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Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

March 11, 2019 10:14 am / Leave a comment

A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.

Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

Yasunori Aoyama *^†

, Toshikazu Hakogi^‡, Yuki Fukui^†, Daisuke Yamada^†, Takao Ooyama^§, Yutaka Nishino^‡, Shoji Shinomoto^†, Masahiko Nagai^§, Naoki Miyake^‡, Yoshiyuki Taoda^§, Hiroshi Yoshida^§, and Tatsuro Yasukata^†

^† API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

^‡ Production Technology Department, Manufacturing Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan

^§ Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00409

Publication Date (Web): March 1, 2019

*E-mail: yasunori.aoyama@shionogi.co.jp.

This article is part of the Japanese Society for Process Chemistry special issue.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00409

///////Dolutegravir

Cenobamate

March 8, 2019 10:24 am / Leave a comment

Cenobamate
CAS: 913088-80-9
Chemical Formula: C10H10ClN5O2
Molecular Weight: 267.67

Related CAS #: 913088-80-9 913087-59-9

Synonym: YKP-3089; YKP3089; YKP3089; Cenobamate

IUPAC/Chemical Name: (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate

2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, carbamate (ester), (αR)- (9CI)
(1R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
Carbamic acid (R)-(+)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl ester
2H-Tetrazole-2-ethanol, α-(2-chlorophenyl)-, 2-carbamate, (αR)-

Cenobamate, also known as YKP-3089, is a novel new antiepileptic drug candidate. Cenobamate showed broad-spectrum anticonvulsant activity. Cenobamate entered into clinical trials and was discontinued in 2015.

PATENT

WO 2006112685

SK HOLDINGS CO., LTD. [KR/KR]; 99 Seorin-dong Jongro-ku Seoul 110-110, KR

CHOI, Yong-Moon; US

KIM, Choon-Gil; KR

KANG, Young-Sun; KR

YI, Han-Ju; KR

LEE, Hyun-Seok; KR

KU, Bon-Chul; KR

LEE, Eun-Ho; KR

IM, Dae-Joong; KR

SHIN, Yu-Jin; KR

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006112685

Patent

US 20100323410

PATENT

WO 2011046380

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=9CF54FB903EC3DFB7B3237259E6419EB.wapp2?docId=WO2011046380&recNum=36&office=&queryString=&prevFilter=%26fq%3DOF%3AIL%26fq%3DICF_M%3A%22C07D%22&sortOption=Relevance&maxRec=1345

As disclosed in U. S. Patent Application Publication No. 2006/0258718 A1, carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl esters (hereinafter referred to as “the carbamate compounds”) with anticonvulsant activity are useful in the treatment of disorders of the central nervous system, especially including anxiety, depression, convulsion, epilepsy, migraines, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorders, neuropathic pain, strokes, cognitive impairment, neurodegeneration, strokes and muscle spasms.

Depending on the position of N in the tetrazole moiety thereof, the carbamate compounds are divided into two positional isomers: tetrazole-1-yl (hereinafter referred to as “1N tetrazole”) and treatzole-2-yl (hereinafter referred to as “2N tetrazole”). The introduction of tetrazole for the preparation of the carbamate compounds results in a 1:1 mixture of the two positional isomers which are required to be individually isolated for pharmaceutical use.

Having chirality, the carbamate compounds must be in high optical purity as well as chemical purity as they are used as medications.

In this regard, U. S. Patent Application Publication No. 2006/0258718 A1 uses the pure enantiomer (R)-aryl-oxirane as a starting material which is converted into an alcohol intermediate through a ring-opening reaction by tetrazole in the presence of a suitable base in a solvent, followed by introducing a carbamoyl group into the alcohol intermediate. For isolation and purification of the 1N and 2N positional isomers thus produced, column chromatography is set after the formation of an alcohol intermediate or carbamate.

For use in the preparation, (R)-2-aryl-oxirane may be synthesized from an optically active material, such as substituted (R)-mandelic acid derivative, via various routes or obtained by asymmetric reduction-ring formation reaction of α-halo arylketone or by separation of racemic 2-aryl-oxirane mixture into its individual enantiomers. As such, (R)-2-aryl-oxirane is an expensive compound.

In addition, the ring-opening reaction of (R)-2-aryl-oxirane with tetrazole is performed at relatively high temperatures because of the low nucleophilicity of the tetrazole. However, the ring opening reaction includes highly likely risk of a runaway reaction because tetrazoles start to spontaneously degrade at 110 ~ 120℃.

In terms of a selection of reaction, as there are two reaction sites in each (R)-2-aryl-oxirane and tetrazole, the ring-opening reaction therebetween affords the substitution of 1N- or 2N-tetrazole at the benzyl or terminal position, resulting in a mixture of a total of 4 positional isomers. Therefore, individual positional isomers are low in production yield and difficult to isolate and purify.

Preparation Example 1: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one

To a suspension of 2-bromo-2′-chloroacetophenone (228.3 g, 0.978 mol) and potassium carbonate (161.6 g, 1.170 mol) in acetonitrile (2000 mL) was added a 35 w/w% 1H-tetrazole dimethylformamide solution (215.1 g, 1.080 mol) at room temperature. These reactants were stirred for 2 h at 45℃ and distilled under reduced pressure to remove about 1500 mL of the solvent. The concentrate was diluted in ethyl acetate (2000 mL) and washed with 10% brine (3 x 2000 mL). The organic layer thus separated was distilled under reduced pressure to afford 216.4 g of an oily solid residue. To a solution of the solid residue in ethyl acetate (432 mL) was slowly added heptane (600 mL). The precipitate thus formed was filtered at room temperature and washed to yield 90.1 g (0.405 mol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (hereinafter referred to as 1N ketone ).

¹H-NMR(CDCl ₃) 8.87(s, 1H), d7.77(d, 1H), d7.39-7.62(m, 3H), d5.98(s, 2H)

Preparation Example 2: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one

After the filtration of Preparation Example 1, the filtrate was concentrated and dissolved in isopropanol (100 mL), and to which heptane (400 mL) was then added to complete the crystallization. Filtering and washing at 5℃ afforded 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (hereinafter referred to as “2N ketone”) as a solid. 94.7 g (0.425 mol).

¹H-NMR(CDCl ₃) d8.62(s, 1H), d7.72(d, 1H), d7.35-7.55(m, 3H), d6.17(s, 2H)

PREPARATION EXAMPLE 3: Preparation of Alcohol Compound of (R)-Configuration by enantioselective enzymatic reduction via various oxidoreductases

The following four solutions were prepared as follows:

Enzyme Solution 1

Competent Escherichia coli StarBL21(De3) cells (Invitrogen) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25 ℃ and 220 rpm, the cells were harvested and frozen at -20 ℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.

Enzyme Solution 2

RB791 cells ( E.coli genetic stock, Yale, USA) were transformed with the expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2. The Escherichia coli colonies transformed with the resulting expression constructs were then cultivated in 200 mL of LB medium (1% tryptone, 0.5 % yeast and 1% sodium chloride) with 50 micrograms/mL of ampicillin or 40 micrograms/mL of kanamycin, respectively, until an optical density of 0.5, measured at 550 nm, was achieved. The expression of the desired recombinant protein was induced by the addition of isopropylthiogalactoside (IPTG) to a concentration of 0.1 mM. After 16 hours of induction at 25℃ and 220 rpm, the cells were harvested and frozen at -20℃. In the preparation of the enzyme solutions, 30 g of cells were resuspended in 150 mL of triethanolamine buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8) and homogenized in a high pressure homogenizer. The resultant enzyme solution was mixed with 150 mL glycerol and stored at -20℃.

Enzyme Solution 3

Enzyme solutions 3 was prepared in the same manner as described in Enzyme solution 1 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 3 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 1 was used.

Enzyme Solution 4

Enzyme solutions 4 was prepared in the same manner as described for enzyme solution 2 except that expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 4 instead of expression constructs pET21-MIX coding for oxidoreductase SEQ ID NO 2 was used.

Different oxidoreductases contained in each enzyme solutions 1 to 4 were examined as follows for the conversion of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (1N ketone) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (2N ketone) to the corresponding 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (hereinafter, referred to as 1N alcohol ) and 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (hereinafter, referred to as “2N alcohol”), respectively.

Reaction batch A

160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

100 ㎕ NADPH (40 mg/ml)

40 ㎕ 2-propanol

50 ㎕ enzyme solution 1

2 mg 1N ketone or 2N ketone

Reaction batch B

160 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

100 ㎕ NADPH (40 mg/ml)

40 ㎕ 2-propanol

50 ㎕ enzyme solution 2

2 mg 1N ketone or 2N ketone

Reaction batch C

350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8)

0,05 mg NADP

50 ㎕ enzyme solution 3

10 mg 1N ketone or 2N ketone

250 ㎕ 4-methyl-2-pentanol

50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor

Reaction batch D

350 ㎕ buffer (TEA 100 nM, 2 mM MgCl2, 10% glycerol, pH 8

0,05 mg NADP

50 ㎕ enzyme solution 4

10 mg 1N ketone or 2N ketone

250 ㎕ 4-methyl-2-pentanol

50 ㎕ enzyme (oxidoreductase from Thermoanerobium brockii) solution for regeneration of cofactor

After 24h of incubating each reaction batch A, B, C and D, 1 mL of acetonitrile was added to each reaction batch which was centrifuged and transferred into a HPLC analysis vessel for enantiomeric excess and conversion. Conversion and ee-value of products are listed in Table 1 below calculated using the following equations:

Conversion Rate (%) = [(Area of Product)/(Area of Reactant + Area of Product)]x100

ee-value(%) = [(Area of R-Configuration – Area of S-Configuration)/(Area of R-Configuration + Area of S-Configuration)] x 100

Table 1 [Table 1]

PREPARATION EXAMPLE 4: Enzymatic reduction via oxidoreductase SEQ NO: 2

For the conversion of 1N/2N ketone to R-1N/R-2N alcohol, 30㎕ of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 300㎕ of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 100mg of a mixture of 1N ketone and 2N ketone (1N:2N=14%:86%), 0.04mg NADP and 300㎕ 2-butanol. The reaction mixture was incubated at room temperature under constant thorough mixing. After 48 hours, more than 98% of the ketones were reduced to an alcohol mixture of the following composition(R-2N alcohol 80%; S-2N alcohol 0%; R-1N alcohol 20%, S-1N alcohol 0%; 1N ketone 0%; 2N ketone 0%).

After general work up and recrystallization with ethyl acetate/hexane, optically pure alcohols were obtained as below:

(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (1N alcohol

¹H-NMR(CDCl ₃) d8.74(s, 1H), d7.21-7.63(m, 4H), d5.57(m, 1H), d4.90(d, 1H), d4.50(d, 1H), d3.18(d, 1H);

(R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (2N alcohol)

¹H-NMR(CDCl ₃) d8.55(s, 1H), d7.28-7.66(m, 4H), d5.73(d, 1H), d4.98(d, 1H), d4.83(d, 1H), d3.38(br, 1H).

Preparation of Carbamate

Preparation Example 5: Preparation of Carbamic Acid (R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl)ethyl ester

50ml of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 250ml of a buffer (100 mM TEA, pH 8, 1mM MgCl2, 10% glycerol), 50g (225mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one(2N ketone), 4mg NAD, 300 ml of 2-propanol and 150mL of butyl acetate. The reaction mixture was stirred at room temperature. After 48 hours more than 98% of 2N ketone was reduced to corresponding (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol) with >99%ee values. To this resulting mixture, 500mL of ethyl acetate was added. After being separated, the organic layer thus formed was washed with 10% brine (3 x 500mL). The organic layer thus formed was dried over magnesium sulfate and filtered and the filtrate was distilled under reduced pressure to give 50.4g (224 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol, optical purity 99.9%) as an oily residue. To this resulting crude product, 450mL of tetrahydrofuran was added. After cooling to -15℃, 38g (267mmol) of chlorosulfonyl isocyanate was slowly added and stirred at -10℃ for 2 h. The slow addition of water induced termination of the reaction. The resulting solution was concentrated under reduced pressure until about 300 mL of the solvent was removed. The concentrate was diluted with 600mL of ethyl acetate and washed with 10% brine (3 x 500 mL). The organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (90 mL) to which heptane (180 mL) was slowly added, leading to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 51.8 g (194 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester (optical purity 99.9%).

¹H-NMR(Acetone-d ₆) d8.74(s, 1H), d7.38-7.54(m, 4H), d6.59(m, 1H), d6.16(Br, 2H), d4.90(d, 1H), d5.09(m, 2H)

As described hitherto, carbamate compounds with high optical and chemical purity can be produced with an economical benefit in accordance with the present invention.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

AMINO ACID SEQUENCES

SEQ ID NO 1: Oryctolagus cuniculus from rabbit DSMZ 22167

SEQ ID NO 2: Candida magnoliae DSMZ 22052 protein sequence carbonyl reductase

SEQ ID NO 3: Candida vaccinii CBS7318 protein sequence carbonyl reductase

SEQ ID NO 4: Candida magnoliae CBS6396 protein sequence carbonyl reductase

NUCLEIC ACID SEQUENCES

SEQ ID NO 5: Oryctolagus cuniculus from rabbit DSMZ 22167

SEQ ID NO 6: Candida magnoliae DSMZ 22052 nucleic acid sequence carbonyl reductase

SEQ ID NO 7: Candida vaccinii CBS7318 nucleic acid sequence carbonyl reductase

SEQ ID NO 8: Candida magnoliae CBS6396 nucleic acid sequence carbonyl reductase

Clip

Our team enjoyed celebrating the news of FDA acceptance of our new drug application (NDA) for investigational antiepileptic drug, cenobamate. A special thank you to everyone on our team who worked tirelessly to make this milestone possible!

https://www.linkedin.com/company/sk-life-science-inc./

https://www.sklifescienceinc.com/

https://www.sklifescienceinc.com/pdf/SKLSI%20NDA%20Acceptance%20Press%20Release%20-FINAL-Updated%202-3-19.pdf

SK life science announces FDA acceptance of NDA submission for cenobamate, an investigational antiepileptic drug PDUFA date set for November 21, 2019 Fair Lawn, New Jersey, February 4, 2019 – SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals Co., Ltd., an innovative biopharmaceutical company focused on developing and bringing to market treatments for central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has accepted the filing of its New Drug Application (NDA) for cenobamate. Cenobamate, an investigational antiepileptic drug for the potential treatment of partial-onset seizures in adult patients, is the first molecule discovered and developed from inception through to the submission of an NDA without partnering or out-licensing from a Korean pharmaceutical company.

SK life science plans to commercialize cenobamate independently. The NDA submission is based on data from pivotal trials that evaluated the efficacy and safety of cenobamate. Results from the clinical trial program, which enrolled more than 1,900 patients, have been presented at medical conferences including the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) Annual Meetings. “The FDA’s acceptance of our NDA filing is a critical step toward our goal of introducing a new treatment option for people with uncontrolled epilepsy,” said Marc Kamin, M.D., chief medical officer at SK life science. “We look forward to working with the FDA during their review of our data on cenobamate.” Despite the availability and introduction of many new AEDs, overall treatment outcomes for people with epilepsy have not improved in 20 years

1 and the CDC states that nearly 60 percent of people with epilepsy are still experiencing seizures, showcasing a great unmet need for patients and their families. 2 Additionally, while some patients may experience a reduction in seizure frequency with current treatments, they continue to live with seizures.

2 The impact of continued seizures can be debilitating and life-altering and the complications of epilepsy can include depression and anxiety, cognitive impairment and SUDEP (sudden unexpected death in epilepsy).

3 About Epilepsy Epilepsy is a common neurological disorder characterized by seizures.

4 There are approximately 3.4 million people in the U.S. living with epilepsy, and approximately 65 million worldwide.

5 The majority of people with epilepsy (60%) have partial-onset seizures, which are located in just one part of the brain.

6 People with epilepsy are also at risk for accidents and other health complications including falling, drowning, car accidents, depression and anxiety and SUDEP. 3

About Cenobamate Cenobamate (YKP3089) was discovered by SK Biopharmaceuticaals and SK life science and is being investigated for the potential treatment of partial-onset seizures in adult patients. Cenobamate’s mechanism of action is not fully understood, but it is believed to work through two separate mechanisms: enhancing inhibitory currents through positive modulation of GABA-A receptors and decreasing excitatory currents by inhibiting the persistent sodium current. Global trials for adults with partial-onset seizures are ongoing to evaluate cenobamate safety.

Additional clinical trials are investigating cenobamate safety and efficacy in other seizure types. The U.S. Food and Drug Administration (FDA) accepted the filing of the New Drug Application for cenobamate for the potential treatment of partial-onset seizures in adults in February 2019. Cenobamate is not approved by the FDA or any other regulatory authorities. Safety and efficacy have not been established. About SK life science SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals, Co., Ltd., is focused on developing and commercializing treatments for disorders of the central nervous system (CNS).

Both are a part of the global conglomerate SK Group, the second largest company in Korea. SK life science is located in Fair Lawn, New Jersey. We have a pipeline of eight compounds in development for the treatment of CNS disorders including epilepsy, sleep disorder and attention deficit hyperactivity disorder, among others. The first product the company is planning to commercialize independently is cenobamate (YKP3089), an investigational compound for the potential treatment of partial-onset seizures in adult patients, currently in a Phase 3 global clinical trial.

For more information, visit SK life science’s website at http://www.SKLifeScienceInc.com.

For more information, visit SK Biopharmaceuticals’ website at http://www.skbp.com/eng. —-

1. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. https://www.ncbi.nlm.nih.gov/pubmed/29279892 Published online December 26, 2017.

2. Center for Disease Control and Prevention. Active Epilepsy and Seizure Control in Adults — United States, 2013 and 2015. https://www.cdc.gov/mmwr/volumes/67/wr/mm6715a1.htm?s_cid=mm6715a1 Accessed December 27, 2018.

3. Epilepsy Foundation. Staying Safe. https://www.epilepsy.com/learn/seizure-first-aid-and-safety/staying-safe Accessed November 20, 2018.

4. Epilepsy Foundation. What Is Epilepsy? https://www.epilepsy.com/learn/about-epilepsy-basics/what-epilepsy Accessed November 20, 2018.

5. Epilepsy Foundation. Facts about Seizures and Epilepsy. https://www.epilepsy.com/learn/about-epilepsybasics/facts-about-seizures-and-epilepsy Accessed November 20, 2018.

6. National Institute of Neurological Disorders and Stroke. The Epilepsies and Seizures: Hope through Research. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Epilepsies-andSeizures-Hope-Through#3109_9 Accessed November 20, 2018.

REFERENCES

1: Mula M. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2013
Mar;18(1):87-95. doi: 10.1517/14728214.2013.750294. Epub 2012 Nov 26. Review.
PubMed PMID: 23176519.

2: Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress
report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT
IX). Epilepsy Res. 2009 Jan;83(1):1-43. doi: 10.1016/j.eplepsyres.2008.09.005.
Epub 2008 Nov 12. PubMed PMID: 19008076.

/////////////YKP-3089, YKP3089, YKP3089, Cenobamate

NC(O[C@H](C1=CC=CC=C1Cl)CN2N=CN=N2)=O

Rovafovir Etalafenamide

March 6, 2019 11:37 am / Leave a comment

2D chemical structure of 912809-27-9

Rovafovir etalafenamide

GS-9131

UNII-U8S0IC8DY7

ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate

L-Alanine, N-((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydro-2-furanyl)oxy)methyl)phenoxyphosphinyl)-, ethyl ester
CAS: 912809-27-9
Chemical Formula: C21H24FN6O6P
Molecular Weight: 506.43

Originator Gilead Sciences
Class Antiretrovirals; Purine nucleosides; Small molecules
Mechanism of Action Nucleoside reverse transcriptase inhibitors

Phase II HIV-1 infections

03 Apr 2018 Phase-II clinical trials in HIV-1 infections (Treatment-experienced) in Uganda (PO) (NCT03472326)
21 Mar 2018 Gilead Sciences plans a phase II study for HIV-1 infections in March 2018 (NCT03472326)
26 Mar 2009 Preclinical pharmacokinetics data in HIV-1 infections presented at the 237th American Chemical Society National Meeting (237th-ACS-2009)

Rovafovir Etalafenamide, also known as GS-9131, is an anti-HIV Nucleoside Phosphonate prodrug.

POSTER

http://www.croiconference.org/sites/default/files/posters-2017/436_White.pdf

Patent

WO 2006110157

WO 2008103949

WO 2010005986

PATENT

WO 2012159047

PATENT

WO-2019027920

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019027920&tab=PCTDESCRIPTION&maxRec=1000

As discussed in U.S. Pat. Nos. 7,871,991, 9,381,206, 8,951,986, and 8,658,617, ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate is a reverse transcriptase inhibitor that blocks the replication of HIV viruses, in vivo and in vitro, and has limited undesirable side effects when administered to human beings. This compound has a favorable in vitro resistance profile with activity against Nucleoside RT Inhibitor (NRTI)-Resistance Mutations, such as Ml 84V, K65R, L74V, and one or more (e.g., 1, 2, 3, or 4) TAMs (thymidine analogue mutations). It has the following formula (see, e.g., U.S. Pat. No. 7,871,991), which is referred to as Formula I:

[0004] Ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate is difficult to isolate, purify, store for an extended period, and formulate as a pharmaceutical composition.

[0005] The compound of formula la was previously identified as the most chemically stable form of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-

yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate. See, e.g. , U.S. Pat. Nos. 8,658,617,

8,951,986, and 9,381,206. However, a total degradation increase of 2.6% was observed when the compound of formula (la) was stored at 25 °C/60% RH over 6 months. Therefore, the compound of formula la requires refrigeration for long-term storage.

[0006] Accordingly, there is a need for stable forms of the compound of Formula I with suitable chemical and physical stability for the formulation, therapeutic use, manufacturing, and storage of the compound. New forms, moreover, can provide better stability for the active pharmaceutical substance in a pharmaceutical formulation.

PAPER

Bioorganic & Medicinal Chemistry (2010), 18(10), 3606-3617.

https://www.sciencedirect.com/science/article/pii/S0968089610002452?via%3Dihub

Image result for Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

PAPER

RSC Drug Discovery Series (2011), 4(Accounts in Drug Discovery), 215-237.

PAPER

https://aac.asm.org/content/52/2/648

Image result for GS-9131

REFERENCES

1: Rai MA, Pannek S, Fichtenbaum CJ. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs. 2018 May 10:1-9. doi: 10.1080/14728214.2018.1474202. [Epub ahead of print] PubMed PMID: 29737220.

2: Mackman RL. Anti-HIV Nucleoside Phosphonate GS-9148 and Its Prodrug GS-9131: Scale Up of a 2′-F Modified Cyclic Nucleoside Phosphonate and Synthesis of Selected Amidate Prodrugs. Curr Protoc Nucleic Acid Chem. 2014 Mar 26;56:14.10.1-21. doi: 10.1002/0471142700.nc1410s56. Review. PubMed PMID: 25606977.

3: De Clercq E. The clinical potential of the acyclic (and cyclic) nucleoside phosphonates: the magic of the phosphonate bond. Biochem Pharmacol. 2011 Jul 15;82(2):99-109. doi: 10.1016/j.bcp.2011.03.027. Epub 2011 Apr 8. Review. PubMed PMID: 21501598.

4: Mackman RL, Ray AS, Hui HC, Zhang L, Birkus G, Boojamra CG, Desai MC, Douglas JL, Gao Y, Grant D, Laflamme G, Lin KY, Markevitch DY, Mishra R, McDermott M, Pakdaman R, Petrakovsky OV, Vela JE, Cihlar T. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg Med Chem. 2010 May 15;18(10):3606-17. doi: 10.1016/j.bmc.2010.03.041. Epub 2010 Mar 27. PubMed PMID: 20409721.

5: Cihlar T, Laflamme G, Fisher R, Carey AC, Vela JE, Mackman R, Ray AS. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother. 2009 Jan;53(1):150-6. doi: 10.1128/AAC.01183-08. Epub 2008 Nov 10. PubMed PMID: 19001108; PubMed Central PMCID: PMC2612154.

6: Cihlar T, Ray AS, Boojamra CG, Zhang L, Hui H, Laflamme G, Vela JE, Grant D, Chen J, Myrick F, White KL, Gao Y, Lin KY, Douglas JL, Parkin NT, Carey A, Pakdaman R, Mackman RL. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother. 2008 Feb;52(2):655-65. Epub 2007 Dec 3. PubMed PMID: 18056282; PubMed Central PMCID: PMC2224772.

7: Ray AS, Vela JE, Boojamra CG, Zhang L, Hui H, Callebaut C, Stray K, Lin KY, Gao Y, Mackman RL, Cihlar T. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob Agents Chemother. 2008 Feb;52(2):648-54. Epub 2007 Dec 3. PubMed PMID: 18056281; PubMed Central PMCID: PMC2224749.

8: Birkus G, Wang R, Liu X, Kutty N, MacArthur H, Cihlar T, Gibbs C, Swaminathan S, Lee W, McDermott M. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007 Feb;51(2):543-50. Epub 2006 Dec 4. PubMed PMID: 17145787; PubMed Central PMCID: PMC1797775.

//////////////Rovafovir etalafenamide, GS-9131, PHASE 2

C[C@@H](C(OCC)=O)N[P@@](OC1=CC=CC=C1)(CO[C@H]2O[C@@H](N3C=NC4=C(N)N=CN=C34)C(F)=C2)=O

OLACAFTOR, VX 440

March 1, 2019 10:05 am / Leave a comment

Image result for VX 440

OLACAFTOR, VX 440

CAS 1897384-89-2

Molecular Formula:	C₂₉H₃₄FN₃O₄S
Molecular Weight:	539.666 g/mol

CFTR corrector; UNII-RZ7027HK8F; RZ7027HK8F;

Target-based Actions, CFTR modulator

Indications, Cystic fibrosis

CS-0044588

UNII-RZ7027HK8F

RZ7027HK8F

Olacaftor (VX-440, VX440) is a next-generation CFTR corrector, shows the potential to enhance the amount of CFTR protein at the cell’s surface and for treatment of cystic fibrosis..

Originator Vertex Pharmaceuticals
Class Pyridines; Pyrrolidines
Mechanism of Action Cystic fibrosis transmembrane conductance regulator stimulants

Phase II Cystic fibrosis

01 Jun 2018 Chemical structure information added
01 Aug 2017 Vertex Pharmaceuticals completes a phase II trial in Cystic fibrosis (In adolescents, In adults, In the elderly, Combination therapy) in USA, Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Spain, Netherlands and United Kingdom (PO) (NCT02951182) (EudraCT2016-000454-36)
18 Jul 2017 Efficacy and events data from a phase II trial in Cystic fibrosis released by Vertex Pharmaceuticals

PATENT

WO2016057572

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B67642F2D5C265D1AF3AC60194173694.wapp1nB?docId=WO2016057572&recNum=6&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A01N%22&sortOption=Pub+Date+Desc&maxRec=22922

PATENT

US9782408

PATENT

WO-2019028228

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019028228&tab=PCTDESCRIPTION&maxRec=1000

Processes for preparing (S)-2,2,4-trimethylpyrrolidine and its salts, particularly hydrochloride comprising the reaction of 2,2,6,6-tetramethyl-piperidin-4-one with chloroform and a base (sodium hydroxide), followed by reaction with an acid (hydrochloric acid), hydrogenation, reduction and salt synthesis is claimed. Also claimed is a process for the preparation of an intermediate of (S)-2,2,4-trimethylpyrrolidine hydrochloride. The compound is useful as an intermediate for the synthesis of CFTR modulators, useful for treating cystic fibrosis.
(5)-2,2,4-trimethylpyrrolidine free base and salt forms thereof, (R)-2,2,4-trimethylpyrrolidine free base and salt forms thereof, (,S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, and 5,5-dimethyl-3-methylenepyrrolidin-2-one are useful molecules that can be used in the synthesis of pharmaceutically active molecules, such as modulators of CFTR activity, for example those disclosed in PCT Publication Nos. WO 2016/057572, WO 2018/064632, and WO 2018/107100, including the following molecules, which are being investigated in clinical trials for the treatment of cystic fibrosis:

[0003] There remains, however, a need for more efficient, convenient, and/or economical processes for the preparation of these molecules.

[0004] Disclosed herein are processes for preparing 5,5-dimethyl-3-methylenepyrrolidin-2-one, (,S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, (,S)-2,2,4-trimethylpyrrolidine, and (R)-2,2,4-trimethylpyrrolidine, and their salt forms:

trimethylpyrrolidine-2-one)); ((R)-3,5,5-trimethylpyrrolidine-2-one));

((,S)-2,2,4-trimethylpyrrolidine) ;and

Scheme 1. Synthesis of (S)-2,2,4-trimethylpyrrolidine

(2) (3) (4S) (1 S)

Scheme 2. Synthesis of (R)-2,2,4-trimethylpyrrolidine

(2) (3) (4R) (1 R)

Scheme 3. Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

3 C

EXAMPLES

Example 1. Reaction (a) and (b): Synthesis of 5,5-dimethyl-3-methylenepyrrolidin- 2-one

(2) (3) C (3)

Example 1A:

[0055] 2,2,6,6-tetramethylpiperidin-4-one (50.00 g, 305.983 mmol, 1.000 equiv), tributylmethylammonium chloride (2.89 g, 3.0 mL, 9.179 mmol, 0.030 equiv), chloroform (63.92 g, 43.2 mL, 535.470 mmol, 1.750 equiv), and DCM (dichloromethane) (100.0 mL, 2.00 vol) were charged to a 1000 mL three-neck round bottom flask equipped with an overhead stirrer. The reaction mixture was stirred at 300 rpm, and 50 wt% NaOH (195.81 g, 133.2 mL, 2,447.863 mmol, 8.000 equiv) was added dropwise (via addition funnel) over 1.5 h while maintaining the temperature below 25 °C with intermittent ice/acetone bath. The reaction mixture was stirred at 500 rpm for 18 h, and monitored by GC (3% unreacted piperidinone after 18 h). The suspension was diluted with DCM (100.0 mL, 2.00 vol) and H2O (300.0 mL, 6.00 vol), and the phases were separated. The aqueous phase was extracted with DCM (100.0 mL, 2.00 vol). The organic phases were combined and 3 M hydrochloric acid (16.73 g, 153.0 mL, 458.974 mmol, 1.500 equiv) was added. The mixture was stirred at 500 rpm for 2 h. The conversion was complete after approximately 1 h. The aqueous phase was saturated with NaCl, H2O (100.0 mL, 2.00 vol) was added to help reduce the emulsion, and the phases were separated. The aqueous phase was extracted with DCM (100.0 mL, 2.00 vol) twice. H2O (100.0 mL, 2.00 vol) was added to help with emulsion separation. The organic phases were combined, dried (MgS0₄), and

concentrated to afford 32.6 g (85%) of crude Compound (3) as a pale orange clumpy solid. The crude was recrystallized from hot (90°C) iPrOAc (isopropyl acetate) (71.7 mL, 2.2 vol. of crude), cooled to 80 °C, and -50 mg of crystalline Compound (3) was added for seeding. Crystallization started at 77 °C, the mixture was slowly cooled to ambient temperature, and aged for 2 h. The solid was collected by filtration, washed with 50/50 iPrOAc/heptane (20.0 mL, 0.40 vol) twice, and dried overnight in the vacuum oven at 40 °C to afford the desired product (23.70 g, 189.345 mmol, 62% yield) as a white sand colored crystalline solid. ¾ MR (400 MHz, CDCh, 7.26 ppm) δ 7.33 (bs, 1H), 5.96-5.95 (m, 1H), 5.31-5.30 (m, 1H), 2.6 (t, J= 2.5 Hz, 2H), 1.29 (s, 6H).

Synthesis IB:

[0056] i. Under a nitrogen atmosphere, 2,2,6,6-tetramethylpiperidin-4-one (257.4 kg, 1658.0 mol, 1.00 eq.), tri-butyl methyl ammonium chloride (14.86 kg, 63.0 mol, 0.038 eq.), chloroform (346.5 kg, 2901.5 mol, 1.75 eq.) and DCM (683.3 kg) were added to a 500 L enamel reactor. The reaction was stirred at 85 rpm and cooled to 15~17°C. The solution of 50wt% sodium hydroxide (1061.4 kg, 13264.0 mol, 8.00 eq.) was added dropwise over 40 h while maintaining the temperature between 15~25°C. The reaction mixture was stirred and monitored by GC.

ii. The suspension was diluted with DCM (683.3 kg) and water (1544.4 kg). The organic phase was separated. The aqueous phase was extracted with DCM (683.3 kg). The organic phases were combined, cooled to 10°C and then 3 M hydrochloric acid (867.8 kg, 2559.0 mol, 1.5 eq.) was added. The mixture was stirred at 10-15 °C for 2 h. The organic phase was separated. The aqueous phase was extracted with DCM (683.3 kg x 2). The organic phases were combined, dried over Na₂S04 (145.0 kg) for 6 h. The solid was filtered off and washed with DCM (120.0 kg). The filtrate was stirred with active charcoal (55 kg) for 6 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure (30~40°C, -O. lMPa). Then isopropyl acetate (338 kg) was added and the mixture was heated to 87-91°C, stirred for 1 h. Then the solution was cooled to 15 °C in 18 h and stirred for 1 h at 15 °C. The solid was collected by filtration, washed with 50% isopropyl acetate/hexane (80.0 kg x 2) and dried overnight in the vacuum oven at 50 °C to afford 5,5-dimethyl-3-methylenepyrrolidin-2-one as an off white solid, 55% yield.

Example 2. Reaction (c): Synthesis of (S)-3,5,5-trimethyl-pyrrolidin-2-one from 5,5-dimethyl-3-methylenepyrrolidin-2-one

(3) (4S)

Example 2A: Use of Rh Catalyst

[0057] Step 1 : Preparation of Rh Catalyst Formation: In a 3 L Schlenk flask, 1.0 L of tetrahydrofuran (THF) was degassed with an argon stream. Mandyphos Ligand SL-M004-1 (1.89 g) and [Rh(nbd)Cl]₂ (98%, 0.35 g) (chloronorbornadiene rhodium(I) dimer) were added. The resulting orange catalyst solution was stirred for 30 min at room temperature to form a catalyst solution.

[0058] Step 2: A 50 L stainless steel autoclave was charged with 5,5-dimethyl-3-^■methylenepyrrolidin-2-one (6.0 kg, Compound (3)) and THF (29 L). The autoclave was

sealed and the resulting suspension was flushed with nitrogen (3 cycles at 10 bar), and then released of pressure. Next the catalyst solution from Step 1 was added. The autoclave was flushed with nitrogen without stirring (3 cycles at 5 bar) and hydrogen (3 cycles at 5 bar). The pressure was set to 5 bar and a 50 L reservoir was connected. After 1.5 h with stirring at 1000 rpm and no hydrogen uptake the reactor was flushed again with nitrogen (3 cycles at 10 bar) with stirring and additional catalyst solution was added. The autoclave was again flushed to hydrogen with the above described procedure (3 x 5 bar N2, 3 x 5 bar H2) and adjusted to 5 bar. After 2 h, the pressure was released, the autoclave was flushed with nitrogen (3 cycles at 5 bar) and the product solution was discharged into a 60 L inline barrel. The autoclave was charged again with THF (5 L) and stirred with 1200 rpm for 5 min. The wash solution was added to the reaction mixture.

[0059] Step 3 : The combined solutions were transferred into a 60 L reactor. The inline barrel was washed with 1 L THF which was also added into the reactor. 20 L THF were removed by evaporation at 170 mbar and 40°C. 15 L heptane were added. The distillation was continued and the removed solvent was continuously replaced by heptane until the THF content in the residue was 1% w/w (determined by NMR). The reaction mixture was heated to 89°C (turbid solution) and slowly cooled down again (ramp: 14°C/h). Several heating and cooling cycles around 55 to 65°C were made. The off-white suspension was transferred to a stirred pressure filter and filtered (ECTFE-pad, d = 414 mm, 60 my, Filtration time = 5 min). 10 L of the mother liquor was transferred back into the reactor to wash the crystals from the reactor walls and the obtained slurry was also added to the filter. The collected solid was washed with 2 x 2.5 1 heptane, discharged and let dry on the rotovap at 40°C and 4 mbar to obtain the product, (S)-3,5,5-trimethyl-pyrrolidin-2-one; 5.48 Kg (91%), 98.0% ee.

Synthesis 2B: Use of Ru Catalyst

[0060] The reaction was performed in a similar manner as described above in Example 2A except the use of a Ru catalyst instead of a Rh catalyst.

[0061] Compound (3) (300 g) was dissolved in THF (2640 g, 10 Vol) in a vessel. In a separate vessel, a solution of [RuCl(p-cymene){(R)-segphos}]Cl (0.439g, 0.0002 eq) in THF (660 g, 2.5 Vol) was prepared. The solutions were premixed in situ and passed

through a Plug-flow reactor (PFR). The flow rate for the Compound (3) solution was at 1.555 mL/min and the Ru catalyst solution was at 0.287 mL/min. Residence time in the PFR was 4 hours at 30 °C, with hydrogen pressure of 4.5 MPa. After completion of reaction, the TFIF solvent was distilled off to give a crude residue. Heptane (1026 g, 5 vol) was added and the resulting mixture was heated to 90 °C. The mixture was seeded with 0.001 eq. of Compound 4S seeds. The mixture was cooled to -15 °C at 20 °C/h. After cooling, heptane (410 g, 2 vol) was added and the solid product was recovered by filtration. The resulting product was dried in a vacuum oven at 35 °C to give (S)-3,5,5-trimethyl-pyrrolidin-2-one (281.77 g, 98.2 % ee, 92 % yield).

Example 2C: Analytical Measurements

[0062] Analytical chiral HPLC method for the determination of the conversion, chemoselectivity and enantiomeric excess of the products form Example 2A and 2B was made under the following conditions: Instrument: Agilent Chemstation 1100; Column: Phenomenex Lux 5u Cellulose— 2, 4.6 mm x 250 mm x 5 um, LHS6247; Solvent:

Heptane/iPrOH (90: 10); Flow: 1.0 ml/min; Detection: UV (210 nm); Temperature: 25°C; Sample concentration: 30 μΐ of reaction solution evaporated, dissolved in 1 mL;

heptane/iPrOH (80/20); Injection volume: 10.0
Run time 20 min; Retention times: 5,5–dimethyl-3-methylenepyrrolidin-2-one: 13.8 min, (,S)-3,5,5-trimethyl-pynOlidin-2-one: 10.6 min, and (R)-3,5,5-trimethyl-pyrrolidin-2-one: 12.4 min.

Example 3: Alternate Synthesis of (S)-3,5,5-trimethyl-pyrrolidin-2-one from 5,5-dimethyl-3-methylenepyrrolidin-2-one

Ru(Me-allyl)₂(C0D)₂BF₄

1 eq HBF₄ Et₂0

5 bar H₂ at 45°C

[0063] Mandyphos (0.00479 mmol, 0.12 eq) was weighed into a GC vial. In a separate vial, Ru(Me-allyl)2(COD) (16.87 mg, 0.0528 mmol) was weighed and dissolved in DCM (1328 \iL). In another vial HBF₄ Et₂0 (6.6 μΐ,) and BF₃ Et₂0 (2.0 μΐ,) were dissolved in DCM (240 μΐ.). To the GC vial containing the ligand was added, under a flow of argon, the Ru(Me-allyl)₂(COD) solution (100 μΐ,; 0.00399 mmol, O. leq) and the HBF₄ Et₂0 / BF3 -Et₂0 solution (20 μΐ_^ 1 eq HBF₄ Et₂0 and catalytic BF₃ Et₂0). The resulting mixtures were stirred under a flow of argon for 30 minutes. 5,5-dimethyl-3-methylenepyrrolidin-2-one (5 mg, 0.0399 mmol) in EtOH (1 mL) was added. The vials were placed in the hydrogenation apparatus. The apparatus was flushed with H₂ (3 ^χ) and charged with 5 bar H₂. After standing for 45 minutes, the apparatus was placed in an oil bath at temperature of 45°C. The reaction mixtures were stirred overnight under H₂. 200 μΙ_, of the reaction mixture was diluted with MeOH (800 μΐ.) and analyzed for conversion and ee. ¹H MR (400 MHz, Chloroform-d) δ 6.39 (s, 1H), 2.62 (ddq, J = 9.9, 8.6, 7.1 Hz, 1H), 2.17 (ddd, J = 12.4, 8.6, 0.8 Hz, 1H), 1.56 (dd, J = 12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J = 7.1 Hz, 3H).

IPC analytical method for Asymmetric Hydrogenation

(3) (4S) (4R)

Example 4. Synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride from (S)-3,5,5-trimethyl-pyrrolidin-2-one

(4S) (1S)HCI

Example 4A:

[0064] Anhydrous THF (100 ml) was charged to a dry 750 ml reactor and the jacket temperature was set to 50° C. Once the vessel contents were at 50° C, LiAlH₄pellets (10 g, 263 mmol, 1.34 eq.) were added. The mixture was stirred for 10 minutes, then a solution of (4S) (25 g, 197 mmol) in anhydrous THF (100 ml) was added dropwise over 45 minutes, maintaining the temperature between 50-60° C. Once the addition was complete the jacket temperature was increased to 68° C and the reaction was stirred for 18.5 hrs. The reaction mixture was cooled to 30° C then saturated sodium sulfate solution (20.9 ml) was added dropwise over 30 minutes, keeping the temperature below 40° C. Vigorous evolution of hydrogen was observed and the reaction mixture thickened but remained mixable. The mixture thinned towards the end of the addition. The mixture was cooled to 20° C, diluted with iPrOAc (100 ml) and stirred for an additional 10 minutes. The suspension was then drained and collected through the lower outlet valve, washing through with additional iPrOAc (50 ml). The collected suspension was filtered through a Celite pad on a sintered glass funnel under suction and washed with iPrOAc (2×50 ml).

[0065] The filtrate was transferred back to the cleaned reactor and cooled to 0° C under nitrogen. 4M HCI in dioxane (49.1 ml, 197 mmol, leq.) was then added dropwise over 15 minutes, maintaining the temperature below 20°C. A white precipitate formed. The reactor was then reconfigured for distillation, the jacket temperature was increased to 100 °C, and distillation of solvent was carried out. Additional z-PrOAc (100 mL) was added during concentration, after >100 mL distillate had been collected. Distillation was continued until -250 mL total distillate was collected, then a Dean-Stark trap was attached and reflux continued for 1 hour. No water was observed to collect. The reaction mixture was cooled to 20 °C and filtered under suction under nitrogen. The filtered solid was washed with i-PrOAc (100 mL), dried under suction in nitrogen, then transferred to a glass dish and dried in a vacuum oven at 40 °C with a nitrogen bleed. Compound (1S)^»HC1 was obtained as a white solid (24.2g, 82%).

Synthesis 4B:

[0066] To a glass lined 120 L reactor was charged LiAlH₄ pellets (2.5 kg 66 mol, 1.2 equiv.) and dry THF (60 L) and warmed to 30 °C. To the resulting suspension was charged (¾⁾-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C. After complete addition, the reaction temperature was increased to 60 – 63 °C and maintained overnight. The reaction mixture was cooled to 22 °C and sampled to check for completion, then cautiously quenched with the addition of EtOAc (1.0 L, 10 moles, 0.16 eq) followed by a mixture of THF (3.4 L) and water (2.5 kg, 2.0 eq) then followed by a mixture of water (1.75 kg) with 50 % aqueous sodium hydroxide (750 g, 2 eq water with 1.4 eq sodium hydroxide relative to aluminum), followed by 7.5 L water (6 eq “Fieser” quench). After the addition was completed, the reaction mixture was cooled to room temperature, and the solid was removed by filtration and washed with THF (3 x 25 L). The filtrate and washings were combined and treated with 5.0 L (58 moles) of aqueous 37% HC1 (1.05 equiv.) while maintaining the temperature below 30°C. The resultant solution was concentrated by vacuum distillation to a slurry in two equal part lots on the 20 L Buchi evaporator.

Isopropanol (8 L) was charged and the solution reconcentrated to near dryness by vacuum distillation. Isopropanol (4 L) was added and the product slurried by warming to about 50 °C. Distillation from Isopropanol continued until water content by KF is < 0.1 %. Methyl tertbutyl ether (6 L) was added and the slurry cooled to 2-5 °C. The product was collected by filtration and rinsed with 12 L methyl tert-butyl ether and pulled dry with a strong nitrogen flow and further dried in a vacuum oven (55 °C/300 torr/N₂ bleed) to afford (S)-2,2,4-trimethylpyrrolidine^»HCl ((1S HC1) as a white, crystalline solid (6.21 kg, 75% yield). ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (s, 2H), 3.33 (dd, J= 11.4, 8.4 Hz, 1H), 2.75 (dd, J= 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, 7= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, 7= 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, 7= 6.6 Hz, , 3H).

Synthesis 4C:

[0067] With efficient mechanical stirring, a suspension of LiAlH₄ pellets (100 g 2.65 mol; 1.35 eq.) in THF (1 L; 4 vol. eq.) warmed at a temperature from 20 °C – 36 °C (heat of mixing). A solution of (¾⁾-3,5,5-trimethylpyrrolidin-2-one (250 g; 1.97 mol) in THF (1 L; 4 vol. eq.) was added to the suspension over 30 min. while allowing the reaction temperature to rise to -60 °C. The reaction temperature was increased to near reflux (-68 °C) and maintained for about 16 h. The reaction mixture was cooled to below 40 °C and cautiously quenched with drop-wise addition of a saturated aqueous solution of Na₂S0₄ (209 mL) over 2 h. After the addition was completed, the reaction mixture was cooled to ambient temperature, diluted with /-PrOAc (1 L), and mixed thoroughly. The solid was removed by filtration (Celite pad) and washed with /^‘-PrOAc (2 x 500 mL). With external cooling and N₂ blanket, the filtrate and washings were combined and treated with drop-wise addition of anhydrous 4 M HC1 in dioxane (492 mL; 2.95 mol; 1 equiv.) while maintaining the temperature below 20 °C. After the addition was completed (20 min), the resultant suspension was concentrated by heating at reflux (74 – 85 °C) and removing the distillate. The suspension was backfilled with /^‘-PrOAc (1 L) during concentration. After about 2.5 L of distillate was collected, a Dean-Stark trap was attached and any residual water was azeotropically removed. The suspension was cooled to below 30 °C when the solid was collected by filtration under a N₂ blanket. The solid is dried under N₂ suction and further dried in a vacuum oven (55 °C/300 torr/N₂ bleed) to afford 261 g (89% yield) of (S 2,2,4-trimethylpyrrolidine^»HCl ((1S HC1) as a white, crystalline solid. ¾ NMR (400 MHz, DMSO-^6) δ 9.34 (s, 2H), 3.33 (dd, J = 11 A, 8.4 Hz, 1H), 2.75 (dd, J= 11.4, 8.6 Hz, 1H), 2.50 – 2.39 (m, 1H), 1.97 (dd, J= 12.7, 7.7 Hz, 1H), 1.42 (s, 3H), 1.38 (dd, J = 12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J= 6.6 Hz, 3H). ¾ MR (400 MHz, CDCh) δ 9.55 (d, J= 44.9 Hz, 2H), 3.52 (ddt, J= 12.1, 8.7, 4.3 Hz, 1H), 2.94 (dq, J= 11.9, 5.9 Hz, 1H), 2.70 – 2.51 (m, 1H), 2.02 (dd, J= 13.0, 7.5 Hz, 1H), 1.62 (s, 3H), 1.58 – 1.47 (m, 4H), 1.15 (d, J= 6.7 Hz, 3H).

Synthesis 4D:

[0068] A 1L four-neck round bottom flask was degassed three times. A 2M solution of LiAlHun THF (100 mL) was charged via cannula transfer. (¾⁾-3,5,5-trimethylpyrrolidin-2-one (19.0 g) in THF (150 mL) was added dropwise via an addition funnel over 1.5 hours at 50-60 °C, washing in with THF (19 mL). Upon completion of the addition, the reaction was stirred at 60 °C for 8 hours and allowed to cool to room temperature overnight. GC analysis showed <1% starting material remained. Deionized water (7.6 mL) was added slowly to the reaction flask at 10-15 °C, followed by 15% potassium hydroxide (7.6 mL). Isopropyl acetate (76 mL) was added, the mixture was stirred for 15 minutes and filtered, washing through with isopropyl acetate (76 mL). The filtrate was charged to a clean and dry 500 mL four neck round bottom flask and cooled to 0-5 °C. 36% Hydrochloric acid (15.1 g, 1.0 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (190 mL), was carried out to leave a residual volume of -85 mL. Karl Fischer analysis = 0.11% w/w H2O. MTBE (methyl tertiary butyl ether) (19 mL) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (25 mL) and drying under vacuum at 40-45 °C to give crude (,S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (17.4 g, 78% yield). GC purity = 99.5%. Water content = 0.20% w/w. Chiral GC gave an ee of 99.0% (S). Ruthenium content = 0.004 ppm. Lithium content = 0.07 ppm. A portion of the dried crude ,S)-2,2,4-trimethylpyrrolidine hydrochloride (14.3g) was charged to a clean and dry 250 mL four-neck round bottom flask with isopropanol (14.3 mL) and the mixture held at 80-85 °C (reflux) for 1 hour to give a clear solution. The solution was allowed to cool to 50 °C (solids precipitated on cooling) then MTBE (43 mL) was added and the suspension held at 50-55 °C (reflux) for 3 hours. The solids were filtered off at 10 °C, washing with MTBE (14 mL) and dried under vacuum at 40 °C to give recrystallised (S)- 2.2.4- trimethylpyrrolidine hydrochloride ((1S)^»HC1) as a white crystallised solid (13.5 g, 94% yield on recrystallisation, 73% yield). GC purity = 99.9%. Water content = 0.11% w/w. 99.6% ee (Chiral GC) (S). Ruthenium content = 0.001 ppm. Lithium content = 0.02 ppm.

Synthesis 4E:

[0069] A reactor was charged with lithium aluminum hydride (LAH) (1.20 equiv.) and 2-MeTHF (2-methyltetrahydrofuran) (4.0 vol), and heated to internal temperature of 60 °C while stirring to disperse the LAH. A solution of (¾⁾-3,5,5-trimethylpyrrolidin-2-one (1.0 equiv) in 2-MeTHF (6.0 vol) was prepared and stirred at 25 °C to fully dissolve the (S)- 3.5.5- trimethylpyrrolidin-2-one. The (¾⁾-3,5,5-trimethylpyrrolidin-2-one solution was added slowly to the reactor while keeping the off-gassing manageable, followed by rinsing the addition funnel with 2-MeTHF (1.0 vol) and adding it to the reactor. The reaction was stirred at an internal temperature of 60 ± 5 °C for no longer than 6 h. The internal temperature was set to 5 ± 5 °C and the agitation rate was increased. A solution of water (1.35 equiv.) in 2-MeTHF (4.0v) was prepared and added slowly to the reactor while the internal temperature was maintained at or below 25 °C. Additional water (1.35 equiv.) was charged slowly to the reactor while the internal temperature was maintained at or below 25 °C. Potassium hydroxide (0.16 equiv.) in water (0.40 vol) was added to the reactor over no less than 20 min while the temperature was maintained at or below 25 °C. The resulting solids were removed by filtration, and the reactor and cake were washed with 2-MeTHF (2 x 2.5 vol). The filtrate was transferred back to a jacketed vessel, agitated, and the temperature was adjusted to 15 ± 5 °C. Concentrated aqueous HC1 (35-37%, 1.05 equiv.) was added slowly to the filtrate while maintaining the temperature at or below 25 °C and was stirred no less than 30 min. Vacuum was applied and the solution was distilled down to a total of 4.0 volumes while maintaining the internal temperature at or below 55 °C, then 2-MeTHF (6.00 vol) was added to the vessel. The distillation was repeated until Karl Fischer analysis (KF) < 0.20% w/w H2O. Isopropanol was added (3.00 vol), and the temperature was adjusted to 70 °C (65 – 75 °C) to achieve a homogenous solution, and stirred for no less than 30 minutes at 70 °C. The solution was cooled to 50 °C (47 – 53 °C) over 1 hour and stirred for no less than 1 h, while the temperature was maintained at 50°C (47 – 53 °C). The resulting slurry was cooled to -10 °C (-15 to -5°C) linearly over no less than 12 h. The slurry was stirred at -10 °C for no less than 2 h. The solids were isolated via filtration or centrifugation and were washed with a solution of 2-MeTHF (2.25 vol) and IPA (isopropanol) (0.75 vol). The solids were dried under vacuum at 45 ± 5 °C for not less than 6 h to yield (,S)-2,2,4-trimethylpyrrolidine hydrochloride ((1S)^»HC1).

Example 5: Phase Transfer Catalyst (PTC) Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0070] Various PTCs were tested as described below:

[0071] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq.), PTC (0.05 eq.), and chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added dropwise over 2 min. The reaction mixture was stirred until completion as assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic

phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion and assessed by

HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. The reaction results are summarized in the following table:

Example 6: Solvent Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0072] Various solvents and amounts were tested as described below:

[0073] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”)), tetrabutylammonium hydroxide (0.12 g, 0.153 mmol, 0.050 eq), chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.), and solvent (2v or 4v, as shown below) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion and assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. Reaction results are summarized in the following table:

Example 7: Base Screens for the Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0074] In this experiment, various concentrations of NaOH were tested as described below:

[0075] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”), tetrabutylammonium hydroxide (0.12 g, 0.153 mmol, 0.050 eq), and chloroform (0.64 g, 0.4 mL, 5.36 mmol, 1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath, and a solution of an amount wt% sodium hydroxide as shown in the Table below in water (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion and assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H2O (3.0 mL, 6.0v). The phases were separated and the aqueous phase is extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL,

2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC.

Reaction results are summarized in the following table:

Example 8: Phase Transfer Catalyst (PTC) Synthesis of 5,5-dimethyl-3-methylenepyrrolidin-2-one

[0076] Various amounts of PTCs were tested as described below:

Tetrabutylammonium hydroxide (0.01 eq.), TBAB (0.01 eq.), Tributylmethylammonium chloride (0.01 eq.), Tetrabutylammonium hydroxide (0.02 eq.), TBAB (0.02 eq.), Tributylmethylammonium chloride (0.02 eq.), Tetrabutylammonium hydroxide (0.03 eq.), TBAB (0.03 eq.), Tributylmethylammonium chloride (0.03 eq.).

[0077] 2,2,6,6-tetramethylpiperidin-4-one (500.0 mg, 3.06 mmol, 1.0 eq. (“starting material”)), PTC (0.12 g, 0.153 mmol, 0.050 eq), and chloroform (1.75 eq.) were charged into a vial equipped with a magnetic stir bar. The vial was cooled in an ice bath, and a solution of 50 wt% sodium hydroxide (0.98 g, 24.48 mmol, 8.0 eq.) was added drop wise over 2 min. The reaction mixture was stirred until completion, assessed by GC analysis. The reaction mixture was diluted with DCM (2.0 mL, 4.0v) and H₂0 (3.0 mL, 6.0v). The phases were separated and the aqueous phase was extracted with DCM (1.0 mL, 2.0v). The organic phases were combined and 2 M hydrochloric acid (0.17 g, 2.3 mL, 4.59 mmol, 1.5 eq.) was added. The reaction mixture was stirred until completion, assessed by HPLC. The aqueous phase was saturated with NaCl and the phases were separated. The aqueous phase was extracted with DCM (1.0 mL, 2.0v) twice, the organic phases were combined, and 50 mg of biphenyl in 2 mL of MeCN was added as an internal HPLC standard. Solution yield was assessed by HPLC. The reaction results are summarized in the following table:

Reactions Conditions Result

8D Tetrabutylammonium hydroxide Almost complete

(0.02 eq.) overnight (2% starting

material), 82% solution yield

8E TBAB (0.02 eq.) Almost complete

overnight (2% starting material), 71% solution yield

8F Tributylmethylammonium chloride Incomplete overnight (4%

(0.02 eq.) starting material), 72%

solution yield

8G Tetrabutylammonium hydroxide Almost complete

(0.03 eq.) overnight (3% starting

material), 76% solution yield

8H TBAB (0.03 eq.) Almost complete

overnight (3% starting material), 76% solution yield

81 Tributylmethylammonium chloride Almost complete

(0.03 eq.) overnight (2% starting

material), 78% solution yield

Example 9. Preparation of 2,2,6,6-tetramethylpiperidin-4-one hydrochloride

2,2,6,6-tetramethylpiperidin-4-one 2,2,6,6-tetramethylpiperidin-4-one hydrochloride

[0078] 2,2,6,6-tetramethyl-4-piperidinone (30 g, 193.2 mmol, 1.0 eq) was charged to a 500 mL nitrogen purged three necked round bottomed flask equipped with condenser. IPA (300 mL, 10 vol) was added to the flask and the mixture heated to 60 °C until dissolved.

[0079] To the solution at 60 °C was added 5-6 M HC1 in IPA (40 mL, 214.7 mmol, 1.1 eq) over 10 min and the resulting suspension stirred at 60 °C for 30 min then allowed to cool to ambient temperature. The suspension was stirred at ambient temperature overnight, then filtered under vacuum and washed with IPA (3 x 60 mL, 3 x 2 vol). The cream colored solid was dried on the filter under vacuum for 10 min.

[0080] The wet cake was charged to a 1 L nitrogen purged three necked round bottomed flask equipped with condenser. IPA (450 mL, 15 vol) was added to the flask and the suspension heated to 80 °C until dissolved. The mixture was allowed to cool slowly to ambient temperature over 3 h and the resulting suspension stirred overnight at ambient temperature.

[0081] The suspension was filtered under vacuum, washed with IPA (60 mL, 2 vol) and dried on the filter under vacuum for 30 min. The resulting product was dried in a vacuum oven at 40 °C over the weekend to give a white crystalline solid, 21.4 g, 64% yield.

Example 10. Synthesis of (S)-2,2,4-trimethylpyrrolidine hydrochloride from (S)-3,5,5-trimethyl-pyrrolidin-2-one

[0082] Each reactor was charged with (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF, H₂, and the catalyst shown in the below table. The reactor was heated to 200 C and pressurized to 60 bar, and allowed to react for 12 hours. GC analysis showed that (S)-2,2,4-trimethylpyrrolidine was produced in the columns denoted by “+.”

[0083] A 2.5% solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 2% Pt-0.5%>Sn/SiO₂catalyst immobilized on silica gel. H₂ gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 130 °C under 80 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h^“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%>

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (74.8%> yield, 96.1% ee).

Alternate synthesis

[0084] A 2.5%) solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 4% Pt-2%>Sn/Ti0₂catalyst immobilized on silica gel. H₂ gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 200 °C under 50 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h^“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%

Alternate synthesis

[0085] A 2.5% solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.05 mL/min into a packed bed reactor prepacked with 2% Pt-0.5%>Sn/TiO2 catalyst immobilized on silica gel. H₂ gas was also flowed into the packed bed reactor at 20 mL/min. The reaction was carried out at 150 °C under 50 bar pressure with a WHSV (Weigh Hourly Space Velocity) of 0.01-0.02 h^“1. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36%>

Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H₂0. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (90.9% yield, 98.0%> ee).

Alternate synthesis

[0086] A 2.5%) solution of (,S)-3,5,5-trimethyl-pyrrolidin-2-one in THF was flowed at 0.03 mL/min into a packed bed reactor prepacked with 2% Pt-8%>Sn/Ti0₂catalyst immobilized on silica gel. H₂ gas was also flowed into the packed bed reactor at 40 mL/min. The reaction was carried out at 180 °C under 55 bar pressure with a residence time of 6 min. The product feed was collected in a batch tank and converted to (S)-2,2,4-trimethylpyrrolidine HC1 in batch mode: 36% Hydrochloric acid (1.1 eq.) was added keeping the temperature below 20 °C. Distillation of the solvent, backfilling with isopropyl acetate (4v), was carried out to leave a residual volume of 5v. Karl Fischer analysis < 0.2% w/w H2O. MTBE (methyl tertiary butyl ether) (lv) was added at 20-30 °C and the solids were filtered off under nitrogen at 15-20 °C, washing with isopropyl acetate (1.5v) and drying under vacuum at 40-45 °C to give (,S)-2,2,4-trimethylpyrrolidine hydrochloride as a white crystalline solid (90.4%> yield, 96.8%> ee).

Patent

WO 2019010092

PATENT

US 20160095858

https://patents.google.com/patent/US20160095858A1/en

Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 disease causing mutations in the CF gene have been identified (http://cftr2.org). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as F508del. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.

The deletion of residue 508 in F508del prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of F508del in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to F508del, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.

Accordingly, there is a need for novel treatments of CFTR mediated diseases.

////////////////OLACAFTOR, VX 440, Phase II, Cystic fibrosis, CS-0044588, UNII-RZ7027HK8F, RZ7027HK8F

CC1CC(N(C1)C2=C(C=CC(=N2)C3=CC(=CC(=C3)F)OCC(C)C)C(=O)NS(=O)(=O)C4=CC=CC=C4)(C)C

Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

February 28, 2019 2:19 pm / Leave a comment

Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

Makoto Michida *^†

, Hideaki Ishikawa^†, Takeshi Kaneda^†, Shinya Tatekabe^‡, and Yoshitaka Nakamura^§

^†Process Technology Research Laboratories (PTRL), Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-0014, Japan

^‡Plant Management Department, Daiichi Sankyo Chemical Pharma Co., Ltd., 477 Takada, Odawara-shi, Kanagawa 250-0216, Japan

^§Global Supply Chain – Technology Function, Daiichi Sankyo, Inc., 211 Mt. Airy Road, Basking Ridge, New Jersey 07920, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00413

*E-mail: michida.makoto.wp@daiichisankyo.co.jp.

This article is part of the Japanese Society for Process Chemistry special issue

We report the development of a novel synthetic method to access a key intermediate in the synthesis of edoxaban. The main features of the new synthetic method are an improvement in the approach for the synthesis of a key chiral bromolactone, application of an interesting cyclization reaction utilizing neighboring group participation to construct a differentially protected 1,2-cis-diamine, and implementation of plug-flow reactor technology to enable the reaction of an unstable intermediate on multihundred kilogram scale. The overall yield for the preparation of edoxaban was significantly increased by implementing these changes and led to a more efficient and environmentally friendly manufacturing process.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00413

//////////

Viloxazine, ヴィロキサジン;

February 27, 2019 1:18 pm / Leave a comment

ChemSpider 2D Image | Viloxazine | C13H19NO3

Viloxazine

Molecular FormulaC₁₃H₁₉NO₃
Average mass237.295 Da

update FDA APPROVED 2021/4/2, Qelbree, Viloxazine hydrochloride

Formula	C13H19NO3. HCl
CAS	35604-67-2
Mol weight	273.7558

2-[(2-Ethoxyphenoxy)methyl]morpholine

256-281-7 [EINECS]

3489

46817-91-8 free [RN], Hcl 35604-67-2

5I5Y2789ZF

Emovit [Wiki]

Morpholine, 2-((2-ethoxyphenoxy)methyl)-

Morpholine, 2-[(2-ethoxyphenoxy)methyl]-

UNII:5I5Y2789ZF

Viloxazine hydrochloride

OQW30I1332

35604-67-2

Polymorph

FORM A , B US226136693, US2011032013

NEW DRUG APPROVALS

ONE TIME

$10.00

Viloxazine (trade names Vivalan, Emovit, Vivarint and Vicilan) is a morpholine derivative and is a selective norepinephrine reuptake inhibitor (NRI). It was used as an antidepressant in some European countries, and produced a stimulant effect that is similar to the amphetamines, except without any signs of dependence. It was discovered and brought to market in 1976 by Imperial Chemical Industries and was withdrawn from the market in the early 2000s for business reasons.

Clip

https://www.sciencedirect.com/science/article/pii/S0040402015302659

Patent

US 20180265482

https://patentscope.wipo.int/search/en/detail.jsf?docId=US226136693&tab=PCTDESCRIPTION&maxRec=1000

Viloxazine ((R,S)-2-[(2-ethoxyphenoxy)methyl]morpholine]) is a bicyclic morpholine derivative, assigned CAS No. 46817-91-8 (CAS No. 35604-67-2 for the HCl salt). It is characterized by the formula C ₁₃H ₁₉NO ₃, with a molecular mass of 237.295 g/mol. Viloxazine has two stereoisomers, (S)-(−)- and (R)-(+)-isomer, which have the following chemical structures:

Viloxazine is known to have several desirable pharmacologic uses, including treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism, among others. In vivo, viloxazine acts as a selective norepinephrine reuptake inhibitor (“NRI”).

Between the two stereoisomers, the (S)-(−)-isomer is known to be five times as pharmacologically active as the (R)-(+)-isomer. See, e.g., “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” (Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074) in which it is disclosed that optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine were prepared and absolute configurations assigned. The synthesis of optical isomers of viloxazine analogs of known configuration was accomplished by resolution of the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers.

Some unsatisfactory methods of synthesizing viloxazine are known in the art. For example, as disclosed in U.S. Pat. No. 3,714,161, viloxazine is prepared by reacting ethoxyphenol with epichlorohydrin to afford the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane. This epoxide intermediate is then treated with benzylamine followed with chloroacetyl chloride. The resulting morpholinone is then reduced by lithium aluminum hydride and then by Pd/C-catalyzed hydrogenation to yield viloxazine free base.

Yet another unsatisfactory synthesis of viloxazine is disclosed in U.S. Pat. No. 3,712,890, which describes a process to prepare viloxazine HCl, wherein the epoxide intermediate, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, is reacted with 2-aminoethyl hydrogen sulfate in ethanol in the presence of sodium hydroxide to form viloxazine free base. The product is extracted with diethyl ether from the aqueous solution obtained by evaporating the solvent in the reaction mixture then adding water to the residue. The ethereal extract is dried over a drying agent and the solvent is removed. Viloxazine HCl salt is finally obtained by dissolving the previous residue in isopropanol, concentrated aqueous HCl, and ethyl acetate followed by filtration.

The foregoing methods of synthesizing viloxazine suffer from a number of deficiencies, such as low reaction yield and unacceptably large amount of impurities in the resulting product. Effective elimination or removal of impurities, especially those impurities possessing genotoxicity or other toxicities, is critical to render safe pharmaceutical products. For example, certain reagents traditionally utilized in viloxazine HCl preparation, such as epichlorohydrin and 2-aminoethyl hydrogen sulfate, present a special problem due to their toxicity. There is a need for effective methods to remove or limit harmful impurities down to a level that is appropriate and safe according to contemporary sound medical standards and judgment. Accordingly, a continuing and unmet need exists for new and improved methods of manufacturing viloxazine and its various salts to yield adequate quantities of pharmacologically desirable API with predictable and reliable control of impurities.

Polymorph control is also an important aspect of producing APIs and their associated salts that are used in pharmaceutical products. However, no polymorphs of viloxazine HCl have previously been disclosed. A need therefore exists for new polymorphic forms of viloxazine that have improved pharmacological properties.

PATENT

WO 2011130194

US2011032013

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011130194&recNum=110&docAn=US2011032013&queryString=(%20pheno*%20or%20isopropoxy*%20or%20oxiran*%20or%20bisoprolol*%20)%20and%20(%20C07C213*%20or%20C07C217*%20or%20C07C209*%20or%20C07C41*%20or%20C07D263*%20)&maxRec=2245

For the sake of convenience and without putting any limitations thereof, the methods of manufacture of viloxazine have been separated into several steps, each step being disclosed herein in a multiplicity of non-limiting embodiments. These steps comprise Step 1, during which 2-ethoxyphenol and epichlorhydrin are reacted to produce l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1); Step 2, during which l-(2-ethoxyphenoxy)-2,3-epoxypropane (Epoxide 1) is converted into viloxazine base which is further converted into viloxazine salt, and Step 3, during which viloxazine salt is purified/recrystallized, and various polymorphic forms of viloxazine salt are prepared.

The above-mentioned steps will be considered below in more details.

[0031] The process of the Step 1 may be advantageously carried out in the presence of a phase-transfer catalyst to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane. Alternatively, the process may make use of a Finkelstein catalyst described in more details below. Additionally, the reaction may take place without the use of the catalyst.

FIG. 1, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with Step I of an exemplary synthesis of viloxazine:

STEP I:

Epoxide 1

In one embodiment of the Step 1, the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (epoxide 1) can be effected by the use of a phase transfer catalyst in the presence of a solid or liquid base with a solution of a corresponding phenol and epichlorohydrin in one or more solvents (Fig. 1). The phase transfer catalyst can be selected from ammonium salts, such as benzyltriethylammonium salts, benzyltrimethylammonium salts, and tetrabutylammonium salts, phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The solid or liquid base can be a carbonate such as alkali carbonate, NaOH, KOH, LiOH, LiOH/LiCl, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, or other appropriate base. The solvents used in the solution of a corresponding phenol and epichlorohydrin include but are not limited to ethers such as methyl t-butyl ether, ketones, non-substituted or substituted aromatic solvents (xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, DMF, dioxanes, non-substituted and substituted pyridines, acetonitrile, pyrrolidones, nitromethane , or other appropriate solvent. Additional catalyst, such as, for example, Finkelstein catalyst, can also be used in the process of this embodiment. This reaction preferably takes place at an elevated temperature. In one variation of the embodiment, the temperature is above 50°C. In another variation, epichlorohydrin, potassium carbonate, and a phase transfer catalyst are mixed with a solution of 2-ethoxyphenol in a solvent at an elevated temperature, such as 50 – 60°C. After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Variations of this embodiment of the invention are further disclosed in Examples 1-8.

[0033] In one variation of the above embodiment of the Step 1 , Epoxide 1 is prepared by reacting 2-ethoxyphenol and epichlorohydrin in a solvent in the presence of two different catalysts, and a base in a solid state. The first catalyst is a phase transfer catalyst as described above; the second catalyst is a Finkelstein reaction catalyst. Without putting any limitation

hereon, metal iodide and metal bromide salts, such as potassium iodide, may be used as an example of a Finkelstein catalyst. The phase transfer catalyst and a solvent may be selected from any phase transfer catalysts and solvents known in the art. Potassium carbonate may be used as a non-limiting example of a solid base. Using the solid base in a powdered form may be highly beneficial due to the greatly enhanced interface and limiting the side reactions. This variation of the embodiment is further illustrated by Example 9. In another variation of the embodiment, liquid base such as triethylamine can be used to replace the solid base.

[0034] In a different embodiment of Step 1 , 2-ethoxyphenol and epichlorohydrin are reacted in a solvent-free system that comprises a solid or liquid base, a phase transfer catalyst as listed above and a Finkelstein catalyst.

[0035] FIG. 2, depicted below, schematically illustrates the preparation of l-(2-ethoxyphenoxy)-2,3-epoxypropane (“Epoxide 1”) in accordance with the Step I of another exemplary synthesis of viloxazine ( biphasic):

STEP I (alternative embodiment):

In this embodiment of Step 1, illustrated in Fig. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of l-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after

removal of excess epichlorohydrin, using a base and a solvent. The reaction produces l-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di-or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2C12, CHC13), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60°C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60 – 90°C for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.

[0036] In yet another embodiment of Step 1 , Epoxide 1 can also be prepared by using a catalyst for a so-called Finkelstein reaction in the presence of a Finkelstein catalyst but without the need to use a phase transfer catalyst. Finkelstein catalysts useful herein include metal iodide salts and metal bromide salts, among others. In one variation of this embodiment, 2-ethoxyphenol and epichlorohydrin are dissolved in a polar aprotic solvent such as DMF, and a catalytic amount of an iodide such as potassium iodide and a base, as solid or liquid, are used. Preferably, the base is used as a solid, such as potassium carbonate powder. This embodiment is further illustrated by the Example 11.

[0037] In the alternative embodiment of Step 1 , Epoxide 1 can also be prepared by a different method that comprises reacting epichlorohydrin and the corresponding phenol in the presence of a base at a temperature lower than the ambient temperature, especially when a base solution is used, and without the use of a phase transfer catalyst. This embodiment is illustrated by the Example 10.

[0038] A very high, almost quantitative, yield of 1 -(2-ethoxyphenoxy)-2,3-epoxypropane can be obtained through realizing the above-described embodiments of Step 1 , with less impurities generated in Epoxide 1.

[0039] Epoxide 1 , produced in Step 1 as described above, is used to prepare viloxazine base (viloxazine), which is further converted into viloxazine salt through the processes of Step 2.

[0040] FIG. 3, depicted below, schematically illustrates the preparation of viloxazine

(“Step Ila”) and the preparation of viloxazine hydrochloride (“Step lib”), as well as their purification (“Step III”) in accordance with another example embodiment hereof:

STEP Ila:

Hydrogen Sulfate

STEP lib:

Step III:

Conversion

Viloxazine free base ► Viloxazine salt

Wash/ raction

Recrystallization

Purified viloxazine salt

In the embodiment of Step 2, illustrated in Fig. 3, the preparation of viloxazine base is achieved by reacting the Epoxide 1 intermediate prepared in Step 1 and aminoethyl hydrogen sulfate in presence of a large excess of a base as illustrated by the Examples 5-7 and 14. The base may be present as a solid or in a solution. Preferably, the molar ratio of the base to Epoxide 1 is more than 10. More preferably the ratio is more than 12. Even more preferably, the ratio is between 15 and 40. It was unexpectedly discovered that the use of a higher ratio of a base results in a faster reaction, less impurities, and lower reaction temperature.

[0041] Further advantages may be offered by a specific variation of this embodiment, wherein the base is added to the reaction mixture in several separate steps. For example, a third of the base is added to the reaction mixture, and the mixture is stirred for a period of time. Then the rest of the base is added followed by additional stirring. Alternatively, half of the base is added initially followed by the second half after some period of time, or the base is added in three different parts separated by periods of time. The bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2C03, Na2C03, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine), DMAP, and combinations thereof. . In one embodiment of the invention, the base is KOH. In another embodiment, the base is NaOH. In a further embodiment, the base is K2C03 powder. In yet further embodiment, the base is triethylamine. This embodiment is illustrated further by

Examples 13,15 and 16.

[0042] In another exemplary embodiment of Step 2, viloxazine is produced by cyclization of novel intermediate compound “Diol 1 ,” which is made from Epoxide 1 and N-benzyl-aminoethanol. This method allows one to drastically reduce the use of potentially toxic materials in the manufacturing process, completely eliminating some of them such as aminoethyl hydrogen sulfate. The first stage of the reaction results in the formation of an intermediate of Formula 3 (Diol 1), which is a new, previously unidentified compound.

[0043] Formula 3

Diol 1

FIG. 4, depicted below, schematically illustrates the preparation of viloxazine and its salts via “Diol 1” in accordance with another exemplary embodiment hereof (Bn = benzyl, Et = ethyl):

Viloxazine HCI

As illustrated in Fig. 4, Diol 1 is turned into N-benzyl viloxazine by cyclization. Removal of the benzyl protective group yields viloxazine base. Similarly, FIG. 5, depicted below, schematically illustrates the cyclization of Diol 1, as well as some side-reactions thereof.

Uses

Viloxazine hydrochloride was used in some European countries for the treatment of clinical depression.^[4]^[5]

Side effects

Side effects included nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so was not completely contraindicated in epilepsy,^[6]) and increased libido.^[7]

Drug interactions

Viloxazine increased plasma levels of phenytoin by an average of 37%.^[8] It also was known to significantly increase plasma levels of theophylline and decrease its clearance from the body,^[9] sometimes resulting in accidental overdose of theophylline.^[10]

Mechanism of action

Viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.^[11] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.^[11]

It was also found to up-regulate GABA_B receptors in the frontal cortex of rats.^[12]

Chemical properties

It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.^[13]

History

Viloxazine was discovered by scientists at Imperial Chemical Industries when they recognized that some beta blockers inhibited serotonin reuptake inhibitor activity in the brain at high doses. To improve the ability of their compounds to cross the blood brain barrier, they changed the ethanolamine side chain of beta blockers to a morpholine ring, leading to the synthesis of viloxazine.^[14]^:610^[15]^:9 The drug was first marketed in 1976.^[16] It was never approved by the FDA,^[5] but the FDA granted it an orphan designation (but not approval) for cataplexy and narcolepsy in 1984.^[17] It was withdrawn from markets worldwide in 2002 for business reasons.^[14]^[18]

As of 2015, Supernus Pharmaceuticals was developing formulations of viloxazine as a treatment for ADHD and major depressive disorder under the names SPN-809 and SPN-812.^[19]^[20]

Research

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.^[21]^[22] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.^[23]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM^[24] without really improving daytime somnolence.^[25]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy.^[18]

Viloxazine has also been studied for the treatment of alcoholism, with some success.^[26]

While viloxazine may have been effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia.^[27]

It is also under investigation as a treatment for attention deficit hyperactivity disorder.^[28]

REFERNCES

^ Bouchard JM, Strub N, Nil R (October 1997). “Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial”. Journal of Affective Disorders. 46 (1): 51–8. doi:10.1016/S0165-0327(97)00078-5. PMID 9387086.
^ Case DE, Reeves PR (February 1975). “The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans”. Xenobiotica. 5 (2): 113–29. doi:10.3109/00498257509056097. PMID 1154799.
^ “SID 180462– PubChem Substance Summary”. Retrieved 5 November 2005.
^ Pinder, RM; Brogden, RN; Speight, ™; Avery, GS (June 1977). “Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness”. Drugs. 13 (6): 401–21. doi:10.2165/00003495-197713060-00001. PMID 324751.
^ Jump up to:^a ^b Dahmen, MM, Lincoln, J, and Preskorn, S. NARI Antidepressants, pp 816-822 in Encyclopedia of Psychopharmacology, Ed. Ian P. Stolerman. Springer-Verlag Berlin Heidelberg, 2010. ISBN 9783540687061
^ Edwards JG, Glen-Bott M (September 1984). “Does viloxazine have epileptogenic properties?”. Journal of Neurology, Neurosurgery, and Psychiatry. 47 (9): 960–4. doi:10.1136/jnnp.47.9.960. PMC 1027998. PMID 6434699.
^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). “Antidepressants and sexual stimulation: the correlation” [Antidepressants and sexual stimulation: the correlation]. L’Encéphale (in French). 24 (3): 180–4. PMID 9696909.
^ Pisani F, Fazio A, Artesi C, et al. (February 1992). “Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction”. Journal of Neurology, Neurosurgery, and Psychiatry. 55 (2): 126–7. doi:10.1136/jnnp.55.2.126. PMC 488975. PMID 1538217.
^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). “A study of the interaction of viloxazine with theophylline”. Therapeutic Drug Monitoring. 11 (5): 520–2. doi:10.1097/00007691-198909000-00005. PMID 2815226.
^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). “Theophylline intoxication following viloxazine induced decrease in clearance”. European Journal of Clinical Pharmacology. 30 (3): 351–3. doi:10.1007/BF00541543. PMID 3732375.
^ Jump up to:^a ^b Lippman W, Pugsley TA (August 1976). “Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities”. Canadian Journal of Physiology and Pharmacology. 54 (4): 494–509. doi:10.1139/y76-069. PMID 974878.
^ Lloyd KG, Thuret F, Pilc A (October 1985). “Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock”. The Journal of Pharmacology and Experimental Therapeutics. 235 (1): 191–9. PMID 2995646.
^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). “Behavioral and radioreceptor analysis of viloxazine stereoisomers” [Behavioral and radioreceptor analysis of viloxazine stereoisomers]. Biulleten’ Eksperimental’noĭ Biologii i Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891.
^ Jump up to:^a ^b Williams DA. Antidepressants. Chapter 18 in Foye’s Principles of Medicinal Chemistry, Eds. Lemke TL and Williams DA. Lippincott Williams & Wilkins, 2012. ISBN 9781609133450
^ Wermuth, CG. Analogs as a Means of Discovering New Drugs. Chapter 1 in Analogue-based Drug Discovery. Eds.IUPAC, Fischer, J., and Ganellin CR. John Wiley & Sons, 2006. ISBN 9783527607495
^ Olivier B, Soudijn W, van Wijngaarden I. Serotonin, dopamine and norepinephrine transporters in the central nervous system and their inhibitors. Prog Drug Res. 2000;54:59-119. PMID 10857386
^ FDA. Orphan Drug Designations and Approvals: Viloxazine Page accessed August 1, 2-15
^ Jump up to:^a ^b Vignatelli L, D’Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003724. Review. PMID 18254030
^ Bloomberg Supernus profile Page accessed August 1, 2015
^ Supernus. Psychiatry portfolio Page accessed August 1, 2015
^ Attenburrow AA, Stanley TV, Holland RP (January 1984). “Nocturnal enuresis: a study”. The Practitioner. 228 (1387): 99–102. PMID 6364124.
^ ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). “Viloxazine versus imipramine in the treatment of enuresis”. The Turkish Journal of Pediatrics. 29 (4): 227–30. PMID 3332732.
^ Libert MH (1990). “The use of viloxazine in the treatment of primary enuresis” [The use of viloxazine in the treatment of primary enuresis]. Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930.
^ Guilleminault C, Mancuso J, Salva MA, et al. (1986). “Viloxazine hydrochloride in narcolepsy: a preliminary report”. Sleep. 9 (1 Pt 2): 275–9. PMID 3704453.
^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). “Narcolepsy”. Journal of Clinical Neurophysiology. 7 (1): 93–118. doi:10.1097/00004691-199001000-00008. PMC 2254143. PMID 1968069.
^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). “Alcoholism and depression: a placebo controlled study with viloxazine”. International Journal of Clinical Pharmacology Research. 10 (5): 293–8. PMID 2079386.
^ León CA, Vigoya J, Conde S, Campo G, Castrillón E, León A (March 1994). “Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia” [Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia]. Acta Psiquiátrica Y Psicológica de América Latina (in Spanish). 40 (1): 41–9. PMID 8053353.
^ Mattingly, GW; Anderson, RH (December 2016). “Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems”. CNS Spectrums. 21 (S1): 45–59. doi:10.1017/S1092852916000808. PMID 28044946.

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Clinical data


Routes of administration	By mouth, intravenous infusion^[1]
ATC code	N06AX09 (WHO)
Legal status
Legal status	In general: uncontrolled
Pharmacokinetic data
Elimination half-life	2–5 hours
Excretion	Renal^[2]
Identifiers
IUPAC name [show]
CAS Number	46817-91-8 35604-67-2 (HCl salt)
PubChem CID	5666
ChemSpider	5464
UNII	5I5Y2789ZF
KEGG	D08673
ChEMBL	ChEMBL306700
ECHA InfoCard	100.051.148
Chemical and physical data
Formula	C₁₃H₁₉NO₃
Molar mass	237.295 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES [hide]O(c1ccccc1OCC)CC2OCCNC2
InChI [hide]InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N

/////////////////Viloxazine, ヴィロキサジン , Emovit, Vivalan, Emovit, Vivarint, Vicilan

Macimorelin acetate

February 17, 2019 12:40 pm / Leave a comment

ChemSpider 2D Image | Macimorelin | C26H30N6O3

Macimorelin

Molecular FormulaC₂₆H₃₀N₆O₃
Average mass474.555 Da

CAS 381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

2-Methylalanyl-N-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]-D-tryptophanamide

381231-18-1 [RN]

8680B21W73

9073

D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-

CAS 945212-59-9 (Macimorelin acetate)

(2R)-2-(2-amino-2-methylpropanamido)-3-(1H-indol-3-yl)-N-[(1R)-2-(1H-indol-3-yl)-1-formamidoethyl]propanamide; acetic acid

AEZS-130
ARD-07
D-87875
EP-01572
EP-1572
JMV-1843

USAN (ab-26)
MACIMORELIN ACETATE

AQZ1003RMG

ARD 07

D-87575

D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1) [ACD/Index Name]

EP 1572

THERAPEUTIC CLAIM
Diagnostic agent for adult growth hormone deficiency (AGHD)
CHEMICAL NAMES
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate

MOLECULAR FORMULA
C26H30N6O3.C2H4O2
MOLECULAR WEIGHT
534.6

SPONSOR
Aeterna Zentaris GmbH
CODE DESIGNATIONS
D-87575, EP 1572, ARD 07
CAS REGISTRY NUMBER
945212-59-9

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a diagnostic test for growth hormone deficiencies in adults has been completed.

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

QUEBEC, Nov. 5, 2013 /PRNewswire/ – Aeterna Zentaris Inc. (the “Company”) today announced that it has submitted a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for its ghrelin agonist, macimorelin acetate (AEZS-130). Phase 3 data have demonstrated that the compound has the potential to become the first orally-approved product that induces growth hormone release to evaluate adult growth hormone deficiency (“AGHD”), with accuracy comparable to available intravenous and intramuscular testing procedures. read at

http://www.drugs.com/nda/macimorelin_acetate_131105.html

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

macimorelin (JMV 1843), a ghrelin-mimetic growth hormone secretagogue in Phase III for adult growth hormone deficiency (AGHD)

Macimorelin, a growth hormone modulator, is currently awaiting registration in the U.S. by AEterna Zentaris as an oral diagnostic test of adult growth hormone deficit disorder. The company is also developing the compound in phase II clinical trials for the treatment of cancer related cachexia. The compound was being codeveloped by AEterna Zentaris and Ardana Bioscience; however, the trials underway at Ardana were suspended in 2008 based on a company strategic decision. AEterna Zentaris owns the worldwide rights of the compound. In 2007, orphan drug designation was assigned by the FDA for the treatment of growth hormone deficit in adults.

Macimorelin (INN), or Macrilen (trade name) is a drug being developed by Æterna Zentaris for use in the diagnosis of adult growth hormone deficiency. Macimorelin acetate, the salt formulation, is a synthetic growth hormone secretagogue receptor agonist.^[1]Macimorelin acetate is described chemically as D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-acetate.

As of January 2014, it was in Phase III clinical trials.^[2] The phase III trial for growth hormone deficiency is expected to be complete in December 2016.^[3]

As of December 2017, it became FDA-approved as a method to diagnose growth hormone deficiency.^[4] Traditionally, growth hormone deficiency was diagnosed via means of insulin tolerance test (IST) or glucagon stimulation test (GST). These two means are done parenterally, whereas Macrilen boasts an oral formulation for ease of administration for patients and providers.

Macimorelin is a growth hormone secretagogue receptor (ghrelin receptor) agonist causing release of growth hormone from the pituitary gland.^[5]^[6]^[7]

Macimorelin, a novel and orally active ghrelin mimetic that stimulates GH secretion, is used in the diagnosis of adult GH deficiency (AGHD). More specifically, macimorelin is a peptidomimetic growth hormone secretagogue (GHS) that acts as an agonist of GH secretagogue receptor, or ghrelin receptor (GHS-R1a) to dose-dependently increase GH levels ^[3]. Growth hormone secretagogues (GHS) represent a new class of pharmacological agents which have the potential to be used in numerous clinical applications. They include treatment for growth retardation in children and cachexia associated with chronic disease such as AIDS and cancer.

Growth hormone (GH) is classically linked with linear growth during childhood. In deficiency of this hormone, AGHD is commonly associated with increased fat mass (particularly in the abdominal region), decreased lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or glucose intolerance overtime. In addition, individuals with may be susceptible to cardiovascular complications from altered structures and function ^[5]. Risk factors of AGHD include a history of childhood-onset GH deficiency or with hypothalamic/pituitary disease, surgery, or irradiation to these areas, head trauma, or evidence of other pituitary hormone deficiencies ^[3]. While there are various therapies available such as GH replacement therapy, the absence of panhypopituitarism and low serum IGF-I levels with nonspecific clinical symptoms pose challenges to the detection and diagnosis of AGHD. The diagnosis of AGHD requires biochemical confirmation with at least 1 GH stimulation test ^[3]. Macimorelin is clinically useful since it displays good stability and oral bioavailability with comparable affinity to ghrelin receptor as its endogenous ligand. In clinical studies involving healthy subjects, macimorelin stimulated GH release in a dose-dependent manner with good tolerability ^[3].

Macimorelin, developed by Aeterna Zentaris, was approved by the FDA in December 2017 under the market name Macrilen for oral solution.

New active series of growth hormone secretagogues
J Med Chem 2003, 46(7): 1191

WO 2001096300

WO 2007093820

PAPER

J Med Chem 2003, 46(7): 1191

http://pubs.acs.org/doi/full/10.1021/jm020985q

Abstract Image

Synthetic Pathway for JMV 1843 and Analogues^a

^a Reagents and conditions: (a) IBCF, NMM, DME, 0 °C; (b) NH₄OH; (c) H₂, Pd/C, EtOH, HCl; (d) BOP, NMM, DMF, Boc-(d)-Trp-OH; (e) Boc₂O, DMAP cat., anhydrous CH₃CN; (f) BTIB, pyridine, DMF/H₂O; (g) 2,4,5-trichlorophenylformate, DIEA, DMF; (h) TFA/anisole/thioanisole (8:1:1), 0 °C; (i) BOP, NMM, DMF, Boc-Aib-OH; (j) TFA/anisole/thioanisole (8:1:1), 0 °C; (k) RP preparative HPLC.

TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO (7). 6 (1 g, 1.7 mmol) was dissolved in a mixture of trifluoroacetic acid (8 mL), anisole (1 mL), and thioanisole (1 mL) for 30 min at 0 °C. The solvents were removed in vacuo, the residue was stirred in ether, and the precipitated TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO was filtered. 7 was purified by preparative HPLC and obtained in 52% yield. ¹H NMR (400 MHz, DMSO-d₆) + correlation ¹H−¹H: δ 1.21 (s, 3H, CH₃ (Aib)), 1.43 (s, 3H, CH₃(Aib)), 2.97 (m, 2H, (CH₂)_β), 3.1 (m, 2H, (CH₂)_β_‘), 4.62 (m, 1H, (CH)α_A and (CH)α_B), 5.32 (q, 0.4H, (CH)α‘_B), 5.71 (q, 0.6H, (CH)α‘_A), 7.3 (m, 4H, H₅ and H₆(2 indoles)), 7.06−7.2 (4d, 2H, H_2A and H_2B (2 indoles)), 7.3 (m, 2H, H₄ or H₇ (2 indoles)), 7.6−7.8 (4d, 2H, H_4A and H_4B or H_7A and H_7B), 7.97 (s, 3H, NH₂ (Aib) and CHO (formyl)), 8.2 (d, 0.4H, NH_1B (diamino)), 8.3 (m,1H, NH_A and NH_B), 8.5 (d, 0.6H, NH_1A (diamino)), 8.69 (d, 0.6H, NH_2A (diamino)), 8.96 (d, 0.4H, NH_2B(diamino)), 10.8 (s, 0.6H, N¹H_1A (indole)), 10.82 (s, 0.4H, N¹H_1B (indole)), 10.86 (s, 0.6H, N¹H_2A (indole)), 10.91 (s, 0,4H, N¹H_2B (indole)). MS (ES), m/z: 475 [M + H]⁺, 949 [2M + H]⁺. HPLC t_R: 16.26 min (conditions A).

PATENTS

http://www.google.com/patents/US8192719

The inventors have now found that the oral administration of growth hormone secretagogues (GHSs) EP 1572 and EP 1573 can be used effectively and reliably to diagnose GHD.

EP 1572 (Formula I) or EP 1573 (Formula II) are GHSs (see WO 01/96300, Example 1 and Example 58 which are EP 1572 and EP 1573, respectively) that may be given orally.

EP 1572 and EP 1573 can also be defined as H-Aib-D-Trp-D-gTrp-CHO and H-Aib-D-Trp-D-gTrp-C(O)NHCH₂CH₃. Wherein, His hydrogen, Aib is aminoisobutyl, D is the dextro isomer, Trp is tryptophan and gTrp is a group of Formula III:

PATENT

http://www.google.com/patents/US6861409

H-Aib-D-Trp-D-gTrp-CHO:

Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesis as described below):

Z-D-Tr-NH₂

Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were added successively. The mixture was diluted with water (100 ml), and the product Z-D-Trp-NH₂precipitated. It was filtered and dried in vacuo to afford 8.58 g of a white solid.

Yield=98%.

C₁₉H₁₉N₃O₃, 337 g.mol⁻¹.

Rf=0.46 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

¹H NMR (250 MHZ, DMSO-d⁶): δ 2.9 (dd, 1H, H_β, J_ββ′=14.5 Hz; J_βα=9.8 Hz); 3.1 (dd, 1H, H_β′, J_β′β=14.5 Hz; J_β′α=4.3 Hz); 4.2 (sextuplet, 1H, H_α); 4.95 (s, 2H, CH₂(Z); 6.9-7.4 (m, 11H); 7.5 (s, 1H, H²); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N¹H).

Mass Spectrometry (Electrospray), m/z 338 [M+H]⁺, 360 [M+Na]⁺, 675 [2M+H]⁺, 697 [2M+Na]⁺.

Boc-D-Trp-D-Trp-NH₂

Z-D-Trp-NH₂(3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH₂as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH₂(8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NH₂as a white solid.

Yield=85%.

C₂₇H₃₁N₅O₄, 489 g.mol⁻¹.

Rf=0.48 {Chloroform/Methanol/Acetic Acid (85/10/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H, 2 (CH₂)_β; 4.14 (m, 1H, CH_α); 4.52 (m, 1H, CH_α′); 6.83-7.84 (m, 14H, 2 indoles (10H), NH₂, NH (urethane) and NH (amide)); 10.82 (d, 1H, J=2 Hz, N¹H); 10.85 (d, 1H, J=2 Hz, N¹H).

Mass Spectrometry (Electrospray), m/z 490 [M+H]⁺, 512 [M+Na]⁺, 979 [2M+H]⁺.

Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH₂

Boc-D-Trp-D-Trp-NH₂(3 g; 6.13 mmol; 1 eq.) was dissolved in acetonitrile (25 ml).

To this solution, di-tert-butyl-dicarbonate (3.4 g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) were successively added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.53 g of Boc-D-(NⁱBoc)Trp-D-(NⁱBoc)Trp-NH₂as a white solid.

Yield=60%.

C₃₇H₄₇N₅O₈, 689 g.mol⁻¹.

Rf=0.23 {ethyl acetate/hexane (5/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH₂)_β); 4.2 (m, 1H, CH_α′); 4.6 (m, 1H, CH_α); 7.06-8 (m, 14H, 2 indoles (10H), NH (urethane), NH and NH₂(amides)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺, 1401 [2M+Na]⁺.

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-H

Boc-D-(NⁱBoc)Trp-D-(NⁱBoc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturated sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Boc-D-NⁱBoc)Trp-D-g(NⁱBoc)Trp-H was used immediately for the next reaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}.

C₃₆H₄₇N₅O₇, 661 g.mol⁻¹.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s, 2H, NH₂(amine)); 3.1-2.8 (m, 4H, 2 (CH₂)_β); 4.2 (m, 1H, CH_α′); 4.85 (m, 1H, CH_α); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH (amide)).

Mass Spectrometry (Electrospray), m/z 662 [M+H]⁺, 684 [M+Na]⁺.

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-H (4.3 mmol; 1 eq.) was dissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.07 g of Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO as a white solid.

Yield=70%.

C₃₇H₄₇N₅O₈, 689 g.mol⁻¹.

Rf=0.27 {ethyl acetate/hexane (5/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH₂)_β); 4.25 (m, 1H, (CH)α_A&B); 5.39 (m, 0.4H, (CH)α′_B); 5.72 (m, 0.6H, (CH)α′_A); 6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO (formyl)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]⁺, 712 [M+Na]⁺, 1379 [2M+H]⁺.

Boc-Aib-D-Trp-D-gTrp-CHO

Boc-D-(NⁱBoc)Trp-D-g(NⁱBoc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) was dissolved in a -mixture of trifluoroacetic acid (16 ml), anisole (2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively added in 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.

Yield=70%.

C₃₁H₃₈N₆O₅, 574 g.mol⁻¹.

Rf=0.26 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

¹H NMR (200 MHZ, DMSO-d⁶): δ 1.21 (s, 6H, 2 CH₃(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH₂)_β); 4.47 (m, 1H, (CH)α_A&B); 5.2 (m, 0.4H, (CH)α′_B); 5.7 (m, 0.6H, (CH)α′_A); 6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane) CHO (formyl)); 10.89 (m, 2H, 2 N¹H (indoles)).

Mass Spectrometry (Electrospray), ml/z 575 [M+H]⁺, 597 [M+Na]⁺, 1149 [2M+H]⁺, 1171 [2M+Na]⁺.

H-Aib-D-Trp-D-gTrT-CHO

Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 nmmol) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).

Yield=52%.

C₂₆H₃₀N₆O₃, 474 g.mol⁻¹.

¹H NMR (400 MHZ, DMSO-d⁶)+¹H/¹H correlation: δ 1.21 (s, 3H, CH₃(Aib)); 1.43 (s, 3H, CH₃(Aib)); 2.97 (m, 2H, (CH₂)_β); 3.1 (m, 2H, (CH₂)_β′); 4.62 (m, 1H, (CH)α_A&B); 5.32 (q, 0.4H, (CH)α′_B); 5.71 (q, 0.6H, (CH)α′_A); 7.3 (m, 4H₅and H₆(2 indoles)); 7.06-7.2 (4d, 2H, H_2Aet H_2B(2 indoles)); 7.3 (m, 2H, H₄or H₇(2 indoles)); 7.6-7.8 (4d, 2H, H_4Aand H_4Bor H_7Aet H_7B); 7.97 (s, 3H, NH₂(Aib) and CHO (Formyl));8.2 (d, 0.4H, NH_1B(diamino)); 8.3 (m,1H, NH_A&B); 8.5 (d, 0.6H, NH_1A(diamino)); 8.69 (d, 0.6H, NH₂A (diamino)); 8.96 (d, 0.4H, NH_2B(diamino)); 10.8 (s, 0.6H, N¹H_1A(indole)); 10.82 (s, 0.4H, N¹H_1B(indole)); 10.86 (s, 0.6H, N¹H₂A (indole)); 10.91 (s, 0.4, N¹H_2B(indole)).

Mass Spectrometry (Electrospray), m/z 475 [M+H]⁺, 949 [2M+H]⁺.

CLIP

UPDATED INFO AS ON JAN 6 2014

Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

Quebec City, Canada, January 6, 2014 – Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) (the “Company”) today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing the Company’s New Drug Application (“NDA”) for its ghrelin agonist, macimorelin acetate, in Adult Growth Hormone Deficiency (“AGHD”). The acceptance for filing of the NDA indicates the FDA has determined that the application is sufficiently complete to permit a substantive review.

The Company’s NDA, submitted on November 5, 2013, seeks approval for the commercialization of macimorelin acetate as the first orally-administered product that induces growth hormone release to evaluate AGHD. Phase 3 data have demonstrated the compound to be well tolerated, with accuracy comparable to available intravenous and intramuscular testing procedures. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (“PDUFA”) date of November 5, 2014. The PDUFA date is the goal date for the FDA to complete its review of the NDA.

David Dodd, President and CEO of Aeterna Zentaris, commented, “The FDA’s acceptance of this NDA submission is another significant milestone in our strategy to commercialize macimorelin acetate as the first approved oral product for AGHD evaluation. We are finalizing our commercial plan for this exciting new product. We are also looking to broaden the commercial application of macimorelin acetate in AGHD for use related to traumatic brain injury victims and other developmental areas, which would represent significant benefit to the evaluation of growth hormone deficiency, while presenting further potential revenue growth opportunities for the Company.”

About Macimorelin Acetate

Macimorelin acetate, a ghrelin agonist, is a novel orally-active small molecule that stimulates the secretion of growth hormone. The Company has completed a Phase 3 trial for use in evaluating AGHD, and has filed an NDA to the FDA in this indication. Macimorelin acetate has been granted orphan drug designation by the FDA for use in AGHD. Furthermore, macimorelin acetate is in a Phase 2 trial as a treatment for cancer-induced cachexia. Aeterna Zentaris owns the worldwide rights to this novel patented compound.

About AGHD

AGHD affects about 75,000 adults across the U.S., Canada and Europe. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean mass, exercise capacity, and overall quality of life.

About Aeterna Zentaris

Aeterna Zentaris is a specialty biopharmaceutical company engaged in developing novel treatments in oncology and endocrinology. The Company’s pipeline encompasses compounds from drug discovery to regulatory approval.

References

^ “Macrilen Prescribing Information” (PDF). Retrieved 2018-07-25.
^ “Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA”. Wall Street Journal. January 6, 2014.
^ https://clinicaltrials.gov/ct2/show/NCT02558829
^ Research, Center for Drug Evaluation and. “Drug Approvals and Databases – Drug Trials Snapshots: Marcrilen”. http://www.fda.gov. Retrieved 2018-07-25.
^ “Macimorelin”. NCI Drug Dictionary. National Cancer Institute.
^ Koch, Linda (2013). “Growth hormone in health and disease: Novel ghrelin mimetic is safe and effective as a GH stimulation test”. Nature Reviews Endocrinology. 9 (6): 315. doi:10.1038/nrendo.2013.89.
^ Garcia, J. M.; Swerdloff, R.; Wang, C.; Kyle, M.; Kipnes, M.; Biller, B. M. K.; Cook, D.; Yuen, K. C. J.; Bonert, V.; Dobs, A.; Molitch, M. E.; Merriam, G. R. (2013). “Macimorelin (AEZS-130)-Stimulated Growth Hormone (GH) Test: Validation of a Novel Oral Stimulation Test for the Diagnosis of Adult GH Deficiency”. Journal of Clinical Endocrinology & Metabolism. 98 (6): 2422. doi:10.1210/jc.2013-1157. PMC 4207947.

Patent ID	Title	Submitted Date	Granted Date
US2015099709	GHRELIN RECEPTOR AGONISTS FOR THE TREATMENT OF ACHLORHYDRIA	2013-05-27	2015-04-09
US2013060029	QUINAZOLINONE DERIVATIVES USEFUL AS VANILLOID ANTAGONISTS	2012-09-12	2013-03-07
US8835444	Cyclohexyl amide derivatives as CRF receptor antagonists	2011-01-31	2014-09-16
US8163785	PYRAZOLO[5, 1B]OXAZOLE DERIVATIVES AS CRF-1 RECEPTOR ANTAGONISTS	2011-08-04	2012-04-24

Patent ID	Title	Submitted Date	Granted Date
US7297681	Growth hormone secretagogues	2004-11-18	2007-11-20
US2018071367	METHODS OF TREATING COGNITIVE IMPAIRMENTS OR DYSFUNCTION	2016-03-08
US2012295942	Pyrazolo[5, 1b]oxazole Derivatives as CRF-1 Receptor Antagonists	2011-01-28	2012-11-22
US8349852	Quinazolinone Derivatives Useful as Vanilloid Antagonists	2010-08-05
US2017266257	METHODS OF TREATING TRAUMATIC BRAIN INJURY	2015-08-18

Patent ID	Title	Submitted Date	Granted Date
US2015265680	THERAPEUTIC AGENT FOR AMYOTROPHIC LATERAL SCLEROSIS	2013-10-23	2015-09-24
US2011201629	CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS	2011-08-18
US8614213	Organic compounds	2011-06-23
US7994203	Organic compounds	2010-02-11	2011-08-09
US8273900	Organic compounds	2010-02-11

Patent ID	Title	Submitted Date	Granted Date
US6861409	Growth hormone secretagogues	2002-11-07	2005-03-01
US8192719	Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds	2009-12-10	2012-06-05
US2017121385	METHODS OF TREATING NEURODEGENERATIVE CONDITIONS	2016-10-28
US2017281732	METHODS OF TREATING MILD BRAIN INJURY	2015-08-18
US2014088105	Cyclohexyl Amide Derivatives and Their Use as CRF-1 Receptor Antagonists	2013-11-22	2014-03-27

Macimorelin
Names

IUPAC name 2-Amino-N-[(2R)-1-[[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]amino]-3-1H-indol-3-yl)-1-oxopropan-2-yl]-2-methylpropanamide
Other names Aib-Trp-gTrp-CHO; AEZS-130; JMV 1843; Macimorelin acetate
Identifiers
CAS Number	381231-18-1 945212-59-9 (acetate)
3D model (JSmol)	Interactive image
ChemSpider	7980698
KEGG	D10563
PubChem CID	9804938
UNII	8680B21W73
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₆H₃₀N₆O₃
Molar mass	474.565 g·mol⁻¹
Pharmacology
ATC code	V04CD06 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205598Orig1s000ChemR.pdf

///////////macimorelin, FDA 2017, Aeterna Zentaris, AEZS-130, ARD-07, D-87875, EP-01572, EP-1572, JMV-1843, USAN (ab-26), MACIMORELIN ACETATE, orphan drug designation

CC(O)=O.CC(C)(N)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)NC=O

Caplacizumab-yhdp, カプラシズマブ

February 8, 2019 11:25 am / Leave a comment

FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ , for the treatment of adult patients with a rare blood clotting disorder

FDA

February 6, 2019

Release

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm630851.htm?utm_campaign=020919_PR_FDA%20approves%20therapy%20for%20treatment%20of%20adult%20patients%20with%20rare%20blood%20clotting%20disorder&utm_medium=email&utm_source=Eloqua

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

The FDA granted this application Priority Review designation. Cablivi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Cablivi to Ablynx.

EU

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP 1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP 2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

1 http://hugin.info/152918/R/2213684/863478.pdf

2 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA

51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG

101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR

151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT

201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG

251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

1: PN: WO2011067160 SEQID: 1 claimed protein
98: PN: WO2006122825 SEQID: 98 claimed protein
ALX 0081
ALX 0681
Caplacizumab

FORMULA	C1213H1891N357O380S10
CAS	915810-67-2
MOL WEIGHT	27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.^[1]^[2]

This drug was developed by Ablynx NV.^[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.^[4]

It is an anti-von Willebrand factor humanized immunoglobulin.^[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.^[5] Results of the phase II TITAN trial have been reported.^[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. ^[6]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Caplacizumab
Monoclonal antibody
Type	Single domain antibody
Source	Humanized
Target	VWF
Clinical data
Synonyms	ALX-0081
ATC code	B01AX07 (WHO)
Identifiers
CAS Number	915810-67-2
DrugBank	DB06081
ChemSpider	none
UNII	2R27AB6766
KEGG	D11160
Chemical and physical data
Formula	C₁₂₁₃H₁₈₉₁N₃₅₇O₃₈₀S₁₀
Molar mass	27.88 kg/mol

CLIP

https://www.tandfonline.com/doi/full/10.1080/19420862.2016.1269580

Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).³⁹Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, Artoni A, Westwood JP, Mansouri Taleghani M, Jilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):511–22; PMID:26863353; http://dx.doi.org/10.1056/NEJMoa1505533[Crossref], [PubMed], [Web of Science ®], , [Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.

References

^ Statement On A Nonproprietary Name Adopted By The USAN Council – Caplacizumab, American Medical Association.
^ World Health Organization (2011). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 106”(PDF). WHO Drug Information. 25 (4).
^ A Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES)
^ European Medicines Agency. “An overview of Cablivi and why it is authorised in the EU” (PDF). Retrieved 1 October 2018.
^ Jump up to:^a ^b ^c Immune Drug Tackles Microvascular Thrombosis Disorder. Feb 2016
^ “FDA approved caplacizumab-yhdp”. 2019-02-07.

///////////////caplacizumab, Cablivi, Ablynx, Priority Review, Orphan Drug designation, fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ , PEPTIDE, ALX 0081

Cannabidiol, カンナビジオール;

February 5, 2019 11:44 am / Leave a comment

ChemSpider 2D Image | GWP42003-P | C21H30O2

Cannabidiol

カンナビジオール;

Formula	C21H30O2
CAS	13956-29-1
Mol weight	314.4617

FDA APPROVED, 2018/6/25, Epidiolex

(Greenwich Biosciences)

Efficacy	Anticonvulsant, Antiepileptic, Cannabinoid receptor agonist
Comment	Treatment of seizures

1,3-Benzenediol, 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-3-cyclohexen-1-yl]-5-pentyl-

2-[(1R,6R)-6-Isopropenyl-3-methyl-3-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol

GWP42003-P

UNII:19GBJ60SN5

GW Research Ltd

APH-1501
BRCX-014
BTX-1204
BTX-1503
CBD
GW-42003
GWP-42003
GWP-42003-P
PLT-101
PTL-101
ZYN-002

Cannabidiol

CAS Registry Number: 13956-29-1

CAS Name: 2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol

Additional Names:trans-(-)-2-p-mentha-1,8-dien-3-yl-5-pentylresorcinol

Molecular Formula: C21H30O2

Molecular Weight: 314.46

Percent Composition: C 80.21%, H 9.62%, O 10.18%

Literature References: Major nonpsychoactive constituent of cannabis, q.v. (Cannabis sativa L., Cannabinaceae). Exhibits multiple bioactivities including anticonvulsant, anxiolytic and anti-inflammatory effects. Isoln from wild hemp: R. Adams et al.,J. Am. Chem. Soc.62, 196, 2194 (1940); from hashish: A. Jacob, A. R. Todd, J. Chem. Soc.1940, 649. Structure: R. Mechoulam, Y. Shvo, Tetrahedron19, 2073 (1963). Crystal and molecular structure: T. Ottersen et al.,Acta Chem. Scand. B31, 807 (1977). Abs config: Y. Gaoni, R. Mechoulam, J. Am. Chem. Soc.93, 217 (1971). Synthesis of (±)-form: eidem, ibid.87, 3273 (1965); of (-)-form: T. Petrzilka et al.,Helv. Chim. Acta52, 1102 (1969); H. J. Kurth et al.,Z. Naturforsch.36B, 275 (1981). LC-IT-MS determn in cannabis products: A. A. M. Stolker et al.,J. Chromatogr. A1058, 143 (2004). Review of isoln, chemistry and metabolism: R. Mechoulam, L. Hanus, Chem. Phys. Lipids121, 35-43 (2002); of pharmacology and bioactivity: R. Mechoulam et al., J. Clin. Pharmacol.42, 11S-19S (2002).

Properties: Pale yellow resin or crystals, mp 66-67°. bp2 187-190° (bath temp 220°). bp0.001 130°. d440 1.040. nD20 1.5404. [a]D27 -125° (0.066 g in 5 ml 95% ethanol). [a]D18 -129° (c = 0.45 in ethanol). uv max (ethanol): 282, 274 nm (log e 3.10, 3.12). Practically insol in water or 10% NaOH. Sol in ethanol, methanol, ether, benzene, chloroform, petr ether.

Melting point: mp 66-67°

Boiling point: bp2 187-190° (bath temp 220°); bp0.001 130°

Optical Rotation: [a]D27 -125° (0.066 g in 5 ml 95% ethanol); [a]D18 -129° (c = 0.45 in ethanol)

Index of refraction:nD20 1.5404

Absorption maximum: uv max (ethanol): 282, 274 nm (log e 3.10, 3.12)

Density: d440 1.040

Cannabinol

CAS Registry Number: 521-35-7

CAS Name: 6,6,9-Trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol

Additional Names: 3-amyl-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran; CBN

Molecular Formula: C21H26O2

Molecular Weight: 310.43

Percent Composition: C 81.25%, H 8.44%, O 10.31%

Literature References: Nonpsychoactive constituent of cannabis, q.v. (Cannabis sativa L. Cannabinaceae); weak cannabinoid receptor ligand. Isoln from cannabis resin: T. B. Wood et al.,J. Chem. Soc.69, 539 (1896); R. S. Cahn, J. Chem. Soc.1931, 630; T. S. Work et al.,Biochem. J.33, 123 (1939). Structural studies: R. S. Cahn, J. Chem. Soc.1932, 1342; 1933, 1400; F. Bergel, K. Vögele, Ann.493, 250 (1932). Structure and synthesis: R. Adams et al.,J. Am. Chem. Soc.62, 2204 (1940). Crystal structure: T. Ottersen et al.,Acta Chem. Scand. B31, 781 (1977). Improved syntheses: P. C. Meltzer et al.,Synthesis1981, 985; J. Novák, C. A. Salemink, Tetrahedron Lett.23, 253 (1982). Pharmacology: I. Yamamoto et al., Chem. Pharm. Bull.35, 2144 (1987); F. Petitet et al., Life Sci.63, 1 (1998). Review of chromatographic determn methods in biological samples: C. Staub, J. Chromatogr. B733, 119-126 (1999). Comparison of pharmacology with other cannabinoids: I. Yamamoto et al., J. Toxicol. Toxin Rev.22, 577-589 (2003).

Properties: Leaflets from petr ether, mp 76-77°. Sublimes at 4 mm with a bath temp of 180-190°. bp0.05 185°. Insol in water. Sol in methanol, ethanol, aq alkaline solns.

Melting point: mp 76-77°

Boiling point: bp0.05 185°

Cannabis

Additional Names: Hemp; Indian hemp

Literature References: Annual, dioecious plant, Cannabis sativa L. Cannabinaceae. Used since antiquity for its edible seed, fiber to produce rope and cloth, and medicinally as an analgesic, anti-emetic, hypnotic and intoxicant. Habit. Temporate to tropical regions, originally in central Asia, China and India. Constit. More than 60 known cannabinoids, primarily isomeric tetrahydrocannabinols, cannabidiol, cannabinol, q.q.v.; other constituents include alkaloids, proteins, sugars, steroids, flavonoids and vitamins. Seeds and seed oil contain fatty acids, including linoleic, oleic, stearic, and palmetic acids, vitamin E, phytosterols, carotenes. Pistillate plants secrete a cannabinoid containing resin from which hashish or charas is prepared. Preparations of dried flowering tops from these plants are known as bhang, ganja, or marijuana. Comprehensive description of constituents: C. E. Turner et al., J. Nat. Prod. 43, 169-234 (1980). Review of analytical methods: T. J. Raharjo, R. Verpoorte, Phytochem. Anal. 15, 79-94 (2004); of pharmacology and toxicology: I. B. Adams, B. R. Martin, Addiction 91, 1585-1614 (1996). Series of articles on psychiatric effects, pharmacology and therapeutic uses: Br. J. Psychiatry 178, 101-128 (2001). Book: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential, F. Grotenhermen, E. Russo, Eds. (Haworth Press, New York, 2002) 439 pp.

Derivative Type: Extract

Manufacturers’ Codes: GW-1000

Trademarks: Sativex (GW Pharma)

Literature References: Medicinal preparation containing approximately equal amounts of D9-tetrahydrocannabinol and cannabidiol. Prepn of extracts from dried leaf and flowerhead: B. Whittle, G. Guy, WO 02064109 (2002 to GW Pharma); eidem, US04192760 (2004). Clinical evaluation for relief of neuropathic pain: J. S. Berman et al., Pain 112, 299 (2004); in multiple sclerosis: C. M. Brady et al., Mult. Scler. 10, 425 (2004). Review of development and clinical experience: P. F. Smith, Curr. Opin. Invest. Drugs 5, 748-754 (2004).

CAUTION: This is a controlled substance (hallucinogen): 21 CFR, 1308.11. Acute intoxication is frequently due to recreational use by ingestion or by inhalation of smoke. Psychological responses include euphoria, feelings of detachment and relaxation, visual and auditory hallucinations, anxiety, panic, paranoia, depression, drowsiness, psychotic symptoms. Other effects include impairment of cognitive and psychomotor performance, tachycardia, vasodilation, reddening of the conjuctivae, dry mouth, increased appetite. Chronic inhalation of smoke causes respiratory tract irritation and bronchoconstriction, and may be a significant risk factor for lung cancer. See Grotenhermen, Russo, loc. cit.

Therap-Cat: Analgesic.

Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of some 113 identified cannabinoids in Cannabis plants, accounting for up to 40% of the plant’s extract.^[6] As of 2018, preliminary clinical research on cannabidiol included studies of anxiety, cognition, movement disorders, and pain.^[7]

Cannabidiol can be taken into the body in multiple different ways, including by inhalation of cannabis smoke or vapor, as an aerosol spray into the cheek, and by mouth. It may be supplied as CBD oil containing only CBD as the active ingredient (no added THC or terpenes), a full-plant CBD-dominant hemp extract oil, capsules, dried cannabis, or as a prescription liquid solution.^[2] CBD does not have the same psychoactivity as THC,^[8]^[9]^[10] and may affect the actions of THC.^[6]^[7]^[8]^[11] Although in vitro studies indicate CBD may interact with different biological targets, including cannabinoid receptors and other neurotransmitter receptors,^[8]^[12] the mechanism of action for its possible biological effects has not been determined, as of 2018.^[7]^[8]

In the United States, the cannabidiol drug Epidiolex has been approved by the Food and Drug Administration for treatment of two epilepsy disorders.^[13] Side effects of long-term use listed on the Epidiolex label include somnolence, decreased appetite, diarrhea, fatigue, malaise, weakness, sleeping problems, and others.^[2]

The U.S. Drug Enforcement Administration has assigned Epidiolex a Schedule V classification while non-Epidiolex CBD remains a Schedule I drug prohibited for any use.^[14] CBD is not scheduled under any United Nations drug control treaties, and in 2018 the World Health Organization recommended that it remain unscheduled.^[15]

Medical uses

Epilepsy

Medical reviews published in 2017 and 2018 incorporating numerous clinical trials concluded that cannabidiol is an effective treatment for certain types of childhood epilepsy.^[16]^[17]

An orally administered cannabidiol solution (brand name Epidiolex) was approved by the US Food and Drug Administration in June 2018 as a treatment for two rare forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.^[13]

Other uses

Preliminary research on other possible therapeutic uses for cannabidiol include several neurological disorders, but the findings have not been confirmed by sufficient high-quality clinical research to establish such uses in clinical practice.^[5]^[8]^[18]^[19]^[20]^[21]

Side effects

Preliminary research indicates that cannabidiol may reduce adverse effects of THC, particularly those causing intoxication and sedation, but only at high doses.^[22] Safety studies of cannabidiol showed it is well-tolerated, but may cause tiredness, diarrhea, or changes in appetite as common adverse effects.^[23] Epidiolex documentation lists sleepiness, insomnia and poor quality sleep, decreased appetite, diarrhea, and fatigue.^[2]

Potential interactions

Laboratory evidence indicated that cannabidiol may reduce THC clearance, increasing plasma concentrations which may raise THC availability to receptors and enhance its effect in a dose-dependent manner.^[24]^[25] In vitro, cannabidiol inhibited receptors affecting the activity of voltage-dependent sodium and potassium channels, which may affect neural activity.^[26] A small clinical trial reported that CBD partially inhibited the CYP2C-catalyzed hydroxylation of THC to 11-OH-THC.^[27]

Pharmacology

Pharmacodynamics

Cannabidiol has very low affinity for the cannabinoid CB₁ and CB₂ receptors but is said to act as an indirect antagonist of these receptors.^[28]^[29] At the same time, it may potentiate the effects of THC by increasing CB₁ receptor density or through another CB₁receptor-related mechanism.^[30]

Cannabidiol has been found to act as an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain.^[31] It has also been found to act as an inverse agonist of GPR3, GPR6, and GPR12.^[12] Although currently classified as orphan receptors, these receptors are most closely related phylogenetically to the cannabinoid receptors.^[12] In addition to orphan receptors, CBD has been shown to act as a serotonin 5-HT_1A receptor partial agonist,^[32] and this action may be involved in its antidepressant,^[33]^[34] anxiolytic,^[34]^[35] and neuroprotective effects.^[36]^[37] It is an allosteric modulator of the μ- and δ-opioid receptorsas well.^[38] The pharmacological effects of CBD have additionally been attributed to PPARγ agonism and intracellular calcium release.^[6]

Research suggests that CBD may exert some of its pharmacological action through its inhibition of fatty acid amide hydrolase (FAAH), which may in turn increase the levels of endocannabinoids, such as anandamide, produced by the body.^[6] It has also been speculated that some of the metabolites of CBD have pharmacological effects that contribute to the biological activity of CBD.^[39]

Pharmacokinetics

The oral bioavailability of CBD is 13 to 19%, while its bioavailability via inhalation is 11 to 45% (mean 31%).^[3]^[4] The elimination half-life of CBD is 18–32 hours.^[5]

Cannabidiol is metabolized in the liver as well as in the intestines by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.^[2]

Pharmaceutical preparations

Nabiximols (brand name Sativex) is a patented medicine containing CBD and THC in equal proportions. The drug was approved by Health Canada in 2005 for prescription to treat central neuropathic pain in multiple sclerosis, and in 2007 for cancer related pain.^[40]^[41]

Chemistry

Cannabidiol is insoluble in water but soluble in organic solvents such as pentane. At room temperature, it is a colorless crystalline solid.^[42] In strongly basic media and the presence of air, it is oxidized to a quinone.^[43] Under acidic conditions it cyclizes to THC,^[44] which also occurs during pyrolysis (smoking).^[45] The synthesis of cannabidiol has been accomplished by several research groups.^[46]^[47]^[48]

Biosynthesis

Cannabidiol and THC biosynthesis^[49]

Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase.^[50]

Isomerism

History

CBD was isolated from the cannabis plant in 1940, and its chemical structure was established in 1963.^[7]

Society and culture

Names

Cannabidiol is the generic name of the drug and its INN.^[51]

Food and beverage

An example of CBD-infused cold brew coffee & tea on a grocery store shelf.

Food and beverage products containing CBD were introduced in the United States in 2017.^[52] Similar to energy drinks and protein barswhich may contain vitamin or herbal additives, food and beverage items can be infused with CBD as an alternative means of ingesting the substance.^[53] In the United States, numerous products are marketed as containing CBD, but in reality contain little or none.^[54] Some companies marketing CBD-infused food products with claims that are similar to the effects of prescription drugs have received warning lettersfrom the Food and Drug Administration for making unsubstantiated health claims.^[55]

Plant sources

Selective breeding of cannabis plants has expanded and diversified as commercial and therapeutic markets develop. Some growers in the U.S. succeeded in lowering the proportion of CBD-to-THC to accommodate customers who preferred varietals that were more mind-altering due to the higher THC and lower CBD content.^[56] Hemp is classified as any part of the cannabis plant containing no more than 0.3% THC in dry weight form (not liquid or extracted form).^[57]

Legal status

Non-psychoactivity

CBD does not appear to have any psychotropic (“high”) effects such as those caused by ∆9-THC in marijuana, but may have anti-anxiety and anti-psychotic effects.^[9] As the legal landscape and understanding about the differences in medical cannabinoids unfolds, it will be increasingly important to distinguish “medical marijuana” (with varying degrees of psychotropic effects and deficits in executive function) – from “medical CBD therapies” which would commonly present as having a reduced or non-psychoactive side-effect profile.^[9]^[58]

Various strains of “medical marijuana” are found to have a significant variation in the ratios of CBD-to-THC, and are known to contain other non-psychotropic cannabinoids.^[59] Any psychoactive marijuana, regardless of its CBD content, is derived from the flower (or bud) of the genus Cannabis. Non-psychoactive hemp (also commonly-termed industrial hemp), regardless of its CBD content, is any part of the cannabis plant, whether growing or not, containing a ∆-9 tetrahydrocannabinol concentration of no more than 0.3% on a dry-weight basis.^[60] Certain standards are required for legal growing, cultivating, and producing the hemp plant. The Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the dry-weight THC concentration does not exceed 0.3%.^[60]

United Nations

Cannabidiol is not scheduled under the Convention on Psychotropic Substances or any other UN drug treaty. In 2018, the World Health Organization recommended that CBD remain unscheduled.^[15]

United States

In the United States, non-FDA approved CBD products are classified as Schedule I drugs under the Controlled Substances Act.^[61] This means that production, distribution, and possession of non-FDA approved CBD products is illegal under federal law. In addition, in 2016 the Drug Enforcement Administration added “marijuana extracts” to the list of Schedule I drugs, which it defined as “an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin (whether crude or purified) obtained from the plant.”^[62] Previously, CBD had simply been considered “marijuana”, which is a Schedule I drug.^[61]^[63]

In September 2018, following its approval by the FDA for rare types of childhood epilepsy,^[13] Epidiolex was rescheduled (by the Drug Enforcement Administration) as a Schedule V drug to allow for its prescription use.^[14] This change applies only to FDA-approved products containing no more than 0.1 percent THC.^[14] This allows GW Pharmaceuticals to sell Epidiolex, but it does not apply broadly and all other CBD-containing products remain Schedule I drugs.^[14] Epidiolex still requires rescheduling in some states before it can be prescribed in those states.^[64]^[65]

A CNN program that featured Charlotte’s Web cannabis in 2013 brought increased attention to the use of CBD in the treatment of seizure disorders.^[66]^[67] Since then, 16 states have passed laws to allow the use of CBD products with a doctor’s recommendation (instead of a prescription) for treatment of certain medical conditions.^[68] This is in addition to the 30 states that have passed comprehensive medical cannabis laws, which allow for the use of cannabis products with no restrictions on THC content.^[68] Of these 30 states, eight have legalized the use and sale of cannabis products without requirement for a doctor’s recommendation.^[68]

Some manufacturers ship CBD products nationally, an illegal action which the FDA has not enforced in 2018, with CBD remaining the subject of an FDA investigational new drugevaluation, and is not considered legal as a dietary supplement or food ingredient as of December 2018.^[69]^[70] Federal illegality has made it difficult historically to conduct research on CBD.^[71] CBD is openly sold in head shops and health food stores in some states where such sales have not been explicitly legalized.^[72]^[73]

The 2014 Farm Bill^[74] legalized the sale of “non-viable hemp material” grown within states participating in the Hemp Pilot Program.^[75] This legislation defined hemp as cannabis containing less than 0.3% of THC delta-9, grown within the regulatory framework of the Hemp Pilot Program.^[76] The 2018 Farm Bill allowed for interstate commerce of hemp derived products, though these products still fall under the purview of the FDA.^[77]^[78]

Australia

Prescription medicine (Schedule 4) for therapeutic use containing 2 per cent (2.0%) or less of other cannabinoids commonly found in cannabis (such as ∆9-THC). A schedule 4 drug under the SUSMP is Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription.^[79]

New Zealand

Cannabidiol is currently a class B1 controlled drug in New Zealand under the Misuse of Drugs Act. It is also a prescription medicine under the Medicines Act. In 2017 the rules were changed so that anyone wanting to use it could go to the Health Ministry for approval. Prior to this, the only way to obtain a prescription was to seek the personal approval of the Minister of Health.

Associate Health Minister Peter Dunne said restrictions would be removed, which means a doctor will now be able to prescribe cannabidiol to patients.^[80]

Canada

On October 17, 2018, cannabidiol became legal for recreational and medical use.^[81]^[82]

Europe

In 2019, the European Food Safety Authority (EFSA) announced that CBD and other cannabinoids would be classified as “novel foods“,^[83] meaning that CBD products would require authorization under the EU Novel Food Regulation stating: because “this product was not used as a food or food ingredient before 15 May 1997, before it may be placed on the market in the EU as a food or food ingredient, a safety assessment under the Novel Food Regulation is required.”^[84] The recommendation – applying to CBD extracts, synthesized CBD, and all CBD products, including CBD oil – was scheduled for a final ruling by the European Commission in March 2019.^[83] If approved, manufacturers of CBD products would be required to conduct safety tests and prove safe consumption, indicating that CBD products would not be eligible for legal commerce until at least 2021.^[83]

Cannabidiol is listed in the EU Cosmetics Ingredient Database (CosIng).^[85] However, the listing of an ingredient, assigned with an INCI name, in CosIng does not mean it is to be used in cosmetic products or is approved for such use.^[85]

Several industrial hemp varieties can be legally cultivated in Western Europe. A variety such as “Fedora 17” has a cannabinoid profile consistently around 1%, with THC less than 0.1%.^[86]

Sweden

CBD is classified as a medical product in Sweden.^[87]

United Kingdom

Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, is a product available (by prescription only until 2017) for relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been effective).^[88]

Until 2017, products containing cannabidiol marketed for medical purposes were classed as medicines by the UK regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) and could not be marketed without regulatory approval for the medical claims.^[89]^[90] Cannabis oil is illegal to possess, buy, and sell.^[91] In January 2019, the UK Food Standards Agency indicated it would regard CBD products, including CBD oil, as a novel food in the UK, having no history of use before May 1997, and indicating they must have authorization and proven safety before being marketed.^[83]^[92]

Switzerland

While THC remains illegal, CBD is not subject to the Swiss Narcotic Acts because this substance does not produce a comparable psychoactive effect.^[93] Cannabis products containing less than 1% THC can be sold and purchased legally.^[94]

Research

A 2016 literature review indicated that cannabidiol was under basic research to identify its possible neurological effects,^[10] although as of 2016, there was limited high-quality evidence for such effects in people.^[20]^[95]^[96] A 2018 meta-analysis compared the potential therapeutic properties of “purified CBD” with full-plant, CBD-rich cannabis extracts with regard to treating refractory (treatment-resistant) epilepsy, noting several differences.^[97] The daily average dose of people using full-plant extracts was more than four times lower than of those using purified CBD, a possible entourage effect of CBD interacting with THC.^[97]

Image result for cannabidiol synthesis

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https://cen.acs.org/pharmaceuticals/CBD-Medicine-marijuana/96/i30

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Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: Chemical aspects

https://www.researchgate.net/publication/6080805_Cannabidiol_An_overview_of_some_chemical_and_pharmacological_aspects_Part_I_Chemical_aspects/figures?lo=1

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https://www.sciencedirect.com/science/article/pii/S0076687917301490

Image result for cannabidiol synthesis

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Image result for cannabidiol synthesis

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Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability

William A. Kinney ^*^†, Mark E. McDonnell^†, Hua Marlon Zhong^‡, Chaomin Liu^‡, Lanyi Yang^‡, Wei Ling^‡, Tao Qian^‡, Yu Chen^‡, Zhijie Cai^‡, Dean Petkanas^†, and Douglas E. Brenneman^†

^† KannaLife Sciences, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States

^‡ PharmaAdvance, Inc., 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China

ACS Med. Chem. Lett., 2016, 7 (4), pp 424–428

DOI: 10.1021/acsmedchemlett.6b00009

*E-mail: wkinney@iteramed.com. Phone: 215-630-5433.

Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and “drug likeness”, while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.

Discovery of KLS-13019, a cannabidiol-derived neuroprotective agent, with improved potency, safety, and permeability
ACS Med Chem Lett 2016, 7(4): 424

Synthesis of cannabidiol by condensation of olivetol with 4(R)-isopropenyl-1(S)-methyl-2-cyclohexen-1-ol is described.

Cannabidiol is prepared by the condensation of olivetol with 4(R)-isopropenyl-1(S)-methyl-2-cyclohexen-1-ol in the presence of p-TsOH in toluene .

https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00009/suppl_file/ml6b00009_si_001.pdf

A solution of olivetol (1-1) (0.40 g, 2.2 mol, 1 equiv.), p-TsOH (40 mg, 0.21 mmol, 0.1 equiv.) and compound 6 (0.47 g, 3.1 mmol, 1.4 equiv.) in toluene (28 mL) was stirred at RT for 1.5 hours. TLC analysis indicated ~70% conversion of the starting olivetol. The reaction was stopped at this point and EtOAc (30 mL) was added to dilute the reaction mixture, which was then washed by saturated NaHCO3 aqueous solution (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give crude compound 1 (0.9 g). It was purified by column chromatography to give compound 1 (140 mg, yield 20%). HPLC purity: 97%. LC/MS (ESI): m/z 315 (M+1). 1H-NMR (300 MHz, CDCl3) δ 6.40-6.20 (br s, 2H), 6.10-5.90 (br s, 1H), 5.59 (s, 1H), 4.68 (s, 2H), 4.58 (s, 1H), 3.90-3.80 (m, 1H), 2.50-2.40 (m, 3H), 2.30-2.00 (m, 2H), 1.90-1.70 (m, 5H), 1.67 (s, 3H), 1.65-1.50 (m, 2H), 1.40-1.20 (m, 4H), 0.90 (t, J = 6.6 Hz, 3H). The analytical data are attached below. Optical Rotation of 1: [α]D 22= -121.4 (c 1.00, EtOH), the average of two measurements: -121.7 and -121.1 Literature: [α]D 22= -125 (Ben-Shabat, 2006).

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https://onlinelibrary.wiley.com/doi/pdf/10.1002/pca.787

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J Am Chem Soc 1940, 62(1): 196

The red oil ethanolic extract from Minnesota wild hemp containing the carboxylated compound is submitted to a fractionated distillation with simultaneous thermal decarboxylation.

The fraction distilling at 190-210º C (2 mmHg) contains the desired compound as an intermediate oil, which is purified by treatment with 3,5-dinitrobenzoyl chloride in pyridine to yield the crystalline bis(3,5-dinitrobenzoate) .

Finally this compound is treated with liq ammonia at room temperature in a high pressure bomb to obtain the FINAL cannabidiol.

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Open Babel bond-line chemical structure with annotated hydrogens. Click to toggle size.

1H NMR spectrum of C21H30O2 in CDCL3 at 400 MHz. Click to toggle size.

¹H NMR spectrum of C₂₁H₃₀O₂ in CDCL3 at 400 MHz.

R.J. Abraham, M. Mobli Modelling 1H NMR Spectra of Organic Compounds:
  Theory, Applications and NMR Prediction Software, Wiley, Chichester, 2008.

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Cannabidiol


Clinical data
Trade names	Sativex (with THC), Epidiolex
Synonyms	CBD
AHFS/Drugs.com	International Drug Names
Routes of administration	Inhalation (smoking, vaping), buccal (aerosol spray), oral (solution)^[1]^[2]
Drug class	Cannabinoid
ATC code	N03AX24 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) or Dietary Supplement US: Schedule I (except Epidiolex, Schedule V)
Pharmacokinetic data
Bioavailability	• Oral: 13–19%^[3] • Inhaled: 31% (11–45%)^[4]
Elimination half-life	18–32 hours^[5]
Identifiers
IUPAC name [show]
CAS Number	13956-29-1
PubChem CID	644019
IUPHAR/BPS	4150
DrugBank	DB09061
ChemSpider	24593618
UNII	19GBJ60SN5
KEGG	D10915
ChEBI	CHEBI:69478
ECHA InfoCard	100.215.986
Chemical and physical data
Formula	C₂₁H₃₀O₂
Molar mass	314.464 g/mol
3D model (JSmol)	Interactive image
Melting point	66 °C (151 °F)
SMILES [hide] Oc1c(c(O)cc(c1)CCCCC)[C@@H]2\C=C(/CC[C@H]2\C(=C)C)C
InChI [hide] InChI=1S/C21H30O2/c1-5-6-7-8-16-12-19(22)21(20(23)13-16)18-11-15(4)9-10-17(18)14(2)3/h9,12-13,17-18,22-23H,2,5-8,10-11H2,1,3-4H3/t17-,18+/m0/s1 Key:ZTGXAWYVTLUPDT-ZWKOTPCHSA-N
(verify)

Voretigene neparvovec , ボレチジーンネパルボベック;

February 4, 2019 9:44 am / Leave a comment

Voretigene neparvovec
Voretigene neparvovec-rzyl;
Luxturna (TN)

ボレチジーンネパルボベック;

DNA (synthetic adeno-associated virus 2 vector AAV2-hRPE65v2)

CAS: 1646819-03-5
2017/12/19, FDA Luxturna, SPARK THERAPEUTICS

Vision loss treatment, Retinal dystrophy

AAV2-hRPE65v2
AAV2.RPE65
LTW-888
SPK-RPE65
rAAV.hRPE65v2
rAAV2-CBSB-hRPE65
2SPI046IKD (UNII code)

melting point (°C)

72-90ºC

Rayaprolu V. et al. J. Virol. vol. 87. no. 24. (2013)

FDA

https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM592766.pdf

LUXTURNA

STN: 125610
Proper Name: voretigene neparvovec-rzyl
Trade Name: LUXTURNA
Manufacturer: Spark Therapeutics, Inc.
Indication:

Is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s).

Product Information

Package Insert – LUXTURNA (PDF – 602KB)
Demographic Subgroup Information – voretigene neparvovec [LUXTURNA] (PDF – 2.7MB)
Refer to Section 1.1 of the clinical reviewer memo for information about participation in the clinical trials and any analysis of demographic subgroup outcomes that is notable.

Supporting Documents

Related Information

FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss

Voretigene neparvovec (Luxturna) is a novel gene therapy for the treatment of Leber’s congenital amaurosis.^[1] It was developed by Spark Therapeutics and Children’s Hospital of Philadelphia.^[2]^[3] It is the first in vivo gene therapy approved by the FDA.^[4]

Leber’s congenital amaurosis, or biallelic RPE65-mediated inherited retinal disease, is an inherited disorder causing progressive blindness. Voretigene is the first treatment available for this condition.^[5] The gene therapy is not a cure for the condition, but substantially improves vision in those treated.^[6] It is given as an subretinal injection.

It was developed by collaboration between the University of Pennsylvania, Yale University, the University of Florida and Cornell University. In 2018, the product was launched in the U.S. by Spark Therapeutics for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The same year, Spark Therapeutics received approval for the product in the E.U. for the same indication.

Chemistry and production

Voretigene neparvovec is an AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence. The virus is grown in HEK 293 cells and purified for administration.^[7]

History

Married researchers Jean Bennett and Albert Maguire, among others, worked for decades on studies of congenital blindness, culminating in approval of a novel therapy, Luxturna.^[8]

It was granted orphan drug status for Leber congenital amaurosis and retinitis pigmentosa.^[9]^[10] A biologics license application was submitted to the FDA in July 2017 with Priority Review.^[5] Phase III clinical trial results were published in August 2017.^[11] On 12 October 2017, a key advisory panel to the Food and Drug Administration (FDA), composed of 16 experts, unanimously recommended approval of the treatment.^[12] The US FDA approved the drug on December 19, 2017. With the approval, Spark Therapeutics received a pediatric disease priority review voucher.^[13]

The first commercial sale of voretigene neparvovec — the first for any gene therapy product in the US — occurred in March 2018.^[14]^[14]^[4] The price of the treatment has been announced at $425,000 per eye.^[15]

INDICATION

LUXTURNA (voretigene neparvovec-rzyl) is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Patients must have viable retinal cells as determined by the treating physicians.

IMPORTANT SAFETY INFORMATION FOR LUXTURNA

Warnings and Precautions

Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA, and monitor for and advise patients to report any signs or symptoms of infection or inflammation to permit early treatment of any infection.
Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances.
Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy, including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.
Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately.
Expansion of intraocular air bubbles Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.
Cataract Subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.

Adverse Reactions

In clinical studies, ocular adverse reactions occurred in 66% of study participants (57% of injected eyes), and may have been related to LUXTURNA, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products.
The most common adverse reactions (incidence ≥5% of study participants) were conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma) (7%), macular hole (7%), subretinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula) (5%).

Immunogenicity

Immune reactions and extra-ocular exposure to LUXTURNA in clinical studies were mild. No clinically significant cytotoxic T-cell response to either AAV2 or RPE65 has been observed.

In clinical studies, the interval between the subretinal injections into the two eyes ranged from 7 to 14 days and 1.7 to 4.6 years. Study participants received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye, which may have decreased the potential immune reaction to either AAV2 or RPE65.

Pediatric Use

Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during the cell proliferation. The safety and efficacy of LUXTURNA have been established in pediatric patients. There were no significant differences in safety between the different age subgroups.

Please see US Full Prescribing Information for LUXTURNA.

References:

1. LUXTURNA [package insert]. Philadelphia, PA: Spark Therapeutics, Inc; 2017. 2. Gupta PR, Huckfeldt RM. Gene therapy for inherited retinal degenerations: initial successes and future challenges. J Neural Eng. 2017;14(5):051002. 3. Kay C. Gene therapy: the new frontier for inherited retinal disease. Retina Specialist. March 2017. http://www.retina-specialist.com/CMSDocuments/2017/03/RS/rs0317I.pdf. Accessed November 14, 2017 4. Polinski NK, Gombash SE, Manfredsson FP, et al. Recombinant adeno-associated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging. 2015;36(2):1110-1120. 5. Moore T. Restoring retinal function in a mouse model of hereditary blindness. PLoS Med. 2005;2(11):e399. 6. McBee JK, Van Hooser JP, Jang GF, Palczewski K. Isomerization of 11-cis-retinoids to all-trans-retinoids in vitro and in vivo. J Biol Chem. 2001;276(51):48483-48493. 7. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4(5):346-358. 8. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108-128. 9. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.

Illustration of the RPE65 gene delivery method

Illustration of the RPE65 protein production cycle

PAPERS

Progress in Retinal and Eye Research (2018), 63, 107-131

Lancet (2017), 390(10097), 849-860.

References

^ “Luxturna (voretigene neparvovec-rzyl) label” (PDF). FDA. December 2017. Retrieved 31 December 2017. (for label updates, see FDA index page)
^ “Spark’s gene therapy for blindness is racing to a historic date with the FDA”. Statnews.com. 9 October 2017. Retrieved 9 October 2017.
^ Clarke,Reuters, Toni. “Gene Therapy for Blindness Appears Initially Effective, Says U.S. FDA”. Scientific American. Retrieved 2017-10-12.
^ Jump up to:^a ^b “First Gene Therapy For Inherited Disease Gets FDA Approval”. NPR.org. 19 Dec 2017.
^ Jump up to:^a ^b “Press Release – Investors & Media – Spark Therapeutics”. Ir.sparktx.com. Retrieved 9 October 2017.
^ McGinley, Laurie (19 December 2017). “FDA approves first gene therapy for an inherited disease”. Washington Post.
^ Russell, Stephen; Bennett, Jean; Wellman, Jennifer A.; Chung, Daniel C.; Yu, Zi-Fan; Tillman, Amy; Wittes, Janet; Pappas, Julie; Elci, Okan; McCague, Sarah; Cross, Dominique; Marshall, Kathleen A.; Walshire, Jean; Kehoe, Taylor L.; Reichert, Hannah; Davis, Maria; Raffini, Leslie; George, Lindsey A.; Hudson, F Parker; Dingfield, Laura; Zhu, Xiaosong; Haller, Julia A.; Sohn, Elliott H.; Mahajan, Vinit B.; Pfeifer, Wanda; Weckmann, Michelle; Johnson, Chris; Gewaily, Dina; Drack, Arlene; et al. (2017). “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial”. The Lancet. 390 (10097): 849–860. doi:10.1016/S0140-6736(17)31868-8. PMC 5726391. PMID 28712537.
^ “FDA approves Spark’s gene therapy for rare blindness pioneered at CHOP – Philly”. Philly.com. Retrieved 2018-03-24.
^ “Voretigene neparvovec – Spark Therapeutics – AdisInsight”. adisinsight.springer.com.
^ Ricki Lewis, PhD (October 13, 2017). “FDA Panel Backs Gene Therapy for Inherited Blindness”. Medscape.
^ Lee, Helena; Lotery, Andrew (2017). “Gene therapy for RPE65 -mediated inherited retinal dystrophy completes phase 3”. The Lancet. 390 (10097): 823–824. doi:10.1016/S0140-6736(17)31622-7. PMID 28712536.
^ “Landmark Therapy to Treat Blindness Gets One Step Closer to FDA Approval”. Bloomberg.com. 2017-10-12. Retrieved 2017-10-12.
^ “Spark grabs FDA nod for Luxturna, a breakthrough gene therapy likely bearing a pioneering price”. FiercePharma.
^ Jump up to:^a ^b “The anxious launch of Luxturna, a gene therapy with a record sticker price”. STAT. 2018-03-21. Retrieved 2018-03-24.
^ Tirrell, Meg (3 January 2018). “A US drugmaker offers to cure rare blindness for $850,000”. CNBC. Retrieved 3 January 2018.

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Gene therapy
Vector	Adeno-associated virusserotype 2
Nucleic acid type	DNA
Editing method	RPE65
Clinical data
Trade names	Luxturna
Pregnancy category	US: N (Not classified yet)
Routes of administration	subretinal injection
ATC code	S01XA (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
KEGG	D11008

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Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis

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Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

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FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ , for the treatment of adult patients with a rare blood clotting disorder

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Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability

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