Home » Uncategorized (Page 119)

Category Archives: Uncategorized

Japanese scientists say they have found a way to slow down the ageing process in flowers by up to a half, meaning bouquets could remain fresh for much longer.

Researchers at the National Agriculture and Food Research Organisation in Tsukuba, east of Tokyo, said they had found the gene believed to be responsible for the short shelf-life of flowers in one Japanese variety of morning glory.

“Morning glory” is the popular name for a hundreds of species of flowering plants whose short-lived blooms usually unfold early in the day and are gone by nightfall.

By suppressing the gene—named “EPHEMERAL1″—the lifespan of each flower was almost doubled, said Kenichi Shibuya, one of the lead researchers in a study carried out jointly with Kagoshima University in southern Japan.

“Unmodified flowers started withering 13 hours after they opened, but flowers that had been genetically modified stayed open for 24 hours,” he said.

This…

View original post 166 more words

Edible flowers may inhibit chronic diseases

July 5, 2014 3:57 am / Leave a comment

Lyra Nara Blog

A new study in the Journal of Food Science, published by the Institute of Food Technologists (IFT), found that common edible flowers in China are rich in phenolics and have excellent antioxidant capacity.

Edible flowers, which have been used in the culinary arts in China for centuries, are receiving renewed interest. Flowers can be used as an essential ingredient in a recipe, provide seasoning to a dish, or simply be used as a garnish. Some of these flowers contain phenolics that have been correlated with anti-inflammatory activity and a reduced risk of cardiovascular disease and certain cancers.

The findings of this study show that common edible flowers have the potential to be used as an additive in food to prevent chronic disease, help health promotion and prevent food oxidization. However, the antioxidant mechanisms, the anti-tumor, anti-inflammation and anti-aging activity of the edible flower extracts should be further studied to…

View original post 13 more words

Cebranopadol GRT 6005 セブラノパドール a Potent Analgesic NOP and Opioid Receptor Agonist

July 4, 2014 6:14 am / 1 Comment on Cebranopadol GRT 6005 セブラノパドール a Potent Analgesic NOP and Opioid Receptor Agonist

Cebranopadol

(GRT-6005; GRT 6005; GRT6005)

CAS: 863513-91-1

(1r,4r)-6′-Fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine

Spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-

C₂₄H₂₇FN₂O
Average mass: 378.482391 Da

Grünenthal GmbH innovator

Cebranopadol(GRT-6005) is a novel first in class compounds with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor.

Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several experimental model models of acute and chronic pain (tail–flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5–5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side–effect profile.

GRT-6005 is a centrally active analgesic in phase II clinical development for the oral treatment of neuropathic pain in patients with painful diabetic polyneuropathy and for the treatment of pain due to osteoarthritis of the knee. It is being developed by Grüenenthal and Forest. No recent development has been reported for research into the treatment of moderate to severe pain following bunionectomy. In 2010, GRT-6005 was licensed to Forest and Grünenthal in Canada and the U.S. for the treatment of moderate to severe chronic pain.

ChemSpider 2D Image | Cebranopadol | C24H27FN2O

Description: IC50 Value: N/A Cebranopadol and GRT 6006 are novel first-in-class compounds with unique pharmacological and pharmacokinetic profiles that may enhance their effect in certain pain conditions. The unique mode of action of these compounds builds on the ORL-1 receptor and, supported by the established mu opioid receptor, is particularly suitable for the treatment of moderate to severe chronic pain [1]. in vitro: N/A in vivo: N/A Clinical trial: Cebranopadol has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with further Phase II studies planned prior to initiation of Phase III studies.

A Randomized 4 Week Phase IIa Trial Evaluating the Efficacy, Safety, and Tolerability of GRT6005, a New Centrally Acting Analgesic, in Subjects With Moderate to Severe Pain Due to Osteoarthritis (OA) of the Knee

Neuropathic pain

Neuropathic pain is caused when peripheral nerves are damaged by mechanical, metabolic or inflammatory way. The pain occurring images are mainly due to the occurrence of spontaneous pain, hyperalgesia and allodynia (pain is already triggered by non-noxious stimuli) in. As a result, the lesions to increased expression of Na + channels and thus to spontaneous activity in the damaged axons and their Nachbaraxonen (England et al., Neurology, 1996, 47, 272-276).The excitability of the neurons is increased and they react to incoming stimuli with an increased discharge frequency. This results in an increased sensitivity to pain, which contributes to the development of hyperalgesia and spontaneous pain (Baron, Clin J Pain 2000;. 16 (2 Suppl), 12-20). The causes and manifestations, and therefore the treatment needs of neuropathischerm pain are varied. They arise as a result of injury or disease of the brain, spinal cord or peripheral nerves.Causes may be operations, such as phantom pain after amputation, stroke, multiple sclerosis, spinal cord injury, alcohol or drug abuse or other toxins, cancers but also

Metabolic diseases such as diabetes, gout, kidney failure or liver cirrhosis, or infectious diseases such as mononucleosis, ehrlichiosis, typhoid, diphtheria, HIV, syphilis or Lyme disease. The pain experience is very different signs and symptoms that can change over time in number and intensity. Paradoxically, patients with neuropathic pain outline a slowdown or failure of acute pain perception and the simultaneous increase of neuropathic pain. The typical symptoms of neuropathic pain as tingling, burning, shooting or described, or radiating electrifying. Pharmacological basis for treatment of neuropathic pain include tricyclic antidepressants and anticonvulsants, which are used as monotherapy or in combination with opioids. These drugs usually provide only a certain pain relief during a pain-free but is often not achieved. The often-adjusting side effects are dose increases while the drug to achieve adequate pain relief often in the way. In fact, a higher dosage of a μ-opioid is often required as the treatment of acute pain, thereby reducing the side effects get even more important for satisfactory treatment of neuropathic pain. By the occurrence of typical μ-opioid tolerance development and the concomitant need for dose escalation of this problem is exacerbated. In summary it can be stated that neuropathic pain is difficult to treat and today is alleviated by high doses of μ-opioids only partially (Saudi Pharm J. 2002, 10 (3), 73-85). There is therefore an urgent need for medicines for the treatment of chronic pain, the dose should not be increased until the occurrence of intolerable side effects to ensure a satisfactory pain treatment.

……………

http://www.google.com/patents/US7547707

Example 24 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×60 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The solid contained in the suspension was filtered off with suction and dried. 955 mg of the more non-polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole were obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hot ethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2 mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 h. The solid formed was filtered off with suction. 640 mg of the hemicitrate were obtained as a white solid (m.p. 258-282° C.).

Example 25 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1 mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture was stirred at RT for 16 h. For working up, the mixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC (3×20 ml). The combined organic phases were dried with sodium sulfate and evaporated. The residue (364 mg of white solid) was suspended in hot ethanol (20 ml), and a similarly hot solution of citric acid (185 mg, 0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolved completely and no longer precipitated out even on cooling to approx. 5° C. Ethanol was removed on a rotary evaporator and the hemicitrate of the more polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained in this way in a yield of 548 mg as a white solid (m.p. 148-155° C.).

24	hemicitrate	more non-polar diastereomer

25	hemicitrate	more polar diastereomer

………………..

WO 2013113690

(1 r,4r)-6′-fluoro-N,N- dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1 ,1 ‘-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):

http://www.google.com/patents/WO2013113690A1?cl=en

…………………

http://www.google.com/patents/WO2008040481A1?cl=en

see A4

…………………………

http://www.google.com/patents/US20130231381

One particular drug that is of great interest for use in treating cancer pain (and other acute, visceral, neuropathic and chronic pain pain disorders) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine. This drug is depicted below as the compound of formula (I).

The solid forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine that are known so far are not satisfactory in every respect and there is a demand for advantageous solid forms

A) Synthesis of Crystalline Form A100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by FT Raman, TG-FTIR and PXRD.

……………………

In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

http://pubs.acs.org/doi/full/10.1021/ml500117c

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml500117c

synthesis…………http://pubs.acs.org/doi/suppl/10.1021/ml500117c/suppl_file/ml500117c_si_001.pdf

6′-Fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)

hemicitrate were obtained as a white solid (mp 258-282 °C).1H-NMR (300 MHz; DMSO-d6): 1.75-1.87 (m, 4 H); 2.14 (s, 6 H); 2.27 (t, 2 H); 2.61-
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).

13C-NMR (75.47 MHz; DMSO-d6): 22.1; 27.6; 30.2 (2 C); 38.0 (2 C); 43.1; 58.8 (2 C,
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);

112.0 (3JC,F = 10 Hz); 126.5; 126.6; 126.7 (2 C); 127.4 (2 C); 132.4; 138.7; 141.5;
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+

…………………………..

US20120034297 *	Aug 4, 2011	Feb 9, 2012	Gruenenthal Gmbh	Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

WO2004043967A1	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2008040481A1	Sep 26, 2007	Apr 10, 2008	Gruenenthal Gmbh	MIXED ORL 1/μ AGONISTS FOR TREATING PAIN

CORAL – Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer

Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.Average amount of daily rescue medication at the end of the maintenance period.

UK Clinical Trials Gateway, 07 October 2013
+

CORAL XT – Open-label Extension Trial of the CORAL Trial

An Open-label, Multi-site Trial to Describe the Safety and Tolerability of Oral Cebranopadol Administered for 26 Weeks in Subjects With Cancer-related Pain Who Have Completed Treatment in the KF6005/07 Trial.Absolute…

UK Clinical Trials Gateway, 12 December 2013

WO2004043967A1 *	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2005066183A1 *	Dec 21, 2004	Jul 21, 2005	Gruenenthal Gmbh	Spirocyclic cyclohexane derivatives with affinity for the orl1-receptor
US20050153998 *	Aug 19, 2004	Jul 14, 2005	Fumitaka Ito	Tetrahydroisoquinoline or isochroman compounds

Citing Patent	Filing date	Publication date	Applicant	Title
US7799931 *	Feb 17, 2009	Sep 21, 2010	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US7951948 *	Apr 19, 2010	May 31, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US7960404	Aug 21, 2009	Jun 14, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US8034936	Nov 4, 2010	Oct 11, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds useful to treat substance dependency
US8053576	Feb 17, 2009	Nov 8, 2011	Gruenenthal Gmbh	Treating conditions associated with the nociceptin/ORL1 receptor system, e.g. pain, drug withdrawal, anxiety, muscle relaxants, anxiolytic agents; e.g. 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluorene
US8288406	Sep 22, 2010	Oct 16, 2012	Gruenenthal Gmbh	Hydroxymethylcyclohexylamines
US8288430	Mar 25, 2009	Oct 16, 2012	Grunenthal Gmbh	Spiro(5.5)undecane derivatives
US8293758 *	Mar 25, 2009	Oct 23, 2012	Grunenthal Gmbh	Substituted spirocyclic cyclohexane derivatives
US8357705	Mar 25, 2009	Jan 22, 2013	Gruenenthal Gmbh	Substituted cyclohexyldiamines
US8404740	Aug 21, 2009	Mar 26, 2013	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US8614245 *	Jan 8, 2013	Dec 24, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US8618156 *	Jul 6, 2012	Dec 31, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , INDIA
web link

ABOUTME

BRAND ANTHONYCRASTO

COLLECTION OF SITE LINKS

http://amcrasto.bravesites.com/

http://anthonycrasto.jimdo.com/

Congratulations! Your presentation titled “Anthony Crasto Glenmark scientist, helping millions with websites” has just crossed MILLION views.

アンソニー安东尼 Энтони 안토니 أنتوني

join my process development group on google

organic-process-development group

you can post articles and will be administered by me on the google group which is very popular across the world

https://sites.google.com/site/amcrasto/

SKILLPAGES

MIXXT

APNACIRCLE

LinkedIn group

SYNTHETIC ORGANIC CHEMISTRY

blogs are

MY BLOG ON MED CHEM

New Drug Approvals

ALL ABOUT DRUGS

WORLD DRUG TRACKER

MEDICINAL CHEM INTERNATIONAL

DRUG SYN INTERNATIONAL

SCALEUP OF DRUGS

ALL FOR DRUGS ON WEB

http://scholar.google.co.uk/citations?user=bxm3kYkAAAAJ

http://www.stumbleupon.com/stumbler/amcrasto

MY CHINA AND JAPAN BLOGS

http://amcrasto.blog.fc2.com/

http://blog.sina.com.cn/u/5030268874

http://ameblo.jp/medchem-amcrasto/

VIETNAM

http://me.zing.vn/u/amcrasto

ICELAND

http://amcrasto.bland.is/

RUSSIA

http://www.100zakladok.ru/amcrasto/

http://bobrdobr.ru/people/amcrasto/

========================

BI launches COPD drug Striverdi, olodaterol in UK and Ireland

July 3, 2014 8:07 am / 2 Comments on BI launches COPD drug Striverdi, olodaterol in UK and Ireland

Olodaterol

BI-1744
BI-1744-CL (hydrochloride) marketed as drug

Boehringer Ingelheim Pharma innovator

synthesis…..http://wendang.baidu.com/view/d4f95541e518964bcf847c22.html

Olodaterol (trade name Striverdi) is a long acting beta-adrenoceptor agonist used as an inhalation for treating patients with chronic obstructive pulmonary disease (COPD), manufactured by Boehringer-Ingelheim.^[1]

see……….https://www.thieme-connect.de/DOI/DOI?10.1055/s-0029-1219649 ……… synfacts

Olodaterol is a potent agonist of the human β₂-adrenoceptor with a high β₁/β₂ selectivity. Its crystalline hydrochloride salt is suitable for inhalation and is currently undergoing clinical trials in man for the treatment of asthma. Olodaterol has a duration of action that exceeds 24 hours in two preclinical animal models of bronchoprotection and it has a better safety margin compared with formoterol.

Olodaterol hydrochloride [USAN]

Bi 1744 cl
Bi-1744-cl
Olodaterol hydrochloride
Olodaterol hydrochloride [usan]
UNII-65R445W3V9

868049-49-4 [RN] FREE FORM

CAS 869477-96-3 HCL SALT

R ENANTIOMER

2H-1,4-Benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

2H-1,4-benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

6-Hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)- 2H-1,4-benzoxazin-3(4H)-one hydrochloride

clinical trialshttp://clinicaltrials.gov/search/intervention=Olodaterol+OR+BI+1744

Boehringer Ingelheim has launched a new chronic obstructive pulmonary disease drug, Striverdi in the UK and Ireland.
Striverdi (olodaterol) is the second molecule to be licenced for delivery via the company’s Respimat Soft Mist inhaler, following the COPD blockbuster Spiriva (tiotropium). The drug was approved in Europe in November based on results from a Phase III programme that included more than 3,000 patients with moderate to very severe disease.http://www.pharmatimes.com/Article/14-07-01/BI_launches_COPD_drug_Striverdi_in_UK_and_Ireland.aspx

Olodaterol hydrochloride is a drug candidate originated by Boehringer Ingelheim. The product, delivered once-daily by the Respimat Soft Mist Inhaler, was first launched in Denmark and the Netherlands in March 2014 for the use as maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. In 2013, approval was obtained in Russia and Canada for the same indication, and in the U.S, the product was recommended for approval. Phase III clinical trials for the treatment of COPD are ongoing in Japan.

ChemSpider 2D Image | Olodaterol | C21H26N2O5

Systematic (IUPAC) name
6-hydroxy-8-{(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl}-4H-1,4-benzoxazin-3-one
Clinical data
Trade names	Striverdi
AHFS/Drugs.com	UK Drug Information
Pregnancy cat.	No experience
Legal status	POM (UK)
Routes	Inhalation
Identifiers
CAS number	868049-49-4; 869477-96-3 (hydrochloride)
ATC code	R03AC19
PubChem	CID 11504295
ChemSpider	9679097
UNII	VD2YSN1AFD
ChEMBL	CHEMBL605846
Synonyms	BI 1744 CL
Chemical data
Formula	C₂₁H₂₆N₂O₅^{free form}C21 H26 N2 O5 . Cl H; of hcl salt
Mol. mass	386.44 g/mol free form; 422.902 as hyd salt

BI launches COPD drug Striverdi in UK and Ireland

Medical uses

Olodaterol is a once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema, and is administered in an inhaler called Respimat Soft Mist Inhaler.^[2]^[3]^[4]^[5]^[6]^[7]

As of December 2013, olodaterol is not approved for the treatment of asthma. Olodaterol monotherapy was previously evaluated in four Phase 2 studies in asthma patients. However, currently there are no Phase 3 studies planned for olodaterol monotherapy in patients with asthma.

In late January 2013, Olodaterol CAS# 868049-49-4 was the focus of an FDA committee reviewing data for the drug’s approval as a once-daily maintenance bronchodilator to treat chronic obstructive pulmonary disease (COPD), as well as chronic bronchitis and emphysema. The FDA Pulmonary-Allergy Drugs Advisory Committee recommended that the clinical data from the Boehringer Ingelheim Phase III studies be included in their NDA.

Also known as the trade name Striverdi Respimat, Olodaterol is efficacious as a long-acting beta-agonist, which patients self-administer via an easy to use metered dose inhaler. While early statistics from clinical trials of Olodaterol were encouraging, a new set of data was released earlier this week, which only further solidified the effectual and tolerable benefits of this COPD drug.

On September 10, 2013 results from two Phase 3 studies of Olodaterol revealed additional positive results from this formidable COPD treatment. The conclusion from these two 48 week studies, which included over 3,000 patients, showed sizable and significant improvements in the lung function of patients who were dosed with Olodaterol. Patients in the aforementioned studies were administered either a once a day dosage of Olodaterol via the appropriate metered-dose inhaler or “usual care”. The “usual care” included a variety of treatment options, such as inhaled corticosteroids (not Olodaterol), short and long acting anticholinergics, xanthines and beta agonists, which were short acting. The clinical trial participants who were dosed with Olodaterol displayed a rapid onset of action from this drug, oftentimes within the first five minutes after taking this medication. Additionally, patients dispensed the Olodaterol inhaler were successfully able to maintain optimum lung function for longer than a full 24 hour period. The participants who were given Olodaterol experienced such an obvious clinical improvement in their COPD symptoms, and it quickly became apparent that the “usual care” protocol was lacking in efficacy and reliability.

A staggering 24 million patients in the United States suffer from chronic obstructive pulmonary disease, and this patient population is in need of an effectual, safe and tolerable solution. Olodaterol is shaping up to be that much needed solution. Not only have the results from studies of Olodaterol been encouraging, the studies themselves have actually been forward thinking and wellness centered. Boehringer Ingelheim is the first company to included studies to evaluate exercise tolerance in patients with COPD, and compare the data to those patients who were dosed with Olodaterol. By including exercise tolerance as an important benchmark in pertinent data for Olodaterol, Boehringer Ingelheim has created a standard for COPD treatment expectations. The impaired lung function for patients with COPD contributes greatly to their inability to exercise and stay healthy. Patients who find treatments and management techniques to combat the lung hyperinflation that develops during exercise have a distinct advantage to attaining overall good health.

– See more at: http://www.lgmpharma.com/blog/olodaterol-offers-encouraging-results-patients-copd/#sthash.DOjcrGxc.dpuf

Data has demonstrated that Striverdi, a once-daily long-acting beta2 agonist, significantly improved lung function versus placebo and is comparable to improvements shown with the older LABA formoterol. The NHS price for the drug is £26.35 for a 30-day supply.

Boehringer cited Richard Russell at Wexham Park Hospital as saying that the licensing of Stirverdi will be welcomed by clinicians as it provides another option. He added that the trial results showing improvements in lung function “are particularly impressive considering the study design, which allowed participants to continue their usual treatment regimen. This reflects more closely the real-world patient population”.

Significantly, the company is also developing olodaterol in combination with Spiriva, a long-acting muscarinic antagonist. LAMA/LABA combinations provide the convenience of delivering the two major bronchodilator classes.

Olodaterol is a novel, long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. It is by this mechanism that olodaterol is used for the treatment of chronic obstructive pulmonary disease (COPD) and the progressive airflow obstruction that is characteristic of it. Treatment with bronchodilators helps to mitigate associated symptoms such as shortness of breath, cough, and sputum production. Single doses of olodaterol have been shown to improve forced expiratory volume in 1 sec (FEV1) for 24 h in patients with COPD, allowing once daily dosing. A once-a-day treatment with a LABA has several advantages over short-acting bronchodilators and twice-daily LABAs including improved convenience and compliance and improved airflow over a 24-hour period. Despite similarities in symptoms, olodaterol is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Adverse effects

Adverse effects generally were rare and mild in clinical studies. Most common, but still affecting no more than 1% of patients, were nasopharyngitis (running nose), dizziness and rash. To judge from the drug’s mechanism of action and from experiences with related drugs, hypertension (high blood pressure), tachycardia (fast heartbeat), hypokalaemia (low blood levels of potassium), shaking, etc., might occur in some patients, but these effects have rarely, if at all, been observed in studies.^[1]

Interactions

Based on theoretical considerations, co-application of other beta-adrenoceptor agonists, potassium lowering drugs (e. g. corticoids, many diuretics, and theophylline), tricyclic antidepressants, and monoamine oxidase inhibitors could increase the likelihood of adverse effects to occur. Beta blockers, a group of drugs for the treatment of hypertension (high blood pressure) and various conditions of the heart, could reduce the efficacy of olodaterol.^[1] Clinical data on the relevance of such interactions are very limited.

Pharmacology

Mechanism of action

Like all beta-adrenoceptor agonists, olodaterol mimics the effect of epinephrine at beta-2 receptors (β₂-receptors) in the lung, which causes the bronchi to relax and reduces their resistance to airflow.^[3]

Olodaterol is a nearly full β₂-agonist, having 88% intrinsic activity compared to the gold standard isoprenaline. Its half maximal effective concentration (EC₅₀) is 0.1 nM. It has a higher in vitro selectivity for β₂-receptors than the related drugs formoterol and salmeterol: 241-fold versus β₁- and 2299-fold versus β₃-receptors.^[2] The high β₂/β₁ selectivity may account for the apparent lack of tachycardia in clinical trials, which is mediated by β₁-receptors on the heart.

Pharmacokinetics

Once bound to a β₂-receptor, an olodaterol molecule stays there for hours – its dissociation half-life is 17.8 hours –, which allows for once-a-day application of the drug^[3] like with indacaterol. Other related compounds generally have a shorter duration of action and have to be applied twice daily (e.g. formoterol, salmeterol). Still others (e. g. salbutamol, fenoterol) have to be applied three or four times a day for continuous action, which can also be an advantage for patients who need to apply β₂-agonists only occasionally, for example in an asthma attack.^[8]

History

On 29 January 2013 the U.S. Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee (PADAC) recommended that the clinical data included in the new drug application (NDA) for olodaterol provide substantial evidence of safety and efficacy to support the approval of olodaterol as a once-daily maintenance bronchodilator treatment for airflow obstruction in patients with COPD.^[9]

On 18 October 2013 approval of olodaterol in the first three European countries – the United Kingdom, Denmark and Iceland – was announced by the manufacturer.^[10]

Figure Chemical structures of salmeterol, formoterol, inda- caterol, and emerging once-daily long-acting β2-agonists

CLIP

Synthetic approaches to the 2013 new drugs – ScienceDirect

Science Direct

Synthesis of olodaterol hydrochloride (XVI).

Image result for OLODATEROL DRUG FUTURE

Olodaterol hydrochloride was approved for long-term, once-daily maintenance treatment of chronic
obstructive pulmonary disease (COPD) in 2013 in the following countries: Canada, Russia, United
Kingdom, Denmark, and Iceland.142, 143 The drug has been recommended by a federal advisory panel for
approval by the FDA.142, 143 Developed and marketed by Boehringer Ingelheim, olodaterol is a longacting
β2-adrenergic receptor agonist with high selectivity over the β1- and β3-receptors (219- and 1622-fold, respectively).144 Upon binding to and activating the β2-adrenergic receptor in the airway, olodaterol
stimulates adenyl cyclase to synthesize cAMP, leading to the relaxation of smooth muscle cells in the
airway. Administered by inhalation using the Respimat®
Soft Mist inhaler, it delivers significant
bronchodilator effects within five minutes of the first dose and provides sustained improvement in
forced expiratory volume (FEV1) for over 24 hours.143 While several routes have been reported in the
patent and published literature,144-146 the manufacturing route for olodaterol hydrochloride disclosed in
2011 is summarized in Scheme 19 below.147
Commercial 2’,5’-dihydroxyacetophenone (122) was treated with one equivalent of benzyl bromide
and potassium carbonate in methylisobutylketone (MIBK) to give the 5’-monobenzylated product in
76% yield. Subsequent nitration occurred at the 4’-position to provide nitrophenol 123 in 87% yield.
Reduction of the nitro group followed by subjection to chloroacetyl chloride resulted in the construction
of benzoxazine 124 in 82% yield. Next, monobromination through the use of tetrabutylammonium
tribromide occurred at the acetophenone carbon to provide bromoketone 125, and this was followed by
asymmetric reduction of the ketone employing (−)-DIP chloride to afford an intermediate bromohydrin,
which underwent conversion to the corresponding epoxide 126 in situ upon treatment with aqueous
NaOH. This epoxide was efficiently formed in 85% yield and 98.3% enantiomeric excess. Epoxide
126 underwent ring-opening upon subjection to amine 127 to provide amino-alcohol 128 in in 84-90%
yield and 89.5-99.5% enantiomeric purity following salt formation with HCl. Tertiary amine 127 was
itself prepared in three steps by reaction of ketone 129 with methylmagnesium chloride, Ritter reaction
of the tertiary alcohol with acetonitrile, and hydrolysis of the resultant acetamide with ethanolic
potassium hydroxide. Hydrogenative removal of the benzyl ether within 128 followed by
recrystallization with methanolic isopropanol furnished olodaterol hydrochloride (XVI) in 63-70%
yield. Overall, the synthesis of olodaterol hydrochloride required 10 total steps (7 linear) from
commercially available acetophenone 122.

142. Gibb, A.; Yang, L. P. H. Drugs 2013, 73, 1841.
143. http://www.boehringeringelheim.com/news/news_releases/press_releases/2013/18_october_2013_olodaterol.html.

144. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine,
C.; Buettner, F. H.; Schnapp, A.; Konetzki, I. Bioorg. Med. Chem. Lett. 2010, 20, 1410.
145. Trunk, M. J. F.; Schiewe, J. US Patent 20050255050A1, 2005.
146. Lustenberger, P.; Konetzki, I.; Sieger, P. US Patent 20090137578A1, 2009.
147. Krueger, T.; Ries, U.; Schnaubelt, J.; Rall, W.; Leuter, Z. A.; Duran, A.; Soyka, R. US Patent
20110124859A1, 2011.

PATENT

WO 2004045618 or

http://www.google.com/patents/EP1562603B1?cl=en

Example

To a solution of 3.6 g 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine in 100 mL of ethanol at 70 ° C. 7.5 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one )-glyoxal added and allowed to stir for 15 minutes. Then within 30 minutes at 10 to 20 ° C. 1 g of sodium borohydride added. It is stirred for one hour, with 10 mL of acetone and stirred for another 30 minutes. The reaction mixture is diluted with 150 mL ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in 50 mL of methanol and 100 mL ethyl acetate and acidified with conc. Hydrochloric acid. After addition of 100 mL of diethyl ether, the product precipitates. The crystals are filtered, washed and recrystallized from 50 mL of ethanol. Yield: 7 g (68%; hydrochloride), mp = 232-234 ° C.

6.8 g of the above obtained benzyl compound in 125 mL of methanol with the addition of 1 g of palladium on carbon (5%) was hydrogenated at room temperature and normal pressure. The catalyst is filtered and the filtrate was freed from solvent. Recrystallization of the residue in 50 mL of acetone and a little water, a solid is obtained, which is filtered and washed.
Yield: 5.0 g (89%; hydrochloride), mp = 155-160 ° C.

The (R) – and (S)-enantiomers of Example 3 can be obtained from the racemate, for example, by chiral HPLC (for example, column: Chirobiotic T, 250 x 1.22 mm from the company Astec). As the mobile phase, methanol with 0.05% triethylamine and 0.05% acetic acid. Silica gel with a grain size of 5 microns, to which is covalently bound the glycoprotein teicoplanin can reach as column material used. Retention time (R enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9 min. The two enantiomers can be obtained by this method in the form of free bases. According to the invention of paramount importance is the R enantiomer of Example 3

PATENT

WO 2005111005

http://www.google.fm/patents/WO2005111005A1?cl=en

Scheme 1.

Scheme 1:

Example 1 6-Hydroxy-8-{(1-hydroxy-2-r2-(4-methoxy-phenyl) – 1, 1-dimethyl-ethylamino]-ethyl)-4H-benzor 41oxazin-3-one – Hvdrochlorid

a) l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone

To a solution of 81.5 g (0.34 mol) l-(5-benzyloxy-2-hydroxy-phenyl)-ethanone in 700 ml of acetic acid are added dropwise under cooling with ice bath, 18 mL of fuming nitric acid, the temperature does not exceed 20 ° C. increases. The reaction mixture is stirred for two hours at room temperature, poured onto ice water and filtered. The product is recrystallized from isopropanol, filtered off and washed with isopropanol and diisopropyl ether. Yield: 69.6 g (72%), mass spectroscopy [M + H] ⁺ = 288

b) l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone

69.5 g (242 mmol) of l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone are dissolved in 1.4 L of methanol and in the presence of 14 g of rhodium on carbon (10%) as catalyst at 3 bar room temperature and hydrogenated. Then the catalyst is filtered off and the filtrate concentrated. The residue is reacted further without additional purification. Yield: 60.0 g (96%), R _{f value} = 0.45 (silica gel, dichloromethane).

c) 8-acetyl-6-benzyloxy-4H-benzoπ .4] oxazin-3-one

To 60.0 g (233 mmol) of l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) of potassium carbonate while cooling with ice bath, 21.0 ml (258 mmol) of chloroacetyl chloride added dropwise. Then stirred overnight at room temperature and then for 6 hours under reflux. The hot reaction mixture is filtered and then concentrated to about 400 mL and treated with ice water. The precipitate is filtered off, dried and purified by chromatography on a short silica gel column (dichloromethane: methanol = 99:1). The product-containing fractions are concentrated, suspended in isopropanol, diisopropyl ether, and extracted with

Diisopropyl ether. Yield: 34.6 g (50%), mass spectroscopy [M + H] ⁺ = 298

d) 6-Benzyloxy-8-(2-chloro-acetyl)-4H-benzoFl, 4] oxazin-3-one 13.8 g (46.0 mmol) of 8-benzyloxy-6-Acetyl-4H-benzo [l, 4] oxazin -3-one and 35.3 g (101.5 mmol) of benzyltrimethylammonium dichloriodat are stirred in 250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hours at 65 ° C. After cooling to room temperature, treated with 5% aqueous sodium hydrogen sulfite solution and stirred for 30 minutes. The precipitated solid is filtered off, washed with water and diethyl ether and dried. Yield: 13.2 g (86%), mass spectroscopy [M + H] ⁺ = 330/32.

e) 6-Benzyloxy-8-((R-2-chloro-l-hydroxy-ethyl)-4H-benzori ,41-oxazin-3-one The procedure is analogous to a procedure described in the literature (Org. Lett ., 2002, 4, 4373-4376).

To 13:15 g (39.6 mmol) of 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo [l, 4] oxazin-3-one and 25.5 mg (0:04 mmol) Cρ * RhCl [(S, S) -TsDPEN] (Cp * = pentamethylcyclopentadienyl and TsDPEN = (lS, 2S)-Np-toluenesulfonyl-l ,2-diphenylethylenediamine) in 40 mL of dimethylformamide at -15 ° C and 8 mL of a mixture of formic acid and triethylamine (molar ratio = 5: 2) dropwise. It is allowed for 5 hours at this temperature, stirring, then 25 mg of catalyst and stirred overnight at -15 ° C. The reaction mixture is mixed with ice water and filtered. The filter residue is dissolved in dichloromethane, dried with sodium sulfate and the solvent evaporated. The residue is recrystallized gel (dichloromethane / methanol gradient) and the product in diethyl ether / diisopropyl ether. Yield: 10.08 g (76%), R _f value = 00:28 (on silica gel, dichloromethane ethanol = 50:1).

f) 6-Benzyloxy-8-(R-oxiranyl-4H-benzo ^[“L4] oxazin-3-one 6.10 g (30.1 mmol) of 6-benzyloxy-8-((R)-2-chloro-l-hydroxy- ethyl)-4H-benzo [l, 4] oxazin-3-one are dissolved in 200 mL of dimethylformamide. added to the solution at 0 ° C with 40 mL of a 2 molar sodium hydroxide solution and stirred at this temperature for 4 hours. the reaction mixture is poured onto ice water, stirred for 15 minutes, and then filtered The solid is washed with water and dried to give 8.60 g (96%), mass spectroscopy [M + H] ⁺ = 298..

g) 6-Benyloxy-8-{(R-l-hydroxy-2-r2-(4-methoxy-phenyl)-dimethyl-ll-ethvIaminol-ethyl)-4H-benzo-3-Tl A1oxazin

5.25 g (17.7 mmol) of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo [l, 4] oxazin-3-one and 6.30 g (35.1 mmol) of 2 – (4-methoxy-phenyl 1, 1 – dimethyl-ethyl to be with 21 mL

Of isopropanol and stirred at 135 ° C for 30 minutes under microwave irradiation in a sealed reaction vessel. The solvent is distilled off and the residue chromatographed (alumina, ethyl acetate / methanol gradient). The product thus obtained is purified by recrystallization from a mixture further Diethylether/Diisopropylether-. Yield: 5:33 g (63%), mass spectroscopy [M + H] ⁺ = 477 h) 6-Hydroxy-8-{(R)-l-hydroxy-2-[2 – (4-methoxy-phenyl)-l, l-dimethyl-ethylamino] – ethyl}-4H-benzo [1, 4, 1 oxazin-3-one hydrochloride

A suspension of 5:33 g (11.2 mmol) of 6-Benyloxy-8-{(R)-l-hydroxy-2-[2 – (4-methoxy-phenyl)-l, l-dimethyl-ethylamino]-ethyl}-4H -benzo [l, 4] oxazin-3-one in 120 mL of methanol with 0.8 g of palladium on carbon (10%), heated to 50 ° C and hydrogenated at 3 bar hydrogen pressure. Then the catalyst is filtered off and the filtrate concentrated. The residue is dissolved in 20 mL of isopropanol, and 2.5 mL of 5 molar hydrochloric acid in isopropanol. The product is precipitated with 200 mL of diethyl ether, filtered off and dried. Yield: 4.50 g (95%, hydrochloride), mass spectroscopy [M + H] ⁺ = 387

PATENT

WO 2007020227

http://www.google.com.ar/patents/WO2007020227A1?cl=en

PATENT

WO 2008090193

http://www.google.com/patents/EP2125759B1?cl=en

PAPER

Discovery of olodaterol, a novel inhaled beta(2)-adrenoceptor agonist with a 24h bronchodilatory efficacy
Bioorg Med Chem Lett 2010, 20(4): 1410

http://www.sciencedirect.com/science/article/pii/S0960894X09018101

The discovery of the β₂-adrenoceptor agonist (R)-4p designated olodaterol is described. The preclinical profile of the compound suggests a bronchoprotective effect over 24 h in humans.

CLIP

Australia

http://www.tga.gov.au/pdf/auspar/auspar-olodaterol-140327-pi.pdf

CLIP

DUTCH

http://mri.medagencies.org/download/NL_H_2498_001_PAR.pdf

FDA

Click to access 203108Orig1s000ChemR.pdf

NDA 203108
Striverdi® Respimat® (olodaterol) Inhalation Spray
Boehringer Ingelheim Pharmaceuticals, Inc.

References

Striverdi UK Drug Information
Bouyssou, T.; Casarosa, P.; Naline, E.; Pestel, S.; Konetzki, I.; Devillier, P.; Schnapp, A. (2010). “Pharmacological Characterization of Olodaterol, a Novel Inhaled 2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models”. Journal of Pharmacology and Experimental Therapeutics 334 (1): 53–62. doi:10.1124/jpet.110.167007. PMID 20371707. edit
Casarosa, P.; Kollak, I.; Kiechle, T.; Ostermann, A.; Schnapp, A.; Kiesling, R.; Pieper, M.; Sieger, P.; Gantner, F. (2011). “Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol”. Journal of Pharmacology and Experimental Therapeutics 337 (3): 600–609. doi:10.1124/jpet.111.179259. PMID 21357659. edit
Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine, C.; Büttner, F. H.; Schnapp, A.; Konetzki, I. (2010). “Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy”. Bioorganic & Medicinal Chemistry Letters 20 (4): 1410–1414. doi:10.1016/j.bmcl.2009.12.087. PMID 20096576. edit
Joos G, Aumann JL, Coeck C, et al. ATS 2012 Abstract: Comparison of 24-Hour FEV1 Profile for Once-Daily versus Twice-Daily Treatment with Olodaterol, A Novel Long-Acting ß2-Agonist, in Patients with COPD^{[dead link]}
Van Noord, J. A.; Smeets, J. J.; Drenth, B. M.; Rascher, J.; Pivovarova, A.; Hamilton, A. L.; Cornelissen, P. J. G. (2011). “24-hour Bronchodilation following a single dose of the novel β2-agonist olodaterol in COPD”. Pulmonary Pharmacology & Therapeutics 24 (6): 666–672. doi:10.1016/j.pupt.2011.07.006. PMID 21839850. edit
van Noord JA, Korducki L, Hamilton AL and Koker P. Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß2-Agonist, is Effective in COPD Patients. Am. J. Respir. Crit. Care Med. 2009; 179: A6183^{[dead link]}
Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
Hollis A (31 January 2013). “Panel Overwhelmingly Supports Boehringer COPD Drug Striverdi”. FDA News/Drug Industry Daily.
“New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries”. Boehringer-Ingelheim. 18 October 2013.

External links

Striverdi package leaflet (UK)

The active moiety olodaterol is a selective beta₂-adrenergic bronchodilator. The drug substance, olodaterol hydrochloride, is chemically described as 2H-1,4- Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]-amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C₂₁H₂₆N₂O₅ x HCl as a hydrochloride. The conversion factor from salt to free base is 1.094.

The structural formula is:

STRIVERDI® RESPIMAT® (olodaterol) Structural Formula Illustration

The drug product, STRIVERDI RESPIMAT, is composed of a sterile, aqueous solution of olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STRIVERDI RESPIMAT cartridge) for use with the STRIVERDI RESPIMAT inhaler.

Excipients include water for injection, benzalkonium chloride, edetate disodium, and anhydrous citric acid. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler. The STRIVERDI RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The STRIVERDI RESPIMAT inhaler has a yellow-colored cap.

When used with the STRIVERDI RESPIMAT inhaler, each cartridge containing a minimum of 4 grams of a sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each dose (1 dose equals 2 actuations) from the STRIVERDI RESPIMAT inhaler delivers 5 mcg olodaterol in 22.1 mcL of solution from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).

WO2002030928A1	28 Sep 2001	11 Apr 2003	Boehringer Ingelheim Pharma	Crystalline monohydrate, method for producing the same and the use thereof in the production of a medicament
WO2003000265A1	8 Jun 2002	3 Jan 2003	Boehringer Ingelheim Pharma	Crystalline anticholinergic, method for its production, and use thereof in the production of a drug
WO2004045618A2 *	11 Nov 2003	3 Jun 2004	Boehringer Ingelheim Pharma	Novel medicaments for the treatment of chronic obstructive pulmonary diseases
EP0073505A1 *	28 Aug 1982	9 Mar 1983	Boehringer Ingelheim Kg	Benzo-heterocycles
EP0321864A2 *	15 Dec 1988	28 Jun 1989	Boehringer Ingelheim Kg	Ammonium compounds, their preparation and use
US4460581	12 Oct 1982	17 Jul 1984	Boehringer Ingelheim Kg	Antispasmodic agents, antiallergens
US4656168 *	13 Oct 1983	7 Apr 1987	Merck & Co., Inc.	Vision defects; adrenergic blocking and hypotensive agents

Organic spectroscopy should be brushed up and you get confidence

read my blog

ORGANIC SPECTROSCOPY INTERNATIONAL is the blog

Organic chemists from Industry and academics to interact on Spectroscopy techniques for Organic compounds ie NMR, MASS, IR, UV Etc. email me ……….. amcrasto@gmail.com

http://orgspectroscopyint.blogspot.in/ is the link

feder-0005.gif from 123gifs.eu amcrasto@gmail.com

BMS 587101…….The LFA-1 receptor antagonist in preclinical for the treatment of a variety of autoimmune and inflammatory diseases such as rheumatoid arthritis and psoriasis.

July 3, 2014 4:38 am / Leave a comment

C₂₆H₂₀Cl₂N₄O₄S
mass: 555.432373 Da

Bristol-Myers Squibb Company

read poster

http://www.cerep.fr/cerep/users/pages/news/Publications/123.pdf

BMS-587101 acts as a leukocyte function-associated antigen-1 (LFA-1) receptor antagonist. Ref: Synfacts. 2010; 8, 0865-0865.

5-[(5s,9r)-9-(4-Cyanophenyl)-3-(3,5-Dichlorophenyl)-1-Methyl-2,4-Dioxo-1,3,7-Triazaspiro [4.4]non-7-Yl]methyl]-3-Thiophenecarboxylicacid

5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-ylmethyl]-thiophene-3-carboxylic Acid

3-Thiophenecarboxylic acid, 5-[[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl]- [ACD/Index Name]

5-{[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl}-3-thiophenecarboxylic acid [ACD/IUPAC Name]

5-{[(5S,9R)-9-(4-Cyanphenyl)-3-(3,5-dichlorphenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl}-3-thiophencarbonsäure [German] [ACD/IUPAC Name]

Acide 5-{[(5S,9R)-9-(4-cyanophényl)-3-(3,5-dichlorophényl)-1-méthyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]méthyl}-3-thiophènecarboxylique [French] [ACD/IUPAC Name]

2IC

BMS-587101

BMS-688521

data

MS (ESI)m/z553 (M-H)-;

1H NMR(500 MHz, DMSO-d6)δ

8.17 (1 H, s), 7.62 (2 H, d,J=8.07 Hz), 7.44 (1 H, s), 7.27 (3 H, m), 6.64 (2 H, s),

4.11 (1 H, d,J=13.45 Hz), 3.96 (1 H, d,J=14.12 Hz), 3.88 (1 H, dd,J=11.76, 5.71 Hz), 3.43 (2 H, br. s.),

3.27 (1 H, br. s.), 3.23 (3 H, s), 3.06 (1 H, d,J=10.08 Hz);

Anal.(C26H20Cl2N4O4S)Calcd.: C,56.22; H,3.63;Cl, 12.77; N,10.09; S,5.77;.

Found: C,55.95; H,3.59;Cl, 12.54; N,10.01; S,5.79;

ee =99.26±0.00 % [Chiralcel OJ-R, 150 x 4.6 mm, 5 um particle size, MeOH: CH3CN: 0.2% aq.H3PO4 (30:30:40)];

[α]D=-6.324 (c = 8.967 mg/mL, CHCl3);

ChemSpider 2D Image | 5-{[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]methyl}-3-thiophenecarboxylic acid | C26H20Cl2N4O4S

Interaction between leukocyte function-associated antigen-1 (LFA-1), expressed on the surface of cytokine-stimulated cells, and intercellular adhesion molecule (I-CAM), found on the surface of both leukocytes and endothelium, plays a key function in the intercellular immune response, causing T-cell adhesion and subsequent migration through the blood vessel wall to the inflamed area.(1)

Small molecules which inhibit the LFA-1/I-CAM interaction are targeted as potential drugs for the treatment of a variety of autoimmune and inflammatory diseases such as rheumatoid arthritis and psoriasis.(2, 3) The LFA-1 receptor antagonist, BMS-587101, 1,(4, 5) was selected for clinical development, and we required a synthesis that would reliably generate kilogram quantities of API. This paper details the identification and development of a synthesis which enabled the realization of this goal.

BMS-587101 inhibits the interaction between leukocyte function-associated antigen-1 (LFA-1) and the intercellular adhesion molecule (ICAM), thereby offering a potential treatment for various autoimmune and inflammatory diseases, such as rheumatoid arthritis and psoriasis. A four-step multikilogram route to BMS-587101 (22% overall yield ) from the commercial hydantoin B features an efficient dipolar cycloaddition of an azomethine ylide generated by reaction of glycine with hexamethylenetetramine (HMTA).

Chemical structure for 2ica

………….

paper

http://pubs.acs.org/doi/abs/10.1021/op9003168

Org. Process Res. Dev., 2010, 14 (3), pp 553–561

DOI: 10.1021/op9003168

The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

Preparation of 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-ylmethyl]-thiophene-3-carboxylic Acid (1) Directly from 6

To a solution of 6 (46.9 kg, 77.6 mol) and 1,2-propanediol (11.8 kg) in tetrahydrofuran (41.7 kg) and water (266.8 kg) was added cold (0−10 °C) potassium hydroxide solution (1 N, 244.5 kg) at 8−12 °C in 0.5 h. The resulting biphasic mixture was stirred at 8−12 °C for 18−24 h until the reaction was complete (<1% 6 remaining as monitored by HPLC). The reaction mixture was washed with n-heptane (385.7 kg). The pH was adjusted to 7.5 with addition of 1.5 M citric acid (22.9 kg). Isopropyl acetate (817.8 kg) was charged, and 1.5 M citric acid_(aq) (

22.9 kg) was added until a pH of 6.5 was attained. After agitating for 15 min and holding for 30 min, the aqueous layer was discarded, and the organic layer was washed with H₂O (470 kg). The solution was then polish filtered, and isopropylacetate (52.2 kg) was used to rinse the polish filter assembly. The solution was concentrated under reduced pressure (240 Torr) to a volume of 718 L at <45 °C. Seeds (500 g) were charged, and the distillation was continued until a volume of

207 L was attained. Heptane (117.8 kg) was charged, the slurry was cooled to 20 °C over 1.5 h and was subsequently wet milled until d₉₀ < 60 μm. The slurry was held for >2 h and filtered. The cake was washed with a 1:1 isopropyl acetate/heptane solution (109.7 kg) isopropyl acetate and dried in vacuum at 35−40 °C to a constant weight. Acid 1 (39.6 kg, 91.5% yield and 99.33 HPLC area % purity) was obtained as a white and sandy crystalline solid.

…………………………

U.S. Patent 7,381,737 B2

http://www.google.com/patents/US7381737

IIIn:

Also provided are crystalline forms of solvates and salts of the substituted spiro-hydantoin compound (IIIn).

5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid.

EXAMPLES

The following examples illustrate embodiments of the inventive process, and are not intended to limit the scope of the claims. For ease of reference, the following abbreviations are used herein:

ABBREVIATIONS

DMSO=dimethyl sulfoxide
DTTA=(+)-Di-p-toluoyl-D-tartaric acid

Preparation 13-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione

Triethylamine (0.78 kg, 7.75 mol) was added in 15-30 minutes with stirring to a thin suspension of sarcosine ethylene hydrochloride (1.00 kg, 6.51 mol) in dichloromethane (6.00 L). After stirring at room temperature for 1.5-2.0 hours, the mixture was filtered to remove the resulting triethylamine hydrochloride salt. The salt cake was washed with dichloromethane (2.00 L). The filtrate was cooled to 0-5° C.

A solution of 3,5-dichlorophenyl isocyanate (1.47 kg, 7.81 mol) in dichloromethane was prepared at 20-25° C. The solution was added to the above cooled filtrate slowly in 30-60 minutes. The temperature was maintained below 10° C. during the addition. After the addition, the mixture was stirred at 20-25° C. for 12-14 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (16.00 L) was added in one portion. The resulting suspension was stirred at 20-25° C. for 2-3 hours and was then filtered. The filter cake was washed with TBME (4.50 L) and dried at maximum 40° C. to a constant weight. A suspension of the above filter cake in water (17.0 L, 10 L/kg input) was prepared and stirred at 20-25° C. for at least 16 hours. The suspension was filtered and the filter cake was washed with water (3×1.36 L) and dried at maximum 40° C. to a constant weight to a constant weight. 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.52 kg, 90%) was obtained as a white crystalline solid. mp=202-204° C. ¹H NMR (DMSO-d₆): 7.66 (1H, m), 7.51 (2H, m), 4.10 (2H, s), 3.35 (3H, s). ¹³C NMR (DMSO-d₆): 8 Carbons (169.30, 155.00, 134.98, 134.15, 127.59, 125.30, 51.75, 29.79). Anal. Calcd for C₁₀H₈Cl₂N₂O₂: C, 46.35; H, 3.11; N, 10.81; Cl, 27.36. Found: C, 46.43; H, 2.9; N, 10.73; Cl, 27.33.

Preparation 2(E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile

A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol) and pyrrolidone (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20-24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5-10 minutes. The suspension was cooled to 20-25° C. in 3-4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239-241° C. ¹H NMR (DMSO-d₆): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). ¹³C NMR (DMSO-d₆): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C₁₈H₁₁Cl₂N₃O₂: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.

Example 14-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt

A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.00 kg, 2.69 mol), glycine (0.50 kg, 6.72 mol) and hexamethylenetetramine (0.28 kg, 2.02 mol) in 1-methyl-2-pyrrolidinone (5.00 L) and toluene (2.50 L) was heated at 140° C. for 7-8 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, the mixture was cooled to 40-50° C. and filtered. The filtered solid was washed with toluene (0.67 L). To the filtrate was added HCl (1M, 13.33 L, 13.33 mol). The resulting biphasic mixture was heated to 50-60° C. and was stirred for 10-15 minutes. The aqueous phase was separated and the organic phase was washed with HCl (1M, 1.67 L, 1.67 mol) at 60-80° C. The aqueous phases were combined and were stirred at 80° C. for 2 hours. The solution was cooled slowly in 3-4 hours to 20-25° C. with gentle stirring and seeding. Crystallization occurred and the resulting suspension was put aside at 20-25° C. for at least 16 hours with occasional stirring, cooled to 0-5° C. in 2 hours, stirred gently at 0-5° C. for 2 hours and then filtered. The filter cake was washed with ice water (2×2.50 L) and dried at maximum 40° C. to a constant weight. 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt (1.09 kg, 90%) was obtained as beige crystalline solid. mp=183-185° C. ¹H NMR (DMSO-d₆): 7.87(2H, d, J=8.1 Hz), 7.61 (1H, m), 7.40 (2H, d, J=8.1 Hz), 6.68 (2H, m), 4.17 (1H, m), 3.85 (2H, m), 3.76 (2H, m), 3.43 (3H, s), 3.24(2H, s). ¹³C NMR (DMSO-d₆): 14 Carbons (170.84, 152.92, 137.35, 133.94, 132.87, 132.35, 128.01, 124.50, 118.12, 111.30, 71.42, 46.57, 45.11, 25.51). Anal. Calcd for C₂₀H₁₇Cl₃N₄O₂+1.3 H₂O: C, 50.51; H, 3.91; N, 11.79; Cl, 22.39. Found: C, 50.56; H, 3.86; N, 11.58; Cl, 21.98; KF, 5.12.

Example 2a4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt

To a suspension of 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt (1.00 kg, 2.21 mol) in dichloromethane (10.67 L) was added diispopropylethylamine (0.29 kg, 2.21 mol). The mixture was stirred to a clear solution, to which (+)-Di-p-toluoyl-D-tartaric acid (0.21 kg, 0.55 mol) was added. The resulting solution was warmed to 34-36° C. and seeded immediately. It was cooled to 20-25° C. in 1.5-2.0 hours. Crystallization occurred during cooling. TBME (2.75 L) was added in 0.5 hours. The suspension was stirred at 20-25° C. for 16 hours and then filtered. The filter cake was washed with dichloromethane/TBME (2/1, 1.00 L), TBME (1 L) and dried at maximum 35° C. to a constant weight. 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (0.47 kg, 35%) was obtained as a white crystalline solid. mp=175-177° C. ¹H NMR (DMSO-d₆): 7.86 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz), 7.61 (1H, m), 7.28 (2H, d, J=8.1 Hz), 7.22 (2H, 8.5 Hz), 6.68 (2H, m), 5.71 (1H, s), 3.81(1H, m), 3.50 (4H, m), 3.06 (3H, s), 2.34 (3H, s). ¹³C NMR (DMSO-d₆): 24 Carbons (171.45, 169.40, 165.04, 152.88, 143.61, 138.99, 133.88, 133.08, 132.16, 129.26, 129.20, 128.76, 127.84, 126.99, 124.51, 118.25, 110.78, 72.81, 73.38, 48.15, 47.51, 46.30, 24.90, 21.14). Anal. Calcd for C₃₀H₂₅Cl₂N₄O₆+0.5 H₂O: C, 58.40; H, 4.17; N, 9.08; Cl, 11.49. Found C, 58.58; H, 4.06; N, 8.94; Cl, 11.38; KF, 1.59.

Example 2b4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt

A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (10.0 g, 26.9 mmol), glycine (5.06 g, 67.4 mmol), hexamethylenetetramine (2.82 g, 20.1 mmol) in 50 mL N-methylpyrrolidinone and 25 mL of toluene under nitrogen was heated to 138° C. for approximately 12 h. Next, 25 mL toluene and 25 mL H₂O were added. The aqueous and nonaqueous layers were split, and the aqueous layer was washed with 25 mL of toluene, and the nonaqueous layers were combined to form a nonaqueous mixture. The nonaqueous mixture was heated to 45-50° C. and ethylene diamine (7.0 mL) was added. The nonaqueous mixture was stirred for 3 hours and then cooled to room temperature. Next, 50 mL H₂O was added, followed by the addition of 10 mL brine. The next addition was 25 mL toluene, which was followed by the addition of 125 mL CH₂Cl₂. The bottom layer of the mixture was removed through a filter. Next, (+)-Di-p-toluoyl-D-tartaric acid (2.59 g, 6.7 mmol) was added and the mixture was stirred for 18 h to form a slurry. Slowly 40 mL of MTBE was added to the slurry. A wash solution containing 7 mL of MTBE and 11 mL of CH₂Cl₂was prepared. Filter paper was wetted with 1 mL of the wash solution. The slurry was filtered and then the filtered to form a cake. The filter, the wash reaction flask, and the cake were washed with the remaining 16 mL of the wash solution. Next, the cake was washed with 10 mL MTBE. 4-[(5S, 9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (4.0 g, 20% yield) was obtained as a white solid (98.7% HPLC AP and 98.3% ee).

Example 2c4-[(5S,9R)-3-3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]non-9-yl]-benzonitrile semi (+)-DTTA salt

A mixture of (E)-4-((1-(3,5)-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (40.0 g, 107.5 mmol), glycine (19.76 g, 263.2 mmol), hexamethylenetetramine (9.07 g, 64.7 mmol) in 200 mL N-methyl-2-pyrrolidinone and 100 mL of toluene was heated under nitrogen to 143° C. for approximately 5.5 h. Next, the mixture was cooled to 50° C. and a solution of 25 mL of ethylenediamine in 200 mL of tetrahydrofuran was added. The mixture was maintained at a temperature of 50° C. for 30 minutes and then was cooled to room temperature. Next, 520 mL of 20 wt % NaCl aqueous solution was added. The aqueous and nonaqueous layers were separated. The nonaqueous layer was transferred to a vacuum distillation apparatus and solvent was distilled off until the temperature of the residue in the flask reached 58° C. at a pressure of 60 torr. Next, 360 mL of methylene chloride was added, followed by the additions of 20 mL of methanol and 2 mL of water. The next addition was (+)-Di-p-toluoyl-D-tartaric acid (10.38 g, 26.9 mmol), followed by 120 mL of methylene chloride and 0.200 g of seeds of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]non-9-yl]-benzonitrile semi (+)-DTTA salt. A-slurry was formed and was stirred at room temperature for 24 hours. The slurry was filtered and the cake of crystals was washed with 200 mL of methylene chloride in two portions. The washed cake was then dried at 50° C. under vacuum for 24 hours. A total amount of 20.11 g (yield 31%) of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4,4]non-9-yl]-benzonitrile semi (+)-DTTA salt, which was of greater than 99.5% area percent purity, 98.4% potency and 99.2% ee was obtained after drying.

Example 35-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt

To a suspension of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (7.50 kg, 12.30 mmol) and methyl 5-formylthiophene-3-carboxylate (2.2 kg, 13.10 mol) was added triethylamine (2.08 kg, 20.60 mol) at 20-25° C. The mixture was stirred to a clear solution, to which acetic acid (1.24 kg, 20.60 mol) was added. The resulting mixture was stirred at 20-25° C. for 1 hour and then cooled to 15° C. Solid sodium triacetoxyborohydride (1.31 kg, 6.17 mol) was added and the reaction mixture was stirred for 0.5 hours. The addition of sodium triacetoxyborohydride was repeated three more times. At the end, a total of 5.22 kg (24.7 mol) sodium triacetoxyborohydride was added in 2 hours. The reaction mixture was stirred at 20-25° C. for 16 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, TBME (48.1 L) was added to the resulting jelly reaction mixture. The mixture was washed with saturated sodium hydrogen carbonate solution (60.0 L×3). The combined aqueous phase was extracted with TBME (48.1 L). All organic layers were combined, washed with brine (48.1 L) and concentrated in vacuum to a volume of 10.6 L. Isopropanol (192.3 L) was added to the residue and the resulting oil precipitates were dissolved upon warming up to 70-75° C. The solvent volume was reduced to 160.0 L by distillation at 70-75° C. Concentrated HCl (1.5 L) was added at 75° C. in 10 minutes followed by the addition of seed crystals. Crystallization occurred upon cooling to 20-25° C. in 16 hours. The mixture was filtered. The cake was washed with isopropanol (9.6 L×2) and dried at maximum 40° C. to a constant weight. 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt (6.57 kg, 88.0%) was obtained as white crystalline solid. mp=204-207° C. ¹H NMR (CDCl₃): 14.22 (1H, b), 8.18 (1H, d, J=0.9 Hz), 7.86 (1H, m), 7.67 (2H, d, J=8.1 Hz), 7.24 (1H, m), 7.23 (2H, d, J=8.1 Hz), 6.67 (2H, m), 4.76 (2H, m), 4.46 (1H, m), 4.16 (1H, m), 4.02 (2H, m), 3.86 (3H, s), 3.75 (1H, m), 3.38 (3H, s). ¹³C NMR (CDCl₃): 18 Carbons (171.24, 162.32, 152.98, 136.05, 135.27, 134.03, 132.83, 131.94, 130.46, 128.85, 128.56, 123.92, 117.52, 113.43, 71.13, 52.43, 52.22, 46.73). Anal. Calcd for C₂₇H₂₃Cl₃N₄O₄S: C, 53.52; H, 3.83; N, 9.25; S, 5.29; Cl, 17.55. Found: C, 53.07; H, 3.69; N, 9.08; S, 5.23; Cl, 17.20.

Example 45-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid

To a solution of 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid methyl ester hydrochloride salt (20.00 g, 33.00 mmol) and 1,2-propanediol (5.0 g) in tetrahydrofuran (200 mL) and water (100 mL) was added slowly potassium hydroxide solution (0.85M, 116 mL) at 8-12° C. in 0.5 hours. The resulting biphasic mixture was stirred at 8-12° C. for 20-27 hours until the reaction was complete. The reaction mixture was washed with n-heptane (200 mL). The pH was adjusted to 6.5 with addition of water (100 mL) and acetic acid (2.5 mL). Tetrahydrofuran was removed under reduced pressure at internal temperature <40° C. The pH was adjusted to 4.5 with addition of isopropyl acetate (400 mL) and acetic acid (11 mL). After 10 minutes of stirring, the aqueous layer was separated and was extracted with isopropylacetate (200 mL). The organic layers were combined, washed with water (100 mL) and concentrated under reduced pressure to a volume of 190 mL at bath temperature <40° C. Crystallization occurred during concentration. The crystal slurry was stirred at 20-25° C. for 16 hours and was then filtered. The cake was washed with cold isopropylacetate (15 mL×3) and dried in vacuum at 35-40° C. to a constant weight.

5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid (14.35 g, 78.3%) was obtained as white and sandy crystalline solid.

mp=209-230° C. ¹H NMR (Acetone-d₆): 8.19 (1H, d, J=1.3 Hz), 7.76 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.2 Hz), 7.43 (1H, d, J=1.0 Hz), 7.41 (1H, t, J=1.9 Hz), 6.87 (2H, d, J=1.9 Hz), 4.16 (1H, dd, J1=13.9 Hz J2=0.8 Hz), 4.10 (1H, dd, J1=11.7 Hz, J2=6.2 Hz), 3.99 (1H, d, J=14.0 Hz), 3.48(1H, d, J=10.6 Hz), 3.47 (1H, dd, J1=9.6 Hz, J2=6.2 Hz), 3.25 (3H, s), 3.24 (1H, dd, J1=9.6 Hz, J2=11.7 Hz), 3.01 (1H, d, J=11.3 Hz).

¹³C NMR (Acetone-d₆): 22 Carbons (172.69, 163.7, 153.98, 144.55, 142.23, 135.26, 135.09, 134.41, 133.89, 132.96, 130.33, 128.27, 126.98, 125.18, 119.07, 112.44, 74.28, 59.09, 56.45, 54.33, 50.73, 25.75).

Anal. Calcd for C₂₆H₂₀Cl₂N₄O₄S: C, 56.22; H, 3.62; N, 10.08; S, 5.77; Cl, 12.76. Found: C, 56.27; H, 3.20; N, 9.97; S, 5.65; Cl, 12.68.

…………………………..

paper

J. Med. Chem. 2006, 49, 6946

http://pubs.acs.org/doi/abs/10.1021/jm0610806

Abstract Image

LFA-1 (leukocyte function-associated antigen-1), is a member of the β2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

http://pubs.acs.org/doi/suppl/10.1021/jm0610806/suppl_file/jm0610806si20060913_101747.pdf synthesis as compd 8

says

a white solid: Anal.RP-HPLCtR= 3.09min (method D, purity 99%);

MS (ESI)m/z553 (M-H)-;

1H NMR(500 MHz, DMSO-d6)δ

8.17 (1 H, s), 7.62 (2 H, d,J=8.07 Hz), 7.44 (1 H, s), 7.27 (3 H, m), 6.64 (2 H, s),

4.11 (1 H, d,J=13.45 Hz), 3.96 (1 H, d,J=14.12 Hz), 3.88 (1 H, dd,J=11.76, 5.71 Hz), 3.43 (2 H, br. s.),

3.27 (1 H, br. s.), 3.23 (3 H, s), 3.06 (1 H, d,J=10.08 Hz);

Anal.(C26H20Cl2N4O4S)

Calcd.: C,56.22; H,3.63;Cl, 12.77; N,10.09; S,5.77;.

Found: C,55.95; H,3.59;Cl, 12.54; N,10.01; S,5.79;

ee =99.26±0.00 % [Chiralcel OJ-R, 150 x 4.6 mm, 5 um particle size, MeOH: CH3CN: 0.2% aq.H3PO4 (30:30:40)];

[α]D=-6.324 (c = 8.967 mg/mL, CHCl3);

………………….

U.S. Patent 7,199,125 B2

http://www.google.com/patents/US7199125

………………………..

.U.S. Patent 6,710,064 B2

http://www.google.com/patents/US6710064

………….

REFERENCES

For a discussion on the inhibition of LFA-1/ICAM-1as an approach to treating autoimmune diseases see:

Yusuf-Makagiansar, H.; Anderson, M. E.; Yakovleva, T. V.; Murray, J. S.; Siahaan, T. J. Medicinal Research Reviews 2002, 22, 146
2.

For a discussion of therapeutic options for treatment of psoriasis, see:

Gottlieb, A. B. J. Acad. Dermatol 2005, 53, S3

Larson, R. S.; Davis, T.; Bologa, C.; Semenuk, G.; Vijayan, S.; Li, Y.; Oprea, T.; Chigaev, A.; Buranda, T.; Wagner, C. R.; Sklar, L. A.
3.

For other small molecule LFA-1/ICAM-1 antagonists as potential drugs please see:

(a) Pei, Z.; Xin, Z.; Liu, G.; Li, Y.; Reilly, E. B.; Lubbers, N. L.; Huth, J. R.; Link, J. T.; von Geldern, T. W.; Cox, B. F.; Leitza, S.; Gao, Y.; Marsh, K. C.; DeVries, P.; Okasinski, G. F. J. Med. Chem. 2001, 44, 2913

(b) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries, P.; Leitza, S.; Reilly, E. B.; Olasinski, G. F.; Fesik, S. W.; von Geldern, T. W. J. Med. Chem. 2001, 44, 1202

(c) Wu, J.-P.; Emeigh, J.; Gao, D. A.; Goldberg, D. R.; Kuzmich, D.; Miao, C.; Potocki, I.; Qian, K. C.; Sorcek, R. J.; Jeanfavre, D. D.; Kishimoto, K.; Mainolfi, E. A.; Nabozny, G.; Peng, C.; Reilly, P.; Rothlein, R.; Sellati, R. H.; Woska, J. R.; Chen, S.; Gunn, J. A.; O’Brien, D.; Norris, S. H.; Kelly, T. A. J. Med. Chem. 2004, 47, 5356

(d) Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon, C. a.; Hopkins, J. L.; Jeanfavre, D. D.; Pav, S.; Qian, C.; Stevenson, J. M.; Tong, L.; Zindell, R.; Kelly, T. A. J. Am. Chem. Soc. 2001, 123, 5643

(e) Wang, G. T.; Wang, S.; Gentles, R.; Sowin, T.; Leitza, S.; Reilly, E. B.; von Geldern, T. W. Bioorg. Med. Chem. Lett. 2005, 15, 195

(f) Wattanasin, S.; Albert, R.; Ehrhardt, C.; Roche, D.; Savio, M.; Hommel, U.; Welzenbach, K.; Weitz-Schmidt, G. Bioorg. Med. Chem. Lett. 2003, 12, 499
4.

The Discovery work towards this target compound BMS-587101 is described in:

Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.; Fabreguettes, M.; Fouquet, A.; Maillet, M.; Nicolai, E.; Dorgeret, L.; Chevallier, F.; Besse, D.; Dufort, M.; Caussade, F.; Ahmad, S. Z.; Stetsko, D. K.; Skala, S.; Davis, P. M.; Balimane, P.; Patel, K.; Yang, Z.; Marathe, P.; Postelneck, J.; Townsend, R. M.; Goldfarb, V.; Sheriff, S.; Einspahr, H.; Kish, K.; Malley, M. F.; DiMarco, J. D.; Gougoutas, J. Z.; Kadiyala, P.; Cheney, D. L.; Tejwani, R. W.; Murphy, D. K.; Mcintyre, K. W.; Yang, X.; Chao, S.; Leith, L.; Xiao, Z.; Mathur, A.; Chen, B.-C.; Wu, D.-R.; Traeger, S. C.; McKinnon, M.; Barrish, J. C.; Robl, J. A.; Iwanowicz, E. J.; Suchard, S. J.; Dhar, M. T. G. J. Med. Chem. 2006, 49, 6946
5.

For additional information related to this compound see:

(a) Chen, B.-C.; DelMonte, A. J.; Dhar, T. G. M.; Fan, Y.; Gougoutas, J. Z.; Malley, M. F.; McLeod, D. D.; Waltermire, R.; Wei, C. Crystalline Forms and Process for Preparing Spiro-Hydantoin Compounds. (Bristol-Myers Squibb). U.S. Patent 7,381,737 B2 .

(b) Dhar, T. G. M.; Potin, D.; Maillet, M.; Launay, M.; Nicolai, E.; Iwanowicz, E. Spiro-cyclic compounds useful as anti-inflammatory agents. Bristol-Myers Squibb and Cerep). U.S. Patent 7,199,125 B2.

(c) Launay, M.; Potin, D.; Maillet, M.; Nicolai, E.; Dhar, T. G. M.; Iwanowicz, E. Hydantoin compounds useful as anti-inflammatory agents. (Bristol-Myers Squibb).U.S. Patent 6,710,064 B2.

For the radiolabelled synthesis of BMS-587101 see:

Tran, S. B.; Maxwell, B. D.; Chen, S.-Y.; Bonacorsi, S. J.; Leith, L.; Ogan, M.; Rinehart, J. K.; Balasubramanian, B. J. Labelled Compd. Radiopharm. 2009, 52, 236

US2008269499	10-31-2008	CRYSTALLINE FORMS AND PROCESS FOR PREPARING SPIRO-HYDANTOIN COMPOUNDS
US7381737	6-4-2008	Crystalline forms and process for preparing spiro-hydantoin compounds
US7186727	3-7-2007	Pyridyl-substituted spiro-hydantoin compounds and use thereof
US7078420	7-19-2006	Spiro-hydantoin compounds useful as anti-inflammatory agents
US2006142319	6-30-2006	Pyridyl-substituted spiro-hydantoin crystalline forms and process
US6977267	12-21-2005	Spiro-hydantoin compounds useful as anti-inflammatory agents

US8710058 *	Dec 4, 2009	Apr 29, 2014	Merck Patent Gmbh	Polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof
US20110269767 *	Dec 4, 2009	Nov 3, 2011	Merck Patent Gesellschaft Mit Beschrankter Haftung	Novel Polymorphic Forms of 3-(1–6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile Hydrochloride Salt and Processes of Manufacturing Thereof

Low levels of omega-3 fatty acids may cause memory problems

July 3, 2014 1:23 am / Leave a comment

CLINICALNEWS.ORG

09 Mar 2012

ST. PAUL, Minn. – A diet lacking in omega-3 fatty acids, nutrients commonly found in fish, may cause your brain to age faster and lose some of its memory and thinking abilities, according to a study published in the February 28, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology. Omega-3 fatty acids include the nutrients called docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

View original post 225 more words

Biomarker predicts effectiveness of brain cancer treatment

July 2, 2014 1:05 pm / 3 Comments on Biomarker predicts effectiveness of brain cancer treatment

Lyra Nara Blog

Researchers at the University of California, San Diego School of Medicine have identified a new biomarker that predicts whether glioblastoma – the most common form of primary brain cancer – will respond to chemotherapy. The findings are published in the July print issue of Oncotarget.

“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”

To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase…

View original post 163 more words

Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor…….

July 2, 2014 6:16 am / Leave a comment

AMPRENAVIR

Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.

Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available.

HIV-1 Protease dimer with Amprenavir (sticks) bound in the active site. PDB entry 3nu3 ^[1]

Systematic (IUPAC) name
(3S)-oxolan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-1-phenylbutan-2-yl]carbamate
Clinical data
Trade names	Agenerase
AHFS/Drugs.com	monograph
MedlinePlus	a699051
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	C (US)

Routes	oral
Pharmacokinetic data
Protein binding	90%
Metabolism	hepatic
Half-life	7.1-10.6 hours
Excretion	<3% renal
Identifiers
CAS number	161814-49-9
ATC code	J05AE05
PubChem	CID 65016
DrugBank	DB00701
ChemSpider	58532
UNII	5S0W860XNR
KEGG	D00894
ChEBI	CHEBI:40050
ChEMBL	CHEMBL116
NIAID ChemDB	006080
Chemical data
Formula	C₂₅H₃₅N₃O₆S
Mol. mass	505.628 g/mol

Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available

………………….

New approaches to the industrial synthesis of HIV protease inhibitors

http://pubs.rsc.org/en/content/articlelanding/2004/ob/b404071f/unauth#!divAbstract

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

Graphical abstract: New approaches to the industrial synthesis of HIV protease inhibitors

…………………………………………………………………

http://www.scielo.br/scielo.php?pid=S1984-82502010000300003&script=sci_arttext

AGENERASE (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate. Amprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C₂₅H₃₅N₃O₆S and a molecular weight of 505.64. It has the following structural formula:

AGENERASE® (amprenavir) Structural Formula Illustration

Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C.

AGENERASE Capsules (amprenavir capsules) are

available for oral administration. Each 50- mg capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene glycol 19 mg. The capsule shell contains the inactive ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 50- mg AGENERASE Capsule contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin E in the recommended daily adult dose of AGENERASE is 1,744 IU.

External links

Amprenavir bound to proteins in the PDB

RedHill Biopharma Ltd. Acquires Phase 2 Oncology Drug Upamostat MESUPRON From Wilex AG

July 1, 2014 4:00 am / Leave a comment

Upamostat

CAS: 590368-25-5

Chemical Formula: C32H47N5O6S

Exact Mass: 629.32470

Synonym: WX 671; WX-671; WX671. Upamostat; Brand name: Mesupron.

IUPAC/Chemical name:

(S)-ethyl 4-(3-(3-(N-hydroxycarbamimidoyl)phenyl)-2-(2,4,6-triisopropylphenylsulfonamido)propanoyl)piperazine-1-carboxylate

RedHill Biopharma Ltd. , an Israeli biopharmaceutical company focused on late clinical-stage drugs for inflammatory and gastrointestinal diseases, including cancer, and WILEX AG , a biopharmaceutical company focused on oncology, based in Munich, Germany, today announced that they have signed an exclusive license agreement for the oncology drug … (more)

http://www.topix.com/de/munich/2014/06/redhill-biopharma-ltd-acquires-phase-2-oncology-drug-mesupron-from-wilex-ag

Upamostat, also known as Mesupron, WX-671, is an orally bioavailable, 3-amidinophenylalanine-derived, second generation serine protease inhibitor prodrug targeting the human urokinase plasminogen activator (uPA) system with potential antineoplastic and antimetastatic activities. After oral administration, serine protease inhibitor WX-671 is converted to the active Nα-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenyla lanine-4-ethoxycarbonylpiperazide (WX-UK1), which inhibits several serine proteases, particularly uPA; inhibition of uPA may result in the inhibition of tumor growth and metastasis. uPA is a serine protease involved in degradation of the extracellular matrix and tumor cell migration and proliferation.

Information about this agent

WX-671 (Mesupron) is an orally available prodrug of WX-UK1, a serine protease inhibitor that inhibits uPA as well as other serine proteases. WX-UK1 (Setyono-Han et al., Thromb Haemost 2005) and WX-671 have shown to efficiently reduce primary tumor growth and metastasis formation in a variety of animal models. The proteolytic factor uPA and its inhibitor PAI-1 belong to those biological factors which have provided the highest level of evidence (LOE1) in terms of their prognostic and predictive significance. WX-671 is currently the only drug in Phase II aiming at this target.Results: All 95 patients were accrued between Jun 2007 and Aug 2008. Efficacy is assessed by a central reader at regular intervals based on digital CT images. By end of 2009, 2 patients were still on treatment without signs of progression, 64 patients had died. Preliminary analysis of overall survival showed an increase in overall survival from 10.2 mo (gemcitabine alone) to 13.5 mo for the combination of gemcitabine and WX-671. 1-year survival increased from 37% with gemcitabine to 53% when combined with 400 mg WX- 671. Conclusions: The combination of daily oral WX-671 in combination with weekly i.v. gemcitabine was well tolerated. see asco.com’s website.

References

1. Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes) By Kotthaus, Joscha; Steinmetzer, Torsten; van de Locht, Andreas; Clement, Bernd From Journal of Enzyme Inhibition and Medicinal Chemistry (2011), 26(1), 115-122.

2. Combined treatment of cancer by urokinase inhibition and a cytostatic anti-cancer agent for enhancing the anti-metastatic effect By Schmalix, Wolfgang; Schneider, Anneliese; Setyono-Han, Buddy; Foekens, Johannes From U.S. Pat. Appl. Publ. (2008), US 20080226624 A1 20080918.

3. Peptides and small molecules targeting the plasminogen activation system: towards prophylactic anti-metastasis drugs for breast cancer By Tyndall, Joel D. A.; Kelso, Michael J.; Clingan, Phillip; Ranson, Marie From Recent Patents on Anti-Cancer Drug Discovery (2008), 3(1), 1-13.

4. Synthesis of hydroxyamidine and hydroxyguanidine amino acid or oligopeptide derivatives for use as urokinase plasminogen activator inhibitors for the treatment of cancer and its metastasis By Sperl, Stefan; Buergle, Markus; Schmalix, Wolfgang; Wosikowski, Katja; Clement, Bernd From U.S. Pat. Appl. Publ. (2006), US 20060142305 A1 20060629.

5. Crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or its salts By Grunenberg, Alfons; Lenz, Jana From PCT Int. Appl. (2006), WO 2006056448 A1 20060601.

6. Synthesis of hydroxyamidine and hydroxyguanidine amino acid or oligopeptide derivatives for use as urokinase plasminogen activator inhibitors for the treatment of cancer and its metastasis By Sperl, Stefan; Burgle, Markus; Schmalix, Wolfgang; Wosikowski, Katja; Clement, Bernd From PCT Int. Appl. (2004), WO 2004103984 A1 20041202.

7. Preparation of 3-amidinophenylalanine derivatives from 3-cyanophenylalanines via reduction and hydrogenation under mild conditions By Ziegler, Hugo; Wikstroem, Peter From PCT Int. Appl. (2003), WO 2003072559 A1 20030904.

1. Buddy et al, Suppression of Rat Brest Cancer Metastasis and Reduction of Primary Tumor Growth by the Small Synthetic Urokinase Inhibitor WX-UK1. Thromb Haemost. 2005, 93:779-786.

2. Ertongur S, Lang S, Mack B, Wosikowski K, Muehlenweg B, Gires O. Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system. Int J Cancer. 2004, 110(6):815-24.

3. Setyono-Han B, Stürzebecher J, Schmalix WA, Muehlenweg B, Sieuwerts AM, Timmermans M, Magdolen V, Schmitt M, Klijn JG, Foekens JA. Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1. Thromb Haemost. 2005, 93(4):779-86.

FDA grants orphan drug designation to Insys Therapeutics’ pharmaceutical cannabidiol

July 1, 2014 3:48 am / Leave a comment

Systematic (IUPAC) name
2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
Clinical data
Trade names	Epidiolex
AHFS/Drugs.com	International Drug Names
Legal status	Schedule I (US)Schedule II (Can)(THC – Schedule/Level I; THC and CBD two main chemicals in cannabis)
Pharmacokinetic data
Bioavailability	13-19% (oral),^[1] 11-45% (mean 31%; inhaled)^[2]
Half-life	9 h^[1]
Identifiers
CAS number	13956-29-1
ATC code	None
PubChem	CID 644019
ChemSpider	24593618
UNII	19GBJ60SN5
Chemical data
Formula	C₂₁H₃₀O₂
Mol. mass	314.4636

Physical data
Melt. point	66 °C (151 °F)
Boiling point	180 °C (356 °F) (range: 160–180 °C)^[3]

FDA grants orphan drug designation to Insys Therapeutics’ pharmaceutical cannabidiol – Pharmaceutical Technology

US-based specialty pharmaceutical company Insys Therapeutics has obtained orphan drug designation from the US Food and Drug Administration (FDA) for its pharmaceutical cannabidiol for treatment of Lennox-Gastaut Syndrome.

Insys Therapeutics president and CEO Michael Babich said: “With no cure and persistence of seizures with current antiepileptic medications, the orphan drug designation recognises the significant, unmet need that exists among children with this severe form of epilepsy and the teams who provide their care.

“We have the unique opportunity to test a controlled pharmaceutical CBD product for Lennox-Gastaut Syndrome, and our company is committed to advancing cannabinoid therapies that have the potential to provide significant medical benefits to patients across multiple indications.

“With no cure and persistence of seizures with current antiepileptic medications, the orphan drug designation recognises the significant, unmet need that exists among children with this severe form of epilepsy and the teams who provide their care.”

“We expect to file an investigational new drug application (IND) for CBD in the second half of 2014.”

http://www.pharmaceutical-technology.com/news/newsfda-grants-orphan-drug-designation-to-insys-therapeutics-pharmaceutical-cannabidiol-4303148

Cannabidiol (CBD) is one of at least 60 active cannabinoids identified in cannabis.^[4] It is a major phytocannabinoid, accounting for up to 40% of the plant’s extract.^[5] CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol(THC).^[5] An orally-administered liquid containing CBD has received orphan drug status in the US, for use as a treatment for dravet syndrome under the brand name, Epidiolex.^[6]

Clinical applications

The bud of a Cannabis sativa flower coated with trichomes

Antimicrobial actions

CBD absorbed transcutaneously may attenuate the increased sebum production at the root of acne, according to an untested hypothesis.^[7]

Neurological effects

A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of CBD. The researchers attributed this attenuation of memory effects to CBD’s role as a CB₁ antagonist. Transdermal CBD is neuroprotective in animals.^[8]

Cannabidiol’s strong antioxidant properties have been shown to play a role in the compound’s neuroprotective and anti-ischemiceffects.^[9]

Parkinson’s disease

It has been proposed that CBD may help people with Parkinson’s disease, but promising results in animal experiments were not confirmed when CBD was trialled in humans.^[10]

Psychotropic effect

CBD has anti-psychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latentschizophrenia;^[5] some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated.^[11] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.^[11]^[12] Leweke et al. performed a double blind, 4 week, explorative controlled clinical trial to compare the effects of purified cannabidiol and the atypical antipsychoticamisulpride on improving the symptoms of schizophrenia in 42 patients with acute paranoid schizophrenia. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric Rating Scale andPositive and Negative Syndrome Scale. While there was no statistical difference between the two treatment groups, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.^[13]

Studies have shown cannabidiol decreases activity of the limbic system^[14] and decreases social isolation induced by THC.^[15] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.^[16]^[17] However, chronic cannabidiol administration in rats was recently found to produce anxiogenic-like effects, indicating that prolonged treatment with cannabidiol might incite anxiogenic effects.^[18]

Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.^[19]^[20]^[21]

Cancer

The American Cancer Society says: “There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer.”^[22] Laboratory experiments have been performed on the potential use of cannabinoids for cancer therapy but as of 2013 results have been contradictory and knowledge remains poor.^[23] Cannabinoids have been recommended for cancer pain but the adverse effects may make them a less than ideal treatment; two cannabinoid-based medicines have been approved as a backup remedy for nausea associated withchemotherapy.^[4]

Dravet syndrome

CBD-enhanced cannabis

Decades ago, selective breeding by growers in US dramatically lowered the CBD content of cannabis; their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.^[27] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.^[28]

In November 2012, Tikun Olam, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.^[29]^[30] The researchers said the cannabis plant, enriched with CBD, “can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes”. Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said “…Avidekel is thought to be the first CBD-enriched cannabis plant with no THC to have been developed in Israel”.^[31]

Pharmacology

Pharmacodynamics

Cannabidiol has a very low affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of their agonists.^[9] While one would assume that this would cause cannabidiol to reduce the effects of THC, it may potentiate THC’s effects by increasing CB₁ receptor density or through another CB₁-related mechanism.^[32] It is also an inverse agonist of CB₂receptors.^[9]^[33] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.^[34]Cannabidiol has also been shown to act as a 5-HT_1A receptor agonist,^[35] an action which is involved in its antidepressant,^[19]^[36] anxiolytic,^[36]^[37] and neuroprotective^[38]^[39]effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.^[40] Cannabidiol’s pharmacologial effects have also been attributed to PPAR-γ receptor agonism andintracellular calcium release.^[5]

Pharmacokinetic interactions

There is some preclinical evidence to suggest that cannabidiol may reduce THC clearance, modestly increasing THC’s plasma concentrations resulting in a greater amount of THC available to receptors, increasing the effect of THC in a dose-dependent manner.^[41]^[42] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.^[43]

Pharmaceutical preparations

Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC. The drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis.^[44]^[45]^[46]

Isomerism

7 double bond isomers and their 30 stereoisomers
Formal numbering			Terpenoid numbering		Number of stereoisomers	Natural occurrence	Convention on Psychotropic SubstancesSchedule	Structure
Short name	Chiral centers	Full name	Short name	Chiral centers	Number of stereoisomers	Natural occurrence	Convention on Psychotropic SubstancesSchedule	Structure
Δ⁵-cannabidiol	1 and 3	2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol	Δ⁴-cannabidiol	1 and 3	4	No	unscheduled
Δ⁴-cannabidiol	1, 3 and 6	2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol	Δ⁵-cannabidiol	1, 3 and 4	8	No	unscheduled
Δ³-cannabidiol	1 and 6	2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol	Δ⁶-cannabidiol	3 and 4	4	?	unscheduled
Δ^3,7-cannabidiol	1 and 6	2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol	Δ^1,7-cannabidiol	3 and 4	4	No	unscheduled
Δ²-cannabidiol	1 and 6	2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol	Δ¹-cannabidiol	3 and 4	4	Yes	unscheduled
Δ¹-cannabidiol	3 and 6	2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol	Δ²-cannabidiol	1 and 4	4	No	unscheduled
Δ⁶-cannabidiol	3	2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol	Δ³-cannabidiol	1	2	No	unscheduled

Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of delta-3-cannabidiol and the derived rigid analogs, Arizona University 1987.

Chemistry

Cannabidiol is insoluble in water but soluble in organic solvents, such as pentane. At room temperature it is a colorless crystalline solid.^[47] In strongly basic medium and the presence of air it is oxidized to a quinone.^[48] Under acidic conditions it cyclizes to THC.^[49] The synthesis of cannabidiol has been accomplished by several research groups.^[50]^[51]^[52]

http://pubs.rsc.org/en/content/articlelanding/2005/ob/b416943c#!divAbstract

https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1964-01-01_4_page005.html

http://pubs.rsc.org/en/content/articlelanding/2005/ob/b416943c#!divAbstract

Biosynthesis

Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the last step, where CBDA synthase performs catalysis instead of THCA synthase.^[53]

Legal status

Cannabidiol is not scheduled by the Convention on Psychotropic Substances.

Cannabidiol is a Schedule II drug in Canada.^[54]

Cannabidiol’s legal status in the United States:

The DEA Drug Schedule classifies synthetic THC (Tetrahydrocannabinol) as a schedule III substance (eg Marinol); while the natural marijuana plant is listed as Schedule I. Cannabidiol is not named specifically on the list.^[55] However the CSA does mention all natural Phytocannabinoids in Schedule 1 Code 7372, which would include CBD.^[55]

Marijuana (along with all of its cannabinoids) is defined by 21 U.S.C. §802(16), which is part of the Controlled Substances Act.^[56]^[57]^[58] There is an exemption for certain Hemp products produced abroad. Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year. Hemp finished products which meet the specific definitions including hemp oil which may contain cannabidiol are legal in the United States but aren’t used for getting high.^[59]

Some cannabidiol oil is derived from marijuana and therefore contains higher levels of THC.^[60] This type of cannabidiol oil would be considered a Schedule I as a result of the THC present.^[60]

US patent

In October 2003, U.S. patent #6630507 entitled “Cannabinoids as antioxidants and neuroprotectants” was assigned to “The United States Of America As Represented By The Department Of Health And Human Services.” The patent was filed in April 1999 and listed as the inventors: Aidan J. Hampson, Julius Axelrod, and Maurizio Grimaldi, who all held positions at the National Institute of Mental Health (NIMH) in Bethesda, MD, which is part of the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). The patent mentions cannabidiol’s ability as an antiepileptic, to lower intraocular pressure in the treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties, its ability to prevent neurotoxicity mediated by NMDA, AMPA, or kainate receptors; its ability to attenuate glutamate toxicity, its ability to protect against cellular damage, its ability to protect brains from ischemic damage, its anxiolytic effect, and its superior antioxidant activity which can be used in the prophylaxis and treatment of oxidation associated diseases.^[61]

“

“Oxidative associated diseases include, without limitation, free radical associated diseases, such as ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents (such as a thromboembolic or hemorrhagic stroke) that can lead to ischemia or an infarct in the brain, operative ischemia, traumatic hemorrhage (for example a hypovolemic stroke that can lead to CNS hypoxia or anoxia), spinal cord trauma, Down’s syndrome, Crohn’s disease, autoimmune diseases (e.g. rheumatoid arthritis or diabetes), cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellular apoptosis, radiation sickness, and others. The present invention is believed to be particularly beneficial in the treatment of oxidative associated diseases of the CNS, because of the ability of the cannabinoids to cross the blood brain barrier and exert their antioxidant effects in the brain. In particular embodiments, the pharmaceutical composition of the present invention is used for preventing, arresting, or treating neurological damage in Parkinson’s disease, Alzheimer’s disease and HIV dementia; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest or cardiac arrest, and anoxia caused by drowning, brain surgery or trauma (such as concussion or spinal cord shock).”^[61]

”

On November 17, 2011, the Federal Register published that the National Institutes of Health of the United States Department of Health and Human Services was “contemplating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507” to the company KannaLife based in New York, for the development and sale of cannabinoid and cannabidiol based therapeutics for the treatment of hepatic encephalopathy in humans.^[62]^[63]^[64]

References

Mechoulam R, Parker LA, Gallily R (November 2002). “Cannabidiol: an overview of some pharmacological aspects”. J Clin Pharmacol (Review) 42 (11 Suppl): 11S–19S.doi:10.1177/0091270002238789. PMID 12412831.
Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G (May 2009). “Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders”.Phytother Res (Review) 23 (5): 597–602. doi:10.1002/ptr.2625. PMID 18844286.
McPartland JM, Russo EB (2001). “Cannabis and cannabis extracts: greater than the sum of their parts?”. Journal of Cannabis Therapeutics 1(3/4): 103–132. doi:10.1300/J175v01n03_08.
Borgelt LM, Franson KL, Nussbaum AM, Wang GS (February 2013). “The pharmacologic and clinical effects of medical cannabis”. Pharmacotherapy (Review) 33(2): 195–209. doi:10.1002/phar.1187. PMID 23386598.
Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012). “Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders”. Philos. Trans. R. Soc. Lond., B, Biol. Sci.(Review) 367 (1607): 3364–78. doi:10.1098/rstb.2011.0389. PMC 3481531.PMID 23108553.
Wilner, AN (25 March 2014). “Marijuana for Epilepsy: Weighing the Evidence”.Medscape Neurology. WebMD. Retrieved 2 April 2014.
Russo EB (August 2011). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects”. Br. J. Pharmacol. (Review) 163 (7): 1344–64. doi:10.1111/j.1476-5381.2011.01238.x. PMC 3165946. PMID 21749363.
Liput, D. J.; Hammell, D. C.; Stinchcomb, A. L.; Nixon, K (2013). “Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder”. Pharmacology Biochemistry and Behavior 111: 120–7.doi:10.1016/j.pbb.2013.08.013. PMID 24012796. edit
Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (August 2007). “Cannabidiol–recent advances”. Chem. Biodivers. (Review) 4 (8): 1678–92.doi:10.1002/cbdv.200790147. PMID 17712814.
Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L (2009). “Cannabidiol: a promising drug for neurodegenerative disorders?”. CNS Neurosci Ther 15 (1): 65–75.doi:10.1111/j.1755-5949.2008.00065.x. PMID 19228180.
Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS (April 2006).“Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug”. Braz. J. Med. Biol. Res. (Review) 39 (4): 421–9. doi:10.1590/S0100-879X2006000400001.PMID 16612464.
Long, L. E.; Malone, D. T.; Taylor, D. A. (2005). “Cannabidiol Reverses MK-801-Induced Disruption of Prepulse Inhibition in Mice”. Neuropsychopharmacology 31 (4): 795–803. doi:10.1038/sj.npp.1300838. PMID 16052245. edit
Leweke, FM; Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M and Koethe D. (2012). “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia”. Translational Psychiatry 2 (3): e94–.doi:10.1038/tp.2012.15. PMC 3316151. PMID 22832859.
José Alexandre de Souza Crippa, Antonio Waldo Zuardi, Griselda E J Garrido, Lauro Wichert-Ana, Ricardo Guarnieri, Lucas Ferrari, Paulo M Azevedo-Marques, Jaime Eduardo Cecílio Hallak, Philip K McGuire and Geraldo Filho Busatto (October 2003). “Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow”.Neuropsychopharmacology 29 (2): 417–426. doi:10.1038/sj.npp.1300340.PMID 14583744.
Daniel Thomas Malone, Dennis Jongejana and David Alan Taylora (August 2009). “Cannabidiol reverses the reduction in social interaction produced by low dose Δ9-tetrahydrocannabinol in rats”. Pharmacology Biochemistry and Behavior 93 (2): 91–96.doi:10.1016/j.pbb.2009.04.010. PMID 19393686.
Mateus M Bergamaschi, Regina Helena Costa Queiroz, Marcos Hortes Nisihara Chagas, Danielle Chaves Gomes de Oliveira, Bruno Spinosa De Martinis, Flávio Kapczinski, João Quevedo, Rafael Roesler, Nadja Schröder, Antonio E Nardi, Rocio Martín-Santos, Jaime Eduardo Cecílio (May 2011). “Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients”.Neuropsychopharmacology 36 (6): 1219–1226. doi:10.1038/npp.2011.6.PMC 3079847. PMID 21307846.
Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK, Zuardi AW, Busatto GF, Hallak JE. (January 2011). “Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report”. J Psychopharmacol. 25 (1): 121–130.doi:10.1177/0269881110379283. PMID 20829306.
ElBatsh, MM; Assareh, N; Marsden, CA; Kendall, DA (May 2012). “Anxiogenic-like effects of chronic cannabidiol administration in rats”. Psychopharmacology 221 (2): 239–247. doi:10.1007/s00213-011-2566-z. PMID 22083592.
Zanelati, T; Biojone, C; Moreira, F; Guimarães, F; Joca, S (January 2010).“Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors”. British Journal of Pharmacology 159 (1): 122–8. doi:10.1111/j.1476-5381.2009.00521.x. PMC 2823358. PMID 20002102.
Réus, GZ; Stringari, RB; Ribeiro, KF; Luft, T; Abelaira, HM; Fries, GR; Aguiar, BW; Kapczinski, F; Hallak, JE; Zuardi, AW; Crippa JA; Quevedo, J (October 2011). “Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala”. Acta Neuropsychiatrica 23 (5): 241–248. doi:10.1111/j.1601-5215.2011.00579.x.
El-Alfy, AT; Ivey, K; Robinson, K; Ahmed, S; Radwan, M; Slade, D; Khan, I; ElSohly, M; Ross, S (June 2010). “Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”. Pharmacology Biochemistry and Behavior 95 (4): 434–442. doi:10.1016/j.pbb.2010.03.004. PMC 2866040.PMID 20332000.
Young, Saundra (15 Jan 2014), 3-year-old is focus of medical marijuana battle, CNN, retrieved 2014-01-16
Cridge BJ, Rosengren RJ (2013). “Critical appraisal of the potential use of cannabinoids in cancer management”. Cancer Manag Res 5: 301–13.doi:10.2147/CMAR.S36105. PMC 3770515. PMID 24039449.
http://www.dravetfoundation.org/dravet-syndrome/what-is-dravet-syndrome#sthash.jAC0bZ89.dpuf What is Dravet Syndrome?
Melville, Nancy A. (14 Aug 2013), Seizure Disorders Enter Medical Marijuana Debate, Medscape Medical News, retrieved 2014-01-14
Gloss D, Vickrey B (13 June 2012). “Cannabinoids for epilepsy”. Cochrane Database Syst Rev (Review) 6: CD009270. doi:10.1002/14651858.CD009270.pub2.PMID 22696383.
Romney, Lee (13 September 2012). “On the frontier of medical pot to treat boy’s epilepsy”. Los Angeles Times.
Jump up^ Good, Alastair (26 October 2010). “Growing marijuana that won’t get you high”. The Daily Telegraph (London).
Jump up^ Sidner, Sara (8 November 2012). Medical marijuana without the high (video). CNN. “An Israeli company has cultivated a new type of medical marijuana.”
Jump up^ Solon, Olivia (5 July 2012). “Medical Marijuana Without the High”. Wired.com
Jump up^ Lubell, Maayan (3 July 2012). “What a drag, Israeli firm grows ‘highless’ marijuana”.Reuters. Retrieved 31 Jan 2014.
Jump up^ Hayakawa, K.; Mishima, K.; Hazekawa, M.; Sano, K.; Irie, K.; Orito, K.; Egawa, T.; Kitamura, Y.; Uchida, N.; Nishimura, R.; Egashira, N.; Iwasaki, K.; Fujiwara, M. (2008). “Cannabidiol potentiates pharmacological effects of Δ9-tetrahydrocannabinol via CB1 receptor-dependent mechanism”. Brain Research 1188: 157–164.doi:10.1016/j.brainres.2007.09.090. PMID 18021759. edit
Jump up^ Pertwee, R. G. (2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin”.British Journal of Pharmacology 153 (2): 199–215. doi:10.1038/sj.bjp.0707442.PMC 2219532. PMID 17828291. edit
Jump up^ Ryberg E, Larsson N, Sjögren S, et al. (2007). “The orphan receptor GPR55 is a novel cannabinoid receptor”. British Journal of Pharmacology 152 (7): 1092–101.doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302.
Jump up^ Russo EB, Burnett A, Hall B, Parker KK (August 2005). “Agonistic properties of cannabidiol at 5-HT1a receptors”. Neurochemical Research 30 (8): 1037–43.doi:10.1007/s11064-005-6978-1. PMID 16258853.
^ Jump up to:^a ^b Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (January 2009). “5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats”. British Journal of Pharmacology 156 (1): 181–8. doi:10.1111/j.1476-5381.2008.00046.x.PMC 2697769. PMID 19133999.
Jump up^ Campos AC, Guimarães FS (August 2008). “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x.PMID 18446323.
Jump up^ Mishima K, Hayakawa K, Abe K, et al. (May 2005). “Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism”.Stroke; a Journal of Cerebral Circulation 36 (5): 1077–82.doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890.
Jump up^ Hayakawa K, Mishima K, Nozako M, et al. (March 2007). “Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance”. Neuropharmacology 52 (4): 1079–87.doi:10.1016/j.neuropharm.2006.11.005. PMID 17320118.
Jump up^ Kathmann, Markus; Flau, Karsten; Redmer, Agnes; Tränkle, Christian; Schlicker, Eberhard (2006). “Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors”. Naunyn-Schmiedeberg’s Archives of Pharmacology 372 (5): 354–361.doi:10.1007/s00210-006-0033-x. PMID 16489449.
Jump up^ Bornheim, LM; Kim, KY; Li, J; Perotti, BY; Benet, LZ (August 1995). “Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain”. Drug Metabolism and Disposition 23 (8): 825–831. PMID 7493549.
Jump up^ Klein, C; Karanges, E; Spiro, A; Wong, A; Spencer, J; Huynh, T; Gunasekaran, N; Karl, T; Long, LE; Huang, XF; Liu, K; Arnold, JC; McGregor, IS (November 2011). “Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats”.Psychopharmacology 218 (2): 443–457. doi:10.1007/s00213-011-2342-0.PMID 21667074.
Jump up^ Hunt, CA; Jones, RT; Herning, RI; Bachman, J (June 1981). “Evidence that Cannabidiol Does Not Significantly Alter the Pharmacokinetics of Tetrahydrocannabinol in Man”.Journal of Pharmacokinetics and Biopharmaceutics 9 (3): 245–260.doi:10.1007/BF01059266. PMID 6270295.
Jump up^ United States Adopted Names Council: Statement on a nonproprietary name
Jump up^ “Fact Sheet – Sativex”. Health Canada. Retrieved 16 May 2013.
Jump up^ GWPharma- Welcome
Jones PG, Falvello L, Kennard O, Sheldrick GM Mechoulam R (1977). “Cannabidiol”.Acta Cryst. B33 (10): 3211–3214. doi:10.1107/S0567740877010577.
Mechoulam R, Ben-Zvi Z (1968). “Hashish—XIII On the nature of the beam test”.Tetrahedron 24 (16): 5615–5624. doi:10.1016/0040-4020(68)88159-1. PMID 5732891.
Gaoni Y, Mechoulam R (1966). “Hashish—VII The isomerization of cannabidiol to tetrahydrocannabinols”. Tetrahedron 22 (4): 1481–1488. doi:10.1016/S0040-4020(01)99446-3.
Petrzilka T, Haefliger W, Sikemeier C, Ohloff G, Eschenmoser A (1967). “Synthese und Chiralität des (-)-Cannabidiols”. Helv. Chim. Acta 50 (2): 719–723.doi:10.1002/hlca.19670500235. PMID 5587099.
Gaoni Y, Mechoulam R (1985). “Boron trifluoride etherate on alumuna – a modified Lewis acid reagent. An improved synthesis of cannabidiol”. Tetrahedron Letters 26 (8): 1083–1086. doi:10.1016/S0040-4039(00)98518-6.
Kobayashi Y, Takeuchi A, Wang YG (2006). “Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate”. Org. Lett. 8 (13): 2699–2702.doi:10.1021/ol060692h. PMID 16774235.
Marks, M.; Tian, L.; Wenger, J.; Omburo, S.; Soto-Fuentes, W.; He, J.; Gang, D.; Weiblen, G.; Dixon, R. (2009). “Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa”. Journal of Experimental Botany60 (13): 3715–3726. doi:10.1093/jxb/erp210. PMC 2736886. PMID 19581347. edit
Controlled Drugs and Substances Act – Schedule II
CSA Schedule, List of drugs by schedule.
Definition of marijuana under the Controlled Substances Act.
Title 21 US Code Controlled Substances Act, text of the CSA.
Hemp Industries Assn., v. Drug Enforcement Admin., 9th Circuit Court of Appeals case involving industrial hemp.
Hemp, Many definitions of common terms associated with hemp, including the history of hemp use.
Cannabidiol: The side of marijuana you don’t know
US patent 6630507, Hampson, Aidan J.; Axelrod, Julius; Grimaldi, Maurizio, “Cannabinoids as antioxidants and neuroprotectants”, issued 2003-10-07
“Federal Register | Prospective Grant of Exclusive License: Development of Cannabinoid(s) and Cannabidiol(s) Based Therapeutics To Treat Hepatic Encephalopathy in Humans”. Federalregister.gov. November 17, 2011. Retrieved August 13, 2013.
“KannaLife Sciences, Inc. Signs Exclusive License Agreement With National Institutes Of Health Office Of Technology Transfer (NIH-OTT)”. thestreet.com. Retrieved 2012-07-09.
“KannaLife in R&D Collaboration for Cannabinoid-Based Drugs”. Genengnews.com. Retrieved 2013-04-04.

External links

Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.

OLD CUT PASTE


Cannabidiol

Seven Expanded Access INDs granted by FDA to U.S. 
physicians to treat with Epidiolex 125 children suffering 
from intractable epilepsy syndromes -

LONDON, Nov. 15, 2013

GW Pharmaceuticals plc (AIM: GWP, Nasdaq: GWPH, “GW”) announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for Epidiolex(R), our product candidate that contains plant-derived Cannabidiol (CBD) as its active ingredient, for use in treating children with Dravet syndrome, a rare and severe form of infantile-onset, genetic, drug-resistant epilepsy syndrome. Epidiolex is an oral liquid formulation of a highly purified extract of CBD, a non-psychoactive molecule from the cannabis plant. Following receipt of this orphan designation, GW anticipates holding a pre-IND meeting with the FDA in the near future to discuss a development plan for Epidiolex in Dravet syndrome.

Dravet syndrome is a rare pediatric epilepsy syndrome with a distinctive but complex electroclinical presentation. Onset of Dravet syndrome occurs during the first year of life with clonic and tonic-clonic seizures in previously healthy and developmentally normal infants. Prognosis is poor and patients typically develop intellectual disability and life-long ongoing seizures. There are approximately 5,440 patients with Dravet in the United States and an estimated 6,710 Dravet patients in Europe. These figures may be an underestimate as this syndrome is reportedly underdiagnosed.

In addition to GW’s clinical development program for Epidiolex in Dravet syndrome, which is expected to commence in 2014, GW has also made arrangements to enable independent U.S. pediatric epilepsy specialists to treat high need pediatric epilepsy cases with Epidiolex immediately. To date in 2013, a total of seven “expanded access” INDs have been granted by the FDA to U.S. clinicians to allow treatment with Epidiolex of approximately 125 children with epilepsy. These children suffer from Dravet syndrome, Lennox-Gastaut syndrome, and other pediatric epilepsy syndromes. GW is aware of further interest from additional U.S. and ex-U.S. physicians to host similar INDs for Epidiolex. GW expects data generated under these INDs to provide useful observational data during 2014 on the effect of Epidiolex in the treatment of a range of pediatric epilepsy syndromes.

“I, together with many colleagues in the U.S. who specialize in the treatment of childhood epilepsy, very much welcome the opportunity to investigate Epidiolex in the treatment of Dravet syndrome. The FDA’s timely approval of the orphan drug designation for Epidiolex in Dravet syndrome is a key milestone that comes after many years of reported clinical cases that suggest encouraging evidence of efficacy for CBD in this intractable condition,” stated Dr. Orrin Devinsky, Professor of Neurology, Neurosurgery and Psychiatry in New York City. “With GW now making plans to advance Epidiolex through an FDA development program, we have the prospect for the first time of fully understanding the science of CBD in epilepsy with a view to making an appropriately tested and approved prescription medicine available in the future for children who suffer from this debilitating disease.”

“GW is proud to be at the forefront of this important new program to treat children with Dravet Syndrome and potentially other forms of intractable childhood epilepsy. For families in these circumstances, their lives are significantly impacted by constant and often times very severe seizures in children where all options to control these seizures have been exhausted,” stated Dr. Stephen Wright, GW’s R&D Director. “GW intends to advance a full clinical development program for Epidiolex in Dravet syndrome as quickly as possible, whilst at the same time helping families in the short term through supporting physician-led INDs to treat intractable cases. Through its efforts, GW aims to provide the necessary evidence to confirm the promise of CBD in epilepsy and ultimately enabling children to have access to an FDA-approved prescription CBD medicine.”

“This orphan program for Epidiolex in childhood epilepsy is an important corporate strategic priority for GW. Following receipt of today’s orphan designation, GW now intends to commence discussions with the FDA regarding the U.S. regulatory pathway for Epidiolex,” stated Justin Gover, GW’s Chief Executive Officer. “GW intends to pursue this development in-house and retains full commercial rights to Epidiolex.”

About Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition — generally a disease or condition that affects fewer than 200,000 individuals in the U.S. The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the U.S. for that product, for that indication.

About GW Pharmaceuticals plc

Founded in 1998, GW is a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform in a broad range of disease areas. GW commercialized the world’s first plant-derived cannabinoid prescription drug, Sativex(R), which is approved for the treatment of spasticity due to multiple sclerosis in 22 countries. Sativex is also in Phase 3 clinical development as a potential treatment of pain in people with advanced cancer. This Phase 3 program is intended to support the submission of a New Drug Application for Sativex in cancer pain with the U.S. Food and Drug Administration and in other markets around the world. GW has established a world leading position in the development of plant-derived cannabinoid therapeutics and has a deep pipeline of additional clinical-stage cannabinoid product candidates targeting epilepsy (including an orphan pediatric epilepsy program), Type 2 diabetes, ulcerative colitis, glioma and schizophrenia. For further information, please visit http://www.gwpharm.com.

Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.It is a major constituent of the plant, second totetrahydrocannabinol (THC), and represents up to 40% in its extracts. Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC, including to epilepsy, multiple sclerosis spasms, anxiety disorders, bipolar disorder,schizophrenia,nausea, convulsion and inflammation, as well as inhibiting cancer cell growth. There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.Cannabidiol has displayed sedative effects in animal tests. Other research indicates that CBD increases alertness. CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Category Archives: Uncategorized

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Share this:

Share this:

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

Share this:

Medical uses

Adverse effects

Interactions

Pharmacology

Mechanism of action

Pharmacokinetics

History

NDA 203108 Striverdi® Respimat® (olodaterol) Inhalation Spray Boehringer Ingelheim Pharmaceuticals, Inc.

References

External links

Organic spectroscopy should be brushed up and you get confidence

read my blog

ORGANIC SPECTROSCOPY INTERNATIONAL is the blog

Share this:

Share this:

Share this:

Share this:

New approaches to the industrial synthesis of HIV protease inhibitors

See also

External links

Share this:

Share this:

Clinical applications

Antimicrobial actions

Neurological effects

Psychotropic effect

Cancer

Dravet syndrome

CBD-enhanced cannabis

Pharmacology

Pharmacodynamics

Pharmacokinetic interactions

Pharmaceutical preparations

Isomerism

Chemistry

Biosynthesis

Legal status

US patent

References

External links

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

NDA 203108
Striverdi® Respimat® (olodaterol) Inhalation Spray
Boehringer Ingelheim Pharmaceuticals, Inc.