Top Selling Schizophrenia Drug Abilify (Aripiprazole)

 

Aripiprazole (brand names: Abilify, Aripiprex, OPC-14597,) is an atypical antipsychotic drug with the chemical name 7-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy]-3,4-dihydro-2(1H)-quinolinone. It was first discovered by the Otsuka Pharmaceutical Company, Ltd., based in Japan, and in collaboration with Bristol-Myers Squibb began to market the drug in the United States following the approval by the Food and Drug Administration for schizophrenia in November 2002. According to IMS Health, Abilify was the fourth top-selling drug in the United States in 2011, with sales of $5.2 billion.

Chemical Structure of Aripiprazole (brand names: Abilify)

Chemical Synthesis of Aripiprazole(active ingredient for Abilify)

Experimental Procedures for the preparation of Aripiprazole (Abilify)

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)quinolinone (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: d₁₀=15.83 m, d₅₀=60.12 m, d₉₀=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: d₁₀=22.01 m, d₅₀=105.10 m, d₉₀=232.97 m

References For the Process of Aripiprazole (Abilify,)

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; US 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

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. / SHANGHAI ZHONGXI PHARMACEUTICAL January 2013: WO 2013/000391

CN 201210235157

CN102846543A

CN102850268A;

CN101781246A 

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 U.S. 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®. (see the pdf file for the decision upholding the Otsuka patent here). The Federal Circuit affirmed a decision of the U.S. District Court for the District of New Jersey holding that the asserted claims of U.S. Patent No. 5,006,528 (pdf file here) 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. Sandoz Inc., 2011-1126 and 2011-1127, U.S. Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, U.S. District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole(active ingredient for Abilify): 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one
CAS number 129722-12-9

Aripiprazole  brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation class of atypical antipsychotics with additional antidepressant properties that is primarily used in the treatment ofschizophrenia, bipolar disorder, major depressive disorder, and irritability associated with autism.^[1] 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;^[2] and to treat irritability in children with autism on 20 November 2009.^[3] Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.

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

1.  U.S. Patent 5,006,528

Furiex Pharmaceuticals Announces Completion of Patient Enrollment for Its Phase III Clinical Trials of Eluxadoline for IBS-d

http://www.ama-assn.org/resources/doc/usan/eluxadoline.pdf  
get the structure of eluxadoline here
 name
 Benzoic acid, 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-
oxopropyl][(1S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy-

MOLECULAR FORMULA C32H35N5O5
MOLECULAR WEIGHT 569.7
TRADEMARK None as yet
SPONSOR Furiex Pharmaceuticals, Inc.
CODE DESIGNATIONS JNJ-27018966
CAS REGISTRY NUMBER 864821-90-9
WHO NUMBER 9749

Eluxadoline nonproprietary drug name - AMA

www.ama-assn.org/resources/doc/usan/eluxadoline.pdf‎

• 
  
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November 28, 2012. N11/133. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-82). ELUXADOLINE.

Furiex Pharmaceuticals Announces Completion of Patient Enrollment for Its Phase III Clinical Trials of Eluxadoline for IBS-d

Furiex Pharmaceuticals Inc.Posted on:15 Jul 13

• 
  

Furiex Pharmaceuticals Inc. (NASDAQ: FURX) today announced completion of patient enrollment in the company’s two ongoing Phase III clinical trials studying eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome or IBS-d. Both studies met their target enrollments and Furiex expects to release top line results in the first quarter of 2014.
The two Phase III trials have the same overall design and efficacy endpoints but differ in overall duration. One study has a 52-week treatment period and the other a 30-week treatment period. Each study has three treatment arms placebo 75 mg eluxadoline twice a day and 100 mg eluxadoline twice a day with approximately 375 patients per arm and is designed to capture both the U.S. Food

read all at
http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=76787#.UeUl4EHDBZg

need phase 2 data see here
 In a phase 2 study of the mixed μ-opioid receptor agonist/δ-opioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D. ClinicalTrials.gov number, NCT01130272

Research in HIV therapies -A review- The global community has made significant strides forward in its mission to eradicate the HIV epidemic

 

Over the last 30 years, the face of human immunodeficiency virus (HIV) has changed from one largely associated with homosexuality, drug addicts, prejudice, fear and rejection without much hope of a future, to one involving innocent children born of mothers living with HIV for whom it is hoped the disease will be curable and even eradicated. 

According to the World Health Organization (WHO) and UNAIDS, 34 million people were living with HIV worldwide in 2011. Sub-Saharan Africa was, and still is, the most severely affected area. Approximately 5 per cent of adults in this region live with HIV, representing almost 70 per cent of the global HIV-infected population. On a positive note, the number of newly infected people has declined by approximately 25 per cent over the past ten years and, importantly, over the past two years, half of the reductions in HIV infections has been in children.

Treatment and prevention
The approach to, and success of, HIV treatment and prevention has.....................cont

read all at

 http://www.pmlive.com/pharma_news/research_in_hiv_therapies_488697
THE NAMES OF DRUGS USED ARE LISTED HERE, PLEASE READ IT

 

 article by
Wendy McNeely

Adis International (Springer Healthcare), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or email her Daniela.Ranzani@springer.com

Role of computers in drug design1

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Role of computers in drug design1 from Educationcareer,authorstream




 

PROSTRATE CANCER

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Prostate cancer from morwenna2

Vical's Allovectin Phase III Trial Results: Consider The Possibilities

Vical's Allovectin Phase III Trial Results: Consider The Possibilities ... Cohen: We saw that happen last year when JNJ prematurely unblinded the pre- chemo Phase III study for the prostate cancer drug Zytiga. The trial achieved ... http://seekingalpha.com/article/1538852-vical-s-allovectin-phase-iii-trial-results-consider-the-possibilities Allovectin-7 is a substance that is being studied as a gene therapy agent in the treatment of cancer, such as malignant melanoma. It is a plasmid/lipid complex containing the DNA sequences encoding HLA-B7 and ß2 microglobulin - two components of major histocompatibility complex (MHC, class I). It increases the ability of the immune system to recognize cancer cells and kill them. In 1999, FDA granted Allovectin-7 orphan drug designation for the treatment of invasive and metastatic melanoma. Allovectin-7 entry in the public domain NCI Dictionary of Cancer Terms

Ohr Pharmaceutical Achieves 50% Enrollment Milestone in Squalamine Eye Drop Phase II Clinical Trial

squalamine

July 10, 2013 /
Ohr Pharmaceutical, Inc. , a pharmaceutical company focused on the development of novel therapeutics for large unmet medical needs, today announced that it has enrolled the first 60 patients in the Company's ongoing OHR-002 Phase II clinical trial evaluating Squalamine Eye Drops for the treatment of the wet form of age-related macular degeneration ("wet-AMD").
The study is a randomized, double blind, placebo controlled study enrolling patients at more than twenty clinical sites in the U.S. "We are excited to have reached the halfway point in the enrollment of our Squalamine Eye Drop study," said Dr. Irach B. Taraporewala, CEO of Ohr.
"This milestone sets the stage for the planned interim analysis once the 60 patients complete the nine month treatment protocol, and we expect the data to be available in the second quarter of 2014.
" "I am pleased with the continued progress in the trial to evaluate Squalamine Eye Drops for exudative AMD," commented Dr. Jason Slakter, retinal disease specialist at Vitreous-Retina-Macula Consultants of NY, and member of Ohr's scientific advisory board. "The Company's eye drop for treating wet-AMD would potentially offer patients a convenient, self-administered, treatment alternative or adjunct to currently used intravitreal injections directly into the eye. This could be a significant advancement in the future treatment of wet-AMD." Study OHR-002 is a randomized, double blind, placebo controlled Phase II study to evaluate the efficacy and safety of Squalamine Eye Drops for the treatment of wet-AMD.
The study will enroll 120 treatment naive wet-AMD patients at more than twenty clinical sites in the U.S., who will be treated with Squalamine Eye Drops or placebo eye drops twice daily for a nine month period.
The primary and secondary endpoints include visual acuity parameters, need for rescue intravitreal injections, and safety. The protocol includes an interim analysis upon the completion of the treatment period in 50% of the patients (60). More information on the clinical trial can be found at clinicaltrials.gov. About Ohr Pharmaceutical, Inc. Ohr Pharmaceutical, Inc. (NasdaqCM:OHRP) is a pharmaceutical company dedicated to the clinical development of new drugs for underserved therapeutic needs in large and growing markets. The Company is focused on advancing its pipeline products currently in phase II clinical development: Squalamine Eye Drops for the treatment of the wet form of age-related macular degeneration, and OHR/AVR118 for the treatment of cancer cachexia. Additional information on the Company can be found at www.ohrpharmaceutical.com.