yield 90.24 V0o

1H NMR (400MHz, CDCl3, 6 ppm): 1. 75 (4H, bs); 1. 87 (4H, bs); 2. 95-2. 51 (32H, m); 3. 54 (4H, s); 4. 23 (4H, bs); 7. 30 (4H, s). 

IR (KBr) 3280,2927,2883,2805,1458,1264,1117 cm,

 

 

NEW PATENT…………….WO-2014125499

Improved and commercially viable process for the preparation of high pure plerixafor base

Process for the preparation of more than 99.8% pure plerixafor base by HPLC. Also claims solid forms of plerixafor base and composition comprising the same. Appears to be the first filing from the assignee on this API. FDA Orange book lists US6987102 and US7897590, expire in July 2023.

3-5-1997
Process for preparing 1,4,8,11-tetraazacyclotetradecane
2-26-1997
Process for preparing 1,1′-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane
12-11-1996
Aromatic-linked polyamine macrocyclic compounds with anti-HIV activity
11-8-1996
PROCESS FOR PREPARING 1,1′-[1,4-PHENYLENEBIS-(METHYLENE)]-BIS-1,4,8,11-TETRAAZACYCLOTETRADECANE
10-4-1996
PROCESS FOR PREPARING 1,1′-[1,4-PHENYLENEBIS-(METHYLENE)]-BIS-1,4,8,11-TETRAAZACYCLOTETRADECANE
7-14-1995
CYCLIC POLYAMINES
6-25-1993
LINKED CYCLIC POLYAMINES WITH ACTIVITY AGAINST HIV

 

 

9-2-2005
Substituted benzodiazepines as inhibitors of the chemokine receptor CXCR4
2-4-2005
Methods and compositions for the treatment or prevention of human immunodeficiency virus and related conditions using cyclooxygenase-2 selective inhibitors and antiviral agents
12-4-2002
Process for preparation of N-1 protected N ring nitrogen containing cyclic polyamines and products thereof
10-2-2002
Prodrugs
10-25-2001
PROCESS FOR PREPARING 1,1′- 1,4-PHENYLENEBIS-(METHYLENE)]-BIS-1,4,8,11-TETRAAZACYCLOTETRADECANE
9-29-2000
CHEMOKINE RECPETOR BINDING HETEROCYCLIC COMPOUNDS
8-11-2000
METHODS AND COMPOSITIONS TO ENHANCE WHITE BLOOD CELL COUNT
1-15-1998
PROCESS FOR PREPARING 1,1′- 1,4-PHENYLENEBIS-(METHYLENE) -BIS-1,4,8,11-TETRAAZACYCLOTETRADECANE
3-19-1997
Process for preparing 1,1′-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane
3-7-1997
PROCESS FOR PREPARING 1,4,8,11-TETRAAZACYCLOTETRADECANE PROCESS FOR PREPARING 1,4,8,11-TETRAAZACYCLOTETRADECANE

 

6-24-2011
BETULINIC ACID DERIVATIVES AS ANTI-HIV AGENTS
11-3-2010
Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
2-5-2010
Chemokine Receptor Modulators
1-29-2010
NOVEL POLYNITROGENATED SYSTEMS AS ANTI-HIV AGENTS
9-4-2009
Combination of CXCR4 Antagonist and Morphogen to Increase Angiogenesis
11-28-2008
Chemokine receptor modulators
10-24-2008
Chemokine receptor modulators
8-32-2006
Compositions and methods for treating tissue ischemia
7-5-2006
ANTIVIRAL METHODS EMPLOYING DOUBLE ESTERS OF 2′, 3′-DIDEOXY-3′-FLUOROGUANOSINE
12-14-2005
Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine

 

References

  1. Jump up^ Ciampolini, M.; Fabbrizzi, L.; Perotti, A.; Poggi, A.; Seghi, B.; Zanobini, F. (1987). “Dinickel and dicopper complexes with N,N-linked bis(cyclam) ligands. An ideal system for the investigation of electrostatic effects on the redox behavior of pairs of metal ions”.Inorganic Chemistry 26 (21): 3527. doi:10.1021/ic00268a022edit
  2. Jump up^ Davies, S. L.; Serradell, N.; Bolós, J.; Bayés, M. (2007). “Plerixafor Hydrochloride”.Drugs of the Future 32 (2): 123. doi:10.1358/dof.2007.032.02.1071897edit
  3. Jump up^ Davies, S. L.; Serradell, N.; Bolós, J.; Bayés, M. (2007). “Plerixafor Hydrochloride”.Drugs of the Future 32 (2): 123. doi:10.1358/dof.2007.032.02.1071897edit
  4. Jump up to:a b &Na; (2007). “Plerixafor”. Drugs in R & D 8 (2): 113–119. doi:10.2165/00126839-200708020-00006PMID 17324009edit
  5. Jump up to:a b c d e Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
  6. Jump up^ Wagstaff, A. J. (2009). “Plerixafor”. Drugs 69 (3): 319. doi:10.2165/00003495-200969030-00007PMID 19275275edit
  7. Jump up to:a b “CHMP Assessment Report for Mozobil”European Medicines Agency.
  8. Jump up^ Esté, J. A.; Cabrera, C.; De Clercq, E.; Struyf, S.; Van Damme, J.; Bridger, G.; Skerlj, R. T.; Abrams, M. J.; Henson, G.; Gutierrez, A.; Clotet, B.; Schols, D. (1999). “Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor”. Molecular Pharmacology 55 (1): 67–73.PMID 9882699edit
  9. Jump up^ Bridger, G.; et al. (1993). “Linked cyclic polyamines with activity against HIV. WO/1993/012096″.
  10. Jump up^ Kalatskaya, I.; Berchiche, Y. A.; Gravel, S.; Limberg, B. J.; Rosenbaum, J. S.; Heveker, N. (2009). “AMD3100 is a CXCR7 Ligand with Allosteric Agonist Properties”.Molecular Pharmacology 75: 1240. doi:10.1124/mol.108.053389.PMID 19255243edit
  11. Jump up^ Cashen, A. F.; Nervi, B.; Dipersio, J. (2007). “AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent”. Future Oncology 3 (1): 19–27.doi:10.2217/14796694.3.1.19PMID 17280498edit
  12. Jump up^ “Mozobil approved for non-Hodgkin’s lymphoma and multiple myeloma” (Press release). Monthly Prescribing Reference. December 18, 2008. Retrieved January 3, 2009.
  13. Jump up^ Notice of Decision for MOZOBIL
  14. Jump up^ Smith, M. C. P.; Luker, K. E.; Garbow, J. R.; Prior, J. L.; Jackson, E.; Piwnica-Worms, D.; Luker, G. D. (2004). “CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer”. Cancer Research 64 (23): 8604–8612. doi:10.1158/0008-5472.CAN-04-1844PMID 15574767edit
  15. Jump up^ Kioi, M.; Vogel, H.; Schultz, G.; Hoffman, R. M.; Harsh, G. R.; Brown, J. M. (2010).“Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice”Journal of Clinical Investigation 120 (3): 694–705. doi:10.1172/JCI40283PMC 2827954PMID 20179352edit
  16. Jump up^ Pitchford, S.; Furze, R.; Jones, C.; Wengner, A.; Rankin, S. (2009). “Differential Mobilization of Subsets of Progenitor Cells from the Bone Marrow”. Cell Stem Cell 4 (1): 62–72. doi:10.1016/j.stem.2008.10.017PMID 19128793edit
  17. Jump up^ Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA (March 2011). “CXCR4 Signaling Mediates Morphine-induced Tactile Hyperalgesia”Brain, Behavior, and Immunity 25(3): 565–73. doi:10.1016/j.bbi.2010.12.014PMC 3039030PMID 21193025.
  18. http://worlddrugtracker.blogspot.in/2013/11/plerixafor-new-treatment-approaches-for.html

External links

 

Synthetic routes to produce the novel chelators 2 and 3.

http://pubs.rsc.org/en/content/articlehtml/2012/dt/c2dt31137b

Theranostics 03: 0047 image No. 04

Theranostics 03: 0047 image No. 18

 

http://www.thno.org/v03p0047.htm

 

SEE ALSO……….http://www.scipharm.at/download.asp?id=1427

 

SEE…………..https://www.academia.edu/5549712/2011531154034454SCHEME 15 IS SYNTHESIS OF PLEXIXAFOR

read

ncur_powerpoint Courtney.ppt

faculty.swosu.edu/tim.hubin/share/ncur_powerpoint%20Courtney.ppt 

… trials against cancer and for stem cell mobilization as “Mozobil” or “Plerixafor” …NMR studies of AMD-3100 suggest that complex configuration is important.

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: